Lower-grade gliomas(including low-and intermediate-grade gliomas,World Health Organization grades II and III)are diffusely infiltrative neoplasms that arise most often in the cerebral hemispheres of adults and have tr...Lower-grade gliomas(including low-and intermediate-grade gliomas,World Health Organization grades II and III)are diffusely infiltrative neoplasms that arise most often in the cerebral hemispheres of adults and have traditionally been classified based on their presumed histogenesis as astrocytomas,oligodendrogliomas,or oligoastrocytomas.Although the histopathologic classification of lower-grade glioma has been the accepted standard for nearly a century,it suffers from high intra-and inter-observer variability and does not adequately predict clinical outcomes.Based on integrated analysis of multiplatform genomic data from The Cancer Genome Atlas,lower-grade gliomas have been found to segregate into three cohesive,clinically relevant molecular classes.Molecular classes were closely aligned with the status of isocitrate dehydrogenase(IDH)mutations,tumor protein 53 mutations and the co-deletion of chromosome arms 1 p and 19q,but were not closely aligned with histologic classes.These findings emphasize the potential for improved definition of clinically relevant disease subsets using integrated molecular approaches and highlight the importance of biomarkers for brain tumor classification.展开更多
Background:Mutations in the isocitrate dehydrogenase 1(IDH1)and IDH2 genes are important for both the integrated diagnosis and the prognosis of diffuse gliomas.The p.R132H mutation of IDH1 is the most frequently obser...Background:Mutations in the isocitrate dehydrogenase 1(IDH1)and IDH2 genes are important for both the integrated diagnosis and the prognosis of diffuse gliomas.The p.R132H mutation of IDH1 is the most frequently observed IDH mutation,while IDH2 mutations were relatively rarely studied.The aim of the study was to determine the pathological and genetic characteristics of lowergrade gliomas that carry IDH2 mutations.Methods:Data from 238 adult patients with lower-grade gliomas were retrospectively analyzed.The status of IDH1/2 gene mutations,telomerase reverse transcriptase(TERT)promoter mutations,O^6-methylguanine-DNA-methyltransferase(MGMT)promoter methylation,1p/19q co-deletion and the expressions of IDH1 R132H,alpha-thalassemia X-linked mental retardation,and p53 were evaluated.Progression-free survival(PFS)and overall survival(OS)were calculated via Kaplan-Meier estimation using the log-rank test.Results:Totally,71%(169/238)of patients were positive for IDH mutations,including 12 patients harboring mutations in IDH2.Among the 12 patients with IDH2 mutations,ten patients harbored the R172K mutation,one patient harbored the R172S mutation and one harbored the R172W mutation.Of these,11 tumors occurred in the frontal lobe and showed morphology typical of oligodendroglioma.The proportion of grade II tumors was higher than that of grade III tumors in IDH2 mutant-gliomas.IDH2 mutations were frequently associated with TERT promoter mutations,1p/19q co-deletion and MGMT promoter methylation.IDH2 mutations were associated with better outcomes compared with IDH wild-type gliomas(P<0.05).However,the PFS and OS did not differ from that of IDH1 mutant patients(P=0.95 and P=0.60,respectively).Conclusions:IDH2 mutations are more frequent in oligodendrogliomas and associated with a better prognosis.IDH2 mutations may segregate in distinct clinico-pathological and genetic subtypes of gliomas,and therefore may merit routine investigation.展开更多
Paragangliomas,also known as pheochromocytomas(1–9 cases per million),arise in the paraganglia.[1]Pheochromocytomas occur in the adrenal glands,while paragangliomas occur elsewhere.[2]Paragangliomas originate from pa...Paragangliomas,also known as pheochromocytomas(1–9 cases per million),arise in the paraganglia.[1]Pheochromocytomas occur in the adrenal glands,while paragangliomas occur elsewhere.[2]Paragangliomas originate from paraganglion cells,which are derived from the neural ectoderm of the nerves and migrate along both sides of the median axis from the base of the skull to the pelvis during embryonic development.展开更多
Background:IQGAP3 plays a crucial role in regulating cell proliferation,division,and cytoskeletal organization.Abnormal expression of IQGAP3 has been linked to various tumors,but its function in glioma is not well und...Background:IQGAP3 plays a crucial role in regulating cell proliferation,division,and cytoskeletal organization.Abnormal expression of IQGAP3 has been linked to various tumors,but its function in glioma is not well understood.Methods:Various methods,including genetic differential analysis,single-cell analysis,ROC curve analysis,Cox regression,Kaplan-Meier analysis,and enrichment analysis,were employed to analyze the expression patterns,diagnostic potential,prognostic implications,and biological processes involving IQGAP3 in normal and tumor tissues.The impact of IQGAP3 on immune infiltration and the immune microenvironment in gliomas was evaluated using immunofluorescence.Additionally,the cBioPortal database was used to analyze copy number variations and mutation sites of IQGAP3.Experimental validation was also performed to assess the effects of IQGAP3 on glioma cells and explore underlying mechanisms.Results:High IQGAP3 expression in gliomas is associated with an unfavorable prognosis,particularly in wild-type IDH and 1p/19q non-codeleted gliomas.Enrichment analysis revealed that IQGAP3 is involved in regulating the cell cycle,PI3K/AKT signaling,p53 signaling,and PLK1-related pathways.Furthermore,IQGAP3 expression may be closely related to the immunosuppressive microenvironment of glioblastoma.BRD-K88742110 and LY-303511 are potential drugs for targeting IQGAP3 in anti-glioma therapy.In vitro experiments showed that downregulation of IQGAP3 inhibits the proliferation and migration of glioma cells,with the PLK1/PI3K/AKT pathway potentially playing a crucial role in IQGAP3-mediated glioma progression.Conclusion:IQGAP3 shows promise as a valuable biomarker for diagnosis,prognosis,and immunotherapeutic strategies in gliomas.展开更多
Gliomas are primary brain tumors derived from glial cells of the central nervous system,afflicting both adults and children with distinct characteristics and therapeutic challenges.Recent developments have ushered in ...Gliomas are primary brain tumors derived from glial cells of the central nervous system,afflicting both adults and children with distinct characteristics and therapeutic challenges.Recent developments have ushered in novel clinical and molecular prognostic factors,reshaping treatment paradigms based on classi-fication and grading,determined by histological attributes and cellular lineage.This review article delves into the diverse treatment modalities tailored to the specific grades and molecular classifications of gliomas that are currently being discussed and used clinically in the year 2023.For adults,the therapeutic triad typically consists of surgical resection,chemotherapy,and radiotherapy.In contrast,pediatric gliomas,due to their diversity,require a more tailored approach.Although complete tumor excision can be curative based on the location and grade of the glioma,certain non-resectable cases demand a chemotherapy approach usually involving,vincristine and carboplatin.Addi-tionally,if surgery or chemotherapy strategies are unsuccessful,Vinblastine can be used.Despite recent advancements in treatment methodologies,there remains a need of exploration in the literature,particularly concerning the efficacy of treatment regimens for isocitrate dehydrogenase type mutant astrocytomas and fine-tuned therapeutic approaches tailored for pediatric cohorts.This review article explores into the therapeutic modalities employed for both adult and pediatric gliomas in the context of their molecular classification.展开更多
