Targeting S1PR1/STAT3 loop abrogates desmoplasia and chemosensitizes pancreatic cancer to gemcitabine.

Rationale: Pancreatic cancer is associated with poor prognosis with a 5-year survival rate of less than 6%. Approximately 90% of pancreatic cancer patients harbor somatic mutations in the KRAS gene. Multiple lines of evidence suggest a persistent activation of STAT3 in KRAS-driven oncogenesis contributing to desmoplasia and gemcitabine resistance. Sphingosine 1-phosphate receptor 1 (S1PR1) is an integral component of tumor progression and maintains an activated state of STAT3. FTY720 is an approved drug for multiple sclerosis and acts as a functional antagonist for S1PR1. Here we explored the potential utility of FTY720 to target S1PR1/STAT3 and other major signaling pathways in pancreatic cancer, and sought proof-of-principle for repurposing FTY720 for the treatment of pancreatic cancer. Methods: We examined the activity of FTY720 in the proliferation, apoptosis, and cell cycle assays in human and mouse pancreatic cancer model systems. Further, we studied the efficacy of using a combination of FTY720 and gemcitabine as opposed to individual agents in vitro as well as in vivoResults: Treatment of human and mouse pancreatic cancer cells with FTY720 resulted in inhibition of growth, increased apoptosis, and cell cycle arrest. FTY720 in combination with gemcitabine breached the mitochondrial membrane potential, altered the S1PR1-STAT3 loop, and inhibited epithelial to mesenchymal (EMT) transition. Data from murine models exhibited a marked reduction in the tumor size, increased apoptosis, inhibited NF-κB, S1PR1/STAT3, Shh signaling and desmoplasia, modulated the expression of gemcitabine-metabolizing transport enzymes, and restored the expression of tumor suppressor gene PP2A. Conclusion: Taken together, our results established FTY720 as a propitious molecule, which increases the efficacy of gemcitabine and represents a promising agent in the management of pancreatic cancer.

Cardamonin inhibits colonic neoplasia through modulation of MicroRNA expression.

Colorectal cancer is currently the third leading cause of cancer related deaths. There is considerable interest in using dietary intervention strategies to prevent chronic diseases including cancer. Cardamonin is a spice derived nutraceutical and herein, for the first time we evaluated the therapeutic benefits of cardamonin in Azoxymethane (AOM) induced mouse model of colorectal cancer. Mice were divided into 4 groups of which three groups were given six weekly injections of AOM. One group served as untreated control and remaining groups were treated with either vehicle or Cardamonin starting from the same day or 16 weeks after the first AOM injection. Cardamonin treatment inhibited the tumor incidence, tumor multiplicity, Ki-67 and ß-catenin positive cells. The activation of NF-kB signaling was also abrogated after cardamonin treatment. To elucidate the mechanism of action a global microRNA profiling of colon samples was performed. Computational analysis revealed that there is a differential expression of miRNAs between these groups. Subsequently, we extend our findings to human colorectal cancer and found that cardamonin inhibited the growth, induces cell cycle arrest and apoptosis in human colorectal cancer cell lines. Taken together, our study provides a better understanding of chemopreventive potential of cardamonin in colorectal cancer.

Diabetes in Asian Indians-How much is preventable? Ten-year follow-up of the Chennai Urban Rural Epidemiology Study (CURES-142).

We sought to evaluate the contribution of various modifiable risk factors to the partial population attributable risk (PARp) for diabetes in an Asian Indian population. Of a cohort of 3589 individuals, representative of Chennai, India, followed up after a period of ten years, we analyzed data from 1376 individuals who were free of diabetes at baseline. A diet risk score was computed incorporating intake of refined cereals, fruits and vegetables, dairy products, and monounsaturated fatty acid. Abdominal obesity was found to contribute the most to incident diabetes [Relative Risk (RR) 1.63(95%CI 1.21-2.20)]; (PARp 41.1% (95%CI 28.1-52.6)]. The risk for diabetes increased with increasing quartiles of the diet risk score [highest quartile RR 2.14(95% CI 1.26-3.63)] and time spent viewing television [(RR 1.84(95%CI 1.36-2.49] and sitting [(RR 2.09(95%CI 1.42-3.05)]. The combination of five risk factors (obesity, physical inactivity, unfavorable diet risk score, hypertriglyceridemia and low HDL cholesterol) could explain 80.7% of all incident diabetes (95%CI 53.8-92.7). Modifying these easily identifiable risk factors could therefore prevent the majority of cases of incident diabetes in the Asian Indian population. Translation of these findings into public health practice will go a long way in arresting the progress of the diabetes epidemic in this region.

Pattern and trend of deliberate self-harm in western Nepal.

Acts of deliberate self-harm (DSH) not only affect the people directly involved, but also have grave psychological and social impact on the family and community. In the present study, a cohort of 173 cases of DSH reported from April 2002 to March 2005 was retrospectively analyzed, by perusing the medicolegal register maintained by the Emergency Department at the Western Regional Hospital, Pokhara in the Western Development Region of Nepal. The data were entered and analyzed using SPSS Version 10.1. More than two-thirds of total cases were females. About 60% of cases were observed in the age group of 15-24 years. Poisoning (89.6%) was the most preferred method of deliberate self-harm. Organophosphate pesticides were consumed in nearly two-thirds of the poisoning cases. The majority of cases were reported during the months of May to July and had occurred during the last quarter of the day. More than a twofold increase was observed in the frequency of cases during the 3-year study period. The said observations were compared and contrasted with the available literature across the globe. The presentation is concluded by highlighting the limitations encountered in Nepal and the scope to overcome the same.