Clinical and Translational Medicine最新文献

{"title":"Preclinical B cell depletion and safety profile of a brain-shuttled crystallizable fragment-silenced CD20 antibody","authors":"Vanessa L. Schumacher,&nbsp;Solen Pichereau,&nbsp;Juliana Bessa,&nbsp;Juergen Bachl,&nbsp;Sylvia Herter,&nbsp;Felix C. Weber,&nbsp;Johannes Auer,&nbsp;Anja Kipar,&nbsp;Michael Winter,&nbsp;Martina Stirn,&nbsp;Michael B. Otteneder,&nbsp;Kevin Brady,&nbsp;Anne Eichinger-Chapelon,&nbsp;Adrian Roth,&nbsp;Nadine Stokar-Regenscheit,&nbsp;Nicole Clemann,&nbsp;Shanon Seger,&nbsp;Claudia Senn,&nbsp;Juliane Hönig,&nbsp;Cordula Jany,&nbsp;Elisa Di Lenarda,&nbsp;Alain C. Tissot,&nbsp;Christian Klein,&nbsp;H.-Christian von Büdingen,&nbsp;Robert Mader,&nbsp;Mohammed Ullah,&nbsp;Niels Janssen,&nbsp;Eduard Urich","doi":"10.1002/ctm2.70178","DOIUrl":"10.1002/ctm2.70178","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The blood–brain barrier (BBB) presents a major challenge for the development of monoclonal antibody (mAb)-based therapies for brain disorders. To improve the likelihood of success of such therapies, Roche Brainshuttle technology utilizes a single anti-transferrin receptor 1 (TfR1)-antigen-binding antibody fragment linked to a therapeutic antibody, allowing engagement with TfR1 to transport the therapeutic antibody into the brain via receptor-mediated transcytosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We compared Fc-silenced and Fc-competent variants of the Brainshuttle and the parental (non-shuttled) type II CD20 mAb, obinutuzumab in in vitro and in vivo (mouse and cynomolgus macaque) models. Endpoints assessed included B cell binding, B cell killing, tolerability, and ability to cross the BBB.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The Fc-silenced Brainshuttle construct showed a superior safety profile compared with the Fc-competent construct while maintaining the ability to cross the BBB and to deplete B cells in head-to-head comparisons in human and mouse in vitro and in mouse and cynomolgus macaque in vivo models.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Together, our data provide a path forward for the future development of safe and efficacious brain-targeted B-cell-depleting therapies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>The BBB hinders mAb-based brain disorder therapies</li>\u0000 \u0000 <li>A brain-targeted B-cell-depleting mAb for MS that efficiently crosses the BBB via hTfR1 was developed using Brainshuttle^™ technology (1a and 1b)</li>\u0000 \u0000 <li>The Brainshuttle^™-CD20 mAb was well tolerated (2a and 2b) and displayed B-cell-killing properties (1c), paving the way for future development and clinical translation of TfR1-targetingtherapies for increased brain penetration</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 3","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70178","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143673401","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":"HIF-1α-induced long noncoding RNA LINC02776 promotes drug resistance of ovarian cancer by increasing polyADP-ribosylation","authors":"Yangjun Wu,&nbsp;Yu Zeng,&nbsp;Yong Wu,&nbsp;Xinyu Ha,&nbsp;Zheng Feng,&nbsp;Chaohua Liu,&nbsp;Ziqi Liu,&nbsp;Jiajia Wang,&nbsp;Xingzhu Ju,&nbsp;Shenglin Huang,&nbsp;Linhui Liang,&nbsp;Bin Zheng,&nbsp;Lulu Yang,&nbsp;Jun Wang,&nbsp;Xiaohua Wu,&nbsp;Shengli Li,&nbsp;Hao Wen","doi":"10.1002/ctm2.70244","DOIUrl":"10.1002/ctm2.70244","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Chemoresistance remains a major hurdle in ovarian cancer (OC) treatment, as many patients eventually develop resistance to platinum-based chemotherapy and/or PARP inhibitors (PARPi).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We performed transcriptome-wide analysis by RNA sequencing (RNA-seq) data of platinum-resistant and -sensitive OC tissues. We demonstrated the role of LINC02776 in platinum resistance in OC cells, mice models and patient-derived organoid (PDO) models.