Clinical and Translational Medicine最新文献

{"title":"Single-cell transcriptomic atlas of different endometriosis indicating that an interaction between endometriosis-associated mesothelial cells (EAMCs) and ectopic stromal cells may influence progesterone resistance","authors":"Shengdi Hou, Jing Zhang, Zhiqiang Zhang, Hong Qu, Shuhong Li, Ying Jiang, Chongdong Liu","doi":"10.1002/ctm2.70216","DOIUrl":"https://doi.org/10.1002/ctm2.70216","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Endometriosis is a hormone-dependent disease, which can usually be divided into peritoneal endometriosis (PEM), deep-infiltrating endometriosis (DIE) and ovarian endometriosis (OEM). Although the three pathologic types are essentially the same disease, they differ in pathological manifestations, molecular features, pain symptoms and hormonal responsiveness. However, there is limited literature focusing on the differences among these types. In this study, we employed single-cell RNA sequencing (scRNA-seq) to profile the transcriptome of each type using surgical biopsy samples obtained from six patients. We aimed to explore and elucidate the variations among these different types of endometriosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We identified five major cell types and 44 subpopulations, including the presence of mesothelial cells in all pathological types, including OEM. Furthermore, we characterised the variations in cell types across different pathological types by employing enrichment analysis to assess functions and pathways. Notably, our findings reveal distinct levels of epithelial–mesenchymal transition (EMT) processes experienced by mesothelial cells within the microenvironment of endometriotic lesions. Through ligand–receptor analysis and referencing relevant literature, we propose that mesothelial cells exert an influence on progesterone resistance in stromal cells through intercellular communication mediated by the FN1-AKT pathway.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our study comprehensively characterises the heterogeneity of the different pathologic types of endometriosis and offers valuable insights into the underlying mechanisms contributing to variations in progesterone resistance across the three subtypes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Single-cell RNA (ScRNA) atlas across types of endometriosis is established.</li>\u0000 \u0000 <li>Mesothelial cells are founded in ovarian endometriosis.</li>\u0000 \u0000 <li>Endometriosis-associated mesothelial cells (EAMCs) experience various level of epithelial–mesenchymal transition (EMT) process in different subtypes.</li>\u0000 \u0000 <li>EAMCs may exert an influence on progesterone resistance in stromal cells through intercellular communication mediated by the FN1-AKT pathway.</li>\u0000 </ul>\u0000 </div>\u0000 </secti","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 2","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70216","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143438794","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":"A comparative genomic study across 396 liver biopsies provides deep insight into FGF21 mode of action as a therapeutic agent in metabolic dysfunction-associated steatotic liver disease","authors":"Shifang Tang, Jürgen Borlak","doi":"10.1002/ctm2.70218","DOIUrl":"https://doi.org/10.1002/ctm2.70218","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Metabolic dysfunction-associated steatotic liver disease (MASLD) is a systemic disease with insulin resistance at its core. It affects one-third of the world population. Fibroblast growth factor (FGF21)-based therapies are effective in lowering hepatic fat content and fibrosis resolution; yet, its molecular functions remain uncertain. To gain insight into FGF21 mode of action (MoA), we investigated the transcriptomes of MASLD liver biopsies in relation to FGF21 expression.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We compared <i>N</i> = 66 healthy controls with 396 MASLD patients and considered clinical characteristics relative to NAS disease activity scores (steatosis, lobular inflammation and ballooning), fibrosis grades and sex. We performed comparative genomics to identify FGF21-responsive DEGs, utilised information from FGF21-transgenic and FGF21-knockout mice and evaluated DEGs following FGF21 treatment of MASLD animal models. Eventually, we explored 188 validated FGF21 targets, and for ≥10 patients showing the same changes, we constructed MASLD-associated networks to determine the effects of FGF21 in reverting metabolic dysfunction.