CD90low glioma-associated mesenchymal stromal/stem cells promote temozolomide resistance by activating FOXS1-mediated epithelial-mesenchymal transition in glioma cells.

BACKGROUND: The tumour microenvironment contributes to chemotherapy resistance in gliomas, and glioma-associated mesenchymal stromal/stem cells (gaMSCs) are important stromal cell components that play multiple roles in tumour progression. However, whether gaMSCs affect chemotherapy resistance to the first-line agent temozolomide (TMZ) remains unclear. Herein, we explored the effect and mechanism of gaMSCs on resistance to TMZ in glioma cells. METHODS: Human glioma cells (cell line U87MG and primary glioblastoma cell line GBM-1) were cultured in conditioned media of gaMSCs and further treated with TMZ. The proliferation, apoptosis and migration of glioma cells were detected by Cell Counting Kit-8 (CCK-8), flow cytometry and wound-healing assays. The expression of FOXS1 in glioma cells was analysed by gene microarray, PCR and Western blotting. Then, FOXS1 expression in glioma cells was up- and downregulated by lentivirus transfection, and markers of the epithelial-mesenchymal transformation (EMT) process were detected. Tumour-bearing nude mice were established with different glioma cells and treated with TMZ to measure tumour size, survival time and Ki-67 expression. Finally, the expression of IL-6 in gaMSC subpopulations and its effects on FOXS1 expression in glioma cells were also investigated. RESULTS: Conditioned media of gaMSCs promoted the proliferation, migration and chemotherapy resistance of glioma cells. The increased expression of FOXS1 and activation of the EMT process in glioma cells under gaMSC-conditioned media were detected. The relationship of FOXS1, EMT and chemotherapy resistance in glioma cells was demonstrated through the regulation of FOXS1 expression in vitro and in vivo. Moreover, FOXS1 expression in glioma cells was increased by secretion of IL-6 mainly from the CD90low gaMSC subpopulation. CONCLUSIONS: CD90low gaMSCs could increase FOXS1 expression in glioma cells by IL-6 secretion, thereby activating epithelial-mesenchymal transition and resistance to TMZ in glioma cells. These results indicate a new role of gaMSCs in chemotherapy resistance and provide novel therapeutic targets.

Long-term outcome in meningiomas involving the major dural sinuses with combined therapy of subtotal resection and early postoperative gamma knife radiosurgery.

INTRODUCTION: Total resection of meningiomas involving the major dural sinuses (MIMDS) is still challenging for neurosurgeons. Gamma knife radiosurgery (GKRS) was shown to have a high probability of tumor control. The current study evaluated the clinical outcomes of patients who underwent subtotal resection alone or in combination with postoperative GKRS for the treatment of WHO grade I MIMDS. METHODS: From January 2006 to December 2016, 204 patients with MIMDS underwent Simpson IV subtotal resection in Wuhan Union Hospital. In 151 patients, no additional treatment was performed, while the tumor remnant was treated with GKRS in 53 patients. All patients were monitored with regular MR follow-ups. We retrospectively reviewed the clinical data, radiological characteristics, and outcomes of these 204 patients. Progression-free survival (PFS) was determined by Kaplan-Meier analysis. Related factors were determined by univariate Cox regression analyses. RESULTS: The mean follow-up period was 75.5 months. The tumor recurrence/progression rates were 13.9% in the microsurgery group and 3.8% in the combined therapy group (p = 0.045). The 5- and 10- year progression-free survival (PFS) rates were 92.3 and 80.7%, respectively, in the microsurgery group and 100.0 and 88.5% in the combined therapy group. Treatment approach was found to be an independent prognostic factor for tumor recurrence/progression in the univariable analyses (p=0.04). CONCLUSIONS: Compared with microsurgery alone, targeted Simpson grade IV resection combined with early gamma knife treatment resulted in longer progression-free survival without increased complications for WHO grade I MIMDS.

Similar Long-Term Clinical Outcomes of Deep Brain Stimulation With Different Electrode Targets for Primary Meige Syndrome: One Institution's Experience of 17 Cases.