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We identify the long noncoding RNA LINC02776 as a critical factor of platinum resistance. Elevated expression of LINC02776 is observed in platinum-resistant OC and serves as an independent prognostic factor for OC patients. Functionally, silencing LINC02776 reduces proliferation and DNA damage repair in OC cells, thereby enhancing sensitivity to platinum and PARPi in both xenograft mouse models and patient-derived organoid (PDO) models with acquired chemoresistance. Mechanistically, LINC02776 binds to the catalytic domain of poly (ADP-ribose) polymerase 1 (PARP1), promoting PARP1-dependent polyADP-ribosylation (PARylation) and facilitating homologous recombination (HR) restoration. Additionally, high HIF-1α expression in platinum-resistant tissues further stimulates LINC02776 transcription.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our findings suggest that targeting LINC02776 represents a promising therapeutic strategy for OC patients who have developed resistance to platinum or PARPi.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>LINC02776 promotes OC cell proliferation by regulating DNA damage and apoptosis signaling pathways.</li>\u0000 \u0000 <li>LINC02776 binds PARP1 to promote DNA damage-triggered PARylation in OC cells.</li>\u0000 \u0000 <li>LINC02776 mediates cisplatin and olaparib resistance in OC cells by enhancing PARP1-mediated PARylation activity and regulating the PARP1-mediated HR pathway.</li>\u0000 \u0000 <li>The high expression of LINC02776 is induced by HIF-1α in platinum-resistant OC cells and tissues.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 3","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70244","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143673398","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":"Interleukin 27 deficiency drives dilated cardiomyopathy by ferroptosis","authors":"Yan Zhao,&nbsp;Jing Dai,&nbsp;Angwei Gong,&nbsp;Sheng Jin,&nbsp;Chengjian Guan,&nbsp;Keke Wang,&nbsp;Qianli Ma,&nbsp;Haijuan Hu,&nbsp;Yuming Wu,&nbsp;Bing Xiao","doi":"10.1002/ctm2.70269","DOIUrl":"10.1002/ctm2.70269","url":null,"abstract":"&lt;p&gt;Dear Editor,&lt;/p&gt;&lt;p&gt;The molecular mechanisms underlying dilated cardiomyopathy (DCM) pathogenesis remain incompletely understood. In this study, we provide comprehensive evidence demonstrating that interleukin 27 (IL27) exerts protective effects in DCM by inhibiting ferroptosis, potentially opening new therapeutic options for DCM.&lt;/p&gt;&lt;p&gt;DCM features ventricular dilation with impaired cardiac function, demonstrating substantial morbidity and mortality. Despite therapeutic advancements, the 10-year survival rate remains approximately 60%, emphasizing the urgent need for innovative therapeutic strategies.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; IL27, originating from immune cells, plays a key role in regulating the progression of various cardiovascular diseases.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; Recent clinical studies have indicated the cardiac tissues from DCM patients had higher IL27 mRNA levels, suggesting a potential link between IL27 and DCM.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; However, the precise mechanism through which IL27 influences DCM progression has remained elusive.&lt;/p&gt;&lt;p&gt;To establish a potential causal relationship between IL27 and DCM, we conducted Mendelian randomization analysis using genome-wide association study data. The study design principles and framework are shown in Figure S1A,B, respectively. Through systematic analysis, we identified a previously unreported single nucleotide polymorphism (SNP), rs181209. The Wald ratio method suggested a significant inverse correlation between plasma IL27 levels and DCM risk (odds ratio 0.91, 95% confidence interval 0.84–0.98, &lt;i&gt;p&lt;/i&gt; = .01) (Supplementary Figure 1C). This finding expanded upon previous research linking IL27 polymorphisms to DCM susceptibility, particularly the previously identified SNP rs153109.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; Notably, our identification of rs181209 provided new insights into the genetic architecture underlying IL27's cardioprotective effects and strengthened the evidence for a causal relationship between IL27 and DCM pathogenesis.&lt;/p&gt;&lt;p&gt;To validate our genetic findings and explore underlying mechanisms, we constructed multiple experimental models. First, we developed a doxorubicin (Dox)-induced DCM model based on previous studies.