Delineating cytokine signaling pathways in ulcerative colitis and Crohn's disease through colonic mucosa gene expression profiles.
Bibliographic record
Abstract
Cytokine signaling pathways play a central role in the pathogenesis of inflammatory bowel disease (IBD). Numerous clinical studies have shown that several inflammatory cytokines are elevated in active IBD and recent genome-wide association studies have provided evidence of intricate immune pathways that confer susceptibility to IBD. Despite this extensive knowledge on molecular mechanisms of IBD pathogenesis, the main diagnostic modality for IBD and differentiation between ulcerative colitis (UC) and Crohn's disease (CD) is the histopathologic evaluation of colon biopsy samples. This study aims to delineate the cytokine signaling pathways in colonic mucosa of CD and UC patients, explore possible molecular markers for IBD diagnosis, and identify novel immune-mediators of IBD pathogenesis. The study quantifies gene expression levels from formalin-fixed, paraffin-embedded (FFPE) archived colonic mucosa samples. Based on established clinical diagnosis and strict histopathological inclusion/exclusion criteria, fifty colon biopsy samples were assigned into five categories: 1) severe/active UC, 2) severe/active CD 3) quiescent UC, 4) quiescent CD, and 5) normal control subjects. Gene expression is analyzed by quantitative real-time RT-PCR. Highly efficient mRNA isolation techniques, RT-PCR enzymes, cDNA conversion using random hexamers, and gene-specific primers generating short amplicons (70-150bp) allows successful quantification of gene expression from these formalin-fixed tissues. This study investigates the expression of more than twenty genes, including the cytokines TNF- α, IFN-γ, IL-12, IL-23, IL-17, IL-10, IL-13, IL-33. Also, downstream cytokine-induced inflammatory genes are quantified, including the transcription factors T-bet, GATA-3, FoxP3, the chemokines MCP-1, IP-10, CCL17, the proteases ADAM8, MMP3, Kallikrein 6, the adhesion molecules VCAM, ICAM-1, VLA-4, and the enzymes iNOS, COX2, NOX2/gp91phox. These data should provide insights into the pathogenesis of IBD though identifying novel immune-mediators and elucidating distinct signaling networks in CD and UC. Furthermore, gene profiling utilizing FFPE tissue is practical, it can be used retrospectively, and importantly it has been successfully integrated into clinical practice with good prognostic value in cancer patients. Thus, this study aims to develop additional practical molecular tools for the diagnosis and prognosis of IBD and differentiate between UC and CD. Finally, several biologic agents targeting TNF-α, IL-12/23 p40, IL-6r, α4 integrins, CCR9, CD40, and MyD88 are novel promising IBD treatments and this study provides a convenient approach that can be used to identify molecular markers that can predict the response to these treatments.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".