tbuckley/cabot-search huggingface dataset:
JAB-3312, a Potent Allosteric SHP2 Inhibitor that Enhances the Efficacy of RTK/RAS/MAPK and PD-1 Blockade Therapies
Authors: Di Kang, Yanping Wang, Yiwei Lin, Wen Wee Ma, Daniel Morgensztern, Konstantinos Leventakos, Chao Bi, Yuli Ding, Jing Xiong, Man Yan, Xin Sun, Peng Wang, Cunbo Ma, Yinxiang Wang
Journal: Clinical Cancer Research (2025)

Abstract Purpose: Recent advances have seen the development of targeted therapeutics against the RTK/RAS/MAPK pathway which, when aberrantly activated, drives malignant transformation of many cancer indications. However, efficacy of inhibitors targeting single molecules is dampened by pathway feedback activation and acquired drug resistance. We seek to evaluate the application of JAB-3312 (Sitneprotafib), a potent inhibitor of SHP2, in the RTK/RAS/MAPK pathway-targeted combination therapies. Furthermore, SHP2 plays a vital role in PD-1-mediated immunosuppression. Rational combination of JAB-3312 with PD-1 blocking therapies is also explored. Experimental Design: Biochemical and cellular assays were applied to evaluate the potency of JAB-3312 in SHP2 inhibition. Tumor cell lines, cell line- and patient-derived xenografts were used to test different combinations of JAB-3312 with KRASG12C, MEK, EGFR, and PD-1 inhibitors. Results: JAB-3312 produced potent in vitro inhibition of SHP2 activity and downstream ERK phosphorylation, with IC50s of 1.44 nM and 0.68 to 4.84 nM, respectively. When in combination, JAB-3312 significantly increased the anti-tumor activity of KRASG12C inhibitor glecirasib in naïve and resistant models. Combination of JAB-3312 with MEK inhibitors significantly delayed RTK signaling reactivation and enhanced tumor growth inhibition in KRAS-mutated cancer models. JAB-3312-osimertinib combination exhibited great efficacy in osimertinib-resistant non-small cell lung cancer models. Besides, JAB-3312 enhanced the efficacy of PD-1 blockade therapies by promoting anti-tumor microenvironment. Representative cases of patients with response to the combination therapies from two ongoing clinical trials (NCT05288205, NCT04720976) were reported. Conclusions: JAB-3312 in combination with RTK/RAS/MAPK or PD-1 blockage therapies is a promising strategy that warrants further clinical investigation.
Cross-Species Framework for Emotional Well-Being and Brain Aging
Authors: F. Vankee Lin, Janine M. Simmons, Adam Turnbull, Yi Zuo, Yeates Conwell, Kuan Hong Wang
Journal: JAMA Psychiatry (2025)

Importance Emotional well-being (EWB) is an emerging therapeutic target for managing and preventing symptoms associated with Alzheimer disease and related dementias (ADRD). However, more research is needed to establish causal inferences between brain changes, EWB, and behavioral changes observed in typical aging and ADRD. Observations This article presents a framework for using a cross-species behavioral neuroscience approach to study EWB and brain aging, adopting a well-established biobehavioral model that highlights the reciprocal roles of brain changes, EWB, and ADRD symptoms. First, the challenges and opportunities in this field are reviewed. Then, a practical solution to improve comparability between animal and human studies is proposed. Conclusions and Relevance The goal is to draw comprehensive parallels and distinctions that could enhance the understanding of the mechanisms linking brain aging, EWB, and ADRD symptomatic disturbances across different species.
