Clinical and Translational Medicine最新文献

{"title":"RNA splicing factor RBFOX2 is a key factor in the progression of cancer and cardiomyopathy","authors":"Jinze Shen,&nbsp;Jianqiao Shentu,&nbsp;Chenming Zhong,&nbsp;Qiankai Huang,&nbsp;Shiwei Duan","doi":"10.1002/ctm2.1788","DOIUrl":"10.1002/ctm2.1788","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Alternative splicing of pre-mRNA is a fundamental regulatory process in multicellular eukaryotes, significantly contributing to the diversification of the human proteome. RNA-binding fox-1 homologue 2 (RBFOX2), a member of the evolutionarily conserved RBFOX family, has emerged as a critical splicing regulator, playing a pivotal role in the alternative splicing of pre-mRNA. This review provides a comprehensive analysis of RBFOX2, elucidating its splicing activity through direct and indirect binding mechanisms. RBFOX2 exerts substantial influence over the alternative splicing of numerous transcripts, thereby shaping essential cellular processes such as differentiation and development.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Main body of the abstract</h3>\u0000 \u0000 <p>Dysregulation of RBFOX2-mediated alternative splicing has been closely linked to a spectrum of cardiovascular diseases and malignant tumours, underscoring its potential as a therapeutic target. Despite significant progress, current research faces notable challenges. The complete structural characterisation of RBFOX2 remains elusive, limiting in-depth exploration beyond its RNA-recognition motif. Furthermore, the scarcity of studies focusing on RBFOX2-targeting drugs poses a hindrance to translating research findings into clinical applications.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This review critically assesses the existing body of knowledge on RBFOX2, highlighting research gaps and limitations. By delineating these areas, this analysis not only serves as a foundational reference for future studies but also provides strategic insights for bridging these gaps. Addressing these challenges will be instrumental in unlocking the full therapeutic potential of RBFOX2, paving the way for innovative and effective treatments in various diseases.</p>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 9","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.1788","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142145247","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":"ALKBH5-mediated m6A demethylation ameliorates extracellular matrix deposition in cutaneous pathological fibrosis","authors":"Ruoqing Xu,&nbsp;En Yang,&nbsp;Hsin Liang,&nbsp;Shenying Luo,&nbsp;Yunhan Liu,&nbsp;Yimin Khoong,&nbsp;Haizhou Li,&nbsp;Xin Huang,&nbsp;Yixuan Zhao,&nbsp;Tao Zan","doi":"10.1002/ctm2.70016","DOIUrl":"10.1002/ctm2.70016","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Elevated extracellular matrix (ECM) accumulation is a major contributing factor to the pathogenesis of fibrotic diseases. Recent studies have indicated that N6-methyladenosine (m⁶A) RNA modification plays a pivotal role in modulating RNA stability and contribute to the initiation of various pathological conditions. Howbeit, the precise mechanism by which m⁶A influences ECM deposition remains unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In this study, we used hypertrophic scars (HTSs) as a paradigm to investigate ECM-related diseases. We focused on the role of ALKBH5-mediated m⁶A demethylation within the pathological progression of HTSs and examined its correlation with clinical stages. The effects of ALKBH5 ablation on ECM components were studied both in vivo and in vitro. Downstream targets of ALKBH5, along with their underlying mechanisms, were identified using integrated high-throughput analysis, RNA-binding protein immunoprecipitation and RNA pull-down assays. Furthermore, the therapeutic potential of exogenous ALKBH5 overexpression was evaluated in fibrotic scar models.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>ALKBH5 was decreased in fibroblasts derived from HTS lesions and was negatively correlated with their clinical stages. Importantly, ablation of ALKBH5 promoted the expression of COL3A1, COL1A1, and ELN, leading to pathological deposition and reconstruction of the ECM both in vivo and in vitro. From a therapeutic perspective, the exogenous overexpression of ALKBH5 significantly inhibited abnormal collagen deposition in fibrotic scar models. As determined by integrated high-throughput analysis, key ECM components including COL3A1, COL1A1, and ELN are direct downstream targets of ALKBH5. By means of its mechanism, ALKBH5 inhibits the expression of COL3A1, COL1A1, and ELN by removing m⁶A from mRNAs, thereby decreasing their stability in a YTHDF1-dependent manner.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our study identified ALKBH5 as an endogenous suppressor of pathological ECM deposition, contributing to the development of a reprogrammed m6A-targeted therapy for HTSs.