EBioMedicine最新文献

{"title":"The presynaptic protein bassoon is a biofluid biomarker of synaptic pathology in multiple sclerosis.","authors":"Marcel S Woo, Nicola Rothammer, Lukas C Bal, Christoph Krisp, Mario Kreutzfeldt, Susanne Witt, Aleksandra Maleska Maceski, Bente Siebels, Lukas Raich, Christina Mayer, Ingo Winschel, Anne Willing, Benjamin Schattling, Simone Bauer, Hartmut Schlüter, Sina C Rosenkranz, Jens Kuhle, Jan-Patrick Stellmann, Jan Broder Engler, Doron Merkler, Manuel A Friese","doi":"10.1016/j.ebiom.2026.106282","DOIUrl":"https://doi.org/10.1016/j.ebiom.2026.106282","url":null,"abstract":"<p><strong>Background: </strong>Neuroaxonal and synaptic loss are hallmarks of multiple sclerosis (MS), the most common autoimmune disorder of the central nervous system. However, it remains unclear at which disease stages synaptic pathology occurs. We hypothesised that synaptic proteins in plasma and cerebrospinal fluid (CSF) reflect synaptic injury in MS.</p><p><strong>Methods: </strong>To identify synaptic proteins lost during neuroinflammation, we performed proteomic analysis of synaptoneurosomes from mice with experimental autoimmune encephalomyelitis (EAE), the model of MS. The findings were validated by histology in the cortex of EAE mice and postmortem MS tissue. Next, we developed an ELISA with knockout-validated antibodies for the presynaptic protein Bassoon (BSN) and quantified BSN in the cortex, spinal cords and plasma of EAE mice and in the CSF (total n = 30) and serum (total n = 146) of an observational cohort study with people with MS (pwMS) and controls. We further compared longitudinal trajectories of serum BSN (sBSN) and serum neurofilament light chain (sNfL) in a cohort of people with primary progressive MS (PPMS) (n = 26) using linear mixed-effects models.</p><p><strong>Findings: </strong>The synaptoneurosome screen revealed reduced levels of several presynaptic proteins, including BSN, in the cortex of EAE mice. The loss of synaptic BSN was validated in EAE and human postmortem tissues of pwMS. Notably, BSN simultaneously accumulated in neuronal soma during EAE and MS, suggesting that BSN may serve as a suitable biomarker for monitoring disease pathology. Our ELISA showed a gradual loss of BSN in the cortex of EAE mice and consistently, plasma BSN levels were elevated in two independent acute and chronic EAE cohorts. In pwMS, BSN was detectable in all CSF samples and in 81% of the serum samples. CSF BSN levels were higher in both relapsing and PPMS compared with controls, whereas sBSN was elevated in secondary progressive MS (SPMS) and PPMS. In the longitudinal PPMS cohort, sBSN and sNfL remained unchanged over an average follow-up of 37 months and did not correlate with each other.</p><p><strong>Interpretation: </strong>In conclusion, the presynaptic protein BSN can be quantified in plasma and CSF to assess synaptic pathologies. BSN elevation was already detectable at the earliest disease stages and persisted in progressive MS, underscoring continuous neurodegeneration in MS. Measuring synaptic proteins may complement established biomarkers of neuronal injury to enhance our understanding of neurodegeneration in MS.</p><p><strong>Funding: </strong>This work was funded by the Hamburg Innovation Call for Transfer (C4T959 to M.A.F.), Deutschen Multiple Sklerose Gesellschaft (V6.2 to M.A.F.). This work is supported by the Deutsche Forschungsgemeinschaft (FOR 5705, 523862973 to M.A.F., S.C.R., J.B.E.; 247354600, 247377969, 426788273, 518551069, 516868494 to H.S.).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"128 ","pages":"106282"},"PeriodicalIF":10.8,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147856016","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":"Who receives psychiatry-focused pharmacogenomic testing, and is it associated with prescribing patterns and acute care utilisation in depression? Real-world evidence from a large health system.","authors":"Lusi Zhang, Anthony J Tholkes, Kathryn R Cullen, Meredith L Gunlicks-Stoessel, Pawel Mroz, Joel F Farley, Steven G Johnson, Jeffrey R Bishop","doi":"10.1016/j.ebiom.2026.106275","DOIUrl":"https://doi.org/10.1016/j.ebiom.2026.106275","url":null,"abstract":"<p><strong>Background: </strong>Depression is highly prevalent, and antidepressant response and tolerability vary widely. Pharmacogenomic (PGx) testing is increasingly used to support antidepressant selection, but its real-world uptake, equity, and associations with prescribing and healthcare utilisation remain incompletely characterised.