Ribosomal S6 protein kinase 4 promotes resistance to EZH2 inhibitors in glioblastoma.

Glioblastoma (GBM) is a highly malignant type of brain tumor with limited treatment options. Recent research has focused on epigenetic regulatory factors, such as Enhancer of Zeste Homolog 2 (EZH2), which plays a role in gene expression through epigenetic modifications. EZH2 inhibitors have been developed as potential therapeutic agents for GBM, but resistance to these inhibitors remains a considerable challenge. This study aimed to investigate the role of ribosomal S6 protein kinase 4 (RSK4) in GBM and its association with resistance to EZH2 inhibitors. We first induced drug resistance in primary GBM cell lines by treatment with an EZH2 inhibitor and observed increases in the expression of stemness markers associated with glioblastoma stem cells (GSCs) in the drug-resistant cells. We also found high expression of RSK4 in GBM patient samples and identified the correlation of high RSK4 expression with poor prognosis and GSC marker expression. Further experiments showed that knocking down RSK4 in drug-resistant GBM cells restored their sensitivity to EZH2 inhibitors and decreased the expression of GSC markers, thus reducing their self-renewal capacity. From a mechanistic perspective, we discovered that RSK4 directly phosphorylates EZH2, activating the EZH2/STAT3 pathway and promoting resistance to EZH2 inhibitors in GBM. We also found that combining EZH2 inhibitors with an RSK4 inhibitor called BI-D1870 had better inhibitory effects on GBM occurrence and progression in both in vitro and in vivo experiments. In conclusion, this study demonstrates that RSK4 enhances cancer stemness and mediates resistance to EZH2 inhibitors in GBM. Combination treatment with EZH2 inhibitors and RSK4 inhibitors is a promising potential therapeutic strategy for GBM. Collectively, our results strongly demonstrate that RSK4 regulates the EZH2/STAT3 pathway to promote GSC maintenance and EZH2i resistance in a PRC2-independent manner, indicating that RSK4 is a promising therapeutic target for GBM.

The Expression of Hippocampal NRG1/ErbB4 Correlates With Neuronal Apoptosis, but Not With Glial Activation During Chronic Cerebral Hypoperfusion.

Permanent bilateral common carotid occlusion (2VO) is well-established to investigate the chronic cerebral hypoperfusion (CCH)-induced cognitive deficits. Besides, previous studies suggested that disturbance of Neuregulin1 (NRG1)/ErbB4 signaling is associated with cognitive impairments, as well as neuronal apoptosis and neuroinflammation in CNS. However, the expression pattern of hippocampal NRG1/ErbB4 has not been systematically investigated during CCH. Here, we aim to investigate the temporal changes of hippocampal NRG1/ErbB4 during CCH and their possible relationship with neuronal apoptosis and glial activation. Morris water maze (MWM) and Radial arm water maze (RAWM) tests were used to analyze cognitive impairment in 2VO rats at 28 days post-surgery, and Enzyme-Linked Immunosorbent Assay (ELISA), western blotting and immunostaining were performed at different time points (24 h, 7 days, 14 days, 28 days) to detect the expression pattern of NRG1/ErbB4 and the distribution of ErbB4. Neuronal nuclei (NeuN), NeuN/TUNEL, Iba1 and GFAP immunostaining and caspase activity in hippocampal CA1 subarea were assessed during CCH as well. We found that the expression of NRG1 and phosphorylated ErbB4 (pErbB4)/ErbB4 changed in a time-dependent manner (up-regulated in the acute phase and then decreased in the chronic phase of CCH). Besides, ErbB4-expressed neurons and selective types of GABAergic cells decreased after CCH, but the distribution pattern of ErbB4 remained unchanged. In addition, the expression of hippocampal NRG1/ErbB4 positively correlated with the level of neuronal apoptosis (both NeuN/TUNEL immunostaining and caspase-3 activity), but not with glial activation according to Pearson's correlation. These findings indicated that hippocampal NRG1/ErbB4 may be involved in the pathogenesis of CCH, especially neuronal apoptosis during CCH.