OBJECTIVE: Deep brain stimulation (DBS) is considered an effective and safe treatment for patients with primary Meige syndrome (MS). Both the subthalamic nucleus (STN) and globus pallidus pars internus (Gpi) have been shown to be optional targets for electrode implantation to improve clinical symptoms, but the relationship between clinical outcomes and target is still unclear. The current study aims to compare the clinical outcomes of DBS with different electrode targets for primary MS. MATERIALS AND METHODS: We performed a retrospective study to assess the clinical outcomes for 17 consecutive patients with primary MS in Wuhan Union Hospital from January 2016 to September 2019. Six patients were treated by Gpi-DBS and 11 patients were treated by STN-DBS. All patients were assessed before surgery and at the last follow-up after surgery. The Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) including the movement and disability scales was used to evaluate the dystonia severity of the eyes, the mouth, speech, and swallowing. The median follow-up duration was 30.1 ± 13.1 months (range 6 months-52 months). RESULTS: In our study, DBS improved the BFMDRS-M scores by 70.52 ± 7.45% and the BFMDRS-D scores by 70.51 ± 8.38% for patients with MS. STN-DBS and Gpi-DBS had similar effects not only on the BFMDRS-M and BFMDRS-D scores, but also on the subitems including eyes, mouth, speech, and swallowing. The stimulation voltage for the Gpi was significantly higher than that for the STN. The improvements were similar in the general anesthesia and local anesthesia groups (p > 0.05). CONCLUSION: The curative effects of STN-DBS and Gpi-DBS on patients with primary MS are similar. Both the STN and Gpi could be effective targets of DBS for primary MS.

Roles of long non-coding RNAs in the hallmarks of glioma.

Glioma is one of the most common types of tumor of the central nervous system. Due to the aggressiveness and invasiveness of high-level gliomas, the survival time of patients with these tumors is short, at ~15 months, even after combined treatment with surgery, radiotherapy and/or chemotherapy. Recently, a number of studies have demonstrated that long non-coding RNA (lncRNAs) serve crucial roles in the multistep development of human gliomas. Gliomas acquire numerous biological abilities during multistep development that collectively constitute the hallmarks of glioma. Thus, in this review, the roles of lncRNAs associated with glioma hallmarks and the current and future prospects for their development are summarized.

Accuracy of ADC derived from DWI for differentiating high-grade from low-grade gliomas: Systematic review and meta-analysis.

OBJECTIVE: Quantitative apparent diffusion coefficient (ADC) values of diffusion weighted imaging (DWI) could be applied to grade gliomas. This meta-analysis was conducted to assess the accuracy of ADC analysis in differentiating high-grade (HGGs) from low-grade gliomas (LGGs). METHODS: PubMed, Cochrane library, Science Direct, and Embase were searched to identify suitable studies up to September 1, 2018. The quality of studies was evaluated by the quality assessment of diagnostic accuracy studies (QUADAS 2). We estimated the pooled sensitivity, specificity, positive and negative likelihood ratios (LR), diagnostic accuracy ratio (DOR) with 95% confidence intervals (CI), and determined the accuracy of the data by using the summary receiver operating characteristic (SROC) and calculating the area under the curve (AUC) to identity the accuracy of ADC analysis in grading gliomas. RESULTS: Eighteen studies including 1172 patients were included and analyzed. The pooled sensitivity, specificity, PLR, NLR, DOR, and AUC with 95% CIs of DWI with b values of 1000 s/mm for separating HGGs from LGGs were 0.81 (95% CI 0.75-0.86), 0.87 (95% CI 0.81-0.91), 6.1 (95% CI 4.2-8.9), 0.22 (95% CI 0.17-0.29), 28 (95% CI 17-45), and 0.91 (95% CI 0.88-0.93), respectively. DWI with b values of 3000 s/mm showed slightly higher accuracy than that of 1000 (sensitivity 0.80, specificity 0.90 and AUC 0.92). Meta-regression analyses showed that field strengths and b values had significant impacts on diagnostic efficacy. Deeks testing confirmed no significant publication bias in all studies. CONCLUSIONS: This meta-analysis suggested that ADC analysis of DWI have high accuracy in differentiating HGGs from LGGs. Standardized methodology is warranted to guide the use of this technique for clinical decision-making.

Preoperative MRI Evaluation of Relationship between Trigeminal Nerve and Superior Petrosal Vein: Its Role in Treating Trigeminal Neuralgia.

