EBioMedicine最新文献

{"title":"Consistent performance of large language models in rare disease diagnosis across ten languages and 4917 cases.","authors":"Leonardo Chimirri, J Harry Caufield, Yasemin Bridges, Nicolas Matentzoglu, Michael Gargano, Mario Cazalla, Shihan Chen, Daniel Danis, Alexander J M Dingemans, Klara Gehle, Petra Gehle, Adam S L Graefe, Weihong Gu, Markus S Ladewig, Pablo Lapunzina, Julián Nevado, Enock Niyonkuru, Soichi Ogishima, Dominik Seelow, Jair A Tenorio Castaño, Marek Turnovec, Bert B A de Vries, Kai Wang, Kyran Wissink, Zafer Yüksel, Gabriele Zucca, Melissa A Haendel, Christopher J Mungall, Justin Reese, Peter N Robinson","doi":"10.1016/j.ebiom.2025.105957","DOIUrl":"https://doi.org/10.1016/j.ebiom.2025.105957","url":null,"abstract":"<p><strong>Background: </strong>Large language models (LLMs) are increasingly used medicine for diverse applications including differential diagnostic support. The training data used to create LLMs such as the Generative Pretrained Transformer (GPT) predominantly consist of English-language texts, but LLMs could be used across the globe to support diagnostics if language barriers could be overcome. Initial pilot studies on the utility of LLMs for differential diagnosis in languages other than English have shown promise, but a large-scale assessment on the relative performance of these models in a variety of European and non-European languages on a comprehensive corpus of challenging rare-disease cases is lacking.</p><p><strong>Methods: </strong>We created 4917 clinical vignettes using structured data captured with Human Phenotype Ontology (HPO) terms with the Global Alliance for Genomics and Health (GA4GH) Phenopacket Schema. These clinical vignettes span a total of 360 distinct genetic diseases with 2525 associated phenotypic features. We used translations of the Human Phenotype Ontology together with language-specific templates to generate prompts in English, Chinese, Czech, Dutch, French, German, Italian, Japanese, Spanish, and Turkish. We applied GPT-4o, version gpt-4o-2024-08-06, and the medically fine-tuned Meditron3-70B to the task of delivering a ranked differential diagnosis using a zero-shot prompt. An ontology-based approach with the Mondo disease ontology was used to map synonyms and to map disease subtypes to clinical diagnoses in order to automate evaluation of LLM responses.</p><p><strong>Findings: </strong>For English, GPT-4o placed the correct diagnosis at the first rank 19.9% and within the top-3 ranks 27.0% of the time. In comparison, for the nine non-English languages tested here the correct diagnosis was placed at rank 1 between 16.9% and 20.6%, within top-3 between 25.4% and 28.6% of cases. The Meditron3 model placed the correct diagnosis within the first 3 ranks for 20.9% of cases in English and between 19.9% and 24.0% for the other nine languages.</p><p><strong>Interpretation: </strong>The differential diagnostic performance of LLMs across a comprehensive corpus of rare-disease cases was largely consistent across the ten languages tested. This suggests that the utility of LLMs in clinical settings may extend to non-English clinical settings.</p><p><strong>Funding: </strong>NHGRI 5U24HG011449, 5RM1HG010860, R01HD103805 and R24OD011883. P.N.R. was supported by a Professorship of the Alexander von Humboldt Foundation; P.L. was supported by a National Grant (PMP21/00063 ONTOPREC-ISCIII, Fondos FEDER). C.M., J.R. and J.H.C. were supported in part by the Director, Office of Science, Office of Basic Energy Sciences, of the US Department of Energy (Contract No. DE-AC0205CH11231).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"121 ","pages":"105957"},"PeriodicalIF":10.8,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145299365","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Global childhood diarrhoea prevalence and its determinants: a systematic meta-analytic assessment, 1985-2024.","authors":"Zahir M Tag, Hadeel Alashwal, Hiam Chemaitelly, Laith J Abu-Raddad","doi":"10.1016/j.ebiom.2025.105956","DOIUrl":"https://doi.org/10.1016/j.ebiom.2025.105956","url":null,"abstract":"<p><strong>Background: </strong>Childhood diarrhoea is a major contributor to morbidity and mortality among children under five years of age. This study provides an analysis of global childhood diarrhoea prevalence, drawing on standardised, nationally representative survey data collected from 1985 to 2024.