@article {pmid37716365, year = {2023}, author = {Dayan, GH and Rouphael, N and Walsh, SR and Chen, A and Grunenberg, N and Allen, M and Antony, J and Asante, KP and Bhate, AS and Beresnev, T and Bonaparte, MI and Celle, M and Ceregido, MA and Corey, L and Dobrianskyi, D and Fu, B and Grillet, MH and Keshtkar-Jahromi, M and Juraska, M and Kee, JJ and Kibuuka, H and Koutsoukos, M and Masotti, R and Michael, NL and Neuzil, KM and Reynales, H and Robb, ML and Villagómez Martínez, SM and Sawe, F and Schuerman, L and Tong, T and Treanor, J and Wartel, TA and Diazgranados, CA and Chicz, RM and Gurunathan, S and Savarino, S and Sridhar, S and , }, title = {Efficacy of a bivalent (D614 + B.1.351) SARS-CoV-2 recombinant protein vaccine with AS03 adjuvant in adults: a phase 3, parallel, randomised, modified double-blind, placebo-controlled trial.}, journal = {The Lancet. Respiratory medicine}, volume = {}, number = {}, pages = {}, doi = {10.1016/S2213-2600(23)00263-1}, pmid = {37716365}, issn = {2213-2619}, abstract = {BACKGROUND: COVID-19 vaccines with alternative strain compositions are needed to provide broad protection against newly emergent SARS-CoV-2 variants of concern. This study aimed to describe the clinical efficacy and safety of a bivalent SARS-CoV-2 recombinant protein vaccine as a two-injection primary series during a period of circulation of the omicron (B.1.1.529) variant.
METHODS: We conducted a phase 3, parallel, randomised, modified double-blind, placebo-controlled trial in adults aged 18 years or older at 54 clinical research centres in eight countries (Colombia, Ghana, India, Kenya, Mexico, Nepal, Uganda, and Ukraine). Participants were recruited from the community and randomly assigned (1:1) by use of an interactive response technology system to receive two intramuscular 0·5 mL injections, 21 days apart, of the bivalent vaccine (5 μg of ancestral [D614] and 5 μg of beta [B.1.351] variant spike protein, with AS03 adjuvant) or placebo (0·9% normal saline). All participants, outcome assessors, and laboratory staff performing assays were masked to group assignments; those involved in the preparation and administration of the vaccines were unmasked. Participants were stratified by age (18-59 years and ≥60 years) and baseline SARS-CoV-2 rapid serodiagnostic test positivity. Symptomatic COVID-19 was defined as laboratory-confirmed (via nucleic acid amplification test or PCR test) COVID-19 with COVID-19-like illness symptoms. The primary efficacy endpoint was the clinical efficacy of the bivalent vaccine for prevention of symptomatic COVID-19 at least 14 days after the second injection (dose 2). Safety was assessed in all participants receiving at least one injection of the study vaccine or placebo. This trial is registered with ClinicalTrials.gov (NCT04904549) and is closed to recruitment.
FINDINGS: Between Oct 19, 2021, and Feb 15, 2022, 13 002 participants were enrolled and randomly assigned to receive the first dose of the study vaccine (n=6512) or placebo (n=6490). 12 924 participants (6472 in the vaccine group and 6452 in the placebo group) received at least one study injection, of whom 7542 (58·4%) were male and 9693 (75·0%) were SARS-CoV-2 non-naive. Of these 12 924 participants, 11 543 (89·3%) received both study injections (5788 in the vaccine group and 5755 in the placebo group). The efficacy-evaluable population after dose 2 comprised 11 416 participants (5736 in the vaccine group and 5680 in the placebo group). The median duration of follow-up was 85 days (IQR 50-95) after dose 1 and 58 days (29-70) after dose 2. 121 symptomatic COVID-19 cases were reported at least 14 days after dose 2 (32 in the vaccine group and 89 in the placebo group), with an overall vaccine efficacy of 64·7% (95% CI 46·6 to 77·2). Vaccine efficacy against symptomatic COVID-19 was 75·1% (95% CI 56·3 to 86·6) in SARS-CoV-2 non-naive participants and 30·9% (-39·3 to 66·7) in SARS-CoV-2-naive participants. Viral genome sequencing identified the infecting strain in 68 (56·2%) of 121 cases (omicron [BA.1 and BA.2] in 63; delta in four; and both omicron and delta in one). Immediate unsolicited adverse events were reported by four (<0·1%) participants in the vaccine group and seven (0·1%) participants in the placebo group. Immediate unsolicited adverse reactions within 30 min after any injection were reported by four (<0·1%) participants in the vaccine group and six (<0·1%) participants in the placebo group. In the reactogenicity subset with available data, solicited reactions (solicited injection-site reactions and solicited systemic reactions) within 7 days after any injection occurred in 1398 (57·8%) of 2420 vaccine recipients and 983 (40·9%) of 2403 placebo recipients. Grade 3 solicited reactions were reported by 196 (8·1%; 95% CI 7·0 to 9·3) of 2420 vaccine recipients and 118 (4·9%; 4·1 to 5·9) of 2403 placebo recipients within 7 days after any injection, with comparable frequencies after dose 1 and dose 2 in the vaccine group. At least one serious adverse event occurred in 30 (0·5%) participants in the vaccine group and 26 (0·4%) in the placebo group. The proportion of adverse events of special interest and deaths was less than 0·1% in both study groups. No adverse event of special interest, serious adverse event, or death was deemed to be treatment related. There were no reported cases of thrombosis with thrombocytopenia syndrome, myocarditis, pericarditis, Bell's Palsy, or Guillain-Barré syndrome, or other immune-mediated diseases.
INTERPRETATION: The bivalent variant vaccine conferred heterologous protection against symptomatic SARS-CoV-2 infection in the epidemiological context of the circulating contemporary omicron variant. These findings suggest that vaccines developed with an antigen from a non-predominant strain could confer cross-protection against newly emergent SARS-CoV-2 variants, although further investigation is warranted.
FUNDING: Sanofi, US Biomedical Advanced Research and Development Authority, and the US National Institute of Allergy and Infectious Diseases.}, }
@article {pmid37714749, year = {2023}, author = {Reid, MC and Mittler, JE and Murphy, JT and Stansfield, SE and Goodreau, SM and Abernethy, N and Herbeck, JT}, title = {Evolution of HIV virulence in response to disease-modifying vaccines: A modeling study.}, journal = {Vaccine}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.vaccine.2023.08.071}, pmid = {37714749}, issn = {1873-2518}, abstract = {Pathogens face a tradeoff with respect to virulence; while more virulent strains often have higher per-contact transmission rates, they are also more likely to kill their hosts earlier. Because virulence is a heritable trait, there is concern that a disease-modifying vaccine, which reduces the disease severity of an infected vaccinee without changing the underlying pathogen genotype, may result in the evolution of higher pathogen virulence. We explored the potential for such virulence evolution with a disease-modifying HIV-1 vaccine in an agent-based stochastic epidemic model of HIV in United States men who have sex with men (MSM). In the model, vaccinated agents received no protection against infection, but experienced lower viral loads and slower disease progression. We compared the genotypic set point viral load (SPVL), a measure of HIV virulence, in populations given vaccines that varied in the degree of SPVL reduction they induce. Sensitivity analyses were conducted under varying vaccine coverage scenarios. With continual vaccination rollout under ideal circumstances of 90 % coverage over thirty years, the genotypic SPVL of vaccinated individuals evolved to become greater than the genotypic SPVL of unvaccinated individuals. This virulence evolution in turn diminished the public health benefit of the vaccine, and in some scenarios resulted in an accelerated epidemic. These findings demonstrate the complexity of viral evolution and have important implications for the design and development of HIV vaccines.}, }
@article {pmid37714742, year = {2023}, author = {Sridhar, SS and Powles, T and Climent Durán, MÁ and Park, SH and Massari, F and Thiery-Vuillemin, A and Valderrama, BP and Ullén, A and Tsuchiya, N and Aragon-Ching, JB and Gupta, S and Petrylak, DP and Bellmunt, J and Wang, J and Laliberte, RJ and di Pietro, A and Costa, N and Grivas, P and Sternberg, CN and Loriot, Y}, title = {Avelumab First-line Maintenance for Advanced Urothelial Carcinoma: Analysis from JAVELIN Bladder 100 by Duration of First-line Chemotherapy and Interval Before Maintenance.}, journal = {European urology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.eururo.2023.08.001}, pmid = {37714742}, issn = {1873-7560}, abstract = {BACKGROUND: In the JAVELIN Bladder 100 phase 3 trial, avelumab first-line maintenance + best supportive care (BSC) prolonged overall survival (OS) and progression-free survival (PFS) versus BSC alone in patients with advanced urothelial carcinoma (advanced UC) without progression after first-line platinum-based chemotherapy.
OBJECTIVE: To report post hoc analyses of subgroups defined by the duration of first-line chemotherapy and interval before maintenance.
Patients with advanced UC without progression after four to six cycles of platinum-based chemotherapy and a 4-10-wk interval after chemotherapy (n = 700) were randomized to receive avelumab + BSC or BSC alone. Subgroups were defined by duration (quartile [Q]) and estimated number of cycles of chemotherapy, and interval between chemotherapy and maintenance. The median follow-up was >19 mo in both arms.
OS (primary endpoint), PFS, and safety were assessed.
RESULTS AND LIMITATIONS: Hazard ratios (95% confidence interval) for OS with avelumab + BSC versus BSC alone were as follows: by chemotherapy duration-Q3: 0.63 (0.39-1.00); by number of cycles-four cycles: 0.69 (0.48-1.00), five cycles: 0.98 (0.57-1.71), and six cycles: 0.66 (0.47-0.92); and by interval-4-<6 wk: 0.75 (0.54-1.04), 6-<8 wk: 0.67 (0.43-1.06), and 8-10 wk: 0.69 (0.47-1.02). Results were similar for PFS. Safety was similar across subgroups. All analyses were exploratory.
CONCLUSIONS: Post hoc analyses of OS and PFS in subgroups defined by first-line chemotherapy duration and interval before maintenance were generally consistent with the results in the overall population, with similar safety findings. Prospective trials are warranted to confirm these findings.
PATIENT SUMMARY: Avelumab maintenance treatment helped patients with advanced urothelial cancer without disease progression after at least four cycles of prior chemotherapy, and who started maintenance treatment at least 4 wk after chemotherapy, to live longer.}, }
@article {pmid37712873, year = {2023}, author = {Martin, TM and Robinson, ST and Huang, Y}, title = {Discovery medicine - the HVTN's iterative approach to developing an HIV-1 broadly neutralizing vaccine.}, journal = {Current opinion in HIV and AIDS}, volume = {}, number = {}, pages = {}, doi = {10.1097/COH.0000000000000821}, pmid = {37712873}, issn = {1746-6318}, abstract = {PURPOSE OF REVIEW: In the past two decades, there has been an explosion in the discovery of HIV-1 broadly neutralizing antibodies (bnAbs) and associated vaccine strategies to induce them. This abundance of approaches necessitates a system that accurately and expeditiously identifies the most promising regimens. We herein briefly review the background science of bnAbs, provide a description of the first round of phase 1 discovery medicine studies, and suggest an approach to integrate these into a comprehensive HIV-1-neutralizing vaccine.
RECENT FINDINGS: With recent preclinical success including induction of early stage bnAbs in mouse knockin models and rhesus macaques, successful priming of VRC01-class bnAbs with eOD-GT8 in a recent study in humans, and proof-of-concept that intravenous infusion of VRC01 prevents sexual transmission of virus in humans, the stage is set for a broad and comprehensive bnAb vaccine program. Leveraging significant advances in protein nanoparticle science, mRNA technology, adjuvant development, and B-cell and antibody analyses, the HVTN has reconfigured its HIV-1 vaccine strategy by developing the Discovery Medicine Program to test promising vaccine candidates targeting six key epitopes.
SUMMARY: The HVTN Discovery Medicine program is testing multiple HIV-1-neutralizing vaccine candidates.}, }
@article {pmid37712859, year = {2023}, author = {Stamatatos, L}, title = {'Immunization during ART and ATI for HIV-1 vaccine discovery/development'.}, journal = {Current opinion in HIV and AIDS}, volume = {}, number = {}, pages = {}, doi = {10.1097/COH.0000000000000817}, pmid = {37712859}, issn = {1746-6318}, abstract = {PURPOSE OF REVIEW: Explore whether immunization with germline-targeting Env immunogens during ART, followed by ATI, leads to the identification of viral envelope glycoproteins (Envs) that promote and guide the full maturation of broadly neutralizing antibody responses.
RECENT FINDINGS: The HIV-1 envelope glycoprotein (Env) does not efficiently engage the germline precursors of broadly neutralizing antibodies (bnAbs). However, Env-derived proteins specifically designed to precisely do that, have been recently developed. These 'germline-targeting' Env immunogens activate naïve B cells that express the germline precursors of bnAbs but by themselves cannot guide their maturation towards their broadly neutralizing forms. This requires sequential immunizations with heterologous sets of Envs. These 'booster' Envs are currently unknown.
SUMMARY: Combining germline-targeting Env immunization approaches during ART with ATI could lead to the identification of natural Envs that are responsible for the maturation of broadly neutralizing antibody responses during infection. Such Envs could then serve as booster immunogens to guide the maturation of glBCRs that have become activated by germline-targeting immunogens in uninfected subjects.}, }
@article {pmid37712852, year = {2023}, author = {Janes, H and Buchbinder, S}, title = {Control groups for HIV prevention efficacy trials: what does the future hold?.}, journal = {Current opinion in HIV and AIDS}, volume = {}, number = {}, pages = {}, doi = {10.1097/COH.0000000000000818}, pmid = {37712852}, issn = {1746-6318}, abstract = {PURPOSE OF REVIEW: Ending the HIV epidemic will require the development of additional effective immune-mediated and nonimmune-mediated means of HIV prevention. Evaluating novel interventions requires large, controlled trials demonstrating efficacy. Recent advances in the field of HIV prevention necessitate new approaches to efficacy trial design.
RECENT FINDINGS: Three classes of efficacy trial designs are possible: standard of prevention-controlled trials, active-controlled trials, and active-controlled trials augmented with external control data. Recent experience with these approaches provides lessons on considerations around and success of the designs. Additional experience and development is needed for the augmented active-controlled trial design.
SUMMARY: Efficacy trials of new HIV prevention interventions are feasible but require careful consideration, given the complexity and dynamic state of the prevention field. While standard of prevention-controlled efficacy trials are reasonable approaches for HIV vaccine and monoclonal antibody efficacy trials, trials of new antiretroviral agents may require active-controlled designs.}, }
@article {pmid37711623, year = {2023}, author = {Buchta Rosean, C and Leyder, EC and Hamilton, J and Carter, JJ and Galloway, DA and Koelle, DM and Nghiem, P and Heiland, T}, title = {LAMP1 targeting of the large T antigen of Merkel cell polyomavirus results in potent CD4 T cell responses and tumor inhibition.}, journal = {Frontiers in immunology}, volume = {14}, number = {}, pages = {1253568}, pmid = {37711623}, issn = {1664-3224}, support = {P01 CA225517/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Antigens, Viral, Tumor/genetics ; CD4-Positive T-Lymphocytes ; Lysosomal-Associated Membrane Protein 1 ; *Merkel cell polyomavirus ; *Cancer Vaccines ; *Carcinoma, Merkel Cell ; *Skin Neoplasms/therapy ; Tumor Microenvironment ; Lysosome-Associated Membrane Glycoproteins ; }, abstract = {INTRODUCTION: Most cases of Merkel cell carcinoma (MCC), a rare and highly aggressive type of neuroendocrine skin cancer, are associated with Merkel cell polyomavirus (MCPyV) infection. MCPyV integrates into the host genome, resulting in expression of oncoproteins including a truncated form of the viral large T antigen (LT) in infected cells. These oncoproteins are an attractive target for a therapeutic cancer vaccine.
METHODS: We designed a cancer vaccine that promotes potent, antigen-specific CD4 T cell responses to MCPyV-LT. To activate antigen-specific CD4 T cells in vivo, we utilized our nucleic acid platform, UNITE™ (UNiversal Intracellular Targeted Expression), which fuses a tumor-associated antigen with lysosomal-associated membrane protein 1 (LAMP1). This lysosomal targeting technology results in enhanced antigen presentation and potent antigen-specific T cell responses. LT[S220A], encoding a mutated form of MCPyV-LT that diminishes its pro-oncogenic properties, was introduced into the UNITE™ platform.
RESULTS: Vaccination with LT[S220A]-UNITE™ DNA vaccine (ITI-3000) induced antigen-specific CD4 T cell responses and a strong humoral response that were sufficient to delay tumor growth of a B16F10 melanoma line expressing LT[S220A]. This effect was dependent on the CD4 T cells' ability to produce IFNγ. Moreover, ITI-3000 induced a favorable tumor microenvironment (TME), including Th1-type cytokines and significantly enhanced numbers of CD4 and CD8 T cells as well as NK and NKT cells. Additionally, ITI-3000 synergized with an α-PD-1 immune checkpoint inhibitor to further slow tumor growth and enhance survival.
CONCLUSIONS: These findings strongly suggest that in pre-clinical studies, DNA vaccination with ITI-3000, using the UNITE™ platform, enhances CD4 T cell responses to MCPyV-LT that result in significant anti-tumor immune responses. These data support the initiation of a first-in-human (FIH) Phase 1 open-label study to evaluate the safety, tolerability, and immunogenicity of ITI-3000 in patients with polyomavirus-positive MCC (NCT05422781).}, }
@article {pmid37710306, year = {2023}, author = {Tarlock, K and Liu, X and Minard, CG and Isikwei, EA and Reid, JM and Horton, TM and Fox, E and Weigel, BJ and Cooper, T}, title = {Feasibility of pevonedistat combined with azacitidine, fludarabine, cytarabine in pediatric relapsed/refractory AML: Results from COG ADVL1712.}, journal = {Pediatric blood & cancer}, volume = {}, number = {}, pages = {e30672}, doi = {10.1002/pbc.30672}, pmid = {37710306}, issn = {1545-5017}, support = {UM1CA228823/CA/NCI NIH HHS/United States ; P30 CA015083/CA/NCI NIH HHS/United States ; T32GM 08685/GM/NIGMS NIH HHS/United States ; }, abstract = {BACKGROUND: Outcomes for children with relapsed/refractory (R/R) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are poor, and new therapies are needed. Pevonedistat is an inhibitor of the NEDD-8 activating enzyme, a key regulator of the ubiquitin proteasome system that is responsible for protein turnover, with protein degradation regulating cell growth and survival.
PROCEDURE: We evaluated the feasibility, toxicity, and pharmacokinetics (PK) of pevonedistat (20 mg/m[2] days 1, 3, 5) in combination with azacitidine, fludarabine, cytarabine (aza-FLA) in children with R/R AML and MDS (NCT03813147). Twelve patients were enrolled, median age was 13 years (range 1-21). Median number of prior chemotherapeutic regimens was two (range one to five), and two (25%) patients had prior hematopoietic cell transplantation. Diagnoses were AML NOS (n = 10, 83%), acute monocytic leukemia (n = 1), and therapy-related AML (n = 1).
RESULTS: Overall, three of 12 (25%) patients experienced DLTs. The day 1 mean ± SD (n = 12) Cmax , VSS , T1/2 , and CL were 223 ± 91 ng/mL, 104 ± 53.8 L/m[2] , 4.3 ± 1.2 hours, and 23.2 ± 6.9 L/h/m[2] , respectively. T1/2 , VSS , and Cmax , but not CL, were significantly different between age groups. The overall response rate was 25%, with n = 3 patients achieving a complete remission with incomplete hematologic recovery (CRi).
CONCLUSIONS: Pevonedistat 20 mg/m[2] combined with Aza-FLA was tolerable in children with R/R AML with similar toxicity profile to other intensive AML regimens. However, within the confines of a phase 1 study, we did not observe that the pevonedistat + Aza-FLA combination demonstrated significant anti-leukemic activity.}, }
@article {pmid37707851, year = {2023}, author = {Okeke, NL and Ware, KB and Campbell, R and Taylor, J and Hung, F and Questell, C and Brickler, MP and Smith, UD and Nawas, GT and Hanlen-Rosado, E and Chan, C and Bosworth, HB and Aifah, A and Corneli, A}, title = {Evidence2Practice (E2P): Leveraging Implementation Science to Promote Careers in HIV Research Among Students From Historically Black Colleges and Universities.}, journal = {Journal of acquired immune deficiency syndromes (1999)}, volume = {94}, number = {Suppl 2}, pages = {S65-S72}, doi = {10.1097/QAI.0000000000003263}, pmid = {37707851}, issn = {1944-7884}, support = {P30 AI117970/AI/NIAID NIH HHS/United States ; P30 AI064518/AI/NIAID NIH HHS/United States ; }, mesh = {Female ; Humans ; *HIV Infections ; *Implementation Science ; Students ; Universities ; *Career Choice ; Black or African American ; *Biomedical Research ; }, abstract = {BACKGROUND: The HIV research workforce is not representative of populations most affected by the epidemic. Innovative educational programs are needed to motivate diverse student populations to pursue careers in HIV research.
METHODS: The Duke University Center for AIDS Research Evidence2Practice (E2P) program is a 3-day interactive workshop that introduces students from Historically Black Colleges and Universities (HBCU) to HIV pre-exposure prophylaxis, implementation science, and human-centered design. Participants develop 1-page action plans to increase awareness and uptake of pre-exposure prophylaxis on their campus. The program was evaluated using a partially mixed-method concurrent equal status study design with pre-program and post-program surveys and in-depth interviews.
RESULTS: Among the 52 participating students, 44 completed the preworkshop survey, 45 completed the postworkshop survey, and 10 participated in an in-depth interview. Most participants identified as Black or African American and cisgender female. Participating in the E2P program was associated with: (1) an increase in median interest in pursuing a career in HIV research (P < 0.01) and (2) a decrease in median perceived difficulty in starting a career in HIV research (P < 0.01). Several students described that a lack of knowledge about initiating an HIV research career, a perceived lack of qualifications and knowledge about HIV science, and limited experience were major barriers to considering careers in HIV research.
CONCLUSIONS: The E2P program enhanced HBCU students' interest in careers related to HIV research and improved their self-efficacy to pursue such careers. On-campus educational enrichment initiatives, led by active HIV researchers and clinicians, should be a critical part of diversifying the HIV workforce.}, }
@article {pmid37707388, year = {2023}, author = {Vaidya, R and Unger, JM and Loomba, R and Hwang, JP and Chugh, R and Tincopa, MA and Arnold, KB and Hershman, DL and Ramsey, SD}, title = {Universal Viral Screening of Newly Diagnosed Cancer Patients in the United States: A Cost Efficiency Evaluation.}, journal = {Cancer research communications}, volume = {}, number = {}, pages = {}, doi = {10.1158/2767-9764.CRC-23-0255}, pmid = {37707388}, issn = {2767-9764}, abstract = {Recommendations for universal screening of cancer patients for HBV, HCV, and HIV are inconsistent. A recent multi-site screening study (S1204) from the SWOG Cancer Research Network found that a substantial number of newly diagnosed cancer patients had previously unknown viral infections. The objective of this study was to determine the cost-efficiency of universal screening of newly diagnosed cancer patients. We estimated the cost-efficiency of universal screening of new cancer cases for HBV, HCV, or HIV, expressed as cost per virus detected, from the health care payer perspective. The prevalence of each virus among this cohort was derived from S1204. Direct medical expenditures included costs associated with laboratory screening tests. Costs per case detected were estimated for each screening strategy. Secondary analysis examined the cost efficiency of screening patients whose viral status at cancer diagnosis was unknown. Among the possible options for universal screening, screening for HBV alone ($581), HCV alone ($782), HBV and HCV ($631) and HBV, HCV, and HIV ($841) were most efficient in terms of cost per case detected. When screening was restricted to patients with unknown viral status, screening for HBV alone ($684), HBV and HCV ($872), HBV and HIV ($1,157), and all three viruses ($1,291) were most efficient in terms of cost per newly detected case. Efficient viral testing strategies represent a relatively modest addition to the overall cost of managing a cancer patient. Screening for HBV, HCV, and HIV infections may be reasonable from both a budget and clinical standpoint.}, }
@article {pmid37706363, year = {2023}, 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 = {Ultra-deep mutational landscape in chronic lymphocytic leukemia uncovers dynamics of resistance to targeted therapies.}, journal = {Haematologica}, volume = {}, number = {}, pages = {}, doi = {10.3324/haematol.2023.283372}, pmid = {37706363}, issn = {1592-8721}, abstract = {BTK inhibitors, Bcl-2 inhibitors, and other targeted therapies have significantly improved outcomes for patients with chronic lymphocytic leukemia (CLL). With increased survivorship, monitoring disease and deciphering potential mechanisms of resistance to these agents are critical for devising effective treatment strategies. We used duplex sequencing, a technology that enables detection of mutations at ultra-low allelic frequencies, to identify mutations in five genes associated with drug resistance in CLL and followed their evolution in two patients who received multiple targeted therapies and ultimately developed disease progression on pirtobrutinib. In both patients, we detected variants that expanded and reached significant cancer cell fraction (CCF). In patient R001, multiple known resistance mutations in both BTK and PLCG2 appeared following progression on zanubrutinib (BTK p.L528W, p.C481S, PLCG2 S707F, L845F, R665W, and D993H). In contrast, patient R002 developed multiple BTK mutations following acalabrutinib treatment including known resistance mutations p.C481R, p.T474I and p.C481S. We found that pirtobrutinib was able to suppress, but not completely eradicate, BTK p.C481S mutations in both patients, but other resistance mutations such as mutations in PLCG2 and new BTK mutations increased while receiving pirtobrutinib. For example, BTK p.L528W in patient R001 increased in frequency more than 1000-fold (from CCF 0.02% to 35%), and p.T474I in patient R002 increased in CCF from 0.03% to 4.2% (more than 100-fold). Our data illuminates the evolutionary dynamics of resistant clones over the patients' disease course and under selective pressure from different targeted treatments.}, }
@article {pmid37706330, year = {2023}, author = {Holtan, SG and El Jurdi, N and Rashidi, A and Betts, BC and Demorest, C and Galvin, JP and MacMillan, ML and Weisdorf, DJ and Panoskaltsis-Mortari, A and Pratta, MA}, title = {Amphiregulin as monitoring biomarker for life-threatening acute graft-versushost disease: secondary analysis of two prospective clinical trials.}, journal = {Haematologica}, volume = {}, number = {}, pages = {}, doi = {10.3324/haematol.2023.283215}, pmid = {37706330}, issn = {1592-8721}, abstract = {Not available.}, }
@article {pmid37673117, year = {2023}, author = {Bevers, TB and Niell, BL and Baker, JL and Bennett, DL and Bonaccio, E and Camp, MS and Chikarmane, S and Conant, EF and Eghtedari, M and Flanagan, MR and Hawley, J and Helvie, M and Hodgkiss, L and Hoyt, TL and Ivanovich, J and Jochelson, MS and Kulkarni, S and Lancaster, RB and Mauer, C and Maxwell, J and Patel, BK and Pearlman, M and Philpotts, L and Plecha, D and Plichta, JK and Shakeri, S and Smith, ML and Streibert, CL and Strigel, RM and Tumyan, L and Winkler, NS and Wolverton, DE and Bergman, MA and Kumar, R and Stehman, K}, title = {NCCN Guidelines® Insights: Breast Cancer Screening and Diagnosis, Version 1.2023.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {21}, number = {9}, pages = {900-909}, doi = {10.6004/jnccn.2023.0046}, pmid = {37673117}, issn = {1540-1413}, mesh = {Humans ; Female ; *Early Detection of Cancer ; *Breast Neoplasms/diagnosis ; Family Practice ; Health Personnel ; Medical Oncology ; }, abstract = {The NCCN Guidelines for Breast Cancer Screening and Diagnosis provide health care providers with a practical, consistent framework for screening and evaluating a spectrum of clinical presentations and breast lesions. The NCCN Breast Cancer Screening and Diagnosis Panel is composed of a multidisciplinary team of experts in the field, including representation from medical oncology, gynecologic oncology, surgical oncology, internal medicine, family practice, preventive medicine, pathology, diagnostic and interventional radiology, as well as patient advocacy. The NCCN Breast Cancer Screening and Diagnosis Panel meets at least annually to review emerging data and comments from reviewers within their institutions to guide updates to existing recommendations. These NCCN Guidelines Insights summarize the panel's decision-making and discussion surrounding the most recent updates to the guideline's screening recommendations.}, }
@article {pmid37673108, year = {2023}, author = {Ettinger, DS and Wood, DE and Stevenson, J and Aisner, DL and Akerley, W and Bauman, JR and Bharat, A and Bruno, DS and Chang, JY and Chirieac, LR and DeCamp, M and Dilling, TJ and Dowell, J and Durm, GA and Gettinger, S and Grotz, TE and Gubens, MA and Hegde, A and Lackner, RP and Lanuti, M and Lin, J and Loo, BW and Lovly, CM and Maldonado, F and Massarelli, E and Morgensztern, D and Mullikin, TC and Ng, T and Otterson, GA and Patel, SP and Patil, T and Polanco, PM and Riely, GJ and Riess, J and Shapiro, TA and Singh, AP and Tam, A and Tanvetyanon, T and Yanagawa, J and Yang, SC and Yau, E and Gregory, KM and Hughes, M}, title = {Mesothelioma: Peritoneal, Version 2.2023, NCCN Clinical Practice Guidelines in Oncology.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {21}, number = {9}, pages = {961-979}, doi = {10.6004/jnccn.2023.0045}, pmid = {37673108}, issn = {1540-1413}, mesh = {Humans ; Medical Oncology ; *Mesothelioma/diagnosis/therapy ; *Mesothelioma, Malignant ; Peritoneum ; }, abstract = {Mesothelioma is a rare cancer originating in mesothelial surfaces of the peritoneum, pleura, and other sites. These NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) focus on peritoneal mesothelioma (PeM). The NCCN Guidelines for PeM provide recommendations for workup, diagnosis, and treatment of primary as well as previously treated PeM. The diagnosis of PeM may be delayed because PeM mimics other diseases and conditions and because the disease is so rare. The pathology section was recently updated to include new information about markers used to identify mesothelioma, which is difficult to diagnose. The term "malignant" is no longer used to classify mesotheliomas, because all mesotheliomas are now defined as malignant.}, }
@article {pmid37705993, year = {2023}, author = {Bensson-Ravunniarath, M and Bryan Ringel, J and Avgar, A and Wiggins, F and Lee, A and McDonald, MV and Guerrero, LR and Kallas, J and Gusoff, G and Shen, M and Tseng, E and Dell, N and Czaja, S and Lindquist, LA and Sterling, MR}, title = {Having a Say Matters: The Association Between Home Health Aides' Voice and Job Satisfaction.}, journal = {Risk management and healthcare policy}, volume = {16}, number = {}, pages = {1791-1800}, pmid = {37705993}, issn = {1179-1594}, abstract = {PURPOSE: Despite a rapidly growing need for home health aides (HHAs), turnover rates are high. While this is driven in large part by the demanding nature of their work and low wages, another factor may be that HHAs are often not considered part of the medical team which can leave them feeling unheard by other healthcare professionals. We sought to determine whether this concept, or HHAs' perceived voice, was associated with job satisfaction.
METHODS AND DESIGN: This cross-sectional survey of English- and Spanish-speaking HHAs caring for adults with heart failure (HF) was conducted from June 2020 to July 2021 in New York, NY in partnership with a labor management fund of a large healthcare union that provides benefits and training to HHAs. Voice was assessed with a validated 5-item scale (total score range 5 to 25). Job Satisfaction was assessed with the 5-item Work Domain Satisfaction Scale (total score range 5 to 35). Multivariable linear regression analysis was used to examine the association between voice and job satisfaction.
RESULTS: A total of 413 HHAs employed by 56 unique home care agencies completed the survey; they had a mean age of 48 years, 97.6% were female, 60.2% were Hispanic, and they worked as HHAs for a median of 10 years (IQR, 5, 17). They had a median Voice score of 18 (IQR 15-20) and mean job satisfaction score of 26.4 (SD 5.6). Higher levels of voice (1.75 [0.46-3.04]) were associated with greater job satisfaction (p=0.008). When adjusting for Race/Ethnicity, HF training, and HF knowledge, the association between Voice and job satisfaction remained significant ((1.77 [0.40-3.13]).
CONCLUSION: HHAs with a voice in the care of their patients experienced greater job satisfaction. Voice may be an important target for interventions aiming to improve HHAs' retention in the field.}, }
@article {pmid37705524, year = {2023}, author = {Palmieri, R and Paterno, G and Mallegni, F and Frenza, F and De Bernardis, I and Moretti, F and Meddi, E and Del Principe, MI and Maurillo, L and Venditti, A and Buccisano, F}, title = {Therapy-related Myeloid Neoplasms: Considerations for Patients' Clinical Evaluation.}, journal = {Mediterranean journal of hematology and infectious diseases}, volume = {15}, number = {1}, pages = {e2023051}, pmid = {37705524}, issn = {2035-3006}, abstract = {Therapy-related myeloid neoplasms (t-MNs) encompass a specific sub-group of myeloid malignancies arising after exposure to radio/cytotoxic agents for the treatment of unrelated diseases. Such malignancies present unique features, including advanced age, high comorbidities burden, and unfavorable genetic profiles. All these features justify the need for a specific diagnostic work-up and dedicated treatment algorithms. However, as new classification systems recognize the unique clinical characteristics exhibited by t-MN patients, how to assess fitness status in this clinical setting is largely unexplored. Optimizing fitness assessment would be crucial in the management of t-MN patients, considering that factors usually contributing to a worse or better outcome (like age, comorbidities, and treatment history) are patient-specific. In the absence of specific tools for fitness assessment in this peculiar category of AML, the aim of this review is to describe all those factors related to patient, treatment, and disease that allow planning treatments with an optimal risk/benefit ratio.}, }
@article {pmid37214988, year = {2023}, author = {Stafford, E and Dimitrov, D and Ceballos, R and Campelia, G and Matrajt, L}, title = {Retrospective Analysis of Equity-Based Optimization for COVID-19 Vaccine Allocation.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {37214988}, support = {NU38OT000297/CC/CDC HHS/United States ; UM1 AI068617/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; }, abstract = {Marginalized racial and ethnic groups in the United States were disproportionally affected by the COVID-19 pandemic. To study these disparities, we construct an age-and-race-stratified mathematical model of SARS-CoV-2 transmission fitted to age-and-race-stratified data from 2020 in Oregon and analyze counter-factual vaccination strategies in early 2021. We consider two racial groups: non-Hispanic White persons and persons belonging to BIPOC groups (including non-Hispanic Black persons, non-Hispanic Asian persons, non-Hispanic American Indian or Alaska Native persons, and Hispanic or Latino persons). We allocate a limited amount of vaccine to minimize overall disease burden (deaths or years of life lost), inequity in disease outcomes between racial groups (measured with five different metrics), or both. We find that, when allocating small amounts of vaccine (10% coverage), there is a trade-off between minimizing disease burden and minimizing inequity. Older age groups, who are at a greater risk of severe disease and death, are prioritized when minimizing measures of disease burden, and younger BIPOC groups, who face the most inequities, are prioritized when minimizing measures of inequity. The allocation strategies that minimize combinations of measures can produce middle-ground solutions that similarly improve both disease burden and inequity, but the trade-off can only be mitigated by increasing the vaccine supply. With enough resources to vaccinate 20% of the population the trade-off lessens, and with 30% coverage, we can optimize both equity and mortality. Our goal is to provide a race-conscious framework to quantify and minimize inequity that can be used for future pandemics and other public health interventions.}, }
@article {pmid37704610, year = {2023}, author = {Roy, A and Shi, L and Chang, A and Dong, X and Fernandez, A and Kraft, JC and Li, J and Le, VQ and Winegar, RV and Cherf, GM and Slocum, D and Poulson, PD and Casper, GE and Vallecillo-Zúniga, ML and Valdoz, JC and Miranda, MC and Bai, H and Kipnis, Y and Olshefsky, A and Priya, T and Carter, L and Ravichandran, R and Chow, CM and Johnson, MR and Cheng, S and Smith, M and Overed-Sayer, C and Finch, DK and Lowe, D and Bera, AK and Matute-Bello, G and Birkland, TP and DiMaio, F and Raghu, G and Cochran, JR and Stewart, LJ and Campbell, MG and Van Ry, PM and Springer, T and Baker, D}, title = {De novo design of highly selective miniprotein inhibitors of integrins αvβ6 and αvβ8.}, journal = {Nature communications}, volume = {14}, number = {1}, pages = {5660}, pmid = {37704610}, issn = {2041-1723}, mesh = {Animals ; Mice ; *Integrins ; Cell Membrane ; Cryoelectron Microscopy ; Disease Models, Animal ; *Pulmonary Fibrosis ; }, abstract = {The RGD (Arg-Gly-Asp)-binding integrins αvβ6 and αvβ8 are clinically validated cancer and fibrosis targets of considerable therapeutic importance. Compounds that can discriminate between homologous αvβ6 and αvβ8 and other RGD integrins, stabilize specific conformational states, and have high thermal stability could have considerable therapeutic utility. Existing small molecule and antibody inhibitors do not have all these properties, and hence new approaches are needed. Here we describe a generalized method for computationally designing RGD-containing miniproteins selective for a single RGD integrin heterodimer and conformational state. We design hyperstable, selective αvβ6 and αvβ8 inhibitors that bind with picomolar affinity. CryoEM structures of the designed inhibitor-integrin complexes are very close to the computational design models, and show that the inhibitors stabilize specific conformational states of the αvβ6 and the αvβ8 integrins. In a lung fibrosis mouse model, the αvβ6 inhibitor potently reduced fibrotic burden and improved overall lung mechanics, demonstrating the therapeutic potential of de novo designed integrin binding proteins with high selectivity.}, }
@article {pmid37703278, year = {2023}, author = {Arnold, EA and Kaai, RJ and Leung, K and Brinkley, MR and Kelnhofer-Millevolte, LE and Guo, MS and Avgousti, DC}, title = {Adenovirus protein VII binds the A-box of HMGB1 to repress interferon responses.}, journal = {PLoS pathogens}, volume = {19}, number = {9}, pages = {e1011633}, doi = {10.1371/journal.ppat.1011633}, pmid = {37703278}, issn = {1553-7374}, abstract = {Viruses hijack host proteins to promote infection and dampen host defenses. Adenovirus encodes the multifunctional protein VII that serves both to compact viral genomes inside the virion and disrupt host chromatin. Protein VII binds the abundant nuclear protein high mobility group box 1 (HMGB1) and sequesters HMGB1 in chromatin. HMGB1 is an abundant host nuclear protein that can also be released from infected cells as an alarmin to amplify inflammatory responses. By sequestering HMGB1, protein VII prevents its release, thus inhibiting downstream inflammatory signaling. However, the consequences of this chromatin sequestration on host transcription are unknown. Here, we employ bacterial two-hybrid interaction assays and human cell culture to interrogate the mechanism of the protein VII-HMGB1 interaction. HMGB1 contains two DNA binding domains, the A- and B-boxes, that bend DNA to promote transcription factor binding while the C-terminal tail regulates this interaction. We demonstrate that protein VII interacts directly with the A-box of HMGB1, an interaction that is inhibited by the HMGB1 C-terminal tail. By cellular fractionation, we show that protein VII renders A-box containing constructs insoluble, thereby acting to prevent their release from cells. This sequestration is not dependent on HMGB1's ability to bind DNA but does require post-translational modifications on protein VII. Importantly, we demonstrate that protein VII inhibits expression of interferon β, in an HMGB1-dependent manner, but does not affect transcription of downstream interferon-stimulated genes. Together, our results demonstrate that protein VII specifically harnesses HMGB1 through its A-box domain to depress the innate immune response and promote infection.}, }
@article {pmid37702920, year = {2023}, author = {Satram, S and Ghafoori, P and Reyes, CM and Keeley, TJH and Birch, HJ and Brintziki, D and Aldinger, M and Alexander, E and Lopuski, A and Sarkis, EH and Gupta, A and Shapiro, AE and Powers, JH}, title = {Assessment of symptoms in COMET-ICE, a phase 2/3 study of sotrovimab for early treatment of non-hospitalized patients with COVID-19.}, journal = {Journal of patient-reported outcomes}, volume = {7}, number = {1}, pages = {92}, pmid = {37702920}, issn = {2509-8020}, mesh = {Humans ; *COVID-19 ; Antibodies, Monoclonal, Humanized/adverse effects ; Antibodies, Neutralizing ; Disease Progression ; }, abstract = {BACKGROUND: The COMET-ICE trial demonstrated that sotrovimab clinically and statistically significantly reduces the risk of all-cause > 24-h hospitalization or death due to any cause among patients with COVID-19 at high risk of disease progression. Patient-reported outcomes are important to capture symptom burden of COVID-19 and assess treatment effectiveness. This study investigated symptoms and their impact over the acute phase of COVID-19 infection among patients on sotrovimab versus placebo.
METHODS: Randomized (1:1), double-blind, multicenter, placebo-controlled, phase 2/3 study in 57 centers across five countries. Participants were non-hospitalized patients with symptomatic, mild-to-moderate COVID-19 and ≥ 1 baseline risk factor for disease progression (aged ≥ 55 years or ≥ 1 of the following: diabetes requiring medication, obesity, chronic kidney disease, congestive heart failure, chronic obstructive pulmonary disease, or moderate-to-severe asthma). An intravenous infusion of sotrovimab 500 mg or placebo was administered on Day 1. The FLU-PRO Plus questionnaire was administered once-daily with 24-h recall from Day 1-21, and at Day 29. Intensity and duration of COVID-19 symptoms were determined from area under the curve (AUC) and mean change in total and individual domain scores through Days 7, 14, and 21. Time to symptom alleviation was assessed.
RESULTS: In total, 1057 patients were randomized to sotrovimab (n = 528) or placebo (n = 529). At Day 7, mean decrease in FLU-PRO Plus total score (measured by AUC) was statistically significantly greater for patients on sotrovimab (-3.05 [95% confidence interval (CI) -3.27 to -2.83]) than placebo (-1.98 [95% CI -2.20 to -1.76]; difference -1.07 [95% CI -1.38 to -0.76]; p < 0.001). Significant differences were also observed at Days 14 and 21. A more rapid decline in symptom severity was observed with sotrovimab versus placebo through Week 1 and the first 21 days post-treatment. By Day 21, 41% of patients on sotrovimab and 34% on placebo reported symptom resolution. In a post-hoc analysis, median time to symptom alleviation was 4 and 6 days, respectively.
CONCLUSIONS: Sotrovimab provides significant and rapid improvements in patient-reported COVID-19 symptoms, as measured by the FLU-PRO Plus. These results further show the benefits of sotrovimab in alleviating symptoms among high-risk patients with COVID-19. Trial registration ClinicalTrials.Gov: NCT04545060 (https://clinicaltrials.gov/ct2/show/NCT04545060). Date of registration: September 10, 2020 (retrospectively registered).}, }
@article {pmid37702631, year = {2023}, author = {Dacic, S and Travis, W and Redman, M and Saqi, A and Cooper, WA and Borczuk, A and Chung, JH and Glass, C and Lopez, JM and Roden, AC and Sholl, L and Weissferdt, A and Posadas, J and Walker, A and Zhu, H and Wijeratne, MT and Connolly, C and Wynes, M and Bota-Rabassedas, N and Sanchez-Espiridion, B and Lee, JJ and Berezowska, S and Chou, TY and Kerr, K and Nicholson, A and Poleri, C and Schalper, KA and Tsao, MS and Ready, N and Cascone, T and Heymach, J and Sepesi, B and Shu, C and Rizvi, N and Sonett, J and Altorki, N and Provencio, M and Bunn, PA and Kris, MG and Belani, CP and Kelly, K and Wistuba, I and , }, title = {International Association for the Study of Lung Cancer Study of Reproducibility in Assessment of Pathologic Response in Resected Lung Cancers After Neoadjuvant Therapy.}, 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.2023.07.017}, pmid = {37702631}, issn = {1556-1380}, abstract = {INTRODUCTION: Pathologic response has been proposed as an early clinical trial end point of survival after neoadjuvant treatment in clinical trials of NSCLC. The International Association for the Study of Lung Cancer (IASLC) published recommendations for pathologic evaluation of resected lung cancers after neoadjuvant therapy. The aim of this study was to assess pathologic response interobserver reproducibility using IASLC criteria.
METHODS: An international panel of 11 pulmonary pathologists reviewed hematoxylin and eosin-stained slides from the lung tumors of resected NSCLC from 84 patients who received neoadjuvant immune checkpoint inhibitors in six clinical trials. Pathologic response was assessed for percent viable tumor, necrosis, and stroma. For each slide, tumor bed area was measured microscopically, and pre-embedded formulas calculated unweighted and weighted major pathologic response (MPR) averages to reflect variable tumor bed proportion.
RESULTS: Unanimous agreement among pathologists for MPR was observed in 68 patients (81%), and inter-rater agreement (IRA) was 0.84 (95% confidence interval [CI]: 0.76-0.92) and 0.86 (95% CI: 0.79-0.93) for unweighted and weighted averages, respectively. Overall, unweighted and weighted methods did not reveal significant differences in the classification of MPR. The highest concordance by both methods was observed for cases with more than 95% viable tumor (IRA = 0.98, 95% CI: 0.96-1) and 0% viable tumor (IRA = 0.94, 95% CI: 0.89-0.98). The most common reasons for discrepancies included interpretations of tumor bed, presence of prominent stromal inflammation, distinction between reactive and neoplastic pneumocytes, and assessment of invasive mucinous adenocarcinoma.
CONCLUSIONS: Our study revealed excellent reliability in cases with no residual viable tumor and good reliability for MPR with the IASLC recommended less than or equal to 10% cutoff for viable tumor after neoadjuvant therapy.}, }
@article {pmid37700859, year = {2023}, author = {Nichols, HB and Wernli, KJ and Chawla, N and O'Meara, ES and Gray, MF and Green, LE and Baggett, CD and Casperson, M and Chao, C and Jones, SMW and Kirchhoff, AC and Kuo, TM and Lee, C and Malogolowkin, M and Quesenberry, CP and Ruddy, KJ and Wun, T and Zebrack, B and Chubak, J and Hahn, EE and Keegan, THM and Kushi, LH}, title = {Challenges and Opportunities of Epidemiological Studies to Reduce the Burden of Cancers in Young Adults.}, journal = {Current epidemiology reports}, volume = {10}, number = {3}, pages = {115-124}, pmid = {37700859}, issn = {2196-2995}, support = {P01 CA233432/CA/NCI NIH HHS/United States ; }, abstract = {There are >1.9 million survivors of adolescent and young adult cancers (AYA, diagnosed at ages 15-39) living in the U.S. today. Epidemiologic studies to address the cancer burden in this group have been a relatively recent focus of the research community. In this article, we discuss approaches and data resources for cancer epidemiology and health services research in the AYA population. We consider research that uses data from cancer registries, vital records, healthcare utilization, and surveys, and the accompanying challenges and opportunities of each. To illustrate the strengths of each data source, we present example research questions or areas that are aligned with these data sources and salient to AYAs. Integrating the respective strengths of cancer registry, vital records, healthcare data, and survey-based studies sets the foundation for innovative and impactful research on AYA cancer treatment and survivorship to inform a comprehensive understanding of diverse AYA needs and experiences.}, }
@article {pmid37700526, year = {2023}, author = {Li, X and Hoogland, AI and Small, BJ and Crowder, SL and Gonzalez, BD and Oswald, LB and Sleight, AG and Nguyen, N and Lorona, NC and Damerell, V and Komrokji, KR and Mooney, K and Playdon, MC and Ulrich, CM and Li, CI and Shibata, D and Toriola, AT and Ose, J and Peoples, AR and Siegel, EM and Bower, JE and Schneider, M and Gigic, B and Figueiredo, JC and Jim, HSL}, title = {Trajectories and risk factors of fatigue following colorectal cancer diagnosis.}, journal = {Colorectal disease : the official journal of the Association of Coloproctology of Great Britain and Ireland}, volume = {}, number = {}, pages = {}, doi = {10.1111/codi.16746}, pmid = {37700526}, issn = {1463-1318}, support = {R01NR018762/NR/NINR NIH HHS/United States ; KL2TR00-2539/NH/NIH HHS/United States ; T32 HG008962/NH/NIH HHS/United States ; 1A1 R01 CA189184/CA/NCI NIH HHS/United States ; R2 U01 CA206110/CA/NCI NIH HHS/United States ; T32CA009168/CA/NCI NIH HHS/United States ; R01CA211705/CA/NCI NIH HHS/United States ; R01CA254108/CA/NCI NIH HHS/United States ; R03CA270473/CA/NCI NIH HHS/United States ; R01CA207371/CA/NCI NIH HHS/United States ; P30-CA076292/CA/NCI NIH HHS/United States ; }, abstract = {AIM: This study sought to identify groups of colorectal cancer patients based upon trajectories of fatigue and examine how demographic, clinical and behavioural risk factors differentiate these groups.
METHOD: Patients were from six cancer centres in the United States and Germany. Fatigue was measured using the fatigue subscale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) at five time points (baseline/enrolment and 3, 6, 12 and 24 months after diagnosis). Piecewise growth mixture models identified latent trajectories of fatigue. Logistic regression models examined differences in demographic, clinical and behavioural characteristics between fatigue trajectory groups.
RESULTS: Among 1615 participants (57% men, 86% non-Hispanic White, mean age 61 ± 13 years at diagnosis), three distinct groups were identified. In the high fatigue group (36%), fatigue significantly increased in the first 6 months after diagnosis and then showed statistically and clinically significant improvement from 6 to 24 months (P values < 0.01). Throughout the study period, average fatigue met or exceeded cutoffs for clinical significance. In the moderate (34%) and low (30%) fatigue groups, fatigue levels remained below or near population norms across the study period. Patients who were diagnosed with Stage II-IV disease and/or current smokers were more likely to be in the high fatigue than in the moderate fatigue group (P values < 0.05).
CONCLUSION: A large proportion of colorectal cancer patients experienced sustained fatigue after initiation of cancer treatment. Patients with high fatigue at the time of diagnosis may benefit from early supportive care.}, }
@article {pmid37699001, year = {2023}, author = {Sala-Torra, O and Reddy, S and Hung, LH and Beppu, L and Wu, D and Radich, J and Yeung, KY and Yeung, CCS}, title = {Rapid detection of myeloid neoplasm fusions using single-molecule long-read sequencing.}, journal = {PLOS global public health}, volume = {3}, number = {9}, pages = {e0002267}, pmid = {37699001}, issn = {2767-3375}, support = {R21 CA280520/CA/NCI NIH HHS/United States ; R01 GM126019/GM/NIGMS NIH HHS/United States ; P01 CA018029/CA/NCI NIH HHS/United States ; UG1 CA233338/CA/NCI NIH HHS/United States ; U24 HG012674/HG/NHGRI NIH HHS/United States ; R01 CA175008/CA/NCI NIH HHS/United States ; }, abstract = {Recurrent gene fusions are common drivers of disease pathophysiology in leukemias. Identifying these structural variants helps stratify disease by risk and assists with therapy choice. Precise molecular diagnosis in low-and-middle-income countries (LMIC) is challenging given the complexity of assays, trained technical support, and the availability of reliable electricity. Current fusion detection methods require a long turnaround time (7-10 days) or advance knowledge of the genes involved in the fusions. Recent technology developments have made sequencing possible without a sophisticated molecular laboratory, potentially making molecular diagnosis accessible to remote areas and low-income settings. We describe a long-read sequencing DNA assay designed with CRISPR guides to select and enrich for recurrent leukemia fusion genes, that does not need a priori knowledge of the abnormality present. By applying rapid sequencing technology based on nanopores, we sequenced long pieces of genomic DNA and successfully detected fusion genes in cell lines and primary specimens (e.g., BCR::ABL1, PML::RARA, CBFB::MYH11, KMT2A::AFF1) using cloud-based bioinformatics workflows with novel custom fusion finder software. We detected fusion genes in 100% of cell lines with the expected breakpoints and confirmed the presence or absence of a recurrent fusion gene in 12 of 14 patient cases. With our optimized assay and cloud-based bioinformatics workflow, these assays and analyses could be performed in under 8 hours. The platform's portability, potential for adaptation to lower-cost devices, and integrated cloud analysis make this assay a candidate to be placed in settings like LMIC to bridge the need of bedside rapid molecular diagnostics.}, }
@article {pmid37698881, year = {2023}, author = {Rodríguez-Arbolí, E and Lee, CJ and Caballero-Velázquez, T and Martínez, C and García-Calderón, C and Jiménez-León, MR and Bermúdez-Rodríguez, MA and López-Corral, L and Triguero, A and Onstad, L and Horwitz, ME and Sarantopoulos, S and Lee, SJ and Pérez-Simón, JA}, title = {Targeting Hedgehog Signaling with Glasdegib in Patients with Refractory Sclerotic Chronic GVHD: A Report of Two Phase I/II Trials.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {}, number = {}, pages = {OF1-OF11}, doi = {10.1158/1078-0432.CCR-23-0666}, pmid = {37698881}, issn = {1557-3265}, abstract = {PURPOSE: Sclerotic chronic GVHD (scGVHD) is characterized by progressive skin fibrosis and frequent refractoriness to available therapies. Aberrant activation of Hedgehog signaling in dermal fibroblasts has been implicated in scGVHD. Here, we report the results of two phase I/II studies (NCT03415867, GETH-TC; NCT04111497, FHD) that evaluated glasdegib, a smoothened antagonist, as a novel therapeutic agent in refractory scGVHD.
PATIENTS AND METHODS: Adult patients with active scGVHD after ≥1 (FHD) or ≥2 (GETH-TC) lines of therapy were enrolled. Primary endpoints were dose-limiting toxicity (DLT) and MTD in the GETH-TC trial, and safety and tolerability measures in the FHD trial. Glasdegib was administered once daily in 28-day cycles. Responses were scored per 2014 NIH cGVHD criteria. Correlative studies were performed to evaluate the role of fibroblast-independent immune mechanisms on clinical activity.
RESULTS: Twenty (GETH-TC) and 15 (FHD) patients were recruited. Treatment-emergent grade (G) ≥2 adverse events (AE) in the GETH-TC trial included muscle cramps (85%), alopecia (50%), and dysgeusia (35%). Two patients experienced a DLT (G3 muscle cramps), and the MTD was established at 50 mg. G3 muscle cramps were the most frequently reported AE (33%) in the FHD trial. At 12-months, the skin/joint scGVHD overall response rate was 65% (all partial responses) in the GETH-TC trial and 47% (6 partial responses, 1 complete response) in the FHD cohort. No immune correlates of response were identified.
CONCLUSIONS: Glasdegib demonstrated promising responses in patients with refractory scGVHD, but tolerability was limited by muscle cramping.}, }
@article {pmid37697031, year = {2023}, author = {Onega, T and Abraham, L and Miglioretti, DL and Lee, CI and Henderson, LM and Kerlikowske, K and Tosteson, ANA and Weaver, D and Sprague, BL and Bowles, EJA and di Florio-Alexander, RM}, title = {Digital mammography and digital breast tomosynthesis for detecting invasive lobular and ductal carcinoma.}, journal = {Breast cancer research and treatment}, volume = {}, number = {}, pages = {}, pmid = {37697031}, issn = {1573-7217}, support = {P01CA154292/CA/NCI NIH HHS/United States ; U54CA163303/CA/NCI NIH HHS/United States ; R01CA149365/CA/NCI NIH HHS/United States ; R50CA211115/CA/NCI NIH HHS/United States ; PCS-1504-30370/PCORI/Patient-Centered Outcomes Research Institute/United States ; }, abstract = {PURPOSE: Invasive lobular carcinoma (ILC) is a distinct histological subtype of breast cancer that can make early detection with mammography challenging. We compared imaging performance of digital breast tomosynthesis (DBT) to digital mammography (DM) for diagnoses of ILC, invasive ductal carcinoma (IDC), and invasive mixed carcinoma (IMC) in a screening population.
METHODS: We included screening exams (DM; n = 1,715,249 or DBT; n = 414,793) from 2011 to 2018 among 839,801 women in the Breast Cancer Surveillance Consortium. Examinations were followed for one year to ascertain incident ILC, IDC, or IMC. We measured cancer detection rate (CDR) and interval invasive cancer rate/1000 screening examinations for each histological subtype and stratified by breast density and modality. We calculated relative risk (RR) for DM vs. DBT using log-binomial models to adjust for the propensity of receiving DBT vs. DM.
RESULTS: Unadjusted CDR per 1000 mammograms of ILC overall was 0.33 (95%CI: 0.30-0.36) for DM; 0.45 (95%CI: 0.39-0.52) for DBT, and for women with dense breasts- 0.33 (95%CI: 0.29-0.37) for DM and 0.54 (95%CI: 0.43-0.66) for DBT. Similar results were noted for IDC and IMC. Adjusted models showed a significantly increased RR for cancer detection with DBT compared to DM among women with dense breasts for all three histologies (RR; 95%CI: ILC 1.53; 1.09-2.14, IDC 1.21; 1.02-1.44, IMC 1.76; 1.30-2.38), but no significant increase among women with non-dense breasts.
CONCLUSION: DBT was associated with higher CDR for ILC, IDC, and IMC for women with dense breasts. Early detection of ILC with DBT may improve outcomes for this distinct clinical entity.}, }
@article {pmid37696934, year = {2023}, author = {Wang, Y and Ronckers, CM and van Leeuwen, FE and Moskowitz, CS and Leisenring, W and Armstrong, GT and de Vathaire, F and Hudson, MM and Kuehni, CE and Arnold, MA and Demoor-Goldschmidt, C and Green, DM and Henderson, TO and Howell, RM and Ehrhardt, MJ and Neglia, JP and Oeffinger, KC and van der Pal, HJH and Robison, LL and Schaapveld, M and Turcotte, LM and Waespe, N and Kremer, LCM and Teepen, JC and , }, title = {Subsequent female breast cancer risk associated with anthracycline chemotherapy for childhood cancer.}, journal = {Nature medicine}, volume = {}, number = {}, pages = {}, pmid = {37696934}, issn = {1546-170X}, support = {No. 325//Stichting Kinderen Kankervrij (KiKa)/ ; No. 325//Stichting Kinderen Kankervrij (KiKa)/ ; No. 325//Stichting Kinderen Kankervrij (KiKa)/ ; No. 325//Stichting Kinderen Kankervrij (KiKa)/ ; No. 325//Stichting Kinderen Kankervrij (KiKa)/ ; DCOG2011-5027; UVA2012-5517//KWF Kankerbestrijding (Dutch Cancer Society)/ ; DCOG2011-5027; NKI 2010-4720//KWF Kankerbestrijding (Dutch Cancer Society)/ ; UVA2012-5517//KWF Kankerbestrijding (Dutch Cancer Society)/ ; CA054498//U.S. Department of Health and Human Services | NIH | National Cancer Institute (NCI)/ ; CA55727//U.S. Department of Health and Human Services | NIH | National Cancer Institute (NCI)/ ; CA195547//U.S. Department of Health and Human Services | NIH | National Cancer Institute (NCI)/ ; Pediatric Program "Guérir le Cancer de l'Enfant"//Institut Gustave-Roussy (Gustave Roussy)/ ; PopHARC Grant//Fondation ARC pour la Recherche sur le Cancer (ARC Foundation for Cancer Research)/ ; }, abstract = {Anthracycline-based chemotherapy is associated with increased subsequent breast cancer (SBC) risk in female childhood cancer survivors, but the current evidence is insufficient to support early breast cancer screening recommendations for survivors treated with anthracyclines. In this study, we pooled individual patient data of 17,903 survivors from six well-established studies, of whom 782 (4.4%) developed a SBC, and analyzed dose-dependent effects of individual anthracycline agents on developing SBC and interactions with chest radiotherapy. A dose-dependent increased SBC risk was seen for doxorubicin (hazard ratio (HR) per 100 mg m[-][2]: 1.24, 95% confidence interval (CI): 1.18-1.31), with more than twofold increased risk for survivors treated with ≥200 mg m[-2] cumulative doxorubicin dose versus no doxorubicin (HR: 2.50 for 200-299 mg m[-][2], HR: 2.33 for 300-399 mg m[-][2] and HR: 2.78 for ≥400 mg m[-][2]). For daunorubicin, the associations were not statistically significant. Epirubicin was associated with increased SBC risk (yes/no, HR: 3.25, 95% CI: 1.59-6.63). For patients treated with or without chest irradiation, HRs per 100 mg m[-][2] of doxorubicin were 1.11 (95% CI: 1.02-1.21) and 1.26 (95% CI: 1.17-1.36), respectively. Our findings support that early initiation of SBC surveillance may be reasonable for survivors who received ≥200 mg m[-][2] cumulative doxorubicin dose and should be considered in SBC surveillance guidelines for survivors and future treatment protocols.}, }
@article {pmid37694915, year = {2023}, author = {Lupo, PJ and Chambers, TM and Mueller, BA and Clavel, J and Dockerty, JD and Doody, DR and Erdmann, F and Ezzat, S and Filippini, T and Hansen, J and Heck, JE and Infante-Rivard, C and Kang, AY and Magnani, C and Malagoli, C and Metayer, C and Bailey, HD and Mora, AM and Ntzani, E and Petridou, ET and Pombo-de-Oliveira, MS and Rashed, WM and Roman, E and Schüz, J and Wesseling, C and Spector, LG and Scheurer, ME}, title = {Nonchromosomal birth defects and risk of childhood acute leukemia: An assessment in 15 000 leukemia cases and 46 000 controls from the Childhood Cancer and Leukemia International Consortium.}, journal = {International journal of cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/ijc.34720}, pmid = {37694915}, issn = {1097-0215}, support = {R01CA249867/NH/NIH HHS/United States ; R01CA266253/NH/NIH HHS/United States ; R03CA272955/NH/NIH HHS/United States ; R01CA284531/NH/NIH HHS/United States ; }, abstract = {Although recent studies have demonstrated associations between nonchromosomal birth defects and several pediatric cancers, less is known about their role on childhood leukemia susceptibility. Using data from the Childhood Cancer and Leukemia International Consortium, we evaluated associations between nonchromosomal birth defects and childhood leukemia. Pooling consortium data from 18 questionnaire-based and three registry-based case-control studies across 13 countries, we used multivariable logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between a spectrum of birth defects and leukemia. Our analyses included acute lymphoblastic leukemia (ALL, n = 13 115) and acute myeloid leukemia (AML, n = 2120) cases, along with 46 172 controls. We used the false discovery rate to account for multiple comparisons. In the questionnaire-based studies, the prevalence of birth defects was 5% among cases vs 4% in controls, whereas, in the registry-based studies, the prevalence was 11% among cases vs 7% in controls. In pooled adjusted analyses, there were several notable associations, including (1) digestive system defects and ALL (OR = 2.70, 95% CI: 1.46-4.98); (2) congenital anomalies of the heart and circulatory system and AML (OR = 2.86, 95% CI: 1.81-4.52) and (3) nervous system defects and AML (OR = 4.23, 95% CI: 1.50-11.89). Effect sizes were generally larger in registry-based studies. Overall, our results could point to novel genetic and environmental factors associated with birth defects that could also increase leukemia susceptibility. Additionally, differences between questionnaire- and registry-based studies point to the importance of complementary sources of birth defect phenotype data when exploring these associations.}, }
@article {pmid37694593, year = {2023}, author = {Bonini, C and Chapuis, AG and Hudecek, M and Guedan, S and Magnani, C and Qasim, W}, title = {Genome editing in engineered T cells for cancer immunotherapy.}, journal = {Human gene therapy}, volume = {}, number = {}, pages = {}, doi = {10.1089/hum.2023.128}, pmid = {37694593}, issn = {1557-7422}, abstract = {Advanced gene transfer technologies and profound immunological insights have enabled substantial increases in the efficacy of anti-cancer adoptive cellular therapy (ACT). In recent years, the U.S. Food and Drug Administration and European Medicines Agency have approved six engineered T cell therapeutic products, all chimeric antigen receptor (CAR) engineered T cells directed against B cell malignancies. Despite encouraging clinical results, engineered T cell ACT is still constrained by challenges, which could be addressed by genome editing. As RNA-guided Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) technology passes its 10-year anniversary, we review emerging applications of genome editing approaches designed to: 1) overcome resistance to therapy, including cancer immune evasion mechanisms; 2) avoid unwanted immune reactions related to allogeneic T cell products; 3) increase fitness, expansion capacity, persistence and potency of engineered T cells, while preserving their safety profile; and 4) improve the ability of therapeutic cells to resist immunosuppressive signals active in the tumor microenvironment. Overall, these innovative approaches should widen the safe and effective use of ACT to larger numbers of patients affected by cancer.}, }
@article {pmid37693211, year = {2023}, author = {Stafford, E and Dimitrov, D and Ceballos, R and Campelia, G and Matrajt, L}, title = {Retrospective analysis of equity-based optimization for COVID-19 vaccine allocation.}, journal = {PNAS nexus}, volume = {2}, number = {9}, pages = {pgad283}, pmid = {37693211}, issn = {2752-6542}, abstract = {Marginalized racial and ethnic groups in the United States were disproportionally affected by the COVID-19 pandemic. To study these disparities, we construct an age-and-race-stratified mathematical model of SARS-CoV-2 transmission fitted to age-and-race-stratified data from 2020 in Oregon and analyze counterfactual vaccination strategies in early 2021. We consider two racial groups: non-Hispanic White persons and persons belonging to BIPOC groups (including non-Hispanic Black persons, non-Hispanic Asian persons, non-Hispanic American-Indian or Alaska-Native persons, and Hispanic or Latino persons). We allocate a limited amount of vaccine to minimize overall disease burden (deaths or years of life lost), inequity in disease outcomes between racial groups (measured with five different metrics), or both. We find that, when allocating small amounts of vaccine (10% coverage), there is a trade-off between minimizing disease burden and minimizing inequity. Older age groups, who are at a greater risk of severe disease and death, are prioritized when minimizing measures of disease burden, and younger BIPOC groups, who face the most inequities, are prioritized when minimizing measures of inequity. The allocation strategies that minimize combinations of measures can produce middle-ground solutions that similarly improve both disease burden and inequity, but the trade-off can only be mitigated by increasing the vaccine supply. With enough resources to vaccinate 20% of the population the trade-off lessens, and with 30% coverage, we can optimize both equity and mortality. Our goal is to provide a race-conscious framework to quantify and minimize inequity that can be used for future pandemics and other public health interventions.}, }
@article {pmid37691529, year = {2023}, author = {Ganguly, AP and Baker, KK and Redman, MW and McClintock, AH and Yung, RL}, title = {Racial disparities in the screening mammography continuum within a heterogeneous health care system.}, journal = {Cancer}, volume = {129}, number = {S19}, pages = {3171-3181}, doi = {10.1002/cncr.34632}, pmid = {37691529}, issn = {1097-0142}, support = {//Pfizer Inc/ ; }, mesh = {Humans ; Female ; *Mammography ; *Breast Neoplasms/diagnostic imaging ; Early Detection of Cancer ; Black People ; Academic Medical Centers ; }, abstract = {BACKGROUND: Decreased mammography drives breast cancer disparities. Black women have lower rates of mammography completion than White women, and this contributes to disparities in outcomes. Points of disparity along the continuum for screening mammography remain underresearched.
METHODS: The authors compared mammography referrals for Black and White women aged 40-74 years at a heterogeneous academic medical center. Completion of steps of the screening mammography continuum was compared between Black and White women within two age cohorts: 40-49 and 50-74 years. Multivariable logistic regression was used to evaluate the association between race and mammogram completion.
RESULTS: Among 26,476 women, 3090 (12%) were Black, and 23,386 (88%) were White. Among Black women aged 50-74 years who were due for mammography, 40% had referrals, 39% were scheduled, and 21% completed mammography; the corresponding values for White women were 42%, 41%, and 27%, respectively. Similar differences in referral outcomes were noted for women aged 40-49 years, although Black women had lower rates of provider-initiated referrals (9% vs. 13%). Adjusted analyses for those aged 40-49 and 50-74 years demonstrated an association between Black race and lower rates of mammography completion (odds ratio [OR] for 40-49 years, 0.74; 95% CI, 0.57-0.95; p = .02; OR for 50-74 years, 0.85; 95% CI, 0.74-0.98; p = .02). In multivariable analyses, noncommercial insurance and higher comorbidity were associated with lower rates of mammography. Provider-initiated referral was positively correlated to mammogram completion.
CONCLUSIONS: Black race was associated with 15%-26% lower mammography completion (adjusted). Both groups experienced the highest attrition after scheduling mammograms, although attrition was more precipitous for Black women. These findings have implications for future interventions, including increasing provider-initiated referrals and decreasing barriers to attending scheduled mammograms.}, }
@article {pmid37691147, year = {2023}, author = {Smith, AA and Nip, Y and Bennett, SR and Hamm, DC and Lemmers, RJLF and van der Vliet, PJ and Setty, M and van der Maarel, SM and Tapscott, SJ}, title = {DUX4 expression in cancer induces a metastable early embryonic totipotent program.}, journal = {Cell reports}, volume = {42}, number = {9}, pages = {113114}, doi = {10.1016/j.celrep.2023.113114}, pmid = {37691147}, issn = {2211-1247}, abstract = {The transcription factor DUX4 regulates a portion of the zygotic gene activation (ZGA) program in the early embryo. Many cancers express DUX4 but it is unknown whether this generates cells similar to early embryonic stem cells. Here we identified cancer cell lines that express DUX4 and showed that DUX4 is transiently expressed in a small subset of the cells. DUX4 expression activates the DUX4-regulated ZGA transcriptional program, the subsequent 8C-like program, and markers of early embryonic lineages, while suppressing steady-state and interferon-induced MHC class I expression. Although DUX4 was expressed in a small number of cells under standard culture conditions, DNA damage or changes in growth conditions increased the fraction of cells expressing DUX4 and its downstream programs. Our demonstration that transient expression of endogenous DUX4 in cancer cells induces a metastable early embryonic stem cell program and suppresses antigen presentation has implications for cancer growth, progression, and immune evasion.}, }
@article {pmid37691139, year = {2023}, author = {Irwin, T and Yeung, CCS and Shinohara, MM}, title = {Desmoplakin I/II immunohistochemical staining may be a helpful tool in differentiating cutaneous graft versus host disease from the erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis spectrum disorders.}, journal = {Journal of cutaneous pathology}, volume = {}, number = {}, pages = {}, doi = {10.1111/cup.14513}, pmid = {37691139}, issn = {1600-0560}, support = {//University of Washington/ ; }, abstract = {Cutaneous graft versus host disease (cGVHD) has substantial clinical and histopathologic overlap with erythema multiforme (EM), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). This overlap can make it difficult to distinguish these disorders in patients who have received hematopoietic transplants. We sought to evaluate the utility of Dp I/II immunohistochemical stain in differentiating EM/SJS/TEN and cGVHD in a large cohort. Skin biopsy specimens from patients with cGVHD (n = 58) and EM/SJS/TEN (n = 60) were evaluated for Dp I/II expression by immunohistochemistry. We found a statistically significant difference in Dp I/II staining between cGVHD (all grades) and EM/SJS/TEN (mean scores 1.62 and 2.14, respectively; p < 0.005), as well as between Grades 2 + 3 cGVHD and EM/SJS/TEN (mean scores 2.26 and 1.62, respectively; p < 0.005), while we did not find a significant difference between Grade 4 cGVHD and EM/SJS/TEN (mean scores 1.69 and 1.62, respectively; p = 0.71). Dp I/II immunostain may be useful for differentiating EM/SJS/TEN from Grade 2 and Grade 3 cGVHD, especially in clinically ambiguous cases without extracutaneous GVHD.}, }
@article {pmid37162835, year = {2023}, author = {Despres, HW and Mills, MG and Schmidt, MM and Gov, J and Perez, Y and Jindrich, M and Crawford, AML and Kohl, WT and Rosenblatt, E and Kubinski, HC and Simmons, BC and Nippes, MC and Goldenberg, AJ and Murtha, KE and Nicoloro, S and Harris, MJ and Feeley, AC and Gelinas, TK and Cronin, MK and Frederick, RS and Thomas, M and Johnson, ME and Murphy, J and Lenzini, EB and Carr, PA and Berger, DH and Mehta, SP and Floreani, CJ and Koval, AC and Young, AL and Fish, JH and Wallace, J and Chaney, E and Ushay, G and Ross, RS and Vostal, EM and Thisner, MC and Gonet, KE and Deane, OC and Pelletiere, KR and Rockafeller, VC and Waterman, M and Barry, TW and Goering, CC and Shipman, SD and Shiers, AC and Reilly, CE and Duff, AM and Shirley, DJ and Jerome, KR and Pérez-Osorio, AC and Greninger, AL and Fortin, N and Mosher, BA and Bruce, EA}, title = {Surveillance of Vermont wildlife in 2021-2022 reveals no detected SARS-CoV-2 viral RNA.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {37162835}, support = {P30 GM118228/GM/NIGMS NIH HHS/United States ; }, abstract = {Previous studies have documented natural infections of SARS-CoV-2 in various domestic and wild animals. More recently, studies have been published noting the susceptibility of members of the Cervidae family, and infections in both wild and captive cervid populations. In this study, we investigated the presence of SARS-CoV-2 in mammalian wildlife within the state of Vermont. 739 nasal or throat samples were collected from wildlife throughout the state during the 2021 and 2022 harvest season. Data was collected from red and gray foxes (Vulpes vulples and Urocyon cineroargentus , respectively), fishers (Martes pennati), river otters (Lutra canadensis), coyotes (Canis lantrans), bobcats (Lynx rufus rufus), black bears (Ursus americanus), and white-tailed deer (Odocoileus virginianus). Samples were tested for the presence of SARS-CoV-2 via quantitative RT-qPCR using the CDC N1/N2 primer set and/or the WHO-E gene primer set. Our results indicate that no sampled wildlife were positive for SARS-CoV-2. This finding is surprising, given that most published North America studies have found SARS-CoV-2 within their deer populations. The absence of SARS-CoV-2 RNA in populations sampled here may provide insights in to the various environmental and anthropogenic factors that reduce spillover and spread in North American's wildlife populations.}, }
@article {pmid37689393, year = {2023}, author = {Lamble, AJ and Moskop, A and Pulsipher, MA and Maude, SL and Summers, C and Annesley, C and Baruchel, A and Gore, L and Amrolia, P and Shah, N}, title = {INSPIRED Symposium Part 2: Prevention and Management of Relapse Following CAR T-cell therapy for B-ALL.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2023.08.030}, pmid = {37689393}, issn = {2666-6367}, abstract = {While CD19-directed chimeric antigen receptor (CAR) T cell therapy for relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) has been transformative in in inducing and sustaining remission, relapse rates remain unacceptably high, with about 50% of children and young adults experiencing relapse within the first-year post-infusion. Emerging strategies to extend the durability of remission involve the use of prognostic biomarkers to identify those at high risk of relapse or incorporate strategies aimed to enhancing functional CAR T cell persistence. Nonetheless, with antigen loss/downregulation or evolution to lineage switch as major mechanisms of relapse, optimizing single antigen targeting alone is insufficient. With a focus on relapse prevention strategies, including post-infusion surveillance and treatment approaches being explored to optimize post-CAR management (e.g., combinatorial antigen targeting strategies, pre-emptive hematopoietic cell transplantation), we review the current state of the art in the prevention and management of post CAR T cell relapse. We highlight the advancements made within the field as well as identify gaps in the literature to guide future research in optimizing the prevention and management of post-CAR T cell relapses in children and young adults with B-ALL.}, }
@article {pmid37688569, year = {2023}, author = {Papini, C and Mirzaei, S and Xing, M and Tonning Olsson, I and de Blank, P and Lange, KR and Salloum, R 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 = {Evolving therapies, neurocognitive outcomes and functional independence in adult survivors of childhood glioma.}, journal = {Journal of the National Cancer Institute}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnci/djad190}, pmid = {37688569}, issn = {1460-2105}, abstract = {BACKGROUND: Treatment of childhood glioma has evolved to reduce radiotherapy exposure with the goal of limiting late toxicity. However, the associations between treatment changes and neurocognition, and the contribution of neurocognition and chronic health conditions (CHCs) to attainment of adult independence, remain unknown.
METHODS: Adult survivors of childhood glioma diagnosed 1970-1999 in the Childhood Cancer Survivor Study (n = 1,284; median [min-max] 30 [18-51] years at assessment; 22 [15-34] years from diagnosis) self-reported neurocognitive impairment and CHCs. Multivariable models evaluated associations between changes in treatment exposures (surgery only, chemotherapy [±surgery], cranial radiation [±chemotherapy/surgery]) and neurocognitive impairment. Latent class analysis with five indicators (employment, independent living, assistance with routine/personal care needs, driver's license, marital/partner status) identified classes of functional independence. Path analysis tested associations among treatment exposures, neurocognitive impairment, CHCs, and functional independence. Statistical tests were 2-sided.
RESULTS: Cranial radiation exposure decreased over time [51% (1970s), 46% (1980s), 27% (1990s)]. However, compared to siblings, survivors with any treatment exposure were at elevated risk for neurocognitive impairment, including surgery only (e.g., memory: relative risk [RR]=2.22; task efficiency: RR = 1.88; both P's<.001). Three classes of functional independence were identified: independent (58%), moderately independent (20%), and non-independent (22%). Cranial radiation was associated with non-independence through impaired task efficiency (β = 0.06), sensorimotor (β = 0.06) and endocrine (β = 0.10) CHCs, and through the associations between these CHCs and task efficiency (each β = 0.04). Sensorimotor and endocrine CHCs were associated with non-independence through memory.
CONCLUSION: Most long-term glioma survivors achieve adult independence. However, functional non-independence is associated with treatment-related neurocognitive impairment and CHCs.}, }
@article {pmid37686613, year = {2023}, author = {Kennedy, LC and Kazerouni, AS and Chau, B and Biswas, D and Alvarez, R and Durenberger, G and Dintzis, SM and Stanton, SE and Partridge, SC and Gadi, V}, title = {Associations of Multiparametric Breast MRI Features, Tumor-Infiltrating Lymphocytes, and Immune Gene Signature Scores Following a Single Dose of Trastuzumab in HER2-Positive Early-Stage Breast Cancer.}, journal = {Cancers}, volume = {15}, number = {17}, pages = {}, pmid = {37686613}, issn = {2072-6694}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; P30CA015704/CA/NCI NIH HHS/United States ; T32 CA009515/CA/NCI NIH HHS/United States ; T32-CA009515/NH/NIH HHS/United States ; R01CA248192/CA/NCI NIH HHS/United States ; R01 CA248192/CA/NCI NIH HHS/United States ; }, abstract = {Dynamic biomarkers that permit the real-time monitoring of the tumor microenvironment response to therapy are an unmet need in breast cancer. Breast magnetic resonance imaging (MRI) has demonstrated value as a predictor of pathologic complete response and may reflect immune cell changes in the tumor microenvironment. The purpose of this pilot study was to investigate the value of breast MRI features as early markers of treatment-induced immune response. Fourteen patients with early HER2+ breast cancer were enrolled in a window-of-opportunity study where a single dose of trastuzumab was administered and both tissue and MRIs were obtained at the pre- and post-treatment stages. Functional diffusion-weighted and dynamic contrast-enhanced MRI tumor measures were compared with tumor-infiltrating lymphocytes (TILs) and RNA immune signature scores. Both the pre-treatment apparent diffusion coefficient (ADC) and the change in peak percent enhancement (DPE) were associated with increased tumor-infiltrating lymphocytes with trastuzumab therapy (r = -0.67 and -0.69, p < 0.01 and p < 0.01, respectively). Low pre-treatment ADC and a greater decrease in PE in response to treatment were also associated with immune-activated tumor microenvironments as defined by RNA immune signatures. Breast MRI features hold promise as biomarkers of early immune response to treatment in HER2+ breast cancer.}, }
@article {pmid37686150, year = {2023}, author = {Wakabayashi, N and Yagishita, Y and Joshi, T and Kensler, TW}, title = {Forced Hepatic Expression of NRF2 or NQO1 Impedes Hepatocyte Lipid Accumulation in a Lipodystrophy Mouse Model.}, journal = {International journal of molecular sciences}, volume = {24}, number = {17}, pages = {}, pmid = {37686150}, issn = {1422-0067}, support = {R35 CA197222/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Mice ; Kelch-Like ECH-Associated Protein 1/genetics ; *NF-E2-Related Factor 2/genetics ; Hepatomegaly ; Hepatocytes ; *Fatty Liver/genetics ; Disease Models, Animal ; Lipids ; }, abstract = {Lipodystrophy is a disorder featuring loss of normal adipose tissue depots due to impaired production of normal adipocytes. It leads to a gain of fat deposition in ectopic tissues such as liver and skeletal muscle that results in steatosis, dyslipidemia, and insulin resistance. Previously, we established a Rosa [NIC/NIC]::AdiCre lipodystrophy model mouse. The lipodystrophic phenotype that included hepatomegaly accompanied with hepatic damage due to higher lipid accumulation was attenuated substantially by amplified systemic NRF2 signaling in mice with hypomorphic expression of Keap1; whole-body Nrf2 deletion abrogated this protection. To determine whether hepatic-specific NRF2 signaling would be sufficient for protection against hepatomegaly and fatty liver development, direct, powerful, transient expression of Nrf2 or its target gene Nqo1 was achieved by administration through hydrodynamic tail vein injection of pCAG expression vectors of dominant-active Nrf2 and Nqo1 in Rosa [NIC/NIC]::AdiCre mice fed a 9% fat diet. Both vectors enabled protection from hepatic damage, with the pCAG-Nqo1 vector being the more effective as seen with a ~50% decrease in hepatic triglyceride levels. Therefore, activating NRF2 signaling or direct elevation of NQO1 in the liver provides new possibilities to partially reduce steatosis that accompanies lipodystrophy.}, }
@article {pmid37683137, year = {2023}, author = {Deng, L and Jiang, C and Attwood, K and Zhao, JJ and Perimbeti, S and Hu, C and Puzanov, I and Dy, GK}, title = {Risk of Further Progression or Death Among Durable Progression-Free Survivors With Melanoma or Non-Small-Cell Lung Cancer in PD-1 Blockade Trials: Implications for Imaging Surveillance.}, journal = {JCO oncology practice}, volume = {}, number = {}, pages = {OP2300353}, doi = {10.1200/OP.23.00353}, pmid = {37683137}, issn = {2688-1535}, abstract = {PURPOSE: Durable progression-free survivors (dPFSors) over 2 years have been reported among patients with melanoma or non-small-cell lung cancer (NSCLC) who received PD-(L)1 therapy. However, risk of progression still exists and the optimal imaging surveillance interval is unknown.
METHODS: Individual patient data for progression-free survival (PFS) were extracted from PD-1 blockade clinical trials with a follow-up of at least 5 years. Patients with a PFS of at least 2 years were considered as dPFSors. Conditional risks of progression/death (P/D) every 3, 4, 6, and 12 months in each subsequent year were calculated. We prespecified three different levels of risk between scans (10%, 15%, or 20%) to allow clinicians and patients to decide on the scanning interval on the basis of considerations of imaging frequency and risk tolerance. An interval is considered acceptable if the upper bound of the 95% CI of the risk at each scan is lower than a prespecified level.
RESULTS: Of 1,495 and 3,752 patients with melanoma and NSCLC, 474 (31.7%) and 586 (15.6%) were dPFSors, respectively. Among them, the PFS probability for an additional 3 years was 76.4% and 48.1%, respectively. Not more than 8% of patients had P/D in any quarter in the 3 years. With a risk threshold of 10%, melanoma dPFSors can be scanned every 6 months during the third year and then every 12 months in years 4 and 5. The interval for NSCLC would be every 3 months in the third year and every 4 months in years 4 and 5. The higher risk tolerance of 15% and 20% would allow for less frequent scans.
CONCLUSION: On the basis of their own risk tolerance level, our findings allow clinicians and dPFSors make data-driven decisions regarding the imaging surveillance schedule beyond every 3 months.}, }
@article {pmid37682870, year = {2023}, author = {Sadowska-Klasa, A and Leisenring, WM and Limaye, AP and Boeckh, M}, title = {Cytomegalovirus Viral Load Threshold to Guide Preemptive Therapy in Hematopoietic Cell Transplant Recipients: Correlation with CMV Disease.}, journal = {The Journal of infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1093/infdis/jiad386}, pmid = {37682870}, issn = {1537-6613}, abstract = {A systematic review of recent randomized and observational studies demonstrated that antiviral preemptive therapy started at cytomegalovirus (CMV) viral load thresholds between 2 and 3 log10 IU/mL were associated with similar CMV disease rates. Thus, viral thresholds in this range appear to effectively protect patients not receiving prophylaxis.}, }
@article {pmid37679276, year = {2023}, author = {Tieu, HV and Karuna, S and Huang, Y and Sobieszczyk, ME and Zheng, H and Tomaras, GD and Montefiori, DC and Shen, M and DeRosa, S and Cohen, K and Isaacs, MB and Regenold, S and Heptinstall, J and Seaton, KE and Sawant, S and Furch, B and Pensiero, M and Corey, L and Bar, KJ and , }, title = {Safety and immunogenicity of a recombinant oligomeric gp145 subtype C Env protein (gp145 C.6980) HIV vaccine candidate in healthy, HIV-1-uninfected adult participants in the US.}, journal = {Vaccine}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.vaccine.2023.07.046}, pmid = {37679276}, issn = {1873-2518}, abstract = {BACKGROUND: An approach to a preventive HIV vaccine is induction of effective broadly neutralizing antibodies (bnAbs) and effector binding antibodies (bAbs). Preclinical studies suggest that trimeric envelope (Env) proteins may elicit nAbs, which led to the development of the recombinant gp145 subtype C Env protein (gp145 C.6980) immunogen. HVTN 122 was a Phase 1 trial that evaluated the safety, tolerability, and immunogenicity of gp145 C.6980 in adults.
METHODS: Healthy, HIV-1 seronegative adults received three intramuscular injections of gp145 C.6980 with aluminum hydroxide (alum) at months 0, 2, and 6 at either 300 mcg (high dose, n = 25) or 100 mcg (low dose, n = 15), or placebo/saline (placebo, n = 5). Participants were followed for 12 months.
RESULTS: Forty-five participants were enrolled. High and low doses of the study protein were well-tolerated, with mild or moderate reactogenicity commonly reported. Only one adverse event (mild injection site pruritis) in one participant (low dose) was considered product-related; there were no dose-limiting toxicities. High and low dose recipients demonstrated robust bAb responses to vaccine-matched consensus gp140 Env and subtype-matched gp120 Env proteins two weeks post-last vaccination (response rates >90 %), while no responses were detected to a heterologous subtype-matched V1V2 antigen. No significant differences were seen between high and low dose groups. Participants in both experimental arms demonstrated nAb response rates of 76.5 % to a tier 1 virus (MW9635.26), but no responses to tier 2 isolates. Env-specific CD4 + T-cell responses were elicited in 36.4 % of vaccine recipients, without significant differences between groups; no participants demonstrated CD8 + T-cell responses.
CONCLUSIONS: Three doses of novel subtype C gp145 Env protein with alum were safe and well-tolerated. Participants demonstrated bAb, Env-specific CD4 + T-cell, and tier 1 nAb responses, but the regimen failed to induce tier 2 or heterologous nAb responses.
CLINICAL TRIALS REGISTRATION: NCT03382418.}, }
@article {pmid37677122, year = {2023}, author = {Vaidya, R and Unger, JM and Qian, L and Minichiello, K and Herbst, RS and Gandara, DR and Neal, JW and Leal, TA and Patel, JD and Dragnev, KH and Waqar, SN and Edelman, MJ and Sigal, EV and Adam, SJ and Malik, S and Blanke, CD and LeBlanc, ML and Kelly, K and Gray, JE and Redman, MW}, title = {Representativeness of Patients Enrolled in the Lung Cancer Master Protocol (Lung-MAP).}, journal = {JCO precision oncology}, volume = {7}, number = {}, pages = {e2300218}, doi = {10.1200/PO.23.00218}, pmid = {37677122}, issn = {2473-4284}, mesh = {United States/epidemiology ; Humans ; Female ; Male ; *Lung Neoplasms/therapy ; *Carcinoma, Non-Small-Cell Lung/therapy ; Molecular Targeted Therapy ; Patients ; Lung ; }, abstract = {PURPOSE: Lung Cancer Master Protocol (Lung-MAP), a public-private partnership, established infrastructure for conducting a biomarker-driven master protocol in molecularly targeted therapies. We compared characteristics of patients enrolled in Lung-MAP with those of patients in advanced non-small-cell lung cancer (NSCLC) trials to examine if master protocols improve trial access.
METHODS: We examined patients enrolled in Lung-MAP (2014-2020) according to sociodemographic characteristics. Proportions for characteristics were compared with those for a set of advanced NSCLC trials (2001-2020) and the US advanced NSCLC population using SEER registry data (2014-2018). Characteristics of patients enrolled in Lung-MAP treatment substudies were examined in subgroup analysis. Two-sided tests of proportions at an alpha of .01 were used for all comparisons.
RESULTS: A total of 3,556 patients enrolled in Lung-MAP were compared with 2,215 patients enrolled in other NSCLC studies. Patients enrolled in Lung-MAP were more likely to be 65 years and older (57.2% v 46.3%; P < .0001), from rural areas (17.3% v 14.4%; P = .004), and from socioeconomically deprived neighborhoods (42.2% v 36.7%, P < .0001), but less likely to be female (38.6% v 47.2%; P < .0001), Asian (2.8% v 5.1%; P < .0001), or Hispanic (2.4% v 3.8%; P = .003). Among patients younger than 65 years, Lung-MAP enrolled more patients using Medicaid/no insurance (27.6% v 17.8%; P < .0001). Compared with the US advanced NSCLC population, Lung-MAP under represented patients 65 years and older (57.2% v 69.8%; P < .0001), females (38.6% v 46.0%; P < .0001), and racial or ethnic minorities (14.8% v 21.5%; P < .0001).
CONCLUSION: Master protocols may improve access to trials using novel therapeutics for older patients and socioeconomically vulnerable patients compared with conventional trials, but specific patient exclusion criteria influenced demographic composition. Further research examining participation barriers for under represented racial or ethnic minorities in precision medicine clinical trials is warranted.}, }
@article {pmid37676656, year = {2023}, author = {, and Cunha, ARD and Compton, K and Xu, R and Mishra, R and Drangsholt, MT and Antunes, JLF and Kerr, AR and Acheson, AR and Lu, D and Wallace, LE and Kocarnik, JM and Fu, W and Dean, FE and Pennini, A and Henrikson, HJ and Alam, T and Ababneh, E and Abd-Elsalam, S and Abdoun, M and Abidi, H and Abubaker Ali, H and Abu-Gharbieh, E and Adane, TD and Addo, IY and Ahmad, A and Ahmad, S and Ahmed Rashid, T and Akonde, M and Al Hamad, H and Alahdab, F and Alimohamadi, Y and Alipour, V and Al-Maweri, SA and Alsharif, U and Ansari-Moghaddam, A and Anwar, SL and Anyasodor, AE and Arabloo, J and Aravkin, AY and Aruleba, RT and Asaad, M and Ashraf, T and Athari, SS and Attia, S and Azadnajafabad, S and Azangou-Khyavy, M and Badar, M and Baghcheghi, N and Banach, M and Bardhan, M and Barqawi, HJ and Bashir, NZ and Bashiri, A and Benzian, H and Bernabe, E and Bhagat, DS and Bhojaraja, VS and Bjørge, T and Bouaoud, S and Braithwaite, D and Briko, NI and Calina, D and Carreras, G and Chakraborty, PA and Chattu, VK and Chaurasia, A and Chen, MX and Cho, WCS and Chu, DT and Chukwu, IS and Chung, E and Cruz-Martins, N and Dadras, O and Dai, X and Dandona, L and Dandona, R and Daneshpajouhnejad, P and Darvishi Cheshmeh Soltani, R and Darwesh, AM and Debela, SA and Derbew Molla, M and Dessalegn, FN and Dianati-Nasab, M and Digesa, LE and Dixit, SG and Dixit, A and Djalalinia, S and El Sayed, I and El Tantawi, M and Enyew, DB and Erku, DA and Ezzeddini, R and Fagbamigbe, AF and Falzone, L and Fetensa, G and Fukumoto, T and Gaewkhiew, P and Gallus, S and Gebrehiwot, M and Ghashghaee, A and Gill, PS and Golechha, M and Goleij, P and Gomez, RS and Gorini, G and Guimaraes, ALS and Gupta, B and Gupta, S and Gupta, VB and Gupta, VK and Haj-Mirzaian, A and Halboub, ES and Halwani, R and Hanif, A and Hariyani, N and Harorani, M and Hasani, H and Hassan, AM and Hassanipour, S and Hassen, MB and Hay, SI and Hayat, K and Herrera-Serna, BY and Holla, R and Horita, N and Hosseinzadeh, M and Hussain, S and Ilesanmi, OS and Ilic, IM and Ilic, MD and Isola, G and Jaiswal, A and Jani, CT and Javaheri, T and Jayarajah, U and Jayaram, S and Joseph, N and Kadashetti, V and Kandaswamy, E and Karanth, SD and Karaye, IM and Kauppila, JH and Kaur, H and Keykhaei, M and Khader, YS and Khajuria, H and Khanali, J and Khatib, MN and Khayat Kashani, HR and Khazeei Tabari, MA and Kim, MS and Kompani, F and Koohestani, HR and Kumar, GA and Kurmi, OP and La Vecchia, C and Lal, DK and Landires, I and Lasrado, S and Ledda, C and Lee, YH and Libra, M and Lim, SS and Listl, S and Lopukhov, PD and Mafi, AR and Mahumud, RA and Malik, AA and Mathur, MR and Maulud, SQ and Meena, JK and Mehrabi Nasab, E and Mestrovic, T and Mirfakhraie, R and Misganaw, A and Misra, S and Mithra, P and Mohammad, Y and Mohammadi, M and Mohammadi, E and Mokdad, AH and Moni, MA and Moraga, P and Morrison, SD and Mozaffari, HR and Mubarik, S and Murray, CJL and Nair, TS and Narasimha Swamy, S and Narayana, AI and Nassereldine, H and Natto, ZS and Nayak, BP and Negru, SM and Nggada, HA and Nouraei, H and Nuñez-Samudio, V and Oancea, B and Olagunju, AT and Omar Bali, A and Padron-Monedero, A and Padubidri, JR and Pandey, A and Pardhan, S and Patel, J and Pezzani, R and Piracha, ZZ and Rabiee, N and Radhakrishnan, V and Radhakrishnan, RA and Rahmani, AM and Rahmanian, V and Rao, CR and Rao, SJ and Rath, GK and Rawaf, DL and Rawaf, S and Rawassizadeh, R and Razeghinia, MS and Rezaei, N and Rezaei, N and Rezaei, N and Rezapour, A and Riad, A and Roberts, TJ and Romero-Rodríguez, E and Roshandel, G and S, M and S N, C and Saddik, B and Saeb, MR and Saeed, U and Safaei, M and Sahebazzamani, M and Sahebkar, A and Salek Farrokhi, A and Samy, AM and Santric-Milicevic, MM and Sathian, B and Satpathy, M and Šekerija, M and Senthilkumaran, S and Seylani, A and Shafaat, O and Shahsavari, HR and Shamsoddin, E and Sharew, MM and Sharifi-Rad, J and Shetty, JK and Shivakumar, KM and Shobeiri, P and Shorofi, SA and Shrestha, S and Siddappa Malleshappa, SK and Singh, P and Singh, JA and Singh, G and Sinha, DN and Solomon, Y and Suleman, M and Suliankatchi Abdulkader, R and Taheri Abkenar, Y and Talaat, IM and Tan, KK and Tbakhi, A and Thiyagarajan, A and Tiyuri, A and Tovani-Palone, MR and Unnikrishnan, B and Vo, B and Volovat, SR and Wang, C and Westerman, R and Wickramasinghe, ND and Xiao, H and Yu, C and Yuce, D and Yunusa, I and Zadnik, V and Zare, I and Zhang, ZJ and Zoladl, M and Force, LM and Hugo, FN}, title = {The Global, Regional, and National Burden of Adult Lip, Oral, and Pharyngeal Cancer in 204 Countries and Territories: A Systematic Analysis for the Global Burden of Disease Study 2019.}, journal = {JAMA oncology}, volume = {}, number = {}, pages = {}, pmid = {37676656}, issn = {2374-2445}, abstract = {IMPORTANCE: Lip, oral, and pharyngeal cancers are important contributors to cancer burden worldwide, and a comprehensive evaluation of their burden globally, regionally, and nationally is crucial for effective policy planning.
OBJECTIVE: To analyze the total and risk-attributable burden of lip and oral cavity cancer (LOC) and other pharyngeal cancer (OPC) for 204 countries and territories and by Socio-demographic Index (SDI) using 2019 Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study estimates.
EVIDENCE REVIEW: The incidence, mortality, and disability-adjusted life years (DALYs) due to LOC and OPC from 1990 to 2019 were estimated using GBD 2019 methods. The GBD 2019 comparative risk assessment framework was used to estimate the proportion of deaths and DALYs for LOC and OPC attributable to smoking, tobacco, and alcohol consumption in 2019.
FINDINGS: In 2019, 370 000 (95% uncertainty interval [UI], 338 000-401 000) cases and 199 000 (95% UI, 181 000-217 000) deaths for LOC and 167 000 (95% UI, 153 000-180 000) cases and 114 000 (95% UI, 103 000-126 000) deaths for OPC were estimated to occur globally, contributing 5.5 million (95% UI, 5.0-6.0 million) and 3.2 million (95% UI, 2.9-3.6 million) DALYs, respectively. From 1990 to 2019, low-middle and low SDI regions consistently showed the highest age-standardized mortality rates due to LOC and OPC, while the high SDI strata exhibited age-standardized incidence rates decreasing for LOC and increasing for OPC. Globally in 2019, smoking had the greatest contribution to risk-attributable OPC deaths for both sexes (55.8% [95% UI, 49.2%-62.0%] of all OPC deaths in male individuals and 17.4% [95% UI, 13.8%-21.2%] of all OPC deaths in female individuals). Smoking and alcohol both contributed to substantial LOC deaths globally among male individuals (42.3% [95% UI, 35.2%-48.6%] and 40.2% [95% UI, 33.3%-46.8%] of all risk-attributable cancer deaths, respectively), while chewing tobacco contributed to the greatest attributable LOC deaths among female individuals (27.6% [95% UI, 21.5%-33.8%]), driven by high risk-attributable burden in South and Southeast Asia.
CONCLUSIONS AND RELEVANCE: In this systematic analysis, disparities in LOC and OPC burden existed across the SDI spectrum, and a considerable percentage of burden was attributable to tobacco and alcohol use. These estimates can contribute to an understanding of the distribution and disparities in LOC and OPC burden globally and support cancer control planning efforts.}, }
@article {pmid37675967, year = {2023}, author = {Tham, K and Prelewicz, S and deHoll, S and Stephens, DM and Gomez, CA}, title = {Infectious complications among patients receiving ibrutinib for the treatment of hematological malignancies.}, journal = {American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists}, volume = {}, number = {}, pages = {}, doi = {10.1093/ajhp/zxad210}, pmid = {37675967}, issn = {1535-2900}, abstract = {DISCLAIMER: In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time.
PURPOSE: Ibrutinib is a Bruton's tyrosine kinase inhibitor used to treat multiple hematologic malignancies and graft-versus-host disease. Though less myelosuppressive than cytotoxic chemotherapy, increased infections, including invasive fungal infections (IFIs), have been reported with ibrutinib use. This study aimed to determine the characteristics and risk factors for infection associated with ibrutinib at our institution.
METHODS: Patients who received ibrutinib between June 2014 and August 2019 were included. Primary endpoints were the incidence of any infection and the incidence of serious infection (defined as hospitalization, parenteral antimicrobial therapy, or pneumonia regardless of hospitalization). Infection risk factors were assessed using logistic regression.
RESULTS: One hundred thirty-two patients were identified (78% male; median age, 71 years). The most common indications for ibrutinib were chronic lymphocytic leukemia (67%) and mantle cell lymphoma (12%). The median time from ibrutinib initiation to first infection was 125 days. Prior allogeneic hematopoietic stem cell transplantation (allo-HSCT) (odds ratio [OR], 4.60; 95% CI, 1.22-17.4) and corticosteroid use (OR, 5.55; 95% CI, 1.52-20.3) were significant risk factors for serious infection. IFIs were diagnosed in 7 patients (5%): 5 had Pneumocystis jirovecii pneumonia and 2 were infected with invasive molds.
CONCLUSION: Serious infection and IFI rates are high but similar to those previously described. Risk factors for serious infection included allo-HSCT and corticosteroid use. Targeted antimicrobial prophylaxis should be evaluated in prospective studies in patients on ibrutinib to reduce serious infections and IFI.}, }
@article {pmid37675839, year = {2023}, author = {Bacsik, DJ and Dadonaite, B and Butler, A and Greaney, AJ and Heaton, NS and Bloom, JD}, title = {Influenza virus transcription and progeny production are poorly correlated in single cells.}, journal = {eLife}, volume = {12}, number = {}, pages = {}, pmid = {37675839}, issn = {2050-084X}, support = {75N93021C00015/AI/NIAID NIH HHS/United States ; R01 AI165821/AI/NIAID NIH HHS/United States ; R01AI165821/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Influenza, Human ; Viral Transcription ; Genes, Viral ; Genome, Viral ; Mutation ; }, abstract = {The ultimate success of a viral infection at the cellular level is determined by the number of progeny virions produced. However, most single-cell studies of infection quantify the expression of viral transcripts and proteins, rather than the amount of progeny virions released from infected cells. Here, we overcome this limitation by simultaneously measuring transcription and progeny production from single influenza virus-infected cells by embedding nucleotide barcodes in the viral genome. We find that viral transcription and progeny production are poorly correlated in single cells. The cells that transcribe the most viral mRNA do not produce the most viral progeny and often represent aberrant infections that fail to express the influenza NS gene. However, only some of the discrepancy between transcription and progeny production can be explained by viral gene absence or mutations: there is also a wide range of progeny production among cells infected by complete unmutated virions. Overall, our results show that viral transcription is a relatively poor predictor of an infected cell's contribution to the progeny population.}, }
@article {pmid37675834, year = {2023}, author = {Mujugira, A and Nakyanzi, A and Donnell, D and Boyer, J and Stein, G and Bulterys, M and Naddunga, F and Kyomugisha, J and Birungi, JE and Ssendiwala, P and Nsubuga, R and Muwonge, TR and Musinguzi, J and Sharma, M and Celum, CL}, title = {Partner testing with HIV self-test distribution by Ugandan pregnant women living with HIV: a randomized trial.}, journal = {Journal of the International AIDS Society}, volume = {26}, number = {9}, pages = {e26156}, pmid = {37675834}, issn = {1758-2652}, support = {R01MH113434/MH/NIMH NIH HHS/United States ; UL1 TR002319/TR/NCATS NIH HHS/United States ; KL2 TR002317/TR/NCATS 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 ; TL1 TR002318/TR/NCATS NIH HHS/United States ; }, mesh = {Pregnancy ; Infant ; Humans ; Female ; Male ; Adult ; Uganda/epidemiology ; *Pregnant Women ; Self-Testing ; *HIV Infections/diagnosis/drug therapy ; HIV Testing ; Anti-Retroviral Agents ; }, abstract = {INTRODUCTION: Secondary distribution of HIV self-tests (HIVST) by HIV-negative pregnant women to male partners increases men's testing rates. We examined whether this strategy promotes male partner testing for pregnant women living with HIV (PWLHIV).
METHODS: We conducted an open-label individually randomized trial in Kampala, Uganda, in which PWLHIV ≥18 years who reported a partner of unknown HIV status were randomized 2:1 to secondary distribution of HIVST for male partner(s) or standard-of-care (SOC; invitation letter to male partner for fast-track testing). Women were followed until 12 months post-partum. Male partners were offered confirmatory HIV testing and facilitated linkage to antiretroviral treatment (ART) or oral pre-exposure prophylaxis (PrEP). Using intention-to-treat analysis, primary outcomes were male partner testing at the clinic and initiation on PrEP or ART evaluated through 12 months post-partum (ClinicalTrials.gov, NCT03484533).
RESULTS: From November 2018 to March 2020, 500 PWLHIV were enrolled with a median age of 27 years (interquartile range [IQR] 23-30); 332 were randomized to HIVST and 168 to SOC with 437 PWLHIV (87.4%) completing 12 months follow-up post-partum. Of 236 male partners who tested at the clinic and enrolled (47.2%), their median age was 31 years (IQR 27-36), 45 (88.3%) men with HIV started ART and 113 (61.1%) HIV-negative men started PrEP. There was no intervention effect on male partner testing (hazard ratio [HR] 1.04; 95% confidence interval [CI]: 0.79-1.37) or time to ART or PrEP initiation (HR 0.96; 95% CI: 0.69-1.33). Two male partners and two infants acquired HIV for an incidence of 0.99 per 100 person-years (95% CI: 0.12-3.58) and 1.46 per 100 person-years (95% CI: 0.18%-5.28%), respectively. Social harms related to study participation were experienced by six women (HIVST = 5, SOC = 1).
CONCLUSIONS: Almost half of the partners of Ugandan PWLHIV tested for HIV with similar HIV testing rates and linkage to ART or PrEP among the secondary distribution of HIVST and SOC arms. Although half of men became aware of their HIV serostatus and linked to services, additional strategies to reach male partners of women in antenatal care are needed to increase HIV testing and linkage to services among men.}, }
@article {pmid37674528, year = {2023}, author = {O'Brien, VP and Kang, Y and Shenoy, MK and Finak, G and Young, WC and Dubrulle, J and Koch, L and Rodriguez Martinez, AE and Williams, J and Donato, E and Batra, SK and Yeung, CCS and Grady, WM and Koch, MA and Gottardo, R and Salama, NR}, title = {Single-cell Profiling Uncovers a Muc4-Expressing Metaplastic Gastric Cell Type Sustained by Helicobacter pylori-driven Inflammation.}, journal = {Cancer research communications}, volume = {3}, number = {9}, pages = {1756-1769}, pmid = {37674528}, issn = {2767-9764}, mesh = {Humans ; Animals ; Mice ; *Helicobacter pylori ; *Stomach Neoplasms ; Proto-Oncogene Proteins p21(ras) ; Disease Models, Animal ; Inflammation ; }, abstract = {UNLABELLED: Mechanisms for Helicobacter pylori (Hp)-driven stomach cancer are not fully understood. In a transgenic mouse model of gastric preneoplasia, concomitant Hp infection and induction of constitutively active KRAS (Hp+KRAS+) alters metaplasia phenotypes and elicits greater inflammation than either perturbation alone. Gastric single-cell RNA sequencing showed that Hp+KRAS+ mice had a large population of metaplastic pit cells that expressed the intestinal mucin Muc4 and the growth factor amphiregulin. Flow cytometry and IHC-based immune profiling revealed that metaplastic pit cells were associated with macrophage and T-cell inflammation. Accordingly, expansion of metaplastic pit cells was prevented by gastric immunosuppression and reversed by antibiotic eradication of Hp. Finally, MUC4 expression was significantly associated with proliferation in human gastric cancer samples. These studies identify an Hp-associated metaplastic pit cell lineage, also found in human gastric cancer tissues, whose expansion is driven by Hp-dependent inflammation.
SIGNIFICANCE: Using a mouse model, we have delineated metaplastic pit cells as a precancerous cell type whose expansion requires Hp-driven inflammation. In humans, metaplastic pit cells show enhanced proliferation as well as enrichment in precancer and early cancer tissues, highlighting an early step in the gastric metaplasia to cancer cascade.}, }
@article {pmid37674004, year = {2023}, author = {Despres, HW and Mills, MG and Schmidt, MM and Gov, J and Perez, Y and Jindrich, M and Crawford, AML and Kohl, WT and Rosenblatt, E and Kubinski, HC and Simmons, BC and Nippes, MC and Goldenberg, AJ and Murtha, KE and Nicoloro, S and Harris, MJ and Feeley, AC and Gelinas, TK and Cronin, MK and Frederick, RS and Thomas, M and Johnson, ME and Murphy, J and Lenzini, EB and Carr, PA and Berger, DH and Mehta, SP and Floreani, CJ and Koval, AC and Young, AL and Fish, JH and Wallace, J and Chaney, E and Ushay, G and Ross, RS and Vostal, EM and Thisner, MC and Gonet, KE and Deane, OC and Pelletiere, KR and Rockafeller, VC and Waterman, M and Barry, TW and Goering, CC and Shipman, SD and Shiers, AC and Reilly, CE and Duff, AM and Madruga, SL and Shirley, DJ and Jerome, KR and Pérez-Osorio, AC and Greninger, AL and Fortin, N and Mosher, BA and Bruce, EA}, title = {Surveillance of Vermont wildlife in 2021-2022 reveals no detected SARS-CoV-2 viral RNA.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {14683}, pmid = {37674004}, issn = {2045-2322}, support = {P30 GM118228/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Animals, Wild ; *COVID-19/epidemiology ; *Deer ; RNA, Viral/genetics ; SARS-CoV-2/genetics ; Vermont/epidemiology ; *Coyotes ; Foxes ; *Lynx ; *Otters ; }, abstract = {Previous studies have documented natural infections of SARS-CoV-2 in various domestic and wild animals. More recently, studies have been published noting the susceptibility of members of the Cervidae family, and infections in both wild and captive cervid populations. In this study, we investigated the presence of SARS-CoV-2 in mammalian wildlife within the state of Vermont. 739 nasal or throat samples were collected from wildlife throughout the state during the 2021 and 2022 harvest season. Data was collected from red and gray foxes (Vulpes vulples and Urocyon cineroargentus, respectively), fishers (Martes pennati), river otters (Lutra canadensis), coyotes (Canis lantrans), bobcats (Lynx rufus rufus), black bears (Ursus americanus), and white-tailed deer (Odocoileus virginianus). Samples were tested for the presence of SARS-CoV-2 via quantitative RT-qPCR using the CDC N1/N2 primer set and/or the WHO-E gene primer set. Surprisingly, we initially detected a number of N1 and/or N2 positive samples with high cycle threshold values, though after conducting environmental swabbing of the laboratory and verifying with a second independent primer set (WHO-E) and PCR without reverse transcriptase, we showed that these were false positives due to plasmid contamination from a construct expressing the N gene in the general laboratory environment. Our final results indicate that no sampled wildlife were positive for SARS-CoV-2 RNA, and highlight the importance of physically separate locations for the processing of samples for surveillance and experiments that require the use of plasmid DNA containing the target RNA sequence. These negative findings are surprising, given that most published North America studies have found SARS-CoV-2 within their deer populations. The absence of SARS-CoV-2 RNA in populations sampled here may provide insights in to the various environmental and anthropogenic factors that reduce spillover and spread in North American's wildlife populations.}, }
@article {pmid36778430, year = {2023}, author = {Olson, AT and Kang, Y and Ladha, AM and Lim, CB and Lagunoff, M and Gujral, TS and Geballe, AP}, title = {Polypharmacology-based kinome screen identifies new regulators of KSHV reactivation.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {36778430}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R01 CA189986/CA/NCI NIH HHS/United States ; R01 CA217788/CA/NCI NIH HHS/United States ; R21 CA240479/CA/NCI NIH HHS/United States ; }, abstract = {UNLABELLED: Kaposi's sarcoma-associated herpesvirus (KSHV) causes several human diseases including Kaposi's sarcoma (KS), a leading cause of cancer in Africa and in patients with AIDS. KS tumor cells harbor KSHV predominantly in a latent form, while typically <5% contain lytic replicating virus. Because both latent and lytic stages likely contribute to cancer initiation and progression, continued dissection of host regulators of this biological switch will provide insights into fundamental pathways controlling the KSHV life cycle and related disease pathogenesis. Several cellular protein kinases have been reported to promote or restrict KSHV reactivation, but our knowledge of these signaling mediators and pathways is incomplete. We employed a polypharmacology-based kinome screen to identifiy specific kinases that regulate KSHV reactivation. Those identified by the screen and validated by knockdown experiments included several kinases that enhance lytic reactivation: ERBB2 (HER2 or neu), ERBB3 (HER3), ERBB4 (HER4), MKNK2 (MNK2), ITK, TEC, and DSTYK (RIPK5). Conversely, ERBB1 (EGFR1 or HER1), MKNK1 (MNK1) and FRK (PTK5) were found to promote the maintenance of latency. Mechanistic characterization of ERBB2 pro-lytic functions revealed a signaling connection between ERBB2 and the activation of CREB1, a transcription factor that drives KSHV lytic gene expression. These studies provided a proof-of-principle application of a polypharmacology-based kinome screen for the study of KSHV reactivation and enabled the discovery of both kinase inhibitors and specific kinases that regulate the KSHV latent-to-lytic replication switch.
AUTHOR SUMMARY: Kaposi's sarcoma-associated herpesvirus (KSHV) causes Kaposi's sarcoma, a cancer particularly prevalent in Africa. In cancer cells, the virus persists in a quiescent form called latency, in which only a few viral genes are made. Periodically, the virus switches into an active replicative cycle in which most of the viral genes are made and new virus is produced. What controls the switch from latency to active replication is not well understood, but cellular kinases, enzymes that control many cellular processes, have been implicated. Using a cell culture model of KSHV reactivation along with an innovative screening method that probes the effects of many cellular kinases simultaneously, we identified drugs that significantly limit KSHV reactivation, as well as specific kinases that either enhance or restrict KSHV replicative cycle. Among these were the ERBB kinases which are known to regulate growth of cancer cells. Understanding how these and other kinases contribute to the switch leading to production of more infectious virus helps us understand the mediators and mechanisms of KSHV diseases. Additionally, because kinase inhibitors are proving to be effective for treating other diseases including some cancers, identifying ones that restrict KSHV replicative cycle may lead to new approaches to treating KSHV-related diseases.}, }
@article {pmid37673111, year = {2023}, author = {Blayney, DW and Kuderer, NM and Cummings Joyner, AK and Jarvis, J and Nunag, D and Wells, J and Huang, L and Monhanlal, R and Lyman, GH}, title = {Real-World Impact of Prophylactic Growth Factor Use on Timing of Febrile Neutropenia and Infection After High-Risk Chemotherapy.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {21}, number = {9}, pages = {945-950.e16}, doi = {10.6004/jnccn.2023.7044}, pmid = {37673111}, issn = {1540-1413}, mesh = {United States ; Humans ; Aged ; Female ; Male ; Docetaxel ; Retrospective Studies ; Medicare ; Intercellular Signaling Peptides and Proteins ; *Breast Neoplasms ; Granulocyte Colony-Stimulating Factor/therapeutic use ; *Febrile Neutropenia/epidemiology/etiology/prevention & control ; }, abstract = {BACKGROUND: Prophylactic growth-factor therapy with granulocyte colony-stimulating factor (G-CSF) reduces the risk of febrile neutropenia (FN) in patients with breast cancer initiating myelosuppressive chemotherapy. However, little is known about the protective benefit early in the chemotherapy cycle.
METHODS: To assess the relationship between G-CSF prophylaxis and incidence of FN/infection in week 1 versus beyond week 1 of the first chemotherapy cycle, a retrospective study was conducted using Medicare claims from 2005 through 2020 among patients with breast cancer initiating high-risk chemotherapy. Two cohorts were compared based on G-CSF prophylaxis within 3 days following chemotherapy initiation. The primary outcome was FN or infection, defined as hospitalization with neutropenia, fever, or infection diagnosis. Secondary outcomes were a stricter definition of FN and infection-related hospitalization. Unadjusted and regression-adjusted proportions of patients experiencing each outcome during week 1 versus beyond week 1 of the first chemotherapy cycle were compared.
RESULTS: Of 78,810 patients meeting all inclusion criteria (>98% female; mean age, 69 years), 79% initiated TC (docetaxel/cyclophosphamide), 14% TCH (docetaxel/carboplatin/trastuzumab), and 7% TAC (docetaxel/doxorubicin/cyclophosphamide). Among patients receiving G-CSF (74%), incidence of first-cycle FN/infection was lower compared with patients not receiving G-CSF (overall, 6% vs 13%; TAC, 12% vs 19%; TC, 6% vs 12%; TCH, 5% vs 15%). However, patients who received G-CSF were generally more likely to experience FN/infection in week 1 (adjusted odds ratio [aOR], 1.24 for all; 1.73 for TAC; 1.35 for TC; and 0.76 for TCH). Results were similar for strictly defined FN (overall aOR, 1.29 for week 1 and 0.12 for beyond week 1) and infection-related hospitalization (overall aOR, 1.33 for week 1 and 0.27 for beyond week 1).
CONCLUSIONS: Overall, the rates of chemotherapy-related FN and infection in week 1 of the first chemotherapy cycle are similar for patients receiving and not receiving G-CSF, suggesting continued risk in week 1 despite prophylactic G-CSF.}, }
@article {pmid37671748, year = {2023}, author = {Hoffman-Censits, J and Grivas, P and Powles, T and Hawley, J and Tyroller, K and Seeberger, S and Guenther, S and Jacob, N and Mehr, KT and Hahn, NM}, title = {The JAVELIN Bladder Medley trial: avelumab-based combinations as first-line maintenance in advanced urothelial carcinoma.}, journal = {Future oncology (London, England)}, volume = {}, number = {}, pages = {}, doi = {10.2217/fon-2023-0492}, pmid = {37671748}, issn = {1744-8301}, support = {//Merck (CrossRef Funder ID: 10.13039/100009945)/ ; }, abstract = {Results from JAVELIN Bladder 100 established avelumab (anti-PD-L1) first-line maintenance as the standard-of-care treatment for patients with advanced urothelial carcinoma (UC) that has not progressed with first-line platinum-based chemotherapy. We describe the design of JAVELIN Bladder Medley (NCT05327530), an ongoing phase II, multicenter, randomized, open-label, parallel-arm, umbrella trial. Overall, 252 patients with advanced UC who are progression-free following first-line platinum-based chemotherapy will be randomized 1:2:2:2 to receive maintenance therapy with avelumab alone (control group) or combined with sacituzumab govitecan (anti-Trop-2/topoisomerase inhibitor conjugate), M6223 (anti-TIGIT) or NKTR-255 (recombinant human IL-15). Primary end points are progression-free survival per investigator and safety/tolerability of the combination regimens. Secondary end points include overall survival, objective response and duration of response per investigator, and pharmacokinetics.}, }
@article {pmid37671649, year = {2023}, author = {Ravandi, F and Cloos, J and Buccisano, F and Dillon, R and Döhner, K and Freeman, SD and Hourigan, CS and Ossenkoppele, GJ and Roboz, GJ and Subklewe, M and Thiede, C and Arnhardt, I and Valk, PJM and Venditti, A and Wei, AH and Walter, RB and Heuser, M}, title = {Measurable residual disease monitoring in patients with acute myeloid leukemia treated with lower-intensity therapy: Roadmap from an ELN-DAVID expert panel.}, journal = {American journal of hematology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ajh.27087}, pmid = {37671649}, issn = {1096-8652}, support = {P30 CA016672/CA/NCI NIH HHS/United States ; }, abstract = {With the availability of effective targeted agents, significant changes have occurred in the management of patients with acute myeloid leukemia (AML) over the past several years, particularly for those considered unfit for intensive chemotherapy. While testing for measurable residual disease (MRD) is now routinely performed in patients treated with intensive chemotherapy to refine prognosis and, possibly, inform treatment decision-making, its value in the context of lower-intensity regimens is unclear. As such regimens have gained in popularity and can be associated with higher response rates, the need to better define the role of MRD assessment and the appropriate time points and assays used for this purpose has increased. This report outlines a roadmap for MRD testing in patients with AML treated with lower-intensity regimens. Experts from the European LeukemiaNet (ELN)-DAVID AML MRD working group reviewed all available data to propose a framework for MRD testing in future trials and clinical practice. A Delphi poll served to optimize consensus. Establishment of uniform standards for MRD assessments in lower-intensity regimens used in treating patients with AML is clinically relevant and important for optimizing testing and, ultimately, improving treatment outcomes of these patients.}, }
@article {pmid37671022, year = {2023}, author = {Azulay, A and Cohen-Lavi, L and Friedman, LM and McGargill, MA and Hertz, T}, title = {Mapping antibody footprints using binding profiles.}, journal = {Cell reports methods}, volume = {3}, number = {8}, pages = {100566}, pmid = {37671022}, issn = {2667-2375}, mesh = {Humans ; Antibodies, Monoclonal ; Epitopes ; Binding Sites ; *Influenza, Human ; *Medicine ; }, abstract = {The increasing use of monoclonal antibodies (mAbs) in biology and medicine necessitates efficient methods for characterizing their binding epitopes. Here, we developed a high-throughput antibody footprinting method based on binding profiles. We used an antigen microarray to profile 23 human anti-influenza hemagglutinin (HA) mAbs using HA proteins of 43 human influenza strains isolated between 1918 and 2018. We showed that the mAb's binding profile can be used to characterize its influenza subtype specificity, binding region, and binding site. We present mAb-Patch-an epitope prediction method that is based on a mAb's binding profile and the 3D structure of its antigen. mAb-Patch was evaluated using four mAbs with known solved mAb-HA structures. mAb-Patch identifies over 67% of the true epitope when considering only 50-60 positions along the antigen. Our work provides proof of concept for utilizing antibody binding profiles to screen large panels of mAbs and to down-select antibodies for further functional studies.}, }
@article {pmid37671020, year = {2023}, author = {Einav, T and Ma, R}, title = {Using interpretable machine learning to extend heterogeneous antibody-virus datasets.}, journal = {Cell reports methods}, volume = {3}, number = {8}, pages = {100540}, pmid = {37671020}, issn = {2667-2375}, mesh = {Animals ; Humans ; *Ferrets ; Antibodies ; Hemagglutination Inhibition Tests ; Machine Learning ; *Oils, Volatile ; }, abstract = {A central challenge in biology is to use existing measurements to predict the outcomes of future experiments. For the rapidly evolving influenza virus, variants examined in one study will often have little to no overlap with other studies, making it difficult to discern patterns or unify datasets. We develop a computational framework that predicts how an antibody or serum would inhibit any variant from any other study. We validate this method using hemagglutination inhibition data from seven studies and predict 2,000,000 new values ± uncertainties. Our analysis quantifies the transferability between vaccination and infection studies in humans and ferrets, shows that serum potency is negatively correlated with breadth, and provides a tool for pandemic preparedness. In essence, this approach enables a shift in perspective when analyzing data from "what you see is what you get" into "what anyone sees is what everyone gets."}, }
@article {pmid37670560, year = {2023}, author = {Zarling, LC and Stevenson, PA and Soma, LA and Martino, CH and Percival, MM and Halpern, AB and Ghiuzeli, CM and Becker, PS and Oehler, VG and Cooper, JP and Orozco, JJ and Hendrie, PC and Walter, RB and Estey, EH and Cassaday, RD}, title = {Hyper-CVAD versus dose-adjusted EPOCH as initial treatment for adults with acute lymphoblastic leukemia.}, journal = {European journal of haematology}, volume = {}, number = {}, pages = {}, doi = {10.1111/ejh.14089}, pmid = {37670560}, issn = {1600-0609}, abstract = {OBJECTIVES: We recently performed a single-arm phase II trial of DA-EPOCH in adults with acute lymphoblastic leukemia (ALL). We sought to compare these results to those with standard Hyper-CVAD.
