Clinical and Translational Medicine最新文献

{"title":"Immune profiling of the macroenvironment in colorectal cancer unveils systemic dysfunction and plasticity of immune cells","authors":"Haoxian Ke, Peisi Li, Zhihao Li, Xian Zeng, Chi Zhang, Shuzhen Luo, Xiaofang Chen, Xinlan Zhou, Shichen Dong, Shaopeng Chen, Junfeng Huang, Ming Yuan, Runfeng Yu, Shubiao Ye, Tuo Hu, Zhonghui Tang, Dongbin Liu, Kui Wu, Xianrui Wu, Ping Lan","doi":"10.1002/ctm2.70175","DOIUrl":"https://doi.org/10.1002/ctm2.70175","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Tumour immune macroenvironment is comprised of tumour and surrounding organs responding to tumourigenesis and immunotherapy. The lack of comprehensive analytical methods hinders its application for prediction of survival and treatment response in colorectal cancer (CRC) patients.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Cytometry by time-of-flight (CyTOF) and RNA-seq was applied to characterise immune cell heterogeneity in a discovery cohort including tumour, blood and intestinal architecture comprising epithelium, lamina propria, submucosa, muscularis propria of normal bowel and tumour–adjacent bowel tissues. Immunoprofiling was also validated by a validation cohort using single-cell RNA sequencing, spatial transcription, CyTOF and multiplex immunofluorescent staining.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Based on cell phenotype and transcription, we identify distinct immunotypes in the CRC macroenvironment including blood, tumour and different intestinal architecture, showing disturbed immune cell compositions, increasing expression of immunosuppressive markers and cell–cell interactions contributing to immunosuppressive regulation. Furthermore, we evaluate immune macroenvironment influencing factors including tertiary lymphoid structures (TLSs), consensus molecular subtypes (CMSs) and immune checkpoint inhibitors (ICIs). TLS presence fuels anti-tumour immunity by promoting CD8<sup>+</sup> T cell infiltration and altering activation or suppression of T cell systematically. TLS presence correlates with patient survival, intrinsic CMS and therapeutic efficacy of ICI. PD-1 and CD69 expressed in effector memory CD8<sup>+</sup> T cells from blood can predict TLS presence in the CRC macroenvironment, serving as potential biomarkers for stratifying CRC patients into immunotherapy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our findings provide insights into the CRC immune macroenvironment, highlighting immune cell suppression and activation in tumourigenesis. Our study illustrates the potential utility of blood for predicting immunotherapy response.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Distinct immunotypes are identified in the CRC macroenvironment.</li>\u0000 \u0000 <li>TLS and immunotherapy exert influence on the immune macroenvironment.</li>\u0000 \u0000 ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 2","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70175","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143389004","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":"Role of the FOXM1/CMA/ER stress axis in regulating the progression of nonalcoholic steatohepatitis","authors":"Shuoyi Ma, Erzhuo Xia, Miao Zhang, Yinan Hu, Siyuan Tian, Xiaohong Zheng, Bo Li, Gang Ma, Rui Su, Keshuai Sun, Qingling Fan, Fangfang Yang, Guanya Guo, Changcun Guo, Yulong Shang, Xinmin Zhou, Xia Zhou, Jingbo Wang, Ying Han","doi":"10.1002/ctm2.70202","DOIUrl":"https://doi.org/10.1002/ctm2.70202","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background/aims</h3>\u0000 \u0000 <p>The molecular mechanisms driving nonalcoholic steatohepatitis (NASH) progression are poorly understood. This research examines the involvement of chaperone-mediated autophagy (CMA) in NASH progression.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Hepatic CMA activity was analysed in NASH mice and patients. Lysosome-associated membrane protein 2A (LAMP2A) was knocked down or overexpressed to assess the effects of hepatocyte-specific CMA on NASH progression. Mice received a high-fat diet or a methionine and choline-deficient diet to induce NASH. Palmitic acid was employed to mimic lipotoxicity-induced hepatocyte damage in vitro. The promoter activity of FOXM1 was evaluated via ChIP and dual-luciferase reporter assays.