Genomic Analysis of Glioblastoma Multiforme Reveals a Key Transcription Factor Signature Relevant to Prognosis and the Immune Processes

IntroductionGlioblastoma multiforme (GBM) develops through the accumulation of both genetic and expression alterations. Although many gene signatures have been developed as prognostic and predictive biomarkers, their robustness and functional aspects are less well characterized. The expression of most genes is regulated by transcription factors (TFs); therefore, we aimed to investigate a TF signature relevant to GBM prognosis.MethodsWe used bioinformatic methods and data from public databases to establish four clusters of key TF genes, among which cluster 1, comprising 24 TFs, showed significant prognostic value. Further in silico functional analyses were applied to investigate the utility of the TF signature.ResultsDifferent mutation and copy number variation patterns were observed between different risk score groups (based on the TF signature). In silico analyses suggested that the cases with relative high risk scores were involved in immune and inflammatory processes or pathways.ConclusionThe TF signature has significant prognostic value in different cohorts or subgroups of patients with GBM and could lead to the development immunotherapy for GBM.

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Gene Signature And Prognostic Values of m5C-Related Regulators In Colon Adenocarcinoma

10.21203/rs.3.rs-952509/v1 ◽

2021 ◽

Author(s):

Yuancheng Huang ◽

Chaoyuan Huang ◽

Xiaotao Jiang ◽

Yanhua Yan ◽

Kunhai Zhuang ◽

...

Keyword(s):

Prognostic Value ◽

Cox Regression ◽

Colon Adenocarcinoma ◽

Predictive Biomarkers ◽

Roc Curves ◽

The Cancer Genome Atlas ◽

Risk Scores ◽

Rna Modification ◽

Regression Analyses ◽

Prognostic Features

Abstract Objectives: The purpose of this study was to investigate the role of 13 m5C-related regulators in colon adenocarcinoma (COAD) and determine their prognostic value.Main Methods: Gene expression and clinicopathological data were obtained from The Cancer Genome Atlas (TCGA) datasets. The expression of m5C-related regulators were analyzed with clinicopathological characteristics and alterations within m5C-related regulators. Subsequently, different subtypes of patients with COAD were identified. Then, the prognostic value of m5C-related regulators in COAD were confirmed via univariate Cox regression and least absolute shrinkage and selection operator (LASSO) Cox regression analyses. The prognostic value of risk scores was evaluated using the Kaplan-Meier method, receiver operating characteristic (ROC) curves, and univariate and multivariate regression analyses. Additionally, Gene Set Enrichment Analysisc (GSEA), Kyoto Encyclopedia of Genes and Genomes c (KEGG) pathways, and Gene Ontologyc (GO) analysis were performed for biological functional analysis.Results: m5C-related regulators were found to be differentially expressed in COAD with different clinicopathological features. We observed a high alteration frequency in these genes, which were significantly correlated with their mRNA expression levels. Two clusters with different prognostic features were identified. Based on two independent prognostic m5C-related regulators (NSUN6 and ALYREF), a risk signature with good predictive significance was constructed. Univariate and multivariate Cox regression analyses suggested that the risk score was an independent prognostic factor. Biological processes and pathways associated with cancer, immune response, and RNA processing were identified.Conclusion: We revealed the genetic signatures and prognostic values of m5C-related regulators in COAD. Together, this has improved our understanding of m5C RNA modification and provided novel insights to identify predictive biomarkers and develop molecular targeted therapy for COAD.

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Genomic analysis of primary and recurrent gliomas reveals clinical outcome related molecular features

Scientific Reports ◽

10.1038/s41598-019-52515-9 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 3

Author(s):

Longbo Zhang ◽

Zhiqiang Liu ◽

Jin Li ◽

Tianxiang Huang ◽

Ying Wang ◽

...

