Genome-Wide Profiling of Airway Epithelial Cells in Asthmatics, Smokers and Healthy Controls
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE4302 | GEO | 2007/10/12
SECONDARY ACCESSION(S): PRJNA94683
REPOSITORIES: GEO
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Project description:We collected airway epithelial brushings for microarray analysis from 42 asthmatics and two control groups â 28 healthy subjects and 16 smokers. A subgroup of 32 asthmatics completed a randomized placebo-controlled trial of fluticasone propionate in which collection of brushings was repeated after 1 week of treatment. Experiment Overall Design: 1) Comparison of gene expression in asthmatics to healthy controls Experiment Overall Design: 2) Comparison of smokers to healthy controls Experiment Overall Design: 3) Comparison of change in gene expression in the fluticasone treated group to the change in the placebo treated group
2008-06-13 | E-GEOD-4302 | biostudies-arrayexpress
Project description:A chemopreventive effect of aspirin (ASA) on lung cancer risk is supported by epidemiologic and preclinical studies. We conducted a randomized, double-blind, placebo controlled study in current heavy smokers to compare modulating effects of intermittent versus continuous low dose ASA on gene signatures of smoking and lung cancer from nasal brushings. Fifty-four participants were randomized to intermittent ASA (ASA 81 mg daily for one week alternating with placebo daily for one week) or continuous ASA (81 mg daily) for 12 weeks. The primary endpoint was modulation of a smoking gene signature in nasal brushings. Other [JB1] endpoints included modulation of nasal and bronchial gene signatures for smoking, lung cancer and chronic obstructive pulmonary disease (COPD) and changes in cyclooxygenase (COX)- and 5-lipoxygenase (LOX)-mediated arachidonic acid (ARA) metabolism. Low dose ASA intervention caused minimal changes in smoking and lung cancer gene signature scores in nasal epithelium of current heavy smokers. The small sample size of the intervention groups may have limited the ability to detect modulation of the gene signatures. Low dose ASA lowered urinary prostaglandin E metabolite, a marker of COX-mediated ARA metabolic pathway with no change in urinary leukotriene E4, a marker of 5-LOX-mediated pathway. Exploratory genomic analysis showed that ASA intervention induced wide-ranging genomic changes in the nasal epithelium, including modulation of the arachidonic acid pathway and wound healing. A companion study is underway using ASA plus zileuton to test dual suppression of COX- and 5-LOX-mediated pathways on these gene signature scores in current heavy smokers.
2019-12-24 | GSE124637 | GEO
Project description:Introduction: In the recently completed Dutch GLUCOLD study, treatment of COPD patients with fluticasone ± salmeterol reduced the rate of decline in FEV1. These results indicate that ICS can have therapeutic efficacy in COPD. Aim: To explore the molecular mechanisms by which ICS exert their effects, we performed genome-wide gene expression profiling on bronchial biopsies from COPD patients who participated in the GLUCOLD study. Methods: An Affymetrix Human Gene Array ST version 1.0 was performed in a total of 221 bronchial biopsies that were available from 90 COPD patients at baseline and after 6 and 30 months of therapy. Linear mixed effects modeling was used to analyze treatment-specific changes in gene expression. A validation set was included and pathway analysis was performed with Gene Set Enrichment Analysis (GSEA). Results: The expression of 138 genes significantly decreased after both 6 and 30 months of treatment with fluticasone ± salmeterol versus placebo, whereas the expression of 140 genes increased. A more pronounced treatment-induced change in expression of 51 of these 278 genes was associated with a slower rate of decline in FEV1. Genes that decreased with treatment were involved in pathways related to cell cycle, oxidative phosphorylation, epithelial cell signaling, p53 signaling and T cell signaling. Genes that increased with treatment were involved in pathways related to focal adhesion, gap junction and extracellular matrix deposition. Conclusion: The present study suggests that gene expression in biological pathways of COPD is dynamic with treatment and reflects disease activity. This study opens the gate to targeted and phenotype-driven therapy of COPD. First, a total of 162 samples were analysed (RNA derived from bronchial biopsies from COPD patients before and after treatment with fluticasone +/- salmeterol or placebo [GLUCOLD study]), 107 samples before and after 6 and 30 months of treatment with fluticasone +/- salmeterol and 55 samples before and after treatment with placebo. A total of 278 genes were found that changed in expression after both 6 and 30 months of treatment with fluticasone +/- salmeterol versus placebo. Next, an additional number of 59 samples from the fouth GLUCOLD treatment were put on array. In this study arm, COPD patients were treated for 6 months with fluticasone and then fluticasone was discontinued and patients switched to placebo for the remaining 24 months of the study.
