Markers of early pancreatic cancer and its precursors are needed to improve the uniformly poor prognosis of this disease. Fatty acid synthase (FAS) catalyzes the synthesis of long-chain fatty acids and is overexpressed in most human solid tumors. We therefore evaluated serum FAS as a marker of pancreatic adenocarcinoma. FAS expression patterns in primary pancreatic adenocarcinomas, intraductal papillary mucinous neoplasms (IPMN), and chronic pancreatitis tissues were analyzed by immunohistochemistry. Serum FAS levels were determined by ELISA in 102 patients with pancreatic adenocarcinomas, in 42 patients with IPMNs, in 27 patients with chronic pancreatitis, and in 39 healthy control subjects. FAS protein was overexpressed in the ductal epithelium of 343 of 399 primary pancreatic adenocarcinomas (86.0%) and 28 of 30 IPMNs (93.3%), and in the islet and ductal cells in 3 of 54 chronic pancreatitis tissues (5.6%), whereas normal ductal epithelium lacked FAS expression. Serum FAS levels were significantly higher in patients with pancreatic ductal adenocarcinoma (first quartile median, 22.0; 4.5 ng/mL), in patients with IPMNs (20.7; 9.4 ng/mL), and in patients with chronic pancreatitis (31.1; 11.9 ng/mL) than in healthy controls (0; 0 ng/mL). FAS levels declined postoperatively in 8 of 9 patients with pancreatic adenocarcinoma and elevations of their preoperative serum FAS. In conclusion, serum FAS levels are elevated in patients with pancreatic cancer and IPMNs and are associated with neoplastic overexpression of FAS. (Cancer Epidemiol Biomarkers Prev 2009;18(9):2380-5)
Advanced glycation end-products (AGEs) initiate cellular inflammation and contribute to cardiovascular disease in the elderly. AGE can be inhibited by Alagebrium (ALT), an AGE cross-link breaker. Moreover, the beneficial effects of exercise on aging are well recognized. Thus, we investigated the effects of ALT and exercise (Ex) on cardiovascular function in a rat aging model. Compared to young (Y) rats, in sedentary old (O) rats, end-systolic elastance (Ees) decreased (0.9±0.2 vs 1.7±0.4 mm Hg/μL, P<0.05), dP/dtmax was attenuated (6054±685 vs 9540±939 mm Hg/s, P<0.05), ventricular compliance (end-diastolic pressure–volume relationship (EDPVR)) was impaired (1.4±0.2 vs 0.5±0.4 mm Hg/μL, P<0.05) and diastolic relaxation time (tau) was prolonged (21±3 vs 14±2 ms, P<0.05). In old rats, combined ALT+Ex (4 weeks) increased dP/dtmax and Ees (8945±665 vs 6054±685 mm Hg/s, and 1.5±0.2 vs 0.9±0.2 respectively, O with ALT+Ex vs O, P<0.05 for both). Diastolic function (exponential power of EDPVR and tau) was also substantially improved by treatment with Alt+Ex in old rats (0.4±0.1 vs 0.9±0.2 and 16±2 vs 21±3 ms, respectively, O with ALT+EX vs O, P<0.05 for both). Pulse wave velocity (PWV) was increased in old rats (7.0±0.7 vs 3.8± 0.3 ms, O vs Y, P<0.01). Both ALT and Ex alone decreased PWV in old rats but the combination decreased PWV to levels observed in young (4.6±0.5 vs 3.8±0.3 ms, O with ALT+Ex vs Y, NS). These results suggest that prevention of the formation of new AGEs (with exercise) and breakdown of already formed AGEs (with ALT) may represent a therapeutic strategy for age-related ventricular and vascular stiffness.
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