scholarly journals OCTAD: an open workplace for virtually screening therapeutics targeting precise cancer patient groups using gene expression features

2019 ◽  
Author(s):  
Billy Zeng ◽  
Benjamin S. Glicksberg ◽  
Patrick Newbury ◽  
Jing Xing ◽  
Ke Liu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cancer Patient ◽  
Precision Medicine ◽  
Experimental Testing ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Cost Effective ◽  
Specific Expression ◽  
Drug Candidates ◽  
Patient Groups

AbstractOne approach to precision medicine is to discover drugs that target molecularly defined diseases. Voluminous cancer patient gene expression profiles have been accumulated in public databases, enabling the creation of a cancer-specific expression signature. By matching this signature to perturbagen-induced gene expression profiles from large drug libraries, researchers can prioritize small molecules that present high potency to reverse expression of signature genes for further experimental testing of their efficacy. This approach has proven to be an efficient and cost-effective way to identify efficacious drug candidates. However, the success of this approach requires multiscale procedures, imposing significant challenges to many labs. Therefore, we present OCTAD: an open workplace for virtually screening compounds targeting precise cancer patient groups using gene expression features. We release OCTAD as a web portal and standalone R workflow to allow experimental and computational scientists to easily navigate the tool. In this work, we describe this tool and demonstrate its potential for precision medicine.

Monitoring expression of genes involved in drug metabolism and toxicology using DNA microarrays

2001 ◽  
Vol 5 (4) ◽  
pp. 161-170 ◽  
Author(s):  
DAVID GERHOLD ◽  
MEIQING LU ◽  
JIAN XU ◽  
CHRISTOPHER AUSTIN ◽  
C. THOMAS CASKEY ◽  
...  
Keyword(s):  
Gene Expression ◽  
Drug Metabolism ◽  
Stress Responses ◽  
Dna Microarrays ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Metabolic Effects ◽  
Microarray Technology ◽  
Drug Candidates ◽  
Expression Of Genes

Oligonucleotide DNA microarrays were investigated for utility in measuring global expression profiles of drug metabolism genes. This study was performed to investigate the feasibility of using microarray technology to minimize the long, expensive process of testing drug candidates for safety in animals. In an evaluation of hybridization specificity, microarray technology from Affymetrix distinguished genes up to a threshold of ∼90% DNA identity. Oligonucleotides representing human cytochrome P-450 gene CYP3A5 showed heterologous hybridization to CYP3A4 and CYP3A7 RNAs. These genes could be clearly distinguished by selecting a subset of oligonucleotides that hybridized selectively to CYP3A5. Further validation of the technology was performed by measuring gene expression profiles in livers of rats treated with vehicle, 3-methylcholanthrene (3MC), phenobarbital, dexamethasone, or clofibrate and by confirming data for six genes using quantitative RT-PCR. Responses of drug metabolism genes, including CYPs, epoxide hydrolases ( EHs), UDP-glucuronosyl transferases ( UGTs), glutathione sulfotransferases ( GSTs), sulfotransferases ( STs), drug transporter genes, and peroxisomal genes, to these well-studied compounds agreed well with, and extended, published observations. Additional gene regulatory responses were noted that characterize metabolic effects or stress responses to these compounds. Thus microarray technology can provide a facile overview of gene expression responses relevant to drug metabolism and toxicology.

scholarly journals On transformative adaptive activation functions in neural networks for gene expression inference

PLoS ONE ◽  
2021 ◽  
Vol 16 (1) ◽  
pp. e0243915
Author(s):  
Vladimír Kunc ◽  
Jiří Kléma
Keyword(s):  
Gene Expression ◽  
Neural Networks ◽  
Mean Absolute Error ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Cost Effective ◽  
Absolute Error ◽  
Activation Function ◽  
Training Procedure ◽  
Activation Functions

Gene expression profiling was made more cost-effective by the NIH LINCS program that profiles only ∼1, 000 selected landmark genes and uses them to reconstruct the whole profile. The D–GEX method employs neural networks to infer the entire profile. However, the original D–GEX can be significantly improved. We propose a novel transformative adaptive activation function that improves the gene expression inference even further and which generalizes several existing adaptive activation functions. Our improved neural network achieves an average mean absolute error of 0.1340, which is a significant improvement over our reimplementation of the original D–GEX, which achieves an average mean absolute error of 0.1637. The proposed transformative adaptive function enables a significantly more accurate reconstruction of the full gene expression profiles with only a small increase in the complexity of the model and its training procedure compared to other methods.

