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R E Tarone

Publications and source records attributed to R E Tarone.

At least 127 records · Page 7Linked to original sources
PubMed1987

On the efficiency of age-adjusted tests in animal carcinogenicity experiments.

Based on asymptotic relative efficiency calculations, Ryan (1985, Biometrics 41, 525-531) concludes that, in the analysis of animal carcinogenicity experiments, age-adjusted tests of tumor rates should be routinely preferred to simple proportions tests for both lethal and nonlethal tumors. We recalculate the asymptotic efficiencies of the simple proportions test relative to the log-rank test for the lethal tumor case. For a simplified model it is shown that the relative efficiency may be easily computed as a function of the crude tumor rate and the survival rate at the time of terminal sacrifice. More generally, we calculate by numerical quadrature the asymptotic relative efficiency for all models considered by Ryan and, using simulations, examine the relevance of asymptotic efficiencies to typical sample sizes. Contrary to the numerical results of Ryan, we find, for experiments with good survival and typical tumor rates, that the relative efficiencies are greater than 95%, usually about 99%. In the nonlethal tumor case, similar results follow from Ryan for tumor rates and survival rates typically encountered in practice. As it is often difficult to determine whether or not a tumor is lethal, we conclude for equal interim mortality rates, that the simple proportions test is usually adequate in evaluating animal carcinogenicity experiments.

Age Factors↗
PubMed1986

Chromosomal radiosensitivity during the G2 cell cycle period and cytopathology of human normal x tumor cell hybrids.

The relationship between tumorigenicity and enhanced chromosomal radiosensitivity during the G2 cell cycle phase was examined through the use of nontumorigenic human cell hybrids and their nontumorigenic and tumorigenic segregants. The hybrid cells were produced by fusion of a normal and tumor cell. The parental lines, including HeLa and three fibroblast lines, one of skin and two of fetal lung origin, were also examined. The tumorigenic lines, which had cytological features associated with clinical cancer, showed a significantly higher incidence of chromatid breaks and gaps following X-irradiation during G2 than the normal skin line or the nontumorigenic hybrids. The hybrids and their nontumorigenic subclones had cytological features which are predominantly found with a benign clinical course and had the G2 chromosomal radiosensitivity more characteristic of the normal parental cells. Like tumorigenic cells, fetal cells exhibited enhanced G2 chromosomal radiosensitivity which could be suppressed in fetal X tumor cell hybrids. This observation suggests that the molecular basis for radiosensitivity in fetal cells differs from that of tumor cells. The enhanced G2 chromosomal radiosensitivity of a tumor cell, which appears to result from deficient DNA repair, is suppressed by fusion with a normal cell. Thus, the radiosensitivity, like tumorigenicity, behaves as a recessive trait. Although a Mendelian analysis is not possible with this material, the segregation of enhanced G2 chromosomal radiosensitivity with the neoplastic phenotype suggests that the two may be genetically linked.

Cell Line↗
PubMed1985

G2 chromosomal radiosensitivity of ataxia-telangiectasia heterozygotes.

Five lines of skin fibroblasts from individuals heterozygous for ataxia-telangiectasia (A-T), compared with six cell lines from age-matched normal controls, show a much higher frequency of chromatid breaks and gaps following x-irradiation during the G2 phase of the cell cycle. The magnitude of this difference suggests that G2 chromatid radiosensitivity could provide the basis for an assay to detect A-T heterozygotes. Though clinically normal, A-T heterozygotes share a high risk of cancer with A-T homozygotes and constitute approximately 1% of the human population. Further, we propose that G2 chromosomal radiosensitivity, which appears to result from a DNA repair deficiency, may be associated with a genetic predisposition to cancer.

Ataxia Telangiectasia↗
PubMed1985

History, survival, and growth patterns of B6C3F1 mice and F344 rats in the National Cancer Institute Carcinogenesis Testing Program.

