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Bibliography on: Publications by FHCRC Researchers

The Electronic Scholarly Publishing Project: Providing world-wide, free access to classic scientific papers and other scholarly materials, since 1993.


ESP: PubMed Auto Bibliography 23 Apr 2024 at 01:47 Created: 

Publications by FHCRC Researchers

The Fred Hutchinson Cancer Research Center began in 1975, with critical help from Washington State's U.S. Senator Warren Magnuson. Fred Hutch quickly became the permanent home to Dr. E. Donnall Thomas, who had spent decades developing an innovative treatment for leukemia and other blood cancers. Thomas and his colleagues were working to cure cancer by transplanting human bone marrow after otherwise lethal doses of chemotherapy and radiation. At the Hutch, Thomas improved this treatment and readied it for widespread use. Since then, the pioneering procedure has saved hundreds of thousands of lives worldwide. While improving bone marrow transplantation remains central to Fred Hutch's research, it is now only part of its efforts. The Hutch is home to five scientific divisions, three Nobel laureates and more than 2,700 faculty, who collectively have published more than 10,000 scientific papers, presented here as a full bibliography.

NOTE: From 1995 to 2009 I served as the Hutch's vice president for information technology — hence my interest in the organization. Although my role was in the admin division, if you dig through this bibliography, you will find a couple of papers with me as an author.

Created with PubMed® Query: ( fhcrc[Affiliation] OR "fred hutchinson"[Affiliation] OR "Fred Hutchinson Cancer Research"[Affiliation] OR "Fred Hutch"[affiliation] ) NOT pmcbook NOT ispreviousversion

Citations The Papers (from PubMed®)


RevDate: 2024-04-22
CmpDate: 2024-04-22

Oswald LB, Bloomer A, Li X, et al (2024)

Functional quality of life among newly diagnosed young adult colorectal cancer survivors compared to older adults: results from the ColoCare Study.

Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer, 32(5):298.

PURPOSE: Colorectal cancer (CRC) incidence and mortality are increasing among young adults (YAs) aged 18-39. This study compared quality of life (QOL) between YA and older adult CRC survivors in the ColoCare Study.

METHODS: Participants were grouped by age (years) as follows: 18-39 (YA), 40-49, 50-64, and 65 + . Functional QOL (physical, social, role, emotional, cognitive) and global QOL were assessed with the EORTC-QLQ-C30 at enrollment, 3, 6, and 12 months. Average scores were compared between groups over time using longitudinal mixed-effect modeling. Proportions with clinically meaningful QOL impairment were calculated using age-relevant thresholds and compared between groups over time using logistic regression with mixed effects.

RESULTS: Participants (N = 1590) were n = 81 YAs, n = 196 aged 40-49, n = 627 aged 50-64, and n = 686 aged 65 + . Average physical function was better among YAs than participants aged 50-64 (p = 0.010) and 65 + (p < 0.001), and average social function was worse among YAs than aged 65 + (p = 0.046). Relative to YAs, all age groups were less likely to report clinically meaningful social dysfunction (aged 40-49 OR = 0.13, 95%CI = 0.06-0.29; aged 50-64 OR = 0.10, 95%CI = 0.05-0.21; aged 65 + OR = 0.07, 95%CI = 0.04-0.15) and role dysfunction (aged 40-49 OR = 0.36, 95%CI = 0.18-0.75; aged 50-64 OR = 0.41, 95%CI = 0.22-0.78; aged 65 + OR = 0.32, 95%CI = 0.17-0.61). Participants aged 40-49 were also less likely to report physical dysfunction (OR = 0.42, 95%CI = 0.19-0.93).

CONCLUSION: YA CRC survivors reported better physical and worse social function compared to older CRC survivors, and YA CRC survivors were more likely to report clinically meaningful social, role, and physical disfunction. Future work should further investigate QOL using age-relevant benchmarks to inform best practices for CRC survivorship care.

TRIAL REGISTRATION: NCT02328677, registered December 2014.

RevDate: 2024-04-20

Harrison J, Stokes T, Hahne J, et al (2023)

Ca-HELP: Adaptation of a Communication Tool to Help Geriatric Cancer Patients in Rural Settings Talk to Their Doctors About Pain.

Innovation in aging, 7(10):igad087.

BACKGROUND AND OBJECTIVES: Among the older adult population living in the rural United States, undertreated cancer pain is very common. The need for interventions targeting pain management communication between older adults with cancer in rural communities and their doctors outpaces the current evidence base. Adaptation of existing pain interventions may improve the speed at which clinicians can respond to pain in this vulnerable population.

RESEARCH DESIGN AND METHODS: The Cancer Health Empowerment for Living without Pain (Ca-HELP) is an evidence-based communication tool that coaches patients to communicate about pain by asking questions, making requests, and signaling distress to their physicians in order to achieve improved pain control. Guided by the Method for Program Adaptation through Community Engagement (M-PACE) model, which utilizes detailed stakeholder feedback to guide the adaptation of an intervention for an appropriate target audience, we proactively adapted the Ca-HELP and its delivery for use among geriatric cancer patients living in rural settings using qualitative feedback from patients, informal caregivers, and providers as a planned step in a multiphase pilot study.

RESULTS: All stakeholders agreed that the Ca-HELP was a promising candidate intervention to improve pain among older adults with cancer. They suggested modifications to the delivery, context, and content of the intervention. A multidisciplinary team of nurse leaders and researchers evaluated stakeholder feedback and recommendations before determining which adaptations were made. Adaptations were cataloged and reported using the Framework for Reporting Adaptations and Modifications-Enhanced model.

DISCUSSION AND IMPLICATIONS: Our multistakeholder team proactively modified the Ca-HELP intervention tool using end-user feedback with a goal to optimize fit for use by older adults with cancer in rural settings without compromising the active ingredients. Documenting and reporting modifications to interventions are critical to their implementation and will lay the groundwork for further testing of the efficacy of the adapted Ca-HELP intervention.

RevDate: 2024-04-22
CmpDate: 2024-04-22

Keller MD, Hanley PJ, Chi YY, et al (2024)

Antiviral cellular therapy for enhancing T-cell reconstitution before or after hematopoietic stem cell transplantation (ACES): a two-arm, open label phase II interventional trial of pediatric patients with risk factor assessment.

Nature communications, 15(1):3258.

Viral infections remain a major risk in immunocompromised pediatric patients, and virus-specific T cell (VST) therapy has been successful for treatment of refractory viral infections in prior studies. We performed a phase II multicenter study (NCT03475212) for the treatment of pediatric patients with inborn errors of immunity and/or post allogeneic hematopoietic stem cell transplant with refractory viral infections using partially-HLA matched VSTs targeting cytomegalovirus, Epstein-Barr virus, or adenovirus. Primary endpoints were feasibility, safety, and clinical responses (>1 log reduction in viremia at 28 days). Secondary endpoints were reconstitution of antiviral immunity and persistence of the infused VSTs. Suitable VST products were identified for 75 of 77 clinical queries. Clinical responses were achieved in 29 of 47 (62%) of patients post-HSCT including 73% of patients evaluable at 1-month post-infusion, meeting the primary efficacy endpoint (>52%). Secondary graft rejection occurred in one child following VST infusion as described in a companion article. Corticosteroids, graft-versus-host disease, transplant-associated thrombotic microangiopathy, and eculizumab treatment correlated with poor response, while uptrending absolute lymphocyte and CD8 T cell counts correlated with good response. This study highlights key clinical factors that impact response to VSTs and demonstrates the feasibility and efficacy of this therapy in pediatric HSCT.

RevDate: 2024-04-22

Lane DD, Gottimukkala KSV, Cunningham RA, et al (2024)

Cas9 RNP Physiochemical Analysis for Enhanced CRISPR-AuNP Assembly and Function.

bioRxiv : the preprint server for biology.

CRISPR therapy for hematological disease has proven effective for transplant dependent beta thalassemia and sickle cell anemia, with additional disease targets in sight. The success of these therapies relies on high rates of CRISPR-induced double strand DNA breaks in hematopoietic stem and progenitor cells (HSPC). To achieve these levels, CRISPR complexes are typically delivered by electroporation ex vivo which is toxic to HSPCs. HSPCs are then cultured in stimulating conditions that promote error-prone DNA repair, requiring conditioning with chemotherapy to facilitate engraftment after reinfusion. In vivo delivery by nanocarriers of CRISPR gene editing tools has the potential to mitigate this complexity and toxicity and make this revolutionary therapy globally available. To achieve in vivo delivery, the inherent restriction factors against oligonucleotide delivery into HSPCs, that make ex vivo manipulation including electroporation and stimulation essential, must be overcome. To this end, our group developed a CRISPR carrying gold nanoparticle (CRISPR-AuNP) capable of delivering either Cas9 or Cas12a CRISPRs as ribonucleoprotein complexes (RNP) without compromising HSPC fitness. However, the most commonly used CRISPR, Cas9, demonstrated inconsistent activity in this delivery system, with lower activity relative to Cas12a. Investigation of Cas9 RNP biophysics relative to Cas12a revealed duplex RNA instability during the initial loading onto Au cores, resulting in undetectable Cas9 loading to the particle surface. Here we demonstrate preformation of RNP before loading, coupled with optimization of the loading chemistry and conditions, resulted in 39.6 ± 7.0 Cas9 RNP/AuNP without compromising RNP activity in both in vitro assays and primary human HSPC. The same alterations improved Cas12a RNP/AuNP loading 10-fold over previously reported levels. To achieve particle stability, the reported polyethyleneimine outer coating was altered to include PEGylation and the resulting 2[nd] generation CRISPR-AuNP demonstrates favorable nanoformulation characteristics for in vivo administration, with a hydrophilic, more neutral nanoparticle surface. Direct treatment of HSPC in vitro showed 72.5 ± 7.37% uptake of 2[nd] generation CRISPR-AuNP in primary human HSPC, but with endosomal accumulation and low rates of gene editing consistent with low levels of endosomal escape.

RevDate: 2024-04-18

Sidahmed E, Freedland SJ, Wang M, et al (2024)

Dietary Fiber Intake and Risk of Advanced and Aggressive Forms of Prostate Cancer: A Pooled Analysis of 15 Prospective Cohort Studies.

Journal of the Academy of Nutrition and Dietetics pii:S2212-2672(24)00163-1 [Epub ahead of print].

BACKGROUND: Evidence of an association between dietary fiber intake and risk of advanced and aggressive forms of prostate cancer (PC) and PC mortality is limited.

OBJECTIVE: To examine associations between intakes of dietary fiber overall and by food source and risk of advanced and aggressive forms of PC.

DESIGN: Pooled analysis of the primary data in 15 cohorts in three continents. Baseline dietary fiber intake was assessed using a validated food frequency questionnaire or diet history in each study.

PARTICIPANTS/SETTING: 842,149 men were followed for up to 9-22 years between 1985-2009 across studies.

MAIN OUTCOME MEASURES: The primary outcome measures were advanced (stage T4, N1, or M1 or PC mortality), advanced restricted (excluded men with missing stage and those with localized PC who died of PC), high grade (Gleason score ≥8 or poorly differentiated/undifferentiated) PC, and PC mortality.

STATISTICAL ANALYSIS: Study-specific multivariable hazard ratios (MVHR) were calculated using Cox proportional hazards regression and pooled using random effects models.

RESULTS: Intake of dietary fiber overall, from fruits, and from vegetables was not associated with risk of advanced (n=4,863), advanced restricted (n=2,978), or high-grade PC (n=9,673) or PC mortality (n=3,097). Dietary fiber intake from grains was inversely associated with advanced PC (MVHR comparing the highest vs. lowest quintile=0.84, 95% confidence interval [CI] 0.76-0.93), advanced restricted PC (MVHR=0.85, 95%CI 0.74-0.97), and PC mortality (MVHR=0.78, 95%CI 0.68-0.89); statistically significant trends were noted for each of these associations (p≤0.03), while a null association was observed for high grade PC for the same comparison (MVHR=1.00, 95%CI 0.93-1.07). The comparable results were 1.06 (95%CI 1.01-1.10, p-value, test for trend=0.002) for localized (n=35,199) and 1.05 (95%CI 0.99-1.11, , p-value, test for trend=0.04) for low/intermediate grade (n=34,366) PC.

CONCLUSIONS: Weak nonsignificant associations were observed between total dietary fiber intake and risk of advanced forms of PC, high grade PC, and PC mortality. High dietary fiber intake from grains was associated with a modestly lower risk of advanced forms of PC and PC mortality.

RevDate: 2024-04-18

Sun Q, Yang Y, Rosen JD, et al (2024)

MagicalRsq-X: A cross-cohort transferable genotype imputation quality metric.

American journal of human genetics pii:S0002-9297(24)00116-2 [Epub ahead of print].

Since genotype imputation was introduced, researchers have been relying on the estimated imputation quality from imputation software to perform post-imputation quality control (QC). However, this quality estimate (denoted as Rsq) performs less well for lower-frequency variants. We recently published MagicalRsq, a machine-learning-based imputation quality calibration, which leverages additional typed markers from the same cohort and outperforms Rsq as a QC metric. In this work, we extended the original MagicalRsq to allow cross-cohort model training and named the new model MagicalRsq-X. We removed the cohort-specific estimated minor allele frequency and included linkage disequilibrium scores and recombination rates as additional features. Leveraging whole-genome sequencing data from TOPMed, specifically participants in the BioMe, JHS, WHI, and MESA studies, we performed comprehensive cross-cohort evaluations for predominantly European and African ancestral individuals based on their inferred global ancestry with the 1000 Genomes and Human Genome Diversity Project data as reference. Our results suggest MagicalRsq-X outperforms Rsq in almost every setting, with 7.3%-14.4% improvement in squared Pearson correlation with true R[2], corresponding to 85-218 K variant gains. We further developed a metric to quantify the genetic distances of a target cohort relative to a reference cohort and showed that such metric largely explained the performance of MagicalRsq-X models. Finally, we found MagicalRsq-X saved up to 53 known genome-wide significant variants in one of the largest blood cell trait GWASs that would be missed using the original Rsq for QC. In conclusion, MagicalRsq-X shows superiority for post-imputation QC and benefits genetic studies by distinguishing well and poorly imputed lower-frequency variants.

RevDate: 2024-04-18

Kampouri E, Krantz EM, Xie H, et al (2024)

Human Herpesvirus-6 Reactivation and Disease Are Infrequent in Chimeric Antigen Receptor T-cell Therapy Recipients.

Blood pii:515778 [Epub ahead of print].

Human herpesvirus-6B (HHV-6B) reactivation and disease are increasingly reported after CAR-T-cell therapy (CARTx). HHV-6 reactivation in the CAR-T-cell product was recently reported, raising questions about product and patient management. Due to overlapping manifestations with immune effector cell-associated neurotoxicity syndrome, diagnosing HHV-6B encephalitis is challenging. We provide two lines of evidence assessing the incidence and outcomes of HHV-6B after CARTx. First, in a prospective study with weekly HHV-6B testing for up to 12 weeks post-infusion, HHV-6B reactivation occurred in eight of 89 participants; three had chromosomally integrated HHV-6 and were excluded, resulting in a cumulative incidence of HHV-6B reactivation of 6% (95% confidence interval (CI), 2.2-12.5%). HHV-6B detection was low level (median peak, 435 copies/mL; IQR, 164-979) and did not require therapy. Second, we retrospectively analyzed HHV-6B detection in blood and/or cerebrospinal fluid (CSF) within 12 weeks post-infusion in CARTx recipients. Of 626 patients, 24 had symptom-driven plasma testing with detection in one. Among 34 patients with CSF HHV-6 testing, one patient had possible HHV-6 encephalitis for a cumulative incidence of 0.17% (95% CI, 0.02-0.94%), although symptoms improved without treatment. Our data demonstrate that HHV-6B reactivation and disease are infrequent after CARTx. Routine HHV-6 monitoring is not warranted.

RevDate: 2024-04-18

Locke FL, Siddiqi T, Jacobson CA, et al (2024)

Real-World and Clinical Trial Outcomes in Large B-cell Lymphoma with Axicabtagene Ciloleucel Across Race and Ethnicity.

Blood pii:515777 [Epub ahead of print].

Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for treatment of relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Despite extensive data supporting the use of axi-cel in patients with LBCL, outcomes stratified by race and ethnicity groups are limited. Here, we report clinical outcomes with axi-cel in patients with R/R LBCL by race and ethnicity in both real-world and clinical trial settings. In the real-world setting, 1290 patients with R/R LBCL who received axi-cel between 2017-2020 were identified from the Center for International Blood and Marrow Transplant Research database; 106 and 169 patients were included from the ZUMA-1 and ZUMA-7 clinical trials, respectively. Adjusted odds ratio (OR) and hazard ratio (HR) for race and ethnicity groups are reported. Overall survival was consistent across race/ethnicity groups. However, non-Hispanic (NH) Black patients had lower overall response rate (OR, 0.37, [95% CI, 0.22-0.63]) and lower complete response rate (OR, 0.57, [95% CI, 0.33-0.97]) than NH-white patients. NH-Black patients also had a shorter progression-free survival versus NH-white (HR, 1.41, [95% CI, 1.04-1.90]) and NH-Asian patients (HR, 1.67, [95% CI, 1.08-2.59]). NH-Asian patients had a longer duration of response compared with NH-white (HR, 0.56, [95% CI, 0.33-0.94]) and Hispanic patients (HR, 0.54, [95% CI, 0.30-0.97]). There was no difference in cytokine release syndrome by race/ethnicity; however, higher rates of any-grade ICANS were observed in NH-white patients compared with other patients. These results provide important context when treating patients with R/R LBCL with axi-cel across different racial and ethnic groups. ZUMA-1 (NCT02348216) and ZUMA-7 (NCT03391466), both registered on

RevDate: 2024-04-20

Larouche JD, Laumont CM, Trofimov A, et al (2024)

Transposable elements regulate thymus development and function.

eLife, 12:.

Transposable elements (TEs) are repetitive sequences representing ~45% of the human and mouse genomes and are highly expressed by medullary thymic epithelial cells (mTECs). In this study, we investigated the role of TEs on T-cell development in the thymus. We performed multiomic analyses of TEs in human and mouse thymic cells to elucidate their role in T-cell development. We report that TE expression in the human thymus is high and shows extensive age- and cell lineage-related variations. TE expression correlates with multiple transcription factors in all cell types of the human thymus. Two cell types express particularly broad TE repertoires: mTECs and plasmacytoid dendritic cells (pDCs). In mTECs, transcriptomic data suggest that TEs interact with transcription factors essential for mTEC development and function (e.g., PAX1 and REL), and immunopeptidomic data showed that TEs generate MHC-I-associated peptides implicated in thymocyte education. Notably, AIRE, FEZF2, and CHD4 regulate small yet non-redundant sets of TEs in murine mTECs. Human thymic pDCs homogenously express large numbers of TEs that likely form dsRNA, which can activate innate immune receptors, potentially explaining why thymic pDCs constitutively secrete IFN ɑ/β. This study highlights the diversity of interactions between TEs and the adaptive immune system. TEs are genetic parasites, and the two thymic cell types most affected by TEs (mTEcs and pDCs) are essential to establishing central T-cell tolerance. Therefore, we propose that orchestrating TE expression in thymic cells is critical to prevent autoimmunity in vertebrates.

RevDate: 2024-04-18

Tosoian JJ, Zhang Y, Xiao L, et al (2024)

Development and Validation of an 18-Gene Urine Test for High-Grade Prostate Cancer.

JAMA oncology pii:2817657 [Epub ahead of print].

IMPORTANCE: Benefits of prostate cancer (PCa) screening with prostate-specific antigen (PSA) alone are largely offset by excess negative biopsies and overdetection of indolent cancers resulting from the poor specificity of PSA for high-grade PCa (ie, grade group [GG] 2 or greater).

OBJECTIVE: To develop a multiplex urinary panel for high-grade PCa and validate its external performance relative to current guideline-endorsed biomarkers.

RNA sequencing analysis of 58 724 genes identified 54 markers of PCa, including 17 markers uniquely overexpressed by high-grade cancers. Gene expression and clinical factors were modeled in a new urinary test for high-grade PCa (MyProstateScore 2.0 [MPS2]). Optimal models were developed in parallel without prostate volume (MPS2) and with prostate volume (MPS2+). The locked models underwent blinded external validation in a prospective National Cancer Institute trial cohort. Data were collected from January 2008 to December 2020, and data were analyzed from November 2022 to November 2023.

EXPOSURE: Protocolized blood and urine collection and transrectal ultrasound-guided systematic prostate biopsy.