Antineutrophil Cytoplasmic Autoantibodies
Authors: Nicole E. Wyatt, Vimal K. Derebail, Ronald J. Falk, Koyal Jain
Journal: Journal of the American Society of Nephrology (2025)

Antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis is a rare and potentially fatal autoimmune disorder characterized by pauci-immune necrotizing vasculitis affecting small to medium sized blood vessels. The pathogenic role of ANCAs in ANCA-associated vasculitis is supported by both clinical and experimental evidence, and when used in the proper clinical setting ANCA testing is highly specific for ANCA-associated vasculitis. Testing with both indirect immunofluorescence assay (IFA) and enzyme immunoassay (EIA) may increase sensitivity for ANCA-associated vasculitis, however testing with a high-quality EIA may be used alone. Non-vasculitic conditions and drugs can cause ANCA positivity without manifestations of ANCA-associated vasculitis. We review ANCA testing itself, performance characteristics and specific conditions for the laboratory test, and various conditions when ANCA testing is useful in diagnosis, disease monitoring and selecting treatment.
<i>APOE4</i>, Blood Neurodegenerative Biomarkers, and Cognitive Decline in Community-Dwelling Older Adults
Authors: Ted K. S. Ng, Todd Beck, Patricia Boyle, Klodian Dhana, Pankaja Desai, Denis A. Evans, Kumar B. Rajan
Journal: JAMA Network Open (2025)

Importance Scarce population-based data exist on whether APOE4 modifies associations of blood-based neurodegenerative biomarkers with cognitive decline, particularly in a diverse, biracial population of community-dwelling older adults without dementia. Objective To assess whether APOE4 carrier status is associated with an accelerated rate of cognitive decline in older adults without dementia and with elevated neurodegenerative burden. Design, Setting, and Participants This 20-year prospective cohort study started in 1993 and was conducted through 2012 on the South Side of Chicago among community-dwelling older adults without dementia from the longitudinal biracial Chicago Health and Aging Project. The interaction of APOE4 carrier status with prospective associations of serum neurodegenerative biomarkers with global cognitive decline was examined using a mixed-effects regression model, adjusting for demographics and chronic health conditions. Statistical analyses were conducted from June 2024 to January 2025. Exposure APOE4 carrier status and serum biomarker levels for total tau (t-tau), neurofilament light (NfL) chain, and glial fibrillary acidic protein (GFAP) measured with a Quanterix Neuroplex kit at baseline. Main Outcomes and Measures Cognitive decline calculated from composite global cognition scores across study waves. Results Among 1038 community-dwelling older adults (mean [SD] age, 77.1 [5.9] years; 615 Black [59.2%] and 423 White [40.8%]; 651 female [62.7%]), there was a mean (SD) of 12.8 (3.4) years of education and 343 individuals (33.0%) were APOE4 carriers. Higher levels of blood-based neurodegenerative biomarkers (ie, t-tau, NfL, and GFAP) were associated with a faster rate of cognitive decline among APOE4 carriers than noncarriers. Specifically, compared with noncarriers, APOE4 carriers had annual rates of cognitive decline per 1–log 10 unit higher levels in t-tau and GFAP that were accelerated by a β (SD) of −0.03 (0.02) ( P = .046) and −0.07 (0.03) ( P = .02), respectively. Similarly, compared with noncarriers and participants in the lower NfL tertile, APOE4 carriers with middle and upper tertiles of NfL levels experienced accelerated cognitive decline, with a β (SD) of −0.04 (0.02) ( P = .006) and −0.03 (0.02) ( P = .07), respectively, although the difference was not significant for upper tertiles. Conclusions and Relevance This study found that higher levels of neurodegeneration (t-tau), axonal injury (NfL), and reactive astrocytes and neuroinflammation (GFAP) biomarkers were associated with accelerated cognitive decline in genetically susceptible APOE4 carriers. These findings highlight the association of APOE4 with exacerbation of neurodegenerative processes, with not only significant implications for understanding and tracking the progression of neurodegenerative diseases, but also a call for inclusivity of APOE4 status in scientific investigations and clinical trials.
