Intermediate nerve neuralgia (INN) is a rare craniofacial pain syndrome. The diagnosis of INN is challenging because of the complex ear sensory innervation that results in a clinical overlap with both trigeminal neuralgia (TN) and glossopharyngeal neuralgia (GPN). A 76-year-old woman with a remarkable medical history presented with right otalgia and mandibular pain for 7 years. Neurological examination revealed a diminished sensation in the distribution of the intermediate nerve (IN). Magnetic resonance imaging demonstrated an impression of the anterior inferior cerebellar artery (AICA) on the facial–vestibulocochlear nerve complex (VII/VIII complex). The patient underwent microvascular decompression (MVD) after long-term oral medication. We confirmed that the responsible vessel was close to the VII/VIII complex and isolated the vessel under the microscope via a right-sided suboccipital retrosigmoid approach. The patient's otalgia and mandibular pain disappeared after the operation. There were no additional neurological deficits. In conclusion, MVD is a safe and feasible option for patients with INN who fail to respond to adequate pharmacotherapy.

Glioma is the most prevalent type of brain tumor characterized by a poor 5-year survival rate and a high mortality rate. Malignant gliomas are commonly treated by surgery, chemotherapy and radiotherapy. However, due to toxicity and resistance to chemoradiotherapy, these treatments can be ineffective. Anxiety and depression are highly prevalent in patients with glioma, adversely affecting disease prognosis and posing societal concerns. Ferroptosis is a type of non-apoptotic, iron-dependent cell death characterized by the accumulation of lethal reactive oxygen species produced by iron metabolism, and it serves a key role in numerous diseases. Regulation of iron phagocytosis may serve as a therapeutic strategy for the development of novel glioma treatments. The present review discusses the mechanisms underlying the occurrence and regulation of ferroptosis, its role in the genesis and evolution of gliomas, and its association with glioma-related anxiety and depression. By exploring potential targets for glioma treatment, the present review provides a theoretical basis for the development of novel therapeutic strategies against glioma.

Cerebral ischemia-reperfusion injury (CIRI) mostly occurs in the treatment stage of ischemic diseases and aggravate brain tissue damage. Although studies have demonstrated that miR-489-3p is closely related to CIRI, the effects of miR-489-3p on neural function in CIRI have not been directly studied. The transient middle cerebral artery occlusion (tMCAO) model was established by suture method, and the corresponding plasmids that interfered with the expression of miR-489-3p or Sirtuin1 (SIRT1) were injected into the model mice, and the behavioral changes of the mice were observed. Then the concentration of serum neuronal injury markers and oxidative stress indices were examined. Next, the pathological conditions, neuronal loss and apoptosis of brain tissue were observed by hematoxylin-eosin staining, Nissl staining, and Transferase-mediated deoxyuridine triphosphate-biotin nick end labeling staining. Finally, the hemoglobin content and cerebral edema in the mouse brain were determined. In addition, the expression levels of miR-489-3p and SIRT1 were detected by reverse transcription quantitative polymerase chain reaction or Western blot, and the targeting relationship between miR-489-3p and SIRT1 was verified by bioinformatics analysis and luciferase reporter assay. The experimental results found that in tMCAO mice, miR-489-3p in brain tissue was up-regulated and SIRT1 was down-regulated. Down-regulating miR-489-3p or up-regulating SIRT1 ameliorated behavioral dysfunction, neuronal damage and apoptosis, oxidative stress and brain histopathology. miR-489-3p targeted the regulation of SIRT1 expression, and down-regulating SIRT1 can reverse the protective effect of silenced miR-489-3p on brain injury. Taken together, by targeting SIRT1, elevated miR-489-3p aggravates CIRI-induced neuronal apoptosis and oxidative stress.

