Updates on management of gliomas in the molecular age

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.

Current challenges in the treatment of gliomas:The molecular era

Gliomas originate from glial cells in the central nervous system.Approximately 80%-85%of malignant brain tumors in adults are gliomas.The most common central nervous system tumor in children is low-grade pediatric glioma.Diagnosis was determined by histological features until 2016 when the World Health Organization classification integrated molecular data with anatomopathological information to achieve a more integral diagnosis.Molecular characterization has led to better diagnostic and prognostic staging,which in turn has increased the precision of treatment.Current efforts are focused on more effective therapies to prolong survival and improve the quality of life of adult and pediatric patients with glioma.However,improvements in survival have been modest.Currently,clinical guidelines,as well as the article by Mohamed et al accompanying this editorial piece,are adapting treatment recommendations(surgery,chemotherapy,and radiotherapy)according to diagnosis and prognosis guided by molecular biomarkers.Furthermore,this paves the way for the design of clinical trials with new therapies,which is especially important in pediatric gliomas.

Scinderin promotes glioma cell migration and invasion via remodeling actin cytoskeleton

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.

Multimodal cardiac imaging assisted tumor characterization and surgical planning of a patient with rare primary cardiac paraganglioma

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.

Revealing the role of honokiol in human glioma cells by RNA-seq analysis

Background:Glioma is a kind of tumor that easily deteriorates and originates from glial cells in nerve tissue.Honokiol is a bisphenol compound that is an essential monomeric compound extracted from the roots and bark of Magnoliaceae plants.It also has anti-infection,antitumor,and immunomodulatory effects.In this study,we found that honokiol induces cell apoptosis in the human glioma cell lines U87-MG and U251-MG.However,the mechanism through which honokiol regulates glioma cell apoptosis is still unknown.Methods:We performed RNA-seq analysis of U251-MG cells treated with honokiol and control cells.Protein-protein interaction(PPI)network analysis was performed,and the 10 top hub unigenes were examined via real-time quantitative PCR.Furthermore,MAPK signaling and ferroptosis were detected via western blotting.Results:332 differentially expressed genes(DEGs)were found,comprising 163 increased and 169 decreased genes.Analysis of the DEGs revealed that various biological processes were enriched,including‘response to hypoxia’,‘cerebellum development cellular response to hypoxia,’‘iron ion binding,’‘oxygen transporter activity,’‘oxygen binding,’‘ferric iron binding,’and‘structural constituent of cytoskeleton.’Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway analysis revealed that the DEGs were enriched in the following pathways:‘mitogen-activated protein kinases(MAPK)’,‘Hypoxia-inducible factor 1(HIF-1)’,‘ferroptosis,’‘Peroxisome proliferator-activated receptor(PPAR),’‘Phosphatidylinositol-4,5-bisphosphate 3-kinase(PI3K)-protein kinase B(Akt),’and‘phagosome.’Among these pathways,the MAPK signaling pathway and ferroptosis were verified.Conclusion:This study revealed the potential mechanism by which honokiol induces apoptosis and provided a comprehensive analysis of DEGs in honokiol-treated U251-MG cells and the associated signaling pathways.These data could lead to new ideas for future research and therapy for patients with glioma.

ATM Activation is Key in Vasculogenic Mimicry Formation by Glioma Stem-like Cells