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We identified patients with increased 30% (<i>N</i> = 117), decreased 40% (<i>N</i> = 159) or unchanged 30% (<i>N</i> = 120) FGF21 expression, and the differences are caused by changes in FGF21 transcriptional control with ATF4 functioning as a key regulator. Based on comparative genomics, we discovered molecular circuitries of FGF21 in MASLD, notably FGF21-dependent induction of autophagy and oxidative phosphorylation/mitochondrial respiration. Conversely, FGF21 repressed hepatic glycogen-storage, its glucose release and gluconeogenesis, and therefore reduced glucose flux in conditions of insulin resistance. Furthermore, FGF21 repressed lipid transporters, and acetyl-CoA carboxylase-β to attenuate hepatic lipid overload and lipogenesis. Strikingly, FGF21 dampened immune response by repressing complement factors, MARCO, CD163, MRC1/CD206, CD4, CD45 and pro-inflammatory cytokine receptors. It also reverted procoagulant imbalance in MASLD, stimulated extracellular matrix degradation, repressed TGFβ- and integrin-signalling and lessened liver sinusoidal endothelial cell defenestration in support of fibrosis resolution.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>We gained deep insight into FGF21-MoA in MASLD. However, heterogeneity in FGF21 expression calls for molecular stratifications as to identify patients which likel","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 2","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70218","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143431616","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":"Muscle-specific gene editing improves molecular and phenotypic defects in a mouse model of myotonic dystrophy type 1","authors":"Mariapaola Izzo, Jonathan Battistini, Elisabetta Golini, Christine Voellenkle, Claudia Provenzano, Tiziana Orsini, Georgios Strimpakos, Ferdinando Scavizzi, Marcello Raspa, Denisa Baci, Svetlana Frolova, Spyros Tastsoglou, Germana Zaccagnini, Jose Manuel Garcia-Manteiga, Genevieve Gourdon, Silvia Mandillo, Beatrice Cardinali, Fabio Martelli, Germana Falcone","doi":"10.1002/ctm2.70227","DOIUrl":"https://doi.org/10.1002/ctm2.70227","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Myotonic dystrophy type 1 (DM1) is a genetic multisystemic disease, characterised by pleiotropic symptoms that exhibit notable variability in severity, nature and age of onset. The genetic cause of DM1 is the expansion of unstable CTG-repeats in the 3′ untranslated region (UTR) of the <i>DMPK</i> gene, resulting in the accumulation of toxic CUG-transcripts that sequester RNA-binding proteins and form nuclear foci in DM1 affected tissues and, consequently, alter various cellular processes. Therapeutic gene editing for treatment of monogenic diseases is a powerful technology that could in principle remove definitively the disease-causing genetic defect. The precision and efficiency of the molecular mechanisms are still under investigation in view of a possible use in clinical practice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Here, we describe the application of the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) strategy to remove the CTG-expansion in the <i>DMPK</i> gene in a mouse model carrying the human transgene from a DM1 patient. To optimise the editing efficiency in vivo, we identified new tools that allowed to improve the expression levels and the activity of the CRISPR/Cas9 machinery. Newly designed guide RNA pairs were tested in DM1-patient derived cells before in vivo application. Edited cells were analysed to assess the occurrence of off-target and the accuracy of on-target genomic events. Gene editing-dependent and -independent mechanisms leading to decreased accumulation of the mutated <i>DMPK</i> transcripts were also evaluated.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results and Conclusion</h3>\u0000 \u0000 <p>Systemic delivery of CRISPR/Cas9 components in DM1 mice, through myotropic adeno-associated viral vectors, led to significant improvement of molecular alterations in the heart and skeletal muscle. Importantly, a persistent increase of body weight, improvement of muscle strength and body composition parameters were observed in treated animals. Accurate evaluation of CRISPR/Cas9-mediated-phenotypic recovery in vivo is a crucial preclinical step for the development of a gene therapy for DM1 patients.