Nonpolypoid colorectal neoplasms: a challenge in endoscopic surveillance of patients with Lynch syndrome

Background and study aims: Patients with Lynch syndrome may develop colorectal cancer (CRC), despite intensive colonoscopic surveillance. Nonpolypoid colorectal neoplasms might be a major contributor to the occurrence of these cancers. The aim of this case - control study was to compare the endoscopic appearance of colorectal neoplasms between patients with Lynch syndrome and control individuals at average risk for CRC. Patients and methods: The endoscopists at the Maastricht University Medical Center were first given training to ensure familiarity with the appearance and classification of nonpolypoid lesions. Patients with Lynch syndrome and patients at average risk for CRC who underwent elective colonoscopy at the Center were prospectively included. Nonpolypoid lesions were defined as lesions with a height of less than half the diameter, and advanced histology was defined as the presence of high grade dysplasia or early cancer. Results: A total of 59 patients with Lynch syndrome (mean age 48.7 years, 47.5% men) and 590 matched controls (mean age 50.2 years, 47.5% men) were included. In patients with Lynch syndrome, adenomas were significantly more likely to be nonpolypoid than they were in controls: 43.3% vs. 16.9% (OR 3.60, 95%CI 1.90-6.83; P <0.001). This was particularly true for proximal adenomas: 58.1% vs. 16.3% (OR 6.93, 95%CI 2.92-16.40; P <0.001). Adenomas containing advanced histology were more often nonpolypoid in patients with Lynch syndrome than in controls (4/5, 80.0% vs. 5/17, 29.4%; P = 0.19). Serrated polyps were also more often nonpolypoid in patients with Lynch syndrome than in controls: 49.2% vs. 20.4% (OR 3.57, 95%CI 1.91-6.68; P <0.001). Conclusions: In patients with Lynch syndrome, colorectal neoplasms are more likely to have a nonpolypoid shape than those from average risk patients, especially in the proximal colon. These findings suggest that proficiency in recognition and endoscopic resection of nonpolypoid colorectal lesions are needed to ensure colonoscopic prevention against CRC in this high risk population

Agonist-induced down regulation of type 1 and type 3 inositol 1,4,5-tris-phosphate receptors in A7r5 and DDT1 MF-2 smooth muscle cells

Prolonged stimulation of rat A7r5 aortic smooth muscle cells with 3 mu M vasopressin, or of hamster DDT1 MF-2 smooth muscle cells with 10 mu M bradykinin or 100 mu M histamine led within 4 h to a 40-50% down-regulation of the type 1 InsP(3) receptor (InsP(3)R-1) and of the type 3 InsP(3) receptor (InsP(3)R-3). InsP(3)R down-regulation was a cell- and agonist-specific process, since several other agonists acting on PLC-coupled receptors did not change the expression level of the InsP(3)R isoforms in these cell types and since no agonist-induced down-regulation of InsP(3)Rs was observed in HeLa cells. Down-regulation of InsP(3)Rs was prevented by an inhibitor of proteasomal protease activity, N-acetyl-Leu-Leu-norleucinal (ALLN). The Ca2+ channel blocker verapamil (2 mu M) also induced InsP(3)R-l down-regulation (43%) in A7r5 cells, which was inhibited by ALLN. In A7r5 cells transiently transfected with a cDNA construct, bearing a luciferase coding sequence under control of the rat InsP(3)R-l promoter, reduced luciferase activity could be demonstrated upon stimulation of cells with vasopressin or verapamil. Thus, besides enhanced protein degradation, a reduction of InsP(3)R promoter activity might contribute to the down-regulation of InsP(3)Rs in A7r5 cells. We next investigated the effect of InsP(3)R down-regulation on Ca2+ responses in A7r5 cells. A rightward shift in the dose-response curve for InsP(3)-induced Ca2+ release was observed in permeabilized monolayers of vasopressin-pretreated A7r5 cells (EC50 630 nM and 400 nM for pretreated and non-pretreated cells, respectively). The Ca2+ responses to threshold doses of vasopressin were markedly reduced in intact vasopressin-pretreated cells. We conclude that prolonged agonist-exposure leads to down-regulation of InsP(3)Rs in A7r5 and DDT1 MF-2 smooth muscle cells. The mechanism of down-regulation likely involves proteasomal degradation and reduction of InsP(3)R promoter activity. Moreover, down-regulation of InsP(3)Rs resulted in desensitization of Ca2+ release from InsP(3) sensitive stores

Synergism between hypotonically induced calcium release and fatty acyl-CoA esters induced calcium release from intracellular stores

The non-mitochondrial Ca2+ stores in permeabilized A7r5 cells responded to a decrease in Mg-ATP concentration with a pronounced Ca2+ release if 20 mu M CoA was present. This release was rather specific for the preincubation or removal of ATP. ATP gamma S was much less effective and AMP-PNP, GTP, ITP, CTP, UTP, ADP, AMP, adenosine and adenine had no effect. CoA activated with an EC50 of 6 mu M. Dephospho-CoA was a less effective cofactor and desulfo-CoA was ineffective. The release induced by Mg-ATP removal did not occur in the presence of 2% fatty acid-free bovine serum albumin and did not develop at 4 degrees C. All these findings suggest that CoA had to be acylated by endogenous fatty-acyl-CoA synthetase to become effective. Myristoyl-and palmitoyl-CoA esters were identified as the most effective cofactors for the release. Ca2+ release induced by removing Mg-ATP did not occur if the osmolality of the medium was kept constant by addition of mannitol, sucrose, KCl, MgCl2 or Mg-GTP, indicating that the decrease in tonicity was the trigger for the release. Mg-ATP plus CoA also synergized with Ca2+ release induced by a hypotonic shock imposed by diluting the medium with H2O. Osmolality changes induced by decreasing the Mg-ATP concentration were more effective in releasing Ca2+ than equal decreases in concentration of all solutes. We conclude that fatty acyl-CoA esters sensitize the hypotonically induced Ca2+ release from the non-mitochondrial Ca2+ stores