</p><p><strong>Methods: </strong>A systematic review of Demographic and Health Surveys and Multiple Indicator Cluster Surveys conducted up to October 30, 2024, was undertaken, with findings reported in accordance with PRISMA guidelines. Random-effects meta-analyses and meta-regression analyses were conducted. Factor analysis was employed to construct a Socioeconomic and Child Nutrition Index, integrating socioeconomic, water, sanitation, hygiene, and nutrition indicators.</p><p><strong>Findings: </strong>The analysis identified 593 relevant studies, estimating a global pooled mean childhood diarrhoea prevalence of 14.4% (95% CI: 13.8-15.0%) across all regions and time periods. Prevalence declined at a rate of 1% per year, falling from 22.3% in 1985-1989 to 10.9% in 2020-2024, with consistent declines observed in all regions except the Eastern Mediterranean Region. Prevalence was highest in the African Region and lowest in the European Region. Higher prevalence was observed in countries with larger household sizes, longer water collection times, and higher rates of underweight, stunting, and wasting. In contrast, lower prevalence was associated with higher levels of urbanisation, maternal education, population density, Human Development Index, income per capita, and access to improved water sources and sanitation facilities. A higher Socioeconomic and Child Nutrition Index was strongly and consistently associated with lower diarrhoea prevalence, demonstrating a dose-response relationship.</p><p><strong>Interpretation: </strong>Childhood diarrhoea prevalence has declined over recent decades, apparently reflecting the synergistic effects of targeted public health interventions and broader socioeconomic progress in addressing upstream determinants of child health.</p><p><strong>Funding: </strong>This work was supported by the Biostatistics, Epidemiology, and Biomathematics Research Core at Weill Cornell Medicine-Qatar. The statements made herein are solely the responsibility of the authors.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":" ","pages":"105956"},"PeriodicalIF":10.8,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145299317","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Respiratory syncytial virus (RSV) vaccine effectiveness and antibody correlates of protection among older adults in the Community Vaccine Effectiveness (CoVE) observational study.","authors":"Elie-Tino Godonou, Amy P Callear, Casey L Juntila-Raymond, Dolapo Raji, Matthew Smith, Kalee E Rumfelt, Claire M Midgley, Leora R Feldstein, Jefferson M Jones, Melissa Briggs Hagen, Marisa C Eisenberg, Adam S Lauring, Arnold S Monto, Abram L Wagner, Emily T Martin","doi":"10.1016/j.ebiom.2025.105961","DOIUrl":"https://doi.org/10.1016/j.ebiom.2025.105961","url":null,"abstract":"<p><strong>Background: </strong>The first RSV vaccines for adults 60 years and older were approved prior to the 2023-2024 respiratory virus season. This study aims to evaluate RSV vaccine effectiveness (VE) in preventing RSV infections among older adults, and to examine antibody correlates of protection.</p><p><strong>Methods: </strong>This study used data from adults 60 years and older, enrolled into the Community Vaccine Effectiveness (CoVE) prospective cohort study, in Michigan, U.S.A. A Cox regression model was used to compare incidence of symptomatic/all RSV infections in those vaccinated versus unvaccinated. RSV-specific (preF) binding antibodies were measured in serum specimens and assessed longitudinally. A correlates of protection analysis was conducted using logistic regression.