Peripheral Blood Mononuclear Cell Gene Expression Profiles May Predict Poor Outcome in Idiopathic Pulmonary Fibrosis
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE28221 | GEO | 2013/10/15
SECONDARY ACCESSION(S): PRJNA139675
REPOSITORIES: GEO
Similar Datasets
Project description:Background: In this study we aimed to identify peripheral blood mononuclear cell (PBMC) gene expression profiles predictive of poor outcomes in idiopathic pulmonary fibrosis (IPF) Methods: Microarray analyses of PBMC were performed in 120 patients from discovery (n=45) and replication cohorts (n=75). Genes and pathways associated with transplant-free survival (TFS) were identified and confirmed by qRT-PCR. Findings: 52 genes were predictive of TFS in a discovery cohort (FDR<5%, Cox score above 2.5 or below -2.5). Clustering the replication cohort samples using these genes distinguished two patient groups with significantly different TFS (hazard ratio 1.96, 95%CI 1.01-3.8, P=0.018). Decreased expression of M-bM-^@M-^\The co-stimulatory signaling during T cell activationM-bM-^@M-^] Biocarta pathway and in particular CD28, ICOS, LCK and ITK was associated with shorter TFS times in each cohort (FDR<5%). qRT-PCR expression of CD28, ICOS, LCK and ITK correlated with the microarray results in the discovery cohort (P<0.05) and their decreased expression was predictive of shorter TFS in the replication cohort (P<0.05). A genomic and clinical model demonstrated an area under the ROC curve of 78.5% at 2.4 months for death and lung transplant prediction. Interpretation: Our results suggest that CD28, ICOS, LCK and ITK are outcome biomarkers in IPF. They should be further evaluated for patient prioritization for lung transplantation and stratification in drug studies. This submission represents the Affymetrix component of the study (discovery cohort)
2013-10-15 | E-GEOD-27957 | biostudies-arrayexpress
Project description:Background: In this study we aimed to identify peripheral blood mononuclear cell (PBMC) gene expression profiles predictive of poor outcomes in idiopathic pulmonary fibrosis (IPF) Methods: Microarray analyses of PBMC were performed in 120 patients from discovery (n=45) and replication cohorts (n=75). Genes and pathways associated with transplant-free survival (TFS) were identified and confirmed by qRT-PCR. Findings: 52 genes were predictive of TFS in a discovery cohort (FDR<5%, Cox score above 2.5 or below -2.5). Clustering the replication cohort samples using these genes distinguished two patient groups with significantly different TFS (hazard ratio 1.96, 95%CI 1.01-3.8, P=0.018). Decreased expression of M-bM-^@M-^\The co-stimulatory signaling during T cell activationM-bM-^@M-^] Biocarta pathway and in particular CD28, ICOS, LCK and ITK was associated with shorter TFS times in each cohort (FDR<5%). qRT-PCR expression of CD28, ICOS, LCK and ITK correlated with the microarray results in the discovery cohort (P<0.05) and their decreased expression was predictive of shorter TFS in the replication cohort (P<0.05). A genomic and clinical model demonstrated an area under the ROC curve of 78.5% at 2.4 months for death and lung transplant prediction. Interpretation: Our results suggest that CD28, ICOS, LCK and ITK are outcome biomarkers in IPF. The 'GeneID_matched_gene_expression_dataset_of_IPF_cohorts.txt' supplementary data file contains the matched gene expression data of the subseries GSE28042 with the subseries GSE27957 by gene ID (details in the readme.txt) This SuperSeries is composed of the SubSeries listed below.