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>In vivo application of a therapeutic gene editing strategy for permanent deletion of the pathogenetic CTG-repeat amplification in the <i>DMPK</i> gene that causes myotonic dystrophy type 1.</li>\u0000 \u0000 <","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 2","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70227","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143423725","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":"5-hydroxymethylcytosine features of portal venous blood predict metachronous liver metastases of colorectal cancer and reveal phosphodiesterase 4 as a therapeutic target","authors":"Nuo Xu,&nbsp;Zhaoya Gao,&nbsp;Deyan Wu,&nbsp;Hangyu Chen,&nbsp;Zijian Zhang,&nbsp;Lei Zhang,&nbsp;Yuchen Wang,&nbsp;Xuyang Lu,&nbsp;Xu Yao,&nbsp;Xuelan Liu,&nbsp;Yi-You Huang,&nbsp;Meiying Qiu,&nbsp;Sen Wang,&nbsp;Jinqiang Liang,&nbsp;Can Mao,&nbsp;Feng Zhang,&nbsp;Huimin Xu,&nbsp;Yujiao Wang,&nbsp;Xian Li,&nbsp;Zhexin Chen,&nbsp;Dandan Huang,&nbsp;Jingyi Shi,&nbsp;Wensheng Huang,&nbsp;Fuming Lei,&nbsp;Zeruo Yang,&nbsp;Long Chen,&nbsp;Chuan He,&nbsp;Haichuan Zhu,&nbsp;Hai-Bin Luo,&nbsp;Jin Gu,&nbsp;Jian Lin","doi":"10.1002/ctm2.70189","DOIUrl":"https://doi.org/10.1002/ctm2.70189","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>Metachronous liver metastases (MLM) are characterised by high incidence and high mortality in clinical colorectal cancer treatment. Currently traditional clinical methods cannot effectively predict and prevent the occurrence of metachronous liver metastasis in colorectal cancer. Based on 5hmC-Seal analysis of blood and tissue samples, this study found that portal venous blood was more relevant to tumour gDNA than peripheral blood. We performed a novel epigenetic liquid biopsy strategy using the 10 5hmC epigenetic alterations, to accurately distinguish MLM patients from patients without metastases. Among these epigenetic alterations, phosphodiesterase 4 (PDE4D) was highly increased in MLM patients and correlated with poor survival. Moreover, our studies demonstrated that PDE4D was a key metastasis-driven target for drug development. Interfering with the function of PDE4D significantly repressed liver metastases. Similarly, roflumilast, a PDE4 inhibitor for chronic obstructive pulmonary disease (COPD) therapy, also inhibits liver metastases. Further studies indicate that blocking the function of PDE4D can affect CRC invasion through the HIF-1α-CCN2 pathway. To develop a more efficient PDE4 inhibitor and reduce the occurrence of adverse events, we also designed several new compounds based on 2-arylbenzofurans and discovered lead L11 with potent affinity for PDE4D and significant suppression of liver metastases. In this work, our study provides a promising strategy for predicting metachronous liver metastasis and discovers L11 as a potential repurposed drug for inhibiting liver metastasis, which have the potential to benefit patients with CRC in the future.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>5hmC epigenetic markers derived from portal venous blood could accurately predict metachronous metastasis of colorectal cancer.</li>\u0000 \u0000 <li>PDE4D was a key metastasis-driven target that promoted metachronous metastasis via the HIF-1α-CCN2 pathway.</li>\u0000 \u0000 <li>The newly synthesised compound L11 could specifically inhibit PDE4D and abolish metachronous metastasis of colorectal cancer without obvious toxic side effects.</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":"2025-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70189","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143424156","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 transcriptomics reveals regional characteristics of lupus nephritis in murine kidneys and immune response to prednisolone or Gancao Nourishing-Yin decoction therapies","authors":"Yanjuan Chen,&nbsp;Yong Chen,&nbsp;Xufa Yang,&nbsp;Zhenyou Jiang,&nbsp;Dongzhou Liu,&nbsp;Xiaoping Hong","doi":"10.1002/ctm2.70236","DOIUrl":"https://doi.org/10.1002/ctm2.70236","url":null,"abstract":"&lt;p&gt;Dear Editor,&lt;/p&gt;&lt;p&gt;This study reveals the spatial immune landscape in Lupus nephritis (LN) mouse kidneys and evaluates the therapeutic effects of prednisolone (PDL) and Gancao Nourishing-Yin decoction (GCNY).