tbuckley/cabot-search huggingface dataset:
Depletion of Acetyl‐CoA Carboxylase 1 Facilitates Epithelial‐Mesenchymal Transition in Prostate Cancer Cells by Activating the MAPK/ERK Pathway
Authors: Jiarun Lai, Shaoyou Liu, Yupeng Chen, Jian Chen, Jinchuang Li, Zhenguo Liang, Xinyue Mei, Yuanfa Feng, Zhaodong Han, Funeng Jiang, Shengbang Yang, Yongding Wu, Huijing Tan, Junchen Liu, Huichan He, Weide Zhong
Journal: MedComm (2025)

Hyperactivation of fatty acid biosynthesis holds promise as a targeted therapeutic strategy in prostate cancer (PCa). However, inhibiting these enzymes could potentially promote metastatic progression in various other cancers. Herein, we found that depletion of acetyl-CoA carboxylase 1 (encoded by ACACA), the enzyme responsible for the first and rate-limiting step of de novo fatty acid biosynthesis, facilitated epithelial-mesenchymal transition (EMT) and migration of PCa cells. This finding was validated in vitro through cell migration assays and in vivo using a metastatic model established by tail vein injection of ACACA-depleted cells into BALB/c nude mice. Additionally, depletion of ACACA activated the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated protein kinases (ERK) pathway. Inhibition of the MAPK/ERK signaling pathway reduced EMT and migration in ACACA-depleted cells. Our study is the first to indicate targeting ACACA induces an "unexpected" escape program through activation of the MAPK/ERK signaling pathway in PCa, ultimately leading to EMT and metastasis. Therefore, we strongly recommend that the potential adverse effects of targeting ACACA or its derived therapeutic agents must be given extreme attention, especially in MAPK-related cancers.
Association of clonal haematopoiesis with heart failure incidence and outcomes: A systematic review and meta‐analysis
Authors: Paschalis Karakasis, Eleftheria Lefkou, Konstantinos Pamporis, Dimitrios Farmakis, Dimitrios Patoulias, Antonios P. Antoniadis, Stephane Heymans, Gerasimos Filippatos, Nikolaos Fragakis
Journal: European Journal of Heart Failure (2025)

Clonal haematopoiesis (CH) is recognized as a significant risk factor for various non-haematologic conditions, including cardiovascular diseases. However, recent studies examining its relationship with heart failure (HF) have reported conflicting findings. To address these inconsistencies, the present meta-analysis aimed to evaluate the association of CH with the incidence and clinical outcomes of HF. MEDLINE, Cochrane Library and Scopus were searched until 12 December 2024. Triple-independent study selection, data extraction and quality assessment were performed. Evidence was pooled using three-level mixed-effects meta-analyses. Participants (n = 57 755) with CH had significantly greater risk of new-onset HF compared to the non-CH group (hazard ratio [HR] 1.23, 95% confidence interval [CI] 1.12-1.35, p < 0.0001; I2 = 0%), irrespective of a prior history of coronary artery disease. CH was also correlated with a higher risk of the composite outcome of all-cause mortality and hospitalization for HF (HHF) compared to the non-CH group in patients with established HF (HR 1.84, 95% CI 1.25-2.70, p = 0.002; I2 = 0%). Specifically, CH was associated with a 95% higher risk of all-cause mortality (HR 1.95, 95% CI 1.54-2.47, p < 0.0001; I2 = 0%), with a 3% increase in risk for every 1% increase in variant allele fraction. Participants with concomitant HF and CH had a 56% higher risk of HHF compared to non-CH HF patients (HR 1.56, 95% CI 1.05-2.33, p = 0.029; I2 = 19%). Clonal haematopoiesis is associated with an increased risk of incident HF and worse prognosis in individuals affected by HF. These findings highlight the potential of CH to contribute to a deeper understanding of HF, improve risk stratification, and support more personalized approaches to its management.
Carabrone Attenuates Metabolic Dysfunction–Associated Steatohepatitis by Targeting STAT3 in Mice
Authors: An Pan, Jiaming Jin, Yuze Wu, Qiang Zhang, Huanhuan Chen, Yang Hu, Wen Xiao, Anqi Shi, Yang Yang, Lina Jiang, Minghui Tan, Junwei Wang, Lihong Hu
Journal: MedComm (2025)

