tbuckley/cabot-search huggingface dataset:
Endocrine disrupting chemicals and persistent nausea among pregnant women enrolled in the Illinois Kids Development Study (I-KIDS)
Authors: Brad A. Ryva, Blair J. Wylie, Max T. Aung, Susan L. Schantz, Rita S. Strakovsky
Journal: Environmental Health Perspectives (2025)

Pregnant women are exposed to numerous endocrine disrupting chemicals (EDCs). Pregnancy-related nausea likely has hormonal etiology and may persist beyond the first trimester. Therefore, we aimed to determine the relationship between EDC biomarkers and pregnancy nausea characteristics. Illinois Kids Development Study (I-KIDS) pregnant women (n=467) reported nausea symptoms monthly from conception to delivery. We categorized women as never having nausea (9%), or as having typical (ends by 17 weeks gestation; 42%), persistent (ends after 17 weeks gestation; 25%), or irregular (24%) nausea. Women provided five urine samples across pregnancy, which we pooled and analyzed for phthalate/replacement, phenol, and triclocarban biomarkers. Using covariate-adjusted logistic regression, we evaluated relationships of EDCs with nausea and used quantile-based g-computation (QGComp) and Bayesian kernel machine regression (BKMR) to evaluate joint associations of EDCs with nausea symptoms. We also considered differences in associations by fetal sex. Only the sum of urinary biomarkers of di(isononyl) cyclohexane-1,2-dicarboxylate (ΣDiNCH) was associated with higher risk of persistent nausea compared to typical nausea (OR: 1.18; 95% CI: 1.01, 1.37) in all women. However, using QGComp, a 10% higher concentration of the EDC mixture was associated with 14% higher risk of persistent nausea (RR: 1.14; 95% CI:1.01,1.30), due to ΣDiNCH, ethylparaben, and the sum of di-2-ethylhexyl phthalate (ΣDEHP) metabolites. Similarly, using BMKR, the EDC mixture was associated with greater odds of persistent nausea in all women. In women carrying male offspring, ethylparaben was associated with persistent nausea, and a 10% higher concentration of the QGComp mixture was associated with 26% higher risk of persistent nausea (RR: 1.26; 95%CI:1.13,1.41), driven by ethylparaben and ΣDiNCH. Consistently, using BKMR, EDCs were positively associated with persistent nausea in women carrying males. We did not identify associations between EDC biomarkers and persistent nausea in women carrying females or between EDC biomarkers and other nausea patterns. Non-persistent EDCs, modeled as a mixture, are associated with persistent nausea in pregnancy, primarily in women carrying males. Future work should explore possible mechanisms, clinical implications, and interventions to reduce exposures and symptoms. https://doi.org/10.1289/EHP15547.
The Prolonged Half-Life of the p53 Missense Variant R248Q Promotes Accumulation and Heterotetramer Formation with Wildtype p53 to Exert the Dominant-Negative Effect
Authors: Nancy Klemm, Roman R. Schimmer, Nils K. Konrad, Flavian Thelen, Jonas Fullin, Ebru Topçu, Christian Koch, Milena Treacy, Matthew Joseph. Leventhal, Marco M. Bühler, Veronika Lysenko, Alexandre P. A. Theocharides, Kari J. Kurppa, Stefan Balabanov, Tuncay Baubec, Andrei V. Krivtsov, Peter G. Miller, Scott A. Armstrong, Benjamin L. Ebert, Markus G. Manz, Cesar Nombela-Arrieta, Steffen Boettcher
Journal: Cancer Research (2025)