METHODS: We created a retrospective matched cohort of patients who received Hyper-CVAD (n = 69) at our center and otherwise met eligibility criteria for the DA-EPOCH trial (n = 53).
RESULTS: Our outcomes support the use of Hyper-CVAD over DA-EPOCH in Ph- disease for both overall survival (OS; HR 0.18, p = .004) and event-free survival (EFS; HR 0.51, p = .06). In contrast, outcomes were similar in Ph+ disease (OS HR 0.97, p = .96; EFS HR 0.65, p = .21). Rates of morphologic remission and measurable residual-disease negativity were similar between the regimens. Hyper-CVAD was associated with significantly more febrile neutropenia (OR 1.9, p = .03) and a greater incidence of Grade 4 or 5 adverse events (20% vs. 6%). Average transfusions per cycle of both red blood cells (p < .001) and platelets (p < .001) were five-fold higher with Hyper-CVAD.
CONCLUSIONS: Our findings support continued use of Hyper-CVAD for Ph- ALL but suggest that DA-EPOCH may be a reasonable alternative for Ph+ ALL. These data also highlight a potential role for DA-EPOCH in resource-limited settings or when more intense therapy is not feasible.}, }
@article {pmid37669882, year = {2023}, author = {Grabner, E and Stare, E and Fanedl, L and Zorec, M and Jones, DS and Johnston, CD and Avguštin, G and Accetto, T}, title = {Corrigendum to "Expanding the rumen Prevotella collection: the description of Prevotella communis, sp. nov. of ovine origin" [Syst. Appl. Microbiol. 46(4) (2023) 126437].}, journal = {Systematic and applied microbiology}, volume = {}, number = {}, pages = {126453}, doi = {10.1016/j.syapm.2023.126453}, pmid = {37669882}, issn = {1618-0984}, }
@article {pmid37669313, year = {2023}, author = {Olson, AT and Kang, Y and Ladha, AM and Zhu, S and Lim, CB and Nabet, B and Lagunoff, M and Gujral, TS and Geballe, AP}, title = {Polypharmacology-based kinome screen identifies new regulators of KSHV reactivation.}, journal = {PLoS pathogens}, volume = {19}, number = {9}, pages = {e1011169}, doi = {10.1371/journal.ppat.1011169}, pmid = {37669313}, issn = {1553-7374}, abstract = {Kaposi's sarcoma-associated herpesvirus (KSHV) causes several human diseases including Kaposi's sarcoma (KS), a leading cause of cancer in Africa and in patients with AIDS. KS tumor cells harbor KSHV predominantly in a latent form, while typically <5% contain lytic replicating virus. Because both latent and lytic stages likely contribute to cancer initiation and progression, continued dissection of host regulators of this biological switch will provide insights into fundamental pathways controlling the KSHV life cycle and related disease pathogenesis. Several cellular protein kinases have been reported to promote or restrict KSHV reactivation, but our knowledge of these signaling mediators and pathways is incomplete. We employed a polypharmacology-based kinome screen to identify specific kinases that regulate KSHV reactivation. Those identified by the screen and validated by knockdown experiments included several kinases that enhance lytic reactivation: ERBB2 (HER2 or neu), ERBB3 (HER3), ERBB4 (HER4), MKNK2 (MNK2), ITK, TEC, and DSTYK (RIPK5). Conversely, ERBB1 (EGFR1 or HER1), MKNK1 (MNK1) and FRK (PTK5) were found to promote the maintenance of latency. Mechanistic characterization of ERBB2 pro-lytic functions revealed a signaling connection between ERBB2 and the activation of CREB1, a transcription factor that drives KSHV lytic gene expression. These studies provided a proof-of-principle application of a polypharmacology-based kinome screen for the study of KSHV reactivation and enabled the discovery of both kinase inhibitors and specific kinases that regulate the KSHV latent-to-lytic replication switch.}, }
@article {pmid37292912, year = {2023}, author = {Easterling, D and Jacob, RR and Brownson, RC and Haire-Joshu, D and Gundersen, DA and Angier, H and DeVoe, JE and Likumahuwa-Ackman, S and Vu, T and Glasgow, RE and Schnoll, R}, title = {Participatory Logic Modeling in a Multi-Site Initiative to Advance Implementation Science.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {37292912}, support = {P50 CA244432/CA/NCI NIH HHS/United States ; P50 CA244431/CA/NCI NIH HHS/United States ; P50 CA244688/CA/NCI NIH HHS/United States ; P50 CA244289/CA/NCI NIH HHS/United States ; P50 CA244693/CA/NCI NIH HHS/United States ; P50 CA244433/CA/NCI NIH HHS/United States ; P50 CA244690/CA/NCI NIH HHS/United States ; }, abstract = {Background: It is increasingly being recognized that logic models should be developed through a participatory approach which allows input from those who carry out the program being evaluated. While there are many positive examples of participatory logic modeling, funders have generally not used this approach in the context of multi-site initiatives. This article describes an instance where the funder and evaluator of a multi-site initiative fully engaged the funded organizations in developing the initiative logic model. The focus of the case study is Implementation Science Centers in Cancer Control (ISC [3]), a multi-year initiative funded by the National Cancer Institute (NCI). Methods: The case study was collectively constructed by representatives of the seven centers funded under ISC [3] . Members of the Cross-Center Evaluation (CCE) Work Group jointly articulated the process through which the logic model was developed and refined. Individual Work Group members contributed descriptions of how their respective centers reviewed and used the logic model. Cross-cutting themes and lessons emerged through CCE Work Group meetings and the writing process. Results: The initial logic model for ISC [3] changed in significant ways as a result of the input of the funded groups. Authentic participation in the development of the logic model led to strong buy-in among the centers, as evidenced by their utilization. The centers shifted both their evaluation design and their programmatic strategy to better accommodate the expectations reflected in the initiative logic model. Conclusions: The ISC [3] case study provides a positive example of how participatory logic modeling can be mutually beneficial to funders, grantees and evaluators of multi-site initiatives. Funded groups have important insights about what is feasible and what will be required to achieve the initiative's stated objectives. They can also help identify the contextual factors that either inhibit or facilitate success, which can then be incorporated into both the logic model and the evaluation design. In addition, when grantees co-develop the logic model, they have a better understanding and appreciation of the funder's expectations, and thus are better positioned to meet those expectations.}, }
@article {pmid37666957, year = {2023}, author = {Knight, TE and Ahn, KW and Hebert, KM and Atshan, R and Wall, DA and Chiengthong, K and Lund, TC and Prestidge, T and Rangarajan, HG and Dvorak, CC and Auletta, JJ and Kent, M and Hashem, H and Talano, JA and Rotz, SJ and Fraint, E and Myers, KC and Leung, W and Sharma, A and Bhatt, NS and Driscoll, TA and Yu, LC and Schultz, KR and Qayed, M and Broglie, L and Eapen, M and Yanik, GA}, title = {No impact of CD34[+] cell dose on outcome among children undergoing autologous hematopoietic stem cell transplant for high-risk neuroblastoma.}, journal = {Bone marrow transplantation}, volume = {}, number = {}, pages = {}, pmid = {37666957}, issn = {1476-5365}, }
@article {pmid37666943, year = {2023}, author = {Berndt, SI and Vijai, J and Benavente, Y and Camp, NJ and Nieters, A and Wang, Z and Smedby, KE and Kleinstern, G and Hjalgrim, H and Besson, C and Skibola, CF and Morton, LM and Brooks-Wilson, AR and Teras, LR and Breeze, C and Arias, J and Adami, HO and Albanes, D and Anderson, KC and Ansell, SM and Bassig, B and Becker, N and Bhatti, P and Birmann, BM and Boffetta, P and Bracci, PM and Brennan, P and Brown, EE and Burdett, L and Cannon-Albright, LA and Chang, ET and Chiu, BCH and Chung, CC and Clavel, J and Cocco, P and Colditz, G and Conde, L and Conti, DV and Cox, DG and Curtin, K and Casabonne, D and De Vivo, I and Diepstra, A and Diver, WR and Dogan, A and Edlund, CK and Foretova, L and Fraumeni, JF and Gabbas, A and Ghesquières, H and Giles, GG and Glaser, S and Glenn, M and Glimelius, B and Gu, J and Habermann, TM and Haiman, CA and Haioun, C and Hofmann, JN and Holford, TR and Holly, EA and Hutchinson, A and Izhar, A and Jackson, RD and Jarrett, RF and Kaaks, R and Kane, E and Kolonel, LN and Kong, Y and Kraft, P and Kricker, A and Lake, A and Lan, Q and Lawrence, C and Li, D and Liebow, M and Link, BK and Magnani, C and Maynadie, M and McKay, J and Melbye, M and Miligi, L and Milne, RL and Molina, TJ and Monnereau, A and Montalvan, R and North, KE and Novak, AJ and Onel, K and Purdue, MP and Rand, KA and Riboli, E and Riby, J and Roman, E and Salles, G and Sborov, DW and Severson, RK and Shanafelt, TD and Smith, MT and Smith, A and Song, KW and Song, L and Southey, MC and Spinelli, JJ and Staines, A and Stephens, D and Sutherland, HJ and Tkachuk, K and Thompson, CA and Tilly, H and Tinker, LF and Travis, RC and Turner, J and Vachon, CM and Vajdic, CM and Van Den Berg, A and Van Den Berg, DJ and Vermeulen, RCH and Vineis, P and Wang, SS and Weiderpass, E and Weiner, GJ and Weinstein, S and Doo, NW and Ye, Y and Yeager, M and Yu, K and Zeleniuch-Jacquotte, A and Zhang, Y and Zheng, T and Ziv, E and Sampson, J and Chatterjee, N and Offit, K and Cozen, W and Wu, X and Cerhan, JR and Chanock, SJ and Slager, SL and Rothman, N}, title = {Correction: Distinct germline genetic susceptibility profiles identified for common non-Hodgkin lymphoma subtypes.}, journal = {Leukemia}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41375-023-01978-x}, pmid = {37666943}, issn = {1476-5551}, }
@article {pmid37665649, year = {2023}, author = {Lyman, GH and Lyman, CH and Kuderer, NM}, title = {PERCEPTION, COGNITION AND THOUGHT: Part V Entropy, the Arrow of Time and the Present.}, journal = {Cancer investigation}, volume = {}, number = {}, pages = {1-6}, doi = {10.1080/07357907.2023.2256145}, pmid = {37665649}, issn = {1532-4192}, }
@article {pmid37665212, year = {2023}, author = {Ku, TSN and Al Mohajer, M and Newton, JA and Wilson, MH and Monsees, E and Hayden, MK and Messacar, K and Kisgen, JJ and Diekema, DJ and Morgan, DJ and Sifri, CD and Vaughn, VM}, title = {Improving antimicrobial use through better diagnosis: The relationship between diagnostic stewardship and antimicrobial stewardship.}, journal = {Infection control and hospital epidemiology}, volume = {}, number = {}, pages = {1-8}, doi = {10.1017/ice.2023.156}, pmid = {37665212}, issn = {1559-6834}, abstract = {Antimicrobial stewardship programs (ASPs) exist to optimize antibiotic use, reduce selection for antimicrobial-resistant microorganisms, and improve patient outcomes. Rapid and accurate diagnosis is essential to optimal antibiotic use. Because diagnostic testing plays a significant role in diagnosing patients, it has one of the strongest influences on clinician antibiotic prescribing behaviors. Diagnostic stewardship, consequently, has emerged to improve clinician diagnostic testing and test result interpretation. Antimicrobial stewardship and diagnostic stewardship share common goals and are synergistic when used together. Although ASP requires a relationship with clinicians and focuses on person-to-person communication, diagnostic stewardship centers on a relationship with the laboratory and hardwiring testing changes into laboratory processes and the electronic health record. Here, we discuss how diagnostic stewardship can optimize the "Four Moments of Antibiotic Decision Making" created by the Agency for Healthcare Research and Quality and work synergistically with ASPs.}, }
@article {pmid37664583, year = {2023}, author = {St Germain, R and Bossard, EL and Corey, L and Sholukh, AM}, title = {Serum concentration of antigen-specific IgG can substantially bias interpretation of antibody-dependent phagocytosis assay readout.}, journal = {iScience}, volume = {26}, number = {9}, pages = {107527}, pmid = {37664583}, issn = {2589-0042}, abstract = {Because virus neutralization cannot solely explain vaccine-induced, antibody-mediated protection, antibody effector functions are being considered as a potential correlate of protection (CoP). However, measuring effector functions at a fixed serum dilution for high throughput purposes makes it difficult to distinguish between the effect of serum antibody concentration and antibody properties such as epitopes, subclass, and glycosylation. To address this issue, we evaluated antibody-dependent cellular phagocytosis (ADCP) assay against SARS-CoV-2 spike. Adjustment of serum samples to the same concentration of antigen-specific IgG prior to the ADCP assay revealed concentration-independent differences in ADCP after mRNA vaccination in subjects with and without prior SARS-CoV-2 infection not detectable in assay performed with fixed serum dilution. Phagocytosis measured at different concentrations of spike-specific IgG strongly correlated with the area under the curve (AUC) indicating that ADCP assay can be performed at a standardized antibody concentration for the high throughput necessary for vaccine trial analyses.}, }
@article {pmid37663929, year = {2023}, author = {Besschetnova, A and Han, W and Liu, M and Gao, Y and Li, M and Wang, Z and Labaf, M and Patalano, S and Venkataramani, K and Muriph, RE and Macoska, JA and Siegfried, KR and Evans, J and Balk, SP and Gao, S and Han, D and Cai, C}, title = {Demethylation of EHMT1/GLP Protein Reprograms Its Transcriptional Activity and Promotes Prostate Cancer Progression.}, journal = {Cancer research communications}, volume = {3}, number = {8}, pages = {1716-1730}, pmid = {37663929}, issn = {2767-9764}, support = {P01 CA163227/CA/NCI NIH HHS/United States ; P50 CA090381/CA/NCI NIH HHS/United States ; R01 CA211350/CA/NCI NIH HHS/United States ; U54 CA156734/CA/NCI NIH HHS/United States ; }, mesh = {Male ; Humans ; Lysine ; Histones ; Neoplastic Processes ; *Prostatic Neoplasms/genetics ; *Prostatic Hyperplasia ; Histone-Lysine N-Methyltransferase/genetics ; Chromatin ; Demethylation ; Histocompatibility Antigens ; }, abstract = {UNLABELLED: Epigenetic reprogramming, mediated by genomic alterations and dysregulation of histone reader and writer proteins, plays a critical role in driving prostate cancer progression and treatment resistance. However, the specific function and regulation of EHMT1 (also known as GLP) and EHMT2 (also known as G9A), well-known histone 3 lysine 9 methyltransferases, in prostate cancer progression remain poorly understood. Through comprehensive investigations, we discovered that both EHMT1 and EHMT2 proteins have the ability to activate oncogenic transcription programs in prostate cancer cells. Silencing EHMT1/2 or targeting their enzymatic activity with small-molecule inhibitors can markedly decrease prostate cancer cell proliferation and metastasis in vitro and in vivo. In-depth analysis of posttranslational modifications of EHMT1 protein revealed the presence of methylation at lysine 450 and 451 residues in multiple prostate cancer models. Notably, we found that lysine 450 can be demethylated by LSD1. Strikingly, concurrent demethylation of both lysine residues resulted in a rapid and profound expansion of EHMT1's chromatin binding capacity, enabling EHMT1 to reprogram the transcription networks in prostate cancer cells and activate oncogenic signaling pathways. Overall, our studies provide valuable molecular insights into the activity and function of EHMT proteins during prostate cancer progression. Moreover, we propose that the dual-lysine demethylation of EHMT1 acts as a critical molecular switch, triggering the induction of oncogenic transcriptional reprogramming in prostate cancer cells. These findings highlight the potential of targeting EHMT1/2 and their demethylation processes as promising therapeutic strategies for combating prostate cancer progression and overcoming treatment resistance.
SIGNIFICANCE: In this study, we demonstrate that EHMT1 and EHMT2 proteins drive prostate cancer development by transcriptionally activating multiple oncogenic pathways. Mechanistically, the chromatin binding of EHMT1 is significantly expanded through demethylation of both lysine 450 and 451 residues, which can serve as a critical molecular switch to induce oncogenic transcriptional reprogramming in prostate cancer cells.}, }
@article {pmid37662520, year = {2023}, author = {Trněný, M and Avigdor, A and McKinney, MS and Paneesha, S and Wahlin, BE and Hrom, JS and Cunningham, D and Morley, N and Canales, M and Bastos-Oreiro, M and Belada, D and Devizzi, L and Zheng, F and DeMarini, DJ and Jiang, W and Jiang, P and Lynch, RC}, title = {Parsaclisib, a PI3Kδ inhibitor, in relapsed and refractory follicular lymphoma (CITADEL-203): a phase 2 study.}, journal = {EClinicalMedicine}, volume = {63}, number = {}, pages = {102130}, pmid = {37662520}, issn = {2589-5370}, abstract = {BACKGROUND: Parsaclisib, a potent and highly selective PI3Kδ inhibitor, has shown clinical benefit in patients with relapsed or refractory (R/R) B-cell malignancies. This phase 2 study (CITADEL-203; NCT03126019, EudraCT 2017-001624-22) assessed efficacy and safety of parsaclisib monotherapy in patients with R/R follicular lymphoma (FL).
METHODS: Patients ≥18 years of age with histologically confirmed R/R FL (grade 1-3a) and prior treatment with ≥2 systemic therapies received parsaclisib 20 mg once daily (QD) for 8 weeks then parsaclisib 20 mg once weekly (weekly dosing group [WG]) or parsaclisib 20 mg QD for 8 weeks then parsaclisib 2.5 mg QD (daily dosing group [DG]); DG was selected for further assessment. Primary endpoint was objective response rate (ORR).
FINDINGS: At data cut-off (January 15, 2021), 126 patients had been treated (WG: n = 23; DG: n = 103). ORR (95% confidence interval [CI]) was 77.7% (68.4-85.3) with a complete response rate (95% CI) of 19.4% (12.3-28.4) in DG; median (95% CI) duration of response was 14.7 months (10.4-not estimable [NE]), median progression-free survival was 15.8 months (11.0-NE), and median overall survival was not reached. The most common any-grade treatment-emergent adverse events (TEAEs) among all treated patients included diarrhoea (n = 48, 38.1%), nausea (n = 31, 24.6%), and cough (n = 28, 22.2%); the most common grade ≥3 TEAEs were diarrhoea (n = 15, 11.9%), neutropenia (n = 13, 10.3%), and colitis (n = 7, 5.6%). Dose interruption, reduction, and discontinuation from TEAEs occurred in 46.8% (n = 59), 17.5% (n = 22), and 23.8% (n = 30) of patients, respectively.
INTERPRETATION: Treatment with parsaclisib demonstrated rapid and durable responses, and a manageable safety profile in patients with R/R FL.
FUNDING: Incyte Corporation.}, }
@article {pmid37662440, year = {2023}, author = {Torres Blasco, N and Rosario, L and Shen, MJ}, title = {Latino advanced cancer patients' prognostic awareness and familial cultural influences on advance care planning engagement: a qualitative study.}, journal = {Palliative care and social practice}, volume = {17}, number = {}, pages = {26323524231193038}, pmid = {37662440}, issn = {2632-3524}, support = {K07 CA207580/CA/NCI NIH HHS/United States ; R37 CA246703/CA/NCI NIH HHS/United States ; U54 MD007579/MD/NIMHD NIH HHS/United States ; }, abstract = {BACKGROUND: Advanced cancer patients need an accurate understanding of their prognoses in order to engage in informed end-of-life care treatment decision-making. Latino cancer patients experience disparities around prognostic understanding, in part due to a lack of culturally competent communication around prognosis and advance care planning (ACP).
OBJECTIVE: The objective of the present study of Latino patients with advanced, terminally ill cancer is to examine their understanding of prognosis, and how cultural factors may influence this understanding and engagement in ACP.
METHODS: A mixed methods study was conducted, which consisted of surveys and semi-structured interviews. Descriptive statistics were used for sociodemographic information and self-reported prognostic understanding. Interviews around prognostic understanding and cultural influences on this understanding and engagement in ACP were recorded, transcribed, and then coded and analyzed using thematic content analysis.
FINDINGS: Latino patients with advanced cancer (n = 20) completed a self-reported survey and participated in a semi-structured interview. Results indicate that among terminally ill patients, 50% of the patients inaccurately believed they had early-stage cancer, 85% did not believe their cancer was terminal, and 70% believed their cancer was curable. Moreover, interviews yielded two main themes: varying levels of awareness of the incurability of their cancer and diverse end-of-life care decision-making and treatment preferences based on prognostic understanding. Within these themes, patients expressed denial or acceptance of their prognosis through communication with the oncologist, the importance of family, and incorporating their pre-existing beliefs.
CONCLUSION: Findings indicate the importance of communication, family involvement, and incorporation of beliefs for promoting an accurate prognostic understanding among Latino patients. It is imperative to address disparities in Latino advanced cancer patients' prognostic understanding so they can engage in informed treatment decision-making around end-of-life care.}, }
@article {pmid37661881, year = {2023}, author = {Hua, S and Peters, BA and Lee, S and Fitzgerald, K and Wang, Z and Sollecito, CC and Grassi, E and Wiek, F and St Peter, L and D'Souza, G and Weber, KM and Kaplan, RC and Gustafson, D and Sharma, A and Burk, RD and Rubin, LH and Qi, Q}, title = {Gut Microbiota and Cognitive Function Among Women Living with HIV.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {}, doi = {10.3233/JAD-230117}, pmid = {37661881}, issn = {1875-8908}, abstract = {BACKGROUND: Altered gut microbiota has been associated with cognitive dysfunction and Alzheimer's disease, but little is known among people living with HIV.
OBJECTIVE: To examine associations between gut microbiota and cognitive impairment among women with or without HIV.
METHODS: This is a cross-sectional study of 446 women (302 HIV+) who had completed a neuropsychological test battery and stool sample collected within 1 year. Gut microbiota composition was quantified using 16SV4 rRNA gene sequencing and microbial functional pathways were predicted using PICRUSt. Cognitive domains included attention, executive function, learning, memory, fluency, processing speed, and motor function. Cognitive impairment was defined as two or more domains with T scores < 1 SD below mean. ANCOM-II was used to identify taxa and functional pathways associated with cognitive impairment, and the associations were further examined by multivariable logistic regression.
RESULTS: In overall sample, adjusting for multiple covariates including HIV status, we found that higher abundance of Methanobrevibacter, Odoribacter, Pyramidobacter, Eubacterium, Ruminococcus, and Gemmiger, and lower abundance of Veillonella were associated with cognitive impairment. The associations between these taxa and cognitive impairment were more profound in HIV+ women compared to HIV- women. Most associations with bacterial taxa were observed for learning and memory. We found accompanying microbial functional differences associated with cognitive impairment, including twelve enriched pathways and three depleted pathways.
CONCLUSIONS: In women with or without HIV infection, this study identified multiple altered gut bacterial taxa and functional pathways associated with cognitive impairment, supporting the potential role of gut microbiota in cognitive dysfunction and Alzheimer's disease.}, }
@article {pmid37658805, year = {2023}, author = {An, J and Lu, SE and McDougall, J and Walters, ST and Lin, Y and Heidt, E and Stroup, A and Paddock, L and Grumet, S and Toppmeyer, D and Kinney, AY}, title = {Identifying Mediators of Intervention Effects Within a Randomized Controlled Trial to Motivate Cancer Genetic Risk Assessment Among Breast and Ovarian Cancer Survivors.}, journal = {Annals of behavioral medicine : a publication of the Society of Behavioral Medicine}, volume = {}, number = {}, pages = {}, doi = {10.1093/abm/kaad048}, pmid = {37658805}, issn = {1532-4796}, support = {R01CA211625/NH/NIH HHS/United States ; 3P30CA072720/CA/NCI NIH HHS/United States ; HHSN261201800014I/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: A theory-guided Tailored Counseling and Navigation (TCN) intervention successfully increased cancer genetic risk assessment (CGRA) uptake among cancer survivors at increased risk of hereditary breast and ovarian cancer (HBOC). Understanding the pathways by which interventions motivate behavior change is important for identifying the intervention's active components.
PURPOSE: We examined whether the TCN intervention exerted effects on CGRA uptake through hypothesized theoretical mediators.
METHODS: Cancer survivors at elevated risk for HBOC were recruited from three statewide cancer registries and were randomly assigned to three arms: TCN (n = 212), Targeted Print (TP, n = 216), and Usual Care (UC, n = 213). Theoretical mediators from the Extended Parallel Process Model, Health Action Planning Approach, and Ottawa Decision Support Framework were assessed at baseline and 1-month follow-up; CGRA uptake was assessed at 6 months. Generalized structural equation modeling was used for mediation analysis.
RESULTS: The TCN effects were most strongly mediated by behavioral intention alone (β = 0.49 and 0.31) and by serial mediation through self-efficacy and intention (β = 0.041 and 0.10) when compared with UC and TP, respectively. In addition, compared with UC, the TCN also increased CGRA through increased perceived susceptibility, knowledge of HBOC, and response efficacy.
CONCLUSIONS: Risk communication and behavioral change interventions for hereditary cancer should stress a person's increased genetic risk and the potential benefits of genetic counseling and testing, as well as bolster efficacy beliefs by helping remove barriers to CGRA. System-level and policy interventions are needed to further expand access.}, }
@article {pmid37660077, year = {2023}, author = {Coffey, DG and Maura, F and Gonzalez-Kozlova, E and Diaz-Mejia, JJ and Luo, P and Zhang, Y and Xu, Y and Warren, EH and Dawson, T and Lee, B and Xie, H and Smith, E and Ciardiello, A and Cho, HJ and Rahman, A and Kim-Schulze, S and Diamond, B and Lesokhin, A and Kazandjian, D and Pugh, TJ and Green, DJ and Gnjatic, S and Landgren, O}, title = {Immunophenotypic correlates of sustained MRD negativity in patients with multiple myeloma.}, journal = {Nature communications}, volume = {14}, number = {1}, pages = {5335}, pmid = {37660077}, issn = {2041-1723}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; P30 CA240139/CA/NCI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; }, mesh = {Humans ; *Multiple Myeloma/drug therapy ; Lenalidomide ; Immunophenotyping ; Patients ; Receptors, Antigen, T-Cell, alpha-beta ; Tumor Microenvironment ; }, abstract = {The role of the immune microenvironment in maintaining disease remission in patients with multiple myeloma (MM) is not well understood. In this study, we comprehensively profile the immune system in patients with newly diagnosed MM receiving continuous lenalidomide maintenance therapy with the aim of discovering correlates of long-term treatment response. Leveraging single-cell RNA sequencing and T cell receptor β sequencing of the peripheral blood and CyTOF mass cytometry of the bone marrow, we longitudinally characterize the immune landscape in 23 patients before and one year after lenalidomide exposure. We compare patients achieving sustained minimal residual disease (MRD) negativity to patients who never achieved or were unable to maintain MRD negativity. We observe that the composition of the immune microenvironment in both the blood and the marrow varied substantially according to both MRD negative status and history of autologous stem cell transplant, supporting the hypothesis that the immune microenvironment influences the depth and duration of treatment response.}, }
@article {pmid37659695, year = {2023}, author = {Connelly-Smith, L and Gooley, T and Roberts, L and Mielcarek, M and Linenberger, M and Petersdorf, E and Sandmaier, BM and Milano, F}, title = {Cryopreservation of Growth Factor-Mobilized Peripheral Blood Stem Cells Does Not Compromise Major Outcomes after Allogeneic Hematopoietic Cell Transplantation - A Single Center Experience.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2023.08.025}, pmid = {37659695}, issn = {2666-6367}, abstract = {INTRODUCTION: During the COVID-19 pandemic, cryopreservation of allogeneic donor stem cell products ensured availability of products at the start of conditioning for hematopoietic cell transplantation (HCT). Following recommendations from unrelated donor registries, including the National Marrow Donor Program (NMDP), many centers started to cryopreserve related donor peripheral blood stem cell (PBSC) products. Throughout the process, several centers have published outcomes with cryopreserved versus fresh products, some with conflicting results. Even though cryopreservation was initially considered only a temporary measure driven by the pandemic, potential advantages include greater flexibility of transplant timing. However, concern about detrimental effects of cryopreservation including increased risks of graft rejection, relapse and consequently mortality remained.
OBJECTIVE: The primary objective was to describe our center's experience comparing outcomes following PBSC transplantation with cryopreserved versus fresh grafts.
METHODS: This was an observational case study with retrospective review comparing cryopreserved grafts (N=213), to a recent historical cohort (controls) using fresh grafts (N=167).
RESULTS: In multivariable analyses, the adjusted hazard ratio (fresh vs. cryo) we for overall mortality was HR= 1.20 (95% confidence interval (CI), 0.79-1.82; p=0.40), for non-relapse mortality HR=0.99 (95% CI, 0.55-1.77; p=0.98), and for relapse HR=0.94 (95% CI, 0.60 -1.48; p=0.80). The adjusted hazard ratio for platelet engraftment was HR=1.31 (95% CI, 1.05-1.63; p=.02) and the odds ratio of grades III-IV acute GVHD was OR=1.75 (95% CI 1.01-3.04; p=.05) with fresh compared to cryopreserved grafts.
CONCLUSION: There was no demonstrable difference in the risk of chronic GHVD. Although longer-term follow-up is needed, these data provide preliminary reassurance that in the event of another pandemic or should the logistical need arise in individual patients, cryopreservation of PBSC products constitutes a reasonably safe alternative.}, }
@article {pmid37659505, year = {2023}, author = {Chandrasekaran, P and Han, Y and Zerbe, CS and Heller, T and DeRavin, SS and Kreuzberg, SA and Marciano, BE and Siu, Y and Jones, DR and Abraham, RS and Stephens, MC and Tsou, AM and Snapper, S and Conlan, S and Subramanian, P and Quinones, M and Grou, C and Calderon, V and Deming, C and Leiding, JW and Arnold, DE and Logan, BR and Griffith, LM and Petrovic, A and Mousallem, TI and Kapoor, N and Heimall, JR and Barnum, JL and Kapadia, M and Wright, N and Rayes, A and Chandra, S and Broglie, LA and Chellapandian, D and Deal, CL and Grunebaum, E and Lim, SS and Mallhi, K and Marsh, RA and Murguia-Favela, L and Parikh, S and Touzot, F and Cowan, MJ and Dvorak, CC and Haddad, E and Kohn, DB and Notarangelo, L and Pai, SY and Puck, JM and Pulsipher, MA and Torgerson, TR and Kang, EM and Malech, HL and Segre, JA and Bryant, CE and Holland, SM and Falcone, EL}, title = {Intestinal microbiome and metabolome signatures in patients with chronic granulomatous disease.}, journal = {The Journal of allergy and clinical immunology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaci.2023.07.022}, pmid = {37659505}, issn = {1097-6825}, abstract = {BACKGROUND: CGD is caused by defects in any of the 6 subunits forming the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex 2 (NOX2), leading to severely reduced or absent phagocyte-derived ROS production. Almost 50% of patients with chronic granulomatous disease (CGD) have IBD (CGD-IBD). While conventional IBD therapies can treat CGD-IBD, their benefits must be weighed against the risk of infection. Understanding the impact of NOX2 defects on the intestinal microbiota may lead to the identification of novel CGD-IBD treatments.
OBJECTIVE: To identify microbiome and metabolome signatures that can distinguish patients with CGD and CGD-IBD.
METHODS: We conducted a cross-sectional, observational study of 79 patients with CGD, 8 pathogenic variant carriers and 19 healthy controls followed at the National Institutes of Health Clinical Center (NIH CC). We profiled the intestinal microbiome (amplicon sequencing) and stool metabolome, and validated our findings in a second cohort of 36 CGD patients recruited through the Primary Immune Deficiency Treatment Consortium (PIDTC).
RESULTS: We identified distinct intestinal microbiome and metabolome profiles in patients with CGD compared to healthy individuals. We observed enrichment for Erysipelatoclostridium spp., Sellimonas spp. and Lachnoclostridium spp. in CGD stool samples. Despite differences in bacterial alpha and beta diversity between the NIH CC and PIDTC cohorts, several taxa correlated significantly between both cohorts. We further demonstrated that patients with CGD-IBD have a distinct microbiome and metabolome profile compared to patients without CGD-IBD.
CONCLUSION: Intestinal microbiome and metabolome signatures distinguished patients with CGD and CGD-IBD, and identified potential biomarkers and therapeutic targets.}, }
@article {pmid37658231, year = {2023}, author = {Anwar, MY and Graff, M and Highland, HM and Smit, R and Wang, Z and Buchanan, VL and Young, KL and Kenny, EE and Fernandez-Rhodes, L and Liu, S and Assimes, T and Garcia, DO and Daeeun, K and Gignoux, CR and Justice, AE and Haiman, CA and Buyske, S and Peters, U and Loos, RJF and Kooperberg, C and North, KE}, title = {Assessing efficiency of fine-mapping obesity-associated variants through leveraging ancestry architecture and functional annotation using PAGE and UKBB cohorts.}, journal = {Human genetics}, volume = {}, number = {}, pages = {}, pmid = {37658231}, issn = {1432-1203}, support = {HHSN268201200008I/HL/NHLBI NIH HHS/United States ; 3R01DK122503-02W1/DK/NIDDK NIH HHS/United States ; R01DK122503/DK/NIDDK NIH HHS/United States ; R01DK101855/DK/NIDDK NIH HHS/United States ; R01HG010297/HG/NHGRI NIH HHS/United States ; R01HG009974/HG/NHGRI NIH HHS/United States ; R01HG011345/HG/NHGRI NIH HHS/United States ; R01HL142302/HL/NHLBI NIH HHS/United States ; R01HL143885/HL/NHLBI NIH HHS/United States ; R01HL151152/HL/NHLBI NIH HHS/United States ; }, abstract = {Inadequate representation of non-European ancestry populations in genome-wide association studies (GWAS) has limited opportunities to isolate functional variants. Fine-mapping in multi-ancestry populations should improve the efficiency of prioritizing variants for functional interrogation. To evaluate this hypothesis, we leveraged ancestry architecture to perform comparative GWAS and fine-mapping of obesity-related phenotypes in European ancestry populations from the UK Biobank (UKBB) and multi-ancestry samples from the Population Architecture for Genetic Epidemiology (PAGE) consortium with comparable sample sizes. In the investigated regions with genome-wide significant associations for obesity-related traits, fine-mapping in our ancestrally diverse sample led to 95% and 99% credible sets (CS) with fewer variants than in the European ancestry sample. Lead fine-mapped variants in PAGE regions had higher average coding scores, and higher average posterior probabilities for causality compared to UKBB. Importantly, 99% CS in PAGE loci contained strong expression quantitative trait loci (eQTLs) in adipose tissues or harbored more variants in tighter linkage disequilibrium (LD) with eQTLs. Leveraging ancestrally diverse populations with heterogeneous ancestry architectures, coupled with functional annotation, increased fine-mapping efficiency and performance, and reduced the set of candidate variants for consideration for future functional studies. Significant overlap in genetic causal variants across populations suggests generalizability of genetic mechanisms underpinning obesity-related traits across populations.}, }
@article {pmid37657974, year = {2023}, author = {Kassamali Escobar, Z and Shively, NR}, title = {Health System and Tele-Antimicrobial Stewardship: The Role of Building Networks.}, journal = {Infectious disease clinics of North America}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.idc.2023.07.005}, pmid = {37657974}, issn = {1557-9824}, abstract = {Tele-antimicrobial stewardship programs (tele-ASPs) use technology and remote access to resources and clinical expertise to expand antimicrobial services within and outside of health systems. Models of tele-ASPs are workforce multiplying and workforce extending, depending on how they are structured. Building rapport and strong interpersonal networks are essential for successful ASPs. The available evidence suggests that an optimal model for tele-ASP includes hands-on involvement from remote infectious disease (ID) expertise with implementation by local pharmacists. However, this model remains limited by the available time and cost of ID-trained specialists.}, }
@article {pmid37657769, year = {2023}, author = {Rashid, N and Gooley, T and Furlong, T and Lee, SJ and Martin, PJ and Storb, R and Mielcarek, M}, title = {Impact of Donor Statin Treatment on Graft-versus-Host Disease after Allogeneic Hematopoietic Cell Transplantation.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2023.08.027}, pmid = {37657769}, issn = {2666-6367}, abstract = {BACKGROUND: Some retrospective studies suggested that long-term donor statin use may protect against graft-versus-host disease (GVHD) in patients receiving cyclosporine (CSP)-based immunosuppression after allogeneic hematopoietic cell transplantation (HCT), but prospective studies of short-term treatment of donors with statin have shown conflicting results.
OBJECTIVES: We performed two consecutive prospective clinical trials to assess whether donor statin treatment was associated with protection against severe acute GVHD.
STUDY DESIGN: In a single-arm phase II trial (Study 1), we evaluated whether short-term statin treatment of HLA-matched related donors for 14 days before HCT prevented grades III-IV acute GVHD. In a prospective observational cohort study (Study 2), we evaluated whether longer-term (> 14 days) donor statin use was required for GVHD-protective effects.
RESULTS: Study 1 was terminated after 6 of the 35 (17%) recipients developed grades III-IV GVHD. For Study 2, we identified 135 patients whose unrelated donors had received long-term treatment with statins up to the time of HCT and 4,942 patients whose donors had not. The adjusted odds ratio for grades III-IV acute GVHD (statin vs. no-statin) was 0.83 (95% confidence interval, 0.46-1.50; p=0.54). Multivariable analysis showed no statistically significant differences in the risks of grades II-IV acute GVHD, chronic GVHD, non-relapse mortality, recurrent malignancy or overall mortality between the two groups. Among patients receiving CSP-based immunosuppression, 35 having donors with long-term statin treatment and 973 without, the adjusted odds ratio of grades III-IV acute GVHD was 0.30 (0.07-1.35; p=0.12).
CONCLUSIONS: In Study 1, short-term statin treatment of donors was ineffective in preventing grades III-IV GVHD. In Study 2, in the pre-specified subgroup of recipients given CSP-based immunosuppression, non-definitive evidence suggested that donor statin use was associated with a reduced risk of severe acute GVHD.}, }
@article {pmid37657462, year = {2023}, author = {Hurvitz, SA and Bardia, A and Quiroga, V and Park, YH and Blancas, I and Alonso-Romero, JL and Vasiliev, A and Adamchuk, H and Salgado, M and Yardley, DA and Berzoy, O and Zamora-Auñón, P and Chan, D and Spera, G and Xue, C and Ferreira, E and Badovinac Crnjevic, T and Pérez-Moreno, PD and López-Valverde, V and Steinseifer, J and Fernando, TM and Moore, HM and Fasching, PA and , }, title = {Neoadjuvant palbociclib plus either giredestrant or anastrozole in oestrogen receptor-positive, HER2-negative, early breast cancer (coopERA Breast Cancer): an open-label, randomised, controlled, phase 2 study.}, journal = {The Lancet. Oncology}, volume = {24}, number = {9}, pages = {1029-1041}, doi = {10.1016/S1470-2045(23)00268-1}, pmid = {37657462}, issn = {1474-5488}, mesh = {Humans ; Female ; Middle Aged ; Anastrozole ; *Breast Neoplasms/drug therapy/genetics ; Receptors, Estrogen ; Neoadjuvant Therapy/adverse effects ; Ki-67 Antigen ; }, abstract = {BACKGROUND: The development of more potent selective oestrogen receptor antagonists and degraders (SERDs) that can be orally administered could help to address the limitations of current endocrine therapies. We report the primary and final analyses of the coopERA Breast Cancer study, designed to test whether giredestrant, a highly potent, non-steroidal, oral SERD, would show a stronger anti-proliferative effect than anastrozole after 2 weeks for oestrogen receptor-positive, HER2-negative, untreated early breast cancer.
METHODS: In this open-label, randomised, controlled, phase 2 study, postmenopausal women were eligible if they were aged 18 years or older; had clinical T stage (cT)1c to cT4a-c (≥1·5 cm within cT1c) oestrogen receptor-positive, HER2-negative, untreated early breast cancer; an Eastern Cooperative Oncology Group performance status of 0-1; and baseline Ki67 score of at least 5%. The study was conducted at 59 hospital or clinic sites in 11 countries globally. Participants were randomly assigned (1:1) to giredestrant 30 mg oral daily or anastrozole 1 mg oral daily on days 1-14 (window-of-opportunity phase) via an interactive web-based system with permuted-block randomisation with block size of four. Randomisation was stratified by cT stage, baseline Ki67 score, and progesterone receptor status. A 16-week neoadjuvant phase comprised the same regimen plus palbociclib 125 mg oral daily on days 1-21 of a 28-day cycle, for four cycles. The primary endpoint was geometric mean relative Ki67 score change from baseline to week 2 in patients with complete central Ki67 scores at baseline and week 2 (window-of-opportunity phase). Safety was assessed in all patients who received at least one dose of study drug. The study is registered with ClinicalTrials.gov (NCT04436744) and is complete.
FINDINGS: Between Sept 4, 2020, and June 22, 2021, 221 patients were enrolled and randomly assigned to the giredestrant plus palbociclib group (n=112; median age 62·0 years [IQR 57·0-68·5]) or anastrozole plus palbociclib group (n=109; median age 62·0 [57·0-67·0] years). 15 (7%) of 221 patients were Asian, three (1%) were Black or African American, 194 (88%) were White, and nine (4%) were unknown races. At data cutoff for the primary analysis (July 19, 2021), the geometric mean relative reduction of Ki67 from baseline to week 2 was -75% (95% CI -80 to -70) with giredestrant and -67% (-73 to -59) with anastrozole (p=0·043), meeting the primary endpoint. At the final analysis (data cutoff Nov 24, 2021), the most common grade 3-4 adverse events were neutropenia (29 [26%] of 112 in the giredestrant plus palbociclib group vs 29 [27%] of 109 in the anastrozole plus palbociclib group) and decreased neutrophil count (17 [15%] vs 16 [15%]). Serious adverse events occurred in five (4%) patients in the giredestrant plus palbociclib group and in two (2%) patients in the anastrozole plus palbociclib group. There were no treatment-related deaths. One patient died due to an adverse event in the giredestrant plus palbociclib group (myocardial infarction).
INTERPRETATION: Giredestrant offers encouraging anti-proliferative and anti-tumour activity and was well tolerated, both as a single agent and in combination with palbociclib. Results justify further investigation in ongoing trials.
FUNDING: F Hoffmann-La Roche.}, }
@article {pmid37656930, year = {2023}, author = {Sanft, T and Harrigan, M and McGowan, C and Cartmel, B and Zupa, M and Li, FY and Ferrucci, LM and Puklin, L and Cao, A and Nguyen, TH and Neuhouser, ML and Hershman, DL and Basen-Engquist, K and Jones, BA and Knobf, T and Chagpar, AB and Silber, A and Tanasijevic, A and Ligibel, JA and Irwin, ML}, title = {Randomized Trial of Exercise and Nutrition on Chemotherapy Completion and Pathologic Complete Response in Women With Breast Cancer: The Lifestyle, Exercise, and Nutrition Early After Diagnosis Study.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {}, number = {}, pages = {JCO2300871}, doi = {10.1200/JCO.23.00871}, pmid = {37656930}, issn = {1527-7755}, abstract = {PURPOSE: Successful completion of chemotherapy is critical to improve breast cancer outcomes. Relative dose intensity (RDI), defined as the ratio of chemotherapy delivered to prescribed, is a measure of chemotherapy completion and is associated with cancer mortality. The effect of exercise and eating a healthy diet on RDI is unknown. We conducted a randomized trial of an exercise and nutrition intervention on RDI and pathologic complete response (pCR) in women diagnosed with breast cancer initiating chemotherapy.
METHODS: One hundred seventy-three women with stage I-III breast cancer were randomly assigned to usual care (UC; n = 86) or a home-based exercise and nutrition intervention with counseling sessions delivered by oncology-certified registered dietitians (n = 87). Chemotherapy dose adjustments and delays and pCR were abstracted from electronic medical records. T-tests and chi-square tests were used to examine the effect of the intervention versus UC on RDI and pCR.
RESULTS: Participants randomly assigned to intervention had greater improvements in exercise and diet quality compared with UC (P < .05). RDI was 92.9% ± 12.1% and 93.6% ± 11.1% for intervention and UC, respectively (P = .69); the proportion of patients in the intervention versus UC who achieved ≥85% RDI was 81% and 85%, respectively (P = .44). The proportion of patients who had at least one dose reduction and/or delay was 38% intervention and 36% UC (P = .80). Among 72 women who received neoadjuvant chemotherapy, women randomly assigned to intervention were more likely to have a pCR than those randomly assigned to UC (53% v 28%; P = .037).
CONCLUSION: Although a diet and exercise intervention did not affect RDI, the intervention was associated with a higher pCR in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative and triple-negative breast cancer undergoing neoadjuvant chemotherapy.}, }
@article {pmid37655310, year = {2023}, author = {Martinov, T and Greenberg, PD}, title = {Targeting Driver Oncogenes and Other Public Neoantigens Using T Cell Receptor-Based Cellular Therapy.}, journal = {Annual review of cancer biology}, volume = {7}, number = {1}, pages = {331-351}, pmid = {37655310}, issn = {2472-3428}, support = {P01 CA018029/CA/NCI NIH HHS/United States ; P01 CA225517/CA/NCI NIH HHS/United States ; R01 CA264090/CA/NCI NIH HHS/United States ; }, abstract = {T cell reactivity to tumor-specific neoantigens can drive endogenous and therapeutically induced antitumor immunity. However, most tumor-specific neoantigens are unique to each patient (private) and targeting them requires personalized therapy. A smaller subset of neoantigens includes epitopes that span recurrent mutation hotspots, translocations, or gene fusions in oncogenic drivers and tumor suppressors, as well as epitopes that arise from viral oncogenic proteins. Such antigens are likely to be shared across patients (public), uniformly expressed within a tumor, and required for cancer cell survival and fitness. Although a limited number of these public neoantigens are naturally immunogenic, recent studies affirm their clinical utility. In this review, we highlight efforts to target mutant KRAS, mutant p53, and epitopes derived from oncogenic viruses using T cells engineered with off-the-shelf T cell receptors. We also discuss the challenges and strategies to achieving more effective T cell therapies, particularly in the context of solid tumors.}, }
@article {pmid37654470, year = {2023}, author = {Williamson, BD and Magaret, CA and Karuna, S and Carpp, LN and Gelderblom, HC and Huang, Y and Benkeser, D and Gilbert, PB}, title = {Application of the SLAPNAP statistical learning tool to broadly neutralizing antibody HIV prevention research.}, journal = {iScience}, volume = {26}, number = {9}, pages = {107595}, pmid = {37654470}, issn = {2589-0042}, abstract = {Combination monoclonal broadly neutralizing antibody (bnAb) regimens are in clinical development for HIV prevention, necessitating additional knowledge of bnAb neutralization potency/breadth against circulating viruses. Williamson et al. (2021) described a software tool, Super LeArner Prediction of NAb Panels (SLAPNAP), with application to any HIV bnAb regimen with sufficient neutralization data against a set of viruses in the Los Alamos National Laboratory's Compile, Neutralize, and Tally Nab Panels repository. SLAPNAP produces a proteomic antibody resistance (PAR) score for Env sequences based on predicted neutralization resistance and estimates variable importance of Env amino acid features. We apply SLAPNAP to compare HIV bnAb regimens undergoing clinical testing, finding improved power for downstream sieve analyses and increased precision for comparing neutralization potency/breadth of bnAb regimens due to the inclusion of PAR scores of Env sequences with much larger sample sizes available than for neutralization outcomes. SLAPNAP substantially improves bnAb regimen characterization, ranking, and down-selection.}, }
@article {pmid37650342, year = {2023}, author = {Puac-Polanco, V and Ziobrowski, HN and Ross, EL and Liu, H and Turner, B and Cui, R and Leung, LB and Bossarte, RM and Bryant, C and Joormann, J and Nierenberg, AA and Oslin, DW and Pigeon, WR and Post, EP and Zainal, NH and Zaslavsky, AM and Zubizarreta, JR and Luedtke, A and Kennedy, CJ and Cipriani, A and Furukawa, TA and Kessler, RC}, title = {Development of a model to predict antidepressant treatment response for depression among Veterans.}, journal = {Psychological medicine}, volume = {53}, number = {11}, pages = {5001-5011}, doi = {10.1017/S0033291722001982}, pmid = {37650342}, issn = {1469-8978}, mesh = {Humans ; *Veterans ; *Depressive Disorder, Major/drug therapy ; Depression ; Antidepressive Agents/therapeutic use ; Machine Learning ; }, abstract = {BACKGROUND: Only a limited number of patients with major depressive disorder (MDD) respond to a first course of antidepressant medication (ADM). We investigated the feasibility of creating a baseline model to determine which of these would be among patients beginning ADM treatment in the US Veterans Health Administration (VHA).
METHODS: A 2018-2020 national sample of n = 660 VHA patients receiving ADM treatment for MDD completed an extensive baseline self-report assessment near the beginning of treatment and a 3-month self-report follow-up assessment. Using baseline self-report data along with administrative and geospatial data, an ensemble machine learning method was used to develop a model for 3-month treatment response defined by the Quick Inventory of Depression Symptomatology Self-Report and a modified Sheehan Disability Scale. The model was developed in a 70% training sample and tested in the remaining 30% test sample.
RESULTS: In total, 35.7% of patients responded to treatment. The prediction model had an area under the ROC curve (s.e.) of 0.66 (0.04) in the test sample. A strong gradient in probability (s.e.) of treatment response was found across three subsamples of the test sample using training sample thresholds for high [45.6% (5.5)], intermediate [34.5% (7.6)], and low [11.1% (4.9)] probabilities of response. Baseline symptom severity, comorbidity, treatment characteristics (expectations, history, and aspects of current treatment), and protective/resilience factors were the most important predictors.
CONCLUSIONS: Although these results are promising, parallel models to predict response to alternative treatments based on data collected before initiating treatment would be needed for such models to help guide treatment selection.}, }
@article {pmid37648373, year = {2023}, author = {Lee, MP and Dimos, SF and Raffield, LM and Wang, Z and Ballou, AF and Downie, CG and Arehart, CH and Correa, A and de Vries, PS and Du, Z and Gignoux, CR and Gordon-Larsen, P and Guo, X and Haessler, J and Howard, AG and Hu, Y and Kassahun, H and Kent, ST and Lopez, JAG and Monda, KL and North, KE and Peters, U and Preuss, MH and Rich, SS and Rhodes, SL and Yao, J and Yarosh, R and Tsai, MY and Rotter, JI and Kooperberg, CL and Loos, RJF and Ballantyne, C and Avery, CL and Graff, M}, title = {Ancestral diversity in lipoprotein(a) studies helps address evidence gaps.}, journal = {Open heart}, volume = {10}, number = {2}, pages = {}, pmid = {37648373}, issn = {2053-3624}, support = {HHSN268201100037C/HL/NHLBI NIH HHS/United States ; 75N92021D00005/WH/WHI NIH HHS/United States ; R01 HL059367/HL/NHLBI NIH HHS/United States ; U01 HL120393/HL/NHLBI NIH HHS/United States ; R01 HL086694/HL/NHLBI NIH HHS/United States ; HHSN268201800015I/HB/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 ; HHSN268201800012I/HB/NHLBI NIH HHS/United States ; HHSN268201800012C/HL/NHLBI NIH HHS/United States ; U01 HG007419/HG/NHGRI 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 ; UL1 RR025005/RR/NCRR NIH HHS/United States ; HHSN268201800004I/HL/NHLBI NIH HHS/United States ; N01HC95163/HL/NHLBI NIH HHS/United States ; UL1 TR001079/TR/NCATS NIH HHS/United States ; F32 HL149256/HL/NHLBI 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 ; U01 HG004402/HG/NHGRI NIH HHS/United States ; N01HC95164/HL/NHLBI NIH HHS/United States ; HHSN268201800014C/HL/NHLBI NIH HHS/United States ; N01HC95162/HL/NHLBI NIH HHS/United States ; R01 HL093029/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 ; R01 HG011345/HG/NHGRI NIH HHS/United States ; HHSN268201200008C/HL/NHLBI NIH HHS/United States ; U01 HG004729/HG/NHGRI NIH HHS/United States ; HHSN268201800003I/HL/NHLBI NIH HHS/United States ; P30 DK063491/DK/NIDDK NIH HHS/United States ; HHSN268201800007I/HL/NHLBI NIH HHS/United States ; HHSN268201700002C/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 ; R01 HL151152/HL/NHLBI NIH HHS/United States ; HHSN268201700004I/HL/NHLBI NIH HHS/United States ; N01HC95165/HL/NHLBI NIH HHS/United States ; N01HC95159/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 ; HHSN268201500003I/HL/NHLBI NIH HHS/United States ; KL2 TR002490/TR/NCATS NIH HHS/United States ; HHSN268201700005C/HL/NHLBI NIH HHS/United States ; HHSN268201700001C/HL/NHLBI NIH HHS/United States ; N01HC95167/HL/NHLBI NIH HHS/United States ; HHSN268201700003C/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 ; HHSN268201700005I/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 ; R01 HL087641/HL/NHLBI NIH HHS/United States ; UL1 TR001881/TR/NCATS NIH HHS/United States ; HHSN268201800011I/HB/NHLBI NIH HHS/United States ; HHSN268201800005I/HL/NHLBI NIH HHS/United States ; T32 HL007055/HL/NHLBI NIH HHS/United States ; HHSN268201700003I/HL/NHLBI NIH HHS/United States ; R01 HG010297/HG/NHGRI NIH HHS/United States ; HHSN268201200008I/HL/NHLBI NIH HHS/United States ; HHSN268201800006I/HL/NHLBI NIH HHS/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; }, mesh = {Humans ; Lipoprotein(a)/genetics ; Evidence Gaps ; Risk Factors ; *Coronary Artery Disease/diagnosis/epidemiology/genetics ; *Myocardial Ischemia ; }, abstract = {INTRODUCTION: The independent and causal cardiovascular disease risk factor lipoprotein(a) (Lp(a)) is elevated in >1.5 billion individuals worldwide, but studies have prioritised European populations.
METHODS: Here, we examined how ancestrally diverse studies could clarify Lp(a)'s genetic architecture, inform efforts examining application of Lp(a) polygenic risk scores (PRS), enable causal inference and identify unexpected Lp(a) phenotypic effects using data from African (n=25 208), East Asian (n=2895), European (n=362 558), South Asian (n=8192) and Hispanic/Latino (n=8946) populations.
RESULTS: Fourteen genome-wide significant loci with numerous population specific signals of large effect were identified that enabled construction of Lp(a) PRS of moderate (R[2]=15% in East Asians) to high (R[2]=50% in Europeans) accuracy. For all populations, PRS showed promise as a 'rule out' for elevated Lp(a) because certainty of assignment to the low-risk threshold was high (88.0%-99.9%) across PRS thresholds (80th-99th percentile). Causal effects of increased Lp(a) with increased glycated haemoglobin were estimated for Europeans (p value =1.4×10[-6]), although inverse effects in Africans and East Asians suggested the potential for heterogeneous causal effects. Finally, Hispanic/Latinos were the only population in which known associations with coronary atherosclerosis and ischaemic heart disease were identified in external testing of Lp(a) PRS phenotypic effects.
CONCLUSIONS: Our results emphasise the merits of prioritising ancestral diversity when addressing Lp(a) evidence gaps.}, }
@article {pmid37648261, year = {2023}, author = {Shah, BD and Cassaday, RD and Park, JH and Houot, R and Oluwole, OO and Logan, AC and Boissel, N and Leguay, T and Bishop, MR and Topp, MS and Tzachanis, D and O'Dwyer, KM 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, PJ and Jeyakumar, D and Mao, D and Adhikary, S and Zhou, L and Schuberth, PC and Damico Khalid, R and Ghobadia, A}, title = {Impact of prior therapies and subsequent transplantation on outcomes in adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia treated with brexucabtagene autoleucel in ZUMA-3.}, journal = {Journal for immunotherapy of cancer}, volume = {11}, number = {8}, pages = {}, pmid = {37648261}, issn = {2051-1426}, mesh = {Humans ; Adult ; Immunotherapy, Adoptive ; *Hematopoietic Stem Cell Transplantation ; Adaptor Proteins, Signal Transducing ; Antigens, CD19 ; Cytokine Release Syndrome ; *Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy ; }, abstract = {BACKGROUND: Brexucabtagene autoleucel (brexu-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved in the USA for adults with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) and in the European Union for patients ≥26 years with R/R B-ALL. After 2 years of follow-up in ZUMA-3, the overall complete remission (CR) rate (CR+CR with incomplete hematological recovery (CRi)) was 73%, and the median overall survival (OS) was 25.4 months in 78 Phase 1 and 2 patients with R/R B-ALL who received the pivotal dose of brexu-cel. Outcomes by prior therapies and subsequent allogeneic stem cell transplantation (alloSCT) are reported.
METHODS: Eligible adults had R/R B-ALL and received one infusion of brexu-cel (1×10⁶ CAR T cells/kg) following conditioning chemotherapy. The primary endpoint was the CR/CRi rate per central review. Post hoc subgroup analyses were exploratory with descriptive statistics provided.
RESULTS: Phase 1 and 2 patients (N=78) were included with median follow-up of 29.7 months (range, 20.7-58.3). High CR/CRi rates were observed across all prior therapy subgroups examined: 1 prior line of therapy (87%, n=15) and ≥2 prior lines (70%, n=63); prior blinatumomab (63%, n=38) and no prior blinatumomab (83%, n=40); prior inotuzumab (59%, n=17) and no prior inotuzumab (77%, n=61); and prior alloSCT (76%, n=29) and no prior alloSCT (71%, n=49). The frequency of Grade ≥3 cytokine release syndrome, neurological events, and treatment-related Grade 5 adverse events were largely similar among prior therapy subgroups.Median duration of remission (DOR) in responders with (n=14) and without (n=43) subsequent alloSCT was 44.2 (95% CI, 8.1 to not estimable (NE)) and 18.6 months (95% CI, 9.4 to NE); median OS was 47.0 months (95% CI, 10.2 to NE) and not reached (95% CI, 23.2 to NE), respectively. Median DOR and OS were not reached in responders without prior or subsequent alloSCT (n=22).
CONCLUSIONS: In ZUMA-3, adults with R/R B-ALL benefited from brexu-cel, regardless of prior therapies and subsequent alloSCT status, though survival appeared better in patients without certain prior therapies and in earlier lines of therapy. Additional studies are needed to determine the impact prior therapies and subsequent alloSCT have on outcomes of patients who receive brexu-cel.}, }
@article {pmid37647637, year = {2023}, author = {Brothers, AW and Pak, DJ and Poole, NM and Kronman, MP and Bettinger, B and Wilkes, JJ and Carpenter, PA and Englund, JA and Weissman, SJ}, title = {Individualized antibiotic plans as a quality improvement initiative to reduce carbapenem use for hematopoietic cell transplant patients at a freestanding pediatric hospital.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {}, number = {}, pages = {}, doi = {10.1093/cid/ciad518}, pmid = {37647637}, issn = {1537-6591}, abstract = {BACKGROUND: Providers must balance effective empiric therapy against toxicity risks and collateral damage when selecting antibiotic therapy for patients receiving hematopoietic cell transplant (HCT). Antimicrobial stewardship (AMS) interventions during HCT are often challenging due to concern for undertreating potential infections.
METHODS: In an effort to decrease unnecessary carbapenem exposure for patients undergoing HCT at our pediatric center, we implemented individualized antibiotic plans (IAPs) to provide recommendations for pre-engraftment neutropenia prophylaxis, empiric treatment of febrile neutropenia, and empiric treatment for hemodynamic instability. We compared monthly antibiotic days of therapy adjusted per 1000 patient days (DOT/1000 pt-days) for carbapenems, anti-pseudomonal cephalosporins, and all antibiotics during two 3-year periods immediately before and after the implementation of IAPs to measure the impact of IAP on prescribing behavior. Bloodstream infections (BSI) and Clostridioides difficile (CD) positive test rates were also compared between cohorts. Lastly, providers were surveyed to assess their experience of using IAPs in antibiotic decision-making.
RESULTS: Overall antibiotic use decreased after the implementation of IAP (monthly reduction of 19.6 DOT/1000 pt-days, p=0.004) with carbapenems showing a continuing decline after IAP implementation. BSI and CD positivity rates were unchanged. Over 90% of providers found IAPs to be either extremely or very valuable for their practice.
CONCLUSIONS: Implementation of IAPs in this high-risk HCT population led to reduction in overall antibiotic use without increase in rate of BSI or CD test positivity. The program was well-received by providers.}, }
@article {pmid37646879, year = {2023}, author = {Nash, S and Weeks, K and Kahl, AR and Del Vecchio, NJ and Gao, X and Guyton, K and Charlton, M}, title = {Diagnosing Provider, Referral Patterns, Facility Type, and Patient Satisfaction Among Iowa Rectal Cancer Patients.}, journal = {Journal of gastrointestinal cancer}, volume = {}, number = {}, pages = {}, pmid = {37646879}, issn = {1941-6636}, support = {HHSN261201800012I/ HHSN26100001/CA/NCI NIH HHS/United States ; HHSN261201800012I/ HHSN26100001/CA/NCI NIH HHS/United States ; HHSN261201800012I/ HHSN26100001/CA/NCI NIH HHS/United States ; T32 CA 148062/NH/NIH HHS/United States ; }, abstract = {PURPOSE: Rectal cancer treatment at high-volume centers is associated with higher likelihood of guideline-concordant care and improved outcomes. Whether rectal cancer patients are referred for treatment at high-volume hospitals may depend on diagnosing provider specialty. We aimed to determine associations of diagnosing provider specialty with treating provider specialty and characteristics of the treating facility for rectal cancer patients in Iowa.
METHODS: Rectal cancer patients identified using the Iowa Cancer Registry completed a mailed survey on their treatment experience and decision-making process. Provider type was defined by provider specialty and whether the provider referred patients elsewhere for surgery. Multivariable-adjusted logistic regression models were used to examine predictors of being diagnosed by a general surgeon who also performed the subsequent surgery.
RESULTS: Of 417 patients contacted, 381 (76%) completed the survey; our final analytical sample size was 267. Half of respondents were diagnosed by a gastroenterologist who referred them elsewhere; 30% were diagnosed by a general surgeon who referred them elsewhere, and 20% were diagnosed by a general surgeon who performed the surgery. Respondents who were ≥ 65 years old, had less than a college education, and who made < $50,000 per year were more likely to be diagnosed by a general surgeon who performed surgery. In multivariable-adjusted models, respondents diagnosed and treated by the same general surgeon were more likely to have surgery at hospitals with low annual colorectal cancer surgery volume and less likely to be satisfied with their care.
CONCLUSIONS: Among rectal cancer patients in Iowa, respondents who were diagnosed and treated by the same provider were less likely to get treatment at a high-volume facility. This study informs the importance of provider referral in centralization of rectal cancer care.}, }
@article {pmid36993223, year = {2023}, author = {Twentyman, J and Khalifeh, A and Felton, AL and Emerman, M and OhAinle, M}, title = {Primate TRIM34 is a broadly-acting, TRIM5-dependent lentiviral restriction factor.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {36993223}, support = {DP1 DA051110/DA/NIDA NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; R01 AI147877/AI/NIAID NIH HHS/United States ; U54 AI170856/AI/NIAID NIH HHS/United States ; T32 AI083203/AI/NIAID NIH HHS/United States ; }, abstract = {Human immunodeficiency virus (HIV) and other lentiviruses adapt to new hosts by evolving to evade host-specific innate immune proteins that differ in sequence and often viral recognition between host species. Understanding how these host antiviral proteins, called restriction factors, constrain lentivirus replication and transmission is key to understanding the emergence of pandemic viruses like HIV-1. Human TRIM34, a paralogue of the well-characterized lentiviral restriction factor TRIM5α, was previously identified by our lab via CRISPR-Cas9 screening as a restriction factor of certain HIV and SIV capsids. Here, we show that diverse primate TRIM34 orthologues from non-human primates can restrict a range of Simian Immunodeficiency Virus (SIV) capsids including SIV AGM-SAB , SIV AGM-TAN and SIV MAC capsids, which infect sabaeus monkeys, tantalus monkeys, and rhesus macaques, respectively. All primate TRIM34 orthologues tested, regardless of species of origin, were able to restrict this same subset of viral capsids. However, in all cases, this restriction also required the presence of TRIM5α. We demonstrate that TRIM5α is necessary, but not sufficient, for restriction of these capsids, and that human TRIM5α functionally interacts with TRIM34 from different species. Finally, we find that both the TRIM5α SPRY v1 loop and the TRIM34 SPRY domain are essential for TRIM34-mediated restriction. These data support a model in which TRIM34 is a broadly-conserved primate lentiviral restriction factor that acts in tandem with TRIM5α, such that together, these proteins can restrict capsids that neither can restrict alone.}, }
@article {pmid37646212, year = {2023}, author = {Zhao, SX and Tindle, HA and Larson, JC and Woods, NF and Crawford, MH and Hoover, V and Salmoirago-Blotcher, E and Shadyab, AH and Stefanick, ML and Perez, MV}, title = {Association Between Insomnia, Stress Events, and Other Psychosocial Factors and Incident Atrial Fibrillation in Postmenopausal Women: Insights From the Women's Health Initiative.}, journal = {Journal of the American Heart Association}, volume = {}, number = {}, pages = {e030030}, doi = {10.1161/JAHA.123.030030}, pmid = {37646212}, issn = {2047-9980}, abstract = {Background The association between psychosocial factors and atrial fibrillation (AF) is poorly understood. Methods and Results Postmenopausal women from the Women's Health Initiative were retrospectively analyzed to identify incident AF in relation to a panel of validated psychosocial exposure variables, as assessed by multivariable Cox proportional hazard regression and hierarchical cluster analysis. Among the 83 736 women included, the average age was 63.9±7.0 years. Over an average of 10.5±6.2 years follow-up, there were 23 954 cases of incident AF. Hierarchical cluster analysis generated 2 clusters of highly correlated psychosocial variables: the Stress Cluster included stressful life events, depressive symptoms, and insomnia, and the Strain Cluster included optimism, social support, social strain, cynical hostility, and emotional expressiveness. Incident AF was associated with higher values in the Stress Cluster (hazard ratio [HR], 1.07 per unit cluster score [95% CI, 1.05-1.09]) and the Strain Cluster (HR, 1.03 per unit cluster score [95% CI, 1.00-1.05]). Of the 8 individual psychosocial predictors that were tested, insomnia (HR, 1.04 [95% CI, 1.03-1.06]) and stressful life events (HR, 1.02 [95% CI, 1.01-1.04]) were most strongly associated with increased incidence of AF in Cox regression analysis after multivariate adjustment. Subgroup analyses showed that the Strain Cluster was more strongly associated with incident AF in those with lower traditional AF risks (P for interaction=0.02) as determined by the cohorts for heart and aging research in genomic epidemiology for atrial fibrillation score. Conclusions Among postmenopausal women, 2 clusters of psychosocial stressors were found to be significantly associated with incident AF. Further research is needed to validate these associations.}, }
@article {pmid37644850, year = {2023}, author = {Guo, B and Knerr, S and Kauffman, TL and Mittendorf, KF and Keast, E and Gilmore, MJ and Feigelson, HS and Lynch, FL and Muessig, KR and Okuyama, S and Zepp, JM and Veenstra, DL and Hsu, L and Phipps, AI and Lindström, S and Leo, MC and Goddard, KAB and Wilfond, BS and Devine, B and , }, title = {Risk management actions following genetic testing in the Cancer Health Assessments Reaching Many (CHARM) Study: A prospective cohort study.}, journal = {Cancer medicine}, volume = {}, number = {}, pages = {}, doi = {10.1002/cam4.6485}, pmid = {37644850}, issn = {2045-7634}, support = {U01HG007292/HG/NHGRI NIH HHS/United States ; U24HG007307/HG/NHGRI NIH HHS/United States ; }, abstract = {BACKGROUND: Genetic testing can identify cancer risk early, enabling prevention and early detection. We describe use of risk management interventions following genetic testing in the Cancer Health Assessment Reaching Many (CHARM) study. CHARM assessed risk and provided genetic testing to low income, low literacy, and other underserved populations that historically face barriers to accessing cancer genetic services.
METHODS: CHARM was implemented in Kaiser Permanente Northwest (KPNW) and Denver Health (DH) between 2018 and 2020. We identified post-testing screening (mammography, breast MRI, colonoscopy) and surgical (mastectomy, oophorectomy) procedures using electronic health records. We examined utilization in participants who did and did not receive actionable risk management recommendations from study genetic counselors following national guidelines.
RESULTS: CHARM participants were followed for an average of 15.4 months (range: 0.4-27.8 months) after results disclosure. Less than 2% (11/680) received actionable risk management recommendations (i.e., could be completed in the initial years following testing) based on their test result. Among those who received actionable recommendations, risk management utilization was moderate (54.5%, 6/11 completed any procedure) and varied by procedure (mammogram: 0/3; MRI: 2/4; colonoscopy: 4/5; mastectomy: 1/5; oophorectomy: 0/3). Cancer screening and surgery procedures were rare in participants without actionable recommendations.
CONCLUSION: Though the number of participants who received actionable risk management recommendations was small, our results suggest that implementing CHARM's risk assessment and testing model increased access to evidence-based genetic services and provided opportunities for patients to engage in recommended preventive care, without encouraging risk management overuse.}, }
@article {pmid37644495, year = {2023}, author = {Easterling, DV and Jacob, RR and Brownson, RC and Haire-Joshu, D and Gundersen, DA and Angier, H and DeVoe, JE and Likumahuwa-Ackman, S and Vu, T and Glasgow, RE and Schnoll, R}, title = {Participatory logic modeling in a multi-site initiative to advance implementation science.}, journal = {Implementation science communications}, volume = {4}, number = {1}, pages = {106}, pmid = {37644495}, issn = {2662-2211}, support = {P50 CA244690/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Logic models map the short-term and long-term outcomes that are expected to occur with a program, and thus are an essential tool for evaluation. Funding agencies, especially in the United States (US), have encouraged the use of logic models among their grantees. They also use logic models to clarify expectations for their own funding initiatives. It is increasingly recognized that logic models should be developed through a participatory approach which allows input from those who carry out the program being evaluated. While there are many positive examples of participatory logic modeling, funders have generally not engaged grantees in developing the logic model associated with their own initiatives. This article describes an instance where a US funder of a multi-site initiative fully engaged the funded organizations in developing the initiative logic model. The focus of the case study is Implementation Science Centers in Cancer Control (ISC[3]), a multi-year initiative funded by the National Cancer Institute.
METHODS: The reflective case study was collectively constructed by representatives of the seven centers funded under ISC[3]. Members of the Cross-Center Evaluation (CCE) Work Group jointly articulated the process through which the logic model was developed and refined. Individual Work Group members contributed descriptions of how their respective centers reviewed and used the logic model. Cross-cutting themes and lessons emerged through CCE Work Group meetings and the writing process.
RESULTS: The initial logic model for ISC[3] changed in significant ways as a result of the input of the funded groups. Authentic participation in the development of the logic model led to strong buy-in among the centers, as evidenced by their utilization. The centers shifted both their evaluation design and their programmatic strategy to better accommodate the expectations reflected in the initiative logic model.
CONCLUSIONS: The ISC[3] case study demonstrates how participatory logic modeling can be mutually beneficial to funders, grantees and evaluators of multi-site initiatives. Funded groups have important insights about what is feasible and what will be required to achieve the initiative's stated objectives. They can also help identify the contextual factors that either inhibit or facilitate success, which can then be incorporated into both the logic model and the evaluation design. In addition, when grantees co-develop the logic model, they have a better understanding and appreciation of the funder's expectations and thus are better positioned to meet those expectations.}, }
@article {pmid37643897, year = {2023}, author = {Peters, BA and Hanna, DB and Wang, Y and Weber, KM and Topper, E and Appleton, AA and Sharma, A and Hodis, HN and Santoro, N and Guillemette, C and Caron, P and Knight, R and Burk, RD and Kaplan, RC and Qi, Q}, title = {Sex hormones, the stool microbiome, and subclinical atherosclerosis in women with and without HIV.}, journal = {The Journal of clinical endocrinology and metabolism}, volume = {}, number = {}, pages = {}, doi = {10.1210/clinem/dgad510}, pmid = {37643897}, issn = {1945-7197}, abstract = {BACKGROUND: The cardio-protective roles of endogenous estrogens may be particularly important in women with HIV, who have reduced estrogen exposure and elevated cardiovascular disease risk. The gut microbiome metabolically interacts with sex hormones, but little is known regarding how such interplay may impact cardiovascular risk.
METHODS: Among 197 post-menopausal women in the Women's Interagency HIV Study, we measured 15 sex hormones in serum and assessed the gut microbiome in stool. B-mode ultrasound was used to determine presence of carotid artery plaque in a subset (n = 134). We examined associations of (1) sex hormones and stool microbiome, (2) sex hormones and plaque, and (3) sex hormone-related stool microbiota and plaque, adjusting for potential confounders.
RESULTS: Participant median age was 58 years and the majority were living with HIV (81%). Sex hormones (estrogens, androgens, and adrenal precursors) were associated with stool microbiome diversity and specific species, similarly in women with and without HIV. For example, estrogens were associated with higher diversity, higher abundance of species from Alistipes, Collinsella, Erysipelotrichia, and Clostridia, and higher abundance of microbial β-glucuronidase and aryl-sulfatase orthologs, which are involved in hormone metabolism. Several hormones were associated with lower odds of carotid artery plaque, including dihydrotestosterone, 3α-diol-17G, estradiol, and estrone. Exploratory mediation analysis suggested that estrone-related species, particularly from Collinsella, may mediate the protective association of estrone with plaque.
CONCLUSION: Serum sex hormones are significant predictors of stool microbiome diversity and composition, likely due in part to metabolic interactions. The gut microbiome may play a role in estrogen-related cardiovascular protection.}, }
@article {pmid37643386, year = {2023}, author = {Unger, JM and Stires, H and Levit, LA and Stewart, M and McKelvey, BA and Canin, B and Dressler, E and Flaherty, K and Fredette, P and Jones, L and McCann, P and Miller, T and Onitilo, AA and Palmieri, F and Patel, T and Paul, R and Smith, GL and Bruinooge, SS and Garrett-Mayer, E and Lei, XJ and Alva, A and Schenkel, C}, title = {Sponsor Perspectives on the Impact of the COVID-19 Pandemic on Interventional Cancer Clinical Trial Protocols and Data Quality.}, journal = {JCO oncology practice}, volume = {}, number = {}, pages = {OP2300185}, doi = {10.1200/OP.23.00185}, pmid = {37643386}, issn = {2688-1535}, abstract = {PURPOSE: The onset of the COVID-19 pandemic created major disruptions in the conduct of cancer clinical trials. In response, regulators and sponsors allowed modifications to traditional trial processes to enable clinical research and care to continue. We systematically evaluated how these mitigation strategies affected data quality and overall trial conduct.
METHODS: This study used surveys and live interviews. Forty-one major industry and National Cancer Institute Network groups (sponsors) overseeing anticancer treatment trials open in the United States from January 2015 to May 2022 were invited to participate. Descriptive statistics were used for survey data summaries. Key themes from interviews were identified.
RESULTS: Twenty sponsors (48.8%; 15 industry and five Network groups) completed the survey; 11/20 (55.0%) participated in interviews. Sponsors predominantly (n = 12; 60.0%) reported large (≥11 trials) portfolios of phase II and/or phase III trials. The proportion of sponsors reporting a moderate (9) or substantial (8) increase in protocol deviations in the initial pandemic wave versus the pre-pandemic period was 89.5% (17/19); the proportion reporting a substantial increased dropped from 42.1% (n = 8/19) in the initial wave to 15.8% (n = 3/19) thereafter. The most commonly adopted mitigation strategies were remote distribution of oral anticancer therapies (70.0%), remote adverse event monitoring (65.0%), and remote consenting (65.0%). Most respondents (15/18; 83.3%) reported that the pandemic had minimal (n = 14) or no impact (n = 1) on overall data integrity.
CONCLUSION: Despite nearly all sponsors observing a temporary increase in protocol deviations, most reported the pandemic had minimal/no impact on overall data integrity. The COVID-19 pandemic accelerated an emerging trend toward greater flexibility in trial conduct, with potential benefits of reduced burden on trial participants and sites and improved patient access to research.}, }
@article {pmid37643290, year = {2023}, author = {Skalland, T and Ayles, H and Bock, P and Bwalya, J and Shanaube, K and Kasese, N and Dupré, M and Kosloff, B and Floyd, S and Wilson, E and Moore, A and Eshleman, S and Fidler, S and Hayes, R and Donnell, D and , }, title = {Community- and individual-level correlates of HIV incidence in HPTN 071 (PopART).}, journal = {Journal of the International AIDS Society}, volume = {26}, number = {8}, pages = {e26155}, pmid = {37643290}, issn = {1758-2652}, mesh = {Adult ; Humans ; Male ; *Circumcision, Male ; *Epidemics ; *HIV Infections/epidemiology/prevention & control ; Incidence ; Sexual Behavior ; }, abstract = {INTRODUCTION: Universal HIV testing and treatment aims to identify all people living with HIV and offer them treatment, decreasing the number of individuals with unsuppressed HIV and thus reducing HIV transmission. Longitudinal follow-up of individuals with and without HIV in a cluster-randomized trial of communities allowed for the examination of community- and individual-level measures of HIV risk and HIV incidence.
METHODS: HPTN 071 (PopART) was a three-arm cluster-randomized trial conducted between 2013 and 2018 that evaluated the use of two combination HIV prevention strategies implemented at the community level to reduce HIV incidence compared to the standard of care. The trial, conducted in 21 communities in Zambia and South Africa, measured HIV incidence over 36 months in a population cohort of ∼2000 randomly selected adults per community aged 18-44. Multilevel models were used to assess the association between HIV incidence and community- and individual-level socio-demographic and behavioural risk factors, as well as prevalence of detectable virus (PDV) defined as the estimated proportion of the community with unsuppressed viral load.
RESULTS: Overall HIV incidence was 1.49/100 person-years. Communities with less financial wealth and communities with more individuals reporting having sex partners outside of the community or two or more sexual partners had higher HIV incidence. PDV at 2 years of study was 6.8% and was strongly associated with HIV incidence: for every 50% relative reduction in community PDV, there was a 49% (95% confidence interval [CI]: 37%-58%, p < 0.001) relative decrease in HIV incidence. At the individual level; socio-economic status, AUDIT score, medical male circumcision and certain sexual behaviours were associated with HIV risk.
CONCLUSIONS: Using data from the PopART randomized trial, we found several associations of HIV incidence with community-level measures reflecting the sexual behaviour and socio-economic make-up of each community. We also found a strong association between community PDV and HIV incidence supporting the use of PDV as a tool for monitoring progress in controlling the epidemic. Lastly, we found significant individual-level factors of HIV risk that are generally consistent with previous HIV epidemiological research. These results have the potential to identify high high-incidence communities, inform structural-level interventions, and optimize individual-level interventions for HIV prevention.
CLINICAL TRIAL NUMBER: ClinicalTrials.gov number, NCT01900977, HPTN 071 [PopArt].}, }
@article {pmid37643248, year = {2023}, author = {Ruiz, RA and Lehavot, K and Heffner, JL and Kava, CM and Ornelas, IJ}, title = {Cigarette Smoking Motives and Stages of Change in Smoking Cessation Among Veterans: Differences by Gender and Sexual Orientation.}, journal = {American journal of health promotion : AJHP}, volume = {}, number = {}, pages = {8901171231197147}, doi = {10.1177/08901171231197147}, pmid = {37643248}, issn = {2168-6602}, abstract = {PURPOSE: To examine differences across gender and sexual orientation in cigarette smoking motives and stages of change in smoking cessation among Veterans.
DESIGN: Secondary data analysis of cross-sectional baseline surveys from a prospective cohort study.
SETTING: United States, self-administered online survey.
PARTICIPANTS: Cisgender Veterans who reported past-year smoking (N = 146); 66.4% identified as lesbian, gay, or bisexual and 52.1% were men.
MEASURES: Smoking motives (i.e., social, self-confidence, boredom relief, and affect regulation), with higher scores indicating stronger motivation to smoke. Stages of change categories included precontemplation, contemplation/preparation, and action/maintenance.
ANALYSIS: Analyses were stratified by gender and sexual orientation. Age-adjusted linear regression models estimated differences in smoking motives scores and multinomial logistic regression models estimated differences in stages of change categories relative to the precontemplation stage (reference category).
RESULTS: In this Veteran sample, gay men reported higher social smoking motives vs heterosexual men (β = 1.50 (95% CI: .04, 2.97), P-value = .045) and higher boredom relief smoking motives vs bisexual men (β = 1.53 (95% CI: .06, 2.29), P-value = .041) in age-adjusted models. Lesbian women were more likely to be in the action/maintenance stage relative to the precontemplation stage when compared to both heterosexual women (aRRR = 4.88 (95% CI: 1.00, 23.79) P-value = .050) and bisexual women (aRRR = 16.46 (95% CI: 2.12, 127.57), P-value = .007) after adjusting for age.
CONCLUSION: Smoking cessation interventions may benefit from enhancing peer support for gay men. Given bisexual and heterosexual women were in less advance stages of change, there may be a greater need for motivational interventions to encourage quitting and additional support to assist with cessation efforts. Overall, findings highlight the diversity of cigarette use within LGB communities.}, }
@article {pmid37640860, year = {2023}, author = {Branche, AR and Rouphael, NG and Diemert, DJ and Falsey, AR and Losada, C and Baden, LR and Frey, SE and Whitaker, JA and Little, SJ and Anderson, EJ and Walter, EB and Novak, RM and Rupp, R and Jackson, LA 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 Malkin, E and Bethony, JM and Walsh, EE and Graciaa, DS and Samaha, H and Sherman, AC and Walsh, SR and Abate, G and Oikonomopoulou, Z and El Sahly, HM and Martin, TCS and Kamidani, S and Smith, MJ and Ladner, BG and Porterfield, L and Dunstan, M and Wald, A and Davis, T and Atmar, RL and Mulligan, MJ and Lyke, KE and Posavad, CM and Meagher, MA and Stephens, DS and Neuzil, KM and Abebe, K and Hill, H and Albert, J and Telu, K and Mu, J and Lewis, TC and Giebeig, LA and Eaton, A and Netzl, A and Wilks, SH and Türeli, S and Makhene, M and Crandon, S and Montefiori, DC and Makowski, M and Smith, DJ and Nayak, SU and Roberts, PC and Beigel, JH and , }, title = {Comparison of bivalent and monovalent SARS-CoV-2 variant vaccines: the phase 2 randomized open-label COVAIL trial.}, journal = {Nature medicine}, volume = {}, number = {}, pages = {}, pmid = {37640860}, issn = {1546-170X}, support = {Contract No. 75N91019D00024 Task Order No. 75N91022F00007//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; Contract No. 75N91019D00024 Task Order No. 75N91022F00007//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; Contract No. 75N91019D00024 Task Order No. 75N91022F00007//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; Contract No. 75N91019D00024 Task Order No. 75N91022F00007//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; Contract No. 75N91019D00024 Task Order No. 75N91022F00007//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; Contract No. 75N91019D00024 Task Order No. 75N91022F00007//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; Contract No. 75N91019D00024 Task Order No. 75N91022F00007//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; Contract No. 75N91019D00024 Task Order No. 75N91022F00007//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; Contract No. 75N91019D00024 Task Order No. 75N91022F00007//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; Contract No. 75N91019D00024 Task Order No. 75N91022F00007//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; Contract No. 75N91019D00024 Task Order No. 75N91022F00007//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; Contract No. 75N91019D00024 Task Order No. 75N91022F00007//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; Contract No. 75N91019D00024 Task Order No. 75N91022F00007//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; Contract No. 75N91019D00024 Task Order No. 75N91022F00007//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; Contract No. 75N91019D00024 Task Order No. 75N91022F00007//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; Contract No. 75N91019D00024 Task Order No. 75N91022F00007//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; Contract No. 75N91019D00024 Task Order No. 75N91022F00007//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; Contract No. 75N91019D00024 Task Order No. 75N91022F00007//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; Contract No. 75N91019D00024 Task Order No. 75N91022F00007//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; Contract No. 75N91019D00024 Task Order No. 75N91022F00007//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; Contract No. 75N91019D00024 Task Order No. 75N91022F00007//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; Contract No. 75N91019D00024 Task Order No. 75N91022F00007//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; Contract No. 75N91019D00024 Task Order No. 75N91022F00007//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; Contract No. 75N91019D00024 Task Order No. 75N91022F00007//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; Contract No. 75N91019D00024 Task Order No. 75N91022F00007//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; Contract No. 75N91019D00024 Task Order No. 75N91022F00007//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; Contract No. 75N91019D00024 Task Order No. 75N91022F00007//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; Contract No. 75N91019D00024 Task Order No. 75N91022F00007//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; Contract No. 75N91019D00024 Task Order No. 75N91022F00007//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; Contract No. 75N91019D00024 Task Order No. 75N91022F00007//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; Contract No. 75N91019D00024 Task Order No. 75N91022F00007//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; Contract No. 75N91019D00024 Task Order No. 75N91022F00007//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; Contract No. 75N91019D00024 Task Order No. 75N91022F00007//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; Contract No. 75N91019D00024 Task Order No. 75N91022F00007//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; Contract No. 75N91019D00024 Task Order No. 75N91022F00007//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; Contract No. 75N91019D00024 Task Order No. 75N91022F00007//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; Contract No. 75N91019D00024 Task Order No. 75N91022F00007//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; Contract No. 75N91019D00024 Task Order No. 75N91022F00007//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; Contract No. 75N91019D00024 Task Order No. 75N91022F00007//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; Contract No. 75N91019D00024 Task Order No. 75N91022F00007//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; Contract No. 75N91019D00024 Task Order No. 75N91022F00007//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; Contract No. 75N91019D00024 Task Order No. 75N91022F00007//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; Contract No. 75N91019D00024 Task Order No. 75N91022F00007//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; Contract No. 75N91019D00024 Task Order No. 75N91022F00007//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; Contract No. 75N91019D00024 Task Order No. 75N91022F00007//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; Contract No. 75N91019D00024 Task Order No. 75N91022F00007//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; Contract No. 75N91019D00024 Task Order No. 75N91022F00007//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; Contract No. 75N91019D00024 Task Order No. 75N91022F00007//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; Contract No. 75N91019D00024 Task Order No. 75N91022F00007//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; Contract No. 75N91019D00024 Task Order No. 75N91022F00007//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; Contract No. 75N91019D00024 Task Order No. 75N91022F00007//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; Contract No. 75N91019D00024 Task Order No. 75N91022F00007//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; Contract No. 75N91019D00024 Task Order No. 75N91022F00007//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; Contract No. 75N91019D00024 Task Order No. 75N91022F00007//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; Contract No. 75N91019D00024 Task Order No. 75N91022F00007//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; Contract No. 75N91019D00024 Task Order No. 75N91022F00007//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; Contract No. 75N91019D00024 Task Order No. 75N91022F00007//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; Contract No. 75N91019D00024 Task Order No. 75N91022F00007//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; Contract No. 75N91019D00024 Task Order No. 75N91022F00007//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; Contract No. 75N91019D00024 Task Order No. 75N91022F00007//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; Contract No. 75N91019D00024 Task Order No. 75N91022F00007//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; Contract No. 75N91019D00024 Task Order No. 75N91022F00007//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; Contract No. 75N91019D00024 Task Order No. 75N91022F00007//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; }, abstract = {Vaccine protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection wanes over time, requiring updated boosters. In a phase 2, open-label, randomized clinical trial with sequentially enrolled stages at 22 US sites, we assessed safety and immunogenicity of a second boost with monovalent or bivalent variant vaccines from mRNA and protein-based platforms targeting wild-type, Beta, Delta and Omicron BA.1 spike antigens. The primary outcome was pseudovirus neutralization titers at 50% inhibitory dilution (ID50 titers) with 95% confidence intervals against different SARS-CoV-2 strains. The secondary outcome assessed safety by solicited local and systemic adverse events (AEs), unsolicited AEs, serious AEs and AEs of special interest. Boosting with prototype/wild-type vaccines produced numerically lower ID50 titers than any variant-containing vaccine against all variants. Conversely, boosting with a variant vaccine excluding prototype was not associated with decreased neutralization against D614G. Omicron BA.1 or Beta monovalent vaccines were nearly equivalent to Omicron BA.1 + prototype or Beta + prototype bivalent vaccines for neutralization of Beta, Omicron BA.1 and Omicron BA.4/5, although they were lower for contemporaneous Omicron subvariants. Safety was similar across arms and stages and comparable to previous reports. Our study shows that updated vaccines targeting Beta or Omicron BA.1 provide broadly crossprotective neutralizing antibody responses against diverse SARS-CoV-2 variants without sacrificing immunity to the ancestral strain. ClinicalTrials.gov registration: NCT05289037 .}, }
@article {pmid37640106, year = {2023}, author = {Bouras, E and Kim, AE and Lin, Y and Morrison, J and Du, M and Albanes, D and Barry, EL and Baurley, JW and Berndt, SI and Bien, SA and Bishop, TD and Brenner, H and Budiarto, A and Burnett-Hartman, A and Campbell, PT and Carreras-Torres, R and Casey, G and Cenggoro, TW and Chan, AT and Chang-Claude, J and Conti, DV and Cotterchio, M and Devall, M and Diez-Obrero, V and Dimou, N and Drew, DA and Figueiredo, JC and Giles, GG and Gruber, SB and Gunter, MJ and Harrison, TA and Hidaka, A and Hoffmeister, M and Huyghe, JR and Joshi, AD and Kawaguchi, ES and Keku, TO and Kundaje, A and Le Marchand, L and Lewinger, JP and Li, L and Lynch, BM and Mahesworo, B and Männistö, S and Moreno, V and Murphy, N and Newcomb, PA and Obón-Santacana, M and Ose, J and Palmer, JR and Papadimitriou, N and Pardamean, B and Pellatt, AJ and Peoples, AR and Platz, EA and Potter, JD and Qi, L and Qu, C and Rennert, G and Ruiz-Narvaez, E and Sakoda, LC and Schmit, SL and Shcherbina, A and Stern, MC and Su, YR and Tangen, CM and Thomas, DC and Tian, Y and Um, CY and van Duijnhoven, FJ and Van Guelpen, B and Visvanathan, K and Wang, J and White, E and Wolk, A and Woods, MO and Ulrich, CM and Hsu, L and Gauderman, WJ and Peters, U and Tsilidis, KK}, title = {Genome-wide interaction analysis of folate for colorectal cancer risk.}, journal = {The American journal of clinical nutrition}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ajcnut.2023.08.010}, pmid = {37640106}, issn = {1938-3207}, abstract = {BACKGROUND: Epidemiological and experimental evidence suggests that higher folate intake is associated with a decreased colorectal cancer (CRC) risk; however, the mechanisms underlying this relationship are not fully understood. Genetic variation that may have a direct or indirect impact on folate metabolism can provide insights into folate's role in CRC.
OBJECTIVE: Our aim was to perform a genome-wide interaction analysis to identify genetic variants that may modify the association of folate on CRC risk.
METHODS: We applied traditional case-control logistic regression, joint 3-degree of freedom (3DF), and a two-step weighted hypothesis approach to test the interactions of common variants (allele frequency >1%) across the genome and dietary folate, folic acid supplement use, and total folate in relation to risk of CRC, in 30,550 cases and 42,336 controls from 51 studies from 3 genetic consortia (CCFR, CORECT, GECCO).
RESULTS: Inverse associations of dietary, total folate, and folic acid supplement with CRC were found [odds ratio: 0.93 (95% confidence intervals [CI]: 0.90-0.96), and 0.91 (0.89-0.94) per quartile higher intake, and 0.82 (0.78-0.88) for users vs. non-users, respectively]. Interactions (P-interaction <5×10[-8]) of folic acid supplement and variants in the 3p25.2 locus [in the region of Synapsin II (SYN2)/tissue inhibitor of metalloproteinase 4 (TIMP4)] were found using the traditional interaction analysis, with variant rs150924902 (located upstream to SYN2) showing the strongest interaction. In stratified analyses by rs150924902 genotypes, folate supplement was associated with decreased CRC risk among those carrying the TT genotype (OR = 0.82; 95%CI: 0.79-0.86) but increased CRC risk among those carrying the TA genotype (OR = 1.63; 95%CI: 1.29-2.05), suggesting a qualitative interaction (P-interaction = 1.4×10[-8]). No interactions were observed for dietary and total folate.
CONCLUSIONS: Variation in 3p25.2 locus may modify the association of folate supplement with CRC risk. Experimental studies and studies incorporating other relevant -omics data are warranted to validate this finding.}, }
@article {pmid37639360, year = {2023}, author = {Galy, A and Berkhout, B and Breckpot, K and Pichon, C and Bloom, K and Kiem, HP and Mühlebach, MD and McCune, JM}, title = {Recent advances using genetic therapies against infectious diseases and for vaccination.}, journal = {Human gene therapy}, volume = {}, number = {}, pages = {}, doi = {10.1089/hum.2023.123}, pmid = {37639360}, issn = {1557-7422}, abstract = {The development of prophylatic or therapeutic medicines for infectious diseases is one of the priorities for health organizations worldwide. Innovative solutions are required to achieve effective, safe, and accessible treatments for most if not all infectious diseases, particularly those that are chronic in nature or that emerge unexpectedly over time. Genetic technologies offer versatile possibilities to design therapies against pathogens. Recent developments such as mRNA vaccines, CRISPR gene editing, and immunotherapies provide unprecendented hope to achieve significant results in the field of infectious diseases. This review will focus on advances in this domain, showcasing the cross-fertilization with other fields (e.g., oncology), and addressing some of the logistical and economical concerns important to consider when making these advances accessible to diverse populations around the world.}, }
@article {pmid37638432, year = {2023}, author = {de Oliveira Otto, MC and Wu, JHY and Thacker, EL and Lai, HTM and Lemaitre, RN and Padhye, N and Song, X and King, IB and Lopez, O and Siscovick, DS and Mozaffarian, D}, title = {Circulating Omega-3 and Omega-6 Fatty Acids, Cognitive Decline, and Dementia in Older Adults.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {}, doi = {10.3233/JAD-230083}, pmid = {37638432}, issn = {1875-8908}, abstract = {BACKGROUND: Comprising nearly 35% of brain lipids, polyunsaturated fatty acids (PUFA) are essential for optimal brain function. However, the role of PUFA on cognitive health outcomes later in life is largely unknown.
OBJECTIVE: We investigated prospective associations of plasma phospholipid omega-3 (ALA [18 : 3], EPA [20 : 5], DPA [22 : 5], DHA [22 : 6]) and omega-6 (LA [18 : 2], AA [20 : 4]) PUFA with cognitive decline, risk of cognitive impairment and dementia among adults aged≥65 years in the Cardiovascular Health Study.
METHODS: Circulating fatty acid concentrations were measured serially at baseline (1992/1993), 6 years, and 13 years later. Cognitive decline and impairment were assessed using the 100-point Modified Mini-Mental State Examination (3MSE) up to 7 times. Clinical dementia was identified using adjudicated neuropsychological tests, and ICD-9 codes.
RESULTS: Among 3,564 older adults free of stroke and dementia at baseline, cognitive function declined annually by approximately -0.5 3MSE points; 507 participants developed cognitive impairment and 499 dementia over up to 23 years of follow-up. In multivariable models, higher circulating arachidonic acid (AA) concentrations were associated with slower cognitive decline and lower dementia risk, with associations growing stronger with greater length of follow-up (hazard ratio [HR,95% CI] of dementia per interquintile range, 0.74 [0.56-0.97] at 5 years, and 0.53 [0.37-0.77] at 15 years). Circulating docosapentaenoic (DPA) concentrations were associated with slower cognitive decline and lower risk of cognitive impairment (extreme-quintile HR, 0.72 [95% CI: 0.55, 0.95]). Findings were generally null or inconsistent for other omega-3 or omega-6 PUFA.
CONCLUSION: Circulating AA and DPA, but not other PUFA, are associated with slower rate of cognitive decline and lower risk of dementia or cognitive impairment later in life.}, }
@article {pmid37634942, year = {2023}, author = {Celum, C and Seidman, D and Travill, D and Dehlendorf, C and Gumede, S and Zewdie, K and Wilson, W and Morton, JF and Baeten, JM and Donnell, D and Delany-Moretlwe, S}, title = {A decision support tool has similar high PrEP uptake and increases early PrEP persistence in adolescent girls and young women in South Africa: results from a randomized controlled trial.}, journal = {Journal of the International AIDS Society}, volume = {26}, number = {8}, pages = {e26154}, pmid = {37634942}, issn = {1758-2652}, support = {R01MH114544//the National Institutes of Mental Health/ ; OAA-A-15-00034//United States Agency for International Development/ ; }, mesh = {Humans ; Adolescent ; Female ; Young Adult ; Adult ; South Africa ; *HIV Infections/prevention & control ; Ambulatory Care Facilities ; Black People ; Cognition ; }, abstract = {INTRODUCTION: African adolescent girls and young women (AGYW) have high rates of HIV acquisition and are a priority population for HIV pre-exposure prophylaxis (PrEP). PrEP implementation has been limited by AGYW's low perceived HIV risk and provider demands. A decision support tool (DST) with information about PrEP could improve clients' risk perception, knowledge about PrEP, informed decision-making and motivation to use PrEP based on their risk, facilitating PrEP delivery in primary healthcare (PHC) clinics.
METHODS: We designed MyPrEP, a client-facing DST about PrEP and HIV prevention, with youth-friendly information and images. The impact of the MyPrEP tool was assessed among HIV-negative women aged 18-25 years presenting to a PHC clinic in Johannesburg, South Africa from March 2019 to 2020. AGYW were randomized by day to the DST or a general health website as the control condition. A clinician blinded to DST versus control allocation provided standard of care counselling about PrEP, offered PrEP, administered a questionnaire and conducted sexually transmitted infection testing. The primary outcome was PrEP initiation and the secondary outcome was PrEP persistence at 1 month, determined by pharmacy dispensation records.
RESULTS: Of 386 AGYW screened, 353 were randomized (DST n = 172, control n = 181) with a median age of 21 years (interquartile range [IQR] 20, 23) and 56% (199/353) attending the clinic for HIV testing, 46% (164/353) using contraception, 15% (53/353) using condoms consistently and 37% (108/353) with a curable sexually transmitted infection. PrEP was initiated by 97% in the DST group and 94% in the control group (OR 1.79; 95% confidence interval, CI = 0.79-1.53), of whom two-thirds planned to continue PrEP until they decided if they liked PrEP. At 1 month, PrEP persistence was 19% in the DST and 10% in the control group (OR 1.97, 95% CI 1.08-3.69). Ninety-nine percent randomized to the DST reported satisfaction with MyPrEP.
CONCLUSIONS: Among AGYW attending a South African PHC clinic, PrEP uptake was >90% with two-fold higher PrEP persistence at 1 month in those randomized to use the MyPrEP DST. Given the need for strategies to support PrEP implementation and improve low PrEP persistence among African AGYW, a PrEP DST warrants further evaluation.}, }
@article {pmid37634844, year = {2023}, author = {Portuguese, AJ and Holmberg, L and Hill, GR and Lee, SJ and Green, DJ and Mielcarek, M and Gooley, T and Yeh, AC}, title = {Revisiting the utility of G-CSF post-autologous hematopoietic stem cell transplantation for outpatient-based transplants.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2023.08.021}, pmid = {37634844}, issn = {2666-6367}, abstract = {BACKGROUND: The use of granulocyte colony-stimulating factor (G-CSF) after autologous stem cell transplant (ASCT) has been shown to reduce time to neutrophil engraftment as well as duration of hospitalization post-transplant. However, prior studies have focused on inpatient-based transplants, where patients are routinely admitted for conditioning and frequently remain hospitalized until signs of neutrophil recovery. Given improvements in post-transplant care, an increasing number of patients, particularly those receiving ASCT for multiple myeloma, are now being transplanted in an outpatient setting.
OBJECTIVE: We hypothesize that the routine use of G-CSF for outpatient-based ASCT may not result in the same benefit with respect to reduction of duration of hospitalization and therefore should be reconsidered in this setting.
STUDY DESIGN: We performed a retrospective cohort study of 633 patients with multiple myeloma (MM; n=484) and non-Hodgkin lymphoma (NHL; n=149) who were transplanted consecutively between 9/2018 and 2/2023. Outpatient ASCT comprised 258 (53%) of MM and no NHL cases. Starting September 2021, post-transplant G-CSF was incorporated into the supportive care regimen for all ASCTs. There were 410 (309 MM, 101 NHL) and 223 patients (175 MM, 48 NHL) transplanted in the pre- and post-G-CSF policy periods, respectively. The primary outcome focused on the duration of hospitalization within the first 30 days following graft infusion.
RESULTS: As expected, after implementation of the G-CSF policy, the time to neutrophil engraftment was reduced among patients with MM (mean -2.8 days, p<.0001) and NHL (mean -2.9 days, p<.0001). However, among patients with MM, roughly half of whom underwent outpatient-based ASCT, the inpatient duration during the first 30 days was not reduced after G-CSF implementation (p=.40). Comparatively, the inpatient duration (mean -1.8 days, p=.030) was reduced among patients with NHL, all of whom were electively admitted for ASCT.
CONCLUSIONS: For patients with MM at an outpatient-based transplant center, incorporation of G-CSF post-ASCT resulted in reduced time to neutrophil engraftment but did not significantly reduce the time spent in the inpatient setting through day +30.}, }
@article {pmid37633678, year = {2023}, author = {Fares, AF and Li, Y and Jiang, M and Brown, MC and Lam, ACL and Aggarwal, R and Schmid, S and Leighl, NB and Shepherd, FA and Wang, Z and Diao, N and Wenzlaff, AS and Xie, J and Kohno, T and Caporaso, NE and Harris, C and Ma, H and Barnett, MJ and Leal, LF and Fernandez-Tardon, G and Pérez-Ríos, M and Davies, MPA and Taylor, F and Schöttker, B and Brennan, P and Zaridze, D and Holcatova, I and Lissowska, J and Świątkowska, B and Mates, D and Savic, M and Brenner, H and Andrew, A and Cox, A and Field, JK and Ruano-Ravina, A and Shete, SS and Tardon, A and Wang, Y and Le Marchand, L and Reis, RM and Schabath, MB and Chen, C and Shen, H and Ryan, BM and Landi, MT and Shiraishi, K and Zhang, J and Schwartz, AG and Tsao, MS and Christiani, DC and Yang, P and Hung, RJ and Xu, W and Liu, G}, title = {Association between duration of smoking abstinence before non-small-cell lung cancer diagnosis and survival: a retrospective, pooled analysis of cohort studies.}, journal = {The Lancet. Public health}, volume = {8}, number = {9}, pages = {e691-e700}, doi = {10.1016/S2468-2667(23)00131-7}, pmid = {37633678}, issn = {2468-2667}, mesh = {Humans ; Female ; Male ; Retrospective Studies ; *Carcinoma, Non-Small-Cell Lung/diagnosis ; *Lung Neoplasms/diagnosis ; Cohort Studies ; Smoking/epidemiology ; }, abstract = {BACKGROUND: The association between duration of smoking abstinence before non-small-cell lung cancer (NSCLC) diagnosis and subsequent survival can influence public health messaging delivered in lung-cancer screening. We aimed to assess whether the duration of smoking abstinence before diagnosis of NSCLC is associated with improved survival.
METHODS: In this retrospective, pooled analysis of cohort studies, we used 26 cohorts participating in Clinical Outcomes Studies of the International Lung Cancer Consortium (COS-ILCCO) at 23 hospitals. 16 (62%) were from North America, six (23%) were from Europe, three (12%) were from Asia, and one (4%) was from South America. Patients enrolled were diagnosed between June 1, 1983, and Dec 31, 2019. Eligible patients had smoking data before NSCLC diagnosis, epidemiological data at diagnosis (obtained largely from patient questionnaires), and clinical information (retrieved from medical records). Kaplan-Meier curves and multivariable Cox models (ie, adjusted hazard ratios [aHRs]) were generated with individual, harmonised patient data from the consortium database. We estimated overall survival for all causes, measured in years from diagnosis date until the date of the last follow-up or death due to any cause and NSCLC-specific survival.
FINDINGS: Of 42 087 patients with NSCLC in the COS-ILCCO database, 21 893 (52·0%) of whom were male and 20 194 (48·0%) of whom were female, we excluded 4474 (10·6%) with missing data. Compared with current smokers (15 036 [40·0%] of 37 613), patients with 1-3 years of smoking abstinence before NSCLC diagnosis (2890 [7·7%]) had an overall survival aHR of 0·92 (95% CI 0·87-0·97), patients with 3-5 years of smoking abstinence (1114 [3·0%]) had an overall survival aHR of 0·90 (0·83-0·97), and patients with more than 5 years of smoking abstinence (10 841 [28·8%]) had an overall survival aHR of 0·90 (0·87-0·93). Improved NSCLC-specific survival was observed in 4301 (44%) of 9727 patients who had quit cigarette smoking and was significant at abstinence durations of more than 5 years (aHR 0·87, 95% CI 0·81-0·93). Results were consistent across age, sex, histology, and disease-stage distributions.
INTERPRETATION: In this large, pooled analysis of cohort studies across Asia, Europe, North America, and South America, overall survival was improved in patients with NSCLC whose duration of smoking abstinence before diagnosis was as short as 1 year. These findings suggest that quitting smoking can improve overall survival, even if NSCLC is diagnosed at a later lung-cancer screening visit. These findings also support the implementation of public health smoking cessation strategies at any time.
FUNDING: The Alan B Brown Chair, The Posluns Family Fund, The Lusi Wong Fund, and the Princess Margaret Cancer Foundation.}, }
@article {pmid37633269, year = {2023}, author = {Zhang, Z and Zhu, XQ and Yang, F and Lai, NN and Zhu, L and Cole, K and Hu, BY and Li, TE and Zhu, Y and Zhang, LM and Wang, S and Zheng, Y and Mao, H and Zhao, Y and Bruns, C and Vago, R and Tu, B and Wong, JWH and Fu, DL and Qin, LX and Dong, QZ}, title = {Single-cell mapping reveals several immune subsets associated with liver metastasis of pancreatic ductal adenocarcinoma.}, journal = {Med (New York, N.Y.)}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.medj.2023.07.010}, pmid = {37633269}, issn = {2666-6340}, abstract = {BACKGROUND: Identifying a metastasis-correlated immune cell composition within the tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) will help to develop promising and innovative therapeutic strategies. However, the dynamics of immune cell lineages in the TME of advanced PDAC remains elusive.
METHODS: Twenty-six samples from 11 patients (including 11 primary tumor tissues, 10 blood, and 5 lymph nodes) with different stages were used to develop a multiscale immune profile. High-dimensional single-cell analysis with mass cytometry was performed to search for metastasis-correlated immune changes in the microenvironment. The findings were further validated by published single-cell RNA sequencing (scRNA-seq) data and multiplex fluorescent immunohistochemistry.
FINDINGS: High-dimensional single-cell profiling revealed that the three immune-relevant sites formed a distinct immune atlas. Interestingly, the PDAC microenvironment with the potential for metastatic spread to the liver was characterized by a decreased proportion of CD103[+]PD-1[+]CD39[+] T cells with cytotoxic and exhausted functional status and an increased proportion of CD73[+] macrophages. Analysis of scRNA-seq data of PDAC further confirmed the identified subsets and revealed strong potential interactions via various ligand-receptor pairs between the identified T subsets and the macrophages. Moreover, stratified patients with different immune compositions correlated with clinical outcomes of PDAC.
CONCLUSIONS: Our study uncovered metastasis-correlated immune changes, suggesting that ecosystem-based patient classification in PDAC will facilitate the identification of candidates likely to benefit from immunotherapy.
FUNDING: This work was supported by the National Key Research and Development Program of China, the Shanghai International Science and Technology Collaboration Program, the Shanghai Sailing Program, and the Key Laboratory of diagnosis and treatment of severe hepato-pancreatic diseases of Zhejiang Province.}, }
@article {pmid37632791, year = {2023}, author = {Chen, Z and Song, W and Shu, XO and Wen, W and Devall, M and Dampier, C and Moratalla-Navarro, F and Cai, Q and Long, J and Van Kaer, L and Wu, L and Huyghe, JR and Thomas, M and Hsu, L and Woods, MO and Albanes, D and Buchanan, DD and Gsur, A and Hoffmeister, M and Vodicka, P and Wolk, A and Marchand, LL and Wu, AH and Phipps, AI and Moreno, V and Ulrike, P and Zheng, W and Casey, G and Guo, X}, title = {Novel insights into genetic susceptibility for colorectal cancer from transcriptome-wide association and functional investigation.}, journal = {Journal of the National Cancer Institute}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnci/djad178}, pmid = {37632791}, issn = {1460-2105}, abstract = {BACKGROUND AND AIMS: Transcriptome-wide association studies (TWAS) have been successful in identifying candidate susceptibility genes for colorectal cancer (CRC). To strengthen susceptibility gene discovery, we conducted a large TWAS and an alternative splicing-TWAS (sp-TWAS) in CRC using improved genetic prediction models and performed in-depth functional investigations.
METHODS: We analyzed RNA-sequencing (RNA-seq) data from normal colon tissues and genotype data from 423 European descendants to build genetic prediction models of gene expression and alternative splicing, and evaluated model performance using independent RNA-seq data from normal colon tissues of the Genotype-Tissue Expression Project. We applied the verified models to genome-wide association studies (GWAS) summary statistics among 58,131 CRC cases and 67,347 controls of European ancestry to evaluate associations of genetically predicted gene expression and alternative splicing with CRC risk. We performed in vitro functional assays for three selected genes in multiple CRC cell lines.
RESULTS: We identified a total of 57 putative CRC susceptibility genes, which included the 48 genes from TWAS and 15 genes from sp-TWAS, at Bonferroni-corrected P < 0.05. Of these, 16 genes were not previously implicated in CRC susceptibility, including a gene PDE7B (6q23.3) at locus previously not reported by CRC GWAS. Gene knockdown experiments confirmed the oncogenic roles for two unreported genes, TRPS1 and METRNL, and a recently reported gene, C14orf166.
CONCLUSION: This study discovered new putative susceptibility genes of CRC and provided novel insights into the biological mechanisms underlying CRC development.}, }
@article {pmid37632740, year = {2023}, author = {Singer, J and Rerick, P and Elliott, L and Fadalla, C and McLean, E and Jump, A and Molinar-Lopez, V and Neugebauer, V}, title = {Investigating the Relationship Between Marital Status and Ethnicity on Neurocognitive Functioning in a Rural Older Population: A Project Frontier Study.}, journal = {The journals of gerontology. Series B, Psychological sciences and social sciences}, volume = {}, number = {}, pages = {}, doi = {10.1093/geronb/gbad126}, pmid = {37632740}, issn = {1758-5368}, abstract = {OBJECTIVE: Research indicates being married is related to better physical and psychological health. Little is known regarding the relationship between marital status and neurocognitive functioning and whether it differs based on ethnicity (Hispanic vs. non-Hispanic). This is the first study to examine this relationship in a sample of aging adults in rural Texas.
METHOD: Data from 1864 participants (Mage=59.68, SDage=12.21), who were mostly Hispanic (n=1053), women (n=1295), and married (n=1,125) from Project FRONTIER were analyzed. Neuropsychological testing comprised RBANS, Trails Making Test, and Clock Drawing. Participants were dichotomized, married and unmarried.
RESULTS: There was a significant interaction between Hispanic identity and marital status on overall neurocognitive functioning (F(1,1480) =4.79, p < .05, ηp2=.003). For non-Hispanic individuals, married individuals had higher overall neurocognitive functioning compared to unmarried individuals, whereas neurocognitive functioning for Hispanic individuals did not significantly differ between married and unmarried individuals. There were significant main effects as married individuals (M=84.95, SD=15.56) had greater overall neurocognitive functioning than unmarried individuals (M=83.47, SD=15.86; F(1,1480) = 14.67, p < .001, ηp2=.01), Hispanic individuals (M=78.02, SD=14.25) had lower overall neurocognitive functioning than non-Hispanic individuals (M=91.43, SD=15.07; F(1,1480) = 284.99, p < .001, ηp2=.16).
DISCUSSION: Hispanics living in rural areas experience additional stressors that could lead to worse neurocognitive functioning, which is supported by the Lifespan Biopsychosocial Model of Cumulative Vulnerability and Minority Health, which postulates that race/ethnicity/SES-related stressors exacerbate the impact of other life stressors. Reduction of stress on rural Hispanics should be a priority as it could positively affect their neurocognitive functioning.}, }
@article {pmid37630753, year = {2023}, author = {Koch, PA and Paul, R and Contento, IR and Gray, HL and Marín-Chollom, AM and Santiago-Torres, M and Shen, H and Jones, SMW and Hershman, DL and Greenlee, H}, title = {Mi Vida Saludable: Content Validity and Reliability of The Preferences and Self-Efficacy of Diet and Physical Activity Behaviors Questionnaire for Latina Women (PSEDPALW) for Cancer Survivors.}, journal = {Nutrients}, volume = {15}, number = {16}, pages = {}, pmid = {37630753}, issn = {2072-6643}, support = {R01CA186080/CA/NCI NIH HHS/United States ; UL1TR001873/TR/NCATS NIH HHS/United States ; }, mesh = {Female ; Humans ; *Cancer Survivors ; Self Efficacy ; Reproducibility of Results ; Diet ; *Breast Neoplasms ; Exercise ; Hispanic or Latino ; Surveys and Questionnaires ; }, abstract = {The purpose of this study is to conduct validity and reliability testing of a new instrument, the Preferences and Self-Efficacy of Diet and Physical Activity Behaviors Questionnaire for Latina Women (PSEDPALW), which is for women who identify as Latina and are breast cancer survivors. PSEDPALW measures preferences and self-efficacy for four behaviors: physical activity (PA), fruit and vegetable (FV) intake, dietary fat (DF) intake, and added sugar (AS) intake (eight scales in total). Validity testing was conducted through an expert panel review and a cognitive interviewing focus group (n = 4). Reliability was tested via internal consistency reliability (n = 118) and test-retest reliability (n = 30). Validity testing was used to refine PSEDPALW. Reliability testing was conducted on three versions with 104, 47, and 41 items. PA scales had acceptable Cronbach's α (>0.70) but low ICC (NS). FV and DF scales had acceptable Cronbach's α (>0.70), with preferences for the shorter (47- and 41-item) versions (Cronbach's α < 0.70), and all scales had moderate ICC (p < 0.05, except the FV scale on the 104-item version (p = 0.07)). The AS preferences scale had Cronbach's α < 0.70, with self-efficacy > 0.70 for all versions and ICC moderate for all versions (p ≤ 0.01). PSEDPALW may be useful to assess diet and physical activity preferences and self-efficacy in theory-based diet and physical activity interventions in women who identify as Latina and are breast cancer survivors.}, }
@article {pmid37628824, year = {2023}, author = {Wan, M and Yang, X and Sun, J and Giorgi, EE and Ding, X and Zhou, Y and Zhang, Y and Su, W and Jiang, C and Shan, Y and Gao, F}, title = {Enhancement of Neutralization Responses through Sequential Immunization of Stable Env Trimers Based on Consensus Sequences from Select Time Points by Mimicking Natural Infection.}, journal = {International journal of molecular sciences}, volume = {24}, number = {16}, pages = {}, pmid = {37628824}, issn = {1422-0067}, support = {2021YFC2301500//National Key Research and Development Program of China/ ; }, mesh = {Animals ; Guinea Pigs ; *Immunization ; Vaccination ; Antibodies ; *AIDS Vaccines ; Consensus Sequence ; }, abstract = {HIV-1 vaccines have been challenging to develop, partly due to the high level of genetic variation in its genome. Thus, a vaccine that can induce cross-reactive neutralization activities will be needed. Studies on the co-evolution of antibodies and viruses indicate that mimicking the natural infection is likely to induce broadly neutralizing antibodies (bnAbs). We generated the consensus Env sequence for each time point in subject CH505, who developed broad neutralization activities, and selected five critical time points before broad neutralization was detected. These consensus sequences were designed to express stable Env trimers. Priming with the transmitted/founder Env timer and sequential boosting with these consensus Env trimers from different time points induced broader and more potent neutralizing activities than the BG505 Env trimer in guinea pigs. Analysis of the neutralization profiles showed that sequential immunization of Env trimers favored nAbs with gp120/gp41 interface specificity while the BG505 Env trimer favored nAbs with V2 specificity. The unique features such as consensus sequences, stable Env trimers and the sequential immunization to mimic natural infection likely has allowed the induction of improved neutralization responses.}, }
@article {pmid37627136, year = {2023}, author = {Gandhi, AP and Lee, CJ}, title = {Telemedicine in Hematopoietic Cell Transplantation and Chimeric Antigen Receptor-T Cell Therapy.}, journal = {Cancers}, volume = {15}, number = {16}, pages = {}, pmid = {37627136}, issn = {2072-6694}, abstract = {Telemedicine has played an important role in delivering healthcare for primary care, chronic disease patients, and those with solid organ malignancies. However, its application in subspecialties such as hematologic malignancies, hematopoietic cell transplantation (HCT), or chimeric antigen receptor-T cell (CAR-T) therapy is not widespread since physical examination is a vital component in delivering care. During the COVID-19 pandemic, we widely used telemedicine, since protecting our immunocompromised patients became our top priority. The employment of HCT and CAR-T therapies continues to grow for high-risk hematologic malignancies, particularly in older and frail patients who must visit specialty centers for treatment access. Generally, HCT and CAR-T therapy care is highly complex, necessitating commitment from patients, caregivers, and a multidisciplinary team at specialty academic centers. All healthcare systems adapted to the crisis and implemented rapid changes during the COVID-19 public health emergency (PHE). Telemedicine, a vital modality for delivering healthcare in underserved areas, experienced rapid expansion, regardless of the geographic region, during the COVID-19 PHE. The data emerging from practices implemented during the PHE are propelling the field of telemedicine forward, particularly for specialties with complex medical treatments such as HCT and CAR-T therapy. In this review, we examine the current data on telemedicine in HCT and cellular therapy care models for the acute and long-term care of our patients.}, }
@article {pmid37622738, year = {2023}, author = {Nooka, AK and Cohen, AD and Lee, HC and Badros, A and Suvannasankha, A and Callander, N and Abdallah, AO and Trudel, S and Chari, A and Libby, EN and Chaudhry, M and Hultcrantz, M and Kortüm, KM and Popat, R and Sborov, D and Hakim, S and Lewis, E and Gorsh, B and Bhushan, B and McKeown, A and Gupta, I and Opalinska, J and Richardson, PG and Lonial, S}, title = {Single-agent belantamab mafodotin in patients with relapsed/refractory multiple myeloma: Final analysis of the DREAMM-2 trial.}, journal = {Cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/cncr.34987}, pmid = {37622738}, issn = {1097-0142}, support = {205678//GSK/ ; }, abstract = {BACKGROUND: Patients with relapsed/refractory multiple myeloma (RRMM) have a high unmet treatment need. Belantamab mafodotin (belamaf), a first-in-class, B-cell maturation antigen-binding antibody-drug conjugate, eliminates myeloma cells through direct cell killing and an anti-myeloma immune response.
