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R E Tarone

Publications and source records attributed to R E Tarone.

At least 109 records · Page 6Linked to original sources
PubMed1990

A modified Bonferroni method for discrete data.

The Bonferroni adjustment for multiple comparisons is a simple and useful method of controlling the overall false positive error rate when several significance tests are performed in the evaluation of an experiment. In situations with categorical data, the test statistics have discrete distributions. The discreteness of the null distributions can be exploited to reduce the number of significance tests taken into account in the Bonferroni procedure. This reduction is accomplished by using only the information contained in the marginal totals.

Animals↗
PubMed1990

Chromosome aberrations in relation to radiation dose following partial-body exposures in three populations.

Structural chromosome aberrations were evaluated in peripheral blood samples obtained from three populations exposed to partial-body irradiation. These included 143 persons who received radiotherapy for enlarged thymus glands during infancy and 50 sibling controls; 79 persons irradiated for enlarged tonsils and 81 persons surgically treated for the same condition during childhood; and 77 women frequently exposed as young adults to fluoroscopic chest X rays during lung collapse treatment for tuberculosis (TB) and 66 women of similar ages treated for TB with other therapies. Radiation exposures occurred 30 and more years before blood was drawn. Doses to active bone marrow averaged over the entire body were 21, 6, and 14 cGy for the exposed thymic, tonsil, and TB subjects, respectively. Two hundred metaphases were scored for each subject, and the frequencies of symmetrical (stable) and asymmetrical (unstable) chromosome aberrations were quantified in 97,200 metaphases. Cells with stable aberrations were detected with greater frequency in the irradiated subjects compared with nonirradiated subjects in all three populations, and an overall test for an association between stable aberrations and partial-body ionizing radiation was highly significant (P less than 0.001). We found no evidence that radiation-induced aberrations varied by age at exposure. These data show that exposure of children or young adults to partial-body fractionated radiation can result in detectable increased frequencies of stable chromosome aberrations in circulating lymphocytes 30 years later, and that these aberrations appear to be informative as biological markers of population exposure.

Chromosome Aberrations↗
PubMed1989

Factors affecting and significance of G2 chromatin radiosensitivity in predisposition to cancer.

The frequencies of chromatid breaks and gaps in metaphase cells fixed 2 h after G2 phase X-irradiation (1 Gy) were in almost all cases at least two- to three-fold higher in skin fibroblasts from individuals with genetic conditions predisposing to cancer than in comparable cells from clinically normal controls. Previously, we reported this response in all cancer-prone genetic disorders tested including ataxia telangiectasia, Bloom's syndrome, Fanconi's anemia, xeroderma pigmentosum (XP), familial polyposis, Gardner's syndrome, hereditary malignant melanoma, dysplastic nevus syndrome and cancer family members. One exception was XP-A. In this report we add information on skin fibroblasts from retinoblastoma, Wilms' tumor and XP-C patients, 13 clinically normal controls and six cell lines from fetal or infant cells. Factors affecting the response are identified and include pH, temperature, cell density, culture medium or serum, microbial contamination and visible light exposure (effective wavelength 405 nm). Because of experimental variability, known normal controls should be used in each group of assays. With adequate control of the above factors this response could provide the basis of a test for detecting individuals carrying genes that predispose to a high risk of cancer.

Cell Line↗
PubMed1989

Deficient G2 phase repair of radiation-induced chromatin damage in the SENCAR mouse.

The SENCAR mouse, selectively bred for sensitivity to skin tumor induction by two-stage chemical carcinogenesis, is also genetically hypersensitive to skin carcinogenesis by high doses of UV. Skin fibroblasts from the SENCAR mouse exposed during G2 phase to radiation associated with intracellular hydroxyl radical formation, i.e. X-rays or near UV/visible light, showed a higher frequency of chromatid breaks at 2 h post-irradiation than skin fibroblasts from six other inbred strains of mice including C3H/HeN. However the level was similar to that reported previously for the BALB/cAn mouse known to be resistant to chemical carcinogenesis of skin. When exposed for 2 h to visible light (8 W/m2), chromatid breaks persisted in fibroblasts from the SENCAR mouse during the 4 h post-irradiation period, but showed an abrupt decline in C3H/HeN fibroblasts within 1 h after irradiation. Skin fibroblasts from the tumor-sensitive SENCAR mouse differed from those of the resistant BALB/cAn in response to beta-cytosine arabinoside (ara-C) an inhibitor of the repair polymerase. Ara-C added to cultures of SENCAR and BALB/cAn cells after G2 X-irradiation (68R) increased chromatid gaps 18-fold and breaks 2-fold in BALB/cAn cells but had no effect on SENCAR cells even though incorporated into DNA to the same extent. The present results suggest that the SENCAR mouse is deficient in at least two aspects of DNA repair: (i) ligation or a prior step in the repair process leading to ligation and (ii) repair endonucleolytic incision at DNA lesions induced by irradiation.