BACKGROUND Glioma is one of the most common intracranial tumors,characterized by invasive growth and poor prognosis.Actin cytoskeletal rearrangement is an essential event of tumor cell migration.The actin dynamics-rel...BACKGROUND Glioma is one of the most common intracranial tumors,characterized by invasive growth and poor prognosis.Actin cytoskeletal rearrangement is an essential event of tumor cell migration.The actin dynamics-related protein scinderin(SCIN)has been reported to be closely related to tumor cell migration and invasion in several cancers.AIM To investigate the role and mechanism of SCIN in glioma.METHODS The expression and clinical significance of SCIN in glioma were analyzed based on public databases.SCIN expression was examined using real-time quantitative polymerase chain reaction and Western blotting.Gene silencing was performed using short hairpin RNA transfection.Cell viability,migration,and invasion were assessed using cell counting kit 8 assay,wound healing,and Matrigel invasion assays,respectively.F-actin cytoskeleton organization was assessed using F-actin staining.RESULTS SCIN expression was significantly elevated in glioma,and high levels of SCIN were associated with advanced tumor grade and wild-type isocitrate dehydrogenase.Furthermore,SCIN-deficient cells exhibited decreased proliferation,migration,and invasion in U87 and U251 cells.Moreover,knockdown of SCIN inhibited the RhoA/focal adhesion kinase(FAK)signaling to promote F-actin depolymerization in U87 and U251 cells.CONCLUSION SCIN modulates the actin cytoskeleton via activating RhoA/FAK signaling,thereby promoting the migration and invasion of glioma cells.This study identified the cancer-promoting effect of SCIN and provided a potential therapeutic target for the treatment of glioma.展开更多
Objective:This study was aimed at analyzing the efficacy and safety of an injectable form of chlorogenic acid(CGA)in patients with recurrent high-grade glioma after standard of care treatments,through a first-in-human...Objective:This study was aimed at analyzing the efficacy and safety of an injectable form of chlorogenic acid(CGA)in patients with recurrent high-grade glioma after standard of care treatments,through a first-in-human,open-label,dose-escalation phase I trial.Methods:A total of 26 eligible patients were enrolled,received intramuscular CGA injections at 5 dose levels,and were followed up for 5 years.CGA was well tolerated,and the maximum tolerated dose was 5.5 mg/kg.Results:The most common treatment-related adverse events occurred at the sites of injection.No grade 3 or 4 adverse events(e.g.,drug allergy)were reported for these patients except for induration at the injection sites.A clinical pharmacokinetic study showed that CGA was rapidly eliminated from the plasma,with a t_(1/2)of 0.95–1.27 h on day 1 and 1.19–1.39 h on day 30,and no detectable CGA was observed on days 9,11,13,23,25,27,and 29 before CGA administration.After the first treatment cycle,52.2%of patients(12 of 23)achieved stable disease.Long-term follow-up indicated an estimated median overall survival of 11.3 months for all 23 evaluable patients.Of the 18 patients with grade 3 glioma,the median overall survival was 9.5 months.Two patients remained alive at the cutoff day.Conclusions:This phase I study demonstrated that CGA has a favorable safety profile(with no severe toxicity),and provides preliminary clinical benefits for patients with high grade glioma relapsing after prior standard therapies,thus shedding light on the potential clinical application of CGA for recurrent grade 4 glioma.展开更多
Objective To construct and verificate an RNA-binding protein(RBP)-associated prognostic model for gliomas using integrated bioinformatics analysis.Methods RNA-sequencing and clinic pathological data of glioma patients...Objective To construct and verificate an RNA-binding protein(RBP)-associated prognostic model for gliomas using integrated bioinformatics analysis.Methods RNA-sequencing and clinic pathological data of glioma patients from The Cancer Genome Atlas(TCGA)database and the Chinese Glioma Genome Atlas database(CGGA)were downloaded.The aberrantly expressed RBPs were investigated between gliomas and normal samples in TCGA database.We then identified prognosis related hub genes and constructed a prognostic model.This model was further validated in the CGGA-693 and CGGA-325 cohorts.Results Totally 174 differently expressed genes-encoded RBPs were identified,containing 85 down-regulated and 89 up-regulated genes.We identified five genes-encoded RBPs(ERI1,RPS2,BRCA1,NXT1,and TRIM21)as prognosis related key genes and constructed a prognostic model.Overall survival(OS)analysis revealed that the patients in the high-risk subgroup based on the model were worse than those in the low-risk subgroup.The area under the receiver operator characteristic curve(AUC)of the prognostic model was 0.836 in the TCGA dataset and 0.708 in the CGGA-693 dataset,demonstrating a favorable prognostic model.Survival analyses of the five RBPs in the CGGA-325 cohort validated the findings.A nomogram was constructed based on the five genes and validated in the TCGA cohort,confirming a promising discriminating ability for gliomas.Conclusion The prognostic model of the five RBPs might serve as an independent prognostic algorithm for gliomas.展开更多
Temozolomide(TMZ)resistance is a major obstacle in glioma treatment.Nuclear protein-1(NUPR1)is a regulator of glioma progression.This study investigated the mechanism of NUPR1 in TMZ resistance in hypoxiatreated gliom...Temozolomide(TMZ)resistance is a major obstacle in glioma treatment.Nuclear protein-1(NUPR1)is a regulator of glioma progression.This study investigated the mechanism of NUPR1 in TMZ resistance in hypoxiatreated glioma cells and its mechanism in modulating autophagy.We treated TMZ-resistant cells U251-TMZ and T98G-TMZ to normoxia or hypoxia and silenced NUPR1 in hypoxia-treated U251-TMZ and T98G-TMZ cells to assess cell viability,proliferation,apoptosis,LC3-II/LC3-I and p62 expressions,and autophagic flux under different concentrations of TMZ.We found that hypoxia upregulated NUPR1 expression and autophagy while NUPR1 silencing suppressed hypoxia-induced TMZ resistance and autophagy in glioma cells.We also investigated the interaction between NUPR1 and lysine demethylase 3A(KDM3A),as well as the enrichments of KDM3A and H3 lysine 9 dimethylation(H3K9me2)in the transcription factor EB(TFEB)promoter region.Our results suggest that hypoxia-induced NUPR1 promotes TFEB transcription by binding to KDM3A and reducing H3K9me2 levels,thereby augmenting glioma cell autophagy and TMZ resistance.Moreover,the overexpression of KDM3A or TFEB promoted glioma cell autophagy.In a xenograft tumor model,silencing NUPR1 suppressed TMZ resistance in glioma cells in vivo.Overall,our findings highlight a mechanism by which NUPR1 enhances glioma cell autophagy and TMZ resistance via the KDM3A/TFEB axis.展开更多
BACKGROUND Anti-leucine-rich glioma inactivated protein 1(anti-LGI1) encephalitis is an infrequent type of autoimmune encephalitis(AE) characterized by acute or subacute cognitive and psychiatric disturbance, facio-br...BACKGROUND Anti-leucine-rich glioma inactivated protein 1(anti-LGI1) encephalitis is an infrequent type of autoimmune encephalitis(AE) characterized by acute or subacute cognitive and psychiatric disturbance, facio-brachial dystonic seizures(FBDSs), and hyponatremia. Anti-LGI1 AE has increasingly been considered a primary form of AE. Early identification and treatment of this disease are clearly very important.CASE SUMMARY Here, we report that a male patient developed severe anti-LGI1 encephalitis, which was initially misdiagnosed as a sleep disturbance. He was hospitalized for epileptic seizures and typical FBDSs half a month after he developed sleep disturbances. LGI1 antibodies were detected in his cerebrospinal fluid and serum(1:100 and 1:3.2, respectively), which led to the diagnosis of classic anti-LGI1 AE. No obvious abnormality was observed on brain computed tomography images. T2-weighted fluid-attenuated inversion recovery and T2-weighted scans of brain magnetic resonance imaging(MRI) showed slightly elevated signals within the left basal ganglia area. No tumor was detected within the brain of this patient using MRI. After hormone and antiepileptic drug treatment, the patient’s symptoms improved significantly.CONCLUSION Anti-LGI1 antibody-associated encephalitis has characteristic clinical manifestations, such as cognitive impairment, psychiatric symptoms, seizures, sleep disorders, hyponatremia, and FBDSs. LGI1 antibodies are present in the serum and/or cerebrospinal fluid, but their production is sensitive to immunosuppressants, and this disease has a relatively good prognosis. In particular, we should be aware of the possibility of anti-LGI1 antibody-associated encephalitis in adolescents with sleep disorders to avoid missed diagnoses and misdiagnoses.展开更多
