EBioMedicine最新文献

{"title":"Higher levels of host-cell DNA methylation markers ZNF582 and ASCL1 on anal smears are predictive for progression to anal cancer in patients with previous high-grade lesions.","authors":"Valentine Marie Ferré, Axelle Dupont, Mélanie Draullette, Emy Valette, Gilles Collin, Margot Bucau, Laurent Siproudhis, Ghislain Staumont, Carine Roy, Albertus Theodorus Hesselink, Dominique Bouchard, Sylvie Radenne, Lucas Spindler, Anas Naji, Christine Bergeron, Anne Couvelard, Diane Descamps, Renske D M Steenbergen, Charlotte Charpentier, Laurent Abramowitz","doi":"10.1016/j.ebiom.2025.105936","DOIUrl":"https://doi.org/10.1016/j.ebiom.2025.105936","url":null,"abstract":"<p><strong>Background: </strong>French and International anal cancer screening recommendations for at-risk populations, published in 2024, are based on cytology and/or high-risk human papillomavirus (HPV) detection on anal smears. Biological markers to triage the patients most at-risk for anal cancer are crucial in prioritising patients needing high-resolution anoscopy consultations, which are frequently overwhelmed.</p><p><strong>Methods: </strong>The AIN3 cohort is a French national multicenter study including patients with a history of high-grade anal lesions (AIN3). Patients were followed-up for at least 3 years, with anal smears and clinical examinations performed yearly. Levels of ZNF582 and ASCL1 gene methylation were quantified using real-time PCR on anal smears collected at the time of inclusion.</p><p><strong>Findings: </strong>Overall, 514 anal smears were contributive for host-cell DNA methylation analysis. Patients' mean age was 50.8 years and 40% were women. Among the 41% who were living with HIV, 91% were men. Median follow-up duration was 48 months, and 22 patients (4%) developed anal cancer during follow-up. Higher methylation levels of ZNF582 and ASCL1 were significantly associated with high-grade squamous cell intraepithelial lesion (HSIL) cytology, p16-Ki67 dual-staining positivity, and high-risk HPV and HPV16 positivity on the same anal smear. Both methylation markers showed an AUC of 0.72 for discrimination between HSIL and non-HSIL cytology on the same anal smear. Higher methylation levels of both markers were significantly associated with evolution to anal cancer in univariate and multivariable analyses adjusted for age and HIV status (p < 0.001). When assessing the AUC over 1 and 3 years of follow-up, methylation markers demonstrated superior predictive value for anal cancer compared to other markers.</p><p><strong>Interpretation: </strong>We have demonstrated the predictive value of host-cell DNA methylation marker levels in anal smears with regard to evolution to anal cancer in a very high-risk population.</p><p><strong>Funding: </strong>This study was funded by the Agence Nationale de Recherche sur le Sida et les hépatites virales (ANRS) I Maladies Infectieuses Emergentes.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"120 ","pages":"105936"},"PeriodicalIF":10.8,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145148022","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":"Transposition of insertion sequence element from KPC plasmid enhances intracellular survival of Klebsiella pneumoniae.","authors":"Yingzhou Xie, Zu Cao, Yi-Han Shi, Xiyue Shen, Le-Le Wang, Dong Weng, Jianfeng Zhang, Yiting Wang, Gang Li, Jin-Fu Xu","doi":"10.1016/j.ebiom.2025.105944","DOIUrl":"https://doi.org/10.1016/j.ebiom.2025.105944","url":null,"abstract":"<p><strong>Background: </strong>The convergence of plasmids encoding Klebsiella pneumoniae carbapenemase (KPC) and virulence determinants is increasingly reported in K. pneumoniae (Kpn). However, how KPC plasmids interfere with the virulence plasmid-mediated pathogen-host interactions, and the significance of this interference in the within-host adaption of hypervirulent carbapenem-resistant K. pneumoniae (Hv-CR-Kpn), remain unclear.</p><p><strong>Methods: </strong>An Hv-CR-Kpn variant based on ST11 CR-Kpn was created to determine the impact of capsular polysaccharide (CPS) in Kpn intracellular proliferation. Whole genome sequencing was conducted to find the cause of CPS loss. The biological significance of spontaneous CPS loss in Hv-CR-Kpn was ascertained with cell lines and murine model.