Down's syndrome suppression of tumour growth and the role of the calcineurin inhibitor DSCR1.

The incidence of many cancer types is significantly reduced in individuals with Down's syndrome, and it is thought that this broad cancer protection is conferred by the increased expression of one or more of the 231 supernumerary genes on the extra copy of chromosome 21. One such gene is Down's syndrome candidate region-1 (DSCR1, also known as RCAN1), which encodes a protein that suppresses vascular endothelial growth factor (VEGF)-mediated angiogenic signalling by the calcineurin pathway. Here we show that DSCR1 is increased in Down's syndrome tissues and in a mouse model of Down's syndrome. Furthermore, we show that the modest increase in expression afforded by a single extra transgenic copy of Dscr1 is sufficient to confer significant suppression of tumour growth in mice, and that such resistance is a consequence of a deficit in tumour angiogenesis arising from suppression of the calcineurin pathway. We also provide evidence that attenuation of calcineurin activity by DSCR1, together with another chromosome 21 gene Dyrk1a, may be sufficient to markedly diminish angiogenesis. These data provide a mechanism for the reduced cancer incidence in Down's syndrome and identify the calcineurin signalling pathway, and its regulators DSCR1 and DYRK1A, as potential therapeutic targets in cancers arising in all individuals.

In a Randomized, Placebo-Controlled Cross-Over Study, Administration of 6 and 12 G Fortetropin® Does Not Reduce Serum Myostatin in Healthy Adult Dogs Over 72-Hours.

Objective: To evaluate the effect of a single administration of 6 and 12 g of Fortetropin compared to placebo on serum myostatin in healthy, adult dogs over a 72-h period. Methods: Prospective, placebo-controlled, randomized, double-blind, crossover study. Ten hospital-employee-owned healthy adult dogs aged 2 to 8 years old were enrolled in the study. Blood samples were collected prior to and then 12-, 24-, 36-, 48-, and 72-h following administration of the test agent (6 and 12 g) or placebo. Serum samples were processed according to manufacturer's guidelines for canine serum using GDF-8/Myostatin Quantikine ELISA kit (R&D Systems). Analysis-of-variance (ANOVA) analyses were carried out where P < 0.05 was deemed significant. Results: Mean serum myostatin was not significantly lower in treatment groups of either low or high dose compared to placebo at any time point. Baseline mean serum myostatin in low and high dose treatment groups was 29,481 (SD = 5,224) and 32,214 pg/mL (SD = 7,353), respectively. Placebo group low and high dose baseline mean serum myostatin was 30,247 (SD = 5,875) and 28,512 (SD = 5,028). Conclusion: The results of this study indicate that administration of single 6 or 12 g dose of Fortetropin does not reduce serum myostatin in healthy adult dogs over a 72-h period. Clinical Importance: Oral supplements, like Fortetropin, require further studies to determine the efficacy and bioavailability in order to guide clinical use in dogs.