tbuckley/cabot-search huggingface dataset:
Efruxifermin in Compensated Liver Cirrhosis Caused by MASH
Authors: Mazen Noureddin, Mary E. Rinella, Naga P. Chalasani, Guy W. Neff, K. Jean Lucas, Manuel E. Rodriguez, Madhavi Rudraraju, Rashmee Patil, Cynthia Behling, Mark Burch, Doreen C. Chan, Erik J. Tillman, Arian Zari, Brittany de Temple, Reshma Shringarpure, Meena Jain, Timothy Rolph, Andrew Cheng, Kitty Yale
Journal: New England Journal of Medicine (2025)

In phase 2 trials involving patients with stage 2 or 3 fibrosis caused by metabolic dysfunction-associated steatohepatitis (MASH), efruxifermin, a bivalent fibroblast growth factor 21 (FGF21) analogue, reduced fibrosis and resolved MASH. Data are needed on the efficacy and safety of efruxifermin in patients with compensated cirrhosis (stage 4 fibrosis) caused by MASH. In this phase 2b, randomized, placebo-controlled, double-blind trial, we assigned patients with MASH who had biopsy-confirmed compensated cirrhosis (stage 4 fibrosis) to receive subcutaneous efruxifermin (at a dose of 28 mg or 50 mg once daily) or placebo. The primary outcome was a reduction of at least one stage of fibrosis without worsening of MASH at week 36. Secondary outcomes included the same criterion at week 96. A total of 181 patients underwent randomization and received at least one dose of efruxifermin or placebo. Of these patients, liver biopsy was performed in 154 patients at 36 weeks and in 134 patients at 96 weeks. At 36 weeks, a reduction in fibrosis without worsening of MASH occurred in 8 of 61 patients (13%) in the placebo group, in 10 of 57 patients (18%) in the 28-mg efruxifermin group (difference from placebo after adjustment for stratification factors, 3 percentage points; 95% confidence interval [CI], -11 to 17; P = 0.62), and in 12 of 63 patients (19%) in the 50-mg efruxifermin group (difference from placebo, 4 percentage points; 95% CI, -10 to 18; P = 0.52). At week 96, a reduction in fibrosis without worsening of MASH occurred in 7 of 61 patients (11%) in the placebo group, in 12 of 57 patients (21%) in the 28-mg efruxifermin group (difference from placebo, 10 percentage points; 95% CI, -4 to 24), and in 18 of 63 patients (29%) in the 50-mg efruxifermin group (difference from placebo, 16 percentage points; 95% CI, 2 to 30). Gastrointestinal adverse events were more common with efruxifermin; most events were mild or moderate. In patients with compensated cirrhosis caused by MASH, efruxifermin did not significantly reduce fibrosis at 36 weeks. (Funded by Akero Therapeutics; SYMMETRY ClinicalTrials.gov number, NCT05039450.).
Use of healthcare services preceding HIV diagnosis – missed opportunities for earlier diagnosis, Finland, 1996 to 2019
Authors: Sanna Isosomppi, Mikaela Mutru, Jukka Ollgren, Henrikki Brummer-Korvenkontio, Kirsi Liitsola, Jussi Sutinen, Inka Aho, Pia Kivelä
Journal: Eurosurveillance (2025)

Background HIV testing based on indicator conditions is recommended to diagnose HIV earlier. Aim Our aim was to assess opportunities for earlier diagnosis of HIV. Method This is a retrospective study on people living with HIV (PLWH) included in the national HIV register. We collected data on public primary outpatient healthcare (PHC) (2011–2019), secondary and tertiary outpatient healthcare (STHC), and all inpatient care (1996–2019) from the Care Register for Health Care from the presumed acquisition, estimated by CD4 + T-cell count at diagnosis, until the diagnosis of HIV. Results Of 907 PLWH diagnosed between 2011 and 2019, 522 (58%) had ≥ 1 healthcare contact at any level between HIV acquisition and &gt; 30 days before diagnosis. At least one European Centre for Disease Prevention and Control (ECDC) indicator condition was recorded for 119 (23% of 522), and 112 (21%) were born in a high-prevalence country. In total, 384 of 907 (42%) had visited a PHC physician, and 58% of those with CD4 + T-cell count &lt; 200 cells/μL at diagnosis. Of 2,082 PLWH diagnosed between 1996 and 2019, 869 (42%) had STHC outpatient contacts &gt; 30 days before diagnosis, 18% with ≥ 1 ECDC indicator condition, and 367 (18%) had been hospitalised, 20% with ≥ 1 ECDC indicator condition. The most common ECDC indicator conditions &gt; 30 days before diagnosis at all levels of healthcare were pneumonia, sexually transmitted infections, unexplained fever, herpes zoster, pregnancy and lymphadenopathy. Conclusion We recommend enhancing indicator condition-based HIV testing by all healthcare providers, particularly for gonorrhoea, syphilis and, for persons younger than 50 years, also herpes zoster and lymphadenopathy.
