Abstract LB-182: Effects of methyl donor status on intestinal tumorigenesis in ApcMin/+ mice
Bibliographic record
Abstract
Abstract The goal of the present study is to determine the effects of folate deficiency on intestinal tumorigenesis in ApcMin/+ mice, a widely used animal model for human familial adenomatous polyposis (FAP). Since folate plays an important role in maintaining methyl donor status, dietary folate levels were reduced in combination with a panel of methyl donors, including choline, methionine and vitamin B12. Although the impact of folate on colorectal cancer (CRC) has been studied extensively, its role in cancer chemoprevention remains controversial. For example, folate supplementation has been widely discussed as a strategy for lowering cancer incidence. However, excess folate has also been associated with increased cancer risk. The following studies were designed to evaluate the effects of folate deficiency on intestinal tumorigenesis in ApcMin/+ mice. In Study 1, methyl donor sufficient diet (MDS) and methyl donor deficient diet (MDD) were fed to mice, beginning at either 5 or 10 weeks of age. Intestinal tumors were evaluated at 16 weeks of age. MDD diet suppressed intestinal tumor formation in ApcMin/+ mice by ∼80% when started at 5 weeks of age. Importantly, the protective effect was lost when the MDD diet was started at 10 weeks of age, indicating an important time-dependency on cancer suppression. Gene expression profiling of normal colonic mucosa after 11 weeks on MDD diet identified the most significantly down-regulated genes related to immune response and inflammation, data that are consistent with a recently published human colon expression profiling study (Protiva et al., 2011). The cancer suppression, however, was associated with reduced food intake and lowered body weight gain (up to 40%) throughout the experimental period. To control for this effect, Study 2 was performed in which ApcMin/+ mice were pair-fed with either methyl donor sufficient (MDS) or methyl donor deficient (MDD) diet, beginning at 5 weeks of age for a total of 11 weeks. A third group received MDS ad libitum. At 16 weeks of age, intestinal tumor formation was significantly reduced (54%, p<0.001) in the caloric-restricted MDS group. In the MDD group, however, tumor suppression was almost complete (∼96%, p<0.001). Associated with tumor protection were increased numbers of apoptotic cells within the villous epithelium of the small intestine, with a concomitant reduction in cell proliferation assessed by Ki-67 and Phospho-histone H3 (pHH3). While cancer protection by methyl donor deficiency is partially dependent on reduced caloric intake, additional mechanisms dependent on altered cell turnover must be invoked to explain these results. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-182. doi:1538-7445.AM2012-LB-182
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 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".