EBioMedicinePub Date : 2025-03-14DOI: 10.1016/j.ebiom.2025.105645
Bo Hu, Mei-Yu Yin, Chu-Yi Zhang, Zhe Shi, Lu Wang, Xiaoming Lei, Ming Li, Shi-Wu Li, Qin-Hui Tuo
{"title":"The INO80E at 16p11.2 locus increases risk of schizophrenia in humans and induces schizophrenia-like phenotypes in mice.","authors":"Bo Hu, Mei-Yu Yin, Chu-Yi Zhang, Zhe Shi, Lu Wang, Xiaoming Lei, Ming Li, Shi-Wu Li, Qin-Hui Tuo","doi":"10.1016/j.ebiom.2025.105645","DOIUrl":"https://doi.org/10.1016/j.ebiom.2025.105645","url":null,"abstract":"<p><strong>Background: </strong>Chromosome 16p11.2 is one of the most significant loci in the genome-wide association studies (GWAS) of schizophrenia. Despite several integrative analyses and functional genomics studies having been carried out to identify possible risk genes, their impacts in the pathogenesis of schizophrenia remain to be fully characterized.</p><p><strong>Methods: </strong>We performed expression quantitative trait loci (eQTL) and summary-data-based Mendelian randomization (SMR) analyses to identify schizophrenia risk genes in the 16p11.2 GWAS locus. We constructed a murine model with dysregulated expression of risk gene in the medial prefrontal cortex (mPFC) using stereotaxic injection of adeno-associated virus (AAV), followed by behavioural assessments, dendritic spine analyses and RNA sequencing.</p><p><strong>Findings: </strong>We identified significant associations between elevated INO80E mRNA expression in the frontal cortex and risk of schizophrenia. The mice overexpressing Ino80e in mPFC (Ino80e-OE) exhibited schizophrenia-like behaviours, including increased anxiety behaviour, anhedonia, and impaired prepulse inhibition (PPI) when compared with control group. The neuronal sparse labelling assay showed that the density of stubby spines in the pyramidal neurons of mPFC was significantly increased in Ino80e-OE mice compared with control mice. Transcriptomic analysis in the mPFC revealed significant alterations in the mRNA levels of schizophrenia-related genes and processes related to synapses upon overexpressing Ino80e.</p><p><strong>Interpretation: </strong>Our results suggest that upregulation of the Ino80e gene in mPFC may induce schizophrenia-like behaviours in mice, further supporting the hypothesis that INO80E is an authentic risk gene.</p><p><strong>Funding: </strong>This project received support from the National Key Research and Development Program of China, National Natural Science Foundation of China, Key Research and Development Projects of Hunan Provincial Science and Technology Department, Science and Technology Innovation team of Hunan Province, etc.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"114 ","pages":"105645"},"PeriodicalIF":9.7,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143633523","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}
EBioMedicinePub Date : 2025-03-14DOI: 10.1016/j.ebiom.2025.105646
Yuening Jiang, Jie Li, Tianzhen Wang, Xiaoyang Gu, Xinyu Li, Zhaofei Liu, Wei Yue, Mo Li
{"title":"VIPAS39 confers ferroptosis resistance in epithelial ovarian cancer through exporting ACSL4.","authors":"Yuening Jiang, Jie Li, Tianzhen Wang, Xiaoyang Gu, Xinyu Li, Zhaofei Liu, Wei Yue, Mo Li","doi":"10.1016/j.ebiom.2025.105646","DOIUrl":"https://doi.org/10.1016/j.ebiom.2025.105646","url":null,"abstract":"<p><strong>Background: </strong>The high mortality rate associated with epithelial ovarian cancer (EOC) is primarily due to recurrence and chemoresistance, underscoring the urgent need for innovative therapeutic approaches that leverage newly identified vulnerabilities in cancer cells. While conventional chemotherapies induce apoptosis by targeting DNA or mitotic machinery, ferroptosis represents a new distinct form of programmed cell death characterised by the accumulation of lipid peroxides.