Roflumilast Foam, 0.3%, for Psoriasis of the Scalp and Body
Authors: Melinda J. Gooderham, Javier Alonso-Llamazares, Jerry Bagel, Neal Bhatia, Michael Bukhalo, Janet DuBois, Laura K. Ferris, Lawrence Green, Leon H. Kircik, Benjamin Lockshin, Wei Jing Loo, Kim A. Papp, Jennifer Soung, Melissa S. Seal, Scott Snyder, Saori Kato, David Krupa, Patrick Burnett, David R. Berk, David H. Chu
Journal: JAMA Dermatology (2025)

Importance Current topical treatments for scalp psoriasis are limited by formulation, efficacy, and/or safety. Objective To assess safety and efficacy of roflumilast foam, 0.3%, in patients with psoriasis of the scalp and body. Design, Setting, and Participants This was a phase 3 double-blinded, vehicle-controlled randomized clinical trial conducted between August 24, 2021, and June 3, 2022, at 49 sites in Canada and the US. Eligible participants were 12 years and older with plaque psoriasis affecting up to 25% of the scalp and body, at least 10% of the scalp, and up to 20% of nonscalp areas, with a minimum Scalp−Investigator Global Assessment (S-IGA) score of 3 (moderate), and minimum Body−IGA (B-IGA) score of 2 (mild). Data analyses were performed from September 9 to December 30, 2022. Interventions Once-daily roflumilast foam, 0.3%, or vehicle for 8 weeks. Main Outcomes and Measures Coprimary end points were S-IGA and B-IGA success (clear [0] or almost clear [1] plus ≥2-grade improvement) at week 8. Secondary end points included S-IGA success at weeks 2 and 4, change in Scalp Itch−Numeric Rating Scale (SI-NRS), and SI-NRS and Worst Itch−NRS (WI-NRS) success (≥4-point improvement in patients with baseline score of ≥4). Safety and tolerability were also assessed. Results A total of 432 patients (mean [SD] age, 47.3 [14.8] years; 243 women [56.3%]) were randomized to roflumilast foam (n = 281) or vehicle (n = 151). At week 8, 66.4% of the roflumilast group achieved S-IGA success vs 27.8% of the vehicle group ( P &amp;amp;lt; .001); and 45.5% of the roflumilast group achieved B-IGA success compared with 20.1% of the vehicle group ( P &amp;amp;lt; .001). Rates for S-IGA success at week 2 and SI-NRS and WI-NRS success at weeks 2, 4, and 8 were significantly higher for roflumilast vs vehicle. Improvements in SI-NRS were greater for the roflumilast vs the vehicle group as early as the first assessment (24 hours after the first application). Both study groups had low rates of adverse events and favorable tolerability profiles. Conclusions and Relevance This randomized clinical trial found that roflumilast foam, 0.3%, improved signs and symptoms of psoriasis on the scalp and body, including pruritus, with low rates of adverse events in patients 12 years and older. These results demonstrate the potential of roflumilast foam, 0.3%, as monotherapy for patients with psoriasis of the scalp and body. Trial Registration ClinicalTrials.gov Identifier: NCT05028582
Enzalutamide and Prostate-Specific Antigen Levels in Metastatic Prostate Cancer
Authors: Arun A. Azad, Daniel P. Petrylak, Taro Iguchi, Neal D. Shore, Arnauld Villers, Francisco Gomez-Veiga, Antonio Alcaraz, Boris Alekseev, Russell Z. Szmulewitz, Jeffrey Holzbeierlein, Brad Rosbrook, Jie Ma, Fabian Zohren, Nader N. El-Chaar, Gabriel P. Haas, Arnulf Stenzl, Andrew J. Armstrong
Journal: JAMA Network Open (2025)

Importance In men with metastatic hormone-sensitive prostate cancer (mHSPC), prostate-specific antigen (PSA) decline after treatment has been associated with improved survival. However, the data on PSA decline are limited in men with mHSPC after treatment with enzalutamide plus androgen deprivation therapy (ADT). Objective To evaluate the association of enzalutamide plus ADT in men with mHSPC by PSA level at study enrollment in individuals with prior ADT and by degree of PSA reduction with clinical end points. Design, Setting, and Participants This post hoc secondary analysis was performed on data collected from the ARCHES multinational, double-blind, phase 3 randomized clinical trial. In the ARCHES trial, men with mHSPC were randomized between March 21, 2016, and January 12, 2018. Analyses were performed in October 2018 (median follow-up, 14.4 months; IQR, 11.2-17.7 months) and May 2021 (median follow-up, 44.6 months; IQR, 41.3-48.6 months). Intervention Patients were randomized 1:1 to enzalutamide (160 mg/d) plus ADT or placebo plus ADT. ADT received for 3 to 6 months before study enrollment was permitted. Main Outcomes and Measures Radiographic progression-free