Journal of Translational Medicine最新文献

{"title":"Dietary and circulating omega-6 fatty acids and their impact on cardiovascular disease, cancer risk, and mortality: a global meta-analysis of 150 cohorts and meta-regression.","authors":"Reza Sadeghi, Mostafa Norouzzadeh, Minoo HasanRashedi, Sanaz Jamshidi, Hamid Ahmadirad, Mahdi Alemrajabi, Mohammadreza Vafa, Farshad Teymoori","doi":"10.1186/s12967-025-06336-2","DOIUrl":"10.1186/s12967-025-06336-2","url":null,"abstract":"<p><strong>Background: </strong>Despite the significant increase in omega-6 fatty acid consumption, evidence regarding their health impacts remains inconsistent. This study performs an umbrella review and updated meta-analysis to evaluate the association between dietary and circulating omega-6 levels and the risks of cardiovascular diseases (CVDs), cancer, and mortality.</p><p><strong>Methods: </strong>A systematic search was conducted in PubMed, Scopus, and Web of Science until January 2024 to identify eligible meta-analyses of prospective observational studies. The Cochrane risk of bias and GRADE tools were used to assess the risk of bias and certainty of the evidence, respectively.</p><p><strong>Results: </strong>Analysis of 150 publications revealed that higher dietary intake and circulating levels of omega-6 were associated with lower risks of CVDs, cancer incidence, and all-cause mortality in the general population, particularly for coronary heart disease and stroke. While omega-6 intake was linked to lower risks of lung and prostate cancers, it was associated with higher risks of ovarian and endometrial cancers. Subgroup analyses revealed that these protective associations were more pronounced in cohort studies and absent in populations with pre-existing health conditions.</p><p><strong>Conclusions: </strong>Higher dietary intake and circulating levels of omega-6 fatty acids were associated with lower risks of CVDs, cancers, and all-cause mortality. However, the associations vary by cancer type and are less evident in individuals with pre-existing health conditions. These findings highlight the potential benefits of omega-6 fatty acids for public health while underscoring the need for further research to address specific risks and underlying mechanisms.</p><p><strong>Trial registration: </strong>Registration number (PROSPERO): CRD42024522842.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"314"},"PeriodicalIF":6.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11899657/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143615881","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":"Decreased complement 4 and interleukin-10 as biomarkers in aqueous humour for non-exudative age-related macular degeneration: a case control study.","authors":"Juliane Schikora, Aaron Dort, Hannah N Wolf, Mihály Józsi, Richard B Pouw, Thomas Bertelmann, Dirk Bahlmann, Christian van Oterendorp, Nicolas Feltgen, Hans Hoerauf, Diana Pauly, Jannis Klemming","doi":"10.1186/s12967-024-05909-x","DOIUrl":"10.1186/s12967-024-05909-x","url":null,"abstract":"<p><strong>Background: </strong>The development of age-related macular degeneration (AMD) is influenced by risk factors that contribute to inflammatory processes, cellular stress responses, and a dysregulation of the complement system. Given the incomplete understanding of the pathogenesis of AMD and the necessity for novel therapeutics, biomarker studies investigating aqueous humour from the anterior chamber of the eye serve as a valuable tool. This pilot study aimed to assess inflammatory mediators and complement components in aqueous humour of non-exudative AMD patients in comparison with a control group.</p><p><strong>Methods: </strong>The aqueous humour of 12 non-exudative AMD patients and 21 control subjects was collected during cataract surgery. Levels of 78 inflammatory proteins and complement components were measured using multiplex immunoassays. The influence of sex or smoking on the AMD status was assessed using Pearson's chi-square test. Biomarker levels between AMD patients vs. controls, smokers vs. non-smokers, and females vs. males were compared. Parametric datasets were analysed using independent-means t-test, while non-parametric data analysis was conducted utilising Wilcoxon's rank-sum test. Spearman's correlation investigated associations between drusen volume and biomarker levels, as well as biomarker levels and subject age.