Clinical and Translational Medicine最新文献

{"title":"Commentary: Shared decision making for weight-lowering medications in China","authors":"Qingyi Jia, Sheyu Li","doi":"10.1002/ctm2.70065","DOIUrl":"10.1002/ctm2.70065","url":null,"abstract":"<p>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.<span><sup>1, 2</sup></span> The increasing disease burden costs an estimating 2.15 million US dollars in China 2024.</p><p>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.<span><sup>3</sup></span> 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.<span><sup>4, 5</sup></span> 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.<span><sup>4</sup></span></p><p>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.</p><p>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.<span><sup>6</sup></span> 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":null,"pages":null},"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, Hong Lou, Thang Pham, Han Do, Mary E. Soliman, Taylor Badger, Ramya Balasubramanian, Victoria Huyhn, Maria De La Luz Sierra, Jacqueline C. Yano Maher, Veronica Gomez-Lobo","doi":"10.1002/ctm2.70043","DOIUrl":"10.1002/ctm2.70043","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Classic galactosemia (CG) is an inborn error of galactose metabolism caused by mutations in the <i>GALT</i> 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.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>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.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>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 <i>PTEN</i> 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.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>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.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Created a comprehensive single-nucleus transcriptomic atlas a","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":null,"pages":null},"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, Yinchao Li, Yaqian Zhang, Yubao Fang, Lei Lei, Jiabin Yu, Hongping Tan, Lisen Sui, Qiang Guo, Liemin Zhou","doi":"10.1002/ctm2.70072","DOIUrl":"10.1002/ctm2.70072","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>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.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>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.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>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 <i>DAB1</i><sup>high</sup> 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.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>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.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>\u0000 <p>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.</p>\u0000 ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":null,"pages":null},"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, Xiaoyuan Feng","doi":"10.1002/ctm2.70071","DOIUrl":"10.1002/ctm2.70071","url":null,"abstract":"<p>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 (<0.1 T).<span><sup>1-5</sup></span> However, these developments are limited to brain and extremity imaging and their image quality is generally poor.</p><p>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.<span><sup>6</sup></span> 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<span><sup>5, 7, 8</sup></span> (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<span><sup>9, 10</sup></span> that integrates image reconstruction and super-res","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":null,"pages":null},"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}

{"title":"Unconventional microRNA role: Enhancing the human leukocyte antigen class I antigen processing pathway via interacting with a silencer","authors":"Yuan Wang, Maria-Filothei Lazaridou, Theresa Kordaß, Chiara Massa, Christoforos K. Vaxevanis, Stefan Eichmüller, Barbara Seliger","doi":"10.1002/ctm2.70010","DOIUrl":"10.1002/ctm2.70010","url":null,"abstract":"<p>Dear Editor,</p><p>The unconventional functional mechanisms of microRNA (miRNA)-mediated RNA or protein activation are complex and diverse,<span><sup>1</sup></span> like miRNA binding to AU-rich elements (ARE)<span><sup>2</sup></span> or competing with RNA-binding proteins.<span><sup>3</sup></span> Our own data demonstrated that miR-16 could bind to the coding sequence (CDS) of classical and non-classical human leukocyte antigen class I (HLA-I) molecules, thereby inducing their expression.<span><sup>4</sup></span> However, the interaction of silencers with miRNAs has not yet been investigated. Silencer features include a high GC content,<span><sup>5</sup></span> DNase hypersensitivity sites<span><sup>6</sup></span> and H3K27me3 regions.