Comprehensive understanding of glioblastoma molecular phenotypes:classification,characteristics,and transition

Among central nervous system-associated malignancies,glioblastoma(GBM)is the most common and has the highest mortality rate.The high heterogeneity of GBM cell types and the complex tumor microenvironment frequently lead to tumor recurrence and sudden relapse in patients treated with temozolomide.In precision medicine,research on GBM treatment is increasingly focusing on molecular subtyping to precisely characterize the cellular and molecular heterogeneity,as well as the refractory nature of GBM toward therapy.Deep understanding of the different molecular expression patterns of GBM subtypes is critical.Researchers have recently proposed tetra fractional or tripartite methods for detecting GBM molecular subtypes.The various molecular subtypes of GBM show significant differences in gene expression patterns and biological behaviors.These subtypes also exhibit high plasticity in their regulatory pathways,oncogene expression,tumor microenvironment alterations,and differential responses to standard therapy.Herein,we summarize the current molecular typing scheme of GBM and the major molecular/genetic characteristics of each subtype.Furthermore,we review the mesenchymal transition mechanisms of GBM under various regulators.

化学史与方法论课程思政案例探索与实践

化学史与方法论作为化学专业的选修课程,承担着重要的育人使命。为探索新时代背景下化学史与方法论课程思政协同育人功能,本文在探讨化学史与方法论课程重要定位及融入思政教育重要意义的基础上,深入挖掘课程所蕴含的思政元素,并以安徽师范大学化学史与方法论特色专题“化学家评传”之“中国化学工业先驱”为例,以科学家精神为基点进行课程思政教学案例开发与实践,问卷和访谈两种调查形式均表明本次课程取得良好教学效果。

Omics-based integrated analysis identified ATRX as a biomarker associated with glioma diagnosis and prognosis

Objective:ATRX is a multifunctional protein that is tightly regulated by and implicated in transcriptional regulation and chromatin remodeling.Numerous studies have shown that genetic alterations in ATRX play a significant role in gliomas.This study aims to further determine the relationship between ATRX and glioma prognosis and identify possible mechanisms for exploring the biological significance of ATRX using large data sets.Methods:We used The Cancer Genome Atlas(TCGA)database and 130 immunohistochemical results to confirm the difference in ATRX mutations in high-and low-grade gliomas.An online analysis of the TCGA glioma datasets using the cBioPortal platform was performed to study the relationship between ATRX mutations and IDH1,TP53,CDKN2 A and CDKN2 B mutations in the corresponding TCGA glioma dataset.In combination with clinical pathology data,the biological significance of the relationships were analyzed.Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway analyses and annotations of all adjacent genes in the network were performedin the Database for Annotation,Visualization and Integrated Discovery(DAVID)and R language.A protein-protein interaction(PPI)network was constructed,and the interactions of all adjacent nodes were analyzed by the String database and using Cytoscape software.Results:In the selected TCGA glioma datasets,a total of 2,228 patients were queried,21%of whom had ATRX alterations,which co-occurred frequently with TP53 and IDH1 mutations.ATRX alterations are associated with multiple critical molecular events,which results in a significantly improved overall survival(OS)rate.In low-grade gliomas,ATRX mutations are significantly associated with multiple important molecular events,such as ZNF274 and FDXR at mRNA and protein levels.A functional cluster analysis revealed that these genes played a role in chromatin binding and P53,and a link was observed between ATRX and IDH1 and TP53 in the interaction network.ATRX and TP53 are important nodes in the network and have potential links with the blood oxygen imbalance.Conclusions:ATRX mutations have clinical implications for the molecular diagnosis of gliomas and can provide diagnostic and prognostic information for gliomas.ATRX is expected to serve as a new therapeutic target.

Development of glioblastoma organoids and their applications in personalized therapy

Glioblastomas(GBMs)are the brain tumors with the highest malignancy and poorest prognoses.GBM is characterized by high heterogeneity and resistance to drug treatment.Organoids are 3-dimensional cultures that are constructed in vitro and comprise cell types highly similar to those in organs or tissues in vivo,thus simulating specific structures and physiological functions of organs.Organoids have been technically developed into an advanced ex vivo disease model used in basic and preclinical research on tumors.Brain organoids,which simulate the brain microenvironment while preserving tumor heterogeneity,have been used to predict patients’therapeutic responses to antitumor drugs,thus enabling a breakthrough in glioma research.GBM organoids provide an effective supplementary model that reflects human tumors’biological characteristics and functions in vitro more directly and accurately than traditional experimental models.Therefore,GBM organoids are widely applicable in disease mechanism research,drug development and screening,and glioma precision treatments.This review focuses on the development of various GBM organoid models and their applications in identifying new individualized therapies against drug-resistant GBM.