</p><p><strong>Findings: </strong>Of the 281 participants (n = 117 vaccinated) enrolled (August 1, 2023, to March 1, 2024), 14 tested positive for RSV. Adjusted RSV VE against any RSV infection was 50.8% (95% CI: -79.1% to 86.5%), and 59.8% (95% CI: -105.2% to 92.1%) against symptomatic RSV. There were 61.2 (95% CI: 16.9, 163.2) RSV infections per 1000 person-years among participants who were vaccinated compared to 165.8 infections (95% CI: 88.0, 287.0) per 1000 person-years among those unvaccinated. A 31% decrease in odds (OR: 0.69, 95% CI: 0.44-1.07) of RSV infection per 2-fold increase in antibody concentration was observed.</p><p><strong>Interpretation: </strong>Our findings suggest that higher antibody levels may be associated with a reduced risk of RSV infection, but further research is needed to confirm this relationship. RSV incidence appeared to be lowest among adults who were vaccinated, though the difference was not statistically significant. Low number of RSV events and limited availability of serology data limit the precision of the estimates. Continued monitoring of reduction of RSV infection in years following vaccination is warranted.</p><p><strong>Funding: </strong>National Center for Immunisation and Respiratory Diseases, U.S. Centers for Disease Control and Prevention (75D30122C13149) and National Institute of Allergy and Infectious Diseases (75N93021C00015). The findings and conclusions in this report are those of the author(s) and do not necessarily represent the official position of the Centers for Disease Control and Prevention.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"121 ","pages":"105961"},"PeriodicalIF":10.8,"publicationDate":"2025-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145279077","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Using gene-environment interactions to explore pathways for colorectal cancer risk.","authors":"Emmanouil Bouras, Ren Yu, Andre E Kim, Georgios Markozannes, Neil Murphy, Demetrius Albanes, Laura N Anderson, Elizabeth L Barry, Sonja I Berndt, D Timothy Bishop, Hermann Brenner, Andrea Burnett-Hartman, Peter T Campbell, Robert Carreras-Torres, Andrew T Chan, Iona Cheng, Matthew A Devall, Virginia Diez-Obrero, Niki Dimou, David A Drew, Stephen B Gruber, Andrea Gsur, Michael Hoffmeister, Li Hsu, Jeroen R Huyghe, Eric Kawaguchi, Temitope O Keku, Anshul Kundaje, Sébastien Küry, Loïc Le Marchand, Juan Pablo Lewinger, Li Li, Brigid M Lynch, Victor Moreno, John L Morrison, Christina C Newton, Mireia Obón-Santacana, Julie R Palmer, Nikos Papadimitriou, Andrew J Pellatt, Anita R Peoples, Paul D P Pharoah, Elizabeth A Platz, Conghui Qu, Edward Ruiz-Narvaez, Joel Sanchez Mendez, Robert E Schoen, Mariana C Stern, Claire E Thomas, Yu Tian, Caroline Y Um, Kala Visvanathan, Pavel Vodicka, Veronika Vymetalkova, Emily White, Alicja Wolk, Michael O Woods, Anna H Wu, Marc J Gunter, W James Gauderman, Ulrike Peters, Marina Evangelou, Konstantinos K Tsilidis","doi":"10.1016/j.ebiom.2025.105964","DOIUrl":"https://doi.org/10.1016/j.ebiom.2025.105964","url":null,"abstract":"<p><strong>Background: </strong>Colorectal cancer (CRC) is a significant public health concern, highlighting the critical need for identifying novel intervention targets for its prevention.</p><p><strong>Methods: </strong>We conducted genome-wide interaction analyses for 15 exposures with established or putative CRC risk [body mass index (BMI), height, physical activity, smoking, type 2 diabetes, use of menopausal hormone therapy, non-steroidal anti-inflammatory drugs, and intake of alcohol, calcium, fibre, folate, fruits, processed meat, red meat, and vegetables], and used interaction estimates to explore pathways and genes underlying CRC risk. The adaptive combination of Bayes Factors (ADABF), and over-representation analysis (ORA) were used for pathway analyses, and findings were further investigated using publicly available resources [hallmarks of cancer, Open Targets Platform (OTP)].</p><p><strong>Findings: </strong>A total of 1973 pathways using ADABF, and 840 pathways using ORA, out of the 2950 analysed, were enriched (P < 0.05) for at least one exposure, as well as 1227 genes within the enriched pathways. Data were available for 811/1227 coding genes in the OTP, 241 of which were supported by strong relative abundance of prior evidence (overall OTP score > 0.05). Fifty percent of the genes (617/1227) mapped to at least one hallmark of cancer, most of which (388/617) pertained to the Sustaining Proliferative Signalling hallmark. Our findings reflect previously established pathways for CRC risk and highlight the emerging importance of several less studied genes. Common pathways were found for several combinations of exposures, potentially suggesting common underlying mechanisms.