Clinical and Translational Medicine最新文献

{"title":"Genetic variants explain ancestry-related differences in type 2 diabetes risk","authors":"Aaron J. Deutsch, Kirk Smith, Miriam S. Udler","doi":"10.1002/ctm2.70076","DOIUrl":"10.1002/ctm2.70076","url":null,"abstract":"<p>Type 2 diabetes (T2D) is a global epidemic, affecting over 400 million people around the world.<span><sup>1</sup></span> T2D causes devasting complications and is a leading risk factor for ischaemic heart disease and stroke, which are among the top causes of global morbidity and mortality.<span><sup>1</sup></span> Classically, T2D occurs in adulthood in the setting of obesity and insulin resistance. Increasingly, however, T2D is understood to arise from a complex interplay of environmental and genetic factors, leading to heterogeneity in patient clinical presentation and disease course.<span><sup>2, 3</sup></span> There have been many attempts to define T2D subtypes using a range of analytic methods, but few efforts have shown real-world clinical utility or given insight into disease pathophysiology.<span><sup>4</sup></span></p><p>Over recent years, advances in large-scale genome-wide association studies (GWASs) have uncovered hundreds of genetic variants that modulate T2D risk. This genetic information has the potential to provide insight into disease biology; yet, clinical translation has been limited, often because the strongest genetic associations are not found in protein-coding regions, which makes it more challenging to identify causal genes and pathways. By leveraging the power of GWAS, our laboratory has developed a complex, high-throughput approach to define T2D disease mechanisms, which may help to identify T2D patient subtypes<span><sup>5, 6</sup></span> (Figure 1). This approach aggregates GWAS results to assess the link between genetic variants and diabetes-related clinical traits, such as glucose, haemoglobin A1c and body mass index (BMI). We then apply a machine learning method called Bayesian non-negative matrix factorisation to group together closely related variants and traits into clusters. By analysing the top-weighted variants and traits in each cluster, we can infer the most likely biological mechanism contributing to that cluster. Notably, this ‘soft’ clustering method allows a given variant or trait to be assigned to more than one cluster.</p><p>Most prior genetic analyses have focused on European populations, potentially limiting the applicability for other ancestry groups. To address this limitation, we recently applied our high-throughput pipeline to investigate T2D clusters using current large, multi-ancestry genetic studies.<span><sup>7</sup></span> Through this approach, we confirmed our previously identified T2D genetic clusters and found three new clusters, yielding a total of 12 clusters. Three clusters were associated with beta cell dysfunction and insulin deficiency, while seven were associated with insulin resistance. Among the insulin resistance clusters, certain clusters were associated with obesity and above-average BMI, whereas two other clusters were associated with a ‘lipodystrophy-like’<span><sup>8</sup></span> abnormal fat distribution and below-average BMI. Furthermore, we demonstrated significant ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11537768/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582078","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":"Induced collagen type-I secretion by hepatocytes of the melanoma liver metastasis is associated with a reduction in tumour-infiltrating lymphocytes","authors":"Shodai Mizuno, Matias A. Bustos, Yoshinori Hayashi, Kodai Abe, Satoru Furuhashi, Yalda Naeini, Xiaowei Xu, Anton J Bilchik, Dave S. B. Hoon","doi":"10.1002/ctm2.70067","DOIUrl":"10.1002/ctm2.70067","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Overall patients with melanoma liver metastasis (MLiM) have a dismal prognosis and poor responses to the standard of care treatment. Understanding the role of the tumour microenvironment (TME) is critical for discovering better strategies to overcome intrinsic therapy resistance in MLiM. The aim was to understand the crosstalk signalling pathways between hepatocytes and metastatic melanoma cells in the TME of MLiM.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Hepatocytes and melanoma tumour cells of MLiM were assessed using transcriptomic NanoString GeoMx digital spatial profiling (NGDSP) assay. Functional assays were performed using normal hepatocytes and MLiM-derived cell lines. Validation was performed using multiplex immunofluorescence.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In NGDSP analysis adjacent normal hepatocytes (ANH) had higher CXCR4 and COL1A1/2 levels than distant normal hepatocytes (DNH), while melanoma cells had higher TNF-α levels. In vitro, MLiM cell lines released TNF-α which upregulated CXCR4 and CXCL12 levels in ANH. CXCL12 activated CXCR4, which triggered AKT and NFκB signalling pathways. Consequently, AKT signalling induced the upregulation of collagen type I. MLiM were significantly encircled by a shield of collagen, whereas other liver metastases showed reduced levels of collagen. Of all the liver metastasis analyzed, the presence of collagen in melanoma liver metastasis was associated with a reduction in tumour-infiltrating lymphocytes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>MLiM modified ANH to increase collagen production and created a physical barrier. The collagen barrier was associated with a reduction of immune cell infiltration which could potentially deter MLiM immune surveillance and treatment responses.