Cyclooxygenase-2 expression is up-regulated in human pancreatic cancer.
(17/9206)
A large body of evidence suggests that cyclooxygenase-2 (COX-2) is important in gastrointestinal cancer. The purpose of this study was to determine whether COX-2 was expressed in adenocarcinoma of the human pancreas. Quantitative reverse transcription-PCR, immunoblotting, and immunohistochemistry were used to assess the expression of COX-2 in pancreatic tissue. Levels of COX-2 mRNA were increased by >60-fold in pancreatic cancer compared to adjacent nontumorous tissue. COX-2 protein was present in 9 of 10 cases of adenocarcinoma of the pancreas but was undetectable in nontumorous pancreatic tissue. Immunohistochemical analysis showed that COX-2 was expressed in malignant epithelial cells. In cultured human pancreatic cancer cells, levels of COX-2 mRNA and protein were induced by treatment with tumor-promoting phorbol esters. Taken together, these results suggest that COX-2 may be a target for the prevention or treatment of pancreatic cancer. (+info)
Pancreatic polypeptide hyperplasia causing watery diarrhea syndrome: a case report.
(18/9206)
Neuroendocrine tumours of the pancreas can secrete numerous peptides, leading to various recognizable clinical syndromes. The secretion of pancreatic polypeptide has been used as a marker for neuroendocrine tumours but is considered to be a biologically inert peptide. A 37-year-old woman had watery diarrhea syndrome from pancreatic polypeptide hyperplasia. Only 2 other reported cases in the literature have described pancreatic polypeptide hyperplasia; however, this is the first reported case in which the patient was successfully treated by surgical resection, with a 2-year follow-up. This report and review of the literature illustrate that pancreatic polypeptide hypersecretion may present as a clinical endocrinopathy. (+info)
The Hdj-2/Hsc70 chaperone pair facilitates early steps in CFTR biogenesis.
(19/9206)
The cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride ion channel constructed from two membrane-spanning domains (MSDs), two nucleotide-binding domains (NBD) and a regulatory (R) domain. The NBDs and R-domain are cytosolic and how they are assembled with the MSDs to achieve the native CFTR structure is not clear. Human DnaJ 2 (Hdj-2) is a co-chaperone of heat shock cognate 70 (Hsc70) which is localized to the cytosolic face of the ER. Whether Hdj-2 directs Hsc70 to facilitate the assembly of cytosolic regions on CFTR was investigated. We report that immature ER forms of CFTR and DeltaF508 CFTR can be isolated in complexes with Hdj-2 and Hsc70. The DeltaF508 mutation is localized in NBD1 and causes the CFTR to misfold. Levels of complex formation between DeltaF508 CFTR and Hdj-2/Hsp70 were approximately 2-fold higher than those with CFTR. The earliest stage at which Hdj-2/Hsc70 could bind CFTR translation intermediates coincided with the expression of NBD1 in the cytosol. Interestingly, complex formation between Hdj-2 and nascent CFTR was greatly reduced after expression of the R-domain. In experiments with purified components, Hdj-2 and Hsc70 acted synergistically to suppress NBD1 aggregation. Collectively, these data suggest that Hdj-2 and Hsc70 facilitate early steps in CFTR assembly. A putative step in the CFTR folding pathway catalyzed by Hdj-2/Hsc70 is the formation of an intramolecular NBD1-R-domain complex. Whether this step is defective in the biogenesis of DeltaF508 CFTR will be discussed. (+info)
Chemotherapy for advanced pancreatic cancer: it may no longer be ignored.
(20/9206)
Two case histories are reported here in which a chemotherapeutic approach improved the clinical conditions of patients with advanced pancreatic cancer. Until recently, chemotherapy was considered ineffective in pancreatic cancer, and most oncologists treated these patients with best-supportive-care only. Enthusiasm for systemic therapy of advanced pancreatic cancer is again growing, spurred by the advent of new drugs and new treatment endpoints such as life quality and symptom palliation. Gemcitabine, the most intensively-investigated new drug in pancreatic cancer, has shown an advantage in both survival and clinical benefit over that of 5-fluorouracil (5-FU). Other new drugs such as taxanes have shown interesting levels of activity, and are deserving of further evaluation. Although these results are far from conclusive and are only partially satisfactory, they represent a significant step forward in the treatment of advanced pancreatic cancer. (+info)
Reexploration for periampullary carcinoma: resectability, perioperative results, pathology, and long-term outcome.
