Clinical and Translational Medicine最新文献

{"title":"ANKRD1 aggravates renal ischaemia‒reperfusion injury via promoting TRIM25-mediated ubiquitination of ACSL3","authors":"Shangting Han, Jiayu Guo, Chenyang Kong, Jun Li, Fangyou Lin, Jiefu Zhu, Tianyu Wang, Qi Chen, Yiting Liu, Haochong Hu, Tao Qiu, Fan Cheng, Jiangqiao Zhou","doi":"10.1002/ctm2.70024","DOIUrl":"https://doi.org/10.1002/ctm2.70024","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Renal ischaemia‒reperfusion injury (IRI) is the primary cause of acute kidney injury (AKI). To date, effective therapies for delaying renal IRI and postponing patient survival remain absent. Ankyrin repeat domain 1 (ANKRD1) has been implicated in some pathophysiologic processes, but its role in renal IRI has not been explored.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The mouse model of IRI-AKI and in vitro model were utilised to investigate the role of ANKRD1. Immunoprecipitation-mass spectrometry was performed to identify potential ANKRD1-interacting proteins. Protein‒protein interactions and protein ubiquitination were examined using immunoprecipitation and proximity ligation assay and immunoblotting, respectively. Cell viability, damage and lipid peroxidation were evaluated using biochemical and cellular techniques.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>First, we unveiled that ANKRD1 were significantly elevated in renal IRI models. Global knockdown of ANKRD1 in all cell types of mouse kidney by recombinant adeno-associated virus (rAAV9)-mitigated ischaemia/reperfusion-induced renal damage and failure. Silencing <i>ANKRD1</i> enhanced cell viability and alleviated cell damage in human renal proximal tubule cells exposed to hypoxia reoxygenation or hydrogen peroxide, while ANKRD1 overexpression had the opposite effect. Second, we discovered that ANKRD1's detrimental function during renal IRI involves promoting lipid peroxidation and ferroptosis by directly binding to and decreasing levels of acyl-coenzyme A synthetase long-chain family member 3 (ACSL3), a key protein in lipid metabolism. Furthermore, attenuating ACSL3 in vivo through pharmaceutical approach and in vitro via RNA interference mitigated the anti-ferroptotic effect of <i>ANKRD1</i> knockdown. Finally, we showed ANKRD1 facilitated post-translational degradation of ACSL3 by modulating E3 ligase tripartite motif containing 25 (TRIM25) to catalyse K63-linked ubiquitination of ACSL3, thereby amplifying lipid peroxidation and ferroptosis, exacerbating renal injury.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our study revealed a previously unknown function of ANKRD1 in renal IRI. By driving ACSL3 ubiquitination and degradation, ANKRD1 aggravates ferroptosis and ultimately exacerbates IRI-AKI, underlining ANKRD1's potential as a therapeutic target for kidney IRI.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Points/Highlights</h3>\u0000 \u0000 <div>\u0000 ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70024","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142245048","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":"NY-ESO-1 antigen: A promising frontier in cancer immunotherapy","authors":"Alaa Alsalloum, Julia A. Shevchenko, Sergey Sennikov","doi":"10.1002/ctm2.70020","DOIUrl":"https://doi.org/10.1002/ctm2.70020","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>Significant strides have been made in identifying tumour-associated antigens over the past decade, revealing unique epitopes crucial for targeted cancer therapy. Among these, the New York esophageal squamous cell carcinoma (NY-ESO-1) protein, a cancer/testis antigen, stands out. This protein is presented on the cell surface by major histocompatibility complex class I molecules and exhibits restricted expression in germline cells and various cancers, marking it as an immune-privileged site. Remarkably, NY-ESO-1 serves a dual role as both a tumour-associated antigen and its own adjuvant, implying a potential function as a damage-associated