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Hepatic CMA activity was substantially low in NASH mice and patients. LAMP2A knockdown resulted in hepatocyte-specific CMA deficiency, which promoted fibrosis and hepatic inflammation in NASH mice. Both in vitro and in vivo, CMA deficiency also exacerbated hepatocyte damage and endoplasmic reticulum (ER) stress. Mechanistically, CMA deficiency in hepatocytes increased cholesterol accumulation by blocking the degradation of 3-hydroxy-3-methylglutaryl coenzyme A (HMGCR), a key cholesterol synthesis-related enzyme, and the accumulated cholesterol subsequently induced ER stress and hepatocyte damage. The restoration of hepatocyte-specific CMA activity effectively ameliorated diet-induced NASH and ER stress in vivo and in vitro. FOXM1 directly bound to LAMP2A promoter and negatively regulated its transcription. The upregulation of FOXM1 expression impaired CMA and enhanced ER stress, which in turn increased FOXM1 expression, resulting in a vicious cycle and promoting NASH development.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>This study highlights the significance of the FOXM1/CMA/ER stress axis in NASH progression and proposes novel therapeutic targets for NASH.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Chaperone-mediated autophagy (CMA) deficiency in hepatocytes promotes hepatic inflammation and fibrosis in mice with nonalcoholic steatohepatitis (NASH) by inducing cholesterol accumulation and endoplasmic reticulum (ER) stress.</li>\u0000 \u0000 <li>Upregulated FOXM1 impairs CMA by suppressing the transcription of lysosome-associated ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 2","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70202","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143380079","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":"Spatial‒temporal heterogeneities of liver cancer and the discovery of the invasive zone","authors":"Jiayan Yan,&nbsp;Zhifeng Jiang,&nbsp;Shiyu Zhang,&nbsp;Qichao Yu,&nbsp;Yijun Lu,&nbsp;Runze Miao,&nbsp;Zhaoyou Tang,&nbsp;Jia Fan,&nbsp;Liang Wu,&nbsp;Dan G. Duda,&nbsp;Jian Zhou,&nbsp;Xinrong Yang","doi":"10.1002/ctm2.70224","DOIUrl":"https://doi.org/10.1002/ctm2.70224","url":null,"abstract":"<p>Solid tumours are intricate and highly heterogeneous ecosystems, which grow in and invade normal organs. Their progression is mediated by cancer cells’ interaction with different cell types, such as immune cells, stromal cells and endothelial cells, and with the extracellular matrix. Owing to its high incidence, aggressive growth and resistance to local and systemic treatments, liver cancer has particularly high mortality rates worldwide. In recent decades, spatial heterogeneity has garnered significant attention as an unfavourable biological characteristic of the tumour microenvironment, prompting extensive research into its role in liver tumour development. Advances in spatial omics have facilitated the detailed spatial analysis of cell types, states and cell‒cell interactions, allowing a thorough understanding of the spatial and temporal heterogeneities of tumour microenvironment and informing the development of novel therapeutic approaches. This review illustrates the latest discovery of the invasive zone, and systematically introduced specific macroscopic spatial heterogeneities, pathological spatial heterogeneities and tumour microenvironment heterogeneities of liver cancer.</p>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 2","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70224","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143380080","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":"Paclitaxel biological synthesis promotes the innovation of anti-cancer drugs","authors":"Xiaolin Zhang,&nbsp;Gang Liu,&nbsp;Jianbin Yan","doi":"10.1002/ctm2.70230","DOIUrl":"https://doi.org/10.1002/ctm2.70230","url":null,"abstract":"&lt;p&gt;Paclitaxel, as a star natural drug with significant anti-tumour activity, has become the frontline chemotherapy medication to treat various cancers since its advent in 1992.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Different from other anticarcinogens, paclitaxel uniquely promotes the assembly of tubulin subunits into stable, non-dynamic states that impede cancer cell proliferation, thereby effectively controlling the development of the disease. With the increasing number of cancer patients worldwide and the continuous advancement of medical technology, the market demand for paclitaxel is expected to expand continually. The market for the paclitaxel injection alone is estimated to reach 15.8 billion USD by 2032.