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Biomedical subjects

C Arlett

Publications and source records attributed to C Arlett.

13 recordsLinked to original sources
PubMed2003

Effects of selenium compounds on induction of DNA damage by broadband ultraviolet radiation in human keratinocytes.

Background Ultraviolet radiation (UVR), a ubiquitous environmental genotoxin for the skin, produces DNA damage. The trace element selenium induces synthesis of the glutathione peroxidase and thioredoxin reductase enzyme families. These selenoenzymes detoxify a range of toxic compounds generated by free radicals. Objectives To assess the effects of pretreatment of primary human keratinocytes with selenium on UVR-induced DNA damage. Methods Cells were irradiated with UVR from FS-20 lamps and were subjected to comet assay. Results Comet tail length due to UVR-induced T4 endonuclease V-sensitive sites (caused by cyclopyrimidine dimers, CPDs) increased to 35 +/- 4.5 microm (mean +/- SD) immediately after irradiation (time 0 h, 100%). After 4 h, 68% of the damage remained and after 24 h, 23% of the damage was still present. Treatment with up to 200 nmol L-1 selenomethionine or 50 nmol L-1 sodium selenite had no effect on CPD formation or rates of repair, or on the number of excision repair sites as measured by cytosine arabino furanoside and hydroxyurea treatment. However, selenite and selenomethionine protected against oxidative damage to DNA as measured by formation of formamidopyrimidine (FaPy) glycosylase-sensitive sites, which are indicative of 8-hydroxy-2-deoxyguanosine photoproduct formation. In this assay, irradiation of keratinocytes increased mean +/- SD glycosylase-specific comet tail length from 5 +/- 1.5 microm to 19 +/- 3.3 microm. Preincubation for 18 h with 50 nmol L-1 selenite abolished the UVR-induced increase in comet length. Preincubation with 200 nmol L-1 selenomethionine was similarly protective. Conclusions Selenite and selenomethionine protect keratinocytes from UVR-induced oxidative damage, but not from formation of UVR-induced excision repair sites.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1998

The radiosensitive cell line 180BR is not defective in the major DNA damage-sensing proteins.

The fibroblast culture 180BR, established from a patient showing an adverse response to radiotherapy, has been shown previously to be hypersensitive to ionizing radiation and to be defective in the repair of DNA double-strand breaks. We demonstrate here that the products of the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) and its regulatory subunits (Ku 70 and Ku 80) are present at normal levels and possess functional activity. The product of the gene mutated in the human genetic disorder ataxia-telangiectasia was also detected in these cells. Apoptosis was detected after high-dose ionizing radiation exposure, and this process was accompanied by specific degradation of DNA-PKcs, ATM, and poly(ADP-ribose) polymerase. Activation of CPP32, an interleukin 1beta converting enzyme-like protease implicated in apoptosis, was also observed in 180BR cells in response to radiation damage. The radiosensitivity observed in 180BR cells can be accounted for, at least in part, by radiation-induced apoptosis, and the defect in these cells is not a gross one in DNA-PKcs or ATM.

Ataxia Telangiectasia↗
PubMed1996

Dose-rate effects on the survival of irradiated hypersensitive and normal human fibroblasts.

The linear-quadratic model describes cell killing by radiation as due to two processes defined by the linear (alpha) component and by the quadratic (beta) component. As alpha and beta are interdependent, it is difficult to evaluate accurately the alpha component (which characterizes the intrinsic radiosensitivity). It has been suggested that irradiation at low dose-rate (around 1 cGy/min) allows the disappearance of the beta component and thus gives a direct measure of alpha. The present results verify this hypothesis with plateau phase cells. The survival of five human fibroblast cell lines in exponentially growing and density-inhibited, confluent cultures maintained at 37 degrees C following exposure to 60Co gamma-rays at dose-rates of 0.33-100 cGy/min followed by delayed plating (only for plateau phase cells) was monitored. Three of these cell lines are considered to be 'normal' and two are derived from hypersensitive individuals. The mean inactivation doses (D) of the five cell lines for acute doses with immediate plating were 173, 163, 136, 107 and 67 cGy. (D) increased with delayed plating recovery for 4 of the 5 cell lines and the survival of the 5 cell lines increased after low dose-rate exposure (1 cGy/min) without altering the ranking. The differences between cell lines (absolute values of (D) increased with decreasing the dose-rate. Analysis of the survival curves with the General Linear Quadratic (GLQ) model gave repair half-times for each cell line which were not correlated with the intrinsic radiosensitivities. Surprisingly, the alpha component decreased with decreasing dose-rate for all 5 cell lines (only in plateau phase). Thus low dose-rates do not allow direct measurement of the alpha component; the decrease in alpha could be interpreted as adaptive radioresistance.

Cell Line↗
PubMed1995

Induction and rejoining of DNA double-strand breaks and interphase chromosome breaks after exposure to X rays in one normal and two hypersensitive human fibroblast cell lines.