molecular pattern. It elicits strong humoural immune responses, with specific antibody frequencies significantly correlating with disease progression. These characteristics make NY-ESO-1 an appealing candidate for developing effective and specific immunotherapy, particularly for advanced stages of disease. In this review, we provide a comprehensive overview of NY-ESO-1 as an immunogenic tumour antigen. We then explore the diverse strategies for targeting NY-ESO-1, including cancer vaccination with peptides, proteins, DNA, mRNA, bacterial vectors, viral vectors, dendritic cells and artificial adjuvant vector cells, while considering the benefits and drawbacks of each strategy. Additionally, we offer an in-depth analysis of adoptive T-cell therapies, highlighting innovative techniques such as next-generation NY-ESO-1 T-cell products and the integration with lymph node-targeted vaccines to address challenges and enhance therapeutic efficacy. Overall, this comprehensive review sheds light on the evolving landscape of NY-ESO-1 targeting and its potential implications for cancer treatment, opening avenues for future tailored directions in NY-ESO-1-specific immunotherapy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>\u0000 <p>Endogenous immune response: NY-ESO-1 exhibited high immunogenicity, activating endogenous dendritic cells, T cells and B cells.</p>\u0000 </li>\u0000 \u0000 <li>\u0000 <p>NY-ESO-1-based cancer vaccines: NY-ESO-1 vaccines using protein/peptide, RNA/DNA, microbial vectors and artificial adjuvant vector cells have shown promise in enhancing immune responses against tumours.</p>\u0000 </li>\u0000 \u0000 <li>\u0000 <p>NY-ESO-1-specific T-cell receptor-engineered cells: NY-ESO-1-targeted T cells, along with ongoing innovations in engineered natural killer cells and other cell therapies, have improved the efficacy of immunotherapy.</p>\u0000 </li>\u0000 </ul>\u0000 ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70020","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142233217","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":"STING-ATF3/type I interferon crosstalk: A potential target to improve anti-tumour immunity in chemotherapy-treated urothelial carcinoma","authors":"Alexandra Fauvre, Margot Machu, Audrey Merienne, Nadia Vie, Thomas Bessede, Mathilde Robin, Veronique Garambois, Clara Taffoni, Nadine Laguette, Nadine Gervois-Segain, Anne Jarry, Nathalie Labarriere, Yves Allory, Christel Larbouret, Laurent Gros, Diego Tosi, David B. Solit, Philippe Pourquier, Nadine Houédé, Celine Gongora","doi":"10.1002/ctm2.70011","DOIUrl":"https://doi.org/10.1002/ctm2.70011","url":null,"abstract":"<p>Dear Editor,</p><p>In this study, we present the first demonstration that activation of the cGAS-STING pathway in tumour cells by chemotherapies does not necessarily lead to the production of type I interferon. Indeed, we show that the transcription factor ATF3, also induced by chemotherapies, acts as a transcriptional inhibitor of type I Interferon.</p><p>Upper tract urothelial carcinomas (UTUCs) are extremely aggressive and immunosuppressed tumours.<span><sup>1</sup></span> UTUC management is based on the combination of cisplatin and gemcitabine (CisGem) or carboplatin and gemcitabine (CarboGem); however, the relapse rate is > 50%.<span><sup>2</sup></span> Here, we investigated CisGem and CarboGem effects in UTUC (UM-UC-14, UCC-03, UCC-14 and UCC-17) and bladder cancer cell lines (HT-1197 and MB49) to identify additional targets that might improve their efficiency.</p><p>First, using a full-range dose matrix approach<span><sup>3</sup></span> SRB cytotoxicity assays we found that CisGem and CarboGem displayed an additive effect in 2D cultures and areas of synergistic effects in 3D cultures of UM-UC-14, HT-1197, MB49, UCC-03 and UCC-17 cells (Figure S1A), independently of their sensitivity (IC<sub>50</sub> in Figure S1B) to these drugs. Moreover, H2AX, ATM, ATR, CHK1 and CHK2 (but not DNA-PKcs) phosphorylation was increased in cells incubated with CisGem or CarboGem, indicating DNA damage induction and DNA damage response pathway activation (multiplexed immunofluorescence analysis; Figure S2A).