The history of, and rationale for, the selection of the hybrid B6C3F1 mouse (C57BL/6 female X C3h/He male) and the inbred F344 rat for National Cancer Institute (NCI) bioassays is described. Survival percentages at the end of 2-year tests and weight-gain patterns during the tests of control animals are presented to guide investigators using these same animals in similar long-term experiments. Because information on a large number of animals (9385 mice and 10,023 rats) from a number of laboratories is presented, the conclusions should serve to give general guidance to investigators holding the same animals under a diversity of husbandry conditions. The program experience has been that the B6C3F1 mouse survival at the end of a 24-month study (25.5 months of age) is 80%; the F344 survival for the same period is 75%. This contrasts with the generally held assumption that rats are longer lived than mice. For the period of time from which animal data were collected, there was a progressively slight decrease overall in survival percentage. This observation cannot be explained, and contravenes the expectation that methodological improvements in producing the animals and marked physical improvements in the testing laboratories should have resulted in improving the survival. Weight gain patterns have a distinct and somewhat similar sexual dimorphism for both rat and mouse. The males of each species grow much faster initially and then essentially level off. The female mouse grows slowly and steadily, and by 2 years of age almost equals the male; the female rat shows the same steady gain, but is much lighter than the male at 2 years of age.

Aging↗
PubMed1985

Influence of added catalase on chromosome stability and neoplastic transformation of mouse cells in culture.

The generation of hydrogen peroxide (H2O2) and the derivative free hydroxyl radical (. OH) in cultures of mouse cells grown in the presence of visible light and ambient oxygen was shown previously to be implicated in chromatid damage. Furthermore, chromosome alterations appear to be associated with the spontaneous neoplastic transformation of mouse cells in culture. An attempt was made in this study to reduce the incidence of chromosomal aberrations and delay or prevent the onset of spontaneous neoplastic transformation of freshly isolated mouse cells, both fibroblasts and epidermal keratinocytes, by adding catalase to the culture medium, shielding the cultures from wavelengths less than 500 nm and providing a gas phase of 0-1% O2. These conditions significantly decreased the incidence of chromosomal aberrations in both cell types, and in fibroblasts prevented tumourigenicity in non-irradiated syngeneic mice, and increased latent periods for tumour development in X-irradiated mice. The epidermal keratinocytes were particularly resistant to spontaneous neoplastic transformation under all conditions tested. These observations on the protective effect of extracellular catalase suggest that H2O2, a normal metabolite, and/or the derivative .OH can directly or indirectly produce genetic damage and neoplastic transformation in mouse fibroblasts.

Animals↗
PubMed1985

Parkinson's disease and Alzheimer's disease: hypersensitivity to X rays in cultured cell lines.

Fibroblast and/or lymphoblastoid lines from patients with several inherited primary neuronal degenerations are hypersensitive to DNA-damaging agents. Therefore, lymphoblastoid lines were irradiated from patients with sporadic Parkinson's disease (PD), Alzheimer's disease, and amyotrophic lateral sclerosis. The mean survival values of the eight Parkinson's disease and of the six Alzheimer's disease lines, but not of the five amyotrophic lateral sclerosis lines, were less than that of the 28 normal lines. Our results with Parkinson's disease and Alzheimer's disease cells can be explained by a genetic defect arising as a somatic mutation during embryogenesis, causing defective repair of the X-ray type of DNA damage. Such a DNA repair defect could cause an abnormal accumulation of spontaneously occurring DNA damage in Parkinson's disease and Alzheimer's disease neurons in vivo, resulting in their premature death.

Adolescent↗
PubMed1985

Cockayne syndrome: clinicopathologic and tissue culture studies of affected siblings.

Two siblings with Cockayne syndrome (CS) had extremely severe and early onset cachectic dwarfism, developmental delay, cataracts, microcephaly, peripheral neuropathy, and spastic quadriplegia. In order to study the inherited DNA-repair defect known to be present in cultured CS cells, a lymphoblastoid line was established from the younger sibling. Tissue culture studies revealed the line to have a hypersensitivity to the lethal effects of 254-nm ultraviolet radiation (UV) equivalent to that of lymphoblastoid lines from CS patients who had either the usual severity or a very mild form of CS. Autopsy of the older sibling at six years of age showed the brain to be severely atrophic, with particularly severe cerebellar atrophy. There was a marked reduction in the number of granule cells in the cerebellum and irregular patchy myelination throughout the brain. Many astrocytes contained either a large, bizarre-shaped nucleus or multiple nuclei. Some Purkinje cells of the cerebellum and pyramidal neurons of the hippocampus were binucleated. It is suggested that the DNA-repair defect of CS causes abnormalities in nuclear DNA replication and cell division which result in cell death and in the observed nuclear abnormalities.

