Clinical and Translational Medicine最新文献

{"title":"Fruquintinib as first-line or second-line treatment in unresectable or metastatic soft-tissue sarcoma: A prospective, single-arm phase II study","authors":"Xiaowei Zhang, Ting Zhao, Biqiang Zheng, Wangjun Yan, Yong Chen, Yu Xu, Chunmeng Wang, Junhua Zhang, Jian Wang, Lin Yu, Xin Liu, Zhiguo Luo","doi":"10.1002/ctm2.70308","DOIUrl":"https://doi.org/10.1002/ctm2.70308","url":null,"abstract":"<p>Dear Editor,</p><p>We conducted the first prospective, single-arm phase II study and confirmed that fruquintinib is an effective and well-tolerated chemo-free regimen for the first-line or second-line therapy of patients with unresectable or metastatic soft-tissue sarcoma (STS), particularly for those with the histopathologic subtype of angiosarcoma (AS).</p><p>STS are rare tumours that comprise over 50 distinct histologic subtypes, accounting for 1% of all adult malignancies.<span><sup>1, 2</sup></span> For individuals with unresectable or metastatic STS, the median overall survival (OS) varies between 12 and 16 months, while the 5-year OS rate is 60%–80%.<span><sup>3</sup></span> Over the past decade, anti-angiogenic therapy has been utilised to treat advanced STS.<span><sup>4</sup></span> Pazopanib was the first tyrosine kinase inhibitor approved for advanced STS,<span><sup>5</sup></span> followed by regorafenib and anlotinib, both of which have shown excellent performance in the treatment of advanced STS.<span><sup>6</sup></span></p><p>Fruquintinib, a multi-target inhibitor of VEGF receptors 1, 2 and 3, has shown overall response rate (ORR) of 13.1% and 17.7% in two retrospective studies<span><sup>7</sup></span> underscoring its promise as a chemo-free treatment for advanced STS. However, due to the inherent limitations of retrospective studies, further investigation is necessary to assess the efficacy and safety of fruquintinib in unresectable or metastatic STS.</p><p>In our study, a total of 31 individuals were evaluated for eligibility and assigned to receive fruquintinib monotherapy (Figure 1A). Details of the study design and statistical analysis are described in Supporting Information. All patients were aged between 19 and 78 years. Among them, there were 15 (48.4%) males and 16 (51.6%) females. In the total population, 22 (71.0%) participants had distant metastases at first diagnosis, while another nine (29.0%) were categorised as unresectable STS without metastases. Among the 22 metastatic STSs, 15 (68.2%) had metastatic lesions in two or more organs. The most common primary lesions were trunk and extremity (36.7%), followed by lung (20.0%), brain (16.7%), head (13.3%), spleen (10.0%) and breast (3.3%). During metastasis, most cases spread to lungs (63.6%), followed by other sites including bones (50.0%), lymph nodes (36.4%), liver (27.3%), pleura (13.6%) and muscle (9.1%). Of them, 18 (58.1%) underwent prior surgery, 12 (38.7%) received prior first-line therapy and four (12.9%) received prior radiotherapy (Table S1).</p><p>As of the data cutoff on 26 November 2024, patients received between 1 and 35 treatment cycles, with a median of eight cycles. The median follow-up duration was 19.2 months (95% confidence interval [CI]: 16.3‒34.0). Among them, 18 patients (58.1%) experienced progression-free survival (PFS) events, and 12 patients (38.7%) died. ORR was 25.8% (95% CI: 10.4‒41.2), and the disease control rate (DCR) was 90.3% (95% ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 4","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70308","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143836029","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":"An important step to translate single-cell measurement into clinical practice: Stereoscopic cells","authors":"Xiangdong Wang, Wanxin Duan, Xuanqi Liu, Jia Fan","doi":"10.1002/ctm2.70304","DOIUrl":"https://doi.org/10.1002/ctm2.70304","url":null,"abstract":"<p>Clinical single-cell measurements are gaining increasing attention of clinicians and researchers to conventional parameters in clinical biochemistry of haematology. However, significant challenges need to be overcome before these technologies can be fully integrated into clinical practice.