Surgical Clipping of Intracranial Aneurysms Using a Transcranial Neuroendoscopic Approach.

OBJECTIVE: This retrospective study was performed to evaluate the feasibility and safety of surgically clipping intracranial aneurysms using a transcranial neuroendoscopic approach. METHODS: A total of 229 patients with cerebral aneurysms were included in our study, all of whom were treated with clamping surgery at Wuhan University People's Hospital. They were divided into neuroendoscopic and microscopic groups, according to whether or not neuroendoscopy was used for the clamping surgery. We statistically analyzed the patients' baseline data, surgical outcomes, and complications, which were then evaluated to assess the treatment effect. RESULTS: The baseline characteristics were not statistically significant, except for gender, for which the proportions of female patients in the two groups were 69 (56.1%) and 46 (43.4%). There were no patients with incomplete aneurysm clamping or parent vessel occlusion in the neuroendoscopic group, and there were 4 (3.8%) and 2 (1.9%) in the microscopic group, respectively; however, there was no statistically significant difference in the comparison of the two groups. The mean operative times of the two groups were 181 min and 154 min, respectively, and were statistically different. However, the mRS scores of the two groups showed no significant difference in patient prognosis. The differences in complications (including limb hemiplegia, hydrocephalus, vision loss, and intracranial infection) were not statistically significant, except for cerebral ischemia, for which the proportions of patients in the two groups were 8 (6.5%) and 16 (15.1%). CONCLUSIONS: Neuroendoscopy can provide clear visualization and multi-angle views during aneurysm clipping, which is helpful for ensuring adequate clipping and preventing complications.

Ursolic Acid Alleviates Neuroinflammation after Intracerebral Hemorrhage by Mediating Microglial Pyroptosis via the NF-κB/NLRP3/GSDMD Pathway.

The neuroinflammatory response after intracerebral hemorrhage (ICH) causes a large amount of neuronal loss, and inhibiting the inflammatory response can improve the prognosis. In previous laboratory studies and clinical trials, ursolic acid (UA) inhibited the inflammatory response, but whether it can be administered to inhibit the neuroinflammatory response after cerebral hemorrhage is unknown. The aim of this study was to investigate the effects of ursolic acid after cerebral hemorrhage. Online databases were used to obtain potential therapeutic targets of ursolic acid for the treatment of cerebral hemorrhage, and possible mechanisms were analyzed by KEGG, GO, and molecular docking. A rat model of cerebral hemorrhage was established using collagenase, and an in vitro cerebral hemorrhage model was constructed by adding hemin to BV2 cell culture medium. Enzyme-linked immunosorbent assay (ELISA), Western blotting (WB), immunofluorescence, TUNEL staining, and calcein/PI staining were used to investigate the degree of microglial M1 polarization, changes in the levels of inflammatory factors, activation of the NF-κB pathway, and changes in the indicators of cellular death after ursolic acid treatment. In addition, phorbol 12-myristate 13-acetate (PMA) was used to activate the NF-κB pathway to verify that ursolic acid exerts its anti-neuroinflammatory effects by regulating the NF-κB/NLRP3/GSDMD pathway. Network pharmacology and bioinformatics analyses revealed that ursolic acid may exert its therapeutic effects on cerebral hemorrhage through multiple pathways. Together, in vivo and in vitro experiments showed that ursolic acid inhibited microglial M1 polarization and significantly reduced the levels of p-NF-κB, GSDMD-N, cleaved caspase-1, TNF-α, IL-6, and IL-1ß, which were significantly inhibited by the use of PMA. Ursolic acid inhibits microglial pyroptosis via the NF-κB/NLRP3/GSDMD pathway to alleviate neuroinflammatory responses after cerebral hemorrhage.

BCL2A1 is associated with tumor-associated macrophages and unfavorable prognosis in human gliomas.