survival (rPFS) and overall survival (OS) were correlated post hoc with PSA level at enrollment in patients with prior ADT and additionally with PSA decline at 6 months or undetectable PSA (&amp;amp;lt;0.2 ng/mL) during study treatment. Results A total of 1150 men (median age, 70 years; range, 46-92 years) were enrolled. Improvement in clinical outcomes such as rPFS was seen with enzalutamide plus ADT in men with PSA levels at enrollment of 0.2 to 4 ng/mL and above 4 ng/mL. Hazard ratios (HRs) for improved rPFS in men with PSA levels up to 0.2 ng/mL, above 0.2 to 4 ng/mL, and above 4 ng/mL were 0.59 (95% CI, 0.27-1.30), 0.32 (95% CI, 0.20-0.50), and 0.44 (95% CI, 0.32-0.62), respectively. Patients treated with enzalutamide plus ADT who achieved undetectable PSA had an 86.0% reduced risk of radiographic disease progression (HR, 0.14 [95% CI, 0.09-0.23]; P &amp;amp;lt; .001) and a 76.0% reduced risk of death (HR, 0.24 [95% CI, 0.17-0.34]; P &amp;amp;lt; .001). Conclusions and Relevance In this secondary analysis of a randomized clinical trial, patients with mHSPC treated with enzalutamide plus ADT vs placebo plus ADT had improved clinical outcomes regardless of PSA level at enrollment. Undetectable PSA was associated with improved clinical outcomes with enzalutamide treatment. Future studies are required to further characterize the clinical utility of further treatment intensification among men with mHSPC for whom ADT plus enzalutamide fails to achieve undetectable PSA. Trial Registration ClinicalTrials.gov Identifier: NCT02677896
Epidemiological and Translational Study of Calprotectin and Atherosclerotic Cardiovascular Disease
Authors: Yu Zuo, Somanathapura K. NaveenKumar, Sherwin Navaz, Wenying Liang, Kavya Sugur, Katarina Kmetova, Colby R. Ayers, Lyndsay Kluge, Emily Chong, Amil M. Shah, Anand Rohatgi, Jarett D. Berry, Jason S. Knight, James A. de Lemos
Journal: JAMA Cardiology (2025)

Importance Innate immunity, particularly neutrophil activation, plays a crucial role in the pathogenesis of atherosclerotic cardiovascular disease (ASCVD). The potential of calprotectin, a biomarker of neutrophil activation, as a mechanistically informed biomarker for ASCVD in an ethnically diverse population requires further investigation. Objective To examine the prospective association between circulating calprotectin and ASCVD in a diverse, population-based cohort while also exploring calprotectin’s mechanistic contributions to ASCVD in vitro. Design, Setting, and Participants Circulating calprotectin was measured in plasma collected from 2412 participants during phase 2 of the Dallas Heart Study, a multiethnic, population-based cohort study. The median follow-up after plasma collection was 8 years. Main Outcomes and Measures Associations with future ASCVD events (defined as first nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or death from a cardiovascular cause) were assessed using Cox proportional hazards models, adjusted for known cardiovascular disease risk factors as well as high-sensitivity C-reactive protein (hs-CRP), N-terminal pro–brain natriuretic peptide (NT-proBNP), and high-sensitivity cardiac troponin T (hs-cTnT). Results Higher calprotectin levels were associated with older age, male sex, Black race, hypertension, diabetes, and smoking history. Individuals with higher calprotectin had higher hemoglobin A 1c , very low-density lipoprotein cholesterol, and triglycerides, and lower high-density lipoprotein cholesterol and cholesterol efflux capacity. Log-transformed calprotectin levels were associated with an increased risk of ASCVD events over 8 years (hazard ratio [HR], 1.98 per log increase [95% CI, 1.54-2.53]). This association remained statistically significant after adjusting for prior ASCVD and traditional risk factors (HR, 1.61 [95% CI, 1.22-2.13]) and hs-CRP, NT-proBNP, and hs-cTnT (HR, 1.43 [95% CI, 1.04-1.96]). Higher calprotectin also correlated with higher coronary artery calcium scores ( P &amp;amp;lt; .001). In vitro studies revealed that calprotectin impaired coronary endothelial integrity, diminished nitric oxide production, and fostered endothelial to mesenchymal transition, providing potential mechanisms for ASCVD progression. Conclusions and Relevance The findings suggest that calprotectin may serve as a mechanistically informed biomarker for ASCVD, independent of traditional and contemporary cardiovascular risk factors and biomarkers. However, its clinical utility warrants further evaluation.