Glioma is the most common primary tumor of the central nervous system (CNS) that develops chemotherapy resistance. The microRNA (miRNA) miR-9 is a tissue-specific miRNA of the CNS that may serve a key role in the modulation of chemotherapy sensitivity. The aim of the present study was to investigate the effect of miR-9 on glioma chemotherapy sensitivity by altering the expression of miR-9 in U251 glioma cells by viral transfection and subsequently treating with gradient concentrations of temozolomide (TMZ). Cell viability, apoptosis and the cell cycle were examined, and drug resistance genes were analyzed by western blotting. The role of nuclear factor B (NF-B) in this regulation was also examined. The results revealed that the susceptibility of glioma cells to TMZ was enhanced by miR-9 overexpression. When miR-9 and TMZ were applied together, the apoptotic rate and percentage of cells arrested at the G2/M stage were significantly higher compared with either treatment alone. Topoisomerase II expression was suppressed by miR-9 via the NF-B signaling pathway, which may be responsible for the sensitization. The results of the present study suggested that miR-9 may be a potential target for glioma chemotherapy.

Through the microarray analysis, long noncoding RNA TPT1-AS1 (TPT1-AS1) was identified in the development of glioma. However, the specific effect of TPT1-AS1 on glioma autophagy in the recent years has not fully been investigated. Therefore, the purpose of our present study is to investigate the function of TPT1-AS1 on affecting autophagy of glioma cells through regulation of microRNA-770-5p (miR-770-5p)-mediated stathmin 1 (STMN1). Initially, the expression of TPT1-AS1, miR-770-5p, and STMN1 were determined in glioma cell lines, followed by the prediction and validation of their interaction. After that, the effects of TPT1-AS1, miR-770-5p, and STMN1 on the in vitro glioma cell proliferation and autophagy were assessed using EdU assay and macrophage-derived chemokine (MDC) and on the in vivo tumor development and autophagy were evaluated using a nude mouse xenograft tumor assay and immunofluorescence assay. In comparison with the normal cells, the glioma cells displayed upregulated expression of TPT1-AS1 and STMN1, but a downregulated miR-770-5p expression. miR-770-5p, which directly targeted STMN1, could be downregulated by TPT1-AS1. Subsequently, in glioma cells, TPT1-AS1 can function to competitively bind to miR-770-5p, thus regulatEing STMN1 expression. Moreover, glioma cell proliferation and autophagy could be mediated through the TPT1-AS1/miR-770-5p/STMN1 axis. From our data we conclude an inhibitory function of TPT1-AS1 in glioma cell autophagy by downregulating miR-770-5p and upregulating STMN1, which may be instrumental for the therapeutic targeting and clinical management of glioma.

Background: Malignant gliomas are heterogeneous brain tumors with the potential for aggressive disease progression, as influenced by suppressive immunoediting. Given the success and enhanced potential of immune-checkpoint inhibitors in immunotherapy, we focused on the connections between genetic alterations affected by IDH1 mutations and immunological landscape changes and PDL-1 expression in gliomas. Methods: Paired surgically resected tumors from lower-grade gliomas (LGGs) and glioblastomas (GBM) were investigated, and a genetic analysis of patients' primary tumor samples culled from TCGA datasets was performed. Results: The results demonstrate that when compared with IDH1-mutant tumors, IDH1 wildtype tumors represent an immunosuppression landscape and elevated levels of PD-L1 expression. DNA hypo-methylation of the PD-L1 gene, as well as high gene and protein expressions, were observed in the wildtype tumors. We also found that quantitative levels of IDH1 mutant proteins were positively associated with recurrence-free survival (RFS). A key product of the IDH1 mutation (2-hydroxyglutarate) was found to transiently increase DNA methylation and suppress PD-L1 expression. Conclusions: IDH1 mutations impact the immune landscape of gliomas by affecting immune infiltrations and manipulating checkpoint ligand PD-L1 expression. Applications of immune checkpoint inhibitors may be beneficial for chemoradiation-insensitive IDH1-wildtype gliomas.

18 Background: For malignant gliomas, current treatment modalities are rarely curative, necessitating development of novel therapies. Cancer immunotherapy has represented one of the most promising new treatment strategies for patients with gliomas based on the evidence that patients with brain tumors are able to mount immune responses against the autologous tumors. However, very few tumor specific targets have been discovered in this malignancy. Thus, identifying clinical useful targets for immunotherapeutic approaches is desperately needed. Methods: CD70 expression was tested from primary GBM and low grade gliomas patient tissues. CD70 gene expression and clinical outcomes were culled from TCGA datasets. CD70 inducing CD8 T cells death was performed by flowcytometry. Results: We demonstrate that CD70, a member of the TNF ligand family, was constitutively overexpressed by primary IDH-wild-type LGG and GBMs with mesenchymal gene signatures. Elevated CD70 expression was also found in recurrent tumors and correlated with tumor progression and poor survival outcome in LGGs and GBMs. CD70 was shown to be directly involved in tumor-chemokine production and associated with sustained T regulatory cells in tumor. Importantly, CD70 played a role inducing CD8+T- specific cell death via engagement of the EREG-EGFR axis in glioma. Conclusions: CD70 is a multi-pronged modulator of immunosuppression in gliomas and enhances tumor progression.

