Detection of glycated gastric inhibitory polypeptide within the intestines of diabetic obese (ob/ob) mice

Gastric inhibitory polypeptide (GIP) is produced within endocrine cells of the small intestine and released into the circulation upon nutrient ingestion. This study has quantified the levels of this insulinotropic peptide in the intestines of lean and diabetic obese ob/ob mice and estimated the proportion that is glycated. The total intestinal GIP concentration and content of the diabetic mice were significantly greater (p

Improved glycaemic control in obese diabetic ob/ob mice using N-terminally modified gastric inhibitory polypeptide

Gastric inhibitory polypeptide (GIP) is an important insulin-releasing hormone of the enteroinsular axis which is rapidly inactivated by the exopeptidase dipeptidyl peptidase (DPP) IV. The present study has examined the ability of Tyr(1)-glucitol GIP to be protected from plasma degradation and to enhance insulin-releasing and antihyperglycaemic activity in 20- to 25-week-old obese diabetic ob/ob mice. Degradation of GIP by incubation at 37 degrees C with obese mouse plasma was clearly evident after 3 h (35% degraded). After 6 h, more than 61% of GIP was converted to GIP(3-42) whereas N-terminally modified Tyr(1)-glucitol GIP was resistant to degradation in plasma (>99% intact after 6 h). The formation of GIP(3-42) was almost completely abolished by inhibition of plasma DPP IV with diprotin A. Effects of GIP and Tyr(1)-glucitol GIP were examined in overnight-fasted obese mice following i.p. injection of either peptide (20 nmol/kg) together with glucose (18 mmol/kg) or in association with feeding. Most prominent effects were observed in the former group where plasma glucose values at 60 min together with the area under the curve (AUC) for glucose were significantly lower following GIP (AUC, 874 +/- 72 mmol/l.min; P

A study of HER2 gene amplification and protein expression in gastric cancer

Background Gastric cancer is a leading cause of cancer-related mortality, and current treatment outcomes for advanced disease remain poor. HER2 has been identified as a potential candidate for targeted therapy in gastric cancers displaying HER2 gene amplification and protein overexpression.

MicroRNA-130b regulates the tumour suppressor RUNX3 in gastric cancer

Aim: Accumulating evidence indicates that RUNX3 is an important tumour suppressor that is inactivated in many cancer types. This study aimed to assess the role of microRNA (miRNA) in the regulation of RUNX3.

Claudin-1 Has Tumor Suppressive Activity and Is a Direct Target of RUNX3 in Gastric Epithelial Cells

BACKGROUND & AIMS: The transcription Factor RUNX3 is a gastric tumor suppressor. Tumorigenic Runx3(-/-) gastric epithelial cells attach weakly to each other, compared with nontumorigenic Runx3(+/+) cells. We alined to identify RUNX3 target genes that promote cell-cell contact to Improve our understanding of RUNX3's role in Suppressing gastric carcinogenesis. METHODS: We compared gene expression profiles of Runx3(+/+) and Runx3(-/-) cells and observed down-regulation of genes associated with cell-cell adhesion in Runx3(-/-) cells. Reporter, mobility shift, and chromatin immunoprecipitation assays were used to examine the regulation of these genes by RUNX3. Tumorigenesis assays and immunohistologic, analyses of human gastric tumors were performed to confirm the role of the candidate genes ill gastric tumor development. RESULTS: Mobility shift and chromatin immunoprecipitation assays revealed that the promoter activity of the gene that encodes the tight Junction protein claudin-1 was up-regulated via the binding of RUNX3 to the RUNX consensus sites. The tumorigenicity of gastric epithelial cells From Runx3(-/-) mice was significantly reduced by restoration of claudin-1 expression, whereas knockdown of claudin-1. increased the tumorigenicity of human gastric cancer cells. Concomitant expression of RUNX3 and claudin-1 was observed in human normal gastric epithelium and cancers. CONCLUSIONS: The tight junction protein claudin-1 has gastric tumor suppressive activity and is a direct transcriptional target of RUNX3. Claudin-1 is down-regulated during the epithelial-mesenchymal transition; RUNX3 might therefore act as a tumor suppressor to antagonize the epithelial-mesenchymal transition.

