Clinical and Translational Medicine最新文献

{"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}

{"title":"Excitatory neurons and oligodendrocyte precursor cells are vulnerable to focal cortical dysplasia type IIIa as suggested by single-nucleus multiomics","authors":"Yingying Liu,&nbsp;Yinchao Li,&nbsp;Yaqian Zhang,&nbsp;Yubao Fang,&nbsp;Lei Lei,&nbsp;Jiabin Yu,&nbsp;Hongping Tan,&nbsp;Lisen Sui,&nbsp;Qiang Guo,&nbsp;Liemin Zhou","doi":"10.1002/ctm2.70072","DOIUrl":"10.1002/ctm2.70072","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;Focal cortical dysplasia (FCD) is a heterogeneous group of cortical developmental malformations that constitute a common cause of medically intractable epilepsy. FCD type IIIa (FCD IIIa) refers to temporal neocortex alterations in architectural organisation or cytoarchitectural composition in the immediate vicinity of hippocampal sclerosis. Slight alterations in the temporal neocortex of FCD IIIa patients pose a challenge for the preoperative diagnosis and definition of the resection range.&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 have performed multimodal integration of single-nucleus RNA sequencing and single-nucleus assay for transposase-accessible chromatin sequencing in the epileptogenic cortex of four patients with FCD IIIa, and three relatively normal temporal neocortex were chosen as controls.&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 study revealed that the most significant dysregulation occurred in excitatory neurons (ENs) and oligodendrocyte precursor cells (OPCs) in the epileptogenic cortex of FCD IIIa patients. In ENs, we constructed a transcription factor (TF)-hub gene regulatory network and found &lt;i&gt;DAB1&lt;/i&gt;&lt;sup&gt;high&lt;/sup&gt; ENs subpopulation mediates neuronal immunity characteristically in FCD IIIa. Western blotting and immunofluorescence were used to validate the changes in protein expression levels caused by some of the key genes. The OPCs were activated and exhibited aberrant phenotypes in FCD IIIa, and TFs regulating reconstructed pseudotime trajectory were identified. Finally, our results revealed aberrant intercellular communication between ENs and OPCs in FCD IIIa patients.&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 revealed significant and intricate alterations in the transcriptomes and epigenomes in ENs and OPCs of FCD IIIa patients, shedding light on their cell type-specific regulation and potential pathogenic involvement in this disorder. This work will help evaluate the pathogenesis of cortical dysplasia and epilepsy and explore potential therapeutic targets.&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;Paired snRNA-seq and snATAC-seq data were intergrated and analysed to identify crucial subpopulations of ENs and OPCs in the epileptogenic cortex of FCD IIIa patients and explore their possible pathogenic role in the disease.&lt;/p&gt;\u0000 ","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://www.ncbi.nlm.nih.gov/pmc/articles/PMC11497056/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142496130","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":"Reinventing magnetic resonance imaging for accessible healthcare: Whole-body imaging at 0.05 Tesla","authors":"Ed X. Wu,&nbsp;Xiaoyuan Feng","doi":"10.1002/ctm2.70071","DOIUrl":"10.1002/ctm2.70071","url":null,"abstract":"&lt;p&gt;Magnetic resonance imaging (MRI) technology has revolutionized the field of medical imaging by providing a non-invasive, non-ionizing and quantitative approach to visualizing different tissue types and assessing their structural and physiological integrity. Despite its importance and five decades of engineering development, the accessibility of MRI is low and extremely inhomogeneous around the world. This is due to the high cost and complex infrastructure requirements of existing high-field superconducting MRI scanners, which limit their availability in low and middle-income countries, and exclude their easy access in many healthcare facilities such as neurology clinics, trauma centres, surgical suites, neonatal/pediatric centres and community clinics. We and others have made intensive efforts in recent years to engineer low-cost and shielding-free MRI scanners for brain imaging at ultra-low-field (ULF) strengths (&lt;0.1 T).&lt;span&gt;&lt;sup&gt;1-5&lt;/sup&gt;&lt;/span&gt; However, these developments are limited to brain and extremity imaging and their image quality is generally poor.&lt;/p&gt;&lt;p&gt;Recently we have developed a compact, low-power and highly simplified ULF MRI scanner that enables whole-body imaging with high image quality via computing.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; In this work, we designed and prototyped a cost-effective whole-body 0.05 T MRI scanner that operates on a standard AC wall power outlet without any radiofrequency (RF) or magnetic shielding cages. The system utilized a compact 0.05 T permanent neodymium ferrite boron magnet with a double-plate structure and required no RF shielding cages (Figure 1A). To address electromagnetic interference (EMI) during scanning, we deployed active EMI sensing during scanning and deep learning direct signal prediction (Deep-DSP) strategy to retrospectively predict EMI-free MR signals prior to image reconstruction&lt;span&gt;&lt;sup&gt;5, 7, 8&lt;/sup&gt;&lt;/span&gt; (Figure 1B). We implemented and experimentally optimized the commonly used imaging protocols using phantoms and volunteers, keeping scan time at 8 min or less for each protocol. Our Deep-DSP strategy showed superior performance compared to other EMI reduction methods. Using traditional Fourier image reconstruction, we were able to image various anatomical structures with different MRI contrasts, including the brain, spine, abdomen, lung, extremities and heart (Figure 2A). We were also able to estimate cardiac function and visualize major vessels in the neck using time-of-flight magnetic resonance angiography without any exogenous contrast agent. However, these images exhibited a high level of noise and artefacts due to a drastically reduced MR signal at 0.05 T versus the standard 3 T. To address this challenge, we developed novel data-driven deep-learning image reconstruction methods to significantly advance ULF MRI image quality. We formulated a 3D partial Fourier super-resolution (PF-SR) strategy&lt;span&gt;&lt;sup&gt;9, 10&lt;/sup&gt;&lt;/span&gt; that integrates image reconstruction and super-res","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://www.ncbi.nlm.nih.gov/pmc/articles/PMC11496770/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142496131","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}