Background Angiogenesis and immune cell infiltration are key features of gliomas and their manipulation of the microenvironment, but their prognostic significance remains indeterminate. We evaluate the interconnection between tumor-infiltrating lymphocyte (TIL) and tumor blood-vasculatures in the context of glioma progression. Methods Paired tumor tissues of 44 patients from three tumor-recurrent groups: diffuse astrocytomas (DA) recurred as DA, DA recurred as glioblastomas (GBM), and GBM recurred as GBM were evaluated by genetic analysis, immunohistochemistry for tumor blood vessel density, TIL subsets, and clinical outcomes. These cells were geographically divided into perivascular and intratumoral TILs. Associations were examined between these TILs, CD34+ tumor blood vessels, and clinical outcomes. To determine key changes in TIL subsets, microarray data of 15-paired tumors from patients who failed antiangiogenic therapy- bevacizumab, and 16-paired tumors from chemo-naïve recurrent GBM were also evaluated and compared. Results Upon recurrence in primary gliomas, similar kinetic changes were found between tumor blood vessels and each TIL subset in all groups, but only CD4+ including Foxp3+ TILs, positively correlated with the density of tumor blood vessels. CD4 was the predominant T cell population based on the expression of gene-transcripts in primary GBMs, and increased activated CD4+ T cells were revealed in Bevacizumab-resistant recurrent tumors (not in chemo-naïve recurrent tumors). Among these TILs, 2/3 of them were found in the perivascular niche; Foxp3+ T cells in these niches not only correlated with the tumor vessels but were also an independent predictor of shortened recurrence-free survival (RFS) (HR = 4.199, 95% CI 1.522–11.584, p = 0.006). Conclusion The minimal intratumoral T cell infiltration and low detection of CD8 transcripts expression in primary GBMs can potentially limit antitumor response. CD4+ and perivascular Foxp3+ TILs associate with tumor angiogenesis and tumor progression in glioma patients. Our results suggest that combining antiangiogenic agents with immunotherapeutic approaches may help improve the antitumor efficacy for patients with malignant gliomas.

BACKGROUND:Long noncoding RNAs (lncRNAs) can act as competitive endogenous RNAs (ceRNAs) to compete with mRNAs for binding miroRNAs (miRNAs). The dysregulated triplets, composed by mRNAs, lncRNAs, and miRNAs, contributed to the development and progression of diseases, such as cancer. However, the roles played by triplet biomarkers are not fully understand in glioblastoma multiforme (GBM) patient survival. OBJECTIVES:Here, we constructed a differential triplet interaction network (TriNet) between GBM and normal tissues and identified GBM survival related triplets. METHODS:Four significantly dysregulated modules, enriched differentially expressed molecules, were identified by integrating affinity propagation method and hypergeometric method. Furthermore, knockdown of TP73-AS1 was implemented by siRNA and the expression of RFX1 was examined in U87 cells by qRT-PCR. The apoptosis of U87 cells was investigated using MTT assay and Acridine orange/Ethidium bromide (AO/EB) assay. RESULTS:We randomly split GBM samples into training and testing sets, and found that these four modules can robustly and significantly distinguish low- and high-survival patients in both two sets. By manually curated literatures for triplets mediated by core interactions, we found that members involved tumor invasion, proliferation, and migration. The dysregulated triplets may cause the poor survival of GBM patients. We finally experimentally verified that knockdown of TP73-AS1, an lncRNA of one triplet, could not only reduce the expression of RFX1, an mRNA of this triplet, but also induce apoptosis in U87 cells. CONCLUSIONS:These results can provide further insights to understand the functions of triplet biomarkers that associated with GBM prognosis.

