Clinical and Translational Medicine最新文献

{"title":"Reprogrammed MDSCs promote Th1-dominant antitumour response via CD40 induced by autocrine TNF-α after combining cryo-thermal therapy with IL6 and IL17A neutralization.","authors":"Yuankai Hao, Shicheng Wang, Junjun Wang, Zelu Zhang, Yichen Yao, Ke Wang, Ping Liu, Lisa X Xu","doi":"10.1002/ctm2.70493","DOIUrl":"https://doi.org/10.1002/ctm2.70493","url":null,"abstract":"<p><strong>Background: </strong>Mounting evidence shows that myeloid-derived suppressor cells (MDSCs) reprogramming can significantly enhance the outcomes of immunotherapy. However, the therapeutic potential of targeting MDSCs alone is limited by persistent immunosuppressive cytokines and cellular crosstalk. In our previous study, we found that novel cryo-thermal therapy (CTT) can drive MDSCs maturation and induce CD4⁺ T helper type (Th)1-dominant differentiation, improving long-term survival in spontaneous high metastatic mouse models. Considering the established roles of Interleukin (IL)-6 and IL-17A in non-small cell lung cancer (NSCLC) progression and immune evasion, we developed a combination strategy integrating cytokine neutralization with CTT (combination therapy) in LLC1 tumor-bearing mice. Although the combination therapy successfully promoted MDSCs maturation and Th1 differentiation, the underlying mechanistic basis remained unclear.</p><p><strong>Methods: </strong>The combination therapy was implemented in LLC1 tumor-bearing mice. We then observed its impacts on MDSCs maturation and Th1 differentiation and explored the related mechanisms by examining various aspects including the expression of CD40, the reactive oxygen species (ROS)-nuclear factor-kappa B (NF-κB) pathway, and the induction of tumor necrosis factor-α (TNF-α).</p><p><strong>Results: </strong>It was observed that the combination therapy increased the expression of CD40 on MDSCs through the ROS-NF-κB pathway-dependent TNF-α induction. This TNF-α-mediated CD40 upregulation facilitated Th1 polarization via CD40L engagement on CD4⁺ T cells. Our results provided the first mechanistic evidence that autocrine TNF-α production by reprogrammed MDSCs governs CD40 expression following combination therapy.</p><p><strong>Conclusion: </strong>Our research elucidated the methods and mechanisms of MDSCs reprogramming and offered a promising therapeutic strategy for patients with NSCLC and other types of cancer.</p>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 10","pages":"e70493"},"PeriodicalIF":6.8,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145285681","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Distinct molecular subtypes of KRASG12C-mutant lung adenocarcinoma: Insights into clinical outcomes, tumour microenvironments and therapeutic strategies","authors":"Haitang Yang,&nbsp;Anshun Zhu,&nbsp;Yongliang Niu,&nbsp;Wenyan Ma,&nbsp;Ke Xu,&nbsp;Yunxuan Jia,&nbsp;Weijiao Xu,&nbsp;Baicheng Zhao,&nbsp;Enshuo Zhang,&nbsp;Jiaying Jia,&nbsp;Shunqing Liang,&nbsp;Patrick Dorn,&nbsp;Gang Liu,&nbsp;Ren-Wang Peng,&nbsp;Feng Yao","doi":"10.1002/ctm2.70490","DOIUrl":"10.1002/ctm2.70490","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;&lt;i&gt;KRAS&lt;/i&gt;&lt;sup&gt;G12C&lt;/sup&gt; is the most common &lt;i&gt;KRAS&lt;/i&gt; mutation in lung adenocarcinoma (LUAD), yet clinical responses to KRAS&lt;sup&gt;G12C&lt;/sup&gt;-selective inhibitors (G12Ci) and immunotherapy remain variable.&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;Transcriptomic analysis of &lt;i&gt;KRAS&lt;sup&gt;G12C&lt;/sup&gt;&lt;/i&gt;-mutant LUAD was performed using machine learning algorithms to classify molecular subtypes. Subtype-specific features, including genomic alterations, tumour microenvironment and therapeutic vulnerabilities, were systematically evaluated.