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; Echocardiographic analysis revealed significant cardiac abnormities in Dox-treated mice, characterized by reduced left ventricular ejection fraction and fractional shortening (LVEF and LVFS), thinning of both anterior and posterior left ventricular walls during systole (LVAWs and LVPWs), and enlarged left ventricular end-systolic internal diameter (LVIDs) (Figure S2A–F). Histological analysis using Masson staining exposed a conspicuous rise in the myocardial fibrotic area (Figure S2G,H). Importantly, Dox treatment significantly decreased IL27 levels in both plasmas (Figure S2J) and cardiac tissue (Figure S2I,L), accompanied by increased IL27 receptor (IL27Ra) expression in cardiac tissue (Figure S2I,K), possibly reflecting a compensatory r","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 4","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70269","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143673403","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":"Interferon regulatory factor 5 suppresses epithelial-to-mesenchymal transition and metastasis by inducing GATA2 expression in colorectal cancer","authors":"Teng Pan,&nbsp;Zaoqu Liu,&nbsp;Xue Feng,&nbsp;Deyu zhang,&nbsp;Lifeng Li,&nbsp;Yu Song,&nbsp;Qi Luo,&nbsp;Xiaojin Luo,&nbsp;Xiaohang Chen,&nbsp;Yao Yao,&nbsp;Guanglin Zhou,&nbsp;Jose M Vicencio,&nbsp;Weilong Zhang,&nbsp;Mingzhu Yin,&nbsp;Dan Wang,&nbsp;Jinhai Deng,&nbsp;Xuerui Tan,&nbsp;Fengxiang Wei","doi":"10.1002/ctm2.70077","DOIUrl":"10.1002/ctm2.70077","url":null,"abstract":"&lt;p&gt;Dear Editor,&lt;/p&gt;&lt;p&gt;Approximately one-third of colorectal cancer (CRC) patients develop metastasis, resulting in a mere 15% five-year relative overall survival rate, underscoring metastasis as a pressing clinical concern. &lt;sup&gt;[&lt;/sup&gt;&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt;&lt;sup&gt;]&lt;/sup&gt; Epithelial-to-mesenchymal transition (EMT) is a biological process that confers high plasticity to cells and is heavily implicated in cancer metastasis and progression. &lt;sup&gt;[&lt;/sup&gt;&lt;span&gt;&lt;sup&gt;2, 3&lt;/sup&gt;&lt;/span&gt;&lt;sup&gt;]&lt;/sup&gt; Interferon regulatory factor 5 (IRF5) can induce target gene expression by binding to their promoters upon translocation to the nucleus upon activation. &lt;sup&gt;[&lt;/sup&gt;&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt;&lt;sup&gt;]&lt;/sup&gt; Despite its well-known role as a key mediator of immune regulation, IRF5 has been reported to regulate the migratory capacity of cancer cells through transcription-dependent/independent mechanisms. &lt;sup&gt;[&lt;/sup&gt;&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt;&lt;sup&gt;]&lt;/sup&gt; We, here, investigated the role of IRF5 in CRC metastasis regulation.&lt;/p&gt;&lt;p&gt;We first performed gene set enrichment analysis on normalized IRF5 expression data from the Cancer Genome Atlas (TCGA) database. IRF5 expression was strongly associated with EMT signalling (Figure 1A). Three pairs of primary colorectal tumour tissues and liver metastatic counterparts were collected for RNA-Seq analysis. Results showed significantly downregulated expression of IRF5 in metastatic tissues compared to primary ones, with other key regulators of metastasis showing up, including SFRP2, OLFML2B, PLVAP, IBSP, COL11A1, MMP, etc. (Figure 1B). Immunohistochemistry (IHC) analysis of tumour samples revealed significant downregulation of IRF5 in tissues with distant metastasis (Figure 1C,D). Real-time quantitative polymerase chain reaction (RT-qPCR) and western blot showed that IRF5 expression had a decrease in CRC tissues with metastasis compared to counterparts without metastasis, confirming decreased IRF5 expression at both transcriptional and translational levels (Figure 1E,F). Using the chi-square test, we found an inverse correlation between IRF5 and tumour metastasis, including N stage and M stage (Table S1).