EBioMedicine最新文献

{"title":"Oligogenic analysis across broad phenotypes of 46,XY differences in sex development associated with NR5A1/SF-1 variants: findings from the international SF1next study.","authors":"Chrysanthi Kouri, Idoia Martinez de Lapiscina, Rawda Naamneh-Elzenaty, Grit Sommer, Kay-Sara Sauter, Christa E Flück","doi":"10.1016/j.ebiom.2025.105624","DOIUrl":"10.1016/j.ebiom.2025.105624","url":null,"abstract":"<p><strong>Background: </strong>Oligogenic inheritance has been suggested as a possible mechanism to explain the broad phenotype observed in individuals with differences of sex development (DSD) harbouring NR5A1/SF-1 variants.</p><p><strong>Methods: </strong>We investigated genetic patterns of possible oligogenicity in a cohort of 30 individuals with NR5A1/SF-1 variants and 46,XY DSD recruited from the international SF1next study, using whole exome sequencing (WES) on family trios whenever available. WES data were analysed using a tailored filtering algorithm designed to identify rare variants in DSD and SF-1-related genes. Identified variants were subsequently tested using the Oligogenic Resource for Variant Analysis (ORVAL) bioinformatics platform for a possible combined pathogenicity with the individual NR5A1/SF-1 variant.</p><p><strong>Findings: </strong>In 73% (22/30) of the individuals with NR5A1/SF-1 related 46,XY DSD, we identified one to seven additional variants, predominantly in known DSD-related genes, that might contribute to the phenotype. We found identical variants in eight unrelated individuals with DSD in DSD-related genes (e.g., TBCE, FLNB, GLI3 and PDGFRA) and different variants in eight genes frequently associated with DSD (e.g., CDH23, FLNB, GLI2, KAT6B, MYO7A, PKD1, SPRY4 and ZFPM2) in 15 index cases. Our study also identified combinations with NR5A1/SF-1 variants and variants in novel candidate genes.</p><p><strong>Interpretation: </strong>These findings highlight the complex genetic landscape of DSD associated with NR5A1/SF-1, where in several cases, the use of advanced genetic testing and filtering with specific algorithms and machine learning tools revealed additional genetic hits that may contribute to the phenotype.</p><p><strong>Funding: </strong>Swiss National Science Foundation and Boveri Foundation Zurich.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"113 ","pages":"105624"},"PeriodicalIF":9.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11925193/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143555968","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":"Extracellular vesicles: new horizons in neurodegeneration.","authors":"Jun Chen, Chen Tian, Xiao Xiong, Ying Yang, Jing Zhang","doi":"10.1016/j.ebiom.2025.105605","DOIUrl":"10.1016/j.ebiom.2025.105605","url":null,"abstract":"<p><p>Extracellular vesicles (EVs) are lipid-enclosed nanovesicles secreted by diverse cell types that orchestrate intercellular communication through cargo delivery. Their pivotal roles span from supporting the development of normal central nervous system (CNS) to contributing to the pathogenesis of neurological diseases. Particularly noteworthy is their involvement in the propagation of pathogenic proteins, such as those involved in neurodegenerative disorders, and nucleic acids, closely linking them to disease onset and progression. Moreover, EVs have emerged as promising diagnostic biomarkers for neurological disorders and as tools for disease staging, owing to their ability to traverse the blood-brain barrier and their specific, stable, and accessible properties. This review comprehensively explores the realm of CNS-derived EVs found in peripheral blood, encompassing their detection methods, transport mechanisms, and diverse roles in various neurodegenerative diseases. Furthermore, we evaluate the potentials and limitations of EVs in clinical applications and highlight prospective research directions in this rapidly evolving field.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"113 ","pages":"105605"},"PeriodicalIF":9.