</p>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 9","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11374695/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142132010","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":"Single-cell multi-modal chromatin profiles revealing epigenetic regulations of cells in hepatocellular carcinoma","authors":"Chunqing Wang,&nbsp;Waidong Huang,&nbsp;Yu Zhong,&nbsp;Xuanxuan Zou,&nbsp;Shang Liu,&nbsp;Jie Li,&nbsp;Yunfan Sun,&nbsp;Kaiqian Zhou,&nbsp;Xi Chen,&nbsp;Zihao Li,&nbsp;Shanshan Wang,&nbsp;Yaling Huang,&nbsp;Yinqi Bai,&nbsp;Jianhua Yin,&nbsp;Xin Jin,&nbsp;Shiping Liu,&nbsp;Yue Yuan,&nbsp;Qiuting Deng,&nbsp;Miaomiao Jiang,&nbsp;Chuanyu Liu,&nbsp;Longqi Liu,&nbsp;Xun Xu,&nbsp;Liang Wu","doi":"10.1002/ctm2.70000","DOIUrl":"https://doi.org/10.1002/ctm2.70000","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Various epigenetic regulations systematically govern gene expression in cells involving various biological processes. Dysregulation of the epigenome leads to aberrant transcriptional programs and subsequently results in diseases, such as cancer. Therefore, comprehensive profiling epigenomics is essential for exploring the mechanisms underlying gene expression regulation during development and disease.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;In this study, we developed single-cell chromatin proteins and accessibility tagmentation (scCPA-Tag), a multi-modal single-cell epigenetic profile capturing technique based on barcoded Tn5 transposases and a droplet microfluidics platform. scCPA-Tag enables the simultaneous capture of DNA profiles of histone modification and chromatin accessibility in the same cell.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;By applying scCPA-Tag to K562 cells and a hepatocellular carcinoma (HCC) sample, we found that the silence of several chromatin-accessible genes can be attributed to lysine-27-trimethylation of the histone H3 tail (H3K27me3) modification. We characterized the epigenetic features of the tumour cells and different immune cell types in the HCC tumour tissue by scCPA-Tag. Besides, a tumour cell subtype (C2) with more aggressive features was identified and characterized by high chromatin accessibility and a lower abundance of H3K27me3 on tumour-promoting genes.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusions&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Our multi-modal scCPA-Tag provides a comprehensive approach for exploring the epigenetic landscapes of heterogeneous cell types and revealing the mechanisms of gene expression regulation during developmental and pathological processes at the single-cell level.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Highlights&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ul&gt;\u0000 \u0000 &lt;li&gt;scCPA-Tag offers a highly efficient and high throughput technique to simultaneously profile histone modification and chromatin accessibility within a single cell.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;scCPA-Tag enables to uncover multiple epigenetic modification features of cellular compositions within tumor tissues.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;scCPA-Tag facilitates the exploration of the epigenetic landscapes of heterogeneous cell types and provides the mechanisms governing gene expression regulation.&lt;/li&gt;\u0000 &lt;/ul&gt;\u0000 ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 9","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70000","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142100455","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":"Ecological and evolutionary dynamics to design and improve ovarian cancer treatment","authors":"Grace Y. Q. Han,&nbsp;Monica Alexander,&nbsp;Julia Gattozzi,&nbsp;Marilyn Day,&nbsp;Elayna Kirsch,&nbsp;Narges Tafreshi,&nbsp;Raafat Chalar,&nbsp;Soraya Rahni,&nbsp;Gabrielle Gossner,&nbsp;William Burke,&nbsp;Mehdi Damaghi","doi":"10.1002/ctm2.70012","DOIUrl":"https://doi.org/10.1002/ctm2.70012","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>Ovarian cancer ecosystems are exceedingly complex, consisting of a high heterogeneity of cancer cells. Development of drugs such as poly ADP-ribose polymerase (PARP) inhibitors, targeted therapies and immunotherapies offer more options for sequential or combined treatments. Nevertheless, mortality in metastatic ovarian cancer patients remains high because cancer cells consistently develop resistance to single and combination therapies, urging a need for treatment designs that target the evolvability of cancer cells. The evolutionary dynamics that lead to resistance emerge from the complex tumour microenvironment, the heterogeneous populations, and the individual cancer cell's plasticity. We propose that successful management of ovarian cancer requires consideration of the ecological and evolutionary dynamics of the disease. Here, we review current options and challenges in ovarian cancer treatment and discuss principles of tumour evolution. We conclude by proposing evolutionarily designed strategies for ovarian cancer, with the goal of integrating such principles with longitudinal, quantitative data to improve the treatment design and management of drug resistance.