tbuckley/cabot-search huggingface dataset:
All-Cause Mortality and Life Expectancy by Birth Cohort Across US States
Authors: Theodore R. Holford, Lisa McKay, Jamie Tam, Jihyoun Jeon, Rafael Meza
Journal: JAMA Network Open (2025)

Importance Although overall US mortality rates declined from 1969 to 2020, they vary considerably by state and generation, especially when evaluated by birth cohort. Trends in mortality and life expectancy by birth cohort for US states and Washington, DC, have yet to be characterized. Objective To estimate cohort mortality trends for each state and Washington, DC, and quantify life expectancy at birth and 40 years of age and the rate of increase after 35 years of age. Design, Setting, and Participants In this cohort study, all-cause mortality rates by single years of age (0-119) and birth cohort (1900-2000) were estimated for each state in January 2025. Mortality data and population estimates were obtained from the National Center for Health Statistics, the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research website, and the Surveillance, Epidemiology, and End Results database for each state and Washington, DC, by single years of ages 0 to 84 and calendar years 1969 to 2020. An age-period-cohort model with constrained cubic splines for temporal effect estimates was used to estimate mortality from 1900 to 2000. Main Outcomes and Measures Life expectancy for each cohort from birth or 40 years of age was estimated by sex and state, along with doubling time for the death rate after 35 years of age. Results Analyses included 179 million deaths (77 million female and 102 million male). In the West and Northeast, cohort life expectancy improved from 1900 to 2000, but in some Southern states, it changed less than 3 years since 1900 in females and less than 2 years since 1950 in males. Washington, DC, had the lowest life expectancy in the 1900 birth cohort but a greater increase than the other states (from 61.1 to 72.8 years of age). After 35 years of age, the highest rate-doubling time in a state was 9.39 years in New York for females and 11.47 years for males in Florida. The shortest rate-doubling times were 7.96 years for females in Oklahoma and 8.95 years for males in Iowa. Conclusions and Relevance Cohort-specific patterns across states reveal wide disparities in mortality. Some states have experienced little or no improvements in life expectancy from the 1900 to 2000 birth cohorts. Understanding how mortality patterns vary by birth cohort within each state can inform decision-making around resource allocation and public health interventions.
Revised free light chain reference intervals enhance risk stratification in monoclonal gammopathy of undetermined significance and reduce overdiagnosis
Authors: Cecilie Velsoe Maeng, Sæmundur Rögnvaldsson, Thórir Einarsson Long, Christian Brieghel, Emil Hermansen, Carsten Utoft Niemann, Kirsten Grønbæk, Sigurður Yngvi Kristinsson, Sigrún Thorsteinsdóttir
Journal: Blood Cancer Journal (2025)
Response and Resistance to RAS Inhibition in Cancer
Authors: Richard Y. Ebright, Julien Dilly, Alice T. Shaw, Andrew J. Aguirre
Journal: Cancer Discovery (2025)

Abstract RAS inhibition has the potential to transform cancer treatment for many patients. The landscape of RAS inhibitor therapies is rapidly evolving, with two mutant-selective KRAS inhibitors now approved and multiple other mutant-selective, pan-KRAS, and pan-RAS inhibitors in development. However, monotherapy efficacy has been limited by primary and acquired resistance. In this article, we review preclinical and clinical data on RAS inhibition in cancer and describe multiple genetic and nongenetic mechanisms of resistance. Moreover, we highlight future opportunities for the design of rational combination therapy strategies, which will ultimately be needed to overcome resistance and enhance the efficacy of these promising treatments. Significance: RAS inhibitors have shown early evidence of efficacy in multiple cancer types, but clinical benefit is limited by acquired resistance. Development of best-in-class inhibitors, with optimal potency, selectivity, and pharmacokinetic properties, as well as effective and tolerable combination therapies will be needed to overcome resistance and maximize the clinical impact of RAS-targeted therapy.
Combining Spatial Transcriptomics, Pseudotime, and Machine Learning Enables Discovery of Biomarkers for Prostate Cancer
Authors: Martin Smelik, Daniel Diaz-Roncero Gonzalez, Xiaojing An, Rakesh Heer, Lars Henningsohn, Xinxiu Li, Hui Wang, Yelin Zhao, Mikael Benson
Journal: Cancer Research (2025)

