Journal of Translational Medicine最新文献

{"title":"Prioritizing gut microbial SNPs linked to immunotherapy outcomes in NSCLC patients by integrative bioinformatics analysis.","authors":"Muhammad Faheem Raziq, Nadeem Khan, Haseeb Manzoor, Hafiz Muhammad Adnan Tariq, Mehak Rafiq, Shahzad Rasool, Masood Ur Rehman Kayani, Lisu Huang","doi":"10.1186/s12967-025-06370-0","DOIUrl":"10.1186/s12967-025-06370-0","url":null,"abstract":"<p><strong>Background: </strong>The human gut microbiome has emerged as a potential modulator of treatment efficacy for different cancers, including non-small cell lung cancer (NSCLC) patients undergoing immune checkpoint inhibitor (ICI) therapy. In this study, we investigated the association of gut microbial variations with response against ICIs by analyzing the gut metagenomes of NSCLC patients.</p><p><strong>Methods: </strong>Strain identification from the publicly available metagenomes of 87 NSCLC patients, treated with nivolumab and collected at three different timepoints (T0, T1, and T2), was performed using StrainPhlAn3. Variant calling and annotations were performed using Snippy and associations between microbial genes and genomic variations with treatment responses were evaluated using MaAsLin2. Supervised machine learning models were developed to prioritize single nucleotide polymorphisms (SNPs) predictive of treatment response. Structural bioinformatics approaches were employed using MUpro, I-Mutant 2.0, CASTp and PyMOL to access the functional impact of prioritized SNPs on protein stability and active site interactions.</p><p><strong>Results: </strong>Our findings revealed the presence of strains for several microbial species (e.g., Lachnospira eligens) exclusively in Responders (R) or Non-responders (NR) (e.g., Parabacteroides distasonis). Variant calling and annotations for the identified strains from R and NR patients highlighted variations in genes (e.g., ftsA, lpdA, and nadB) that were significantly associated with the NR status of patients. Among the developed models, Logistic Regression performed best (accuracy > 90% and AUC ROC > 95%) in prioritizing SNPs in genes that could distinguish R and NR at T0. These SNPs included Ala168Val (lpdA) in Phocaeicola dorei and Tyr233His (lpdA), Leu330Ser (lpdA), and His233Arg (obgE) in Parabacteroides distasonis. Lastly, structural analyses of these prioritized variants in objE and lpdA revealed their involvement in the substrate binding site and an overall reduction in protein stability. This suggests that these variations might likely disrupt substrate interactions and compromise protein stability, thereby impairing normal protein functionality.</p><p><strong>Conclusion: </strong>The integration of metagenomics, machine learning, and structural bioinformatics provides a robust framework for understanding the association between gut microbial variations and treatment response, paving the way for personalized therapies for NSCLC in the future. These findings emphasize the potential clinical implications of microbiome-based biomarkers in guiding patient-specific treatment strategies and improving immunotherapy outcomes.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"343"},"PeriodicalIF":6.1,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11916936/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143649519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Complement C3a promotes the formation of osteoclasts by inhibiting Sirt1 to activate the PI3K/PDK1/SGK3 pathway in patients with multiple myeloma.","authors":"Fengjuan Jiang, Yunhe Zhang, Fengping Peng, Hui Liu, Kai Ding, Panpan Cao, Xiaohan Liu, Lijuan Li, Zhaoyun Liu, Rong Fu","doi":"10.1186/s12967-025-06319-3","DOIUrl":"10.1186/s12967-025-06319-3","url":null,"abstract":"<p><strong>Background: </strong>Myeloma bone disease (MBD) is the most common complication of multiple myeloma (MM). Our previous study showed that the complement C3a activates osteoclasts to participate in the pathogenesis of MBD; however, its mechanism of action is diverse and complex. Studies have shown that the Sirtuin (Sirt) family of proteins (i.e., Sirt1-7) are expressed in human bone and cartilage, and participate in bone metabolic balance.</p><p><strong>Methods and results: </strong>We measured the levels of complement C3a, Sirt1, osteoclast-related genes, and bone disease-related biological indicators using enzyme-linked immunosorbent assay (ELISA), quantitative real-time PCR and western blotting. Sirt1 expression in osteoclasts was observed to be lower in patients with MM compared to healthy donors and negatively correlated with complement C3a levels, osteoclast-related gene expression, and osteolysis-related markers. Co-immunoprecipitation (Co-IP) and immunostaining were used to verify the interaction between C3a and Sirt1 in RAW264.7 cells. Osteoclasts were then induced from bone marrow mononuclear cells (BMMCs) in patients with MM or cultured RAW264.7 cells, using C3a and/or Sirt1 activator (SRT1720)/inhibitors (EX527) in vitro. Sirt1 inhibits osteoclast formation and complement C3a reverses this inhibitory function of Sirt1 to activate osteoclasts. RAW264.7 cells with induced overexpression or knockdown Sirt1 were transfected with plasmid or shRNA, and RNA-seq analysis was performed. Increased Sirt1 expression resulted in the inhibition of the PI3K/PDK1/SGK3 pathway, which could be reactivated by complement C3a. Sirt1 knockdown activated the PI3K/PDK1/SGK3 pathway, which was further enhanced by complement C3a. A mouse model of MBD was successfully constructed. We injected this model with complement C3a or SRT1720, which further verified that complement C3a can significantly increase the degree of MBD bone damage, whereas SRT1720 can reduce the bone damage aggravated by C3a and treat MBD.