Animals↗
PubMed1989

Testing for non-randomness of events in sparse data situations.

In experiments involving cytogenetic assays or mutation assays it is often of interest to determine if there are hot spots for certain events, that is, to determine if the events occur more often at certain sites than would be expected under the assumption of randomness. In examining chromosome aberrations using banded chromosome preparations, for example, it may be of interest to determine if a particular type of aberration occurs more often in a particular band than would be expected given the relative length of the band. In a mutation assay it may be of interest to determine if a mutation occurs more often at a particular nucleotide in a given sequence than would be expected given the length of the sequence in question. Such experiments typically result in data following a multinomial distribution with a large number of classes and relatively few observations. For such data, De Braekeleer & Smith (1988) have suggested analysis of the frequencies in individual classes using an exact binomial test. Two cautions are noted for application of the binomial analysis in the usual situation in which the locations of potential hot spots are not specified beforehand.

Biometry↗
PubMed1989

A deficiency in chromatin repair, genetic instability, and predisposition to cancer.

This review traces steps leading to malignant neoplastic transformation of rodent and human cells in culture and in vivo. Emphasis is placed on an abnormal response characterized by persistent chromatid damage following irradiation of cells in culture with X-rays or fluorescent light during G2 phase of the cell cycle. Evidence is presented that deficient or unbalanced DNA repair during G2 accounts for the abnormal response. This G2 repair deficiency can be inherited or acquired by normal tissue cells during the process of or following attainment of infinite lifespan. It appears as an early, possibly initiating step in neoplastic transformation. It characterizes all human tumor cells examined irrespective of histopathology or tissue of origin. It has a genetic basis. In an animal model, the BALB/c mouse, this phenotype is associated with genes on chromosomes 1 and 4. It characterizes skin fibroblasts and blood lymphocytes from individuals with genetic or familial conditions predisposing to cancer and can be used to identify clinically normal family members carrying a gene(s) for any one of the three cancer-prone genetic disorders studied to date. Furthermore, it can provide the basis of a test for carriers of genes predisposing to a high risk of cancer. We conclude that the G2 repair deficiency, whether inherited or acquired, is a prerequisite for cancer development and that it accounts for the genetic instability of the cancer cell.

Animals↗
PubMed1989

Chromosome aberrations in peripheral lymphocytes and radiation dose to active bone marrow in patients treated for cancer of the cervix.

An international study of cervical cancer patients reported a doubling of the risk for leukemia following radiotherapy. To evaluate the extent of residual chromosome damage in circulating T-cell lymphocytes in this population, approximately 200 metaphases were examined from each of 96 irradiated and 26 nonirradiated cervical cancer patients treated more than 17 years ago (average 23 years). Radiation dose averaged over the total red bone marrow was estimated to be 8.1 Gy. The type and frequency of stable and unstable chromosome aberrations were quantified in 24,117 metaphases. Unstable aberrations did not differ significantly between irradiated and nonirradiated patients (P greater than 0.5). Stable aberrations (i.e., translocations, inversions, or chromosomes with deleted segments), however, were significantly higher among irradiated (2.8 per 100 cells) compared to nonirradiated (0.7 per 100 cells) women (P less than 10(4). The frequency of these stable aberrations was found to increase significantly with increasing dose to the bone marrow. These data indicate that a direct relationship between radiation dose and extent of damage to somatic cells persists in populations and can be detected many years after partial-body radiation exposure. The stable aberration rate in irradiated cervical cancer patients was 50 to 75% lower than those observed 25 years or more after radiation exposure in atomic bomb survivors and in ankylosing spondylitis patients treated with radiotherapy. The average marrow dose was only 1 Gy in the examined atomic bomb survivors and 3.5 Gy in the ankylosing spondylitis patients. It appears, then, that a very high dose delivered to the pelvic cavity in fractionated doses resulted in far fewer persistent stable aberrations than lower doses delivered either in acute whole-body exposure or in fractionated doses to the spinal column and sacroiliac joints. The higher radiation dose and the concentration of that dose in a smaller area of the body appear to be responsible for the lower rate of persistent aberrations observed in cervical cancer patients.

Bone Marrow↗
PubMed1989

Significance tests for cancer screening trials.