Boosting of the enhanced permeability and retention effect with nanocapsules improves the therapeutic effects of cetuximab

Objective:The introduction of therapeutic antibodies(tAbs)into clinical practice has revolutionized tumor treatment strategies,but their tumor therapy efficiency is still far below expectations because of the rapid degradation and limited tumor accumulation of tAbs.Methods:We developed a nanocapsule-based delivery system to induce the self-augmentation of the enhanced permeability and retention(EPR)effect.This system constantly penetrated across the blood-tumor barrier into the tumor while avoiding the attack of tAbs by the immune system.The biodistribution and therapeutic effect were tested with single dose administration of nanocapsule-tAbs in vivo.Results:The accumulation of Nano(cetuximab)within subcutaneous PC9 tumors was gradually enhanced over 6 days after single dose administration,which was contrary to the biodistribution of native cetuximab.Nano(cetuximab)accumulated in tumor tissues via the EPR effect and released cetuximab.The released cetuximab acted on vascular endothelial cells to destroy the blood-tumor barrier and induce self-augmentation of the EPR effect,which in turn contributed to further tumor accumulation of long-circulating Nano(cetuximab).Compared with single dose administration of native cetuximab,Nano(cetuximab)showed an effective tumor suppressive effect for 3 weeks.Conclusions:The nanocapsule-based delivery system efficiently delivered tAbs to tum or tissues and released them to boost the EPR effect,which facilitated further tumor accumulation of the tAbs.This novel self-augmentation of the EPR effect facilitated by the biological characteristics of tAbs and nanotechnology contributed to the improvement of the therapeutic effect of tAbs,and stimulated new ideas for antibody-based tumor therapy.

Clinical and pathological features in 49 elderly patients with meningiomas

BACKGROUND： As aging in elderly people, their brain tissue has degeneration and brain atrophy of different severity, and the volume of cranial cavity is relatively enlarged, it has greater compensatory ability to the space occupying lesion, and it is difficult to detect the meningioma because it grows to expand slowly, the tumor locates in non-functional region, and there are atypical symptoms and deficiency of localization signs. OBJECTIVE： To investigate the clinicopathologic features of senile meningiomas. DESIGN： A retrospective analysis. SETTING： Affiliated Hospital of Hebei University. PARTICIPANTS： Forty-nine elderly patients with meningioma were selected from the Department of Neurosurgery, Affiliated Hospital of Hebei University from May 1999 to March 2005, including 15 males and 34 females, 60-74 years of age, and they were all diagnosed by CT and MRI. METHODS： The sites of tumors were identified by CT and MRI examinations in all the patients. The tumors were partially or totally resected according to their own conditions. The types of the resected tumor were pathologically observed. The conditions of postoperative recovery were observed after 1, 3 and 6 months, and without new neurological dysfunction or complication was considered as good outcome. MAIN OUTCOME MEASURES： ① Sites and pathological types of the tumor; ② Postoperative outcomes and complications. RESULTS： All the 49 patients were involved in the analysis of results. ① The tumors had wide distributions with a main location in brain convexity. Among the 49 cases of meningioma, there were 25 cases of fibrocystic type, 12 cases of meningothelial type, 6 cases of psammomatous type, 4 cases of angiomatous type and 2 cases of microcystic type. ② Among the 49 patients, 35 had good outcome, 8 had self-care ability, 4 required care by others, 2 （4.1%） died postoperatively. No long-term complication related to the operation was observed during the follow-up postoperatively. CONCLUSION： Meningioma has a main location in brain convexity, and its pathological type is mainly fibrocystic one, and there is good operative outcome.

