The relationship between RRM1 gene polymorphisms and effectiveness of gemcitabine-based first-line chemotherapy in advanced NSCLC patient.

PURPOSE: Chemotherapy with platinum compounds and gemcitabine is frequently used in first-line treatment of advanced non-small cell lung cancer (NSCLC) patients in which tyrosine kinase inhibitors (EGFR or ALK) cannot be administered. Unfortunately, less than half of the patients achieve the benefit from chemotherapy. Gemcitabine is an analog of deoxycytidine (pyrimidine antimetabolite) with antitumor activity. The excess of deoxycytidine synthesized by RRM1 enzyme activity may be a cause of competitive displacement of gemcitabine, which reduces the efficacy of this cytostatic. The aim of this study was to determine the association between single nucleotide polymorphisms (SNPs) of the RRM1 promoter (-37C>A, -524C>T) and the effectiveness of first-line chemotherapy based on platinum compounds and gemcitabine in NSCLC patients. PATIENTS AND METHODS: SNPs were determined by SNaPshot PCR(®) in DNA isolated from peripheral blood of 91 NSCLC patients. RESULTS: The median progression-free survival (PFS) was significantly longer in carriers of AA (-37C>A) as well as CC (-524C>T) genotype of RRM1 compared to patients with other genotypes (10.5 vs 3.5 months, p = 0.0437; HR = 2.17, 95 % CI 1.02-4.62 and 10.5 vs 3.5 months, p = 0.0343; HR = 2.12, 95 % CI 1.06-4.27). In addition, the CC genotype carriers (-37C>A) showed a significant increase in the risk of shortening overall survival (OS) in comparison to patients with AA or AC genotypes (9.5 vs 18 months, p = 0.0193; HR = 2.13, 95 % CI 1.13-4.03). CONCLUSIONS: Presence of rare AA (-37C>A) and CC (-524C>T) genotypes of the RRM1 may be favorable predictive factors for chemotherapy with platinum compounds and gemcitabine in NSCLC patients.

The relationship between polymorphisms of genes regulating DNA repair or cell division and the toxicity of platinum and vinorelbine chemotherapy in advanced NSCLC patients.

INTRODUCTION: Platinum-based chemotherapy and 3rd generation drugs is still the main treatment option for advanced non-small cell lung cancer (NSCLC) patients without activating EGFR mutations or ALK rearrangements. However, the side effects associated with cytostatics are well known. Changes in the genes (e.g. single nucleotide polymorphisms, SNPs) encoding proteins regulating DNA repair or cell division could potentially influence on both the susceptibility of cancer cells to chemotherapy, and the occurrence of toxicities. MATERIALS AND METHODS: In presented study, the relationship between the fourteen SNPs in nine DNA repair and cell division regulating genes: ERCC1, XPD, XPA, XPC, XRCC1, XPG, RRM1, BRCA1, STMN1 and the toxicity of first-line chemotherapy in NSCLC patients were investigated. SNPs were determined by SNaPshot PCR® in DNA isolated from peripheral blood of 55 NSCLC patients treated with platinum compound and vinorelbine. The toxicity of therapy was evaluated according to the Common Toxicity Criteria (CTC) Version 4.03. RESULTS: The odds ratio (OR) of severe haematological toxicity was significantly lower in carriers of the T allele of XRCC1 gene (1196A > G, OR = 0.22, 95 % CI: 0.06-0.82, p = 0.018) and higher in the carriers of the T allele (2704C > A) of XPC gene (OR: 7.50, 95 % CI: 0.89-63.17, p = 0.036) compared to the remaining patients. Risk of severe hepatotoxicity was significantly lower in carriers of the C allele of STMN1 (-2166T > C, OR = 0.09, 95 % CI: 0.01-1.12, p = 0.025) than in patients with T allele of this gene. In carriers of G allele (2251A > C, OR: 0.24, 95 % CI: 0.07-0.81, p = 0.017) and T (934G > A, OR: 0.26, 95 % CI: 0.07-0.90, p = 0.029) of XPD gene, risk of severe nephrotoxicity was significantly lower than in other patients. CONCLUSIONS: Selected SNPs of genes encoding DNA repair enzymes and cell division regulation proteins could be useful biomarkers for prediction of platinum and vinorelbine-based chemotherapy toxicity in patients with advanced NSCLC.

