There is a large number of healthcare workers who may be exposed to anticancer drugs in different healthcare settings in Russia. Contamination of working environment, throughout the hospital medication system from hospital pharmacy to medical waste facilities, is found in a number of studies. Monitoring of the environmental contamination with these drugs was performed by different methods in various countries. Daily uptake of the anticancer drugs by the personnel exposed for many years may be realized in reproductive impairments and increased cancer risk. The female healthcare workers who handle antineoplastic drugs showed a greater risk of birth defects in offspring, spontaneous abortions, breast cancer and a number of other cancer site revealed by epidemiological methods. Data on the cancer incidence of pharmacists and laboratory workers potentially exposed to the cytostatic drugs are provided. In Russia, the monitoring of occupational cytostatic exposure is required as it would not be correct to apply data obtained in other countries to the Russian conditions. The data for biological and epidemiological monitoring are considered as the background for effective prevention of adverse health effects in healthcare personnel exposed to antineoplastic drugs.

In wide number of approaches to treatment of cancer immunotherapy plays special role. This approach exploits capabilities of immune system to support genetic constancy of different cells and tissues of the organism. Immunotherapy is designed to induce tumor cell destruction  by T-lymphocytes whose receptors can recognize peptides of mutant proteins complexed with the molecules of the major histocompatibility complex. In clinical practice T-lymphocytes can result in sustained and complete responses in patients whose cancers were resistant to available treatment options. Recent evidences suggest that efficiency of such therapy generally depends on metabolic properties of T-lymphocytes. A number of approaches allows modulate T-cell metabolism providing strategies to optimize activity of anti-tumor T-lymphocytes.

MicroRNA miR-155 is one of the most characterized and actively studied microRNAs that regulate processes closely related to carcinogenesis, including cell differentiation, adhesion, migration and invasion of the tumor cells, metastasis, apoptosis and immunosuppression.  In addition, this miRNA is involved in differentiation of hematopoetic cells and developing of inflammation. The association between specific deregulation of the expression of miR-155 and carcinogenesis is confirmed by a number of both fundamental and clinical studies and is due to the posttranscriptional regulation of the most important genes of the tumor associated pathways. Modulation of the levels of expression  of miR-155 is associated with the emergence of a number of leukemias and lymphomas, as well as some solid tumors. An increase of the level of cellular and/or circulating miR-155 in some cancers can serve as a marker for progression and drug resistance. In addition, inhibition  of the expression of miR-155 can be a promising method for developing new approaches in antitumor therapy.

The article describes the role of epigenetic processes in the tumorigenesis of neurofibromatosis type 1. The clinical manifestations of neurofibromatosis type 1 is characterized by a pronounced polymorphism erased from with single neurofibromas to severe forms with thousands  of tumors and complications even in patients with the same mutations. More than 1400 mutations in the NF1 gene have been reported, but have not yet identified genotype-phenotype correlations. Detected in the majority of neurofibromas mutation of the second allele of the gene NF1 and loss of heterozygosity may result from common disorders of genome stability and cell cycle regulation. Chance of tissue-specific  inactivation of the second allele is extremely low and can not prove the detection of neurofibromas in most patients with neurofibromatosis type 1. At the same time, the role of epigenetic factors for blocking of oncosupressors has been proven and can be applied to the development  of malignant tumors and neurofibromas. This assumption is proved by the fact that the majority of neurofibromas are formed in puberty, while inheriting the disease from mother to clinical manifestations more severe. This review presents the research on the role of miRNAs and specific methylation in the promoter region of NF1 tumorogenesis in neurofibromatosis type 1. Mutations in the NF1 gene are of great importance in the development of many malignancies. Due to the possibility of pharmacological correction of activity of microRNAs using antisense sequences, the study of epigenetic processes in neurofibromatosis type 1 promising to diagnose and treat not only the disease but also sporadic malignancies.