</p><p>RNA-sequencing analysis of UM-UC-14 cells incubated with CisGem for 24 h identified 482 upregulated genes (particularly <i>ATF3</i>) and 376 downregulated genes (Figure S3A). Gene Set Enrichment Analysis indicated that four of the ten most differentially expressed gene sets were related to inflammation (Figure 1A). The enrichment scores for these four gene sets were high (<i>p</i> = 0.0026) and many IFN-stimulated genes (ISGs) were upregulated (Figure 1B and Figure S3B). We obtained similar results with CarboGem (Figure S3C–E). Moreover, in vitro analysis of calreticulin exposure, ATP release and HMGB1 release (Figure 2C–E) showed that the combinations induce immunogenic cell death markers, unlike cisplatin and carboplatin alone. Both combinations also upregulated <i>PD-L1</i> transcript, protein levels and PD-L1 cell surface expression (Figure S4A–D).</p><p>As DNA damage can activate the cGAS-STING pathway,<span><sup>4, 5</sup></span> particularly by releasing damaged DNA into the cytosol, we monitored the presence of DNA in the cytoplasm, TBK1 (STING target) and IRF3 phosphorylation, and ISG expression (RT-qPCR) after incubation (or not) with CisGem and CarboGem. The amount of cytosolic DNA was slightly higher (Figure 1F and Figure S2B), and phosphorylation of TBK1 and IRF3 (Figure 1G and Figure S2C), but not of NF-κB (Figure S4E) was increased in treated than untreated cultures. Moreover, CisGem and CarboGem induced expression of ISGs (Figur","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70011","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142230951","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 senescence-associated secretory phenotypes to remodel the tumour microenvironment and modulate tumour outcomes","authors":"Jiaqiang Xiong,&nbsp;Lu Dong,&nbsp;Qiongying Lv,&nbsp;Yutong Yin,&nbsp;Jiahui Zhao,&nbsp;Youning Ke,&nbsp;Shixuan Wang,&nbsp;Wei Zhang,&nbsp;Meng Wu","doi":"10.1002/ctm2.1772","DOIUrl":"https://doi.org/10.1002/ctm2.1772","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>Tumour cell senescence can be induced by various factors, including DNA damage, inflammatory signals, genetic toxins, ionising radiation and nutrient metabolism. The senescence-associated secretory phenotype (SASP), secreted by senescent tumour cells, possesses the capacity to modulate various immune cells, including macrophages, T cells, natural killer cells and myeloid-derived suppressor cells, as well as vascular endothelial cells and fibroblasts within the tumour microenvironment (TME), and this modulation can result in either the promotion or suppression of tumorigenesis and progression. Exploring the impact of SASP on the TME could identify potential therapeutic targets, yet limited studies have dissected its functions. In this review, we delve into the causes and mechanisms of tumour cell senescence. We then concentrate on the influence of SASP on the tumour immune microenvironment, angiogenesis, extracellular matrix and the reprogramming of cancer stem cells, along with their associated tumour outcomes. Last, we present a comprehensive overview of the diverse array of senotherapeutics, highlighting their prospective advantages and challenge for the treatment of cancer patients.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Senescence-associated secretory phenotype (SASP) secretion from senescent tumour cells significantly impacts cancer progression and biology.</li>\u0000 \u0000 <li>SASP is involved in regulating the remodelling of the tumour microenvironment, including immune microenvironment, vascular, extracellular matrix and cancer stem cells.</li>\u0000 \u0000 <li>Senotherapeutics, such as senolytic, senomorphic, nanotherapy and senolytic vaccines, hold promise for enhancing cancer treatment efficacy.