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Biomedical subjects

C C Harris

Publications and source records attributed to C C Harris.

At least 289 records · Page 16Linked to original sources
PubMed1986

Type beta transforming growth factor is the primary differentiation-inducing serum factor for normal human bronchial epithelial cells.

Type beta transforming growth factor (TGF-beta) was shown to be the serum factor responsible for inducing normal human bronchial epithelial (NHBE) cells to undergo squamous differentiation. NHBE cells were shown to have high-affinity receptors for TGF-beta. TGF-beta induced the following markers of terminal squamous differentiation in NHBE cells: (i) increase in Ca ionophore-induced formation of crosslinked envelopes; (ii) increase in extracellular activity of plasminogen activator; (iii) irreversible inhibition of DNA synthesis; (iv) decrease in clonal growth rate; and (v) increase in cell surface area. The IgG fraction of anti-TGF-beta antiserum prevented both the inhibition of DNA synthesis and the induction of differentiation by either TGF-beta or whole blood-derived serum. Therefore, TGF-beta is the primary differentiation-inducing factor in serum for NHBE cells. In contrast, TGF-beta did not inhibit DNA synthesis of human lung carcinoma cells even though the cells possess comparable numbers of TGF-beta receptors with similar affinities for the factor. Epinephrine antagonized the TGF-beta-induced inhibition of DNA synthesis and squamous differentiation of NHBE cells. Although epinephrine increased the cyclic AMP levels in NHBE cells, TGF-beta did not alter the intracellular level in NHBE cells in either the presence or absence of epinephrine. Therefore, epinephrine and TGF-beta appear to affect different intracellular pathways that control growth and differentiation processes of NHBE cells.

Bronchi↗
PubMed1986

Studies on the role of oxygen radicals in asbestos-induced cytopathology of cultured human lung mesothelial cells.

The possible role of oxygen radicals in mediating the cytopathologic effects of asbestos was studied using human mesothelial cells in culture. Electron paramagnetic resonance measurements of intact cells using the spin trap 5,5-dimethyl-1-pyrroline-1-oxide failed to detect any increase in oxygen radicals in mesothelial cells after exposure to amosite asbestos, although oxygen radicals were readily detected in cells exposed to menadione, an uncoupler of oxidation-reduction reactions. Cellular thiol levels were reduced after exposure to menadione, but were not affected by exposure to asbestos. Addition to the culture media of the free radical scavengers superoxide dismutase, reduced glutathione, N-acetylcysteine, or D-alpha-tocopherol had no affect on the dose-dependent cytotoxicity of amosite fibers. Furthermore, exposure of the mesothelial cells to amosite fibers resulted in no significant increase in the level of DNA single-strand breaks. These results all suggest that for cultured human mesothelial cells, oxygen free radicals are not important mediators of the cytopathic effect of asbestos.

Asbestos↗
PubMed1986

Fecapentaene-12 causes DNA damage and mutations in human cells.

Fecapentaenes are mutagens found in human feces and may play a role in the pathogenesis of colon carcinoma. However, the genotoxic effects of fecapentaenes have not been previously studied in mammalian cells. We now report that fecapentaene-12 (fec-12), a prototype for these compounds, causes DNA single strand breaks, sister chromatid exchanges and mutations in cultured human fibroblasts. These results indicate that fec-12 is a potent genotoxic agent in human cells.

Cells, Cultured↗
PubMed1986

Regional pulmonary distribution of iodine-125-labeled oleic acid. Its relationship to the pattern of oleic acid edema and pulmonary blood flow.