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; Furthermore, integrating multiple disciplines, including medicine, biology and materials science, has the potential to expand the applications of paclitaxel significantly into medical devices. As an active pharmaceutical ingredient in drug-coated balloons and stents, paclitaxel is crucial in inhibiting intimal proliferation and preventing in-stent restenosis, thus providing a novel treatment option for patients with cardiovascular disease. This application improves the efficacy of paclitaxel and expands its clinical applications.&lt;/p&gt;&lt;p&gt;As precision medicine continues to advance, the personalisation of paclitaxel treatment is set to become a key focus for the future.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; Utilising advanced genomic and phenomic analysis techniques enables the precise identification of tumour types in patients. This capability allows for the development of tailored treatment plans, which can significantly enhance the therapeutic efficacy of the medication and improve the overall quality of life for patients. The ongoing optimisation of paclitaxel in combination with other medications and therapies will continue to advance, with an emphasis on enhancing treatment efficacy and targeting capability while minimising adverse effects. The advancement of paclitaxel precision medicine necessitates the enhancement of its yield and purity (Figure 1A). More crucially, it involves developing new paclitaxel derivatives that improve patient compliance with medication regimens.&lt;/p&gt;&lt;p&gt;The rapid development of synthetic biology makes it possible to efficiently synthesise and directly generate novel paclitaxel derivatives tailored to different medical needs. It is reported that 600 taxoids have been identified from various &lt;i&gt;Taxus&lt;/i&gt; species,&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; among which about 24 taxoids exhibit cytotoxicity to tumour cells, thus providing a promising resource for discovering new agents with potent cytotoxic properties and reduced susceptibility to resistance. Recent breakthroughs in paclitaxel biosynthesis open new avenues for developing paclitaxel derivatives.&lt;span&gt;&lt;sup&gt;5, 6&lt;/sup&gt;&lt;/span&gt; The enzymes that play a pivotal role in paclitaxel synthesis, especially those belonging to the cytochrome P450 family (CYP450s), demonstrate impr","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 2","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70230","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143380082","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":"N6-Methyladenosine modification mediated by METTL3 promotes DNA-PKcs expression to induce anlotinib resistance in osteosarcoma","authors":"Yining Zhang,&nbsp;Guohong Shen,&nbsp;Dan Zhang,&nbsp;Tingting Meng,&nbsp;Zhaorui Lv,&nbsp;Lei Chen,&nbsp;Jianmin Li,&nbsp;Ka Li","doi":"10.1002/ctm2.70228","DOIUrl":"https://doi.org/10.1002/ctm2.70228","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;Acquired anlotinib resistance is still a key challenge in osteosarcoma treatment. Unravelling the mechanisms underlying anlotinib resistance is the key to optimising its efficacy for treating osteosarcoma. Previous studies have explored the pivotal function of the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) with regard to osteosarcoma chemoresistance.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;We used bioinformatics analysis to predict DNA-PKcs and Beclin-1 interactions, confirmed through immunofluorescence (IF) and co-immunoprecipitation (co-IP). Dual-luciferase analyses and Methylated RNA immunoprecipitation (MeRIP) were implemented to detect the detected m&lt;sup&gt;6&lt;/sup&gt;A modifications. RNA fluorescence in situ hybridisation (FISH)—IF co-localisation and RNA immunoprecipitation (RIP) were conducted to explore the interplay between PRKDC mRNA and the indicated proteins.