</p><p><strong>Interpretation: </strong>The results of the present analysis provide a basis for further functional research. If confirmed, they may help elucidate the etiological associations between risk factors and CRC risk and ultimately inform personalized prevention strategies.</p><p><strong>Funding: </strong>This study was funded by Cancer Research UK (CRUK; grant number:PPRCPJT∖100005) and World Cancer Research Fund International (WCRF; IIG_FULL_2020_022). Funding for grant IIG_FULL_2020_022 was obtained from Wereld Kanker Onderzoek Fonds (WKOF) as part of the World Cancer Research Fund International grant programme. Full funding details for the individual consortia are provided in the acknowledgements.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"121 ","pages":"105964"},"PeriodicalIF":10.8,"publicationDate":"2025-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145279089","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The effects of interleukin-6-receptor inhibition on monocytes in STEMI: a substudy of the ASSAIL-MI trial.","authors":"Camilla Huse, Sarah Louise Murphy, Kuan Yang, Nora Reka Balzer, Mathis K Stokke, Anne Kristine Anstensrud, Vigdis Bjerkeli, Thiago Rentz, Prabhash Kumar Jha, Hege Katrin Ugland, Annika E Michelsen, Thor Ueland, Sverre Holm, Ingvild Maria Tøllefsen, Bjørn Bendz, Ola Kleveland, Geir Øystein Andersen, Lars Gullestad, William E Louch, Sindre Woxholt, Liv Osnes, Kaspar Broch, Thomas Ulas, Pål Aukrust, Peter Libby, Bente Halvorsen, Tuva B Dahl","doi":"10.1016/j.ebiom.2025.105960","DOIUrl":"https://doi.org/10.1016/j.ebiom.2025.105960","url":null,"abstract":"<p><strong>Background: </strong>Interleukin-6 receptor (IL-6R) inhibition by tocilizumab improves myocardial salvage index (MSI) in ST-elevation myocardial infarction (STEMI). However, the mechanisms for this effect remain unclear.</p><p><strong>Methods: </strong>This pre-defined exploratory sub-study of the ASSAIL-MI trial enumerated circulating monocytes and examined their transcriptome profile in relation to the MSI and peak troponin T (TnT) in STEMI patients randomiseded to tocilizumab (n = 101) or placebo (n = 98). RNA sequencing was performed on peripheral monocytes in 14 patients. To elaborate the in vivo findings, in vitro chemotaxis and apoptosis assays were performed on THP-1 monocytes and cardiomyocyte (HL-1) cell lines, respectively.</p><p><strong>Findings: </strong>STEMI patients had increased monocyte counts at 24 h and 3-7 days after hospitalisation/PCI and this increase was attenuated by tocilizumab. Lower monocyte levels at 24 h were associated with lower TnT levels and higher MSI. Monocyte gene expression suggested that tocilizumab modulated cytokine signalling pathways related to myocardial remodelling, apoptosis, and chemotaxis, potentially through a decrease in suppressor of cytokine signalling 3 (SOCS3). In vitro, tocilizumab limited apoptosis of cardiomyocytes exposed to ischemia/reperfusion and reduced chemotaxis in monocytes exposed to IL-6.</p><p><strong>Interpretation: </strong>These findings suggest that IL-6R inhibition by tocilizumab during STEMI is associated with reduced monocyte counts and cardioprotective alterations in monocyte signalling potentially linked to the downregulation of SOCS3.</p><p><strong>Funding: </strong>This work was supported by the South-Eastern Norway Regional Health Authority (no. 2019067) and The Research Council of Norway (no. 282867) The ASSAIL-MI main study was supported by an independent grant from ROCHE who also provided drugs/placebo for infusion.