Clinical and Translational Medicine最新文献

{"title":"PRAME promotes invasion and metastasis of salivary adenoid cystic carcinoma by regulating RARα stability via the cullin2 ubiquitin-proteasome system","authors":"Xudong Wang, Tingyao Ma, Yixin Jing, Tianyi Li, Xi Zhao, Guohan Zhao, Ran Gao, Lu Kong, Xiaohong Chen","doi":"10.1002/ctm2.70787","DOIUrl":"10.1002/ctm2.70787","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>All-trans retinoic acid (ATRA) exerts its biological functions primarily through nuclear receptors, but its therapeutic efficacy in solid tumours remains limited. This study aimed to elucidate the regulatory role of the cancer-testis antigen PRAME in posttranslational modifications (PTMs) of the ATRA receptor RARα, and to assess its consequent impact on tumour progression in salivary adenoid cystic carcinoma (SACC).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Transcriptome sequencing was performed on public datasets from the Gene Expression Omnibus (GEO) and on clinical tissue samples to identify overlapping differentially expressed genes. The expression pattern of PRAME across human pan-cancer and its correlation with overall survival were analyzed using the TCGA database. Cellular transcriptome sequencing, cellular functional assays, co‑immunoprecipitation (Co-IP), western blotting, protein stability assays, nude mouse xenograft tumour and lung metastasis models, and bioinformatic analyses were conducted to investigate the potential regulatory mechanism by which PRAME promotes metastasis in SACC through degradation of RARα and regulation of the EMT pathway.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>PRAME was found to be highly expressed in 33 common human tumour types, with minimal expression in normal tissues, and its upregulation correlated with poor prognosis. In SACC clinical specimens and cell lines, PRAME expression was significantly elevated. Functionally, PRAME upregulated Twist1 expression and promoted epithelial–mesenchymal transition, thereby enhancing the invasive and metastatic capabilities of SACC cells. In vivo, PRAME silencing attenuated subcutaneous tumorigenesis and pulmonary metastasis. Mechanistically, PRAME bound to the Cullin2 ubiquitin ligase complex, destabilizing RARα protein and promoting epithelial–mesenchymal transition (EMT).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Collectively, our findings reveal that PRAME drives SACC metastasis by accelerating RARα degradation through the Cullin2 ubiquitin–proteasome pathway while simultaneously inducing Twist1-mediated EMT. These results position PRAME as a candidate biomarker and an actionable therapeutic target in SACC.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>\u0000 <p>In salivary adenoid cystic carcinoma (SACC), PRAME drives","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 9","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70787","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148839374","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":"NSUN4-dependent m5C modification facilitates mitochondrial fission to accelerate diabetic nephropathy process via regulating SMURF1/CAMK1 axis","authors":"Danyi Yang,&nbsp;Yinyin Chen,&nbsp;Hao Li,&nbsp;Guoyong Liu,&nbsp;Yang Gao,&nbsp;Liyu He","doi":"10.1002/ctm2.70783","DOIUrl":"10.1002/ctm2.70783","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>NOP2/Sun RNA methyltransferase family member 4 (NSUN4)-mediated 5-methylcytosine (m5C) modification has been implicated in diabetes-related diseases. However, its role and molecular mechanism in diabetic nephropathy (DN) remain unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>DN mouse model was constructed by injecting with streptozotocin (STZ). High glucose (HG)-induced HK-2 cells were used to establish a cellular model of DN. The levels of NSUN4, SMAD ubiquitination regulatory factor 1 (SMURF1), calcium/calmodulin-dependent protein kinase 1 (CAMK1), and mitochondrial-related proteins were analyzed using qRT-PCR, western blot, or immunohistochemical staining. Renal injury in mice was evaluated using relevant kits and histological staining. Cell apoptosis, ROS production and proliferation were examined by TUNEL, dihydroethidium, MitoSOX Red and EdU staining. The interaction between SMURF1 and Aly/REF export factor (ALYREF) or CAMK1 was confirmed by RNA immunoprecipitation, Co-IP and ubiquitination assay.