tbuckley/cabot-search huggingface dataset:
Identification of Hepatic-like EPO as a Cause of Polycythemia
Authors: Laurent Martin, Darko Maric, Salam Idriss, Marine Delamare, Amandine Le Roy, Nada Maaziz, Amandine Caillaud, Karim Si-Tayeb, Florence Robriquet, Marion Lenglet, Lucie Erceau, Christine Bellanné-Chantelot, Isabelle Plo, Bernard Aral, Céline Garrec, Fabrice Airaud, Clara Gianfermi, Vincent Antunes, Anna Keppner, Sarah Mathilda Vincent, Alexis Desfontaine, Nina Modé, Fabien Laporte, Anne Gaignerie, Caroline Chariau, Isabelle Leray, Coline Rogue, Laurent David, Richard Redon, Stéphane Bézieau, Lamisse Mansour-Hendili, Frédéric Galactéros, Thibault Maillet, Marlène Pasquet, Pierre Cougoul, Anne-Marie Nloga, Claude Gardin, Corinne Guitton, Viviane Dubruille, Vannina Giacobbi-Milet, Thierry Leblanc, Zuhre Kaya, Denis Semama, Chloé James, Serge Carillo, Marlène Ochmann, Anders Waage, Erwan Mortier, Mike Maillasson, Agnès Quéméner, Holger Cario, Radek C. Skoda, Yaël Zermati, David Hoogewijs, Alexandre Marchand, François Girodon, Betty Gardie
Journal: New England Journal of Medicine (2025)

Secondary erythrocytosis often results from conditions that cause tissue hypoxia or an improper increase in erythropoietin (EPO) production. EPO, the major regulator of erythropoiesis, has a complex and tightly regulated expression during development, with a liver-to-kidney switch shortly after birth. We identified six families with erythrocytosis that was associated with circulating EPO levels within the normal range and characterized as a novel molecular and functional entity. We investigated the effect of the identified pathogenic variants using EPO promoter-driven luciferase reporter genes. Induced pluripotent stem cells (iPSCs) were generated from patient cells and differentiated into hepatocyte-like EPO-producing cells. Samples of circulating EPO from patients with hereditary erythrocytosis and from healthy newborns were analyzed by means of isoelectric focusing, and EPO activity was assessed. Three novel variants were identified in the noncoding regions of EPO. Experiments with reporter assays and iPSC-derived hepatocyte-like cells showed that the variants targeted previously uncharacterized regulatory elements of the gene, which, when the variants were present, showed high responsiveness to hypoxia. EPO samples from all the patients showed a modified isoelectric-focusing profile, identical to hepatic EPO that is expressed in premature neonates and in patients with acquired erythrocytosis associated with liver diseases. EPO that was purified from patient plasma and umbilical-cord blood samples showed enhanced EPO receptor signaling activity in vitro, which suggests a potential gain of function linked to the liver-type glycosylation of EPO. We found that secondary erythrocytosis can be related to variants in EPO that lead to the production of hepatic-like EPO with an atypical glycosylation pattern and increased activity. (Funded by Région des Pays de la Loire and others; ClinicalTrials.gov number, NCT03957863.).
Phase 3 Trial of Semaglutide in Metabolic Dysfunction–Associated Steatohepatitis
Authors: Arun J. Sanyal, Philip N. Newsome, Iris Kliers, Laura Harms Østergaard, Michelle T. Long, Mette Skalshøi Kjær, Anna M.G. Cali, Elisabetta Bugianesi, Mary E. Rinella, Michael Roden, Vlad Ratziu
Journal: New England Journal of Medicine (2025)

