Clinical and Translational Medicine最新文献

{"title":"Cannabinoid receptor 2 facilitates the Schwann cells-dependent peripheral nerve regeneration","authors":"Heng Xu, Lu Wen, Yi Luo, Jiaying Zhou, Sheng Yao, Wei Ding, Jing Feng","doi":"10.1002/ctm2.70184","DOIUrl":"10.1002/ctm2.70184","url":null,"abstract":"<p>Dear Editor:</p><p>Here, we demonstrated that cannabinoid receptor 2 (CB2) plays a pivotal role in Schwann cells (SCs) by promoting the remyelination process following peripheral nerve injury (PNI). Selective activation of CB2 shows potential as a therapeutic approach to enhance nerve repair in these injuries.</p><p>Schwann cells form Büngner bands to guide axonal regeneration during PNI. However, the slow pace of axonal growth (∼1–3 mm/day) often leads to the degradation of these structures within 8 weeks, thereby disrupting the regenerative process.<span><sup>1, 2</sup></span> CB2 activation has been shown to promote remyelination and enhance nerve regeneration by modulating inflammatory responses and supporting cellular processes essential for nerve repair.<span><sup>3, 4</sup></span> However, the cellular mechanisms of CB2 function in remyelination remain unclear. This prompted the hypothesis that selective activation of CB2 could maintain Schwann cell function and create a more conducive environment for axonal regeneration.</p><p>To investigate this, we employed a mouse model of crush injury and treated the mice with delta-9-tetrahydrocannabinol (Δ<sup>9</sup>-THC, a partial agonist of both CB1 and CB2 receptors, for 16 consecutive days; Figure S1A). Interestingly, Δ<sup>9</sup>-THC treatment resulted in significantly increased growth rate of injured axons and improved behaviour in mice, including reflexive mechanical allodynia and walking parameters (Figure S1B–K). To exclude the possibility that Δ<sup>9</sup>-THC exerts its effect via CB1 activation, we used CB2-specific agonists. Although the agonist (GW842166X, EC50: ∼63 nM) did not improve mechanical pain (Figure S2A), the more efficient agonist, AM1241 (EC50: ∼3.4 nM), showed therapeutic efficacy. As expected, compared with vehicle treatment, daily administration of AM1241 significantly improved mechanical allodynia, gait abnormalities and motor function in mice. These improvements were further abolished when AM1241 was co-administered with the CB2 antagonist AM630 (Figure 1 and Figure S2B). Consistent with these behavioural data, immunofluorescence staining showed that while nerves in the control group began to extend along their original growth direction, this change appeared to be more pronounced after AM1241 treatment (Figure S3A–C). We also examined the mRNA expression of genes related to myelination in the sciatic nerve tissues using real-time quantitative PCR (RT-qPCR). In the presence of AM1241, pro-myelination-related genes including Sox10, Egr2 and Tprv4 were significantly upregulated, whereas AM630 blocked CB2-dependent gene upregulation. Trpv4 has been proved to delay the re-myelination after nerve injury.<span><sup>5, 6</sup></span> Interestingly, the expression of the SCs dedifferentiation-related genes Sox2 and c-Jun was not affected (Figure S3D). Moreover, Aniline Blue staining and electron microscopy demonstrated that CB2 stimulation significantly increased myelin t","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11707426/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945714","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":"Commentary: Molecular responses in pig heart to human xenotransplantation unveiled by longitudinal multi-omic profiling","authors":"Brendan J. Keating, Eloi Schmauch, Michael P. Snyder, Jennifer D. Motter, Brian D. Piening","doi":"10.1002/ctm2.70132","DOIUrl":"10.1002/ctm2.70132","url":null,"abstract":"<p>Orthotopic heart transplantation is considered to be the best treatment for end-stage heart failure, with improved survival and quality of life for patients.<span><sup>1</sup></span> Despite the number of adult and pediatric heart transplants performed in the US having reached >4000 annually, the number of patients waiting for a heart allograft continues to exceed the available supply.<span><sup>2</sup></span> Xenotransplantation has emerged as a promising alternative to address the demand by providing a source of organs that is readily available and practically inexhaustible.