scholarly journals A Computational Framework to Identify Biomarkers for Glioma Recurrence and Potential Drugs Targeting Them

2022 ◽  
Vol 12 ◽  
Author(s):  
Shuzhi Ma ◽  
Zhen Guo ◽  
Bo Wang ◽  
Min Yang ◽  
Xuelian Yuan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Glioblastoma Multiforme ◽  
Signaling Pathway ◽  
Primary Tumor ◽  
New Drugs ◽  
Low Grade ◽  
Recurrent Tumor ◽  
Protein Subunit ◽  
Driver Genes ◽  
Key Driver

Background: Recurrence is still a major obstacle to the successful treatment of gliomas. Understanding the underlying mechanisms of recurrence may help for developing new drugs to combat gliomas recurrence. This study provides a strategy to discover new drugs for recurrent gliomas based on drug perturbation induced gene expression changes.Methods: The RNA-seq data of 511 low grade gliomas primary tumor samples (LGG-P), 18 low grade gliomas recurrent tumor samples (LGG-R), 155 glioblastoma multiforme primary tumor samples (GBM-P), and 13 glioblastoma multiforme recurrent tumor samples (GBM-R) were downloaded from TCGA database. DESeq2, key driver analysis and weighted gene correlation network analysis (WGCNA) were conducted to identify differentially expressed genes (DEGs), key driver genes and coexpression networks between LGG-P vs LGG-R, GBM-P vs GBM-R pairs. Then, the CREEDS database was used to find potential drugs that could reverse the DEGs and key drivers.Results: We identified 75 upregulated and 130 downregulated genes between LGG-P and LGG-R samples, which were mainly enriched in human papillomavirus (HPV) infection, PI3K-Akt signaling pathway, Wnt signaling pathway, and ECM-receptor interaction. A total of 262 key driver genes were obtained with frizzled class receptor 8 (FZD8), guanine nucleotide-binding protein subunit gamma-12 (GNG12), and G protein subunit β2 (GNB2) as the top hub genes. By screening the CREEDS database, we got 4 drugs (Paclitaxel, 6-benzyladenine, Erlotinib, Cidofovir) that could downregulate the expression of up-regulated genes and 5 drugs (Fenofibrate, Oxaliplatin, Bilirubin, Nutlins, Valproic acid) that could upregulate the expression of down-regulated genes. These drugs may have a potential in combating recurrence of gliomas.Conclusion: We proposed a time-saving strategy based on drug perturbation induced gene expression changes to find new drugs that may have a potential to treat recurrent gliomas.

scholarly journals A blood-based gene expression and signaling pathway analysis to differentiate between high and low grade gliomas

2016 ◽  
Vol 37 (1) ◽  
pp. 10-22 ◽  
Author(s):  
Stephen N. Ponnampalam ◽  
Nor Rizan Kamaluddin ◽  
Zubaidah Zakaria ◽  
Vickneswaran Matheneswaran ◽  
Dharmendra Ganesan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Signaling Pathway ◽  
Pathway Analysis ◽  
Low Grade ◽  
Low Grade Gliomas

scholarly journals Agent Repurposing for the Treatment of Advanced Stage Diffuse Large B-Cell Lymphoma Based on Gene Expression and Network Perturbation Analysis

2021 ◽  
Vol 12 ◽  
Author(s):  
Chenxi Xiang ◽  
Huimin Ni ◽  
Zhina Wang ◽  
Binbin Ji ◽  
Bo Wang ◽  
...  
Keyword(s):  
Gene Expression ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Advanced Stage ◽  
Driver Genes ◽  
Large B Cell Lymphoma ◽  
Key Driver ◽  
Driver Analysis ◽  
Large B Cell