Parent-of-origin regulation by maternal auts2 shapes neurodevelopment and behavior in fish
Authors: Antoine Emile Clément, Constance Merdrignac, Sergi Roig Puiggros, Dorine Sévère, Aurélien Brionne, Thomas Lafond, Thaovi Nguyen, Jérôme Montfort, Cervin Guyomar, Alexandra Dauvé, Amaury Herpin, Denis Jabaudon, Violaine Colson, Florent Murat, Julien Bobe
Journal: Genome biology (2025)
Endometrial tumorigenesis involves epigenetic plasticity demarcating non-coding somatic mutations and 3D-genome alterations
Authors: Sebastian Gregoricchio, Aleksandar Kojic, Marlous Hoogstraat, Karianne Schuurman, Suzan Stelloo, Tesa M Severson, Tracy A O'Mara, Marjolein Droog, Abhishek A Singh, Dylan M Glubb, Lodewyk F A Wessels, Michiel Vermeulen, Flora E van Leeuwen, Wilbert Zwart
Journal: Genome biology (2025)
Deciphering the longitudinal trajectories of glioblastoma ecosystems by integrative single-cell genomics
Authors: Avishay Spitzer, Kevin C Johnson, Masashi Nomura, Luciano Garofano, Djamel Nehar-Belaid, Noam Galili Darnell, Alissa C Greenwald, Lillian Bussema, Young Taek Oh, Frederick S Varn, Fulvio D'Angelo, Simon Gritsch, Kevin J Anderson, Simona Migliozzi, L Nicolas Gonzalez Castro, Tamrin Chowdhury, Nicolas Robine, Catherine Reeves, Jong Bae Park, Anuja Lipsa, Frank Hertel, Anna Golebiewska, Simone P Niclou, Labeeba Nusrat, Sorcha Kellet, Sunit Das, Hyo-Eun Moon, Sun Ha Paek, Franck Bielle, Alice Laurenge, Anna Luisa Di Stefano, Bertrand Mathon, Alberto Picca, Marc Sanson, Shota Tanaka, Nobuhito Saito, David M Ashley, Stephen T Keir, Keith L Ligon, Jason T Huse, W K Alfred Yung, Anna Lasorella, Antonio Iavarone, Roel G W Verhaak, Itay Tirosh, Mario L Suvà
Journal: Nature Genetics (2025)

The evolution of isocitrate dehydrogenase (IDH)-wildtype glioblastoma (GBM) after standard-of-care therapy remains poorly understood. Here we analyzed matched primary and recurrent GBMs from 59 patients using single-nucleus RNA sequencing and bulk DNA sequencing, assessing the longitudinal evolution of the GBM ecosystem across layers of cellular and molecular heterogeneity. The most consistent change was a lower malignant cell fraction at recurrence and a reciprocal increase in glial and neuronal cell types in the tumor microenvironment (TME). The predominant malignant cell state differed between most matched pairs, but no states were exclusive or highly enriched in either time point, nor was there a consistent longitudinal trajectory across the cohort. Nevertheless, specific trajectories were enriched in subsets of patients. Changes in malignant state abundances mirrored changes in TME composition and baseline profiles, reflecting the co-evolution of the GBM ecosystem. Our study provides a blueprint of GBM's diverse longitudinal trajectories and highlights the treatment and TME modifiers that shape them.