</p><p><strong>Findings: </strong>The acquisition of virulence plasmid resulted in CPS hyperproduction of CR-Kpn, attenuating the bacterial adherence to eukaryotic cells and intracellular proliferation. Spontaneous CPS loss was observed in the Hv-CR-Kpn after phagocytosis by macrophage, as a result from insertion sequence (IS) element transposition from KPC plasmid to chromosomal CPS gene cluster. The loss of capsule hyperproduction enhanced both the in vitro intramacrophage proliferation and evasion of antibiotic killing in vivo of CR-Kpn. The IncF plasmids, the vector for multidrug resistance genes, were characterised as the main reservoir of IS elements in Kpn genomes.</p><p><strong>Interpretation: </strong>Loss of CPS production enhances the Kpn intracellular proliferation, facilitating evasion of antimicrobial killing. In addition to encoding carbapenemase, IS element transposition acts as an auxiliary mechanism by which the KPC plasmid promotes the adaptive evolution of Hv-CR-Kpn, aiding bacterial survival within the host environment.</p><p><strong>Funding: </strong>Noncommunicable Chronic Diseases-National Science and Technology Major Project of China, National Natural Science Foundation of China, Key Scientific Innovation Project of Shanghai Municipal Education Commission and Shanghai Sailing Program.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"120 ","pages":"105944"},"PeriodicalIF":10.8,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145136934","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":"DNA demethylation mediated endogenous retroviruses transcription promotes aberrant T cell differentiation in systemic lupus erythematosus via RIG-I pathway.","authors":"Xiaoli Min, Yaqin Yu, Zhi Hu, Lianlian Ouyang, Yueqi Qiu, Hongjun Zhao, Jiali Wu, Chun Zou, Meiling Zheng, Shuang Yang, Sujie Jia, Di Yu, Qianjin Lu, Ming Zhao","doi":"10.1016/j.ebiom.2025.105934","DOIUrl":"https://doi.org/10.1016/j.ebiom.2025.105934","url":null,"abstract":"<p><strong>Background: </strong>Systemic lupus erythematosus (SLE) displays quantitative and/or qualitative deficiencies of regulatory T cells (Treg) and expansion and hyperfunction of pathogenic T cells. However, the underlying mechanism of dysregulated T lymphocyte differentiation in SLE remains unclear.</p><p><strong>Methods: </strong>Transcriptome sequencing and functional assays were performed to elucidate the mechanisms and function of human endogenous retroviruses (HERVs) on T cell differentiation in SLE. The effect of retinoic acid-inducible gene I (RIG-I) deficiency on lupus pathogenesis were assessed in lupus-like mouse models.</p><p><strong>Findings: </strong>We found that many transcripts derived from HERVs were highly expressed in CD4⁺ T cells from patients with SLE due to DNA hypomethylation, some of which were characterized by double strand RNAs (dsRNAs). Excessive dsRNAs promoted Th1 cell differentiation and inhibited Treg cell differentiation via the activation of the dsRNA sensor RIG-I pathway, accompanied by a high level of type I interferons (IFN-I) and interferon-stimulated gene expression. In contrast, T cell-specific ablation of RIG-I alleviated disease progression in lupus-like mouse models by reducing the proportion of pathogenic T cells, restoring the percentage of Treg cells, and diminishing cytokine and autoantibody release. Importantly, we demonstrated that the dsRNA-induced RIG-I/IRF3 pathway regulated Th1 cell differentiation in a IFN-I/STAT1 signalling-dependent manner and inhibited Treg cell differentiation via SMAD3 signalling.</p><p><strong>Interpretation: </strong>Our findings reveal the roles of HERV-derived dsRNA/RIG-I pathway in regulating the aberrant differentiation of T cells in patients with SLE and may facilitate the development of potential therapeutic targets for SLE.</p><p><strong>Funding: </strong>A full list of funding sources can be found in the Funding section.