Munish Ashat

Risk factors for pancreatic cancer: underlying mechanisms and potential targets

Purpose of the review: Pancreatic cancer is extremely aggressive, forming highly chemo-resistant tumors, and has one of the worst prognoses. The evolution of this cancer is multi-factorial. Repeated acute pancreatic injury and inflammation are important contributing factors in the development of pancreatic cancer. This article attempts to understand the common pathways linking pancreatitis to pancreatic cancer. Recent findings: Intracellular activation of both pancreatic enzymes and the transcription factor NF-κB are important mechanisms that induce acute pancreatitis (AP). Recurrent pancreatic injury due to genetic susceptibility, environmental factors such as smoking, alcohol intake, and conditions such as obesity lead to increases in oxidative stress, impaired autophagy and constitutive activation of inflammatory pathways. These processes can stimulate pancreatic stellate cells, thereby increasing fibrosis and encouraging chronic disease development. Activation of oncogenic Kras mutations through inflammation, coupled with altered levels of tumor suppressor proteins (p53 and p16) can ultimately lead to development of pancreatic cancer. Summary: Although our understanding of pancreatitis and pancreatic cancer has tremendously increased over many years, much remains to be elucidated in terms of common pathways linking these conditions.

Sa1788 Tobacco Toxin NNK (4-[Methylnitrosamino]-1-[3-Pyridyl]-1-Butanone) Mediates Zymogen Activation in Murine and Human Pancreatic Acini

Clinical observations indicate that cigarette smoking is an independent and dose-dependent risk factor for acute pancreatitis. Cigarette smoke has many potentially toxic components; one of the most active and injurious is the nicotine metabolite, NNK (4-[methylnitrosamino]1-[3-pyridyl]-1-butanone). Previously we have shown in rats that NNK mediates premature zymogen activation, a pivotal early pancreatitis event. Furthermore, pharmacologic evidence indicates this response occurs through non-neuronal α7 nicotinic acetylcholine receptors (α7nAChR) on the acini. In our current study we used a genetic mouse model to confirm whether NNK mediates zymogen activation through α7nAChR. In addition, we investigated whether NNK could similarly induce zymogen activation in isolated human acinar cells. Isolated acini from C57BL6 (wild type) mice were treated for 30 minutes with 100 nM NNK and zymogen (trypsinogen) activation was measured using a fluorogenic assay. NNK increased trypsinogen activation 3-fold. The presence of non-neuronal nicotinic acetylcholine receptors (α7 nAChR), a target for NNK, was detected in wild type mouse acinar cells using PCR. Treatment of acini isolated from α7 nAChR-/mice, with NNK, did not initiate zymogen activation. To further confirm the in vitro studies, NNK was given to mice (C57BL & α7 nAChR-/-) by IP injection (100 mg/kg/hour over 6 hours) and zymogen activation was assessed. In C57BL6 mice, the in vivo NNK treatment induced zymogen activation, whereas in α7 nAChR-/mice it did not. Finally, the presence of α7 nAChR was also detected by PCR in isolated human acinar cells. Treatment of these cells with 100 nM NNK caused a 3-fold increase in zymogen activation, versus an unstimulated control, similar to that seen in wild type mice. Levels of NNK-mediated zymogen activation in human acini were also comparable to that induced by hyperstimulatory concentrations of the muscarinic agonist carbachol, an agent used to induce pancreatitis responses in human acini. These studies suggest that exposure to the tobacco toxin NNK increases zymogen activation in both murine and humanmodels of acute pancreatitis. Further, activation of anα7 nAChR on the pancreatic acinar cell may have an important role in mediating pancreatitis effects of cigarette smoke.

Risk of small intestinal bacterial overgrowth in patients receiving proton pump inhibitors versus proton pump inhibitors plus prokinetics

Intestinal dysmotility is considered a risk factor for small intestinal bacterial overgrowth (SIBO). Prokinetics improve intestinal motility and are often prescribed with proton pump inhibitors (PPIs) in patients with gastroesophageal reflux disease (GERD) and/or functional dyspepsia. The present study aimed to evaluate the prevalence of SIBO and the orocecal transit time (OCTT) in patients taking PPI compared with those taking PPI plus prokinetics.