LncRNA SOX2OT promotes temozolomide resistance by elevating SOX2 expression via ALKBH5-mediated epigenetic regulation in glioblastoma.

Temozolomide (TMZ) resistance is a major cause of recurrence and poor prognosis in glioblastoma (GBM). Recently, increasing evidences suggested that long noncoding RNAs (LncRNAs) modulate GBM biological processes, especially in resistance to chemotherapy, but their role in TMZ chemoresistance has not been fully illuminated. Here, we found that LncRNA SOX2OT was increased in TMZ-resistant cells and recurrent GBM patient samples, and abnormal expression was correlated with high risk of relapse and poor prognosis. Knockdown of SOX2OT suppressed cell proliferation, facilitated cell apoptosis, and enhanced TMZ sensitivity. In addition, we identified that SOX2OT regulated TMZ sensitivity by increasing SOX2 expression and further activating the Wnt5a/ß-catenin signaling pathway in vitro and in vivo. Mechanistically, further investigation revealed that SOX2OT recruited ALKBH5, which binds with SOX2, demethylating the SOX2 transcript, leading to enhanced SOX2 expression. Together, these results demonstrated that LncRNA SOX2OT inhibited cell apoptosis, promoted cell proliferation, and TMZ resistance by upregulating SOX2 expression, which activated the Wnt5a/ß-catenin signaling pathway. Our findings indicate that LncRNA SOX2OT may serve as a novel biomarker for GBM prognosis and act as a therapeutic target for TMZ treatment.

Sirtuin 1 knockdown inhibits glioma cell proliferation and potentiates temozolomide toxicity via facilitation of reactive oxygen species generation.

Malignant glioma is one of the most common types of primary malignancies in the human central nervous system. Temozolomide (TMZ) is the most commonly used drug in clinical therapy of glioma; however, chemoresistance makes glioma difficult to cure and relapse likely. Sirtuin 1 (SIRT1) serves important roles in cell proliferation, differentiation and metabolism, but the role of SIRT1 in human glioma remains largely unexplored. In the present study, SIRT1 expression was assessed in human glioma tissues and cells. RNA interference and SIRT1 inhibitor were used to determine the effect of SIRT1 on glioma growth inhibition and glioma cell chemoresistance in vitro and in vivo. The levels of reactive oxygen species (ROS) in glioma cells were detected with the dihydroethidium probe following SIRT1 inhibition. The results demonstrated that SIRT1 was overexpressed in glioma tissues and cells, and patients with higher SIRT1 expression exhibited poorer prognosis. SIRT1 inhibition inhibited the proliferation of U87 and U251 cells. In addition, SIRT1 knockdown and SIRT1 inhibitor could significantly sensitize glioma cells to TMZ treatment in vitro and in vivo. The expression of Ki67 and p53 was demonstrated to be regulated by SIRT1. Finally, SIRT1 could regulate intracellular ROS generation in TMZ. In summary, SIRT1 was essential for glioma tumorigenesis and glioma cell chemoresistance. SIRT1 inhibition increased the sensitivity of glioma cells for TMZ via the facilitation of intracellular ROS generation, which suggested that SIRT1 may serve as a target for clinical therapy of glioma.

Effect of Tranexamic Acid in Patients with Traumatic Brain Injury: A Systematic Review and Meta-Analysis.

OBJECTIVE: Tranexamic acid (TXA) reduces hemorrhage volume and consequently the need for operative intervention. However, its effectiveness and safety in patients with traumatic brain injury (TBI) is unclear. We conducted this systematic review and meta-analysis to evaluate the safety and efficacy of TXA in patients with TBI. METHODS: In July 2018, a systematic search for studies including patients with TBI treated with TXA was conducted using PubMed, Embase, and the Cochrane Library databases. Only related randomized controlled trials were included. Main outcomes included hematoma expansion, surgery rate, death rate, neurologic outcome, and any thrombosis events. RESULTS: Of the identified 426 studies, 5 randomized controlled trials involving 917 patients met our inclusion criteria. For hematoma expansion, pooled results showed that TXA significantly decreased hemorrhage growth rate and total hemorrhage growth in patients with TBI. Regarding clinical outcomes, pooled results of surgery, mortality, and neurologic outcome showed no significant difference between the groups, and rate of thrombosis events was similar. Following sensitivity analysis, one study was excluded due to low quality. Then, results of TXA effect on mortality and neurologic outcomes became significant. We confirm that the earlier the TXA treatment is performed, the smaller the size of hematoma will be. CONCLUSIONS: TXA demonstrates significant effect in reducing the risk of hematoma expansion by lowering the mortality rate and improving favorable neurologic outcomes in patients with TBI while not affecting thrombosis event rates. In addition, early TXA treatment is more effective in decreasing hematomas.

Value of the Application of Neuroendoscope in the Treatment of Ventriculoperitoneal Shunt Blockage.