Objective Vasculogenic mimicry(VM)is a novel vasculogenic process integral to glioma stem cells(GSCs)in glioblastoma(GBM).However,the relationship between VM and ataxia-telangiectasia mutated(ATM)serine/threonine kinase activation,which confers chemoradiotherapy resistance,remains unclear.Methods We investigated VM formation and phosphorylated ATM(pATM)levels by CD31/GFAPperiodic acid-Schiff dual staining and immunohistochemical staining in 145 GBM specimens.Glioma stem-like cells(GSLCs)derived from the formatted spheres of U87 and U251 cell lines and their pATM level and VM formation ability were examined using western blot and three-dimensional culture.For the examination of the function of pATM in VM formation by GSLCs,ATM knockdown by shRNAs and deactivated via ATM phosphorylation inhibitor KU55933 were studied.Results VM and high pATM expression occurred in 38.5% and 41.8% of tumors,respectively,and were significantly associated with reduced progression-free and overall survival.Patients with VM-positive GBMs exhibited higher pATM levels(r_(s)=0.425,P=0.01).The multivariate analysis established VM as an independent negative prognostic factor(P=0.002).Furthermore,GSLCs expressed high levels of pATM and formed vascular-like networks in vitro.ATM inactivation or knockdown hindered VM-like network formation concomitant with the downregulation of pVEGFR-2,VE-cadherin,and laminin B2.Conclusion VM may predict a poor GBM prognosis and is associated with pATM expression.We propose that pATM promotes VM through extracellular matrix modulation and VE-Cadherin/pVEGFR-2 activation,thereby highlighting ATM activation as a potential target for enhancing anti-angiogenesis therapies for GBM.

IQGAP3 promotes the progression of glioma as an immune and prognostic marker

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.

Survival Analysis of Patients Undergoing Intraoperative Contrast-enhanced Ultrasound in the Surgical Treatment of Malignant Glioma

Objective:Complete resection of malignant gliomas is often challenging.Our previous study indicated that intraoperative contrast-enhanced ultrasound(ICEUS)could aid in the detection of residual tumor remnants and the total removal of brain lesions.This study aimed to investigate the survival rates of patients undergoing resection with or without the use of ICEUS and to assess the impact of ICEUS on the prognosis of patients with malignant glioma.Methods:A total of 64 patients diagnosed with malignant glioma(WHO grade HI and IV)who underwent surgery between 2012 and 2018 were included.Among them,29 patients received ICEUS.The effects of ICEUS on overall survival(OS)and progression-free survival(PFS)of patients were evaluated.A quantitative analysis was performed to compare ICEUS parameters between gliomas and the surrounding tissues.Results:The ICEUS group showed better survival rates both in OS and PFS than the control group.The univariate analysis revealed that age,pathology and ICEUS were significant prognostic factors for PFS,with only age being a significant prognostic factor for OS.In multivariate analysis,age and ICEUS were significant prognostic factors for both OS and PFS.The quantitative analysis showed that the intensity and transit time of microbubbles reaching the tumors were significantly different from those of microbubbles reaching the surrounding tissue.Conclusion:ICEUS facilitates the identification of residual tumors.Age and ICEUS are prognostic factors for malignant glioma surgery,and use of ICEUS offers a better prognosis for patients with malignant glioma.

Multi-cohort comprehensive analysis unveiling the clinical value and therapeutic effect of GNAL in glioma

Clinical data indicates that glioma patients have poor treatment outcomes and clinical prognosis.The role of olfactory signaling pathway-related genes(OSPRGs)in glioma has not been fully elucidated.In this study,we aimed to investigate the role and relationship between OSPRGs and glioma.Univariate and multivariate Cox regression analyses were performed to assess the relationship between OSPRGs and the overall survival of glioma based on public cohorts,and the target gene(G Protein Subunit Alpha L,GNAL)was screened.The association of GNAL expression with clinicopathological characteristics,gene mutation landscape,tumor immune microenvironment(TIME),deoxyribonucleic acid(DNA)methylation,and naris-occlusion controlled genes(NOCGs)was performed.Immunohistochemistry was used to evaluate GNAL level in glioma.Further analysis was conducted to evaluate the drug sensitivity,immunotherapy response,and functional enrichment of GNAL.GNAL was an independent prognostic factor,and patients with low GNAL expression have a poor prognosis.Expression of GNAL was closely associated with clinicopathological characteristics,DNA methylation,and several immune-related pathways.Immune infiltration analysis indicated that GNAL levels were negatively correlated with immune scores.GNAL low-expression group showed efficacy with anti-PD-1 therapy.Ten compounds with significantly different half-maximal inhibitory concentration(IC50)values between the GNAL high and low-expression groups were identified.Furthermore,its expression was associated with several immune cells,immune-related genes,and NOCGs.The expression of GNAL is closely associated with clinicopathological characteristics,TIME,and the response to therapeutic interventions,highlighting its potential as a prognostic biomarker for glioma.

