Metformin inhibits urothelial tumorigenesis in the UPII-mutant Ha-ras transgenic mouse model
Bibliographic record
Abstract
Background Bladder cancer occurs mainly in older people and is expensive to manage. As the population continues to age, bladder cancer may remain to be a major public health burden. Therefore, we hypothesized that an agent, like metformin, with anti-aging property could have preventive activity against the development and progression of human urinary bladder cancer. Materials and methods The UPII mutant Ha-ras transgenic mouse model mimics human papillary transitional urothelial cell carcinoma and exhibits enhanced mTOR activity in tumor tissues. Homozygous UPII mutant Ha-ras transgenic mice were identified through genotyping using the Southern blotting method. Genotyped Ha-ras mice were then fed orally with normal drinking water or 0.1% or 0.05% metformin in drinking water starting at 6 weeks of age and ending at 6 months of age. Death rate, body weight, tumor burden, and proliferative and apoptotic indices at the end of treatments will be evaluated by pathological and statistical analyses. Results About 62% of male, homozygous mutant Ha-ras transgenic mice which drank normal water died of urinary tract obstruction and hydronephrosis within 6 months of age, while only about 11% or 15% of mice which drank 0.1% or 0.05% metformin containing water died. Drinking metformin dramatically increased the survival of mutant Ha-ras tumor bearing mice by 51 to 47% (Ps<0.01). Metformin drinking also significantly decreased the mean bladder weights of male, homozygous mutant Ha-ras transgenic mice by up to 62%. Histological analysis of H&E stained bladder sections from metformin treated mice demonstrated more differentiated tumors compared to those in control groups. The in vivo mechanisms of metformin’s action are associated with anti-proliferation, reduction of phospho-mTOR and 4E-BP1 expression and induction of TSC2 expression in bladder tissues. Conclusions Our results demonstrated strong in vivo anti-urothelial tumorigenesis activity of metformin drinking in the UPIImutant H-ras model via inhibition of the mTOR pathway. These results suggested the potential of metformin in preventing recurrence of clinical bladder cancer and in improving quality of life for patients.
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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 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".