Abstract Missense mutants of p53 - such as the frequent hotspot variant R248Q - exert a dominant-negative effect (DNE) on wildtype (WT) p53 in cancer cells with monoallelic TP53 mutations. However, the precise functional and molecular mechanisms of the DNE have remained elusive due to a lack of appropriate model systems. Here, we developed a variety of model systems, including CRISPR-edited human isogenic cell lines and transcriptional reporter cell lines, and targeted protein degradation assays that were combined with functional and molecular analyses to functionally characterize the DNE. Formation of heterotetramers between R248Q and WT p53 impaired proper WT p53 functionality by preventing DNA binding and subsequent target gene transactivation. Furthermore, the markedly increased protein half-life of R248Q led to supraphysiologic levels of R248Q, which was critically required for the DNE. Drug-induced targeted protein degradation of R248Q to lower the R248Q:WT ratio restored the transcriptional activity of WT p53, induced anti-proliferative effects in cancer cells in vitro, and elicited strong therapeutic activity in vivo. Together, this study provides mechanistic insights into the DNE of p53 missense mutants and indicates that the DNE represents a promising therapeutic target.
Ammonia Suppresses the Antitumor Activity of Natural Killer Cells and T Cells by Decreasing Mature Perforin
Authors: Joanna Domagala, Tomasz M. Grzywa, Iwona Baranowska, Magdalena Justyniarska, Ryan Tannir, Agnieszka Graczyk-Jarzynka, Aleksandra Kusowska, Maria Lecka, Marcin Poreba, Klaudyna Fidyt, Katsiaryna Marhelava, Zofia Pilch, Lea K. Picard, Tomasz Wegierski, Kamil Jastrzebski, Marta Krawczyk, Marta Klopotowska, Monika Granica, Doris Urlaub, Szymon Hajduk, Alexandra Neeser, Spencer Moros, Pawel Kozlowski, Malgorzata Bobrowicz, Marta Miaczynska, Leyuan Ma, Carsten Watzl, Magdalena Winiarska
Journal: Cancer Research (2025)

Abstract Immunotherapy revolutionized cancer treatment in the last decade. Both natural killer (NK) cells and T cells are key components of host immunity against malignant cells that are being extensively investigated in the field of cancer immunotherapy. While approaches have been developed to improve the antitumor activity of NK and T cells, the tumor microenvironment remains an obstacle to effective NK and T cell-based therapies. Here, we demonstrated that cancer-conditioned medium suppresses the antitumor activity of NK cells. Ammonia, a by-product of cancer cell metabolism, accumulated in cancer-conditioned medium and in the tumor microenvironment, and impaired the cytotoxicity of NK cells as well as the efficacy of antibody-based and chimeric antigen receptor (CAR)-NK and CAR-T cell-based therapies in vitro. Ammonia induced NK and T cell dysfunction by decreasing the amount of mature perforin in secretory lysosomes, which was dependent on its lysosomotropic features and ability to increase pH in acidic compartments. These findings demonstrate that, in addition to its previously described role in promoting tumor growth as a source of nitrogen for tumor biomass, ammonia promotes tumor immune escape by inhibiting both NK and CAR-T cell cytotoxicity.
Trade Tariffs on Canadian Pharmaceuticals—Implications for US Drug Supply and Costs
Authors: Mina Tadrous, Shanzeh Chaudhry, Jan Panhuysen, Ioannis Konstantinidis, Katie J. Suda
Journal: JAMA (2025)

This cross-sectional study analyzes data from the National Institutes of Health, IQVIA, and the US Food and Drug Administration on pharmaceutical drugs manufactured in Canada and exported to the US.
Factor XI inhibitors for the prevention and treatment of venous and arterial thromboembolism
Authors: Davide Capodanno, John H Alexander, M Cecilia Bahit, John W Eikelboom, C Michael Gibson, Shaun G Goodman, Vijay Kunadian, Gregory Y H Lip, Renato D Lopes, Roxana Mehran, Shamir R Mehta, Manesh R Patel, Jonathan P Piccini, Sunil V Rao, Christian T Ruff, P Gabriel Steg, Jeffrey I Weitz, Dominick J Angiolillo
Journal: Nature Reviews Cardiology (2025)
PROX1: a key regulator of hepatocyte identity and tumorigenesis
Authors: Terence Kin Wah. Lee, Stephanie Ma
Journal: Cancer Research (2025)