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"120 ","pages":"105934"},"PeriodicalIF":10.8,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145136969","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":"A mouse model of HIV in pregnancy: the EcoHIV+ pregnancy model.","authors":"Michelle Ranjbar, Ingrid Hsieh, Maud Collomb, Lena Serghides","doi":"10.1016/j.ebiom.2025.105943","DOIUrl":"https://doi.org/10.1016/j.ebiom.2025.105943","url":null,"abstract":"<p><strong>Background: </strong>HIV infection during pregnancy poses risks to maternal and foetal health. Identifying underlying mechanisms can be challenging in humans. While humanised mouse models exist, they are unsuitable for pregnancy research, highlighting the need for alternative models. Here we introduce a mouse pregnancy model using infection with EcoHIV, a chimeric ecotropic HIV virus.</p><p><strong>Methods: </strong>Female C57BL/6J mice were infected with 2.5 × 10⁶ pg/mL EcoHIV, or mock infected, either 7 days prior to mating, or on gestational day (GD) 11.5. Dam weight gain was monitored. Pregnant dams were euthanised on GD14.5 or GD18.5. Foetal and placenta weights, foetal viability, litter size and resorptions were recorded. Placenta efficiency (foetal to placental weight ratio) was calculated. Infection was assessed using HIV Gag expression quantified by qPCR in RNA isolated from maternal blood, spleen, and foetal body.</p><p><strong>Findings: </strong>EcoHIV infection was detectable in 90% of dams infected prior to pregnancy and 100% of dams infected during pregnancy. Maternal weight gain was lower in EcoHIV infected mice, with the greatest reduction seen in those infected during pregnancy. EcoHIV infection was associated with significantly lower foetal weight, higher placenta weight, and lower placenta efficiency compared to controls at GD18.5. Perinatal EcoHIV transmission occurred in a portion of foetuses, with litter average transmission rates ranging from 3.1% with infection during pregnancy to 17.9% with infection prior to pregnancy.</p><p><strong>Interpretation: </strong>The EcoHIV pregnancy model mimics clinical aspects and can be a valuable tool to understand HIV infection in pregnancy and its consequences on maternal and foetal health.</p><p><strong>Funding: </strong>This project has been funded by the Canadian Institutes of Health Research (CIHR) (award # PJT-180630, PJH-192202, HAL-157984). MR received salary support from NSERC/CIHR Canada Graduate Scholarship, Institute of Medical Science Fellowship Award, and Emerging & Pandemic Infections Consortium (EPIC) Doctoral Award. LS holds a Tier 1 Canada Research Chair in Maternal-Child Health and HIV.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"120 ","pages":"105943"},"PeriodicalIF":10.8,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145136945","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":"α-Synuclein seed amplification assay positivity beyond synucleinopathies.","authors":"Ivan Martinez-Valbuena, Sarah Fullam, Sean O'Dowd, M Carmela Tartaglia, Gabor G Kovacs","doi":"10.1016/j.ebiom.2025.105925","DOIUrl":"https://doi.org/10.1016/j.ebiom.2025.105925","url":null,"abstract":"<p><p>Neurodegenerative diseases are increasingly recognized as complex disorders involving multiple protein pathologies, with α-synuclein frequently observed beyond classical synucleinopathies such as Parkinson's disease and multiple system atrophy. Recent advances in seed amplification assays (SAAs) have enabled the highly sensitive and specific detection of misfolded α-synuclein in vivo, particularly in cerebrospinal fluid (CSF). This review focuses on CSF-based α-synuclein SAAs and their application in detecting co-pathology across non-synucleinopathies, including Alzheimer's disease, progressive supranuclear palsy, corticobasal syndrome, idiopathic normal pressure hydrocephalus, and traumatic brain injury. Evidence indicates a role for α-synuclein in clinical heterogeneity and disease progression. Emerging diagnostic frameworks increasingly support integrating co-pathologies into classification and therapeutic strategies. Addressing key knowledge gaps, such as α-synuclein interactions with other protein pathologies, and current limitations of α-syn SAA, such as the lack of quantification of misfolded α-synuclein seeds, will refine precision medicine and improve outcomes for patients with neurodegenerative diseases.