EBioMedicine最新文献

{"title":"Spatially resolved T cell receptor diversity mapping uncovers variability of the cancer immune microenvironment.","authors":"Anastasia Magoulopoulou, Maria Chatzinikolaou, Andreas Metousis, Taobo Hu, Hui Yu, Ioannis Zerdes, Kang Wang, Theodoros Foukakis, Mengping Long, Karin Leandersson, Patrick Micke, Carina Strell, Mats Nilsson","doi":"10.1016/j.ebiom.2026.106264","DOIUrl":"10.1016/j.ebiom.2026.106264","url":null,"abstract":"<p><strong>Background: </strong>T cell receptor (TCR) binding properties have been related to a wide range of pathological conditions, including infections, autoimmunity and cancer. Characterising the TCR repertoire is of great biomedical interest but it has been challenging due to its high structural diversity.</p><p><strong>Methods: </strong>In situ sequencing (ISS) is a suitable technique for spatial cell typing and linking gene patterns directly to specific histopathological features of large biopsy areas. We applied ISS through the commercial Xenium platform, with the addition of a custom panel specifically designed for TCR gene detection. Based on the IMGT database, we selected unique target sequences for TCR genes encoding the constant, variable and joining TCR chains. Additionally, we developed an analysis pipeline for the assignment of putative clonotypes based on simultaneous expression of alpha and beta variable TCR chains (TCRVβ/Vα pairs) at the single-cell level.</p><p><strong>Findings: </strong>Our approach captured specific immune cell distributions in relation to the individual sample clonality, as well as regional dominance of certain TCRVβ/Vα pairs in surgical non-small cell lung cancer (NSCLC) specimens and matching lymph node samples. Furthermore, we were able to study the spatiotemporal evolution of TCR repertoire on longitudinal FFPE biopsies from patients with breast cancer, during neoadjuvant treatment.</p><p><strong>Interpretation: </strong>This study highlights the implementation of target-based spatially resolved transcriptomics for the spatial characterisation of TCRVβ/Vα pairs at the single-cell level, without the need for prior sequencing. Our approach allows for spatial immune characterisation of diagnostic tissue samples with emphasis on T cell biology and accompanying T cell diversity.</p><p><strong>Funding: </strong>This study was supported from Cancerfonden (CAN 2021/1726), Swedish Research Council (Dnr: 2019-01238), U-CAN and the Trond Mohn Foundation.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"127 ","pages":"106264"},"PeriodicalIF":10.8,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13127328/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147766009","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":"MechanoAge, a machine learning platform to identify individuals susceptible to breast cancer based on mechanical properties of single cells.","authors":"Stefan Hinz, Sturla M Grøndal, Masaru Miyano, Jennifer C Lopez, Kristen L Cotner, Taylor Thomsen, Chang Chen, Edward J Hester, Lisa D Yee, Victoria E Seewaldt, James B Lorens, Lydia L Sohn, Mark A LaBarge","doi":"10.1016/j.ebiom.2026.106241","DOIUrl":"https://doi.org/10.1016/j.ebiom.2026.106241","url":null,"abstract":"<p><strong>Background: </strong>Emerging evidence links cellular ageing and biophysical alterations with cancer susceptibility. Existing breast cancer risk models inadequately identify individuals at latent risk, particularly among women without known genetic mutations or family history. Risk is often underestimated or overestimated due to reliance on population-level data and absence of individualised tissue-based markers of breast cancer risk.</p><p><strong>Methods: </strong>We profiled primary human mammary epithelial cells (HMECs) from women of varying ages and risk backgrounds using mechano-node-pore sensing (mechano-NPS), a high-throughput microfluidic platform that measures single-cell physical and mechanical properties. We developed a machine learning classifier, MechanoAge, to estimate chronological age based on mechanical phenotypes, and a biological age-based risk index, Mechano-RISQ. We further assessed cytoskeletal protein keratin 14 (KRT14) as a key mediator of underlying mechanical states through overexpression and knockdown experiments.