TGFβ signaling-induced miRNA participates in autophagic regulation by targeting PRAS40 in mesenchymal subtype of glioblastoma

Objective:Mesenchymal subtype of glioblastoma(mesGBM)is a refractory disease condition characterized by therapeutic failure and tumor recurrence.Hyperactive transforming growth factor-β(TGF-β)signaling could be a signature event in mesGBM,which leads to dysregulation of downstream targets and contribute to malignant transformation.In this study we aimed to investigate the hyperactive TGFβsignaling-mediated pathogenesis and possible downstream targets for the development of novel therapeutic interventions for mesGBM.Methods:GBM-BioDP is an online resource for accessing and displaying interactive views of the TCGA GBM data set.Transcriptomic sequencing followed by bioinformatic analysis was performed to identify dysregulated microRNAs.Target prediction by MR-microT and dual luciferase reporter assay were utilized to confirm the predicted target of novel_miR56.CCK-8 assays was used to assesse cell viability.The miRNA manipulation was proceeded by cell transfection and lentivirus delivery.A plasmid expressing GFP-LC3 was introduced to visualize the formation of autophagosomes.Orthotopic GBM model was constructed forin vivo study.Results:TGFβ1 and TGFβreceptor type II(TβRII)were exclusively upregulated in mesGBM(P<0.01).Dysregulated miRNAs were identified after LY2109761(a TβRI/II inhibitor)treatment in a mesGBM-derived cell line,and novel_miR56 was selected as a promising candidate for further functional verification.Novel_miR56 was found to potentially bind to PRAS40 via seed region complementarity in the 3'untranslated region,and we also confirmed that PRAS40 is a direct target of novel_miR56 in glioma cells.In vitro,over expression of novel_miR56 in tumor cells significantly promoted proliferation and inhibited autophagy(P<0.05).The expression levels of P62/SQSTM was significantly increased accompanied by the decrease of BECN1 and LC3B-II/I,which indicated that autophagic activity was reduced after novel_miR56 treatment.In addition,over expression of novel_miR56 also promoted tumor growth and inhibited autophagyin vivo,which is associated with worse prognosis(P<0.05).Conclusions:In summary,we provide novel insight into TGFβsignaling-mediated pathogenesis in mesGBM and TGFβsignaling-induced novel_miR56 may be a novel target for mesGBM management.

Blockage of EGFR/AKT and mevalonate pathways synergize the antitumor effect of temozolomide by reprogramming energy metabolism in glioblastoma

Background Metabolism reprogramming plays a vital role in glioblastoma(GBM)progression and recurrence by producing enough energy for highly proliferating tumor cells.In addition,metabolic reprogramming is crucial for tumor growth and immune-escape mechanisms.Epidermal growth factor receptor(EGFR)amplification and EGFR-vIII mutation are often detected in GBM cells,contributing to the malignant behavior.This study aimed to investigate the functional role of the EGFR pathway on fatty acid metabolism remodeling and energy generation.Methods Clinical GBM specimens were selected for single-cell RNA sequencing and untargeted metabolomics analysis.A metabolism-associated RTK-fatty acid-gene signature was constructed and verified.MK-2206 and MK-803 were utilized to block the RTK pathway and mevalonate pathway induced abnormal metabolism.Energy metabolism in GBM with activated EGFR pathway was monitored.The antitumor effect of Osimertinib and Atorvastatin assisted by temozolomide(TMZ)was analyzed by an intracranial tumor model in vivo.Results GBM with high EGFR expression had characteristics of lipid remodeling and maintaining high cholesterol levels,supported by the single-cell RNA sequencing and metabolomics of clinical GBM samples.Inhibition of the EGFR/AKT and mevalonate pathways could remodel energy metabolism by repressing the tricarboxylic acid cycle and modulating ATP production.Mechanistically,the EGFR/AKT pathway upregulated the expressions of acyl-CoA synthetase short-chain family member 3(ACSS3),acyl-CoA synthetase long-chain family member 3(ACSL3),and long-chain fatty acid elongation-related gene ELOVL fatty acid elongase 2(ELOVL2)in an NF-κB-dependent manner.Moreover,inhibition of the mevalonate pathway reduced the EGFR level on the cell membranes,thereby affecting the signal transduction of the EGFR/AKT pathway.Therefore,targeting the EGFR/AKT and mevalonate pathways enhanced the antitumor effect of TMZ in GBM cells and animal models.Conclusions Our findings not only uncovered the mechanism of metabolic reprogramming in EGFR-activated GBM but also provided a combinatorial therapeutic strategy for clinical GBM management.