Metabolic dysfunction-associated steatohepatitis (MASH) has become one of the most common progressive liver diseases worldwide, but effective treatment options are severely unmet. Carabrone, a sesquiterpene lactone from the traditional Chinese herb Carpesium abrotanoides L., shows various pharmacological properties, whereas its effect on the improvement of MASH and the underlying mechanisms have not yet been reported. In this work, we revealed for the first time the beneficial effect of carabrone on MASH, including reducing liver lipid accumulation, inflammatory cell infiltration, and fibrosis in multiple diet-induced mice. Carabrone also alleviated lipid accumulation and inflammation in palmitic acid/oleic acid-stimulated hepatocytes. Mechanically, we identified signal transducers and transcriptional activator 3 (STAT3) as a key target of carabrone for treating MASH through quantitative chemical proteomic analysis, as well as the verification by the overexpression of STAT3 in vivo and in vitro. Further studies demonstrated that carabrone blocks MASH progression by inhibiting the activation of STAT3. More importantly, a new carabrone derivative CA-21 with stronger anti-MASH activity and affinity for STAT3 was discovered through rational structural modification. Taken together, our findings suggest that carabrone and CA-21 could be developed as promising drug candidates for MASH treatment.
Pulmonary Hypertension: Molecular Mechanisms and Clinical Studies
Authors: Joseph Adu‐Amankwaah, Qiang You, Xiaoer Liu, Jiayi Jiang, Dongqi Yang, Kuntao Liu, Jinxiang Yuan, Yanfang Wang, Qinghua Hu, Rubin Tan
Journal: MedComm (2025)

Pulmonary hypertension (PH) stands as a tumor paradigm cardiovascular disease marked by hyperproliferation of cells and vascular remodeling, culminating in heart failure. Complex genetic and epigenetic mechanisms collectively contribute to the disruption of pulmonary vascular homeostasis. In recent years, advancements in research technology have identified numerous gene deletions and mutations, in addition to bone morphogenetic protein receptor type 2, that are closely associated with the vascular remodeling process in PH. Additionally, epigenetic modifications such as RNA methylation, DNA methylation, histone modification, and noncoding RNAs have been shown to precisely regulate PH molecular networks in a cell-type-specific manner, emerging as potential biomarkers and therapeutic targets. This review summarizes and analyzes the roles and molecular mechanisms of currently identified genes and epigenetic factors in PH, emphasizing the pivotal role of long ncRNAs in its regulation. Additionally, it examines current clinical and preclinical therapies for PH targeting these genes and epigenetic factors and explores potential new treatment strategies.
Endocrine therapy and risk of cardiovascular disease and mortality in postmenopausal breast cancer survivors
Authors: Yuhan Huang, Marilyn L Kwan, Susan R Heckbert, Nicholas L Smith, Megan Othus, Cecile A Laurent, Janise M Roh, Eileen Rillamas-Sun, Valerie S Lee, Tatjana Kolevska, Richard K Cheng, Carlos Irribarren, Mai Nguyen-Huynh, Dawn L Hershman, Lawrence H Kushi, Heather Greenlee
Journal: JNCI Journal of the National Cancer Institute (2025)

