tbuckley/cabot-search huggingface dataset:
Mavacamten in Symptomatic Nonobstructive Hypertrophic Cardiomyopathy
Authors: Milind Y Desai, Steve E Nissen, Theodore Abraham, Iacopo Olivotto, Pablo Garcia-Pavia, Renato D Lopes, Nicolas Verheyen, Omar Wever-Pinzon, Kathy Wolski, Wael Jaber, Lisa Mitchell, Deborah Davey, Jonathan Myers, Thomas Rano, Vandana Bhatia, Yue Zhong, Suzanne Carter-Bonanza, Victoria Florea, Ron Aronson, Anjali T Owens
Journal: JACC Heart Failure (2025)

There are no approved therapies for patients with symptomatic nonobstructive hypertrophic cardiomyopathy (nHCM). The authors describe the baseline characteristics of ODYSSEY-HCM (A Study of Mavacamten in Non-Obstructive Hypertrophic Cardiomyopathy), a phase 3, randomized, double-blind, placebo-controlled trial conducted worldwide at 201 sites evaluating mavacamten in symptomatic adult patients with nHCM. The 2 primary endpoints are the changes from baseline to week 48 in: 1) Kansas City Cardiomyopathy Questionnaire 23-item Clinical Summary Score; and 2) peak oxygen consumption (pVO2) on cardiopulmonary exercise testing. Dose titrations are made on blinded core laboratory assessments. Of 1,088 patients screened, 580 are randomized (mean age 56 ± 15 years, 46% women, 43% with family histories). All patients are nonobstructive and symptomatic (70% in NYHA functional class II and 30% class III), with a mean Kansas City Cardiomyopathy Questionnaire 23-item Clinical Summary Score of 58 ± 20, and 77% are on beta-blockers. The mean left ventricular ejection fraction and pVO2 are 66% ± 4% and 18 ± 6 mL/kg/min, respectively. ODYSSEY-HCM will report if mavacamten improves patient-reported health status and exercise capacity in patients with symptomatic nHCM. (A Study of Mavacamten in Non-Obstructive Hypertrophic Cardiomyopathy (ODYSSEY-HCM); NCT05582395).
EuroQol 5-Dimension Questionnaire in Heart Failure With Reduced, Mildly Reduced, and Preserved Ejection Fraction
Authors: Mingming Yang, Toru Kondo, Atefeh Talebi, Pardeep S Jhund, Kieran F Docherty, Brian L Claggett, Muthiah Vaduganathan, Erasmus Bachus, Adrian F Hernandez, Carolyn S P Lam, Felipe A Martinez, Rudolf A de Boer, Mikhail N Kosiborod, Akshay S Desai, Lars Køber, Piotr Ponikowski, Marc S Sabatine, Scott D Solomon, John J V McMurray
Journal: JACC Heart Failure (2025)