Vehicle Age and Driver Assistance Technologies in Fatal Crashes Involving Teen and Middle-Aged Drivers
Authors: Fangda Zhang, Christopher R. M. Rundus, Enas Alshaikh, Corinne Peek-Asa, Jingzhen Yang
Journal: JAMA Network Open (2025)

Importance Motor vehicle crashes are the leading cause of death for US teens. Newer vehicles and driver assistance technologies show promise in reducing crashes and injury severities; however, research on the age and technologies of vehicles driven by teens involved in fatal crashes is limited. Objective To examine the differences in vehicle age and driver assistance technologies between vehicles driven by teen and middle-aged drivers involved in fatal crashes and to investigate the associations among vehicle age, driver assistance technologies, and driver death in these crashes. Design, Setting, and Participants This retrospective cohort study used fatal crash data (2016-2021) obtained from the Fatality Analysis Reporting System. Data analysis was restricted to passenger vehicles. Participants included teen drivers (15-18 years old) and middle-aged drivers (31-55 years old). All analyses were performed between December 1, 2023, and July 25, 2024. Exposures Exposures include the vehicle age (≤5, 6-15, or &amp;amp;gt;15 years) and the number of driver assistance technologies installed (0 to 4). Main Outcomes and Measures The main outcome was whether the driver died in fatal crashes. Multivariable logistic regressions examined the associations between vehicle age (or driver assistance technologies installed) and driver death in fatal crashes, adjusting for driver sex, restraint use, and crash year. Results Among 81 145 drivers (49 838 male [61.4%]) involved in fatal crashes, there were 9809 teen drivers (mean [SD] age, 17.2 [0.9] years) and 71 336 middle-aged drivers (mean [SD] age, 41.7 [7.3] years). A higher proportion of teen drivers were operating vehicles older than 15 years compared with middle-aged drivers (2706 drivers [27.6%] vs 16 239 drivers [22.8%]). Driving vehicles aged 6 to 15 years (adjusted risk ratio [aRR], 1.19; 95% CI, 1.17-1.22) or older than 15 years (aRR, 1.31; 95% CI, 1.28-1.34) was associated with significantly higher odds of driver death in fatal crashes compared with driving vehicles 5 years old or newer, independently of driver age. Additionally, each installed driver assistance technology was associated with a 6% reduction (aRR, 0.94; 95% CI, 0.90-0.98) in the risk of driver death in fatal crashes. Conclusions and Relevance These findings suggest that older vehicles and those with fewer driver assistance technologies are associated with increased risk of driver death in fatal crashes; thus, teens should drive the safest vehicles available, not older family cars. The findings underscore the urgent need to ensure teens drive safer vehicles to protect their lives.
Association of Stratified Benchmarks With Financial Penalties in the ESRD Treatment Choices Model
Authors: Sri Lekha Tummalapalli, Yuvaram N. V. Reddy, Yueming Zhao, Nuo Chen, Seojeong Hong, Yuntian Shi, Zhimeng Yan, Amol S. Navathe
Journal: JAMA (2025)

This study compares proportions of facilities receiving penalties based on stratified benchmarks in the Centers for Medicare &amp;amp;amp; Medicaid Services’ End-Stage Renal Disease Treatment Choices (ETC) model, a pay-for-performance program incentivizing home dialysis and kidney transplant waitlisting.