This article, the purpose of which is to deal with some problems in studying and teaching English, is merely for the students of English to read, who have just entered the second year at a foreign languages institute....This article, the purpose of which is to deal with some problems in studying and teaching English, is merely for the students of English to read, who have just entered the second year at a foreign languages institute. When teaching the second-year students, I have often been asked this awkward question: "What do you think is the correct way to study English?" It took me quite a time to answer it. Now after many years of teaching I think I have some ideas on this subject.展开更多
Gliomas are the most common group of malignant central nervous system tumors across all ages and have high heterogeneity.According to histopathologic criteria and molecular pathology,gliomas are classified as grades 1...Gliomas are the most common group of malignant central nervous system tumors across all ages and have high heterogeneity.According to histopathologic criteria and molecular pathology,gliomas are classified as grades 1–4.High-grade gliomas(HGG),including the most aggressive subtype,glioblastoma(GBM),belong to grade 3 or 4.Although a standard therapy comprising surgical resection,chemotherapy,and radiation is available,almost all patients with HGG experience recurrence within several months and a dismal prognosis1.展开更多
BACKGROUND Intracranial hemorrhage is extremely rare during the initial stages of glioma.Here,we report a case of glioma with unclassified pathology and intracranial bleeding.CASE SUMMARY After the second surgery for ...BACKGROUND Intracranial hemorrhage is extremely rare during the initial stages of glioma.Here,we report a case of glioma with unclassified pathology and intracranial bleeding.CASE SUMMARY After the second surgery for intracerebral hemorrhage,the patient experienced weakness in the left arm and leg,but could walk unassisted.One month after discharge,the weakness in the left limbs had exacerbated and the patient also suffered from headaches and dizziness.A third surgery was ineffective against the rapidly growing tumor.Intracerebral hemorrhage may be the initial symptom of glioma in some rare cases,and atypical perihematomal edema can be used for diagnosis during an emergency.Certain histological and molecular features seen in our case were similar to that of glioblastoma with a primitive neuronal component,which is termed diffuse glioneuronal tumor with features similar to oligodendroglioma and nuclear clusters(DGONC).The patient underwent three surgeries to remove the tumor.The first tumor resection had been performed when the patient was 14-years-old.Resection of the hemorrhage and bone disc decompression were performed when the patient was 39-years-old.One month after the last discharge,the patient underwent neuronavigation-assisted resection of the right frontotemporal parietal lesion plus extended flap decompression.On the 50^(th)d after the third operation,computed tomography imaging showed rapid tumor growth accompanied by brain hernia.The patient was discharged and died 3 d later.CONCLUSION Glioma can present as bleeding in the initial stage and should be considered in such a setting.We have reported a case of DGONC,which is a rare molecular subtype of glioma with a unique methylation profile.展开更多
Objective Protein disulfide isomerase A2(PDIA2),a member of the protein disulfide isomerase family,plays a key role in the folding of nascent proteins in the endoplasmic reticulum by forming disulfide bonds,together w...Objective Protein disulfide isomerase A2(PDIA2),a member of the protein disulfide isomerase family,plays a key role in the folding of nascent proteins in the endoplasmic reticulum by forming disulfide bonds,together with enzymes such as thiol isomerase,oxidase,and reductase.This study investigated the clinical significance and potential functions of PDIA2 in glioma.Methods The expression of PDIA2 in gliomas was explored using The Cancer Genome Atlas and Gene Expression Omnibus databases.We analyzed the clinical characteristics of glioma patients and the prognostic and diagnostic value of PDIA2 expression.Kaplan-Meier and Cox regression analyses were used to examine the effect of PDIA2 expression on overall survival,progression-free interval,and disease-specific survival.Furthermore,we performed Gene Set Enrichment Analysis and immune infiltration analysis to investigate the functions of PDIA2.PDIA2 mRNA and protein expression was evaluated in cell lines and glioma tissues.Results PDIA2 was expressed at low levels in glioma patients.Kaplan-Meier survival analysis showed that glioma patients with low PDIA2 levels had a worse prognosis than those with high PDIA2 levels.Receiver operating characteristic curve analysis indicated the diagnostic and prognostic ability of PDIA2(area under the curve=0.918).Pathways associated with PD1,PI3K/AKT,cancer immunotherapy via PD1 blockade,Fceri-mediated NF-kB activation,FOXM1,and DNA repair were enriched in glioma patients with low levels of PDIA2.PDIA2 expression levels were negatively correlated with immune cell infiltrate levels.Conclusion PDIA2 levels are significantly downregulated in glioma.PDIA2 expression may be a potential biomarker for the diagnosis and prognosis of glioma patients.展开更多
Objective:A high-fat,low-carbohydrate ketogenic diet has been used to treat malignant glioma,in which the Raf/MEK/ERK signaling pathway is overactivated.However,whether the Raf/MEK/ERK signaling pathway is involved in...Objective:A high-fat,low-carbohydrate ketogenic diet has been used to treat malignant glioma,in which the Raf/MEK/ERK signaling pathway is overactivated.However,whether the Raf/MEK/ERK signaling pathway is involved in the therapeutic effect of ketone bodies remains unknown.In this study,we investigated the effects of a major ketone body,3-hydroxybutyric acid(3-HBA),on the proliferation and metastasis of malignant glioblastoma cells and the underlying mechanism.Methods:Two human malignant glioblastoma cell lines(U87 and U251)were treated with different concentrations of 3-HBA with or without the Raf inhibitor PAF C-16 for 24 h.Cell proliferation,cell cycle,cell invasion,and phospholipase D1(PLD1)activity were determined.Protein and gene expression levels of Raf/MEK/ERK signaling pathway members were examined.Results:3-HBA significantly decreased cell proliferation,invasion,and intracellular PLD1 activity in both U87 and U251 glioblastoma cell lines.3-HBA treatment significantly increased the proportion of cells in the G1 phase and decreased the proportion of cells in S phase in U87 cells.In the U251 line,the proportion of treated cells in S phase was increased and proportion of cells in G2 was decreased.3-HBA treatment also significantly decreased the protein expression levels of Raf,MEK,p-MEK,ERK,p-ERK,and PLD1 while increasing p53 expression;an effect that was similar to treatment with the Raf inhibitor.Co-treatment of 3-HBA with the Raf inhibitor further enhanced the effects of the 3-HBA in both cell lines.Conclusion:We confirmed that a ketogenic microenvironment can inhibit glioma cell proliferation and invasion by downregulating the expression of PLD1 through the Raf/MEK/ERK signaling pathway.展开更多
Obiective:To investigate the prognostic value of ORMDL2 in human glioma and its relationship with immune invasion.Methods:The clinical survival data from TCGA-LGG&GBM,CGGA and GEO were used to evaluate the clinica...Obiective:To investigate the prognostic value of ORMDL2 in human glioma and its relationship with immune invasion.Methods:The clinical survival data from TCGA-LGG&GBM,CGGA and GEO were used to evaluate the clinical prognostic value of ORMDL2.The cut off value of ORMDL2 was detected with pROC package to draw ROC curve to prove its value in differential diagnosis of glioma.The first 300 genes with the most significant positive correlation with ORMDL2 were selected to establish PPI network through STRING database and conduct GO and pathway analysis.The relationship between the expression of ORMDL2 mRNA and immune cell infiltration was investigated by using ssGSEA and TIMER2.0 databases.Results:The expression of ORMDL2 mRNA in glioma was significantly higher than that in adjacent normal tissues,and the difference was most significant in high-grade glioma.The expression of ORMDL2 was increased in human glioma,which was related to the clinicopathological characteristics and poor prognosis of glioma patients.In addition,the increased expression of ORMDL2 was associated with a series of immune infiltrating cells,including macrophages.Conclusion:ORMDL2 plays an important role in glioma immune cell infiltration and is a biomarker of prognosis of glioma patients.展开更多