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"120 ","pages":"105925"},"PeriodicalIF":10.8,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145112316","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":"Prospective associations of obesity heterogeneity, serum proteins, and carotid atherosclerosis risk.","authors":"Haili Zhong, Jieteng Chen, Shize Jia, Hanzu Chen, Yue Xi, Yan Yan, Zilong Lu, Congmei Xiao, Fengzhe Xu, Jun Tang, Ju-Sheng Zheng, Yu-Ming Chen","doi":"10.1016/j.ebiom.2025.105935","DOIUrl":"https://doi.org/10.1016/j.ebiom.2025.105935","url":null,"abstract":"<p><strong>Background: </strong>Obese individuals exhibit considerable heterogeneity in developing cardiovascular diseases, yet the underlying molecular mechanisms remain unclear. We aimed to investigate the prospective associations between obesity phenotypes, serum proteomics, and carotid atherosclerosis (CAS) incidence.</p><p><strong>Methods: </strong>This cohort study included 3162 participants from the Guangzhou Nutrition and Health Study, with 413 proteins profiled from 6803 serum samples collected at three time-points. Obesity phenotypes included metabolically healthy non-obesity (MHNO) and metabolically healthy/unhealthy obesity (MHO/MUO).</p><p><strong>Findings: </strong>We identified 11 proteins influenced by MUO (vs. MHO) over time, with their combined score positively associated with incident CAS (HR: 1.16; 95% CI: 1.01-1.34). Additionally, 8 proteins were prospectively associated with MHO-to-MUO transition, which increased the performance of traditional risk factors in predicting this transition (P < 0.001). Among the 8 proteins, bidirectional mediation effects were observed between pigment epithelium-derived factor (PEDF) (36.8%; P = 0.025) and the MHO-to-MUO transition (20.5%; P = 0.010) on CAS incidence. The PEDF genetic risk score was positively associated with MHO-to-MUO transition (OR: 1.20; 95% CI: 1.00-1.43). Our main findings were validated in both the internal and external validation cohorts.</p><p><strong>Interpretation: </strong>This population-scale proteomics study broadens our understanding of the mechanisms underlying obesity heterogeneity and CAS, providing potential targets for the prevention of CAS.</p><p><strong>Funding: </strong>This study was supported by the National Natural Science Foundation of China, the Key Research and Development Program of Guangzhou, \"Pioneer\" and \"Leading goose\" R&D Program of Zhejiang, and the 5010 Program for Clinical Researches of the Sun Yat-sen University.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"120 ","pages":"105935"},"PeriodicalIF":10.8,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145112242","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":"Comparative analysis of cerebrospinal fluid neurofilament medium, light and heavy chain in neurodegenerative diseases using an in-house assay for the detection of neurofilament medium chain.","authors":"Badrieh Fazeli, Sara Botzenhardt, Franziska Bachhuber, Paula Klassen, Veronika Klose, Johannes Dorst, Maximilian Wiesenfarth, Zeljko Uzelac, Sarah Jesse, David Brenner, Sarah Anderl-Straub, Albert C Ludolph, Markus Otto, Jochen Weishaupt, Hayrettin Tumani, Steffen Halbgebauer","doi":"10.1016/j.ebiom.2025.105930","DOIUrl":"10.1016/j.ebiom.2025.105930","url":null,"abstract":"<p><strong>Background: </strong>Neurofilaments are key axonal proteins, with neurofilament light (NfL) and heavy (NfH) chain recognised as promising biomarkers for neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). However, neurofilament medium chain (NfM) remained previously underexplored due to a lack of quantitative assays. In this study, we developed a sensitive immunoassay to measure NfM in cerebrospinal fluid (CSF) and analysed its levels in ALS, Alzheimer's disease (AD), frontotemporal dementia (FTD), and Lewy body dementia (LBD). Correlations among neurofilaments and their diagnostic performance were also evaluated.