</p><p><strong>Results: </strong>All examined 78 immunological factors were detectable in aqueous humour. The proteins were categorised into high, medium, and low level groups. Aqueous humour contained high levels of complement proteins, including iC3b, FH/FHL-1, C4B, and FI. Non-exudative AMD patients exhibited decreased levels of C4 (P = 0.020), IL-10 (P = 0.033), and FI (P = 0.082). A positive correlation was observed between drusen volume and CCL4 levels (r_S = 0.78, P = 0.013). Furthermore, smokers demonstrated significantly increased levels of pro-inflammatory proteins (CCL7, IL-7; P = 0.027, P = 0.030). MMP-1 was positively correlated with age (r_S = 0.44, P = 0.010), while sex differences were observed in FB (P = 0.027) and C4B (P = 0.036) levels.</p><p><strong>Conclusions: </strong>This pilot study presents an initial overview of inflammation-associated biomarkers in the aqueous humour, highlighting potential roles for C4 and IL-10 in the development of non-exudative AMD. A larger, more-focused follow-up study is in progress to further investigate biomarkers localised to the eye and refine our understanding of AMD.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"317"},"PeriodicalIF":6.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11905602/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143615878","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":"IP6K2 mutations as a novel mechanism of resistance to oncolytic virus therapy.","authors":"Zhijian Huang, Xiangqian Zhao, Zirong Jiang, Xiaoting Qiu, Xinhao Sun, Dawei Wang, Hucheng Zhang, Qi Chen, Ruirong Tan, Yangkun Shen","doi":"10.1186/s12967-025-06265-0","DOIUrl":"10.1186/s12967-025-06265-0","url":null,"abstract":"<p><strong>Background: </strong>Oncolytic virus therapy (OVT) represents a promising frontier in cancer treatment. Despite its efficacy in clinical trials, variability in patient response, particularly resistance development, highlights the need for tailored therapeutic strategies.</p><p><strong>Methods: </strong>The Inositol Hexakisphosphate Kinase 2 (IP6K2) gene knock out was carried by CRISPR/Cas9 system. The evaluation of biomarkers of apoptosis and relevant pathways was conducted to be assessed. Attachment assay was conducted to verify the binding ability of virus to the host cells. Cell proliferation and apoptosis was assessed. Subcutaneous xenograft model was used to evaluate IP6K2 knock out influence in vivo. cBioPortal and TCGA database were applied to analyze genomic alterations in pan-cancer.</p><p><strong>Results: </strong>IP6K2 was essential for effective Herpes Simplex Virus Type1 (HSV-1) replication and subsequent cell apoptosis, acting through the tumor Protein p53 (p53) and Cyclin-Dependent Kinase Inhibitor 1 A (p21) signaling axis. The tumor model demonstrated that tumors lacking IP6K2 exhibited resistance to HSV-1 oncolysis, resulting in diminished therapeutic outcomes. Analysis of cBioPortal and TCGA databases corroborated the potential resistance stemming from IP6K2 mutations across various cancer types, underscoring the necessity for pre-treatment IP6K2 status assessment.</p><p><strong>Conclusions: </strong>This study underscores the role of IP6K2 as potential markers of resistance, which opens avenues for precision medicine approaches in OVT.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"311"},"PeriodicalIF":6.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11900485/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143615892","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":"Notch signaling in the tumor immune microenvironment of colorectal cancer: mechanisms and therapeutic opportunities.","authors":"Jiachun Sun, Yi Chen, Ziyi Xu, Weizheng Wang, Penghui Li","doi":"10.1186/s12967-025-06282-z","DOIUrl":"10.1186/s12967-025-06282-z","url":null,"abstract":"<p><p>Colorectal cancer (CRC) remains a leading cause of cancer-related morbidity and mortality worldwide, driven by a complex interplay of genetic, environmental, and immune-related factors. Among the pivotal pathways implicated in CRC tumorigenesis, the Notch signaling pathway is instrumental in governing cell fate decisions, tissue renewal, homeostasis, and immune cell development. As a highly conserved mechanism, Notch signaling not only modulates tumor cell behavior but also shapes the immune landscape within the tumor microenvironment (TME). Aberrant Notch signaling in CRC fosters immune evasion and tumor progression through its effects on the balance and functionality