EBioMedicine最新文献

{"title":"Intraneoplastic fungal dysbiosis is associated with colorectal cancer progression and host gene mutation.","authors":"Kai Yuan, Hongzhi Xu, Shengmian Li, Olabisi Oluwabukola Coker, Weixin Liu, Luyao Wang, Xiang Zhang, Jun Yu","doi":"10.1016/j.ebiom.2025.105608","DOIUrl":"10.1016/j.ebiom.2025.105608","url":null,"abstract":"<p><strong>Background: </strong>The relationship between intraneoplastic fungi and colorectal cancer (CRC) progression remains largely unclear. Here, we investigated fungal community changes in adenoma and CRC and their correlation with host genetic mutations.</p><p><strong>Methods: </strong>We obtained 261 tissue biopsies from two geographically distinct cohorts of CRC and adenoma patients, with each individual contributing 2-5 biopsies from lesions and 2 from adjacent normal tissues. 18S ribosomal RNA gene sequencing was used for microbial profiling. Host genetic alterations including KRAS mutations and microsatellite instability (MSI) were detected concurrently.</p><p><strong>Findings: </strong>Intra-neoplastic fungal composition significantly differed between CRC and adenoma in two independent cohorts, with enrichment of highly variable fungi (HVF) in CRC. Six HVFs exhibited higher abundances in adenoma and CRC compared to adjacent normal tissues with Malassezia showing a progressive increase from adenoma to CRC. Fungi intratumoral heterogeneity index also increased from adenoma through stages I to IV of CRC. Intra-tumoral fungi-fungi co-abundance analysis indicated stronger positive interactions in CRC than in adenoma, with increasingly robust links among intra-tumoral fungi along adenoma-CRC progression, primarily driven by Malassezia and Aspergillus. Furthermore, fungal heterogeneity was significantly correlated with host genetic mutations, with higher risk indices in CRC tissues harboring KRAS and MSI mutations. Thirteen fungi stratified CRC samples with KRAS mutations, achieving an area under the curve (AUC) of 0.86, while those associated with MSI status showed an AUC of 0.89.</p><p><strong>Interpretation: </strong>This study demonstrates that intraneoplastic fungal community alterations occur between adenoma and CRC, with increasing heterogeneity associated with host genetic mutations, emphasizing the role of fungal dysbiosis in CRC.</p><p><strong>Funding: </strong>This work was supported by RGC Research Impact Fund Hong Kong (R4032-21F); RGC-CRF (C4008-23W); Strategic Seed Funding Collaboration Research Scheme CUHK (3133344); Strategic Impact Enhancement Fund CUHK (3135509); Impact case for RAE CUHK (3134277).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"113 ","pages":"105608"},"PeriodicalIF":9.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11876754/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143457180","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":"Altered spatiotemporal brain dynamics of interoception in behavioural-variant frontotemporal dementia.","authors":"Jessica L Hazelton, Gabriel Della Bella, Pablo Barttfeld, Martin Dottori, Raul Gonzalez-Gomez, Joaquín Migeot, Sebastian Moguilner, Agustina Legaz, Hernan Hernandez, Pavel Prado, Jhosmary Cuadros, Marcelo Maito, Matias Fraile-Vazquez, María Luz González Gadea, Yasir Çatal, Bruce Miller, Olivier Piguet, Georg Northoff, Agustin Ibáñez","doi":"10.1016/j.ebiom.2025.105614","DOIUrl":"10.1016/j.ebiom.2025.105614","url":null,"abstract":"<p><strong>Background: </strong>Dysfunctional allostatic-interoception, altered processing of bodily signals in response to environmental demands, occurs in behavioural-variant frontotemporal dementia (bvFTD) patients. Previous research has not investigated the dynamic nature of interoception using methods like intrinsic neural timescales. We hypothesised that longer intrinsic neural timescales of interoception would occur in bvFTD patients, evidencing dysfunctional allostatic-interoception.</p><p><strong>Methods: </strong>One-hundred and twelve participants (31 bvFTD patients, 35 Alzheimer's disease patients, AD and 46 healthy controls) completed a well-validated task measuring cardiac-interoception and exteroception. Simultaneous EEG and ECG were recorded. Intrinsic neural timescales were measured via the autocorrelation window (ACW) of broadband EEG signals from each heartbeat and a time-lagged version of itself. Spatiotemporal clustering analyses identified clusters with significant between-group differences in each condition. Voxel-based morphometry was used to target the allostatic-interoceptive network. Neuropsychological tests of cognition and social cognition were assessed.