scholarly journals A Study of Gene Expression Changes in Human Spinal and Oculomotor Neurons; Identifying Potential Links to Sporadic ALS

Genes ◽  
2020 ◽  
Vol 11 (4) ◽  
pp. 448
Author(s):  
Aayan N. Patel ◽  
Dennis Mathew
Keyword(s):  
Gene Expression ◽  
Disease Progression ◽  
Motor Neurons ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Tissue Samples ◽  
Disease Symptoms ◽  
Sporadic Als ◽  
Oculomotor Neurons ◽  
Als Patients

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease that causes compromised function of motor neurons and neuronal death. However, oculomotor neurons are largely spared from disease symptoms. The underlying causes for sporadic ALS as well as for the resistance of oculomotor neurons to disease symptoms remain poorly understood. In this bioinformatic-analysis, we compared the gene expression profiles of spinal and oculomotor tissue samples from control individuals and sporadic ALS patients. We show that the genes GAD2 and GABRE (involved in GABA signaling), and CALB1 (involved in intracellular Ca2+ ion buffering) are downregulated in the spinal tissues of ALS patients, but their endogenous levels are higher in oculomotor tissues relative to the spinal tissues. Our results suggest that the downregulation of these genes and processes in spinal tissues are related to sporadic ALS disease progression and their upregulation in oculomotor neurons confer upon them resistance to ALS symptoms. These results build upon prevailing models of excitotoxicity that are relevant to sporadic ALS disease progression and point out unique opportunities for better understanding the progression of neurodegenerative properties associated with sporadic ALS.

scholarly journals Gene Expression Network Analysis Provides Potential Targets Against SARS-CoV-2

2020 ◽  
Author(s):  
Ana I. Hernández Cordero ◽  
Xuan Li ◽  
Chen Xi Yang ◽  
Stephen Milne ◽  
Yohan Bossé ◽  
...  
Keyword(s):  
Gene Expression ◽  
Network Analysis ◽  
Host Cell ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Tissue Samples ◽  
Drug Compounds ◽  
Bioinformatics Databases ◽  
Novel Coronavirus ◽  
Transmembrane Serine Protease

ABSTRACTBACKGROUNDCell entry of SARS-CoV-2, the novel coronavirus causing COVID-19, is facilitated by host cell angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2). We aimed to identify and characterize genes that are co-expressed with ACE2 and TMPRSS2, and to further explore their biological functions and potential as druggable targets.METHODSUsing the gene expression profiles of 1,038 lung tissue samples, we performed a weighted gene correlation network analysis (WGCNA) to identify modules of co-expressed genes. We explored the biology of co-expressed genes using bioinformatics databases, and identified known drug-gene interactions.RESULTSACE2 was in a module of 681 co-expressed genes; 12 genes with moderate-high correlation with ACE2 (r>0.3, FDR<0.05) had known interactions with existing drug compounds. TMPRSS2 was in a module of 1,086 co-expressed genes; 15 of these genes were enriched in the gene ontology biologic process ‘Entry into host cell’, and 53 TMPRSS2-correlated genes had known interactions with drug compounds.CONCLUSIONDozens of genes are co-expressed with ACE2 and TMPRSS2, many of which have plausible links to COVID-19 pathophysiology. Many of the co-expressed genes are potentially targetable with existing drugs, which may help to fast-track the development of COVID-19 therapeutics.

scholarly journals Cervical Cancer Development: Implications of HPV16 E6E7-NFX1-123 Regulated Genes

Cancers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 6182
Author(s):  
Kevin M. Quist ◽  
Isaiah Solorzano ◽  
Sebastian O. Wendel ◽  
Sreenivasulu Chintala ◽  
Cen Wu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cervical Cancer ◽  
Disease Progression ◽  
Patient Survival ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Cell Models ◽  
Cervical Precancer ◽  
Regulatory Effects ◽  
Cervical Cancer Development

