Predictive factors influencing outcome of early cranioplasty after decompressive craniectomy: a outcome prediction model study.

Objective: The timing of cranioplasty (CP) has become a widely debated topic in research, there is currently no unified standard. To this end, we established a outcome prediction model to explore the factors influencing the outcome of early CP. Our aim is to provide theoretical and practical basis for whether patients with skull defects after decompressive craniectomy (DC) are suitable for early CP. Methods: A total of 90 patients with early CP after DC from January 2020 to December 2021 were retrospectively collected as the training group, and another 52 patients with early CP after DC from January 2022 to March 2023 were collected as the validation group. The Nomogram was established to explore the predictive factors that affect the outcome of early CP by Least absolute shrinkage analysis and selection operator (LASSO) regression and Logistic regression analysis. Receiver operating characteristic (ROC) curve was used to evaluate the discrimination of the prediction model. Calibration curve was used to evaluate the accuracy of data fitting, and decision curve analysis (DCA) diagram was used to evaluate the benefit of using the model. Results: Age, preoperative GCS, preoperative NIHSS, defect area, and interval time from DC to CP were the predictors of the risk prediction model of early CP in patients with skull defects. The area under ROC curve (AUC) of the training group was 0.924 (95%CI: 0.867-0.980), and the AUC of the validation group was 0.918 (95%CI, 0.842-0.993). Hosmer-Lemeshow fit test showed that the mean absolute error was small, and the fit degree was good. The probability threshold of decision risk curve was wide and had practical value. Conclusion: The prediction model that considers the age, preoperative GCS, preoperative NIHSS, defect area, and interval time from DC has good predictive ability.

Network pharmacology-based strategy to investigate the effect and mechanism of α-solanine against glioma.

BACKGROUND: An anti-tumour activity has been demonstrated for α-solanine, a bioactive compound extracted from the traditional Chinese herb Solanum nigrum L. However, its efficacy in the treatment of gliomas and the underlying mechanisms remain unclear. The aim of this study was to investigate the inhibitory effects of α-solanine on glioma and elucidate its mechanisms and targets using network pharmacology, molecular docking, and molecular biology experiments. METHODS: Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) was utilized to predict the potential targets of α-solanine. GeneCards was used to gather glioma-related targets, and the STRING online database was used to analyze protein-protein interaction (PPI) networks for the shared targets. Hub genes were identified from the resulting PPI network and further investigated using Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Additionally, prognostic and gene set enrichment analyses (GSEA) were carried out to identify potential therapeutic targets and their underlying mechanisms of action in relation to the prognosis of gliomas. In vitro experiments were conducted to verify the findings from the network pharmacology analysis. RESULTS: A total of 289 α-solanine targets and 1149 glioma-related targets were screened, of which 78 were common targets. 11 hub genes were obtained, including SRC, HRAS, HSP90AA1, IGF1, MAPK1, MAPK14, KDR, STAT1, JAK2, MAP2K1, and IGF1R. The GO and KEGG pathway analyses unveiled that α-solanine was strongly associated with several signaling pathways, including positive regulation of MAP kinase activity and PI3K-Akt. Moreover, α-solanine (10 µM and 15 µM) inhibited the proliferation and migration but promoted the apoptosis of glioma cells. Finally, STAT1 was identified as a potential mediator of the effect of α-solanine on glioma prognosis. CONCLUSION: α-Solanine can inhibit the proliferation and migration of gliomas by regulating multiple targets and signalling pathways. These findings lay the foundation for the creation of innovative clinical anti-glioma agents.

Unveiling Mechanical Activation: GAIN Domain Unfolding and Dissociation in Adhesion GPCRs.

Adhesion G protein-coupled receptors (aGPCRs) have extracellular regions (ECRs) containing GPCR autoproteolysis-inducing (GAIN) domains. The GAIN domain enables the ECR to self-cleave into N- and C-terminal fragments. However, the impact of force on the GAIN domain's conformation, critical for mechanosensitive aGPCR activation, remains unclear. Our study investigated the mechanical stability of GAIN domains in three aGPCRs (B, G, and L subfamilies) at a loading rate of 1 pN/s. We discovered that forces of a few piconewtons can destabilize the GAIN domains. In autocleaved aGPCRs ADGRG1/GPR56 and ADGRL1/LPHN1, these forces cause the GAIN domain detachment from the membrane-proximal Stachel sequence, preceded by partial unfolding. In noncleavable aGPCR ADGRB3/BAI3 and cleavage-deficient mutant ADGRG1/GPR56-T383G, complex mechanical unfolding of the GAIN domain occurs. Additionally, GAIN domain detachment happens during cell migration. Our findings support the mechanical activation hypothesis of aGPCRs, emphasizing the sensitivity of the GAIN domain structure and detachment to physiological force ranges.