<span><sup>3</sup></span> Given their anatomical and physiological similarity to humans, pigs are considered the most suitable donor species for xenotransplantation,<span><sup>4</sup></span> with immunologic barriers steadily being overcome through advances in targeted genetic engineering of the porcine genome and immunosuppression therapies.<span><sup>4, 5</sup></span> In 2022, two brain-dead human recipients “decedents” received 10-gene-edited porcine hearts. Over the two ∼3-day studies, there was sustained cardiac function, without evidence of acute-onset rejection or zoonotic transmission.<span><sup>6</sup></span> To better elucidate the molecular processes in the peripheral blood and pig heart xenograft tissues, Schmauch and colleagues recently reported in <i>Nature Medicine</i> the dynamic molecular interactions following these pig heart to human decedent xenotransplants using comprehensive, longitudinal multi-omic profiling.<span><sup>7</sup></span> This commentary dissects their key findings, emphasising the clinical translational implications and highlighting future research avenues in this evolving field.</p><p>Over the last decade, methodological and technical advances have led to the development of high-throughput, low-cost technologies where millions of biomolecules spanning nucleic acids, proteins, lipids and metabolites can be measured simultaneously.<span><sup>8</sup></span> This includes advances in high-throughput sequencing, with current platforms able to produce large high-quality human and pig whole genome sequencing (WGS), RNA-sequencing, epigenetic and genomic structure profiling e.g., bisulfite WGS and <span>A</span>ssay for <span>T</span>ransposase-<span>a</span>ccessible <span>c</span>hromatin with <span>seq</span>uencing (ATAC-seq), a technique that assesses chromatin accessibility across the genome. A number of these sequencing approaches can be performed in tissues as well as in cell-free fractions of DNA and RNA in peripheral fluids including blood and urine. Concomitantly, advances in biochemical preparation and mass spectrometry technologies have enabled the large-scale quantitative profiling of proteins (proteomics), metabolites (metabolomics) and lipids (lipidomics) in tissues and bodily fluids. Current advances have afforded the ability to perform a variety of assays at single cell resolution, for example, scRNA-seq and scATAC-seq, wh","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11707427/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945715","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":"Somatic mutation correlation with lymph node metastasis and prognosis in T1/2 stage colorectal cancer patients: A propensity score matching analysis","authors":"Junwei Tang, Yue Zhang, Dongjian Ji, Lu Wang, Han Zhuo, Yaping Wang, Yueming Sun","doi":"10.1002/ctm2.70179","DOIUrl":"10.1002/ctm2.70179","url":null,"abstract":"<p>Dear Editor,</p><p>Our study provides a comprehensive analysis of the correlation between specific somatic mutations and the lymph node metastasis in colorectal cancer (CRC) patients with T1/2 stage, addressing a significant gap in the early-stage prognosis and individualised treatment of CRC. By leveraging next-generation sequencing (NGS) and clinical data, we identified key mutations and pathological characteristics that can serve as robust predictors of lymph node metastasis, thereby enhancing clinicians' ability to stratify T1/2 CRC patients based on metastatic risk.</p><p>CRC remains a prevalent malignancy worldwide, with early-stage cases, particularly T1/2 stages, generally associated with favourable outcomes.<span><sup>1</sup></span> However, when lymph node metastasis is present, the prognosis worsens significantly.<span><sup>2</sup></span> Lymph node involvement in early-stage CRC is a strong indicator of potential distant metastasis and recurrence, highlighting the urgency of effective preoperative risk assessment in T1/2 patients.<span><sup>3</sup></span> Existing imaging techniques, such as enhanced computed tomography and magnetic resonance imaging, offer limited sensitivity and specificity for lymph node assessment, especially in early stages where inflammation or small metastatic nodes may escape detection.<span><sup>4, 5</sup></span> Therefore, identifying molecular markers that can predict lymph node involvement with high accuracy is paramount to guiding treatment decisions in early-stage CRC. Our study contributes to this goal by identifying specific genetic mutations and clinical features associated with metastatic risk, thus enabling a more refined preoperative evaluation of T1/2 stage CRC patients.