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Bibliography on: Publications by FHCRC Researchers

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ESP: PubMed Auto Bibliography 25 Jul 2025 at 01:48 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®)

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RevDate: 2025-07-24

Conley H, Oh SY, Garrett N, et al (2025)

IgG and Fc receptor genetic variation associates with functional antibody responses in a DNA and protein candidate HIV vaccine trial.

Journal of acquired immune deficiency syndromes (1999) pii:00126334-990000000-00678 [Epub ahead of print].

BACKGROUND: The HVTN108 trial evaluated the safety and immunogenicity of a DNA prime, adjuvanted protein boost HIV vaccine in the US and South Africa. The underlying factors influencing individual variation in vaccine responsiveness are unknown. Here, we defined the IgG Fc and Fc receptor (FcR) genotypes in the HVTN108 cohort to test our hypothesis that IgG and FcR genetic variation can affect vaccine-elicited functional antibody responses.

METHODS: IgG Fc and FcR alleles were determined by targeted PCR amplification and next-generation sequencing. Vaccine-elicited functional antibody responses, including binding antibody multiplex assay (BAMA), antibody-dependent cellular cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP) activity were measured utilizing standardized and qualified methods. Relationships between alleles and antibody responses were identified by linear regression controlling for treatment group and region.

RESULTS: The distribution of many polymorphisms significantly differed between the US and South Africa. Within the subset of the cohort tested for functional antibody responses (IgG, n=41; FcR, n=55), IgG genotypes such as IGHG1*12 (p=0.012), IGHG3*11 (p=0.033), IGHG2*02 (p=0.038), IGHG4*07 (p=0.076), and others were associated with ADCC antibody responses when corrected for vaccine group and regional effects. In the same way, we identified that the FCER1A rs2427827 mutation had a significant association with lower peak ADCC activity and the FCER2 rs2228137 mutation was associated with lower antibody binding to Con6 gp120 protein.

CONCLUSION: Genetic variation in both antibodies and FcRs associated with levels of HIV- vaccine-elicited functional antibodies. Significant regional differences in distribution of this variation support the need for vaccine testing in diverse populations.

RevDate: 2025-07-24

Campian JL, Grossman SA, Kask AS, et al (2025)

Phase I study of NT-I7, a long-acting interleukin-7, in severe treatment-related lymphopenia following standard radiation and temozolomide for high-grade glioma.

Neuro-oncology advances, 7(1):vdaf117.

BACKGROUND: High-grade gliomas (HGG) have a poor prognosis despite aggressive treatment. Severe, persistent lymphopenia occurring in HGG patients after concurrent chemoradiation is associated with worse survival. NT-I7, a long-acting interleukin-7 analog, has been shown to increase CD4 and CD8 counts in healthy, septic, and HIV-positive adults. This multi-institutional, NCI-funded dose-escalation trial is the first to evaluate NT-I7 safety and activity in HGG patients with severe treatment-related lymphopenia (TRL) and the effect of co-administered glucocorticoids.

METHODS: Eligible HGG patients had CD4 counts <300 cells/mm[3] after 5 weeks of standard chemoradiation and were receiving either ≤0.75 or ≥4 mg/day of dexamethasone. Patients received a single intramuscular dose of NT-I7 (60 or 360 µg/kg) post-chemoradiation, followed by safety evaluation and multi-parameter, longitudinal monitoring of lymphocyte populations and immunologic function.

RESULTS: NT-I7 was well tolerated in all 12 patients (median age 64; median CD4 count 161 cells/mm³) before the study closed prematurely. Absolute lymphocyte counts doubled in 83% (10/12; 95% CI: 51.6%-97.9%) of patients, and CD4 counts doubled in 42% (5/12; 95% CI: 15.2%-72.3%) of patients. Glucocorticoid use did not significantly affect CD4 or lymphocyte increases. Correlative immune profiling revealed increased Ki67 expression in CD4 (P < .005) and CD8 (P < .05) after one week, along with the expansion of CD4 and CD8 T-cell subsets and CD56 + natural killer cells.

CONCLUSIONS: NT-I7 is well tolerated and effectively increases lymphocyte and CD4 counts in severe TRL patients, regardless of glucocorticoid use, suggesting its potential to mitigate TRL and improve outcomes in HGG.

RevDate: 2025-07-23

Dai Y, Aizenbud L, Qin K, et al (2025)

Humoral determinants of checkpoint immunotherapy.

Nature [Epub ahead of print].

Although the role of cellular immunity in checkpoint immunotherapy (CPI) for cancer is well established[1,2], the effect of antibody-mediated humoral immunity is comparably underexplored. Here we used rapid extracellular antigen profiling[3] to map the autoantibody reactome within a cohort of 374 patients with cancer treated with CPIs and 131 healthy control participants for autoantibodies to 6,172 extracellular and secreted proteins (the 'exoproteome'). Globally, patients with cancer treated with CPIs had diverse autoreactivities that were elevated relative to control individuals but changed minimally with treatment. Autoantibody signatures in patients treated with CPI strikingly distinguished them from healthy individuals. Although associations of specific autoantibodies with immune-related adverse events were sparse, we detected numerous individual autoantibodies that were associated with greatly altered odds ratios for response to therapy. These included autoantibodies to immunomodulatory proteins, such as cytokines, growth factors and immunoreceptors, as well as tumour surface proteins. Functional evaluation of several autoantibody responses indicated that they neutralized the activity of their target proteins, which included type I interferons (IFN-I), IL-6, OSM, TL1A, and BMPR1A and BMPR2. Modelling the effects of autoantibodies to IFN-I and TL1A in preclinical mouse tumour models resulted in enhanced CPI efficacy, consistent with their effects in patients. In conclusion, these findings indicate that autoantibodies to the exoproteome modify CPI responses and highlight therapeutically actionable pathways that can be exploited to augment immunotherapy.

RevDate: 2025-07-23
CmpDate: 2025-07-24

Nemutlu GS, Mercaldo ND, Thayumanavan E, et al (2025)

Forecasting global progress in breast cancer control in the context of the sustainable development goals.

BMJ global health, 10(7): pii:bmjgh-2025-019497.

INTRODUCTION: The United Nations Sustainable Development Goal (UN-SDG) 3.4 aims to reduce premature mortality from non-communicable diseases, including breast cancer, by one-third by 2030 relative to 2015. However, many countries, particularly those with lower income, appear off track. Although mortality rates are commonly used to gauge progress, mortality-to-incidence ratios (MIRs) may provide additional insight by accounting for varying incidence and the effectiveness of cancer control measures.

METHODS: We obtained age-standardised breast cancer incidence and mortality rates for women aged 30-69 years from 2000 to 2019, covering 199 countries stratified by World Bank income groups (low, lower middle, upper middle and high) from the Institute for Health Metrics and Evaluation Global Burden of Disease (GBD) 2019 study. Using vector autoregressive time-series analyses, we modelled and forecasted income-level and county-level mortality rates and MIRs for female breast cancer from 2020 to 2030.

RESULTS: From 2015 to 2030, breast cancer mortality is projected to increase by 22.8% and 7.8% in low-income and lower middle-income countries, while decreasing by 10% and 5.4% in upper middle-income and high-income countries. MIR is projected to decrease across all income groups, with the most significant reductions seen in lower income countries, highlighting incremental improvements in breast cancer control initiatives. Only nine countries, predominantly higher income, are expected to achieve the one-third mortality reduction target. Despite MIR improvements in lower income countries, substantial mortality reductions remain elusive.

CONCLUSION: Relying solely on mortality underestimates progress in breast cancer control. Although most countries are unlikely to meet the SDG 3.4 target, concurrent use of mortality and MIR provides a more nuanced understanding of screening, diagnosis and treatment advances. Integrating MIR trends into global health evaluations may better inform breast cancer prevention strategies.

RevDate: 2025-07-23

Alberts NM, Stratton KL, Leisenring WM, et al (2025)

Intolerance of uncertainty, psychological symptoms, and pain in long-term childhood cancer survivors: a report from the Childhood Cancer Survivor Study.

Journal of cancer survivorship : research and practice [Epub ahead of print].

PURPOSE: Intolerance of uncertainty is central to many psychological disorders and may contribute to pain. Despite the uncertainty inherent in childhood cancer survivorship, little is known about intolerance of uncertainty in this population. This study aimed to characterize intolerance of uncertainty, its risk factors, and its associations with psychological symptoms and pain in childhood cancer survivors.

METHODS: Survivors from the Childhood Cancer Survivor Study completed psychosocial measures via online survey, including the Intolerance of Uncertainty Scale-12 (score range = 12-60). Cancer and treatment variables were abstracted from medical records. Multivariable regression models with 95% confidence intervals (CI) adjusted for age and sex examined the effects of demographic, disease, treatment, pain, and psychological variables on intolerance of uncertainty.

RESULTS: Participants included 228 adult survivors of childhood cancer (mean age = 39.6 years, 50.4% female, n = 93 chronic pain). Mean level of intolerance of uncertainty among survivors was 26.2 (SD = 10.0, 95% CI 24.9 to 27.5). Intolerance of uncertainty was associated with female sex (β [95% CI]; 2.7 [0.2-5.3]), unemployment (5.2 [1.9-8.5]), neurologic (4.1 [0.5-7.7]) and cardiovascular (5.0 [2.2-7.8]) chronic health conditions, elevated anxiety (10.9 [8.1-13.7]), and perceived poor health status (4.5 [1.4-7.6]). Higher levels of intolerance of uncertainty were observed in survivors with chronic pain (LS mean = 29.2) compared to survivors without (LS mean = 23.5; p < 0.01).

CONCLUSIONS: Mean levels of intolerance of uncertainty in childhood cancer survivors are comparable to the general population and associated with psychological symptoms and chronic pain.

Intolerance of uncertainty may be a modifiable target for transdiagnostic interventions in survivorship care.

RevDate: 2025-07-24
CmpDate: 2025-07-24

Escherich CS, Li Z, Barnett KR, et al (2025)

Differentiation-dependent EBF1 activity determines CD22 transcription and leukemia sensitivity to inotuzumab ozogamicin.

Blood, 146(4):471-481.

Inotuzumab ozogamicin (InO) is an antibody-calicheamicin conjugate with high efficacy in lymphoid malignancies. It targets the B-cell surface protein CD22, which is expressed in most B-cell acute lymphoblastic leukemia (B-ALL) cases, albeit with variable intensity. However, factors governing CD22 expression and thus leukemia sensitivity to InO remain incompletely understood. Using multiomic characterization of 196 human B-ALL samples, coupled with ex vivo InO sensitivity profiling, we showed that early leukemia differentiation arrest at the pre-pro-B stage is associated with resistance to InO. Screening of 1639 transcription factor genes identified early B-cell factor 1 (EBF1) as a key regulator of CD22 expression (false discovery rate of 7.1 Ɨ 10-4). When comparing the assay for transposase-accessible chromatin with sequencing profiling results of the most InO-sensitive and -resistant cases (50% lethal concentration <10th vs >90th percentile, n = 18), the binding motif for EBF1 was strikingly enriched in regions with differential open chromatin status (P = 8 Ɨ 10-174). CRISPR interference targeting EBF1 binding sites at the CD22 locus led to an ∼50-fold reduction in cell surface CD22 expression and, consequently, an ∼22-fold increase in InO resistance in ALL cell lines. Interestingly, within BCR::ABL1 ALL, we observed intrasubtype heterogeneity linked to EBF1 transcriptional downregulation (P = 1.1 Ɨ 10-15) and/or somatic alteration (P = .004), which led to reduced CD22 expression (P = 8.3 Ɨ 10-11) and ex vivo and in vivo resistance to InO. Collectively, these findings point to the direct impact of EBF1 on CD22 expression during B-cell development, which, in turn, contributes to interpatient variability in InO response, even within the same subtype of B-ALL.

RevDate: 2025-07-23

Stankiewicz Karita HC, Magaret AS, Selke S, et al (2025)

Stability of Spiked Chlamydia Trachomatis and Neisseria Gonorrhea in Urine and Swab Specimens After Prolonged Storage at Room and Freezer Temperatures Using Aptima Combo-2 Test.

Open forum infectious diseases, 12(7):ofaf388.

We evaluated whether prolonged storage at room and freezer temperatures affects detection of Chlamydia trachomatis and Neisseria gonorrhoeae (CT/GC) using Aptima Combo-2 assay for research studies. Three hundred specimens were spiked with CT/GC; half were stored at room temperature and half at -80°C. All specimens remained CT/GC positive for 36 months.

RevDate: 2025-07-22

Takle M, Andrews A, Riggle BA, et al (2025)

Using Electroencephalography to Assess Coma Etiology in Children with Retinopathy-Negative Cerebral Malaria.

The American journal of tropical medicine and hygiene pii:tpmd250377 [Epub ahead of print].

Autopsy studies of children dying of cerebral malaria (CM) have revealed that those with malarial retinopathy exhibited high levels of sequestration in the cerebral vasculature, whereas children with retinopathy-negative CM exhibited lower sequestration levels and possible nonmalarial causes of death. This suggests that children dying of retinopathy-negative CM have nonmalarial coma etiologies with concomitant incidental parasitemia, which is common in high malaria transmission areas. Subsequent studies have challenged this assertion, positing that retinopathy-negative CM and retinopathy-positive CM are variants of the same disease pathophysiology or host biology, both caused by acute malaria infection. We recently determined that electroencephalography (EEG) can be used to discriminate between a malarial coma (CM) and a nonmalarial coma. To better understand the contribution of acute malaria infection in the pathophysiology of retinopathy-negative CM, we compared qualitative and quantitative EEG findings from 30-minute EEG recordings of Malawian children aged 3 months to 14 years hospitalized at Queen Elizabeth Central Hospital with retinopathy-negative CM, retinopathy-positive CM, and nonmalarial coma. Neither qualitative nor quantitative EEG interpretation methods allow for the discrimination between children with retinopathy-positive CM and those with retinopathy-negative CM. Conversely, quantitative EEG readily differentiated children with retinopathy-negative CM from those with nonmalarial coma (area under the receiving operating characteristic [AUROC] curve of 0.83). When combining qualitative and quantitative EEG interpretation methods, the ability of EEG to distinguish retinopathy-negative CM from nonmalarial EEG increases (AUROC of 0.87). The EEGs of children with retinopathy-negative CM are similar to those of children with retinopathy-positive CM and significantly different from those of children with nonmalarial coma, supporting the hypothesis that acute malarial infection is pathophysiologically important in retinopathy-negative CM.

RevDate: 2025-07-22

Farland LV, Degnan WJ, Harris HR, et al (2025)

Laparoscopically confirmed endometriosis and midlife plasma markers of inflammation, cholesterol, and adipokines among participants in the Nurses' Health Study II.

Maturitas, 200:108663 pii:S0378-5122(25)00471-2 [Epub ahead of print].

OBJECTIVE: Endometriosis may increase the risk of cardiovascular disease, possibly through a detrimental impact on circulating biomarkers. However, there is a paucity of research on endometriosis and inflammation, lipids, and adipokines at midlife.

METHODS: We used generalized linear models to determine the association between laparoscopically confirmed endometriosis and log-transformed levels of plasma C-reactive protein (n = 3936), interleukin-6 (n = 3495), tumor necrosis factor-alpha receptor 2 (n = 2967), high-density lipoprotein cholesterol (n = 1533), low-density lipoprotein cholesterol (n = 1324), total cholesterol (n = 4898), leptin (n = 2480), and adiponectin (n = 4262) among participants with existing biomarker measurements in the Nurses' Health Study II (average age 44 years). We investigated heterogeneity by body mass index (<25 kg/m[2] vs. ≥ 25 kg/m[2]).

RESULTS: We did not observe associations between endometriosis and midlife inflammatory biomarkers (C-reactive protein % difference: -4.6, 95 % CI [-15.7,7.9]; interleukin-6: -0.4 % [-7.2,7.1]; tumor necrosis factor-alpha receptor 2: -1.3 % [-4.1,1.6]) or levels of high-density lipoprotein cholesterol (0.8 % [-3.7,5.6]), low-density lipoprotein cholesterol (-0.2 % [-5.2,5.1]), total cholesterol (1.0 % [-0.7,2.7]), or adiponectin (-4.0 [-8.8,1.0]). Women with endometriosis had higher leptin levels (9.0 % [0.5, 18.1]). Associations varied by body mass index for total cholesterol (p-value 0.05) and leptin (p-value 0.02). Among women with a body mass index ≥25 kg/m[2], those with endometriosis had a mean total cholesterol level that was 2.7 % higher (0.2,5.2) than among those without; among those with a body mass index <25 kg/m[2], those with endometriosis had a mean leptin level that was 15.7 % higher (4.6, 28.1) than among those without endometriosis.

CONCLUSIONS: Endometriosis was not associated with midlife systemic inflammation, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, or adiponectin. Endometriosis was associated with higher leptin among those with a body mass index <25 kg/m[2] and higher total cholesterol among those with a body mass index ≥25 kg/m[2]. These findings suggest that endometriosis may influence cardiovascular disease risk via midlife cholesterol and leptin.

RevDate: 2025-07-22

Pete D, Lampe JW, Liu H, et al (2025)

A Cross-Sectional Study of Dietary Patterns and Helicobacter pylori Infection Among American Indian Adults in the Southwest.

Nutrition and cancer [Epub ahead of print].

High sodium diets have been shown to promote stomach colonization and the induction of tissue damage by Helicobacter pylori (H. pylori), a risk factor for gastric cancer. Among American Indians in the Southwest, where the H. pylori prevalence is 60%, the association between diet and H. pylori infection has not been studied. We conducted a cross-sectional pilot study with 93 adults (51%, 18-44 years, 73% female) in the Navajo Nation to assess their diet with self-administered food questionnaires and to detect H. pylori from stool samples using droplet digital PCR. Three diet patterns were identified using Principal Component Analysis: 1) Western, 2) Soups and Mixed Dishes, and 3) Fruits and Vegetables. Participants in the highest and middle tertiles of the Soups and Mixed Dishes pattern scores had higher odds of having H. pylori (ORHighest=5.59, 95% CI, 1.50-23.70; ORMiddle=3.48, 95% CI, 1.08-12.32) than those in the lowest tertile. This positive association may be linked to the sodium content of foods in this diet pattern. Soups and Mixed Dishes may contribute to H. pylori infection and may be incorporated in nutrition education for individuals positive for H. pylori infection in the Navajo Nation.

RevDate: 2025-07-22

Rebolj M, Brentnall AR, Geppert J, et al (2025)

LATE-STAGE OUTCOMES AS SURROGATES FOR MORTALITY IN CANCER SCREENING TRIALS: A SYSTEMATIC REVIEW AND META-ANALYSIS.

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology pii:763736 [Epub ahead of print].

Late-stage cancer incidence has been proposed as a surrogate outcome for cancer-specific mortality in future screening trials. Two previous meta-analyses with 33 and 39 trials assessed trial-level surrogacy but provided inconsistent conclusions about the suitability of late-stage cancer endpoints replacing mortality. Our systematic review and meta-analysis (PROSPERO, CRD42023369320) investigated the association between the effect of cancer screening on incidence of late-stage cancer and cancer-specific mortality. From 57 trials with 61 trial arm comparisons, correlation between late-stage incidence and mortality outcomes was 0.69 (95% confidence interval (CI): 0.47-0.84) for all cancers combined. Specifically, correlations were: 0.58 (0.27-0.93) for bowel (N=11 trials), 0.79 (0.49-0.94) for breast (N=13), and 0.91 (0.84-0.96) for lung cancer (N=14). Trial point estimates of the screening effect on mortality were within each trial's 95% CI late-stage incidence estimates in 56/61 (92%) trial-arm comparisons, and in 16/19 (84%) trial arm comparisons where the entire 95% CI for screening effect on late-stage incidence was below 1. Evidence suggests potential for late-stage cancer incidence as a key outcome in screening trials, but further research is needed to clarify when to measure late-stage outcomes, extrapolation for cancer types without trials, and the conditions when late-stage cancer does not accurately predict mortality.