</p><p><strong>Methods: </strong>The sensitivity of different EOC cell lines to ferroptosis inducers was evaluated using cell viability assays and lipid peroxidation measurements. Live-cell imaging with the pH-sensitive CD63-pHuji reporter was performed to track the extracellular export of acyl-CoA synthetase long-chain family member 4 (ACSL4) via exosomes. The upstream regulator of ACSL4 were identified through immunoprecipitation-mass spectrometry (IP-MS) and validated using protein binding assays. Finally, cell-derived xenograft (CDX) and patient-derived xenograft (PDX) models were utilised to evaluate the therapeutic potential overcoming ferroptosis resistance.</p><p><strong>Findings: </strong>In this study, we found that interferon (IFN)-γ combined with arachidonic acid (AA), which are endogenous ferroptosis inducers, could initiate ferroptosis in most EOC cells. However, some EOC cells displayed significant resistance. Contrary to the typical increase in ACSL4 protein observed in ferroptosis-sensitive cells, resistant EOC cells exhibited surprisingly low levels of this pro-ferroptotic lipid metabolic protein. Intriguingly, this reduction is attributed to the exosomal expulsion of ACSL4 protein, revealing a distinct cellular mechanism to evade ferroptosis. We further identified VIPAS39 as a pivotal regulator in sorting ACSL4 into late endosomes, thereby facilitating their subsequent release as exosomes. Notably, targeting VIPAS39 not only overcomes the resistance to ferroptotic cell death but also markedly suppresses tumour growth.</p><p><strong>Interpretation: </strong>Our findings uncover the crucial role of VIPAS39 in ferroptosis evasion by facilitating the exporting of ACSL4 protein via exosomes, highlighting VIPAS39 as a promising target for ferroptosis-based anti-cancer therapy.</p><p><strong>Funding: </strong>Funded by Beijing Municipal Natural Science Foundation (Key program Z220011), National Natural Science Foundation of China (NSFC) (T2225006, T2488301, 82272948), Peking University Medicine Youth Science and Technology Innovation 'Sail Plan' Project Type B Medical Interdisciplinary Seed Fund (71006Y3171), GuangDong Basic and Applied Basic Research Foundation (2021A1515110820), and the special fund of the National Clinical Key Speciality Construction Program, P. R. China (2023).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"114 ","pages":"105646"},"PeriodicalIF":9.7,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143633538","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}
EBioMedicinePub Date : 2025-03-12DOI: 10.1016/j.ebiom.2025.105634
Wenjing Ruan, Pengyue Gao, Xiao Qu, Junlan Jiang, Zhennan Zhao, Shitong Qiao, He Zhang, Ting Yang, Dedong Li, Pei Du, Xuancheng Lu, Qihui Wang, Xin Zhao, George Fu Gao
{"title":"SARS-CoV-2 serotyping based on spike antigenicity and its implications for host immune evasion.","authors":"Wenjing Ruan, Pengyue Gao, Xiao Qu, Junlan Jiang, Zhennan Zhao, Shitong Qiao, He Zhang, Ting Yang, Dedong Li, Pei Du, Xuancheng Lu, Qihui Wang, Xin Zhao, George Fu Gao","doi":"10.1016/j.ebiom.2025.105634","DOIUrl":"10.1016/j.ebiom.2025.105634","url":null,"abstract":"<p><strong>Background: </strong>As SARS-CoV-2 continues to spread and evolve, new variants/sub-variants emerge, raising concerns about vaccine-induced immune escape. Here, we conducted a systematic analysis of the serology and immunogenicity of major circulating variants/sub-variants of SARS-CoV-2 since the outbreak.</p><p><strong>Methods: </strong>We expressed and purified trimeric S proteins from 21 SARS-CoV-2 variants, with SARS-CoV included as an outgroup. Mice were immunized, and the resulting antisera were tested for binding antibodies after the third dose injection, and for neutralizing antibodies (NAbs) after both the second and third doses. Using pseudovirus neutralization assays, we evaluated cross-neutralization among major circulating variants. By integrating serological classification, antigenic mapping, and 3D landscape analysis, we explored the antigenic relationships among different SARS-CoV-2 variants and their impact on serological responses.