Tumor migration/metastasis and immunosuppression are major obstacles in effective cancer therapy. Incidentally, these 2 hurdles usually coexist inside tumors, therefore making therapy significantly more complicated, as both oncogenic mechanisms must be addressed for successful therapeutic intervention. Our recent report highlights that the tumor expression of a TNF family member, CD70, is correlated with poor survival for primary gliomas. In this study, we investigated how CD70 expression by GBM affects the characteristics of tumor cells and the tumor microenvironment. We found that the ablation of CD70 in primary GBM decreased CD44 and SOX2 gene expression, and inhibited tumor migration, growth and the ability to attract monocyte-derived M2 macrophages in vitro. In the tumor microenvironment, CD70 was associated with immune cell infiltrates, such as T cells; myeloid-derived suppressor cells; and monocytes/macrophages based on the RNA-sequencing profile. The CD163+ macrophages were far more abundant than T cells were. This overwhelming level of macrophages was identified only in GBM and not in low-grade gliomas and normal brain specimens, implying their tumor association. CD70 was detected only on tumor cells, not on macrophages, and was highly correlated with CD163 gene expression in primary GBM. Additionally, the co-expression of the CD70 and CD163 genes was found to correlate with decreased survival for patients with primary GBM. Together, these data suggest that CD70 expression is involved in promoting tumor aggressiveness and immunosuppression via tumor-associated macrophage recruitment/activation. Our current efforts to target this molecule using chimeric antigen receptor T cells hold great potential for treating patients with GBM.

148 Background: Gliomas are the most common primary malignant brain tumor and are uniformly lethal. Cancer immunotherapy has the potential to target gliomas; however, its antitumor effects are restricted by limitations in clinically useful tumor specific targets. Chimeric antigen receptor modified T-cell (CAR-T) therapy is a highly promising option for cancer treatment, due to its combination of precision antibody recognition and T-cell tumor-specific killing. CD70 is an antigen expressed by limited subsets of normal lymphocytes and dendritic cells but is aberrantly overexpressed by glioma cells, which makes it an outstanding glioma-antigen target. Methods: The gene and protein expression of CD70 were evaluated to identify its potential as a glioma target. Human and mouse versions of CD70-specific CAR-T cells were generated, and human primary GBM lines as well as murine lines (GL-261, KR-158B) were used as human and mouse tumor targets, respectively. The antitumor effect of the human and mouse CD70-sepecific CARs were tested in vitro and in orthotopic xenograft and syngeneic murine models. Results: CD70 is only overexpressed by tumor cells in a subset of low-grade gliomas and GBM. The elevated gene and protein expression are associated with increased tumor grade and poor patient survival. Co-culturing CD70-specific CAR-T cells with CD70-positive glioma cells resulted in potent secretion of IFN-gamma and tumor-specific killing in a CD70-dependent manner. Irradiation enhances CD70 expression on glioma cells and thus increases CAR T-cell recognition. Adoptive transfer of the human and mouse CD70 CAR-T cells resulted in tumor regression of immunocompetent and immunodeficient mice, respectively. Conclusions: CD70 can be an excellent tumor target for gliomas, and CD70-specific CAR-T cells have potent antitumor activity against CD70-positive gliomas both in vitro and in vivo. Our study provides crucial preclinical evidence to support the future clinical application of CD70 CAR-T cells to treat gliomas.

IDH1 R132H mutation is an important marker of survival in patients with gliomas. Although there are many changes of genes in tumour malignant progression, IDH1 R132H mutation status in glioma progression remained unclear. Here, an in-depth characterization of IDH1 R132H mutations were assessed by immunohistochemistry in 55 paired primary-recurrent astrocytomas tissues, including 5 paired primary pilocytic astrocytoma (pPA, WHO grade I), 35 paired primary low grade astrocytoma (pLGA, WHO grade II and III) and 15 paired primary high grade astrocytoma (pHGA/ Glioblastoma, WHO grade IV). Meanwhile, the DNA was isolated from paired samples, and PCR amplification was used for IDH1 exon4 sequencing. Nonparametric test, KM and Cox models were used to examine the statistical difference and survival function. We found that the percent of IDH1 R132H mutation was 68.6% (24/35) in pLGA group, but no IDH1 mutation was found in pPA and pHGA groups. Meanwhile, the results from immunohistochemistry and DNA sequencing showed that, compared with primary astrocytoma, there was no change of IDH1 status in recurrent astrocytoma whatever tumour pathological grade raise or indolent. The pPA group has the longest recurrence-free period (RFP) and overall survival (OS) in three groups (p<0.01), while the pHGA group has the shortest ones (p<0.01). In pLGA group, the IDH1 R132H mutation subgroup has longer RFP than IDH1 wild type subgroup (p<0.01), but the OS has no statistical difference between two subgroups (p>0.6). Additionally, IDH1 R132H mutation independently predicted a long RFP in patients with pLGA (HR 1.073, 95% CI 0.151-0.775, p<0.01).