</p><p><strong>Findings: </strong>In bvFTD patients, longer interoceptive-ACWs than controls were observed in the bilateral fronto-temporal and parietal regions. In AD patients, longer interoceptive-ACWs than controls were observed in central and occipitoparietal brain regions. No differences were observed during exteroception. In bvFTD patients only, longer interoceptive-ACW was linked to worse sociocognitive performance. Structural neural correlates of interoceptive-ACW in bvFTD involved the anterior cingulate, insula, orbitofrontal cortex, hippocampus, and angular gyrus.</p><p><strong>Interpretation: </strong>Our findings suggest a core allostatic-interoceptive deficit occurs in people with bvFTD. Further, altered interoceptive intrinsic neural timescales may provide a neurobiological mechanism underpinning the complex behaviours observed in bvFTD patients. Our findings support synergistic models of brain disease and can inform clinical practice.</p><p><strong>Funding: </strong>All funding sources are reported in the Acknowledgements.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"113 ","pages":"105614"},"PeriodicalIF":9.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11894334/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143482128","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":"Urgent need for scaling up vaccine research on WHO priority fungal pathogens.","authors":"Ivaan Pitua, Morrish Okello-Obol","doi":"10.1016/j.ebiom.2025.105583","DOIUrl":"10.1016/j.ebiom.2025.105583","url":null,"abstract":"","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":" ","pages":"105583"},"PeriodicalIF":9.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11959649/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074174","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":"A humanised ACE2, TMPRSS2, and FCGRT mouse model reveals the protective efficacy of anti-receptor binding domain antibodies elicited by SARS-CoV-2 hybrid immunity.","authors":"Fernanda Ana-Sosa-Batiz, Shailendra Kumar Verma, Norazizah Shafee, Robyn Miller, Chris Conner, Kathryn M Hastie, Julia Timis, Erin Maule, Michael N Nguyen, Linda Tran, Krithik Varghese, Henry Madany, Audrey Elizabeth Street, Michelle Zandonatti, Meng Ling Moi, Kurt Jarnagin, David R Webb, Erica Ollmann Saphire, Kenneth Kim, Sujan Shresta","doi":"10.1016/j.ebiom.2025.105619","DOIUrl":"10.1016/j.ebiom.2025.105619","url":null,"abstract":"<p><strong>Background: </strong>Despite the importance of vaccination- and infection-elicited antibodies (Abs) to SARS-CoV-2 immunity, current mouse models do not fully capture the dynamics of Ab-mediated immunity in vivo, including potential contributions of the neonatal Fc receptor, encoded by FCGRT.</p><p><strong>Methods: </strong>We generated triple knock-in (TKI) mice expressing human ACE2, TMPRSS2, and FCGRT; and evaluated the protective efficacy of anti-SARS-CoV-2 monoclonal Abs (mAbs) and plasma from individuals with immunity elicited by vaccination alone plus SARS-CoV-2 infection-induced (hybrid) immunity.</p><p><strong>Findings: </strong>A human anti-SARS-CoV-2 mAb harbouring a half-life-extending mutation, but not the wild-type mAb, exhibited prolonged half-life in TKI mice and protected against lung infection with Omicron BA.2, validating the utility of these mice for evaluating therapeutic Abs. Pooled plasma from individuals with hybrid immunity to Delta, but not from vaccinated-only individuals, cleared infectious Delta from the lungs of TKI mice (P < 0.01), even though the two plasma pools had similar Delta-binding and -neutralising Ab titres in vitro. Similarly, plasma from individuals with hybrid Omicron BA.1/2 immunity, but not hybrid Delta immunity, decreased lung infection (P < 0.05) with BA.5 in TKI mice, despite the plasma pools having comparable BA.5-binding and -neutralising titres in vitro. Depletion of receptor-binding domain-targeting Abs from hybrid immune plasma abrogated their protection against infection.</p><p><strong>Interpretation: </strong>These results demonstrate the utility of TKI mice as a tool for the development of anti-SARS-CoV-2 mAb therapeutics, show that in vitro neutralisation assays do not accurately predict in vivo protection, and highlight the importance of hybrid immunity for eliciting protective anti-receptor-binding domain Abs.</p><p><strong>Funding: </strong>This work was funded by grants from the e-Asia Joint Research Program (N10A650706 and N10A660577 to MLM, in collaboration with SS); the NIH (U19 AI142790-02S1 to EOS and SS and R44 AI157900 to KJ); the GHR Foundation (to SS and EOS); the Overton family (to SS and EOS); the Arvin Gottlieb Foundation (to SS and EOS), the Prebys Foundation (to SS); and the American Association of Immunologists Fellowship Program for Career Reentry (to FASB).