An inflammatory gene-related prognostic risk score model for prognosis and immune infiltration in glioblastoma.

This study aimed to screen for key genes related to the prognosis of patients with glioblastoma (GBM). First, bioinformatics analysis was performed based on databases such as TCGA and MSigDB. Inflammatory-related genes were obtained from the MSigDB database. The TCGA-tumor samples were divided into cluster A and B groups based on consensus clustering. Multivariate Cox regression was applied to construct the risk score model of inflammatory-related genes based on the TCGA database. Second, to understand the effects of model characteristic genes on GBM cells, U-87 MG cells were used for knockdown experiments, which are important means for studying gene function. PLAUR is an unfavorable prognostic biomarker for patients with glioma. Therefore, the model characteristic gene PLAUR was selected for knockdown experiments. The prognosis of cluster A was significantly better than that of cluster B. The verification results also demonstrate that the risk score could predict overall survival. Although the immune cells in cluster B and high-risk groups increased, no matching survival advantage was observed. It may be that stromal activation inhibits the antitumor effect of immune cells. PLAUR knockdown inhibits tumor cell proliferation, migration, and invasion, and promoted tumor cell apoptosis. In conclusion, a prognostic prediction model for GBM composed of inflammatory-related genes was successfully constructed. Increased immune cell expression may be linked to a poor prognosis for GBM, as stromal activation decreased the antitumor activity of immune cells in cluster B and high-risk groups. PLAUR may play an important role in tumor cell proliferation, migration, invasion, and apoptosis.

Uncover DNA damage and repair-related gene signature and risk score model for glioma.

BACKGROUND: Glioma is a common primary central nervous system tumor with complex pathogenesis. DNA damage and repair (DDR) is widely involved in regulating cell proliferation and tumorigenesis by correcting and repairing DNA damage mechanisms. Recent studies have reported the following properties in cancer cells in glioma, increased DNA damage and reduced DNA repair capacity. However, the relationship between glioma and DDR-related genes was unclear. METHODS: DDR-related risk score model was built. The validity of this model was validated in detail through the Kaplan-Meier survival analysis, tumor mutational burden (TMB) analysis, immune cell infiltration, sensitivity to treatment regimens. Moreover, the model's adaptability was validated in different glioma data cohorts and different glioma subgroups. To further investigate the molecular mechanism of one of DDR-related gene (NUDT1) in glioma, U251 cell was used for the knockdown experiment, followed by MTT, wound healing and transwell analysis. RESULTS: Ten prognostic-related DDR-related signature genes were obtained, including EID3, MGMT, YWHAG, PMS1, SHPRH, HUS1, NUDT1, GADD45G, APEX1 and FAM175A. The RT-qPCR results suggested that the latter five genes were highly expressed in glioma patients. Interestingly, high TMB score had longer survival. In high-risk score groups, reduced immune cell infiltration in the tumor microenvironment lead to poorer patient outcomes. Sensitivity to treatment regimens analysis indicated that low-risk score groups were more sensitive to chemotherapeutics. Moreover, the risk score model had a good prediction effect on different glioma datasets and different glioma subgroups. In vitro mechanism study showed that knockdown of NUDT1 reduced tumorigenesis. Furthermore, knockdown of NUDT1 remarkably reduced the expression level of HIF-1α. CONCLUSION: DDR-related risk score model built-in this work has good predictive performance for glioma.Key messagesTen prognostic-related DDR-related signature genes were obtained, including EID3, MGMT, YWHAG, PMS1, SHPRH, HUS1, NUDT1, GADD45G, APEX1 and FAM175A.In high-risk score groups, reduced immune cell infiltration in the tumor microenvironment leads to poorer patient outcomes.The risk score model had a good prediction effect on different glioma datasets and different glioma subgroups.Knockdown of NUDT1 reduced tumorigenesis of glioma and remarkably reduced the expression level of HIF-1α.

Extracellular vesicles derived from bone marrow mesenchymal stem cells alleviate neurological deficit and endothelial cell dysfunction after subarachnoid hemorrhage via the KLF3-AS1/miR-83-5p/TCF7L2 axis.