</p><p>We conducted a retrospective cohort study including 212 T1/2 CRC patients (Figure S1), who were categorised based on lymph node involvement into T1/2N+ and T1/2N‒ groups and matched using propensity score analysis (Figure 1 and Table S1). Our NGS data showed that mutations in four genes (LRP1B, KMT2B, TSC2 and BRAF) were significantly more frequent in the T1/2N+ group (Figure 2), and the presence of any of these mutations correlated with reduced overall survival (Figure S2). Among the four, BRAF mutations have been widely recognised in literature as a poor prognostic factor in advanced CRC,<span><sup>6</sup></span> but their impact in early stages has remained largely unexplored until now. Additionally, LRP1B, KMT2B and TSC2 mutations appear to be novel findings in the context of early-stage lymph node metastasis in CRC, indicating that they could potentially be unique markers for predicting outcomes in T1/2 patients (Figure 3). Our analysis also showed that patients with LRP1B mutations had particularly poor survival outcomes, with a median survival of 22.2 months.</p><p>In addition to these molecular findings, there was no significant difference in the distribution of MSI status and TMB between the two groups; however, ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11705726/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945556","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":"Integrating multi-omics features enables non-invasive early diagnosis and treatment response prediction of diffuse large B-cell lymphoma","authors":"Weilong Zhang,&nbsp;Bangquan Ye,&nbsp;Yang Song,&nbsp;Ping Yang,&nbsp;Wenzhe Si,&nbsp;Hairong Jing,&nbsp;Fan Yang,&nbsp;Dan Yuan,&nbsp;Zhihong Wu,&nbsp;Jiahao Lyu,&nbsp;Kang Peng,&nbsp;Xu Zhang,&nbsp;Lingli Wang,&nbsp;Yan Li,&nbsp;Yan Liu,&nbsp;Chaoling Wu,&nbsp;Xiaoyu Hao,&nbsp;Yuqi Zhang,&nbsp;Wenxin Qi,&nbsp;Jing Wang,&nbsp;Fei Dong,&nbsp;Zijian Zhao,&nbsp;Hongmei Jing,&nbsp;Yanzhao Li","doi":"10.1002/ctm2.70174","DOIUrl":"10.1002/ctm2.70174","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Multi-omics features of cell-free DNA (cfDNA) can effectively improve the performance of non-invasive early diagnosis and prognosis of cancer. However, multimodal characterization of cfDNA remains technically challenging.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We developed a comprehensive multi-omics solution (COMOS) to specifically obtain an extensive fragmentomics landscape, presented by breakpoint characteristics of nucleosomes, CpG islands, DNase clusters and enhancers, besides typical methylation, copy number alteration of cfDNA. The COMOS was tested on 214 plasma samples of diffuse large B-cell lymphoma (DLBCL) and matched healthy controls.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>For early diagnosis, COMOS improved the area under the curve (AUC) value to .993 compared with the individual omics model, with a sensitivity of 95% at 98% specificity. Detection sensitivity achieved 91% at 99% specificity in early-stage patients, while the AUC values of the individual omics model were 0.942, 0.968, 0.989, 0.935, 0.921, 0.781 and 0.917, respectively, with lower sensitivity and specificity. In the treatment response cohort, COMOS yielded a superior sensitivity of 88% at 86% specificity (AUC, 0.903). COMOS has achieved excellent performance in early diagnosis and treatment response prediction.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our study provides an effectively improved approach with high accuracy for the diagnosis and prognosis of DLBCL, showing great potential for future clinical application.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>A comprehensive multi-omics solution to specifically obtain an extensive fragmentomics landscape, presented by breakpoint characteristics of nucleosomes, CpG islands, DNase clusters and enhancers, besides typical methylation, copy number alteration of cfDNA.</li>\u0000 \u0000 <li>Integrated model of cfDNA multi-omics could be used for non-invasive early diagnosis of DLBCL.</li>\u0000 \u0000 <li>Integrated model of cfDNA multi-omics could effectively evaluate the efficacy of R-CHOP before DLBCL treatment.