Clinical and Translational Medicine最新文献

{"title":"Therapeutic potential of mesenchymal stem cell-derived extracellular vesicles: A focus on inflammatory bowel disease","authors":"Laura Clua-Ferré, Roger Suau, Irene Vañó-Segarra, Iris Ginés, Carolina Serena, Josep Manyé","doi":"10.1002/ctm2.70075","DOIUrl":"10.1002/ctm2.70075","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have emerged as key regulators of intercellular communication, orchestrating essential biological processes by delivering bioactive cargoes to target cells. Available evidence suggests that MSC-EVs can mimic the functions of their parental cells, exhibiting immunomodulatory, pro-regenerative, anti-apoptotic, and antifibrotic properties. Consequently, MSC-EVs represent a cell-free therapeutic option for patients with inflammatory bowel disease (IBD), overcoming the limitations associated with cell replacement therapy, including their non-immunogenic nature, lower risk of tumourigenicity, cargo specificity and ease of manipulation and storage.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Main Topics Covered</h3>\u0000 \u0000 <p>This review aims to provide a comprehensive examination of the therapeutic efficacy of MSC-EVs in IBD, with a focus on their mechanisms of action and potential impact on treatment outcomes. We examine the advantages of MSC-EVs over traditional therapies, discuss methods for their isolation and characterisation, and present mechanistic insights into their therapeutic effects through transcriptomic, proteomic and lipidomic analyses of MSC-EV cargoes. We also discuss available preclinical studies demonstrating that MSC-EVs reduce inflammation, promote tissue repair and restore intestinal homeostasis in IBD models, and compare these findings with those of clinical trials.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Finally, we highlight the potential of MSC-EVs as a novel therapy for IBD and identify challenges and opportunities associated with their translation into clinical practice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>The source of mesenchymal stem cells (MSCs) strongly influences the composition and function of MSC-derived extracellular vesicles (EVs), affecting their therapeutic potential. Adipose-derived MSC-EVs, known for their immunoregulatory properties and ease of isolation, show promise as a treatment for inflammatory bowel disease (IBD).</li>\u0000 \u0000 <li>MicroRNAs are consistently present in MSC-EVs across cell types and are involved in pathways that are dysregulated in IBD, making them potential therapeutic agents. For example, miR-let-7a is associated with inhibition of apoptosis, miR-100 supports cell survival, miR-125b helps suppress pro-inflammatory cytokines and miR-20 promotes anti-inflammatory M2 macrophage polar","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 11","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70075","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142563856","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":"Chaperonin-containing TCP1 subunit 6A inhibition via TRIM21-mediated K48-linked ubiquitination suppresses triple-negative breast cancer progression through the AKT signalling pathway.","authors":"Mengdi Yang, Jianing Cao, Tiantian Liu, Bin Li, Jinyan Wang, Shuangyue Pan, Duancheng Guo, Zhonghua Tao, Xichun Hu","doi":"10.1002/ctm2.70097","DOIUrl":"10.1002/ctm2.70097","url":null,"abstract":"<p><strong>Background: </strong>Triple-negative breast cancer (TNBC) is distinguished by a significant likelihood of distant recurrence and an unfavourable prognosis. However, the underlying molecules and mechanisms have not been fully elucidated.</p><p><strong>Methods: </strong>We investigated the expression profile and clinical relevance of chaperonin-containing TCP1 subunit 6A (CCT6A) in TNBC. We performed cell function assays on TNBC cells with CCT6A knockdown or overexpression. To further explore the mechanism of action of CCT6A, RNA sequencing and co-immunoprecipitation-mass spectrometry analyses were utilized. Rescue and ubiquitination assays evaluated the impact of TRIM21-mediated CCT6A ubiquitination and degradation on TNBC progression in vitro and in vivo. Finally, we studied the potential of Ipatasertib, a pharmacological AKT inhibitor, and/or anti-PD1 therapy in inhibiting TNBC progression.