RevDate: 2025-07-22

Koo J, Cooper R, Edwards SL, et al (2025)

High Prevalence of Abnormal Baseline Lung Function in Pediatric and Young Adult Hematopoietic Stem Cell Transplant Recipients: A Report from the TRANSPIRE Study.

Pediatric blood & cancer [Epub ahead of print].

BACKGROUND: Pulmonary complications are a major cause of morbidity and mortality in pediatric and young adult hematopoietic stem cell transplant (HSCT) recipients. The impact of preexisting lung dysfunction on posttransplant outcomes remains understudied.

METHODS: In a multi-institutional prospective cohort of 444 patients (≤24 years) undergoing allogeneic HSCT at eight centers, baseline lung function was categorized as normal or abnormal using clinical history, imaging, pulmonary function tests (PFTs), and pulmonologist review. Spirometry and diffusion capacity were assessed at baseline, Day 100, 1 year, and 2 years post-HSCT.

RESULTS: Baseline pulmonary dysfunction was present in 224 patients (50.4%), including impaired spirometry (46.4%), low diffusion capacity (33.8%), and imaging abnormalities (e.g., nodules 19%, interstitial changes 7.9%). These patients had significantly lower median z-scores for forced expiratory volume in 1 s (FEV1) (-2.3 vs. -0.5), forced vital capacity (FVC) (-2.0 vs. -0.3), and diffusion capacity of the lung for carbon monoxide (-2.4 vs. -0.7; all p < 0.001). Lung function impairments persisted through 2 years post-HSCT. FEV1 and FVC remained significantly lower at all time points; FEV1/FVC ratios were similar. Overall survival was lower in the abnormal group (88.4 vs. 95.9%). Seven respiratory-related deaths occurred, including acute respiratory distress syndrome (n = 3), respiratory failure (n = 2), diffuse alveolar hemorrhage (n = 1), and fibrotic lung disease (n = 1).

CONCLUSIONS: Pretransplant pulmonary dysfunction is common and predicts sustained posttransplant impairment and lower survival. Comprehensive baseline assessment may aid in risk stratification and guide early interventions to improve long-term respiratory outcomes in pediatric and young adult HSCT patients.

RevDate: 2025-07-21

Smit RAJ, Wade KH, Hui Q, et al (2025)

Polygenic prediction of body mass index and obesity through the life course and across ancestries.

Nature medicine [Epub ahead of print].

Polygenic scores (PGSs) for body mass index (BMI) may guide early prevention and targeted treatment of obesity. Using genetic data from up to 5.1 million people (4.6% African ancestry, 14.4% American ancestry, 8.4% East Asian ancestry, 71.1% European ancestry and 1.5% South Asian ancestry) from the GIANT consortium and 23andMe, Inc., we developed ancestry-specific and multi-ancestry PGSs. The multi-ancestry score explained 17.6% of BMI variation among UK Biobank participants of European ancestry. For other populations, this ranged from 16% in East Asian-Americans to 2.2% in rural Ugandans. In the ALSPAC study, children with higher PGSs showed accelerated BMI gain from age 2.5 years to adolescence, with earlier adiposity rebound. Adding the PGS to predictors available at birth nearly doubled explained variance for BMI from age 5 onward (for example, from 11% to 21% at age 8). Up to age 5, adding the PGS to early-life BMI improved prediction of BMI at age 18 (for example, from 22% to 35% at age 5). Higher PGSs were associated with greater adult weight gain. In intensive lifestyle intervention trials, individuals with higher PGSs lost modestly more weight in the first year (0.55 kg per s.d.) but were more likely to regain it. Overall, these data show that PGSs have the potential to improve obesity prediction, particularly when implemented early in life.

RevDate: 2025-07-21

Banerjee R, Mohan M, Rejeski K, et al (2025)

IVIG prophylaxis should be initiated following bispecific antibody therapy in multiple myeloma regardless of IgG levels.

Blood advances pii:546292 [Epub ahead of print].

Bispecific antibodies (bsAbs) such as teclistamab, elranatamab, linvoseltamab, and talquetamab have impressive efficacy in multiple myeloma (MM) but come with substantial infectious risks that do not dissipate over time. Immunoglobulin replacement therapy (IgRT), which includes intravenous immunoglobulin (IVIG) and subcutaneous immunoglobulin (SCIG), may lower these risks. In this Viewpoint, we contrast primary IgRT prophylaxis (initiation regardless of IgG levels) with preemptive IgRT treatment (initiation only once IgG levels fall below a certain threshold) in this setting. We make evidence-based arguments for primary prophylaxis as a safer and simpler approach compared to preemptive IgG-guided IgRT. We also discuss strategies to improve the cost-effectiveness of IVIG and SCIG across the world. Given the overwhelmingly favorable benefit-risk profile of IgRT coupled with the limitations inherent to IgG measurements in MM, withholding IgRT access based on arbitrary IgG thresholds is neither scientifically sound nor clinically appropriate for patients with MM receiving bsAb therapy.

RevDate: 2025-07-21

Ding S, Tauzin A, Pinto-Santini D, et al (2025)

CD4-mimetics sensitize HIV-infected cells to ADCC mediated by plasma from persons with early-stage HIV-1 infection.

Journal of virology [Epub ahead of print].

UNLABELLED: The viral reservoir in long-lived memory CD4+ cells, established in the early stages of HIV infection, represents the main obstacle to an HIV cure. Some strategies being developed to target the reservoir rely on rendering HIV-1 envelope glycoproteins (Env) visible to the immune system. Small molecule CD4-mimetics (CD4mcs) expose vulnerable Env epitopes, which can be targeted by non-neutralizing antibodies (nnAbs) that are abundant in the plasma of people living with HIV (PLWH) and can mediate antibody-dependent cellular cytotoxicity (ADCC). Administration of CD4mcs in combination with plasma from PLWH or nnAbs efficiently reduces the size of the HIV-1 reservoir and postpones viral rebound upon antiretroviral therapy (ART) interruption in humanized mice. However, it remains unclear when these nnAbs are elicited after HIV infection. In this study, we collected longitudinal plasma samples before acquisition, at diagnosis, and at multiple time points up to 33 weeks after the estimated date of detectable infection (EDDI) and before ART treatment initiation. We found that plasma samples collected as early as 3 to 10 weeks after EDDI neutralized viral particles and mediated ADCC in the presence of the CJF-III-288 CD4mc. Recognition of HIV-1-infected cells and ADCC progressively increased over time, reaching a plateau by 19-25 weeks after EDDI. ADCC activity increased concomitantly with the elicitation of anti-gp120 and anti-gp41 CD4-induced (CD4i) Abs and improved over time with the appearance of anti-coreceptor binding site antibodies. Our results show that CD4i nnAbs, able to eliminate HIV-1-infected cells in the presence of CD4mc, are elicited within a few weeks after HIV acquisition.

IMPORTANCE: A viral reservoir is established at the early stages of HIV-1 infection. This reservoir persists during antiretroviral therapy (ART) treatment, and viral rebound is observed after ART interruption. New strategies are needed to reduce the size of the viral reservoir and prevent virus rebound. Several families of non-neutralizing antibodies, which are abundant in plasma from people living with HIV-1, neutralize viral particles and mediate the elimination of HIV-1-infected cells through antibody-dependent cellular cytotoxicity (ADCC) when combined with CD4-mimetic compounds. The presence of non-neutralizing antibodies in plasma during early-stage HIV-1 infection would support the use of CD4-mimetic compounds as an early intervention to decrease the size of the latent HIV-1 reservoir by eliminating infected cells.

RevDate: 2025-07-20

Mehra N, Antonarakis ES, Park SH, et al (2025)

Patient-reported Outcomes in KEYLYNK-010: Pembrolizumab Plus Olaparib Versus Abiraterone or Enzalutamide for Participants with Biomarker-unselected, Previously Treated Metastatic Castration-resistant Prostate Cancer.

European urology oncology pii:S2588-9311(25)00112-9 [Epub ahead of print].

BACKGROUND AND OBJECTIVE: Pembrolizumab plus olaparib did not significantly improve radiographic progression-free survival or overall survival versus a next-generation hormonal agent (NHA) in participants with biomarker-unselected, pretreated metastatic castration-resistant prostate cancer (mCRPC) in the phase 3 KEYLYNK-010 trial. We present prespecified patient-reported outcomes (PROs) from KEYLYNK-010.

METHODS: Participants were randomly assigned 2:1 to receive pembrolizumab plus olaparib or an NHA (abiraterone acetate or enzalutamide). PROs were evaluated using the Brief Pain Inventory-Short Form (BPI-SF), Functional Assessment of Cancer Therapy-Prostate Cancer (FACT-P), and EuroQol 5-Dimension 5-Level (EQ-5D-5L) questionnaires. The PRO endpoints included time to pain progression (TTPP) as per BPI-SF and the least squares mean (LSM) change from baseline to week 15 in FACT-P total, BPI-SF, and EQ-5D visual analog scale (VAS) scores.

KEY FINDINGS AND LIMITATIONS: The PRO analysis population included 774 participants (pembrolizumab plus olaparib, n = 520; NHA, n = 254). The median follow-up was 18.7 (range, 6.1-31.7) mo. No meaningful differences were observed in TTPP for pembrolizumab plus olaparib versus NHA (median: 13.5 vs 12.0 mo; hazard ratio 0.95; 95% confidence interval 0.72-1.26). From baseline to week 15, no meaningful LSM differences were observed between the treatment groups in FACT-P total, BPI-SF, and EQ-5D VAS scores. Limitations include no formal hypothesis testing.

No meaningful differences were observed in health-related quality of life (HRQoL) or disease-related symptom scores for pembrolizumab plus olaparib versus NHA in participants with biomarker-unselected, pretreated mCRPC. These findings suggest that pembrolizumab plus olaparib did not negatively impact HRQoL in participants with pretreated mCRPC.

CLINICAL TRIAL REGISTRY: NCT03834519.

RevDate: 2025-07-20

Leu J, Narra LR, Gooley T, et al (2025)

Evaluating risk factors for skeletal-related events among bone metastases from solid tumors.

Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology pii:S0167-8140(25)04552-9 [Epub ahead of print].

BACKGROUND AND PURPOSE: Skeletal-related events (SRE) are a major source of morbidity and mortality across cancer types. Identification of risk factors for SRE and association with survival would facilitate more targeted preventive treatment.

MATERIALS AND METHODS: This retrospective cohort study included patients with bone metastases from solid tumors undergoing systemic imaging from February-March 2022 who had not received radiation within one year. Survival was analyzed using Cox models, and multi-state models assessed factors linked to SRE with death as a competing risk. Outcomes were SRE (including radiation for pain) and all-cause death. Variables included tumor type, metastasis site, and trial eligibility.

RESULTS: Among 410 patients (median age 67 years; 48 % male), 162 (40 %) experienced SRE over a median follow-up of 26.8 months. Seventy-five (18.3 %) received radiation for pain alone. Experiencing any type of SRE (HR 1.98, 95 % CI 1.47-2.67, p < 0.001) or radiation for pain alone (HR 2.14, 95 % CI 1.57-2.92, p < 0.001) were both associated with increased mortality. Patients eligible for a trial of early radiation were more likely to develop SRE (HR 1.67, 95 % CI 1.18-2.37, p = 0.004). Prostate cancer histology (HR 1.70, p = 0.02) and metastases to the hip/acetabulum (HR 2.55, p = 0.02) were associated with SRE.

CONCLUSION: Patients treated with radiation for pain alone demonstrated similar risk of death as those experiencing any type of SRE, supporting the inclusion of radiation in endpoint definitions. Prostate cancer type and hip/acetabulum metastasis location may help identify patients and lesions at elevated SRE risk, informing future preventive strategies.

RevDate: 2025-07-18

Goodsell KE, Chauhan SSB, Pillarisetty VG, et al (2025)

ASO Visual Abstract: Somatostatin Analogues for Preventing Postoperative Pancreatic Fistula: Past Evidence Reveals New Opportunities.

Annals of surgical oncology pii:10.1245/s10434-025-17828-2 [Epub ahead of print].

RevDate: 2025-07-21

Kenaston MW, Cherkashchenko L, Skawinski CLS, et al (2025)

Yellow Fever Virus Interactomes Reveal Common and Divergent Strategies of Replication and Evolution for Mosquito-borne Flaviviruses.

bioRxiv : the preprint server for biology.

Pathogenic mosquito-borne flaviviruses infect mosquito and human hosts, relying on host protein interactions to replicate, evade immunity, and mediate pathogenesis. Prior proteomic studies mapped such interactions for some flaviviruses, but yellow fever virus (YFV)-a pathogen of resurgent concern-remains understudied. Here, we map YFV interactomes in human and mosquito cells to identify interactions common among divergent flaviviruses or unique to YFV. Functional assays reveal a previously unrecognized YFV restriction factor: RBBP6 inhibits YFV genome replication by interacting with the viral polymerase NS5. We enhance the identification of dual-host interactions using structural modeling and holistic network integration. Extending our holistic approach to other flavivirus interactomes, we distinguish conserved mechanisms of host targeting from those unique to YFV. Contrary to expectations that conserved viral proteins lead to conserved protein interactions, we find that Capsid, a divergent structural protein, shares more host interactions than NS5, a conserved enzyme. Integrating proteomics with complementary analyses defines new principles of host-targeting strategies across flavivirus and host evolution, offering a versatile resource for navigating the complex landscape of flavivirus biology.

RevDate: 2025-07-21

Arimura Y, Konishi HA, H Funabiki (2025)

MagIC-Cryo-EM: Structural determination on magnetic beads for scarce macromolecules in heterogeneous samples.

bioRxiv : the preprint server for biology.

Cryo-EM single-particle analyses typically require target macromolecule concentration at 0.05~5.0 mg/ml, which is often difficult to achieve. Here, we devise Magnetic Isolation and Concentration (MagIC)-cryo-EM, a technique enabling direct structural analysis of targets captured on magnetic beads, thereby reducing the targets' concentration requirement to < 0.0005 mg/ml. Adapting MagIC-cryo-EM to a Chromatin Immunoprecipitation protocol, we characterized structural variations of the linker histone H1.8-associated nucleosomes that were isolated from interphase and metaphase chromosomes in Xenopus egg extract. Combining Duplicated Selection To Exclude Rubbish particles (DuSTER), a particle curation method that excludes low signal-to-noise ratio particles, we also resolved the 3D cryo-EM structures of nucleoplasmin NPM2 co-isolated with the linker histone H1.8 and revealed distinct open and closed structural variants. Our study demonstrates the utility of MagIC-cryo-EM for structural analysis of scarce macromolecules in heterogeneous samples and provides structural insights into the cell cycle-regulation of H1.8 association to nucleosomes.

RevDate: 2025-07-18

Lauro FD, Probert WJM, Pickles M, et al (2025)

Large connected components in sexual networks and their role in HIV transmission in Sub-Saharan Africa: A model-based analysis of HPTN 071(PopART) data.

Journal of theoretical biology pii:S0022-5193(25)00184-5 [Epub ahead of print].

The HIV epidemic in sub-Saharan Africa is historically characterised by high levels of prevalence and incidence. With the global effort to reach UNAIDS 95-95-95 targets, the scaling-up of HIV treatment, and focused preventive interventions, incidence has been declining over the past decade, albeit non-consistently across different sex and age groups. Two questions remain to be addressed to help tailor setting-specific interventions and allocate resources optimally. Firstly, are there unidentified demographic groups that are sources of transmission? Secondly, what are the patterns of decline in incidence across different groups? Model-based assessment is a valuable tool for the design of focused interventions and to answer these questions. PopART-IBM, an individual-based model calibrated to (anonymised) age-and-sex stratified data, was developed in the context of the HPTN-071 (PopART) trial, and it offers a unique opportunity to explore such questions in the context of high-burden HIV communities in Zambia and South Africa. The outputs of the model include the full HIV transmission and partnership networks. In this work, we explore these and show that the sexual partnership network exhibits a large connected component, usually comprising over 40 % of the population, in each of the studied communities. An analysis of the large connected component reveals that it is formed by young people (20-40 years old) and is centered around the most sexually active individuals of the community. At the same time, many individuals in the large connected component only have one partner, highlighting the complex dynamics of risk correlations in a population. Inspecting the transmission network reveals that, on average, more than 80% of transmissions occur among individuals belonging to the large connected component. These findings indicate that populations consisting of young and highly sexually active individuals should be given high priority when designing or deploying interventions.

RevDate: 2025-07-18

DeFilipp Z, Choe HK, Efebera YA, et al (2025)

---RGI-2001 for the Prophylaxis of Acute Graft-Versus-Host Disease Following Allogeneic HCT.

Blood pii:546275 [Epub ahead of print].

RGI-2001, a liposomal glycolipid that binds CD1d receptor of antigen-presenting cells, can activate invariant natural killer T cells and stimulate cytokine-dependent proliferation of regulatory T-cells (Tregs). This open-label, single-arm, multicenter phase 2b trial evaluated the safety and efficacy of RGI-2001 in combination with standard graft-versus-host disease (GVHD) prophylaxis in participants receiving myeloablative allogeneic hematopoietic cell transplantation (HCT) for hematologic malignancies. RGI-2001 was infused at a dose of 100 ug/kg for six weekly doses starting on Day 0 of HCT. The primary endpoint was grades II-IV acute GVHD by Day 100 after HCT. Forty-nine participants received RGI-2001 in combination with tacrolimus and methotrexate. RGI-2001 was well tolerated, with no serious infusion reactions. Sixteen participants experienced grade ≄3 treatment-related adverse events, with the most common being decreased appetite, leukopenia, thrombocytopenia and stomatitis. The estimated probability of grades II-IV and III-IV acute GVHD were 24.9% and 4.1%, respectively. Compared to controls from the Center for International Blood and Marrow Research Transplant registry, participants receiving RGI-2001 experienced superior clinical outcomes, including Day-180 grades II-IV acute GVHD-free survival (70.8% vs 50.7%, adjusted hazard ratio 0.45, 95% CI 0.30-0.68). Increasing NKT and Treg populations were observed after HCT, consistent with the proposed action of RGI-2001. In conclusion, RGI-2001 was well tolerated and was associated with low rates of acute GVHD and encouraging survival after myeloablative HCT. These results support strategies that target NKT and Treg cell populations to augment immunological changes in allogeneic HCT recipients. This trial was registered at www.clinicaltrials.gov as NCT04014790.

RevDate: 2025-07-20
CmpDate: 2025-07-20

Scadden AW, Kakar A, Litkowski EM, et al (2025)

Type 2 Diabetes Polygenic Risk Score Interactions with Lifestyle Risk Factors in Black Americans.

Lifestyle genomics, 18(1):90-97.

INTRODUCTION: Prior work in predominantly European ancestry populations has explained how the risk associated with demographic, lifestyle, and health factors differs with underlying genetic susceptibility to type 2 diabetes (T2D), but less is known about these relationships in Black Americans.