Network pharmacology -based study on the mechanism of traditional Chinese medicine in the treatment of glioblastoma multiforme.

BACKGROUND: Glioblastoma multiforme (GBM) is one of the most common primary malignant brain tumors. Yi Qi Qu Yu Jie Du Fang (YYQQJDF) is a traditional Chinese medicine (TCM) prescription for GBM. The present study aimed to use a network pharmacology method to analyze the underlying mechanism of YQQYJDF in treating GBM. METHODS: GBM sample data, active ingredients and potential targets of YQQYJDF were obtained from databases. R language was used to screen differentially expressed genes (DEGs) between GBM tissues and normal tissues, and to perform enrichment analysis and weighted gene coexpression network analysis (WGCNA). The Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database was used to perform a protein‒protein interaction (PPI) analysis. A Venn diagram was used to obtain the core target genes of YQQYJDF for GBM treatment. Molecular docking was used to verify the binding between the active ingredient molecules and the proteins corresponding to the core target genes. Cell proliferation assays and invasion assays were used to verify the effect of active ingredients on the proliferation and invasion of glioma cells. RESULTS: A total of 73 potential targets of YQQYJDF in the treatment of GBM were obtained. Enrichment analyses showed that the biological processes and molecular functions involved in these target genes were related to the activation of the G protein-coupled receptor (GPCR) signaling pathway and the regulation of hypoxia. The neuroactive ligand‒receptor pathway, the cellular senescence pathway, the calcium signaling pathway, the cell cycle pathway and the p53 signaling pathway might play important roles. Combining the results of WGCNA and PPI analysis, five core target genes and their corresponding four core active ingredients were screened. Molecular docking indicated that the core active ingredient molecules and the proteins corresponding to the core target genes had strong binding affinities. Cell proliferation and invasion assays showed that the core active ingredients of YQQYJDF significantly inhibited the proliferation and invasion of glioma cells (P < 0.01). CONCLUSIONS: The present study predicted the possible active ingredients and targets of YQQYJDF in treating GBM, and analyzed its possible mechanism. These results may provide a basis and ideas for further research.

Improving the mapping accuracy of soil heavy metals through an adaptive multi-fidelity interpolation method.

Soil heavy metal pollution poses a serious threat to environmental safety and human health. Accurately mapping the soil heavy metal distribution is a prerequisite for soil remediation and restoration at contaminated sites. To improve the accuracy of soil heavy metal mapping, this study proposed an error correction-based multi-fidelity technique to adaptively correct the biases of traditional interpolation methods. The inverse distance weighting (IDW) interpolation method was chosen and combined with the proposed technique to form the adaptive multi-fidelity interpolation framework (AMF-IDW). In AMF-IDW, sampled data were first divided into multiple data groups. Then one data group was used to build the low-fidelity interpolation model through IDW, while the other data groups were treated as high-fidelity data and used for adaptively correcting the low-fidelity model. The capability of AMF-IDW to map the soil heavy metal distribution was evaluated in both hypothetical and real-world scenarios. Results showed that AMF-IDW provided more accurate mapping results compared with IDW and the superiority of AMF-IDW became more evident as the number of adaptive corrections increased. Eventually, after using up all data groups, AMF-IDW improved the R2 values for mapping results of different heavy metals by 12.35-24.32%, and decreased the RMSE values by 30.35%-42.86%, indicating a much higher level of mapping accuracy relative to IDW. The proposed adaptive multi-fidelity technique can be equally combined with other interpolation methods and provide promising potential in improving the soil pollution mapping accuracy.

3D multimodal image fusion based on MRI in the preoperative evaluation of microvascular decompression: A meta­analysis.

