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Biomedical subjects

C C Harris

Publications and source records attributed to C C Harris.

At least 307 records · Page 17Linked to original sources
PubMed1985

Asbestos-associated chromosomal changes in human mesothelial cells.

Replicative cultures of human pleural mesothelial cells were established from noncancerous adult donors. The cells exhibited normal mesothelial cell characteristics including keratin, hyaluronic acid mucin, and long branched microvilli, and they retained the normal human karyotype until senescence. The mesothelial cells were 10 and 100 times more sensitive to the cytotoxic effects of asbestos fibers than normal human bronchial epithelial or fibroblastic cells, respectively. In addition, cultures of mesothelial cells that survived two cytotoxic exposures of amosite fibers were aneuploid with consistent specific chromosomal losses indicative of clonal origin. These aneuploid cells exhibit both altered growth control properties and a population doubling potential of greater than 50 divisions beyond the culture life span (30 doublings) of the control cells.

Asbestos↗
PubMed1985

Detection of benzo[a]pyrene diol epoxide-DNA adducts in peripheral blood lymphocytes and antibodies to the adducts in serum from coke oven workers.

Coke oven workers are exposed to high levels of carcinogenic polycyclic aromatic hydrocarbons, including benzo[a]pyrene (B[a]P), and are at increased risk of lung cancer. Since B[a]P is enzymatically activated to 7 beta,8 alpha-dihydroxy(9 alpha, 10 alpha)epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (B[a]PDE) that forms adducts with DNA, the presence of these adducts was measured in DNA from peripheral blood lymphocytes by synchronous fluorescence spectrophotometry and enzyme radioimmunoassay. Approximately two-thirds of the workers had detectable levels of B[a]PDE-DNA adducts. Antibodies to the DNA adducts were also found in the serum of 27% of the workers. B[a]PDE-DNA adducts were not detectable in lymphocytes and antibodies to the adducts were not detected in sera from a control group of nonsmoking laboratory workers. DNA adducts and/or antibodies to the adducts indicate exposure to B[a]P and its metabolic activation to the carcinogenic metabolite that covalently binds to and damages DNA. Detection of adducts and antibodies to them may also be useful as internal dosimeters of the pathobiological effective doses of chemical carcinogens.

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

Cytotoxicity, thiol depletion and inhibition of O6-methylguanine-DNA methyltransferase by various aldehydes in cultured human bronchial fibroblasts.

Lipid peroxidation aldehydes of the 4-hydroxy-alpha, beta-unsaturated type, as well as the tobacco-smoke related alpha, beta-unsaturated aldehyde, acrolein, were highly cytotoxic and decreased the intracellular thiol content in cultured human bronchial fibroblasts after treatment with micromolar concentrations. In comparison, formaldehyde and acetaldehyde were less toxic and 100- to 300-fold higher doses were required to affect cell survival or thiol levels. The unsaturated aldehydes also markedly inhibited the DNA repair enzyme O6-methylguanine-DNA methyltransferase known to have a cysteine residue in its active site, but had no effect on the activity of uracil-DNA glycosylase. Our results indicate that reactive aldehydes of either exogenous or endogenous origin have direct cytotoxic effects and may also make cells more susceptible to other toxic chemicals due to an impairment in cellular defense mechanisms, e.g., DNA repair and detoxification by systems requiring glutathione.

Aldehydes↗
PubMed1985

An applied synchronous fluorescence spectrophotometric assay to study benzo[a]pyrene-diolepoxide-DNA adducts.

Synchronous scanning fluorescence with a fixed wavelength difference (delta lambda) of 34 nm between excitation and emission was used to quantitate benzo[a]pyrene-diol epoxide (BPDE)-DNA adducts. Fluorescence emission maxima occurred at 382 nm for BPDE-DNA and at 379 nm for benzo[a]pyrene-tetrols and -triol, which are hydrolysis products of BPDE. Similarly, the peak for pyrene was at 372 nm and for 1-nitropyrene at 386 nm. The minimum detectable amount of BPDE-moieties in in vitro modified BPDE-DNA, after hydrolysis in HCl, was 20 fmol in 100 micrograms of DNA, which is equivalent to 1 adduct per 1.4 X 10(7) nucleotides. The correlation of fluorescence intensity and the amount of BPDE-moieties was linear between 20 fmol and 1 pmol. DNA isolated from human lymphoblasts incubated with BPDE had the same fluorescence peak and the correlation between the fluorescence intensity and the amount of BPDE in the incubation mixture was linear. Among the DNA-samples from peripheral blood lymphocytes of 30 aluminum plant workers, only one sample was found to contain a peak similar to BPDE-DNA. None of the DNA-samples from 10 persons not occupationally exposed were positive. Measurement of BPDE-DNA adducts by synchronous fluorescence spectrophotometry should be useful in monitoring human exposure to benzo[a]pyrene.

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

Esophageal source measurement of Tc-99m attenuation coefficients for use in left ventricular volume determinations.