of immune cells, including myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs). Elevated Notch pathway activation correlates with advanced clinicopathological features and poorer clinical outcomes, highlighting its relevance as both a prognostic biomarker and a therapeutic target. Therapeutic approaches aimed at inhibiting the Notch pathway, such as γ-secretase inhibitors (GSIs) or monoclonal antibodies (mAbs) in combination with other therapies, have demonstrated promising efficacy in preclinical and clinical settings. This review examines the impact of Notch signaling on CRC immunity, elucidating its regulatory mechanisms within immune cells and its role in promoting tumor progression. Additionally, this review discusses therapeutic strategies targeting Notch signaling, including GSIs, mAbs, and potential combination therapies designed to overcome resistance and improve patient outcomes. By elucidating the multifaceted role of Notch within the CRC TME, this review underscores its potential as a target for innovative therapeutic strategies.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"315"},"PeriodicalIF":6.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11900264/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143615831","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":"Metabolic expression profiling analysis reveals pyruvate-mediated EPHB2 upregulation promotes lymphatic metastasis in head and neck squamous cell carcinomas.","authors":"Jingjing Miao, Boyu Chen, Lu Zhang, Zhongming Lu, Rui Wang, Chunyang Wang, Xingyu Jiang, Qi Shen, Yue Li, Dongni Shi, Ying Ouyang, Xiangfu Chen, Xiaowu Deng, Siyi Zhang, Hequn Zou, Shuwei Chen","doi":"10.1186/s12967-025-06305-9","DOIUrl":"10.1186/s12967-025-06305-9","url":null,"abstract":"<p><p>Lymphatic metastasis is a well-known factor for initiating distant metastasis of head and neck squamous cell carcinoma (HNSCC), which caused major death in most patients with cancer. Meanwhile, metabolic reprogramming to support metastasis is regarded as a prominent hallmark of cancers. However, how metabolic disorders drive in HNSCC remains unclear. We firstly established a new classification of HNSCC patients based on metabolism gene expression profiles from the TCGA and GEO database, and identified an enriched carbohydrate metabolism subgroup which was significantly associated with lymphatic metastasis and worse clinical outcome. Moreover, we found that highly activated pyruvate metabolism endowed tumors with EPHB2 upregulation and promoted tumor lymphangiogenesis independently of VEGF-C/VEGFR3 signaling pathway. Mechanically, high nuclear acetyl-CoA production from pyruvate metabolism promoted histone acetylation, which in turn transcriptionally upregulated EPHB2 expression and secretion in tumor cells. EPHB2 bound with EFNB1 in lymphatic endothelial cells promoted YAP/TAZ cytoplasmic retention, which alleviated YAP/TAZ-mediated prospero homeobox protein 1 (PROX1) transcriptional repression, and then triggered tumor lymphangiogenesis. Importantly, combined treatment with EFNB1-Fc and VEGFR3 inhibitor synergistic abrogated lymphangiogenesis in vitro and in vivo, suggesting that targeting EPHB2 might be a potential strategy to patients with no or slight response to VEGFR3 inhibitor. These findings uncover the mechanism by which pyruvate metabolism is linked to lymphatic metastasis of tumor and provides a promising therapeutic strategy for the prevention of HNSCC metastasis.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"316"},"PeriodicalIF":6.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11899055/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143615898","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":"The FKBPL-based therapeutic peptide, AD-01, protects the endothelium from hypoxia-induced damage by stabilising hypoxia inducible factor-α and inflammation.","authors":"Sahar Ghorbanpour, Siân Peta Cartland, Hao Chen, Sanchit Seth, Rupert C Ecker, Claire Richards, Dunja Aksentijevic, Matthew P Padula, Louise Cole, Majid Ebrahimi Warkiani, Mary Meltem Kavurma, Lana McClements","doi":"10.1186/s12967-025-06118-w","DOIUrl":"10.1186/s12967-025-06118-w","url":null,"abstract":"<p><strong>Background: </strong>Endothelial dysfunction is a hallmark feature of cardiovascular disease (CVD), yet the underlying mechanisms are still poorly understood. This has impeded the development of effective therapies, particularly for peripheral artery disease. FK506-binding protein like (FKBPL) and its therapeutic peptide mimetic, AD-01, are crucial negative regulators of angiogenesis, however their roles in CVD are unknown. In this study, we aimed to elucidate the FKBPL-mediated mechanisms involved in regulating endothelial dysfunction induced by hypoxia or inflammation, and to determine whether AD-01 can effectively restore endothelial function under these conditions.