Neurovascular compression (NVC) is the main cause of hemifacial spasm (HFS) or trigeminal neuralgia (TN), and frequently occurs at the root entry zone of cranial nerves. Microvascular decompression (MVD) is an effective surgical treatment for TN and HFS caused by NVC. The accurate preoperative diagnosis of NVC is crucial to the evaluation of MVD as an appropriate treatment for TN and HFS. Three-dimensional (3D) time-of-flight magnetic resonance angiography (3D TOF MRA) and high resolution T2-weighted imaging (HR T2WI) are used to detect NVC prior to MVD; however, this combination alone has certain disadvantages. Multimodal image fusion (MIF) may combine two or more images from the same or different modalities, allowing neurosurgeons to use the reconstructed 3D model to observe anatomical details more clearly from different perspectives. The aim of the present meta-analysis was to evaluate the effect of 3D MIF based on 3D TOF MRA combined with HR T2WI in the preoperative diagnosis of NVC, and thus to evaluate its clinical application value in the preoperative evaluation of MVD. Relevant studies available on PubMed, Embase, Web of Science, Scopus, China National Knowledge Infrastructure and the Cochrane Library, and published from the inception of each database to September 2022, were retrieved. Studies using 3D MIF based on 3D TOF MRA combined with HR T2WI to diagnose NVC in patients with TN or HFS were included. The Quality Assessment of Diagnostic Accuracy Studies checklist was used to evaluate the quality of the included studies. The statistical software Stata 16.0 was used to perform the meta-analysis. Data extraction was performed by two independent investigators and discrepancies were resolved by discussion. Pooled sensitivities, specificities, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR) and the area under the receiver operating characteristic curve (AUROC) were calculated as the main summary effect size. The I² and Q-test were used to assess heterogeneity. The present search identified 702 articles, of which 7 (comprising 390 patients) fulfilled the inclusion criteria. Bivariate analysis indicated that the pooled sensitivity and specificity of 3D MIF based on 3D TOF MRA combined with HR T2WI for detecting NVC were 0.97 (95% CI, 0.95-0.99) and 0.89 (95% CI, 0.77-0.95), respectively. The pooled PLR was 8.8 (95% CI, 4.1-18.6), the pooled NLR was 0.03 (95% CI, 0.02-0.06) and the pooled DOR was 291 (95% CI, 99-853). The AUROC was 0.98 (95% CI, 0.97-0.99). The studies had no substantial heterogeneity (I2=0; Q=0.000; P=0.50). The present results suggested that 3D MIF based on 3D TOF MRA combined with HR T2WI had excellent sensitivity and specificity for diagnosing NVC in patients with TN or HFS. Therefore, this method should serve a key role in MVD preoperative evaluation.

Development of a novel angiogenesis-related lncRNA signature to predict the prognosis and immunotherapy of glioblastoma multiforme.

Background: Long noncoding RNA (lncRNA) can regulate tumorigenesis, angiogenesis, proliferation, and other tumor biological behaviors, and is closely related to the growth and progression of glioma. The purpose of this research was to investigate the role of angiogenesis-related lncRNA in the prognosis and immunotherapy of glioblastoma multiforme (GBM). Methods: Differential analysis was carried out to acquire angiogenesis-related differentially expressed lncRNAs (AR-DElncRNAs). The AR-DElncRNAs were then subjected to univariate Cox and least absolute shrinkage and selection operator (LASSO) analyses to construct a prognostic model. Based on the median risk score, patients were classified into high-risk and low-risk groups. Kaplan-Meier survival analysis was conducted to estimate the prognostic value of the prognostic model. In addition, a nomogram was built to predict individual survival probabilities by combining clinicopathological characteristics and a prognostic model. Furthermore, immune infiltration, immunotherapy, and drug sensitivity analyses were administered to investigate the differences between the high- and low-risk groups. Results: We identified 3 lncRNAs (DGCR5, PRKAG2-AS1, and ACAP2-IT1) that were significantly associated with the survival of GBM patients from the 255 AR-DElncRNAs based on univariate Cox and LASSO analyses. Then, a prognostic model was structured according to these 3 lncRNAs, from which we found that high-risk GBM patients had a worse prognosis than that of low-risk patients. Moreover, the risk score was determined to be an independent prognostic factor [hazard ratio (HR) =1.444; 95% confidence interval (CI): 1.014-2.057; P<0.05]. The immune microenvironment analysis revealed that the immune score, stromal score, and Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data (ESTIMATE) score were significantly higher in the high-risk group than in the low-risk group. Neutrophils, macrophages, immature dendritic cells (iDCs), natural killer (NK) CD56dim cells, activated DCs (aDCs), and uncharacterized cells were different in the high- and low-risk groups. In addition, the high-risk group had a stronger sensitivity to immunotherapy. Furthermore, the sensitivity of 28 potential chemotherapeutic drugs differed significantly between the high- and low-risk groups. Conclusions: A novel angiogenesis-related lncRNA signature could be used to predict the prognosis and treatment of GBM.

Targeting of MALT1 May Improve Functional Recovery and Attenuate Microglia M1 Polarization-Mediated Neuroinflammation During Spinal Cord Injury.

Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is involved in neural injury, neuroinflammation, microglia activation, and polarization, while its function in spinal cord injury (SCI) remains unclear. Thus, this study aimed to evaluate the role of MALT1 modification on SCI recovery and its underlying mechanism. SCI surgery or sham surgery was performed in Sprague-Dawley rats. Then, MALT1 knockdown or negative control lentivirus was injected into SCI rats. Subsequently, MALT1 expression, locomotor capability, neural injury, markers for microglia activation and polarization, inflammatory cytokine expressions, and nuclear factor (NF)-κB pathway were detected. SCI rats exhibited higher MALT1 expression, microglia activation and M1 polarization, neuroinflammation, and NF-κB pathway activation, while worse locomotor capacity compared to sham rats (all P < 0.05). In SCI rats, MALT1 knockdown alleviated Basso, Beattie, and Bresnahan score from 10 to 28 days and attenuated HE staining reflected neural injury (all P < 0.05). Besides, MALT1 knockdown declined the number of IBA1+ cells, IBA1+ iNOS+ cells, and IBA1+ CD86+ cells, while enhanced the number of IBA1+ Arg1+ cells and IBA1+ CD206+ cells in SCI rats (all P < 0.05). Meanwhile, MALT1 knockdown declined the expressions of IL-1ß, IL-6, and TNF-α in SCI (all P < 0.05), but did not affect IL-10 expression (P > 0.05). Furthermore, MALT1 knockdown suppressed NF-κB pathway activation validated by immunofluorescence staining and western blot assays (all P < 0.05). MALT1 knockdown improves functional recovery, attenuates microglia activation, M1 polarization, and neuroinflammation via inhibiting NF-κB pathway in SCI.

Three-dimensional time-of-flight magnetic resonance angiography combined with high resolution T2-weighted imaging in preoperative evaluation of microvascular decompression.

BACKGROUND: Neurovascular compression (NVC) is the main cause of primary trigeminal neuralgia (TN) and hemifacial spasm (HFS). Microvascular decompression (MVD) is an effective surgical method for the treatment of TN and HFS caused by NVC. The judgement of NVC is a critical step in the preoperative evaluation of MVD, which is related to the effect of MVD treatment. Magnetic resonance imaging (MRI) technology has been used to detect NVC prior to MVD for several years. Among many MRI sequences, three-dimensional time-of-flight magnetic resonance angiography (3D TOF MRA) is the most widely used. However, 3D TOF MRA has some shortcomings in detecting NVC. Therefore, 3D TOF MRA combined with high resolution T2-weighted imaging (HR T2WI) is considered to be a more effective method to detect NVC. AIM: To determine the value of 3D TOF MRA combined with HR T2WI in the judgment of NVC, and thus to assess its value in the preoperative evaluation of MVD. METHODS: Related studies published from inception to September 2022 based on PubMed, Embase, Web of Science, and the Cochrane Library were retrieved. Studies that investigated 3D TOF MRA combined with HR T2WI to judge NVC in patients with TN or HFS were included according to the inclusion criteria. Studies without complete data or not relevant to the research topics were excluded. The Quality Assessment of Diagnostic Accuracy Studies checklist was used to assess the quality of included studies. The publication bias of the included literature was examined by Deeks' test. An exact binomial rendition of the bivariate mixed-effects regression model was used to synthesize data. Data analysis was performed using the MIDAS module of statistical software Stata 16.0. Two independent investigators extracted patient and study characteristics, and discrepancies were resolved by consensus. Individual and pooled sensitivities and specificities were calculated. The I² statistic and Q test were used to test heterogeneity. The study was registered on the website of PROSERO (registration No. CRD42022357158). RESULTS: Our search identified 595 articles, of which 12 (including 855 patients) fulfilled the inclusion criteria. Bivariate analysis showed that the pooled sensitivity and specificity of 3D TOF MRA combined with HR T2WI for detecting NVC were 0.96 [95% confidence interval (CI): 0.92-0.98] and 0.92 (95%CI: 0.74-0.98), respectively. The pooled positive likelihood ratio was 12.4 (95%CI: 3.2-47.8), pooled negative likelihood ratio was 0.04 (95%CI: 0.02-0.09), and pooled diagnostic odds ratio was 283 (95%CI: 50-1620). The area under the receiver operating characteristic curve was 0.98 (95%CI: 0.97-0.99). The studies showed no substantial heterogeneity (I2 = 0, Q = 0.001 P = 0.50). CONCLUSION: Our results suggest that 3D TOF MRA combined with HR T2WI has excellent sensitivity and specificity for judging NVC in patients with TN or HFS. This method can be used as an effective tool for preoperative evaluation of MVD.

miR-452-3p Targets HDAC3 to Inhibit p65 Deacetylation and Activate the NF-κB Signaling Pathway in Early Brain Injury after Subarachnoid Hemorrhage.