MAIN OUTCOMES AND MEASURES: Multiple biomarker tests were assessed in the validation cohort, including serum PSA alone, the Prostate Cancer Prevention Trial risk calculator, and the Prostate Health Index (PHI) as well as derived multiplex 2-gene and 3-gene models, the original 2-gene MPS test, and the 18-gene MPS2 models. Under a testing approach with 95% sensitivity for PCa of GG 2 or greater, measures of diagnostic accuracy and clinical consequences of testing were calculated. Cancers of GG 3 or greater were assessed secondarily.

RESULTS: Of 761 men included in the development cohort, the median (IQR) age was 63 (58-68) years, and the median (IQR) PSA level was 5.6 (4.6-7.2) ng/mL; of 743 men included in the validation cohort, the median (IQR) age was 62 (57-68) years, and the median (IQR) PSA level was 5.6 (4.1-8.0) ng/mL. In the validation cohort, 151 (20.3%) had high-grade PCa on biopsy. Area under the receiver operating characteristic curve values were 0.60 using PSA alone, 0.66 using the risk calculator, 0.77 using PHI, 0.76 using the derived multiplex 2-gene model, 0.72 using the derived multiplex 3-gene model, and 0.74 using the original MPS model compared with 0.81 using the MPS2 model and 0.82 using the MPS2+ model. At 95% sensitivity, the MPS2 model would have reduced unnecessary biopsies performed in the initial biopsy population (range for other tests, 15% to 30%; range for MPS2, 35% to 42%) and repeat biopsy population (range for other tests, 9% to 21%; range for MPS2, 46% to 51%). Across pertinent subgroups, the MPS2 models had negative predictive values of 95% to 99% for cancers of GG 2 or greater and of 99% for cancers of GG 3 or greater.

CONCLUSIONS AND RELEVANCE: In this study, a new 18-gene PCa test had higher diagnostic accuracy for high-grade PCa relative to existing biomarker tests. Clinically, use of this test would have meaningfully reduced unnecessary biopsies performed while maintaining highly sensitive detection of high-grade cancers. These data support use of this new PCa biomarker test in patients with elevated PSA levels to reduce the potential harms of PCa screening while preserving its long-term benefits.

RevDate: 2024-04-18

Konecny AJ, Mage PL, Tyznik AJ, et al (2024)

OMIP-102: 50-color phenotyping of the human immune system with in-depth assessment of T cells and dendritic cells.

Cytometry. Part A : the journal of the International Society for Analytical Cytology [Epub ahead of print].

We report the development of an optimized 50-color spectral flow cytometry panel designed for the in-depth analysis of the immune system in human blood and tissues, with the goal of maximizing the amount of information that can be collected using currently available flow cytometry platforms. We established and tested this panel using peripheral blood mononuclear cells (PBMCs), but included CD45 to enable its future use for the analysis of human tissue samples. The panel contains lineage markers for all major immune cell subsets, and an extensive set of phenotyping markers focused on the activation and differentiation status of the T cell and dendritic cell (DC) compartment. We outline the biological insight that can be gained from the simultaneous measurement of such a large number of proteins and propose that this approach provides a unique opportunity for the comprehensive exploration of the immune status in human samples with a limited number of cells. Of note, we tested the panel to be compatible with cell sorting for further downstream applications. Furthermore, to facilitate the wide-spread implementation of such a panel across different cohorts and samples, we established a trimmed-down 45-color version which can be used with different spectral cytometry platforms. Finally, to generate this panel, we utilized not only existing panel design guidelines, but also developed new metrics to systematically identify the optimal combination of 50 fluorochromes and evaluate fluorochrome-specific resolution in the context of a 50-color unmixing matrix.

RevDate: 2024-04-18

De Rosa SC, YD Mahnke (2024)

Setting the gold standard: Commentary on designing and optimizing high-parameter flow cytometry panels.

Cytometry. Part A : the journal of the International Society for Analytical Cytology [Epub ahead of print].

RevDate: 2024-04-18

Webster AP, Ecker S, Moghul I, et al (2024)

Donor whole blood DNA methylation is not a strong predictor of acute graft versus host disease in unrelated donor allogeneic haematopoietic cell transplantation.

Frontiers in genetics, 15:1242636.

Allogeneic hematopoietic cell transplantation (HCT) is used to treat many blood-based disorders and malignancies, however it can also result in serious adverse events, such as the development of acute graft-versus-host disease (aGVHD). This study aimed to develop a donor-specific epigenetic classifier to reduce incidence of aGVHD by improving donor selection. Genome-wide DNA methylation was assessed in a discovery cohort of 288 HCT donors selected based on recipient aGVHD outcome; this cohort consisted of 144 cases with aGVHD grades III-IV and 144 controls with no aGVHD. We applied a machine learning algorithm to identify CpG sites predictive of aGVHD. Receiver operating characteristic (ROC) curve analysis of these sites resulted in a classifier with an encouraging area under the ROC curve (AUC) of 0.91. To test this classifier, we used an independent validation cohort (n = 288) selected using the same criteria as the discovery cohort. Attempts to validate the classifier failed with the AUC falling to 0.51. These results indicate that donor DNA methylation may not be a suitable predictor of aGVHD in an HCT setting involving unrelated donors, despite the initial promising results in the discovery cohort. Our work highlights the importance of independent validation of machine learning classifiers, particularly when developing classifiers intended for clinical use.

RevDate: 2024-04-18

Patterson JG, McQuoid J, Heffner JL, et al (2024)

Resonating with Pride: Considerations for Tailoring Tobacco Interventions for LGBTQ+ Communities.

Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco pii:7649684 [Epub ahead of print].

RevDate: 2024-04-17

Banack HR, Wactawski-Wende J, Ochs-Balcom HM, et al (2024)

A protocol for remote collection of skeletal muscle mass via D3-creatine dilution in community-dwelling postmenopausal women from the Women's Health Initiative.

PloS one, 19(4):e0300140.

BACKGROUND: There is emerging evidence that cancer and its treatments may accelerate the normal aging process, increasing the magnitude and rate of decline in functional capacity. This accelerated aging process is hypothesized to hasten the occurrence of common adverse age-related outcomes in cancer survivors, including loss of muscle mass and decrease in physical function. However, there is no data describing age-related loss of muscle mass and its relation to physical function in the long-term in cancer survivors.

METHODS: This study protocol describes the use of a novel method of muscle mass measurement, D3-creatine dilution method (D3Cr), in a large sample (n~6000) of community dwelling postmenopausal women from the Women's Health Initiative (WHI). D3Cr will be used to obtain a direct measure of muscle mass remotely. Participants will be drawn from two sub-cohorts embedded within the WHI that have recently completed an in-home visit. Cancer survivors will be drawn from the Life and Longevity After Cancer (LILAC) cohort, and cancer-free controls will be drawn from the WHI Long Life Study 2. The overall objective of this study is to examine the antecedents and consequences of low muscle mass in cancer survivors. The study aims are to: 1) create age-standardized muscle mass percentile curves and z-scores to characterize the distribution of D3- muscle mass in cancer survivors and non-cancer controls, 2) compare muscle mass, physical function, and functional decline in cancer survivors and non- cancer controls, and 3) use machine learning approaches to generate multivariate risk-prediction algorithms to detect low muscle mass.

DISCUSSION: The D3Cr method will transform our ability to measure muscle mass in large-scale epidemiologic research. This study is an opportunity to advance our understanding of a key source of morbidity among older and long-term female cancer survivors. This project will fill knowledge gaps, including the antecedents and consequences of low muscle mass, and use innovative methods to overcome common sources of bias in cancer research. The results of this study will be used to develop interventions to mitigate the harmful effects of low muscle mass in older adults and promote healthy survivorship in cancer survivors in the old (>65) and oldest-old (>85) age groups.

RevDate: 2024-04-18
CmpDate: 2024-04-18

Greteman BB, Del Vecchio NJ, Garcia-Auguste CJ, et al (2024)

Identifying predictors of COVID-related delays in cancer-specific medical care.

Cancer medicine, 13(8):e7183.

PURPOSE: Evidence of the impact of the COVID-19 pandemic on cancer prevention and control is growing, but little is known about patient-level factors associated with delayed care. We analyzed data from a survey focused on Iowan cancer patients' COVID-19 experiences in the early part of the pandemic.

METHODS: Participants were recruited from the University of Iowa Holden Comprehensive Cancer Center's Patients Enhancing Research Collaborations at Holden (PERCH) program. We surveyed respondents on demographic characteristics, COVID-19 experiences and reactions, and delays in any cancer-related health care appointment, or cancer-related treatment appointments. Two-sided significance tests assessed differences in COVID-19 experiences and reactions between those who experienced delays and those who did not.

RESULTS: There were 780 respondents (26% response), with breast, prostate, kidney, skin, and colorectal cancers representing the majority of respondents. Delays in cancer care were reported by 29% of respondents. In multivariable-adjusted models, rural residents (OR 1.47; 95% CI 1.03, 2.11) and those experiencing feelings of isolation (OR 2.18; 95% CI 1.37, 3.47) were more likely to report any delay, where experiencing financial difficulties predicted delays in treatment appointments (OR 5.72; 95% CI 1.96, 16.67). Health insurance coverage and concern about the pandemic were not statistically significantly associated with delays.

CONCLUSION: These findings may inform cancer care delivery during periods of instability when treatment may be disrupted by informing clinicians about concerns that patients have during the treatment process. Future research should assess whether delays in cancer care impact long-term cancer outcomes and whether delays exacerbate existing disparities in cancer outcomes.

RevDate: 2024-04-18
CmpDate: 2024-04-18

Ergas IJ, Cheng RK, Roh JM, et al (2024)

Diet quality and cardiovascular disease risk among breast cancer survivors in the Pathways Study.

JNCI cancer spectrum, 8(2):.

BACKGROUND: Women with breast cancer are at higher risk of cardiovascular disease (CVD) compared with women without breast cancer. Whether higher diet quality at breast cancer diagnosis lowers this risk remains unknown. We set out to determine if higher diet quality at breast cancer diagnosis was related to lower risk of CVD and CVD-related death.

METHODS: This analysis included 3415 participants from the Pathway Study, a prospective cohort of women diagnosed with invasive breast cancer at Kaiser Permanente Northern California between 2005 and 2013 and followed through December 31, 2021. Scores from 5 diet quality indices consistent with healthy eating were obtained at the time of breast cancer diagnosis. Scores were categorized into ascending quartiles of concordance for each diet quality index, and multivariable adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated. P values were 2-sided.

RESULTS: The Dietary Approaches to Stop Hypertension diet quality index was associated with lower risk of heart failure (HR = 0.53, 95% CI = 0.33 to 0.87; Ptrend = .03), arrhythmia (HR = 0.77, 95% CI = 0.62 to 0.94; Ptrend = .008), cardiac arrest (HR = 0.77, 95% CI = 0.61 to 0.96; Ptrend = .02), valvular heart disease (HR = 0.79, 95% CI = 0.64 to 0.98; Ptrend = .046), venous thromboembolic disease (HR = 0.75, 95% CI = 0.60 to 0.93; Ptrend = .01), and CVD-related death (HR = 0.70, 95% CI = 0.50 to 0.99; Ptrend = .04), when comparing the highest with lowest quartiles. Inverse associations were also found between the healthy plant-based dietary index and heart failure (HR = 0.60, 95% CI = 0.39 to 0.94; Ptrend = .02), as well as the alternate Mediterranean dietary index and arrhythmia (HR = 0.74, 95% CI = 0.60 to 0.93; Ptrend = .02).

CONCLUSION: Among newly diagnosed breast cancer patients, higher diet quality at diagnosis was associated with lower risk of CVD events and death.

RevDate: 2024-04-16

Liang EC, Rejeski K, Fei T, et al (2024)

Development and validation of an automated computational approach to grade immune effector cell-associated hematotoxicity.

Bone marrow transplantation [Epub ahead of print].

Hematologic toxicity frequently complicates chimeric antigen receptor (CAR) T-cell therapy, resulting in significant morbidity and mortality. In an effort to standardize reporting, the European Hematology Association (EHA) and European Society of Blood and Marrow Transplantation (EBMT) devised the immune effector cell-associated hematotoxicity (ICAHT) grading system, distinguishing between early (day 0-30) and late (after day +30) events based on neutropenia depth and duration. However, manual implementation of ICAHT grading criteria is time-consuming and susceptible to subjectivity and error. To address these challenges, we introduce a novel computational approach, utilizing the R programming language, to automate early and late ICAHT grading. Given the complexities of early ICAHT grading, we benchmarked our approach both manually and computationally in two independent cohorts totaling 1251 patients. Our computational approach offers significant implications by streamlining grading processes, reducing manual time and effort, and promoting standardization across varied clinical settings. We provide this tool to the scientific community alongside a comprehensive implementation guide, fostering its widespread adoption and enhancing reporting consistency for ICAHT.

RevDate: 2024-04-18
CmpDate: 2024-04-18

Schaeffer EM, Srinivas S, Adra N, et al (2024)

Prostate Cancer, Version 3.2024.

Journal of the National Comprehensive Cancer Network : JNCCN, 22(3):140-150.

The NCCN Guidelines for Prostate Cancer include recommendations for staging and risk assessment after a prostate cancer diagnosis and for the care of patients with localized, regional, recurrent, and metastatic disease. These NCCN Guidelines Insights summarize the panel's discussions for the 2024 update to the guidelines with regard to initial risk stratification, initial management of very-low-risk disease, and the treatment of nonmetastatic recurrence.

RevDate: 2024-04-18
CmpDate: 2024-04-18

Wierda WG, Brown J, Abramson JS, et al (2024)

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Version 2.2024.

Journal of the National Comprehensive Cancer Network : JNCCN, 22(3):175-204.

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are essentially different manifestations of the same disease that are similarly managed. A number of molecular and cytogenetic variables with prognostic implications have been identified. Undetectable minimal residual disease at the end of treatment with chemoimmunotherapy or venetoclax-based combination regimens is an independent predictor of improved survival among patients with previously untreated or relapsed/refractory CLL/SLL. The selection of treatment is based on the disease stage, presence or absence of del(17p) or TP53 mutation, immunoglobulin heavy chain variable region mutation status, patient age, performance status, comorbid conditions, and the agent's toxicity profile. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with CLL/SLL.

RevDate: 2024-04-16

Wang L, Slaughter F, Nguyen AT, et al (2024)

Impact of the COVID-19 pandemic on mental health and viral suppression among persons living with HIV in western Washington.

AIDS care [Epub ahead of print].

The COVID-19 pandemic and social distancing measures elevated stress levels globally, exacerbating mental health challenges for people with HIV (PWH). We examined the effect of COVID-19-related stress on mental health among PWH in western Washington, exploring whether social support and coping self-efficacy were protective. Data on COVID-19-related stress, mental health, social support, and coping self-efficacy were collected using online surveys during the pandemic. Pre-COVID-19 mental health data were available for a subset of participants and were linked with the survey data. In the total sample (N = 373), COVID-19-stress was associated with elevated depression (PHQ-8, β = 0.21, 95%CI [0.10, 0.32]) and anxiety (GAD-7, β = 0.28, 95%CI [0.17, 0.39]). Among the subset of respondents with pre-pandemic mental health data (N = 103), COVID-19-related stress was associated with elevated PHQ-8 scores (β = 0.35, 95%CI [0.15, 0.56]) and GAD-7 scores (β = 0.35, 95%CI [0.16, 0.54]), adjusted for baseline mental health and other confounders. Coping self-efficacy was negatively associated with GAD-7 scores (β = -0.01, 95%CI [-0.01, 0.00]), while social support was negatively associated with PHQ-8 scores (β = -0.06, 95%CI [-0.12, -0.01]). Viral suppression before and during the pandemic did not differ among participants with available data. While COVID-19-related stress predicted elevated depression and anxiety symptoms among PWH, social support and coping self-efficacy were protective.

RevDate: 2024-04-18

Persky V, Abasilim C, Tsintsifas K, et al (2024)

Thyroid Hormones and Diabetes in Euthyroid Hispanic/Latino Adults of Diverse Backgrounds: HCHS/SOL.

Journal of the Endocrine Society, 8(6):bvae039.

CONTEXT: Previous studies have demonstrated associations of endogenous thyroid hormones with diabetes; less is known about stages of diabetes development at which they are operative, mechanisms of associations, and the role of the hypothalamic-pituitary-thyroid axis.

OBJECTIVE: This study examined associations of thyroid hormones with incident prediabetes and diabetes and with changes in glycemic traits in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), the largest cohort of Hispanic/Latino adults with diverse backgrounds in the United States.

METHODS: The study includes 592 postmenopausal euthyroid women and 868 euthyroid men aged 45 to 74 years without diabetes at baseline participating in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). Baseline hormones included thyrotropin (TSH), free thyroxine (FT4), total triiodothyronine (T3), and indices calculated from thyroid hormones evaluating pituitary sensitivity to thyroid hormone. Transitions to diabetes and prediabetes, and changes in glycemic traits determined at the 6-year follow-up visit, were examined using multivariable Poisson and linear regressions.

RESULTS: Among women, T3 (incident rate ratio [IRR] = 1.65; 95% CI, 1.22-2.24; P = .001) and TSH (IRR = 2.09; 95% CI, 1.01-4.33; P = .047) were positively, while FT4 (IRR = 0.59; 95% CI, 0.39-0.88; P = .011) was inversely, associated with transition from prediabetes to diabetes. Among men, the T3/FT4 ratio was positively associated with transition from normoglycemia to prediabetes but not from prediabetes to diabetes. Indices measuring sensitivity of the pituitary to thyroid hormone suggested increased sensitivity in men who transitioned from prediabetes to diabetes.

CONCLUSION: Positive associations in women of T3 and TSH and inverse associations of FT4, as well as inverse associations of thyroid indices in men with transition from prediabetes to diabetes, but not from normoglycemia to diabetes, suggest decreased pituitary sensitivity to thyroid hormones in women and increased sensitivity in men later in the development of diabetes.

RevDate: 2024-04-17
CmpDate: 2024-04-17

Lim JJ, Chen EY, Schaub SK, et al (2024)

Reclassification of a spindle cell sarcoma after identification of a TFG-ROS1 fusion: A case demonstrating the clinical benefit of next-generation sequencing in sarcoma.

Molecular genetics & genomic medicine, 12(4):e2423.

BACKGROUND: Inflammatory myofibroblastic tumors (IMTs) are rare mesenchymal soft tissue sarcomas that often present diagnostic challenges due to their wide and varied morphology. A subset of IMTs have fusions involving ALK or ROS1. The role of next-generation sequencing (NGS) for classification of unselected sarcomas remains controversial.

METHODS AND RESULTS: We report a case of a metastatic sarcoma in a 34-year-old female originally diagnosed as an unclassified spindle cell sarcoma with myofibroblastic differentiation and later reclassified as IMT after NGS revealed a TFG-ROS1 rearrangement. Histologically, the neoplasm had spindle cell morphology with a lobulated to focally infiltrative growth pattern with scant inflammatory cell infiltrate. Immunohistochemistry demonstrated focal desmin and variable smooth muscle actin staining but was negative for SOX10, S100, and CD34. Fluorescence in situ hybridization was negative for USP6 or ALK gene rearrangements. NGS revealed a TFG-ROS1 rearrangement and the patient was treated with crizotinib with clinical benefit.

CONCLUSIONS: We discuss the role of NGS as well as its potential benefit in patients with unresectable, ALK-negative metastatic disease. Considering this case and previous literature, we support the use of NGS for patients requiring systemic treatment.

RevDate: 2024-04-16
CmpDate: 2024-04-16

Hansen UK, Church CD, Carnaz Simões AM, et al (2024)

T antigen-specific CD8+ T cells associate with PD-1 blockade response in virus-positive Merkel cell carcinoma.

The Journal of clinical investigation, 134(8): pii:177082.

Merkel cell carcinoma (MCC) is a highly immunogenic skin cancer primarily induced by Merkel cell polyomavirus, which is driven by the expression of the oncogenic T antigens (T-Ags). Blockade of the programmed cell death protein-1 (PD-1) pathway has shown remarkable response rates, but evidence for therapy-associated T-Ag-specific immune response and therapeutic strategies for the nonresponding fraction are both limited. We tracked T-Ag-reactive CD8+ T cells in peripheral blood of 26 MCC patients under anti-PD1 therapy, using DNA-barcoded pMHC multimers, displaying all peptides from the predicted HLA ligandome of the oncoproteins, covering 33 class I haplotypes. We observed a broad T cell recognition of T-Ags, including identification of 20 T-Ag-derived epitopes we believe to be novel. Broadening of the T-Ag recognition profile and increased T cell frequencies during therapy were strongly associated with clinical response and prolonged progression-free survival. T-Ag-specific T cells could be further boosted and expanded directly from peripheral blood using artificial antigen-presenting scaffolds, even in patients with no detectable T-Ag-specific T cells. These T cells provided strong tumor-rejection capacity while retaining a favorable phenotype for adoptive cell transfer. These findings demonstrate that T-Ag-specific T cells are associated with the clinical outcome to PD-1 blockade and that Ag-presenting scaffolds can be used to boost such responses.