</p><p><strong>Conclusion: </strong>We demonstrated that complement C3a interacts with Sirt1 in osteoclasts to participate in the pathogenesis of MBD. Complement C3a promotes osteoclast formation by inhibiting Sirt1 to activate the PI3K/PDK1/SGK3 pathway in patients with MM, which is reduced by treatment with a Sirt1 activator. The application of a Sirt1 activator can reduce the formation of osteoclasts and reduce the severity of bone diseases in vivo and may be useful for the treatment of MBD. This study identified novel potential therapeutic targets and strategies for patients with MBD.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"338"},"PeriodicalIF":6.1,"publicationDate":"2025-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11912697/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143649473","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic insights into idiopathic pulmonary fibrosis: a multi-omics approach to identify potential therapeutic targets.","authors":"Zhuofeng Wen, Weixuan Liang, Ziyang Yang, Junjie Liu, Jing Yang, Runge Xu, Keye Lin, Jia Pan, Zisheng Chen","doi":"10.1186/s12967-025-06368-8","DOIUrl":"10.1186/s12967-025-06368-8","url":null,"abstract":"<p><strong>Objective: </strong>To identify potential therapeutic targets and evaluate the safety profiles for Idiopathic Pulmonary Fibrosis (IPF) using a comprehensive multi-omics approach.</p><p><strong>Method: </strong>We integrated genomic and transcriptomic data to identify therapeutic targets for IPF. First, we conducted a transcriptome-wide association study (TWAS) using the Omnibus Transcriptome Test using Expression Reference Summary data (OTTERS) framework, combining plasma expression quantitative trait loci (eQTL) data with IPF Genome-Wide Association Studies (GWAS) summary statistics from the Global Biobank (discovery) and Finngen (duplication). We then applied Mendelian randomization (MR) to explore causal relationships. RNA-seq co-expression analysis (bulk, single-cell and spatial transcriptomics) was used to identify critical genes, followed by molecular docking to evaluate their druggability. Finally, phenome-wide MR (PheW-MR) using GWAS data from 679 diseases in the UK Biobank assessed the potential adverse effects of the identified genes.</p><p><strong>Result: </strong>We identified 696 genes associated with IPF in the discovery dataset and 986 genes in the duplication dataset, with 126 overlapping genes through TWAS. MR analysis revealed 29 causal genes in the discovery dataset, with 13 linked to increased and 16 to decreased IPF risk. Summary data-based MR (SMR) confirmed six essential genes: ANO9, BRCA1, CCDC200, EZH1, FAM13A, and SFR1. Bulk RNA-seq showed FAM13A upregulation and SFR1 and EZH1 downregulation in IPF. Single-cell RNA-seq revealed gene expression changes across cell types. Molecular docking identified binding solid affinities for essential genes with respiratory drugs, and PheW-MR highlighted potential side effects.</p><p><strong>Conclusion: </strong>We identified six key genes-ANO9, BRCA1, CCDC200, EZH1, FAM13A, and SFR1-as potential drug targets for IPF. Molecular docking revealed strong drug affinities, while PheW-MR analysis highlighted therapeutic potential and associated risks. These findings offer new insights for IPF treatment and further investigation of potential side effects.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"337"},"PeriodicalIF":6.1,"publicationDate":"2025-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11912729/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143649484","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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 transcriptomic analysis reveals dynamic changes in the liver microenvironment during colorectal cancer metastatic progression.","authors":"Yue Jiang, Guojie Long, Xiaoming Huang, Wenyu Wang, Bing Cheng, Weidong Pan","doi":"10.1186/s12967-025-06351-3","DOIUrl":"10.1186/s12967-025-06351-3","url":null,"abstract":"<p><strong>Background: </strong>Metastasis is a leading cause of cancer-related deaths, with the liver being the most frequent site of metastasis in colorectal cancer. Previous studies have predominantly focused on the influence of the primary tumor itself on metastasis, with relatively limited research examining the changes within target organs.