BACKGROUND: New data are accumulating on the effects of mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) in cerebrovascular diseases. We explored the potential role of KLF3-AS1-containing bone marrow MSC-EVs (BMSC-EVs) in a rat model of subarachnoid hemorrhage (SAH). METHODS: A rat model of SAH was established by endovascular perforation method, into which KLF3-AS1-containing EVs from BMSCs or miR-183-5p mimic were injected. Further, brain microvascular endothelial cells (BMECs) were induced by oxyhemoglobin (OxyHb) to simulate in vitro setting, which were co-cultured with KLF3-AS1-containing EVs from BMSCs. Effects of KLF3-AS1 on neurological deficits in vivo and endothelial cell dysfunction in vitro were investigated. We also performed bioinformatics analysis to predict downstream factors miR-183-5p and TCF7L2, which were verified by RIP, RNA pull-down and luciferase activity assays. RESULTS: BMSC-EVs was demonstrated to alleviate neurological deficits in SAH rats and endothelial cell dysfunction in OxyHb-induced BMECs. In addition, BMSC-EVs were shown to deliver KLF3-AS1 to BMECs, where KLF3-AS1 bound to miR-183-5p and miR-183-5p targeted TCF7L2. In vivo results confirmed that BMSC-EVs regulated the KLF3-AS1/miR-183-5p/TCF7L2 signaling axis to attenuate neurological deficit and endothelial dysfunction after SAH. CONCLUSION: Overall, KLF3-AS1 delivered by BMSC-EVs upregulate TCF7L2 expression by binding to miR-138-5p, thus attenuating neurological deficits and endothelial dysfunction after SAH.

Mesenchymal stem cell-derived extracellular vesicles prevent glioma by blocking M2 polarization of macrophages through a miR-744-5p/TGFB1-dependent mechanism.

AIM: Our current study is conducted with intention to explore the regulatory mechanism of mesenchymal stem cell (MSC)-derived extracellular vesicle (EV)-miR-744-5p in glioma. METHODS: Expression patterns of TGFB1, TGFBR1, and miR-744-5p were determined. EVs were isolated from human MSCs, which were characterized. Then, macrophages were co-cultured with MSCs with ectopic miR-744-5p expression to explore its role in cell proliferation, invasion, and migration capabilities. A nude mouse model of glioma xenograft was developed to observe the tumorigenesis and metastasis ability of glioma in vivo. RESULTS: TGFB1 and TGFBR1 were upregulated in glioma. TGFB1 promoted M2 polarization of macrophages through theMAPK signaling, thereby promoting the progression of glioma. MSC-EVs suppressed TGFB1 expression in macrophages and inhibited M2 polarization of macrophages. MSC-EVs-miR-744-5p/TGFB1/MAPK axis inhibited M2 polarization of macrophages and reduced the malignant phenotypes of glioma cells. In vivo experiments verified that MSC-EVs-miR-744-5p inhibited the polarization of macrophage M2 and prevented glioma progression. CONCLUSION: Taken together, MSC-EVs-miR-744-5p may suppress the MAPK signaling activity by downregulating TGFB1, and then inhibit polarization of macrophages M2, thereby preventing the progression of glioma. Graphical Headlights 1. TGFB1 promotes the M2 polarization of macrophages via the MAPK signaling. 2. miR-744-5p carried by MSC-EVs targets and inhibits TGFB1. 3. MSC-EV-miR-744-5p inhibits M2 polarization of macrophages to prevent glioma progression. 4. miR-744-5p loaded by MSC-EVs may be a preventive strategy against glioma.

Transcription Factor ELF1 Activates MEIS1 Transcription and Then Regulates the GFI1/FBW7 Axis to Promote the Development of Glioma.