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11705727/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945528","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of acetylation and deacetylation in cancer metabolism","authors":"Cuicui Wang,&nbsp;Xiaoxin Ma","doi":"10.1002/ctm2.70145","DOIUrl":"10.1002/ctm2.70145","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>As a hallmark of cancer, metabolic reprogramming adjusts macromolecular synthesis, energy metabolism and redox homeostasis processes to adapt to and promote the complex biological processes of abnormal growth and proliferation. The complexity of metabolic reprogramming lies in its precise regulation by multiple levels and factors, including the interplay of multiple signalling pathways, precise regulation of transcription factors and dynamic adjustments in metabolic enzyme activity. In this complex regulatory network, acetylation and deacetylation, which are important post-translational modifications, regulate key molecules and processes related to metabolic reprogramming by affecting protein function and stability. Dysregulation of acetylation and deacetylation may alter cancer cell metabolic patterns by affecting signalling pathways, transcription factors and metabolic enzyme activity related to metabolic reprogramming, increasing the susceptibility to rapid proliferation and survival. In this review, we focus on discussing how acetylation and deacetylation regulate cancer metabolism, thereby highlighting the central role of these post-translational modifications in metabolic reprogramming, and hoping to provide strong support for the development of novel cancer treatment strategies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Protein acetylation and deacetylation are key regulators of metabolic reprogramming in tumour cells.</li>\u0000 \u0000 <li>These modifications influence signalling pathways critical for tumour metabolism.</li>\u0000 \u0000 <li>They modulate the activity of transcription factors that drive gene expression changes.</li>\u0000 \u0000 <li>Metabolic enzymes are also affected, altering cellular metabolism to support tumour growth.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11706801/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945562","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":"PINK1 modulates Prdx2 to reduce lipotoxicity-induced apoptosis and attenuate cardiac dysfunction in heart failure mice with a preserved ejection fraction","authors":"Hao Zhang,&nbsp;Tianyu Xu,&nbsp;Xiyuan Mei,&nbsp;Qiming Zhao,&nbsp;Qiling Yang,&nbsp;Xianghui Zeng,&nbsp;Zhuang Ma,&nbsp;Haobin Zhou,&nbsp;Qingchun Zeng,&nbsp;Dingli Xu,&nbsp;Hao Ren","doi":"10.1002/ctm2.70166","DOIUrl":"10.1002/ctm2.70166","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Introduction&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Heart failure with preserved ejection fraction (HFpEF) is a complex condition characterized by metabolic dysfunction and myocardial lipotoxicity. The roles of PTEN-induced kinase 1 (PINK1) and peroxiredoxin-2 (Prdx2) in HFpEF pathogenesis remain unclear.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Objective&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;This study aimed to investigate the interaction between PINK1 and Prdx2 to mitigate cardiac diastolic dysfunction in HFpEF.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;In vivo, PINK1-knockout mice and cardiac-specific PINK1-overexpressing transgenic mice were used to establish an HFpEF mouse model via a high-fat diet and L-NAME. Myocardial lipotoxicity was induced by palmitic acid in vitro. Immunoprecipitation, western blotting and immunofluorescence analysis were performed to elucidate the molecular mechanisms involved.&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 determined that PINK1 and Prdx2 were downregulated in the HFpEF mouse model. In vivo, PINK1 ablation exacerbated the reduction in Prdx2 expression, worsening cardiac dysfunction in HFpEF mice. Conversely, PINK1 overexpression restored Prdx2 levels and decreased reactive oxygen species and apoptosis, thereby reducing fibrosis and inflammation and ameliorating cardiac diastolic dysfunction in HFpEF mice. In vitro, an interaction between the N-terminal region (amino acids 1–133) of PINK1 and Prdx2 was identified. The overexpression of PINK1 induced Prdx2 expression and effectively attenuated palmitic acid-induced apoptosis through the c-Jun amino-terminal kinase (JNK) and mitogen-activated protein kinase (p38) pathways, whereas siRNA-mediated Prdx2 knockdown abolished the protective effect of PINK1.