&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;We identified three distinct molecular subtypes (KC1, KC2 and KC3) of &lt;i&gt;KRAS&lt;sup&gt;G12C&lt;/sup&gt;&lt;/i&gt;-mutant LUAD through transcriptomic analysis using machine learning algorithms. KC1 subtype is characterised by a neuroendocrine phenotype associated with SMARCA4 loss-of-function and frequent &lt;i&gt;STK11&lt;/i&gt; co-mutations, with a relatively good prognosis. It exhibits poor immune infiltration and demonstrates resistance to G12Ci and immunotherapy but shows sensitivity to MEK1/2 inhibitors; KC2 subtype exhibits a highly malignant phenotype with high proliferation, increased glucose metabolism, and the poorest prognosis. It is enriched with T-cell infiltration and responds best to G12Ci monotherapy and immunotherapy. KC3 subtype is distinguished by well differentiation and the best survival, with an immune-enriched microenvironment featuring abundant immune-suppressive cancer-associated fibroblasts. It demonstrates limited sensitivity to G12Ci and a moderate response to immunotherapy. Notably, KC1‒3 subtype-specific molecular signatures predict drug sensitivity more accurately than classical &lt;i&gt;KRAS&lt;sup&gt;G12C&lt;/sup&gt;&lt;/i&gt; signalling models.&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 illuminate the intricate interplay between tumour subtypes, microenvironmental factors and therapeutic responses, offering a robust framework for improved patient stratification and the development of personalised therapeutic strategies &lt;i&gt;KRAS&lt;sup&gt;G12C&lt;/sup&gt;&lt;/i&gt;-mutant LUAD.&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;Three novel molecular subtypes (KC1, KC2 and KC3) of &lt;i&gt;KRAS&lt;sup&gt;G12C&lt;/sup&gt;&lt;/i&gt;-mutant lung adenocarcinoma were identified, each with distinct molecular and clinical characteristics.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;These subtypes de","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 10","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12481212/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145191311","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":"Targeting gut microbiota and metabolites in cancer radiotherapy","authors":"Shuling Ma,&nbsp;Xinpei Li,&nbsp;Shijie Shang,&nbsp;Zijun Zhai,&nbsp;Meng Wu,&nbsp;Qian Song,&nbsp;Dawei Chen","doi":"10.1002/ctm2.70481","DOIUrl":"10.1002/ctm2.70481","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>Radiotherapy (RT) is a cornerstone in cancer treatment, but often causes radiation-induced injury. Accumulating evidence points to the gut microbiota in modulating immune functions and maintaining intestinal integrity to impact RT efficacy. This review examines the current understanding of intestinal flora and their metabolites within the context of RT. We outlined the current research applications in how microbiota-targeted strategies such as probiotics, prebiotics, dietary interventions, and faecal microbiota transplantation could restore microbial balance, reduce toxicity, and improve patient prognosis. Microbial byproducts such as short-chain fatty acids, bile acids and tryptophan exhibit protective effects against radiation damage, supporting immune modulation and enhancing tumour radiosensitivity. These microbial products underscore the potential of gut microbiota-targeted therapies as adjunctive treatments in RT, with implications for reducing toxicity and personalizing cancer care. All these strategies targeting gut microbiota and metabolites potentially aim to develop innovative therapies that boost RT effectiveness while minimizing side effects, and finally revolutionizing personalized cancer treatment.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>RT alters gut microbiota composition and contributes to intestinal injury and systemic toxicity.</li>\u0000 \u0000 <li>Gut microbiota regulate mucosal integrity, immune responses and therapeutic outcomes of RT.</li>\u0000 \u0000 <li>Microbial metabolites, including SCFAs, BAs and tryptophan derivatives, protect against radiation injury and enhance tumour radiosensitivity.</li>\u0000 \u0000 <li>Microbiota-targeted interventions (e.g. probiotics, prebiotics, dietary strategies, FMT) show promise for reducing RT-related toxicity and improving patient prognosis.