Objective To evaluate the therapeutic outcome of microsurgery for dural arteriovenous fistulas (DAVF). Methods Clinical data of 6 patients with DAVF underwent microsurgery were analyzed retrospectively, including onset as subarachnoid hemorrhage in 2 patients, cerebral hemorrhage in 2, epilepsy in 1 and exophthalmos in 1. Results All the vascular malformations were resected, and the preoperative symptoms improved to different degree. DSA or CTA examinations were performed in all the patients 6 months after the operation. All the lesions were resected completely, and there was no recurrence or residue of vascular malformation. Six patients were followed up for mean period of 2.1 years, ranged from 1 to 5.5 years. However, there was no newly occurred cerebral hemorrhage or nervous dysfunction during the follow-up period, and the activities of daily living achieved gradeⅠ in 5 patients and gradeⅡ in 1. Conclusion Microsurgery is a safe and effective therapeutic method for DAVF.

Cancer immunotherapy represents a promising treatment approach for malignant gliomas but is hampered by the limited number of ubiquitously expressed tumor antigens and the profoundly immunosuppressive tumor microenvironment. We identified cluster of differentiation (CD)70 as a novel immunosuppressive ligand and glioma target. Normal tissues derived from 52 different organs and primary and recurrent low-grade gliomas (LGGs) and glioblastomas (GBMs) were thoroughly evaluated for CD70 gene and protein expression. The association between CD70 and patients' overall survival and its impact on T-cell death was also evaluated. Human and mouse CD70-specific chimeric antigen receptors (CARs) were tested respectively against human primary GBMs and murine glioma lines. The antitumor efficacies of these CARs were also examined in orthotopic xenograft and syngeneic models. CD70 was not detected in peripheral and brain normal tissues but was constitutively overexpressed by isocitrate dehydrogenase (IDH) wild-type primary LGGs and GBMs in the mesenchymal subgroup and recurrent tumors. CD70 was also associated with poor survival in these subgroups, which may link to its direct involvement in glioma chemokine productions and selective induction of CD8+ T-cell death. To explore the potential for therapeutic targeting of this newly identified immunosuppressive axis in GBM tumors, we demonstrate that both human and mouse CD70-specific CAR T cells recognize primary CD70+ GBM tumors in vitro and mediate the regression of established GBM in xenograft and syngeneic models without illicit effect. These studies identify a previously uncharacterized and ubiquitously expressed immunosuppressive ligand CD70 in GBMs that also holds potential for serving as a novel CAR target for cancer immunotherapy in gliomas.

Malignant gliomas are heterogeneous brain tumors with capacity for aggressive disease progression influenced by suppressive immunoediting. Identifying key factors involved in glioma immunosuppression is critical for the development of effective immunotherapy for chemo/radiation resistant gliomas. We hypothesize that the genetic landscape created by IDH-mutant gliomas predominantly controls tumor immune infrastructure. Paired surgical resected tumors from 35 LGGs and 15 GBMs were evaluated pre- and post-progression; genetic analysis of primary tumors culled from TCGA datasets was performed to determine the link between IDH-mutant status and immune-suppression. We found that there were distinct immune landscapes between IDH-mutant versus IDH-wild-type gliomas. IDH-wild-type tumors displayed higher tumor infiltrating inhibitory immune cell populations (i.e. T regulatory cells and tumor-associated macrophages). The genetic analysis of large cohort of patients demonstrated that the IDH wild-type is coupled with elevated gene expressions associated immunosuppression than mutant tumors. Elevated gene expression levels of the programmed death-1 ­receptor (PD-1) ligands CD274 and PDCD1LG2 were mainly detected in IDH-wild-type tumors that were linked with tumor associated their promoter hypo-methylation. These results suggest that IDH mutations associate with glioma immunosuppressive networks by attracting inhibitory cell populations and manipulating checkpoint ligand expression. Immunotherapeutic strategies exploiting the tumor immune-landscape may be a beneficial alternative for chemotherapy/ radiation therapy insensitive IDH-wild-type gliomas.

