Identification of VASH1 as a Potential Prognostic Biomarker of Lower-Grade Glioma by Quantitative Proteomics and Experimental Verification.

Background: VASH1 is a novel angiogenic regulatory factor, that participates in the process of carcinogenesis and the development of diverse tumors. Our study aimed to investigate the expression and prognostic value of the VASH1 in Lower-Grade Glioma (LGG), to explore its functional network in LGG and its effects on biological behaviors. Methods: LGG transcriptome data, somatic mutation profiles and clinical features analyzed in the present study were obtained from the TCGA, GTEx, CCLE, CGGA, UALCAN, and GEPIA2 databases, as well as clinical data and tissue sections of 83 LGG patients in our hospital. The expression characteristics of VASH1 in LGG were investigated by univariate, multivariate, immunohistochemistry, qRT-PCR, and western-blot. Subsequently, we analyzed the prognostic significance of VASH1 in LGG patients by survival analysis, subject operation characteristic curve, correlation analysis, external validation, independent prognostic significance analysis, and clinical stratification, and confirmed its biological effect on glioma cell lines in vitro. Finally, we performed GO, KEGG, and GSEA to clarify biological functions and related pathways. CIBERSORT and ESTIMATE algorithms were used to calculate the proportion of immune cells and immune microenvironment fraction in LGG. Result: We found that VASH1 is highly expressed in LGG tissues and is associated with poor prognosis, WHO grade, IDH1 wild-type, and progressive disease (P < 0.05). Multivariate and the Nomogram model showed that high VASH1 expression was an independent risk factor for glioma prognosis and had better prognostic prediction efficacy in different LGG Patient cohorts (HR = 4.753 and P=0.002). In vitro experiments showed that knockdown of VASH1 expression in glioma cell lines caused increased glioma cell proliferation, invasion, and migration capacity. The mechanism may be related to VASH1 promoting microtubule formation and remodeling of immune microenvironment. Conclusion: Our study firstly found that high VASH1 expression was associated with poor prognosis. In addition, We identified the possible mechanism by which VASH1 functioned in LGG. VASH1 inhibits the invasion and migration of tumor cells by affecting microtubule formation and immune infiltration in the tumor microenvironment. May be an important endogenous anti-tumor factor for LGG and provide a potential biomarker for individualized treatment of LGG.

Tumor microenvironment and exosomes in brain metastasis: Molecular mechanisms and clinical application.

Metastasis is one of the important biological features of malignant tumors and one of the main factors responsible for poor prognosis. Although the widespread application of newer clinical technologies and their continuous development have significantly improved survival in patients with brain metastases, there is no uniform standard of care. More effective therapeutic measures are therefore needed to improve prognosis. Understanding the mechanisms of tumor cell colonization, growth, and invasion in the central nervous system is of particular importance for the prevention and treatment of brain metastases. This process can be plausibly explained by the "seed and soil" hypothesis, which essentially states that tumor cells can interact with various components of the central nervous system microenvironment to produce adaptive changes; it is this interaction that determines the development of brain metastases. As a novel form of intercellular communication, exosomes play a key role in the brain metastasis microenvironment and carry various bioactive molecules that regulate receptor cell activity. In this paper, we review the roles and prospects of brain metastatic tumor cells, the brain metastatic tumor microenvironment, and exosomes in the development and clinical management of brain metastases.

Efficacy and safety of endostar combined with chemoradiotherapy versus chemoradiotherapy alone in locally advanced cervical cancer: A PRISMA-compliant systematic review and meta-analysis.

BACKGROUND: To evaluate the role and safety of endostar in cervical cancer by comparing the efficacy and adverse reactions of endostar combined with concurrent chemoradiotherapy in patients with locally advanced cervical carcinoma. METHODS: The quality of the included literature was evaluated by searching the database for the comparison of endostar combined with concurrent radiotherapy and chemotherapy in cervical cancer patients; objective response rate (ORR) and disease control rate (DCR) were used as the main outcome indicators, and statistical analysis was performed using RevMan5.3 and State15.3 software. RESULTS: A total of 13 studies were included in this study, including 1057 patients with locally advanced cervical cancer, suggesting that endostar combined with chemoradiotherapy can significantly improve the objective response rate (ORR: odds ratio 3.88, 95% confidence interval 2.77-5.45, P < .00001) and disease control rate (DCR: odds ratio 4.43, 95% confidence interval 2.78-7.04; P < .00001), and there was no significant increase in treatment-related adverse reactions. CONCLUSIONS: In this meta-analysis, endostar combined with concurrent chemoradiotherapy significantly improved ORR and DCR in patients with locally advanced cervical cancer without increasing toxicity. However, this study only analyzed the short-term efficacy of endostar, and its influence on overall survival and progression-free survival needs to be further verified in large randomized controlled trials with long-term follow-up.