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 10","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12483842/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145198594","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":"Targeting c-Myc enhances immunotherapy efficacy in combination with Ras inhibitor in triple-negative breast cancer","authors":"Xiaojie Liang,&nbsp;Yiqiu Liu,&nbsp;Ye Zhu,&nbsp;Yuhan Zhao,&nbsp;Fan Ye,&nbsp;Fangyan Gao,&nbsp;Yaqin Shi,&nbsp;Xiaoxiang Guan","doi":"10.1002/ctm2.70484","DOIUrl":"10.1002/ctm2.70484","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Triple-negative breast cancer (TNBC), which lacks hormone receptors and HER2 expression, presents substantial therapeutic challenges in breast cancer treatment. The efficacy of immunotherapy frequently suffers from the immunosuppressive nature of tumour microenvironment (TME). Hence, discovering effective targets to hinder TNBC progression and bolster immunotherapy's effectiveness is paramount. Previous research from our team indicated notable upregulation of c-Myc in TNBC, and suppressing c-Myc enhances the efficacy of PD-L1 blockade in murine models; nevertheless, the precise mechanisms underlying this phenomenon remain elusive.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We analysed c-Myc expression and implemented a systematic drug library screening strategy alongside c-Myc knockdown to pinpoint potential synergistic agents in TNBC cells. To decipher the regulatory mechanisms of this synergy on cellular malignancy, we conducted cell cycle analysis, cell interaction assays, and RNA-sequencing. Additionally, we established orthotopic and lung metastasis murine models assess how combination therapy influences PD-L1 blockade efficacy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Elevated c-Myc was observed in TNBC and the Ras inhibitor Salirasib was identified as a potent synergistic agent from cell cycle drug library in c-Myc-overexpressing TNBC. The application of Salirasib combined with c-Myc knockdown markedly suppressed tumour cell aggressiveness and induced apoptosis in vitro. Mechanistically, RNA sequencing revealed that the combination therapy blocked MCM2-mediated DNA replication in TNBC cells, causing G1/S phase arrest and enhancing tumour suppression. In vivo, the combination significantly improved PD-L1 blockade efficacy, leading to reduction of tumour volume, inhibition of lung metastases, and remodelling of the immune microenvironment in murine TNBC models.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>In summary, our investigation identifies a molecular vulnerability in c-Myc-driven TNBC, where Ras inhibition reinforces c-Myc-targeted therapy and potentiates immune checkpoint blockade, presenting a promising strategy to improve immunotherapy efficacy in TNBC.</p>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 10","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12477544/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145184702","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/ctm2.70497","DOIUrl":"https://doi.org/10.1002/ctm2.70497","url":null,"abstract":"","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 10","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70497","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145224258","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":"Lactylation in cancer: Advances and opportunities for treatment resistance","authors":"Keke Xu,&nbsp;Yiyi Shou,&nbsp;Ruiqi Liu,&nbsp;Hao Xiong,&nbsp;Xiaomeng Dai,&nbsp;Xuanwen Bao,&nbsp;Xiaoyan Chen,&nbsp;Luanluan Huang,&nbsp;Hailong Sheng,&nbsp;Haibo Zhang,&nbsp;Yanwei Lu","doi":"10.1002/ctm2.70478","DOIUrl":"10.1002/ctm2.70478","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Lactylation, a recently identified post-translational modification that utilizes lactic acidas a substrate, has emerged as an important regulator of gene expression andprotein function. Since its discovery in 2019, lactylation has beenincreasingly recognized for its roles in cancer biology and treatment response.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Main text</h3>\u0000 \u0000 <p>Lactylationis strongly associated with tumor progression and malignancy, underscoring itspotential as a therapeutic target. Recent studies also link lactylation tocancer treatment resistance, suggesting that modulating this modification couldenhance therapeutic efficacy. As treatment resistance remains a major clinicalchallenge in oncology, accumulating evidence indicates that dysregulatedlactylation contributes to resistance across chemotherapy, immunotherapy, targeted therapy, and radiotherapy. Preclinical and clinical research has begunto delineate the molecular pathways through which lactylation shapes theseresistance processes, and experimental approaches targeting lactylation arebeing explored to restore therapeutic sensitivity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This review systematically summarizes the mechanisms of lactylation and its roles intreatment resistance, highlighting the interplay between lactylation andtherapeutic response. We discuss current and emerging strategies that targetlactylation, providing a foundation for future therapeutic development aimed atovercoming resistance and improving cancer treatment outcomes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Lactylation links glycolysis to tumor progression and therapeutic response.