Clinical and Translational Medicine最新文献

{"title":"Decidualised endometrial stromal cell-derived extracellular vesicles induce bystander decidualisation and cAMP-mediated attenuation of natural killer cell cytotoxicity","authors":"Maryam Mousavi, Negar Vanaki, Kayhan Zarnani, Zahra Aghazadeh, Soheila Arefi, Jila Abedi-Asl, Fazel Shokri, Seyed-Alireza Razavi, Amir-Hassan Zarnani","doi":"10.1002/ctm2.70500","DOIUrl":"https://doi.org/10.1002/ctm2.70500","url":null,"abstract":"<p>Dear Editor,</p><p>Decidualisation, the process of differentiation of endometrial stromal cells (EnSCs) into secretory decidual cells, is fundamental to blastocyst implantation and endometrial immune modulation. Defective decidualisation has been closely linked to implantation failure and miscarriage. Decidualisation triggers a metabolic and immunomodulatory shift in EnSCs, enabling them to regulate uterine natural killer (NK) cells and T cells.<span><sup>1</sup></span></p><p>Understanding how decidual cell signalling influences neighbouring uterine cells is critical for elucidating key adaptations in early pregnancy, particularly maternal‒foetal crosstalk. A growing body of evidence highlights extracellular vesicles (EVs) as a novel axis of cell to cell communication, playing a pivotal role in tissue homeostasis and immune regulation.<span><sup>2</sup></span> Here, we sought metabolic reprograming of EnSCs during decidualisation and unrevealed new aspects of endometrial EVs by showing that EVs from decidualised endometrial stromal cells (D-EnSCs-EVs) induce decidualisation in neighbouring cells and modulate NK cell function.</p><p>Here, EnSCs were isolated from luteal-phase endometrial biopsies and characterised (Figure S1). Metabolome analysis of isolated cells demonstrated that decidualisation significantly alters the amino acid metabolome of EnSCs, effectively distinguishing undecidualised (uD) from decidualised (D) EnSCs by days 4 and 6 of decidualisation (Figure 1A,B). Cluster analysis revealed greater similarity in metabolomic profiles of late-stage D-EnSCs compared to earlier time points (Figure 1C). Metabolite analysis revealed methionine (Met) and phenylalanine (Phe) as key discriminators between uD-EnSCs and D-EnSCs (Figure 1D), and showed a coordinated shift in amino acid metabolism that may underpin the functional transformation of EnSCs during decidualisation (days 2–6; Figure 1E,F). Decidualised stromal cells are known to support decidual NK (dNK) cell generation from peripheral blood NK cells via secretion of transforming growth factor beta (TGF-β), interleukin (IL)-1β and IL-15.<span><sup>1</sup></span> Our finding that decidualisation induces methionine production provides a novel metabolic underpinning for this process, aligning with methionine's established epigenetic role in regulating IL-5 transcription and promoting endometrial receptivity.<span><sup>3</sup></span> Based on GLUT1 expression, it is thought that decidualisation relies on glucose metabolism.<span><sup>4</sup></span> Our findings, however, demonstrated that the process was characterised by a reduction in glucose consumption and lactate production (Figure 1G), consistent with lower proliferation capacity of D-EnSCs compared to uD-EnSCs (Figure S2). Notably, high cyclic adenosine monophosphate (cAMP) concentration (.5 mM, as used in this study) suppress GLUT1 expression.<span><sup>5</sup></span> Furthermore, decidualisation led to sustained pro-inflammatory cy","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 10","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70500","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145273033","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":"CircHPCAL1 promotes the progression of pancreatic cancer via the regulation of STEAP2","authors":"Xiaomeng He, Yang Di, Lixiang Sun, Wenchuan Wu, Zehuan Li, Qiuyue Li, Shanshan Liu, Mengting Luo, Xin Zhang, Li Xu, Xiaoyan Zhang, Jianqing Xu, Christopher Corpe, Jin Wang","doi":"10.1002/ctm2.70501","DOIUrl":"10.1002/ctm2.70501","url":null,"abstract":"<p>Dear Editor,</p><p>Pancreatic cancer (PaCa) has emerged as the fourth leading cause of cancer-related mortality, accounting for approximately 8% of all cancer deaths globally.