[A study of genetic variants in patients with ischemic stroke in human rat gene orthologues]. / Izuchenie geneticheskikh variantov u patsientov s ishemicheskim insul'tom v chelovecheskikh ortologakh krysinykh genov.

OBJECTIVE: To study the associations of nine genetic variants with the risk and dynamics of recovery (outcome) of ischemic stroke (IS) using the developed protocol for the search for genomic markers based on a bioinformatic approach to the study of single nucleotide polymorphisms (SNPs) in human orthologues of rat genes differentially expressed under conditions of induced cerebral ischemia. MATERIAL AND METHODS: We identified and analyzed nine SNPs in 553 Russians (331 IS patients and 222 controls). The National Institutes of Health Stroke Scale (NIHSS) was used to assess stroke severity. Functional recovery after stroke was assessed using the modified Rankin scale (mRS). The principles of selection of polymorphic markers analyzed in the study were determined according to the protocol developed by us earlier. Selected SNP tags were genotyped using real-time polymerase chain reaction (PCR) TaqMan. RESULTS: The relationship of SNP with both the risk of IS and the dynamics of its recovery was investigated. SNP rs66782529 (LGALS3) was associated with negative IS outcomes (p=0.048). SNPs rs62278647 and rs2316710 (PTX3) were significantly associated with IS risk (p=0.000029 and p=0.0025, respectively). The associations for rs62278647 and rs2316710 were found only in females, suggesting a gender-related PTX3 polymorphism. CONCLUSION: This study not only reveals some new genetic links to IS and its consequences, but also shows how the study of gene variations in a rat model of cerebral ischemia can be useful in the search for genetic markers of this disease in humans.

[Analysis of a GSTM1 gene deletion in the context of the GSTM genomic cluster diversity in three Russian populations].

A total of 16 to 60% of individuals in human populations are homozygous with respect to a deletion of the Glutathione-S-transferase M1 gene. In this study, we evaluated the relationship between the GSTM1 gene deletion and genetic diversity of the GSTM cluster, which includes this gene, in three Russian populations. The study was based on the comparison of the haplotype distribution in two groups of individuals subdivided accordingly to the presence of the deletion. The first group included individuals with completely deleted GSTM1 gene, and the second group comprised individuals having at least one functional variant of GSTM1 gene. The analysis of the haplotype frequencies in groups revealed no specificity in their distribution both within the populations and between them.

[Pharmacogenomics of cisplatin-based chemotherapy in ovarian cancer patients from Yakutia].

DNA polymorphism is an important component of the interindividual variation in reactions of patients to the same drugs. In this work, evaluation of the association between polymorphisms in 106 genes involved in key processes of cellular activity (xenobiotic metabolism, DNA repair, the cell cycle, and apoptosis), and outcomes in a cohort of Yakut ovarian cancer patients receiving cisplatin-based chemotherapy was carried out. The polymorphism in the CDKN1B gene (rs34330) was found to be associated with complete tumor response and progression-free survival. SNPs in EPXH1 gene (rs2234922 and rs2260863) were correlated with hearing impairment. A SNP in NBN gene (rs1063045) was associated with severe emesis.

[Association of polymorphisms in glutathione-S-transferase and DNA repair genes with ovarian cancer risk in the Russian population].

Polymorphism ofglutathione-S-transferase (GSTA1, GSTM1, GSTM3, GSTP1, and GSTT1) and DNA repair (ERCC1, ERCC2, and XRCC1) genes in samples of ovarian cancer patients and healthy women of the Russian ethnic group was studied. A trend in the allele frequency variation of ERCC2 gene single nucleotide polymorphism (rs13181, A > C) was revealed. The A allele frequency was higher in the sample of patients (60,6% versus 52,9%, P = 0.058).

[CYP2E1 gene polymorphism and ovarian cancer risk in the Yakut population].

The CYP2E1 gene polymorphism has been studied in Yakut women with ovarian cancer and without cancer. The two groups have been found to substantially differ in the frequency of the CYP2E1* 1D allele (with a 96-bp insertion in the promoter region of the gene): it is more frequent in healthy women (16.3 versus 7.4%, P = 0.007).

[Polymorphisms of DNA repair genes ERCC2 and XRCC1 in populations of Russia].

We have conducted a comparative study of allele frequencies of single nucleotide polymorphisms (SNPs) rs1799793 and rs13181 of the ERCC2 gene as well as rs1799782 and rs25487 of the XRCC1 gene in population samples from European regions of Russia as well as in populations of Izhemsk and Priluzsk Komi and Yakuts. Significant differences in the distribution of polymorphic variants of the ERCC2 gene were demonstrated between populations of Yakuts and populations of Russians and Komi. In case of XRCC1 gene Izhemsk Komi population exhibited dissimilar allele frequencies compared to other populations.