Abstract Early cancer diagnosis is crucial but challenging owing to the lack of reliable biomarkers that can be measured using routine clinical methods. The identification of biomarkers for early detection is complicated by each tumor involving changes in the interactions between thousands of genes. In addition to this staggering complexity, these interactions can vary among patients with the same diagnosis as well as within the same tumor. We hypothesized that reliable biomarkers that can be measured with routine methods could be identified by exploiting three facts: (1) the same tumor can have multiple grades of malignant transformation; (2) these grades and their molecular changes can be characterized using spatial transcriptomics; and (3) these changes can be integrated into models of malignant transformation using pseudotime. Pseudotime models were constructed based on spatial transcriptomic data from three independent prostate cancer studies to prioritize the genes that were most correlated with malignant transformation. The identified genes were associated with cancer grade, copy number aberrations, hallmark pathways, and drug targets, and they encoded candidate biomarkers for prostate cancer in mRNA, immunohistochemistry, and proteomics data from the sera, prostate tissue, and urine of more than 2,000 patients with prostate cancer and controls. Machine learning-based prediction models revealed that the biomarkers in urine had an AUC of 0.92 for prostate cancer and were associated with cancer grade. Overall, this study demonstrates the diagnostic potential of combining spatial transcriptomics, pseudotime, and machine learning for prostate cancer, which should be further tested in prospective studies.
Gadolinium-Ceria Hybrid System Enables Synergistic Alleviation of Oxidative Stress and Metabolic Thrombo-Inflammation for Efficient Ischemic Stroke Treatment
Authors: Jin Nan, Chundongqiu Xia, Jingyi Zhang, Yujie Xie, Shuyu Shi, Wei Yang, Meihua Yu, Yu Chen, Jun Zhang
Journal: Biomaterials (2025)
A 6-tsRNA signature for early detection, treatment response monitoring, and prognosis prediction in diffuse large B cell lymphoma
Authors: Jun Rao, Lin Xia, Qiong Li, NaYa Ma, Xinlei Li, Jiali Li, Lidan Zhu, Pan Zhao, Yunjing Zeng, Sha Zhou, Huanping Guo, Shijia Lin, Song Dong, Shifeng Lou, Fangyi Fan, Jin Wei, Jiang F Zhong, Li Gao, Shengwen Calvin Li, Xi Zhang
Journal: Blood Cancer Journal (2025)
Changing climate and socioeconomic factors contribute to global antimicrobial resistance
Authors: Weibin Li, Tingting Huang, Chaojie Liu, Haishaerjiang Wushouer, Xinyi Yang, Ruonan Wang, Haohai Xia, Xiying Li, Shengyue Qiu, Shanquan Chen, Hung Chak Ho, Cunrui Huang, Luwen Shi, Xiaodong Guan, Guobao Tian, Gordon Liu, Kristie L Ebi, Lianping Yang
Journal: Nature Medicine (2025)
Pulsed Field Ablation for Persistent Atrial Fibrillation
Authors: Vivek Y Reddy, Edward P Gerstenfeld, Boris Schmidt, Devi Nair, Andrea Natale, Walid Saliba, Atul Verma, Philipp Sommer, Andreas Metzner, Mohit Turagam, Stanislav Weiner, Jean Champagne, Ignacio Garcio-Bolao, Hugh Calkins, Jeffrey Olson, Ziad Issa, Marshall Winner, Wilber Su, Gery Tomassoni, Jamie Kim, Bruce Hook, David B Delurgio, Douglas N Gibson, Marcos Daccarett, Chinmay Patel, Karan Bhalla, Michael Shehata, John D Harding, Jim W Cheung, Jonathan D Raybuck, Stephanie Roelke, Torri Schwartz, Brad S Sutton, Moussa Mansour
Journal: Journal of the American College of Cardiology (2025)
Regional and aging-specific cellular architecture of non-human primate brains
Authors: Yun-Mei Wang, Wen-Chao Wang, Yongzhang Pan, Lin Zeng, Jing Wu, Zheng-Bo Wang, Xiao-Lin Zhuang, Ming-Li Li, David N Cooper, Sheng Wang, Yong Shao, Li-Min Wang, Ying-Yin Fan, Yonghan He, Xin-Tian Hu, Dong-Dong Wu
Journal: Genome Medicine (2025)
A bacteriophage-conditional mouse model reveals the impact of phages within a conventionally colonized gut microbiota
Authors: Hollyn C Franklin, Rita Makhlouf, Anh D Ha, Rogerio A Bataglioli, Zachary R Baker, Sydney A Murphy, Hannah Jirsa, Joshua Heuler, Teresa Southard, Frank O Aylward, Bryan B Hsu
Journal: Cell Host & Microbe (2025)
A genome-wide One Health study of Klebsiella pneumoniae in Norway reveals overlapping populations but few recent transmission events across reservoirs
Authors: Marit A K Hetland, Mia A Winkler, Håkon P Kaspersen, Fredrik Håkonsholm, Ragna-Johanne Bakksjø, Eva Bernhoff, Jose F Delgado-Blas, Sylvain Brisse, Annapaula Correia, Aasmund Fostervold, Margaret M C Lam, Bjørn-Tore Lunestad, Nachiket P Marathe, Niclas Raffelsberger, Ørjan Samuelsen, Marianne Sunde, Arnfinn Sundsfjord, Anne Margrete Urdahl, Ryan R Wick, Iren H Löhr, Kathryn E Holt
Journal: Genome Medicine (2025)
Pretargeting: Bridging the two worlds of radiopharmaceutical probes
Authors: Yuriko Mori, Jens Cardinale, Frederik L. Giesel
Journal: Clinical Cancer Research (2025)

