Disruption of mechanisms that maintain genome stability is an essential factor of tumor progression. Accordingly, predisposition to the development of neoplasms is often associated with germline mutations in genes involved in DNA damage detection and repair. At the same time, impairment of DNA repair systems may be a predictor of antitumor treatment efficacy while overexpression of genes involved in DNA repair is a frequent event in various types of malignancies that can lead to development of tumor cells’ resistance to chemo- and radiotherapy. NBN (nibrin) gene encodes the subunit of the MRN complex which acts as a sensor of double-strand DNA breaks and participates in their repair by homologous recombination. Germline variants in NBN which are associated with increased risk of tumor development are generally represented by frameshift mutations that lead to the synthesis of truncated protein as well as by nonsense and some missense mutations which occur in functionally significant domains. These germline mutations result in partial loss of nibrin function and in increased frequency of spontaneous and induced chromosomal aberrations in the cells of the carriers. On the contrary, amplification of NBN locus is a predominant type of somatic mutations affecting this gene, which indicates a dual role of NBN protein in tumor progression. The results of several studies demonstrate the influence of NBN expression level and its mutational status on anti-tumor drug resistance in particular types of tumor cells and on the survival rate of patients. These data indicate that an in-depth study of different variants and their functional significance is necessary since NBN status may be essential for the choice of treatment tactics for some types of tumors.

Immunological tolerance is one of the reasons for the development and progression of malignant tumors. The tumor immune cycle regulates the normal antitumor immune response, and it’s disruption is responsible for the development of immunological tolerance. This article provides a review of russian and foreign literature published in databases such as PubMed, Medline, and Cochrane, eLibrary in the last 5 years, focusing on the emergence of immunological tolerance in breast cancer from the perspective of disrupted regulation of tumor immune cycle phases: expression of antigens on the surface of tumor cells, cancer antigen presentation, priming and activation T cells, immune infiltration of the tumor site, recognition, and elimination of tumor cells. Understanding the mechanisms underlying tumor immune cycle disruption is important for identifying new immunopathogenetic links in the development of breast cancer, as well as identifying targets to improve the effectiveness of therapy for advanced breast cancer.

The article presents a review of modern literature data on molecular-genetic and biochemical profiles of malignant tumors of varying locations. It is shown that molecular-genetic and transcription profiles of pregnancy-associated malignant tumors are systems consisting of various components, many of which remain poorly researched. Additionally, morphological and biochemical characteristics of the placenta and tumor tissue are discussed. In the recent years, individual researchers and research groups have demonstrated heightened interests in this problem which undoubtedly soon will lead to a deeper and stronger understanding of mechanisms of progression and metastasis of oncological diseases during pregnancy. The knowledge of the principles of normal embryogenesis as a process of intrauterine development of a fetus, as well as investigation of molecular basis of pathogenesis of spontaneous abortion will undoubtedly help in determination of new targets and development of new therapeutical molecules for cancer treatment.

One of the factors associated with increased morbidity of malignant neoplasms is environmental pollution with cancerogenic compounds including pesticides. Until recently, stable organic pollutant insecticide dichlorodiphenyltrichloroethane (DDT) was the single tool for fighting malaria carriers. Despite vast evidence of its negative effect on human health, DDT is still used in some countries.
Aim. To perform a comprehensive analysis of the dynamics of DDT pesticide use and the consequences of its use on the global healthcare as well as to investigate the mechanism of its action on the human body including the endocrine system and cancerogenic effects.
The review was composed using the PubMed (2853 publications), Elsevier (3139 publications), eLibrary (784 publications) biomedical literature databases. Full-text articles were retrieved through PubMed Central (PMC), Science Direct, Research Gate, CyberLeninka electronic resources.