Oleic acid infusion in dogs produces a patchy, predominantly peripheral lesion on CT scans. This study correlates the pattern of oleic acid injury with the distribution of infused oleic acid and pulmonary blood flow. Radiolabeled oleic acid (I-125, 0.05 ml/kg) and radiolabeled 15-micron microspheres (Co-57) were infused into the right atria of 11 dogs. Oleic acid was given after the microspheres in six dogs and before microspheres in five dogs. Ten minutes after infusion, the lungs were removed. Four transverse slices (0.5 cm thick) of the lower lobes were taken from each dog and cubed. Samples were grouped into three regions of the transverse slice: outer, middle, and inner concentric rings. In both groups, I-125 (oleic acid) activity was greater in the outer than the middle and inner concentric layers (P less than 0.001). When Cobalt-57 microspheres were given before oleic acid, Cobalt-57 activity was marginally lower in the outer layer compared with the middle and inner layers. However, when oleic acid was given first, microsphere activity in the outer layer was significantly lower (P less than 0.001) than the middle layer. Thus, oleic acid was preferentially distributed to the peripheral regions of the lung, similar to the regions of injury on CT. This distribution did not correspond to the pattern of pulmonary blood flow as indicated by the microspheres. Immediately after oleic acid infusion, pulmonary blood flow to the periphery was reduced, reflecting a response to the predominantly peripheral injury by oleic acid.

Animals↗
PubMed1986

Immunocytochemical evaluation of human esophageal neoplasms and preneoplastic lesions for beta-chorionic gonadotropin, placental lactogen, alpha-fetoprotein, carcinoembryonic antigen, and nonspecific cross-reacting antigen.

Human esophageal neoplasms were studied in comparison to normal, uninvolved, and preneoplastic human esophageal epithelium for the presence of human chorionic gonadotropin (HCG), human placental lactogen (HPL), alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), and nonspecific cross-reacting antigen (NCA) using the unlabeled antibody peroxidase-antiperoxidase technique. HCG immunoreactivity was identified in 10 of 33 squamous cell carcinomas (33%), in 1 of 6 adenocarcinomas (17%), and 1 of 6 preneoplastic esophageal lesions (17%); while 9 of 33 squamous cell carcinomas (33%) and 1 of 6 adenocarcinomas (17%) contained immunoreactive AFP. Immunoreactive HPL was detected in 6 of 33 squamous cell carcinomas (20%), but in none of the adenocarcinomas. Neither AFP nor HPL immunoreactivity was identified in the 6 hyperplastic lesions which were studied. When stained with an antiserum that was able to detect both CEA and NCA, 27 of 33 squamous cell tumors (82%) and 6 of 6 adenocarcinomas (100%) showed positive immunostaining reactions. Of these, 8 squamous cell carcinomas and 1 adenocarcinoma were subsequently shown to contain only NCA immunoreactivity, while 19 squamous cell carcinomas and 5 adenocarcinomas contained both NCA and CEA immunoreactivity. NCA immunoreactivity alone was identified in 3 of 6 preneoplastic lesions and NCA and CEA immunoreactivity in 1 of 6 preneoplastic lesions. None of the markers was detected in 8 specimens of normal esophageal epithelium which were studied as controls, nor in 6 specimens of uninvolved esophageal epithelium obtained from patients with esophageal cancer. Most tumors expressed 2 or 3 markers, and some tumors were identified which expressed up to 4 of the 5 markers investigated. Only 3 tumors failed to express any of the markers studied. No association was found between the degree of tumor differentiation and presence or absence of HCG immunoreactivity. However, HPL immunoreactivity was more common in poorly differentiated squamous cell carcinomas. In contrast, immunoreactive AFP was more common in well-differentiated squamous cell carcinomas than in other tumor types. Similarly, both CEA and NCA were more frequently expressed in well-differentiated squamous cell carcinomas, adenosquamous carcinomas, and adenocarcinomas than in less differentiated tumors. Our results suggest that HCG, HPL, AFP, CEA, and NCA are tumor-associated antigens in esophageal cancer. Therefore, they could be of value in screening tests for esophageal neoplasms and could be useful in subclassification of esophageal neoplasms.

Antigens, Neoplasm↗
PubMed1986

Immunocytochemical evaluation of primary human esophageal carcinomas and their xenografts for keratin, beta-chorionic gonadotropin, placental lactogen, alpha-fetoprotein, carcinoembryonic antigen, and nonspecific cross-reacting antigen.