</li>\u0000 \u0000 <li>Modulating lactylation writers and erasers restores treatment sensitivity.</li>\u0000 \u0000 <li>Aberrant lactylation drives resistance tomultiple cancer therapies.</li>\u0000 \u0000 <li>Crosstalk with other post-translational modifications suggests novel combination strategies.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 10","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12477887/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145184699","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":"Colorectal cancer molecular profiling: Opportunities for early detection","authors":"Alexandra Sala,&nbsp;Lisa van den Driest,&nbsp;Nicholas J. W. Rattray,&nbsp;Caroline H. Johnson,&nbsp;James M. Cameron,&nbsp;Sajid A. Khan,&nbsp;David S. Palmer,&nbsp;Matthew J. Baker","doi":"10.1002/ctm2.70474","DOIUrl":"10.1002/ctm2.70474","url":null,"abstract":"<p>Colorectal cancer (CRC) is one of the most common and deadliest cancers worldwide, and incidence rates are rising. However, early detection and intervention can improve the survival rates and quality of life of affected patients. Current screening tests used to streamline patients into colonoscopy either lack test adherence or sensitivity for detecting premalignant and early-stage CRC, reducing the advantages of screening measures. Cost-effective and minimally invasive diagnostic tests which can detect immune system and metabolic changes are key to lower the incidence of CRC advanced stages. We herein discuss the statistics, risk factors and unique genetic characteristics of CRC, focussing on the importance of understanding non tumour-derived information in premalignant states for developing comprehensive techniques to achieve earlier diagnosis of CRC. Moreover, the advantages and limitations of current UK and USA screening programmes and emerging detection tools are discussed, along with prospective diagnostics such as genomics, proteomics and spectroscopy.</p>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 10","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12477549/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145184659","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-nucleus transcriptomic profiling reveals temporal dynamics of neuroinflammation and myelin repair after intracerebral haemorrhage","authors":"Zhan Chen,&nbsp;Qinglin Wang,&nbsp;Rong Xiang,&nbsp;Ruoqi Ding,&nbsp;Jin Tao,&nbsp;Qinfeng Peng,&nbsp;Shaoshuai Wang,&nbsp;Nannan Cheng,&nbsp;Mengke Zhao,&nbsp;Jiaxin Li,&nbsp;Qidi Xue,&nbsp;Chuanyu Liu,&nbsp;Xuemei Chen,&nbsp;Longqi Liu,&nbsp;Junmin Wang,&nbsp;Jian Wang,&nbsp;Mingyue Wang","doi":"10.1002/ctm2.70486","DOIUrl":"10.1002/ctm2.70486","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;Intracerebral haemorrhage (ICH) progresses rapidly with complex pathology and limited treatment options, making it a severe subtype of stroke. The extravasation of blood into the brain parenchyma triggers a cascade of inflammatory responses, contributing to secondary injury. Single-nucleus RNA sequencing (snRNA-seq) data have enabled more profound insights into the cellular heterogeneity and dynamic interactions within the haemorrhagic brain. Immune cells play a crucial role in shaping neuroinflammation. However, the lack of comprehensive longitudinal studies limits our understanding of the temporal evolution of these inflammatory processes, posing a challenge to the development of targeted therapeutic strategies.&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 used snRNA-seq in collagenase-induced ICH mouse models at Days 1, 3, 7, 14 and 28 post-injury, alongside naive controls, to profile the dynamics of gene expression over time.