Clinical and Translational Medicine最新文献

{"title":"Arginase 2 deficiency mitigates sepsis-associated acute kidney injury by alleviating lipid accumulation","authors":"Yu Xin, Yanqi Liu, Ning Zhang, Pengfei Huang, Qianqian Zhang, Yinghao Luo, Xinran Wang, Xiuhua Zhang, Tao Wu, Fengye Liu, Yu Xiao, Lifeng Shen, Weiting Zhang, Xibo Wang, Xianglin Meng, Yuping Bai, Xuan Wang, Nan Zhang, Qianghong Xu, Hongxue Meng, Xubin Zheng, Lixin Cheng, Kaijiang Yu, Changsong Wang","doi":"10.1002/ctm2.70770","DOIUrl":"https://doi.org/10.1002/ctm2.70770","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Sepsis-associated acute kidney injury (S-AKI) imposes substantial morbidity and mortality burdens in critically ill populations. This study aimed to construct a spatiotemporal multi-omics atlas of kidneys in a mouse model of S-AKI using spatial metabolomics and proteomics, and to explore potential therapeutic targets for S-AKI.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A spatiotemporal multi-omics atlas of S-AKI mouse kidneys was constructed using spatial metabolomics and proteomics. Arginine metabolism was evaluated via L-arginine supplementation. ARG2 was inhibited by nor-NOHA or renal tubule-specific knockdown. Kidney injury was assessed by histopathology, real-time glomerular filtration rate (RT-GFR), serum serum urea nitrogen (BUN), and injury markers. RNA-seq and serum metabolomics elucidated nor-NOHA's mechanism, with in vivo verification of pathway activation and lipid reduction. In vitro studies used ARG2 KO renal primary tubular epithelial cells (RPTCs) and kidney organoids.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Arginine metabolism played a crucial role, but L-arginine supplementation did not improve renal function. ARG2 was significantly upregulated in proximal and distal tubules of the renal outer medulla and in macrophages. Treatment with the arginase inhibitor nor-NOHA or knockdown of ARG2 in renal tubules significantly alleviated kidney injury, as evidenced by reduced tubular injury, increased RT-GFR, decreased BUN, and reduced injury markers. RNA-seq and serum metabolomics showed that nor-NOHA significantly reduced lipid accumulation in renal tubules and serum, with significant enrichment of the peroxisome proliferator-activated receptor (PPAR) pathway centered around PPARγ. In vivo experiments confirmed pathway activation and alleviation of lipid accumulation. In vitro experiments using RPTCs from ARG2 knockout mice and human kidney organoid model revealed that ARG2 knockout restored PPARγ expression and reduced tubular lipid accumulation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Inhibiting ARG2 in renal tubules during S-AKI may alleviate lipid accumulation and kidney injury by activating PPARγ, providing a new therapeutic strategy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>\u0000 <p>Spatiotemporal multi-omics analysis constructed a detailed atlas of S-AKI kidneys, revealing ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 9","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70770","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148994495","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/ctm2.70849","DOIUrl":"https://doi.org/10.1002/ctm2.70849","url":null,"abstract":"","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 9","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70849","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148994582","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 blood-brain barrier-like vascular gate in neuroendocrine cancers opens new avenues for immunotherapy","authors":"Andrew Y. Chen, Yiyun Wang","doi":"10.1002/ctm2.70807","DOIUrl":"10.1002/ctm2.70807","url":null,"abstract":"<p>Immune checkpoint blockade (ICB) has emerged as a major pillar of modern cancer treatment. The basic principle of ICB is to release the “brakes” on the immune system, such as the PD-1/PD-L1 and CTLA-4 pathways, thereby enabling T cells to attack tumors. A prerequisite for successful immunotherapy is the presence of sufficient numbers of T cells within the tumor microenvironment, as well as their direct physical access to tumor cells. Both T cells already present within tumors before treatment and those recruited during therapy have been shown to play critical roles in tumor killing.<span><sup>1, 2</sup></span> Therefore, efficient recruitment of T cells from the circulation into tumors is essential. Tumors that fail to recruit T cells are classified as “cold” tumors and generally respond poorly to immunotherapy. However, the mechanisms underlying the formation of cold tumors remain largely unclear.