&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;PINK1 alleviates lipotoxicity-induced myocardial apoptosis and improves diastolic dysfunction in HFpEF through Prdx2, highlighting PINK1 overexpression as a potential therapeutic strategy for HFpEF.&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;Our investigation discloses a pivotal relationship between PINK1 and Prdx2 in the context of HFpEF.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Notably, PINK1, in addition to its role in mitochondrial autophagy, can increase Prdx2 expression, effectively remove ROS and attenuate c","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11705485/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945553","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The N1-methyladenosine methyltransferase TRMT61A promotes bladder cancer progression and is targetable by small molecule compounds","authors":"Jianjian Yin,&nbsp;Xin Fan,&nbsp;Qi Chang,&nbsp;Yuanheng Dai,&nbsp;Tao Wang,&nbsp;Lei Shi,&nbsp;Linlin Yang,&nbsp;Xiaoming Yang,&nbsp;Xudong Zhang,&nbsp;Lei Jin,&nbsp;Tao Liu,&nbsp;Fengmin Shao,&nbsp;Lirong Zhang,&nbsp;Dongkui Song","doi":"10.1002/ctm2.70137","DOIUrl":"10.1002/ctm2.70137","url":null,"abstract":"&lt;p&gt;Dear Editor,&lt;/p&gt;&lt;p&gt;Bladder cancer (BLCA) is the most common malignant tumour of the urinary system and has a high recurrence rate.&lt;span&gt;&lt;sup&gt;1, 2&lt;/sup&gt;&lt;/span&gt; N&lt;sup&gt;1&lt;/sup&gt;-methyladenosine (m&lt;sup&gt;1&lt;/sup&gt;A) methylation is a key mechanism of post-transcriptional regulation.&lt;span&gt;&lt;sup&gt;3-5&lt;/sup&gt;&lt;/span&gt; m&lt;sup&gt;1&lt;/sup&gt;A levels in the urine of BLCA patients are higher than in the urine of normal people, and TRMT61A is highly expressed in human BLCA tissues.&lt;span&gt;&lt;sup&gt;6, 7&lt;/sup&gt;&lt;/span&gt; Although some reports are consistent with our previous results,&lt;span&gt;&lt;sup&gt;8&lt;/sup&gt;&lt;/span&gt; the biological functions and potential mechanisms of action of m&lt;sup&gt;1&lt;/sup&gt;A methylation in BLCA remain unknown.&lt;/p&gt;&lt;p&gt;Here, the role of TRMT61A in BLCA was assessed in vitro and in vivo. Silencing TRMT61A inhibited 5637 cell proliferation, clonogenicity, migration and invasion, while its overexpression was promoted in T24 cells (Figure S1A,B and Figure 1A–F). Total m&lt;sup&gt;1&lt;/sup&gt;A levels in RNA decreased and increased following TRMT61A knocking-down, and over-expression, respectively. Quantitative ultra-performance liquid chromatography/mass spectrometry analysis confirmed these results (Figure 1G–J). In vivo, tumour growth was effectively suppressed, as reflected by the significant reduction in tumour size and weight in the short hairpin RNA (shRNA) TRMT61A group. Immunohistochemistry staining showed a marked decrease in the proportion of tumour cells positively stained by anti-Ki-67 antibody in the shRNA TRMT61A group (Figure S1C and Figure 1K–M). Overall, TRMT61A promotes m&lt;sup&gt;1&lt;/sup&gt;A modification and BLCA progression.&lt;/p&gt;&lt;p&gt;To identify the target mRNAs of TRMT61A in BLCA, we conducted MeRIP-seq and RNA-seq analyses between control shRNA and TRMT61A shRNA. According to MeRIP-seq analysis, m&lt;sup&gt;1&lt;/sup&gt;A peaks were particularly abundant in the vicinity of 5′ untranslated regions near coding sequence regions and were found throughout the genome and across all chromosomes (Figure 2A and Figure S2A). HMOX2 mRNA was evidently m&lt;sup&gt;1&lt;/sup&gt;A de-methylated in the MeRIP-seq data and downregulated in RNA-seq data after TRMT61A knockdown, and overexpressed in human BLCA tissues; the same result was obtained with The Cancer Genome Atlas (TCGA) database (Figure 2B,C and Figure S2E). AGGCUGG/A was the top m&lt;sup&gt;1&lt;/sup&gt;A-modified motif; the HMOX2 mRNA m&lt;sup&gt;1&lt;/sup&gt;A peak diminished upon TRMT61A knockdown (Figure S2F,G). Therefore, further investigations focused on HMOX2 as a TRMT61A target. We observed that HMOX2 was downregulated following TRMT61A knockdown in 5637 cells and upregulated in T24 cells overexpressing TRMT61A (Figure 2D). Using samples from BLCA patients, a positive correlation was observed between HMOX2 and TRMT61A expression; HMOX2 expression decreased in tumour tissues from mice xenografted with TRMT61A shRNA and increased in tumour tissues from BBN-driven urinary BLCA mice (Figures S2H–K and S3). TRMT61A promoted BLCA progression by upregulating the HMOX2 level (Figure