Search

The results of the study of frequency and spectrum of cytogenetic anomalies in 657 healthy employees of the main facilities of the Siberian Group of Chemical Enterprises exposed to external, internal and combined irradiation are presented. No dependence between age and chromosome aberrations frequency was revealed. Chronic external exposure appeared to be the main factor of induction of chromosome aberrations. The frequency of aberrant cells, chromosome type aberrations, paired fragments and rings was statistically significantly higher in employees exposed to external irradiation as compared to persons exposed to combined irradiation. A nonlinear dependence the dose of irradiation and frequency of chromosome aberrations was revealed. A statistically significant decrease of prevalence of aberrant cells, aberration of chromatid and chromosome type was established in employees exposed to irradiation at a dose range of > 0-10 mSv compared to the control group. This agrees with the phenomenon of radiation hormesis. A significant increase of the frequency of chromosome aberrations was not observed at doses below > 40 mSv. In employees exposed to irradiation at a dose range > 40-100 mSv, a statistically significant increase of frequencies of aberrant metaphases, aberrations of chromatid and chromosome types was established. Same was found for dicentrics at dose range of >100-200 mSv. This supports a well known linear threshold model. Dose-effect curve has a plateau at doses ranged from 100 to 500 mSv.

The results from the research into the association between polymorphisms of genes-candidates for individual radiosensitivity and the frequency and spectrum of cytogenetic abnormalities are analyzed. The study was conducted among Siberian Group of Chemical Enterprises healthy employees exposed to professional irradiation in a dose range of 100-300 mSv. Genotyping of DNA samples from 96 employees was carried out by oligonucleotide microarray: "Cancer_SNP_Panel GT-17-211" ("Illumina") containing 1, 421 SNP-markers (Single Nucleotide Polymorphisms) of 406 genes. The standard cytogenetic analysis was performed in the entire examined group. We have also analyzed the association of these SNP with the frequencies of aberrant cells and following chromosomal aberrations: single chromatid fragments, chromatid exchanges, paired fragments, dicentric, ring and frequencies, translocations. We have found that 40 SNP (rs1800389, rs1051690, rs2392221, rs1041163, rs2114443, rs6083, rs1760904, rs4986894, rs488133, rs7462102, rs11249938, rs34206126, rs33945943, rs34324628, rs5742694, rs978458, rs5742667, rs2373721, rs2162679, rs889162, rs2233679, rs2010457, rs2873950, rs1574154, rs10934500, rs4688046, rs10934503, rs4624596, rs2288729, rs4227, rs1367696, rs751087, rs1269486, rs1149901, rs1800404, rs887477, rs696405, rs751087, rs81 92284, rs312016) are associated with the frequency of different types of chromosomal abnormalities (p-value with FDR of Benjamini-Hochberg--equal less than 0.05). 24 SNP (underlined) are associated with more than one type of chromosome abnormalities. In the future, we are going to confirm the results in further studies on the cohort of more than 600 persons.

Previously, we showed the association of neoadjuvant chemotherapy (NAC) response with changing the expression vector (increase or decrease) of multidrug resistance genes (MDR) in breast tumors during chemotherapy. The aim of the present study was to evaluate the relation between changes in the expression vector of MDR genes and distant metastasis-free survival. Patients (n = 120) with breast cancer (T1-4N0-3M0) treated by 2-4 cycles of NAC (CAX, FAC, and taxane regimes) and 4 cycles of adjuvant chemotherapy (FAC) were included. TaqMan-based quantitative reverse transcriptase PCR (qRT-PCR) was used to estimate the expression of the following MDR genes: ABCB1, ABCC1, ABCC2, ABCC5, ABCG1, ABCG2, GSTP1, and MVP--in biopsies before NAC and in tumor samples after chemotherapy. Comparing the corresponding expression levels allowed us to identify the vector of expression change during NAC. The results showed that 5-year distant metastasis-free survival was 73-78% in patients with a decrease in ABCB1, ABCC2, and ABCG1 expression. The up-regulation of these genes during NAC was related to a significant decrease (up to 50-55%) in metastasis-free survival (Kaplan-Meier analysis: log-rank p value = 0.006-0.03). The association of changing the expression vector of MDR genes with metastasis-free survival did not depend on tumor size, lymph node involvement, histological form, receptor status, molecular subtype, and others clinicopathological parameters of breast cancer. The obtained data suggest that changing the expression vector of MDR genes in breast tumors during NAC may be used as a new potential prognostic marker of breast cancer. An increase in tumor expression of ABCB1, ABCC2, and ABCG1 during chemotherapy is a factor of poor prognosis, whereas down-regulation of these genes--a favorable prognostic marker.