&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;Anlotinib-treated osteosarcoma cells exhibited increased DNA-PKcs levels, and silencing DNA-PKcs augmented osteosarcoma sensitivity to anlotinib. DNA-PKcs affects anlotinib-induced autophagy by interacting with Beclin-1 and regulating its ubiquitination. Notably, PRKDC mRNA, encoding DNA-PKcs, underwent N&lt;sup&gt;6&lt;/sup&gt;-Methyladenosine (m&lt;sup&gt;6&lt;/sup&gt;A) modification. Methyltransferase-like 3 (METTL3) positively regulated DNA-PKcs expression. Functionally, METTL3 enhances anlotinib resistance in osteosarcoma, which is reversed by PRKDC knockdown. Mechanistically, METTL3 binds to PRKDC mRNA and facilitates m&lt;sup&gt;6&lt;/sup&gt;A methylation. Additionally, m&lt;sup&gt;6&lt;/sup&gt;A methylated PRKDC mRNA is identified via YTH N&lt;sup&gt;6&lt;/sup&gt;-methyladenosine RNA-binding protein 1 (YTHDF1), augmenting its expression.&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;These findings revealed that DNA-PKcs promotes anlotinib resistance by regulating protective autophagy, while METTL3 induces PRKDC m&lt;sup&gt;6&lt;/sup&gt;A modification, enhancing its expression. Thus, targeting METTL3/PRKDC may be a novel strategy for improving therapeutic efficacy in human osteosarcoma.&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;DNA-PKcs knockdown heightens osteosarcoma sensitivity to anlotinib.&lt;/p&gt;\u0000 &lt;/li&gt;\u0000 \u0000 &lt;li&gt;\u0000 &lt;p&gt;DNA-PKcs modulates anlotinib-induced pr","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 2","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70228","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143380081","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":"RNF31 induces paclitaxel resistance by sustaining ALYREF cytoplasmic–nuclear shuttling in human triple-negative breast cancer","authors":"Shumei Huang,&nbsp;Dongni Shi,&nbsp;Shuqin Dai,&nbsp;Xingyu Jiang,&nbsp;Rui Wang,&nbsp;Muwen Yang,&nbsp;Boyu Chen,&nbsp;Xuwei Chen,&nbsp;Lingzhi Kong,&nbsp;Lixin He,&nbsp;Pinwei Deng,&nbsp;Xiangfu Chen,&nbsp;Chuyong Lin,&nbsp;Yue Li,&nbsp;Jun Li,&nbsp;Libing Song,&nbsp;Yawei Shi,&nbsp;Weidong Wei","doi":"10.1002/ctm2.70203","DOIUrl":"https://doi.org/10.1002/ctm2.70203","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;Resistance to paclitaxel-based chemotherapy is the major obstacle in triple-negative breast cancer (TNBC) treatment. However, overcoming paclitaxel resistance remains an unsolved problem. The present study aimed to determine whether paclitaxel treatment impairs Aly/REF export factor (ALYREF) cytoplasmic–nuclear shuttling, its mechanism, and the role of ubiquitinated ALYREF in paclitaxel resistance.&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 subcellular proportion of ALYREF was detected in samples from patients with TNBC using immunohistochemistry to analyze the relationship between ALYREF distribution and paclitaxel response. Cell viability assays, immunofluorescence assays, quantitative real-time reverse transcription PCR assays, western blotting, and terminal deoxynucleotidyl transferase nick-end-labelling assays were conducted to measure the biological function of the subcellular proportion of ALYREF and E3 ligase ring finger protein 31 (RNF31) on paclitaxel sensitivity in TNBC. The synergistic effects of an RNF31 inhibitor plus paclitaxel on TNBC were evaluated. Cox regression models were adopted to assess the prognostic role of RNF31 in TNBC.&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;Herein, we showed that regulation of ALYREF cytoplasmic–nuclear shuttling is associated with the paclitaxel response in TNBC. In paclitaxel-sensitive TNBC, ALYREF was trapped in the cytoplasm by paclitaxel, while in paclitaxel-resistant TNBC, ALYREF was efficiently transported into the nucleus to exert its function, allowing the export of the mRNAs encoding paclitaxel-resistance-related factors, including tubulin beta 3 class III (TUBB3), stathmin 1 (STMN1), and microtubule-associated protein Tau (TAU), ultimately inducing paclitaxel resistance in TNBC. Mechanistically, we found that RNF31 interacts with and ubiquitinates ALYREF, which facilitates ALYREF nuclear transportation via importin 13 (IPO13) under paclitaxel treatment. Notably, the RNF31 inhibitor and paclitaxel synergistically repressed tumour growth in vivo and in TNBC patient-derived organoids. In addition, analysis of patients with TNBC showed that elevated RNF31 levels correlated with poor prognosis.&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;These data indicated that RNF31-mediated ALYREF ubiquitylation could represent a potent target to reverse paclitaxel resistance in TNBC.