</p><p>In our recent study, we identified a blood-brain barrier-like vascular gate (BVG) in small cell lung cancer (SCLC), a prototypical cold tumor.<span><sup>3</sup></span> Paradoxically, SCLC often carries a high tumor mutation burden but is characterised by low levels of T cell infiltration and derives only modest clinical benefit from ICB. The BVG consists of endothelial tight junctions, a thickened basement membrane, and dense pericyte coverage. Together, these features form a highly restrictive vascular barrier that resembles the blood-brain barrier (BBB) and blocks entry of immune cells from the circulation into tumor tissue. The BVG therefore provides a structural explanation for how SCLC can remain immunologically cold despite its high mutational burden.</p><p>Barrier-like tumor vessels are not entirely unprecedented. In brain tumors, the blood-tumor barrier (BTB) is thought to arise from the pre-existing BBB. In contrast, the BVG is actively induced by SCLC cells themselves through the ASCL1-IGFBP5-IGF1R axis. ASCL1 induces IGFBP5 expression in tumor cells, and tumor-derived IGFBP5 promotes IGF1-IGF1R signalling in neighbouring endothelial cells to drive BVG formation. Disruption of ASCL1 or IGFBP5 in tumor cells, or of downstream IGF1R signalling in endothelial cells, compromises the BVG and increases T cell infiltration. Conversely, expression of ASCL1 or IGFBP5 is sufficient to induce BVG-like structures in tumor models that normally lack them. Together, these findings define a tumor-to-endothelium signalling pathway through which neuroendocrine tumor cells establish a vascular barrier to immune-cell entry.</p><p>Defining this pathway also creates a direct therapeutic opportunity. Genetic loss of <i>IGFBP5</i> disrupts the BVG and increases CD8<sup>+</sup> T cell infiltration, providing proof of principle that the barrier can be reversed. More importantly, linsitinib (OSI-906), an IGF1R inhibitor with established clinical safety, had previously shown little benefit as a single agent in SCLC. In the present study, OSI-906 reduced BVG fea","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 9","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13535828/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148873307","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":"Beyond the single biopsy: Sampling dynamic disease ecosystems for patient stratification and translational validation.","authors":"Kangjie Shen, Xin Huang, Tao Zan","doi":"10.1002/ctm2.70809","DOIUrl":"10.1002/ctm2.70809","url":null,"abstract":"","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 9","pages":"e70809"},"PeriodicalIF":7.9,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13554419/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148911000","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":"Adjunct low-dose interleukin-2, protein nitration and early neurologic changes after acute ischaemic stroke: A pilot observational study.","authors":"Xue Li, Haiping Zhao, Xiang Lin, Xunming Ji, Jing He","doi":"10.1002/ctm2.70824","DOIUrl":"10.1002/ctm2.70824","url":null,"abstract":"","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 9","pages":"e70824"},"PeriodicalIF":7.9,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13554415/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148910928","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":"Integrative analysis of single-cell multi-omics reveals heterogeneity in piriform cortex principal neurons and their selective vulnerability in Alzheimer's disease.","authors":"Jiayue Meng, Miaomiao Zhang, Yujie Chen, Mengyao Han, Nianhao Cheng, Ruifang Cao, Qinwen He, Yaya Zhao, Liyun Yuan, Guoqing Zhang","doi":"10.1002/ctm2.70781","DOIUrl":"10.1002/ctm2.70781","url":null,"abstract":"<p><strong>Background: </strong>The piriform cortex (PIR) is a key region of the olfactory system and is increasingly implicated in Alzheimer's disease (AD). However, the cellular heterogeneity of principal neurons (PN) in this region and their selective vulnerability in AD remain poorly understood.</p><p><strong>Methods: </strong>Here, we integrated single-cell multi-omics datasets to systematically characterize PIR PN heterogeneity. We identified four transcriptionally and epigenetically distinct PN subtypes with different spatial distributions across the anterior and posterior PIR.