OBJECTIVES: Subarachnoid hemorrhage (SAH) is a subtype of stroke, and early brain injury (EBI) is a contributor to its unfavorable outcome. microRNA (miRNA) is abundantly expressed in the brain and participates in brain injury. This study investigated the effect of miR-452-3p on EBI after SAH. METHODS: The murine model of SAH was established. miR-452-3p expression was detected 48 h after the model establishment. Neurobehavioral function, blood-brain barrier permeability, brain water content, neuronal apoptosis, and inflammatory factors were evaluated. The cell model of SAH was induced by oxygen hemoglobin. Apoptosis rate, lactate dehydrogenase, and reactive oxygen species were detected. The targeting relationship between miR-452-3p and histone deacetylase 3 (HDAC3) was verified. The acetylation of p65 and the binding of HDAC3 to p65 were detected. The inhibitory protein of the nuclear factor κB pathway (IκBα) was detected. Suberoylanilide hydroxamic acid was injected into the SAH mice treated with miR-452-3p inhibitor. RESULTS: SAH mice showed upregulated miR-452-3p expression; reduced the neurological score; increased blood-brain barrier permeability, brain water content, and neuronal apoptosis; elevated pro-inflammatory factors; and reduced anti-inflammatory factors. SAH increased the apoptosis rate, lactate dehydrogenase release, and reactive oxygen species levels in oxygen-hemoglobin-treated neuron cells. Inhibition of miR-452-3p reversed the above trends. miR-452-3p targeted HDAC3. SAH upregulated p65 acetylation. miR-452-3p inhibitor promoted the binding of HDAC3 to p65, decreased p65 acetylation, and upregulated IκBα. Suberoylanilide hydroxamic acid reversed the protective effect of miR-452-3p inhibitor on SAH mice and aggravated brain injury. CONCLUSIONS: miR-452-3p targeted HDAC3 to inhibit the deacetylation of p65 and activate the nuclear factor κB pathway, thus aggravating EBI after SAH.

Downregulation of Astrocyte Elevated Gene-1 Expression Combined with All-Trans Retinoic Acid Inhibits Development of Vasculogenic Mimicry and Angiogenesis in Glioma.

OBJECTIVE: This study aimed to investigate the effects of downregulating astrocyte elevated gene-1 (AEG-1) expression combined with all-trans retinoic acid (ATRA) on vasculogenic mimicry (VM) formation and angiogenesis in glioma. METHODS: U87 glioma cells were transfected with AEG-1 shRNA lentiviral vectors (U87-siAEG-1) and incubated in a medium containing 20 µmol/L ATRA. Matrigel-based tube formation assay was performed to evaluate VM formation, and the cell counting kit-8 (CCK-8) assay was used to analyze the proliferation of glioma cells in vitro. Reverse transcription-quantitative polymerase chain reaction and Western blot analysis were used to investigate the mRNA and protein expression of related genes, respectively. Glioma xenograft models were generated via subcutaneous implantation of glioma cells in nude mice. Tumor-bearing mice received an intraperitoneal injection of ATRA (10 mg/kg per day). Immunohistochemistry was used to evaluate the expression of related genes and the microvessel density (MVD) in glioma xenograft models. CD34/periodic acid-Schiff double staining was performed to detect VM channels in vivo. The volume and weight of tumors were measured, and a tumor growth curve was drawn to evaluate tumor growth. RESULTS: A combination of ATRA intervention and downregulation of AEG-1 expression significantly inhibited the proliferation of glioma cells in vitro and glioma VM formation in vitro and in vivo. It also significantly decreased MVD and inhibited tumor growth. Further, the expression levels of matrix metalloproteinase (MMP)-2, MMP-9, vascular endothelial-cadherin (VE-cadherin), and vascular endothelial growth factor (VEGF) in glioma significantly decreased in vivo and in vivo. CONCLUSION: Hence, a combinatorial approach might be effective in treating glioma through regulating MMP-2, MMP-9, VEGF, and VE-cadherin expression.

Modified surgical method of supra- and infratentorial epidural hematoma and the related anatomical study of the squamous part of the occipital bone.