</p><p><strong>Results: </strong>Elevated CCT6A expression in TNBC patients was associated with an adverse prognosis and lymph node metastasis. Mechanistically, CCT6A facilitated cell migration, invasion, epithelial-mesenchymal transition and proliferation by activating the phosphatidylinositol 3-kinase (PI3K)/AKT pathway. The TRIM21 RING domain is an E3 ligase, facilitating the K48-linked ubiquitination-mediated degradation of CCT6A, thereby impeding TNBC progression. Moreover, in the tumour tissues of the CCT6A-overexpressing mice, the quantity of CD8+ T cells and the concentration of secreted interferon-gamma were decreased, whereas in the group double-overexpression of CCT6A and TRIM21, they were elevated; the opposite was observed in the knockdown and double-knockdown groups. Ipatasertib demonstrated enhanced efficacy in inhibiting cell proliferation, invasion and migration in TNBC cells ectopically expressing CCT6A. When Ipatasertib and anti-PD1 therapies were combined, both the tumour volume and mass exhibited a notable reduction, while the expression of CD45+CD8+ T cells increased, and that of CD45+CD4+CTLA4+ and CD45+CD4+PD1+ T cells decreased.</p><p><strong>Conclusions: </strong>Our findings indicate that TRIM21 inhibits TNBC progression by facilitating the K48-linked ubiquitination-mediated degradation of CCT6A via the PI3K/AKT signalling pathway. This highlights the potential of Ipatasertib and/or anti-PD1 as therapeutic strategies, particularly for TNBC patients overexpressing CCT6A.</p><p><strong>Key points: </strong>Chaperonin TCP1 subunit 6A (CCT6A) plays an oncogenic role in triple-negative breast cancer (TNBC) through the AKT signaling pathway. TRIM21 facilitated K48-linked ubiquitination-mediated degradation of CCT6A, thereby impeding TNBC progression. Our study collectively underscores the potential of Ipatasertib in conjunction with anti-PD1 therapy as a promising strategy to counteract CCT6A/AKT hyperactivity-driven TNBC progression.</p>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 11","pages":"e70097"},"PeriodicalIF":7.9,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70097","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142647036","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":"Natural killer cell engagers: From bi-specific to tri-specific and tetra-specific engagers for enhanced cancer immunotherapy","authors":"An Zhu,&nbsp;Yu Bai,&nbsp;Yanyang Nan,&nbsp;Dianwen Ju","doi":"10.1002/ctm2.70046","DOIUrl":"10.1002/ctm2.70046","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>Natural killer cell engagers (NKCEs) are a specialised subset of antibodies capable of simultaneously targeting endogenous NK cells and tumour cells, generating precise and effective cytolytic responses against cancer. This review systematically explores NK engagers as a rising star in NK-mediated immunotherapy, specifically focusing on multi-specific engagers. It examines the diverse configuration of NKCEs and how certain biologics could be employed to boost NK activity, including activating receptor engagement and cytokine incorporation. Some challenges and future perspectives of current NKCEs therapy are also discussed, including optimising pharmacokinetics, addressing the immunosuppressive tumour microenvironment and exploring potential combinatorial approaches. By offering an in-depth analysis of the current landscape and future trajectories of multi-specific NKCEs in cancer treatment, this review serves as a valuable resource for understanding this promising field of immunotherapy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>\u0000 <p><b>Innovative NKCEs</b>: NK cell engagers (NKCEs) represent a promising new class of immunotherapeutics targeting tumours by activating NK cells.</p>\u0000 </li>\u0000 \u0000 <li>\u0000 <p><b>Multi-specific formats</b>: The transition from bi-specific to multi-specific NKCEs enhances their versatility and therapeutic efficacy.</p>\u0000 </li>\u0000 \u0000 <li>\u0000 <p><b>Mechanisms of action</b>: NKCEs have the potential to improve NK cell activation by engaging activating receptors and incorporating cytokines.</p>\u0000 </li>\u0000 \u0000 <li>\u0000 <p><b>Clinical potential</b>: Current clinical trials demonstrate the safety and efficacy of various NKCEs across different cancer types.</p>\u0000 </li>\u0000 \u0000 <li>\u0000 <p><b>Future research directions</b>: Optimising NKCE designs and exploring combination therapies are essential for overcoming challenges in cancer treatment.