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11925178/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143555421","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 of an oral regimen of unithiol for the treatment of snakebite envenoming: a phase 1 open-label dose-escalation safety trial and pharmacokinetic analysis in healthy Kenyan adults.","authors":"Michael Abouyannis, Yvonne K Nyambura, Samson Ngome, Debra Riako, Jennifer Musyoki, Charles Muiruri, Benedict Orindi, Laura Else, Alieu Amara, Laura Dickinson, Rachel H Clare, Laura-Oana Albulescu, Adam P Westhorpe, Jeroen Kool, Ifedayo Adetifa, Francis M Ndungu, Richard FitzGerald, Saye Khoo, David G Lalloo, Nicholas R Casewell, Mainga Hamaluba","doi":"10.1016/j.ebiom.2025.105600","DOIUrl":"10.1016/j.ebiom.2025.105600","url":null,"abstract":"<p><strong>Background: </strong>Viperidae snakes are responsible for many of the 94,000 deaths caused by snakebite envenoming each year. The most pathological venom component of this globally diverse family of snakes are the zinc-dependent snake venom metalloproteinase (SVMP) enzymes, which can be inhibited by the metal chelator, unithiol. A short-course oral regimen, readily available and rapidly deployed ahead of hospital admission is needed.</p><p><strong>Methods: </strong>This open-label, phase 1 clinical trial assessed the safety of single ascending oral, multiple ascending oral, and single ascending intravenous doses of unithiol in 64 healthy adult volunteers from Kilifi County, Kenya. The multiple dose stage was informed by an interim safety and pharmacokinetic analysis, and predefined target plasma concentrations. Plasma concentrations of unithiol were measured using high-performance liquid chromatography-mass spectrometry, and safety was described by full adverse event reporting.</p><p><strong>Findings: </strong>175 individuals were screened, and 64 (median age 30 years, IQR 25-38 years) received the study drug. There were no dose limiting toxicities or serious adverse events. There were 61 solicited adverse events, 17 related unsolicited adverse events, and 53 laboratory adverse events, all of mild or moderate severity. The maximum oral dose of 1500 mg was well tolerated and associated with the following pharmacokinetic parameters: C_max 14.7 μg/mL, T_max 2.9 h, T_1/2 18.4 h, and AUC_0-∞ 204.5 μg.h/mL.</p><p><strong>Interpretation: </strong>The phase 2 recommended dose (1500 mg loading dose, followed by 900 mg doses at 6-h and 24-h) has no safety concerns, and has promising pharmacokinetic properties for clinical use. Unithiol is affordable, stable at room temperature, and has the potential to be given orally in remote rural clinics. Its further development for snakebite indication is warranted.</p><p><strong>Funding: </strong>Wellcome Trust, Bloomsbury Set, and Cures Within Reach.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"113 ","pages":"105600"},"PeriodicalIF":9.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11919382/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143527936","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 systematic analysis of the contribution of genetics to multimorbidity and comparisons with primary care data.","authors":"Olivia Murrin, Ninon Mounier, Bethany Voller, Linus Tata, Carlos Gallego-Moll, Albert Roso-Llorach, Lucía A Carrasco-Ribelles, Chris Fox, Louise M Allan, Ruby M Woodward, Xiaoran Liang, Jose M Valderas, Sara M Khalid, Frank Dudbridge, Sally E Lamb, Mary Mancini, Leon Farmer, Kate Boddy, Jack Bowden, David Melzer, Timothy M Frayling, Jane A H Masoli, Luke C Pilling, Concepción Violán, João Delgado","doi":"10.1016/j.ebiom.2025.105584","DOIUrl":"10.1016/j.ebiom.2025.105584","url":null,"abstract":"<p><strong>Background: </strong>Multimorbidity, the presence of two or more conditions in one person, is common but studies are often limited to observational data and single datasets. We address this gap by integrating large-scale primary-care and genetic data from multiple studies to interrogate multimorbidity patterns and producing digital resources to support future research.</p><p><strong>Methods: </strong>We defined chronic, common, and heritable conditions in individuals aged ≥65 years, using two large primary-care databases [CPRD (UK) N = 2,425,014 and SIDIAP (Spain) N = 1,053,640], and estimated heritability using the same definitions in UK Biobank (N = 451,197). We used logistic regression to estimate the co-occurrence of pairs of conditions in the primary care data. Linkage disequilibrium score regression was used to estimate genetic similarity between pairs of conditions. Meta-analyses were conducted across databases, and up to three sources of genetic data, for each pair of conditions. We classified pairs of conditions as across or within-domain based on the international classification of disease.