&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 ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 2","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70203","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143362668","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":"HSPG2 could promote normal haematopoiesis in acute myeloid leukaemia patients after complete remission by repairing bone marrow endothelial progenitor cells","authors":"Chen-Yuan Li,&nbsp;Zhen-Kun Wang,&nbsp;Tong Xing,&nbsp;Meng-Zhu Shen,&nbsp;Xin-Yan Zhang,&nbsp;Dan-Dan Chen,&nbsp;Yu Wang,&nbsp;Hao Jiang,&nbsp;Qian Jiang,&nbsp;Xiao-Jun Huang,&nbsp;Yuan Kong","doi":"10.1002/ctm2.70220","DOIUrl":"https://doi.org/10.1002/ctm2.70220","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;Even after achieving complete remission (CR), many acute myeloid leukaemia (AML) patients suffer from poor haematopoietic recovery after chemotherapy. Previous studies have shown that the damage of bone marrow endothelial progenitor cell (BM EPC) hinders haematopoietic recovery after chemotherapy in mice. Therefore, elucidation of the mechanism and repair strategy of chemotherapy-induced BM EPC damage is urgent needed.&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 prospective case–control study enrolled 40 AML patients after CR (CR patients), who received idarubicin and cytarabine (IA) regimen (&lt;i&gt;n&lt;/i&gt; = 20), or homoharringtonine, aclarubicin and cytarabine (HAA) regimen (&lt;i&gt;n&lt;/i&gt; = 20) as induction chemotherapy, and their age-matched healthy controls (HCs, &lt;i&gt;n&lt;/i&gt; = 20). The HSPG2 expression level in BM EPCs and BM plasma were determined via flow cytometry and enzyme-linked immunosorbent assays. The BM EPC's functions were evaluated by apoptosis, reactive oxygen species (ROS) level, migration and tube formation assays. The haematopoiesis-supporting ability and leukaemia cell-supporting ability of BM EPCs were assessed through coculture assay. Moreover, RNA sequencing and qPCR were performed to further explore the underlying mechanism.&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;HSPG2 levels decreased in both the BM plasma and BM EPCs of CR patients after IA and HAA induction chemotherapy. Moreover, the BM EPC's functions of CR patients were reduced. In vitro experiments demonstrated that the &lt;i&gt;HSPG2&lt;/i&gt; gene knockdown or cytosine arabinoside treatment led to BM EPC dysfunction, whereas the HSPG2 treatment promoted repair of the BM EPC function in vitro. In addition, we found that the HSPG2 treatment restored the BM EPC function from CR patients without affecting their leukaemia cell-supporting ability. Mechanistically, BM EPC functions and haematopoietic regulation-related genes were significantly decreased after the &lt;i&gt;HSPG2&lt;/i&gt; gene knockdown.&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;Our findings demonstrate a significant role of HSPG2 in BM EPC functions. This discovery uncovers that HSPG2 is a potential therapeutic target for promoting the BM EPC function of AML-CR patients after chemotherapy.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Highlights&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ul&gt;\u0000 \u0000 &lt;li&gt;\u0000 &lt;p&gt;The HSPG2 level in the BM EPCs of AML-CR patien","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 2","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70220","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143362669","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":"Cell-free epigenomes enhanced fragmentomics-based model for early detection of lung cancer","authors":"Yadong Wang,&nbsp;Qiang Guo,&nbsp;Zhicheng Huang,&nbsp;Liyang Song,&nbsp;Fei Zhao,&nbsp;Tiantian Gu,&nbsp;Zhe Feng,&nbsp;Haibo Wang,&nbsp;Bowen Li,&nbsp;Daoyun Wang,&nbsp;Bin Zhou,&nbsp;Chao Guo,&nbsp;Yuan Xu,&nbsp;Yang Song,&nbsp;Zhibo Zheng,&nbsp;Zhongxing Bing,&nbsp;Haochen Li,&nbsp;Xiaoqing Yu,&nbsp;Ka Luk Fung,&nbsp;Heqing Xu,&nbsp;Jianhong Shi,&nbsp;Meng Chen,&nbsp;Shuai Hong,&nbsp;Haoxuan Jin,&nbsp;Shiyuan Tong,&nbsp;Sibo Zhu,&nbsp;Chen Zhu,&nbsp;Jinlei Song,&nbsp;Jing Liu,&nbsp;Shanqing Li,&nbsp;Hefei Li,&nbsp;Xueguang Sun,&nbsp;Naixin Liang","doi":"10.1002/ctm2.70225","DOIUrl":"https://doi.org/10.1002/ctm2.70225","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;Lung cancer is a leading cause of cancer mortality, highlighting the need for innovative non-invasive early detection methods. Although cell-free DNA (cfDNA) analysis shows promise, its sensitivity in early-stage lung cancer patients remains a challenge. This study aimed to integrate insights from epigenetic modifications and fragmentomic features of cfDNA using machine learning to develop a more accurate lung cancer detection model.