The value of generic quality of life (QoL) instruments in heart failure (HF) is uncertain. In this study, the authors sought to quantify individual dimension scores and the EuroQol 5-Dimension questionnaire (EQ-5D) Level Sum Score (LSS) in patients with HF with reduced, mildly reduced, or preserved ejection fraction, the association between those scores and outcomes, and the impact of treatment with dapagliflozin on the scores. Analyses were conducted using patient-level data from DAPA-HF and DELIVER trials. Cox proportional hazards regression models were used to assess the association between EQ-5D scores (each dimension and LSS) and clinical outcomes. Sankey diagrams were used to illustrate changes in individual patient EQ-5D dimensions from baseline to 8 months' follow-up. Of the 11,007 patients randomized in DAPA-HF and DELIVER, 10,135 (92.1%) completed the instrument at baseline. Scores varied markedly by question with 37%, 30%, and 33% of patients reporting no, slight, or moderate or greater problem, respectively for mobility; 67%, 20%, and 13% for self-care; 40%, 33%, and 27% for usual activities; 45%, 32%, and 23% for pain/discomfort; and 57%, 27%, and 16% for anxiety/depression. Patients with higher (worse) EQ-5D-LSS were more frequently female, had more comorbidities, and had worse HF status. Compared with patients free from any problem across all dimensions (ie, an EQ-5D-LSS of 5), the HRs for the composite outcome of time to first cardiovascular death or worsening HF were 1.27 (95% CI: 1.10-1.47), 1.70 (95% CI: 1.46-1.98), and 2.31 (95% CI: 1.88-2.85) in patients with EQ-5D-LSS of 6-10, 11-15, and 16-25 points, respectively. Dapagliflozin led to greater improvement and less worsening in mobility (OR: 1.13 [95% CI: 1.04-1.23]; P = 0.004), self-care (OR: 1.13 [95% CI: 1.02-1.24]; P = 0.016), usual activities (OR: 1.11 [95% CI: 1.02-1.21]; P = 0.015), and anxiety/depression (OR: 1.10 [95% CI: 1.01-1.21]; P = 0.034) after 8 months. The number needed to treat for 1 patient to report improvement in EQ-5D-LSS was 31 (95% CI: 20-72). The EQ-5D revealed problems not often associated (eg, pain) with HF or commonly quantified in HF (eg, anxiety/depression). Dapagliflozin improved multiple QoL dimensions, and possibly anxiety/depression. (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure [DAPA-HF]; NCT03036124; Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213).
Hiding in plain sight: NUT carcinoma is an unrecognized subtype of squamous cell carcinoma of the lungs and head and neck
Authors: Jia Luo, Justin A Bishop, Steven G DuBois, Glenn J Hanna, Lynette M Sholl, Edward B Stelow, Lester D R Thompson, Geoffrey I Shapiro, Christopher A French
Journal: Nature Reviews Clinical Oncology (2025)
Application of multimodal large language models for safety indicator calculation and contraindication prediction in laser vision correction
Authors: Joon Yul Choi, Doo Eun Kim, Sung Jin Kim, Hannuy Choi, Tae Keun Yoo
Journal: npj Digital Medicine (2025)

This study demonstrates the potential of multimodal large language models in calculating safety indicators and predicting contraindications for laser vision correction. ChatGPT-4 effectively analyzed ocular data, calculated key indicators, generated calculator codes, and outperformed traditional machine learning models and indicators in handling unstructured data and corneal topography. Its modality-independent system enabled efficient and accurate data analysis. Despite longer processing times, ChatGPT-4's performance highlights its potential as a decision-support tool, offering advancements in improving safety.
Measuring Representativeness in Clinical Trials
Authors: Allen Sanyi, Samuel Byiringiro, Sanaz Dabiri, Mireille Jacobson, Amanda Boyd, Modele O. Ogunniyi, Alanna A. Morris, Rachel Kohn, Neal W. Dickert, Meghan B. Lane-Fall, Eldrin F. Lewis, Scott D. Halpern, Alexander C. Fanaroff
Journal: Circulation (2025)

