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Biomedical subjects

A Haugen

Publications and source records attributed to A Haugen.

At least 73 records · Page 4Linked to original sources
PubMed1991

Human CYP1A1 (cytochrome P(1)450) gene: lack of association between the Msp I restriction fragment length polymorphism and incidence of lung cancer in a Norwegian population.

In this study of 221 lung cancer patients and 212 controls, no association between a Msp I polymorphism in the CYP1A1 gene and an increased risk of lung cancer was found. Histological type, smoking habits and family history were also examined. No associations between the Msp I restriction fragment length polymorphism in the CYP1A1 gene and any of these parameters were found. These results are in contrast to a previous report by a Japanese group (Kawajiri et al., 1990) who found an association between the less common allele and an increased susceptibility to lung cancer in their population. The frequency of the less common Msp I 1.9 kb fragment allele (C2) appears to be three times greater in the Japanese population than in the Norwegian population and a Caucasian population of North America. It is possible that in the Asian population this Msp I polymorphism is in linkage disequilibrium with another mutation important for CYP1A1 gene expression, whereas in the Caucasian population these mutations are in equilibrium.

Adenocarcinoma↗
PubMed1990

Neoplastic transformation of a human kidney epithelial cell line transfected with v-Ha-ras oncogene.

We have recently shown that normal human kidney epithelial (NHKE) cells were immortalized by treatment with Ni(II) alone. In the present study the immortalized human kidney cell line (IHKE) was transfected with a plasmid construct containing the v-Ha-ras oncogene (pZipras). After transfection, the cell lines formed tumors in athymic nude mice, whereas the ZipNeoSV(X)-transfected IHKE control cultures formed no tumors. Tumor cell lines (THKE) were established from the tumors in nude mice. These cells appear to be of human epithelial origin and express high levels of Ha-ras transcript. Karyotypic analysis was performed. The cell lines were tri-, tetra- or pentaploid. A consistent finding in the IHKE, IHKZE and THKE cells was increased numbers of chromosomes 17 and 7p+. Some marker chromosomes were identical in the IHKE and THKE cell lines, underlining their common origin and their possible importance in the carcinogenic process. This shows that the combined action of a chemical carcinogen [i.e., Ni(II)] and v-Ha-ras oncogene resulted in fully transformed human kidney epithelial cells, consistent with a step-wise progression of human epithelial cell transformation.

Animals↗
PubMed1990

Ha-ras-1 alleles in Norwegian lung cancer patients.

We have examined DNA restriction fragment length polymorphisms (RFLP) of the Ha-ras-1 gene in DNA from 118 lung cancer patients and 123 unaffected controls. When DNA samples were digested with MspI/HpaII restriction endonucleases. Southern blot analysis demonstrated 4 common, 4 intermediate and 7 different rare alleles in the combined population after hybridization to the pGDa1 probe. Six of the rare alleles were unique for the lung cancer group and 1 rare allele for the control group. The frequency of rare alleles in lung cancer patients (10/236) was significantly different (P less than 0.01) from the control group (1/246). The lung cancer group also had a significantly lower frequency of the common 2.57 kb fragment than the controls (P less than 0.02). The results thus indicate that Ha-ras genotyping may be of value in lung cancer risk assessment.

Alleles↗
PubMed1990

Nematode related spinal myelomeningitis and posterior ataxia in muskoxen (Ovibos moschatus).

In the fall of 1988 all five animals in a herd of muskoxen (Ovibos moschatus) developed clinical signs of posterior ataxia. Postmortem investigation revealed inflammatory lesions of the caudal part of the spinal cord, mainly as leptomeningitis. Nematodes were seen in close association with the lesions. Although not identified, the parasites were probably an Elaphostrongylus sp.

Animals↗
PubMed1990

Polycyclic aromatic hydrocarbon-DNA adducts in coke-oven workers.

Different approaches for measuring occupational exposure to polycyclic aromatic hydrocarbons (PAHs) are presented, (i) determination of PAHs in the workplace by personal sampling, (ii) determination of urinary PAHs and PAH metabolites, and (iii) measurements of aromatic DNA adducts in white blood cells by ultra-sensitive enzyme radioimmunoassay (USERIA) and 32P-postlabelling. Large amounts of PAHs, including benzo[a]pyrene (BP), are released from the coke ovens. Mean PAH exposure levels were reduced by 60% when the workers used masks during work. However, low PAH concentrations were found in the urine of the exposed workers. Approximately 40% of the coke-oven workers had detectable levels of benzo[a]pyrene diol epoxide (BPDE)-DNA adducts in the white blood cells measured by USERIA and 90% had levels of aromatic adducts detectable by the 32P-postlabelling assay. In this study there was a correlation between DNA adduct levels and estimated exposure.

Air Pollutants, Occupational↗
PubMed1989

[Cancer--occupational exposure and genetics].