Genetic polymorphisms and the efficacy and toxicity of cisplatin-based chemotherapy in ovarian cancer patients.

Platinum drugs are among the most active and widely used agents in the treatment of different cancers. However, the great individual variability in both outcome and toxicity of platinum chemotherapy requires the identification of genetic markers that can be used to screen patients before treatment. In this study, 21 polymorphisms in 10 genes, the protein activities of which may be addressed in different aspects of cisplatin metabolism, were tested for correlations with efficacy and toxicity of cisplatin-cyclophosphamide regimen in 104 ovarian cancer patients. The glutathione S-transferase P1 (GSTP1) Ile105Val polymorphism was strongly associated with progression-free survival (chi(2)=12.12, P=0.002). The allelic status of the GSTA1 -69 C>T polymorphism correlated with the overall survival: patients with T/T genotype survived longer than C/C carriers (P=0.044). Thrombocytopenia, anemia and neuropathy were less frequent among patients with the GSTM1-null or GSTM3 intron 6 AGG/AGG genotypes. Severe neutropenia was associated with the TP53 72 Pro/Pro, XPD 312 Asp/Asn and XRCC1 399 Arg/Arg genotypes. A higher risk of nephrotoxicity was noted for patients with the heterozygous ERCC1 19007 T/C and 8092 C/A genotypes. No correlations were found between genotypes and complete tumor responses.

[Glutathione-S-transferase gene polymorphism in Russian populations of European Russia].

Distribution of several widespread, extensively studied polymorphic variants of genes of the cytosol glutathione-S-transferase subfamily (GSTA1, GSTM1, GSTM3, GSTP1, and GSTT1) has been studied in samples from Russian populations of European Russia, as well as Komi and Yakut populations used for comparison. Analysis of the GSTP1 and GSTM3 polymorphisms has not shown significant differences in the distribution of alleles of these loci, including two-site GSTP1 haplotypes, in most Russian populations or between Komi populations. Only in the Yakut sample have a significant difference been found with respect to these loci in each pairwise comparison. Regarding the GSTT1 and GSTA1 genes, in addition to differences between the Yakut populations and all other populations with respect to the GSTA1 gene, it has been found that the frequencies of the GSTT1 0/0 deletion genotype and GSTA1-69T allele in the Russian sample from Mezen' (Arkhangel'sk oblast) are substantially lower than in other Russian populations and Komi populations. The significance of these differences has been confirmed by tests for heterogeneity of the entire pool of Russian populations.

[Polymorphism of Y-chromosomal microsatellites in Russian populations from the northern and southern Russia as exemplified by the populations of Kursk and Arkhangel'sk Oblast].

Allelic polymorphisms at five Y-chromosomal microsatellite loci (DYS19, DYS390, DYS391, DYS392, and DYS393) were typed in 87 individuals from male population samples from two geographically isolated regions (Arkhangelsk oblast and Kursk oblast) of the European part of Russia. The populations examined demonstrated substantial differences in the distribution of the DYS392 (P = 0.005) and DYS393 (P = 0.003) alleles. Estimates of genetic relationships between these populations and some other European populations (including Eastern-Slavic) showed that irrespectively of the measure of genetic distance chosen, Arkhangelsk population was closer to the populations belonging to the Finno-Ugric linguistic group (Saami and Estonians) and to the Estonian geographical neighbors, Latvians, while Kursk population was the member of a cluster formed by Eastern-Slavic populations (Russians of Novgorod oblast, Ukrainians, and Belarussians). Phylogenetic analysis of the most frequent haplotypes indicated that these differences between Kursk and Arkhangelsk populations were associated with high prevalence in the latter of major haplotypes characteristic primarily of the Finno-Ugric populations.

p53 polymorphisms in Russia and Belarus: correlation of the 2-1-1 haplotype frequency with longitude.

