Gene expression changes associated with resistance to intravenous corticosteroid therapy in children with severe ulcerative colitis
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE21231 | GEO | 2010/08/31
SECONDARY ACCESSION(S): PRJNA126499
REPOSITORIES: GEO
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Project description:Although corticosteroids remain a mainstay of therapy for UC, a meta-regression of cohort studies in acute severe ulcerative colitis (UC) showed that 29% of patients fail corticosteroid therapy and require escalation of medical management or colectomy. We aimed to determine whether genes expressed in whole blood early following initiation of intravenous corticosteroid treatment can be associated with response. 20 corticosteroid responsive (PUCAI < 35 by day 5) and 20 corticosteroid resistant patients (PUCAI ≥ 35 by day 5 and need for 2nd line medical therapy or colectomy by hospital discharge) were selected from a prospectively accrued cohort of patients hospitalized for intravenous corticosteroid treatment of severe UC. Total RNA was extracted from blood samples collected on day 3 of intravenous corticosteroid therapy. The eluted transcriptomes were quantified on Affymetrix Human Gene 1.0 ST arrays. The data was analysed by the local-pooled error method for discovery of differential gene expression and false discovery rate correction was applied to adjust for multiple comparisons. P-values less than 0.05 after correction were considered significant.
2010-08-31 | E-GEOD-21231 | biostudies-arrayexpress
Project description:Background: Ulcerative colitis (UC) develops from chronic inflammation of the colon. Most patients respond favorably to medical management, however around 25% of UC patients will require surgery to treat their disease. While surgery is the only curative treatment for UC, it can carry its own risks, particularly when the surgery is emergent. Time from diagnosis to surgery varies dramatically amongst UC patients, thus a better understanding of how the colonic microenvironment relates to disease severity is needed to improve patient outcomes. Methods: We conducted RNA-seq on full-thickness sigmoid colonic tissues from 26 UC patients undergoing colectomy for their disease. Hierarchical clustering of the transcriptomes identified disease subsets. Subsets were characterized using differential gene expression analysis, cell type deconvolution, and network analysis. Results: We identified two distinct UC subsets in our cohort that were distinguished by 957 differentially expressed genes. Cluster 1 was enriched in genes associated with intestinal epithelial cell differentiation, while cluster 2 was enriched in genes associated with epithelial-to-mesenchymal transition and inflammatory responses. Cluster 1 was associated with an extended time from UC diagnosis to colectomy. Of cluster 1 genes, elevated MUC5B, MUC4, and MUC2 expression displayed the strongest correlation with increased time to surgery. Conclusion: Our transcriptome analysis indicates that UC can be subclassified into at least two distinct molecular signatures. We find that elevated mucin gene expression correlates with prolonged time to colectomy after diagnosis. These results identified MUC5B, MUC4, and MUC2 as potential prognostic indicators of disease severity, as reflected in time to surgery.
2020-04-18 | GSE130038 | GEO
Project description:Circulating corticosteroids orchestrate stress adaptation, including inhibition of inflammation. While pathways governing corticosteroid biosynthesis and intracellular signaling are understood, less is known about mechanisms controlling plasma corticosteroid transport. Here, we show hepatocyte KLF15 (Kruppel-like factor 15) controls plasma corticosteroid transport and inflammatory responses through direct transcriptional activation of Serpina6, which encodes corticosteroid binding globulin (CBG). Klf15-deficient mice have profoundly low CBG, reduced plasma corticosteroid binding capacity, and heightened mortality during inflammatory stress. These defects are completely rescued by reconstituting CBG, supporting that KLF15 works primarily through CBG to control plasma corticosterone homeostasis. To understand transcriptional mechanisms, we generated the first KLF15 cistromes using newly engineered Klf153xFLAG mice. Unexpectedly, liver KLF15 is predominantly promoter-enriched, including Serpina6, where it binds a palindromic GC-rich motif, opens chromatin, and transactivates genes with minimal associated gene repression. Overall, we provide new mechanistic insight into KLF15 function and identify a hepatocyte-intrinsic transcriptional module that potently regulates systemic corticosteroid transport and inflammation.
2021-12-28 | GSE166083 | GEO
Project description:The aim of this study is to identify early pathogenic changes in ileal gene expression that precede the development of macroscopic disease in inflammatory bowel diseases (IBDs). We focused on two IBD phenotypes that were unlikely to overlap: 1) ileal Crohn’s disease (CD) patients undergoing initial ileocolic resection of diseased ileum; and 2) ulcerative colitis (UC) patients undergoing total colectomy. The Control patients were those patients without IBD undergoing initial right hemicolectomy or total colectomy.
