IMPORTANCE Chronic subdural hematoma (CSDH) is a trauma-associated condition commonly found in elderly patients. Surgery is currently the treatment of choice, but it carries a significant risk of recurrence and death. Nonsurgical treatments remain limited and ineffective. Our recent studies suggest that atorvastatin reduces hematomas and improves the clinical outcomes of patients with CSDH.OBJECTIVE To investigate the safety and therapeutic efficacy of atorvastatin to nonsurgically treat patients with CSDH. DESIGN, SETTING, AND PARTICIPANTSThe Effect of Atorvastatin on Chronic Subdural Hematoma (ATOCH) randomized, placebo-controlled, double-blind phase II clinical trial was conducted in multiple centers in China from February 2014 to November 2015. For this trial, we approached 254 patients with CSDH who received a diagnosis via a computed tomography scan; of these, 200 (78.7%) were enrolled because 23 patients (9.1%) refused to participate and 31 (12.2%) were disqualified.INTERVENTIONS Patients were randomly assigned to receive either 20 mg of atorvastatin or placebo daily for 8 weeks and were followed up for an additional 16 weeks. MAIN OUTCOMES AND MEASURESThe primary outcome was change in hematoma volume (HV) by computed tomography after 8 weeks of treatment. The secondary outcomes included HV measured at the 4th, 12th, and 24th weeks and neurological function that was evaluated using the Markwalder grading scale/Glasgow Coma Scale and the Barthel Index at the 8th week.RESULTS One hundred ninety-six patients received treatment (169 men [86.2%]; median [SD] age, 63.6 [14.2] years). The baseline HV and clinical presentations were similar between patients who were taking atorvastatin (98 [50%]) and the placebo (98 [50%]). After 8 weeks, the HV reduction in patients who were taking atorvastatin was 12.55 mL more than those taking the placebo (95% CI, 0.9-23.9 mL; P = .003). Forty-five patients (45.9%) who were taking atorvastatin significantly improved their neurological function, but only 28 (28.6%) who were taking the placebo did, resulting in an adjusted odds ratio of 1.957 for clinical improvements (95% CI, 1.07-3.58; P = .03). Eleven patients (11.2%) who were taking atorvastatin and 23 (23.5%) who were taking the placebo underwent surgery during the trial for an enlarging hematoma and/or a deteriorating clinical condition (hazard ratio, 0.47; 95% CI, 0.24-0.92; P = .03). No significant adverse events were reported.CONCLUSIONS AND RELEVANCE Atorvastatin may be a safe and efficacious nonsurgical alternative for treating patients with CSDH.

Background: Metabotropic glutamate receptors (mGluRs) are G-protein-coupled receptors that mediate neuronal excitability and synaptic plasticity in the central nervous system, and emerging evidence suggests a role of mGluRs in the biology of cancer. Previous studies showed that mGluR1 was a potential therapeutic target for the treatment of breast cancer and melanoma, but its role in human glioma has not been determined. Methods: In the present study, we investigated the effects of mGluR1 inhibition in human glioma U87 cells using specific targeted small interfering RNA (siRNA) or selective antagonists Riluzole and BAY36-7620. The anti-cancer effects of mGluR1 inhibition were measured by cell viability, lactate dehydrogenase (LDH) release, TUNEL staining, cell cycle assay, cell invasion and migration assays in vitro, and also examined in a U87 xenograft model in vivo. Results: Inhibition of mGluR1 significantly decreased the cell viability but increased the LDH release in a dose-dependent fashion in U87 cells. These effects were accompanied with the induction of caspase-dependent apoptosis and G0/G1 cell cycle arrest. In addition, the results of Matrigel invasion and cell tracking assays showed that inhibition of mGluR1 apparently attenuated cell invasion and migration in U87 cells. All these anti-cancer effects were ablated by the mGluR1 agonist L-quisqualic acid. The results of western blot analysis showed that mGluR1 inhibition overtly decreased the phosphorylation of PI3K, Akt, mTOR and P70S6K, indicating the mitigated activation of PI3K/Akt/mTOR pathway. Moreover, the anti-tumor activity of mGluR1 inhibition in vivo was also demonstrated in a U87 xenograft glioma model in athymic nude mice. Conclusion: The remarkable efficiency of mGluR1 inhibition to induce cell death in U87 cells may find therapeutic application for the treatment of glioma patients.

Our data suggest that EGFL7 expression is a novel predictive factor for the clinical progression of malignant glioma, and may constitute a therapeutic target for anti-angiogenesis therapy in patients with the disease.