</p><p><strong>Findings: </strong>We identified 72 chronic conditions, with 43.6% of 2546 pairs showing higher co-occurrence than chance in primary care and evidence of shared genetics. Many across-domain pairs exhibited substantial shared genetics (e.g., iron deficiency anaemia and peripheral arterial disease: genetic correlation R_g = 0.45 [95% Confidence Intervals 0.27:0.64]). 33 pairs displayed negative genetic correlations, such as skin cancer and rheumatoid arthritis (R_g = -0.14 [-0.21:-0.06]), due to potential adverse drug effects. Discordance between genetic and primary care data was also observed, e.g., abdominal aortic aneurysm and bladder cancer co-occurred in primary care but were not genetically correlated (Odds-Ratio = 2.23 [2.09:2.37], R_g = 0.04 [-0.20:0.28]) and schizophrenia and fibromyalgia were less likely to co-occur together in primary care but were positively genetically correlated (OR = 0.84 [0.75:0.94], R_g = 0.20 [0.11:0.29]).</p><p><strong>Interpretation: </strong>Most pairs of chronic conditions show evidence of shared genetics, and co-occurrence in primary care, suggesting shared mechanisms. The identified patterns of shared genetics, negative correlations and discordance between genetic and observational data provide a foundation for future multimorbidity research.</p><p><strong>Funding: </strong>UK Medical Research Council [MR/W014548/1].</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"113 ","pages":"105584"},"PeriodicalIF":9.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11848100/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143370570","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":"Speeding up drug susceptibility testing in Mycobacterium tuberculosis using RNA biomarkers.","authors":"Amandine Sury, Margo Maex, Alain Baulard, Roby P Bhattacharyya, Stéphanie Depickère, Deborah T Hung, Paul Cos, Fadel Sayes, Wafa Frigui, Roland Brosch, Vanessa Mathys, Elizabeth M Streicher, Frederik De Keersmaeker, Leen Rigouts, Pieter-Jan Ceyssens, An Van den Bossche","doi":"10.1016/j.ebiom.2025.105611","DOIUrl":"10.1016/j.ebiom.2025.105611","url":null,"abstract":"<p><strong>Background: </strong>Efficient management of drug-resistant tuberculosis relies on fast diagnostics. To accelerate phenotypic drug susceptibility testing [pDST] for Mycobacterium tuberculosis [TB], we introduce TRACeR-TB, a test that infers drug resistance from antibiotic-specific mRNA biomarkers.</p><p><strong>Methods: </strong>To develop TRACeR-TB, target genes were first identified through RNA sequencing experiments conducted on two drug-exposed, susceptible strains for four antitubercular drugs. Based on these findings, we designed drug-specific multiplex Quantigene panels to quantify mRNA levels of 8-9 biomarkers per drug (class), directly from crude cell lysates. The performance of TRACeR-TB was compared to the widely used Mycobacteria Growth Indicator Tube [MGIT] pDST by subjecting 238 strains with diverse drug resistance profiles to both methods, and aligning results to genotypic data. Furthermore, we explored TRACeR-TB's potential for evaluating molecules that enhance antibiotic efficacy, and investigated its applicability in macrophage models to assess Mtb's intracellular stress responses to drugs.</p><p><strong>Findings: </strong>Antituberculosis drugs trigger distinct transcriptional stress responses in susceptible, but not resistant bacilli, enabling a differentiation of the antibiotic phenotype in only 6 h. Validation on 238 strains showed TRACeR-TB had 100% (95% CI: 93·1-100%) sensitivity and 89·5% (95% CI: 74·7-97·2%) specificity compared to, respectively, 82·3% (95% CI: 69·2%-91·5%) and 94·8% (95% CI: 81·9%-99·4%) for MGIT pDST. TRACeR-TB specificity is likely underestimated due to the inclusion of isolates harbouring uncharacterised mutations. TRACeR-TB demonstrated 100% concordance with MGIT for drugs with reliable MGIT outcomes (moxifloxacin and isoniazid). Additionally, its sensitivity outperformed current rifampicin testing, detecting resistance in all borderline-resistant strains that MGIT missed, and bedaquiline testing. Furthermore, the assay detected the predicted effect of a novel drug booster and the intracellular drug-induced stress in macrophage models, highlighting its potential for drug optimisation.