tbuckley/cabot-search huggingface dataset:
Management of Heart Failure With Improved Ejection Fraction
Authors: Nandan Kodur, W H Wilson Tang
Journal: JACC Heart Failure (2025)

Heart failure with improved ejection fraction (HFimpEF) is defined by improved left ventricular ejection fraction (LVEF) among patients who previously had reduced LVEF. HFimpEF is associated with improved prognosis, albeit with persistent risk of relapse and adverse events in some patients. Current guidelines thus recommend sustained and indefinite guideline-directed medical therapy (GDMT) for all patients with HFimpEF. Emerging clinical experience suggests that heart failure arising from acute etiologies that fully resolve along with complete LVEF recovery may have a favorable prognosis with lower risk of relapse. Indeed, cohort and case series studies have demonstrated the feasibility of safe de-escalation of GDMT in select patients with specific etiologies, with multiple small trials ongoing. Future studies should investigate whether advanced imaging or blood biomarkers could aid in risk stratifying patients with recovered LVEF, whether partial de-escalation of GDMT could be safe and feasible, and whether implantable cardioverter-defibrillator therapy can be safely discontinued.
The Deep Evolutionary Roots of the Nervous System
Authors: Maria Sachkova, Vengamanaidu Modepalli, Maike Kittelmann
Journal: Annual Review of Neuroscience (2025)

The evolutionary success of animals can, at least in part, be attributed to the presence of neurons that allow long-distance communication between tissues, coordination of movements, and the capacity for learning. However, the evolutionary origin and relationship of neurons to other cell types are fundamental questions that remain unsolved. The first neurons probably evolved shortly after the rise of the first animals over 600 million years ago. Studies on early-diverging animal lineages have provided key insights into the mechanisms underlying the origin of neurons. Recent discoveries in morphology, molecular signatures, and function of neurons in cnidarians and comb jellies, as well as neuron-like cells in nerveless placozoans, sponges, and other eukaryotes, may prompt a redefinition of what constitutes a neuron. Here we review the latest insights into the origin of neurons and nervous systems, while also highlighting exciting technological advancements that not only are accelerating our understanding of nervous system evolution, morphology, and function but also hold the potential to revolutionize the field.
Obtaining and evaluating information on the use, release, and health effects of two types of long-chain PFAS used as alternatives for legacy long-chain perfluoroalkyl acids: a case study
Authors: Gloria B. Post
Journal: Environmental Health Perspectives (2025)

Short-chain per- and polyfluoroalkyl substances (PFAS) that are less bioaccumulative have been introduced as replacements for long-chain perfluoroalkyl acids (PFAAs) with the intent of reducing health risks. In contrast, alternative PFAS with longer chain lengths may be at least as bioaccumulative and toxic as phased-out long-chain PFAAs. Such alternative PFAS were used and released unbeknownst to regulatory authorities or the public, causing environmental contamination of public health concern. The objective was to examine issues encountered in learning about use, release, and toxicity of alternative PFAS and to demonstrate development of human health benchmarks for alternative PFAS from previously unavailable health effects information. Environmental contamination with chloroperfluoropolyether carboxylates (ClPFPECAs) near a New Jersey fluoropolymer manufacturing facility was revealed through a joint New Jersey Department of Environmental Protection (NJDEP)-United States Environmental Protection Agency (USEPA) Office of Research and Development study. Previously unavailable information on use, release, and toxicity of ClPFPECAs and another alternative PFAS, perfluoropolyether dicarboxylates, was obtained through a NJDEP legal directive requiring submission of information on such PFAS used in the state. It was learned that the facility discharged large amounts of these alternative PFAS to air and water for many years, both before and after use of long-chain PFAAs ended, and that they are at least as bioaccumulative and toxic in rats as long-chain PFAAs. Additionally, information from exposed workers shows that ClPFPECAs have a human half-life of several years and are associated with numerous health endpoints. Reference Doses and water concentrations protective of chronic drinking water exposure for these alternative PFAS are below those developed by NJDEP for long-chain PFAAs. The use and release of alternative PFAS described herein created concerning human health risks, unknown to regulatory authorities and the public. Such situations in other locations must be identified to allow for regulatory intervention and prevented in the future. https://doi.org/10.1289/EHP15995.
Neurobiology of Thirst and Hunger Drives
Authors: Lucas Encarnacion-Rivera, Karl Deisseroth, Liqun Luo
Journal: Annual Review of Neuroscience (2025)

