Clinical and Translational Medicine最新文献

{"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}

{"title":"Aberrant DNA methylation of genes regulating CD4+ T cell HIV-1 reservoir in women with HIV","authors":"Ke Xu,&nbsp;Xinyu Zhang,&nbsp;Kesava Asam,&nbsp;Bryan C. Quach,&nbsp;Grier P. Page,&nbsp;Deborah Konkle-Parker,&nbsp;Claudia Martinez,&nbsp;Cecile D. Lahiri,&nbsp;Elizabeth F. Topper,&nbsp;Mardge H. Cohen,&nbsp;Seble G. Kassaye,&nbsp;Jack DeHovitz,&nbsp;Mark H. Kuniholm,&nbsp;Nancie M. Archin,&nbsp;Amir Valizadeh,&nbsp;Phyllis C. Tien,&nbsp;Vincent C. Marconi,&nbsp;Dana B. Hancock,&nbsp;Eric O. Johnson,&nbsp;Bradley E. Aouizerat","doi":"10.1002/ctm2.70267","DOIUrl":"https://doi.org/10.1002/ctm2.70267","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The HIV-1 reservoir in CD4+ T cells (HR_CD4) pose a major challenge to curing HIV, with many of its mechanisms still unclear. HIV-1 DNA integration and immune responses may alter the host's epigenetic landscape, potentially silencing HIV-1 replication.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This study used bisulphite capture DNA methylation sequencing in CD4+ T cells from the blood of 427 virally suppressed women with HIV to identify differentially methylated sites and regions associated with HR_CD4.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The average total HR_CD4 size was 1409 copies per million cells, with most proviruses defective and only a small proportion intact. The study identified 245 differentially methylated CpG sites and 85 regions linked to HR_CD4 size, with 52% of significant sites in intronic regions. Genes associated with HR_CD4 were involved in viral replication, HIV-1 latency and cell growth and apoptosis. HR_CD4 size was inversely related to DNA methylation of interferon signalling genes and positively associated with methylation at known HIV-1 integration sites. HR_CD4-associated genes were enriched on the pathways related to immune defence, transcription repression and host–virus interactions.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>These findings suggest that HIV-1 reservoir is linked to aberrant DNA methylation in CD4+ T cells, offering new insights into epigenetic mechanisms of HIV-1 latency and potential molecular targets for eradication strategies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Study involved 427 women with HIV.</li>\u0000 \u0000 <li>Identified 245 aberrant DNA methylation sites and 85 methylation regions in CD4+ T cells linked to the HIV-1 reservoir.</li>\u0000 \u0000 <li>Highlighted genes are involved in viral replication, immune defence, and host genome integration.</li>\u0000 \u0000 <li>Findings suggest potential molecular targets for eradication strategies.</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":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70267","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143595347","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":"Integrated spatial multi-omics profiling of Fusobacterium nucleatum in breast cancer unveils its role in tumour microenvironment modulation and cancer progression","authors":"Feng Zhao,&nbsp;Rui An,&nbsp;Yilei Ma,&nbsp;Shaobo Yu,&nbsp;Yuzhen Gao,&nbsp;Yanzhong Wang,&nbsp;Haitao Yu,&nbsp;Xinyou Xie,&nbsp;Jun Zhang","doi":"10.1002/ctm2.70273","DOIUrl":"https://doi.org/10.1002/ctm2.70273","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;p&gt;Tumour-associated microbiota are integral components of the tumour microenvironment (TME). However, previous studies on intratumoral microbiota primarily rely on bulk tissue analysis, which may obscure their spatial distribution and localized effects. In this study, we applied in situ spatial-profiling technology to investigate the spatial distribution of intratumoral microbiota in breast cancer and their interactions with the local TME. Using 5R 16S rRNA gene sequencing and RNAscope FISH/CISH on patients’ tissue, we identified significant spatial heterogeneity in intratumoral microbiota, with &lt;i&gt;Fusobacterium nucleatum&lt;/i&gt; (&lt;i&gt;F. nucleatum&lt;/i&gt;) predominantly localized in tumour