Representativeness in randomized clinical trials remains a critical concern, affecting the external validity of trial results, equitable access to the risks and benefits of research participation, and public trust in clinical research. Although representative participation by members of groups traditionally underrepresented in clinical trials is just a surrogate for true diversity, equity, inclusion, and belonging in clinical trials, it can be quantified, allowing stakeholders to add empirical rigor to diversity, equity, inclusion, and belonging efforts. Multiple ways to measure representativeness have been proposed, including the participation-to-prevalence ratio, raw participation proportions or numbers for relevant subgroups, and enrollment fraction for relevant subgroups. These methods have strengths and weaknesses and may be appropriate to report in certain circumstances, depending on why stakeholders seek to assess representativeness. Stakeholders—including regulatory agencies, journal editors, clinical trial investigators, and trial sponsors—may use quantitative measures of representativeness to establish trial enrollment standards, monitor equitable participation in ongoing trials, and condition funding or drug or device approval on achieving specific representativeness targets. However, using quantitative measures of representativeness in this way could have unintended consequences, including researchers “gaming” recruitment strategies to meet target numbers, overlooking nuanced variations within communities, and potentially incentivizing problematic and exploitative recruitment strategies. Although no single method of measuring representativeness offers a comprehensive solution for increasing diversity, equity, inclusion, and belonging in all randomized clinical trials, a carefully designed, multifaceted approach to measuring representativeness may provide stakeholders with useful perspectives for measuring progress in increasing the diversity of clinical trial participation. For stakeholders seeking a single number to assess the representativeness of a trial enrolling patients with a disease state with well-delineated demographics, the participation-to-prevalence ratio is ideal; however, for a more nuanced view of representativeness, the combination of enrollment fraction in subgroups of relevance plus a full report of the demographics of patients approached for enrollment may be more appropriate.
Genetically Predicted IL-18 Inhibition and Risk of Cardiovascular Events: A Mendelian Randomization Study
Authors: Stephen O. Brennan, Peter J. Kelly, Sarah Gorey, Pádraig Synnott, Dipender Gill, Martin Dichgans, Marios K. Georgakis, Marie-Joe Dib, Eloi Gagnon, Niall Mahon, Gavin J. Blake, Christina Jern, Hugh S. Markus, William Whiteley, John J. McCabe
Journal: Circulation (2025)
Risk of Atrial Fibrillation After Hemorrhagic Stroke: A Nationwide Cohort Study With Propensity Score Matching
Authors: Jihun Kang, Jung Eun Yoo, Byeoung-Jun Jeon, Sung Il Im, Bongseong Kim, Won Hyuk Chang, Kyungdo Han, Dong Wook Shin
Journal: Circulation (2025)
Updated Expert Opinion Guidelines Regarding the Effects of Immunosuppressive Agents on Patch Testing
Authors: Mykayla Sandler, Brandon L Adler, Amber R Atwater, Donald V Belsito, Nina C Botto, Joel G DeKoven, Vincent A DeLeo, Cory A Dunnick, Joseph F Fowler, Marie-Claude Houle, Howard I Maibach, Christen M Mowad, Margo J Reeder, James S Taylor, Erin M Warshaw, Peggy A Wu, Jonathan H Zippin, JiaDe Yu
Journal: Journal of the American Academy of Dermatology (2025)
What Are Baskets, Umbrellas, and Platforms Doing in Nephrology Clinical Trials?
Authors: Julie Lin, Jai Radhakrishnan
Journal: Journal of the American Society of Nephrology (2025)

1Sanofi, Cambridge, MA and Brigham and Women's Hospital, Boston, MA, USA 2Columbia University Medical Center, New York, NY, USA aCorresponding author: Dr. Jai Radhakrishnan, Columbia University Medical Center, New York, NY, USA, [email protected]
Review of Category A bioweapons with cutaneous features: Epidemiology, clinical presentation, and contemporary management strategies
Authors: Sara Osborne, Olivia Kam, Shivani Thacker, Raquel Wescott, Carolynne Vo, Jashin J Wu, Nathan W Rojek, Scott A Norton
Journal: Journal of the American Academy of Dermatology (2025)

Major health organizations recognize various pathogens as potential bioweapons. Category A bioweapons (anthrax, plague, smallpox, tularemia, and viral hemorrhagic fevers) are the highest priority due to their ease of spread and high mortality rates. As these conditions have cutaneous manifestations, dermatologists may have an important role as front-line responders to indolent or bioterrorism threats. Few dermatologists are adequately prepared to approach the diagnosis and management of these conditions if encountered. Furthermore, despite improvements made in identifying, diagnosing, and treating these conditions over the past ten years, there persists an absence of a synthesized distribution of these updates customized to adequately equip dermatologists. In this paper, we review the epidemiology, transmission, and dermatologic signs and symptoms of the Category A bioweapons listed above. We also offer an overview of the evidence-based strategies for diagnosis and management and provide access to each states' guidelines for reporting these conditions.
Characterization of the Cystic Phenotype Associated with Monoallelic ALG8 and ALG9 Pathogenic Variants
Authors: Tabinda Jawaid, Doaa E. Elbarougy, Sravanthi Lavu, Guillaume Buia, Sarah R. Senum, Eric Olinger, Hana Yang, Shannon K. McDonnell, Joshua T. Bublitz, Jun Ma, Marie-Pierre Audrézet, Charles D. Madsen, Rachel S. Schauer, Tracy A. Baker, Adriana V. Gregory, Sarah G. Orr, Miguel Barroso-Gil, Ruxandra Neatu, Giancarlo Joli, Neera K. Dahl, Timothy L. Kline, Valentine Gillion, Karin Dahan, Francois Jouret, Ronald D. Perrone, Theodore I. Steinman, Dorien J.M. Peters, Berenice Y. Gitomer, Terry J. Watnick, Eliecer Coto, Fouad T. Chebib, Marie C. Hogan, Janet E. Olson, Nicholas B. Larson, Elisabet Ars, Jan Halbritter, Nathalie Demoulin, Vicente E. Torres, John A. Sayer, Emilie Cornec-Le Gall, Peter C. Harris
Journal: Journal of the American Society of Nephrology (2025)

