Bone neoplasms - are a rare group of diseases, which ethiology and pathogenesis are not fully understood. We have studied 6 single nucleotide polymorphisms rs792/(GHI), rs7956547(IGFI), rs3761243(GNRH2), rs11737764(FGF2), rs6599400(FGFR3), and rs1690916(MDM2) associations with bone tumors. In our work we've detected significant associations with some single nucleotide polymorphisms: IGFl.rs7956547, GNRH2.rs3761243 and FGFR3.rs6599400 in patients with malignant and borderline bone tumors.

Medulloepithelioma is a rare malignant tumor arising in cerebral hemispheres. Microscopically, medulloepithelioma is characterized by epithelial structures that mimic the embryonic neural tube. Immunohistochemical analysis revealed that tumor cells are immunopositive for LIN28A and fluorescence in situ hybridization showed an amplification of a miRNA cluster at 19q13.42. Presence of these both aberrations suggesting that medulloepithelioma, ependymoblastoma and embryonal tumor with multilayered rosettes are the same entity.

Matrix metalloproteinases (MMP) play a key role in development of tumor invasion and metestasis. The purpose of the work is the elucidation of peculiarities of expression of MMP-1, MMP-2, MMP-9 and their activity regulators: plasminogen activator uPA and tissue inhibitors of MMPs - TIMP-1 and TIMP-2 in human cell lines of squoamous cell carcinoma (SCC). Comparative study of MMPs' expression was carried out on cell lines SCC which differed in HPV types (HPV-16 and HPV-18): SiHa, Caski - HPV16, Hela, C4-1 - HPV18). As a control, the C33A line was used where HPV copies were absent. The human papilloma viruses (HPV) of high risk--HPV-16, HPV-18, as etiological factors of initiation of cervical cancer, are most widespread and most aggressive among oncogenic HPVs. Study of MMP expression involved estimation of expression of mRNA using the RT-PCR method and determination of collagenolytic activity by hydrolysis of fluorogenic type 1 collagen and also by the zymography method. It was shown that: 1. In both types of cell lines, the MMP-1 expression was essentially increased (2 to 8 times), and in HPV18 lines it was most expressed. The exception was made by the SiHa line in which the decrease of expression of this enzyme was observed. MMP-2 expression was at the control level in both types of cell lines. 2. Expression of inhibitors generally was at the control level. The only exception was the C4-1 line where the expression of TIMP-1 and TIMP-2 was increased in 1,7 and 2,6 times accordingly. Expression of uPA was increased 2 to 4, 5 times in all cell lines except Siha where was lowered to 20%. 3. Collagenolytic activity in the Caski and Hela cell line was 2-3 times higher that it was in control, while the activity in the SiHa cell line was compatible with that in the control. Research of gelatinolytic activity also as well as the data on an expression MPHK has revealed only presence MMFP-2, but not MMP-9 in all cervical carcinoma cell lines. The data obtained provide evidence for a significant disturbance in transformed cells of enzyme/inhibitor/activator ratio--which occurs, for the most part, at the cost of elevated expression of MMP-1 and its activator whereas the expression of MMP-2 and inhibitors remains virtually unchanged, which leads to the increase of the destructive potential of transformed cells.