</p><p><strong>Results: </strong>In AD mouse models, the abundance of the Reln-positive superficial-layer (Reln+ SL) subtype was spatially associated with amyloid-β pathology, and its reduced proportion was confirmed by multiplex immunofluorescence. Cross-region comparison revealed that Reln+ SL neurons shared a Gpc5-high/Sort1-low molecular signature with vulnerable layer II excitatory neurons in the entorhinal cortex (EC). In human AD, this vulnerability-associated signature showed progressive enrichment in EC layer II neurons across Braak stages I-III. Furthermore, A Sort1-containing co-expression module captured regional differences between lateral and medial EC layer II populations and was enriched for proteostasis-related pathways.</p><p><strong>Conclusions: </strong>These findings reveal shared molecular features associated with selective vulnerability across PIR and EC layer II neurons and identify a proteostasis-related program linked to regional differences in neuronal vulnerability during AD.</p><p><strong>Key points: </strong>Single-cell multi-omics reveals molecular heterogeneity among piriform cortex principal neurons. Reln+ superficial-layer neurons show selective vulnerability in AD. Cross-region comparison identifies a shared Gpc5-high/Sort1-low signature in vulnerable layer II neurons of EC and PIR.</p>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 9","pages":"e70781"},"PeriodicalIF":7.9,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13570217/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148954900","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":"PRMT7-mediated arginine methylation of FOXK activates Wnt/β-catenin signalling to drive doxorubicin resistance in diffuse large B-cell lymphoma.","authors":"Xiaoyan Zhao, Jiasi Zhang, Yao Teng, Yaqin Wang, Wen Yu, Yan Sun, Zhou Wu, Aiguo Liu","doi":"10.1002/ctm2.70802","DOIUrl":"10.1002/ctm2.70802","url":null,"abstract":"<p><strong>Background: </strong>Doxorubicin, an anthracycline chemotherapeutic agent, is widely used in diffuse large B‑cell lymphoma (DLBCL) treatment, yet its clinical efficacy is often compromised by drug resistance. Protein arginine methyltransferase 7 (PRMT7) is a methyltransferase implicated in tumourigenesis and cancer progression. However, its precise role and underlying mechanisms in DLBCL progression and doxorubicin resistance remain unclear.</p><p><strong>Methods: </strong>We analysed PRMT7 expression in DLBCL cell lines and patient specimens using bioinformatic databases, western blotting, reverse Transcription Polymerase Chain Reactionand immunohistochemistry. Functional studies were performed in DLBCL cell lines through CRISPR/Cas9‑mediated knockout and overexpression systems, combined with in vitro assays for proliferation, apoptosis and doxorubicin sensitivity, as well as in vivo xenograft models. Mechanistically, co‑immunoprecipitation, arginine methylation assays and immunofluorescence were employed to characterise the PRMT7-Forkhead box K (FOXK)1/2-Dishevelled Segment Polarity Protein 2 (DVL2) axis and its modulation of Wnt/ (beta) β‑catenin signalling. In addition, we designed and evaluated FOXK‑methylation‑competitive inhibitory peptides for their capacity to sensitise DLBCL cells to doxorubicin.</p><p><strong>Results: </strong>Our study revealed that PRMT7 is upregulated in DLBCL and promotes both tumour proliferation and doxorubicin resistance. Conversely, knockdown of PRMT7 inhibited DLBCL cell proliferation and enhanced sensitivity to doxorubicin. Mechanistically, PRMT7 catalyses arginine methylation of FOXK1 at arginine (R) 191 and FOXK2 at R144, which markedly increases their binding affinity for DVL2 and facilitates DVL2 nuclear translocation. This event leads to constitutive activation of the Wnt/β‑catenin signalling pathway. Importantly, we developed a FOXK‑derived peptide that competitively inhibits FOXK methylation, suppresses Wnt/β‑catenin signalling and significantly potentiates the antitumour efficacy of doxorubicin in DLBCL.</p><p><strong>Conclusion: </strong>Our findings indicate that the PRMT7/FOXK/DVL2/Wnt-β-catenin axis serves as a novel driver of DLBCL progression and doxorubicin resistance. Targeting the PRMT7-FOXK methylation interface may offer a potential therapeutic approach for overcoming doxorubicin resistance in DLBCL, although further validation in clinical settings is warranted.</p><p><strong>Key points: </strong>Upregulated PRMT7 drives DLBCL progression and doxorubicin resistance PRMT7 methylates FOXK1 at arginine 191 and FOXK2 at arginine 144 FOXK1/2 methylation enhances interaction with DVL2 and promotes nuclear translocation FOXK1/2 methylation dactivate Wnt/ß-catenin signaling through DVL2 nuclear entry A novel peptide inhibitory blocks FOXK1/2 methylation and restores doxorubicin sensitivity.