Semaglutide, a glucagon-like peptide-1 receptor agonist, is a candidate for the treatment of metabolic dysfunction-associated steatohepatitis (MASH). In this ongoing phase 3, multicenter, randomized, double-blind, placebo-controlled trial, we assigned 1197 patients with biopsy-defined MASH and fibrosis stage 2 or 3 in a 2:1 ratio to receive once-weekly subcutaneous semaglutide at a dose of 2.4 mg or placebo for 240 weeks. The results of a planned interim analysis conducted at week 72 involving the first 800 patients are reported here (part 1). The primary end points for part 1 were the resolution of steatohepatitis without worsening of liver fibrosis and reduction in liver fibrosis without worsening of steatohepatitis. Resolution of steatohepatitis without worsening of fibrosis occurred in 62.9% of the 534 patients in the semaglutide group and in 34.3% of the 266 patients in the placebo group (estimated difference, 28.7 percentage points; 95% confidence interval [CI], 21.1 to 36.2; P<0.001). A reduction in liver fibrosis without worsening of steatohepatitis was reported in 36.8% of the patients in the semaglutide group and in 22.4% of those in the placebo group (estimated difference, 14.4 percentage points; 95% CI, 7.5 to 21.3; P<0.001). Results for the three secondary outcomes that were included in the plan to adjust for multiple testing were as follows: combined resolution of steatohepatitis and reduction in liver fibrosis was reported in 32.7% of the patients in the semaglutide group and in 16.1% of those in the placebo group (estimated difference, 16.5 percentage points; 95% CI, 10.2 to 22.8; P<0.001). The mean change in body weight was -10.5% with semaglutide and -2.0% with placebo (estimated difference, -8.5 percentage points; 95% CI, -9.6 to -7.4; P<0.001). Mean changes in bodily pain scores did not differ significantly between the two groups. Gastrointestinal adverse events were more common in the semaglutide group. In patients with MASH and moderate or advanced liver fibrosis, once-weekly semaglutide at a dose of 2.4 mg improved liver histologic results. (Funded by Novo Nordisk; ClinicalTrials.gov number, NCT04822181.).
Predicting progression events in multiple myeloma from routine blood work
Authors: Maximilian Ferle, Nora Grieb, Markus Kreuz, Jonas Ader, Hartmut Goldschmidt, Elias K Mai, Uta Bertsch, Uwe Platzbecker, Thomas Neumuth, Kristin Reiche, Alexander Oeser, Maximilian Merz
Journal: npj Digital Medicine (2025)

This study introduces a system for predicting disease progression events in multiple myeloma patients from the CoMMpass study (N = 1186). Utilizing a hybrid neural network architecture, our model predicts future blood work from historical lab results with high accuracy, significantly outperforming baseline estimators for key disease parameters. Disease progression events are annotated in the forecasted data, predicting these events with significant reliability. We externally validated our model using the GMMG-MM5 study dataset (N = 504), and could reproduce the main results of our study. Our approach enables early detection and personalized monitoring of patients at risk of impeding progression. Designed modularly, our system enhances interpretability, facilitates integration of additional modules, and uses routine blood work measurements to ensure accessibility in clinical settings. With this, we contribute to the development of a scalable, cost-effective virtual human twin system for optimized healthcare resource utilization and improved outcomes in multiple myeloma patient care.
Mepolizumab to Prevent Exacerbations of COPD with an Eosinophilic Phenotype
Authors: Frank C. Sciurba, Gerard J. Criner, Stephanie A. Christenson, Fernando J. Martinez, Alberto Papi, Nicolas Roche, Jean Bourbeau, Stephanie Korn, Mona Bafadhel, MeiLan K. Han, Stefanie Kolterer, Karen Miller, Dalal Mouneimne, Joanne Fletcher, Bhabita Mayer, Jeff Min, Ian D. Pavord
Journal: New England Journal of Medicine (2025)