Abstract Background There are increasing concerns of cardiovascular safety related to endocrine therapy use in women with breast cancer (BC). We examined risk of cardiovascular disease (CVD) events and mortality associated with endocrine therapy use in postmenopausal women with early-stage BC. Methods Postmenopausal women diagnosed with stage I-III hormone receptor-positive BC from 2005 to 2013 were included (n = 8,495). Women were classified as aromatase inhibitor (AI) users, tamoxifen users, and non-users of endocrine therapy in the 12 months after BC diagnosis. Likelihood ratio tests examined whether the association of endocrine therapy use with CVD and mortality outcomes varied by body mass index (BMI) and history of CVD before BC diagnosis. Results Over a median follow-up of 7.5 years, women who used AIs were less likely to develop major adverse cardiovascular events (MACE) (HR = 0.84, 95% CI: 0.73-0.97) and heart failure (HR = 0.81, 95% CI: 0.66-0.99) compared with non-users of endocrine therapy. No associations between tamoxifen use and CVD outcomes were observed. AI use was associated with lower risk all-cause, CVD-related, and non-CVD-related mortality, compared with non-use of endocrine therapy. Tamoxifen use was associated with lower risk of all-cause mortality and non-CVD-related mortality, compared with non-use of endocrine therapy, and the association was modified by BMI (P for interaction &amp;lt;0.05). Conclusion Our findings suggest endocrine therapy use reduces all-cause mortality risk and may not increase CVD risk in postmenopausal women with early-stage hormone receptor-positive BC.
Comparative effectiveness of various nonpharmacological interventions, including traditional Chinese medicine-based interventions for cancer-related cognitive impairment: a comprehensive network meta-analysis
Authors: Mu-Hsing Ho, Lizhen Wang, Justin Wei Ho Wong, Gongkai Xin, Qianyi Zhang, Yen-Kuang Lin, Denise Shuk Ting Cheung, Janette L Vardy, Chia-Chin Lin
Journal: JNCI Journal of the National Cancer Institute (2025)

Abstract Background Cancer-related cognitive impairment is a common complication of cancer and its treatment. The effectiveness of Traditional Chinese Medicine (TCM)-based interventions in improving subjective and objective cognitive function has not yet been investigated in previous network meta-analyses. This study aimed to evaluate the comparative effectiveness of nonpharmacological interventions including TCM-based interventions, and to rank the best option for improving cognitive function among adults with non-central nervous system cancer. Methods PubMed, Embase, ProQuest, Scopus, and CNKI were searched from their inception until May 2024, for relevant randomized controlled trials. A random-effects model was utilized for conducting network meta-analysis. The primary endpoint evaluated the impact of interventions on subjective or objective cognitive function. Results In total, 84 randomized controlled trials were included and 15 nonpharmacological interventions were identified with no reported significant adverse events. Tai Chi/Qigong demonstrated the highest probability (SMD = 2.10, 95% CI 0.62 to 3.59) of improving subjective cognitive function. Cognitive rehabilitation was ranked the best with the highest probability for improving overall cognitive function (SMD = 1.49, 95% CI 0.41 to 2.58) and executive function as well as language domains. Acupoint stimulation was the top-ranking approach for enhancing visuospatial and motor function domain (SUCRA 84.3%, SMD = 0.94, 95% CI 0.13 to 1.76). Conclusions Tai Chi/Qigong demonstrated the highest effectiveness in addressing subjective cognitive complaints. Cognitive rehabilitation was the most effective intervention across various domains including overall objective cognitive function, executive function, and language. Acupoint simulation was the most effective intervention for improving visuospatial and motor domain functions.
Germline analysis of an international cohort of pediatric diffuse midline glioma patients
Authors: Marion K Mateos, Pamela Ajuyah, Noemi Fuentes-Bolanos, Sam El-Kamand, Paulette Barahona, Ann-Kristin Altekoester, Chelsea Mayoh, Holly Holliday, Jie Liu, Louise Cui, Elke Pfaff, Alan Mackay, Adam C Resnick, Mark Pinese, Loretta M S Lau, Dong-Anh Khuong-Quang, Kimberly Dias, Catherine Goudie, Alison Salkeld, Jo Lynne Rokita, David T W Jones, Nikoleta Juretic, Elisha Hayden, Stefan M Pfister, Christof M Kramm, Mirjam Blattner-Johnson, Nada Jabado, Maria Tsoli, Orazio Vittorio, Sabine Mueller, Yiran Guo, Katherine Tucker, Sebastian M Waszak, Sebastien Perreault, Chris Jones, Marie Wong-Erasmus, Mark J Cowley, David S Ziegler
Journal: Neuro-Oncology (2025)