The unlabeled antibody peroxidase-antiperoxidase technique was used to examine esophageal neoplasms for the tumor markers beta-human chorionic gonadotropin, human placental lactogen (HPL), alpha-fetoprotein, carcinoembryonic antigen (CEA), and nonspecific cross-reacting antigen (NCA) before and after xenotransplantation to athymic nude mice. In addition, keratin was used as an epithelial cell marker. Immunoreactive beta-human chorionic gonadotropin was detected in four of seven primary tumors and in three of seven xenografts. Two of seven primary tumors contained HPL immunoreactive cells while four of seven tumor xenografts had HPL immunoreactivity. alpha-Fetoprotein was detected in two of seven primary tumors and in one of seven xenografts. NCA and CEA were detected in six of seven primary tumors and in all tumor xenografts. Five of seven primary neoplasms and six of seven tumor xenografts were found to contain both NCA and CEA, while one tumor and its xenografts displayed only NCA immunoreactivity. All seven primary carcinomas displayed keratin immunoreactivity, but only six of the seven xenograft tumors showed keratin positive cells. When a tumor marker was detected in a primary tumor, it was usually found in at least some of the xenografts arising from that tumor. However, marker loss did occur with repeated passage of tumors in some cases. On the other hand, markers were expressed in xenografts which were not present in the corresponding primary tumor. In three instances, HPL was detected in xenografts derived from HPL negative primary carcinomas. This was also true for CEA and NCA in one case. These results show that tumor markers are expressed to varying degrees by tumors growing as xenografts in nude mice. In primary tumors, HPL is associated with poorly differentiated squamous cell carcinomas and this marker was found to appear in HPL negative tumors as the tumor cells became less differentiated while growing as xenografts in nude mice.

Animals↗
PubMed1986

Interactive effects of chemical carcinogens and hepatitis B virus in the pathogenesis of hepatocellular carcinoma.

Liver cancer is one of the most prevalent forms of cancer in the world. Hepatitis B virus (HBV) is considered to be a major aetiological factor. Evidence from epidemiological studies has also indicated that environmental contaminants such as mycotoxins may, either in combination with HBV or independently, be important aetiological factors in the pathogenesis of primary hepatocellular carcinoma (PHC). Laboratory data also suggest an interplay between viral and chemical factors in the multifactorial aetiology of PHC. Aflatoxin B1, the chemical carcinogen most frequently implicated in the aetiology of hepatocellular carcinoma is a procarcinogen that must be activated by mixed-function oxidases to an electrophilic metabolite before it can exert its carcinogenic effects. Interindividual differences (greater than 10-fold) in the metabolic activation of aflatoxin B1 are observed. These differences may play a part in an individual's oncogenic susceptibility to aflatoxin B1. Chemical carcinogens and integrated HBV may activate cellular oncogenes, eg N-ras, and inactivate tumour suppressor genes. Recently developed methods that allow monitoring of aflatoxin B1 and HBV exposures and also genetic damage caused by these agents in individuals should help in biochemical and molecular epidemiological studies concerning the aetiology of hepatocellular carcinoma. We identify areas of uncertainties and of future experimentation and propose a hypothesis of liver carcinogenesis.

Aflatoxin B1↗
PubMed1986

Measurement of aflatoxin B1, its metabolites, and DNA adducts by synchronous fluorescence spectrophotometry.

Sensitive and specific methods are needed for measuring human exposure to carcinogens. Synchronous fluorescence spectrophotometry can be used to measure fmol of aflatoxins, their metabolites, and DNA adducts. Computer-assisted analysis of spectra of these agents obtained by synchronous fluorescence spectrophotometry can be displayed as contour maps which are highly specific for each agent. Individual agents in mixtures, e.g. aflatoxins B1 and M1, can be identified by fourth derivative spectral analysis. This physical method should complement immunological and other methods to measure aflatoxin B1, its metabolites, and nucleic acid adducts.

Aflatoxin B1↗
PubMed1986

Determination of polycyclic aromatic hydrocarbons in the urine, benzo(a)pyrene diol epoxide-DNA adducts in lymphocyte DNA, and antibodies to the adducts in sera from coke oven workers exposed to measured amounts of polycyclic aromatic hydrocarbons in the work atmosphere.