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.1772","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142230958","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":"Low methylthioadenosine phosphorylase expression is associated with worse survival in patients with acute myeloid leukaemia","authors":"Yiyu Xiao,&nbsp;Qianqian Peng,&nbsp;Advaith Maya Sanjeev Kumar,&nbsp;Houda Alachkar","doi":"10.1002/ctm2.70015","DOIUrl":"https://doi.org/10.1002/ctm2.70015","url":null,"abstract":"&lt;p&gt;Dear Editor,&lt;/p&gt;&lt;p&gt;Deletions of methylthioadenosine phosphorylase (&lt;i&gt;MTAP&lt;/i&gt;) are frequent in several malignancies and lead to 5′-deoxy-5′-methylthioadenosine (MTA) accumulation, competing with S-adenosylmethionine (SAM) for binding to Protein Arginine Methyltransferase 5 (PRMT5) and enhancing tumour sensitivity to PRMT5 inhibitors.&lt;span&gt;&lt;sup&gt;1, 2&lt;/sup&gt;&lt;/span&gt; Although MTAP enzyme deficiency has been documented in acute myeloid leukaemia (AML), deletions of the MTAP gene have not been identified in this haematological malignancy. Here we evaluated MTAP downregulation in AML datasets (TCGA and OHSU)&lt;span&gt;&lt;sup&gt;3-7&lt;/sup&gt;&lt;/span&gt; and its associations with clinical and molecular characteristics and patient's clinical outcome.&lt;/p&gt;&lt;p&gt;When comparing the &lt;i&gt;MTAP&lt;/i&gt; expression between AML bone marrow (BM) (&lt;i&gt;n&lt;/i&gt; = 542) and healthy BM (&lt;i&gt;n&lt;/i&gt; = 73), different &lt;i&gt;MTAP&lt;/i&gt; probes showed different results (MILE dataset,&lt;span&gt;&lt;sup&gt;8&lt;/sup&gt;&lt;/span&gt; Figure 1A–F). However, when comparing the GTEx and TCGA datasets on UCSC Xena,&lt;span&gt;&lt;sup&gt;9&lt;/sup&gt;&lt;/span&gt; we found higher &lt;i&gt;MTAP&lt;/i&gt; expression in AML blood (&lt;i&gt;n&lt;/i&gt; = 173) than normal blood samples (&lt;i&gt;n&lt;/i&gt; = 337) (median-log2: 4.040 vs. −0.199, &lt;i&gt;p &lt;/i&gt;= 6.596e&lt;sup&gt;−197&lt;/sup&gt;, Figure 1G). Thirteen transcripts of MTAP were differentially expressed (Figure 1H). While only one deep deletion case was identified in AML in the TCGA dataset, using Z-score &lt; −1 to define low expressor &lt;i&gt;MTAP&lt;/i&gt;, we found 10.40% and 16.84% of cases have low &lt;i&gt;MTAP&lt;/i&gt; expression in the TCGA and OHSU, respectively (Figure 1I).&lt;/p&gt;&lt;p&gt;To investigate whether low expression of &lt;i&gt;MTAP&lt;/i&gt; is associated with specific baseline clinical features in patients with AML, we compared the frequency of &lt;i&gt;MTAP&lt;/i&gt; low expression according to diagnosis age, sex, BM blast percentage, white blood cell count, peripheral blasts percentage, cytogenetic risk and molecular risk (Tables S1 and S2). In the TCGA dataset, we found &lt;i&gt;MTAP&lt;/i&gt; low expression to be more frequent in older patients (diagnosis age ≥ 65 years) than in younger patients (diagnosis age &lt; 65 years) (18.87% vs. 6.67%, &lt;i&gt;p &lt;/i&gt;= .027). &lt;i&gt;MTAP&lt;/i&gt; expression levels were found to be lower in patients with AML M3 (&lt;i&gt;n&lt;/i&gt; = 16) than AML M2 (&lt;i&gt;n&lt;/i&gt; = 38) (&lt;i&gt;p&lt;/i&gt; = .030, Figure 2A).&lt;/p&gt;&lt;p&gt;We also assessed the association between &lt;i&gt;MTAP&lt;/i&gt; low expression and AML molecular characteristics in terms of the presence of certain AML mutations (Tables S3 and S4). We compared the frequencies of &lt;i&gt;FLT3&lt;/i&gt;, &lt;i&gt;DNMT3A&lt;/i&gt;, &lt;i&gt;NPM1&lt;/i&gt;, &lt;i&gt;IDH2&lt;/i&gt;, &lt;i&gt;IDH1&lt;/i&gt; and &lt;i&gt;TP53&lt;/i&gt; mutations between low and unaltered/high &lt;i&gt;MTAP&lt;/i&gt; patients. In OHSU, patients with MTAP low expression have a lower frequency of FLT3 mutations (17.3% vs. 32.1%, &lt;i&gt;p&lt;/i&gt; = .036) and NPM1 mutation (3.8% vs. 30.6%, &lt;i&gt;p&lt;/i&gt; &lt; .001) compared with unaltered/high MTAP group. &lt;i&gt;MTAP&lt;/i&gt; was expressed at significantly higher levels in patients with &lt;i&gt;NPM1&lt;/i&gt; mutation (median-log2, TCGA: 1037 vs. 857.5, &lt;i&gt;p &lt;","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70015","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142170231","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 emerging roles of UFMylation in the modulation of immune responses","authors":"Zhengyan Liang,&nbsp;Rongxuan Ning,&nbsp;Zhaoxiang Wang,&nbsp;Xia Kong,&nbsp;Yubin Yan,&nbsp;Yafei Cai,&nbsp;Zhiwei He,&nbsp;Xin-guang Liu,&nbsp;Yongkang Zou,&nbsp;Junzhi Zhou","doi":"10.1002/ctm2.70019","DOIUrl":"https://doi.org/10.1002/ctm2.70019","url":null,"abstract":"<p>Post-translational modification is a rite of passage for cellular functional proteins and ultimately regulate almost all aspects of life. Ubiquitin-fold modifier 1 (UFM1) system represents a newly identified ubiquitin-like modification system with indispensable biological functions, and the underlying biological mechanisms remain largely undiscovered. The field has recently experienced a rapid growth of research revealing that UFMylation directly or indirectly regulates multiple immune processes. Here, we summarised important advances that how UFMylation system responds to intrinsic and extrinsic stresses under certain physiological or pathological conditions and safeguards immune homeostasis, providing novel perspectives into the regulatory framework and functions of UFMylation system, and its therapeutic applications in human diseases.</p>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70019","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142170134","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":"Unveiling the functional roles of patient-derived tumour organoids in assessing the tumour microenvironment and immunotherapy","authors":"Di Chen,&nbsp;Lixia Xu,&nbsp;Mengjuan Xuan,&nbsp;Qingfei Chu,&nbsp;Chen Xue","doi":"10.1002/ctm2.1802","DOIUrl":"10.1002/ctm2.1802","url":null,"abstract":"<p>Recent studies have established the pivotal roles of patient-derived tumour organoids (PDTOs), innovative three-dimensional (3D) culture systems, in various biological and medical applications. PDTOs, as promising tools, have been established and extensively used for drug screening, prediction of immune response and assessment of immunotherapeutic effectiveness in various cancer types, including glioma, ovarian cancer and so on. The overarching goal is to facilitate the translation of new therapeutic modalities to guide personalised immunotherapy. Notably, there has been a recent surge of interest in the co-culture of PDTOs with immune cells to investigate the dynamic interactions between tumour cells and immune microenvironment. A comprehensive and in-depth investigation is necessary to enhance our understanding of PDTOs as promising testing platforms for cancer immunotherapy. This review mainly focuses on the latest updates on the applications and challenges of PDTO-based methods in anti-cancer immune responses. We strive to provide a comprehensive understanding of the potential and prospects of PDTO-based technologies as next-generation strategies for advancing immunotherapy approaches.</p>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.1802","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142153258","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":"Tailored chemotherapy: Innovative deep-learning model customizing chemotherapy for high-grade serous ovarian carcinoma","authors":"Se Ik Kim,&nbsp;Sangick Park,&nbsp;Eunyong Ahn,&nbsp;Jeunhui Kim,&nbsp;HyunA Jo,&nbsp;Juwon Lee,&nbsp;Untack Cho,&nbsp;Maria Lee,&nbsp;Cheol Lee,&nbsp;Danny N. Dhanasekaran,&nbsp;Taejin Ahn,&nbsp;Yong Sang Song","doi":"10.1002/ctm2.1774","DOIUrl":"10.1002/ctm2.1774","url":null,"abstract":"&lt;p&gt;Dear Editor,&lt;/p&gt;&lt;p&gt;The study presents a novel RNA-seq-based deep-learning model for predicting the chemoresistance of platinum-based therapy in high-grade serous ovarian carcinoma (HGSOC), aiming to personalize chemotherapy and improve patient outcomes. By leveraging diverse transcriptome datasets of ovarian tissue and employing deep ensemble learning techniques, the model prioritized to predict chemo-resistant HGSOC patients after initial platinum-based chemotherapy with high performance prioritized to sensitivity (sensitivity 100%, specificity 54.1% and area under the curve [AUC] 0.85). This may offer treatment strategies and enhance clinical reliability.