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"121 ","pages":"105960"},"PeriodicalIF":10.8,"publicationDate":"2025-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145279055","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Optimised machine learning for time-to-event prediction in healthcare applied to timing of gastrostomy in ALS: a multi-centre, retrospective model development and validation study.","authors":"Marcel Weinreich, Harry McDonough, Mark Heverin, Éanna Mac Domhnaill, Nancy Yacovzada, Iddo Magen, Yahel Cohen, Calum Harvey, Ahmed Elazzab, Sarah Gornall, Sarah Boddy, James J P Alix, Julian M Kurz, Kevin P Kenna, Sai Zhang, Alfredo Iacoangeli, Ahmad Al-Khleifat, Michael P Snyder, Esther Hobson, Adriano Chio, Andrea Malaspina, Andreas Hermann, Caroline Ingre, Juan Vazquez Costa, Leonard van den Berg, Monica Povedano Panadés, Philip van Damme, Phillipe Corcia, Mamede de Carvalho, Ammar Al-Chalabi, Eran Hornstein, Eran Elhaik, Pamela J Shaw, Orla Hardiman, Christopher McDermott, Johnathan Cooper-Knock","doi":"10.1016/j.ebiom.2025.105962","DOIUrl":"https://doi.org/10.1016/j.ebiom.2025.105962","url":null,"abstract":"<p><strong>Background: </strong>Amyotrophic lateral sclerosis (ALS) is invariably fatal but there are large variations in the rate of progression. The lack of predictability can make it difficult to plan clinical interventions. This includes the requirement for gastrostomy where early or late placement can adversely impact quality of life and survival.</p><p><strong>Methods: </strong>We designed a model to predict the timing of gastrostomy requirement in ALS as indicated by 5% weight loss from diagnosis. We considered >5000 different prediction model configurations including spline models and a set of deep learning (DL) models designed for time-to-event prediction. The optimal prediction model was chosen via a Bayesian framework to avoid overfitting. Model covariates were measurements routinely collected at diagnosis; a separate longitudinal model also incorporated weight at six months. We employed a training dataset of 3000 patients from Europe, and two external validation cohorts spanning distinct populations and clinical contexts (United States, n = 299; and Sweden, n = 215). Missing data was imputed using a random forest model.</p><p><strong>Findings: </strong>The optimal model configuration was a logistic hazard DL model. The optimal model achieved a median absolute error (MAE) between predicted and measured time of 3.7 months, with AUROC 0.75 for gastrostomy requirement at 12 months. To increase accuracy we updated predictions for those who had not received gastrostomy at six months after diagnosis: here MAE was 2.6 months (AUROC 0.86). Combining both models achieved MAE of 1.2 months for the modal group of patients. Prediction performance is stable across both validation cohorts. Missing data was imputed without degrading model performance.</p><p><strong>Interpretation: </strong>To enter routine clinical practice a prospective study will be required, but we have demonstrated stable performance across multiple populations and clinical contexts suggesting that our prediction model can be used to guide individualised gastrostomy decision making for patients with ALS.</p><p><strong>Funding: </strong>Research Ireland (RI) and Biogen have supported the PRECISION ALS programme.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"121 ","pages":"105962"},"PeriodicalIF":10.8,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145274050","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"B7-H3-mediated reversal of CAR-T cell exhaustion induces a notable antitumour response in ovarian cancer models.","authors":"Qun Liu, Mengqi Deng, Junyi Jiang, Fan Tang, Xiangyu Chang, Ruiye Yang, Penglin Liu, Yanqin Zhang, Di Wu, Wenzhi Kong, Qingqing Ma, Junqi He, Jinwei Miao","doi":"10.1016/j.ebiom.2025.105949","DOIUrl":"10.1016/j.ebiom.2025.105949","url":null,"abstract":"<p><strong>Background: </strong>Functional CAR-T cell exhaustion in the immunosuppressive tumour microenvironment remains the main barrier to the success of CAR-T cell therapy for treating solid tumours. Mesothelin (MSLN) has emerged as an attractive target for CAR-T cell therapy for several solid malignancies, including ovarian cancer. In this study, we aimed to investigate the role and mechanism of lipid metabolites in anti-MSLN CAR-T cell exhaustion in ovarian cancer cells.