Biomedical subjects

J Kleibeuker

Publications and source records attributed to J Kleibeuker.

5 recordsLinked to original sources

PubMed2006

Cell cycle regulators and apoptosis-associated proteins in relation to proliferative activity and degree of apoptosis in HNPCC versus sporadic endometrial carcinoma.

AIMS: Mismatch repair gene malfunction occurs early in the carcinogenesis of hereditary non-polyposis colorectal cancers (HNPCCs), leading to an accelerated accumulation of mutations and possibly to change in expression of cell cycle proteins. There is strong evidence that tumorigenesis in HNPCCs differs from sporadic ones. HNPCC-related endometrial cancers are less well studied. Our aim was to compare expression of cell cycle and apoptosis-related proteins in relation to proliferation and apoptosis in HNPCC-related and sporadic endometrial cancers to identify differences in their carcinogenetic pathways. METHODS AND RESULTS: Eighteen HNPCC-related endometrial cancers, each matched by tumour type, stage and grade with two sporadic endometrial cancers, were examined for proliferation, apoptosis and the expression of oestrogen and progesterone receptors, cyclin B1, D3 and E, p21, p27, bcl-2, bax, p53 and COX-2. No differences in proliferation or apoptotic indices were detected between HNPCC-related and sporadic endometrial cancers. Cyclin B1 expression was significantly higher in HNPCC-related cancers than in sporadic endometrial cancers. More HNPCC-related endometrial cancers had total loss of bax expression. CONCLUSIONS: Apart from differences in cyclin B1 and bax expression, HNPCC-related and sporadic endometrial cancers are comparable. The subtle differences detected are consistent with the minor clinical diversity between HNPCC-related and sporadic endometrial cancers.

Adenocarcinoma↗

PubMed2000

Inclusion of malignant fibrous histiocytoma in the tumour spectrum associated with hereditary non-polyposis colorectal cancer.

Sarcomas, including the malignant fibrous histiocytomas (MFHs), are not known to be part of the tumour spectrum of hereditary non-polyposis colorectal cancer (HNPCC) as epidemiologically established. Therefore, occurrence of MFH in an HNPCC family may very well be coincidental. HNPCC is associated with germline mutations in DNA mismatch repair genes, including the MSH2 gene. We analysed an MFH diagnosed in a 45-year-old male HNPCC patient carrying a germline MSH2 mutation for HNPCC-associated molecular characteristics, to investigate a possible relationship between the tumour and that mutation. DNA analysis revealed microsatellite instability and loss of one MSH2 copy, and immunohistochemistry showed absence of nuclear MSH2 protein staining. To investigate whether this is a common finding in MFH, microsatellite instability and nuclear MSH2 protein staining was tested for in 5 and 6 sporadic MFHs, respectively. None showed microsatellite instability and all stained positively for MSH2. Together, these findings show that in rare cases, MFH may be part of the HNPCC tumour spectrum.

Adenocarcinoma↗

PubMed1996

Majority of hMLH1 mutations responsible for hereditary nonpolyposis colorectal cancer cluster at the exonic region 15-16.

Hereditary nonpolyposis colorectal cancer (HNPCC) is a common autosomal dominant cancer susceptibility condition. Inherited mutations in at least four DNA mismatch repair genes, hMSH2, hMLH1, hPMS1, and hPMS2, are known to cause HNPCC. In this study we used denaturing gradient gel electrophoresis (DGGE) to screen for hMLH1 mutations in 34 unrelated HNPCC families (30 Dutch, 3 Italian, and 1 Danish). Ten novel pathogenic germ-line mutations (seven affecting splice sites, two frameshifts, and one in-frame deletion of a single amino acid) have been identified in 12 (35%) of these families. In a previous study, hMSH2 mutations were found in 21% of the same families. While the spectrum of mutations at the hMSH2 gene among HNPCC patients appears heterogeneous, a cluster of hMLH1 mutations has been found in the region encompassing exons 15 and 16, which accounts for 50% of all the independent hMLH1 mutations described to date and for > 20% of the unrelated HNPCC kindreds here analyzed. This unexpected finding has a great practical value in the clinical scenario of genetic services.

Adaptor Proteins, Signal Transducing↗

PubMed1984

Glucose perfusion intragastric titration.

A comparison was made between use of isotonic 0.15 M sodium chloride and 5.8 g/100 ml glucose solutions for measurement of gastric acid secretion by intragastric titration in normal and ulcer subjects. Glucose distention did not cause significantly different acid secretion than saline distention in either group. The total amounts of glucose entering the duodenum over the 3.5-hr study period were 99 g in normal subjects and 122 g in ulcer subjects. In normal subjects, circulating gastrin-related acid secretion curves were not significantly different during endogenous peptone and exogenous G-17 stimulation using either the glucose or the saline meals. This finding provides evidence that glucose meals of this size do not alter sensitivity to gastrin. With glucose meals, inhibition of gastric emptying caused retention of a sufficient volume in the stomach to permit accurate continuous intragastric titration. Saline meals caused pronounced diarrhea which was not seen after glucose meals. Glucose distention intragastric titration allows reliable comparisons of endogenously and exogenously stimulated gastric acid secretion without serious side effects and is especially suitable for studying acid secretion in duodenal ulcer subjects.

Adult↗

PubMed1983

Pathological acid secretion not due to gastrinoma.

There are few detailed studies of patients with pathological hypergastrinaemia of antral origin. We have identified four patients with severe acid hypersecretion associated with peptic ulcer disease and in whom no evidence for gastrinoma or isolated retained antrum could be found. Three of these patients also had hypergastrinaemia. In two patients, one with gastric ulcers and one with duodenal ulcer disease, the hypergastrinaemia appeared to be due to antral gastrin cell hyperfunction and there was also evidence for mild antral gastrin cell hyperplasia. In the other hypergastrinaemic patient, a primary intestinal gastrin cell hyperfunction syndrome was suspected, but a hidden gastrinoma could not be excluded. The remaining patient had nearly fatal hypersecretory ulcer disease and cimetidine failed to control the hypersecretory state. In this patient the hypersecretion responded to a more potent H2 antagonist with resolution of a metabolic encephalopathy. No general pathophysiological mechanism could be identified in these patients or in larger groups of patients with gastric or duodenal ulcer disease.

Adult↗