Keyword(s):

Cell Cycle ◽

Copy Number ◽

Disease Free Survival ◽

Genomic Analysis ◽

Predictive Biomarkers ◽

Recurrent Gliomas ◽

Molecular Features ◽

Significant Difference ◽

Number Variation ◽

Cell Cycle Pathway

Abstract Tremendous efforts have been made to explore biomarkers for classification and grading on gliomas. The goal of this study was to identify more molecular features that are associated with clinical outcomes by comparing the genomic profiles of primary and recurrent gliomas and determine potential recurrence leading factors that are significantly enriched in relapse tumors. Hybrid capture based next generation sequencing (NGS) analysis was performed on 64 primary and 17 recurrent glioma biopsies. Copy number variation (CNV) was more frequent in recurrent tumors and CDKN2A/B loss was significantly enriched. In addition, overall mutations in cell cycle pathway are more common in relapse tumors. The patterns of gene sets, including IDH1/TERT and IDH1/TP53 exhibited significant difference between the groups. Survival analysis uncovered the worse disease-free survival (DFS) and overall survival (OS) associated with altered copy number and excessive activation of CELL CYCLE pathway. High Tumor Mutation Burden (TMB) was also a biomarker with great potential for poor prognosis. The assessment of genomic characteristics in primary versus recurrent gliomas aids the discovery of potential predictive biomarkers. The prognostic value of TMB in gliomas was raised for the first time.

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Faculty Opinions recommendation of An integrated genomic analysis of human glioblastoma multiforme.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1123072.580191 ◽

2008 ◽

Author(s):

David Louis

Keyword(s):

Glioblastoma Multiforme ◽

Genomic Analysis ◽

Human Glioblastoma ◽

Human Glioblastoma Multiforme

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Prognostic Value of D-dimer in patients with acute coronary syndrome treated by percutaneous coronary intervention: a retrospective cohort study

Thrombosis Journal ◽

10.1186/s12959-021-00281-y ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Runzhen Chen ◽

Chen Liu ◽

Peng Zhou ◽

Yu Tan ◽

Zhaoxue Sheng ◽

...

Keyword(s):

Risk Factors ◽

Percutaneous Coronary Intervention ◽

Prognostic Value ◽

Coronary Intervention ◽

Risk Scores ◽

Risk Of Death ◽

Clinical Risk ◽

Percutaneous Coronary ◽

D Dimer

Abstract Background Associations between D-dimer and outcomes of patients with acute coronary syndromes (ACS) remain controversial. This study aimed to investigate the prognostic value of D-dimer in ACS patients treated by percutaneous coronary intervention (PCI). Methods In this observational study, 3972 consecutive patients with ACS treated by PCI were retrospectively recruited. The X-tile program was used to determine the optimal D-dimer thresholds for risk stratifications. Cox regression with multiple adjustments was used for outcome analysis. Restricted cubic spline (RCS) analysis was performed to assess the dose-response association between D-dimer and outcomes. The C-index was calculated to evaluate the additional prognostic value of D-dimer when added to clinical risk factors and commonly used clinical risk scores, with internal validations using bootstrapping methods. The primary outcome was all-cause death. Results During a median follow-up of 720 days, 225 deaths occurred. Based on the thresholds generated by X-tile, ACS-PCI patients with median (420–1150 ng/mL, hazard ratio [HR]: 1.58, 95 % confidence interval [CI]: 1.14–2.20, P = 0.007) and high (≥ 1150 ng/mL, HR: 1.98, 95 % CI: 1.36–2.89, P < 0.001) levels of D-dimer showed substantially higher risk of death compared to those with low D-dimer (< 420 ng/mL). RCS analysis depicted a constant relation between D-dimer and various outcomes. The addition of D-dimer levels significantly improved risk predictions for all-cause death when combined with the fully adjusted models (C-index: 0.853 vs. 0.845, P difference = 0.021), the GRACE score (C-index: 0.826 vs. 0.814, P difference = 0.027), and the TIMI score (C-index: 0.804 vs. 0.776, P difference < 0.001). The predicted mortality at the median follow-up (two years) was 1.7 %, 5.2 %, and 10.9 % for patients with low, median, and high D-dimer, respectively, which was well matched with the observed mortality (low D-dimer group: 1.2 %, median D-dimer group: 5.2 %, and high D-dimer group: 12.6 %). Conclusions For ACS patients treated by PCI, D-dimer level was an independent predictor for adverse outcomes, and provided additional prognostic value when combined with clinical risk factors and risk scores. Risk stratifications based on D-dimer was plausible to differentiate ACS-PCI patients with higher risk of death.