</p><p><strong>Methods: </strong>We engineered anti-MSLN CAR-T cells targeting ovarian cancer cells with high MSLN expression as a pivotal tool for in vitro and in vivo experiments. Moreover, liquid chromatography-tandem mass spectrometry (LC-MS/MS) revealed the critical role of oxylipin 12-HETE in the exhaustion of CAR-T cells. By employing structure-based high-throughput virtual screening (HTVS), we identified the inhibitor targeting B7-H3.</p><p><strong>Findings: </strong>We demonstrated that GPR31-dependent 12-HETE accumulation in the ovarian cancer microenvironment drives CAR-T cell exhaustion via lipid peroxidation, impairing their antitumour efficacy. Genetic or pharmacological inhibition of the 12-HETE/GPR31 axis restored CAR-T cell cytotoxicity and proliferation, leading to significant tumour regression in murine models. Silencing B7-H3 relieved repression of FOXO3, leading to reduced 12-LOX expression and lower 12-HETE levels, which places B7-H3 upstream of this metabolic checkpoint. Through structure-based screening, we identified HI-TOPK-032 as a potent B7-H3 inhibitor that synergised with CAR-T cell therapy by reversing exhaustion markers (e.g., PD-1, TIM-3) and enhancing cytokine polyfunctionality. Combined HI-TOPK-032 and anti-PD-1 treatment achieved superior tumour control compared to monotherapies, particularly in B7-H3/12-LOX-high patient-derived xenografts, underscoring its precision therapeutic potential.</p><p><strong>Interpretation: </strong>CAR-T cell therapy combined with HI-TOPK-032 is a promising novel strategy for treating MSLN-expressing solid tumours.</p><p><strong>Funding: </strong>This study was funded by the National Natural Science Foundation of China (Grant number: 82503173), Beijing Hospitals Authority's Ascent Plan (Grant number: DFL20221201), Beijing Hospitals Authority Clinical Medicine Development of Special Funding Support (Grant number: ZYLX202120), Beijing Natural Science Foundation (Grant number: 7162063), Capital Medical University Laboratory for Clinical Medicine and Gynecological Tumour Precise Diagnosis and Treatment Innovation Studio.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"121 ","pages":"105949"},"PeriodicalIF":10.8,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12539249/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145250110","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fitness costs of mobilised colistin resistance gene 3 (mcr-3): systematic review, epidemiological study, and functional analysis.","authors":"Lujie Liang, Yaxin Li, Lin Wang, Wenli Wang, Yihao Zhang, Hui Zhao, Yaxuan Wang, Lingxuan Lyu, Jiachen Li, Dianrong Zhou, Zhe Hu, Lizhen Luo, Guanxiu Wang, Jia Wan, Lin Xu, Meisong Li, Min Dai, Meiting Yang, Shun Xiong, Lan-Lan Zhong, Fang Bai, Siyuan Feng, Guo-Bao Tian","doi":"10.1016/j.ebiom.2025.105923","DOIUrl":"10.1016/j.ebiom.2025.105923","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;The rapid evolution and dissemination of mobilised colistin resistance gene (mcr) family has revealed as a severe threat to the global public health. Nevertheless, dramatic reduction in the prevalence of mcr-1, the major member of mcr family, was observed after the withdrawal of colistin in animal fodder in China since 2017, demonstrating that colistin acts as a selective stress to promote the dissemination of mcr-1. As the second largest lineage, mcr-3 was firstly discovered in 2017 and has been identified from numerous sources. However, whether the spreading of mcr-3 is driven by colistin remains unknown.