Tetraspanin 8-rictor-integrin α3 complex is required for glioma cell migration.

The malignant glioma remains one of the most aggressive human malignancies with extremely poor prognosis. Glioma cell invasion and migration are the main causes of death. In the current study, we studied the expression and the potential functions of tetraspanin 8 (Tspan8) in malignant gliomas. We found that Tspan8 expression level is high in both malignant glioma tissues and in several human glioma cell lines, where it formed a complex integrin α3 and rictor, the latter is a key component of mammalian target of rapamycin (mTOR) complex 2 (mTORC2). Disruption of this complex, through siRNA-mediated knockdown of anyone of these three proteins, inhibited U251MG glioma cell migration in vitro. We further showed that Tspan8-rictor association appeared required for mTORC2 activation. Knockdown of Tspan8 by the targeted siRNAs prevented mTOR-rictor (mTORC2) assembly as well as phosphorylation of AKT (Ser-473) and protein kinase C α (PKCα) in U251MG cells. Together, these results demonstrate that over-expressed Tspan8 in malignant glioma forms a complex with rictor and integrin α3 to mediate mTORC2 activation and glioma cell migration. Therefore, targeting Tspan8-rictor-integrin α3 complex may provide a potential therapeutic intervention for malignant glioma.

Altered immune pathways in patients of temporal lobe epilepsy with and without hippocampal sclerosis.

Over the past decades, the immune responses have been suspected of participating in the mechanisms for epilepsy. To assess the immune related pathway in temporal lobe epilepsy (TLE), we explored the altered immune pathways in TLE patients with and without hippocampal sclerosis (HS). We analyzed RNA-seq data from 3 TLE-HS and 3 TLE-nonHS patients, including identification of differentially expressed RNA, function pathway enrichment, the protein-protein interaction network and construction of ceRNA regulatory network. We illustrated the immune related landscape of molecules and pathways on human TLE-HS. Also, we identified several differential immune related genes like HSP90AA1 and SOD1 in TLE-HS patients. Further ceRNA regulatory network analysis found SOX2-OT connected to miR-671-5p and upregulated the target gene SPP1 in TLE-HS patients. Also, we identified both SOX2-OT and SPP1 were significantly upregulated in five different databases including TLE-HS patients and animal models. Our findings established the first immune related genes and possible regulatory pathways in TLE-HS patients and animal models, which provided a novel insight into disease pathogenesis in both patients and animal models. The immune related SOX2-OT/miR-671-5p/SPP1 axis may be the potential therapeutic target for TLE-HS.

Bilateral anterior capsulotomy enhances medication compliance in patients with epilepsy and psychiatric comorbidities.

OBJECTIVES: Patients with epilepsy and refractory comorbid psychiatric disorders often experience functional impairments and a lower quality of life as well as showing a lack of compliance with anti-epileptic medication regimens. We reasoned that widespread clinical benefits could be gained if the psychiatric comorbidities among these patients were reduced. In this study, we assessed the utility of anterior capsulotomy in managing medication-refractory comorbid psychotic symptoms and aggression in patients with epilepsy. METHODS: In this retrospective case series, we evaluated the clinical outcomes of 13 epilepsy patients with severe psychiatric comorbidities who had received bilateral anterior capsulotomy. Clinical outcome assessments were performed at 1 week, 6 months, 1 year, and several years after surgery focusing on: (a) severity of psychotic symptoms, as assessed by the 18-item Brief Psychiatric Rating Scale and the Positive and Negative Syndrome Scale; (b) severity of impulsivity and aggression, measured by the Barratt Impulsiveness Scale-11 and the Buss-Perry Aggression Scale; and (c) social function and quality of life, assessed by the Social Disability Screening Scale and the Quality of Life in Epilepsy. RESULTS: After anterior capsulotomy, patients displayed significant improvements of psychotic symptoms, as well as of impulsivity and aggression, along with improvements of social function and quality of life. The clinical benefits to patients were evident within 6 months after surgery and remained stable or continued to improve at a much slower rate thereafter. Furthermore, after anterior capsulotomy all patients complied with epilepsy interventions that they did not comply with prior to surgery. No significant side effects or complications occurred during the study. CONCLUSION: Anterior capsulotomy seems to be a safe and effective treatment for epilepsy patients with otherwise intractable comorbid psychotic symptoms and aggression. Moreover, this neurosurgical treatment may improve the patients' social function, quality of life, and compliance with anti-epilepsy medication regimens.

Modulations on cortical oscillations by subthalamic deep brain stimulation in patients with Parkinson disease: A MEG study.

OBJECTIVE: The study aimed to explore the modification to cortical oscillations of Parkinson disease (PD) patients by subthalamic nucleus deep brain stimulation (STN DBS). METHODS: With Magnetoencephalogram (MEG) detection, we examined the changes in absolute power spectrum of cortical oscillations in the PD patients with the treatment of STN DBS. RESULTS: The power analysis of PD patients showed a dominant over-synchronization of alpha and beta bands in temporal and occipital areas relative to the healthy control subjects. STN DBS on-state showed marked power increase in the gamma band of PD patients in the frontal and parietal relative to the DBS off-state. The alleviation of motor symptoms by STN DBS negatively correlated to the increase of high gamma oscillation in the right frontal cortex, and also correlated to the suppression of the alpha and beta oscillations in the right temporal cortex. CONCLUSION: The treatment of STN DBS to PD patients might involve the augmentation of gamma activity and suppression of alpha and beta activities in cortical oscillations.