&lt;/p&gt;&lt;p&gt;HGSOC remains a significant health burden with high mortality rates worldwide, often diagnosed late due to ineffective screening.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Furthermore, despite extensive surgery and chemotherapy, chemo-resistance remains a major challenge of platinum-based therapy in HGSOC, necessitating accurate prediction methods to improve patient outcomes and guide treatment decisions. Predicting the chemo-sensitivity of platinum-based therapy is the very first step of the personalized medicine for HGSOC, as it may offer incorporation of targeted agents.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; Genetic profiles offer potential in predicting resistance of platinum-based chemotherapy in HGSOC, supplementing clinicopathologic data inadequacies.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; Yet, reliance solely on genomic data faces challenges due to tumour heterogeneity.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; However, epigenetic factors, and DNA methylation patterns, offer promise in chemotherapy response prediction, while RNA-seq data aids in chemo-resistance prediction, requiring further validation for the clinical applicability of a small number of samples.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; Gene expression difference among racial groups in HGSOC is also confounding for accurate prediction of survival outcome.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Here, we adopt strategical approaches to extract universal chemo-resistance traits from public data with diverse ethnic backgrounds aiming for prediction accuracy in a small sample size. We utilized RNA-seq of fresh-frozen primary ovarian cancer tissue from The Cancer Genome Atlas (TCGA), Seoul National University (SNUH) and Patch et al.’s dataset (Patch).&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt; TCGA includes a majority of Caucasians, comprising 208 (chemo-resistant group: 149, chemo-sensitive group: 59) HGSOC patients. Patch comprises 40 (24, 16) Australian HGSOC patients. SNUH included 86 (14, 72) Korean HGSOC patients, who applied the same resistance criteria (no recurrence within 6 months) after initial platinum-based chemotherapy. No significant differences were observed in age, CA-125 levels, or FIGO stage between chemo-resistant and chemo-sensitive cases (Table S1).&lt;/p&gt;&lt;p&gt;The study proceeded through three phases: data preprocessing, gene selection, and deep learning (Figure 1).&lt;/p&gt;&lt;p&gt;We aligned TCGA and SNUH fast","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.1774","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142145248","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":"RNA splicing factor RBFOX2 is a key factor in the progression of cancer and cardiomyopathy","authors":"Jinze Shen,&nbsp;Jianqiao Shentu,&nbsp;Chenming Zhong,&nbsp;Qiankai Huang,&nbsp;Shiwei Duan","doi":"10.1002/ctm2.1788","DOIUrl":"10.1002/ctm2.1788","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Alternative splicing of pre-mRNA is a fundamental regulatory process in multicellular eukaryotes, significantly contributing to the diversification of the human proteome. RNA-binding fox-1 homologue 2 (RBFOX2), a member of the evolutionarily conserved RBFOX family, has emerged as a critical splicing regulator, playing a pivotal role in the alternative splicing of pre-mRNA. This review provides a comprehensive analysis of RBFOX2, elucidating its splicing activity through direct and indirect binding mechanisms. RBFOX2 exerts substantial influence over the alternative splicing of numerous transcripts, thereby shaping essential cellular processes such as differentiation and development.