&lt;/p&gt;&lt;p&gt;LN is a major cause of end-stage renal disease and increases mortality in systemic lupus erythematosus patients.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Current treatments—glucocorticoid, cytotoxic drugs, and biological agents are effective but come with notable side effects.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; Traditional Chinese medicine (TCM) has recently shown promise in addressing LN-related kidney injury.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; Our previous research found GCNY, a TCM formulation, demonstrated anti-inflammatory and antioxidative effects,&lt;span&gt;&lt;sup&gt;4, 5&lt;/sup&gt;&lt;/span&gt; suggesting that GCNY could be a complementary or alternative treatment for LN by modulating immune responses. Since glucocorticoids are considered a fundamental therapy,&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; PDL was chosen as the control for GCNY treatment.&lt;/p&gt;&lt;p&gt;Spatial transcriptomics (ST) is a powerful tool for investigating the cellular dynamics and therapeutic effect in LN kidneys.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; In 2023, Tang et al. applied ST to LN patient kidney biopsies, identifying elevated &lt;i&gt;APOE&lt;/i&gt;&lt;sup&gt;+&lt;/sup&gt; monocytes that facilitated macrophage trafficking.&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt; In this study, we conducted ST on kidney tissues from lupus-prone MRL/Lpr (Lpr) mice, Lpr mice treated with either PDL or GCNY, and MRL/Mpj (Mpj) control mice, using 10× Genomics Visium platform (Figure S1A). After bioinformatic analysis, totally 16 428 spatial spots and 32 285 genes were identified, exceeding 670 spots and averaging 3984 genes and 15 404 unique molecular identifiers (UMIs) per sample (Figure S1B). UMAP analysis showed effective integration across all groups (Figure S1C). Unsupervised clustering classified the spots into six regions 1–6, with region 2 having the fewest genes and UMIs, possibly due to its unique cell types (Figure 1A, Figure S1D). Region 1 was the largest, followed by regions 2 and 3 (Figure 1B).&lt;/p&gt;&lt;p&gt;Using the scRNA-seq data as a reference (Figure S1E),&lt;span&gt;&lt;sup&gt;8&lt;/sup&gt;&lt;/span&gt; the multimodal intersection analysis (MIA) indicated region 4, 5 and 6 mainly comprised podocytes, macrophages, neutrophils, T/B lymphocytes and natural killer cells (Figure 1C). The abundance of immune cells in regions 4–6 was highest in Lpr mice and reduced in PDL-treated or GCNY-treated mice (Figure 1B). Aligning with MIA results, spatial deconvolution analysis showed region 1 as predominantly proximal tubule cells and region 3 as mainly ascending loop of Henle cells (Figure 1D,E). Regions 4 and 6 exhibited the greatest variety of immune cell types, such as B lymphocytes and macrophages (Figure 1E). Based on spatial localization, regions 4 and 6 are scattered in the renal cortex, indicating their potential involvement in glomerular inflammation (Figure 1F). The characteristics of regions are detailed in F","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 2","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70236","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143423867","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":"Erratum for the article “Medial septum tau accumulation induces spatial memory deficit via disrupting medial septum-hippocampus cholinergic pathway” by Wu et al.","authors":"","doi":"10.1002/ctm2.70234","DOIUrl":"https://doi.org/10.1002/ctm2.70234","url":null,"abstract":"<p>Dear editor,</p><p>We are writing this letter to apply for an erratum of our published paper by Wu et al. We sincerely apologize for the mistakes and deeply regret any inconvenience this may have caused you.</p><p>Original version of Figure 5</p><p>The red block highlights the incorrect image of Vector control group.</p><p>The new version of Figure 5</p><p>A correct image of the vector control group (3 M) is included in Figure 5C.