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points/Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>\u0000 <p>Tumours are ecosystems in which cancer and non-cancer cells interact and evolve in complex and dynamic ways.</p>\u0000 </li>\u0000 \u0000 <li>\u0000 <p>Conventional therapies for ovarian cancer inevitably lead to the development of resistance because they fail to consider tumours’ heterogeneity and cellular plasticity.</p>\u0000 </li>\u0000 \u0000 <li>\u0000 <p>Eco-evolutionarily designed therapies should consider cancer cell plasticity and patient-specific characteristics to improve clinical outcome and prevent relapse.</p>\u0000 </li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 9","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70012","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142100452","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":"CLINICAL AND TRANSLATIONAL MEDICINE","authors":"","doi":"10.1002/ctm2.1820","DOIUrl":"https://doi.org/10.1002/ctm2.1820","url":null,"abstract":"","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 9","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.1820","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142089844","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":"Advances in understanding the immunity of the brain and its borders: Focus on brain macrophages","authors":"Patrick Süß,&nbsp;Martin Diebold,&nbsp;Roman Sankowski","doi":"10.1002/ctm2.70014","DOIUrl":"10.1002/ctm2.70014","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>A recent study outlines the phenotypes of brain border region macrophages in developing, normal and glioblastoma-affected brains. For the first time, the authors show in-vivo turnover of human brain border macrophages. The findings have implications for the understanding of brain border immunity and potential macrophage targeting therapies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> keypoints</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Human border region macrophages are distinct from microglia.</li>\u0000 \u0000 <li>These distinct phenotypes are established early during embryonal development - Brain border macrophages are partially replaced by bone marrow-derived myeloid cells.</li>\u0000 \u0000 <li>The transcriptional phenotypes of glioblastoma-associated macrophage are determined by the anatomical region.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 9","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70014","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142079335","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":"Effect of oral faecal microbiota transplantation intervention for children with autism spectrum disorder: A randomised, double-blind, placebo-controlled trial","authors":"Lin Wan,&nbsp;Huan Wang,&nbsp;Yan Liang,&nbsp;Xun Zhang,&nbsp;Xinyun Yao,&nbsp;Gang Zhu,&nbsp;Jun Cai,&nbsp;Guoyin Liu,&nbsp;Xinting Liu,&nbsp;Qianqian Niu,&nbsp;Siwen Li,&nbsp;Bo Zhang,&nbsp;Jing Gao,&nbsp;Jing Wang,&nbsp;Xiuyu Shi,&nbsp;Linyan Hu,&nbsp;Xiaoyan Liu,&nbsp;Zhiyong Zou,&nbsp;Guang Yang","doi":"10.1002/ctm2.70006","DOIUrl":"10.1002/ctm2.70006","url":null,"abstract":"&lt;p&gt;To the Editor:&lt;/p&gt;&lt;p&gt;We conducted a randomised, double-blind, placebo-controlled trial of an oral faecal microbiota transplantation (FMT) intervention in children with autism spectrum disorder (ASD), and observed that there were differences in pre- and post-FMT intervention changes in the social domain scores of the Vineland Adaptive Behaviour Scale, third version (Vineland-3), with no severe adverse events (AEs) related to FMT occurring.&lt;/p&gt;&lt;p&gt;Multiple studies have documented variations in the gut microbiota (GM) between children with ASD and typically developing children.&lt;span&gt;&lt;sup&gt;1, 2&lt;/sup&gt;&lt;/span&gt; Furthermore, specific gut microbes may modulate ASD-related behaviour through their metabolites.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; However, another study proposed that the GM is not the central driver of ASD symptoms; rather, the presence of restricted interests associated with ASD and a more limited dietary variety have been linked to reduced diversity in the GM.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; The relationship between the GM and ASD remains enigmatic and complex as the age-old philosophical conundrum that has long been debated: which came first, the chicken or the egg? Some open-label studies&lt;span&gt;&lt;sup&gt;4-6&lt;/sup&gt;&lt;/span&gt; have demonstrated that FMT improved the core symptoms of patients with ASD, though these studies lacked comparable control groups, which may lead to disregard of potential placebo effects on efficacy evaluation. Therefore, we conducted this study.