S4).","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11705484/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945559","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":"Enhancement of anti-sarcoma immunity by NK cells engineered with mRNA for expression of a EphA2-targeted CAR","authors":"Pui Yeng Lam,&nbsp;Natacha Omer,&nbsp;Josh K. M. Wong,&nbsp;Cui Tu,&nbsp;Louisa Alim,&nbsp;Gustavo R. Rossi,&nbsp;Maria Victorova,&nbsp;Hannah Tompkins,&nbsp;Cheng-Yu Lin,&nbsp;Ahmed M. Mehdi,&nbsp;Amos Choo,&nbsp;Melissa R. Elliott,&nbsp;Elaina Coleborn,&nbsp;Jane Sun,&nbsp;Timothy Mercer,&nbsp;Orazio Vittorio,&nbsp;Lachlan J. Dobson,&nbsp;Alexander D. McLellan,&nbsp;Andrew Brooks,&nbsp;Zewen Kelvin Tuong,&nbsp;Seth W. Cheetham,&nbsp;Wayne Nicholls,&nbsp;Fernando Souza-Fonseca-Guimaraes","doi":"10.1002/ctm2.70140","DOIUrl":"10.1002/ctm2.70140","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;Paediatric sarcomas, including rhabdomyosarcoma, Ewing sarcoma and osteosarcoma, represent a group of malignancies that significantly contribute to cancer-related morbidity and mortality in children and young adults. These cancers share common challenges, including high rates of metastasis, recurrence or treatment resistance, leading to a 5-year survival rate of approximately 20% for patients with advanced disease stages. Despite the critical need, therapeutic advancements have been limited over the past three decades. The advent of chimeric antigen receptor (CAR)-based immunotherapies offers a promising avenue for novel treatments. However, CAR-T cells have faced significant challenges and limited success in treating solid tumours due to issues such as poor tumour infiltration, immunosuppressive tumour microenvironments and off-target effects. In contrast, the adaptation of CAR technology for natural killer (NK) cells has demonstrated potential in both haematological and solid tumours, suggesting a new therapeutic strategy for paediatric sarcomas.&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;This study developed and validated a novel CAR-NK cell therapy targeting the ephrin type-A receptor-2 (EphA2) antigen, which is highly expressed in various paediatric sarcomas.&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;CAR expression was successfully detected on the surface of NK cells post-electroporation, indicating successful transfection. Significantly, EphA2-specific CAR-NK cells demonstrated enhanced cytotoxic activity against several paediatric sarcoma cell lines in vitro, including those of rhabdomyosarcoma, Ewing sarcoma and osteosarcoma, compared to unmodified NK cells. Transient messenger RNA (mRNA) transfection of NK cells is a safe approach in genetic engineering, with further chemical modifications to mRNA enhancing stability of temporal EphA2-CAR expression in NK cells, thereby promoting prolonged protein expression. Additionally, in vivo EphA2-CAR-NK cells showed promising anti-cancer activity in rhabdomyosarcoma and osteosarcoma mouse 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;The study provides a foundational basis for the clinical evaluation of EphA2-targeted CAR-NK cell therapy across a spectrum of paediatric sarcomas. The enhanced anti-tumour effects observed in vitro/vivo suggests potential for improved therapeutic outcomes in hard-to-cure paediatric sarcomas.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Key points&lt;/h3&gt;\u0000 ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11705447/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945718","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":"Transforming precision medicine: The potential of the clinical artificial intelligent single-cell framework","authors":"Christian Baumgartner,&nbsp;Dagmar Brislinger","doi":"10.1002/ctm2.70096","DOIUrl":"10.1002/ctm2.70096","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>The editorial, “Clinical and translational mode of single-cell measurements: An artificial intelligent single-cell,” introduces the innovative clinical artificial intelligence single-cell (caiSC) system, which merges AI with single-cell informatics to advance real-time diagnostics, disease monitoring, and treatment prediction. By combining clinical data and multimodal molecular inputs, caiSC facilitates personalized medicine, promising enhanced diagnostic precision and tailored therapeutic approaches. Despite its potential, caiSC lacks comprehensive data coverage across cell types and diseases, presenting challenges in data quality and model robustness. The article explores