METHODS: We used covariate-adjusted logistic regression models of T2D to examine interactions between a published trans-ancestry derived T2D polygenic risk score (PRS) and various demographic, lifestyle, and health-related factors among 28,251 self-identified Black Americans from six cohort studies.

RESULTS: The results are generally consistent with prior work in White populations. The PRS showed a significant interaction with body mass index, with a greater effect on T2D risk in individuals who were leaner (pinteraction = 0.038).

CONCLUSION: These results contribute to understanding the relationship between genetics and other T2D risk factors in Black Americans who have a high burden of T2D, potentially informing targeted prevention strategies.

RevDate: 2025-07-18
CmpDate: 2025-07-18

McCrady A, Friedman S, Wang L, et al (2025)

3D finite element models reveal regional fatty infiltration modulates tibialis anterior force generating capacity in FSHD.

PloS one, 20(7):e0319881.

Facioscapulohumeral muscular dystrophy (FSHD) is a progressive neuromuscular disorder characterized by muscle damage, fibro-fatty infiltration, and ultimately weakness. The tibialis anterior (TA), very often involved relatively early in FSHD, is a primary dorsiflexor and important for ambulation. Recent work using magnetic resonance imaging to quantify fat infiltration in the TA volume observed a steep decline in force generation after fat reached ~20% in volume. Additional imaging studies have identified regional fat infiltration patterns that may contribute to the non-linear relationship between fat volume and muscle strength due to the distribution of fat within the muscle structure. The goals of this study were to 1) develop a pipeline for creating subject-specific models of the TA that include fat infiltration patterns measured from MRI and predict force generation, 2) compare models created using this pipeline with clinical measures of muscle strength, and 3) use the models to investigate the impact of regional fat distribution on muscle force generation. Twelve subject-specific models were created, and the model-predicted forces strongly correlate to clinical measures of strength in the same subjects (manual muscle testing (MMT): r = 0.75, and quantitative muscle testing (QMT): r = 0.54). The models showed fat amount accounts for 48% and muscle volume accounts for 74% of the variation in force. To investigate the impact of fat distribution, we developed eight pseudo maps to systematically vary fat location and amount in all subject-specific geometries. The models revealed that fat location modulates force generation, with the middle region involvement having the greatest impact in reducing force. This work highlights the need to characterize and understand the impact of intra-muscular fat distributions in neuromuscular diseases.

RevDate: 2025-07-18
CmpDate: 2025-07-18

Gilad M, Partridge SC, Iima M, et al (2025)

Radiomics-based Machine Learning Prediction of Neoadjuvant Chemotherapy Response in Breast Cancer Using Physiologically Decomposed Diffusion-weighted MRI.

Radiology. Imaging cancer, 7(4):e240312.

Purpose To evaluate the performance of a machine learning model developed using radiomics data derived from physiologically decomposed diffusion-weighted MRI data for predicting pathologic complete response (pCR) following neoadjuvant chemotherapy for breast cancer compared with baseline and benchmark models. Materials and Methods This retrospective study included data from the Breast Multiparametric MRI for prediction of neoadjuvant chemotherapy Response (BMMR2) challenge dataset, comprising longitudinal multiparametric breast MRI studies (diffusion-weighted imaging [DWI] and dynamic contrast-enhanced MRI) from participants enrolled in the I-SPY 2/ACRIN 6698 trial (ClinicalTrials.gov: NCT01042379). Piecewise linear physiologic decomposition was applied to DWI data (PD DWI) to isolate pseudo-diffusion, pure-diffusion, and pseudo-diffusion fraction components for radiomics feature extraction. These features were used to develop a boosted decision tree model to predict pCR following neoadjuvant chemotherapy. Model performance was compared with performance of baseline models, including data on tumor size and mean apparent diffusion coefficient, and the BMMR2 challenge benchmark model using area under the receiver operating characteristic curve, F1 score, and positive and negative predictive values. Model calibration was assessed via the Brier score, and a decision curve analysis was performed to estimate the potential reduction in unnecessary interventions when using the proposed model. Results The study included multiparametric MRI scans from 190 female participants (mean age ± SD, 48.4 years ± 10.5). PD DWI achieved the highest area under the receiver operating characteristic curve (0.89, 95% CI: 0.81, 0.96) among all evaluated models, demonstrating statistically significant improvements over baseline approaches (all P < .04). Decision curve analysis showed that the PD DWI model provided a greater net benefit compared with the BMMR2 challenge benchmark model (0.17, 95% CI: 0.13, 0.21 vs 0.09, 95% CI: 0.05, 0.13; P < .001). Conclusion A machine learning model using radiomics data derived from PD DWI achieved higher performance than baseline and benchmark models in predicting pCR following neoadjuvant chemotherapy for breast cancer. Keywords: Image Postprocessing, MR-Diffusion Weighted Imaging, Breast, Tumor Response, Experimental Investigations ClinicalTrials.gov: NCT01042379 © RSNA, 2025.

RevDate: 2025-07-17
CmpDate: 2025-07-18

Rajabli F, Benchek P, Tosto G, et al (2025)

Multi-ancestry genome-wide meta-analysis of 56,241 individuals identifies known and novel cross-population and ancestry-specific associations as novel risk loci for Alzheimer's disease.

Genome biology, 26(1):210.

BACKGROUND: Limited ancestral diversity has impaired our ability to detect risk variants more prevalent in ancestry groups of predominantly non-European ancestral background in genome-wide association studies (GWAS). We construct and analyze a multi-ancestry GWAS dataset in the Alzheimer's Disease Genetics Consortium (ADGC) to test for novel shared and population-specific late-onset Alzheimer's disease (LOAD) susceptibility loci and evaluate underlying genetic architecture in 37,382 non-Hispanic White (NHW), 6728 African American, 8899 Hispanic (HIS), and 3232 East Asian individuals, performing within ancestry fixed-effects meta-analysis followed by a cross-ancestry random-effects meta-analysis.

RESULTS: We identify 13 loci with cross-population associations including known loci at/near CR1, BIN1, TREM2, CD2AP, PTK2B, CLU, SHARPIN, MS4A6A, PICALM, ABCA7, APOE, and two novel loci not previously reported at 11p12 (LRRC4C) and 12q24.13 (LHX5-AS1). We additionally identify three population-specific loci with genome-wide significance at/near PTPRK and GRB14 in HIS and KIAA0825 in NHW. Pathway analysis implicates multiple amyloid regulation pathways and the classical complement pathway. Genes at/near our novel loci have known roles in neuronal development (LRRC4C, LHX5-AS1, and PTPRK) and insulin receptor activity regulation (GRB14).

CONCLUSIONS: Using cross-population GWAS meta-analyses, we identify novel LOAD susceptibility loci in/near LRRC4C and LHX5-AS1, both with known roles in neuronal development, as well as several novel population-unique loci. Reflecting the power of diverse ancestry in GWAS, we detect the SHARPIN locus with only 13.7% of the sample size of the NHW GWAS study (n = 409,589) in which this locus was first observed. Continued expansion into larger multi-ancestry studies will provide even more power for further elucidating the genomics of late-onset Alzheimer's disease.

RevDate: 2025-07-17

Moon HH, Aragon-Ching JB, Thompson A, et al (2025)

Early real-world utilization of avelumab switch maintenance among patients with advanced urothelial carcinoma without progression following treatment with first-line platinum-based chemotherapy.

Urologic oncology pii:S1078-1439(25)00208-X [Epub ahead of print].

BACKGROUND: A standard treatment option for patients with locally advanced/metastatic urothelial carcinoma (la/mUC) is first-line platinum-based chemotherapy (1L PBC) followed by avelumab 1L switch maintenance (1LM) in patients without progression. This study aimed to evaluate the real-world treatment patterns and outcomes in patients with la/mUC in the US treated with 1L PBC and characterize the early adoption of avelumab 1LM following FDA approval in June 2020.

METHODS: This retrospective cohort study identified adults diagnosed with la/mUC between January 2017 and September 2021 using electronic health records from the Flatiron Health database. Patients were grouped based on real-world response to 1L PBC: complete or partial response (rwCR/PR) or stable disease (rwSD). Baseline characteristics and treatment patterns were described. Clinical outcomes, including real-world overall survival (rwOS) and progression-free survival (rwPFS), were analyzed using the Kaplan-Meier method.

RESULTS: Of 1,703 identified patients with la/mUC treated with 1L PBC, 1,245 (73%) had response data available during the study period, with 998 (80%) having a best response of rwCR/PR (60%) or rwSD (20%). Demographic and clinical characteristics were similar between patients with rwCR/PR and rwSD. Patients with rwCR/PR had longer median rwOS and rwPFS from 1L PBC initiation vs patients with rwSD. Of patients evaluated after FDA approval of avelumab 1LM on June 30, 2020, 435 discontinued 1L PBC. Of these patients, 339 had response data, and 138 of those without progression were considered avelumab 1LM eligible. Of these, 97 (70%) initiated avelumab 1LM within 180 days following last administration of 1L PBC, with 40 patients receiving second-line (2L) treatment, most commonly enfortumab vedotin (60%).

CONCLUSION: In the post-FDA approval period, uptake of avelumab 1LM was high (70%) in patients with rwSD or rwCR/PR following 1L PBC, and 41% of these patients received 2L treatment, most commonly with enfortumab vedotin.

RevDate: 2025-07-17

Weinstein E, Paredes R, Gardner A, et al (2025)

Extended nirmatrelvir-ritonavir treatment durations for immunocompromised patients with COVID-19 (EPIC-IC): a placebo-controlled, randomised, double-blind, phase 2 trial.

The Lancet. Infectious diseases pii:S1473-3099(25)00221-X [Epub ahead of print].

BACKGROUND: Nirmatrelvir-ritonavir is approved for adults with mild-to-moderate COVID-19 who are at risk of severe disease. There are little clinical data to guide the duration of therapy in patients who are immunocompromised. We aimed to compare the approved 5-day regimen of nirmatrelvir-ritonavir with 10-day and 15-day regimens.

METHODS: This placebo-controlled, randomised, double-blind, phase 2 trial enrolled non-hospitalised, immunocompromised individuals aged 12 years or older with symptomatic COVID-19 from 73 sites across nine countries. Participants were randomly assigned (1:1:1) to receive 300 mg nirmatrelvir and 100 mg ritonavir orally twice per day for 5, 10, or 15 days. Randomisation was stratified according to whether participants were considered immunocompromised due to use of corticosteroids or tumour necrosis factor blockers. Investigators, participants, and caregivers were masked to the assigned study group. The primary endpoint was proportion of randomly assigned and dosed participants with sustained nasopharyngeal SARS-CoV-2 RNA concentrations below the lower limit of quantification (2·0 log10 copies per mL) from days 15 to 44. Secondary endpoints included the incidence of viral rebound after the end of treatment up to day 44. Safety, a secondary endpoint, was assessed in all randomly assigned participants who received at least one dose of nirmatrelvir-ritonavir. This trial was registered with ClinicalTrials.gov (NCT05438602) and is completed.

FINDINGS: Among 156 participants (84 female, 72 male) randomly assigned from Aug 3, 2022 to July 17, 2023, 150 comprised the analysis population. The primary endpoint was reached in 32 (61·5%, 95% CI 48·3-74·8) of 52 participants in the 5-day treatment group, 34 (70·8%, 58·0-83·7) of 48 participants in the 10-day treatment group, and 33 (66·0%, 52·9-79·1) of 50 participants in the 15-day treatment group. Viral rebound occurred in 17·3% (95% CI 8·2-30·3) of participants in the 5-day group, 2·1% (0·1-11·1) in the 10-day group, and 2·0% (0·1-10·6) in the 15-day group. Adverse events occurred in 28 (52·8%) of 53, 34 (66·7%) of 51, and 31 (60·8%) of 51 participants across the 5-day, 10-day, and 15-day groups, respectively. Two COVID-19-related hospitalisations were reported, both in the 5-day treatment group.

INTERPRETATION: No difference was observed between the three treatment durations in the primary endpoint. Extending nirmatrelvir-ritonavir treatment beyond 5 days resulted in a nominal improvement in the frequency of viral rebound and was generally well tolerated.

FUNDING: Pfizer.

RevDate: 2025-07-17

Yang X, Zhao F, Ren T, et al (2025)

OmicsTweezer: A distribution-independent cell deconvolution model for multi-omics Data.

Cell genomics pii:S2666-979X(25)00206-X [Epub ahead of print].

Cell deconvolution estimates cell type proportions from bulk omics data, enabling insights into tissue microenvironments and disease. However, practical applications are often hindered by batch effects between bulk data and referenced single-cell data, a challenge that is frequently overlooked. To address this discrepancy, we developed OmicsTweezer, a distribution-independent cell deconvolution model. By integrating optimal transport with deep learning, OmicsTweezer aligns simulated and real data in a shared latent space, effectively mitigating data shifts and inter-omics distribution differences. OmicsTweezer is versatile, capable of deconvolving bulk RNA-seq, bulk proteomics, and spatial transcriptomics. Extensive evaluations on simulated and real-world datasets demonstrate its robustness and accuracy. Furthermore, applications in prostate and colon cancer showcase OmicsTweezer's ability to identify biologically meaningful cell types. As a unified deconvolution framework for multi-omics data, OmicsTweezer offers an efficient and powerful tool for studying disease microenvironments.

RevDate: 2025-07-17

Hadland B (2025)

Unusual suspects: a surprise cast in making blood stem cells.

Blood, 146(3):265-266.

RevDate: 2025-07-17

Rini BI, Best AF, Bowman MD, et al (2025)

Risk Factors for COVID-19-Related Hospitalization and Death in Patients With Cancer: The National Cancer Institute COVID-19 in Cancer Patients Study (NCCAPS).

JAMA oncology pii:2836492 [Epub ahead of print].

IMPORTANCE: Retrospective case series have identified having cancer and receiving treatment for cancer as risk factors for inferior COVID-19 outcomes.

OBJECTIVE: To determine risk factors for hospitalization and death in patients with cancer with COVID-19 infection.

The National Cancer Institute COVID-19 in Cancer Patients Study (NCCAPS) is a prospective longitudinal natural history cohort study examining the impact of COVID-19 on patients with cancer. Adults were eligible within 14 days of an initial positive SARS-CoV-2 test result if they were receiving active treatment for cancer or had prior stem cell/bone marrow transplant or CAR T-cell treatment. The statistical analysis took place between September 2024 and April 2025.

MAIN OUTCOMES AND MEASURES: The primary objective of the study was to determine patient factors, therapy types, and cancer types associated with COVID-19 severity, defined as hospitalization for or death from COVID-19 within 30 and 90 days after the first positive SARS-CoV-2 test result. Multivariable regressions were performed for COVID-19-specific hospitalization and mortality (proportional hazard and cause-specific hazard models).

RESULTS: Of 1572 eligible adult patients (median [range] age, 60 [18-93] years; 840 female [53.4%]), 1066 (67.8%) had a solid tumor, with 683 (64.0%) having metastatic disease; breast (252 [23.6%]) and lung cancer (148 [13.9%]) were most common. At enrollment, 1013 patients (64.4%) were unvaccinated for SARS-CoV-2. COVID-19-related mortality at 90 days was 3.0% and did not increase at subsequent time points. The cumulative incidence of COVID-19-specific death in the first 90 days was highest in patients with lymphoma, intermediate in patients with acute leukemia and lung cancer, and lowest in patients with other solid tumors and other hematologic cancers. In multivariable analysis, receipt of chemotherapy (hazard ratio [HR], 1.97; 95% CI, 1.52-2.54) and baseline history of stroke, atrial fibrillation, or pulmonary embolism (HR, 1.78; 95% CI, 1.33-2.38) were associated with a higher risk of hospitalization. Vaccination prior to SARS-CoV-2 infection was associated with a lower risk of hospitalization (HR, 0.52; 95% CI, 0.38-0.70). Over 2 years of follow-up, there were 1739 cancer treatment disruptions, of which 881 (50.7%) were attributed to COVID-19, with most disruptions occurring within the first 30 days.

CONCLUSIONS AND RELEVANCE: The results of this prospective cohort study showed that COVID-19 had a significant impact on patients with cancer, including hospitalization, treatment disruptions, and death.

RevDate: 2025-07-17

Nakasone ES, AL Coveler (2025)

Targeting metabolism in pancreatic ductal adenocarcinoma: challenges and insights from the AVENGER 500 trial.

Journal of gastrointestinal oncology, 16(3):1351-1355.

RevDate: 2025-07-17
CmpDate: 2025-07-17

Heffner JL, Giustini N, Anderson N, et al (2025)

Implementation of sexual orientation and gender identity data collection in a cancer care setting.

Journal of the National Cancer Institute. Monographs, 2025(69):139-146.

Cancer research focusing on sexual and gender minority populations is limited by lack of sexual orientation and gender identity data in medical records and cancer registries. We implemented multimethod sexual orientation and gender identity data collection in 2 pilot clinics at a National Cancer Institute-Designated Comprehensive Cancer Center, with first-line collection by telephone intake schedulers and second-line via physical form in clinics. Changes in data completion were compared with 2 control clinics, and staff shared intervention experiences. In pilot clinics, completion rates statistically significantly increased for gender identity (from 55.6% to 65.1%), sex assigned at birth (from 58.4% to 63.2%), sexual orientation (from 45.1% to 53.7%), and all 3 (from 37.8% to 44.7%) when compared with control clinics (P < .05). Staff reported a mix of patient reactions to sexual orientation and gender identity data collection. Sexual orientation and gender identity data collection can be enhanced in the cancer care setting with multimethod approaches.

RevDate: 2025-07-16
CmpDate: 2025-07-17

Zhou HJ, Ge X, JJ Li (2025)

ClipperQTL: ultrafast and powerful eGene identification method.

Genome biology, 26(1):207.

A central task in expression quantitative trait locus analysis is to identify cis-eGenes, i.e., genes whose expression levels are regulated by at least one local genetic variant. Existing cis-eGene identification methods are either computationally expensive, requiring thousands of permutations per gene (FastQTL), or statistically underpowered (eigenMT and TreeQTL). We propose ClipperQTL, which requires only one permutation for data sets with large sample sizes (>450; ClipperQTL works on smaller data sets too). We show that ClipperQTL performs as well as FastQTL and runs up to 500 times faster. The R package ClipperQTL is available at https://github.com/heatherjzhou/ClipperQTL .

RevDate: 2025-07-16

Rejeski K, Hill JA, Dahiya S, et al (2025)

Noncanonical and mortality-defining toxicities of CAR T cell therapy.

Nature medicine [Epub ahead of print].

Chimeric antigen receptor (CAR) T cell therapy is associated with a unique spectrum of toxicities that drive morbidity, mortality and patient quality of life. Previous efforts yielded consensus grading systems for the prototypical immunotoxicities-namely, cytokine-release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). These grading systems set the stage for severity-based and standardized treatment protocols that have contributed to a reduction in the acute toxicity burden of CAR T cell therapy and have enabled outpatient administration. However, understanding of CAR T cell therapy has since grown to encompass new targets, new diseases and broader patient populations-including long-term survivors. As side effects are better defined and novel toxicities emerge, there is a need to understand their mechanisms and standardize reporting to improve clinical management. Here we review the current state of knowledge for mortality-defining and rare toxicities of CAR T cell therapies, beyond CRS and ICANS. We discuss mechanisms, including on-target injury, cytokine-associated inflammation and dysregulated recovery, and how these mechanisms affect the timing and management of toxicities. Finally, we define key unmet needs and delineate future priorities and research directions.

RevDate: 2025-07-16
CmpDate: 2025-07-16

Blemker SS, Riem L, DuCharme O, et al (2025)

Multi-scale machine learning model predicts muscle and functional disease progression.