&lt;/p&gt;&lt;p&gt;A total of 103 eligible participants (Figure 1) were enrolled and randomised to receive either FMT or a placebo. These agents were administered during two 6-day periods in the hospital, the first occurring in the initial week and the second in the fifth week of the study. Patients were not hospitalised during the interval between treatments. FMT capsules from five healthy donors were randomly provided to 8, 8, 11, 7 and 18 patients, respectively, with each patient receiving capsules from the same donor throughout the treatment process. The Social Responsiveness Scale, Second Edition (SRS-2), Vineland-3, and Autism Behaviour Checklist (ABC) scales were administered to measure outcomes before the start of the treatment as well as at Weeks 9 and 17 of the experiment for repeated measures (see Appendix S1).&lt;/p&gt;&lt;p&gt;The primary outcome was the difference in the change in the SRS-2 &lt;i&gt;T&lt;/i&gt;-score between groups from baseline to Week 9 or Week 17, analysed using a mixed model for repeated measures. The secondary outcomes included Vineland-3 and ABC scores. Sensitivity analysis was conducted by comparing the changes in the scores of these scales between the FMT group with a donor gut microbiota colonisation rate of ≥20% or less than 20% and the placebo group. AEs were assessed (see Appendix S1).&lt;/p&gt;&lt;p&gt;No notable between-group differences were detected between the FMT (&lt;i&gt;n&lt;/i&gt; = 52) and placebo (&lt;i&gt;n&lt;/i&gt; = 51) groups in terms of demographic and baseline characteristics or scales (Appendix S1; Tables S1 and","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 9","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70006","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142072152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A severe asthma phenotype of excessive airway Haemophilus influenzae relative abundance associated with sputum neutrophilia","authors":"Ali Versi,&nbsp;Adnan Azim,&nbsp;Fransiskus Xaverius Ivan,&nbsp;Mahmoud I Abdel-Aziz,&nbsp;Stewart Bates,&nbsp;John Riley,&nbsp;Mohib Uddin,&nbsp;Nazanin Zounemat Kermani,&nbsp;Anke-H Maitland-Van Der Zee,&nbsp;Sven-Eric Dahlen,&nbsp;Ratko Djukanovic,&nbsp;Sanjay H Chotirmall,&nbsp;Peter Howarth,&nbsp;Ian M Adcock,&nbsp;Kian Fan Chung,&nbsp;the U-BIOPRED study group","doi":"10.1002/ctm2.70007","DOIUrl":"10.1002/ctm2.70007","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Severe asthma (SA) encompasses several clinical phenotypes with a heterogeneous airway microbiome. We determined the phenotypes associated with a low α-diversity microbiome.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Metagenomic sequencing was performed on sputum samples from SA participants. A threshold of 2 standard deviations below the mean of α-diversity of mild-moderate asthma and healthy control subjects was used to define those with an abnormal abundance threshold as relative dominant species (RDS).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Findings</h3>\u0000 \u0000 <p>Fifty-one out of 97 SA samples were classified as RDSs with <i>Haemophilus influenzae</i> RDS being most common (<i>n</i> = 16), followed by <i>Actinobacillus unclassified</i> (<i>n</i> = 10), <i>Veillonella unclassified</i> (<i>n</i> = 9)<i>, Haemophilus aegyptius</i> (<i>n</i> = 9)<i>, Streptococcus pseudopneumoniae</i> (<i>n = 7</i>), <i>Propionibacterium acnes</i> (<i>n = 5), Moraxella catarrhalis</i> (<i>n </i>=<i> 5</i>) and <i>Tropheryma whipplei</i> (<i>n</i> = 5). <i>Haemophilus influenzae</i> RDS had the highest duration of disease, more exacerbations in previous year and greatest number on daily oral corticosteroids. Hierarchical clustering of RDSs revealed a C2 cluster (<i>n</i> = 9) of highest relative abundance of exclusively <i>Haemophilus influenzae</i> RDSs with longer duration of disease and higher sputum neutrophil counts associated with enrichment pathways of MAPK, NF-κB, TNF, mTOR and necroptosis, compared to the only other cluster, C1, which consisted of 7 <i>Haemophilus influenzae</i> RDSs out of 42. Sputum transcriptomics of C2 cluster compared to C1 RDSs revealed higher expression of neutrophil extracellular trap pathway (NETosis), IL6-transignalling signature and neutrophil activation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>We describe a <i>Haemophilus influenzae</i> cluster of the highest relative abundance associated with neutrophilic inflammation and NETosis indicating a host response to the bacteria. This phenotype of severe asthma may respond to specific antibiotics.</p>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 9","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70007","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142072151","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 co-location of CD14+APOE+ cells and MMP7+ tumour cells contributed to worse immunotherapy response in non-small cell lung cancer","authors":"Guangyu Fan,&nbsp;Tongji Xie,&nbsp;Le Tang,&nbsp;Lin Li,&nbsp;Xiaohong Han,&nbsp;Yuankai Shi","doi":"10.1002/ctm2.70009","DOIUrl":"10.1002/ctm2.70009","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>Intra-tumour immune infiltration is a crucial determinant affecting immunotherapy response in non-small cell lung cancer (NSCLC). However, its phenotype and related spatial structure have remained