<span><sup>1</sup></span> With the rapid development of biotechnology and methodology, single-cell multi-omics and trans-omics analyses have become increasingly feasible, stable and reproducible. The comprehensive profiles generated at the single-cell level provide novel insights into molecular phenomes, functional states, microenvironmental configurations, disease mechanisms and potential therapeutic targets. This emerging field—termed <i>clinical single-cell biomedicine</i>—is opening new frontiers in precision medicine.<span><sup>2</sup></span> In particular, spatial transcriptome furthermore enables the spatiotemporal cellular and molecular mapping, which brings the development of functional histopathology, by defining the precise locations and interactions of target cells, and integrating clinical image phenomes.<span><sup>3, 4</sup></span> A spatial enhanced resolution omics-sequencing, Stereo-Seq (Figure 1B), utilises DNA nanoball-patterned arrays for high-resolution in situ RNA capture to demonstrate tissue/organ spatiotemporal transcriptomes at a single-cell level.<span><sup>5</sup></span> This technology enables multi-dimensional, single-cell–level visualisation of transcriptomic data across tissues and organs. By integrating continuous transcriptomic images, stereoscopic molecular maps of cells can be reconstructed, providing detailed insights into cellular heterogeneity, lineage trajectories and functional states.<span><sup>5, 6</sup></span> Such stereoscopic and temporal resolution of transcriptomics enables the identification of spatiotemporal variations, classifications, architectonics and functional communications of cells, all of which can be translated into clinical strategies. The application of single-cell multi-omics, combined with multi-dimensional genomic data, to human pathology has been proposed as a transformative milestone in stereoscopic diagnosis and therapeutic strategies.<span><sup>7</sup></span></p><p>Stereo-Cell is a breakthrough spatially enhanced-resolution single-cell sequencing technology utilising high-density DNA nanoball-patterned arrays (Figure 1A). It enables the capture of intact individual cells or microstructures, and facilitates the profiling of stereoscopic, spatiotemporal multi-omics at true single-cell resolution.<span><sup>8</sup></span> Unlike Stereo-Seq (Figure 1B), Stereo-Cell is designed to acquire stereoscopic multi-omic information from entire, structurally preserved cells, including complete morphological characteristics, surface protein profiles and intracellular molecular landscapes (Figure 1A). In contrast to conventional instrument-based cell separation methods, the DNA nanoball-oriented chips used ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 4","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70304","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143827027","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":"ATG16L1 restrains macrophage NLRP3 activation and alveolar epithelial cell injury during septic lung injury","authors":"Yan Bai, Xinyu Zhan, Qing Zhu, Xingyue Ji, Yingying Lu, Yiyun Gao, Fei Li, Zhu Guan, Haoming Zhou, Zhuqing Rao","doi":"10.1002/ctm2.70289","DOIUrl":"https://doi.org/10.1002/ctm2.70289","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The lung is the organ most commonly affected by sepsis. Additionally, acute lung injury (ALI) resulting from sepsis is a major cause of death in intensive care units. Macrophages are essential for maintaining normal lung physiological functions and are implicated in various pulmonary diseases. An essential autophagy protein, autophagy-related protein 16-like 1 (ATG16L1), is crucial for the inflammatory activation of macrophages.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>ATG16L1 expression was measured in lung from mice with sepsis. ALI was induced in myeloid <i>ATG16L1-</i>, <i>NLRP3-</i> and <i>STING</i>-deficient mice by intraperitoneal injection of lipopolysaccharide (LPS, 10 mg/kg). Using immunofluorescence and flow cytometry to assess the inflammatory status of LPS-treated bone marrow-derived macrophages (BMDMs). A co-culture system of BMDMs and MLE-12 cells was established in vitro.