Impacts of Nutlin-3a and exercise on murine double minute 2-enriched glioma treatment

Recent research has demonstrated the impact of physical activity on the prognosis of glioma patients,with evidence suggesting exercise may reduce mortality risks and aid neural regeneration.The role of the small ubiquitin-like modifier(SUMO)protein,especially post-exercise,in cancer progression,is gaining attention,as are the potential anti-cancer effects of SUMOylation.We used machine learning to create the exercise and SUMO-related gene signature(ESLRS).This signature shows how physical activity might help improve the outlook for low-grade glioma and other cancers.We demonstrated the prognostic and immunotherapeutic significance of ESLRS markers,specifically highlighting how murine double minute 2(MDM2),a component of the ESLRS,can be targeted by nutlin-3.This underscores the intricate relationship between natural compounds such as nutlin-3 and immune regulation.Using comprehensive CRISPR screening,we validated the effects of specific ESLRS genes on low-grade glioma progression.We also revealed insights into the effectiveness of Nutlin-3a as a potent MDM2 inhibitor through molecular docking and dynamic simulation.Nutlin-3a inhibited glioma cell proliferation and activated the p53 pathway.Its efficacy decreased with MDM2 overexpression,and this was reversed by Nutlin-3a or exercise.Experiments using a low-grade glioma mouse model highlighted the effect of physical activity on oxidative stress and molecular pathway regulation.Notably,both physical exercise and Nutlin-3a administration improved physical function in mice bearing tumors derived from MDM2-overexpressing cells.These results suggest the potential for Nutlin-3a,an MDM2 inhibitor,with physical exercise as a therapeutic approach for glioma management.Our research also supports the use of natural products for therapy and sheds light on the interaction of exercise,natural products,and immune regulation in cancer treatment.

Role of glioma stem cells in promoting tumor chemo- and radioresistance: A systematic review of potential targeted treatments

BACKGROUND Gliomas pose a significant challenge to effective treatment despite advancements in chemotherapy and radiotherapy.Glioma stem cells(GSCs),a subset within tumors,contribute to resistance,tumor heterogeneity,and plasticity.Recent studies reveal GSCs’role in therapeutic resistance,driven by DNA repair mechanisms and dynamic transitions between cellular states.Resistance mechanisms can involve different cellular pathways,most of which have been recently reported in the literature.Despite progress,targeted therapeutic approaches lack consensus due to GSCs’high plasticity.AIM To analyze targeted therapies against GSC-mediated resistance to radio-and chemotherapy in gliomas,focusing on underlying mechanisms.METHODS A systematic search was conducted across major medical databases(PubMed,Embase,and Cochrane Library)up to September 30,2023.The search strategy utilized relevant Medical Subject Heading terms and keywords related to including“glioma stem cells”,“radiotherapy”,“chemotherapy”,“resistance”,and“targeted therapies”.Studies included in this review were publications focusing on targeted therapies against the molecular mechanism of GSC-mediated re-sistance to radiotherapy resistance(RTR).RESULTS In a comprehensive review of 66 studies on stem cell therapies for SCI,452 papers were initially identified,with 203 chosen for full-text analysis.Among them,201 were deemed eligible after excluding 168 for various reasons.The temporal breakdown of studies illustrates this trend:2005-2010(33.3%),2011-2015(36.4%),and 2016-2022(30.3%).Key GSC models,particularly U87(33.3%),U251(15.2%),and T98G(15.2%),emerge as significant in research,reflecting their representativeness of glioma characteristics.Pathway analysis indicates a focus on phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin(mTOR)(27.3%)and Notch(12.1%)pathways,suggesting their crucial roles in resistance development.Targeted molecules with mTOR(18.2%),CHK1/2(15.2%),and ATP binding cassette G2(12.1%)as frequent targets underscore their importance in overcoming GSC-mediated resistance.Various therapeutic agents,notably RNA inhibitor/short hairpin RNA(27.3%),inhibitors(e.g.,LY294002,NVP-BEZ235)(24.2%),and monoclonal antibodies(e.g.,cetuximab)(9.1%),demonstrate versatility in targeted therapies.among 20 studies(60.6%),the most common effect on the chemotherapy resistance response is a reduction in temozolomide resistance(51.5%),followed by reductions in carmustine resistance(9.1%)and doxorubicin resistance(3.0%),while resistance to RTR is reduced in 42.4%of studies.CONCLUSION GSCs play a complex role in mediating radioresistance and chemoresistance,emphasizing the necessity for precision therapies that consider the heterogeneity within the GSC population and the dynamic tumor microenvironment to enhance outcomes for glioblastoma patients.