COQ10B Knockdown Modulates Cell Proliferation, Invasion, Migration, and Apoptosis in Esophageal Squamous Cell Carcinoma.

Objective: Esophageal squamous-cell carcinoma (ESCC) is an aggressive malignant tumor, accounting for more than 90% of esophageal cancers. However, treatments such as surgical resection, radiotherapy, and chemotherapy are unable to achieve ideal clinical outcomes. The purpose of this study was to explore the effects of COQ10B on proliferation, apoptosis, migration, and invasion of esophageal squamous-cell carcinoma (ESCC) cells. Methods: Quantitative real-time PCR (qRT-PCR) was used to detect the expression of COQ10B in ESCC and normal tissues and in ESCC cell lines (KYSE-15 and TE-1). MTT assay and flow cytometry were applied to investigate the effects of COQ10B shRNA lentivirus (LV-shCOQ10B) on ESCC cell proliferation and apoptosis, respectively. The effect of COQ10B silencing on ESCC cell migration and invasion was determined by wound healing assay and transwell invasion assay, respectively. Results: The expression of COQ10B mRNA in ESCC tissues was higher than that in surrounding tissues. The decreased COQ10B level in KYSE-15 and TE-1 cells by LV-shCOQ10B could inhibit cell proliferation, promote cell apoptosis, and reduce the ability of invasion and migration (all P < 0.05). Conclusion: COQ10B was highly expressed in human ESCC tissues. COQ10B silencing contributed to the inhibition of proliferation, invasion, and migration of ESCC cells and the promotion of cell apoptosis, suggesting COQ10B may be a potential molecular target for the diagnosis and treatment of ESCC.

The RPL4P4 Pseudogene Is a Prognostic Biomarker and Is Associated with Immune Infiltration in Glioma.

Objective: Research over the past decade has suggested important roles for pseudogenes in gliomas. Our previous study found that the RPL4P4 pseudogene is highly expressed in gliomas. However, its biological function in gliomas remains unclear. Methods: In this study, we analyzed clinical data on patients with glioma obtained from The Cancer Genome Atlas (TCGA), the Chinese Glioma Genome Atlas (CGGA), the Genotype-Tissue Expression (GTEx), and the GEPIA2 databases. We used the R language for the main analysis. Correlations among RPL4P4 expression, pathological characteristics, clinical outcome, and biological function were evaluated. In addition, the correlations of RPL4P4 expression with immune cell infiltration and glioma progression were analyzed. Finally, wound healing, Transwell, and CCK-8 assays were performed to analyze the function of RPL4P4 in glioma cells. Result: We found that RPL4P4 is highly expressed in glioma tissues and is associated with poor prognosis, IDH1 wild type, codeletion of 1p19q, and age. Multivariate analysis and the nomogram model showed that high RPL4P4 expression was an independent risk factor for glioma prognosis and had better prognostic prediction power. Moreover, high RPL4P4 expression correlated with immune cell infiltration, which showed a significant positive association with M2-type macrophages. Finally, RPL4P4 knockdown in glioma cell lines caused decreased glioma cell proliferation, invasion, and migration capacity. Conclusion: Our data suggest that RPL4P4 can function as an independent prognostic predictor of glioma. It also shows that RPL4P4 expression correlates with immune cell infiltration and that targeting RPL4P4 may be a new strategy for the treatment of glioma patients.

Computational Drug Repurposing Approach to Identify Novel Inhibitors of ILK Protein for Treatment of Esophageal Squamous Cell Carcinoma.