The aim of this work was to measure simultaneously and in a quantitative manner double-strand breaks (DSBs), interphase chromosome breaks and cell lethality either immediately after irradiation, or at various times thereafter (up to 24 h), in cells of three nontransformed human fibroblast cell lines of widely different intrinsic radiosensitivity. We wished to assess initial damage, repair kinetics and residual damage at the DNA and the chromosome level, and to correlate these parameters with cell killing. We employed HF19 cells, a normal fibroblast cell line, AT2 cells, a radiosensitive cell line from a patient suffering from ataxia telangiectasia (AT), and 180BR cells, a radiosensitive cell line from a patient with no clinical symptoms of AT. AT2 and 180BR cells, in addition to being radiosensitive, also display a reduced ability to repair potentially lethal damage compared to HF19 cells. The yield of DSBs, as measured by pulsed-field gel electrophoresis, is similar in all three cell lines (slopes correspond to 1.6-1.7% Gy-1 of DNA-associated radioactivity released from the gel well into the lane). In contrast, residual DSBs measured 24 h after irradiation are almost zero for HF19 cells (0.1% confidence interval = 0-1.4%), but are 12.5% (+/- 2.3%) and 43.8% (+/- 1.2%) of those measured immediately after irradiation in AT2 and 180BR cells, respectively. Residual interphase chromosome breaks are 11.6% (+/- 1.6%), 29.7% (+/- 5.7%) and 41.4% (+/- 2.2%) of those measured immediately after irradiation in HF19, AT2 and 180BR cells, respectively. Neither the initial yield of DSBs nor that of excess interphase chromosome breaks can explain the differences in radiosensitivity between the three cell lines; however, there is a correlation between residual DSBs, rate of DSB rejoining at 24 h, residual interphase chromosome breaks on the one hand and cell survival on the other hand.

Cell Line↗
PubMed1993

Xeroderma pigmentosum-Cockayne syndrome complex in two patients: absence of skin tumors despite severe deficiency of DNA excision repair.

Two brothers had a complex combination of two DNA repair disorders: Cockayne syndrome and xeroderma pigmentosum. This rare combination has previously been observed in only two other patients. The clinical signs shared by these two brothers and the two other previously described patients include severe sun sensitivity, freckling, diminished stature, hearing and movement impairment, and neurologic degeneration. Although defective UV-induced unscheduled DNA synthesis has been demonstrated (5% of normal), no skin cancers have appeared in these 38- and 41-year-old brothers, whereas skin cancers developed at a relatively early age in the two previously described patients who also had defective UV-induced unscheduled DNA synthesis.

Adult↗
PubMed1992

Prenatal diagnosis in a subset of trichothiodystrophy patients defective in DNA repair.

Trichothiodystrophy (TTD) is an autosomal recessive disorder characterized by brittle hair with reduced sulphur content, and mental and physical retardation. Numerous additional clinical features may be present, producing a very heterogeneous syndrome. Many cases exhibit ichthyosis and photosensitivity. Cells from photosensitive TTD patients show reduced DNA repair levels similar to those found in xeroderma pigmentosum. TTD patients have a short life expectancy, and no treatment is known or envisaged. We report the prenatal diagnosis of TTD in two French families, based on DNA repair measurements in trophoblasts or amniotic cells, with later confirmation by microscopic analysis of the fetal hairs. Although the DNA repair defect was less marked in the fetal cells when compared with fibroblasts from the index case, measurement of DNA repair by unscheduled DNA synthesis provided unambiguous evidence of defective DNA repair in the fetal cells. This method is therefore a suitable prenatal diagnostic test for those TTD families in which a DNA repair defect has been identified.

Adult↗
PubMed1989

Relationship of cataract to radiation sensitivity.

Considerable exposure to radiation always causes posterior subcapsular cataract (PSC). This investigation was conducted to ascertain whether cellular hypersensitivity to radiation may be identified as a possible cause of cataract in persons exposed to low levels of radiation. Patients were studied in whom PSC had followed probable exposure to low levels of radiation or in whom PSC had developed before the age of 60 without known exposure. The patients with cataract were compared with age and sex matched controls without cataract. Radiation sensitivity was estimated by measuring clonal growth of skin fibroblasts and peripheral blood lymphocytes after exposure to graded doses of radiation and by measuring postirradiation reconstruction of separated nuclear material from lymphocytes. The results show variations in the level of radiation sensitivity between the patients, without significant differences from the controls. It is concluded that radiation hypersensitivity, as tested by the methods used in this study, is not normally associated with the development of posterior subcapsular cataract.

Cataract↗
PubMed1983

Acute leukemia after radiotherapy in a patient with Turcot's syndrome. Impaired colony formation in skin fibroblast cultures after irradiation.

Colonic polyposis and carcinoma developed in a woman with Turcot's syndrome at the age of 31 years; astrocytoma developed when she was 37. Her brother and sister had died of astrocytoma at the ages of 18 and 33 years, respectively. Progressive neutropenia developed in the patient three months after radiotherapy for her brain tumor and acute myelomonocytic leukemia 19 months after treatment. Three laboratories independently evaluated cultures of her skin fibroblasts for in vitro sensitivity to cell killing (loss of colony-forming ability) by x-rays. Survival assays consistently revealed slight but significant radiosensitivity in an early-passage (six to 10 doublings) fibroblast subculture. A later subculture (21 to 29 doublings) showed no abnormality, a possible effect of selective in vitro loss of radiosensitive cells.

Adenocarcinoma↗
PubMed1976

The influence of interviewer self-disclosure and verbal reinforcement on personality tests.

The effects of prior interview experiences on subsequent test responding were examined by comparing the influence of three interviewer behaviors: interviewer self-disclosure, interviewer verbal reinforcement of self-referent statements, and direct instructions to be self-disclosive. Performance was contrasted with a control interview condition characterized by no interviewer self-disclosure or self-referent reinforcement and with a no-interview condition. Responses on measures of self-disclosure and anxiety indicated that female Ss tended to be more self-disclosive than males in general, but were relatively uninfluenced by experimental condition. For male Ss, verbal reinforcement increased self-disclosure relative to the interviewer seld-disclosure condition. Interviewer self-disclosure was shown to result in more favorable perceptions of the self and the interviewer, particularly for males, and greater social evaluative anxiety for females. Both these factors are discussed as possibly counteracting the modelling effects of interviewer self-disclosure. An interpretation of the results in terms of interactions between S sex, interviewer sex, and experimental condition is proposed and implications for related research discussed.

Anxiety↗