Objective:To investigate whether macrophage-derived exosomal mir-222 regulates Caspase-10 and whether macrophage-derived exosomes promote glioma proliferation by targeting Caspase-10 through mir-222.Methods:Macrophage...Objective:To investigate whether macrophage-derived exosomal mir-222 regulates Caspase-10 and whether macrophage-derived exosomes promote glioma proliferation by targeting Caspase-10 through mir-222.Methods:Macrophages were transfected with mir-222 mimics,and then macrophage-derived exosomes carrying mir-222 were transfected into glioma cells.Caspase-10 overexpression vector was constructed on this basis.RT-PCR was used to detect mir-222 expression in macrophages and glioma cells.CCK-8 assay was used to detect the proliferative activity of glioma cells.Dual-luciferase reporter assay was used to verify the targeting binding of mir-222 with Caspase-10 gene.Western blot was used to detect Caspase-10 expression.Results:Transmission electron microscopy showed that macrophagederived exosomes had spherical structures with a diameter of about 100 nm;mir-222 mimic significantly promoted the expression of mir-222 in macrophages;macrophage-derived exosomal mir-222 increased mir-222 expression and promoted proliferation in glioma cells;mir-222 could target bind with Caspase-10;mir-222 mimic significantly inhibited Caspase-10 expression.Conclusion:Macrohpage-derived exosomal mir-222 plays an important role in promoting glioma proliferation by downregulating Caspase-10 expression through targeted binding.展开更多
Glioma is the most malignant brain cancer.The neurons,macrophages,T cells and other immune ellls constitute the glioma immunosuppressive microenvironment.The accurate spatial distri-bution of these cells in the glioma...Glioma is the most malignant brain cancer.The neurons,macrophages,T cells and other immune ellls constitute the glioma immunosuppressive microenvironment.The accurate spatial distri-bution of these cells in the glioma microenvironment and its relationship with glioma metastasis is unknown.We constructed a mouse gliomna cell line stably expressing the large Stokes shifted yellow fluorescent protein and applied it to the multicolor immunofluorescence imaging.The inaging data revealed that the neurons were sparsely distributed in the glioma core and the mumber of neurons decreased by 90%compared with normal brain site.The spatial distribution of monocyte-macrophages and microglia is heterogeneous.The monocyte macrophages and T cells were heavily recrnuited into the glioma core and metastasis.There was no significant difference in the distribution of microglia amnong glioma core,margin,and normal brain site.Our results provided new perspectives for targeting immune regulation cells and developing new immuno-therapy strategies for glioma.展开更多
ATP binding cassette subfamily C member 8(ABCC8)encodes a protein regulating the ATP-sensitive potassium channel.Whether the level of ABCC8 mRNA in lower grade glioma(LGG)correlates with immune cell infiltration and p...ATP binding cassette subfamily C member 8(ABCC8)encodes a protein regulating the ATP-sensitive potassium channel.Whether the level of ABCC8 mRNA in lower grade glioma(LGG)correlates with immune cell infiltration and patient outcomes has not been evaluated until now.Comparisons of ABCC8 expression between different tumors and normal tissues were evaluated by exploring publicly available datasets.The association between ABCC8 and tumor immune cell infiltration,diverse gene mutation characteristics,tumor mutation burden(TMB),and survival in LGG was also investigated in several independent datasets.Pathway enrichment analysis was conducted to search for ABCC8-associated signaling pathways.Through an online database,we found that ABCC8 expression in LGG was lower than in normal tissues.Then,the association of ABCC8 expression and immune cell infiltration in LGG was discussed.As we expected,the ABCC8 mRNA levels were negatively associated with non-T immune cell infiltration levels in all datasets.Consistently,TCGA_LGG RNA-seq data revealed that ABCC8 downregulated several non-T immune cell-associated signaling pathways in gene set enrichment analysis.Different ABCC8 expression groups showed diverse gene mutation characteristics and TMB.The high expression of ABCC8 was linked to improved survival of LGG patients.A pathway enrichment analysis of ABCC8-associated genes indicated that the GABAergic synapse signaling pathway might be involved in regulating immunity in LGG.Our findings show that ABCC8 reflects LGG tumor immunity and is an ideal prognostic biomarker for LGG.展开更多
[Objectives] To explore the inhibitory effect of octadecadienoic acid (ODA) on proliferation and apoptosis of glioma cells and its mechanism. [Methods] Cultured human glioma cells (cell density 2×10^(6) cells/L) ...[Objectives] To explore the inhibitory effect of octadecadienoic acid (ODA) on proliferation and apoptosis of glioma cells and its mechanism. [Methods] Cultured human glioma cells (cell density 2×10^(6) cells/L) were divided into three groups: solvent control group (DMSO, 30 μL/L), 5-FU group (10 mg/L) and octadecadienoic acid group (0.3, 0.6, 1.2 mg/L). The toxic effects of ODA on glioma cells were detected by trypan blue and thiazolium blue (MTT). The expression of P53, PI3K, P21, PKB/Akt and caspase-9 protein in glioma cells were detected by enzyme-linked immunosorbent assay (ELISA). [Results] The cell count under optical microscope showed that the inhibition rate of cell proliferation in low, medium and high dose ODA groups and 5-FU group was significantly higher than that in solvent control group ( P <0.01), but there was no significant difference compared with 5-FU group ( P >0.05). The results of MTT showed that compared with the solvent control group, the inhibition rate of cell proliferation in low, medium and high dose ODA groups and 5-FU group significantly increased ( P <0.01);compared with 5-FU group, the inhibition rate of cell proliferation in high dose ODA group significantly increased ( P <0.01). The results of flow cytometry showed that compared with the solvent control group, the number of cells in G_(0)/G_(1) phase increased significantly ( P <0.05, P <0.01), the number of cells in G_(2)/M phase decreased significantly ( P <0.01) and the apoptosis rate increased significantly ( P <0.01) in the low, medium and high dose ODA groups and 5-FU group;compared with 5-FU group, the number of cells in G_(2)/M phase decreased significantly ( P <0.01) and the apoptosis rate increased significantly ( P <0.01) in ODA group. ELISA testing results showed that the expression levels of P53, P13K and PKB/Akt in low, medium and high dose ODA groups and 5-FU group were significantly lower than those in solvent control group ( P <0.01), and only the expression level of protein in high dose ODA group was significantly lower than that in 5-FU group ( P <0.01);the expression levels of P21 and caspase-9 in low, medium and high dose ODA groups and 5-FU group were significantly higher than those in solvent control group ( P <0.05, P <0.01), but the expression level of protein in high dose ODA group was significantly higher than that in 5-FU group ( P <0.01). [Conclusions] ODA can obviously inhibit the proliferation of glioma cells and induce apoptosis. The mechanism is related to up-regulation of P21, caspase-9, down-regulation of P53, PI3K, PKB/Akt, inhibition of cell division cycle and decrease of PI3K-Akt signal transduction pathway.展开更多
文摘Lower-grade gliomas(including low-and intermediate-grade gliomas,World Health Organization grades II and III)are diffusely infiltrative neoplasms that arise most often in the cerebral hemispheres of adults and have traditionally been classified based on their presumed histogenesis as astrocytomas,oligodendrogliomas,or oligoastrocytomas.Although the histopathologic classification of lower-grade glioma has been the accepted standard for nearly a century,it suffers from high intra-and inter-observer variability and does not adequately predict clinical outcomes.Based on integrated analysis of multiplatform genomic data from The Cancer Genome Atlas,lower-grade gliomas have been found to segregate into three cohesive,clinically relevant molecular classes.Molecular classes were closely aligned with the status of isocitrate dehydrogenase(IDH)mutations,tumor protein 53 mutations and the co-deletion of chromosome arms 1 p and 19q,but were not closely aligned with histologic classes.These findings emphasize the potential for improved definition of clinically relevant disease subsets using integrated molecular approaches and highlight the importance of biomarkers for brain tumor classification.
