THE ROLE OF RECEPTOR TYROSINE KINASE AXL IN PANCREATIC DUCTAL ADENOCARCINOMA AND ITS REGULATION BY HEMATOPOIETIC PROGENITOR KINASE 1

Pancreatic ductal adenocarcinoma (PDA) is one of the most aggressive malignancies with less than 5% of five year survival rate. New molecular markers and new therapeutic targets are urgently needed for patients with PDA. Oncogenic receptor tyrosine kinase Axl has been reported to be overexpressed in many types of human malignancies, including diffuse glioma, melanoma, osteosarcoma, and carcinomas of lung, colon, prostate, breast, ovary, esophagus, stomach, and kidney. However, the expression and functions of Axl in PDA are unclear. We hypothesized that Axl contributes to the development and progression of PDA. We examined Axl expression in 54 human PDA samples and their paired benign pancreatic tissue by immunohistochemistry, we found that Axl was overexpressed in 70% of stage II PDAs, but only 22% of benign ducts (P=0.0001). Axl overexpression was associated with higher frequencies of distant metastasis and was an independent prognostic factor for both poor overall and recurrence-free survivals in patients with stage II PDA (p = 0.03 and 0.04). Axl silencing by shRNA in pancreatic cancer cell lines, panc-28 and Panc-1, decreased tumor cell migration and invasion and sensitized PDA cells to apoptosis stimuli such as γ-irradiation and serum starvation. In addition, we found that Axl-mediated Akt and NF-κB activation and up regulation of MMP2 were involved in the invasion, migration and survival of PDA cells. Thus, we demonstrate that Axl plays an important role in the development and progression of PDA. Targeting Axl signaling pathway may represent a new approach for the treatment of PDA. To understand the molecular mechanisms of Axl overexpression in PDA, we found that Axl expression was down-regulated by hematopoietic progenitor kinase 1 (HPK1), a newly identified tumor suppressor in PDA. HPK1 is lost in over 95% of PDAs. Restoration of HPK1 in PDA cells down-regulated Axl expression. HPK1-mediated Axl degradation was inhibited by leupeptin, baflomycin A1, and monensin, suggesting that HPK1-mediated Axl degradation was through endocytosis-lysosome pathway. HPK1 interacted with and phosphorylated dynamin, a critical component of endocytosis pathway. Overexpression of dominant negative form of dynamin blocked the HPK1-mediated Axl degradation. Therefore we concluded that HPK1-mediated Axl degradation was through endocytosis-lysosome pathway and loss of HPK1 expression may contribute to Axl overexpression in PDAs.

The Choosing Healthy Options of Starches (CHOOS) diet and dietary intake self-monitoring for weight loss among adolescent females

Previous research has shown dietary intake self-monitoring, and culturally tailored weight loss interventions to be effective tools for weight loss. Technology can be used to tailor weight loss interventions to better suit adolescents. There is a lack of research to date on the use of personal digital assistants (PDAs) to self-monitor dietary intake among adolescents. The objective of this study was to determine the difference in dietary intake self-monitoring frequency between using a Personal Digital Assistant (PDA) or paper logs as a diet diary in obese adolescent females; and to describe differences in diet adherence, as well as changes in body size and self-efficacy to resist eating. We hypothesized dietary intake self-monitoring frequency would be greater during PDA use than during paper log use. This study was a randomized crossover trial. Participants recorded their diet for 4 weeks: 2 weeks on a PDA and 2 weeks on paper logs. Thirty-four obese females ages 12-20 were recruited for participation. Thirty were included in analyses. Participants recorded more entries/day while using the paper logs (4.10 entries/day ± 0.63) than while using the PDA (3.01 entries/day ±0.75) (p<0.001). Significantly more meals and snacks were skipped during paper log use (0.81/day ± 0.65) than during PDA use (0.23/day ± 0.22) (p=0.011). Changes in body size (BMI, weight, and waist circumference) and self-efficacy to resist eating did not differ significantly between PDA and paper log use. When compared to paper logs, participants felt the PDA was more convenient (p=0.020), looked forward to using the PDA more (p=0.008), and would rather continue using the PDA than the paper logs (p=0.020). The findings of this study indicate use of a PDA as a dietary intake self-monitoring tool among adolescents would not result in increased dietary intake self-monitoring to aid in weight loss. Use of paper logs would result in greater data returned to clinicians, though use of PDAs would likely get adolescents more excited about adhering to recommendations to record their diet. Future research should look at updated communication devices, such as cell phones and other PDAs with additional features, and the role they can play in increasing dietary intake self-monitoring among adolescents.^