</p><p><strong>Methods: </strong>In this study CSF levels of three neurofilament proteins were measured in 305 participants, including patients with ALS (n = 91), AD (n = 59), FTD (n = 38), LBD (n = 18), non-neurodegenerative controls (CTRL, n = 51), and 48 individuals initially evaluated for ALS but ultimately diagnosed with other conditions (CTRL.DD). NfM levels were quantified using a homemade sandwich ELISA, while NfL and NfH were measured using commercialised Ella cartridges.</p><p><strong>Findings: </strong>All three neurofilaments were significantly elevated in ALS compared to CTRL and CTRL.DD groups (p < 0.0001 for both), with NfM and NfL also increased in FTD (p < 0.0001 for both) and AD (NfM, p < 0.0001; NfL, p = 0.0001) compared to CTRL. NfH demonstrated the greatest distinction between ALS and FTD (p < 0.0001). Strong correlations were observed among neurofilament subunits, particularly between NfM and NfL (r = 0.93, 95% CI: 0.91-0.94, p < 0.0001). All neurofilaments effectively distinguished ALS from CTRL and CTRL.DD, with AUC values ranging from 0.92 to 0.99. NfM and NfL showed high accuracy in differentiating AD (NfM, AUC: 0.91; NfL, AUC: 0.89) and FTD (NfM, AUC: 0.91; NfL, AUC: 0.92) from CTRL, while NfH best separated ALS from FTD (AUC: 0.96).</p><p><strong>Interpretation: </strong>This study provides a quantitative comparison of NfM with NfL and NfH in a neurodegenerative cohort, highlighting its potential diagnostic value. Further research with larger cohorts, longitudinal studies, and investigations into neurofilament distribution in different compartments is needed to clarify the distinct roles of NfM, NfL, and NfH in the diagnosis and treatment of neurological diseases.</p><p><strong>Funding: </strong>The present study was supported by the Else Kroener-Fresenius Foundation (2024-EKEA.126) and Chemische Fabrik Karl Bucher GmbH.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"120 ","pages":"105930"},"PeriodicalIF":10.8,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12481134/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102664","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":"Plasma neurology-related proteins associated with cognition are modulated by lifestyle in adults.","authors":"Hernando Joaquin Margara-Escudero, Indira Paz-Graniel, Jesús Francisco García-Gavilán, Montse Fitó, Janita Bralten, Silke Matura, Jeffrey Colm Glennon, Carmen Schiweck, Elisabet Vilella, José Manuel Santos-Lozano, Nancy Babio, Jordi Salas-Salvadó","doi":"10.1016/j.ebiom.2025.105933","DOIUrl":"10.1016/j.ebiom.2025.105933","url":null,"abstract":"<p><strong>Background: </strong>Cognitive decline (CD) is an age-related process exacerbated by metabolic syndrome (MetS), which may be mitigated by lifestyle interventions. Plasma biomarkers hold promise for early CD detection, but prospective evidence is limited. Therefore, we aimed to prospectively determine associations between peripheral neurology-related proteins and CD, and to assess whether the lifestyle intervention of the PREDIMED-Plus trial could modify these associations.</p><p><strong>Methods: </strong>A 6-year observational study including 314 PREDIMED-Plus participants with overweight/obesity and MetS (mean age: 65 years, 44% women) were randomised to an intensive weight-loss intervention or a control group. At baseline and 3-year follow-up, plasma neurological and inflammatory proteins were quantified using proximity extension assay (OLINK neurology panel, n = 92), ELISA (C-reactive protein, amyloid-beta 40, phosphorylated tau 231 and adiponectin, n = 4) and Luminex (interleukin-6, n = 1). Cognitive performance was assessed at baseline, 2, 4, and 6 years. Elastic net regression identified proteins predictive of four cognitive domains, and protein composite scores of cognitive function were generated. Linear-mixed models assessed their associations with 6-year CD and tested for interactions with intervention.</p><p><strong>Findings: </strong>Distinct baseline protein composite scores, including 18, 18, 16, and 17 proteins, were identified for global cognitive function (GCF), attention, executive function, and general cognitive function (GenCF), respectively. Of these, seven proteins (RSPO1, CD200, EDA2R, VWC2, GDNF, CD38, and ADAM23) were consistently associated across all cognitive domains. Protein composite scores of GCF and GenCF were significantly associated with 6-year CD, with PREDIMED-Plus interventions modulating these associations only for changes in GCF (P = 0·01).