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Upregulation of NSUN4 increased the m5C level in DN. Knockout of NSUN4 alleviated STZ-induced renal injury in mice by repressing renal tubule cell mitochondrial fission and promoting mitochondrial fusion. NSUN4 downregulation reduced mitochondrial fission and promoted mitochondrial fusion to relieve HG-induced HK-2 cell apoptosis. NSUN4-mediated m5C modification promoted SMURF1 mRNA stability by regulating ALYREF. SMURF1 overexpression rescued the suppressive effect of NSUN4 knockdown on cell mitochondrial fission and apoptosis. Besides, SMURF1 facilitated the ubiquitination and degradation of CAMK1. Furthermore, sh-CAMK1 abolished the inhibitory effect of sh-SMURF1 on cell mitochondrial fission and apoptosis. Meanwhile, downregulation of NSUN4 relieved STZ-induced renal injury in DN mice by reducing mitochondrial fission via the SMURF1/CAMK1 axis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>NSUN4-mediated upregulation of SMURF1 promoted mitochondrial fission to accelerate DN progression via increasing CAMK1 ubiquitination. The discovery of the NSUN4/SMURF1/CAMK1 axis provides new insights into DN pathogenesis.</p>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 9","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70783","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148839465","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/ctm2.70819","DOIUrl":"https://doi.org/10.1002/ctm2.70819","url":null,"abstract":"","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 8","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70819","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148848867","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 injection to inhalation: A STING-activating mucosal adjuvant reprograms vaccination","authors":"Weijie Wang,&nbsp;Muzhuo Wang,&nbsp;Lu Lu,&nbsp;Shibo Jiang,&nbsp;Zezhong Liu","doi":"10.1002/ctm2.70798","DOIUrl":"https://doi.org/10.1002/ctm2.70798","url":null,"abstract":"&lt;p&gt;The respiratory mucosa of the nasal cavity and conducting airways is a major portal of entry for respiratory viruses and an important site for vaccine-induced protection. Local immunity acts at the earliest stage of infection, when viral replication remains largely confined to the respiratory epithelium.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Secretory immunoglobulin A (sIgA) is a key component of mucosal adaptive immunity and can block viral attachment to host receptors and limit entry into epithelial cells. Tissue-resident memory T (T&lt;sub&gt;RM&lt;/sub&gt;) cells can respond rapidly within the respiratory tract and help eliminate infected cells without relying on the recruitment of circulating lymphocytes. These responses are difficult to establish after intramuscular vaccination.&lt;span&gt;&lt;sup&gt;2, 3&lt;/sup&gt;&lt;/span&gt; Intramuscular vaccines induce strong systemic antibody and T-cell responses and reduce the risk of severe respiratory infection. However, their protection in the upper respiratory tract is often weaker and less durable. This limitation has renewed interest in mucosal vaccination.&lt;span&gt;&lt;sup&gt;4, 5&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Effective mucosal vaccines remain difficult to develop. Although several mucosal COVID-19 vaccines based on adenoviral or influenza virus vectors have been authorized in some countries for aerosol inhalation or intranasal administration, approved protein-subunit mucosal vaccines remain rare. Respiratory mucosal subunit vaccines face three main challenges. First, protein antigens must diffuse through the mucus layer and then be transported across, or sampled at, the epithelial barrier to reach antigen-presenting cells (APCs) in the underlying lamina propria. During this process, they must also resist proteolytic degradation and rapid mucociliary clearance. Second, soluble protein antigens are often weakly immunogenic at mucosal surfaces and, without sufficient innate immune stimulation, may induce weak responses or mucosal tolerance. Third, approved adjuvanted protein-based mucosal vaccines remain rare and no broadly established adjuvant platform is currently available for intranasal protein-subunit vaccination (Figure 1).