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Myeloid <i>ATG16L1</i>-deficient mice exhibited exacerbated septic lung injury and a more intense inflammatory response following LPS treatment. Mechanistically, <i>ATG16L1</i>-deficient macrophages exhibited impaired LC3B lipidation, damaged mitochondria and reactive oxygen species (ROS) accumulation. These abnormalities led to the activation of NOD-like receptor family pyrin domain-containing protein 3 (NLRP3), subsequently enhancing proinflammatory response. Overactivated <i>ATG16L1</i>-deficient macrophages aggravated the damage to alveolar epithelial cells and enhanced the release of double-stranded DNA (dsDNA), thereby promoting STING activation and subsequent NLRP3 activation in macrophages, leading to positive feedback activation of macrophage NLRP3 signalling. Scavenging mitochondrial ROS or inhibiting STING activation effectively suppresses NLRP3 activation in macrophages and alleviates ALI. Furthermore, overexpression of myeloid <i>ATG16L1</i> limits NLRP3 activation and reduces the severity of ALI.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our findings reveal a new role for ATG16L1 in regulating macrophage NLRP3 feedback activation during sepsis, suggesting it as a potential therapeutic target for treating sepsis-induced ALI.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Myeloid-specific ATG16L1 deficiency exacerbates sepsis-induced lung injury.</li>\u0000 \u0000 ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 4","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70289","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143818657","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":"Transcriptomic miRNA and mRNA signatures in primary prostate cancer that are associated with lymph-node invasion","authors":"Matias A. Bustos, Kelly K. Chong, Yoko Koh, SooMin Kim, Eleanor Ziarnik, Romela I. Ramos, Gianna Jimenez, David L. Krasne, Warren M. Allen, Timothy G. Wilson, Dave S. B. Hoon","doi":"10.1002/ctm2.70288","DOIUrl":"https://doi.org/10.1002/ctm2.70288","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Nomograms or comparable techniques can be used to determine which patients with prostate cancer (PCa) will benefit from extended pelvic lymph node dissection (ePLND). While nomograms help guide clinical decisions, ∼80% of the patients undergo unnecessary ePLND. This pilot study aims to identify both transcriptomic mRNA and microRNA (miR) signatures in primary PCa tumours that are associated with the presence of lymph node metastasis (LNM).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Primary PCa tumours obtained from 88 patients (pathologically diagnosed as N0 [pN0, <i>n</i> = 44] or as N1 [pN1, <i>n</i> = 44]) were profiled using two different probe-based captured direct assays based on next-generation sequencing and targeting 19398 mRNA transcripts (human transcriptome panel [HTP] dataset) and 2083 miRs (miRs whole-transcriptome assay [WTA] dataset). The TCGA-PRAD (pN0 [<i>n</i> = 382] and pN1 [<i>n</i> = 70]) and GSE220095 (pN0 [<i>n</i> = 138] and pN1 [<i>n</i> = 17]) datasets were used for validation using bioinformatic analyses.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A four-mRNA signature (<i>CHRNA2</i>, <i>NPR3</i>, <i>VGLL3</i> and <i>PAH</i>) was found in primary tumour tissue samples from pN1 PCa patients, and then it was validated using the TCGA-PRAD and GSE220095 datasets. Adding serum prostate-specific antigen (PSA) values to the four-gene signature increased the performance to identify pN1 (HTP [AUC = .8487, <i>p </i>= 2.18e-09], TCGA-PRAD [AUC = .7150, <i>p </i>= 8.66e-08] and GSE220095 datasets [AUC = .8772, <i>p </i>= 4.09e-07]). Paired miR analyses showed that eight miRs were significantly upregulated in primary PCa that were pN1 (<i>p</i> < .01). The eight-miR signature performance increased when adding PSA (WTA dataset [AUC = .8626, <i>p </i>= 4.66e-10]) or Grade group (WTA dataset [AUC = .8689, <i>p </i>= 2e-10]). When combining the miR/mRNA signatures (miR-663b, <i>CHRNA2</i> and <i>PAH</i>) with PSA levels, it showed the best performance to distinguish pN1 from pN0 PCa patients.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This study found miR/mRNA signatures in primary PCa tumours that in combination with serum PSA levels may complement nomograms for better detection of PCa patients with LNM and triage patients into better surgical decision-making.