</p><p><strong>Interpretation: </strong>TRACeR-TB is a complementary addition to current DSTs and can have a substantial impact on the TB diagnostics field. This tool can also play a vital role in identifying resistance mutations, thereby closing gaps in genotypic knowledge, and contribute to drug discovery and development.</p><p><strong>Funding: </strong>Institut Pasteur, Agence Nationale de la Recherche.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"113 ","pages":"105611"},"PeriodicalIF":9.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11905850/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143515072","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":"Multivariate predictive model of the therapeutic effects of metoprolol in paediatric vasovagal syncope: a multi-centre study.","authors":"Yaxi Cui, Jing Zhang, Yuwen Wang, Ying Liao, Keyu Liu, Wenrui Xu, Shu Wu, Chufan Sun, Chunyu Zhang, Qingyou Zhang, Ping Liu, Yuli Wang, Yanjun Deng, Chen Shen, Yao Lin, Hong Cai, Juan Zhang, Runmei Zou, Ping Liu, Shuo Wang, Hongfang Jin, Lin Shi, Cheng Wang, Junbao Du","doi":"10.1016/j.ebiom.2025.105595","DOIUrl":"10.1016/j.ebiom.2025.105595","url":null,"abstract":"<p><strong>Background: </strong>Metoprolol therapy for paediatric vasovagal syncope (VVS) has yielded inconsistent results, necessitating predictive markers. We aimed to develop and validate models to identify paediatric VVS patients likely to benefit from metoprolol.</p><p><strong>Methods: </strong>478 metoprolol-treated paediatric patients with VVS were enrolled from three syncope units and divided into retrospective training (March 2017-March 2023, n = 323) and prospective validation cohorts (April 2023-March 2024, n = 155). Fourteen patients (2.9%) were excluded for lacking follow-up data. Patients were classified as responders or non-responders based on symptom improvement after 1-3 months of metoprolol therapy. Univariate analysis and logistic regression were used to select the candidate predictors. A nomogram and a scoring model were established to predict treatment efficacy. The model values were analysed using a receiver operating characteristic (ROC) curve. Consistency was evaluated using the Hosmer-Lemeshow (H-L) test, calibration curve, and concordance index (C-index). The clinical utility of model was assessed through the decision curve analysis (DCA). Internal validation was performed using the bootstrap approach. The predictive model derived from the training cohort was validated in the validation cohort to assess its accuracy and feasibility.</p><p><strong>Findings: </strong>Increased heart rate during positive response in head-up tilt test (ΔHR), corrected QT interval dispersion (QTcd), and standard deviation of all normal-to-normal intervals (SDNN) were selected as independent predictors to develop a predictive model. A nomogram model was built (AUC: 0.900, 95% CI: 0.867-0.932); the H-L test and calibration curves showed a strong alignment between predicted and actual results. The scoring model was established in the training cohort (AUC: 0.941, 95% CI: 0.897-0.985), yielding a sensitivity of 82.8% and a specificity of 96.5%, with a cut-off value of 2.5 points. In the external validation cohort, the scoring model achieved a sensitivity, specificity, and accuracy of 93.6%, 80.9%, and 87.7%, respectively.</p><p><strong>Interpretation: </strong>The nomogram and scoring model were constructed to predict the efficacy of metoprolol for children with VVS, which will greatly assist paediatricians in the individual management of VVS in children and adolescents.</p><p><strong>Funding: </strong>This research was funded by National High-Level Hospital Clinical Research Funding (Clinical Research Project of Peking University First Hospital, grant number 2022CR59).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"113 ","pages":"105595"},"PeriodicalIF":9.