2013-10-15 | E-GEOD-28221 | biostudies-arrayexpress
Project description:Background: In this study we aimed to identify peripheral blood mononuclear cell (PBMC) gene expression profiles predictive of poor outcomes in idiopathic pulmonary fibrosis (IPF) Methods: Microarray analyses of PBMC were performed in 120 patients from discovery (n=45) and replication cohorts (n=75). Genes and pathways associated with transplant-free survival (TFS) were identified and confirmed by qRT-PCR. Findings: 52 genes were predictive of TFS in a discovery cohort (FDR<5%, Cox score above 2.5 or below -2.5). Clustering the replication cohort samples using these genes distinguished two patient groups with significantly different TFS (hazard ratio 1.96, 95%CI 1.01-3.8, P=0.018). Decreased expression of M-bM-^@M-^\The co-stimulatory signaling during T cell activationM-bM-^@M-^] Biocarta pathway and in particular CD28, ICOS, LCK and ITK was associated with shorter TFS times in each cohort (FDR<5%). qRT-PCR expression of CD28, ICOS, LCK and ITK correlated with the microarray results in the discovery cohort (P<0.05) and their decreased expression was predictive of shorter TFS in the replication cohort (P<0.05). A genomic and clinical model demonstrated an area under the ROC curve of 78.5% at 2.4 months for death and lung transplant prediction. Interpretation: Our results suggest that CD28, ICOS, LCK and ITK are outcome biomarkers in IPF. PBMC from 75 patients with the diagnosis of IPF were obtained within 30 minutes from blood draw. Total RNA was extracted, labeled and hybridized to Agilent Whole Human Genome Oligo Microarray, 4 x 44K. Patients were followed from blood draw until death, transplant or last follow up. Hierarchical clustering and gene-set analysis with censored outcome data were used to study the association of gene expression and outcome in this cohort (replication cohort)
2013-10-15 | E-GEOD-28042 | biostudies-arrayexpress
Project description:Background: In this study we aimed to identify peripheral blood mononuclear cell (PBMC) gene expression profiles predictive of poor outcomes in idiopathic pulmonary fibrosis (IPF) Methods: Microarray analyses of PBMC were performed in 120 patients from discovery (n=45) and replication cohorts (n=75). Genes and pathways associated with transplant-free survival (TFS) were identified and confirmed by qRT-PCR. Findings: 52 genes were predictive of TFS in a discovery cohort (FDR<5%, Cox score above 2.5 or below -2.5). Clustering the replication cohort samples using these genes distinguished two patient groups with significantly different TFS (hazard ratio 1.96, 95%CI 1.01-3.8, P=0.018). Decreased expression of “The co-stimulatory signaling during T cell activation” Biocarta pathway and in particular CD28, ICOS, LCK and ITK was associated with shorter TFS times in each cohort (FDR<5%). qRT-PCR expression of CD28, ICOS, LCK and ITK correlated with the microarray results in the discovery cohort (P<0.05) and their decreased expression was predictive of shorter TFS in the replication cohort (P<0.05). A genomic and clinical model demonstrated an area under the ROC curve of 78.5% at 2.4 months for death and lung transplant prediction. Interpretation: Our results suggest that CD28, ICOS, LCK and ITK are outcome biomarkers in IPF.
2013-10-15 | GSE28042 | GEO
Project description:Background: In this study we aimed to identify peripheral blood mononuclear cell (PBMC) gene expression profiles predictive of poor outcomes in idiopathic pulmonary fibrosis (IPF) Methods: Microarray analyses of PBMC were performed in 120 patients from discovery (n=45) and replication cohorts (n=75). Genes and pathways associated with transplant-free survival (TFS) were identified and confirmed by qRT-PCR. Findings: 52 genes were predictive of TFS in a discovery cohort (FDR<5%, Cox score above 2.5 or below -2.5). Clustering the replication cohort samples using these genes distinguished two patient groups with significantly different TFS (hazard ratio 1.96, 95%CI 1.01-3.8, P=0.018). Decreased expression of “The co-stimulatory signaling during T cell activation” Biocarta pathway and in particular CD28, ICOS, LCK and ITK was associated with shorter TFS times in each cohort (FDR<5%). qRT-PCR expression of CD28, ICOS, LCK and ITK correlated with the microarray results in the discovery cohort (P<0.05) and their decreased expression was predictive of shorter TFS in the replication cohort (P<0.05). A genomic and clinical model demonstrated an area under the ROC curve of 78.5% at 2.4 months for death and lung transplant prediction. Interpretation: Our results suggest that CD28, ICOS, LCK and ITK are outcome biomarkers in IPF. They should be further evaluated for patient prioritization for lung transplantation and stratification in drug studies.