基金This work was supported by grants from the Capital Health Research and Development of Special Program(No.2014-2-2013)the Beijing Excellent Talent Training Project Grant(No.201600026833ZK07)+1 种基金the National Science-Technology Support Plan(No.2014BAI04B02)the Project of Beijing Municipal Health Commission(No.PXM 2019_026283_000002).
文摘Background:Mutations in the isocitrate dehydrogenase 1(IDH1)and IDH2 genes are important for both the integrated diagnosis and the prognosis of diffuse gliomas.The p.R132H mutation of IDH1 is the most frequently observed IDH mutation,while IDH2 mutations were relatively rarely studied.The aim of the study was to determine the pathological and genetic characteristics of lowergrade gliomas that carry IDH2 mutations.Methods:Data from 238 adult patients with lower-grade gliomas were retrospectively analyzed.The status of IDH1/2 gene mutations,telomerase reverse transcriptase(TERT)promoter mutations,O^6-methylguanine-DNA-methyltransferase(MGMT)promoter methylation,1p/19q co-deletion and the expressions of IDH1 R132H,alpha-thalassemia X-linked mental retardation,and p53 were evaluated.Progression-free survival(PFS)and overall survival(OS)were calculated via Kaplan-Meier estimation using the log-rank test.Results:Totally,71%(169/238)of patients were positive for IDH mutations,including 12 patients harboring mutations in IDH2.Among the 12 patients with IDH2 mutations,ten patients harbored the R172K mutation,one patient harbored the R172S mutation and one harbored the R172W mutation.Of these,11 tumors occurred in the frontal lobe and showed morphology typical of oligodendroglioma.The proportion of grade II tumors was higher than that of grade III tumors in IDH2 mutant-gliomas.IDH2 mutations were frequently associated with TERT promoter mutations,1p/19q co-deletion and MGMT promoter methylation.IDH2 mutations were associated with better outcomes compared with IDH wild-type gliomas(P<0.05).However,the PFS and OS did not differ from that of IDH1 mutant patients(P=0.95 and P=0.60,respectively).Conclusions:IDH2 mutations are more frequent in oligodendrogliomas and associated with a better prognosis.IDH2 mutations may segregate in distinct clinico-pathological and genetic subtypes of gliomas,and therefore may merit routine investigation.
文摘Paragangliomas,also known as pheochromocytomas(1–9 cases per million),arise in the paraganglia.[1]Pheochromocytomas occur in the adrenal glands,while paragangliomas occur elsewhere.[2]Paragangliomas originate from paraganglion cells,which are derived from the neural ectoderm of the nerves and migrate along both sides of the median axis from the base of the skull to the pelvis during embryonic development.
基金supported by the Doctoral Foundation of HuBei University of Science and Technology(Grant Numbers BK202007 and BK202028 to L.W.and Z.Z.)Special Research Fund Project of School of Stomatology and Optometry,Xianning Medical College,Hubei University of Science and Technology(Grant Number 2020XZ37 to L.W.)+3 种基金Hubei Provincial Department of Education“Hundred Schools and Hundred Counties”(Grant Number BXLBX0806 to Z.Z.)the Foundation of Hubei University of Science and Technology“Double Hundred Project”(Grant Number 2022HKSB01 to Z.Z.)the Foundation of Innovation Team of Hubei University of Science and Technology(Grant Number 2023T13 to S.Y.)Natural Science Foundation of Hubei Province(Grant Number 2023AFB1027 to Z.Z.).
文摘Background:IQGAP3 plays a crucial role in regulating cell proliferation,division,and cytoskeletal organization.Abnormal expression of IQGAP3 has been linked to various tumors,but its function in glioma is not well understood.Methods:Various methods,including genetic differential analysis,single-cell analysis,ROC curve analysis,Cox regression,Kaplan-Meier analysis,and enrichment analysis,were employed to analyze the expression patterns,diagnostic potential,prognostic implications,and biological processes involving IQGAP3 in normal and tumor tissues.The impact of IQGAP3 on immune infiltration and the immune microenvironment in gliomas was evaluated using immunofluorescence.Additionally,the cBioPortal database was used to analyze copy number variations and mutation sites of IQGAP3.Experimental validation was also performed to assess the effects of IQGAP3 on glioma cells and explore underlying mechanisms.Results:High IQGAP3 expression in gliomas is associated with an unfavorable prognosis,particularly in wild-type IDH and 1p/19q non-codeleted gliomas.Enrichment analysis revealed that IQGAP3 is involved in regulating the cell cycle,PI3K/AKT signaling,p53 signaling,and PLK1-related pathways.Furthermore,IQGAP3 expression may be closely related to the immunosuppressive microenvironment of glioblastoma.BRD-K88742110 and LY-303511 are potential drugs for targeting IQGAP3 in anti-glioma therapy.In vitro experiments showed that downregulation of IQGAP3 inhibits the proliferation and migration of glioma cells,with the PLK1/PI3K/AKT pathway potentially playing a crucial role in IQGAP3-mediated glioma progression.Conclusion:IQGAP3 shows promise as a valuable biomarker for diagnosis,prognosis,and immunotherapeutic strategies in gliomas.
文摘Gliomas are primary brain tumors derived from glial cells of the central nervous system,afflicting both adults and children with distinct characteristics and therapeutic challenges.Recent developments have ushered in novel clinical and molecular prognostic factors,reshaping treatment paradigms based on classi-fication and grading,determined by histological attributes and cellular lineage.This review article delves into the diverse treatment modalities tailored to the specific grades and molecular classifications of gliomas that are currently being discussed and used clinically in the year 2023.For adults,the therapeutic triad typically consists of surgical resection,chemotherapy,and radiotherapy.In contrast,pediatric gliomas,due to their diversity,require a more tailored approach.Although complete tumor excision can be curative based on the location and grade of the glioma,certain non-resectable cases demand a chemotherapy approach usually involving,vincristine and carboplatin.Addi-tionally,if surgery or chemotherapy strategies are unsuccessful,Vinblastine can be used.Despite recent advancements in treatment methodologies,there remains a need of exploration in the literature,particularly concerning the efficacy of treatment regimens for isocitrate dehydrogenase type mutant astrocytomas and fine-tuned therapeutic approaches tailored for pediatric cohorts.This review article explores into the therapeutic modalities employed for both adult and pediatric gliomas in the context of their molecular classification.