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Pr","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 4","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70288","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143822167","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":"Diverse potential of chimeric antigen receptor-engineered cell therapy: Beyond cancer","authors":"Lvying Wu,&nbsp;Lingfeng Zhu,&nbsp;Jin Chen","doi":"10.1002/ctm2.70306","DOIUrl":"https://doi.org/10.1002/ctm2.70306","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Chimeric antigen receptor (CAR)-engineered cell therapies have made significant progress in haematological cancer treatment. This success has motivated researchers to investigate its potential applications in non-cancerous diseases, with substantial strides already made in this field.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Main Body</h3>\u0000 \u0000 <p>This review summarises the latest research on CAR-engineered cell therapies, with a particular focus on CAR-T cell therapy for non-cancerous diseases, including but not limited to infectious diseases, autoimmune diseases, cardiac diseases and immune-mediated disorders in transplantation. Additionally, the review discusses the current obstacles that need to be addressed for broader clinical applications.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>With ongoing research and continuous improvements, CAR-engineered cell therapy holds promise as a potent tool for treating various diseases in the future.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>CAR-engineered cell therapy has expanded beyond cancer to treat autoimmune diseases, infections, cardiac diseases, and transplant-related rejection.</li>\u0000 \u0000 <li>The CAR platform is diverse, with various cell types such as CAR-T, CAR-NK, and CAR-M potentially suited for different disease contexts.</li>\u0000 \u0000 <li>The safety, efficacy, and practicality of CAR cell therapy in non-cancer diseases remain challenging, requiring further technological optimization and clinical translation.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 4","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70306","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143809716","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":"Genetic variants associated with physiological and biochemical indicators: A multi-centre whole-exome sequencing study of Chinese healthy participants","authors":"Zhe Wang,&nbsp;Zhiyan Liu,&nbsp;Guangyan Mu,&nbsp;Qiufen Xie,&nbsp;Shuang Zhou,&nbsp;Zining Wang,&nbsp;Yimin Cui,&nbsp;Qian Xiang,&nbsp;IMPACT Study Group","doi":"10.1002/ctm2.70300","DOIUrl":"https://doi.org/10.1002/ctm2.70300","url":null,"abstract":"&lt;p&gt;Dear Editor,&lt;/p&gt;&lt;p&gt;Disease onset and progression manifest through quantifiable alterations in organ function biomarkers, including hepatic, renal and lipid profiles. Even within normal reference ranges, these indicators could predict disease risk.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Physiological and biochemical profiles in Asians display distinct characteristics compared to those in Caucasians.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; Identifying factors that influence these markers in Asian populations may therefore enhance early disease prediction and intervention, improving clinical outcomes.&lt;/p&gt;&lt;p&gt;Given the heritability of physiological and biochemical indicators,&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; linking genetic variations with these indicators differences through genome-wide association studies (GWAS) has become a highly promising approach, particularly in lipid metabolism.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; However, databases such as UK Biobank and FinnGen present limitation due to ethnic diversity and lack of stringent screening. This study employed whole-exome sequencing to analyse genes associated with key physiological indicators in clinically screened Chinese healthy participants, providing insights into their genetic correlations.&lt;/p&gt;&lt;p&gt;A total of 778 participants in IMPACT study were included in this cohort.&lt;span&gt;&lt;sup&gt;5-8&lt;/sup&gt;&lt;/span&gt; Briefly, healthy volunteers were enrolled in this study based on the absence of clinically significant abnormalities in blood pressure, heart rate, routine blood, blood biochemistry, chest X-ray, urinalysis and electrocardiogram, as well as confirmation of no infectious diseases or non-pregnancy status. Figure 1 shows the flow diagram. The physiological and biochemical indicators of participants are presented in Table 1. In discovery cohort, correlation analysis and linear regression were conducted to choose the covariates (Figure S1 and Table S1). Consequently, age, male proportion and body mass index were included as covariates in subsequent genetic association analyses. Identity-by-descent analysis excluded first-degree relatives (Proportion of identity by descent: PI_HAT ≤ .5) prior to genetic modeling.