Phosphorylation is the universal regulatory mechanism in key physiological processes such as development, cell differentiation, proliferation, survival and malignant transformation. In this review we analyze serine/threonine protein kinases of the Pim (proviral integration of Moloney virus) family that have been initially discovered in experimental lymphomas. We provide data on gene structure, evolution, functions and substrates of Pim protein kinases. Focusing on Pim-1 as the major isoform, we analyze its role in the biology of hematopoietic malignancies. Pim-1 is a pro-proliferative and pro-survival protein kinase. It is constitutively active due to autophosphorylation, and its downstream partners positively regulate the cell cycle. Pim-1 cooperates with c-Myc oncoprotein in leukemogenesis; furthermore, Pim-1, like the Akt protein kinase, prevents cell death. Thus, Pim kinases are regarded as new therapeutic targets. Finally, we present an original test system f or screening of Pim inhibitors. In this test system the growth of a genetically engineered Escherichia coli strain in the presence of kanamycin is dependent on the phosphorylation of aminoglycoside-3' phosphotransferase VIII by Pim-1: pharmacological inhibition of this phosphorylation increases the bacterial cell lysis.

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).

The crucial predictor of renal cell carcinoma (RCC) is a clinical stage, although the significance of this parameter isn 't confirmed for all histological types of carcinomas. It remains unknown what factors ensure the sensitivity of the tumor to chemotherapy and why metastasis is accompanied by the development of resistance to therapy. The data about the prognosis of RCC rare variants are extremely scarce. Ubiquitin-dependent proteolysis plays an important role in the development of RCC, but the prognostic significance of this signal way's proteins is poorly understood. In order to find out significant factors for prognosis of RCC clinical course it's necessary to use the complex spectrum of tumor growth regulation factors and genetic tests.

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal neoplasms of the gastrointestinal tract. Analysis of GIST morphology is necessary for selection of primary patients with the high risk of tumor progression for adjuvant treatment with gleevek following complete gross resection of KIT (CD 117)-positive GIST. In this study we've analyzed morphological parameters and survival of 120 GIST patients before target therapy. According to risk stratification of primary GIST by tumor location, size and mitotic index (mitoses per 50 visual fields) 44% of gastric GISTs, 87,5% of small bowel GISTs and 100% of rectum GISTs have been classified as high risk group. There was no significant difference between survival of patients with different type of GIST, Ki-67 proliferative index and presence of necrosis.

Hyperexpression of oncogene c-kit is found in 80% patients with acute myeloid leukemia (AML). The transgenic model cell line expressing the oncogene c-kit was obtained by transduction with recombinant retrovirus. We have designed small interfering RNAs (siRNA) efficiently suppressing the expression of activated oncogene c-kit. Further small hairpin RNAs (shRNA) targeting c-kit mRNA were designed and expressed in lentiviral vectors. We report a stable reduction in c-kit expression following the introduction of shRNAs into model cells as well as Kasumi-1 cells from the patient with AML.

We have investigated deletions of 3p14, 9p21, 9q34, 17p13 (TP53) loci, activating FGFR3 mutations in exon 9 and aberrant methylation of RASSF1, RARbeta, P16, P14, CDH1 genes with the aim of the molecular pathogenesis pathways analysis of bladder cancer. FGFR3 activating mutations and 9p21 deletions were observed significantly more frequent in the group of non-invasive bladder cancer pTa than in minimally-invasive cancers pT1 (p = 0.004 and 0.006 respectively). It was shown that groups of superficial and invasive bladder cancer are significantly differing in the frequency of 17p13 (p = 0.006) and 9q34 (p = 0.04) deletions and in aberrant methylation of the gene P16 (p = 0.02). We have revealed some differing molecular-genetic alterations in groups of superficial and invasive bladder cancers. Therefore we suppose that these two types of bladder cancer might have different pathways of development.

The destruction of stable cell-cell adhesion and the acquisition of the ability to migrate are consistent stages of neoplastic evolution of tumor cells of epithelial origin. We studied the morphologic and mi gration characteristics of epithelial cells of Iar1162 and IAR1170 clones derived from a mixed culture of on cogene N-RasV12-transformed cell line IAR-2. It was found that the mutant oncogene RAS can cause two types of morphological changes in IAR-2 epithelial cells. Cells of one type (IAR1162 clones) underwent epithelial-mesenchymal transition: they stopped to express E-cadherin, acquired fibroblast-like morphology, and did not form tight junctions. Cells of the other type (IAR1170 clones) retained a morphology close to the morphology of nontransformed progenitor cells, formed E-cadherin-based adherens junctions and tight junctions, and formed a monolayer in confluent culture. However, in both IAR1162 and IAR1170 cells, the mutant oncogene RAS caused the destruction of marginal actin bundle and the reorganization of cell-cell adherens junctions. RAS-transformed IAR1162 and IAR1170 epithelial cells acquired the ability to migrate on a flat substrate as well as through narrow pores in membranes of migration chambers. A videomicroscopic study of transformed epithelial cell cultures demonstrated the instability of cell-cell contacts and the independent nature of cell migration. IAR 1170 epithelial cells, which had E-cadherin-based adherens junctions, were also able to move as a group (collective migration). 1162D3 cells, which lost the ability to express endogenous E-cadherin as a result of Ras-transformation, were transfected with a plasmid carrying the CDH1. As a result of transfection, clones of cells with different levels of expression of exogenous E-cadherin were obtained. The high level of expression of exogenous E-cadherin in transformed epithelial cells led to a decrease in the rate of migration on a two-dimensional substrate of the cells that were in contact with neighboring cells but almost had no effect on the migration of single cells, at the same time increasing the number of cells that migrated through the pores in migration chambers. Thus, the destruction of marginal actin bundle and the change in the spatial organization of cell-cell adherens junctions, irrespective of the presence or absence of E-cadherin, was accompanied by destruction of stable cell-cell adhesion and the appearance of locomotor activity in Ras-transformed epithelial cells. The retaining of E-cadherin in cell-cell adhesion junctions affects the locomotor activity of transformed epithelial cells and plays an important role in their collective migration.