2013-10-15 | GSE27957 | GEO
Project description:Background: Idiopathic pulmonary fibrosis (IPF) is a fatal disease with variable outcome. Currently, there is little information whether changes in molecular pathways in the alveolar compartment of patients with IPF are indicative of disease progression. To address this question we analyzed gene expression signatures in cells obtained from bronchoalveolar lavage (BAL) of patients with IPF. Methods: BAL cells were harvested from 212 IPF patients and 20 healthy donors at the time of diagnosis. RNA was extracted, labeled and hybridized to Agilent gene expression arrays. Our study included a discovery cohort of 62 patients from Freiburg, Germany, and two independent validation cohorts, Siena, Italy (50 patients) and Leuven, Belgium (64 patients). Survival analysis was performed by applying Cox models and component-wise boosting. Results: We found 1582 genes predictive of mortality in the discovery cohort in univariate analyses adjusted for age and gender at FDR<0.05. A nine gene signature, developed by component-wise boosting in the Freiburg array dataset, performed well in both validation cohorts, Siena (p<0.0032) and Leuven (p=0.0033). The genes associated with mortality in BAL cells were significantly enriched for genes expressed in airway basal epithelial cells, airway progenitor cells recently implicated in fibrosis. Conclusions: Our results identify and validate a BAL cell gene expression signature that predicts mortality in IPF. This signature unmasks a potential novel role for airway basal epithelial cells in IPF.
2018-12-31 | GSE70866 | GEO
Project description:The Tec-family kinase Itk plays an important role during T-cell activation and function, and controls also conventional versus innate-like T-cell development. We have characterized the transcriptome of Itk-deficient CD3+ T-cells, including CD4+ and CD8+ subsets, using Affymetrix microarrays. The largest difference between Itk-/- and Wt CD3+ T-cells was found in unstimulated cells, e.g. for killer cell lectin-like receptors. Compared to anti-CD3-stimulation, anti-CD3/CD28 significantly decreased the number of transcripts suggesting that the CD28 co-stimulatory pathway is mainly independent of Itk. The signatures of CD4+ and CD8+ T-cell subsets identified a greater differential expression than in total CD3+ cells. Cyclosporin (CsA)-treatment had a stronger effect on transcriptional regulation than Itk-deficiency, suggesting that only a fraction of TCR-mediated calcineurin/NFAT-activation is dependent on Itk. Bioinformatic analysis of NFAT-sites of the group of transcripts similarly regulated by Itk-deficiency and CsA-treatment, followed by chromatin-immunoprecipitation, revealed NFATc1-binding to the Bub1, IL7R, Ctla2a, Ctla2b, and Schlafen1 genes. Finally, to identify transcripts that are regulated by Tec-family kinases in general, we compared the expression profile of Itk-deficient T-cells with that of Btk-deficient B-cells and a common set of transcripts was found. Taken together, our study provides a general overview about the global transcriptional changes in the absence of Itk. Experiment Overall Design: CD3+ T-cells from pooled suspensions of spleen and lymph nodes of Wt and Itk knockout mice on C57BL/6 background were isolated after negative depletion. Unstimulated as well as stimulated T-cells were studied. Stimulations were done with anti-CD3 (1 mg/ml) with or without anti-CD28 (3 mg/ml) in the presence or absence of CsA (1 mg/ml) for 24 hrs. For each stimulus, at least duplicate samples were used.