&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 address this issue, a multi-centre prospective cohort study was conducted, with participants harbouring suspicious malignant lung nodules and healthy volunteers recruited from two clinical centres. Plasma cfDNA was analysed for its epigenetic and fragmentomic profiles using chromatin immunoprecipitation sequencing, reduced representation bisulphite sequencing and low-pass whole-genome sequencing. Machine learning algorithms were then employed to integrate the multi-omics data, aiding in the development of a precise lung cancer detection model.&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;Cancer-related changes in cfDNA fragmentomics were significantly enriched in specific genes marked by cell-free epigenomes. A total of 609 genes were identified, and the corresponding cfDNA fragmentomic features were utilised to construct the ensemble model. This model achieved a sensitivity of 90.4% and a specificity of 83.1%, with an AUC of 0.94 in the independent validation set. Notably, the model demonstrated exceptional sensitivity for stage I lung cancer cases, achieving 95.1%. It also showed remarkable performance in detecting minimally invasive adenocarcinoma, with a sensitivity of 96.2%, highlighting its potential for early detection in clinical settings.&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;With feature selection guided by multiple epigenetic sequencing approaches, the cfDNA fragmentomics-based machine learning model demonstrated outstanding performance in the independent validation cohort. These findings highlight its potential as an effective non-invasive strategy for the early detection of lung cancer.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Keypoints&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ul&gt;\u0000 \u0000 &lt;li&gt;Our study elucidated the regulatory relationships between epigenetic modifications and their effects on fragmentomic features.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Identifying epigeneticall","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 2","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70225","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143248467","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":"Sodium pump subunit NKAα1 protects against diabetic endothelial dysfunction by inhibiting ferroptosis through the autophagy-lysosome degradation of ACSL4","authors":"Xue-Xue Zhu,&nbsp;Jia-Bao Su,&nbsp;Fang-Ming Wang,&nbsp;Xiao-Ying Chai,&nbsp;Guo Chen,&nbsp;An-Jing Xu,&nbsp;Xin-Yu Meng,&nbsp;Hong-Bo Qiu,&nbsp;Qing-Yi Sun,&nbsp;Yao Wang,&nbsp;Zhuo-Lin Lv,&nbsp;Yuan Zhang,&nbsp;Yao Liu,&nbsp;Zhi-Jun Han,&nbsp;Na Li,&nbsp;Hai-Jian Sun,&nbsp;Qing-Bo Lu","doi":"10.1002/ctm2.70221","DOIUrl":"https://doi.org/10.1002/ctm2.70221","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>The sodium pump Na+/K+-ATPase (NKA), an enzyme ubiquitously expressed in various tissues and cells, is a critical player in maintaining cellular ion homeostasis. Dysregulation of α1 subunit of NKA (NKAα1) has been associated with cardiovascular and metabolic disorders, yet the exact role of NKAα1 in diabetes-induced endothelial malfunction remains incompletely understood. The NKAα1 expression and NKA activity were examined in high-glucose (HG)-exposed endothelial cells (ECs) and mouse aortae, as well as in high-fat-diet (HFD)-fed mice. Acetylcholine (Ach) was utilised to assess endothelium-dependent relaxation (EDR) in isolated mouse aortae. We found that both NKAα1 protein and mRNA levels were significantly downregulated in the aortae of HFD-fed mice, and HG-incubated mouse aortae and ECs. Gain- and loss-of-function experiments revealed that NKAα1 preserves EDR by mitigating oxidative/nitrative stresses in ECs. Overexpression of NKAα1 facilitated EC viability, migration, and angiogenesis by inhibiting the overproduction of superoxide and peroxynitrite. Mechanistically, dysfunctional NKAα1 impaired autophagy process, and prevented the transfer of acyl-CoA synthetase long-chain family member 4 (ACSL4) to the lysosome for degradation, thereby resulting in lipid peroxidation and ferroptosis in ECs. Induction of ferroptosis and inhibition of the autophagy-lysosome pathway blocked the protective effects of NKAα1 on EDR. Eventually, we identified Hamaudol as a potent activator of NKAα1 by restraining the phosphorylation and endocytosis of NKAα1, restoring EDR in obese diabetic mice. Overall, NKAα1 facilitates the autophagic degradation of ACSL4 via the lysosomal pathway, preventing ferroptosis and oxidative/nitrative stress in ECs. NKAα1 may serve as an attractive candidate for the management of vascular disorders associated with diabetes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>NKAα1 downregulation impairs endothelial function in diabetes by promoting oxidative/nitrative stress and ferroptosis.