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S F Moss

Publications and source records attributed to S F Moss.

At least 55 records · Page 3Linked to original sources
PubMed1998

Review article: Cellular markers in the gastric precancerous process.

Gastric cancer is the end result of a chronic process, which usually starts as Helicobacter pylori-associated chronic gastritis. Although some differences exist in the histological intermediary stages and in the frequency and timing of certain molecular alterations, both diffuse and intestinal cancer are accompanied by some important common cellular changes. These include an increase in cell proliferation, and an alteration in apoptosis, which may be secondary to loss of function of p53 and loss of growth inhibition by growth factor (TGF)-beta, due to mutation of the TGF-beta receptor type II. This review examines the potential role of H. pylori in the aetiology of the molecular changes during the progression to gastric cancer, and explores the usefulness of these changes as biomarkers of increased risk of neoplasia in the intermediate steps of gastric carcinogenesis.

Animals↗
PubMed1998

Helicobacter pylori--more light, less heat.

Several areas of broad agreement exist concerning the management of specific patient groups with clear-cut complications of H. pylori-colonization. Other aspects of this infection remain less well defined. These include the mode of transmission and pathogenesis of H. pylori, the clinical management of patients who do not have ulcer disease, and the approach to populations at risk of the clinical consequences of this bacterium. This review focuses on the unresolved issues of H. pylori infection that are of concern to the clinical gastroenterologist.

Disease Models, Animal↗
PubMed1998

Novel C-2 substituted carbapenem derivatives. Part IV. Synthesis and biological activity of five membered heteroaromatic derivatives.

The synthesis, antibacterial activity, and stability to human dehydropeptidase-1 (DHP-1) of a novel series of (5R,6S)-6-[(1R)-1-hydroxyethyl]-2-heterocyclylcarbapen-2-em-3-carb oxylates are described. Of the compounds investigated 1,5-disubstituted pyrazol-3-yl and 3-substituted isoxazol-5-yl derivatives have the best combination of antibacterial activity and stability to DHP-1. They are particularly active against community-acquired respiratory tract pathogens and have stabilities to DHP-1 superior to that of meropenem.

Carbapenems↗
PubMed1997

Apoptosis in gastric epithelial cells is induced by Helicobacter pylori and accompanied by increased expression of BAK.

Carriage of the bacterium H. pylori in the human stomach is associated with evidence of increased epithelial cell apoptosis. This may be of significance in the etiology of gastritis, peptic ulcers, and neoplasia. The ability of H. pylori to directly induce epithelial apoptosis was examined in vitro by fluorescence and electron microscopy, flow cytometry, and DNA fragmentation ELISA. The induction of apoptosis by H. pylori was time and concentration-dependent and inhibited by preventing direct bacterial-epithelial cell contact. Apoptosis was accompanied by increased expression of Bak, with little change in expression of other Bcl-2 family proteins. The expression of Bak was also increased in gastric biopsies from patients colonized by H. pylori. Thus, H. pylori induces gastric epithelial cell apoptosis, by a Bak-dependent pathway.

Apoptosis↗
PubMed1997

Helicobacter pylori cagA+ strains and dissociation of gastric epithelial cell proliferation from apoptosis.