Abstract During ontogeny, the modulation of cell fate plasticity in stem cells is meticulously controlled as they undergo differentiation into distinct cell lineages. Dysregulation of this plasticity can result in pathological conditions, such as oncogenesis. Transcription factors are pivotal in orchestrating this cellular transition by initiating gene expression programs that define cell identity. Notably, the investigation of transcriptional repressors has garnered significant attention in elucidating the susceptibility of cancer development. A recent research article published in Nature Genetics unveiled the identification of a liver-specific protein, named PROX1, which maintains cellular identity and impedes the initiation and advancement of liver cancer. Analysis of liver cancer patient specimens demonstrated a positive association between elevated levels of PROX1 and improved prognosis as well as extended survival. Utilizing various liver cancer mouse models, the researchers demonstrated that PROX1 can impede tumor initiation and decelerate cancer progression. This study offers valuable insights for potential therapeutic interventions and introduces novel opportunities for investigating "safeguard repressors" in diverse tissue types.
Cardiac Biomarkers in Patients with Asymptomatic Severe Aortic Stenosis: Analysis from the EARLY TAVR Trial
Authors: Brian R. Lindman, Philippe Pibarot, Allan Schwartz, J. Bradley Oldemeyer, Yan Ru Su, Kashish Goel, David J. Cohen, William F. Fearon, Vasilis Babaliaros, David Daniels, Adnan Chhatriwalla, Hussam S. Suradi, Pinak Shah, Molly Szerlip, Michael J. Mack, Thom Dahle, William W. O'Neill, Charles J. Davidson, Raj Makkar, Tej Sheth, Jeremiah Depta, James T. DeVries, Jeffrey Southard, Andrei Pop, Paul Sorajja, Rebecca T. Hahn, Yanglu Zhao, Martin B. Leon, Philippe Généreux
Journal: Circulation (2025)

Background: The EARLY TAVR trial demonstrated that early transcatheter aortic valve replacement (TAVR) intervention was superior to clinical surveillance (CS) with delayed TAVR in patients with asymptomatic, severe aortic stenosis (AS). Cardiac biomarkers are associated with maladaptive remodeling, symptom onset, and worse outcomes after TAVR. Whether elevated biomarkers identify asymptomatic patients more likely to benefit from early intervention is unknown. Methods: A core laboratory measured N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high sensitivity cardiac troponin T (hs-cTnT). Associations between biomarker levels and risk of the trial primary endpoint (death, stroke, or unplanned cardiovascular hospitalization) and other secondary endpoints were examined with Kaplan-Meier curves and Cox proportional hazard models. Interaction tests were performed to assess whether the treatment effect of early TAVR, compared with CS, differed according to biomarker levels. Results: Among 901 patients randomized in EARLY TAVR, 798 (89%) had biospecimens measured (median NT-proBNP 287 [145, 601]; median hs-cTnT 14.6 [10.5, 21.0]). Higher levels of NT-proBNP and hs-cTnT were broadly associated with higher event rates for multiple endpoints. In general, there was no significant interaction between baseline biomarkers and treatment group with respect to any composite or individual endpoint examined, although trends broadly demonstrated a greater relative benefit of early TAVR at lower biomarker levels. There was a significant interaction between hs-cTnT and treatment group with respect to death or heart failure hospitalization (HFH) (interaction p=0.04) and HFH alone (interaction p=0.03) such that the relative benefit of early TAVR was greater for patients with normal, rather than elevated, levels of hs-cTnT at baseline. For some endpoints, higher baseline NT-proBNP was associated with numerically greater absolute risk reduction with early TAVR than lower NT-proBNP levels. Conclusions: In patients with asymptomatic severe high gradient AS, higher NT-proBNP and hs-cTnT levels were broadly associated with higher event rates as expected. However, the relative benefit of an early TAVR strategy was consistent regardless of baseline biomarker levels and, contrary to our hypothesis, tended to be more pronounced in those with the lowest biomarker levels. These findings suggest limited value for single measurements of these biomarkers to guide the timing of TAVR in asymptomatic patients.
Lipid peroxidation and immune activation: TRAF3’s double-edged strategy against glioblastoma
Authors: Tzu-Yi Chia, Nishanth S Sadagopan, Jason Miska
Journal: Journal of Clinical Investigation (2025)