</p>\u0000 </li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 11","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70046","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142544077","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":"Comprehensive review and updated analysis of DNA methylation in hepatocellular carcinoma: From basic research to clinical application","authors":"Lin Su,&nbsp;Jiawen Bu,&nbsp;Jiahui Yu,&nbsp;Mila Jin,&nbsp;Guanliang Meng,&nbsp;Xudong Zhu","doi":"10.1002/ctm2.70066","DOIUrl":"10.1002/ctm2.70066","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>Hepatocellular carcinoma (HCC) is a primary malignant tumour, ranking second in global mortality rates and posing significant health threats. Epigenetic alterations, particularly DNA methylation, have emerged as pivotal factors associated with HCC diagnosis, therapy, prognosis and malignant progression. However, a comprehensive analysis of the DNA methylation mechanism driving HCC progression and its potential as a therapeutic biomarker remains lacking. This review attempts to comprehensively summarise various aspects of DNA methylation, such as its mechanism, detection methods and biomarkers aiding in HCC diagnosis, treatment and prognostic assessment of HCC. It also explores the role of DNA methylation in regulating HCC's malignant progression and sorafenib resistance, alongside elaborating the therapeutic effects of DNA methyltransferase inhibitors on HCC. A detailed examination of these aspects underscores the significant research on DNA methylation in tumour cells to elucidate malignant progression mechanisms, identify diagnostic markers and develop new tumour-specific inhibitors for HCC.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>\u0000 <p>A comprehensive summary of various aspects of DNA methylation, such as its mechanism, detection methods and biomarkers aiding in diagnosis and treatment.</p>\u0000 </li>\u0000 \u0000 <li>\u0000 <p>The role of DNA methylation in regulating hepatocellular carcinoma's (HCC) malignant progression and sorafenib resistance, alongside elaborating therapeutic effects of DNA methyltransferase inhibitors.</p>\u0000 </li>\u0000 \u0000 <li>\u0000 <p>Deep research on DNA methylation is critical for discovering novel tumour-specific inhibitors for HCC.</p>\u0000 </li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 11","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11513202/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142496135","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":"Lactylation in cancer: Mechanisms in tumour biology and therapeutic potentials","authors":"Yipeng He,&nbsp;Tianbao Song,&nbsp;Jinzhuo Ning,&nbsp;Zefeng Wang,&nbsp;Zhen Yin,&nbsp;Pengcheng Jiang,&nbsp;Qin Yuan,&nbsp;Weimin Yu,&nbsp;Fan Cheng","doi":"10.1002/ctm2.70070","DOIUrl":"10.1002/ctm2.70070","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>Lactylation, a recently identified form of protein post-translational modification (PTM), has emerged as a key player in cancer biology. The Warburg effect, a hallmark of tumour metabolism, underscores the significance of lactylation in cancer progression. By regulating gene transcription and protein function, lactylation facilitates metabolic reprogramming, enabling tumours to adapt to nutrient limitations and sustain rapid growth. Over the past decade, extensive research has revealed the intricate regulatory network underlying lactylation in tumours. Large-scale sequencing and machine learning have confirmed the widespread occurrence of lactylation sites across the tumour proteome. Targeting lactylation enzymes or metabolic pathways has demonstrated promising anti-tumour effects, highlighting the therapeutic potential of this modification. This review comprehensively explores the mechanisms of lactylation in cancer cells and the tumour microenvironment. We expound on the application of advanced omics technologies for target identification and data modelling within the lactylation field. Additionally, we summarise existing anti-lactylation drugs and discuss their clinical implications. By providing a comprehensive overview of recent advancements, this review aims to stimulate innovative research and accelerate the translation of lactylation-based therapies into clinical practice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>\u0000 <p>Lactylation significantly influences tumour metabolism and gene regulation, contributing to cancer progression.