2010-09-26 | GSE24287 | GEO
Project description:The aim of this study is to identify early pathogenic changes in ileal gene expression that precede the development of macroscopic disease in inflammatory bowel diseases (IBDs). We focused on two IBD phenotypes that were unlikely to overlap: 1) ileal Crohn’s disease (CD) patients undergoing initial ileocolic resection of diseased ileum; and 2) ulcerative colitis (UC) patients undergoing total colectomy. The Control patients were those patients without IBD undergoing initial right hemicolectomy or total colectomy. In order to identify early pathogenic changes in the human ileum in inflammatory bowel diseases, we analyzed 99 two-color whole human genome expression profiles (Agilent 4410A) of a test human ileal cRNA probe vs. a common reference human ileal RNA from a Control patient (N17). A minimum of four biopsies were taken from the macroscopically disease-unaffected proximal ileal margin of freshly resected specimens from 47 ileal Crohn's disease patients undergoing initial ileocolic resection, 27 ulcerative colitis patients undergoing total colectomy and 25 Control patients undergoing either right hemicolectomy or total colectomy. The test and common reference probes were synthesized using the Agilent Low Input Linear Amplification Kit. Hybridization was carried out in DNA hybridization chambers, washed and scanned on an Axon GenePix 4000B scanner. The preprocessing, filtering and normalization of the array data was carried out using the R package LIMMA.
2010-09-26 | E-GEOD-24287 | biostudies-arrayexpress
Project description:PROTECT is a multicenter pediatric inception cohort study of response to standardized colitis therapy. In order to more explicitly model progression to colectomy within one year of diagnosis, we performed differential expression analysis between baseline rectal RNAseq biopsies of 21 patients who progressed to colectomy, and 310 who did not. We report rectal gene expression of pediatric patients with ulcerative colitis at diagnosis and at one year follow-up.
2021-05-20 | GSE150961 | GEO
Project description:Infliximab, an anti-TNF-alpha monoclonal antibody, is an effective treatment for ulcerative colitis (UC) with over 60% of patients responding to treatment and up to 30% reaching remission. The mechanism of resistance to anti-TNF-alpha is unknown. This study used colonic mucosal gene expression to provide a predictive response signature for infliximab treatment in UC. Keywords: drug response Twenty-four patients with active UC, refractory to corticosteroids and/or immunosuppression, underwent colonoscopy with biopsies from diseased colon within a week prior to the first intravenous infusion of 5 mg infliximab per kg body weight. Response to infliximab was defined as endoscopic and histologic healing at 4-6 weeks after first infliximab treatment. Six control patients with normal colonoscopy were included. Total RNA was isolated from colonic mucosal biopsies, labelled and hybridized to Affymetrix Human Genome U133 Plus 2.0 Arrays.
2010-01-06 | E-GEOD-14580 | biostudies-arrayexpress
Project description:Our group used rectal biopsies from patients with active ulcerative colitis (UC) and differential response to glucocorticoid treatment, to generate a predictive computational strategy based on systems biology. Contrasting mRNA and miRNAs intestinal expression profiles with updated molecular information related to UC and glucocorticoids, we were able to identify a mechanism of action (MoA) associated with corticosteroid failure in UC. ith the aim of transferring these results to clinical practice, the MoA-models created previously were implemented with plasmatic miRNAs profiles, to describe in silico non-invasive potential biomarkers of glucocorticoid refractoriness. Small RNA-seq analysis was perfomed using Illumina next generation sequencing and standard statistical criteria were applied to compare the miRNA profiles, incluidng paired samples before clucocorticoid treatment to the third day of the steroidal treatment. The selection these miRNA with predictive capacity was done using two complementary strategies: the first one using all the obtained miRNAs, and the second taking into account those miRNAs that are directly related to MoA, through various statistical restrictions (RELIEF, ENTROPY + CORRELATION, WILCOXON, ROC, and simple REGRESSION). These computational approaches from all miRNAs identified hsa-miR218-5p as the best to classify patients according their respond at basal time (Accuracy = 84.21%, Generalization Capability = 84.21%, Sensitivity = 100% and Specificity = 66.67%). In addition, the combination of this miRNA with hsa-miR6754-5p and hsa-miR4767, increases the diagnosis accuracy of the disease (Accuracy = 94.74%, Generalization Capability = 75.44%, Sensitivity = 70% and specificity = 81.48%). On the other hand, the combination of hsa-miR218-5p and the plasma levels of the Protein C Reactive increases the ability to classify patients towards their response to glucocorticoids up to 89%. Taking in account all this data, we can conclude that by means of a computer strategy based on Biology of Systems we have identified the plasmatic miR-218-5p as a potential biomarker to glucocorticoid response in UC before start the treatment.