For patients with glioblastoma (GBM) in particular, current treatment modalities (surgery, chemotherapy/radiation) are rarely curative. Cancer immunotherapy has been one of the most promising new treatment strategies for patients with GBM, yet finding better treatment options especially by identifying clinically useful targets for immunotherapy are desperately needed. We demonstrate here that CD70 is only constitutively expressed by tumors in primary and recurrent low-grade gliomas (LGG) and GBM. Relatively higher gene expression of CD70 was observed in a subgroup of LGG (IDH wild-type) and GBM (mesenchymal), and was inversely correlated with the overall survival of LGG (hazard ratio: 3.52, P < .001) and GBM (hazard ratio: 1.8, P < .05) patients. Intriguingly, glioma-specific and dramatically lower levels of CD8 gene transcripts (30-fold) as well as fewer viable tumor-infiltrating CD8+ T cells were found in primary GBM, as compared to CD4 transcript/CD4+ T cells, and CD70 was found to be the key factor that was directly involved in this skewed numbers of CD4 vs. CD8. Results from in vitro experiments using CD70-manipulated GBM lines co-culturing with allogenic PBMCs showed that CD70 tumor expression specifically induced CD8+ T-cell death and maintained T regulatory cells. Furthermore, CD70 expression in GBM was highly associated with cytokine/chemokine-signaling pathways by enhancing IL-8, CCL2, and CCL20 productions from the tumor cells, which potentiate the attraction of immunosuppressive infiltrates in GBM. In summary, our data suggest that CD70 is a key mediator of glioma tumor immunosuppression and progression, and that therapeutic approaches targeting CD70 may help treat patients with gliomas.

Gliomas are the most common primary malignant brain tumor and are uniformly lethal. Cancer immunotherapy has the potential to target gliomas; however, its antitumor effects are restricted by limitations in clinically useful tumor specific targets. Chimeric antigen receptor modified T-cell (CAR-T) therapy is a highly promising option for cancer treatment, due to its combination of precision antibody recognition and T-cell tumor-specific killing. CD70 is an antigen expressed by limited subsets of normal lymphocytes and dendritic cells but is aberrantly overexpressed by glioma cells, which makes it an outstanding glioma-antigen target. The gene and protein expression of CD70 were evaluated to identify its potential as a glioma target. Human and mouse versions of CD70-specific CAR-T cells were generated, and human primary GBM lines as well as murine lines (GL-261, KR-158B) were used as human and mouse tumor targets, respectively. The antitumor effect of the human and mouse CD70-sepecific CARs were tested in vitro and in an orthotopic murine syngeneic model in vivo. CD70 is only overexpressed by tumor cells in a subset of low-grade gliomas and GBM. The elevated gene and protein expression are associated with increased tumor grade and poor patient survival. Co-culturing CD70-specific CAR-T cells with CD70-positive glioma cells resulted in potent secretion of IFN-gamma and tumor-specific killing in a CD70-dependent manner. Irradiation enhances CD70 expression on glioma cells and thus increases CAR T-cell recognition. Adoptive transferring of the CD70 CAR-T cells resulted in total regression of gliomas in the brain of immunocompetent mice. CD70 can be an excellent tumor target for gliomas, and CD70-specific CAR-T cells have potent antitumor activity against CD70-positive gliomas both in vitro and in vivo. Our study provides crucial preclinical evidence to support the future clinical application of CD70 CAR-T cells to treat gliomas.