</p><p><strong>Interpretation: </strong>This study identified protein signatures that are associated with CD and observed that a weight loss, energy-reduced Mediterranean diet, and physical activity may influence the relationship between these protein signatures and cognitive outcomes in older adults with MetS. However, further research is needed to confirm these findings and clarify causal relationships.</p><p><strong>Funding: </strong>Instituto de Salud Carlos III (ISCIII) co-funded by the European Union, CIBER de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), European Union's Horizon 2020 research and innovation programme, UCD Ad Astra Programme, ICREA Academia program, Sociedad Española de Endocrinología y Nutrición (SEEN), Agència Catalana de Recerca i Universitats (AGAUR).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"120 ","pages":"105933"},"PeriodicalIF":10.8,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12478270/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145091232","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":"Safety and immunogenicity of two Tau-targeting active immunotherapies, ACI-35.030 and JACI-35.054, in participants with early Alzheimer's disease: a phase 1b/2a, multicentre, double-blind, randomised, placebo-controlled study.","authors":"Olivier Sol, Julien Mermoud, Merja Hallikainen, Sudhir Kurl, Juha Rinne, Paul Dautzenberg, Everard G B Vijverberg, Catherine Mummery, Anne Börjesson-Hanson, Michael Jonsson, Craig Ritchie, Catherine Pennington, Marija Vukicevic, Eva Gollwitzer, Emma Fiorini, David T Hickman, Valérie Hliva, Julian Gray, Viktoriia Gerasymchuk, Jonathan Wagg, Nicolas Fournier, Bénédicte Lê, Iva Kezic, Lennert Steukers, Gallen Triana-Baltzer, Clara Theunis, Johannes Streffer, Marie Kosco-Vilbois, Andrea Pfeifer, Philip Scheltens","doi":"10.1016/j.ebiom.2025.105940","DOIUrl":"10.1016/j.ebiom.2025.105940","url":null,"abstract":"<p><strong>Background: </strong>Active immunotherapies targeting C-terminal phosphorylated Tau species have the potential to efficiently reduce Tau spreading. ACI-35.030, a SupraAntigen®-based liposome, and JACI-35.054, a CRM197 carrier-protein conjugate, share the same immunogenic pTau sequence and were assessed to determine the best formulation for preferential activation of B cells specific to pathological Tau forms.</p><p><strong>Methods: </strong>Individuals with early AD were enrolled in this randomised, double-blind, placebo-controlled study (NCT04445831). Participants were randomly assigned to 2 cohorts (ACI-35.030 at 300, 900, 1800 μg or placebo; and JACI-35.054 at 15, 60 μg or placebo) and received 4 intramuscular injections over 48 weeks, followed up to week 74. Participants receiving at least one dose of study drug were included in the intention-to-treat analysis. The primary objectives were safety, tolerability and immunogenicity.</p><p><strong>Findings: </strong>Among the 57 randomised participants, 41 were assigned to the ACI-35.030 cohort and 16 to the JACI-35.054 cohort. The most frequent adverse events observed consistently in both active groups were injection site reactions (16.7%-100%) and headaches (16.7%-50%). No relevant MRI findings and no adverse events leading to study discontinuation were reported. ACI-35.030 required only one injection to induce anti-pTau IgG titres in all participants and consistently boosted levels with subsequent immunisations. JACI-35.054 raised a strong but more heterogenous anti-pTau IgG response and required multiple administrations to reach consistent titres in all participants. ACI-35.030 induced a robust polyclonal antibody response binding enriched PHF from AD brain tissue while concurrently sparing the response to non-phosphorylated Tau. A post-hoc statistical analysis revealed statistically significant differences between some randomised actively treated groups and the pooled placebo group on plasma pTau217 and brain-derived Tau changes from baseline.