MicroRNAs targeting oncogenes are down-regulated in pancreatic malignant transformation from benign tumors

BACKGROUND MicroRNA (miRNA) expression profiles have been described in pancreatic ductal adenocarcinoma (PDAC), but these have not been compared with pre-malignant pancreatic tumors. We wished to compare the miRNA expression signatures in pancreatic benign cystic tumors (BCT) of low and high malignant potential with PDAC, in order to identify miRNAs deregulated during PDAC development. The mechanistic consequences of miRNA dysregulation were further evaluated. METHODS Tissue samples were obtained at a tertiary pancreatic unit from individuals with BCT and PDAC. MiRNA profiling was performed using a custom microarray and results were validated using RT-qPCR prior to evaluation of miRNA targets. RESULTS Widespread miRNA down-regulation was observed in PDAC compared to low malignant potential BCT. We show that amongst those miRNAs down-regulated, miR-16, miR-126 and let-7d regulate known PDAC oncogenes (targeting BCL2, CRK and KRAS respectively). Notably, miR-126 also directly targets the KRAS transcript at a "seedless" binding site within its 3'UTR. In clinical specimens, miR-126 was strongly down-regulated in PDAC tissues, with an associated elevation in KRAS and CRK proteins. Furthermore, miR-21, a known oncogenic miRNA in pancreatic and other cancers, was not elevated in PDAC compared to serous microcystic adenoma (SMCA), but in both groups it was up-regulated compared to normal pancreas, implicating early up-regulation during malignant change. CONCLUSIONS Expression profiling revealed 21 miRNAs down-regulated in PDAC compared to SMCA, the most benign lesion that rarely progresses to invasive carcinoma. It appears that miR-21 up-regulation is an early event in the transformation from normal pancreatic tissue. MiRNA expression has the potential to distinguish PDAC from normal pancreas and BCT. Mechanistically the down-regulation of miR-16, miR-126 and let-7d promotes PDAC transformation by post-transcriptional up-regulation of crucial PDAC oncogenes. We show that miR-126 is able to directly target KRAS; re-expression has the potential as a therapeutic strategy against PDAC and other KRAS-driven cancers

Η αιμοδυναμική φαρμακινητική μελέτη της Fenoldopam σε ασθενείς με κίρρωση του ύπατος

In the present study the haemodynamic and pharmacodynamic effects, as well as the pharmacokynetics of fenoldopam, a selective agonist of the postsynaptic dopaminergic receptors were studied, in patients with liver cirrhosis. A pilot study of intravenously administered fenoldopam was initially carried out in 5 patients, in increasing doses od 0,05 to 1,6 μg /kg/min. On the basis of the results, the dose to be used in the haemodynamic study (0,05, 0,5, 1 and 1,6 μg/kg.min) was defined, each infusion lasting for 30 minutes. In this study the haemodynamic effect of fenoldpam was assessed, on the systematic and splanchic haemodynamic parameters, in 12 patients with cirrhosis and portal hypertention (in 6 with compensated and 6 with decompensated liver disease). Finally, a pharmacokinetic asseaament of fenoldopam was carried out, in another 12 patients with compensated cirrhosis. In these patients fenoldopam was given either per os (50 mg) or interavenously (0,5 μg/kg/min for 2 hours) in a radom order in two different days at least one week apart. Intravenous fenoldopam administration resulted in dose dependent reduction in blood pressure and reduction of the systemic Vascular resistance with concomitant increase in cardiac output. The portial pressure was significantly increased due to increase in portial blod flow, as a result of splanchnic atrerial vasodilation. All the haemodynamic parametrs were rapidly returned to baseline, 30 minutes after stopping the drug infusion.ABSTRACT TRUNCATE

Surgery remains the best option for the management of pain in patients with chronic pancreatitis: A systematic review and meta-analysis

Controversy related to endoscopic or surgical management of pain in patients with chronic pancreatitis remains. Despite improvement in endoscopic treatments, surgery remains the best option for pain management in these patients

Surgery remains the best option for the management of pain in patients with chronic pancreatitis: A systematic review and meta-analysis

Controversy related to endoscopic or surgical management of pain in patients with chronic pancreatitis remains. Despite improvement in endoscopic treatments, surgery remains the best option for pain management in these patients

Diagnostic utility of single-user peroral cholangioscopy in sclerosing cholangitis.

Abstract Objective. To evaluate the diagnostic utility of single-operator peroral cholangioscopy (SOC) in patients with sclerosing cholangitis. Methods. All patients with sclerosing cholangitis who underwent SOC procedures due to suspicious biliary strictures, in one Swedish and four UK tertiary centers in 2008-2012, were retrospectively enrolled. For each SOC procedure in sclerosing cholangitis, another one attempted due to a single biliary stricture in the same center and calendar year was randomly selected as control. Patients were followed up until death or last clinic visit until November 2012. Results. Fifty-four SOC procedures were attempted in 52 sclerosing cholangitis patients (48 with primary sclerosing cholangitis, 4 with IgG4-related sclerosing cholangitis). Cannulation with the SOC system failed more frequently in sclerosing cholangitis (15% vs. 2% in controls; p = 0.015). The sensitivity, specificity, and accuracy of SOC (including tissue sampling) for cancer diagnosis were similar in sclerosing cholangitis and controls (50% vs. 55%, 100% vs. 97%, and 88% vs. 80%, respectively) with largely overlapping confidence intervals. Adverse events were more common in sclerosing cholangitis, due to an increased frequency of cholangitis (11% vs. 2% in controls; p = 0.051). Conclusions. SOC is equally accurate in cancer diagnosis in sclerosing cholangitis and patients with single biliary strictures. However, cholangioscope insertion may be hampered by bile duct narrowing and post-SOC cholangitis is more common in sclerosing cholangitis