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;To this end, we investigated the global prevalence of mcr-3 from 2005 to 2022 by an up-to-date systematic review, along with a nation-wide epidemiological study to establish the change of mcr-3 prevalence in China before and after 2017. To investigate the fitness cost imposed by MCR-3 upon bacterial host, in vitro and in vivo competitive assays were employed, along with morphological study and fluorescent observation. Moreover, by replacing non-optimal codons with optimal codons, synonymous mutations were introduced into the 5'-coding regions of mcr-3 to study mechanisms accounting for the distinct fitness cost conferred by MCR-1 and MCR-3. Furthermore, by combining AlphaFold and molecular dynamics (MD) simulation, we provided a complete characterisation on the putative lipid A binding pocket localised at the linker domain of MCR-3. Crucially, inhibitors targeting at the putative binding pocket of MCR-1 or MCR-3 were identified from small molecules library using the pipeline of virtual screening.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Findings: &lt;/strong&gt;The global prevalence of mcr-3 increased continuously from 2005 to 2022. The average prevalence was 0.18% during 2005-2014 and rapidly increased to 3.41% during 2020-2022. The prevalence of mcr-3 in China increased from 0.79% in 2016 to 5.87% in 2019. We found that the fitness of mcr-3-bearing Escherichia coli and empty plasmid control was comparable but higher than that of mcr-1-positive strain. Although the putative lipid A binding pocket of MCR-3 was similar to that of in MCR-1, mcr-3 occupies remarkable codon bias at the 5'-end of coding region that disrupted the stability of mRNA, further reduced its protein expression in E. coli, resulting in the low fitness burden of bacterial host. Moreover, the 5'-end codon usage frequency appeared as a critical factor related with the evolution of mcr family. Furthermore, based on the similar lipid A binding pocket among MCR family protein, we identified three MCR inhibitors targeting at such pocket by screening from small-molecule library, which effectively restored the colistin susceptibility of mcr-bearing E. coli.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Interpretation: &lt;/strong&gt;We found that the prevalence of mcr-3 increased continuously during 2016-2019 in China, demonstrating that the withdrawal of colistin in husbandry failed to pr","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"120 ","pages":"105923"},"PeriodicalIF":10.8,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058304","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New standards in HER2-low testing: the CASI-01 comparative methods study.","authors":"David J Dabbs, Emina Torlakovic, Søren Nielsen, Suzanne C Parry, Jing Yu, Catherine Stoos, Beth Clark, Henrik Høeg, Jeppe Thagaard, Seshi R Sompuram, Stephen P Naber, Yukako Yagi, James Sayre, Kodela Vani, Mélissande Cossutta, Francoise Soussaline, Alexandre Papine, Nils A t'Hart, Matthias J Szabolcs, Bharat Jasani, Mary Kinloch, Luis Chiriboga, Keith Miller, Steve Bogen","doi":"10.1016/j.ebiom.2025.105919","DOIUrl":"10.1016/j.ebiom.2025.105919","url":null,"abstract":"<p><strong>Background: </strong>The introduction of Trastuzumab deruxtecan (T-Dxd) has exposed clinically significant limitations in accurately detecting HER2-low expression testing when using immunohistochemistry (IHC) assays originally developed to detect HER2 over-expression. While HER2 testing is widely used to determine T-Dxd eligibility, no HER2-low assay was ever validated against HER2 protein expression.</p><p><strong>Methods: </strong>To address this pressing need, the Consortium for Analytic Standardization in Immunohistochemistry (CASI) conducted the CASI-01 study, involving 54 IHC laboratories across Europe and the U.S. The study aimed to identify optimal assay conditions for accurate HER2 testing, differentiating between HER2 overexpression (3+) for Trastuzumab eligibility and HER2-low expression (1+ or ultra-low) for T-Dxd eligibility. The conventional FDA-cleared HER2 assay (\"predicate\") was compared with higher-sensitivity assays using pathologist versus image analysis readouts. HER2 overexpression was validated against HER2 gene amplification via in situ hybridisation (ISH), while HER2-low accuracy was evaluated using newly introduced HER2 reference standards and a novel IHC parameter-dynamic range.