METHODS: DREAMM-2 (NCT03525678) was a phase 2, two-arm, open-label trial in patients with heavily pretreated RRMM who had three or more prior therapies, were refractory to an immunomodulatory agent and a proteasome inhibitor, and refractory or intolerant to an anti-CD38 monoclonal antibody. Belamaf was given at 2.5 or 3.4 mg/kg every 3 weeks. The primary end point was overall response rate (ORR); secondary end points included progression-free survival (PFS), overall survival (OS), safety, ocular symptoms, and health-related quality of life (HRQOL).
RESULTS: This final analysis (cutoff date, March 31, 2022), N = 223, with median follow-up of 12.5 and 13.8 months, demonstrated an ORR of 32% and 35%, median PFS of 2.8 and 3.9 months, and median OS of 15.3 and 14.0 months in the 2.5 mg/kg and 3.4 mg/kg cohorts, respectively. Median duration of response was 12.5 and 6.2 months. No new safety signals were observed; the most common Grade 3 and 4 adverse events were keratopathy (29% vs. 25%), thrombocytopenia (22% vs. 29%), and anemia (21% vs. 28%). HRQOL outcomes suggest that overall global health status/quality of life, physical and role functioning, and overall disease symptoms were maintained or improved during treatment.
CONCLUSIONS: This final analysis of DREAMM-2 confirms that in patients with triple-class refractory RRMM, single-agent belamaf results in durable and clinically meaningful responses with a manageable safety profile.}, }
@article {pmid37622035, year = {2023}, author = {Reiersen, AM and Mattar, C and Bender Ignacio, RA and Boulware, DR and Lee, TC and Hess, R and Lankowski, AJ and McDonald, EG and Miller, JP and Powderly, WG and Pullen, MF and Rado, JT and Rich, MW and Schiffer, JT and Schweiger, J and Spivak, AM and Stevens, A and Vigod, SN and Agarwal, P and Yang, L and Yingling, M and Gettinger, TR and Zorumski, CF and Lenze, EJ}, title = {The STOP COVID 2 Study: Fluvoxamine vs Placebo for Outpatients With Symptomatic COVID-19, a Fully Remote Randomized Controlled Trial.}, journal = {Open forum infectious diseases}, volume = {10}, number = {8}, pages = {ofad419}, pmid = {37622035}, issn = {2328-8957}, abstract = {BACKGROUND: Prior randomized clinical trials have reported benefit of fluvoxamine ≥200 mg/d vs placebo for patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
METHODS: This randomized, double-blind, placebo-controlled, fully remote multisite clinical trial evaluated whether fluvoxamine prevents clinical deterioration in higher-risk outpatients with acute coronavirus disease 2019 (COVID-19). Between December 2020 and May 2021, nonhospitalized US and Canadian participants with confirmed symptomatic infection received fluvoxamine (50 mg on day 1, 100 mg twice daily thereafter) or placebo for 15 days. The primary modified intent-to-treat (mITT) population included participants who started the intervention within 7 days of symptom onset with a baseline oxygen saturation ≥92%. The primary outcome was clinical deterioration within 15 days of randomization, defined as having both (1) shortness of breath (severity ≥4 on a 0-10 scale or requiring hospitalization) and (2) oxygen saturation <92% on room air or need for supplemental oxygen.
RESULTS: A total of 547 participants were randomized and met mITT criteria (n = 272 fluvoxamine, n = 275 placebo). The Data Safety Monitoring Board recommended stopping early for futility related to lower-than-predicted event rates and declining accrual concurrent with vaccine availability in the United States and Canada. Clinical deterioration occurred in 13 (4.8%) participants in the fluvoxamine group and 15 (5.5%) participants in the placebo group (absolute difference at day 15, 0.68%; 95% CI, -3.0% to 4.4%; log-rank P = .91).
CONCLUSIONS: This trial did not find fluvoxamine efficacious in preventing clinical deterioration in unvaccinated outpatients with symptomatic COVID-19. It was stopped early and underpowered due to low primary outcome rates.
CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov Identifier: NCT04668950.}, }
@article {pmid37620824, year = {2023}, author = {Mossavar-Rahmani, Y and Lin, J and Pan, S and Song, RJ and Xue, X and Spartano, NL and Xanthakis, V and Sotres-Alvarez, D and Marquez, DX and Daviglus, M and Carlson, JA and Parada, H and Evenson, KR and Talavera, AC and Gellman, M and Perreira, KM and Gallo, LC and Vasan, RS and Kaplan, RC}, title = {Characterizing longitudinal change in accelerometry-based moderate-to-vigorous physical activity in the Hispanic Community Health Study/Study of Latinos and the Framingham Heart Study.}, journal = {BMC public health}, volume = {23}, number = {1}, pages = {1614}, pmid = {37620824}, issn = {1471-2458}, support = {75N92019D00031/HL/NHLBI NIH HHS/United States ; HHSN268201500001I/HL/NHLBI NIH HHS/United States ; P30 DK111022/DK/NIDDK NIH HHS/United States ; K01 CA234317/CA/NCI NIH HHS/United States ; R01 DK106209/DK/NIDDK NIH HHS/United States ; R01 HL136266/HL/NHLBI NIH HHS/United States ; }, mesh = {Adult ; Humans ; Female ; Male ; Aged ; Middle Aged ; *Public Health ; *Hispanic or Latino ; Accelerometry ; Exercise ; Pain ; Longitudinal Studies ; }, abstract = {BACKGROUND: Physical activity promotes health and is particularly important during middle and older age for decreasing morbidity and mortality. We assessed the correlates of changes over time in moderate-to-vigorous physical activity (MVPA) in Hispanic/Latino adults from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL: mean [SD] age 49.2 y [11.5]) and compared them to a cohort of primarily White adults from the Framingham Heart Study (FHS: mean [SD] 46.9 y [9.2]).
METHODS: Between 2008 and 2019, we assessed accelerometry-based MVPA at two time points with an average follow-up of: 7.6 y, SD 1.3 for HCHS/SOL, and 7.8 y, SD 0.7 for FHS. We used multinomial logistic regression to relate socio-demographic and health behaviors with changes in compliance with 2018 US recommendations for MVPA from time 1 to time 2 (remained active or inactive; became active or inactive) across the two cohorts.
RESULTS: In HCHS/SOL mean MVPA was 22.6 (SD, 23.8) minutes at time 1 and dropped to 16.7 (19.0) minutes at time 2. In FHS Mean MVPA was 21.7 min (SD, 17.7) at time 1 and dropped to 21.3 min (SD, 19.2) at time 2. Across both cohorts, odds of meeting MVPA guidelines over time were about 6% lower in individuals who had lower quality diets vs. higher, about half in older vs. younger adults, about three times lower in women vs. men, and 9% lower in individuals who had a higher vs. lower BMI at baseline. Cohorts differed in how age, gender, income, education, depressive symptoms, marital status and perception of general health and pain associated with changes in physical activity. High income older Hispanics/Latino adults were more likely to become inactive at the follow-up visit as were HCHS/SOL women who were retired and FHS participants who had lower levels of education and income. Higher depressive symptomology was associated with becoming active only in HCHS/SOL women. Being male and married was associated with becoming inactive in both cohorts. Higher perception of general health and lower perception of pain were associated with remaining active only in FHS adults.
CONCLUSIONS: These findings highlight potentially high-risk groups for targeted MVPA intervention.}, }
@article {pmid37615984, year = {2023}, author = {Xiao, H and Wang, Z and Liu, F and Unger, JM}, title = {Excess All-Cause Mortality in China After Ending the Zero COVID Policy.}, journal = {JAMA network open}, volume = {6}, number = {8}, pages = {e2330877}, pmid = {37615984}, issn = {2574-3805}, mesh = {Humans ; Cohort Studies ; *COVID-19 ; China/epidemiology ; Beijing ; Policy ; }, abstract = {IMPORTANCE: In China, the implementation of stringent mitigation measures kept COVID-19 incidence and excess mortality low during the first years of the pandemic. However, China's decision to end its dynamic zero COVID policy (a proactive strategy that deploys mass testing and strict quarantine measures to stamp out any outbreak before it can spread) in December 2022 resulted in a surge in COVID-19 incidence and hospitalizations. Despite worldwide attention given to this event, the actual impact of this sudden shift in policy on population mortality has not been empirically estimated.
OBJECTIVE: To assess the association of the sudden shift in China's dynamic zero COVID policy with mortality using empirical and syndromic surveillance data.
This cohort study analyzed published obituary data from 3 universities in China (2 in Beijing and 1 in Heilongjiang) and search engine data from the Baidu index (BI; weighted frequency of unique searches for a given keyword relative to the total search volume on the Baidu search engine) in each region of China from January 1, 2016, to January 31, 2023. Using an interrupted time-series design, analyses estimated the relative change in mortality among individuals 30 years and older in the universities and the change in BI for mortality-related terms in each region of China from December 2022 to January 2023. Analysis revealed a strong correlation between Baidu searches for mortality-related keywords and actual mortality burden. Using this correlation, the relative increase in mortality in Beijing and Heilongjiang was extrapolated to the rest of China, and region-specific excess mortality was calculated by multiplying the proportional increase in mortality by the number of expected deaths. Data analysis was performed from February 10, 2023, to March 5, 2023.
EXPOSURE: The end to the dynamic zero COVID policy in December 2022 in China.
MAIN OUTCOMES AND MEASURES: Monthly all-cause mortality by region.
RESULTS: An estimated 1.87 million (95% CI, 0.71 million-4.43 million; 1.33 per 1000 population) excess deaths occurred among individuals 30 years and older in China during the first 2 months after the end of the zero COVID policy. Excess deaths predominantly occurred among older individuals and were observed across all provinces in mainland China except Tibet.
CONCLUSIONS AND RELEVANCE: In this cohort study of the population in China, the sudden lifting of the zero COVID policy was associated with significant increases in all-cause mortality. These findings provide valuable insights for policy makers and public health experts and are important for understanding how the sudden propagation of COVID-19 across a population may be associated with population mortality.}, }
@article {pmid37615810, year = {2023}, author = {Al Achkar, M and Roy, UB and Manley, E and Standifer, M and Baik, C and Walsh, CA}, title = {Correction to: A qualitative study of interactions with oncologists among patients with advanced lung cancer.}, journal = {Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer}, volume = {31}, number = {9}, pages = {534}, doi = {10.1007/s00520-023-07995-x}, pmid = {37615810}, issn = {1433-7339}, }
@article {pmid37614575, year = {2023}, author = {Noyd, DH and Liu, Q and Yasui, Y and Chow, EJ and Bhatia, S and Nathan, PC and Landstrom, AP and Tonorezos, E and Casillas, J and Berkman, A and Ness, KK and Mulrooney, DA and Leisenring, WM and Howell, CR and Shoag, J and Kirchhoff, A and Howell, RM and Gibson, TM and Zullig, LL and Armstrong, GT and Oeffinger, KC}, title = {Cardiovascular Risk Factor Disparities in Adult Survivors of Childhood Cancer Compared With the General Population.}, journal = {JACC. CardioOncology}, volume = {5}, number = {4}, pages = {489-500}, pmid = {37614575}, issn = {2666-0873}, abstract = {BACKGROUND: It is unknown whether a history of childhood cancer modifies the established disparities in cardiovascular risk factors (CVRFs) observed in the general population.
OBJECTIVES: We sought to determine if disparities in CVRFs by race/ethnicity are similar among childhood cancer survivors compared with the general population.
METHODS: The Childhood Cancer Survivor Study (CCSS) is a retrospective cohort with a longitudinal follow-up of 24,084 5-year survivors diagnosed between 1970 and 1999. Multivariable piecewise exponential regression estimated incidence rate ratios (IRRs) for hypertension, hyperlipidemia, diabetes, obesity, and ≥2 CVRFs by race/ethnicity. The CCSS sibling cohort and the National Health and Nutrition Examination Survey cohort were used to compare the sociodemographic-adjusted IRRs for same-race/same-ethnicity disparities.
RESULTS: Non-Hispanic Black (NHB) (n = 1,092) and Hispanic (n = 1,405) survivors compared with non-Hispanic White (NHW) (n = 13,960) survivors reported a higher cumulative incidence of diabetes (8.4%, 9.7%, and 5.1%, respectively); obesity (47.2%, 48.9%, and 30.2%, respectively); multiple CVRFs (17.7%, 16.6%, and 12.3%, respectively); and, for NHB survivors, hypertension (19.5%, 13.6%, and 14.3%, respectively) by 40 years of age (P < 0.001). Controlling for sociodemographic and treatment factors compared with NHW survivors, IRRs for NHB were increased for hypertension (IRR: 1.4; 95% CI: 1.1-1.8), obesity (IRR: 1.7; 95% CI: 1.4-2.1), and multiple CVRFs (IRR: 1.6; 95% CI: 1.2-2.1). IRRs for Hispanic survivors were increased for diabetes (IRR: 1.8; 95% CI: 1.2-2.6) and obesity (IRR: 1.4; 95% CI: 1.2-1.7). The pattern of IRRs for CVRF differences was similar among CCSS sibling and National Health and Nutrition Examination Survey cohorts.
CONCLUSIONS: The higher burden of CVRFs among NHB and Hispanic survivors compared with NHW survivors was similar to the general population. The promotion of cardiovascular health equity is critical in this high-risk population.}, }
@article {pmid37232001, year = {2023}, author = {Boop, S and Bonda, D and Randle, S and Leary, S and Vitanza, N and Crotty, E and Novotny, E and Friedman, S and Ellenbogen, RG and Durfy, S and Goldstein, H and Ojemann, JG and Hauptman, JS}, title = {A Comparison of Clinical Outcomes for Subependymal Giant Cell Astrocytomas Treated with Laser Interstitial Thermal Therapy, Open Surgical Resection, and mTOR Inhibitors.}, journal = {Pediatric neurosurgery}, volume = {58}, number = {3}, pages = {150-159}, doi = {10.1159/000531210}, pmid = {37232001}, issn = {1423-0305}, abstract = {INTRODUCTION: Subependymal giant cell astrocytoma (SEGA) is the most common CNS tumor in patients with tuberous sclerosis complex (TSC). Although these are benign, their proximity to the foramen of Monroe frequently causes obstructive hydrocephalus, a potentially fatal complication. Open surgical resection has been the mainstay of treatment; however, this can cause significant morbidity. The development of mTOR inhibitors has changed the treatment landscape, but there are limitations to their use. Laser interstitial thermal therapy (LITT) is an emerging treatment modality that has shown promise in treatment of a variety of intracranial lesions, including SEGAs. We present a single institution, retrospective study of patients treated for SEGAs with LITT, open resection, mTOR inhibitors, or a combination of these modalities. The primary study outcome was tumor volume at most recent follow-up compared with volume at treatment initiation. The secondary outcome was clinical complications associated with treatment modality.
METHODS: Retrospective chart review was performed to identify patients with SEGAs treated at our institution from 2010 to 2021. Demographics, treatment information, and complications were collected from the medical record. Tumor volumes were calculated from imaging obtained at initiation of treatment and at most recent follow-up. Kruskal-Wallis nonparametric testing was used to assess differences in tumor volume and follow-up duration between groups.
RESULTS: Four patients underwent LITT (3 with LITT only), three underwent open surgical resection, and four were treated with mTOR inhibitors only. Mean percent tumor volume reduction for each group was 48.6 ± 13.8, 90.7 ± 39.8, and 67.1 ± 17.2%, respectively. No statistically significant difference was identified comparing percent tumor volume reduction between the three groups (p = 0.0513). Additionally, there was no statistically significant difference in follow-up duration between groups (p = 0.223). Only 1 patient in our series required permanent CSF diversion and 4 discontinued or decreased the dose of mTOR inhibitor due to either cost or side effects.
CONCLUSIONS: Our study suggests that LITT could be considered as a treatment option for SEGAs as it was effective in reducing tumor volume with very few complications. This modality is less invasive than open resection and may be an alternative for patients who are not candidates for mTOR inhibitors. We recommend an updated paradigm for SEGA treatment which includes LITT in select cases after consideration of patient-specific factors.}, }
@article {pmid37612656, year = {2023}, author = {Brenner, AT and Rohweder, CL and Wangen, M and Atkins, DL and Ceballos, RM and Correa, S and Ferrari, RM and Issaka, RB and Ittes, A and Odebunmi, OO and Reuland, DS and Waters, AR and Wheeler, SB and Shah, PD}, title = {Primary care provider perspectives on the role of community pharmacy in colorectal cancer screening: a qualitative study.}, journal = {BMC health services research}, volume = {23}, number = {1}, pages = {892}, pmid = {37612656}, issn = {1472-6963}, support = {U48 DP006400/CC/CDC HHS/United States ; }, mesh = {Adult ; Humans ; Early Detection of Cancer ; *Pharmacies ; *Pharmacy ; *Colorectal Neoplasms/diagnosis ; Primary Health Care ; }, abstract = {BACKGROUND: The United States Preventive Services Task Force (USPSTF) lists 32 grade A or B recommended preventive services for non-pregnant United States (US) adults, including colorectal cancer screening (CRC). Little guidance is given on how to implement these services with consistency and fidelity in primary care. Given limited patient visit time and competing demands, primary care providers (PCPs) tend to prioritize a small subset of these recommendations. Completion rates of some of these services, including CRC screening, are suboptimal. Expanding delivery of preventive services to other healthcare providers, where possible, can improve access and uptake, particularly in medically underserved areas or populations. Fecal immunochemical testing (FIT) (at-home, stool-based testing) for CRC screening can be distributed and resulted without PCP involvement. Pharmacists have long delivered preventive services (e.g., influenza vaccination) and may be a good option for expanding CRC screening delivery using FIT, but it is not clear how PCPs would perceive this expansion.
METHODS: We used semi-structured interviews with PCPs in North Carolina and Washington state to assess perceptions and recommendations for a potential pharmacy-based FIT distribution program (PharmFIT™). Transcripts were coded and analyzed using a hybrid inductive-deductive content analysis guided by the Consolidated Framework for Implementation Research (CFIR) to elucidate potential multi-level facilitators of and barriers to implementation of PharmFIT™.
RESULTS: We completed 30 interviews with PCPs in North Carolina (N = 12) and Washington state (N = 18). PCPs in both states were largely accepting of PharmFIT™, with several important considerations. First, PCPs felt that pharmacists should receive appropriate training for identifying patients eligible and due for FIT screening. Second, a clear understanding of responsibility for tracking tests, communication, and, particularly, follow-up of positive test results should be established and followed. Finally, clear electronic workflows should be established for relay of test result information between the pharmacy and the primary care clinic.
CONCLUSION: If the conditions are met regarding pharmacist training, follow-up for positive FITs, and transfer of documentation, PCPs are likely to support PharmFIT™ as a way for their patients to obtain and complete CRC screening using FIT.}, }
@article {pmid37612207, year = {2023}, author = {Lin, OM and Paine, D and Gramling, E and Menon, M}, title = {Disparities in Time to Diagnosis Among Patients With Multiple Myeloma.}, journal = {Clinical lymphoma, myeloma & leukemia}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.clml.2023.08.003}, pmid = {37612207}, issn = {2152-2669}, abstract = {BACKGROUND: Multiple myeloma (MM) is one of the most diagnosed hematologic malignancies in the United States. Despite improvements in therapy, health disparities persist among patients with MM. Here, we aim to determine whether there are disparities in time to diagnosis (TTD) among MM patients with regard to income, race/ethnicity, and gender.
PATIENTS: Patients with a monoclonal protein detected in the serum and/or urine and a subsequent bone marrow biopsy confirmed diagnosis of MM were included in the study.
METHODS: We extracted data on patients with MM and assessed whether the predictor variables were associated with the primary outcome of TTD, which we define as the time between detection of a monoclonal protein in the serum or urine and bone marrow biopsy diagnosis of MM.
RESULTS: Compared to patients with commercial insurance, patients receiving Medicaid (HR: 0.408, 95% CI: 0.206-0.808; P = .010) and patients without insurance (HR: 0.428, 95% CI: 0.207-0.885; P = .022) were significantly more likely to have delayed TTD. TTD was also prolonged if the provider who ordered the testing for the detection of a monoclonal protein was not a hematologist (HR: 0.435, 95% CI: 0.284-0.668; P < .0001). No disparities were found with regard to race/ethnicity or gender.
CONCLUSION: This study suggests there may be socioeconomic disparities in TTD among patients with MM. Interventions such as patient navigation may be useful to reduce TTD among socioeconomically disadvantaged patient populations. Further studies need to be conducted to elucidate reasons for delays.}, }
@article {pmid37611156, year = {2023}, author = {Popat, UR and Pasvolsky, O and Bassett, R and Mehta, RS and Olson, AL and Chen, J and Alousi, AM and Al-Atrash, G and Bashir, Q and Gulbis, AM and Hosing, CM and Im, JS and Kebriaei, P and Khouri, IF and Marin, DC and Nieto, Y and Oran, B and Saini, NY and Shigle, TL and Srour, SA and Ramdial, JL and Rezvani, K and Qazilbash, MH and Andersson, BS and Champlin, RE and Shpall, EJ}, title = {Myeloablative Fractionated Busulfan for Allogeneic Stem Cell Transplant in Older Patients or Patients with Comorbidities.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2023010850}, pmid = {37611156}, issn = {2473-9537}, abstract = {Traditional conditioning regimens for patients undergoing allogeneic hematopoietic stem cell transplantation (alloHCT) provide suboptimal outcomes, especially for older patients and those with comorbidities. We hypothesized that a fractionated myeloablative busulfan dose delivered over an extended period would reduce non-relapse mortality (NRM), while retaining anti-leukemic effects. Here, we performed a phase II trial for adults with hematological malignancies receiving matched related or unrelated alloHCT. Participants received busulfan 80mg/m2 outpatient on days -20 and -13 before transplant. Fludarabine 40mg/m2 was given on days -6 to -2 followed by busulfan dosed to achieve a target area under the curve of 20,000mol/min for the whole course. The primary endpoint was day 100 NRM. Seventy-eight patients were included, with a median age of 61 (range 39-70) years, transplanted for acute leukemia (24%), MDS (27%), or MPD/CML (44%). HCT specific comorbidity index (HCT-CI) was >3 in 34 (44%). With a median follow-up of 36.4 (range 2.9-51.5) months, 100-day, 1-year and 3-year NRM was 3.8% (95%CI, 0-8.1%), 8% (95%CI, 2-14%), and 9.3% (95%CI, 2.6-15.9%), without a significant difference by age or HCT-CI score. One-year and 3-year relapse incidence was 10% (95%CI, 4-17%) and 18% (95%CI, 9-27%), respectively. Three-year overall survival was 80% (95%CI, 72-90%) and was similar for patients >60 and <60 years of age, as well as those with HCT-CI>3 and HCT-CI<3. Overall, we found that a myeloablative fractionated busulfan regimen has low NRM without an increase in relapse rate, resulting in promising survival, even in older patients or in patients with comorbidities.}, }
@article {pmid37608645, year = {2023}, author = {Dubé, K and Barr, E and Philbin, M and Perez-Brumer, A and Minalga, B and Peterson, B and Averitt, D and Picou, B and Martel, K and Chung, C and Mejía, M and Cameron, M and Graham, G and Dee, L and Dixon Diallo, D and Gordon, E and Korolkova, A and Dyer, T and Auerbach, JD and Scully, E and Dong, KL and Gianella, S}, title = {Increasing the meaningful involvement of women in HIV cure-related research: a qualitative interview study in the United States.}, journal = {HIV research & clinical practice}, volume = {24}, number = {1}, pages = {2246717}, pmid = {37608645}, issn = {2578-7470}, support = {R01 MH126768/MH/NIMH NIH HHS/United States ; R21 MH118120/MH/NIMH NIH HHS/United States ; UM1 AI126620/AI/NIAID NIH HHS/United States ; UM1 AI164570/AI/NIAID NIH HHS/United States ; }, mesh = {Female ; Humans ; Male ; United States/epidemiology ; Qualitative Research ; Empirical Research ; *Academies and Institutes ; Biopsy ; *HIV Infections/drug therapy/epidemiology ; }, abstract = {BACKGROUND: Cisgender women represent over half of people living with HIV globally. However, current research efforts toward a cure for HIV focus predominantly on cisgender men. The under-representation of women in HIV cure clinical studies is particularly problematic given data suggesting that sex-dependent phenotypes limit scientific discovery.
OBJECTIVE: We aimed to generate considerations to increase the meaningful involvement of women in HIV cure-related research.
MATERIALS AND METHODS: We conducted in-depth interviews with biomedical researchers and community members to better understand factors that could increase the meaningful involvement of women in HIV cure clinical trials. Participants were affiliated with academia, industry, community advisory boards, and community-based organizations, and were identified using listings from the AIDS Clinical Trials Group and the Martin Delaney Collaboratories. We used conventional content analysis to analyze the qualitative data.
RESULTS: We recruited 27 participants, of whom 11 were biomedical researchers and 16 were community members. Participants included 25 cisgender women, 1 transgender woman, and 1 cisgender man. Key considerations emerged, including the need to ensure that HIV cure studies reflect HIV epidemiologic trends and having accurate representation by sex and gender in HIV cure research. To increase the meaningful involvement of women, recommendations included instituting intentional enrollment goals, frequent and mandatory reporting on enrollment, and incentives for sites to enroll women. Additional themes included the need for agency and self-determination, attention to lived experiences, trauma and healing, and adequate support for women (e.g. logistical, psychosocial, mental, emotional, and physical). Participants noted that women would be willing to participate in HIV cure trials, related procedures (e.g. biopsies), and analytical treatment interruptions. They also expressed a desired for women-centered and holistic clinical trial designs that account for intersectionality.
CONCLUSIONS: Our empirical inquiry extends recent calls to action to increase diversity of people involved in HIV cure research. Redressing the under-inclusion of women in HIV cure research is an urgent imperative. The entire field must mobilize and reform to achieve this goal. Meaningfully involving women across the gender spectrum in HIV cure research is needed to ensure that interventions are safe, effective, scalable, and acceptable for all people with HIV.}, }
@article {pmid37608289, year = {2023}, author = {Twentyman, J and Khalifeh, A and Felton, AL and Emerman, M and Ohainle, M}, title = {Primate TRIM34 is a broadly-acting, TRIM5-dependent lentiviral restriction factor.}, journal = {Retrovirology}, volume = {20}, number = {1}, pages = {15}, pmid = {37608289}, issn = {1742-4690}, support = {R01-AI147877//National Institute of Allergy and Infectious Diseases/ ; U54-AI170856//National Institute of Allergy and Infectious Diseases/ ; DP1-DA051110//National Institute of Allergy and Infectious Diseases/ ; }, mesh = {Animals ; Macaca mulatta ; Lentivirus ; *Simian Immunodeficiency Virus/genetics ; Antiviral Agents ; *HIV Infections ; }, abstract = {Human immunodeficiency virus (HIV) and other lentiviruses adapt to new hosts by evolving to evade host-specific innate immune proteins that differ in sequence and often viral recognition between host species. Understanding how these host antiviral proteins, called restriction factors, constrain lentivirus replication and transmission is key to understanding the emergence of pandemic viruses like HIV-1. Human TRIM34, a paralogue of the well-characterized lentiviral restriction factor TRIM5α, was previously identified by our lab via CRISPR-Cas9 screening as a restriction factor of certain HIV and SIV capsids. Here, we show that diverse primate TRIM34 orthologues from non-human primates can restrict a range of Simian Immunodeficiency Virus (SIV) capsids including SIVAGM-SAB, SIVAGM-TAN and SIVMAC capsids, which infect sabaeus monkeys, tantalus monkeys, and rhesus macaques, respectively. All primate TRIM34 orthologues tested, regardless of species of origin, were able to restrict this same subset of viral capsids. However, in all cases, this restriction also required the presence of TRIM5α. We demonstrate that TRIM5α is necessary, but not sufficient, for restriction of these capsids, and that human TRIM5α functionally interacts with TRIM34 from different species. Finally, we find that both the TRIM5α SPRY v1 loop and the TRIM34 SPRY domain are essential for TRIM34-mediated restriction. These data support a model in which TRIM34 is a broadly-conserved primate lentiviral restriction factor that acts in tandem with TRIM5α, such that together, these proteins can restrict capsids that neither can restrict alone.}, }
@article {pmid37607272, year = {2023}, author = {Hill, PC and Cobelens, F and Martinez, L and Behr, MA and Churchyard, G and Evans, T and Fiore-Gartland, AJ and Garcia-Basteiro, AL and Hanekom, W and Rangaka, MX and Vekemans, J and White, RG}, title = {An aspiration to radically shorten phase 3 TB vaccine trials.}, journal = {The Journal of infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1093/infdis/jiad356}, pmid = {37607272}, issn = {1537-6613}, abstract = {A new tuberculosis (TB) vaccine is a high priority. However, the classical development pathway is a major deterrent. Most TB cases arise within two years after M. tuberculosis exposure, suggesting a three-year trial period should be possible if sample size is large to maximise the number of early exposures. Increased sample size could be facilitated by working alongside optimised routine services for case ascertainment, with strategies for enhanced case detection and safety monitoring. Shortening enrolment could be achieved by simplifying screening criteria and procedures and strengthening site capacity. Together, these measures could enable radically shortened phase 3 TB vaccine trials.}, }
@article {pmid37605043, year = {2023}, author = {Glögl, M and Friedrich, N and Cerutti, G and Lemmin, T and Kwon, YD and Gorman, J and Maliqi, L and Mittl, PRE and Hesselman, MC and Schmidt, D and Weber, J and Foulkes, C and Dingens, AS and Bylund, T and Olia, AS and Verardi, R and Reinberg, T and Baumann, NS and Rusert, P and Dreier, B and Shapiro, L and Kwong, PD and Plückthun, A and Trkola, A}, title = {Trapping the HIV-1 V3 loop in a helical conformation enables broad neutralization.}, journal = {Nature structural & molecular biology}, volume = {}, number = {}, pages = {}, pmid = {37605043}, issn = {1545-9985}, abstract = {The third variable (V3) loop on the human immunodeficiency virus 1 (HIV-1) envelope glycoprotein trimer is indispensable for virus cell entry. Conformational masking of V3 within the trimer allows efficient neutralization via V3 only by rare, broadly neutralizing glycan-dependent antibodies targeting the closed prefusion trimer but not by abundant antibodies that access the V3 crown on open trimers after CD4 attachment. Here, we report on a distinct category of V3-specific inhibitors based on designed ankyrin repeat protein (DARPin) technology that reinstitute the CD4-bound state as a key neutralization target with up to >90% breadth. Broadly neutralizing DARPins (bnDs) bound V3 solely on open envelope and recognized a four-turn amphipathic α-helix in the carboxy-terminal half of V3 (amino acids 314-324), which we termed 'αV3C'. The bnD contact surface on αV3C was as conserved as the CD4 binding site. Molecular dynamics and escape mutation analyses underscored the functional relevance of αV3C, highlighting the potential of αV3C-based inhibitors and, more generally, of postattachment inhibition of HIV-1.}, }
@article {pmid37603953, year = {2023}, author = {Noll, A and Myers, C and Biery, MC and Meechan, M and Tahiri, S and Rajendran, A and Berens, ME and Paine, D and Byron, S and Zhang, J and Winter, C and Pakiam, F and Leary, SES and Cole, BL and Jackson, ER and Dun, MD and Foster, JB and Evans, MK and Pattwell, SS and Olson, JM and Vitanza, NA}, title = {Therapeutic HDAC inhibition in hypermutant diffuse intrinsic pontine glioma.}, journal = {Neoplasia (New York, N.Y.)}, volume = {43}, number = {}, pages = {100921}, doi = {10.1016/j.neo.2023.100921}, pmid = {37603953}, issn = {1476-5586}, abstract = {Constitutional mismatch repair deficiency (CMMRD) is a cancer predisposition syndrome associated with the development of hypermutant pediatric high-grade glioma, and confers a poor prognosis. While therapeutic histone deacetylase (HDAC) inhibition of diffuse intrinsic pontine glioma (DIPG) has been reported; here, we use a clinically relevant biopsy-derived hypermutant DIPG model (PBT-24FH) and a CRISPR-Cas9 induced genetic model to evaluate the efficacy of HDAC inhibition against hypermutant DIPG. We screened PBT-24FH cells for sensitivity to a panel of HDAC inhibitors (HDACis) in vitro, identifying two HDACis associated with low nanomolar IC50s, quisinostat (27 nM) and romidepsin (2 nM). In vivo, quisinostat proved more efficacious, inducing near-complete tumor regression in a PBT-24FH flank model. RNA sequencing revealed significant quisinostat-driven changes in gene expression, including upregulation of neural and pro-inflammatory genes. To validate the observed potency of quisinostat in vivo against additional hypermutant DIPG models, we tested quisinostat in genetically-induced mismatch repair (MMR)-deficient DIPG flank tumors, demonstrating that loss of MMR function increases sensitivity to quisinostat in vivo. Here, we establish the preclinical efficacy of quisinostat against hypermutant DIPG, supporting further investigation of epigenetic targeting of hypermutant pediatric cancers with the potential for clinical translation. These findings support further investigation of HDAC inhibitors against pontine high-grade gliomas, beyond only those with histone mutations, as well as against other hypermutant central nervous system tumors.}, }
@article {pmid37603866, year = {2023}, 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 = {}, number = {}, pages = {}, doi = {10.7326/M23-1230}, pmid = {37603866}, issn = {1539-3704}, }
@article {pmid37603594, year = {2023}, author = {Steiner, RE and Hwang, SR and Khurana, A and Habermann, TM and Epperla, N and Annunzio, K and Allen, PB and Baird, K and Paulino, D and Alderuccio, JP and Lossos, IS and David, KA and Evens, AM and Pandya, K and Bair, SM and Kamdar, M and Ba Aqeel, SH and Torka, P and Lynch, RC and Smith, SD and Feng, L and Noorani, M and Ahmed, S and Nair, R and Vega, F and Wu, S and Fang, PQ and Pinnix, CC and Gunther, JR and Dabaja, BS and Lee, HJ}, title = {Impact of Cumulative Dose of Brentuximab Vedotin on Outcomes of Frontline Therapy for Advanced Stage Hodgkin Lymphoma.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2023010700}, pmid = {37603594}, issn = {2473-9537}, abstract = {In the pivotal study ECHELON-1, brentuximab vedotin (BV), doxorubicin, vinblastine, and dacarbazine (A+AVD) demonstrated superior efficacy compared to bleomycin+AVD (ABVD) for the treatment of advanced-stage classic Hodgkin's lymphoma (cHL). However, there is minimal available data regarding the frequency of dose reductions or omission of BV during curative therapy and the potential impact on patient outcomes. In a real-world analysis, we retrospectively reviewed the characteristics and outcomes of 179 stage III and IV cHL patients treated with frontline A+AVD from January 2010 through April 2022. Treatment consisted of up to 1.2 mg/kg of BV and standard dose AVD intravenously on days 1 and 15 of each 28-day cycle for up to 6 cycles. At the time of treatment, the median age was 37 years, and high-risk International Prognostic Score was observed in 46% of patients. Overall, 91% of patients received six cycles of AVD; 55% of patients did not receive the intended cumulative dose of BV (CDB); 28% of patients received two-thirds or less than the planned CDB. At a median follow-up time of 27.4 months (95% CI: 24.8 - 29 months), the median progression-free survival (PFS) was not reached, and the 12-month PFS was 90.3% (95% confidence interval [CI], 85.9-95.0). The impact of CDB on PFS was not significant (p-value=0.15), nor was high CDB significantly associated with increased adverse events (AE). In real-world experience, A+AVD is a highly effective treatment for patients with advanced-stage cHL, including for patients with prominent dose reductions of BV.}, }
@article {pmid37603552, year = {2023}, author = {Nikas, A and Ahmed, H and Moore, MR and Zarnitsyna, VI and Antia, R}, title = {When does humoral memory enhance infection?.}, journal = {PLoS computational biology}, volume = {19}, number = {8}, pages = {e1011377}, doi = {10.1371/journal.pcbi.1011377}, pmid = {37603552}, issn = {1553-7358}, abstract = {Antibodies and humoral memory are key components of the adaptive immune system. We consider and computationally model mechanisms by which humoral memory present at baseline might increase rather than decrease infection load; we refer to this effect as EI-HM (enhancement of infection by humoral memory). We first consider antibody dependent enhancement (ADE) in which antibody enhances the growth of the pathogen, typically a virus, and typically at intermediate 'Goldilocks' levels of antibody. Our ADE model reproduces ADE in vitro and enhancement of infection in vivo from passive antibody transfer. But notably the simplest implementation of our ADE model never results in EI-HM. Adding complexity, by making the cross-reactive antibody much less neutralizing than the de novo generated antibody or by including a sufficiently strong non-antibody immune response, allows for ADE-mediated EI-HM. We next consider the possibility that cross-reactive memory causes EI-HM by crowding out a possibly superior de novo immune response. We show that, even without ADE, EI-HM can occur when the cross-reactive response is both less potent and 'directly' (i.e. independently of infection load) suppressive with regard to the de novo response. In this case adding a non-antibody immune response to our computational model greatly reduces or completely eliminates EI-HM, which suggests that 'crowding out' is unlikely to cause substantial EI-HM. Hence, our results provide examples in which simple models give qualitatively opposite results compared to models with plausible complexity. Our results may be helpful in interpreting and reconciling disparate experimental findings, especially from dengue, and for vaccination.}, }
@article {pmid37601974, year = {2023}, author = {Surakka, I and Wu, KH and Hornsby, W and Wolford, BN and Shen, F and Zhou, W and Huffman, JE and Pandit, A and Hu, Y and Brumpton, B and Skogholt, AH and Gabrielsen, ME and Walters, RG and , and , and Hveem, K and Kooperberg, C and Zöllner, S and Wilson, PWF and Sutton, NR and Daly, MJ and Neale, BM and Willer, CJ and , }, title = {Multi-ancestry meta-analysis identifies 5 novel loci for ischemic stroke and reveals heterogeneity of effects between sexes and ancestries.}, journal = {Cell genomics}, volume = {3}, number = {8}, pages = {100345}, pmid = {37601974}, issn = {2666-979X}, abstract = {Stroke is the second leading cause of death and disability worldwide. Stroke prevalence varies by sex and ancestry, possibly due to genetic heterogeneity between subgroups. We performed a genome-wide meta-analysis of 16 biobanks across multiple ancestries to study the genetics of ischemic stroke (60,176 cases, 1,310,725 controls) as part of the Global Biobank Meta-analysis Initiative (GBMI) and further combined the results with previously published MegaStroke. Five novel loci for ischemic stroke (LAMC1, CALCRL, PLSCR1, CDKN1A, and SWAP70) were identified after replication in four additional datasets. One previously reported locus showed significant ancestry heterogeneity (ABO), and one showed significant sex heterogeneity (ALDH2). The ALDH2 association was male specific (males p = 1.67e-24, females p = 0.126) and was additionally observed only in the East Asian ancestry (male) samples. These findings emphasize the need for more diverse datasets with large sample sizes to further understand the genetic predisposition of stroke in different ancestry and sex groups.}, }
@article {pmid37601218, year = {2023}, author = {Ramirez, M and Bishop, S and Ibarra, G and Shah, P and Duran, MC and Chae, HY and Hassell, L and Garza, L and Linde, S and Garrison, MM and Drain, PK and Ko, LK}, title = {An agricultural community's perspectives on COVID-19 testing to support safe school reopening.}, journal = {Frontiers in public health}, volume = {11}, number = {}, pages = {1215385}, pmid = {37601218}, issn = {2296-2565}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Adolescent ; *COVID-19/diagnosis/prevention & control ; COVID-19 Testing ; Schools ; Agriculture ; Emotions ; }, abstract = {INTRODUCTION: School-based COVID-19 testing may be an effective strategy for reducing transmission in schools and keeping schools open. The study objective was to examine community perspectives on school-based COVID-19 testing as a mitigation strategy to support safe school reopening.
METHODS: We conducted a qualitative study in Yakima County, an agricultural region of Washington state, where over half of residents are Hispanic/Latino. From June to July 2021, we interviewed 18 students (13 years old, on average) and 19 school employees, and conducted four focus groups (2 in Spanish, 2 in English) with 26 parents. We audio-recorded the semi-structured interviews and focus group discussions which were then transcribed. We used an inductive, constant comparison approach to code the transcripts and conducted a thematic analysis to generate themes.
RESULTS: We identified four main themes. Students, parents, and school employees desired a return to in-person learning (Theme 1). Schools implemented numerous COVID-19 mitigation strategies (e.g., masking) to facilitate a safe return to school but felt that adding testing would not be feasible due to a lack of resources and overworked staff (Theme 2). Parents and school employees' familiarity with COVID-19 testing procedures influenced their support for testing (Theme 3). Parents and school employees felt there were inadequate resources for individuals who test positive for COVID-19 (Theme 4).
DISCUSSION: Schools require adequate resources and medical personnel to implement COVID-19 testing. Individuals also need resources after testing positive, including physical space to isolate, financial resources for those without paid time off, and delivery of food and other necessities to households in rural communities.}, }
@article {pmid37599686, year = {2023}, author = {Zhang, Y and Dai, R and Huang, Y and Prentice, RL and Zheng, C}, title = {Regression calibration utilizing biomarkers developed from high-dimensional metabolites.}, journal = {Frontiers in nutrition}, volume = {10}, number = {}, pages = {1215768}, pmid = {37599686}, issn = {2296-861X}, abstract = {Addressing systematic measurement errors in self-reported data is a critical challenge in association studies of dietary intake and chronic disease risk. The regression calibration method has been utilized for error correction when an objectively measured biomarker is available; however, biomarkers for only a few dietary components have been developed. This paper proposes to use high-dimensional objective measurements to construct biomarkers for many more dietary components and to estimate the diet disease associations. It also discusses the challenges in variance estimation in high-dimensional regression methods and presents a variety of techniques to address this issue, including cross-validation, degrees-of-freedom corrected estimators, and refitted cross-validation (RCV). Extensive simulation is performed to study the finite sample performance of the proposed estimators. The proposed method is applied to the Women's Health Initiative cohort data to examine the associations between the sodium/potassium intake ratio and the total cardiovascular disease.}, }
@article {pmid37599317, year = {2023}, author = {Pham, TT and Nimptsch, K and Papadimitriou, N and Aleksandrova, K and Jenab, M and Gunter, MJ and Le Marchand, L and Li, L and Lynch, BM and Castellví-Bel, S and Phipps, AI and Schmit, SL and Brenner, H and Ogino, S and Giovannucci, E and Pischon, T}, title = {Genetically determined circulating resistin concentrations and risk of colorectal cancer: a two-sample Mendelian randomization study.}, journal = {Journal of cancer research and clinical oncology}, volume = {}, number = {}, pages = {}, pmid = {37599317}, issn = {1432-1335}, abstract = {PURPOSE: Resistin, a novel pro-inflammatory protein implicated in inflammatory processes, has been suggested to play a role in colorectal development. However, evidence from observational studies has been inconsistent. Mendelian randomization may be a complementary method to examine this association.
METHODS: We conducted a two-sample Mendelian randomization to estimate the association between genetically determined circulating resistin concentrations and risk of colorectal cancer (CRC). Protein quantitative trait loci (pQTLs) from the SCALLOP consortium were used as instrumental variables (IVs) for resistin. CRC genetic summary data was obtained from GECCO/CORECT/CCFR (the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry), and FinnGen (Finland Biobank). The inverse variance weighted method (IVW) was applied in the main analysis, and other robust methods were used as sensitivity analyses. Estimates for the association from the two data sources were then pooled using a meta-analysis approach.
RESULTS: Thirteen pQTLs were identified as IVs explaining together 7.80% of interindividual variation in circulating resistin concentrations. Based on MR analyses, genetically determined circulating resistin concentrations were not associated with incident CRC (pooled-IVW-OR per standard deviation of resistin, 1.01; 95% CI 0.96, 1.06; p = 0.67. Restricting the analyses to using IVs within or proximal to the resistin-encoding gene (cis-IVs), or to IVs located elsewhere in the genome (trans-IVs) provided similar results. The association was not altered when stratified by sex or CRC subsites.
CONCLUSIONS: We found no evidence of a relationship between genetically determined circulating resistin concentrations and risk of CRC.}, }
@article {pmid37319437, year = {2023}, author = {Takahashi, T and Al-Kofahi, M and Jaber, M and Bratrude, B and Betz, K and Suessmuth, Y and Yu, A and Neuberg, DS 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 Watkins, B and Langston, A and Qayed, M and Kean, LS}, title = {Higher abatacept exposure after transplant decreases acute GVHD risk without increasing adverse events.}, journal = {Blood}, volume = {142}, number = {8}, pages = {700-710}, doi = {10.1182/blood.2023020035}, pmid = {37319437}, issn = {1528-0020}, abstract = {In the ABA2 study, the T-cell costimulation blockade agent, abatacept, was safe and effective in preventing acute graft-versus-host disease (aGVHD) after unrelated-donor hematopoietic cell transplant (HCT), leading to US Food and Drug Administration approval. Here, we performed a determination of abatacept pharmacokinetics (PK), which enabled an examination of how abatacept exposure-response relationships affected clinical outcomes. We performed a population PK analysis of IV abatacept using nonlinear mixed-effect modeling and assessed the association between abatacept exposure and key transplant outcomes. We tested the association between the trough after dose 1 (Ctrough_1) and grade (GR) 2 or 4 aGVHD (GR2-4 aGVHD) through day +100. An optimal Ctrough_1 threshold was identified via recursive partitioning and classification tree analysis. This demonstrated that abatacept PK was characterized by a 2-compartment model with first-order elimination. The ABA2 dosing regimen was based on previous work targeting a steady-state abatacept trough of 10 μg/mL. However, a higher Ctrough_1 (≥39 μg/mL, attained in ∼60% of patients on ABA2) was associated with a favorable GR2-4 aGVHD risk (hazard ratio, 0.35; 95% confidence interval, 0.19-0.65; P < .001), with a Ctrough_1 <39 μg/mL associated with GR2-4 aGVHD risk indistinguishable from placebo (P = .37). Importantly, no significant association was found between Ctrough_1 and key safety indicators, including relapse, and cytomegalovirus or Epstein-Barr virus viremia. These data demonstrate that a higher abatacept Ctrough_1 (≥39 μg/mL) was associated with a favorable GR2-4 aGVHD risk, without any observed exposure-toxicity relationships. This trial was registered at www.clinicaltrials.gov as #NCT01743131.}, }
@article {pmid37126658, year = {2023}, author = {Sajulga, R and Bolon, YT and Maiers, MJ and Petersdorf, EW}, title = {Assessment of HLA-DPB1 genetic variation using an HLA-DP tool and its implications in clinical transplantation.}, journal = {Blood advances}, volume = {7}, number = {17}, pages = {4809-4821}, doi = {10.1182/bloodadvances.2022009554}, pmid = {37126658}, issn = {2473-9537}, abstract = {HLA-DP is a classic transplantation antigen that mediates alloreactivity through T-cell epitope (TCE) diversity and expression levels. A current challenge is to integrate these functional features into the prospective selection of unrelated donor candidates for transplantation. Genetically, HLA-DPB1 exon 2 defines the permissive and nonpermissive TCE groups, and exons 2 and 3 (in linkage with rs9277534) indicate low- and high-expression allotypes. In this study, we analyzed 356 272 exon 2-exon 3-phased sequences from individuals across 5 self-identified race and ethnicity categories: White, Hispanic, Asian or Pacific Islander, Black or African American, and American Indian or Alaskan Native. This sequence data set revealed the complex relationship between TCE and expression models and the importance of exon 3 sequence data. We also studied archived donor search lists for 2545 patients who underwent transplantation from an HLA-11/12 unrelated donor mismatched for a single HLA-DPB1 allele. Depending on the order in which the TCE and expression criteria were considered, some patients had different TCE- and expression-favorable donors. In addition, this data set revealed that many expression-favorable alternatives existed in the search lists. To improve the selection of candidate donors, we provide, disseminate, and automate our findings through our multifaceted tool called Expression of HLA-DP Assessment Tool, consisting of a public web application, Python package, and analysis pipeline.}, }
@article {pmid37597686, year = {2023}, author = {Ma, S and Bhar, S and Guffey, D and Kim, RB and Jamil, M and Amos, CI and Lee, SJ and Hingorani, SR and Sartain, SE and Li, A}, title = {Prospective clinical and biomarker validation of the ASTCT consensus definition for transplant-associated thrombotic microangiopathy (TA-TMA).}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2023.08.015}, pmid = {37597686}, issn = {2666-6367}, abstract = {INTRODUCTION: Transplantation-associated thrombotic microangiography (TA-TMA) is a disorder that causes severe complications post-allogeneic hematopoietic cell transplantation (allo-HCT). Diagnosing TA-TMA is challenging due to non-standardized criteria. In this study, we aimed to evaluate the new TA-TMA consensus definition from the American Society for Transplantation and Cellular Therapy (ASTCT) panel as part of an ongoing prospective pediatric cohort study and to compare the impact and outcomes of employing the current clinical TMA definition (cTMA) versus the new consensus definition.
METHODS: We included patients aged 0 to 18 years who underwent their first allo-HCT from May 2021 to January 2023 at Texas Children's Hospital. We compared the incidence, biomarkers, and outcomes of TA-TMA applying the previous and recently proposed screening algorithms and definitions.
RESULTS: While the classic microangiopathic hemolytic anemia (MAHA)-based cTMA definition led to an incidence of 12.7%, the ASTCT-HR definition doubled the incidence to 28.5% by day 100. In contrast to patients with concordant diagnosis (+/+) who had significantly worse post-transplant survival, those reclassified as TA-TMA by the new definition only (-/+) had significantly different prognosis (100% survival at day 100) despite the lack of TMA-directed therapy. Furthermore, biomarkers of the terminal and alternative complement pathways (sC5b9 and Ba, respectively) were significantly elevated around day 15 in the concordant group (+/+) but not in the discordant group (-/+) when compared to the non-TMA patients.
CONCLUSIONS: The recently proposed ASTCT consensus TA-TMA diagnosis is more sensitive and allows earlier recognition of manifestation that requires closer clinical monitoring but risks over-diagnosis and over-treatment. We recommend additional prospective validation.}, }
@article {pmid37597423, year = {2023}, author = {Baird, L and Taguchi, K and Zhang, A and Takahashi, Y and Suzuki, T and Kensler, TW and Yamamoto, M}, title = {A NRF2-induced secretory phenotype activates immune surveillance to remove irreparably damaged cells.}, journal = {Redox biology}, volume = {66}, number = {}, pages = {102845}, doi = {10.1016/j.redox.2023.102845}, pmid = {37597423}, issn = {2213-2317}, abstract = {While it is well established that the KEAP1-NRF2 pathway regulates the main inducible cellular response to oxidative stress, this cytoprotective function of NRF2 could become deleterious to the host if it confers survival onto irreparably damaged cells. In this regard, we have found that in diseased states, NRF2 promotes the transcriptional activation of a specific subset of the senescence-associated secretory phenotype (SASP) gene program, which we have named the NRF2-induced secretory phenotype (NISP). In two models of hepatic disease using Pten::Keap1 and Keap1::Atg7 double knockout mice, we found that the NISP functions in the liver to recruit CCR2 expressing monocytes, which function as immune system effector cells to directly remove the damaged cells. Through activation of this immune surveillance pathway, in non-transformed cells, NRF2 functions as a tumour suppressor to mitigate the long-term survival of damaged cells which otherwise would be detrimental for host survival. This pathway represents the final stage of the oxidative stress response, as it allows cells to be safely removed if the macromolecular damage caused by the original stressor is so extensive that it is beyond the repair capacity of the cell.}, }
@article {pmid37597186, year = {2023}, author = {Biswas, S and Kang, K and Ng, KP and Radivoyevitch, T and Schalper, K and Zhang, H and Lindner, DJ and Thomas, A and MacPherson, D and Gastman, B and Schrump, DS and Wong, KK and Velcheti, V and Saunthararajah, Y}, title = {Neuroendocrine lineage commitment of small cell lung cancers can be leveraged into p53-independent non-cytotoxic therapy.}, journal = {Cell reports}, volume = {42}, number = {8}, pages = {113016}, doi = {10.1016/j.celrep.2023.113016}, pmid = {37597186}, issn = {2211-1247}, abstract = {Small cell lung cancers (SCLCs) rapidly resist cytotoxic chemotherapy and immune checkpoint inhibitor (ICI) treatments. New, non-cross-resistant therapies are thus needed. SCLC cells are committed into neuroendocrine lineage then maturation arrested. Implicating DNA methyltransferase 1 (DNMT1) in the maturation arrests, we find (1) the repression mark methylated CpG, written by DNMT1, is retained at suppressed neuroendocrine-lineage genes, even as other repression marks are erased; (2) DNMT1 is recurrently amplified, whereas Ten-Eleven-Translocation 2 (TET2), which functionally opposes DNMT1, is deleted; (3) DNMT1 is recruited into neuroendocrine-lineage master transcription factor (ASCL1, NEUROD1) hubs in SCLC cells; and (4) DNMT1 knockdown activated ASCL1-target genes and released SCLC cell-cycling exits by terminal lineage maturation, which are cycling exits that do not require the p53/apoptosis pathway used by cytotoxic chemotherapy. Inhibiting DNMT1/corepressors with clinical compounds accordingly extended survival of mice with chemorefractory and ICI-refractory, p53-null, disseminated SCLC. Lineage commitment of SCLC cells can hence be leveraged into non-cytotoxic therapy able to treat chemo/ICI-refractory SCLC.}, }
@article {pmid37596830, year = {2023}, author = {Chiu, V and Urbanek, JK and Wanigatunga, AA and Allison, MA and Ballew, SH and Mossavar-Rahmani, Y and Sotres-Alvarez, D and Gallo, LC and Xue, X and Talavera, GA and Evenson, KR and Kaplan, RC and Matsushita, K and Schrack, JA}, title = {The Association between Ankle-Brachial Index and Daily Patterns of Physical Activity: Results from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL).}, journal = {The journals of gerontology. Series A, Biological sciences and medical sciences}, volume = {}, number = {}, pages = {}, doi = {10.1093/gerona/glad200}, pmid = {37596830}, issn = {1758-535X}, abstract = {BACKGROUND: Peripheral artery disease (PAD) is associated with lower physical activity but less is known about its association with daily patterns of activity. We examined the cross-sectional association between ankle-brachial index (ABI) and objectively measured patterns of physical activity among Hispanic/Latino adults.
METHODS: We analyzed data from 7,688 participants (aged 45-74 years) in the Hispanic Community Health Study/Study of Latinos. ABI was categorized as low (≤0.90, indicating PAD), borderline low (0.91-0.99), normal (1.00-1.40), and high (>1.40, indicating incompressible ankle arteries). Daily physical activity metrics derived from accelerometer data included: log of total activity counts (LTAC), total log-transformed activity counts (TLAC), and active-to-sedentary transition probability (ASTP). Average differences between ABI categories in physical activity, overall and by 4-hour time-of-day intervals, were assessed using linear regression and mixed-effects models, respectively.
RESULTS: In Hispanic/Latino adults, 5.3% and 2.6% had low and high ABIs, respectively. After adjustment, having a low compared to a normal ABI was associated with lower volume (LTAC=-0.13, p<0.01; TLAC=-74.4, p=0.04) and more fragmented physical activity (ASTP=1.22%, p<0.01). Having a low ABI was linked with more fragmented physical activity after 12PM (p<0.01). Having a high ABI was associated with lower volumes of activity (TLAC=-132.0, p=0.03).
CONCLUSIONS: Having a low or high ABI is associated with lower and more fragmented physical activity in Hispanic/Latino adults. In adults with low ABI, physical activity is more fragmented in the afternoon to evening. Longitudinal research is warranted to expand these findings to guide targeted interventions for PAD or incompressible ankle arteries.}, }
@article {pmid37594474, year = {2023}, author = {Chtourou, A and Sanchez, PV and Golden, T and Chen, HS and Schwartz, SM and Wu, XC and Hernandez, BY and Harrison, JN and Penberthy, L and Negoita, S}, title = {Impact on the Volume of Pathology Reports Before and During the COVID-19 Pandemic in SEER Cancer Registries.}, journal = {Cancer epidemiology, biomarkers & 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-23-0066}, pmid = {37594474}, issn = {1538-7755}, abstract = {BACKGROUND: Health care procedures including cancer screening and diagnosis were interrupted due to the COVID-19 pandemic; The extent of this impact on cancer care in the U.S. is not fully understood. We investigated pathology report volume as a reflection of trends in oncology services pre-pandemic and during the pandemic.
METHODS: Electronic pathology reports were obtained from 11 U.S. central cancer registries from NCI's SEER Program. The reports were sorted by cancer site and document type using a validated algorithm. Joinpoint regression was used to model temporal trends from January 2018-February 2020, project expected counts from March 2020-February 2021 and calculate observed-to-expected ratios. Results were stratified by sex, age, cancer site and report type.
RESULTS: During the first three months of the pandemic, pathology report volume decreased by 25.5% and 17.4% for biopsy and surgery reports, respectively. The 12-month O/E ratio (Mar 2020-Feb 2021) was lowest for women (O/E 0.90) and patients 65 yrs. and older (O/E 0.91) and lower for cancers with screening (melanoma skin, O/E 0.86; breast, O/E 0.88; lung O/E 0.89, prostate, O/E 0.90; colorectal, O/E 0.91) when compared to all other cancers combined.
CONCLUSIONS: These findings indicate a decrease in cancer diagnosis, likely due to the COVID-19 pandemic. This decrease in the number of pathology reports may result in a stage shift causing a subsequent longer-term impact on survival patterns.
IMPACT: Investigation on the longer-term impact of the pandemic on pathology services is vital to understand if cancer care delivery levels continue to be affected.}, }
@article {pmid37594221, year = {2023}, author = {Tverdek, F and Escobar, ZK and Liu, C and Jain, R and Lindsay, J}, title = {Antimicrobials in patients with hematologic malignancies and recipients of hematopoietic cell transplantation and other cellular therapies.}, journal = {Transplant infectious disease : an official journal of the Transplantation Society}, volume = {}, number = {}, pages = {e14129}, doi = {10.1111/tid.14129}, pmid = {37594221}, issn = {1399-3062}, abstract = {BACKGROUND: Appropriate use of antimicrobials for hematologic malignancy, hematopoietic stem cell transplant recipients, and other cellular therapies is vital, with infection causing significant morbidity and mortality in this unique population of immunocompromised hosts. However, often in this population the choice and management of antimicrobial therapy is complex. When selecting an antimicrobial agent, key considerations include the need for dose adjustments due to renal or hepatic impairment, managing drug interactions, the potential for additive drug toxicity among those receiving polypharmacy and therapeutic drug monitoring. Other factors include leveraging pharmacodynamic principles to enable optimization of directed therapy against challenging pathogens, as well as judicious use of antimicrobials to limit drug resistance and adverse drug reactions.
SUMMARY: This review summarizes the clinical considerations for commonly used antimicrobials in this setting, including antibacterial, antiviral, and antifungal agents.}, }
@article {pmid37592104, year = {2023}, author = {VanderWalde, A and Bellasea, SL and Kendra, KL and Khushalani, NI and Campbell, KM and Scumpia, PO and Kuklinski, LF and Collichio, F and Sosman, JA and Ikeguchi, A and Victor, AI and Truong, TG and Chmielowski, B and Portnoy, DC and Chen, Y and Margolin, K and Bane, C and Dasanu, CA and Johnson, DB and Eroglu, Z and Chandra, S and Medina, E and Gonzalez, CR and Baselga-Carretero, I and Vega-Crespo, A and Garcilazo, IP and Sharon, E and Hu-Lieskovan, S and Patel, SP and Grossmann, KF and Moon, J and Wu, MC and Ribas, A}, title = {Ipilimumab with or without nivolumab in PD-1 or PD-L1 blockade refractory metastatic melanoma: a randomized phase 2 trial.}, journal = {Nature medicine}, volume = {}, number = {}, pages = {}, pmid = {37592104}, issn = {1546-170X}, support = {P01 CA244118/CA/NCI NIH HHS/United States ; R35 CA197633/CA/NCI NIH HHS/United States ; }, abstract = {In this randomized phase 2 trial, blockade of cytotoxic T-lymphocyte protein 4 (CTLA-4) with continuation of programmed death protein 1 (PD-1) blockade in patients with metastatic melanoma who had received front-line anti-PD-1 or therapy against programmed cell death 1 ligand 1 and whose tumors progressed was tested in comparison with CTLA-4 blockade alone. Ninety-two eligible patients were randomly assigned in a 3:1 ratio to receive the combination of ipilimumab and nivolumab, or ipilimumab alone. The primary endpoint was progression-free survival. Secondary endpoints included the difference in CD8 T cell infiltrate among responding and nonresponding tumors, objective response rate, overall survival and toxicity. The combination of nivolumab and ipilimumab resulted in a statistically significant improvement in progression-free survival over ipilimumab (hazard ratio = 0.63, 90% confidence interval (CI) = 0.41-0.97, one-sided P = 0.04). Objective response rates were 28% (90% CI = 19-38%) and 9% (90% CI = 2-25%), respectively (one-sided P = 0.05). Grade 3 or higher treatment-related adverse events occurred in 57% and 35% of patients, respectively, which is consistent with the known toxicity profile of these regimens. The change in intratumoral CD8 T cell density observed in the present analysis did not reach statistical significance to support the formal hypothesis tested as a secondary endpoint. In conclusion, primary resistance to PD-1 blockade therapy can be reversed in some patients with the combination of CTLA-4 and PD-1 blockade. Clinicaltrials.gov identifier: NCT03033576 .}, }
@article {pmid37591951, year = {2023}, author = {Duplaquet, L and Li, Y and Booker, MA and Xie, Y and Olsen, SN and Patel, RA and Hong, D and Hatton, C and Denize, T and Walton, E and Laimon, YN and Li, R and Jiang, Y and Bronson, RT and Southard, J and Li, S and Signoretti, S and Qiu, X and Cejas, P and Armstrong, SA and Long, HW and Tolstorukov, MY and Haffner, MC and Oser, MG}, title = {KDM6A epigenetically regulates subtype plasticity in small cell lung cancer.}, journal = {Nature cell biology}, volume = {}, number = {}, pages = {}, pmid = {37591951}, issn = {1476-4679}, support = {CI-101-19//Damon Runyon Cancer Research Foundation (Cancer Research Fund of the Damon Runyon-Walter Winchell Foundation)/ ; K08CA222657//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; R37CA269990//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; R50CA251956//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; CA176745//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; CA066996//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; }, abstract = {Small cell lung cancer (SCLC) exists broadly in four molecular subtypes: ASCL1, NEUROD1, POU2F3 and Inflammatory. Initially, SCLC subtypes were thought to be mutually exclusive, but recent evidence shows intra-tumoural subtype heterogeneity and plasticity between subtypes. Here, using a CRISPR-based autochthonous SCLC genetically engineered mouse model to study the consequences of KDM6A/UTX inactivation, we show that KDM6A inactivation induced plasticity from ASCL1 to NEUROD1 resulting in SCLC tumours that express both ASCL1 and NEUROD1. Mechanistically, KDM6A normally maintains an active chromatin state that favours the ASCL1 subtype with its loss decreasing H3K4me1 and increasing H3K27me3 at enhancers of neuroendocrine genes leading to a cell state that is primed for ASCL1-to-NEUROD1 subtype switching. This work identifies KDM6A as an epigenetic regulator that controls ASCL1 to NEUROD1 subtype plasticity and provides an autochthonous SCLC genetically engineered mouse model to model ASCL1 and NEUROD1 subtype heterogeneity and plasticity, which is found in 35-40% of human SCLCs.}, }
@article {pmid37590895, year = {2023}, author = {Karra, P and Hardikar, S and Winn, M and Anderson, GL and Haaland, B and Krick, B and Thomson, CA and Shadyab, A and Luo, J and Saquib, N and Strickler, HD and Chlebowski, R and Arthur, RS and Summers, SA and Holland, WL and Jalili, T and Playdon, MC}, title = {New-onset diabetes after an obesity-related cancer diagnosis and survival outcomes in the Women's Health Initiative.}, journal = {Cancer epidemiology, biomarkers & 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-23-0278}, pmid = {37590895}, issn = {1538-7755}, abstract = {BACKGROUND: Individuals diagnosed with an obesity-related cancer (ORC survivors) are at an elevated risk of incident diabetes compared to cancer-free individuals, but whether this confers survival disadvantage is unknown.
METHODS: We assessed the rate of incident diabetes in ORC survivors and evaluated the association of incident diabetes with all-cause and cancer-specific mortality among females with ORC in the Women's Health Initiative (WHI) cohort (N=14,651). Cox proportional hazards regression models stratified by exposure risk periods (0-1, >1-3, >3-5, >5-7, and >7-10 years) from ORC diagnosis and time-varying exposure (diabetes) analyses were performed.
RESULTS: Among the ORC survivors, a total of 1.3% developed diabetes within 1 year of follow-up and 2.5%, 2.3%, 2.3%, 3.6% at 1-3, 3-5, 5-7, and 7-10 years of follow-up respectively after an ORC diagnosis. The median survival 1 year after cancer diagnosis among those with versus without diabetes was 8.8 (95% CI=7.0-14.5) years and 16.6 (95% CI=16.1-17.0) years, respectively. New-onset diabetes as a time-varying exposure was associated with higher risk of all-cause (HR 1.27, 95% CI=1.16-1.40) and cancer-specific (HR 1.17, 95% CI=0.99-1.38) mortality. When stratified by exposure risk periods, incident diabetes in 1 year of follow-up was associated with higher all-cause (HR 1.76, 95% CI=1.40-2.20) and cancer-specific (HR0-1 1.82, 95% CI=1.28-2.57) mortality, compared with no diabetes diagnosis.
CONCLUSION: Incident diabetes was associated with worse cancer-specific and all-cause survival, particularly in the year after cancer diagnosis.
IMPACT: These findings draw attention to the importance of diabetes prevention efforts among cancer survivors to improve survival outcomes.}, }
@article {pmid37590492, year = {2023}, author = {Watt, GP and Smith, SA and Howell, RM and Pérez-Andújar, A and Reiner, AS and Cerviño, L and McCormick, B and Hess, D and Knight, JA and Malone, KE and John, EM and Bernstein, L and Lynch, CF and Mellemkjær, L and Shore, RE and Liang, X and Woods, M and Boice, JD and Dauer, LT and Bernstein, JL}, title = {Trends in Radiation Dose to the Contralateral Breast During Breast Cancer Radiation Therapy.}, journal = {Radiation research}, volume = {}, number = {}, pages = {}, doi = {10.1667/RADE-23-00014.1}, pmid = {37590492}, issn = {1938-5404}, abstract = {Over 4 million survivors of breast cancer live in the United States, 35% of whom were treated before 2009. Approximately half of patients with breast cancer receive radiation therapy, which exposes the untreated contralateral breast to radiation and increases the risk of a subsequent contralateral breast cancer (CBC). Radiation oncology has strived to reduce unwanted radiation dose, but it is unknown whether a corresponding decline in actual dose received to the untreated contralateral breast has occurred. The purpose of this study was to evaluate trends in unwanted contralateral breast radiation dose to inform risk assessment of second primary cancer in the contralateral breast for long-term survivors of breast cancer. Individually estimated radiation absorbed doses to the four quadrants and areola central area of the contralateral breast were estimated for 2,132 women treated with radiation therapy for local/regional breast cancers at age <55 years diagnosed between 1985 and 2008. The two inner quadrant doses and two outer quadrant doses were averaged. Trends in dose to each of the three areas of the contralateral breast were evaluated in multivariable models. The population impact of reducing contralateral breast dose on the incidence of radiation-associated CBC was assessed by estimating population attributable risk fraction (PAR) in a multivariable model. The median dose to the inner quadrants of the contralateral breast was 1.70 Gy; to the areola, 1.20 Gy; and to the outer quadrants, 0.72 Gy. Ninety-two percent of patients received ≥1 Gy to the inner quadrants. For each calendar year of diagnosis, dose declined significantly for each location, most rapidly for the inner quadrants (0.04 Gy/year). Declines in dose were similar across subgroups defined by age at diagnosis and body mass index. The PAR for CBC due to radiation exposure >1 Gy for women <40 years of age was 17%. Radiation dose-reduction measures have reduced dose to the contralateral breast during breast radiation therapy. Reducing the dose to the contralateral breast to <1 Gy could prevent an estimated 17% of subsequent radiation-associated CBCs for women treated under 40 years of age. These dose estimates inform CBC surveillance for the growing number of breast cancer survivors who received radiation therapy as young women in recent decades. Continued reductions in dose to the contralateral breast could further reduce the incidence of radiation-associated CBC.}, }
@article {pmid37590003, year = {2023}, author = {Unger, JM and Xiao, H and Vaidya, R and LeBlanc, M and Hershman, DL}, title = {Medicaid Expansion of the Patient Protection and Affordable Care Act and Participation of Patients With Medicaid in Cancer Clinical Trials.}, journal = {JAMA oncology}, volume = {}, number = {}, pages = {}, pmid = {37590003}, issn = {2374-2445}, abstract = {IMPORTANCE: The Patient Protection and Affordable Care Act (ACA) Medicaid expansion resulted in increased use of Medicaid insurance nationwide. However, the association between Medicaid expansion and access to clinical trials has not been examined to date.
OBJECTIVE: To examine whether the implementation of ACA Medicaid expansion was associated with increased participation of patients with Medicaid insurance in cancer clinical trials.
Data for this cohort study of 51 751 patients were from the SWOG Cancer Research Network. All patients aged 18 to 64 years and enrolled in treatment trials with Medicaid or private insurance between April 1, 1992, and February 29, 2020, were included. Interrupted time-series analysis with segmented logistic regression was used. The monthly unemployment rate and presidential administration were adjusted to reflect potential differences in Medicaid use associated with economic conditions and national administrative policies, respectively. Data analysis was conducted between June 22, 2021, and August 5, 2022.
EXPOSURE: Implementation of Medicaid expansion on January 1, 2014, was the independent exposure variable.
MAIN OUTCOMES AND MEASURES: The number and proportion of patients by insurance type enrolled in cancer clinical trials over time were analyzed.
RESULTS: Overall, data for 51 751 patients were analyzed. Mean (SD) age was 50.6 (9.8) years, 67.3% of patients were female, 41.1% were younger than 50 years, and 9.1% used Medicaid. A 19% annual increase (odds ratio [OR], 1.19; 95% CI, 1.11-1.28; P < .001) was identified in the odds of patients using Medicaid after the ACA Medicaid expansion, resulting in a 52% increase (OR, 1.52; 95% CI, 1.29-1.78; P < .001) compared with what was expected in the number of Medicaid patients enrolled over time. The association was greater in states that adopted Medicaid expansion in 2014 to 2015 (OR, 1.26; 95% CI, 1.15-1.38; P < .001) compared with other states (OR, 1.08; 95% CI, 0.96-1.21; P = .20; P = .04 for interaction). By February 2020, the proportion of patients with Medicaid insurance was 17.8% (95% CI, 15.0%-20.8%; P < .001), whereas the expected proportion had ACA Medicaid expansion not occurred was 6.9% (95% CI, 4.4%-10.3%; P < .001).
CONCLUSIONS AND RELEVANCE: Findings suggest that implementation of ACA Medicaid expansion was associated with increased participation of patients using Medicaid in cancer clinical trials. Improved participation in clinical trials for Medicaid-insured patients is critical for socioeconomically vulnerable patients seeking access to the newest treatments available in trials and for improving confidence that trial findings apply to patients of all backgrounds.}, }
@article {pmid37589970, year = {2023}, author = {Gulati, S and Hsu, CY and Shah, S and Shah, PK and Zon, R and Alsamarai, S and Awosika, J and El-Bakouny, Z and Bashir, B and Beeghly, A and Berg, S and de-la-Rosa-Martinez, D and Doroshow, DB and Egan, PC and Fein, J and Flora, DB and Friese, CR and Fromowitz, A and Griffiths, EA and Hwang, C and Jani, C and Joshi, M and Khan, H and Klein, EJ and Heater, NK and Koshkin, VS and Kwon, DH and Labaki, C and Latif, T and McKay, RR and Nagaraj, G and Nakasone, ES and Nonato, T and Polimera, HV and Puc, M and Razavi, P and Ruiz-Garcia, E and Saliby, RM and Shastri, A and Singh, SRK and Tagalakis, V and Vilar-Compte, D and Weissmann, LB and Wilkins, CR and Wise-Draper, TM and Wotman, MT and Yoon, JJ and Mishra, S and Grivas, P and Shyr, Y and Warner, JL and Connors, JM and Shah, DP and Rosovsky, RP and , }, title = {Systemic Anticancer Therapy and Thromboembolic Outcomes in Hospitalized Patients With Cancer and COVID-19.}, journal = {JAMA oncology}, volume = {}, number = {}, pages = {}, pmid = {37589970}, issn = {2374-2445}, abstract = {IMPORTANCE: Systematic data on the association between anticancer therapies and thromboembolic events (TEEs) in patients with COVID-19 are lacking.
OBJECTIVE: To assess the association between anticancer therapy exposure within 3 months prior to COVID-19 and TEEs following COVID-19 diagnosis in patients with cancer.
This registry-based retrospective cohort study included patients who were hospitalized and had active cancer and laboratory-confirmed SARS-CoV-2 infection. Data were accrued from March 2020 to December 2021 and analyzed from December 2021 to October 2022.
EXPOSURE: Treatments of interest (TOIs) (endocrine therapy, vascular endothelial growth factor inhibitors/tyrosine kinase inhibitors [VEGFis/TKIs], immunomodulators [IMiDs], immune checkpoint inhibitors [ICIs], chemotherapy) vs reference (no systemic therapy) in 3 months prior to COVID-19.
MAIN OUTCOMES AND MEASURES: Main outcomes were (1) venous thromboembolism (VTE) and (2) arterial thromboembolism (ATE). Secondary outcome was severity of COVID-19 (rates of intensive care unit admission, mechanical ventilation, 30-day all-cause mortality following TEEs in TOI vs reference group) at 30-day follow-up.
RESULTS: Of 4988 hospitalized patients with cancer (median [IQR] age, 69 [59-78] years; 2608 [52%] male), 1869 had received 1 or more TOIs. Incidence of VTE was higher in all TOI groups: endocrine therapy, 7%; VEGFis/TKIs, 10%; IMiDs, 8%; ICIs, 12%; and chemotherapy, 10%, compared with patients not receiving systemic therapies (6%). In multivariable log-binomial regression analyses, relative risk of VTE (adjusted risk ratio [aRR], 1.33; 95% CI, 1.04-1.69) but not ATE (aRR, 0.81; 95% CI, 0.56-1.16) was significantly higher in those exposed to all TOIs pooled together vs those with no exposure. Among individual drugs, ICIs were significantly associated with VTE (aRR, 1.45; 95% CI, 1.01-2.07). Also noted were significant associations between VTE and active and progressing cancer (aRR, 1.43; 95% CI, 1.01-2.03), history of VTE (aRR, 3.10; 95% CI, 2.38-4.04), and high-risk site of cancer (aRR, 1.42; 95% CI, 1.14-1.75). Black patients had a higher risk of TEEs (aRR, 1.24; 95% CI, 1.03-1.50) than White patients. Patients with TEEs had high intensive care unit admission (46%) and mechanical ventilation (31%) rates. Relative risk of death in patients with TEEs was higher in those exposed to TOIs vs not (aRR, 1.12; 95% CI, 0.91-1.38) and was significantly associated with poor performance status (aRR, 1.77; 95% CI, 1.30-2.40) and active/progressing cancer (aRR, 1.55; 95% CI, 1.13-2.13).
CONCLUSIONS AND RELEVANCE: In this cohort study, relative risk of developing VTE was high among patients receiving TOIs and varied by the type of therapy, underlying risk factors, and demographics, such as race and ethnicity. These findings highlight the need for close monitoring and perhaps personalized thromboprophylaxis to prevent morbidity and mortality associated with COVID-19-related thromboembolism in patients with cancer.}, }
@article {pmid37589839, year = {2023}, author = {Lenz, L and Neff, C and Solimeno, C and Cogan, ES and Abramson, VG and Boughey, JC and Falkson, C and Goetz, MP and Ford, JM and Gradishar, WJ and Jankowitz, RC and Kaklamani, VG and Marcom, PK and Richardson, AL and Storniolo, AM and Tung, NM and Vinayak, S and Hodgson, DR and Lai, Z and Dearden, S and Hennessy, BT and Mayer, EL and Mills, GB and Slavin, TP and Gutin, A and Connolly, RM and Telli, ML and Stearns, V and Lanchbury, JS and Timms, KM}, title = {Identifying homologous recombination deficiency in breast cancer: genomic instability score distributions differ among breast cancer subtypes.}, journal = {Breast cancer research and treatment}, volume = {}, number = {}, pages = {}, pmid = {37589839}, issn = {1573-7217}, support = {Myriad Genetics//Myriad Genetics/ ; }, abstract = {PURPOSE: A 3-biomarker homologous recombination deficiency (HRD) score is a key component of a currently FDA-approved companion diagnostic assay to identify HRD in patients with ovarian cancer using a threshold score of ≥ 42, though recent studies have explored the utility of a lower threshold (GIS ≥ 33). The present study evaluated whether the ovarian cancer thresholds may also be appropriate for major breast cancer subtypes by comparing the genomic instability score (GIS) distributions of BRCA1/2-deficient estrogen receptor-positive breast cancer (ER + BC) and triple-negative breast cancer (TNBC) to the GIS distribution of BRCA1/2-deficient ovarian cancer.
METHODS: Ovarian cancer and breast cancer (ER + BC and TNBC) tumors from ten study cohorts were sequenced to identify pathogenic BRCA1/2 mutations, and GIS was calculated using a previously described algorithm. Pathologic complete response (pCR) to platinum therapy was evaluated in a subset of TNBC samples. For TNBC, a threshold was set and threshold validity was assessed relative to clinical outcomes.
RESULTS: A total of 560 ovarian cancer, 805 ER + BC, and 443 TNBC tumors were included. Compared to ovarian cancer, the GIS distribution of BRCA1/2-deficient samples was shifted lower for ER + BC (p = 0.015), but not TNBC (p = 0.35). In the subset of TNBC samples, univariable logistic regression models revealed that GIS status using thresholds of ≥ 42 and ≥ 33 were significant predictors of response to platinum therapy.
CONCLUSIONS: This study demonstrated that the GIS thresholds used for ovarian cancer may also be appropriate for TNBC, but not ER + BC. GIS thresholds in TNBC were validated using clinical response data to platinum therapy.}, }
@article {pmid37587851, year = {2023}, author = {Sather, CL and Yang, P and Zhang, C and Fitzgibbon, MP and Fournier, M and Toloza, E and Tandon, A and Schabath, M and Yoder, S and Nair, VS}, title = {Protocol optimization of a targeted sequencing panel for genomic profiling of bronchoalveolar lavage fluid in lung cancer.}, journal = {Cancer medicine}, volume = {}, number = {}, pages = {}, doi = {10.1002/cam4.6380}, pmid = {37587851}, issn = {2045-7634}, support = {U01CA253166/NH/NIH HHS/United States ; }, abstract = {INTRODUCTION: We investigated a commercially available sequencing panel to study the effect of sequencing depth, variant calling strategy, and targeted sequencing region on identifying tumor-derived variants in cell-free bronchoalveolar lavage (cfBAL) DNA compared with plasma cfDNA.
METHODS: Sequencing was performed at low or high coverage using two filtering algorithms to identify tumor variants on two panels targeting 77 and 197 genes respectively.
RESULTS: One hundred and four sequencing files from 40 matched DNA samples of cfBAL, plasma, germline leukocytes, and archival tumor specimens in 10 patients with early-stage lung cancer were analyzed. By low-coverage sequencing, tumor-derived cfBAL variants were detected in 4/10 patients (40%) compared with 2/10 (20%) for plasma. High-coverage sequencing did not affect the number of tumor-derived variants detected in either biospecimen type. Accounting for germline mutations eliminated false-positive plasma calls regardless of coverage (0/10 patients with tumor-derived variants identified) and increased the number of cfBAL calls (5/10 patients with tumor-derived variants identified). These results were not affected by the number of targeted genes.}, }
@article {pmid37587260, year = {2023}, author = {Eifert, T and Hsu, CJ and Becker, AL and Graessle, S and Horne, A and Bemmann, F and Zhang, Q and Heuser, M and Vasioukhin, V and Scholl, S and Hochhaus, A and Siegerist, F and Endlich, N and Bullinger, L and Lane, SW and Haas, S and Schnoeder, TM and Heidel, FH}, title = {Cell fate determinant Llgl1 is required for propagation of acute myeloid leukemia.}, journal = {Leukemia}, volume = {}, number = {}, pages = {}, pmid = {37587260}, issn = {1476-5551}, support = {HE6233/2-1//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; 70112607//Deutsche Krebshilfe (German Cancer Aid)/ ; }, abstract = {Scribble complex proteins can influence cell fate decisions and self-renewal capacity of hematopoietic cells. While specific cellular functions of Scribble complex members are conserved in mammalian hematopoiesis, they appear to be highly context dependent. Using CRISPR/Cas9-based genetic screening, we have identified Scribble complex-related liabilities in AML including LLGL1. Despite its reported suppressive function in HSC self-renewal, inactivation of LLGL1 in AML confirms its relevant role for proliferative capacity and development of AML. Its function was conserved in human and murine models of AML and across various genetic backgrounds. Inactivation of LLGL1 results in loss of stemness-associated gene-expression including HoxA-genes and induces a GMP-like phenotype in the leukemia stem cell compartment. Re-expression of HoxA9 facilitates functional and phenotypic rescue. Collectively, these data establish LLGL1 as a specific dependency and putative target in AML and emphasizes its cell-type specific functions.}, }
@article {pmid37584517, year = {2023}, author = {Modi, A and Lopez, G and Conkrite, KL and Su, C and Leung, TC and Ramanan, S and Manduchi, E and Johnson, ME and Cheung, D and Gadd, S and Zhang, J and Smith, MA and Guidry Auvil, JM and Meshinchi, S and Perlman, EJ and Hunger, SP and Maris, JM and Wells, AD and Grant, SFA and Diskin, SJ}, title = {Integrative genomic analyses identify lncRNA regulatory networks across pediatric leukemias and solid tumors.}, journal = {Cancer research}, volume = {}, number = {}, pages = {}, doi = {10.1158/0008-5472.CAN-22-3186}, pmid = {37584517}, issn = {1538-7445}, abstract = {Long non-coding RNAs (lncRNAs) play an important role in gene regulation and contribute to tumorigenesis. While pan-cancer studies of lncRNA expression have been performed for adult malignancies, the lncRNA landscape across pediatric cancers remains largely uncharted. Here, we curated RNA sequencing data for 1,044 pediatric leukemia and extra-cranial solid tumors and integrated paired tumor whole genome sequencing and epigenetic data in relevant cell line models to explore lncRNA expression, regulation, and association with cancer. A total of 2,657 lncRNAs were robustly expressed across six pediatric cancers, including 1,142 exhibiting histotype-elevated expression. DNA copy number alterations contributed to lncRNA dysregulation at a proportion comparable to protein coding genes. Application of a multi-dimensional framework to identify and prioritize lncRNAs impacting gene networks revealed that lncRNAs dysregulated in pediatric cancer are associated with proliferation, metabolism, and DNA damage hallmarks. Analysis of upstream regulation via cell-type specific transcription factors further implicated distinct histotype-elevated and developmental lncRNAs. Integration of these analyses prioritized lncRNAs for experimental validation, and silencing of TBX2-AS1, the top-prioritized neuroblastoma-specific lncRNA, resulted in significant growth inhibition of neuroblastoma cells, confirming the computational predictions. Taken together, these data provide a comprehensive characterization of lncRNA regulation and function in pediatric cancers and pave the way for future mechanistic studies.}, }
@article {pmid37584286, year = {2023}, author = {Kwon, R and Yeung, CCS}, title = {Advances in next-generation sequencing and emerging technologies for haematologic malignancies.}, journal = {Haematologica}, volume = {}, number = {}, pages = {}, doi = {10.3324/haematol.2022.282442}, pmid = {37584286}, issn = {1592-8721}, abstract = {Innovations in molecular diagnostics have often evolved through the study of haematologic malignancies. Examples include the pioneering characterization of the Philadelphia chromosome by cytogenetics in the 1970s, the implementation of PCR for high-sensitivity detection and monitoring of mutations, and, most recent, targeted next-generation sequencing (NGS) to drive the prognostic and therapeutic assessment of leukaemia. Haematologists and haematopathologists continue to advance with new innovations in the past decade by improving the type, amount, and quality of data generated for each molecule of nucleic acid. In this review article, we will touch on these new developments and discuss their implications for diagnostics in haematopoietic malignancies. We will review advances in sequencing platforms and library preparation chemistry that can lead to faster turnaround times; novel sequencing techniques; the development of mobile labs with implications for worldwide benefits; the current status of sample types; improvements to quality and reference materials; bioinformatic pipelines; and the integration of machine learning and artificial intelligence into molecular diagnostic tools for haematologic malignancies.}, }
@article {pmid37584167, year = {2023}, author = {Lyman, GH and Lyman, CH and Kuderer, NM}, title = {PERCEPTION, COGNITION AND THOUGHT: Part IV Consciousness, Awareness, and "I".}, journal = {Cancer investigation}, volume = {}, number = {}, pages = {1-8}, doi = {10.1080/07357907.2023.2248785}, pmid = {37584167}, issn = {1532-4192}, }
@article {pmid37582946, year = {2023}, author = {Tolkach, Y and Ovtcharov, V and Pryalukhin, A and Eich, ML and Gaisa, NT and Braun, M and Radzhabov, A and Quaas, A and Hammerer, P and Dellmann, A and Hulla, W and Haffner, MC and Reis, H and Fahoum, I and Samarska, I and Borbat, A and Pham, H and Heidenreich, A and Klein, S and Netto, G and Caie, P and Buettner, R}, title = {An international multi-institutional validation study of the algorithm for prostate cancer detection and Gleason grading.}, journal = {NPJ precision oncology}, volume = {7}, number = {1}, pages = {77}, pmid = {37582946}, issn = {2397-768X}, abstract = {Pathologic examination of prostate biopsies is time consuming due to the large number of slides per case. In this retrospective study, we validate a deep learning-based classifier for prostate cancer (PCA) detection and Gleason grading (AI tool) in biopsy samples. Five external cohorts of patients with multifocal prostate biopsy were analyzed from high-volume pathology institutes. A total of 5922 H&E sections representing 7473 biopsy cores from 423 patient cases (digitized using three scanners) were assessed concerning tumor detection. Two tumor-bearing datasets (core n = 227 and 159) were graded by an international group of pathologists including expert urologic pathologists (n = 11) to validate the Gleason grading classifier. The sensitivity, specificity, and NPV for the detection of tumor-bearing biopsies was in a range of 0.971-1.000, 0.875-0.976, and 0.988-1.000, respectively, across the different test cohorts. In several biopsy slides tumor tissue was correctly detected by the AI tool that was initially missed by pathologists. Most false positive misclassifications represented lesions suspicious for carcinoma or cancer mimickers. The quadratically weighted kappa levels for Gleason grading agreement for single pathologists was 0.62-0.80 (0.77 for AI tool) and 0.64-0.76 (0.72 for AI tool) for the two grading datasets, respectively. In cases where consensus for grading was reached among pathologists, kappa levels for AI tool were 0.903 and 0.855. The PCA detection classifier showed high accuracy for PCA detection in biopsy cases during external validation, independent of the institute and scanner used. High levels of agreement for Gleason grading were indistinguishable between experienced genitourinary pathologists and the AI tool.}, }
@article {pmid37582233, year = {2023}, author = {Nagana Gowda, GA and Pascua, V and Raftery, D}, title = {Anomalous Dynamics of Labile Metabolites in Cold Human Blood Detected Using [1]H NMR Spectroscopy.}, journal = {Analytical chemistry}, volume = {}, number = {}, pages = {}, doi = {10.1021/acs.analchem.3c02478}, pmid = {37582233}, issn = {1520-6882}, support = {R01 GM131491/GM/NIGMS NIH HHS/United States ; R01 GM138465/GM/NIGMS NIH HHS/United States ; }, abstract = {Recent efforts in our laboratory have enabled access to an unprecedented number (∼90) of quantifiable metabolites in human blood by a simple nuclear magnetic resonance (NMR) spectroscopy method, which includes energy coenzymes, redox coenzymes, and antioxidants that are fundamental to cellular functions [ J. Magn. Reson. Open 2022, 12-13, 100082]. The coenzymes and antioxidants, however, are notoriously labile and are extremely sensitive to specimen harvesting, extraction, and measurement conditions. This problem is largely underappreciated and carries the risk of grossly inaccurate measurements and incorrect study outcomes. As a part of addressing this challenge, in this study, human blood specimens were comprehensively and quantitatively investigated using [1]H NMR spectroscopy. Freshly drawn human blood specimens were treated or not treated with methanol, ethanol, or a mixture of methanol and chloroform, and stored on ice or on bench, at room temperature for different time periods from 0 to 24 h, prior to storing at -80 °C. Interestingly, the labile metabolite levels were stable in blood treated with an organic solvent. However, their levels in blood in untreated samples increased or decreased by factors of up to 5 or more within 3 h. Further, surprisingly, and contrary to the current knowledge about metabolite stability, the variation of coenzyme levels was more dramatic in blood stored on ice than on bench, at room temperature. In addition, unlike the generally observed phenomenon of oxidation of redox coenzymes, reduction was observed in untreated blood. Such preanalytical dynamics of the labile metabolites potentially arises from the active cellular metabolism. From the metabolomics perspective, the massive variation of the labile metabolite levels even in blood stored on ice is alarming and stresses the critical need to immediately quench the cellular metabolism for reliable analyses. Overall, the results provide compelling evidence that warrants a paradigm shift in the sample collection protocol for blood metabolomics involving labile metabolites.}, }
@article {pmid37581498, year = {2023}, author = {Lawson, MB and Partridge, SC and Hippe, DS and Rahbar, H and Lam, DL and Lee, CI and Lowry, KP and Scheel, JR and Parsian, S and Li, I and Biswas, D and Bryant, ML and Lee, JM}, title = {Comparative Performance of Contrast-enhanced Mammography, Abbreviated Breast MRI, and Standard Breast MRI for Breast Cancer Screening.}, journal = {Radiology}, volume = {308}, number = {2}, pages = {e230576}, doi = {10.1148/radiol.230576}, pmid = {37581498}, issn = {1527-1315}, support = {R01 CA207290/CA/NCI NIH HHS/United States ; R37 CA240403/CA/NCI NIH HHS/United States ; R13 CA275171/CA/NCI NIH HHS/United States ; R01 CA203883/CA/NCI NIH HHS/United States ; }, mesh = {Female ; Humans ; Middle Aged ; *Breast Neoplasms/diagnostic imaging/pathology ; Prospective Studies ; Sensitivity and Specificity ; Early Detection of Cancer/methods ; Mammography/methods ; Magnetic Resonance Imaging/methods ; }, abstract = {Background Contrast-enhanced mammography (CEM) and abbreviated breast MRI (ABMRI) are emerging alternatives to standard MRI for supplemental breast cancer screening. Purpose To compare the diagnostic performance of CEM, ABMRI, and standard MRI. Materials and Methods This single-institution, prospective, blinded reader study included female participants referred for breast MRI from January 2018 to June 2021. CEM was performed within 14 days of standard MRI; ABMRI was produced from standard MRI images. Two readers independently interpreted each CEM and ABMRI after a washout period. Examination-level performance metrics calculated were recall rate, cancer detection, and false-positive biopsy recommendation rates per 1000 examinations and sensitivity, specificity, and positive predictive value of biopsy recommendation. Bootstrap and permutation tests were used to calculate 95% CIs and compare modalities. Results Evaluated were 492 paired CEM and ABMRI interpretations from 246 participants (median age, 51 years; IQR, 43-61 years). On 49 MRI scans with lesions recommended for biopsy, nine lesions showed malignant pathology. No differences in ABMRI and standard MRI performance were identified. Compared with standard MRI, CEM demonstrated significantly lower recall rate (14.0% vs 22.8%; difference, -8.7%; 95% CI: -14.0, -3.5), lower false-positive biopsy recommendation rate per 1000 examinations (65.0 vs 162.6; difference, -97.6; 95% CI: -146.3, -50.8), and higher specificity (87.8% vs 80.2%; difference, 7.6%; 95% CI: 2.3, 13.1). Compared with standard MRI, CEM had significantly lower cancer detection rate (22.4 vs 36.6; difference, -14.2; 95% CI: -28.5, -2.0) and sensitivity (61.1% vs 100%; difference, -38.9%; 95% CI: -66.7, -12.5). The performance differences between CEM and ABMRI were similar to those observed between CEM and standard MRI. Conclusion ABMRI had comparable performance to standard MRI and may support more efficient MRI screening. CEM had lower recall and higher specificity compared with standard MRI or ABMRI, offset by lower cancer detection rate and sensitivity compared with standard MRI. These trade-offs warrant further consideration of patient population characteristics before widespread screening with CEM. Clinical trial registration no. NCT03517813 © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Chang in this issue.}, }
@article {pmid37581231, year = {2023}, author = {Ortiz-Espinosa, S and Srivastava, S}, title = {Bursting Tumor Bubbles to Improve CAR T-cell Therapy.}, journal = {Cancer research}, volume = {83}, number = {16}, pages = {2637-2639}, doi = {10.1158/0008-5472.CAN-23-1484}, pmid = {37581231}, issn = {1538-7445}, mesh = {Humans ; *Immunotherapy, Adoptive ; *B7-H1 Antigen ; Receptors, Antigen, T-Cell/genetics/immunology ; Cell Line, Tumor ; T-Lymphocytes/immunology ; }, abstract = {Chimeric antigen receptor (CAR) T cells have had dramatic success in B-cell malignancies, but this efficacy has not yet translated to more common solid tumors. In this issue of Cancer Research, Zhong and colleagues demonstrated that tumor-derived small extracellular vesicles (sEV) contain CAR target antigens like mesothelin, enabling them to preferentially interact with and suppress the activity of CAR T cells in vivo. PD-L1 in tumor-derived sEVs increased upon CAR T-cell infusion and induced PD-L1-dependent suppression of CAR T cells that could be completely reversed by PD-L1 blockade. Strategies to inhibit sEV secretion, via genetic manipulation of tumor cells or pharmacologic inhibition, significantly improved CAR T-cell accumulation, function, and antitumor activity in vivo, suggesting that therapeutic targeting of sEV secretion could be a promising new approach to improving the efficacy of CAR T-cell therapy. See related article by Zhong et al., p. 2790.}, }
@article {pmid37579304, year = {2023}, author = {Banerjee, SC and Malling, CD and Shen, MJ and Williamson, TJ and Bylund, CL and Studts, JL and Mullett, T and Carter-Bawa, L and Hamann, HA and Parker, PA and Steliga, M and Feldman, J and Pantelas, J and Borondy-Kitts, A and Rigney, M and King, JC and Fathi, JT and Rosenthal, LS and Smith, RA and Ostroff, JS}, title = {Getting ready for prime time: Recommended adaptations of an Empathic Communication Skills training intervention to reduce lung cancer stigma for a national multi-center trial.}, journal = {Translational behavioral medicine}, volume = {}, number = {}, pages = {}, doi = {10.1093/tbm/ibad048}, pmid = {37579304}, issn = {1613-9860}, support = {R01CA255522/CA/NCI NIH HHS/United States ; }, abstract = {Building upon prior work developing and pilot testing a provider-focused Empathic Communication Skills (ECS) training intervention, this study sought feedback from key invested partners who work with individuals with lung cancer (i.e. stakeholders including scientific and clinical advisors and patient advocates) on the ECS training intervention. The findings will be used to launch a national virtually-delivered multi-center clinical trial that will examine the effectiveness and implementation of the evidence-based ECS training intervention to reduce patients' experience of lung cancer stigma. A 1-day, hybrid, key invested partners meeting was held in New York City in Fall 2021. We presented the ECS training intervention to all conference attendees (N = 25) to seek constructive feedback on modifications of the training content and platform for intervention delivery to maximize its impact. After participating in the immersive training, all participants engaged in a group discussion guided by semi-structured probes. A deductive thematic content analysis was conducted to code focus group responses into 12 distinct a priori content modification recommendations. Content refinement was suggested in 8 of the 12 content modification themes: tailoring/tweaking/refining, adding elements, removing elements, shortening/condensing content, lengthening/extending content, substituting elements, re-ordering elements, and repeating elements. Engagement and feedback from key invested multi-sector partner is a valuable resource for intervention content modifications. Using a structured format for refining evidence-based interventions can facilitate efforts to understand the nature of modifications required for scaling up interventions and the impact of these modifications on outcomes of interest. ClinicalTrials.gov Identifier: NCT05456841.}, }
@article {pmid37578979, year = {2023}, author = {Murillo, OD and Petrosyan, V and LaPlante, EL and Dobrolecki, LE and Lewis, MT and Milosavljevic, A}, title = {Deconvolution of cancer cell states by the XDec-SM method.}, journal = {PLoS computational biology}, volume = {19}, number = {8}, pages = {e1011365}, doi = {10.1371/journal.pcbi.1011365}, pmid = {37578979}, issn = {1553-7358}, abstract = {Proper characterization of cancer cell states within the tumor microenvironment is a key to accurately identifying matching experimental models and the development of precision therapies. To reconstruct this information from bulk RNA-seq profiles, we developed the XDec Simplex Mapping (XDec-SM) reference-optional deconvolution method that maps tumors and the states of constituent cells onto a biologically interpretable low-dimensional space. The method identifies gene sets informative for deconvolution from relevant single-cell profiling data when such profiles are available. When applied to breast tumors in The Cancer Genome Atlas (TCGA), XDec-SM infers the identity of constituent cell types and their proportions. XDec-SM also infers cancer cells states within individual tumors that associate with DNA methylation patterns, driver somatic mutations, pathway activation and metabolic coupling between stromal and breast cancer cells. By projecting tumors, cancer cell lines, and PDX models onto the same map, we identify in vitro and in vivo models with matching cancer cell states. Map position is also predictive of therapy response, thus opening the prospects for precision therapy informed by experiments in model systems matched to tumors in vivo by cancer cell state.}, }
@article {pmid37578112, year = {2023}, author = {Constantinescu, AE and Bull, CJ and Jones, N and Mitchell, R and Burrows, K and Dimou, N and Bézieau, S and Brenner, H and Buchanan, DD and D'Amato, M and Jenkins, MA and Moreno, V and Pai, RK and Um, CY and White, E and Murphy, N and Gunter, M and Timpson, NJ and Huyghe, JR and Vincent, EE}, title = {Circulating white blood cell traits and colorectal cancer risk: A Mendelian randomisation study.}, journal = {International journal of cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/ijc.34691}, pmid = {37578112}, issn = {1097-0215}, support = {C18281/A29019/CRUK_/Cancer Research UK/United Kingdom ; 17/0005587/DUK_/Diabetes UK/United Kingdom ; MC_UU_00011/1/MRC_/Medical Research Council/United Kingdom ; MC_UU_00011/4/MRC_/Medical Research Council/United Kingdom ; MR/N0137941/1/MRC_/Medical Research Council/United Kingdom ; R21CA230486/CA/NCI NIH HHS/United States ; 202802/Z/16/Z/WT_/Wellcome Trust/United Kingdom ; 204813/Z/16/Z/WT_/Wellcome Trust/United Kingdom ; 217065/Z/19/Z/WT_/Wellcome Trust/United Kingdom ; }, abstract = {Observational studies have suggested a protective role for eosinophils in colorectal cancer (CRC) development and implicated neutrophils, but the causal relationships remain unclear. Here, we aimed to estimate the causal effect of circulating white blood cell (WBC) counts (N = ~550 000) for basophils, eosinophils, monocytes, lymphocytes and neutrophils on CRC risk (N = 52 775 cases and 45 940 controls) using Mendelian randomisation (MR). For comparison, we also examined this relationship using individual-level data from UK Biobank (4043 incident CRC cases and 332 773 controls) in a longitudinal cohort analysis. The inverse-variance weighted (IVW) MR analysis suggested a protective effect of increased basophil count and eosinophil count on CRC risk [OR per 1-SD increase: 0.88, 95% CI: 0.78-0.99, P = .04; OR: 0.93, 95% CI: 0.88-0.98, P = .01]. The protective effect of eosinophils remained [OR per 1-SD increase: 0.88, 95% CI: 0.80-0.97, P = .01] following adjustments for all other WBC subtypes, to account for genetic correlation between the traits, using multivariable MR. A protective effect of increased lymphocyte count on CRC risk was also found [OR: 0.84, 95% CI: 0.76-0.93, P = 6.70e-4] following adjustment. Consistent with MR results, a protective effect for eosinophils in the cohort analysis in the fully adjusted model [RR per 1-SD increase: 0.96, 95% CI: 0.93-0.99, P = .02] and following adjustment for the other WBC subtypes [RR: 0.96, 95% CI: 0.93-0.99, P = .001] was observed. Our study implicates peripheral blood immune cells, in particular eosinophils and lymphocytes, in CRC development, highlighting a need for mechanistic studies to interrogate these relationships.}, }
@article {pmid37577924, year = {2023}, author = {Eichenberger, EM and Zamora, D and Schaenman, J and Hill, JA}, title = {Like watching a soccer game through a keyhole: Cytomegalovirus cell-mediated immunity incompletely reveals risk for clinically significant cytomegalovirus reactivation in cord blood transplant recipients.}, journal = {Transplant infectious disease : an official journal of the Transplantation Society}, volume = {}, number = {}, pages = {e14116}, doi = {10.1111/tid.14116}, pmid = {37577924}, issn = {1399-3062}, }
@article {pmid37577112, year = {2023}, author = {Shapiro, AE and Sarkis, E and Acloque, J and Free, A and Gonzalez-Rojas, Y and Hussain, R and Juarez, E and Moya, J and Parikh, N and Inman, D and Cebrik, D and Nader, A and Noormohamed, N and Wang, Q and Skingsley, A and Austin, D and Peppercorn, A and Agostini, ML and Parra, S and Chow, S and Mogalian, E and Pang, PS and Hong, DK and Sager, JE and Yeh, WW and Alexander, EL and Gaffney, LA and Kohli, A}, title = {Intramuscular vs Intravenous SARS-CoV-2 Neutralizing Antibody Sotrovimab for Treatment of COVID-19 (COMET-TAIL): A Randomized Noninferiority Clinical Trial.}, journal = {Open forum infectious diseases}, volume = {10}, number = {8}, pages = {ofad354}, pmid = {37577112}, issn = {2328-8957}, abstract = {BACKGROUND: Convenient administration of coronavirus disease 2019 (COVID-19) treatment in community settings is desirable. Sotrovimab is a pan-sarbecovirus dual-action monoclonal antibody formulated for intravenous (IV) or intramuscular (IM) administration for early treatment of mild/moderate COVID-19.
METHOD: This multicenter phase 3 study based on a randomized open-label design tested the noninferiority of IM to IV administration according to an absolute noninferiority margin of 3.5%. From June to August 2021, patients aged ≥12 years with COVID-19, who were neither hospitalized nor receiving supplemental oxygen but were at high risk for progression, were randomized 1:1:1 to receive sotrovimab as a single 500-mg IV infusion or a 500- or 250-mg IM injection. The primary composite endpoint was progression to (1) all-cause hospitalization for >24 hours for acute management of illness or (2) all-cause death through day 29.
RESULTS: Sotrovimab 500 mg IM was noninferior to 500 mg IV: 10 (2.7%) of 376 participants vs 5 (1.3%) of 378 met the primary endpoint, respectively (absolute adjusted risk difference, 1.06%; 95% CI, -1.15% to 3.26%). The 95% CI upper limit was lower than the prespecified noninferiority margin of 3.5%. The 250-mg IM group was discontinued early because of the greater proportion of hospitalizations vs the 500-mg groups. Serious adverse events occurred in <1% to 2% of participants across groups. Four participants experienced serious disease-related events and died (500 mg IM, 2/393, <1%; 250 mg IM, 2/195, 1%).
CONCLUSIONS: Sotrovimab 500-mg IM injection was well tolerated and noninferior to IV administration. IM administration could expand outpatient treatment access for COVID-19.
CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov: NCT04913675.}, }
@article {pmid37576889, year = {2023}, author = {Kwok, C and Khorasanchi, A and Psutka, SP and Hinkley, M and Dason, S and Sundi, D and Yang, Y and Yang, Y and Verschraegen, C and Gross, EE and Orcutt, D and Yin, M}, title = {Salvage lenvatinib/everolimus combination therapy after immune checkpoint inhibitor and VEGFR tyrosine kinase inhibitor for metastatic renal cell carcinoma.}, journal = {Frontiers in oncology}, volume = {13}, number = {}, pages = {1231831}, pmid = {37576889}, issn = {2234-943X}, abstract = {BACKGROUND: The optimal treatment for metastatic renal cell carcinoma (mRCC) patients who have progressed after both immune checkpoint inhibitor (ICI) and VEGFR tyrosine kinase inhibitor (TKI) remains uncertain. Lenvatinib and everolimus (LE) are frequently used in combination as salvage therapy because of their different antitumor mechanisms, but efficacy and toxicity data in this setting are lacking.
METHODS: We retrospectively reviewed charts from two academic centers for 71 adult mRCC patients who received LE after prior ICI and TKI exposure. We evaluated patient demographics, histology, International mRCC Database Consortium (IMDC) risk group, treatment history, and toxicity details. Outcomes of interest included objective response rate (ORR), time to treatment failure (TTF), overall survival (OS), ≥grade 3 toxicities, and schedule or dosage changes, which were evaluated using descriptive statistics, chi-square test, Cox proportional hazards model, and the Kaplan-Meier method.
RESULTS: The median age was 64 (range 31-84). Most patients had clear cell histology (84.5%) and had undergone nephrectomy (80.3%). IMDC risks were favorable (19.7%), intermediate (int) (66.2%), poor (11.3%), and unknown (2.8%). The average ORR was 26.8%, while the median TTF was 5.5 months (95% confidence interval [CI], 3.5-7.6) and the median OS was 9 months (95% CI, 7.6-12.9). Intermediate and poor IMDC risks were independently associated with a significantly worse TTF compared to favorable risk (hazard ratio (HR), 3.03, 95% CI, 1.18-7.79), as was ≥4L treatment vs. 2L/3L treatment (HR, 2.02, 95% CI, 1.08-3.8). Of the 71 patients, 57.7% had ≥grade 3 adverse events, 60% had treatment interruption, 44.3% had dose reduction, and 21% stopped treatment due to intolerance.
CONCLUSIONS: LE therapy is feasible but has modest efficacies following ICI/TKI treatment. Patients with favorable risk or treated earlier may have a better treatment response. These observations need to be confirmed in prospective studies.}, }
@article {pmid37575091, year = {2023}, author = {Murray, J and Einhaus, T and Venkataraman, R and Radtke, S and Zhen, A and Carrillo, MA and Kitchen, SG and Peterson, CW and Kiem, HP}, title = {Efficient manufacturing and engraftment of CCR5 gene-edited HSPCs following busulfan conditioning in nonhuman primates.}, journal = {Molecular therapy. Methods & clinical development}, volume = {30}, number = {}, pages = {276-287}, pmid = {37575091}, issn = {2329-0501}, support = {P51 OD010425/OD/NIH HHS/United States ; R01 AI135953/AI/NIAID NIH HHS/United States ; R01 AI167004/AI/NIAID NIH HHS/United States ; U42 OD011123/OD/NIH HHS/United States ; U19 AI149504/AI/NIAID NIH HHS/United States ; R01 AI170214/AI/NIAID NIH HHS/United States ; U19 HL156247/HL/NHLBI NIH HHS/United States ; }, abstract = {Hematopoietic stem cell gene therapy has been successfully used for a number of genetic diseases and is also being explored for HIV. However, toxicity of the conditioning regimens has been a major concern. Here we compared current conditioning approaches in a clinically relevant nonhuman primate model. We first customized various aspects of the therapeutic approach, including mobilization and cell collection protocols, conditioning regimens that support engraftment with minimal collateral damage, and cell manufacturing and infusing schema that reflect and build on current clinical approaches. Through a series of iterative in vivo experiments in two macaque species, we show that busulfan conditioning significantly spares lymphocytes and maintains a superior immune response to mucosal challenge with simian/human immunodeficiency virus, compared to total body irradiation and melphalan regimens. Comparative mobilization experiments demonstrate higher cell yield relative to our historical standard, primed bone marrow and engraftment of CRISPR-edited hematopoietic stem and progenitor cells (HSPCs) after busulfan conditioning. Our findings establish a detailed workflow for preclinical HSPC gene therapy studies in the nonhuman primate model, which in turn will support testing of novel conditioning regimens and more advanced HSPC gene editing techniques tailored to any disease of interest.}, }
@article {pmid36798400, year = {2023}, author = {Stoddard, CI and Sung, K and Yaffe, ZA and Weight, H and Beaudoin-Bussières, G and Galloway, J and Gantt, S and Adhiambo, J and Begnel, ER and Ojee, E and Slyker, J and Wamalwa, D and Kinuthia, J and Finzi, A and Matsen, FA and Lehman, DA and Overbaugh, J}, title = {Elevated binding and functional antibody responses to SARS-CoV-2 in infants versus mothers.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {36798400}, support = {R01 HD092311/HD/NICHD NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; R00 DK107923/DK/NIDDK NIH HHS/United States ; R01 AI138709/AI/NIAID NIH HHS/United States ; R01 AI146028/AI/NIAID NIH HHS/United States ; F30 AI165112/AI/NIAID NIH HHS/United States ; K99 AI171000/AI/NIAID NIH HHS/United States ; }, abstract = {Infant antibody responses to viral infection can differ from those in adults. However, data on the specificity and function of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies in infants, and direct comparisons between infants and adults are limited. We characterized antibody binding and functionality in convalescent plasma from postpartum women and their infants infected with SARS-CoV-2 from a vaccine-naïve prospective cohort in Nairobi, Kenya. Antibody titers against SARS-CoV-2 Spike, receptor binding domain and N-terminal domain, and Spike-expressing cell-surface staining levels were significantly higher in infants than in mothers. Plasma antibodies from mothers and infants bound to similar regions of the Spike S2 subunit, including the fusion peptide (FP) and stem helix-heptad repeat 2. However, infants displayed higher antibody levels and more consistent antibody escape pathways in the FP region compared to mothers. Finally, infants had significantly higher levels of antibody-dependent cellular cytotoxicity (ADCC), though, surprisingly, neutralization titers between infants and mothers were similar. These results suggest infants develop distinct SARS-CoV-2 binding and functional antibody repertoires and reveal age-related differences in humoral immunity to SARS-CoV-2 infection that could be relevant to protection and COVID-19 disease outcomes.}, }
@article {pmid37574711, year = {2023}, author = {Leachman, SA and Latour, E and Detweiler-Bedell, B and Detweiler-Bedell, JB and Zell, A and Wenzel, E and Stoos, E and Nelson, JH and Wiedrick, J and Berry, EG and Lange, J and Etzioni, R and Lapidus, JA}, title = {Melanoma literacy among the general population of three western US states.}, journal = {Pigment cell & melanoma research}, volume = {}, number = {}, pages = {}, doi = {10.1111/pcmr.13106}, pmid = {37574711}, issn = {1755-148X}, support = {//Knight Cancer Institute, Oregon Health and Science University/ ; //School of Medicine, Oregon Health and Science University/ ; }, abstract = {Melanoma is a significant cause of cancer death, despite being detectable without specialized or invasive technologies. Understanding barriers to preventive behaviors such as skin self-examination (SSE) could help to define interventions for increasing the frequency of early detection. To determine melanoma knowledge and beliefs across three high-incidence US states, 15,000 surveys were sent to a population-representative sample. We aimed to assess (1) melanoma literacy (i.e., knowledge about melanoma risks, attitudes, and preventive behaviors) and (2) self-reported SSE and its association with melanoma literacy, self-efficacy, and belief in the benefits of SSE. Of 2326 respondents, only 21.2% provided responses indicating high knowledge of melanoma, and 62.8% reported performing an SSE at any time in their lives. Only 38.3% and 7.3% reported being "fairly" or "very" confident about doing SSE, respectively. SSE performance among respondents was most strongly associated with higher melanoma knowledge, higher self-efficacy, and personal history of melanoma. Melanoma literacy among survey respondents was modest, with greater literacy associated with a higher likelihood of reported preventive behavior. This assessment establishes a baseline and provides guidance for public health campaigns designed to increase prevention and early detection of this lethal cancer.}, }
@article {pmid37573572, year = {2023}, author = {Wirsching, HG and Felsberg, J and Prummer, M and Moisoiu, V and Lourman, R and Hertler, C and Antonios, M and Cimino, PJ and Roth, P and Gorlia, T and Prins, RM and Cloughesy, T and Wen, PY and Holland, EC and Reifenberger, G and Weller, M}, title = {Spatial immune profiling of glioblastoma identifies an inflammatory, perivascular phenotype associated with longer survival.}, journal = {Acta neuropathologica}, volume = {}, number = {}, pages = {}, pmid = {37573572}, issn = {1432-0533}, support = {P2SKP3-158656//Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung/ ; KLS-4870-08-2019//Oncosuisse/ ; ImmunoCure//University of Zurich CRPP/ ; }, }
@article {pmid37572683, year = {2023}, author = {Shallis, RM and Daver, N and Altman, JK and Komrokji, RS and Pollyea, DA and Badar, T and Bewersdorf, JP and Bhatt, VR and de Botton, S and de la Fuente Burguera, A and Carraway, HE and Desai, P and Dillon, R and Duployez, N and El Chaer, F and Fathi, AT and Freeman, SD and Gojo, I and Grunwald, MR and Jonas, BA and Konopleva, M and Lin, TL and Mannis, GN and Mascarenhas, J and Michaelis, LC and Mims, AS and Montesinos, P and Pozdnyakova, O and Pratz, KW and Schuh, AC and Sekeres, MA and Smith, CC and Stahl, M and Subklewe, M and Uy, GL and Voso, MT and Walter, RB and Wang, ES and Zeidner, JF and Žučenka, A and Zeidan, AM}, title = {Standardising acute myeloid leukaemia classification systems: a perspective from a panel of international experts.}, journal = {The Lancet. Haematology}, volume = {}, number = {}, pages = {}, doi = {10.1016/S2352-3026(23)00159-X}, pmid = {37572683}, issn = {2352-3026}, abstract = {The existence of two acute myeloid leukaemia classification systems-one put forth by WHO and one by the International Consensus Classification in 2022-is concerning. Although both systems appropriately move towards genomic disease definitions and reduced emphasis on blast enumeration, there are consequential disagreements between the two systems on what constitutes a diagnosis of acute myeloid leukaemia. This fundamental problem threatens the ability of heath-care providers to diagnose acute myeloid leukaemia, communicate with patients and other health-care providers, and deliver appropriate and consistent management strategies for patients with the condition. Clinical trial eligibility, standardised response assessments, and eventual drug development and regulatory pathways might also be negatively affected by the discrepancies. In this Viewpoint, we review the merits and limitations of both classification systems and illustrate how the coexistence, as well as application of both systems is an undue challenge to patients, clinicians, hematopathologists, sponsors of research, and regulators. Lastly, we emphasise the urgency and propose a roadmap, by which the two divergent classification systems can be harmonised.}, }
@article {pmid37571809, year = {2023}, author = {Richie, TL and Church, LWP and Murshedkar, T and Billingsley, PF and James, ER and Chen, MC and Abebe, Y and Natasha Kc, and Chakravarty, S and Dolberg, D and Healy, SA and Diawara, H and Sissoko, MS and Sagara, I and Cook, DM and Epstein, JE and Mordmüller, B and Kapulu, M and Kreidenweiss, A and Franke-Fayard, B and Agnandji, ST and López Mikue, MA and McCall, MBB and Steinhardt, L and Oneko, M and Olotu, A and Vaughan, AM and Kublin, JG and Murphy, SC and Jongo, S and Tanner, M and Sirima, SB and Laurens, MB and Daubenberger, C and Silva, JC and Lyke, KE and Janse, CJ and Roestenberg, M and Sauerwein, RW and Abdulla, S and Dicko, A and Kappe, SHI and Sim, BKL and Duffy, PE and Kremsner, PG and Hoffman, SL}, title = {Sporozoite immunization: Innovative Translational Science to Support the Fight against malaria.}, journal = {Expert review of vaccines}, volume = {}, number = {}, pages = {}, doi = {10.1080/14760584.2023.2245890}, pmid = {37571809}, issn = {1744-8395}, abstract = {INTRODUCTION: Malaria, a devastating febrile illness caused by protozoan parasites, sickened 247,000,000 people in 2021 and killed 619,000, mostly children and pregnant women in sub-Saharan Africa. A highly effective vaccine is urgently needed, especially for Plasmodium falciparum (Pf), the deadliest human malaria parasite.
AREAS COVERED: Sporozoites (SPZ), the parasite stage transmitted by Anopheles mosquitoes to humans, are the only vaccine immunogen achieving > 90% efficacy against Pf infection. This review describes > 30 clinical trials of PfSPZ vaccines in the U.S.A., Europe, Africa, and Asia, based on first-hand knowledge of the trials and PubMed searches of 'sporozoites,' 'malaria,' and 'vaccines.'