Over 50% of diffuse large B-cell lymphoma (DLBCL) patients are diagnosed at an advanced stage. Although there are a few therapeutic strategies for DLBCL, most of them are more effective in limited-stage cancer patients. The prognosis of patients with advanced-stage DLBCL is usually poor with frequent recurrence and metastasis. In this study, we aimed to identify gene expression and network differences between limited- and advanced-stage DLBCL patients, with the goal of identifying potential agents that could be used to relieve the severity of DLBCL. Specifically, RNA sequencing data of DLBCL patients at different clinical stages were collected from the cancer genome atlas (TCGA). Differentially expressed genes were identified using DESeq2, and then, weighted gene correlation network analysis (WGCNA) and differential module analysis were performed to find variations between different stages. In addition, important genes were extracted by key driver analysis, and potential agents for DLBCL were identified according to gene-expression perturbations and the Crowd Extracted Expression of Differential Signatures (CREEDS) drug signature database. As a result, 20 up-regulated and 73 down-regulated genes were identified and 79 gene co-expression modules were found using WGCNA, among which, the thistle1 module was highly related to the clinical stage of DLBCL. KEGG pathway and GO enrichment analyses of genes in the thistle1 module indicated that DLBCL progression was mainly related to the NOD-like receptor signaling pathway, neutrophil activation, secretory granule membrane, and carboxylic acid binding. A total of 47 key drivers were identified through key driver analysis with 11 up-regulated key driver genes and 36 down-regulated key diver genes in advanced-stage DLBCL patients. Five genes (MMP1, RAB6C, ACCSL, RGS21 and MOCOS) appeared as hub genes, being closely related to the occurrence and development of DLBCL. Finally, both differentially expressed genes and key driver genes were subjected to CREEDS analysis, and 10 potential agents were predicted to have the potential for application in advanced-stage DLBCL patients. In conclusion, we propose a novel pipeline to utilize perturbed gene-expression signatures during DLBCL progression for identifying agents, and we successfully utilized this approach to generate a list of promising compounds.

GLIOBLASTOMA MULTIFORME: PATHOGENESIS AND MOLECULAR MARKERS

2017 ◽  
Vol 63 (5) ◽  
pp. 695-702
Author(s):  
Oleg Kit ◽  
Dmitriy Vodolazhskiy ◽  
Yelena Frantsiyants ◽  
Svetlana Panina ◽  
E. Rastorguev ◽  
...  
Keyword(s):  
Gene Expression ◽  
Brain Tumor ◽  
Molecular Markers ◽  
Glioblastoma Multiforme ◽  
Somatic Mutations ◽  
Web Of Science ◽  
Molecular Subtypes ◽  
Regulation Of Gene Expression ◽  
Signal Pathways ◽  
Poorly Differentiated

Glioblastoma multiforme (GBM) is the most common and invasive poorly differentiated brain tumor with nearly 100 % rate of recurrence and unfavorable prognosis. The aim of the present review is to analyze recent studies and experimental results (Scopus, Web of Science, PubMed) concerning somatic mutations in glioblastoma, aberrant regulation of gene expression of signal pathways including EGFR, TGFß, etc. and markers for GBM progression. Particularly the molecular subtypes of glioblastoma and NGS results are considered in this review.

scholarly journals Single-Oocyte Gene Expression Suggests That Curcumin Can Protect the Ovarian Reserve by Regulating the PTEN-AKT-FOXO3a Pathway

2021 ◽  
Vol 22 (12) ◽  
pp. 6570
Author(s):  
Yue Lv ◽  
Rui-Can Cao ◽  
Hong-Bin Liu ◽  
Xian-Wei Su ◽  
Gang Lu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Ovarian Reserve ◽  
Primordial Follicle ◽  
Term Treatment ◽  
New Drugs ◽  
Gene Profiling ◽  
Primordial Follicles ◽  
Long Term Treatment ◽  
Follicle Activation

A better understanding of the mechanism of primordial follicle activation will help us better understand the causes of premature ovarian insufficiency (POI), and will help us identify new drugs that can be applied to the clinical treatment of infertility. In this study, single oocytes were isolated from primordial and primary follicles, and were used for gene profiling with TaqMan array cards. Bioinformatics analysis was performed on the gene expression data, and Ingenuity Pathway Analysis was used to analyze and predict drugs that affect follicle activation. An ovarian in vitro culture system was used to verify the function of the drug candidates, and we found that curcumin maintains the ovarian reserve. Long-term treatment with 100 mg/kg curcumin improved the ovarian reserve indicators of AMH, FSH, and estradiol in aging mice. Mechanistic studies show that curcumin can affect the translocation of FOXO3, thereby inhibiting the PTEN-AKT-FOXO3a pathway and protecting primordial follicles from overactivation. These results suggest that curcumin is a potential drug for the treatment of POI patients and for fertility preservation.