cell-rich areas. GeoMx digital spatial profiling (DSP) revealed that regions colonized by &lt;i&gt;F. nucleatum&lt;/i&gt; exhibit significant influence on the expression of RNAs and proteins involved in proliferation, migration and invasion. In vitro studies indicated that co-culture with &lt;i&gt;F. nucleatum&lt;/i&gt; significantly stimulates the proliferation and migration of breast cancer cells. Integrative spatial multi-omics and co-culture transcriptomic analyses highlighted the MAPK signalling pathways as key altered pathways. By intersecting these datasets, VEGFD and PAK1 emerged as critical upregulated proteins in &lt;i&gt;F. nucleatum&lt;/i&gt;-positive regions, showing strong positive correlations with MAPK pathway proteins. Moreover, the upregulation of VEGFD and PAK1 by &lt;i&gt;F. nucleatum&lt;/i&gt; was confirmed in co-culture experiments, and their knockdown significantly reduced &lt;i&gt;F. nucleatum&lt;/i&gt;-induced proliferation and migration. In conclusion, intratumoral microbiota in breast cancer exhibit significant spatial heterogeneity, with &lt;i&gt;F. nucleatum&lt;/i&gt; colonization markedly altering tumour cell protein expression to promote progression and migration. These findings provide novel perspectives on the role of microbiota in breast cancer, identify potential therapeutic targets, and lay the foundation for future cancer treatments.&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;Intratumoral &lt;i&gt;Fusobacterium nucleatum&lt;/i&gt; exhibits significant spatial heterogeneity within breast cancer tissues.&lt;/p&gt;\u0000 &lt;/li&gt;\u0000 \u0000 &lt;li&gt;\u0000 &lt;p&gt;&lt;i&gt;F. nucleatum&lt;/i&gt; colonization alters the expression of key proteins involved in tumour progression and migration.&lt;/p&gt;\u0000 &lt;/li&gt;\u0000 \u0000 &lt;li&gt;\u0000 &lt;p&gt;The MAPK signalling pathway is a critical mediator of &lt;i&gt;F. nucleatum&lt;/i&gt;-induced breast cancer cell proliferation and migration.&lt;/p&gt;\u0000 &lt;/li&gt;\u0000 \u0000 ","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/ctm2.70273","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143594895","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":"Exon junction complexes regulate osteoclast-induced bone resorption by influencing the NFATc1 m6A distribution through the “shield effect”","authors":"Bao Sun,&nbsp;Jin-Gang Yang,&nbsp;Zhe Wang,&nbsp;Zheng Wang,&nbsp;Wei Feng,&nbsp;Xing Li,&nbsp;Sheng-Nan Liu,&nbsp;Jiang Li,&nbsp;Ya-Qin Zhu,&nbsp;Ping Zhang,&nbsp;Wei Wang","doi":"10.1002/ctm2.70266","DOIUrl":"https://doi.org/10.1002/ctm2.70266","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;The distribution of the m6A methylation modification on the transcriptome is highly regionally selective and is mainly concentrated in abnormally long exons and stop codons. However, in-depth research on the selective mechanism of m6A methylation is still lacking.&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 research, meRIP sequencing, mRNA sequencing, meRIP, luciferase reporter assays and CRISPR/Cas9 conditional knockout mice were used to elucidate the distribution characteristics of NFATc1 m6A.&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;METTL14 controls osteoclast-mediated bone resorption by means of the methylation (4249 A) of the NFATc1 gene during osteoclast differentiation. Exon junction complexes (EJCs) selectively protect the m6A methylation sites of the NFATc1 gene. When the methylation sites are located within short exon fragments (50–200 nt), EJCs prevent their hypermethylation and degradation through the “shield effect”; when the methylation sites are located in the 3′ UTR region or long exon fragments (greater than 300 nt), the “shield effect” disappears. Downstream, YTHDF2 induced the degradation of hypermethylation NFATc1 transcripts without site restriction.&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;EJCs act as “shields” to regulate the m6A region selectivity of the NFATc1 gene, thereby determining the characteristics of m6A distribution in the gene. Importantly, EJCs can raise the level of m6A methylation of NFATc1 and degrade its mRNA, thereby inhibiting osteoclast differentiation and preserving bone mass. These results will be helpful for identifying potential molecular targets for osteoporosis treatment.