</p><p><strong>Methods: </strong>Using an orthotopic mouse model of colorectal cancer, single-cell sequencing was employed to profile the transcriptomic landscape of pre-metastatic and metastatic livers. The analysis focused on identifying cellular and molecular changes within the hepatic microenvironment, with particular emphasis on inflammatory pathways and immune cell populations.</p><p><strong>Results: </strong>A neutrophil subpopulation with high Prok2 expression was identified, showing elevated levels in the pre-metastatic and metastatic liver. Increased infiltration of Prok2⁺ neutrophils correlated with poor prognosis in liver metastatic colorectal cancer patients. In the liver metastatic niche (MN), these neutrophils showed high App and Cd274 (PD-L1) expression, suppressing macrophage phagocytosis and promoting T-cell exhaustion.</p><p><strong>Conclusion: </strong>A Prok2⁺ neutrophil subpopulation infiltrated both pre-metastatic and macro-metastatic liver environments, potentially driving immunosuppression through macrophage inhibition and T-cell exhaustion. Targeting Prok2⁺ neutrophils could represent a novel therapeutic strategy for preventing liver metastasis in colorectal cancer patients.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"336"},"PeriodicalIF":6.1,"publicationDate":"2025-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11910851/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143649545","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"F-box protein FBXO21 overexpression inhibits the proliferation and metastasis of clear cell renal cell carcinoma and is closely related to the CREB pathway and tumor immune cell infiltration.","authors":"Wuping Yang, Taile Jing, Cunjin Wu, Minghao Lu, Xiaolin Yao, Dan Xia, Ding Peng","doi":"10.1186/s12967-025-06356-y","DOIUrl":"10.1186/s12967-025-06356-y","url":null,"abstract":"<p><strong>Background: </strong>Many studies have shown that F-box proteins regulate epithelial-mesenchymal transition, which is closely related to tumor metastasis. However, there is still limited research on the role of F-box proteins in renal cell carcinoma (RCC).</p><p><strong>Methods: </strong>Public databases were used to screen differentially expressed genes among 37 F-box proteins in clear cell RCC (ccRCC). The expression of the differential gene FBXO21 and its prognostic value were verified by RT-qPCR and immunohistochemistry. Pyrosequencing was used to detect the regulatory effect of DNA methylation on FBXO21 expression. The effects of FBXO21 expression on cell proliferation and metastasis were clarified through cell phenotype experiments and animal models. The relationship between FBXO21 expression and the infiltration levels of tumor immune cells was also analyzed. GSEA and Western blot were used to identify the downstream molecular pathways associated with FBXO21 expression.</p><p><strong>Results: </strong>Our results revealed that FBXO21 was significantly underexpressed in ccRCC and that increased FBXO21 expression predicted a better patient prognosis. The promoter region of FBXO21 exhibited DNA hypermethylation, and FBXO21 expression was significantly restored after demethylation. In addition, FBXO21 overexpression significantly inhibited the proliferation and metastasis of ccRCC cells both in vitro and in vivo. Mechanistically, FBXO21 expression was related to the stroma score and the infiltration levels of immune infiltrating cells associated with prognosis. Moreover, FBXO21 overexpression increased the expression of key molecules in the CREB pathway.</p><p><strong>Conclusions: </strong>These results suggest that FBXO21 is a novel prognostic biomarker for ccRCC patients and functions as a tumor suppressor gene. Moreover, FBXO21 may regulate the CREB pathway and is closely related to tumor immune cell infiltration in ccRCC.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"335"},"PeriodicalIF":6.1,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11909812/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143634281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multidimensional bioinformatics perspective on smoking-linked driver genes and immune regulatory mechanisms in non-small cell lung cancer.","authors":"Can Ouyang, Xiaopeng Yu, Huazhong Wang, Puhua Zeng","doi":"10.1186/s12967-025-06301-z","DOIUrl":"10.1186/s12967-025-06301-z","url":null,"abstract":"<p><strong>Background: </strong>Lung cancer, one of the leading causes of cancer-related morbidity and mortality worldwide, is strongly associated with smoking as its primary carcinogenic factor. However, despite the strong link between smoking and lung cancer, not all smokers develop the disease, suggesting that individual genetic susceptibility and molecular mechanisms may play a critical role in the onset of lung cancer. Understanding the gene-driving mechanisms and immune regulatory pathways involved in smoking-related lung cancer remains one of the key challenges in current lung cancer research.