EXPERT OPINION: First generation (radiation-attenuated) PfSPZ vaccines are safe, well tolerated, 80-100% efficacious against homologous controlled human malaria infection (CHMI) and provide 18-19 months protection without boosting in Africa. Second generation chemo-attenuated PfSPZ are more potent, 100% efficacious against stringent heterologous (variant strain) CHMI, but require a co-administered drug, raising safety concerns. Third generation, late liver stage-arresting, replication competent (LARC), genetically-attenuated PfSPZ are expected to be both safe and highly efficacious. Overall, PfSPZ vaccines meet safety, tolerability, and efficacy requirements for protecting pregnant women and travelers, with licensure for these populations possible within five years. Protecting children and mass vaccination programs to block transmission and eliminate malaria are long-term objectives.}, }
@article {pmid37567924, year = {2023}, author = {Stoddard, CI and Sung, K and Yaffe, ZA and Weight, H and Beaudoin-Bussières, G and Galloway, J and Gantt, S and Adhiambo, J and Begnel, ER and Ojee, E and Slyker, J and Wamalwa, D and Kinuthia, J and Finzi, A and Matsen, FA and Lehman, DA and Overbaugh, J}, title = {Elevated binding and functional antibody responses to SARS-CoV-2 in infants versus mothers.}, journal = {Nature communications}, volume = {14}, number = {1}, pages = {4864}, pmid = {37567924}, issn = {2041-1723}, support = {R01 HD092311/HD/NICHD NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; R00 DK107923/DK/NIDDK NIH HHS/United States ; R01 AI138709/AI/NIAID NIH HHS/United States ; R01 AI146028/AI/NIAID NIH HHS/United States ; F30 AI165112/AI/NIAID NIH HHS/United States ; K99 AI171000/AI/NIAID NIH HHS/United States ; }, mesh = {Adult ; Humans ; Infant ; Female ; *SARS-CoV-2 ; Mothers ; *COVID-19 ; Antibody Formation ; Prospective Studies ; COVID-19 Serotherapy ; Kenya ; Antibodies ; Spike Glycoprotein, Coronavirus ; Antibodies, Viral ; Antibodies, Neutralizing ; }, abstract = {Infant antibody responses to viral infection can differ from those in adults. However, data on the specificity and function of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies in infants, and direct comparisons between infants and adults are limited. Here, we characterize antibody binding and functionality against Wuhan-Hu-1 (B lineage) strain SARS-CoV-2 in convalescent plasma from 36 postpartum women and 14 of their infants infected with SARS-CoV-2 from a vaccine-naïve prospective cohort in Nairobi, Kenya. We find significantly higher antibody titers against SARS-CoV-2 Spike, receptor binding domain and N-terminal domain, and Spike-expressing cell-surface staining levels in infants versus mothers. Plasma antibodies from mothers and infants bind to similar regions of the Spike S2 subunit, including the fusion peptide (FP) and stem helix-heptad repeat 2. However, infants display higher antibody levels and more consistent antibody escape pathways in the FP region compared to mothers. Finally, infants have significantly higher levels of antibody-dependent cellular cytotoxicity (ADCC), though, surprisingly, Spike pseudovirus neutralization titers between infants and mothers are similar. These results suggest infants develop distinct SARS-CoV-2 binding and functional antibody activities and reveal age-related differences in humoral immunity to SARS-CoV-2 infection that could be relevant to protection and COVID-19 disease outcomes.}, }
@article {pmid37563237, year = {2023}, author = {Keshawarz, A and Bui, H and Joehanes, R and Ma, J and Liu, C and Huan, T and Hwang, SJ and Tejada, B and Sooda, M and Courchesne, P and Munson, PJ and Demirkale, CY and Yao, C and Heard-Costa, NL and Pitsillides, AN and Lin, H and Liu, CT and Wang, Y and Peloso, GM and Lundin, J and Haessler, J and Du, Z and Cho, M and Hersh, CP and Castaldi, P and Raffield, LM and Wen, J and Li, Y and Reiner, AP and Feolo, M and Sharopova, N and Vasan, RS and DeMeo, DL and Carson, AP and Kooperberg, C and Levy, D}, title = {Expression quantitative trait methylation analysis elucidates gene regulatory effects of DNA methylation: the Framingham Heart Study.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {12952}, pmid = {37563237}, issn = {2045-2322}, support = {75N92021D00002/HL/NHLBI NIH HHS/United States ; R01 HL120393/HL/NHLBI NIH HHS/United States ; 75N92021D00005/WH/WHI NIH HHS/United States ; HHSN268201600032C/ES/NIEHS NIH HHS/United States ; R01 AG075884/AG/NIA NIH HHS/United States ; HHSN268201800014C/HL/NHLBI NIH HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; HHSN268201800011C/HL/NHLBI NIH HHS/United States ; 75N92019D00031/HL/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 ; 75N92021D00004/WH/WHI NIH HHS/United States ; HHSN268201800012I/HB/NHLBI NIH HHS/United States ; HHSN268201800012C/HL/NHLBI NIH HHS/United States ; HHSN268201500001C/HL/NHLBI NIH HHS/United States ; HHSN268201800014I/HB/NHLBI NIH HHS/United States ; R01 HL092577/HL/NHLBI NIH HHS/United States ; T32 ES007018/ES/NIEHS NIH HHS/United States ; U01 HL120393/HL/NHLBI NIH HHS/United States ; R01 HL129132/HL/NHLBI NIH HHS/United States ; HHSN268201800001C/HL/NHLBI NIH HHS/United States ; HHSN268201800013I/MD/NIMHD NIH HHS/United States ; HHSN268201600038C/HL/NHLBI NIH HHS/United States ; HHSN268201500001I/HL/NHLBI NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; N01HC25195/HL/NHLBI NIH HHS/United States ; HHSN268201800015I/HB/NHLBI NIH HHS/United States ; }, mesh = {Humans ; Female ; *DNA Methylation ; Quantitative Trait Loci ; Gene Expression Regulation ; Longitudinal Studies ; *Cardiovascular Diseases/genetics ; CpG Islands/genetics ; Genome-Wide Association Study ; }, abstract = {Expression quantitative trait methylation (eQTM) analysis identifies DNA CpG sites at which methylation is associated with gene expression. The present study describes an eQTM resource of CpG-transcript pairs derived from whole blood DNA methylation and RNA sequencing gene expression data in 2115 Framingham Heart Study participants. We identified 70,047 significant cis CpG-transcript pairs at p < 1E-7 where the top most significant eGenes (i.e., gene transcripts associated with a CpG) were enriched in biological pathways related to cell signaling, and for 1208 clinical traits (enrichment false discovery rate [FDR] ≤ 0.05). We also identified 246,667 significant trans CpG-transcript pairs at p < 1E-14 where the top most significant eGenes were enriched in biological pathways related to activation of the immune response, and for 1191 clinical traits (enrichment FDR ≤ 0.05). Independent and external replication of the top 1000 significant cis and trans CpG-transcript pairs was completed in the Women's Health Initiative and Jackson Heart Study cohorts. Using significant cis CpG-transcript pairs, we identified significant mediation of the association between CpG sites and cardiometabolic traits through gene expression and identified shared genetic regulation between CpGs and transcripts associated with cardiometabolic traits. In conclusion, we developed a robust and powerful resource of whole blood eQTM CpG-transcript pairs that can help inform future functional studies that seek to understand the molecular basis of disease.}, }
@article {pmid37562068, year = {2023}, author = {Carnahan, LR and Hallock, C and Soto, B and Kasebier, L and Dracos, E and Martinez, E and Newsome, J and Mersha, T and Pluta, D and Henderson, V and Khare, M}, title = {Creating and Implementing a Community Engagement Strategy for the 2022-2027 Illinois Comprehensive Cancer Control Plan Through an Academic-State Public Health Department Partnership.}, journal = {Preventing chronic disease}, volume = {20}, number = {}, pages = {E69}, doi = {10.5888/pcd20.220422}, pmid = {37562068}, issn = {1545-1151}, mesh = {Humans ; Black or African American/statistics & numerical data ; *Delivery of Health Care/ethnology/standards/statistics & numerical data ; Illinois/epidemiology ; *Neoplasms/epidemiology/ethnology/prevention & control/therapy ; *Public Health ; Hispanic or Latino/statistics & numerical data ; Health Inequities ; *Health Equity/standards/statistics & numerical data ; }, abstract = {INTRODUCTION: Comprehensive cancer control (CCC) plans are state-level blueprints that identify regional cancer priorities and health equity strategies. Coalitions are encouraged to engage with community members, advocacy groups, people representing multiple sectors, and working partners throughout the development process. We describe the community and legislative engagement strategy developed and implemented during 2020-2022 for the 2022-2027 Illinois CCC plan.
METHODS: The engagement strategies were grounded in theory and evidence-based tools and resources. It was developed and implemented by coalition members representing the state health department and an academic partner, with feedback from the larger coalition. The strategy included a statewide town hall, 8 focus groups, and raising awareness of the plan among state policy makers.
RESULTS: A total of 112 people participated in the town hall and focus groups, including 40 (36%) cancer survivors, 31 (28%) cancer caregivers, and 18 (16%) Latino and 26 (23%) African American residents. Fourteen of 53 (26%) focus group participants identified as rural. Participants identified drivers of cancer disparities (eg, lack of a comprehensive health insurance system, discrimination, transportation access) and funding and policy priorities. Illinois House Resolution 0675, the Illinois Cancer Control Plan, was passed in March 2022.
CONCLUSION: The expertise and voices of community members affected by cancer can be documented and reflected in CCC plans. CCC plans can be brought to the attention of policy makers. Other coalitions working on state plans may consider replicating our strategy. Ultimately, CCC plans should reflect health equity principles and prioritize eliminating cancer disparities.}, }
@article {pmid37562003, year = {2023}, author = {Leiding, JW and Arnold, DE and Parikh, SH and Logan, BR and Marsh, RA and Griffith, LM and Wu, R and Kidd, S and Mallhi, KK and Chellapandian, D and Si Lim, S and Grunebaum, E and Falcone, EL and Murguia-Favela, L and Grossman, D and Prasad, VK and Heimall, JR and Touzot, F and Burroughs, L and Bleesing, J and Kapoor, N and Dara, J and Williams, O and Kapadia, M and Oshrine, BR and Bednarski, JJ and Rayes, A and Chong, H and Cuvelier, GDE and Forbes Satter, LR and Martinez, C and Vander Lugt, MT and Yu, LC and Chandrakasan, S and Joshi, A and Prockop, SE and Dávila Saldaña, BJ and Aquino, V and Broglie, L and Ebens, CL and Madden, LM and DeSantes, K and Milner, J and Rangarajan, HG and Shah, A and Gilio, AP and Knutsen, AP and Miller, HK and Moore, TB and Graham, P and Bauchat, A and Bunin, NJ and Teira, P and Petrovic, A and Chandra, S and Abdel-Azim, H and Dorsey, M and Birbrayer, O 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}, title = {Genotype, Oxidase Status, and Preceding Infection or Autoinflammation Do Not Affect Allogeneic HCT Outcomes for CGD.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood.2022019586}, pmid = {37562003}, issn = {1528-0020}, abstract = {Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by life-threatening infections and inflammatory conditions. Hematopoietic cell transplantation (HCT) is the definitive treatment for CGD, but questions remain regarding patient selection and impact of active disease on transplant outcomes. We performed a multi-institutional retrospective and prospective study of 391 patients with CGD treated either conventionally (non-HCT;n=151) enrolled from 2004-2018 or who underwent HCT (n=240) from 1996-2018. Median follow-up post-HCT was 3.7 years with a 3-year overall survival of 82% and event-free survival of 69%. In multivariate analysis, Lansky/Karnofsky score <90 and use of HLA-mismatched donors negatively impacted survival. Age, genotype, and oxidase status did not impact outcomes. Pre-HCT, patients had higher infection density, higher frequency of non-infectious lung and liver disease, and more steroid use compared to conventionally-treated patients, yet these issues did not adversely affect HCT survival. Presence of pre-HCT inflammatory conditions was associated with chronic graft versus host disease. Graft failure or receipt of second HCT occurred in 17.6% and was associated with melphalan-based conditioning and/or early mixed chimerism. By 3-5 years post-HCT, patients had improved growth and nutrition, resolved infections and inflammatory disease, and lower rates of anti-microbial prophylaxis or corticosteroid use compared to both their baseline and to conventionally-treated patients. HCT leads to durable resolution of CGD symptoms and lowers burden of disease. Patients with active infection or inflammation are candidates for transplant; HCT should be considered prior to the development of co-morbidities that could impact performance status. Clinical trial # NCT02082353.}, }
@article {pmid37561111, year = {2023}, author = {Bell-Brown, A and Watabayashi, K and Delaney, D and Carlos, RC and Langer, SL and Unger, JM and Vaidya, RR and Darke, AK and Hershman, DL and Ramsey, SD and Shankaran, V}, title = {Assessment of Financial Screening and Navigation Capabilities at NCI Community Oncology Clinics.}, journal = {JNCI cancer spectrum}, volume = {}, number = {}, pages = {}, doi = {10.1093/jncics/pkad055}, pmid = {37561111}, issn = {2515-5091}, abstract = {BACKGROUND: Cancer-related financial hardship is a side effect of cancer diagnosis and treatment, and impacts both patients and caregivers. While many oncology clinics have increased financial navigation services, few have resources to proactively provide financial counseling and assistance to families impacted by cancer before financial hardship occurs. As part of an ongoing randomized study testing a proactive financial navigation intervention (S1912CD) among NCI Community Oncology Research Program (NCORP) sites, we conducted a baseline survey to learn more about existing financial resources available to patients and caregivers.
METHODS: NCORP sites participating in the S1912CD study completed a required 10-question survey about their available financial resources and an optional 5-question survey focused on financial screening and navigation workflow and challenges prior to starting recruitment. Proportion of NCORP sites offering financial navigation services was calculated and responses to the optional survey were reviewed to determine current screening and navigation practices and identify any challenges.
RESULTS: Most sites (96%) reported offering financial navigation for cancer patients. Sites primarily identified patients needing financial assistance through social work evaluations (78%) or distress screening tools (76%). Sites revealed challenges in addressing financial needs at the outset and through diagnosis, including lack of proactive screening and referral to financial navigation services and staffing challenges.
CONCLUSIONS: While most participating NCORP sites offer some form of financial assistance, surveys identified gaps and challenges in providing services. Utilizing community partners to deliver comprehensive financial navigation to cancer patients and caregivers may help meet needs while reducing site burden.}, }
@article {pmid37561027, year = {2023}, author = {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 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 Netzl, A and Smith, DJ and Telu, K and Mu, J and McQuarrie, LJ and Makowski, M and Makhene, MK and Crandon, S and Montefiori, DC and Roberts, PC and Beigel, JH}, title = {Immunogenicity of a Two Dose Regimen of Moderna mRNA Beta/Omicron BA.1 Bivalent Variant Vaccine Boost in a Randomized Clinical Trial.}, journal = {The Journal of infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1093/infdis/jiad323}, pmid = {37561027}, issn = {1537-6613}, abstract = {We compared the serologic responses of one versus two doses of a variant vaccine (Moderna mRNA-1273 Beta/Omicron BA.1 bivalent vaccine) in adults. A two-dose boosting regimen with a variant vaccine did not increase the magnitude or the durability of the serological responses compared to a single variant vaccine boost.}, }
@article {pmid37559436, year = {2023}, author = {Isaacs, JT and Dalrymple, SL and Antony, L and Marc Rosen, D and Coleman, IM and Nelson, PS and Kostova, M and Murray, IA and Perdew, GH and Denmeade, SR and Akinboye, ES and Brennen, WN}, title = {Third generation quinoline-3-carboxamide transcriptional disrupter of HDAC4, HIF-1α, and MEF-2 signaling for metastatic castration-resistant prostate cancer.}, journal = {The Prostate}, volume = {}, number = {}, pages = {}, doi = {10.1002/pros.24606}, pmid = {37559436}, issn = {1097-0045}, support = {/NH/NIH HHS/United States ; }, abstract = {BACKGROUND: The quinoline-3-carboxamide, Tasquinimod (TasQ), is orally active as a maintenance therapy with an on-target mechanism-of-action via allosteric binding to HDAC4. This prevents formation of the HDAC4/NCoR1/HDAC3 complex, disrupting HIF-1α transcriptional activation and repressing MEF-2 target genes needed for adaptive survival signaling in the compromised tumor micro environment. In phase 3 clinical testing against metastatic castration-resistant prostate cancer(mCRPC), TasQ (1 mg/day) increased time-to-progression, but not overall survival.
METHODS: TasQ analogs were chemically synthesized and tested for activity compared to the parental compound. These included HDAC4 enzymatic assays, qRT-PCR and western blot analyses of gene and protein expression following treatment, in vitro and in vivo efficacy against multiple prostate cancer models including PDXs, pharmacokinetic analyses,AHR binding and agonist assays, SPR analyses of binding to HDAC4 and NCoR1, RNAseq analysis of in vivo tumors, 3D endothelial sprouting assays, and a targeted kinase screen. Genetic knockout or knockdown controls were used when appropriate.
RESULTS: Here, we document that, on this regimen (1 mg/day), TasQ blood levels are 10-fold lower than the optimal concentration (≥2 μM) needed for anticancer activity, suggesting higher daily doses are needed. Unfortunately, we also demonstrate that TasQ is an arylhydrocarbon receptor (AHR) agonist, which binds with an EC50 of 1 μM to produce unwanted off-target side effects. Therefore, we screened a library of TasQ analogsto maximize on-target versus off-target activity. Using this approach, we identified ESATA-20, which has ~10-fold lower AHR agonism and 5-fold greater potency against prostate cancer patient-derived xenografts.
CONCLUSION: This increased therapeuticindex nominates ESATA-20 as a lead candidate forclinical development as an orally active third generation quinoline-3-carboxamide analog thatretains its on-target ability to disrupt HDAC4/HIF-1α/MEF-2-dependent adaptive survival signaling in the compromisedtumor microenvironment found in mCRPC.}, }
@article {pmid37559094, year = {2023}, author = {Middha, P and Wang, X and Behrens, S and Bolla, MK and Wang, Q and Dennis, J and Michailidou, K and Ahearn, TU and Andrulis, IL and Anton-Culver, H and Arndt, V and Aronson, KJ and Auer, PL and Augustinsson, A and Baert, T and Freeman, LEB and Becher, H and Beckmann, MW and Benitez, J and Bojesen, SE and Brauch, H and Brenner, H and Brooks-Wilson, A and Campa, D and Canzian, F and Carracedo, A and Castelao, JE and Chanock, SJ and Chenevix-Trench, G and , and Cordina-Duverger, E and Couch, FJ and Cox, A and Cross, SS and Czene, K and Dossus, L and Dugué, PA and Eliassen, AH and Eriksson, M and Evans, DG and Fasching, PA and Figueroa, JD and Fletcher, O and Flyger, H and Gabrielson, M and Gago-Dominguez, M and Giles, GG and González-Neira, A and Grassmann, F and Grundy, A and Guénel, P and Haiman, CA and Håkansson, N and Hall, P and Hamann, U and Hankinson, SE and Harkness, EF and Holleczek, B and Hoppe, R and Hopper, JL and Houlston, RS and Howell, A and Hunter, DJ and Ingvar, C and , and , and Isaksson, K and Jernström, H and John, EM and Jones, ME and Kaaks, R and Keeman, R and Kitahara, CM and Ko, YD and Koutros, S and Kurian, AW and Lacey, JV and Lambrechts, D and Larson, NL and Larsson, S and Le Marchand, L and Lejbkowicz, F and Li, S and Linet, M and Lissowska, J and Martinez, ME and Maurer, T and Mulligan, AM and Mulot, C and Murphy, RA and Newman, WG and Nielsen, SF and Nordestgaard, BG and Norman, A and O'Brien, KM and Olson, JE and Patel, AV and Prentice, R and Rees-Punia, E and Rennert, G and Rhenius, V and Ruddy, KJ and Sandler, DP and Scott, CG and Shah, M and Shu, XO and Smeets, A and Southey, MC and Stone, J and Tamimi, RM and Taylor, JA and Teras, LR and Tomczyk, K and Troester, MA and Truong, T and Vachon, CM and Wang, SS and Weinberg, CR and Wildiers, H and Willett, W and Winham, SJ and Wolk, A and Yang, XR and Zamora, MP and Zheng, W and Ziogas, A and Dunning, AM and Pharoah, PDP and García-Closas, M and Schmidt, MK and Kraft, P and Milne, RL and Lindström, S and Easton, DF and Chang-Claude, J}, title = {A genome-wide gene-environment interaction study of breast cancer risk for women of European ancestry.}, journal = {Breast cancer research : BCR}, volume = {25}, number = {1}, pages = {93}, pmid = {37559094}, issn = {1465-542X}, mesh = {Adult ; Female ; Humans ; *Gene-Environment Interaction ; Genetic Predisposition to Disease ; *Breast Neoplasms/etiology/genetics ; Bayes Theorem ; Genome-Wide Association Study ; Risk Factors ; Polymorphism, Single Nucleotide ; Case-Control Studies ; }, abstract = {BACKGROUND: Genome-wide studies of gene-environment interactions (G×E) may identify variants associated with disease risk in conjunction with lifestyle/environmental exposures. We conducted a genome-wide G×E analysis of ~ 7.6 million common variants and seven lifestyle/environmental risk factors for breast cancer risk overall and for estrogen receptor positive (ER +) breast cancer.
METHODS: Analyses were conducted using 72,285 breast cancer cases and 80,354 controls of European ancestry from the Breast Cancer Association Consortium. Gene-environment interactions were evaluated using standard unconditional logistic regression models and likelihood ratio tests for breast cancer risk overall and for ER + breast cancer. Bayesian False Discovery Probability was employed to assess the noteworthiness of each SNP-risk factor pairs.
RESULTS: Assuming a 1 × 10[-5] prior probability of a true association for each SNP-risk factor pairs and a Bayesian False Discovery Probability < 15%, we identified two independent SNP-risk factor pairs: rs80018847(9p13)-LINGO2 and adult height in association with overall breast cancer risk (ORint = 0.94, 95% CI 0.92-0.96), and rs4770552(13q12)-SPATA13 and age at menarche for ER + breast cancer risk (ORint = 0.91, 95% CI 0.88-0.94).
CONCLUSIONS: Overall, the contribution of G×E interactions to the heritability of breast cancer is very small. At the population level, multiplicative G×E interactions do not make an important contribution to risk prediction in breast cancer.}, }
@article {pmid37555839, year = {2023}, author = {Ma, C and Wang, X and Dai, JY and Turman, C and Kraft, P and Stopsack, KH and Loda, M and Pettersson, A and Mucci, LA and Stanford, JL and Penney, KL}, title = {Germline genetic variants associated with somatic TMPRSS2:ERG fusion status in prostate cancer: a genome-wide association study.}, journal = {Cancer epidemiology, biomarkers & 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-23-0275}, pmid = {37555839}, issn = {1538-7755}, abstract = {BACKGROUND: The prostate cancer subtype defined by the presence of TMPRSS2:ERG has been shown to be molecularly and epidemiologically distinct. However, few studies have investigated germline genetic variants associating with TMPRSS2:ERG fusion status.
METHODS: We performed a genome-wide association study with 396 TMPRSS2:ERG(+) cases, 390 TMPRSS2:ERG(-) cases and 2,386 cancer-free controls from the Physicians' Health Study (PHS), the Health Professionals Follow-up Study (HPFS), and a Seattle-based Fred Hutchinson (FH) Cancer Center Prostate Cancer Study. We applied logistic regression models to test the associations between ~5 million SNPs with TMPRSS2:ERG fusion status accounting for population stratification.
RESULTS: We did not identify genome-wide significant variants comparing the TMPRSS2:ERG(+) to the TMPRSS2:ERG(-) prostate cancer cases in the meta-analysis. When comparing TMPRSS2:ERG(+) prostate cancer cases with controls without prostate cancer, 10 genome-wide significant SNPs on chromosome 17q24.3 were observed in the meta-analysis. When comparing TMPRSS2:ERG(-) prostate cancer cases with controls without prostate cancer, two SNPs on chromosome 8q24.21 in the meta-analysis reached genome-wide significance.
CONCLUSIONS: We observed SNPs at several known prostate cancer risk loci (17q24.3, 1q32.1, and 8q24.21) that were differentially and exclusively associated with the risk of developing prostate tumors either with or without the gene fusion.
IMPACT: Our findings suggest that tumors with the TMPRSS2:ERG fusion exhibit a different germline genetic etiology compared to fusion negative cases.}, }
@article {pmid37552991, year = {2023}, author = {Mayer-Blackwell, K and Ryu, H and Codd, AS and Parks, KR and MacMillan, HR and Cohen, KW and Stewart, TL and Seese, A and Lemos, MP and De Rosa, SC and Czartoski, JL and Moodie, Z and Nguyen, LT and McGuire, DJ and Ahmed, R and Fiore-Gartland, A and McElrath, MJ and Newell, EW}, title = {mRNA vaccination boosts S-specific T cell memory and promotes expansion of CD45RAint TEMRA-like CD8[+] T cells in COVID-19 recovered individuals.}, journal = {Cell reports. Medicine}, volume = {}, number = {}, pages = {101149}, doi = {10.1016/j.xcrm.2023.101149}, pmid = {37552991}, issn = {2666-3791}, abstract = {SARS-CoV-2 infection and mRNA vaccination both elicit spike (S)-specific T cell responses. To analyze how T cell memory from prior infection influences T cell responses to vaccination, we evaluated functional T cell responses in naive and previously infected vaccine recipients. Pre-vaccine S-specific responses are predictive of subsequent CD8[+] T cell vaccine-response magnitudes. Comparing baseline with post-vaccination TCRβ repertoires, we observed large clonotypic expansions correlated with the frequency of spike-specific T cells. Epitope mapping the largest CD8[+] T cell responses confirms that an HLA-A∗03:01 epitope was highly immunodominant. Peptide-MHC tetramer staining together with mass cytometry and single-cell sequencing permit detailed phenotyping and clonotypic tracking of these S-specific CD8[+] T cells. Our results demonstrate that infection-induced S-specific CD8[+] T cell memory plays a significant role in shaping the magnitude and clonal composition of the circulating T cell repertoire after vaccination, with mRNA vaccination promoting CD8[+] memory T cells to a TEMRA-like phenotype.}, }
@article {pmid37552302, year = {2023}, author = {Zhao, L and Zhang, X and Coday, M and Garcia, DO and Li, X and Mossavar-Rahmani, Y and Naughton, MJ and Lopez-Pentecost, M and Saquib, N and Shadyab, AH and Simon, MS and Snetselaar, LG and Tabung, FK and Tobias, DK and VoPham, T and McGlynn, KA and Sesso, HD and Giovannucci, E and Manson, JE and Hu, FB and Tinker, LF and Zhang, X}, title = {Sugar-Sweetened and Artificially Sweetened Beverages and Risk of Liver Cancer and Chronic Liver Disease Mortality.}, journal = {JAMA}, volume = {330}, number = {6}, pages = {537-546}, pmid = {37552302}, issn = {1538-3598}, support = {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 = {Female ; Humans ; *Artificially Sweetened Beverages/adverse effects ; Beverages/adverse effects ; Carbonated Beverages/adverse effects ; Liver Cirrhosis/epidemiology/etiology/mortality ; *Liver Neoplasms/epidemiology/etiology/mortality ; Non-alcoholic Fatty Liver Disease/epidemiology/etiology/mortality ; Prospective Studies ; Risk Factors ; Sugars/adverse effects ; Sweetening Agents/adverse effects ; *Sugar-Sweetened Beverages/adverse effects ; Liver Diseases/epidemiology/etiology/mortality ; Chronic Disease ; Middle Aged ; Aged ; }, abstract = {IMPORTANCE: Approximately 65% of adults in the US consume sugar-sweetened beverages daily.
OBJECTIVE: To study the associations between intake of sugar-sweetened beverages, artificially sweetened beverages, and incidence of liver cancer and chronic liver disease mortality.
A prospective cohort with 98 786 postmenopausal women aged 50 to 79 years enrolled in the Women's Health Initiative from 1993 to 1998 at 40 clinical centers in the US and were followed up to March 1, 2020.
EXPOSURES: Sugar-sweetened beverage intake was assessed based on a food frequency questionnaire administered at baseline and defined as the sum of regular soft drinks and fruit drinks (not including fruit juice); artificially sweetened beverage intake was measured at 3-year follow-up.
MAIN OUTCOMES AND MEASURES: The primary outcomes were (1) liver cancer incidence, and (2) mortality due to chronic liver disease, defined as death from nonalcoholic fatty liver disease, liver fibrosis, cirrhosis, alcoholic liver diseases, and chronic hepatitis. Cox proportional hazards regression models were used to estimate multivariable hazard ratios (HRs) and 95% CIs for liver cancer incidence and for chronic liver disease mortality, adjusting for potential confounders including demographics and lifestyle factors.
RESULTS: During a median follow-up of 20.9 years, 207 women developed liver cancer and 148 died from chronic liver disease. At baseline, 6.8% of women consumed 1 or more sugar-sweetened beverage servings per day, and 13.1% consumed 1 or more artificially sweetened beverage servings per day at 3-year follow-up. Compared with intake of 3 or fewer servings of sugar-sweetened beverages per month, those who consumed 1 or more servings per day had a significantly higher risk of liver cancer (18.0 vs 10.3 per 100 000 person-years [P value for trend = .02]; adjusted HR, 1.85 [95% CI, 1.16-2.96]; P = .01) and chronic liver disease mortality (17.7 vs 7.1 per 100 000 person-years [P value for trend <.001]; adjusted HR, 1.68 [95% CI, 1.03-2.75]; P = .04). Compared with intake of 3 or fewer artificially sweetened beverages per month, individuals who consumed 1 or more artificially sweetened beverages per day did not have significantly increased incidence of liver cancer (11.8 vs 10.2 per 100 000 person-years [P value for trend = .70]; adjusted HR, 1.17 [95% CI, 0.70-1.94]; P = .55) or chronic liver disease mortality (7.1 vs 5.3 per 100 000 person-years [P value for trend = .32]; adjusted HR, 0.95 [95% CI, 0.49-1.84]; P = .88).
CONCLUSIONS AND RELEVANCE: In postmenopausal women, compared with consuming 3 or fewer servings of sugar-sweetened beverages per month, those who consumed 1 or more sugar-sweetened beverages per day had a higher incidence of liver cancer and death from chronic liver disease. Future studies should confirm these findings and identify the biological pathways of these associations.}, }
@article {pmid37552106, year = {2023}, author = {Oh, ST and Mesa, RA and Harrison, CN and Bose, P and Gerds, AT and Gupta, V and Scott, BL and Kiladjian, JJ and Lucchesi, A and Kong, T and Buckley, SA and Tyavanagimatt, S and Harder, BG and Roman-Torres, K and Smith, J and Craig, AR and Mascarenhas, JO and Verstovsek, S}, title = {Pacritinib is a potent ACVR1 inhibitor with significant anemia benefit in patients with myelofibrosis.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2023010151}, pmid = {37552106}, issn = {2473-9537}, abstract = {In patients with cytopenic myelofibrosis, treatment with the JAK2/IRAK1 inhibitor pacritinib was associated with anemia benefit in the phase 3 PERSIST-2 study. The impact of pacritinib on transfusion independence (TI) has not been previously described, nor has the mechanism by which pacritinib improves anemia been elucidated. As it has been previously postulated that inhibition of activin A receptor, type 1 (ACVR1) / activin receptor-like kinase-2 (ALK2) improves anemia in patients with myelofibrosis via suppression of hepcidin production, we assessed the relative inhibitory potency of pacritinib compared to other JAK2 inhibitors against ACVR1. Pacritinib inhibited ACVR1 with greater potency (IC50 = 16.7 nM; Cmax:IC50 = 12.7) than momelotinib (IC50 = 52.5 nM; Cmax:IC50 = 3.2), fedratinib (IC50 = 273 nM; Cmax:IC50 = 1.0), or ruxolitinib (IC50 >1000; Cmax:IC50 <0.01). Pacritinib's inhibitory activity against ACVR1 was corroborated via inhibition of downstream SMAD signaling in conjunction with marked suppression of hepcidin production. Among patients on PERSIST-2 who were not TI at baseline based on Gale criteria, a significantly greater proportion became TI on pacritinib compared to best available therapy (37% vs. 7%, P=0.001), and significantly more had a ≥50% reduction in transfusion burden (49% vs. 9%, P<0.0001). These data indicate that the anemia benefit of the JAK2/IRAK1 inhibitor pacritinib may be a function of potent ACVR1 inhibition.}, }
@article {pmid37550965, year = {2023}, author = {Berckmueller, K and Thomas, J and Taha, EA and Choo, S and Madhu, R and Kanestrom, G and Rupert, PB and Strong, R and Kiem, HP and Radtke, S}, title = {CD90-targeted lentiviral vectors for HSC gene therapy.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ymthe.2023.08.003}, pmid = {37550965}, issn = {1525-0024}, abstract = {HSC gene therapy is currently performed on CD34[+] hematopoietic stem and progenitor cells (HSPCs) containing less than 1% true HSCs and requiring a highly specialized infrastructure for cell manufacturing and transplantation. We have previously identified the CD34[+]CD90[+] subset to be exclusively responsible for short- and long-term engraftment. However, purification and enrichment of this subset is laborious and expensive. HSC-specific delivery agents for the direct modification of rare HSCs are currently lacking. Here, we developed novel targeted viral vectors to specifically transduce CD90-expressing HSCs. Anti-CD90 single chain variable fragments (scFvs) were engineered onto measles- and VSV-G-pseudotyped lentiviral vectors that were knocked out for native targeting. We further developed a custom hydrodynamic titration methodology to assess the loading of surface-engineered capsids, measure antigen recognition of the scFv, and predict the performance on cells. Engineered vectors formed with minimal impairment in the functional titer, maintained their ability to fuse with the target cells, and showed highly specific recognition of CD90 on cells ex vivo. Most importantly, targeted vectors selectively transduced human HSCs with secondary colony-forming potential. Our novel HSC-targeted viral vectors have the potential to significantly enhance the feasibility of ex vivo gene therapy and pave the way for future in vivo applications.}, }
@article {pmid37550294, year = {2023}, author = {Lee, EHJ and Murad, JP and Christian, L and Gibson, J and Yamaguchi, Y and Cullen, C and Gumber, D and Park, AK and Young, C and Monroy, I and Yang, J and Stern, LA and Adkins, LN and Dhapola, G and Gittins, B and Chang, WC and Martinez, C and Woo, Y and Cristea, M and Rodriguez-Rodriguez, L and Ishihara, J and Lee, JK and Forman, SJ and Wang, LD and Priceman, SJ}, title = {Antigen-dependent IL-12 signaling in CAR T cells promotes regional to systemic disease targeting.}, journal = {Nature communications}, volume = {14}, number = {1}, pages = {4737}, pmid = {37550294}, issn = {2041-1723}, support = {P30 CA033572/CA/NCI NIH HHS/United States ; }, mesh = {Female ; Humans ; Mice ; Animals ; Immunotherapy, Adoptive ; Interleukin-12 ; *Receptors, Chimeric Antigen/genetics ; T-Lymphocytes ; *Ovarian Neoplasms/therapy ; Xenograft Model Antitumor Assays ; Cell Line, Tumor ; Tumor Microenvironment ; }, abstract = {Chimeric antigen receptor (CAR) T cell therapeutic responses are hampered by limited T cell trafficking, persistence, and durable anti-tumor activity in solid tumors. However, these challenges can be largely overcome by relatively unconstrained synthetic engineering strategies. Here, we describe CAR T cells targeting tumor-associated glycoprotein-72 (TAG72), utilizing the CD28 transmembrane domain upstream of the 4-1BB co-stimulatory domain as a driver of potent anti-tumor activity and IFNγ secretion. CAR T cell-mediated IFNγ production facilitated by IL-12 signaling is required for tumor cell killing, which is recapitulated by engineering an optimized membrane-bound IL-12 (mbIL12) molecule in CAR T cells. These T cells show improved antigen-dependent T cell proliferation and recursive tumor cell killing in vitro, with robust in vivo efficacy in human ovarian cancer xenograft models. Locoregional administration of mbIL12-engineered CAR T cells promotes durable anti-tumor responses against both regional and systemic disease in mice. Safety and efficacy of mbIL12-engineered CAR T cells is demonstrated using an immunocompetent mouse model, with beneficial effects on the immunosuppressive tumor microenvironment. Collectively, our study features a clinically-applicable strategy to improve the efficacy of locoregionally-delivered CAR T cells engineered with antigen-dependent immune-modulating cytokines in targeting regional and systemic disease.}, }
@article {pmid37549914, year = {2023}, author = {Bhatia, S and Pappo, AS and Acquazzino, M and Allen-Rhoades, WA and Barnett, M and Borinstein, SC and Casey, R and Choo, S and Chugh, R and Dinner, S and Ermoian, R and Fair, D and Federman, N and Folbrecht, J and Gandhi, S and Germann, J and Goldsby, R and Hayashi, R and Huang, AY and Huang, MS and Jacobs, LA and Lee-Miller, C and Link, MP and Livingston, JA and Lustberg, M and Malogolowkin, M and Oeffinger, KC and Pratilas, CA and Reed, D and Skiles, J and von Mehren, M and Yeager, N and Montgomery, S and Hang, L}, title = {Adolescent and Young Adult (AYA) Oncology, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {21}, number = {8}, pages = {851-880}, doi = {10.6004/jnccn.2023.0040}, pmid = {37549914}, issn = {1540-1413}, mesh = {Humans ; Adolescent ; Young Adult ; Aged ; *Medical Oncology ; *Neoplasms/diagnosis/therapy/psychology ; Counseling ; Survivorship ; Risk Factors ; }, abstract = {This selection from the NCCN Guidelines for Adolescent and Young Adult (AYA) Oncology focuses on considerations for the comprehensive care of AYA patients with cancer. Compared with older adults with cancer, AYA patients have unique needs regarding treatment, fertility counseling, psychosocial and behavioral issues, and supportive care services. The complete version of the NCCN Guidelines for Adolescent and Young Adult (AYA) Oncology addresses additional aspects of caring for AYA patients, including risk factors, screening, diagnosis, and survivorship.}, }
@article {pmid37549906, year = {2023}, author = {Sanft, T and Day, A and Ansbaugh, S and Armenian, S and Baker, KS and Ballinger, T and Demark-Wahnefried, W and Dickinson, K and Fairman, NP and Felciano, J and Flores, TF and Friedman, DL and Gabel, NM and Goldman, M and Henry, NL and Hill-Kayser, C and Hudson, M and Koura, D and Lee, K and McDonough, AL and Melisko, M and Mooney, K and Moore, HCF and Moryl, N and Neuman, H and O'Connor, T and Overholser, L and Paskett, ED and Patel, C and Peterson, L and Pirl, W and Porpiglia, A and Rodriguez, MA and Schapira, L and Schwartz, AL and Smith, S and Tevaarwerk, A and Yang, E and Zee, P and McMillian, NR and Freedman-Cass, DA}, title = {NCCN Guidelines® Insights: Survivorship, Version 1.2023.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {21}, number = {8}, pages = {792-803}, doi = {10.6004/jnccn.2023.0041}, pmid = {37549906}, issn = {1540-1413}, mesh = {Adult ; Humans ; Survivorship ; *Neoplasms/diagnosis/therapy/psychology ; Survivors ; *Cancer Survivors/psychology ; Immunization ; }, abstract = {The NCCN Guidelines for Survivorship are intended to help healthcare professionals address the complex and varied needs of cancer survivors. The NCCN Guidelines provide screening, evaluation, and treatment recommendations for psychosocial and physical problems resulting from adult-onset cancer and its treatment; recommendations to help promote healthy behaviors and immunizations in survivors; and a framework for care coordination. These NCCN Guidelines Insights summarize recent guideline updates and panel discussions pertaining to sleep disorders, fatigue, and cognitive function in cancer survivors.}, }
@article {pmid37547455, year = {2023}, author = {Cosby, AG and Arino, T and Bailey, TA and Buerger, M and Woods, JJ and Aguirre Quintana, LM and Alvarenga Vasquez, JV and Wacker, JN and Gaiser, AN and Strong, RK and Abergel, RJ}, title = {Siderocalin fusion proteins enable a new [86]Y/[90]Y theranostic approach.}, journal = {RSC chemical biology}, volume = {4}, number = {8}, pages = {587-591}, pmid = {37547455}, issn = {2633-0679}, abstract = {The mammalian protein siderocalin binds bacterial siderophores and their iron complexes through cation-π and electrostatic interactions, but also displays high affinity for hydroxypyridinone complexes of trivalent lanthanides and actinides. In order to circumvent synthetic challenges, the use of siderocalin-antibody fusion proteins is explored herein as an alternative targeting approach for precision delivery of trivalent radiometals. We demonstrate the viability of this approach in vivo, using the theranostic pair [90]Y (β[-], t1/2 = 64 h)/[86]Y (β[+], t1/2 = 14.7 h) in a SKOV-3 xenograft mouse model. Ligand radiolabeling with octadentate hydroxypyridinonate 3,4,3-LI(1,2-HOPO) and subsequent protein binding were achieved at room temperature. The results reported here suggest that the rapid non-covalent binding interaction between siderocalin fusion proteins and the negatively charged Y(iii)-3,4,3-LI(1,2-HOPO) complexes could enable purification-free, cold-kit labeling strategies for the application of therapeutically relevant radiometals in the clinic.}, }
@article {pmid37545808, year = {2023}, author = {Grady, ST and Hart, JE and Laden, F and Roscoe, C and Nguyen, DD and Nelson, EJ and Bozigar, M and VoPham, T and Manson, JE and Weuve, J and Adar, SD and Forman, JP and Rexrode, K and Levy, JI and Peters, JL}, title = {Associations between long-term aircraft noise exposure, cardiovascular disease, and mortality in US cohorts of female nurses.}, journal = {Environmental epidemiology (Philadelphia, Pa.)}, volume = {7}, number = {4}, pages = {e259}, pmid = {37545808}, issn = {2474-7882}, abstract = {UNLABELLED: There is limited research examining aircraft noise and cardiovascular disease (CVD) risk. The objective of this study was to investigate associations of aircraft noise with CVD among two US cohorts, the Nurses' Health Study (NHS) and Nurses' Health Study II (NHSII).
METHODS: Between 1994 and 2014, we followed 57,306 NHS and 60,058 NHSII participants surrounding 90 airports. Aircraft noise was modeled above 44 A-weighted decibels (dB(A)) and linked to geocoded addresses. Based on exposure distributions, we dichotomized exposures at 50 dB(A) and tested sensitivity of this cut-point by analyzing aircraft noise as categories (<45, 45-49, 50-54, ≥55) and continuously. We fit cohort-specific Cox proportional hazards models to estimate relationships between time-varying day-night average sound level (DNL) and CVD incidence and CVD and all-cause mortality, adjusting for fixed and time-varying individual- and area-level covariates. Results were pooled using random effects meta-analysis.
RESULTS: Over 20 years of follow-up, there were 4529 CVD cases and 14,930 deaths. Approximately 7% (n = 317) of CVD cases were exposed to DNL ≥50 dB(A). In pooled analyses comparing ≥50 with <50 dB(A), the adjusted hazard ratio for CVD incidence was 1.00 (95% confidence interval: 0.89, 1.12). The corresponding adjusted hazard ratio for all-cause mortality was 1.02 (95% confidence interval: 0.96, 1.09). Patterns were similar for CVD mortality in NHS yet underpowered.
CONCLUSIONS: Among participants in the NHS and NHSII prospective cohorts who generally experience low exposure to aircraft noise, we did not find adverse associations of aircraft noise with CVD incidence, CVD mortality, or all-cause mortality.}, }
@article {pmid37544374, year = {2023}, author = {Zuercher, MD and Harvey, DJ and Au, LE and Shadyab, AH and Santiago-Torres, M and Liu, S and Shivappa, N and Hebert, JR and Robbins, JA and Garcia, L}, title = {Energy-Adjusted Dietary Inflammatory Index and Diabetes Risk in Postmenopausal Hispanic Women.}, journal = {Journal of the Academy of Nutrition and Dietetics}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jand.2023.08.002}, pmid = {37544374}, issn = {2212-2672}, abstract = {BACKGROUND: Type 2 diabetes is a major public health concern in the U.S. and worldwide. The dietary inflammatory index (DII®) and the energy-adjusted DII (E-DII[TM]) are tools that assess dietary inflammation. Previous evidence suggests that obesity can modify the association between inflammation and disease.
OBJECTIVE: The aim of this study was to evaluate the association between the DII/E-DII and incident diabetes in self-identified Hispanic women from the Women's Health Initiative (WHI). The secondary aim was to evaluate whether obesity modifies the association between the DII/E-DII scores and incident diabetes.
DESIGN: Participants were from the WHI Observational Study and the Clinical Trial Components (except women from the treatment arm in the Dietary Modification Trial) conducted among postmenopausal women in the U.S. DII/E-DII scores were calculated from a self-administered food frequency questionnaire at baseline that included 122 food items of which 12 are representative of Hispanic eating patterns.
PARTICIPANTS/SETTINGS: Participants included 3,849 postmenopausal women who self-identified as Hispanic that were recruited for the WHI from 1993 to 1998 at 40 U.S. clinical centers.
MAIN OUTCOME MEASURES: The outcome was incident diabetes.
Cox regression models were used to assess the association between DII/E-DII and incident diabetes. Models were adjusted for age at baseline, lifestyle-related risk factors, known T2DM risk factors, and neighborhood socioeconomic status. Interaction was tested between the DII/E-DII scores and obesity.
RESULTS: The incidence of diabetes was 13.1% after a median follow-up of 13 years. Higher E-DII scores were associated with a higher risk of incident diabetes (HR 1.09; 95% CI: 1.04, 1.14). There was no interaction between E-DII scores and obesity (p=0.73).
CONCLUSIONS: Pro-inflammatory diets, as measured by higher E-DII scores, were associated with a higher risk of incident diabetes. Future research is needed for understanding how the inflammatory potential of diets can be decreased.}, }
@article {pmid37544360, year = {2023}, author = {Bacher, JW and Udho, EB and Strauss, EE and Vyazunova, I and Gallinger, S and Buchanan, DD and Pai, RK and Templeton, AS and Storts, DR and Eshleman, JR and Halberg, RB}, title = {A Highly Sensitive Pan-Cancer Test for Microsatellite Instability.}, journal = {The Journal of molecular diagnostics : JMD}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jmoldx.2023.07.003}, pmid = {37544360}, issn = {1943-7811}, abstract = {Microsatellite instability (MSI) is an evolving biomarker for cancer detection and treatment. MSI was first used to identify patients with Lynch syndrome, a hereditary form of colorectal cancer (CRC), but has recently become indispensable in predicting patient response to immunotherapy. To address the need for pan-cancer MSI detection, a new multiplex assay was developed that utilizes novel long mononucleotide repeat markers (LMR) to improve sensitivity. 469 tumor samples from 20 different cancer types, including 319 from patients with Lynch syndrome, were tested for MSI using the new LMR MSI Analysis System. Results were validated using mismatch repair deficiency status by immunohistochemistry (dMMR-IHC) as the reference standard and compared to Promega's pentaplex MSI panel. The sensitivity of the LMR panel for detection of dMMR-IHC was 99% for CRC and 96% for non-CRC. The overall percent agreement between the LMR and pentaplex panels was 99% for CRC and 89% for non-CRC tumors. An increased number of unstable markers and the larger size shifts observed in dMMR tumors using the LMR panel increased confidence in MSI determinations. The LMR MSI Analysis System expands the spectrum of cancer types in which MSI can be accurately detected.}, }
@article {pmid37543212, year = {2023}, author = {Handley, G and Pasikhova, Y and Hill, JA}, title = {Letter to the Editor Regarding "Once-Daily Foscarnet Is Effective for Human Herpesvirus 6 Reactivation after Hematopoietic Stem Cell Transplantation".}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2023.08.002}, pmid = {37543212}, issn = {2666-6367}, }
@article {pmid37541329, year = {2023}, author = {Buchbinder, D and Bhatt, NS and Wang, H and Yasui, Y and Armenian, S and Bhatia, S and Chow, EJ and Huang, IC and Kirchoff, AC and Leisenring, W and Park, ER and Yabroff, KR and Armstrong, GT and Nathan, PC and Khera, N}, title = {Financial hardship in childhood cancer survivors treated with hematopoietic cell transplant: A report from the Childhood Cancer Survivor Study.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2023.07.024}, pmid = {37541329}, issn = {2666-6367}, support = {U24 CA055727/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Long-term survivors of childhood cancer are at risk for financial hardship. However, it is not known if HCT leads to an incremental change in financial hardship for survivors who received it vs. those who did not. We examined financial outcomes among adult survivors of childhood cancer who had undergone HCT.
METHODS: Using a cross-sectional survey in the Childhood Cancer Survivor Study population between 2017-2019, self-reported financial hardship was compared between survivors who received HCT, survivors treated without HCT ("non-HCT"), and siblings and categorized into 3 domains (material hardship/financial sacrifices, behavioral, and psychological hardship). The standardized score of each domain of financial hardship was calculated by adding the item responses and dividing by the standard deviation among siblings. Multivariable linear and logistic regression evaluated associations between socio-demographics, cancer diagnosis, post-treatment complications and financial hardship among survivors.
RESULTS: Mean adjusted score for each hardship domain among HCT survivors (n=133) was not significantly different from non-HCT survivors (n=2711): material hardship/financial sacrifices (mean difference 0.18, 95% confidence interval [CI] [-0.05, 0.41]), behavioral hardship (0.07, [-0.18, 0.32]), psychological hardship (0.19, [-0.04, 0.42]). Within specific items, a higher proportion of survivors treated with HCT reported greater financial hardship compared to non-HCT survivors. HCT survivors also had significantly higher mean domain scores compared to sibling controls (n=1027) in all domains. Household income and chronic health conditions, but not HCT, were associated with financial hardship among all survivors.
CONCLUSIONS: Adult survivors of childhood cancer treated with HCT do not report greater overall financial hardship compared to non-HCT survivors; but greater overall financial hardship compared to sibling controls. Surveillance and intervention may be necessary for all survivors regardless of HCT status.}, }
@article {pmid37034683, year = {2023}, author = {Dillon, LW and Higgins, J and Nasif, H and Othus, M and Beppu, L and Smith, TH and Schmidt, E and Valentine, CC and Salk, JJ and Wood, BL and Erba, HP and Radich, JP and Hourigan, CS}, title = {Quantification of measurable residual disease using duplex sequencing in adults with acute myeloid leukemia.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {37034683}, support = {R01 CA175008/CA/NCI NIH HHS/United States ; R44 CA233381/CA/NCI NIH HHS/United States ; }, abstract = {The presence of measurable residual disease (MRD) is strongly associated with treatment outcomes in acute myeloid leukemia (AML). Despite the correlation with clinical outcomes, MRD assessment has yet to be standardized or routinely incorporated into clinical trials. Discrepancies have been observed between different techniques for MRD assessment and there remains a need to compare centralized, high-quality multiparametric flow cytometry (MFC) and ultrasensitive next-generation sequencing (NGS) in AML patients with diverse mutational profiles. In 62 patients with AML, aged 18-60, in first complete remission after intensive induction therapy on the randomized phase 3 SWOG-S0106 clinical trial, MRD detection by MFC was compared with a 29 gene panel utilizing duplex sequencing (DS), an NGS method that generates double-stranded consensus sequences to reduce false positive errors. Using DS, detection of a persistent mutation utilizing defined criteria was seen in 22 (35%) patients and was strongly associated with higher rates of relapse (68% vs 13% at year 5; HR, 8.8; 95% CI, 3.2-24.5; P<0.001) and decreased survival (32% vs 82% at year 5; HR, 5.6; 95% CI, 2.3-13.8; P<0.001). MRD as defined by DS strongly outperformed MFC, which was observed in 10 (16%) patients and marginally associated with higher rates of relapse (50% vs 30% at year 5; HR, 2.4; 95% CI, 0.9-6.7; P=0.087) and decreased survival (40% vs 68% at year 5; HR, 2.5; 95% CI, 1.0-6.3; P=0.059). Furthermore, the prognostic significance of DS MRD status at the time of remission was similar on both randomized arms of the trial, predicting S0106 clinical trial outcomes. These findings suggest that DS is a powerful tool that could be used in patient management and for early treatment assessment in clinical trials.}, }
@article {pmid37541263, year = {2023}, author = {Krouse, RS and Anderson, GL and Arnold, KB and Thomson, CA and Nfonsam, VN and Al-Kasspooles, MF and Walker, JL and Sun, V and Alvarez Secord, A and Han, ES and Leon-Takahashi, AM and Isla-Ortiz, D and Rodgers, P and Hendren, S and Sanchez Salcedo, M and Laryea, JA and Graybill, WS and Flaherty, DC and Mogal, H and Miner, TJ and Pimiento, JM and Kitano, M and Badgwell, B and Whalen, G and Lamont, JP and Guevara, OA and Senthil, MS and Dewdney, SB and Silberfein, E and Wright, JD and Friday, B and Fahy, B and Anantha Sathyanarayana, S and O'Rourke, M and Bakitas, M and Sloan, J and Grant, M and Deutsch, GB and Deneve, JL}, title = {Surgical versus non-surgical management for patients with malignant bowel obstruction (S1316): a pragmatic comparative effectiveness trial.}, journal = {The lancet. Gastroenterology & hepatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/S2468-1253(23)00191-7}, pmid = {37541263}, issn = {2468-1253}, abstract = {BACKGROUND: Malignant small bowel obstruction has a poor prognosis and is associated with multiple related symptoms. The optimal treatment approach is often unclear. We aimed to compare surgical versus non-surgical management with the aim to determine the optimal approach for managing malignant bowel obstruction.
METHODS: S1316 was a pragmatic comparative effectiveness trial done within the National Cancer Trials Network at 30 hospital and cancer research centres in the USA, Mexico, Peru, and Colombia. Participants had an intra-abdominal or retroperitoneal primary cancer confirmed via pathological report and malignant bowel disease; were aged 18 years or older with a Zubrod performance status 0-2 within 1 week before admission; had a surgical indication; and treatment equipoise. Participants were randomly assigned (1:1) to surgical or non-surgical treatment using a dynamic balancing algorithm, balancing on primary tumour type. Patients who declined consent for random assignment were offered a prospective observational patient choice pathway. The primary outcome was the number of days alive and out of the hospital (good days) at 91 days. Analyses were based on intention-to-treat linear, logistic, and Cox regression models combining data from both pathways and adjusting for potential confounders. Treatment complications were assessed in all analysed patients in the study. This completed study is registered with ClinicalTrials.gov, NCT02270450.
FINDINGS: From May 11, 2015, to April 27, 2020, 221 patients were enrolled (143 [65%] were female and 78 [35%] were male). There were 199 evaluable participants: 49 in the randomised pathway (24 surgery and 25 non-surgery) and 150 in the patient choice pathway (58 surgery and 92 non-surgery). No difference was seen between surgery and non-surgery for the primary outcome of good days: mean 42·6 days (SD 32·2) in the randomised surgery group, 43·9 days (29·5) in the randomised non-surgery group, 54·8 days (27·0) in the patient choice surgery group, and 52·7 days (30·7) in the patient choice non-surgery group (adjusted mean difference 2·9 additional good days in surgical versus non-surgical treatment [95% CI -5·5 to 11·3]; p=0·50). During their initial hospital stay, six participants died, five due to cancer progression (four patients from the randomised pathway, two in each treatment group, and one from the patient choice pathway, in the surgery group) and one due to malignant bowel obstruction treatment complications (patient choice pathway, non-surgery). The most common grade 3-4 malignant bowel obstruction treatment complication was anaemia (three [6%] patients in the randomised pathway, all in the surgical group, and five [3%] patients in the patient choice pathway, four in the surgical group and one in the non-surgical group).
INTERPRETATION: In our study, whether patients received a surgical or non-surgical treatment approach did not influence good days during the first 91 days after registration. These findings should inform treatment decisions for patients hospitalised with malignant bowel obstruction.
FUNDING: Agency for Healthcare Research and Quality and the National Cancer Institute.
TRANSLATION: For the Spanish translation of the abstract see Supplementary Materials section.}, }
@article {pmid37541199, year = {2023}, author = {Chowdhury, S and Kennedy, JJ and Ivey, RG and Murillo, OD and Hosseini, N and Song, X and Petralia, F and Calinawan, A and Savage, SR and Berry, AB and Reva, B and Ozbek, U and Krek, A and Ma, W and da Veiga Leprevost, F and Ji, J and Yoo, S and Lin, C and Voytovich, UJ and Huang, Y and Lee, SH and Bergan, L and Lorentzen, TD and Mesri, M and Rodriguez, H and Hoofnagle, AN and Herbert, ZT and Nesvizhskii, AI and Zhang, B and Whiteaker, JR and Fenyo, D and McKerrow, W and Wang, J and Schürer, SC and Stathias, V and Chen, XS and Barcellos-Hoff, MH and Starr, TK and Winterhoff, BJ and Nelson, AC and Mok, SC and Kaufmann, SH and Drescher, C and Cieslik, M and Wang, P and Birrer, MJ and Paulovich, AG}, title = {Proteogenomic analysis of chemo-refractory high-grade serous ovarian cancer.}, journal = {Cell}, volume = {186}, number = {16}, pages = {3476-3498.e35}, doi = {10.1016/j.cell.2023.07.004}, pmid = {37541199}, issn = {1097-4172}, support = {U01 CA214114/CA/NCI NIH HHS/United States ; R50 CA211499/CA/NCI NIH HHS/United States ; U24 CA210993/CA/NCI NIH HHS/United States ; U24 CA271114/CA/NCI NIH HHS/United States ; U24 CA210954/CA/NCI NIH HHS/United States ; U24 CA210967/CA/NCI NIH HHS/United States ; U24 CA210972/CA/NCI NIH HHS/United States ; P30 CA240139/CA/NCI NIH HHS/United States ; P50 CA136393/CA/NCI NIH HHS/United States ; P30 CA015083/CA/NCI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; }, mesh = {Female ; Humans ; *Cystadenocarcinoma, Serous/drug therapy/genetics ; *Ovarian Neoplasms/drug therapy/genetics ; *Proteogenomics ; }, abstract = {To improve the understanding of chemo-refractory high-grade serous ovarian cancers (HGSOCs), we characterized the proteogenomic landscape of 242 (refractory and sensitive) HGSOCs, representing one discovery and two validation cohorts across two biospecimen types (formalin-fixed paraffin-embedded and frozen). We identified a 64-protein signature that predicts with high specificity a subset of HGSOCs refractory to initial platinum-based therapy and is validated in two independent patient cohorts. We detected significant association between lack of Ch17 loss of heterozygosity (LOH) and chemo-refractoriness. Based on pathway protein expression, we identified 5 clusters of HGSOC, which validated across two independent patient cohorts and patient-derived xenograft (PDX) models. These clusters may represent different mechanisms of refractoriness and implicate putative therapeutic vulnerabilities.}, }
@article {pmid37541161, year = {2023}, author = {Jacobsen, DP and Fjeldstad, HE and Sugulle, M and Johnsen, GM and Olsen, MB and Kanaan, SB and Staff, AC}, title = {Fetal microchimerism and the two-stage model of preeclampsia.}, journal = {Journal of reproductive immunology}, volume = {159}, number = {}, pages = {104124}, doi = {10.1016/j.jri.2023.104124}, pmid = {37541161}, issn = {1872-7603}, abstract = {Fetal cells cross the placenta during pregnancy and some have the ability to persist in maternal organs and circulation long-term, a phenomenon termed fetal microchimerism. These cells often belong to stem cell or immune cell lineages. The long-term effects of fetal microchimerism are likely mixed, potentially depending on the amount of fetal cells transferred, fetal-maternal histocompatibility and fetal cell-specific properties. Both human and animal data indicate that fetal-origin cells partake in tissue repair and may benefit maternal health overall. On the other hand, these cells have been implicated in inflammatory diseases by studies showing increased fetal microchimerism in women with autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis. During pregnancy, preeclampsia is associated with increased cell-transfer between the mother and fetus, and an increase in immune cell subsets. In the current review, we discuss potential mechanisms of transplacental transfer, including passive leakage across the compromised diffusion barrier and active recruitment of cells residing in the placenta or fetal circulation. Within the conceptual framework of the two-stage model of preeclampsia, where syncytiotrophoblast stress is a common pathophysiological pathway to maternal and fetal clinical features of preeclampsia, we argue that microchimerism may represent a mechanistic link between stage 1 placental dysfunction and stage 2 maternal cardiovascular inflammation and endothelial dysfunction. Finally, we postulate that fetal microchimerism may contribute to the known association between placental syndromes and increased long-term maternal cardiovascular disease risk. Fetal microchimerism research represents an exciting opportunity for developing new disease biomarkers and targeted prophylaxis against maternal diseases.}, }
@article {pmid37540787, year = {2023}, author = {Schmeusser, BN and Biermann, H and Nicaise, EH and Ali, AA and Patil, DH and Midenberg, E and Helman, T and Armas-Phan, M and Nabavizadeh, R and Joshi, SS and Narayan, VM and Bilen, MA and Psutka, SP and Ogan, K and Master, VA}, title = {Creatinine to Cystatin-C Ratio in Renal Cell Carcinoma: A Clinically Pragmatic Prognostic Factor and Sarcopenia Biomarker.}, journal = {The oncologist}, volume = {}, number = {}, pages = {}, doi = {10.1093/oncolo/oyad218}, pmid = {37540787}, issn = {1549-490X}, support = {//John Robinson Family Foundation/ ; //Christopher Churchill Foundation/ ; //Cox Immunology/ ; }, abstract = {INTRODUCTION: Low creatinine to cystatin-C ratio (Cr/Cys-C) may be a biomarker for low-muscle mass. Furthermore, low Cr/Cys-C is associated with decreased overall survival (OS), but to date, has not been examined in patients with renal cell carcinoma (RCC). Our objective is to evaluate associations between low Cr/Cys-C ratio and OS and recurrence-free survival (RFS) in patients with RCC treated with nephrectomy.
METHODS: We performed a retrospective review of patients with RCC treated with nephrectomy. Patients with end-stage renal disease and less than 1-year follow up were excluded. Cr/Cys-C was dichotomized at the median for the cohort (low vs. high). OS and RFS for patients with high versus low Cr/Cys-C were estimated with the Kaplan-Meier method, and associations with the outcomes of interest were modeled using Cox proportional Hazards models. Associations between Cr/Cys-C and skeletal muscle mass were assessed with correlations and logistic regression.
RESULTS: A total of 255 patients were analyzed, with a median age of 64. Median (IQR) Cr/Cys-C was 1 (0.8-1.2). Low Cr/Cys-C was associated with age, female sex, Eastern Cooperative Oncology Group Performance Status ≥1, TNM stage, and tumor size. Kaplan-Meier and Cox regression analysis demonstrated an association between low Cr/Cys-C and decreased OS (HR = 2.97, 95%CI, 1.12-7.90, P =0.029) and RFS (HR = 3.31, 95%CI, 1.26-8.66, P = .015). Furthermore, a low Cr/Cys-C indicated a 2-3 increase in risk of radiographic sarcopenia.
CONCLUSIONS: Lower Cr/Cys-C is associated with inferior oncologic outcomes in RCC and, pending validation, may have utility as a serum biomarker for the presence of sarcopenia in patients with RCC treated with nephrectomy.}, }
@article {pmid37540676, year = {2023}, author = {McClymont, E and Bone, J and Orem, J and Okuku, F and Kalinaki, M and Saracino, M and Huang, ML and Selke, S and Wald, A and Corey, L and Casper, C and Boucoiran, I and Johnston, C and Gantt, S}, title = {Increased frequency and quantity of mucosal and plasma cytomegalovirus replication among Ugandan Adults Living with HIV.}, journal = {PloS one}, volume = {18}, number = {8}, pages = {e0287516}, pmid = {37540676}, issn = {1932-6203}, support = {K23 AI079394/AI/NIAID NIH HHS/United States ; K24 AI071113/AI/NIAID NIH HHS/United States ; P30 AI027757/AI/NIAID NIH HHS/United States ; P01 AI030731/AI/NIAID NIH HHS/United States ; }, mesh = {Male ; Humans ; Adult ; Female ; Cytomegalovirus/genetics ; Uganda/epidemiology ; *Coinfection/epidemiology/complications ; *HIV Infections/complications ; *Cytomegalovirus Infections ; Viral Load ; }, abstract = {BACKGROUND: Co-infection with HIV can result in impaired control of cytomegalovirus (CMV) replication, increasing the likelihood of disease and onward transmission. The objective of this analysis was to measure the impact of HIV on CMV replication in an intensively-sampled cohort in Kampala, Uganda.
METHODS: CMV seropositive men and women aged 18-65, with or without HIV co-infection, were followed for one month. Daily oral swabs and weekly anogenital swabs and plasma were collected. Quantitative CMV PCR was performed on all samples.
RESULTS: Eighty-five participants were enrolled and provided ≥1 oral swab; 43 (51%) were HIV-seropositive. People living with HIV (PLWH; median CD4 count 439 cells/mm3; none on antiretrovirals) had 2-4 times greater risk of CMV detection at each anatomical site assessed. At the oral site, 773 of 1272 (61%) of samples from PLWH had CMV detected, compared to 214 of 1349 (16%) among people without HIV. Similarly, the mean CMV quantity was higher among PLWH at all anatomical sites, with the largest difference seen for oral swabs (mean difference 1.63 log/mL; 95% CI 1.13-2.13). Among PLWH, absolute quantity of CD4+ T-cells was not associated with risk of CMV detection. HIV plasma RNA quantity was positively correlated with oral CMV shedding frequency, but not detection at other sites.
CONCLUSIONS: Mucosal and systemic CMV replication occurs at higher levels in PLWH than people without HIV, particularly oral shedding, which is a major mode of CMV transmission. Increased CMV replication despite relatively preserved CD4+ T-cell counts suggests that additional interventions are required to improve CMV control in PLWH.}, }
@article {pmid37539667, year = {2023}, author = {Park, HA and Edelmann, D and Canzian, F and Seibold, P and Harrison, TA and Hua, X and Shi, Q and Silverman, A and Benner, A and Macauda, A and Schneider, M and Goldberg, RM and Alberts, SR and Hoffmeister, M and Brenner, H and Chan, AT and Peters, U and Newcomb, PA and Chang-Claude, J}, title = {Genome-wide study of genetic polymorphisms predictive for outcome from first-line oxaliplatin-based chemotherapy in colorectal cancer patients.}, journal = {International journal of cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/ijc.34663}, pmid = {37539667}, issn = {1097-0215}, support = {CA25224/CA/NCI NIH HHS/United States ; CA37404/CA/NCI NIH HHS/United States ; CA35103/CA/NCI NIH HHS/United States ; CA35113/CA/NCI NIH HHS/United States ; CA35272/CA/NCI NIH HHS/United States ; CA114740/CA/NCI NIH HHS/United States ; CA32102/CA/NCI NIH HHS/United States ; CA14028/CA/NCI NIH HHS/United States ; CA49957/CA/NCI NIH HHS/United States ; CA21115/CA/NCI NIH HHS/United States ; CA31946/CA/NCI NIH HHS/United States ; CA180868/CA/NCI NIH HHS/United States ; CA189867/CA/NCI NIH HHS/United States ; R01CA176272/CA/NCI NIH HHS/United States ; U10CA180821/NH/NIH HHS/United States ; U10CA180882/NH/NIH HHS/United States ; }, abstract = {We conducted the first large genome-wide association study to identify novel genetic variants that predict better (or poorer) prognosis in colorectal cancer patients receiving standard first-line oxaliplatin-based chemotherapy vs chemotherapy without oxaliplatin. We used data from two phase III trials, NCCTG N0147 and NCCTG N9741 and a population-based patient cohort, DACHS. Multivariable Cox proportional hazards models were employed, including an interaction term between each SNP and type of treatment for overall survival (OS) and progression-free survival. The analysis was performed for studies individually, and the results were combined using fixed-effect meta-analyses separately for resected stage III colon cancer (3098 patients from NCCTG N0147 and 549 patients from DACHS) and mCRC (505 patients from NCCTG N9741 and 437 patients from DACHS). We further performed gene-based analysis as well as in silico bioinformatics analysis for CRC-relevant functional genomic annotation of identified loci. In stage III colon cancer patients, a locus on chr22 (rs11912167) was associated with significantly poorer OS after oxaliplatin-based chemotherapy vs chemotherapy without oxaliplatin (Pinteraction < 5 × 10[-8]). For mCRC patients, three loci on chr1 (rs1234556), chr12 (rs11052270) and chr15 (rs11858406) were found to be associated with differential OS (P < 5 × 10[-7]). The locus on chr1 located in the intronic region of RCSD1 was replicated in an independent cohort of 586 mCRC patients from ALGB/SWOG 80405 (Pinteraction = .04). The GWA gene-based analysis yielded for RCSD1 the most significant association with differential OS in mCRC (P = 6.6 × 10[-6]). With further investigation into its biological mechanisms, this finding could potentially be used to individualize first-line treatment and improve clinical outcomes.}, }
@article {pmid37537116, year = {2023}, author = {Isabella, AJ and Moens, CB}, title = {Development and regeneration of the vagus nerve.}, journal = {Seminars in cell & developmental biology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.semcdb.2023.07.008}, pmid = {37537116}, issn = {1096-3634}, abstract = {The vagus nerve, with its myriad constituent axon branches and innervation targets, has long been a model of anatomical complexity in the nervous system. The branched architecture of the vagus nerve is now appreciated to be highly organized around the topographic and/or molecular identities of the neurons that innervate each target tissue. However, we are only just beginning to understand the developmental mechanisms by which heterogeneous vagus neuron identity is specified, patterned, and used to guide the axons of particular neurons to particular targets. Here, we summarize our current understanding of the complex topographic and molecular organization of the vagus nerve, the developmental basis of neuron specification and patterned axon guidance that supports this organization, and the regenerative mechanisms that promote, or inhibit, the restoration of vagus nerve organization after nerve damage. Finally, we highlight key unanswered questions in these areas and discuss potential strategies to address these questions.}, }
@article {pmid37534515, year = {2023}, author = {Dillon, LW and Higgins, J and Nasif, H and Othus, M and Beppu, L and Smith, TH and Schmidt, E and Valentine Iii, CC and Salk, JJ and Wood, BL and Erba, HP and Radich, JP and Hourigan, CS}, title = {Quantification of measurable residual disease using duplex sequencing in adults with acute myeloid leukemia.}, journal = {Haematologica}, volume = {}, number = {}, pages = {}, doi = {10.3324/haematol.2023.283520}, pmid = {37534515}, issn = {1592-8721}, abstract = {The presence of measurable residual disease (MRD) is strongly associated with treatment outcomes in acute myeloid leukemia (AML). Despite the correlation with clinical outcomes, MRD assessment has yet to be standardized or routinely incorporated into clinical trials and discrepancies have been observed between different techniques for MRD assessment. In 62 patients with AML, aged 18-60, in first complete remission after intensive induction therapy on the randomized phase 3 SWOG-S0106 clinical trial, MRD detection by centralized, high-quality multiparametric flow cytometry (MFC) was compared with a 29 gene panel utilizing duplex sequencing (DS), an ultrasensitive next-generation sequencing method that generates doublestranded consensus sequences to reduce false positive errors. MRD as defined by DS was observed in 22 (35%) patients and was strongly associated with higher rates of relapse (68% vs 13%; HR, 8.8; 95% CI, 3.2-24.5; P.}, }
@article {pmid36607839, year = {2023}, author = {Masih, KE and Gardner, RA and Chou, HC and Abdelmaksoud, A and Song, YK and Mariani, L and Gangalapudi, V and Gryder, BE and Wilson, AL and Adebola, SO and Stanton, BZ and Wang, C and Milewski, D and Kim, YY and Tian, M and Cheuk, AT and Wen, X and Zhang, Y and Altan-Bonnet, G and Kelly, MC and Wei, JS and Bulyk, ML and Jensen, MC and Orentas, RJ and Khan, J}, title = {A stem cell epigenome is associated with primary nonresponse to CD19 CAR T cells in pediatric acute lymphoblastic leukemia.}, journal = {Blood advances}, volume = {7}, number = {15}, pages = {4218-4232}, doi = {10.1182/bloodadvances.2022008977}, pmid = {36607839}, issn = {2473-9537}, abstract = {CD19 chimeric antigen receptor T-cell therapy (CD19-CAR) has changed the treatment landscape and outcomes for patients with pre-B-cell acute lymphoblastic leukemia (B-ALL). Unfortunately, primary nonresponse (PNR), sustained CD19+ disease, and concurrent expansion of CD19-CAR occur in 20% of the patients and is associated with adverse outcomes. Although some failures may be attributable to CD19 loss, mechanisms of CD19-independent, leukemia-intrinsic resistance to CD19-CAR remain poorly understood. We hypothesize that PNR leukemias are distinct compared with primary sensitive (PS) leukemias and that these differences are present before treatment. We used a multiomic approach to investigate this in 14 patients (7 with PNR and 7 with PS) enrolled in the PLAT-02 trial at Seattle Children's Hospital. Long-read PacBio sequencing helped identify 1 PNR in which 47% of CD19 transcripts had exon 2 skipping, but other samples lacked CD19 transcript abnormalities. Epigenetic profiling discovered DNA hypermethylation at genes targeted by polycomb repressive complex 2 (PRC2) in embryonic stem cells. Similarly, assays of transposase-accessible chromatin-sequencing revealed reduced accessibility at these PRC2 target genes, with a gain in accessibility of regions characteristic of hematopoietic stem cells and multilineage progenitors in PNR. Single-cell RNA sequencing and cytometry by time of flight analyses identified leukemic subpopulations expressing multilineage markers and decreased antigen presentation in PNR. We thus describe the association of a stem cell epigenome with primary resistance to CD19-CAR therapy. Future trials incorporating these biomarkers, with the addition of multispecific CAR T cells targeting against leukemic stem cell or myeloid antigens, and/or combined epigenetic therapy to disrupt this distinct stem cell epigenome may improve outcomes of patients with B-ALL.}, }
@article {pmid37533944, year = {2023}, author = {Marcelin, HN and Dasse, RS and Yeboah, RO and Tariam, AD and Kagambega, AGZ and Oseni, AM and Kouassi, YKK and Bilé, MA and Toure, M and Thakar, M and Adoubi, I and Kizub, D}, title = {Circulating natural killer cells and their association with breast cancer and its clinico-pathological characteristics.}, journal = {Ecancermedicalscience}, volume = {17}, number = {}, pages = {1567}, pmid = {37533944}, issn = {1754-6605}, abstract = {PURPOSE: Natural killer (NK) cells play a critical role in cancer immunosurveillance and hold promise as both therapies and prognostic markers in advanced disease. We explore factors that may influence NK cell concentration in the peripheral blood of women with breast cancer in Côte d'Ivoire compared to healthy controls and implications for future research in our context.
METHODS: In this cross-sectional case-control study, blood samples were taken from 30 women diagnosed with breast cancer within 6 months of diagnosis and fifteen healthy women at University Teaching Hospital [Centre Hospitalier Universitaire (CHU)] Treichville in Abidjan, Côte d'Ivoire, from March to September 2018. The blood draw could take place at any time following diagnosis and through treatment. Demographic and clinical data were collected. NK cells were isolated, stained, analysed and counted using the flow cytometer at the Department of Immunology at CHU of Cocody. All p-values were two-sided.
RESULTS: Mean age among 30 women with breast cancer was 49 years old compared to 45 years old for 15 controls (p = 0.41). Among 30 women with breast cancer, 4 (13.3%) had Stage 2 disease, 14 (46.7 %) at Stage 3, and 12 (40%) at Stage 4. Fourteen (46.7%) had breast cancer that was hormone receptor-positive (HR+) HER2-negative, 10 (33.3%) had triple-negative cancer, three (10.0%) had HR+HER2+ disease, and three (10.0%) HR-HER2+ cancer. NK cell concentration was not associated with cancer diagnosis, age, cancer stage, subtype, or type of treatment patients received (p > 0.05).
CONCLUSION: Although we did not find an association between NK cell concentration, cancer characteristics or treatment, our results be limited by the small sample size and timing of blood draw. Our next steps include a larger study to explore circulating NK cells prior to any treatment and NK cell infiltration within breast cancer tumour and correlating this with response to treatment and prognosis.}, }
@article {pmid37533407, year = {2023}, author = {Gil da Costa, RM and Levesque, C and Bianchi-Frias, D and Chatterjee, P and Lam, HM and Santos, C and Coleman, IM and Ferreirinha, P and Vilanova, M and da Cunha, NP and Carvalho, H and Moreira-Pais, A and Faustino-Rocha, A and Neto, T and da Costa, JB and Wright, JL and Ferreira, R and Oliveira, PA and Mendes, J and Bastos, MMSM and Colaço, B and Lopes, C and Black, PC and Sweeney, CJ and Nelson, PS}, title = {Pharmacological NF-κB inhibition decreases cisplatin chemoresistance in muscle-invasive bladder cancer and reduces cisplatin-induced toxicities.}, journal = {Molecular oncology}, volume = {}, number = {}, pages = {}, doi = {10.1002/1878-0261.13504}, pmid = {37533407}, issn = {1878-0261}, abstract = {Most patients with muscle-invasive bladder cancer (MIBC) are not cured with platinum chemotherapy. Up-regulation of nuclear factor kappa light chain enhancer of activated B cells (NF-κB) is a major mechanism underlying chemoresistance, suggesting that its pharmacological inhibition may increase platinum efficacy. NF-κB signaling was investigated in two patient cohorts. The Cancer Genome Atlas (TCGA) was used to correlate NF-κB signaling and patient survival. The efficacy of cisplatin plus the NF-κB inhibitor dimethylaminoparthenolide (DMAPT) versus cisplatin or DMAPT alone was tested in vitro. Xenografted and immunocompetent MIBC mouse models were studied in vivo. Platinum-naive claudin-low MIBC showed constitutive NF-κB signaling and this was associated with reduced disease-specific survival in TCGA patients. Chemotherapy up-regulated NF-κB signaling and chemoresistance-associated genes, including SPHK1, PLAUR and SERPINE1. In mice, DMAPT significantly improved the efficacy of cisplatin in both models. The combination preserved body weight, renal function and morphology, reduced muscle fatigue and IL-6 serum levels, and did not aggravate immuno-hematological toxicity compared with cisplatin alone. These data provide a rationale for combining NF-κB inhibition with platinum-based chemotherapy and conducting a clinical trial in MIBC patients.}, }
@article {pmid37533195, year = {2023}, author = {Zhang, B}, title = {Efficient algorithms for building representative matched pairs with enhanced generalizability.}, journal = {Biometrics}, volume = {}, number = {}, pages = {}, doi = {10.1111/biom.13919}, pmid = {37533195}, issn = {1541-0420}, abstract = {Many recent efforts center on assessing the ability of real-world evidence (RWE) generated from non-randomized, observational data to produce results compatible with those from randomized controlled trials (RCTs). One noticeable endeavor is the RCT DUPLICATE initiative. To better reconcile findings from an observational study and an RCT, or two observational studies based on different databases, it is desirable to eliminate differences between study populations. We outline an efficient, network-flow-based statistical matching algorithm that designs well-matched pairs from observational data that resemble the covariate distributions of a target population, for instance, the target-RCT-eligible population in the RCT DUPLICATE initiative studies or a generic population of scientific interest. We demonstrate the usefulness of the method by revisiting the inconsistency regarding a cardioprotective effect of the hormone replacement therapy (HRT) in the Women's Health Initiative (WHI) clinical trial and corresponding observational study. We found that the discrepancy between the trial and observational study persisted in a design that adjusted for the difference in study populations' cardiovascular risk profile, but seemed to disappear in a study design that further adjusted for the difference in HRT initiation age and previous estrogen-plus-progestin use. The proposed method is integrated into the R package match2C.}, }
@article {pmid37424310, year = {2023}, author = {Rogers, JH and Cox, SN and Link, AC and Nwanne, G and Han, PD and Pfau, B and Chow, EJ and Wolf, CR and Boeckh, M and Hughes, JP and Halloran, ME and Uyeki, TM and Shim, MM and Duchin, J and Englund, JA and Mosites, E and Rolfes, MA and Starita, LA and Chu, HY}, title = {Incidence of SARS-CoV-2 infection and associated risk factors among staff and residents at homeless shelters in King County, Washington: an active surveillance study.}, journal = {Epidemiology and infection}, volume = {151}, number = {}, pages = {e129}, doi = {10.1017/S0950268823001036}, pmid = {37424310}, issn = {1469-4409}, support = {75D30120C09322/CC/CDC HHS/United States ; }, abstract = {Homeless shelter residents and staff may be at higher risk of SARS-CoV-2 infection. However, SARS-CoV-2 infection estimates in this population have been reliant on cross-sectional or outbreak investigation data. We conducted routine surveillance and outbreak testing in 23 homeless shelters in King County, Washington, to estimate the occurrence of laboratory-confirmed SARS-CoV-2 infection and risk factors during 1 January 2020-31 May 2021. Symptom surveys and nasal swabs were collected for SARS-CoV-2 testing by RT-PCR for residents aged ≥3 months and staff. We collected 12,915 specimens from 2,930 unique participants. We identified 4.74 (95% CI 4.00-5.58) SARS-CoV-2 infections per 100 individuals (residents: 4.96, 95% CI 4.12-5.91; staff: 3.86, 95% CI 2.43-5.79). Most infections were asymptomatic at the time of detection (74%) and detected during routine surveillance (73%). Outbreak testing yielded higher test positivity than routine surveillance (2.7% versus 0.9%). Among those infected, residents were less likely to report symptoms than staff. Participants who were vaccinated against seasonal influenza and were current smokers had lower odds of having an infection detected. Active surveillance that includes SARS-CoV-2 testing of all persons is essential in ascertaining the true burden of SARS-CoV-2 infections among residents and staff of congregate settings.}, }
@article {pmid37533140, year = {2023}, author = {Cai, Y and Franceschini, N and Surapaneni, A and Garrett, ME and Tahir, UA and Hsu, L and Telen, MJ and Yu, B and Tang, H and Li, Y and Liu, S and Gerszten, RE and Coresh, J and Manson, JE and Wojcik, GL and Kooperberg, C and Auer, PL and Foster, MW and Grams, ME and Ashley-Koch, AE and Raffield, LM and Reiner, AP}, title = {Differences in the Circulating Proteome in Individuals with versus without Sickle Cell Trait.}, journal = {Clinical journal of the American Society of Nephrology : CJASN}, volume = {}, number = {}, pages = {}, doi = {10.2215/CJN.0000000000000257}, pmid = {37533140}, issn = {1555-905X}, support = {R01-DK117445/DK/NIDDK NIH HHS/United States ; U01-HG011720/HG/NHGRI NIH HHS/United States ; R01-MD012765/MD/NIMHD NIH HHS/United States ; U01-HG011720/HG/NHGRI NIH HHS/United States ; }, abstract = {BACKGROUND: Sickle cell trait affects ∼ 8% of African American individuals, along with many other individuals with ancestry from malaria-endemic regions worldwide. While traditionally considered a benign condition, recent evidence suggests sickle cell trait is associated with lower eGFR and higher risk of kidney diseases, including end-stage kidney disease. The mechanisms underlying these associations remain poorly understood. We utilized proteomic profiling to gain insight into the pathobiology of sickle cell trait.
METHODS: We measured proteomics (N=1,285 proteins assayed by Olink Explore) using baseline plasma samples from 592 African American participants with sickle cell trait and 1:1 age-matched African American participants without sickle cell trait from the prospective Women's Health Initiative (WHI) cohort. Age-adjusted linear regression was used to assess the association between protein levels and sickle cell trait.
RESULTS: In age-adjusted models, 35 proteins were significantly associated with sickle cell trait after correction for multiple testing. Several of the sickle cell trait-protein associations were replicated in two independent cohorts of African American individuals (Atherosclerosis Risk in Communities study and Jackson Heart Study) assayed using an orthogonal aptamer-based proteomic platform (SomaScan). Many of the validated sickle cell trait-associated proteins are either known biomarkers of kidney function or injury (e.g., KIM-1, UMOD, ephrins), related to red cell physiology or hemolysis (EPO, HMOX1, AHSP), and/or inflammation (fractalkine, MCP-1, UPAR). A protein risk score constructed from the top sickle cell trait-associated biomarkers was associated with incident kidney failure among those with sickle cell trait during WHI follow-up (odds ratio 1.32; 95%CI 1.10 - 1.58).
CONCLUSIONS: We identified and replicated the association of sickle cell trait with a number of plasma proteins related to hemolysis, kidney injury, and inflammation.}, }
@article {pmid37532890, year = {2023}, author = {Yaghjyan, L and McLaughlin, E and Lehman, A and Neuhouser, ML and Rohan, T and Lane, DS and Snetselaar, L and Paskett, E}, title = {Correction: Associations of coffee/caffeine consumption with postmenopausal breast cancer risk and their interactions with postmenopausal hormone use.}, journal = {European journal of nutrition}, volume = {}, number = {}, pages = {}, doi = {10.1007/s00394-023-03216-7}, pmid = {37532890}, issn = {1436-6215}, }
@article {pmid37532126, year = {2023}, author = {Kampouri, E and Zamora, D and Kiem, ES and Liu, W and Ibrahimi, S and Blazevic, RL and Lovas, EA and Kimball, LE and Huang, ML and Jerome, KR and Oshima, MU and Mielcarek, M and Zerr, DM and Boeckh, MJ and Krantz, EM and Hill, JA}, title = {HHV-6 Reactivation and Disease after Allogeneic Hematopoietic Cell Transplantation in the Era of Letermovir for CMV Prophylaxis.}, journal = {Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.cmi.2023.07.026}, pmid = {37532126}, issn = {1469-0691}, abstract = {OBJECTIVES: Letermovir for CMV prophylaxis in allogeneic hematopoietic cell transplant (HCT) recipients has decreased anti-CMV therapy use. Contrary to letermovir, anti-CMV antivirals are also active against HHV-6. We assessed changes in HHV-6 epidemiology in the post-letermovir era.
METHODS: We conducted a retrospective cohort study of CMV-seropositive allogeneic HCT recipients comparing time periods prior to and after routine use of prophylactic letermovir. HHV-6 testing was at the discretion of clinicians. We computed the cumulative incidence of broad-spectrum antiviral initiation (foscarnet, (val)ganciclovir, and/or cidofovir), HHV-6 testing, and HHV-6 detection in blood and cerebrospinal fluid within 100 days after HCT. We used Cox proportional-hazards models with stabilized inverse probability of treatment weights to compare outcomes between cohorts balanced for baseline factors.
RESULTS: We analyzed 738 patients, 376 in the pre-letermovir and 362 in the post-letermovir cohort. Broad-spectrum antiviral initiation incidence decreased from 65% (95% confidence interval [CI], 60%-70%) pre-letermovir to 21% (95% CI, 17%-25%) post-letermovir. The cumulative incidence of HHV-6 testing (17% (95% CI,13%-21%) pre-letermovir versus 13% [95% CI, 10%-16%] post-letermovir), detection (3% [95% CI, 1%-5%] in both cohorts), and HHV-6 encephalitis (0.5% [95% CI, 0.1%-1.8%] pre-letermovir and 0.6% [95% CI, 0.1%-1.9%] post-letermovir) were similar between cohorts. First HHV-6 detection occurred at a median of 37 days (IQR, 18-58) in the pre-letermovir cohort and 27 (IQR, 25-34) in the post-letermovir cohort. In a weighted model, there was no association between the pre-versus post-letermovir cohort and HHV-6 detection (adjusted hazard ratio, 1.08; 95% confidence interval, 0.44-2.62).
CONCLUSIONS: Despite a large decrease in broad-spectrum antivirals after the introduction of letermovir prophylaxis in CMV-seropositive allogeneic HCT recipients, there was no evidence for increased clinically detected HHV-6 reactivation and disease.}, }
@article {pmid37531658, year = {2023}, author = {Heimonen, J and Chow, EJ and Wang, Y and Hughes, JP and Rogers, J and Emanuels, A and O'Hanlon, J and Han, PD and Wolf, CR and Logue, JK and Ogokeh, CE and Rolfes, MA and Uyeki, TM and Starita, L and Englund, JA and Chu, HY}, title = {Risk of Subsequent Respiratory Virus Detection After Primary Virus Detection in a Community Household Study - King County, Washington 2019-2021.}, journal = {The Journal of infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1093/infdis/jiad305}, pmid = {37531658}, issn = {1537-6613}, abstract = {BACKGROUND: The epidemiology of respiratory viral infections is complex. How infection with one respiratory virus affects risk of subsequent infection with the same or another respiratory virus is not well described.
METHODS: We retrospectively analyzed data from a longitudinal household cohort study from October 2019-June 2021. Enrolled households completed active surveillance for acute respiratory illness (ARI), and participants with ARI self-collected nasal swabs; after April 2020, participants with ARI or laboratory-confirmed SARS-CoV-2 and their household members self-collected nasal swabs. Specimens were tested via multiplex RT-PCR for respiratory viruses. A Cox regression model with a time-dependent covariate examined risk of subsequent detections following a specific primary viral detection.
RESULTS: Rhinovirus was the most frequently detected pathogen in study specimens (n=406, 9.5%). Among 51 participants with multiple viral detections, rhinovirus to seasonal coronavirus (8, 14.8%) was the most common viral detection pairing. Relative to no primary detection, there was a 1.03-2.06-fold increase in risk of subsequent virus detection in the 90 days following primary detection; risk varied by primary virus: parainfluenza, rhinovirus, and respiratory syncytial virus were statistically significant.
CONCLUSIONS: Primary virus detection was associated with higher risk of subsequent virus detection within the first 90 days after primary detection.}, }
@article {pmid37531417, year = {2023}, author = {Quintanal-Villalonga, A and Durani, V and Sabet, A and Redin, E and Kawasaki, K and Shafer, M and Karthaus, WR and Zaidi, S and Zhan, YA and Manoj, P and Sridhar, H and Shah, NS and Chow, A and Bhanot, UK and Linkov, I and Asher, M and Yu, HA and Qiu, J and de Stanchina, E and Patel, RA and Morrissey, C and Haffner, MC and Koche, RP and Sawyers, CL and Rudin, CM}, title = {Exportin 1 inhibition prevents neuroendocrine transformation through SOX2 down-regulation in lung and prostate cancers.}, journal = {Science translational medicine}, volume = {15}, number = {707}, pages = {eadf7006}, doi = {10.1126/scitranslmed.adf7006}, pmid = {37531417}, issn = {1946-6242}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; P01 CA163227/CA/NCI NIH HHS/United States ; T32 CA160001/CA/NCI NIH HHS/United States ; K08 CA248723/CA/NCI NIH HHS/United States ; R01 CA264078/CA/NCI NIH HHS/United States ; P50 CA097186/CA/NCI NIH HHS/United States ; R35 CA263816/CA/NCI NIH HHS/United States ; U24 CA213274/CA/NCI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; }, mesh = {Humans ; Male ; *Adenocarcinoma/pathology ; Down-Regulation ; *Lung Neoplasms/pathology ; *Prostatic Neoplasms/drug therapy/pathology ; *Small Cell Lung Carcinoma/genetics ; *SOXB1 Transcription Factors/genetics/metabolism ; Animals ; }, abstract = {In lung and prostate adenocarcinomas, neuroendocrine (NE) transformation to an aggressive derivative resembling small cell lung cancer (SCLC) is associated with poor prognosis. We previously described dependency of SCLC on the nuclear transporter exportin 1. Here, we explored the role of exportin 1 in NE transformation. We observed up-regulated exportin 1 in lung and prostate pretransformation adenocarcinomas. Exportin 1 was up-regulated after genetic inactivation of TP53 and RB1 in lung and prostate adenocarcinoma cell lines, accompanied by increased sensitivity to the exportin 1 inhibitor selinexor in vitro. Exportin 1 inhibition prevented NE transformation in different TP53/RB1-inactivated prostate adenocarcinoma xenograft models that acquire NE features upon treatment with the aromatase inhibitor enzalutamide and extended response to the EGFR inhibitor osimertinib in a lung cancer transformation patient-derived xenograft (PDX) model exhibiting combined adenocarcinoma/SCLC histology. Ectopic SOX2 expression restored the enzalutamide-promoted NE phenotype on adenocarcinoma-to-NE transformation xenograft models despite selinexor treatment. Selinexor sensitized NE-transformed lung and prostate small cell carcinoma PDXs to standard cytotoxics. Together, these data nominate exportin 1 inhibition as a potential therapeutic target to constrain lineage plasticity and prevent or treat NE transformation in lung and prostate adenocarcinoma.}, }
@article {pmid37531271, year = {2023}, author = {Gong, I and Cheung, MC and Chan, KKW and Arya, S and Faught, N and Calzavara, A and Liu, N and Odejide, OO and Abel, G and Kurdyak, P and Raphael, MJ and Kuczmarski, T and Prica, A and Mozessohn, L}, title = {Mortality among patients with diffuse large B-cell lymphoma with mental disorders: a population-based study.}, journal = {Journal of the National Cancer Institute}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnci/djad149}, pmid = {37531271}, issn = {1460-2105}, abstract = {BACKGROUND: While mental disorders have been reported in patients with diffuse large B-cell lymphoma (DLBCL), studies examining their association with mortality are lacking.
METHODS: We conducted a population-based study using linked administrative healthcare databases from Ontario, Canada. All patients with DLBCL aged ≥18 years treated with rituximab-based therapy between January 1st, 2005 and December 31st, 2017 were identified and followed until March 1, 2020. Mental disorders were defined as either pre-existing or post-diagnosis (after lymphoma treatment initiation). Cox proportional hazard models were used to estimate the adjusted hazard ratio (aHR) between mental disorders and outcomes 1-year and all-cause mortality, while controlling for covariates.
RESULTS: We identified 10,299 patients with DLBCL; median age 67 years; 46% female; 28% with a pre-existing mental disorder. At 1-year follow-up, 892 (9%) had a post-diagnosis mental disorder, and a total of 2,008 (20%) patients died. Pre-existing mental disorders were not associated with 1-year mortality (aHR 1.06, 95% confidence interval [CI] 0.96-1.17, p = 0.25) while post-diagnosis disorders were (aHR 1.51, 95% CI 1.26-1.82, p = 0.0001). During a median follow-up of 5.2 years, 2,111 (22%) patients had a post-diagnosis mental disorder, and 4,084 (40%) patients died. Both pre-existing and post-diagnosis mental disorders were associated with worse all-cause mortality (pre-existing aHR 1.12, 95% CI 1.04-1.20, p = 0.0024; post-diagnosis aHR 1.63, 95% CI 1.49-1.79, p < 0.0001).
CONCLUSIONS: Patients with DLBCL and mental disorders had worse short-term and long-term mortality, particularly those with post-diagnosis mental disorders. Further studies are needed to examine mental health service utilization and factors mediating the relationship between mental disorders and inferior mortality.}, }
@article {pmid37531248, year = {2023}, author = {Harris, LN and Blanke, CD and Erba, HP and Ford, JM and Gray, RJ and LeBlanc, ML and Hu-Lieskovan, S and Litzow, MR and Luger, SM and Meric-Bernstam, F and O'Dwyer, PJ and Othus, MKD and Politi, K and Shepherd, LE and Allegra, CJ and Chen, HX and Ivy, SP and Korde, LA and Little, RF and McShane, LM and Moscow, JA and Patton, DR and Thurin, M and Yee, LM and Doroshow, JH}, title = {The New NCI Precision Medicine Trials.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {}, number = {}, pages = {}, doi = {10.1158/1078-0432.CCR-23-0917}, pmid = {37531248}, issn = {1557-3265}, abstract = {Basket, umbrella, and platform trial designs (master protocols) have emerged over the last decade to study precision medicine approaches in oncology. First generation trials like NCI-MATCH have proven the principle that studying targeted therapies on a large scale is feasible both from the laboratory and clinical perspectives. However, single agent targeted therapies have shown limited ability to control metastatic disease, despite careful matching of drug to target. As such, newer approaches employing combinations of targeted therapy, or targeted therapy with standard therapies, need to be considered. The NCI has recently embarked on three 2nd generation precision medicine trials to address this need: ComboMATCH, iMATCH, and myeloMATCH. The design of these trials and necessary infrastructure are discussed in the following perspective.}, }
@article {pmid37526910, year = {2023}, author = {Kadro, ZO and Snyder, S and Benn, R and Fouladbakhsh, JM and Greenlee, H and Harris, RE and Henry, NL and Klein, KC and Mayhew, S and Spratke, L and Walker, EM and Zebrack, B and Zick, SM}, title = {Impact of the Integrative Oncology Scholars Program on Oncology Providers' Key Knowledge of Dietary Supplements and Antioxidants for Providing Evidence-based Oncology Care.}, journal = {Journal of cancer education : the official journal of the American Association for Cancer Education}, volume = {}, number = {}, pages = {}, pmid = {37526910}, issn = {1543-0154}, support = {R25CA203651/CA/NCI NIH HHS/United States ; 5T32AT003378/AT/NCCIH NIH HHS/United States ; }, abstract = {Dietary supplements are commonly used among cancer survivors. Oncology providers rarely receive training about dietary supplements. We evaluated whether e-learning modules could improve oncology providers' dietary supplement knowledge. Oncology providers participated in the National Cancer Institute funded Integrative Oncology Scholars (IOS) program. We used posttest readiness assurance tests (RAT) to measure knowledge acquisition from modules. One cohort completed a pre and posttest RAT to assess change in knowledge. Multivariate linear regression models adjusted for gender, race, profession, and years in practice were used to determine if these characteristics were associated with posttest RAT performance and change in pre to posttest RAT scores. Scholars (N = 101) included 86% (N = 87) females; age 44 ± 10 years; 72% (N = 73) Non-Hispanic White; years in practice mean range 11-15 ± 10. There were 37 physicians, 11 physician assistants, 23 nurses, 21 social workers, 2 psychologists, 4 pharmacists, and 2 physical therapists. The posttest dietary supplement and antioxidant RAT scores for all Scholars were 67 ± 18% and 71 ± 14%. In adjusted models there were no significant associations between dietary supplement and antioxidant posttest RAT scores with Scholar characteristics. Change in RAT scores for dietary supplement and antioxidants were 25% ± 23 and 26% ± 27 (P < 0.0001). In adjusted models, there were no significant predictors of change in dietary supplement RATs. For antioxidant RATs, profession was associated with change in scores (P = 0.021). Improvement in Scholar's test scores demonstrate the IOS program can significantly increase oncology providers' knowledge of dietary supplements and antioxidants.}, }
@article {pmid37526606, year = {2023}, author = {Yeung, CCS and Woolston, DW and Wu, V and Voutsinas, JM and Basom, R and Davis, C and Hirayama, AV and Naresh, KN}, title = {Abnormal bone marrow findings in patients following treatment with chimeric antigen receptor-T cell therapy.}, journal = {European journal of haematology}, volume = {}, number = {}, pages = {}, doi = {10.1111/ejh.14068}, pmid = {37526606}, issn = {1600-0609}, abstract = {BACKGROUND: Bone marrow (BM) assessment after CAR-T cell immunotherapy infusion is not routinely performed to monitor adverse events such as cytopenias, hemophagocytic lymphohistiocytosis, or infections. Our institution has performed BM biopsies as part of CAR-T cell treatment protocols, encompassing pre- and post-treatment time points and during long-term follow-up.
METHODS: We conducted a systematic retrospective review of BM abnormalities observed in samples from 259 patients following CAR-T cell immunotherapy. We correlated BM pathology findings with mortality, relapse/residual disease, and laboratory values.
RESULTS: At a median of 35.5 days post-CAR-T infusion, 25.5% showed severe marrow hypocellularity, and 6.2% showed serous atrophy, and peripheral blood cytopenias corroborated these observations. Marrow features associated with reduced disease burden post-CAR-T infusion include increased lymphocytes seen in 16 patients and an increase of macrophages or granulomatous response seen in 25 patients. However, a 100-day landmark analysis also showed increased marrow histiocytes were associated with lower survival (median OS 6.0 vs. 21.4 months, p = .026), as was grade 2-3 marrow reticulin (18 patients) (median OS 12.5 vs. 24.2 months, p = .034).
CONCLUSIONS: These data represent the first systematic observations of BM changes in patients receiving CAR-T cell immunotherapy.}, }
@article {pmid37526150, year = {2023}, author = {Shen, MJ and Prigerson, HG and Maciejewski, PK and Daly, B and Adelman, R and McConnell Trevino, KM}, title = {A communication intervention to improve prognostic understanding and engagement in advance care planning among diverse advanced cancer patient-caregiver dyads: A pilot study.}, journal = {Palliative & supportive care}, volume = {}, number = {}, pages = {1-9}, doi = {10.1017/S1478951523000901}, pmid = {37526150}, issn = {1478-9523}, support = {K07CA207580/CA/NCI NIH HHS/United States ; P30CA008748/CA/NCI NIH HHS/United States ; R21CA224874/CA/NCI NIH HHS/United States ; UL1TR002384/CA/NCI NIH HHS/United States ; }, abstract = {OBJECTIVES: Accurate prognostic understanding among patients with advanced cancer and their caregivers is associated with greater engagement in advance care planning (ACP) and receipt of goal-concordant care. Poor prognostic understanding is more prevalent among racial and ethnic minority patients. The purpose of this study was to examine the feasibility, acceptability, and impact of a patient-caregiver communication-based intervention to improve prognostic understanding, engagement in ACP, and completion of advance directives among a racially and ethnically diverse, urban sample of patients and their caregivers.
METHODS: Patients with advanced cancer and their caregivers (n = 22 dyads) completed assessments of prognostic understanding, engagement in ACP, and completion of advance directives at baseline and post-intervention, Talking About Cancer (TAC). TAC is a 7-session intervention delivered remotely by licensed social workers that includes distress management and communication skills, review of prognosis, and information on ACP.
RESULTS: TAC met a priori benchmarks for feasibility, acceptability, and fidelity. Prognostic understanding and engagement in ACP did not change over time. However, patients showed increases in completion of advance directives.
SIGNIFICANCE OF RESULTS: TAC was feasible, acceptable, and delivered with high fidelity. Involvement of caregivers in TAC may provide added layers of support to patients facing advanced cancer diagnoses, especially among racial and ethnic minorities. Trends indicated greater completion of advance directives but not in prognostic understanding or engagement in ACP. Future research is needed to optimize the intervention to improve acceptability, tailor to diverse patient populations, and examine the efficacy of TAC in a randomized controlled trial.}, }
@article {pmid37526084, year = {2023}, author = {Li, Q and Wang, X and Song, Q and Yang, S and Wu, X and Yang, D and Marié, IJ and Qin, H and Zheng, M and Nasri, U and Kong, X and Wang, B and Lizhar, E and Cassady, K and Tompkins, J and Levy, D and Martin, PJ and Zhang, X and Zeng, D}, title = {Donor T cell STAT3 deficiency enables tissue PD-L1-dependent prevention of graft-versus-host disease while preserving graft-versus-leukemia activity.}, journal = {The Journal of clinical investigation}, volume = {133}, number = {15}, pages = {}, pmid = {37526084}, issn = {1558-8238}, support = {R01 CA228465/CA/NCI NIH HHS/United States ; R01 HL162847/HL/NHLBI NIH HHS/United States ; }, mesh = {Mice ; Animals ; B7-H1 Antigen/genetics/metabolism ; Programmed Cell Death 1 Receptor/metabolism ; *Graft vs Host Disease/genetics/prevention & control ; T-Lymphocytes/metabolism ; *Leukemia ; Graft vs Leukemia Effect/genetics ; Bone Marrow Transplantation ; }, abstract = {STAT3 deficiency (STAT3-/-) in donor T cells prevents graft-versus-host disease (GVHD), but the impact on graft-versus-leukemia (GVL) activity and mechanisms of GVHD prevention remains unclear. Here, using murine models of GVHD, we show that STAT3-/- donor T cells induced only mild reversible acute GVHD while preserving GVL effects against nonsusceptible acute lymphoblastic leukemia (ALL) cells in a donor T cell dose-dependent manner. GVHD prevention depended on programmed death ligand 1/programmed cell death protein 1 (PD-L1/PD-1) signaling. In GVHD target tissues, STAT3 deficiency amplified PD-L1/PD-1 inhibition of glutathione (GSH)/Myc pathways that regulate metabolic reprogramming in activated T cells, with decreased glycolytic and mitochondrial ATP production and increased mitochondrial ROS production and dysfunction, leading to tissue-specific deletion of host-reactive T cells and prevention of GVHD. Mitochondrial STAT3 deficiency alone did not reduce GSH expression or prevent GVHD. In lymphoid tissues, the lack of host-tissue PD-L1 interaction with PD-1 reduced the inhibition of the GSH/Myc pathway despite reduced GSH production caused by STAT3 deficiency and allowed donor T cell functions that mediate GVL activity. Therefore, STAT3 deficiency in donor T cells augments PD-1 signaling-mediated inhibition of GSH/Myc pathways and augments dysfunction of T cells in GVHD target tissues while sparing T cells in lymphoid tissues, leading to prevention of GVHD while preserving GVL effects.}, }
@article {pmid37526081, year = {2023}, author = {Logan, BR and Fu, D and Howard, A and Fei, M and Kou, J and Little, MR and Adom, D and Mohamed, FA and Blazar, BR and Gafken, PR and Paczesny, S}, title = {Validated graft-specific biomarkers identify patients at risk for chronic graft-versus-host disease and death.}, journal = {The Journal of clinical investigation}, volume = {133}, number = {15}, pages = {}, pmid = {37526081}, issn = {1558-8238}, support = {R01 CA168814/CA/NCI NIH HHS/United States ; R21 HL139934/HL/NHLBI NIH HHS/United States ; T32 AI007313/AI/NIAID NIH HHS/United States ; R01 CA264921/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Mice ; *Bronchiolitis Obliterans Syndrome ; Matrix Metalloproteinase 3 ; *Hematopoietic Stem Cell Transplantation/adverse effects ; Bone Marrow Transplantation/adverse effects ; Biomarkers ; *Graft vs Host Disease ; Chronic Disease ; }, abstract = {BACKGROUNDChronic graft-versus-host disease (cGVHD) is a serious complication of allogeneic hematopoietic cell transplantation (HCT). More accurate information regarding the risk of developing cGVHD is required. Bone marrow (BM) grafts contribute to lower cGVHD, which creates a dispute over whether risk biomarker scores should be used for peripheral blood (PB) and BM.METHODSDay 90 plasma proteomics from PB and BM recipients developing cGVHD revealed 5 risk markers that were added to 8 previous cGVHD markers to screen 982 HCT samples of 2 multicenter Blood and Marrow Transplant Clinical Trials Network (BMTCTN) cohorts. Each marker was tested for its association with cause-specific hazard ratios (HRs) of cGVHD using Cox-proportional-hazards models. We paired these clinical studies with biomarker measurements in a mouse model of cGVHD.RESULTSSpearman correlations between DKK3 and MMP3 were significant in both cohorts. In BMTCTN 0201 multivariate analyses, PB recipients with 1-log increase in CXCL9 and DKK3 were 1.3 times (95% CI: 1.1-1.4, P = 0.001) and 1.9 times (95%CI: 1.1-3.2, P = 0.019) and BM recipients with 1-log increase in CXCL10 and MMP3 were 1.3 times (95%CI: 1.0-1.6, P = 0.018 and P = 0.023) more likely to develop cGVHD. In BMTCTN 1202, PB patients with high CXCL9 and MMP3 were 1.1 times (95%CI: 1.0-1.2, P = 0.037) and 1.2 times (95%CI: 1.0-1.3, P = 0.009) more likely to develop cGVHD. PB patients with high biomarkers had increased likelihood to develop cGVHD in both cohorts (22%-32% versus 8%-12%, P = 0.002 and P < 0.001, respectively). Mice showed elevated circulating biomarkers before the signs of cGVHD.CONCLUSIONBiomarker levels at 3 months after HCT identify patients at risk for cGVHD occurrence.FUNDINGNIH grants R01CA168814, R21HL139934, P01CA158505, T32AI007313, and R01CA264921.}, }
@article {pmid37525535, year = {2023}, author = {Zaorsky, NG and Proudfoot, JA and Jia, AY and Zuhour, R and Vince, R and Liu, Y and Zhao, X and Hu, J and Schussler, NC and Stevens, JL and Bentler, S and Cress, RD and Doherty, JA and Durbin, EB and Gershman, S and Cheng, I and Gonsalves, L and Hernandez, BY and Liu, L and Morawski, BM and Schymura, M and Schwartz, SM and Ward, KC and Wiggins, C and Wu, XC and Shoag, J and Ponsky, L and Dal Pra, A and Schaeffer, E and Ross, A and Sun, Y and Davicioni, E and Petkov, V and Spratt, DE}, title = {Use of the Decipher genomic classifier among men with prostate cancer in the United States.}, journal = {JNCI cancer spectrum}, volume = {}, number = {}, pages = {}, doi = {10.1093/jncics/pkad052}, pmid = {37525535}, issn = {2515-5091}, abstract = {UNLABELLED: Records of prostate cancer cases from participating SEER program registries, diagnosed during the period from 2010 through 2018, were linked to records of testing with the Decipher 22-gene genomic classifier (GC) prognostic test. Multivariable analysis was used to quantify the association between GC scores or risk groups and use of definitive local therapy after diagnosis in the GC biopsy tested cohort, and post-operative radiotherapy in the GC tested cohort as well as adverse pathology after prostatectomy.A total of 572,545 patients were included in the analysis, of which 8,927 patients underwent GC testing. GC biopsy tested patients were more likely to undergo active surveillance/watchful waiting (AS/WW) compared to untested patients (OR [95% CI] 2.21 [2.04 to 2.38], p < 0.001). AS/WW was highest for those with GC low risk classification (41%) as compared to those with intermediate (27%) or high (11%) GC risk (p < 0.001). Among NCCN low- and favorable-intermediate patients, higher GC risk was associated with greater use of local therapy (OR 4.79 [3.51 to 6.55], p < 0.001). Within this subset of patients who were subsequently treated with prostatectomy, high GC risk was associated with harboring adverse pathology (OR 2.94 [1.38 to 6.27], p = 0.005). Use of radiation after prostatectomy was significantly associated with higher GC risk group (OR 2.69 [1.89 - 3.84]).There is a strong association between use of the biopsy GC test and likelihood of conservative management. Higher genomic classifier scores are associated with higher rates of adverse pathology at time of surgery and greater use of post-operative radiotherapy.
PATIENT SUMMARY: This study linked the use of the Decipher Genomic Classifier (GC) to a US national database of men with prostate cancer. Use of GC was associated with conservative management (ie, active surveillance). Among men who had high-risk GC scores and then had surgery, there was a three-fold higher chance of having worrisome findings in surgical specimens.}, }
@article {pmid37525243, year = {2023}, author = {Jun, SH and Nasif, H and Jennings-Shaffer, C and Rich, DH and Kooperberg, A and Fourment, M and Zhang, C and Suchard, MA and Matsen, FA}, title = {A topology-marginal composite likelihood via a generalized phylogenetic pruning algorithm.}, journal = {Algorithms for molecular biology : AMB}, volume = {18}, number = {1}, pages = {10}, pmid = {37525243}, issn = {1748-7188}, support = {R01 AI162611/NH/NIH HHS/United States ; R01 AI153044/AI/NIAID NIH HHS/United States ; }, abstract = {Bayesian phylogenetics is a computationally challenging inferential problem. Classical methods are based on random-walk Markov chain Monte Carlo (MCMC), where random proposals are made on the tree parameter and the continuous parameters simultaneously. Variational phylogenetics is a promising alternative to MCMC, in which one fits an approximating distribution to the unnormalized phylogenetic posterior. Previous work fit this variational approximation using stochastic gradient descent, which is the canonical way of fitting general variational approximations. However, phylogenetic trees are special structures, giving opportunities for efficient computation. In this paper we describe a new algorithm that directly generalizes the Felsenstein pruning algorithm (a.k.a. sum-product algorithm) to compute a composite-like likelihood by marginalizing out ancestral states and subtrees simultaneously. We show the utility of this algorithm by rapidly making point estimates for branch lengths of a multi-tree phylogenetic model. These estimates accord with a long MCMC run and with estimates obtained using a variational method, but are much faster to obtain. Thus, although generalized pruning does not lead to a variational algorithm as such, we believe that it will form a useful starting point for variational inference.}, }
@article {pmid37524920, year = {2023}, author = {Shih, L and Othus, M and Schonhoff, K and Shaw, C and Appelbaum, J and Halpern, AB and Becker, PS and Walter, RB and Estey, E and Percival, ME}, title = {Comparison between measurable residual disease relapse and morphologic relapse in acute myeloid leukemia and high-grade myeloid neoplasms.}, journal = {Leukemia}, volume = {}, number = {}, pages = {}, pmid = {37524920}, issn = {1476-5551}, support = {NCI 5 P30 CA015704-47; UW/Fred Hutch Cancer Consortium P30 CCSG//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; T32CA009515//U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ ; }, }
@article {pmid37214809, year = {2023}, author = {Makhsous, N and Goya, S and Avendaño, C and Rupp, J and Kuypers, J and Jerome, KR and Boeckh, M and Waghmare, A and Greninger, AL}, title = {Within-host rhinovirus evolution in upper and lower respiratory tract highlights capsid variability and mutation-independent compartmentalization.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {37214809}, support = {K23 AI114844/AI/NIAID NIH HHS/United States ; }, abstract = {BACKGROUND: Human rhinovirus (HRV) infections can progress from the upper (URT) to lower (LRT) respiratory tract in immunocompromised individuals, causing high rates of fatal pneumonia. Little is known about how HRV evolves within hosts during infection.
METHODS: We sequenced HRV complete genomes from 12 hematopoietic cell transplant patients with prolonged infection for up to 190 days from both URT (nasal wash, NW) and LRT (bronchoalveolar lavage, BAL) specimens. Metagenomic (mNGS) and amplicon-based NGS were used to study the emergence and evolution of intra-host single nucleotide variants (iSNVs).
RESULTS: Identical HRV intra-host populations in matched NW and BAL specimens indicated no genetic adaptation is required for HRV to progress from URT to LRT. Microbial composition between matched NW and BAL confirmed no cross-contamination during sampling procedure. Coding iSNVs were 2.3-fold more prevalent in capsid over non-structural genes, adjusted for length. iSNVs modeled onto HRV capsid structures were significantly more likely to be found in surface residues, but were not preferentially located in known HRV neutralizing antibody epitopes. Newly emergent, serotype-matched iSNV haplotypes from immunocompromised individuals from 2008-2010 could be detected in Seattle-area community HRV sequences from 2020-2021.
CONCLUSION: HRV infections in immunocompromised hosts can progress from URT to LRT with no specific evolutionary requirement. Capsid proteins carry the highest variability and emergent mutations can be detected in other, including future, HRV sequences.}, }
@article {pmid37524919, year = {2023}, author = {Hochman, MJ and Othus, M and Hasserjian, RP and Ambinder, A and Brunner, A and Percival, MM and Hourigan, CS and Swords, R and DeZern, AE and Estey, EH and Karp, JE}, title = {Prognostic impact of secondary versus de novo ontogeny in acute myeloid leukemia is accounted for by the European LeukemiaNet 2022 risk classification.}, journal = {Leukemia}, volume = {}, number = {}, pages = {}, pmid = {37524919}, issn = {1476-5551}, abstract = {Secondary AML (sAML), defined by either history of antecedent hematologic disease (AHD) or prior genotoxic therapy (tAML), is classically regarded as having worse prognosis than de novo disease (dnAML). Clinicians may infer a new AML diagnosis is secondary based on a history of antecedent blood count (ABC) abnormalities in the absence of known prior AHD, but whether abnormal ABCs are associated with worse outcomes is unclear. Secondary-type mutations have recently been incorporated into the European LeukemiaNet (ELN) 2022 guidelines as adverse-risk features, raising the question of whether clinical descriptors of ontogeny (i.e., de novo or secondary) are prognostically significant when accounting for genetic risk by ELN 2022. In a large multicenter cohort of patients (n = 734), we found that abnormal ABCs are not independently prognostic after adjusting for genetic characteristics in dnAML patients. Furthermore, history of AHD and tAML do not confer increased risk of death compared to dnAML on multivariate analysis, suggesting the prognostic impact of ontogeny is accounted for by disease genetics as stratified by ELN 2022 risk and TP53 mutation status. These findings emphasize the importance that disease genetics should play in risk stratification and clinical trial eligibility in AML.}, }
@article {pmid37520418, year = {2023}, author = {Saidi, AM and Zhang, B and Jiang, M and Kawaza, K and Musaya, J and Taylor, T and Seydel, K}, title = {Differential Effects of Antimalarial Drugs on Parasite Clearance Rates Are Reflected by Plasmodium falciparum Ring Ratio.}, journal = {Open forum infectious diseases}, volume = {10}, number = {7}, pages = {ofad380}, pmid = {37520418}, issn = {2328-8957}, abstract = {BACKGROUND: The location of Plasmodium falciparum within the body is determined by the life cycle of the parasite; young rings are in the peripheral blood, whereas mature parasites are sequestered in deep tissues. We can calculate a "ring ratio," the proportion of parasites in the periphery to the total number of parasites in the body. Artesunate acts on all parasite life stages, whereas quinine is effective only on sequestered parasites. Children with cerebral malaria (CM) treated with artesunate clear parasites faster than those treated with quinine. In this study, we established the relationship between ring ratio and parasite clearance rate and used the ring ratio to determine if the benefit derived from artesunate treatment could be attributed to its broader effect on life cycle stages.
METHODS: Ring ratios were calculated for 400 hospitalized children with CM in Blantyre, Malawi between 2010 and 2019 (quinine: 2010-2013, artesunate: 2014-2019).
RESULTS: In both treatment groups, parasite clearance rates were positively associated with the ring ratios, with a stronger association in the artesunate era than the quinine era. In the quinine era, an increase of 1-unit log10 difference between parasitemia and plasma P falciparum histidine-rich protein 2 (a proxy for ring ratio) resulted in a 0.27-unit increase in the parasite clearance rate, whereas in the artesunate era an equal increase resulted in a 0.41-unit increase (P = .04 for the difference).
CONCLUSIONS: This analysis provides in vivo evidence supporting the hypothesis that more rapid parasite clearance rates in artesunate recipients are due to its superiority over quinine in killing ring-stage parasites.}, }
@article {pmid37517846, year = {2023}, author = {Sorror, ML}, title = {Initial steps towards improving quality of care for allogeneic hematopoietic cell transplantation recipients at individual centers.}, journal = {Transplantation and cellular therapy}, volume = {29}, number = {8}, pages = {482-483}, doi = {10.1016/j.jtct.2023.07.006}, pmid = {37517846}, issn = {2666-6367}, mesh = {Humans ; Transplantation, Homologous ; *Hematopoietic Stem Cell Transplantation ; Transplant Recipients ; Quality of Health Care ; }, }
@article {pmid37517612, year = {2023}, author = {Gillis, N and Padron, E and Wang, T and Chen, K and DeVos, JD and Spellman, SR and Lee, SJ and Kitko, CL and MacMillan, ML and West, J and Tang, YH and Teng, M and McNulty, S and Druley, TE and Pidala, JA and Lazaryan, A}, title = {A pilot study of donor-engrafted clonal hematopoiesis evolution and clinical outcomes in allogeneic hematopoietic cell transplant recipients using a national registry.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2023.07.021}, pmid = {37517612}, issn = {2666-6367}, abstract = {BACKGROUND: Improved treatment options, such as reduced-intensity conditioning, enable older patients to receive potentially curative allogeneic hematopoietic cell transplantation (HCT). This progress has increased use of older HLA-matched sibling donors. An unintended potential risk associated with older donors is transplantation of donor cells with clonal hematopoiesis (CH) into patients.
OBJECTIVE: We aimed to determine the prevalence of CH in older HLA-matched sibling donors pre-transplant and to assess the clinical impact of donor-engrafted CH on HCT outcomes.
STUDY DESIGN: This was an observational study using donor peripheral blood samples from the Center for International Blood and Marrow Transplant Research repository, linked with corresponding recipient outcomes. To explore engraftment efficiency and evolution of CH mutations following HCT, recipient follow-up samples available through the Bone Marrow Transplant Clinical Trials Network (#1202) were included. Older donors and patients (both ≥ 55 yrs) receiving first reduced-intensity HCT for myeloid malignancies were eligible. DNA from archived donor blood samples was used for targeted deep sequencing to identify CH. The associations between donor CH status and recipient outcomes, including acute GVHD (aGVHD), chronic graft-versus-host disease (cGVHD), overall survival, relapse, non-relapse mortality, disease-free survival, composite GVHD-free and relapse-free survival, and cGVHD-free and relapse-free survival, were analyzed.