</p>\u0000 </li>\u0000 \u0000 <li>\u0000 <p>Advanced sequencing and machine learning reveal widespread lactylation sites in tumours.</p>\u0000 </li>\u0000 \u0000 <li>\u0000 <p>Targeting lactylation enzymes shows promise in enhancing anti-tumour drug efficacy and overcoming chemotherapy resistance.</p>\u0000 </li>\u0000 \u0000 <li>\u0000 <p>This review outlines the clinical implications and future research directions of lactylation in oncology.</p>\u0000 </li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 11","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11511673/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142496137","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":"Exome sequencing for assessing the risk of 453 monogenic disorders in offspring: A study of 832 Chinese couples","authors":"Xulong Ding,&nbsp;Miao Jiang,&nbsp;Qin Hu,&nbsp;Ruiqing Tong,&nbsp;Lin Wang,&nbsp;Jinxing Lv,&nbsp;Ling Pan,&nbsp;Jianquan Hou,&nbsp;Jun He,&nbsp;Peng Zhou","doi":"10.1002/ctm2.70074","DOIUrl":"10.1002/ctm2.70074","url":null,"abstract":"&lt;p&gt;Dear Editor,&lt;/p&gt;&lt;p&gt;Birth defects are abnormalities that occur during intrauterine life,&lt;span&gt;&lt;sup&gt;1-4&lt;/sup&gt;&lt;/span&gt; in particular, monogenic disorders stand out as a substantial contributor to birth defects,&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; constituting approximately 22.2% of all birth defects.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; Due to the lack of evident abnormalities during fetal development in most autosomal recessive and X-linked genetic disorders, identification of recessive monogenic disorders often occurs only after the birth of an affected child.&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt; Early screening and diagnosis play a crucial role in the control of these diseases and have important scientific and social significance. In China, the incidence of birth defects is approximately 5.6%,&lt;span&gt;&lt;sup&gt;8&lt;/sup&gt;&lt;/span&gt; current routine newborn screening in most parts of China is still limited and specific and includes screening for four genetic metabolic diseases (phenylketonuria, congenital hypothyroidism, congenital adrenal hyperplasia and galactosemia) and hearing disorders, and we has not yet established a comprehensive system for the prevention and control of birth defects caused by other monogenic disorders. Here, we developed a detection system based on whole exome sequencing (ES) that includes 453 monogenic disorders with high prevalence in the Chinese population and the associated genetic variants. This system was applied to test 832 couples, followed by a 2-year follow-up. We identified genes with higher variant frequencies for individuals and couples, as well as cases of birth defects identified through ES results during follow-up. These findings further underscore the importance of ES in assessing the risk of monogenic disorders in offspring, enabling informed reproductive decisions.&lt;/p&gt;&lt;p&gt;The overall study design was described in Figure S1. A total of 832 couples were screened for eligibility for inclusion between December 2021 and 3 December 2022. The participant demographics of the cohort were listed in Table S1. The mean (± SD) age was 29.29 ± 3.29 years for females and 30.27 ± 3.60 years for males. Most couples had either not had offspring (36.5%, 304/832) or were still pregnant (6.0%, 50/832), with only 59 (7.1%, 59/832) couples having a reproductive history of one or more pregnancies. Furthermore, there was a significant number of couples who experienced miscarriages (14.4%, 120/832).&lt;/p&gt;&lt;p&gt;According to the carrier rates in the Chinese and Asian populations,&lt;span&gt;&lt;sup&gt;9&lt;/sup&gt;&lt;/span&gt; we included 453 types of monogenic disorders (Table S2), the classification and inheritance patterns were shown in Figure 1A and Table S2. Subsequently, we analysed the ES results and categorised mutations related to monogenic disorders in 832 couples, as depicted in Figure 1B. There were no significant differences in the proportions of the six categories between males and females, with pathogenic [P] constituting the largest proportion (female: 46.2%; male: 46.9%). Next, we classifi","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 11","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11511670/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142496136","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":"Spatially