&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;We obtained 281 577 high-quality transcriptional profiles representing 21 distinct cell types. Co-expression network analysis revealed a prominent ‘inflammation module’ that remained active throughout ICH. Integrative single-cell transcriptomic and immunofluorescence staining suggested that the various &lt;i&gt;Mif&lt;/i&gt;-expressing cells may contribute to local inflammation, potentially engaging macrophages via receptor–ligand pairs such as &lt;i&gt;Cd44&lt;/i&gt; and &lt;i&gt;Cd74&lt;/i&gt;. Over time, microglia appeared to serve as key recipients of pro-inflammatory signals increasingly. During the resolution phase, oligodendrocytes exhibited transcriptional signatures consistent with enhanced maturation and remyelination, which T cell-mediated interactions may have facilitated.&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 offer a systems-level perspective on cell-type–specific responses and immune-mediated interactions during ICH progression and resolution.&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;Establish intracerebral haemorrhage (ICH) mouse models at various time points (Days 1, 3, 7, 14, 28) and construct a high-quality single-nucleus RNA sequencing (snRNA-seq) atlas.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Computational analyses suggest that macrophage recruitment in the early stage of ICH potentially involves migration inhibitory factor (MIF) si","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 10","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12477064/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145184652","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":"Distant metastases of melanoma exhibit varying extent of intrapatient proteogenomic heterogeneity","authors":"Beata Szeitz,&nbsp;Yanick Paco Hagemeijer,&nbsp;Zoltan Gabor Pahi,&nbsp;Zsuzsanna Ujfaludi,&nbsp;Magdalena Kuras,&nbsp;Jimmy Rodriguez,&nbsp;Viktoria Doma,&nbsp;Reka Mohacsi,&nbsp;Magdolna Herold,&nbsp;Zoltan Herold,&nbsp;Zsolt Horvath,&nbsp;Indira Pla,&nbsp;Yutaka Sugihara,&nbsp;Bo Baldetorp,&nbsp;Henrik Lindberg,&nbsp;Henriett Oskolas,&nbsp;Melinda Rezeli,&nbsp;Jeovanis Gil,&nbsp;Roger Appelqvist,&nbsp;Lajos V. Kemeny,&nbsp;Jessica Guedes,&nbsp;Johan Malm,&nbsp;Aniel Sanchez,&nbsp;Imre Miklos Boros,&nbsp;Istvan Balazs Nemeth,&nbsp;Victor Guryev,&nbsp;Tibor Pankotai,&nbsp;Krzysztof Pawłowski,&nbsp;Elisabet Wieslander,&nbsp;Attila Marcell Szasz,&nbsp;David Fenyö,&nbsp;Peter Horvatovich,&nbsp;Jozsef Timar,&nbsp;György Marko-Varga,&nbsp;Lazaro Hiram Betancourt","doi":"10.1002/ctm2.70477","DOIUrl":"10.1002/ctm2.70477","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;Metastatic melanoma is a highly aggressive disease with poor survival rates despite recent therapeutic advancements with immunotherapy. The proteomic landscape of advanced melanoma remains poorly understood, especially regarding proteomic heterogeneity across metastases within patients.&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 collected 83 melanoma metastases from 19 different metastatic sites in 24 patients with advanced metastatic melanoma almost exclusively from the pre-immunotherapy era, using semi-rapid autopsies. The metastases were subjected to histopathological evaluation, RNA-sequencing and mass spectrometry-based proteomics for protein quantitation and non-reference peptide (NRP) sequence detection using a proteogenomic data integration approach.&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;NRPs associated with mutations frequently occurred in proteins related to focal adhesion, vesicle-mediated transport, MAPK signalling and immune response pathways across the cohort. Intrapatient heterogeneity was negligible when considering morphology and driver gene mutation status but was substantial at the proteogenomic level. This heterogeneity was not driven by metastasis location, albeit liver metastases exhibited distinct proteogenomic patterns, including upregulation of metabolic pathways. Cluster analysis outlined four proteomic clusters (C1–4) of the metastases, characterised by the upregulation of cell cycle and RNA-splicing (C1), mitochondrial processes (C3), extracellular matrix (ECM) and immune pathways (C2) and ECM and vesicle-mediated transport pathways (C4). Around two-thirds of patients had metastases that had strongly distinct phenotypes. Patients in our cohort whose metastases were primarily assigned to clusters C1 and C3 exhibited shorter overall survival than patients whose metastases were categorised mainly into the C2 and C4 clusters.