RESULTS: A total of 299 donors were successfully sequenced to detect CH. At a variant allele frequency ≥ 2%, there were 44 CH mutations in 13.7% (41/299) of HLA-matched sibling donors. CH mostly involved DNMT3A (27, 61.4%) and TET2 (9, 20.5%). Post-HCT samples from 13 recipients were also sequenced, of which 7 had CH+ donors. All of the donor CH mutations (7/7, 100%) were detected in recipients at day 56 or 90 post-HCT. Overall, mutation VAFs remained relatively constant up to day 90 post-HCT (median change 0.005, range -0.008 - 0.024). Doubling time analysis of recipient day 56 and 90 data showed that donor-engrafted CH mutations initially expand then decrease to a stable VAF; germline mutations had longer doubling times than CH mutations. The cumulative incidence of grade II-IV aGVHD at day 100 was higher in recipients with CH+ donors (37.5% vs. 25.1%); however, risk for aGVHD by donor CH status did not reach statistical significance (HR 1.35, 95% CI 0.61-3.01, p=0.47). There were no statistically significant differences in cumulative incidence of cGVHD or any secondary outcomes by donor CH status. In subset analysis, incidence of cGVHD was lower in recipients with DNMT3A-CH+ donors versus donors without DNMT3A-CH (34.4% vs 57%, p=0.035). Donor cell leukemia was not reported in any donor-recipient pairs.
CONCLUSION: CH in older HLA-matched sibling donors is relatively common and successfully engrafts and persists in recipients. In a homogenous population (myeloid malignancies, older donors and recipients, reduced-intensity conditioning, non-cyclophosphamide-containing GVHD prophylaxis), we did not detect a difference in cGVHD risk or other secondary outcomes by donor CH status. Subgroup analyses suggest potential of differential effects by clinical characteristics and CH mutations. Larger prospective studies are needed to robustly determine which subsets of patients and CH mutations elicit meaningful impacts on clinical outcomes.}, }
@article {pmid37516914, year = {2023}, author = {Lewis, HC and Kelnhofer-Millevolte, LE and Brinkley, MR and Arbach, HE and Arnold, EA and Sanders, S and Bosse, JB and Ramachandran, S and Avgousti, DC}, title = {HSV-1 exploits host heterochromatin for nuclear egress.}, journal = {The Journal of cell biology}, volume = {222}, number = {9}, pages = {}, pmid = {37516914}, issn = {1540-8140}, support = {209250/Z/17/Z/WT_/Wellcome Trust/United Kingdom ; R35 GM133434/GM/NIGMS NIH HHS/United States ; T32 AI083203/AI/NIAID NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; R35 GM133441/GM/NIGMS NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; AI083203/NH/NIH HHS/United States ; }, mesh = {*Heterochromatin/genetics ; *Herpesvirus 1, Human/genetics ; Histones/genetics ; Cell Nucleus/genetics ; Chromatin ; }, abstract = {Herpes simplex virus (HSV-1) progeny form in the nucleus and exit to successfully infect other cells. Newly formed capsids navigate complex chromatin architecture to reach the inner nuclear membrane (INM) and egress. Here, we demonstrate by transmission electron microscopy (TEM) that HSV-1 capsids traverse heterochromatin associated with trimethylation on histone H3 lysine 27 (H3K27me3) and the histone variant macroH2A1. Through chromatin profiling during infection, we revealed global redistribution of these marks whereby massive host genomic regions bound by macroH2A1 and H3K27me3 correlate with decreased host transcription in active compartments. We found that the loss of these markers resulted in significantly lower viral titers but did not impact viral genome or protein accumulation. Strikingly, we discovered that loss of macroH2A1 or H3K27me3 resulted in nuclear trapping of capsids. Finally, by live-capsid tracking, we quantified this decreased capsid movement. Thus, our work demonstrates that HSV-1 takes advantage of the dynamic nature of host heterochromatin formation during infection for efficient nuclear egress.}, }
@article {pmid37516771, year = {2023}, author = {Hertz, T and Levy, S and Ostrovsky, D and Oppenheimer, H and Zismanov, S and Kuzmina, A and Friedman, LM and Trifkovic, S and Brice, D and Chun-Yang, L and Cohen-Lavi, L and Shemer-Avni, Y and Cohen-Lahav, M and Amichay, D and Keren-Naus, A and Voloshin, O and Weber, G and Najjar-Debbiny, R and Chazan, B and McGargill, MA and Webby, R and Chowers, M and Novack, L and Novack, V and Taube, R and Nesher, L and Weinstein, O}, title = {Correlates of protection for booster doses of the SARS-CoV-2 vaccine BNT162b2.}, journal = {Nature communications}, volume = {14}, number = {1}, pages = {4575}, pmid = {37516771}, issn = {2041-1723}, support = {75N93021C00016/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *COVID-19 Vaccines ; BNT162 Vaccine ; Prospective Studies ; *COVID-19/prevention & control ; SARS-CoV-2 ; Immunoglobulin A ; Immunoglobulin G ; }, abstract = {Vaccination, especially with multiple doses, provides substantial population-level protection against COVID-19, but emerging variants of concern (VOC) and waning immunity represent significant risks at the individual level. Here we identify correlates of protection (COP) in a multicenter prospective study following 607 healthy individuals who received three doses of the Pfizer-BNT162b2 vaccine approximately six months prior to enrollment. We compared 242 individuals who received a fourth dose to 365 who did not. Within 90 days of enrollment, 239 individuals contracted COVID-19, 45% of the 3-dose group and 30% of the four-dose group. The fourth dose elicited a significant rise in antibody binding and neutralizing titers against multiple VOCs reducing the risk of symptomatic infection by 37% [95%CI, 15%-54%]. However, a group of individuals, characterized by low baseline titers of binding antibodies, remained susceptible to infection despite significantly increased neutralizing antibody titers upon boosting. A combination of reduced IgG levels to RBD mutants and reduced VOC-recognizing IgA antibodies represented the strongest COP in both the 3-dose group (HR = 6.34, p = 0.008) and four-dose group (HR = 8.14, p = 0.018). We validated our findings in an independent second cohort. In summary combination IgA and IgG baseline binding antibody levels may identify individuals most at risk from future infections.}, }
@article {pmid37516102, year = {2023}, author = {Schuster, SL and Arora, S and Wladyka, CL and Itagi, P and Corey, L and Young, D and Stackhouse, BL and Kollath, L and Wu, QV and Corey, E and True, LD and Ha, G and Paddison, PJ and Hsieh, AC}, title = {Multi-level functional genomics reveals molecular and cellular oncogenicity of patient-based 3' untranslated region mutations.}, journal = {Cell reports}, volume = {}, number = {}, pages = {112840}, doi = {10.1016/j.celrep.2023.112840}, pmid = {37516102}, issn = {2211-1247}, abstract = {3' untranslated region (3' UTR) somatic mutations represent a largely unexplored avenue of alternative oncogenic gene dysregulation. To determine the significance of 3' UTR mutations in disease, we identify 3' UTR somatic variants across 185 advanced prostate tumors, discovering 14,497 single-nucleotide mutations enriched in oncogenic pathways and 3' UTR regulatory elements. By developing two complementary massively parallel reporter assays, we measure how thousands of patient-based mutations affect mRNA translation and stability and identify hundreds of functional variants that allow us to define determinants of mutation significance. We demonstrate the clinical relevance of these mutations, observing that CRISPR-Cas9 endogenous editing of distinct variants increases cellular stress resistance and that patients harboring oncogenic 3' UTR mutations have a particularly poor prognosis. This work represents an expansive view of the extent to which disease-relevant 3' UTR mutations affect mRNA stability, translation, and cancer progression, uncovering principles of regulatory functionality and potential therapeutic targets in previously unexplored regulatory regions.}, }
@article {pmid37510283, year = {2023}, author = {Bonner, EA and Lee, SC}, title = {Therapeutic Targeting of RNA Splicing in Cancer.}, journal = {Genes}, volume = {14}, number = {7}, pages = {}, pmid = {37510283}, issn = {2073-4425}, mesh = {Humans ; *RNA Splicing/genetics ; *Neoplasms/drug therapy/genetics ; Spliceosomes/genetics/metabolism ; RNA Splicing Factors/genetics/metabolism ; RNA/metabolism ; }, abstract = {RNA splicing is a key regulatory step in the proper control of gene expression. It is a highly dynamic process orchestrated by the spliceosome, a macro-molecular machinery that consists of protein and RNA components. The dysregulation of RNA splicing has been observed in many human pathologies ranging from neurodegenerative diseases to cancer. The recent identification of recurrent mutations in the core components of the spliceosome in hematologic malignancies has advanced our knowledge of how splicing alterations contribute to disease pathogenesis. This review article will discuss our current understanding of how aberrant RNA splicing regulation drives tumor initiation and progression. We will also review current therapeutic modalities and highlight emerging technologies designed to target RNA splicing for cancer treatment.}, }
@article {pmid37509333, year = {2023}, author = {Barbour, AB and Kirste, S and Grosu, AL and Siva, S and Louie, AV and Onishi, H and Swaminath, A and Teh, BS and Psutka, SP and Weg, ES and Chen, JJ and Zeng, J and Gore, JL and Hall, E and Liao, JJ and Correa, RJM and Lo, SS}, title = {The Judicious Use of Stereotactic Ablative Radiotherapy in the Primary Management of Localized Renal Cell Carcinoma.}, journal = {Cancers}, volume = {15}, number = {14}, pages = {}, pmid = {37509333}, issn = {2072-6694}, abstract = {Localized renal cell carcinoma is primarily managed surgically, but this disease commonly presents in highly comorbid patients who are poor operative candidates. Less invasive techniques, such as cryoablation and radiofrequency ablation, are effective, but require percutaneous or laparoscopic access, while generally being limited to cT1a tumors without proximity to the renal pelvis or ureter. Active surveillance is another management option for small renal masses, but many patients desire treatment or are poor candidates for active surveillance. For poor surgical candidates, a growing body of evidence supports stereotactic ablative radiotherapy (SABR) as a safe and effective non-invasive treatment modality. For example, a recent multi-institution individual patient data meta-analysis of 190 patients managed with SABR estimated a 5.5% five-year cumulative incidence of local failure with one patient experiencing grade 4 toxicity, and no other grade ≥3 toxic events. Here, we discuss the recent developments in SABR for the management of localized renal cell carcinoma, highlighting key concepts of appropriate patient selection, treatment design, treatment delivery, and response assessment.}, }
@article {pmid37509284, year = {2023}, author = {Shen, MJ and Cho, S and De Los Santos, C and Yarborough, S and Maciejewski, PK and Prigerson, HG}, title = {Planning for Your Advance Care Needs (PLAN): A Communication Intervention to Improve Advance Care Planning among Latino Patients with Advanced Cancer.}, journal = {Cancers}, volume = {15}, number = {14}, pages = {}, pmid = {37509284}, issn = {2072-6694}, support = {K07CA207580/CA/NCI NIH HHS/United States ; R01MD007652/CA/NCI NIH HHS/United States ; UL1 TR002384/NH/NIH HHS/United States ; }, abstract = {BACKGROUND: The goal of this study was to develop and optimize an intervention designed to address barriers to engagement in advance care planning (ACP) among Latino patients with advanced cancer. The resulting intervention, titled Planning Your Advance Care Needs (PLAN), is grounded in theoretical models of communication competence and sociocultural theory.
MATERIALS AND METHODS: An initial version of the PLAN manual was developed based on a prior intervention, Ca-HELP, that was designed to improve communication around pain among cancer patients. PLAN uses this framework to coach patients on how to plan for and communicate their end-of-life care needs through ACP. In the present study, feedback was obtained from key stakeholders (n = 11 patients, n = 11 caregivers, n = 10 experts) on this preliminary version of the PLAN manual. Participants provided ratings of acceptability and feedback around the intervention content, format, design, modality, and delivery through quantitative survey questions and semi-structured qualitative interviews.
RESULTS: Results indicated that the PLAN manual was perceived to be helpful and easy to understand. All stakeholder groups liked the inclusion of explicit communication scripts and guidance for having conversations about ACP with loved ones and doctors. Specific feedback was given to modify PLAN to ensure it was optimized and tailored for Latino patients. Some patients noted reviewing the manual motivated engagement in ACP.
CONCLUSIONS: Feedback from stakeholders resulted in an optimized, user-centered version of PLAN tailored to Latino patients. Future research will examine the acceptability, feasibility, and potential efficacy of this intervention to improve engagement in ACP.}, }
@article {pmid37507217, year = {2023}, author = {Pooler, BD and Kim, DH and Matkowskyj, KA and Newton, MA and Halberg, RB and Grady, WM and Hassan, C and Pickhardt, PJ}, title = {Growth rates and histopathological outcomes of small (6-9 mm) colorectal polyps based on CT colonography surveillance and endoscopic removal.}, journal = {Gut}, volume = {}, number = {}, pages = {}, doi = {10.1136/gutjnl-2022-326970}, pmid = {37507217}, issn = {1468-3288}, abstract = {BACKGROUND AND AIMS: The natural history of small polyps is not well established and rests on limited evidence from barium enema studies decades ago. Patients with one or two small polyps (6-9 mm) at screening CT colonography (CTC) are offered CTC surveillance at 3 years but may elect immediate colonoscopy. This practice allows direct observation of the growth of subcentimetre polyps, with histopathological correlation in patients undergoing subsequent polypectomy.
DESIGN: Of 11 165 asymptomatic patients screened by CTC over a period of 16.4 years, 1067 had one or two 6-9 mm polyps detected (with no polyps ≥10 mm). Of these, 314 (mean age, 57.4 years; M:F, 141:173; 375 total polyps) elected immediate colonoscopic polypectomy, and 382 (mean age 57.0 years; M:F, 217:165; 481 total polyps) elected CTC surveillance over a mean of 4.7 years. Volumetric polyp growth was analysed, with histopathological correlation for resected polyps. Polyp growth and regression were defined as volume change of ±20% per year, with rapid growth defined as +100% per year (annual volume doubling). Regression analysis was performed to evaluate predictors of advanced histology, defined as the presence of cancer, high-grade dysplasia (HGD) or villous components.
RESULTS: Of the 314 patients who underwent immediate polypectomy, 67.8% (213/314) harboured adenomas, 2.2% (7/314) with advanced histology; no polyps contained cancer or HGD. Of 382 patients who underwent CTC surveillance, 24.9% (95/382) had polyps that grew, while 62.0% (237/382) remained stable and 13.1% (50/382) regressed in size. Of the 58.6% (224/382) CTC surveillance patients who ultimately underwent colonoscopic resection, 87.1% (195/224) harboured adenomas, 12.9% (29/224) with advanced histology. Of CTC surveillance patients with growing polyps who underwent resection, 23.2% (19/82) harboured advanced histology vs 7.0% (10/142) with stable or regressing polyps (OR: 4.0; p<0.001), with even greater risk of advanced histology in those with rapid growth (63.6%, 14/22, OR: 25.4; p<0.001). Polyp growth, but not patient age/sex or polyp morphology/location were significant predictors of advanced histology.
CONCLUSION: Small 6-9 mm polyps present overall low risk to patients, with polyp growth strongly associated with higher risk lesions. Most patients (75%) with small 6-9 mm polyps will see polyp stability or regression, with advanced histology seen in only 7%. The minority of patients (25%) with small polyps that do grow have a 3-fold increased risk of advanced histology.}, }
@article {pmid37500574, year = {2023}, author = {Lee, JM and Ichikawa, LE and Wernli, KJ and Bowles, EJA and Specht, JM and Kerlikowske, K and Miglioretti, DL and Lowry, KP and Tosteson, ANA and Stout, NK and Houssami, N and Onega, T and Buist, DSM}, title = {Impact of Surveillance Mammography Intervals Less Than One Year on Performance Measures in Women With a Personal History of Breast Cancer.}, journal = {Korean journal of radiology}, volume = {24}, number = {8}, pages = {729-738}, doi = {10.3348/kjr.2022.1038}, pmid = {37500574}, issn = {2005-8330}, support = {P01CA154292/CA/NCI NIH HHS/United States ; U54CA163303/CA/NCI NIH HHS/United States ; R50CA211115/CA/NCI NIH HHS/United States ; PCS-1504-30370/PCORI/Patient-Centered Outcomes Research Institute/United States ; }, mesh = {Female ; Humans ; *Breast Neoplasms/pathology ; Mammography ; *Carcinoma, Intraductal, Noninfiltrating/pathology ; Registries ; Mass Screening/methods ; }, abstract = {OBJECTIVE: When multiple surveillance mammograms are performed within an annual interval, the current guidance for one-year follow-up to determine breast cancer status results in shared follow-up periods in which a single breast cancer diagnosis can be attributed to multiple preceding examinations, posing a challenge for standardized performance assessment. We assessed the impact of using follow-up periods that eliminate the artifactual inflation of second breast cancer diagnoses.
MATERIALS AND METHODS: We evaluated surveillance mammograms from 2007-2016 in women with treated breast cancer linked with tumor registry and pathology outcomes. Second breast cancers included ductal carcinoma in situ or invasive breast cancer diagnosed during one-year follow-up. The cancer detection rate, interval cancer rate, sensitivity, and specificity were compared using different follow-up periods: standard one-year follow-up per the American College of Radiology versus follow-up that was shortened at the next surveillance mammogram if less than one year (truncated follow-up). Performance measures were calculated overall and by indication (screening, evaluation for breast problem, and short interval follow-up).
RESULTS: Of 117971 surveillance mammograms, 20% (n = 23533) were followed by another surveillance mammogram within one year. Standard follow-up identified 1597 mammograms that were associated with second breast cancers. With truncated follow-up, the breast cancer status of 179 mammograms (11.2%) was revised, resulting in 1418 mammograms associated with unique second breast cancers. The interval cancer rate decreased with truncated versus standard follow-up (3.6 versus 4.9 per 1000 mammograms, respectively), with a difference (95% confidence interval [CI]) of -1.3 (-1.6, -1.1). The overall sensitivity increased to 70.4% from 63.7%, for the truncated versus standard follow-up, with a difference (95% CI) of 6.6% (5.6%, 7.7%). The specificity remained stable at 98.1%.
CONCLUSION: Truncated follow-up, if less than one year to the next surveillance mammogram, enabled second breast cancers to be associated with a single preceding mammogram and resulted in more accurate estimates of diagnostic performance for national benchmarks.}, }
@article {pmid37500339, year = {2023}, author = {Powles, T and Assaf, ZJ and Degaonkar, V and Grivas, P and Hussain, M and Oudard, S and Gschwend, JE and Albers, P and Castellano, D and Nishiyama, H and Daneshmand, S and Sharma, S and Sethi, H and Aleshin, A and Shi, Y and Davarpanah, N and Carter, C and Bellmunt, J and Mariathasan, S}, title = {Updated Overall Survival by Circulating Tumor DNA Status from the Phase 3 IMvigor010 Trial: Adjuvant Atezolizumab Versus Observation in Muscle-invasive Urothelial Carcinoma.}, journal = {European urology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.eururo.2023.06.007}, pmid = {37500339}, issn = {1873-7560}, abstract = {BACKGROUND: Interim results from IMvigor010 showed an overall survival (OS) benefit for adjuvant atezolizumab (anti-PD-L1) versus observation in patients with circulating tumor DNA (ctDNA)-positive muscle-invasive urothelial carcinoma (MIUC).
OBJECTIVE: To report updated OS and safety by ctDNA status.
This ad hoc analysis from a global, open-label, randomized, phase 3 trial (NCT02450331) included intention-to-treat (ITT) population with evaluable cycle 1 day 1 (C1D1) ctDNA samples.
INTERVENTION: Atezolizumab (1200 mg every 3 wk) or observation for ≤1 yr.
OS, relapse rates, and safety by ctDNA status were assessed.
RESULTS AND LIMITATIONS: Among 581 of 809 ITT patients included, 214 (37%) were ctDNA positive. Atezolizumab did not improve OS versus observation in ITT patients (hazard ratio [HR] 0.91 [95% confidence interval {CI} 0.73-1.13]; median follow-up 46.8 mo [interquartile range, 36.1-53.6]). In the observation arm, ctDNA positivity versus negativity was associated with shorter OS (HR 6.3 [95% CI 4.3-9.3]). The ctDNA positivity identified patients with an OS benefit favoring atezolizumab versus observation (HR 0.59 [95% CI 0.42-0.83]). A greater reduction in ctDNA levels with atezolizumab (C3D1) was associated with longer OS (100% clearance, 60.0 mo [95% CI 35.5-not estimable]; 50-99% reduction, 34.3 mo [95% CI 15.2-not estimable]; <50% reduction, 19.9 mo [95% CI 16.4-32.2]). The ctDNA positivity at C1D1 + C3D1 was associated with relapse with greater sensitivity than C1D1 alone (68% vs 57%). Adverse events were more frequent with atezolizumab than with observation, regardless of ctDNA status. A study limitation was its exploratory design.
CONCLUSIONS: Evidence suggests that ctDNA positivity in MIUC predicts a benefit with atezolizumab. An in-progress prospective study will further evaluate these findings.
PATIENT SUMMARY: Among patients with urothelial cancer after surgery, survival was poorer if tumor-derived DNA was detected in their bloodstream; these patients' survival was longer with atezolizumab versus observation. Bloodstream tumor-derived DNA may identify patients who benefit from atezolizumab.}, }
@article {pmid37500295, year = {2023}, author = {Zhu, J and Abaci, HE}, title = {Human skin-on-a-chip for mpox pathogenesis studies and preclinical drug evaluation.}, journal = {Trends in pharmacological sciences}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.tips.2023.07.001}, pmid = {37500295}, issn = {1873-3735}, abstract = {Timely intervention of preventative and therapeutic measures abated a 2022 mpox global outbreak. However, the high transmissibility and unique pathological characteristics of mpox demand further investigation. Here, we discuss the potentials of human skin-on-a-chip as a valuable model for mpox disease evaluation, to achieve in-depth physiological understanding and desirable therapeutic predictive capabilities.}, }
@article {pmid37497748, year = {2023}, author = {Higano, CS and Cheng, HH}, title = {Poly-ADP ribose polymerase inhibitor and androgen receptor signaling inhibitor for all comers for first-line treatment of metastatic castration-resistant prostate cancer: is gene sequencing out?.}, journal = {Current opinion in urology}, volume = {}, number = {}, pages = {}, pmid = {37497748}, issn = {1473-6586}, abstract = {PURPOSE OF REVIEW: The landscape for first-line therapy (1L) of metastatic castration-resistant prostate cancer (mCRPC) is rapidly shifting. In the past 2 years, three phase 3 trials have examined the addition of a poly-ADP ribose polymerase inhibitor (PARPi) to an androgen receptor-signaling inhibitor (ARSI) in 1L. The FDA and the EMA recently considered whether one of these combinations should be approved for "all comers." Here, we review the trial designs, assays for homologous recombination repair mutations (HRRm) and BRCA mutations (BRCAm), and predictive capacity of mutational status on treatment efficacy to understand the basis for the FDA decision.
RECENT FINDINGS: The phase 3 trials, PROpel, MAGNITUDE, and TALAPRO-2, each compared PARPi and ARSI to placebo (PBO) plus ARSI. PROpel and TALAPRO-2 (cohort 1) included all comers (i.e., no prospective biomarker selection), while MAGNITUDE prospectively assigned patients to HRRm and HRR nonmutated cohorts and TALAPRO-2 (cohort 2) included only those with HRRm. Radiographic progression-free survival (rPFS) was the primary endpoint, and overall survival (OS) was a key secondary endpoint in all trials. Although rPFS with a PARPi and ARSI was improved versus PBO with ARSI, major conclusions differed.
SUMMARY: The nuances and interpretation of these trials provide an understanding of the rationale for the FDA's decision to restrict the approval of olaparib and abiraterone and prednisone (AAP) as 1L therapy to those with biomarker evidence of BRCAm.}, }
@article {pmid37495615, year = {2023}, author = {Hatcher, C and Richenberg, G and Waterson, S and Nguyen, LH and Joshi, AD and Carreras-Torres, R and Moreno, V and Chan, AT and Gunter, M and Lin, Y and Qu, C and Song, M and Casey, G and Figueiredo, JC and Gruber, SB and Hampe, J and Hampel, H and Jenkins, MA and Keku, TO and Peters, U and Tangen, CM and Wu, AH and Hughes, DA and Rühlemann, MC and Raes, J and Timpson, NJ and Wade, KH}, title = {Author Correction: Application of Mendelian randomization to explore the causal role of the human gut microbiome in colorectal cancer.}, journal = {Scientific reports}, volume = {13}, number = {1}, pages = {12131}, doi = {10.1038/s41598-023-38170-1}, pmid = {37495615}, issn = {2045-2322}, }
@article {pmid37495373, year = {2023}, author = {Radich, JP}, title = {The (near) miracle of therapy in chronic myeloid leukaemia.}, journal = {British journal of haematology}, volume = {}, number = {}, pages = {}, doi = {10.1111/bjh.18956}, pmid = {37495373}, issn = {1365-2141}, }
@article {pmid37494828, year = {2023}, author = {Zhao, B and Sotres-Alvarez, D and Evenson, KR and Greenlee, H and Mossavar-Rahmani, Y and Qi, Q and Marquez, DX and Vidot, DC and Elfassy, T and Arredondo, EM and Diaz, KM}, title = {Day-of-the-Week and Time-of-the-Day Patterns of Sedentary Behavior in the Hispanic Community Health Study / Study of Latinos.}, journal = {Medicine and science in sports and exercise}, volume = {}, number = {}, pages = {}, doi = {10.1249/MSS.0000000000003266}, pmid = {37494828}, issn = {1530-0315}, abstract = {PURPOSE: Existing sedentary behavior interventions have largely achieved mixed results. Conventionally, interventions have attempted to reduce sedentary behavior using a full-day approach. An alternative strategy may be to target specific periods during the day and/or week. This study examined the day-of-the-week (Monday to Sunday) and time-of-the-day patterns (3-hr and 6-hr periods) of sedentary behavior among U.S. Hispanics/Latinos adults.
METHODS: Participants (n = 12,241) from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), a multi-site community-based prospective cohort study of Hispanic/Latino adults, were studied. Sedentary behavior was assessed for one week using a hip-mounted accelerometer through total sedentary time, sedentary time in bouts ≥60 minutes, and total number of sedentary breaks. The temporal patterns of sedentary behavior metrics were evaluated using linear mixed effect models accounting for HCHS/SOL complex survey design.
RESULTS: There were statistically significant variations in temporal patterns across day-of-the-week and time-of-the-day periods for all three metrics (p < .001). Adults were more sedentary on weekends than on weekdays, and most sedentary on Sundays. The time-of-the-day patterns had a U-curve pattern wherein adults were most sedentary late at night, became less sedentary throughout the day, reached peak activeness around noon, then gradually became more sedentary into the evening. These patterns were largely robust across seasonality and most sociodemographic characteristics including age, employment status, work shift schedule, acculturation, and field center.
CONCLUSIONS: Our findings suggest that early mornings, evenings, and weekends were the more sedentary periods in this cohort of Hispanic/Latino adults, characterized by higher volumes of sedentary time, higher volumes of time in prolonged sedentary bouts, and fewer number of sedentary breaks than other time periods, highlighting important windows of opportunity to reduce sedentary behavior.}, }
@article {pmid37494469, year = {2023}, author = {DeWolf, S and Elhanati, Y and Nichols, K and Waters, NR and Nguyen, CL and Slingerland, JB and Rodriguez, N and Lyudovyk, O and Giardina, PA and Kousa, AI and Andrlová, H and Ceglia, N and Fei, T and Kappagantula, R and Li, Y and Aleynick, N and Baez, P and Murali, R and Hayashi, A and Lee, N and Gipson, B and Rangesa, M and Katsamakis, Z and Dai, A and Blouin, AG and Arcila, M and Masilionis, I and Chaligne, R and Ponce, DM and Landau, HJ and Politikos, I and Tamari, R and Hanash, AM and Jenq, RR and Giralt, SA and Markey, KA and Zhang, Y and Perales, MA and Socci, ND and Greenbaum, BD and Iacobuzio-Donahue, CA and Hollmann, TJ and van den Brink, MRM and Peled, JU}, title = {Tissue-specific features of the T cell repertoire after allogeneic hematopoietic cell transplantation in human and mouse.}, journal = {Science translational medicine}, volume = {15}, number = {706}, pages = {eabq0476}, doi = {10.1126/scitranslmed.abq0476}, pmid = {37494469}, issn = {1946-6242}, support = {T32 CA009512/CA/NCI NIH HHS/United States ; P50 CA254838/CA/NCI NIH HHS/United States ; R01 CA228308/CA/NCI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; P01 CA023766/CA/NCI NIH HHS/United States ; R01 HL123340/HL/NHLBI NIH HHS/United States ; R01 HL147584/HL/NHLBI NIH HHS/United States ; P01 AG052359/AG/NIA NIH HHS/United States ; K08 HL143189/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; Mice ; Animals ; T-Lymphocytes/pathology ; *Hematopoietic Stem Cell Transplantation ; *Graft vs Host Disease/pathology ; Receptors, Antigen, T-Cell ; }, abstract = {T cells are the central drivers of many inflammatory diseases, but the repertoire of tissue-resident T cells at sites of pathology in human organs remains poorly understood. We examined the site-specificity of T cell receptor (TCR) repertoires across tissues (5 to 18 tissues per patient) in prospectively collected autopsies of patients with and without graft-versus-host disease (GVHD), a potentially lethal tissue-targeting complication of allogeneic hematopoietic cell transplantation, and in mouse models of GVHD. Anatomic similarity between tissues was a key determinant of TCR repertoire composition within patients, independent of disease or transplant status. The T cells recovered from peripheral blood and spleens in patients and mice captured a limited portion of the TCR repertoire detected in tissues. Whereas few T cell clones were shared across patients, motif-based clustering revealed shared repertoire signatures across patients in a tissue-specific fashion. T cells at disease sites had a tissue-resident phenotype and were of donor origin based on single-cell chimerism analysis. These data demonstrate the complex composition of T cell populations that persist in human tissues at the end stage of an inflammatory disorder after lymphocyte-directed therapy. These findings also underscore the importance of studying T cell in tissues rather than blood for tissue-based pathologies and suggest the tissue-specific nature of both the endogenous and posttransplant T cell landscape.}, }
@article {pmid37494438, year = {2023}, author = {Chia, WN and Tan, CW and Tan, AWK and Young, B and Starr, TN and Lopez, E and Fibriansah, G and Barr, J and Cheng, S and Yeoh, AY and Yap, WC and Lim, BL and Ng, TS and Sia, WR and Zhu, F and Chen, S and Zhang, J and Kwek, MSS and Greaney, AJ and Chen, M and Au, GG and Paradkar, PN and Peiris, M and Chung, AW and Bloom, JD and Lye, D and Lok, S and Wang, LF}, title = {Potent pan huACE2-dependent sarbecovirus neutralizing monoclonal antibodies isolated from a BNT162b2-vaccinated SARS survivor.}, journal = {Science advances}, volume = {9}, number = {30}, pages = {eade3470}, pmid = {37494438}, issn = {2375-2548}, mesh = {Animals ; Humans ; Antibodies, Viral ; Neutralization Tests ; BNT162 Vaccine ; *Severe acute respiratory syndrome-related coronavirus ; Antibodies, Monoclonal/chemistry ; Cryoelectron Microscopy ; *COVID-19/prevention & control ; SARS-CoV-2 ; }, abstract = {The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern such as Omicron hampered efforts in controlling the ongoing coronavirus disease 2019 pandemic due to their ability to escape neutralizing antibodies induced by vaccination or prior infection, highlighting the need to develop broad-spectrum vaccines and therapeutics. Most human monoclonal antibodies (mAbs) reported to date have not demonstrated true pan-sarbecovirus neutralizing breadth especially against animal sarbecoviruses. Here, we report the isolation and characterization of highly potent mAbs targeting the receptor binding domain (RBD) of huACE2-dependent sarbecovirus from a SARS-CoV survivor vaccinated with BNT162b2. Among the six mAbs identified, one (E7) showed better huACE2-dependent sarbecovirus neutralizing potency and breadth than any other mAbs reported to date. Mutagenesis and cryo-electron microscopy studies indicate that these mAbs have a unique RBD contact footprint and that E7 binds to a quaternary structure-dependent epitope.}, }
@article {pmid37493847, year = {2023}, author = {Nareddy, VR and Machta, J and Abbott, K and Esmaeili, S and Hastings, A}, title = {Modeling and prediction of phase shifts in noisy two-cycle oscillations.}, journal = {Journal of mathematical biology}, volume = {87}, number = {2}, pages = {33}, pmid = {37493847}, issn = {1432-1416}, mesh = {*Models, Theoretical ; *Ecosystem ; Population Density ; }, abstract = {Understanding and predicting ecological dynamics in the presence of noise remains a substantial and important challenge. This is particularly true in light of the poor quality of much ecological data and the imprecision of many ecological models. As a first approach to this problem, we focus here on a simple system expressed as a discrete time model with 2-cycle behavior, reflecting alternating high and low population sizes. Such dynamics naturally arise in ecological systems with overcompensatory density dependence. We ask how the amount of detail included in the population estimates affects the ability to forecast the likelihood of changes in the phase of oscillation, meaning whether high populations occur in odd or in even years. We adjust the level of detail by converting continuous population levels to simple, coarse-grained descriptions using two-state and four-state models. We also consider a cubic noisy over-compensatory model with three parameters. The focus on phase changes is what distinguishes the question we are asking and the methods we use from more standard time series approaches. Obviously, adding observation states improves the ability to forecast phase shifts. In particular, the four-state model and cubic model outperform the two-state model because they include a transition state, through which the dynamics typically pass during a phase change. Nonetheless, at high noise levels the improvement in forecast skill is relatively modest. Additionally, the frequency of phase changes depends strongly on the noise level, and is much less affected by the parameter determining amplitude in the population model, so phase shift frequencies could possibly be used to infer noise levels.}, }
@article {pmid37490631, year = {2023}, author = {Dong, TQ and Brown, ER}, title = {A joint Bayesian hierarchical model for estimating SARS-CoV-2 genomic and subgenomic RNA viral dynamics and seroconversion.}, journal = {Biostatistics (Oxford, England)}, volume = {}, number = {}, pages = {}, doi = {10.1093/biostatistics/kxad016}, pmid = {37490631}, issn = {1468-4357}, support = {/GATES/Bill & Melinda Gates Foundation/United States ; }, abstract = {Understanding the viral dynamics of and natural immunity to the severe acute respiratory syndrome coronavirus 2 is crucial for devising better therapeutic and prevention strategies for coronavirus disease 2019 (COVID-19). Here, we present a Bayesian hierarchical model that jointly estimates the genomic RNA viral load, the subgenomic RNA (sgRNA) viral load (correlated to active viral replication), and the rate and timing of seroconversion (correlated to presence of antibodies). Our proposed method accounts for the dynamical relationship and correlation structure between the two types of viral load, allows for borrowing of information between viral load and antibody data, and identifies potential correlates of viral load characteristics and propensity for seroconversion. We demonstrate the features of the joint model through application to the COVID-19 post-exposure prophylaxis study and conduct a cross-validation exercise to illustrate the model's ability to impute the sgRNA viral trajectories for people who only had genomic RNA viral load data.}, }
@article {pmid37489578, year = {2023}, author = {Kumar, S and Stainer, A and Dubrulle, J and Simpkins, C and Cooper, JA}, title = {Cas phosphorylation regulates focal adhesion assembly.}, journal = {eLife}, volume = {12}, number = {}, pages = {}, doi = {10.7554/eLife.90234}, pmid = {37489578}, issn = {2050-084X}, abstract = {Integrin-mediated cell attachment rapidly induces tyrosine kinase signaling. Despite years of research, the role of this signaling in integrin activation and focal adhesion assembly is unclear. We provide evidence that the Src-family kinase (SFK) substrate Cas (Crk-associated substrate, p130Cas, BCAR1) is phosphorylated, and associated with its effectors, Crk/CrkL, in clusters that are precursors of focal adhesions. The initial phospho-Cas clusters contain integrin b1 in its inactive, bent closed, conformation. Later, phospho-Cas and total Cas levels decrease as integrin b1 is activated and core focal adhesion proteins including vinculin, talin, kindlin and paxillin are recruited. Cas is required for cell spreading and focal adhesion assembly in epithelial and fibroblast cells on collagen and fibronectin. Cas cluster formation requires Cas, Crk/CrkL, SFKs and Rac1 but not vinculin. Rac1 provides positive feedback onto Cas through reactive oxygen, opposed by negative feedback from the ubiquitin proteasome system. The results suggest a two-step model for focal adhesion assembly in which clusters of phospho-Cas, effectors and inactive integrin b1 grow through positive feedback prior to integrin activation and recruitment of core focal adhesion proteins.}, }
@article {pmid37489536, year = {2023}, author = {Schuermans, A and Nakao, T and Uddin, MM and Hornsby, W and Ganesh, S and Shadyab, AH and Liu, S and Haring, B and Shufelt, CL and Taub, MA and Mathias, RA and Kooperberg, C and Reiner, AP and Bick, AG and Manson, JE and Natarajan, P and Honigberg, MC}, title = {Age at Menopause, Leukocyte Telomere Length, and Coronary Artery Disease in Postmenopausal Women.}, journal = {Circulation research}, volume = {}, number = {}, pages = {}, doi = {10.1161/CIRCRESAHA.123.322984}, pmid = {37489536}, issn = {1524-4571}, abstract = {BACKGROUND: Premature menopause is a risk factor for accelerated cardiovascular aging, but underlying mechanisms remain incompletely understood. This study investigated the role of leukocyte telomere length (LTL), a marker of cellular aging and genomic instability, in the association of premature menopause with cardiovascular disease.
METHODS: Participants from the UK Biobank and Women's Health Initiative with complete reproductive history and LTL measurements were included. Primary analyses tested the association between age at menopause and LTL using multivariable-adjusted linear regression. Secondary analyses stratified women by history of gynecologic surgery. Mendelian randomization was used to infer causal relationships between LTL and age at natural menopause. Multivariable-adjusted Cox regression and mediation analyses tested the joint associations of premature menopause and LTL with incident coronary artery disease.
RESULTS: This study included 130 254 postmenopausal women (UK Biobank: n=122 224; Women's Health Initiative: n=8030), of whom 4809 (3.7%) had experienced menopause before age 40. Earlier menopause was associated with shorter LTL (meta-analyzed ß=-0.02 SD/5 years of earlier menopause [95% CI, -0.02 to -0.01]; P=7.2×10[-12]). This association was stronger and significant in both cohorts for women with natural/spontaneous menopause (meta-analyzed ß=-0.04 SD/5 years of earlier menopause [95% CI, -0.04 to -0.03]; P<2.2×10[-16]) and was independent of hormone therapy use. Mendelian randomization supported a causal association of shorter genetically predicted LTL with earlier age at natural menopause. LTL and age at menopause were independently associated with incident coronary artery disease, and mediation analyses indicated small but significant mediation effects of LTL in the association of menopausal age with coronary artery disease.
CONCLUSIONS: Earlier age at menopause is associated with shorter LTL, especially among women with natural menopause. Accelerated telomere shortening may contribute to the heightened cardiovascular risk associated with premature menopause.}, }
@article {pmid37486790, year = {2023}, author = {Makhsous, N and Goya, S and Avendaño, CC and Rupp, J and Kuypers, J and Jerome, KR and Boeckh, M and Waghmare, A and Greninger, AL}, title = {Within-host rhinovirus evolution in upper and lower respiratory tract highlights capsid variability and mutation-independent compartmentalization.}, journal = {The Journal of infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1093/infdis/jiad284}, pmid = {37486790}, issn = {1537-6613}, abstract = {BACKGROUND: Rhinovirus (RV) infections can progress from the upper (URT) to lower (LRT) respiratory tract in immunocompromised individuals, causing high rates of fatal pneumonia. Little is known about how RV evolves within hosts during infection.
METHODS: We sequenced RV complete genomes from 12 hematopoietic cell transplant patients with infection for up to 190 days from both URT (nasal wash, NW) and LRT (bronchoalveolar lavage, BAL). Metagenomic (mNGS) and amplicon NGS were used to track the emergence and evolution of intra-host single nucleotide variants (iSNVs).
RESULTS: Identical RV intra-host populations in matched NW and BAL specimens indicated no genetic adaptation is required for RV to progress from URT to LRT. Coding iSNVs were 2.3-fold more prevalent in capsid over non-structural genes. iSNVs modeled were significantly more likely to be found in capsid surface capsid residues, but were not preferentially located in known RV neutralizing antibody epitopes. Newly emergent, genotype-matched iSNV haplotypes from immunocompromised individuals from 2008-2010 could be detected in Seattle-area community RV sequences from 2020-2021.
CONCLUSION: RV infections in immunocompromised hosts can progress from URT to LRT with no specific evolutionary requirement. Capsid proteins carry the highest variability and emergent mutations can be detected in other, including future, RV sequences.}, }
@article {pmid35341357, year = {2023}, author = {Jones, SMW and Edwards, TC and Leroux, BG and Kapp-Simon, KA and Patrick, DL and Stueckle, LP and Rosenberg, JM and Albert, M and Bellucci, CC and Aspinall, CL and Vick, K and Heike, CL}, title = {Exploration of Caregiver Interrater Agreement and Test-Retest Reliability on the Infant Cleft Observer Outcomes (iCOO).}, journal = {The Cleft palate-craniofacial journal : official publication of the American Cleft Palate-Craniofacial Association}, volume = {60}, number = {8}, pages = {1032-1040}, pmid = {35341357}, issn = {1545-1569}, support = {KL2 TR002317/TR/NCATS NIH HHS/United States ; R01 DE024986/DE/NIDCR NIH HHS/United States ; TL1 TR002318/TR/NCATS NIH HHS/United States ; UL1 TR002319/TR/NCATS NIH HHS/United States ; }, abstract = {Caregiver and observer-reported measures are frequently used as outcomes for research on infants and young children who are unable to report on their own health. Our team developed the Infant with Clefts Observation Outcomes Instrument (iCOO) for infants with cleft lip with or without cleft palate. This exploratory study compared test-retest and interrater reliabilities to inform whether differences in caregiver perspective might affect the iCOO. This study is a secondary analysis comparing caregiver interrater agreement to test-retest reliability. Twenty-five pairs of caregivers completed the iCOO before surgery, 1 week later for test-retest reliability, 2 days after surgery, and 2 months after surgery. Reliability was assessed using intraclass correlations (ICCs) and t-tests were used to compare ratings between caregivers. Infants had cleft lip (28%) or cleft lip and palate (72%). Primary caregivers were predominantly mothers (92%) and secondary caregivers were predominantly fathers (80%). Test-retest reliability met psychometric standards for most items on the iCOO (81%-86% of items). Caregiver agreement on the iCOO items was lower than test-retest reliability (33%-46% of items met psychometric standards). Caregivers did not systematically differ in whether they rated infants as healthier or less healthy than the other caregiver (5%-16% of items had statistically significant differences). Caregivers used the measure consistently, but had different experiences and perceptions of their infant's health and functioning. Future studies are needed to explore mechanisms for the differences in test-retest and interrater reliability. Whenever possible, the same caregiver should provide ratings of the infant, including on the iCOO.}, }
@article {pmid37484765, year = {2023}, author = {Bennett, JC and Emanuels, A and Heimonen, J and O'Hanlon, J and Hughes, JP and Han, PD and Chow, EJ and Ogokeh, CE and Rolfes, MA and Lockwood, CM and Pfau, B and Uyeki, TM and Shendure, J and Hoag, S and Fay, K and Lee, J and Sibley, TR and Rogers, JH and Starita, LM and Englund, JA and Chu, HY}, title = {Streptococcus pneumoniae nasal carriage patterns with and without common respiratory virus detections in households in Seattle, WA, USA before and during the COVID-19 pandemic.}, journal = {Frontiers in pediatrics}, volume = {11}, number = {}, pages = {1198278}, pmid = {37484765}, issn = {2296-2360}, abstract = {BACKGROUND: Respiratory viruses might influence Streptococcus pneumoniae nasal carriage and subsequent disease risk. We estimated the association between common respiratory viruses and semiquantitative S. pneumoniae nasal carriage density in a household setting before and during the COVID-19 pandemic.
METHODS: From November 2019-June 2021, we enrolled participants in a remote household surveillance study of respiratory pathogens. Participants submitted weekly reports of acute respiratory illness (ARI) symptoms. Mid-turbinate or anterior nasal swabs were self-collected at enrollment, when ARI occurred, and, in the second year of the study only, from household contacts after SARS-CoV-2 was detected in a household member. Specimens were tested using multiplex reverse-transcription PCR for respiratory pathogens, including S. pneumoniae, rhinovirus, adenovirus, common human coronavirus, influenza A/B virus, respiratory syncytial virus (RSV) A/B, human metapneumovirus, enterovirus, and human parainfluenza virus. We estimated differences in semiquantitative S. pneumoniae nasal carriage density, estimated by the inverse of S. pneumoniae relative cycle threshold (Crt) values, with and without viral detection for any virus and for specific respiratory viruses using linear generalized estimating equations of S. pneumoniae Crt values on virus detection adjusted for age and swab type and accounting for clustering of swabs within households.
RESULTS: We collected 346 swabs from 239 individuals in 151 households that tested positive for S. pneumoniae (n = 157 with and 189 without ≥1 viruses co-detected). Difficulty breathing, cough, and runny nose were more commonly reported among individuals with specimens with viral co-detection compared to without (15%, 80% and 93% vs. 8%, 57%, and 51%, respectively) and ear pain and headache were less commonly reported (3% and 26% vs. 16% and 41%, respectively). For specific viruses among all ages, semiquantitative S. pneumoniae nasal carriage density was greater with viral co-detection for enterovirus, RSV A/B, adenovirus, rhinovirus, and common human coronavirus (P < 0.01 for each). When stratified by age, semiquantitative S. pneumoniae nasal carriage density was significantly greater with viral co-detection among children aged <5 (P = 0.002) and 5-17 years (P = 0.005), but not among adults aged 18-64 years (P = 0.29).
CONCLUSION: Detection of common respiratory viruses was associated with greater concurrent S. pneumoniae semiquantitative nasal carriage density in a household setting among children, but not adults.}, }
@article {pmid37481462, year = {2023}, author = {Nyame, YA and Baker, KK and Montgomery, B and Grivas, P and Redman, MW and Wright, JL}, title = {Racial and sex differences in tumor genomics in urothelial carcinoma.}, journal = {Urologic oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.urolonc.2023.06.020}, pmid = {37481462}, issn = {1873-2496}, abstract = {PURPOSE: Differences in bladder cancer outcomes have been demonstrated by sex and race/ethnicity, with studies showing a higher burden of adverse outcomes among women and racially minoritized populations. Despite these epidemiologic differences, populations with disproportionally adverse outcomes are often underrepresented in genomic cohorts. This exclusion impacts the accuracy and generalizability of genomic studies in bladder cancer and has the potential to widen disparities by sex and/or race/ethnicity.
BASIC PROCEDURES: We analyzed pooled somatic mutational data from publicly available cohorts in the cBioPortal open access platform.
FINDINGS: A total of 796 unique patients were identified. Average age for the cohort was 67 years (range: 25-98 years), 188 (24%) were female, and the majority were White (n = 423, 85% among those who report race). Median total mutation count was 91 (IQR: 20, 202) per patient. We used multivariable logistic regression to independently evaluate the association between race/sex and mutation status in each of 122 genes of interest, identified from TCGA, adjusting for age and bladder cancer invasive status. In adjusted analyses, male sex was associated with increased risk of mutation in ARID1A, CHD6, and NCOR1 compared with female sex. White race was associated with increased risk of mutation in ARID1A, EP300, PIK3CA, and TP53 and decreased risk of mutation in HRAS compared with non-White race.
CONCLUSIONS: These differences highlight the importance of enriching cohorts for female and non-White patients in genomic studies and clinical trials, especially as we test the use of molecular biomarkers to personalize care for patients with bladder cancer.}, }
@article {pmid37480848, year = {2023}, author = {Koyama, M and Hippe, DS and Srinivasan, S and Proll, SC and Miltiadous, O and Li, N and Zhang, P and Ensbey, KS and Hoffman, NG and Schmidt, CR and Yeh, AC and Minnie, SA and Strenk, SM and Fiedler, TL and Hattangady, N and Kowalsky, J and Grady, WM and Degli-Esposti, MA and Varelias, A and Clouston, AD and van den Brink, MRM and Dey, N and Randolph, TW and Markey, KA and Fredricks, DN and Hill, GR}, title = {Intestinal microbiota controls graft-versus-host disease independent of donor-host genetic disparity.}, journal = {Immunity}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.immuni.2023.06.024}, pmid = {37480848}, issn = {1097-4180}, abstract = {Acute graft-versus-host disease (aGVHD) remains a major limitation of allogeneic stem cell transplantation (SCT), and severe intestinal manifestation is the major cause of early mortality. Intestinal microbiota control MHC class II (MHC-II) expression by ileal intestinal epithelial cells (IECs) that promote GVHD. Here, we demonstrated that genetically identical mice of differing vendor origins had markedly different intestinal microbiota and ileal MHC-II expression, resulting in discordant GVHD severity. We utilized cohousing and antibiotic treatment to characterize the bacterial taxa positively and negatively associated with MHC-II expression. A large proportion of bacterial MHC-II inducers were vancomycin sensitive, and peri-transplant oral vancomycin administration attenuated CD4[+] T cell-mediated GVHD. We identified a similar relationship between pre-transplant microbes, HLA class II expression, and both GVHD and mortality in a large clinical SCT cohort. These data highlight therapeutically tractable mechanisms by which pre-transplant microbial taxa contribute to GVHD independently of genetic disparity.}, }
@article {pmid37480258, year = {2023}, author = {Symonds, LK and Davidson, NE}, title = {Are we there yet? Optimal duration of endocrine therapy in women with postmenopausal early-stage hormone receptor-positive breast cancer.}, journal = {Journal of the National Cancer Institute}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnci/djad111}, pmid = {37480258}, issn = {1460-2105}, support = {//Breast Cancer Research Foundation/ ; }, }
@article {pmid37090655, year = {2023}, author = {Wrenn, ED and Apfelbaum, AA and Rudzinski, ER and Deng, X and Jiang, W and Sud, S and Van Noord, RA and Newman, EA and Garcia, NM and Hoglund, VJ and Bhise, SS and Kanaan, SB and Waltner, OG and Furlan, SN and Lawlor, ER}, title = {Carcinoma-associated fibroblast-like tumor cells remodel the Ewing sarcoma tumor microenvironment.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {37090655}, support = {F31 CA247104/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; R01 CA215981/CA/NCI NIH HHS/United States ; }, abstract = {Tumor heterogeneity is a major driver of cancer progression. In epithelial-derived malignancies, carcinoma-associated fibroblasts (CAFs) contribute to tumor heterogeneity by depositing extracellular matrix (ECM) proteins that dynamically remodel the tumor microenvironment (TME). Ewing sarcomas (EwS) are histologically monomorphous, mesenchyme-derived tumors that are devoid of CAFs. Here we identify a previously uncharacterized subpopulation of transcriptionally distinct EwS tumor cells that deposit pro-tumorigenic ECM. Single cell analyses revealed that these CAF-like cells differ from bulk EwS cells by their upregulation of a matrisome-rich gene signature that is normally repressed by EWS::FLI1, the oncogenic fusion transcription factor that underlies EwS pathogenesis. Further, our studies showed that ECM-depositing tumor cells express the cell surface marker CD73, allowing for their isolation ex vivo and detection in situ. Spatial profiling of tumor xenografts and patient biopsies demonstrated that CD73 [+] EwS cells and tumor cell-derived ECM are prevalent along tumor borders and invasive fronts. Importantly, despite loss of EWS::FLI1-mediated gene repression, CD73 [+] EwS cells retain expression of EWS::FLI1 and the fusion-activated gene signature, as well as tumorigenic and proliferative capacities. Thus, EwS tumor cells can be reprogrammed to adopt CAF-like properties and these transcriptionally and phenotypically distinct cell subpopulations contribute to tumor heterogeneity by remodeling the TME.}, }
@article {pmid36711558, year = {2023}, author = {Popchock, AR and Larson, JD and Dubrulle, J and Asbury, CL and Biggins, S}, title = {Direct observation of coordinated assembly of individual native centromeric nucleosomes.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {36711558}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R01 GM064386/GM/NIGMS NIH HHS/United States ; R35 GM134842/GM/NIGMS NIH HHS/United States ; T32 HL007312/HL/NHLBI NIH HHS/United States ; }, abstract = {Eukaryotic chromosome segregation requires the kinetochore, a megadalton-sized machine that forms on specialized centromeric chromatin containing CENP-A, a histone H3 variant. CENP-A deposition requires a chaperone protein HJURP that targets it to the centromere, but it has remained unclear whether HJURP has additional functions beyond CENP-A targeting and why high AT DNA content, which disfavors nucleosome assembly, is widely conserved at centromeres. To overcome the difficulties of studying nucleosome formation in vivo, we developed a microscopy assay that enables direct observation of de novo centromeric nucleosome recruitment and maintenance with single molecule resolution. Using this assay, we discover that CENP-A can arrive at centromeres without its dedicated centromere-specific chaperone HJURP, but stable incorporation depends on HJURP and additional DNA-binding proteins of the inner kinetochore. We also show that homopolymer AT runs in the yeast centromeres are essential for efficient CENP-A deposition. Together, our findings reveal requirements for stable nucleosome formation and provide a foundation for further studies of the assembly and dynamics of native kinetochore complexes.}, }
@article {pmid37480164, year = {2023}, author = {Cooper, TM and Alonzo, TA and Tasian, SK and Kutny, MA and Hitzler, J and Pollard, JA and Aplenc, R and Meshinchi, S and Kolb, EA}, title = {Children's Oncology Group's 2023 blueprint for research: Myeloid neoplasms.}, journal = {Pediatric blood & cancer}, volume = {}, number = {}, pages = {e30584}, doi = {10.1002/pbc.30584}, pmid = {37480164}, issn = {1545-5017}, support = {U10CA180899/CA/NCI NIH HHS/United States ; UG1CA233249/CA/NCI NIH HHS/United States ; U10CA098543/CA/NCI NIH HHS/United States ; U24CA196173/CA/NCI NIH HHS/United States ; U10CA180886/CA/NCI NIH HHS/United States ; /NH/NIH HHS/United States ; U10 CA180899/CA/NCI NIH HHS/United States ; U10CA098413/CA/NCI NIH HHS/United States ; }, abstract = {During the past decade, the outcomes of pediatric patients with acute myeloid leukemia (AML) have plateaued with 5-year event-free survival (EFS) and overall survival (OS) of approximately 46 and 64%, respectively. Outcomes are particularly poor for those children with high-risk disease, who have 5-year OS of 46%. Substantial survival improvements have been observed for a subset of patients treated with targeted therapies. Specifically, children with KMT2A-rearranged AML and/or FLT3 internal tandem duplication (FLT3-ITD) mutations benefitted from the addition of gemtuzumab ozogamicin, an anti-CD33 antibody-drug conjugate, in the AAML0531 clinical trial (NCT00372593). Sorafenib also improved response and survival in children with FLT3-ITD AML in the AAML1031 clinical trial (NCT01371981). Advances in characterization of prognostic cytomolecular events have helped to identify patients at highest risk of relapse and facilitated allocation to consolidative hematopoietic stem cell transplant (HSCT) in first remission. Some patients clearly have improved survival with HSCT, although the benefit is largely unknown for most patients. Finally, data-driven refinements in supportive care recommendations continue to evolve with meaningful and measurable reductions in toxicity and improvements in EFS and OS. As advances in application of targeted therapies, risk stratification, and improved supportive care measures are incorporated into current trials and become standard-of-care, there is every expectation that we will see improved survival with a reduction in toxic morbidity and mortality. The research agenda of the Children's Oncology Group's Myeloid Diseases Committee continues to build upon experience and outcomes with an overarching goal of curing more children with AML.}, }
@article {pmid37479875, year = {2023}, author = {Dong, X and Zheng, Y and Lin, DW and Newcomb, L and Zhao, YQ}, title = {Constructing time-invariant dynamic surveillance rules for optimal monitoring schedules.}, journal = {Biometrics}, volume = {}, number = {}, pages = {}, doi = {10.1111/biom.13911}, pmid = {37479875}, issn = {1541-0420}, abstract = {Dynamic surveillance rules (DSRs) are sequential surveillance decision rules informing monitoring schedules in clinical practice, which can adapt over time according to a patient's evolving characteristics. In many clinical applications, it is desirable to identify and implement optimal time-invariant DSRs, where the parameters indexing the decision rules are shared across different decision points. We propose a new criterion for DSRs that accounts for benefit-cost tradeoff during the course of disease surveillance. We develop two methods to estimate the time-invariant DSRs optimizing the proposed criterion, and establish asymptotic properties for the estimated parameters of biomarkers indexing the DSRs. The first approach estimates the optimal decision rules for each individual at every stage via regression modeling, and then estimates the time-invariant DSRs via a classification procedure with the estimated time-varying decision rules as the response. The second approach proceeds by optimizing a relaxation of the empirical objective, where a surrogate function is utilized to facilitate computation. Extensive simulation studies are conducted to demonstrate the superior performances of the proposed methods. The methods are further applied to the Canary Prostate Active Surveillance Study (PASS).}, }
@article {pmid37478973, year = {2023}, author = {Lundeen, RA and Kennedy, JJ and Murillo, OD and Ivey, RG and Zhao, L and Schoenherr, RM and Hoofnagle, AN and Wang, P and Whiteaker, JR and Paulovich, AG}, title = {Monitoring both extended and tryptic forms of stable isotope-labeled standard peptides provides an internal quality control of proteolytic digestion in targeted mass spectrometry-based assays.}, journal = {Molecular & cellular proteomics : MCP}, volume = {}, number = {}, pages = {100621}, doi = {10.1016/j.mcpro.2023.100621}, pmid = {37478973}, issn = {1535-9484}, abstract = {Targeted mass spectrometry (MS)-based proteomic assays, such as multiplexed multiple reaction monitoring (MRM)-MS assays, enable sensitive and specific quantification of proteotypic peptides as stoichiometric surrogates for proteins. Efforts are underway to expand the use of MRM-MS assays in clinical environments, which requires a reliable strategy to monitor proteolytic digestion efficiency within individual samples. Towards this goal, extended stable isotope-labeled standard (SIS) peptides (hE), which incorporate native proteolytic cleavage sites, can be spiked into protein lysates prior to proteolytic (trypsin) digestion, and release of the tryptic SIS peptide (hT) can be monitored. However, hT measurements alone cannot monitor the extent of digestion and may be confounded by matrix effects specific to individual patient samples; therefore they are not sufficient to monitor sample-to-sample digestion variability. We hypothesized that measuring undigested hE, along with its paired hT, would improve detection of digestion issues compared to only measuring hT. We tested the ratio of the SIS pair measurements, or hE/hT, as a quality control (QC) metric of trypsin digestion for two MRM assays: a direct-MRM (398 targets) and an immuno-MRM assay (126 targets requiring immunoaffinity peptide enrichment), with extended SIS peptides observable for 54% (216) and 62% (78) of the targets, respectively. We evaluated the quantitative bias for each target in a series of experiments that adversely affected proteolytic digestion (e.g., variable digestion times, pH, temperature). We identified a subset of SIS pairs (36 for the direct-MRM, 7 for the immuno-MRM assay) for which the hE/hT ratio reliably detected inefficient digestion that resulted in decreased assay sensitivity and unreliable endogenous quantification. The hE/hT ratio was more responsive to a decrease in digestion efficiency than a metric based on hT measurements alone. For clinical-grade MRM-MS assays, this study describes a ready-to-use QC panel and also provides a road map for designing custom QC panels.}, }
@article {pmid37478390, year = {2023}, author = {Dimopoulos, MA and Opat, S and D'Sa, S and Jurczak, W and Lee, HP and Cull, G and Owen, RG and Marlton, P and Wahlin, BE and Garcia-Sanz, R and McCarthy, H and Mulligan, S and Tedeschi, A and Castillo, JJ and Czyz, J and Fernández de Larrea, C and Belada, D and Libby, E and Matous, J and Motta, M and Siddiqi, T and Tani, M and Trněný, M and Minnema, MC and Buske, C and Leblond, V and Treon, SP and Trotman, J and Chan, WY and Schneider, J and Allewelt, H and Patel, S and Cohen, A and Tam, CS}, title = {Zanubrutinib Versus Ibrutinib in Symptomatic Waldenström Macroglobulinemia: Final Analysis From the Randomized Phase III ASPEN Study.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {}, number = {}, pages = {JCO2202830}, doi = {10.1200/JCO.22.02830}, pmid = {37478390}, issn = {1527-7755}, abstract = {The phase III ASPEN study demonstrated the comparable efficacy and improved safety of zanubrutinib versus ibrutinib in patients with Waldenström macroglobulinemia (WM). Here, we report long-term follow-up outcomes from ASPEN. The primary end point was the sum of very good partial response (VGPR) + complete response (CR) rates; secondary and exploratory end points were also reported. Cohort 1 comprised 201 patients (myeloid differentiation primary response 88-mutant WM: 102 receiving zanubrutinib; 99 receiving ibrutinib); cohort 2 comprised 28 patients (myeloid differentiation primary response 88 wild-type WM: 28 zanubrutinib; 26 efficacy evaluable). At 44.4-month median follow-up, VGPR + CR rates were 36.3% with zanubrutinib versus 25.3% with ibrutinib in cohort 1 and 30.8% with one CR in cohort 2. In patients with CXC motif chemokine receptor 4 mutation, VGPR + CR rates were 21.2% with zanubrutinib versus 10.0% with ibrutinib (cohort 1). Median progression-free survival and overall survival were not reached. Any-grade adverse events (AEs) of diarrhea (34.7% v 22.8%), muscle spasms (28.6% v 11.9%), hypertension (25.5% v 14.9%), atrial fibrillation/flutter (23.5% v 7.9%), and pneumonia (18.4% v 5.0%) were more common with ibrutinib versus zanubrutinib; neutropenia (20.4% v 34.7%) was less common with ibrutinib versus zanubrutinib (cohort 1). Zanubrutinib was associated with lower risk of AE-related treatment discontinuation. Overall, these findings confirm the long-term response quality and tolerability associated with zanubrutinib.}, }
@article {pmid37477921, year = {2023}, author = {Unger, JM}, title = {A Ground's-Eye View on Racial and Ethnic Disparities in Cancer Clinical Trial Participation.}, journal = {JAMA network open}, volume = {6}, number = {7}, pages = {e2322436}, doi = {10.1001/jamanetworkopen.2023.22436}, pmid = {37477921}, issn = {2574-3805}, mesh = {Humans ; *Neoplasms/therapy ; *Racial Groups ; Clinical Trials as Topic ; }, }
@article {pmid37477588, year = {2023}, author = {Kordelas, L and Terzer, T and Gooley, TA and Davis, C and Sandmaier, BM and Sorror, ML and Penack, O and Schaeper, NDE and Blau, IW and Beelen, DW and Radujkovic, A and Dreger, P and Luft, T}, title = {EASIX-1 year and late mortality after allogeneic stem cell transplantation.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2022008617}, pmid = {37477588}, issn = {2473-9537}, abstract = {Patients with haematological malignancies who survive the first year after allogeneic stem cell transplantation (alloSCT) without relapse have a substantial risk of non-relapse mortality (NRM), and predictive markers are missing. The Endothelial Activation and Stress Index (EASIX) predicts endothelial complications and NRM early after alloSCT. We hypothesised that EASIX assessed 1 year after alloSCT in disease-free survivors may predict late NRM. Relapse-free survivors at one year after alloSCT were retrospectively studied in two independent cohorts (training cohort: n=610, merged validation cohort: n=852). EASIX determined one year after alloSCT was correlated with overall survival (OS), NRM, and relapse. Serum endothelial and inflammatory markers were measured in the training cohort and correlated with EASIX-1y. EASIX-1year predicted OS and NRM but not relapse risk in both, training and validation cohort in univariable and multivariable Cox regression analyses. Brier score and c-index analyses validated the univariable EASIX effects. There was no significant interaction between EASIX-1year and incidence of chronic GvHD on OS. EASIX-1year predicted outcome irrespective of pre-existing comorbidities. Principal causes of NRM in both, training and validation cohorts were infections with and without GvHD, as well as cardiovascular complications. EASIX-1y correlated with sCD141 and interleukin-18, but not with C-reactive protein, suppressor of tumorigenicity (ST)-2, angiopoietin-2, CXCL9 or CXCL8. EASIX-1year is the first validated predictor of late overall and non-relapse mortality. High-risk patients as defined by EASIX-1year might be considered for intensified surveillance and prophylactic measures.}, }
@article {pmid37476185, year = {2023}, author = {Liu, C and Shatila, M and Mathew, A and Machado, AP and Thomas, A and Zhang, HC and Thomas, AS and Faleck, D and Funchain, P and Philpott, J and Grivas, P and Obeid, M and Carbonnel, F and Wang, Y}, title = {Role of C-Reactive Protein in Predicting the Severity and Response of Immune-Mediated Diarrhea and Colitis in Patients with Cancer.}, journal = {Journal of Cancer}, volume = {14}, number = {10}, pages = {1913-1919}, pmid = {37476185}, issn = {1837-9664}, abstract = {Background: Immune-mediated diarrhea and colitis (IMDC) frequently develop after treatment with immune checkpoint inhibitors. C-reactive protein (CRP) is a serum inflammatory biomarker used to stratify and monitor disease severity in many inflammatory conditions. However, CRP level is not specific and is widely influenced by various factors non-specific to bowel inflammation. We aimed to study the utility of CRP as a predictor of disease severity and therapy response in IMDC. Methods: We performed a retrospective analysis of patients diagnosed with IMDC who had CRP measured at IMDC onset and after treatment with selective immunosuppressive therapy (SIT: infliximab and vedolizumab), between 01/2016 and 02/2022 at MD Anderson Cancer Center. Patient demographics, clinical characteristics, and IMDC data were collected and analyzed. Results: Our sample of 128 patients had a median age of 67 years; most were white (89.8%); and male (65.6%). Prior to development of IMDC, 15 (11.7%) were initially treated with anti-CTLA-4, 42 (32.8%) with anti-PD-1 or PD-L1, and 71 (55.5%) with a combination of both. We found higher CRP level was associated with higher CTCAE grade of clinical symptoms such as diarrhea (p=0.015), colitis (p=0.013), and endoscopic findings (p=0.016). While CRP levels decreased after IMDC treatment, there was no significant association between CRP levels with clinical remission, endoscopic remission or histologic remission. There also was no significant correlation between CRP level and recurrence of IMDC, or with fecal calprotectin levels. Conclusion: CRP level may be useful to assess initial severity of IMDC, including grade of diarrhea and colitis and degree of endoscopic inflammation. However, CRP is not a robust surrogate biomarker for assessing treatment response or disease recurrence. Despite the reduction of CRP levels observed following IMDC treatment, this finding might be nonspecific and potentially confounded by concurrent clinical factors, such as underlying malignancy, other inflammatory processes, and systemic anti-cancer therapy. Further studies of the role of CRP are warranted in patients with cancer and IMDC.}, }
@article {pmid37473727, year = {2023}, author = {Leichter, SM and Henikoff, S}, title = {β-catenin repositions over time.}, journal = {Cell systems}, volume = {14}, number = {7}, pages = {549-550}, doi = {10.1016/j.cels.2023.06.008}, pmid = {37473727}, issn = {2405-4720}, mesh = {*beta Catenin/genetics ; *Wnt Proteins/genetics ; Cell Nucleus/metabolism ; Chromatin/metabolism ; Wnt Signaling Pathway ; }, abstract = {How β-catenin, the nuclear activator of the Wnt pathway, affects the chromatin environment of its targets is unknown. Over a time course of stimulation, β-catenin repositions itself around the genome in a cell-type-specific manner, eliciting transient chromatin changes in differentiated cells and progressive shaping of undifferentiated cells.}, }
@article {pmid37473584, year = {2023}, author = {Fjeldstad, HE and Jacobsen, DP and Johnsen, GM and Sugulle, M and Chae, A and Kanaan, SB and Gammill, HS and Staff, AC}, title = {Poor glucose control and markers of placental dysfunction correlate with increased circulating fetal microchimerism in diabetic pregnancies.}, journal = {Journal of reproductive immunology}, volume = {159}, number = {}, pages = {104114}, doi = {10.1016/j.jri.2023.104114}, pmid = {37473584}, issn = {1872-7603}, abstract = {Fetal microchimerism (FMc) arises during pregnancy as fetal cells enter maternal circulation and remain decades postpartum. Circulating FMc is increased in preeclampsia, fetal growth restriction, and as we recently showed, is associated with biomarkers of placental dysfunction in normotensive term pregnancies. Diabetes mellitus (DM) also correlates with placental dysfunction. We hypothesize that poor glucose control and markers of placental dysfunction are associated with increased circulating FMc in diabetic pregnancies. We included 122 pregnancies preceding active labor (pregestational DM, n = 77, gestational DM (GDM), n = 45) between 2001 and 2017. Maternal and fetal samples were genotyped for various human leukocyte antigen (HLA) loci, and other polymorphisms to identify fetus-specific alleles. We used validated polymerase chain reaction (PCR) assays to quantify FMc in maternal peripheral blood buffy coat. Negative binomial regression with adjustment for confounders was used to assess FMc quantity. In pregestational DM, increased circulating FMc correlated with elevation of HbA1c (≥ 6.0 %) (detection rate ratio (DRR) = 4.9, p = 0.010) and a 1000 pg/mL rise in the anti-angiogenic biomarker soluble fms-like tyrosine kinase-1 (sFlt-1) (DRR = 1.1, p = 0.011). In GDM, increased FMc correlated with elevated 2-hour oral glucose tolerance test results (DRR = 2.3, p = 0.046) and birthweight < 10th or > 90th percentile (DRR = 4.2, p = 0.049). These findings support our novel hypothesis that FMc correlates with poor glucose control and various aspects of placental dysfunction in DM. Whether increased FMc in pregnancies with poor glucose control and placental dysfunction contributes to the risk of preeclampsia in diabetic pregnancies and to the increased risk of chronic cardiovascular disease later in life remains to be investigated.}, }
@article {pmid37471639, year = {2023}, author = {Luyapan, J and Bossé, Y and Li, Z and Xiao, X and Rosenberger, A and Hung, RJ and Lam, S and Zienolddiny, S and Liu, G and Kiemeney, LA and Chen, C and McKay, J and Johansson, M and Johansson, M and Tardon, A and Fernandez-Tardon, G and Brennan, P and Field, JK and Davies, MP and Woll, PJ and Cox, A and Taylor, F and Arnold, SM and Lazarus, P and Grankvist, K and Landi, MT and Christiani, DC and MacKenzie, TA and Amos, CI}, title = {Candidate pathway analysis of surfactant proteins identifies CTSH and SFTA2 that influences lung cancer risk.}, journal = {Human molecular genetics}, volume = {}, number = {}, pages = {}, doi = {10.1093/hmg/ddad095}, pmid = {37471639}, issn = {1460-2083}, abstract = {Pulmonary surfactant is a lipoprotein synthesized and secreted by alveolar type II cells in lung. We evaluated the associations between 200 139 SNPs of 40 surfactant-related genes and lung cancer risk using genotyped data from two independent lung cancer GWAS. Discovery data included 18 082 cases and 13 780 controls of European ancestry. Replication data included 1914 cases and 3065 controls of European descent. Using multivariate logistic regression, we found novel SNPs in surfactant-related genes CTSH (rs34577742 C > T, OR = 0.90, 95% CI = 0.89-0.93, P = 7.64x10-9) and SFTA2 (rs3095153 G > A, OR = 1.16, 95% CI = 1.10-1.21, P = 1.27x10-9) associated with overall lung cancer in the discovery data and validated in an independent replication data-CTSH (rs34577742 C > T, OR = 0.88, 95% CI = 0.80-0.96, P = 5.76x10-3) and SFTA2 (rs3095153 G > A, OR = 1.14, 95% CI = 1.01-1.28, P = 3.25x10-2). Among ever smokers, we found SNPs in CTSH (rs34577742 C > T, OR = 0.89, 95% CI = 0.85-0.92, P = 1.94x10-7) and SFTA2 (rs3095152 G > A, OR = 1.20, 95% CI = 1.14-1.27, P = 4.25x10-11) associated with overall lung cancer in the discovery data and validated in the replication data-CTSH (rs34577742 C > T, OR = 0.88, 95% CI = 0.79-0.97, P = 1.64x10-2) and SFTA2 (rs3095152 G > A, OR = 1.15, 95% CI = 1.01-1.30, P = 3.81x10-2). Subsequent TWAS using expression weights from a lung eQTL study revealed genes most strongly associated with lung cancer are CTSH (PTWAS = 2.44x10-4) and SFTA2 (PTWAS = 2.32x10-6).}, }
@article {pmid37471463, year = {2023}, author = {Wrenn, ED and Apfelbaum, AA and Rudzinski, ER and Deng, X and Jiang, W and Sud, S and Van Noord, RA and Newman, EA and Garcia, NM and Miyaki, A and Hoglund, VJ and Bhise, SS and Kanaan, SB and Waltner, OG and Furlan, SN and Lawlor, ER}, title = {Cancer-associated fibroblast-like tumor cells remodel the Ewing sarcoma tumor microenvironment.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {}, number = {}, pages = {}, doi = {10.1158/1078-0432.CCR-23-1111}, pmid = {37471463}, issn = {1557-3265}, abstract = {PURPOSE: Despite limited genetic and histologic heterogeneity, Ewing sarcoma (EwS) tumor cells are transcriptionally heterogeneous and display varying degrees of mesenchymal lineage specification in vitro. In this study, we investigated if and how transcriptional heterogeneity of EwS cells contributes to heterogeneity of tumor phenotypes in vivo.
EXPERIMENTAL DESIGN: Single cell proteogenomic-sequencing of EwS cell lines was performed and integrated with patient tumor transcriptomic data. Cell subpopulations were isolated by FACS for assessment of gene expression and phenotype. Digital spatial profiling and human whole transcriptome analysis interrogated transcriptomic heterogeneity in EwS xenografts. Tumor cell subpopulations and matrix protein deposition were evaluated in xenografts and patient tumors using multiplex immunofluorescence staining.
RESULTS: We identified CD73 as a biomarker of highly mesenchymal EwS cell subpopulations in tumor models and patient biopsies. CD73+ tumor cells displayed distinct transcriptional and phenotypic properties, including selective upregulation of genes that are repressed by EWS::FLI1, and increased migratory potential. CD73+ cells were distinguished in vitro and in vivo by increased expression of matrisomal genes and abundant deposition of extracellular matrix (ECM) proteins. In epithelial-derived malignancies, ECM is largely deposited by cancer-associated fibroblasts (CAFs) and we thus labeled CD73+ EwS cells, CAF-like tumor cells. Marked heterogeneity of CD73+ EwS cell frequency and distribution were detected in tumors in situ, and CAF-like tumor cells and associated ECM were observed in peri-necrotic regions and invasive foci.
CONCLUSIONS: EwS tumor cells can adopt CAF-like properties and these distinct cell subpopulations contribute to tumor heterogeneity by remodeling the tumor microenvironment.}, }
@article {pmid37470152, year = {2023}, author = {Le Gouill, S and Długosz-Danecka, M and Rule, S and Zinzani, PL and Goy, A and Smith, SD and Doorduijn, JK and Panizo, C and Shah, BD and Davies, AJ and Eek, R and Jacobsen, E and Kater, AP and Robak, T and Jain, P and Calvo, R and Tao, L and Wang, M}, title = {Final results and overall survival data from a phase II study of acalabrutinib monotherapy in patients with relapsed/refractory mantle cell lymphoma, including those with poor prognostic factors.}, journal = {Haematologica}, volume = {}, number = {}, pages = {}, doi = {10.3324/haematol.2022.282469}, pmid = {37470152}, issn = {1592-8721}, abstract = {Not available.}, }
@article {pmid37469281, year = {2023}, author = {Popchock, AR and Larson, JD and Dubrulle, J and Asbury, CL and Biggins, S}, title = {Direct observation of coordinated assembly of individual native centromeric nucleosomes.}, journal = {The EMBO journal}, volume = {}, number = {}, pages = {e114534}, doi = {10.15252/embj.2023114534}, pmid = {37469281}, issn = {1460-2075}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; }, abstract = {Eukaryotic chromosome segregation requires the kinetochore, a megadalton-sized machine that forms on specialized centromeric chromatin containing CENP-A, a histone H3 variant. CENP-A deposition requires a chaperone protein HJURP that targets it to the centromere, but it has remained unclear whether HJURP has additional functions beyond CENP-A targeting and why high AT DNA content, which disfavors nucleosome assembly, is widely conserved at centromeres. To overcome the difficulties of studying nucleosome formation in vivo, we developed a microscopy assay that enables direct observation of de novo centromeric nucleosome recruitment and maintenance with single molecule resolution. Using this assay, we discover that CENP-A can arrive at centromeres without its dedicated centromere-specific chaperone HJURP, but stable incorporation depends on HJURP and additional DNA-binding proteins of the inner kinetochore. We also show that homopolymer AT runs in the yeast centromeres are essential for efficient CENP-A deposition. Together, our findings reveal requirements for stable nucleosome formation and provide a foundation for further studies of the assembly and dynamics of native kinetochore complexes.}, }
@article {pmid37468552, year = {2023}, author = {Alaggio, R and Amador, C and Anagnostopoulos, I and Attygalle, AD and de Oliveira Araujo, IB and Berti, E and Bhagat, G and Borges, AM and Boyer, D and Calaminici, M and Chadburn, A and Chan, JKC and Cheuk, W and Chng, WJ and Choi, JK and Chuang, SS and Coupland, SE and Czader, M and Dave, SS and de Jong, D and Di Napoli, A and Du, MQ and Elenitoba-Johnson, KS and Ferry, J and Geyer, J and Gratzinger, D and Guitart, J and Gujral, S and Harris, M and Harrison, CJ and Hartmann, S and Hochhaus, A and Jansen, PM and Karube, K and Kempf, W and Khoury, J and Kimura, H and Klapper, W and Kovach, AE and Kumar, S and Lazar, AJ and Lazzi, S and Leoncini, L and Leung, N and Leventaki, V and Li, XQ and Lim, MS and Liu, WP and Louissaint, A and Marcogliese, A and Medeiros, LJ and Michal, M and Miranda, RN and Mitteldorf, C and Montes-Moreno, S and Morice, W and Nardi, V and Naresh, KN and Natkunam, Y and Ng, SB and Oschlies, I and Ott, G and Parrens, M and Pulitzer, M and Rajkumar, SV and Rawstron, AC and Rech, K and Rosenwald, A and Said, J and Sarkozy, C and Sayed, S and Saygin, C and Schuh, A and Sewell, W and Siebert, R and Sohani, AR and Suzuki, R and Tooze, R and Traverse-Glehen, A and Vega, F and Vergier, B and Wechalekar, AD and Wood, B and Xerri, L and Xiao, W and , }, title = {Correction: "The 5th edition of The World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms" Leukemia. 2022 Jul;36(7):1720-1748.}, journal = {Leukemia}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41375-023-01962-5}, pmid = {37468552}, issn = {1476-5551}, }
@article {pmid37468430, year = {2023}, author = {Joshi, AD and Rahnavard, A and Kachroo, P and Mendez, KM and Lawrence, W and Julián-Serrano, S and Hua, X and Fuller, H and Sinnott-Armstrong, N and Tabung, FK and Shutta, KH and Raffield, LM and Darst, BF and , }, title = {An epidemiological introduction to human metabolomic investigations.}, journal = {Trends in endocrinology and metabolism: TEM}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.tem.2023.06.006}, pmid = {37468430}, issn = {1879-3061}, abstract = {Metabolomics holds great promise for uncovering insights around biological processes impacting disease in human epidemiological studies. Metabolites can be measured across biological samples, including plasma, serum, saliva, urine, stool, and whole organs and tissues, offering a means to characterize metabolic processes relevant to disease etiology and traits of interest. Metabolomic epidemiology studies face unique challenges, such as identifying metabolites from targeted and untargeted assays, defining standards for quality control, harmonizing results across platforms that often capture different metabolites, and developing statistical methods for high-dimensional and correlated metabolomic data. In this review, we introduce metabolomic epidemiology to the broader scientific community, discuss opportunities and challenges presented by these studies, and highlight emerging innovations that hold promise to uncover new biological insights.}, }
@article {pmid37467515, year = {2023}, author = {Lyman, GH and Kuderer, NM}, title = {Perception, Cognition and thought: Part III: Reasoning, Judgement and Decision-Making.}, journal = {Cancer investigation}, volume = {}, number = {}, pages = {1-7}, doi = {10.1080/07357907.2023.2238944}, pmid = {37467515}, issn = {1532-4192}, }
@article {pmid37467017, year = {2023}, author = {Kanaan, SB and Urselli, F and Radich, JP and Nelson, JL}, title = {Ultrasensitive Chimerism Enhances Measurable Residual Disease Testing Post-Allogeneic Hematopoietic Cell Transplantation.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2023010332}, pmid = {37467017}, issn = {2473-9537}, abstract = {Increasing mixed chimerism (reemerging recipient cells) after allogeneic hematopoietic cell transplantation (allo-HCT) can indicate relapse, the leading factor determining mortality in blood malignancies. Most clinical chimerism tests have limited sensitivity and are primarily designed to monitor engraftment. We developed a panel of qPCR assays using TaqMan chemistry capable of quantifying chimerism on the order of 1-in-a-million. At such analytic sensitivity, we hypothesized it could inform on relapse risk. As a proof-of-concept, we applied our panel on a retrospective cohort of acute leukemia patients with known outcomes post-allo-HCT. Recipient cells in bone marrow aspirates (BMA) remained detectable in 97.8% of tested samples. Absolute recipient chimerism proportions and rates at which these proportions increased in BMA in the first 540 days post-allo-HCT were associated with relapse. Detectable MRD (measurable residual disease) by flow cytometry in BMA post-allo-HCT showed limited correlation with relapse. This correlation noticeably strengthened when combined with increased recipient chimerism in BMA, demonstrating the ability of our ultrasensitive chimerism assay to augment MRD data. Our technology reveals an underappreciated usefulness of clinical chimerism. Used side-by-side with MRD assays, it promises to improve identification of patients with the highest risk of disease reoccurrence for a chance for early intervention.}, }
@article {pmid37467016, year = {2023}, author = {Curran, KJ and Nikiforow, S and Bachier, C and Hsu, YM and Maloney, DG and Maus, MV and McCarthy, PL and Porter, DL and Shi, PA and Shpall, EJ and William, B and Wacker, K and Warkentin, P and Heslop, HE}, title = {Robust Quality Infrastructure is Key to Safe and Effective Delivery of Immune Effector Cells: How FACT-Finding Can Help.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2023010401}, pmid = {37467016}, issn = {2473-9537}, abstract = {Immune effector cells (IEC) include a broad range of immune cells capable of modulating several disease states including malignant and non-malignant conditions. The growth in use of IECs as both investigational and commercially available products has required medical institutions to develop workflows/processes to safely implement and deliver this transformative therapy. Adding to the complexity of this therapy is the variety of targets, diseases, sources, and unique toxicities that a patient experiences following IEC therapy. For over 25 years the Foundation for the Accreditation of Cellular Therapy (FACT) has established the standard for use of cellular therapy, initially with hematopoietic cell transplant (HCT) and more recently with their development of standards to encompass IEC products such as chimeric antigen receptor (CAR) T cells. To date, IEC therapy has challenged the bandwidth and infrastructure of institutions offering this therapy. To address these challenges FACT has established a programmatic framework to improve the delivery of IEC therapy. In this manuscript we outline the current state of IEC program development, accreditation, and solutions to the challenges that programs face as they expand their application of novel IEC therapy.}, }
@article {pmid37466945, year = {2023}, author = {Nyame, YA and Lee, JR}, title = {Exploring the Association Between Online Health Information and Racial Disparities in Prostate Cancer.}, journal = {JAMA network open}, volume = {6}, number = {7}, pages = {e2324359}, doi = {10.1001/jamanetworkopen.2023.24359}, pmid = {37466945}, issn = {2574-3805}, mesh = {Male ; Humans ; *Racial Groups ; *Prostatic Neoplasms ; }, }
@article {pmid37466697, year = {2023}, author = {Leiser, CL and Whitsel, EA and Reiner, A and Rich, SS and Rotter, JI and Taylor, KD and Tracy, RP and Kooperberg, C and Smith, AV and Mason, JE and Mychaleckyj, JC and Bick, AG and Szpiro, AA and Kaufman, JD}, title = {Associations between ambient air pollutants and clonal hematopoiesis of indeterminate potential (CHIP).}, journal = {Cancer epidemiology, biomarkers & 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-23-0305}, pmid = {37466697}, issn = {1538-7755}, abstract = {Background Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related somatic mutation associated with incident hematologic cancer. Environmental stressors which, like air pollution, generate oxidative stress at the cellular level, may induce somatic mutations and some mutations may provide a selection advantage for persistence and expansion of specific clones. Materials and Methods We used data from the Multi-Ethnic Study of Atherosclerosis (MESA) N=4,379 and the Women's Health Initiative (WHI) N=7,701 to estimate cross-sectional associations between annual average air pollution concentrations at participant address the year before blood draw using validated spatiotemporal models. We used covariate-adjusted logistic regression to estimate risk of CHIP per interquartile range increases in PM2.5 (4 ug/m3) and NO2 (10 ppb) as odds ratios (95% confidence intervals). Results Prevalence of CHIP at blood draw (variant allele fraction > 2%) was 4.4% and 8.7% in MESA and WHI, respectively. The most common CHIP driver mutation was in DNMT3A. Neither pollutant was associated with CHIP: ORMESA PM2.5=1.00 (0.68-1.45), ORMESA NO2=1.05 (0.69-1.61), ORWHI PM2.5=0.97 (0.86-1.09), ORWHI NO2=0.98 (0.88-1.10); or with DNMT3A-driven CHIP. Conclusions We did not find evidence that air pollution contributes to CHIP prevalence in two large observational cohorts. Impact This is the first study to estimate associations between air pollution and CHIP.}, }
@article {pmid37466644, year = {2023}, author = {Kamounah, S and Tayob, N and Chiang, S and Wei, F and Park, JK and Kwon, HM and Feng, Z and Chia, D and Pedersen, AML and Song, YW and Wong, DTW}, title = {Immunoassay Detects Salivary Anti-SSA/Ro-52 Autoantibodies in Seronegative Patients with Primary Sjögren's Syndrome.}, journal = {ImmunoHorizons}, volume = {7}, number = {7}, pages = {554-561}, doi = {10.4049/immunohorizons.2300043}, pmid = {37466644}, issn = {2573-7732}, abstract = {The diagnostic work-up for Sjögren's syndrome is challenging and complex, including testing for serum autoantibodies to SSA/Ro and a labial salivary gland biopsy. Furthermore, the diagnosis is often delayed. In this study, we tested the hypothesis that anti-SSA/Ro autoantibodies are detectable in the saliva of patients with primary Sjögren's syndrome (pSS) because the disease affects the salivary glands, and these autoantibodies display greater discriminatory performance in saliva than in serum. SSA/Ro-52 Ags were used to develop what is, to our knowledge, a novel quantitative electrochemical-based immunoassay: the electric field-induced release and measurement (EFIRM) platform. The clinical utility was determined by measuring salivary anti-SSA/Ro-52 autoantibodies in patients with pSS and sicca (n = 34), patients without pSS with sicca (n = 35), and healthy subjects (n = 41). The statistical analysis of discrimination included the area under the receiver operating characteristic curve. Salivary anti-SSA/Ro-52 autoantibodies were measured in 94% (32 of 34) of patients with pSS with 85% (29 of 34) seropositivity. Four of the five seronegative patients with pSS had EFIRM-measurable anti-SSA/Ro-52 autoantibodies in saliva. Additionally, 60% (21 of 35) of the seronegative patients without pSS who had sicca had EFIRM-detectable SSA/Ro-52 autoantibodies in saliva, indicating the onset of autoimmune disease. Two of the 41 healthy control subjects had EFIRM-detectable SSA/Ro-52 autoantibodies in their saliva. Salivary SSA/Ro-52 autoantibodies significantly discriminated patients with pSS or patients with the initial stage of autoimmune disease from healthy subjects with an area under the receiver operating characteristic curve of 0.91. Our findings suggest that the proposed saliva SSA/Ro-52 immunoassay improves early and accurate diagnosis of seronegative patients with pSS and patients with early-onset autoimmune disease.}, }
@article {pmid37466213, year = {2023}, author = {Hedskog, C and Rodriguez, L and Roychoudhury, P and Huang, ML and Jerome, KR and Hao, L and Ireton, RC and Li, J and Perry, JK and Han, D and Camus, G and Greninger, AL and Gale, M and Porter, DP}, title = {Viral Resistance Analyses From the Remdesivir Phase 3 Adaptive COVID-19 Treatment Trial-1 (ACTT-1).}, journal = {The Journal of infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1093/infdis/jiad270}, pmid = {37466213}, issn = {1537-6613}, abstract = {BACKGROUND: Remdesivir is approved for the treatment of COVID-19 in non-hospitalized and hospitalized adult and pediatric patients. Here we present SARS-CoV-2 resistance analyses from the Phase 3 ACTT-1 randomized placebo-controlled trial conducted in adult participants hospitalized with COVID-19.
METHODS: Swab samples were collected at baseline and longitudinally through Day 29. SARS-CoV-2 genomes were sequenced using next-generation sequencing. Phenotypic analysis was conducted directly on participant virus isolates and/or using SARS-CoV-2 subgenomic replicons expressing mutations identified in the Nsp12 target gene.
RESULTS: Among participants with both baseline and post-baseline sequencing data, emergent Nsp12 substitutions were observed in 12/31 (38.7%) and 12/30 (40.0%) participants in the remdesivir and placebo arms, respectively. No emergent Nsp12 substitutions in the remdesivir arm were observed in more than one participant. Phenotyping showed low to no change in susceptibility to remdesivir relative to wild-type Nsp12 reference for the substitutions tested: A16V (0.8-fold change in EC50), P323L+V792I (2.2-fold), C799F (2.5-fold), K59N (1.0-fold), and K59N+V792I (3.4-fold).
CONCLUSIONS: The similar rate of emerging Nsp12 substitutions in remdesivir and placebo arms and the minimal change in remdesivir susceptibility among tested substitutions support a high barrier to remdesivir resistance development in COVID-19 patients.}, }
@article {pmid37463855, year = {2023}, author = {Nyame, YA and Gore, JL and Lin, DW}, title = {Putting patients first to redefine prostate cancer classifications.}, journal = {Journal of the National Cancer Institute}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnci/djad124}, pmid = {37463855}, issn = {1460-2105}, }
@article {pmid37463757, year = {2023}, author = {Bresalier, RS and Senore, C and Young, GP and Allison, J and Benamouzig, R and Benton, S and Bossuyt, PMM and Caro, L and Carvalho, B and Chiu, HM and Coupé, VMH and de Klaver, W and de Klerk, CM and Dekker, E and Dolwani, S and Fraser, CG and Grady, W and Guittet, L and Gupta, S and Halloran, SP and Haug, U and Hoff, G and Itzkowitz, S and Kortlever, T and Koulaouzidis, A and Ladabaum, U and Lauby-Secretan, B and Leja, M and Levin, B and Levin, TR and Macrae, F and Meijer, GA and Melson, J and O'Morain, C and Parry, S and Rabeneck, L and Ransohoff, DF and Sáenz, R and Saito, H and Sanduleanu-Dascalescu, S and Schoen, RE and Selby, K and Singh, H and Steele, RJC and Sung, JJY and Symonds, EL and Winawer, SJ and , }, title = {An efficient strategy for evaluating new non-invasive screening tests for colorectal cancer: the guiding principles.}, journal = {Gut}, volume = {}, number = {}, pages = {}, doi = {10.1136/gutjnl-2023-329701}, pmid = {37463757}, issn = {1468-3288}, abstract = {OBJECTIVE: New screening tests for colorectal cancer (CRC) are rapidly emerging. Conducting trials with mortality reduction as the end point supporting their adoption is challenging. We re-examined the principles underlying evaluation of new non-invasive tests in view of technological developments and identification of new biomarkers.
DESIGN: A formal consensus approach involving a multidisciplinary expert panel revised eight previously established principles.
RESULTS: Twelve newly stated principles emerged. Effectiveness of a new test can be evaluated by comparison with a proven comparator non-invasive test. The faecal immunochemical test is now considered the appropriate comparator, while colonoscopy remains the diagnostic standard. For a new test to be able to meet differing screening goals and regulatory requirements, flexibility to adjust its positivity threshold is desirable. A rigorous and efficient four-phased approach is proposed, commencing with small studies assessing the test's ability to discriminate between CRC and non-cancer states (phase I), followed by prospective estimation of accuracy across the continuum of neoplastic lesions in neoplasia-enriched populations (phase II). If these show promise, a provisional test positivity threshold is set before evaluation in typical screening populations. Phase III prospective studies determine single round intention-to-screen programme outcomes and confirm the test positivity threshold. Phase IV studies involve evaluation over repeated screening rounds with monitoring for missed lesions. Phases III and IV findings will provide the real-world data required to model test impact on CRC mortality and incidence.
CONCLUSION: New non-invasive tests can be efficiently evaluated by a rigorous phased comparative approach, generating data from unbiased populations that inform predictions of their health impact.}, }
@article {pmid37463058, year = {2023}, author = {Chung, DJ and Shah, N and Wu, J and Logan, B and Bisharat, L and Callander, N and Cheloni, G and Anderson, K and Chodon, T and Dhakal, B and Devine, S and Somaiya Dutt, P and Efebera, Y and Geller, N and Ghiasuddin, H and Hematti, P and Holmberg, L and Howard, A and Johnson, B and Karagkouni, D and Lazarus, HM and Malek, E and McCarthy, P and McKenna, D and Mendizabal, A and Nooka, A and Munshi, N and O'Donnell, L and Rapoport, AP and Reese, J and Rosenblatt, J and Soiffer, R and Stroopinsky, D and Uhl, L and Vlachos, IS and Waller, EK and Young, JW and Pasquini, MC and Avigan, D}, title = {Randomized Trial of a Personalized Dendritic Cell Vaccine after Autologous Stem Cell Transplant for Multiple Myeloma.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {}, number = {}, pages = {}, doi = {10.1158/1078-0432.CCR-23-0235}, pmid = {37463058}, issn = {1557-3265}, abstract = {PURPOSE: Vaccination with dendritic cell (DC)/multiple myeloma (MM) fusions has been shown to induce the expansion of circulating MM-reactive lymphocytes and consolidation of clinical response following autologous hematopoietic cell transplant (autoHCT).
PATIENTS AND METHODS: In this randomized phase II trial (NCT02728102), we assessed the effect of DC/MM fusion vaccination, GM-CSF, and lenalidomide maintenance as compared to control arms of GM-CSF and lenalidomide or lenalidomide maintenance alone on clinical response rates and induction of MM-specific immunity at 1-year post-transplant.
RESULTS: The study enrolled 203 patients, with 140 randomized post-transplantation. Vaccine production was successful in 63/68 patients. At 1 year, rates of CR were 52.9% (vaccine) and 50% (control) (p=0.37, 80% CI 44.5%, 61.3% and 41.6%, 58.4%, respectively), and rates of VGPR or better were 85.3% (vaccine) and 77.8% (control) (p=0.2). Conversion to CR at 1 year was 34.8% (vaccine) and 27.3% (control) (p=0.4). Vaccination induced a statistically significant expansion of MM-reactive T cells at 1 year as compared to prior to vaccination (p=0.024) and in contrast to the non-vaccine arm (p=0.026). Single-cell transcriptomics revealed clonotypic expansion of activated CD8 cells and shared dominant clonotypes between patients at 1-year post-transplant.
CONCLUSIONS: DC/MM fusion vaccination with lenalidomide did not result in a statistically significant increase in CR rates at 1-year post-transplant but was associated with a significant increase in circulating MM-reactive lymphocytes indicative of tumor-specific immunity. Site-specific production of a personalized cell therapy with centralized product characterization was effectively accomplished in the context of a multicenter cooperative group study.}, }
@article {pmid37461045, year = {2023}, author = {Reynolds, KM and Horimoto, ARVR and Lin, BM and Zhang, Y and Kurniansyah, N and Yu, B and Boerwinkle, E and Qi, Q and Kaplan, R and Daviglus, M and Hou, L and Zhou, LY and Cai, J and Shaikh, SR and Sofer, T and Browning, SR and Franceschini, N}, title = {Ancestry-driven metabolite variation provides insights into disease states in admixed populations.}, journal = {Genome medicine}, volume = {15}, number = {1}, pages = {52}, pmid = {37461045}, issn = {1756-994X}, support = {R01 DK117445/DK/NIDDK NIH HHS/United States ; R01 MD012765/MD/NIMHD NIH HHS/United States ; N01HC65233/HL/NHLBI NIH HHS/United States ; N01HC65234/HL/NHLBI NIH HHS/United States ; N01HC65235/HL/NHLBI NIH HHS/United States ; N01HC65236/HL/NHLBI NIH HHS/United States ; N01HC65237/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Tandem Mass Spectrometry ; *Genome-Wide Association Study/methods ; Hispanic or Latino/genetics ; Black People ; Genome, Human ; Polymorphism, Single Nucleotide ; }, abstract = {BACKGROUND: Metabolic pathways are related to physiological functions and disease states and are influenced by genetic variation and environmental factors. Hispanics/Latino individuals have ancestry-derived genomic regions (local ancestry) from their recent admixture that have been less characterized for associations with metabolite abundance and disease risk.
METHODS: We performed admixture mapping of 640 circulating metabolites in 3887 Hispanic/Latino individuals from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). Metabolites were quantified in fasting serum through non-targeted mass spectrometry (MS) analysis using ultra-performance liquid chromatography-MS/MS. Replication was performed in 1856 nonoverlapping HCHS/SOL participants with metabolomic data.
RESULTS: By leveraging local ancestry, this study identified significant ancestry-enriched associations for 78 circulating metabolites at 484 independent regions, including 116 novel metabolite-genomic region associations that replicated in an independent sample. Among the main findings, we identified Native American enriched genomic regions at chromosomes 11 and 15, mapping to FADS1/FADS2 and LIPC, respectively, associated with reduced long-chain polyunsaturated fatty acid metabolites implicated in metabolic and inflammatory pathways. An African-derived genomic region at chromosome 2 was associated with N-acetylated amino acid metabolites. This region, mapped to ALMS1, is associated with chronic kidney disease, a disease that disproportionately burdens individuals of African descent.
CONCLUSIONS: Our findings provide important insights into differences in metabolite quantities related to ancestry in admixed populations including metabolites related to regulation of lipid polyunsaturated fatty acids and N-acetylated amino acids, which may have implications for common diseases in populations.}, }
@article {pmid37460640, year = {2023}, author = {Veatch, JR and Riddell, SR}, title = {Stem-cell-like CD4[+] T cells prey on MHC class II-negative tumors.}, journal = {Nature immunology}, volume = {}, number = {}, pages = {}, pmid = {37460640}, issn = {1529-2916}, support = {P50 CA228944/CA/NCI NIH HHS/United States ; P50 CA228944/CA/NCI NIH HHS/United States ; }, }
@article {pmid37460638, year = {2023}, author = {Matsumoto, R and Gray, J and Rybkina, K and Oppenheimer, H and Levy, L and Friedman, LM and Khamaisi, M and Meng, W and Rosenfeld, AM and Guyer, RS and Bradley, MC and Chen, D and Atkinson, MA and Brusko, TM and Brusko, M and Connors, TJ and Luning Prak, ET and Hershberg, U and Sims, PA and Hertz, T and Farber, DL}, title = {Induction of bronchus-associated lymphoid tissue is an early life adaptation for promoting human B cell immunity.}, journal = {Nature immunology}, volume = {}, number = {}, pages = {}, pmid = {37460638}, issn = {1529-2916}, support = {AI100119//U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; AI106697//U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; AI128949//U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; AI168634//U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; AI142288//U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; AI141686//U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; }, abstract = {Infants and young children are more susceptible to common respiratory pathogens than adults but can fare better against novel pathogens like severe acute respiratory syndrome coronavirus 2. The mechanisms by which infants and young children mount effective immune responses to respiratory pathogens are unknown. Through investigation of lungs and lung-associated lymph nodes from infant and pediatric organ donors aged 0-13 years, we show that bronchus-associated lymphoid tissue (BALT), containing B cell follicles, CD4[+] T cells and functionally active germinal centers, develop during infancy. BALT structures are prevalent around lung airways during the first 3 years of life, and their numbers decline through childhood coincident with the accumulation of memory T cells. Single-cell profiling and repertoire analysis reveals that early life lung B cells undergo differentiation, somatic hypermutation and immunoglobulin class switching and exhibit a more activated profile than lymph node B cells. Moreover, B cells in the lung and lung-associated lymph nodes generate biased antibody responses to multiple respiratory pathogens compared to circulating antibodies, which are mostly specific for vaccine antigens in the early years of life. Together, our findings provide evidence for BALT as an early life adaptation for mobilizing localized immune protection to the diverse respiratory challenges during this formative life stage.}, }
@article {pmid37460062, year = {2023}, author = {Zhang, X and Zhao, L and Christopher, CN and Tabung, FK and Bao, W and Garcia, DO and Shadyab, AH and Saquib, N and Neuhouser, ML and Tinker, LF and Zhang, X}, title = {Association of dietary insulinemic and inflammatory potential with risk of liver cancer and chronic liver disease mortality in postmenopausal women: a prospective cohort study.}, journal = {The American journal of clinical nutrition}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ajcnut.2023.07.009}, pmid = {37460062}, issn = {1938-3207}, abstract = {BACKGROUND: Low diet quality, diabetes, and chronic inflammation are risk factors of liver cancer and chronic liver disease (CLD), but the extent to which insulinemic and inflammatory diets are independently associated with risk of liver cancer and CLD mortality is unknown.
METHODS: We conducted a prospective cohort analysis among 78,356 postmenopausal women in the Women's Health Initiative Observational Study. Two validated dietary indices, the empirical dietary index for hyperinsulinemia (EDIH) and the empirical dietary inflammation pattern (EDIP), were estimated from a food frequency questionnaire. Incident cases of liver cancer and CLD mortality were adjudicated via review of medical records and linkage to National Death Index. Multivariable hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using Cox proportional hazard models, adjusted for age, diabetes, body mass index (BMI), and other covariates.
RESULTS: During a median 22.1 years of follow-up, we documented 176 primary liver cancer cases and 156 CLD mortality cases. EDIH was positively associated with incident liver cancer (HRQuartile 4 vs. Quartile 1=1.68; 95% CI:1.00-2.83; p-trend=0.05) and CLD mortality (HRQ4vs.Q1=2.28; 95% CI: 1.25-4.15; p-trend=0.002) in the multivariable model. EDIP was also positively associated with liver cancer (HRQ4vs.Q1=1.88; 95% CI:1.17-3.03; p-trend=0.009) and CLD mortality (HRQ4vs.Q1=1.85; 95% CI:1.09-3.15; p-trend=0.007). Estimates remained significant and robust in sensitivity analyses. Further analyses indicated positive associations for refined grains, processed meat, sugary beverages, and eggs, and inverse associations for coffee and poultry.
CONCLUSIONS: Dietary insulinemic and inflammatory potentials were independently associated with higher risk of liver cancer and CLD mortality in U.S. postmenopausal women. These findings suggest a potential role for diet modification to reduce risk of liver cancer and CLD.}, }
@article {pmid37456587, year = {2023}, author = {Kumar, L and Murray-Krezan, C and Singh, N and Brennan, DC and Rakita, RM and Dasgupta, S and Fisher, CE and Limaye, AP}, title = {A Systematic Review and Meta-analysis of Optimized CMV Preemptive Therapy and Antiviral Prophylaxis for CMV Disease Prevention in CMV High-Risk (D+R-) Kidney Transplant Recipients.}, journal = {Transplantation direct}, volume = {9}, number = {8}, pages = {e1514}, pmid = {37456587}, issn = {2373-8731}, support = {K23 HL143050/HL/NHLBI NIH HHS/United States ; }, abstract = {UNLABELLED: The optimal strategy for cytomegalovirus (CMV) disease prevention in CMV donor/recipient kidney transplant recipients remains uncertain. Conclusions of prior meta-analyses that CMV disease rates with preemptive therapy (PET) and universal prophylaxis (UP) were comparable may have been affected by inclusion of studies lacking key determinants of efficacy of the respective strategies.
METHODS: We conducted a systematic review and meta-analysis of PET with weekly CMV polymerase chain reaction monitoring for ≥3 mo and UP with 6 mo of valganciclovir. PubMed and Embase databases were reviewed from January 1, 2010, to April 1, 2022. Risk of bias was assessed with 3 instruments (Cochrane RoB, Cochrane RoBINS-I, and an instrument for assessing risk in observational studies). The primary outcome was CMV disease incidence by 1-y posttransplant. Secondary outcomes by 1-y were graft loss, acute allograft rejection, and mortality. Results were synthesized using generalized linear mixed model meta-analysis. PET studies were stratified into low-threshold (LT) and high-threshold (HT) PET based on the viral load threshold for initiation of antiviral therapy.
RESULTS: Twenty-five studies met inclusion criteria (6 PET, 19 UP). CMV disease incidence was significantly higher in HT (0.30 [95% confidence interval (CI), 0.22-0.39]) versus LT PET (0.06 [95% CI, 0.03-0.12]). LT PET was associated with a significantly lower CMV disease incidence (0.06 [95% CI, 0.03-0.12]) versus UP (0.21 [95% CI, 0.17-0.27]). Incidence of graft loss, acute allograft rejection, or mortality was not significantly different between LT PET and UP (P > 0.05 for all comparisons). Receipt of lymphocyte-depleting antibodies was not associated with a significant difference in CMV disease incidence (odds ratio = 1.34 [95% CI, 0.80-2.25]).
CONCLUSIONS: LT PET is associated with a significantly lower incidence of CMV disease compared to UP with similar rates of other clinical outcomes. These findings provide rationale and preliminary data for a randomized superiority trial of optimized LT-PET versus UP in donor seropositive recipient seronegative kidney transplant recipients.}, }
@article {pmid37454978, year = {2023}, author = {van den Berg, DMN and de Lima, PN and Knudsen, AB and Rutter, CM and Weinberg, D and Lansdorp-Vogelaar, I and , }, title = {NordICC trial results in line with expected colorectal cancer mortality reduction after colonoscopy: a modelling study.}, journal = {Gastroenterology}, volume = {}, number = {}, pages = {}, doi = {10.1053/j.gastro.2023.06.035}, pmid = {37454978}, issn = {1528-0012}, }
@article {pmid37453812, year = {2023}, author = {Mistry, NA and Sweis, J and Ofori, B and McKoy, JM and Langford, A and Psutka, SP and Perazza, E and Raman, JD and Murphy, AB}, title = {Engaging disparities in prostate cancer: Piloting an interactive, virtual workshop to educate providers on shared decision-making for underserved populations.}, journal = {Urologic oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.urolonc.2023.06.021}, pmid = {37453812}, issn = {1873-2496}, abstract = {OBJECTIVE: Shared decision-making (SDM) is an approach to patient-centered care that is strongly recommended when counseling patients for screening and treatment of prostate cancer. However, providers report lack of comfort with SDM and particularly in disparate populations. We report our experience designing and piloting an online workshop to educate practicing urologists on SDM in diverse populations. Our objective was to create a valued interactive SDM workshop to help urologists learn to lead SDM discussions with men form underserved populations. Therefore, we tested the hypothesis that urologists would agree or strongly agree that we met our learning objectives on postcourse survey.
MATERIALS AND METHODS: With the support of the American Urologic Association, we developed a case-based workshop with interactive role-playing to demonstrate and teach integration of SDM into clinical care. Cases were centered around screening and treatment decisions for localized prostate cancer in diverse patients. Brief surveys were used to track success with learning objectives and urologists' satisfaction with the workshop.
RESULTS: The session included 14 participants from 6 countries. A postworkshop survey indicated that 100% of respondents (8 of 8) "strongly agreed" that the activity met learning objectives, and 100% rated the session as "good" (1), "very good" (1), or "excellent" (6). Participants' knowledge also improved on shared decision-making concepts and the knowledge was maintained one month after the workshop.
CONCLUSION: We successfully created and piloted an interactive online workshop to improve urologists' comfort using shared decision-making in caring for diverse patient populations. The course met its objectives and participant feedback for the course was positive. Sharing this process and framework for development of this intervention may inform future workshops that can be applied to medical students, residents, and providers.}, }
@article {pmid37453563, year = {2023}, author = {Mahmood, K and Thomas, M and Qu, C and , and Hsu, L and Buchanan, DD and Peters, U}, title = {Elucidating the risk of colorectal cancer for variants in hereditary colorectal cancer genes.}, journal = {Gastroenterology}, volume = {}, number = {}, pages = {}, doi = {10.1053/j.gastro.2023.06.032}, pmid = {37453563}, issn = {1528-0012}, }
@article {pmid37452528, year = {2023}, author = {Truong, L and Matern, BM and El-Lagta, N and Mobegi, FM and Askar, M and Ogret, Y and Oguz, FS and Kwok, J and D'Orsogna, L and Martinez, P and Petersdorf, E and Tilanus, MGJ and De Santis, D}, title = {Report from the extended HLA-DPA1 ~ promoter ~ HLA-DPB1 haplotype of the 18th international HLA and immunogenetics workshop.}, journal = {HLA}, volume = {}, number = {}, pages = {}, doi = {10.1111/tan.15155}, pmid = {37452528}, issn = {2059-2310}, abstract = {The primary goal of the HLA-DPA1 ~ promoter ~ HLA-DPB1 haplotype component of the 18th IHIWS was to characterise the extended haplotypes within the HLA-DP region and survey the extent of genetic diversity in this region across human populations. In this report, we analysed single-nucleotide polymorphisms (SNPs) in 255 subjects from 6 different cohorts. The results from the HLA-DP haplotype component have validated findings from the initial pilot study. SNPs in this region were inherited in strong linkage, particularly HLA-DPA1, SNP-linked promoter haplotypes and motifs in exon 2 of HLA-DPB1. We reported 17 SNP-linked haplotypes in the promoter region. Together with HLA-DPA1 and HLA-DPB1 alleles, they formed 74 distinct extended HLA-DP haplotypes in 438 sequences. We also observed the presence of region-specific alleles and promoter haplotypes. Our approach involved phasing extended SNPs including promoter SNPs, HLA-DPA1 and HLA-DPB1 alleles, in a 22 kb region, GRCh38/hg38 (chr6:33,064,111-33,086,679), followed by clustering of these SNPs as one extended haplotype. This hierarchical clustering revealed four major clades, suggesting that haplotypes within each clade may have diverged from a common ancestral haplotype and undergone similar evolutionary processes. The correlation between HLA-DPA1 and the promoter region raises questions about the role of HLA-DPA1 antigen in the heterodimer. This finding requires validation on a larger sample size specifically designed for anthropological analysis. Nevertheless, the results from this study highlight the clinical potential of selecting better-matched donors for patients awaiting haematopoietic stem cell transplants from genetically overlapping groups that share common ancestral haplotypes.}, }
@article {pmid37457919, year = {2016}, author = {Buser, JR and Zhang, X and Byrnes, SA and Ladd, PD and Heiniger, EK and Wheeler, MD and Bishop, JD and Englund, JA and Lutz, B and Weigl, BH and Yager, P}, title = {A disposable chemical heater and dry enzyme preparation for lysis and extraction of DNA and RNA from microorganisms.}, journal = {Analytical methods : advancing methods and applications}, volume = {8}, number = {14}, pages = {2880-2886}, pmid = {37457919}, issn = {1759-9679}, support = {R01 AI096184/AI/NIAID NIH HHS/United States ; }, abstract = {Sample preparation, including bacterial lysis, remains a hurdle in the realization of complete point-of-care tests for many pathogens. Here, we developed a sample preparation methodology for enzymatic lysis and sample heating for low-resource, point-of-care applications. We show an instrument-free chemical heater system for rapid lysis of a gram-positive bacterium (Staphylococcus aureus) and an RNA virus (human respiratory syncytial virus) using a dried lysis enzyme mixture (achromopeptidase) for S. aureus. After a lysis step (<1 minute), lysis enzymes are heat deactivated (<5 minutes) using a simple disposable chemical heater. We demonstrated that both DNA and RNA in the heat-treated sample could be directly amplified without purification, even in the presence of a clinically-obtained human nasal sample. This simple approach to dry enzyme storage and sample heating is adaptable to many applications where samples need to be lysed, including use in low-resource laboratories and in single-use or cartridge-based point-of-care diagnostic devices.}, }
@article {pmid37452102, year = {2023}, author = {Cuglievan, B and Connors, J and He, J and Khazal, S and Yedururi, S and Dai, J and Garces, S and Quesada, AE and Roth, M and Garcia, M and McCall, D and Gibson, A and Ragoonanan, D and Petropoulos, D and Tewari, P and Nunez, C and Mahadeo, KM and Tasian, SK and Lamble, AJ and Pawlowska, A and Hammond, D and Maiti, A and Haddad, FG and Senapati, J and Daver, N and Gangat, N and Konopleva, M and Meshinchi, S and Pemmaraju, N}, title = {Blastic plasmacytoid dendritic cell neoplasm: a comprehensive review in pediatrics, adolescents, and young adults (AYA) and an update of novel therapies.}, journal = {Leukemia}, volume = {}, number = {}, pages = {}, pmid = {37452102}, issn = {1476-5551}, abstract = {Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy that can involve the bone marrow, peripheral blood, skin, lymph nodes, and the central nervous system. Though more common in older adults, BPDCN has been reported across all age groups, including infants and children. The incidence of pediatric BPDCN is extremely low and little is known about the disease. Pediatric BPDCN is believed to be clinically less aggressive but often with more dissemination at presentation than adult cases. Unlike adults who almost always proceed to a hematopoietic stem cell transplantation in first complete remission if transplant-eligible, the majority of children can be cured with a high-risk acute lymphoblastic leukemia-like regimen. Hematopoietic stem cell transplantation is recommended for children with high-risk disease, the definition of which continues to evolve, or those in relapse and refractory settings where outcomes continue to be dismal. Novel agents used in other hematologic malignancies and CD123 targeted agents, including chimeric antigen receptor T-cells and monoclonal/bispecific antibodies, are being brought into research and practice. Our goal is to provide a comprehensive review of presentation, diagnosis, and treatment by review of pediatric cases reported for the last 20 years, and a review of novel targeted therapies and therapies under investigation for adult and pediatric patients.}, }
@article {pmid37451878, year = {2023}, author = {Munoz, FM and Posavad, CM and Richardson, BA and Badell, ML and Bunge, KE and Mulligan, MJ and Parameswaran, L and Kelly, CW and Olson-Chen, C and Novak, RM and Brady, RC and Pasetti, MF and Defranco, EA and Gerber, JS and Shriver, MC and Suthar, MS and Coler, RN and Berube, BJ and Kim, SH and Piper, JM and Miller, AM and Cardemil, CV and Neuzil, KM and Beigi, RH and , }, title = {COVID-19 booster vaccination during pregnancy enhances maternal binding and neutralizing antibody responses and transplacental antibody transfer to the newborn.}, journal = {Vaccine}, volume = {}, number = {}, pages = {}, pmid = {37451878}, issn = {1873-2518}, abstract = {The immune response to COVID-19 booster vaccinations during pregnancy for mothers and their newborns and the functional response of vaccine-induced antibodies against Omicron variants are not well characterized. We conducted a prospective, multicenter cohort study of participants vaccinated during pregnancy with primary or booster mRNA COVID-19 vaccines from July 2021 to January 2022 at 9 academic sites. We determined SARS-CoV-2 binding and live virus and pseudovirus neutralizing antibody (nAb) titers pre- and post-vaccination, and at delivery for both maternal and infant participants. Immune responses to ancestral and Omicron BA.1 SARS-CoV-2 strains were compared between primary and booster vaccine recipients in maternal sera at delivery and in cord blood, after adjusting for days since last vaccination. A total of 240 participants received either Pfizer or Moderna mRNA vaccine during pregnancy (primary 2-dose series: 167; booster dose: 73). Booster vaccination resulted in significantly higher binding and nAb titers, including to the Omicron BA.1 variant, in maternal serum at delivery and in cord blood compared to a primary 2-dose series (range 0.44-0.88 log10 higher, p < 0.0001 for all comparisons). Live virus nAb to Omicron BA.1 were present at delivery in 9 % (GMT ID50 12.7) of Pfizer and 22 % (GMT ID50 14.7) of Moderna primary series recipients, and in 73 % (GMT ID50 60.2) of mRNA boosted participants (p < 0.0001), although titers were significantly lower than to the D614G strain. Transplacental antibody transfer was efficient for all regimens with median transfer ratio range: 1.55-1.77 for IgG, 1.00-1.78 for live virus nAb and 1.79-2.36 for pseudovirus nAb. COVID-19 mRNA vaccination during pregnancy elicited robust immune responses in mothers and efficient transplacental antibody transfer to the newborn. A booster dose during pregnancy significantly increased maternal and cord blood binding and neutralizing antibody levels, including against Omicron BA.1. Findings support the use of a booster dose of COVID-19 vaccine during pregnancy.}, }
@article {pmid37451576, year = {2023}, author = {Ma, X and Fisher, JA and VoPham, T and Vasiliou, V and Jones, RR}, title = {Associations between per- and polyfluoroalkyl substances, liver function, and daily alcohol consumption in a sample of U.S. adults.}, journal = {Environmental research}, volume = {}, number = {}, pages = {116651}, doi = {10.1016/j.envres.2023.116651}, pmid = {37451576}, issn = {1096-0953}, abstract = {BACKGROUND AND AIM: Per- and polyfluoroalkyl substances (PFAS) are ubiquitous in the environment and in the serum of the U.S.
POPULATION: We sought to evaluate the association of PFAS independently and jointly with alcohol intake on liver function biomarkers in a sample of the U.S. general population.
METHODS: Using data from the National Health and Nutrition Examination Survey (2003-2016; N = 11,794), we examined the five most historically prevalent PFAS with >75% detection rates. We estimated odds ratios (OR) and 95% confidence intervals (CI) for the association between PFAS (quartiles and log-transformed continuous, ng/mL) and high levels (>95th percentile) of liver injury biomarkers using logistic regression models adjusted for key confounders. We evaluated interactions between PFAS and alcohol consumption and sex via stratified analyses and conducted sub-analyses adjusting for daily alcohol intake among those with available drinking history (N = 10,316).
RESULT: Serum perfluorooctanoic acid (PFOA) was positively associated with high levels of alanine transferase (ALT) without monotonic trend (ORQ4vsQ1 = 1.45, CI: 0.99 2.12; p-trend = 0.18), and with increased aspartate transaminase when modeled continuously (ORcon = 1.15, CI: 1.02-1.30; p-trend = 0.03). Perfluorooctane sulfonate (PFOS) and perfluorohexane sulfonate (PFHxS) were both inversely associated with alkaline phosphatase while the trend was statistically significant only for PFHxS (p = 0.02). A non-monotonic inverse association was observed with PFOA (p-trend = 0.10). The highest quartile of PFOS was associated with high total bilirubin (TB) (ORQ4vsQ1 = 1.57, CI: 1.01-2.43, p-trend = 0.02). No significant associations were found between any PFAS and γ-glutamyl transpeptidase. We found no associations for perfluorodecanoic acid and perfluorononanoic acid. We observed some suggestive interactions with alcohol intake, particularly among heavy drinkers.