&lt;/p&gt;&lt;p&gt;To test the involvement of immune regulation, multiple public datasets were analyzed to examine the relationship between IRF5 expression and diverse immune cell types. Unexpectedly, the results showed that IRF5 was found to be significantly positively correlated with M2 macrophages (Figure S1). However, M2 macrophages have been identified to facilitate tumour metastasis. &lt;sup&gt;[&lt;/sup&gt;&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt;&lt;sup&gt;]&lt;/sup&gt; Thus, the role of IRF5 involved in metastasis was not dependent on immune regulation. Further, we knocked out &lt;i&gt;IRF5&lt;/i&gt; (&lt;i&gt;IKO&lt;/i&gt;) in HCT116 and HCT15 cells by CRISPR-Cas9 (Figure 2A) and analyzed transcriptional profiles of control (&lt;i&gt;NTC&lt;/i&gt;) and &lt;i&gt;IKO&lt;/i&gt; cells using RNA sequencing, revealing that cell migration and EMT-related pathways were observed (Figure 2B, Figure S2 and Table S2). Functional a","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 3","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11925600/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143669302","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-cell RNA sequencing of peripheral blood mononuclear cells from bronchopulmonary dysplasia","authors":"Yufeng Liu,&nbsp;Chun Yan,&nbsp;Yushan Li,&nbsp;Ruoxing Zhou,&nbsp;Xiaoyu Lin,&nbsp;Qiong Meng,&nbsp;Sitao Li,&nbsp;Limei Zhong,&nbsp;Yanfang Tan,&nbsp;Wangkai Liu","doi":"10.1002/ctm2.70276","DOIUrl":"https://doi.org/10.1002/ctm2.70276","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Bronchopulmonary dysplasia (BPD) is a severe respiratory disease that primarily affects premature infants, characterized by persistent inflammation and abnormal immune activation. This study aimed to elucidate the immunological mechanisms underlying BPD by integrating single-cell RNA sequencing with T/B cell receptor profiling of peripheral blood mononuclear cells (PBMCs) from preterm infants with BPD, complemented by validation in a murine BPD model.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We profiled PBMCs from preterm infants diagnosed with BPD and healthy controls, identifying 22 distinct cell clusters corresponding to major immune cell types.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Significant alterations were observed in myeloid and lymphoid subsets, with neutrophils undergoing metabolic reprogramming toward oxidative phosphorylation. T and B cell subsets exhibited phenotypic and functional changes, with B cells serving as crucial interaction hubs in cell communication networks. Progenitor cell analysis in BPD mouse models revealed specific alterations in hematopoietic stem cells. Analysis of cell–cell communication networks highlighted intricate intercellular interactions in BPD, emphasizing a pivotal role for the BTLA-TNFRSF14 signaling axis in disease pathogenesis. Additionally, pharmacological blockade of BTLA in mouse models alleviated disease severity, suggesting its potential therapeutic effects through modulation of the BTLA-TNFRSF14 pathway.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>These findings enhance the understanding of the BPD immune microenvironment and lay the foundation for developing targeted immunomodulatory therapies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Single-cell sequencing revealed immune cell profiles in bronchopulmonary dysplasia (BPD).</li>\u0000 \u0000 <li>Neutrophils underwent metabolic changes, and B cells were key in immune communication.</li>\u0000 \u0000 <li>Targeting B and T lymphocyte attenuator (BTLA)-TNFRSF14 signalling reduced BPD severity in mouse models, suggesting a potential therapy.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 3","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70276","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143638760","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 YBX1-m5C mediates RNF115 mRNA circularisation and translation to enhance vulnerability of ferroptosis in hepatocellular carcinoma","authors":"Ouwen Li,&nbsp;Ke An,&nbsp;Han Wang,&nbsp;Xianbin Li,&nbsp;Yueqin Wang,&nbsp;Lan Huang,&nbsp;Yue Du,&nbsp;Nuo Qin,&nbsp;Jiasheng Dong,&nbsp;Jingyao Wei,&nbsp;Ranran Sun,&nbsp;Yong Shi,&nbsp;Yanjia Guo,&nbsp;Xiangyi Sun,&nbsp;Ying Yang,&nbsp;Yun-Gui Yang,&nbsp;Quancheng Kan,&nbsp;Xin Tian","doi":"10.1002/ctm2.70270","DOIUrl":"https://doi.org/10.1002/ctm2.70270","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;RNA 5-methylcytosine (m5C) plays an important role in the progression of hepatocellular carcinoma (HCC). Dysregulation of ferroptosis is closely associated with HCC. However, the effect of the epigenetic mRNA m5C modification on ferroptosis in HCC remains unclear.