</p><p><strong>Findings: </strong>Epithelial cells from normal tissue of young BRCA1/2 mutation carriers (n = 4), women with family history of breast cancer (n = 3), and tissue contralateral to a tumour-bearing breast (n = 9) exhibited elevated Mechano-RISQ scores, which reflects accelerated biological ageing compared to age-matched controls (n = 18). KRT14 overexpression induced a biologically aged phenotype in cells obtained from younger women, whereas knockdown partially reversed this state in cells from older women. CyTOF profiling and modelling showed KRT14 modulation impacted protein expression signatures associated with ageing and risk.</p><p><strong>Interpretation: </strong>Mechano-RISQ offers a proof of principle approach for identifying individuals at elevated risk of breast cancer, especially among average-risk populations, and may complement existing risk models by incorporating biophysical measures of mammary epithelial cell ageing.</p><p><strong>Funding: </strong>NIH R01EB024989, R01CA237602, and P30CA033572, DOD BC181737, American Cancer Society-Fred Ross Desert Spirit Postdoctoral Fellowship (PF-21-184-01-CSM).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":" ","pages":"106241"},"PeriodicalIF":10.8,"publicationDate":"2026-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147765977","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":"Safety and efficacy of allogeneic umbilical cord-derived mesenchymal stem cell infusion for frailty: a phase 2, single-centre, randomised, open-label controlled trial.","authors":"Liem T Nguyen, Kien T Nguyen, Lan T M Dao, Van T Hoang, Trang T K Phan, Nhung T H Dinh, Ha T Nguyen, Anh T P Nguyen, Thuy T N Nguyen, Thanh T K Ho, Quyet M Nguyen","doi":"10.1016/j.ebiom.2026.106268","DOIUrl":"https://doi.org/10.1016/j.ebiom.2026.106268","url":null,"abstract":"<p><strong>Background: </strong>Frailty syndrome in older adults is a growing public health concern associated with increased vulnerability and adverse outcomes. Umbilical cord-derived mesenchymal stem cell (UC-MSC) therapy shows promise in improving physical function and quality of life. This study evaluated the safety and efficacy of intravenous UC-MSC infusion in older frail adults.</p><p><strong>Methods: </strong>A phase 2 randomised controlled trial at Vinmec Times City International General Hospital (2021-2024) enrolled 147 frail adults aged 60-85 (Modified Fried Criteria ≥3). Participants were randomly assigned to receive two intravenous UC-MSC infusions (1.5 × 10⁶ cells/kg, three months apart) plus oral supplements, or supplements alone, with nine months of follow-up. Safety was assessed by adverse events (AEs) and serious adverse events (SAEs). Efficacy outcomes included Short Physical Performance Battery (SPPB), handgrip strength, physical activity (CHAMPS), fatigue (MFI), knee function (WOMAC), and quality of life (SF-36).</p><p><strong>Findings: </strong>No UC-MSC therapy-related SAEs occurred. Twelve mild AEs (headache, dizziness, chest discomfort) resolved spontaneously. At nine months, the UC-MSC group showed higher SPPB scores than controls (least-squares mean difference 1.1 points, 95% CI: 0.6-1.6).</p><p><strong>Interpretation: </strong>In this study, UC-MSC infusion was associated with no safety concerns and was associated with higher SPPB scores than in the control group. These findings provide the necessary rationale and foundation for larger, double-blind, multicentre phase 3 trials.</p><p><strong>Funding: </strong>Vingroup Joint Stock Company, grant ISC.21.11.