A bile acid-induced apoptosis assay for colon cancer risk and associated quality control studies.
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Bile acids are important in the etiology of colorectal cancer. Bile acids induce apoptosis in colonic goblet cells at concentrations comparable to those found in fecal water after high-fat meals. Preliminary evidence indicated that cells of the normal-appearing (nontumorous) portion of the colon epithelium of colon cancer patients are more resistant to bile salt-induced apoptosis than are cells from normal individuals. In the present study, 68 patients were examined, and biopsies were taken at 20 cm from the anal verge, cecum, and descending colon. The patients included 17 individuals with a history of colorectal cancer, 37 individuals with adenomas, and 14 individuals who were neoplasia free. The mean bile salt-induced apoptotic index among normal individuals was 57.6 +/- 3.47 (SE), which differed significantly (P < 0.05) from the mean value of 36.41 +/- 3.12 in individuals with a history of colon cancer. The correlation between independent observers was 0.89 (P < 0.001), indicating good interobserver reliability. Components of variance comparing interindividual versus intraindividual sources of variation suggested that site-to-site variability, both between regions of the colon and for adjacent biopsies, was larger than the interpatient variability for individuals with a history of neoplasia. Therefore, there was "patchiness" of the susceptibility of regions of the colon to bile acid-induced apoptosis in individuals with a history of neoplasia (a patchy field effect). There was no obvious correlation of low-apoptotic index regions with regions in which previous neoplasias had been found and removed. On the other hand, for normal, i.e., neoplasia-free, individuals, there was relatively less intraindividual variation compared to interindividual variation. Our assay shows an association between resistance to bile acid-induced apoptosis, measured at 20 cm from the anal verge, and colon cancer risk. Thus, this assay may prove useful as a biomarker of colon cancer risk. (+info)
A case of aldosterone-producing adenoma with severe postoperative hyperkalemia.
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It is known that some patients with primary aldosteronism show postoperative hyperkalemia, which is due to inability of the adrenal gland to secrete sufficient amounts of aldosterone. However, hyperkalemia is generally neither severe nor prolonged, in which replacement therapy with mineralocorticoid is seldom necessary. We report a case of a 46-year-old woman with an aldosterone-producing adenoma associated with severe postoperative hyperkalemia. After unilateral adrenalectomy, the patient showed episodes of severe hyperkalemia for four months, which required not only cation-exchange resin, but also mineralocorticoid replacement. Plasma aldosterone concentration (PAC) was low, although PAC was increased after rapid ACTH test. Histological examination indicated the presence of adrenocortical tumor and paradoxical hyperplasia of zona glomerulosa in the adjacent adrenal. Immunohistochemistry demonstrated that the enzymes involved in aldosterone synthesis, such as cholesterol side chain cleavage (P-450scc), 3beta-hydroxysteroid dehydrogenase (3beta-HSD), and 21-hydroxylase (P-450c21), or the enzyme involved in glucocorticoid synthesis, 11beta-hydroxylase (P-450c11beta), were expressed in the tumor, but they were completely absent in zona glomerulosa of the adjacent adrenal. These findings were consistent with the patterns of primary aldosteronism. Serum potassium level was gradually decreased with concomitant increase in PAC. These results suggest that severe postoperative hyperkalemia of the present case was attributable to severe suppression of aldosterone synthesis in the adjacent and contralateral adrenal, which resulted in slow recovery of aldosterone secretion. It is plausible that aldosterone synthesis of adjacent and contralateral adrenal glands is severely impaired in some cases with primary aldosteronism, as glucocorticoid synthesis in Cushing syndrome. (+info)
Centrosome abnormalities in pancreatic ductal carcinoma.
