Tianjin Medical University Cancer Institute and Hospital (TMUCIH) is the birthplace of oncology in China. It has developed into one of the largest cancer centers in China..
Abstract Background The role of extrachromosomal DNA (ecDNA)-related genes in osteosarcoma remains largely unexplored. The aim of this study is to investigate the association between ecDNA-related genes and prognosis and tumor microenvironment (TME) in osteosarcoma. Methods Differential gene expression analysis of GEO datasets was conducted to identify ecDNA-related genes in osteosarcoma. Based on bulk RNA-seq data, a novel ecDNA-related Gene Prognostic Score Model (EGPSM) was developed using an integrated framework of 101 machine learning algorithms, which was validated in training, testing, and external cohorts. The associations between risk scores, prognosis, and TME characteristics were comprehensively evaluated. Single-cell RNA sequencing (scRNA-seq) data were further analyzed to elucidate the relationship between EGPSM, pro-tumor behaviors, and immune modulation in osteosarcoma, as well as to identify key prognostic genes involved in tumor progression. Lastly, we conducted in vitro and in vivo assays to characterize the biological roles of MTDH and to elucidate its regulatory effects on CD8⁺ T cell function. Results A robust EGPSM was constructed, demonstrating superior predictive accuracy with a maximum C-index of 0.803. High-risk patients exhibited poorer survival, higher metastatic potential, and an "immune-cold" TME characterized by diminished CD8⁺ T/NK cell infiltration and impaired effector functions. Single-cell analysis confirmed the enrichment of malignant cells and depletion of T/NK populations with lower effector scores in the high-risk group. MTDH was identified as a key driver; functional assays showed it promotes proliferation and invasion while inhibiting apoptosis. Notably, MTDH knockdown potentiated CD8⁺ T-cell cytotoxicity by increasing the levels of granzyme B, IFN-γ, and perforin. Conclusion The newly developed EGPSM represents an effective tool for prognostic assessment and therapeutic stratification in osteosarcoma. MTDH may serve as a promising prognostic biomarker and therapeutic target.
Molecular characterization of non-muscle-invasive bladder cancer (NMIBC) provides critical insights into the heterogeneity of clinical outcomes and treatment responses. The integration of existing transcriptomic subtyping systems to reconcile inconsistencies would facilitate clinical translation. The Markov cluster algorithm was utilized to construct a network integrating five published bladder cancer classification systems based on transcriptional profiles, aiming to establish an integrated molecular classification framework and identify different prognostics clusters. Four integrated molecular clusters (IMC1-4) with distinct transcriptomic, genomic, proteomic and clinical characteristics were identified. IMC2 exhibited significant enrichment of FGFR3 mutations, whereas IMC4 showed predominant TP53 alterations. IMC1 and IMC3 demonstrated improved PFS following Bacillus Calmette–Guérin (BCG) instillation in patients recommended for BCG treatment per the European Association of Urology (EAU) guidelines. Using transcriptomic profiles, a single-sample classifier was developed to categorize tumors into integrated molecular clusters. This study provides an integrated classification system to understand the heterogeneity of NMIBC and establish a preclinical framework for clinical management, therapeutic targets, and monitoring of clinical trials.
Hepatocellular carcinoma (HCC) progresses rapidly with a poor prognosis due to the lack of reliable recurrence risk markers. Accurate prognostic stratification and individualized recurrence prediction remain major clinical challenges, hindering treatment optimization, particularly for adjuvant or neoadjuvant therapy. Although defects in mismatch repair (MMR) mechanisms are well studied, the role of elevated MMR protein expression-particularly post-meiotic segregation increased 2 (PMS2)-has remained unclear. This study aimed to investigate the prognostic value of PMS2 overexpression and develop an integrated predictive model to improve risk stratification and guide therapy selection. We analyzed 173 HCC patients and demonstrated that elevated PMS2 expression was significantly associated with poorer disease-free survival (DFS) (p<0.001) and overall survival (OS) (p<0.001). Cellular and animal models confirmed the pro-proliferative role of PMS2 in HCC progression. Multivariate analysis identified high PMS2 expression [HR: 3.109 (2.019-4.786), p<0.001], high Phosphorylated-Protein Kinase B (p-AKT) expression [HR: 2.201 (1.304-3.715), p=0.003], Barcelona Clinic Liver Cancer (BCLC) stage [HR: 2.635 (1.156-5.992), p=0.021], and poor pathological differentiation [HR: 1.729 (1.098-2.722), p=0.018] as independent risk factors for poor DFS. The nomogram based on these factors demonstrated good predictive performance and effectively stratified patients into high-risk and low-risk groups (p<0.001). In an exploratory analysis of a separate cohort receiving neoadjuvant immunotherapy, preliminary data suggested that high-risk patients might derive greater survival benefit (p=0.044). These findings highlight PMS2 overexpression as a potential prognostic biomarker and provide a promising predictive tool for personalized treatment planning in HCC, warranting further validation in prospective studies.
