Multimedia communications in health care.
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Computer Communication Networks↗
Biomedical subjects
D Brenner
Publications and source records attributed to D Brenner.
Casein kinase II is a negative regulator of c-Jun DNA binding and AP-1 activity.
c-Jun, a major component of the inducible transcription factor AP-1, is a phosphoprotein. In nonstimulated fibroblasts and epithelial cells, c-Jun is phosphorylated on a cluster of two to three sites abutting its DNA-binding domain. Phosphorylation of these sites inhibits DNA binding, and their dephosphorylation correlates with increased AP-1 activity. We show that two of these sites, Thr-231 and Ser-249, are phosphorylated by casein kinase II (CKII). Substitution of the third site, Ser-243, by Phe interferes with phosphorylation of the inhibitory sites in vivo and by purified CKII in vitro. Microinjection into living cells of synthetic peptides that are specific competitive substrates or inhibitors of CKII results in induction of AP-1 activity and c-Jun expression. Microinjection of CKII suppresses induction of AP-1 by either phorbol ester or an inhibitory peptide. These results suggest that one of the roles of CKII, a major nuclear protein kinase with no known functions, is to attenuate AP-1 activity through phosphorylation of c-Jun.
Amino Acid Sequence↗
DNA adducts and related biomarkers in populations exposed to environmental carcinogens.
Prevention of environmentally related cancer will be enhanced by the availability of sensitive early warning systems and by improvements in quantitative assessment of human risks. Accordingly, we have carried out a series of molecular epidemiologic studies aimed at validating a panel of biologic markers, including carcinogen-DNA and -protein adducts, sister chromatid exchange, micronucleus formation, DNA strand breaks, and DNA repair capacity. Results from three such studies illustrate the usefulness of these biomarkers in elucidating low-dose-response relationships, correlations between biomarkers, and the range of variation in biomarkers between individuals exposed to similar concentrations of carcinogens. Low-level workplace or ambient exposures to styrene, ethylene oxide, and polycyclic aromatic hydrocarbons (PAH) were associated with significant increases in both molecular dose of carcinogens (adducts) and various markers of preclinical effects. Correlations between biomarkers varied by exposure. For example, in the styrene study, sister chromatid exchange frequency was not correlated with any of the markers, in contrast to the studies of ethylene oxide and PAH. Significant molecular effects were observed not only in occupationally exposed people but also in residents of an area in Poland characterized by high levels of air pollution. For example, the mean PAH-DNA level in exposed residents (winter sample) was 30.4 adducts per 10(8) nucleotides. This level was significantly higher than that of adducts seen in summer samples from the same area (4.2/10(8), or in winter samples from residents of a rural area (11.01/10(8). Significant seasonal variation in PAH-DNA adduct formation in this group was consistent with recorded fluctuations in air pollution levels. Striking interindividual variation was observed in all three exposed populations.
Biomarkers↗
[Epidemiology of hypertension in old age].
This article shows the epidemiologic dimension of hypertension in the elderly. The number of the elderly in Switzerland is expected to increase significantly until the first decades of the new millenium; therefore, geriatric medicine and hypertension in the elderly in particular will become even more important than it is at present. Cardiovascular disease is blamed for a major share of prematurely lost years of life. In the past few years the age-standardized mortality of ischaemic heart disease has declined in Switzerland, while the rate for cerebrovascular disease has gone down earlier. The project MONICA may explain the reasons for these trends. Hypertension shows also in Switzerland a high prevalence, which even increases in older age groups. In the Framingham cohort study (USA) it was shown that hypertension is the most important risk factor for cardiovascular morbidity and mortalitity in the elderly. This is particularly true for the most common form of hypertension in the elderly, the isolated systolic hypertension. Because of the described demographic development, hypertension in the elderly, its prevention, diagnosis and management will become even more significant.
Adult↗
Biologic markers in risk assessment for environmental carcinogens.
The potential of biologic markers to provide more timely and precise risk assessments for environmental carcinogens is viewed against the current state-of-the-art in biological monitoring/molecular epidemiology. Biologic markers such as carcinogen-DNA adducts and oncogene activation are currently considered valid qualitative indicators of potential risk, but for most chemical exposures research is needed to establish their validity as quantitative predictors of cancer risk. Biologic markers have, however, already provided valuable insights into the magnitude of interindividual variation in response to carcinogenic exposures, with major implications for risk assessment.