<span><sup>1</sup></span> This high mortality rate is attributed primarily to the late diagnosis of PaCa due to the absence of discernible early symptoms.<span><sup>2</sup></span> Circular RNAs (circRNAs) play pivotal roles in various cellular biological processes and have emerged as promising diagnostic biomarkers and therapeutic targets.<span><sup>3-6</sup></span> The crucial roles of circRNAs in processes such as cell proliferation, migration and invasion have been identified in many cancer cells.<span><sup>7-9</sup></span> Accumulating evidence has revealed that circRNAs are involved in PaCa progression and have shown promise as diagnostic biomarkers for PaCa.<span><sup>10</sup></span></p><p>In this study, we revealed that a novel circRNA (circHPCAL1) identified in the plasma of patients with PaCa using high-throughput circRNA sequencing was also upregulated in pancreatic tumour tissues compared with that in adjacent normal tissues from 78 PaCa patients (Figure 1A). Similarly, a panel of PaCa cell lines (BxPC-3, CFPAC-1, AsPC-1, PANC-1 and KP-3) presented higher expression levels of circHPCAL1 than normal HPNE cell did (Figure 1B). Because circHPCAL1 originates from exon 1 and a portion of the 5′ untranslated region of the HPCAL1 gene, we designed specific divergent and convergent primers for PCR amplification (Figure 1C) and found that circRNAs could be amplified by both divergent and convergent primers, whereas genomic DNA could be amplified via only convergent primers. RNA fluorescence in situ hybridisation analysis revealed that circHPCAL1 is predominantly localised in the cytoplasm of BxPC-3 and PANC-1 cells (Figure 1D). Upregulation of circHPCAL1 significantly increased the proliferation and viability of BxPC-3 and PANC-1 cells, whereas si-circHPCAL1 inhibited PaCa cell growth (Figure 1E,F). The colony-forming ability of BxPC-3 and PANC-1 cells was significantly augmented by circHPCAL1 upregulation and impaired by the circHPCAL1 inhibitor (Figure 1I–K). The migration and invasion abilities of BxPC-3 and PANC-1 cells were also analysed via wound healing (Figure S1A–C) and Transwell (Figure 1L,M) assays. We also treated BxPC-3 and PANC-1 cells with gemcitabine and found that overexpression of circHPCAL1 attenuated the sensitivity of BxPC-3 (IC<sub>50</sub> = 2.093 µM) and PANC-1 (IC<sub>50</sub> = 15.610 µM) cells to gemcitabine, whereas si-circHPCAL1 increased their sensitivity (BxPC-3: IC<sub>50 </sub>= 0.694 µM; PANC-1: IC<sub>50 </sub>= 3.986 µM) (Figure 1G,H).</p><p>To identify potential target miRNAs of circHPCAL1, 11 overlapping candidate miRNAs were selected via starBase, circBank, and circRNA interactome analyses (Figure 2A). Overexpression of circHPCAL1 led to decreased expression of miR-671-5p, miR-338-3p, and miR-7-5p in BxPC-3 and PANC-1 cells, wherea","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 10","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70501","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145249982","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":"MUC1 drives ferroptosis resistance in ICC via Src-mediated FSP1 deubiquitination and myristoylation","authors":"Yuqiao Zhao, Shifeng Yang, Lei Huang, Xuyun Liu, Qixiang Han, Qichao Niu, Siyi Li, Chuanlie Zhou, Boshi Sun, Yanmei Yang, Xinyu Zhang","doi":"10.1002/ctm2.70495","DOIUrl":"10.1002/ctm2.70495","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Intrahepatic cholangiocarcinoma (ICC) exhibits poor prognosis and limited therapeutic options. Ferroptosis represents a promising therapeutic strategy, yet resistance mechanisms remain poorly understood. This study investigated the role of mucin 1 (MUC1) in regulating ferroptosis sensitivity in ICC.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Bioinformatic analyses of GEO and TCGA datasets identified ferroptosis-related factors in ICC. MUC1 expression was validated in ICC cell lines and clinical specimens. Ferroptosis sensitivity was assessed through RSL3-induced cell death assays, lipid peroxidation measurements, and iron detection. Mechanistic studies employed immunoprecipitation-mass spectrometry, co-immunoprecipitation, kinase assays, and deubiquitination assays. In vivo efficacy was evaluated using subcutaneous tumor models.