Identification of Patients At High Risk for Recurrent Venous Thromboembolism by Whole Blood Gene Expression Analysis

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2305-2305
Author(s):  
Thomas L. Ortel ◽  
Michele Beckman ◽  
W Craig Hooper ◽  
Deborah A Lewis ◽  
Jen-Tsan A. Chi ◽  
...  
Keyword(s):  
Gene Expression ◽  
High Risk ◽  
Whole Blood ◽  
Antiphospholipid Antibodies ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Low Risk ◽  
Risk Patients ◽  
Patient Groups ◽  
Recurrent Vte

Abstract Abstract 2305 Background. Recurrent venous thromboembolism (VTE) occurs in ∼30% of patients with spontaneous VTE after completion of a standard course of anticoagulant therapy. D-dimer levels and selected clinical parameters have been used to identify patients at low risk for recurrent VTE, who may safely discontinue antithrombotic therapy. We have used gene expression profiles to distinguish patients with a single VTE from patients with recurrent VTE. The purpose of this study was to extend this initial report and identify unique gene expression patterns from whole blood that correlate with different risk profiles for VTE recurrence. Methods. Patients with ≥1 prior VTE, with the first event occurring at age 18 years or older and >3 months from the most recent event were recruited for this study. Patients were allocated into 4 groups: (1) ‘low-risk’ patients had sustained ≥1 provoked VTE; (2) ‘moderate-risk’ patients had sustained 1 unprovoked VTE (with or without provoked VTE); (3) ‘high-risk’ patients had sustained ≥2 unprovoked VTE and had no evidence for antiphospholipid antibodies; and (4) antiphospholipid syndrome (APS) patients met established consensus criteria for APS. A similar number of individuals with no prior history of VTE were enrolled as a control population. Citrated plasma, serum and PAXgene RNA tubes were collected, processed and stored at −80°C until shipped to the CDC for analysis. Antiphospholipid testing was performed on all participants to confirm correct group distribution. Total RNA was isolated from whole blood drawn into PAXgene tubes. Following sample labeling and normalization, cRNA samples were hybridized to Illumina HT-12 Beadchips to assay whole genome gene expression with over 47,000 probes against human transcripts. Two hundred and twenty six unique samples passed initial quality control measures. Quality assessment of raw data was done using GenomeStudio. The raw data files were converted to a text file using the IlluminaExpression FileCreator in GenePattern and then log transformed, normalized and median-centered using Cluster. Both unsupervised (hierarchical clustering using Cluster) and supervised analyses (SAM) were used to identify genes that were differentially expressed between the groups. GATHER was used to help understand the biological processes and gene ontology of the gene lists generated by Cluster and SAM. Results. A total of 226 participants were enrolled into the study. Characteristics of the patient groups are summarized in the Table. Demographically, the groups were similar except that patients in the high-risk group tended to be older and were more likely male. The number of events per patient, and the proportion on anticoagulant therapy, increased with the risk group. Antiphospholipid antibodies were detected in several patients in each of the 3 non-APS VTE patient groups, but in most cases this was a single test positive; antiphospholipid antibodies were present in the majority of patients with APS, typically with more than one test positive (37 of 45 with complete testing, 82%). Preliminary analysis of the gene expression profiles using an unsupervised clustering by gene on the high-risk and low-risk groups identified multiple genes that distinguished the two groups, including 18 immune response genes identified by GATHER. These two patient groups were also distinguished by SAM analysis, and multiple genes in the MAPK signaling pathway that separated the two groups were identified by the KEGG pathways in GATHER. Additional analyses are being performed on all of the groups. Conclusions. Whole blood gene expression profiling can be used to develop profiles that distinguish patients with VTE who differ based on their risk of recurrent events. Individual genes identified in these profiles may provide biological insights into the molecular basis for recurrent VTE. Disclosures: Heit: Daiichi Sankyo: Honoraria; Ortho-McNeil Janssen: Honoraria; Covidien: Honoraria. Manco-Johnson:Octapharma AG: Consultancy; Bayer: Research Funding.

Microarray analysis reveals pivotal divergent mRNA expression profiles early in the development of either compensated ventricular hypertrophy or heart failure

2005 ◽  
Vol 21 (3) ◽  
pp. 314-323 ◽  
Author(s):  
Henk P. J. Buermans ◽  
Everaldo M. Redout ◽  
Anja E. Schiel ◽  
René J. P. Musters ◽  
Marian Zuidwijk ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Ventricular Remodeling ◽  
Contractile Function ◽  
Pyrrolizidine Alkaloid ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Pressure Overload ◽  
High Dose ◽  
Specific Expression