Workers in coke oven plants have a higher incidence of lung cancer than the general population. They are exposed to a variety of chemicals, in particular the polycyclic aromatic hydrocarbons (PAH), including benzo(a)pyrene. To evaluate the genotoxic effects of PAH exposure, air samples and urine samples were analyzed for PAH by capillary gas chromatography and high-performance liquid chromatography, respectively. Since benzo(a)pyrene is activated to 7 beta,8 alpha-dihydroxy-(9 alpha,10 alpha)-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene (BPDE) and binds to DNA, we have used ultrasensitive enzymatic radioimmunoassay and synchronous fluorescence spectrophotometry to measure BPDE-DNA adducts in lymphocyte DNA. The results show that workers were exposed to high concentrations of atmospheric PAH. However, the mean PAH exposure levels are reduced 60% when the workers wore masks during work. When compared to exposure levels, the urinary excretion of PAH was relatively low. Approximately one-third of the workers had detectable putative BPDE-DNA adducts in lymphocytes by ultrasensitive enzymatic radioimmunoassay, and 10% of the samples had emission peaks at 379 nm by synchronous fluorescence spectrophotometry. The four most positive samples were the same in both of the assays. Antibodies to an epitope(s) on BPDE-DNA were found in the sera of approximately one-third of the workers. Detection of DNA adducts and antibodies to these adducts are internal indicators of exposure to benzo(a)pyrene.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1985

Genotoxicity of formaldehyde in cultured human bronchial fibroblasts.

Formaldehyde, a common environmental pollutant, inhibits repair of O6-methylguanine and potentiates the mutagenicity of an alkylating agent, N-methyl-N-nitrosourea, in normal human fibroblasts. Because formaldehyde alone also causes mutations in human cells, the compound may cause genotoxicity by a dual mechanism of directly damaging DNA and inhibiting repair of mutagenic and carcinogenic DNA lesions caused by other chemical and physical carcinogens.

Bronchi↗
PubMed1985

Transformation of human bronchial epithelial cells transfected by Harvey ras oncogene.

Transfection of normal human bronchial epithelial (NHBE) cells with a plasmid carrying the ras oncogene of Harvey murine sarcoma virus (v-Ha ras) changed the growth requirements, terminal differentiation, and tumorigenicity of the recipient cells. One of the cell lines isolated after transfection (TBE-1) was studied extensively and shown to contain v-Ha ras DNA. Total cellular RNA from TBE-1 cells hybridized to v-Ha ras structural gene fragment probes five to eight times more than RNA from parental NHBE cells. The TBE-1 cells expressed phosphorylated v-Ha ras polypeptide p21, showed a reduced requirement for growth-factor supplements, and became aneuploid as an early cellular response to v-Ha ras expression. As the transfectants acquire an indefinite life-span and anchorage independence they became transplantable tumor cells and showed many phenotypic changes suggesting a pleiotropic mechanism for the role of Ha ras in human carcinogenesis.

Animals↗
PubMed1985

Normal human bronchial epithelial cells do not show an adaptive response after treatment with N-methyl-N'-nitro-N-nitrosoguanidine.

Normal human bronchial epithelial cells cultured in serum-free medium were exposed to low doses o N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) to examine whether increased cellular resistance and increased activity of the DNA-repair enzyme O6-methylguanine-DNA methyltransferase could be induced. After treatment with single doses of MNNG a dose-dependent decrease in O6-methylguanine-DNA methyltransferase activity was observed, as expected for this unique repair system. The activity recovered to the starting level in about 24 h when a dose that consumed approximately 65% of the enzyme activity (0.2 micrograms/ml) was given, but did not exceed the activity in the untreated control. Furthermore, treatment every 6 h for 4-5 days with non-toxic concentrations of MNNG (0.04-0.12 micrograms/ml) did not increase O6-methylguanine-DNA methyltransferase activity. Neither was cell survival following a range of challenge doses significantly increased. Our data suggest that human bronchial epithelial cells do not adapt to MNNG.

Bronchi↗