Glioblastoma (GBM), the most aggressive type of primary brain tumor, continues to defy therapeutic advances with its metabolic adaptability and resistance to treatment. In this issue of the JCI, Zeng et al. delve into a pivotal mechanism underpinning this adaptability. They identified an important role for TNF receptor-associated factor 3 (TRAF3) in regulating lipid metabolism through its interaction with enoyl-CoA hydratase 1 (ECH1). These findings elucidate a unique signaling axis that shields GBM cells from lipid peroxidation and antitumor immunity, advancing therapeutic strategies for GBM that may also carry over to other cancers with similar metabolic vulnerabilities.
Spermidine restricts neonatal inflammation via metabolic shaping of polymorphonuclear myeloid-derived suppressor cells
Authors: Jiale Chen, Lin Zhu, Zhaohai Cui, Yuxin Zhang, Ran Jia, Dongmei Zhou, Bo Hu, Wei Zhong, Jin Xu, Lijuan Zhang, Pan Zhou, Wenyi Mi, Haitao Wang, Zhi Yao, Ying Yu, Qiang Liu, Jie Zhou
Journal: Journal of Clinical Investigation (2025)

Newborns exhibit a heightened vulnerability to inflammatory disorders due to their underdeveloped immune system, yet the underlying mechanisms remain poorly understood. Here we report that plasma spermidine is correlated with the maturity of human newborns and reduced risk of inflammation. Administration of spermidine led to the remission of neonatal inflammation in mice. Mechanistic studies revealed that spermidine enhanced the generation of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) via downstream eIF5A hypusination. Genetic deficiency or pharmacological inhibition of deoxyhypusine synthase (DHPS), a key enzyme of hypusinated eIF5A (eIF5AHyp), diminished the immunosuppressive activity of PMN-MDSCs, leading to aggravated neonatal inflammation. The eIF5AHyp pathway was found to enhance the immunosuppressive function via histone acetylation-mediated epigenetic transcription of immunosuppressive signatures in PMN-MDSCs. These findings demonstrate the spermidine-eIF5AHyp metabolic axis as a master switch to restrict neonatal inflammation.
Human genetics of metabolic dysfunction–associated steatotic liver disease: from variants to cause to precision treatment
Authors: Vincent L Chen, Annapurna Kuppa, Antonino Oliveri, Yanhua Chen, Prabhu Ponnandy, Puja B Patel, Nicholette D Palmer, Elizabeth K Speliotes
Journal: Journal of Clinical Investigation (2025)

Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by increased hepatic steatosis with cardiometabolic disease and is a leading cause of advanced liver disease. We review here the genetic basis of MASLD. The genetic variants most consistently associated with hepatic steatosis implicate genes involved in lipoprotein input or output, glucose metabolism, adiposity/fat distribution, insulin resistance, or mitochondrial/ER biology. The distinct mechanisms by which these variants promote hepatic steatosis result in distinct effects on cardiometabolic disease that may be best suited to precision medicine. Recent work on gene-environment interactions has shown that genetic risk is not fixed and may be exacerbated or attenuated by modifiable (diet, exercise, alcohol intake) and nonmodifiable environmental risk factors. Some steatosis-associated variants, notably those in patatin-like phospholipase domain-containing 3 (PNPLA3) and transmembrane 6 superfamily member 2 (TM6SF2), are associated with risk of developing adverse liver-related outcomes and provide information beyond clinical risk stratification tools, especially in individuals at intermediate to high risk for disease. Future work to better characterize disease heterogeneity by combining genetics with clinical risk factors to holistically predict risk and develop therapies based on genetic risk is required.
Phase I/II Study of Adaptive Manufactured Lentiviral Anti-CD20/Anti-CD19 Chimeric Antigen Receptor T Cells for Relapsed, Refractory Mantle Cell Lymphoma
Authors: Nirav N. Shah, Alfredo S. Colina, Bryon D. Johnson, Aniko Szabo, Fateeha Furqan, Tyce Kearl, Dina Schneider, Marlenny Vargas-Cortes, Jessica L. Schmeling, Michael B. Dwinell, Katie Palen, Walter Longo, Peiman Hematti, Anthony E. Zamora, Parameswaran Hari, Daniel Bucklan, Ashley Cunningham, Mehdi Hamadani, Timothy S. Fenske
Journal: Journal of Clinical Oncology (2025)