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Combining experiments and in silico modeling to infer the role of adhesion and proliferation on the collective dynamics of cells

10.1101/2021.03.29.437400 ◽

2021 ◽

Author(s):

Hygor P. M. Melo ◽

F. Raquel Maia ◽

André S. Nunes ◽

Rui L. Reis ◽

Joaquim M. Oliveira ◽

...

Keyword(s):

Tissue Engineering ◽

Cell Adhesion ◽

Glioblastoma Multiforme ◽

In Silico ◽

Relative Importance ◽

Collective Dynamics ◽

Surfaces And Interfaces ◽

In Silico Modeling ◽

Cell Cell

ABSTRACTThe collective dynamics of cells on surfaces and interfaces poses technological and theoretical challenges in the study of morphogenesis, tissue engineering, and cancer. Different mechanisms are at play, including, cell-cell adhesion, cell motility, and proliferation. However, the relative importance of each one is elusive. Here, experiments with a culture of glioblastoma multiforme cells on a substrate are combined with in silico modeling to infer the rate of each mechanism. By parametrizing these rates, the time-dependence of the spatial correlation observed experimentally is reproduced. The obtained results suggest a reduction in cell-cell adhesion with the density of cells. The reason for such reduction and possible implications for the collective dynamics of cancer cells are discussed.

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Prognostic Value of Atherosclerotic Extent in Diabetic Patients with Nonobstructive Coronary Artery Disease

Journal of Diabetes Research ◽

10.1155/2021/5597467 ◽

2021 ◽

Vol 2021 ◽

pp. 1-6

Author(s):

Yipu Ding ◽

Zinuan Liu ◽

Guanhua Dou ◽

Xia Yang ◽

Xi Wang ◽

...

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

High Risk ◽

Prognostic Value ◽

Risk Scores ◽

Plaque Burden ◽

Major Adverse Cardiovascular Events ◽

Diabetic Patients ◽

Nonobstructive Coronary Artery Disease ◽

Artery Disease

Background and Objective. Atherosclerotic extent was proved to be associated with adverse cardiac events. Risk scores derived by coronary computed tomography angiography (CCTA) could identify high-risk group among patients with nonobstructive coronary artery disease (CAD), but the ability is still uncertain in the presence of diabetes mellitus (DM). The purpose of this study was to investigate the prognostic value of the atherosclerotic extent shown by CCTA in diabetic patients with nonobstructive CAD. Methods and Results. 813 DM patients (mean age 58.9 ± 9.9 years, 48.1% male) referred for CCTA due to suspected CAD in 2015-2017 were consecutively included. During a median follow-up of 31.77 months, 50 major adverse cardiovascular events (MACEs) (6.15%) were experienced, including 2 cardiovascular deaths, 14 nonfatal myocardial infarctions, 27 unstable anginas requiring hospitalization, and 7 strokes. Three groups were defined based on coronary stenosis combined with Leiden score as normal, nonobstructive Leiden < 5 , and nonobstructive Leiden ≥ 5 . Cox models were used to assess the prognosis of plaque burden within these groups. An incremental incidence of MACE rates was observed. After adjustment for age, gender, and presence of high-risk plaque, the group of Leiden ≥ 5 showed a higher risk than Leiden < 5 (HR: 1.88, 95% CI: 1.03-3.42, p = 0.039 ). Similar results were observed when segment involvement score (SIS) was used for sensitivity analysis. Conclusion. Atherosclerotic extent was associated with the prognosis of DM patients with nonobstructive coronary artery disease, highlighting the importance of better risk stratification and management.