Mepolizumab is a humanized monoclonal antibody that targets interleukin-5, a cytokine that plays a central role in eosinophilic inflammation, which is present in 20 to 40% of patients with chronic obstructive pulmonary disease (COPD). In a phase 3, double-blind, randomized, placebo-controlled trial, patients with COPD, a history of exacerbations, and a blood eosinophil count of at least 300 cells per microliter who were receiving triple inhaled therapy were assigned, in a 1:1 ratio, to receive mepolizumab (at a dose of 100 mg) or placebo subcutaneously every 4 weeks for 52 to 104 weeks. The primary end point was the annualized rate of moderate or severe exacerbations. Secondary end points, tested hierarchically to control for multiplicity, were moderate or severe exacerbation as assessed in a time-to-first-event analysis, measures of health-related quality of life and symptoms, and the annualized rate of exacerbations leading to an emergency department visit, hospitalization, or both. Of the 804 patients who underwent randomization, 403 were assigned to receive mepolizumab and 401 to receive placebo. The annualized rate of moderate or severe exacerbations was significantly lower with mepolizumab than with placebo (0.80 vs. 1.01 events per year; rate ratio, 0.79; 95% confidence interval [CI], 0.66 to 0.94; P = 0.01). The time to the first moderate or severe exacerbation was longer with mepolizumab than with placebo (Kaplan-Meier median time to the first moderate or severe exacerbation, 419 vs. 321 days; hazard ratio, 0.77; 95% CI, 0.64 to 0.93; P = 0.009). Between-group differences in measures of health-related quality of life and symptoms were not significant; thus, no statistical inferences regarding subsequent secondary end points in the statistical testing hierarchy were made. The incidence of adverse events was similar in the mepolizumab and placebo groups. Treatment with mepolizumab led to a lower annualized rate of moderate or severe exacerbations when added to background triple inhaled therapy among patients with COPD and an eosinophilic phenotype. (Funded by GSK; MATINEE ClinicalTrials.gov number, NCT04133909.).
Impaired Aire-dependent IFN signaling in the thymus precedes the protective autoantibodies to IFNα
Authors: Artur Stoljar, Maksym Zarodniuk, Rudolf Bichele, Elise Helene Armulik, Uku Haljasorg, Romain Humeau, Marine Besnard, Liis Haljasmägi, Liina Tserel, Merili Peltser, Ahto Salumets, Eliisa Kekäläinen, Kai Kisand, Carole Guillonneau, Martti Laan, Pärt Peterson
Journal: The Journal of Experimental Medicine (2025)

Recent studies have highlighted the role of the thymus in maintaining immune tolerance to type 1 interferons (T1 IFNs). Individuals with thymic abnormalities, such as autoimmune regulator (AIRE) gene mutations, frequently develop neutralizing autoantibodies to interferon-alpha (IFNα). Unlike mice, Aire-deficient rats develop robust autoantibodies to IFNα. Using this rat model, we show that Aire regulates the thymic expression of interferon-stimulated genes (ISGs), which occurs before developing anti-IFNα autoantibodies. In the periphery, we observed a widespread downregulation of ISGs across immune cells and reduced activation of natural killer (NK) cells. Furthermore, the presence of anti-IFNα autoantibodies correlated with reduced peripheral tissue inflammation, suggesting their role in dampening T1 IFN signaling and minimizing tissue infiltration. Our findings reveal that Aire-mediated regulation of thymic T1 IFN signaling is linked to the production of protective anti-IFNα autoantibodies, which inversely correlate with autoimmune pathology in peripheral tissues.
Integration of Optical Genome Mapping in the Cytogenomic and Molecular Work‐Up of Hematological Malignancies: Expert Recommendations From the International Consortium for Optical Genome Mapping
Authors: Rashmi Kanagal‐Shamanna, Anna Puiggros, Isabel Granada, Gordana Raca, Katrina Rack, Mar Mallo, Barbara Dewaele, Adam C. Smith, Yassmine Akkari, Brynn Levy, Robert P. Hasserjian, Adela Cisneros, Marta Salido, Guillermo Garcia‐Manero, Hui Yang, M. Anwar Iqbal, Ravindra Kolhe, Francesc Solé, Blanca Espinet
Journal: American Journal of Hematology (2025)