resolved metabolomics: From metabolite mapping to function visualising","authors":"Xinyue Min,&nbsp;Yiran Zhao,&nbsp;Meng Yu,&nbsp;Wenchao Zhang,&nbsp;Xinyi Jiang,&nbsp;Kaijing Guo,&nbsp;Xiangyi Wang,&nbsp;Jianpeng Huang,&nbsp;Tong Li,&nbsp;Lixin Sun,&nbsp;Jiuming He","doi":"10.1002/ctm2.70031","DOIUrl":"10.1002/ctm2.70031","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>Mass spectrometry imaging (MSI)-based spatially resolved metabolomics addresses the limitations inherent in traditional liquid chromatography-tandem mass spectrometry (LC–MS)-based metabolomics, particularly the loss of spatial context within heterogeneous tissues. MSI not only enhances our understanding of disease aetiology but also aids in the identification of biomarkers and the assessment of drug toxicity and therapeutic efficacy by converting invisible metabolites and biological networks into visually rendered image data. In this comprehensive review, we illuminate the key advancements in MSI-driven spatially resolved metabolomics over the past few years. We first outline recent innovations in preprocessing methodologies and MSI instrumentation that improve the sensitivity and comprehensiveness of metabolite detection. We then delve into the progress made in functional visualization techniques, which enhance the precision of metabolite identification and annotation. Ultimately, we discuss the significant potential applications of spatially resolved metabolomics technology in translational medicine and drug development, offering new perspectives for future research and clinical translation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>MSI-driven spatial metabolomics preserves metabolite spatial information, enhancing disease analysis and biomarker discovery.</li>\u0000 \u0000 <li>Advances in MSI technology improve detection sensitivity and accuracy, expanding bioanalytical applications.</li>\u0000 \u0000 <li>Enhanced visualization techniques refine metabolite identification and spatial distribution analysis.</li>\u0000 \u0000 <li>Integration of MSI with AI promises to advance precision medicine and accelerate drug development.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 11","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11511672/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142496138","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 CBP revers chemoresistance to 5-FU of CDX2/REG4 double-positive gastric cancer","authors":"Zhiyuan Fan,&nbsp;Fangyuan Li,&nbsp;Xiao Jiang,&nbsp;Tao Pan,&nbsp;Mingde Zang,&nbsp;Jianfang Li,&nbsp;Beiqin Yu,&nbsp;Qingqing Sang,&nbsp;Wentao Liu,&nbsp;Liping Su,&nbsp;Chen Li,&nbsp;Zhenggang Zhu,&nbsp;Min Yan,&nbsp;Chao Yan,&nbsp;Fei Yuan,&nbsp;Bingya Liu","doi":"10.1002/ctm2.70069","DOIUrl":"10.1002/ctm2.70069","url":null,"abstract":"&lt;p&gt;Dear Editor,&lt;/p&gt;&lt;p&gt;We conducted a study exploring the potential of cyclic-AMP response element binding protein (CBP) inhibitors in overcoming the chemoresistance of CDX2/REG4 double-positive gastric cancer (GC) to 5-FU chemotherapy.&lt;/p&gt;&lt;p&gt;CDX2 is a classical transcription factor belonging to the caudal-related homeobox gene family, which determines the development and maintenance of intestinal differentiation in the gut and is overexpressed  in part of GC.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Our study aims to investigate the heterogeneity of CDX2+ GC, which accounts for approximately 50% of all GC,&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; and discover potential therapies. Using 111 GC samples, molecular classification based on CDX2 expression revealed that CDX2+ GC could be further divided into two subtypes: REG4&lt;sup&gt;hi&lt;/sup&gt; and REG4&lt;sup&gt;lo&lt;/sup&gt; (Figure 1A). REG4 is a direct target of CDX2 and has been implicated in the progression and chemoresistance of GC.