</p><p><strong>Methods: </strong>Hindlimb ischemia was induced in mice by ligating the proximal and distal ends of the right femoral artery, and, after three days, the gastrocnemius muscle was collected for immunofluorescence staining, and RNA extraction. A 3D in vitro microfluidics model was developed to determine the endothelial cell migration and impact of FKBPL following treatments with: (i) 24 µM FKBPL targeted siRNA, (ii) 1 mM hypoxia inducible factor (HIF-1)α activator (DMOG), (iii) 50% (v/v) macrophage conditioned media (MCM), ± 100 nM AD-01. Unbiased, untargeted proteomic analysis was conducted via LC-MS/MS to identify protein targets of AD-01.</p><p><strong>Results: </strong>FKBPL expression is substantially downregulated in mice after hindlimb ischemia (p < 0.05, protein; p < 0.001, mRNA), correlating with increased neovascularization and altered vascular adhesion molecule expression. In our real-time advanced 3D microfluidics model, hypoxia suppressed FKBPL (p < 0.05) and VE-cadherin (p < 0.001) expression, leading to increased endothelial cell number and migration (p < 0.001), which was restored by AD-01 treatment (p < 0.01). Under inflammatory conditions, FKBPL (p < 0.01) and HIF-1α (p < 0.05) expression was elevated, correlating with increased endothelial cell migration (p < 0.05). Unlike hypoxia, AD-01 did not influence endothelial cell migration under inflammatory conditions, but normalized FKBPL (p < 0.001), HIF-1α (p < 0.05) and CD31 (P < 0.05), expression, in 3D microfluidic cell culture. Proteomic analysis revealed that AD-01 treatment in hypoxia enhanced the abundance of tissue remodelling and vascular integrity proteins including collagen alpha-1(XIX) chain and junctional cadherin associated-5 (JCAD) proteins.</p><p><strong>Conclusions: </strong>FKBPL represents an important novel mechanism in hypoxia and inflammation-induced angiogenesis. The FKBPL-based therapeutic peptide, AD-01, could be a viable treatment option for CVD-related endothelial cell dysfunction.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"309"},"PeriodicalIF":6.1,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11895374/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143605028","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 analysis identifies MKI67⁺ microglia as drivers of neovascularization in proliferative diabetic retinopathy.","authors":"Keyi Zou, Xue Li, Bibo Ren, Fu Cheng, Jian Ye, Zelin Ou","doi":"10.1186/s12967-025-06320-w","DOIUrl":"10.1186/s12967-025-06320-w","url":null,"abstract":"<p><strong>Background: </strong>Proliferative diabetic retinopathy (PDR) is among the primary causes of blindness in individuals with diabetes. Elevated lactate levels have been identified as a critical biomarker associated with the prognosis of PDR. While significant lactate accumulation has been observed in the vitreous fluid of PDR patients, the detailed pathways through which lactate impacts pathological neovascularization remain insufficiently elucidated.</p><p><strong>Methods: </strong>The study employed single-cell RNA sequencing (scRNA-seq) to identify and characterize lactate-associated cell type in PDR patients. Key gene expression profiles and molecular pathways associated with lactate metabolism were analyzed. In vitro experiments were conducted using microglial cell cultures treated with high-glucose conditions (50 mM) to assess the induction of lactate metabolism-related genes. Additionally, an oxygen-induced retinopathy (OIR) mouse model was used to evaluate the impact of abemaciclib, an FDA-approved proliferation inhibitor, on retinal neovascularization.</p><p><strong>Results: </strong>To the best of our knowledge, this investigation is the first to delineate a novel microglial subset, designated as MKI67⁺ microglia, distinguished by robust upregulation of genes implicated in lactate metabolic processes and proliferation, such as MKI67, PARK7 and LDHA, as well as a pronounced enrichment of glycolysis-associated molecular pathways. This unique cell type promotes angiogenesis by interacting with endothelial cells via secreted phosphoprotein 1 (SPP1)-Integrin alpha 4 (ITGA4) signaling. In vitro experiments have shown the use of 50 mM high glucose to simulate microglia in PDR environment and observe its promotion of vascular proliferation. In the in vivo OIR model, treatment with abemaciclib, a FDA-approved proliferation inhibitor, significantly reduced neovascularization.