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"127 ","pages":"106268"},"PeriodicalIF":10.8,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13123506/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147766016","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":"Proteomic profiling and molecular reclassification of high-grade serous ovarian cancer identifies prognostic subtypes and immunotherapy biomarkers.","authors":"Mengyan Tu, Sangsang Tang, Qiao Zhang, Tianchen Guo, Yixuan Cen, Xiaomeng Xu, Shenglong Wu, Xin Chen, Weiguo Lu, Chen Ding, Junfen Xu","doi":"10.1016/j.ebiom.2026.106248","DOIUrl":"10.1016/j.ebiom.2026.106248","url":null,"abstract":"<p><strong>Background: </strong>High-grade serous ovarian cancer (HGSOC) is the most lethal histological subtype of ovarian cancer, exhibiting significant heterogeneity and limited therapeutic options. A comprehensive characterisation of proteomic landscape across disease stages is needed to identify actionable biomarkers and therapeutic targets.</p><p><strong>Methods: </strong>We performed proteomic profiling of 116 primary HGSOC tumours, followed by integrative bioinformatics analyses incorporating clinical annotation. Key findings were validated using multiplex immunohistochemistry, in vitro and in vivo functional assays, and external datasets.</p><p><strong>Findings: </strong>We identified FIGO stage IIA as a crucial turning point distinguishing early-from advanced-stage disease, marked by a transition from oxidative stress to cell cycle-driven programmes. Trajectory analysis of tumour progression revealed GOSR2 as a key regulator of stage transition. Mechanistically, GOSR2 interacted with SEC24D to inhibit the secretion of CXCL9 and CXCL12, resulting in reduced CD8+ T cell infiltration. Unsupervised clustering defined three reproducible proteomic subtypes (S-I to S-III), which were validated in TCGA and single-cell transcriptomic datasets and associated with distinct clinical outcomes. The S-III subtype was characterised by ECM-receptor interaction, immune evasion, and poor prognosis. Transcription factors network analysis identified regulators potentially driving these phenotypes. In parallel, three immune-contexture subtypes (IC1-IC3) were delineated, reflecting differential tumour immune microenvironment states with prognostic relevance. Advanced-stage HGSOC was further stratified using ISG15, ITGB2, and RELA expression, idenfifying a subgroup with potential susceptibility to immunotherapy.</p><p><strong>Interpretation: </strong>Our findings provide a framework for biomarker-guided stratification and the development of precision therapeutic strategies in HGSOC.</p><p><strong>Funding: </strong>Key R&D Program of Zhejiang, NSFC, and 4+X CRP of WHZJU.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"127 ","pages":"106248"},"PeriodicalIF":10.8,"publicationDate":"2026-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13101710/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147722203","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":"Genotype-first approach reveals monogenic lipodystrophy is underdiagnosed, with health and mortality risks.","authors":"Luke N Sharp, Kevin Colclough, Jacques Murray Leech, Amy V Evans, Andrew T Hattersley, Michael N Weedon, Rebecca J Brown, Kashyap A Patel","doi":"10.1016/j.ebiom.2026.106255","DOIUrl":"10.1016/j.ebiom.2026.106255","url":null,"abstract":"<p><strong>Background: </strong>Monogenic lipodystrophy is a metabolic disorder that predisposes to diabetes and cardiovascular disease, yet its true prevalence and clinical spectrum remain uncertain. We used a genotype-first approach with an aim to estimate the prevalence, phenotypic spectrum, risk of cardiometabolic disorders and all-cause mortality associated with monogenic lipodystrophy in the population. We also assessed how these clinically unselected cases differ from clinically identified cases.</p><p><strong>Methods: </strong>We analysed whole-genome sequencing data from 490,414 UK Biobank participants to identify pathogenic variants in 23 lipodystrophy genes. Individuals carrying a pathogenic genotype were compared with non-carriers for anthropometric traits, metabolic biomarkers, cardiometabolic outcomes, and all-cause mortality. We also compared UK Biobank cases with a clinically identified cohort of 58 individuals with monogenic lipodystrophy.