RUNX3, a novel tumor suppressor, is frequently inactivated in gastric cancer by protein mislocalization

Loss of RUNX3 expression is suggested to be causally related to gastric cancer as 45% to 60% of gastric cancers do not express RUNX3 mainly due to hypermethylation of the RUNX3 promoter. Here, we examined for other defects in the properties of RUNX3 in gastric cancers that express RUNX3. Ninety-seven gastric cancer tumor specimens and 21 gastric cancer cell lines were examined by immunohistochemistry using novel anti-RUNX3 monoclonal antibodies. In normal gastric mucosa, RUNX3 was expressed most strongly in the nuclei of chief cells as well as in surface epithelial cells. In chief cells, a significant portion of the protein was also found in the cytoplasm. RUNX3 was not detectable in 43 of 97 (44%) cases of gastric cancers tested and a further 38% showed exclusive cytoplasmic localization, whereas only 18% showed nuclear localization. Evidence is presented suggesting that transforming growth factor-beta is an inducer of nuclear translocation of RUNX3, and RUNX3 in the cytoplasm of cancer cells is inactive as a tumor suppressor. RUNX3 was found to be inactive in 82% of gastric cancers through either gene silencing or protein mislocalization to the cytoplasm. In addition to the deregulation of mechanisms controlling gene expression, there would also seem to be at least one other mechanism controlling nuclear translocation of RUNX3 that is impaired frequently in gastric cancer.

Intrinsic subtypes of gastric cancer, based on gene expression pattern, predict survival and respond differently to chemotherapy

BACKGROUND & AIMS:
Gastric cancer (GC) is a heterogeneous disease comprising multiple subtypes that have distinct biological properties and effects in patients. We sought to identify new, intrinsic subtypes of GC by gene expression analysis of a large panel of GC cell lines. We tested if these subtypes might be associated with differences in patient survival times and responses to various standard-of-care cytotoxic drugs.
METHODS:
We analyzed gene expression profiles for 37 GC cell lines to identify intrinsic GC subtypes. These subtypes were validated in primary tumors from 521 patients in 4 independent cohorts, where the subtypes were determined by either expression profiling or subtype-specific immunohistochemical markers (LGALS4, CDH17). In vitro sensitivity to 3 chemotherapy drugs (5-fluorouracil, cisplatin, oxaliplatin) was also assessed.
RESULTS:
Unsupervised cell line analysis identified 2 major intrinsic genomic subtypes (G-INT and G-DIF) that had distinct patterns of gene expression. The intrinsic subtypes, but not subtypes based on Lauren's histopathologic classification, were prognostic of survival, based on univariate and multivariate analysis in multiple patient cohorts. The G-INT cell lines were significantly more sensitive to 5-fluorouracil and oxaliplatin, but more resistant to cisplatin, than the G-DIF cell lines. In patients, intrinsic subtypes were associated with survival time following adjuvant, 5-fluorouracil-based therapy.
CONCLUSIONS:
Intrinsic subtypes of GC, based on distinct patterns of expression, are associated with patient survival and response to chemotherapy. Classification of GC based on intrinsic subtypes might be used to determine prognosis and customize therapy.

Exome sequencing of gastric adenocarcinoma identifies recurrent somatic mutations in cell adhesion and chromatin remodelling genes

Gastric cancer is a major cause of global cancer mortality. We surveyed the spectrum of somatic alterations in gastric cancer by sequencing the exomes of 15 gastric adenocarcinomas and their matched normal DNAs. Frequently mutated genes in the adenocarcinomas included TP53 (11/15 tumors), PIK3CA (3/15) and ARID1A (3/15). Cell adhesion was the most enriched biological pathway among the frequently mutated genes. A prevalence screening confirmed mutations in FAT4, a cadherin family gene, in 5% of gastric cancers (6/110) and FAT4 genomic deletions in 4% (3/83) of gastric tumors. Frequent mutations in chromatin remodeling genes (ARID1A, MLL3 and MLL) also occurred in 47% of the gastric cancers. We detected ARID1A mutations in 8% of tumors (9/110), which were associated with concurrent PIK3CA mutations and microsatellite instability. In functional assays, we observed both FAT4 and ARID1A to exert tumor-suppressor activity. Somatic inactivation of FAT4 and ARID1A may thus be key tumorigenic events in a subset of gastric cancers.

Gastric emptying in patients with flatulent dyspepsia, with and without gallbladder disease

It has been suggested that the symptoms of flatulent dyspepsia are caused by a functional disturbance of the upper gastrointestinal tract. The aim of this study was to investigate delayed gastric emptying as the basis of symptoms in patients with and without gallbladder disease and after cholecystectomy. There were 13 dyspeptic patients with gallbladder disease, 12 with normal gallbladders, and 13 post-cholecystectomy patients. Gastric emptying was measured by means of a 99mTc-labelled scrambled egg meal and external scintillation counter. The rate of emptying in the symptomatic groups was compared with that in 24 asymptomatic normal control subjects and 12 non-dyspeptic patients with gallbladder disease. Delayed gastric emptying tended to occur in patients with gallbladder disease with and without dyspepsia and was not specifically associated with symptoms.

Gastric corpus atrophy following eradication of Helicobacter pylori

Atrophic gastritis can develop in patients with Helicobacter pylori infection leading to a reduction in basal acid output. Whether the atrophy that develops is reversible is controversial.