</p>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 9","pages":"e70802"},"PeriodicalIF":7.9,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13535836/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148872751","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":"From biomarkers to intervention: Translational potential of endogenous retrovirus-derived chimeric RNAs.","authors":"Ziyi Ouyang, Hongqing Liang, Dan Zhang","doi":"10.1002/ctm2.70834","DOIUrl":"10.1002/ctm2.70834","url":null,"abstract":"","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 9","pages":"e70834"},"PeriodicalIF":7.9,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13579372/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148975860","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":"Bridging model performance and clinical utility in T cell receptor-epitope binding prediction.","authors":"Yuyan Wang, Yanping Lu, Shengbao Suo","doi":"10.1002/ctm2.70837","DOIUrl":"10.1002/ctm2.70837","url":null,"abstract":"","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 9","pages":"e70837"},"PeriodicalIF":7.9,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13579375/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148975887","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":"Dysregulated circRNA expression profile and associated miRNA sponging in abnormal lung development in congenital diaphragmatic hernia.","authors":"Marietta Jank, Arzu Ozturk Aptekmann, Rina Tanaka, Muntahi Mourin, Nolan De Leon, Matthew Kraljevic, Daywin Patel, Wai Hei Tse, Claire McCallum, Richard Wagner, Shana Kahnamoui, Yuichiro Miyake, Athanasios Zovoilis, Takashi Doi, Michael Boettcher, Richard LeDuc, Richard Keijzer","doi":"10.1002/ctm2.70752","DOIUrl":"10.1002/ctm2.70752","url":null,"abstract":"<p><strong>Rationale: </strong>Circular RNAs (circRNAs) are stable, tissue- and developmental-stage-specific regulators of gene expression and candidate disease biomarkers. Their expression profile in abnormal lung development in congenital diaphragmatic hernia (CDH) is unknown.</p><p><strong>Objective: </strong>To evaluate circRNA expression profile in CDH-associated abnormal lung development.</p><p><strong>Methods: </strong>We profiled circRNAs in rat CDH and control lungs at embryonic day (E)15 and E21 by microarray. We validated identified circRNAs using back‒splice junction amplicon sequencing, RT-qPCR and in situ hybridisation. We modified a circRNA function prediction tool to predict circRNA::micro(mi)RNA::messenger(m)RNA interactions and compared these with Oxford Nanopore RNA sequencing and existing human CDH datasets.</p><p><strong>Measurements and main results: </strong>Microarrays revealed a unique circRNA biosignature during CDH lung development. CircAnp32e was expressed in a sex-specific and spatiotemporal expression pattern in the epithelium at E15. The predicted mature sequence of circAnp32e overlapped 90% with its human orthologue. circRNA::miRNA::mRNA interaction networks at E15 and E21 revealed enrichment in inflammation/infection, smooth muscle cell function, cell proliferation/cell cycle regulation and response to hypoxia pathways. Parental genes of differentially expressed circRNAs at E15 enriched pathways linked to cell proliferation/cell cycle/cancer, while at end-gestation, inflammation and cardiovascular processes were also overrepresented. Rat and human CDH lungs showed overlapping pathways with additional enrichment for RNA processing and protein binding/modification in humans. In a human bronchial epithelial (BEAS-2B) nitrofen-injury model, ANP32E and circANP32E were downregulated, and the predicted let-7 target was significantly dysregulated.</p><p><strong>Conclusion: </strong>A unique circRNA signature during abnormal lung development in CDH may mediate inflammatory responses, smooth muscle cell function and cell proliferation regulation via miRNA sponging. Overlap of downstream pathways in rat and human CDH suggests conserved functions across species. This circRNA biosignature defines strong candidate biomarkers for CDH and a basis for future prospective prenatal investigation.</p>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 9","pages":"e70752"},"PeriodicalIF":7.9,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13563360/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148929120","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}