</p><p><strong>Findings: </strong>We identified 31 carriers of pathogenic monogenic lipodystrophy variants, giving a prevalence of 1 in 15,820 (95% CI: 1 in 23,282-1 in 11,145). Variants in PPARG and LMNA were most frequent, and prevalence did not differ by sex (P = 0.37). Compared with non-carriers, carriers had similar BMI but lower total body fat percentage (24.7% vs. 31.4%, P = 1.25 × 10^-5), higher waist-hip ratio adjusted for BMI (0.91 vs. 0.87, P = 0.0044), elevated triglycerides (2.9 vs. 1.7 mmol/L, P = 6.69 × 10^-5), and reduced HDL cholesterol (0.99 vs. 1.45 mmol/L, P = 6.26 × 10^-9). These features were similar between men and women. None of the carriers had a diagnosis of lipodystrophy in electronic health records. Carriers had increased risk of diabetes (Adjusted HR 4.41, 95% CI 2.5-7.76), coronary artery disease (Adjusted HR 2.97, 95% CI 1.42-6.24), and heart failure (Adjusted HR 5.28, 95% CI 2.52-11.07). They also had almost fourfold higher mortality (Adjusted HR 4.02, 95% CI 2.16-7.48) over a mean follow-up of 13.6 years. Compared with clinically identified cases, UK Biobank carriers had milder phenotypes.</p><p><strong>Interpretation: </strong>Monogenic lipodystrophy is more common than currently recognised and most cases remain undiagnosed despite significant cardiometabolic and mortality risks. These findings highlight the value of genotype-first approaches in studying lipodystrophy and support the need for earlier recognition and treatment in clinical practice.</p><p><strong>Funding: </strong>This work is funded by Diabetes UK (19/0005994 and 21/0006335), the MRC (MR/T00200X/1) and the Wellcome Trust (219606/Z/19/Z).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"127 ","pages":"106255"},"PeriodicalIF":10.8,"publicationDate":"2026-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13098338/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147722193","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":"Genetics of educational resilience after adverse childhood experiences.","authors":"Huazhen Yang, Hilda Björk Daníelsdóttir, Yu Zeng, Can Hou, Hongxi Wang, Arna Hauksdottir, Edda Björk Thordardottir, Gunnar Tómasson, Jóhanna Jakobsdóttir, Thor Aspelund, Jie Song, Fang Fang, Unnur Anna Valdimarsdóttir, Huan Song","doi":"10.1016/j.ebiom.2026.106260","DOIUrl":"10.1016/j.ebiom.2026.106260","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Adverse childhood experiences (ACEs) are associated with poorer mental health and may hinder educational attainment. Yet, some ACEs survivors still achieve higher education, suggesting the presence of educational resilience, whilst its underlying mechanisms remain unclear. This study aimed to evaluate the cross-cultural consistency of the ACEs-education association and to identify the underlying genetic determinants of educational resilience.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;This multi-cohort study included 127,571 UK Biobank participants, 27,128 from the Icelandic Stress-and-Gene-Analysis (SAGA) Cohort, and 4910 from the China Severe Trauma Cohort (CSTC). Associations between ACEs and educational attainment (i.e., achieving a college education or years of education) were examined using multivariable regression models. In the UK Biobank and CSTC, we performed stratification analyses by polygenic score (PGS) for educational attainment to evaluate the modifying role of genetic predisposition. We then conducted a genome-wide association study (GWAS) in the UK Biobank to identify genetic variants associated with educational resilience. Resilient cases were defined as individuals exposed to ACEs in the top 10&lt;sup&gt;th&lt;/sup&gt; percentile of residuals (i.e., those with the lowest 10&lt;sup&gt;th&lt;/sup&gt; percentile of predicted probability of completing college who nonetheless achieved a college degree), while the remaining ACE-exposed participant served as controls. Gene-ACEs interaction analyses among all UK Biobank participants studied were used to verify the modification effects of identified variants.