SAT-454 Therapeutic Effects of GLP-1 agonist versus SGLT2-i on patients with T2D and MASLD
Authors: Ermina Stratina, Robert Nastasa, Remus Stafie, Adrian Rotaru, Sebastian Zenovia, Cristina-Maria Muzica, Laura Huiban, Irina Girleanu, Catalin Sfarti, Cojocariu Salloum, Horia Minea, Ana-Maria Singeap, Carol Stanciu, Anca Trifan
Journal: Journal of Hepatology (2025)
THU-337 Is the POISE really valid as a surrogate endpoint for patients with PBC treated with UDCA and PPAR agonist? – a retrospective validation study from the real-world data in Japan
Authors: Ryo Miura, Katsunori Yoshida, Masanori Abe, Tadashi Namisaki, Kyoko Oura, Kazuhito Kawata, Chiaki Maeyashiki, Yasuaki Kuwata, Atsushi Takahashi, Tatehiro Kagawa, Atsushi Fukunaga, Shiho Miyase, Tomokazu Kawaoka, Kosuke Matsumoto, Akihito Takeuchi, Shinji Shimoda, Yoshitaka Arase, Hiromasa Ohira, Kaoru Tsuchiya, Tsutomu Masaki, Hitoshi Yoshiji, Noriyo Yamashiki, Yuki Kugiyama, Toshiaki Nakano, Atsumasa Komori, Atsushi Tanaka
Journal: Journal of Hepatology (2025)
SAT-197-YI Smoking aggravates inflammation, fibrogenesis, angiogenesis and cancer risk in patients with cirrhosis
Authors: Nina Dominik, Benedikt Simbrunner, Bernhard Scheiner, Michael Schwarz, Lukas Hartl, Mathias Jachs, Lorenz Balcar, Georg Semmler, Georg Kramer, Christian Sebesta, Michael Trauner, Matthias Pinter, Mattias Mandorfer, Thomas Reiberger, Benedikt Hofer
Journal: Journal of Hepatology (2025)
WED-230-YI A novel MELD-copeptin score accurately predicts ACLF and liver- related death in patients with decompensated cirrhosis
Authors: Marlene Hintersteininger, Lukas Hartl, Benedikt Simbrunner, Mathias Jachs, Benedikt Hofer, David Bauer, Annarein Kerbert, Minneke Coenraad, Thierry Thévenot, Richard Moreau, Jonel Trebicka, Joan Clària, Nina Dominik, Michael Schwarz, Lorenz Balcar, Georg Kramer, Rodrig Marculescu, Michael Trauner, Mattias Mandorfer, Thomas Reiberger
Journal: Journal of Hepatology (2025)
WED-500-YI Evaluation of novel point-of-care ultrasound for hepatitis “PUSH” for healthcare workers managing hepatitis B infection in Zambia
Authors: Costanza Bertoni, Annie Kanunga, Edford Sinkala, Enock Syabbalo, Helen Chitundu, Carolyn Chibundi, Guy Muula, Samuel Bosomprah, Giulia Morsica, Antonella Castagna, Claudia Wallrauch, Tom Heller, Michael Vinikoor
Journal: Journal of Hepatology (2025)
FRI-295-YI Pharmacological modulation of hepatocyte glucocorticoid receptor alpha can toggle enclysis, the deletion of regulatory T cells by hepatocytes
Authors: Yiyu Fan, Madeleine Hill, Robert Bryce, Fei Wang, Hanan Almakhayitah, Yuxin Li, Kulvinder Gill, Daniel Kearns, Gary Reynolds, Nicholas Barnes, Omar Qureshi, Aekkachai Tuekprakhon, Zania Stamataki
Journal: Journal of Hepatology (2025)