Thirst and hunger drives are fundamental survival mechanisms that transform physiological need into motivated behavior. In the brain, discrete types of circumventricular and hypothalamic neurons serve as neural circuit elements underlying thirst and hunger drives. These neurons receive signals of dehydration and starvation arising from outside the brain and communicate these homeostatic needs to downstream neural circuit elements. Recent advances in neural circuit activity recording and control in behaving mammals have elucidated how direct and indirect targets of these cells encode goal-relevant, affective, autonomic, and behavioral components of the drives, resulting in a finely tuned, robust, and flexible set of survival-appropriate behaviors.
Sensory Feedback and the Dynamic Control of Movement
Authors: Martyn Goulding, Tejapratap Bollu, Ansgar Büschges
Journal: Annual Review of Neuroscience (2025)

Motor systems in animals are highly dependent on sensory information for optimal control and precision, with mechanosensory feedback from the somatosensory system playing a critical role. These mechanosensory pathways are woven into the descending feedforward pathways and local central pattern generator circuits that control and generate movement, respectively. Somatosensory feedback in mammals and insects, the two animal classes this review touches upon, is complex due to the increased demands that limbed locomotion, weight-bearing, and corrective movements place on sensorimotor control. In this review, we outline the salient features of the proprioceptive and exteroceptive sensory feedback pathways animals rely on for controlling movement and highlight some of the key principles of sensory feedback that are shared across the animal kingdom.
Prenatal Immune Stress: Its Impact on Brain Development and Neuropsychiatric Disorders
Authors: Navneet A. Vasistha, Akira Sawa
Journal: Annual Review of Neuroscience (2025)

Many epidemiological studies have indicated that prenatal immune stress, frequently elicited by maternal immune activation, underlies a major risk for neuropsychiatric disorders of neurodevelopmental origin, such as schizophrenia and autism spectrum disorders. Animal models have been utilized to understand the biological processes of how immune stress influences brain development and resultant behavioral changes. Through such studies, the impacts of orchestrated immune-inflammatory mechanisms led by interleukin-6 (IL-6) on several developing cells, such as neural progenitors, neurons, and microglia, have been deciphered. In addition to prenatal immune stress from adverse maternal environments, mechanisms regulated by intrinsic factors directly associated with the offspring also exist. This review also introduces human stem cell models for addressing this topic and refers to potential modifiers of prenatal immune stress that could influence the eventual behavioral outcomes. Altogether, a mechanistic understanding of the impact of prenatal immune stress on brain development provides a fundamental addition in translational and clinical neurology and psychiatry.
How the Hippocampal Cognitive Map Supports Flexible Navigation
Authors: John O'Keefe
Journal: Annual Review of Neuroscience (2025)