scholarly journals DIPG-40. TARGETING MASTER REGULATOR DEPENDENCIES IN DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii294-iii295
Author(s):  
Jovana Pavisic ◽  
Chankrit Sethi ◽  
Chris Jones ◽  
Stergios Zacharoulis ◽  
Andrea Califano
Keyword(s):  
Gene Expression ◽  
Expression Profiles ◽  
Treatment Options ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Low Grade ◽  
Precision Oncology ◽  
Pontine Glioma ◽  
Convection Enhanced Delivery ◽  
Master Regulator

Abstract Diffuse intrinsic pontine glioma (DIPG) remains a fatal disease with no effective drugs to date. Mutation-based precision oncology approaches are limited by lack of targetable mutations and genetic heterogeneity. We leveraged systems biology methodologies to discover common targetable disease drivers—master regulator proteins (MRs)—in DIPG to expand treatment options. Using the metaVIPER algorithm, we interrogated an integrated low grade glioma and GBM gene regulatory network with 31 DIPG-gene expression signatures to identify tumor-specific MRs by differential expression of their transcriptional targets. Unsupervised clustering identified MR signatures of upregulated activity in RRM2/TOP2A in 13 patients, CD3D in 5 patients, and MMP7, TACSTD2, RAC2 and SLC15A1/SLC34A2 in individual patients, all of which can be targeted. Notably, intratumoral administration of etoposide by convection enhanced delivery was effective in murine proneural gliomas in which TOP2 was identified as a MR while RRM2—targetable by drugs such as cladribine—has been shown to be a positive regulator of glioma progression whose knock-down inhibits tumor growth. We also prioritized drugs by their ability to reverse MR-activity signatures using a large drug-perturbation database. Patients clustered by predicted drug sensitivities with distinct groups of tumors predicted to respond to proteasome inhibitors, Thiotepa or Volasertib all of which have early evidence in treating gliomas. We will refine this analysis in a multi-institutional study of >100 patient gene expression profiles to define MR signatures driving known biological/molecular disease subtypes, use DIPG cell lines recapitulating common MR architectures to optimize therapy prioritization, and validate our findings in vivo.

scholarly journals NCMP-14. SKULL BASE OSTEOMYELITIS DUE TO COMMUNITY-ACQUIRED ASPERGILLUS FUMIGATUS MIMICKING RECURRENT CHONDROSARCOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii125-ii126
Author(s):  
Kevin Lillehei ◽  
B K Kleinschmidt-Demasters
Keyword(s):  
Risk Factors ◽  
Aspergillus Fumigatus ◽  
Skull Base ◽  
Replacement Therapy ◽  
Perceived Risk ◽  
Opportunistic Infections ◽  
Low Grade ◽  
Recurrent Tumor ◽  
Her Family ◽  
Patient Use

Abstract Skull base chondrosarcomas are often low grade tumors that do not metastasize, but are locally invasive and often recur locally. Thus, when patients with these tumors re-present with new onset symptoms, even decades later, recurrent tumor is presumed. A 50 year old woman with skull base chondrosarcoma initially diagnosed 30 years prior developed the subacute onset of worsening confusion and vision, with progressive blindness. Imaging disclosed a bony-erosive skull base mass without associated sinusitis/sinus opacification; additional small cerebral infarcts were identified. She had been on physiologic replacement therapy for panhypopituitarism since the original surgery, but had not received recent radiation therapy or chemotherapy and did not have neutropenia. RESULTS: Biopsy disclosed a chronic inflammation and necrotic debris; only on permanent sections were septated, 45-degree angle-branching fungi identified in one area. These had morphological features of, and were polymerase chain reaction-proven, Aspergillus fumigatus. No recurrent tumor was present. Given the lack of perceived risk factors, further questioning of the patient and her mother disclosed that precisely 1 year prior to surgery she and her family had participated in “cleaning out an old very dirty and dusty barn” in southern Colorado without the use of face masks; only the proband experienced sequelae. Anti-fungal therapy (voriconazole) was recommended although patient use was intermittent and symptoms have progressed. CONCLUSION: Community-acquired Aspergillus infections due to exposure to silage or barn detritus contaminated by fungal hyphae is almost never seen today, in comparison to opportunistic infections due to known risk factors of neutropenia and/or steroid usage. Replacement therapy may have added to this patient’s risk. Infections all too often mimic recurrent tumor.