The goal of a cancer screening program is to reduce cancer mortality by detecting tumors at earlier stages of their development. For some types of cancer, screening tests may allow the preclinical detection of benign precursors of a tumor, and thus a screening program could result in reductions in both cancer incidence and mortality. For other types of cancer, a screening program will not reduce cancer incidence, and thus the expected outcome in a randomized cancer screening trial would be equal cancer incidence rates in control and study groups, but reduced cancer mortality in the study group. For the latter situation, we employ a variety of Poisson models for cancer incidence and mortality to derive optimal tests for equality of cancer mortality rates in a cancer screening trial, and we compare the asymptotic relative efficiencies of the test statistics under various alternatives. We demonstrate that testing equality of case mortality rates using Fisher's exact test or its Pearson chi-square approximation is nearly optimal when cancer incidence rates are equal and is fully efficient when cancer incidence rates are unequal. When valid, this comparison of case mortality rates in the study and control groups can be considerably more powerful than the standard comparison of population mortality rates. We illustrate the results using data from a clinical trial of a breast cancer screening program.

Adult↗
PubMed1988

Analysis of breast cancer mortality and stage distribution by age for the Health Insurance Plan clinical trial.

The Health Insurance Plan (HIP) of Greater New York conducted a clinical trial to determine if screening for breast cancer with mammography and clinical examination would decrease breast cancer mortality. The extent of disease at diagnosis among breast cancers detected by screening and the effect of screening on breast cancer mortality have been evaluated in the cohort of all HIP women diagnosed with breast cancer within 6 years of entry into the trial and followed at least 18 years after trial entry. Six years was the earliest time at which the number of cases diagnosed in the control group was equal to the number of cases diagnosed in the study group. In the cohorts of women 40-49 and 50-64 years of age at entry, shifts were significant to lower stages for screen-detected cases. As a result, the study group women in each age cohort had significantly lower breast cancer mortality than control group women when statistical analyses were restricted to data from cases only. In the 40-49 age-at-entry cohort, the reduced breast cancer mortality in the study group appears to result from lower mortality in stage I cases as well as from earlier case detection, and this may explain differences between the two age-at-entry cohorts in the length of follow-up time required to demonstrate a mortality reduction due to screening.

Adult↗
PubMed1988

Prevention of skin cancer in xeroderma pigmentosum with the use of oral isotretinoin.

To confirm reports that skin cancer can be prevented with retinoids, we conducted a three-year controlled prospective study of oral isotretinoin (also called 13-cis retinoic acid) in five patients with xeroderma pigmentosum who had a history of multiple cutaneous basal-cell or squamous-cell carcinomas. Patients were treated with isotretinoin at a dosage of 2 mg per kilogram of body weight per day for two years and then followed for an additional year, without the drug. Before, during, and after treatment, biopsies of all suspicious lesions were performed, and skin cancers were surgically removed. The patients had a total of 121 tumors (mean, 24; range, 8 to 43) in the two-year interval before treatment. During two years of treatment with isotretinoin, there were 25 tumors (mean, 5; range, 3 to 9), with an average reduction in skin cancers of 63 percent (P = 0.019). After the drug was discontinued, the tumor frequency increased a mean of 8.5-fold (range, 2- to 19-fold) over the frequency during treatment (P = 0.007). Although all patients experienced mucocutaneous toxic effects, and triglyceride, liver-function, or skeletal abnormalities developed in some, high-dose oral isotretinoin was effective in the chemoprophylaxis of skin cancers in patients with xeroderma pigmentosum.

Administration, Oral↗
PubMed1988

Radiosensitive Down syndrome lymphoblastoid lines have normal ionizing-radiation-induced inhibition of DNA synthesis.

The extent of X-ray-induced inhibition of DNA synthesis was determined in radiosensitive lymphoblastoid lines from 3 patients with Down syndrome and 3 patients with ataxia telangiectasia (AT). Compared to 6 normal control lines, the 3 AT lines were abnormally resistant to X-ray-induced inhibition of DNA synthesis, while the 3 Down syndrome lines had normal inhibition. These results demonstrate that radiosensitive human cells can have normal X-ray-induced inhibition of DNA synthesis and provide new evidence for the dissociation of radiosensitivity from radioresistant DNA synthesis.

Ataxia Telangiectasia↗
PubMed1988

Genes on chromosomes 1 and 4 in the mouse are associated with repair of radiation-induced chromatin damage.