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>MUC1 was identified as a critical ferroptosis suppressor in ICC. MUC1 overexpression conferred RSL3 resistance by inhibiting lipid peroxidation and reducing ferrous iron accumulation, independent of the GPX4-glutathione pathway. Mechanistically, MUC1 recruited Src kinase, which phosphorylated deubiquitinating enzyme ubiquitin-specific protease 10 (USP10) at tyrosines 359 and 364, enhancing ferroptosis suppressor protein 1 (FSP1) deubiquitination at lysine 246 and stabilizing FSP1 protein. Concurrently, Src phosphorylated N-myristoyltransferase 1 (NMT1) at tyrosine 41, augmenting FSP1 membrane localization through myristoylation. This dual mechanism potentiated the FSP1- coenzyme Q10 (CoQ10) antioxidant system. MUC1 knockdown significantly enhanced ferroptotic sensitivity in vitro and suppressed tumor growth in vivo.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>MUC1 orchestrates ferroptosis resistance in ICC through the Src-USP10/NMT1-FSP1 axis. Targeting this signaling cascade represents a potential therapeutic strategy for overcoming ferroptosis resistance in ICC.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>MUC1 suppresses ferroptosis in ICC via Src-mediated post-translational modifications.</li>\u0000 \u0000 <li>Src phosphorylation of USP10 stabilizes FSP1 by removing K48-linked polyubiquitin.</li>\u0000 \u0000 <li>Src activates NMT1 to enhance FSP1 myristoylation and membrane localization.</li","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 10","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70495","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145257516","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":"Role of tertiary lymphoid structures in the tumour microenvironment and immunotherapy response of renal cell carcinoma","authors":"Lin Yang,&nbsp;Wentai Shangguan,&nbsp;Weijia Li,&nbsp;Wenxue Huang,&nbsp;Zhuohang Li,&nbsp;Boyuan Sun,&nbsp;Cunzhen Ma,&nbsp;Xunguo Yang,&nbsp;Bisheng Cheng,&nbsp;Peng Wu","doi":"10.1002/ctm2.70455","DOIUrl":"10.1002/ctm2.70455","url":null,"abstract":"<p>In the tumour microenvironment (TME) of renal cell carcinoma (RCC), tertiary lymphoid structures (TLS) play a crucial role in anti-tumour immune responses. Resembling secondary lymphoid organs, TLS comprises B cells, T cell zones, high endothelial venules, and antigen-presenting cells, facilitating local immune activation. While TLS has shown correlations with improved immune checkpoint inhibitors (ICIs) outcomes in other cancers, its role in RCC is still under investigation. Emerging evidence indicates that mature TLS enhances anti-tumour activity by activating T and B cells, whereas immature TLS may contribute to immune suppression. The RCC TME is highly immunosuppressive, marked by regulatory T cells, myeloid-derived suppressor cells, and elevated pro-angiogenic and immunosuppressive cytokines. In this context, TLS, particularly mature TLS, can counteract immunosuppression, boost local immune responses, and improve ICIs efficacy. However, TLS in RCC is heterogeneous, with their formation and function affected by factors like CXCL13 expression. The presence, maturity, and functionality of TLS may serve as valuable predictors of ICIs response and patient prognosis. Further research is required to understand TLS regulation and leverage their potential to enhance personalised immunotherapy for RCC.</p>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 10","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12498089/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145231565","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":"Cardiomyocyte USP20 alleviates septic cardiomyopathy by deubiquitinating and inhibiting NLRP3 activity","authors":"Shanshan Dai,&nbsp;Yucong Zhang,&nbsp;Ziyi Huang,&nbsp;Yunxuan Chen,&nbsp;Zexin Yang,&nbsp;Ruihan Zheng,&nbsp;Keke Ye,&nbsp;Lingfeng Zhong,&nbsp;Xiangtao Zheng,&nbsp;Xueli Cai,&nbsp;Weijian Huang","doi":"10.1002/ctm2.70494","DOIUrl":"10.1002/ctm2.70494","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Objectives&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Although extensive research on septic cardiomyopathy has been conducted, effective therapies are still limited. Ubiquitin-specific peptidase 20 (USP20), a deubiquitinating enzyme, is critical in regulating protein ubiquitination and various cellular processes. whether USP20 is involved in the pathogenesis of septic cardiomyopathy remains unclear. This study investigated the impact of USP20 on septic cardiomyopathy.