BACKGROUND: Infection with Helicobacter pylori induces chronic gastritis in virtually all infected persons, and such gastritis has been associated with an increased risk of developing gastric cancer. This risk is further enhanced with cagA+ (positive for cytotoxin-associated gene A) H. pylori strains and may be a consequence of induced gastric cell proliferation and/or alteration in apoptosis (programmed cell death) in the gastric epithelium. PURPOSE: To determine whether the H. pylori cagA genotype and another virulence-related characteristic, the vacA (vacuolating cytotoxin A) s1a genotype, differentially affect epithelial cell proliferation, apoptosis, and the histologic parameters of inflammation and injury, we quantitated these characteristics in infected and uninfected persons. METHODS: Fifty patients underwent upper gastrointestinal endoscopy, and biopsy specimens were taken. Apoptotic cells in the specimens were quantitated after terminal deoxynucleotidyl transferase labeling of DNA fragments with digoxigenin-deoxyuridine triphosphate; epithelial cell proliferation was scored by immunohistochemical analysis of the proliferation-associated antigen Ki-67. Antibodies directed against H. pylori and CagA protein were measured in the serum of patients by means of enzyme-linked immunosorbent assays. Analysis of H. pylori genomic DNA, by use of the polymerase chain reaction, was performed to determine the cagA and vacA genotypes. Acute and chronic inflammation, epithelial cell degeneration, mucin depletion, intestinal metaplasia, glandular atrophy, and vacuolation were each scored in a blinded manner. Reported P values are two-sided. RESULTS: Persons harboring cagA+ strains (n = 20) had significantly higher gastric epithelial proliferation scores than persons infected with cagA-strains (n = 9) or uninfected persons (n = 21) (P = .025 and P<.001, respectively), but the difference in cell proliferation between the latter two groups was not statistically significant. The number of apoptotic cells per 100 epithelial cells (apoptotic index) in persons infected with cagA+ strains was lower than in persons infected with cagA-strains (P = .05). Apoptotic indices in the cagA+ group were similar to those in the uninfected group (P = .2). Epithelial cell proliferation was significantly correlated with acute gastric inflammation, but only in the cagA+ group (r = .44; P = .006). The cagA+ and vacA s1a genotypes were found to be concordant, confirming the close relationship between these virulence-related genotypes. CONCLUSIONS: Gastric mucosal proliferation was significantly correlated with the severity of acute gastritis in persons infected with cagA+ vacA s1a strains of H. pylori. This increased proliferation was not accompanied by a parallel increase in apoptosis. IMPLICATIONS: Increased cell proliferation in the absence of a corresponding increase in apoptosis may explain the heightened risk for gastric carcinoma that is associated with infection by cagA+ vacA s1a strains of H. pylori.

Antigens, Bacterial↗
PubMed1997

Is Ki-67 a better proliferative marker in the colon than proliferating cell nuclear antigen?

Endogenous markers of proliferating cells have increasingly supplanted the use of incubation of biopsy tissues in vitro with tritiated thymidine or with bromodeoxyuridine, thus avoiding the potential variation resulting from the incubation procedure. Antibodies to proliferating cell nuclear antigen (PCNA) such as PC10 have been promoted as optimal for this purpose, although considerable variation in colonic proliferating cells with this antibody has been reported. We have compared the detection of colonic proliferating cells in normal mucosa and adenomata using the PC10 monoclonal antibody (mAb) to PCNA and the Mib-1 mAb to Ki-67 in formalin-fixed tissues using antigen retrieval solutions with microwaving. The PC10 antibody showed variable immunostaining of proliferating and nonproliferating cells with minor changes in primary antibody concentration or microwave conditions and between normal and adenomatous tissue. In contrast, Mib-1 immunostaining was quite constant with differing antigen retrieval and antibody conditions and similar staining of proliferating cells in colonic adenomas. Some loss of immunoreactivity occurred if the cut sections were not immunostained within approximately 1 week. These data suggest that whereas PCNA immunohistochemistry is satisfactory when carefully controlled in large chemopreventive studies, the Mib-1 mAb to Ki-67 is superior to PCNA antibodies in immunostaining proliferating cells in the formalin-fixed human colon.

Adenoma↗
PubMed1997

Novel C-2 substituted carbapenem derivatives. Part III. Synthesis and biological activity of 2-(functionalised ethenyl, oxyiminomethyl and alpha-[hydroxy]benzyl)-carbapenems.

The synthesis, antibacterial activity and stability to human dehydropeptidase-1 (DHP-1) of three small series of carbapenems carrying carbon-linked substituents at C-2 are described. C-2 Ethenyl carbapenems showed moderate antibacterial activity but poor stability to DHP-1, C-2 Oxyiminomethyl carbapenems demonstrated variable activity and stability C-2 alpha-(Hydroxy)benzyl carbapenems were the most promising and showed good potency and DHP-1 stability.