&lt;/p&gt;&lt;p&gt;To investigate genetic variants associated with liver function, genetic association analysis was conducted in total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), high-density lipoprotein (HDL), alanine aminotransferase (ALT) and aspartate aminotransferase (AST). The Manhattan plot of discovery cohort is shown in Figure 2. Single nucleotide polymorphisms (SNPs) correlated with liver function and disease are listed in Tables S2-S7.  Notably, &lt;i&gt;RBM19&lt;/i&gt; rs117916372 was associated with both ALT and AST. Compared with AA carriers of rs117916372, homozygous GG carriers exhibited lower level of ALT (AA vs. GG: 16.20 ± 8.66 U/L vs. 12.75 ± 4.43 U/L, &lt;i&gt;p &lt;/i&gt;= 1.53 × 10&lt;sup&gt;−7&lt;/sup&gt;) and AST (AA vs. GG: 18.38 ± 4.61 U/L vs. 15.00 ± 4.24 U/L, &lt;i&gt;p = &lt;/i&gt;2.56 × 10&lt;sup&gt;−10&lt;/sup&gt;). Rs3851 on &lt;i&gt;TM4SF5&lt;/i&gt; exhibited a corre","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 4","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70300","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143809717","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":"Severe SARS-CoV-2 infection in diabetes was rescued in mice supplemented with metformin and/or αKG, and patients taking metformin, via HIF1α-IFN axis","authors":"Garima Joshi,&nbsp;Garima Verma,&nbsp;Simrandeep Kaur,&nbsp;Ellango Ramasamy,&nbsp;Navya Chauhan,&nbsp;Savita Singh,&nbsp;Pradipta Jana,&nbsp;Zaigham Abbas Rizvi,&nbsp;Pallavi Kshetrapal,&nbsp;Shinjini Bhatnagar,&nbsp;Anil Kumar Pandey,&nbsp;Amit Awasthi,&nbsp;Bhabatosh Das,&nbsp;Prasenjit Guchhait","doi":"10.1002/ctm2.70275","DOIUrl":"https://doi.org/10.1002/ctm2.70275","url":null,"abstract":"&lt;p&gt;Dear Editor,&lt;/p&gt;&lt;p&gt;Studies report a higher prevalence of COVID-19 and worse outcomes in diabetic patients, typically 1.5-3-fold greater than similar populations without diabetes&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; and the individuals taking the hypoglycaemic drug metformin have better survival.&lt;span&gt;&lt;sup&gt;2, 3&lt;/sup&gt;&lt;/span&gt; We investigated the mechanisms for the above reports and observed that the hyperglycaemic mice with either type 1 or type 2 diabetes (T1D/T2D) have elevated SARS-CoV-2 infection in the lungs at day-5 post infection (5DPI, Figure 1 A, B) with aggressive inflammation, indicated by infiltration of immune cells (Figure 1C,D) and accumulation of cytokines TNFα and IL6 (Figure S1C,D) as compared to non-diabetic counterparts, (T2D mice data in Figure 1L–O, Figure S2C-D). Both T1D/T2D mice showed decreased levels of interferons in lung tissue lysate (type-1 and -2; IFN-α/IFN-β/IFN-γ, Figure 1H–J/S–U) alongside decreased expression of IFNA1/IFNB1/IFNG1 and IFN-regulatory factor (IRF)-3/IRF-7 genes (Figure-1E–G/P–R, Figures S1E,F and S2E,F) in the lung tissue and in the spleen (Figures S1I–M and S2I–M) but elevated HIF-1α in the lungs (Figure 1K,V and Figures S1G and S2G). The supplementation with metformin and/or alpha-ketoglutarate (αKG, previously used by us&lt;span&gt;&lt;sup&gt;4, 5&lt;/sup&gt;&lt;/span&gt;) significantly reduced viral load, and rescued inflamed lungs and IFNs synthesis (Figure-1K,V and Figure S1 H/S2 H). Unlike IFNs, the levels of IgG and the neutralization antibody titre against SARS-CoV-2 were found unaltered between WT and diabetic (T1D/T2D) mice even after metformin+αKG treatment (Figures S1N–Q and S2N,O). The repetition of above experiment in K-18 mice and high fat diet induced T2D model of K-18 showed similar observations (Figure S4A–M). In mechanism, we described that hyperglycaemic microenvironment (25 mM glucose) increased SARS-CoV-2 infection (Figure 2A) and decreased IFNA1/IFNB1 expression in the insulin resistant Huh-7 cells model (Figure S3A,B). The metformin and/or alpha-ketoglutarate treatment increased the IFN synthesis and decreased viral load (Figure 2A–C). The expression of HIF-1α inversely corelated with P-IRF3 suggesting a decreased IFN synthesis in these cells in diabetic microenvironment, and its improvement following metformin and/or αKG treatment (Figure 2D and Figure S3E,F). The inhibition of HIF-1α function by CAY10585 was found to