OBJECTIVE: To explore the value of the application of neuroendoscopy techniques in the treatment of ventriculoperitoneal (VP) shunt blockage. METHODS: Our study included 3 plans for revision surgeries for VP shunt blockage. In plan A, the choroid plexus or ependyma growing inside the ventricular catheter was completely removed. In plan B, the terminal part of the ventricular catheter was clipped and removed. In plan C, the ventricular catheter was carefully extracted with the aid of neuroendoscopy, and the tissues blocking the catheter were removed. The ventricular catheter was then reinserted into the lateral ventricle. RESULTS: The side holes of the tube may be blocked by cerebral tissue, granulation tissue, newly formed blood vessels, choroid plexus, or ependyma. Five patients successfully underwent plan A revision surgery, 8 patients underwent plan B revision surgery, and the remaining 22 patients underwent plan C revision surgery. After the operation, 34 patients experienced relief of symptoms of elevated intracranial pressure. In all patients, the shunt obstruction was resolved. CONCLUSIONS: Neuroendoscopy techniques can be used to reveal the various causes of shunt obstruction. Any attempt to extract the tube should be performed with the aid of a neuroendoscope. The 3 surgical revision strategies for a blocked catheter are described for the first time in the literature. These approaches can reduce the operation time, the incidence of intraventricular hemorrhage, and the risk of infection.

Downregulation of LKB1 promotes tumor progression and predicts unfavorable prognosis in patients with glioma.

The liver kinase B1 (LKB1)/5'-adenosine monophosphate-activated protein kinase pathway has been reported to facilitate glioma cell growth by improving growth conditions. To investigate the clinical significance of LKB1 in human gliomas western blot analysis and quantitative polymerase chain reaction experiments were performed. The present study demonstrated that LKB1 expression was markedly decreased at the messenger RNA and protein levels in 30 freshly prepared glioma tissues, compared with non-neoplastic brain tissues (P<0.001). Subsequently, immunohistochemical analysis demonstrated that LKB1 immunostaining in 180 glioma tissues was significantly decreased compared with that in the corresponding non-neoplastic brain tissues (P<0.001). Notably, this downregulation frequently occurred in high-grade gliomas, and statistical analysis revealed that low LKB1 expression was significantly associated with large tumor size (P=0.02), advanced World Health Organization grade (P=0.006) and low Karnofsky performance scale (P=0.01). The prognostic value of LKB1 expression in patients with glioma was additionally evaluated using Kaplan-Meier survival curves and Cox proportional hazards regression models. As a result, the overall survival time of patients with glioma with low LKB1 expression was shorter compared with that of patients with high LKB1 expression (P<0.001), and low LKB1 expression also indicated decreased survival time in patients with high-grade glioma (P<0.001). Collectively, the present data indicated that the downregulation of LKB1 was closely associated with the malignant degree of human gliomas, exhibiting lower expression at a higher grade. Notably, LKB1 may serve as a potential prognostic biomarker for patients with glioma following surgery.

Collaborative overexpression of matrix metalloproteinase-1 and vascular endothelial growth factor-C predicts adverse prognosis in patients with gliomas.

BACKGROUND AND AIM: Matrix metalloproteinase-1 (MMP-1), a member of the MMP family of zinc-dependent endopeptidases, has been detected to be strongly expressed in gliomas with high tumor grade and to be correlated with increased tumor invasiveness. Vascular endothelial growth factor-C (VEGF-C), which is able to induce MMP-1 transcription, has been found to be upregulated in glioblastoma compared to low grade gliomas and non-neoplastic brain. The aim of the present study was to investigate the clinical significance of the co-expression of MMP-1 and VEGF-C in glioma patients on determining the prognosis. METHODS: One hundred and sixteen glioma patients (26 World Health Organization (WHO) grade I, 30 WHO grade II, 30 WHO grade III, and 30 WHO grade IV) and 15 non-neoplastic brain specimens acquired from 15 patients undergoing surgery for epilepsy as control were collected. Immunohistochemistry was used to evaluate the expression of MMP-1 and VEGF-C in glioma and non-neoplastic brain tissues. The correlations of collaborative MMP-1 and VEGF-C expression with selected clinicopathologic parameters and clinical outcome of glioma patients were also assessed. RESULTS: Both MMP-1 and VEGF-C expression were significantly higher in glioma tissues compared to non-neoplastic brain tissues (both P<0.001). Of 116 glioma patients, 68 (58.62%) overexpressed MMP-1 and VEGF-C simultaneously. In addition, combined MMP-1 and VEGF-C expression was significantly associated with WHO grade (P<0.001) and Karnofsky performance status (KPS) score (P=0.01). Moreover, glioma patients expressing both MMP-1 and VEGF-C exhibited markedly poorer overall survival (P<0.001). According to the multivariate analyses, collaborative overexpression of MMP-1 and VEGF-C was found to be an independent prognostic factor for overall survival (P=0.009). CONCLUSIONS: Our data demonstrated for the first time that overexpression of both MMP-1 and VEGF-C may be an independent poor prognostic factor in gliomas, suggesting the interaction between MMP-1 and VEGF-C collaboratively stimulated advanced tumor progression and adverse outcome. Inhibiting both MMP-1 and VEGF-C could be a novel therapeutic approach for gliomas.