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Findings: &lt;/strong&gt;ACEs were associated with lower odds of obtaining a college degree across all three cohorts (odds ratio [95% confidence interval] = 0.75 [0.72-0.77] for the UK Biobank, 0.69 [0.66-0.73] for SAGA cohort, and 0.46 [0.39-0.54] for CSTC). These associations were comparable across different PGS strata both in the UK Biobank and CSTC. GWAS in the UK Biobank identified a potential novel locus (rs2743239) associated with educational resilience, mapped to several neuroprotective and immune-related pathways. We further detected a significant gene-ACEs interaction (p for interaction &lt;0.0001) in the UK biobank, indicating that among ACEs exposed individuals, TT carriers of rs2743239 had higher odds of college completion than AA carriers (1.44 [1.21-1.71]); this trend was not observed among individuals without ACEs (1.01 [0.95-1.09]).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Interpretation: &lt;/strong&gt;ACEs were associated with lower educational attainment, irrespective of genetic predisposition to education. A potential novel variant, rs2743239, was linked to educational resilience specifically among ACEs-exposed individuals. While further validation is required, these findings offer suggestive evidence for a genetic basis of educational resilience that may inform future intervention strategies for risk management among ACEs survivors.&lt;/p&gt;&lt;p&gt;","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"127 ","pages":"106260"},"PeriodicalIF":10.8,"publicationDate":"2026-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13101721/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147722218","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":"Genome-wide association studies of brain diffusion kurtosis imaging phenotypes.","authors":"Jilian Fu, Jianhua Wang, Hui Xue, Meiyun Wang, Bing Zhang, Wenzhen Zhu, Shijun Qiu, Zuojun Geng, Guangbin Cui, Quan Zhang, Yongqiang Yu, Weihua Liao, Bo Gao, Xiaojun Xu, Tong Han, Zhenwei Yao, Mulin Jun Li, Feng Liu, Meng Liang, Sijia Wang, Qiang Xu, Jiayuan Xu, Peng Zhang, Wei Li, Dapeng Shi, Caihong Wang, Su Lui, Zhihan Yan, Feng Chen, Jing Zhang, Jiance Li, Wen Shen, Yanwei Miao, Dawei Wang, Junfang Xian, Jia-Hong Gao, Xiaochu Zhang, Kai Xu, Xi-Nian Zuo, Longjiang Zhang, Zhaoxiang Ye, Jingliang Cheng, Wen Qin, Hui Zhang, Chunshui Yu","doi":"10.1016/j.ebiom.2026.106261","DOIUrl":"10.1016/j.ebiom.2026.106261","url":null,"abstract":"<p><strong>Background: </strong>As an extension of diffusion tensor imaging (DTI), diffusion kurtosis imaging (DKI) quantifies non-Gaussian water diffusion and has been applied to explore brain disorders. However, the genetic architecture of brain DKI phenotypes remains unknown.</p><p><strong>Methods: </strong>Here, we estimated heritability and conducted genome-wide association studies (GWASs) for 804 DKI phenotypes across 188 brain structures in 4183 participants. To determine whether DKI-GWASs provides genetic insights beyond DTI-GWASs, we compared results from 804 DKI-GWASs and 752 DTI-GWASs in the same cohort. To clarify the biological significance of DKI phenotypes, we examined associations between DKI phenotypes and brain health-related outcomes within the CHIMGEN, and explored associations between polygenic risk scores (PRSs) of DKI phenotypes and mental disorders in the UK Biobank.</p><p><strong>Findings: </strong>Of 804 DKI phenotypes, 275 showed significant heritability (P < 0.05; h² range: 0.143-0.602). We detected 280 significant associations (P < 5 × 10^-8), with 38 surviving Bonferroni correction (P < 1.54 × 10^-10). These associations were unevenly distributed across chromosomes, DKI phenotype subgroups, and brain structures. Among 229 independent variant-structure associations for DKI, 175 (76.4%) were DKI-specific. We observed 930 associations between DKI phenotypes and brain health-related outcomes (P < 0.05; ten Bonferroni-significant with P < 1.02 × 10^-5), and 200 between PRSs and mental disorders (P < 0.05; one Bonferroni-significant with P < 9.61 × 10^-5).</p><p><strong>Interpretation: </strong>This study delineates the genetic architecture of brain DKI phenotypes, identifies complementary genetic insights into brain microstructure, and provides biologically relevant endophenotypes for investigating neural mechanisms underlying brain disorders.