Myocardial right ventricular (RV) hypertrophy due to pulmonary hypertension is aimed at normalizing ventricular wall stress. Depending on the degree of pressure overload, RV hypertrophy may progress to a state of impaired contractile function and heart failure, but this cannot be discerned during the early stages of ventricular remodeling. We tested whether critical differences in gene expression profiles exist between ventricles before the ultimate development of either a compensated or decompensated hypertrophic phenotype. Both phenotypes were selectively induced in Wistar rats by a single subcutaneous injection of either a low or a high dose of the pyrrolizidine alkaloid monocrotaline (MCT). Spotted oligonucleotide microarrays were used to investigate pressure-dependent cardiac gene expression profiles at 2 wk after the MCT injections, between control rats and rats that would ultimately develop either compensated or decompensated hypertrophy. Clustering of significantly regulated genes revealed specific expression profiles for each group, although the degree of hypertrophy was still similar in both. The ventricles destined to progress to failure showed activation of pro-apoptotic pathways, particularly related to mitochondria, whereas the group developing compensated hypertrophy showed blocked pro-death effector signaling via p38-MAPK, through upregulation of MAPK phosphatase-1. In summary, we show that, already at an early time point, pivotal differences in gene expression exist between ventricles that will ultimately develop either a compensated or a decompensated phenotype, depending on the degree of pressure overload. These data reveal genes that may provide markers for the early prediction of clinical outcome as well as potential targets for early intervention.

scholarly journals Gene Expression Profiles of the Cochlea and Vestibular Endorgans

2015 ◽  
Vol 124 (1_suppl) ◽  
pp. 6S-48S ◽  
Author(s):  
Shin-ya Nishio ◽  
Mitsuru Hattori ◽  
Hideaki Moteki ◽  
Keita Tsukada ◽  
Maiko Miyagawa ◽  
...  
Keyword(s):  
Gene Expression ◽  
Hearing Loss ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Gene Expression Profiles ◽  
Vestibular Function ◽  
Specific Expression ◽  
Hereditary Hearing Loss ◽  
Vestibular Endorgans ◽  
Gene Symbols

Objectives:We sought to elucidate the gene expression profiles of the causative genes as well as the localization of the encoded proteins involved in hereditary hearing loss.Methods:Relevant articles (as of September 2014) were searched in PubMed databases, and the gene symbols of the genes reported to be associated with deafness were located on the Hereditary Hearing Loss Homepage using localization, expression, and distribution as keywords.Results:Our review of the literature allowed us to systematize the gene expression profiles for genetic deafness in the inner ear, clarifying the unique functions and specific expression patterns of these genes in the cochlea and vestibular endorgans.Conclusions:The coordinated actions of various encoded molecules are essential for the normal development and maintenance of auditory and vestibular function.

scholarly journals Infants with evolving bronchopulmonary dysplasia demonstrate monocyte-specific expression of IL-1 in tracheal aspirates

2019 ◽  
Vol 317 (1) ◽  
pp. L49-L56 ◽  
Author(s):  
Laurie C. Eldredge ◽  
Rane S. Creasy ◽  
Scott Presnell ◽  
Jason S. Debley ◽  
Sandra E. Juul ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bronchopulmonary Dysplasia ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Myeloid Cell ◽  
Double Positive ◽  
Specific Expression ◽  
Single Positive ◽  
Respiratory Outcomes ◽  
Tracheal Aspirates

Bronchopulmonary dysplasia (BPD) remains a devastating consequence of prematurity. Repeated inflammatory insults worsen lung injury, but there are no predictors for BPD-related respiratory outcomes or targeted therapies. We sought to understand inflammatory mechanisms in evolving BPD through molecular characterization of monocytes in tracheal aspirates from infants at risk for developing BPD. We performed flow cytometry targeting myeloid cell populations on prospectively collected tracheal aspirates from intubated patients born before 29 wk of gestation and <30 days old. We identified CD14+CD16+ (double-positive) and CD14+CD16− (single-positive) monocytes and characterized their gene expression profiles by RNA sequencing and quantitative PCR. We further analyzed differential gene expression between time points to evaluate changes in monocyte function over the first weeks of life. Expression of IL-1A, IL-1B, and IL-1 receptor antagonist mRNA was increased in monocytes collected at day of life ( DOL) 7, DOL 14, and DOL 28 compared with those collected at DOL 3. This study suggests that early changes in monocyte-specific IL-1 cytokine pathways may be associated with evolving BPD.

scholarly journals Prioritization of novel ADPKD drug candidates from disease-stage specific gene expression profiles

EBioMedicine ◽  
2020 ◽  
Vol 51 ◽  
pp. 102585 ◽  
Author(s):  
Tareq B. Malas ◽  
Wouter N. Leonhard ◽  
Hester Bange ◽  
Zoraide Granchi ◽  
Kristina M. Hettne ◽  
...  
Keyword(s):  
Gene Expression ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Disease Stage ◽  
Specific Gene ◽  
Specific Gene Expression ◽  
Drug Candidates
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