High-risk human papillomavirus (HR HPV) causes nearly all cervical cancers, half of which are due to HPV type 16 (HPV16). HPV16 oncoprotein E6 (16E6) binds to NFX1-123, and dysregulates gene expression, but their clinical implications are unknown. Additionally, HPV16 E7’s role has not been studied in concert with NFX1-123 and 16E6. HR HPVs express both oncogenes, and transformation requires their expression, so we sought to investigate the effect of E7 on gene expression. This study’s goal was to define gene expression profiles across cervical precancer and cancer stages, identify genes correlating with disease progression, assess patient survival, and validate findings in cell models. We analyzed NCBI GEO datasets containing transcriptomic data linked with cervical cancer stage and utilized LASSO analysis to identify cancer-driving genes. Keratinocytes expressing 16E6 and 16E7 (16E6E7) and exogenous NFX1-123 were tested for LASSO-identified gene expression. Ten out of nineteen genes correlated with disease progression, including CEBPD, NOTCH1, and KRT16, and affected survival. 16E6E7 in keratinocytes increased CEBPD, KRT16, and SLPI, and decreased NOTCH1. Exogenous NFX1-123 in 16E6E7 keratinocytes resulted in significantly increased CEBPD and NOTCH1, and reduced SLPI. This work demonstrates the clinical relevance of CEBPD, NOTCH1, KRT16, and SLPI, and shows the regulatory effects of 16E6E7 and NFX1-123.

scholarly journals Potential Biomarkers of Colorectal Adenoma–Dysplasia–Carcinoma Progression: mRNA Expression Profiling and In Situ Protein Detection on TMAs Reveal 15 Sequentially Upregulated and 2 Downregulated Genes

2009 ◽  
Vol 31 (1) ◽  
pp. 19-29
Author(s):  
Orsolya Galamb ◽  
Ferenc Sipos ◽  
Sándor Spisák ◽  
Barnabás Galamb ◽  
Tibor Krenács ◽  
...  
Keyword(s):  
Gene Expression ◽  
Disease Progression ◽  
Colorectal Adenoma ◽  
Protein Level ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Protein Detection ◽  
Yield Potential ◽  
Prostaglandin D2 ◽  
Potential Biomarkers

Background: As most colorectal cancers (CRC) develop from villous adenomas, studying alterations in gene expression profiles across the colorectal adenoma–dysplasia–carcinoma sequence may yield potential biomarkers of disease progression.Methods: Total RNA was extracted, amplified, and biotinylated from colonic biopsies of 15 patients with CRC, 15 with villous adenoma and 8 normal controls. Gene expression profiles were evaluated using HGU133Plus2.0 microarrays and disease progression associated data were validated with RT-PCR. The potential biomarkers were also tested at the protein level using tissue microarray samples of 103 independent and 16 overlapping patients.Results: 17 genes were validated to show sequentially altered expression at mRNA level through the normal–adenoma–dysplasia–carcinoma progression. Prostaglandin-D2 receptor (PTGDR) and amnionless homolog (AMN) genes revealed gradually decreasing expression while the rest of 15 genes including osteonectin, osteopontin, collagen IV–alpha 1, biglycan, matrix GLAprotein, and von Willebrand factor demonstrated progressively increasing expression. Similar trends of expression were confirmed at protein level for PTGDR, AMN, osteopontin and osteonectin.Conclusion: Downregulated AMN and PTGDR and upregulated osteopontin and osteonectin were found as potential biomarkers of colorectal carcinogenesis and disease progression to be utilized for prospective biopsy screening both at mRNA and protein levels. Gene alterations identified here may also add to our understanding of CRC progression.

scholarly journals Subnetwork-based analysis of chronic lymphocytic leukemia identifies pathways that associate with disease progression

Blood ◽  
2012 ◽  
Vol 120 (13) ◽  
pp. 2639-2649 ◽  
Author(s):  
Han-Yu Chuang ◽  
Laura Rassenti ◽  
Michelle Salcedo ◽  
Kate Licon ◽  
Alexander Kohlmann ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chronic Lymphocytic Leukemia ◽  
Disease Progression ◽  
Expression Profiles ◽  
Treatment Strategies ◽  
Gene Expression Profiles ◽  
Lymphocytic Leukemia ◽  
Cancer Evolution ◽  
Sample Collection ◽  
Over Time

Abstract The clinical course of patients with chronic lymphocytic leukemia (CLL) is heterogeneous. Several prognostic factors have been identified that can stratify patients into groups that differ in their relative tendency for disease progression and/or survival. Here, we pursued a subnetwork-based analysis of gene expression profiles to discriminate between groups of patients with disparate risks for CLL progression. From an initial cohort of 130 patients, we identified 38 prognostic subnetworks that could predict the relative risk for disease progression requiring therapy from the time of sample collection, more accurately than established markers. The prognostic power of these subnetworks then was validated on 2 other cohorts of patients. We noted reduced divergence in gene expression between leukemia cells of CLL patients classified at diagnosis with aggressive versus indolent disease over time. The predictive subnetworks vary in levels of expression over time but exhibit increased similarity at later time points before therapy, suggesting that degenerate pathways apparently converge into common pathways that are associated with disease progression. As such, these results have implications for understanding cancer evolution and for the development of novel treatment strategies for patients with CLL.