</p><p><strong>Methods: </strong>Using electronic health record data from a large health system (2013-2023), we identified 1563 patients with depression who received psychiatry-focused PGx testing and compared them with 248,017 indexed non-PGx controls. We examined demographic and clinical factors associated with receipt of PGx testing, evaluated changes in antidepressant and adjunctive psychiatric medication use pre/post-testing using within-person and difference-in-differences analyses with propensity-score-matched controls. Associations between PGx testing and acute care utilisation, including emergency department (ED) visits and hospitalisations, were examined.</p><p><strong>Findings: </strong>PGx testing was more common among youth and adults with complex clinical histories but less frequent among older adults and racially minoritized groups; Black, American Indian/Alaska Native, and Asian/Native Hawaiian/Other Pacific Islander patients had 55-65% lower odds of testing than patients identifying as White. Testing clustered among individuals with greater psychiatric comorbidity burden and prior antidepressant trials. Following testing, antidepressant prescribing patterns shifted away from CYP2C19/2D6-sensitive SSRIs and toward agents less dependent on these pathways. Adjunctive anxiolytic and hypnotic prescribing showed modest pre/post declines but these patterns did not significantly differ compared to matched controls. Psychiatric ED visits showed no significant overall difference-in-differences association with PGx testing when compared with matched controls, although exploratory sensitivity analyses suggested a signal of reduced ED utilisation among patients with higher baseline psychiatric complexity. Hospitalisation patterns showed no substantial change.</p><p><strong>Interpretation: </strong>In routine clinical practice, PGx testing is preferentially used in youth and adults with clinically complex histories and is associated with shifts in antidepressant prescribing patterns. Exploratory findings suggest hypothesis-generating signals of reduced psychiatric ED utilisation among patients with higher psychiatric complexity, which requires further confirmation. Observed racial disparities highlight the need for earlier and more equitable implementation. Prospective studies incorporating symptom-level and safety outcomes are needed to determine whether PGx-guided prescribing translates into meaningful clinical benefit.</p><p><strong>Funding: </strong>Supported by NIH (UL1TR002494), American Association of Psychiatric Pharmacists Foundation and University of Minnesota College of Pharmacy.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"128 ","pages":"106275"},"PeriodicalIF":10.8,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147856104","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":"Modelling the impact of ivermectin-based optimal strategies on malaria control: the role of formulation, coverage, and mosquitocidal efficacy timing.","authors":"Franck J Dongmo, Angelique Porciani, Nicolas Moiroux, Hermann S Pooda, Roch K Dabiré, Samuel Beneteau, Sophie Le Lamer-Déchamps, Charles S Wondji, Karine Mouline, Ramsès Djidjou-Demasse","doi":"10.1016/j.ebiom.2026.106278","DOIUrl":"https://doi.org/10.1016/j.ebiom.2026.106278","url":null,"abstract":"<p><strong>Background: </strong>Despite wide use of insecticidal nets and indoor spraying, residual malaria transmission persists due to insecticide resistance and mosquito behaviours like early and outdoor biting. Ivermectin (IVM) can kill mosquitoes after blood feeding, regardless of the timing or location of the bite. However, oral IVM's short efficacy duration and required frequent dosing limits epidemiological impact. Using mosquitocidal efficacy data from a long-acting injectable IVM formulation (BEPO® technology), we modelled its effect on malaria transmission, comparing it with oral regimens evaluated in the fields.</p><p><strong>Methods: </strong>We developed a mathematical model incorporating IVM's pharmacodynamic persistence and stratifying humans by age and sex. Three regimens were evaluated: (i) monthly oral IVM at 3 × 300 μg/kg for 4 months, (ii) monthly oral IVM at 1 × 400 μg/kg for 3 months, and (iii) long-acting BEPO® injection at 0.6 or 1.0 mg/kg. The model includes post-exposure effects on mosquitoes and the target population excludes women of childbearing age or pregnant women, and children under 15 kg. Mosquitocidal efficacy data were derived from published human oral studies and from preclinical studies in livestock (cattle) for injectable formulations.