Risk Factors and Predictive Nomogram for Survival in Elderly Patients with Brain Glioma

Objective To determine the factors that contribute to the survival of elderly individuals diagnosed with brain glioma and develop a prognostic nomogram.Methods Data from elderly individuals(age≥65 years)histologically diagnosed with brain glioma were sourced from the Surveillance,Epidemiology,and End Results(SEER)database.The dataset was randomly divided into a training cohort and an internal validation cohort at a 6:4 ratio.Additionally,data obtained from Tangdu Hospital constituted an external validation cohort for the study.The identification of independent prognostic factors was achieved through the least absolute shrinkage and selection operator(LASSO)and multivariate Cox regression analysis,enabling the construction of a nomogram.Model performance was evaluated using C-index,ROC curves,calibration plot and decision curve analysis(DCA).Results A cohort of 20483 elderly glioma patients was selected from the SEER database.Five prognostic factors(age,marital status,histological type,stage,and treatment)were found to significantly impact overall survival(OS)and cancer-specific survival(CSS),with tumor location emerging as a sixth variable independently linked to CSS.Subsequently,nomogram models were developed to predict the probabilities of survival at 6,12,and 24 months.The assessment findings from the validation queue indicate a that the model exhibited strong performance.Conclusion Our nomograms serve as valuable prognostic tools for assessing the survival probability of elderly glioma patients.They can potentially assist in risk stratification and clinical decision-making.

Prognostic significance of oligodendrocyte transcription factor 2 expression in glioma patients:A systematic review and metaanalys

BACKGROUND Gliomas are the most common primary central nervous system neoplasm.Despite recent advances in the diagnosis and treatment of gliomas,patient prognosis remains dismal.Therefore,it is imperative to identify novel diagnostic biomarkers and therapeutic targets of glioma to effectively improve treatment outcomes.AIM To investigate the association between oligodendrocyte transcription factor 2(Olig2)expression and the outcomes of glioma patients.METHODS The PubMed,Embase,Cochrane Library,and China National Knowledge Infrastructure databases were searched for studies(published up to October 2023)that investigated the relationship between Olig2 expression and prognosis of glioma patients.The quality of the studies was assessed using the Newcastle Ottawa Scale.Data analyses were performed using Stata Version 12.0 software.RESULTS A total of 1205 glioma patients from six studies were included in the metaanalysis.High Olig2 expression was associated with better outcomes in glioma patients[hazard ratio(HR):0.81;95%(confidence interval)CI:0.51-1.27;P=0.000].Furthermore,the results of subgroup meta-analysis showed that high expression of Olig2 was associated with poor overall survival in European patients(HR:1.34;95%CI:0.79-2.27)and better prognosis in Asian patients(HR:0.43;95%CI:0.22-0.84).The sensitivity analysis showed that no single study had a significant effect on pooled HR,and there was also no indication of publication bias according to the Egger’s and Begger’s P value test or funnel plot test.CONCLUSION High Olig2 expression may have a positive impact on the prognosis of glioma patients,and should be investigated further as a prognostic biomarker and therapeutic target for glioma.