</p><p><strong>Findings: </strong>CASI-01 revealed variability in predicate HER2 assays, with detection thresholds ranging from 30,000 to 60,000 among laboratories. Despite this variability, these assays demonstrated high accuracy for identifying HER2 overexpression (3+), with 85.7% (18/21) sensitivity (95% confidence limits 63.66-96.95%) and 100% (49/49) specificity (95% confidence limits 92.75-100%), though sensitivity may have been limited by the use of older tissue specimens, with loss or reduced expression levels of the HER2 protein. However, these same assays exhibited poor dynamic range for detecting HER2-low scores. Enhanced analytic sensitivity of IHC assays combined with image analysis overcame this limitation with HER2-low scores, achieving a six-fold improvement (p = 0.0017).</p><p><strong>Interpretation: </strong>IHC assays with detection thresholds in the range of 30,000-60,000 HER2 molecules per cell yield accurate results for determination of Trastuzumab eligibility (HER2 3+) but fail to demonstrate the dynamic range for accurate HER2-low scores. Enhanced analytic sensitivity of HER2 assays combined with image analysis addresses this critical gap in HER2-low testing. More generally, CASI-01 introduces pivotal advancements in precision medicine: (a) the importance of reporting IHC analytic sensitivity and ability to demonstrate an assay dynamic range, and (b) image analysis can surpass pathologist readout accuracy in specific clinical contexts.</p><p><strong>Funding: </strong>This work was supported by the National Cancer Institute of the National Institutes of Health under Award Number R44CA268484.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"120 ","pages":"105919"},"PeriodicalIF":10.8,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058389","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterisation of a secreted MFSD6-Fc microbody as a decoy receptor for respiratory enterovirus D68.","authors":"Zhaoxue Li, Huili Li, Xize Liu, Junfeng Zhou, Delong Gao, Wanying Yang, Huiming Xia, Chao Dou, Zhenglei Yu, Haoran Guo, Wei Wei","doi":"10.1016/j.ebiom.2025.105915","DOIUrl":"10.1016/j.ebiom.2025.105915","url":null,"abstract":"<p><strong>Background: </strong>Enterovirus D68 (EV-D68) is a prominent non-polio enterovirus known to cause severe respiratory infections and poliomyelitis-like illnesses in children. Recently, we identified MFSD6 as a receptor for EV-D68, providing a potential target for blocking viral entry into cells. This study aimed to develop an MFSD6-based decoy receptor to neutralise EV-D68 and elucidate its mechanism of action.</p><p><strong>Methods: </strong>In this study, we engineered a secreted MFSD6-Fc microbody (secMFSD6 Mb) and evaluated its efficacy using in vitro binding assays (co-immunoprecipitation, RT-qPCR), electron microscopy, and functional studies in EV-D68-infected respiratory cell lines (Calu-3, BEAS-2B, A549), primary human bronchial epithelial cells (HBECs), and a neonatal ICR mouse model (n = 9 per group) infected with EV-D68. Statistical significance was determined by two-way ANOVA and t-test (GraphPad Prism 8.0.2; significance threshold P < 0.05).</p><p><strong>Findings: </strong>secMFSD6 Mb occupies the receptor-binding sites on the viral surface, reducing virus attachment to cells by >90% (n = 3 biological replicates). Electron microscopy showed conversion of intact virions to empty capsids after Mb treatment, and sucrose-gradient analysis demonstrated a 6-fold increase in free viral RNA (F2 fraction) compared with control. In mice challenged with 1 × 10⁷ TCID₅₀ of US/MO/14-18947, secMFSD6 Mb increased 15-day survival from 11% (1/9) to 89% (8/9).</p><p><strong>Interpretation: </strong>This decoy receptor strategy may support the development of effective therapeutic approaches against EV-D68 infection.</p><p><strong>Funding: </strong>HYPNSFC Excellent Young Scientist Fund (32222005), the National Natural Science Foundation of China (82372226, 82172246), the National Major Project for Infectious Disease Control and Prevention (2018ZX10731-101-001-016).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"120 ","pages":"105915"},"PeriodicalIF":10.8,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12452593/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145029339","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}