</li>\u0000 \u0000 <li>NKAα1 supports lysosomal degradation of ACSL4 via autophagy, preventing lipid peroxidation and ferroptosis.\u0000</li>\u0000 \u0000 <li>Hamaudol, an activator of NKAα1, restores endothelial relaxation in diabetic mice by inhibiting NKAα1 phosphorylation and endocytosis.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 2","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70221","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143111844","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":"Monocyte–macrophage dynamics as key in disparate lung and peripheral immune responses in severe anti-melanoma differentiation-associated gene 5-positive dermatomyositis-related interstitial lung disease","authors":"Jia Shi,&nbsp;Xiaoya Pei,&nbsp;Jinmin Peng,&nbsp;Chanyuan Wu,&nbsp;Yulin Lv,&nbsp;Xiaoman Wang,&nbsp;Yangzhong Zhou,&nbsp;Xueting Yuan,&nbsp;Xingbei Dong,&nbsp;Shuang Zhou,&nbsp;Dong Xu,&nbsp;Jiuliang Zhao,&nbsp;Jun Liu,&nbsp;Jiao Huang,&nbsp;Bin Du,&nbsp;Chen Yao,&nbsp;Xiaofeng Zeng,&nbsp;Mengtao Li,&nbsp;Houzao Chen,&nbsp;Qian Wang","doi":"10.1002/ctm2.70226","DOIUrl":"https://doi.org/10.1002/ctm2.70226","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;Anti-melanoma differentiation-associated gene 5-positive dermatomyositis (anti-MDA5+ DM) is a rare inflammatory autoimmune disorder often complicated by life-threatening rapidly progressive interstitial lung disease (RP-ILD). The underlying mechanisms driving immune dysfunction and lung injury, however, remain poorly understood. The study aims to gain insights into the disrupted immune landscape in peripheral and pulmonary compartments of severe anti-MDA5+ DM and explore potential therapeutic targets.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;We employed single-cell RNA sequencing to examine cellular constituents within five patients’ bronchoalveolar lavage fluid and paired peripheral blood mononuclear cells. Luminex assay and flow cytometry were further applied to validate the results.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Our analysis revealed starkly contrasting immune landscapes between the periphery and lungs, with peripheral immune suppression juxtaposed against pulmonary immune hyperactivation. Central to this dysregulation was the monocyte–macrophage lineage. Circulating monocytes exhibited an immunosuppressive phenotype, characterised by diminished cytokine production, reduced MHC II expression, and features resembling myeloid-derived suppressor cells. These monocytes were recruited to the lungs, where they differentiated into monocyte-derived alveolar macrophages (Mo-AMs) with robust proinflammatory and profibrotic activities. Mo-AMs drove cytokine storms and produced chemokines that amplified inflammatory cell recruitment and lung tissue remodelling. Additionally, peripheral T and NK cells exhibited increased cell death and active migration into the lungs, which may be the cause of lymphopenia.&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;Our study underscores the pivotal role of monocyte–macrophage dynamics in the immunopathogenesis of anti-MDA5+-associated RP-ILD, offering critical insights into compartment-specific immune dysregulation. These findings suggest potential therapeutic strategies targeting monocyte recruitment and macrophage activation to mitigate disease progression.&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;Peripheral immune suppression and pulmonary immune hyperactivation characterise the distinct immune landscapes in anti-MDA5+DM with RP-ILD.&lt;/li&gt;\u0000 \u0000 ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 2","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70226","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143111849","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}