&lt;span&gt;&lt;sup&gt;6, 7&lt;/sup&gt;&lt;/span&gt; An effective mucosal adjuvant must therefore promote rapid antigen uptake and presentation while limiting local inflammation and systemic exposure. Several established adjuvants have been tested through the nasal route. MF59 enhanced mucosal antibody responses in animal studies, while CpG oligodeoxynucleotides, such as CpG 1018, promoted both mucosal and systemic immunity. Neither MF59 nor CpG 1018 is approved for intranasal use. MF59 is licensed in injectable influenza vaccines and CpG 1018 is used in an injectable hepatitis B vaccine. Their safety and activity after injection cannot be directly extended to the respiratory tract.&lt;span&gt;&lt;sup&gt;8, 9&lt;/sup&gt;&lt;/span&gt; Bacterial toxins and their derivatives, including cholera toxin-based adjuvants, have shown stronger mucosal activity, but safety remains a major conc","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 9","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70798","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148811243","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 a developmental atlas to maps of disease origin","authors":"Jiexue Pan,&nbsp;Zhongliang Lin,&nbsp;Junlin Feng,&nbsp;Gaochen Zhang,&nbsp;Zejun Fu,&nbsp;Hefeng Huang,&nbsp;Guolian Ding","doi":"10.1002/ctm2.70790","DOIUrl":"https://doi.org/10.1002/ctm2.70790","url":null,"abstract":"&lt;p&gt;Many congenital disorders and diseases that present later in life may originate during embryonic development, long before structural abnormalities or clinical symptoms become detectable. Genetic testing can identify aneuploidies, copy-number changes and pathogenic variants, but it often remains difficult to determine how a genetic lesion perturbs a developing human tissue and why the same genomic alteration can produce different organ involvement or disease severity. Interpreting pathology therefore requires a sufficiently detailed definition of normal development.&lt;/p&gt;&lt;p&gt;The recently established spatiotemporal transcriptomic atlas of post-gastrulation human embryos provides such a reference. By profiling 77 sagittal sections from 13 euploid embryos spanning Carnegie stages 12–23 and integrating Stereo-seq with single-nucleus RNA sequencing, the study resolved transcriptional programmes across 50 organs and 198 substructures. Its translational value (Figure 1) may lie less in immediate clinical prediction than in providing a spatiotemporal coordinate system against which abnormal development can be measured, and in which the earliest deviations leading to disease can be located.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;The biological consequence of a genetic abnormality depends on more than the variant itself. Gene dosage, developmental timing, cell identity, tissue interactions and parental origin can all shape the phenotype. The atlas mapped 1922 developmental disease-associated genes and showed organ-restricted, shared and broader multi-organ expression patterns. It also identified spatially resolved allelic imbalance, adding another layer to the study of dosage and parent-of-origin effects.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Recent disease studies illustrate why this normal reference matters. In trisomy 21, the pathogenic effect is not simply a uniform increase in chromosome 21 gene expression. Human iPSC and perturbation studies identified HMGN1 as a dosage-sensitive regulator of atrioventricular cardiomyocyte states,&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; while a recent single-cell study of the developing Down syndrome cortex identified BACH1, PKNOX1 and GABPA as dosage-sensitive regulatory hubs.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; In monosomy X, transcriptomic analysis of foetal tissues showed tissue-dependent consequences involving both pseudoautosomal genes and genes escaping X inactivation.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; Evidently, the path from a fixed genomic abnormality to a variable clinical phenotype is not linear, but mediated by the changing landscape of gene regulation across different cell lineages and gestational windows. These findings support viewing chromosomal disorders as stage- and tissue-dependent disturbances of developmental programmes.