Human myeloid cells with Ph chromosome (Ph+ cells) from chronic myeloid leukemia (CML) in the course of proliferation and differentiation ex vivo are regulated under alternation of cell proliferation and neutrophil maturation stages by consecutive blocking and inducing apoptosis with of neutrophils participation as well bcr/abl, bax and bcl2 genes expression. Apoptosis regulation of three main Ph+ cells types from CML patients depends on alternation sequences of proliferation (1) and maturation (2) cell stages and realized by two ways. The first one is performed by consecutive blocking and inducing apoptosis under 2/1/2 stage alternation. The way is not described early. Neutrophils accumulation correlates with apoprosis blocking. Apoptosis level enhances under neutrophils exhausted. Apoptosis blockage allows cells to proliferate and, thus, to form new portion of neutrophils with consecutive regular their death as well a consequent alternation of apoptosis blocking and inducing. This way regulates proliferation efficiency indexes P/D that reflect Ph+ cells proliferating potential and performs cycle completion for proliferation and differentiation. The second way of apoptosis regulation starts from proliferation stage and performs for 1/2/1 alternations under diminished content of neutrophils and a little increase under next maturation. It leads to resistant depressed apoptosis levels that, at maximal points, are 3-8 times lower than those under alternation 2/1/2. Resistant apoptosis blocking is observed in the Ph+ cells with prolong proliferation or maturation stages, when blasts and myelosytes are accumulated under enhanced bcr/abl and bcl2 > box gene expression and remain under next maturation. Stable apoptosis blocking is accompanied by increasing amounts of blasts and myelocytes and enhancing bcr/abl and bcl 2 > bax expression. This is observed under CML progression. Ph+ cells cultivation may be useful for more distinct diagnostics of CML phases of individual CML patients and optimization of the treatment.

With the completion of large scale genomic sequencing, a great number of non-conding RNAs (ncRNAs) have been discovered and capture the attention of the biological sciences community. All known ncRNAs may be divided into two groups, namely: i) small ncRNAs, which comprise microRNAs (miRNAs), PIWI-interacting RNAs (piRNAs) and short interfering RNAs (siRNAs), and ii) several thousands of long ncRNAs (IncRNAs). NcRNAs were shown to be involved in eukaryotic growth and development, cell proliferation and differentiation, apoptosis, epigenetic modifications, and also the complex control and pathogenesis of various diseases. In this paper, knowledge on the ncRNAs, which functioning is associated with human diseases, has been summarized.

A hypothesis has been suggested, according to which destruction of the body that occurs during senescence and carcinogenesis is likely to be regulated by the atavistic mechanism of apical dominance described by plant physiologists. This mechanism is inherited from the first on Earth multicellular animals that behaved the mode of life attached to benthos and to underwater objects and probably were modular sessile invertebrates.

MicroRNAs play an important role in the regulation of expression of many genes and are involved in carcinogenesis. The regulation of miRNA gene expression can involve the methylation of promoter CpG islands. In this work, the methylation of six miRNA genes (mir-107, mir-125b-1, mir-130b, mir-137, mir-375, and mir-1258) in non-small-cell lung cancer (NSCLC) was studied for the first time by methylation-specific PCR using a representative set of specimens (39 cases). Four new genes (mir-125b-1, mir-137, mir-375, and mir-1258) methylated in primary NSCLC tumors were identified with frequencies of 56, 31, 56, and 36%, respectively. The frequencies of miRNA promoter methylation in DNA of tumors and histologically normal tissues differed significantly (P < or = 0.05 by Fisher's test). In lung tissues of 20 donors without a history of cancer, these genes were only methylated in a few cases. It was also shown that the previously unstudied promoter CpG islands of mir-107 and mir-130b were not methylated in NSCLC. The frequencies of mir-125b-1 and mir-137 methylation were shown for the first time to correlate with NSCLC progression (clinical stage and metastasis).

Glycolysis is a main catabolic pathway of glucose metabolism, accompanied by ATP synthesis. More than 30 enzymes are involved in glycolysis, and genes that encode them can be considered housekeeping genes due to the high conservatism and evolutionary antiquity of the process. We studied the expression of these genes in kidney papillary cancer and planocellular lung cancer via the bioinformatic analysis of transcriptome database and method of quantitative real time PCR. Quantitative analysis of mRNA level demonstrated that only a part ofgenes that encode glycolysis enzymes maintain relatively stable mRNA level, including the HK1, ADPGK, GPI, PGK1, and PKM2 genes in kidney papillary cancer and the ADPGK, ALDOA, GAPDH, PGK1, BPGM, ENO1, and PKM2 genes in planocellular lung cancer. The frequent increase in the mRNA expression of PFKP, ALDOA, and GAPDH genes in kidney cancer, as well as the GPI gene in lung cancer, were detected for the first time by real time PCR. For other genes, their differential expression was demonstrated; the cases of both a decrease and increase in the mRNA level were detected. Thus, several genes that can be used as control genes in transcriptome analysis by real time PCR in kidney and lung cancer, as well as a number of differentially expressed genes that can be potential oncomarkers, were identified.