OBJECTIVE: To assess the value of high-resolution magnetic resonance imaging (MRI) and three-dimensional (3D) reconstruction of the trigeminal nerve and the superior petrosal vein (SPV) in visualizing their anatomical relationship in patients with trigeminal neuralgia (TN). PATIENTS AND METHODS: This study included 97 patients with primary TN who underwent preoperative 3D constructive interference in steady state (CISS) MRI. Image analysis was performed by an independent observer blinded to the operative findings and then compared with surgical data. The 3D reconstruction was assessed dynamically using MIMICS software (Materialise Inc., Leuven, Belgium). RESULTS: The 3D relationship between visible structures seen on MRI was consistent with the intraoperative findings in all patients. All cases were divided into three groups by the degree of trigeminal nerve encroachment by SPV. Statistical analysis revealed that the distance from the SPV to the trigeminal nerve was significantly different among the three groups. The diameter of the SPV also differed among the three groups. CONCLUSION: Preoperative 3D imaging provides reliable and detailed information about the intraoperative anatomical relationship between the trigeminal nerve and the SPV. This evaluation is useful for preoperative planning.

Synchronous bilateral hemifacial spasm: case-report and literature review.

Bilateral hemifacial spasm (biHFS) is an infrequent cranial nerve disorder that causes patients to suffer from severe psychological stress, and there are no reported cases of synchronous biHFS. In this study, a 46-year-old right-handed woman was diagnosed with a synchronous biHFS. After one unilateral microvascular decompression (MVD) surgery, the left facial twitching movements relieved immediately, and the right side twitching movements self-relieved the next day. Although there was a delayed hemorrhage, the patient achieved a satisfactory outcome defined as cessation of the twitching movements without recurrence. Based on the present case and related literature, we speculate that anatomical connections between bilateral facial nuclei and hyperactivity of facial nuclei play important roles in the biHFS, and they may, at least in some cases, be the decisive factors regarding the origin, development, and relief of the consequent contralateral spasm.

CD90 determined two subpopulations of glioma-associated mesenchymal stem cells with different roles in tumour progression.

Human glioma-associated mesenchymal stem cells (gbMSCs) are the stromal cell components that contribute to the tumourigenesis of malignant gliomas. Recent studies have shown that gbMSCs consist of two distinct subpopulations (CD90+ and CD90- gbMSCs). However, the different roles in glioma progression have not been expounded. In this study, we found that the different roles of gbMSCs in glioma progression were associated with CD90 expression. CD90high gbMSCs significantly drove glioma progression mainly by increasing proliferation, migration and adhesion, where as CD90low gbMSCs contributed to glioma progression chiefly through the transition to pericytes and stimulation of vascular formation via vascular endothelial cells. Furthermore, discrepancies in long non-coding RNAs and mRNAs expression were verified in these two gbMSC subpopulations, and the potential underlying molecular mechanism was discussed. Our data confirm for the first time that CD90high and CD90low gbMSCs play different roles in human glioma progression. These results provide new insights into the possible future use of strategies targeting gbMSC subpopulations in glioma patients.

Current status and potential challenges of mesenchymal stem cell-based therapy for malignant gliomas.

Glioma, which accounts for more than 30% of primary central nervous system tumours, is characterised by symptoms such as headaches, epilepsy, and blurred vision. Glioblastoma multiforme is the most aggressive, malignant, and lethal brain tumour in adults. Even with progressive combination treatment with surgery, radiotherapy, and chemotherapy, the prognosis for glioma patients is still extremely poor. Compared with the poor outcome and slowly developing technologies for surgery and radiotherapy, the application of targeted chemotherapy with a new mechanism has become a research focus in this field.Moreover, targeted therapy is promising for most solid tumours. The tumour-tropic ability of stem cells, including neural stem cells and mesenchymal stem cells, provides an alternative therapeutic approach. Thus, mesenchymal stem cell-based therapy is based on a tumour-selective capacity and has been thought to be an effective anti-tumour option over the past decades. An increasing number of basic studies on mesenchymal stem cell-based therapy for gliomas has yielded complex outcomes.In this review, we summarise the biological characteristics of human mesenchymal stem cells, and the current status and potential challenges of mesenchymal stem cell-based therapy in patients with malignant gliomas.

Gamma Knife Radiosurgery of the Superior Laryngeal Neuralgia: A Report of 3 Cases.

BACKGROUND: Superior laryngeal neuralgia (SLN) is a relatively rare disorder that is characterized by neck pain. There are only a few reported cases and treatment options for SLN to date. In this study, we report 3 patients with SLN who were treated with Gamma Knife radiosurgery (GKRS) at the time of diagnosis. CASE DESCRIPTION: For all 3 patients, GKRS was administered using a 4-mm collimator to deliver a single shot of 80 Gy of radiation (100% isodose line). The target was set at the jugular foramen where the vagus and glossopharyngeal nerves emerge from the skull. Follow-up assessments were performed at 32, 31, and 30 months after GKRS. The 3 patients described pain relief at 3 months, 2 days, and 6 weeks. None of the patients developed neurologic deficits during the follow-up period. CONCLUSIONS: This preliminary report provides encouraging evidence that GKRS represents an effective, safe, and relatively durable noninvasive treatment option for patients with SLN.