Scientific reports, 15(1):25339.

Facioscapulohumeral muscular dystrophy (FSHD) is a genetic neuromuscular disorder characterized by progressive muscle degeneration with substantial variability in severity and progression patterns. FSHD is a highly heterogeneous disease; however, current clinical metrics used for tracking disease progression lack sensitivity for personalized assessment, which greatly limits the design and execution of clinical trials. This study introduces a multi-scale machine learning framework leveraging whole-body magnetic resonance imaging (MRI) and clinical data to predict regional, muscle, joint, and functional progression in FSHD. The goal this work is to create a 'digital twin' of individual FSHD patients that can be leveraged in clinical trials. Using a combined dataset of over 100 patients from seven studies, MRI-derived metrics-including fat fraction, lean muscle volume, and fat spatial heterogeneity at baseline-were integrated with clinical and functional measures. A three-stage random forest model was developed to predict annualized changes in muscle composition and a functional outcome (timed up-and-go (TUG)). All model stages revealed strong predictive performance in separate holdout datasets. After training, the models predicted fat fraction change with a root mean square error (RMSE) of 2.16% and lean volume change with a RMSE of 8.1 ml in a holdout testing dataset. Feature analysis revealed that metrics of fat heterogeneity within muscle predicts muscle-level progression. The stage 3 model, which combined functional muscle groups, predicted change in TUG with a RMSE of 0.6 s in the holdout testing dataset. This study demonstrates the machine learning models incorporating individual muscle and performance data can effectively predict MRI disease progression and functional performance of complex tasks, addressing the heterogeneity and nonlinearity inherent in FSHD. Further studies incorporating larger longitudinal cohorts, as well as comprehensive clinical and functional measures, will allow for expanding and refining this model. As many neuromuscular diseases are characterized by variability and heterogeneity similar to FSHD, such approaches have broad applicability.

RevDate: 2025-07-16
CmpDate: 2025-07-16

Elias-Warren A, Bennett JC, Iwu CD, et al (2025)

Epidemiology of Human Metapneumovirus Infection in a Community Setting, Seattle, Washington, USA.

The Journal of infectious diseases, 232(Supplement_1):S78-S92.

BACKGROUND: The clinical and genomic epidemiology of human metapneumovirus (hMPV) infections in community settings is not well understood.

METHODS: From 2018 to 2022, individuals with respiratory symptoms were recruited and enrolled from the greater Seattle, Washington community in the United States. Residual clinical specimens from individuals presenting with respiratory symptoms were additionally collected. Specimens were tested for hMPV by reverse-transcription polymerase chain reaction, with whole genome sequencing performed on a subset (209/1002).

RESULTS: hMPV positivity was higher among clinical specimens (835/21 539 [3.9%]) compared to community specimens (167/28 348 [0.6%]). Children aged 0-4 years had the highest percent positivity across both clinical and community settings (497/10 213 [4.9%] and 28/1640 [1.7%], respectively). In multivariate analysis, a household income of ≤US$100 000 (adjusted odds ratio [aOR], 1.72 [95% confidence interval {CI}, 1.07-2.85]), and recent international travel (aOR, 6.51 [95% CI, 3.11-12.22]) were associated with hMPV positivity. A subset of 209 of 1002 samples (21%) was sequenced; the distribution of subtypes A2b, A2c, B1, and B2 were similar across both community and clinical settings, with an increase in the proportion of subtype B1 after the start of the pandemic.

CONCLUSIONS: Risk factors of testing positive for hMPV in a community setting included lower household income and recent international travel. Co-circulation of hMPV subtypes was observed across community and clinical settings.

RevDate: 2025-07-16

Corello H, Pang S, Bustillos H, et al (2025)

Clinical considerations for pharmacists regarding the use of radiopharmaceuticals in oncology.

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

BackgroundRadiopharmaceutical therapy encompasses the targeted delivery of radioactive atoms to sites of malignancy within the body and represent a rapidly growing area of drug development in oncology. In comparison to cytotoxic chemotherapy, radiopharmaceutical therapy has the potential for fewer adverse effects and is able to produce a strong anti-cancer response in a wide range of malignancies.ObjectiveThis article reviews radiopharmaceutical therapy mechanisms and discusses four well-established agents that are used in clinical practice, their place in therapy, safety, utilization of concomitant therapies, and contact precautions for each agent.SourcesInformation presented in this article is sourced from the available literature on radiopharmaceutical development, oncology clinical practice guidelines, clinical trial results, and package insert data.SummaryRadiopharmaceuticals possess significant differences in drug mechanism and design from that of traditional cytotoxic chemotherapy agents. The basic functional and structural variances in combination with isotope selection drive the clinical efficacy of radiopharmaceutical therapy and inform pharmacists of the important considerations of each therapy's distribution, off-target effects, clearance, and toxicities.ConclusionThe drug and safety information presented in this article pertaining to select radiopharmaceuticals is pertinent to an oncology pharmacist's role in patient care as radioactive therapies continue to expand the complexity of the oncology treatment landscape.

RevDate: 2025-07-16

Muchadeyi MT, Hao S, Hernandez-Villafuerte K, et al (2025)

Cost effectiveness analysis of prostate cancer screening strategies in Germany: A microsimulation study.

International journal of cancer [Epub ahead of print].

Prostate cancer (PCa) represents a significant public health challenge in Germany, with increasing incidence and economic impact. This study assessed the cost-effectiveness of 10 screening strategies: prostate-specific antigen-based risk-adaptive screening (PSA-RAS), with or without magnetic resonance imaging (MRI), in men starting at age 45 or 50 and stopping at 60 or 70, digital rectal examination (DRE) for ages 45-75 years, and no screening. Using a well calibrated microsimulation model (Swedish Prostata) from a statutory health insurance perspective, lifetime outcomes were evaluated, including cancer incidence, mortality, overdiagnosis, biopsies, life-years, and quality-adjusted life-years (QALYs) discounted annually at 3%. Cost and utility inputs were derived from the German diagnostic-related group schedule, fee-for-service catalogues, literature, and expert opinion. DRE-only was the least cost-effective, yielding high biopsy and overdiagnosis rates with minimal QALY gains. PSA-RAS reduced overdiagnosis and biopsy rates, with PSA-RAS (50-60 years) without MRI emerging as the most cost-efficient strategy, saving approximately €1.2 million per 100,000 men compared with no screening. Extending the PSA-RAS to 70 years improved its effectiveness in terms of QALYs. PSA-RAS (50-70) with MRI could become cost-effective at an increasing willingness to pay threshold or decreasing MRI cost. This study suggests the potential of PSA-RAS to improve PCa screening in Germany. Incorporating MRI, reducing MRI cost within the screening setting, and extending screening to 70 to align with EU recommendations could improve the cost-effectiveness of PSA-RAS with MRI. Future research should explore the integration of MRI with ancillary tests, such as 4K-score or risk calculators, to reduce MRI use and associated costs.

RevDate: 2025-07-17

Paredes MI, Liang C, Suen SC, et al (2025)

Viral introductions and return to baseline sexual behaviors maintain low-level mpox incidence in Los Angeles County, USA, 2023-2024.

medRxiv : the preprint server for health sciences.

In 2022, mpox clade IIb disseminated around the world, causing outbreaks in more than 117 countries. Despite the decay of the 2022 epidemic and the accumulation of immunity within queer sexual networks, mpox continues to persist at low incidence in North America without extinction, raising concerns of future outbreaks. We combined phylodynamic inference and microsimulation modeling to understand the heterogeneous dynamics governing local mpox persistence in Los Angeles County (LAC) from 2023-2024. Our Bayesian phylodynamic analysis revealed a time-varying pattern of viral importations into the county that seeded a skewed distribution of mpox outbreak clusters that display a "stuttering chains" dynamic. Our phylodynamics-informed microsimulation model demonstrated that the persistent number of mpox cases in LAC can be explained by a combination of waves of viral introductions, a median Rt significantly below one, and a return to near-baseline sexual behaviors that were altered during the 2022 epidemic. Finally, our counterfactual scenario modeling showed that public health interventions that either promote increased isolation of symptomatic, infectious individuals or enact behavior-modifying campaigns during the periods with the highest viral importation intensity are both actionable and effective at curbing mpox cases. Our work highlights the heterogeneous factors that maintain present-day mpox dynamics in a large, urban US county and describes how to leverage these results to design timely and community-centered public health interventions.

RevDate: 2025-07-16

Watt GP, Reiner AS, Shu X, et al (2025)

Polygenic risk of coronary artery disease for long-term survivors of breast cancer.

Journal of the National Cancer Institute pii:8203076 [Epub ahead of print].

AIM: Cardiovascular disease is a leading cause of death for long-term breast cancer survivors. We evaluated whether a polygenic risk score for coronary artery disease (CAD-PRS) was associated with the risk of incident CAD for survivors of unilateral or contralateral breast cancer.

METHODS: The study included 1,307 women with breast cancer first diagnosed at age <55 years who participated in the WECARE Follow-up Study. The CAD-PRS was based on a PRS developed and validated in a separate population. We modelled the association between incident CAD and the CAD-PRS, adjusting for age, CAD risk factors, first (and second) breast cancer treatment, study recruitment phase, and genetic population stratification. We also explored whether the risk of CAD depended on interactions between the CAD-PRS and cardiotoxic cancer treatment.

RESULTS: There were 65 incident CAD diagnoses reported at a median of 16 years after breast cancer diagnosis. Participants with CAD-PRS≥median had a 2.48-times increased risk of CAD (95%CI = 1.44-4.29) relative to participants with CAD-PRS
CONCLUSIONS: A genome-wide CAD-PRS was associated with non-fatal CAD risk for long-term breast cancer survivors, providing potential utility for personalized cardiovascular care, particularly after RT.

RevDate: 2025-07-15
CmpDate: 2025-07-15

Miller NJ, Kwan SW, Leary JB, et al (2025)

Concurrent treatment with transarterial immunoembolization of hepatic metastases and systemic immune checkpoint inhibitors to overcome immune evasion in patients with metastatic uveal melanoma.

Cancer immunology, immunotherapy : CII, 74(8):270.

BACKGROUND: Metastatic uveal melanoma (mUM) is an uncommon melanoma subtype, poorly immunogenic with low objective response rates (ORR) to immune checkpoint inhibitors (ICI). Liver-directed therapies (LDT) are commonly used given the strong predilection for hepatic metastases. Transarterial immunoembolization (TAIE) with granulocyte-macrophage colony stimulating factor (GM-CSF) can potentially synergize with concurrent systemic ICI to overcome immune evasion.

METHODS: This single-center, retrospective study includes mUM patients with liver-predominant metastases who received TAIE, with/without concurrent systemic ICI (≤ 3 months before/during TAIE). Endpoints included ORR, progression-free survival (PFS), overall survival (OS), and adverse events (AEs).

RESULTS: Between 2016 and 2023, 18 mUM patients (median age 64 years) received TAIE (median 4 procedures/patient). Fourteen patients (78%) received concurrent ICI. ORR was 17% (3/18), all in patients receiving ICI, with partial responses lasting 4.2, 35 + and 46 months. Disease control rate (stable disease or better) was 56% (10/18). Median time to next systemic therapy or death was 19.5 months (range 1.6- 46). Median PFS and OS from first TAIE treatment were 4.9 months (range 0.7-46) and 35 months (range 1.7- 46). Immune-related AEs (IRAE) during concurrent therapy occurred in seven of 10 patients receiving anti-CTLA-4/PD-1 combination, including hepatitis (n = 5; grade 2 in 1, grade 3 in 4). Four of seven patients resumed anti-PD-1 monotherapy without recurrent IRAE.

CONCLUSIONS: Concurrent LDT with GM-CSF TAIE and ICI, including anti-CTLA-4/PD-1 combination, is feasible, safe, and can lead to sustained clinical benefit in a subset of mUM patients. OS with this combination compares favorably to published outcomes for systemic therapy or LDT alone.

RevDate: 2025-07-15
CmpDate: 2025-07-15

Thiele K, Urbschat C, Riquelme JIA, et al (2025)

Pregnancy-acquired memory CD4[+] regulatory T cells improve pregnancy outcome in mice.

Nature communications, 16(1):6522.

Subsequent pregnancies are generally less prone to obstetric complications. A successful pregnancy outcome requires pivotal immunological adaptation to ensure immune tolerance towards the foetus. Thus, the lower risk for pregnancy complication during subsequent pregnancies may be attributable to immune memory mounted during first pregnancies. Here we identify higher frequencies of fetal-antigen-specific CD4[+] regulatory T (Treg) cells both postpartum and in subsequent pregnancies in mice which are partly originating from trans-differentiated Th17 cells. Our functional experiments demonstrate that these CD4[+] Treg cells have memory functions (CD4[+] mTreg) and account for an improved fetal development and pregnancy outcome, also during adverse conditions, such as gestational sound stress. Using a high-throughput single-cell quantification method, we identify candidate markers for the detection of CD4[+] mTreg cells, which include CXCR4 and CD274. Our findings thus contribute to the improved understanding of pregnancy-induced immune memory and foster the identification of immune targets aiming to reduce the risk for immune-mediated pregnancy complications.

RevDate: 2025-07-16

Sung K, Johnson MM, Dumm W, et al (2025)

Thrifty wide-context models of B cell receptor somatic hypermutation.

bioRxiv : the preprint server for biology.

Somatic hypermutation (SHM) is the diversity-generating process in antibody affinity maturation. Probabilistic models of SHM are needed for analyzing rare mutations, for understanding the selective forces guiding affinity maturation, and for understanding the underlying biochemical process. High throughput data offers the potential to develop and fit models of SHM on relevant data sets. In this paper we model SHM using modern frameworks. We are motivated by recent work suggesting the importance of a wider context for SHM, however, assigning an independent rate to each k-mer leads to an exponential proliferation of parameters. Thus, using convolutions on 3-mer embeddings, we develop "thrifty" models of SHM of various sizes; these can have fewer free parameters than a 5-mer model and yet have a significantly wider context. These offer a slight performance improvement over a 5-mer model, and other modern model elaborations worsen performance. We also find that a per-site effect is not necessary to explain SHM patterns given nucleotide context. Also, the two current methods for fitting an SHM model - on out-of-frame sequence data and on synonymous mutations - produce significantly different results, and augmenting out-of-frame data with synonymous mutations does not aid out-of-sample performance.

RevDate: 2025-07-15
CmpDate: 2025-07-15

Miller NJ, Baik C, Neal JW, et al (2025)

Napsin A-specific T-cell clonotypes are associated with improved clinical outcomes in patients receiving checkpoint immunotherapy for metastatic non-small cell lung cancer.

Journal for immunotherapy of cancer, 13(7): pii:jitc-2025-011907.

BACKGROUND: Napsin A is normally expressed in human lung pneumocytes and is a highly expressed cancer antigen in lung adenocarcinoma. We examined whether T cells specific for Napsin A may play a role in immune checkpoint inhibitor (ICI)-mediated responses. We used bulk T-cell receptor (TCR) repertoire data to assess whether the presence of Napsin A-specific clonotypes in the peripheral blood was associated with improved clinical responses to ICI.

METHODS: Patients with metastatic non-small cell lung cancer (NSCLC) receiving anti-programmed cell death protein 1 (PD-1) and/or programmed death-ligand 1 (PD-L1) were enrolled at Fred Hutchinson Cancer Center and Stanford University Medical Center (n=62; histology of adenocarcinoma n=48, squamous n=9, NSCLC/other n=5). Peripheral blood mononuclear cells were collected for genomic DNA isolation at one pretreatment and one post-treatment time point (range 3 weeks to 3 months). TCRβ was bulk sequenced via the immunoSEQ platform (Adaptive Biotechnologies). Napsin A-specific TCRβ sequences were identified from publicly available data and their frequencies were quantified in each patient sample. We examined whether overall survival (OS) and progression-free survival (PFS) outcomes differed in patients with or without detectable Napsin A-specific TCRs (herein Napsin TCRs). We used Cox proportional hazards regression to assess the association between detectable Napsin TCRs and PFS or OS in univariable and multivariable analyses.

RESULTS: Napsin TCRs were detectable in the blood in a large fraction of our cohort (n=25/62 (40%) pretreatment; n=21/42 (50%) post-treatment). Patients with detectable Napsin TCRs had a significant improvement in OS compared with patients without these TCRs (median OS 45.4 vs 14.8 months, p=0.0043 pretreatment; median OS 55.4 vs 18.9 months, p=0.0066 post-treatment). Among 27 HLA-A*02 carriers of 55 human leukocyte antigen-typed patients (49%), patients with detectable pretreatment Napsin TCRs had a significant improvement in OS (median 60.2 vs 16.5 months, p=0.0054) and PFS (median 21.5 vs 7.2 months, p=0.031) compared with patients without these TCRs. In univariate and multivariate analysis, the presence of Napsin TCRs pretreatment was associated with improved OS (p=0.0057, HR 0.40, 95% CI 0.21 to 0.76 univariate; p=0.033, HR 0.45, 95% CI 0.23 to 0.91 multivariate).

CONCLUSIONS: Napsin TCRs are frequently detected in patients with NSCLC and are associated with improved OS in patients with NSCLC receiving ICI.

RevDate: 2025-07-15

Brooks TR, Zabor EC, Bedelu Y, et al (2025)

Real-world outcomes of patients with aggressive B-cell lymphoma treated with epcoritamab or glofitamab.

Blood pii:546196 [Epub ahead of print].

Epcoritamab and glofitamab are CD20-directed bispecific antibodies approved in the US for relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL). Limited data exist for patients treated outside of trials. Patients with R/R DLBCL receiving commercial epcoritamab or glofitamab between January 1, 2023 and October 15, 2024 were collected from 21 US institutions. Among 245 patients, 156 received epcoritamab and 89 received glofitamab, 113 were refractory to front-line therapy, 40 had MYC and BCL2 and/or BCL6 rearrangements, 147 received prior chimeric antigen receptor T-cell therapy, and 174 patients would have been ineligible for registrational trials. The overall response rate (ORR) for epcoritamab and glofitamab was 51% (23% complete response, [CR]) and 53% (30% CR), respectively. Median progression-free survival (mPFS) was 2.6 months (95% confidence interval [CI] 2.0 to 3.8 months), and median overall survival (mOS) was 7.8 months (95% CI 6.2 to 11.0 months). The 6-month PFS was 36% (95% CI 30% to 44%) and the 6-month OS was 60% (95% CI 54% to 67%). Both trial ineligibility and undetectable CD20 pre-bispecific portended shorter PFS and OS. Of 17 individuals with paired biopsies, 15 (88.2%) lost CD20 expression after bispecifics with a median time to progression of 3.7 months. This analysis including R/R DLBCL patients shows the ORR to CD3/CD20 BsAbs was comparable to pivotal trials, although PFS and OS were lower. Baseline undetectable levels of CD20 was associated with poor outcomes. These results demonstrate the activity of BsAbs in R/R DLBCL and underscore the importance of target antigen expression.

RevDate: 2025-07-15
CmpDate: 2025-07-15

Oviedo F, Kazerouni AS, Liznerski P, et al (2025)

Cancer Detection in Breast MRI Screening via Explainable AI Anomaly Detection.

Radiology, 316(1):e241629.