Carbapenems↗
PubMed1996

30 KDa phosphorylated form of Bcl-2 protein in human colon.

Bcl-2 expression was studied in a human colon cell line (HT-29) and in human colonic biopsies by Western and Northern blotting. Polyclonal antibodies raised against the Bcl-2 protein detected the expected 26 KDa protein in human colon. However, although Bcl-2 mRNA was present, the 26 KDa Bcl-2 protein was absent in HT-29 cells. Instead, a 30 KDa protein band strongly reacting with anti-Bcl-2 antibodies was found in HT-29 cells, and also in human colon, tonsil, and some other tissues. Alkaline phosphatase shifted the 30 KDa protein to the 26 KDa position in a time-dependent manner. 32P-labeling of HT-29 cells showed that the 30 KDa protein was phosphorylated. A 27 KDa phosphorylated protein was also immunoprecipitated by anti-Bcl-2 antibody. Phosphopeptide mapping showed that the 27 KDa protein contained a minimum of 3 and the 30 KDa protein at least an additional four phosphorylation sites. Phosphoamino acid analysis revealed that both the 30 KDa and 27 KDa proteins were phosphorylated on serine residues. These findings strongly suggest that the 30 KDa protein is a phosphorylated form of Bcl-2, which is widely distributed in human tissues.

Binding Sites↗
PubMed1996

Increased intestinal Bak expression results in apoptosis.

Cells in the human intestinal epithelium have a life-span of around 5 days before being lost by apoptosis at the luminal surface. We examined changes in expression of the Bcl-2 gene family which may be responsible for epithelial cell loss. In the normal and neoplastic colon, mucosal expression of immunoreactive Bak co-localized with sites of epithelial cell apoptosis. Inducing apoptosis in the human colon cancer cell line HT29 and the rat normal small intestinal cell line IEC 18 in culture was accompanied by increased Bak expression without consistent changes in expression of other Bcl-2 homologous proteins. Bak appears to be the endogenous Bcl-2 family member best correlated with intestinal cell apoptosis.

Animals↗
PubMed1996

Elevated expression of Bcl-X and reduced Bak in primary colorectal adenocarcinomas.

Expression of several members of the BCL-2 family of genes was investigated by immunohistochemical methods in 30 primary colorectal adenocarcinomas and 24 adenomatous polyps. When compared to the intensity observed in adjacent normal mucosal epithelial cells, the intensity of Bcl-X immunostaining was elevated in 18 of 30 (60%) carcinomas (P = 0.0001) and 12 of 24 (50%) adenomatous polyps (P = 0.0001). Immunoblot analysis of five pairs of tumors and adjacent normal colonic tissue indicated marked elevations in the relative levels of the anti-apoptotic Bcl-XL, protein in all cases. In contrast to the increased Bcl-X expression, the intensity of Bcl-2 immunostaining was greater than that of normal colonic mucosa in only 3 of 30 (10%) carcinomas and, in fact, was lower than that of adjacent normal epithelia] cells in 25 (83%) cases (P = 0.0001). Furthermore, the percentage of Bcl-2 immunopositive cells was generally lower in carcinomas than in adenomas (mean +/- SE, 44 +/- 6% versus 73 +/- 5%, respectively; P = 0.001) and in moderately or poorly differentiated tumors than in well-differentiated tumors (39 +/- 6% versus 70 +/- 11%, respectively; P = 0.045). In addition, the proportion of tumors in which the Bcl-2 immunointensity was more than or equal to that of normal colonic mucosa was significantly lower in carcinomas than adenomas (5 of 30 versus 15 of 24, respectively; P < 0.001), suggesting that decreases in Bcl-2 expression represent a later event associated with the progression of colorectal cancers. When compared to that of normal adjacent colonic epithelium, the intensity of Mcl-1 immunostaining was reduced in 20 of 30 (67%) of carcinomas (P = 0.0001) compared to only 1 of 24 adenomas, suggesting that decreases in Mcl-1 expression represent a later event associated with progression from a benign to a malignant phenotype or with transition to a less-differentiated state, because most of the carcinomas evaluated here (25 of 30; 83%) were not well differentiated. The intensity of immunostaining for the pro-apoptotic protein Bak was reduced compared to that of normal mucosal epithelial cells in 27 of 30 (90%) carcinomas and 22 of 24 (92%) adenomas, suggesting that reductions in Bak expression occur early in colorectal tumor progression (P = 0.0001). In contrast, the intensity of immunostaining for the pro-apoptotic protein Bax was not significantly altered in carcinomas; compared to that of normal colonic mucosa, Bax immunointensity was reduced in only 7 of 30 (23%) carcinomas and 3 of 24 (13%) adenomas, and the percentage of Bax immunopositive cells was also not significantly different in any of the histological subgroups. Taken together, these results suggest that expression of Bcl-XL is increased in undifferentiated primary colorectal cancers, often with accompanying reciprocal decreases in the anti-apoptotic proteins Bcl-2 and Mcl-1 and the pro-apoptotic protein Bak, whereas Bax expression is relatively constant. Thus, a shift from expression of the anti-apoptotic proteins Bcl-2 and Mcl-1 to the Bcl-XL protein may occur during progression of colorectal tumors.

