Overexpression of pterin-4a-carbinolamine dehydratase/dimerization cofactor of hepatocyte nuclear factor 1 in human colon cancer.

Pterin-4a-carbinolamine dehydratase (PCD) is a bifunctional protein also known as DCoH (dimerization co-factor of hepatocyte nuclear factor 1 (HNF1)). PCD/DCoH modulates the DNA binding specificity of HNF1, thus acting on its transcriptional activity. In addition, it participates in the recycling of tetrahydrobiopterin (BH(4)), an essential cofactor of several metabolic reactions. We investigated colorectal tumors and colorectal tumor cell lines as compared to normal colon samples in search of a potential differential expression of PCD/DCoH. Immunohistochemistry was conducted on 20 human colorectal tumors and 20 normal samples using a specific polyclonal antibody. Immunoblotting and RT-PCR analysis for PCD/DCoH and HNF1 were also performed on both human tissues and CACO-2 and HT-29 cell lines. All of the 20 tumors and both colon cancer cell lines presented a strong and widespread immunoreactivity for PCD/DCoH, contrasting with the absence of expression in the normal epithelia. We thus report the massive overexpression of PCD/DCoH in colon tumors, which is in striking contrast with the absence of staining in normal counterparts. The sharp contrast in the expression of a modulator of transcriptional activity between tumoral and normal cells may have a physiopathological role. PCD/DCoH could potentially be a new marker of malignant colon cells in vivo.

One-month mortality rate after liver transplantation for parenchymal cirrhosis: analysis of risk factors in a ten year period.

Accurate prediction of short-term survival rate after liver transplantation is one way of selecting recipients and should improve organ allocation. We observed, during the first ten years of our program a striking decline in postoperative mortality with time, a well known observation in Europe as well as in the United States. In 65 adults with parenchymal cirrhosis having received a liver transplant between 1984 and 1994, we examined the possible influence of various preoperative risk factors on one-month mortality rate which was 13.8% in this series. Univariate analysis led to the identification of five significant risk factors: date of transplantation, low serum sodium, previous history of jaundice, ascites and encephalopathy. In the final multivariate analysis however, the date of transplantation emerged as the sole predictive factor of early mortality rate. Therefore, factors such as pretransplantation state of the patient and poor hepatic reserve are counterbalanced by the improvement of surgical skill and other technical aspects, as well as by better perioperative management which have all contributed to the improved results of liver transplantation with time.

Multisystemic production of interleukin 10 limits the severity of acute pancreatitis in mice.

BACKGROUND: Interleukin 10 (IL-10) decreases the severity of experimental acute pancreatitis. The role of endogenous IL-10 in modulating the course of pancreatitis is currently unknown. AIMS: To examine the systemic release of IL-10 and its messenger RNA production in the pancrease, liver, and lungs and analyse the effects of IL-10 neutralisation in caerulein induced acute pancreatitis in mice. METHODS: Acute necrotising pancreatitis was induced by intraperitoneal caerulein. Serum levels of IL-10 and tumour necrosis factor (TNF), and tissue IL-10 and TNF-alpha gene expression were assessed. After injecting control antibody or after blocking the activity of endogenous IL-10 by a specific monoclonal antibody, the severity of acute pancreatitis was assessed in terms of serum enzyme release, histological changes, and systemic and tissue TNF production. RESULTS: In control conditions, serum IL-10 levels increased and correlated with the course of pancreatitis, with a maximal value eight hours after induction. Both IL-10 and TNF-alpha messengers showed a similar course, and were identified in the pancreas, liver, and lungs. Neutralisation of endogenous IL-10 significantly increased the severity of pancreatitis and associated lung injury as well as serum TNF protein levels (+75%) and pancreatic, pulmonary, and hepatic TNF messenger expression (+33%, +29%, +43%, respectively). CONCLUSIONS: In this non-lethal model, systemic release of IL-10 correlates with the course of acute pancreatitis. This anti-inflammatory response parallels the release of TNF and both cytokines are produced multisystemically. Endogenous IL-10 controls TNF-alpha production and plays a protective role in the local and systemic consequences of the disease.

Expression of transforming growth factor beta receptors in normal human colon and sporadic adenocarcinomas.

BACKGROUND & AIMS: An absence or a presence of mutated transforming growth factor (TGF)-beta receptors is a possible hypothesis explaining the resistance of cancer cells to the growth-inhibitory effect of TGF-beta. Mutations involving microsatellite-like regions of the type II TGF-beta receptor have been described in subgroups of colorectal cancers. The aim of this study was to investigate the expression and distribution of TGF-beta receptors in sporadic colorectal cancers and normal tissues. METHODS: Thirty-three sporadic colorectal cancers and 20 normal colonic tissues were explored by immunohistochemistry for the expression of type I and type II TGF-beta receptors. Eighteen tumor and 20 normal samples were used for radioactive thermocycling and sequencing of the two microsatellite-like regions of the type II receptor. RESULTS: Both receptors were overexpressed in tumors compared with normal samples. There was a relationship between the abundance of type II receptor expression and the degree of differentiation of the tumors but not the Dukes' staging or the localization of the neoplasias. No mutation was observed in the microsatellite-like regions of receptor II in any of the samples. CONCLUSIONS: Sporadic colorectal cancers do not show an absence or a presence of mutated TGF-beta receptors that could explain a resistance to TGF-beta-mediated growth inhibition. The pathways to tumorigenesis of sporadic colorectal cancers may be different from those of some hereditary ones.

Glucose responsiveness and acetylcholine sensitivity of pancreatic beta-cells after vagotomy.

The chronic effects of removal of parasympathetic neural input to the pancreas on in vitro insulin secretion were assessed. Groups of Wistar and Long-Evans rats received total subdiaphragmatic vagotomy or sham operation. Four to ten weeks later, after the return of food intake and body weight in the vagotomized groups to values similar to the sham-operated groups, pancreatic islets were isolated and statically incubated with selected concentrations of glucose and acetylcholine. Two experimental protocols were used. In the first experiment, insulin secretion in response to basal (5 mM) glucose was 59 +/- 15 (SE) and 65 +/- 13% greater in islets from the vagotomized Wistar and Long-Evans groups, respectively, than in the corresponding sham groups. The enhancement of insulin secretion by several doses of acetylcholine observed in islets from sham-operated groups was totally absent in islets from both vagotomized strains. In the second experiment, insulin secretion was determined in response to selected glucose concentrations by using islets from Wistar rats. An upward and leftward shift of the dose-response curve was observed in the vagotomized group causing 5 mM to become a stimulatory glucose concentration and increasing the stimulatory potency of 10 mM glucose. These results suggest that interruption of vagal input to pancreatic beta-cells may induce a compensatory increase in responsiveness to glucose and a functional suppression of acetylcholine receptors. These data provide further support for the hypothesis that vagal input plays a functionally important role in the control of insulin secretion and maintenance of acetylcholine sensitivity.