Background Artificial intelligence (AI) models hold potential to increase the accuracy and efficiency of breast MRI screening; however, existing models have not been rigorously evaluated in populations with low cancer prevalence and lack interpretability, both of which are essential for clinical adoption. Purpose To develop an explainable AI model for cancer detection at breast MRI that is effective in both high- and low-cancer-prevalence settings. Materials and Methods This retrospective study included 9738 breast MRI examinations from a single institution (2005-2022), with external testing in a publicly available multicenter dataset (221 examinations). In total, 9567 consecutive examinations were used to develop an explainable fully convolutional data description (FCDD) anomaly detection model to detect malignancies on contrast-enhanced MRI scans. Performance was evaluated in three cohorts: grouped cross-validation (for both balanced [20.0% malignant] and imbalanced [1.85% malignant] detection tasks), an internal independent test set (171 examinations), and an external dataset. Explainability was assessed through pixelwise comparisons with reference-standard malignancy annotations. Statistical significance was assessed using the Wilcoxon signed rank test. Results FCDD outperformed the benchmark binary cross-entropy (BCE) model in cross-validation for both balanced (mean area under the receiver operating characteristic curve [AUC] = 0.84 ± 0.01 [SD] vs 0.81 ± 0.01; P < .001) and imbalanced (mean AUC = 0.72 ± 0.03 vs 0.69 ± 0.03; P < .001) detection tasks. At a fixed 97% sensitivity in the imbalanced setting, mean specificity across folds was 13% for FCDD and 9% for BCE (P = .02). In the internal test set, FCDD outperformed BCE for balanced (mean AUC = 0.81 ± 0.02 vs 0.72 ± 0.02; P < .001) and imbalanced (mean AUC = 0.78 ± 0.05 vs 0.76 ± 0.01; P < .02) detection tasks. For model explainability, FCDD demonstrated better spatial agreement with reference-standard annotations than BCE (internal test set: mean pixelwise AUC = 0.92 ± 0.10 vs 0.81 ± 0.13; P < .001). External testing confirmed that FCDD performed well, and better than BCE, in the balanced detection task (AUC = 0.86 ± 0.01 vs 0.79 ± 0.01; P < .001). Conclusion The developed explainable AI model for cancer detection at breast MRI accurately depicted tumor location and outperformed commonly used models in both high- and low-cancer-prevalence scenarios. © RSNA, 2025 Supplemental material is available for this article. See also the editorial by Bae and Ham in this issue.

RevDate: 2025-07-15

Read C, Bhatia S, M Totonchy (2025)

Programmed cell death 1 blockade in the setting of severe ocular sarcoidosis: Cancer immunotherapy in a patient with autoimmunity.

JAAD case reports, 62:43-45.

RevDate: 2025-07-15

Hope A, Mundis M, Sonke JJ, et al (2025)

Three discipline collaborative radiation therapy (3DCRT) special debate: AI structure segmentation is better than clinician contouring for both OARs and targets.

Journal of applied clinical medical physics, 26(7):e70183.

RevDate: 2025-07-14

Ehret F, Ebner DK, Kutuk T, et al (2025)

Stereotactic Body Radiotherapy for the Treatment of Adrenal Metastases - A Case-Based Radiosurgery Society Practice Guide and Review.

Practical radiation oncology pii:S1879-8500(25)00174-2 [Epub ahead of print].

PURPOSE: Adrenal metastases are frequently diagnosed in patients with common solid tumors. Surgical adrenalectomy has historically been used for their management. However, stereotactic body radiotherapy (SBRT) has emerged as a safe and effective alternative. Careful treatment planning is essential, considering multiple factors such as tumor size and location, motion management, dose and fractionation, and proximity to adjacent organs at risk. This case-based practice guide and review provides an overview of SBRT for the management of adrenal tumors, with a particular focus on adrenal metastases.

METHODS AND MATERIALS: Three clinical scenarios were selected to illustrate the use of SBRT in managing adrenal tumors. These include a small right-sided metastasis treated with single-fraction, fiducial-based SBRT, a large left-sided metastasis treated with fractionated SBRT under magnetic resonance imaging guidance, and a case of bilateral metastases, which emphasizes the potential risk of adrenal insufficiency. We also address the limited evidence available regarding the management of primary adrenal gland tumors with SBRT.

RESULTS: SBRT is an effective treatment modality for most adrenal tumors, demonstrating a favorable safety profile. Thoughtful treatment planning and an understanding of potential pitfalls, limitations, and risks are essential to ensure the appropriate use of SBRT.

CONCLUSIONS: This case-based guide and review provides a comprehensive overview of SBRT for treating adrenal tumors, specifically metastases. We present and discuss clinical cases and relevant literature, highlighting key considerations specific to adrenal SBRT.

RevDate: 2025-07-14
CmpDate: 2025-07-14

Tsai CS, Szewczyk W, Drerup M, et al (2025)

A Personalized, Texting-Based Conversational Agent to Address Sleep Disturbance in Individuals Who Have Survived Breast Cancer: Protocol for a Pilot Waitlist Randomized Controlled Trial.

JMIR research protocols, 14:e62712 pii:v14i1e62712.

BACKGROUND: Sleep disturbance is one of the most common health concerns reported by individuals who have survived breast cancer (BC) and is associated with poor quality of life (QoL) and greater mortality after treatment. Cognitive behavioral therapy for insomnia (CBTi) has shown efficacy for improving sleep and QoL for this population. Considered the gold standard for insomnia treatment, CBTi can be delivered remotely, including via digital intervention. Despite the potential for wider dissemination of CBTi via digital means, these modalities have unique challenges, including technology barriers and poor adherence. We developed a conversational agent (CA) to deliver CBTi via a SMS text messaging intervention, supported by mobile-ready web content. Named "Cecebot," this CA delivers sleep education, implements sleep compression, provides just-in-time interventions for sleep-disrupting behaviors, and includes enhanced support for physical activity (PA) beyond what is typically included in CBTi. This represents a novel modality for a CBTi and PA intervention among individuals who have survived BC.

OBJECTIVE: We aim to examine the safety and acceptability of the Cecebot intervention, developed by an academic partnership between Dr Reding's research team and Moby Inc, for individuals who have survived BC and experience symptoms of insomnia, and to explore its efficacy.

METHODS: This trial will recruit 60 individuals who have survived BC and are experiencing moderate to severe sleep disturbance. Participants will be assigned to the Cecebot intervention or waitlist control group at a 1:1 ratio. The treatment group will receive the Cecebot intervention during weeks 1-6 of the study, while the waitlist control condition will receive the Cecebot intervention during weeks 6-12. The Cecebot intervention uses SMS text messaging technology paired with a Fitbit. Participants will be assessed at baseline, week 6, and week 12. Measurements will include feasibility and acceptability and will explore the effect of the Cecebot intervention. Feasibility will be assessed through recruitment, enrollment, and retention rates. Acceptability will be evaluated using a satisfaction survey and open-ended responses. Quantitative analysis, such as t test, Fisher exact tests, and generalized linear models, will be used to assess feasibility, baseline group differences, and the outcomes of the intervention.

RESULTS: Recruitment of participants began in Fall 2024. The completion of data collection is anticipated to be by Fall 2025.

CONCLUSIONS: The study results will give insight into the potential for an SMS text messaging-based CA to improve sleep in individuals who have survived BC and experience sleep disturbances.

TRIAL REGISTRATION: ClinicalTrials.gov NCT06392789; https://clinicaltrials.gov/study/NCT06392789.

DERR1-10.2196/62712.

RevDate: 2025-07-15

Ishida T, Mercoli J, Heck AM, et al (2025)

Differentiation latency, cell division symmetry, and dormancy signatures define fetal liver HSCs at single cell resolution.

bioRxiv : the preprint server for biology.

Decoding the gene regulatory mechanisms and signaling interactions that orchestrate the self-renewal of hematopoietic stem cells (HSCs) during their expansion in the fetal liver (FL) could unlock novel therapeutic strategies to expand transplantable HSCs, a long-standing challenge. Here, to explore intrinsic and extrinsic regulation of FL-HSC self-renewal at the single cell level, we engineered a culture platform designed to recapitulate the FL endothelial niche, which supports the ex vivo amplification of serially engraftable HSCs. Leveraging this platform in combination with single cell index flow cytometry, live imaging, serial transplantation assays, and single cell RNA-sequencing, we uncovered previously unrecognized heterogeneity within immunophenotypically defined FL-HSCs. Specifically, we demonstrated that differentiation latency, symmetric cell divisions, and transcriptional signatures of biosynthetic dormancy and lipid metabolism are distinguishing properties of rare FL-HSCs capable of serial, long-term multilineage hematopoietic reconstitution. Our findings support a paradigm in which intrinsic programs and extrinsic signals combinatorially facilitate the symmetric self-renewal and expansion of nascent HSCs in the FL niche while delaying their active participation in hematopoiesis. Additionally, our study provides a valuable resource for future investigations into the intrinsic and niche-derived signaling pathways that govern FL-HSC self-renewal.

RevDate: 2025-07-14
CmpDate: 2025-07-14

McGrosky A, Luke A, Arab L, et al (2025)

Energy expenditure and obesity across the economic spectrum.

Proceedings of the National Academy of Sciences of the United States of America, 122(29):e2420902122.

Global economic development has been associated with an increased prevalence of obesity and related health problems. Increased caloric intake and reduced energy expenditure are both cited as development-related contributors to the obesity crisis, but their relative importance remains unresolved. Here, we examine energy expenditure and two measures of obesity (body fat percentage and body mass index, BMI) for 4,213 adults from 34 populations across six continents and a wide range of lifestyles and economies, including hunter-gatherer, pastoralist, farming, and industrialized populations. Economic development was positively associated with greater body mass, BMI, and body fat, but also with greater total, basal, and activity energy expenditure. Body size-adjusted total and basal energy expenditures both decreased approximately 6 to 11% with increasing economic development, but were highly variable among populations and did not correspond closely with lifestyle. Body size-adjusted total energy expenditure was negatively, but weakly, associated with measures of obesity, accounting for roughly one-tenth of the elevated body fat percentage and BMI associated with economic development. In contrast, estimated energy intake was greater in economically developed populations, and in populations with available data (n = 25), the percentage of ultraprocessed food in the diet was associated with body fat percentage, suggesting that dietary intake plays a far greater role than reduced energy expenditure in obesity related to economic development.

RevDate: 2025-07-14

Kanaya AM, GL Anderson (2025)

MOSAAIC to Capture Key Measures of Aging Across the Lifespan.

JAMA internal medicine pii:2836531 [Epub ahead of print].

RevDate: 2025-07-14

Shadman M, Brown JR, Williams R, et al (2025)

Efficacy of zanubrutinib versus acalabrutinib for relapsed or refractory chronic lymphocytic leukemia (R/R CLL): a matching-adjusted indirect comparison (MAIC).

Therapeutic advances in medical oncology, 17:17588359251340554.

BACKGROUND: There are no head-to-head studies comparing the efficacy of the Bruton tyrosine kinase inhibitors, zanubrutinib and acalabrutinib, in relapsed or refractory chronic lymphocytic leukemia (R/R CLL).

OBJECTIVE: To compare the relative efficacy of zanubrutinib and acalabrutinib in R/R CLL using indirect treatment comparison.

DESIGN: An unanchored matching-adjusted indirect comparison (MAIC) was performed.

METHODS: Individual patient-level data from ALPINE (zanubrutinib) were reweighted using prognostic/effect-modifying variables to match aggregate data from ASCEND (acalabrutinib). MAIC outcomes included investigator-assessed progression-free survival (PFS-INV), overall survival (OS), and complete response (CR).

RESULTS: Post-matching, PFS-INV was improved significantly for zanubrutinib versus acalabrutinib (hazard ratio (HR) = 0.68 (95% confidence interval (CI): 0.46-0.99); p = 0.0448) and OS showed a trend toward improvement for zanubrutinib (HR = 0.60; 95% CI: 0.35-1.02, p = 0.0575). CR was significantly higher for zanubrutinib versus acalabrutinib (odds ratio = 2.90 (95% CI: 1.13-7.43); p = 0.0270).

CONCLUSION: Zanubrutinib was associated with a significant PFS-INV and CR advantage over acalabrutinib, with a trend toward improvement in OS.

RevDate: 2025-07-14

Zhang T, Ameen S, Ghosh S, et al (2025)

Enhanced extracellular matrix remodeling due to embedded spheroid fluidization.

New journal of physics, 27(7):073301.

Embedding a collective of tumor cells, i.e. a tumor spheroid, in a fibrous environment, such as a collagen network, provides an essential in vitro platform to investigate the biophysical mechanisms of tumor invasion. To predict new mechanisms, we develop a three-dimensional computational model of an embedded spheroid using a vertex model, with cells represented as deformable polyhedrons, mechanically coupled to a fiber network via active linker springs. As the linker springs actively contract, the fiber network remodels. As we tune the rheology of the spheroid and the fiber network stiffness, we find that both factors affect the remodeling of the fiber network with fluid-like spheroids densifying and radially realigning the fiber network more on average than solid-like spheroids but only for a range of intermediate fiber network stiffnesses. Our predictions are supported by experimental studies comparing non-tumorigenic MCF10A spheroids and malignant MDA-MB-231 spheroids embedded in collagen networks. The spheroid rheology-dependent effects are the result of cellular motility generating spheroid shape fluctuations. These shape fluctuations lead to emergent feedback between the spheroid and the fiber network to further remodel the fiber network. This emergent feedback occurs only at intermediate fiber network stiffness since at low fiber network stiffness, the mechanical response of the coupled system is dominated by the spheroid and for high fiber network stiffness, the mechanical response is dominated by the fiber network. We are therefore able to quantify the regime of optimal spheroid-fiber network mechanical reciprocity. Our results uncover intricate morphological-mechanical interplay between an embedded spheroid and its surrounding fiber network with both spheroid contractile strength and spheroid shape fluctuations playing important roles in the pre-invasion stages of tumor invasion.

RevDate: 2025-07-14

Krawczuk P, Fox ZR, Petkov V, et al (2025)

Large-scale deep learning for metastasis detection in pathology reports.

JAMIA open, 8(4):ooaf070.

OBJECTIVES: No existing algorithm can reliably identify metastasis from pathology reports across multiple cancer types and the entire US population. In this study, we develop a deep learning model that automatically detects patients with metastatic cancer by using pathology reports from many laboratories and of multiple cancer types.

MATERIALS AND METHODS: We use 60 471 unstructured pathology reports from 4 Surveillance, Epidemiology, and End Results (SEER) registries. The reports were coded into 1 of 3 labels: metastasis negative, metastases positive, or metastasis undetermined. We utilize a task-specific deep neural network trained from scratch and compare its performance with a widely used large language model (LLM).

RESULTS: Our deep learning architecture trained on task-specific data outperforms a general-purpose LLM, with a recall of 0.894 compared to 0.824. We quantified model uncertainty and used it to defer reports for human review. We found that retaining 72.9% of reports increased recall from 0.894 to 0.969.

DISCUSSION: A smaller deep learning architecture trained on task-specific data outperforms a general LLM. Equally critical to model performance is the incorporation of uncertainty quantification, achieved here through an abstention mechanism.

CONCLUSIONS: This study's finding demonstrate the feasibility of developing algorithms to automatically identify metastatic cancer cases from unstructured pathology reports.

RevDate: 2025-07-12

Smith D, Fleming T, Gianella S, et al (2025)

Salvaging information from paused or stopped clinical studies.

RevDate: 2025-07-11

Apperley JF, Milojkovic D, Cross NCP, et al (2025)

2025 European LeukemiaNet recommendations for the management of chronic myeloid leukemia.

Leukemia [Epub ahead of print].

In this 5th version of the European LeukemiaNet guidance for adult patients, there are important changes in several areas of management based on evidence available since 2020, including the World Health Organisation's reclassification of CML as a biphasic disease. Previous advice to switch the tyrosine kinase inhibitor (TKI) on failure of molecular milestones, is modified to better account for individual patient circumstances. Our recommendations are summarized in tables designed to be read in conjunction with the text which offers justification and additional advice. We describe decision-making for first-line treatment, both in available drugs and their initial dosing. Similarly we elaborate on dose reduction rather than drug switching to manage toxicities and discuss treatment sequencing. Data have matured for the outcome of treatment discontinuation and for management of parenting for both men and women. We acknowledge that most patients will remain on treatment for many years and emphasize the needs to minimize side effects, manage co-morbidities and optimize quality of life. Recent advances in allogeneic stem cell transplantation have broadened access to alternative donors, and lessened limitations of age and co-morbidities such that transplant remains a valuable option for patients for whom long-term disease control is not achieved through TKI therapy.

RevDate: 2025-07-14

Ellison ST, Hayman I, Derr K, et al (2025)

Limitations of acyclovir and identification of potent HSV antivirals using 3D bioprinted human skin equivalents.

bioRxiv : the preprint server for biology.

Herpes simplex virus (HSV) infection has worldwide public health concerns and lifelong medical impacts. The standard therapy, acyclovir, has limited efficacy in preventing HSV subclinical virus shedding, and drug resistance occurs in immunocompromised patients, highlighting the need for novel therapeutics. HSV manifests in the skin and mucosal epithelium. Here, we found acyclovir significantly less effective in skin-derived keratinocytes than donor-matched fibroblasts. To recapitulate in vivo tissue architecture, we 3D bioprinted human skin equivalents (HSE) in a 96-well plate format amenable for antiviral screening and preclinical testing. We screened a library of 738 compounds with broad targets and mechanisms of action and identified potent antivirals, including 23 known or experimental HSV treatments, validating the translational relevance of our assay. Unlike acyclovir, antivirals against HSV helicase/primase or host replication pathways displayed similar potency across cell types and donor sources in 2D and 3D models. Our 3D bioprinted platform allowed for integrating patient-derived cells and incorporating genetic variability early in drug development. The reduced potency in keratinocytes helps explain the limited benefit acyclovir and its congeners play in reducing sexual transmission. These data indicate that the 3D bioprinted HSE assay platform provides a more physiologically relevant approach to identifying potential antivirals for HSV.

RevDate: 2025-07-14

Chang YH, Bresnahan ST, Head ST, et al (2025)

Isoform-level analyses of 6 cancers uncover extensive genetic risk mechanisms undetected at the gene-level.

medRxiv : the preprint server for health sciences.

Integrating genome-wide association study (GWAS) and transcriptomic datasets can help identify mediators for genetic risk of cancer. Traditional methods often are insufficient as they rely on total gene expression measures and overlook alternative splicing, which generates different transcript-isoforms with potentially distinct effects. Here, we integrate multi-tissue isoform expression data from the Genotype Tissue-Expression Project with GWAS summary statistics (all N > 20,000 cases) to identify isoform- and gene-level associations with six cancers (breast, endometrial, colorectal, lung, ovarian, prostate) and six related cancer subtype classifications (N = 12 total). Directly modeling isoforms using transcriptome-wide association studies (isoTWAS) significantly improves discovery of genetic associations compared to gene-level approaches, identifying 164% more significant associations (6,163 vs. 2,336) with isoTWAS-prioritized genes enriched 4-fold for evolutionarily-constrained genes. isoTWAS tags transcriptomic associations at 52% more independent GWAS loci across the six cancers. Isoform expression mediates an estimated 63% greater proportion of cancer risk SNP heritability compared to gene expression. We highlight several isoTWAS associations that demonstrate GWAS colocalization at the isoform level but not at the gene level, including CLPTM1L (lung cancer), LAMC1 (colorectal), and BABAM1 (breast). These results underscore the importance of modeling isoforms to maximize discovery of genetic risk mechanisms for cancers.

RevDate: 2025-07-14

Frank S, Persse T, Coleman I, et al (2025)

Molecular consequences of acute versus chronic CDK12 loss in prostate carcinoma nominates distinct therapeutic strategies.

bioRxiv : the preprint server for biology.