RevDate: 2024-04-16

VoPham T, Ton M, MD Weaver (2024)

Spatiotemporal light exposure modeling for environmental circadian misalignment and solar jetlag.

Environmental epidemiology (Philadelphia, Pa.), 8(2):e301.

BACKGROUND: Light exposure is the most powerful resetting signal for circadian rhythms. The objective of this study was to develop and validate a high-resolution geospatial light exposure model that measures environmental circadian misalignment (or solar jetlag) as the mismatch between the social clock and sun clock, which occurs from geographic variation in light exposure leading to delayed circadian phase from relatively less morning light exposure and greater evening light exposure with increasing westward position within a time zone.

METHODS: The light exposure model (30 m[2] spatial resolution) incorporated geospatial data across the United States on time zones, elevation (using Google Earth Engine), sunrise time, and sunset time to estimate solar jetlag scores (higher values indicate higher environmental circadian misalignment). The validation study compared the light exposure model in 2022, which was linked with geocoded residential addresses of n = 20 participants in Boston, MA (eastern time zone position) and Seattle, WA (western time zone position) using a geographic information system, with illuminance values captured from wearable LYS light sensors and with sun times from the Solar Calculator.

RESULTS: Western versus eastern positions within a time zone were associated with higher solar jetlag scores from the light exposure model (P < 0.01) and relatively larger differences in sunset time measured using light sensors (social clock) and the Solar Calculator (sun clock) (P = 0.04).

CONCLUSION: We developed and validated a geospatial light exposure model, enabling high spatiotemporal resolution and comprehensive characterization of geographic variation in light exposure potentially impacting circadian phase in epidemiologic studies.

RevDate: 2024-04-16
CmpDate: 2024-04-15

Wagner C, Kistler KE, Perchetti GA, et al (2024)

Positive selection underlies repeated knockout of ORF8 in SARS-CoV-2 evolution.

Nature communications, 15(1):3207.

Knockout of the ORF8 protein has repeatedly spread through the global viral population during SARS-CoV-2 evolution. Here we use both regional and global pathogen sequencing to explore the selection pressures underlying its loss. In Washington State, we identified transmission clusters with ORF8 knockout throughout SARS-CoV-2 evolution, not just on novel, high fitness viral backbones. Indeed, ORF8 is truncated more frequently and knockouts circulate for longer than for any other gene. Using a global phylogeny, we find evidence of positive selection to explain this phenomenon: nonsense mutations resulting in shortened protein products occur more frequently and are associated with faster clade growth rates than synonymous mutations in ORF8. Loss of ORF8 is also associated with reduced clinical severity, highlighting the diverse clinical impacts of SARS-CoV-2 evolution.

RevDate: 2024-04-13

Baek G, Kim M, Lee M, et al (2024)

Retrospective review of the toxicities and change in dosing patterns for pegaspargase in patients with acute lymphoblastic leukemia/lymphoma and T-cell lymphoma.

Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners [Epub ahead of print].

INTRODUCTION: Pegaspargase (PEG) is a key component of standard regimens for acute lymphoblastic leukemia/lymphoma (ALL) and extranodal natural killer/T-cell lymphoma (NKTCL). Emerging evidence suggests an opportunity to decrease incidence of PEG-associated toxicities with dose capping, but evidence is limited. This study aims to evaluate whether a significant difference in PEG-associated toxicities related to dosing strategy exists and to identify patient-specific or regimen-specific factors for PEG-related toxicity.

METHODS: A retrospective analysis of PEG-associated toxicities was completed in adult patients with ALL or NKTCL who received PEG within Cancer and Leukemia Group B (CALGB) 10403 or modified dexamethasone, methotrexate, ifosfamide, L-asparaginase, etoposide (mSMILE) regimens at the UW Medical Center/Fred Hutchinson Cancer Center. PEG-associated toxicities that occurred through 8 weeks after PEG doses were noted.

RESULTS: Twenty-eight patients received dose-capped PEG, and 29 received noncapped PEG. Fewer all-grade and grade 3/4 toxicities were observed in the dose-capped cohort. Grade 3/4 toxicities observed were hepatotoxicity, hyperglycemia, hypersensitivity, and hypertriglyceridemia. In addition, fewer grade 3/4 pancreatitis and thrombosis events occurred in the dose-capped cohort. Hypertriglyceridemia and hepatotoxicity were associated with the highest cumulative incidence proportions among all toxicities.

CONCLUSION: Dose capping of PEG was associated with a similar or later median onset for most toxicities, a less heterogeneic toxicity profile, and a lower recurrence of most toxicities upon PEG rechallenge compared to the non-dose-capped cohort. Standardizing PEG dose capping in the CALGB 10403 and mSMILE regimens may translate to improved tolerance compared to a historical standard of no dose capping PEG.

RevDate: 2024-04-15
CmpDate: 2024-04-15

Wagner MJ, Ravi V, Schaub SK, et al (2024)

Incidence and Presenting Characteristics of Angiosarcoma in the US, 2001-2020.

JAMA network open, 7(4):e246235.

IMPORTANCE: Angiosarcoma is an aggressive vascular malignant neoplasm presenting either as a primary or secondary cancer, often arising after radiotherapy or in the context of preexisting lymphedema. Comprehensive data describing its incidence and presentation patterns are needed.

OBJECTIVE: To describe the incidence, presenting characteristics, and change over time of angiosarcoma in the US.

This retrospective cross-sectional study used data from the US Cancer Statistics (USCS) National Program of Cancer Registries-Surveillance, Epidemiology, and End Results Combined Database, which captures more than 99% of newly diagnosed cancers in the US. The study included all 19 289 patients in the US with a new diagnosis of angiosarcoma between 2001 and 2020 captured in the USCS database. Statistical analysis was performed from June to September 2023.

MAIN OUTCOMES AND MEASURES: Incidence of angiosarcoma, demographics of patients with angiosarcoma, and extent of disease at presentation.

RESULTS: The study included 19 289 patients (median age, 71 years [IQR, 59-80 years]; 10 506 women [54.5%]) with a new diagnosis of angiosarcoma. The US incidence of angiosarcoma doubled between 2001 (657 cases) and 2019 (1312 cases), reflecting both an increase in the adjusted incidence rate of 1.6% per year (P = .001), to 3.3 cases per 1 000 000 person-years (95% CI, 3.1-3.5 cases per 1 000 000 person-years), and an increase in the population at risk. In 2020, the reported incidence rate (3.0 cases per 1 000 000 person-years) and cases of angiosarcoma (n = 1159) were modestly lower than in 2019. Overall, 72.3% of cases of angiosarcoma (n = 13 955) were cutaneous, subcutaneous, or breast angiosarcomas; 24.4% were visceral (n = 4701); and 3.3% were located in unknown or rare primary sites (n = 633). Secondary breast and chest wall angiosarcomas among women represented the largest contribution to increasing incidence. Among breast angiosarcomas, 99.2% (2684 of 2705) were in women and 71.9% (1944 of 2705) were secondary. A total of 80.4% of chest wall or thorax cases among women (1861 of 2316) were secondary vs 26.5% among men (112 of 422), and 63.9% of upper extremity cases among women (205 of 321) were secondary vs 26.8% (56 of 209) among men (P = .001). Rates of secondary angiosarcoma in the abdomen and lower extremities were similar between men and women. The incidence rate of visceral angiosarcoma was also found to be increasing (1.5% per year; P = .001).

CONCLUSIONS AND RELEVANCE: This cross-sectional study describes angiosarcoma presentation patterns and incidence rates in the US over a 20-year period and shows that the number of cases in men and women increased, with the greatest increase among women with secondary angiosarcoma of the chest, breast, and upper extremity. These data increase awareness of a rare but highly morbid disease and highlight the need for improved early detection of angiosarcoma among patients at high risk, such as women with a history of breast cancer.

RevDate: 2024-04-12

Liu M, Su YR, Liu Y, et al (2024)

Structured testing of genetic association with mixed clinical outcomes.

Genetic epidemiology [Epub ahead of print].

Genetic factors play a fundamental role in disease development. Studying the genetic association with clinical outcomes is critical for understanding disease biology and devising novel treatment targets. However, the frequencies of genetic variations are often low, making it difficult to examine the variants one-by-one. Moreover, the clinical outcomes are complex, including patients' survival time and other binary or continuous outcomes such as recurrences and lymph node count, and how to effectively analyze genetic association with these outcomes remains unclear. In this article, we proposed a structured test statistic for testing genetic association with mixed types of survival, binary, and continuous outcomes. The structured testing incorporates known biological information of variants while allowing for their heterogeneous effects and is a powerful strategy for analyzing infrequent genetic factors. Simulation studies show that the proposed test statistic has correct type I error and is highly effective in detecting significant genetic variants. We applied our approach to a uterine corpus endometrial carcinoma study and identified several genetic pathways associated with the clinical outcomes.

RevDate: 2024-04-11

Ahmad K, Brahma S, S Henikoff (2024)

Response to "Learning from chromatin reconstitution: Pioneering factors enabling nucleosome remodelers".

RevDate: 2024-04-15
CmpDate: 2024-04-15

Jin J, Zhan J, Zhang J, et al (2024)

MUSSEL: Enhanced Bayesian polygenic risk prediction leveraging information across multiple ancestry groups.

Cell genomics, 4(4):100539.

Polygenic risk scores (PRSs) are now showing promising predictive performance on a wide variety of complex traits and diseases, but there exists a substantial performance gap across populations. We propose MUSSEL, a method for ancestry-specific polygenic prediction that borrows information in summary statistics from genome-wide association studies (GWASs) across multiple ancestry groups via Bayesian hierarchical modeling and ensemble learning. In our simulation studies and data analyses across four distinct studies, totaling 5.7 million participants with a substantial ancestral diversity, MUSSEL shows promising performance compared to alternatives. For example, MUSSEL has an average gain in prediction R[2] across 11 continuous traits of 40.2% and 49.3% compared to PRS-CSx and CT-SLEB, respectively, in the African ancestry population. The best-performing method, however, varies by GWAS sample size, target ancestry, trait architecture, and linkage disequilibrium reference samples; thus, ultimately a combination of methods may be needed to generate the most robust PRSs across diverse populations.

RevDate: 2024-04-10

Sherman A, Tuan J, Cantos VD, et al (2024)

COVID-19 vaccine efficacy in participants with weakened immune systems from four randomized-controlled trials.

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America pii:7643769 [Epub ahead of print].

BACKGROUND: Although the SARS-CoV-2 vaccines are highly efficacious at preventing severe disease in the general population, current data are lacking regarding vaccine efficacy (VE) for individuals with mild immunocompromising conditions.

METHODS: A post-hoc, cross-protocol analysis of participant-level data from the blinded phase of four randomized, placebo-controlled, COVID-19 vaccine phase 3 trials (Moderna, AstraZeneca, Janssen, and Novavax) was performed. We defined a "tempered immune system" (TIS) variable via a consensus panel based on medical history and medications to determine VE against symptomatic and severe COVID-19 cases in TIS participants versus non-TIS (NTIS) individuals starting at 14 days after completion of the primary series through the blinded phase for each of the four trials. An analysis of participants living with well-controlled HIV was conducted using the same methods.

RESULTS: 3,852/30,351 (12.7%) Moderna participants, 3,088/29,868 (10.3%) Novavax participants, 3,549/32,380 (11.0%) AstraZeneca participants, and 5,047/43,788 (11.5%) Janssen participants were identified as having a TIS. Most TIS conditions (73.9%) were due to metabolism and nutritional disorders. Vaccination (versus placebo) significantly reduced the likelihood of symptomatic and severe COVID-19 for all participants for each trial. VE was not significantly different for TIS participants vs NTIS for either symptomatic or severe COVID-19 for each trial, nor was VE significantly different in the symptomatic endpoint for participants with HIV.

CONCLUSIONS: For individuals with mildly immunocompromising conditions, there is no evidence of differences in VE against symptomatic or severe COVID-19 compared to those with non-tempered immune systems in the four COVID-19 vaccine randomized controlled efficacy trials.

RevDate: 2024-04-12
CmpDate: 2024-04-12

Hiatt JB, Doebley AL, Arnold HU, et al (2024)

Molecular phenotyping of small cell lung cancer using targeted cfDNA profiling of transcriptional regulatory regions.

Science advances, 10(15):eadk2082.

We report an approach for cancer phenotyping based on targeted sequencing of cell-free DNA (cfDNA) for small cell lung cancer (SCLC). In SCLC, differential activation of transcription factors (TFs), such as ASCL1, NEUROD1, POU2F3, and REST defines molecular subtypes. We designed a targeted capture panel that identifies chromatin organization signatures at 1535 TF binding sites and 13,240 gene transcription start sites and detects exonic mutations in 842 genes. Sequencing of cfDNA from SCLC patient-derived xenograft models captured TF activity and gene expression and revealed individual highly informative loci. Prediction models of ASCL1 and NEUROD1 activity using informative loci achieved areas under the receiver operating characteristic curve (AUCs) from 0.84 to 0.88 in patients with SCLC. As non-SCLC (NSCLC) often transforms to SCLC following targeted therapy, we applied our framework to distinguish NSCLC from SCLC and achieved an AUC of 0.99. Our approach shows promising utility for SCLC subtyping and transformation monitoring, with potential applicability to diverse tumor types.

RevDate: 2024-04-15

Lichauco C, Foss EJ, Gatbonton-Schwager T, et al (2024)

Sir2 and Fun30 regulate ribosomal DNA replication timing via Mcm helicase positioning and nucleosome occupancy.

bioRxiv : the preprint server for biology.

The association between late replication timing and low transcription rates in eukaryotic heterochromatin is well-known, yet the specific mechanisms underlying this link remain uncertain. In Saccharomyces cerevisiae, the histone deacetylase Sir2 is required for both transcriptional silencing and late replication at the repetitive ribosomal DNA arrays (rDNA). We have previously reported that in the absence of SIR2, a derepressed RNA PolII repositions MCM replicative helicases from their loading site at the ribosomal origin, where they abut well-positioned, high-occupancy nucleosomes, to an adjacent region with lower nucleosome occupancy. By developing a method that can distinguish activation of closely spaced MCM complexes, here we show that the displaced MCMs at rDNA origins have increased firing propensity compared to the non-displaced MCMs. Furthermore, we found that both, activation of the repositioned MCMs and low occupancy of the adjacent nucleosomes critically depend on the chromatin remodeling activity of FUN30. Our study elucidates the mechanism by which Sir2 delays replication timing, and it demonstrates, for the first time, that activation of a specific replication origin in vivo relies on the nucleosome context shaped by a single chromatin remodeler.

RevDate: 2024-04-12
CmpDate: 2024-04-12

Triplette M, Kross EK, Snidarich M, et al (2024)

An alternating-intervention pilot trial on the impact of an informational handout on patient-reported outcomes and follow-up after lung cancer screening.

PloS one, 19(4):e0300352.

INTRODUCTION: Lung cancer screening (LCS) can reduce lung cancer mortality; however, poor understanding of results may impact patient experience and follow-up. We sought to determine whether an informational handout accompanying LCS results can improve patient-reported outcomes and adherence to follow-up.

STUDY DESIGN: This was a prospective alternating intervention pilot trial of a handout to accompany LCS results delivery.

SETTING/PARTICIPANTS: Patients undergoing LCS in a multisite program over a 6-month period received a mailing containing either: 1) a standardized form letter of LCS results (control) or 2) the LCS results letter and the handout (intervention).

INTERVENTION: A two-sided informational handout on commonly asked questions after LCS created through iterative mixed-methods evaluation with both LCS patients and providers.

OUTCOME MEASURES: The primary outcomes of 1)patient understanding of LCS results, 2)correct identification of next steps in screening, and 3)patient distress were measured through survey. Adherence to recommended follow-up after LCS was determined through chart review. Outcomes were compared between the intervention and control group using generalized estimating equations.

RESULTS: 389 patients were eligible and enrolled with survey responses from 230 participants (59% response rate). We found no differences in understanding of results, identification of next steps in follow-up or distress but did find higher levels of knowledge and understanding on questions assessing individual components of LCS in the intervention group. Follow-up adherence was overall similar between the two arms, though was higher in the intervention group among those with positive findings (p = 0.007).

CONCLUSIONS: There were no differences in self-reported outcomes between the groups or overall follow-up adherence. Those receiving the intervention did report greater understanding and knowledge of key LCS components, and those with positive results had a higher rate of follow-up. This may represent a feasible component of a multi-level intervention to address knowledge and follow-up for LCS.


RevDate: 2024-04-10

Neal JW, Minichiello K, Brennick R, et al (2024)

A process to reanalyze clinical DNA sequencing data for biomarker matching in the Lung-MAP Master Protocol.

The oncologist pii:7643282 [Epub ahead of print].

For cancer clinical trials that require central confirmation of tumor genomic profiling, exhaustion of tissue from standard-of-care testing may prevent enrollment. For Lung-MAP, a master protocol that requires results from a defined centralized clinical trial assay to assign patients to a therapeutic substudy, we developed a process to repurpose existing commercial vendor raw genomic data for eligibility: genomic data reanalysis (GDR). Molecular results for substudy assignment were successfully generated for 369 of the first 374 patients (98.7%) using GDR for Lung-MAP, with a median time from request to result of 9 days. During the same period, 691 of 791 (87.4%) tissue samples received successfully yielded results, in a median of 14 days beyond sample acquisition. GDR is a scalable bioinformatic pipeline that expedites reanalysis of existing data for clinical trials in which validated integral biomarker testing is required for participation.

RevDate: 2024-04-11

Hotca A, Sindhu KK, Lehrer EJ, et al (2024)

Reirradiation With Proton Therapy for Recurrent Malignancies of the Esophagus and Gastroesophageal Junction: Results of the Proton Collaborative Group Multi-Institutional Prospective Registry Trial.

Advances in radiation oncology, 9(5):101459.

PURPOSE: Treatment options for recurrent esophageal cancer (EC) previously treated with radiation therapy (RT) are limited. Reirradiation (reRT) with proton beam therapy (PBT) can offer lower toxicities by limiting doses to surrounding tissues. In this study, we present the first multi-institutional series reporting on toxicities and outcomes after reRT for locoregionally recurrent EC with PBT.

METHODS AND MATERIALS: Analysis of the prospective, multicenter, Proton Collaborative Group registry of patients with recurrent EC who had previously received photon-based RT and underwent PBT reRT was performed. Patient/tumor characteristics, treatment details, outcomes, and toxicities were collected. Local control (LC), distant metastasis-free survival (DMFS), and overall survival (OS) were estimated using the Kaplan-Meier method. Event time was determined from reRT start.

RESULTS: Between 2012 and 2020, 31 patients received reRT via uniform scanning/passive scattering (61.3%) or pencil beam scanning (38.7%) PBT at 7 institutions. Median prior RT, PBT reRT, and cumulative doses were 50.4 Gy (range, 37.5-110.4), 48.6 Gy (relative biological effectiveness) (25.2-72.1), and 99.9 Gy (79.1-182.5), respectively. Of these patients, 12.9% had 2 prior RT courses, and 67.7% received PBT with concurrent chemotherapy. Median follow-up was 7.2 months (0.9-64.7). Post-PBT, there were 16.7% locoregional only, 11.1% distant only, and 16.7% locoregional and distant recurrences. Six-month LC, DMFS, and OS were 80.5%, 83.4%, and 69.1%, respectively. One-year LC, DMFS, and OS were 67.1%, 83.4%, and 27%, respectively. Acute grade ≥3 toxicities occurred in 23% of patients, with 1 acute grade 5 toxicity secondary to esophageal hemorrhage, unclear if related to reRT or disease progression. No grade ≥3 late toxicities were reported.

CONCLUSIONS: In the largest report to date of PBT for reRT in patients with recurrent EC, we observed acceptable acute toxicities and encouraging rates of disease control. However, these findings are limited by the poor prognoses of these patients, who are at high risk of mortality. Further research is needed to better assess the long-term benefits and toxicities of PBT in this specific patient population.

RevDate: 2024-04-09

Irwin T, Donlan AW, Owens L, et al (2024)

Enhancing upper tract urothelial carcinoma diagnosis: Utility of cytokeratin 17 and CK20/CD44/p53 immunohistochemical panel.

Human pathology pii:S0046-8177(24)00053-4 [Epub ahead of print].