No abstract

Background: Valproic acid (VPA), an established antiepileptic drug, was assessed for antitumor activity, including its effects on glioblastoma, but its role has not been determined. Methods: In the present study, we investigated VPA-induced apoptosis effects on human U87 cells by cell viability, lactate dehydrogenase (LDH) release, TUNEL/Hoechst staining and flow cytometric in vitro, then we further explored the underlying molecular mechanisms using the selective antagonists PD98059, LY294002 and SB216763. Results: The data showed that VPA dose-dependent induction of glioma U87 cells to undergo apoptosis through the mitochondria-dependent pathway in vitro. VPA activated the ERK/Akt pathways by increasing their protein phosphorylation and in turn inhibited GKS3β activation by the induction of GKS3β phosphorylation. However, the MAPK inhibitor PD98059 and/or PI3K inhibitor LY294002 were able to antagonize the effects of VPA by abolishing ERK/Akt activations and cancelling GSK3β suppression, thus it impaired VPA apoptosis-inducing effects on glioma cells. Furthermore, the GSK3β inhibitor SB216763 caused a strong suppression of GSK3β activity, which showed similar effects of VPA on regulation of protein expression and apoptosis. Conclusion: These findings suggest that GSK3β may be the central hub for VPA-induced apoptosis and VPA can be further evaluated as a novel agent for glioma therapy.

Purpose: AHNAK is originally identified as a giant protein based on the estimated size of approximately 700 kDa. The aim of this study is to identify the role of AHNAK in the pathogenesis of glioma.Methods: We tested AHNAK mRNA level in a panel of six human glioma cell lines, and in 30 cases of normal brain tissues and 73 cases of glioma tissue samples using a qRT-PCR method. Further, we analyzed the relationship of AHNAK expression with clinicopathological characteristics in glioma patients. Meanwhile, we analyzed the relationship of expression of AHNAK and survival of glioma patients in survival analyses. Then, in vitro, we analyzed the biological effects of AHNAK in glioma cell lines (U87 and U251) including proliferation assay, cell transwell assay, and apoptosis. And in vivo, we examined the effects of AHNAK on tumor growth using xenograft model of human glioma cells in nude mice. Then we examined the expression of Ki-67-positive cells in these tumors.Results: We found that the mRNA levels of AHNAK were down-regulated in 4 of 6 human glioma cell lines, especially in U87 and U251 cell lines. Meanwhile, in glioma patients, a negative correlation was found between the expression of AHNAK and the glioma histopathology. And a low expression of AHNAK was a significant and independent prognostic factor for poor survival of glioma patients. Through over expression of AHNAK in both of U87 and U251, we demonstrated that overexpression of AHNAK could inhibit glioma cell proliferation and invasion, induce apoptosis, and inhibit in vivo glioma tumor growth and ki-67 expression.Conclusions: The AHNAK acts as a potential tumor suppressor. Our study provides a preclinical basis for developing AHNAK as a reliable clinical prognostic indicator for glioma patients, and a new biomarker for treatment response, and a potentially therapeutic target in glioma management options.

No abstract

Glioblastoma multiforme (GBM) is the most malignant and common brain tumor; it is aggressive growth pattern means that GBM patients face a poor prognosis even when receiving the best available treatment modalities. In recent years, an increasing number of reports suggest that the discovery of microRNAs (miRNAs) might provide a novel therapeutic target for human cancers, including GBM. One miRNA in particular, microRNA-25 (miR-25), is overexpressed in several cancers, wherein accumulating evidence indicates that it functions as an oncogene. However, the function of miR-25 in GBM has not been totally elucidated. In this study, we demonstrated that miR-25 was significantly up-regulated in astrocytoma tissues and glioblastoma cell lines. In vitro studies further demonstrated that overexpressed miR-25 was able to promote, while its antisense oligos inhibited cell proliferation and invasion in U251 cells. Moreover, we identified neurofilament light polypeptide (NEFL) as a novel target molecule of miR-25. Also of note was the fact that NEFL was down-regulated with increased levels of miR-25 expression in human astrocytoma clinical specimens. In addition, via the mTOR signaling pathway, NEFL-siRNA could significantly attenuate the inhibitory effects of knockdown miR-25 on the proliferation and invasion of U251 cells. Overall, our results showed an important role for miR-25 in regulating NEFL expression in GBM, and suggest that miR-25 could be a potential target for GBM treatment.