Early-passage skin fibroblasts from different inbred and congenic strains of mice were X-irradiated (1 Gy), and the number of chromatid breaks was determined at 2.0 h after irradiation. The cells from DBA/2N, C3H/HeN, STS/A, C57BL/6N, BALB/cJ, and AKR/N had 25 to 42 chromatid breaks per 100 metaphase cells (efficient repair phenotype). NZB/NJ had greater than 78 and BALB/cAn had 87 to 110 chromatid breaks per 100 cells (inefficient repair phenotype). Differences between BALB/cAn and BALB/c. DBA/2 congenic strains which carry less than 1% of the DBA/2 genome indicate that two genes, one on chromosome 1 linked to bcl-2-Pep-3 and the other on chromosome 4 closely linked to Fv-1, affect the efficiency with which the cells repair radiation-induced chromatin damage.

Animals↗
PubMed1988

Ultraviolet light-induced chromosomal aberrations in cultured cells from Cockayne syndrome and complementation group C xeroderma pigmentosum patients: lack of correlation with cancer susceptibility.

Both Cockayne syndrome (CS) and xeroderma pigmentosum (XP) are inherited diseases with defective repair of damage induced in DNA by UV. Patients with XP, but not those with CS, have an increased susceptibility to formation of sunlight-induced skin tumors. We determined the frequency of UV-induced chromosomal aberrations in cultured lymphoblastoid cell lines from five CS patients and three complementation-group-C XP patients to determine whether such aberrations were abnormally increased only in the XP cells. We found that CS cells had the same abnormally increased number of induced aberrations as the XP cells, indicating that the number of UV-induced aberrations in XP group C cells does not account for the susceptibility of these XP patients to sunlight-induced skin cancer.

Cells, Cultured↗
PubMed1987

Hypersensitivity to G2 chromatid radiation damage in familial dysplastic naevus syndrome.

Skin fibroblasts from 25 members of nine kindreds with familial dysplastic naevus syndrome (DNS), 12 apparently normal spouses, and 11 additional unrelated normal individuals were tested for G2 cell-cycle phase sensitivity to ionising radiation. The cells from individuals with DNS or hereditary cutaneous malignant melanoma with DNS (HCMM/DNS) had significantly more chromatid breaks and gaps when entering metaphase 0.5-1.5 h after G2 phase X-irradiation (1 Gy) than those from unaffected controls. In two cases, the test results positively identified individuals before the clinical diagnosis of DNS. A clinically normal obligate carrier of the HCMM/DNS gene showed the enhanced G2 radiosensitivity. Moreover, in a test on 1 proband, the sensitivity was apparent in peripheral blood lymphoblasts. Enhanced G2 chromatid radiosensitivity may be a marker of genetic susceptibility to HCMM/DNS.

Adult↗
PubMed1987

Radiation sensitivity of fibroblast strains from patients with Usher's syndrome, Duchenne muscular dystrophy, and Huntington's disease.

The colony-forming ability of 10 normal human fibroblast cell strains and of 10 strains representing 3 degenerative diseases of either nerve or muscle cells was determined after exposure of the cells to X-rays or beta-particles from tritiated water. Both methods of irradiation yielded similar comparative results. The fibroblast strains from the 5 Usher's syndrome patients and from 1 of the 2 Huntington's disease patients were hypersensitive to radiation, while those from the 3 Duchenne muscular dystrophy patients and the second Huntington's disease patient had normal sensitivity to radiation. These results indicate both disease-specific and strain-specific differences in the survival of fibroblasts after exposure to ionizing radiation.

Cell Survival↗
PubMed1987

Differentiating among proposed mechanisms for tumor promotion in mouse skin with the use of the multievent model for cancer.

Numerous mechanisms for tumor promotion in mouse skin have been recently proposed. These include the multistage, genetic view of Slaga, Furstenberger, and Marks; the multistage, genetic and/or epigenetic view of Parkinson; and the two-stage view of Yuspa and Hennings. With the use of the multievent model, a mathematical model for cancer that can incorporate cell proliferation phenomena, these tumor promotion mechanisms were modeled mathematically. It was found that the models had different predictions about the incidence of papillomas in initiator-promoter-initiator experiments and the incidence of carcinomas in initiator-promoter experiments with varying periods of tumor promotion. Upon analysis, existing data were shown to be in agreement with the Yuspa and Hennings two-stage model. The analysis also supported the view, formulated by Scribner and co-workers, that different types of initiated cells were created, some capable of transformation to carcinomas and some not. Phenomena determined by use of benign tumors as the end point may need to be demonstrated with the use of the carcinoma as the end point, prior to the acceptance of these phenomena being applicable to the human carcinogenic process.

4-Nitroquinoline-1-oxide↗