Testicular germ cell tumors (TGCTs) commonly occur in males between the ages of 15 and 34, accounting for 98% of testicular malignancies. Long non-coding RNAs (LncRNAs) have been reported to play important roles in TGCT proliferation, invasion, and functioned as prognostic biomarkers. Testis-specific transcript, Y-linked 14 (TTTY14), a long non-coding RNA localized on Chr Y q11.222, has been found to be a potential prognostic biomarker for laryngeal squamous cell carcinoma, gastric cancer, and osteosarcoma. The biological role of TTTY14 in TGCT is not well understood. In this study, we aim to clarify the biological role of TTTY14 in TGCT, as well as its role in TGCT survival prognosis and immunotherapy efficacy prediction through the deep mining of public data combined with the verification of cell biological experiments. We found that high TTTY14 expression was a poor survival prognostic factor in TGCT patients and the expression of TTTY14 might be regulated by copy number variation and DNA methylation. TTTY14 knockdown significantly inhibited the proliferation of TGCT in vitro. TTTY14 expression was positively correlated with immune cell dysfunction, and significantly negatively correlated with B cells, CD8⁺ T cells, and macrophages, suggesting that TTTY14 may also affect the drug sensitivity by regulating the tumor immune microenvironment. In conclusion, we revealed that lncRNA TTTY14 was a novel oncogene and a biomarker in TGCT. TTTY14 may influence the drugs sensitivity through regulating the tumor immune microenvironment.

Objective: To explore a method for evaluating the bioequivalence of acarbose based on pharmacodynamic parameters using a single-dose, randomized-sequence, three-way crossover study of acarbose test (T) and reference (R) formulations. Methods: Baseline-adjusted, pre-dose value deduction, and direct comparison methods were used to evaluate the geometric T/R ratios and 90% confidence intervals (CIs) of the ln-transformed pharmacodynamic parameters to identify the most suitable evaluation system. Twelve participants were randomly divided into three groups to receive treatment in the following sequences: TRR, RTR, and RRT, each including a 7-day washout period between treatment periods. The serum glucose concentration (baseline) was determined. Pharmacodynamic parameters, including the maximum reduction in serum glucose concentrations (ΔC_SG,max) and difference of the AUC of glucose between before and after acarbose exposure (ΔAUEC), were tested. Results: Using the direct comparison method, the geometric mean ratios of C_SG,max, AUEC_(0-2h), and AUEC_(0-4h) were 94.13%, 97.82% and 99.76%, respectively. The 90% CIs of the geometric T/R ratios for C_SG,max, AUEC_(0-2h), and AUEC_(0-4h) all fell between 80% and 125%. Conversely, ΔC_SG,max and ΔAUEC_(0-4h) were less reliable measures of acarbose bioequivalence. Conclusions: Pre-dose value deduction and direct comparison methods can be initially considered suitable for assessing acarbose bioequivalence.

Testicular germ cell tumors (TGCTs) are the most common solid malignant tumor in young men aged 20–34 years. Currently, the diagnosis and differentiation of TGCTs depend on immunohistochemical analysis, and the treatment methods are mainly surgery and chemoradiotherapy. Although immunotherapy has been applied in clinic, the response rate is not high, and also there is a lack of effective biomarkers. In this study, through high‐throughput transcriptome sequencing and public data mining, the expression of hepatitis A virus cellular receptor 2 (HAVCR2) was found to be significantly upregulated in TGCT tissue and correlated with poor prognosis. Additionally, the expression level of HAVCR2 was negatively correlated with its DNA methylation but positively correlated with its copy number level. The HAVCR2 expression level was significantly positively correlated with the infiltration of six types of immune cells, including B cells, CD4+ T cells, CD8+ T cells, neutrophils, macrophages, and myeloid dendritic cells. Also, the higher its expression level, the higher the immune cell abundance. Tumor immune dysfunction and exclusion (TIDE) scoring analysis showed that HAVCR2 was related to the responsiveness to TGCT immunotherapy. Drug sensitivity analysis revealed that HAVCR2 was related to the sensitivity of multiple antitumor drugs. This study demonstrated that HAVCR2 has high potential as a biomarker for the diagnosis, prognosis, and treatment of TGCTs.

Testicular germ cell tumors (TGCT) are the most common reproductive system malignancies in men aged 15-44 years, accounting for 95 % of all testicular tumors. Our previous studies have been shown that long non-coding RNAs (lncRNAs), such as LINC00313, TTTY14 and RFPL3S, were associated with development of TGCT. Subgrouping TGCT according to differential expressed lncRNAs and immunological characteristics is helpful to comprehensively describe the characteristics of TGCT and implement precise treatment. In this study, the TGCT transcriptome data in The Cancer Genome Atlas Program (TCGA) database was used to perform consensus clustering analysis to construct a prognostic model for TGCT. TGCT was divided into 3 subtypes C1, C2, and C3 based on the differentially expressed lncRNAs. C1 subtype was sensitive to chemotherapy drugs, while the C2 subtype was not sensitive to chemotherapy drugs, and C3 subtype may benefit from immunotherapy. We defined the C1 subtype as epidermal progression subtype, the C2 subtype as mesenchymal progression subtype, and the C3 subtype as T cell activation subtype. Subgrouping based on differentially expressed genes (DEGs) and immunological characteristics is helpful for the precise treatment of TGCT.

Rheumatoid arthritis (RA) is a chronic autoimmune disorder affecting approximately 1% of adults globally, characterized by synovial inflammation and cartilage destruction. A connection between RA and mitochondrial DNA copy number (mtDNA-CN) has been found in observational studies, but the causal relationship remains unresolved. This study is the first to integrate bidirectional Mendelian randomization (MR) and mediation analysis to explore whether RA causally affects mtDNA-CN and to identify immune cell phenotypes, particularly CD28 on CD4 + CD45RA + T cells, that mediate this relationship. This study uses publicly available summary-level data from genome-wide association studies and performs a 2-step MR analysis to investigate causal relationships between RA,731 immune cell phenotypes, and blood leukocyte mtDNA-CN. First, we used genetically predicted RA to estimate its causal effect on blood leukocyte mtDNA-CN. Second, we assessed the mediating role of 731 immune cell phenotypes in the relationship between RA and blood leukocyte mtDNA-CN. Forward MR analysis indicated that genetically predicted increased risk of RA was causally related with decreased blood leukocyte mtDNA-CN (inverse variance weighting [IVW], Beta = -0.012, standard errors = 0.004, P = .007). Reverse MR study showed no significant effect of mtDNA-CN on RA (IVW, P = .724). Replication forward MR analysis confirmed these findings (IVW, Beta = -1.174, standard errors = 0.282, P < .001). No pleiotropy was detected in the sensitivity analysis (all P > .05). Mediation MR analysis identified CD28 expression on CD4 + CD45RA + T cells as a significant mediator, accounting for 10.3% of the total effect between RA and mtDNA-CN. Our findings demonstrate a causal link between RA and reduced blood leukocyte mtDNA-CN, primarily mediated by CD28 on CD4 + CD45RA + T cells. This mediation provides novel insights into the underlying mechanisms connecting RA pathology and mitochondrial dysfunction, potentially through chronic inflammation and oxidative stress.