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; The REG4&lt;sup&gt;hi&lt;/sup&gt; subtype showed significantly shorter overall survival (OS, Figure 1B, hazard ratio: CDX2&lt;sup&gt;hi&lt;/sup&gt; REG4&lt;sup&gt;hi&lt;/sup&gt; vs. CDX2&lt;sup&gt;lo&lt;/sup&gt; .99, 95% CI .60–1.64, &lt;i&gt;p&lt;/i&gt; = .973; CDX2&lt;sup&gt;hi&lt;/sup&gt; REG4&lt;sup&gt;lo&lt;/sup&gt; vs. CDX2&lt;sup&gt;lo&lt;/sup&gt; .11, 95% CI .04–.30, &lt;i&gt;p&lt;/i&gt; &lt; .001; CDX2&lt;sup&gt;hi&lt;/sup&gt; REG4&lt;sup&gt;lo&lt;/sup&gt; vs. CDX2&lt;sup&gt;hi&lt;/sup&gt; REG4&lt;sup&gt;hi&lt;/sup&gt; .12, 95% CI .04–.30, &lt;i&gt;p&lt;/i&gt; &lt; .001) and poorer differentiation compared to REG4&lt;sup&gt;lo&lt;/sup&gt; (Figure 1C, Tables S1 and S2). REG4 positive expression was significantly associated with CDX2+ cases (Figure 1D). Additionally, CDX2+ REG4&lt;sup&gt;hi&lt;/sup&gt; GC patients were more resistant to 5-FU-based chemotherapy (Figure 1E). We identified CDX2+ GC cell lines (Figure 1F) with high or low REG4 expression (Figure 1G) using the CCLE database. The IC&lt;sub&gt;50&lt;/sub&gt; of CDX2+ REG4&lt;sup&gt;hi&lt;/sup&gt; GC cells to 5-FU were much higher than those of CDX2+ REG4&lt;sup&gt;lo&lt;/sup&gt; GC cells (Figure 1H–J).&lt;/p&gt;&lt;p&gt;We selected GC cell lines which showed consistent expression patterns of CDX2 and REG4 with specific GC types suggested by CCLE database and confirmed by immunoblotting (Figure 2A). A screen of 17 small molecule inhibitors targeting epigenetic regulators (Table S3) identified CPI-637, a CBP/p300 inhibitor, as particularly effective against CDX2+ REG4&lt;sup&gt;hi&lt;/sup&gt; GC cells (Figure 2A and B). These cells showed significant growth inhibition (Figure 2C) and lower IC50 values (Figure 2D) with CPI-637 compared to CDX2+ REG4&lt;sup&gt;lo&lt;/sup&gt; cells. In vivo experiments demonstrated that CPI-637 significantly inhibited tumour growth in CDX2+ REG4&lt;sup&gt;hi&lt;/sup&gt; cell derived xenograft CDX (Figure 2E), resulting in smaller tumour volumes (Figure 2F), less tumour weight (Figure 2G) and higher tumour growth inhibition rates (Figure 2H).&lt;/p&gt;&lt;p&gt;CPI-637 is a selective inhibitor targeting both CBP and p300&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; and its role have been investigated in tumour treatment.&lt;span&gt;&lt;sup&gt;4, 5&lt;/sup&gt;&lt;/span&gt; CBP/p300 activates gene expression using its prote","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 11","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11511671/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142516270","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":"Commentary: Shared decision making for weight-lowering medications in China","authors":"Qingyi Jia,&nbsp;Sheyu Li","doi":"10.1002/ctm2.70065","DOIUrl":"10.1002/ctm2.70065","url":null,"abstract":"&lt;p&gt;One in eight adults are suffering from obesity and its complication in 2022 worldwide, with the US leading the top prevalence of 67% adults with overweight adults. Following the western countries, China is entering a pandemic of obesity with 34.8% of adults with overweight and 14.1% with obesity and the most rapid increase of the population.&lt;span&gt;&lt;sup&gt;1, 2&lt;/sup&gt;&lt;/span&gt; The increasing disease burden costs an estimating 2.15 million US dollars in China 2024.&lt;/p&gt;&lt;p&gt;NuSH agonists including GLP-1 receptor agonists, GLP-1/GIP dual agonists, GLP-1/glucagon receptor dual agonists, GLP-1/GIP/glucagon receptor triple agonists showed their efficacies in weight lowering.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; Recent large systematic reviews demonstrated the weight-lowering effects of IH semaglutide in adults with overweight and obesity and trizepatide in people with type 2 diabetes.&lt;span&gt;&lt;sup&gt;4, 5&lt;/sup&gt;&lt;/span&gt; Both received or applied their approvals to the Chinese FDA. Retatrurtide, the triple agonist, in its phase 2 trials, indicated an almost certainly 10% body weight loss adding to lifestyle modification, the efficacy might surpass any other existing weight-lowering medications including Beinaglutide, Danuglipron, Dulaglutide, Exenatide, Loxenatide, Liraglutide, Orforglipron Mazdutide, Efinopegdutide, Surbodutide (Tirzepatide). All these medications represent competitive alternative therapies for bariatric surgery. The latest large trial for the first time demonstrated the cardiovascular benefits of semaglutide in adults with obesity but not diabetes.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;The plentifulness of obesity treatment medications does not mean a one-pill-fit-all strategy in prescribing these medications. Generally, patients need these medications if they have difficulty in changing their lifestyles, reaching further achievements after all their efforts, or needing time-sensitive body weight loss.