Glioma is the most common malignancy in the central nervous system with no immediate prospect of a cure. Comprehensive understanding on the pathogenesis of the disorder contributes to a better outcome. Herein, we aimed to investigate whether transcription factors erythroblast transformation-specific (ETS) transcription factor (ELF1), myeloid ecotropic viral integration site 1 (MEIS1), and growth factor independence 1 (GFI1)/F-box/WD repeat-containing protein 7 (FBW7) mediate progression of glioma. ELF1, MEIS1, and GFI1 were upregulated in glioma cells and tissues, as ELF1 was correlated with poor prognosis. Bioinformatics analysis identified the binding between ELF1 and MEIS1 as well as between GFI1 and FBW7, confirmed by chromatin immunoprecipitation (ChIP) experiments. Functional experiment indicated that silencing of ELT1 decreased MEIS1 expression and that overexpression of MEIS1 increased GFI1 expression by activating GFI1 enhancer but decreased FBW7 expression. Importantly, silencing of ELF1 decreased the capacities of proliferation, migration, and invasion of glioma cells whereas it increased apoptosis, supported by increased capase-3 and decreased matrix metalloproteinase-9 (MMP-9) and proliferating cell nuclear antigen (PCNA) expression. Moreover, an in vivo experiment confirmed the inhibitory role of silenced ELF1 in tumor growth, with a decreased level of MEIS1 and GFI1. Taken together, our study elucidated a potential mechanism that ELF1 promoted cell progression by increasing GFI1 and METS1 as well as decreasing FBW7 expression in glioma.

Endovascular Intervention with a Low-profile Visualized Intraluminal Support Stent Versus Surgical Clipping for Blood Blister-like Aneurysms : A Retrospective Study.

PURPOSE: Blood blister-like aneurysms (BBAs) have a high risk of early recurrence and postoperative rebleeding. This study compared the clinical outcomes and complications between endovascular intervention with low-profile visualized intraluminal support (LVIS) stent-assisted coiling and the surgical clipping in patients with BBAs. METHODS: This retrospective study enrolled 39 patients with BBAs who underwent endovascular intervention with LVIS stent-assisted coiling (n = 21) or surgical clipping (n = 18) between January 2013 and July 2018. Primary outcomes were mortality and modified Rankin scale (mRS). Secondary outcomes were hospital stay, intensive care unit (ICU) stay and operation parameters. Complications were also retrospectively collated. RESULTS: At baseline, the two groups were well balanced in patient characteristics. The hospital stays, ICU stays, operation time and intraoperative infusion volume were all significantly lower in LVIS group than that in clipping group (p < 0.05). A second operation was performed in 6 cases in the clipping group but none in the LVIS group (p = 0.006). The mean mRS score in the LVIS group was significantly lower than that of the clipping group both at hospital discharge and final follow-up (p < 0.001). Adverse outcomes occurred in 1 case in LVIS group and 7 in clipping group, with significant difference (p = 0.015). Complications were reported in 8 cases in LVIS group and 16 cases in clipping group, with significant difference (p < 0.001). CONCLUSION: The endovascular intervention with LVIS stent-assisted coiling has better prognosis than surgical clipping. It decreased the risk of a second operation and procedure-related complications compared with surgical clipping.

Exome Sequencing Identifies LOXL2 Mutation as a Cause of Familial Intracranial Aneurysm.

BACKGROUND: Genetic risk factors can contribute to the etiology of intracranial aneurysms (IAs), and the genetic predisposition of IAs is largely unknown. Our study aimed to explore the role of rare variations in IA susceptibility. METHODS: Whole-exome sequencing (WES) was performed in a representative family with a history of multiple cases of IAs. WES variants were prioritized by various filtering strategies, including frequency, predicted pathogenicity, and functional prediction. Sanger sequencing also was performed in an additional 2 families and sporadic IA cases. RESULTS: After WES and filtering, 15 single-nucleotide variants and 3 insertion/deletions (indels) were prioritized in the family. Among them, we selected 5 candidate variants (located in DHRS3, OR2G3, LOXL2, FGL1, and KLC3) by considering known disease genes or ontology association with cardiovascular morphogenesis or other known diseases. Genotyping results revealed that only c.C133T/p.H45Y in exon 2 of LOXL2 gene was segregated fully with definite IA phenotypes in the family. Moreover, LOXL2 has been reported as a susceptibility gene for IAs. CONCLUSIONS: LOXL2 c.C133T is a pathogenic mutation that is responsible for a fraction of familial IAs.