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The centrosome plays an important role in microtubule nucleation and organization, ensuring the establishment of cell polarity and balanced chromosome segregation. Recent studies have suggested that the loss of cell polarity and/or chromosome missegregation (aneuploidy) in human malignant tumors could result from defects in centrosome function. Using immunofluorescence analysis with an antibody to gamma-tubulin (a well-characterized centrosomal component), we examined surgically resected human pancreatic tissues for centrosome abnormalities. The tissues included ductal carcinomas (n = 13), adenomas (n = 3), endocrine tumors (n = 3), chronic pancreatitis (n = 5), and normal pancreatic tissues (n = 12). We found that most (85%) carcinomas and some adenomas displayed abnormal centrosome profiles, characterized by an increase in size and number of centrosomes, and by their irregular distribution. In contrast, none of normal ductal and stromal tissues showed these abnormalities. These findings suggest that centrosome abnormalities may develop at a relatively early stage of pancreatic ductal carcinogenesis. (+info)
Chronic toxicity/oncogenicity evaluation of 60 Hz (power frequency) magnetic fields in F344/N rats.
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A 2-yr whole-body exposure study was conducted to evaluate the chronic toxicity and possible oncogenicity of 60 Hz (power frequency) magnetic fields in rats. Groups of 100 male and 100 female F344/N rats were exposed continuously to pure, linearly polarized, transient-free 60 Hz magnetic fields at flux densities of 0 Gauss (G) (sham control), 20 milligauss (mG), 2 G, and 10 G; an additional group of 100 male and 100 female F344/N rats received intermittent (1 hr on/1 hr off) exposure to 10 G fields. Mortality patterns, body weight gains throughout the study, and the total incidence and number of malignant and benign tumors in all groups exposed to magnetic fields were similar to those found in sex-matched sham controls. Statistically significant increases in the combined incidence of C-cell adenomas and carcinomas of the thyroid were seen in male rats chronically exposed to 20 mG and 2 G magnetic fields. These increases were not seen in male rats exposed continuously or intermittently to 10 G fields or in female rats at any magnetic field exposure level. No increases in the incidence of neoplasms, which have been identified in epidemiology studies as possible targets of magnetic field action (leukemia, breast cancer, and brain cancer), were found in any group exposed to magnetic fields. There was a decrease in leukemia in male rats exposed to 10 G intermittent fields. The occurrence of C-cell tumors at the 2 lower field intensities in male rats is interpreted as equivocal evidence of carcinogenicity; data from female rats provides no evidence of carcinogenicity in that sex. These data, when considered as a whole, are interpreted as indicating that chronic exposure to pure linearly polarized 60 Hz magnetic fields has little or no effect on cancer development in the F344/N rat. (+info)
Chronic toxicity/oncogenicity evaluation of 60 Hz (power frequency) magnetic fields in B6C3F1 mice.
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A 2-yr whole-body exposure study was conducted to evaluate the chronic toxicity and possible oncogenicity of 60 Hz (power frequency) magnetic fields in mice. Groups of 100 male and 100 female B6C3F1 mice were exposed to pure, linearly polarized, transient-free 60 Hz magnetic fields at flux densities of 0 Gauss (G) (sham control), 20 milligauss (mG), 2 G, and 10 G; an additional group of 100 male and 100 female B6C3F1 mice received intermittent (1 hr on/1 hr off) exposure to 10 G fields. A small but statistically significant increase in mortality was observed in male mice exposed continuously to 10 G fields; mortality patterns in all other groups of mice exposed to magnetic fields were comparable to those found in sex-matched sham controls. Body weight gains and the total incidence and number of malignant and benign tumors were similar in all groups. Magnetic field exposure did not increase the incidence of neoplasia in any organ, including those sites (leukemia, breast cancer, and brain cancer) that have been identified in epidemiology studies as possible targets of magnetic field action. A statistically significant decrease in the incidence of malignant lymphoma was observed in female mice exposed continuously to 10 G fields, and statistically significant decreases in the incidence of lung tumors were seen in both sexes exposed continuously to 2 G fields. These data do not support the hypothesis that chronic exposure to pure, linearly polarized 60 Hz magnetic fields is a significant risk factor for neoplastic development in mice. (+info)
Metabolic proficiency and benzo[a]pyrene DNA adduct formation in APCMin mouse adenomas and uninvolved mucosa.