BACKGROUND: Supra- and infratentorial acute epidural hematoma (SIEDH) is a common posterior cranial fossa epidural hematoma located at the inner surface of the squamous part of the occipital bone (SOB). Traditionally, surgical treatment of the SIEDH requires a combined supra-infratentorial craniotomy. AIM: To analyze the morphological characteristics of the SOB and introduce a single supratentorial craniotomy for SIEDH. METHODS: Skull computed tomography (CT) scan data from 32 adult patients were collected from January 1, 2019 to January 31, 2020. On the median sagittal plane of the CT scan, the angle of the SOB (ASOB) was defined by two lines: Line A was defined from the lambdoid suture (LambS) to the external occipital protuberance (EOP), while line B was defined from the EOP to the posterior edge of the foramen magnum (poFM). The operative angle for the SIEDH (OAS) from the supra- to infratentorial epidural space was determined by two lines: The first line passes from the midpoint between the EOP and the LambS to the poFM, while the second line passes from the EOP to the poFM. The ASOB and OAS were measured and analyzed. RESULTS: Based on the anatomical study, a single supratentorial craniotomy was performed in 8 patients with SIEDH. The procedure and the results of the modified surgical method were demonstrated in detail. For males, the ASOB was 118.4 ± 4.7 and the OAS was 15.1 ± 1.8; for females, the ASOB was 130.4 ± 5.1 and the OAS was 12.8 ± 2.0. There were significant differences between males and females both in ASOB and OAS. The smaller the ASOB was, the larger the OAS was. The bone flaps in 8 patients were designed above the transverse sinus intraoperatively, and the SIEDH was completely removed without suboccipital craniotomy. The SOB does not present as a single straight plane but bends at an angle around the EOP and the superior nuchal lines. The OAS was negatively correlated with the ASOB. CONCLUSION: The single supratentorial craniotomy for SIEDH is reliable and effective.

Prognostic Potential of METTL7B in Glioma.

OBJECTIVE: Methyltransferase-like 7B (METTL7B) is a member of methyltransferase-like family. Little is known about the exact role of METTL7B in cancer. This study aims to investigate the role of METTL7B in gliomas. METHODS: The expression of METTL7B in glioma and adjacent normal tissues were examined by using TCGA, Chinese Glioma Genome Atlas (CGGA) database, and clinical tissues. RESULTS: The results showed that METTL7B was highly expressed in glioma. Patients with high levels of METTL7B usually had poor survival in glioma, especially in low-grade glioma (LGG). Data from CGGA showed that METTL7B was an independent risk factor of glioma and can be used to evaluate the survival time of glioma patients. Hypomethylation in the METTL7B CpG islands was lower in LGG, and all the hypomethylated METTL7B islands were correlated with poor LGG survival. Furthermore, METTL7B levels were correlated with high numbers of tumor infiltrated immune cells in glioma, especially in LGG. ). Gene Set Enrichment Analysis found METTL7B was correlated with leukocyte proliferation, T-cell proliferation, peptidase activity, lymphocyte activation, etc. TCGA and CGGA database analysis showed that there were 1,546 and 1,117 genes that had a synergistic effect with METTL7B in glioma, respectively, and there were 372 genes overlapped between the 2 groups, including PD-L1. Data from clinical tissues also showed PD-L1 was highly expressed in glioma tissues and was positively correlated with METTL7B. CONCLUSION: Our study suggested that METTL7B was a potential prognostic biomarker for glioma and other cancers, and it may act as an oncogenic driver and may be a potential therapeutic target in human cancer, especially in LGG.

Extracellular vesicles carry miR-27a-3p to promote drug resistance of glioblastoma to temozolomide by targeting BTG2.

OBJECTIVE: Glioblastoma (GBM) is the most common central nervous system tumor. Temozolomide (TMZ) is a commonly used drug for GBM management. This study explored the mechanism of extracellular vesicles (EVs) regulating TMZ-resistance in GBM. METHODS: LN229 cells were inducted into TMZ-resistant LN229r strain by stepwise induction. After the intervention of miR-27a-3p expression, cell viability of GBM cells treated with different concentrations of TMZ was detected by MTT and IC50 value was calculated. Cell proliferation and apoptosis were detected by colony formation and flow cytometry. EVs extracted from LN18 cells were identified and the internalization of EVs by LN229r cells was evaluated. The 100 µmol/L TMZ-treated LN229r cells were treated with EVs or EVs with downregulated miR-27a-3p to verify the effect of EVs-carried miR-27a-3p on TMZ resistance. The binding relation between BTG2 and miR-27a-3p was verified. miR-27a-3p and BTG2 expressions in GBM cells and EVs were detected by RT-qPCR. The BTG2 effect on TMZ-resistance in GBM was verified. The xenograft tumor nude mouse model was established by injecting LN229r cells and treated with EVs and 100 µmol/L TMZ. RESULTS: miR-27a-3p was highly expressed in LN229r cells. IC50 value and proliferation of LN229r cells with silenced miR-27a-3p were decreased and apoptosis was increased, indicating that miR-27a-3p silencing reduced the drug-resistant cell LN229r resistance to TMZ. LN18-derived EVs could be internalized by LN229r cells, and release its encapsulated miR-27a-3p into LN229r cells and increase miR-27a-3p expression. EV treatment increased LN229r cell proliferation and reduced apoptosis, while EVs with silenced miR-27a-3p showed the opposite trend. miR-27a-3p targeted BTG2. BTG2 overexpression reduced LN229r cell resistance to TMZ. In vivo, after EVs treatment, tumor volume and weight, Ki67-positive rate, and miR-27a-3p were increased, while BTG2 expression was decreased. CONCLUSION: GBM-derived EVs were internalized by GBM cells, released miR-27a-3p into GBM cells, upregulated miR-27a-3p expression, and targeted BTG2, thus promoting TMZ resistance.