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusion&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Our unique multi-metastasis cohort captured the proteogenomic heterogeneity of immunotherapy-naïve melanoma distant metastases, establishing a foundation for future studies aimed at identifying novel therapeutic targets to complement current immunotherapies.&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;Comprehensive proteogenomic profiling of post-mortem melanoma metastases, collected primarily before the immunotherapy era.&lt;/l","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 10","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12477065/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145184631","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":"CRISPR-driven diagnostics: Molecular mechanisms, clinical efficacy and translational challenges","authors":"Zilong Wang,&nbsp;Qianqian Wang,&nbsp;Jiaming Zhang,&nbsp;Bingyu Li,&nbsp;Yuke Li,&nbsp;Zhengbo Chen,&nbsp;Dandan Guo,&nbsp;Shuying Feng","doi":"10.1002/ctm2.70482","DOIUrl":"https://doi.org/10.1002/ctm2.70482","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;In the realm of public health, among the primary perils menacing human well-being, the issue of pathogen infection persists as a significant concern. Precise and timely diagnosis of diseases constitutes the bedrock for effective therapeutic interventions and epidemiological monitoring. Hence, it is crucial to develop quick, sensitive, and highly effective methods for identifying pathogen and their variants.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Material and methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;This article reviews the recent research progress in the CRISPR/Cas system for detecting nucleic acids, with an emphasis on CRISPR/Cas9, CRISPR/Cas12, and CRISPR/Cas13. Initially, we provided a concise overview of the nucleic acid detection mechanism utilizing the CRISPR/Cas system. Subsequently, we dissect the molecular mechanisms of CRISPR tools, compare their clinical efficacy against traditional methods, and explore frontier innovations such as amplification-free detection and AI integration.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusion&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Ultimately, we argue that CRISPR diagnostics must evolve beyond technical optimization to embrace ecological adaptability, ensuring that precision medicine serves as a bridge-rather than a barrier-to global health equity.&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;&lt;b&gt;Core Mechanism&lt;/b&gt;: Explains the molecular basis of CRISPR-Cas (Cas9, Cas12, Cas13) for nucleic acid detection, leveraging crRNA-guided targeting and trans-cleavage activity for ultra-sensitive (aM level) and specific pathogen identification.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;&lt;b&gt;Superior Performance&lt;/b&gt;: Outperforms traditional methods in speed, sensitivity, and cost, making it ideal for point-of-care use in resource-limited settings.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;&lt;b&gt;Cutting-Edge Innovations&lt;/b&gt;: Covers key advances like amplification-free detection, portable device integration, and multiplex platforms.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;&lt;b&gt;Translation Challenges&lt;/b&gt;: Discusses hurdles in clinical adoption, including inhibitor interference in complex samples, scalability limitations, the need for multi-center clinical data, and varying regional regulations.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;&lt;b&gt;Future Outlook&lt;/b&gt;: Highlights emerging directions such as integrated “sample-to-result” systems and AI integration, while also addressing associated biosafety and ethical concerns, calling for robust reg","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 10","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70482","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145135716","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}