During navigation to a goal, a portion of the hippocampal place cells exhibit directional preferences, firing more in some directions than in others. These directional preferences create vector fields oriented toward locations scattered around the environment called ConSinks. The population vector field averaged across all of the cells recorded in each animal flows toward an average ConSink located close to the goal, providing a means for navigation in unobstructed environments. Closer examination of the ConSink place cell directional firing reveals a fantail representation in which alternative paths to the goal are evaluated, providing the basis for flexible navigation. Additional assumptions about how obstructions might be represented suggest a solution for navigation in more complicated environments. Implications for the phenomena of directionality on linear tracks and splitter cells are discussed.
Regorafenib as maintenance therapy after first-line doxorubicin-based chemotherapy in advanced non-adipocytic soft tissue sarcomas patients: a double-blind randomised trial
Authors: N Penel, A Italiano, J Wallet, L Chaigneau, B Verret, N Firmin, S Watson, T Valentin, E Bompas, F Bertucci, M Brahmi, C Henon, A Brunot, M Spalato-Ceruso, M Vanseymortier, E Heyman-Decoupigny, T Ryckewaert, M C LE Deley, C Perrin, J Y Blay
Journal: Annals of Oncology (2025)
Convergent Genetic Adaptation in Human Tumors Developed Under Systemic Hypoxia and in Populations Living at High Altitudes
Authors: Carlota Arenillas, Lucía Celada, José Ruiz-Cantador, Bruna Calsina, Debayan Datta, Eduardo García-Galea, Roberta Fasani, Ana Belén Moreno-Cárdenas, Juan José Alba-Linares, Berta Miranda-Barrio, Ángel M. Martínez-Montes, Cristina Alvarez-Escola, Beatriz Lecumberri, Ana González García, Shahida K. Flores, Emmanuel Esquivel, Yanli Ding, Mirko Peitzsch, José-Ángel Robles-Guirado, Rita Maria Regojo Zapata, José Juan Pozo-Kreilinger, Carmela Iglesias, Trisha Dwight, Christopher A. Muir, Amelia Oleaga, Maria Elvira Garrido-Lestache Rodríguez-Monte, Maria Jesús Del Cerro, Isaac Martínez-Bendayán, Enol Álvarez-González, Tamara Cubiella, Delmar Muniz Lourenço, Maria Adelaide A. Pereira, Nelly Burnichon, Alexandre Buffet, Craig Broberg, Paxton V. Dickson, Mario F. Fraga, José Luis Llorente Pendás, Joaquín Rueda Soriano, Francisco Buendía Fuentes, Sergio P.A. Toledo, Roderick Clifton-Bligh, Rodrigo Dienstmann, Josep Villanueva, Jaume Capdevila, Anne-Paule Gimenez-Roqueplo, Judith Favier, Paolo Nuciforo, William F. Young, Nicole Bechmann, Alexander R. Opotowsky, Anand Vaidya, Irina Bancos, Donate Weghorn, Mercedes Robledo, Anna Casteràs, Laura Dos-Subirà, Igor Adameyko, María-Dolores Chiara, Patricia L.M. Dahia, Rodrigo A. Toledo
Journal: Cancer Discovery (2025)

Abstract This study explores parallels between systemic hypoxia adaptation in high-altitude populations and tumorigenesis. We identified EPAS1, a gene critical for hypoxia adaptation in populations such as Tibetans and Sherpas, as playing a similar adaptive role in tumors arising under hypoxic conditions. Tumors from patients with chronic hypoxia displayed impaired DNA repair and frequent emergence of EPAS1 variants, with frequencies reaching up to 90%, echoing the positive selection seen in high-altitude dwellers. Mechanistically, EPAS1 gain-of-function mutations promote COX4I2 expression, reducing cellular oxygen consumption and supporting tumor proliferation in hypoxia. Analysis of clinical data from patients with hypoxia revealed tissue-specific and time-sensitive tumorigenic effects, particularly impacting oxygen-sensitive cells in the postnatal period. Our findings suggest that EPAS1-driven adaptation mechanisms in high-altitude populations provide a model for understanding tumor evolution under hypoxic stress, highlighting how genetic adaptations to diverse stressors in natural populations may yield insights into tumorigenesis and cancer progression. Significance: This study reveals a broad convergence in genetic adaptation to hypoxia between natural populations and tumors, suggesting that insights from natural populations could enhance our understanding of cancer biology and identify novel therapeutic targets.
A Phase 3 Trial of Inebilizumab in Generalized Myasthenia Gravis
Authors: Richard J. Nowak, Michael Benatar, Emma Ciafaloni, James F. Howard, M. Isabel Leite, Kimiaki Utsugisawa, John Vissing, Mikhail Rojavin, Qing Li, Fengming Tang, Yanping Wu, Nishi Rampal, Sue Cheng
Journal: New England Journal of Medicine (2025)