&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;The cardiomyocyte-specific USP20 knockout mice (USP20CKO) and NLRP3 knockout mice (NLRP3-/-) were used in the present study. A sepsis mouse model was established using lipopolysaccharide (LPS) administration and the cecal ligation and puncture (CLP) procedure. Recombinant adeno-associated virus serotype 9 (AAV9) was used to achieve overexpression of USP20. Myocardial function, histopathological changes, and pyroptosis levels in heart tissues were evaluated. Liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis and co-immunoprecipitation (co-IP) were performed to identify the molecular mechanism of USP20 in septic cardiomyopathy.&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;Our results showed that USP20 was downregulated in the myocardium of septic mice. Cardiomyocyte-specific USP20 deficiency worsened myocardial injury and cardiac dysfunction induced by LPS and CLP. LC-MS/MS analysis and co-IP revealed NLRP3 as a substrate protein of USP20. Mechanistically, USP20 removed K63-linked ubiquitin from K243 via its active site C154, inhibiting NLRP3's interaction with ASC and suppressing its activation and subsequent pyroptosis. Moreover, overexpressing USP20 in cardiomyocytes reduced LPS-induced myocardial injury. Additionally, the protective effect of USP20 against LPS-induced damage was nullified in the absence of NLRP3 in mice.&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;These findings suggest that cardiomyocyte-derived USP20 is crucial in septic cardiomyopathy progression and may serve as a novel therapeutic target for managing septic cardiomyopathy.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Key points&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ul&gt;\u0000 \u0000 &lt;li&gt;Cardiomyocyte-derived USP20 is crucial in septic cardiomyopathy progression.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;NLRP3 is identified as a substrate protein of USP20.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;USP20 deubiquitinates NLRP3 by remo","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 10","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70494","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145211958","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":"DNA-mediated UCP1 overexpression in adipose tissue: A promising anti-obesity gene therapy","authors":"Ze-Wei Zhao,&nbsp;Longyun Hu,&nbsp;Bigui Song,&nbsp;Qian Wu,&nbsp;Jiejing Lin,&nbsp;Qingqing Liu,&nbsp;Siqi Liu,&nbsp;Jin Li,&nbsp;Molin Wang,&nbsp;Jin Li,&nbsp;Zhonghan Yang","doi":"10.1002/ctm2.70491","DOIUrl":"10.1002/ctm2.70491","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;Obesity has emerged as a global health challenge. Although GLP-1 receptor agonists are showing considerable promise in weight loss, their clinical utility is partly limited by gastrointestinal adverse reactions and non-fat weight loss side effects. UCP1-mediated adipose thermogenesis is a critical process for body temperature maintenance and weight management. However, the lack of effective and specific adipose thermogenesis therapies has restricted its clinical application. We aimed to explore the potential of inducing adipose-specific UCP1 overexpression via modified plasmids as an innovative therapeutic approach for obesity.&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;We replaced the cytomegalovirus (CMV) promoter in the plasmids with two types of adipose-specific promoters: mouse adiponectin (mADP) promoter and human adiponectin (hADP) promoter, to selectively overexpress UCP1 in adipocytes. The expression level of UCP1, weight loss, metabolic homeostasis and adipose thermogenesis effects were evaluated by immunohistochemistry, western blot, weight measurements, thermography, and comprehensive lab animal monitoring system.