Bomin Sun

Deep-Brain Stimulation for Anorexia Nervosa

OBJECTIVE Anorexia nervosa (AN) is a complex and severe, sometimes life-threatening, psychiatric disorder with high relapse rates under standard treatment. After decades of brain-lesioning procedures offered as a last resort, deep-brain stimulation (DBS) has come under investigation in the last few years as a treatment option for severe and refractory AN. METHODS AND RESULTS In this jointly written article, Sun et al. (the Shanghai group) report an average of 65% increase in body weight in four severe and refractory patients with AN after they underwent the DBS procedure (average follow-up: 38 months). All patients weighed greater than 85% of expected body weight and thus no longer met the diagnostic criteria of AN at last follow-up. Nuttin et al. (the Leuven group) describe other clinical studies that provide evidence for the use of DBS for AN and further discuss patient selection criteria, target selection, and adverse event of this evolving therapy. CONCLUSION Preliminary results from the Shanghai group and other clinical centers showed that the use of DBS to treat AN may be a valuable option for weight restoration in otherwise-refractory and life-threatening cases. The nature of this procedure, however, remains investigational and should not be viewed as a standard clinical treatment option. Further scientific investigation is essential to warrant the long-term efficacy and safety of DBS for AN.

Consensus on guidelines for stereotactic neurosurgery for psychiatric disorders

Background For patients with psychiatric illnesses remaining refractory to ‘standard’ therapies, neurosurgical procedures may be considered. Guidelines for safe and ethical conduct of such procedures have previously and independently been proposed by various local and regional expert groups. Methods To expand on these earlier documents, representative members of continental and international psychiatric and neurosurgical societies, joined efforts to further elaborate and adopt a pragmatic worldwide set of guidelines. These are intended to address a broad range of neuropsychiatric disorders, brain targets and neurosurgical techniques, taking into account cultural and social heterogeneities of healthcare environments. Findings The proposed consensus document highlights that, while stereotactic ablative procedures such as cingulotomy and capsulotomy for depression and obsessive-compulsive disorder are considered ‘established’ in some countries, they still lack level I evidence. Further, it is noted that deep brain stimulation in any brain target hitherto tried, and for any psychiatric or behavioural disorder, still remains at an investigational stage. Researchers are encouraged to design randomised controlled trials, based on scientific and data-driven rationales for disease and brain target selection. Experienced multidisciplinary teams are a mandatory requirement for the safe and ethical conduct of any psychiatric neurosurgery, ensuring documented refractoriness of patients, proper consent procedures that respect patients capacity and autonomy, multifaceted preoperative as well as postoperative long-term follow-up evaluation, and reporting of effects and side effects for all patients. Interpretation This consensus document on ethical and scientific conduct of psychiatric surgery worldwide is designed to enhance patient safety.

Subthalamus deep brain stimulation for primary dystonia patients: a long-term follow-up study.

Deep brain stimulation has generated sustained improvement in motor function for patients with dystonia, but the long‐term impact of subthalamic nucleus stimulation on dystonia has not been elucidated.

Over-expression of tetraspanin 8 in malignant glioma regulates tumor cell progression.

Tumor cell invasion and proliferation remain the overwhelming causes of death for malignant glioma patients. To establish effective therapeutic methods, new targets implied in these processes have to be identified. Tetraspanin 8 (Tspn8) forms complexes with a large variety of trans-membrane and/or cytosolic proteins to regulate several important cellular functions. In the current study, we found that Tspn8 was over-expressed in multiple clinical malignant glioma tissues, and its expression level correlated with the grade of tumors. Tspn8 expression in malignant glioma cells (U251MG and U87MG lines) is important for cell proliferation and migration. siRNA-mediated knockdown of Tspn8 markedly reduced in vitro proliferation and migration of U251MG and U87MG cells. Meanwhile, Tspn8 silencing also increased the sensitivity of temozolomide (TMZ), and significantly increased U251MG or U87MG cell death and apoptosis by TMZ were achieved with Tspn8 knockdown. We observed that Tspn8 formed a complex with activated focal adhesion kinase (FAK) in both human malignant glioma tissues and in above glioma cells. This complexation appeared required for FAK activation, since Tspn8 knockdown inhibited FAK activation in U251MG and U87MG cells. These results provide evidence that Tspn8 contributes to the pathogenesis of glioblastoma probably by promoting proliferation, migration and TMZ-resistance of glioma cells. Therefore, targeting Tspn8 may provide a potential therapeutic intervention for malignant glioma.