ABSTRACT The latest updates to the classification of hematolymphoid malignancies using the World Health Organization (WHO, 5th ed.) and ICC (International Consensus Classification) criteria highlight the critical need for comprehensive and precise cytogenomic data for diagnosis, prognostication, and treatment. This presents significant challenges for clinical laboratories, requiring a complex workflow using multiple assays to detect different types of structural chromosomal variants (copy number changes, fusions, inversions) across the entire genome. Optical genome mapping (OGM) is an advanced cytogenomic tool for genome‐wide detection of structural chromosomal alterations at the gene/exon level. Studies demonstrate that OGM facilitates the identification of novel cytogenomic biomarkers, improves risk stratification, and expands therapeutic targets and personalized treatment strategies. OGM is easy to implement and highly accurate in detecting structural variants (SVs) across various diagnostic entities. Consequently, many centers are integrating OGM into the clinical cytogenetic workflow for hematological malignancies. However, systemic clinical adoption has remained limited due to the lack of expert recommendations on clinical indications, testing algorithms, and result interpretation. To address this, experts from the International Consortium for OGM and relevant multidisciplinary fields developed recommendations for the integration of OGM as a standard‐of‐care cytogenetic assay for the diagnostic workflow in various clinical settings. These recommendations standardize the use of OGM across laboratories, ensure high‐quality cytogenetic data, guide clinical trial design and development, and provide a basis for updates to diagnostic and classification models.
Author Correction: Conditional ablation of Stat3 or Socs3 discloses a dual role for reactive astrocytes after spinal cord injury
Authors: Seiji Okada, Masaya Nakamura, Hiroyuki Katoh, Tamaki Miyao, Takuya Shimazaki, Ken Ishii, Junichi Yamane, Akihiko Yoshimura, Yukihide Iwamoto, Yoshiaki Toyama, Hideyuki Okano
Journal: Nature Medicine (2025)
Bio‐Nano Innovations Targeting the Neurovascular Complex for Epilepsy Treatment
Authors: Xin Wang, Yanlong Cheng, Zhengzhuo Qi, Jing Zhao, Cong Wang
Journal: Advanced Healthcare Materials (2025)

Abstract Epilepsy is a prevalent chronic neurological disorder characterized by seizures resulting from an imbalance between excitatory and inhibitory neurons. While pharmacotherapy remains the standard treatment, traditional pharmacotherapy faces significant challenges, including poor brain penetration, high drug resistance rates, and providing only symptomatic relief, rather than addressing the underlying causes for a comprehensive cure. Recently, the neurovascular complex (NVC) has gained attention for its critical role in the development and progression of epilepsy. Simultaneously, various innovative bio‐nanotechnology systems have emerged, specifically designed to enhance drug delivery across the brain and enable precise targeting within the lesion. Herein, this review begins by outlining the core NVC involved in epilepsy treatment, breaking it down into four key components: the blood‐brain barrier (BBB), neurons, glial cells, and the microenvironment. The viability of targeting NVC to improve epilepsy therapy is analyzed. Next, innovative bio‐nanotechnology systems, detailing their design principles, construction strategies, and preclinical evaluations in epilepsy therapy are highlighted. Finally, the prospects for next‐generation nanotechnologies and the challenges that must be overcome for effective clinical translation are discussed. Overall, this review aims to guide the development of more efficient and precise bio‐nano therapies, ultimately enhancing treatment outcomes for epilepsy patients.
A pH/STEAP Cascade‐Responsive Nanomedicine with Self‐Supplied Peroxide for Precise Chemodynamic Therapy
Authors: Huilan Cai, Shenghan Chen, Yang Zhu, Shaoru Zhuang, Jun Wang, Xuegang Niu, Tingting Cui, Hongwei Huang, Rujiang Ao, Meili Yu, Shanshan Peng, Yu He, Huanghao Yang, Lisen Lin
Journal: Advanced Healthcare Materials (2025)