(21/9206)
OBJECTIVE: This single-institution experience retrospectively reviews the outcomes of patients undergoing reexploration for periampullary carcinoma at a high-volume center. SUMMARY BACKGROUND DATA: Many patients are referred to tertiary centers with periampullary carcinoma after their tumors were deemed unresectable at previous laparotomy. In carefully selected patients, tumor resection is often possible; however, the perioperative results and long-term outcome have not been well defined. METHODS: From November 1991 through December 1997, 78 patients who underwent previous exploratory laparotomy and/or palliative surgery for suspected periampullary carcinoma underwent reexploration. The operative outcome, resectability rate, pathology, and long-term survival rate were compared with 690 concurrent patients who had not undergone previous exploratory surgery. RESULTS: Fifty-two of the 78 patients (67%) undergoing reexploration underwent successful resection by pancreaticoduodenectomy; the remaining 26 patients (34%) were deemed to have unresectable disease. Compared with the 690 patients who had not undergone recent related surgery, the patients in the reoperative group were similar with respect to gender, race, and resectability rate but were significantly younger. The distribution of periampullary cancers by site in the reoperative group undergoing pancreaticoduodenectomy (n = 52) was 60%, 19%, 15%, and 6% for pancreatic, ampullary, distal bile duct, and duodenal tumors, respectively. These figures were similar to the 65%, 14%, 16% and 5% for resectable periampullary cancers found in the primary surgery group (n = 460). Intraoperative blood loss and transfusion requirements did not differ between the two groups. However, the mean operative time was 7.4 hours in the reoperative group, significantly longer than in the control group. On pathologic examination, reoperative patients had smaller tumors, and the percentage of patients with positive lymph nodes in the resection specimen was significantly less. The incidence of positive margins was similar between the two groups. Postoperative lengths of stay, complication rates, and perioperative mortality rates were not higher in reoperative patients. The long-term survival rate was similar between the two resected groups, with a median survival of 24 months in the reoperative group and 20 months in those without previous exploration. CONCLUSIONS: These data demonstrate that patients undergoing reoperation for periampullary carcinoma have similar resectability, perioperative morbidity and mortality, and long-term survival rates as patients undergoing initial exploration. The results suggest that selected patients considered to have unresectable disease at previous surgery should undergo restaging and reexploration at specialized high-volume centers. (+info)
Essential role of caspase-3 in apoptosis of mouse beta-cells transfected with human Fas.
(22/9206)
Several recent studies have indicated that the Fas-Fas ligand system may be critical for pancreatic beta-cell destruction in type 1 diabetes. Although the fundamental roles of caspases in the mammalian apoptotic machinery have been elucidated, it is not known which caspase or caspases play a major role in Fas-mediated apoptosis of beta-cells. In this study, we transfected human Fas cDNA into a mouse beta-cell line (betaTC1) and established a beta-cell clone expressing human Fas. This clone, designated hFas/betaTC1, underwent apoptosis when exposed to anti-Fas, showing hallmarks of apoptosis (chromatin condensation, nucleolar disintegration, internucleosomal DNA fragmentation, and annexin V staining), indicating that the mouse beta-cell line has the intact machinery of Fas-mediated apoptosis. The cross-linking of Fas by anti-Fas resulted in the elevation of caspase-3-like, but not caspase-1-like, protease activity 2-12 h after the addition of the anti-Fas. A caspase-3 inhibitor, Z-Asp-Glu-Val-Asp-fluoromethyl ketone, attenuated the Fas-mediated beta-cell apoptosis, while a caspase-1 inhibitor, acetyl-Tyr-Val-Ala-Asp-chloromethylketone, failed to suppress the apoptosis. Thus the Fas-induced death signal apparently bypassed caspase-1 in the cells. Furthermore, an antisense caspase-3 construct blocked caspase-3 activation and substantially suppressed Fas-triggered apoptosis of hFas/betaTC1 cells. These observations suggest the essential role of caspase-3 in Fas-mediated apoptosis of the beta-cell line. (+info)
Site-specific phosphorylation of synapsin I by Ca2+/calmodulin-dependent protein kinase II in pancreatic betaTC3 cells: synapsin I is not associated with insulin secretory granules.