&lt;/p&gt;&lt;p&gt;Spatial context is equally important for microdeletion and single-gene disorders. In 22q11.2 deletion syndrome, TBX1 is not strongly expressed in the cardiac neural crest cells that contribute to affected structures. Inst","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 9","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70790","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148811242","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":"Dissecting diffuse large B-cell lymphoma heterogeneity: New insights from a state-specific molecular characterisation","authors":"Robel Papotti,&nbsp;Filippo Vit,&nbsp;Tamara Bittolo,&nbsp;Federico Pozzo,&nbsp;Stefania Bettelli,&nbsp;Samantha Pozzi,&nbsp;Luca Braglia,&nbsp;Elisa Forti,&nbsp;Arianna Di Napoli,&nbsp;M. Christina Cox,&nbsp;Tamar Tadmor,&nbsp;Pellegrino Musto,&nbsp;Leonardo Flenghi,&nbsp;Martina Quintini,&nbsp;Giovanna R. Mansueto,&nbsp;Sara Galimberti,&nbsp;Valentina Donati,&nbsp;Michele Spina,&nbsp;Alberto Zamò,&nbsp;Andreas Rosenwald,&nbsp;Riccardo Bomben,&nbsp;Stefano Sacchi,&nbsp;Valter Gattei","doi":"10.1002/ctm2.70757","DOIUrl":"https://doi.org/10.1002/ctm2.70757","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Diffuse large B-cell lymphoma (DLBCL) is a biologically and clinically heterogeneous disease.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In this study, we analysed a real-world cohort of 178 newly diagnosed DLBCL patients homogeneously treated with R-CHOP-like regimens, integrating RNA sequencing, targeted mutational profiling and digital deconvolution using the EcoTyper algorithm.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Five malignant B-cell states (S1–S5) were identified, each reflecting distinct differentiation and transcriptional programs with prognostic relevance, S1 and S5 representing the most favourable and adverse subtypes, respectively. EcoTyper-defined lymphoma ecotypes (LE1–LE9), capturing co-associations between malignant and microenvironmental cell states, further refined prognostic classification, with LE1/LE2 and LE9 associated with the worst and most favourable prognosis, respectively. Both B-cell states and LE retained independent prognostic value in multivariable analyses after adjusting for the cell of origin and the revised international prognostic index. Mutational profiling revealed state-specific patterns: S1 harboured mutations in genes involved in epigenetic regulation, cytoskeletal organisation and tumour microenvironment (TME) interactions (<i>CREBBP</i>, <i>EZH2</i> and <i>ACTB</i>), whereas S5 was enriched for mutations promoting survival signalling, immune evasion and differentiation blockade (<i>MYD88</i>, <i>CD79B</i> and <i>TP53</i>). In vitro validation using human five DLBCL cell lines independently recapitulated the S1 and S5 transcriptomic states, supporting the existence of intrinsic, cell-autonomous biological programs. Pathway analysis indicated that S1 was linked to cell adhesion, extracellular matrix remodelling and inflammatory signalling, while S5 displayed enrichment of cell-cycle deregulation, metabolic reprogramming and immune evasion. Accordingly, S1 tumours appear reliant on TME interactions, whereas S5 tumours adopt a predominantly TME independent, intrinsically aggressive phenotype.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Collectively, these findings delineate a biologically coherent framework linking pathway deregulation with cell state and ecotype-specific mutational landscapes, refining DLBCL risk classification and adding an additional dimension to conventional prognostic models.</p>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 8","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70757","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148783964","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":"Precision post-translational modification of PML defines neuroblastoma clinical behaviour","authors":"Sreenidhi Mohanvelu,&nbsp;Poorvi Subramanian,&nbsp;Sheeja Aravindan,&nbsp;Madhi Oli Ramamurthy,&nbsp;Sivaroopan Aravindan,&nbsp;Afsana Parveen Jahir Hussain,&nbsp;Natarajan Aravindan","doi":"10.1002/ctm2.70763","DOIUrl":"https://doi.org/10.1002/ctm2.70763","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;Promyelocytic leukaemia protein (PML), a key regulator of nuclear architecture and cellular homeostasis, is increasingly recognised for its tumour-suppressive functions. In neuroblastoma (NBL), a clinically heterogeneous and aggressive paediatric malignancy, the prognostic role of PML and its post-translational modifications remains largely unexplored.