&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;The experiments demonstrated that the mADP promoter-modified plasmids failed to drive UCP1 overexpression. In contrast, the hADP promoter-modified &lt;i&gt;Ucp1&lt;/i&gt; overexpression (hADP-&lt;i&gt;Ucp1&lt;/i&gt; OE) plasmids achieved robust adipose-specific UCP1 protein expression both in vitro and in vivo. In vitro experiments revealed that delivery of the hADP promoter-modified &lt;i&gt;UCP1&lt;/i&gt; overexpression (hADP-&lt;i&gt;UCP1&lt;/i&gt; OE) plasmids reduced lipid droplet size and enhanced energy consumption in human adipocytes. In obese mice, administration of the hADP-&lt;i&gt;Ucp1&lt;/i&gt; OE plasmids resulted in significant weight loss and improved metabolic homeostasis.&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;These findings highlight the therapeutic potential of hADP-&lt;i&gt;UCP1&lt;/i&gt; OE plasmids in obesity management.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Key points&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ul&gt;\u0000 \u0000 &lt;li&gt;The hADP promoter-modified plasmids selectively overexpress protein in adipose tissue.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Overexpression of UCP1 driven by hADP promoter induces thermogenesis in mouse and human adipocytes in vitro.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;The hADP-&lt;i&gt;Ucp1&lt;/i&gt; OE treatment promotes","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 10","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70491","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145211927","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":"Dynamics of the intratumoural microbiome across malignant transformation and treatment in breast cancer","authors":"Liuliu Quan,&nbsp;Mengwu Shi,&nbsp;Zixuan Yang,&nbsp;Huiteng Rong,&nbsp;Jingyi Zhou,&nbsp;Die Sang,&nbsp;Jing Xu,&nbsp;Jian Yue,&nbsp;Shuyue Chen,&nbsp;Jingsong Liu,&nbsp;Peng Yuan","doi":"10.1002/ctm2.70492","DOIUrl":"10.1002/ctm2.70492","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>Breast cancer (BC) is the most common malignancy in women, yet the dynamics of the intratumoural microbiome during tumour initiation, progression, and treatment remain poorly understood. Prior studies are predominantly cross-sectional and limited by indirect microbial inference from RNA-seq data. This study presents a comprehensive analysis of intratumoural microbiota across breast tissue samples by high-depth 16S rRNA sequencing (11 W tags), featuring two longitudinally paired cohorts for dynamic microbial profiling during tumour progression and treatment. Samples included 165 benign nodules (82 non-transforming, 83 that later progressed to cancer with matched malignant tissues); 180 primary BC tissues and 165 benign controls; and 101 neoadjuvant therapy (NAT) specimens (15 pCR, 86 non-pCR, with paired pre/post-treatment samples). We identified a cluster of taxa (Aeromicrobium, Halomonas, Dietzia, Nesterenkonia, Delftia, Nitriliruptor) depleted in nodules undergoing malignant transformation, declining with disease progression and partially restored after NAT, with transient enrichment early in transformation. Opposing trends were observed for <i>Paenibacillus</i> and <i>Methyloversatilis</i>. These changes corresponded to shifts in amino acid, lipid, and glycan metabolism. FISH and TEM analyses identified <i>Paenibacillus pasadenensis</i> and <i>Halomonas hamiltonii</i> within tumour cells, with opposing effects on tumour proliferation and activation. In addition, we developed two predictive models with high clinical relevance: one stratifying malignancy risk in nodules, and another predicting NAT response, both of which achieved strong performance in external validation. This longitudinal characterisations of intratumoural microbiota during breast tumourigenesis and treatment offer novel insights for precision oncology and microbiome-based interventions in breast cancer.