Adenocarcinoma↗
PubMed1996

Abnormalities of epithelial apoptosis in multistep colorectal neoplasia demonstrated by terminal deoxyuridine nick end labeling.

Colonic carcinogenesis is accompanied by progressive genetic changes and alterations in growth control. To examine whether abnormalities of apoptosis are involved in carcinogenesis, we examined epithelial apoptosis in formalin-fixed normal and neoplastic colon by terminal uridine deoxynucleotide nick end-labeling (TUNEL) histochemistry. In normal colon, resection margins, and hyperplastic polyps, TUNEL-positive cells comprised around 3% of total colonocytes, with over 85% of these cells located in surface epithelium between crypts. In adenomas, there were significantly fewer TUNEL-positive cells at the luminal surface than normal (1.82 +/- 0.51% of epithelial cells, compared with 12.1 +/- 2.3%, P < 0.05) and a trend to increased numbers at the crypt base (2.70 +/- 0.98% compared with 0.65 +/- 0.15%). Carcinomas contained fewer TUNEL-positive cells than normal (1.7 +/- 0.27%), and they are randomly distributed. Transitional mucosa had significantly more TUNEL-positive colonocytes than normal (11.0 +/- 3.0%, P < 0.005), both at the surface and crypt base. These results show that colonocyte apoptosis normally occurs mainly in luminal cells but that early during carcinogenesis the distribution and quantity of apoptotic cells changes.

Apoptosis↗
PubMed1996

Frequent K-ras mutations in small bowel adenocarcinomas.

The reasons for the relatively rare occurrence of small bowel adenocarcinomas when compared to the high frequency of colonic adenocarcinomas are unknown. Activating mutations in the K-ras oncogene occur in about 40% of colonic adenocarcinomas, possibly reflecting the consequences of carcinogenic exposure. To study whether the low incidence of small bowel adenocarcinomas might be due to the absence of activation of cellular oncogenes in small bowel adenocarcinomas, we examined the frequency of K-ras mutations in small bowel adenocarcinomas. K-ras mutations were determined using a polymerase chain reaction (PCR)-based method to detect codon 12 mutations by restriction fragment length polymorphism. PCR amplification was successful in six of nine small bowel adenocarcinoma samples, and revealed point mutations of K-ras at codon 12 in five of these six cases. We conclude that the small bowel might be exposed to carcinogens similar to those responsible for colorectal cancer, but may have developed protective mechanisms against cancer formation.

Adenocarcinoma↗
PubMed1996

Inward growth of colonic adenomatous polyps.