Apolipoprotein E mimetic peptide CN-105 improves outcome in a murine model of SAH

Objective Subarachnoid haemorrhage(SAH)accounts for 3%of all strokes,and is associated with significant morbidity and mortality.There is growing evidence implicating apolipoprotein E(apoE)in mediating adaptive anti-inflammatory and neuroprotective responses following ischaemic and traumatic brain injury.In the current study,we test the efficacy of a small apoE mimetic peptide,CN-105 in a murine model of SAH.Methods Mice subjected to SAH received repeated intravenous injections of CN-105 every 12 hours for 3 days,with the first dose given 2 hours after injury.Daily functional outcomes were assessed by rotarod and neurological severity score.Haemorrhage grade and cerebral vascular diameters were measured at 5 days post-SAH.Cerebral microgliosis,neuronal degeneration and survival were analysed at 5 and 35 days post-SAH,respectively.results CN-105 reduces histological evidence of inflammation,reduces vasospasm and neuronal injury and is associated with improved long-term behavioural outcomes in a murine model of SAH.Conclusions Given its favourable pharmacokinetic profile,central nervous system penetration and demonstration of clinical safety,CN-105 represents an attractive therapeutic candidate for treatment of brain injury associated with SAH.

Causal Effect of Genetically Determined Blood Copper Concentrations on Multiple Diseases: A Mendelian Randomization and Phenome-Wide Association Study

Exposures to copper have become a health concern.We aim to explore the broad clinical effects of blood copper concentrations.A total of 376,346 Caucasian subjects were enrolled.We performed a Mendelian randomization and phenome-wide association study(MR-PheWAS)to evaluate the causal association between copper and a wide range of outcomes in UK Biobank,and we constructed a protein-protein interaction network.We found association between blood copper concentrations and five diseases in the overall population and nine diseases in male.MR analysis implicated a causal role of blood copper in five diseases(overall population),including prostate cancer(OR=0.87,95%CI 0.77-0.98),malignant and unknown neoplasms of the brain and nervous system(OR=0.58,95%CI 0.38-0.89),and hypertension(OR=0.94,95%CI 0.90-0.98),essential hypertension(OR=0.94,95%CI 0.90-0.98)and cancer of brain and nervous system(OR=0.63,95%CI 0.41-0.98).For male,except for dysphagia being newly associated with blood copper(OR=1.39,95%CI 1.18-1.63),other MR results were consistent with the overall population.In addition,the PPI network showed possible relationship between blood copper and four outcomes,namely brain cancer,prostate cancer,hypertension,and dysphagia.Blood copper may have causal association with prostate cancer,malignant and unknown neoplasms of the brain and nervous system,hypertension,and dysphagia.Considering that copper is modifiable,exploring whether regulation of copper levels can be used to optimize health outcomes might have public health importance.

Temporal and spatial stability of the EM/PM molecular subtypes in adult diffuse glioma

Detailed characterizations of genomic alterations have not identified subtype-specific vulnerabilities in adult gliomas. Mapping gliomas into developmental programs may uncover new vulnerabilities that are not strictly related to genomic alterations. After identifying conserved gene modules co-expressed with EGFR or PDGFRA (EM or PM), we recently proposed an EM/PM classification scheme for adult gliomas in a histological subtype- and grade-independent manner. By using cohorts of bulk samples, paired primary and recurrent samples, multi-region samples from the same glioma, single-cell RNA-seq samples, and clinical samples, we here demonstrate the temporal and spatial stability of the EM and PM subtypes. The EM and PM subtypes, which progress in a subtype-specific mode, are robustly maintained in paired longitudinal samples. Elevated activities of cell proliferation, genomic instability and microenvironment, rather than subtype switching, mark recurrent gliomas. Within individual gliomas, the EM/PM subtype was preserved across regions and single cells. Malignant cells in the EM and PM gliomas were correlated to neural stem cell and oligodendrocyte progenitor cell compartment, respectively. Thus, while genetic makeup may change during progression and/or within different tumor areas, adult gliomas evolve within a neurodevelopmental framework of the EM and PM molecular subtypes. The dysregulated developmental pathways embedded in these molecular subtypes may contain subtype-specific vulnerabilities.