</p><p><strong>Conclusion: </strong>The identification of MKI67⁺ microglia as a cell type strongly associated with lactate metabolism provides a novel perspective on the mechanisms underlying PDR onset. These findings expand our understanding of the cellular and metabolic dynamics in PDR, emphasizing potential implications for targeted therapeutic interventions.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"310"},"PeriodicalIF":6.1,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11899098/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143604909","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":"Targeted long-read sequencing facilitates effective carrier screening for complex monogenic diseases including spinal muscular atrophy, α-/β-thalassemia, 21-hydroxylase deficiency, and fragile-X syndrome.","authors":"Shuyuan Li, Renyi Hua, Xu Han, Yan Xu, Ming Li, Li Gao, Ruiyu Ma, Wanli Meng, Aiping Mao, Jian Wang, Yanlin Wang","doi":"10.1186/s12967-025-06345-1","DOIUrl":"10.1186/s12967-025-06345-1","url":null,"abstract":"<p><strong>Background: </strong>Next-generation sequencing (NGS) has been applied for carrier screening, effectively reducing the incidence of severe diseases. However, some severe, high-prevalent and complex diseases, including spinal muscular atrophy (SMA), α-/β-thalassemia, 21-hydroxylase deficiency (21-OHD), and fragile-X syndrome (FXS), cannot be fully addressed by NGS, resulting in a high residual risk ratio. This study aims to evaluate the clinical utility of a long-read sequencing (LRS) panel for carrier screening of these five complex diseases.</p><p><strong>Methods: </strong>A total of 2926 participants were retrospectively enrolled from International Peace Maternity and Child Health Hospital from Jan 2019 to Dec 2022. All the participants were previously screened for 149 genes correlated to 147 diseases by NGS. The samples were collected and analyzed with the LRS panel targeting the five complex diseases.</p><p><strong>Results: </strong>LRS identified 236 carrier variants, including 54 for SMA, 113 for α-thalassemia, 19 for β-thalassemia, 47 for 21-OHD, and three for FXS. NGS identified only 56.4% (133/236) of the variants detected by LRS. NGS failed to detect three SMA carriers with SMN1 intragenic variants, while reported 10 false-positive carriers for α-thalassemia (HKαα miscalled as -α3.7). Both 21-OHD and FXS were beyond its detection scope. NGS identified only three of the seven at-risk couples determined by LRS. The total estimated at-risk couple rate for 151 genes in NGS and LRS panels was 1.0996%. SMA, α-/β-thalassemia, 21-OHD, and FXS were among the top 30 high-prevalent diseases and had a combined at-risk couple rate of 0.2433%, accounting for 22.1% of the total ratio. NGS could only identify 22.7% of the at-risk couples for the five diseases in the LRS panel.</p><p><strong>Conclusions: </strong>Comprehensive carrier screening for high-prevalent diseases had higher clinical utility than expanding the list of low-prevalent diseases. Incorporating LRS into the NGS carrier screening strategy would facilitate more effective carrier screening.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"307"},"PeriodicalIF":6.1,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11895162/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143604932","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":"CNV-mediated dysregulation of the ceRNA network mechanism revealed heterogeneity in diffuse and intestinal gastric cancers.","authors":"Rongji Xu, Danni He, Rui Sun, Jiaqi Zhou, Mengyu Xin, Qian Liu, Yifan Dai, Houxing Li, Yujie Zhang, Jiatong Li, XinXin Shan, Yuting He, Borui Xu, Qiuyan Guo, Shangwei Ning, Yue Gao, Peng Wang","doi":"10.1186/s12967-025-06222-x","DOIUrl":"10.1186/s12967-025-06222-x","url":null,"abstract":"<p><strong>Background: </strong>Gastric cancer (GC) is a highly heterogeneous tumour with high morbidity. Approximately 95% of GC cases are gastric adenocarcinomas, which are further categorized into two predominant subtypes: diffuse gastric cancer (DGC) and intestinal gastric cancer (IGC). These subtypes exhibit distinct pathophysiological and molecular characteristics, reflecting their unique tumorigenic mechanisms.