Introduction. Human papillomavirus (HPV) infection with high-risk HPVs is an etiological factor in the development of cervical cancer, with HPV type 16 (HPV16) being the most common. The mechanisms leading to disruption of viral oncogene expression and initiation of epithelial cell transformation are poorly understood. Epigenetic regulatory factors, including cellular miRNAs, may play an important role in HPV-induced carcinogenesis, and aberrantly expressed miRNAs may be promising markers for the diagnosis of HPV-associated lesions.
Aim. To search for miRNAs involved in the pathogenesis of HPV16-associated cervical cancer and to evaluate their diagnostic potential for the detection of cervical cancer and precancerous lesions.
Materials and methods. MiRNA expression in clinical samples was assessed by both next generation sequencing and quantitative stem-loop polymerase chain reaction (sl-qPCR). Plasma miRNAs from patients with precancerous and cancerous lesions and healthy donors were analyzed using sl-qPCR. Loss of heterozygosity in cervical cancer samples was assessed by copy number ratio of MIR135A1 and ACTB genes. A total of 67 patients with cervical cancer, 21 with precancerous cervical lesions and 24 healthy donors were included in the study. The effect of DNA methylation on miRNA-135A1 expression was evaluated after treatment with a demethylating agent of the cervical HPV16-positive SiHa cell line. Changes in the expression of the HPV16 E6 oncogene were analyzed after transfection with synthetic analogues of the mature forms of miRNA-135А1 (miRNA-135a-3p and miRNA-135a-5p).
Results. A significant decrease in the expression of miRNA-135A1 and miRNA-135A2 was detected in tumor tissue samples from HPV16-positive cervical cancer, which was confirmed by sl-qPCR in an independent panel of tumor samples. A decrease in miRNA-135A1 expression was shown to result from both loss of heterozygosity of the gene and aberrant DNA methylation. Transfection of mature forms of miRNA-135A1 into SiHa cells resulted in decreased expression of the E6 oncogene of HPV16. Blood plasma samples from patients with cervical cancer and precancerous lesions showed lower levels of miRNA-135a-3p than healthy donors, and ROC analysis indicated its high diagnostic potential.
Conclusion. Levels of miRNA-135A1 are significantly reduced in cervical lesions, both in tumor tissue and plasma, and the ability of this miRNA to suppress the expression of the HPV16 E6 oncogene suggests its oncosuppressive properties. Thus, miRNA-135A1 can be used as a promising new marker for the diagnosis of HPV-associated lesions.

Introduction. Epidermal growth factor receptor (EGFR) is a transmembrane protein of the receptor tyrosine kinase family that is activated in various cancers (non-small cell lung cancer, colorectal cancer, head and neck tumors). In glial brain tumors, increased EGFR expression levels are characteristic of the most aggressive subtype, glioblastoma. Frequent structural changes of EGFR in glioblastoma are amplification of the chromosome region where the EGFR gene is located, point mutations, as well as deletion of exons 2–7 of the EGFR gene leading to the formation of EGFRvIII transcript.
Aim. To determine structural changes of the EGFR gene (point mutations and amplification of the EGFR gene, EGFRvIII transcript) in tumor samples using different methods and to evaluate their potential clinical significance.
Materials and methods. The study included 75 patients with brain gliomas (70 of them glioblastoma) aged 34 to 78 years (mean age 56 years). DNA and RNA isolation was performed from fresh frozen tumor tissue, as well as from peripheral blood leukocytes. EGFR gene mutations were determined by next-generation sequencing (NGS), and β allele frequency (BAF) comparative analysis (normal-tumor) was performed to determine the copy number of chromosome 7 regions. Quantitative polymerase chain reaction was used to confirm the EGFR gene amplification in tumor samples, and reverse transcription-PCR was used to detect EGFRvIII variant.
Results. The NGS method revealed 11/70 (16 %) mutations in coding regions of EGFR gene in glioblastoma samples, the EGFR gene amplification was detected in 26/70 (37 %) cases; no structural changes of the EGFR gene were detected in 5 glioma samples (astrocytoma, oligodendroglioma). All cases of EGFR gene amplification detected by NGS were confirmed by quantitative polymerase chain reaction. To search for EGFRvIII transcript, 31 tumor RNA samples were examined, of which EGFR amplification was present in 12 samples. EGFRvIII transcript was detected only in samples with EGFR gene amplification – 4/12 (33 %). To assess the clinical significance of structural gene alterations, the frequency of occurrence in primary and recurrent glioblastoma samples was compared.
Conclusion. The NGS method allows to detect both point mutations and amplification of the EGFR gene. The EGFR gene amplification was associated with EGFRvIII mutation in 33 % of cases. No statistically significant differences in the frequency of structural changes in the EGFR gene between primary and relapsed glioblastomas were found.