</p><p><strong>Findings: </strong>Campaigns delivering ivermectin are projected to lower clinical prevalence, with slightly greater benefits in Burkina Faso-like seasonal settings when aligned with the transmission peak. Under perennial transmission and 50-90% target population coverage, oral regimens reduced total cases (all ages) by 7-11%, 9-14%, and 24-38% over one year, depending on the regimen and the data source. A single long-acting injectable IVM campaign achieved 16-29%, rising to 33-57%, 48-74%, and 59-78% with two, three, and four campaigns, respectively.</p><p><strong>Interpretation: </strong>Long-acting injectable ivermectin offers increased and sustained efficacy and simpler delivery to tackle residual malaria transmission. Phase 1 trials are timely and warranted.</p><p><strong>Funding: </strong>The African Consortium in Modelling for Effective Vector Control (ACoMVeC) project INV-047049, IMPACT (Unitaid) and Institut de Recherche pour le Développement (IRD).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"127 ","pages":"106278"},"PeriodicalIF":10.8,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147835063","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":"Biological maturation drives the hepatic-to-renal switch in erythropoietin production at birth.","authors":"Salam Idriss, Laurent Martin, Nada Maaziz, Esther Juguet, Denis Semama, Laure Merle, Stuart S Winter, Amandine Caillaud, Alexandre Marchand, François Girodon, Betty Gardie","doi":"10.1016/j.ebiom.2026.106277","DOIUrl":"https://doi.org/10.1016/j.ebiom.2026.106277","url":null,"abstract":"<p><strong>Background: </strong>Erythropoietin (EPO) is essential for erythropoiesis, with production shifting from the foetal liver to the kidney after birth. This hepatic-to-renal transition is a hallmark of neonatal adaptation, but the relative contribution of oxygen exposure versus intrinsic developmental processes remains unclear.</p><p><strong>Methods: </strong>We studied plasma EPO isoform profiles in 89 neonates (developmental age 29-56 weeks; chronological age 1-92 days). Isoforms were classified as hepatic-like or renal-like based on isoelectric focusing patterns. Profiles were correlated with developmental and chronological age to assess the influence of oxygen exposure versus maturation. In parallel, human induced pluripotent stem cells (hiPSCs) were differentiated into liver organoids and cultured under hypoxic or normoxic conditions. Transcriptome and EPO mRNA expression were measured throughout differentiation to evaluate developmental and oxygen-dependent regulation.</p><p><strong>Findings: </strong>Neonatal EPO profiles shifted progressively from hepatic-like to renal-like with increasing developmental age. This transition was independent of time spent in atmospheric oxygen; preterm infants retained hepatic-like profiles for weeks after birth despite continuous oxygen exposure. In cellulo, immature hepatocytes expressed EPO robustly under hypoxia, but expression declined sharply as hepatocyte maturation advanced and was absent at later stages, regardless of oxygen tension. Maintaining the immature state of hepatic cells may be critical for responsiveness to hypoxia and for EPO production.</p><p><strong>Interpretation: </strong>These findings indicate that intrinsic hepatic maturation, rather than oxygenation, governs the silencing of hepatic-derived EPO after birth. Clarifying this process could support novel therapeutic strategies aimed at reactivating foetal-like hepatic EPO production to treat anaemia, particularly in preterm infants and in conditions associated with insufficient renal EPO production, such as chronic kidney disease.</p><p><strong>Funding: </strong>This study was mainly supported by the Région des Pays de la Loire, The French National Agency for Research (ANR), the Fonds Européen de Développement Régional Bourgogne Franche Comté, the Marie Skłodowska-Curie action, and the Fondation Génavie.