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Spatial analyses of melanoma liver metastasis show that adjacent normal hepatocytes have increased collagen-type I levels.</li>\u0000 \u0000 <li>Melanoma liver metastases tumour cells secrete enhanced levels of TNF-α to stimulate CXCR4/CXCL12 upregulation in adjacent normal hepatocytes.</li>\u0000 \u0000 <li>Activation of CXCR4 promotes AKT and NF-κB signalling pathways to promote collagen-type I secretion in adjacent normal hepatocytes.</li>\u0000 \u0000 ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70067","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142575382","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":"Neutrophil pyroptosis regulates corneal wound healing and post-injury neovascularisation","authors":"Peng Chen,&nbsp;Zhentao Zhang,&nbsp;Lilian Sakai,&nbsp;Yanping Xu,&nbsp;Shanzhi Wang,&nbsp;Kyung Eun Lee,&nbsp;Bingchuan Geng,&nbsp;Jongsoo Kim,&nbsp;Bao Zhao,&nbsp;Qiang Wang,&nbsp;Haitao Wen,&nbsp;Heather L. Chandler,&nbsp;Hua Zhu","doi":"10.1002/ctm2.1762","DOIUrl":"10.1002/ctm2.1762","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Rationale</h3>\u0000 \u0000 <p>The cornea is a unique structure that maintains its clarity by remaining avascular. Corneal injuries can lead to neovascularisation (CNV) and fibrosis and are the third most common cause of blindness worldwide.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Corneal injuries induce an immune cell infiltration to initiate reparative processes. However, inflammation caused by sustained immune cell infiltration is known to be detrimental and can delay the healing process. This study was designed to understand the potential role of neutrophil and epithelial cell crosstalk in post-injury CNV.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods and results</h3>\u0000 \u0000 <p>Western blotting and immunostaining assays demonstrated that neutrophils infiltrated corneas and underwent pyroptosis following acute alkali injury. In vivo studies showed that genetic ablation of Gasdermin D (GsdmD), a key effector of pyroptosis, enhanced corneal re-epithelialisation and suppressed post-injury CNV. In vitro co-culture experiments revealed that interleukin-1β (IL-1β) was released from pyroptotic neutrophils which suppressed migration of murine corneal epithelial cells. Real-time RT-PCR and immunostaining assays identified two factors, Wnt5a and soluble fms-like tyrosine kinase-1 (sflt-1), highly expressed in newly healed epithelial cells. sflt-1 is known to promote corneal avascularity. Bone marrow transplantation, antibody mediated neutrophil depletion, and pharmacological inhibition of pyroptosis promoted corneal wound healing and inhibited CNV in an in vivo murine corneal injury model.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Taken together, our study reveals the importance of neutrophil/epithelium crosstalk and neutrophil pyroptosis in response to corneal injuries. Inhibition of neutrophil pyroptosis may serve as a potential treatment to promote corneal healing without CNV.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Neutrophil pyroptosis delays re-epithelialization after corneal injury</li>\u0000 \u0000 <li>Compromised re-epithelialization promotes corneal neovascularization after injury</li>\u0000 \u0000 <li>Inhibition of post-injury pyroptosis could be an effective therapy to promote corneal wound healing.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.1762","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142575384","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":"Therapeutic potential of mesenchymal stem cell-derived extracellular vesicles: A focus on inflammatory bowel disease","authors":"Laura Clua-Ferré,&nbsp;Roger Suau,&nbsp;Irene Vañó-Segarra,&nbsp;Iris Ginés,&nbsp;Carolina Serena,&nbsp;Josep Manyé","doi":"10.1002/ctm2.70075","DOIUrl":"10.1002/ctm2.70075","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;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.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Main Topics Covered&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;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.&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;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.&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;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).&lt;/li&gt;\u0000 \u0000 &lt;li&gt;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":null,"pages":null},"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":"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":null,"pages":null},"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":null,"pages":null},"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":null,"pages":null},"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":"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":null,"pages":null},"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":"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":null,"pages":null},"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":"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":null,"pages":null},"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}