Focus on current and emerging treatment options for glioma:A comprehensive review

This comprehensive review delves into the current updates and challenges associated with the management of low-grade gliomas(LGG),the predominant primary tumors in the central nervous system.With a general incidence rate of 5.81 per 100000,gliomas pose a significant global concern,necessitating advancements in treatment techniques to reduce mortality and morbidity.This review places a particular focus on immunotherapies,discussing promising agents such as Zotiraciclib and Lerapolturev.Zotiraciclib,a CDK9 inhibitor,has demonstrated efficacy in glioblastoma treatment in preclinical and clinical studies,showing its potential as a therapeutic breakthrough.Lerapolturev,a viral immunotherapy,induces inflammation in glioblastoma and displays positive outcomes in both adult and pediatric patients.Exploration of immunotherapy extends to Pembrolizumab,Nivolumab,and Entrectinib,revealing the challenges and variabilities in patient responses.Despite promising preclinical data,the monoclonal antibody Depatuxizumab has proven ineffective in glioblastoma treatment,emphasizing the critical need to understand resistance mechanisms.The review also covers the success of radiation therapy in pediatric LGG,with evolving techniques,such as proton therapy,showing potential improvements in patient quality of life.Surgical treatment is discussed in the context of achieving a balance between preserving the patient’s quality of life and attaining gross total resection,with the extent of surgical resection significantly influencing the survival outcomes.In addition to advancements in cancer vaccine development,this review highlights the evolving landscape of LGG treatment,emphasizing a shift toward personalized and targeted therapies.Ongoing research is essential for refining strategies and enhancing outcomes in the management of LGG.

New targets for cancer promotion and therapy in gliomas: Scinderin

Glioma is one of the most common primary intracranial tumors,characterized by invasive growth and poor prognosis.Actin cytoskeletal rearrangement is an essential event in tumor cell migration.Scinderin(SCIN),an actin severing and capping protein that regulates the actin cytoskeleton,is involved in the prolif-eration and migration of certain cancer cells.However,its biological role and molecular mechanism in glioma remain unclear.Lin et al explored the role and mechanism of SCIN in gliomas.The results showed that SCIN mechanically affected cytoskeleton remodeling and inhibited the formation of lamellipodia via RhoA/FAK signaling pathway.This study identifies the cancer-promoting role of SCIN and provides a potential therapeutic target for SCIN in glioma treatment.

Exploratory therapy for brainstem gliomas

Brainstem gliomas comprise both slow-growing and highly aggressive tumors,the latter carrying a dismal prognosis of approximately 10 months in children.Given their common locations along the brainstem,they are often not amenable to surgical resection.There are currently a host of exploratory therapies under investigation ranging from immunotherapy,small molecular inhibitors,epigenetic-modifying agents,and radiation protocols to combat these difficult-to-treat tumors.Recent discoveries highlighting the role of H3 histone mutations in diffuse midline glioma oncogenesis have yielded a variety of new targetable antigens and aberrant signaling pathways.Although many of these studies have shown promise in terms of inhibiting tumor growth and disease progression,results to date have been modest in their ability to translate into meaningful clinical benefit.This review will serve as an updated report on the current state of literature concerning pre-clinical and clinical therapies being investigated for brainstem glioma.In addition,this review will serve as a guide for clinicians as we review the evolving nomenclature of brainstem gliomas,commonly presenting symptoms,diagnostic tools,and standard therapies.

PhaseⅠstudy of chlorogenic acid injection for recurrent high-grade glioma with long-term follow-up

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.

Anti-leucine-rich glioma inactivated protein 1 encephalitis with sleep disturbance as the first symptom: A case report and review of literature

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.

Construction and Verification of an RNA-Binding Protein-Associated Prognostic Model for Gliomas

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.

Mechanism of NURP1 in temozolomide resistance in hypoxiatreated glioma cells via the KDM3A/TFEB axis

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.