B-cell lymphoma 2-related protein A1 (BCL2A1) is a member of the BCL-2 family. Previous studies have shown that BCL2A1 is closely related to the tumorigenesis and resistance to chemotherapy of multiple solid tumors, such as breast cancer. However, the expression pattern and potential biological function of BCL2A1 in glioma remain unknown. For the first time, we found that the expression of BCL2A1 was higher in human glioma tissues than in normal brain tissues (NBTs) in both public datasets and an in-house cohort. High BCL2A1 expression was associated with advanced WHO grade, IDH 1/2 wild type and the mesenchymal (ME) subtype, and its overexpression in glioma predicted resistance to temozolomide (TMZ) chemotherapy and unfavorable prognosis. In addition, Gene set enrichment analysis (GSEA), Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated that BCL2A1 was significantly correlated with the immune response and immune-related pathways, and BCL2A1 expression was positively correlated with microenvironmental parameters (immune, stromal, and ESTIMATE scores) and macrophage infiltration. Interestingly, bioinformatic prediction and immunohistochemical/immunofluorescence staining analysis revealed that BCL2A1 expression was obviously associated with the tumor-associated macrophages (TAMs) markers CD68 and CCL2. Notably, knockdown of BCL2A1 significantly inhibited cell proliferation of U87 and U251 in vitro, induced smaller tumor size and prolonged survival time of mice in vivo. Co-culture experiments of macrophages and GBM cells showed that BCL2A1 knockdown inhibited macrophage migration. Meanwhile, knockdown of BCL2A1 was associated with low expression of CD68 and CCL2 in intracranial xenograft model. This may suggest that BCL2A1 promotes the progression of glioma and influences the prognosis of patients by participating in TAMs infiltration. In conclusion, these findings suggest that BCL2A1 could serve as a promising prognostic indicator and immunotherapy target in gliomas.

Post-operative rebleeding in patients with spontaneous supratentorial intracerebral hemorrhage: factors and clinical outcomes.

OBJECTIVE: To explore factors affecting postoperative rebleeding in patients with spontaneous supratentorial intracerebral hemorrhage (SSICH). METHODS: We retrospectively analyzed data from 724 patients with SSICH treated at Renmin Hospital of Wuhan University from December 2018 to October 2021. Finally, 294 people were eligible to be included in this study. Hematoma locations were classified as basal ganglia, thalamus, subcortex, or intraventricular. Surgery was categorized as neuroendoscopic surgery, burr hole (stereotactic drilling and drainage), or open craniotomy. Postoperative rebleeding was recorded. The incidence, risk factors, and prognosis of postoperative rebleeding were evaluated. RESULTS: All procedures were successfully completed. Postoperative rebleeding occurred in 57 patients (19.83%, 57/294). Univariate logistic regression analysis identified these risk factors for rebleeding: admission Glasgow Coma Scale (GCS) score, irregular hematoma morphology by preoperative Computed Tomography (CT), postoperative hypertension, hematoma location, surgical method (P<0.05), and preoperative hematoma volume (P<0.1). Multivariate logistic regression analysis confirmed admission GCS score, irregular hematoma morphology by preoperative CT, postoperative hypertension, hematoma location, and surgical method as significant risk factors (P<0.05). Burr hole surgery and basal ganglia hematomas were associated with increased odds of rebleeding, and the mortality rates in patients with rebleeding versus no rebleeding were 7.02% versus 0.84%. CONCLUSIONS: Neuroendoscopic surgery, craniotomy, and burr hole are all effective for treating SSICH, but burr hole surgery was an important risk factor for rebleeding and an adverse outcome. Admission GCS score, irregular hematoma morphology, blood pressure control, hematoma location, and surgical method are affected the risk of postoperative rebleeding. 3D Slicer-assisted neuroendoscopic surgery may be the most effective treatment for many patients with SSICH.

Perihematomal edema after minimally invasive surgery: a matter of concern to neurosurgeons.