文摘BACKGROUND Glioma is one of the most common intracranial tumors,characterized by invasive growth and poor prognosis.Actin cytoskeletal rearrangement is an essential event of tumor cell migration.The actin dynamics-related protein scinderin(SCIN)has been reported to be closely related to tumor cell migration and invasion in several cancers.AIM To investigate the role and mechanism of SCIN in glioma.METHODS The expression and clinical significance of SCIN in glioma were analyzed based on public databases.SCIN expression was examined using real-time quantitative polymerase chain reaction and Western blotting.Gene silencing was performed using short hairpin RNA transfection.Cell viability,migration,and invasion were assessed using cell counting kit 8 assay,wound healing,and Matrigel invasion assays,respectively.F-actin cytoskeleton organization was assessed using F-actin staining.RESULTS SCIN expression was significantly elevated in glioma,and high levels of SCIN were associated with advanced tumor grade and wild-type isocitrate dehydrogenase.Furthermore,SCIN-deficient cells exhibited decreased proliferation,migration,and invasion in U87 and U251 cells.Moreover,knockdown of SCIN inhibited the RhoA/focal adhesion kinase(FAK)signaling to promote F-actin depolymerization in U87 and U251 cells.CONCLUSION SCIN modulates the actin cytoskeleton via activating RhoA/FAK signaling,thereby promoting the migration and invasion of glioma cells.This study identified the cancer-promoting effect of SCIN and provided a potential therapeutic target for the treatment of glioma.
基金funded by Sichuan Jiuzhang Biological Science and Technology Co.,Ltd.the Drug Innovation Major Project in China(Grant No.2016ZX09101017)the National Nature Science Foundation(Grant No.81972338)。
文摘Objective:This study was aimed at analyzing the efficacy and safety of an injectable form of chlorogenic acid(CGA)in patients with recurrent high-grade glioma after standard of care treatments,through a first-in-human,open-label,dose-escalation phase I trial.Methods:A total of 26 eligible patients were enrolled,received intramuscular CGA injections at 5 dose levels,and were followed up for 5 years.CGA was well tolerated,and the maximum tolerated dose was 5.5 mg/kg.Results:The most common treatment-related adverse events occurred at the sites of injection.No grade 3 or 4 adverse events(e.g.,drug allergy)were reported for these patients except for induration at the injection sites.A clinical pharmacokinetic study showed that CGA was rapidly eliminated from the plasma,with a t_(1/2)of 0.95–1.27 h on day 1 and 1.19–1.39 h on day 30,and no detectable CGA was observed on days 9,11,13,23,25,27,and 29 before CGA administration.After the first treatment cycle,52.2%of patients(12 of 23)achieved stable disease.Long-term follow-up indicated an estimated median overall survival of 11.3 months for all 23 evaluable patients.Of the 18 patients with grade 3 glioma,the median overall survival was 9.5 months.Two patients remained alive at the cutoff day.Conclusions:This phase I study demonstrated that CGA has a favorable safety profile(with no severe toxicity),and provides preliminary clinical benefits for patients with high grade glioma relapsing after prior standard therapies,thus shedding light on the potential clinical application of CGA for recurrent grade 4 glioma.
基金supported by the National Natural Science Foundation of China(No.82072795).
文摘Objective To construct and verificate an RNA-binding protein(RBP)-associated prognostic model for gliomas using integrated bioinformatics analysis.Methods RNA-sequencing and clinic pathological data of glioma patients from The Cancer Genome Atlas(TCGA)database and the Chinese Glioma Genome Atlas database(CGGA)were downloaded.The aberrantly expressed RBPs were investigated between gliomas and normal samples in TCGA database.We then identified prognosis related hub genes and constructed a prognostic model.This model was further validated in the CGGA-693 and CGGA-325 cohorts.Results Totally 174 differently expressed genes-encoded RBPs were identified,containing 85 down-regulated and 89 up-regulated genes.We identified five genes-encoded RBPs(ERI1,RPS2,BRCA1,NXT1,and TRIM21)as prognosis related key genes and constructed a prognostic model.Overall survival(OS)analysis revealed that the patients in the high-risk subgroup based on the model were worse than those in the low-risk subgroup.The area under the receiver operator characteristic curve(AUC)of the prognostic model was 0.836 in the TCGA dataset and 0.708 in the CGGA-693 dataset,demonstrating a favorable prognostic model.Survival analyses of the five RBPs in the CGGA-325 cohort validated the findings.A nomogram was constructed based on the five genes and validated in the TCGA cohort,confirming a promising discriminating ability for gliomas.Conclusion The prognostic model of the five RBPs might serve as an independent prognostic algorithm for gliomas.
基金supported by Scientific Research Project of Education Department of Liaoning Province(Grant Number LJKZ0854).
文摘Temozolomide(TMZ)resistance is a major obstacle in glioma treatment.Nuclear protein-1(NUPR1)is a regulator of glioma progression.This study investigated the mechanism of NUPR1 in TMZ resistance in hypoxiatreated glioma cells and its mechanism in modulating autophagy.We treated TMZ-resistant cells U251-TMZ and T98G-TMZ to normoxia or hypoxia and silenced NUPR1 in hypoxia-treated U251-TMZ and T98G-TMZ cells to assess cell viability,proliferation,apoptosis,LC3-II/LC3-I and p62 expressions,and autophagic flux under different concentrations of TMZ.We found that hypoxia upregulated NUPR1 expression and autophagy while NUPR1 silencing suppressed hypoxia-induced TMZ resistance and autophagy in glioma cells.We also investigated the interaction between NUPR1 and lysine demethylase 3A(KDM3A),as well as the enrichments of KDM3A and H3 lysine 9 dimethylation(H3K9me2)in the transcription factor EB(TFEB)promoter region.Our results suggest that hypoxia-induced NUPR1 promotes TFEB transcription by binding to KDM3A and reducing H3K9me2 levels,thereby augmenting glioma cell autophagy and TMZ resistance.Moreover,the overexpression of KDM3A or TFEB promoted glioma cell autophagy.In a xenograft tumor model,silencing NUPR1 suppressed TMZ resistance in glioma cells in vivo.Overall,our findings highlight a mechanism by which NUPR1 enhances glioma cell autophagy and TMZ resistance via the KDM3A/TFEB axis.
文摘BACKGROUND Anti-leucine-rich glioma inactivated protein 1(anti-LGI1) encephalitis is an infrequent type of autoimmune encephalitis(AE) characterized by acute or subacute cognitive and psychiatric disturbance, facio-brachial dystonic seizures(FBDSs), and hyponatremia. Anti-LGI1 AE has increasingly been considered a primary form of AE. Early identification and treatment of this disease are clearly very important.CASE SUMMARY Here, we report that a male patient developed severe anti-LGI1 encephalitis, which was initially misdiagnosed as a sleep disturbance. He was hospitalized for epileptic seizures and typical FBDSs half a month after he developed sleep disturbances. LGI1 antibodies were detected in his cerebrospinal fluid and serum(1:100 and 1:3.2, respectively), which led to the diagnosis of classic anti-LGI1 AE. No obvious abnormality was observed on brain computed tomography images. T2-weighted fluid-attenuated inversion recovery and T2-weighted scans of brain magnetic resonance imaging(MRI) showed slightly elevated signals within the left basal ganglia area. No tumor was detected within the brain of this patient using MRI. After hormone and antiepileptic drug treatment, the patient’s symptoms improved significantly.CONCLUSION Anti-LGI1 antibody-associated encephalitis has characteristic clinical manifestations, such as cognitive impairment, psychiatric symptoms, seizures, sleep disorders, hyponatremia, and FBDSs. LGI1 antibodies are present in the serum and/or cerebrospinal fluid, but their production is sensitive to immunosuppressants, and this disease has a relatively good prognosis. In particular, we should be aware of the possibility of anti-LGI1 antibody-associated encephalitis in adolescents with sleep disorders to avoid missed diagnoses and misdiagnoses.
