A ROLE FOR TGF?? IN CONTROLLING HUMAN ISLET PLASTICITY
Bibliographic record
Abstract
The plasticity of pancreatic cells is well documented in the context of both regeneration and carcinogenesis, and extends to the cells of the islet. The regenerative capacity of the pancreas is such that upon 90% pancreatectomy, the organ regains 45% of its lost endocrine cell mass within 8 weeks. However, cell types that exhibit plasticity are also subject to increased rates of carcinogenesis. TGFβ has been implicated in pancreatic regeneration and loss of TGFβ signaling is common in pancreatic cancer. Human islet-enriched fractions (>70% purity) were embedded in a type 1 collagen matrix and cultured in serum-free DMEM/F12 with 1 μM dexamethasone, 10 ng/ml EGF, 24 mU/ml insulin and 200 ng/ml cholera toxin. Over the course of 8 days, islets transformed into duct-like structures (DLS) in a process characterized by β-cell apoptosis and mantle cell transdifferentiation. These DLS express markers of pancreatic ductal epithelium as well as endocrine progenitors. These culture conditions caused 55.2 ± 4.4% (mean ± SEM) of islets to form DLS. Addition of TGFβ1 to the culture medium caused a dose-dependent decrease in DLS formation, with 10, 100 and 1000 pM TGFβ1 limiting DLS formation to 74.6 ± 2.9, 28.2 ± 5.8 and 6.2 ± 1.8% of control (p < 0.001 vs. control). Conversely, addition of neutralizing antibody (10 μg/ml) increased DLS formation rates to 129.6 ± 6.1% of control (p < 0.02), suggesting endogenous TGFβ production in islet cultures. Analysis of conditioned media samples detected as much as 0.35 ± 0.08 pM TGFβ1/2000IE·day, peaking in the first 2 days of culture and declining thereafter. Inhibition studies determined that the effects of TGFβ1 were mediated by the TGFβRI kinase and were p38 dependent. While TGFβRI and II and SMAD2 were detected in β-cells within the islet, suggesting inhibition of β-cell apoptosis as a possible mechanism of action, DLS cells expressed higher levels of these TGFβ signaling molecules. Thus, TGFβ appears to play a role in determining islet phenotype. Based on the TGFβ response, the islet-to-DLS model may be of use to study pancreatic carcinogenesis and regeneration.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| 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) | 0.000 | 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 teacher head, 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".