</p><p>The amended Figure 5</p><p>The reason for correction:</p><p>I recently discovered an error in Figure 5 while reviewing my paper. In the original version of Figure 5C, for 3 months after virus injection (upper panel), the image from Vector control group was inadvertently replaced by hTau group. Upon reviewing the original data, we realized that the mistake was made by inadvertently duplicated the layers during figure preparation. We have now included the correct image of Vector control group in the amended Figure 5. There were no significant differences in ChAT+ signals between the vector and overexpressing hTau groups (3 months). The experimental conclusions remain unchanged by this revision; therefore, no adjustments to the article's text are necessary.</p><p>Thank you for your consideration. We look forward to your kind response.</p><p>Sincerely yours,</p><p>Dr. Dongqin Wu</p><p>Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China</p>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 2","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70234","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143424155","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":"EpCAM deficiency causes the premature ageing of intestinal stem cells via EGFR/SP1/mTORC1 pathway","authors":"Keying Li,&nbsp;Changlong Xu,&nbsp;Lulu Liu,&nbsp;Yunjuan Wang,&nbsp;Jun Chen,&nbsp;Chunyuan Li,&nbsp;Zitong Peng,&nbsp;Xiaoqian Li,&nbsp;Gang Chang,&nbsp;Zili Lei,&nbsp;Yanhong Yang","doi":"10.1002/ctm2.70219","DOIUrl":"https://doi.org/10.1002/ctm2.70219","url":null,"abstract":"&lt;p&gt;Dear Editor,&lt;/p&gt;&lt;p&gt;We reported a precise molecular mechanism underlying the longevity of intestinal stem cells (ISCs) maintained by EpCAM via the EGFR/SP1/mTORC1 pathway. EpCAM is highly expressed in ISCs,&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; and most patients of congenital tufting enteropathy (CTE), caused by EpCAM mutations,&lt;span&gt;&lt;sup&gt;2, 3&lt;/sup&gt;&lt;/span&gt; die of intestinal failure.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; EpCAM deficiency induces premature ageing of ISCs via downregulating TSC1 to hyperactivate the mTORC1 pathway.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; However, upstream signals through which EpCAM regulates the expression of TSC1 remain unknown.&lt;/p&gt;&lt;p&gt;As previous report,&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; EpCAM&lt;sup&gt;−/−&lt;/sup&gt; mice showed no significant differences in appearance compared to wild type (WT) littermates at the E18.5 stage (Figure S1A,B). However, the mutant pups started to have diarrhoea after birth and most died within 1 week. The tufting and erosion of the intestinal villi were observed in mutants at both E18.5 and P3 stages (Figures S1C,D and S2A,B). &lt;i&gt;Tert&lt;/i&gt;, encoding the protein component of telomerase, was significantly downregulated but γH2AX, the DNA damage accumulation-associated protein, was considerably increased in the E18.5 mutant small intestines (Figure S1E−G), confirming the premature ageing of these tissues.&lt;/p&gt;&lt;p&gt;SP1 is involved in various tissue and cellular senescence processes.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; At the E18.5 stage, the expression and activity of SP1 were reduced in the mutant small intestines (Figure 1A,B). The p-SP1 was predominantly present in the nucleus of epithelial cells in the inter villi region of the duodenum and decreased in the mutants at both E18.5 and P3 stages (Figures S3A and S4A−F).&lt;/p&gt;&lt;p&gt;The SP1 inhibitor Mithramycin A (MitA) reduced the expression and activity of SP1 in Caco-2 cells (Figures 1C,D and S3B,C). With the inhibition of SP1, TSC1 and TSC2 downregulated, and the activation of the mTORC1 pathway dramatically increased (Figures 1E and S3D). The TERT significantly decreased, but γH2AX increased with the MitA administration (Figure 1F−H).&lt;/p&gt;&lt;p&gt;Subsequently, Caco-2 cells were simultaneously treated with MitA and rapamycin (RAP). The p-SP1 and SP1 were significantly decreased in MitA and MitA+RAP groups (Figures 1I,K and S3E). In the MitA+RAP group, the activation of the mTORC1 pathway was markedly lower than in the MitA group (Figures 1J and S3E). The TERT was increased but γH2AX was decreased in the MitA+RAP group compared with the MitA group (Figures 1K,L and S3E).