<span><sup>7</sup></span> Here we identified for the first time that miR-155-5p can directly bind a silencer in the 3′untranslated region (3′UTR) of TAP-binding protein (tpn) thereby increasing the HLA-I surface expression.</p><p>Using miRNA trapping by RNA in vitro affinity purification (miTRAP),<span><sup>8</sup></span> in silico analyses and molecular experiments, we identified miR-155-5p targeting of tpn 3′ UTR in melanoma cells affecting tpn and cell surface HLA-I expression, which has also clinical relevance. Interestingly, upon deletion of the predicted binding site within tpn 3´UTR (Figure 1A), luciferase (luc) reporter assays indicated higher relative luc activity of the wild type (wt) compared to the del 3′UTR in HEK293T cells (Figure 1B), which is opposite to the conventional function of miRNAs leading to a downregulation. Overexpression of miR-155-5p in three melanoma cell lines (Figure 1C) increased their tpn messenger RNA (mRNA) (Figure 1D) and protein levels (Figure 1E,F). This upregulation was specific for tpn since the mRNA of programmed death ligand 1 (PD-L1), another target of miR-155-5p,<span><sup>9</sup></span> was downregulated in the miR-155-5p-transfected MZ-Mel2 cell line (Figure 1G). Despite the overall expression levels of the HLA-I heavy chain (HC) were not altered in the miR-155-5p transfectants (Figure 1F,H), a tpn-mediated upregulation of the HLA-ABC and HLA-BC surface antigens was found on FM81 and MZ-Mel2 cells (Figure 1I,J), but not on FM3 cells, which might be probably due to the high HLA-I surface expression when compared to FM81 and MZ-Mel2 cells (Figure 1F). Actinomycin D treatment revealed a significant increase in the tpn mRNA half-life in FM81 miR-155-5p transfectants (Figure 1K). Using a CD107a degranulation assay, a reduced NK cell-mediated cytotoxicity against miR-155-5p transfected MZ-Mel2 cells expressing increased HLA-I surface antigens was shown by lower numbers of CD107a-positive NK cells (Figure 1L).</p><p>The overall survival (OS) analysis of 214 metastatic melanoma cases with patients’ outcomes demonstrated a positive correlation of miR-155 (miR-155HG) (Figure 2A), tpn (Figure 2B) and HLA-A (Figure 2C) expression levels with the OS of patients, thereby confirmi","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11496566/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142496133","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":"CircRNome-wide characterisation reveals the promoting role of circAATF in anti-PD-L1 immunotherapy of gallbladder carcinoma","authors":"Yueqi Wang,&nbsp;Shengli Li,&nbsp;Xiaobo Bo,&nbsp;Yuan Li,&nbsp;Changcheng Wang,&nbsp;Lingxi Nan,&nbsp;Dexiang Zhang,&nbsp;Houbao Liu,&nbsp;Jiwei Zhang","doi":"10.1002/ctm2.70060","DOIUrl":"10.1002/ctm2.70060","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>Circular RNAs (circRNAs) have been shown to play important roles in tumour development and tumour immunology. However, genome-wide characterisation of circRNAs and their roles in the immunology and immunotherapy of gallbladder carcinoma (GBC) has been lacking. We present a comprehensive characterisation of the circRNA landscape in GBC, revealing GBC-specific circRNAs. Our analysis found that circRNAs are significantly enriched in cell proliferation and are involved in cancer-related hallmarks. In particular, circAATF was upregulated in GBC, which was positively correlated with AATF mRNA expression, and promoted GBC cell growth. Through integrating computational and experimental approaches, we revealed that circAATF is positively associated with the CD4⁺ T cell abundance and PD-L1 level, and enhances the clinical benefits of anti-PD-L1 immunotherapy for GBC. We further demonstrate that circAATF elevates the PD-L1 level by activating phosphorylated AKT and acting as a sponge for miR-142-5p. CircAATF is positively associated with CD4⁺ T cells and PD-L1 levels and shows potential to aid anti-PD-L1 immunotherapy for GBC. Our study provides insights into roles of circAATF in the tumour development and immunology of GBC and accelerates the development of therapeutic strategies for GBC immunotherapy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>\u0000 <p>We present a comprehensive characterisation of circRNA landscape in gallbladder carcinoma (GBC).</p>\u0000 </li>\u0000 \u0000 <li>\u0000 <p>CircAATF is positively associated with CD4⁺ T cell abundance and PD-L1 expression and is shown to promote PD-L1 treatment in mouse model.</p>\u0000 </li>\u0000 \u0000 <li>\u0000 <p>CircAATF can elevate PD-L1 level through phosphorylated AKT and linear AATF, which upregulates PD-L1 by acting as a sponge of miR-142-5p.