&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 investigated the prognostic and predictive significance of PML expression and its site-specific phosphorylation at serine 518 (S&lt;sup&gt;518&lt;/sup&gt;) in a cohort of 121 NBL patients. Custom-synthesised antibodies and high-resolution tissue microarrays were used to quantitatively profile PML and pPML S&lt;sup&gt;518&lt;/sup&gt; expression via automated immunohistochemistry and digital image analysis. Survival outcomes were assessed using Kaplan-Meier and Cox regression analyses. Mechanistic insights were obtained using reverse‑engineered phospho‑mutant models enabling selective modulation of S518 phosphorylation.&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 findings reveal a striking inverse relationship between PML abundance and S&lt;sup&gt;518&lt;/sup&gt; phosphorylation, with low PML and high pPML S&lt;sup&gt;518&lt;/sup&gt; strongly associated with advanced disease stage, metastasis, relapse, and therapy resistance. Survival analyses demonstrate that low PML predicts poor overall survival (OS), progression-free survival (PFS), and relapse-free survival (RFS), while elevated pPML S&lt;sup&gt;518&lt;/sup&gt; correlates with significantly worse outcomes across all endpoints. Multivariate Cox regression confirms both markers as independent predictors of survival. Mechanistically, reverse-engineered phospho-mutant models that enable selective switch-on/switch-off modulation of S&lt;sup&gt;518&lt;/sup&gt; phosphorylation demonstrated that phosphorylation at this site reduces PML abundance and promotes invasive cellular phenotype.&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;PML loss and site-specific phosphorylation of PML at S&lt;sup&gt;518&lt;/sup&gt; represent robust prognostic and predictive biomarkers with potential utility in risk stratification. Targeting PML phosphorylation may offer a promising translational strategy to improve therapeutic efficacy in high‑risk NBL.&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;\u0000 &lt;p&gt;PML depletion is a defining feature of aggressive neuroblastom","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 8","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70763","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148784252","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":"Germline predisposition and somatic mutational landscape in synchronous mucinous metaplasia and neoplasia of the female genital tract","authors":"Ying Yuan,&nbsp;Li Zhang,&nbsp;Jiongbo Liao,&nbsp;Bo Wang,&nbsp;Linghui Lu,&nbsp;Dongchen Chu,&nbsp;Yue Shi,&nbsp;Jiaqi Liu,&nbsp;Feng Zhang,&nbsp;Shuyan Tang,&nbsp;Chao Wang","doi":"10.1002/ctm2.70768","DOIUrl":"10.1002/ctm2.70768","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;Synchronous mucinous metaplasia and neoplasia of the female genital tract (SMMN-FGT) with gastric-type differentiation is a rare disorder with genetic predisposition. Pathogenic &lt;i&gt;STK11&lt;/i&gt; variants explain only a minority of reported cases, suggesting additional susceptibility genes. However, the genetic landscape of SMMN-FGT remains poorly characterised.&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;Whole-exome sequencing was performed on 19 lesions and matched normal tissues from 13 cases with SMMN-FGT. Pathogenic germline variants in cancer-predisposition genes were identified, and their carrier frequencies were compared with those in common gynaecologic cancers. The somatic mutational landscape of SMMN-FGT was characterised and compared with conventional cervical cancers. Clonal analyses were performed to identify candidate driver genes, and the functional effects of &lt;i&gt;KDM5C&lt;/i&gt; were evaluated in vitro using siRNA-mediated knockdown and plasmid-mediated overexpression assays.