Genomic loss of the transcriptional kinase CDK12 occurs in ~6% of metastatic castration-resistant prostate cancers (mCRPC) and correlates with poor patient outcomes. Prior studies demonstrate that acute CDK12 loss confers a homologous recombination (HR) deficiency (HRd) phenotype via premature intronic polyadenylation (IPA) of key HR pathway genes, including ATM. However, mCRPC patients have not demonstrated benefit from therapies that exploit HRd such as inhibitors of polyADP ribose polymerase (PARP). Based on this discordance, we sought to test the hypothesis that an HRd phenotype is primarily a consequence of acute CDK12 loss and the effect is greatly diminished in prostate cancers adapted to CDK12 loss. Analyses of whole genome sequences (WGS) and RNA sequences (RNAseq) of human mCRPCs determined that tumors with biallelic CDK12 alterations (CDK12 [BAL]) lack genomic scar signatures indicative of HRd, despite carrying bi-allelic loss and the appearance of the hallmark tandem-duplicator phenotype (TDP). Experiments confirmed that acute CDK12 inhibition resulted in aberrant polyadenylation and downregulation of long genes (including BRCA1 and BRCA2) but such effects were modest or absent in tumors adapted to chronic CDK12 [BAL] . One key exception was ATM, which did retain transcript shortening and reduced protein expression in the adapted CDK12 [BAL] models. However, CDK12 [BAL] cells demonstrated intact HR as measured by RAD51 foci formation following irradiation. CDK12 [BAL] cells showed a vulnerability to targeting of CDK13 by sgRNA or CDK12/13 inhibitors and in vivo treatment of prostate cancer xenograft lines showed that tumors with CDK12 [BAL] responded to the CDK12/13 inhibitor SR4835, while CDK12-intact lines did not. Collectively, these studies show that aberrant polyadenylation and long HR gene downregulation is primarily a consequence of acute CDK12 deficiency, which is largely compensated for in cells that have adapted to CDK12 loss. These results provide an explanation for why PARPi monotherapy has thus far failed to consistently benefit patients with CDK12 alterations, though alternate therapies that target CDK13 or transcription are candidates for future research and testing.

RevDate: 2025-07-14

Gao Y, AF Feder (2025)

Detecting branching rate heterogeneity with tree balance statistics in lineage tracing trees.

bioRxiv : the preprint server for biology.

Understanding variation in cellular growth rates among cells in tumors is crucial for predicting cancer progression and interpreting tumor-derived genetic data. Advances in lineage tracing technologies enable the reconstruction of high-resolution, single-cell phylogenies of cancer cell populations, but methods to detect cellular growth rate differences on these phylogenies remain limited. Tree balance statistics offer a way forward, but it is unknown if and how these statistics are distorted when applied to phylogenetic reconstructions built from lineage tracing data, and if these distortions limit the utility of tree balance statistics to distinguish between evolutionary scenarios characterized by variable or homogeneous cellular growth rates. Here, we examined two tree balance statistics, J 1 and the Sackin index, and benchmarked their performance in distinguishing lineage tracing trees derived from populations with and without variable cellular growth rates. We found that when tumor population sizes and lineage tracing editing rates are approximately known and in favorable ranges, J 1 detects departures from homogenous growth rates just as well on lineage tracing trees as on true genealogical trees, while the Sackin index loses most of its power even under the most favorable conditions. We applied our J 1 -based test to data derived from cancer lineage tracing experiments and found widespread signals of growth rate heterogeneity in murine autochthonous lung cancers, and lung and PDAC xenograft experiments in mice. Our results demonstrate the potential and challenges of tree balance statistics in analyzing growth dynamics in lineage tracing data.

RevDate: 2025-07-11

Huang J, M Shadman (2025)

First-line Therapy: Time-Limited Venetoclax Doublet Therapy.

Hematology/oncology clinics of North America pii:S0889-8588(25)00079-6 [Epub ahead of print].

Studies examining venetoclax in combination with anti-CD20 monoclonal antibodies and covalent Bruton tyrosine kinase inhibitors (BTKi) demonstrated a progression-free survival and in some cases overall survival benefit over chemoimmunotherapy. It is currently unclear what is the most optimal combination partner for a B-cell leukemia/lymphoma 2 inhibitor (BCL2i). We are eagerly awaiting results from studies to determine the most effective BCL2i and BTKi combination for the first-line treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma given the development of second-generation drugs.

RevDate: 2025-07-11

Chiou SH, D Tseng (2025)

Blood TCRs go to town with early NPC detection.

Cancer cell pii:S1535-6108(25)00266-1 [Epub ahead of print].

In this issue of Cancer Cell, Zhang et al. report an innovative approach utilizing patients' blood T cell receptor (TCR) sequences for the early detection of nasopharyngeal cancer. This study highlights the potential of harnessing highly public TCRs in the peripheral blood as biomarkers for virally associated malignancies.

RevDate: 2025-07-11

Koric A, Chang CE, Lee YA, et al (2025)

Incident depression after breast cancer among older Asian, Native Hawaiian, and Pacific Islander women.

JNCI cancer spectrum pii:8196819 [Epub ahead of print].

INTRODUCTION: Longitudinal studies focusing on the mental health of older (≄66 years) Asian, Native Hawaiian, and Pacific Islander (ANHPI) women diagnosed with breast cancer are limited. We evaluated incident depression after breast cancer among specific groups of older ANHPI compared with older non-Hispanic White (NHW) women. Predictors of depression and the risk of death following early onset of depression after breast cancer were also evaluated.

METHODS: A cohort of 26,776 older ANHPI women in the US diagnosed with breast cancer between 2000-2017 was identified from the SEER-Medicare linked claims. There were 6,694 older ANHPI and 20,082 older NHW women diagnosed with breast cancer. Adjusted hazard ratios (HRs) were assessed using Cox proportional hazards model with 99% confidence intervals (CI) to evaluate incident depression and death among older ANHPI compared with age-matched NHW counterparts.

RESULTS: Compared with older NHW women with breast cancer, older Japanese (HR = 0.43, 99%CI 0.31, 0.66), Chinese (HR = 0.46, 99%CI 0.31, 0.67), Filipino (HR = 0.43, 99%CI 0.30, 0.60), and Asian Indian/Pakistani women (HR = 0.49, 99%CI 0.28, 0.84) had a lower risk of depression overall and within 5 years of follow-up; lower risk persisted for Japanese and Chinese women >5 years. ANHPI breast cancer patients with early onset of depression had a higher risk of death (HR = 1.46, 99%CI 1.30, 1.65) compared to those without depression.

CONCLUSION: Compared with older NHW women, older ANHPI women had a lower incidence of depression, although disentangling the stigma surrounding depression by race and ethnicity remains challenging.

RevDate: 2025-07-12

Chakraborty H, Sun Q, Bhupathiraju SN, et al (2025)

The Dietary Biomarkers Development Consortium: An Initiative for Discovery and Validation of Dietary Biomarkers for Precision Nutrition.

Current developments in nutrition, 9(5):107435.

UNLABELLED: Diet is a complex exposure that affects health across the lifespan. Objective biomarkers that can reliably reflect intake of nutrients, foods, and dietary patterns with sufficient accuracy are an important tool for assessing associations of diet with health outcomes. Advances in metabolomics, coupled with feeding trials and high-dimensional bioinformatics analyses, pave the way for discovering compounds that can serve as sensitive and specific biomarkers of dietary exposures. The Dietary Biomarkers Development Consortium (DBDC) is leading the first major effort to improve dietary assessment through the discovery and validation of biomarkers for foods commonly consumed in the United States diet. To achieve this goal, a 3-phase approach will be implemented to identify, evaluate, and validate food biomarkers. In phase 1, 3 controlled feeding trial designs will be implemented by administering test foods in prespecified amounts to healthy participants, followed by metabolomic profiling of blood and urine specimens collected during the feeding trials to identify candidate compounds. Data from these studies will characterize the pharmacokinetic parameters of candidate biomarkers associated with specific foods. In phase 2, the ability of candidate biomarkers to identify individuals eating the biomarker-associated foods will be evaluated using controlled feeding studies of various dietary patterns. In phase 3, the validity of candidate biomarkers to predict recent and habitual consumption of specific test foods will be evaluated in independent observational settings. Data generated during all study phases will be archived in a publicly accessible database as a resource for the research community. The DBDC aims to significantly expand the list of validated biomarkers of intake for foods consumed in the United States diet, which can help advance understanding of how diet influences human health. This manuscript discusses the DBDC's organizational infrastructure, study design, laboratory methods, and strategies for dietary biomarker discovery and validation.

TRIAL REGISTRATION NUMBER: This trial was registered at Phase 1 Seattle Dietary Biomarkers Development Center (P1-SDBDC) as NCT05580653, at Fruit and Vegetable Biomarker Discovery (UCD-DBDC) as NCT05621863, and at Dietary Biomarkers Intervention Core as NCT05616585.

RevDate: 2025-07-10

Cai Y, Johnson M, Haessler J, et al (2025)

Protein quantitative trait locus analysis in African American and non-Hispanic White individuals.

Genome biology, 26(1):200.

BACKGROUND: Substantial efforts have been dedicated to exploring the link between genetic regulation and the proteome, informing studies of complex trait mechanisms. Most of these efforts have been limited to populations of European ancestry.

RESULTS: We conduct an Olink protein quantitative trait locus (pQTL) analysis on 1245 proteins involving 1033 self-identified African American (AA) and 1764 non-Hispanic White (NHW) participants from the Women's Health Initiative and Framingham Heart Study. For replication of candidate pQTLs, we use data from 534 self-identified AA adults from the Jackson Heart Study and protein genome-wide association analysis statistics from the UK Biobank Pharma Proteomics Project, including 54,219 participants, of whom 931 are of African ancestry. In total, we identify and validate 5103 pQTLs (4496 or 88% cis- and 602 or 12% trans-pQTLs) for 983 proteins. Among these, 195 are previously unreported, with most (166 or 85%) identified in our AA sample, many of which were essentially monomorphic in European reference populations. Several of these newly identified African ancestry-specific pQTLs have been reported in ClinVar; our results suggest impact on circulating protein levels, potentially bolstering evidence for clinical significance. We identify a "cis pQTL hotspot" within the leukocyte receptor gene cluster on human chromosome 19q13.4. We also provide examples where a particular cis-pQTL, identified through conditional analysis, offers biological insights into an overlapping GWAS signal for disease susceptibility.

CONCLUSIONS: The identification of previously undescribed African ancestry-specific pQTLs contributes to understanding protein genetic regulation and highlights the significance of proteomic analysis in diverse populations.

RevDate: 2025-07-10

Zheng C, Casjens SR, Davidson AR, et al (2025)

Lambdoid phages with abundant Chi recombination hotspots reflect diverse viral strategies for recombination-dependent growth.

Genome research pii:gr.280248.124 [Epub ahead of print].

Many phages encode recombination-mediating enzymes, but characterization of their roles in phage lifecycles is limited, and their impact on phage replication is controversial. To address these issues, we have searched for phages whose growth is impacted by the major recombination-promoting helicase-nuclease of Escherichia coli, the RecBCD enzyme. Although no phages inhibited by RecBCD are identified, growth of a newly isolated phage, named LLS, is enhanced by RecBCD. LLS's genome sequence reveals it is related to bacteriophage Ī» but encodes no recombination-promoting (Rec) proteins or associated RecBCD inhibitor. However, it contains an unexpectedly high number of Chi sites, activators of RecBCD-dependent recombination. Through analysis of 325 genomes of phages related to Ī» (lambdoid phages), we have found 71 other phage genomes that encode no Rec proteins but mostly possess large numbers of Chi sites. Conversely, phages encoding Rec proteins and a RecBCD inhibitor (collectively a Rec module) mostly lack Chi sites. Lambdoid phages of both diverse enteric bacteria and a pseudomonad have these properties. For this study, we thoroughly analyze the Rec modules of 246 lambdoid phage genomes. These analyses reveal a remarkable heterogeneity of Rec module protein types, both in sequence and in function, and allow us to identify phages that do not contain Rec modules. We conclude that phages lacking their own recombination systems have compensated by becoming enriched in Chi sites, enabling them to use the host's RecBCD to fulfill the requirement for recombination to efficiently replicate. This study highlights the importance of recombination for phage survival and the diversity of strategies to achieve it.

RevDate: 2025-07-10

Parnes M, Gonzalez E, Tran N, et al (2025)

Adherence to 24-Hour Movement Guidelines and Behavioral Health in Children With Attention Deficit Hyperactivity Disorder in the United States.

Journal of physical activity & health [Epub ahead of print].

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is a 24-hour disorder that both impacts, and, is impacted by, daily activity and sleep. Children with ADHD are less likely to meet recommended 24-hour movement guidelines (ie, on average 60 min of moderate to vigorous physical activity and several hours of light activity per day, less than 2 h of screen time, and 9-11 h of sleep). The current study examined associations between meeting 24-hour movement guidelines with ADHD symptoms, sleep problems, and media use.

METHODS: Accelerometer data measured physical activity and sleep among a sample of 93 children with ADHD (mean age = 8.10, SDage = 1.37, 58.9% male). Parent-report measures assessed ADHD symptoms, sleep difficulties, and media use. Multivariate analysis of covariance analyses explored associations between meeting 24-hour movement guidelines and outcomes. Latent class analysis (LCA) identified unique combinations of 24-hour movement guideline adherence. Associations were examined between classes and outcomes.

RESULTS: Overall, 41.5% of children met physical activity guidelines, 23.4% met sedentary behavior guidelines, and 45.7% met sleep guidelines. Multivariate analysis of covariance analyses found that meeting more guidelines was associated with less sleep difficulties and problematic media use. LCA revealed 2 classes: Hypoactive children who were unlikely to meet activity guidelines and Work Hard, Play Hard children who were likely to meet activity and sleep guidelines. Children in the Work Hard, Play Hard class had less bedtime resistance compared with the Hypoactive class.

CONCLUSION: Findings have implications for clinicians and caregivers supporting children with ADHD to take a holistic approach to improve health behaviors throughout the whole day.

RevDate: 2025-07-10

Dima D, Logue JM, Waqar SHB, et al (2025)

Cytopenias and infections following ciltacabtagene autoleucel in heavily-pretreated relapsed or refractory multiple myeloma.

Haematologica [Epub ahead of print].

Ciltacabtagene autoleucel (cilta-cel) was FDA-approved in February 2022 for the treatment of relapsed/refractory multiple myeloma after 4 lines of therapy. On CARTITUDE-1 trial, grade ≄3 cytopenias and infections were common. Herein, we sought to characterize cytopenias and infections after cilta-cel infusion in the standard-of-care setting. This multicenter retrospective study included 105 patients who received cilta-cel; 91 reached day-90 and 49 reached day-180 follow-up. Grade ≄3 cytopenia was present among 52% of patients on day-30, and 24% of patients on day-90. Based on the newer immune effector cell-associated hematotoxicity (ICAHT) grading for neutropenia severity, 11 patients (10%) experienced grade ≄3 early ICAHT in the first 30 days, while only 3 (3.3%) experienced grade ≄3 late ICAHT after day-30. On univariate analysis, any grade thrombocytopenia at apheresis was associated with grade ≄3 cytopenia at both days 30 and 90. Granulocyte colony-stimulating factor was administered to 65%, transfusion support to 38%, thrombopoietin agonists to 10%, intravenous immunoglobulin to 52%, and CD34+ stem cell boosts to 9.5% of patients. Infections occurred in 49% of patients and were severe in 32%. Earlier infections in the first 30 days were equally bacterial (42%) and viral (42%). Later infections between days 31-100 and after day 100 were mostly viral (59% and 60%), with only 32% and 12% being grade ≄3 at each time period. On univariate analysis, worse ECOG performance status at lymphodepletion, higher maximum grade of CRS, delayed neurotoxicity, steroid and anakinra use, and lower IgA levels at day 90 were associated with severe infections.

RevDate: 2025-07-09

Rosenthal EA, Wei WQ, Luo Y, et al (2025)

Phenome-wide association study identifies multiple traits associated with a polygenic risk score for colorectal cancer.

Human genomics, 19(1):77 pii:10.1186/s40246-025-00791-0.

BACKGROUND: Many factors, including environmental and genetic variables, contribute to Colorectal Cancer (CRC) risk. The genetic components of risk can be divided into monogenic and polygenic factors. Just as monogenic factors can increase risk for more than one condition, polygenic factors may also underlie multiple phenotypes, including behavioral traits. In order to understand the biology of CRC risk better, it is important to understand the shared polygenic genetic architecture contributing to CRC risk and other phenotypes, including CRC associated risk factors.

METHODS: We investigated potential shared genetics by performing a Phenome-wide association study (PheWAS) with a multi-ancestry CRC polygenic risk score (PRS). The discovery cohort (N = 426,464) consisted of ancestrally diverse participants from the United Kingdom Biobank. The replication cohort (N = 87,271) consisted of ancestrally diverse participants from the electronic Medical Records and Genomics Network phase 3. We used a mixed-effects model to adjust for the presence of related individuals. To preserve power, we limited the number of tests by restricting analysis to ancestor phecodes derived from the electronic health record (EHR) that were not likely to be a result of CRC or its treatment.

RESULTS: We discovered and replicated associations between the CRC PRS and breast cancer, prostate cancer, obesity, smoking and alcohol use (discovery p < 1.1e-4; replication p < 0.0019). The association between CRC risk and prostate cancer may be a novel finding, whereas the association with breast cancer has been previously observed using orthogonal methods. The association between CRC risk and behavioral risk factors corroborate previous studies, also using orthogonal methods, and may reveal potential prevention or treatment strategies.

CONCLUSIONS: As these results corroborate findings from other studies using orthogonal methods, we demonstrate that a CRC PRS can be used as a proxy for genetic risk for CRC when investigating shared genetics between CRC and other phenotypes. Further study of the relationship between PRS from multiple traits with EHR data may reveal additional shared genetic factors. Ultimately, understanding these underlying genetic correlations may identify prevention and treatment strategies for CRC.

RevDate: 2025-07-09

Tortorici MA, Choi A, Gibson CA, et al (2025)

Loss of FCoV-23 spike domain 0 enhances fusogenicity and entry kinetics.

Nature [Epub ahead of print].

The ability of coronaviruses to recombine and cross species barriers affects human and animal health globally and is a pandemic threat[1,2]. FCoV-23 is a recently emerged, highly pathogenic recombinant coronavirus responsible for a widespread outbreak of feline infectious peritonitis. Here we report cryogenic electron microscopy structures of two FCoV-23 spike isoforms that correspond to the in-host loss of domain 0 observed in clinical samples. The loss of domain 0 markedly enhances the fusogenicity and kinetics of entry into cells and possibly enables biotype switching and lethality. We show that FCoV-23 can use several aminopeptidase N orthologues as receptors and reveal the molecular determinants of receptor species tropism, including a glycan that modulates human receptor engagement. We define antigenic relationships among alphacoronaviruses that infect humans and other mammalian species and identify a cross-reactive alphacoronavirus monoclonal antibody that inhibits FCoV-23 entry. Our results pave the way for the development of vaccines and therapeutics that target this highly pathogenic virus.

RevDate: 2025-07-09

Chari ST, Wu B, Lopez C, et al (2025)

RISK OF PANCREATIC CANCER IN GLYCEMICALLY DEFINED NEW-ONSET DIABETES: A PROSPECTIVE COHORT STUDY.