One of the main criteria of pluripotency is ability of cell lines to differentiate into the germ line. Pluripotent stem cell lines in ground state of pluripotency differ from the lines in primed state by their ability to give rise to the mature gametes. To understand molecular mechanisms involved in regulation of different states of pluripotency we investigated the expression patterns of germ line specific genes in different type pluripotent stem cells and mouse and human embryonic teratocarcinoma cells. We found that pluripotent stem cells in vitro, in blastocyst and gonocytes at stage E13.5 had similar expression patterns in contrast to the epiblast cells at stage E6.5. Quantitative real time PCR analysis showed that Vasa/Ddx4 expression in mouse and human embryonic stem cells was significantly lower than in blastocyst and gonocytes. Moreover, Vasa/Ddx4 and E_ras expression was significantly higher in mouse embryonic stem cells than in human embryonic stem cells. Our analysis of germ line specific gene expression in differentiating mouse embryonic stem and embryonic germ as well as in mouse embryonic teratocarcinoma cells maintained under conditions promoting cell reprogramming from primed to ground state of pluripotency (2i + LIF) revealed that only pluripotent stem cells are able to regulate the expression level of Oct4 and Vasa/Ddx4 and restore initial ground state, while in embryonic teratocarcinoma cells the expression level of these genes remained unchanged. We suggest that expression patterns of germ lines specific genes, in particular of Vasa/Ddx4, can underlie the regulation of ground and primed states of pluripotency. [corrected].

This study represents the analysis of the data available in the literature and the author's findings concerning the issue of a shape of the dose stochastic effect curve in the range of low levels of radiation (LLR). The data obtained from radioepidemiological and experimental investigations are used. Also considered are the arguments "pro" and "contra" regarding approximation of these curves by means of a linear function (linear non-threshold conception) or as a quasi-plateau (threshold conception). The above analysis allows us to conclude that the threshold conception is more reliable than the non-threshold one from the standpoint of the analysis of postulate bases, theoretical paradigms, the mechanisms for radiobiological effects, epidemiological and experimental data. It is suggested that a separate radiogenic cancer risk estimation should be used in case of LLR and high level radiation instead of one overall estimation by means of the linear non-threshold model.

The review analyzes telomere lengthening mechanisms in cancer cells of two different tumor types--carcinomas and sarcomas. Basic attention is given to sarcomas which cells lengthen their telomeres through alternative mechanisms for lengthening telomeres (ALT). The features of ALT mechanisms functioning in these cells have been examined in detail. Moreover, the actually existing anti-telomerase drugs and their efficiency in carcinomas treatment were analyzed. The experimental data showing that, contrary to theoretical expectations, activation of ALT was not observed on a background of such anti-telomerase, are presented. This portends a good prognosis in the treatment of the patients with carcinoma. Finally, on the basis of the data analyzed the candidates for a role of targets are proposed for development of anti-ALT antineoplastic therapy. Expected efficiency and toxicity of such drugs are considered in detail.

This article presents the results of experience of application of a technique fluorescent in situ hybridization (FISH) in early diagnostics of relapses of a superficial bladder cancer in 103 middle-aged, old and senile persons who had transurethral resection of the bladder.

The fallopian tubes and ovaries samples from 5 breast cancer patients and 12 practically healthy women considered to be at high risk for developing ovarian cancer underwent evaluation for morphological features and immunohistochemical expression of Ki-67 and p53. In high-risk patients the multiple follicular, serous, epithelial inclusion cysts (often with epithelial hyperplasia), surface papillomatosis, fibromatosis, cortical stromal hyperplasia in ovaries and fibres' sclerosis, paratubal cysts in fallopian tubes were discovered. Immunohistochemical study revealed strong expression of Ki-67 (LI 16-53,6%) in epithelial cells of follicular and inclusion cysts in 25% (3/12) of practically healthy women of reproductive age. P53 expression was determined in epithelium of inclusion cysts with high proliferative activity in 16,6% (2/12) of practically healthy women with BRCAI/2 mutation. The current results suggest histological evidence for the existent of pre-neoplastic phenotype defined by above-described histologic features in the high-risk ovaries, especially in carriers of BRCA1/2 mutations. P53 and Ki-67 expression in epithelium of inclusion cysts in women with BRCA1/2 mutations indicates the early genetic alterations in these cells and high risk of malignant transformation.