Overexpression of Tau Rescues Nogo-66-Induced Neurite Outgrowth Inhibition In Vitro.

Nogo-66 plays a central role in the myelin-mediated inhibition of neurite outgrowth. Tau is a microtubule-associated protein involved in microtubule assembly and stabilization. It remains unverified whether tau interacts directly with growth factor receptors, or engages in cross-talk with regeneration inhibitors like Nogo-66. Here, we report that plasmid overexpression of tau significantly elevated the protein levels of total tau, phosphorylated tau, and microtubule-affinity regulating kinase (MARK). Nogo-66 transiently elevated the total tau protein level and persistently reduced the level of p-S262 tau (tau phosphorylated at serine 262), whereas it had little influence on the level of p-T205 tau (tau phosphorylated at threonine 205). Nogo-66 significantly decreased the protein level of MARK. Hymenialdisine, an inhibitor of MARK, significantly reduced the level of p-S262 tau. Overexpression of tau rescued the Nogo-66-induced inhibition of neurite outgrowth in neuroblastoma 2a (N2a) cells and primary cortical neurons. However, concomitant inhibition of MARK abolished the rescue of neurite outgrowth by tau in N2a cells. We conclude that dephosphorylation of tau at S262 is able to regulate Nogo-66 signaling, and that overexpression of tau can rescue the Nogo-66-induced inhibition of neurite outgrowth in vitro.

Stereotactic injection of shrna GSK-3ß-AAV promotes axonal regeneration after spinal cord injury.

Evidence suggested that glycogen synthase kinase-3ß (GSK-3ß) is involved in Nogo-66 inhibiting axonal regeneration in vitro, but its effect in vivo was poorly understood. We showed that stereotactic injection of shRNA GSK-3ß-adeno associated virus (GSK-3ß-AAV) diminished syringomyelia and promoted axonal regeneration after spinal cord injury (SCI), using stereotactic injection of shRNA GSK-3ß-AAV (tested with Western blotting and RT-PCR) into the sensorimotor cortex of rats with SCI and by the detection of biotin dextran amine (BDA)-labeled axonal regeneration. We also determined the right position to inject into the sensorimotor cortex. Our findings consolidate the hypothesis that downregulation of GSK-3ß promotes axonal regeneration after SCI.

Gamma Knife Radiosurgery for Glossopharyngeal Neuralgia by Targeting the Medial Cisternal Segment of the Glossopharyngeal Nerve: Report of 3 Cases.

Gamma knife surgery (GKS) is now used as a treatment option for glossopharyngeal neuralgia (GPN). Most authors have selected the distal part of the nerve as the gamma knife target. Here we report on 3 patients with medically intractable GPN who were treated with GKS. All 3 patients had a single shot with a 4-mm collimator which was used to deliver 80 Gy to the 100% isodose line. The GKS targets were the medial cisternal segments of the glossopharyngeal nerve. Patients were investigated prospectively, treated, and then assessed periodically with respect to pain relief and neurological function. Three patients felt pain reduced at 2, 7, and 11 days, respectively. None of them have suffered recurrent pain since becoming pain free. The follow-up after radiosurgery was 25 months, 22 months, and 20 months, respectively. This preliminary experience provides encouraging evidence that choosing the medial cisternal segment of the glossopharyngeal nerve as the target is also an option for the treatment of GPN with stereotactic radiosurgery and is consistent with previous reports. Additional follow-ups and a larger number of patients are needed to demonstrate the long-term safety and effectiveness for this indication.

Vagoglossopharyngeal neuralgia treated by microvascular decompression and glossopharyngeal rhizotomy: clinical results of 21 cases.