improve IFN synthesis and inhibiting SARS-CoV-2 infection in these cells (Figure 2E and Figure S3G,H). We validated the above mechanism using HIF1α-depleted (using HIF1A-shRNA previously used by us&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt;) U937 monocytic cells transiently expressing hACE2. HIF1A-depleted cells have a decreased viral load as compared to cells with control-shRNA (Figure 2F). Conversely, the IFNA1/IFNB1/IFNG1 transcripts were elevated in HIF1A-depleted cells than controls (Figure 2G–I). We also observed an elevated P-IRF3 in the HIF1A-depleted cells as compared to controls (Figure 2J, Figure S3M","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 4","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70275","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143801303","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":"The role of cancer-associated fibroblasts in the tumour microenvironment of urinary system","authors":"Ri Hong,&nbsp;Puguang Yu,&nbsp;Xiaoli Zhang,&nbsp;Peng Su,&nbsp;Hongyuan Liang,&nbsp;Dan Dong,&nbsp;Xuesong Wang,&nbsp;Kefeng Wang","doi":"10.1002/ctm2.70299","DOIUrl":"https://doi.org/10.1002/ctm2.70299","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>Urological tumours are a type of neoplasms that significantly jeopardise human life and wellbeing. Cancer-associated fibroblasts (CAFs), serving as the primary component of the stromal cellular milieu, form a diverse cellular cohort that exerts substantial influence on tumourigenesis and tumour progression. In this review, we summarised the literatures regarding the functions of CAFs in the urinary tumour microenvironment (TME). We primarily examined the multifaceted activities of CAFs in the TME of urological system tumours, including inhibiting tumour immunity, remodelling the extracellular matrix, promoting tumour growth, metastasis, drug resistance and their clinical applications. We also discussed potential future directions for leveraging artificial intelligence in CAFs research.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>The interaction of CAFs with various cell secretory factors in the TME of urological tumors.</li>\u0000 \u0000 <li>The application of CAFs in diagnosis, treatment and prognosis of urological tumors.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 4","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70299","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143793729","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":"MiR-146a engineered extracellular vesicles derived from mesenchymal stromal cells more potently attenuate ischaemia–reperfusion injury in lung transplantation","authors":"Xiucheng Yang,&nbsp;Shanchao Hong,&nbsp;Tao Yan,&nbsp;Mingzhao Liu,&nbsp;Mingyao Liu,&nbsp;Jin Zhao,&nbsp;Bingqing Yue,&nbsp;Di Wu,&nbsp;Jingbo Shao,&nbsp;Man Huang,&nbsp;Jingyu Chen","doi":"10.1002/ctm2.70298","DOIUrl":"https://doi.org/10.1002/ctm2.70298","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;The limited donor lung pool for lung transplantation (LTx) is largely due to concerns over ischaemia–reperfusion injury (IRI), a major cause of primary graft dysfunction (PGD). NLRP3 inflammasome activation is known to play a pivotal role in the onset of IRI. While human umbilical cord mesenchymal stromal cell-derived extracellular vesicles (hucMSC-EVs) have shown potential in reducing acute lung injury, their effects on NLRP3 activation in the context of LTx remain unclear.&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, engineered hucMSC-EVs were delivered via nebulisation to mitigate IRI in rat LTx models. We utilised both a rat orthotopic LTx model and a cell cold preservation reperfusion model to evaluate the therapeutic efficacy of hucMSC-EVs. Bulk-RNA sequencing, single-cell sequencing analysis, immunofluorescence and Western blot techniques were employed to assess NLRP3 inflammasome activation and inflammation.&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;Nebulised hucMSC-EVs were efficiently internalised by alveolar macrophages (AMs), significantly reducing lung injury and improving oxygenation in the LTx models. Mechanistically, the engineered hucMSC-EVs, which enhance the expression of miR-146a, can more effectively suppress the activation of the NLRP3 inflammasome by targeting the IRAK1/TRAF6/NF-κB pathway, resulting in decreased levels of IL-1β, IL-18 and other inflammatory cytokines. These findings highlight the potential of miR-146a-modified EVs in modulating innate immune responses to alleviate IRI.