Long-term follow-up of bilateral subthalamic deep brain stimulation for refractory tardive dystonia.

BACKGROUND: No effective treatment for tardive dystonia (TD) has been well established. Deep brain stimulation (DBS) can ameliorate motor manifestations in primary dystonia, and may also be an effective approach for TD. OBJECTIVES: This study aimed to illuminate the long-term efficacy and safety of subthalamic nucleus (STN)-DBS in treating TD. METHODS: Ten patients with refractory TD underwent STN-DBS therapy and were assessed by the Burke-Fahn-Marsden dystonia rating scale (BFMDRS), Abnormal Involuntary Movement Scale (AIMS), Hamilton Depression Scale (HAMD), Hamilton Anxiety Scale (HAMA), and the Short Form (36) Health Survey (SF-36) at four time points: pre-operation, 1 week post-operation, 6 months post-operation, and at a final long-term postsurgical follow-up time point. RESULTS: The mean follow-up time was 65.6 ± 30.4 months (range, 12-105 months). At the first follow-up, BFMDRS motor and disability scores had improved by 55.9± 28.3% and 62.6± 32.0%, respectively, while AIMS scores improved by 53.3± 26.7%. At the second follow-up, BFMDRS motor and disability scores improved further, by 87.3± 17.0% and 84.3% ± 22.9%, respectively, while AIMS scores improved by 88.4 ± 16.1%. At the last follow-up, this benefit was sustained and had plateaued. Quality of life was improved significantly at the long-term follow-up, and the HAMA and HAMD scores displayed a significant reduction that persisted after the first follow-up. CONCLUSION: STN-DBS may be an effective and acceptable procedure for TD, leading to persistent and significant improvement in both movement and psychiatric symptoms.

GSK621 Targets Glioma Cells via Activating AMP-Activated Protein Kinase Signalings.

Here, we studied the anti-glioma cell activity by a novel AMP-activated protein kinase (AMPK) activator GSK621. We showed that GSK621 was cytotoxic to human glioma cells (U87MG and U251MG lines), possibly via provoking caspase-dependent apoptotic cell death. Its cytotoxicity was alleviated by caspase inhibitors. GSK621 activated AMPK to inhibit mammalian target of rapamycin (mTOR) and downregulate Tetraspanin 8 (Tspan8) in glioma cells. AMPK inhibition, through shRNA knockdown of AMPKα or introduction of a dominant negative (T172A) AMPKα, almost reversed GSK621-induced AMPK activation, mTOR inhibition and Tspan8 degradation. Consequently, GSK621's cytotoxicity in glioma cells was also significantly attenuated by AMPKα knockdown or mutation. Further studies showed that GSK621, at a relatively low concentration, significantly potentiated temozolomide (TMZ)'s sensitivity and lethality against glioma cells. We summarized that GSK621 inhibits human glioma cells possibly via activating AMPK signaling. This novel AMPK activator could be a novel and promising anti-glioma cell agent.

Ubiquitin-protein ligase E3C promotes glioma progression by mediating the ubiquitination and degrading of Annexin A7.

The ubiquitin-protein ligase E3C (UBE3C) belongs to the E3 ligase enzyme family and implicates in the ubiquitin-proteasome pathway, thus regulates physiological and cancer-related processes. Here, we investigated the expression and roles of UBE3C in glioma. We demonstrated that UBE3C was overexpressed in glioma tissues and cell lines. Inhibition of UBE3C expression in glioma cells significantly decreased cell migration and invasion in vitro. Mechanistically, we disclosed that UBE3C physically interacted with and ubiquitinated tumor suppressor gene annexin A7 (ANXA7), resulting in ubiquitination and degradation of ANXA7. Our results also revealed that increased UBE3C expression was accompanied by a reduction in ANXA7 protein expression in glioma tissues, but not ANXA7 mRNA. Importantly, the inhibition of ANXA7 expression in gliomas cells with UBE3C interference could rescue the cell invasion. Clinically, UBE3C overexpression significantly correlated with high-grade tumors (p < 0.05), poor overall survival, and early tumor recurrence. Thus, our data reveal that high UBE3C expression contributes to glioma progression by ubiquitination and degradation of ANXA7, and thus presents a novel and promising target for glioma therapy.

S-100B and neuron specific enolase in outcome prediction of severe head injury.

OBJECTIVE: To elucidate the role of S-100B and neuron specific enolase (NSE) in predicting the outcomes of patients with severe head injury. METHODS: Forty patients with severe head injury were included in this study. The serum concentrations of S-100B and NSE were measured within 12 hours after head injury to investigate the correlation between serum levels of S-100B and NSE and outcome. Validity of both S-100B and NSE in outcome prediction was assessed with Receiver Operator Characteristic (ROC) curve. RESULTS: The serum concentrations of S-100B and NSE of both groups, with favorable or unfavorable outcomes, were significantly higher than those of the normal group. The serum concentrations within 12 hours after head injury were closely correlated with the prognosis. Furthermore, according to the ROC curves of S-100B and NSE, S-100B was found better in predicting outcomes than NSE. CONCLUSIONS: S-100B and NSE may play important roles in outcome prediction after severe head injury. Moreover, S-100B is clearly superior to NSE in terms of predictive value and appears to be a more promising serum marker in outcome prediction after severe head injury.