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"127 ","pages":"106277"},"PeriodicalIF":10.8,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147835110","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":"Antibody-mediated targeting of SOSIP HIV-1 Env to skin Langerhans cells potentiates humoral responses.","authors":"Adele Hammoudi, Mathieu Surenaud, Jade Legros, Florence Picard, Guillaume Hypolite, Justine Manso, Tugba Agyar, Anaïs Kembou, Michela Esposito, Emma Sicherre, Guillaume Flor, Borys Pedenko, Delphine Guilligay, Tahar Bouceba, Craig Fenwick, Christiane Moog, Sandra Zurawski, Gerard Zurawski, Giuseppe Pantaleo, Winfried Weissenhorn, Mireille Centlivre, Véronique Godot, Yves Lévy, Sylvain Cardinaud","doi":"10.1016/j.ebiom.2026.106269","DOIUrl":"https://doi.org/10.1016/j.ebiom.2026.106269","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Despite decades of research and multiple phase 2b/3 trials, an effective HIV vaccine remains out of reach. A key obstacle is the need for innovative delivery strategies that can induce potent and durable protective immune responses. Targeting antigen-presenting cells in the skin, specifically Langerhans cells (LCs), offers a promising approach to enhance vaccine efficacy by promoting early and efficient activation of the humoral immune system.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;We developed an Antibody-Mediated targeting Vaccine (AMV) platform that delivers HIV-1 Env trimeric antigens directly to LCs via an anti-Langerin scFv domain. Two constructs were tested: LC&lt;sup&gt;3&lt;/sup&gt;.Env&lt;sup&gt;3&lt;/sup&gt;, carrying a trimeric gp140z Env fusion protein, and LC&lt;sup&gt;3&lt;/sup&gt;.SOSIP, carrying the well-characterised BG505 SOSIP.664 trimer. Immunogenicity of these constructs was evaluated in mice and rabbits without adjuvant, assessing the germinal centre (GC)/Tfh reaction in draining lymph nodes (dLN), Env-IgG production and HIV-1 neutralisation.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Findings: &lt;/strong&gt;We show that, as compared to an anti-Langerin mAb fused with Env monochains, LC-targeted delivery of Env&lt;sup&gt;3&lt;/sup&gt; through LC&lt;sup&gt;3&lt;/sup&gt;.Env&lt;sup&gt;3&lt;/sup&gt; significantly enhanced Tfh and GC B cells (B&lt;sub&gt;GC&lt;/sub&gt;) formation (p &lt; 0.0001), with an expansion of Env-specific B&lt;sub&gt;GC&lt;/sub&gt; cells in mice (p &lt; 0.05). Env IgG responses was enhanced with LC&lt;sup&gt;3&lt;/sup&gt;.Env&lt;sup&gt;3&lt;/sup&gt; as compared to non-targeted trimeric Env (p &lt; 0.05). Results were extended using LC&lt;sup&gt;3&lt;/sup&gt;.SOSIP constructs which maintained the structural integrity of trimeric Env, but also markedly promoted as compared to Env&lt;sup&gt;3&lt;/sup&gt; and LC&lt;sup&gt;3&lt;/sup&gt;Env&lt;sup&gt;3&lt;/sup&gt; the presentation of the native-like, prefusion-closed structure that displays all major quaternary-dependent broadly neutralising antibodies (bNAbs) regions. LC&lt;sup&gt;3&lt;/sup&gt;.SOSIP elicited in rabbits robust, Env-specific antibody responses with cross-clade reactivity, including neutralising antibodies (NeutAbs), without the use of adjuvants. Finally, as compared to non-targeted SOSIP, LC&lt;sup&gt;3&lt;/sup&gt;.SOSIP elicited stronger Env IgG responses (p &lt; 0.01), even at low antigen doses, and neutralising activity against to Tier-1A but also autologous BG505 Tier-2 viruses (2 rabbits out of 8).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Interpretation: &lt;/strong&gt;These results validate LC-targeting as an efficient, adjuvant-free, strategy for inducing potent humoral responses against HIV-1. The AMV platform enables precise delivery of structurally intact Env trimers to skin-resident LCs facilitating early B cell activation and maturation. This approach offers distinct advantages over conventional adjuvanted sub-unit protein vaccines supporting its potential for clinical translation.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Funding: &lt;/strong&gt;This work was supported by Inserm, the Vaccine Research Institute (VRI), the French National Research Agency (ANR-10-LABX-77, ANR-10-INBS-05-02, ANR-10-EURE-0003","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"127 ","pages":"106269"},"PeriodicalIF":10.8,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147835133","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":"Multi-omics analysis of the gut microbiome and carotid artery atherosclerosis in men with and without HIV.","authors":"Zheng Wang, Yi Wang, Brandilyn A Peters, Wendy S Post, Todd T Brown, Frank J Palella, Charles R Rinaldo, Mallory D Witt, Stephen J Gange, Mark H Kuniholm, Beverly E Sha, Natalie E Chichetto, Clary B Clish, Robert E Gerszten, Howard N Hodis, Anjali Sharma, Kathryn Anastos, Robert D Burk, Robert C Kaplan, Qibin Qi, David B Hanna","doi":"10.1016/j.ebiom.2026.106281","DOIUrl":"https://doi.org/10.1016/j.ebiom.2026.106281","url":null,"abstract":"<p><strong>Background: </strong>How gut microbiota alterations may contribute to host inflammation and metabolomic profiles affecting atherosclerosis is not fully elucidated, especially in the context of HIV.