</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":"2024-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11491271/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142459357","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":"Evolution of aberrant brain-wide spatiotemporal dynamics of resting-state networks in a Huntington's disease mouse model","authors":"Tamara Vasilkovska,&nbsp;Marlies Verschuuren,&nbsp;Dorian Pustina,&nbsp;Monica van den Berg,&nbsp;Johan Van Audekerke,&nbsp;Isabel Pintelon,&nbsp;Roger Cachope,&nbsp;Winnok H. De Vos,&nbsp;Annemie Van der Linden,&nbsp;Mohit H. Adhikari,&nbsp;Marleen Verhoye","doi":"10.1002/ctm2.70055","DOIUrl":"https://doi.org/10.1002/ctm2.70055","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;Huntington's disease (HD) is marked by irreversible loss of neuronal function for which currently no availability for disease-modifying treatment exists. Advances in the understanding of disease progression can aid biomarker development, which in turn can accelerate therapeutic discovery.&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 characterised the progression of altered dynamics of whole-brain network states in the zQ175DN mouse model of HD using a dynamic functional connectivity (FC) approach to resting-state fMRI and identified quasi-periodic patterns (QPPs) of brain activity constituting the most prominent resting-state networks.&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;The occurrence of the normative QPPs, as observed in healthy controls, was reduced in the HD model as the phenotype progressed. This uncovered progressive cessation of synchronous brain activity with phenotypic progression, which is not observed with the conventional static FC approaches. To better understand the potential underlying cause of the observed changes in these brain states, we further assessed how mutant huntingtin (mHTT) protein deposition affects astrocytes and pericytes – one of the most important effectors of neurovascular coupling, along phenotypic progression. Increased cell-type dependent mHTT deposition was observed at the age of onset of motor anomalies, in the caudate putamen, somatosensory and motor cortex, regions that are prominently involved in HD pathology as seen in humans.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusion&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Our findings provide meaningful insights into the development and progression of altered functional brain dynamics in this HD model and open new avenues in assessing the dynamics of whole brain states, through QPPs, in clinical HD research.&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;Hyperactivity in the LCN-linked regions within short QPPs observed before motor impairment onset.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;DMLN QPP presents a progressive decrease in DMLN activity and occurrence along HD-like phenotype development.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Breakdown of the LCN DMLN state flux at motor onset leads to a subsequent absence of the LCN DMLN QPP at an advanced HD-like stage.&lt;/li&gt;\u0000 &lt;/ul&gt;\u0000 &lt;/div&gt;\u0000 &lt;/section&gt;\u0000 ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70055","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142449207","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-cell characterization of differentiation trajectories and drug resistance features in gastric cancer with peritoneal metastasis","authors":"Haoxin Peng,&nbsp;Lei Jiang,&nbsp;Jiajia Yuan,&nbsp;Xiangrong Wu,&nbsp;Nan Chen,&nbsp;Dan Liu,&nbsp;Yueting Liang,&nbsp;Yi Xie,&nbsp;Keren Jia,&nbsp;Yanyan Li,&nbsp;Xujiao Feng,&nbsp;Jian Li,&nbsp;Xiaotian Zhang,&nbsp;Lin Shen,&nbsp;Yang Chen","doi":"10.1002/ctm2.70054","DOIUrl":"https://doi.org/10.1002/ctm2.70054","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;Gastric cancer patients with peritoneal metastasis (GCPM) experience a rapidly deteriorating clinical trajectory characterized by therapeutic resistance and dismal survival, particularly following the development of malignant ascites. However, the intricate dynamics within the peritoneal microenvironment (PME) during the treatment process remain largely unknown.&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;Matched samples from primary tumours (PT), peritoneal metastases (PM), and paired pre-treatment and post-chemo/immunotherapy (anti-PD-1/PD-L1) progression malignant ascites samples, were collected from 48 patients. These samples were subjected to single-cell RNA sequencing (&lt;i&gt;n&lt;/i&gt; = 30), multiplex immunofluorescence (&lt;i&gt;n&lt;/i&gt; = 30), and spatial transcriptomics (&lt;i&gt;n&lt;/i&gt; = 3). Furthermore, post hoc analyses of a phase 1 clinical trial (&lt;i&gt;n&lt;/i&gt; = 20, NCT03710265) and an in-house immunotherapy cohort (&lt;i&gt;n&lt;/i&gt; = 499) were conducted to validate the findings.