Ethnic diversity of the population in the region of Siberia suggests the existence of different germline mutations in the BRCA1/2 genes associated with breast and ovarian cancer in different ethnic populations, but spectrum of these mutations has not been studied.

Radioprotection appeared to be an important problem of today due to atom energetic development and utilization of radiation material in the industry, science and medicine. It has been shown that mitochondrial targeted antioxidant SkQR1 could attenuate radiation injury of human erythroleukemia K562 cells. Pretreatment with SkQR1 before irradiation decreased DNA double strand breaks formation, diminished the number of chromosomal aberrations and suppressed delayed ROS production. Prevention of oxidative stress and normalization of mitochondrial function by mitochondria-targeted antioxidants may be a potential therapeutic strategy not only against immediate consequences of radiation, but, either against its late consequences such as genomic instability. SkQR1 did not protect against radiation-induced damage the K562 subline with high level of multidrug resistance (MDR) due to SkQR1 extrusion with Pgp 170 MDR pump. We suggest that mitochondria-targeted antioxidants might be used for selective protection of normal cells against radiation-induced damage without interference with radiotherapy of MDR-positive tumors.

The purpose of the review--to analyze the basic data on modifiable and genetic risk factors of pancreatic cancer (PC). PC is the most fatal disease that kills about 95% of patients. Among the known risk factors for PC only for smoking, obesity, and family history a positive association with the PC risk in meta-analyzes confirmed. The PC etiology remains unclear, more than 90% of patients acquire it sporadically. Currently, the most significant genes for PC include KRAS2, p16/CDKN2, TP53, SMAD4/DPC4. Mutations in the KRAS noted in 90% of cases of pancreatic ducts adenocarcinoma. p16/CDKN2A mutation is accompanied by a 38-fold increased risk of PC compared with the general population. TP53 mutations are associated not only with carcinogenesis but also PC metastasis, as well as SMAD4/DPC4 mutations. Study of the role of genetic aspects in the PC development is necessary both to identify individuals with high PC risk, as well as for the development of gene-specific treatments, such as inhibitors of proteins, histone deacetylase, and histone acetyltransferase (vorinostat, belinostat, entinostat, panobinostat, curcumin) are in clinical trials.

Phylogenetic analysis of the sequenced segments of the provirus BLV locus env-gene and the strategy of the PCR-PDRF-genotyping consistent with phylogenetic classification of pathogenic agent and suggested in our works provided taxonomic identification of BLV isolates identified in cattle in Tatarstan (Russian Federation) as representatives of the 4th, 7th, and 8th BLV genotypes. Of 100 identified isolates, 64 represent the 4th BLV genotype, 28 representatives of BLV belong to cluster of the 7th genotype, whereas the other 8 samples of the provirus belong to the new 8th genotype of pathologic agent. The strategy VBL PCR-PDRF-genotyping suggested in our work on the basis of 5 restriction endonucleases (PvuII, SspI, HphI, HaeIII, and BstYI) provided correct genotyping identification of the viral pathogen.