Autoimmune generalized myasthenia gravis is a disease that manifests with fluctuating muscle weakness. Inebilizumab is a monoclonal antibody that depletes CD19+ B cells, which are central to disease pathogenesis. In this phase 3, double-blind, randomized, placebo-controlled trial, we enrolled participants with myasthenia gravis who had anti-acetylcholine receptor antibodies or anti-muscle-specific kinase antibodies. Participants were randomly assigned, in a 1:1 ratio, to receive intravenous inebilizumab (300 mg administered on days 1 and 15 for all, and additionally on day 183 for participants who were acetylcholine receptor antibody-positive) or matching placebo for 52 weeks (in participants who were acetylcholine receptor antibody-positive) or 26 weeks (in those who were muscle-specific kinase antibody-positive). Glucocorticoid therapy was tapered, starting at week 4, to a target of 5 mg per day by week 24. The primary end point was the change from baseline in the score on the Myasthenia Gravis Activities of Daily Living scale (MG-ADL; scores range from 0 to 24, with higher scores indicating greater disease activity) at week 26 in the combined acetylcholine receptor antibody-positive and muscle-specific kinase antibody-positive trial populations. A key secondary end point was the change from baseline in the score on the Quantitative Myasthenia Gravis scale (QMG; scores range from 0 to 39, with higher scores indicating greater disease activity) at week 26 in the combined population. Safety was assessed. A total of 238 participants underwent randomization (119 per group). Participants who received inebilizumab had a greater reduction in the MG-ADL score than those who received placebo (least-squares mean change, -4.2 vs. -2.2; adjusted difference, -1.9; 95% confidence interval [CI], -2.9 to -1.0; P<0.001) at week 26. Participants who received inebilizumab had a greater reduction in the QMG score than those who received placebo (least-squares mean change, -4.8 vs. -2.3; adjusted difference, -2.5; 95% CI, -3.8 to -1.2; P<0.001). The most common adverse events with inebilizumab were headache, cough, nasopharyngitis, infusion-related reactions, and urinary tract infections. Inebilizumab was not associated with a higher incidence of serious adverse events. In participants with acetylcholine receptor antibody-positive or muscle-specific kinase antibody-positive generalized myasthenia gravis, inebilizumab improved function and reduced disease severity. (Funded by Amgen; MINT ClinicalTrial.gov number, NCT04524273.).
<i>JAK3</i><sup>A573V</sup>and<i>JAK3</i><sup>M511I</sup>mutations in peripheral T-cell lymphoma mediating resistance to anti-PD-1 therapy through the STAT3/PD-L1 pathway
Authors: Ning Lou, Mengwei Yang, Zucheng Xie, Ruyun Gao, Lei Zhang, Le Tang, Jiarui Yao, Xiaohong Han, Yuankai Shi
Journal: Journal for ImmunoTherapy of Cancer (2025)

Background Clinical evidence has established anti-PD-1 antibody as a transformative treatment modality for relapsed/refractory peripheral T-cell lymphoma (r/r PTCL), yet reveals a therapeutic plateau with drug resistance observed in 60% of r/r PTCL. The biological determinants underlying this resistance—particularly the complex interplay between tumor-intrinsic characteristics (including tumor mutation burden and oncogenic mutations) and immune microenvironment features (notably PD-L1 expression)—remain insufficiently illustrated. Therefore, we systematically depicted the comprehensive mutation profile of r/r PTCL patients and correlated them with the efficacy and prognosis of anti-PD-1 therapy. Methods Here, we enrolled a cohort of 109 patients with r/r PTCL and performed targeted next-generation sequencing of 440 cancer-associated genes. Clinical information was collected and correlated with genetic mutations. We constructed JAK3 mutant models using Jurkat and BA/F3 cell lines. We performed single-cell transcriptomics, western blotting, and flow cytometry to elucidate the molecular mechanism. Additionally, we built a JAK3 -mutant syngeneic mouse model to demonstrate in vivo antitumor efficacy of Tofacitinib and anti-PD-1 therapy. Results We identified and validated that PD-L1 was a predictor for the efficacy of anti-PD-1 therapy in PTCL patients. The subset of PTCL patients (13.5%) characterized by enrichment of the APOBEC-related mutation signature had worse overall survival (p=0.031) compared with non-APOBEC-enriched samples. JAK3 and EZH2 mutations were associated with lower PD-L1 expression (p&lt;0.05), and JAK3 mutations were independently correlated with shorter progression-free survival (HR=6.07, p=0.0144). Among all types of JAK3 mutations, single-cell transcriptomics, western blotting, and flow cytometry revealed that JAK3 p.A573V and p.M511I mutations led to decreased PD-L1 expression in Jurkat and BA/F3 cell lines through inactivation of STAT3. Compared with JAK3 wild-type syngeneic mouse models, JAK3 p.A573V and p.M511I mutant mice were more sensitive to Tofacitinib but not anti-PD-1 antibody. Conclusions In conclusion, we found that JAK3 mutations, especially JAK3 p.A573V and JAK3 p.M511I mutations, lead to poor prognosis of anti-PD-1 therapy through the STAT3/PD-L1 pathway. Tofacitinib is more suitable than anti-PD-1 antibody for JAK3 mutant PTCL patients. Trial registration number NCT03502629 .
Bevacizumab, tislelizumab and nab-paclitaxel for previously untreated metastatic triple-negative breast cancer: a phase II trial
Authors: Meiting Chen, Riqing Huang, Qixiang Rong, Wei Yang, Xiujiao Shen, Qi Sun, Ditian Shu, Kuikui Jiang, Cong Xue, Jing Peng, Xin An, Haifeng Li, Fei Xu, Yanxia Shi
Journal: Journal for ImmunoTherapy of Cancer (2025)