A linear attenuation coefficient for water (mu = .15 cm-1) at 140 keV has been used in the determination of left ventricular volumes (LVV) by attenuation-corrected equilibrium methods. This theoretical value ignores the effect of Compton scatter and thus may be too high for human LVV determinations. The effective attenuation coefficient, mu', of the human chest was determined in ten normal volunteers using a Tc-99m esophageal source imaged with a gamma camera. Values for mu' at 30 degrees LAO in end-expiration, quiet breathing, and end-inspiration were .125 +/- .006 cm-1, .125 +/- .005 cm-1, and .113 +/- .007 cm-1, respectively (95% confidence interval). Values of mu' at 45 degrees LAO were .122 +/- .006 cm-1, .119 +/- .007 cm-1, and .099 +/- .009 cm-1, respectively, for the same conditions. The measured value of mu' for the source in a water phantom was .127 +/- .001 cm-1. This suggests that a value of mu' of .125 cm-1 may be appropriate for use in determining LVV in patients.

Adult↗
PubMed1985

Benzo(a)pyrene diolepoxide-DNA adducts detected by synchronous fluorescence spectrophotometry.

Using benzo(a)pyrene (BP) as a model carcinogen we are currently applying a fluorescence technique to detect the very low levels of carcinogen-DNA adducts in human populations due to environmental exposure. In synchronous fluorescence spectrophotometry for detection of BP-diol epoxide-DNA, excitation and emission wavelengths are scanned simultaneously with a fixed wavelength difference (delta lambda) of 34 nm. Compared to conventional fluorescence methods only one peak emerges because excitation and emission peaks have to match delta lambda to show. Because of the quenching effect of DNA, samples are hydrolyzed by acid. After this, BP-diol epoxide (BPDE)- -modified DNA gives a peak at the same wavelength and of the same fluorescence yield as BP-tetrols. When DNA from peripheral blood lymphocytes of 44 coke oven workers were analyzed, 10 had a sharp peak at 379. Among 36 coke oven workers from another factory, 4 had detectable levels of adducts. A much smaller percentage of samples was positive in a group of aluminum plant workers. We have also found BPDE-DNA adducts in DNA from pulmonary alveolar macrophages and peripheral blood lymphocytes from tobacco smokers and some of the nonsmokers.

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

Detection of 8,9-dihydro-(7'-guanyl)-9-hydroxyaflatoxin B1 in human urine.

A possible role of aflatoxin B1 (AFB) in the etiology of human liver cancer has been suggested from several epidemiological studies. This has been based upon the association between consumption of AFB-contaminated food and the liver cancer incidence in different parts of the world. To further establish the role of AFB as a major factor, we initiated a pilot study in three different districts of Kenya to determine the number of individuals exposed to significant amounts of AFB as measured by the urinary excretion of 8,9-dihydro-8-(7-guanyl)-9-hydroxyaflatoxin B1 (AFB-Gua), an adduct formed between the ultimate carcinogenic form of AFB and nucleic acids. This product has previously been detected in urine from rats treated with AFB. Urine collected at the outpatient clinics at the district hospitals were concentrated on C18 Sep-Pak columns and analyzed by high-pressure liquid chromatography under two different chromatographic conditions. The chemical identity of the samples showing a positive response in both chromatographic systems was verified by synchronous scanning fluorescence spectrophotometry. The highest number of individuals with detectable urinary AFB-Gua lived in either Murang'a district or the neighboring Meru and Embu districts. In Murang'a district a rate of 12% was observed in the January-March period, while only 1 of 32 patients (3%) had a detectable exposure in July-August.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1985

Future directions in the use of DNA adducts as internal dosimeters for monitoring human exposure to environmental mutagens and carcinogens.

Scientific opportunities generally arise when two or more research areas converge and/or advances in methodology occur. This occurred at the turn of the 19th century in the field of infectious bacterial and fungal diseases. As we draw near to the 21st century, research in the laboratory is providing us with both critical information on mechanisms of carcinogenesis and new technological advancements, including those in immunology, biochemistry, and molecular biology. Investigations in the field of epidemiology have clearly demonstrated the importance of environmental exposure to carcinogens and have identified populations at high cancer risk. It is now practical to integrate laboratory determinations into classic epidemiological approaches. Several markers, e.g., carcinogen-DNA adducts, related to tumor initiation and perhaps to tumor conversion, are currently being evaluated. We also need to develop indicators of tumor promotion and progression. The potential of biochemical and molecular epidemiology to predict cancer risk in an individual prior to the onset of clinically evident cancer provides an exciting new opportunity in cancer research and prevention.

Animals↗
PubMed1985

In vitro studies of human lung carcinogenesis.