Most human DNA replication initiation is dispersed throughout the genome with only a minority within previously identified initiation zones
Authors: Jamie T Carrington, Rosemary H C Wilson, Eduardo de La Vega, Sathish Thiyagarajan, Tom Barker, Leah Catchpole, Alex Durrant, Vanda Knitlhoffer, Chris Watkins, Karim Gharbi, Conrad A Nieduszynski
Journal: Genome biology (2025)
Atezolizumab plus personalized neoantigen vaccination in urothelial cancer: a phase 1 trial
Authors: Mansi Saxena, Jonathan F Anker, Julia Kodysh, Timothy O'Donnell, Anna M Kaminska, Marcia Meseck, Olivia Hapanowicz, Scot Anthony Niglio, Andres M Salazar, Hardik R Shah, Yayoi Kinoshita, Rachel Brody, Alex Rubinsteyn, Robert P Sebra, Nina Bhardwaj, Matthew D Galsky
Journal: Nature Cancer (2025)
The multilayered transcriptional architecture of glioblastoma ecosystems
Authors: Masashi Nomura, Avishay Spitzer, Kevin C Johnson, Luciano Garofano, Djamel Nehar-Belaid, Noam Galili Darnell, Alissa C Greenwald, Lillian Bussema, Young Taek Oh, Frederick S Varn, Fulvio D'Angelo, Simon Gritsch, Kevin J Anderson, Simona Migliozzi, L Nicolas Gonzalez Castro, Tamrin ChowdhFury, Nicolas Robine, Catherine Reeves, Jong Bae Park, Anuja Lipsa, Frank Hertel, Anna Golebiewska, Simone P Niclou, Labeeba Nusrat, Sorcha Kellet, Sunit Das, Hyo Eun Moon, Sun Ha Paek, Franck Bielle, Alice Laurenge, Anna Luisa Di Stefano, Bertrand Mathon, Alberto Picca, Marc Sanson, Shota Tanaka, Nobuhito Saito, David M Ashley, Stephen T Keir, Keith L Ligon, Jason T Huse, W K Alfred Yung, Anna Lasorella, Roel G W Verhaak, Antonio Iavarone, Mario L Suvà, Itay Tirosh
Journal: Nature Genetics (2025)

In isocitrate dehydrogenase wildtype glioblastoma (GBM), cellular heterogeneity across and within tumors may drive therapeutic resistance. Here we analyzed 121 primary and recurrent GBM samples from 59 patients using single-nucleus RNA sequencing and bulk tumor DNA sequencing to characterize GBM transcriptional heterogeneity. First, GBMs can be classified by their broad cellular composition, encompassing malignant and nonmalignant cell types. Second, in each cell type we describe the diversity of cellular states and their pathway activation, particularly an expanded set of malignant cell states, including glial progenitor cell-like, neuronal-like and cilia-like. Third, the remaining variation between GBMs highlights three baseline gene expression programs. These three layers of heterogeneity are interrelated and partially associated with specific genetic aberrations, thereby defining three stereotypic GBM ecosystems. This work provides an unparalleled view of the multilayered transcriptional architecture of GBM. How this architecture evolves during disease progression is addressed in the companion manuscript by Spitzer et al.