The purpose of this study is to explore the evolution of brain edema after minimally invasive surgery in deep spontaneous cerebral hemorrhage (DSICH) treatment and to analyze the differences in edema after different surgical methods. The clinical data of 105 patients with DSICH treated at Renmin Hospital of Wuhan University from January 2020 to June 2022 were analyzed retrospectively. Among them, 54 patients were treated with minimally invasive puncture and drainage surgery (MIPDS group), and 51 were treated with neuroendoscopic surgery (NES group). Continuous computed tomography images of patients in the hospital and 3D Slicer software were used to quantitatively calculate the edematous area to explore the changes in perihematomal edema volume in the two groups after the operation. The peak volume of postoperative edema (37.36±10.51 mL) in the MIPDS group was more extensive than that in the NES group, and its net increase in edema volume was 16.86±10.01 mL more than that in the NES group. The relative edema index (0.86±0.26) was lower in the NES group than in the MIPDS group (P < 0.05). The peak of postoperative edema in the MIPDS group was at 6-8 days after the operation, and that in the NES group was most often at 3-5 days after the operation. There are differences in perihematomal edema of DSICH treated by different minimally invasive methods. Compared with the MIPDS group, the NES group showed earlier peak of cerebral edema and lower degree of cerebral edema. The absolute regression volume of edema in the MIDPs group was greater than that in the NEs group, but there was no difference in the regression rate of edema between the two groups.

Development and Validation of a Nomograph Model for Post-Operative Central Nervous System Infection after Craniocerebral Surgery.

PURPOSE: A nomograph model of predicting the risk of post-operative central nervous system infection (PCNSI) after craniocerebral surgery was established and validated. METHODS: The clinical medical records of patients after cranial surgery in Renmin Hospital of Wuhan University from January 2020 to September 2022 were collected, of whom 998 patients admitted to Shouyi Hospital District were used as the training set and 866 patients admitted to Guanggu Hospital District were used as the validation set. Lasso regression was applied to screen the independent variables in the training set, and the model was externally validated in the validation set. RESULTS: A total of 1864 patients after craniocerebral surgery were included in this study, of whom 219 (11.75%) had PCNSI. Multivariate logistic regression analysis showed that age > 70 years, a previous history of diabetes, emergency operation, an operation time ≥ 4 h, insertion of a lumbar cistern drainage tube ≥ 72 h, insertion of an intracranial drainage tube ≥ 72 h, intraoperative blood loss ≥ 400 mL, complicated with shock, postoperative albumin ≤ 30 g/L, and an ICU length of stay ≥ 3 days were independent risk factors for PCNSI. The area under the curve (AUC) of the training set was 0.816 (95% confidence interval (95%CI), 0.773-0.859, and the AUC of the validation set was 0.760 (95%CI, 0.715-0.805). The calibration curves of the training set and the validation set showed p-values of 0.439 and 0.561, respectively, with the Hosmer-Lemeshow test. The analysis of the clinical decision curve showed that the nomograph model had high clinical application value. CONCLUSION: The nomograph model constructed in this study to predict the risk of PCNSI after craniocerebral surgery has a good predictive ability.

TMEM2 induces epithelial-mesenchymal transition and promotes resistance to temozolomide in GBM cells.

Glioblastoma multiforme (GBM) is the most common intracranial malignant tumor and is notorious for its poor prognosis. An important element in the short overall survival of GBM patients is the lack of understanding the pathogenesis and progression of tumor and deficiency biomarkers that can be used for early diagnosis and therapeutic sensitivity monitoring. Studies have shown that transmembrane protein 2 (TMEM2) is participated in tumorigenesis of various human tumors, including rectal and breast cancers. Although Qiuyi Jiang et al. have reported that TMEM2 combined with IDH1/2 and 1p19q can predict the survival time of glioma patients based on bioinformatics, its expression and biological role of glioma remain unclear. In our study, we investigated the effect of TMEM2 expression level on glioma malignancy in public datasets and an independent internal dataset. We revealed TEMM2 expression was higher in GBM tissues than in non-tumor brain tissues (NBT). Moreover, the increase in TMEM2 expression level was closely related to tumor malignancy. The survival analysis showed that TMEM2 high expression reduces survival time in all glioma patients, including GBM and LGG patients. Subsequent experiments demonstrated that knockdown TMEM2 inhibited proliferation of GBM cells. In addition, we analyzed TMEM2 mRNA levels in different GBM subtypes, and demonstrated that TMEM2 expression was upregulated in mesenchymal subtype. Meanwhile, bioinformatics analysis and transwell assay indicated that knockdown TMEM2 suppressed epithelial-mesenchymal transition (EMT) in GBM. Importantly, Kaplan-Meier analysis demonstrated that TMEM2 high expression reduced the treatment response to TMZ in GBM patients. Knockdown of TMEM2 alone did not reduce apoptosis GBM cells, but significant apoptotic cells were observed in the group treated with additional TMZ. These studies may contribute to improving the accuracy of early diagnosis and evaluating the effectiveness of TMZ treatment in GBM patients.