Bias↗
DNA adducts and other biological markers in risk assessment for environmental carcinogens.
In order to validate a number of biologic markers as indicators of effective dose or potential risk, we have applied them in related cross-sectional, longitudinal and case-control studies. Biologic markers such as carcinogen-DNA adducts and activated oncogenes have already provided insights into mechanisms of chemical carcinogenesis. They have also given information regarding the extent of interindividual variation in biologic response within the human population. These results are directly relevant to quantitative risk assessment. However, more research is needed to establish quantitative links between biologic markers and human risk of cancer.
Biomarkers↗
Macromolecular adducts and related biomarkers in biomonitoring and epidemiology of complex exposures.
In order to evaluate the potential of biological markers in epidemiology and risk assessment of complex exposures, we review recent studies of macromolecular adducts and oncogene activation in human populations. Results are discussed in terms of the strengths and weaknesses of various study designs in order to identify the most promising approaches for future research.
Biomarkers, Tumor↗
[Omega-3-fatty acids: their value in nutrition and prevention].
Based on epidemiological, experimental and physiological evidence, this review examines whether omega-3 fatty acids (omega-3-PUFA) are cardioprotective and whether they are therefore relevant to the primary prevention of cardiovascular diseases. The high intake of omega-3-PUFA among Greenlandic Eskimos has been supposed to be a key factor for their low mortality rate of coronary heart disease (CHD). Other ecological studies from Norway and Japan suggest that higher fish consumption might be cardioprotective. Three cohort studies have shown an unequivocal inverse relation between fish-intake and CHD mortality, while two others--possibly for methodological reasons--have not shown clear overall associations. Several biological effects of omega-3-PUFA are known which may moderate and influence positively the pathogenesis of atherosclerosis. However, double-blind trials with clinical endpoints are not yet available to confirm these effects. For the time being, fish oil capsules should not be recommended as cardioprotective dietary supplementation, because some uncertainty about their long-term safety and dosage remains. Fish consumption is safe and modifies the FA-pattern of the diet favourably. From the point of view of prevention, rising fish intake up to twice or three times weekly can therefore be recommended for people residing in Switzerland.
Coronary Disease↗
Molecular epidemiology and cancer prevention.
A review of recent studies of biologic markers in populations with model exposures to carcinogens (cigarette smoke and polycyclic aromatic hydrocarbons) illustrates their potential role in cancer prevention. Data on macromolecular adducts and oncogene activation from cross-sectional, serial sampling and case-control studies demonstrate the usefulness of biologic markers in signalling a potential carcinogenic risk and in estimating the magnitude of interindividual variation within exposed groups. Recommendations for future research include nested case-control studies to establish the relationship between markers of biologic dose and effect (e.g., adducts, gene mutation, oncogene activation) and cancer risk.
Air Pollutants↗
Comparison of DNA adducts and sister chromatid exchange in lung cancer cases and controls.
In a molecular epidemiological study of lung cancer cases (n = 81) and noncancer controls (n = 67), polycyclic aromatic hydrocarbon (PAH)-DNA adducts were evaluated in peripheral blood leukocytes from all subjects and in a smaller number of lung tissue specimens collected prior to or at surgery. Sister chromatid exchanges (SCE) in lymphocytes were also studied in a subset of cases and controls. Questionnaire, medical record, or tumor registry data provided a family history of cancer, as well as information on cigarette smoking, dietary and occupational exposure to PAHs, and other factors related to SCEs. In both cases and controls PAH-DNA adducts in leukocytes measured by an enzyme-linked immunosorbent assay were not significantly related to age, sex, ethnicity, amount of cigarette smoking, passive smoking, dietary charcoal, or caffeine consumption. Nor did family history of cancer or histological type of cancer significantly affect adduct levels. However, when subjects were stratified by smoking status (current, former, and nonsmoker), lung cancer cases who were current smokers had significantly higher levels of covalent adducts than current smoker controls. A seasonal variation was observed in PAH-DNA binding, with a peak in adduct levels during July-October. This peak corresponds to that seen in a prior study of aryl hydrocarbon hydroxylase inducibility by other investigators. The finding of significant levels of PAH-DNA adducts in former smokers and non-smokers supports an earlier observation that this marker is not smoking specific but reflects a pervasive and variable "background" exposure to PAH. These results are consistent with a genetically determined enhancement of PAH-DNA adduct formation in leukocytes of lung cancer cases which is evident in current smokers. The results in lung tissue are limited by the small number of samples. Adduct levels were not significantly increased in lung tissue of smokers compared with nonsmokers. An inverse linear correlation was seen between adduct values in lung tissue and age of the donors. SCEs were significantly related to pack years of smoking. However, there was no difference in the frequency of SCE between cases and controls; nor were SCE and DNA adducts significantly correlated in this small sample.