CONCLUSION: Consistent with other studies, serum levels of PFOA, PFHxS and PFNA were positively associated with high levels of ALT, and we also observed weak positive associations between selected PFAS and TB. Positive associations observed among heavy drinkers warrant additional evaluation.}, }
@article {pmid37450838, year = {2023}, author = {Dalmat, RR and Ziebell, RA and Kamineni, A and Phipps, AI and Weiss, NS and Breslau, ES and Burnett-Hartman, AN and Corley, DA and Doria-Rose, VP and Green, BB and Halm, EA and Levin, TR and Schottinger, JE and Chubak, J}, title = {Risk of colorectal cancer and colorectal cancer mortality beginning one year after a negative fecal occult blood test, among screen-eligible 76-85-year-olds.}, journal = {Cancer epidemiology, biomarkers & 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-23-0265}, pmid = {37450838}, issn = {1538-7755}, abstract = {BACKGROUND: Colorectal cancer (CRC) screening is universally recommended for adults ages 45-75 years. Noninvasive fecal occult blood tests are effective screening tests recommended by guidelines. However, empirical evidence to inform older adults' decisions about whether to continue screening is sparse, especially for individuals with prior screening.
METHODS: This study used a retrospective cohort of older adults at three Kaiser Permanente integrated healthcare systems (Northern California, Southern California, Washington) and Parkland Health (Dallas, Texas). Beginning one year following a negative stool-based screening test, cumulative risks of CRC incidence, CRC mortality (accounting for deaths from other causes), and non-CRC mortality were estimated.
RESULTS: Cumulative incidence of CRC in screen-eligible adults aged 76-85 with a negative fecal occult blood test one year ago (N=118,269) was 0.23% (95% confidence interval [CI]: 0.20-0.26%) after two years and 1.21% (95% CI:1.13-1.30%) after eight years. Cumulative CRC mortality was 0.03% (95% CI: 0.02-0.04%) after two years and 0.33% (95% CI: 0.28-0.39%) after eight years. Cumulative risk of death from non-CRC causes was 4.81% (95% CI: 4.68-4.96%) after two years and 28.40% (95% CI: 27.95-28.85%) after eight years.
CONCLUSION: Among 76-85 year-olds with a recent negative stool-based test, cumulative CRC incidence and mortality estimates were low, especially within two years; death from other causes was over 100 times more likely than death from CRC.
IMPACT: These findings of low absolute CRC risk, and comparatively higher risk of death from other causes, can inform decision-making regarding whether and when to continue CRC screening beyond age 75 among screen-eligible adults.}, }
@article {pmid37450436, year = {2023}, author = {Larmarange, J and Bachanas, P and Skalland, T and Balzer, LB and Iwuji, C and Floyd, S and Mills, LA and Pillay, D and Havlir, D and Kamya, MR and Ayles, H and Wirth, K and Dabis, F and Hayes, R and Petersen, M and , }, title = {Population-level viremia predicts HIV incidence at the community level across the Universal Testing and Treatment Trials in eastern and southern Africa.}, journal = {PLOS global public health}, volume = {3}, number = {7}, pages = {e0002157}, pmid = {37450436}, issn = {2767-3375}, abstract = {Universal HIV testing and treatment (UTT) strategies aim to optimize population-level benefits of antiretroviral treatment. Between 2012 and 2018, four large community randomized trials were conducted in eastern and southern Africa. While their results were broadly consistent showing decreased population-level viremia reduces HIV incidence, it remains unclear how much HIV incidence can be reduced by increasing suppression among people living with HIV (PLHIV). We conducted a pooled analysis across the four UTT trials. Leveraging data from 105 communities in five countries, we evaluated the linear relationship between i) population-level viremia (prevalence of non-suppression-defined as plasma HIV RNA >500 or >400 copies/mL-among all adults, irrespective of HIV status) and HIV incidence; and ii) prevalence of non-suppression among PLHIV and HIV incidence, using parametric g-computation. HIV prevalence, measured in 257 929 persons, varied from 2 to 41% across the communities; prevalence of non-suppression among PLHIV, measured in 31 377 persons, from 3 to 70%; population-level viremia, derived from HIV prevalence and non-suppression, from < 1% to 25%; and HIV incidence, measured over 345 844 person-years (PY), from 0.03/100PY to 3.46/100PY. Decreases in population-level viremia were strongly associated with decreased HIV incidence in all trials (between 0.45/100PY and 1.88/100PY decline in HIV incidence per 10 percentage points decline in viremia). Decreases in non-suppression among PLHIV were also associated with decreased HIV incidence in all trials (between 0.06/100PY and 0.17/100PY decline in HIV incidence per 10 percentage points decline in non-suppression). Our results support both the utility of population-level viremia as a predictor of incidence, and thus a tool for targeting prevention interventions, and the ability of UTT approaches to reduce HIV incidence by increasing viral suppression. Implementation of universal HIV testing approaches, coupled with interventions to leverage linkage to treatment, adapted to local contexts, can reduce HIV acquisition at population level.}, }
@article {pmid37444527, year = {2023}, author = {Lastwika, KJ and Wu, W and Zhang, Y and Ma, N and Zečević, M and Pipavath, SNJ and Randolph, TW and Houghton, AM and Nair, VS and Lampe, PD and Kinahan, PE}, title = {Multi-Omic Biomarkers Improve Indeterminate Pulmonary Nodule Malignancy Risk Assessment.}, journal = {Cancers}, volume = {15}, number = {13}, pages = {}, pmid = {37444527}, issn = {2072-6694}, support = {P30CA015704/NH/NIH HHS/United States ; P50CA228944/NH/NIH HHS/United States ; }, abstract = {The clinical management of patients with indeterminate pulmonary nodules is associated with unintended harm to patients and better methods are required to more precisely quantify lung cancer risk in this group. Here, we combine multiple noninvasive approaches to more accurately identify lung cancer in indeterminate pulmonary nodules. We analyzed 94 quantitative radiomic imaging features and 41 qualitative semantic imaging variables with molecular biomarkers from blood derived from an antibody-based microarray platform that determines protein, cancer-specific glycan, and autoantibody-antigen complex content with high sensitivity. From these datasets, we created a PSR (plasma, semantic, radiomic) risk prediction model comprising nine blood-based and imaging biomarkers with an area under the receiver operating curve (AUROC) of 0.964 that when tested in a second, independent cohort yielded an AUROC of 0.846. Incorporating known clinical risk factors (age, gender, and smoking pack years) for lung cancer into the PSR model improved the AUROC to 0.897 in the second cohort and was more accurate than a well-characterized clinical risk prediction model (AUROC = 0.802). Our findings support the use of a multi-omics approach to guide the clinical management of indeterminate pulmonary nodules.}, }
@article {pmid37443365, year = {2023}, author = {Reeves, DB and Gaebler, C and Oliveira, TY and Peluso, MJ and Schiffer, JT and Cohn, LB and Deeks, SG and Nussenzweig, MC}, title = {Impact of misclassified defective proviruses on HIV reservoir measurements.}, journal = {Nature communications}, volume = {14}, number = {1}, pages = {4186}, pmid = {37443365}, issn = {2041-1723}, support = {UL1 TR001866/TR/NCATS NIH HHS/United States ; UM1 AI126611/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; Male ; Proviruses/genetics ; *HIV-1/genetics ; *HIV Infections ; DNA, Viral/genetics ; CD4-Positive T-Lymphocytes ; Viral Load ; }, abstract = {Most proviruses persisting in people living with HIV (PWH) on antiretroviral therapy (ART) are defective. However, rarer intact proviruses almost always reinitiate viral rebound if ART stops. Therefore, assessing therapies to prevent viral rebound hinges on specifically quantifying intact proviruses. We evaluated the same samples from 10 male PWH on ART using the two-probe intact proviral DNA assay (IPDA) and near full length (nfl) Q4PCR. Both assays admitted similar ratios of intact to total HIV DNA, but IPDA found ~40-fold more intact proviruses. Neither assay suggested defective proviruses decay over 10 years. However, the mean intact half-lives were different: 108 months for IPDA and 65 months for Q4PCR. To reconcile this difference, we modeled additional longitudinal IPDA data and showed that decelerating intact decay could arise from very long-lived intact proviruses and/or misclassified defective proviruses: slowly decaying defective proviruses that are intact in IPDA probe locations (estimated up to 5%, in agreement with sequence library based predictions). The model also demonstrates how misclassification can lead to underestimated efficacy of therapies that exclusively reduce intact proviruses. We conclude that sensitive multi-probe assays combined with specific nfl-verified assays would be optimal to document absolute and changing levels of intact HIV proviruses.}, }
@article {pmid37442868, year = {2023}, author = {Ko, LK and Vu, T and Bishop, S and Leeman, J and Escoffery, C and Winer, RL and Duran, MC and Masud, M and Rait, Y}, title = {Implementation studio: implementation support program to build the capacity of rural community health educators serving immigrant communities to implement evidence-based cancer prevention and control interventions.}, journal = {Cancer causes & control : CCC}, volume = {}, number = {}, pages = {}, pmid = {37442868}, issn = {1573-7225}, support = {U48 DP006398/CC/CDC HHS/United States ; U48 DP006398/CC/CDC HHS/United States ; U48 DP006398/CC/CDC HHS/United States ; U48 DP006400/CC/CDC HHS/United States ; U48 DP006377/CC/CDC HHS/United States ; U48 DP006398/CC/CDC HHS/United States ; U48 DP006398/CC/CDC HHS/United States ; U48 DP006398/CC/CDC HHS/United States ; U48 DP006398/CC/CDC HHS/United States ; UL1 TR002319/TR/NCATS NIH HHS/United States ; }, abstract = {PURPOSE: Rural community-based organizations (CBOs) serving immigrant communities are critical settings for implementing evidence-based interventions (EBIs). The Implementation Studio is a training and consultation program focused on facilitating the selection, adaptation, and implementation of cancer prevention and control EBIs. This paper describes implementation and evaluation of the Implementation Studio on CBO's capacity to implement EBIs and their clients' knowledge of colorectal cancer (CRC) screening and intention to screen.
METHODS: Thirteen community health educators (CHEs) from two CBOs participated in the Implementation Studio. Both CBOs selected CRC EBIs during the Studio. The evaluation included two steps. The first step assessed the CHEs' capacity to select, adapt, and implement an EBI. The second step assessed the effect of the CHEs-delivered EBIs on clients' knowledge of CRC and intention to screen (n = 44).
RESULTS: All CHEs were Hispanic and women. Pre/post-evaluation of the Studio showed an increase on CHEs knowledge about EBIs (pre: 23% to post: 75%; p < 0.001). CHEs' ability to select, adapt, and implement EBIs also increased, respectively: select EBI (pre: 21% to post: 92%; p < 0.001), adapt EBI (pre: 21% to post: 92%; p < 0.001), and implement EBI (pre: 29% to post: 75%; p = 0.003). Pre/post-evaluation of the CHE-delivered EBI showed an increase on CRC screening knowledge (p < 0.5) and intention to screen for CRC by their clients.
CONCLUSION: Implementation Studio can address unique needs of low resource rural CBOs. An implementation support program with training and consultation has potential to build the capacity of rural CBOs serving immigrant communities to implementation of cancer prevention and control EBIs.
NCT04208724 registered.}, }
@article {pmid37442349, year = {2023}, author = {Amonoo, HL and Lam, JA and Daskalakis, E and Deary, EC and Celano, C and Onyeaka, HK and Newcomb, R and Barata, A and Horick, N and Cutler, C and Pirl, WF and Lee, SJ and Huffman, JC and El-Jawahri, A}, title = {Positive Psychological Well-Being in Hematopoietic Stem Cell Transplantation Survivors.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2023.07.010}, pmid = {37442349}, issn = {2666-6367}, abstract = {BACKGROUND: Positive thoughts and emotions contribute to overall psychological health in diverse medical populations, including patients undergoing HSCT. However, there have been minimal studies that describe positive psychological well-being (e.g., optimism, gratitude, flourishing) in patients undergoing HSCT using well-established, validated patient-reported outcome measures.
METHODS: We conducted a cross-sectional secondary analyses of baseline data in 156 patients at 100 days post-HSCT enrolled in a randomized controlled trial of a psychological intervention (NCT05147311) and a prospective study assessing medication adherence at a tertiary care academic cancer center, from September 2021 to December 2022. We used descriptive statistics to outline participant reports of positive psychological well-being (PPWB) using validated measures for optimism, gratitude, positive affect, life satisfaction, and flourishing.
RESULTS: Participants had a mean (standard deviation) age of 57.4 (13.1) years, and 51% of participants were male (n=79). Many, but not all, participants reported high levels of PPWB (i.e., optimism, gratitude, positive affect, life satisfaction, and flourishing), defined as agreement with items on a given PPWB measure. For example, for optimism, 29% of participants did not agree that "overall, I expect more good things to happen to me than bad." Aside from life satisfaction, mean PPWB scores in the HSCT population were higher than in other illness populations.
CONCLUSIONS: Although many patients with hematologic malignancies undergoing HSCT report high levels of PPWB, a substantial minority of patients reported low PPWB (i.e., no agreement with items on a given PPWB measure). Because PPWB is associated with important clinical outcomes in medical populations, further research should determine whether an intervention to promote PPWB can improve quality of life in HSCT recipients.}, }
@article {pmid37441747, year = {2023}, author = {Tsao, PA and Fann, JR and Nevedal, AL and Bloor, LE and Krein, SL and Caram, MEV}, title = {A Positive Distress Screen…Now What? An Updated Call for Integrated Psychosocial Care.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {}, number = {}, pages = {JCO2202719}, doi = {10.1200/JCO.22.02719}, pmid = {37441747}, issn = {1527-7755}, }
@article {pmid37440313, year = {2023}, author = {Kumaraswamy, A and Duan, Z and Flores, D and Zhang, C and Sehrawat, A and Hu, YM and Swaim, OA and Rodansky, E and Storck, WK and Kuleape, JA and Bedi, K and Mannan, R and Wang, XM and Udager, AM and Ravikumar, V and Bankhead Iii, A and Coleman, I and Lee, JK and Morrissey, C and Nelson, PS and Chinnaiyan, A and Rao, A and Xia, Z and Yates, JA and Alumkal, JJ}, title = {LSD1 promotes prostate cancer cell reprogramming by repressing TP53 signaling independently of its demethylase function.}, journal = {JCI insight}, volume = {}, number = {}, pages = {}, doi = {10.1172/jci.insight.167440}, pmid = {37440313}, issn = {2379-3708}, abstract = {Lysine-specific demethylase 1 (LSD1) is a histone demethylase that promotes stemness and cancer cell survival, including in prostate cancer. Most prostate malignancies are adenocarcinomas with luminal differentiation. However, some tumors undergo cellular reprogramming to a more lethal subset termed neuroendocrine prostate cancer (NEPC) with neuronal differentiation. The frequency of NEPC is increasing since widespread use of potent androgen receptor signaling inhibitors. Currently, there are no effective treatments for NEPC. We previously determined that LSD1 promotes survival of prostate adenocarcinoma tumors. However, the role of LSD1 in NEPC is unknown. Here, we determined that LSD1 is highly upregulated in NEPC vs. adenocarcinoma patient tumors. LSD1 suppression with RNAi or allosteric LSD1 inhibitors-but not catalytic inhibitors-reduced NEPC cell survival. RNA-seq analysis revealed that LSD1 represses pathways linked to luminal differentiation, and TP53 was the top reactivated pathway. We confirmed that LSD1 suppressed the TP53 pathway by reducing TP53 occupancy at target genes while LSD1's catalytic function was dispensable for this effect. Mechanistically, LSD1 inhibition disrupted LSD1-HDAC interactions, increasing histone acetylation at TP53 targets. Finally, LSD1 inhibition suppressed NEPC tumor growth in vivo. These findings suggest that blocking LSD1's non-catalytic function may be a promising new treatment strategy for NEPC.}, }
@article {pmid37440227, year = {2023}, author = {Theodore, DA and Branche, AR and Zhang, L and Graciaa, DS and Choudhary, M and Hatlen, TJ and Osman, R and Babu, TM and Robinson, ST and Gilbert, PB and Follmann, D and Janes, H and Kublin, JG and Baden, LR and Goepfert, P and Gray, GE and Grinsztejn, B and Kotloff, KL and Gay, CL and Leav, B and Miller, J and Hirsch, I and Sadoff, J and Dunkle, LM and Neuzil, KM and Corey, L and Falsey, AR and El Sahly, HM and Sobieszczyk, ME and Huang, Y and , }, title = {Clinical and Demographic Factors Associated With COVID-19, Severe COVID-19, and SARS-CoV-2 Infection in Adults: A Secondary Cross-Protocol Analysis of 4 Randomized Clinical Trials.}, journal = {JAMA network open}, volume = {6}, number = {7}, pages = {e2323349}, pmid = {37440227}, issn = {2574-3805}, abstract = {IMPORTANCE: Current data identifying COVID-19 risk factors lack standardized outcomes and insufficiently control for confounders.
OBJECTIVE: To identify risk factors associated with COVID-19, severe COVID-19, and SARS-CoV-2 infection.
This secondary cross-protocol analysis included 4 multicenter, international, randomized, blinded, placebo-controlled, COVID-19 vaccine efficacy trials with harmonized protocols established by the COVID-19 Prevention Network. Individual-level data from participants randomized to receive placebo within each trial were combined and analyzed. Enrollment began July 2020 and the last data cutoff was in July 2021. Participants included adults in stable health, at risk for SARS-CoV-2, and assigned to the placebo group within each vaccine trial. Data were analyzed from April 2022 to February 2023.
EXPOSURES: Comorbid conditions, demographic factors, and SARS-CoV-2 exposure risk at the time of enrollment.
MAIN OUTCOMES AND MEASURES: Coprimary outcomes were COVID-19 and severe COVID-19. Multivariate Cox proportional regression models estimated adjusted hazard ratios (aHRs) and 95% CIs for baseline covariates, accounting for trial, region, and calendar time. Secondary outcomes included severe COVID-19 among people with COVID-19, subclinical SARS-CoV-2 infection, and SARS-CoV-2 infection.
RESULTS: A total of 57 692 participants (median [range] age, 51 [18-95] years; 11 720 participants [20.3%] aged ≥65 years; 31 058 participants [53.8%] assigned male at birth) were included. The analysis population included 3270 American Indian or Alaska Native participants (5.7%), 7849 Black or African American participants (13.6%), 17 678 Hispanic or Latino participants (30.6%), and 40 745 White participants (70.6%). Annualized incidence was 13.9% (95% CI, 13.3%-14.4%) for COVID-19 and 2.0% (95% CI, 1.8%-2.2%) for severe COVID-19. Factors associated with increased rates of COVID-19 included workplace exposure (high vs low: aHR, 1.35 [95% CI, 1.16-1.58]; medium vs low: aHR, 1.41 [95% CI, 1.21-1.65]; P < .001) and living condition risk (very high vs low risk: aHR, 1.41 [95% CI, 1.21-1.66]; medium vs low risk: aHR, 1.19 [95% CI, 1.08-1.32]; P < .001). Factors associated with decreased rates of COVID-19 included previous SARS-CoV-2 infection (aHR, 0.13 [95% CI, 0.09-0.19]; P < .001), age 65 years or older (aHR vs age <65 years, 0.57 [95% CI, 0.50-0.64]; P < .001) and Black or African American race (aHR vs White race, 0.78 [95% CI, 0.67-0.91]; P = .002). Factors associated with increased rates of severe COVID-19 included race (American Indian or Alaska Native vs White: aHR, 2.61 [95% CI, 1.85-3.69]; multiracial vs White: aHR, 2.19 [95% CI, 1.50-3.20]; P < .001), diabetes (aHR, 1.54 [95% CI, 1.14-2.08]; P = .005) and at least 2 comorbidities (aHR vs none, 1.39 [95% CI, 1.09-1.76]; P = .008). In analyses restricted to participants who contracted COVID-19, increased severe COVID-19 rates were associated with age 65 years or older (aHR vs <65 years, 1.75 [95% CI, 1.32-2.31]; P < .001), race (American Indian or Alaska Native vs White: aHR, 1.98 [95% CI, 1.38-2.83]; Black or African American vs White: aHR, 1.49 [95% CI, 1.03-2.14]; multiracial: aHR, 1.81 [95% CI, 1.21-2.69]; overall P = .001), body mass index (aHR per 1-unit increase, 1.03 [95% CI, 1.01-1.04]; P = .001), and diabetes (aHR, 1.85 [95% CI, 1.37-2.49]; P < .001). Previous SARS-CoV-2 infection was associated with decreased severe COVID-19 rates (aHR, 0.04 [95% CI, 0.01-0.14]; P < .001).
CONCLUSIONS AND RELEVANCE: In this secondary cross-protocol analysis of 4 randomized clinical trials, exposure and demographic factors had the strongest associations with outcomes; results could inform mitigation strategies for SARS-CoV-2 and viruses with comparable epidemiological characteristics.}, }
@article {pmid37439269, year = {2023}, author = {Sharon, E and Othus, M and Quandt, ZE}, title = {Signal detection in real-world data and confirmation in clinical trials: Diabetes as a case study for a conversation worth having.}, journal = {Cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/cncr.34939}, pmid = {37439269}, issn = {1097-0142}, support = {K12DK133995/DK/NIDDK NIH HHS/United States ; }, }
@article {pmid37439080, year = {2023}, author = {Stansfield, SE and Heitner, J and Mitchell, KM and Doyle, CM and Milwid, RM and Moore, M and Donnell, DJ and Hanscom, B and Xia, Y and Maheu-Giroux, M and Vijver, DV and Wang, H and Barnabas, R and Boily, MC and Dimitrov, DT}, title = {Population-level impact of expanding PrEP coverage by offering long-acting injectable PrEP to MSM in three high-resource settings: a model comparison analysis.}, journal = {Journal of the International AIDS Society}, volume = {26 Suppl 2}, number = {Suppl 2}, pages = {e26109}, pmid = {37439080}, issn = {1758-2652}, support = {//CIHR/Canada ; }, mesh = {Humans ; Male ; Black People ; Canada ; Emtricitabine/therapeutic use ; *HIV Infections/epidemiology/prevention & control ; Homosexuality, Male ; *Sexual and Gender Minorities ; Tenofovir/therapeutic use ; *Pre-Exposure Prophylaxis ; White ; Georgia ; Netherlands ; }, abstract = {INTRODUCTION: Long-acting injectable cabotegravir (CAB-LA) demonstrated superiority to daily tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) for HIV pre-exposure prophylaxis (PrEP) in the HPTN 083/084 trials. We compared the potential impact of expanding PrEP coverage by offering CAB-LA to men who have sex with men (MSM) in Atlanta (US), Montreal (Canada) and the Netherlands, settings with different HIV epidemics.
METHODS: Three risk-stratified HIV transmission models were independently parameterized and calibrated to local data. In Atlanta, Montreal and the Netherlands, the models, respectively, estimated mean TDF/FTC coverage starting at 29%, 7% and 4% in 2022, and projected HIV incidence per 100 person-years (PY), respectively, decreasing from 2.06 to 1.62, 0.08 to 0.03 and 0.07 to 0.001 by 2042. Expansion of PrEP coverage was simulated by recruiting new CAB-LA users and by switching different proportions of TDF/FTC users to CAB-LA. Population effectiveness and efficiency of PrEP expansions were evaluated over 20 years in comparison to baseline scenarios with TDF/FTC only.
RESULTS: Increasing PrEP coverage by 11 percentage points (pp) from 29% to 40% by 2032 was expected to avert a median 36% of new HIV acquisitions in Atlanta. Substantially larger increases (by 33 or 26 pp) in PrEP coverage (to 40% or 30%) were needed to achieve comparable reductions in Montreal and the Netherlands, respectively. A median 17 additional PYs on PrEP were needed to prevent one acquisition in Atlanta with 40% PrEP coverage, compared to 1000+ in Montreal and 4000+ in the Netherlands. Reaching 50% PrEP coverage by 2032 by recruiting CAB-LA users among PrEP-eligible MSM could avert >45% of new HIV acquisitions in all settings. Achieving targeted coverage 5 years earlier increased the impact by 5-10 pp. In the Atlanta model, PrEP expansions achieving 40% and 50% coverage reduced differences in PrEP access between PrEP-indicated White and Black MSM from 23 to 9 pp and 4 pp, respectively.
CONCLUSIONS: Achieving high PrEP coverage by offering CAB-LA can impact the HIV epidemic substantially if rolled out without delays. These PrEP expansions may be efficient in settings with high HIV incidence (like Atlanta) but not in settings with low HIV incidence (like Montreal and the Netherlands).}, }
@article {pmid37438862, year = {2023}, author = {Barton, KS and Steineck, A and Walsh, CA and Lau, N and O'Donnell, MB and Rosenberg, AR}, title = {"I won't get to live my life the way I planned it": A qualitative analysis of the experiences of adolescents and young adults with advanced cancer.}, journal = {Pediatric blood & cancer}, volume = {}, number = {}, pages = {e30554}, doi = {10.1002/pbc.30554}, pmid = {37438862}, issn = {1545-5017}, support = {//Seattle/ ; 5T32CA009351-40//Children's Guild Association and the Young Adult Cancer Fund/ ; NIH/NCI 5T32 CA092408//St. Baldrick's Foundation/ ; K08CA263474//NIH/NCI/ ; T32HL125195//T32 Training Grant/ ; R01CA222486-05//T32 Training Grant/ ; R01CA225629-05//T32 Training Grant/ ; R01CA267107-01//T32 Training Grant/ ; R01CA269574-01//T32 Training Grant/ ; }, abstract = {BACKGROUND: Individuals with advanced cancer face complex challenges, including prognostic uncertainty and evolving goals of care. Despite the unique psychosocial support needs of adolescents and young adults (AYAs), few studies have specifically examined AYA perspectives of and experiences with advanced cancer. The objective of this study was to describe the experience, needs, and perspectives of pediatric AYAs with advanced cancer.
PROCEDURE: We invited English-speaking AYAs (age 14-25 years) who were receiving treatment for advanced cancer at our single tertiary pediatric cancer center to participate in semi-structured interviews. We used directed content analysis for codebook development and then applied in-depth thematic network analysis to describe their perspectives and experiences with advanced cancer.
RESULTS: A total of 32 AYAs (86% of approached) completed interviews. A slight majority were male (59%) and non-Hispanic White (56%). Most were diagnosed with leukemia/lymphoma, had recurrent disease (84%), and were a mean 53 months from initial diagnosis. Organizing themes of "not being able to beat this," "not wanting to miss out," and "living each day" generated the global theme "do I have a future?" "Making tough medical decisions," "adjusting life/plans/perspectives," and "decisions about dying" were organized into the global theme "those decisions … were really hard." "Feeling like there is no one to talk to," "being away from family and friends," and "feeling like a burden" generated the global theme "I felt very alone."
CONCLUSIONS: Pediatric AYAs with advanced cancer describe unique challenges. Psychological support interventions are needed to empower AYAs to navigate difficult decisions and to cope with isolation.}, }
@article {pmid37438589, year = {2023}, author = {Cohen, SA and Liu, MC and Aleshin, A}, title = {Practical recommendations for using ctDNA in clinical decision making.}, journal = {Nature}, volume = {619}, number = {7969}, pages = {259-268}, pmid = {37438589}, issn = {1476-4687}, mesh = {Humans ; *Clinical Decision-Making ; *Circulating Tumor DNA/genetics ; Peer Review ; }, abstract = {The continuous improvement in cancer care over the past decade has led to a gradual decrease in cancer-related deaths. This is largely attributed to improved treatment and disease management strategies. Early detection of recurrence using blood-based biomarkers such as circulating tumour DNA (ctDNA) is being increasingly used in clinical practice. Emerging real-world data shows the utility of ctDNA in detecting molecular residual disease and in treatment-response monitoring, helping clinicians to optimize treatment and surveillance strategies. Many studies have indicated ctDNA to be a sensitive and specific biomarker for recurrence. However, most of these studies are largely observational or anecdotal in nature, and peer-reviewed data regarding the use of ctDNA are mainly indication-specific. Here we provide general recommendations on the clinical utility of ctDNA and how to interpret ctDNA analysis in different treatment settings, especially in patients with solid tumours. Specifically, we provide an understanding around the implications, strengths and limitations of this novel biomarker and how to best apply the results in clinical practice.}, }
@article {pmid37436712, year = {2023}, author = {Phung, MT and Lee, AW and McLean, K and Anton-Culver, H and Bandera, EV and Carney, ME and Chang-Claude, J and Cramer, DW and Doherty, JA and Fortner, RT and Goodman, MT and Harris, HR and Jensen, A and Modugno, F and Moysich, KB and Pharoah, PDP and Qin, B and Terry, KL and Titus, LJ and Webb, PM and , and Wu, AH and Zeinomar, N and Ziogas, A and Berchuck, A and Cho, KR and Hanley, GE and Meza, R and Mukherjee, B and Pike, MC and Pearce, CL and Trabert, B and , }, title = {A framework for assessing interactions for risk stratification models: the example of ovarian cancer.}, journal = {Journal of the National Cancer Institute}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnci/djad137}, pmid = {37436712}, issn = {1460-2105}, abstract = {Generally, risk stratification models for cancer use effect estimates from risk/protective factor analyses that have not assessed potential interactions between these exposures. We have developed a four-criterion framework for assessing interactions which includes statistical, qualitative, biological, and practical approaches. Using ovarian cancer, we present the application of the framework as this is an important step in developing more accurate risk stratification models. Using data from nine case-control studies in the Ovarian Cancer Association Consortium, we conducted a comprehensive analysis of interactions between 15 unequivocal risk/protective factors for ovarian cancer (including 14 non-genetic factors and a 36-variant polygenic score) with age and menopausal status. Pairwise interactions between the risk/protective factors were also assessed. We found that menopausal status modifies the association between endometriosis, first degree family history of ovarian cancer, breastfeeding, and depot-medroxyprogesterone acetate use and disease risk, highlighting the importance of understanding multiplicative interactions when developing risk prediction models.}, }
@article {pmid37436080, year = {2023}, author = {Maya, S and Hershkovich, L and Cardozo-Ojeda, EF and Shirvani-Dastgerdi, E and Srinivas, J and Shekhtman, L and Uprichard, SL and Berneshawi, AR and Cafiero, TR and Dahari, H and Ploss, A}, title = {Hepatitis delta virus RNA decline post-inoculation in human NTCP transgenic mice is biphasic.}, journal = {mBio}, volume = {}, number = {}, pages = {e0100823}, doi = {10.1128/mbio.01008-23}, pmid = {37436080}, issn = {2150-7511}, abstract = {Chronic infection with hepatitis B and delta viruses (HDV) is the most serious form of viral hepatitis due to more severe manifestations of an accelerated progression to liver fibrosis, cirrhosis, and hepatocellular carcinoma. We characterized early HDV kinetics post-inoculation and incorporated mathematical modeling to provide insights into host-HDV dynamics. We analyzed HDV RNA serum viremia in 192 immunocompetent (C57BL/6) and immunodeficient (NRG) mice that did or did not transgenically express the HDV receptor-human sodium taurocholate co-transporting polypeptide (hNTCP). Kinetic analysis indicates an unanticipated biphasic decline consisting of a sharp first-phase and slower second-phase decline regardless of immunocompetence. HDV decline after re-inoculation again followed a biphasic decline; however, a steeper second-phase HDV decline was observed in NRG-hNTCP mice compared to NRG mice. HDV-entry inhibitor bulevirtide administration and HDV re-inoculation indicated that viral entry and receptor saturation are not major contributors to clearance, respectively. The biphasic kinetics can be mathematically modeled by assuming the existence of a non-specific-binding compartment with a constant on/off-rate and the steeper second-phase decline by a loss of bound virus that cannot be returned as free virus to circulation. The model predicts that free HDV is cleared with a half-life of 35 minutes (standard error, SE: 6.3), binds to non-specific cells with a rate of 0.05 per hour (SE: 0.01), and returns as free virus with a rate of 0.11 per hour (SE: 0.02). Characterizing early HDV-host kinetics elucidates how quickly HDV is either cleared or bound depending on the immunological background and hNTCP presence. IMPORTANCE The persistence phase of HDV infection has been studied in some animal models; however, the early kinetics of HDV in vivo is incompletely understood. In this study, we characterize an unexpectedly HDV biphasic decline post-inoculation in immunocompetent and immunodeficient mouse models and use mathematical modeling to provide insights into HDV-host dynamics.}, }
@article {pmid37433788, year = {2023}, author = {Lyke, KE and Atmar, RL and Dominguez Islas, C and Posavad, CM and Deming, ME and Branche, AR and Johnston, C and El Sahly, HM and Edupuganti, S and Mulligan, MJ and Jackson, LA and Rupp, RE and Rostad, CA and Coler, RN and Bäcker, M and Kottkamp, AC and Babu, TM and Dobrzynski, D and Martin, JM and Brady, RC and Frenck, RW and Rajakumar, K and Kotloff, K and Rouphael, N and Szydlo, D and PaulChoudhury, R and Archer, JI and Crandon, S and Ingersoll, B and Eaton, A and Brown, ER and McElrath, MJ and Neuzil, KM and Stephens, DS and Post, DJ and Lin, BC and Serebryannyy, L and Beigel, JH and Montefiori, DC and Roberts, PC and , }, title = {Immunogenicity of NVX-CoV2373 heterologous boost against SARS-CoV-2 variants.}, journal = {NPJ vaccines}, volume = {8}, number = {1}, pages = {98}, pmid = {37433788}, issn = {2059-0105}, support = {UM1 AI148452/AI/NIAID NIH HHS/United States ; UM1 AI148573/AI/NIAID NIH HHS/United States ; UM1 AI148373/AI/NIAID NIH HHS/United States ; UM1 AI148684/AI/NIAID NIH HHS/United States ; 75N93019C00050/AI/NIAID NIH HHS/United States ; UM1 AI148574/AI/NIAID NIH HHS/United States ; UM1 AI148689/AI/NIAID NIH HHS/United States ; UM1 AI148450/AI/NIAID NIH HHS/United States ; UM1 AI148575/AI/NIAID NIH HHS/United States ; UM1 AI148576/AI/NIAID NIH HHS/United States ; }, abstract = {As part of a multicenter study evaluating homologous and heterologous COVID-19 booster vaccines, we assessed the magnitude, breadth, and short-term durability of binding and pseudovirus-neutralizing antibody (PsVNA) responses following a single booster dose of NVX-CoV2373 in adults primed with either Ad26.COV2.S, mRNA-1273, or BNT162b2 vaccines. NVX-CoV2373 as a heterologous booster was immunogenic and associated with no safety concerns through Day 91. Fold-rises in PsVNA titers from baseline (Day 1) to Day 29 were highest for prototypic D614G variant and lowest for more recent Omicron sub-lineages BQ.1.1 and XBB.1. Peak humoral responses against all SARS-CoV-2 variants were lower in those primed with Ad26.COV2.S than with mRNA vaccines. Prior SARS CoV-2 infection was associated with substantially higher baseline PsVNA titers, which remained elevated relative to previously uninfected participants through Day 91. These data support the use of heterologous protein-based booster vaccines as an acceptable alternative to mRNA or adenoviral-based COVID-19 booster vaccines. This trial was conducted under ClinicalTrials.gov: NCT04889209.}, }
@article {pmid37433437, year = {2023}, author = {Chiorean, EG and Chiaro, MD and Tempero, MA and Malafa, MP and Benson, AB and Cardin, DB and Christensen, JA and Chung, V and Czito, B and Dillhoff, M and Donahue, TR and Dotan, E and Fountzilas, C and Glazer, ES and Hardacre, J and Hawkins, WG and Klute, K and Ko, AH and Kunstman, JW and LoConte, N and Lowy, AM and Masood, A and Moravek, C and Nakakura, EK and Narang, AK and Nardo, L and Obando, J and Polanco, PM and Reddy, S and Reyngold, M and Scaife, C and Shen, J and Truty, MJ and Vollmer, C and Wolff, RA and Wolpin, BM and Rn, BM and Lubin, S and Darlow, SD}, title = {Ampullary Adenocarcinoma, Version 1.2023, NCCN Clinical Practice Guidelines in Oncology.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {21}, number = {7}, pages = {753-782}, doi = {10.6004/jnccn.2023.0034}, pmid = {37433437}, issn = {1540-1413}, mesh = {Humans ; *Ampulla of Vater ; *Common Bile Duct Neoplasms/diagnosis/therapy ; *Duodenal Neoplasms/diagnosis/therapy ; *Adenocarcinoma/diagnosis/therapy ; }, abstract = {Ampullary cancers refer to tumors originating from the ampulla of Vater (the ampulla, the intraduodenal portion of the bile duct, and the intraduodenal portion of the pancreatic duct), while periampullary cancers may arise from locations encompassing the head of the pancreas, distal bile duct, duodenum, or ampulla of Vater. Ampullary cancers are rare gastrointestinal malignancies, and prognosis varies greatly based on factors such as patient age, TNM classification, differentiation grade, and treatment modality received. Systemic therapy is used in all stages of ampullary cancer, including neoadjuvant therapy, adjuvant therapy, and first-line or subsequent-line therapy for locally advanced, metastatic, and recurrent disease. Radiation therapy may be used in localized ampullary cancer, sometimes in combination with chemotherapy, but there is no high-level evidence to support its utility. Select tumors may be treated surgically. This article describes NCCN recommendations regarding management of ampullary adenocarcinoma.}, }
@article {pmid37433432, year = {2023}, author = {Benson, AB and D'Angelica, MI and Abrams, T and Abbott, DE and Ahmed, A and Anaya, DA and Anders, R and Are, C and Bachini, M and Binder, D and Borad, M and Bowlus, C and Brown, D and Burgoyne, A and Castellanos, J and Chahal, P and Cloyd, J and Covey, AM and Glazer, ES and Hawkins, WG and Iyer, R and Jacob, R and Jennings, L and Kelley, RK and Kim, R and Levine, M and Palta, M and Park, JO and Raman, S and Reddy, S and Ronnekleiv-Kelly, S and Sahai, V and Singh, G and Stein, S and Turk, A and Vauthey, JN and Venook, AP and Yopp, A and McMillian, N and Schonfeld, R and Hochstetler, C}, title = {NCCN Guidelines® Insights: Biliary Tract Cancers, Version 2.2023.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {21}, number = {7}, pages = {694-704}, doi = {10.6004/jnccn.2023.0035}, pmid = {37433432}, issn = {1540-1413}, mesh = {Humans ; *Biliary Tract Neoplasms/diagnosis/therapy ; *Gallbladder Neoplasms/diagnosis/therapy ; *Cholangiocarcinoma/diagnosis/therapy ; *Liver Neoplasms/diagnosis/therapy ; *Bile Duct Neoplasms ; Bile Ducts, Intrahepatic ; }, abstract = {In 2023, the NCCN Guidelines for Hepatobiliary Cancers were divided into 2 separate guidelines: Hepatocellular Carcinoma and Biliary Tract Cancers. The NCCN Guidelines for Biliary Tract Cancers provide recommendations for the evaluation and comprehensive care of patients with gallbladder cancer, intrahepatic cholangiocarcinoma, and extrahepatic cholangiocarcinoma. The multidisciplinary panel of experts meets at least on an annual basis to review requests from internal and external entities as well as to evaluate new data on current and emerging therapies. These Guidelines Insights focus on some of the recent updates to the NCCN Guidelines for Biliary Tract Cancers as well as the newly published section on principles of molecular testing.}, }
@article {pmid37433275, year = {2023}, author = {Nakamura, M and Parkhurst, SM}, title = {Wound repair: Two distinct Rap1 pathways close the gap.}, journal = {Current biology : CB}, volume = {33}, number = {13}, pages = {R724-R726}, doi = {10.1016/j.cub.2023.05.059}, pmid = {37433275}, issn = {1879-0445}, mesh = {*Wound Healing ; *Cytoskeleton ; Intercellular Junctions ; Microtubules ; Movement ; }, abstract = {Groups of cells often coordinate their movements during normal development, cancer invasion, and wound repair. These coordinated migrations require dynamic cytoskeleton and cell-junction remodeling. Two distinct Rap1 pathways are required to regulate this dynamic remodeling for rapid wound closure.}, }
@article {pmid37432690, year = {2023}, author = {Robertson, DJ and Dominitz, JA and Beed, A and Boardman, KD and Del Curto, BJ and Guarino, PD and Imperiale, TF and LaCasse, A and Larson, MF and Gupta, S and Lieberman, D and Planeta, B and Shaukat, A and Sultan, S and Menees, SB and Saini, SD and Schoenfeld, P and Goebel, S and von Rosenvinge, EC and Baffy, G and Halasz, I and Pedrosa, MC and Kahng, LS and Cassim, R and Greer, KB and Kinnard, MF and Bhatt, DB and Dunbar, KB and Harford, WV and Mengshol, JA and Olson, JE and Patel, SG and Antaki, F and Fisher, DA and Sullivan, BA and Lenza, C and Prajapati, DN and Wong, H and Beyth, R and Lieb, JG and Manlolo, J and Ona, FV and Cole, RA and Khalaf, N and Kahi, CJ and Kohli, DR and Rai, T and Sharma, P and Anastasiou, J and Hagedorn, C and Fernando, RS and Jackson, CS and Jamal, MM and Lee, RH and Merchant, F and May, FP and Pisegna, JR and Omer, E and Parajuli, D and Said, A and Nguyen, TD and Tombazzi, CR and Feldman, PA and Jacob, L and Koppelman, RN and Lehenbauer, KP and Desai, DS and Madhoun, MF and Tierney, WM and Ho, MQ and Hockman, HJ and Lopez, C and Carter Paulson, E and Tobi, M and Pinillos, HL and Young, M and Ho, NC and Mascarenhas, R and Promrat, K and Mutha, PR and Pandak, WM and Shah, T and Schubert, M and Pancotto, FS and Gawron, AJ and Underwood, AE and Ho, SB and Magno-Pagatzaurtundua, P and Toro, DH and Beymer, CH and Kaz, AM and Elwing, J and Gill, JA and Goldsmith, SF and Yao, MD and Protiva, P and Pohl, H and Kyriakides, T and , }, title = {Baseline Features and Reasons for Nonparticipation in the Colonoscopy Versus Fecal Immunochemical Test in Reducing Mortality From Colorectal Cancer (CONFIRM) Study, a Colorectal Cancer Screening Trial.}, journal = {JAMA network open}, volume = {6}, number = {7}, pages = {e2321730}, pmid = {37432690}, issn = {2574-3805}, mesh = {Adult ; Humans ; Female ; Male ; Middle Aged ; *Early Detection of Cancer ; Occult Blood ; Cross-Sectional Studies ; *Neoplasms ; Colonoscopy ; }, abstract = {IMPORTANCE: The Colonoscopy Versus Fecal Immunochemical Test in Reducing Mortality From Colorectal Cancer (CONFIRM) randomized clinical trial sought to recruit 50 000 adults into a study comparing colorectal cancer (CRC) mortality outcomes after randomization to either an annual fecal immunochemical test (FIT) or colonoscopy.
OBJECTIVE: To (1) describe study participant characteristics and (2) examine who declined participation because of a preference for colonoscopy or stool testing (ie, fecal occult blood test [FOBT]/FIT) and assess that preference's association with geographic and temporal factors.
This cross-sectional study within CONFIRM, which completed enrollment through 46 Department of Veterans Affairs medical centers between May 22, 2012, and December 1, 2017, with follow-up planned through 2028, comprised veterans aged 50 to 75 years with an average CRC risk and due for screening. Data were analyzed between March 7 and December 5, 2022.
EXPOSURE: Case report forms were used to capture enrolled participant data and reasons for declining participation among otherwise eligible individuals.
MAIN OUTCOMES AND MEASURES: Descriptive statistics were used to characterize the cohort overall and by intervention. Among individuals declining participation, logistic regression was used to compare preference for FOBT/FIT or colonoscopy by recruitment region and year.
RESULTS: A total of 50 126 participants were recruited (mean [SD] age, 59.1 [6.9] years; 46 618 [93.0%] male and 3508 [7.0%] female). The cohort was racially and ethnically diverse, with 748 (1.5%) identifying as Asian, 12 021 (24.0%) as Black, 415 (0.8%) as Native American or Alaska Native, 34 629 (69.1%) as White, and 1877 (3.7%) as other race, including multiracial; and 5734 (11.4%) as having Hispanic ethnicity. Of the 11 109 eligible individuals who declined participation (18.0%), 4824 (43.4%) declined due to a stated preference for a specific screening test, with FOBT/FIT being the most preferred method (2820 [58.5%]) vs colonoscopy (1958 [40.6%]; P < .001) or other screening tests (46 [1.0%] P < .001). Preference for FOBT/FIT was strongest in the West (963 of 1472 [65.4%]) and modest elsewhere, ranging from 199 of 371 (53.6%) in the Northeast to 884 of 1543 (57.3%) in the Midwest (P = .001). Adjusting for region, the preference for FOBT/FIT increased by 19% per recruitment year (odds ratio, 1.19; 95% CI, 1.14-1.25).
CONCLUSIONS AND RELEVANCE: In this cross-sectional analysis of veterans choosing nonenrollment in the CONFIRM study, those who declined participation more often preferred FOBT or FIT over colonoscopy. This preference increased over time and was strongest in the western US and may provide insight into trends in CRC screening preferences.}, }
@article {pmid37432541, year = {2023}, author = {Stoner, MCD and Hawley, I and Mathebula, F and Horne, E and Etima, J and Kemigisha, D and Mutero, P and Dandadzi, A and Seyama, L and Fabiano, Z and Scheckter, R and Noguchi, L and Owor, M and Balkus, JE and Montgomery, ET}, title = {Acceptability and Use of the Dapivirine Vaginal Ring and Daily Oral Pre-exposure Prophylaxis (PrEP) During Breastfeeding in South Africa, Malawi, Zimbabwe, and Uganda.}, journal = {AIDS and behavior}, volume = {}, number = {}, pages = {}, pmid = {37432541}, issn = {1573-3254}, support = {UM1AI068633/NR/NINR NIH HHS/United States ; UM1AI068615/NR/NINR NIH HHS/United States ; UM1AI106707/NR/NINR NIH HHS/United States ; }, abstract = {This study examines qualitative acceptability of the dapivirine vaginal ring (DVR) and oral daily pre-exposure prophylaxis (PrEP) among breastfeeding persons participating in Microbicide Trials Network 043/B-PROTECTED, a phase 3B safety and drug detectability study of DVR and oral PrEP in breastfeeding. A subsample of 52 participants were purposively sampled to participate in an in-depth interview (IDI). Breastfeeding participants found both study products to be acceptable, and easy to use. A common motivation for product use was to protect the baby from HIV, although participants' understanding of how the study drug would work to protect their babies was often unclear. While most participants did not report experiencing side effects, fears about side effects were common as both initial worries about how the study products would affect their health and the health of their baby, and increased anxiety that health issues experienced by them, or their baby were from the products.}, }
@article {pmid37432369, year = {2023}, author = {Buscemi, J and Figueroa, R and Bell, BM and Dulin, A and Shen, M and Schneider, KL and Pagoto, S and Fitzgibbon, M}, title = {Advocacy efforts of the Society of Behavioral Medicine: a 6-year update.}, journal = {Translational behavioral medicine}, volume = {}, number = {}, pages = {}, doi = {10.1093/tbm/ibad042}, pmid = {37432369}, issn = {1613-9860}, abstract = {Six years ago, we published a paper describing the Society of Behavioral Medicine's (SBM) health policy organizational leadership structure and policy initiatives. The purpose of the current paper is to provide an update on changes in the infrastructure and new policy initiatives that have been developed since 2017. We review each of the policy leadership arms of SBM including details of the work of each and goals for the future. The SBM engages in several health policy advocacy efforts through their Advocacy Council and Position Statements Committee. The Advocacy Council launched the Health Policy Ambassador Program in 2020. The Ambassador Program serves to train members to develop longer-term relationships with legislative staff around key policy priority areas. The Position Statements Committee is responsible for overseeing the development and dissemination of health policy position statements. Both groups work together and with partner organizations to increase the impact of our science. Over the last 6 years, developing a stronger infrastructure and implementing metrics for progress such as tracking social media engagement has helped to move SBM's policy agenda forward. The work of the policy-related leadership teams can serve as a model for other organizations who are interested in further developing their policy advocacy efforts.}, }
@article {pmid37431225, year = {2023}, author = {Barbour, AB and Zaki, P and McGranahan, TM and Venur, V and Vellayappan, B and Palmer, J and Halasz, LM and Yang, JT and Blau, M and Tseng, YD and Chao, ST and Suh, JH and Foote, M and Redmond, KJ and Combs, SE and Chang, EL and Sahgal, A and Lo, SS}, title = {Emergent radiotherapy for brain and leptomeningeal metastases: a narrative review.}, journal = {Annals of palliative medicine}, volume = {}, number = {}, pages = {}, doi = {10.21037/apm-22-1276}, pmid = {37431225}, issn = {2224-5839}, abstract = {BACKGROUND AND OBJECTIVE: As novel systemic therapies allow patients to live longer with cancer, the risk of developing central nervous system (CNS) metastases increases and providers will more frequently encounter emergent presentation of brain metastases (BM) and leptomeningeal metastases (LM). Management of these metastases requires appropriate work-up and well-coordinated multidisciplinary care. We set out to perform a review of emergent radiotherapy (RT) for CNS metastases, specifically focusing on BM and LM.
METHODS: We review the appropriate pathways for workup and initial management of BM and LM, while reviewing the literature supporting emergent treatment of these entities with surgery, systemic anti-cancer therapy, and RT. To inform this narrative review, literature searches in PubMed and Google Scholar were conducted, with preference given to articles employing modern RT techniques, when applicable. Due to the paucity of high-quality evidence for management of BM and LM in the emergent setting, discussion was supplemented by the authors' expert commentary.
KEY CONTENT AND FINDINGS: This work highlights the importance of surgical evaluation, particularly for patients presenting with significant mass effect, hemorrhagic metastases, or increased intracranial pressure. We review the rare situations where emergent initiation of systemic anti-cancer therapy is indicated. When defining the role of RT, we review factors guiding selection of appropriate modality, treatment volume, and dose-fractionation. Generally, 2D- or 3D-conformal treatment techniques prescribed as 30 Gy in 10 fractions or 20 Gy in 5 fractions, should be employed in the emergent setting.
CONCLUSIONS: Patients with BM and LM present from a diverse array of clinical situations, requiring wellcoordinated multidisciplinary management, and there is a paucity of high-quality evidence guiding such management decisions. This narrative review aims to more thoroughly prepare providers for the challenging situation of emergent management of BM and LM.}, }
@article {pmid37429366, year = {2023}, author = {Reddy, KR and McLerran, D and Marsh, T and Parikh, N and Roberts, LR and Schwartz, M and Nguyen, MH and Befeler, A and Page-Lester, S and Tang, R and Srivastava, S and Rinaudo, JA and Feng, Z and Marrero, JA}, title = {Incidence and Risk Factors for Hepatocellular Carcinoma in Cirrhosis: the Multi-center Hepatocellular Carcinoma Early Detection Strategy (HEDS) Study.}, journal = {Gastroenterology}, volume = {}, number = {}, pages = {}, doi = {10.1053/j.gastro.2023.06.027}, pmid = {37429366}, issn = {1528-0012}, abstract = {BACKGROUND AND AIMS: Worldwide, hepatocellular carcinoma (HCC) is a common malignancy. We aimed to prospectively determine the incidence and risk factors of HCC in a United States cohort.
METHODS: The multi-center Hepatocellular Carcinoma Early Detection Strategy study of the National Institutes of Health prospectively enrolled patients with cirrhosis who underwent standard surveillance for HCC. Demographics, medical and family history, etiology of liver disease, and clinical features were evaluated for associations with HCC.
RESULTS: Between 4/10/2013 and 12/31/2021, 1,723 patients were enrolled and confirmed eligible. During median follow up of 2.2 years (range: 0-8.7 years), there were 109 incident cases of HCC for an incidence rate of 2.4 per 100 person-years; 88 (81%) patients with very early/early BCLC stage (0, A), 20 (18%) intermediate stage (B), 1 (1%) unknown stage. Risk factor analyses were restricted to 1,325 patients, including 95 incident HCC, with at least 6 months of follow up. The majority were men (53.2%), obese or severely obese (median body mass index [BMI] 30.2 kg/m[2]), and white (86.3%); 42.0% had history of HCV infection, 20.7% had alcoholic liver disease (ALD), and 24.9% had nonalcoholic fatty liver disease (NAFLD). Fourteen risk factors for HCC were significant (p<0.05) in univariate analyses, and a multivariate subset was selected by stepwise logistic regression. The multivariate subset contained gender (p<0.001, male, OR=2.47, 95% C.I. 1.54-4.07), years with cirrhosis (p=0.004, OR=1.06, 95% C.I. 1.02-1.1), family history of liver cancer (p=0.02, yes, OR=2.69, 95% C.I. 1.11-5.86), age (per 5-years, p=0.02, OR=1.17, 95% C.I. 1.03-1.33), obesity (p=0.02, yes, OR=1.7, 95% C.I. 1.08-2.73), aspartate aminotransferase (log(1+AST), p=0.06, OR=1.54 95% C.I. 0.97-2.42), alpha-fetoprotein (log(1+AFP), p=0.07, OR=1.32, 95% C.I. 0.97-1.77), and albumin (p=0.10, OR=0.7, 95% C.I. 0.46-1.07).
CONCLUSIONS: Thus far, this is the largest prospective and geographically diverse study of a United States cohort of patients with cirrhosis that validates known risk factors for HCC (gender, age, obesity, years with cirrhosis, family history of liver cancer, baseline AFP, albumin, and AST). The incidence of HCC was 2.4 % per 100 person years.}, }
@article {pmid37428754, year = {2023}, author = {Jebeile, H and Lister, NB and Libesman, S and Hunter, KE and McMaster, CM and Johnson, BJ and Baur, LA and Paxton, SJ and Garnett, SP and Ahern, AL and Wilfley, DE and Maguire, S and Sainsbury, A and Steinbeck, K and Askie, L and Braet, C and Hill, AJ and Nicholls, D and Jones, RA and Dammery, G and Grunseit, AM and Cooper, K and Kyle, TK and Heeren, FA and Quigley, F and Barnes, RD and Bean, MK and Beaulieu, K and Bonham, M and Boutelle, KN and Branco, BHM and Calugi, S and Cardel, MI and Carpenter, K and Cheng, HL and Dalle Grave, R and Danielsen, YS and Demarzo, M and Dordevic, A and Eichen, DM and Goldschmidt, AB and Hilbert, A and Houben, K and Lofrano do Prado, M and Martin, CK and McTiernan, A and Mensinger, JL and Pacanowski, C and do Prado, WL and Ramalho, SM and Raynor, HA and Rieger, E and Robinson, E and Salvo, V and Sherwood, NE and Simpson, SA and Skjakodegard, HF and Smith, E and Partridge, S and Tanofsky-Kraff, M and Taylor, RW and Van Eyck, A and Varady, KA and Vidmar, AP and Whitelock, V and Yanovski, J and Seidler, AL and , }, title = {Eating disorders in weight-related therapy (EDIT): Protocol for a systematic review with individual participant data meta-analysis of eating disorder risk in behavioural weight management.}, journal = {PloS one}, volume = {18}, number = {7}, pages = {e0282401}, pmid = {37428754}, issn = {1932-6203}, support = {MC_UU_00006/6/MRC_/Medical Research Council/United Kingdom ; /DH_/Department of Health/United Kingdom ; K23 DK092279/DK/NIDDK NIH HHS/United States ; R01 DK098492/DK/NIDDK NIH HHS/United States ; K23 DK114480/DK/NIDDK NIH HHS/United States ; UL1 TR000130/TR/NCATS NIH HHS/United States ; /CRUK_/Cancer Research UK/United Kingdom ; /CSO_/Chief Scientist Office/United Kingdom ; MC_UU_00022/1/MRC_/Medical Research Council/United Kingdom ; R01 DK128180/DK/NIDDK NIH HHS/United States ; R01 CA257807/CA/NCI NIH HHS/United States ; R01 DK119783/DK/NIDDK NIH HHS/United States ; K01 HL141535/HL/NHLBI NIH HHS/United States ; ZIA HD000641/ImNIH/Intramural NIH HHS/United States ; R01 DK116616/DK/NIDDK NIH HHS/United States ; R01 DK114794/DK/NIDDK NIH HHS/United States ; R01 DK111106/DK/NIDDK NIH HHS/United States ; R01 DK108682/DK/NIDDK NIH HHS/United States ; R01 DK103554/DK/NIDDK NIH HHS/United States ; R01 DK122504/DK/NIDDK NIH HHS/United States ; R01 DK075861/DK/NIDDK NIH HHS/United States ; K02 HL112042/HL/NHLBI NIH HHS/United States ; R21 DK080266/DK/NIDDK NIH HHS/United States ; R01 CA105204/CA/NCI NIH HHS/United States ; U54 CA116847/CA/NCI NIH HHS/United States ; R21 CA131676/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; }, mesh = {Adult ; Adolescent ; Humans ; *Overweight/complications/therapy ; Obesity ; *Feeding and Eating Disorders/therapy ; Behavior Therapy ; Systematic Reviews as Topic ; Meta-Analysis as Topic ; }, abstract = {The Eating Disorders In weight-related Therapy (EDIT) Collaboration brings together data from randomised controlled trials of behavioural weight management interventions to identify individual participant risk factors and intervention strategies that contribute to eating disorder risk. We present a protocol for a systematic review and individual participant data (IPD) meta-analysis which aims to identify participants at risk of developing eating disorders, or related symptoms, during or after weight management interventions conducted in adolescents or adults with overweight or obesity. We systematically searched four databases up to March 2022 and clinical trials registries to May 2022 to identify randomised controlled trials of weight management interventions conducted in adolescents or adults with overweight or obesity that measured eating disorder risk at pre- and post-intervention or follow-up. Authors from eligible trials have been invited to share their deidentified IPD. Two IPD meta-analyses will be conducted. The first IPD meta-analysis aims to examine participant level factors associated with a change in eating disorder scores during and following a weight management intervention. To do this we will examine baseline variables that predict change in eating disorder risk within intervention arms. The second IPD meta-analysis aims to assess whether there are participant level factors that predict whether participation in an intervention is more or less likely than no intervention to lead to a change in eating disorder risk. To do this, we will examine if there are differences in predictors of eating disorder risk between intervention and no-treatment control arms. The primary outcome will be a standardised mean difference in global eating disorder score from baseline to immediately post-intervention and at 6- and 12- months follow-up. Identifying participant level risk factors predicting eating disorder risk will inform screening and monitoring protocols to allow early identification and intervention for those at risk.}, }
@article {pmid37426948, year = {2023}, author = {Yaffe, ZA and Sung, K and Bosire, R and Farquhar, C and Ngacha, DM and Lohman-Payne, B and Nduati, R and John-Stewart, G and Matsen, FA and Overbaugh, J}, title = {Passively Acquired Constant Region 5-Specific Antibodies Associated With Improved Survival in Infants Who Acquire Human Immunodeficiency Virus.}, journal = {Open forum infectious diseases}, volume = {10}, number = {7}, pages = {ofad316}, pmid = {37426948}, issn = {2328-8957}, abstract = {Studying vertical human immunodeficiency virus (HIV) transmission enables the impact of passively transferred antibodies on HIV transmission and pathogenesis to be examined. Using phage display of HIV envelope peptides and peptide enzyme-linked immunosorbent assay (ELISA), we found that, in infants who acquired HIV, passive antibody responses to constant region 5 (C5) were associated with improved survival in 2 cohorts. In a combined analysis, C5 peptide ELISA activity was correlated directly with survival and estimated infection time and inversely with set point viral load. These results suggest that preexisting C5-specific antibodies may be correlated with the survival of infants living with HIV, motivating additional research into their protective potential.}, }
@article {pmid37426750, year = {2023}, author = {Jones, DC and Danaher, P and Kim, Y and Beechem, JM and Gottardo, R and Newell, EW}, title = {An information theoretic approach to detecting spatially varying genes.}, journal = {Cell reports methods}, volume = {3}, number = {6}, pages = {100507}, pmid = {37426750}, issn = {2667-2375}, support = {P01 CA225517/CA/NCI NIH HHS/United States ; U19 AI128914/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; Algorithms ; *Carcinoma, Renal Cell/genetics ; Gene Expression Profiling ; Technology ; *Kidney Neoplasms/genetics ; }, abstract = {A key step in spatial transcriptomics is identifying genes with spatially varying expression patterns. We adopt an information theoretic perspective to this problem by equating the degree of spatial coherence with the Jensen-Shannon divergence between pairs of nearby cells and pairs of distant cells. To avoid the notoriously difficult problem of estimating information theoretic divergences, we use modern approximation techniques to implement a computationally efficient algorithm designed to scale with in situ spatial transcriptomics technologies. In addition to being highly scalable, we show that our method, which we call maximization of spatial information (Maxspin), improves accuracy across several spatial transcriptomics platforms and a variety of simulations when compared with a variety of state-of-the-art methods. To further demonstrate the method, we generated in situ spatial transcriptomics data in a renal cell carcinoma sample using the CosMx Spatial Molecular Imager and used Maxspin to reveal novel spatial patterns of tumor cell gene expression.}, }
@article {pmid37423351, year = {2023}, author = {Cheng, M and Lee, CI}, title = {Harnessing the potential of AI for quality assurance in radiology practice.}, journal = {Journal of the American College of Radiology : JACR}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jacr.2023.06.011}, pmid = {37423351}, issn = {1558-349X}, }
@article {pmid37422195, year = {2023}, author = {Toomey, D and Phan, TL and Phan, T and Hill, JA and Zerr, DM}, title = {Viral Encephalitis After Hematopoietic Cell Transplantation: A Systematic Review.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2023.06.022}, pmid = {37422195}, issn = {2666-6367}, abstract = {BACKGROUND: Viral encephalitis is a rare but serious complication after hematopoietic cell transplantation (HCT). The non-specific early signs and symptoms and rapid progression can make it difficult to diagnose and treat in a timely fashion.
OBJECTIVES: In order to better inform clinical decision making in post-HCT viral encephalitis, a systematic review of prior studies of viral encephalitis was performed with the goal of characterizing the frequency of various infectious etiologies and their clinical course, including treatments and outcomes.
STUDY DESIGN: A systematic review of studies of viral encephalitis was performed. Studies were included if they described a cohort of HCT recipients who were tested for at least one pathogen.
RESULTS: Of 1,613 unique articles initially identified, 68 met inclusion criteria for a total of 72,423 patients studied. A total of 778 cases of encephalitis were reported (1.1%). HHV-6 (n=596), EBV (n=76), and CMV (n=33) were the most commonly reported causes of encephalitis and HHV-6 encephalitis tended to occur the earliest, accounting for most cases prior to day +100 post-transplant. Of 29,671 patients whose transplant data were available, encephalitis was diagnosed in 282 (6.0%) of 4,707 cord blood transplant (CBT) recipients, 372 (1.5%) of 24,664 non-CBT allogeneic transplant recipients, and 5 (1.7%) of 300 autologous transplant recipients. Of the 282 CBT encephalitis cases, 270 (95.7%) were caused by HHV-6. Overall, 288 (37.0%) of the 778 patients with encephalitis died and 75 deaths were attributable to encephalitis with a range of 3 to 192 days between diagnosis and death.
CONCLUSIONS: Viral encephalitis occurs in approximately 1% of HCT recipients and HHV-6 is the most common cause. Mortality following encephalitis in HCT recipients is high, indicating an urgent need for advancement in preventative and therapeutic strategies.}, }
@article {pmid37422194, year = {2023}, author = {Kanate, AS and Majhail, N and DeFilipp, ZM and Dhakal, B and Dholaria, B and Hamilton, B and Herrera, AF and Inamoto, Y and Jain, T and Perales, MA and Carpenter, PA and Hamadani, M}, title = {Updated Indications for Immune Effector Cell Therapy: 2023 Guidelines from the American Society for Transplantation and Cellular Therapy.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2023.07.002}, pmid = {37422194}, issn = {2666-6367}, abstract = {The American Society for Transplantation and Cellular Therapy (ASTCT) published its guidelines on indications for autologous and allogeneic hematopoietic cell transplantation (HCT) and immune effector cell therapy (IECT) in 2020. Since then we have witnessed rapid advancements in the field of IECT, resulting in several new chimeric antigen receptor T-cell (CAR-T) products and disease indications being approved by the U.S. Food and Drug Administration (FDA). To keep abreast of these practice changes, the ASTCT Committee on Practice Guidelines commissioned a focused update covering CAR-T therapy indications. This brief manuscript presents updated ASTCT recommendations on indications for CAR-T therapy. Only FDA approved indications for CAR-T were recommended and categorized as "standard of care" (S), where indication is well defined and supported by evidence. The ASTCT will continue to periodically review these guidelines and update them as new evidence becomes available.}, }
@article {pmid37421504, year = {2023}, author = {Schraw, JM and Petridou, ET and Bonaventure, A and Dockerty, JD and Karalexi, M and Ntzani, E and Infante-Rivard, C and Clavel, J and Bracci, PM and McKean-Cowdin, R and Roman, E and Kane, E and Erdmann, F and Schüz, J and Mueller, BA and Scheurer, ME}, title = {Breastfeeding and risk of childhood brain tumors: a report from the Childhood Cancer and Leukemia International Consortium.}, journal = {Cancer causes & control : CCC}, volume = {}, number = {}, pages = {}, pmid = {37421504}, issn = {1573-7225}, support = {CA47082/CA/NCI NIH HHS/United States ; R13ES031473/ES/NIEHS NIH HHS/United States ; }, abstract = {PURPOSE: Studies report mixed findings regarding the association of breastfeeding with childhood brain tumors (CBT), the leading causes of cancer-related mortality in young people. Our objective was to determine whether breastfeeding is associated with CBT incidence.
METHODS: We pooled data on N = 2610 cases with CBT (including 697 cases with astrocytoma, 447 cases with medulloblastoma/primitive neuroectodermal tumor [PNET], 167 cases with ependymoma) and N = 8128 age- and sex-matched controls in the Childhood Cancer and Leukemia International Consortium. We computed unconditional logistic regression models to estimate the odds ratio (OR) and 95% confidence interval (CI) of CBT, astrocytoma, medulloblastoma/PNET, and ependymoma according to breastfeeding status, adjusting for study, sex, mode of delivery, birthweight, age at diagnosis/interview, maternal age at delivery, maternal educational attainment, and maternal race/ethnicity. We evaluated any breastfeeding versus none and breastfeeding ≥ 6 months versus none. We subsequently performed random effects meta-analysis to confirm our findings, identify potential sources of heterogeneity, and evaluate for outliers or influential studies.
RESULTS: Breastfeeding was reported by 64.8% of control mothers and 64.5% of case mothers and was not associated with CBT (OR 1.04, 95% CI 0.94-1.15), astrocytoma (OR 1.01, 95% CI 0.87-1.17), medulloblastoma/PNET (OR 1.11, 95% CI 0.93-1.32), or ependymoma (OR 1.06, 95% CI 0.81-1.40). Results were similar when we restricted to breastfeeding ≥ 6 months and in meta-analyses.
CONCLUSION: Our data suggest that breastfeeding does not protect against CBT.}, }
@article {pmid37420108, year = {2023}, 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 Lipton, RB and Kaplan, RC and Gonzalez, HM and Isasi, CR}, title = {Childhood and life-course socioeconomic position and cognitive function in adult population of the Hispanic Community Health Study/Study of Latinos (HCHS/SOL).}, journal = {American journal of epidemiology}, volume = {}, number = {}, pages = {}, doi = {10.1093/aje/kwad157}, pmid = {37420108}, issn = {1476-6256}, abstract = {The Hispanic/Latino population experiences socioeconomic adversities across the lifespan and is at greater risk of cognitive impairment, yet little is known about the role of life-course socioeconomic position (SEP) on cognitive function in this population. Using baseline data (2008-2011) from adults (45-74 years) of the Hispanic Community Health Study/Study of Latinos, we assessed the association between childhood SEP and socioeconomic mobility with cognitive function, and whether this association was mediated by midlife SEP. Childhood SEP was assessed using parental education. An index combining participants' education and household income represented midlife SEP. Socioeconomic mobility was categorized as stable low, downward and upward mobility, and stable high-SEP. Cognitive function measures were modeled using survey linear regression with inverse-probability weighting, accounting for covariates. Mediation analysis estimated the indirect effect of childhood SEP on cognition through midlife SEP. High childhood SEP was associated with global cognition in adulthood (Coefficient for parental education >high school (HS) vs. 12 months), consolidation with auto-HCT is recommended in those achieving chemosensitivity to salvage therapy (CR or partial response), and CAR T-cell therapy is recommended in those not achieving remission. These clinical practice recommendations will serve as a tool to guide clinicians managing patients with newly diagnosed and R/R DLBCL.}, }
@article {pmid37418836, year = {2023}, author = {Castelo-Branco, L and Lee, R and Brandão, M and Cortellini, A and Freitas, A and Garassino, M and Geukens, T and Grivas, P and Halabi, S and Oliveira, J and Pinato, DJ and Ribeiro, J and Peters, S and Pentheroudakis, G and Warner, JL and Romano, E}, title = {Learning lessons from the COVID-19 pandemic for real-world evidence research in oncology-shared perspectives from international consortia.}, journal = {ESMO open}, volume = {8}, number = {4}, pages = {101596}, pmid = {37418836}, issn = {2059-7029}, }
@article {pmid37418600, year = {2023}, author = {Weerdenburg, H and Lindsay, J}, title = {Expanding the scope of the infectious diseases pharmacist in HCT: Beyond antimicrobial stewardship.}, journal = {Transplant infectious disease : an official journal of the Transplantation Society}, volume = {}, number = {}, pages = {e14094}, doi = {10.1111/tid.14094}, pmid = {37418600}, issn = {1399-3062}, abstract = {BACKGROUND: Infectious disease (ID) pharmacists and antimicrobial stewardship (AMS) programs are integral to the infection management of hematopoietic cell transplant (HCT) recipients demonstrating effective implementation of clinical pathways, de-escalation of empirical antibiotics for febrile neutropenia (FN), allergy assessments, and use of rapid diagnostic testing. The HCT procedure is complex, dynamic, and a high risk for infectious complications. Therefore, there is an important role for an ID and AMS pharmacist to collaborate with the primary treating team, with ongoing care, involving the optimal individual patient prophylactic, pre-emptive and treatment management of infections in this high-risk population.
CONCLUSION: This review highlights key factors for consideration of ID/AMS Pharmacists in relation to HCT, including important aspects in the evaluation of infection risk prior to transplant, risk from donor sources, length of, and changes in immunosuppression, and potential drug-drug interactions from other essential supportive care therapies.}, }
@article {pmid37417868, year = {2023}, author = {Kulsuptrakul, J and Turcotte, EA and Emerman, M and Mitchell, PS}, title = {A human-specific motif facilitates CARD8 inflammasome activation after HIV-1 infection.}, journal = {eLife}, volume = {12}, number = {}, pages = {}, doi = {10.7554/eLife.84108}, pmid = {37417868}, issn = {2050-084X}, support = {DP1 DA051110/DA/NIDA NIH HHS/United States ; T32 GM007270/GM/NIGMS NIH HHS/United States ; }, abstract = {Inflammasomes are cytosolic innate immune complexes that assemble upon detection of diverse pathogen-associated cues and play a critical role in host defense and inflammatory pathogenesis. Here, we find that the human inflammasome-forming sensor CARD8 senses HIV-1 infection via site-specific cleavage of the CARD8 N-terminus by the HIV protease (HIV-1[PR]). HIV-1[PR] cleavage of CARD8 induces pyroptotic cell death and the release of pro-inflammatory cytokines from infected cells, processes regulated by Toll-like receptor stimulation prior to viral infection. In acutely infected cells, CARD8 senses the activity of both de novo translated and packaged HIV-1[PR] that is released from the incoming virion. Moreover, our evolutionary analyses reveal that the HIV-1[PR] cleavage site in human CARD8 arose after the divergence of chimpanzees and humans. Although chimpanzee CARD8 does not recognize proteases from HIV or simian immunodeficiency viruses from chimpanzees (SIVcpz), SIVcpz doescleave human CARD8, suggesting that SIVcpz was poised to activate the human CARD8 inflammasome prior to its cross-species transmission into humans. Our findings suggest a unique role for CARD8 inflammasome activation in response to lentiviral infection of humans.}, }
@article {pmid37416758, year = {2023}, author = {Brown, ER and O'Brien, MP and Snow, B and Isa, F and Forleo-Neto, E and Chan, KC and Hou, P and Cohen, MS and Herman, G and Barnabas, RV}, title = {A Prospective Study of Key Correlates for Household Transmission of Severe Acute Respiratory Syndrome Coronavirus 2.}, journal = {Open forum infectious diseases}, volume = {10}, number = {7}, pages = {ofad271}, pmid = {37416758}, issn = {2328-8957}, abstract = {BACKGROUND: Randomized controlled trials evaluated monoclonal antibodies for the treatment (Study 2067) and prevention (Study 2069) of coronavirus disease 2019 (COVID-19). Household contacts of the infected index case in Study 2067 were enrolled in Study 2069 and prospectively followed; these cohorts provided a unique opportunity to evaluate correlates of transmission, specifically viral load.
METHODS: This post hoc analysis was designed to identify and evaluate correlates of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission, adjusting for potential confounding factors related to source SARS-CoV-2 viral load and risk of SARS-CoV-2 acquisition in this population. Correlates of transmission were evaluated in potential transmission pairs (any infected household member plus susceptible household contact).
RESULTS: In total, 943 participants were included. In multivariable regression, 2 potential correlates were determined to have a statistically significant (P < .05) association with transmission risk. A 10-fold increase in viral load was associated with a 40% increase in odds of transmission; sharing a bedroom with the index participant was associated with a 199% increase in odds of transmission.
CONCLUSIONS: In this prospective, post hoc analysis that controlled for confounders, the 2 key correlates for transmission of SARS-CoV-2 within a household are sharing a bedroom and increased viral load, consistent with increased exposure to the infected individual.}, }
@article {pmid37414705, year = {2023}, author = {Flaig, TW and Tangen, CM and Daneshmand, S and Alva, AS and Lucia, MS and McConkey, DJ and Theodorescu, D and Goldkorn, A and Milowsky, MI and Bangs, R and MacVicar, GR and Bastos, BR and Fowles, JS and Gustafson, DL and Plets, M and Thompson, IM and Lerner, SP}, title = {Long-term Outcomes from a Phase 2 Study of Neoadjuvant Chemotherapy for Muscle-invasive Bladder Cancer (SWOG S1314; NCT02177695).}, journal = {European urology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.eururo.2023.06.014}, pmid = {37414705}, issn = {1873-7560}, abstract = {BACKGROUND: The COXEN gene expression model was evaluated for prediction of response to neoadjuvant chemotherapy for muscle-invasive bladder cancer (MIBC).
OBJECTIVE: To conduct a secondary analysis of the association of each COXEN score with event-free survival (EFS) and overall survival (OS) and by treatment arm.
This was a randomized phase 2 trial of neoadjuvant gemcitabine-cisplatin (GC) or dose-dense methotrexate-vinblastine-adriamycin-cisplatin (ddMVAC) in MIBC.
INTERVENTION: Patients were randomized to ddMVAC (every 14 d) or GC (every 21 d), both for four cycles.
EFS events were defined as progression or death before scheduled surgery, a decision to not undergo surgery, recurrence, or death due to any cause after surgery. Cox regression was used to evaluate the COXEN score or treatment arm association with EFS and OS.
RESULTS AND LIMITATIONS: A total of 167 evaluable patients were included in the COXEN analysis. The COXEN scores were not significantly prognostic for OS or EFS in the respective arms, but the GC COXEN score had a hazard ratio (HR) of 0.45 (95% confidence interval [CI] 0.20-0.99; p = 0.047) when the arms were pooled. In the intent-to-treat analysis (n = 227), there was no significant difference between ddMVAC and GC for OS (HR 0.87, 95% CI 0.54-1.40; p = 0.57) or EFS (HR 0.86, 95% CI 0.59-1.26; p = 0.45). Among the 192 patients who underwent surgery, pathologic response (pT0 vs downstaging vs no response) was strongly correlated with superior postsurgical survival (5-yr OS 90%, 89% and 52%, respectively).
CONCLUSIONS: The COXEN GC score has prognostic value for patients receiving cisplatin-based neoadjuvant treatment. The randomized, prospective design provides estimates of OS and EFS for GC and ddMVAC in this population. Pathologic response (
PATIENT SUMMARY: In this study, we evaluated a biomarker to predict the response to chemotherapy. The results did not meet the preset study parameters, but our study provides information on clinical outcomes with the use of chemotherapy before surgery for bladder cancer.}, }
@article {pmid37414620, year = {2023}, author = {Bakaloudi, DR and Talukder, R and Lin, GI and Makrakis, D and Diamantopoulos, LN and Tripathi, N and Agarwal, N and Zakopoulou, R and Bamias, A and Brown, JR and Pinato, DJ and Korolewicz, J and Jindal, T and Koshkin, VS and Murgić, J and Miletić, M and Frobe, A and Johnson, J and Zakharia, Y and Drakaki, A and Rodriguez-Vida, A and Rey-Cárdenas, M and Castellano, D and Buznego, LA and Duran, I and Carballeira, CC and Barrera, RM and Marmorejo, D and McKay, RR and Stewart, T and Gupta, S and Ruplin, AT and Yu, EY and Khaki, AR and Grivas, P}, title = {Response and Outcomes of Maintenance Avelumab After Platinum-Based Chemotherapy (PBC) in Patients With Advanced Urothelial Carcinoma (aUC): "Real World" Experience.}, journal = {Clinical genitourinary cancer}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.clgc.2023.06.008}, pmid = {37414620}, issn = {1938-0682}, abstract = {BACKGROUND: Platinum-based chemotherapy (PBC) followed by avelumab switch maintenance in nonprogressors is standard first line (1L) treatment for advanced urothelial carcinoma (aUC). We describe clinical features and outcomes in a "real-world' cohort treated with avelumab maintenance for aUC.
MATERIALS AND METHODS: This was a retrospective cohort study of patients (pts) who received 1L switch maintenance avelumab after no progression on PBC for aUC. We calculated progression-free survival (PFS) and overall survival (OS) from initiation of maintenance avelumab. We also described OS and PFS for specific subsets using Cox regression and observed response rate (ORR).
RESULTS: A total of 108 pts with aUC from 14 sites treated with maintenance avelumab were included. There was a median of 6 weeks[1-30] from end of PBC to avelumab initiation; median follow-up time from avelumab initiation was 8.8 months (1-42.7). Median [m]PFS was 9.6 months (95%CI 7.5-12.1) and estimated 1-year OS was 72.5%. CR/PR (vs. SD) to 1L PBC (HR = 0.33, 95% CI 0.13-0.87) and ECOG PS 0 (vs. ≥1), (HR = 0.15, 95% CI 0.05-0.47) were associated with longer OS. The presence of liver metastases was associated with shorter PFS (HR = 2.32, 95% CI 1.17-4.59). ORR with avelumab maintenance was 28.7% (complete response 17.6%, partial response 11.1%), 29.6% stable disease, 26.9% progressive disease as best response (14.8% best response unknown).
CONCLUSIONS: Results seem relatively consistent with findings from JAVELIN Bladder100 trial and recent "real world" studies. Prior response to platinum-based chemotherapy, ECOG PS 0, and absence of liver metastases were favorable prognostic factors. Limitations include the retrospective design, lack of randomization and central scan review, and possible selection/confounding biases.}, }
@article {pmid37414327, year = {2023}, author = {Saba, SK and Davis, JP and Bricker, JB and Christie, NC and Pedersen, ER}, title = {Pain Trajectories among U.S. Veterans during COVID-19.}, journal = {The journal of pain}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jpain.2023.06.018}, pmid = {37414327}, issn = {1528-8447}, abstract = {Physical pain is highly prevalent among military veterans. As stress can impact pain, COVID-19-related stressors may have heightened pain among veterans. A prospective analysis of pain could advance understanding of how veterans fared during COVID-19 and lend knowledge of risk factors important beyond the pandemic. The present study employs growth mixture modeling with a sample of U.S. veterans high in pain (N=1230) followed from just before COVID-19 (February 2020) to 12 months later (February 2021; 81.7% retention). We explored heterogeneous pain trajectories as well as baseline and COVID-19-related predictors of pain. Results revealed four pain trajectory classes: (1) Chronic Pain (17.3% of sample); (2) Decreasing Pain (57.2% of sample); (3) Stable Mild Pain (19.8% of sample); and (4) Increasing Pain (5.7% of sample). Those with childhood trauma exposure were especially likely to report chronic pain. Female and racial/ethnic minority veterans were also relatively likely to fare poorly in pain. Loneliness was associated with subsequent pain among several classes. Most veterans in our sample fared better than expected in terms of pain. However, as those with childhood trauma and certain disadvantaged groups were less likely to fare well, we add to the important literature on disparities in pain. Clinicians should identify whether loneliness and other factors impacted pain during COVID-19 among their patients to inform ongoing, person-centered pain management approaches.}, }
@article {pmid37414012, year = {2023}, author = {Cowan, AJ and Pont, MJ and Sather, BD and Turtle, CJ and Till, BG and Libby, EN and Coffey, DG and Tuazon, SA and Wood, B and Gooley, T and Wu, VQ and Voutsinas, J and Song, X and Shadman, M and Gauthier, J and Chapuis, AG and Milano, F and Maloney, DG and Riddell, SR and Green, DJ}, title = {γ-Secretase inhibitor in combination with BCMA chimeric antigen receptor T-cell immunotherapy for individuals with relapsed or refractory multiple myeloma: a phase 1, first-in-human trial.}, journal = {The Lancet. Oncology}, volume = {24}, number = {7}, pages = {811-822}, doi = {10.1016/S1470-2045(23)00246-2}, pmid = {37414012}, issn = {1474-5488}, abstract = {BACKGROUND: γ-Secretase inhibitors (GSIs) increase B cell maturation antigen (BCMA) density on malignant plasma cells and enhance antitumour activity of BCMA chimeric antigen receptor (CAR) T cells in preclinical models. We aimed to evaluate the safety and identify the recommended phase 2 dose of BCMA CAR T cells in combination with crenigacestat (LY3039478) for individuals with relapsed or refractory multiple myeloma.
METHODS: We conducted a phase 1, first-in-human trial combining crenigacestat with BCMA CAR T-cells at a single cancer centre in Seattle, WA, USA. We included individuals aged 21 years or older with relapsed or refractory multiple myeloma, previous autologous stem-cell transplant or persistent disease after more than four cycles of induction therapy, and Eastern Cooperative Oncology Group performance status of 0-2, regardless of previous BCMA-targeted therapy. To assess the effect of the GSI on BCMA surface density on bone marrow plasma cells, participants received GSI during a pretreatment run-in, consisting of three doses administered 48 h apart. BCMA CAR T cells were infused at doses of 50 × 10[6] CAR T cells, 150 × 10[6] CAR T cells, 300 × 10[6] CAR T cells, and 450 × 10[6] CAR T cells (total cell dose), in combination with the 25 mg crenigacestat dosed three times a week for up to nine doses. The primary endpoints were the safety and recommended phase 2 dose of BCMA CAR T cells in combination with crenigacestat, an oral GSI. This study is registered with ClinicalTrials.gov, NCT03502577, and has met accrual goals.
FINDINGS: 19 participants were enrolled between June 1, 2018, and March 1, 2021, and one participant did not proceed with BCMA CAR T-cell infusion. 18 participants (eight [44%] men and ten [56%] women) with multiple myeloma received treatment between July 11, 2018, and April 14, 2021, with a median follow up of 36 months (95% CI 26 to not reached). The most common non-haematological adverse events of grade 3 or higher were hypophosphataemia in 14 (78%) participants, fatigue in 11 (61%), hypocalcaemia in nine (50%), and hypertension in seven (39%). Two deaths reported outside of the 28-day adverse event collection window were related to treatment. Participants were treated at doses up to 450 × 10[6] CAR[+] cells, and the recommended phase 2 dose was not reached.
INTERPRETATIONS: Combining a GSI with BCMA CAR T cells appears to be well tolerated, and crenigacestat increases target antigen density. Deep responses were observed among heavily pretreated participants with multiple myeloma who had previously received BCMA-targeted therapy and those who were naive to previous BCMA-targeted therapy. Further study of GSIs given with BCMA-targeted therapeutics is warranted in clinical trials.
FUNDING: Juno Therapeutics-a Bristol Myers Squibb company and the National Institutes of Health.}, }
@article {pmid37410908, year = {2023}, author = {Harbecke, R and Oxman, MN and Selke, S and Ashbaugh, ME and Lan, KF and Koelle, DM and Wald, A}, title = {Prior Herpes Simplex Virus Infection and the Risk of Herpes Zoster.}, journal = {The Journal of infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1093/infdis/jiad259}, pmid = {37410908}, issn = {1537-6613}, abstract = {BACKGROUND: The incidence of herpes zoster (HZ) has increased in the United States concurrent with decrease in herpes simplex virus (HSV) prevalence. We hypothesized that lack of HSV-elicited cross-reactive immunity to varicella-zoster virus (VZV) results in an increased risk of HZ. Using specimens from the placebo arm of the Shingles Prevention Study, we investigated whether persons who develop HZ are less likely to have prior HSV infection than persons who do not develop HZ, and whether HZ is less severe in persons with HSV than in HSV seronegative persons.
METHODS: We conducted a nested case-control (1:2) study comparing the seroprevalence of HSV-1 and HSV-2 in cases (persons with PCR-confirmed HZ) to age-, sex- and health-matched controls (persons without HZ).
RESULTS: Sera from 639 study participants (213 cases and 426 controls) yielded definitive HSV antibody results and were analyzed. Overall, HSV seropositivity rate was 75%. HSV seronegativity was significantly higher in HZ cases than controls (30.5% vs 22.3%; P = .024), with a 55% higher risk of HZ in HSV seronegative than HSV seropositive participants. HSV seropositivity was associated with more severe HZ (P = .021).
CONCLUSION: Our study demonstrated that prior infection with HSV partly protects against HZ.}, }
@article {pmid37410340, year = {2023}, author = {Rencsok, EM and Slopen, N and Autio, K and Morgans, A and McSwain, L and Barata, P and Cheng, HH and Dreicer, R and Heath, E and McKay, RR and Pomerantz, M and Rathkopf, D and Tagawa, S and Whang, YE and Ragin, C and Odedina, FT and George, DJ and Kantoff, PW and Vinson, J and Villanti, P and Haneuse, S and Mucci, LA and , }, title = {Quality of life in the year after new diagnosis with advanced prostate cancer for Black and White individuals living in the US.}, journal = {Quality of life research : an international journal of quality of life aspects of treatment, care and rehabilitation}, volume = {}, number = {}, pages = {}, pmid = {37410340}, issn = {1573-2649}, support = {F30CA264965/CA/NCI NIH HHS/United States ; T32GM007753/GM/NIGMS NIH HHS/United States ; T32GM144273/GM/NIGMS NIH HHS/United States ; }, abstract = {PURPOSE: To assess differences in baseline and longitudinal quality of life among Black and White individuals in the US with advanced prostate cancer.
METHODS: Secondary analysis of data from the International Registry for Men with Advanced Prostate Cancer (IRONMAN) including US participants newly diagnosed with advanced prostate cancer and identifying their race as Black or White from 2017 to 2023. Participants completed the EORTC QLQ-C30 Quality of Life (QoL) Survey at study enrollment and every 3 months thereafter for up to 1 year of follow-up reporting 15 scale scores ranging from 0 to 100 (higher functioning and lower symptom scores represent better quality of life). Linear mixed effects models with race and month of questionnaire completion were fit for each scale, and model coefficients were used to assess differences in baseline and longitudinal QoL by race.
RESULTS: Eight hundred and seventy-nine participants were included (20% identifying as Black) at 38 US sites. Compared to White participants at baseline, Black participants had worse constipation (mean 6.3 percentage points higher; 95% CI 2.9-9.8), financial insecurity (5.7 (1.4-10.0)), and pain (5.1 (0.9-9.3)). QoL decreased over time similarly by race; most notably, role functioning decreased by 0.7 percentage points (95% CI -0.8, -0.5) per month.
CONCLUSION: There are notable differences in quality of life at new diagnosis of advanced prostate cancer for Black and White individuals, and quality of life declines similarly in the first year for both groups. Interventions that address specific aspects of quality of life in these patients could meaningfully improve the overall survivorship experience.}, }
@article {pmid37409953, year = {2023}, author = {Carson, D and Nyame, YA}, title = {Editorial Comment.}, journal = {Urology practice}, volume = {}, number = {}, pages = {101097UPJ000000000000042101}, doi = {10.1097/UPJ.0000000000000421.01}, pmid = {37409953}, issn = {2352-0787}, }
@article {pmid37408748, year = {2023}, author = {Rogers, JH and Hawes, SE and Wolf, CR and Hughes, JP and Englund, JA and Starita, LM and Chu, HY}, title = {Care-seeking correlates of acute respiratory illness among sheltered adults experiencing homelessness in Seattle, WA, 2019: a community-based cross-sectional study.}, journal = {Frontiers in public health}, volume = {11}, number = {}, pages = {1090148}, pmid = {37408748}, issn = {2296-2565}, mesh = {Humans ; Adult ; *Respiratory Tract Infections/epidemiology ; Cross-Sectional Studies ; Washington/epidemiology ; *Virus Diseases ; *Viruses ; *Ill-Housed Persons ; Patient Acceptance of Health Care ; }, abstract = {OBJECTIVE: Multifarious barriers to accessing healthcare services among people experiencing homelessness (PEH) lead to delays in seeking care for acute infections, including those caused by respiratory viruses. PEH are at high risk of acute respiratory illness (ARI)-related complications, especially in shelter settings that may facilitate virus spread, yet data characterizing healthcare utilization for ARI episodes among sheltered PEH remained limited.
METHODS: We conducted a cross-sectional study of viral respiratory infection among adult residents at two homeless shelters in Seattle, Washington between January and May 2019. We assessed factors associated with seeking medical care for ARI via self-report. We collected illness questionnaires and nasal swabs were tested for respiratory viruses by reverse transcription quantitative real-time PCR (RT-qPCR).
RESULTS: We observed 825 encounters from 649 unique participants; 241 (29.2%) encounters reported seeking healthcare for their ARI episode. Seasonal influenza vaccine receipt (adjusted prevalence ratio [aPR] 1.39, 95% CI 1.02-1.88), having health insurance (aPR 2.77, 95% CI 1.27-6.02), chronic lung conditions (aPR 1.55, 95% CI 1.12-2.15), and experiencing influenza-like-illness symptoms (aPR 1.63, 95% CI 1.20 - 2.20) were associated with increased likelihood of seeking care. Smoking (aPR 0.65, 95% CI 0.45-0.92) was associated with decreased likelihood of seeking care.
DISCUSSION: Findings suggest that care seeking for viral respiratory illness among PEH may be supported by prior engagement with primary healthcare services. Strategies to increase healthcare utilization may lead to earlier detection of respiratory viruses.}, }
@article {pmid37408448, year = {2023}, author = {Tordoff, DM and Minalga, B and Trejo, A and Shook, A and Kerani, RP and Herbeck, JT}, title = {Lessons learned from community engagement regarding phylodynamic research with molecular HIV surveillance data.}, journal = {Journal of the International AIDS Society}, volume = {26 Suppl 1}, number = {Suppl 1}, pages = {e26111}, pmid = {37408448}, issn = {1758-2652}, support = {R01AI127232//National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID)/ ; R01AI127232//National Institute of Allergy and Infectious Diseases/ ; }, mesh = {Male ; Humans ; Homosexuality, Male ; *HIV Infections/drug therapy/epidemiology ; Phylogeny ; *Sexual and Gender Minorities ; *HIV Seropositivity ; }, abstract = {INTRODUCTION: The widespread implementation of molecular HIV surveillance (MHS) has resulted in an increased discussion about the ethical, human rights and public health implications of MHS. We narrate our process of pausing our research that uses data collected through MHS in response to these growing concerns and summarize the key lessons we learned through conversations with community members.
METHODS: The original study aimed to describe HIV transmission patterns by age and race/ethnicity among men who have sex with men in King County, Washington, by applying probabilistic phylodynamic modelling methods to HIV-1 pol gene sequences collected through MHS. In September 2020, we paused the publication of this research to conduct community engagement: we held two public-facing online presentations, met with a national community coalition that included representatives of networks of people living with HIV, and invited two members of this coalition to provide feedback on our manuscript. During each of these meetings, we shared a brief presentation of our methods and findings and explicitly solicited feedback on the perceived public health benefit and potential harm of our analyses and results.
RESULTS: Some community concerns about MHS in public health practice also apply to research using MHS data, namely those related to informed consent, inference of transmission directionality and criminalization. Other critiques were specific to our research study and included feedback about the use of phylogenetic analyses to study assortativity by race/ethnicity and the importance of considering the broader context of stigma and structural racism. We ultimately decided the potential harms of publishing our study-perpetuating racialized stigma about men who have sex with men and eroding the trust between phylogenetics researchers and communities of people living with HIV-outweighed the potential benefits.
CONCLUSIONS: HIV phylogenetics research using data collected through MHS data is a powerful scientific technology with the potential to benefit and harm communities of people living with HIV. Addressing criminalization and including people living with HIV in decision-making processes have the potential to meaningfully address community concerns and strengthen the ethical justification for using MHS data in both research and public health practice. We close with specific opportunities for action and advocacy by researchers.}, }
@article {pmid37407001, year = {2023}, author = {Mato, AR and Woyach, JA and Brown, JR and Ghia, P and Patel, K and Eyre, TA and Munir, T and Lech-Maranda, E and Lamanna, N and Tam, CS and Shah, NN and Coombs, CC and Ujjani, CS and Fakhri, B and Cheah, CY and Patel, MR and Alencar, AJ and Cohen, JB and Gerson, JN and Flinn, IW and Ma, S and Jagadeesh, D and Rhodes, JM and Hernandez-Ilizaliturri, F and Zinzani, PL and Seymour, JF and Balbas, M and Nair, B and Abada, P and Wang, C and Ruppert, AS and Wang, D and Tsai, DE and Wierda, WG and Jurczak, W}, title = {Pirtobrutinib after a Covalent BTK Inhibitor in Chronic Lymphocytic Leukemia.}, journal = {The New England journal of medicine}, volume = {389}, number = {1}, pages = {33-44}, doi = {10.1056/NEJMoa2300696}, pmid = {37407001}, issn = {1533-4406}, abstract = {BACKGROUND: Patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) have poor outcomes after the failure of covalent Bruton's tyrosine kinase (BTK) inhibitor treatment, and new therapeutic options are needed. Pirtobrutinib, a highly selective, noncovalent (reversible) BTK inhibitor, was designed to reestablish BTK inhibition.
METHODS: We conducted a phase 1-2 trial in which patients with relapsed or refractory B-cell cancers received pirtobrutinib. Here, we report efficacy results among patients with CLL or SLL who had previously received a BTK inhibitor as well as safety results among all the patients with CLL or SLL. The primary end point was an overall response (partial response or better) as assessed by independent review. Secondary end points included progression-free survival and safety.
RESULTS: A total of 317 patients with CLL or SLL received pirtobrutinib, including 247 who had previously received a BTK inhibitor. Among these 247 patients, the median number of previous lines of therapy was 3 (range, 1 to 11), and 100 patients (40.5%) had also received a B-cell lymphoma 2 (BCL2) inhibitor such as venetoclax. The percentage of patients with an overall response to pirtobrutinib was 73.3% (95% confidence interval [CI], 67.3 to 78.7), and the percentage was 82.2% (95% CI, 76.8 to 86.7) when partial response with lymphocytosis was included. The median progression-free survival was 19.6 months (95% CI, 16.9 to 22.1). Among all 317 patients with CLL or SLL who received pirtobrutinib, the most common adverse events were infections (in 71.0%), bleeding (in 42.6%), and neutropenia (in 32.5%). At a median duration of treatment of 16.5 months (range, 0.2 to 39.9), some adverse events that are typically associated with BTK inhibitors occurred relatively infrequently, including hypertension (in 14.2% of patients), atrial fibrillation or flutter (in 3.8%), and major hemorrhage (in 2.2%). Only 9 of 317 patients (2.8%) discontinued pirtobrutinib owing to a treatment-related adverse event.
CONCLUSIONS: In this trial, pirtobrutinib showed efficacy in patients with heavily pretreated CLL or SLL who had received a covalent BTK inhibitor. The most common adverse events were infections, bleeding, and neutropenia. (Funded by Loxo Oncology; BRUIN ClinicalTrials.gov number, NCT03740529.).}, }
@article {pmid37405403, year = {2023}, author = {Heldman, MR and Ahmed, AA and Liu, W and Vo, A and Keane-Candib, J and Stevens-Ayers, T and Boeckh, M and Blauwkamp, TA and Fisher, CE and Hill, JA}, title = {Serial quantitation of plasma microbial cell-free DNA before and after diagnosis of pulmonary invasive mold infections in hematopoietic cell transplant recipients.}, journal = {The Journal of infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1093/infdis/jiad255}, pmid = {37405403}, issn = {1537-6613}, abstract = {BACKGROUND: Plasma microbial cell-free DNA sequencing (mcfDNA-Seq) is a non-invasive test for microbial diagnosis of invasive mold infection (IMI). The utility of mcfDNA-Seq for predicting IMI onset and the clinical implications of mcfDNA concentrations are unknown.
METHODS: We retrospectively tested plasma from hematopoietic cell transplant (HCT) recipients with pulmonary IMI and ≥1 mold identified by mcfDNA-Seq in plasma collected within 14 days of clinical diagnosis. Samples collected from up to four weeks before and four weeks after IMI diagnosis were evaluated using mcfDNA-Seq.
RESULTS: Thirty-five HCT recipients with 39 IMIs (16 Aspergillus and 23 non-Aspergillus infections) were included. Pathogenic molds were detected in 38%, 26%, 11%, and 0% of samples collected during the first, second, third, and fourth week before clinical diagnosis, respectively. In non-Aspergillus infections, median mcfDNA concentrations in samples collected within three days of clinical diagnosis were higher in infections with versus without extrapulmonary spread (4.3 vs. 3.3 log10 mpm, p=0.02), and all patients (8/8) with mcfDNA concentrations >4.0 log10 mpm died within 42 days after clinical diagnosis.
CONCLUSIONS: Plasma mcfDNA-Seq can identify pathogenic molds up to three weeks before clinical diagnosis of pulmonary IMI. Plasma mcfDNA concentrations may correlate with extrapulmonary spread and mortality in non-Aspergillus IMI.}, }
@article {pmid37403227, year = {2023}, author = {Ning, X and Pan, Y and Sun, Y and Gilbert, PB}, title = {A semiparametric Cox-Aalen transformation model with censored data.}, journal = {Biometrics}, volume = {}, number = {}, pages = {}, doi = {10.1111/biom.13895}, pmid = {37403227}, issn = {1541-0420}, support = {R37 AI054165/AI/NIAID NIH HHS/United States ; UM1 AI68635/NH/NIH HHS/United States ; }, abstract = {We propose a broad class of so-called Cox-Aalen transformation models that incorporate both multiplicative and additive covariate effects on the baseline hazard function within a transformation. The proposed models provide a highly flexible and versatile class of semiparametric models that include the transformation models and the Cox-Aalen model as special cases. Specifically, it extends the transformation models by allowing potentially time-dependent covariates to work additively on the baseline hazard and extends the Cox-Aalen model through a predetermined transformation function. We propose an estimating equation approach and devise an expectation-solving (ES) algorithm that involves fast and robust calculations. The resulting estimator is shown to be consistent and asymptotically normal via modern empirical process techniques. The ES algorithm yields a computationally simple method for estimating the variance of both parametric and nonparametric estimators. Finally, we demonstrate the performance of our procedures through extensive simulation studies and applications in two randomized, placebo-controlled human immunodeficiency virus (HIV) prevention efficacy trials. The data example shows the utility of the proposed Cox-Aalen transformation models in enhancing statistical power for discovering covariate effects.}, }
@article {pmid37403049, year = {2023}, author = {Daniel, AK and Casmir, E and Oluoch, L and Micheni, M and Kiptinness, C and Wald, A and Mugo, NR and Roxby, AC and Ngure, K}, title = {"I was just concerned about getting pregnant": Attitudes toward pregnancy and contraceptive use among adolescent girls and young women in Thika, Kenya.}, journal = {BMC pregnancy and childbirth}, volume = {23}, number = {1}, pages = {493}, pmid = {37403049}, issn = {1471-2393}, support = {P01 AI 030731/HD/NICHD NIH HHS/United States ; }, mesh = {Pregnancy ; Humans ; Female ; Adolescent ; Contraceptive Agents ; *HIV Infections/epidemiology ; Kenya ; Longitudinal Studies ; *Sexually Transmitted Diseases/prevention & control ; Attitude ; }, abstract = {BACKGROUND: Adolescent girls and young women (AGYW) have a high incidence of unplanned pregnancies, especially in low-resource settings. AGYW assess the overlapping risks of pregnancy, contraception, and STIs as they navigate relationships. Few studies have examined how AGYW consider the comparative risks of their decisions around sexual and reproductive health in this context or how risk perception influences contraceptive use.
METHODS: Twenty in-depth interviews (IDIs) and 5 focus group discussions (FGDs) were conducted with a subset of sexually active AGYW enrolled in the Girls Health Study (GHS), a longitudinal cohort study in Thika, Kenya, assessing HSV-2 incidence in a cohort of AGYW aged 16-20. Interview questions were focused on perspectives and decision-making around sexual and reproductive health. Interviews were conducted in both English and Kiswahili, transcribed, and coded using inductive and deductive approaches to identify emerging themes.
RESULTS: Misconceptions about long-acting reversible contraceptives (LARCs), injectables, and daily oral contraceptive pills strongly disincentivized their use among AGYW. Participants described pregnancy as undesirable, and AGYW reported prioritizing contraceptive methods that were effective and reliable in pregnancy prevention, even if not effective in preventing STI/HIV infection. Participants reported that AGYW relied heavily on emergency contraceptive (EC) pills for pregnancy prevention.
CONCLUSIONS: Though the goal of avoiding unintended pregnancy was common, this did not suffice to motivate the uptake of long-term contraceptives among AGYWs. Given the convenience, cost-effectiveness, and lower perceived risk of side effects, EC pills were more likely to be accepted as a form of contraception. Understanding the reasons for AGYW's acceptance of certain contraceptive methods over others can help future interventions better target communication and counseling about contraception and influence key drivers of AGYW behavior and decision-making around sexual and reproductive health.}, }
@article {pmid37402281, year = {2023}, author = {Mitchell, CM and Larson, JC and Reed, SD and Guthrie, KA}, title = {The complexity of genitourinary syndrome of menopause: number, severity, and frequency of vulvovaginal discomfort symptoms in women enrolled in a randomized trial evaluating treatment for genitourinary syndrome of menopause.}, journal = {Menopause (New York, N.Y.)}, volume = {}, number = {}, pages = {}, pmid = {37402281}, issn = {1530-0374}, abstract = {OBJECTIVE: The aim of the study is to describe the location, severity, and frequency of genitourinary symptoms in postmenopausal women enrolled in a randomized trial of treatment for vulvovaginal discomfort.
METHODS: This is a post hoc analysis of enrollment responses for participants in the MsFLASH Vaginal Health Trial. Participants were asked about the severity (0-3), frequency (in days per week) and location (vulvar or vaginal) of itch, dryness, pain/soreness, irritation, as well as severity and frequency of pain with penetration, vaginal discharge, urinary incontinence, and urinary urgency.
RESULTS: A total of 302 participants were enrolled, with a mean age of 60.9 ± 4.1 years. The mean number of moderate-severe vulvovaginal symptoms experienced by trial participants in the month before enrollment was 3.4 ± 1.5, with a range from 1 to 7. The most commonly reported symptom across all severity categories was vaginal dryness (285/302, 94%), but the one most frequently rated as severe was pain with vaginal penetration (121/302, 40%). Vaginal dryness was the symptom with highest frequency; 53% of participants with that symptom reported experiencing it ≥4 d/wk. For vaginal symptoms, 80% of participants (241/302) reported that at least one of these symptoms occurred during or after sex while only 43% (158/302) reported that at least one vulvar symptom occurred during or after sex. Urinary incontinence (202/302, 67%) and urinary frequency (128/302, 43%) were the two most commonly reported urinary issues.
CONCLUSIONS: Our data highlight the complexity of genitourinary syndrome of menopause symptoms in quantity, severity, and frequency, suggesting that measuring distress, bother, or interference may be the most comprehensive measure.}, }
@article {pmid37400577, year = {2023}, author = {Lässig, M and Mustonen, V and Nourmohammad, A}, title = {Steering and controlling evolution - from bioengineering to fighting pathogens.}, journal = {Nature reviews. Genetics}, volume = {}, number = {}, pages = {}, pmid = {37400577}, issn = {1471-0064}, abstract = {Control interventions steer the evolution of molecules, viruses, microorganisms or other cells towards a desired outcome. Applications range from engineering biomolecules and synthetic organisms to drug, therapy and vaccine design against pathogens and cancer. In all these instances, a control system alters the eco-evolutionary trajectory of a target system, inducing new functions or suppressing escape evolution. Here, we synthesize the objectives, mechanisms and dynamics of eco-evolutionary control in different biological systems. We discuss how the control system learns and processes information about the target system by sensing or measuring, through adaptive evolution or computational prediction of future trajectories. This information flow distinguishes pre-emptive control strategies by humans from feedback control in biotic systems. We establish a cost-benefit calculus to gauge and optimize control protocols, highlighting the fundamental link between predictability of evolution and efficacy of pre-emptive control.}, }
@article {pmid37400528, year = {2023}, author = {Zhou, Z and Jia, D and Kwon, O and Li, S and Sun, H and Roudier, MP and Lin, DW and True, L and Morrissey, C and Creighton, CJ and Lee, JK and Xin, L}, title = {Androgen-regulated stromal complement component 7 (C7) suppresses prostate cancer growth.}, journal = {Oncogene}, volume = {}, number = {}, pages = {}, pmid = {37400528}, issn = {1476-5594}, support = {W81XWH-20-1-0218//U.S. Department of Defense (United States Department of Defense)/ ; }, abstract = {The complement system is a major component of the innate immune system that works through the cytolytic effect of the membrane attack complex (MAC). Complement component 7 (C7) is essential for MAC assembly and its precisely regulated expression level is crucial for the cytolytic activity of MAC. We show that C7 is specifically expressed by the stromal cells in both mouse and human prostates. The expression level of C7 inversely correlates with clinical outcomes in prostate cancer. C7 is positively regulated by androgen signaling in the mouse prostate stromal cells. The androgen receptor directly transcriptionally regulates the mouse and human C7. Increasing C7 expression in the C57Bl/6 syngeneic RM-1 and Pten-Kras allografts suppresses tumor growth in vivo. Conversely, C7 haploinsufficiency promotes tumor growth in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. Interestingly, replenishing C7 in androgen-sensitive Pten-Kras tumors during androgen depletion only slightly enhances cellular apoptosis, highlighting the diverse mechanisms employed by tumors to counteract complement activity. Collectively, our research indicates that augmenting complement activity could be a promising therapeutic approach to impede the development of castration resistance in prostate cancer.}, }
@article {pmid37399491, year = {2023}, author = {Blair, LM and Akhund-Zade, J and Katsamakis, ZA and Smibert, OC and Wolfe, AE and Giardina, P and Slingerland, J and Bercovici, S and Perales, MA and Taur, Y and van den Brink, MRM and Peled, JU and Markey, KA}, title = {Circulating microbial cell-free DNA is increased during neutropenia following hematopoietic stem cell transplantation.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2023010208}, pmid = {37399491}, issn = {2473-9537}, abstract = {We used a next-generation sequencing platform to characterize microbial cell-free DNA (mcfDNA) in plasma samples from patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HCT). In this observational study, we sought to characterize plasma mcfDNA in order to understand its potential association with the immunologic complications of transplantation. We compared serially-collected patient samples with plasma collected from healthy control subjects. We observed changes in total mcfDNA burden in plasma after transplantation, which was most striking during the early post-transplant neutropenic phase. This elevation could be attributed to a number of specific bacterial taxa, including Veillonella, Bacteroides and Prevotella (genus level). For an additional cohort of patients, we compared mcfDNA from plasma with 16S-rRNA sequencing data from stool samples collected at matched time points. In a number of patients, we confirmed that mcfDNA derived from specific microbial taxa (e.g. Enterococcus) could also be observed in the matched stool sample. Quantification of mcfDNA may generate novel insights into mechanisms by which the intestinal microbiome influences systemic cell populations and thus has been associated with outcomes for cancer patients.}, }
@article {pmid37399393, year = {2023}, author = {Prasad, PV and Steele, MK and Reed, C and Meyers, LA and Du, Z and Pasco, R and Alfaro-Murillo, JA and Lewis, B and Venkatramanan, S and Schlitt, J and Chen, J and Orr, M and Wilson, ML and Eubank, S and Wang, L and Chinazzi, M and Pastore Y Piontti, A and Davis, JT and Halloran, ME and Longini, I and Vespignani, A and Pei, S and Galanti, M and Kandula, S and Shaman, J and Haw, DJ and Arinaminpathy, N and Biggerstaff, M}, title = {Multimodeling approach to evaluating the efficacy of layering pharmaceutical and nonpharmaceutical interventions for influenza pandemics.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {120}, number = {28}, pages = {e2300590120}, doi = {10.1073/pnas.2300590120}, pmid = {37399393}, issn = {1091-6490}, mesh = {Humans ; *Influenza, Human/drug therapy/epidemiology/prevention & control ; Pharmaceutical Preparations ; Pandemics/prevention & control ; *Influenza Vaccines/therapeutic use ; Antiviral Agents/pharmacology/therapeutic use ; }, abstract = {When an influenza pandemic emerges, temporary school closures and antiviral treatment may slow virus spread, reduce the overall disease burden, and provide time for vaccine development, distribution, and administration while keeping a larger portion of the general population infection free. The impact of such measures will depend on the transmissibility and severity of the virus and the timing and extent of their implementation. To provide robust assessments of layered pandemic intervention strategies, the Centers for Disease Control and Prevention (CDC) funded a network of academic groups to build a framework for the development and comparison of multiple pandemic influenza models. Research teams from Columbia University, Imperial College London/Princeton University, Northeastern University, the University of Texas at Austin/Yale University, and the University of Virginia independently modeled three prescribed sets of pandemic influenza scenarios developed collaboratively by the CDC and network members. Results provided by the groups were aggregated into a mean-based ensemble. The ensemble and most component models agreed on the ranking of the most and least effective intervention strategies by impact but not on the magnitude of those impacts. In the scenarios evaluated, vaccination alone, due to the time needed for development, approval, and deployment, would not be expected to substantially reduce the numbers of illnesses, hospitalizations, and deaths that would occur. Only strategies that included early implementation of school closure were found to substantially mitigate early spread and allow time for vaccines to be developed and administered, especially under a highly transmissible pandemic scenario.}, }
@article {pmid36993197, year = {2023}, author = {Radford, CE and Schommers, P and Gieselmann, L and Crawford, KHD and Dadonaite, B and Yu, TC and Dingens, AS and Overbaugh, J and Klein, F and Bloom, JD}, title = {Mapping the neutralizing specificity of human anti-HIV serum by deep mutational scanning.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {36993197}, support = {R01 AI140891/AI/NIAID NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; T32 GM007270/GM/NIGMS NIH HHS/United States ; INV-004949/GATES/Bill & Melinda Gates Foundation/United States ; S10 OD020069/OD/NIH HHS/United States ; R01 AI141707/AI/NIAID NIH HHS/United States ; U01 AI169385/AI/NIAID NIH HHS/United States ; F30 AI149928/AI/NIAID NIH HHS/United States ; T32 AI083203/AI/NIAID NIH HHS/United States ; }, abstract = {Understanding the specificities of human serum antibodies that broadly neutralize HIV can inform prevention and treatment strategies. Here we describe a deep mutational scanning system that can measure the effects of combinations of mutations to HIV envelope (Env) on neutralization by antibodies and polyclonal serum. We first show that this system can accurately map how all functionally tolerated mutations to Env affect neutralization by monoclonal antibodies. We then comprehensively map Env mutations that affect neutralization by a set of human polyclonal sera known to target the CD4-binding site that neutralize diverse strains of HIV. The neutralizing activities of these sera target different epitopes, with most sera having specificities reminiscent of individual characterized monoclonal antibodies, but one sera targeting two epitopes within the CD4 binding site. Mapping the specificity of the neutralizing activity in polyclonal human serum will aid in assessing anti-HIV immune responses to inform prevention strategies.}, }
@article {pmid37399224, year = {2023}, author = {Lyman, GH}, title = {PERCEPTION, COGNITION AND THOUGHT: Part II Symbolic Processing and Language.}, journal = {Cancer investigation}, volume = {}, number = {}, pages = {1-6}, doi = {10.1080/07357907.2023.2233317}, pmid = {37399224}, issn = {1532-4192}, }
@article {pmid37397090, year = {2023}, author = {Xia, P and Chen, J and Sapkota, Y and Scott, EN and Liu, Y and Hudson, MM and Rassekh, SR and Carleton, BC and Ross, CJD and Chow, EJ and Cheng, Z}, title = {RBL2 Regulates Cardiac Sensitivity to Anthracycline Chemotherapy.}, journal = {JACC. CardioOncology}, volume = {5}, number = {3}, pages = {360-373}, pmid = {37397090}, issn = {2666-0873}, abstract = {BACKGROUND: Anthracycline chemotherapies cause heart failure in a subset of cancer patients. We previously reported that the anthracycline doxorubicin (DOX) induces cardiotoxicity through the activation of cyclin-dependent kinase 2 (CDK2).
OBJECTIVES: The aim of this study was to determine whether retinoblastoma-like 2 (RBL2/p130), an emerging CDK2 inhibitor, regulates anthracycline sensitivity in the heart.
METHODS: Rbl2[-/-] mice and Rbl2[+/+] littermates received DOX (5 mg/kg/wk for 4 weeks intraperitoneally, 20 mg/kg cumulative). Heart function was monitored with echocardiography. The association of RBL2 genetic variants with anthracycline cardiomyopathy was evaluated in the SJLIFE (St. Jude Lifetime Cohort Study) and CPNDS (Canadian Pharmacogenomics Network for Drug Safety) studies.
RESULTS: The loss of endogenous Rbl2 increased basal CDK2 activity in the mouse heart. Mice lacking Rbl2 were more sensitive to DOX-induced cardiotoxicity, as evidenced by rapid deterioration of heart function and loss of heart mass. The disruption of Rbl2 exacerbated DOX-induced mitochondrial damage and cardiomyocyte apoptosis. Mechanistically, Rbl2 deficiency enhanced CDK2-dependent activation of forkhead box O1 (FOXO1), leading to up-regulation of the proapoptotic protein Bim. The inhibition of CDK2 desensitized Rbl2-depleted cardiomyocytes to DOX. In wild-type cardiomyocytes, DOX exposure induced Rbl2 expression in a FOXO1-dependent manner. Importantly, the rs17800727 G allele of the human RBL2 gene was associated with reduced anthracycline cardiotoxicity in childhood cancer survivors.
CONCLUSIONS: Rbl2 is an endogenous CDK2 inhibitor in the heart and represses FOXO1-mediated proapoptotic gene expression. The loss of Rbl2 increases sensitivity to DOX-induced cardiotoxicity. Our findings suggest that RBL2 could be used as a biomarker to predict the risk of cardiotoxicity before the initiation of anthracycline-based chemotherapy.}, }
@article {pmid37396148, year = {2023}, author = {Yu, T and Wu, L and Qiu, J and Gilbert, PB}, title = {Robust joint modelling of left-censored longitudinal data and survival data with application to HIV vaccine studies.}, journal = {The annals of applied statistics}, volume = {17}, number = {2}, pages = {1017-1037}, pmid = {37396148}, issn = {1932-6157}, support = {UM1 AI068635/AI/NIAID NIH HHS/United States ; }, abstract = {In jointly modelling longitudinal and survival data, the longitudinal data may be complex in the sense that they may contain outliers and may be left censored. Motivated from an HIV vaccine study, we propose a robust method for joint models of longitudinal and survival data, where the outliers in longitudinal data are addressed using a multivariate t-distribution for b-outliers and using an M-estimator for e-outliers. We also propose a computationally efficient method for approximate likelihood inference. The proposed method is evaluated by simulation studies. Based on the proposed models and method, we analyze the HIV vaccine data and find a strong association between longitudinal biomarkers and the risk of HIV infection.}, }
@article {pmid37396147, year = {2023}, author = {Kang, C and Huang, Y}, title = {IDENTIFICATION OF IMMUNE RESPONSE COMBINATIONS ASSOCIATED WITH HETEROGENEOUS INFECTION RISK IN THE IMMUNE CORRELATES ANALYSIS OF HIV VACCINE STUDIES.}, journal = {The annals of applied statistics}, volume = {17}, number = {2}, pages = {1199-1219}, pmid = {37396147}, issn = {1932-6157}, support = {UM1 AI068635/AI/NIAID NIH HHS/United States ; }, abstract = {In HIV vaccine/prevention research, probing into the vaccine-induced immune responses that can help predict the risk of HIV infection provides valuable information for the development of vaccine regimens. Previous correlate analysis of the Thai vaccine trial aided the discovery of interesting immune correlates related to the risk of developing an HIV infection. The present study aimed to identify the combinations of immune responses associated with the heterogeneous infection risk. We explored a "change-plane" via combination of a subset of immune responses that could help separate vaccine recipients into two heterogeneous subgroups in terms of the association between immune responses and the risk of developing infection. Additionally, we developed a new variable selection algorithm through a penalized likelihood approach to investigate a parsimonious marker combination for the change-plane. The resulting marker combinations can serve as candidate correlates of protection and can be used for predicting the protective effect of the vaccine against HIV infection. The application of the proposed statistical approach to the Thai trial has been presented, wherein the marker combinations were explored among several immune responses and antigens.}, }
@article {pmid37394987, year = {2023}, author = {Karvonen, KA and Balay-Dustrude, E and Do, A and Bradford, MC and Phipps, A and Rosenberg, AR}, title = {Race, ethnicity, and experienced racism are associated with adverse physical and mental health outcomes among cancer survivors.}, journal = {Cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/cncr.34913}, pmid = {37394987}, issn = {1097-0142}, support = {T32 Grant 5T32AR7108-42/NH/NIH HHS/United States ; T32 Grant T32CA009351/NH/NIH HHS/United States ; }, abstract = {INTRODUCTION: Survivors of cancer are at risk for adverse mental and physical health outcomes. It is not well understood, however, how these outcomes are differentially experienced according to an individual's exposure to racism. This study sought to evaluate associations of race/ethnicity, and experiences of racism, with adverse health outcomes in survivors of cancer.
METHODS: Using the Behavioral Risk Factor Surveillance System database, data from 48,200 survivors between 2014 and 2020 were evaluated. Survey items included negative physical and emotional symptoms as a result of race-based treatment. Outcomes of interest included days of poor mental and physical health, activity limitations, depression, and inadequate sleep. Associations using prevalence ratios were evaluated.
RESULTS: All historically marginalized racial/ethnic groups were more likely to experience at least one adverse health outcome compared with non-Hispanic White survivors. Those who physically experienced racism were 2.1 (95% CI, 1.64-2.69) times as likely to report poor physical health, 3.51 (95% CI, 2.61-4.71) times as likely to report poor mental health, 2.14 (95% CI, 1.77-2.58) times as likely to report inadequate sleep, 2.33 (95% CI: 1.91-2.83) times as likely to report depression, and 1.42 (95% CI, 1.04-1.93) times as likely to report activity limitations compared with those who have not experienced racism. Similar associations were observed for emotionally experienced racism.
DISCUSSION: Racial inequities in health outcomes for survivors of cancer from marginalized racial/ethnic groups are well-established. Experienced racism contributes to adverse health outcomes and widens these disparities. Improving outcomes for survivors of cancer may require screening for experienced racism.