&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 this study, ferroptosis was evaluated by detecting lipid reactive oxygen species (lipid ROS), ferrous ion and 4-hydroxynonenal (4-HNE) in xenograft mouse model, diethylnitrosamine (DEN)-initiated HCC model and so forth. The regulatory mechanisms of YBX1 in mRNA translation were elucidated using RNA sequencing, ribosome sequencing, RNA immunoprecipitation (RIP)-sequencing, bisulphite sequencing and immunoprecipitation (IP)–mass spectrometry assays. Dual-luciferase reporter, RIP-qPCR, Co-IP, RNA pulldown and methylated RNA immunoprecipitation (MeRIP)-quantitative polymerase chain reaction (qPCR) assays were performed to validate the mechanism of YBX1 in regulating mRNA translation by m5C modification.&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;Here, we found that YBX1 promoted the translation of Ring Finger Protein 115 (RNF115) mRNA through m5C modification, thereby inhibiting ferroptosis and promoting HCC development. Moreover, RNF115 was identified as an E3 ubiquitin ligase for dihydroorotate dehydrogenase (DHODH), promoting Lys27 (K27) ubiquitination and inhibiting its autophagic degradation to counteract ferroptosis. In addition, YBX1 bound to the m5C modification sites of &lt;i&gt;RNF115&lt;/i&gt; 3′-untranslated region (UTR) and interacted with Eukaryotic Translation Initiation Factor 4A1 (EIF4A1) to bridge the 5′-UTR regions, promoting mRNA circularisation and translation, while NOP2/Sun RNA methyltransferase 2 (NSUN2) was identified as responsible for m5C modification of &lt;i&gt;RNF115&lt;/i&gt; mRNA in HCC.&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 current work revealed that YBX1 promoted &lt;i&gt;RNF115&lt;/i&gt; mRNA translation in an m5C-dependent manner, thereby regulating DHODH ubiquitination and expression to suppress ferroptosis. This research sheds light on the mechanism of YBX1 in m5C-modified mRNAs translation and ferroptosis, highlighting its promise as a biomarker for prognosis and a target for therapy in HCC.&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;YBX1 inhibits ferroptosis in HCC by regulatin","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 3","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70270","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143629808","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":"PADI4 facilitates stem-like properties and cisplatin resistance through upregulating PRMT2/IDs family in oesophageal squamous cell carcinoma","authors":"Zeyu Wang,&nbsp;Hao Wu,&nbsp;Zhaoxing Li,&nbsp;Zhukai Chen,&nbsp;Anqi Feng,&nbsp;Yuan Chu,&nbsp;Kang Fang,&nbsp;Zehua Zhang,&nbsp;Ziying Zhao,&nbsp;Zhuyun Leng,&nbsp;Shihan Zhang,&nbsp;Xiaoyuan Wang,&nbsp;Lingnan He,&nbsp;Tao Chen,&nbsp;Meidong Xu","doi":"10.1002/ctm2.70272","DOIUrl":"https://doi.org/10.1002/ctm2.70272","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;Oesophageal squamous cell carcinoma (OSCC) is a highly lethal cancer characterized by its aggressive nature and chemotherapy resistance. Peptidylarginine deiminase 4 (PADI4) regulates protein citrullination and is associated with various cancer developments. The role of PADI4 in OSCC progression and chemoresistance remains 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;The protein interactions were conducted by immunoprecipitation assays. Quantitative real-time PCR and western blotting were utilized to quantifyexpression levels in cancer cells. The stem-like properties were assessed through spheroid growth assays and Cancer Stem Cells (CSCs) markers. Additionally, the resistance of cancer cells to cisplatin was evaluated using CCK8 assay.&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;This study shows that PADI4 promotes cellular stemness, contributing to the progression and chemoresistance of OSCC. Mechanistically, PADI4 facilitates the citrullination of protein arginine methyltransferase 2 (PRMT2), a process essential for the stabilization of PRMT2 expression and the enhancement of its function in promoting the transcription of IDs family (ID1 and ID2) via histone arginine methylation. This mechanism subsequently increases tumour stemness and contributes to the cisplatin resistance observed in OSCC. Mutations at the R312 site or inhibition by GSK484 can attenuate tumour stemness in OSCC, thereby reducing cisplatin resistance.