&lt;/p&gt;&lt;p&gt;The naringenin (NAR), an effective activator of SP1,&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt; was administrated to the pregnant females to activate SP1 in the intestines of EpCAM&lt;sup&gt;−/−&lt;/sup&gt; embryos (Figure S5A). The duodenum and jejunum showed improved intestinal villi tufting and breakage in the NAR-treated mutants (Figure S5B). The expression and activity of SP1 were significantly restored in the small intestines of the EpCAM&lt;sup&gt;−/−&lt;/sup&gt;+NAR group (Figu","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 2","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70219","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143396809","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":"METTL14-mediated m6A modification of ZFP14 inhibits clear cell renal cell carcinoma progression via promoting STAT3 ubiquitination","authors":"Zhuonan Liu,&nbsp;Tianshui Sun,&nbsp;Zhe Zhang,&nbsp;Chiyuan Piao,&nbsp;Chuize Kong,&nbsp;Xiaotong Zhang","doi":"10.1002/ctm2.70232","DOIUrl":"https://doi.org/10.1002/ctm2.70232","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>Therapeutic options for advanced clear cell renal cell carcinoma (ccRCC) are currently inadequate. Earlier research has shown that the enzyme methyltransferase-like 14 (METTL14) can suppress ccRCC development through the modification of N6-methyladenosine (m6A). This study further explored its complex biological functions and underlying molecular mechanisms. Here, we identified zinc finger protein 14 (ZFP14) as a novel target of METTL14-mediated m6A, and its under-expression was associated with ccRCC tumourigenesis and progression. Detailed investigations revealed that METTL14 interacted directly with the 3′ untranslated region of ZFP14 mRNA, promoting m6A modification at two specific sites. These modifications were recognised by the protein insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2), which stabilised and enhanced the expression of ZFP14 mRNA. Functionally, the METTL14/ZFP14 axis suppressed in vitro growth, migration and invasiveness and in vivo proliferation and metastasis of ccRCC cells. ZFP14 potentially regulated numbers of transcripts, among which matrix metalloproteinase 1/3 (MMP1/3) were validated to be under-expressed by ZFP14. Crucially, ZFP14 interacted with the signal transducer and activator of transcription 3 (STAT3), augmenting its K48-linked ubiquitination and destabilising it via the proteasome pathway. Moreover, ZFP14 repressed ccRCC cell in vivo growth and metastasis as well as decreasing MMP1/3 levels by under-expressing STAT3. These observations confirmed that ZFP14 served as both a novel target for METTL14-mediated m6A modification and a significant tumour suppressor in ccRCC, shedding light on the cellular and molecular operations in ccRCC and opening up possibilities for novel therapeutic strategies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>\u0000 <p>ZFP14 under-expression is associated with ccRCC tumourigenesis and progression.</p>\u0000 </li>\u0000 \u0000 <li>\u0000 <p>METTL14-mediated m6A enhances ZFP14 mRNA stability and expression with IGF2BP2 as the reader in ccRCC.</p>\u0000 </li>\u0000 \u0000 <li>\u0000 <p>ZFP14 promotes the degradation of STAT3 by enhancing its K48-linked ubiquitination, inhibiting ccRCC progression.</p>\u0000 </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":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70232","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143389115","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":"Large-scale cluster randomised trial reveals effectiveness of Helicobacter pylori eradication for gastric cancer prevention","authors":"Zong-Chao Liu,&nbsp;Wen-Qing Li","doi":"10.1002/ctm2.70229","DOIUrl":"https://doi.org/10.1002/ctm2.70229","url":null,"abstract":"&lt;p&gt;Gastric cancer (GC) remains a critical public health concern, ranking among the most prevalent cancers and leading causes of cancer-related deaths globally.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; The burden is particularly pronounced in East Asia, Latin America and Eastern Europe, with nearly half of all new cases and related deaths occurring in China alone. &lt;i&gt;Helicobacter pylori&lt;/i&gt;, classified as a Group I carcinogen, plays a crucial role in gastric carcinogenesis. &lt;i&gt;H. pylori&lt;/i&gt; infection in China accounts for approximately 340 000 new cancer cases annually,&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; contributing to more than 70% of all GC cases nationwide. In 2018, the infection was responsible for 78.5% of non-cardia GC and 62.1% of cardia GC.