Abstract Self‐supply of peroxo compounds has been regarded as a promising strategy to enhance Fenton chemistry‐based chemodynamic therapy (CDT). However, the inherent selectivity of CDT will be affected after introducing peroxide‐supplementing functionality into chemodynamic agents due to the lack of ability to distinguish cancer cells from normal cells. Here, an intelligent CDT nanomedicine is reported with both cascade‐responsive and peroxide self‐supplying performances for specific and efficient cancer treatment. Upon endocytosis into acidic endo/lysosomes, the CDT nanomedicine comprising methyl linoleate hydroperoxide (MLH)‐loaded amorphous iron oxide nanoparticles (AIO@MLH NPs) can be decomposed to release MLH and Fe 3+ that is further reduced into Fe 2+ by endo/lysosomal six‐transmembrane epithelial antigen of the prostate (STEAP) with metalloreductase activity, enabling the occurrence of Fenton‐type reaction between high‐active Fe 2+ and MLH for free radical generation, which causes endo/lysosomal damage and cancer cell apoptosis. Noteworthily, AIO@MLH NPs exhibit potent chemodynamic cytotoxicity to cancerous cells rather than non‐cancerous cells benefiting from the overexpressed STEAP in multiple cancers, thereby leading to precise tumor CDT. This work highlights the use of endogenous STEAP to improve the selectivity of peroxide self‐supplying chemodynamic agents and paves the way for the development of precision medicine.
Targeted Anti‐Inflammatory Nanozymes with Pro‐Angiogenic Activity for Myocardial Infarction Therapy
Authors: Wenling Yang, Xuelian Li, Jie Lei, Shijiu Jiang, Jinpeng Sun, Qingyi Liu, Ruiyu Zhang, Chuansheng Zheng, Xiaopeng Guo, Yumiao Wei
Journal: Advanced Healthcare Materials (2025)

Abstract Myocardial infarction (MI) poses a significant threat to human health. Current treatments emphasize early revascularization to restore blood supply to the myocardium, often overlooking the extensive oxidative damage and autophagy dysfunction resulting from reactive oxygen species (ROS) release after MI. Therefore, timely and effective interventions to clear ROS in the early stages of MI are crucial for inhibiting the MI pathological progression and restoring cardiac function. This study constructed a ROS‐responsive biomimetic nanoparticle (PNP@Nb 2 C‐MSN) by integrating niobium carbide MXenes (Nb 2 C) onto mesoporous silica nanoparticle (MSN) coated with platelet membrane. During the MI acute phase, these nanoparticles are targeted and delivered to the infarcted heart via intravenous injection. The MSN mesoporous structure enhances the ROS scavenging capacity of Nb 2 C, eliminating excess ROS in the infarct region and inhibiting the oxidative stress progression. Silicon ions released from MSN further promote angiogenesis within the infarct region. PNP@Nb 2 C‐MSN reduces inflammation by downregulating the NF‐κB pathway and enhances autophagy by activating the AMPK pathway, thereby blocking pathological microenvironmental progression after MI and improving cardiac function. In vitro and in vivo results highlight the therapeutic potential of PNP@Nb 2 C‐MSN in MI, offering a promising MI treatment strategy.
A scoping review of large language models for generative tasks in mental health care
Authors: Yining Hua, Hongbin Na, Zehan Li, Fenglin Liu, Xiao Fang, David Clifton, John Torous
Journal: npj Digital Medicine (2025)