DNA, Neoplasm↗
Detection of polycyclic aromatic hydrocarbon-DNA adducts in white blood cells of foundry workers.
Iron foundry workers, exposed to high levels of polycyclic aromatic hydrocarbons (PAHs), silica, and metal fumes and dusts, are at elevated risk of lung cancer. Benzo(a)pyrene and a number of structurally related PAHs are metabolically activated to diol epoxides (e.g., 7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10-tetrahydrobenzo(a) pyrene) which are mutagenic, carcinogenic in experimental animals, and form covalent adducts with DNA. The levels of these adducts were measured in an enzyme-linked immunosorbent assay using a polyclonal anti-benzo(a)pyrene diol epoxide-I-DNA antibody which cross-reacts with DNA modified by diol epoxides of structurally related PAHs. DNA was analyzed from peripheral blood cells of 35 Finnish foundry workers and 10 controls. Workers were classified as having low (less than 0.05 micrograms/m3), medium (0.05-0.2 micrograms/m3), or high (greater than 0.2 micrograms/m3) exposure to benzo(a)pyrene (as an indicator of PAH). When adjustment was made for cigarette smoking and time since vacation, benzo(a)pyrene exposure was significantly related to adduct levels (P = 0.0001). Each of the three exposure groups had significantly elevated adduct levels compared to controls. Among the exposed workers, the low group differed significantly from the high and medium categories. This study supports the usefulness of monitoring adduct formation in a population occupationally exposed to carcinogens.
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
Application of biological markers to the study of lung cancer causation and prevention.
Lung cancer is now the major cause of cancer deaths in the USA and is an increasingly significant cancer worldwide. Biological markers could be used to prevent lung cancer by allowing more timely and precise understanding of the role of environmental factors. So far, biological markers that can serve as carcinogen dosimeters have been investigated in only a small number of pilot studies of populations with current or past exposure to lung carcinogens. We describe several of our collaborative studies involving smokers, various worker populations, lung cancer cases and controls in order to illustrate the advantages and the limitations of 'molecular epidemiology'. The enzyme-linked immunosorbent assay (ELISA) with antibodies to polycyclic aromatic hydrocarbon (PAH)-DNA adducts has been used in conjunction with one or more of the following: physicochemical techniques to monitor carcinogen adducts on haemoglobin, cytogenetic methods to quantify sister chromatid exchange (SCE) and chromosomal aberrations, and Southern and western blot analyses of oncogene activation. Increased levels of markers of biologically effective doses have generally been seen in exposed and high-risk groups when compared to controls. We have also observed significant background levels of such markers and interindividual variation in levels of certain biological markers resulting from exposures to carcinogens. Thus, these methods may be particularly useful in identifying segments of the population that have received a significant effective dose and hence can be considered to be at elevated risk of cancer. Such studies are necessary to validate laboratory methods and lay the groundwork for more definitive molecular epidemiological investigations of lung cancer.
Biomarkers↗
DNA adducts, protein adducts, and sister chromatid exchange in cigarette smokers and nonsmokers.