Abstract The human trophoblast cell-surface antigen 2 (Trop-2) is expressed in a variety of malignant diseases. Using pretargeting methodology, a novel antibody against Trop-2 was radiolabeled and evaluated in a preclinical setting. This showed promising characteristics lending itself as potential basis for further clinical trials as imaging agent and potential theranostic.
Antibody Drug Conjugates in Non-Small Cell Lung Cancer: Where is the Target and the Biomarker?
Authors: Fred R. Hirsch
Journal: Clinical Cancer Research (2025)

Summary Antibody–drug conjugates are an emerging treatment of non–small cell lung cancer. Some do not require biomarkers, whereas others require mutations and/or protein expression. New diagnostic technologies give opportunities for better target identification and selection of patients. Combination therapies might broaden relevant patient populations but might call for combined biomarker selection paradigms. See related article by Trontzas et al., p. XX .
Venetoclax plus modified-intensity Idarubicin and Cytarabine treatment as first-line treatment for newly diagnosed pediatric acute myeloid leukemia
Authors: Shiyuan Wang, Mingyan Jiang, Yaqin Wang, Lixian Chang, Beibei Zhao, Xiaoming Liu, Benquan Qi, Shuchun Wang, Tianfeng Liu, Xiaoyan Zhang, Yumei Chen, Fang Liu, Ye Guo, Xiaojuan Chen, Li Zhang, Yao Zou, Wenyu Yang, Ju Gao, Xiaofan Zhu, Min Ruan
Journal: Clinical Cancer Research (2025)