PLAIN LANGUAGE SUMMARY: Survivors of cancer from marginalized racial/ethnic populations are more likely to have poor mental and physical health than their non-Hispanic White counterparts. Whether survivors from certain racial/ethnic populations of smaller size also have poorer health is less well understood. Generally, individuals who report experienced racism also report poor health, this association has not been studied in survivors of cancer. This study, from a national survey of survivors of cancer, describes disparities in health outcomes experienced by a variety of racial and ethnic populations. Our findings suggest racism is associated with poor mental and physical health in survivors of cancer.}, }
@article {pmid37394512, year = {2023}, author = {Goldman, JL and Kalu, IC and Schuster, JE and Erickson, T and Mast, DK and Zimmerman, K and Benjamin, DK and Kalb, LG and Gurnett, C and Newland, JG and Sherby, M and Godambe, M and Shinde, N and Watterson, T and Walsh, T and Foxe, J and Zand, M and Dewhurst, S and Coller, R and DeMuri, GP and Archuleta, S and Ko, LK and Inkelas, M and Manuel, V and Lee, R and Oh, H and Murugan, V and Kramer, J and Okihiro, M and Gwynn, L and Pulgaron, E and McCulloh, R and Broadhurst, J and McDaniels-Davidson, C and Kiene, S and Oren, E and Wu, Y and Wetter, DW and Stump, T and Brookhart, MA and Fist, A and Haroz, E}, title = {Building School-Academic Partnerships to Implement COVID-19 Testing in Underserved Populations.}, journal = {Pediatrics}, volume = {152}, number = {Suppl 1}, pages = {}, pmid = {37394512}, issn = {1098-4275}, abstract = {OBJECTIVE: In April 2021, the US government made substantial investments in students' safe return to school by providing resources for school-based coronavirus disease 2019 (COVID-19) mitigation strategies, including COVID-19 diagnostic testing. However, testing uptake and access among vulnerable children and children with medical complexities remained unclear.
METHODS: The Rapid Acceleration of Diagnostics Underserved Populations program was established by the National Institutes of Health to implement and evaluate COVID-19 testing programs in underserved populations. Researchers partnered with schools to implement COVID-19 testing programs. The authors of this study evaluated COVID-19 testing program implementation and enrollment and sought to determine key implementation strategies. A modified Nominal Group Technique was used to survey program leads to identify and rank testing strategies to provide a consensus of high-priority strategies for infectious disease testing in schools for vulnerable children and children with medical complexities.
RESULTS: Among the 11 programs responding to the survey, 4 (36%) included prekindergarten and early care education, 8 (73%) worked with socioeconomically disadvantaged populations, and 4 focused on children with developmental disabilities. A total of 81 916 COVID-19 tests were performed. "Adapting testing strategies to meet the needs, preferences, and changing guidelines," "holding regular meetings with school leadership and staff," and "assessing and responding to community needs" were identified as key implementation strategies by program leads.
CONCLUSIONS: School-academic partnerships helped provide COVID-19 testing in vulnerable children and children with medical complexities using approaches that met the needs of these populations. Additional work is needed to develop best practices for in-school infectious disease testing in all children.}, }
@article {pmid37394113, year = {2023}, author = {Liang, EC and Onstad, LE and Carpenter, P and Pergam, SA and Flowers, ME and Lee, SJ and Liu, C}, title = {Association of Self-Reported COVID-19 Vaccination Status with COVID-19 Infection Among Adult Long-Term Hematopoietic Cell Transplantation Survivors.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2023.06.017}, pmid = {37394113}, issn = {2666-6367}, abstract = {BACKGROUND: Hematopoietic cell transplantation (HCT) recipients experience significant morbidity and mortality from coronavirus disease 19 (COVID-19) infection. Data are limited regarding long-term HCT survivors' uptake of and experiences with COVID-19 vaccination and infection.
OBJECTIVE: To characterize COVID-19 vaccination uptake, use of other prevention measures, and COVID-19 infection outcomes in adult HCT recipients at our institution.
STUDY DESIGN: From July 1, 2021 to June 30, 2022, long-term adult HCT survivors were surveyed regarding overall health, chronic graft-versus-host (cGVHD) status, and experiences with COVID-19 vaccinations, prevention measures, and infections. Patient-reported COVID-19 vaccination status, vaccine-related adverse effects, use of non-pharmaceutical prevention measures, and infection. Comparisons by response and vaccination status were performed using Chi-square test and Fisher's exact test for categorical variables and Kruskal-Wallis test for continuous variables.
RESULTS: Of 4758 adult HCT survivors who underwent HCT from 1971-2021 and consented to receive annual surveys, 1719 (36%) completed the COVID-19 module. 1598/1705 (94%) reported receiving ≥1 dose of COVID-19 vaccine. Severe vaccine-related adverse effects were infrequent (5%). Among respondents receiving mRNA vaccine, completion of doses according to the Centers for Disease Control (CDC) vaccine recommendations at time of survey return was: 2 doses (675/759 [89%]); 3 (610/778 [78%]); 4 doses (26/55 [47%]). 250 (15%) respondents reported COVID-19 infection; 25 (10%) required hospitalization. Vaccinated respondents reported significantly higher uptake of household vaccination (1284/1404 [91%] vs. 18/88 [20%], p < 0.001) and use of non-pharmaceutical interventions (p < 0.001). Among those vaccinated prior to infection, vaccinated respondents were significantly less likely to have contracted COVID-19 (85/1480 [6%] vs. 130/190 [68%], p < 0.001) as were their household members (149/1451 [10%] vs. 85/185 [46%], p < 0.001). Receipt of additional COVID-19 vaccine doses beyond the first dose was associated with a reduced risk of COVID-19 infection (OR = 0.63, 95% CI, 0.47-0.85, p = 0.002).
CONCLUSIONS: Vaccination was well-tolerated and associated with a lower risk of COVID-19 infection among HCT survivors and their household contacts. Vaccination and booster doses should be encouraged as part of a multi-faceted approach in this high-risk population.}, }
@article {pmid37392736, year = {2023}, author = {Evrard, M and Becht, E and Fonseca, R and Obers, A and Park, SL and Ghabdan-Zanluqui, N and Schroeder, J and Christo, SN and Schienstock, D and Lai, J and Burn, TN and Clatch, A and House, IG and Beavis, P and Kallies, A and Ginhoux, F and Mueller, SN and Gottardo, R and Newell, EW and Mackay, LK}, title = {Single-cell protein expression profiling resolves circulating and resident memory T cell diversity across tissues and infection contexts.}, journal = {Immunity}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.immuni.2023.06.005}, pmid = {37392736}, issn = {1097-4180}, abstract = {Memory CD8[+] T cells can be broadly divided into circulating (TCIRCM) and tissue-resident memory T (TRM) populations. Despite well-defined migratory and transcriptional differences, the phenotypic and functional delineation of TCIRCM and TRM cells, particularly across tissues, remains elusive. Here, we utilized an antibody screening platform and machine learning prediction pipeline (InfinityFlow) to profile >200 proteins in TCIRCM and TRM cells in solid organs and barrier locations. High-dimensional analyses revealed unappreciated heterogeneity within TCIRCM and TRM cell lineages across nine different organs after either local or systemic murine infection models. Additionally, we demonstrated the relative effectiveness of strategies allowing for the selective ablation of TCIRCM or TRM populations across organs and identified CD55, KLRG1, CXCR6, and CD38 as stable markers for characterizing memory T cell function during inflammation. Together, these data and analytical framework provide an in-depth resource for memory T cell classification in both steady-state and inflammatory conditions.}, }
@article {pmid37392271, year = {2023}, author = {Silhol, R and Nordsletten, A and Maheu-Giroux, M and Elmes, J and Staunton, R and Owen, B and Shacklett, B and McGowan, I and Feliciano, KG and van der Straten, A and Eller, LA and Robb, M and Marrazzo, J and Dimitrov, D and Boily, MC}, title = {The Association Between Heterosexual anal Intercourse and HIV Acquisition in Three Prospective Cohorts of Women.}, journal = {AIDS and behavior}, volume = {}, number = {}, pages = {}, pmid = {37392271}, issn = {1573-3254}, support = {MR/R015600/1/MRC_/Medical Research Council/United Kingdom ; R01AI057020 and UM1AI068619/NH/NIH HHS/United States ; }, abstract = {The extent to which receptive anal intercourse (RAI) increases the HIV acquisition risk of women compared to receptive vaginal intercourse (RVI) is poorly understood. We evaluated RAI practice over time and its association with HIV incidence during three prospective HIV cohorts of women: RV217, MTN-003 (VOICE), and HVTN 907. At baseline, 16% (RV 217), 18% (VOICE) of women reported RAI in the past 3 months and 27% (HVTN 907) in the past 6 months, with RAI declining during follow-up by around 3-fold. HIV incidence in the three cohorts was positively associated with reporting RAI at baseline, albeit not always significantly. The adjusted hazard rate ratios for potential confounders (aHR) were 1.1 (95% Confidence interval: 0.8-1.5) for VOICE and 3.3 (1.6-6.8) for RV 217, whereas the ratio of cumulative HIV incidence by RAI practice was 1.9 (0.6-6.0) for HVTN 907. For VOICE, the estimated magnitude of association increased slightly when using a time-varying RAI exposure definition (aHR = 1.2; 0.9-1.6), and for women reporting RAI at every follow-up survey (aHR = 2.0 (1.3-3.1)), though not for women reporting higher RAI frequency (> 30% acts being RAI vs. no RAI in the past 3 months; aHR = 0.7 (0.4-1.1)). Findings indicated precise estimation of the RAI/HIV association, following multiple RVI/RAI exposures, is sensitive to RAI exposure definition, which remain imperfectly measured. Information on RAI practices, RAI/RVI frequency, and condom use should be more systematically and precisely recorded and reported in studies looking at sexual behaviors and HIV seroconversions; standardized measures would aid comparability across geographies and over time.}, }
@article {pmid37392268, year = {2023}, author = {Young, AM and Mancuso, N and Atujuna, M and Tenza, S and Chitukuta, M and Kemigisha, D and Ngure, K and van der Straten, A and Garcia, M and Szydlo, D and Soto-Torres, L and Roberts, ST}, title = {Adolescent Girls and Young Women's Experiences with Disclosing Oral PrEP or Dapivirine Vaginal Ring Use: a Multi-Country Qualitative Analysis.}, journal = {AIDS and behavior}, volume = {}, number = {}, pages = {}, pmid = {37392268}, issn = {1573-3254}, support = {UM1AI068633//National Institute of Allergy and Infectious Diseases/ ; UM1AI068615//National Institute of Allergy and Infectious Diseases/ ; UM1AI106707//National Institute of Allergy and Infectious Diseases/ ; }, abstract = {Effective use of oral pre-exposure prophylaxis (PrEP) has been low among adolescent girls and young women (AGYW) in Eastern and Southern Africa, partly due to stigma and opposition from key influencers. Understanding AGYW's experiences of disclosure of different PrEP modalities to key influencers may inform strategies to motivate uptake and adherence. We analyzed qualitative in-depth interviews and focus group discussions data from 119 participants in the MTN-034/REACH (Reversing the Epidemic in Africa with Choices in HIV Prevention) study of oral PrEP and the dapivirine vaginal ring (ring) to explore AGYW's disclosure experiences. We found that AGYW disclosure experiences varied across influencers and product type. The ring was disclosed less often to most influencers, except partners, because it was discreet. Oral PrEP was disclosed more often, because pills were more common and to avoid HIV stigma given that oral PrEP resembled HIV treatment. Ultimately, disclosure typically led most key influencers to support product use through reminders and encouragement. While disclosure yielded positive support from influencers, further community awareness of both PrEP products is essential to reduce potential opposition and perceived stigma.Clinical Trial Number: NCT03593655.}, }
@article {pmid37392020, year = {2023}, author = {Prudden, HJ and Tatoud, R and Janes, H and Wallace, S and Miller, V and Bekker, LG and Donnell, D}, title = {Perspectives on Design Approaches for HIV Prevention Efficacy Trials.}, journal = {AIDS research and human retroviruses}, volume = {}, number = {}, pages = {}, doi = {10.1089/AID.2022.0150}, pmid = {37392020}, issn = {1931-8405}, abstract = {The challenge of designing future HIV prevention efficacy trials in a rapidly evolving HIV prevention landscape was explored through a series of virtual stakeholder's engagement meetings convened online between October 2020 and April 2021. A broad array of stakeholders from the HIV prevention research community reviewed current trial designs and lessons learned, explored issues specific to unique product classes, and concluded with specialist-focused examinations of statistical design concepts and the importance of community engagement in research. The aim was to reflect on current approaches and evaluate new trial design approaches for evaluating efficacy of a candidate prevention strategy in the context of an active-controlled trial, which does not include a placebo arm. Here, we provide a summary of the discussion points that included gaps in understanding and logical next steps in the prevention research pathway. The technical challenges involved in the statistical design approaches are described in a companion paper.}, }
@article {pmid37391114, year = {2023}, author = {Babu, TM and Wald, A and Restar, AJ}, title = {Health equity necessitates the inclusion of gender identity data in COVID-19 clinical trials.}, journal = {Annals of epidemiology}, volume = {}, number = {}, pages = {}, pmid = {37391114}, issn = {1873-2585}, abstract = {COVID-19 has highlighted the importance of studying differences by sex and gender. The underreporting of gender identity in COVID-19 studies limits the generalizability of study results to nonbinary persons. Some of the data on sex-assigned associated complications of both COVID-19 infection and COVID-19 immunizations is presented in this manuscript.}, }
@article {pmid37391005, year = {2023}, author = {Roxby, AC and Mugo, NR and Oluoch, LM and Tapia, K and Wang, M and Selke, S and Chohan, B and Micheni, M and Sycuro, L and Yuh, T and Casmir, E and Kimani, E and Maina, SG and Kiptinness, C and Ngure, K and Wald, A}, title = {Low prevalence of bacterial vaginosis in Kenyan adolescent girls, and rapid incidence after first sex.}, journal = {American journal of obstetrics and gynecology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ajog.2023.06.044}, pmid = {37391005}, issn = {1097-6868}, abstract = {BACKGROUND: Bacterial vaginosis (BV) is a risk factor for sexually transmitted infections (STI) including HIV. Adult African women have high prevalence of BV, but it is not known when first BV occurs.
OBJECTIVES: We sought to describe BV in younger African women, before and after first sex, and to determine incidence of BV and significant correlates of BV incidence and recurrence.
STUDY DESIGN: In a prospective observational cohort study enrolling adolescents with limited sexual experience, young women ages 16-21 were recruited in Thika, Kenya. Eligible participants were HIV and HSV-2 seronegative and reported zero or one lifetime sexual partner. Nugent score was determined at quarterly visits from vaginal Gram stains. Trends in BV were described over time; hazard ratios were calculated using Cox regression and relative risk of BV was estimated using generalized estimating equations and Poisson regression.
RESULTS: We enrolled 400 participants with a median age of 18.6 years (IQR 16-21). The majority (322, 80.5%) reported no history of sex, while 78 (19.5%) reported sex with 1 partner. At enrollment, BV (Nugent score ≥7) was uncommon (21 of 375, 5.6%). Overall, 144 participants had BV at least once, for an incidence rate of 16.5 cases per 100 person-years. Prior to first sex, BV was present at 2.8% of visits, compared to 13.7% of visits post-first sex. An adjusted model of BV incidence observed that first sex was associated with more than twofold increased BV risk (aHR 2.44, p=0.009, CI 1.25-4.76). Chlamydia diagnosis (aHR 1.73, p=0.02, CI 1.1-2.8) and HSV-2 seropositivity (aHR 2.88, p=0.021, CI 1.17-7.09) were both associated with incident BV. A multivariate GEE model including all episodes of BV demonstrated risk factors including first sex, STIs, urban residence, recent sex and no income; the most important risk factor was first sex (aRR 1.92, p=0.018, CI 1.12-3.31). Probability of BV increased with each subsequent episode; mean Nugent scores increased after each BV episode.
CONCLUSIONS: Using detailed longitudinal observation, we found that Kenyan adolescents have almost no BV prior to first sex, and that initiation of sexual activity was the strongest risk factor for both prevalent and incident BV.}, }
@article {pmid37390387, year = {2023}, author = {Farrar, JE and Othus, M and Wang, YC and Alonzo, TA and Meshinchi, S}, title = {Reply to Z.R. McCaw et al.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {}, number = {}, pages = {JCO2300986}, doi = {10.1200/JCO.23.00986}, pmid = {37390387}, issn = {1527-7755}, }
@article {pmid37211266, year = {2023}, author = {Hanna, M and Dey, N and Grady, WM}, title = {Reply.}, journal = {Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.cgh.2023.05.012}, pmid = {37211266}, issn = {1542-7714}, }
@article {pmid37388413, year = {2023}, author = {April-Sanders, AK and Daviglus, ML and Lee, UJ and Perreira, KM and Kaplan, RC and Blaha, MJ and Pirzada, A and Giachello, AL and Bhatnagar, A and Robertson, RM and Thanh-Huyen, TV and Rodriguez, CJ}, title = {Prevalence of electronic cigarette use and its determinants in us persons of Hispanic/Latino background: The Hispanic community health study / study of Latinos (HCHS/SOL).}, journal = {American journal of medicine open}, volume = {9}, number = {}, pages = {}, pmid = {37388413}, issn = {2667-0364}, support = {R03 HL144902/HL/NHLBI NIH HHS/United States ; }, abstract = {OBJECTIVE: To determine the prevalence and determinants of electronic nicotine delivery systems (ENDS) use among Hispanic/Latino adults from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL).
METHODS: Cross-sectional data collected between the years 2015-2017 were analyzed to assess ENDS use (ever (current: use ≤ past 30 days; former: use > past 30 days) and never) among 11,623 adults (mean age 47 years±0.3 years; 52% women). Weighted prevalence estimates were reported, and age-adjusted logistic regression models were used to examine associations between sociodemographic and clinical exposures with ENDS use.
RESULTS: The prevalence of current and former ENDS use was 2.0% and 10.4%, respectively. Having ever used ENDS was associated with prevalent coronary artery disease. Current ENDS use was higher in males and associated with higher education, English language preference, and Puerto Rican background compared with nonsmokers and cigarette-only smokers (all p<0.05).
CONCLUSIONS: Hispanic/Latino individuals who are young adults, male, US-born, and have high acculturation were more likely to report current ENDS use. These findings could inform preventive and regulatory interventions targeted to Hispanics/Latinos.}, }
@article {pmid37388275, year = {2023}, author = {Lees, WD and Christley, S and Peres, A and Kos, JT and Corrie, B and Ralph, D and Breden, F and Cowell, LG and Yaari, G and Corcoran, M and Karlsson Hedestam, GB and Ohlin, M and Collins, AM and Watson, CT and Busse, CE and , }, title = {AIRR community curation and standardised representation for immunoglobulin and T cell receptor germline sets.}, journal = {Immunoinformatics (Amsterdam, Netherlands)}, volume = {10}, number = {}, pages = {}, pmid = {37388275}, issn = {2667-1190}, support = {R24 AI138963/AI/NIAID NIH HHS/United States ; }, abstract = {Analysis of an individual's immunoglobulin or T cell receptor gene repertoire can provide important insights into immune function. High-quality analysis of adaptive immune receptor repertoire sequencing data depends upon accurate and relatively complete germline sets, but current sets are known to be incomplete. Established processes for the review and systematic naming of receptor germline genes and alleles require specific evidence and data types, but the discovery landscape is rapidly changing. To exploit the potential of emerging data, and to provide the field with improved state-of-the-art germline sets, an intermediate approach is needed that will allow the rapid publication of consolidated sets derived from these emerging sources. These sets must use a consistent naming scheme and allow refinement and consolidation into genes as new information emerges. Name changes should be minimised, but, where changes occur, the naming history of a sequence must be traceable. Here we outline the current issues and opportunities for the curation of germline IG/TR genes and present a forward-looking data model for building out more robust germline sets that can dovetail with current established processes. We describe interoperability standards for germline sets, and an approach to transparency based on principles of findability, accessibility, interoperability, and reusability.}, }
@article {pmid37388194, year = {2023}, author = {McCoy, BM and Brassington, L and Jin, K and Dolby, GA and Shrager, S and Collins, D and Dunbar, M and , and Ruple, A and Snyder-Mackler, N}, title = {Social determinants of health and disease in companion dogs: a cohort study from the Dog Aging Project.}, journal = {Evolution, medicine, and public health}, volume = {11}, number = {1}, pages = {187-201}, pmid = {37388194}, issn = {2050-6201}, abstract = {Exposure to social environmental adversity is associated with health and survival across many social species, including humans. However, little is known about how these health and mortality effects vary across the lifespan and may be differentially impacted by various components of the environment. Here, we leveraged a relatively new and powerful model for human aging, the companion dog, to investigate which components of the social environment are associated with dog health and how these associations vary across the lifespan. We drew on comprehensive survey data collected on 21,410 dogs from the Dog Aging Project and identified five factors that together explained 33.7% of the variation in a dog's social environment. Factors capturing financial and household adversity were associated with poorer health and lower physical mobility in companion dogs, while factors that captured social support, such as living with other dogs, were associated with better health when controlling for dog age and weight. Notably, the effects of each environmental component were not equal: the effect of social support was 5× stronger than financial factors. The strength of these associations depended on the age of the dog, including a stronger relationship between the owner's age and the dog's health in younger as compared to older dogs. Taken together, these findings suggest the importance of income, stability and owner's age on owner-reported health outcomes in companion dogs and point to potential behavioral and/or environmental modifiers that can be used to promote healthy aging across species.}, }
@article {pmid37386298, year = {2023}, author = {Dominguez-Sola, D and Ying, CY and Grandori, C and Ruggiero, L and Chen, B and Li, M and Galloway, DA and Gu, W and Gautier, J and Dalla-Favera, R}, title = {Author Correction: Non-transcriptional control of DNA replication by c-Myc.}, journal = {Nature}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41586-023-06284-1}, pmid = {37386298}, issn = {1476-4687}, }
@article {pmid37385888, year = {2023}, author = {Turley, CB and Tables, L and Fuller, T and Sanders, LJ and Scott, H and Moodley, A and Woodward Davis, A and Leav, B and Miller, J and Schoemaker, K and Vandebosch, A and Sadoff, J and Woo, W and Cho, I and Dunkle, LM and Li, S and van der Laan, L and Gilbert, PB and Follmann, D and Jaynes, H and Kublin, JG and Baden, LR and Goepfert, P and Kotloff, K and Gay, CL 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 Rouphael, N and Luedtke, A and , }, title = {Modifiers of COVID-19 vaccine efficacy: Results from four COVID-19 prevention network efficacy trials.}, journal = {Vaccine}, volume = {}, number = {}, pages = {}, pmid = {37385888}, issn = {1873-2518}, abstract = {Questions remain regarding the effect of baseline host and exposure factors on vaccine efficacy (VE) across pathogens and vaccine platforms. We report placebo-controlled data from four Phase 3 COVID-19 trials during the early period of the pandemic. This was a cross-protocol analysis of four randomized, placebo-controlled efficacy trials (Moderna/mRNA1273, AstraZeneca/AZD1222, Janssen/Ad26.COV2.S, and Novavax/NVX-CoV2373) using a harmonized design. Trials were conducted in the United States and international sites in adults ≥ 18 years of age. VE was assessed for symptomatic and severe COVID-19. We analyzed 114,480 participants from both placebo and vaccine arms, enrolled July 2020 to February 2021, with follow up through July 2021. VE against symptomatic COVID-19 showed little heterogeneity across baseline socio-demographic, clinical or exposure characteristics, in either univariate or multivariate analysis, regardless of vaccine platform. Similarly, VE against severe COVID-19 in the single trial (Janssen) with sufficient endpoints for analysis showed little evidence of heterogeneity. COVID-19 VE is not influenced by baseline host or exposure characteristics across efficacy trials of different vaccine platforms and countries when well matched to circulating virus strains. This supports use of these vaccines, regardless of platform type, as effective tools in the near term for reducing symptomatic and severe COVID-19, particularly for older individuals and those with common co-morbidities during major variant shifts. Clinical trial registration numbers: NCT04470427, NCT04516746, NCT04505722, and NCT04611802.}, }
@article {pmid37385724, year = {2023}, author = {Coveler, AL and Smith, DC and Phillips, T and Curti, BD and Goel, S and Mehta, AN and Kuzel, TM and Markovic, SN and Rixe, O and Bajor, DL and Gajewski, TF and Gutierrez, M and Lee, HJ and Gopal, AK and Caimi, P and Heath, EI and Thompson, JA and Ansari, S and Jacquemont, C and Topletz-Erickson, A and Zhou, P and Schmitt, MW and Grilley-Olson, JE}, title = {Phase 1 dose-escalation study of SEA-CD40: a non-fucosylated CD40 agonist, in advanced solid tumors and lymphomas.}, journal = {Journal for immunotherapy of cancer}, volume = {11}, number = {6}, pages = {}, doi = {10.1136/jitc-2022-005584}, pmid = {37385724}, issn = {2051-1426}, abstract = {BACKGROUND: SEA-CD40 is an investigational, non-fucosylated, humanized monoclonal IgG1 antibody that activates CD40, an immune-activating tumor necrosis factor receptor superfamily member. SEA-CD40 exhibits enhanced binding to activating FcγRIIIa, possibly enabling greater immune stimulation than other CD40 agonists. A first-in-human phase 1 trial was conducted to examine safety, pharmacokinetics, and pharmacodynamics of SEA-CD40 monotherapy in patients with advanced solid tumors and lymphoma.
METHODS: SEA-CD40 was administered intravenously to patients with solid tumors or lymphoma in 21-day cycles with standard 3+3 dose escalation at 0.6, 3, 10, 30, 45, and 60 µg/kg. An intensified dosing regimen was also studied. The primary objectives of the study were to evaluate the safety and tolerability and identify the maximum tolerated dose of SEA-CD40. Secondary objectives included evaluation of the pharmacokinetic parameters, antitherapeutic antibodies, pharmacodynamic effects and biomarker response, and antitumor activity.
RESULTS: A total of 67 patients received SEA-CD40 including 56 patients with solid tumors and 11 patients with lymphoma. A manageable safety profile was observed, with predominant adverse events of infusion/hypersensitivity reactions (IHRs) reported in 73% of patients. IHRs were primarily ≤grade 2 with an incidence associated with infusion rate. To mitigate IHRs, a standardized infusion approach was implemented with routine premedication and a slowed infusion rate. SEA-CD40 infusion resulted in potent immune activation, illustrated by dose dependent cytokine induction with associated activation and trafficking of innate and adaptive immune cells. Results suggested that doses of 10-30 µg/kg may result in optimal immune activation. SEA-CD40 monotherapy exhibited evidence of antitumor activity, with a partial response in a patient with basal cell carcinoma and a complete response in a patient with follicular lymphoma.
CONCLUSIONS: SEA-CD40 was tolerable as monotherapy and induced potent dose dependent immune cell activation and trafficking consistent with immune activation. Evidence of monotherapy antitumor activity was observed in patients with solid tumors and lymphoma. Further evaluation of SEA-CD40 is warranted, potentially as a component of a combination regimen.
TRIAL REGISTRATION NUMBER: NCT02376699.}, }
@article {pmid37384864, year = {2023}, author = {Bailey, CN and Martin, BJ and Petkov, VI and Schussler, NC and Stevens, JL and Bentler, S and Cress, RD and Doherty, JA and Durbin, EB and Gomez, SL and Gonsalves, L and Hernandez, BY and Liu, L and Morawski, BM and Schymura, MJ and Schwartz, SM and Ward, KC and Wiggins, C and Wu, XC and Goldberg, MS and Siegel, JJ and Cook, RW and Covington, KR and Kurley, SJ}, title = {31-Gene Expression Profile Testing in Cutaneous Melanoma and Survival Outcomes in a Population-Based Analysis: A SEER Collaboration.}, journal = {JCO precision oncology}, volume = {7}, number = {}, pages = {e2300044}, doi = {10.1200/PO.23.00044}, pmid = {37384864}, issn = {2473-4284}, abstract = {PURPOSE: The DecisionDx-Melanoma 31-gene expression profile (31-GEP) test is validated to classify cutaneous malignant melanoma (CM) patient risk of recurrence, metastasis, or death as low (class 1A), intermediate (class 1B/2A), or high (class 2B). This study aimed to examine the effect of 31-GEP testing on survival outcomes and confirm the prognostic ability of the 31-GEP at the population level.
METHODS: Patients with stage I-III CM with a clinical 31-GEP result between 2016 and 2018 were linked to data from 17 SEER registries (n = 4,687) following registries' operation procedures for linkages. Melanoma-specific survival (MSS) and overall survival (OS) differences by 31-GEP risk category were examined using Kaplan-Meier analysis and the log-rank test. Crude and adjusted hazard ratios (HRs) were calculated using Cox regression model to evaluate variables associated with survival. 31-GEP tested patients were propensity score-matched to a cohort of non-31-GEP tested patients from the SEER database. Robustness of the effect of 31-GEP testing was assessed using resampling.
RESULTS: Patients with a 31-GEP class 1A result had higher 3-year MSS and OS than patients with a class 1B/2A or class 2B result (MSS: 99.7% v 97.1% v 89.6%, P < .001; OS: 96.6% v 90.2% v 79.4%, P < .001). A class 2B result was an independent predictor of MSS (HR, 7.00; 95% CI, 2.70 to 18.00) and OS (HR, 2.39; 95% CI, 1.54 to 3.70). 31-GEP testing was associated with a 29% lower MSS mortality (HR, 0.71; 95% CI, 0.53 to 0.94) and 17% lower overall mortality (HR, 0.83; 95% CI, 0.70 to 0.99) relative to untested patients.
CONCLUSION: In a population-based, clinically tested melanoma cohort, the 31-GEP stratified patients by their risk of dying from melanoma.}, }
@article {pmid37384759, year = {2023}, author = {Mkhize, NN and Yssel, A and Kaldine, H and van Dorsten, RT and Woodward Davis, AS and Beaume, N and Matten, D and Lambson, B and Modise, T and Kgagudi, P and York, T and Westfall, DH and Giorgi, EE and Korber, B and Anthony, C and Mapengo, RE and Bekker, V and Domin, E and Eaton, A and Deng, W and DeCamp, A and Huang, Y and Gilbert, PB and Gwashu-Nyangiwe, A and Thebus, R and Ndabambi, N and Mielke, D and Mgodi, N and Karuna, S and Edupuganti, S and Seaman, MS and Corey, L and Cohen, MS and Hural, J and McElrath, MJ and Mullins, JI and Montefiori, D and Moore, PL and Williamson, C and Morris, L}, title = {Neutralization profiles of HIV-1 viruses from the VRC01 Antibody Mediated Prevention (AMP) trials.}, journal = {PLoS pathogens}, volume = {19}, number = {6}, pages = {e1011469}, doi = {10.1371/journal.ppat.1011469}, pmid = {37384759}, issn = {1553-7374}, abstract = {The VRC01 Antibody Mediated Prevention (AMP) efficacy trials conducted between 2016 and 2020 showed for the first time that passively administered broadly neutralizing antibodies (bnAbs) could prevent HIV-1 acquisition against bnAb-sensitive viruses. HIV-1 viruses isolated from AMP participants who acquired infection during the study in the sub-Saharan African (HVTN 703/HPTN 081) and the Americas/European (HVTN 704/HPTN 085) trials represent a panel of currently circulating strains of HIV-1 and offer a unique opportunity to investigate the sensitivity of the virus to broadly neutralizing antibodies (bnAbs) being considered for clinical development. Pseudoviruses were constructed using envelope sequences from 218 individuals. The majority of viruses identified were clade B and C; with clades A, D, F and G and recombinants AC and BF detected at lower frequencies. We tested eight bnAbs in clinical development (VRC01, VRC07-523LS, 3BNC117, CAP256.25, PGDM1400, PGT121, 10-1074 and 10E8v4) for neutralization against all AMP placebo viruses (n = 76). Compared to older clade C viruses (1998-2010), the HVTN703/HPTN081 clade C viruses showed increased resistance to VRC07-523LS and CAP256.25. At a concentration of 1μg/ml (IC80), predictive modeling identified the triple combination of V3/V2-glycan/CD4bs-targeting bnAbs (10-1074/PGDM1400/VRC07-523LS) as the best against clade C viruses and a combination of MPER/V3/CD4bs-targeting bnAbs (10E8v4/10-1074/VRC07-523LS) as the best against clade B viruses, due to low coverage of V2-glycan directed bnAbs against clade B viruses. Overall, the AMP placebo viruses represent a valuable resource for defining the sensitivity of contemporaneous circulating viral strains to bnAbs and highlight the need to update reference panels regularly. Our data also suggests that combining bnAbs in passive immunization trials would improve coverage of global viruses.}, }
@article {pmid37384599, year = {2023}, author = {Sun, B and Kim, H and Mello, CC and Priess, JR}, title = {The CERV protein of Cer1, a C. elegans LTR retrotransposon, is required for nuclear export of viral genomic RNA and can form giant nuclear rods.}, journal = {PLoS genetics}, volume = {19}, number = {6}, pages = {e1010804}, pmid = {37384599}, issn = {1553-7404}, abstract = {Retroviruses and closely related LTR retrotransposons export full-length, unspliced genomic RNA (gRNA) for packaging into virions and to serve as the mRNA encoding GAG and POL polyproteins. Because gRNA often includes splice acceptor and donor sequences used to splice viral mRNAs, retroelements must overcome host mechanisms that retain intron-containing RNAs in the nucleus. Here we examine gRNA expression in Cer1, an LTR retrotransposon in C. elegans which somehow avoids silencing and is highly expressed in germ cells. Newly exported Cer1 gRNA associates rapidly with the Cer1 GAG protein, which has structural similarity with retroviral GAG proteins. gRNA export requires CERV (C. elegans regulator of viral expression), a novel protein encoded by a spliced Cer1 mRNA. CERV phosphorylation at S214 is essential for gRNA export, and phosphorylated CERV colocalizes with nuclear gRNA at presumptive sites of transcription. By electron microscopy, tagged CERV proteins surround clusters of distinct, linear fibrils that likely represent gRNA molecules. Single fibrils, or groups of aligned fibrils, also localize near nuclear pores. During the C. elegans self-fertile period, when hermaphrodites fertilize oocytes with their own sperm, CERV concentrates in two nuclear foci that are coincident with gRNA. However, as hermaphrodites cease self-fertilization, and can only produce cross-progeny, CERV undergoes a remarkable transition to form giant nuclear rods or cylinders that can be up to 5 microns in length. We propose a novel mechanism of rod formation, in which stage-specific changes in the nucleolus induce CERV to localize to the nucleolar periphery in flattened streaks of protein and gRNA; these streaks then roll up into cylinders. The rods are a widespread feature of Cer1 in wild strains of C. elegans, but their function is not known and might be limited to cross-progeny. We speculate that the adaptive strategy Cer1 uses for the identical self-progeny of a host hermaphrodite might differ for heterozygous cross-progeny sired by males. For example, mating introduces male chromosomes which can have different, or no, Cer1 elements.}, }
@article {pmid37383986, year = {2023}, author = {Tisoncik-Go, J and Voss, KM and Lewis, TB and Muruato, AE and Kuller, L and Finn, EE and Betancourt, D and Wangari, S and Ahrens, J and Iwayama, N and Grant, RF and Murnane, RD and Edlefsen, PT and Fuller, DH and Barber, GN and Gale, M and O'Connor, MA}, title = {Evaluation of the immunogenicity and efficacy of an rVSV vaccine against Zika virus infection in macaca nemestrina.}, journal = {Frontiers in virology}, volume = {3}, number = {}, pages = {}, pmid = {37383986}, issn = {2673-818X}, abstract = {Zika virus (ZIKV) is a mosquito-borne flavivirus that causes an acute febrile illness. ZIKV can be transmitted between sexual partners and from mother to fetus. Infection is strongly associated with neurologic complications in adults, including Guillain-Barré syndrome and myelitis, and congenital ZIKV infection can result in fetal injury and congenital Zika syndrome (CZS). Development of an effective vaccine is imperative to protect against ZIKV vertical transmission and CZS. Recombinant Vesicular Stomatitis virus (rVSV) is a highly effective and safe vector for the delivery of foreign immunogens for vaccine purposes. Here, we evaluate an rVSV vaccine expressing the full length pre-membrane (prM) and ZIKV envelope (E) proteins (VSV-ZprME), shown to be immunogenic in murine models of ZIKV infection, for its capacity to induce immune responses in nonhuman primates. Moreover, we assess the efficacy of the rVSVΔM-ZprME vaccine in the protection of pigtail macaques against ZIKV infection. Administration of the rVSVΔM-ZprME vaccine was safe, but it did not induce robust anti-ZIKV T-cell responses, IgM or IgG antibodies, or neutralizing antibodies in most animals. Post ZIKV challenge, animals that received the rVSVΔM control vaccine lacking ZIKV antigen had higher levels of plasma viremia compared to animals that received the rVSVΔM-ZprME vaccine. Anti-ZIKV neutralizing Ab titers were detected in a single animal that received the rVSVΔM-ZprME vaccine that was associated with reduced plasma viremia. The overall suboptimal ZIKV-specific cellular and humoral responses post-immunization indicates the rVSVΔM-ZprME vaccine did not elicit an immune response in this pilot study. However, recall antibody response to the rVSVΔM-ZprME vaccine indicates it may be immunogenic and further developments to the vaccine construct could enhance its potential as a vaccine candidate in a nonhuman primate pre-clinical model.}, }
@article {pmid37383248, year = {2023}, author = {Liu, C and Yoke, LH and Bhattacharyya, P and Cassaday, RD and Cheng, GS and Escobar, ZK and Ghiuzeli, C and McCulloch, DJ and Pergam, SA and Roychoudhury, P and Tverdek, F and Schiffer, JT and Ford, ES}, title = {Successful Treatment of Persistent Symptomatic Coronavirus Disease 19 Infection With Extended-Duration Nirmatrelvir-Ritonavir Among Outpatients With Hematologic Cancer.}, journal = {Open forum infectious diseases}, volume = {10}, number = {6}, pages = {ofad306}, pmid = {37383248}, issn = {2328-8957}, abstract = {Persistent symptomatic coronavirus disease 2019 (COVID-19) is a distinct clinical entity among patients with hematologic cancer and/or profound immunosuppression. The optimal medical management is unknown. We describe 2 patients who had symptomatic COVID-19 for almost 6 months and were successfully treated in the ambulatory setting with extended courses of nirmatrelvir-ritonavir.}, }
@article {pmid37383028, year = {2023}, author = {Lin, W and Zou, J and Di, C and Sears, DD and Rock, CL and Natarajan, L}, title = {Longitudinal Associations Between Timing of Physical Activity Accumulation and Health: Application of Functional Data Methods.}, journal = {Statistics in biosciences}, volume = {15}, number = {2}, pages = {309-329}, pmid = {37383028}, issn = {1867-1764}, abstract = {Accelerometers are widely used for tracking human movement and provide minute-level (or even 30 Hz level) physical activity (PA) records for detailed analysis. Instead of using day-level summary statistics to assess these densely sampled inputs, we implement functional principal component analysis (FPCA) approaches to study the temporal patterns of PA data from 245 overweight/obese women at three visits over a 1-year period. We apply longitudinal FPCA to decompose PA inputs, incorporating subject-specific variability, and then test the association between these patterns and obesity-related health outcomes by multiple mixed effect regression models. With the proposed methods, the longitudinal patterns in both densely sampled inputs and scalar outcomes are investigated and connected. The results show that the health outcomes are strongly associated with PA variation, in both subject and visit-level. In addition, we reveal that timing of PA during the day can impact changes in outcomes, a finding that would not be possible with day-level PA summaries. Thus, our findings imply that the use of longitudinal FPCA can elucidate temporal patterns of multiple levels of PA inputs. Furthermore, the exploration of the relationship between PA patterns and health outcomes can be useful for establishing weight-loss guidelines.}, }
@article {pmid37382423, year = {2023}, author = {Habibi, S and Rashidi, A}, title = {Fecal microbiota transplantation in hematopoietic cell transplant and cellular therapy recipients: lessons learned and the path forward.}, journal = {Gut microbes}, volume = {15}, number = {1}, pages = {2229567}, doi = {10.1080/19490976.2023.2229567}, pmid = {37382423}, issn = {1949-0984}, abstract = {Disruptions to the gut microbiota have been associated with adverse outcomes including graft-versus-host disease, infections, and mortality after hematopoietic cell transplantation and cellular therapy. Evidence for causal links is accumulating, thus supporting therapeutic interventions targeting the microbiota with the goal of preventing and treating adverse outcomes. One such intervention is fecal microbiota transplantation (FMT) by which an entire community of gut microbiota is transferred to the patient with dysbiosis. As this approach in transplant and cellular therapy recipients is still in its infancy, no best approach has been defined and many open questions need to be addressed before FMT becomes a standard treatment. In this review, we highlight microbiota-outcome associations with the highest level of evidence, provide an overview of the main FMT trials, and suggest some paths forward.}, }
@article {pmid37381676, year = {2023}, author = {Bacci, JL and Shah, PD and Arnold, J and Atkins, DL and Weiner, BJ}, title = {Readying Community Pharmacies to Participate in COVID-19 Testing and Vaccination.}, journal = {Disaster medicine and public health preparedness}, volume = {17}, number = {}, pages = {e424}, doi = {10.1017/dmp.2023.84}, pmid = {37381676}, issn = {1938-744X}, abstract = {OBJECTIVE: Washington State established a Memorandum of Understanding (MOU) and operational plan in 2012 to coordinate pharmacy infrastructure and workforce during a public health emergency. The objectives of this study were to adapt the MOU operational plan to the context of the coronavirus disease 2019 (COVID-19) pandemic and assess community pharmacies' organizational readiness to implement COVID-19 testing and vaccination.
METHODS: This mixed methods study was conducted June-August 2020. Three facilitated discussions were conducted with community pharmacists and local health jurisdiction (LHJ) representatives to test the MOU operational plan. Facilitated discussions were thematically analyzed to inform adaptations to the operational plan. Pharmacists were surveyed to assess their organization's readiness for COVID-19 testing and vaccination before and after the facilitated discussions using the Organizational Readiness for Implementing Change (ORIC) measure. Survey responses were analyzed using descriptive statistics.
RESULTS: Six pharmacists from 5 community pharmacy organizations and 4 representatives from 2 LHJs participated in at least 1 facilitated discussion. Facilitated discussions resulted in 3 themes and 16 adaptations to the operational plan. Five of 6 community pharmacists (83% response rate) completed both surveys. Mean organizational readiness decreased from baseline to follow-up for COVID-19 testing and vaccination.
CONCLUSIONS: Operational plan adaptations highlight opportunities to strengthen MOUs between local and state health departments and community pharmacies to support future emergency preparedness and readiness efforts.}, }
@article {pmid37380943, year = {2023}, author = {Obermayer, AN and Chang, D and Nobles, G and Teng, M and Tan, AC and Wang, X and Chen, YA and Eschrich, S and Rodriguez, PC and Grass, GD and Meshinchi, S and Tarhini, A and Chen, DT and Shaw, TI}, title = {PATH-SURVEYOR: pathway level survival enquiry for immuno-oncology and drug repurposing.}, journal = {BMC bioinformatics}, volume = {24}, number = {1}, pages = {266}, pmid = {37380943}, issn = {1471-2105}, support = {P30-CA076292/GF/NIH HHS/United States ; P30-CA076292/GF/NIH HHS/United States ; P30-CA076292/GF/NIH HHS/United States ; P30-CA076292/GF/NIH HHS/United States ; P30-CA076292/GF/NIH HHS/United States ; P30-CA076292/GF/NIH HHS/United States ; P30-CA076292/GF/NIH HHS/United States ; }, abstract = {Pathway-level survival analysis offers the opportunity to examine molecular pathways and immune signatures that influence patient outcomes. However, available survival analysis algorithms are limited in pathway-level function and lack a streamlined analytical process. Here we present a comprehensive pathway-level survival analysis suite, PATH-SURVEYOR, which includes a Shiny user interface with extensive features for systematic exploration of pathways and covariates in a Cox proportional-hazard model. Moreover, our framework offers an integrative strategy for performing Hazard Ratio ranked Gene Set Enrichment Analysis and pathway clustering. As an example, we applied our tool in a combined cohort of melanoma patients treated with checkpoint inhibition (ICI) and identified several immune populations and biomarkers predictive of ICI efficacy. We also analyzed gene expression data of pediatric acute myeloid leukemia (AML) and performed an inverse association of drug targets with the patient's clinical endpoint. Our analysis derived several drug targets in high-risk KMT2A-fusion-positive patients, which were then validated in AML cell lines in the Genomics of Drug Sensitivity database. Altogether, the tool offers a comprehensive suite for pathway-level survival analysis and a user interface for exploring drug targets, molecular features, and immune populations at different resolutions.}, }
@article {pmid37380887, year = {2023}, author = {Šikrová, D and Testa, AM and Willemsen, I and van den Heuvel, A and Tapscott, SJ and Daxinger, L and Balog, J and van der Maarel, SM}, title = {SMCHD1 and LRIF1 converge at the FSHD-associated D4Z4 repeat and LRIF1 promoter yet display different modes of action.}, journal = {Communications biology}, volume = {6}, number = {1}, pages = {677}, pmid = {37380887}, issn = {2399-3642}, support = {W.OR15-26//Prinses Beatrix Spierfonds/ ; W.OP14-01//Prinses Beatrix Spierfonds/ ; }, abstract = {Facioscapulohumeral muscular dystrophy (FSHD) is caused by the epigenetic derepression of the 4q-linked D4Z4 macrosatellite repeat resulting in inappropriate expression of the D4Z4 repeat-encoded DUX4 gene in skeletal muscle. In 5% of FSHD cases, D4Z4 chromatin relaxation is due to germline mutations in one of the chromatin modifiers SMCHD1, DNMT3B or LRIF1. The mechanism of SMCHD1- and LRIF1-mediated D4Z4 repression is not clear. We show that somatic loss-of-function of either SMCHD1 or LRIF1 does not result in D4Z4 chromatin changes and that SMCHD1 and LRIF1 form an auxiliary layer of D4Z4 repressive mechanisms. We uncover that SMCHD1, together with the long isoform of LRIF1, binds to the LRIF1 promoter and silences LRIF1 expression. The interdependency of SMCHD1 and LRIF1 binding differs between D4Z4 and the LRIF1 promoter, and both loci show different transcriptional responses to either early developmentally or somatically perturbed chromatin function of SMCHD1 and LRIF1.}, }
@article {pmid37380777, year = {2023}, author = {Shih, J and Sarmashghi, S and Zhakula-Kostadinova, N and Zhang, S and Georgis, Y and Hoyt, SH and Cuoco, MS and Gao, GF and Spurr, LF and Berger, AC and Ha, G and Rendo, V and Shen, H and Meyerson, M and Cherniack, AD and Taylor, AM and Beroukhim, R}, title = {Cancer aneuploidies are shaped primarily by effects on tumour fitness.}, journal = {Nature}, volume = {}, number = {}, pages = {}, pmid = {37380777}, issn = {1476-4687}, abstract = {Aneuploidies-whole-chromosome or whole-arm imbalances-are the most prevalent alteration in cancer genomes[1,2]. However, it is still debated whether their prevalence is due to selection or ease of generation as passenger events[1,2]. Here we developed a method, BISCUT, that identifies loci subject to fitness advantages or disadvantages by interrogating length distributions of telomere- or centromere-bounded copy-number events. These loci were significantly enriched for known cancer driver genes, including genes not detected through analysis of focal copy-number events, and were often lineage specific. BISCUT identified the helicase-encoding gene WRN as a haploinsufficient tumour-suppressor gene on chromosome 8p, which is supported by several lines of evidence. We also formally quantified the role of selection and mechanical biases in driving aneuploidy, finding that rates of arm-level copy-number alterations are most highly correlated with their effects on cellular fitness[1,2]. These results provide insight into the driving forces behind aneuploidy and its contribution to tumorigenesis.}, }
@article {pmid37380021, year = {2023}, author = {Cohen, SA and Veleber, S and Siman, J and Guthrie, KA and McMillen, K and Heit, M and Wadhera, S and Daniels, J and Hansen, K and Jacoby, M and Taromina, K and Chin, S and Romeo, M and Langley, BO and Coveler, AL and Hannan, LM and King, G and Purcell, T and Safyan, RA and Shankaran, V and Zhen, DB and Chiorean, EG and Greenlee, H}, title = {Use of acupuncture with acupressure in addition to standard-of-care cryotherapy to decrease chemotherapy-associated neuropathy in patients with gastrointestinal malignancies receiving oxaliplatin-based chemotherapy: Study protocol for a randomized, controlled pilot and feasibility study.}, journal = {Contemporary clinical trials}, volume = {}, number = {}, pages = {107273}, doi = {10.1016/j.cct.2023.107273}, pmid = {37380021}, issn = {1559-2030}, abstract = {BACKGROUND: Oxaliplatin is a key chemotherapeutic agent in the treatment of local and metastatic gastrointestinal (GI) malignancies. Dose density and treatment adherence can be limited by chemotherapy-induced peripheral neuropathy (CIPN). Early research suggests CIPN incidence and severity may be mitigated by acupuncture, but rigorous data in GI oncology patients is limited. Here, we describe the protocol of a randomized, waitlist-controlled pilot study testing the use of preemptive of acupuncture plus acupressure to decrease CIPN and chemotherapy-related toxicities.
METHODS: Patients with a GI malignancy (n = 56) with planned 5-fluorouracil (5-FU) and oxaliplatin IV (FOLFOX, FOLFIRINOX) every 2 weeks are being recruited. Additional concurrent anti-neoplastic agents may be used. Enrolled patients are randomized 1:1 to a 3-month intervention of Arm A: acupuncture with acupressure and standard-of-care treatment, or Arm B: standard-of-care alone. In Arm A, on days 1 and 3 of each chemotherapy cycle a standardized acupuncture protocol is administered and patients are taught self-acupressure to perform daily between chemotherapy treatments. Patients in both arms are given standard-of-care oral and peripheral (hands/ft) ice chip cryotherapy during oxaliplatin administration. CIPN and other symptoms are assessed at baseline, 6 weeks, and 3 months from registration. The primary endpoint is CIPN severity at 3 months (EORTC-CIPN 20). Additional endpoints evaluate CIPN incidence (CTCAE, Neuropen, tuning fork); incidence of pain, fatigue, nausea, oral dysesthesia, and anxiety; and feasibility (recruitment, retention, adherence, acceptability). If warranted, trial results will inform the design of a multi-center trial to expand testing of the intervention to a larger patient cohort.}, }
@article {pmid37379844, year = {2023}, author = {O'Neill, RS and Sodeinde, AK and Welsh, FC and Fagerstrom, CJ and Galletta, BJ and Rusan, NM}, title = {Spd-2 gene duplication reveals cell-type-specific pericentriolar material regulation.}, journal = {Current biology : CB}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.cub.2023.06.020}, pmid = {37379844}, issn = {1879-0445}, abstract = {Centrosomes are multi-protein organelles that function as microtubule (MT) organizing centers (MTOCs), ensuring spindle formation and chromosome segregation during cell division.[1][,][2][,][3] Centrosome structure includes core centrioles that recruit pericentriolar material (PCM) that anchors γ-tubulin to nucleate MTs.[1][,][2] In Drosophila melanogaster, PCM organization depends on proper regulation of proteins like Spd-2, which dynamically localizes to centrosomes and is required for PCM, γ-tubulin, and MTOC activity in brain neuroblast (NB) mitosis and male spermatocyte (SC) meiosis.[4][,][5][,][6][,][7][,][8] Some cells have distinct requirements for MTOC activity due to differences in characteristics like cell size[9][,][10] or whether they are mitotic or meiotic.[11][,][12] How centrosome proteins achieve cell-type-specific functional differences is poorly understood. Previous work identified alternative splicing[13] and binding partners[14] as contributors to cell-type-specific differences in centrosome function. Gene duplication, which can generate paralogs with specialized functions,[15][,][16] is also implicated in centrosome gene evolution,[17] including cell-type-specific centrosome genes.[18][,][19] To gain insight into cell-type-specific differences in centrosome protein function and regulation, we investigated a duplication of Spd-2 in Drosophila willistoni, which has Spd-2A (ancestral) and Spd-2B (derived). We find that Spd-2A functions in NB mitosis, whereas Spd-2B functions in SC meiosis. Ectopically expressed Spd-2B accumulates and functions in mitotic NBs, but ectopically expressed Spd-2A failed to accumulate in meiotic SCs, suggesting cell-type-specific differences in translation or protein stability. We mapped this failure to accumulate and function in meiosis to the C-terminal tail domain of Spd-2A, revealing a novel regulatory mechanism that can potentially achieve differences in PCM function across cell types.}, }
@article {pmid37379494, year = {2023}, author = {Irajizad, E and Fahrmann, JF and Marsh, T and Vykoukal, J and Dennison, JB and Long, JP and Do, KA and Feng, Z and Hanash, S and Ostrin, EJ}, title = {Mortality Benefit of a Blood-Based Biomarker Panel for Lung Cancer on the Basis of the Prostate, Lung, Colorectal, and Ovarian Cohort.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {}, number = {}, pages = {JCO2202424}, doi = {10.1200/JCO.22.02424}, pmid = {37379494}, issn = {1527-7755}, abstract = {PURPOSE: To investigate the utility of integrating a panel of circulating protein biomarkers in combination with a risk model on the basis of subject characteristics to identify individuals at high risk of harboring a lethal lung cancer.
METHODS: Data from an established logistic regression model that combines four-marker protein panel (4MP) together with the Prostate, Lung, Colorectal, and Ovarian (PLCO) risk model (PLCOm2012) assayed in prediagnostic sera from 552 lung cancer cases and 2,193 noncases from the PLCO cohort were used in this study. Of the 552 lung cancer cases, 387 (70%) died of lung cancer. Cumulative incidence of lung cancer death and subdistributional and cause-specific hazard ratios (HRs) were calculated on the basis of 4MP + PLCOm2012 risk scores at a predefined 1.0% and 1.7% 6-year risk thresholds, which correspond to the current and former US Preventive Services Task Force screening criteria, respectively.
RESULTS: When considering cases diagnosed within 1 year of blood draw and all noncases, the area under receiver operation characteristics curve estimate of the 4MP + PLCOm2012 model for risk prediction of lung cancer death was 0.88 (95% CI, 0.86 to 0.90). The cumulative incidence of lung cancer death was statistically significantly higher in individuals with 4MP + PLCOm2012 scores above the 1.0% 6-year risk threshold (modified χ[2], 166.27; P < .0001). Corresponding subdistributional and lung cancer death-specific HRs for test-positive cases were 9.88 (95% CI, 6.44 to 15.18) and 10.65 (95% CI, 6.93 to 16.37), respectively.
CONCLUSION: The blood-based biomarker panel in combination with PLCOm2012 identifies individuals at high risk of a lethal lung cancer.}, }
@article {pmid37379368, year = {2023}, author = {Tkachev, V and Vanderbeck, A and Perkey, E and Furlan, SN and McGuckin, C and Gómez Atria, D and Gerdemann, U and Rui, X and Lane, J and Hunt, DJ and Zheng, H and Colonna, L and Hoffman, M and Yu, A and Outen, R and Kelly, S and Allman, A and Koch, U and Radtke, F and Ludewig, B and Burbach, B and Shimizu, Y and Panoskaltsis-Mortari, A and Chen, G and Carpenter, SM and Harari, O and Kuhnert, F and Thurston, G and Blazar, BR and Kean, LS and Maillard, I}, title = {Notch signaling drives intestinal graft-versus-host disease in mice and nonhuman primates.}, journal = {Science translational medicine}, volume = {15}, number = {702}, pages = {eadd1175}, doi = {10.1126/scitranslmed.add1175}, pmid = {37379368}, issn = {1946-6242}, abstract = {Notch signaling promotes T cell pathogenicity and graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (allo-HCT) in mice, with a dominant role for the Delta-like Notch ligand DLL4. To assess whether Notch's effects are evolutionarily conserved and to identify the mechanisms of Notch signaling inhibition, we studied antibody-mediated DLL4 blockade in a nonhuman primate (NHP) model similar to human allo-HCT. Short-term DLL4 blockade improved posttransplant survival with durable protection from gastrointestinal GVHD in particular. Unlike prior immunosuppressive strategies tested in the NHP GVHD model, anti-DLL4 interfered with a T cell transcriptional program associated with intestinal infiltration. In cross-species investigations, Notch inhibition decreased surface abundance of the gut-homing integrin α4β7 in conventional T cells while preserving α4β7 in regulatory T cells, with findings suggesting increased β1 competition for α4 binding in conventional T cells. Secondary lymphoid organ fibroblastic reticular cells emerged as the critical cellular source of Delta-like Notch ligands for Notch-mediated up-regulation of α4β7 integrin in T cells after allo-HCT. Together, DLL4-Notch blockade decreased effector T cell infiltration into the gut, with increased regulatory to conventional T cell ratios early after allo-HCT. Our results identify a conserved, biologically unique, and targetable role of DLL4-Notch signaling in intestinal GVHD.}, }
@article {pmid37379309, year = {2023}, author = {Kuppers, DA and Linton, J and Ortiz Espinosa, S and McKenna, KM and Rongvaux, A and Paddison, PJ}, title = {Gene knock-outs in human CD34+ hematopoietic stem and progenitor cells and in the human immune system of mice.}, journal = {PloS one}, volume = {18}, number = {6}, pages = {e0287052}, pmid = {37379309}, issn = {1932-6203}, abstract = {Human CD34+ hematopoietic stem and progenitor cells (HSPCs) are a standard source of cells for clinical HSC transplantations as well as experimental xenotransplantation to generate "humanized mice". To further extend the range of applications of these humanized mice, we developed a protocol to efficiently edit the genomes of human CD34+ HSPCs before transplantation. In the past, manipulating HSPCs has been complicated by the fact that they are inherently difficult to transduce with lentivectors, and rapidly lose their stemness and engraftment potential during in vitro culture. However, with optimized nucleofection of sgRNA:Cas9 ribonucleoprotein complexes, we are now able to edit a candidate gene in CD34+ HSPCs with almost 100% efficiency, and transplant these modified cells in immunodeficient mice with high engraftment levels and multilineage hematopoietic differentiation. The result is a humanized mouse from which we knocked out a gene of interest from their human immune system.}, }
@article {pmid37379264, year = {2023}, author = {Burack, WR and Li, H and Adlowitz, DG and Spence, JM and Rimsza, LM and Shadman, M and Spier, C and Kaminski, MS and Leonard, JP and Leblanc, M and Smith, SM and Friedberg, JW}, title = {Subclonal TP53 mutation are frequent and predict resistance to radio-immunotherapy in follicular lymphoma.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2022009467}, pmid = {37379264}, issn = {2473-9537}, abstract = {Although TP53 is commonly mutated in transformed follicular lymphoma, mutations are reported in fewer than 5% of pre-treatment follicular lymphoma (FL) specimens. We assayed archival follicular B-cell non-Hodgkin lymphoma specimens from a completed clinical trial, SWOG S0016, a phase III randomized intergroup trial of CHOP chemotherapy plus rituximab (R-CHOP) compared with CHOP chemotherapy plus 131-iodine tositumomab (radio-immunotherapy (RIT)-CHOP). Subclonal TP53 mutation (median allele frequency 0.02) were found in 25% of diagnostic FL specimens and 27% of a separate validation cohort. In the R-CHOP arm, pathogenic TP53 mutations were not associated with progression-free survival (PFS) (10-year PFS 43% vs 44%). In contrast, among patients with no detectable pathogenic TP53 mutation, RIT-CHOP was associated with a longer PFS than R-CHOP (10 year PFS 67% vs 44%; HR=0.49; p=0.008). No relationship was detected between PFS and the extent of Activation-induced cytidine deaminase (AICDA)-mediated heterogeneity. In summary, subclonal TP53 mutations are common in FL and are a distinct phenomenon from AICDA-mediated genetic heterogeneity. The absence of a detectable subclonal mutation in TP53 defined a population that particularly benefited from RIT.}, }
@article {pmid36993531, year = {2023}, author = {Rillamas-Sun, E and Kwan, ML and Carlos, C and Cheng, R and Neugebauer, R and Rana, JS and Nguyen-Huynh, M and Shi, Z and Laurent, CA and Lee, VS and Roh, JM and Huang, Y and Shen, H and Hershman, DL and Kushi, LH and Greenlee, H}, title = {Development of cardiometabolic risk factors following endocrine therapy in women with breast cancer.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {36993531}, abstract = {PURPOSE: Studies comparing the effect of aromatase inhibitor (AI) and tamoxifen use on cardiovascular disease (CVD) risk factors in hormone-receptor positive breast cancer (BC) survivors report conflicting results. We examined associations of endocrine therapy use with incident diabetes, dyslipidemia, and hypertension.
METHODS: The Pathways Heart Study examines cancer treatment exposures with CVD-related outcomes in Kaiser Permanente Northern California members with BC. Electronic health records provided sociodemographic and health characteristics, BC treatment, and CVD risk factor data. Hazard ratios (HR) and 95% confidence intervals (CI) of incident diabetes, dyslipidemia, and hypertension in hormone-receptor positive BC survivors using AIs or tamoxifen compared with survivors not using endocrine therapy were estimated using Cox proportional hazards regression models adjusted for known confounders.
RESULTS: In 8,985 BC survivors, mean baseline age and follow-up time was 63.3 and 7.8 years, respectively; 83.6% were postmenopausal. By treatment, 77.0% used AIs, 19.6% used tamoxifen, and 16.0% used neither. Postmenopausal women who used tamoxifen had an increased rate (HR: 1.43, 95% CI: 1.06-1.92) of developing hypertension relative to those who did not use endocrine therapy. Tamoxifen use was not associated with incident diabetes, dyslipidemia, or hypertension in premenopausal BC survivors. Postmenopausal AI users had higher hazard rates of developing diabetes (HR: 1.37, 95% CI: 1.05-1.80), dyslipidemia (HR: 1.58, 95% CI: 1.29-1.92) and hypertension (HR: 1.50, 95% CI: 1.24-1.82) compared with non-endocrine therapy users.
CONCLUSION: Hormone-receptor positive BC survivors treated with AIs may have higher rates of developing diabetes, dyslipidemia, and hypertension over an average 7.8 years post-diagnosis.}, }
@article {pmid36778406, year = {2023}, author = {Einson, J and Glinos, D and Boerwinkle, E and Castaldi, P and Darbar, D and de Andrade, M and Ellinor, P and Fornage, M and Gabriel, S and Germer, S and Gibbs, R and Hersh, CP and Johnsen, J and Kaplan, R and Konkle, BA and Kooperberg, C and Nassir, R and Loos, RJF and Meyers, DA and Mitchell, BD and Psaty, B and Vasan, RS and Rich, SS and Rienstra, M and Rotter, JI and Saferali, A and Shoemaker, MB and Silverman, E and Smith, AV and , and Mohammadi, P and Castel, SE and Iossifov, I and Lappalainen, T}, title = {Genetic control of mRNA splicing as a potential mechanism for incomplete penetrance of rare coding variants.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {36778406}, support = {R01 GM140287/GM/NIGMS NIH HHS/United States ; }, abstract = {Exonic variants present some of the strongest links between genotype and phenotype. However, these variants can have significant inter-individual pathogenicity differences, known as variable penetrance. In this study, we propose a model where genetically controlled mRNA splicing modulates the pathogenicity of exonic variants. By first cataloging exonic inclusion from RNA-seq data in GTEx v8, we find that pathogenic alleles are depleted on highly included exons. Using a large-scale phased WGS data from the TOPMed consortium, we observe that this effect may be driven by common splice-regulatory genetic variants, and that natural selection acts on haplotype configurations that reduce the transcript inclusion of putatively pathogenic variants, especially when limiting to haploinsufficient genes. Finally, we test if this effect may be relevant for autism risk using families from the Simons Simplex Collection, but find that splicing of pathogenic alleles has a penetrance reducing effect here as well. Overall, our results indicate that common splice-regulatory variants may play a role in reducing the damaging effects of rare exonic variants.}, }
@article {pmid37379059, year = {2023}, author = {McClure, JB and Heffner, JL and Krakauer, C and Mun, S and Klasnja, P and Catz, SL}, title = {Feasibility, Acceptability, and Potential Impact of a Novel mHealth App for Smokers Ambivalent About Quitting: Randomized Pilot Study.}, journal = {JMIR mHealth and uHealth}, volume = {11}, number = {}, pages = {e46155}, doi = {10.2196/46155}, pmid = {37379059}, issn = {2291-5222}, abstract = {BACKGROUND: Most smokers are ambivalent about quitting-they want to quit someday, but not now. Interventions are needed that can engage ambivalent smokers, build their motivation for quitting, and support future quit attempts. Mobile health (mHealth) apps offer a cost-effective platform for such interventions, but research is needed to inform their optimal design and assess their acceptability, feasibility, and potential effectiveness.
OBJECTIVE: This study aims to assess the feasibility, acceptability, and potential impact of a novel mHealth app for smokers who want to quit smoking someday but are ambivalent about quitting in the near term.
METHODS: We enrolled adults across the United States who smoked more than 10 cigarettes a day and were ambivalent about quitting (n=60). Participants were randomly assigned to 1 of 2 versions of the GEMS app: standard care (SC) versus enhanced care (EC). Both had a similar design and identical evidence-based, best-practice smoking cessation advice and resources, including the ability to earn free nicotine patches. EC also included a series of exercises called experiments designed to help ambivalent smokers clarify their goals, strengthen their motivation, and learn important behavioral skills for changing smoking behavior without making a commitment to quit. Outcomes were analyzed using automated app data and self-reported surveys at 1 and 3 months post enrollment.
RESULTS: Participants who installed the app (57/60, 95%) were largely female, White, socioeconomically disadvantaged, and highly nicotine dependent. As expected, key outcomes trended in favor of the EC group. Compared to SC users, EC participants had greater engagement (mean sessions 19.9 for EC vs 7.3 for SC). An intentional quit attempt was reported by 39.3% (11/28) of EC users and 37.9% (11/29) of SC users. Seven-day point prevalence smoking abstinence at the 3-month follow-up was reported by 14.7% (4/28) of EC users and 6.9% (2/29) of SC users. Among participants who earned a free trial of nicotine replacement therapy based on their app usage, 36.4% (8/22) of EC participants and 11.1% (2/18) of SC participants requested the treatment. A total of 17.9% (5/28) of EC and 3.4% (1/29) of SC participants used an in-app feature to access a free tobacco quitline. Other metrics were also promising. EC participants completed an average of 6.9 (SD 3.1) out of 9 experiments. Median helpfulness ratings for completed experiments ranged from 3 to 4 on a 5-point scale. Finally, satisfaction with both app versions was very good (mean 4.1 on a 5-point Likert scale) and 95.3% (41/43) of all respondents would recommend their app version to others.
CONCLUSIONS: Ambivalent smokers were receptive to the app-based intervention, but the EC version, which combined best-practice cessation advice with self-paced, experiential exercises, was associated with greater use and evidence of behavior change. Further development and evaluation of the EC program is warranted.
TRIAL REGISTRATION: ClinicalTrials.gov NCT04560868; https://clinicaltrials.gov/ct2/show/NCT04560868.}, }
@article {pmid37379001, year = {2023}, author = {Serrano, E and Voldal, EC and Machado-Aranda, D and DeUgarte, DA and Kao, L and Drake, T and Winchell, R and Cuschieri, J and Krishnadasan, A and Talan, DA and Siparsky, N and Ayoung-Chee, P and Self, WH and McGonagill, P and Mandell, KA and Liang, MK and Dodwad, SJ and Thompson, CM and Padilla, RM and Fleischman, R and Price, TP and Jones, A and Bernardi, K and Garcia, L and Evans, HL and Sanchez, SE and Odom, S and Comstock, BA and Heagerty, PJ and Lawrence, SO and Monsell, SE and Fannon, EEC and Kessler, LG and Flum, DR and Davidson, GH and , }, title = {Trial Participation and Outcomes Among English-Speaking and Spanish-Speaking Patients With Appendicitis Randomized to Antibiotics: A Secondary Analysis of the CODA Randomized Clinical Trial.}, journal = {JAMA surgery}, volume = {}, number = {}, pages = {}, doi = {10.1001/jamasurg.2023.2277}, pmid = {37379001}, issn = {2168-6262}, abstract = {IMPORTANCE: Spanish-speaking participants are underrepresented in clinical trials, limiting study generalizability and contributing to ongoing health inequity. The Comparison of Outcomes of Antibiotic Drugs and Appendectomy (CODA) trial intentionally included Spanish-speaking participants.
OBJECTIVE: To describe trial participation and compare clinical and patient-reported outcomes among Spanish-speaking and English-speaking participants with acute appendicitis randomized to antibiotics.
This study is a secondary analysis of the CODA trial, a pragmatic randomized trial comparing antibiotic therapy with appendectomy in adult patients with imaging-confirmed appendicitis enrolled at 25 centers across the US from May 1, 2016, to February 28, 2020. The trial was conducted in English and Spanish. All 776 participants randomized to antibiotics are included in this analysis. The data were analyzed from November 15, 2021, through August 24, 2022.
INTERVENTION: Randomization to a 10-day course of antibiotics or appendectomy.
MAIN OUTCOMES AND MEASURES: Trial participation, European Quality of Life-5 Dimensions (EQ-5D) questionnaire scores (higher scores indicating a better health status), rate of appendectomy, treatment satisfaction, decisional regret, and days of work missed. Outcomes are also reported for a subset of participants that were recruited from the 5 sites with a large proportion of Spanish-speaking participants.
RESULTS: Among eligible patients 476 of 1050 Spanish speakers (45%) and 1076 of 3982 of English speakers (27%) consented, comprising the 1552 participants who underwent 1:1 randomization (mean age, 38.0 years; 976 male [63%]). Of the 776 participants randomized to antibiotics, 238 were Spanish speaking (31%). Among Spanish speakers randomized to antibiotics, the rate of appendectomy was 22% (95% CI, 17%-28%) at 30 days and 45% (95% CI, 38%-52%) at 1 year, while in English speakers, these rates were 20% (95% CI, 16%-23%) at 30 days and 42% (95% CI 38%-47%) at 1 year. Mean EQ-5D scores were 0.93 (95% CI, 0.92-0.95) among Spanish speakers and 0.92 (95% CI, 0.91-0.93) among English speakers. Symptom resolution at 30 days was reported by 68% (95% CI, 61%-74%) of Spanish speakers and 69% (95% CI, 64%-73%) of English speakers. Spanish speakers missed 6.69 (95% CI, 5.51-7.87) days of work on average, while English speakers missed 3.76 (95% CI, 3.20-4.32) days. Presentation to the emergency department or urgent care, hospitalization, treatment dissatisfaction, and decisional regret were low for both groups.
CONCLUSIONS AND RELEVANCE: A high proportion of Spanish speakers participated in the CODA trial. Clinical and most patient-reported outcomes were similar for English- and Spanish-speaking participants treated with antibiotics. Spanish speakers reported more days of missed work.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02800785.}, }
@article {pmid37370143, year = {2023}, author = {Bell-Mandla, N and Wilson, E and Sharma, D and Sloot, R and Bwalya, J and Schaap, A and Donnell, D and Piwowar-Manning, E and Floyd, S and Makola, N and Nkonki, L and Simwinga, M and Moore, A and Hayes, R and Fidler, S and Ayles, H and Bock, P and , }, title = {Predictors of participant retention in a community-based HIV prevention cohort: perspectives from the HPTN 071 (PopART) study.}, journal = {Trials}, volume = {24}, number = {1}, pages = {434}, pmid = {37370143}, issn = {1745-6215}, 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/ ; UM1-AI068619//Bill and Melinda Gates Foundation/ ; UM1-AI068617//Bill and Melinda Gates Foundation/ ; UM1-AI068613//Bill and Melinda Gates Foundation/ ; }, abstract = {INTRODUCTION: In 2021, there were 38.4 million people living with HIV (PLHIV) globally, of which 20.6 million (54%) were living in Eastern and Southern Africa. Longitudinal studies, inclusive of community randomized trials (CRTs), provide critical evidence to guide a broad range of health care interventions including HIV prevention. In this study, we have used an individual-level cohort study design to evaluate the association between sex and other baseline characteristics and participant retention in the HPTN 071 (PopART) trial in Zambia and South Africa.
METHODS: HPTN 071 (PopART) was a community randomized trial (CRT) conducted from 2013 to 2018, in 21 communities. The primary outcome was measured in a randomly selected population cohort (PC), followed up over 3 to 4 years at annual rounds. PC retention was defined as completion of an annual follow-up questionnaire. Baseline characteristics were described by study arm and Poisson regression analyses used to measure the association between baseline factors and retention. In addition, we present a description of researcher-documented reasons for study withdrawal by PC participants.
RESULTS: Of the 38,474 participants enrolled during the first round of the trial (PC0), most were women (27,139, 71%) and 73% completed at least one follow-up visit. Retention was lower in men (adj RR: 0.90; 95% CI: 0.88, 0.91) and higher among older participants (adj RR: 1.23; 95% CI 1.20, 1.26) when comparing ages 35-44 to 18-24 years. Retention was higher among individuals with high socioeconomic status (SES) (adj RR 1.16; 95% CI 1.14, 1.19) and medium SES (adj RR 1.12; 95% CI 1.09, 1.14) compared to low SES. The most common reasons for study withdrawal were study refusal (23%) and relocation outside the CRT catchment area (66%).
CONCLUSION: Despite challenges, satisfactory retention outcomes were achieved in PopART with limited variability across study arms. In keeping with other studies, younger age, male sex, and lower SES were associated with lower levels of retention. Relocation outside of catchment area was the most common reason for non-retention in this CRT.}, }
@article {pmid37366170, year = {2023}, author = {Gertz, MA and Cohen, AD and Comenzo, RL and Kastritis, E and Landau, HJ and Libby, EN and Liedtke, M and Sanchorawala, V and Schönland, S and Wechalekar, AD and Zonder, JA and Palladini, G and Walling, J and Guthrie, S and Nie, C and Karp, C and Jin, Y and Kinney, GG and Merlini, G}, title = {Birtamimab plus standard of care in light chain amyloidosis: the phase 3 randomized placebo-controlled VITAL trial.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood.2022019406}, pmid = {37366170}, issn = {1528-0020}, abstract = {Amyloid light chain (AL) amyloidosis is a rare, typically fatal disease characterized by accumulation of misfolded immunoglobulin light chains (LCs). Birtamimab is an investigational humanized monoclonal antibody designed to neutralize toxic LC aggregates and deplete insoluble organ-deposited amyloid via macrophage-induced phagocytosis. VITAL was a phase 3 randomized, double-blind, placebo-controlled clinical trial assessing the efficacy and safety of birtamimab + standard of care (SOC) in 260 newly diagnosed, treatment-naïve patients with AL amyloidosis. Patients received 24 mg/kg intravenous birtamimab + SOC or placebo + SOC every 28 days. The primary composite endpoint was time to all-cause mortality (ACM) or centrally adjudicated cardiac hospitalization ≥91 days after first study drug infusion. The trial was terminated early after an interim futility analysis; there was no significant difference in the primary composite endpoint (hazard ratio [HR] = 0.826; 95% confidence interval [CI] 0.574-1.189; log-rank P = .303). A post hoc analysis in Mayo Stage IV patients, those at highest risk of early mortality, showed significant improvement in time to ACM with birtamimab at month 9 (HR = 0.413; 95% CI: 0.191-0.895; log-rank P = .021). At month 9, 74% of Mayo Stage IV patients treated with birtamimab and 49% of those given placebo survived. Overall, the rates of treatment-emergent adverse events (TEAEs) and serious TEAEs were generally similar between treatment arms. A confirmatory phase 3 randomized, double-blind, placebo-controlled clinical trial of birtamimab in patients with Mayo Stage IV AL amyloidosis (AFFIRM-AL; NCT04973137) is currently enrolling. The VITAL trial was registered at www.clinicaltrials.gov as #NCT02312206.}, }
@article {pmid37365505, year = {2023}, author = {Madewell, ZJ and Yang, Y and Longini, IM and Halloran, ME and Vespignani, A and Dean, NE}, title = {Rapid review and meta-analysis of serial intervals for SARS-CoV-2 Delta and Omicron variants.}, journal = {BMC infectious diseases}, volume = {23}, number = {1}, pages = {429}, pmid = {37365505}, issn = {1471-2334}, mesh = {Humans ; *COVID-19 ; *Epidemics ; Family ; SARS-CoV-2/genetics ; }, abstract = {BACKGROUND: The serial interval is the period of time between symptom onset in the primary case and symptom onset in the secondary case. Understanding the serial interval is important for determining transmission dynamics of infectious diseases like COVID-19, including the reproduction number and secondary attack rates, which could influence control measures. Early meta-analyses of COVID-19 reported serial intervals of 5.2 days (95% CI: 4.9-5.5) for the original wild-type variant and 5.2 days (95% CI: 4.87-5.47) for Alpha variant. The serial interval has been shown to decrease over the course of an epidemic for other respiratory diseases, which may be due to accumulating viral mutations and implementation of more effective nonpharmaceutical interventions. We therefore aggregated the literature to estimate serial intervals for Delta and Omicron variants.
METHODS: This study followed Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. A systematic literature search was conducted of PubMed, Scopus, Cochrane Library, ScienceDirect, and preprint server medRxiv for articles published from April 4, 2021, through May 23, 2023. Search terms were: ("serial interval" or "generation time"), ("Omicron" or "Delta"), and ("SARS-CoV-2" or "COVID-19"). Meta-analyses were done for Delta and Omicron variants using a restricted maximum-likelihood estimator model with a random effect for each study. Pooled average estimates and 95% confidence intervals (95% CI) are reported.
RESULTS: There were 46,648 primary/secondary case pairs included for the meta-analysis of Delta and 18,324 for Omicron. Mean serial interval for included studies ranged from 2.3-5.8 days for Delta and 2.1-4.8 days for Omicron. The pooled mean serial interval for Delta was 3.9 days (95% CI: 3.4-4.3) (20 studies) and Omicron was 3.2 days (95% CI: 2.9-3.5) (20 studies). Mean estimated serial interval for BA.1 was 3.3 days (95% CI: 2.8-3.7) (11 studies), BA.2 was 2.9 days (95% CI: 2.7-3.1) (six studies), and BA.5 was 2.3 days (95% CI: 1.6-3.1) (three studies).
CONCLUSIONS: Serial interval estimates for Delta and Omicron were shorter than ancestral SARS-CoV-2 variants. More recent Omicron subvariants had even shorter serial intervals suggesting serial intervals may be shortening over time. This suggests more rapid transmission from one generation of cases to the next, consistent with the observed faster growth dynamic of these variants compared to their ancestors. Additional changes to the serial interval may occur as SARS-CoV-2 continues to circulate and evolve. Changes to population immunity (due to infection and/or vaccination) may further modify it.}, }
@article {pmid37365285, year = {2023}, author = {Dimou, N and Kim, AE and Flanagan, O and Murphy, N and Diez-Obrero, V and Shcherbina, A and Aglago, EK and Bouras, E and Campbell, PT and Casey, G and Gallinger, S and Gruber, SB and Jenkins, MA and Lin, Y and Moreno, V and Ruiz-Narvaez, E and Stern, MC and Tian, Y and Tsilidis, KK and Arndt, V and Barry, EL and Baurley, JW and Berndt, SI and Bézieau, S and Bien, SA and Bishop, DT and Brenner, H and Budiarto, A and Carreras-Torres, R and Cenggoro, TW and Chan, AT and Chang-Claude, J and Chanock, SJ and Chen, X and Conti, DV and Dampier, CH and Devall, M and Drew, DA and Figueiredo, JC and Giles, GG and Gsur, A and Harrison, TA and Hidaka, A and Hoffmeister, M and Huyghe, JR and Jordahl, K and Kawaguchi, E and Keku, TO and Larsson, SC and Le Marchand, L and Lewinger, JP and Li, L and Mahesworo, B and Morrison, J and Newcomb, PA and Newton, CC and Obon-Santacana, M and Ose, J and Pai, RK and Palmer, JR and Papadimitriou, N and Pardamean, B and Peoples, AR and Pharoah, PDP and Platz, EA and Potter, JD and Rennert, G and Scacheri, PC and Schoen, RE and Su, YR and Tangen, CM and Thibodeau, SN and Thomas, DC and Ulrich, CM and Um, CY and van Duijnhoven, FJB and Visvanathan, K and Vodicka, P and Vodickova, L and White, E and Wolk, A and Woods, MO and Qu, C and Kundaje, A and Hsu, L and Gauderman, WJ and Gunter, MJ and Peters, U}, title = {Probing the diabetes and colorectal cancer relationship using gene - environment interaction analyses.}, journal = {British journal of cancer}, volume = {}, number = {}, pages = {}, pmid = {37365285}, issn = {1532-1827}, support = {C18281/A29019//Cancer Research UK (CRUK)/ ; }, abstract = {BACKGROUND: Diabetes is an established risk factor for colorectal cancer. However, the mechanisms underlying this relationship still require investigation and it is not known if the association is modified by genetic variants. To address these questions, we undertook a genome-wide gene-environment interaction analysis.
METHODS: We used data from 3 genetic consortia (CCFR, CORECT, GECCO; 31,318 colorectal cancer cases/41,499 controls) and undertook genome-wide gene-environment interaction analyses with colorectal cancer risk, including interaction tests of genetics(G)xdiabetes (1-degree of freedom; d.f.) and joint testing of Gxdiabetes, G-colorectal cancer association (2-d.f. joint test) and G-diabetes correlation (3-d.f. joint test).
RESULTS: Based on the joint tests, we found that the association of diabetes with colorectal cancer risk is modified by loci on chromosomes 8q24.11 (rs3802177, SLC30A8 - ORAA: 1.62, 95% CI: 1.34-1.96; ORAG: 1.41, 95% CI: 1.30-1.54; ORGG: 1.22, 95% CI: 1.13-1.31; p-value3-d.f.: 5.46 × 10[-11]) and 13q14.13 (rs9526201, LRCH1 - ORGG: 2.11, 95% CI: 1.56-2.83; ORGA: 1.52, 95% CI: 1.38-1.68; ORAA: 1.13, 95% CI: 1.06-1.21; p-value2-d.f.: 7.84 × 10[-09]).
DISCUSSION: These results suggest that variation in genes related to insulin signaling (SLC30A8) and immune function (LRCH1) may modify the association of diabetes with colorectal cancer risk and provide novel insights into the biology underlying the diabetes and colorectal cancer relationship.}, }
@article {pmid37364297, year = {2023}, author = {Lai, J and Wong, CK and Schmidt, DF and Kapuscinski, MK and Alpen, K and Maclnnis, RJ and Buchanan, DD and Win, AK and Figueiredo, JC and Chan, AT and Harrison, TA and Hoffmeister, M and White, E and Le Marchand, L and Pai, RK and Peters, U and Hopper, JL and Jenkins, MA and Makalic, E}, title = {Using DEPendency of association on the number of Top Hits (DEPTH) as a complementary tool to identify novel colorectal cancer susceptibility loci.}, journal = {Cancer epidemiology, biomarkers & 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-22-1209}, pmid = {37364297}, issn = {1538-7755}, abstract = {BACKGROUND: DEPendency of association on the number of Top Hits (DEPTH) is an approach to identify candidate susceptibility regions by considering the risk signals from overlapping groups of sequential variants across the genome.
METHODS: We conducted a DEPTH analysis using a sliding window of 200 SNPs to colorectal cancer (CRC) data from the Colon Cancer Family Registry (CCFR) (5,735 cases and 3,688 controls), and GECCO (8,865 cases and 10,285 controls) studies. A DEPTH score >1 was used to identify candidate susceptibility regions common to both studies. We compared DEPTH results against those from conventional GWAS analyses of these two studies as well as against 132 published susceptibility regions.
RESULTS: Initial DEPTH analysis revealed 2,622 (CCFR) and 3,686 (GECCO) candidate susceptibility regions, of which 569 were common to both studies. Bootstrapping revealed 40 and 49 candidate susceptibility regions in the CCFR and GECCO data sets, respectively. Notably, DEPTH identified at least 82 regions that would not be detected using conventional GWAS methods, nor had they been identified by previous CRC GWASs. We found four reproducible candidate susceptibility regions (2q22.2, 2q33.1, 6p21.32, 13q14.3). The highest DEPTH scores were in the HLA locus at 6p21 where the strongest associated SNPs were rs762216297, rs149490268, rs114741460, and rs199707618 for the CCFR data, and rs9270761 for the GECCO data.
CONCLUSIONS: DEPTH can identify candidate susceptibility regions for CRC not identified using conventional analyses of larger datasets.
IMPACT: DEPTH has potential as a powerful complementary tool to conventional GWAS analyses for discovering susceptibility regions within the genome.}, }
@article {pmid37363917, year = {2023}, author = {Donnell, D and Gao, F and Hughes, JP and Hanscom, B and Corey, L and Cohen, MS and Edupuganti, S and Mgodi, N and Rees, H and Baeten, JM and Gray, G and Bekker, LG and Hosseinipour, M and Delany-Moretlwe, S}, title = {Counterfactual estimation of efficacy against placebo for novel PrEP agents using external trial data: example of injectable cabotegravir and oral PrEP in women.}, journal = {Journal of the International AIDS Society}, volume = {26}, number = {6}, pages = {e26118}, pmid = {37363917}, issn = {1758-2652}, support = {/DA/NIDA NIH HHS/United States ; UM1AI068619/MH/NIMH NIH HHS/United States ; UM1 AI068614/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; UM1 AI068618/AI/NIAID NIH HHS/United States ; UM1 AI068619/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 ; Emtricitabine/therapeutic use ; *Anti-HIV Agents/therapeutic use ; *HIV Infections/drug therapy/prevention & control ; Adenine ; *Organophosphonates/therapeutic use ; Deoxycytidine/therapeutic use ; *Pre-Exposure Prophylaxis ; }, abstract = {INTRODUCTION: Multiple antiretroviral agents have demonstrated efficacy for human immunodeficiency virus (HIV) pre-exposure prophylaxis (PrEP). As a result, clinical trials of novel agents have transitioned from placebo- to active-controlled designs; however, active-controlled trials do not provide an estimate of efficacy versus no use of PrEP. Counterfactual placebo comparisons using other data sources could be employed to provide this information.
METHODS: We compared the active-controlled study (HPTN 084) of injectable cabotegravir (CAB-LA) versus daily oral emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) among women from seven countries in Africa to three external, contemporaneous randomized HIV prevention trials from which we constructed counterfactual placebo estimates. We used direct standardization via analysis weights to achieve the same distribution of person-years between the external study and HPTN 084, across strata predictive of HIV risk (country and selected risk covariates). We estimated prevention efficacy against a counterfactual placebo to provide information on the use of CAB-LA and FTC/TDF compared to no intervention. We compared the counterfactual placebo findings for FTC/TDF to previous placebo-controlled trials, adjusted for observed adherence to daily pills.
RESULTS: Distribution of age and baseline prevalence of gonorrhoea and chlamydia were similar among matched counterfactual placebo and observed HPTN 084 arms after standardization. Counterfactual estimates of CAB-LA versus placebo in all three settings showed a consistent risk reduction of 93%-94%, with lower bounds of the confidence intervals above 72%. Observed adherence (quantifiable tenofovir in plasma) in HPTN 084 was 54%-56%, and estimated efficacy of daily oral FTC/TDF against a counterfactual placebo was consistent with a predicted risk reduction of 39%-40% for this level of daily pill use.
CONCLUSIONS: Counterfactual placebo rates of HIV acquisition derived from external trial data in similar locations and time can be used to support estimates of placebo-based efficacy of a novel HIV prevention agent. External trial data must be standardized to be representative of the clinical trial cohort testing the novel HIV prevention agent, accounting for confounders.}, }
@article {pmid37358780, year = {2023}, author = {Storm, EM and Makrakis, D and Lin, GI and Talukder, R and Bakaloudi, DR and Shah, EE and Liou, IW and Hockenbery, D and Grivas, P and Khaki, AR}, title = {Role of Underlying Liver Pathology in the Development of Immune-Related Hepatitis: A Case-Control Study.}, journal = {Targeted oncology}, volume = {}, number = {}, pages = {}, pmid = {37358780}, issn = {1776-260X}, abstract = {BACKGROUND: Immune-related hepatitis (irH) is a serious immune-related adverse event (IRAE) that may result in morbidity, immune checkpoint inhibitor (ICI) therapy interruption and, rarely, mortality. The impact of underlying liver pathology, including liver metastasis, on the incidence of irH remains poorly understood.
OBJECTIVES: We hypothesized that the presence of underlying liver pathology increased the risk of irH in patients with cancer treated with ICI.
PATIENTS AND METHODS: We conducted a retrospective case-control study of irH in patients with cancer receiving first ICI treatment from 2016-2020. Provider documented cases of ≥ grade 2 irH were identified and control matched in a 2:1 ratio based on age, sex, time of ICI initiation, and follow-up time. Conditional logistic regression was used to estimate the relationship between irH and liver metastasis at ICI initiation.
RESULTS: Ninety-seven cases of irH were identified, 29% of which had liver metastases at time of ICI initiation. Thirty-eight percent of patients developed grade 2, 47% grade 3, and 14% grade 4 irH. When adjusted for covariates/confounders, the presence of liver metastasis was associated with increased odds of irH (aOR 2.79 95% CI 1.37-5.66, p = 0.005). The presence of liver metastases did not correlate with irH grade or rate of irH recurrence after ICI rechallenge.
CONCLUSIONS: Presence of liver metastases increased the odds of irH in patients with first-time ICI therapy. Limitations include the retrospective nature, moderate sample size, possible selection bias and confounding. Our findings are hypothesis-generating and warrant external validation as well as tissue and circulating biomarker exploration.}, }
@article {pmid37356171, year = {2023}, author = {Avery, J and Guffey, D and Ma, S and Basom, R and Lee, SJ and Garcia, D and Rojas Hernandez, CM and Li, A and Martens, KL}, title = {Risks factors and outcomes for isolated catheter-related deep venous thrombosis in patients undergoing allogeneic hematopoietic stem cell transplantation.}, journal = {Thrombosis research}, volume = {229}, number = {}, pages = {1-6}, doi = {10.1016/j.thromres.2023.06.017}, pmid = {37356171}, issn = {1879-2472}, abstract = {INTRODUCTION: Patients undergoing allogenic hematopoietic stem cell transplantation (allo-HSCT) require indwelling central venous catheters. The comparative incidence, risk, and outcome of isolated catheter-related deep venous thrombosis (CR-DVT) versus pulmonary embolism/lower-extremity DVT (PE/LE-DVT) remains unclear.
MATERIALS AND METHODS: We conducted a retrospective cohort study for patients undergoing allo-HSCT from 2006 to 2019. CR-DVT and PE/LE-DVT outcomes were screened using ICD codes and radiology reports and confirmed by medical record reviews. Cox regression models were used to assess the association between thrombotic outcomes and pertinent baseline and time-varying covariates. The impact of thrombotic events within 1-year post-transplant (time-varying) on overall mortality was also assessed.
RESULTS: Among 2879 patients, the cumulative incidence of isolated CR-DVT and PE/LE-DVT at 12 months was 4.2 % and 4.8 %, respectively. The strongest time-varying predictor for onset of CR-DVT and PE/LE-DVT was hospitalization inpatient status (HR 3.71 [95 % CI 2.16-6.37] and 3.99 [95 % CI 2.00-7.99], respectively). Other overlapping variables included lymphoma diagnosis and BMI > 35 kg/m[2], whereas acute GVHD grades 2-4 were found to be significantly associated with risk of PE/LE-DVT but not CR-DVT. After adjusting for baseline variables and acute GVHD, the occurrences of CR-DVT and PE/LE-DVT were both independently associated with increased overall mortality (HR 1.58 [95 % CI 1.23-2.02] and HR 1.53 [95 % CI 1.19-1.97], respectively).
CONCLUSIONS: We observed a high incidence of both CR-DVT and PE/LE-DVT with overlapping and unique risk factors. CR-DVT was also associated with increased mortality similar to PE/LE-DVT. Standardized strategies targeting high-risk hospitalization periods may help mitigate the development of thrombotic outcomes post-transplant.}, }
@article {pmid37355583, year = {2023}, author = {Laher, F and Malahleha, M and Ramirez, S and Brumskine, W and Otwombe, K and Moodie, Z and Allen, M}, title = {Data quality in an HIV vaccine efficacy clinical trial in South Africa: through natural disasters and with discipline.}, journal = {BMC medical research methodology}, volume = {23}, number = {1}, pages = {147}, pmid = {37355583}, issn = {1471-2288}, support = {UM1 AI069453/NH/NIH HHS/United States ; }, mesh = {Humans ; Communicable Disease Control ; *COVID-19 ; Data Accuracy ; *HIV Infections/prevention & control ; *Natural Disasters ; Pandemics/prevention & control ; South Africa ; Vaccine Efficacy ; Clinical Trials as Topic ; }, abstract = {BACKGROUND: To produce quality data that informs valid clinical trial results and withstands regulatory inspection, trial sites should adhere to many complex and dynamic requirements. Understanding non-conformance to requirements informs the emerging field of improvement science. We describe protocol deviations in South Africa's largest HIV vaccine efficacy trial.
METHODS: We analysed data from the HVTN 702 trial using mixed methods. We obtained descriptive statistics, from protocol deviation case report forms collected from 2016-2022, of deviation by participant, trial site, and time to site awareness. We thematically analysed text narratives of deviation descriptions, corrective and preventive actions, generating categories, codes and themes which emerged from the data.
RESULTS: For 5407 enrollments, 4074 protocol deviations were reported (75 [95% CI: 73.0-77.6] deviations per 100 enrolments). There was a median of 1 protocol deviation per participant (IQR 1-2). Median time from deviation to site awareness was 31 days (IQR 0-146). The most common category of deviation type was omitted data and/or procedures (69%), and 54% of these omissions were stated to have arisen because of the national lockdown at the beginning of the COVID-19 pandemic. The ratio of protocol deviations to cumulative enrolments was highest in the year 2020 (0.34). Major themes of deviations were: COVID-19 and climate disasters giving rise to deviation trends, subroutines introducing an opportunity for deviation, and document fragmentation (such as requirements dispersed across multiple guidance documents) as an obstacle. Preventive action categories were: no preventive measures; discipline, training and/or awareness; quality review, checking and verifying and changing the process and/or implementation tools. Major themes of preventive actions were that systems-based actions are unusual, with people-based actions dominating, and that root cause analysis was rarely mentioned.
CONCLUSIONS: In the age of infectious and climate disaster risks, trials may benefit from simple study designs and trial-related documents. To optimise protocol adherence, sponsors and sites should consider ongoing training, and routinely review deviation reports with a view to adjusting processes. These data quality lessons may inform future trial design, training and implementation.
TRIAL REGISTRATION: HVTN 702 was registered with the South African National Clinical Trials Register (DOH-27-0916-5327) and ClinicalTrials.gov (NCT02968849).}, }
@article {pmid37345872, year = {2023}, author = {Lyman, GH}, title = {Perception, Cognition and Thought: Part I Nature, Evolution and Development of Conceptual and Symbolic Processes.}, journal = {Cancer investigation}, volume = {}, number = {}, pages = {1-4}, doi = {10.1080/07357907.2023.2229539}, pmid = {37345872}, issn = {1532-4192}, }
@article {pmid37355308, year = {2023}, author = {Yorke, AA and Quaye, ANM and Hasford, F and Addison, ECDK}, title = {The State of Clinical Medical Physics and Education in Ghana.}, journal = {International journal of radiation oncology, biology, physics}, volume = {116}, number = {4}, pages = {717-722}, doi = {10.1016/j.ijrobp.2023.01.053}, pmid = {37355308}, issn = {1879-355X}, mesh = {Humans ; Ghana ; Educational Status ; *Curriculum ; Physics/education ; Health Physics/education ; *Education, Medical ; }, }
@article {pmid37353407, year = {2023}, author = {Blinka, S and Mishra, R and Hsieh, AC}, title = {ELAC2 is a functional prostate cancer risk allele.}, journal = {Trends in molecular medicine}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.molmed.2023.06.002}, pmid = {37353407}, issn = {1471-499X}, abstract = {Stentenbach and colleagues have unveiled a functional role of a human germline mutation found in the ribonuclease (RNase) Z enzyme, ELAC2, in prostate cancer. Here, we discuss the importance of these findings in enhancing our understanding of how risk variants enable prostate cancer progression and the post-transcriptional mechanisms underlying oncogenesis.}, }
@article {pmid37352885, year = {2023}, author = {Thakar, MS and Logan, BR and Puck, JM and Dunn, EA and Buckley, RH and Cowan, MJ and O'Reilly, RJ and Kapoor, N and Satter, LF and Pai, SY and Heimall, J and Chandra, S and Ebens, CL and Chellapandian, D and Williams, O and Burroughs, LM and Saldana, BD and Rayes, A and Madden, LM and Chandrakasan, S and Bednarski, JJ and DeSantes, KB and Cuvelier, GDE and Teira, P and Gillio, AP and Eissa, H and Knutsen, AP and Goldman, FD and Aquino, VM and Shereck, EB and Moore, TB and Caywood, EH and Lugt, MTV and Rozmus, J and Broglie, L and Yu, LC and Shah, AJ and Andolina, JR and Liu, X and Parrott, RE and Dara, J and Prockop, S and Martinez, CA and Kapadia, M and Jyonouchi, SC and Sullivan, KE and Bleesing, JJ and Chaudhury, S and Petrovic, A and Keller, MD and Quigg, TC and Parikh, S and Shenoy, S and Seroogy, C and Rubin, T and Decaluwe, H and Routes, JM and Torgerson, TR and Leiding, JW and Pulsipher, MA and Kohn, DB and Griffith, LM and Haddad, E and Dvorak, CC and Notarangelo, LD}, title = {Measuring the effect of newborn screening on survival after haematopoietic cell transplantation for severe combined immunodeficiency: a 36-year longitudinal study from the Primary Immune Deficiency Treatment Consortium.}, journal = {Lancet (London, England)}, volume = {}, number = {}, pages = {}, doi = {10.1016/S0140-6736(23)00731-6}, pmid = {37352885}, issn = {1474-547X}, abstract = {BACKGROUND: Severe combined immunodeficiency (SCID) is fatal unless durable adaptive immunity is established, most commonly through allogeneic haematopoietic cell transplantation (HCT). The Primary Immune Deficiency Treatment Consortium (PIDTC) explored factors affecting the survival of individuals with SCID over almost four decades, focusing on the effects of population-based newborn screening for SCID that was initiated in 2008 and expanded during 2010-18.
METHODS: We analysed transplantation-related data from children with SCID treated at 34 PIDTC sites in the USA and Canada, using the calendar time intervals 1982-89, 1990-99, 2000-09, and 2010-18. Categorical variables were compared by χ[2] test and continuous outcomes by the Kruskal-Wallis test. Overall survival was estimated by the Kaplan-Meier method. A multivariable analysis using Cox proportional hazards regression models examined risk factors for HCT outcomes, including the variables of time interval of HCT, infection status and age at HCT, trigger for diagnosis, SCID type and genotype, race and ethnicity of the patient, non-HLA-matched sibling donor type, graft type, GVHD prophylaxis, and conditioning intensity.
FINDINGS: For 902 children with confirmed SCID, 5-year overall survival remained unchanged at 72%-73% for 28 years until 2010-18, when it increased to 87% (95% CI 82·1-90·6; n=268; p=0·0005). For children identified as having SCID by newborn screening since 2010, 5-year overall survival was 92·5% (95% CI 85·8-96·1), better than that of children identified by clinical illness or family history in the same interval (79·9% [69·5-87·0] and 85·4% [71·8-92·8], respectively [p=0·043]). Multivariable analysis demonstrated that the factors of active infection (hazard ratio [HR] 2·41, 95% CI 1·56-3·72; p<0·0001), age 3·5 months or older at HCT (2·12, 1·38-3·24; p=0·001), Black or African-American race (2·33, 1·56-3·46; p<0·0001), and certain SCID genotypes to be associated with lower overall survival during all time intervals. Moreover, after adjusting for several factors in this multivariable analysis, HCT after 2010 no longer conveyed a survival advantage over earlier time intervals studied (HR 0·73, 95% CI 0·43-1·26; p=0·097). This indicated that younger age and freedom from infections at HCT, both directly driven by newborn screening, were the main drivers for recent improvement in overall survival.
INTERPRETATION: Population-based newborn screening has facilitated the identification of infants with SCID early in life, in turn leading to prompt HCT while avoiding infections. Public health programmes worldwide can benefit from this definitive demonstration of the value of newborn screening for SCID.
FUNDING: National Institute of Allergy and Infectious Diseases, Office of Rare Diseases Research, and National Center for Advancing Translational Sciences.}, }
@article {pmid37352376, year = {2023}, author = {Nyquist, MD and Coleman, IM and Lucas, JM and Li, D and Hanratty, B and Meade, H and Mostaghel, EA and Plymate, SR and Corey, E and Haffner, MC and Nelson, PS}, title = {Supraphysiological Androgens Promote the Tumor Suppressive Activity of the Androgen Receptor Through cMYC Repression and Recruitment of the DREAM Complex.}, journal = {Cancer research}, volume = {}, number = {}, pages = {}, doi = {10.1158/0008-5472.CAN-22-2613}, pmid = {37352376}, issn = {1538-7445}, abstract = {The androgen receptor (AR) pathway regulates key cell survival programs in prostate epithelium. The AR represents a near-universal driver and therapeutic vulnerability in metastatic prostate cancer, and targeting AR has a remarkable therapeutic index. Though most approaches directed toward AR focus on inhibiting AR signaling, laboratory and now clinical data have shown that high dose, supraphysiological androgen treatment (SPA) results in growth repression and improved outcomes in subsets of prostate cancer patients. A better understanding of the mechanisms contributing to SPA response and resistance could help guide patient selection and combination therapies to improve efficacy. To characterize SPA signaling, we integrated metrics of gene expression changes induced by SPA together with cistrome data and protein-interactomes. These analyses indicated that the Dimerization partner, RB-like, E2F and Multi-vulval class B (DREAM) complex mediates growth repression and downregulation of E2F targets in response to SPA. Notably, prostate cancers with complete genomic loss of RB1 responded to SPA treatment whereas loss of DREAM complex components such as RBL1/2 promoted resistance. Overexpression of MYC resulted in complete resistance to SPA and attenuated the SPA/AR-mediated repression of E2F target genes. These findings support a model of SPA-mediated growth repression that relies on the negative regulation of MYC by AR leading to repression of E2F1 signaling via the DREAM complex. The integrity of MYC signaling and DREAM complex assembly may consequently serve as determinants of SPA responses and as pathways mediating SPA resistance.}, }
@article {pmid37352296, year = {2023}, author = {Ngure, K and Friedland, BA and Szydlo, DW and Roberts, ST and Garcia, M and Levy, L and Akello, CA and Reddy, K and Palanee-Phillips, T and Macdonald, P and Siziba, B and Soto-Torres, L and Hosek, S and Hillier, SL and Nair, G and Celum, C and van der Straten, A}, title = {Baseline preferences for oral pre-exposure prophylaxis (PrEP) or dapivirine intravaginal ring for HIV prevention among adolescent girls and young women in South Africa, Uganda and Zimbabwe (MTN-034/IPM-045 study).}, journal = {PloS one}, volume = {18}, number = {6}, pages = {e0287525}, pmid = {37352296}, issn = {1932-6203}, mesh = {Adolescent ; Female ; Humans ; Pregnancy ; *Anti-HIV Agents/therapeutic use ; *HIV Infections/epidemiology/prevention & control/drug therapy ; *Pre-Exposure Prophylaxis/methods ; South Africa/epidemiology ; Uganda/epidemiology ; Zimbabwe/epidemiology ; Young Adult ; }, abstract = {INTRODUCTION: Adolescent girls and young women (AGYW) in sub-Saharan Africa are disproportionately affected by the HIV epidemic and face an array of challenges using proven behavioral and biomedical prevention methods. To address the urgent need for expanding prevention options, we evaluated the baseline preferences of HIV prevention methods among participants enrolled in the MTN-034/REACH crossover trial along with their stated product preference prior to product initiation.
METHODS: AGYW aged 16-21 years were enrolled at 4 study sites: Cape Town and Johannesburg, South Africa; Kampala, Uganda; and Harare, Zimbabwe and randomly assigned to the sequence of using oral PrEP and the dapivirine ring for 6 months each, followed by a choice period in which they could choose either product (or neither) for an additional six months. Eligible AGYW were HIV-negative, not pregnant and using effective contraception for at least two months prior to enrollment. Descriptive statistics were used to summarize demographic and behavioral data while multinomial analysis was used to determine predictors of stated product preference (ring or oral PrEP).
RESULTS: Of the 247 AGYW enrolled in REACH, 34% were aged 16-17 and 89% had a primary partner.The median age of sexual debut was 16 years and 40% had ever been pregnant. At screening, 35% of participants were diagnosed with a sexually transmitted infection (STI), 39% had an AUDIT-C score associated with harmful drinking and 11% reported intimate partner violence in the past 6 months. Overall, 28% of participants, had CESD-10 scores suggestive of depressive symptoms (≥12) in the past week. At baseline, similar proportions stated a preference for the ring and oral PrEP (38.1% and 40.5% respectively), with 19% of participants stating they preferred both products equally. Only study site was significantly associated with product preference (P<0.05) with AGYW from Johannesburg having higher odds of preferring the ring and those from Kampala having higher odds of preferring both options equally.
CONCLUSIONS: We successfully enrolled African AGYW with a clear unmet need for HIV prevention. The balanced preference between the two products suggests that multiple biomedical prevention options may be appealing to this age group and could address their prevention needs.}, }
@article {pmid37352144, year = {2023}, author = {Karuna, S and Gallardo-Cartagena, JA and Theodore, D and Hunidzarira, P and Montenegro-Idrogo, J and Hu, J and Jones, M and Kim, V and De La Grecca, R and Trahey, M and Karg, C and Takalani, A and Polakowski, L and Hutter, J and Miner, MD and Erdmann, N and Goepfert, P and Maboa, R and Corey, L and Gill, K and Li, SS and , }, title = {Post-COVID symptom profiles and duration in a global convalescent COVID-19 observational cohort: Correlations with demographics, medical history, acute COVID-19 severity and global region.}, journal = {Journal of global health}, volume = {13}, number = {}, pages = {06020}, pmid = {37352144}, issn = {2047-2986}, mesh = {Adult ; Humans ; Female ; Adolescent ; Young Adult ; Middle Aged ; Male ; *COVID-19/epidemiology ; SARS-CoV-2 ; COVID-19 Testing ; Quality of Life ; Post-Acute COVID-19 Syndrome ; Botswana ; }, abstract = {BACKGROUND: Post-COVID conditions are characterised by persistent symptoms that negatively impact quality of life after SARS-CoV-2 diagnosis. While post-COVID risk factors and symptoms have been extensively described in localised regions, especially in the global north, post-COVID conditions remain poorly understood globally. The global, observational cohort study HVTN 405/HPTN 1901 characterises the convalescent course of SARS-CoV-2 infection among adults in North and South America and Africa.
METHODS: We categorised the cohort by infection severity (asymptomatic, symptomatic, no oxygen requirement (NOR), non-invasive oxygen requirement (NIOR), invasive oxygen requirement (IOR)). We applied a regression model to assess correlations of demographics, co-morbidities, disease severity, and concomitant medications with COVID-19 symptom persistence and duration across global regions.
RESULTS: We enrolled 759 participants from Botswana, Malawi, South Africa, Zambia, Zimbabwe, Peru, and the USA a median of 51 (interquartile range (IQR) = 35-66) days post-diagnosis, from May 2020 to March 2021. 53.8% were female, 69.8% were 18-55 years old (median (md) = 44 years old, IQR = 33-58). Comorbidities included obesity (42.8%), hypertension (24%), diabetes (14%), human immunodeficiency virus (HIV) infection (11.6%) and lung disease (7.5%). 76.2% were symptomatic (NOR = 47.4%; NIOR = 22.9%; IOR = 5.8%). Median COVID-19 duration among symptomatic participants was 20 days (IQR = 11-35); 43.4% reported symptoms after COVID-19 resolution, 33.6% reported symptoms ≥30 days, 9.9% reported symptoms ≥60 days. Symptom duration correlated with disease severity (P < 0.001, NIOR vs NOR; P = 0.003, IOR vs NOR), lung disease (P = 0.001), race (P < 0.05, non-Hispanic Black vs White), and global region (P < 0.001). Prolonged viral shedding correlated with persistent abdominal pain (odds ratio (OR) = 5.51, P < 0.05) and persistent diarrhoea (OR = 6.64, P < 0.01).
CONCLUSIONS: Post-COVID duration varied with infection severity, race, lung disease, and region. Better understanding post-COVID conditions, including regionally-diverse symptom profiles, may improve clinical assessment and management globally.
REGISTRATION: Clinicaltrials.gov (#NCT04403880).}, }
@article {pmid37351909, year = {2023}, author = {King, SD and Veliginti, S and Brouwers, MCGJ and Ren, Z and Zheng, W and Setiawan, VW and Wilkens, LR and Shu, XO and Arslan, AA and Beane Freeman, LE and Bracci, PM and Canzian, F and Du, M and Gallinger, SJ and Giles, GG and Goodman, PJ and Haiman, CA and Kogevinas, M and Kooperberg, C and Le Marchand, L and Neale, RE and Visvanathan, K and White, E and Albanes, D and Andreotti, G and Babic, A and Berndt, SI and Brais, LK and Brennan, P and Buring, JE and Rabe, KG and Bamlet, WR and Chanock, SJ and Fuchs, CS and Gaziano, JM and Giovannucci, EL and Hackert, T and Hassan, MM and Katzke, V and Kurtz, RC and Lee, IM and Malats, N and Murphy, N and Oberg, AL and Orlow, I and Porta, M and Real, FX and Rothman, N and Sesso, HD and Silverman, DT and Thompson, IM and Wactawski-Wende, J and Wang, X and Wentzensen, N and Yu, H and Zeleniuch-Jacquotte, A and Yu, K and Wolpin, BM and Duell, EJ and Li, D and Hung, RJ and Perdomo, S and McCullough, ML and Freedman, ND and Patel, AV and Peters, U and Riboli, E and Sund, M and Tjønneland, A and Zhong, J and Van Den Eeden, SK and Kraft, P and Risch, HA and Amundadottir, LT and Klein, AP and Stolzenberg-Solomon, RZ and Antwi, SO}, title = {Genetic susceptibility to nonalcoholic fatty liver disease and risk for pancreatic cancer: Mendelian randomization.}, journal = {Cancer epidemiology, biomarkers & 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-23-0453}, pmid = {37351909}, issn = {1538-7755}, abstract = {BACKGROUND: There are conflicting data on whether nonalcoholic fatty liver disease (NAFLD) is associated with susceptibility to pancreatic cancer (PC). Using Mendelian randomization (MR), we investigated the relationship between genetic predisposition to NAFLD and risk for PC.
METHODS: Data from genome-wide association studies within the Pancreatic Cancer Cohort Consortium (PanScan; cases n=5090, controls n=8733) and the Pancreatic Cancer Case Control Consortium (PanC4; cases n=4,163, controls n=3,792) were analyzed. We used data on 68 genetic variants with four different MR methods (inverse variance weighting [IVW], MR-Egger, simple median, and penalized weighted median) separately to predict genetic heritability of NAFLD. We then assessed the relationship between each of the four MR methods and PC risk, using logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for PC risk factors, including obesity and diabetes.
RESULTS: No association was found between genetically predicted NAFLD and PC risk in the PanScan or PanC4 samples (e.g., PanScan, IVW OR=1.04, 95% CI: 0.88-1.22, MR-Egger OR=0.89, 95% CI: 0.65-1.21; PanC4, IVW OR=1.07, 95% CI: 0.90-1.27, MR-Egger OR=0.93, 95% CI: 0.67-1.28). None of the four MR methods indicated an association between genetically predicted NAFLD and PC risk in either sample.
CONCLUSIONS: Genetic predisposition to NAFLD is not associated with PC risk.
IMPACT: Given the close relationship between NAFLD and metabolic conditions, it is plausible that any association between NAFLD and PC might reflect host metabolic perturbations (e.g., obesity, diabetes, or metabolic syndrome) and does not necessarily reflect a causal relationship between NAFLD and PC.}, }
@article {pmid37350639, year = {2023}, author = {Lee, EM and Srinivasan, S and Purvine, SO and Fiedler, TL and Leiser, OP and Proll, SC and Minot, SS and Deatherage Kaiser, BL and Fredricks, DN}, title = {Optimizing metaproteomics database construction: lessons from a study of the vaginal microbiome.}, journal = {mSystems}, volume = {}, number = {}, pages = {e0067822}, doi = {10.1128/msystems.00678-22}, pmid = {37350639}, issn = {2379-5077}, abstract = {Metaproteomics, a method for untargeted, high-throughput identification of proteins in complex samples, provides functional information about microbial communities and can tie functions to specific taxa. Metaproteomics often generates less data than other omics techniques, but analytical workflows can be improved to increase usable data in metaproteomic outputs. Identification of peptides in the metaproteomic analysis is performed by comparing mass spectra of sample peptides to a reference database of protein sequences. Although these protein databases are an integral part of the metaproteomic analysis, few studies have explored how database composition impacts peptide identification. Here, we used cervicovaginal lavage (CVL) samples from a study of bacterial vaginosis (BV) to compare the performance of databases built using six different strategies. We evaluated broad versus sample-matched databases, as well as databases populated with proteins translated from metagenomic sequencing of the same samples versus sequences from public repositories. Smaller sample-matched databases performed significantly better, driven by the statistical constraints on large databases. Additionally, large databases attributed up to 34% of significant bacterial hits to taxa absent from the sample, as determined orthogonally by 16S rRNA gene sequencing. We also tested a set of hybrid databases which included bacterial proteins from NCBI RefSeq and translated bacterial genes from the samples. These hybrid databases had the best overall performance, identifying 1,068 unique human and 1,418 unique bacterial proteins, ~30% more than a database populated with proteins from typical vaginal bacteria and fungi. Our findings can help guide the optimal identification of proteins while maintaining statistical power for reaching biological conclusions. IMPORTANCE Metaproteomic analysis can provide valuable insights into the functions of microbial and cellular communities by identifying a broad, untargeted set of proteins. The databases used in the analysis of metaproteomic data influence results by defining what proteins can be identified. Moreover, the size of the database impacts the number of identifications after accounting for false discovery rates (FDRs). Few studies have tested the performance of different strategies for building a protein database to identify proteins from metaproteomic data and those that have largely focused on highly diverse microbial communities. We tested a range of databases on CVL samples and found that a hybrid sample-matched approach, using publicly available proteins from organisms present in the samples, as well as proteins translated from metagenomic sequencing of the samples, had the best performance. However, our results also suggest that public sequence databases will continue to improve as more bacterial genomes are published.}, }
@article {pmid37349130, year = {2023}, author = {Badran, YR and Zou, F and Durbin, SM and Dutra, BE and Abu-Sbeih, H and Thomas, AS and Altan, M and Thompson, JA and Qiao, W and Leet, DE and Lai, PY and Horick, NK and Postow, MA and Faleck, DM and Wang, Y and Dougan, M}, title = {Concurrent immune checkpoint inhibition and selective immunosuppressive therapy in patients with immune-related enterocolitis.}, journal = {Journal for immunotherapy of cancer}, volume = {11}, number = {6}, pages = {}, doi = {10.1136/jitc-2023-007195}, pmid = {37349130}, issn = {2051-1426}, abstract = {PURPOSE: Immune checkpoint inhibitor (ICI) therapy is often suspended because of immune-related enterocolitis (irEC). We examined the effect of resumption of ICIs with or without concurrent selective immunosuppressive therapy (SIT) on rates of symptom recurrence and survival outcomes.
METHODS: This retrospective, multicenter study examined patients who were treated with ICI and developed irEC requiring SIT (infliximab or vedolizumab) for initial symptom control or to facilitate steroid tapering between May 2015 and June 2020. After symptom resolution, patients were restarted either on ICI alone or on concurrent ICI and SIT at the discretion of the treating physicians. The associations between irEC recurrence and treatment group were assessed via univariate analyses and multivariate logistic regression. Cox proportional hazards model was used for survival analysis.
RESULTS: Of the 138 included patients who required SIT for initial irEC symptom control, 61 (44.2%) patients resumed ICI without concurrent SIT (control group) and 77 (55.8%) patients resumed ICI therapy with concurrent SIT: 33 with infliximab and 44 with vedolizumab. After symptom resolution, patients in the control group were more commonly restarted on a different ICI regimen (65.6%) compared with those receiving SIT (31.2%) (p<0.001). The total number of ICI doses administered after irEC resolution and ICI resumption was similar in both groups (four to five doses). Recurrence of severe colitis or diarrhea after ICI resumption was seen in 34.4% of controls compared with 20.8% of patients receiving concurrent SIT. Concurrent SIT was associated with reduced risk of severe irEC recurrence after ICI resumption in a multivariate logistic regression model (OR 0.34; 95% CI 0.13 to 0.92; p=0.034). There was no difference in survival outcomes between patients in the control group and patients concurrently treated with SIT.