Upper tract urothelial carcinoma (UTUC) presents diagnostic challenges due to small biopsy specimen size, poor orientation, and technical obstacles that can yield equivocal diagnoses. This uncertainty often mandates repeated biopsies to evaluate the necessity of nephroureterectomy. Prior studies have suggested cytokeratin 17 (CK17) immunostain as an adjunctive tool for diagnosing bladder urothelial neoplasia in both urine cytology and tissue biopsy specimens. We evaluated the utility of CK17 in differentiating UTUC from benign urothelium and its ability to stratify low-grade from high-grade neoplasia. Our study involved a cohort of previously diagnosed cytology (n = 29) and tissue specimens from biopsies and resections (n = 85). We evaluated CK17 staining percentage in cytology and tissue samples and localization patterns in biopsy/resection samples. Our findings showed a statistically significant distinction (p < 0.05) between UTUC and benign tissue specimens based on full thickness localization pattern (odds ratio 8.8 [95% CI 1.53-67.4]). The percentage of CK17 staining failed to significantly differentiate neoplastic from non-neoplastic cases in cytology or tissue samples. Additionally, based on prior research showing the efficacy of CK20/CD44/p53 triple panel in bladder urothelial neoplasia, we utilized tissue microarrays to evaluate if these markers could distinguish UTUC from benign urothelium. We found that CK20/CD44/p53, individually or in combination, could not distinguish urothelial neoplasia from non-neoplasia. Full thickness CK17 urothelial localization by immunohistochemistry was highly reproducible with excellent interobserver agreement and may play a supplementary role in distinguishing upper tract urothelial neoplasia from benign urothelium.

RevDate: 2024-04-09

Cooper L, Xu H, Polmear J, et al (2024)

Type I interferons induce an epigenetically distinct memory B cell subset in chronic viral infection.

Immunity pii:S1074-7613(24)00137-7 [Epub ahead of print].

Memory B cells (MBCs) are key providers of long-lived immunity against infectious disease, yet in chronic viral infection, they do not produce effective protection. How chronic viral infection disrupts MBC development and whether such changes are reversible remain unknown. Through single-cell (sc)ATAC-seq and scRNA-seq during acute versus chronic lymphocytic choriomeningitis viral infection, we identified a memory subset enriched for interferon (IFN)-stimulated genes (ISGs) during chronic infection that was distinct from the T-bet[+] subset normally associated with chronic infection. Blockade of IFNAR-1 early in infection transformed the chromatin landscape of chronic MBCs, decreasing accessibility at ISG-inducing transcription factor binding motifs and inducing phenotypic changes in the dominating MBC subset, with a decrease in the ISG subset and an increase in CD11c[+]CD80[+] cells. However, timing was critical, with MBCs resistant to intervention at 4 weeks post-infection. Together, our research identifies a key mechanism to instruct MBC identity during viral infection.

RevDate: 2024-04-09

Dadwal SS, Bansal R, Schuster M, et al (2024)

Final Outcomes from a Phase 2 Trial of Posoleucel in Allogeneic Hematopoietic Cell Transplant Recipients.

Blood advances pii:515666 [Epub ahead of print].

Allogeneic hematopoietic cell transplantation (allo-HCT) recipients are susceptible to viral infections. We conducted a phase 2 trial evaluating the safety and rate of clinically significant infections (CSIs; viremia requiring treatment or end-organ disease) following infusion of posoleucel, a partially HLA-matched, allogeneic, off-the-shelf, multivirus-specific T cell investigational product for preventing CSIs with adenovirus, BK virus, cytomegalovirus, Epstein-Barr virus, human herpesvirus-6, or JC virus. This open-label trial enrolled high-risk allo-HCT recipients based on receiving grafts from umbilical cord blood, haploidentical, mismatched, or matched unrelated donors; post-HCT lymphocytes <180/mm3; or use of T cell depletion. Posoleucel dosing was initiated within 15-49 days of allo-HCT and subsequently every 14 days for up to seven doses. The primary endpoint was the number of CSIs due to the six target viruses by week 14. Of the 26 patients enrolled just three (12%) had a CSI by week 14, each with a single target virus. In vivo expansion of functional virus-specific T cells detected via interferon-γ ELISpot assay was associated with viral control. Persistence of posoleucel-derived T cell clones for up to 14 weeks after the last infusion was confirmed by T cell receptor deep-sequencing. Five patients (19%) had acute GVHD grade II-IV. No patient experienced cytokine release syndrome. All six deaths were due to relapse or disease progression. High-risk allo-HCT patients who received posoleucel had low rates of CSIs from six targeted viruses. Repeat posoleucel dosing was generally safe and well tolerated and associated with functional immune reconstitution. NCT04693637.

RevDate: 2024-04-08

Nuechterlein N, Shelbourn A, Szulzewsky F, et al (2024)

Haploinsufficiency of phosphodiesterase 10A activates PI3K/AKT signaling independent of PTEN to induce an aggressive glioma phenotype.

Genes & development pii:gad.351350.123 [Epub ahead of print].

Glioblastoma is universally fatal and characterized by frequent chromosomal copy number alterations harboring oncogenes and tumor suppressors. In this study, we analyzed exome-wide human glioblastoma copy number data and found that cytoband 6q27 is an independent poor prognostic marker in multiple data sets. We then combined CRISPR-Cas9 data, human spatial transcriptomic data, and human and mouse RNA sequencing data to nominate PDE10A as a potential haploinsufficient tumor suppressor in the 6q27 region. Mouse glioblastoma modeling using the RCAS/tv-a system confirmed that Pde10a suppression induced an aggressive glioma phenotype in vivo and resistance to temozolomide and radiation therapy in vitro. Cell culture analysis showed that decreased Pde10a expression led to increased PI3K/AKT signaling in a Pten-independent manner, a response blocked by selective PI3K inhibitors. Single-nucleus RNA sequencing from our mouse gliomas in vivo, in combination with cell culture validation, further showed that Pde10a suppression was associated with a proneural-to-mesenchymal transition that exhibited increased cell adhesion and decreased cell migration. Our results indicate that glioblastoma patients harboring PDE10A loss have worse outcomes and potentially increased sensitivity to PI3K inhibition.

RevDate: 2024-04-09

Rupert PB, Buerger M, Girard EJ, et al (2024)

Preclinical characterization of Pan-NKG2D ligand-binding NKG2D receptor decoys.

Heliyon, 10(7):e28583.

NKG2D and its ligands are critical regulators of protective immune responses controlling infections and cancer, defining a crucial immune signaling axis. Current therapeutic efforts targeting this axis almost exclusively aim at enhancing NKG2D-mediated effector functions. However, this axis can drive disease processes when dysregulated, in particular, driving stem-like cancer cell reprogramming and tumorigenesis through receptor/ligand self-stimulation on tumor cells. Despite complexities with its structure and biology, we developed multiple novel engineered proteins that functionally serve as axis-blocking NKG2D "decoys" and report biochemical, structural, in vitro, and in vivo evaluation of their functionality.

RevDate: 2024-04-10

Feng X, Zahed H, Onwuka J, et al (2024)

Cancer Stage Compared With Mortality as End Points in Randomized Clinical Trials of Cancer Screening: A Systematic Review and Meta-Analysis.

JAMA [Epub ahead of print].

IMPORTANCE: Randomized clinical trials of cancer screening typically use cancer-specific mortality as the primary end point. The incidence of stage III-IV cancer is a potential alternative end point that may accelerate completion of randomized clinical trials of cancer screening.

OBJECTIVE: To compare cancer-specific mortality with stage III-IV cancer as end points in randomized clinical trials of cancer screening.

This meta-analysis included 41 randomized clinical trials of cancer screening conducted in Europe, North America, and Asia published through February 19, 2024. Data extracted included numbers of participants, cancer diagnoses, and cancer deaths in the intervention and comparison groups. For each clinical trial, the effect of screening was calculated as the percentage reduction between the intervention and comparison groups in the incidence of participants with cancer-specific mortality and stage III-IV cancer.

EXPOSURES: Randomization to a cancer screening test or to a comparison group in a clinical trial of cancer screening.

MAIN OUTCOMES AND MEASURES: End points of cancer-specific mortality and incidence of stage III-IV cancer were compared using Pearson correlation coefficients with 95% CIs, linear regression, and fixed-effects meta-analysis.

RESULTS: The included randomized clinical trials tested benefits of screening for breast (n = 6), colorectal (n = 11), lung (n = 12), ovarian (n = 4), prostate (n = 4), and other cancers (n = 4). Correlation between reductions in cancer-specific mortality and stage III-IV cancer varied by cancer type (I2 = 65%; P = .02). Correlation was highest for trials that screened for ovarian (Pearson ρ = 0.99 [95% CI, 0.51-1.00]) and lung (Pearson ρ = 0.92 [95% CI, 0.72-0.98]) cancers, moderate for breast cancer (Pearson ρ = 0.70 [95% CI, -0.26 to 0.96]), and weak for colorectal (Pearson ρ = 0.39 [95% CI, -0.27 to 0.80]) and prostate (Pearson ρ = -0.69 [95% CI, -0.99 to 0.81]) cancers. Slopes from linear regression were estimated as 1.15 for ovarian cancer, 0.75 for lung cancer, 0.40 for colorectal cancer, 0.28 for breast cancer, and -3.58 for prostate cancer, suggesting that a given magnitude of reduction in incidence of stage III-IV cancer produced different magnitudes of change in incidence of cancer-specific mortality (P for heterogeneity = .004).

CONCLUSIONS AND RELEVANCE: In randomized clinical trials of cancer screening, incidence of late-stage cancer may be a suitable alternative end point to cancer-specific mortality for some cancer types, but is not suitable for others. These results have implications for clinical trials of multicancer screening tests.

RevDate: 2024-04-07

Takahashi T, Watkins B, Bratrude B, et al (2024)

The Adverse Event Landscape of Stem Cell Transplant: Evidence for AGVHD Driving Early Transplant Associated Toxicities.

Transplantation and cellular therapy pii:S2666-6367(24)00317-8 [Epub ahead of print].

BACKGROUND: Although unrelated-donor (URD) hematopoietic cell transplantation (HCT) is associated with many toxicities, a detailed analysis of adverse events, as defined by the Common Terminology Criteria for Adverse Events (CTCAE), has not previously been curated. This represents a major unmet need, especially as it relates to assessing the safety of novel agents.

METHODS: We analyzed a detailed AE database from the 'ABA2' randomized, double-blind, placebo-controlled clinical trial of abatacept for acute graft-versus-host disease (AGVHD) prevention, for which the FDA mandated a detailed AE assessment through Day+180, and weekly neutrophil and platelet counts through Day+100. These were analyzed for their relationship to key transplant outcomes, with a major focus on the impact of AGVHD on the development/severity of AEs.

RESULTS: A total of 2102 AEs and 1816 neutrophil/platelet counts were analyzed from 142 8/8-HLA-matched URD HCT recipients on ABA2 (placebo cohort, n=69, abatacept cohort, n=73). This analysis resulted in two major observations. (1) Amongst graft source, conditioning intensity, age, and Grade 2-4 AGVHD, only AGVHD impacted Grade 3-5 AE acquisition after the first month post-transplant. (2) The development of Grade 3-4 AGVHD was associated with thrombocytopenia.

CONCLUSIONS: We have created a detailed resource for the transplant community by which to contextualize clinical toxicities after transplant. It has identified AGVHD as a major driver of post-HCT Grade 3-5 AEs, and underscored a link between AGVHD and thrombocytopenia. This establishes a critical safety framework upon which the impact of novel post-transplant AGVHD therapeutics should be evaluated. This trial was registered at www.

CLINICALTRIALS: gov (#NCT01743131).

RevDate: 2024-04-05

Zhang X, Zhao X, Chen S, et al (2024)

Addition of ruxolitinib to standard graft-versus-host disease prophylaxis for allogeneic stem cell transplantation in aplastic anemia patients.

Bone marrow transplantation [Epub ahead of print].

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) offers rapid hematopoietic and immune reconstitution for aplastic anemia (AA). As a non-malignant disorder, attenuation of GVHD remains a clinical priority in AA patients. Our study sought to investigate the safety and efficacy of the prophylactic use of ruxolitinib in allogeneic HSCT. A total of 35 AA patients were retrospectively consecutively treated with allo-HSCT whereby ruxolitinib was added to the standard GVHD prophylaxis regimen (rux group). The addition of peri-transplant ruxolitinib did not impact the engraftment and graft function, while better recovery of CD4+ Tregs in the rux group was observed. Interestingly, the rux group demonstrated significantly lower incidence of bacterial/fungal infections (17.14% vs 45.71%). Compared to the control group, the rux group exhibited significantly lower incidence of moderate to severe aGVHD (17.1% vs 48.6%) with a trend toward lower severe aGVHD (8.6% vs 20%) and cGVHD (26.2 vs 38.3). The rux group also demonstrated a trend toward higher GVHD and failure-free survival (GFFS: 85.7% vs 68.6%) and lower TRM (2.9% vs 14.3%). Addition of ruxolitinib to standard GVHD prophylaxis regimen, thus, represents a safe and highly efficient method for the attenuation of GVHD with better outcome of allo-HSCT.

RevDate: 2024-04-05

Pal SK, Grivas P, Gupta S, et al (2024)

Infigratinib Versus Placebo for Patients with High-risk Resected Urothelial Cancer Bearing an FGFR3 Genomic Alteration: Results from the PROOF302 Phase 3 Trial.

RevDate: 2024-04-08
CmpDate: 2024-04-08

Lankowski A, Tollefson D, Sánchez H, et al (2024)

Acceptability of venue-based HIV testing and prevention interventions for men who have sex with transgender women and transgender women in Lima, Perú: a formative, qualitative study.

HIV research & clinical practice, 25(1):2331360.

BACKGROUND: Despite being at elevated risk for HIV, men who have sex with transgender women (MSTW) are an overlooked population in the global HIV response. Venue-based HIV interventions have previously had success reaching other HIV priority populations, including transgender women (TW). Similar approaches could be applied for MSTW.

OBJECTIVE: To evaluate the prospective acceptability of venue-based HIV testing and prevention interventions for MSTW and TW in Lima, Peru.

METHODS: In this exploratory qualitative study, we conducted in-depth interviews (IDI) and focus group discussions (FGD) with three types of participants: MSTW (7 IDIs, 1 FGD), TW (1 FGD), and owners of social venues frequented by MSTW/TW in Lima (2 IDIs). We elicited participants' attitudes and perceptions related to the following four hypothetical interventions delivered at social venues in Lima: rapid HIV testing; HIV self-test distribution; condom/lubricant distribution; and enrolment in a mobile app supporting HIV prevention. We performed a mixed deductive-inductive thematic analysis using the framework method, then applied the Theoretical Framework of Acceptability to classify the overall acceptability of each intervention.

RESULTS: Condom/lubricant distribution and app-based HIV prevention information were highly acceptable among all participant types. The two HIV testing interventions had relatively lower acceptability; however, participants suggested this could be overcome if such interventions focused on ensuring discretion, providing access to healthcare professionals, and offering appropriate incentives.

CONCLUSIONS: Overall, MSTW and TW shared similar favourable attitudes towards venue-based HIV interventions. Venue-based outreach warrants further exploration as a strategy for engaging MSTW and TW in HIV prevention activities.

RevDate: 2024-04-05

Lyu Y, Wu C, Sun W, et al (2024)

Regional analysis to delineate intrasample heterogeneity with RegionalST.

Bioinformatics (Oxford, England) pii:7641536 [Epub ahead of print].

MOTIVATION: Spatial transcriptomics has greatly contributed to our understanding of spatial and intra-sample heterogeneity, which could be crucial for deciphering the molecular basis of human diseases. Intra-tumor heterogeneity, for example, may be associated with cancer treatment responses. However, the lack of computational tools for exploiting cross-regional information and the limited spatial resolution of current technologies present major obstacles to elucidating tissue heterogeneity.

RESULTS: To address these challenges, we introduce RegionalST, an efficient computational method that enables users to quantify cell type mixture and interactions, identify sub-regions of interest, and perform cross-region cell type-specific differential analysis for the first time. Our simulations and real data applications demonstrate that RegionalST is an efficient tool for visualizing and analyzing diverse spatial transcriptomics data, thereby enabling accurate and flexible exploration of tissue heterogeneity. Overall, RegionalST provides a one-stop destination for researchers seeking to delve deeper into the intricacies of spatial transcriptomics data.

AVAILABILITY: The implementation of our method is available as an open-source R/Bioconductor package with a user-friendly manual available at

SUPPLEMENTARY INFORMATION: Supplementary materials are available at Bioinformatics online.

RevDate: 2024-04-09

Plender EG, Prodanov T, Hsieh P, et al (2024)

Structural and genetic diversity in the secreted mucins, MUC5AC and MUC5B.

bioRxiv : the preprint server for biology.

The secreted mucins MUC5AC and MUC5B play critical defensive roles in airway pathogen entrapment and mucociliary clearance by encoding large glycoproteins with variable number tandem repeats (VNTRs). These polymorphic and degenerate protein coding VNTRs make the loci difficult to investigate with short reads. We characterize the structural diversity of MUC5AC and MUC5B by long-read sequencing and assembly of 206 human and 20 nonhuman primate (NHP) haplotypes. We find that human MUC5B is largely invariant (5761-5762aa); however, seven haplotypes have expanded VNTRs (6291-7019aa). In contrast, 30 allelic variants of MUC5AC encode 16 distinct proteins (5249-6325aa) with cysteine-rich domain and VNTR copy number variation. We grouped MUC5AC alleles into three phylogenetic clades: H1 (46%, ~5654aa), H2 (33%, ~5742aa), and H3 (7%, ~6325aa). The two most common human MUC5AC variants are smaller than NHP gene models, suggesting a reduction in protein length during recent human evolution. Linkage disequilibrium (LD) and Tajima's D analyses reveal that East Asians carry exceptionally large MUC5AC LD blocks with an excess of rare variation (p<0.05). To validate this result, we used Locityper for genotyping MUC5AC haplogroups in 2,600 unrelated samples from the 1000 Genomes Project. We observed signatures of positive selection in H1 and H2 among East Asians and a depletion of the likely ancestral haplogroup (H3). In Africans and Europeans, H3 alleles show an excess of common variation and deviate from Hardy-Weinberg equilibrium, consistent with heterozygote advantage and balancing selection. This study provides a generalizable strategy to characterize complex protein coding VNTRs for improved disease associations.

RevDate: 2024-04-08
CmpDate: 2024-04-08

Park JJ, Chu A, Li J, et al (2024)

Repeat Next-Generation Sequencing Testing on Progression in Men With Metastatic Prostate Cancer Can Identify New Actionable Alterations.

JCO precision oncology, 8:e2300567.

PURPOSE: There are limited data available on the real-world patterns of molecular testing in men with advanced prostate cancer. We thus sought to evaluate next-generation sequencing (NGS) testing in the United States, focused on single versus serial NGS testing, the different disease states of testing (hormone-sensitive v castration-resistant, metastatic vs nonmetastatic), tissue versus plasma circulating tumor DNA (ctDNA) assays, and how often actionable data were found on each NGS test.

METHODS: The Prostate Cancer Precision Medicine Multi-Institutional Collaborative Effort clinical-genomic database was used for this retrospective analysis, including 1,597 patients across 15 institutions. Actionable NGS data were defined as including somatic alterations in homologous recombination repair genes, mismatch repair deficiency, microsatellite instability (MSI-high), or a high tumor mutational burden ≥10 mut/MB.

RESULTS: Serial NGS testing (two or more NGS tests with specimens collected more than 60 days apart) was performed in 9% (n = 144) of patients with a median of 182 days in between test results. For the second NGS test and beyond, 82.1% (225 of 274) of tests were from ctDNA assays and 76.1% (217 of 285) were collected in the metastatic castration-resistant setting. New actionable data were found on 11.1% (16 of 144) of second NGS tests, with 3.5% (5 of 144) of tests detecting a new BRCA2 alteration or MSI-high. A targeted therapy (poly (ADP-ribose) polymerase inhibitor or immunotherapy) was given after an actionable result on the second NGS test in 31.3% (5 of 16) of patients.

CONCLUSION: Repeat somatic NGS testing in men with prostate cancer is infrequently performed in practice and can identify new actionable alterations not present with initial testing, suggesting the utility of repeat molecular profiling with tissue or blood of men with metastatic castration-resistant prostate cancer to guide therapy choices.

RevDate: 2024-04-08
CmpDate: 2024-04-08

Sunassee ED, Deutsch RJ, D'Agostino VW, et al (2024)

Optical imaging reveals chemotherapy-induced metabolic reprogramming of residual disease and recurrence.

Science advances, 10(14):eadj7540.