&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;PADI4 promotes citrullination and stabilization of PRMT2, enhancing its function in upregulating ID1 and ID2 expression via histone arginine methylation, which increases stemness and contributes to cisplatin resistance in OSCC; this effect can be mitigated by R312 mutations or GSK484 inhibition, reducing stemness and cisplatin resistance.&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;The role of citrullinization in cisplatin resistance of OSCC.&lt;/p&gt;\u0000 &lt;/li&gt;\u0000 \u0000 &lt;li&gt;\u0000 &lt;p&gt;PADI4 citrullinate of PRMT2 and stabilize PRMT2.&lt;/p&gt;\u0000 &lt;/li&gt;\u0000 \u0000 &lt;li&gt;\u0000 &lt;p&gt;PADI4 citrullinate of PRMT2 promoting the transcription of IDs family (ID1, ID2 and ID3) via histone arginine methylation.&lt;/p&gt;\u0000","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 3","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70272","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143612410","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":"Exploring targets in oropharyngeal cancer – association with immune markers and AI-scoring of B7-H3 expression","authors":"Jacklyn Liu,&nbsp;Helen Bewicke-Copley,&nbsp;Shruti Patel,&nbsp;Oscar Emanuel,&nbsp;Nicholas Counsell,&nbsp;Shachi J. Sharma,&nbsp;Volker Schartinger,&nbsp;Oliver Siefer,&nbsp;Ulrike Wieland,&nbsp;Nora Würdemann,&nbsp;Rocio Garcia-Marin,&nbsp;Jozsef Dudas,&nbsp;Dominic Patel,&nbsp;David Allen,&nbsp;Naomi Guppy,&nbsp;Josep Linares,&nbsp;Adriana Resende-Alves,&nbsp;David J. Howard,&nbsp;Liam Masterson,&nbsp;Francis M. Vaz,&nbsp;Paul O'Flynn,&nbsp;Cillian T. Forde,&nbsp;Luke Williams,&nbsp;Umar Rehman,&nbsp;John A. Hartley,&nbsp;Johannes Haybaeck,&nbsp;Herbert Riechelmann,&nbsp;Amrita Jay,&nbsp;Tim R. Fenton,&nbsp;Martin D. Forster,&nbsp;Oluyori Adegun,&nbsp;Kerry Chester,&nbsp;Jackie McDermott,&nbsp;Ann Sandison,&nbsp;Manuel Rodriguez Justo,&nbsp;Juan P. Rodrigo,&nbsp;Mario Hermsen,&nbsp;John A. Tadross,&nbsp;Jens P. Klussmann,&nbsp;Matt Lechner","doi":"10.1002/ctm2.70265","DOIUrl":"https://doi.org/10.1002/ctm2.70265","url":null,"abstract":"&lt;p&gt;Dear Editor,&lt;/p&gt;&lt;p&gt;OPSCC has one of the most rapidly increasing incidences of all cancers.&lt;span&gt;&lt;sup&gt;1-3&lt;/sup&gt;&lt;/span&gt; Most cases are associated with HPV infection, which confers improved survival outcomes, compared to HPV-independent disease.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; Despite advancements in understanding HPV-associated OPSCC, the role of biomarkers like B7-H3 and CEA, in both HPV-positive and HPV-negative cases remains unclear. This study addresses this gap by evaluating their expression and correlations with clinical and immune parameters. Additionally, we developed a quantitative Digital Image Analysis (DIA) workflow (Supplemental Methods) to assess its feasibility as a companion diagnostic tool for emerging B7-H3-targeted therapies.&lt;/p&gt;&lt;p&gt;We observed widespread B7-H3 expression in OPSCC, while CEA expression was more limited. B7-H3 is a type I transmembrane protein of the Ig superfamily, which modulates T-cell activation through receptor binding.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; It is overexpressed in cervical cancer (HPV-driven disease) and Head and Neck Squamous Cell Carcinoma (HNSCC), where it correlates with poor prognosis.&lt;span&gt;&lt;sup&gt;6, 7&lt;/sup&gt;&lt;/span&gt; We further observed a link between B7-H3 and CD8+ T-cell infiltration, which is promising for B7-H3-targeted therapies. CEA, an oncofetal protein, is widely used in colorectal cancer but less studied in head and neck cancer. Its established clinical role and widespread use in colorectal cancer support its inclusion in this study for potential clinical translation to OPSCC.&lt;span&gt;&lt;sup&gt;8&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;This study included 545 OPSCC cases, with local ethical approval obtained for each institution (Supplemental Methods). The cohort was predominantly male (85.1%) with a mean age of 58.7 years (36–88) (Table 1). Semi-quantitative assessments and DIA-based H-scores were performed to quantify B7-H3 expression, which was then correlated with clinical outcomes and immune markers. Despite weak staining in most cases, 78.4% exhibited positive B7-H3 tumoural expression, while 71.0% showed positive stromal expression based on semi-quantitative assessment, highlighting its widespread prevalence in OPSCC.