&lt;/p&gt;&lt;p&gt;For example, osteoarthritis is a common complication of obesity and dramatically raises the risk of sport-related injury especially when the joint bears great weight load during intensive exercise. In such cases, patients face difficulty in initiating lifestyle modification, especially the exercise. Anti-obesity medications help prevernt such sport-related injuries through a promising body weight loss that frees the weight load of the joint in the early phase of the obesity treatment. Gradually increasing exercise in parallel helps maintain the skeletal muscle mass and function as well as the basal metabolism rate.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; For people reaching their weight-loss plateau, anti-obesity medications may help break the balancing and allow further uptitration of physical exercise. Anaesthesia can be dangerous for some candidates of bariatric surgery and very severe obesity with impaired ventilation. Anti-obesity medications in this case with intensive lifestyle modification may help lose 5–10% of body weight in a short period before bariatric surgery. Simi","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 11","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11502301/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142496134","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-nucleus and spatial transcriptomics of paediatric ovary: Molecular insights into the dysregulated signalling pathways underlying premature ovarian insufficiency in classic galactosemia","authors":"Raghuveer Kavarthapu,&nbsp;Hong Lou,&nbsp;Thang Pham,&nbsp;Han Do,&nbsp;Mary E. Soliman,&nbsp;Taylor Badger,&nbsp;Ramya Balasubramanian,&nbsp;Victoria Huyhn,&nbsp;Maria De La Luz Sierra,&nbsp;Jacqueline C. Yano Maher,&nbsp;Veronica Gomez-Lobo","doi":"10.1002/ctm2.70043","DOIUrl":"10.1002/ctm2.70043","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;Classic galactosemia (CG) is an inborn error of galactose metabolism caused by mutations in the &lt;i&gt;GALT&lt;/i&gt; gene. Premature ovarian insufficiency (POI) is a later complication that affects 80% of women with CG due to a significant decline in ovarian reserve (primordial follicle pool). The definite mechanisms underlying the early onset of POI in CG patients are not fully understood.&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, we performed single-nucleus RNA sequencing (snRNA-seq) and spatial transcriptomics on ovary tissue biopsies from prepubertal girls diagnosed with CG to investigate dynamic changes in gene expression and altered signalling pathways in granulosa cells, oocytes, and stromal cells.&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 generated single-nucleus and spatial transcriptomics atlas of human ovaries from prepubertal girls diagnosed with and without CG. snRNA-seq profiling of the paediatric ovary revealed a diverse ovarian microenvironment with seven distinct major cell types. Our transcriptomic analysis revealed an increase in the expression of several endoplasmic reticulum stress and oxidative stress associated genes, which can promote apoptosis of granulosa cells in CG. PTEN/PI3K/AKT signalling, which is crucial for primordial follicle activation and survival was dysregulated as supported by upregulated &lt;i&gt;PTEN&lt;/i&gt; transcripts and a significant reduction in phospho-AKT levels in the granulosa cells and oocytes. We also found a marked increase in expression of phospho-H2A.X, LC3A/B and CASP9 in the primordial follicles of CG ovaries suggesting DNA damage, autophagy, and accelerated follicular atresia. Furthermore, we noticed genes participating in extracellular matrix organisation, integrin and gap junction signalling, essential for structural support of the ovarian stroma were profoundly altered.&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 molecular insights into the dysregulated cellular signalling pathways essential for primordial follicle growth and survival that can explain the etiology of POI in CG patients. This study has implications in the development of future therapeutic interventions to preserve ovarian function and promote female reproductive health.&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;Created a comprehensive single-nucleus transcriptomic atlas a","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 10","pages":""},"PeriodicalIF":7.9,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70043","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142496132","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}