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.

Subthalamic nucleus deep brain stimulation for Parkinson's disease: 8 years of follow-up.

ObjectiveThe short-term benefits of bilateral stimulation of the subthalamic nucleus (STN) in patients with advanced Parkinson’s disease (PD) are well documented, but long-term benefits are still uncertain. The aim of this study is to evaluate the outcome of 8 years of bilateral STN stimulation to PD patients.MethodsIn this study, 31 consecutive PD patients were treated with bilateral STN stimulation. Their functional status was measured using the Activities of Daily Living section of the Unified Parkinson’s Disease Rating Scale (UPDRS-ADL) at drug on (with medication) and drug off (without medication) states preoperatively and at 1, 5, and 8 years postoperatively. In addition, Levodopa equivalent doses and stimulation parameters were also assessed.ResultsAfter 8 years of STN stimulation, the UPDRS-ADL scores were improved by 4% at drug off status (P > 0.05) and 22% at drug on status (P < 0.05) compared with baseline; the levodopa daily doses were reduced by 28% (P < 0.05) compared with baseline; the stimulation voltage and pulse width were not changed, but the stimulation frequency was decreased remarkably compared with the 5 years of follow-up. Adverse events were observed in 6 patients, including misplacement of the electrode and skin erosion requiring further surgery. All events were resolved without permanent sequelae. 2 patients died of aspiration pneumonia 6 and 7 years after surgery.ConclusionsThe marked improvement in UPDRS-ADL scores were still observed after 8 years of bilateral STN stimulation with medication.

Study on iron purification from aluminium melt by Na2B4O7 flux

Abstract A study was carried out to investigate the effect of Na2B4O7 on the reduction of Fe concentration from commercial purity aluminium. Experiments were conducted and the double barrier layers theory was used to study the kinetics of the purification process. Results showed that the iron reduction ratio increased with the addition of Na2B4O7 and the holding time, which follows the first order exponential decay law. The addition of Na2B4O7 containing flux could reduce iron content from 0·14 wt-% to less than 0·1 wt-% and achieve an optimal ratio of 44%. Thermodynamic calculations and the XRD, SEM and EDX analyses of the molten sludge indicated that formation of Fe2B could occur spontaneously in molten aluminium with the addition of Na2B4O7 containing flux.

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.

Long-Term Follow-Up of MRI-Guided Bilateral Anterior Capsulotomy in Patients with Refractory Schizophrenia

Aim: To determine whether there is a long-term benefit of MRI-guided bilateral anterior capsulotomy in the treatment of refractory schizophrenia. Methods: 116 patients (16 patients did not complete the follow-up evaluation) with refractory schizophrenia who underwent capsulotomy were included. The treatment effect was evaluated using a series of international rating scales. Evaluations were performed at baseline, 3 weeks and 24 months after surgery. Results: The rate of effectiveness was 74% according to the Clinical Global Impression evaluation, and there was an obvious improvement based on the statistical analysis for Positive and Negative Symptom Scale (baseline vs. 24 months after surgery, 6.86 ± 8.12, 10.70 ± 8.70 vs. 26.65 ± 4.85, 21.66 ± 7.19), Brief Psychiatric Rating Scale (14.75 ± 13.21 vs. 44.97 ± 9.36), Activities of Daily Living Scale (18.06 ± 6.58 vs. 24.61 ± 8.95), Social Disability Screening Schedule (6.69 ± 6.12 vs. 15.06 ± 3.18) and Global Assessment Scale (74.35 ± 12.75 vs. 48.74 ± 9.18). Among all the symptoms of schizophrenia, aggressive behavior (82% response rate), hallucination, (71% response rate) and delusion (70% response rate) showed the best response. Conclusion: Our research indicates that capsulotomy is a relatively safe and effective intervention for patients with refractory schizophrenia. It could be an alternative therapy for those patients with chronic and severe schizophrenia. But there must be strict inclusion criteria considering the complications and irreversibility of this procedure.