Ultrasound-Guided Intratumoral Radiofrequency Ablation Coagulation to Facilitate Meningioma Resection: Preliminary Experience.

OBJECTIVES: This study aimed to explore the feasibility and safety of intratumoral radiofrequency ablation (RFA) in meningioma resection. METHODS: This study was approved by the Xijing Ethics Committee, and informed consent was obtained from all of the patients. Thirteen patients with meningiomas were recruited in the Neurosurgery Department of Xijing Hospital. These patients were treated with intratumoral RFA and surgery. We also chose 13 patients with meningiomas treated with traditional surgery as the control group. Two-dimensional ultrasound, color Doppler flow imaging, contrast-enhanced ultrasound, and magnetic resonance imaging were used to identify the location, border, and blood supply of the meningiomas preoperatively and to assess the therapeutic effect intraoperatively. Finally, the meningiomas were dissected and removed by surgery. RESULTS: All procedures were technically successful without serious complications. Intraoperative ultrasound was able to provide a clear display of the location, shape, size, and boundary of the tumor and its relationship with other tissues and reveal the vascular distribution in and around the tumors. With intratumoral RFA, coagulative necrosis was induced, and the meningiomas became hard in texture with a decreased blood supply. Blood loss was significantly lower in the RFA group versus control group (320.0 ± 24.8 versus 390.4 ± 36.8 mL; P < .001). The RFA group spent fewer days in the hospital (6.0 ± 0.9 versus 7.0 ± 1.2 days; P = .022). However, the surgical time of the RFA group was relatively longer (3.5 ± 0.5 versus 3.0 ± 0.3 hours, P = .007). CONCLUSIONS: The application of intratumoral RFA in meningioma resection is effective and safe. It may be a useful adjunct for meningioma treatment.

Efficacy of radio frequency thermocoagulation in surgery for giant supratentorial meningiomas: a historical control study.

BACKGROUND: Surgery for giant meningiomas carries a high risk of bleeding and is time-consuming. This historical control study tests the hypothesis that the use of radio frequency thermocoagulation (RFT) during surgery improves outcome. METHODS: From November 2010 to October 2011, 20 giant vascularized meningiomas were surgically resected with intraoperative use of ultrasound-guided RFT prior to resection. The historical control group consisted of 25 patients in whom tumors were removed without RFT by the same surgical team. Blood loss during resection, changes in tumor consistency, time taken for the operation, and the extent of resection were compared between the two groups. RESULTS: There was less blood lost during resection and the duration of the operation was shorter in RFT-assisted surgery than in the historical control group (P<0.05). Apart from the effect of devascularization, the tumor consistency became soft after RFT, which could also be beneficial. CONCLUSIONS: Satisfactory devascularization and tumor softening were achieved after RFT without incremental complications. RFT-assisted surgery for giant vascularized supratentorial meningiomas is easier and safer than non-RFT surgery.

Basic fibroblast growth factor increases the transplantation­mediated therapeutic effect of bone mesenchymal stem cells following traumatic brain injury.

Basic fibroblast growth factor (bFGF) has proven useful for neural stem and progenitor cells during the transplantation­mediated therapeutic effect of bone mesenchymal stem cells (BMSCs). Endogenous bFGF expression levels increase during brain development and gradually diminish with aging. To date, few studies have been conducted on exogenous bFGF promoting BMSC transplantation­mediated functional recovery in adult rats following traumatic brain injury (TBI). The results of the present study showed that BMSCs in the TBI cortex and dentate gyrus showed differentiation along the glial and neuronal lines, which are possibly enhanced by bFGF. The neuronal differentiation rate was not consistent with neurological functional recovery rate over time. bFGF may promote the transplantation­mediated therapeutic effect of BMSCs more significantly and rapidly in rats following TBI, with a small proportion of differentiated neurons. In conclusion, exogenous bFGF functions as a booster of the transplantation­mediated therapeutic effect of BMSCs following TBI.