</p><p><strong>Methods: </strong>We examined associations between gut microbial features (measured by shotgun metagenomics) and subclinical carotid atherosclerosis, as assessed by high-resolution B-mode ultrasound, in 359 men from the MACS/WIHS Combined Cohort Study. We measured 822 plasma metabolites using LC-MS/MS, and up to 2866 circulating proteins by the Olink Explore 3072/384 platform (with a primary focus on 617 proteins related to inflammation and immune function).</p><p><strong>Findings: </strong>Carotid artery plaque was detected in 115/359 men (32%). Adlercreutzia equolifaciens and Eubacterium sp3131 were associated with lower odds of plaque (OR [95% CI] = 0.57 [0.43, 0.77], 0.84 [0.76, 0.93], respectively), while Coprococcus sp13142 was associated with higher odds of plaque (OR [95% CI] = 1.14 [1.06, 1.23]). Results were consistent in men both with and without HIV. A. equolifaciens was positively correlated with HDL cholesterol and inversely correlated with systolic blood pressure. These plaque-associated microbial species were also associated with a range of circulating metabolites and inflammatory proteins. For example, A. equolifaciens positively correlated with the metabolites palmitoyl-EA and mesobilirubinogen, and inversely correlated with the pro-inflammatory chemokine CXCL9, the immune regulator CD160, and IL-24.</p><p><strong>Interpretation: </strong>We identified gut microbial features associated with carotid artery atherosclerosis, consistent across HIV status; these associations were partially explained by specific microbiota-related metabolites and inflammatory markers. If validated, these findings suggest gut microbiota-related targets for CVD prevention.</p><p><strong>Funding: </strong>The study was funded by the National Heart, Lung, and Blood Institute (U01HL146204-04S1, K01HL169019).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"127 ","pages":"106281"},"PeriodicalIF":10.8,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147835176","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":"TCF1+CD4+ T cells and microglia co-orchestrate tertiary lymphoid structures to enhance prognosis and immunotherapy in non-small cell lung cancer with brain metastases.","authors":"Qian Yu, Rongxin Liao, Haoyu Zheng, Lin Li, Yusheng Huang, Yihao Tao, Rui Deng, Hengqiu He, Li Yu, Jingyao Lin, Shunping Huang, Xiaoyue Zhang, Zaicheng Xu, Zhenzhou Yang, Yuan Peng","doi":"10.1016/j.ebiom.2026.106280","DOIUrl":"https://doi.org/10.1016/j.ebiom.2026.106280","url":null,"abstract":"<p><strong>Background: </strong>Non-small cell lung cancer brain metastases (NSCLC-BM) confer a poor prognosis, with only a minority of patients responding to immune checkpoint inhibitors (ICIs). Tertiary lymphoid structures (TLSs) have been linked to prognosis and response to immunotherapy across various tumours. Given the unique immune environment of brain metastases, TLSs within NSCLC-BM might exhibit distinct characteristics. Nevertheless, the function and formation mechanisms of these intracranial TLSs remain inadequately understood.</p><p><strong>Methods: </strong>We retrospectively analysed 120 resected NSCLC-BM samples. Heterogeneity of TLS characteristics and functional states in NSCLC-BM was assessed using H&E and multiplex immunohistochemistry (mIHC). Associations with OS and iPFS were evaluated, and a nomogram incorporating TLS score was developed. Potential mechanisms underlying TLS formation were explored using public scRNA-seq datasets and mIHC, and were functionally validated in vivo in the LC-BrM mouse model.</p><p><strong>Findings: </strong>TLSs were primarily intratumoral and immature. Elevated intratumoral TLS scores independently predicted prolonged OS and iPFS, and predicted benefit from postoperative ICIs. TLS-rich tumours exhibited increased CD8+ T cells, FOXP3-CD4+ T cells, and B cells. Mechanistically, TCF1+CD4+ T cells and microglia co-localised within TLSs and might facilitate their formation via LTβ/LTβR signalling. Meanwhile, stromal CXCL12 was further identified as a crucial chemoattractant for these cells and correlated with favourable outcomes of ICI therapy. Functionally, the combination of rmCXCL12 and anti-PD-1 promotes TLS formation and intracranial tumour control in an LTβR-dependent manner.