Abstract Background Factors that drive the development of diffuse midline gliomas (DMG) are unknown. Our study aimed to determine the prevalence of pathogenic/likely pathogenic (P/LP) germline variants in pediatric patients with DMG. Methods We assembled an international cohort of 252 pediatric patients with DMG, including diffuse intrinsic pontine glioma (n=153), with germline whole genome or whole exome sequencing. Results We identified P/LP germline variants in cancer predisposition genes in 7.5% (19/252) of patients. Tumor profiles differed, with absence of somatic drivers in the PI3K/mTOR pathway in patients with germline P/LP variants versus those without (P = 0.023). P/LP germline variants were recurrent in homologous recombination (n=9; BRCA1, BRCA2, PALB2) and Fanconi anemia genes (n=4). Somatic findings established that the germline variants definitively contributed to tumorigenesis in at least 1% of cases. One patient with recurrent DMG and pathogenic germline variants (BRCA2, FANCE) showed near-complete radiological response to PARP and immune checkpoint inhibition. Conclusions Our study determined the prevalence of pathogenic germline variants in pediatric DMG, and suggests a role in tumorigenesis for a subset of patients.
Leukemogenic Kras mutation reprograms multipotent progenitors to facilitate its spread through the hematopoietic system
Authors: Geunhyo Jang, Rosa Park, Eduardo Esteva, Pei-Feng Hsu, Jue Feng, Samik Upadhaya, Catherine M. Sawai, Iannis Aifantis, David R. Fooksman, Boris Reizis
Journal: The Journal of Experimental Medicine (2025)

Leukemia-driving mutations are thought to arise in hematopoietic stem cells (HSC), yet the natural history of their spread is poorly understood. We genetically induced mutations within endogenous murine HSC and traced them in unmanipulated animals. In contrast to mutations associated with clonal hematopoiesis (such as Tet2 deletion), the leukemogenic KrasG12D mutation dramatically accelerated HSC contribution to all hematopoietic lineages. The acceleration was mediated by KrasG12D-expressing multipotent progenitors (MPP) that lacked self-renewal but showed increased proliferation and aberrant transcriptome. The deletion of osteopontin, a secreted negative regulator of stem/progenitor cells, delayed the early expansion of mutant progenitors. KrasG12D-carrying cells showed increased CXCR4-driven motility in the bone marrow, and the blockade of CXCR4 reduced the expansion of MPP in vivo. Finally, therapeutic blockade of KRASG12D spared mutant HSC but reduced the expansion of mutant MPP and their mature progeny. Thus, transforming mutations facilitate their own spread from stem cells by reprogramming MPP, creating a preleukemic state via a two-component stem/progenitor circuit.
Midlife Dietary Quality and Body Composition Relevance for Brain Connectivity and Cognitive Performance in Later Life
Authors: Sharmili Edwin Thanarajah
Journal: JAMA Network Open (2025)

Daria E. A. Jensen, DPhil; Klaus P. Ebmeier, MD; Tasnime Akbaraly, PhD; Michelle G. Jansen, MSc; Archana Singh-Manoux, PhD; Mika Kivimäki, PhD; Enikő Zsoldos, DPhil; Miriam C. Klein-Flügge, PhD; Sana Suri, DPhil
Frailty Trajectories Following Adjuvant Chemotherapy and Mortality in Older Women With Breast Cancer
Authors: Emilie D. Duchesneau, Dae Hyun Kim, Til Stürmer, Qoua Her, Zhang Zhang, Nicholas M. Pajewski, Heidi D. Klepin, Kathryn E. Callahan, Jennifer L. Lund
Journal: JAMA Network Open (2025)