CONCLUSION: After resolution of irEC symptoms, reinitiation of ICI with concurrent SIT is safe, reduces severe irEC recurrence, and has no negative impact on survival outcomes.}, }
@article {pmid37348500, year = {2023}, author = {Han, X and Lains, I and Li, J and Li, J and Chen, Y and Yu, B and Qi, Q and Boerwinkle, E and Kaplan, R and Thyagarajan, B and Daviglus, M and Joslin, CE and Cai, J and Guasch-Ferré, M and Tobias, DK and Rimm, E and Ascherio, A and Costenbader, K and Karlson, E and Mucci, L and Eliassen, AH and Zeleznik, O and Miller, J and Vavvas, DG and Kim, IK and Silva, R and Miller, J and Hu, F and Willett, W and Lasky-Su, J and Kraft, P and Richards, JB and MacGregor, S and Husain, D and Liang, L}, title = {Integrating genetics and metabolomics from multi-ethnic and multi-fluid data reveals putative mechanisms for age-related macular degeneration.}, journal = {Cell reports. Medicine}, volume = {}, number = {}, pages = {101085}, doi = {10.1016/j.xcrm.2023.101085}, pmid = {37348500}, issn = {2666-3791}, abstract = {Age-related macular degeneration (AMD) is a leading cause of blindness in older adults. Investigating shared genetic components between metabolites and AMD can enhance our understanding of its pathogenesis. We conduct metabolite genome-wide association studies (mGWASs) using multi-ethnic genetic and metabolomic data from up to 28,000 participants. With bidirectional Mendelian randomization analysis involving 16,144 advanced AMD cases and 17,832 controls, we identify 108 putatively causal relationships between plasma metabolites and advanced AMD. These metabolites are enriched in glycerophospholipid metabolism, lysophospholipid, triradylcglycerol, and long chain polyunsaturated fatty acid pathways. Bayesian genetic colocalization analysis and a customized metabolome-wide association approach prioritize putative causal AMD-associated metabolites. We find limited evidence linking urine metabolites to AMD risk. Our study emphasizes the contribution of plasma metabolites, particularly lipid-related pathways and genes, to AMD risk and uncovers numerous putative causal associations between metabolites and AMD risk.}, }
@article {pmid37348055, year = {2023}, author = {Einson, J and Glinos, D and Boerwinkle, E and Castaldi, P and Darbar, D and de Andrade, M and Ellinor, P and Fornage, M and Gabriel, S and Germer, S and Gibbs, R and Hersh, CP and Johnsen, J and Kaplan, R and Konkle, BA and Kooperberg, C and Nassir, R and Loos, RJF and Meyers, DA and Mitchell, BD and Psaty, B and Vasan, RS and Rich, SS and Rienstra, M and Rotter, JI and Saferali, A and Shoemaker, MB and Silverman, E and Smith, AV and , and Mohammadi, P and Castel, SE and Iossifov, I and Lappalainen, T}, title = {Genetic control of mRNA splicing as a potential mechanism for incomplete penetrance of rare coding variants.}, journal = {Genetics}, volume = {}, number = {}, pages = {}, doi = {10.1093/genetics/iyad115}, pmid = {37348055}, issn = {1943-2631}, abstract = {Exonic variants present some of the strongest links between genotype and phenotype. However, these variants can have significant inter-individual pathogenicity differences, known as variable penetrance. In this study, we propose a model where genetically controlled mRNA splicing modulates the pathogenicity of exonic variants. By first cataloging exonic inclusion from RNA-seq data in GTEx v8, we find that pathogenic alleles are depleted on highly included exons. Using a large-scale phased WGS data from the TOPMed consortium, we observe that this effect may be driven by common splice-regulatory genetic variants, and that natural selection acts on haplotype configurations that reduce the transcript inclusion of putatively pathogenic variants, especially when limiting to haploinsufficient genes. Finally, we test if this effect may be relevant for autism risk using families from the Simons Simplex Collection, but find that splicing of pathogenic alleles has a penetrance reducing effect here as well. Overall, our results indicate that common splice-regulatory variants may play a role in reducing the damaging effects of rare exonic variants.}, }
@article {pmid37347502, year = {2023}, author = {Deeg, HJ}, title = {Reward from half a match.}, journal = {Blood}, volume = {141}, number = {25}, pages = {3009-3010}, doi = {10.1182/blood.2023020724}, pmid = {37347502}, issn = {1528-0020}, }
@article {pmid37347221, year = {2023}, author = {Kim, NJ and Cravero, A and VoPham, T and Vutien, P and Carr, R and Issaka, RB and Johnston, J and McMahon, B and Mera, J and Ioannou, GN}, title = {Addressing racial and ethnic disparities in US liver cancer care.}, journal = {Hepatology communications}, volume = {7}, number = {7}, pages = {}, doi = {10.1097/HC9.0000000000000190}, pmid = {37347221}, issn = {2471-254X}, abstract = {HCC, the most common form of primary liver cancer, is the fastest rising cause of cancer-related death in the United States. HCC disproportionately affects racial and ethnic minorities in the United States. A practical framework is needed to organize the complex patient, provider, health system, and societal factors that drive these racial and ethnic disparities. In this narrative review, we adapted and applied the National Institute on Minority Health and Health Disparities (NIMHD) Research Framework to the HCC care continuum, as a step toward better understanding and addressing existing HCC-related disparities. We first summarize the literature on HCC-related disparities by race and ethnicity organized by the framework's 5 domains (biological, behavioral, physical/built environment, sociocultural environment, and health care system) and 4 levels (individual, interpersonal, community, and societal) of influence. We then offer strategies to guide future research initiatives toward promotion of health equity in HCC care. Clinicians and researchers may help mitigate further inequities and better address racial and ethnic disparities in HCC care by prioritizing the following in HCC research: (1) increasing racial and ethnic minority representation, (2) collecting and reporting HCC-related data by racial and ethnic subgroups, (3) assessing the patient experience of HCC care by race and ethnicity, and (4) evaluating HCC-specific social determinants of health by race and ethnicity. These 4 priorities will help inform the development of future programs and interventions that are tailored to the unique experiences of each racial and ethnic group.}, }
@article {pmid37347091, year = {2023}, author = {Atilla, E}, title = {Editorial: Constructing new motifs in hematology.}, journal = {Frontiers in medicine}, volume = {10}, number = {}, pages = {1220022}, pmid = {37347091}, issn = {2296-858X}, }
@article {pmid37346095, year = {2023}, author = {McCulloch, DJ and Rogers, JH and Wang, Y and Chow, EJ and Link, AC and Wolf, CR and Uyeki, TM and Rolfes, MA and Mosites, E and Sereewit, J and Duchin, JS and Sugg, NK and Greninger, AL and Boeckh, MJ and Englund, JA and Shendure, J and Hughes, JP and Starita, LM and Roychoudhury, P and Chu, HY}, title = {Respiratory syncytial virus and other respiratory virus infections in residents of homeless shelters - King County, Washington, 2019-2021.}, journal = {Influenza and other respiratory viruses}, volume = {17}, number = {6}, pages = {e13166}, pmid = {37346095}, issn = {1750-2659}, abstract = {Respiratory syncytial virus (RSV) causes disproportionate morbidity and mortality in vulnerable populations. We tested residents of homeless shelters in Seattle, Washington for RSV in a repeated cross-sectional study as part of community surveillance for respiratory viruses. Of 15 364 specimens tested, 35 had RSV detected, compared to 77 with influenza. The most common symptoms for both RSV and influenza were cough and rhinorrhea. Many individuals with RSV (39%) and influenza (58%) reported that their illness significantly impacted their ability to perform their regular activities. RSV and influenza demonstrated similar clinical presentations and burden of illness in vulnerable populations living in congregate settings.}, }
@article {pmid37345353, year = {2023}, author = {Bhatt, NS and Shipman, KJ and Rosenberg, AR and Jenssen, KM and Ballard, SA and Baker, KS and Barton, KS}, title = {Barriers and facilitators of the return-to-school process affecting adolescent recipients of allogeneic hematopoietic cell transplantation: A qualitative interview study of caregivers.}, journal = {Pediatric blood & cancer}, volume = {}, number = {}, pages = {e30510}, doi = {10.1002/pbc.30510}, pmid = {37345353}, issn = {1545-5017}, support = {//Seattle Children's Cancer and Blood Disorders Center Research Pilot Fund Program/ ; }, abstract = {BACKGROUND: Adolescent hematopoietic cell transplant (HCT) recipients remain out of school for a prolonged period of time; navigating their return to school after completion of therapy can be challenging for caregivers.
METHODS: Between August 2020 and June 2021, we conducted individual semi-structured interviews of 19 caregivers of adolescent HCT recipients (10-18 years of age at HCT; 1-7 years post HCT) to understand the challenges faced at the time of their child's return to in-person school post HCT. Conventional content analysis was used to analyze interview transcripts, and thematic analysis was used to identify and organize emerging themes.
RESULTS: Three themes emerged from the caregivers' experiences. First, caregivers reported facing several challenges related to lack of communication between their child's healthcare and school teams, which was burdensome for them. Second, some caregivers reported receiving support from school and healthcare professionals, as well as their child's peers, which helped reduce the burden of return to school. Caregivers also reported providing motivational, emotional, and spiritual support to patients. Lastly, caregivers made several recommendations regarding the need for better communication between family, healthcare professionals, and school professionals and availability of supportive care such as mental health counseling and neuropsychological testing. Notably, the need for a return-to-school navigator emerged as a key finding from our analysis.
CONCLUSIONS: Caregivers of adolescent HCT recipients face several challenges supporting their children's return to school post HCT, which are related to lack of communication between patients' healthcare and school teams. While some reported receiving support from school and healthcare professionals and their child's peers, the need to coordinate the return-to-school process was burdensome for several caregivers. Additional work is needed to optimize support for HCT recipients and their caregivers during their return-to-school process to minimize burden. Our study findings have the potential to serve as a framework for developing and testing supportive care interventions to improve the return-to-school experience of HCT survivors and ultimately their quality of life.}, }
@article {pmid37345050, year = {2023}, author = {Atilla, E and Benabdellah, K}, title = {The Black Hole: CAR T Cell Therapy in AML.}, journal = {Cancers}, volume = {15}, number = {10}, pages = {}, doi = {10.3390/cancers15102713}, pmid = {37345050}, issn = {2072-6694}, abstract = {Despite exhaustive studies, researchers have made little progress in the field of adoptive cellular therapies for relapsed/refractory acute myeloid leukemia (AML), unlike the notable uptake for B cell malignancies. Various single antigen-targeting chimeric antigen receptor (CAR) T cell Phase I trials have been established worldwide and have recruited approximately 100 patients. The high heterogeneity at the genetic and molecular levels within and between AML patients resembles a black hole: a great gravitational field that sucks in everything. One must consider the fact that only around 30% of patients show a response; there are, however, consequential off-tumor effects. It is obvious that a new point of view is needed to achieve more promising results. This review first introduces the unique therapeutic challenges of not only CAR T cells but also other adoptive cellular therapies in AML. Next, recent single-cell sequencing data for AML to assess somatically acquired alterations at the DNA, epigenetic, RNA, and protein levels are discussed to give a perspective on cellular heterogeneity, intercellular hierarchies, and the cellular ecosystem. Finally, promising novel strategies are summarized, including more sophisticated next-generation CAR T, TCR-T, and CAR NK therapies; the approaches with which to tailor the microenvironment and target neoantigens; and allogeneic approaches.}, }
@article {pmid37344281, year = {2023}, author = {Ghali, F and Vakar-Lopez, F and Roudier, MP and Garcia, J and Arora, S and Cheng, HH and Schweizer, MT and Haffner, MC and Lee, JK and Yu, EY and Grivas, P and Montgomery, B and Hsieh, AC and Wright, JL and Lam, HM}, title = {Metastatic Bladder Cancer Expression and Subcellular Localization of Nectin-4 and Trop-2 in Variant Histology: A Rapid Autopsy Study.}, journal = {Clinical genitourinary cancer}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.clgc.2023.05.014}, pmid = {37344281}, issn = {1938-0682}, abstract = {BACKGROUND: Nectin-4 and Trop-2 are transmembrane targets of FDA-approved antibody-drug conjugates (ADC) Enfortumab-vedotin (EV) and Sacituzumab govitecan (SG), respectively, for the treatment of metastatic urothelial carcinoma (mUC). The expression and role of Nectin-4 and Trop-2 in mUC variant histology is poorly described.
MATERIALS AND METHODS: We evaluate membranous and cytoplasmic protein expression, and mRNA levels of Nectin-4 and Trop-2 within matched primary and metastatic mUC samples to determine heterogeneity of ADC targets in mUC variants.
RESULTS: Patients with mUC were consented for rapid autopsy immediately after death. Tissues from matched primary and metastatic lesions were collected. A total of 67 specimens from 20 patients were analyzed: 27 were UC, 17 plasmacytoid (PUC), 18 UC with squamous differentiation (UCSD), and 5 neuroendocrine (NE); 10 from primary and 57 from metastatic sites. All histology except NE expressed moderate-high levels of Nectin-4 and Trop-2 by both immunohistochemistry and RNAseq. Nectin-4 demonstrated prominent cytoplasmic staining in metastatic PUC and UCSD. Trop-2 demonstrated strong cytoplasmic and membrane staining in primary and metastatic tumors. Interestingly, Nectin-4 and Trop-2 expression are positively correlated at both mRNA and protein levels.
CONCLUSION: UC and non-NE variants express notable level of Nectin-4 and Trop-2 in both primary and metastatic lesions. Membrane staining of Nectin-4 and Trop-2 is present but cytoplasmic staining is a more common event in both mUC and mUC variant histology. These findings support evaluation of EV and SG in heavily treated variant histology BC and urge attention on the clinical relevance of cytoplasmic localization of ADC targets.}, }
@article {pmid37343766, year = {2023}, author = {Patel, P and Harmon, S and Iseman, R and Ludkowski, O and Auman, H and Hawley, S and Newcomb, LF and Lin, DW and Nelson, PS and Feng, Z and Boyer, HD and Tretiakova, MS and True, LD and Vakar-Lopez, F and Carroll, PR and Cooperberg, MR and Chan, E and Simko, J and Fazli, L and Gleave, M and Hurtado-Coll, A and Thompson, IM and Troyer, D and McKenney, JK and Wei, W and Choyke, PL and Bratslavsky, G and Turkbey, B and Siemens, DR and Squire, J and Peng, YP and Brooks, JD and Jamaspishvili, T}, title = {Artificial Intelligence-Based PTEN Loss Assessment as an Early Predictor of Prostate Cancer Metastasis After Surgery: a Multi-Center Retrospective Study.}, journal = {Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc}, volume = {}, number = {}, pages = {100241}, doi = {10.1016/j.modpat.2023.100241}, pmid = {37343766}, issn = {1530-0285}, abstract = {Phosphatase and tensin homolog (PTEN) loss associates to adverse outcomes in prostate cancer and can be measured via immunohistochemistry (IHC). The purpose of the study was to establish the clinical application of an in-house developed artificial intelligence (AI) image analysis workflow for automated detection of PTEN loss on digital images for identifying patients at risk of early recurrence and metastasis. Post-surgical tissue microarray sections from the Canary Foundation (n=1264) stained with anti-PTEN antibody were evaluated independently by pathologist conventional visual scoring (cPTEN) and an automated AI-based image analysis pipeline (AI-PTEN). The relationship of PTEN evaluation methods with cancer recurrence and metastasis was analyzed using multivariable Cox proportional hazard and decision curve models. Both cPTEN scoring by pathologist and quantification of PTEN loss by AI (High-Risk AI-qPTEN) were significantly associated to shorted MFS in univariable analysis (cPTEN HR: 1.54, CI:1.07-2.21, p=0.019; AI-qPTEN HR: 2.55, CI:1.83,3.56), p<0.001). In multivariable analyses, AI-qPTEN showed a statistically significant association with shorter metastasis-free survival (MFS) (HR:2.17, CI:1.49-3.17, p<0.001) and recurrence-free survival (HR:1.36, CI:1.06-1.75, p=0.016) when adjusting for relevant post-surgical clinical nomogram (CAPRA-S) while cPTEN does not show a statistically significant association (HR:1.33, CI:0.89-2, p=0.2 and HR:1.26, CI:0.99-1.62, p=0.063, respectively) when adjusting for CAPRA-S risk stratification. More importantly, AI-qPTEN was associated with shorter MFS in patients with favorable pathological stage and negative surgical margins (HR: 2.72, CI:1.46-5.06, p=0.002). Workflow also demonstrated enhanced clinical utility in decision curve analysis, more accurately identifying men who might benefit from adjuvant therapy post-surgery. This study demonstrates the clinical value of an affordable and fully automated AI-powered PTEN assessment for evaluating the risk of developing metastasis or disease recurrence after radical prostatectomy. Adding AI-qPTEN assessment workflow to clinical variables may affect post-operative surveillance or management options, particularly in low-risk patients.}, }
@article {pmid37342349, year = {2023}, author = {Wright, ML and Goin, DE and Smed, MK and Jewell, NP and Nelson, JL and Olsen, J and Hetland, ML and Zoffmann, V and Jawaheer, D}, title = {Pregnancy-associated systemic gene expression compared to a pre-pregnancy baseline, among healthy women with term pregnancies.}, journal = {Frontiers in immunology}, volume = {14}, number = {}, pages = {1161084}, pmid = {37342349}, issn = {1664-3224}, abstract = {BACKGROUND: Pregnancy is known to induce extensive biological changes in the healthy mother. Little is known, however, about what these changes are at the molecular level. We have examined systemic expression changes in protein-coding genes and long non-coding (lnc) RNAs during and after pregnancy, compared to before pregnancy, among healthy women with term pregnancies.
METHODS: Blood samples were collected from 14 healthy women enrolled in our prospective pregnancy cohort at 7 time-points (before, during and after pregnancy). Total RNA from frozen whole blood was used for RNA sequencing. Following raw read alignment and assembly, gene-level counts were obtained for protein-coding genes and long non-coding RNAs. At each time-point, cell type proportions were estimated using deconvolution. To examine associations between pregnancy status and gene expression over time, Generalized Estimating Equation (GEE) models were fitted, adjusting for age at conception, and with and without adjusting for changes in cell type proportions. Fold-changes in expression at each trimester were examined relative to the pre-pregnancy baseline.
RESULTS: Numerous immune-related genes demonstrated pregnancy-associated expression, in a time-dependent manner. The genes that demonstrated the largest changes in expression included several that were neutrophil-related (over-expressed) and numerous immunoglobulin genes (under-expressed). Estimated cell proportions revealed a marked increase in neutrophils, and less so of activated CD4 memory T cells, during pregnancy, while most other cell type proportions decreased or remained unchanged. Adjusting for cell type proportions in our model revealed that although most of the expression changes were due to changes in cell type proportions in the bloodstream, transcriptional regulation was also involved, especially in down-regulating expression of type I interferon inducible genes.
CONCLUSION: Compared to a pre-pregnancy baseline, there were extensive systemic changes in cell type proportions, gene expression and biological pathways associated with different stages of pregnancy and postpartum among healthy women. Some were due to changes in cell type proportions and some due to gene regulation. In addition to providing insight into term pregnancy among healthy women, these findings also provide a "normal" reference for abnormal pregnancies and for autoimmune diseases that improve or worsen during pregnancy, to assess deviations from normal.}, }
@article {pmid37339630, year = {2023}, author = {Talwar, JV and Laub, D and Pagadala, MS and Castro, A and Lewis, M and Luebeck, GE and Gorman, BR and Pan, C and Dong, FN and Markianos, K and Teerlink, CC and Lynch, J and Hauger, R and Pyarajan, S and Tsao, PS and Morris, GP and Salem, RM and Thompson, WK and Curtius, K and Zanetti, M and Carter, H}, title = {Autoimmune alleles at the major histocompatibility locus modify melanoma susceptibility.}, journal = {American journal of human genetics}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ajhg.2023.05.013}, pmid = {37339630}, issn = {1537-6605}, abstract = {Autoimmunity and cancer represent two different aspects of immune dysfunction. Autoimmunity is characterized by breakdowns in immune self-tolerance, while impaired immune surveillance can allow for tumorigenesis. The class I major histocompatibility complex (MHC-I), which displays derivatives of the cellular peptidome for immune surveillance by CD8[+] T cells, serves as a common genetic link between these conditions. As melanoma-specific CD8[+] T cells have been shown to target melanocyte-specific peptide antigens more often than melanoma-specific antigens, we investigated whether vitiligo- and psoriasis-predisposing MHC-I alleles conferred a melanoma-protective effect. In individuals with cutaneous melanoma from both The Cancer Genome Atlas (n = 451) and an independent validation set (n = 586), MHC-I autoimmune-allele carrier status was significantly associated with a later age of melanoma diagnosis. Furthermore, MHC-I autoimmune-allele carriers were significantly associated with decreased risk of developing melanoma in the Million Veteran Program (OR = 0.962, p = 0.024). Existing melanoma polygenic risk scores (PRSs) did not predict autoimmune-allele carrier status, suggesting these alleles provide orthogonal risk-relevant information. Mechanisms of autoimmune protection were neither associated with improved melanoma-driver mutation association nor improved gene-level conserved antigen presentation relative to common alleles. However, autoimmune alleles showed higher affinity relative to common alleles for particular windows of melanocyte-conserved antigens and loss of heterozygosity of autoimmune alleles caused the greatest reduction in presentation for several conserved antigens across individuals with loss of HLA alleles. Overall, this study presents evidence that MHC-I autoimmune-risk alleles modulate melanoma risk unaccounted for by current PRSs.}, }
@article {pmid37339483, year = {2023}, author = {Halpern, AB and Rodríguez-Arbolí, E and Othus, M and Garcia, KA and Percival, MM and Cassaday, RD and Oehler, VG and Becker, PS and Appelbaum, J and Abkowitz, JL and Orozco, JJ and Keel, SB and Hendrie, P and Scott, BL and Ghiuzeli, CMM and Estey, E and Walter, RB}, title = {Phase 1/2 Study of Sorafenib Added to Cladribine, High-Dose Cytarabine, G-CSF, and Mitoxantrone in Untreated AML.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2023010392}, pmid = {37339483}, issn = {2473-9537}, abstract = {The multikinase inhibitor sorafenib improves event-free survival (EFS) when used with 7+3 in younger adults with newly diagnosed acute myeloid leukemia (AML) irrespective of FLT3 mutation status. Here, we evaluated adding sorafenib to CLAG-M (cladribine, high-dose cytarabine, G-CSF, mitoxantrone) in a phase 1/2 trial of 81 adults age ≤60 years with newly diagnosed AML or high-grade myeloid neoplasm. Forty-six patients were treated in phase 1 with escalating doses of sorafenib and mitoxantrone. No maximum tolerated dose was reached, and a regimen including mitoxantrone at 18 mg/m2/day and sorafenib 400 mg twice daily was declared the recommended phase 2 dose (RP2D). Among 41 patients treated at the RP2D, a measurable residual disease-negative complete remission (MRDneg CR) rate of 83% (95% confidence interval [CI]: 68-93%) was obtained. Four-week mortality was 2% (95% CI: 0-13%). One-year overall survival (OS) and EFS were 80% (95% CI: 69-94%) and 76% (95% CI 64-90%), without significant difference in MRDneg CR rates, OS, or EFS between patients with or without FLT3-mutated disease. Comparing outcomes with CLAG-M/sorafenib to a matched cohort of 76 patients treated with CLAG-M alone, multivariable adjusted survival estimates were improved for the 41 patients receiving CLAG-M/sorafenib at RP2D (OS: hazard ratio [HR]=0.24 [95% CI: 0.07-0.82], P=0.023; EFS: HR=0.16 [95% CI: 0.05-0.53], P=0.003). Statistically significant benefit was limited to patients with intermediate-risk disease (in univariate analysis, P=0.01 for OS and P=0.02 for EFS). These data suggest CLAG-M/sorafenib is safe and improves OS and EFS relative to CLAG-M alone, with benefit primarily for patients with intermediate-risk disease. The trial is registered on clinicialtrials.gov as NCT02728050.}, }
@article {pmid37292833, year = {2023}, author = {Darst, BF and Shen, J and Madduri, RK and Rodriguez, AA and Xiao, Y and Sheng, X and Saunders, EJ and Dadaev, T and Brook, MN and Hoffmann, TJ and Muir, K and Wan, P and Le Marchand, L and Wilkens, L and Wang, Y and Schleutker, J and MacInnis, RJ and Cybulski, C and Neal, DE and Nordestgaard, BG and Nielsen, SF and Batra, J and Clements, JA and , and Grönberg, H and Pashayan, N and Travis, RC and Park, JY and Albanes, D and Weinstein, S and Mucci, LA and Hunter, DJ and Penney, KL and Tangen, CM and Hamilton, RJ and Parent, MÉ and Stanford, JL and Koutros, S and Wolk, A and Sørensen, KD and Blot, WJ and Yeboah, ED and Mensah, JE and Lu, YJ and Schaid, DJ and Thibodeau, SN and West, CM and Maier, C and Kibel, AS and Cancel-Tassin, G and Menegaux, F and John, EM and Grindedal, EM and Khaw, KT and Ingles, SA and Vega, A and Rosenstein, BS and Teixeira, MR and , and Kogevinas, M and Cannon-Albright, L and Huff, C and Multigner, L and Kaneva, R and Leach, RJ and Brenner, H and Hsing, AW and Kittles, RA and Murphy, AB and Logothetis, CJ and Neuhausen, SL and Isaacs, WB and Nemesure, B and Hennis, AJ and Carpten, J and Pandha, H and De Ruyck, K and Xu, J and Razack, A and Teo, SH and , and Newcomb, LF and Fowke, JH and Neslund-Dudas, C and Rybicki, BA and Gamulin, M and Usmani, N and Claessens, F and GagoDominguez, M and Castelao, JE and Townsend, PA and Crawford, DC and Petrovics, G and Casey, G and Roobol, MJ and Hu, JF and Berndt, SI and Van Den Eeden, SK and Easton, DF and Chanock, SJ and Cook, MB and Wiklund, F and Witte, JS and Eeles, RA and Kote-Jarai, Z and Watya, S and Gaziano, JM and Justice, AC and Conti, DV and Haiman, CA}, title = {Evaluating Approaches for Constructing Polygenic Risk Scores for Prostate Cancer in Men of African and European Ancestry.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {37292833}, support = {R01 CA165862/CA/NCI NIH HHS/United States ; U19 CA214253/CA/NCI NIH HHS/United States ; U19 CA148537/CA/NCI NIH HHS/United States ; R00 CA246063/CA/NCI NIH HHS/United States ; U01 CA257328/CA/NCI NIH HHS/United States ; }, abstract = {Genome-wide polygenic risk scores (GW-PRS) have been reported to have better predictive ability than PRS based on genome-wide significance thresholds across numerous traits. We compared the predictive ability of several GW-PRS approaches to a recently developed PRS of 269 established prostate cancer risk variants from multi-ancestry GWAS and fine-mapping studies (PRS 269). GW-PRS models were trained using a large and diverse prostate cancer GWAS of 107,247 cases and 127,006 controls used to develop the multi-ancestry PRS 269 . Resulting models were independently tested in 1,586 cases and 1,047 controls of African ancestry from the California/Uganda Study and 8,046 cases and 191,825 controls of European ancestry from the UK Biobank and further validated in 13,643 cases and 210,214 controls of European ancestry and 6,353 cases and 53,362 controls of African ancestry from the Million Veteran Program. In the testing data, the best performing GW-PRS approach had AUCs of 0.656 (95% CI=0.635-0.677) in African and 0.844 (95% CI=0.840-0.848) in European ancestry men and corresponding prostate cancer OR of 1.83 (95% CI=1.67-2.00) and 2.19 (95% CI=2.14-2.25), respectively, for each SD unit increase in the GW-PRS. However, compared to the GW-PRS, in African and European ancestry men, the PRS 269 had larger or similar AUCs (AUC=0.679, 95% CI=0.659-0.700 and AUC=0.845, 95% CI=0.841-0.849, respectively) and comparable prostate cancer OR (OR=2.05, 95% CI=1.87-2.26 and OR=2.21, 95% CI=2.16-2.26, respectively). Findings were similar in the validation data. This investigation suggests that current GW-PRS approaches may not improve the ability to predict prostate cancer risk compared to the multi-ancestry PRS 269 constructed with fine-mapping.}, }
@article {pmid36712130, year = {2023}, author = {Wooten, M and Takushi, B and Ahmad, K and Henikoff, S}, title = {Aclarubicin stimulates RNA polymerase II elongation at closely spaced divergent promoters.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {36712130}, support = {T32 HG000035/HG/NHGRI NIH HHS/United States ; }, abstract = {Anthracyclines are a class of widely prescribed anti-cancer drugs that disrupt chromatin by intercalating into DNA and enhancing nucleosome turnover. To understand the molecular consequences of anthracycline-mediated chromatin disruption, we utilized CUT&Tag to profile RNA polymerase II during anthracycline treatment in Drosophila cells. We observed that treatment with the anthracycline aclarubicin leads to elevated levels of elongating RNA polymerase II and changes in chromatin accessibility. We found that promoter proximity and orientation impacts chromatin changes during aclarubicin treatment, as closely spaced divergent promoter pairs show greater chromatin changes when compared to codirectionally-oriented tandem promoters. We also found that aclarubicin treatment changes the distribution of non-canonical DNA G-quadruplex structures both at promoters and at G-rich pericentromeric repeats. Our work suggests that the anti-cancer activity of aclarubicin is driven by the effects of nucleosome disruption on RNA polymerase II, chromatin accessibility and DNA structures.}, }
@article {pmid37338730, year = {2023}, author = {Mariapun, S and Ho, WK and Eriksson, M and Tai, MC and Mohd Taib, NA and Yip, CH and Rahmat, K and Li, J and Hartman, M and Hall, P and Easton, DF and Lindstrom, S and Teo, SH}, title = {Evaluation of SNPs associated with mammographic density in European women with mammographic density in Asian women from South-East Asia.}, journal = {Breast cancer research and treatment}, volume = {}, number = {}, pages = {}, pmid = {37338730}, issn = {1573-7217}, support = {v203477/Z/16/Z/WT_/Wellcome Trust/United Kingdom ; }, abstract = {PURPOSE: Mammographic density (MD), after accounting for age and body mass index (BMI), is a strong heritable risk factor for breast cancer. Genome-wide association studies (GWAS) have identified 64 SNPs in 55 independent loci associated with MD in women of European ancestry. Their associations with MD in Asian women, however, are largely unknown.
METHOD: Using linear regression adjusting for age, BMI, and ancestry-informative principal components, we evaluated the associations of previously reported MD-associated SNPs with MD in a multi-ethnic cohort of Asian ancestry. Area and volumetric mammographic densities were determined using STRATUS (N = 2450) and Volpara™ (N = 2257). We also assessed the associations of these SNPs with breast cancer risk in an Asian population of 14,570 cases and 80,870 controls.
RESULTS: Of the 61 SNPs available in our data, 21 were associated with MD at a nominal threshold of P value < 0.05, all in consistent directions with those reported in European ancestry populations. Of the remaining 40 variants with a P-value of association > 0.05, 29 variants showed consistent directions of association as those previously reported. We found that nine of the 21 MD-associated SNPs in this study were also associated with breast cancer risk in Asian women (P < 0.05), seven of which showed a direction of associations that was consistent with that reported for MD.
CONCLUSION: Our study confirms the associations of 21 SNPs (19/55 or 34.5% out of all known MD loci identified in women of European ancestry) with area and/or volumetric densities in Asian women, and further supports the evidence of a shared genetic basis through common genetic variants for MD and breast cancer risk.}, }
@article {pmid37335349, year = {2023}, author = {Koehne, EL and Psutka, SP}, title = {Adding Stereotactic Radiation to the Multidisciplinary Armamentarium for Localized Renal Cell Carcinoma: Ready for Primetime? : An Editorial Regarding a Recent 5-Year Efficacy and Safety Report of a Multicenter Cohort of Primary RCC Patients Treated with SABR.}, journal = {Annals of surgical oncology}, volume = {}, number = {}, pages = {}, pmid = {37335349}, issn = {1534-4681}, }
@article {pmid37334501, year = {2023}, author = {McConnell, KM and Rogers, M and Prigerson, HG and Maciejewski, PK and Daly, B and Adelman, R and Shen, M}, title = {Advance care planning in an interracial dyad: Case illustration of an intervention to improve engagement in end-of-life care planning.}, journal = {Psycho-oncology}, volume = {}, number = {}, pages = {}, doi = {10.1002/pon.6179}, pmid = {37334501}, issn = {1099-1611}, support = {/CA/NCI NIH HHS/United States ; }, }
@article {pmid37334322, year = {2023}, author = {Wang, JY and Ma, KK and Reiter, DJ and Torvie, A and Swisher, EM}, title = {Sertoli-Leydig cell tumor associated with a germline DICER1 pathogenic variant diagnosed during pregnancy: Considerations for treatment, surveillance, and prevention.}, journal = {Gynecologic oncology reports}, volume = {48}, number = {}, pages = {101215}, pmid = {37334322}, issn = {2352-5789}, abstract = {•This is the first report of a germline DICER1-associated Sertoli-Leydig cell tumor (SLCT) diagnosed in pregnancy.•SLCT is linked to DICER1 pathogenic variants, but little is known about management of DICER1-associated SLCT.•There is an extended risk for metachronous SLCT in patients with germline DICER1 pathogenic variants who retain an ovary.•Prophylactic contralateral salpingo-oophorectomy may be offered with shared decision making to patients with inherited SLCT.•Genetic testing for DICER1 should be offered to all patients with moderately or poorly differentiated SLCT.}, }
@article {pmid37334200, year = {2023}, author = {Chen, K and Heng, S and Long, Q and Zhang, B}, title = {Testing Biased Randomization Assumptions and Quantifying Imperfect Matching and Residual Confounding in Matched Observational Studies.}, journal = {Journal of computational and graphical statistics : a joint publication of American Statistical Association, Institute of Mathematical Statistics, Interface Foundation of North America}, volume = {32}, number = {2}, pages = {528-538}, pmid = {37334200}, issn = {1061-8600}, abstract = {One central goal of design of observational studies is to embed non-experimental data into an approximate randomized controlled trial using statistical matching. Despite empirical researchers' best intention and effort to create high-quality matched samples, residual imbalance due to observed covariates not being well matched often persists. Although statistical tests have been developed to test the randomization assumption and its implications, few provide a means to quantify the level of residual confounding due to observed covariates not being well matched in matched samples. In this article, we develop two generic classes of exact statistical tests for a biased randomization assumption. One important by-product of our testing framework is a quantity called residual sensitivity value (RSV), which provides a means to quantify the level of residual confounding due to imperfect matching of observed covariates in a matched sample. We advocate taking into account RSV in the downstream primary analysis. The proposed methodology is illustrated by re-examining a famous observational study concerning the effect of right heart catheterization (RHC) in the initial care of critically ill patients. Code implementing the method can be found in the supplementary materials.}, }
@article {pmid37333855, year = {2023}, author = {Pan, Y and Laber, EB and Smith, MA and Zhao, YQ}, title = {Reinforced risk prediction with budget constraint using irregularly measured data from electronic health records.}, journal = {Journal of the American Statistical Association}, volume = {118}, number = {542}, pages = {1090-1101}, pmid = {37333855}, issn = {0162-1459}, abstract = {Uncontrolled glycated hemoglobin (HbA1c) levels are associated with adverse events among complex diabetic patients. These adverse events present serious health risks to affected patients and are associated with significant financial costs. Thus, a high-quality predictive model that could identify high-risk patients so as to inform preventative treatment has the potential to improve patient outcomes while reducing healthcare costs. Because the biomarker information needed to predict risk is costly and burdensome, it is desirable that such a model collect only as much information as is needed on each patient so as to render an accurate prediction. We propose a sequential predictive model that uses accumulating patient longitudinal data to classify patients as: high-risk, low-risk, or uncertain. Patients classified as high-risk are then recommended to receive preventative treatment and those classified as low-risk are recommended to standard care. Patients classified as uncertain are monitored until a high-risk or low-risk determination is made. We construct the model using claims and enrollment files from Medicare, linked with patient Electronic Health Records (EHR) data. The proposed model uses functional principal components to accommodate noisy longitudinal data and weighting to deal with missingness and sampling bias. The proposed method demonstrates higher predictive accuracy and lower cost than competing methods in a series of simulation experiments and application to data on complex patients with diabetes.}, }
@article {pmid37330602, year = {2023}, author = {Follmann, D and O'Brien, MP and Fintzi, J and Fay, MP and Montefiori, D and Mateja, A and Herman, GA and Hooper, AT and Turner, KC and Chan, KC and Forleo-Neto, E and Isa, F and Baden, LR and El Sahly, HM and Janes, H and Doria-Rose, N and Miller, J and Zhou, H and Dang, W and Benkeser, D and Fong, Y and Gilbert, PB and Marovich, M and Cohen, MS}, title = {Examining protective effects of SARS-CoV-2 neutralizing antibodies after vaccination or monoclonal antibody administration.}, journal = {Nature communications}, volume = {14}, number = {1}, pages = {3605}, pmid = {37330602}, issn = {2041-1723}, support = {75N91019D00024/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Antibodies, Monoclonal ; SARS-CoV-2 ; 2019-nCoV Vaccine mRNA-1273 ; COVID-19 Vaccines ; *COVID-19/prevention & control ; Antibodies, Viral ; Vaccination ; Antibodies, Neutralizing ; }, abstract = {While new vaccines for SARS-CoV-2 are authorized based on neutralizing antibody (nAb) titer against emerging variants of concern, an analogous pathway does not exist for preventative monoclonal antibodies. In this work, nAb titers were assessed as correlates of protection against COVID-19 in the casirivimab + imdevimab monoclonal antibody (mAb) prevention trial (ClinicalTrials.gov #NCT4452318) and in the mRNA-1273 vaccine trial (ClinicalTrials.gov #NCT04470427). In the mAb trial, protective efficacy of 92% (95% confidence interval (CI): 84%, 98%) is associated with a nAb titer of 1000 IU50/ml, with lower efficacy at lower nAb titers. In the vaccine trial, protective efficacies of 93% [95% CI: 91%, 95%] and 97% (95% CI: 95%, 98%) are associated with nAb titers of 100 and 1000 IU50/ml, respectively. These data quantitate a nAb titer correlate of protection for mAbs benchmarked alongside vaccine induced nAb titers and support nAb titer as a surrogate endpoint for authorizing new mAbs.}, }
@article {pmid37330345, year = {2023}, author = {Carson, DS and Weiss, T and Zhang, LX and Psutka, SP}, title = {Surgical Management of Localized Disease and Small Renal Masses.}, journal = {Hematology/oncology clinics of North America}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.hoc.2023.05.003}, pmid = {37330345}, issn = {1558-1977}, abstract = {The incidence of renal cancer has increased over the past several decades, but mortality has declined. This is thought to be related in part to earlier detection of renal masses which portend excellent 5-year survival rates. Management of small renal masses and localized disease include both nonsurgical and surgical options. The choice of intervention is ultimately based on comprehensive evaluation and shared decision-making. This article provides a comprehensive review of the current surgical management options for localized renal cancer.}, }
@article {pmid37328287, year = {2023}, author = {Fa'ak, F and Buni, M and Falohun, A and Lu, H and Song, J and Johnson, DH and Zobniw, CM and Trinh, VA and Awiwi, MO and Tahon, NH and Elsayes, KM and Ludford, K and Montazari, EJ and Chernis, J and Dimitrova, M and Sandigursky, S and Sparks, JA and Abu-Shawer, O and Rahma, O and Thanarajasingam, U and Zeman, AM and Talukder, R and Singh, N and Chung, SH and Grivas, P and Daher, M and Abudayyeh, A and Osman, I and Weber, J and Tayar, JH and Suarez-Almazor, ME and Abdel-Wahab, N and Diab, A}, title = {Selective immune suppression using interleukin-6 receptor inhibitors for management of immune-related adverse events.}, journal = {Journal for immunotherapy of cancer}, volume = {11}, number = {6}, pages = {}, doi = {10.1136/jitc-2023-006814}, pmid = {37328287}, issn = {2051-1426}, mesh = {Male ; Humans ; Middle Aged ; Female ; Retrospective Studies ; *Melanoma/drug therapy ; *Lung Neoplasms/drug therapy ; *Antirheumatic Agents ; Adrenal Cortex Hormones/therapeutic use ; }, abstract = {BACKGROUND: Management of immune-related adverse events (irAEs) is important as they cause treatment interruption or discontinuation, more often seen with combination immune checkpoint inhibitor (ICI) therapy. Here, we retrospectively evaluated the safety and effectiveness of anti-interleukin-6 receptor (anti-IL-6R) as therapy for irAEs.
METHODS: We performed a retrospective multicenter study evaluating patients diagnosed with de novo irAEs or flare of pre-existing autoimmune disease following ICI and were treated with anti-IL-6R. Our objectives were to assess the improvement of irAEs as well as the overall tumor response rate (ORR) before and after anti-IL-6R treatment.
RESULTS: We identified a total of 92 patients who received therapeutic anti-IL-6R antibodies (tocilizumab or sarilumab). Median age was 61 years, 63% were men, 69% received anti-programmed cell death protein-1 (PD-1) antibodies alone, and 26% patients were treated with the combination of anti-cytotoxic T lymphocyte antigen-4 and anti-PD-1 antibodies. Cancer types were primarily melanoma (46%), genitourinary cancer (35%), and lung cancer (8%). Indications for using anti-IL-6R antibodies included inflammatory arthritis (73%), hepatitis/cholangitis (7%), myositis/myocarditis/myasthenia gravis (5%), polymyalgia rheumatica (4%), and one patient each with autoimmune scleroderma, nephritis, colitis, pneumonitis and central nervous system vasculitis. Notably, 88% of patients had received corticosteroids, and 36% received other disease-modifying antirheumatic drugs (DMARDs) as first-line therapies, but without adequate improvement. After initiation of anti-IL-6R (as first-line or post-corticosteroids and DMARDs), 73% of patients showed resolution or change to ≤grade 1 of irAEs after a median of 2.0 months from initiation of anti-IL-6R therapy. Six patients (7%) stopped anti-IL-6R due to adverse events. Of 70 evaluable patients by RECIST (Response Evaluation Criteria in Solid Tumors) V.1.1 criteria; the ORR was 66% prior versus 66% after anti-IL-6R (95% CI, 54% to 77%), with 8% higher complete response rate. Of 34 evaluable patients with melanoma, the ORR was 56% prior and increased to 68% after anti-IL-6R (p=0.04).
CONCLUSION: Targeting IL-6R could be an effective approach to treat several irAE types without hindering antitumor immunity. This study supports ongoing clinical trials evaluating the safety and efficacy of tocilizumab (anti-IL-6R antibody) in combination with ICIs (NCT04940299, NCT03999749).}, }
@article {pmid37327779, year = {2023}, author = {Radford, CE and Schommers, P and Gieselmann, L and Crawford, KHD and Dadonaite, B and Yu, TC and Dingens, AS and Overbaugh, J and Klein, F and Bloom, JD}, title = {Mapping the neutralizing specificity of human anti-HIV serum by deep mutational scanning.}, journal = {Cell host & microbe}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.chom.2023.05.025}, pmid = {37327779}, issn = {1934-6069}, abstract = {Understanding the specificities of human serum antibodies that broadly neutralize HIV can inform prevention and treatment strategies. Here, we describe a deep mutational scanning system that can measure the effects of combinations of mutations to HIV envelope (Env) on neutralization by antibodies and polyclonal serum. We first show that this system can accurately map how all functionally tolerated mutations to Env affect neutralization by monoclonal antibodies. We then comprehensively map Env mutations that affect neutralization by a set of human polyclonal sera that neutralize diverse strains of HIV and target the site engaging the host receptor CD4. The neutralizing activities of these sera target different epitopes, with most sera having specificities reminiscent of individual characterized monoclonal antibodies, but one serum targeting two epitopes within the CD4-binding site. Mapping the specificity of the neutralizing activity in polyclonal human serum will aid in assessing anti-HIV immune responses to inform prevention strategies.}, }
@article {pmid37326764, year = {2023}, author = {Rillamas-Sun, E and Kwan, ML and Iribarren, C and Cheng, R and Neugebauer, R and Rana, JS and Nguyen-Huynh, M and Shi, Z and Laurent, CA and Lee, VS and Roh, JM and Huang, Y and Shen, H and Hershman, DL and Kushi, LH and Greenlee, H}, title = {Development of cardiometabolic risk factors following endocrine therapy in women with breast cancer.}, journal = {Breast cancer research and treatment}, volume = {}, number = {}, pages = {}, pmid = {37326764}, issn = {1573-7217}, support = {R01 CA214057/CA/NCI NIH HHS/United States ; U01 CA195565/CA/NCI NIH HHS/United States ; }, abstract = {PURPOSE: Studies comparing the effect of aromatase inhibitor (AI) and tamoxifen use on cardiovascular disease (CVD) risk factors in hormone receptor-positive breast cancer (BC) survivors report conflicting results. We examined associations of endocrine therapy use with incident diabetes, dyslipidemia, and hypertension.
METHODS: The Pathways Heart Study examines cancer treatment exposures with CVD-related outcomes in Kaiser Permanente Northern California members with BC. Electronic health records provided sociodemographic and health characteristics, BC treatment, and CVD risk factor data. Hazard ratios (HR) and 95% confidence intervals (CI) of incident diabetes, dyslipidemia, and hypertension in hormone receptor-positive BC survivors using AIs or tamoxifen compared with survivors not using endocrine therapy were estimated using Cox proportional hazards regression models adjusted for known confounders.
RESULTS: In 8985 BC survivors, mean baseline age and follow-up time was 63.3 and 7.8 years, respectively; 83.6% were postmenopausal. By treatment, 77.0% used AIs, 19.6% used tamoxifen, and 16.0% used neither. Postmenopausal women who used tamoxifen had an increased rate (HR 1.43, 95% CI 1.06-1.92) of developing hypertension relative to those who did not use endocrine therapy. Tamoxifen use was not associated with incident diabetes, dyslipidemia, or hypertension in premenopausal BC survivors. Postmenopausal AI users had higher hazard rates of developing diabetes (HR 1.37, 95% CI 1.05-1.80), dyslipidemia (HR 1.58, 95% CI 1.29-1.92), and hypertension (HR 1.50, 95% CI 1.24-1.82) compared with non-endocrine therapy users.
CONCLUSION: Hormone receptor-positive BC survivors treated with AIs may have higher rates of developing diabetes, dyslipidemia, and hypertension over an average 7.8 years post-diagnosis.}, }
@article {pmid35118471, year = {2022}, author = {Addetia, A and Park, YJ and Starr, T and Greaney, AJ and Sprouse, KR and Bowen, JE and Tiles, SW and Van Voorhis, WC and Bloom, JD and Corti, D and Walls, AC and Veesler, D}, title = {Structural changes in the SARS-CoV-2 spike E406W mutant escaping a clinical monoclonal antibody cocktail.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {35118471}, abstract = {The SARS-CoV-2 receptor-binding domain (RBD) E406W mutation abrogates neutralization mediated by the REGEN-CoV therapeutic monoclonal antibody (mAb) COVID-19 cocktail and the cilgavimab (AZD1061) mAb. Here, we show that this residue substitution remodels the ACE2-binding site allosterically, thereby dampening receptor recognition severely and altering the epitopes recognized by these three mAbs. Although vaccine-elicited neutralizing antibody titers are decreased similarly against the E406 mutant and the Delta or Epsilon variants, broadly neutralizing sarbecovirus mAbs, including a clinical mAb, inhibit the E406W spike mutant.}, }
@article {pmid37325087, year = {2023}, author = {Santiago, JC and Westfall, DH and Adams, SV and Okuku, F and Phipps, W and Mullins, JI}, title = {Variation within major internal repeats of KSHV in vivo.}, journal = {Virus evolution}, volume = {9}, number = {1}, pages = {vead034}, pmid = {37325087}, issn = {2057-1577}, abstract = {Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent of Kaposi's sarcoma (KS), yet the viral genetic factors that lead to the development of KS in KSHV-infected individuals have not been fully elucidated. Nearly, all previous analyses of KSHV genomic evolution and diversity have excluded the three major internal repeat regions: the two origins of lytic replication, internal repeats 1 and 2 (IR1 and IR2), and the latency-associated nuclear antigen (LANA) repeat domain (LANAr). These regions encode protein domains that are essential to the KSHV infection cycle but have been rarely sequenced due to their extended repetitive nature and high guanine and cytosine (GC) content. The limited data available suggest that their sequences and repeat lengths are more heterogeneous across individuals than in the remainder of the KSHV genome. To assess their diversity, the full-length IR1, IR2, and LANAr sequences, tagged with unique molecular identifiers (UMIs), were obtained by Pacific Biosciences' single-molecule real-time sequencing (SMRT-UMI) from twenty-four tumors and six matching oral swabs from sixteen adults in Uganda with advanced KS. Intra-host single-nucleotide variation involved an average of 0.16 per cent of base positions in the repeat regions compared to a nearly identical average of 0.17 per cent of base positions in the remainder of the genome. Tandem repeat unit (TRU) counts varied by only one from the intra-host consensus in a majority of individuals. Including the TRU indels, the average intra-host pairwise identity was 98.3 per cent for IR1, 99.6 per cent for IR2 and 98.9 per cent for LANAr. More individuals had mismatches and variable TRU counts in IR1 (twelve/sixteen) than in IR2 (two/sixteen). There were no open reading frames in the Kaposin coding sequence inside IR2 in at least fifty-five of ninety-six sequences. In summary, the KSHV major internal repeats, like the rest of the genome in individuals with KS, have low diversity. IR1 was the most variable among the repeats, and no intact Kaposin reading frames were present in IR2 of the majority of genomes sampled.}, }
@article {pmid37324058, year = {2023}, author = {Zheng, C and Zhang, Y and Huang, Y and Prentice, R}, title = {Using Controlled Feeding Study for Biomarker Development in Regression Calibration for Disease Association Estimation.}, journal = {Statistics in biosciences}, volume = {15}, number = {1}, pages = {57-113}, pmid = {37324058}, issn = {1867-1764}, abstract = {Correction for systematic measurement error in self-reported data is an important challenge in association studies of dietary intake and chronic disease risk. The regression calibration method has been used for this purpose when an objectively measured biomarker is available. However, a big limitation of the regression calibration method is that biomarkers have only been developed for a few dietary components. We propose new methods to use controlled feeding studies to develop valid biomarkers for many more dietary components and to estimate the diet disease associations. Asymptotic distribution theory for the proposed estimators is derived. Extensive simulation is performed to study the finite sample performance of the proposed estimators. We applied our method to examine the associations between the sodium/potassium intake ratio and cardiovascular disease incidence using the Women's Health Initiative cohort data. We discovered positive associations between sodium/potassium ratio and the risks of coronary heart disease, nonfatal myocardial infarction, coronary death, ischemic stroke, and total cardiovascular disease.}, }
@article {pmid37324018, year = {2023}, author = {Jia, D and Li, X and Su, Y}, title = {Editorial: Systems biology and single-cell analysis of cancer metabolism and its role in cancer emergent properties.}, journal = {Frontiers in oncology}, volume = {13}, number = {}, pages = {1217212}, pmid = {37324018}, issn = {2234-943X}, }
@article {pmid37323466, year = {2022}, author = {Wang, Y and Zhao, Y and Zheng, Y}, title = {Targeted Search for Individualized Clinical Decision Rules to Optimize Clinical Outcomes.}, journal = {Statistics in biosciences}, volume = {14}, number = {3}, pages = {564-581}, pmid = {37323466}, issn = {1867-1764}, abstract = {Novel biomarkers, in combination with currently available clinical information, have been sought to enhance clinical decision making in many branches of medicine, including screening, surveillance and prognosis. An individualized clinical decision rule (ICDR) is a decision rule that matches subgroups of patients with tailored medical regimen based on patient characteristics. We proposed new approaches to identify ICDRs by directly optimizing a risk-adjusted clinical benefit function that acknowledges the tradeoff between detecting disease and over-treating patients with benign conditions. In particular, we developed a novel plug-in algorithm to optimize the risk-adjusted clinical benefit function, which leads to the construction of both nonparametric and linear parametric ICDRs. In addition, we proposed a novel approach based on the direct optimization of a smoothed ramp loss function to further enhance the robustness of a linear ICDR. We studied the asymptotic theories of the proposed estimators. Simulation results demonstrated good finite sample performance for the proposed estimators and improved clinical utilities when compared to standard approaches. The methods were applied to a prostate cancer biomarker study.}, }
@article {pmid37323428, year = {2023}, author = {Childs-Kean, LM and Beieler, AM and Coroniti, AM and Cortés-Penfield, N and Keller, SC and Mahoney, MV and Rajapakse, NS and Rivera, CG and Yoke, LH and Ryan, KL}, title = {A Bundle of the Top 10 OPAT Publications in 2022.}, journal = {Open forum infectious diseases}, volume = {10}, number = {6}, pages = {ofad283}, pmid = {37323428}, issn = {2328-8957}, abstract = {Outpatient parenteral antimicrobial therapy (OPAT) has become more common in clinical settings. Correspondingly, OPAT-related publications have also increased; the objective of this article was to summarize clinically meaningful OPAT-related publications in 2022. Seventy-five articles were initially identified, with 54 being scored. The top 20 OPAT articles published in 2022 were reviewed by a group of multidisciplinary OPAT clinicians. This article provides a summary of the "top 10" OPAT publications of 2022.}, }
@article {pmid37321901, year = {2023}, author = {Boot, IWA and Wesselius, A and Yu, EYW and White, E and Brustad, M and Marques, C and Ljungberg, B and Zeegers, MP}, title = {Dietary vitamin D intake and the bladder cancer risk: A pooled analysis of prospective cohort studies.}, journal = {Clinical nutrition (Edinburgh, Scotland)}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.clnu.2023.05.010}, pmid = {37321901}, issn = {1532-1983}, abstract = {BACKGROUND & AIMS: Diet may play an essential role in the aetiology of bladder cancer (BC). Vitamin D is involved in various biological functions which have the potential to prevent BC development. Besides, vitamin D also influences the uptake of calcium and phosphorus, thereby possibly indirectly influencing the risk of BC. The aim of the present study was to investigate the relation between vitamin D intake and BC risk.
METHODS: Individual dietary data were pooled from ten cohort studies. Food item intake was converted to daily intakes of vitamin D, calcium and phosphorus. Pooled multivariate hazard ratios (HRs), with corresponding 95% confidence intervals (CIs) were obtained using Cox-regression models. Analyses were adjusted for gender, age and smoking status (Model 1), and additionally for the food groups fruit, vegetables and meat (Model 2). Dose-response relationships (Model 1) were examined using a nonparametric test for trend.
RESULTS: In total, 1994 cases and 518,002 non-cases were included in the analyses. The present study showed no significant associations between individual nutrient intake and BC risk. A significant decreased BC risk was observed for high vitamin D intake with moderate calcium and low phosphorus intake (Model 2: HRhigh vitD, mod Ca, low P: 0.77, 95% CI: 0.59-1.00). No significant dose-response analyses were observed.
CONCLUSION: The present study showed a decreased BC risk for high dietary vitamin D intake in combination with low calcium intake and moderate phosphorus intake. The study highlights the importance of examining the effect of a nutrient in combination with complementary nutrients for risk assessment. Future research should focus on nutrients in a wider context and in nutritional patterns.}, }
@article {pmid37321403, year = {2023}, author = {Abbott, CA and Freimayer, EL and Tyllis, TS and Norton, TS and Alsharifi, M and H S Heng, A and Pederson, SM and Qu, Z and Armstrong, M and Hill, GR and McColl, SR and Comerford, I}, title = {Determination of Tr1 cell populations correlating with distinct activation states in acute IAV infection.}, journal = {Mucosal immunology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.mucimm.2023.06.003}, pmid = {37321403}, issn = {1935-3456}, abstract = {Type I regulatory (Tr1) cells are defined as FOXP3[-]IL-10-secreting CD4[+] T cells that contribute to immune suppression and typically express the markers LAG-3 and CD49b and other co-inhibitory receptors. These cells have not been studied in detail the context of the resolution of acute infection in the lung. Here, we identify FOXP3[-]IL-10[+] CD4[+] T cells transiently accumulating in the lung parenchyma during resolution of the response to sublethal influenza A virus (IAV) infection in mice. These cells were dependent on IL-27Rα, which was required for timely recovery from IAV-induced weight loss. LAG-3 and CD49b were not generally co-expressed by FOXP3[-] IL-10[+] CD4[+] T cells in this model and four populations of these cells based on LAG-3 and CD49b co-expression were apparent (LAG-3[-]CD49b[-] [DN], LAG-3[+]CD49b[+] [DP], LAG-3[+]CD49b[-] [LAG-3[+]], LAG-3[-]CD49b[+] [CD49b[+]]). However, each population exhibited suppressive potential consistent with the definition of Tr1 cells. Notably, differences between these populations of Tr1 cells were apparent including differential dependence on IL-10 to mediate suppression and expression of markers indicative of different activation states and terminal differentiation. Sort-transfer experiments indicated that LAG-3[+] Tr1 cells exhibited the capacity to convert to DN and DP Tr1 cells, indicative of plasticity between these populations. Together, these data determine the features and suppressive potential of Tr1 cells in the resolution of IAV infection and identify four populations delineated by LAG-3 and CD49b, which likely correspond to different Tr1 cell activation states.}, }
@article {pmid37318804, year = {2023}, author = {Khor, S and Haupt, EC and Hahn, EE and Lyons, LJL and Shankaran, V and Bansal, A}, title = {Racial and Ethnic Bias in Risk Prediction Models for Colorectal Cancer Recurrence When Race and Ethnicity Are Omitted as Predictors.}, journal = {JAMA network open}, volume = {6}, number = {6}, pages = {e2318495}, doi = {10.1001/jamanetworkopen.2023.18495}, pmid = {37318804}, issn = {2574-3805}, abstract = {IMPORTANCE: Including race and ethnicity as a predictor in clinical risk prediction algorithms has received increased scrutiny, but there continues to be a lack of empirical studies addressing whether simply omitting race and ethnicity from the algorithms will ultimately affect decision-making for patients of minoritized racial and ethnic groups.
OBJECTIVE: To examine whether including race and ethnicity as a predictor in a colorectal cancer recurrence risk algorithm is associated with racial bias, defined as racial and ethnic differences in model accuracy that could potentially lead to unequal treatment.
This retrospective prognostic study was conducted using data from a large integrated health care system in Southern California for patients with colorectal cancer who received primary treatment between 2008 and 2013 and follow-up until December 31, 2018. Data were analyzed from January 2021 to June 2022.
MAIN OUTCOMES AND MEASURES: Four Cox proportional hazards regression prediction models were fitted to predict time from surveillance start to cancer recurrence: (1) a race-neutral model that explicitly excluded race and ethnicity as a predictor, (2) a race-sensitive model that included race and ethnicity, (3) a model with 2-way interactions between clinical predictors and race and ethnicity, and (4) separate models by race and ethnicity. Algorithmic fairness was assessed using model calibration, discriminative ability, false-positive and false-negative rates, positive predictive value (PPV), and negative predictive value (NPV).
RESULTS: The study cohort included 4230 patients (mean [SD] age, 65.3 [12.5] years; 2034 [48.1%] female; 490 [11.6%] Asian, Hawaiian, or Pacific Islander; 554 [13.1%] Black or African American; 937 [22.1%] Hispanic; and 2249 [53.1%] non-Hispanic White). The race-neutral model had worse calibration, NPV, and false-negative rates among racial and ethnic minority subgroups than non-Hispanic White individuals (eg, false-negative rate for Hispanic patients: 12.0% [95% CI, 6.0%-18.6%]; for non-Hispanic White patients: 3.1% [95% CI, 0.8%-6.2%]). Adding race and ethnicity as a predictor improved algorithmic fairness in calibration slope, discriminative ability, PPV, and false-negative rates (eg, false-negative rate for Hispanic patients: 9.2% [95% CI, 3.9%-14.9%]; for non-Hispanic White patients: 7.9% [95% CI, 4.3%-11.9%]). Inclusion of race interaction terms or using race-stratified models did not improve model fairness, likely due to small sample sizes in subgroups.
CONCLUSIONS AND RELEVANCE: In this prognostic study of the racial bias in a cancer recurrence risk algorithm, removing race and ethnicity as a predictor worsened algorithmic fairness in multiple measures, which could lead to inappropriate care recommendations for patients who belong to minoritized racial and ethnic groups. Clinical algorithm development should include evaluation of fairness criteria to understand the potential consequences of removing race and ethnicity for health inequities.}, }
@article {pmid37318803, year = {2023}, author = {Ortblad, KF and Bardon, AR and Mogere, P and Kiptinness, C and Gakuo, S and Mbaire, S and Thomas, KK and Mugo, NR and Baeten, JM and Ngure, K}, title = {Effect of 6-Month HIV Preexposure Prophylaxis Dispensing With Interim Self-testing on Preexposure Prophylaxis Continuation at 12 Months: A Randomized Noninferiority Trial.}, journal = {JAMA network open}, volume = {6}, number = {6}, pages = {e2318590}, doi = {10.1001/jamanetworkopen.2023.18590}, pmid = {37318803}, issn = {2574-3805}, abstract = {IMPORTANCE: Daily oral HIV preexposure prophylaxis (PrEP) delivery requires quarterly clinic visits for HIV testing and drug refilling that are costly to health systems and clients.
OBJECTIVE: To evaluate whether 6-month PrEP dispensing supported with interim HIV self-testing (HIVST) results in noninferior PrEP continuation outcomes at 12 months compared with standard quarterly clinic visits.
This randomized noninferiority trial was conducted from May 2018 to May 2021 with 12 months of follow-up among PrEP clients aged 18 years or older who were returning for their first refill at a research clinic in Kiambu County, Kenya.
INTERVENTION: Participants were randomized 2:1 to (1) 6-month PrEP dispensing with semiannual clinic visits and interim HIVST at 3 months or (2) standard-of-care (SOC) PrEP delivery with 3-month dispensing, quarterly clinic visits, and clinic-based HIV testing.
MAIN OUTCOMES AND MEASURES: Prespecified 12-month outcomes included recent HIV testing (any in past 6 months), PrEP refilling, and PrEP adherence (detectable tenofovir-diphosphate concentrations in dried blood spots). Binomial regression models were used to estimate risk differences (RDs), and a 1-sided 95% CI lower bound (LB) of -10% or greater was interpreted as noninferior.
RESULTS: A total of 495 participants were enrolled, with 329 enrolled in the intervention group and 166 enrolled in the SOC group; 330 (66.7%) were women, 295 (59.6%) were in serodifferent relationships, and the median (IQR) age was 33 (27-40) years. At 12 months, 241 individuals in the intervention group (73.3%) and 120 in the SOC group (72.3%) returned to clinic. In the intervention group, recent HIV testing was noninferior (230 individuals [69.9%]) compared with the SOC group (116 [69.9%]; RD, -0.33%, 95% CI LB, -7.44%). PrEP refilling in the intervention group (196 [59.6%]) was inconclusive compared with the SOC group (104 [62.7%]; RD, -3.25%; 95% CI LB, -10.84%), and PrEP adherence was noninferior in the intervention group (151 [45.9%]) compared with the SOC group (70 [42.2%]; RD, 4.96%; 95% CI LB, -2.46%). No HIV seroconversions were observed over the follow-up period.
CONCLUSIONS AND RELEVANCE: In this analysis of secondary trial end points at 1 year, semiannual PrEP dispensing with interim HIVST resulted in noninferior recent HIV testing and PrEP adherence compared with SOC quarterly PrEP dispensing. This novel model has the potential to optimize PrEP delivery.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03593629.}, }
@article {pmid37315172, year = {2023}, author = {Loeb, A and Pattwell, S and Meshinchi, S and Bedalov, A and Loeb, KR}, title = {Donor Bone Marrow Derived Macrophage Engraftment into the Central Nervous System of Allogeneic Transplant Patients.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2023010409}, pmid = {37315172}, issn = {2473-9537}, abstract = {Hematopoietic stem cell transplantation is a well-known treatment of hematologic malignancies wherein nascent stem cells provide a regenerating marrow and immunotherapy against the tumor. The progeny of hematopoietic stem cells also populate a wide spectrum of tissues, including the brain, as bone marrow derived macrophages similar to microglial cells. We developed a sensitive and novel combined IHC and XY FISH assay to detect, quantify and characterize donor cells in the cerebral cortex of 19 female allogeneic stem cell transplant patients. We show that the number of male donor cells ranged from 0.14-3.0% of total cells or 1.2-25% of microglial cells. Using tyramide based fluorescent IHC we found at least 80% of the donor cells express the microglial marker IBA1 consistent with being bone marrow derived macrophages. The percentage of donor cells was related to pretransplant conditioning; donor cells from radiation based myeloablative cases averaged 8.1% of microglial cells, while those from non-myeloablative cases averaged only 1.3%. The number of donor cells in patients conditioned with Busulfan or Treosulfan based myeloablation were similar to TBI based conditioning; donor cells averaged 6.8% of microglial cells. Notably, patients who received multiple transplants and those with the longest post-transplant survival had the highest level of donor engraftment, with donor cells averaging 16.3% of microglial cells. Our work represents the largest study characterizing bone marrow-derived macrophages in post-transplant patients. The efficiency of engraftment observed in our study warrants future research on microglial replacement as a therapeutic option for disorders of the central nervous system.}, }
@article {pmid36763522, year = {2023}, author = {Lee, BM and Summers, C and Chisholm, KM and Bohling, SD and Leger, KJ and Gardner, R and Annesley, C and Lamble, AJ}, title = {Plasticity of lineage switch in B-ALL allows for successful rechallenge with CD19-directed immunotherapy.}, journal = {Blood advances}, volume = {7}, number = {12}, pages = {2825-2830}, doi = {10.1182/bloodadvances.2022009480}, pmid = {36763522}, issn = {2473-9537}, }
@article {pmid37315134, year = {2023}, author = {Wooten, M and Takushi, B and Ahmad, K and Henikoff, S}, title = {Aclarubicin stimulates RNA polymerase II elongation at closely spaced divergent promoters.}, journal = {Science advances}, volume = {9}, number = {24}, pages = {eadg3257}, doi = {10.1126/sciadv.adg3257}, pmid = {37315134}, issn = {2375-2548}, abstract = {Anthracyclines are a class of widely prescribed anticancer drugs that disrupt chromatin by intercalating into DNA and enhancing nucleosome turnover. To understand the molecular consequences of anthracycline-mediated chromatin disruption, we used Cleavage Under Targets and Tagmentation (CUT&Tag) to profile RNA polymerase II during anthracycline treatment in Drosophila cells. We observed that treatment with the anthracycline aclarubicin leads to elevated levels of RNA polymerase II and changes in chromatin accessibility. We found that promoter proximity and orientation affect chromatin changes during aclarubicin treatment, as closely spaced divergent promoter pairs show greater chromatin changes when compared to codirectionally oriented tandem promoters. We also found that aclarubicin treatment changes the distribution of noncanonical DNA G-quadruplex structures both at promoters and at G-rich pericentromeric repeats. Our work suggests that the cancer-killing activity of aclarubicin is driven by the disruption of nucleosomes and RNA polymerase II.}, }
@article {pmid37315132, year = {2023}, author = {Tang, M and Chen, G and Tu, B and Hu, Z and Huang, Y and DuFort, CC and Wan, X and Mao, Z and Liu, Y and Zhu, WG and Lu, W}, title = {SMYD2 inhibition-mediated hypomethylation of Ku70 contributes to impaired nonhomologous end joining repair and antitumor immunity.}, journal = {Science advances}, volume = {9}, number = {24}, pages = {eade6624}, doi = {10.1126/sciadv.ade6624}, pmid = {37315132}, issn = {2375-2548}, abstract = {DNA damage repair (DDR) is a double-edged sword with different roles in cancer susceptibility and drug resistance. Recent studies suggest that DDR inhibitors affect immune surveillance. However, this phenomenon is poorly understood. We report that methyltransferase SMYD2 plays an essential role in nonhomologous end joining repair (NHEJ), driving tumor cells adaptive to radiotherapy. Mechanically, in response to DNA damage, SMYD2 is mobilized onto chromatin and methylates Ku70 at lysine-74, lysine-516, and lysine-539, leading to increased recruitment of Ku70/Ku80/DNA-PKcs complex. Knockdown of SMYD2 or its inhibitor AZ505 results in persistent DNA damage and improper repair, which sequentially leads to accumulation of cytosolic DNA, and activation of cGAS-STING pathway and triggers antitumor immunity via infiltration and activation of cytotoxic CD8[+] T cells. Our study reveals an unidentified role of SMYD2 in regulating NHEJ pathway and innate immune responses, suggesting that SMYD2 is a promising therapeutic target for cancer treatment.}, }
@article {pmid37314481, year = {2023}, author = {Davé, V and Richert-Spuhler, LE and Arkatkar, T and Warrier, L and Pholsena, T and Johnston, C and Schiffer, JT and Prlic, M and Lund, JM}, title = {Recurrent infection transiently expands human tissue T cells while maintaining long-term homeostasis.}, journal = {The Journal of experimental medicine}, volume = {220}, number = {9}, pages = {}, pmid = {37314481}, issn = {1540-9538}, support = {R01 AI123323/NH/NIH HHS/United States ; }, abstract = {Chronic viral infections are known to lead to T cell exhaustion or dysfunction. However, it remains unclear if antigen exposure episodes from periodic viral reactivation, such as herpes simplex virus type-2 (HSV-2) recrudescence, are sufficient to induce T cell dysfunction, particularly in the context of a tissue-specific localized, rather than a systemic, infection. We designed and implemented a stringent clinical surveillance protocol to longitudinally track both viral shedding and in situ tissue immune responses in a cohort of HSV+ volunteers that agreed to avoid using anti-viral therapy for the course of this study. Comparing lesion to control skin biopsies, we found that tissue T cells expanded immediately after reactivation, and then returned numerically and phenotypically to steady state. T cell responses appeared to be driven at least in part by migration of circulating T cells to the infected tissue. Our data indicate that tissue T cells are stably maintained in response to HSV reactivation, resembling a series of acute recall responses.}, }
@article {pmid37313548, year = {2023}, author = {Sun, Y and Zhou, Q and Gilbert, PB}, title = {Analysis of the Cox Model with Longitudinal Covariates with Measurement Errors and Partly Interval Censored Failure Times, with Application to an AIDS Clinical Trial.}, journal = {Statistics in biosciences}, volume = {15}, number = {2}, pages = {430-454}, pmid = {37313548}, issn = {1867-1764}, abstract = {UNLABELLED: Time-dependent covariates are often measured intermittently and with measurement errors. Motivated by the AIDS Clinical Trials Group (ACTG) 175 trial, this paper develops statistical inferences for the Cox model for partly interval censored failure times and longitudinal covariates with measurement errors. The conditional score methods developed for the Cox model with measurement errors and right censored data are no longer applicable to interval censored data. Assuming an additive measurement error model for a longitudinal covariate, we propose a nonparametric maximum likelihood estimation approach by deriving the measurement error induced hazard model that shows the attenuating effect of using the plug-in estimate for the true underlying longitudinal covariate. An EM algorithm is devised to facilitate maximum likelihood estimation that accounts for the partly interval censored failure times. The proposed methods can accommodate different numbers of replicates for different individuals and at different times. Simulation studies show that the proposed methods perform well with satisfactory finite-sample performances and that the naive methods ignoring measurement error or using the plug-in estimate can yield large biases. A hypothesis testing procedure for the measurement error model is proposed. The proposed methods are applied to the ACTG 175 trial to assess the associations of treatment arm and time-dependent CD4 cell count on the composite clinical endpoint of AIDS or death.
SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12561-023-09372-y.}, }
@article {pmid36945124, year = {2023}, author = {Sabo, MC and Balkus, JE and Richardson, BA and Srinivasan, S and Kimani, J and Anzala, O and Schwebke, J and Fiedler, TL and Fredricks, DN and McClelland, RS}, title = {Next generation sequencing to examine associations between vaginal washing and vaginal microbiota: A cohort study.}, journal = {International journal of STD & AIDS}, volume = {34}, number = {8}, pages = {557-566}, doi = {10.1177/09564624231160806}, pmid = {36945124}, issn = {1758-1052}, abstract = {BACKGROUND: The association between vaginal washing and HIV risk may be mediated by vaginal washing-associated changes in vaginal microbiota.
METHODS: Data from a cohort of HIV-negative US and Kenyan women enrolled in the Preventing Vaginal Infections trial were analyzed. Vaginal fluid samples and vaginal washing data were collected every 2 months for 12 months. Bacterial relative abundances were measured by broad-range 16S rRNA gene polymerase chain reaction with next generation sequencing. Generalized estimating equations were used to evaluate the association between vaginal washing and i) the Shannon Diversity Index (SDI); and ii) mean change in percent bacterial relative abundances, with application of a 10% false discovery rate (FDR).
RESULTS: Participants (N = 111) contributed 93/630 (14.8%) vaginal washing visits. Mean SDI was 0.74 points higher (95% CI 0.35, 1.14; p < 0.001) at washing visits among US participants (N = 26). Vaginal washing was not associated with SDI in Kenyan participants (N = 85). There were no associations between vaginal washing and vaginal bacterial relative abundances after applying the FDR.
CONCLUSIONS: The discordant results in Kenyan versus US women suggests the link between vaginal washing and sub-optimal vaginal microbiota may be context specific. Vaginal microbial shifts may not fully explain the association between vaginal washing and HIV acquisition.}, }
@article {pmid36415459, year = {2022}, author = {Gozzi, N and Chinazzi, M and Dean, NE and Longini, IM and Halloran, ME and Perra, N and Vespignani, A}, title = {Estimating the impact of COVID-19 vaccine allocation inequities: a modeling study.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {36415459}, abstract = {Access to COVID-19 vaccines on the global scale has been drastically impacted by structural socio-economic inequities. Here, we develop a data-driven, age-stratified epidemic model to evaluate the effects of COVID-19 vaccine inequities in twenty lower middle and low income countries (LMIC) sampled from all WHO regions. We focus on the first critical months of vaccine distribution and administration, exploring counterfactual scenarios where we assume the same per capita daily vaccination rate reported in selected high income countries. We estimate that, in this high vaccine availability scenario, more than 50% of deaths (min-max range: [56% - 99%]) that occurred in the analyzed countries could have been averted. We further consider a scenario where LMIC had similarly early access to vaccine doses as high income countries; even without increasing the number of doses, we estimate an important fraction of deaths (min-max range: [7% - 73%]) could have been averted. In the absence of equitable allocation, the model suggests that considerable additional non-pharmaceutical interventions would have been required to offset the lack of vaccines (min-max range: [15% - 75%]). Overall, our results quantify the negative impacts of vaccines inequities and call for amplified global efforts to provide better access to vaccine programs in low and lower middle income countries.}, }
@article {pmid37311745, year = {2023}, author = {Ahuja, SK and Manoharan, MS and Lee, GC and McKinnon, LR and Meunier, JA and Steri, M and Harper, N and Fiorillo, E and Smith, AM and Restrepo, MI and Branum, AP and Bottomley, MJ and Orrù, V and Jimenez, F and Carrillo, A and Pandranki, L and Winter, CA and Winter, LA and Gaitan, AA and Moreira, AG and Walter, EA and Silvestri, G and King, CL and Zheng, YT and Zheng, HY and Kimani, J and Blake Ball, T and Plummer, FA and Fowke, KR and Harden, PN and Wood, KJ and Ferris, MT and Lund, JM and Heise, MT and Garrett, N and Canady, KR and Abdool Karim, SS and Little, SJ and Gianella, S and Smith, DM and Letendre, S and Richman, DD and Cucca, F and Trinh, H and Sanchez-Reilly, S and Hecht, JM and Cadena Zuluaga, JA and Anzueto, A and Pugh, JA and , and Agan, BK and Root-Bernstein, R and Clark, RA and Okulicz, JF and He, W}, title = {Immune resilience despite inflammatory stress promotes longevity and favorable health outcomes including resistance to infection.}, journal = {Nature communications}, volume = {14}, number = {1}, pages = {3286}, pmid = {37311745}, issn = {2041-1723}, abstract = {Some people remain healthier throughout life than others but the underlying reasons are poorly understood. Here we hypothesize this advantage is attributable in part to optimal immune resilience (IR), defined as the capacity to preserve and/or rapidly restore immune functions that promote disease resistance (immunocompetence) and control inflammation in infectious diseases as well as other causes of inflammatory stress. We gauge IR levels with two distinct peripheral blood metrics that quantify the balance between (i) CD8[+] and CD4[+] T-cell levels and (ii) gene expression signatures tracking longevity-associated immunocompetence and mortality-associated inflammation. Profiles of IR metrics in ~48,500 individuals collectively indicate that some persons resist degradation of IR both during aging and when challenged with varied inflammatory stressors. With this resistance, preservation of optimal IR tracked (i) a lower risk of HIV acquisition, AIDS development, symptomatic influenza infection, and recurrent skin cancer; (ii) survival during COVID-19 and sepsis; and (iii) longevity. IR degradation is potentially reversible by decreasing inflammatory stress. Overall, we show that optimal IR is a trait observed across the age spectrum, more common in females, and aligned with a specific immunocompetence-inflammation balance linked to favorable immunity-dependent health outcomes. IR metrics and mechanisms have utility both as biomarkers for measuring immune health and for improving health outcomes.}, }
@article {pmid37311464, year = {2023}, author = {Darst, BF and Shen, J and Madduri, RK and Rodriguez, AA and Xiao, Y and Sheng, X and Saunders, EJ and Dadaev, T and Brook, MN and Hoffmann, TJ and Muir, K and Wan, P and Le Marchand, L and Wilkens, L and Wang, Y and Schleutker, J and MacInnis, RJ and Cybulski, C and Neal, DE and Nordestgaard, BG and Nielsen, SF and Batra, J and Clements, JA and Cancer BioResource, AP and Grönberg, H and Pashayan, N and Travis, RC and Park, JY and Albanes, D and Weinstein, S and Mucci, LA and Hunter, DJ and Penney, KL and Tangen, CM and Hamilton, RJ and Parent, MÉ and Stanford, JL and Koutros, S and Wolk, A and Sørensen, KD and Blot, WJ and Yeboah, ED and Mensah, JE and Lu, YJ and Schaid, DJ and Thibodeau, SN and West, CM and Maier, C and Kibel, AS and Cancel-Tassin, G and Menegaux, F and John, EM and Grindedal, EM and Khaw, KT and Ingles, SA and Vega, A and Rosenstein, BS and Teixeira, MR and , and Kogevinas, M and Cannon-Albright, L and Huff, C and Multigner, L and Kaneva, R and Leach, RJ and Brenner, H and Hsing, AW and Kittles, RA and Murphy, AB and Logothetis, CJ and Neuhausen, SL and Isaacs, WB and Nemesure, B and Hennis, AJ and Carpten, J and Pandha, H and De Ruyck, K and Xu, J and Razack, A and Teo, SH and , and Newcomb, LF and Fowke, JH and Neslund-Dudas, C and Rybicki, BA and Gamulin, M and Usmani, N and Claessens, F and Gago-Dominguez, M and Castelao, JE and Townsend, PA and Crawford, DC and Petrovics, G and Casey, G and Roobol, MJ and Hu, JF and Berndt, SI and Van Den Eeden, SK and Easton, DF and Chanock, SJ and Cook, MB and Wiklund, F and Witte, JS and Eeles, RA and Kote-Jarai, Z and Watya, S and Gaziano, JM and Justice, AC and Conti, DV and Haiman, CA}, title = {Evaluating approaches for constructing polygenic risk scores for prostate cancer in men of African and European ancestry.}, journal = {American journal of human genetics}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ajhg.2023.05.010}, pmid = {37311464}, issn = {1537-6605}, abstract = {Genome-wide polygenic risk scores (GW-PRSs) have been reported to have better predictive ability than PRSs based on genome-wide significance thresholds across numerous traits. We compared the predictive ability of several GW-PRS approaches to a recently developed PRS of 269 established prostate cancer-risk variants from multi-ancestry GWASs and fine-mapping studies (PRS269). GW-PRS models were trained with a large and diverse prostate cancer GWAS of 107,247 cases and 127,006 controls that we previously used to develop the multi-ancestry PRS269. Resulting models were independently tested in 1,586 cases and 1,047 controls of African ancestry from the California Uganda Study and 8,046 cases and 191,825 controls of European ancestry from the UK Biobank and further validated in 13,643 cases and 210,214 controls of European ancestry and 6,353 cases and 53,362 controls of African ancestry from the Million Veteran Program. In the testing data, the best performing GW-PRS approach had AUCs of 0.656 (95% CI = 0.635-0.677) in African and 0.844 (95% CI = 0.840-0.848) in European ancestry men and corresponding prostate cancer ORs of 1.83 (95% CI = 1.67-2.00) and 2.19 (95% CI = 2.14-2.25), respectively, for each SD unit increase in the GW-PRS. Compared to the GW-PRS, in African and European ancestry men, the PRS269 had larger or similar AUCs (AUC = 0.679, 95% CI = 0.659-0.700 and AUC = 0.845, 95% CI = 0.841-0.849, respectively) and comparable prostate cancer ORs (OR = 2.05, 95% CI = 1.87-2.26 and OR = 2.21, 95% CI = 2.16-2.26, respectively). Findings were similar in the validation studies. This investigation suggests that current GW-PRS approaches may not improve the ability to predict prostate cancer risk compared to the PRS269 developed from multi-ancestry GWASs and fine-mapping.}, }
@article {pmid37311033, year = {2023}, author = {Carrau, L and Frere, JJ and Golynker, I and Fajardo, A and Rivera, CF and Horiuchi, S and Roonprapunt, T and Minkoff, JM and Blanco-Melo, D and TenOever, B}, title = {Delayed engagement of host defenses enables SARS-CoV-2 viremia and productive infection of distal organs in the hamster model of COVID-19.}, journal = {Science signaling}, volume = {16}, number = {789}, pages = {eadg5470}, doi = {10.1126/scisignal.adg5470}, pmid = {37311033}, issn = {1937-9145}, abstract = {Clinical presentations that develop in response to infection result from interactions between the pathogen and host defenses. SARS-CoV-2, the etiologic agent of COVID-19, directly antagonizes these defenses, leading to delayed immune engagement in the lungs that materializes only as cells succumb to infection and are phagocytosed. Leveraging the golden hamster model of COVID-19, we sought to understand the dynamics between SARS-CoV-2 infection in the airways and the systemic host response that ensues. We found that early SARS-CoV-2 replication was largely confined to the respiratory tract and olfactory system and, to a lesser extent, the heart and gastrointestinal tract but generated a host antiviral response in every organ as a result of circulating type I and III interferons. Moreover, we showed that diminishing the response in the airways by immunosuppression or administration of SARS-CoV-2 intravenously resulted in decreased immune priming, viremia, and increased viral tropism, including productive infection of the liver, kidney, spleen, and brain. Last, we showed that productive infection of the airways was required for mounting an effective and system-wide antiviral response. Together, these data illustrate how COVID-19 can result in diverse clinical presentations in which disease outcomes can be a by-product of the speed and strength of immune engagement. These studies provide additional evidence for the mechanistic basis of the diverse clinical presentations of COVID-19 and highlight the ability of the respiratory tract to generate a systemic immune defense after pathogen recognition.}, }
@article {pmid37310797, year = {2023}, author = {Schröder, CP and van Leeuwen-Stok, E and Cardoso, F and Linderholm, B and Poncet, C and Wolff, AC and Bjelic-Radisic, V and Werutsky, G and Abreu, MH and Bozovic-Spasojevic, I and den Hoed, I and Honkoop, AH and Los, M and Leone, JP and Russell, NS and Smilde, TJ and van der Velden, AWG and Van Poznak, C and Vleugel, MM and Yung, RL and Coens, C and Giordano, SH and Ruddy, KJ}, title = {Quality of Life in Male Breast Cancer: Prospective Study of the International Male Breast Cancer Program (EORTC10085/TBCRC029/BIG2-07/NABCG).}, journal = {The oncologist}, volume = {}, number = {}, pages = {}, doi = {10.1093/oncolo/oyad152}, pmid = {37310797}, issn = {1549-490X}, abstract = {INTRODUCTION: Prospective data about quality of life (QoL) in men with breast cancer (BC) are lacking. A prospective registry (EORTC10085) of men with all BC stages, including a QoL correlative study, was performed as part of the International Male Breast Cancer Program.
METHODS: Questionnaires at BC diagnosis included the EORTC QLQ-C30 and BR23 (BC specific module), adapted for men. High functioning and global health/QoL scores indicate high functioning levels/high QoL; high symptom-focused measures scores indicate high symptoms/problems levels. EORTC reference data for healthy men and women with BC were used for comparisons.
RESULTS: Of 422 men consenting to participate, 363 were evaluable. Median age was 67 years, and median time between diagnosis and survey was 1.1 months. A total of 114 men (45%) had node-positive early disease, and 28 (8%) had advanced disease. Baseline mean global health status score was 73 (SD: 21), better than in female BC reference data (62, SD: 25). Common symptoms in male BC were fatigue (22, SD: 24), insomnia (21, SD: 28), and pain (16, SD: 23), for which women's mean scores indicated more burdensome symptoms at 33 (SD: 26), 30 (SD: 32), and 29 (SD: 29). Men's mean sexual activity score was 31 (SD: 26), with less sexual activity in older patients or advanced disease.
CONCLUSIONS: QoL and symptom burden in male BC patients appears no worse (and possibly better) than that in female patients. Future analyses on impact of treatment on symptoms and QoL over time, may support tailoring of male BC management.}, }
@article {pmid37308917, year = {2023}, author = {van Gent, M and Ouwendijk, WJD and Campbell, VL and Laing, KJ and Verjans, GMGM and Koelle, DM}, title = {Varicella-zoster virus proteome-wide T-cell screening demonstrates low prevalence of virus-specific CD8 T-cells in latently infected human trigeminal ganglia.}, journal = {Journal of neuroinflammation}, volume = {20}, number = {1}, pages = {141}, pmid = {37308917}, issn = {1742-2094}, mesh = {Adult ; Humans ; *Proteome ; Herpesvirus 3, Human ; Prevalence ; Trigeminal Ganglion ; CD8-Positive T-Lymphocytes ; Epitopes ; *Herpesvirus 1, Human ; }, abstract = {BACKGROUND: Trigeminal ganglia (TG) neurons are an important site of lifelong latent varicella-zoster virus (VZV) infection. Although VZV-specific T-cells are considered pivotal to control virus reactivation, their protective role at the site of latency remains uncharacterized.
METHODS: Paired blood and TG specimens were obtained from ten latent VZV-infected adults, of which nine were co-infected with herpes simplex virus type 1 (HSV-1). Short-term TG-derived T-cell lines (TG-TCL), generated by mitogenic stimulation of TG-derived T-cells, were probed for HSV-1- and VZV-specific T-cells using flow cytometry. We also performed VZV proteome-wide screening of TG-TCL to determine the fine antigenic specificity of VZV reactive T-cells. Finally, the relationship between T-cells and latent HSV-1 and VZV infections in TG was analyzed by reverse transcription quantitative PCR (RT-qPCR) and in situ analysis for T-cell proteins and latent viral transcripts.
RESULTS: VZV proteome-wide analysis of ten TG-TCL identified two VZV antigens recognized by CD8 T-cells in two separate subjects. The first was an HSV-1/VZV cross-reactive CD8 T-cell epitope, whereas the second TG harbored CD8 T-cells reactive with VZV specifically and not the homologous peptide in HSV-1. In silico analysis showed that HSV-1/VZV cross reactivity of TG-derived CD8 T-cells reactive with ten previously identified HSV-1 epitopes was unlikely, suggesting that HSV-1/VZV cross-reactive T-cells are not a common feature in dually infected TG. Finally, no association was detected between T-cell infiltration and VZV latency transcript abundance in TG by RT-qPCR or in situ analyses.
CONCLUSIONS: The low presence of VZV- compared to HSV-1-specific CD8 T-cells in human TG suggests that VZV reactive CD8 T-cells play a limited role in maintaining VZV latency.}, }
@article {pmid37312333, year = {2018}, author = {O'Neil, B and Hoffman, KE and Koyama, T and Alvarez, JR and Conwill, RM and Albertsen, PC and Cooperberg, MR and Goodman, M and Greenfield, S and Hamilton, AS and Kaplan, SH and Hashibe, M and Stanford, JL and Stroup, AM and Paddock, LE and Chen, V and Wu, XC and Resnick, MJ and Penson, DF and Barocas, DA}, title = {Patient Reported Comparative Effectiveness of Contemporary Intensity Modulated Radiation Therapy Versus External Beam Radiation Therapy of the Mid 1990s for Localized Prostate Cancer.}, journal = {Urology practice}, volume = {5}, number = {6}, pages = {471-479}, doi = {10.1016/j.urpr.2017.09.008}, pmid = {37312333}, issn = {2352-0787}, abstract = {INTRODUCTION: Little is known about differences in patient reported outcomes between contemporary external beam radiation therapy for localized prostate cancer that delivers higher doses of conformal radiation and older techniques. We examined sexual, urinary and bowel function between men undergoing contemporary intensity modulated radiation therapy vs those undergoing external beam radiation therapy in the mid 1990s.
METHODS: Subjects were selected from 2 large population based prospective cohort studies. Main outcomes were between-group differences in adjusted mean scores at 6 and 12 months. Secondary analyses examined odds ratios comparing groups reporting a clinically significant decline in function.
RESULTS: The cohort consisted of 943 men, 467 diagnosed in 2011 to 2012 and 476 diagnosed in 1994 to 1995. Men undergoing contemporary intensity modulated radiation therapy reported better bowel function at 6 months (mean difference 4.3 points, 95% CI 1.6-7.0) but not at 12 months. Patients receiving contemporary intensity modulated radiation therapy reported statistically worse but probably not clinically meaningful different urinary function at 12 months (2.7, 0.5 to 4.8 points), and no difference at 6 months. No differences in sexual function at 6 or 12 months were found. Secondary analyses demonstrated lower odds of reporting clinically meaningful declines in bowel function at 6 and 12 months and sexual function at 12 months for contemporary intensity modulated radiation therapy. However, patients receiving intensity modulated radiation therapy had higher odds of reporting clinically meaningful declines in urinary continence at 12 months.
CONCLUSIONS: Despite the delivery of higher doses of radiation, men treated with contemporary intensity modulated radiation therapy reported fewer gastrointestinal and possibly fewer sexual side effects than those treated with external beam radiation therapy in the mid 1990s. However, delivery of dose escalated intensity modulated radiation therapy may cause more urinary side effects.}, }
@article {pmid37308127, year = {2023}, author = {Nelson, RA and Soto-Perez-de-Celis, E and Chlebowski, RT and Schonberg, M and Mortimer, J and Pan, K and Hou, L and Neuhouser, ML and Reding, KW and Saquib, N and Wactawski-Wende, J and Wolfson, E and Sedrak, MS and Kruper, L}, title = {Predicting All-Cause Mortality in Women With and Without Breast Cancer Using the Schonberg Index: A Women's Health Initiative Study.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {21}, number = {6}, pages = {636-644.e13}, doi = {10.6004/jnccn.2023.7015}, pmid = {37308127}, issn = {1540-1413}, abstract = {BACKGROUND: When treating older women with breast cancer, life expectancy is an important consideration. ASCO recommends calculating 10-year mortality probabilities to inform treatment decisions. One useful tool is the Schonberg index, which predicts risk-based all-cause 10-year mortality. We investigated the use of this index in women aged ≥65 years with breast cancer in the Women's Health Initiative (WHI).
METHODS: We calculated 10-year mortality risk scores for 2,549 WHI participants with breast cancer ("cases") and 2,549 age-matched breast cancer-free participants ("controls") using Schonberg index risk scoring. Risk scores were grouped into quintiles for comparisons. Risk-stratified observed mortality rates and 95% confidence intervals were compared across cases and controls. Observed 10-year mortality rates in cases and controls were also compared with Schonberg index-based predicted 10-year mortality rates.
RESULTS: Compared with controls, cases were more often white (P=.005), had higher income and education levels (P<.001 for both), more often lived with their husband/partner (P<.001), scored higher on subjective health/happiness (P<.001), and needed less assistance in activities of daily living (P<.001). Participants with breast cancer had similar risk-stratified 10-year mortality rates compared with controls (34% vs 33%, respectively). Stratified results showed that cases had slightly higher mortality rates than controls in the lowest risk quintile and lower mortality rates in the 2 highest risk quintiles. Observed mortality rates in cases and controls were similar to Schonberg index-predicted mortality, with model c-indexes of 0.71 and 0.76, respectively.
CONCLUSIONS: Among women aged ≥65 years with incident breast cancer, the Schonberg index-based risk-stratified 10-year mortality rates were similar to those in women without breast cancer, demonstrating a similar performance of the index among both populations. Along with other health measures, prognostic indexes can help predict survival among older women with breast cancer and support geriatric oncology guidelines that promote using life expectancy calculation tools for shared decision-making.}, }
@article {pmid37308125, year = {2023}, author = {Benson, AB and Venook, AP and Al-Hawary, MM and Azad, N and Chen, YJ and Ciombor, KK and Cohen, S and Cooper, HS and Deming, D and Garrido-Laguna, I and Grem, JL and Hecht, JR and Hoffe, S and Hubbard, J and Hunt, S and Hussan, H and Jeck, W and Johung, KL and Joseph, N and Kirilcuk, N and Krishnamurthi, S and Maratt, J 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 Skibber, JM and Sofocleous, CT and Stotsky-Himelfarb, E and Tavakkoli, A and Willett, CG and Williams, G and Algieri, F and Gurski, L and Stehman, K}, title = {Anal Carcinoma, Version 2.2023, NCCN Clinical Practice Guidelines in Oncology.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {21}, number = {6}, pages = {653-677}, doi = {10.6004/jnccn.2023.0030}, pmid = {37308125}, issn = {1540-1413}, abstract = {This discussion summarizes the NCCN Clinical Practice Guidelines for managing squamous cell anal carcinoma, which represents the most common histologic form of the disease. A multidisciplinary approach including physicians from gastroenterology, medical oncology, surgical oncology, radiation oncology, and radiology is necessary. Primary treatment of perianal cancer and anal canal cancer are similar and include chemoradiation in most cases. Follow-up clinical evaluations are recommended for all patients with anal carcinoma because additional curative-intent treatment is possible. Biopsy-proven evidence of locally recurrent or persistent disease after primary treatment may require surgical treatment. Systemic therapy is generally recommended for extrapelvic metastatic disease. Recent updates to the NCCN Guidelines for Anal Carcinoma include staging classification updates based on the 9th edition of the AJCC Staging System and updates to the systemic therapy recommendations based on new data that better define optimal treatment of patients with metastatic anal carcinoma.}, }
@article {pmid37308117, year = {2023}, 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 Burstein, HJ and Chew, H and Dang, C and Elias, AD and Giordano, SH and Goetz, MP and Goldstein, LJ and Hurvitz, SA and Jankowitz, RC and Javid, SH and Krishnamurthy, J and Leitch, AM and Lyons, J and Mortimer, J and Patel, SA and Pierce, LJ and Rosenberger, LH and Rugo, HS and Schneider, B and Smith, ML and Soliman, H and Stringer-Reasor, EM and Telli, ML and Wei, M and Wisinski, KB and Young, JS and Yeung, K and Dwyer, MA and Kumar, R}, title = {NCCN Guidelines® Insights: Breast Cancer, Version 4.2023.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {21}, number = {6}, pages = {594-608}, doi = {10.6004/jnccn.2023.0031}, pmid = {37308117}, issn = {1540-1413}, abstract = {The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer address all aspects of management for breast cancer. The treatment landscape of metastatic breast cancer is evolving constantly. The therapeutic strategy takes into consideration tumor biology, biomarkers, and other clinical factors. Due to the growing number of treatment options, if one option fails, there is usually another line of therapy available, providing meaningful improvements in survival. This NCCN Guidelines Insights report focuses on recent updates specific to systemic therapy recommendations for patients with stage IV (M1) disease.}, }
@article {pmid37308017, year = {2023}, author = {Potter, JD and Brooks, C and Donovan, G and Cunningham, C and Douwes, J}, title = {A perspective on green, blue, and grey spaces, biodiversity, microbiota, and human health.}, journal = {The Science of the total environment}, volume = {}, number = {}, pages = {164772}, doi = {10.1016/j.scitotenv.2023.164772}, pmid = {37308017}, issn = {1879-1026}, abstract = {Humans have lived from equator to poles for millennia but are now increasingly intruding into the wild spaces of other species and steadily extruding ourselves from our own wild spaces, with a profound impact on: our relationship with the natural world; survival of other species; pollution; climate change; etc. We have yet to grasp how these changes directly impact our own health. The primary focus of this paper is on the beneficial influence of proximity to the natural environment. We summarize the evidence for associations between exposure to green space and blue space and improvements in health. In contrast, grey space - the urban landscape - largely presents hazards as well as reducing exposure to green and blue space and isolating us from the natural environment. We discuss various hypotheses that might explain why green, blue, and grey space affect health and focus particularly on the importance of the biodiversity hypothesis and the role of microbiota. We discuss possible mechanisms and exposure routes - air, soil, and water. We highlight the problem of exposure assessment, noting that many of our current tools are not fit for the purpose of understanding exposure to green and blue space, aerosols, soils, and water. We briefly discuss possible differences between indigenous perspectives on the nature of our relationship with the environment and the more dominant international-science view. Finally, we present research gaps and discuss future directions, particularly focusing on the ways in which we might - even in the absence of a full understanding of the mechanisms by which blue, green, and grey space affect our health - begin to implement policies to restore some balance to our environment of with the aim of reducing the large global burden of ill health.}, }
@article {pmid37307512, year = {2023}, author = {Bates, JE and Shrestha, S and Liu, Q and Smith, SA and Mulrooney, DA and Leisenring, W and Gibson, T and Robison, LL and Chow, EJ and Oeffinger, KC and Armstrong, GT and Constine, LS and Hoppe, BS and Lee, C and Yasui, Y and Howell, RM}, title = {Cardiac Substructure Radiation Dose and Risk of Late Cardiac Disease in 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 = {JCO2202320}, doi = {10.1200/JCO.22.02320}, pmid = {37307512}, issn = {1527-7755}, abstract = {PURPOSE: Radiation-associated cardiac disease is a major cause of morbidity/mortality among childhood cancer survivors. Radiation dose-response relationships for cardiac substructures and cardiac diseases remain unestablished.
METHODS: Using the 25,481 5-year survivors of childhood cancer treated from 1970 to 1999 in the Childhood Cancer Survivor Study, we evaluated coronary artery disease (CAD), heart failure (HF), valvular disease (VD), and arrhythmia. We reconstructed radiation doses for each survivor to the coronary arteries, chambers, valves, and whole heart. Excess relative rate (ERR) models and piecewise exponential models evaluated dose-response relationships.
RESULTS: The cumulative incidence 35 years from diagnosis was 3.9% (95% CI, 3.4 to 4.3) for CAD, 3.8% (95% CI, 3.4 to 4.2) for HF, 1.2% (95% CI, 1.0 to 1.5) for VD, and 1.4% (95% CI, 1.1 to 1.6) for arrhythmia. A total of 12,288 survivors (48.2%) were exposed to radiotherapy. Quadratic ERR models improved fit compared with linear ERR models for the dose-response relationship between mean whole heart and CAD, HF, and arrhythmia, suggesting a potential threshold dose; however, such departure from linearity was not observed for most cardiac substructure end point dose-response relationships. Mean doses of 5-9.9 Gy to the whole heart did not increase the risk of any cardiac diseases. Mean doses of 5-9.9 Gy to the right coronary artery (rate ratio [RR], 2.6; 95% CI, 1.6 to 4.1) and left ventricle (RR, 2.2; 95% CI, 1.3 to 3.7) increased risk of CAD, and to the tricuspid valve (RR, 5.5; 95% CI, 2.0 to 15.1) and right ventricle (RR, 8.4; 95% CI, 3.7 to 19.0) increased risk of VD.
CONCLUSION: Among children with cancer, there may be no threshold dose below which radiation to the cardiac substructures does not increase the risk of cardiac diseases. This emphasizes their importance in modern treatment planning.}, }
@article {pmid37306245, year = {2023}, author = {Gard, CC and Lange, J and Miglioretti, DL and O'Meara, ES and Lee, CI and Etzioni, R}, title = {Risk of cancer versus risk of cancer diagnosis? Accounting for diagnostic bias in predictions of breast cancer risk by race and ethnicity.}, journal = {Journal of medical screening}, volume = {}, number = {}, pages = {9691413231180028}, doi = {10.1177/09691413231180028}, pmid = {37306245}, issn = {1475-5793}, abstract = {OBJECTIVES: Cancer risk prediction may be subject to detection bias if utilization of screening is related to cancer risk factors. We examine detection bias when predicting breast cancer risk by race/ethnicity.
METHODS: We used screening and diagnosis histories from the Breast Cancer Surveillance Consortium to estimate risk of breast cancer onset and calculated relative risk of onset and diagnosis for each racial/ethnic group compared with non-Hispanic White women.
RESULTS: Of 104,073 women aged 40-54 receiving their first screening mammogram at a Breast Cancer Surveillance Consortium facility between 2000 and 2018, 10.2% (n = 10,634) identified as Asian, 10.9% (n = 11,292) as Hispanic, and 8.4% (n = 8719) as non-Hispanic Black. Hispanic and non-Hispanic Black women had slightly lower screening frequencies but biopsy rates following a positive mammogram were similar across groups. Risk of cancer diagnosis was similar for non-Hispanic Black and White women (relative risk vs non-Hispanic White = 0.90, 95% CI 0.65 to 1.14) but was lower for Asian (relative risk = 0.70, 95% CI 0.56 to 0.97) and Hispanic women (relative risk = 0.82, 95% CI 0.62 to 1.08). Relative risks of disease onset were 0.78 (95% CI 0.68 to 0.88), 0.70 (95% CI 0.59 to 0.83), and 0.95 (95% CI 0.84 to 1.09) for Asian, Hispanic, and non-Hispanic Black women, respectively.
CONCLUSIONS: Racial/ethnic differences in mammography and biopsy utilization did not induce substantial detection bias; relative risks of disease onset were similar to or modestly different than relative risks of diagnosis. Asian and Hispanic women have lower risks of developing breast cancer than non-Hispanic Black and White women, who have similar risks.}, }
@article {pmid37306128, year = {2023}, author = {Ortblad, KF and Mogere, P and Omollo, V and Kuo, AP and Asewe, M and Gakuo, S and Roche, S and Mugambi, M and Mugambi, ML and Stergachis, A and Odoyo, J and Bukusi, EA and Ngure, K and Baeten, JM}, title = {Stand-alone model for delivery of oral HIV pre-exposure prophylaxis in Kenya: a single-arm, prospective pilot evaluation.}, journal = {Journal of the International AIDS Society}, volume = {26}, number = {6}, pages = {e26131}, pmid = {37306128}, issn = {1758-2652}, support = {R34 MH120106/MH/NIMH NIH HHS/United States ; K99 MH121166/MH/NIMH NIH HHS/United States ; P30 AI027757/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; Male ; Adult ; Female ; Kenya ; *Pre-Exposure Prophylaxis ; Pilot Projects ; Prospective Studies ; *HIV Infections/drug therapy/prevention & control ; }, abstract = {INTRODUCTION: The delivery of daily, oral HIV pre-exposure prophylaxis (PrEP) at private pharmacies may overcome barriers to PrEP delivery at public healthcare facilities, including HIV-associated stigma, long wait times and overcrowding.
METHODS: At five private, community-based pharmacies in Kenya, a care pathway for PrEP delivery (ClinicalTrials.gov: NCT04558554) was piloted-the first of its kind in Africa. Pharmacy providers screened clients interested in PrEP for HIV risk, then used a prescribing checklist to identify clients without medical conditions that might contraindicate PrEP safety, counsel them on PrEP use and safety, conduct provider-assisted HIV self-testing and dispense PrEP. For complex clinical cases, a remote clinician was available for consultation. Clients who did not meet the checklist criteria were referred to public facilities for free services delivered by clinicians. Pharmacy providers dispensed a 1-month PrEP supply at initiation and a 3-month supply thereafter at a client fee of 300 KES (∼$3 USD) per visit.
RESULTS: From November 2020 to October 2021, pharmacy providers screened 575 clients, identified 476 who met the prescribing checklist criteria and initiated 287 (60%) on PrEP. Among pharmacy PrEP clients, the median age was 26 years (IQR 22-33) and 57% (163/287) were male. The prevalence of behaviours associated with HIV risk among clients was high; 84% (240/287) reported sexual partners with unknown HIV status and 53% (151/287) reported multiple sexual partners (past 6 months). PrEP continuation among clients was 53% (153/287) at 1 month, 36% (103/287) at 4 months and 21% (51/242) at 7 months. During the pilot observation period, 21% (61/287) of clients stopped and restarted PrEP and overall pill coverage was 40% (IQR 10%-70%). Nearly, all pharmacy PrEP clients (≥96%) agreed or strongly agreed with statements regarding the acceptability and appropriateness of pharmacy-delivered PrEP services.
CONCLUSIONS: Findings from this pilot suggest that populations at HIV risk frequently visit private pharmacies and PrEP initiation and continuation at pharmacies is similar to or exceeds that at public healthcare facilities. Private pharmacy-based PrEP delivery, conducted entirely by private-sector pharmacy staff, is a promising new delivery model that has the potential to expand PrEP reach in Kenya and similar settings.}, }
@article {pmid37302348, year = {2023}, author = {Moey, MYY and Hennessy, C and French, B and Warner, JL and Tucker, MD and Hausrath, DJ and Shah, DP and DeCara, JM and Bakouny, Z and Labaki, C and Choueiri, TK and Dent, S and Akhter, N and Ismail-Khan, R and Tachiki, L and Slosky, D and Polonsky, TS and Awosika, JA and Crago, A and Wise-Draper, T and Balanchivadze, N and Hwang, C and Fecher, LA and Gomez, CG and Hayes-Lattin, B and Glover, MJ and Shah, SA and Gopalakrishnan, D and Griffiths, EA and Kwon, DH and Koshkin, VS and Mahmood, S and Bashir, B and Nonato, T and Razavi, P and McKay, RR and Nagaraj, G and Oligino, E and Puc, M and Tregubenko, P and Wulff-Burchfield, EM and Xie, Z and Halfdanarson, TR and Farmakiotis, D and Klein, EJ and Robilotti, EV and Riely, GJ and Durand, JB and Hayek, SS and Kondapalli, L and Berg, S and O'Connor, TE and Bilen, MA and Castellano, C and Accordino, MK and Sibel, B and Weissmann, LB and Jani, C and Flora, DB and Rudski, L and Dutra, MS and Nathaniel, B and Ruíz-García, E and Vilar-Compte, D and Gupta, S and Morgans, A and Nohria, A and , }, title = {COVID-19 severity and cardiovascular outcomes in SARS-CoV-2-infected patients with cancer and cardiovascular disease.}, journal = {Translational oncology}, volume = {34}, number = {}, pages = {101709}, pmid = {37302348}, issn = {1936-5233}, abstract = {BACKGROUND: Data regarding outcomes among patients with cancer and co-morbid cardiovascular disease (CVD)/cardiovascular risk factors (CVRF) after SARS-CoV-2 infection are limited.
OBJECTIVES: To compare Coronavirus disease 2019 (COVID-19) related complications among cancer patients with and without co-morbid CVD/CVRF.
METHODS: Retrospective cohort study of patients with cancer and laboratory-confirmed SARS-CoV-2, reported to the COVID-19 and Cancer Consortium (CCC19) registry from 03/17/2020 to 12/31/2021. CVD/CVRF was defined as established CVD or no established CVD, male ≥ 55 or female ≥ 60 years, and one additional CVRF. The primary endpoint was an ordinal COVID-19 severity outcome including need for hospitalization, supplemental oxygen, intensive care unit (ICU), mechanical ventilation, ICU or mechanical ventilation plus vasopressors, and death. Secondary endpoints included incident adverse CV events. Ordinal logistic regression models estimated associations of CVD/CVRF with COVID-19 severity. Effect modification by recent cancer therapy was evaluated.
RESULTS: Among 10,876 SARS-CoV-2 infected patients with cancer (median age 65 [IQR 54-74] years, 53% female, 52% White), 6253 patients (57%) had co-morbid CVD/CVRF. Co-morbid CVD/CVRF was associated with higher COVID-19 severity (adjusted OR: 1.25 [95% CI 1.11-1.40]). Adverse CV events were significantly higher in patients with CVD/CVRF (all p<0.001). CVD/CVRF was associated with worse COVID-19 severity in patients who had not received recent cancer therapy, but not in those undergoing active cancer therapy (OR 1.51 [95% CI 1.31-1.74] vs. OR 1.04 [95% CI 0.90-1.20], pinteraction <0.001).
CONCLUSIONS: Co-morbid CVD/CVRF is associated with higher COVID-19 severity among patients with cancer, particularly those not receiving active cancer therapy. While infrequent, COVID-19 related CV complications were higher in patients with comorbid CVD/CVRF. (COVID-19 and Cancer Consortium Registry [CCC19]; NCT04354701).}, }
@article {pmid37301468, year = {2023}, author = {Calo, WA and Shah, PD and Fogel, BN and Ruffin, M and Moss, JL and Hausman, BL and Segel, JE and Francis, E and Schaefer, E and Bufalini, CM and Johnston, N and Hogentogler, E and Kraschnewski, JL}, title = {Increasing the adoption of evidence-based communication practices for HPV vaccination in primary care clinics: The HPV ECHO study protocol for a cluster randomized controlled trial.}, journal = {Contemporary clinical trials}, volume = {}, number = {}, pages = {107266}, doi = {10.1016/j.cct.2023.107266}, pmid = {37301468}, issn = {1559-2030}, abstract = {BACKGROUND: The safe, highly-effective human papillomavirus (HPV) vaccine remains underused in the US. The Announcement Approach Training (AAT) has been shown to effectively increase HPV vaccine uptake by training providers to make strong vaccine recommendations and answer parents' common questions. Systems communications, like recall notices, can further improve HPV vaccination by reducing missed clinical opportunities for vaccination. Never tested in supporting HPV vaccination, the ECHO (Extension for Community Healthcare Outcomes) model is a proven implementation strategy to increase best practices among healthcare providers. This trial uses a hybrid effectiveness-implementation design (type II) to evaluate two ECHO-delivered interventions intended to increase HPV vaccination rates.
METHODS: This 3-arm cluster randomized controlled trial will be conducted in 36 primary care clinics in Pennsylvania. Aim 1 evaluates the impact of HPV ECHO (AAT to providers) and HPV ECHO+ (AAT to providers plus recall notices to vaccine-declining parents) versus control on HPV vaccination (≥1 dose) among adolescents, ages 11-14, between baseline and 12-month follow-up (primary outcome). Using a convergent mixed-methods approach, Aim 2 evaluates the implementation of the HPV ECHO and HPV ECHO+ interventions. Aim 3 explores exposure to and impact of vaccine information from providers and other sources (e.g., social media) on secondary acceptance among 200 HPV vaccine-declining parents within 12 months.
DISCUSSION: We expect to demonstrate the effectiveness and evaluate the implementation of two highly scalable interventions to increase HPV vaccination in primary care clinics. Our study seeks to address the communication needs of both providers and parents, increase HPV vaccination, and, eventually, prevent HPV-related cancers.
TRIAL REGISTRATION: ClinicalTrials.govNCT04587167. Registered on October 14, 2020.}, }
@article {pmid37301367, year = {2023}, author = {Molina, Y and Kao, SY and Bergeron, NQ and Strayhorn-Carter, SM and Strahan, DC and Asche, C and Watson, KS and Khanna, AS and Hempstead, B and Fitzpatrick, V and Calhoun, EA and McDougall, J}, title = {The integration of value assessment and social network methods for breast health navigation among African Americans.}, journal = {Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jval.2023.06.001}, pmid = {37301367}, issn = {1524-4733}, abstract = {OBJECTIVES: A major strategy to reduce the impact of breast cancer (BC) among African Americans (AA) is patient navigation, defined here as individualized assistance for reducing barriers to healthcare use. The primary focus of this study was to estimate the added value of incorporating breast health promotion by navigated participants and the subsequent BC screenings that network members may obtain.
METHODS: In this study, we compared the cost-effectiveness of navigation across two scenarios. First, we examine the effect of navigation on AA participants (scenario 1). Second, we examine the effect of navigation on AA participants and their networks (scenario 2). We leverage data from multiple studies in South Chicago. Our primary outcome (BC screening) is intermediate, given limited available quantitative data on the long-term benefits of BC screening for AA populations.
RESULTS: When considering participant effects alone (scenario 1), the incremental cost effectiveness ratio (ICER) was $3,845 per additional screening mammogram. When including participant and network effects (scenario 2), the ICER was $1,098 per additional screening mammogram.
CONCLUSION: Our findings suggest that inclusion of network effects can contribute to a more precise, comprehensive assessment of interventions for underserved communities.}, }
@article {pmid37300931, year = {2023}, author = {Seaton, KE and Huang, Y and Karuna, S and Heptinstall, JR and Brackett, C and Chiong, K and Zhang, L and Yates, NL and Sampson, M and Rudnicki, E and Juraska, M and deCamp, AC and Edlefsen, PT and Mullins, JI and Williamson, C and Rossenkhan, R and Giorgi, EE and Kenny, A and Angier, H and Randhawa, A and Weiner, JA and Rojas, M and Sarzotti-Kelsoe, M and Zhang, L and Sawant, S and Ackerman, ME and McDermott, AB and Mascola, JR and Hural, J and McElrath, MJ and Andrew, P and Hidalgo, JA and Clark, J and Laher, F and Orrell, C and Frank, I and Gonzales, P and Edupuganti, S and Mgodi, N and Corey, L and Morris, L and Montefiori, D and Cohen, MS and Gilbert, PB and Tomaras, GD}, title = {Pharmacokinetic serum concentrations of VRC01 correlate with prevention of HIV-1 acquisition.}, journal = {EBioMedicine}, volume = {93}, number = {}, pages = {104590}, doi = {10.1016/j.ebiom.2023.104590}, pmid = {37300931}, issn = {2352-3964}, abstract = {BACKGROUND: The phase 2b proof-of-concept Antibody Mediated Prevention (AMP) trials showed that VRC01, an anti-HIV-1 broadly neutralising antibody (bnAb), prevented acquisition of HIV-1 sensitive to VRC01. To inform future study design and dosing regimen selection of candidate bnAbs, we investigated the association of VRC01 serum concentration with HIV-1 acquisition using AMP trial data.
METHODS: The case-control sample included 107 VRC01 recipients who acquired HIV-1 and 82 VRC01 recipients who remained without HIV-1 during the study. We measured VRC01 serum concentrations with a qualified pharmacokinetic (PK) Binding Antibody Multiplex Assay. We employed nonlinear mixed effects PK modelling to estimate daily-grid VRC01 concentrations. Cox regression models were used to assess the association of VRC01 concentration at exposure and baseline body weight, with the hazard of HIV-1 acquisition and prevention efficacy as a function of VRC01 concentration. We also compared fixed dosing vs. body weight-based dosing via simulations.
FINDINGS: Estimated VRC01 concentrations in VRC01 recipients without HIV-1 were higher than those in VRC01 recipients who acquired HIV-1. Body weight was inversely associated with HIV-1 acquisition among both placebo and VRC01 recipients but did not modify the prevention efficacy of VRC01. VRC01 concentration was inversely correlated with HIV-1 acquisition, and positively correlated with prevention efficacy of VRC01. Simulation studies suggest that fixed dosing may be comparable to weight-based dosing in overall predicted prevention efficacy.
INTERPRETATION: These findings suggest that bnAb serum concentration may be a useful marker for dosing regimen selection, and operationally efficient fixed dosing regimens could be considered for future trials of HIV-1 bnAbs.
FUNDING: Was provided by the National Institutes of Health, National Institute of Allergy and Infectious Diseases (NIAID) (UM1 AI068614, to the HIV Vaccine Trials Network [HVTN]; UM1 AI068635, to the HVTN Statistical Data and Management Center [SDMC], Fred Hutchinson Cancer Center [FHCC]; 2R37 054165 to the FHCC; UM1 AI068618, to HVTN Laboratory Center, FHCC; UM1 AI068619, to the HPTN Leadership and Operations Center; UM1 AI068613, to the HIV Prevention Trials Network [HPTN] Laboratory Center; UM1 AI068617, to the HPTN SDMC; and P30 AI027757, to the Center for AIDS Research, Duke University (AI P30 AI064518) and University of Washington (P30 AI027757) Centers for AIDS Research; R37AI054165 from NIAID to the FHCC; and OPP1032144 CA-VIMC Bill & Melinda Gates Foundation.}, }
@article {pmid37300832, year = {2023}, author = {Addetia, A and Park, YJ and Starr, T and Greaney, AJ and Sprouse, KR and Bowen, JE and Tiles, SW and Van Voorhis, WC and Bloom, JD and Corti, D and Walls, AC and Veesler, D}, title = {Structural changes in the SARS-CoV-2 spike E406W mutant escaping a clinical monoclonal antibody cocktail.}, journal = {Cell reports}, volume = {42}, number = {6}, pages = {112621}, pmid = {37300832}, issn = {2211-1247}, abstract = {Continued evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is eroding antibody responses elicited by prior vaccination and infection. The SARS-CoV-2 receptor-binding domain (RBD) E406W mutation abrogates neutralization mediated by the REGEN-COV therapeutic monoclonal antibody (mAb) COVID-19 cocktail and the AZD1061 (COV2-2130) mAb. Here, we show that this mutation remodels the receptor-binding site allosterically, thereby altering the epitopes recognized by these three mAbs and vaccine-elicited neutralizing antibodies while remaining functional. Our results demonstrate the spectacular structural and functional plasticity of the SARS-CoV-2 RBD, which is continuously evolving in emerging SARS-CoV-2 variants, including currently circulating strains that are accumulating mutations in the antigenic sites remodeled by the E406W substitution.}, }
@article {pmid37300447, year = {2023}, author = {Lynch, AM and Zanoni, TB and Salk, JJ and Martincorena, I and Young, RR and Kucab, J and Valentine, CC and Yauk, C and Escobar, PA and Witt, KL and Frötschl, R and Reed, SH and Ashford, A}, title = {Next Generation Sequencing Workshop at the Royal Society of Medicine (London, May 2022): How genomics is on the path to modernizing Genetic Toxicology.}, journal = {Mutagenesis}, volume = {}, number = {}, pages = {}, doi = {10.1093/mutage/gead012}, pmid = {37300447}, issn = {1464-3804}, abstract = {The use of error-corrected Next Generation Sequencing (ecNG) to determine mutagenicity has been a subject of growing interest and potentially a disruptive technology that could supplement, and in time, replace current testing paradigms in preclinical safety assessment. Considering this, a Next Generation Sequencing Workshop was held at the Royal Society of Medicine in London in May 2022, supported by the United Kingdom Environmental Mutagen Society (UKEMS) and TwinStrand Biosciences (WA, USA), to discuss progress and future applications of this technology. In this meeting report, the invited speakers provide an overview of the Workshop topics covered and identify future directions for research. In the area of somatic mutagenesis, several speakers reviewed recent progress made with correlating ecNGS to classic in vivo transgenic rodent mutation assays as well as exploring the use of this technology directly in humans and animals, and in complex organoid models. Additionally, ecNGS has been used for detecting off-target effects of gene editing tools and emerging data suggest ecNGS potential to measure clonal expansion of cells carrying mutations in cancer driver genes as an early marker of carcinogenic potential and for direct human biomonitoring. As such, the workshop demonstrated the importance of raising awareness and support for advancing the science of ecNGS for mutagenesis, gene editing and carcinogenesis research. Furthermore, the potential of this new technology to contribute to advances in drug and product development and improve safety assessment were extensively explored.}, }
@article {pmid37296675, year = {2023}, author = {Hui, J and Stjepić, V and Nakamura, M and Parkhurst, SM}, title = {Correction: Hui et al. Wrangling Actin Assemblies: Actin Ring Dynamics during Cell Wound Repair. Cells 2022, 11, 2777.}, journal = {Cells}, volume = {12}, number = {11}, pages = {}, doi = {10.3390/cells12111532}, pmid = {37296675}, issn = {2073-4409}, abstract = {In the original publication [...].}, }
@article {pmid37296110, year = {2023}, author = {Talla, A and Vasaikar, SV and Szeto, GL and Lemos, MP and Czartoski, JL and MacMillan, H and Moodie, Z and Cohen, KW and Fleming, LB and Thomson, Z and Okada, L and Becker, LA and Coffey, EM and De Rosa, SC and Newell, EW and Skene, PJ and Li, X and Bumol, TF and Juliana McElrath, M and Torgerson, TR}, title = {Persistent serum protein signatures define an inflammatory subcategory of long COVID.}, journal = {Nature communications}, volume = {14}, number = {1}, pages = {3417}, pmid = {37296110}, issn = {2041-1723}, abstract = {Long COVID or post-acute sequelae of SARS-CoV-2 (PASC) is a clinical syndrome featuring diverse symptoms that can persist for months following acute SARS-CoV-2 infection. The aetiologies may include persistent inflammation, unresolved tissue damage or delayed clearance of viral protein or RNA, but the biological differences they represent are not fully understood. Here we evaluate the serum proteome in samples, longitudinally collected from 55 PASC individuals with symptoms lasting ≥60 days after onset of acute infection, in comparison to samples from symptomatically recovered SARS-CoV-2 infected and uninfected individuals. Our analysis indicates heterogeneity in PASC and identified subsets with distinct signatures of persistent inflammation. Type II interferon signaling and canonical NF-κB signaling (particularly associated with TNF), appear to be the most differentially enriched signaling pathways, distinguishing a group of patients characterized also by a persistent neutrophil activation signature. These findings help to clarify biological diversity within PASC, identify participants with molecular evidence of persistent inflammation, and highlight dominant pathways that may have diagnostic or therapeutic relevance, including a protein panel that we propose as having diagnostic utility for differentiating inflammatory and non-inflammatory PASC.}, }
@article {pmid37295445, year = {2023}, author = {Siddiqi, T and Maloney, DG and Kenderian, SS and Brander, DM and Dorritie, K and Soumerai, J and Riedell, PA and Shah, NN and Nath, R and Fakhri, B and Stephens, DM and Ma, S and Feldman, T and Solomon, SR and Schuster, SJ and Perna, SK and Tuazon, SA and Ou, SS and Papp, E and Peiser, L and Chen, Y and Wierda, WG}, title = {Lisocabtagene maraleucel in chronic lymphocytic leukaemia and small lymphocytic lymphoma (TRANSCEND CLL 004): a multicentre, open-label, single-arm, phase 1-2 study.}, journal = {Lancet (London, England)}, volume = {}, number = {}, pages = {}, doi = {10.1016/S0140-6736(23)01052-8}, pmid = {37295445}, issn = {1474-547X}, abstract = {BACKGROUND: Patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma for whom treatment has failed with both Bruton tyrosine kinase (BTK) inhibitor and venetoclax have few treatment options and poor outcomes. We aimed to evaluate the efficacy and safety of lisocabtagene maraleucel (liso-cel) at the recommended phase 2 dose in patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma.
METHODS: We report the primary analysis of TRANSCEND CLL 004, an open-label, single-arm, phase 1-2 study conducted in the USA. Patients aged 18 years or older with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma and at least two previous lines of therapy, including a BTK inhibitor, received an intravenous infusion of liso-cel at one of two target dose levels: 50 ×