Purpose: Esophageal squamous cell cancer (ESCC) is a deadly malignant tumor characterized by an overall 5-year survival rate below 20%, with China accounting for approximately 50% of all cases worldwide. Our previous studies have demonstrated that high integrin-linked kinase (ILK) expression plays a key role in development and progression of ESCC both in vitro and in vivo. Here, we employed the drug repurposing approach to identify a novel FDA-approved anticancer inhibitor against ILK-induced tumorigenesis and progression. Methods: We screened the ZINC15 database and predicted the molecular docking ability among FDA-approved and publicly available drugs to ILK and then performed computational docking and visual inspection analyses of the top 10 ranked drugs. Two computer-based virtual screened drugs were evaluated in vitro for their ability to directly bind purified ILK by surface plasmon resonance. Cytotoxicity of the two candidate drugs was validated in vitro using CCK-8 and LDH assays. Results: We initially selected the top 10 compounds, based on their minimum binding energy to the ILK crystal, after molecular docking and subjected them to further screening. Taking the binding energy of -10 kcal/mol as the threshold, we selected two drugs, namely, nilotinib and teniposide, for the wet-lab experiment. Surface plasmon resonance (SPR) revealed that nilotinib and teniposide had equilibrium dissociation constant (KD) values of 6.410E - 6 and 1.793E - 6, respectively, which were lower than 2.643E - 6 observed in ILK-IN-3 used as the positive control. The IC50 values for nilotinib and teniposide in ESCC cell lines were 40 µM and 200-400 nM, respectively. Results of the CCK-8 assay demonstrated that both nilotinib and teniposide significantly inhibited proliferation of cells (P < 0.01). LDH results revealed that both drugs significantly suppressed the rate of cell death (P < 0.01). Conclusion: The drug repositioning procedure can effectively identify new therapeutic tools for ESCC. Our findings suggest that nilotinib and teniposide are efficacious inhibitors of ILK and thus have potential to target ILK-mediated signaling pathways for management of ESCC.

The Role of Exosomal miRNAs in Glioma: Biological Function and Clinical Application.

Gliomas are complex and heterogeneous central nervous system tumors with poor prognosis. Despite the increasing development of aggressive combination therapies, the prognosis of glioma is generally unsatisfactory. Exosomal microRNA (miRNA) has been successfully used in other diseases as a reliable biomarker and even therapeutic target. Recent studies show that exosomal miRNA plays an important role in glioma occurrence, development, invasion, metastasis, and treatment resistance. However, the association of exosomal miRNA between glioma has not been systemically characterized. This will provide a theoretical basis for us to further explore the relationship between exosomal miRNAs and glioma and also has a positive clinical significance in the innovative diagnosis and treatment of glioma.

Liquid biopsy in central nervous system tumors: the potential roles of circulating miRNA and exosomes.

The Central nervous system (CNS) tumor still remains the most lethal cancer, and It is hard to diagnose at an earlier stage on most occasions. It is found that recurrent disease is finally observed in patients who occurred chemo-resistance after completely primary treatment. It is a challenge that monitoring treatment efficacy and tumor recurrence of CNS tumors are full of risks and difficulties by brain biopsies. However, the brain biopsies are considered as an invasive technique with low specificity and low sensitivity. In contrast, the liquid biopsy is based on blood and cerebrospinal fluid (CSF) test, which is going to acceptable among the patients through it's minimally invasive and serial bodily fluids. The advantages of liquid biopsy are to follow the development of tumors, provide new insights in real time, and accurate medical care. The major analytical constituents of liquid biopsy contain the Circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), circulating cell-free microRNAs (cfmiRNAs), and circulating exosomes. Liquid biopsy has been widely utilized in CNS tumors in recent years, and the CTCs and ctDNA have become the hot topics for researching. In this review, we are going to explain the clinical potential of liquid biopsy biomarkers in CNS tumor by testing circulating miRNAs and exosomes to evaluate diagnose, prognosis, and response to treatment.

Excessive fluoride increases the expression of osteocalcin in the mouse testis / 中华男科学杂志

Objective@#To observe the influence of excessive fluoride on the levels of osteocalcin and testosterone in the testis of the male mouse.@*METHODS@#Twenty-four C57BL/6J male mice were equally randomized into a normal control and a fluorosis model group, the former fed on distilled water while the latter on a solution of sodium fluoride (100 mg/L) in distilled water, both for 12 weeks. Then, the level of osteocalcin in the testis tissue was measured with the immunohistochemical streptavidin-peroxidase (SP) method and those of osteocalcin and testosterone in the serum determined by ELISA.@*RESULTS@#After 12 weeks of fluoride intervention, the level of serum osteocalcin was significantly higher in the fluorosis models than in the normal controls (［68.05 ± 5.32］ vs ［47.50 ± 5.73］ pg/mL, F = 11.901, P = 0.008), while that of testosterone markedly lower in the former than the latter group (［8.07 ± 1.35］ vs ［12.94 ± 3.09］ ng/mL, F = 2.313, P = 0.006). The results of immunohistochemical SP showed the expression of osteocalcin in the cell membrane and cytoplasm of the fluorosis models, which was evidently higher than in the normal controls.@*CONCLUSIONS@#Twelve-week intake of 100 mg/L fluoride solution can decrease the level of testosterone and increase the expression of osteocalcin in the testis of the male mouse.