PURPOSE Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy characterized by t(11;14) and bright CD20 expression. To improve outcomes from single targeted CD19 chimeric antigen receptor (CAR) T cells, we used dual targeted lentiviral anti-CD20/anti-CD19 (LV20.19) CAR T cells as part of a phase I/II clinical trial in relapsed, refractory (R/R) MCL (ClinicalTrials.gov identifier: NCT04186520 ). METHODS Patients with MCL who had failed two lines of therapy or relapsed post-transplant were eligible. LV20.19 CAR T cells were manufactured on-site via CliniMACS Prodigy using an adaptive 8- to 12-day process to optimize the final CAR product for increased numbers of naïve and stem-cell memory (SCM) like T cells. RESULTS Seventeen patients with R/R MCL received a single dose of LV20.19 CAR T cells at 2.5 × 10 6 cells/kg (phase I = three patients; phase II = 14 patients). The best overall response rate (ORR) was 100% (complete response [CR] = 88%; partial response = 12%) and the phase II efficacy threshold for day-90 CR rate was exceeded. Two patients have relapsed as of the data cutoff and neither the median progression-free survival nor overall survival has been reached with a median follow-up of 15.8 months. Ninety-four percent (n = 16) experienced cytokine release syndrome, all grade 1-2. Eighteen percent (n = 3) had immune effector cell–associated neurotoxicity syndrome in the first 28-days, two with reversible grade 3 toxicity. Three patients had nonrelapse mortality events; all occurred in the setting of ongoing B-cell aplasia. The final LV20.19 CAR products were enriched for higher percentages of T- SCM /T-naïve cells and most patients received CAR T cells within 8 days of apheresis. CONCLUSION In conclusion, we demonstrate that on-site adaptive manufactured LV20.19 CAR T cells are feasible, safe, and efficacious for R/R MCL with best ORR of 100%, a favorable safety profile, and few relapses to date.
Efficacy and safety of passive immunotherapies targeting amyloid beta in Alzheimer’s disease: A systematic review and meta-analysis
Authors: Reina Tonegawa-Kuji, Yuan Hou, Bo Hu, Noah Lorincz-Comi, Andrew A. Pieper, Babak Tousi, James B. Leverenz, Feixiong Cheng
Journal: PLoS Medicine (2025)