Carcinogenesis involves a complex interplay of environment and heredity. Several steps are involved in carcinogenesis. Oncogenes and anti-oncogenes influence carcinogenesis by becoming respectively activated or inactivated/lost in somatic cells. Damage to DNA in considered as the initial step in carcinogenesis. Metabolic activation of procarcinogen to an electrophilic intermediate may damage cellular DNA (via adduct formation) priming the process of cancer induction, which after promotion may result in cancer. Advances in our understanding of the mechanisms of chemical carcinogens are now being applied to improve assessment of human risk. In the past epidemiologic studies of the workplace have served to identify important human chemical carcinogens. However, molecular methods are now emerging which will serve in the prospective monitoring of genotoxic effects in the tissues of exposed individuals. Predisposing host factors to chemical toxicity and cancer probably exist. Advances in genetics may make it possible to evaluate human susceptibility factors and genes involved in malignant transformation of human cells. Only epidemiological studies can demonstrate that a chemical is a human carcinogen. For numerous chemicals, data relating to human carcinogenicity are insufficient. It is therefore reasonable for practical purposes to regard chemicals for which there is sufficient evidence of carcinogenicity in animals as presenting a carcinogenic risk to humans. Since hazard from chemical carcinogens depends upon how they are used, one should aim at a better education and information to the public about dangerous chemicals.

Animals↗
PubMed1989

Immortalization of normal human kidney epithelial cells by nickel(II).

The occupational and environmental hazards of nickel exposure are of great concern in environmental medicine. Nickel workers have increased risk of cancer of the nose, lung, larynx, and possibly the kidney. In the present investigation we have studied the effects of nickel ions on fetal human kidney cortex explants. The explants were continuously exposed to 5 micrograms/ml NiSO4. After 70-100 days in culture foci of phenotypically altered cells appeared. Immortalized cell lines were established and demonstrated to be of human epithelial origin. Tumorigenicity was not induced, but the cells demonstrated decreased requirement for serum, increased plating efficiency and saturation density, and formation of colonies in soft agar. Chromosome changes in the treated cells were observed. Worth mentioning are change in ploidy (3n) and abnormalities of chromosomes 1, 7, 9, 11, 13, 14 and 20; increased numbers of chromosome 17; and loss of normal chromosomes 20 and 22.

Carcinogens, Environmental↗
PubMed1989

Interleukin-1 alpha gene intron containing variable repeat region coding for the SP1 transcription factor recognition sequence is polymorphic.

Interleukin-1 alpha (IL-1 alpha) is a cytokine produced by a number of cell types including macrophages, fibroblasts, keratinocytes, and mesangial cells. We were interested in identifying a DNA restriction fragment length polymorphism (RFLP) for the IL-1 alpha gene for use in studies of genetic alteration in various human cancers. Human genomic DNA from 32 unrelated individuals was digested with various restriction enzymes, alone and in combination, and subjected to Southern blot analysis. Hybridization to 32P-labeled IL-1 alpha cDNA revealed an insertion-deletion-type polymorphic pattern. After digestion with RsaI, insertion-deletion-type polymorphic bands with sizes of 3.4 kb, 3.1 kb, and 2.8 kb and one invariant band of 0.8 kb were observed. These three alleles, designated A1, A2, and A3, had relative frequencies of 0.18, 0.06, and 0.78 with heterozygosity observed in 38% of the unrelated individuals studied. Evaluation of nine related individuals for this RsaI polymorphism was consistent with a Mendelian inheritance. Comparison of restriction patterns following Southern analysis of DNA digested with several different enzymes showed that the polymorphic region resides within the sixth intron. Furthermore, this RFLP results from a variable length region containing multiple copies of a recognition sequence for SP1, an imperfect copy of viral enhancer elements, and an inverse and complementary sequence of the glucocorticoid receptor binding site. The identified polymorphism may be of value in analyses of chromosome 2 and may help to elucidate mechanisms by which IL-1 alpha transcription is regulated.

Binding Sites↗
PubMed1989

Differential DNA sequence deletions from chromosomes 3, 11, 13, and 17 in squamous-cell carcinoma, large-cell carcinoma, and adenocarcinoma of the human lung.