</p><p><strong>Methods: </strong>This study employs an integrative bioinformatics approach to explore gene expression differences and immune microenvironment characteristics between smokers with non-small cell lung cancer (NSCLC) and normal individuals. First, smoking-linked lung cancer driver genes (SLDCGs) were identified, followed by Mendelian Randomization (MR) and Summary-based Mendelian Randomization (SMR) analyses to further validate their causal relationships. Next, public databases, including TCGA, GEO, and GTEx, were used to systematically analyze the expression differences of SLDCGs across various clinical subgroups, and immune infiltration analysis was conducted to explore their potential roles in the immune microenvironment of NSCLC.</p><p><strong>Results: </strong>The study identified HLA-J and PRMT7 as core driver genes for smoking-associated NSCLC. MR analysis confirmed the potential causal relationship of HLA-J and PRMT7 in the development of NSCLC. Specifically, high expression of PRMT7 was closely associated with the occurrence of NSCLC, while low expression of HLA-J was implicated in immune evasion mechanisms in NSCLC. Additionally, immune microenvironment analysis revealed that HLA-J enhances the activity of immune cells, particularly T cells, to promote tumor immune recognition, whereas PRMT7 suppresses immune cell function, weakening immune surveillance and facilitating immune evasion.</p><p><strong>Conclusion: </strong>This study systematically reveals the molecular mechanisms of smoking-linked NSCLC through multidimensional bioinformatics analysis, highlighting the key roles of SLDCGs in immune evasion. The discovery of HLA-J and PRMT7 provides new theoretical foundations for targeted immunotherapy, with significant potential for early diagnosis and personalized treatment of smoking-induced NSCLC. Future research should focus on validating these genes in clinical samples and exploring their potential in immunotherapy.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"330"},"PeriodicalIF":6.1,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11908013/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143634067","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to: Deciphering the generation of heterogeneity in esophageal squamous cell carcinoma metastasis via singlecell multiomics analysis.","authors":"Kaiwen Sheng, Jun Chen, Ruitang Xu, Haoqiang Sun, Ran Liu, Yongjie Wang, Wenwen Xu, Jiao Guo, Miao Zhang, Shuai Liu, Juan Lei, Yawen Sun, Yang Jia, Dianhao Guo","doi":"10.1186/s12967-025-06211-0","DOIUrl":"10.1186/s12967-025-06211-0","url":null,"abstract":"","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"334"},"PeriodicalIF":6.1,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11909961/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143634262","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Serum Uromodulin as early marker for ischemic acute kidney injury and nephron loss: association with kidney tissue distribution pattern.","authors":"Eva Vonbrunn, Nadja Ebert, Nada Cordasic, Kerstin Amann, Anke Büttner, Maike Büttner-Herold, Jürgen E Scherberich, Christoph Daniel","doi":"10.1186/s12967-025-06125-x","DOIUrl":"10.1186/s12967-025-06125-x","url":null,"abstract":"<p><strong>Background: </strong>Uromodulin (UMOD) is expressed in kidneys and is mainly excreted in the urine, although a smaller amount is also released into the serum. Here, we investigated UMOD in acute kidney injury (AKI), with particular focus on the utility of serum UMOD as marker for nephron loss.</p><p><strong>Methods: </strong>Blood and kidney samples were collected 6 h, 24 h, 3 days and 8 weeks after ischemia/reperfusion (I/R) in a rat model. To investigate the impact of nephron number on UMOD levels, sera and tissue from healthy, uninephrectomized (Unx) and 5/6-nephrectomized (Snx) rats were analyzed. Histological changes, kidney function and cell damage were evaluated and serum UMOD, Umod mRNA expression and distribution of UMOD protein in the kidney were examined.</p><p><strong>Results: </strong>In AKI, kidney function was markedly impaired 24 h after I/R, while kidney injury and serum UMOD was increased transiently. Simultaneously, the amount of UMOD-positive kidney cells rapidly decreased 24 h after I/R compared to healthy kidneys, and mRNA expression of Umod was lowest on days 1-3 after I/R. Serum UMOD correlated with nephron number showing the highest levels in healthy rats, which were reduced after Unx and further reduced after Snx.</p><p><strong>Conclusion: </strong>In an AKI model with severe tubular damage, a transient increase in UMOD serum levels in parallel with loss of UMOD-positive cells suggests temporary release of UMOD from destroyed tubular cells into the blood. Serum UMOD appears to be not only a marker of chronic renal failure but also of acute loss of functional and cellular integrity of kidney epithelia in AKI.