2022-03-30 | GSE122618 | GEO
Project description:Background: A subset of asthmatics does not respond to steroid therapy and therefore is at risk for escalation of disease severity. The cause of corticosteroid resistant (CR) asthma is unknown. Gene microarray technologies have the potential to substantiate new hypotheses regarding the etiology of corticosteroid resistance. Methods: Gene microarray analysis was performed with bronchoalveolar lavage (BAL) cells of CR and corticosteroid sensitive (CS) asthmatics. Increased gene expression was verified with real time PCR and at the protein level by ELISA. Findings: Microarray analyses demonstrated significantly higher levels (over two-fold increase, p<0.05) of TNF-alpha, IL-1alpha, IL-1beta, IL-6, CXCL1, CXCL2, CXCL3, CXCL8 (IL-8), CCL3, CCL4, CCL20 gene expression in BAL cells of CR than CS asthmatics. These findings, confirmed by RT-PCR in additional BAL samples, were consistent with classical macrophage activation by bacterial products. In contrast, markers of alternatively-activated macrophages, Arginase I and CCL24, were decreased in CR asthmatics. Genes associated with activation of the LPS signaling pathway (EGR1, DUSP2, MAIL, TNFAIP3) were significantly elevated in CR BAL samples (p<0.05). CR asthmatics had significantly higher amounts (1444.0±457.3 pg per mg of total protein) of LPS in BAL fluid than CS asthmatics (270.5±216.0 pg; p<0.05). Prolonged exposure to LPS induced functional steroid resistance to dexamethasone (DEX) in normal monocytes, demonstrated by persistently elevated IL-6 levels in the presence of DEX. Interpretation: Classical macrophage activation and induction of LPS signaling pathways along with high endotoxin levels detected in BAL fluid from CR asthmatics suggest that LPS exposure may contribute to CR asthma. Experiment Overall Design: Patients with a diagnosis of asthma according to American Thoracic Society criteria were selected for evaluation. Asthmatics had a baseline FEV1% predicted of 55% to 85% of predicted, a beta2-adrenergic response of â¥12% of baseline FEV1% predicted and/or a methacholine PC20 value of â¤8 mg/ml. Asthma patients were further subdivided in CR and CS groups, based on their response to steroids. The definition was based on change in FEV1 % predicted over a one-week course of 40 mg/day of oral prednisone. Asthmatic patients were defined as CS if they had an increase in FEV1% predicted of greater than 15% after a one-week course of prednisone, and as CR if less than 12% change in FEV1% predicted was observed. None of the asthmatic subjects recruited for this study had evidence for other types of lung diseases. None of the subjects had received systemic corticosteroid therapy for at least one month prior to bronchoscopy. All subjects provided written informed consent to participate in the study. The study was approved by the Institutional Review Board at National Jewish Medical and Research Center, Denver, CO. Gene array studies of BAL macrophages were performed in 3 CR and 3 CS asthmatics.
2009-07-01 | E-GEOD-7368 | biostudies-arrayexpress
Project description:Background: A subset of asthmatics does not respond to steroid therapy and therefore is at risk for escalation of disease severity. The cause of corticosteroid resistant (CR) asthma is unknown. Gene microarray technologies have the potential to substantiate new hypotheses regarding the etiology of corticosteroid resistance. Methods: Gene microarray analysis was performed with bronchoalveolar lavage (BAL) cells of CR and corticosteroid sensitive (CS) asthmatics. Increased gene expression was verified with real time PCR and at the protein level by ELISA. Findings: Microarray analyses demonstrated significantly higher levels (over two-fold increase, p<0.05) of TNF-alpha, IL-1alpha, IL-1beta, IL-6, CXCL1, CXCL2, CXCL3, CXCL8 (IL-8), CCL3, CCL4, CCL20 gene expression in BAL cells of CR than CS asthmatics. These findings, confirmed by RT-PCR in additional BAL samples, were consistent with classical macrophage activation by bacterial products. In contrast, markers of alternatively-activated macrophages, Arginase I and CCL24, were decreased in CR asthmatics. Genes associated with activation of the LPS signaling pathway (EGR1, DUSP2, MAIL, TNFAIP3) were significantly elevated in CR BAL samples (p<0.05). CR asthmatics had significantly higher amounts (1444.0±457.3 pg per mg of total protein) of LPS in BAL fluid than CS asthmatics (270.5±216.0 pg; p<0.05). Prolonged exposure to LPS induced functional steroid resistance to dexamethasone (DEX) in normal monocytes, demonstrated by persistently elevated IL-6 levels in the presence of DEX. Interpretation: Classical macrophage activation and induction of LPS signaling pathways along with high endotoxin levels detected in BAL fluid from CR asthmatics suggest that LPS exposure may contribute to CR asthma. Keywords: Disease state analysis
2009-06-22 | GSE7368 | GEO