Development of targeted drug delivery system is key problem of cancer gene therapy. To ensure specific delivery of these therapeutic compounds to the tumor it is preferable for therapeutic gene expression to occur predominantly in cancer cells. Therefore, when testing drug in vivo, it is necessary to study distribution of therapeutic gene expression products in different tissues of the organism. Sodium iodide symporter (NIS) is attractive reporter because its tissue level is easily quantitatively detected by noninvasive imaging methods. Different promoters are used to direct expression of therapeutic genes in tumor cells: strong nonspecific, moderate tissue-specific and tumor-specific. Tumor-specific promoters function in wide range of tumor cells, however they are relatively weak. Relationship between promoter and sodium iodide symporter activity is unclear to date. In this report we examined activity of different promoters in two melanoma cell lines, functional activity of NIS driven by these promoters, also we compared promoter strength and NIS activity. We demonstrated that in spite of strong differences in promoter activity functional activity of NIS directed by these promoters varies weakly. Relatively weak melanoma-specific promoter directs high NIS activity in melanoma cell, however weaker cancer-specific promoters drive high NIS activity only in certain melanoma cell line.

Recombinant adenovirus encoding the VP2 gene of infectious bursal disease virus (ADV-VP2) has shown potent anti-tumour effects due to its capability of apoptotic induction in cancer cells. In the present study, human breast cancer cells MCF-7 and MDA-MB-231 were infected with ADV-VP2. The expression of VP2 protein was registered 4 h post-infection, particularly in MCF-7 cells. Multiple time-point DNA ladder assay demonstrated that ADV-VP2 infected MDA-MB-231 and MCF-7 cells endured apoptosis as early as 8 and 12 h post-infection, respectively. Apoptosis induction in both MDA-MB-231 and MCF-7 cells, albeit different start points, lasted til 36 h post-infection. The induction of apoptosis by ADV-VP2 was further shown by the TUNEL assay, with dark brown discoloration of apoptotic cells. The present study also explored the different stages of apoptosis by Annexin V/PI double staining flow cytometry quantification. Treated MCF-7 and MDA-MB-231 cells, respectively detected 25.58 +/- 9.02 and 14.51 +/- 3.12% of early apoptotic cells, 6.09 +/- 4.06 and 77.12 +/- 5.09% of late apoptotic cells. Results revealed that there were significant differences in the number of cells of both types which underwent early and late apoptosis. Significant differences were also observed among viable and apoptotic cells which have been post treated with ADV-VP2. The apoptotic effects of ADV-VP2 on human breast cancer cell lines were consistently demonstrated by three apoptosis detection methods. Therefore, a cancer vaccine basing on gene therapy could be developed in the near future using the present construct.

Deregulated expression of proteins involved in the SUMOylation pathway has been detected in several tumors. SUMO1-activating enzyme subunit 1 (SAE1) plays an important role in this process. We found that SAE1 was highly expressed in the colon cancer cell line RKO and used lentivirus-mediated siRNA to suppress SAE1 expressionin RKO cells. RNA-interference efficiently and specifically downregulated the target gene expression in RKO on both mRNA and protein levels. Silencing of SAE1 inhibited proliferation and reduced colony formation of RKO cells. Furthermore, as it has been shown by flow cytometry analysis, specific knockdown of SAE1 slowed down the cell population at G0/G1 phase and induced apoptosis of RKO cells. On the base of results obtained, one can suppose the biological significance of SAE1 in colon tumorigenesis and a use of this protein as a novel molecular target for colon cancer therapy.

State Research Center "GosNIIgenetika", Moscow, 117545 Russia). Association of polymorphic markers Arg72Pro of TP53 gene and T309G of MDM2 gene with risk of non small cell lung cancer has been studied in Russians of Moscow region. We found an association of minor Pro/Pro genotype of polymorphic marker Arg72Pro (OR = 5.46, p = 8 x 10(-6)) and TG genotype of polymorphic marker T309G (OR = 5.57, p = 0.007) with non small cell lung cancer development. We have also showed a strong association of both Pro/Pro and TG genotypes with development of adenocarcinoma (OR = 8.71, p = 3 x 10(-6) and OR = 8.13, p = 0.003) and squamous-cell lung cancer (OR = 4.2, p = 0.001 and OR = 7.02, p = 0.002). We have finally found highly reliable association of combined susceptible genotypes of polymorphic markers Arg72Pro and T309G of TP53 and MDM2 genes with non small cell lung cancer and both its subtypes (OR = 7.9, p = 0.01; OR = 9.12,p = 0.02; OR = 7.31, p = 0.03, respectively).