ARRDC3 polymorphisms may affect the risk of glioma in Chinese Han.

This study ascertained to explore the potential contribution of ARRDC3 polymorphisms in the risk and prognosis of glioma. One thousand sixty-one patients and healthy controls were conducted to assess whether ARDC3 polymorphism was associated with glioma risk and prognosis. Four sites in ARRDC3 were selected and genotyped in MassARRAY platform. The calculated odd ratios and 95% confidence intervals from logistic regression were applied for risk assessment. The relationship between ARRDC3 variants and glioma prognosis was evaluated using log-rank test, Kaplan-Meier analysis, and so on. Also, false-positive report probability (FPRP) and statistical power were also assessed. Our findings suggested the negative role of ARRDC3 polymorphisms in the glioma risk. We also found the effect of candidate SNPs in ARRDC3 on the susceptibility to glioma was dependent on the age, gender, and histology of glioma patients. The results suggested that the genetic polymorphisms of ARRDC3 were related to an increased risk of glioma.

Influence of modulus of alkaline activator on the removal of Pb2+ by mesoporous geopolymer adsorbent.

In this study, we synthesised metakaolin-based mesoporous geopolymer adsorbent and investigated the effect of alkaline activator modulus (molar ratios of SiO2/Na2O) on Pb2+ adsorption. The geopolymer prepared using 1.2 M alkaline activator performs excellent Pb2+ removal with a maximum adsorption capacity of 172.71 mg g-1. The pseudo-second-order model fit the adsorption kinetics satisfactorily, indicating that the adsorption process is dominated by chemical adsorption. The adsorption data appropriately fit the Langmuir isotherm model. The contributions of adsorption methods corresponding to the total quantity adsorbed declined in the following order: EDTA extraction (formation of Pb aluminium oxide and Pb-containing amorphous materials) > residual fraction (Pb stabilisation in the tetrahedral aluminosilicate network) > ion exchange. Overall, the alkaline activator modulus significantly influenced the Pb2+ adsorption characteristics of the geopolymer adsorbent.

Genetic variants of CYP4F12 gene are associated with glioma susceptibility.

Glioma is a common and fatal primary malignant tumor of the central nervous system, and its prognosis is poor. To determine the susceptibility markers of gliomas in Chinese population we conducted a genome-wide association study (GWAS) of glioma in the Han Chinese population, with a total of 485 glioma cases and 485 controls. Genotyping was conducted using the Applied Biosystems Axiom Precision Medicine Diversity Array. Besides, we carried out imputation using IMPUTE 2.0 software, and the 1000 Genomes Phase 3 was used as the reference panel. The logistic regression model was used to analyze the association of each SNP with glioma risk, assuming an additive genetic model, which was implemented in PLINK version 1.9. Odds ratio (OR) and 95% confidence interval (CI) were estimated from logistic regression analysis with adjustment for age and gender. The results revealed that the SNP (rs688755) in the exon region of CYP4F12 at 19p13.12 reached genome-wide significance associated with gliomas (P = 2.35 × 10-8 , OR = 3.55, 95% CI = 2.20-5.74). Our findings provide deeper insight into the genetic contribution to glioma in different populations.

Downregulation of astrocyte elevated gene-1 expression inhibits the development of vasculogenic mimicry in gliomas.

