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Biomedical subjects

D Vlachodimitropoulos

Publications and source records attributed to D Vlachodimitropoulos.

8 recordsLinked to original sources
PubMed2006

Evaluation of the prognostic and predictive value of p53 and Bcl-2 in breast cancer patients participating in a randomized study with dose-dense sequential adjuvant chemotherapy.

PURPOSE: To assess the prognostic and predictive significance of p53 and Bcl-2 protein expression in high risk patients with breast cancer treated with dose-dense sequential chemotherapy. PATIENTS AND METHODS: From June 1997 until November 2000, 595 patients were randomized to three cycles of epirubicin (E) 110 mg/m2 followed by three cycles of paclitaxel (P) 250 mg/m2 followed by three cycles of 'intensified' CMF (cyclophosphamide 840 mg/m2, methotrexate 47 mg/m2 and fluorouracil 840 mg/m2) or to four cycles of E, followed by four cycles of CMF. p53 and Bcl-2 expression was investigated by immunohistochemistry in 392 and 397 patients respectively. RESULTS: Positive expression of p53 was detected in 104 (26.5%) patients and was significantly associated with negative hormonal status, worse histologic grade, higher incidence of disease relapse and higher rate of death. p53 positive expression was a significant negative predictor of overall survival (OS) (P = 0.002) and disease-free survival (DFS) (P = 0.001). Negative expression of Bcl-2 was detected in 203 (51%) patients and was significantly associated with negative hormonal status. Multivariate analysis revealed that, positive p53 expression, higher number of positive nodes and worse tumor grade were related to significantly poorer OS and DFS. CONCLUSIONS: For both treatments, p53 positive expression was a significant negative prognostic factor for OS and DFS while Bcl-2 was not. No predictive ability of p53 status or Bcl-2 status for paclitaxel treatment was evident.

Adult↗
PubMed1998

Chromosomal aberrations, sister-chromatid exchanges, cells with high frequency of SCE, micronuclei and comet assay parameters in 1, 3-butadiene-exposed workers.

The association of occupational exposure to 1,3-butadiene (BD) and induction of cytogenetic damage in peripheral lymphocytes was studied in 19 male workers from a monomer production unit and 19 control subjects from a heat production unit. The exposure to BD was measured by passive personal monitors. The following biomarkers were used: chromosomal aberrations (CA), sister chromatid exchanges (SCE), cells with a high frequency of SCE (HFC), micronuclei, comet assay parameters like tail length (TL) and percentage of DNA in tail [T (%)] and polymorphisms of GSTM1 and GSTT1 genotypes. BD exposure with a median value of 0.53 mg/m3 (range: 0.024-23.0) significantly increased (a) the percentage of cells with chromosomal aberrations in exposed vs. control groups (3.11% vs. 2.03%, P<0.01), (b) the frequency of SCE per cell (6.96 vs. 4.87, P<0.001), and (c) the percentage of HFC (19.9% vs. 4.1%, P<0.001). BD exposure had no significant effects on formation of micronuclei and on comet assay parameters. Effect of smoking was observed only for HFC in BD-exposed group. GSTM1 genotype affected chromosomal aberrations in exposed group, while GSTT1 genotype affected chromosomal aberrations in controls. No effect of GSTM1 or GSTT1 genotypes was observed on any other biomarkers used.

Air Pollutants↗
PubMed1997

GSTT1-dependent induction of centromere-negative and -positive micronuclei by 1,2:3,4-diepoxybutane in cultured human lymphocytes.