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In silico Analysis of Phylogeny and Virulence Genes in STEC Strains Associated with Outbreaks

Türk Mikrobiyoloji Cemiyeti Dergisi ◽

10.5222/tmcd.2021.07769 ◽

2021 ◽

Author(s):

Mehmet Demirci ◽

Akın Yiğin ◽

Fadile Yıldız Zeyrek

Keyword(s):

Foodborne Pathogens ◽

In Silico ◽

Virulence Genes ◽

Genomic Analysis ◽

In Silico Analysis ◽

Comparative Genomic ◽

Phylogeny Analysis ◽

In Silico Study ◽

The World ◽

Different Parts

Objective: Shiga toxin-producing E. coli (STEC) strains are important foodborne pathogens. Significant outbreaks with STEC strains can be encountered, even if the geography, time or resources were different. The aim of our in silico study was to compare the virulance factors and phylogeny of STEC strains such as EDL933 and Sakai, which have been identified as an agent in important outbreaks in different parts of the world and whole genomic data were in open databases. Method: Genomic NCBI data of eight strains were included in our study, including seven different STEC strains associated with significant epidemics in different parts of the world, and one supershedder strain obtained from cattle feces. Results: According to phylogeny analysis, the most similar strain to EDL933 strain was TW14588, with 96.4% similarity. The most distant similarity was Sakai strains with 79.2%. According to the virulence genes analysis; the presence of 333 genes that constitute virulence factors under nine headings were detected. In the first STEC origin, EDL933, 45% of all virulence genes were found to be active. Adherence genes such as Ecp, Elf, Hcp and toxin genes such as clyA were active in all strains except stx genes. Conclusion: In our in silico study of comparative genomic analysis of STEC strains which are associated with outbreaks, it was determined that STEC strains used different virulence genes besides the stx gene. Indeed, they used certain virulence genes, even their sources, time and locations were different, in the pathogenesis

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EXTH-67. THERAPEUTIC EFFICACY OF GC1118, A NOVEL ANTI-EGFR ANTIBODY, AGAINST GLIOBLASTOMA WITH HIGH EGFR AMPLIFICATION IN PATIENT-DERIVED XENOGRAFTS

Neuro-Oncology ◽

10.1093/neuonc/noab196.706 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi178-vi178

Author(s):

Seung Won Choi

Keyword(s):

Therapeutic Efficacy ◽

Growth Factor Receptor ◽

Genomic Analysis ◽

Screening Assay ◽

Egfr Amplification ◽

High Throughput Drug Screening ◽

Number Variation ◽

Drug Screening Assay ◽

Pdx Models

Abstract We aimed to evaluate the preclinical efficacy of GC1118, a novel anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb), against glioblastoma (GBM) tumors using patient-derived xenograft (PDX) models. A total of 15 distinct GBM PDX models were used to evaluate the therapeutic efficacy of GC1118. Genomic data derived from PDX models were analyzed to identify potential biomarkers associated with the anti-tumor efficacy of GC1118. A patient-derived cell-based high-throughput drug screening assay was performed to further validate the efficacy of GC1118. Compared to cetuximab, GC1118 exerted comparable growth inhibitory effects on the GBM tumors in the PDX models. We confirmed that GC1118 accumulated within the tumor by crossing the blood–brain barrier in in vivo specimens and observed the survival benefit in GC1118-treated intracranial models. Genomic analysis revealed high EGFR amplification as a potent biomarker for predicting the therapeutic efficacy of GC1118 in GBM tumors. In summary, GC1118 exerted a potent anti-tumor effect on GBM tumors in PDX models, and its therapeutic efficacy was especially pronounced in the tumors with high EGFR amplification. Our study supports the importance of patient stratification based on EGFR copy number variation in clinical trials for GBM. The superiority of GC1118 over other EGFR mAbs in GBM tumors should be assessed in future studies.

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