Mitochondrial NNT Promotes Diastolic Dysfunction in Cardiometabolic HFpEF
Authors: Mark E. Pepin, Philipp J.M. Konrad, Sumra Nazir, Farhad Bazgir, Christoph Maack, Alexander Nickel, Joshua Gorman, Mathias Hohl, Friederike Schreiter, Matthias Dewenter, Adriano de Britto Chaves Filho, Almut Schulze, Anja Karlstaedt, Norbert Frey, Christine Seidman, Jonathan Seidman, Johannes Backs
Journal: Circulation Research (2025)

BACKGROUND: Clinical management of heart failure with preserved ejection fraction (HFpEF) is hindered by a lack of disease-modifying therapies capable of altering its distinct pathophysiology. Despite the widespread implementation of a 2-hit model of cardiometabolic HFpEF to inform precision therapy, which utilizes ad libitum high-fat diet and 0.5% N(ω)-nitro-L-arginine methyl ester, we observe that C57BL6/J mice exhibit less cardiac diastolic dysfunction in response to high-fat diet and 0.5% N(ω)-nitro-L-arginine methyl ester. METHODS: Genetic strain-specific single-nucleus transcriptomic analysis identified disease-relevant genes that enrich oxidative metabolic pathways within cardiomyocytes. Because C57BL/6J mice are known to harbor a loss-of-function mutation affecting the inner mitochondrial membrane protein Nnt (nicotinamide nucleotide transhydrogenase), we used an isogenic model of Nnt loss-of-function to determine whether intact NNT is necessary for the pathological cardiac manifestations of high-fat diet and 0.5% N(ω)-nitro-L-arginine methyl ester. Twelve-week-old mice cross-bred to isolate wild-type ( Nnt +/+ ) or loss-of-function ( Nnt − / − ) Nnt in the C57BL/6N background were challenged with high-fat diet and 0.5% N(ω)-nitro-L-arginine methyl ester for 9 weeks (n=6–10). RESULTS: Nnt +/+ mice exhibited impaired ventricular diastolic relaxation and pathological remodeling, as assessed via E/e′ (42.8 versus 21.5, P =1.2×10 − 10 ), E/A (2.3 versus 1.4, P =4.1×10 − 2 ), diastolic stiffness (0.09 versus 0.04 mm Hg/μL, P =5.1×10 − 3 ), and myocardial fibrosis ( P =2.3×10 − 2 ). Liquid chromatography and mass spectroscopy exposed a 40.0% reduction in NAD + ( P =8.4×10 − 3 ) and a 38.8% reduction in glutathione:GSSG ( P =2.6×10 − 2 ) among Nnt +/+ mice after high-fat diet and 0.5% N(ω)-nitro-L-arginine methyl ester feeding. Using single-nucleus ligand-receptor analysis, we implicate Fgf1 (fibroblast growth factor 1) as a putative NNT-dependent mediator of cardiomyocyte-to-fibroblast signaling of myocardial fibrosis. CONCLUSIONS: Together, these findings underscore the pivotal role of mitochondrial dysfunction in HFpEF pathogenesis, implicating both NNT and Fgf1 as novel therapeutic targets.
How the Structure of Signaling Regulation Evolves: Insights from an Evolutionary Model
Authors: Danial Asgari, Ann T Tate
Journal: Molecular Biology and Evolution (2025)

Abstract To monitor environmental changes, signaling pathways attenuate their activity with negative feedback loops (NFLs), where proteins produced upon stimulation downregulate the response. NFLs function both upstream of signaling to reduce input and downstream to reduce output. Unlike upstream NFLs, downstream NFLs regulate gene expression without the involvement of intermediate proteins. Thus, we hypothesized that downstream NFLs evolve under more stringent selection than upstream NFLs. Indeed, genes encoding downstream NFLs evolve at a slower and more consistent rate than upstream genes, suggesting that the latter may be under weaker or more context-specific selection. This suggests that downstream NFLs evolve more robustly, whereas upstream NFLs are more susceptible to changes in signaling proteins and stimuli. We tested these assumptions using a minimal model of immune signaling, which predicts robust evolution of downstream NFLs to changes in model parameters. This is consistent with their critical role in regulating signaling and the conservative rate of evolution. Furthermore, we show that the number of signaling steps needed to activate a downstream NFL is influenced by the cost of signaling. Our model predicts that upstream NFLs are more likely to evolve under a shorter half-life of signaling proteins, absence of host-pathogen co-evolution, and a high infection rate. Although it has been proposed that NFLs evolve to reduce the cost of signaling, we show that a high cost does not necessarily predict the evolution of upstream NFLs. The insights from our model have broad implications for understanding the evolution of regulatory mechanisms across signaling pathways.