Activation of protooncogenes and inactivation of putative tumor suppressor genes are genetic lesions considered to be important in lung carcinogenesis. Fifty-four cases of non-small-cell lung cancer (23 adenocarcinomas, 23 squamous-cell carcinomas, and 8 large-cell carcinomas) were examined for loss of DNA sequences at 13 polymorphic genetic loci. Loss of heterozygosity was seen more frequently in squamous-cell carcinoma than in adenocarcinoma. The loss of DNA sequences from the short arm of chromosome 17 (D17S1 locus) was detected in 8 of 9 heterozygous cases of squamous-cell carcinoma and in only 2 of 11 heterozygous cases of adenocarcinomas. Furthermore, in 7 of these 8 squamous-cell carcinomas, loss of heterozygosity from chromosome 17 was accompanied by loss of DNA sequences from chromosome 11. The spectrum of allelic sequences lost from chromosome 11 was, however, similar in every type of carcinoma studied, and the data show two regions commonly deleted from chromosome 11 (11pter-p15.5 and 11p13-q13) that may have a role in the pathogenesis of all these types of non-small-cell bronchogenic carcinoma. Loss of DNA sequences from chromosome 3 was seen in 16 of 31 cases where the constitutive DNA was heterozygous-i.e., informative. These data included only 6 of 16 cases where loss of heterozygosity involved a chromosomal locus previously shown to be lost consistently in small-cell lung cancer (DNF15S2). Loss of heterozygosity at the chromosome 13q locus, D13S3, was seen in 9 of 21 informative cases, and in 2 cases, both adenocarcinomas, duplication of the intact DNA sequences suggested the possibility that mitotic recombination had occurred. Frequent DNA sequence deletions, including those from chromosome 17, in squamous-cell carcinomas may reflect the extensive mutagenic and clastogenic effects of tobacco smoke that may lead to inactivation of putative tumor-suppressor genes.

Adenocarcinoma↗
PubMed1988

The application of immunoassays and fluorometry to the detection of polycyclic hydrocarbon-macromolecular adducts and anti-adduct antibodies in humans.

The metabolic activation of polycyclic aromatic hydrocarbons (PAH) to chemical species that form covalent adducts with cellular macromolecules (DNA and protein) is central to theories of carcinogenesis. Assays are currently being developed that will accurately reflect human macromolecular exposure to these carcinogens. Immunoassays are capable of detecting low levels of PAH-DNA adducts and antibodies directed against these adducts in humans and HPLC/spectrophotofluorimetry allows the detection of carcinogen-DNA or carcinogen-protein adducts in human peripheral blood. Both types of method have inherent advantages and disadvantages, and the use of more than one type of corroborative assay is a feature in our work. Simplified but highly specific synchronous fluorescence spectra have been obtained for BP-tetrols after mild acid hydrolysis and HPLC of sample materials. When using a wavelength difference of 34 nm to drive the excitation and emission monochromators simultaneously, the pyrene fluorophore, when present, has a signature peak at 345 nm (excitation). The results of immunoassays demonstrate human exposure to PAH as a class of carcinogen, since serological cross-reactivity of antibodies does not limit detection in this system to a single chemical compound. In addition the formation in humans of anti-PAH-DNA antibodies has been shown, presumably in response to both past and present exposure to the parent compounds. In summary the results of each assay can indicate human exposure to PAH and have the potential for molecular dosimetry of this exposure.

Antibodies↗
PubMed1988

DNA restriction fragment length polymorphism analysis of human bronchogenic carcinoma.

DNA restriction fragment length polymorphism (RFLP) analysis has been successfully applied both to evaluate possible human susceptibility factors as well as to identify genes involved in malignant transformation of human cells. In this report we review previous applications of RFLP analysis to evaluation of human malignancies and discuss our RFLP studies of human bronchogenic carcinoma, which are in progress. Preliminary results of our analysis of the RFLP associated with the cHa ras variable tandem repeat (VTR) indicate that rare alleles of this VTR are more frequent in patients with bronchogenic carcinoma than in controls.

Carcinoma, Bronchogenic↗
PubMed1986

Nitropyrene-induced DNA repair in Clara cells and alveolar type-II cells isolated from rabbit lung.

DNA excision repair, as measured by unscheduled DNA synthesis (UDS), was examined in different cell types of rabbit lung exposed to nitropolycyclic aromatic hydrocarbons (NO-PAH) in vitro. Dose-related increases in UDS were observed. 1,6-Dinitropyrene (1,6-DNP) and 1,8-dinitropyrene (1,8-DNP) induced UDS more effectively in alveolar type-II cells compared with Clara cells. On the other hand, 1-nitropyrene (1-NP) caused a weak UDS response in Clara cells but no DNA repair in alveolar type-II cells.

Animals↗
PubMed1986

Culture of rabbit pulmonary Clara cells.

Rabbit pulmonary Clara cells isolated by centrifugal elutriation have been cultured for several weeks. Clara cells generally adhered poorly to plastic but the cells did attach to coated substrates. A selected medium supported serial subculture of Clara cells for 4-5 passages (1:2 split). The medium consisted of a basal nutrient medium, alpha MEM, supplemented with insulin, transferrin, epidermal growth factor, D-glucose, biotin, alpha-tocopherol, pituitary extract, trace elements and 2% Sephadex G-10-filtered FBS. Freshly prepared Clara cells showed high capacity to activate 2-aminofluorene (AF) to mutagenic products. However, after 6 weeks of culture the mutagenic activation of AF was reduced by 92.5% indicating loss of cytochrome P-450.

Animals↗