Introduction. Immune checkpoint inhibitors have an exceptional position in cancer immunotherapy. Currently, anti-CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) and anti-PD-1/PD-L1 (PD-1 – programmed cell death 1, PD-L1 – programmed death 1 ligand 1) therapies are most widely applied in clinical practice. Still, immune checkpoint inhibitors therapy is not always successful, and multiple studies have indicated that it should be combined with other immunotherapeutic strategies, including cytokines. Secreted cyclophilin A (CypA) could be of particular interest in this respect. Previously, we showed that recombinant human CypA (rhCypA) had pleiotropic immunostimulatory activity and anti-tumor effects. Studies of rhCypA as an anti-cancer factor pointed to its potential use in cancer chemoimmunotherapy and combination immunotherapy.
Aim. To evaluate anti-tumor effects of combined immunotherapy using rhCypA and immune checkpoint inhibitors in the mouse model of melanoma B16 in vivo.
Materials and methods. C57BL/6 mice were subcutaneously transplanted with melanoma B16. On days 6 and 9 posttumor transplantation, monoclonal antibodies to PD-1, PD-L1 and programmed cell death 1 ligand 2 (PD-L2), CTLA-4, lymphocyte-activation gene 3 (LAG-3), or CD276 were intravenously injected into mice at a dose of 100 μg/mouse. RhCypA was injected s/c on days 6–10 post-tumor transplantation at a dose of 100 μg/mouse. The therapeutic effects of combined immunotherapy were evaluated by melanoma B16 growth dynamics and the survival of tumor-bearing mice.
Results. In combination with anti-CTLA-4 monoclonal antibodies, rhCypA had the most distinct and prolonged synergic anti-tumor effects until day 19 post-immunotherapy, with an increase in animal lifespan of 70 %. When used with anti-LAG-3 monoclonal antibodies, rhCypA exhibited a synergic therapeutic effect by day 12 post-therapy. Combination of rhCypA with anti-PD-L1 or anti-CD276 monoclonal antibodies had short-term synergic effects until day 5 after therapy. Recombinant human CypA impeded the anti-tumor effects of dual anti-PD-1 + anti-LAG-3 therapy.
Conclusion. Our findings pointed out that rhCypA could significantly improve therapeutic effects of individual immune checkpoint inhibitors. Therefore, rhCypA could be potentially proposed as a component of combined anti-tumor immunotherapy.

Introduction. Glucocorticoids (GC) are widely used in breast cancer (BC) therapy to reduce the side effects of cytostatic drugs and may exhibit antiproliferative effects on luminal BC cells. The biological action of GC is mediated by glucocorticoid receptor (GR) by two mechanisms: transrepression, which determines the therapeutic effect of GC, and transactivation (associated with the development of side effects, resistance to cytotoxic drugs, cancer progression and metastasis). Selective GR agonists (SEGRA) which may selective activate transrepression are a promising alternative to GC to use in combination cancer therapy. One of the most studied SEGRA is Compound A (CpdA). The instability of CpdA limits its use in clinical practice. So recently we performed synthesis and evaluation of biological activities of the CpdA analogue, CpdA-03.
Aim. To compare the effects of SEGRA CpdA-03 and CpdA and dexamethasone on proliferative activity of breast cancer cells, as well as receptor nuclear translocation and activation of GR-dependent genes in breast cancer cells.
Materials and methods. Luminal (MCF-7) and triple negative (MDA-MB-231) BC cell lines were used. The effect of CpdA-03 on proliferation was evaluated by direct counting of viable cells with trypan blue staining. The effect of the compound on cell distribution by cell cycle phases was assessed by flow cytofluorimetry with propidium iodide staining. Changes in the expression of GR-dependent genes after incubation with CpdA-03 were evaluated by quantitative polymerase chain reaction. Additionally, the ability of the new SEGRA to induce transactivation-associated translocation of the receptor to the nucleus was evaluated by Western blotting.
Results. CpdA-03 was shown to suppress proliferation of luminal and triple negative BC cells. This compound causes changes in the expression of a number of GC-inducible genes, but does not stimulate GR phosphorylation and translocation to the nucleus in BC cells.
Conclusion. The observed suppression of cell proliferation, as well as the ability of CpdA-03 to reduce gene expression of proteins regulating intercellular adhesion and cell migration, intracellular signaling, stress response, and transcription in BC cells makes it relevant for further development of the drug for use in the combination therapy of cancers including breast cancer.