Several studies have shown, that mutation in CHEK2 gene can increase the risk of different cancers, including breast cancer (BC). Clearly, that character of mutations distribution in the defined regions is depended on genetic structure of the population. We conducted the screening of mutations c.1100delC, c.444 + 1G>A, de15395, p.I157T andIp.R145Win CHEK2 gene in patients with breast cancer (n = 977) and in control group (n = 1069) originating from the Republic of Bashkortostan. The mutation de15395 in CHEK2 gene was detected with frequency of 1,23% (12/977)in woman with BC and 0.09% (1/1069) in controls (OR:13.28, CI 95%: 1.72-102.33, p = 0.003). Mutations c.1100delC and c.444 + 1G>A were found in BC patients and controls with frequencies of 0.4%, 0.4% (4/977) and 0.09% (1/1069), 0.2% (2/1069), respectively. The missense mutation p.I157T in CHEK2 was found as the most common variant in two studied cohorts (approximately 5%), but differences did not achieved statistical significance. We found the ethnic specificity in distribution of truncating mutations, which occurs mainly among the women of Slavic origin. All three mutations were identified in women of Russian and Ukrainian ethnic origin. Mutations c.1100delC and c.444 + 1G>A in CHEK2 gene were not detected in Bashkirs and Tatars, but CHEK2 de15395 mutation was observed in Tatars.

The occurrence of colorectal cancer can be traced in two ways: from conventional adenomas with the APC-gene mutation (model Fearon-Vogelstein) and the "serrated way", that has a unique genetic profile and morphological characteristics at the early stages. These neoplasms are determined from 7 to 9%. The risk of developing cancer of them is 7.5-15%. Precursors of epithelial neoplasia are aberrant crypts foci. About 20% of colorectal cancer demonstrated the common defects in DNA methylation (CIMP-positive profile), mutations BRAF (KRAS)--oncogenes, microsatellite instability (MSI). The serrated lesions may have these mutations. Serrated polyposis syndrome has specific genetic changes associated with biallelic mutation MUTYH also. Risk of colorectal cancer is very high in this syndrome and is more than 50%. Often the synchronous or metachronous cancers presence. They are usually accompanied by MSI-H and represented serrated morphology too. Understanding epigenetic ways and molecular features of serrated lesions gives an knowledge of their clinical significance and provides the evidence for the treatment and monitoring of patients with this disease. This review is devoted to these issues.

Chronic lymphocytic leukemia (CLL) is a multifactorial disease, in which development the important role played the cytokine genes, in particular interleukins. This type of leukemia is more common in the elderly. The purpose of the study was to evaluate the association of genetic polymorphisms of interleukin with the development of chronic lymphocytic leukemia among residents of the Central Chernozem region of Russia. Genotyping of the -889C/T IL-1A, -590C/T IL-4 and VNTR IL-1 Ra was conducted in 206 patients with CLL and 307 individuals of the control group. The study found that the genetic risk factor for the development of CLL is allele -590T IL-4 (OR=-1,45). The development of thrombocytopenia in patients with CLL is associated with genetic variants -889T IL-1A (OR=1,95), -889TT IL-1A (OR=6,2) and IL-1Ra*1 (OR=-2,32).

Numerous available results of investigations confirmed the important role of prophylactic bilateral laparoscopic salpingo-oophorectomy and contralateral prophylactic subcutaneous mastectomy in decrease of risks of malignant tumors of the reproductive system when mutation carriers of BRCA1 and BRCA2 presented. Recommendations to surgical treatment of hereditary breast cancer are considered as a very difficult task which should be based on risks and advantages of prophylactic surgical interventions. Presented surgical operations could be applied in mutation carriers of reparation DNA genes and patients with hereditary breast cancer aimed to improve the indices of general survival rate and quality of life.