文摘This article, the purpose of which is to deal with some problems in studying and teaching English, is merely for the students of English to read, who have just entered the second year at a foreign languages institute. When teaching the second-year students, I have often been asked this awkward question: "What do you think is the correct way to study English?" It took me quite a time to answer it. Now after many years of teaching I think I have some ideas on this subject.
基金financially supported by the Talent Introduction Foundation of Tiantan Hospital (Grant No.RCYJ-2020-2025-LWB)Clinical Major Specialty Projects of Beijing (Grant No.2-1-2-038)。
文摘Gliomas are the most common group of malignant central nervous system tumors across all ages and have high heterogeneity.According to histopathologic criteria and molecular pathology,gliomas are classified as grades 1–4.High-grade gliomas(HGG),including the most aggressive subtype,glioblastoma(GBM),belong to grade 3 or 4.Although a standard therapy comprising surgical resection,chemotherapy,and radiation is available,almost all patients with HGG experience recurrence within several months and a dismal prognosis1.
基金Supported by Zhenjiang Municipal Health Commission,No.SH2019081.
文摘BACKGROUND Intracranial hemorrhage is extremely rare during the initial stages of glioma.Here,we report a case of glioma with unclassified pathology and intracranial bleeding.CASE SUMMARY After the second surgery for intracerebral hemorrhage,the patient experienced weakness in the left arm and leg,but could walk unassisted.One month after discharge,the weakness in the left limbs had exacerbated and the patient also suffered from headaches and dizziness.A third surgery was ineffective against the rapidly growing tumor.Intracerebral hemorrhage may be the initial symptom of glioma in some rare cases,and atypical perihematomal edema can be used for diagnosis during an emergency.Certain histological and molecular features seen in our case were similar to that of glioblastoma with a primitive neuronal component,which is termed diffuse glioneuronal tumor with features similar to oligodendroglioma and nuclear clusters(DGONC).The patient underwent three surgeries to remove the tumor.The first tumor resection had been performed when the patient was 14-years-old.Resection of the hemorrhage and bone disc decompression were performed when the patient was 39-years-old.One month after the last discharge,the patient underwent neuronavigation-assisted resection of the right frontotemporal parietal lesion plus extended flap decompression.On the 50^(th)d after the third operation,computed tomography imaging showed rapid tumor growth accompanied by brain hernia.The patient was discharged and died 3 d later.CONCLUSION Glioma can present as bleeding in the initial stage and should be considered in such a setting.We have reported a case of DGONC,which is a rare molecular subtype of glioma with a unique methylation profile.
基金the Natural Science Foundation of Southwest Medical University(No.2016XNYD217,No.2018-ZRQN-032 and No.2016LZXNYD-G03)the National Natural Science Foundation of China(No.82072780)Sichuan Science and Technology Program(No.2022YFS0630).
文摘Objective Protein disulfide isomerase A2(PDIA2),a member of the protein disulfide isomerase family,plays a key role in the folding of nascent proteins in the endoplasmic reticulum by forming disulfide bonds,together with enzymes such as thiol isomerase,oxidase,and reductase.This study investigated the clinical significance and potential functions of PDIA2 in glioma.Methods The expression of PDIA2 in gliomas was explored using The Cancer Genome Atlas and Gene Expression Omnibus databases.We analyzed the clinical characteristics of glioma patients and the prognostic and diagnostic value of PDIA2 expression.Kaplan-Meier and Cox regression analyses were used to examine the effect of PDIA2 expression on overall survival,progression-free interval,and disease-specific survival.Furthermore,we performed Gene Set Enrichment Analysis and immune infiltration analysis to investigate the functions of PDIA2.PDIA2 mRNA and protein expression was evaluated in cell lines and glioma tissues.Results PDIA2 was expressed at low levels in glioma patients.Kaplan-Meier survival analysis showed that glioma patients with low PDIA2 levels had a worse prognosis than those with high PDIA2 levels.Receiver operating characteristic curve analysis indicated the diagnostic and prognostic ability of PDIA2(area under the curve=0.918).Pathways associated with PD1,PI3K/AKT,cancer immunotherapy via PD1 blockade,Fceri-mediated NF-kB activation,FOXM1,and DNA repair were enriched in glioma patients with low levels of PDIA2.PDIA2 expression levels were negatively correlated with immune cell infiltrate levels.Conclusion PDIA2 levels are significantly downregulated in glioma.PDIA2 expression may be a potential biomarker for the diagnosis and prognosis of glioma patients.
基金supported by the Clinical Innovation Guidance Plan of the Department of Science and Technology of Hunan Province(No.2018SK51502)a Postgraduate Scientific Research Innovation Project of Hunan Province(No.CX20210977)+1 种基金Key Guiding Subjects of the Hunan Provincial Health Commission(No.20201912)the Natural Science Foundation of Hunan Province(Nos.2020JJ8029,2018JJ3461).
文摘Objective:A high-fat,low-carbohydrate ketogenic diet has been used to treat malignant glioma,in which the Raf/MEK/ERK signaling pathway is overactivated.However,whether the Raf/MEK/ERK signaling pathway is involved in the therapeutic effect of ketone bodies remains unknown.In this study,we investigated the effects of a major ketone body,3-hydroxybutyric acid(3-HBA),on the proliferation and metastasis of malignant glioblastoma cells and the underlying mechanism.Methods:Two human malignant glioblastoma cell lines(U87 and U251)were treated with different concentrations of 3-HBA with or without the Raf inhibitor PAF C-16 for 24 h.Cell proliferation,cell cycle,cell invasion,and phospholipase D1(PLD1)activity were determined.Protein and gene expression levels of Raf/MEK/ERK signaling pathway members were examined.Results:3-HBA significantly decreased cell proliferation,invasion,and intracellular PLD1 activity in both U87 and U251 glioblastoma cell lines.3-HBA treatment significantly increased the proportion of cells in the G1 phase and decreased the proportion of cells in S phase in U87 cells.In the U251 line,the proportion of treated cells in S phase was increased and proportion of cells in G2 was decreased.3-HBA treatment also significantly decreased the protein expression levels of Raf,MEK,p-MEK,ERK,p-ERK,and PLD1 while increasing p53 expression;an effect that was similar to treatment with the Raf inhibitor.Co-treatment of 3-HBA with the Raf inhibitor further enhanced the effects of the 3-HBA in both cell lines.Conclusion:We confirmed that a ketogenic microenvironment can inhibit glioma cell proliferation and invasion by downregulating the expression of PLD1 through the Raf/MEK/ERK signaling pathway.