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Main body of the abstract</h3>\u0000 \u0000 <p>Dysregulation of RBFOX2-mediated alternative splicing has been closely linked to a spectrum of cardiovascular diseases and malignant tumours, underscoring its potential as a therapeutic target. Despite significant progress, current research faces notable challenges. The complete structural characterisation of RBFOX2 remains elusive, limiting in-depth exploration beyond its RNA-recognition motif. Furthermore, the scarcity of studies focusing on RBFOX2-targeting drugs poses a hindrance to translating research findings into clinical applications.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This review critically assesses the existing body of knowledge on RBFOX2, highlighting research gaps and limitations. By delineating these areas, this analysis not only serves as a foundational reference for future studies but also provides strategic insights for bridging these gaps. Addressing these challenges will be instrumental in unlocking the full therapeutic potential of RBFOX2, paving the way for innovative and effective treatments in various diseases.</p>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.1788","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142145247","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":"ALKBH5-mediated m6A demethylation ameliorates extracellular matrix deposition in cutaneous pathological fibrosis","authors":"Ruoqing Xu,&nbsp;En Yang,&nbsp;Hsin Liang,&nbsp;Shenying Luo,&nbsp;Yunhan Liu,&nbsp;Yimin Khoong,&nbsp;Haizhou Li,&nbsp;Xin Huang,&nbsp;Yixuan Zhao,&nbsp;Tao Zan","doi":"10.1002/ctm2.70016","DOIUrl":"10.1002/ctm2.70016","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Elevated extracellular matrix (ECM) accumulation is a major contributing factor to the pathogenesis of fibrotic diseases. Recent studies have indicated that N6-methyladenosine (m⁶A) RNA modification plays a pivotal role in modulating RNA stability and contribute to the initiation of various pathological conditions. Howbeit, the precise mechanism by which m⁶A influences ECM deposition remains unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In this study, we used hypertrophic scars (HTSs) as a paradigm to investigate ECM-related diseases. We focused on the role of ALKBH5-mediated m⁶A demethylation within the pathological progression of HTSs and examined its correlation with clinical stages. The effects of ALKBH5 ablation on ECM components were studied both in vivo and in vitro. Downstream targets of ALKBH5, along with their underlying mechanisms, were identified using integrated high-throughput analysis, RNA-binding protein immunoprecipitation and RNA pull-down assays. Furthermore, the therapeutic potential of exogenous ALKBH5 overexpression was evaluated in fibrotic scar models.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>ALKBH5 was decreased in fibroblasts derived from HTS lesions and was negatively correlated with their clinical stages. Importantly, ablation of ALKBH5 promoted the expression of COL3A1, COL1A1, and ELN, leading to pathological deposition and reconstruction of the ECM both in vivo and in vitro. From a therapeutic perspective, the exogenous overexpression of ALKBH5 significantly inhibited abnormal collagen deposition in fibrotic scar models. As determined by integrated high-throughput analysis, key ECM components including COL3A1, COL1A1, and ELN are direct downstream targets of ALKBH5. By means of its mechanism, ALKBH5 inhibits the expression of COL3A1, COL1A1, and ELN by removing m⁶A from mRNAs, thereby decreasing their stability in a YTHDF1-dependent manner.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our study identified ALKBH5 as an endogenous suppressor of pathological ECM deposition, contributing to the development of a reprogrammed m6A-targeted therapy for HTSs.</p>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11374695/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142132010","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}