Brain↗
PubMed1984

Alterations in leukocyte aryl hydrocarbon hydroxylase activity associated with treatment and age in psoriasis patients and healthy individuals.

We have examined the relationship between topical psoriasis treatment and the activity of the mixed function oxidase, aryl hydrocarbon hydroxylase (AHH), in peripheral blood monocytes and lymphocytes from 20 patients with psoriasis. These data were compared to monocyte and lymphocyte AHH activity measured in 20 normal subjects. AHH activity was determined in cells induced with benzanthracene and in uninduced control cells. Monocyte and lymphocyte AHH activity in six untreated psoriasis patients was similar to that in the healthy controls. AHH activity in either uninduced or induced monocytes showed an increase with age in both the healthy and the untreated psoriatic subjects. Lymphocytes from the healthy subjects showed an age-related decline in enzyme activity. Fourteen patients with psoriasis receiving topical tar and/or topical corticosteroid therapy had significantly higher (P less than 0.05) levels of basal and induced monocyte and lymphocyte AHH activity than the healthy controls. AHH activity is age-related and appears to be controlled differently in monocytes and in lymphocytes. AHH activity in circulating monocytes and lymphocytes may be stimulated by topical tar and/or steroid therapy of psoriasis.

Administration, Topical↗
PubMed1984

A sensitive assay for detecting hypersensitivity to ionizing radiation in lymphoblastoid lines from patients with Duchenne muscular dystrophy and primary neuronal degenerations.

Hypersensitivity to the lethal effects of DNA-damaging agents is usually demonstrated using the classical colony-forming ability assay with cultured fibroblast lines. Based on the ability of viable cells in lymphoblastoid lines (Epstein-Barr virus-transformed B lymphocytes) to exclude the vital dye trypan blue, we have developed a more rapid survival assay which has been useful in detecting hypersensitivity to ionizing radiation in certain diseases characterized by primary degeneration of excitable tissue. We now present a complete description of this post-X-ray survival assay. We also demonstrate the suitability of both our assay and our method of data analysis for detecting hypersensitivity to ionizing radiation. This demonstration is based on a detailed analysis of assay results with lymphoblastoid lines from 28 normal donors, 3 ataxia telangiectasia (AT) patients, 2 obligate AT heterozygotes, 7 patients with diseases characterized by cellular hypersensitivity to ultraviolet radiation (UV), and 10 Duchenne muscular dystrophy (DMD) patients.

Adult↗
PubMed1984

Use of lymphoblastoid cell lines to evaluate the hypersensitivity to ultraviolet radiation in Cockayne syndrome.

Cockayne syndrome (CS) is a rare autosomal recessive disease characterized by acute sun sensitivity, cachectic dwarfism, and neurologic and skeletal abnormalities. Cultured skin fibroblasts from patients with this disease are known to be hypersensitive to the lethal effects of 254-nm UV radiation. We have studied the sensitivity of 254-nm UV radiation of lymphoblastoid lines derived from 3 typical CS patients, 1 atypical CS patient who had a very late age of onset of clinical manifestations, 2 patients who had both xeroderma pigmentosum (XP) and typical CS, and 3 heterozygous parents of these patients. Post-UV survival was determined by the trypan-blue dye-exclusion method. The lymphoblastoid lines from the 3 typical CS patients, the atypical CS patient, and the 2 patients with both CS and XP had decreased post-UV viability in comparison with lines from normal donors. Lines from the heterozygous parents had normal post-UV viability. The post-UV viability of the typical CS lines was similar to that of a XP complementation group C line. The relative post-UV viability of lymphoblastoid lines from the typical CS patients was similar to the relative post-UV survival of their fibroblast lines. The lymphoblastoid line from the atypical CS patient had a post-UV viability similar to that of the typical CS patients. Thus, the relative hypersensitivity of CS patients' cells in vitro does not reflect the severity or age of onset of the patients' clinical manifestations. The lymphoblastoid lines from the 2 patients who had both CS and XP were significantly more sensitive to the UV radiation than those from patients with only CS. Our studies demonstrate that lymphoblastoid lines from patients with CS are appropriate and useful cell lines for the study of the inherited hypersensitivity to UV radiation.

