A47 INFLAMMTORY MEMORY/IMIPRINTING OF INTESTINAL STEM CELLS DRIVES RELAPSE IN IBD PATIENTS
Bibliographic record
Abstract
Introduction. Metabolic dysfunction and chronic inflammation are robust molecular drivers of many diseases such as obesity, diabetes and inflammatory bowel disease (IBD). Indeed, since inflammation is essentially a necessary component of tissue repair, it stands to reason that energy is necessary for key repair mechanisms to function properly. The underlying molecular mechanisms driving IBD is currently attributed to a broad spectrum of susceptible genes that modulates the appearance, maintenance and progression of IBD. Precision medicine relies on defining patient specific abnormalities present only in the diseased state. These abnormalities arise from genetic/epigenetic/proteomic alterations of many of the aforementioned IBD susceptibility genes that will perturb inflammatory and metabolic homeostasis. We speculate that the underlying cause of IBD and relapse/flare ups may not be in altered signaling in the epithelial cell/colonocyte of the colonic crypt nor abnormal signaling in immune cells but abnormal intrinsically driven signaling by the intestinal stem cells of the colonic crypt.. Aims: Our aims are to utilize three dimensional (3D) intestinal organoids (formed from the intestinal stem cells) and matched paraffin embedded colon tissue sections to understanding how “inflammatory memory/imprinting” of the intestinal stem cells of the colonic crypt varies in patients, how it can drive disease progression and be a platform for personalized medicine. Methods: 3D organ or organoid cultures will be prepared using methods established by Yin et al. (2013) and others. Immunohistochemistry and immunoblotting carried out as described by Gordon et al., PLOSone 2013. All patients have been consented under our IBD ethics protocol (Pro00001523 and Pro00077868). Analysis of 3D organoids formed from intestinal stem cells of patients with long standing IBD (> 10 years) versus < 2 years with IBD suggest that intestinal stem cells are re-programmed to be inflammatory. We can robustly detect abnormal cytokine and NO production as well an unusual altered insulin production property of the organoids from IBD patients. The presence of this “inflammatory memory/imprinting” will direct a path to chronic disease, relapse/flare ups and possibly progression to malignancy. Furthermore, we can observe elevated kinase activity of the NOD2 obligate kinase, RIPK2, to suggest RIPK2-directed NFkB activity in the intestinal stem cells of patients with long standing IBD. Confirming this observation, RIPK2 inhibitors can eliminate the “inflammatory memory/imprinting” state of the 3D organoid. The concept of “inflammatory imprinting” is novel and strategic targeting of RIPK2 may be an interesting new therapeutic target for IBD None
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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 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.008 | 0.001 |
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".