Large language models (LLMs) show promise in mental health care for handling human-like conversations, but their effectiveness remains uncertain. This scoping review synthesizes existing research on LLM applications in mental health care, reviews model performance and clinical effectiveness, identifies gaps in current evaluation methods following a structured evaluation framework, and provides recommendations for future development. A systematic search identified 726 unique articles, of which 16 met the inclusion criteria. These studies, encompassing applications such as clinical assistance, counseling, therapy, and emotional support, show initial promises. However, the evaluation methods were often non-standardized, with most studies relying on ad-hoc scales that limit comparability and robustness. A reliance on prompt-tuning proprietary models, such as OpenAI's GPT series, also raises concerns about transparency and reproducibility. As current evidence does not fully support their use as standalone interventions, more rigorous development and evaluation guidelines are needed for safe, effective clinical integration.
Analysis of demographic variation and childhood correlates of financial well-being across 22 countries
Authors: Piotr Bialowolski, Christos A Makridis, Matt Bradshaw, Dorota Weziak-Bialowolska, Craig Gundersen, Noémie Le Pertel, Cristina Gibson, Sung Joon Jang, R Noah Padgett, Byron R Johnson, Tyler J VanderWeele
Journal: Nature Human Behaviour (2025)
An organoid library unveils subtype-specific IGF-1 dependency via a YAP–AP1 axis in human small cell lung cancer
Authors: Takahiro Fukushima, Kazuhiro Togasaki, Junko Hamamoto, Katsura Emoto, Toshiki Ebisudani, Akifumi Mitsuishi, Kai Sugihara, Taro Shinozaki, Masahiko Okada, Ayaka Saito, Hatsuyo Takaoka, Fumimaro Ito, Lisa Shigematsu, Yuki Ohta, Sirirat Takahashi, Mami Matano, Yutaka Kurebayashi, Keiko Ohgino, Takashi Sato, Ichiro Kawada, Keisuke Asakura, Tomoyuki Hishida, Hisao Asamura, Shinnosuke Ikemura, Hideki Terai, Kenzo Soejima, Mayumi Oda, Masayuki Fujii, Koichi Fukunaga, Hiroyuki Yasuda, Toshiro Sato
Journal: Nature Cancer (2025)
Low-voltage-area ablation for persistent atrial fibrillation: a randomized controlled trial
Authors: Masaharu Masuda, Akihiro Sunaga, Nobuaki Tanaka, Tetsuya Watanabe, Hitoshi Minamiguchi, Yasuyuki Egami, Takafumi Oka, Tomoko Minamisaka, Takashi Kanda, Masato Okada, Masato Kawasaki, Yasuhiro Matsuda, Koji Tanaka, Tomomi Yamada, Shungo Hikoso, Tomoharu Dohi, Koichi Inoue, Yohei Sotomi, Yasushi Sakata
Journal: Nature Medicine (2025)

Low-voltage areas (LVAs) in the left atrium may promote atrial fibrillation (AF), but the efficacy of LVA ablation for preventing arrhythmia has not been determined. In the present study, we carried out a multicenter, randomized controlled trial (SUPPRESS-AF) to investigate the efficacy of LVA ablation in patients with persistent AF who had left atrial LVAs. Patients with persistent AF and left atrial LVAs that covered ≥5 cm2 of the left atrial surface on a voltage map after pulmonary vein isolation (PVI) were randomized to undergo LVA ablation (PVI + LVA-ABL group) or not (PVI-alone group) in a 1:1 fashion. Recurrence of AF or atrial tachycardia (AT) was monitored using 24-h Holter electrocardiography (ECG) and twice-daily portable ECG recordings. The primary endpoint was freedom from AF or AT recurrence without antiarrhythmic drug use during 1 year of follow-up. Of 1,347 patients (1,003 males and 344 females) who underwent initial ablation for AF, patients with left atrial LVAs were assigned to the PVI + LVA-ABL (n = 170) or the PVI-alone group (n = 171). Although the PVI + LVA-ABL group demonstrated a numerically higher rate of freedom from AF or AT recurrence compared with the PVI-alone group (61% (95% confidence interval (CI) = 53-68%) versus 50% (95% CI = 42-57%)), this difference did not reach statistical significance (P for log(rank) test = 0.127). There was no difference in the procedure-related serious adverse events between the two groups (1.7% versus 1.8%, P < 0.0001). In conclusion, LVA ablation in addition to PVI did not significantly reduce 1-year AF or AT recurrence in patients with persistent AF with left atrial LVAs. Future studies are needed to identify patients who may receive greater benefit from LVA ablation.