Over-expression of Mash1 improves the GABAergic differentiation of bone marrow mesenchymal stem cells in vitro.

Bone marrow mesenchymal stem cells (BMSCs) have been shown to be a promising cell type for the study of neuronal differentiation; however, few attempts had been made to differentiate these cells into inhibitory gamma-aminobutyric acid (GABA)ergic neurons. In this study, we over-expressed mammalian achaete-scute homologue-1 (Mash1), a basic helix-loop-helix (bHLH) transcription factor, in Sprague-Dawley rat BMSCs via lentiviral vectors, and then induced neuronal differentiation of these cells using conditioned medium. Our Western blot results show that, under conditions of differentiation, Mash1-overexpressing BMSCs exhibit an increased expression of neuronal markers and a greater degree of neuronal morphology compared to control, non-Mash1-overexpressing cells. Using immunocytochemistry, we observed increased expression of glutamic acid decarboxylase 67 (GAD67), as well as neuron-specific nuclear protein (NeuN) and ß3-tubulin, in Mash1-overexpressing BMSCs compared to control cells. Moreover, we also found the differentiated cells showed representative traces of action potentials in electrophysiological characterization. In conclusion, our study demonstrated that over-expression of Mash1 can improve GABAergic differentiation of BMSCs in vitro.

The tropism of neurally differentiated bone marrow stromal cells towards C6 glioma.

Recent studies have indicated that bone marrow stromal cells (BMSCs) have significant tropism towards glioma which makes them play an important role in carrying genes/drugs to inhibit the growth of glioma as cell vehicles. But BMSCs may differentiate into neural cells under entocranial environment and few researches support the idea that neurally differentiated bone marrow stromal cells (N-D-BMSCs) still hold the capacity of migrating to the tumor sites. The aim of our study was to investigate the tropism of N-D-BMSCs towards C6 glioma. In vitro migration assay was employed by transwell co-culture system and Student's t-test analysis indicated that N-D-BMSCs had the significant tropism towards C6 glioma-conditioned medium (GCM) (P<0.01). Furthermore, the vascular endothelial growth factor (VEGF) bioactivity of the C6 GCM was neutralized by the anti-rat VEGF antibody and our data suggested that the VEGF from C6 GCM hold chemoattraction for N-D-BMSCs and some other cytokines from the C6 GCM may be responsible for the chemoattraction for N-D-BMSCs. In vivo migration assay was carried out with cells transplantation and one way ANOVA analysis indicated that the tropism of N-D-BMSCs towards C6 glioma sites presented time variation (P-value=2.9E-20). Moreover, multiple comparisons for the time variables with the Student's t-test and the results suggested that the migration capacity of N-D-BMSCs towards C6 glioma sites reach the peak on the 7th day after transplantation. These results demonstrate that N-D-BMSCs as well as BMSCs have significant tropism towards C6 glioma.

Chordoid glioma: a case report and literature review.

BACKGROUND: chordoid glioma is a rare tumor (World Health Organization grade II) with both glial and chordoid features, often located in the suprasellar region and anterior third ventricle. It was first described by Brat in 1998. Because there is no detailed information available from the clinical perspective, we reviewed the literature. METHODS: a literature search through PUBMED and CNKI revealed 64 cases of chordoid glioma. Information on the clinical course was very limited. We reviewed the literature and studied the pathologic and imaging features, postoperative mortality and morbidity in relation to surgical extension and approaches, and the importance of adjuvant treatment. CONCLUSIONS: mortality in the immediate postoperative period is 28%, and postoperative morbidity is 60%, which are statistically higher after gross total resection as compared with subtotal resection. Translamina terminalis approach is considered to be the best approach. The current study cannot document that patients have longer survival and higher quality of life after gross total resection than subtotal resection. The role of postoperative radiotherapy is uncertain and there is no report on the use of chemotherapy. More information about the optimal treatment strategy is needed.