BACKGROUND: Microvascular decompression (MVD) and rhizotomy are all selected for treating vagoglossopharyngeal neuralgia (VGPN). Nonetheless, controversies still exist about their curative effect on VGPN. Here we evaluate the effectiveness of MVD together with rhizotomy of the glossopharyngeal nerve for the treatment of VGPN. METHODS: This study was carried out on 21 patients who were diagnosed with VGPN between the years 2005 and 2010. Patients underwent MVD and glossopharyngeal rhizotomy through a retromastoid keyhole approach. Surgical technique, operation results and complications were our particular concern. RESULTS: Eighteen (85.7%) of 21 patients experienced immediate and complete relief of pain after surgery. In the remaining 3 patients (14.3%), the pain faded away within the following week. No patient complained of dysphonia or dysphagia. All 21 patients reported no change in their outcome at follow-up. CONCLUSIONS: Intracranial vagoglossopharyngeal nerve MVD with glossopharyngeal rhizotomy is an effective and safe procedure to treat VGPN.

GSK-3ß activation mediates Nogo-66-induced inhibition of neurite outgrowth in N2a cells.

The axons of the adult mammalian brain and spinal cord fail to regenerate after injury, and it has been suggested that Nogo-66 could prevent CNS axon repair. However, the mechanism of Nogo-66 inhibiting neurite outgrowth remains unknown. Our previous results indicated that protein kinase B (PKB) is involved in the inhibition of the neurite outgrowth by Nogo-66. Glycogen synthase kinase-3ß (GSK-3ß) is implicated in many processes in the nervous system, including differentiation, specification, polarity, plasticity and axon growth. In addition, GSK-3ß is one of the most important molecules downstream of PKB. In the present study, we report on the role of GSK-3ß signaling on Nogo-66-treated mouse neuroblastoma N2a cells. Nogo-66 reduced the phosphorylation of GSK-3ß at Ser9 in N2a cells. In contrast, pretreatment with SB216763, a specific inhibitor of GSK-3ß, resulted in an amelioration of neurite outgrowth by Nogo-66, compared with the Nogo-66 alone group (P<0.05). Moreover, we performed RNA interference experiments to knock down GSK-3ß expression levels in N2a cells via transient transfection of shRNA plasmids. The inhibition of neurite outgrowth by Nogo-66 was subdued in shRNA cells, compared to the non-RNAi cells (P<0.05). Taken together, these data suggest that GSK-3ß is involved in the inhibition by Nogo-66 of neurite outgrowth in N2a cells.

Effect of Nogo-A gene inhibition on dopamine release in PC12 cells.

OBJECTIVES: Reticulon proteins, which are localized in the endoplasmic reticulum, have recently been shown to be involved in hormone secretion, in particular RTN1 and RTN3. The aim of the present study was to examine the effects of Nogo-A gene expression knockdown by RNA interference (RNAi) on dopamine release in PC12 cells. METHODS: A small hairpin RNA (shRNA) eukaryotic expression vector, targeting the Nogo-A gene, was constructed and transfected into cultured PC12 cells by lipofecamine2000. Inhibition of Nogo-A gene expression was detected by semi-quantitative reverse transcription PCR and Western blot analysis. Following transfection, dopamine release was detected by high performance liquid chromatography. RESULTS: The pGenesil-1-Nogo-A-2 plasmid was identified by gene sequencing. After transfection of the recombinant vector in PC12 cells, Nogo-A gene expression was significantly inhibited (p<0.01). Compared with the empty vector control group, dopamine release significantly decreased within 48 hours after transfection. CONCLUSION: Results from this study suggest that Nogo-A might be involved in the mechanism of DA release in PC12 cells.

Negative correlation of Nogo-A with the malignancy of oligodendroglial tumor.

OBJECTIVE: Nogo-A is an axon regeneration inhibitor, and its function in central nervous system (CNS) is still unknown. The present study is to explore the relationship between the expression of Nogo-A and the malignancy of oligodendroglial tumors in patients. METHODS: Tumor tissue samples with different malignancy grade were obtained from the hospitals. The samples used for detection had been diagnosed as oligodendroglial tumors (oligodendroglioma or anaplastic oligodendroglioma). The expression of Nogo-A was detected by immunohistochemistry and western-blot analysis. The correlation test between the Nogo-A expression and the morphological changes (the percentages of atypical cells and mitotic cells in the tumors) related to the malignancy of tumor tissues was performed. RESULTS: There was significant negative correlation between the Nogo-A expression and the morphological change of tumor tissues according to immunohistochemistry. Western-blot analysis also indicated that the gray value of Nogo-A protein band in the oligodendroglioma group was significantly higher than that in the anaplastic oligodendroglioma group. CONCLUSION: Nogo-A expression was negatively correlated with the malignancy grade of oligodendroglial tumors.