3D slicer combined with neuroendoscope in treatment of a distal segment aneurysm of the anterior choroidal artery complicated intraventricular hemorrhage: A case report and literature review.

Introduction: Pure ventricular hemorrhage is often secondary to Moyamoya disease, rarely caused by rupture of ventricular aneurysm. The surgical treatment of the latter is very challenging. 3D Slicer reconstruction technology can accurately locate small intracranial lesions and combined with minimally invasive surgery with transcranial neuroendoscope is a new attempt to treat the above diseases. Case presentation: We report a case of pure intraventricular hemorrhage secondary to rupture of a distal segment aneurysm of the anterior choroidal artery. Brain computed tomography (CT) before admission showed pure ventricular hemorrhage, and brain CT angiography (CTA) before operation showed a distal segment aneurysm of the anterior choroidal artery. We used 3D Slicer reconstruction and precise location of the focus before the operation and used the minimally invasive surgery technique with transcranial neuroendoscope to completely remove the hematoma in the ventricle, and found the responsible aneurysm located in the ventricle. Conclusion: Pure intraventricular hemorrhage requires vigilance against the distal segment aneurysm of the anterior choroidal artery. At present, conventional microscopic craniotomy and intravascular interventional therapy have limitations, and 3D Slicer reconstruction and precise positioning technology combined with transcranial neuroendoscope minimally invasive surgery may be a good choice.

Fatostatin induces ferroptosis through inhibition of the AKT/mTORC1/GPX4 signaling pathway in glioblastoma.

Glioblastoma multiforme (GBM) is the most common and fatal primary malignant central nervous system tumor in adults. Although there are multiple treatments, the median survival of GBM patients is unsatisfactory, which has prompted us to continuously investigate new therapeutic strategies, including new drugs and drug delivery approaches. Ferroptosis, a kind of regulated cell death (RCD), has been shown to be dysregulated in various tumors, including GBM. Fatostatin, a specific inhibitor of sterol regulatory element binding proteins (SREBPs), is involved in lipid and cholesterol synthesis and has antitumor effects in a variety of tumors. However, the effect of fatostatin has not been explored in the field of ferroptosis or GBM. In our study, through transcriptome sequencing, in vivo experiments, and in vitro experiments, we found that fatostatin induces ferroptosis by inhibiting the AKT/mTORC1/GPX4 signaling pathway in glioblastoma. In addition, fatostatin inhibits cell proliferation and the EMT process through the AKT/mTORC1 signaling pathway. We also designed a p28-functionalized PLGA nanoparticle loaded with fatostatin, which could better cross the blood-brain barrier (BBB) and be targeted to GBM. Our research identified the unprecedented effects of fatostatin in GBM and presented a novel drug-targeted delivery vehicle capable of penetrating the BBB in GBM.

Immunogenic cell death-related risk signature predicts prognosis and characterizes the tumour microenvironment in lower-grade glioma.