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11869975/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143413530","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":"Neolithic introgression of IL23R-related protection against chronic inflammatory bowel diseases in modern Europeans.","authors":"Ben Krause-Kyora, Nicolas Antonio da Silva, Elif Kaplan, Daniel Kolbe, Inken Wohlers, Hauke Busch, David Ellinghaus, Amke Caliebe, Efe Sezgin, Almut Nebel, Stefan Schreiber","doi":"10.1016/j.ebiom.2025.105591","DOIUrl":"10.1016/j.ebiom.2025.105591","url":null,"abstract":"<p><strong>Background: </strong>The hypomorphic variant rs11209026-A in the IL23R gene provides significant protection against immune-related diseases in Europeans, notably inflammatory bowel diseases (IBD). Today, the A-allele occurs with an average frequency of 5% in Europe.</p><p><strong>Methods: </strong>This study comprised 251 ancient genomes from Europe spanning over 14,000 years. In these samples, the investigation focused on admixture-informed analyses and selection scans of rs11209026-A and its haplotypes.</p><p><strong>Findings: </strong>rs11209026-A was found at high frequencies in Anatolian Farmers (AF, 18%). AF later introduced the allele into the ancient European gene-pool. Subsequent admixture caused its frequency to decrease and formed the current southwest-to-northeast allele frequency cline in Europe. The geographic distribution of rs11209026-A may influence the gradient in IBD incidence rates that are highest in northern and eastern Europe.</p><p><strong>Interpretation: </strong>Given the dramatic changes from hunting and gathering to agriculture during the Neolithic, AF might have been exposed to selective pressures from a pro-inflammatory lifestyle and diet. Therefore, the protective A-allele may have increased survival by reducing intestinal inflammation and microbiome dysbiosis. The adaptively evolved function of the variant likely contributes to the high efficacy and low side-effects of modern IL-23 neutralisation therapies for chronic inflammatory diseases.</p><p><strong>Funding: </strong>German Research Foundation (EXC 2167 390884018 and EXC 2150 390870439).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"113 ","pages":"105591"},"PeriodicalIF":9.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11849592/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143381859","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":"Potential therapeutic effects of SIRT1 targeting APOE4-induced microvascular endothelial dysfunction.","authors":"Yorito Hattori, Masafumi Ihara","doi":"10.1016/j.ebiom.2025.105594","DOIUrl":"10.1016/j.ebiom.2025.105594","url":null,"abstract":"","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"113 ","pages":"105594"},"PeriodicalIF":9.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11848784/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143373840","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":"Evolution of SARS-CoV-2 antibody repertoire after successive mRNA vaccinations under immunosuppressive treatment.","authors":"Jim B D Keijser, Eileen W Stalman, Luuk Wieske, Maurice Steenhuis, Koos P J van Dam, Laura Y L Kummer, Zoé L E van Kempen, Joep Killestein, Adriaan G Volkers, Sander W Tas, Laura Boekel, Gerrit J Wolbink, Laura Fernandez Blanco, Niels J M Verstegen, Sofie Keijzer, Gerard van Mierlo, Olvi Cristianawati, Arend J Boogaard, Karlijn van der Straten, Jacqueline van Rijswijk, Marit J van Gils, Anja Ten Brinke, S Marieke van Ham, Taco W Kuijpers, Filip Eftimov, Theo Rispens","doi":"10.1016/j.ebiom.2025.105620","DOIUrl":"10.1016/j.ebiom.2025.105620","url":null,"abstract":"<p><strong>Background: </strong>Repeated antigen exposure can result in a shifting antibody repertoire. The mechanisms by which this occurs and consequences for cross-variant protection against evolving pathogens remain incompletely understood, particularly in the context of immunosuppressive treatments used in patients with immune-mediated inflammatory diseases (IMID).