Importance Frailty assessed at a single time point is associated with mortality in older women with breast cancer. Little is known about how changes in frailty following cancer treatment initiation affect mortality. Objective To evaluate the association between claims-based frailty trajectories following adjuvant chemotherapy initiation and 5-year mortality in older women with stage I to III breast cancer. Design, Setting, and Participants This longitudinal cohort study used the Surveillance, Epidemiology, and End Results cancer registries linked to Medicare claims data (claims from 2003-2019). Women aged 65 years or older with stage I to III breast cancer diagnosed from 2004 to 2017 were included. Eligible women underwent breast surgery followed by adjuvant chemotherapy as initial treatment. A landmark design was used to identify frailty trajectories during the year following chemotherapy initiation. Continuous enrollment in Medicare fee-for-service from 180 days before cancer diagnosis through 360 days following chemotherapy initiation (landmark) was required. Women who died or disenrolled before the landmark were excluded. Analyses were conducted between September 2022 and March 2024. Exposures Claims-based frailty trajectories during the 360 days following chemotherapy initiation were identified using the Faurot frailty index, a validated claims-based proxy for frailty based on demographics and diagnosis, procedure, and durable medical equipment claims. The Faurot frailty index was calculated every 30 days from chemotherapy initiation through the landmark (360 days after chemotherapy initiation). Claims-based frailty trajectory clusters were identified using longitudinal K-means clustering. Main Outcomes and Measures Associations between the claims-based frailty trajectory clusters and 5-year mortality from the landmark were estimated using Kaplan-Meier analysis. Results In total, 20 292 women with breast cancer (median [IQR] age, 70 [67-74] years) were identified. The K-means analysis resulted in 6 trajectory clusters: 3 robust (16 120 women [79.4%]) or resilient (3259 [16.1%]) trajectories and 3 nonresilient trajectories (913 women [4.5%]). Five-year mortality was higher in women belonging to the 3 nonresilient trajectories compared with those belonging to the 3 resilient trajectories (52.1% vs 20.3%; difference, 31.8%; 95% CI, 29.0%-36.2%). Conclusions and Relevance In this cohort study of women with stage I to III breast cancer, frailty changes following chemotherapy initiation were associated with long-term survival. Future research should assess the association of frailty interventions following cancer treatment initiation with survival and patient-centered outcomes in this population.
FFR-Guided Percutaneous Coronary Intervention vs Coronary Artery Bypass Grafting in Patients With Diabetes
Authors: Kuniaki Takahashi, Hisao Otsuki, Frederik M. Zimmermann, Victoria Y. Ding, Thomas Engstrøm, Hans Gustav Hørsted Thyregod, Branko Beleslin, Svetozar Putnik, Luke Tapp, Thomas Barker, Simon Redwood, Christopher Young, G. Jan-Willem Bech, Gerard J. F. Hoohenkerk, Bernard De Bruyne, Nico H. J. Pijls, William F. Fearon
Journal: JAMA Cardiology (2025)