Background While recently U.S. FDA-approved anti-amyloid beta (anti-Aβ) monoclonal antibodies (mAbs) offer new treatment approaches for patients suffering from Alzheimer’s disease (AD), these medications also carry potential safety concerns and uncertainty about their efficacy for improving cognitive function. This study presents an updated meta-analysis of cognitive outcomes and side effects of anti-Aβ mAbs from phase III randomized controlled trials (RCTs) in patients with sporadic AD. Methods and Findings Phase III randomized, placebo-controlled blinded trial evaluating the efficacy and safety of anti-Aβ mAbs in patients with AD were identified through a search in clinical trials.gov, PubMed and Embase on January 14th, 2024. The retrieved studies were further screened from January 15th, 2024, to February 14th, 2024. We included studies that had been published in any language. Quality of trials was assessed using the Jadad score and publication bias was assessed using Egger’s test and Funnel plot. Primary outcomes were mean changes from baseline to post-treatment in Clinical Dementia Rating scale-Sum of Boxes (CDR-SB) and AD Assessment Scale-Cognitive Subscale (ADAS-Cog) scores, and secondary outcomes were adverse events including amyloid-related imaging abnormalities with edema (ARIA-E), and ARIA with hemorrhage (ARIA-H). Random-effects meta-analysis and meta-regression analyses were conducted. The literature search identified 13 phase III RCTs, which included 18,826 patients with mild cognitive impairment or dementia due to AD. Compared with placebo, treatment with mAbs significantly improved cognitive performance on CDR-SB (mean difference −0.25, 95% confidence interval [CI] [−0.38, −0.11]) and ADAS-Cog (standardized mean difference −0.09, 95% CI [−0.12, −0.06]), in which a negative change indicates improvement for both scores. Meta-regression analysis suggested that trials enrolling patients with early-stage AD were associated with better efficacy. Elevated risk of ARIA-E (risk ratio [RR] 9.79, 95% CI [5.32,18.01]), ARIA-H (RR 1.94, 95% CI [1.47,2.57]), and headaches (RR 1.21, 95% CI [1.10,1.32]) were noted. Statistical heterogeneity was relatively high for ARIA-E and ARIA-H, leading to wide confidence intervals and considerable variability in effect sizes, though meta-regression was conducted to address this. Furthermore, differences in trial designs introduce limitations in cross-trial comparisons. Conclusions Anti-Aβ mAb therapy slows cognitive decline, but with small effect sizes, and raises potential concerns about ARIA and headaches.
Unifying Efforts to Empower Equitable Obesity Care: Synopsis of an American College of Physicians and Council of Subspecialty Societies Summit
Authors: Christina C. Wee, Alicia I. Arbaje, Harriet Bering, Linda Blount, Joshua J. Joseph, Scott Kahan, Caroline M. Apovian, Adrienne White-Faines
Journal: Annals of Internal Medicine (2025)

Obesity is a leading cause of morbidity and mortality with health consequences that crosscut most medical specialties. Despite the emergence of effective and promising new therapies, many impediments to comprehensive obesity care remain. As part of their commitment to improving obesity care, the American College of Physicians (ACP) and its Council of Subspecialty Societies (CSS) held a summit on 24 October 2023 to identify barriers to and opportunities for collaborative action in the domains of physician education, health care policy and care delivery, and addressing weight bias. This report summarizes the summit proceedings and provides a postsummit synthesis from ACP and CSS. Key themes were centered on knowledge, advocacy, action, and compassion, including the need for culture change, paradigm shifts, and stakeholder engagement and collaboration; a focus on empowerment of both clinicians and patients; the importance of knowing patients as people to help address social determinants of health; the need to address learned helplessness; and the importance of embracing artificial intelligence and technology as disruptive innovations. Recommendations for next steps for collaborative action include leveraging and improving already available educational and clinical resources, developing obesity education and care standards that incorporate patients' perspectives and address social determinants of health, developing community and public–private partnerships to improve access and public awareness, and coordinating messaging and policy advocacy efforts that align with mitigating the longstanding obesity epidemic.
The Effect of 4:3 Intermittent Fasting on Weight Loss at 12 Months
Authors: Victoria A. Catenacci, Danielle M. Ostendorf, Zhaoxing Pan, Laura K. Kaizer, Seth A. Creasy, Adnin Zaman, Ann E. Caldwell, Jared Dahle, Bryan Swanson, Matthew J. Breit, Kristen Bing, Liza T. Wayland, Shelby L. Panter, Jared J. Scorsone, Daniel H. Bessesen, Paul MacLean, Edward L. Melanson
Journal: Annals of Internal Medicine (2025)

Long-term (≥12 months) randomized trials evaluating the efficacy of intermittent fasting (IMF) as a dietary weight loss strategy are limited. Furthermore, no studies have compared IMF versus daily caloric restriction (DCR) when both interventions are provided in the context of a guidelines-based behavioral weight loss program.