Ki-ras oncogene mutations in chronic pancreatitis: which discriminating ability for malignant potential?

Ki-ras mutations are found in the majority of pancreatic adenocarcinomas (85-100%). Ki-ras analysis was increasingly used in ERCP samples in order to differentiate between chronic pancreatitis and pancreatic cancer. However, its sensitivity was recently reported to be low due to a high prevalence of ras mutations in patients with chronic pancreatitis (25-37%). Detection of Ki-ras mutations in microdissected pancreata confirmed their high frequency (55-83%) in pancreatic intraductal lesions (PILs) observed in chronic pancreatitis specimens and in the vicinity of invasive pancreatic carcinoma. There is now molecular evidence that PILs can be precursors of invasive carcinoma, since they can harbor genetic alterations identical to those of the adjacent carcinoma. Similarly, we observed 2 patients with chronic pancreatitis who developed pancreatic cancer 18 and 24 months after the evidence of Ki-ras mutations in pancreatic brushings. However, besides these findings, ras mutations were also identified in nondiseased pancreata coming from autopsy series. The current data on ras analysis in pancreatic juice and brushings or in microdissected pancreata suggest that PILs with Ki-ras mutations do not inevitably lead toward invasive carcinoma. Ki-ras mutations probably have a low discriminating ability for malignant potential and their detection in pancreatic juice is not justified routinely for differentiating between benign and malignant pancreatic diseases. However, prospective follow-up of patients with chronic pancreatitis harboring a mutant ras is probably of major interest by combining the search for other genetic markers that have the ability to characterize patients with the greater risk of malignant transformation.Journal ArticleReviewFLWINinfo:eu-repo/semantics/publishedCell and Molecular Biology of Pancreatic Carcinomaa: Recent Developments in Research and Experimental Therap

Evidence for functional ATP-sensitive (K ATP) potassium channels in human and equine articular chondrocytes

Chondrocytes are highly sensitive to variations in extracellular glucose and oxygen levels in the extracellular matrix. As such, they must possess a number of mechanisms to detect and respond to alterations in the metabolic state of cartilage. In other organs such as the pancreas, heart and brain, such detection is partly mediated by a family of potassium channels known as K ATP (adenosine 5′-triphosphate-sensitive potassium) channels. Here we investigate whether chondrocytes too express functional K ATP channels, which might, potentially, serve to couple metabolic state with cell activity. Immunohistochemistry was used to explore K ATP channel expression in equine and human chondrocytes. Biophysical properties of equine chondrocyte K ATP channels were investigated with patch-clamp electrophysiology. Polyclonal antibodies directed against the K ATP Kir6.1 subunit revealed high levels of expression in human and equine chondrocytes mainly in superficial and middle zones of normal cartilage. Kir6.1 was also detected in superficial chondrocytes in osteoarthritic (OA) cartilage. In single-channel electrophysiological studies of equine chondrocytes, we found K ATP channels to have a maximum unitary conductance of 47 ± 9 pS ( n = 5) and a density of expression comparable to that seen in excitable cells. We have shown, for the first time, functional K ATP channels in chondrocytes. This suggests that K ATP channels are involved in coupling metabolic and electrical activities in chondrocytes through sensing of extracellular glucose and intracellular adenosine triphosphate (ATP) levels. Altered K ATP channel expression in OA chondrocytes may result in impaired intracellular ATP sensing and optimal metabolic regulation