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"113 ","pages":"105619"},"PeriodicalIF":9.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11910679/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143527935","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":"Development and validation of a quantitative Orthopoxvirus immunoassay to evaluate and differentiate serological responses to Mpox infection and vaccination.","authors":"Joanne Byrne, Gurvin Saini, Alejandro Garcia-Leon, Dana Alalwan, Peter Doran, Alan Landay, Liem Binh Luong Nguyen, Cathal O'Broin, Stefano Savinelli, Jane A O'Halloran, Aoife Cotter, Mary Horgan, Christine Kelly, Corinna Sadlier, Eoghan de Barra, Virginie Gautier, Patrick W G Mallon, Eoin R Feeney","doi":"10.1016/j.ebiom.2025.105622","DOIUrl":"10.1016/j.ebiom.2025.105622","url":null,"abstract":"<p><strong>Background: </strong>The Mpox outbreak, caused by Monkeypox virus (MPXV), underscores the need for a serological assay to assess Mpox immunity. Modified Vaccinia Ankara (MVA) vaccine, an attenuated vaccinia virus (VACV), is authorised for Mpox prevention. We aimed to develop a quantitative immunoassay to differentiate infection- and vaccination-induced immunity and explore serological responses to Mpox infection and vaccination.</p><p><strong>Methods: </strong>We evaluated an electrochemiluminescence assay targeting IgG to 10 MPXV and 3 VACV antigens in plasma from adults in a cohort study with previous Mpox, MVA-vaccination, or historical controls. Sensitivity and specificity to distinguish i) seropositive versus naive and ii) infection- versus vaccination-induced seropositivity were determined using ROC curves. Antibody kinetics were analysed with generalised additive models.</p><p><strong>Findings: </strong>Eight of the thirteen IgG antibodies showed significant titre differences across groups identifying three key antigens: MPXVB6R, MPXVA27L, and VACVB5. A VACVB5 IgG titre of 0.082 IgG normalised units (nu) offered 74% (95% CI: 59-82%) sensitivity and 81% (73-96%) specificity for previous antigen exposure (infection or vaccine). For infection alone, an MPXVB6R IgG titre of 0.075 IgGnu provided 89% (82-98%) sensitivity and 94% (86-100%) specificity. To differentiate infection from vaccination-induced seropositivity, the sum of MPXVA27L IgG and the B6R/VACVB5 ratio provided 89% (80-96%) sensitivity and 80% (74-84%) specificity. VACVB5 IgG titres declined over time, with higher titres post-Mpox than post-vaccination (p < 0.0001).</p><p><strong>Interpretation: </strong>This assay demonstrates high sensitivity and specificity in quantifying and differentiating between antibody responses to Mpox infection and vaccination. Post-Mpox antibody responses were higher than post-vaccination, though both waned over time.</p><p><strong>Funding: </strong>Health Research Board (MONKEYVAX-2022-1), University College Dublin School of Medicine.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"113 ","pages":"105622"},"PeriodicalIF":9.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11904509/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143482319","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":"Global emergence of Carbapenem-resistant Hypervirulent Klebsiella pneumoniae driven by an IncFII_K34 KPC-2 plasmid.","authors":"Jianping Jiang, Leilei Wang, Yiyi Hu, Xin Chen, Pei Li, Jianfeng Zhang, Yixin Zhang, Jiachun Su, Xiaogang Xu, Yonghong Xiao, Zhengyin Liu, Yunsong Yu, Hainv Gao, Yohei Doi, David van Duin, Vance G Fowler, Liang Chen, Minggui Wang","doi":"10.1016/j.ebiom.2025.105627","DOIUrl":"10.1016/j.ebiom.2025.105627","url":null,"abstract":"<p><strong>Background: </strong>Carbapenem-resistant hypervirulent Klebsiella pneumoniae (CR-hvKp) has been increasingly reported worldwide, posing a severe challenge to public health; however, the mechanisms driving its emergence and global dissemination remain unclear.</p><p><strong>Methods: </strong>We analysed CR-hvKp strains derived from canonical hvKp backgrounds, and acquired a carbapenemase-encoding gene. These strains were identified from 485 CRKp isolates in the CRACKLE-2 China cohort, 259 CRKp isolates from a multi-centre study, and 67,631 K. pneumoniae genomes available in GenBank. Clinical isolates harbouring the IncFII_K34 KPC-2 plasmid were selected for genome sequencing, RNA-Seq, conjugation assays, in vivo, ex vivo, and in vitro phenotypic characterisation.