Research during the past decade has shown that epigenetic events have a key role in carcinogenesis and tumour progression. Histone deacetylase inhibitors (HDACi) comprise structurally diverse compounds that are a group of targeted epigenetic anticancer agents. Here we explored the in vitro efficacy of HDACi such as sodium butyrate (BuNa), valproic acid (VaNa) and several novel HDAC inhibitors for the treatment of cancer. Both BuNa and VaNa inhibited cancer cell proliferation in a time--and dose-dependent fashion. In the present study we demonstrated the significant effect of two novel HDACi, Adipo or BuNHOH, able to induce apoptosis of cancer cells, but not of normal line. Since HDAC inhibitors have been proposed as radio--or chemosensitizers in cancer therapy, we have studied the radiosensitizing effect of sodium butyrate on cancer cells. The combination of BuNa and radiation significantly inhibited tumor cell growth. Besides, combining Cisplatin or Gemzar with HDAC inhibitors results in synergistic antiproliferative activity that could be therapeutically exploited. These results suggest that HDACi acts as an antitumor agent and that combining HDAC inhibitors with radio or--chemotherapeutic strategy may provide a novel chemotherapeutic treatment of cancers insensitive to traditional antitumor agents.

Analyzed the association of functional polymorphisms of VEGFA at positions -2578 of promoter region and at position +936 3' of untranslated region in a group of healthy women and breast cancer patients with the aim to detect informative markers associated with the risk of disease. The study included 395 DNA samples from women with breast cancer and 298 healthy women. Genotyping of polymorphisms of C-2578A and C +936 T VEGFA was performed by restrictase analysis of amplification products (RFLP-analysis). There was revealed the increase of the frequency-2578AA genotype in patients with breast cancer (OR 1.55, 95% CI 1,55-2,29), moreover, the frequency of this genotype increased in the group of patients with a common family history and with breast cancer in close relatives of relatively healthy women (OR = 2,03 95% CI 1,26-3,27 and OR = 2,22 95% CI 1,13-4,33, respectively). Genotype frequencies of -2578AA/+ 936 SS and -2578SS/+ 936 CT were significantly higher in the group of patients with a factor of family history as compared to the group of patients without it (OR = 1,84 95% CI 1,01-3,34 and OR = 2,91 95% CI 1,09-8,05 respectively).

A possibility of detection of BRAF mutation has been studied by means of polymerase chain reaction in punctate from the thyroid node with the aim of diagnostics of high-differentiated cancer on pre-operative stage. A study includes 94 patients with nodal lesions of the thyroid. According to cytological investigation of material, received by fine-needle aspiration biopsy, papillary thyroid cancer was revealed in 47 patients, follicular tumor-in 35 and nodal colloid goiter in 12 patients. In case of papillary thyroid cancer data of genetic analysis showed the following indices of sensitivity, specificity and diagnostic accuracy: 86%, 100% and 92% correspondingly. Detection of BRAF mutation could be used in pre-operative differential diagnostics of high-differentiated cancer and benign nodal lesions of the thyroid.

Human papilloma viruses (HPV) of high carcinogenesis risk play important role in development of cancer of oropharyngeal and anogenital areas. Possible malignant transformation of cells, infected by HPV, is due to the expression of three proteins, E6, E7 and E5. These proteins mostly influence on mechanisms that regulate cellular cycle, proliferation and apoptosis inducing and maintaining oncogenesis. This review briefly presents data on malignant tumors induced by HPV as well as biology of these viruses and their vital cycle. Special accent is made on description of current trends in molecular basis of oncogenesis, induced by HPV, which understanding is necessary for elaboration of new methods of treatment for HPV-infection such as therapeutic vaccines.

Our study was concerned with assessing the results of FISH analysis as a procedure to detect occult features of tumor and contribute to individualizing treatment strategies. It included a cohort of 50 patients with primary bladder tumors who had undergone transurethral resection. Washings from all patients were tested using UroVysion protocol immediately prior to surgery. Patients were divided into groups according to stage and grade of tumor. The sensitivities were 81.5%, 91.7% and 100% for Ta, T1 and T2 groups, respectively. In G1, G2 and G3 groups, the sensitivities were 70%, 100% and 100%, respectively. Besides, the rate of detecting genetically abnormal cells was significantly higher at stage T2 as compared with Ta and Ta+T1 groups. It was also higher in G3 group as compared with G1 for Ta and G2. No significant differences in the mean number of signals from each chromosome was reported. Frequency rates of abnormal cells of less than 40% correlated with absence of invasion into the muscular layer and poorly-differentiated cell status. They rose insignificantly in proportion to stage and grade. Detection of less than 40% of genetically abnormal cells correlated with absence of mascular invasion and G3 tumor (90% credibility). FISH diagnostic procedure showed high sensitivity of detecting even at incipient stage of bladder carcinoma and was instrumental in preoperative predicting type of tumor.