The multifunctional protein YB-1 in prokaryotes and eukaryotes participates in various processes, among others performing the functions  of a regulator of transcription and translation of many genes. Intracellular localization and expression of YB-1 is an acknowledged prognostic marker for certain malignant tumors. However, it has recently become clear that YB-1 can be released from cells and present in body fluids, including inside vesicles. The review collected data on the secretion YB-1 (sYB-1) content in blood serum from patients with inflammatory diseases and various tumors. There is analyzed the influence of sYB-1 on normal and tumor cells. Data are presented that show that intracellular YB-1 and sYB-1 affect cells differently. The prognostic significance of sYB-1 and its form YB-1/p18 in malignant neoplasms is discussed.

Tamoxifen is the drug of choice for endocrine therapy of hormone receptor- positive breast cancer in women in the reproductive period.  The metabolic activity of tamoxifen is determined by the activity of the enzyme CYP2D6, encoded by the gene of the same name: under  the action of the enzyme, tamoxifen passes into the metabolically active form, endoxyphene. Pharmacogenetic testing of the CYP2D6 gene  in patients with hormone-positive breast cancer can help predict the effectiveness of therapy and assess the risk of side effects with the aim  of improving long-term treatment outcomes.

Background. The transforming growth factor beta 1 (TGF-β1) is one of the most important tissue factors secreted by the development of epithelial tumors. Increased expression of TGF-β1 in lung tumors promotes cancer cells survival enhancing their growth, migration, invasion, angiogenesis, immune system suppression.

Objective: to study molecular mechanisms of TGF-β1 action on A549 human lung adenocarcinoma cells by means of proteomic high-resolution mass spectrometry. Results. Intracellular signaling pathways responsible for the involvement of TGF-β1 in the oncogenesis of non-small cell lung cancer have been found, which include the differential expressed proteins of the families of cullin, ETS oncogenes, histone diacelases, cyclin-dependent kinases, and the signaling pathway phosphatidylinositol 3-kinase (PI3K).

Conclusions. Important patterns are determined that could be used for the development of new approaches for detection of lung cancer metastasis candidate markers and potential therapy targets of this decease.

Background. Despite advantages in treatment of metastatic melanoma it remains resistant to current therapy. Recent evidence indicates that tumor cells could overcome death through autophagy, a process that degrades cellular proteins and organelles to maintain cellular biosynthesis during nutrient deprivation or lack of energy. Objective: to investigate the involvement of autophagy inhibitors chloroquine (CQ) and LY-294.002 (LY) in temozolomide (TMZ) cytotoxicity in human melanoma cell lines.

Materials and methods. The study was performed on patient-derived melanoma cell lines Mel Z, Mel IL and Mel MTP. The antiproliferative activity of combined TMZ and autophagy inhibitors treatment was determined by MTT assay and colony-forming assay. Cell cycle analysis, apoptosis activation and expression analysis of key autophagy markers under combined treatment was evaluated.

Results. CQ and LY enhanced the cytotoxicity of TMZ and reduced colony formation in 3 melanoma cell lines, moreover both inhibitors increased cell population in G0 / G1 phase of cell cycle in Mel Z, Mel IL cell lines, but not in Mel MTP. CQ and LY synergistically activated apoptosis in all cell lines. The matrix RNA expression analysis of key autophagy genes showed autophagy involvement in enhanced cytotoxicity.

Conclusions. Thus, autophagy inhibition on different stages of this process could overcome resistance to TMZ and be applicable as potent target in metastatic melanoma treatment.

Introduction. Hepatocellular carcinoma (HCC) is characterized by aggressive course, high lethality rate and resistance to current systemic treatment. Analysis of molecular aberrations associated with HCC pathogenesis that control biological properties of HCC allows to evaluate potential efficacy of inhibiting certain oncogenic cascades. The present study is focused on investigation of the impact of reduced expression of the key hepatocyte differentiation regulator, HNF4α, often downregulated in HCC, that influences sensitivity of HCC cells to inhibitors  of the major oncogenic pathways mTOR, CDK4/6-pRb and ROCK.