Advances in the methodology to culture normal human lung cells have provided opportunities to investigate fundamental problems in biomedical research, including the mechanism(s) of carcinogenesis. Using the strategy schematically shown in Figure 1, we have initiated studies of the effects of carcinogens on the normal progenitor cells of the human cancers caused by these carcinogens. Extended lifespans and aneuploidy were found after exposure of mesothelial cells to asbestos and bronchial epithelial cells to nickel sulfate. These abnormal cells may be considered to be preneoplastic and at an intermediate position in the multistage process of carcinogenesis. Human bronchial epithelial cells can also be employed to investigate the role of specific oncogenes in carcinogenesis and tumor progression. Using the protoplast fusion method for high frequency gene transfection, vHa-ras oncogene initiates a cascade of events in the normal human bronchial cells leading to their apparent immortality, aneuploidy, and tumorigenicity in athymic nude mice. These results suggest that oncogenes may play an important role in human carcinogenesis.

Animals↗
PubMed1985

Intermediate filament and cross-linked envelope expression in human lung tumor cell lines.

Human lung tumor cell lines established from the major histological types of lung cancer were examined by immunofluorescent staining techniques for their patterns of intermediate filament (keratin, vimentin, and neurofilament triplet protein) expression. All cell lines examined, both small cell lung carcinoma (SCLC) and non-SCLC (squamous cell carcinoma, adenocarcinoma, large cell carcinoma, and mesothelioma) contained keratin, consistent with their epithelial derivation. These lung carcinoma cell lines also expressed vimentin, the characteristic intermediate filament of mesenchymal cells in vivo. In light of the proposed neuroectodermal origin of SCLC, cell lines were also studied for neurofilament expression. Two of four SCLC tumor cell lines, as well as non-SCLC cell lines, showed no reactivity with antibodies to neurofilament triplet protein. Two of the SCLC cell lines stained weakly with anti-neurofilament antibody. Examination of specific keratin patterns in human lung tumor cell lines by selective immunoprecipitation with keratin antiserum and sodium dodecyl sulfate-polyacrylamide gel electrophoresis indicated that small-sized keratin proteins (Mr 44,000 to 52,000) were present in cell lines derived from SCLC and non-SCLC types of lung cancer. Tumor cell lines exhibiting squamous differentiation by light microscopic criteria (i.e., intracellular keratin, intercellular bridging, "pearl" formation, and/or individual cell keratinization) also displayed a preponderance of intermediate-sized keratins (Mr 57,000 and 59,000) and exhibited another feature of terminal keratinocyte differentiation (cross-linked envelope formation). Mesothelioma cell lines had varying keratin profiles. The presence of keratin proteins in all SCLC cell lines examined argues against a neuroectodermal origin for these tumors and is consistent with the notion that these tumors arise from a common bronchial "stem cell," similar to that from which other types of bronchogenic carcinomas arise.

Animals↗
PubMed1985

Factors affecting ventricular volumes determined by a count-based equilibrium method.

Using a 99mTc-filled source ("ventricle") in an elliptical torso phantom, we analyzed the effect of source depth, region of interest (ROI) size, background concentration and source shape on volumes determined by an attenuation-corrected count-based equilibrium method. The calculated volume of a 96 cc sphere decreased linearly from 103 to 82 cc with increasing depth from 4 to 18 cm [vol = -1.48 X depth (cm) + 109, r = 0.99]. The calculated volume of the same sphere imaged at a depth of 9 cm increased from 98 to 117 cc with ROI sizes increasing from 161 to 1,369 pixels (1 pixel = 0.17 cm2). With increasing background concentration from 0-2 microCi/ml calculated volumes decreased from 95 to 85 cc (vol = -5.3 X background concentration (microCi/ml) + 95, r = 0.97). However, with correction for over-subtraction of background, increasing background activity caused no decrease in calculated volume (mean = 95 cc, s.d. = 1). Calculated volumes for the sphere and various cylinders were accurate, while those for cones were up to 37% lower for actual volumes ranging from 56-608 cc. This study demonstrates that multiple factors produce variability in count-based determination of phantom volumes. A careful consideration of the interaction of these factors with the edge-detection and computational algorithms is required.

Cardiac Output↗
PubMed1985

Detection of benzo(a)pyrene:DNA adducts in human white blood cells.

Metabolic activation of benzo(a)pyrene (BP) to its ultimate carcinogenic form, 7 beta, 8 alpha-diol-9 alpha, 10 alpha-benzo(a)pyrene epoxide (BPDE), and the binding of BPDE to DNA are important steps in BP carcinogenicity in experimental animals. Since people of certain occupations are exposed to high concentrations of BP, we have used enzyme-linked immunosorbent assay and ultrasensitive enzymatic radioimmunoassay to measure BPDE:DNA adducts in white blood cells from 2 of these occupational groups. Seven of 28 samples from roofers and 7 of 20 samples from foundry workers were positive for BPDE:DNA adducts (range, 2 to 120 fmol BPDE/50 micrograms DNA). In a group of nine volunteers without these industrial exposures to BP, the two positive DNA samples were from cigarette smokers. Control DNA obtained from human lymphocyte cell line RPMI 4265 was negative. These results indicate that the metabolic activation of BP and formation of BPDE:DNA adducts occurs in humans.

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