Abstract Purpose: Venetoclax (VEN) has shown excellent activity in eliminating acute myeloid leukemia (AML) blasts in preclinical and clinical trials, but clinical data in pediatric newly diagnosed AML (ND-AML) remain limited. We evaluated VEN plus modified-intensity idarubicin and cytarabine chemotherapy (VIA) in childhood ND-AML. Experimental design: In an open-label, single-arm, multi-center prospective clinical trial, 65 ND-AML pediatric patients received VIA induction (VEN and modified-intensity cytarabine and idarubicin). Consolidation was guided on response to induction and individualized risk stratification. Primary end point was complete remission (CR) and measurable residual disease (MRD) response rates. Results: After induction cycle 1, CR and MRD negativity was 90.8% and 78.5%, increasing to 96.8% and 87.3% following induction cycle 2. 28 (43.2%) patients underwent hematopoietic stem cell transplantation (HSCT) without engraftment failure. CBF AML [t(8;21) and inv(16)/t(16;16)] patients achieved a favorable response rate, but the median log10 reduction of transcript levels was suboptimal [-1.7 (cycle 1) and -2.6 (cycle 2) for RUNX1::RUNX1T1, -2.3 and -2.5 for CBFB::MYH11]. Disease relapse was frequently observed in KIT mutation, RUNX1::RUNX1T1 and CBFB::MYH11. The most common grade 3-4 toxicities were hematological toxicities and febrile neutropenia (FN). No treatment-related deaths occurred. With a median follow-up of 15.7 months, the estimated 12-month overall survival and event-free survival was 92.3% (95% CI 86.0-99.8) and 79.1% (95% CI 69.6-90.0). MRD negativity post cycle 1 correlated with superior long-term survival (P &amp;lt; 0.001). Conclusions: VIA regimen is highly effective and relatively safe in children with ND-AML, with deep remission and favorable survival outcomes.
Blocking the TCA Cycle in Cancer Cells Potentiates CD36+ T-cell–Mediated Antitumor Immunity by Suppressing ER Stress–Associated THBS2 Signaling
Authors: Jianqiang Yang, Fanghui Chen, Zhenzhen Fu, Fan Yang, Nabil F. Saba, Yong Teng
Journal: Cancer Research (2025)

Abstract The tricarboxylic acid (TCA) cycle is often rewired or dysregulated to meet the increased energy and biosynthetic demands of rapidly dividing cancer cells, and targeting the TCA cycle is a potential therapeutic strategy for treating cancer. However, tumor cell metabolism can impact other cells in the tumor microenvironment, and disrupting the TCA cycle in cancer cells could impact the antitumor immune response. In this study, using CPI-613 as a model drug for TCA cycle inhibition, we identified a molecular mechanism by which blocking the TCA cycle enhances T-cell–mediated antitumor immunity in the context of head and neck squamous cell carcinoma (HNSCC). Impairment of mitochondrial metabolism by CPI-613 induced endoplasmic reticulum stress in HNSCC cells, leading to increased expression of spliced X-box–binding protein 1. This, in turn, directly suppressed the transcriptional activity of the thrombospondin-2 gene. Correspondingly, CPI-613 reduced the secretion of thrombospondin-2 from HNSCC cells, enhancing the proliferation and cytotoxic potential of tumor-infiltrating CD36+CD8+ T cells by upregulating AKT-mTOR signaling. This mechanism ultimately enhanced antitumor immunity in a syngeneic mouse model of orthotopic HNSCC following CPI-613 treatment. These findings uncover the immunomodulatory role of the TCA cycle in cancer cells and suggest that targeting it is a promising approach to harness tumor-reactive immune cells. Significance: The immunomodulatory role of the TCA cycle in cancer cells provides a therapeutic opportunity to enhance antitumor immunity by targeting tumor cell metabolism.
The Hsp90β Isoform: An Attractive Target for Drug Development
Authors: Subhabrata Chaudhury, Terin D'Amico, Brian S. J. Blagg
Journal: Medicinal Research Reviews (2025)

ABSTRACT The beta isoform of 90 kDa heat shock protein (Hsp90β) plays a critical role in maintaining cellular proteostasis by assisting in the folding and refolding of proteins, which is essential for both normal cellular function and stress response. It is constitutively expressed in mammalian cells, differentiating it from the inducible Hsp90α isoform. Hsp90β's involvement in diverse cellular processes, such as signal transduction, cell cycle control, and apoptosis, underscores its significant role in various diseases, including cancer and neurodegenerative disorders. The isoform‐specific functions of Hsp90β and its interaction with unique client proteins make it a promising target for therapeutic intervention, particularly in the development of selective inhibitors that avoid the adverse effects observed with pan‐Hsp90 inhibitors. This review delves into the structural and functional intricacies of Hsp90β, its role in disease, and the potential for selective drug development.
A Cyanobacteria-derived RNA aptamer resensitizes prostate cancer to hormone therapy
Authors: Carlos D. Cruz-Hernández, Bethany Smith, Sandrine Billet, Manish Thiruvalluvan, Gabrielle Gonzales, David M. Underhill, Ekihiro Seki, Shelly C. Lu, Neil A. Bhowmick
Journal: Cancer Research (2025)