Lower-grade glioma (LGG) is a common malignant primary tumour in the central nervous system, and most patients eventually develop highly aggressive gliomas despite comprehensive traditional treatment. Tumour molecular subtypes and prognostic biomarkers play a crucial role in LGG diagnosis and treatment. Therefore, the identification of novel biomarkers in LGG patients is crucial for predicting the prognosis of glioma. Immunogenic cell death (ICD) is defined as regulated cell death that is sufficient to activate the adaptive immune response of immunocompetent hosts. The combination of ICD and immunotherapy might exert a greater and more persistent antitumour effect in gliomas. In our study, we explored the expression, function, and genetic alterations of 34 ICD-related genes. Using 12 ICD-related genes, including IL17RA, IL1R1, EIF2AK3, CD4, PRF1, CXCR3, CD8A, BAX, PDIA3, CASP8, MYD88, and CASP1, we constructed and validated an ICD-related risk signature via least absolute shrinkage and selection operator (LASSO) Cox regression analysis. All the information was obtained from public databases, including The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and the Chinese Glioma Genome Atlas (CGGA) databases. Our results revealed that ICD-high risk groups have a poor prognosis and might be more sensitive to immune checkpoint blockade (ICB) immunotherapy. In addition, ICD-high risk groups were associated with 1p19q noncodeletion, higher WHO grade, wild type IDH, and an immunosuppressive tumour microenvironment. We verified the prognostic value of 12 ICD-related genes in TCGA and CGGA databases. Immunohistochemistry was performed to verify the expression of several ICD-related genes at the protein level. Our study provides a novel and comprehensive perspective to elucidate the underlying mechanisms of LGG prognosis and direction for future individualized cancer immunotherapy.

FAIM2 is a potential pan-cancer biomarker for prognosis and immune infiltration.

Fas apoptosis inhibitory molecule 2 (FAIM2) is an important member of the transmembrane BAX inhibitor motif containing (TMBIM) family. However, the role of FAIM2 in tumor prognosis and immune infiltration has rarely been studied. Here, we conducted a pan-cancer analysis to explore the role of FAIM2 in various tumors and further verified the results in glioma through molecular biology experiment. FAIM2 expression and clinical stages in tumor samples and para-cancerous samples were analyzed by TIMER2 database, GEPIA database, and the TISIDB database. The role of FAIM2 on prognosis was analyzed via GEPIA2. We utilized the ESTIMATE algorithm to evaluate the ImmuneScore and StromalScore of various tumors. In addition, we explored the correlation between FAIM2 expression and tumor immune cell infiltration by the TIMER2 database. The immune checkpoint genes, tumor mutation burden (TMB), microsatellite instability (MSI), mismatch repair (MMR), and DNA methylation related to FAIM2 were analyzed based on the TCGA database. The correlation between FAIM2 expression with Copy number variations (CNV) and methylation is explored by GSCA database. Protein-Protein Interaction (PPI) analysis was obtained from the STRING database and the CellMiner database was used to explore the association between FAIM2 expression and drug response. FAIM2 co-expression genes were studied by the LinkedOmics database. Immunohistochemistry, Western Blotting Analysis, Cell Viability Assay, Colony Formation Assay, and Edu staining assay were used in the molecular biology experiments section. The FAIM2 expression was down-regulated in most tumors and highly expressed FAIM2 was associated with a better prognosis in several cancers. FAIM2 plays an essential role in the tumor microenvironment and is closely associated with immune Infiltration in various tumors. The expression of FAIM2 was closely correlated to TMB, MSI, MMR, CNV, and DNA methylation. Furthermore, FAIM2 related genes in the PPI network and its co-expression genes in glioma are involved in a large number of immune-related pathways. Molecular biology experiments verified a cancer suppressor role for FAIM2 in glioma. FAIM2 may serve as a potential pan-cancer biomarker for prognosis and immune infiltration, especially in glioma. Moreover, this study might provide a potential target for tumor immunotherapy.

Development and validation of cuproptosis-associated prognostic signatures in WHO 2/3 glioma.