Background: Autosomal dominant polycystic kidney disease (ADPKD) is a common, inherited nephropathy often resulting in kidney failure. It is genetically heterogeneous; along with the major genes, PKD1 and PKD2 , at least 8 others have been suggested. ALG8 pathogenic variants have been associated with autosomal dominant polycystic liver disease and implicated in ADPKD, while ALG9 has been suggested as an ADPKD gene, but details of the phenotypes and penetrance are unclear. Methods: We screened &gt;3900 families with cystic kidneys and/or livers using global approaches to detect ALG8 or ALG9 pathogenic variants. In addition, population cohorts with sequence data (Genomics England 100kGP (100kGP), UK Biobank (UKBB), and Mayo Clinic Biobank (MCBB)), were screened for ALG8 / ALG9 pathogenic variants. Results: Multicenter screening of individuals with polycystic kidney and/or liver disease identified 51 (1.3%) ALG8 (7 multiplex) and 23 (0.6%) ALG9 (5 multiplex) families; frequencies that were ∼10x and ∼24x greater than non-polycystic kidney disease (PKD) controls. Analysis of individuals with PKD phenotypes in 100kGP, UKBB, and MCBB identified 9 ALG8 (0.39%) and 9 ALG9 (0.39%) families, an enriched frequency over controls. Two individuals had PKD1 and ALG8 pathogenic changes. Eighty-nine percent of individuals with ALG8 mutations with imaging in the entire MCBB had kidney cysts (56%, &gt;10 cysts), with greater median kidney and liver cyst numbers than controls. For ALG9, 78% had kidney cysts (27%, &gt;10 cysts). Individuals with ALG8 mutations typically had mild cystic kidneys with limited enlargement. Liver cysts were common (71%) with enlarged livers (&gt;2L) found in 11/62 patients although surgical intervention was rare. The ALG9 kidney phenotype was also of mild cystic kidneys but enlarged livers were rare; for both genes chronic kidney disease or kidney failure were rare. Conclusions: ALG8 and ALG9 are defined as cystic kidney/liver genes but with limited penetrance for lower eGFR.
Birth Outcomes among Infants Born between 2006 and 2018 after Maternal Exposure during Pregnancy to Ultrafine Particles from Aviation around a Large International Airport in the Netherlands
Authors: José H. Jacobs, Alina Nicolaie, Maciej Strak, Jurriaan Hoekstra, Eline F. de Vries, Joost Wesseling, Danny Houthuijs, Nicole A.H. Janssen
Journal: Environmental Health Perspectives (2025)