Adolescent↗
PubMed1984

Hypersensitivity to DNA-damaging agents in cultured cells from patients with Usher's syndrome and Duchenne muscular dystrophy.

Lymphoblastoid lines from nine Usher's syndrome (recessively inherited retinitis pigmentosa and congenital sensorineural deafness) patients (representing eight kindreds) and from ten Duchenne muscular dystrophy patients (representing seven kindreds) showed a small but statistically significant hypersensitivity to the lethal effects of X-rays, as measured by the cellular ability to exclude the vital dye trypan blue, when compared with lines from 26 normal control subjects. Fibroblast lines from the Usher's syndrome patients, treated with X-rays or the radiomimetic, DNA-damaging chemical N-methyl-N'-nitro-N-nitrosoguanidine, also showed a statistically significant hypersensitivity when compared to normal fibroblast lines. These findings are consistent with the possibility that defective DNA repair mechanisms may be involved in the pathogenesis of these degenerative diseases.

Adolescent↗
PubMed1984

Monoclonal antibody phenotyping of interindividual differences in cytochrome P-450-dependent reactions of single and twin human placenta.

Cytochromes P-450 are a family of enzymes responsible for metabolism of drug and xenobiotics, such as carcinogen, and certain physiological compounds, such as steroids and prostaglandins. We prepared a monoclonal antibody (MAb 1-7-1) to a polycyclic hydrocarbon-induced rat cytochrome P-450 that antigenically defines and inhibits a type of cytochrome P-450 responsible for aryl hydrocarbon hydroxylase (AHH) and 7-ethoxycoumarin deethylase (ECD) activity in human placenta. We examined the placentas from single and twin births from mothers who smoked cigarettes and nonsmokers. The MAb 1-7-1 inhibited the smoking-induced AHH activity of essentially the entire population of placentas by 70 to 95%. Thus, up to 95% of the AHH in a population of human placentas is catalyzed by a type of cytochrome P-450 that contains an antigenic site recognized by MAb 1-7-1. A second type of cytochrome P-450, which is insensitive to MAb 1-7-1, is responsible for the ECD activity in the placentas of nonsmokers. In the placentas from smokers, both types of P-450 contribute to ECD activity. Their ratios can be determined by the amount of inhibition by MAb 1-7-1 which ranges from 0 to 70%. The placentas from both dizygotic and dichorionic monozygotic twins show extraordinarily high intrapair concordance for both the absolute amounts of AHH and ECD and their inhibition by MAb 1-7-1 compared with unrelated individuals, indicating that interindividual differences in these parameters of biological activity are not due to random variation or experimental error. Our results show that the amount of activity of antigenically unique types of cytochrome P-450 responsible for different drug and carcinogen reactions can be measured in different individuals by the amount of their inhibition by highly specific monoclonal antibodies. These findings may have general application to studies on the relationship cytochrome P-450 phenotype to population differences in drug and carcinogen biotransformation.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1983

Statistical methods for in vitro cell survival assays.

Statistical methods are presented for estimating and comparing survival curves obtained from experiments in which cells are exposed in vitro to increasing doses of a DNA-damaging agent. These methods, which are applicable in a variety of cell survival assays, are illustrated in the evaluation of two sets of experiments in which the colony-forming ability of fibroblast cell lines from 9 muscular dystrophy patients and 17 normal individuals were studied after exposure to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG).

Cell Survival↗