Fewer than 20% of triple-negative breast cancer patients experience long-term responses to mainstay chemotherapy. Resistant tumor subpopulations use alternative metabolic pathways to escape therapy, survive, and eventually recur. Here, we show in vivo, longitudinal metabolic reprogramming in residual disease and recurrence of triple-negative breast cancer xenografts with varying sensitivities to the chemotherapeutic drug paclitaxel. Optical imaging coupled with metabolomics reported an increase in non-glucose-driven mitochondrial metabolism and an increase in intratumoral metabolic heterogeneity during regression and residual disease in resistant MDA-MB-231 tumors. Conversely, sensitive HCC-1806 tumors were primarily reliant on glucose uptake and minimal changes in metabolism or heterogeneity were observed over the tumors' therapeutic life cycles. Further, day-matched resistant HCC-1806 tumors revealed a higher reliance on mitochondrial metabolism and elevated metabolic heterogeneity compared to sensitive HCC-1806 tumors. Together, metabolic flexibility, increased reliance on mitochondrial metabolism, and increased metabolic heterogeneity are defining characteristics of persistent residual disease, features that will inform the appropriate type and timing of therapies.

RevDate: 2024-04-08

Erdmann NB, Williams WB, Walsh SR, et al (2024)

A HIV-1 Gp41 Peptide-Liposome Vaccine Elicits Neutralizing Epitope-Targeted Antibody Responses in Healthy Individuals.

medRxiv : the preprint server for health sciences.

BACKGROUND: HIV-1 vaccine development is a global health priority. Broadly neutralizing antibodies (bnAbs) which target the HIV-1 gp41 membrane-proximal external region (MPER) have some of the highest neutralization breadth. An MPER peptide-liposome vaccine has been found to expand bnAb precursors in monkeys.

METHODS: The HVTN133 phase 1 clinical trial (NCT03934541) studied the MPER-peptide liposome immunogen in 24 HIV-1 seronegative individuals. Participants were recruited between 15 July 2019 and 18 October 2019 and were randomized in a dose-escalation design to either 500 mcg or 2000 mcg of the MPER-peptide liposome or placebo. Four intramuscular injections were planned at months 0, 2, 6, and 12.

RESULTS: The trial was stopped prematurely due to an anaphylaxis reaction in one participant ultimately attributed to vaccine-associated polyethylene glycol. The immunogen induced robust immune responses, including MPER+ serum and blood CD4+ T-cell responses in 95% and 100% of vaccinees, respectively, and 35% (7/20) of vaccine recipients had blood IgG memory B cells with MPER-bnAb binding phenotype. Affinity purification of plasma MPER+ IgG demonstrated tier 2 HIV-1 neutralizing activity in two of five participants after 3 immunizations.

CONCLUSIONS: MPER-peptide liposomes induced gp41 serum neutralizing epitope-targeted antibodies and memory B-cell responses in humans despite the early termination of the study. These results suggest that the MPER region is a promising target for a candidate HIV vaccine.

RevDate: 2024-04-08

Percival ME, Zhang M, Othus M, et al (2024)

Association between class III obesity and overall survival in previously untreated younger patients with acute myeloid leukemia enrolled on SWOG S1203.

Research square.

There has been ongoing debate on the association between obesity and outcomes in acute myeloid leukemia (AML). Currently there are few studies that have stratified outcomes by class I obesity, class II obesity, and class III obesity; and a more nuanced understanding is becoming increasingly important with the rising prevalence of obesity. We examined the association between body mass index (BMI) and outcomes in previously untreated AML in younger patients (age ≤60) enrolled in SWOG S1203 (n=729). Class III obesity was associated with an increased rate of early death (p=0.004) and worse overall survival (OS) in multivariate analysis (hazard ratio (HR) 2.48, 95% confidence interval (CI) 1.62-3.80 versus normal weight). Class III obesity was also associated with worse OS after allogeneic hematopoietic cell transplant (HR 2.37, 95% CI 1.24-4.54 versus normal weight). These findings highlight the unique risk of class III obesity in AML, and the importance of further investigation to better characterize this patient population.

RevDate: 2024-04-08

Schmid S, Russell ZR, Yamashita AS, et al (2024)

ERK signaling promotes resistance to TRK kinase inhibition in NTRK fusion-driven glioma mouse models.

bioRxiv : the preprint server for biology.

Pediatric-type high-grade gliomas frequently harbor gene fusions involving receptor tyrosine kinase genes, including neurotrophic tyrosine kinase receptor (NTRK) fusions. Clinically, these tumors show high initial response rates to tyrosine kinase inhibition but ultimately recur due to the accumulation of additional resistance-conferring mutations. Here, we developed a series of genetically engineered mouse models of treatment-naïve and -experienced NTRK1/2/3 fusion-driven gliomas. Both the TRK kinase domain and the N-terminal fusion partners influenced tumor histology and aggressiveness. Treatment with TRK kinase inhibitors significantly extended survival of NTRK fusion-driven glioma mice in a fusion- and inhibitor-dependent manner, but tumors ultimately recurred due to the presence of treatment-resistant persister cells. Finally, we show that ERK activation promotes resistance to TRK kinase inhibition and identify MEK inhibition as a potential combination therapy. These models will be invaluable tools for preclinical testing of novel inhibitors and to study the cellular responses of NTRK fusion-driven gliomas to therapy.

RevDate: 2024-04-07

Crist SB, Azzag K, Kiley J, et al (2024)

The adult environment promotes the transcriptional maturation of human iPSC-derived muscle grafts.

NPJ Regenerative medicine, 9(1):16.

Pluripotent stem cell (PSC)-based cell therapy is an attractive option for the treatment of multiple human disorders, including muscular dystrophies. While in vitro differentiating PSCs can generate large numbers of human lineage-specific tissue, multiple studies evidenced that these cell populations mostly display embryonic/fetal features. We previously demonstrated that transplantation of PSC-derived myogenic progenitors provides long-term engraftment and functional improvement in several dystrophic mouse models, but it remained unknown whether donor-derived myofibers mature to match adult tissue. Here, we transplanted iPAX7 myogenic progenitors into muscles of non-dystrophic and dystrophic mice and compared the transcriptional landscape of human grafts with respective in vitro-differentiated iPAX7 myotubes as well as human skeletal muscle biospecimens. Pairing bulk RNA sequencing with computational deconvolution of human reads, we were able to pinpoint key myogenic changes that occur during the in vitro-to-in vivo transition, confirm developmental maturity, and consequently evaluate their applicability for cell-based therapies.

RevDate: 2024-04-04

Malik FS, Liese AD, Ellyson A, et al (2024)

Household food insecurity and associations with hemoglobin A1c and acute diabetes-related complications in youth and young adults with type 1 diabetes: The SEARCH for diabetes in youth study.

Diabetes research and clinical practice pii:S0168-8227(24)00092-5 [Epub ahead of print].

AIMS: To examine, among youth and young adults (YYA) with type 1 diabetes (T1D), the association of household food insecurity (HFI) with: 1) HbA1c and 2) episodes of diabetic ketoacidosis (DKA) and severe hypoglycemia.

METHODS: HFI was assessed using the U.S. Household Food Security Survey Module in SEARCH for Diabetes in Youth participants with T1D between 2016 and 2019. Linear and logistic regression models adjusted for age, diabetes duration, sex, race, ethnicity, clinic site, parent/participant education, household income, health insurance, and diabetes technology use.

RESULTS: Of 1830 participants (mean age 20.8 ± 5.0 years, 70.0 % non-Hispanic White), HbA1c was collected for 1060 individuals (mean HbA1c 9.2 % ± 2.0 %). The prevalence of HFI was 16.4 %. In the past 12 months, 18.2 % and 9.9 % reported an episode of DKA or severe hypoglycemia, respectively. Compared to participants who were food secure, HFI was associated with a 0.33 % (95 % CI 0.003, 0.657) higher HbA1c level. Those with HFI had 1.58 (95 % CI 1.13, 2.21) times the adjusted odds of an episode of DKA and 1.53 (95 % CI 0.99, 2.37) times the adjusted odds of an episode of severe hypoglycemia as those without HFI.

CONCLUSIONS: HFI is associated with higher HbA1c levels and increased odds of DKA in YYA with T1D.

RevDate: 2024-04-04

Schilsky S, Green Howard A, Moore CC, et al (2024)

Correlates of physical activity and sedentary behavior among cancer survivors and cancer-free women: The Women's Health Accelerometry Collaboration.

PloS one, 19(4):e0301233.

BACKGROUND: Describing correlates of physical activity (PA) and sedentary behavior (SB) among postmenopausal cancer survivors can help identify risk profiles and can be used to support development of targeted interventions to improve PA and reduce SB in this population.

OBJECTIVE: To describe PA/SB and identify correlates of PA/SB among cancer and cancer-free post-menopausal women.

METHODS: Women from the Women's Health Study (N = 16,629) and Women's Health Initiative/Objective Physical Activity and Cardiovascular Health Study (N = 6,079) were asked to wear an accelerometer on the hip for 7 days. Multiple mixed-effects linear regression models were used to identify sociodemographic-, health-, and chronic condition-related correlates (independent variables) associated with PA and SB (dependent variables) among women with (n = 2,554) and without (n = 20,154) a history of cancer. All correlates were mutually adjusted for each other.

RESULTS: In unadjusted analyses, women with a history of cancer took fewer mean daily steps (4,572 (standard deviation 2557) vs 5,029 (2679) steps/day) and had lower mean moderate-to-vigorous PA (74.9 (45.0) vs. 81.6 (46.7) minutes/day) than cancer-free women. In adjusted analyses, for cancer and cancer-free women, age, diabetes, overweight, and obesity were inversely associated with all metrics of PA (average vector magnitude, time in moderate-to-vigorous PA, step volume, time at ≥40 steps/minutes, and peak 30-minute step cadence). In unadjusted analyses, mean SB was similar for those with and without cancer (529.7 (98.1) vs. 521.7 (101.2) minutes/day). In adjusted analyses, for cancer and cancer-free women, age, diabetes, cardiovascular disease, current smoking, overweight, and obesity were positive correlates of SB, while Black or Hispanic race/ethnicity, weekly/daily alcohol intake, and excellent/very good/good self-rated health were inverse correlates of SB.

CONCLUSION: Several sociodemographic, health, and chronic conditions were correlates of PA/SB for postmenopausal women with and without cancer. Future studies should examine longitudinal relationships to gain insight into potential determinants of PA/SB.

RevDate: 2024-04-04

Owens K, Esmaeili S, J Schiffer (2024)

Heterogeneous SARS-CoV-2 kinetics due to variable timing and intensity of immune responses.

JCI insight pii:176286 [Epub ahead of print].

The viral kinetics of documented SARS-CoV-2 infections exhibit a high degree of inter-individual variability. We identified six distinct viral shedding patterns, which differed according to peak viral load, duration, expansion rate and clearance rate, by clustering data from 768 infections in the National Basketball Association cohort. Omicron variant infections in previously vaccinated individuals generally led to lower cumulative shedding levels of SARS-CoV-2 than other scenarios. We then developed a mechanistic mathematical model that recapitulated 1510 observed viral trajectories, including viral rebound and cases of reinfection. Lower peak viral loads were explained by a more rapid and sustained transition of susceptible cells to a refractory state during infection, as well as an earlier and more potent late, cytolytic immune response. Our results suggest that viral elimination occurs more rapidly during omicron infection, following vaccination, and following re-infection due to enhanced innate and acquired immune responses. Because viral load has been linked with COVID-19 severity and transmission risk, our model provides a framework for understanding the wide range of observed SARS-CoV-2 infection outcomes.

RevDate: 2024-04-05
CmpDate: 2024-04-05

Szulzewsky F, Thirimanne HN, EC Holland (2024)

Meningioma: current updates on genetics, classification, and mouse modeling.

Upsala journal of medical sciences, 129:.

Meningiomas, the most common primary brain tumors in adults, are often benign and curable by surgical resection. However, a subset is of higher grade, shows aggressive growth behavior as well as brain invasion, and often recurs even after several rounds of surgery. Increasing evidence suggests that tumor classification and grading primarily based on histopathology do not always accurately predict tumor aggressiveness and recurrence behavior. The underlying biology of aggressive treatment-resistant meningiomas and the impact of specific genetic aberrations present in these high-grade tumors is still only insufficiently understood. Therefore, an in-depth research into the biology of this tumor type is warranted. More recent studies based on large-scale molecular data such as whole exome/genome sequencing, DNA methylation sequencing, and RNA sequencing have provided new insights into the biology of meningiomas and have revealed new risk factors and prognostic subtypes. The most common genetic aberration in meningiomas is functional loss of NF2 and occurs in both low- and high-grade meningiomas, whereas NF2-wildtype meningiomas are enriched for recurrent mutations in TRAF7, KLF4, AKT1, PI3KCA, and SMO and are more frequently benign. Most meningioma mouse models are based on patient-derived xenografts and only recently have new genetically engineered mouse models of meningioma been developed that will aid in the systematic evaluation of specific mutations found in meningioma and their impact on tumor behavior. In this article, we review recent advances in the understanding of meningioma biology and classification and highlight the most common genetic mutations, as well as discuss new genetically engineered mouse models of meningioma.

RevDate: 2024-04-05
CmpDate: 2024-04-05

Stangis MM, Chen Z, Min J, et al (2024)

The Hallmarks of Precancer.

Cancer discovery, 14(4):683-689.

Research on precancers, as defined as at-risk tissues and early lesions, is of high significance given the effectiveness of early intervention. We discuss the need for risk stratification to prevent overtreatment, an emphasis on the role of genetic and epigenetic aging when considering risk, and the importance of integrating macroenvironmental risk factors with molecules and cells in lesions and at-risk normal tissues for developing effective intervention and health policy strategies.

RevDate: 2024-04-05
CmpDate: 2024-04-05

Lee HY, Song M, Stopsack KH, et al (2024)

The Cancer Spectrum Theory.

Cancer discovery, 14(4):589-593.

Biological characteristics of tumors are heterogeneous, forming spectra in terms of several factors such as age at onset, anatomic spatial localization, tumor subtyping, and the degree of tumor aggressiveness (encompassing a neoplastic property spectrum). Instead of blindly using dichotomized approaches, the application of the multicategorical and continuous analysis approaches to detailed cancer spectrum data can contribute to a better understanding of the etiology of cancer, ultimately leading to effective prevention and precision oncology. We provide examples of cancer spectra and emphasize the importance of integrating the cancer spectrum theory into large-scale population cancer research.

RevDate: 2024-04-05
CmpDate: 2024-04-05

Lundin JI, Peters U, Hu Y, et al (2024)

Methylation patterns associated with C-reactive protein in racially and ethnically diverse populations.

Epigenetics, 19(1):2333668.

Systemic low-grade inflammation is a feature of chronic disease. C-reactive protein (CRP) is a common biomarker of inflammation and used as an indicator of disease risk; however, the role of inflammation in disease is not completely understood. Methylation is an epigenetic modification in the DNA which plays a pivotal role in gene expression. In this study we evaluated differential DNA methylation patterns associated with blood CRP level to elucidate biological pathways and genetic regulatory mechanisms to improve the understanding of chronic inflammation. The racially and ethnically diverse participants in this study were included as 50% White, 41% Black or African American, 7% Hispanic or Latino/a, and 2% Native Hawaiian, Asian American, American Indian, or Alaska Native (total n = 13,433) individuals. We replicated 113 CpG sites from 87 unique loci, of which five were novel (CADM3, NALCN, NLRC5, ZNF792, and cg03282312), across a discovery set of 1,150 CpG sites associated with CRP level (p < 1.2E-7). The downstream pathways affected by DNA methylation included the identification of IFI16 and IRF7 CpG-gene transcript pairs which contributed to the innate immune response gene enrichment pathway along with NLRC5, NOD2, and AIM2. Gene enrichment analysis also identified the nuclear factor-kappaB transcription pathway. Using two-sample Mendelian randomization (MR) we inferred methylation at three CpG sites as causal for CRP levels using both White and Black or African American MR instrument variables. Overall, we identified novel CpG sites and gene transcripts that could be valuable in understanding the specific cellular processes and pathogenic mechanisms involved in inflammation.

RevDate: 2024-04-05

Parino F, Gustani-Buss E, Bedford T, et al (2024)

Integrating dynamical modeling and phylogeographic inference to characterize global influenza circulation.

medRxiv : the preprint server for health sciences.

Global seasonal influenza circulation involves a complex interplay between local (seasonality, demography, host immunity) and global factors (international mobility) shaping recurrent epidemic patterns. No studies so far have reconciled the two spatial levels, evaluating the coupling between national epidemics, considering heterogeneous coverage of epidemiological and virological data, integrating different data sources. We propose a novel combined approach based on a dynamical model of global influenza spread (GLEAM), integrating high-resolution demographic and mobility data, and a generalized linear model of phylogeographic diffusion that accounts for time-varying migration rates. Seasonal migration fluxes across global macro-regions simulated with GLEAM are tested as phylogeographic predictors to provide model validation and calibration based on genetic data. Seasonal fluxes obtained with a specific transmissibility peak time and recurrent travel outperformed the raw air-transportation predictor, previously considered as optimal indicator of global influenza migration. Influenza A subtypes supported autumn-winter reproductive number as high as 2.25 and an average immunity duration of 2 years. Similar dynamics were preferred by influenza B lineages, with a lower autumn-winter reproductive number. Comparing simulated epidemic profiles against FluNet data offered comparatively limited resolution power. The multiscale approach enables model selection yielding a novel computational framework for describing global influenza dynamics at different scales - local transmission and national epidemics vs. international coupling through mobility and imported cases. Our findings have important implications to improve preparedness against seasonal influenza epidemics. The approach can be generalized to other epidemic contexts, such as emerging disease outbreaks to improve the flexibility and predictive power of modeling.

RevDate: 2024-04-05

Samorodnitsky S, Campbell K, Ribas A, et al (2024)

A Spatial Omnibus Test (SPOT) for Spatial Proteomic Data.

bioRxiv : the preprint server for biology.

Spatial proteomics can reveal the spatial organization of immune cells in the tumor immune microenvironment. Relating measures of spatial clustering, such as Ripley's K or Besag's L, to patient outcomes may offer important clinical insights. However, these measures require pre-specifying a radius in which to quantify clustering, yet no consensus exists on the optimal radius which may be context-specific. We propose a SPatial Omnibus Test (SPOT) which conducts this analysis across a range of candidate radii. At each radius, SPOT evaluates the association between the spatial summary and outcome, adjusting for confounders. SPOT then aggregates results across radii using the Cauchy combination test, yielding an omnibus p-value characterizing the overall degree of association. Using simulations, we verify that the type I error rate is controlled and show SPOT can be more powerful than alternatives. We also apply SPOT to an ovarian cancer study. An R package and tutorial is provided at

RevDate: 2024-04-05

Kubinski HC, Despres HW, Johnson BA, et al (2024)

Variant mutation in SARS-CoV-2 nucleocapsid enhances viral infection via altered genomic encapsidation.

bioRxiv : the preprint server for biology.

The evolution of SARS-CoV-2 variants and their respective phenotypes represents an important set of tools to understand basic coronavirus biology as well as the public health implications of individual mutations in variants of concern. While mutations outside of Spike are not well studied, the entire viral genome is undergoing evolutionary selection, particularly the central disordered linker region of the nucleocapsid (N) protein. Here, we identify a mutation (G215C), characteristic of the Delta variant, that introduces a novel cysteine into this linker domain, which results in the formation of a disulfide bond and a stable N-N dimer. Using reverse genetics, we determined that this cysteine residue is necessary and sufficient for stable dimer formation in a WA1 SARS-CoV-2 background, where it results in significantly increased viral growth both in vitro and in vivo. Finally, we demonstrate that the N:G215C virus packages more nucleocapsid per virion and that individual virions are larger, with elongated morphologies.

RevDate: 2024-04-03

Leary JB, Enright T, Bakaloudi DR, et al (2024)

Frequency and Nature of Genomic Alterations in ERBB2-Altered Urothelial Bladder Cancer.

Targeted oncology [Epub ahead of print].

BACKGROUND: Human epidermal growth factor-2 (HER2) overexpression is an oncogenic driver in many solid tumors, including urothelial bladder cancer (UBC). In addition, activating mutations in the ERBB2 gene have been shown to play an oncogenic role similar to ERBB2 amplification.

OBJECTIVE: To describe and compare the frequency and nature of genomic alterations (GA) of ERBB2-altered (mutations, amplification) and ERBB2 wild-type UBC.