</p><p><strong>Interpretation: </strong>These findings highlight the significance of TLSs as prognostic biomarkers and potential therapeutic targets in patients with NSCLC-BM.</p><p><strong>Funding: </strong>This work was supported by the Natural Science Foundation of China (82573031); the CQMU Program for Youth Innovation in Future Medicine (W0172); the Postdoctoral Fellowship Program of the China Postdoctoral Science Foundation (GZC20233356).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"127 ","pages":"106280"},"PeriodicalIF":10.8,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147835194","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":"Early transcriptional responses following Ad26.COV2.S vaccination in individuals with prior SARS-CoV-2 infection.","authors":"Veronica V Rezelj, Jeroen Tolboom, Nina Hertoghs, Jan Serroyen, Mathieu Le Gars, Frank Struyf, Jenny Hendriks, Javier Ruiz Guiñazú, Chelsea McLean","doi":"10.1016/j.ebiom.2026.106270","DOIUrl":"https://doi.org/10.1016/j.ebiom.2026.106270","url":null,"abstract":"<p><strong>Background: </strong>Ad26.COV2.S is a recombinant, replication-incompetent human adenovirus serotype 26 (Ad26) vectored vaccine encoding a full-length SARS-CoV-2 spike protein in a prefusion-stabilised conformation. The genes and pathways which are differentially regulated following vaccination with Ad26.COV2.S, how these differ over time, and under different regimens, have not been investigated.</p><p><strong>Methods: </strong>Gene expression changes were profiled via RNAseq following the first and second dose of Ad26.COV2.S in a subset of individuals with pre-existing SARS-CoV-2 immunity due to prior SARS-CoV-2 infection, included in a randomised, double-blind, Phase 3 study (NCT#04908722). Transcriptional responses induced by a 1- and 2-dose regimen were assessed, each at two different dose levels: the marketed 5 × 10¹⁰vp dose level and a lower 1.25 × 10¹⁰vp dose level.</p><p><strong>Findings: </strong>Consistent with other vaccine studies, antiviral, interferon, cytokine, and monocyte blood transcriptional modules were differentially regulated one day post-Ad26.COV2.S vaccination. At three days post-vaccination, innate immunity was still transcriptionally active at lower levels than one day post-vaccination. By seven days post-Ad26.COV2.S, increased immunoglobulin gene expression dominated the transcriptome response, indicating a shift towards humoural and B cell responses and activation of adaptive immunity. Transcriptional responses post-Ad26.COV2.S were generally stronger after the first dose versus the second dose.</p><p><strong>Interpretation: </strong>In this study in whole blood, innate and adaptive immune transcripts were upregulated as early as one and seven days post-Ad26.COV2.S, respectively. These findings add to the limited data on innate immune responses to adenovirus-based vaccines in a clinical setting and contribute to understanding the mechanisms behind the adaptive immune responses that may contribute to protective immunity.</p><p><strong>Funding: </strong>This study was funded by Johnson & Johnson Innovative Medicine.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"127 ","pages":"106270"},"PeriodicalIF":10.8,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147835118","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":"CT-based body composition and its change through time in relation to outcomes in participants screened for lung cancer.","authors":"Stijn Bunk, Edwin Bennink, Grigory Sidorenkov, Marjolein A Heuvelmans, Harry J M Groen, Hester A Gietema, Mathias Prokop, Joachim G Aerts, Colin Jacobs, Geertruida H de Bock, Pim A de Jong, Rozemarijn Vliegenthart, Firdaus Mohamed Hoesein","doi":"10.1016/j.ebiom.2026.106276","DOIUrl":"10.1016/j.ebiom.2026.106276","url":null,"abstract":"<p><strong>Background: </strong>Computed Tomography (CT) scans allow opportunistic evaluation of body composition. We investigated whether body composition and change through time are associated with lung cancer incidence and all-cause/lung cancer-specific mortality in a lung cancer screening cohort.