Molecular signature of late-stage human ALS revealed by expression profiling of postmortem spinal cord gray matter

2004 ◽  
Vol 16 (2) ◽  
pp. 229-239 ◽  
Author(s):  
Fernando Dangond ◽  
Daehee Hwang ◽  
Sandra Camelo ◽  
Piera Pasinelli ◽  
Matthew P. Frosch ◽  
...  
Keyword(s):  
Gene Expression ◽  
Spinal Cord ◽  
Gray Matter ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Gene Expression Profiles ◽  
Terminal State ◽  
Molecular Signature ◽  
Fisher Discriminant Analysis ◽  
Sporadic Als

Little is known about global gene expression patterns in the human neurodegenerative disease amyotrophic lateral sclerosis (ALS). To address this, we used high-density oligonucleotide microarray technology to compare expression levels of ∼6,800 genes in postmortem spinal cord gray matter obtained from individuals with ALS as well as normal individuals. Using Fisher discriminant analysis (FDA) and leave-one-out cross-validation (LOOCV), we discerned an ALS-specific signature. Moreover, it was possible to distinguish familial ALS (FALS) from sporadic ALS (SALS) gene expression profiles. Characterization of the specific genes significantly altered in ALS uncovered a pro-inflammatory terminal state. Moreover, we found alterations in genes involved in mitochondrial function, oxidative stress, excitotoxicity, apoptosis, cytoskeletal architecture, RNA transcription and translation, proteasomal function, and growth and signaling. It is apparent from this study that DNA microarray analysis and appropriate bioinformatics can reveal distinct phenotypic changes that underlie the terminal stages of neurodegeneration in ALS.

scholarly journals A large-scale screening of the normalized mammalian mitochondrial gene expression profiles

2005 ◽  
Vol 86 (2) ◽  
pp. 127-138 ◽  
Author(s):  
SERGEY V. ANISIMOV
Keyword(s):  
Gene Expression ◽  
Large Scale ◽  
Expression Profiles ◽  
Mitochondrial Gene ◽  
Gene Expression Profiles ◽  
Vital Role ◽  
Mitochondrial Genomes ◽  
Mitochondrial Gene Expression ◽  
Tissue Samples ◽  
Large Scale Screening

Mammalian mitochondrial genomes are organized in a conserved and extremely compact manner, encoding molecules that play a vital role in oxidative phosphorylation (OXPHOS) and carry out a number of other important biological functions. A large-scale screening of the normalized mitochondrial gene expression profiles generated from publicly available mammalian serial analysis of gene expression (SAGE) datasets (over 17·7 millions of tags) was performed in this study. Acquired SAGE libraries represent an extensive range of human, mouse, rat, bovine and swine cell and tissue samples (normal and pathological) in a variety of conditions. Using a straightforward in silico algorithm, variations in total mitochondrial gene expression, as well as in the expression of individual genes encoded by mitochondrial genomes are addressed, and common patterns in the species- and tissue-specific mitochondrial gene expression profiles are discussed.

scholarly journals Postmortem Cortex Samples Identify Distinct Molecular Subtypes of ALS: Retrotransposon Activation, Oxidative Stress, and Activated Glia

2019 ◽  
Author(s):  
Oliver H. Tam ◽  
Nikolay V. Rozhkov ◽  
Regina Shaw ◽  
Duyang Kim ◽  
Isabel Hubbard ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Molecular Subtypes ◽  
Machine Learning Algorithms ◽  
Tissue Samples ◽  
Proteotoxic Stress ◽  
Sporadic Als ◽  
History Of ◽  
Als Patients ◽  
Large Survey ◽  
Lateral Sclerosis

SummaryAmyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons. While several inherited pathogenic mutations have been identified as causative, the vast majority of cases are sporadic with no family history of disease. Thus, for the majority of ALS cases, a specific causal abnormality is not known and the disease may be a product of multiple inter-related pathways contributing to varying degrees in different ALS patients. Using unsupervised machine learning algorithms, we stratified the transcriptomes of 148 ALS decedent cortex tissue samples into three distinct and robust molecular subtypes. The largest cluster, identified in 61% of patient samples, displayed hallmarks of oxidative and proteotoxic stress. Another 20% of the ALS patient samples exhibited high levels of retrotransposon expression and other signatures of TDP-43 dysfunction. Finally, a third group showed predominant signatures of glial activation (19%). Together these results demonstrate that at least three distinct molecular signatures contribute to ALS disease. While multiple dysregulated components and pathways comprising these clusters have previously been implicated in ALS pathogenesis, unbiased analysis of this large survey demonstrated that sporadic ALS patient tissues can be segregated into distinct molecular subsets.