The role of the glutathione S-transferase T1 gene (GSTT1) in determining genotoxic response to 1,2:3,4-diepoxybutane (DEB), an epoxide metabolite of 1,3-butadiene, was studied by analysis of micronuclei (MN) in cultured human lymphocytes using the cytokinesis block method. Fluorescence in situ hybridization (FISH) with an alphoid satellite DNA probe specific for the centromeres of all human chromosomes was applied to identify MN harboring whole chromosomes. Whole-blood lymphocyte cultures of 11 GSTM1 (glutathione S-transferase M1)-positive individuals (i.e. having at least one GSTM1 allele), of whom six were GSTT1-positive (with at least one GSTT1 allele) and five GSTT1-null (GSTT1 homozygously deleted), were treated for 48 h (starting 24 h after culture initiation) with two different concentrations (2 and 5 muM) [corrected] of DEB. The GSTT1-null individuals were excessively sensitive to DEB, showing, on average, approximately 2.5 times higher induced MN frequency (control frequency subtracted) than the GSTT1-positive donors, both at 2 muM [corrected] (mean/1000 binucleate cells 29.8 versus 11.8, P < 0.05) and 5 muM [corrected] (87.6 versus 34.0, P < 0.001) DEB. In accordance with the known strong clastogenicity of DEB, MN without centromeric FISH signals were particularly increased, the difference between the two GSTT1 genotypes being statistically significant at both concentrations of DEB (mean induced MN/1000 binucleate cells 23.1 versus 9.9, P < 0.05, at 2 muM [corrected]; 69.7 versus 24.2, P < 0.001, at 5 muM) [corrected]. In addition, centromere-positive (C+) MN were induced, suggesting that DEB also has some aneuploidogenic activity. The GSTT1-null genotype showed a significantly (P < 0.05) higher mean frequency of induced C+ MN than the GSTT1-positive genotype, at both 2 (6.7 versus 1.9) and 5 muM [corrected] (17.9 versus 9.8) DEB. At the higher dose mean nuclear division index was lower in the GSTT1-null group (1.80) than in the GSTT1-positive group (2.05, P < 0.01). These findings support earlier results from the analysis of sister chromatid exchange showing that individual sensitivity to the genotoxic and cytotoxic effects of DEB is largely explained by lack of the GSTT1 gene.

Adult↗
PubMed1996

A comparative study on the effect of MNU on human lymphocyte cultures in vitro evaluated by O6-mdG formation, micronuclei and sister chromatid exchanges induction.

N-Nitroso-compounds are a large group of chemicals present in a number of environmental sources and many of them are mutagens as well as carcinogens in experimental animals. Among the known N-nitroso-compounds, N-nitroso-N-methylurea (MNU) is a strong mutagen. In this study an effort has been made to compare the ability of MNU to methylate the O6-guanosine site in DNA and to induce micronuclei and sister chromatid exchanges in human lymphocyte cultures in vitro. To quantitate O6-methyldeoxyguanosine (O6-mdG) a highly sensitive immunoassay, immuno-slot-blot (ISB), has been used. For the evaluation of micro nuclei (MN) the cytokinesis block micronucleus method has been used. Different concentrations (75, 100, 125 micrograms/ml) were tested. At the highest concentration tested for the MN induction, 125 micrograms/ml, the occurrence of binucleates and micro nuclei is higher than twice in relation to control and a reduction in NDI is also observed. The same concentrations were used for the estimation of sister chromatid exchanges (SCEs) induction. The mean number of SCEs at 125 micrograms/ml is almost three times that of the control level. The concentrations tested for the quantitation of O6-mdG were 200, 300 and 400 micrograms/ml and this was done because for the test system we used and for the given experimental conditions the first indication of O6-mdG formation was at 200 micrograms/ml. Our results show that methylation of O6-guanosine increases with concentration and at 400 micrograms/ml the concentration of O6-mdG is 5.83 fmol/microgram DNA, while at the control level it is 2.40 fmol/microgram DNA. Since O6-mdG formation is observed in higher concentrations than those of MN and SCE induction it would be interpreted that O6-mdG levels are not correlated with the studied cytogenetic effects although one has to take into consideration the total promutagenic lesions in DNA, induced by MNU, as well as AGT repair activity.

Carcinogens↗
PubMed1996

Biological effect monitoring in industrial workers from the Czech Republic exposed to low levels of butadiene.