Abstract Prostate adenocarcinoma (PCa) resistance to androgen receptor (AR) signaling inhibitor therapy is associated with elevated glutamine (L-Gln). Glutamine sensors, present in conserved riboswitches (glnA), control nitrogen metabolism in many organisms, like cyanobacteria. Iterative in silico modifications of glnA found in Synechococcus elongatus and thermodynamic analysis of a 56mer aptamer resulted in high L-Gln specificity and affinity. The optimized aptamer depleted L-Gln from PCa cells by both L-Gln sequestration and extracellular glutaminase activation, serving as an allosteric activator. Glutamine depletion reduced FOXM1 transcriptional occupancy on the promoter of fibroblast growth factor 8 (FGF8), a known mediator of PCa castration resistance. A point mutation in the binding pocket of the 56mer rendered the aptamer ineffective in L-Gln binding and FGF8 regulation. Accordingly, the L-Gln-depleting aptamer, with demonstrated serum stability, limited the proliferation and promoted cell death of castration-resistant PCa alone and in combination therapy with AR antagonists, enzalutamide and apalutamide, in subcutaneous and orthotopic mouse models. Further selective tumor targeting was achieved by functionalizing gold nanoparticles with either the optimized L-Gln aptamer or the point-mutant aptamer. Castration sensitivity was restored by the L-Gln-depleting aptamer but not by the point-mutant. The functionalized nanoparticle demonstrated superior anti-tumor efficacy in an orthotopic PCa model over the untargeted aptamer. The anti-tumor activity of the aptamer helped support L-Gln as an oncometabolite in PCa that can be targeted to sensitize tumors to hormone therapy.
Predictive Effect of IGFBP-3 on Low-Dose Tamoxifen Efficacy in Noninvasive Breast Cancer in the Phase III Tam-01 Trial
Authors: Harriet Johansson, Debora Macis, Martino Oliva, Matteo Puntoni, Eva Blondeaux, Aliana Guerrieri-Gonzaga, Valentina Aristarco, Irene Maria Briata, Tania Buttiron-Webber, Luca Boni, Matteo Lazzeroni, Davide Serrano, Livia Giordano, Maria Digennaro, Laura Cortesi, Francesco Millo, Katia Cagossi, Giuseppe Aprile, Fabio Falcini, Elisa Gallerani, Bernardo Bonanni, Andrea DeCensi
Journal: Clinical Cancer Research (2025)

Abstract Purpose: Low-dose tamoxifen 5 mg/day (babytam) for 3 years can decrease the incidence of new breast cancer events in women with breast intraepithelial neoplasia by 42% with limited toxicity, which provides a new treatment option for these disorders. However, predictive biomarkers of babytam efficacy are lacking. We studied whether baseline levels of insulin-like growth factor-1 (IGF-I), IGF-binding protein-3 (IGFBP-3), estradiol, and sex hormone–binding globulin (SHBG) and their ratios predict babytam efficacy on breast cancer events in a preplanned secondary analysis. Patients and Methods: Within a 1:1 placebo-controlled, multicenter randomized trial of babytam or placebo administered for 3 years after surgery in women with hormone-sensitive or unknown breast intraepithelial neoplasia, including atypical ductal hyperplasia and lobular or ductal carcinoma in situ, 406 of 500 participants consented to blood sampling at baseline and at 1 and 3 years. Serum IGF-I, IGFBP-3, estradiol, and SHBG levels and their ratios were measured using chemiluminescent immunoassays. Biomarker changes were estimated using mixed-effects models, and incidence rate ratios were calculated after 10 years of follow-up with Poisson regression. Subgroup analyses were performed using an interaction test and subpopulation treatment effect pattern plot. Results: Baseline levels of IGFBP-3 in the three top quartiles (≥3.44 µg/mL), but not in the lower quartile, predicted greater babytam efficacy compared with placebo (Pinteraction = 0.006). Baseline IGF-I, estradiol, or SHBG levels were not predictive of babytam efficacy, whereas the IGF-I/IGFBP-3 ratio was borderline significant (Pinteraction = 0.067). Conclusions: High baseline levels of IGFBP-3 (≥3.44 µg/mL) predicted babytam efficacy and may help differentiate which women benefit most from this treatment.
A State of the Science Review of Human Health Effects of the Michigan Polybrominated Biphenyl Contamination after Five Decades
Authors: Susan S. Hoffman, John A. Kaufman, Robert B. Hood, Tamar Wainstock, Kathleen Hartnett, Hillary Barton, Melanie A. Pearson, Metrecia L. Terrell, Michele Marcus
Journal: Environmental Health Perspectives (2025)