2012-03-03 | E-GEOD-36221 | biostudies-arrayexpress
Project description:Lockwood2006 - AlzheimersDisease PBPK
model
A mathematical model to predict the
effectiveness of CI-1017 (muscarinic agonist) for Alzheimer's
disease by evaluating changes in ADAS-cog score.
This model is described in the article:
Application of clinical
trial simulation to compare proof-of-concept study designs for
drugs with a slow onset of effect; an example in Alzheimer's
disease.
Lockwood P, Ewy W, Hermann D,
Holford N.
Pharm. Res. 2006 Sep; 23(9):
2050-2059
Abstract:
OBJECTIVE: Clinical trial simulation (CTS) was used to
select a robust design to test the hypothesis that a new
treatment was effective for Alzheimer's disease (AD).
Typically, a parallel group, placebo controlled, 12-week trial
in 200-400 AD patients would be used to establish drug effect
relative to placebo (i.e., Ho: Drug Effect = 0). We evaluated
if a crossover design would allow smaller and shorter duration
trials. MATERIALS AND METHODS: A family of plausible drug and
disease models describing the time course of the AD assessment
scale (ADAS-Cog) was developed based on Phase I data and
literature reports of other treatments for AD. The models
included pharmacokinetic, pharmacodynamic, disease progression,
and placebo components. Eight alternative trial designs were
explored via simulation. One hundred replicates of each
combination of drug and disease model and trial design were
simulated. A 'positive trial' reflecting drug activity was
declared considering both a dose trend test (p < 0.05) and
pair-wise comparisons to placebo (p < 0.025). RESULTS: A 4 x
4 Latin Square design was predicted to have at least 80% power
to detect activity across a range of drug and disease models.
The trial design was subsequently implemented and the trial was
completed. Based on the results of the actual trial, a
conclusive decision about further development was taken. The
crossover design provided enhanced power over a parallel group
design due to the lower residual variability. CONCLUSION: CTS
aided the decision to use a more efficient proof of concept
trial design, leading to savings of up to US 4 M dollars in
direct costs and a firm decision 8-12 months earlier than a
12-week parallel group trial.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000673.
To cite BioModels Database, please use:
Chelliah V et al. BioModels: ten-year
anniversary. Nucl. Acids Res. 2015, 43(Database
issue):D542-8.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2024-09-02 | BIOMD0000000673 | BioModels
Project description:Samples were obtained as part of a randomized, double blind, placebo-controlled, phase IIb study to determine the effects of myo-inositol in smokers with bronchial dysplasia. Smokers with greater than 1 site of dysplasia identified by autofluorescence bronchoscopy-directed biopsy were randomly assigned to receive oral placebo or myo-inositol, 9 g once/day for two weeks and then twice/day for 6 months. Cytologically normal airway epithelial cells were obtained via bronchoscopy from the right or left mainstem bronchus at baseline and 6 months post-treatment with myo-inositol or placebo from 69 study participants (n=138 samples). The RNA from these samples was isolated and used to prepare libraries for mRNA sequencing. Subjects were classified by response according to their change in dysplasia rate after 6-months. Among subjects with a complete response in the myo-inositol arm, there was a significant decrease in a gene expression signature reflective of PI3K activation.
2016-09-26 | GSE86422 | GEO
Project description:Here we investigate how glucocorticoids affect the response to LPS in human macrophages. Total RNA obtained from monocyte-derived macrophages exposed to lipopolysacharide presceding exposure to fluticasone propionate or left untreated.