scholarly journals Identification of Novel Hub Genes Associated With Gastric Cancer Using Integrated Bioinformatics Analysis

2020 ◽  
Author(s):  
Xiao-Qing Lu ◽  
Jia-qian Zhang ◽  
Jun Qiao ◽  
Sheng-Xiao Zhang ◽  
Meng-Ting Qiu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gastric Cancer ◽  
Malignant Tumors ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Gene Expression Omnibus ◽  
High Recurrence Rate ◽  
Hub Genes ◽  
Tissue Samples ◽  
Qrt Pcr

Abstract Background: Gastric cancer (GC) is one of the most common solid malignant tumors worldwide with a high-recurrence-rate. Identifying the molecular signatures and specific biomarkers of GC might provide novel clues for GC prognosis and targeted therapy.Methods: Gene expression profiles were obtained from the ArrayExpress and Gene Expression Omnibus database. Differentially expressed genes (DEGs) were picked out by R software. The hub genes were screened by cytoHubba plugin. Their prognostic values were assessed by Kaplan–Meier survival analyses and the gene expression profiling interactive analysis (GEPIA). Finally, qRT-PCR in GC tissue samples was established to validate these DEGs. Results: Total of 295 DEGs were identified between GC and their corresponding normal adjacent tissue samples in E-MTAB-1440, GSE79973, GSE19826, GSE13911, GSE27342, GSE33335 and GSE56807 datasets, including 117 up-regulated and 178 down-regulated genes. Among them, 7 vital upregulated genes (HMMR, SPP1, FN1, CCNB1, CXCL8, MAD2L1 and CCNA2) were selected. Most of them had a significantly worse prognosis except SPP1. Using qRT-PCR, we validated that their transcriptions in our GC tumor tissue were upregulated except SPP1 and FN1, which correlated with tumor relapse and predicts poorer prognosis in GC patients.Discussion: We have identified 5 upregulated DEGs (HMMR, CCNB1, CXCL8, MAD2L1, and CCNA2) in GC patients with poor prognosis using integrated bioinformatical methods, which could be potential biomarkers and therapeutic targets for GC treatment.

scholarly journals Circulating Tumor and Invasive Cell Gene Expression Profile Predicts Treatment Response and Survival in Pancreatic Adenocarcinoma

Cancers ◽  
2018 ◽  
Vol 10 (12) ◽  
pp. 467
Author(s):  
Kenneth Yu ◽  
Mark Ricigliano ◽  
Brian McCarthy ◽  
Joanne Chou ◽  
Marinela Capanu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Disease Progression ◽  
Treatment Response ◽  
Peripheral Blood ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Progression Free Survival ◽  
Response Prediction ◽  
Ductal Adenocarcinoma ◽  
Chemotherapy Response

Previous studies have shown that pharmacogenomic modeling of circulating tumor and invasive cells (CTICs) can predict response of pancreatic ductal adenocarcinoma (PDAC) to combination chemotherapy, predominantly 5-fluorouracil-based. We hypothesized that a similar approach could be developed to predict treatment response to standard frontline gemcitabine with nab-paclitaxel (G/nab-P) chemotherapy. Gene expression profiles for responsiveness to G/nab-P were determined in cell lines and a test set of patient samples. A prospective clinical trial was conducted, enrolling 37 patients with advanced PDAC who received G/nab-P. Peripheral blood was collected prior to treatment, after two months of treatment, and at progression. The CTICs were isolated based on a phenotype of collagen invasion. The RNA was isolated, cDNA synthesized, and qPCR gene expression analyzed. Patients were most closely matched to one of three chemotherapy response templates. Circulating tumor and invasive cells’ SMAD4 expression was measured serially. The CTICs were reliably isolated and profiled from peripheral blood prior to and during chemotherapy treatment. Individual patients could be matched to distinct response templates predicting differential responses to G/nab-P treatment. Progression free survival was significantly correlated to response prediction and ΔSMAD4 was significantly associated with disease progression. These findings support phenotypic profiling and ΔSMAD4 of CTICs as promising clinical tools for choosing effective therapy in advanced PDAC, and for anticipating disease progression.

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