</p><p><strong>Findings: </strong>Based on the cross-neutralization activities of the sera from different S protein vaccinations and antigenicity analyses, we grouped the 21 lineages into six serotypes. Particularly, BA.2.86 and JN.1 had very weak cross-neutralization with all other SARS-CoV-2 sub-variants tested and were grouped into a separate serotype, Serotype VI.</p><p><strong>Interpretation: </strong>This systematic study contributes to a better understanding of the evolution of SARS-CoV-2 and its antigenic characteristics and provides valuable insights for vaccine development.</p><p><strong>Funding: </strong>This study was supported by the National Key R&D Program of China (2023YFC2307801, 2020YFA0509202 and 2021YFA1300803), the National Natural Science Foundation of China (82222040 and 82072289), CAS Project for Young Scientists in Basic Research (YSBR-083) and Beijing Nova Program of Science and Technology (20220484181).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"114 ","pages":"105634"},"PeriodicalIF":9.7,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11951033/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143623979","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}
EBioMedicinePub Date : 2025-03-10DOI: 10.1016/j.ebiom.2025.105649
Meng Wang, Hui Wang
{"title":"Carbapenem-resistant hypervirulent Klebsiella pneumoniae: where is it headed in the tug-of-war between virulence and resistance?","authors":"Meng Wang, Hui Wang","doi":"10.1016/j.ebiom.2025.105649","DOIUrl":"10.1016/j.ebiom.2025.105649","url":null,"abstract":"","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"114 ","pages":"105649"},"PeriodicalIF":9.7,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11938087/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143604335","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}
EBioMedicinePub Date : 2025-03-08DOI: 10.1016/j.ebiom.2025.105641
Shahinaz M Gadalla, Hormuzd A Katki, Tsung-Po Lai, Paul L Auer, Casey L Dagnall, Caitrin Bupp, Amy A Hutchinson, James J Anderson, Kyra J W Mendez, Stephen R Spellman, Valerie Stewart, Sharon A Savage, Stephanie J Lee, John E Levine, Wael Saber, Abraham Aviv
{"title":"Donor telomeres and their magnitude of shortening post-allogeneic haematopoietic cell transplant impact survival for patients with early-stage leukaemia or myelodysplastic syndrome.","authors":"Shahinaz M Gadalla, Hormuzd A Katki, Tsung-Po Lai, Paul L Auer, Casey L Dagnall, Caitrin Bupp, Amy A Hutchinson, James J Anderson, Kyra J W Mendez, Stephen R Spellman, Valerie Stewart, Sharon A Savage, Stephanie J Lee, John E Levine, Wael Saber, Abraham Aviv","doi":"10.1016/j.ebiom.2025.105641","DOIUrl":"10.1016/j.ebiom.2025.105641","url":null,"abstract":"<p><strong>Background: </strong>Donor selection is a key success factor in allogeneic haematopoietic cell transplant (HCT). We evaluated the potential impact of donor leucocyte telomere length (LTL) and LTL shortening in recipients at three-month post-HCT (LTL-3MS) on the two-year HCT outcomes.</p><p><strong>Methods: </strong>We identified a cohort of 384 HCT recipients for early-stage leukaemia or myelodysplastic syndrome in the Blood and Marrow Transplant Clinical Trial Network protocol#1202 with blood samples collected three-month post-HCT. Blood samples from respective donors were available at the Centre for International Blood and Marrow Transplant Research biorepository. We used Cox proportional hazards models for statistical analyses.</p><p><strong>Findings: </strong>A better two-year overall survival (OS) was associated with longer donor LTL (adjusted-hazard ratio [HR] = 0.60, 95% confidence interval [CI] = 0.37-0.96, for LTL ≥6.7 kb vs LTL< 6.7 kb, p = 0.03), and higher LTL-3MS (HR = 0.52, 95% CI = 0.34-0.80, for LTL-3MS ≥ 230 vs < 230 bp, p = 0.003). Longer donor LTL was associated with a lower risk of non-relapse mortality (NRM; HR = 0.48, p = 0.05), while higher LTL-3MS was associated with lower relapse risk (HR for relapse risk = 0.53, p = 0.008). The adjusted 2-year cumulative risk of all-cause mortality was reduced by about half for patients with both donor LTL ≥6.7 kb and LTL-3MS ≥ 230 bp vs patients with neither characteristic (21% vs 41%, respectively; p < 0.0001).</p><p><strong>Interpretation: </strong>Selection of donors with longer LTL may improve HCT outcomes. Limited LTL shortening in recipients post-HCT may guide relapse prediction.</p><p><strong>Funding: </strong>The NCI intramural research program and NIH grant U01AG066529.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"114 ","pages":"105641"},"PeriodicalIF":9.7,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11930427/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143585170","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}