Vasculogenic mimicry (VM) contributes to the resistance of anti-angiogenic therapies in glioma. Certain genes, including MMP-2 and VEGF may be associated with the development of VM. Astrocyte elevated gene-1 (AEG-1) is considered to be an oncogene that promotes autophagy, invasion, metastasis, angiogenesis and drug resistance; however, the association between AEG-1 and VM formation is still unknown. The present study investigated the effects of AEG-1 downregulation on VM formation in the U87 glioma cell line in vitro and in xenograft models of glioma, and the potential underlying mechanisms of action. In the present study, U87 glioma cells were infected with the AEG-1 short hairpin RNA lentivirus. A Matrigel-based tube formation assay was performed to evaluate VM formation in vitro. Reverse transcription-quantitative PCR and western blot analysis were conducted to investigate the mRNA and protein expression levels of MMP-2 and VEGF. Glioma xenograft models were generated through the intracerebral implantation of U87 glioma cells into nude rats; CD34/Periodic Acid-Schiff double-staining was performed to detect VM channels in vivo. Following AEG-1 downregulation in U87 cells, the development of VM was significantly decreased in vitro and in vivo. In addition, the expression levels of MMP-2 and VEGF in glioma cells were decreased compared with the control group. These results suggested that downregulation of AEG-1 expression could significantly inhibit the development of VM in gliomas, both in vitro and in vivo, and may be partially related to the regulation of VEGF and MMP-2 expression.

Circ_HECW2 functions as a miR-30e-5p sponge to regulate LPS-induced endothelial-mesenchymal transition by mediating NEGR1 expression.

Endothelial-mesenchymal transition (EndoMT) plays a critical role in the dysfunction of the blood-brain barrier (BBB). Circular RNAs (circRNAs) function as crucial regulatory factors in EndoMT. Nevertheless, the underlying mechanisms of circRNA HECW2 (circ_HECW2, hsa_circ_0057583) in lipopolysaccharide (LPS)-induced EndoMT remain largely unclear. The levels of circ_HECW2, miR-30e-5p and neuronal growth regulator 1 (NEGR1) were detected by quantitative real-time polymerase chain reaction (qRT-PCR) or western blot. Ribonuclease (RNase) R and Actinomycin D assays were performed to validate the stability of circ_HECW2. Cell colony formation, proliferation and apoptosis were tested by a standard colony formation assay, the 3-(4,5-dimethylthiazol-2yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay and flow cytometry, respectively. Targeted relationships among circ_HECW2, miR-30e-5p and NEGR1 were verified by a dual-luciferase reporter assay. Our data indicated that LPS increased circ_HECW2 expression and reduced miR-30e-5p expression in human brain microvascular endothelial cells (HBMECs). Circ_HECW2 silencing promoted cell proliferation and suppressed cell apoptosis and EndoMT in LPS-treated HBMECs. Mechanistically, circ_HECW2 directly interacted with miR-30e-5p by binding to miR-30e-5p. MiR-30e-5p was a functional mediator of circ_HECW2 in regulating LPS-induced cell EndoMT. Furthermore, Circ_HECW2 regulated NEGR1 expression through functioning as a miR-30e-5p sponge. Moreover, miR-30e-5p overexpression repressed the EndoMT of LPS-treated HBMECs by targeting NEGR1. Collectively, our current study demonstrated that circ_HECW2 silencing suppressed LPS-triggered HBMEC EndoMT at least in part through the regulation of the miR-30e-5p/NEGR1 axis, illuminating a promising strategy for EndoMT inhibition.

SOX15 exerts antitumor function in glioma by inhibiting cell proliferation and invasion via downregulation of Wnt/ß-catenin signaling.

AIMS: Sex-determining region of Y chromosome-related high-mobility-group box 15 (SOX15) has recently emerged as a candidate tumor-inhibitor in multiple types of human tumors. To date, the involvement of SOX15 in glioma is undetermined. The purpose of this study was to investigate the expression, function and potential molecular mechanism of SOX15 in glioma. MAIN METHODS: Relative mRNA expression was analyzed by real-time quantitative PCR. Protein expression was determined by Western blot. Cell proliferation was assessed by cell counting kit-8 and colony formation assay. Cell invasion was evaluated by Matrigel invasion assay. Wnt/ß-catenin activation was monitored by luciferase reporter assay. KEY FINDINGS: SOX15 expression was decreased in glioma tissues and cell lines compared with normal controls. Kaplan-Meier analysis revealed that patients with low expression of SOX15 had shorter survival than those who had high expression of SOX15. The upregulation of SOX15 markedly repressed the proliferation and invasion of glioma cells, whereas its depletion enhanced glioma cell proliferation and invasion. Research into the mechanism revealed that SOX15 exerted an inhibitory effect on Wnt/ß-catenin signaling in glioma cells. Notably, overexpression of ß-catenin partially reversed the SOX15 overexpression-mediated tumor-suppressive effect. In addition, SOX15 overexpression significantly impeded tumor formation by glioma cells in vivo in a mouse xenograft model associated with downregulation of active ß-catenin expression. SIGNIFICANCE: These data demonstrate that SOX15 functions as a potential tumor-suppressor in glioma by inhibiting cell proliferation and invasion via the downregulation of Wnt/ß-catenin signaling.