Divergent cardiovascular adaptations and gene regulation in high-elevation natives and recent colonizers of the Qinghai-Tibetan Plateau
Authors: Huishang She, Graham R Scott, Yun Fang, Qingshuo Zhao, Fanwei Meng, Yanhua Qu
Journal: Molecular Biology and Evolution (2025)

Abstract High elevation imposes unrelenting and unavoidable hypoxia on species inhabiting these environments, providing an excellent natural setting for studying convergent or divergent evolution. By integrating measures of phenotypic variation, gene regulation, and functional performance, our study demonstrates that recent colonizers of high-elevation environments exhibit fundamentally different cardiovascular changes compared to long-term natives of these environments. Through the studying of heart morphological phenotypes, we showed that recent colonizers exhibit signs of cardiac hypertrophy, reflected by increased relative heart mass (heart mass/body mass) and cardiomyocyte size compared to their low-elevation relatives. In contrast, native species show no signs of cardiac hypertrophy and instead have three-fold higher capillary densities than the colonizers, a change that likely enhances tissue oxygen diffusing capacity in the former. Using phylogenetic principal component analysis to quantify multivariate trait divergence, we show that native species are similar in cardiovascular phenotype and underlying gene expression, but differ appreciably from recent colonizers. We further demonstrate, using a functional assay, that differential expression of two genes (IRS2 and AKT1) in a conserved regulatory pathway mediates cardiomyocyte hypertrophy, which could explain the observed variation in cardiomyocyte size between native species and recent colonizers. This regulatory basis of variation in cardiac phenotype involves the differential expression of genes in a cardiomyocyte hypertrophy pathway that is conserved across birds, humans and other mammals. Collectively, our study highlights that evolutionary history is a critical determinant of cardiovascular variation in high-elevation environments.
Combining evidence and practice to optimise neck training aimed at reducing head acceleration events in sport: a systematic review and Delphi-consensus study
Authors: Molly Fownes-Walpole, Omar Heyward, Kevin Till, Lois Mackay, Anna Stodter, Marwan Al-Dawoud, Melanie Dawn Bussey, Leigh Gordon, James Hairsine, Christopher Kirk, Rob Madden, Lesley McBride, Alexander McDaniel, Pete McKnight, Nathan Mill, Kerry Peek, Gavin Pratt, Des Ryan, Danielle Salmon, Lindsey Schroeder, Craig Twentyman, Theo Versteegh, Elisabeth Williams, Ben Jones
Journal: British Journal of Sports Medicine (2025)

Head acceleration events (HAEs) can potentially have adverse consequences for athlete brain health. In sports, in which head injuries have the highest incidence, identifying strategies to reduce HAE frequency and magnitude is a priority. Neck training is a potential strategy to mitigate against the magnitude of HAEs. This two-part study aimed to (1) systematically review the literature of neck training interventions in sport and (2) undertake an expert Delphi consensus on the best practices for neck training implementation to reduce HAEs in sport. Part I: a systematic search of four databases was undertaken from the earliest records to September 2024. The PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analysis) guidelines were followed, and a quality assessment was completed using a modified Downs and Black assessment tool and the GRADE (Grading of Recommendations Assessment, Development and Evaluation). Papers were eligible if they both (1) implemented a reproducible exercise intervention targeting the neck within collision, combat or motor sport, and (2) assessed outcomes relating to either: the physical profile of the neck; head/neck injury incidence; and/or HAEs. Part II: 18 international experts, with experience in research and/or applied practice of neck exercise training, concussion and/or HAEs, reviewed the part I findings before completing a three-round Delphi consensus process. Part I included 21 papers, highlighting the heterogeneity of existing interventions. Part II resulted in 57 statements coded into five categories: contextual factors (n=17), neck training periodisation (n=12), training adaptations (n=10), neck training content (n=15) and athlete adherence (n=3). This study presents recommendations for neck exercise training aiming to reduce HAEs in sport, supporting both practice and future research.