People who live near airports are exposed to higher concentrations of ultrafine particles (UFPs) from aviation. Pregnant women and their fetuses, in particular, are considered to be highly susceptible to environmental exposures. Using existing national databases, we investigated associations between adverse birth outcomes and exposure to UFPs from aviation (UFP-aviation) at the residential address during pregnancy. We identified ∼286,000 singleton birth records (from between 2006 and 2018) from mothers who, for at least 6 months during pregnancy, lived in a 50×56km area around Schiphol Airport. This information was linked to modeled monthly averaged UFP-aviation concentrations at the residential address during pregnancy. We modeled the association between exposure to UFP-aviation during pregnancy and pregnancy outcomes through logistic regression, adjusting for individual and neighborhood level covariates. We performed a number of sensitivity analyses to investigate the robustness of the results, including adjustment for other air pollutants and noise. Effect estimates, expressed per 3,500 particles/cm3 (approximately the 5th-9th percentile difference) increase, were generally positive in the main model for preterm birth (PTB) and small for gestational age (SGA) [PTB OR= 1.02 (95% CI: 0.96, 1.07) and SGA OR= 1.02 (95% CI: 0.98, 1.07)] and congenital anomalies (CAs) at birth [any CA OR= 1.05 (95% CI: 0.98, 1.07)]. Associations with UFP-aviation became stronger in some of the sensitivity analyses, such as when the four municipalities with the lowest exposure were excluded (for PTB, SGA, and CA), when the population was restricted to mothers with a Dutch background (PTB), after nonlinear adjustment for nitrogen dioxide (NO2) and elemental carbon (EC) (PTB), after including municipality as a random effect (CA), and in some specific strata of the population. No associations were found with infant mortality, low Apgar score, and low birth weight. We found suggestive evidence for associations between exposure to UFP-aviation during pregnancy and pregnancy outcomes. https://doi.org/10.1289/EHP14398.
Targeting TAK1: Evolution of inhibitors, challenges, and future directions
Authors: Nika Strašek Benedik, Matic Proj, Christian Steinebach, Matej Sova, Izidor Sosič
Journal: Pharmacology & Therapeutics (2025)

The increasing incidence of inflammatory and malignant diseases signifies the need to develop first-in-class drugs with novel mechanisms of action. In this respect, the transforming growth factor (TGF)-β-activated kinase 1 (TAK1), an essential part of several signaling pathways, is considered relevant and promising. This manuscript provides a brief overview of the signal transduction orchestrated by TAK1 within these pathways, followed by an in-depth and thorough analysis of the chemical matter demonstrated to inhibit this kinase. Special attention is given to the selectivity profiling of inhibitors, as well as to the outcomes of their biological characterization. Because published TAK1 inhibitors differ significantly in their kinome selectivity, active-site binding, and biological activity, we hope that this review will allow a judicial estimation of their quality and usefulness for TAK1-addressing assays. Our thoughts on the perspectives and possible developments of the field are also provided to assist scientists who are involved in the design and development of TAK1-targeting modulators.
IARC Workshop on the Key Characteristics of Carcinogens: Assessment of End Points for Evaluating Mechanistic Evidence of Carcinogenic Hazards
Authors: David M. DeMarini, William Gwinn, Emily Watkins, Brad Reisfeld, Weihsueh A. Chiu, Lauren Zeise, Dinesh Barupal, Parveen Bhatti, Kevin Cross, Eugenia Dogliotti, Jason M. Fritz, Dori Germolec, Maria Helena Guerra Andersen, Kathryn Z. Guyton, Jennifer Jinot, David H. Phillips, Roger R. Reddel, Nathaniel Rothman, Martin van den Berg, Roel C.H. Vermeulen, Paolo Vineis, Amy Wang, Maurice Whelan, Akram Ghantous, Michael Korenjak, Jiri Zavadil, Zdenko Herceg, Sandra Perdomo, Laure Dossus, Shirisha Chittiboyina, Danila Cuomo, John Kaldor, Elisa Pasqual, Gabrielle Rigutto, Roland Wedekind, Caterina Facchin, Fatiha El Ghissassi, Aline de Conti, Mary K. Schubauer-Berigan, Federica Madia
Journal: Environmental Health Perspectives (2025)