EBioMedicinePub Date : 2025-03-06DOI: 10.1016/j.ebiom.2025.105635
Anjana Silva, Geoffrey Isbister
{"title":"Understanding the role of small-molecule therapeutics for snake envenoming.","authors":"Anjana Silva, Geoffrey Isbister","doi":"10.1016/j.ebiom.2025.105635","DOIUrl":"10.1016/j.ebiom.2025.105635","url":null,"abstract":"","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"114 ","pages":"105635"},"PeriodicalIF":9.7,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11930210/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143585171","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}
EBioMedicinePub Date : 2025-03-05DOI: 10.1016/j.ebiom.2025.105631
Peter Y F Zeng, R Jun Lin, Kevin Fung, Halema Khan, Matthew J Cecchini, Elissa Woo, Amanda Hu, Jennifer Anderson, Patrick MacInnis, Laura Jarycki, Amir Karimi, Shengjie Ying, MohdWessam Al Jawhri, Sherman Lin, Mushfiq Shaikh, Harrison Pan, Bryan Coburn, Joe S Mymryk, Richard Inculet, John W Barrett, Anthony C Nichols
{"title":"Cellular blueprint of healthy and diseased human epiglottis and subglottis-a study of the Canadian Airways Research (CARE) group.","authors":"Peter Y F Zeng, R Jun Lin, Kevin Fung, Halema Khan, Matthew J Cecchini, Elissa Woo, Amanda Hu, Jennifer Anderson, Patrick MacInnis, Laura Jarycki, Amir Karimi, Shengjie Ying, MohdWessam Al Jawhri, Sherman Lin, Mushfiq Shaikh, Harrison Pan, Bryan Coburn, Joe S Mymryk, Richard Inculet, John W Barrett, Anthony C Nichols","doi":"10.1016/j.ebiom.2025.105631","DOIUrl":"10.1016/j.ebiom.2025.105631","url":null,"abstract":"<p><strong>Background: </strong>The larynx consists of the supraglottis, glottis, and subglottis and each differ in tissue composition, lymphatic drainage, ability to counter infections, and response to injuries. However, the cellular mechanisms driving laryngeal homoeostasis remain largely unexplored. As a result, understanding disease pathogenesis within the larynx including idiopathic subglottic stenosis (iSGS) and intubation-related traumatic stenosis has been challenging. Here, we sought to characterise the cellular processes governing laryngeal health and disease.</p><p><strong>Methods: </strong>As part of the prospective Canadian Airways Research (CARE) iSGS study, we characterised 122,004 high-quality transcriptomes using single nucleus RNA-sequencing to profile 11 human epiglottis and 17 human subglottis biopsies across three different conditions: control, iSGS, and intubation-related traumatic stenosis to define cell populations and pathways associated with disease. We validated our results using cohort-level bulk transcriptomics using 114 human epiglottis and 121 human subglottis.</p><p><strong>Findings: </strong>We defined the single-cell taxonomy of the human subglottis and epiglottis using single-nucleus sequencing in both healthy and disease states. Mechanistically, we discovered the presence of unique epithelial and fibroblast progenitor subsets within the control subglottis but not within the anatomically adjacent epiglottis. The uncontrolled proliferation of these cellular subsets exhibited skewed sex hormone signalling and orchestrated a fibro-inflammatory cascade. We leveraged cohort-level bulk transcriptomics to define hallmarks of iSGS associated with disease covariates and introduced the first biomarker associated with recurrent relapse. Longitudinal sampling demonstrated that the subglottic microenvironment in patients with iSGS is changing dynamically with and without therapeutic intervention.