&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;Germline analysis showed a markedly higher prevalence of pathogenic variants in cancer-associated genes in SMMN-FGT (38.5%) than common gynaecologic cancers (4.4%–8.6%). Two cases carried pathogenic &lt;i&gt;BRCA1&lt;/i&gt; variants, raising the possibility that SMMN-FGT may be part of a broader &lt;i&gt;BRCA1&lt;/i&gt;-associated phenotypic spectrum. Somatic profiling identified &lt;i&gt;TP53&lt;/i&gt; mutations in five (26.3%) of 19 total lesions, four (80.0%) of which were malignant. Gastric-type cervical adenocarcinoma (GCA) was the most common malignant subtype of SMMN-FGT, with &lt;i&gt;TP53&lt;/i&gt; mutations detected in three (42.9%) of seven GCA lesions and no &lt;i&gt;PIK3CA&lt;/i&gt; mutations. By contrast, conventional cervical cancers frequently harbour &lt;i&gt;PIK3CA&lt;/i&gt; mutations (27%–41%), whereas &lt;i&gt;TP53&lt;/i&gt; mutations are relatively uncommon. Clonal analysis identified &lt;i&gt;KDM5C&lt;/i&gt; as a candidate driver. &lt;i&gt;KDM5C&lt;/i&gt; overexpression reduced cell viability, migration and invasion and increased apoptosis, whereas its knockdown produced the opposite effects.&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;SMMN-FGT has a distinct genetic profile characterised by an enrichment of pathogenic germline variants, and recurrent &lt;i&gt;TP53&lt;/i&gt; mutations predominantly affecting malignant lesions. &lt;i&gt;KDM5C&lt;/i&gt; may function as a candidate tumour suppressor. These findings advance our understanding of SMMN-FGT pathogenesis and warrant further investigation of its diagnostic and therapeutic implications.&lt;/p&gt;\u0000 \u0000 &lt;section&gt;\u0000","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 8","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70768","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148764323","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":"Neutrophil-based immunotherapy: A metabolic lens on mechanisms and therapeutic implications","authors":"Wenchao Xu,&nbsp;Yu Su,&nbsp;Li Zhou,&nbsp;Jianzhou Liu,&nbsp;Junchao Guo","doi":"10.1002/ctm2.70780","DOIUrl":"https://doi.org/10.1002/ctm2.70780","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;Tumor-associated neutrophils (TANs) serve as pivotal immune modulators in the tumor microenvironment and exert profound, context-dependent effects on tumor immunity, yet their metabolic features and functional implications remain insufficiently explored.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Main body&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Throughout their lifecycle, neutrophils continuously sense and adapt to shifting microenvironments, maintaining survival and functional homeostasis through metabolic reprogramming. As key hubs of the tumor metabolic network, TANs exhibit pronounced metabolic plasticity and heterogeneity. Whether active or passive, TAN metabolic reprogramming critically contributes to immune evasion via multiple mechanisms, including regulation of immune mediator expression and intercellular metabolite crosstalk. Current research focuses on strategies that induce durable TAN metabolic reprogramming while overcoming inherent limitations, aiming to establish an efficient and safe TAN-directed immunotherapeutic framework. In this review, we systematically summarize recent advances in TAN metabolic reprogramming, emphasizing its intrinsic link to immunological phenotypes and spatiotemporal heterogeneity. We also propose a TAN metabolic classification framework (4-Tier TAN-MetaC) and provide a comprehensive overview of translational opportunities, bottlenecks, and actionable future directions for TAN metabolism-targeted immunotherapies.&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;Overall, TAN metabolic reprogramming represents a central driver of tumor immune evasion and a clinically actionable metabolic vulnerability for cancer immunotherapy.&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;\u0000 &lt;p&gt;Tumour-associated neutrophil (TAN) metabolic reprogramming is tightly linked to their immunosuppressive functions.&lt;/p&gt;\u0000 &lt;/li&gt;\u0000 \u0000 &lt;li&gt;\u0000 &lt;p&gt;Spatiotemporal metabolic heterogeneity shapes TAN-mediated tumour immunity.&lt;/p&gt;\u0000 &lt;/li&gt;\u0000 \u0000 &lt;li&gt;\u0000 &lt;p&gt;A metabolism-based TAN stratification model unifies cross-study frameworks.