The Michigan Polybrominated Biphenyl (PBB) registry, followed since 1976, was created after a 1973 chemical manufacturing mistake. The flame retardant PBB was accidentally mixed into animal feed and distributed to Michigan farms for nearly a year, exposing farm residents and animal product consumers. We synthesize knowledge to date on health effects of PBB exposure within the Michigan PBB Registry, and describe research findings in the context of literature on other persistent organic pollutants (POPs) and endocrine disrupting chemicals (EDCs). We reviewed literature published from 1973-2025 on human health effects of PBB following the Michigan contamination using PubMed and Thompson Reuters (ISI) Web of Science databases. We excluded studies not in English; on exposures besides PBB; animal studies; reviews, abstracts, or letters to the editor; studies without a health outcome; and studies outside of Michigan or unrelated to the 1973 contamination. For each article, two researchers performed title and abstract screening, full article review, and data extraction. We included 79 publications out of 601 identified and screened. Early studies did not find many health outcomes associated with PBB, possibly because of methodological limitations. More recent studies on long-term and multigenerational impacts found an increased breast cancer risk, accelerated pubertal development and earlier menarche for girls exposed in utero, urogenital problems and slower pubertal development in boys exposed in utero, lower estrone 3-glucuronide and follicle-stimulating hormone among women exposed in childhood, and increased miscarriage risk among daughters of exposed women. Epigenetic and metabolomic research reported altered pathways related to estrogenic effects and immune function, and epigenetic alterations of spermatogenic cells. This unique community-academic partnership has produced insights into multigenerational consequences of EDC/POP exposures across the lifecourse. The findings from this cohort underscore the broader relevance of critical windows of vulnerability, particularly during fetal development and childhood.. https://doi.org/10.1289/EHP15012.
The Third Pillar of Precision Medicine — Precision Delivery
Authors: Avnesh S. Thakor
Journal: MedComm (2025)

ABSTRACT Precision Medicine is thought of as having two main pillars: Precision Diagnosis and Precision Therapy. However, for Precision Medicine to reach its full potential, a third pillar is needed that we propose to call Precision Delivery . In the laboratory, many therapies show great efficacy when tested directly with target cells. However, upon clinical translation, they are often given via intravenous or oral administration, resulting in their systemic distribution. To ensure therapies reach target sites at the correct therapeutic levels, they are often given at higher concentrations. However, this can be associated with off‐target effects, side‐effects, and unwanted interactions. Delivery strategies can help mitigate this by “spatially re‐coupling” therapies in vivo with target cells. This review explains the concept of Precision Delivery , which can be thought of as three interconnected, but independent, modules: targeted delivery, microenvironment modulation, and cellular interactions. While locoregional approaches directly deliver therapies into target tissues through endovascular, endoluminal, percutaneous, and implantation techniques, microenvironment modulation technologies facilitate the movement of therapies across biological barriers and through tissue matrices, so optimized therapies can reach and interact with target cells. We highlight new innovations driving advances in Precision Delivery , while also discussing the considerations and challenges that Precision Delivery faces as it becomes increasingly integrated into treatment workflows.