基金Finance Science and Technology Project of Hainan Province(ZDYF2022SHFZ088),Hainan Medical University Postgraduate Innovative Research Project Category B(HYYS2021B16)。
文摘Obiective:To investigate the prognostic value of ORMDL2 in human glioma and its relationship with immune invasion.Methods:The clinical survival data from TCGA-LGG&GBM,CGGA and GEO were used to evaluate the clinical prognostic value of ORMDL2.The cut off value of ORMDL2 was detected with pROC package to draw ROC curve to prove its value in differential diagnosis of glioma.The first 300 genes with the most significant positive correlation with ORMDL2 were selected to establish PPI network through STRING database and conduct GO and pathway analysis.The relationship between the expression of ORMDL2 mRNA and immune cell infiltration was investigated by using ssGSEA and TIMER2.0 databases.Results:The expression of ORMDL2 mRNA in glioma was significantly higher than that in adjacent normal tissues,and the difference was most significant in high-grade glioma.The expression of ORMDL2 was increased in human glioma,which was related to the clinicopathological characteristics and poor prognosis of glioma patients.In addition,the increased expression of ORMDL2 was associated with a series of immune infiltrating cells,including macrophages.Conclusion:ORMDL2 plays an important role in glioma immune cell infiltration and is a biomarker of prognosis of glioma patients.
基金Natural Science Foundation of Hainan(No.822MS205)Hainan Provincial Health Industry Research Project(No.21A200288)。
文摘Objective:To investigate whether macrophage-derived exosomal mir-222 regulates Caspase-10 and whether macrophage-derived exosomes promote glioma proliferation by targeting Caspase-10 through mir-222.Methods:Macrophages were transfected with mir-222 mimics,and then macrophage-derived exosomes carrying mir-222 were transfected into glioma cells.Caspase-10 overexpression vector was constructed on this basis.RT-PCR was used to detect mir-222 expression in macrophages and glioma cells.CCK-8 assay was used to detect the proliferative activity of glioma cells.Dual-luciferase reporter assay was used to verify the targeting binding of mir-222 with Caspase-10 gene.Western blot was used to detect Caspase-10 expression.Results:Transmission electron microscopy showed that macrophagederived exosomes had spherical structures with a diameter of about 100 nm;mir-222 mimic significantly promoted the expression of mir-222 in macrophages;macrophage-derived exosomal mir-222 increased mir-222 expression and promoted proliferation in glioma cells;mir-222 could target bind with Caspase-10;mir-222 mimic significantly inhibited Caspase-10 expression.Conclusion:Macrohpage-derived exosomal mir-222 plays an important role in promoting glioma proliferation by downregulating Caspase-10 expression through targeted binding.
基金supported by the National Natural Science Foundation of China (31700808)the Fundamental Research Funds for the Central Universities (2020kfyXJJS112).
文摘Glioma is the most malignant brain cancer.The neurons,macrophages,T cells and other immune ellls constitute the glioma immunosuppressive microenvironment.The accurate spatial distri-bution of these cells in the glioma microenvironment and its relationship with glioma metastasis is unknown.We constructed a mouse gliomna cell line stably expressing the large Stokes shifted yellow fluorescent protein and applied it to the multicolor immunofluorescence imaging.The inaging data revealed that the neurons were sparsely distributed in the glioma core and the mumber of neurons decreased by 90%compared with normal brain site.The spatial distribution of monocyte-macrophages and microglia is heterogeneous.The monocyte macrophages and T cells were heavily recrnuited into the glioma core and metastasis.There was no significant difference in the distribution of microglia amnong glioma core,margin,and normal brain site.Our results provided new perspectives for targeting immune regulation cells and developing new immuno-therapy strategies for glioma.
基金This work was supported by the Scientific and Technological Innovation Program for Clinical Medicine of Jinan(202019132)to LIPING GONG.
文摘ATP binding cassette subfamily C member 8(ABCC8)encodes a protein regulating the ATP-sensitive potassium channel.Whether the level of ABCC8 mRNA in lower grade glioma(LGG)correlates with immune cell infiltration and patient outcomes has not been evaluated until now.Comparisons of ABCC8 expression between different tumors and normal tissues were evaluated by exploring publicly available datasets.The association between ABCC8 and tumor immune cell infiltration,diverse gene mutation characteristics,tumor mutation burden(TMB),and survival in LGG was also investigated in several independent datasets.Pathway enrichment analysis was conducted to search for ABCC8-associated signaling pathways.Through an online database,we found that ABCC8 expression in LGG was lower than in normal tissues.Then,the association of ABCC8 expression and immune cell infiltration in LGG was discussed.As we expected,the ABCC8 mRNA levels were negatively associated with non-T immune cell infiltration levels in all datasets.Consistently,TCGA_LGG RNA-seq data revealed that ABCC8 downregulated several non-T immune cell-associated signaling pathways in gene set enrichment analysis.Different ABCC8 expression groups showed diverse gene mutation characteristics and TMB.The high expression of ABCC8 was linked to improved survival of LGG patients.A pathway enrichment analysis of ABCC8-associated genes indicated that the GABAergic synapse signaling pathway might be involved in regulating immunity in LGG.Our findings show that ABCC8 reflects LGG tumor immunity and is an ideal prognostic biomarker for LGG.
基金Supported by Gansu Natural Science Foundation(21JR7RA571)Lanzhou Science and Technology Plan Project(2019-1-48)Major Project of Gansu University of Political Science and Law(GZF2021XZD06).
文摘[Objectives] To explore the inhibitory effect of octadecadienoic acid (ODA) on proliferation and apoptosis of glioma cells and its mechanism. [Methods] Cultured human glioma cells (cell density 2×10^(6) cells/L) were divided into three groups: solvent control group (DMSO, 30 μL/L), 5-FU group (10 mg/L) and octadecadienoic acid group (0.3, 0.6, 1.2 mg/L). The toxic effects of ODA on glioma cells were detected by trypan blue and thiazolium blue (MTT). The expression of P53, PI3K, P21, PKB/Akt and caspase-9 protein in glioma cells were detected by enzyme-linked immunosorbent assay (ELISA). [Results] The cell count under optical microscope showed that the inhibition rate of cell proliferation in low, medium and high dose ODA groups and 5-FU group was significantly higher than that in solvent control group ( P <0.01), but there was no significant difference compared with 5-FU group ( P >0.05). The results of MTT showed that compared with the solvent control group, the inhibition rate of cell proliferation in low, medium and high dose ODA groups and 5-FU group significantly increased ( P <0.01);compared with 5-FU group, the inhibition rate of cell proliferation in high dose ODA group significantly increased ( P <0.01). The results of flow cytometry showed that compared with the solvent control group, the number of cells in G_(0)/G_(1) phase increased significantly ( P <0.05, P <0.01), the number of cells in G_(2)/M phase decreased significantly ( P <0.01) and the apoptosis rate increased significantly ( P <0.01) in the low, medium and high dose ODA groups and 5-FU group;compared with 5-FU group, the number of cells in G_(2)/M phase decreased significantly ( P <0.01) and the apoptosis rate increased significantly ( P <0.01) in ODA group. ELISA testing results showed that the expression levels of P53, P13K and PKB/Akt in low, medium and high dose ODA groups and 5-FU group were significantly lower than those in solvent control group ( P <0.01), and only the expression level of protein in high dose ODA group was significantly lower than that in 5-FU group ( P <0.01);the expression levels of P21 and caspase-9 in low, medium and high dose ODA groups and 5-FU group were significantly higher than those in solvent control group ( P <0.05, P <0.01), but the expression level of protein in high dose ODA group was significantly higher than that in 5-FU group ( P <0.01). [Conclusions] ODA can obviously inhibit the proliferation of glioma cells and induce apoptosis. The mechanism is related to up-regulation of P21, caspase-9, down-regulation of P53, PI3K, PKB/Akt, inhibition of cell division cycle and decrease of PI3K-Akt signal transduction pathway.