Sepsis-associated acute kidney injury (SA-AKI) is a serious complication with high mortality and lacks effective diagnostic and treatment strategies. This study aims to investigate the role of the LINC00920/miR-6834-3p/CPN1 axis in SA-AKI and evaluate its diagnostic value. Clinical serum samples and in vitro cell models were used to explore the role of the LINC00920/miR-6834-3p/CPN1 axis in SA-AKI. Serum expression of LINC00920, miR-6834-3p and CPN1 was detected to analyze their expression patterns in SA-AKI, and their diagnostic value was evaluated to verify potential biomarker utility. Dual-luciferase reporter assay, mutant construct and rescue experiments were performed to confirm the regulatory relationship of the LINC00920/miR-6834-3p/CPN1 axis. Functional experiments were conducted to detect cell injury, macrophage polarization and NET formation, so as to clarify the biological function of the axis in SA-AKI progression. Clinical analysis showed LINC00920 and CPN1 were downregulated, miR-6834-3p upregulated in SA-AKI. LINC00920 was negatively correlated with SA-AKI severity, suggesting its association with disease progression. The LINC00920/miR-6834-3p/CPN1 panel had high diagnostic value for SA-AKI and severity (AUC = 0.913, 0.912). In vitro experiments confirmed LINC00920 acts as a ceRNA to sponge miR-6834-3p and upregulate CPN1, exerting a protective role in SA-AKI by alleviating cell injury, M1 polarization and NET formation. The LINC00920/miR-6834-3p/CPN1 axis regulates SA-AKI progression, correlates with disease severity, and is a promising diagnostic biomarker.
BACKGROUND:The prognostic impact of excessive muscle loss (EML) during neoadjuvant chemoradiotherapy (NCRT) in locally advanced esophageal squamous cell carcinoma (LA-ESCC) remains unclear. METHODS:This multicenter retrospective study analyzed consecutive patients with LA-ESCC undergoing NCRT followed by esophagectomy (2014-2023). Skeletal muscle index was measured longitudinally on computed tomography at the L3 vertebra at three time points: pre-NCRT (T1), post-NCRT (T2), and pre-surgery (T3). EML was evaluated across two intervals: stage A (T1 to T2) and stage B (T2 to T3). Survival outcomes were evaluated using Cox proportional hazards and Kaplan-Meier analyses, with a two-sided P < 0.05 threshold for significance. RESULTS:Among 421 eligible patients (median follow-up 39.1 months), the 5-year overall survival (OS) and progression-free survival (PFS) rates were 60.0% and 53.9%, respectively. EML incidence was 26.6% in stage A and 37.1% in stage B. Multivariate analysis confirmed EML in both stages as independent predictors of poorer OS (stage A: hazard ratio [HR] 1.78; 95% confidence interval [CI] 1.18-2.69; P = 0.006; stage B: HR 1.83; 95% CI 1.23-2.72; P = 0.003). Stage B EML was also independently associated with worse PFS (HR 1.75; 95% CI 1.24-2.46; P = 0.001). Among patients without stage A EML, stable muscle mass in stage B predicted improved OS (HR 0.49; 95% CI 0.38-0.81; P = 0.005). No such survival benefit was observed if EML had already occurred in stage A (P > 0.05). CONCLUSIONS:EML during either NCRT or the subsequent preoperative period independently predicts worse survival in LA-ESCC. Nutritional intervention post-NCRT may improve outcomes, particularly for patients who maintain muscle mass during initial therapy.