(23/9206)
Increasing evidence supports a physiological role of Ca2+/calmodulin-dependent protein kinase II (CaM kinase II) in the secretion of insulin from the pancreatic beta-cell, but the precise sites of action are not known. A role of this enzyme in neuroexocytosis is implicated by its phosphorylation of a vesicle-associated protein, synapsin I. Because of emerging similarities to the neuron with respect to exocytotic mechanisms, the expression and phosphorylation of synapsin I in the beta-cell have been studied. Synapsin I expression in clonal mouse beta-cells (betaTC3) and primary rat islet beta-cells was initially confirmed by immunoblot analysis. By immunoprecipitation, in situ phosphorylation of synapsin I was induced in permeabilized betaTC3 cells within a Ca2+ concentration range shown to activate endogenous CaM kinase II under identical conditions. Proteolytic digests of these immunoprecipitates revealed that calcium primarily induced the increased phosphorylation of sites identified as CaM kinase II-specific and distinct from protein kinase A-specific sites. Immunofluorescence and immunogold electron microscopy verified synapsin I expression in betaTC3 cells and pancreatic slices but demonstrated little if any colocalization of synapsin I with insulin-containing dense core granules. Thus, although this study establishes that synapsin I is a substrate for CaM kinase II in the pancreatic beta-cell, this event appears not to be important for the mobilization of insulin granules. (+info)
Molecular cloning of a pancreatic islet-specific glucose-6-phosphatase catalytic subunit-related protein.
(24/9206)
A pancreatic islet-specific glucose-6-phosphatase-related protein (IGRP) was cloned using a subtractive cDNA expression cloning procedure from mouse insulinoma tissue. Two alternatively spliced variants that differed by the presence or absence of a 118-bp exon (exon IV) were detected in normal balb/c mice, diabetic ob/ob mice, and insulinoma tissue. The longer, 1901-bp full-length cDNA encoded a 355-amino acid protein (molecular weight 40,684) structurally related (50% overall identity) to the liver glucose-6-phosphatase and exhibited similar predicted transmembrane topology, conservation of catalytically important residues, and the presence of an endoplasmic reticulum retention signal. The shorter transcript encoded two possible open reading frames (ORFs), neither of which possessed His174, a residue thought to be the phosphoryl acceptor (Pan CJ, Lei KJ, Annabi B, Hemrika W, Chou JY: Transmembrane topology of glucose-6-phosphatase. J Biol Chem 273:6144-6148, 1998). Northern blot and reverse transcription-polymerase chain reaction analysis showed that the mRNA was highly expressed in pancreatic islets and expressed more in beta-cell lines than in an alpha-cell line. It was notably absent in tissues and cell lines of non-islet neuroendocrine origin, and no other major tissue source of the mRNA was found. During development, it was expressed in parallel with insulin mRNA. The mRNA was efficiently translated and glycosylated in an in vitro translation/membrane translocation system and readily transcribed into COS 1, HIT, and CHO cells using cytomegalovirus or Rous sarcoma virus promoters. Whereas the liver glucose-6-phosphatase showed activity in these transfection systems, the IGRP failed to show glucose phosphotransferase or phosphatase activity with p-nitrophenol phosphate, inorganic pyrophosphate, or a range of sugar phosphates hydrolyzed by the liver enzyme. While the metabolic function of the enzyme is not resolved, its remarkable tissue-specific expression warrants further investigation, as does its transcriptional regulation in conditions where glucose responsiveness of the pancreatic islet is altered. (+info)