</p><p><strong>Funding: </strong>National Natural Science Foundation of China, National Key Research and Development Program of China, Tianjin Key Medical Discipline Construction Project, and Tianjin Natural Science Foundation.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"127 ","pages":"106261"},"PeriodicalIF":10.8,"publicationDate":"2026-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13099350/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147715857","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":"An observational study to test the potency of GLP-grade phenol-free lyophilised leishmanin antigen formulation.","authors":"Thalia Pacheco-Fernandez, Laura Klenow, Shin-Ichi Inoue, Kamaleshwar P Singh, Farzaneh Valanezhad, Hannah Markle, Nazli Azodi, Meghan Brino, Shara Bakytbek, Caroline Hobson, Ishaan Jain, Pratik Talgaonkar, Shalu Shukla, Pawan Kardile, Swarnendu Kaviraj, Larissa O Silva, Pedro B Borba, Marina Santana, Taylla Costa, Greg Matlashewski, Lucas P Carvalho, Edgar M Carvalho, Camila I de Oliveira, Abhay R Satoskar, Sanjay Singh, Shinjiro Hamano, Sreenivas Gannavaram, Hira L Nakhasi","doi":"10.1016/j.ebiom.2026.106246","DOIUrl":"https://doi.org/10.1016/j.ebiom.2026.106246","url":null,"abstract":"<p><strong>Background: </strong>Leishmaniasis is a vector-borne disease transmitted through sand fly vectors carrying protozoan parasites from the genus Leishmania. The leishmanin skin test (LST), used to detect exposure to Leishmania parasites, is no longer available due to a lack of well-characterised antigens. Towards reintroducing the LST, we previously developed a preparation of the leishmanin antigens using a freeze-thaw (FT) process, which induced a delayed-type hypersensitivity (DTH) response in hosts exposed to Leishmania parasites. The storage of FT preparation antigens requires refrigeration, which is not practical for use in field settings.</p><p><strong>Methods: </strong>We developed a safe, simple and scalable antigen extraction process and a phenol-free lyophilised-LST antigen formulation that obviates the need for a cold-chain under Good Laboratory Practice conditions (GLP-LST^Lyo). The immunogenicity of GLP-LST^Lyo was evaluated in murine models of Leishmania infections in support of two distinct use cases: (i) to detect latent infections of Leishmania in endemic areas and (ii) as a surrogate of vaccine-induced immunogenicity. Towards this goal, leishmanisation with wild-type Leishmania major and immunisation of mice with the live-attenuated L. major vaccine strain lacking the centrin gene (LmCen^-/-) were used as animal models.</p><p><strong>Findings: </strong>The GLP-LST^Lyo antigen was administered, and its ability to induce a DTH response was monitored for 48 h. Additionally, the potency of the GLP-LST^Lyo was assessed by immune phenotyping of the cells isolated from the DTH tissue via flow cytometry. Only the DTH sites from pre-exposed animals, but not the excipient controls, showed enrichment for predominantly CD8⁺ T cells, along with CD4⁺ T cells and macrophages, consistent with previous studies. Additionally, in an interferon gamma release assay (IGRA), stimulation of whole blood collected from healed, active cutaneous leishmaniasis (CL) cases in a Leishmania endemic area in Brazil with GLP-LST^Lyo induced IFN-γ and IL-10.</p><p><strong>Interpretation: </strong>These results demonstrated the potency of our formulation in IGRA studies, which could aid immunogenicity studies in vaccine trials, and surveillance studies in both endemic and emerging areas of Leishmania infection.</p><p><strong>Funding: </strong>These studies are supported by funding from GHIT Fund, Japan, CIHR, Canada, intramural funding from the FDA, and FIOCRUZ and INCT-DT Brazil.