In order to validate markers of internal dose and biologically effective dose of carcinogens, a battery of measurements was made on blood samples from 22 smokers and 24 nonsmokers. The markers included immunoreactivity in an enzyme-linked immunosorbent assay (ELISA) quantified in white blood cells with the use of a polyclonal anti-benzo[a]pyrene diol epoxide-I-DNA antibody, 4-aminobiphenyl hemoglobin (4-ABP-Hb) adducts measured by negative chemical ionization mass spectrometry, sister chromatid exchange (SCE) in cultured lymphocytes, and cotinine in plasma measured by radioimmunoassay. Several blood samples were drawn from each subject. In blood samples 1 and 3 having detectable levels of DNA adducts, mean femtomole-per-microgram levels were consistently higher among smokers compared to nonsmokers. The borderline significance of this difference may be attributable to the small numbers of subjects. Consistently higher adduct levels were seen in females compared to males. In sample 3, adduct levels were significantly correlated with measurements of active smoking in smokers and with passive smoking in nonsmokers. By contrast to the ELISA data, which may reflect cumulative exposure from multiple background sources, the 4-ABP-Hb assay was able to distinguish clearly between smokers and nonsmokers. SCEs were significantly elevated in the smokers compared to nonsmokers. Also observed were significant correlations between 4-ABP-Hb and both cotinine and SCEs, as well as a positive correlation between the 4-ABP-Hb and DNA adduct levels (sample 3) that was highly significant. The correlation between DNA and 4-ABP-Hb adducts was significant in smokers but not nonsmokers (sample 3). These results support the need for batteries of markers to detect and to quantify the carcinogenic dose to humans resulting from both specific and "background" environmental exposures.
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
Doxorubicin and doxorubicinol-induced alterations in human polymorphonuclear leukocyte oxygen metabolite generation.
The effects of doxorubicin and its primary metabolite doxorubicinol on the polymorphonuclear leukocyte (PMNL) respiratory burst were studied using lucigenin and luminol for detection of oxygen metabolite generation. Although both anthracyclines inhibited PMNL activation at concentrations achieved with therapeutic administration of doxorubicin, doxorubicinol was much more potent than doxorubicin. Preincubation of PMNL with either drug caused a persistent inhibition of cell function after drug washout that was not prevented by inclusion of either free radical scavengers or iron chelators in the incubation medium. Although complete suppression of the PMNL respiratory burst occurred with concentrations of doxorubicinol greater than 0.3 microgram/ml, a marked potentiation of the response was observed at lower concentrations (0.01 or 0.03 microgram/ml) of the same drug. Potentiation occurred only when albumin was present in the reaction medium, was eliminated by iron chelators, was not observed after PMNL incubation with drug and was dependent upon the activating agent. In contrast to doxorubicinol, doxorubicin did not potentiate the PMNL respiratory burst. These results demonstrate potent effects of doxorubicinol on PMNL oxygen metabolite generation that are markedly greater in degree and different in character than those of doxorubicin. Because both inhibitory and enhancing effects are apparent at concentrations of doxorubicinol achieved in vivo, this metabolite may be important in the clinically observed toxicity of doxorubicin.
Adult↗
Phase II trial of diaziquone in anthracycline-resistant adult soft tissue and bone sarcoma patients: a Southeastern Cancer Study Group Trial.
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Adult↗
Computed tomography in invasive carcinoma of the cervix: an appraisal.
The clinical staging, computed tomographic scans, and surgical findings in 42 patients with cervical carcinoma were compared prospectively to determine the accuracy and clinical utility of computed tomography in demonstrating extent of disease and involvement of paraaortic lymph nodes. Computed tomography was of limited value in stage IB and IIB tumors, but was comparable in accuracy to clinical examination in the assessment of IIB disease. Computed tomography was of value in radiation therapy and may detect unsuspected bony metastases (stage IVB). Retroperitoneal adenopathy can be detected by computed tomography with an overall accuracy of 83% and a specificity of 86%. Computed tomography is an important adjunct in determining tumor extent in more advanced disease (stages IIIB and IVB) and in detecting paraaortic adenopathy.
Female↗
Modulation transfer functions of the human visual system revealed by magnetic field measurements.
Properties of a neural source of magnetic field localized in the occipital lobe was measured in a steady-state paradigm using contrast reversing gratings. Comparisons with scalp potentials provided evidence that the evoked field was associated with intracellular currents. Its modulation transfer functions were similar to the analogous functions for the scalp potential and the detection of a grating. Moreover, the amplitude of the evoked field was linearly related to the potential amplitude and their phases were nearly identical. An analysis of the results in terms of theoretical relations between evoked field and potential led us to conclude that these two measures may yield a similar characterization of the source when one dipolar source predominantly gives rise to both measures, but they may yield complementary information when multiple sources contribute to the measures.
Evoked Potentials, Visual↗
Conversations with schizophrenics.
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Chronic Disease↗