&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;Tracing the evolutionary trajectory of epithelial cells unveiled the terminally differentially MUC1+ cancer cells with a high epithelial-to-mesenchymal transition potential, and they demonstrated spatial proximity with fibroblasts and endothelial cells, correlating with poor prognosis. A significant expansion of macrophage infiltrates, which exhibited the highest proangiogenic activity, was observed in the ascites compared with PT and PM. Besides, higher C1Q+ macrophage infiltrates correlated with significantly lower GZMA+ T-lymphocyte infiltrates in therapeutic failure cases, potentially mediated by the LGALS9-CD45 and SPP1-CD44 ligand–receptor interactions. In the chemoresistant group, intimate interactions between C1Q+ macrophages and fibroblasts through the complement activation pathway were found. In the group demonstrating immunoresistance, heightened TGF-β production activity was detected in MUC1+ cancer cells, and they were skewed to interplay with C1Q+ macrophages through the GDF15-TGF-βR2 axis. Ultimately, post hoc analyses indicated that co-targeting TGF-β and PDL1 pathways may confer superior clinical benefits than sole anti-PD-1/PD-L1 therapy for patients presenting with GCPM at the time of diagnosis.&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 elucidated the cellular differentiation trajectories and crucial drug resistance features within PME, facilitating the exploration of effective targets for GCPM treatment.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70054","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142449142","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 genomic analysis of molecular residual disease based on circulating tumour DNA in postoperative patients with colorectal cancer","authors":"Qingqi Hong,&nbsp;Jingtao Zhu,&nbsp;Hexin Lin,&nbsp;Yinan Chen,&nbsp;Haoyu Bai,&nbsp;Linghua Yan,&nbsp;Li Xiao,&nbsp;Jun You","doi":"10.1002/ctm2.70041","DOIUrl":"https://doi.org/10.1002/ctm2.70041","url":null,"abstract":"&lt;p&gt;Dear Editor,&lt;/p&gt;&lt;p&gt;Colorectal cancer (CRC) is a major global health issue with a 40% 5-year mortality rate,&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; and 30%−50% of patients still experience recurrence after curative resection.&lt;span&gt;&lt;sup&gt;2, 3&lt;/sup&gt;&lt;/span&gt; The clinical utility of molecular residual disease (MRD) detection in risk stratification and recurrence detection using circulating tumour DNA (ctDNA) noninvasively has attracted widespread attention but with limited studies.&lt;span&gt;&lt;sup&gt;4-7&lt;/sup&gt;&lt;/span&gt; We measured the value of tumour-agnostic ctDNA-guided MRD for recurrence prediction and monitoring, and explored the biological characteristics of ctDNA from MRD.&lt;/p&gt;&lt;p&gt;We included 104 patients with stage I-IV CRC (Figure S1), aged 26 to 82 years. Fourteen (13.5%) patients had positive landmark MRD, and thirty-two (30.8%) patients had positive longitudinal MRD (Table S1). The most frequently variant genes in tumour tissue were &lt;i&gt;TP53&lt;/i&gt;, &lt;i&gt;KRAS&lt;/i&gt; and &lt;i&gt;APC&lt;/i&gt; (Figure S2A), while in ctDNA were &lt;i&gt;KRAS&lt;/i&gt;, &lt;i&gt;EGFR&lt;/i&gt; and &lt;i&gt;TP53&lt;/i&gt; (Figure S2B).&lt;/p&gt;&lt;p&gt;Patients with negative landmark MRD had a lower recurrence percentage than positive cases (11.1% vs. 57.1%, &lt;i&gt;p&lt;/i&gt; &lt; .001), yielding a negative predictive value (NPV) of 88.9% (Figure 1A). The latter group had a significantly higher recurrence risk (hazard ratio [HR], 7.325; &lt;i&gt;p&lt;/i&gt; &lt; .001, Figure 1B). As for longitudinal MRD, the recurrence percentage was higher in positive-MRD compared to negative-MRD (43.8% vs. 5.6%, &lt;i&gt;p&lt;/i&gt; &lt; .001), yielding a high NPV (94.4%, Figure 1C). Positive longitudinal MRD was correlated with an elevated risk of recurrence (HR: 9.385; &lt;i&gt;p&lt;/i&gt; &lt; .001, Figure 1D). In multivariate analysis for disease-free survival (DFS), landmark and longitudinal MRD-positive were significantly associated with increased recurrence risks (Figure 1E). Furthermore, we explored the effect of longitudinal MRD status in patients receiving and not receiving neoadjuvant therapy (NAT). In both groups, longitudinal positive-MRD patients had higher recurrence risk than negative-MRD patients (NAT: HR, 12.509, &lt;i&gt;p&lt;/i&gt; = .011; non-NAT: HR, 9.611, &lt;i&gt;p&lt;/i&gt; &lt; .001; Figure S3A and B). The recurrence risk was lower in those with negative