PATIENTS AND METHODS: Using a hybrid capture-based comprehensive profiling assay, 9518 UBC cases were grouped by ERBB2 alteration and evaluated for all classes of genomic alterations (GA), tumor mutational burden (TMB), microsatellite instability (MSI), genome-wide loss of heterozygosity (gLOH), and genomic mutational signature. PD-L1 expression was measured by immunohistochemistry (Dako 22C3). Categorical statistical comparisons were performed using Fisher's exact tests.

RESULTS: A total of 602 (6.3%) UBC cases featured ERBB2 extracellular domain short variant (SV) GA (ECDmut+), 253 (2.7%) cases featured ERBB2 kinase domain SV GA (KDmut+), 866 (9.1%) cases had ERBB2 amplification (amp+), and 7797 (81.9%) cases were ERBB2 wild-type (wt). European genetic ancestry of ECDmut+ was higher than ERBB2wt. Numerous significant associations were observed when comparing GA by group. Notably among these, CDKN2A/MTAP loss were more frequent in ERBB2wt versus ECDmut+ and amp+. ERBB3 GA were more frequent in ECDmut+ and KDmut+ than ERBB2wt. TERT GA were more frequent in ECDmut+, KDmut+, and amp+ versus ERBB2wt. TOP2A amplification was significantly more common in ECDmut+ and amp+ versus ERBB2wt, and TP53 SV GA were significantly higher in ERBB2 amp+ versus ERBB2wt. Mean TMB levels were significantly higher in ECDmut+, KDmut+, and amp+ than in ERBB2wt. Apolipoprotein B mRNA-editing enzyme, catalytic polypeptides (APOBEC) signature was more frequent in ECDmut+, KDmut+, and amp+ versus ERBB2wt. No significant differences were observed in PD-L1 status between groups, while gLOH-high status was more common in amp+ versus ERBB2wt. MSI-high status was more frequent in KDmut+ versus ERBB2wt, and in ERBB2wt than in amp+.

CONCLUSIONS: We noted important differences in co-occurring GA in ERBB2-altered (ECDmut+, KDmut+, amp+) versus ERBB2wt UBC, as well as higher mean TMB and higher APOBEC mutational signature in the ERBB2-altered groups. Our results can help refine future clinical trial designs and elucidate possible response and resistance mechanisms for ERBB2-altered UBC.

RevDate: 2024-04-03

Tran-Kiem C, T Bedford (2024)

Estimating the reproduction number and transmission heterogeneity from the size distribution of clusters of identical pathogen sequences.

Proceedings of the National Academy of Sciences of the United States of America, 121(15):e2305299121.

Quantifying transmission intensity and heterogeneity is crucial to ascertain the threat posed by infectious diseases and inform the design of interventions. Methods that jointly estimate the reproduction number R and the dispersion parameter k have however mainly remained limited to the analysis of epidemiological clusters or contact tracing data, whose collection often proves difficult. Here, we show that clusters of identical sequences are imprinted by the pathogen offspring distribution, and we derive an analytical formula for the distribution of the size of these clusters. We develop and evaluate an inference framework to jointly estimate the reproduction number and the dispersion parameter from the size distribution of clusters of identical sequences. We then illustrate its application across a range of epidemiological situations. Finally, we develop a hypothesis testing framework relying on clusters of identical sequences to determine whether a given pathogen genetic subpopulation is associated with increased or reduced transmissibility. Our work provides tools to estimate the reproduction number and transmission heterogeneity from pathogen sequences without building a phylogenetic tree, thus making it easily scalable to large pathogen genome datasets.

RevDate: 2024-04-04
CmpDate: 2024-04-04

Briercheck EL, Wrigglesworth JM, Garcia-Gonzalez I, et al (2024)

Treatment Access for Gastrointestinal Stromal Tumor in Predominantly Low- and Middle-Income Countries.

JAMA network open, 7(4):e244898 pii:2816999.

IMPORTANCE: Gastrointestinal stromal tumor (GIST) is a rare cancer treated with the tyrosine kinase inhibitors imatinib mesylate or sunitinib malate. In general, in low- and middle-income countries (LMICs), access to these treatments is limited.

OBJECTIVE: To describe the demographic characteristics, treatment duration, and survival of patients with GIST in LMICs treated with imatinib and sunitinib through The Max Foundation programs.

This retrospective database cohort analysis included patients in 2 access programs administered by The Max Foundation: the Glivec International Patient Assistance Program (GIPAP), from January 1, 2001, to December 31, 2016, and the Max Access Solutions (MAS) program, January 1, 2017, to October 12, 2020. Sixty-six countries in which The Max Foundation facilitates access to imatinib and sunitinib were included. Participants consisted of patients with approved indications for imatinib, including adjuvant therapy in high-risk GIST by pathologic evaluation of resected tumor or biopsy-proven unresectable or metastatic GIST. All patients were reported to have tumors positive for CD117(c-kit) by treating physicians. A total of 9866 patients received treatment for metastatic and/or unresectable disease; 2100 received adjuvant imatinib; 49 received imatinib from another source and were only included in the sunitinib analysis; and 53 received both imatinib and sunitinib through The Max Foundation programs. Data were analyzed from October 13, 2020, to January 30, 2024.

MAIN OUTCOMES AND MEASURES: Demographic and clinical information was reported by treating physicians. Kaplan-Meier analysis was used to estimate time to treatment discontinuation (TTD) and overall survival (OS). An imputation-based informed censoring model estimated events for patients lost to follow-up after treatment with adjuvant imatinib. Patients who were lost to follow-up with metastatic or unresectable disease were presumed deceased.

RESULTS: A total of 12 015 unique patients were included in the analysis (6890 male [57.6%]; median age, 54 [range, 0-100] years). Of these, 2100 patients were treated with imatinib in the adjuvant setting (median age, 54 [range 8-88] years) and 9866 were treated with imatinib for metastatic or unresectable disease (median age, 55 [range, 0-100] years). Male patients comprised 5867 of 9866 patients (59.5%) with metastatic or unresectable disease and 1023 of 2100 patients (48.7%) receiving adjuvant therapy. The median OS with imatinib for unresectable or metastatic disease was 5.8 (95% CI, 5.6-6.1) years, and the median TTD was 4.2 (95% CI, 4.1-4.4) years. The median OS with sunitinib for patients with metastatic or unresectable GIST was 2.0 (95% CI, 1.5-2.5) years; the median TTD was 1.5 (95% CI, 1.0-2.1) years. The 10-year OS rate in the adjuvant setting was 73.8% (95% CI, 67.2%-81.1%).

CONCLUSIONS AND RELEVANCE: In this cohort study of patients with GIST who were predominantly from LMICs and received orally administered therapy through the GIPAP or MAS programs, outcomes were similar to those observed in high-resource countries. These findings underscore the feasibility and relevance of administering oral anticancer therapy to a molecularly defined population in LMICs, addressing a critical gap in cancer care.

RevDate: 2024-04-03

McConnell KM, MJ Shen (2024)

The need for multilevel supportive care infrastructure for cancer caregivers.

RevDate: 2024-04-04
CmpDate: 2024-04-04

VoPham T, White AJ, RR Jones (2024)

Geospatial Science for the Environmental Epidemiology of Cancer in the Exposome Era.

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 33(4):451-460.

Geospatial science is the science of location or place that harnesses geospatial tools, such as geographic information systems (GIS), to understand the features of the environment according to their locations. Geospatial science has been transformative for cancer epidemiologic studies through enabling large-scale environmental exposure assessments. As the research paradigm for the exposome, or the totality of environmental exposures across the life course, continues to evolve, geospatial science will serve a critical role in determining optimal practices for how to measure the environment as part of the external exposome. The objectives of this article are to provide a summary of key concepts, present a conceptual framework that illustrates how geospatial science is applied to environmental epidemiology in practice and through the lens of the exposome, and discuss the following opportunities for advancing geospatial science in cancer epidemiologic research: enhancing spatial and temporal resolutions and extents for geospatial data; geospatial methodologies to measure climate change factors; approaches facilitating the use of patient addresses in epidemiologic studies; combining internal exposome data and geospatial exposure models of the external exposome to provide insights into biological pathways for environment-disease relationships; and incorporation of geospatial data into personalized cancer screening policies and clinical decision making.

RevDate: 2024-04-04
CmpDate: 2024-04-04

Dahl AM, Brown CE, Brown ER, et al (2024)

Concordance between SARS-CoV-2 index individuals and their household contacts on index individual COVID-19 transmission cofactors: a comparison of self-reported and contact-reported information.

BMC public health, 24(1):950.

BACKGROUND: Following the outbreak of the COVID-19 pandemic, several clinical trials have evaluated postexposure prophylaxis (PEP) among close contacts of an index individual with a confirmed SARS-CoV-2 infection. Because index individuals do not directly inform the efficacy of prevention interventions, they are seldom enrolled in COVID-19 PEP studies. However, adjusting for prognostic covariates such as an index individual's COVID-19 illness and risk behaviors can increase precision in PEP efficacy estimates, so approaches to accurately collecting this information about the index individual are needed. This analysis aimed to assess whether surveying household contacts captures the same information as surveying the index individual directly.

METHODS: REGN 2069/CoVPN 3502, a randomized controlled trial of COVID-19 PEP, enrolled household contacts of SARS-CoV-2 index individuals. CoVPN 3502-01 retrospectively enrolled and surveyed the index individuals. We compared responses to seven similar questions about the index individuals' transmission cofactors that were asked in both studies. We estimated the percent concordance between index individuals and their household contacts on each question, with 50% concordance considered equivalent to random chance.

RESULTS: Concordance between index individuals and contacts was high on the most objective questions, approximately 97% (95% CI: 90-99%) for index individual age group and 96% (88-98%) for hospitalization. Concordance was moderate for symptoms, approximately 85% (75-91%). Concordance on questions related to the index individual's behavior was only slightly better or no better than random: approximately 62% (51-72%) for whether they received COVID-19 treatment, 68% (57-77%) for sharing a bedroom, 70% (59-79%) for sharing a common room, and 49% (39-60%) for mask wearing at home. However, while contacts were surveyed within 96 h of the index individual testing positive for SARS-CoV-2, the median time to enrollment in CoVPN 3502-01 was 240 days, which may have caused recall bias in our results.

CONCLUSIONS: Our results suggest a need to survey index individuals directly in order to accurately capture their transmission cofactors, rather than relying on their household contacts to report on their behavior. The lag in enrolling participants into CoVPN 3502-01 also highlights the importance of timely enrollment to minimize recall bias.

RevDate: 2024-04-02

Singhvi A, Shaham S, G Rapti (2024)

Glia Development and Function in the Nematode Caenorhabditis elegans.

Cold Spring Harbor perspectives in biology pii:cshperspect.a041346 [Epub ahead of print].

The nematode Caenorhabditis elegans is a powerful experimental setting for uncovering fundamental tenets of nervous system organization and function. Its nearly invariant and simple anatomy, coupled with a plethora of methodologies for interrogating single-gene functions at single-cell resolution in vivo, have led to exciting discoveries in glial cell biology and mechanisms of glia-neuron interactions. Findings over the last two decades reinforce the idea that insights from C. elegans can inform our understanding of glial operating principles in other species. Here, we summarize the current state-of-the-art, and describe mechanistic insights that have emerged from a concerted effort to understand C. elegans glia. The remarkable acceleration in the pace of discovery in recent years paints a portrait of striking molecular complexity, exquisite specificity, and functional heterogeneity among glia. Glial cells affect nearly every aspect of nervous system development and function, from generating neurons, to promoting neurite formation, to animal behavior, and to whole-animal traits, including longevity. We discuss emerging questions where C. elegans is poised to fill critical knowledge gaps in our understanding of glia biology.

RevDate: 2024-04-02

Freie B, Carroll PA, Varnum-Finney BJ, et al (2024)

A germline point mutation in the MYC-FBW7 phosphodegron initiates hematopoietic malignancies.

Genes & development pii:gad.351292.123 [Epub ahead of print].

Oncogenic activation of MYC in cancers predominantly involves increased transcription rather than coding region mutations. However, MYC-dependent lymphomas frequently acquire point mutations in the MYC phosphodegron, including at threonine 58 (T58), where phosphorylation permits binding via the FBW7 ubiquitin ligase triggering MYC degradation. To understand how T58 phosphorylation functions in normal cell physiology, we introduced an alanine mutation at T58 (T58A) into the endogenous c-Myc locus in the mouse germline. While MYC-T58A mice develop normally, lymphomas and myeloid leukemias emerge in ∼60% of adult homozygous T58A mice. We found that primitive hematopoietic progenitor cells from MYC-T58A mice exhibit aberrant self-renewal normally associated with hematopoietic stem cells (HSCs) and up-regulate a subset of MYC target genes important in maintaining stem/progenitor cell balance. In lymphocytes, genomic occupancy by MYC-T58A was increased at all promoters compared with WT MYC, while genes differentially expressed in a T58A-dependent manner were significantly more proximal to MYC-bound enhancers. MYC-T58A lymphocyte progenitors exhibited metabolic alterations and decreased activation of inflammatory and apoptotic pathways. Our data demonstrate that a single point mutation stabilizing MYC is sufficient to skew target gene expression, producing a profound gain of function in multipotential hematopoietic progenitors associated with self-renewal and initiation of lymphomas and leukemias.

RevDate: 2024-04-04

Razi A, Lo CC, Wang S, et al (2024)

Genotype prediction of 336,463 samples from public expression data.

bioRxiv : the preprint server for biology.

Tens of thousands of RNA-sequencing experiments comprising hundreds of thousands of individual samples have now been performed. These data represent a broad range of experimental conditions, sequencing technologies, and hypotheses under study. The Recount project has aggregated and uniformly processed hundreds of thousands of publicly available RNA-seq samples. Most of these samples only include RNA expression measurements; genotype data for these same samples would enable a wide range of analyses including variant prioritization, eQTL analysis, and studies of allele specific expression. Here, we developed a statistical model based on the existing reference and alternative read counts from the RNA-seq experiments available through Recount3 to predict genotypes at autosomal biallelic loci in coding regions. We demonstrate the accuracy of our model using large-scale studies that measured both gene expression and genotype genome-wide. We show that our predictive model is highly accurate with 99.5% overall accuracy, 99.6% major allele accuracy, and 90.4% minor allele accuracy. Our model is robust to tissue and study effects, provided the coverage is high enough. We applied this model to genotype all the samples in Recount 3 and provide the largest ready-to-use expression repository containing genotype information. We illustrate that the predicted genotype from RNA-seq data is sufficient to unravel the underlying population structure of samples in Recount3 using Principal Component Analysis.

RevDate: 2024-04-04

Henikoff S, Henikoff JG, Paranal RM, et al (2024)

Direct measurement of RNA Polymerase II hypertranscription in cancer FFPE samples.

bioRxiv : the preprint server for biology.

Hypertranscription is widespread in aggressive human cancers. However detection relies on mRNAs, which are heavily processed and have variable half-lives, and on accurate cell number estimations. Previously we introduced FFPE-CUTAC, a genome-wide method for mapping RNA Polymerase II in formalin-fixed paraffin-embedded (FFPE) sections. Here we apply FFPE-CUTAC on slides and curls to demonstrate hypertranscription at regulatory elements and replication-coupled histone genes. We find that hypertranscription differs between transgene-driven mouse gliomas and scales with enhanced proliferation and reduced mitochondrial DNA. We also apply FFPE-CUTAC to identify tumor-specific patterns in assorted human tumor-normal pairs. We analyze the top-ranked 100 annotated regulatory elements that are hypertranscribed in most of the tumors and identify multiple loci around ERBB2 on Chromosome 17q12-21 in the breast and colon cancer samples, mapping likely HER2 amplifications punctuated by selective sweeps. Our results demonstrate that FFPE-CUTAC measurement of hypertranscription provides an affordable and sensitive genome-wide strategy for cancer diagnosis.

RevDate: 2024-04-02

Unger JM, Shulman LN, Facktor MA, et al (2024)

National Estimates of the Participation of Patients With Cancer in Clinical Research Studies Based on Commission on Cancer Accreditation Data.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology [Epub ahead of print].

PURPOSE: National estimates of cancer clinical trial participation are nearly two decades old and have focused solely on enrollment to treatment trials, which does not reflect the willingness of patients to contribute to other elements of clinical research. We determined inclusive, contemporary estimates of clinical trial participation for adults with cancer using a national sample of data from the Commission on Cancer (CoC).

METHODS: The data were obtained from accreditation information submitted by the 1,200 CoC programs, which represent more than 70% of all cancer cases diagnosed in the United States each year. Deidentified, institution-level aggregate counts of annual enrollment to treatment, biorepository, diagnostic, economic, genetic, prevention, quality-of-life (QOL), and registry studies were examined. Overall, study-type estimates for the period 2013-2017 were estimated. Multiple imputation by chained equations was used to account for missing data, with summary estimates calculated separately by type of program (eg, National Cancer Institute [NCI]-designated cancer centers) and pooled.

RESULTS: The overall estimated patient participation rate to cancer treatment trials was 7.1%. Patients with cancer participated in a wide variety of other studies, including biorepository (12.9%), registry (7.3%), genetic (3.6%), QOL (2.8%), diagnostic (2.5%), and economic (2.4%) studies. Treatment trial enrollment was 21.6% at NCI-designated comprehensive cancer centers, 5.4% at academic (non-NCI-designated) comprehensive cancer programs, 5.7% at integrated network cancer programs, and 4.1% at community programs. One in five patients (21.9%) participated in one or more cancer clinical research studies.

CONCLUSION: In a first-time use of national accreditation information from the CoC, enrollment to cancer treatment trials was 7.1%, higher than historical estimates of <5%. Patients participated in a diverse set of other study types. Contributions of adult patients with cancer to clinical research is more common than previously understood.

RevDate: 2024-04-03

Atilla E (2024)

Editorial: Hematopoietic stem cell transplantation: back to the future.

Frontiers in medicine, 11:1390041.

RevDate: 2024-04-03
CmpDate: 2024-04-03

Verstovsek S, Mesa R, Talpaz M, et al (2024)

Erratum to: Retrospective analysis of pacritinib in patients with myelofibrosis and severe thrombocytopenia.

Haematologica, 109(4):3010.

RevDate: 2024-04-01

Tian Y, Lin Y, Qu C, et al (2024)

Genetic risk impacts the association of menopausal hormone therapy with colorectal cancer risk.

British journal of cancer [Epub ahead of print].

BACKGROUND: Menopausal hormone therapy (MHT), a common treatment to relieve symptoms of menopause, is associated with a lower risk of colorectal cancer (CRC). To inform CRC risk prediction and MHT risk-benefit assessment, we aimed to evaluate the joint association of a polygenic risk score (PRS) for CRC and MHT on CRC risk.

METHODS: We used data from 28,486 postmenopausal women (11,519 cases and 16,967 controls) of European descent. A PRS based on 141 CRC-associated genetic variants was modeled as a categorical variable in quartiles. Multiplicative interaction between PRS and MHT use was evaluated using logistic regression. Additive interaction was measured using the relative excess risk due to interaction (RERI). 30-year cumulative risks of CRC for 50-year-old women according to MHT use and PRS were calculated.

RESULTS: The reduction in odds ratios by MHT use was larger in women within the highest quartile of PRS compared to that in women within the lowest quartile of PRS (p-value = 2.7 × 10[-8]). At the highest quartile of PRS, the 30-year CRC risk was statistically significantly lower for women taking any MHT than for women not taking any MHT, 3.7% (3.3%-4.0%) vs 6.1% (5.7%-6.5%) (difference 2.4%, P-value = 1.83 × 10[-14]); these differences were also statistically significant but smaller in magnitude in the lowest PRS quartile, 1.6% (1.4%-1.8%) vs 2.2% (1.9%-2.4%) (difference 0.6%, P-value = 1.01 × 10[-3]), indicating 4 times greater reduction in absolute risk associated with any MHT use in the highest compared to the lowest quartile of genetic CRC risk.

CONCLUSIONS: MHT use has a greater impact on the reduction of CRC risk for women at higher genetic risk. These findings have implications for the development of risk prediction models for CRC and potentially for the consideration of genetic information in the risk-benefit assessment of MHT use.

RevDate: 2024-04-01

Salit RB, Lee SJ, Bhatt NS, et al (2024)

Returning to Work Following Hematopoietic Cell Transplantation: The Survivor's Perspective.

Transplantation and cellular therapy pii:S2666-6367(24)00301-4 [Epub ahead of print].

BACKGROUND: While curing a patient's underlying disease is the primary goal of physicians performing hematopoietic cell transplantation (HCT), the ultimate objective is to provide patients with optimal post-HCT quality of life. For many survivors, this includes returning to work (RTW).

OBJECTIVE: We conducted a survey of one- to five-year post-HCT survivors at our center to evaluate their perspective on facilitators and barriers to RTW as well as to gauge interest in potentially useful RTW support interventions.