Importance Outcomes in patients with diabetes after fractional flow reserve (FFR)–guided percutaneous coronary intervention (PCI) using current-generation drug-eluting stents (DES) compared with coronary artery bypass grafting (CABG) are unknown. Objectives To investigate the relative treatment effect of PCI vs CABG according to diabetes status with respect to major adverse cardiac and cerebrovascular events (MACCE) at 3 years and to evaluate the impact of the SYNTAX score. Design, Setting, and Participants This is a prespecified subgroup analysis of the FAME (Fractional Flow Reserve vs Angiography for Multivessel Evaluation) 3 trial, an investigator-initiated, randomized clinical trial conducted at 48 centers worldwide. The FAME 3 trial enrolled patients with 3-vessel coronary artery disease not involving the left main undergoing coronary revascularization between August 2014 and December 2019. Data analysis was conducted in August 2023. Clinical follow-up was performed at hospital discharge and at 1 month, 6 months, 1 year, 2 years, and 3 years after randomization. Intervention Either FFR-guided PCI with current-generation DES or CABG. Main Outcomes and Measures The primary end point was MACCE, defined as the composite of all-cause death, myocardial infarction, stroke, or repeat revascularization at 3 years. Results Of 1500 total patients enrolled, mean (SD) patient age was 65.1 (8.4) years, and 265 patients (17.7%) were female. The FAME 3 trial included 428 patients with diabetes (28.5%). Patients with diabetes, especially those receiving insulin, had a higher risk of MACCE at 3 years compared with those without diabetes. Regarding relative treatment effect, the risk of MACCE was higher after FFR-guided PCI compared with CABG in both patients with diabetes (hazard ratio [HR], 1.44; 95% CI, 0.91-2.28; P = .12) and those without diabetes (HR, 1.50; 95% CI, 1.08-2.07; P = .02), with no significant interaction ( P for interaction = .94). In patients with a low SYNTAX score (&amp;amp;lt;23), there was no significant difference in MACCE between PCI and CABG, while in patients with an intermediate to high SYNTAX score (≥23), PCI had a higher risk of MACCE than CABG, regardless of diabetes status. Conclusions and Relevance In this subgroup analysis of the FAME 3 randomized clinical trial, the relative benefit of CABG compared with FFR-guided PCI was similar among patients with and without diabetes. Trial Registration ClinicalTrials.gov Identifier: NCT02100722
Estimated Cancer Risk in Females Who Meet the Criteria to Exit Cervical Cancer Screening
Authors: Shalini L. Kulasingam, Inge M. C. M. de Kok, Abhinav Mehta, Erik E. L. Jansen, Mary Caroline Regan, James W. Killen, Stephen Sy, Ran Zhao, Karen Canfell, Jane J. Kim, Megan A. Smith, Nicole G. Campos
Journal: JAMA Network Open (2025)

Importance Cervical screening guidelines in the US recommend that most females can exit routine screening at age 65 years following 2 recent consecutive negative cotest results (concurrent human papillomavirus and cytology tests). However, empirical data on the subsequent risks of cancer and cancer death in this subgroup of females are limited. Objective To estimate the risks of cervical cancer and cervical cancer death among females who meet the cotesting criteria to exit screening. Design, Setting, and Participants In this decision analytical comparative modeling study, 4 decision analytical models from the Cancer Intervention and Surveillance Modeling Network–Cervical modeling consortium that fit common US epidemiological data targets were validated against published estimates of 3- and 5-year risks of cervical intraepithelial neoplasia grade 3 (CIN3) among females meeting exit criteria at Kaiser Permanente Northern California (KPNC). Main Outcomes and Measures Age-conditional and cumulative risks of cervical cancer and cervical cancer death at ages 65, 70, 75, 80, and 85 years were estimated by performing a comparative modeling analysis of the 4 models to estimate the risks of cervical cancer and cervical cancer death after exiting screening. Results All models estimated a 5-year risk of CIN3 that was within the range of empirical data from KPNC. Projections of the cumulative and age-conditional risks of cervical cancer and cervical cancer death increased with time since exiting screening. The cumulative risks of cervical cancer and cervical cancer death by age 70 years were estimated to range from 0.001% to 0.003% and from 0% to 0.001%, respectively. The cumulative risks of cervical cancer and cervical cancer death by age 85 years ranged from 0.026% to 0.081% and from 0.005% to 0.038%, respectively, across models. Results were sensitive to assumptions about screening test sensitivity and incidence of high-risk human papillomavirus. Conclusions and Relevance In this decision analytical comparative modeling study, a low risk of cervical cancer and cervical cancer death was estimated among females who fulfilled the US criteria to exit screening with cotesting; however, the risks increased with age and/or time since screening exit. The findings suggest that future guidelines should consider acceptable risk levels when defining screening modality and exit age requirements.