&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;METTL14 controls osteoclast-mediated bone resorption by means of the methylation (4249 A) of the NFATc1 gene during osteoclast differentiation.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Exon junction complexes (EJCs) protect the remaining methylation sites of the NFATc1 gene (located in the inner exon fragment of 50–200 nt) from hypermethylation and degradation.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;The “shield effect” disappears when the exon fragment is extended to 300 nt. Downstream, YTHDF2 induced the degradation of hypermethylation NFATc1 transcripts without site restriction.&lt;/li&gt;\u0000 &lt;/ul&gt;\u0000 ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 3","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70266","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143564891","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":"Id2 exacerbates the development of rheumatoid arthritis by increasing IFN-γ production in CD4+ T cells","authors":"Haoyang Sun,&nbsp;Jinlin Miao,&nbsp;Kui Zhang,&nbsp;Peiyan Zhang,&nbsp;Haomiao Shen,&nbsp;Jiawei Wang,&nbsp;Bei Zhang,&nbsp;Junfeng Jia,&nbsp;Zhaohui Zheng,&nbsp;Ping Zhu","doi":"10.1002/ctm2.70242","DOIUrl":"https://doi.org/10.1002/ctm2.70242","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Purpose&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;This research investigates the role of inhibitor of differentiation 2 (Id2) in the synthesis of pro-inflammatory cytokines, specifically interferon-γ (IFN-γ) and interleukin-17 (IL-17), by various subsets of T cells, and its pathogenic role in rheumatoid arthritis (RA).&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;Flow cytometry was employed to assess T-cell activation and Id2 expression in 72 RA patients and 23 healthy controls. In vitro, peripheral blood mononuclear cells were treated with either an Id2 inhibitor or a T-cell co-stimulation inhibitor. An in vivo collagen-induced arthritis (CIA) model was established using T-cell-specific Id2 knockout mice. Additionally, follow-up observations were conducted among treated RA patients.&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;T-cell activation levels in RA synovial fluid were significantly elevated. A positive correlation was found between increased IFN-γ and Id2 expression. In vitro, antagonising Id2 reduced IFN-γ production after T-cell activation. T-cell-specific Id2 knockout mice exhibited a diminished occurrence and severity of CIA, along with a significant decrease in IFN-γ expression. Clinical monitoring indicated that Id2-induced circulating T-cell IFN-γ expression significantly decreased following treatment with the T-cell activation inhibitor abatacept.&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;The data suggest that high Id2 expression is a critical regulator of pro-inflammatory cytokine upregulation, particularly IFN-γ, by hyperactivated T cells in RA, potentially exacerbating the disease. Inhibiting Id2 expression or function may offer new therapeutic approaches for RA joint inflammation.&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;Pro-inflammatory cytokines are significantly upregulated in the synovial fluid T cells in rheumatoid arthritis patients.&lt;/p&gt;\u0000 &lt;/li&gt;\u0000 \u0000 &lt;li&gt;\u0000 &lt;p&gt;The expression of pro-inflammatory cytokine interferon-γ (IFN-γ) positively correlates with the high expression of inhibitor of differentiation 2 (Id2).&lt;/p&gt;\u0000 &lt;/li&gt;\u0000 \u0000 &lt;li&gt;\u0000 &lt;p&gt;The inhibition or ablation of Id2 can effectively suppress IFN-γ production and the onset and progression of arthritis.&lt;/p","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 3","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70242","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143564892","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}