STUDY DESIGN: Survivors aged 18 to 65 years (n=994) were sent an annual survey that included 36 supplementary questions about post-HCT RTW. Survey questions were selected from published national cancer survivor surveys and then modified specifically for HCT survivors.

RESULTS: 344 (35%) survivors with a mean age of 53 years completed the survey, of whom 272 (79%) had worked prior to their diagnosis. Of those 272 patients, 145 (53%) were working currently and another 22 (8%) had attempted to go back to work following HCT but were not presently working. We found that having had an allogeneic vs autologous HCT (p=0.006) was associated with a decreased likelihood of currently working, whereas frequent employer communication (> once a month) (p=0.070) and having a more supportive employer (p=0.036) were associated with a greater chance of currently working. Of survivors currently working, 45% reported that they had made one or more changes to their work schedule (e.g., flexible schedule or part-time work) or environment (e.g., work from home) upon RTW. Ninety-five percent of responders reported that they could have benefited from RTW support provided by the transplant center, but only 13% indicated that they had received it. Education on RTW challenges, information on disability benefits, and access to physical therapy were among the most requested support interventions.

CONCLUSION: To improve post-HCT quality of life for survivors open to assistance, providers should address work status and goals, recognize barriers to successful return, and offer RTW support including working directly with employers. Allogeneic HCT survivors are particularly vulnerable to failing attempts to RTW and should be the target of retention interventions. A previously published manuscript on RTW guidance for providers of stem cell transplant patients endorsed by the American Society of Transplant and Cellular Therapy is available Open Access and can be used as a tool to counsel and support these patients.

RevDate: 2024-04-01

Eichholz K, Fukazawa Y, Peterson CW, et al (2024)

Anti-PD-1 chimeric antigen receptor T cells efficiently target SIV-infected CD4+ T cells in germinal centers.

The Journal of clinical investigation, 134(7): pii:169309.

Programmed cell death protein 1 (PD-1) is an immune checkpoint marker commonly expressed on memory T cells and enriched in latently HIV-infected CD4+ T cells. We engineered an anti-PD-1 chimeric antigen receptor (CAR) to assess the impact of PD-1 depletion on viral reservoirs and rebound dynamics in SIVmac239-infected rhesus macaques (RMs). Adoptive transfer of anti-PD-1 CAR T cells was done in 2 SIV-naive and 4 SIV-infected RMs on antiretroviral therapy (ART). In 3 of 6 RMs, anti-PD-1 CAR T cells expanded and persisted for up to 100 days concomitant with the depletion of PD-1+ memory T cells in blood and tissues, including lymph node CD4+ follicular helper T (TFH) cells. Loss of TFH cells was associated with depletion of detectable SIV RNA from the germinal center (GC). However, following CAR T infusion and ART interruption, there was a marked increase in SIV replication in extrafollicular portions of lymph nodes, a 2-log higher plasma viremia relative to controls, and accelerated disease progression associated with the depletion of CD8+ memory T cells. These data indicate anti-PD-1 CAR T cells depleted PD-1+ T cells, including GC TFH cells, and eradicated SIV from this immunological sanctuary.

RevDate: 2024-04-01

Zhang P, Fleming P, Andoniou CE, et al (2024)

IL-6-mediated endothelial injury impairs antiviral humoral immunity after bone marrow transplantation.

The Journal of clinical investigation, 134(7): pii:174184.

Endothelial function and integrity are compromised after allogeneic bone marrow transplantation (BMT), but how this affects immune responses broadly remains unknown. Using a preclinical model of CMV reactivation after BMT, we found compromised antiviral humoral responses induced by IL-6 signaling. IL-6 signaling in T cells maintained Th1 cells, resulting in sustained IFN-γ secretion, which promoted endothelial cell (EC) injury, loss of the neonatal Fc receptor (FcRn) responsible for IgG recycling, and rapid IgG loss. T cell-specific deletion of IL-6R led to persistence of recipient-derived, CMV-specific IgG and inhibited CMV reactivation. Deletion of IFN-γ in donor T cells also eliminated EC injury and FcRn loss. In a phase III clinical trial, blockade of IL-6R with tocilizumab promoted CMV-specific IgG persistence and significantly attenuated early HCMV reactivation. In sum, IL-6 invoked IFN-γ-dependent EC injury and consequent IgG loss, leading to CMV reactivation. Hence, cytokine inhibition represents a logical strategy to prevent endothelial injury, thereby preserving humoral immunity after immunotherapy.

RevDate: 2024-03-30

D'Angelo SP, Araujo DM, Abdul Razak AR, et al (2024)

Afamitresgene autoleucel for advanced synovial sarcoma and myxoid round cell liposarcoma (SPEARHEAD-1): an international, open-label, phase 2 trial.

Lancet (London, England) pii:S0140-6736(24)00319-2 [Epub ahead of print].

BACKGROUND: Afamitresgene autoleucel (afami-cel) showed acceptable safety and promising efficacy in a phase 1 trial (NCT03132922). The aim of this study was to further evaluate the efficacy of afami-cel for the treatment of patients with HLA-A*02 and MAGE-A4-expressing advanced synovial sarcoma or myxoid round cell liposarcoma.

METHODS: SPEARHEAD-1 was an open-label, non-randomised, phase 2 trial done across 23 sites in Canada, the USA, and Europe. The trial included three cohorts, of which the main investigational cohort (cohort 1) is reported here. Cohort 1 included patients with HLA-A*02, aged 16-75 years, with metastatic or unresectable synovial sarcoma or myxoid round cell liposarcoma (confirmed by cytogenetics) expressing MAGE-A4, and who had received at least one previous line of anthracycline-containing or ifosfamide-containing chemotherapy. Patients received a single intravenous dose of afami-cel (transduced dose range 1·0 × 10[9]-10·0 × 10[9] T cells) after lymphodepletion. The primary endpoint was overall response rate in cohort 1, assessed by a masked independent review committee using Response Evaluation Criteria in Solid Tumours (version 1.1) in the modified intention-to-treat population (all patients who received afami-cel). Adverse events, including those of special interest (cytokine release syndrome, prolonged cytopenia, and neurotoxicity), were monitored and are reported for the modified intention-to-treat population. This trial is registered at, NCT04044768; recruitment is closed and follow-up is ongoing for cohorts 1 and 2, and recruitment is open for cohort 3.

FINDINGS: Between Dec 17, 2019, and July 27, 2021, 52 patients with cytogenetically confirmed synovial sarcoma (n=44) and myxoid round cell liposarcoma (n=8) were enrolled and received afami-cel in cohort 1. Patients were heavily pre-treated (median three [IQR two to four] previous lines of systemic therapy). Median follow-up time was 32·6 months (IQR 29·4-36·1). Overall response rate was 37% (19 of 52; 95% CI 24-51) overall, 39% (17 of 44; 24-55) for patients with synovial sarcoma, and 25% (two of eight; 3-65) for patients with myxoid round cell liposarcoma. Cytokine release syndrome occurred in 37 (71%) of 52 of patients (one grade 3 event). Cytopenias were the most common grade 3 or worse adverse events (lymphopenia in 50 [96%], neutropenia 44 [85%], leukopenia 42 [81%] of 52 patients). No treatment-related deaths occurred.

INTERPRETATION: Afami-cel treatment resulted in durable responses in heavily pre-treated patients with HLA-A*02 and MAGE-A4-expressing synovial sarcoma. This study shows that T-cell receptor therapy can be used to effectively target solid tumours and provides rationale to expand this approach to other solid malignancies.

FUNDING: Adaptimmune.

RevDate: 2024-03-29

van den Puttelaar R, Nascimento de Lima P, Knudsen AB, et al (2024)

Effectiveness and Cost-Effectiveness of Colorectal Cancer Screening With a Blood Test That Meets the Centers for Medicare & Medicaid Services Coverage Decision.

Gastroenterology pii:S0016-5085(24)00174-4 [Epub ahead of print].

BACKGROUND & AIMS: A blood-based colorectal cancer (CRC) screening test may increase screening participation. However, blood tests may be less effective than current guideline-endorsed options. The Centers for Medicare & Medicaid Services (CMS) covers blood tests with sensitivity of at least 74% for detection of CRC and specificity of at least 90%. In this study, we investigate whether a blood test that meets these criteria is cost-effective.

METHODS: Three microsimulation models for CRC (MISCAN-Colon, CRC-SPIN, and SimCRC) were used to estimate the effectiveness and cost-effectiveness of triennial blood-based screening (from ages 45 to 75 years) compared to no screening, annual fecal immunochemical testing (FIT), triennial stool DNA testing combined with an FIT assay, and colonoscopy screening every 10 years. The CMS coverage criteria were used as performance characteristics of the hypothetical blood test. We varied screening ages, test performance characteristics, and screening uptake in a sensitivity analysis.

RESULTS: Without screening, the models predicted 77-88 CRC cases and 32-36 CRC deaths per 1000 individuals, costing $5.3-$5.8 million. Compared to no screening, blood-based screening was cost-effective, with an additional cost of $25,600-$43,700 per quality-adjusted life-year gained (QALYG). However, compared to FIT, triennial stool DNA testing combined with FIT, and colonoscopy, blood-based screening was not cost-effective, with both a decrease in QALYG and an increase in costs. FIT remained more effective (+5-24 QALYG) and less costly (-$3.2 to -$3.5 million) than blood-based screening even when uptake of blood-based screening was 20 percentage points higher than uptake of FIT.

CONCLUSION: Even with higher screening uptake, triennial blood-based screening, with the CMS-specified minimum performance sensitivity of 74% and specificity of 90%, was not projected to be cost-effective compared with established strategies for colorectal cancer screening.

RevDate: 2024-04-02
CmpDate: 2024-04-01

Swanton C, Bernard E, Abbosh C, et al (2024)

Embracing cancer complexity: Hallmarks of systemic disease.

Cell, 187(7):1589-1616.

The last 50 years have witnessed extraordinary developments in understanding mechanisms of carcinogenesis, synthesized as the hallmarks of cancer. Despite this logical framework, our understanding of the molecular basis of systemic manifestations and the underlying causes of cancer-related death remains incomplete. Looking forward, elucidating how tumors interact with distant organs and how multifaceted environmental and physiological parameters impinge on tumors and their hosts will be crucial for advances in preventing and more effectively treating human cancers. In this perspective, we discuss complexities of cancer as a systemic disease, including tumor initiation and promotion, tumor micro- and immune macro-environments, aging, metabolism and obesity, cancer cachexia, circadian rhythms, nervous system interactions, tumor-related thrombosis, and the microbiome. Model systems incorporating human genetic variation will be essential to decipher the mechanistic basis of these phenomena and unravel gene-environment interactions, providing a modern synthesis of molecular oncology that is primed to prevent cancers and improve patient quality of life and cancer outcomes.

RevDate: 2024-03-29

Kittai AS, Bond D, Huang Y, et al (2024)

Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy for Richter Transformation: An International, Multicenter, Retrospective Study.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology [Epub ahead of print].

PURPOSE: Outcomes for Richter transformation (RT) are poor with current therapies. The efficacy and safety of anti-CD19 chimeric antigen receptor T-cell therapy (CAR-T) for RT are not established.

METHODS: We performed an international multicenter retrospective study of patients with RT who received CAR-T. Patient, disease, and treatment characteristics were summarized using descriptive statistics, and modeling analyses were used to determine association with progression-free survival (PFS) and overall survival (OS). PFS and OS were estimated from the date of CAR-T infusion.

RESULTS: Sixty-nine patients were identified. The median age at CAR-T infusion was 64 years (range, 27-80). Patients had a median of four (range, 1-15) previous lines of therapy for CLL and/or RT, including previous Bruton tyrosine kinase inhibitor and/or BCL2 inhibitor therapy in 58 (84%) patients. The CAR-T product administered was axicabtagene ciloleucel in 44 patients (64%), tisagenlecleucel in 17 patients (25%), lisocabtagene maraleucel in seven patients (10%), and brexucabtagene autoleucel in one patient (1%). Eleven patients (16%) and 25 patients (37%) experienced grade ≥3 cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, respectively. The overall response rate was 63%, with 46% attaining a complete response (CR). After a median follow-up of 24 months, the median PFS was 4.7 months (95% CI, 2.0 to 6.9); the 2-year PFS was 29% (95% CI, 18 to 41). The median OS was 8.5 months (95% CI, 5.1 to 25.4); the 2-year OS was 38% (95% CI, 26 to 50). The median duration of response was 27.6 months (95% CI, 14.5 to not reached) for patients achieving CR.

CONCLUSION: CAR-T demonstrates clinical efficacy for patients with RT.

RevDate: 2024-03-30

MacKay EJ, Talham CJ, Zhang B, et al (2024)

Testing clinical selection criteria for intraoperative transoesophageal echocardiography in isolated coronary artery bypass graft surgery.

BJA open, 10:100278.

BACKGROUND: There is a lack of evidence associating intraoperative transoesophageal echocardiography (TOE) use with improved outcomes among coronary artery bypass graft (CABG) surgery subpopulations.

METHODS: This matched retrospective cohort study used a US private claims dataset to compare outcomes among different CABG surgery patient populations with vs without TOE. Statistical analyses involved exact matching on pre-selected subgroups (congestive heart failure, single vessel, and multivessel CABG) and used fine and propensity-score balanced techniques to conduct multiple matched comparisons and sensitivity analyses.

RESULTS: Of 42 249 patients undergoing isolated CABG surgery, 24 919 (59.0%) received and 17 330 (41.0%) did not receive TOE. After matching, intraoperative TOE was significantly associated with a lower, 30-day mortality: 2.63% vs 3.20% (odds ratio [OR]: 0.81; 95% confidence interval [CI]: 0.71-0.92; P=0.002). In the subgroup matched comparisons, intraoperative TOE was significantly associated with a lower, 30-day mortality rate among those with congestive heart failure: 4.20% vs 5.26% (OR: 0.78; 95% CI: 0.66-0.94; P=0.007) and among those undergoing multivessel CABG with congestive heart failure: 4.23% vs 5.24% (OR: 0.80; 95% CI: 0.65-0.97; P=0.025), but not among those undergoing multivessel CABG without congestive heart failure: 1.83% vs 2.15% (OR: 0.85; 95% CI: 0.70-1.02; P=0.089, nor any of the remaining three subgroups.

CONCLUSIONS: Among US adults undergoing isolated CABG surgery, intraoperative TOE was associated with improved outcomes in patients with congestive heart failure (vs without) and among patients undergoing multivessel (vs single vessel) CABG. These findings support prioritised TOE allocation to these patient populations at centres with limited TOE capabilities.

RevDate: 2024-03-29

Dalapati T, Williams CA, Giorgi EE, et al (2024)

Immunogenicity of Monovalent mRNA-1273 and BNT162b2 Vaccines in Children Less Than 5 Years of Age.

Pediatrics pii:196958 [Epub ahead of print].

BACKGROUND AND OBJECTIVES: The mRNA-based COVID-19 vaccines approved for use in children less than 5 years of age have different antigen doses and administration schedules that could affect vaccine immunogenicity and effectiveness. We sought to compare the strength and breadth of serum binding and neutralizing antibodies to SARS-CoV-2 elicited by monovalent mRNA-based COVID-19 vaccines in young children.

METHODS: We conducted a prospective cohort study of children 6 months to 4 years of age who completed primary series vaccination with monovalent mRNA-1273 or BNT162b2 vaccines. Serum was collected one month after primary vaccine series completion for measurement of SARS-CoV-2-specific humoral immune responses, including antibody binding responses to Spike proteins from an ancestral strain (D614G) and major variants of SARS-CoV-2 and antibody neutralizing activity against D614G and Omicron subvariants (BA.1, BA.4/5).

RESULTS: Of 75 participants, 40 (53%) received mRNA-1273 and 35 (47%) received BNT162b2. Children receiving either primary vaccine series developed robust and broad SARS-CoV-2-specific binding and neutralizing antibodies, including to Omicron subvariants. Children with a prior history of SARS-CoV-2 infection developed significantly higher antibody binding responses and neutralization titers to Omicron subvariants, consistent with the occurrence of identified infections during the circulation of Omicron subvariants in the region.

CONCLUSIONS: Monovalent mRNA-1273 and BNT162b2 elicited similar antibody responses one month after vaccination in young children. Further, prior infection significantly enhanced the strength of antibody responses to Omicron subvariants. Future studies should evaluate incorporation of these vaccines into the standard childhood immunization schedule.

RevDate: 2024-03-28

Markey KA (2024)

Lipocalin-2: a novel potential therapy for GVHD.

Trends in immunology pii:S1471-4906(24)00049-8 [Epub ahead of print].

Czech et al. used mouse models of allogeneic hematopoietic stem cell transplantation (allo-HCT) to investigate the role of lipocalin-2 (LCN2) as a newfound regulator of intestinal graft-versus-host disease (GVHD). Administration of recombinant LCN2 protein after disease onset prevented GVHD progression, suggesting that it may play a role in reversing tissue damage that has already begun.

RevDate: 2024-04-01
CmpDate: 2024-04-01

Layman RM, Han HS, Rugo HS, et al (2024)

Gedatolisib in combination with palbociclib and endocrine therapy in women with hormone receptor-positive, HER2-negative advanced breast cancer: results from the dose expansion groups of an open-label, phase 1b study.

The Lancet. Oncology, 25(4):474-487.

BACKGROUND: The PI3K-mTOR pathway is frequently dysregulated in breast cancer. Combining an inhibitor targeting all class I PI3K isoforms and mTOR complex 1 (mTORC1)-mTOR complex 2 (mTORC2) with endocrine therapy and a CDK4/6 inhibitor might provide more effective tumour control than standard-of-care therapy. To evaluate this hypothesis, gedatolisib, a pan-PI3K-mTOR inhibitor, was assessed in a phase 1b trial combined with palbociclib and endocrine therapy in patients with hormone receptor-positive, HER2-negative, advanced breast cancer. Results from the dose expansion portion of this trial are reported herein.

METHODS: This multicentre, open-label, phase 1b study recruited female patients aged at least 18 years from 17 sites across the USA with hormone-receptor-positive, HER2-negative, advanced breast cancer and an Eastern Cooperative Oncology Group performance status of 0-1. Four patient groups were studied in the dose expansion portion of the study: treatment-naive in the advanced setting (first line; group A), progression on 1-2 lines of endocrine therapy but CDK4/6 inhibitor-naive (group B); and one or more previous lines (second-line and higher) of therapy, including a CDK4/6 inhibitor (groups C and D). Gedatolisib 180 mg was administered intravenously weekly in 28-day treatment cycles for groups A-C, and on days 1, 8, and 15 for group D. Letrozole (group A), fulvestrant (groups B-D), and palbociclib (all groups) were administered at standard doses and schedules. The primary endpoint was investigator-assessed objective response rate per RECIST version 1.1 in the evaluable analysis set. This trial is completed and registered with, NCT02684032.

FINDINGS: Between Dec 19, 2017, and June 19, 2019, 103 female participants were enrolled in the dose expansion groups A (n=31), B (n=13), C (n=32), and D (n=27). Median follow-up was 16·6 months (IQR 5·7-48·4) for group A, 11·0 months (7·6-16·9) for group B, 3·6 months (1·8-7·5) for group C, and 9·4 months (5·3-16·7) for group D for the primary endpoint. Gedatolisib, palbociclib, and endocrine therapy induced an objective response in 23 (85·2%; 90% CI 69·2-94·8) of 27 evaluable first-line participants (group A). In the second-line and higher setting, an objective response was observed in eight (61·5%; 90% CI 35·5-83·4) of 13 evaluable group B participants, seven (25·0%; 12·4-41·9) of 28 evaluable group C participants, and 15 (55·6%; 38·2-72·0) of 27 evaluable group D participants; this included participants with both wild-type and mutated PIK3CA tumours. The most common grade 3-4 treatment-related adverse events were neutropenia (65 [63%] of 103), stomatitis (28 [27%]), and rash (21 [20%]). Grade 3-4 hyperglycaemia was reported in six (6%) participants. 23 (22%) of 103 participants had a treatment-related serious adverse event, and there were no treatment-related deaths. Nine (9%) participants discontinued treatment because of a treatment-emergent adverse event.

INTERPRETATION: Gedatolisib plus palbociclib and endocrine therapy showed a promising objective response rate compared with the published results for standard-of-care therapies and had an acceptable safety profile.

FUNDING: Pfizer and Celcuity.

RevDate: 2024-03-28

Budde LE, Assouline S, Sehn LH, et al (2024)

Durable Responses With Mosunetuzumab in Relapsed/Refractory Indolent and Aggressive B-Cell Non-Hodgkin Lymphomas: Extended Follow-Up of a Phase I/II Study.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology [Epub ahead of print].