landmark ctDNA and negative longitudinal ctDNA (Figure S4A–D). Although the NPV for ctDNA was slightly higher than that for MRD, the PPV for ctDNA was lower than that for MRD. The area under the curve (AUC) of 3-year DFS for landmark MRD was  .678, longitudinal MRD was  .895, and landmark and longitudinal MRD had higher AUCs than ctDNA (Figure S4E). Fourteen out of 18 cases with recurrence detected MRD at the postoperative time points (Figure 1F). And 85.7% (12/14) patients had positive MRD detection before computed tomography confirmed recurrence (median: 198.5 days, Figure 1G). For MRD-positive cases, actions such as initiating adjuvant therapies, more aggressive treatment, intensified monitoring, or early intervention before clinical relapse occurs, may be","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70041","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142451203","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":"Cooling wound dressings: Prospects for clinical practice","authors":"Peng Chen,&nbsp;Pingping Zhang,&nbsp;Jiangang Sun,&nbsp;Yangzhe Hou,&nbsp;Xianhu Liu","doi":"10.1002/ctm2.70064","DOIUrl":"https://doi.org/10.1002/ctm2.70064","url":null,"abstract":"&lt;p&gt;The skin, as the largest organ of the human body, is often compromised by trauma, severe burns, ulcers and various other injuries.&lt;span&gt;&lt;sup&gt;1, 2&lt;/sup&gt;&lt;/span&gt; Such injuries not only precipitate pain and scarring but also significantly increase the risk of microbial infection. Consequently, there is an urgent imperative to develop effective treatment strategies to address these concerns. Wound dressings serve as crucial therapeutic tools that safeguard wounds, decrease the likelihood of contamination and infection, and promote tissue repair by absorbing exudates and maintaining a local moist environment. In recent years, a variety of functional polymer-based medical dressings have been developed – including polymer films.&lt;span&gt;&lt;sup&gt;3, 4&lt;/sup&gt;&lt;/span&gt; hydrogels.&lt;span&gt;&lt;sup&gt;5, 6&lt;/sup&gt;&lt;/span&gt; sponges and foams.&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt;, &lt;span&gt;&lt;sup&gt;8&lt;/sup&gt;&lt;/span&gt; demonstrating excellent biocompatibility and significant potential for application in skin tissue engineering. These biocompatible dressings are characterised by antibacterial, antioxidant and controlled drug release properties. Additionally, they can function as flexible electrodes for electrotherapy and facilitate real-time monitoring of wound status, thereby enhancing their value in clinical applications.&lt;/p&gt;&lt;p&gt;Nevertheless, in the development of multifunctional wound dressings, it is imperative to emphasise their fundamental roles in wound protection and environmental regulation, particularly the regulation of wound temperature, which is of paramount importance.&lt;span&gt;&lt;sup&gt;9-11&lt;/sup&gt;&lt;/span&gt; Wounds are often accompanied by inflammation and increased localised temperature, while patients may also experience occasional exposure to direct sunlight and heat. Excessive heat can worsen tissue damage, raise the risk of infection, and slow healing. It may also promote fibroblast tissue overgrowth, increasing the likelihood of scarring. While conventional wound dressings are effective in protecting wounds and promoting healing, they still exhibit notable limitations in temperature regulation.&lt;span&gt;&lt;sup&gt;12-14&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Passive radiative cooling (PRC) works by reflecting sunlight at wavelengths of 0.3 to 2.5 µm and utilising the atmospheric long-wave infrared transmission window (8 to 13 µm) to dissipate excess heat into outer space.&lt;span&gt;&lt;sup&gt;15-17&lt;/sup&gt;&lt;/span&gt; This process occurs without the need for mechanical equipment or energy consumption. Cooling materials with PRC properties can be engineered in various forms and structures to meet diverse application needs. Recent cooling research has also increasingly focused on biodegradable materials with improved biocompatibility.&lt;span&gt;&lt;sup&gt;18, 19&lt;/sup&gt;&lt;/span&gt; making the integration of PRC properties into medical wound dressings a highly promising development. This noninvasive approach optimises clinical treatment by utilising physical cooling mechanisms. It also serves as a carrier for slow-release medications, providing both bacteriostatic eff","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":null,"pages":null},"PeriodicalIF":7.9,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70064","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142449102","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}