WHO 2/3 glioma is a common intracranial tumor that seriously affects the quality of life and survival time of patients. Previous studies have shown that the tricarboxylic acid (TCA) cycle is closely related to the occurrence and development of glioma, while recent studies have shown that cuproptosis, a novel programmed death pathway, is closely related to the inhibition of the TCA cycle. In our study, eight of ten cuproptosis-related genes (CRGs) were found to be differentially expressed between normal and WHO 2/3 glioma tissues. Through the LASSO algorithm, the cuproptosis-associated risk signatures (CARSs) were constructed, which can effectively predict the prognosis of WHO 2/3 glioma patients and are closely related to clinicopathological features. We analyzed the relationship between risk score and immune cell infiltration through Xcell, ssGSEA, TIMER database, and immune checkpoint molecules. In addition, the relationship between risk score and chemotherapeutic drug sensitivity was also investigated. The prognosis-related independent risk factors FDX1 and CDKN2A identified from CARSs are considered potential prognostic biomarkers for WHO 2/3 glioma. The clinical prognosis model based on cuproptosis is expected to provide an effective reference for the diagnosis and treatment of clinical WHO 2/3 glioma patients.

Exploring the inverse association of glioblastoma multiforme and Alzheimer's disease via bioinformatics analysis.

Glioblastoma multiforme (GBM) and Alzheimer's disease (AD) are two major diseases in the nervous system with a similar peak age of onset, which has the typical characteristics of high cost, difficult treatment, and poor prognosis. Epidemiological studies and a few molecular biological studies have hinted at an opposite relationship between AD and GBM. However, there are few studies on their reverse relationship, and the regulatory mechanism is still unclear, indicating that further systematic research is urgently needed. Our study firstly employs advanced bioinformatics methods to explore the inverse relationship between them and find various target drugs. We obtained the gene expression dataset from public databases (GEO, TCGA, and GTEx). Then, we identified 122 differentially expressed genes (DEGs) of AD and GBM. Four significant gene modules were identified through protein-protein interaction (PPI) and module construction, and 13 hub genes were found using cytoHubba. We constructed co-expression networks and found various target drugs through these hub genes. Functional enrichment analysis revealed that the AMPK pathway, cell cycle, and cellular senescence play important roles in AD and GBM. Our study may provide a potential direction for studying the opposite molecular mechanism of AD and GBM in the future.

IRF2-ferroptosis related gene is associated with prognosis and EMT in gliomas.

Ferroptosis is a new type of programmed cell death that has excellent anti-tumor potential in different tumors. However, the research on ferroptosis in glioma is still incomplete. In this study, we aimed to revealed the relationship between ferroptosis-related genes (FRGs) and glioma. We collected gene expression profiles of glioma patients from the TCGA and CGGA databases. All glioma samples were classified into five subtypes using the R software ConsensusClusterPlus. Subsequently, we performed single sample gene set enrichment analysis (ssGSEA) to explore the correlation between different subtypes and immune status and ferroptosis. Then co-expression modules were constructed via weighted gene co-expression network analysis (WGCNA). A Gene Ontology (GO) analysis was conducted to analyze the potential biological functions of the genes in the modules. Finally, we identified 10 hub genes using the PPI network. The in vitro experiments were used to validate our predictions. We found that the expression level of IRF2 is positively correlated with the grade of glioma. The overexpression of IRF2 could protect glioma cells from ferroptosis and enhance the invasive and migratory abilities. Silence of IRF2 had the opposite effect. In conclusion, we demonstrated a novel ferroptosis-related signature for predicting prognosis, and IRF2 could be a potential biomarker for diagnosis and treatment in glioma.

Esterase-responsive and size-optimized prodrug nanoparticles for effective intracranial drug delivery and glioblastoma treatment.

Glioblastoma multiforme (GBM) is the intracranial malignancy with the highest rates of morbidity and mortality. Chemotherapy is often ineffective against GBM due to the presence of the blood-brain barrier (BBB); however, the application of nanotechnology is expected to overcome this limitation. Poly(lactic-co-glycolic acid) (PLGA) is a degradable and nontoxic functional polymer with good biocompatibility that is widely used in the pharmaceutical industry. Previous studies have shown that the ability of PLGA nanoparticles (NPs) to penetrate the BBB is largely determined by their size; however, determination of the optimal PLGA NP size requires further research. Here, we report a tandutinib-based prodrug (proTan), which responds to the GBM microenvironment, that was combined with NPs to overcome the BBB. AMD3100-PLGA NPs loaded with proTan inhibited tumor growth and effectively prolonged the survival of tumor-bearing mice.