As a phosphatase, SHP-2 has been identified to be involved in regulating several cell functions, including growth, division, adhesion and motility. Therefore, SHP‑2 may affect the response of glioma to radiotherapy, such as via enhancing angiogenesis. The present study aimed to investigate the function of SHP‑2, a protein tyrosine phosphatase, in the radiosensitivity of glioma. U251, U87 and SHG44 glioma cell lines were transfected with small interfering (si)RNA against SHP‑2 and cell proliferation was assessed using a cell counting kit 8 assay, cell apoptosis was assessed by fluorescence‑activated cell sorting and immunoblotting, cell invasion was determined by an invasion assay, and the vasculogenic mimicry capacity was assessed by a tube formation assay. SHP‑2 siRNA transfection reduced the proliferation and increased apoptosis in the glioma cell lines. Downregulation of SHP‑2 suppressed glioma cell invasion and vasculogenic mimicry. These results demonstrated that no significant difference was observed between glioma tissues and normal brain tissues, however, silencing of SHP‑2 inhibited cell proliferation, invasion and vasculogenic mimicry in the glioma cell lines. SHP‑2 may be a novel therapeutic target for glioma.

Identifying factors that contribute to the aggressiveness of glioblastoma (GBM) is crucial for treating this deadly brain tumor. We demonstrate here that CD70, a member of the TNF family, is overexpressed by tumor cells in a subset of patients with low grade glioma and GBM. The elevated gene and protein expression is associated with increased tumor grade and recurrences. CD70 expression on primary GBM is correlated with T cells infiltration and tumor MHC class I expression which could potentially promote antitumor immunity based on our result that T cell infiltration is negatively associated with GBM proliferation. However, no correlation between T cell infiltration and prolonged survival is seen, suggesting that other factors may exist to suppress T cell function. Analysis from 155 primary GBM patients using RNA-seq data culled from TCGA indicates that the gene expression of CD70 is highly correlated with markers (CD4, CD25, CD163 and CD14) commonly expressed on immune suppressive cells such as Tregs and tumor associate macrophages. This result is in line with additional finding that CD70 positive tumors display a predominantly mesenchymal gene expression signature, a subtype of GBM that has greater infiltration by immune cells than other subtypes. In addition, tumors derived from patients with MGMT promoter un-methylation express high levels of CD70. Furthermore, our results suggest that CD70 is a key driver of chemokine mediated attraction for these immune suppressive cells infiltrating the tumor. Lastly, shorter overall survival was observed in these patients who have high CD70 expression compared to those with low CD70 expression on tumors. Taken together, the data suggest that CD70 plays a critical role in chemokine-mediated immune suppression and in GBM progression. Targeting GBM with a drug-conjugated CD70 antibody or CD70-CAR T-cells may improve the therapeutic efficacy for patients with GBM.

Background: Glial cell activation and endothelial dysfunction are thought to contribute to the pathophysiology of cerebral small vessel disease (SVD). The purpose of the present study was to determine if levels of S100B, a protein highly expressed in glial cells, and asymmetric dimethylarginine (ADMA), which promotes endothelial dysfunction, are elevated in the serum of patients with SVD and correlate with their cognitive functioning.Methods: The serum levels of S100B and ADMA were measured with enzyme-linked immunosorbent assays in 210 patients with SVD and 207 controls. Cognitive functioning was evaluated using the Montreal Cognitive Assessment. SVD lesions were categorized as isolated lacunar infarcts (ILI), multiple lacunar infarcts, leukoaraiosis (LA), and LA with cerebral atrophy using magnetic resonance imaging.Results: SVD patients were significantly older, and more likely to have hypertension, diabetes, and heart disease, and smoke compared to controls (Ps < 0.05). Plasma levels of S100B and ADMA were significantly higher in SVD patients (Ps < 0.05), though only S100B was significant after adjusting for the confounding factors. Subtype analyses indicated that ADMA levels were differentially altered depending on lesion type, particularly in cases with ILI and LA (Ps < 0.05). Compared with controls, SVD patients had significant cognitive impairment that was most profound in the cases with LA (all Ps < 0.05). Levels of S100B and ADMA were significantly correlated with cognitive decline in patients with LA (P < 0.05).Conclusion: S100B and ADMA are elevated in SVD, and are associated with cognitive impairment in patients with LA lesions. (C) 2015 Elsevier B.V. All rights reserved.