elusive. To overcome these restrictions, we undertook a comprehensive study comprising spatial transcriptomic (ST) data (28 712 spots from six samples). We identified two distinct intra-tumour infiltration patterns: immune exclusion (characterised by myeloid cells) and immune activation (characterised by plasma cells). The immune exclusion and immune activation signatures showed adverse and favourable roles in NSCLC patients' survival, respectively. Notably, CD14+APOE+ cells were recognised as the main cell type in immune exclusion samples, with increased epithelial‒mesenchymal transition and decreased immune activities. The co-location of CD14+APOE+ cells and MMP7+ tumour cells was observed in both ST and bulk transcriptomics data, validated by multiplex immunofluorescence performed on 20 NSCLC samples. The co-location area exhibited the upregulation of proliferation-related pathways and hypoxia activities. This co-localisation inhibited T-cell infiltration and the formation of tertiary lymphoid structures. Both CD14+APOE+ cells and MMP7+ tumour cells were associated with worse survival. In an immunotherapy cohort from the ORIENT-3 clinical trial, NSCLC patients who responded unfavourably exhibited higher infiltration of CD14+APOE+ cells and MMP7+ tumour cells. Within the co-location area, the MK, SEMA3 and Macrophage migration inhibitory factor (MIF) signalling pathway was most active in cell‒cell communication. This study identified immune exclusion and activation patterns in NSCLC and the co-location of CD14+APOE+ cells and MMP7+ tumour cells as contributors to immune resistance.</p>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 9","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70009","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142072153","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":"Multi-omics integration reveals the oncogenic role of eccDNAs in diffuse large B-cell lymphoma through STING signalling","authors":"Zijuan Wu,&nbsp;Wei Zhang,&nbsp;Luqiao Wang,&nbsp;Jiayan Leng,&nbsp;Yongle Li,&nbsp;Zhou Fan,&nbsp;Mengtao Zhan,&nbsp;Lei Cao,&nbsp;Yongning Jiang,&nbsp;Yan Jiang,&nbsp;Bing Sun,&nbsp;Jianxin Fu,&nbsp;Jianyong Li,&nbsp;Wenyu Shi,&nbsp;Hui Jin","doi":"10.1002/ctm2.1815","DOIUrl":"10.1002/ctm2.1815","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Extrachromosomal circular DNAs (eccDNAs), a type of double-stranded DNAs (dsDNAs) that facilitate the activation of the DNA sensing machinery, have been implicated in the progression and prognosis of various diseases. While the roles of eccDNAs remain contentious, their significance in diffuse large B-cell lymphoma (DLBCL) has not been reported.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Circular DNA sequencing (circle-seq) was used to demonstrate the expression profile of eccDNAs in DLBCL, and atomic force microscopy to validate the presence of eccDNAs. CCK-8 and scRNA-seq techniques were employed to uncover the activation of eccDNA in the STING pathway, leading to enhanced cell proliferation. Chemotherapeutic drugs were used to test the hypothesis that DNA damage induces the production of eccDNA, thereby activating the STING pathway independent of cGAS. GEO databases were used for verification of the prognosis of the eccDNA-related genes, and animal models were used to investigate the synergistic effects of DNA damage therapy in combination with STING inhibitors on anti-tumour responses.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;EccDNAs were widely expressed in DLBCL and associated with the prognosis of patients. Elevated abundance of eccDNAs promoted the progression of DLBCL. Chemotherapeutic drugs-induced DNA damage triggered the generation of eccDNAs, resulting in the activation of the STING signalling in a cGAS-independent manner. Moreover, inhibition of STING exerted a synergistic anti-tumour effect with cisplatin.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusions&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;EccDNAs induced by DNA damage exert an oncogenic role in DLBCL via activating the STING signalling independently of cGAS. This finding offers a rational therapeutic strategy combining chemotherapy with targeting STING.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Highlights&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ul&gt;\u0000 \u0000 &lt;li&gt;EccDNAs induced by DNA damage exert an oncogenic role in DLBCL via activating the STING signalling independently of cGAS.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;The combined treatment of chemotherapeutic drugs with STING inhibitor significantly delayed the tumor progression, providing new insights into the therapeutic strategy for patients with DLBCL, particularly the relapsed and/or refractory (R/R) ones.&lt;/li&gt;\u0000 &lt;/ul&gt;\u0000 &lt;/div&gt;\u0000 &lt;/section&gt;\u0000 ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 8","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.1815","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142055108","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}