Population genetic data for HumF13B, HumLPL and HumHPRTB in southeast Poland.

Allele frequencies for the three short tandem repeat systems HumF13B, HumLPL and HumHPRTB were determined in a population sample from southeast Poland. PCR products were separated by electrophoresis on denaturing polyacrylamide gels, followed by silver staining. A total of six alleles for HumF13B, seven for HumLPL and eight alleles for HumHPRTB were detected and no deviations from Hardy-Weinberg equilibrium were observed. The allele frequency data for the three systems were compared with other Caucasian populations.

[Histocompatibility antigens in pregnant women with preeclampsia and in their husbands]. / Antygeny ukladu zgodnosci tkankowej ciezarnych z preeklampsja oraz ich mezów.

OBJECTIVES: Several pedigree and epidemiological studies have suggested that preeclampsia (PE) has an immunogenetic basis. Therefore, we have attempted to disclose a possible association between antigens of the HLA system (HLA-A, B and C) and development of PE. DESIGN AND METHODS: Peripheral blood lymphocytes were typed for HLA-A, B and C antigens by the two-stage microlymphocytotoxic test in 32 pregnant women with PE and in their husbands from south-east Poland. As a control population 411 healthy unrelated inhabitants of south-east Poland were studied. The obtained individual HLA antigens frequencies were compared with these in control individuals using Chi-square test and relative risk (RR) was computed as described by Svejgaard (1974). RESULTS: The frequency of B13 antigen occurrence was significantly higher in the women group with PE as compared to that in general population, and revealed significant association with the development of PE (0.02 < p < 0.05; RR = 2.733), while the frequency of Cw4 antigen was significantly lower (0.02 < p < 0.05; RR = 0.283). The frequency of B22 antigen occurrence in husbands group was significantly higher as compared with that in general population and this difference achieved very high statistical significance and strong association with the development of PE (p < 0.001; RR = 9.452). CONCLUSIONS: Results of our study point to the genetic transmission of susceptibility to PE. Typing for these antigens could be a potentially useful prenatal test for predicting which couples are at risk for PE.

Allele frequency distributions of D1S80 in the Polish population.

The polymorphism of the D1S80 locus has been analyzed in a population sample of 208 unrelated individuals in the Southeast Poland and 103 mother/child pairs. PCR amplified alleles were separated by a vertical discontinuous polyacrylamide gel electrophoresis system. Nineteen different alleles and 52 phenotypes could be distinguished. The alleles 18 (f = 0.267) and 24 (f = 0.300) were most common in Poland. D1S80 genotype frequencies of Poland population do not deviate from Hardy-Weinberg equilibrium. All mother/child pairs shared at least one D1S80 allele.

Rare phenotypes of the phosphoglucomutase locus 1 detectable by isoelectric focusing on Cellogel.

The rare phenotypes PGM1, determined by alleles PGM1(3), PGM1(4), PGM1(6), and PGM1(7) were examined by starch gel electrophoresis and cellulose acetate gel isoelectric focusing and were compared with the commonest phenotypes of PGM1. The frequencies of the rare genes found in the Polish populations were as follows: in Lublin, PGM1(3) = 0.0002, PGM1(4) = 0.0005, PGM1(6) = 0.0010, and PGM1(7) = 0.0005; in Wroclaw, PGM1(3) = 0.0000, PGM1(4) = 0.0005, PGM1(6) = 0.0007, and PGM1(7) = 0.0002. The results suggest that the F and S type variants of the genes PGM1(4) and PGM1(7) probably do not occur. It is still possible that F and S variants exist for the genes PGM1(3) and PGM1(6).

Atypical segregation of esterase D: evidence of a rare "silent" allele EsD0.