&lt;/p&gt;&lt;p&gt;Given B7-H3's widespread expression in the initial 291 cases, a custom DIA workflow was developed. On these same initial cases, the median tumoural and stromal digital H-scores were 78.5 (IQR: 27.6–134.6) and 47.4 (IQR: 19.6–81.1), respectively. The semi-quantitative and H-scores correlated well for both tumoural and stromal expression (H(3)&lt;sub&gt;Tumour&lt;/sub&gt; = 151.2, &lt;i&gt;p&lt;/i&gt; &lt; .001; H(3)&lt;sub&gt;Stroma&lt;/sub&gt; = 36.5, &lt;i&gt;p&lt;/i&gt; &lt; .001; Figure 1). The results were similar when considering HPV-negative cases only, with strong correlations observed between semi-quantitative and H-scores (H(3)&lt;sub&gt;Tumour&lt;/sub&gt; = 119.5, &lt;i&gt;p&lt;/i&gt; &lt; .001; H(3)&lt;sub&gt;Stroma&lt;/sub&gt; = 30.0, &lt;i&gt;p&lt;/i&gt; &lt; .001) and a similar pattern of expression as presented above, with median tumoural and stromal H-scores of 80.3 (IQR: 18.5–157.","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 3","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70265","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143595503","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":"Farletuzumab ecteribulin and MORAb-109, folate receptor alpha and mesothelin targeting antibody–drug conjugates, show activity in poor prognosis gynaecological cancer models","authors":"Ksenija Nesic,&nbsp;Katherine Rybinski,&nbsp;Gayanie Ratnayake,&nbsp;Gwo-Yaw Ho,&nbsp;Ratana Lim,&nbsp;Marc Radke,&nbsp;Chloe Neagle,&nbsp;Elizabeth M. Swisher,&nbsp;Matthew J. Wakefield,&nbsp;Holly E. Barker,&nbsp;Keiji Furuuchi,&nbsp;Clare L. Scott,&nbsp;Cassandra J. Vandenberg","doi":"10.1002/ctm2.70274","DOIUrl":"https://doi.org/10.1002/ctm2.70274","url":null,"abstract":"&lt;p&gt;Dear Editor,&lt;/p&gt;&lt;p&gt;Few therapeutic options are available for aggressive, poor prognosis gynaecological cancers (GC), including uterine serous carcinoma (USC) and ovarian clear cell adenocarcinoma (OCCA). We observed deep and durable responses to the antibody-drug conjugates (ADC), farletuzumab ecteribulin (FZEC, previously known as MORAb-202) or MORAb-109, in GC patient-derived xenograft (PDX) models expressing corresponding target antigens, folate receptor alpha (FRA) or mesothelin (MSLN), providing evidence for clinical trial inclusion of these GC types. Resistance was observed in PDX models with high &lt;i&gt;ABCB1&lt;/i&gt; expression, highlighting this as a potential exclusion criterion in clinical trials of &lt;i&gt;ABCB1&lt;/i&gt; substrates.&lt;/p&gt;&lt;p&gt;The anti-microtubule agent (AMA), paclitaxel, is commonly used in first-line treatment for most GC, in combination with the platinum agent carboplatin, but resistance is common. The AMA, eribulin, has demonstrated efficacy in breast and non-small cell lung cancers&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; and we have shown preclinical efficacy in treating aggressive, poor prognosis GC.&lt;span&gt;&lt;sup&gt;2, 3&lt;/sup&gt;&lt;/span&gt; ADCs have enabled targeted delivery of potent cytotoxic agents, including in GC.&lt;span&gt;&lt;sup&gt;4, 5&lt;/sup&gt;&lt;/span&gt; Both FRA and MSLN are not generally expressed in normal adult tissues, but given high frequency of expression in ovarian, uterine and other solid cancers, they have become attractive ADC targets.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; Here, we investigate the utility of the anti-FRA-eribulin ADC, FZEC, and the anti-MSLN-eribulin ADC, MORAb-109, in the treatment of aggressive GC.