</p><p><strong>Methods: </strong>A machine learning segmentation method was used in this retrospective cohort study to measure skeletal muscle area and density, and subcutaneous adipose tissue area (SAT) on repeated chest CTs from the Dutch-Belgian lung cancer screening trial. Hazard ratios by sex adjusted for age, smoking status, and smoking pack-years (aHR) were calculated for each outcome.</p><p><strong>Findings: </strong>During median follow-up of 12.2 (interquartile range, 1.2) years, 4.1% of 6187 subjects (85.5% male, mean age ± SD, 58.6 ± 5.5 years, smoking pack-years 41.2 ± 18.3) developed lung cancer, 12.2% died, and 2.1% died due to lung cancer. For males, SAT loss was associated with lung cancer incidence (aHR 1.19, 95% CI 1.02-1.39) and lung cancer-specific mortality (aHR 1.26, 95% CI 1.03-1.55), and less baseline muscle and muscle loss with all-cause mortality (aHR 1.20, 95% CI 1.10-1.31 and 1.17, 1.07-1.27). For females, less baseline SAT and SAT loss was associated with all-cause mortality (aHR 1.44, 95% CI 1.06-1.97 and 1.48, 1.13-1.94) and lung cancer-specific mortality (aHR 2.85, 95% CI 1.50-5.39 and aHR 1.96, 1.11-3.44). Models improved by including body composition trends for all-cause mortality (males: p < 0.001; females: p = 0.012) and for lung cancer-specific mortality (males: p = 0.102; females: p = 0.005).</p><p><strong>Interpretation: </strong>Body composition trends based on automated analysis of chest CT are associated with worse outcomes in participants screened for lung cancer.</p><p><strong>Funding: </strong>Dutch Cancer Society, Health Holland, Siemens Healthineers.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"127 ","pages":"106276"},"PeriodicalIF":10.8,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13145877/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147812323","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":"The polygenic score for age at menopause is independently associated with the response of controlled ovarian hyperstimulation in women undergoing IVF.","authors":"Charissa van Zwol-Janssens, Sander Lamballais, Elizabeth A Loehrer, Joop S E Laven, Tjitske Kleefstra, Yvonne V Louwers","doi":"10.1016/j.ebiom.2026.106267","DOIUrl":"10.1016/j.ebiom.2026.106267","url":null,"abstract":"<p><strong>Background: </strong>While Anti-Müllerian hormone (AMH) helps personalise In Vitro Fertilization (IVF) stimulation protocols, a significant number of women still do not achieve an optimal ovarian response. To address this, we explore the utility of a polygenic score for age at natural menopause (ANM) as a predictor for ovarian response during IVF.</p><p><strong>Methods: </strong>This cohort study included 435 women who underwent standardised IVF stimulation, and they were genotyped to calculate a polygenic score (PGS) for ANM. Linear regression and ANCOVA models were used to assess the associations between the PGS and ovarian response, oocyte and embryo quality and pregnancy rates, adjusting for genomic components and age.</p><p><strong>Findings: </strong>A one standard deviation increase in the PGS for ANM was associated with 0.950 (p < 0.001) additional follicles two days before ovum pick-up. While the PGS did not significantly associate with the overall diminished ovarian response (DOR), a mean difference of -0.33 (p < 0.01) in PGS was observed when comparing individuals with fewer than 8 follicles retrieved to those with an optimal ovarian response. No association was found between the PGS and ongoing pregnancy. Causal mediation revealed that the effect of the PGS onto the number of follicles was partly mediated by AMH levels (proportion mediated = 31%, p = 0.002).</p><p><strong>Interpretation: </strong>A lower PGS for ANM, indicative for earlier menopause, is independently associated with a reduced ovarian response during IVF stimulation, specifically fewer follicles retrieved and mostly independent of AMH levels. This highlights the potential of ANM-related genetic variants to inform personalised IVF protocols by predicting ovarian responsiveness.</p><p><strong>Funding: </strong>This study was supported by Ferring Pharmaceuticals.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"127 ","pages":"106267"},"PeriodicalIF":10.8,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13145881/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147812495","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}