BACKGROUND & AIMS: Most colon cancers arise from polypoid adenomas, but how these benign lesions develop into malignant neoplasms is not understood. This study examined the migration of epithelial cells within human adenomatous polyps by determining the distribution of proliferating and apoptotic cells and immunoreactivity to transforming growth factor beta (TGF-beta). METHODS: Sections of surgically resected normal (n = 10) and adenomatous (n = 22) formalin-fixed tissue were examined for proliferating cells and TGF-beta isoenzymes 1-3 by immunohistochemistry and apoptotic cells by terminal deoxyuridine nick end-labeling. RESULTS: The distribution of proliferating, apoptotic, and TGF-beta immunoreactive cells was strikingly reversed in adenomatous polyps compared with normal mucosa. Proliferating cells were located in the base of normal colonic crypts and TGF-beta immunoreactive and apoptotic cells near or at the luminal surface, corresponding to the normal migration of colonocytes. In adenomas, increased numbers of proliferating cells were mainly located at the luminal surface and TGF-beta immunoreactive and apoptotic cells were located principally at the crypt base. CONCLUSIONS: This distribution suggests that cell migration in adenomas is not toward the lumen but instead inward toward the polyp base.

Adenomatous Polyposis Coli↗
PubMed1996

Effects of acarbose on fecal nutrients, colonic pH, and short-chain fatty acids and rectal proliferative indices.

Acarbose, an alpha-glycosidase inhibitor, treats diabetes mellitus by delaying the digestion and intestinal absorption of dietary carbohydrates. In effective doses, acarbose induces some passage of carbohydrates into the colon. The effect of such chronic carbohydrate transfer on colonic structure and function is unknown. We studied the effects of 1 year of acarbose administration in diabetes mellitus on fecal energy, protein, and fat, including short-chain fatty acids (SCFA) output, fecal pH, and several metabolizing bacterial species. Changes in colonic histology and epithelial cell proliferation were investigated in rectal biopsies. Fecal macronutrient output was unaffected by acarbose, but pH decreased and total SCFA, butyrate, and acetate output were markedly greater. Breath hydrogen output increased after acarbose, but digoxin-metabolizing bacteria and diacylglycerol (DAG) production were unaltered. Compared with the control, acarbose did not induce hyperplasia or change rectal proliferation. However, total fecal SCFA and butyrate output correlated inversely with proliferation in the rectal upper crypt-a biomarker of risk for colonic neoplasia. In conclusion, long-term acarbose administration does not adversely affect colonic function or fecal nutrient output. If increased fecal SCFA and butyrate reduces upper-crypt proliferation, then acarbose may reduce the risk of colonic neoplasia.

Acarbose↗
PubMed1996

Increased expression of cyclin D1 is an early event in multistage colorectal carcinogenesis.

BACKGROUND & AIMS: Cyclin D1 gene amplification and/or overexpression occurs in several human cancers. The level of expression of cyclin D1 protein during the multistage process of human colon carcinogenesis was determined. METHODS: Cyclin D1 protein abundance was determined by immunostaining samples of normal colonic mucosa(n=23), transitional normal mucosa adjacent to adenomas or adenocarcinomas (n=41), hyperplastic polyps (n=8), adenomatous polyps (=35), and adenocarcinomas (n=27), using a polyclonal anti-human cyclin D1 antibody. RESULTS: Cyclin D1 nuclear staining occurred in 30% of adenocarcinomas and 34% of adenomatous polyps but not in hyperplastic polyps or normal or transitional mucosa. Nuclear staining did not correlate with sex, age, size, or dysplasia of the adenomatous polyps or with differentiation and Dukes' staging of the adenocarcinomas. Left-sided colon neoplasms showed nuclear staining more frequently than those right-sided lesions. Diffuse or supranuclear cytoplasmic staining occurred in about one third of hyperplastic polyps, adenomas, and adenocarcinomas and in transitional mucosa adjacent to adenocarcinoma. CONCLUSIONS: Increased nuclear expression of cyclin D1 occurs in around one third of colonic tumors as an early event during multistage process of colon carcinogenesis. Increased expression of cyclin D1 may perturb cell-cycle control in benign adenomas and thereby enhance tumor progression.

Adenocarcinoma↗