&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 results demonstrate that nebulised delivery of engineered hucMSC-EVs effectively mitigates IRI in LTx by inhibiting NLRP3 inflammasome activation. This innovative approach presents a promising strategy for enhancing donor lung preservation and improving post-transplant outcomes in LTx.&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;&lt;b&gt;Nebulized Delivery of miR-146a Engineered hucMSC-EVs Mitigates Ischemia-Reperfusion Injury (IRI) in Lung Transplantation&lt;/b&gt;. This study demonstrates the therapeutic potential of nebulized, engineered human umbilical cord mesenchymal stromal cell-derived extracellular vesicles (hucMSC-EVs) modified with miR-146a to alleviate IRI in rat lung transplantation models. The treatment significantly improved lung oxygenation and reduced","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 4","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70298","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143793728","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":"Clinical implement of Probe-Capture Metagenomics in sepsis patients: A multicentre and prospective study","authors":"Qin Sun,&nbsp;Ran Teng,&nbsp;Qiankun Shi,&nbsp;Yun Liu,&nbsp;Xing Cai,&nbsp;Bin Yang,&nbsp;Quan Cao,&nbsp;Chang Shu,&nbsp;Xu Mei,&nbsp;Weiqi Zeng,&nbsp;Bingxue Hu,&nbsp;Junyi Zhang,&nbsp;Haibo Qiu,&nbsp;Ling Liu","doi":"10.1002/ctm2.70297","DOIUrl":"https://doi.org/10.1002/ctm2.70297","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;Accurate pathogen identification is critical for managing sepsis. However, traditional microbiological methods are time-consuming and exhibit limited sensitivity, particularly with blood samples. Metagenomic sequencing of plasma or whole blood was highly affected by the proportion of host nucleic acid.&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 developed a Probe-Capture Metagenomic assay and established a multicentre prospective cohort to assess its clinical utility. In this study, 184 blood samples from patients suspected of sepsis were sent for blood culture and Probe-Capture Metagenomic sequencing before using antibiotics. The pathogen-positive rate and auxiliary abilities in diagnosis were compared among Probe-Capture Metagenomics, blood culture and real-time PCR (RT-PCR). Antibiotic therapy adjustments were based on the identification of pathogens, and changes in the Sequential Organ Failure Assessment (SOFA) score were monitored on days 0, 3 and 7 of admission.&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;A total of 184 sepsis patients were enrolled, with a mean age of 66 years (range 56–74). The Probe-Capture Metagenomics method, confirmed by RT-PCR, demonstrated a significantly higher pathogen detection rate than blood culture alone (51.6% vs. 17.4%, &lt;i&gt;p&lt;/i&gt; &lt; .001). When combining the results of blood culture and RT-PCR, Probe-Capture Metagenomics achieved a concordance rate of 91.8% (169/184), with a sensitivity of 100% and specificity of 87.1%. In terms of clinical impact, antibiotic therapy was adjusted for 64 patients (34.8%) based on the results from Probe-Capture Metagenomics, and 41 patients (22.3%) showed a &gt; 2-point decrease in SOFA score following antibiotic adjustments.&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;Probe-Capture Metagenomics significantly enhances the ability of pathogen detection compared with traditional metagenomics. Compared to blood culture and RT-PCR in sepsis patients, it leads to improved antibiotic treatment and better patient outcomes. This study, for the first time, evaluates the clinical impact of metagenomic sequencing by integrating antibiotic adjustments and SOFA score changes, indicating that approximately one-fifth of sepsis patients benefit from this advanced diagnostic approach.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Trial registration&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;This study has been registered in clinical trials (clinicaltrials.gov) on 30 November 2018, and the regi","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 4","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70297","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143770400","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}