2009-05-29 | E-GEOD-12464 | biostudies-arrayexpress
Project description:The Tec-family kinase Itk plays an important role during T-cell activation and function, and controls also conventional versus innate-like T-cell development. We have characterized the transcriptome of Itk-deficient CD3+ T-cells, including CD4+ and CD8+ subsets, using Affymetrix microarrays. The largest difference between Itk-/- and Wt CD3+ T-cells was found in unstimulated cells, e.g. for killer cell lectin-like receptors. Compared to anti-CD3-stimulation, anti-CD3/CD28 significantly decreased the number of transcripts suggesting that the CD28 co-stimulatory pathway is mainly independent of Itk. The signatures of CD4+ and CD8+ T-cell subsets identified a greater differential expression than in total CD3+ cells. Cyclosporin (CsA)-treatment had a stronger effect on transcriptional regulation than Itk-deficiency, suggesting that only a fraction of TCR-mediated calcineurin/NFAT-activation is dependent on Itk. Bioinformatic analysis of NFAT-sites of the group of transcripts similarly regulated by Itk-deficiency and CsA-treatment, followed by chromatin-immunoprecipitation, revealed NFATc1-binding to the Bub1, IL7R, Ctla2a, Ctla2b, and Schlafen1 genes. Finally, to identify transcripts that are regulated by Tec-family kinases in general, we compared the expression profile of Itk-deficient T-cells with that of Btk-deficient B-cells and a common set of transcripts was found. Taken together, our study provides a general overview about the global transcriptional changes in the absence of Itk.
2009-05-20 | GSE12465 | GEO
Project description:The Tec-family kinase Itk plays an important role during T-cell activation and function, and controls also conventional versus innate-like T-cell development. We have characterized the transcriptome of Itk-deficient CD3+ T-cells, including CD4+ and CD8+ subsets, using Affymetrix microarrays. The largest difference between Itk-/- and Wt CD3+ T-cells was found in unstimulated cells, e.g. for killer cell lectin-like receptors. Compared to anti-CD3-stimulation, anti-CD3/CD28 significantly decreased the number of transcripts suggesting that the CD28 co-stimulatory pathway is mainly independent of Itk. The signatures of CD4+ and CD8+ T-cell subsets identified a greater differential expression than in total CD3+ cells. Cyclosporin (CsA)-treatment had a stronger effect on transcriptional regulation than Itk-deficiency, suggesting that only a fraction of TCR-mediated calcineurin/NFAT-activation is dependent on Itk. Bioinformatic analysis of NFAT-sites of the group of transcripts similarly regulated by Itk-deficiency and CsA-treatment, followed by chromatin-immunoprecipitation, revealed NFATc1-binding to the Bub1, IL7R, Ctla2a, Ctla2b, and Schlafen1 genes. Finally, to identify transcripts that are regulated by Tec-family kinases in general, we compared the expression profile of Itk-deficient T-cells with that of Btk-deficient B-cells and a common set of transcripts was found. Taken together, our study provides a general overview about the global transcriptional changes in the absence of Itk.
2009-05-20 | GSE12464 | GEO
Project description:Rationale: Molecular markers of disease progression in idiopathic pulmonary fibrosis are needed. Objective: Derive and validate a blood transcriptomic predictor of forced vital capacity (FVC) decline. Methods: A training cohort (n=74) of IPF patients was stratified according to the presence of progressive disease, defined as ≥10% relative decline in FVC over 12 months. Baseline to 4-month within-patient changes in gene expression were correlated with categorical FVC decline. Genes predictive of FVC decline were identified by two-group comparison with false discovery rate <5% followed by logistic LASSO regression and 10-Fold Cross-Validation for gene list prioritization. Independent validation cohorts with differing transcriptome assay platforms and blood transcriptome sampling times from UChicago (n=27), UPMC (n=35), and Imperial (n=24) underwent receiver operating characteristic with area under the curve (AUC) analyses for validation. Results: A longitudinally-derived FVC-gene predictor accurately discriminated most patients with stable and progressive IPF across four independent IPF cohorts with variable transcriptomic assay platforms and sampling times. The FVC-gene predictorand demonstrated sensitivity and specificity of 74.3% and 82.4% in the combined replication cohort. The likelihood ratio, LR+ and LR- were 4.11 and 0.32, respectively. TGF-beta was the highest-ranking canonical pathway by Gene Set Enrichment Analysis. An approach using longitudinal gene expression changes approach dramatically reduced within-group variation compared to cross-sectional expression for improved prediction modeling. Conclusions: This novel FVC-gene predictor developed from short-term longitudinal gene expression changes successfully discriminates most patients with high likelihood of one-year 10% FVC decline. This tool may better reflect disease activity and prove useful for predictive enrichment of clinical trial populations.
2019-09-30 | GSE133298 | GEO