Gastroenterology pii:S0016-5085(25)05730-0 [Epub ahead of print].

BACKGROUND: Increased 3-year incidence of pancreatic cancer following new-onset diabetes (NOD) observed in retrospective studies needs prospec4ive validation. It is unknown if incidence varies by race/ethnicity.

METHODS: In a prospective, observational study using active real-time surveillance of electronic health records we identified 18,838 adults >50 years of age with NOD defined by glycemic criteria (GNOD). In this interim analysis, we report 3-year Kaplan-Meier estimates of proportion diagnosed with pancreatic cancer following GNOD (absolute incidence (95% Confidence Intervals)) and associated Standardized Incidence Ratio (SIR) by race/ethnicity; overall 3-year incidence of pancreatic cancer adjusting for racial distribution of incident diabetes in the United States; and interval between GNOD and pancreatic cancer diagnosis.

RESULTS: During median follow-up of 2.3 years, 82 pancreatic cancers have been diagnosed (60% male, mean age 71±8 years). The 3-year estimates for proportion diagnosed with pancreatic cancer (95% CI) and associated SIR (95% CI) by race/ethnicity were: non-Hispanic Whites (n=6,518) 0.84% (CI: 0.60, 1.07) (SIR 6.4 (CI: 4.8, 8.4)); Hispanics (n=5,984) 0.40% (0.20, 0.60) (SIR 4.2 (2.6, 6.3)); African Americans (n=2,192) 0.37% (0.07, 0.67) (SIR 2.4 (1.0, 5.0), and Asian/Pacific Islander (n=3,360) 0.22% (.06, 0.39) (SIR 3.0 (1.4, 6.0). Overall, race-adjusted 3-year pancreatic cancer incidence was 0.62%. On average GNOD occurred 8 months prior to clinical diagnosis; 0-4 months in 30.5%, 4-12 months in 31.3%, 12-24 months in 19.5%, and 24-36 months in 18.7%.

CONCLUSIONS: Glycemically defined new-onset diabetes, identifiable in real-time using active surveillance of electronic health records, is associated with a high 3-year incidence of pancreatic cancer with marked racial/ethnic differences. Longer term risk needs further study.

RevDate: 2025-07-09

Ramachandran D, Wang X, Laisk T, et al (2025)

GWAS meta-analysis identifies five susceptibility loci for endometrial cancer.

EBioMedicine, 118:105830 pii:S2352-3964(25)00274-9 [Epub ahead of print].

BACKGROUND: Endometrial cancer is the most common gynaecological cancer in high-income countries. In addition to environmental risk factors, genetic predisposition contributes towards endometrial cancer development but is still incompletely defined.

METHODS: Building on genome-wide association studies (GWASs) by the Endometrial Cancer Association Consortium, we conducted a GWAS meta-analysis of 17,278 endometrial cancer cases and 289,180 controls, incorporating biobank samples from the UK, Finland, Estonia and Japan.

FINDINGS: GWAS analysis identified five additional risk loci (3p25.2, 3q25.2, 6q22.31, 12q21.2, and 17q24.2). Corresponding gene-based analyses supported findings for three of the five loci, at NAV3 (12q21.2), PPARG (3p25.2), and BPTF (17q24.2), as well as two additional candidate risk regions at ATF7IP2 (16p13.2-p13.13) and RPP21 (6p22.1). Validation genotyping in further independent case-control series replicated the most significant locus at 12q21.2 and corroborated risk variants located intronic to NAV3, the gene for Neuron Navigator 3. Downregulation of NAV3 in endometrial cell lines accelerated cell division and wound healing capacity whereas NAV3 overexpression reduced cell survival and increased cell death, indicating that NAV3 acts as a tumour suppressor in endometrial cells.

INTERPRETATION: Our large study extends the number of genome-wide significant risk loci identified for endometrial carcinoma by about one-third and proposes a role of NAV3 as a tumour suppressor in this common cancer.

FUNDING: This study was mainly supported by funding from the Wilhelm Sander Foundation, Germany, and the National Health and Medical Research Council (NHMRC) of Australia. A complete list of funding organisations is provided in the acknowledgements.

RevDate: 2025-07-09
CmpDate: 2025-07-09

Anbil S, Seewald NJ, Chiorean EG, et al (2025)

LODESTAR: A Single-Arm Phase II Study of Rucaparib in Solid Tumors With Pathogenic Germline or Somatic Variants in Homologous Recombination Repair Genes.

JCO precision oncology, 9:e2500090.

PURPOSE: To explore poly (ADP-ribose) polymerase inhibitor utility across solid tumors and identify biomarkers that predict sensitivity.

PATIENTS AND METHODS: This single-arm phase II study assessed rucaparib monotherapy in patients with solid tumors and pathogenic variants (PVs) in BRCA1, BRCA2, PALB2, RAD51C, and RAD51D (cohort A) or BARD1, BRIP1, FANCA, NBN, and RAD51B (cohort B). The primary end point was overall response rate (ORR) in cohort A. Secondary end points included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. A scar-based homologous recombination deficiency signature (HRDsig) and platinum sensitivity status were explored post hoc.

RESULTS: Fifty-one patients in cohort A and 12 in cohort B were evaluable for efficacy. ORR of cohort A was 18% (95% CI, 10 to 30). A significantly higher ORR was observed with HRDsig+ tumors compared with HRDsig- tumors (32%; 95% CI, 15 to 54 v 0%; 95% CI, 0 to 14; P < .01). In the entire study population, DCR was 65% (95% CI, 53 to 76), median PFS (mPFS) 5.5 months (95% CI, 3.68 to 7.82), and median OS 12.1 months (95% CI, 10.6 to inferred). PFS and hazard of death from any cause was significantly better for platinum-sensitive tumors (mPFS: 7.8 months v 3.5 months; P = .02; hazard ratio, 0.11 [95% CI, 0.02 to 0.55]). Tumor histology was not independently predictive of outcome. Tumors with PVs in cohort A genes were more likely to be HRDsig+ than tumors with PVs in cohort B genes. Analysis of a large commercial database showed that in noncanonical tumors with BRCA PVs, 30.2% were HRDsig+.

CONCLUSION: Rucaparib has activity in HRDsig+ solid tumors with PVs in homologous recombination repair genes, regardless of histology. Platinum sensitivity correlated with improved outcomes.

RevDate: 2025-07-09

Raychaudhuri R, Lin DW, RB Montgomery (2025)

Complexity of Prostate Cancer-Reply.

JAMA pii:2836254 [Epub ahead of print].

RevDate: 2025-07-09

Han C, Zhang Z, Crosse EI, et al (2025)

An isoform-specific RUNX1C-BTG2 axis governs AML quiescence and chemoresistance.

Blood cancer discovery pii:763512 [Epub ahead of print].

Aberrant levels or structures of RNA isoforms are a hallmark of many cancers, including acute myeloid leukemia (AML), yet its role in AML chemoresistance remains unclear. We conducted a paired analysis of RNA isoform changes in AML patients before therapy and at relapse post-chemotherapy, identifying and identified intragenic DNA methylation at the proximal promoter of the transcription factor RUNX1, which resulted in elevated expression of the long isoform RUNX1C through its alternative distal promoter. The N-terminal region of RUNX1C orchestrated an isoform-specific transcriptional program that promoted chemoresistance, with its direct target BTG2 playing a role in chemotherapy resistance. BTG2 promoted ribosomal RNA deadenylation, resulting in decreased mRNA expression and stability. Deletion of ribosomal RNA's increased cellular quiescence. Moreover, RNA-based targeting of RUNX1C reactivated quiescent leukemia cells and enhanced chemotherapy efficacy. These findings delineate an isoform-specific transcriptional circuit that governs chemotherapy response, providing a potential therapeutic strategy to mitigate AML recurrence.

RevDate: 2025-07-09

Razzo BM, Midha S, Portuguese AJ, et al (2025)

Real-World Experience with Teclistamab for Relapsed/ Refractory Multiple Myeloma from the U.S. Myeloma Immunotherapy Consortium.

Blood cancer discovery pii:763462 [Epub ahead of print].

Teclistamab is an anti-CD3xBCMA bispecific antibody approved for use in relapsed/refractory multiple myeloma (MM). We undertook a retrospective study of post-approval, real-world outcomes with teclistamab in the U.S. MM Immunotherapy Consortium. Among 509 patients, 89% would have been ineligible for the MajesTEC-1 trial, primarily due to prior BCMA-directed therapy, cytopenias, or diminished performance status. Cytokine release syndrome occurred in 54% (1.4% grade ≄3) and immune effector cell-associated neurotoxicity syndrome in 11% (2.2% grade ≄3) with no fatal events. Infections occurred in 42% and contributed to death in 5%. Partial response (PR) or better was achieved in 53% and very good PR (VGPR) or better in 45%. With 10.1 months median follow-up, estimated median progression-free survival (PFS) was 5.8 months, and 12-month overall survival was 61%. Independent predictors of

RevDate: 2025-07-08

Simar SR, Tran TT, Rydell KB, et al (2025)

Clinical and Genomic Characterization of Recalcitrant Enterococcal Bacteremia: A Multicenter Prospective Cohort Study (VENOUS).

The Journal of infectious diseases pii:8193993 [Epub ahead of print].

BACKGROUND: Patients with recalcitrant enterococcal bloodstream infections are at greater risk of adverse outcomes. We identified patients in the 2016-2022 Vancomycin-Resistant Enterococcal Bacteremia Outcomes Study (VENOUS) cohort experiencing recalcitrant bloodstream infections for further clinical and genomic characterization.

METHODS: Bacteremia episodes were considered "persistent" if there was a lack of clearance on day four while receiving ≥ 48 hours of active therapy and recurrent if there was clearance during hospitalization with a subsequent positive culture (collectively, "recalcitrant" bacteremia). A matched comparison group of non-recalcitrant bacteremia patients was chosen in a 2:1 control:case ratio. Isolates were subjected to short- and long-read whole-genome sequencing. Hybrid assemblies were created using a custom pipeline.

FINDINGS: A total of 46 recalcitrant infections from 41 patients were identified. Patients with persistent bacteremia were more often admitted to the ICU upon admission relative to controls. E. faecalis strains causing persistent infections had a significantly higher proportion of genes associated with carbohydrate utilization relative to controls. Representation of functional groups associated with mutated genes was disparate between E. faecium and E. faecalis index and persistent isolates, suggesting species-specific adaptation.

DISCUSSION: Enterococcal isolates causing recalcitrant bacteremia were genomically diverse, indicating that strain-specific signatures are not drivers of persistence. However, comparisons of index vs. persistent isolates revealed that E. faecium may be genetically pre-adapted to cause persistent infection, and site-specific structural variation during infection suggests the role of differential gene expression in adaptation and persistence. This data lays groundwork for future studies to define signatures of enterococcal adaptation during bacteremia.

RevDate: 2025-07-08
CmpDate: 2025-07-08

Li Z, Yang W, Wu G, et al (2025)

Inferring chromosome segregation error stage and crossover in trisomic disorders with application to Down syndrome.

Nature communications, 16(1):6316.

Errors in chromosome segregation during gametogenesis, such as nondisjunction (NDJ) errors, have severe consequences in human reproduction, and a better understanding of their etiology is of fundamental interest in genetics. Mapping NDJ errors to meiotic/mitotic stages typically requires proband-parent comparison, limiting its applicability. Herein, we develop Mis-segregation Error Identification through Hidden Markov Models (MeiHMM), a method for inferring NDJ error stage and crossover events based on only genomic data of trisomic probands. Guided by triallelic genotype/haplotype configurations, MeiHMM discerns the allelic origin at each locus, which informs NDJ error during gamete formation, without identifying the parental origin of the trisomy. In 152 Down syndrome (DS) cases, MeiHMM achieved an accuracy of 96.1% in classifying NDJ errors, with a sensitivity of 91.6% in crossover identification, compared to proband-parents trio analysis. 17% of Meiosis II errors were misclassified as Meiosis I, mainly due to small proximal crossover events. Applying MeiHMM to 509 children with DS-associated childhood leukemia, we demonstrate that NDJ error is associated with the age of disease onset, somatic genomic abnormalities, and prognosis. Thus, MeiHMM is an effective method for trisomic NDJ error classification and crossover identification that can be applied broadly to study the etiology of congenital aneuploidy conditions.

RevDate: 2025-07-08

Farrell-Sherman A, de la Force N, Prator CA, et al (2025)

Antiviral Monocytes Increase Prior to Detectable HIV-1 Rebound Viremia.

The Journal of infectious diseases pii:8193933 [Epub ahead of print].

The persistence of HIV-1 proviruses in latently infected cells allows viremia to resume upon treatment cessation. To characterize the resulting immune response, we compare plasma proteomics and single-cell transcriptomics of peripheral blood mononuclear cells (PBMCs) before, during, and after detectable plasma viremia. We observe unique transcriptional signatures prior to viral rebound including a significant increase in CD16++ monocytes with increased antiviral gene expression. Inflammatory proteins were identified in plasma after detectable rebound. Identifying early signals of imminent viral rebound after treatment cessation will aid in the development of strategies to prolong time to viral rebound and cure HIV-1.

RevDate: 2025-07-08

Paatela EM, St Amant FG, Hamm DC, et al (2025)

A discrete region of the D4Z4 is sufficient to initiate epigenetic silencing.

Human molecular genetics pii:8193856 [Epub ahead of print].

The DUX4 transcription factor is briefly expressed in the early embryo and is epigenetically repressed in somatic tissues. Loss of epigenetic repression can result in the aberrant expression of DUX4 in skeletal muscle and can cause facioscapulohumeral dystrophy (FSHD). Multiple factors have been identified as necessary to maintain epigenetic silencing of DUX4 in skeletal muscle, but whether specific sequences at the DUX4 locus are sufficient for initiating epigenetic silencing has not been known. We cloned fragments of the D4Z4 macrosatellite repeat, the DNA region that encompasses the DUX4 retrogene, adjacent to a reporter driven by a constitutive promoter and identified a single fragment sufficient to epigenetically repress reporter gene expression. Previously identified repressors of DUX4 expression-SETDB1, ATF7IP, SIN3A/B, and LRIF1-were necessary for silencing activity and p38 inhibitors enhanced suppression. These findings identify a key regulatory sequence for D4Z4 epigenetic repression and establish a model system for mechanistic and discovery studies.

RevDate: 2025-07-08
CmpDate: 2025-07-08

Chatterjee S, Rückert T, Martin I, et al (2025)

Gut microbiota-derived TMAVA is a modulator of acute CNS-GVHD.

The Journal of experimental medicine, 222(9):.

Acute graft-versus-host disease (aGVHD) can affect the central nervous system (CNS) through microglial activation and T cell infiltration, but the role of gut microbiota in CNS-aGVHD remains unclear. Here, we investigated the role of microbiota in microglial activation during aGVHD using antibiotic-treated specific pathogen-free (SPF), germ-free (GF), and wildling mice. Antibiotic-mediated microbiota depletion led to infiltration of IFN-γ-producing T cells in the brain, activation of microglia via the TLR4/p38 MAPK pathway, and neurocognitive deficits in SPF aGVHD mice. Microglial depletion reversed the neurocognitive deficits. GF and wildling mice treated with antibiotics exhibited similar microglial activation after allogeneic hematopoietic cell transplantation (allo-HCT). Mechanistically, the bacteria-derived metabolite N,N,N-trimethyl-5-aminovaleric acid (TMAVA) was decreased in microglia following antibiotic treatment. TMAVA administration suppressed TLR4/p38 MAPK pathway activity in microglia and alleviated gut microbiota depletion-mediated neurocognitive deficits. Additionally, TMAVA abundance decreased in patient blood after allo-HCT and after GVHD onset. In summary, we identify TMAVA loss as a central causative factor for CNS-aGVHD, opening new perspectives for a metabolite-based therapy.

RevDate: 2025-07-07

Baele G, Ji X, Hassler GW, et al (2025)

BEAST X for Bayesian phylogenetic, phylogeographic and phylodynamic inference.

Nature methods [Epub ahead of print].

Here we present the open-source and cross-platform BEAST X software that combines molecular phylogenetic reconstruction with complex trait evolution, divergence-time dating and coalescent demographics in an efficient statistical inference engine. BEAST X significantly advances the flexibility and scalability of evolutionary models supported. Novel clock and substitution models leverage a large variety of evolutionary processes; discrete, continuous and mixed traits with missingness and measurement errors; and fast, gradient-informed integration techniques that rapidly traverse high-dimensional parameter spaces.

RevDate: 2025-07-07

Templin T, Fort S, Padmanabham P, et al (2025)

Framework for bias evaluation in large language models in healthcare settings.

NPJ digital medicine, 8(1):414.

A critical gap in the adoption of large language models for AI-assisted clinical decisions is the lack of a standardized audit framework to evaluate models for accuracy and bias. Our framework introduces a five-step framework that guides practitioners through stakeholder engagement, model calibration to specific patient populations, and rigorous testing through clinically relevant scenarios. We provide open-access tools for stakeholder engagement and an example of an audit. As the regulation of models becomes more critical, we believe adoption of an audit framework that tests model outputs, rather than regulating specific hyperparameters or inputs, will encourage the responsible use of AI in clinical settings.

RevDate: 2025-07-07

Aragaki AK, Manson JE, LeBlanc ES, et al (2025)

Development and Validation of Body Mass Index-Specific Waist Circumference Thresholds in Postmenopausal Women : A Prospective Cohort Study.

Annals of internal medicine [Epub ahead of print].

BACKGROUND: A 2020 consensus statement proposed body mass index (BMI)-specific waist circumference (WC) thresholds to improve patient care.

OBJECTIVE: To determine whether stratifying BMI categories by BMI-specific WC thresholds improves mortality risk prediction.

DESIGN: Prospective cohort study.

SETTING: Women's Health Initiative multicenter, population-based U.S. study, with enrollment from 1993 to 1998 and follow-up through 2021.

PARTICIPANTS: 139 213 postmenopausal women aged 50 to 79 years were included in a development cohort (n = 67 774) and 2 external validation cohorts. Validation Cohort 1 had high prevalence of overweight or obesity (n = 48 335), and Validation Cohort 2 included diverse, geographically separate centers (n = 23 104).

MEASUREMENTS: Height, weight, and WC measured at enrollment. BMI categories were normal weight (18.5 to <25 kg/m[2]), overweight (25 to <30 kg/m[2]), obesity-1 (30 to <35 kg/m[2]), obesity-2 (35 to <40 kg/m[2]), and obesity-3 (≥40 kg/m[2]), with further stratification by prespecified WC thresholds (≥80, ≥90, ≥105, ≥115, and ≥115 cm, respectively). Mortality was ascertained annually and was supplemented with serial National Death Index queries. Ten- and 20-year mortality prediction models that included BMI categories were compared to models with BMI categories stratified by WC thresholds using c-statistics and continuous net reclassification improvement (NRI).

RESULTS: Over a median of 24 years of follow-up, 69 297 participants died. Multivariable-adjusted mortality risk was consistently greater for BMI categories with large WC than those with normal WC. Compared with women with normal weight and normal WC, women with normal or overweight BMI but large WC (hazard ratios [HRs], 1.17 [95% CI, 1.12 to 1.21] and 1.19 [CI, 1.15 to 1.24], respectively) had risk similar to those with obesity-1 but normal WC (HR, 1.12 [CI, 1.08 to 1.16]). Mortality associated with obesity-1 and large WC (HR, 1.45 [CI, 1.35 to 1.55]) was similar to that with obesity-3 and normal WC (HR, 1.40 [CI, 1.28 to 1.54]). Models with BMI-specific WC thresholds improved discrimination and risk stratification at 10 years for Validation Cohort 1; c-statistics improved by 0.7% (CI, 0.3% to 1.0%) to 61.3% (CI, 60.2% to 62.5%), and continuous NRI was 20.4% (CI, 17.3% to 23.6%). Results were mixed for Validation Cohort 2; risk stratification improved (continuous NRI, 12.3% [CI, 8.5% to 16.0%]), but not discrimination. Results were similar at 20 years.

