The nuclear factor of activated T cell (NFAT) proteins are a family of Ca 2 þ /calcineurin-responsive transcription factors primarily recognized for their central roles in T lymphocyte activation and cardiac valve development. We demonstrate that NFATc1 is commonly overexpressed in pancreatic carcinomas and enhances the malignant potential of tumor cells through transcriptional activation of the c-myc oncogene. Activated NFATc1 directly binds to a specific element within the proximal c-myc promoter and upregulates c-myc transcription, ultimately resulting in increased cell proliferation and enhanced anchorageindependent growth. Conversely, c-myc transcription and anchorage-dependent and -independent cell growth is significantly attenuated by inhibition of Ca 2 þ /calcineurin signaling or siRNA-mediated knock down of NFATc1 expression. Together, these results demonstrate that ectopic activation of NFATc1 and the Ca 2 þ /calcineurin signaling pathway is an important mechanism of oncogenic c-myc activation in pancreatic cancer.

Background & Aims: Induction of immediate early transcription factors (ITF) represents the first transcriptional program controlling mitogen stimulated cell cycle progression in cancer. Here, we examined the transcriptional mechanisms regulating the ITF protein c-Myc and its role in pancreatic cancer growth in vitro and in vivo. Methods: Expression of ITF proteins were examined by RT-PCR and immunoblotting, and their implications in cell cycle progression and growth were determined by flow cytometry and [3H] thymidine incorporation. Intracellular Ca2+ concentrations, calcineurin activity and cellular NFAT distribution were analyzed. Transcription factor complex formations and promoter regulation were examined by immunoprecipitations, reporter gene assays and chromatin immunoprecipitation (ChIP). Using a combination of RNAi knockdown technology and xenograft models we analyzed the significance for pancreatic cancer tumor growth. Results: Serum promotes pancreatic cancer growth through induction of the proproliferative NFAT-c-Myc axis. Mechanistically, serum increases intracellular Ca2+ concentrations and activates the calcineurin/NFAT pathway to induce c-Myc transcription. NFAT binds to a serum responsive element within the proximal promoter, initiates p300-dependent histone acetylation and creates a local chromatin structure permissive for the inducible recruitment of ELK-1, a protein required for maximal activation of the c-Myc promoter. The functional significance of this novel pathway was emphasized by impaired c-Myc expression, G1-arrest and reduced tumor growth upon NFAT depletion in vitro and in vivo. Conclusion: Our study uncovers a novel mechanism regulating cell growth and identifies the NFAT-ELK complex as modulators of early stages of mitogen stimulated proliferation in pancreatic cancer cells.

Background: Duodenogastroesophageal reflux (DGER) is considered an independent risk factor for complicated reflux disease (gastroesophageal reflux disease; GERD). However, the role of DGER in GERD patients refractory to proton pump inhibitors (PPI) remains poorly understood. Methods: 85 patients with clinical reflux symptoms and a history of ineffective response to PPIs were enrolled in the study. Patients with elevated reflux measurement (pH and/or Bilitec measurement; n = 47) received pantoprazole 80 mg for 8 weeks. Clinical outcome was defined as response (≤2 symptoms/week) or nonresponse (≥3 symptoms/week). Results: Of the 47 patients with elevated reflux measurement, 30 were classified as responders and 17 as nonresponders. Treatment with pantoprazole resulted in a significant reduction of acidic reflux in both PPI responders and PPI nonresponders. In contrast, DGER was only significantly reduced in the PPI responder group (22.8 ± 22.8 vs. 6.6 ± 10.8%; p < 0.05) but not in the PPI nonresponder group (24.5 ± 18.6 vs. 22.2 ± 12.7%; p > 0.05). Conclusions: The presented study firstly describes that nonresponsiveness to PPI is associated with a limited effect of PPIs on reducing DGER. Thus, persistent DGER may play a key role in mediating reflux symptoms refractory to high-dose PPIs.

BackgroundAcute pancreatitis is the most common complication of diagnostic and therapeutic endoscopic retrograde cholangiopancreatography (ERCP). In spite of continuing research, no pharmacologic agent capable of effectively reducing the incidence of ERCP-induced pancreatitis has found its way into clinical practise. A number of experimental studies suggest that intrapancreatic calcium concentrations play an important role in the initiation of intracellular protease activation, an initiating step in the course of acute pancreatitis. Magnesium can act as a calcium-antagonist and counteracts effects in calcium signalling. It can thereby attenuate the intracellular activation of proteolytic digestive enzymes in the pancreas and reduces the severity of experimental pancreatitis when administered either intravenously or as a food supplement.MethodsWe designed a randomized, double-blind, placebo-controlled phase III study to test whether the administration of intravenous magnesium sulphate before and after ERCP reduces the incidence and the severity of post-ERCP pancreatitis. A total of 502 adult patients with a medical indication for ERCP are to be randomized to receive either 4930 mg magnesium sulphate (= 20 mmol magnesium) or placebo 60 min before and 6 hours after ERCP. The incidence of clinical post-ERCP pancreatitis, hyperlipasemia, pain levels, use of analgetics and length of hospital stay will be evaluated.ConclusionsIf magnesium sulphate is found to be effective in preventing post-ERCP pancreatitis, this inexpensive agent with limited adverse effects could be used as a routine pharmacological prophylaxis.Trial registrationCurrent Controlled Trials ISRCTN46556454

Our data confirm that high-dose pantoprazole therapy effectively exerts acid suppression in GERD patients with combined pathological reflux. However, DGER could only normalised in 50 % of patients. High levels of DGER at diagnosis enhance the risk of persistent DGER under PPI therapy and are associated with a reduced clinical outcome.