&lt;/p&gt;\u0000 &lt;/li&gt;\u0000 \u0000 &lt;li&gt;\u0000 &lt;p&gt;TAN metabolism-targeted immunotherapy holds promise for improving patient prognosis.&lt;/p&gt;\u0000 &lt;/li&gt;\u0000 &lt;/ul&gt;\u0000 ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 8","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70780","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148753746","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":"Space radiation impairs long-term endothelial integrity and may promote atherosclerosis in ApoE-deficient mice","authors":"Yang Xu,&nbsp;Sabrina Jarrah,&nbsp;Shihong Zhang,&nbsp;Mary K. Khlgatian,&nbsp;Agnieszka Brojakowska,&nbsp;Yifei Du,&nbsp;Abrisham Eskandari,&nbsp;Valentina D'Escamard,&nbsp;Jason C. Kovacic,&nbsp;David A. Goukassian","doi":"10.1002/ctm2.70774","DOIUrl":"10.1002/ctm2.70774","url":null,"abstract":"&lt;p&gt;Dear Editor,&lt;/p&gt;&lt;p&gt;Missions to the Moon and beyond are set to become an increasingly important focus of human space exploration. However, exposure to space radiation is an unavoidable hazard during space missions and may pose a significant risk.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Studies of Apollo astronauts, the only humans with long-term follow-up data who have travelled outside Earth's protective magnetosphere, have suggested increased cardiovascular mortality.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; Although animal mechanistic studies support a causal role for radiation in cardiovascular injury,&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; many studies to date have largely focused on acute or subacute effects.&lt;span&gt;&lt;sup&gt;4-6&lt;/sup&gt;&lt;/span&gt; The long-term cardiovascular consequences of space-relevant radiation, particularly beyond one year after exposure and in the context of atherosclerosis, remain poorly defined.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; Moreover, most previous studies used single-ion beam radiation rather than a mixed radiation field designed to mimic the complex composition of deep-space radiation.&lt;span&gt;&lt;sup&gt;4, 5&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;In this study, we addressed these gaps by investigating the long-term effects of simulated space radiation on endothelial integrity and atherosclerotic remodelling. The development of NASA's galactic cosmic ray simulator for ground-based testing enabled the use of simplified galactic cosmic ray simulation irradiation, referred to here as SimGCRSim, a mixed radiation field designed to better mimic deep-space radiation exposure than traditional single-ion analogues.&lt;span&gt;&lt;sup&gt;3, 6, 7&lt;/sup&gt;&lt;/span&gt; We also included a gamma irradiation group, which provides an ‘Earth-like radiation’ benchmark, allowing contextualization of the biological effects of space-relevant SimGCRSim radiation. Atherosclerosis-prone ApoE-deficient mice were maintained on a normal chow diet prior to and following radiation and were sacrificed at 16 months of age for analyses (Figure 1A). For detailed methods, see Supporting Information.&lt;/p&gt;&lt;p&gt;To evaluate endothelial integrity, we examined the expression of the endothelial markers CD31 and vascular endothelial (VE)-cadherin in the luminal cell layer that was generally overlying aortic root atherosclerotic plaques. Immunofluorescence analysis revealed a significant reduction in CD31&lt;sup&gt;+&lt;/sup&gt; and VE-cadherin&lt;sup&gt;+&lt;/sup&gt; endothelial coverage in irradiated mice compared with sham controls (Figure 1B,C). Both gamma radiation and SimGCRSim groups exhibited decreased endothelial coverage. This indicates significantly reduced arterial endothelial cell integrity more than one year after radiation exposure. We next examined expression of endothelial nitric oxide synthase (eNOS) in the endothelium of atherosclerotic plaques, a key regulator of vascular homeostasis and endothelial function. Consistent with the reduction in CD31&lt;sup&gt;+&lt;/sup&gt; and VE-cadherin&lt;sup&gt;+&lt;/sup&gt; endothelial cell coverage, luminal eNOS expression was reduced in the gamma irradiat","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 8","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70774","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148723816","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}