</p><p><strong>Interpretation: </strong>Together, our data refines our understanding of laryngeal biology, nominates candidate compounds for iSGS treatment, and serves as a transformative platform for future clinical investigations to further precision laryngology.</p><p><strong>Funding: </strong>This study was funded by a grant from the American Laryngology Association (#1082), an Academic Medical Organisation of Southwestern Ontario innovation fund grant (INN21-016), grant support from the Departments of Otolaryngology-Head and Neck Surgery at University of Toronto, Canada and Western University, Canada. ACN was supported by the Wolfe Surgical Research Professorship in the Biology of Head and Neck Cancers Fund. PYFZ was supported by a Vanier Canada Graduate Scholarship and PSI Foundation fellowship.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"114 ","pages":"105631"},"PeriodicalIF":9.7,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11929080/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143572096","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}
EBioMedicinePub Date : 2025-03-05DOI: 10.1016/j.ebiom.2025.105630
Ahmed Bargheet, Hanna Theodora Noordzij, Alise J Ponsero, Ching Jian, Katri Korpela, Mireia Valles-Colomer, Justine Debelius, Alexander Kurilshikov, Veronika Kuchařová Pettersen
{"title":"Dynamics of gut resistome and mobilome in early life: a meta-analysis.","authors":"Ahmed Bargheet, Hanna Theodora Noordzij, Alise J Ponsero, Ching Jian, Katri Korpela, Mireia Valles-Colomer, Justine Debelius, Alexander Kurilshikov, Veronika Kuchařová Pettersen","doi":"10.1016/j.ebiom.2025.105630","DOIUrl":"10.1016/j.ebiom.2025.105630","url":null,"abstract":"<p><strong>Background: </strong>The gut microbiota of infants harbours a higher proportion of antibiotic resistance genes (ARGs) compared to adults, even in infants never exposed to antibiotics. Our study aims to elucidate this phenomenon by analysing how different perinatal factors influence the presence of ARGs, mobile genetic elements (MGEs), and their bacterial hosts in the infant gut.</p><p><strong>Methods: </strong>We searched MEDLINE and Embase up to April 3rd, 2023, for studies reporting infant cohorts with shotgun metagenomic sequencing of stool samples. The systematic search identified 14 longitudinal infant cohorts from 10 countries across three continents, featuring publicly available sequencing data with corresponding metadata. For subsequent integrative bioinformatic analyses, we used 3981 high-quality metagenomic samples from 1270 infants and 415 mothers.</p><p><strong>Findings: </strong>We identified distinct trajectories of the resistome and mobilome associated with birth mode, gestational age, antibiotic use, and geographical location. Geographical variation was exemplified by differences between cohorts from Europe, Southern Africa, and Northern America, which showed variation in both diversity and abundance of ARGs. On the other hand, we did not detect a significant impact of breastfeeding on the infants' gut resistome. More than half of detected ARGs co-localised with plasmids in key bacterial hosts, such as Escherichia coli and Enterococcus faecalis. These ARG-associated plasmids were gradually lost during infancy. We also demonstrate that E. coli role as a primary modulator of the infant gut resistome and mobilome is facilitated by its increased abundance and strain diversity compared to adults.</p><p><strong>Interpretation: </strong>Birth mode, gestational age, antibiotic exposure, and geographical location significantly influence the development of the infant gut resistome and mobilome. A reduction in E. coli relative abundance over time appears as a key factor driving the decrease in both resistome and plasmid relative abundance as infants grow.</p><p><strong>Funding: </strong>Centre for Advanced Study in Oslo, Norway. Centre for New Antibacterial Strategies through the Tromsø Research Foundation, Norway.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"114 ","pages":"105630"},"PeriodicalIF":9.7,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11929092/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143572103","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}