</p><p><strong>Interpretation: </strong>ACI-35.030 and JACI-35.054 were well tolerated. ACI-35.030 induced a more rapid and sustained antibody response selective to p-Tau species with evidence of altering AD-related plasma biomarkers and was selected for testing in the ongoing Phase 2b trial.</p><p><strong>Funding: </strong>AC Immune SA and Johnson & Johnson Innovative Medicine.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"120 ","pages":"105940"},"PeriodicalIF":10.8,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12481106/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145091278","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":"Efficacy of precisely tailored phage cocktails targeting carbapenem-resistant Acinetobacter baumannii reveals evolutionary trade-offs: a proof-of-concept study.","authors":"Ziqiang Liu, Xin Tan, Min Xiong, Shitong Lu, Yongqing Yang, Heng Zhu, Jieqiong Zhang, Xiangying Luo, Caiyun Zhou, Shujiang Wei, Ning Zhou, Xueyan Liu, Changqing Bai, Yongjun Pan, Yingfei Ma","doi":"10.1016/j.ebiom.2025.105942","DOIUrl":"10.1016/j.ebiom.2025.105942","url":null,"abstract":"<p><strong>Background: </strong>The rapid emergence of phage-resistant bacterial mutants and the challenge of developing tailored phage cocktails have significantly hindered the broad application of phage therapy. This is particularly critical for infections caused by highly prevalent strains such as capsule locus 2 (KL2)-type carbapenem-resistant Acinetobacter baumannii (CRAB) in China.</p><p><strong>Methods: </strong>We employed an iterative phage adaptive selection (iPAS) strategy to develop an optimised phage cocktail specifically targeting KL2-type CRAB strains. To facilitate efficient clinical application, we also established a rapid identification method for KL2-type isolates. The efficacy and safety of this rationally designed cocktail were subsequently evaluated in a clinical setting through its application in two compassionate use cases of CRAB infection as a proof-of-concept study. Whole genomic sequencing was conducted on the isolated phage-resistant mutants to reveal the related mutations.</p><p><strong>Findings: </strong>KL2-type A. baumannii was the predominant lineage, accounting for 17.7% (159/896) of isolates reported across China over the past five years, and 33.3% (46/138) of clinical CRAB isolates obtained by our laboratory from five hospitals and one institute in Guangdong Province. The optimised phage cocktail effectively targeted 89.1% (41/46) of these KL2-type isolates. The phage-resistant A. baumannii mutants exhibited beneficial trade-offs, including increased antibiotic sensitivity, reduced virulence, susceptibility to immune clearance, and impaired biofilm formation. Genomic analysis revealed that these trade-offs were driven by concentrated and consistent mutations in genes involved in lipo-oligosaccharide and capsular polysaccharide biosynthesis. Crucially, the application of this cocktail in two clinical cases of CRAB infection demonstrated both clinical efficacy in resolving infections and a favourable safety profile.</p><p><strong>Interpretation: </strong>This research underscores the potential of rational tailored phage cocktails developed through strategies like iPAS, to address the growing threat of CRAB infections. The successful clinical application highlights the translational impact of this study. Furthermore, the study provides valuable insights into the co-evolutionary dynamics between bacteria and phages, paving the way for broader and more effective clinical applications of phage therapy.</p><p><strong>Funding: </strong>This work was supported by National Key R&D Programme of China; Shenzhen Medical Research Funds; Shenzhen Nanshan District Health Technology Major Project; Shenzhen Science and Technology Innovation Commission and Shenzhen Science and Technology Programme.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"120 ","pages":"105942"},"PeriodicalIF":10.8,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12478281/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145091201","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}