Four different polymorphisms in the human p53 gene (a 16-bp duplication in intron 3, and three RFLPs: for Bsh1236I at codon 72, for MspI in intron 6 and for BamHI in the 3' flanking region) and extended haplotypes were studied in nine geographically diverse populations from Russia and Belarus. The Yakuts differed from all other populations, as they had a significantly higher frequency of the BamHI A1 allele. Most populations did not differ significantly from each other in the frequency of the Bsh1236I polymorphism. The 16-bp duplication A1 allele and MspI A2 allele frequencies were significantly higher in the Yakut and Khant populations. Linkage disequilibrium values (D') between BamHI and other polymorphic sites were not significant in many cases; for this reason we have used the 16 bp-Bsh1236I-MspI haplotype frequencies only. Of eight possible haplotypes, five were observed in the populations investigated. Haplotype 1-2-2 was the most frequent in all populations. The next most common haplotype, 1-1-2, was present at very similar frequencies among the Byelorussians and Russians from Smolensk, but was more frequent in other populations. The frequency of haplotype 2-1-1 showed a nearly continuous decrease from West to East (from 17.857% among the Byelorussians to 0.685% in the Yakuts from the Verkhoyansk) and correlated with longitude (Spearman's r = -0.8667, P = 0.0025), which may be due to natural selection and adaptation. The relationships among populations were evaluated by means of Nei's D(A) distances for the 16 bp-Bsh1236I-MspI haplotype frequencies. Based on the multidimensional scaling analysis a correlation between p53 haplotype frequencies and ethnicity is supposed.

Connection between p53 gene Bam HI RFLP polymorphism with the volume of brain infarction in patients with carotid atherothrombotic ischemic stroke.

PURPOSE: The aim of our investigation was to study the connection between p53 gene Bam HI RFLP polymorphism and the brain infarction volume in patients with atherothrombotic ischemic stroke that could highlight certain genetic aspects of the individual sensibility of brain tissue to acute ischemia. MATERIALS AND METHODS: Diallelic Bam HI RFLP polymorphism in 5' flanking region p53 gene was studied in 96 patients with carotid atherothrombotic stroke from Moscow population. Magnetic resonance imaging was conducted on day 7 after the stroke onset. The manual morphometry and "Osiris" morphometric hardware (by the Hospital of the University of Geneva) were used for assessment of the infarction volume. RESULTS: The predominance of small-size infarctions (< 40 cm3) was revealed in patients with (-/-) Bam HI RFLP p53 genotype versus patients with (-/+) (X2 = 19.7; P < 0.001) and (+/+) (X2 = 12.288; P < 0.001) genotypes. According to the Bayesian's statistics, in patients with (-/-) p53 Bam HI genotype the development of a small-size infarction in atherothrombotic ischemic stroke can be prognosticated with probability more than 65%. CONCLUSIONS: A significant association between p53 gene Bam HI RFLP polymorphism and the infarction volume was found in patients with carotid atherothrombotic stroke from Moscow population. These results additionally confirm that apoptosis plays an important role in the formation of ischemic brain lesion and that drugs with anti-apoptotic properties may prove beneficial in stroke patients.

[Interaction with esterases and mechanism of synergistic action of thio- and dithiophosphates containing the fragments of N-acylated glycine and beta-alanine]. / Vzaimodeistvie s ésterazami i mekhanizm sinergisticheskoi aktivnosti tio- i ditifosfatov, soderzhashchikh fragmenty N-atsilirovannykh glitsina i beta-alanina.

We studied the interaction between O,O-diethyl-S-[(N-acyl-N-alkoxycarbonylalkyl)aminomethyl]thiophosphates and mammalian cholinesterases as well as esterases from insect tissue extracts by kinetic methods and disc electrophoresis. The coefficients of combined effect of these compounds or their dithioanalogs with permethrin were determined. The obtained data suggest that the synergistic effect on the common cockroaches and houseflies is chiefly due to carboxylesterase inhibition by monothioderivatives and monooxygenase suppression by dithioderivatives, respectively.

[Specific interaction between esterases and 2-butylthio-2-thio-1,3,2-oxazaphosphorynane and its cyclic and acyclic analogs]. / Osobennosti vzaimodeistviia s ésterazami 2-butiltio-2-tio-1,3,2-oxsazafosforinana i nekotorykh ego tsiklicheskikh i atsiklicheskikh analogov.

We studied the anticholinesterase and anticarboxylesterase effects of 1,3,2-oxazaphosphorynane derivatives and certain cyclic and acyclic analogs on the two enzymes of homoiotherms (ACE from human erythrocytes and BuCE from horse serum) as well as the enzymes from insect tissues (the nerve cord of the American cock-roach and the cephalic region of the domestic fly). The differences in in vitro antiesterase activity of cyclic thionic and the corresponding oxo derivatives of phosphorinane were revealed. The mechanism of the esterase active center phosphorylation not only splitting off the outgoing group (in vivo) but also opening the cycle by P-O bond (in vitro and possibly in vivo) is usually proposed to explain the higher inhibiting activity of the thionic compounds compared to the oxonic ones. The possible involvement of this phosphorylation mechanism in the synergistic activity of the studied compounds is discussed.