Aim. Тo study the molecular genetic characteristics of the tumor microenvironment and the mechanisms of cell death in resistant locally advanced breast cancer.
Materials and methods. The study included 48 patients with breast cancer T2–4N0–3M0–1 (mean age 55.6 ± 9.8 years), and 29 patients of comparable age with breast fibroadenoma. According to the design of the study, patients were divided into groups: Group 1 included women with breast cancer resistant to neoadjuvant chemotherapy (n = 23), Group 2 – with breast cancer and a complete response to neoadjuvant chemotherapy (n = 25), control Group – with fibroadenoma (n = 29). The expression of markers CD4+, CD8+, CD20+, CD68+, tumor necrosis factor α (TNF-α), vascular endothelial growth factor A (VEGF A), Ang-2, matrix metalloproteinase 12 (MMP-12), inducible nitric oxide synthase (iNOS), bcl-2, p53, CD95 was assessed using immunohistochemistry.
Results. When phenotyping immune cells, the following differences were obtained: in the tumor tissue of patients in Group 1, a significant decrease in the number of cytotoxic CD8+ cells was noted compared to Group 2 (p = 0.001) and control (p = 0.032). In Group 2, a significant increase in the number of CD68+ cells was revealed in relation to Group 1 (p = 0.027). The cytokine profile of the tumor microenvironment in Group 1 is characterized by statistically significant overexpression of TNF-α compared to Group 2 (p >0.001) and the control Group (p = 0.01). With regard to apoptotic factors, noteworthy is the significant decrease in the expression of bcl-2 and p53 in Group 1 compared to Group 2 (p = 0.001 and p = 0.02 accordingly).
Conclusion. The presented results can serve as the basis for the creation of diagnostic algorithms that have predictive value regarding the effectiveness of NCT, and also to help identify new targets to justify the use of combined breast cancer treatments in the early stage.

Introduction. In glial tumors, lipid metabolism becomes abnormal. Analysis of lipid metabolism components can be an important characteristic of molecular and genetic profile of gliomas.
Aim. To determine the correlation between plasma lipidome profile and immunohistochemical characteristics of glial tumors and to evaluate clinical significance of blood lipid spectrum analysis in preoperative assessment of molecular profile of gliomas.
Materials and methods. Immunohistochemical measurement of O-6-methylguanine-DNA-methyl transferase (MGMT), Ki-67, p53, IDH1 tumor markers was performed using the corresponding antibody clones. Composition of plasma lipids was assessed using thin layer chromatography.
Results. Even at the early stages of gliomagenesis, significant differences in cholesterol ethers, lysophosphatidylcholines, phosphatidylcholine (PC)/ lysophosphatidylcholine (LPC) ratio, neutral lipids (NL)/phospholipids (PL) in the blood were observed. Significant correlations between Ki-67, MGMT tumor markers and the above-mentioned lipidome parameters were found. The PC/LPC, NL/PL ratios in the blood of the patients from the groups with higher (above 10 %) and lower (below 10 %) Ki-67 mitotic indexes compared to healthy individuals were significantly lower. Therefore, the values of lipidome parameters allow to indirectly assess proliferative activity of gliomas which can be used for preoperative diagnosis of these tumors. No significant differences in the plasma PC/LPC and NL/PL ratios were found between the groups with MGMT promoter methylation and without it. No indirect predictor criteria for MGMT were found.
Conclusion. It is impossible to determine decreased epigenetic activity of corresponding transcripts and preoperative prognosis for alkylating agent therapy based on the parameters of plasma lipid metabolism.

Introduction. Studies have shown that natural compounds from various plants including berries can have antitumor activity. We examined Phlojodicarpus sibiricus extract as well as homogenates of wild berries such as hawthorn, cranberry, brier; all these plants contain a variety of biologically active compounds: flavonoids, carotenoids, anthocyanins and other polyphenols.
Aim. To evaluate cytotoxicity of wild berries and Phlojodicarpus sibiricus growing in Northwestern Siberia in Michigan Cancer Foundation-7 (MCF-7) breast cancer cell line using the МТТ assay.
Materials and methods. We examined homogenates of wild berries including Dahurian hawthorn (Crataegus dahurica Koehne), bog cranberry (Oxycoccus microcarpus Turcz.), Yakut brier (Rosa jacutica Juz.) and extract of the above-ground part (leaves, stems) of Phlojodicarpus sibiricus. Cytotoxicity of the prepared homogenates was evaluated on the MCF-7 cell line. For homogenate screening, colorimetric assay for assessing cell metabolic activity МТТ was used.
Results. Dahurian hawthorn, bog cranberry and Yakut brier have statistically significant cytotoxic effect on tumor cells at concentration of 100 mg/mL in incubation medium. Among the evaluated berries, Yakut brier demonstrated the highest suppression of MCF-7 cell line growth: at dose 100 mg/mL it decreased it by 80.19 % compared to control. Extract of Phlojodicarpus sibiricus at concentration 10 mg/mL left only 4.95 % of the MCF-7 cells alive.
Conclusion. Therefore, wild berries have antiproliferative potential. Being edible, they can be helpful in prevention of oncological diseases. High antiproliferative activity of Phlojodicarpus sibiricus demonstrated by us in this and previous studies indicate that it can be considered a source of effective antitumor compounds.