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":" ","pages":"106246"},"PeriodicalIF":10.8,"publicationDate":"2026-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147715766","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":"Novel evidence for tirzepatide, a dual GLP-1/GIP receptor agonist, to reduce the motivation for cocaine in rodents.","authors":"Lori A Knackstedt","doi":"10.1016/j.ebiom.2026.106257","DOIUrl":"10.1016/j.ebiom.2026.106257","url":null,"abstract":"","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"127 ","pages":"106257"},"PeriodicalIF":10.8,"publicationDate":"2026-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13092657/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147688749","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":"Blood-based biomarker discovery for early pregnancy loss using integrative multi-omics strategies.","authors":"Yue Shi, Yongkang Yang, Xianghao Guo, Shuai Shi, Qin Li, Chi Chiu Wang, Liona C Poon, Pui Wah Chung, Jianan Xia, Yongfei Wang, Xingqiang Lai, Yueqiong Ni, Xiaoyan Chen, Yao Wang","doi":"10.1016/j.ebiom.2026.106253","DOIUrl":"10.1016/j.ebiom.2026.106253","url":null,"abstract":"<p><strong>Background: </strong>Early pregnancy loss (EPL), a spontaneous death of the embryo or foetus occurring within the first trimester, is a major challenge for human reproduction with profound adverse consequences for women's health. Currently, reliable blood-based biomarkers for EPL remain limited. Therefore, there is an urgent need to discover novel biomarkers for EPL using a multi-omics-based approach to facilitate early detection and timely management.</p><p><strong>Methods: </strong>In the discovery cohort, 40 patients with EPL and 40 healthy pregnancies (HP) at 7-13 weeks of gestation were enrolled. Serum proteins and metabolites were assayed by Olink® technology and ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS), respectively. Biomarkers were defined by false discovery rate (FDR) < 0.05 and fold change (FC) > 1.2. Random forest (RF) and logistic regression (LR) models incorporating selected biomarkers were employed to develop diagnostic models for EPL. In the external validation cohort, we prospectively enrolled 142 pregnancies at 7-10 gestational weeks, including 47 subjects who subsequently developed EPL and 95 pregnancies with full-term birth. Serum levels of selected biomarkers were quantified by ELISA.</p><p><strong>Findings: </strong>The combined proteomics and metabolomics screening identified 26 proteins and 21 metabolites significantly changed in the EPL group and tightly associated with EPL-related clinical phenotypes, with functional enrichment in immunoregulation and lipid oxidation processes. Moreover, integrating serum levels of angiopoietin-like 4 (ANGPTL4), programmed death-ligand 1 (PD-L1), neutrophil%, and lymphocyte% achieved an AUC of 0.944 (95% CI: 0.835-1.000) in the random forest model and 0.954 (95% CI: 0.875-1.000) in the logistic regression model to discriminate EPL from HP. Importantly, this four-biomarker model achieved an AUC of 0.857 (95% CI: 0.747-0.968) in the random survival forest model and a C-index of 0.804 (95% CI: 0.685-0.973) in the validation cohort for EPL prediction.</p><p><strong>Interpretation: </strong>Our integrative omics study reveals a panel of potential circulating biomarkers for EPL, which further offer mechanistic insights into EPL pathogenesis, including impaired maternal immune tolerance and dysregulated lipid metabolism pathways. Moreover, the newly identified biomarkers exhibit promising diagnostic and predictive performance for EPL, underscoring its clinical translational value for human reproduction and maternal-foetal health.</p><p><strong>Funding: </strong>This study was supported by Research Grants Council (RGC) Germany/Hong Kong Joint Research Scheme (G-CUHK415/25), 1+1+1 CUHK-CUHK(SZ)-GDST Joint Collaboration Fund (2025A0505000077), CUHK HOPE BWCH Collaborative Medical Research Fund (CF2025002), Shenzhen Medical Research Fund (C2501040), and Shenzhen Science and Technology Program (RCYX20210609104608036).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"127 ","pages":"106253"},"PeriodicalIF":10.8,"publicationDate":"2026-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13092690/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147688813","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}