Circulating miR 218-5p, alone or in combination, predicts corticosteroid failure in ulcerative colitis. Study through computational strategies based on Systems Biology.
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ABSTRACT:
PROVIDER: PRJNA505782 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8197930.fastq.gz | Fastqsanger.gz | |||
| SRR8197940.fastq.gz | Fastqsanger.gz | |||
| SRR8197950.fastq.gz | Fastqsanger.gz | |||
| SRR8197960.fastq.gz | Fastqsanger.gz | |||
| SRR8197931.fastq.gz | Fastqsanger.gz |
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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.
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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.
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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.
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Project description:Receptor tyrosine kinase pathway signalings plays a central role in the growth and progression of glioblastoma, a highly aggressive group of brain tumors. We recently reported that miR-218 repression, an essentially uniform feature of human GBM, directly promotes RTK hyperactivation by increasing the expression of key positive signaling effectors, including EGFR, PLCr1, PIK3CA and ARAF. However, enhanced RTK signaling is known to activate compensatory inhibitory feedback mechanisms in both normal and cancer cells. We demonstrate here that miR-218 repression in GBM cells also increases the abundance of additional up stream and downstream signaling mediators, including PDGFRa, RSK2, and S6K1, which collectively funciton to alleviate inhibitory RTK feedback regulation. In turn, RTK signaling suppresses miR-218 expression via STAT3, which binds to the miR-218 locus, along with BCLAF1, to repress its expression. These data identify novel interacting feedback loops by which miR-218 repression promotes increased RTK signaling in high-grade gliomas.
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