Blood-based methylated DNA gene RARbeta2 in circulating plasma (cir DNA) and one associated with blood cell surface were assayed in patients with non small cell lung cancer before and after combined treatment. The levels in both appeared to be significantly higher than in healthy subjects. Enhanced levels prior to treatment were associated with greater advancement of the disease and unfavorable prognosis (overall survival). After two courses of neoadjuvant therapy plus surgery methylation indices fell down to match those in healthy subjects. Our data may be instrumental in working out additional criteria to be used in diagnosis, prognosis and follow-up of patients with non small cell lung cancer.

This study involved 525 breast cancer (BC) patients of T2-4N0-2M0 stages at the age of 35 years and older. Significant differences in clinical and pathological characteristics between premenopausal and postmenopausal BC patients were found. Mostly marked differences were shown for positive lymph node correlation with distant metastasis, multicentric growth and local recurrence depending on menopause status. The prevalence of various morphological structures in primary tumors was appeared to be associated with different forms of tumor progression in pre- and postmenopausal women. We have studied polymorphisms in 15 genes involved in major cancer related pathways (apoptosis, interleukins, folate metabolism enzymes genes). We found that variant genotypes of MTHFR and DHFR genes were associated with an increased BC risk among premenopausal women while polymorphism in IL-18, p53 genes were associated with BC among postmenopausal women. These results demonstrate novel biological information, which points the different mechanisms contributed to breast cancer progression in premenopausal and postmenopausal women.

In this work is shown that the repetitive high power microwaves is able to exert an inhibitory influence on the process of DNA and RNA syntheses in tumor cells of P-815 mastocytoma. This effect depends on pulse repetition rate. High power microwave pulses inhibit the process of transcription in tumor cells. No activation of DNA reparation system due to the irradiation of non-proliferating mononuclear blood cells was found. This indicates that the repetitive high power microwaves are not able to initiate single-filament rupture in DNA of tumor cells. The conformation of transcription enzymes is assumed to be changed under the influence of the microwave irradiation that makes for significant inhibition of RNA synthesis.

The present review deals with the analysis of biological and functional activities of recombinant bacteria Bacillus subtilis IF-alpha 2335 are producing a human interferon. The interferon-producing bacteria are constructed on a basis commercial probiotic strain B.subtilis 2335, carrying a recombinant plasmid pMBM 105 with the gene of human alpha-2 interferon. The implementation of the recombinant strain in the preparation probiotic, received a designation "Subalin", necessitates to verify a number of immunologic activities and to perform successive protective effects. Interferon, synthesized by recombinant bacteria shows the activity on macroorganism at oral and rectal application of preparation. Subalin was shown antivirus and antitumor activity and preservation by recombinat bacteria of antagonistic properties. The mechanisms of the positive effect of subalin were considered: this effect was shown to be due to the action of interferon excreted by recombinant bacteria into the mucous of different biotopes of host.

The adjuvant properties of subalin, a recombinant probiotic prepared from live bacteria Bacillus subtilis producing human alpha 2-interferon were studied in the scheme of its use with vaccines against parvovirus enteritis and distemper. Subalin was shown to be capable of preventing immunosuppression caused by the injection of vaccines, accelerating the formation of the antigen-specific clone of memory cells and enhancing antigen-specific immune response. The mechanisms of the adjuvant effect of subalin were considered; this effect was shown to be due to the action of interferon excreted by bacteria of B. subtilis into the lumen of the intestine. The advantages of this method of interferon supply and the prospects of using subalin preparation as adjuvant are discussed.

Course administration of the recombinant probiotic subalin was shown to significantly potentiate the cytotoxic action of macrophages from healthy and tumor-bearing mice against mastocytoma P-815 cells and syngeneic target cells of lung sarcoma of Lewis. Carrageenan, an inhibitor of macrophage activity, significantly cut down the antimetastaic effect of subalin. The crucial role of macrophages in the mechanism of this function of the drug is discussed.

A new preparation "subalin" developed on the basis of a recombinant saprophyte strain of Bacillus subtilis 2135/105 producing human interferon alpha-2 has been tested for its ability of increasing the effectiveness of antitumor therapy. The study used Lewis lung carcinoma bearing mice C57B1/6 treated with injections of 60 mg/kg body cyclophosphamide, intraperitoneally, on days 3 and 7 of tumor growth. Subalin was administered per as on days 1-14 after tumor transplantation. Combined treatment with cyclophosphamide and subalin resulted in a significantly higher inhibition of primary tumor growth and metastatic spreading as compared with control receiving cyclophosphamide alone. Also, there were fewer animals with metastasis; the average number of these lesions per animal and the total affected area were less. Subalin proved to exert a moderate antitumor and antimetastatic effect. The cytostatic activity of peritoneal macrophages was higher in mice treated with subalin. It is suggested that the chemo-sensitizing and antitumor effects of subalin are due to its ability to induce endogenous interferon production.