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; While randomised trials have demonstrated the efficacy of &lt;i&gt;H. pylori&lt;/i&gt; eradication for GC prevention,&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; in 2014, the International Agency for Research on Cancer highlighted a lack of data to quantify the overall benefits and risks of implementing large-scale, population-based eradication programs in real world.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Recently, the Mass Intervention Trial in Shandong (MITS), China, a community-based, cluster-randomised controlled superiority intervention trial, provided new evidence on the effectiveness of population-wide &lt;i&gt;H. pylori&lt;/i&gt; intervention in preventing GC (ChiCTR-TRC-10000979, https://www.chictr.org.cn).&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; Conducted across 980 villages in 10 townships in Linqu, Shandong, the trial involved 180 284 participants, divided into three groups based on baseline &lt;i&gt;H. pylori&lt;/i&gt; infection status. &lt;i&gt;H. pylori&lt;/i&gt;-positive individuals were assigned to receive either 10-day quadruple anti-&lt;i&gt;H. pylori&lt;/i&gt; treatment (20 mg omeprazole bid, 750 mg tetracycline tid, 400 mg metronidazole tid and 300 mg bismuth citrate bid, &lt;i&gt;n&lt;/i&gt; = 52 026) or symptom alleviation treatment (a single dosage of 20 mg omeprazole and 300 mg bismuth citrate, &lt;i&gt;n&lt;/i&gt; = 50 304), while &lt;i&gt;H. pylori&lt;/i&gt;-negative individuals (&lt;i&gt;n&lt;/i&gt; = 77 954) did not receive any treatment.&lt;/p&gt;&lt;p&gt;The trial's 11.8-year follow-up (2011–2022) confirmed a 13% reduction in GC incidence among all treated participants and a 19% reduction among those with successful &lt;i&gt;H. pylori&lt;/i&gt; eradication, compared to the symptom alleviation group.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; The authors also reported a more clinically informative measure: a number needed to treat (NNT) of 141 patients to prevent one GC case across all treated individuals, which was improved to 96 among those who achieved successful eradication.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; These NNT estimates from MITS were higher (indicating comparatively modest effect magnitude) than those reported in prior trials and meta-analyses,&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt; mainly due to the usage of a partially effective symptom alleviation treatment in MITS, which included omeprazole and bismuth rather than a pure placebo. Notably, 15.1% of participants in the","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 2","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70229","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143389114","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":"Immune profiling of the macroenvironment in colorectal cancer unveils systemic dysfunction and plasticity of immune cells","authors":"Haoxian Ke,&nbsp;Peisi Li,&nbsp;Zhihao Li,&nbsp;Xian Zeng,&nbsp;Chi Zhang,&nbsp;Shuzhen Luo,&nbsp;Xiaofang Chen,&nbsp;Xinlan Zhou,&nbsp;Shichen Dong,&nbsp;Shaopeng Chen,&nbsp;Junfeng Huang,&nbsp;Ming Yuan,&nbsp;Runfeng Yu,&nbsp;Shubiao Ye,&nbsp;Tuo Hu,&nbsp;Zhonghui Tang,&nbsp;Dongbin Liu,&nbsp;Kui Wu,&nbsp;Xianrui Wu,&nbsp;Ping Lan","doi":"10.1002/ctm2.70175","DOIUrl":"https://doi.org/10.1002/ctm2.70175","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;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.&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;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.&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;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&lt;sup&gt;+&lt;/sup&gt; 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&lt;sup&gt;+&lt;/sup&gt; T cells from blood can predict TLS presence in the CRC macroenvironment, serving as potential biomarkers for stratifying CRC patients into immunotherapy.&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 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.&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;Distinct immunotypes are identified in the CRC macroenvironment.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;TLS and immunotherapy exert influence on the immune macroenvironment.&lt;/li&gt;\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}