development strategies such as data expansion, machine learning advancements, and interpretability improvements. Future applications of caiSC could include digital cell twins, offering in-depth simulations of cellular behavior to support drug discovery and personalized treatments. Regulatory considerations are discussed, underscoring the need for SaMD/AIaMD certifications for clinical use. Ultimately, with further refinement, caiSC could transform clinical decision-making, driving personalized, precision medicine, and improved patient outcomes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Integration of AI with Single-Cell Informatics for Precision Medicine: The caiSC system combines artificial intelligence and single-cell data to improve diagnostics, treatment predictions, and personalized medical decision-making.</li>\u0000 \u0000 <li>Challenges in Data Coverage and Model Robustness: caiSC currently faces limitations due to incomplete data across cell types, diseases, and organs, as well as challenges in data quality and high computational demands, which affect model accuracy and clinical applicability.</li>\u0000 \u0000 <li>Future Potential and Regulatory Needs: The caiSC framework's development could lead to innovations such as digital cell twins, enabling personalized simulations of cellular responses for better treatment planning, though regulatory certification is essential for safe clinical use.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11705532/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945564","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":"Disturbed shear stress promotes atherosclerosis through TRIM21-regulated MAPK6 degradation and consequent endothelial inflammation","authors":"Feng Wang,&nbsp;Shu-Yu Wang,&nbsp;Yue Gu,&nbsp;Shuai Luo,&nbsp;Ai-Qun Chen,&nbsp;Chao-Hua Kong,&nbsp;Wen-Ying Zhou,&nbsp;Li-Guo Wang,&nbsp;Zhi-Mei Wang,&nbsp;Guang-Feng Zuo,&nbsp;Xiao-Fei Gao,&nbsp;Jun-Jie Zhang,&nbsp;Shao-Liang Chen","doi":"10.1002/ctm2.70168","DOIUrl":"10.1002/ctm2.70168","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Rationale</h3>\u0000 \u0000 <p>Coronary artery plaques often develop in regions subjected to disturbed shear stress (DSS), yet the mechanisms underlying this phenomenon remain poorly understood. Our study aimed to elucidate the unknown role of MAPK6 in shear stress and plaque formation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In vitro and in vivo experiments, RNA-seq, CO-IP and proteomic analysis, combined with single-cell RNA-seq datasets were used to reveal the upstream and downstream mechanisms involved. AAV-MAPK6, ApoE^−/−MAPK6^flox/floxTEK^Cre mice and the CXCL12 neutraligand were used to confirm the beneficial effects of MAPK6 against atherosclerosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Our study revealed a substantial decrease in MAPK6 protein levels in endothelial cells in response to DSS, both in vivo and in vitro, which was contingent on the binding of the ubiquitin ligase TRIM21 to MAPK6. Endothelium-specific MAPK6 overexpression exerts antiatherosclerotic effects in ApoE^−/− mice, elucidating the unexplored role of MAPK6 in atherosclerosis. Comprehensive RNA-seq, integrated single-cell mapping and further experiments unveiled the involvement of MAPK6 in inflammation through the EGR1/CXCL12 axis. ApoE^−/−MAPK6^flox/floxTEK^Cre mice finally confirmed that conditional MAPK6 knockout resulted in endothelial inflammation and significant increases in plaque areas. Notably, these effects could be reversed through the neutralization of CXCL12.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our study illuminates the advantages of MAPK6 in decelerating plaque progression, highlighting the potential of safeguarding MAPK6 as a novel therapeutic strategy against atherosclerosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Disturbed flow activates the ubiquitin‒proteasome degradation pathway of MAPK6 in endothelial cells, which is contingent on the binding of the ubiquitin ligase TRIM21 to MAPK6.</li>\u0000 \u0000 <li>Endothelial MAPK6 has an advantageous impact on decelerating plaque progression.</li>\u0000 \u0000 <li>MAPK6 regulates endothelial inflammation via the EGR1/CXCL12 axis.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 1","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11705438/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945716","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}