EBioMedicinePub Date : 2025-03-05DOI: 10.1016/j.ebiom.2025.105629
R Jun Lin, Peter Yf Zeng, Kevin Fung, Halema Khan, Matthew J Cecchini, Elissa Woo, Amanda Hu, Jennifer Anderson, Patrick MacInnis, Amir Karimi, Shengjie Ying, MohdWessam Al Jawhri, Sherman Lin, Laura Jarycki, Mushfiq H Shaikh, Harrison Pan, Bryan Coburn, Joe S Mymryk, Richard Inculet, John W Barrett, Anthony C Nichols
{"title":"Cohort-level clinical trajectory and molecular landscape of idiopathic subglottic stenosis for precision laryngology-a study of the Canadian airways research (CARE) group.","authors":"R Jun Lin, Peter Yf Zeng, Kevin Fung, Halema Khan, Matthew J Cecchini, Elissa Woo, Amanda Hu, Jennifer Anderson, Patrick MacInnis, Amir Karimi, Shengjie Ying, MohdWessam Al Jawhri, Sherman Lin, Laura Jarycki, Mushfiq H Shaikh, Harrison Pan, Bryan Coburn, Joe S Mymryk, Richard Inculet, John W Barrett, Anthony C Nichols","doi":"10.1016/j.ebiom.2025.105629","DOIUrl":"10.1016/j.ebiom.2025.105629","url":null,"abstract":"<p><strong>Background: </strong>First described in 1972, idiopathic subglottic stenosis (iSGS) is a serious chronic orphan disease characterised by recurrent scarring of the subglottis. Although the cause is unknown, iSGS is almost exclusively restricted to Caucasian females typically in their fourth to sixth decade. However, given its rare incidence (1:400,000), understanding the clinical trajectory and molecular factors associated with iSGS disease development and prognosis has been difficult. In the current study we sought to unravel the pathogenesis of iSGS at the clinical, transcriptional, and genetic level in a prospective cohort.</p><p><strong>Methods: </strong>We prospectively enrolled 126 patients with iSGS, 104 controls, and 13 patients with traumatic SGS. Within this cohort, we profiled 114 human epiglottis and 121 human subglottis biopsies across three different conditions: control, iSGS, and intubation-related traumatic stenosis using bulk and single nucleus RNA-sequencing. Whole exome sequencing for germline variants was performed for 70 controls and 75 patients with iSGS.</p><p><strong>Findings: </strong>Patients with iSGS received a median number of five (range 0-18) surgical dilations at a rate of 1.031 dilations (range: 0.12-6.2) per year. Older age at diagnosis and higher Cotton-Myers grade were associated with increased number of surgical dilations over time. Cohort-level bulk transcriptomics found that iSGS pathology was restricted within the subglottis and did not affect anatomically adjacent epiglottis, opposite to previous hypotheses. We further identified cellular subsets associated with iSGS prognosis and severity. Finally, patients with iSGS exhibit lower testosterone predicted using a polygenic score.</p><p><strong>Interpretation: </strong>Together, our data refines our understanding of laryngeal biology and provides insights into the clinical trajectory of subglottic stenoses. Future research should explore the role of testosterone in the development of iSGS.</p><p><strong>Funding: </strong>This study was funded by a grant from the American Laryngology Association (#1082), an Academic Medical Organization of Southwestern Ontario innovation fund grant (INN21-016), grant support from the Departments of Otolaryngology-Head and Neck Surgery at University of Toronto and Western University. ACN was supported by the Wolfe Surgical Research Professorship in the Biology of Head and Neck Cancers Fund. PYFZ was supported by a Vanier Canada Graduate Scholarship and PSI foundation fellowship.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":"114 ","pages":"105629"},"PeriodicalIF":9.7,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11924928/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143572102","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}