</p><p><strong>Findings: </strong>Analysis of clinical CR-hvKp isolates and the 414 genomes from 24 countries available in GenBank identified an IncFII_K34 KPC-2 plasmid as the prevalent KPC plasmid (detected in 25%, 45/178 of KPC-producing CR-hvKp). Compared with the epidemic IncFII_K2 KPC-2 plasmid, the IncFII_K34 KPC-2 plasmid exhibited a 100- to 1000-fold increase in conjugation frequency (10^-4-10^-5 vs. 10^-7) and an in vitro growth advantage under meropenem challenge-likely due to the overexpression of conjugation-related genes and an increased bla_KPC copy number and expression. CR-hvKp isolates and hvKp transconjugants carrying this plasmid often exhibited reduced mucoviscosity, while retaining hypervirulence in both murine models and human neutrophil assays.</p><p><strong>Interpretation: </strong>The IncFII_K34 plasmid may be a key factor driving the global dissemination of CR-hvKp, underscoring the urgent need for enhanced molecular surveillance of this emerging pathogen.</p><p><strong>Funding: </strong>National Natural Science Foundation of China and National Institutes of Health.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"113 ","pages":"105627"},"PeriodicalIF":9.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11919442/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536902","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":"Computational modelling of CAR T-cell therapy: from cellular kinetics to patient-level predictions.","authors":"Adrià Murias-Closas, Clara Prats, Gonzalo Calvo, Daniel López-Codina, Eulàlia Olesti","doi":"10.1016/j.ebiom.2025.105597","DOIUrl":"10.1016/j.ebiom.2025.105597","url":null,"abstract":"<p><p>Chimeric Antigen Receptor (CAR) T-cell therapy is characterised by the heterogeneous cellular kinetic profile seen across patients. Unlike traditional chemotherapy, which displays predictable dose-exposure relationships resulting from well-understood pharmacokinetic processes, CAR T-cell dynamics rely on complex biologic factors that condition treatment response. Computational approaches hold potential to explore the intricate cellular dynamics arising from CAR T therapy, yet their ability to improve cancer treatment remains elusive. Here we present a comprehensive framework through which to understand, construct, and classify CAR T-cell kinetics models. Current approaches often rely on adapted empirical pharmacokinetic methods that overlook dynamics emerging from cellular interactions, or intricate theoretical multi-population models with limited clinical applicability. Our review shows that the utility of a model does not depend on the complexity of its design but on the strategic selection of its biological constituents, implementation of suitable mathematical tools, and the availability of biological measures from which to fit the model.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"113 ","pages":"105597"},"PeriodicalIF":9.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11914757/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536900","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":"Identifying chronic obstructive pulmonary disease subtypes using multi-trait genetics.","authors":"Andrey Ziyatdinov, Brian D Hobbs, Samir Kanaan-Izquierdo, Matthew Moll, Phuwanat Sakornsakolpat, Nick Shrine, Jing Chen, Kijoung Song, Russell P Bowler, Peter J Castaldi, Martin D Tobin, Peter Kraft, Edwin K Silverman, Hanna Julienne, Michael H Cho, Hugues Aschard","doi":"10.1016/j.ebiom.2025.105609","DOIUrl":"10.1016/j.ebiom.2025.105609","url":null,"abstract":"<p><strong>Background: </strong>Chronic Obstructive Pulmonary Disease (COPD) has a broad spectrum of clinical characteristics. The aetiology of these differences is not well understood. The objective of this study is to assess whether respiratory genetic variants cluster by phenotype and associate with COPD heterogeneity.</p><p><strong>Methods: </strong>We clustered genome-wide association studies of COPD, lung function, and asthma and phenotypes from the UK Biobank using non-negative matrix factorization. We constructed cluster-specific genetic risk scores and tested these scores for association with phenotypes in non-Hispanic white subjects in the COPDGene study.</p><p><strong>Findings: </strong>We identified three clusters from 482 variants and 44 traits from genetic associations in 379,337 UK Biobank participants. Variants from asthma, COPD, and lung function were found in all three clusters. Clusters displayed varying effects on white blood cell counts, height, and body mass index (BMI)-related phenotypes in the UK Biobank. In the COPDGene cohort, cluster-specific genetic risk scores were associated with differences in steroid use, BMI, lymphocyte counts, and chronic bronchitis, as well as variations in gene and protein expression.