</p><p><strong>Method: </strong>In this study, we employed a comprehensive approach to identify driver genes associated with DGC and IGC by focusing on copy number variation (CNV) genes within the competing endogenous RNA (ceRNA) network. The influence of driver CNV genes on the molecular, cellular, and clinical differences between DGC and IGC was subsequently analysed. Finally, therapeutic strategies for DGC and IGC were evaluated based on the status and functional pathways of the driver CNV genes.</p><p><strong>Results: </strong>A total of 17 and 22 driver CNV genes were identified in DGC and IGC, respectively. These genes drive subtype differences through the ceRNA network, resulting in alterations in the tumour microenvironment (TME). Based on these differences, personalized treatment strategies for DGC or IGC could be developed. Immune checkpoint inhibitors may be an effective treatment option in IGC. Additionally, DGC patients with homozygous deletion of PPIF might benefit from adjuvant chemotherapy, whereas those with high-level amplification of MTAP could respond to targeted therapy.</p><p><strong>Conclusion: </strong>Driver CNV genes were identified to reveal the underlying cause of heterogeneity in DGC and IGC. Furthermore, specific driver CNV genes were identified as potential therapeutic targets, facilitating personalized treatment.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"308"},"PeriodicalIF":6.1,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11895245/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143605567","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":"Automated deep learning-based assessment of tumour-infiltrating lymphocyte density determines prognosis in colorectal cancer.","authors":"Joshua Millward, Zhen He, Aiden Nibali, Dmitri Mouradov, Lisa A Mielke, Kelly Tran, Angela Chou, Nicholas J Hawkins, Robyn L Ward, Anthony J Gill, Oliver M Sieber, David S Williams","doi":"10.1186/s12967-025-06254-3","DOIUrl":"10.1186/s12967-025-06254-3","url":null,"abstract":"<p><strong>Background: </strong>The presence of tumour-infiltrating lymphocytes (TILs) is a well-established prognostic biomarker across multiple cancer types, with higher TIL counts being associated with lower recurrence rates and improved patient survival. We aimed to examine whether an automated intraepithelial TIL (iTIL) assessment could stratify patients by risk, with the ability to generalise across independent patient cohorts, using routine H&E slides of colorectal cancer (CRC). To our knowledge, no other existing fully automated iTIL system has demonstrated this capability.</p><p><strong>Methods: </strong>An automated method employing deep neural networks was developed to enumerate iTILs in H&E slides of CRC. The method was applied to a Stage III discovery cohort (n = 353) to identify an optimal threshold of 17 iTILs per-mm² tumour for stratifying relapse-free survival. Using this threshold, patients from two independent Stage II-III validation cohorts (n = 1070, n = 885) were classified as \"TIL-High\" or \"TIL-Low\".</p><p><strong>Results: </strong>Significant stratification was observed in terms of overall survival for a combined validation cohort univariate (HR 1.67, 95%CI 1.39-2.00; p < 0.001) and multivariate (HR 1.37, 95%CI 1.13-1.66; p = 0.001) analysis. Our iTIL classifier was an independent prognostic factor within proficient DNA mismatch repair (pMMR) Stage II CRC cases with clinical high-risk features. Of these, those classified as TIL-High had outcomes similar to pMMR clinical low risk cases, and those classified TIL-Low had significantly poorer outcomes (univariate HR 2.38, 95%CI 1.57-3.61; p < 0.001, multivariate HR 2.17, 95%CI 1.42-3.33; p < 0.001).</p><p><strong>Conclusions: </strong>Our deep learning method is the first fully automated system to stratify patient outcome by analysing TILs in H&E slides of CRC, that has shown generalisation capabilities across multiple independent cohorts.</p>","PeriodicalId":17458,"journal":{"name":"Journal of Translational Medicine","volume":"23 1","pages":"298"},"PeriodicalIF":6.1,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11892243/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143597284","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}