</p>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 10","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12485822/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145198654","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":"Soluble IL-2R: A potential therapeutic target for mitochondrial dysfunction in post-COVID fatigue syndrome.","authors":"Laura P Brown, Jai Joshi, Kate Kosmac, Douglas E Long, Logan Scott, Salim El-Amouri, Ashley A Montgomery-Yates, Anna G Kalema, Jamie L Sturgill, Hemendra Vekaria, Patrick G Sullivan, Dylan Wilburn, Panagiotis Koutakis, Christine M Latham, Christopher S Fry, Philip A Kern, Benjamin F Miller, Esther E Dupont-Versteegden, Ahmed Ismaeel, Kirby P Mayer, Yuan Wen","doi":"10.1002/ctm2.70507","DOIUrl":"10.1002/ctm2.70507","url":null,"abstract":"","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 10","pages":"e70507"},"PeriodicalIF":6.8,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12516084/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145279031","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":"Large-scale DNA methylation profiling of urological cancers identifies shared and cancer-specific methylation signatures, and reveals differentially activated pathways for therapeutic targeting.","authors":"Vera Constâncio, João Lobo, Antonio Gomez, João Ramalho-Carvalho, Isa Carneiro, Rui Freitas, Manuel Esteller, Rui Henrique, Carmen Jerónimo","doi":"10.1002/ctm2.70488","DOIUrl":"10.1002/ctm2.70488","url":null,"abstract":"","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 10","pages":"e70488"},"PeriodicalIF":6.8,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12518500/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145285620","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":"Immune cell subset profiling and metabolic dysregulation define the divergent immune microenvironments in HIV immunological non-responders.","authors":"Qingfei Chu, Ningye Fang, Huanhuan Chen, Abdur Rashid, Xia Luo, Jianjun Li, Kang Li","doi":"10.1002/ctm2.70498","DOIUrl":"10.1002/ctm2.70498","url":null,"abstract":"<p><strong>Background: </strong>A subset of people living with HIV (PLWH) exhibit poor immune recovery despite effective antiretroviral therapy (ART), remaining at risk of disease progression. The immunometabolic mechanisms underlying this immunological non-response remain unclear.</p><p><strong>Methods: </strong>We integrated transcriptomic and immunophenotypic approaches to characterise immune differences between immunological responders (IRs) and non-responders (INRs). Public datasets were analysed to identify differentially expressed genes (DEGs), followed by enrichment analysis, predictive modelling, immune infiltration assessment, and regulatory network construction. In parallel, flow cytometry was performed to assess T and B cell subsets in an independent cohort including IRs, INRs, treatment-naïve patients (TNPs), and healthy controls (HCs).</p><p><strong>Results: </strong>DEGs between IRs and INRs were enriched in mitochondrial and ribosomal pathways. INRs showed reduced Th1, Th17, and Tfh cells, alongside increased markers of immune activation and exhaustion. Predictive modelling identified five hub genes (ATP5O, PIGY, UQCRQ, COX7C, and BLVRB) associated with immune recovery, and clustering based on their expression defined two transcriptionally distinct subtypes. Flow cytometry further confirmed that INRs exhibited diminished CD4⁺ T cell counts, increased PD-1⁺ and HLA-DR⁺ expression, and reduced resting memory B cells, reflecting persistent immune dysfunction.</p><p><strong>Conclusions: </strong>This study underscores the pivotal role of immunometabolic dysregulation in shaping heterogeneous immune responses to ART. By integrating computational and experimental data, we identified key biomarkers and regulatory pathways associated with immune recovery. Our findings highlight the central influence of metabolic processes on immune restoration outcomes and propose personalised metabolic interventions as a promising strategy to enhance therapeutic efficacy in HIV-infected individuals.</p>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 10","pages":"e70498"},"PeriodicalIF":6.8,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12518780/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145285652","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}