</p><p><strong>Interpretation: </strong>Our results suggest that multi-phenotype analysis of obstructive lung disease-related risk variants may identify genetically driven phenotypic patterns in COPD.</p><p><strong>Funding: </strong>MHC was supported by R01HL149861, R01HL135142, R01HL137927, R01HL147148, and R01HL089856. HA and HJ were supported by ANR-20-CE36-0009-02 and ANR-16-CONV-0005. The COPDGene study (NCT00608764) is supported by grants from the NHLBI (U01HL089897 and U01HL089856), by NIH contract 75N92023D00011, and by the COPD Foundation through contributions made to an Industry Advisory Committee that has included AstraZeneca, Bayer Pharmaceuticals, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Novartis, Pfizer and Sunovion.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"113 ","pages":"105609"},"PeriodicalIF":9.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11905855/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143515071","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":"Urgent need for scaling up vaccine research on WHO priority fungal pathogens, authors' reply.","authors":"Mateusz Hasso-Agopsowicz, Angela Hwang, Maria-Graciela Hollm-Delgado, Isis Umbelino-Walker, Ruth A Karron, Raman Rao, Kwaku Poku Asante, Meru Sheel, Erin Sparrow, Birgitte Giersing","doi":"10.1016/j.ebiom.2025.105621","DOIUrl":"10.1016/j.ebiom.2025.105621","url":null,"abstract":"","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"113 ","pages":"105621"},"PeriodicalIF":9.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11871497/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143467328","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":"Sex differences in epigenetic ageing for older people living with HIV.","authors":"Carrie D Johnston, Alina P S Pang, Eugenia L Siegler, Charlene Thomas, Chelsie O Burchett, Mia Crowley, Rochelle O'Brien, Lishomwa C Ndhlovu, Marshall J Glesby, Michael J Corley","doi":"10.1016/j.ebiom.2025.105588","DOIUrl":"10.1016/j.ebiom.2025.105588","url":null,"abstract":"<p><strong>Background: </strong>HIV-1 infection impacts biological ageing, and epigenetic clocks highlight epigenetic age acceleration in people with HIV. Despite evidence indicating sex differences in clinical, immunological, and virological measures, females have been underrepresented in most HIV epigenetic studies. Hence, we generated a more representative epigenetic dataset to examine sex differences in epigenetic ageing and relationships to clinical phenotypes and proteomics.</p><p><strong>Methods: </strong>We calculated first, second, and third-generation epigenetic ages using DNA methylation data in an observational cohort of 52 females and 106 males with HIV age 50 and over. We profiled plasma biomarkers with Olink high-throughput proteomics to test associations with epigenetic age acceleration. Survival was ascertained over 5 years.</p><p><strong>Findings: </strong>Epigenetic age acceleration measured by three principal-component based chronological epigenetic age clocks (p = 0.0029, 0.021, 0.010) and one epigenetic mortality risk clock was significantly lower in females living with HIV compared to males (p = 0.0011). Additionally, sex was significantly associated with epigenetic biomarker scores for proportion of naïve CD4+ T cells (p = 0.0006), physical fitness including DNAmGait (p = 0.0010), DNAmGrip (p < 0.0001), and DNAmV02 max (p < 0.0001). We found epigenetic age acceleration associated with plasma proteomic markers involved in inflammation, senescence, immune regulation, kidney function, and tissue homoeostasis (p < 0.0001). Higher epigenetic frailty risk scores were associated with lower CD4 T cell counts (p = 0.0072) and lower CD4/CD8 ratio (p = 0.0017). Slower gait (p = 0.0017), greater frailty (p = 0.0074), and history of smoking (p = 0.042) were associated with increased DNAmFitAge. Risk of death was increased in females with PCPhenoAge acceleration over a 5-year timespan compared to men with PCPhenoAge acceleration (p = 0.03).</p><p><strong>Interpretation: </strong>These results highlight the importance of studying sex-specific differences in epigenetic ageing biomarkers for HIV-related geroscience research.</p><p><strong>Funding: </strong>National Institute on Aging (K23AG072960), National Center for Advancing Translational Sciences (UL1TR000457), National Institute of Mental Health (R21 MH115821).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"113 ","pages":"105588"},"PeriodicalIF":9.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11849644/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143381880","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}