Renal tubular epithelial IGFBP7 interacts with PKM2 to drive renal lipid accumulation and fibrosis
Authors: Ju-Tao Yu, Shuai-Shuai Xie, Xiao-Yu Shen, Zeng Li, Xiao-Wei Hu, Yao Zhang, Ze-Hui Dong, Jia-Nan Wang, Xiang-Yu Li, Yu-Hang Dong, Chao Li, Ming-Lu Ji, Xiao-Guo Suo, Chen Yang, Juan Jin, Wei Wang, Jia-Gen Wen, Ming-Ming Liu, Li Li, Qin Yang, Xiao-Ming Meng
Journal: Molecular Therapy (2025)
Effectiveness of six international guidelines using FIB-4 and FibroScan for risk stratification of MASLD in type 2 diabetes
Authors: Tiphaine Vidal-Trécan, Jean-Baptiste Julla, Tania El Khoury, Nicolas Venteclef, Jean-Pierre Riveline, Valérie Paradis, Dominique Valla, Jean-François Gautier, Laurent Castera
Journal: Clinical Gastroenterology and Hepatology (2025)
Young adults with metabolic dysfunction-associated steatotic liver disease have an increased risk of early-onset cancer
Authors: Joon Ho Moon, Seogsong Jeong, Heejoon Jang, Dong Hyeon Lee, Sae Kyung Joo, Bo Kyung Koo, Qiang Xia, Meng Sha, Yoosoo Chang, Won Kim
Journal: Clinical Gastroenterology and Hepatology (2025)
Three‐Year Outcomes and Latent Class Trajectory Analysis of the Childhood Arthritis and Rheumatology Research Alliance Polyarticular JIA Consensus Treatment Plans Study
Authors: Sarah Ringold, Mei‐Sing Ong, George Tomlinson, Marc D. Natter, Laura E. Schanberg, Vincent Del Gaizo, Brian M. Feldman, Katherine L. Murphy, Yukiko Kimura
Journal: Arthritis & Rheumatology (2025)

Objective To assess the impact of differences in the timing of initial biologic DMARD (bDMARD) therapy using the CARRA STOP‐JIA polyarticular JIA (pJIA) consensus treatment plans (CTPs) study on outcomes through 3 years. Methods STOP‐JIA participants with CARRA Registry follow‐up through 3 years were eligible. Outcomes included ACR clinically inactive disease (CID) off glucocorticoids, clinical Juvenile Arthritis Disease Activity Score (10 joints) inactive disease (cJADAS‐10‐ID: cJADAS‐10≤2.5), clinical remission on medication (CRM), and proportion of time in CID and/or cJADAS‐10‐ID. Latent class trajectory modeling (LCTM) was applied to identify participant subgroups sharing similar disease courses over this period. Results 297 participants were included (n=190 Step Up [SU], 76 Early Combination [EC], 31 Biologic First [BF]). At the 3‐year visit, CID was achieved by 35%, 42% and 44%, respectively (p=0.35 for SU versus EC). EC was superior to SU in achieving CRM (59.9% vs. 40.6%; p=0.012), time spent in CID (38% versus 30%; p=0.04) and cJADAS‐10‐ID (51% versus 41%; p=0.02). Slow, moderate, and rapid improvement trajectories were identified by LCTM; bDMARD initiation within the first (OR 5.33) or second (OR 2.67) month from baseline was associated with the rapid improvement trajectory. Conclusions EC was superior to SU across 3 years for outcomes reflecting time spent in lower disease activity. Starting bDMARD within 2 months predicted rapid improvement and maintenance of inactive disease. These results support the hypothesis that early bDMARD initiation reduces overall disease burden in pJIA.