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Mosunetuzumab is a CD20xCD3 T-cell-engaging bispecific antibody administered as an off-the-shelf, fixed-duration treatment in an outpatient setting. We report an updated analysis of the durability of response, by investigator assessment, after an overall median follow-up of 3.5 years in patients with relapsed/refractory indolent or aggressive B-cell non-Hodgkin lymphoma (iNHL/aNHL) from the dose-escalation stage of a phase I/II study of mosunetuzumab ( identifier: NCT02500407). Across dose levels, 65.7% of patients with iNHL and 36.4% with aNHL achieved a complete or partial response to mosunetuzumab. Median duration of response (DoR) in patients with iNHL for all responders was 23.2 months (95% CI, 13.8 to not estimable [NE]), but was not reached in complete responders (95% CI, 21.0 to NE). After a median time on study of 38.9 months, no relapses were observed beyond 26 months in complete responders. In patients with aNHL, median DoR for all responders was 7.8 months (95% CI, 4.6 to 22.8). Among 12 complete responders who progressed postmosunetuzumab treatment and were retreated with mosunetuzumab, 83.3% had an objective response and 58.3% achieved a second complete response. Our study reports the longest follow-up using bispecific antibodies in patients with B-cell non-Hodgkin lymphoma and demonstrates that mosunetuzumab can mediate durable remissions with time-limited treatment.

RevDate: 2024-03-28

Wang Z, Peters BA, Yu B, et al (2024)

Gut Microbiota and Blood Metabolites Related to Fiber Intake and Type 2 Diabetes.

Circulation research, 134(7):842-854.

BACKGROUND: Consistent evidence suggests diabetes-protective effects of dietary fiber intake. However, the underlying mechanisms, particularly the role of gut microbiota and host circulating metabolites, are not fully understood. We aimed to investigate gut microbiota and circulating metabolites associated with dietary fiber intake and their relationships with type 2 diabetes (T2D).

METHODS: This study included up to 11 394 participants from the HCHS/SOL (Hispanic Community Health Study/Study of Latinos). Diet was assessed with two 24-hour dietary recalls at baseline. We examined associations of dietary fiber intake with gut microbiome measured by shotgun metagenomics (350 species/85 genera and 1958 enzymes; n=2992 at visit 2), serum metabolome measured by untargeted metabolomics (624 metabolites; n=6198 at baseline), and associations between fiber-related gut bacteria and metabolites (n=804 at visit 2). We examined prospective associations of serum microbial-associated metabolites (n=3579 at baseline) with incident T2D over 6 years.

RESULTS: We identified multiple bacterial genera, species, and related enzymes associated with fiber intake. Several bacteria (eg, Butyrivibrio, Faecalibacterium) and enzymes involved in fiber degradation (eg, xylanase EC3.2.1.156) were positively associated with fiber intake, inversely associated with prevalent T2D, and favorably associated with T2D-related metabolic traits. We identified 159 metabolites associated with fiber intake, 47 of which were associated with incident T2D. We identified 18 of these 47 metabolites associated with the identified fiber-related bacteria, including several microbial metabolites (eg, indolepropionate and 3-phenylpropionate) inversely associated with the risk of T2D. Both Butyrivibrio and Faecalibacterium were associated with these favorable metabolites. The associations of fiber-related bacteria, especially Faecalibacterium and Butyrivibrio, with T2D were attenuated after further adjustment for these microbial metabolites.

CONCLUSIONS: Among United States Hispanics/Latinos, dietary fiber intake was associated with favorable profiles of gut microbiota and circulating metabolites for T2D. These findings advance our understanding of the role of gut microbiota and microbial metabolites in the relationship between diet and T2D.

RevDate: 2024-03-30
CmpDate: 2024-03-29

Hershman DL, Vaidya R, Till C, et al (2024)

Socioeconomic Deprivation and Health Care Use in Patients Enrolled in SWOG Cancer Clinical Trials.

JAMA network open, 7(3):e244008.

IMPORTANCE: Reducing acute care use is an important strategy for improving value. Patients with cancer are at risk for unplanned emergency department (ED) visits and hospital stays (HS). Clinical trial patients have homogeneous treatment; despite this, structural barriers to care may independently impact acute care use.

OBJECTIVE: To examine whether ED visits and HS within 12 months of trial enrollment are more common among Medicare enrollees who live in areas of socioeconomic deprivation or have Medicaid insurance.

This cohort study included patients with cancer who were 65 years or older and treated in SWOG Cancer Research Network trials from 1999 to 2018 using data linked to Medicare claims. Data were collected from 1999 to 2019 and analyzed from 2022 to 2024.

MAIN OUTCOMES AND MEASURES: Outcomes were ED visits, HS, and costs in the first year following enrollment. Neighborhood socioeconomic deprivation was measured using patients' zip code linked to the Area Deprivation Index (ADI), measured on a 0 to 100 scale for increasing deprivation and categorized into tertiles (T1 to T3). Type of insurance was classified as Medicare with or without commercial insurance vs dual Medicare and Medicaid. Demographic, clinical, and prognostic factors were captured from trial records. Multivariable regression was used, and the association of ADI and insurance with each outcome was considered separately.

RESULTS: In total, 3027 trial participants were analyzed. The median (range) age was 71 (65-98) years, 1280 (32.3%) were female, 221 (7.3%) were Black patients, 2717 (89.8%) were White patients, 90 (3.0%) had Medicare and Medicaid insurance, and 660 (22.3%) were in the areas of highest deprivation (ADI-T3). In all, 1094 patients (36.1%) had an ED visit and 983 patients (32.4%) had an HS. In multivariable generalized estimating equation, patients living in areas categorized as ADI-T3 were more likely to have an ED visit (OR, 1.34; 95% CI, 1.10-1.62; P = .004). A similar but nonsignificant pattern was observed for HS (OR, 1.36; 95% CI, 0.96-1.93; P = .08). Patients from areas with the highest deprivation had a 62% increase in risk of either an ED visit or HS (OR, 1.62; 95% CI, 1.25-2.09; P < .001). Patients with Medicare and Medicaid were 96% more likely to have an ED visit (OR, 1.96; 95% CI, 1.56-2.46; P < .001).

CONCLUSIONS AND RELEVANCE: In this cohort of older patients enrolled in clinical trials, neighborhood deprivation and economic disadvantage were associated with an increase in ED visits and HS. Efforts are needed to ensure adequate resources to prevent unplanned use of acute care in socioeconomically vulnerable populations.

RevDate: 2024-03-29
CmpDate: 2024-03-29

Buchheit SF, Collins JM, Anthony KM, et al (2024)

Radon Exposure and Incident Stroke Risk in the Women's Health Initiative.

Neurology, 102(4):e209143.

BACKGROUND AND OBJECTIVES: Little is known about the role of radon in the epidemiology of stroke among women. We therefore examined the association between home radon exposure and risk of stroke among middle-aged and older women in the United States.

METHODS: We conducted a prospective cohort study of postmenopausal women aged 50-79 years at baseline (1993-1998) in the Women's Health Initiative. We measured exposures as 2-day, indoor, lowest living-level average radon concentrations in picocuries per liter (pCi/L) as estimated in 1993 by the US Geological Survey and reviewed by the Association of American State Geologists under the Indoor Radon Abatement Act. We used Cox proportional hazards models to estimate risk of incident, neurologist-adjudicated stroke during follow-up through 2020 as a hazard ratio and 95% CI, adjusting for study design and participant demographic, social, behavioral, and clinical characteristics.

RESULTS: Among 158,910 women without stroke at baseline (mean age 63.2 years; 83% white), 6,979 incident strokes were identified over follow-up (mean 13.4 years). Incidence rates were 333, 343, and 349 strokes per 100,000 woman-years at radon concentrations of <2, 2-4, and >4 pCi/L, respectively. Compared with women living at concentrations <2 pCi/L, those at 2-4 and >4 pCi/L had higher covariate-adjusted risks of incident stroke: hazard ratio (95% CI) 1.06 (0.99-1.13) and 1.14 (1.05-1.22). Using nonlinear spline functions to model radon, stroke risk was significantly elevated at concentrations ranging from 2 to 4 pCi/L (p = 0.0004), that is, below the United States Environmental Protection Agency Radon Action Level for mitigation (4 pCi/L). Associations were slightly stronger for ischemic (especially cardioembolic, small vessel occlusive, and large artery atherosclerotic) than hemorrhagic stroke, but otherwise robust in sensitivity analyses.

DISCUSSION: Radon exposure is associated with moderately increased stroke risk among middle-aged and older women in the United States, suggesting that promulgation of a lower Radon Action Level may help reduce the domestic impact of cerebrovascular disease on public health.

RevDate: 2024-03-29

Liu M, Liu Y, Hsu L, et al (2024)

TCRpred: incorporating T-cell receptor repertoire for clinical outcome prediction.

Frontiers in genetics, 15:1345559.

T-cell receptor (TCR) plays critical roles in recognizing antigen peptides and mediating adaptive immune response against disease. High-throughput technologies have enabled the sequencing of TCR repertoire at the single nucleotide level, allowing researchers to characterize TCR sequences with high resolutions. The TCR sequences provide important information about patients' adaptive immune system, and have the potential to improve clinical outcome prediction. However, it is challenging to incorporate the TCR repertoire data for prediction, because the data is unstructured, highly complex, and TCR sequences vary widely in their compositions and abundances across different individuals. We introduce TCRpred, an analytic tool for incorporating TCR repertoire for clinical outcome prediction. The TCRpred is able to utilize features that can be extracted from the TCR amino acid sequences, as well as features that are hidden in the TCR amino acid sequences and are hard to extract. Simulation studies show that the proposed approach has a good performance in predicting clinical outcome and tends to be more powerful than potential alternative approaches. We apply the TCRpred to real cancer datasets and demonstrate its practical utility in clinical outcome prediction.

RevDate: 2024-03-29

Hensley C, Roier S, Zhou P, et al (2024)

mRNA-Based Vaccines Are Highly Immunogenic and Confer Protection in the Gnotobiotic Pig Model of Human Rotavirus Diarrhea.

Vaccines, 12(3):.

Human rotavirus (HRV) is still a leading cause of severe dehydrating gastroenteritis globally, particularly in infants and children. Previously, we demonstrated the immunogenicity of mRNA-based HRV vaccine candidates expressing the viral spike protein VP8* in rodent models. In the present study, we assessed the immunogenicity and protective efficacy of two mRNA-based HRV trivalent vaccine candidates, encoding VP8* of the genotypes P[8], P[6], or P[4], in the gnotobiotic (Gn) pig model of Wa (G1P[8]) HRV infection and diarrhea. Vaccines either encoded VP8* alone fused to the universal T-cell epitope P2 (P2-VP8*) or expressed P2-VP8* as a fusion protein with lumazine synthase (LS-P2-VP8*) to allow the formation and secretion of protein particles that present VP8* on their surface. Gn pigs were randomly assigned into groups and immunized three times with either P2-VP8* (30 µg) or LS-P2-VP8* (30 µg or 12 µg). A trivalent alum-adjuvanted P2-VP8* protein vaccine or an LNP-formulated irrelevant mRNA vaccine served as the positive and negative control, respectively. Upon challenge with virulent Wa HRV, a significantly shortened duration and decreased severity of diarrhea and significant protection from virus shedding was induced by both mRNA vaccine candidates compared to the negative control. Both LS-P2-VP8* doses induced significantly higher VP8*-specific IgG antibody titers in the serum after immunizations than the negative as well as the protein control. The P[8] VP8*-specific IgG antibody-secreting cells in the ileum, spleen, and blood seven days post-challenge, as well as VP8*-specific IFN-γ-producing T-cell numbers increased in all three mRNA-vaccinated pig groups compared to the negative control. Overall, there was a clear tendency towards improved responses in LS-P2-VP8* compared to the P2-VP8*mRNA vaccine. The demonstrated strong humoral immune responses, priming for effector T cells, and the significant reduction of viral shedding and duration of diarrhea in Gn pigs provide a promising proof of concept and may provide guidance for the further development of mRNA-based rotavirus vaccines.

RevDate: 2024-03-29

Kuter DJ, Mayer J, Efraim M, et al (2024)

Long-term treatment with rilzabrutinib in patients with immune thrombocytopenia.

Blood advances, 8(7):1715-1724.

Immune thrombocytopenia (ITP) is an autoimmune disease associated with autoantibody-mediated platelet destruction and impaired platelet production, resulting in thrombocytopenia and a predisposition to bleeding. The ongoing, global phase 1/2 study showed that rilzabrutinib, a Bruton tyrosine kinase inhibitor specifically developed to treat autoimmune disorders, could be an efficacious and well-tolerated treatment for ITP. Clinical activity, durability of response, and safety were evaluated in 16 responding patients who continued rilzabrutinib 400 mg twice daily in the long-term extension (LTE) study. At LTE entry, the median platelet count was 87 × 109/L in all patients, 68 × 109/L in those who had rilzabrutinib monotherapy (n = 5), and 156 × 109/L in patients who received concomitant ITP medication (thrombopoietin-receptor agonists and/or corticosteroids, n = 11). At a median duration of treatment of 478 days (range, 303-764), 11 of 16 patients (69%) continued to receive rilzabrutinib. A platelet count of ≥50 × 109/L was reported in 93% of patients for more than half of their monthly visits. The median percentage of LTE weeks with platelet counts ≥30 × 109/L and ≥50 × 109/L was 100% and 88%, respectively. Five patients discontinued concomitant ITP therapy and maintained median platelet counts of 106 × 109/L at 3 to 6 months after stopping concomitant ITP therapy. Adverse events related to treatment were grade 1 or 2 and transient, with no bleeding, thrombotic, or serious adverse events. With continued rilzabrutinib treatment in the LTE, platelet responses were durable and stable over time with no new safety signals. This trial is registered at as #NCT03395210 and as EudraCT 2017-004012-19.

RevDate: 2024-03-28

Schenk JM, Boynton A, Kulik P, et al (2024)

The Use of Three-Dimensional Images and Food Descriptions from a Smartphone Device Is Feasible and Accurate for Dietary Assessment.

Nutrients, 16(6): pii:nu16060828.

Technology-assisted dietary assessment has the potential to improve the accuracy of self-reported dietary intake. This study evaluates MealScan3D (MS3D), a mobile device-based food recording system, which uses three-dimensional images to obtain food volumes and an application to capture algorithm-driven food intake data. Participants (n = 179) were randomly assigned and trained to record three meals using either MS3D or a written food record (WFR). Generous amounts of standardized meals were provided, and participants self-selected portions for each food. The weights of provided and uneaten/leftover foods were used to determine true intake. For total energy intake (three meals combined), validity (Pearson correlation) was significantly higher for MS3D vs. the WFR (p < 0.001); when interpreted as the percentage of variance in energy intake explained, MS3D explained 84.6% of true variance, a 25.3% absolute and 42.6% relative increase over the 59.3% explained by the WFR. For 9 of 15 individual foods, the Pearson correlations between true and reported portion size estimates were significantly larger for MS3D than the WFR. Bias was smaller (intercepts were closer to the means) for 9 of 15 foods and the regression coefficients for 10 of 15 foods were significantly closer to 1.0 in the MS3D arm. MS3D is feasible for dietary assessment and may provide improvements in accuracy compared to WFRs.

RevDate: 2024-03-28

Radko-Juettner S, Yue H, Myers JA, et al (2024)

Targeting DCAF5 suppresses SMARCB1-mutant cancer by stabilizing SWI/SNF.

Nature [Epub ahead of print].

Whereas oncogenes can potentially be inhibited with small molecules, the loss of tumour suppressors is more common and is problematic because the tumour-suppressor proteins are no longer present to be targeted. Notable examples include SMARCB1-mutant cancers, which are highly lethal malignancies driven by the inactivation of a subunit of SWI/SNF (also known as BAF) chromatin-remodelling complexes. Here, to generate mechanistic insights into the consequences of SMARCB1 mutation and to identify vulnerabilities, we contributed 14 SMARCB1-mutant cell lines to a near genome-wide CRISPR screen as part of the Cancer Dependency Map Project[1-3]. We report that the little-studied gene DDB1-CUL4-associated factor 5 (DCAF5) is required for the survival of SMARCB1-mutant cancers. We show that DCAF5 has a quality-control function for SWI/SNF complexes and promotes the degradation of incompletely assembled SWI/SNF complexes in the absence of SMARCB1. After depletion of DCAF5, SMARCB1-deficient SWI/SNF complexes reaccumulate, bind to target loci and restore SWI/SNF-mediated gene expression to levels that are sufficient to reverse the cancer state, including in vivo. Consequently, cancer results not from the loss of SMARCB1 function per se, but rather from DCAF5-mediated degradation of SWI/SNF complexes. These data indicate that therapeutic targeting of ubiquitin-mediated quality-control factors may effectively reverse the malignant state of some cancers driven by disruption of tumour suppressor complexes.

RevDate: 2024-03-27

Menacho L, Konda KA, Lecca L, et al (2024)

Optimising PrEP uptake and use in Peru: no time to lose!.

The lancet. HIV, 11(4):e204-e206.


ESP Quick Facts

ESP Origins

In the early 1990's, Robert Robbins was a faculty member at Johns Hopkins, where he directed the informatics core of GDB — the human gene-mapping database of the international human genome project. To share papers with colleagues around the world, he set up a small paper-sharing section on his personal web page. This small project evolved into The Electronic Scholarly Publishing Project.

ESP Support

In 1995, Robbins became the VP/IT of the Fred Hutchinson Cancer Research Center in Seattle, WA. Soon after arriving in Seattle, Robbins secured funding, through the ELSI component of the US Human Genome Project, to create the original ESP.ORG web site, with the formal goal of providing free, world-wide access to the literature of classical genetics.

ESP Rationale

Although the methods of molecular biology can seem almost magical to the uninitiated, the original techniques of classical genetics are readily appreciated by one and all: cross individuals that differ in some inherited trait, collect all of the progeny, score their attributes, and propose mechanisms to explain the patterns of inheritance observed.

ESP Goal

In reading the early works of classical genetics, one is drawn, almost inexorably, into ever more complex models, until molecular explanations begin to seem both necessary and natural. At that point, the tools for understanding genome research are at hand. Assisting readers reach this point was the original goal of The Electronic Scholarly Publishing Project.

ESP Usage

Usage of the site grew rapidly and has remained high. Faculty began to use the site for their assigned readings. Other on-line publishers, ranging from The New York Times to Nature referenced ESP materials in their own publications. Nobel laureates (e.g., Joshua Lederberg) regularly used the site and even wrote to suggest changes and improvements.

ESP Content

When the site began, no journals were making their early content available in digital format. As a result, ESP was obliged to digitize classic literature before it could be made available. For many important papers — such as Mendel's original paper or the first genetic map — ESP had to produce entirely new typeset versions of the works, if they were to be available in a high-quality format.

ESP Help

Early support from the DOE component of the Human Genome Project was critically important for getting the ESP project on a firm foundation. Since that funding ended (nearly 20 years ago), the project has been operated as a purely volunteer effort. Anyone wishing to assist in these efforts should send an email to Robbins.

ESP Plans

With the development of methods for adding typeset side notes to PDF files, the ESP project now plans to add annotated versions of some classical papers to its holdings. We also plan to add new reference and pedagogical material. We have already started providing regularly updated, comprehensive bibliographies to the ESP.ORG site.


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Cancer is the generic name for more than 100 diseases in which cells begin to grow and divide in an uncontrolled manner. Usually, when cells get too old or damaged, they die and new cells take their place. Cancer begins when genetic changes impair this orderly process so that some cells start to grow uncontrollably. The Emperor of All Maladies is a "biography" of cancer — from its first documented appearances thousands of years ago through the epic battles in the twentieth century to cure, control, and conquer it to a radical new understanding of its essence. This is a must read book for anyone with an interest in cancer. R. Robbins

Electronic Scholarly Publishing
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Papers in Classical Genetics

The ESP began as an effort to share a handful of key papers from the early days of classical genetics. Now the collection has grown to include hundreds of papers, in full-text format.

Digital Books

Along with papers on classical genetics, ESP offers a collection of full-text digital books, including many works by Darwin and even a collection of poetry — Chicago Poems by Carl Sandburg.


ESP now offers a large collection of user-selected side-by-side timelines (e.g., all science vs. all other categories, or arts and culture vs. world history), designed to provide a comparative context for appreciating world events.


Biographical information about many key scientists (e.g., Walter Sutton).

Selected Bibliographies

Bibliographies on several topics of potential interest to the ESP community are automatically maintained and generated on the ESP site.

ESP Picks from Around the Web (updated 07 JUL 2018 )