scholarly journals The clinical significance of glutathione peroxidase 2 in glioblastoma multiforme

2021 ◽  
Vol 12 (1) ◽  
pp. 032-039
Author(s):  
Bangming Guo ◽  
Wenjuan Liao ◽  
Shusheng Wang
Keyword(s):  
Glioblastoma Multiforme ◽  
Glutathione Peroxidase ◽  
Mrna Expression ◽  
Signaling Pathway ◽  
Clinical Significance ◽  
Cancer Cell ◽  
Statistical Significance ◽  
Adult Brain ◽  
Chemokine Signaling ◽  
Chemokine Signaling Pathway

Abstract Background Glioblastoma multiforme (GBM) is the leading cause of death among adult brain cancer patients. Glutathione peroxidase 2 (GPX2), as a factor in oxidative stress, plays an important role in carcinogenesis. However, its role in GBM has not been well established. The study aimed to investigate the clinical significance of GPX2 with GBM prognosis. Methods Data of GBM and healthy individuals were retrospectively collected from oncomine, cancer cell line encyclopedia (CCLE), gene expression profiling interactive analysis (GEPIA), UALCAN, and Human Protein Atlas. GPX2 mRNA expression was first assessed across various cancer types in oncomine and cancer cell lines from CCLE. The mRNA expression of GPX2 was compared between normal and GBM tissues using GEPIA (normal = 207; GBM = 163) and UALCAN (normal = 5; GBM = 156). The GPX2 methylation was analyzed using data from UALCAN (normal = 2; GBM = 140). The prognostic value of GPX2 in GBM was explored in GEPIA and UALCAN using Kaplan–Meier method. STRING database was used to construct protein–protein interaction (PPI) network and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. Statistical significance was set as <0.05. Results The current study revealed no significant differences in GPX2 expression between normal and GBM from GEPIA data (P > 0.05) and UALCAN (P = 0.257). Patients with higher GPX2 intended to have a poorer prognosis (P = 0.0089). The KEGG pathways found that chemokine-signaling pathway were the more preferred. Conclusions The findings demonstrated that GPX2 might be a potential diagnosis and prognostic indicator for GBM. Chemokine-signaling pathway may be involved in GPX2 function.

scholarly journals Sex-dependent dynamics of metabolism in primary mouse hepatocytes

2021 ◽  
Author(s):  
Luise Hochmuth ◽  
Christiane Körner ◽  
Fritzi Ott ◽  
Daniela Volke ◽  
Kaja Blagotinšek Cokan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Amino Acid ◽  
Sexual Dimorphism ◽  
New Drugs ◽  
Model Systems ◽  
Specific Gene ◽  
Primary Hepatocytes ◽  
Alcoholic Fatty Liver ◽  
Male And Female ◽  
Primary Mouse

AbstractThe liver is one of the most sexually dimorphic organs. The hepatic metabolic pathways that are subject to sexual dimorphism include xenobiotic, amino acid and lipid metabolism. Non-alcoholic fatty liver disease and hepatocellular carcinoma are among diseases with sex-dependent prevalence, progression and outcome. Although male and female livers differ in their abilities to metabolize foreign compounds, including drugs, sex-dependent treatment and pharmacological dynamics are rarely applied in all relevant cases. Therefore, it is important to consider hepatic sexual dimorphism when developing new treatment strategies and to understand the underlying mechanisms in model systems. We isolated primary hepatocytes from male and female C57BL6/N mice and examined the sex-dependent transcriptome, proteome and extracellular metabolome parameters in the course of culturing them for 96 h. The sex-specific gene expression of the general xenobiotic pathway altered and the female-specific expression of Cyp2b13 and Cyp2b9 was significantly reduced during culture. Sex-dependent differences of several signaling pathways increased, including genes related to serotonin and melatonin degradation. Furthermore, the ratios of male and female gene expression were inversed for other pathways, such as amino acid degradation, beta-oxidation, androgen signaling and hepatic steatosis. Because the primary hepatocytes were cultivated without the influence of known regulators of sexual dimorphism, these results suggest currently unknown modulatory mechanisms of sexual dimorphism in vitro. The large sex-dependent differences in the regulation and dynamics of drug metabolism observed during cultivation can have an immense influence on the evaluation of pharmacodynamic processes when conducting initial preclinical trials to investigate potential new drugs.

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