2014-02-10 | E-GEOD-49709 | biostudies-arrayexpress
Project description:Here we investigate how glucocorticoids affect the response to Interferon gamma in human macrophages. Total RNA obtained from monocyte-derived macrophages exposed to Interferon gamma presceding exposure to fluticasone propionate or left untreated.
2014-02-10 | E-GEOD-49706 | biostudies-arrayexpress
Project description:Gene expression profiling was performed on sputum samples obtained from asthmatics and matched healthy controls, to identify markers associated with various asthma subtypes. Sputum samples were collected from asthmatics and healthy controls and subjected to expression profiling using Affymetrix HG-U133Plus2.0 microarrays.
2015-10-23 | E-GEOD-41863 | biostudies-arrayexpress
Project description:Microarray analysis of whole blood samples (collected into PAXgene tubes from PreAnalytiX) during a phase II double-blind, randomized (1:1 ratio) clinical trial in which inhaled IFN-β (SNG001) or placebo treatment was initiated within 24 hours of asthmatics reporting cold symptoms. Patients were dosed once a day for 14 days, with samples collected at day 1 (prior to first dose), day 4 and day 7. Analysis of genome-wide gene expression (only conducted using samples from the BTS Step 4/5, mITT subgroup), showed a treatment-related enhancement of systemic innate immunity, thereby providing compelling evidence for exogenous IFN-β enhancing antiviral responses. Placebo versus SNG001 (IFNbeta). Day 4 (visit 3); Placebo 25 replicates, SNG001 18 replicates. Day 7 (visit 4); Placebo 28 replicates, SNG001 20 replicates.
2014-06-30 | E-GEOD-50943 | biostudies-arrayexpress
Project description:Upregulation of Expression of the Ubiquitin Carboxyl Terminal Hydrolase L1 Gene in Human Airway Epithelium of Cigarette Smokers The microarray data deposited here is from 39 HG-U133 Plus 2.0 GeneChips, from 12 normal non-smokers, 12 phenotypic normal smokers, 9 Early COPD and 6 COPD individuals, all small airways, all small airway. A subset of these samples have been already submitted under GEO Accession Number GSE 4498. These are: 12 non-smokers samples (GSM101095-GSM101106) and 10 smoker samples (GSM101107-GSM101116). These 22 samples that are also in GSE4498 were described in Harvey, B-G; Heguy, A.; Leopold, P.L.; Carolan, B.; Ferris, B. and Crystal R.G. Modification of Gene Expression of the Small Airway Epithelium in Response to Cigarette Smoking. J. Mol. Med (in press). These data are part of a study aimed at understanding how cigarette smoking modifies neuroendocrine cells, in which microarray analysis with TaqMan confirmation was used to assess airway epithelial samples obtained by fiberoptic bronchoscopy from 81 individuals (normal nonsmokers, normal smokers, smokers with early COPD and smokers with established COPD). Of 11 genes considered to be neuroendocrine cell-specific, only ubiquitin C-terminal hydrolase L1(UCHL1), a member of the ubiquitin proteasome pathway, was consistently upregulated in smokers compared to nonsmokers. Up-regulation of UCHL1 at the protein level was observed with immunohistochemistry of bronchial biopsies of smokers compared to nonsmokers. Interestingly, however, while UCHL1 expression was present only in neuroendocrine cells of the airway epithelium in nonsmokers, UCHL1 expression was also expressed in ciliated epithelial cells in smokers, an intriguing observation in light of recent observations that ciliated cells can are capable of transdifferentiating to other airway epithelium. In the context that UCHL1 is involved in the degradation of unwanted, misfolded or damaged proteins within the cell and is overexpressed in >50% of lung cancers, its overexpression in chronic smokers may represent an early event in the complex transformation from normal epithelium to overt malignancy. Keywords: non-smokers vs phenotypic normal smokers, smokers with early COPD, and smokers with COPD
2006-11-21 | GSE5058 | GEO