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"323"},"PeriodicalIF":6.1,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11907908/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143634070","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrating DNA and RNA sequencing for enhanced pathogen detection in respiratory infections.","authors":"Dejian Gu, Jie Liu, Jiaping Wang, Yuting Yi, Yuxing Chu, Rui Gao, Hao Liu, Jun She, Binghuai Lu","doi":"10.1186/s12967-025-06342-4","DOIUrl":"10.1186/s12967-025-06342-4","url":null,"abstract":"<p><strong>Background: </strong>The clinical value of shotgun metagenomic next-generation sequencing (mNGS) in improving the detection rates of respiratory pathogens is well-established. However, mNGS is complex and expensive. This study designed and evaluated the performance of targeted NGS (tNGS) in diagnosing respiratory infections.</p><p><strong>Methods: </strong>We retrospectively included samples from 281 patients with lower respiratory tract infections to establish thresholds of pathogens. Subsequently, target pathogens were selected and a probe hybridization system was established. The performance and clinical manifestations of tNGS for 306 pathogens were evaluated using clinical and simulated samples.</p><p><strong>Results: </strong>The tNGS method took 16 h with sequencing data sizes of 5 M reads. The limit-of-detection of tNGS was 100-200 CFU/mL, respectively. Bioinformatics simulation confirmed the method's high specificity and robustness. In 281 patients of clinical validation cohort, tNGS exhibited a sensitivity of 97.73% and specificity of 75.41% compared to the composite reference standard, which notably surpasses those of culture-based and conventional microbiological methods (CMT). In detecting bacterial and viral infection, tNGS demonstrated superior sensitivity relative to CMT. Notably, 61.40% of target viruses were subtype-resolved with the initial establishment of reliable typing cutoffs, with the subtyping results being completely consistent with the PCR results. tNGS allowed for concurrent identification of antimicrobial resistance (AMR) markers and viral subtyping. 80.56% of AMR markers identified by tNGS were consistent with antimicrobial susceptibility testing.</p><p><strong>Conclusion: </strong>This research established the robust performance of our tailored tNGS assay in the simultaneous detection of DNA and RNA pathogens, underscoring its prospective suitability for widespread use in clinical diagnostics.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"325"},"PeriodicalIF":6.1,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11907987/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143633630","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Apoptotic cell-derived extracellular vesicles-MTA1 confer radioresistance in cervical cancer by inducing cellular dormancy.","authors":"Yuan-Run Deng, Qiao-Zhi Wu, Wan Zhang, Hui-Ping Jiang, Cai-Qiu Xu, Shao-Cheng Chen, Jing Fan, Sui-Qun Guo, Xiao-Jing Chen","doi":"10.1186/s12967-025-06350-4","DOIUrl":"10.1186/s12967-025-06350-4","url":null,"abstract":"<p><strong>Background: </strong>Radioresistance presents a major challenge in the treatment of cervical cancer (CC). Apoptotic tumor cells can create an \"onco-regenerative niche,\" contributing to radioresistance. However, the intercellular signaling mechanisms mediating the transfer of radioresistance from apoptotic to surviving cancer cells remain unclear.</p><p><strong>Methods: </strong>The role of apoptotic tumor cell-derived extracellular vesicles (apoEVs) in mediating radioresistance was investigated through integrated bioinformatics and experimental approaches. The GSE236738 dataset was analyzed to identify potential regulators, with subsequent validation of apoEV-MTA1 function using in vitro and in vivo models. Mechanistic studies focused on caspase-3 activation, p-STAT1 signaling pathway, and dormancy-associated protein networks. Furthermore, therapeutic strategies targeting MTA1 and its downstream signaling were evaluated for radiosensitization potential.</p><p><strong>Results: </strong>MTA1 was identified as a critical factor enriched in and transferred by apoEVs from apoptotic tumor cells to neighboring CC cells. Caspase-3 activation facilitated the nuclear export and encapsulation of MTA1 in apoEVs. Transferred MTA1 retained transcriptional activity, activated the p-STAT1 signaling pathway, and induced cellular dormancy via NR2F1, a key dormancy regulator, resulting in increased radioresistance. Knockdown of MTA1 in apoEVs or inhibition of p-STAT1 in recipient cells enhanced radiosensitivity. Furthermore, apoEV-MTA1 promoted tumor radioresistance and reduced survival rates in irradiated cervical cancer mouse model.</p><p><strong>Conclusions: </strong>This study demonstrates that apoEV-MTA1 confers radioresistance in CC by promoting cellular dormancy via the p-STAT1/NR2F1 signaling axis. Targeting this pathway could improve radiosensitivity and provide a promising therapeutic strategy for CC patients.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"328"},"PeriodicalIF":6.1,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11908104/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143634255","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}