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Tumour formation may involve interactions between genetic factors and environmental carcinogens. Adenoma formation in APCMin/+ mice is associated homozygous adenomatous polyposis coli (APC) gene mutation, but the effects on carcinogen susceptibility are unknown. This study tests the hypothesis that APCMin/+ adenoma formation is accompanied by changes in metabolic proficiency and carcinogen susceptibility. Cytochrome P450 (CYP)1A1/1A2, glutathione S-transferase (GST)alpha, mu and pi classes and DNA adduct formation were assayed in adenomas and uninvolved mucosa from APCMin/+ mice, before and after benzo[a]pyrene (B[a]P) treatment. In untreated adenomas and mucosa, CYP1A1/1A2 and B[a]P-DNA adducts were undetected but GSTalpha, mu and pi class enzymes were constitutively expressed. In adenomas, B[a]P only induced CYP1A1/1A2 to low level while GSTalpha and pi class enzymes were unaffected. A GST mu band which was absent from mucosa, was induced in adenomas. In mucosa, B[a]P induced CYP1A1/1A2 and GSTalpha and pi, to high levels. B[a]P-DNA adduct levels were 56 +/- 15/10(8) nucleotides (median +/- SE) in adenomas versus 89 +/- 19/10(8) nucleotides in mucosa (P < 0.0001). APCMin adenomas show reduced bioactivation capacity and sustain less DNA damage from B[a]P exposure, than APCMin uninvolved mucosa. These properties could influence mutagenesis and subsequent neoplastic transformation of adenomas. (+info)
An acidic environment leads to p53 dependent induction of apoptosis in human adenoma and carcinoma cell lines: implications for clonal selection during colorectal carcinogenesis.
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As tumours are known to acidify their microenvironment and fluctuations in lumenal pH have been reported in a number of colonic disease conditions, we investigated whether loss of p53 function, commonly associated with the adenoma to carcinoma transition in human colorectal epithelium, was implicated in the cellular response to changes in extracellular pH. Human colonic adenoma and carcinoma derived cell lines were incubated at an initial pH range of 5.5-8.0 and the attached cell yield and apoptotic cell yield determined after 4 days. Exposure of all cell lines to an acidic growth environment was associated with a G1 arrest, down regulation of the retinoblastoma protein (pRb) protein and switch to the hypophosphorylated form of the protein, and increased expression of the p21 protein. However, induction of apoptosis, associated with increased p53 protein expression but not with changes in Bcl-2 expression, was only detected in the adenoma derived BH/C1 and AA/C1 cell lines which express wild type p53 activity. Furthermore, this induction of apoptosis was inhibited in the transfected cell line AA/273p53/B, in which the wild type p53 function has been abrogated. These results suggest that acidification of the microenvironment would provide a selective growth advantage for cells that have lost wild type p53 function, leading to clonal expansion of aberrant cell populations. (+info)
Biological effects of vinyl chloride: an experimental study.
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Plasma activities of alkaline phosphatase, (AP), transaminases and total lactate dehydrogenase (LDH) with isoenzymes were determined in mice inhaling 50 and 550 ppm vinyl chloride (VC). The animals were also autopsied and the tissue pathology was studies. The total LDH activity was elevanted in both dose groups along with a shift to cathodic enzymes. AP was increased in animals exposed to 500 ppm and transaminases were not at all changed. Enzyme changes occurred after the appearance of tumors. Alveologenic adenomas occurred in all animals at the higher dosage and in about half of the animals inhaling the lower dose. Subperitoneal and subcutaneous hemangiosarcomas were frequent in both dose groups; but especially among 50 ppm animals. Only one animal had a hemangiosarcoma of the liver. No liver fibrosis was seen. All primary subperitoneal and subcutaneous tumors were located in fat tissue. Telangiectasis was observed in two animals in the 500 ppm series. The importance of blood vessel changes in the toxicology of vinyl chloride is discussed. (+info)