Blood samples were collected twice (in 1993 and 1994) from 19 workers exposed to 1,3-butadiene and 19 matched controls. Three exposed and three control subjects were the same in 1993 and 1994. Personal passive dosimetry was performed in 1993 and twice in 1994 on the day preceding blood sampling. Mean exposure level in 1994 was 1.76 +/- 4.20 ppm (S.D.) and individual exposure levels ranged between 0.012 ppm (detection limit) and 19.77 ppm. Using the clonal assay, geometric mean of hprt mutant frequencies adjusted for cloning efficiency, age and smoking were, respectively, 7.85 (+/- 7.09) x 10(-6) and 10.14 (+/- 9.16) x 10(-6) in pooled (1993 plus 1994) exposed and control subjects. The difference was not statistically significant indicating that 1,3-butadiene did not induce a detectable increase in mutations at the hprt locus. A similar result was obtained for the 1994 subjects alone. There was no difference between adjusted geometric mean mutant frequencies of exposed and unexposed non-smokers or between exposed and unexposed smokers. Analysis of chromosomal aberrations in lymphocytes from 1994 subjects indicated that the percentage of aberrant cells was significantly enhanced in exposed subjects. In 1993 (data not shown), it was impossible to demonstrate a significant increase of aberrant cells in subjects exposed to 1,3-butadiene. Frequencies of micronuclei in cytochalasin-B blocked binucleate lymphocytes in exposed and unexposed 1994 subjects were not significantly different. This was also the case for earlier samples analyzed in the same plant. Using the comet assay for 1994 subjects, no statistically significant difference was found between the whole group of exposed and unexposed subjects. This was true for both the comet tail length and the percentage of DNA in the tail. In exposed smokers, however, the comet tail length was significantly longer than in unexposed smokers. Unexpectedly, in unexposed smokers the tail length was significantly shorter than in unexposed non-smokers. It was also unexpected that the percentage of DNA in the comet tail was significantly lower in exposed non-smokers than in unexposed non-smokers.

Adult↗
PubMed1994

Human cytogenetic biomonitoring of occupational exposure to 1,3-butadiene.

The association of occupational exposure to 1,3-butadiene and chromosomal damage in peripheral blood lymphocytes was studied in 40 workers from two production facilities. Control persons, 30 in all, were chosen from other departments of the same plants, and they were roughly matched for age and smoking habits. The exposure levels to ambient butadiene were measured both by personal sampling using diffuse monitors and by stationary sampling at production and handling sites. Chromosome aberrations (CA), micronuclei (MN) and sister-chromatid exchanges (SCE) in peripheral lymphocytes were analyzed as markers of exposure. Smoking had a slight effect on the frequency of MN, and the mean frequency of SCEs was also higher in smokers than in non-smokers. No effect of smoking, however, was seen in relation to chromosomal aberrations. No exposure related effects were seen in any of the three cytogenetic endpoints in either of the butadiene production plants, representing typical low (below 3 ppm) exposure levels of the butadiene manufacturing industry.

Adult↗
PubMed1989

Acitretin induces an increased adherence of S. aureus to epithelial cells.

Recently, synthetic retinoids have been implicated as causing a rise in the incidence of staphylococcal infections in patients orally treated with these compounds for various disorders of keratinization. Since the adherence of bacteria to epithelia is an important early event in the development of bacterial infections, in the present study we investigated the in vitro effects of acitretin on the adherence of Staphylococcus aureus to epithelial cells of the anterior nares of 15 healthy human subjects. It was found that pre-incubation of nasal epithelial cells with acitretin causes a statistically significant (p less than 0.001) increase in the adherence of S. aureus to these cells, as compared to the controls. The growth of S. aureus cultures in the presence of acitretin exerted no effect on the staphylococcal adherence. These results suggest that the oral acitretin-induced increase in S. aureus colonization and in the incidence of cutaneous staphylococcal infections may be related to the enhancement of staphylococcal adherence to epithelia caused by this compound.

Acitretin↗