Background Optimal first-line therapy for metastatic triple-negative breast cancer (mTNBC) varied in different situations. This phase II trial explores the efficacy and safety of combination regimens with be vacizumab, ti slelizumab and na b-paclitaxel (BETINA) in first-line setting for mTNBC. Methods Patients with previously untreated advanced TNBC received tislelizumab 200 mg and bevacizumab on day 1 and nab-paclitaxel 125 mg/m 2 on day 1, day 8 in 3-week cycles. Patients were randomized to bevacizumab 7.5 mg/kg or 15 mg/kg. The primary endpoint was investigator-assessed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors V.1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. The trial was registered at the Chinese Clinical Trial Registry (No. ChiCTR2200058567). Results 30 female patients were enrolled from March 11, 2021 to February 5, 2024. Nine patients receiving bevacizumab 15 mg/kg experienced significantly higher hypertension rates versus 7.5 mg/kg (55.5% vs 0%), prompting subsequent enrollment of 12 additional patients at 7.5 mg/kg. By November 30, 2024, the ORR was 73.3% and the disease control rate was 90.0%, while the median PFS was 6.0 months and the median OS was 19.8 months. No new safety signal was reported. Common treatment-related adverse events (AEs) included peripheral sensory neuropathy (83.3%), dyspepsia (70.0%), anemia (70.0%), leukocytopenia (66.7%), and pruritus (53.3%). Hypothyroidism (30.0%) was the most frequent immune-related AE. Biomarker analysis indicated that lower baseline interleukin (IL)-1α was associated with poor survival, while IL-2, vascular endothelial growth factor-A and insulin-like growth factor binding protein-7 levels significantly decreased at progression. RNA sequencing highlighted the enrichment of the fatty acid metabolism pathway in poor responders. Conclusions BETINA study demonstrated promising efficacy and favorable tolerance in treating patients with mTNBC with bevacizumab with tislelizumab and nab-paclitaxel.
Mendelian randomization of immune cell phenotypes to discover potential drug targets for B-cell malignancy
Authors: Sina A Beer, Molly Went, Charlie Mills, Codie Wood, Amit Sud, James M Allan, Richard Houlston, Martin F Kaiser
Journal: Blood Cancer Journal (2025)

Abstract Although treatment options for B-cell malignancies have expanded, many patients continue to face limited response rates, highlighting an urgent need for new therapeutic targets. To prioritize candidate drug targets for B-cell malignancies, we employed Mendelian Randomization to estimate potentially causal relationships between 445 immune cell traits and six B-cell cancers: follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), Hodgkin lymphoma (HL), marginal zone lymphoma (MZL), chronic lymphocytic leukemia (CLL), and multiple myeloma (MM), totaling 22,922 cases and 394,204 controls. 163 traits showed a suggestive association with at least one B-cell malignancy ( P &lt; 0.05), with 34 traits being significant after correction for multiple testing ( P &lt; 2 × 10 −4 ). By integrating findings with observational data and clinical trial evidence to support drug target candidacy, 24 cell surface markers were identified as druggable targets. In addition to established therapeutic targets such as CD3, CD20 and CD38, our analysis highlights BAFF-R and CD39 in HL, CD25 in MM, CD27 in CLL, CD80/86 in DLBCL, and CCR2 in FL and MZL as promising candidates for therapeutic inhibition. Our findings provide further support for the potential of human genetics to guide the identification of drug targets and address a productivity-limiting step.