LIMITATION: The study did not include men or younger women.

CONCLUSION: Further stratifying BMI categories by WC thresholds modestly improved mortality risk stratification, with larger WC predicting greater mortality, although the degree of improvement varied by cohort. Discrimination did not improve consistently.

PRIMARY FUNDING SOURCE: National Heart, Lung, and Blood Institute of the National Institutes of Health.

RevDate: 2025-07-07
CmpDate: 2025-07-07

Montano-Campos JF, Hahn E, Haupt E, et al (2025)

Using Early Biomarker Change and Treatment Adherence to Predict Risk of Relapse Among Patients With Chronic Myeloid Leukemia Who Are in Remission.

JCO clinical cancer informatics, 9:e2500003.

PURPOSE: There is little guidance for decision making in chronic myeloid leukemia (CML) after patients achieve molecular remission. Our study addresses this gap by developing a risk prediction model for molecular relapse using early longitudinal factors, such as BCR::ABL1 biomarker-level changes and treatment adherence.

METHODS: We analyzed electronic health record data of patients with CML diagnosed between 2007 and 2019 from an integrated health system. We used a time-to-event modeling framework using a Cox proportional hazards approach where we evaluated time from molecular remission to molecular relapse. The main predictors were early changes in BCR::ABL1 levels from treatment initiation to the first follow-up measurement (typically around 3 months) and treatment adherence in the first 6 months, categorized as perfect (≥0.98) or less-than-perfect (<0.98). Model performance was assessed through five-fold cross-validation combined with 100 Monte Carlo bootstrapping iterations to ensure robustness and minimize bias.

RESULTS: Patients with early improvement in BCR::ABL1 levels had a 70% lower risk relapse (hazard ratio [HR], 0.30 [95% CI, 0.15 to 0.59]) compared with those without early molecular response. Perfect adherence during this critical early phase of treatment was associated with a 56% lower relapse risk (HR, 0.44 [95% CI, 0.22 to 0.85]). Predictive accuracy was high at 6 months (AUC, 0.90; 95% CI, 0.87 to 0.95) and 1-year postremission (AUC, 0.78; 95% CI, 0.74 to 0.81). Relapse risk was significantly higher among Black, Asian, and Hispanic patients compared with non-Hispanic White patients.

CONCLUSION: Early biomarker trends and adherence after treatment initiation are critical for accurately predicting relapse among patients who achieve molecular remission. The proposed model addresses a gap in guidance after molecular remission and has the potential to enable personalized monitoring and optimize surveillance strategies, offering transformative potential for CML care.

RevDate: 2025-07-07

Jochim B, Topalidou I, N Lehrbach (2025)

Protein sequence editing defines distinct and overlapping functions of SKN-1A/Nrf1 and SKN-1C/Nrf2.

PLoS genetics, 21(7):e1011780 pii:PGENETICS-D-25-00366 [Epub ahead of print].

The Nrf/NFE2L family of transcription factors regulates redox balance, xenobiotic detoxification, metabolism, proteostasis, and aging. Nrf1/NFE2L1 is primarily responsible for stress-responsive upregulation of proteasome subunit genes and is essential for adaptation to proteotoxic stress. Nrf2/NFE2L2 is mainly involved in activating oxidative stress responses and promoting xenobiotic detoxification. Nrf1 and Nrf2 contain very similar DNA binding domains and can drive similar transcriptional responses. In C. elegans, a single gene, skn-1, encodes distinct protein isoforms, SKN-1A and SKN-1C, that function analogously to mammalian Nrf1 and Nrf2, respectively, and share an identical DNA binding domain. Thus, the extent to which SKN-1A/Nrf1 and SKN-1C/Nrf2 functions are distinct or overlapping has been unclear. Regulation of the proteasome by SKN-1A/Nrf1 requires post-translational conversion of N-glycosylated asparagine residues to aspartate by the PNG-1/NGLY1 peptide:N-glycanase, a process we term 'sequence editing'. Here, we reveal the consequences of sequence editing for the transcriptomic output of activated SKN-1A. We confirm that activation of proteasome subunit genes is strictly dependent on sequence editing. In addition, we find that sequence edited SKN-1A can also activate genes linked to redox homeostasis and xenobiotic detoxification that are also regulated by SKN-1C, but the extent of these genes' activation is antagonized by sequence editing. Using mutant alleles that selectively inactivate either SKN-1A or SKN-1C, we show that both isoforms promote optimal oxidative stress resistance, acting as effectors for distinct signaling pathways. These findings suggest that sequence editing governs SKN-1/Nrf functions by tuning the SKN-1A/Nrf1 regulated transcriptome.

RevDate: 2025-07-07

Perales MA, Awan FT, Boumendil A, et al (2025)

Outcomes of Allogeneic HCT in Hodgkin Lymphoma in the Era of Checkpoint Inhibitors: A Joint CIBMTR and EBMT Analysis.

Blood pii:546085 [Epub ahead of print].

Checkpoint inhibitors (CPI) have shown remarkable efficacy in patients with Hodgkin lymphoma (HL) and are now used routinely for this disease. While allogeneic hematopoietic cell transplantation (alloHCT) remains a curative option for HL, there are concerns that prior CPI may exacerbate post alloHCT complications, particularly graft-versus-host disease (GVHD), and lead to worse outcomes. Given the relative paucity of data, we performed a CIBMTR/EBMT study to examine the impact of prior CPI in alloHCT outcomes. We included 2186 adult patients > 18 years who received a first alloHCT using a matched related, unrelated or haploidentical donor from 2008-2023. Twenty-seven percent of patients received prior CPI. GVHD prophylaxis was post-transplant cyclophosphamide in 55.8% patients in the CPI cohort and 35% in the non-CPI cohort. Median follow-up among survivors was longer for the non-CPI (39 months) than CPI cohort (16.5 months). In the multivariate analysis, prior CPI exposure did not affect overall survival or non-relapse mortality but resulted in improved progression-free survival (non-CPI vs. CPI HR 0.81, 0.67-0.98, p=0.03) and lower incidence of relapse (HR 0.58, 0.45-0.76, p<0001). While grade II-IV (HR1.26, 1.04-1.53; p=0.02) and III-IV (HR1.41, 1.04-1.92; p=0.03) acute GVHD were increased differences in chronic GVHD were not significant. Use of post-transplant cyclophosphamide based GVHD prophylaxis resulted in improved OS, lower grade II-IV acute GVHD and chronic GVHD in patients with prior CPI exposure. In summary, allo-HCT should still be considered a curative option for patients with HL in the era of checkpoint inhibitors.

RevDate: 2025-07-07

Dhodapkar MV, B Paiva (2025)

Immune Alterations in Myeloma Evolution and Outcomes: Quo Vadis?.

Blood pii:546084 [Epub ahead of print].

The pathogenesis of multiple myeloma (MM) and its precursor monoclonal gammopathy of undetermined significance (MGUS) is linked to an aging immune system. Chronic activation of B/plasma cells may contribute to the origin of MGUS, which is frequent in the elderly. However, only 1% of individuals with MGUS annually experience progression to MM. The immune system can specifically recognize MGUS lesions and preclinical MM models provide evidence for both innate and adaptive immune surveillance. Multiomic studies have identified several systemic alterations at the MGUS stage, suggesting accelerated immune aging prior to evolution into clinical malignancy. MM is further associated with spatial alterations in patterns of tumor growth and in-situ regulation of regional immunity. Both tumor and microenvironment-related factors contribute to immune paresis, which facilitates the dissemination of clonal plasma cells and increases the risk of infections in MM patients. Immune profiles in blood or marrow exhibit considerable heterogeneity and have been linked to outcomes following immune therapies including T cell redirection. Understanding how underlying systemic immune changes impact in-vivo function and durability of natural or synthetic tumor/antigen-specific immunity needs further study. Preserving or restoring immune function may be critical for long-term outcomes both in the context of prevention of clinical MM and of treating active disease. Benchmarking of immune biomarkers followed by its prospective integration into current risk models, together with improved understanding of mechanisms underlying tumor immunity in-vivo, are needed to optimize immune approaches and improve outcomes in MM.

RevDate: 2025-07-07

Naidoo N, Bell-Brown A, Kimura A, et al (2025)

Fecal Immunochemical Test (FIT) Completion by Instruction Type: A Randomized Clinical Trial Comparing QR-Code linked Video to Pictorial Instructions.

The American journal of gastroenterology pii:00000434-990000000-01834 [Epub ahead of print].

BACKGROUND AND AIMS: Low-literacy, pictorial instructions improve fecal immunochemical test (FIT) completion and might enhance colorectal cancer (CRC) screening. The aim of this study was to compare FIT completion among English- and Spanish-speaking patients in an organized CRC screening program based on the type of instructions received (quick response (QR)-code linked to a video vs. pictorial instructions).

METHODS: In this randomized controlled quality improvement study, English- and Spanish-speaking patients eligible for mailed outreach through an organized CRC screening program were randomized 1:1 to receive a FIT kit with either a QR-code linked video or pictorial instructions in their preferred language. Patient demographics (gender, age, race, ethnicity, and insurance type) and clinical outcomes (FIT completion and time to completion) were abstracted from electronic health records.

RESULTS: 13,471 English-speaking patients and 508 Spanish-speaking patients were included. Overall, 31.9% of patients who received mailed outreach completed CRC screening by FIT. However, FIT completion was higher among patients who received QR-code instructions vs. pictorial instructions (33.5% vs 30.4%, absolute difference 3.1%, 95% CI 1.5% - 4.6%). These findings were similar among English- and Spanish-speaking patients. The median time to FIT completion was two days longer (24 days, 95% CI 23-25) for patients who received QR-code instructions versus pictorial instructions, however there was no difference in time to FIT completion by language group.

CONCLUSION: Providing QR-code based education offers a promising format for delivering low literacy instructions, which might be a practical strategy to improve FIT completion for CRC screening.

RevDate: 2025-07-07
CmpDate: 2025-07-07

Chen W, Majovski J, Bhatia S, et al (2025)

A mixed-method analysis of oncologist-patient communications about immune checkpoint inhibitors (COACH).

The oncologist, 30(7):.

BACKGROUND: Despite significant attention in the media and oncology community about improved outcomes associated with immune checkpoint inhibitors (ICIs), there remains a gap in our understanding of how oncologists describe ICIs to their patients. Communication around ICIs represents a challenge as some patients have durable, remarkable benefits while others experience severe toxicities. We investigated oncologist-patient communication practices by performing a mixed-methods study of in-clinic discussions about ICIs.

MATERIALS AND METHODS: This was a mixed-method study in which in-clinic conversations between oncologists and their patients with advanced cancers about ICIs as potential treatments were audio-recorded. Patients were asked to complete a post-discussion survey. Qualitative data was derived from a general inductive thematic approach while descriptive statistics were used to analyze the survey responses.

RESULTS: We recorded and analyzed 13 in-clinic conversations involving 8 oncologists and 13 patients. Twelve patients completed the post-discussion surveys. The conversations involved sophisticated discussions of immune function, cancer and ICI mechanisms, and trade-offs between anticancer benefits and toxicities. Oncologists incorporated metaphors and probabilistic information in their explanations. In the post-discussion surveys, patients indicated a preference for detailed information about ICIs and reported that they received the right depth of information in these discussions.

CONCLUSIONS: During in-clinic discussions of ICI therapy, oncologists provided detailed information about immunology and cancer, often aided by metaphors. Probabilities were commonly used to describe the likelihood of toxicities and benefits. The amount of information provided by the oncologists aligned with the patients' preference for detailed information about their cancer treatments.

RevDate: 2025-07-07

Kauffman ZJ, Koesser K, Helzer KT, et al (2025)

Lossless Altered Histone Modification Analysis System (LAHMAS).

Lab on a chip [Epub ahead of print].

Miniaturized biological assays using microfluidics have the potential to enhance assay sensitivity, reduce reagent consumption, and increase throughput. However, challenges to miniaturization include increased platform complexity and increased surface to volume ratios leading to risk of evaporation and analyte loss through surface binding. Exclusive Liquid Repellency (ELR) enables open microfluidic systems that minimize these challenges through an oil phase that protects small aqueous volumes from temperature fluctuation and evaporation while eliminating surface fouling that leads to sample loss. Here we report a novel microfluidic platform leveraging ELR and Exclusion-based Sample Preparation (ESP) for the miniaturization of CUT&Tag, a complex multistep biological assay. The resultant Lossless Altered Histone Modification Analysis System (LAHMAS) employs a PDMS-silane treated glass surface immersed in silicone oil to facilitate lossless liquid handling and prevent sample evaporation. The device design, compatible with standard laboratory equipment, allows effective processing of cell inputs as low as 100 cells with higher specificity than macroscale CUT&Tag facilitating accurate chromatin profiling of low input and rare cell samples.

RevDate: 2025-07-06

Jimenez Jimenez AM, Spellman SR, Politikos I, et al (2025)

Allogeneic Hematopoietic Cell Donor Selection: Contemporary Guidelines from the NMDP/CIBMTR.

Transplantation and cellular therapy pii:S2666-6367(25)01290-4 [Epub ahead of print].

Allogeneic hematopoietic cell transplantation (HCT) remains a curative therapy for many patients with hematologic malignancies, bone marrow failure syndromes, inborn errors of immunity and metabolic disorders. Current donor selection strategies typically prioritize the selection of an HLA-matched donor over HLA mismatched ("alternative") donor sources, with a hierarchical approach to the donor search. More recent data challenge this rubric, particularly in the context of novel graft versus host disease (GVHD) prophylaxis strategies that demonstrate improved outcomes in alternative donor HCT recipients. In this setting, an increased emphasis on non-HLA factors (both donor characteristics and systemic factors) in determining donor selection is now feasible. In this guideline, we review recent evidence from prospective clinical trials as well as high-quality observational studies and provide expert panel recommendations on donor selection algorithms and prioritization in the era of novel GVHD prophylaxis. We then highlight important questions still to be answered in our field.

RevDate: 2025-07-06

Hullar MAJ, Kahsai O, Curtis KR, et al (2025)

Metabolic plasticity of the gut microbiome in response to diets differing in glycemic load in a randomized, crossover, controlled feeding study.

The American journal of clinical nutrition pii:S0002-9165(25)00383-1 [Epub ahead of print].

BACKGROUND: Dietary patterns characterized by low-glycemic, minimally processed plant foods are associated with lower risk of several chronic diseases.

OBJECTIVE: Evaluate the effects of a low glycemic load (LGL) versus a high glycemic load (HGL) dietary pattern on stool bacterial community structure and metabolism.

METHODS: Participants in this crossover-controlled feeding study were healthy men and women (n=69). We identified genera, species, and genes and transcripts of metabolic pathways and bacterial enzymes using 16S rRNA gene, metagenomic and metatranscriptomic sequencing, and bioinformatic analysis.

RESULTS: Overall community structure measured by alpha and beta diversity were not significantly different across the diets although diet did significantly increase the abundance of 13 out of 161 genera (padj<0.05) and 5 species in the LGL and 7 species in the HGL diet. Gene expression in the hexitol fermentation pathway (β=-1.15, SE=0.24 with 95% CI (-1.63, -0.67); padj=0.002) was significantly higher in the HGL diet, whereas expression in the L-lysine biosynthesis pathway (β =0.20, SE=0.05 with 95% CI (0.09, 0.30); padj=0.03); was enriched in the LGL diet. The beta diversity of expressed carbohydrate-active enzymes (CAZymes) was significantly different between the diets (MiRKAT, p<0.001). CAZymes enriched in the HGL diet reflected dietary additives while CAZymes enriched in the LGL diet reflected diverse phytochemical intake. There was a significant interaction between HOMA IR and the Coenzyme A biosynthesis I pathway involved in bacterial fatty acid biosynthesis (padj=0.035) that was positive in the HGL diet (β=0.20, SE=0.09 with 95% CI (0.02, 0.39)) and negative in the LGL diet (β =-0.23, SE=0.09 with 95% CI (-0.40, -0.06)).

CONCLUSION: In healthy humans, diet impacts microbial metabolism and enzymatic activity but not the overall diversity of the gut microbiome. This emphasizes the relevance of dietary components in activating expression of specific bacterial genes and their impact on host metabolism. This trial was registered at clinicaltrials.gov as NCT00622661.

RevDate: 2025-07-06

White RG, Churchyard GJ, Horton KC, et al (2025)

Evidence required to evaluate the use of bacteriologically confirmed asymptomatic tuberculosis disease as a primary endpoint in prevention of tuberculosis disease vaccine licensure trials.

The Lancet. Respiratory medicine pii:S2213-2600(25)00164-X [Epub ahead of print].

Current licensure trials of new vaccines to prevent tuberculosis disease use bacteriologically confirmed symptomatic tuberculosis disease as the primary endpoint. Globally, the incidence of symptomatic tuberculosis disease is low, making licensure trials large, long, and expensive. New data suggest that bacteriologically confirmed asymptomatic tuberculosis disease might occur more frequently than symptomatic tuberculosis disease. Therefore, if vaccines have efficacy against asymptomatic disease, tuberculosis vaccine licensure trials could include it in the primary endpoint, potentially leading to smaller or shorter trials. We describe the potential benefits and risks of this inclusion in the primary endpoint of tuberculosis vaccine licensure trials. We also simulate licensure trial endpoint accrual and summarise feedback from anonymous regulators and policy makers on the knowledge needed to consider this proposal and research studies needed to fill these evidence gaps. If bacteriologically confirmed asymptomatic tuberculosis disease could be included in the primary endpoint of tuberculosis disease licensure trials, it could lead to cheaper and more rapid tuberculosis vaccine development.

RevDate: 2025-07-05

Petersdorf EW (2025)

Semper Progrediens.

Transplantation and cellular therapy, 31(7):399-400.

RevDate: 2025-07-05
CmpDate: 2025-07-05

Rafati DM, Wang Y, Koppayi AL, et al (2025)

REMOVED: Conditioning Regimen Considerations for Allogeneic Hematopoietic Cell Transplantation in Recipients with Germline Pathogenic Variants in Base-Excision Repair Pathway Genes.

Transplantation and cellular therapy, 31(2S):S338.

This abstract has been removed: please see Elsevier policy on article withdrawal (https://www.elsevier.com/about/policies-and-standards/article-withdrawal). This article has been removed at the request of the author. This abstract has been removed because it was not presented at the 2025 BMT Tandem Meeting.

RevDate: 2025-07-05
CmpDate: 2025-07-05

Rafati DM, Pirsl F, Katki HA, et al (2025)

REMOVED: Genetic Landscape in Myelofibrosis Impacts Post-Hematopoietic Cell Transplantation Outcomes.

Transplantation and cellular therapy, 31(2S):S337.

This abstract has been removed: please see Elsevier policy on article withdrawal (https://www.elsevier.com/about/policies-and-standards/article-withdrawal). This article has been removed at the request of the author. This abstract has been removed because it was not presented at the 2025 BMT Tandem Meeting.

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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

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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.

Timelines

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.

Biographies

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 28 JUL 2024 )