</p><p><strong>Methods: </strong>To investigate this, we characterised longitudinal changes in the anti-SARS-CoV-2 antibody repertoire over the course of three SARS-CoV-2 mRNA vaccinations in patients with IMIDs treated with methotrexate (MTX) and/or tumour necrosis factor-inhibitors (TNFi), anti-CD20 monoclonal antibodies, no systemic therapy, and healthy controls (total N = 878). We determined serum antibody titres against the receptor-binding domain (RBD) of Wuhan-Hu-1 (WH1) and Omicron BA.1 spike proteins, and assessed ratios thereof between groups as a proxy for cross-reactivity.</p><p><strong>Findings: </strong>We observe emerging anti-BA.1 RBD reactivity over time, notably following a third vaccination. This may be partly explained by affinity maturation, as evaluated by inhibition of ACE2-RBD interactions. Similar trends were seen in patients treated with MTX and/or TNFi, but not in patients on anti-CD20 therapy. SARS-CoV-2 infection prior to vaccination accelerated these effects initially while leading to comparable results after three vaccinations.</p><p><strong>Interpretation: </strong>MTX and TNFi do not qualitatively alter the evolution of the antibody repertoire in response to repeated antigen exposure, whereas anti-CD20 does. These insights may help to optimise vaccination strategies for patients with immune-mediated inflammatory diseases.</p><p><strong>Funding: </strong>This study was supported by ZonMw (The Netherlands Organization for Health Research and Development) and SGF (Collaborating Health Funds).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"113 ","pages":"105620"},"PeriodicalIF":9.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11905820/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143515070","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 pilot study of senolytics to improve cognition and mobility in older adults at risk for Alzheimer's disease.","authors":"Courtney L Millar, Ike Iloputaife, Kathryn Baldyga, Amani M Norling, Afroditi Boulougoura, Theodoros Vichos, Tamara Tchkonia, Aaron Deisinger, Tamar Pirtskhalava, James L Kirkland, Thomas G Travison, Lewis A Lipsitz","doi":"10.1016/j.ebiom.2025.105612","DOIUrl":"10.1016/j.ebiom.2025.105612","url":null,"abstract":"<p><strong>Background: </strong>This single-arm study evaluates the feasibility, safety, and preliminary effects of two senolytic agents, Dasatinib and Quercetin (DQ), in older adults at risk of Alzheimer's disease.</p><p><strong>Methods: </strong>Participants took 100 mg of Dasatinib and 1250 mg of Quercetin for two days every two weeks over 12 weeks. Recruitment rate, adverse events, absolute changes in functional outcomes, and percent changes in biomarkers were calculated. Spearman correlations between functional and biomarker outcomes were performed.</p><p><strong>Findings: </strong>Approximately 10% of telephone-screened individuals completed the intervention (n = 12). There were no serious adverse events related to the intervention. Mean Montreal Cognitive Assessment (MoCA) scores non-significantly increased following DQ by 1.0 point (95% CI: -0.7, 2.7), but increased significantly by 2.0 points (95% CI: 0.1, 4.0) in those with lowest baseline MoCA scores. Mean percent change in tumour necrosis factor-alpha (TNF-α), a key product of the senescence-associated secretory phenotype (SASP), non-significantly decreased following DQ by -3.0% (95% CI: -13.0, 7.1). Changes in TNF-α were significantly and inversely correlated with changes in MoCA scores (r = -0.65, p = 0.02), such that reductions in TNF- α were correlated with increases in MoCA scores.</p><p><strong>Interpretation: </strong>This study suggests that intermittent DQ treatment is feasible and safe; data hint at potential functional benefits in older adults at risk of Alzheimer's disease. The observed reduction in TNF-α and its correlation with increases in MoCA scores suggests that DQ may improve cognition by modulating the SASP. However, there was not an appropriate control group. Data are preliminary and must be interpreted cautiously.</p><p><strong>Funding: </strong>National Institute on Ageing grants R21AG073886 and R33AG061456 funded this research.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"113 ","pages":"105612"},"PeriodicalIF":9.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11907475/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143515069","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}