Materials and methods. Changes in cells proliferation and migration caused by HNF4А gene stable knockdown were tested in human HCC cell cultures HepG2 and Huh7 followed by examination of these cellular properties under mTOR (rapamycin), CDK4/6 (PD0332991, palbociclib) and ROCK 1/2 (Y27632) inhibitors treatment. Gene expression levels were estimated by the real-time polymerase chain reaction method (Real-Time PCR).

Results. HNF4А gene knockdown alters HepG2 and Huh7 cell migration associated with E-cadherin and N-cadherin expression changes. The HNF4α repression weakens Y27632-induced blockade of HCC cells migration potential. HNF4А gene knockdown causes resistance  of Huh7 cells and increase of HepG2 cells sensitivity to rapamycin and PD0332991 that block cells migration ability.

Conclusions. Expression level of HNF4α renders influence on migration of HCC cells and contributes to their sensitivity to mTOR, CDK4/6 and ROCK1/2 inhibitors’ impact on cell migration activity.

Objective: to study the role of the intercellular interactions in the progression of the cancer cells resistance to metformin, a biguanide antidiabetic drug exhibited the marked anti-tumor activity.

Results. Earlier we have demonstrated the effect of horizontal transferring of hormonal resistance of breast cancer cells  from cell to cell, and showed the key role of exosomes on the transferring of the resistance. Here we have shown the effect of the horizontal transferring of metformin resistance in breast cancer cells – similar to the progression of hormonal resistance. We found that horizontal transferring of the metformin resistance is mediated via exosomes secreted by the resistant cells. The proteome analysis of the exosomes revealed several proteins differentially expressed in the exosomes of metformin-resistant cells and associated with the regulation of cell response to apoptotic drugs.

Conclusions. Totally, the data presented demonstrate the new mechanism of the development of the cancer cell resistance based on the intercellular interactions, opening the new insights in the target therapy of breast cancer.

A method is proposed for the development of an erythrocyte diagnosticum based on the evidence of patent № 2452501 (10.06.2012) via development of sensitine obtained from the serum of mares in foal, the above factor being used for diagnosis of malignant neoplasms. In order  to reveal the practical significance of the diagnosticum proposed the findings of the testing of the blood serum of 215 patients with variously located tumors and from 67 individuals without malignant tumors are analyzed. Sensitivity of the method was 88 %, specificity – 89 %,  accuracy – 89 %. The accessibility of the method proposed and simplicity of the reaction as well as the rapid response make it possible to use the method under discussion in any medical institution individually or in the course of screening to obtain primary diagnosis or to reveal risk groups.

The fourth edition of the World Health Organization (WHO) classification of endocrine tumors published in 2017 contains substantial new findings in the topics of pancreatic neuroendocrine neoplasms (PanNENs). In this edition, major modifications are mainly based on new molecular knowledge as well as the clinical behaviour of these tumors accommodated since the previous 2010 classification of degestive tumors was published. According to the new classification scheme PanNENs include malignant well-differentiated neuroendocrine neoplasms (NENs), which are called pancreatic neuroendocrine tumors (PanNETs), and poorly differentiated NENs, which are called pancreatic neuroendocrine carcinomas (PanNECs). PanNENs futher divided into three Grade (G) on the base of cell proliferation: G1 (<2 mitoses on 10 HPF (high-power field) and Ki-67 Index <3 %), G2 (2–20 mitoses on 10 HPF or Ki-67 Index 3–20 %), G3 (>20 mitoses on 10 HPF or Ki-67 Index >20 %). The new category NET G3 was first introduced in this edition of the WHO classification. PanNECs is classified as G3 neoplasms (>20 mitoses on 10 HPF or Ki-67 Index >20 %) and additionally divided into small cell NEC and large cell NEC. In this review we focus on some of the new features of PanNETs and recommended changes of their terminology and classification.