Expression and Prognostic Role of Glia Maturation Factor-γ in Gliomas.

Background: Glia maturation factor-γ (GMFG) regulates actin cytoskeletal organization and promotes the invasion of cancer cells. However, its expression pattern and molecular function in gliomas have not been clearly defined. Methods: In this study, public datasets comprising 2,518 gliomas samples were used to explore GMFG expression and its correlation with malignancy in gliomas. Immunohistochemistry (IHC) staining was performed to determine the expression of GMFG in gliomas using an in-house cohort that contained 120 gliomas samples. Gene ontology enrichment analysis was conducted using the DAVID tool. The correlation between GMFG expression and immune cell infiltration was evaluated using TIMER, Tumor Immune Single-Cell Hub (TISCH) database, and IHC staining assays. The Kaplan-Meier analysis was performed to determine the prognostic role of GMFG and its association with temozolomide (TMZ) response in gliomas. Results: The GMFG expression was higher in gliomas compared with non-tumor brain tissues both in public datasets and in-house cohort. High expression of GMFG was significantly associated with WHO grade IV, IDH 1/2 wild-type, and mesenchymal (ME) subtypes. Bioinformatic prediction and IHC analysis revealed that GMFG expression obviously correlated with the macrophage marker CD163 in gliomas. Moreover, both lower grade glioma (LGG) and glioblastoma multiforme (GBM) patients with high GMFG expression had shorter overall survival than those with low GMFG expression. These results indicate that GMFG may be a therapeutic target for the treatment of such patients. Patients with low GMFG expression who received chemotherapy had a longer survival time than those with high GMFG expression. For patients who received ion radiotherapy (IR) only, the GMFG expression level had no effect on the overall survival neither in CGGA and TCGA datasets. Conclusion: The GMFG is a novel prognostic biomarker for patients with both LGG and GBM. Increased GMFG expression is associated with tumor-associated macrophages (TAMs) infiltration and with a bad response to TMZ treatment.

TMCO1 expression promotes cell proliferation and induces epithelial-mesenchymal transformation in human gliomas.

Transmembrane and coiled-coil domains 1 (TMCO1) is a recently discovered transmembrane protein of endoplasmic reticulum (ER), which plays a critical role in maintaining calcium homeostasis. TMCO1 dysfunction has been proved to be closely related to a variety of human diseases, including glaucoma, deformities, mental retardation and tumorigenesis. However, the role of TMCO1 in gliomas remains unclear. The purpose of this study was to detect the role of TMCO1 in the pathogenesis and progression of gliomas. This study demonstrated that TMCO1 was upregulated in gliomas and its overexpression predicted poor prognosis. We also revealed that the expression of TMCO1 was associated with the World Health Organization (WHO) grade of gliomas. Knockdown of TMCO1 inhibited the proliferation and induced apoptosis of U87 and U251 cells. In addition, TMCO1 induced GBM cell migration and invasion by promoting epithelial-mesenchymal transition (EMT). These date collectively proved the crucial role of TMCO1 as a novel prognostic factor and underlying therapeutic target for glioma patients.

TGF-ß induces GBM mesenchymal transition through upregulation of CLDN4 and nuclear translocation to activate TNF-α/NF-κB signal pathway.

Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor. The unregulated expression of Claudin-4 (CLDN4) plays an important role in tumor progression. However, the biological role of CLDN4 in GBM is still unknown. This study aimed to determine whether CLDN4 mediates glioma malignant progression, if so, it would further explore the molecular mechanisms of carcinogenesis. Our results revealed that CLDN4 was significantly upregulated in glioma specimens and cells. The inhibition of CLND4 expression could inhibit mesenchymal transformation, cell invasion, cell migration and tumor growth in vitro and in vivo. Moreover, combined with in vitro analysis, we found that CLDN4 can modulate tumor necrosis factor-α (TNF-α) signal pathway. Meanwhile, we also validated that the transforming growth factor-ß (TGF-ß) signal pathway can upregulate the expression of CLDN4, and promote the invasion ability of GBM cells. Conversely, TGF-ß signal pathway inhibitor ITD-1 can downregulate the expression of CLDN4, and inhibit the invasion ability of GBM cells. Furthermore, we found that TGF-ß can promote the nuclear translocation of CLDN4. In summary, our findings indicated that the TGF-ß/CLDN4/TNF-α/NF-κB signal axis plays a key role in the biological progression of glioma. Disrupting the function of this signal axis may represent a new treatment strategy for patients with GBM.

TMBIM1 promotes proliferation and attenuates apoptosis in glioblastoma cells by targeting the p38 MAPK signalling pathway.

Glioblastoma multiforme (GBM) is the most common and most fatal primary malignant brain tumour in adults. The average survival time of patients after diagnosis is only 12-15 months. And its characteristics of excessive proliferation and apoptosis evasion play a crucial role in the poor prognosis of patients. Therefore, it is worth investigating the molecular mechanism of GBM to find an effective therapeutic target to overcome the dilemma. In the current study, Transmembrane BAX inhibitor motif containing 1 (TMBIM1) was highly expressed in GBM tissues and high TMBIM1 expression in GBM cell lines (U87 and U251) could promote cell proliferation and inhibit cell cycle arrest. In addition, TMBIM1 could significantly attenuate GBM cell apoptosis and decrease the sensitivity of GBM cells to temozolomide (TMZ). In terms of the molecular mechanism, we revealed that TMBIM1 interferes with the p38/MAPK pathway by inhibiting p38 phosphorylation to promote cell proliferation and attenuate cell apoptosis. In vivo experiments showed that the survival time of mice in TMBIM1 knockdown group was significantly prolonged. Our discovery provided an important basis for future intensive molecular mechanism research in GBM and presented a potential target for the treatment of GBM.

Betulinic acid self-assembled nanoparticles for effective treatment of glioblastoma.

BACKGROUND: Glioblastoma (GBM) is the most common and fatal primary tumor in the central nervous system (CNS). Due to the existence of blood-brain barrier (BBB), most therapeutics cannot efficiently reach tumors in the brain, and as a result, they are unable to be used for effective GBM treatment. Accumulating evidence shows that delivery of therapeutics in form of nanoparticles (NPs) may allow crossing the BBB for effective GBM treatment. METHODS: Betulinic acid NPs (BA NPs) were synthesized by the standard emulsion approach and characterized by electron microscopy and dynamic light scattering analysis. The resulting NPs were characterized for their anti-tumor effects by cell viability assay, EdU-DNA synthesis assay, cell cycle assay, mitochondrial membrane potential, and PI-FITC apoptosis assay. Further mechanistic studies were carried out through Western Blot and immunostaining analyses. Finally, we evaluated BA NPs in vivo for their pharmacokinetics and antitumor effects in intracranial xenograft GBM mouse models. RESULTS: BA NPs were successfully prepared and formed into rod shape. BA NPs could significantly suppress glioma cell proliferation, induce apoptosis, and arrest the cell cycle in the G0/G1 phase in vitro. Furthermore, BA NPs downregulated the Akt/NFκB-p65 signaling pathway in a concentration dependent manner. We found that the observed anti-tumor effect of BA NPs was dependent on the function of CB1/CB2 receptors. Moreover, in the intracranial GBM xenograft mouse models, BA NPs could effectively cross the BBB and greatly prolong the survival time of the mice. CONCLUSIONS: We successfully synthesized BA NPs, which could cross the BBB and demonstrated a strong anti-tumor effect. Therefore, BA NPs may potentially be used for effective treatment of GBM.