The 10 key characteristics (KCs) of carcinogens form the basis of a framework to identify, organize, and evaluate mechanistic evidence relevant to carcinogenic hazard identification. The 10 KCs are related to mechanisms by which carcinogens cause cancer. The International Agency for Research on Cancer (IARC) Monographs programme has successfully applied the KCs framework for the mechanistic evaluation of different types of exposures, including chemicals, metals, and complex exposures, such as environmental, occupational, or dietary exposures. The use of this framework has significantly enhanced the identification and organization of relevant mechanistic data, minimized bias in evaluations, and enriched the knowledge base regarding the mechanisms of known and suspected carcinogens. We sought to report the main outcomes of an IARC Scientific Workshop convened by the IARC to establish appropriate, transparent, and uniform application of the KCs in future IARC Monographs evaluations. A group of experts from different disciplines reviewed the IARC Monographs experience with the KCs of carcinogens, discussing three main themes: a) the interpretation of end points forming the evidence base for the KCs, b) the incorporation of data from novel assays on the KCs, and c) the integration of the mechanistic evidence as part of cancer hazard identification. The workshop participants assessed the relevance and the informativeness of multiple KCs-associated end points for the evaluation of mechanistic evidence in studies of exposed humans and experimental systems. Consensus was reached on how to enhance the use of in silico, molecular, and cellular high-output and high-throughput data. In addition, approaches to integrate evidence across the KCs and opportunities to improve methodologies of mechanistic evaluation of cancer hazards were explored. The findings described herein and in a forthcoming IARC technical report will support future working groups of experts in reporting and interpreting results under the KCs framework within the IARC Monographs or in other contexts. https://doi.org/10.1289/EHP15389.
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Authors: Goran Stanajic-Petrovic, Mathilde Keck, Peggy Barbe, Apolline Urman, Evelyne Correia, Pierre Isnard, Jean-Paul Duong Van Huyen, Khawla Chmeis, Sékou Siramakan Diarra, Stefano Palea, Frederic Theodoro, Anvi-Laëtitia Nguyen, Florence Castelli, Alain Pruvost, Wenchao Zhao, Christiane Mendre, Bernard Mouillac, Frank Bienaimé, Philippe Robin, Pascal Kessler, Catherine Llorens-Cortes, Denis Servent, Hervé Nozach, Bernard Maillère, Dong Guo, Charles Truillet, Nicolas Gilles
Journal: Journal of the American Society of Nephrology (2025)
Bcl-Xl Protects ASS1-Deficient Cancers From Arginine Starvation Induced Apoptosis
Authors: Prashanta Kumar. Panda, Ana Carolina. Paschoalini Mafra, Alliny C. S. Bastos, Li Cao, Maria Serra Bonet, Caitlyn B. Brashears, Ethan Yang. Chen, Heather M. Benedict-Hamilton, William Ehrhardt, John Bomalaski, Carina Dehner, Leonard C. Rogers, Toshinao Oyama, Brian A. Van Tine
Journal: Clinical Cancer Research (2025)

Abstract Purpose: Argininosuccinate Synthetase 1 (ASS1) silencing in carcinomas and sarcomas leads to a dependence on extracellular arginine for survival. Arginine deprivation therapies, like PEGylated arginine deiminase (ADI-PEG20), have shown limited effectiveness, which may be due to underlying mechanisms that inhibit apoptosis. Experimental Design: The effects of ADI-PEG20 on cell cycle regulation, apoptosis, and Bcl-xL-mediated survival pathways in ASS1-deficient cancer cells were determined. The mechanism of cell death protection was determined by assessing caspase and PARP cleavage, CDK2 activity, MCL1 expression, and the interactions between Bcl-xL, Bax, and Bak. In vitro synergy was determined, and in vivo efficacy was modeled. Results: Treatment with ADI-PEG20 led to reduced CDK2 activity and inhibited cell cycle progression but did not induce significant cell death. Bcl-xL was found to bind to Bax and Bak, preventing the initiation of apoptosis despite arginine starvation. Inhibition of Bcl-xL allowed proapoptotic Bax and Bak to initiate the intrinsic apoptosis pathway, leading to increased cell death. This was found to be synergistic in vitro and efficacious in combination in vivo. Conclusions: The study identifies Bcl-xL as a key factor limiting the efficacy of arginine starvation therapies. Combining Bcl-xL inhibitors with arginine deprivation strategies may overcome this resistance and enhance therapeutic outcomes. These findings provide a strong preclinical rationale for testing this combination approach in Phase 1 clinical trials for ASS1-deficient cancers.