Electrophoretic study of esterase D in 1027 mother-child pairs showed an atypical segregation of EsD alleles in one pair. The family analysis confirmed the evidence of a 'silent' gene (EsD0), which was observed in child, mother and grandfather. R banding of the metaphasal chromosomes revealed the normal appearance of the No. 13 pair, and no deletion of homologues No. 13 was observed in this family.

Subtypes of the phosphoglucomutase-1 (PGM1) locus detectable in Polish populations by isoelectric focusing on cellogel.

The technique of isoelectric focusing on methylated 'cellogel' strips (CAGIF) was used to confirm the presence of four alleles of PGM1 in human red cell lysates. The subtypes of PGM1 were determined in two Polish population samples, from Southwestern Poland (Wroclaw region, n=321) and Southeastern Poland (Lubin region, n=212). Ten different phenotypes are considered as gene products of four alleles at PGM1, with the following frequencies: Wroclaw: PGM1F, 0.1044; PGM1S, 0.5966; PGM2F, 0.0685; and PGM2S, 0.2305; Lublin: PGM1F, 0.1439; PGM1S, 0.6014; PGM2F, 0.0825; and PGM2S, 0.1722.

Glyoxalase I in studies of paternity cases in Poland.

The distribution of glyoxalase I (GLO) types in cases of disputed paternity is reported. On the basis of 553 paternity cases, it is concluded that the GLO system is a valuable supplement to other systems of genetic markers in cases of disputed paternity. The theoretical probability of paternity exclusion in the GLO system, in the Polish population, is 18.6%.

GLO polymorphism in two Polish population samples.

The red cell GLO phenotypes were determined in two Polish population samples. A total of 1310 people from the region of Lublin (Southeastern Poland, n = 797) and Wroclaw (Southwestern Poland, n = 513) were investigated. The gene frequencies were calculated for GLO1 (= 0.4427) and GLO2 (= 0.5573). The evaluation of 372 mother-child pairs showed no deviation from a hereditary hypothesis.

Radiographic spatial frequencies essential to the diagnosis of incipient interproximal lesions.

The effects of fixed pattern noise on the interpretation of dental radiographs containing known lesions suggest that reliable detection of incipient interproximal caries is influenced by the spatial frequency of information visibly displayed. Frequencies less than the limiting resolution of existinta also permit demonstration that significantly less resolution is required horizontally than vertically to achieve a criterion level of diagnostic accuracy. These findings are consistent with the notion that accurate diagnosis may be possible with less resolution than is currently produced by conventional bitewing radiographic techniques. If this is trut means for radiographically detecting caries can be developed that require less exposure of the patient to ionizing radiation.

The effects of a nonsteroid antiandrogen, flutamide, on sebaceous gland activity.

Flutamide (alpha,alpha,alpha-trifluoro-2-methyl-4'-nitro-m-propionotoluidide), at daily oral doses of 20 mg/day for 24 days, reduced the number and size of skin sebaceous gland cells, and reduced sebum production in ovariectomized, testosterone-stimulated rats. The weight of the preputial glands was also reduced. Unilateral topical application of flutamide (0.1-3.0 mg/day) to flank organs (androgen-sensitive cutaneous sebaceous structures) of testosterone propionate-treated female hamsters for 14 days resulted in bilateral reductions in flank organ weight and in inhibition of in vitro incorporation of 14-C from sodium [1--14C]acetate into lipids. Flutamide inhibition of flank organ weight paralleled the drug effect on lipogenesis. Unilateral topical application of flutamide to flank organs of intact male hamsters for 14 days resulted in significant bilateral reductions of flank organ weight at doses as low as 0.375 mg/day (the lowest dose tested). These weight changes were marked by reduction in sebaceous gland size, accompanied by focal cytoplasmic degeneration, and reductions in cytoplasmic organelles and in the size of the lipid bodies. Flutamide did not, however, seemingly alter the pattern of endogenous total lipids in sebaceous glands, nor did it alter the pattern of 14-C-incorporation into the lipids of male flank organ epidermis and isolated sebaceous glands, when compared to control, untreated preparations.