&lt;span&gt;&lt;sup&gt;6-8&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;We screened 41 GC PDX models covering 11 poor prognosis GC subtypes to determine the frequency and distribution of FRA and MSLN expression (Table S1). For high-grade serous ovarian cancer (HGSOC), 14 PDX models were assessed for FRA expression, with 5/7 chemo-naive and 6/7 post-treatment models being designated as FRA positive (total FRA &gt; 5%, with various staining patterns described; Figure 1A). Three post-treatment HGSOC models, reflecting the target patient group for clinical trials, were selected for FZEC treatment (Table S2). To investigate low versus high expression of FRA, the PDX models #111 (6% FRA+), #206 (32% FRA+) and #931 (43% FRA+) were chosen and treated with a 3-week regimen of eribulin, or with FZEC administered as a &lt;i&gt;single dose&lt;/i&gt; (Figure 1A; the FZEC single dose equates to 0.25 mg/kg eribulin payload). We observed comparable eribulin and FZEC activity in all three models (Figure 1B, Table S3) and progressive disease (PD) was observed 85 days or more after treatment. We next investigated if repeated dosing with FZEC could extend response duration, testing this in PDX #111, which showed PD at 85 days with the single FZEC dose. Three weeks of weekly dosing produced a complete response (CR; tumour &lt; 50 mm&lt;sup&gt;3&lt;/sup&gt; for ≥3 consecutive weeks) for all mice treated, with no PD by 120 days post-treatme","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 3","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70274","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143612508","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":"p53 inhibits OTUD5 transcription to promote GPX4 degradation and induce ferroptosis in gastric cancer","authors":"Junjing Zhang,&nbsp;Tongguan Tian,&nbsp;Xinxing Li,&nbsp;Kai Xu,&nbsp;Yao Lu,&nbsp;Xia Li,&nbsp;Xinyu Zhao,&nbsp;Ziyi Cui,&nbsp;Zhenxiang Wang,&nbsp;Yuefan Zhou,&nbsp;Yixin Xu,&nbsp;Hongchen Li,&nbsp;Yan Zhang,&nbsp;Yu Du,&nbsp;Lei Lv,&nbsp;Yanping Xu","doi":"10.1002/ctm2.70271","DOIUrl":"https://doi.org/10.1002/ctm2.70271","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;Gastric cancer is one of the most prevalent malignant tumors within the digestive system, and ferroptosis playing a crucial role in its progression. Glutathione peroxidase 4 (GPX4), a key negative regulator of ferroptosis, is highly expressed in gastric cancer and contributes to tumor growth. Targeting the regulation of GPX4 has emerged as a promising approach to induce ferroptosis and develop effective therapy for gastric cancer.&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;To confirm that OTUD5 is a deubiquitinase of GPX4 and regulates ferroptosis, we performed Western blotting, Co-IP, immunofluorescence, quantitative real-time PCR, Ub assay and flow cytometry experiments. To explore the physiological function of OUTD5, we knocked out the Otud5 gene in the mouse gastric cancer cell line (MFC) using CRISPR-Cas9 and eatablished the subcutaneous tumour model. Immunohistochemistry (IHC) analysis was used to inveatigate the pathological correlation in human gastric cancer.&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 report that ovarian tumor domain-containing 5 (OTUD5) interacts with, deubiquitylates and stabilizes GPX4. OTUD5 depletion destabilizes GPX4, promotes lipid peroxidation and sensitizes gastric cancer cells to ferroptosis. Moreover, the p53 activator nutlin-3a suppresses OTUD5 transcription, leading to GPX4 degradation and ferroptosis of gastric cancer cells. Notably, only wild-type p53 has the capacity to inhibit OTUD5 transcription, while p53 mutations or deficiencies correlate with increased OTUD5 expression, promoting gastric cancer progression. Additionally, OTUD5 silencing and nutlin-3a-induced GPX4 degradation enhances the sensitivity of gastric cancer cells to ferroptosis in vivo. Subsequently, the p53/OTUD5/GPX4 axis is confirmed in clinical gastric cancer samples.&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;Collectively, these findings elucidate a mechanism whereby p53 inactivation upregulates OTUD5 transcription to deubiquitylate and stablize GPX4, resulting in ferroptosis inhibition and gastric cancer progression. This discovery highlights the potential therapeutic value of targeting OTUD5 to promote ferroptosis in p53-inactivated gastric cancer.&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;OTUD5 mediates GPX4 deubiquitination to regulate its stability.&lt;/li&gt;\u0000 \u0000 &lt;l","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 3","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70271","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143595346","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}