BACKGROUND & AIMS Excessive consumption of ethanol is one of the most common causes of acute and chronic pancreatitis. Alterations to the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) also cause pancreatitis. However, little is known about the role of CFTR in the pathogenesis of alcohol-induced pancreatitis. METHODS We measured CFTR activity based on chloride concentrations in sweat from patients with cystic fibrosis, patients admitted to the emergency department because of excessive alcohol consumption, and healthy volunteers. We measured CFTR levels and localization in pancreatic tissues and in patients with acute or chronic pancreatitis induced by alcohol. We studied the effects of ethanol, fatty acids, and fatty acid ethyl esters on secretion of pancreatic fluid and HCO3− , levels and function of CFTR, and exchange of Cl− for HCO3− in pancreatic cell lines as well as in tissues from guinea pigs and CFTR knockout mice after administration of alcohol. RESULTS Chloride concentrations increased in sweat samples from patients who acutely abused alcohol but not in samples from healthy volunteers, indicating that alcohol affects CFTR function. Pancreatic tissues from patients with acute or chronic pancreatitis had lower levels of CFTR than tissues from healthy volunteers. Alcohol and fatty acids inhibited secretion of fluid and HCO3− , as well as CFTR activity, in pancreatic ductal epithelial cells. These effects were mediated by sustained increases in concentrations of intracellular calcium and adenosine 3’,5’-cyclic monophosphate, depletion of adenosine triphosphate, and depolarization of mitochondrial membranes. In pancreatic cell lines and pancreatic tissues of mice and guinea pigs, administration of ethanol reduced expression of CFTR messenger RNA, reduced the stability of CFTR at the cell surface, and disrupted folding of CFTR at the endoplasmic reticulum. CFTR knockout mice given ethanol or fatty acids developed more severe pancreatitis than mice not given ethanol or fatty acids. CONCLUSIONS Based on studies of human, mouse, and guinea pig pancreata, alcohol disrupts expression and localization of the CFTR. This appears to contribute to development of pancreatitis. Strategies to increase CFTR levels or function might be used to treat alcohol-associated pancreatitis.

S U M M A R Y Heparan sulfate (HS), due to its ability to interact with a multitude of HS-binding factors, is involved in a variety of physiological and pathological processes. Remarkably diverse fine structure of HS, shaped by non-exhaustive enzymatic modifications, influences the interaction of HS with its partners. Here we characterized the HS profile of normal human and rat liver, as well as alterations of HS related to liver fibrogenesis and carcinogenesis, by using sulfation-specific antibodies. The HS immunopattern was compared with the immunolocalization of selected HS proteoglycans. HS samples from normal liver and hepatocellular carcinoma (HCC) were subjected to disaccharide analysis. Expression changes of nine HSmodifying enzymes in human fibrogenic diseases and HCC were measured by quantitative RT-PCR. Increased abundance and altered immunolocalization of HS was paralleled by elevated mRNA levels of HS-modifying enzymes in the diseased liver. The strong immunoreactivity of the normal liver for 3-O-sulfated epitope further increased with disease, along with upregulation of 3-OST-1. Modest 6-O-undersulfation of HCC HS is probably explained by Sulf overexpression. Our results may prompt further investigation of the role of highly 3-O-sulfated and partially 6-O-desulfated HS in pathological processes such as hepatitis virus entry and aberrant growth factor signaling in fibrogenic liver diseases and HCC. (J Histochem Cytochem 58:429-441, 2010)

Xp11.2 translocation carcinoma is a distinct subtype of renal cell carcinoma characterized by translocations involving the TFE3 gene. Our study included the morphological, immunohistochemical and clinicopathological examination of 28 Xp11.2 RCCs. The immunophenotype has been assessed by using CA9, CK7, CD10, AMACR, MelanA, HMB45, Cathepsin K and TFE3 immunostainings. The diagnosis was confirmed by TFE3 break-apart FISH in 25 cases. The ages of 13 male and 15 female patients, without underlying renal disease or having undergone chemotherapy ranged from 8 to 72. The mean size of the tumors was 78.5 mm. Forty-three percent of patients were diagnosed in the pT3/pT4 stage with distant metastasis in 6 cases. Histological appearance was branching-papillary composed of clear cells with voluminous cytoplasm in 13 and variable in 15 cases, including one tumor with anaplastic carcinoma and another with rhabdoid morphology. Three tumors were labeled with CA9, while CK7 was negative in all cases. Diffuse CD10 reaction was observed in 17 tumors and diffuse AMACR positivity was described in 14 tumors. The expression of melanocytic markers and Cathepsin K were seen only in 7 and 6 cases, respectively. TFE3 immunohistochemistry displayed a positive reaction in 26/28 samples. TFE3 rearrangement was detected in all the analyzed cases (25/ 25), including one with the loss of the entire labeled break-point region. The follow-up time ranged from 2 to 300 months, with 7 cancer-related deaths. In summary, Xp11.2 carcinoma is an uncommon form of renal cell carcinoma with a variable histomorphology and rather aggressive clinical course.

Biliary tract cancers are relatively common malignant gastrointestinal tumors in the elderly. Claudins are integral components of tight junctions that play important roles in maintaining epithelial cell polarity, controlling paracellular diffusion, and regulating cell growth and differentiation. The expression profile of claudins has been extensively characterized, but few reports exist on their expression in the normal and neoplastic biliary tract. Our aim was therefore to study claudins by IHC reactions in normal and neoplastic biliary tract samples. We detected that claudin expressions differ in the normal sample groups: the normal gallbladder strongly expressed claudin-2, −3, −4, and −10, but only weak reactions were seen in normal intrahepatic bile ducts. Although each cancer type expressed several claudins with various intensities, only claudin-4 presented especially strong immunoreactions in extrahepatic bile duct cancers and gallbladder carcinomas, whereas claudin-1 and −10 presented in intrahepatic bile duct cancers. Comparing the normal and carcinoma groups, the most significant decrease was detected in the expression of claudin-10. In conclusion, the expression pattern of claudins is different in the various parts of the normal and neoplastic biliary tract; moreover, an unequivocal decrease was detected in the carcinomas compared with their corresponding normal samples. This manuscript contains online supplemental material at http://www.jhc.org . Please visit this article online to view these materials.

This is the first report to describe the tricellulin expression profile in normal and neoplastic human pancreas. Both normal and neoplastic pancreatic exocrine tissues expressed tricellulin, whereas no expression was seen in normal or neoplastic endocrine cells. Tricellulin expression in pancreatic ductal adenocarcinomas showed a significant negative correlation with the degree of differentiation.