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There is a direct association between the functional, morphologic and biochemical atypic features of cellular tumor expression and malignancy. Five molecular-genetic subtypes of breast cancer are recognized. The most aggressive course is known to be characterized by non-luminal subtypes, in particular, a triplenegative breast cancer. The aim of this research is to determine the association between the percentage of the cells showing distinct differentiation types, and cytokine production by breast cancer bioptates in both luminal and non-luminal breast cancer subtypes. Bioptates of 49 women with the invasive breast carcinoma of nonspecific type, at the average age of 59 years, were used as the material for the study. The patients were divided into three groups according to the molecular-genetic subtype of cancer. Group I included patients with luminal subtype A, group II – with luminal B and group III – with non-luminal subtypes of breast cancer. Spontaneous and in vitro stimulated by polyclonal activators production of cytokines was evaluated. The level of cytokineproducing reserve by the biopsy specimens was expressed as the influence index of polyclonal activators, due to its accuracy, thus making it possible to avoid errors due to the similar sizes of bioptates from each patient and their incubation conditions. The percentage of tumor cells of varying degrees of differentiation in the samples was assessed using light microscopy by means of the Nottingham grading system. When assessing spontaneous and stimulated production of cytokines, as well as degree of cell differentiation of tumor samples, direct and reverse correlations were revealed between the study groups. The most important parameter was the influence index of the polyclonal activator which characterized production of IL-10 and VEGF-A by the bioptates. Therefore, we can provide personalized information for each patient, in particular, for these two cytokines, even before starting the treatment.The analysis of ROC-curves showed good quality and optimal level of cytokine concentration and percentage of low-differentiated cells. This approach could predict the presence of unfavorable non-luminal breast cancer subtypes in the best way. In general, we can make a conclusion that cytokine-producing reserve is connected with cellular differentiation and depends on molecular-genetic subtype of the tumor.

Non-malignant breast diseases (NMBD) may increase the risk of developing a malignant neoplasm. Therefore, it seems relevant to search for criteria for cell malignancy in NMBD. Aim of the study was to investigate the relationship between expression of proliferation and epithelial-mesenchymal transition (EMT) markers and histidine-rich glycoprotein (HRG) mRNA in breast diseases. Material and methods. In breast biopsy specimens of 37 patients with invasive carcinoma of a non-specific type (ICNT) and 17 patients with NMBD expression of proliferation markers (Ki-67, cyclin D1 (CCND1)) and EMT markers (E-cadherin (CDH1), type II collagen (CII) and β1-integrin (CD29)) was determined immunohistochemically. HRG mRNA expression was estimated using real time PCR. Results. HRG mRNA expression was detected in 91.9 % cases (34 of 37) in ICNT, 82.4 % (14 of 17) in NMBD and in the latter case was inversely related to the expression of CDH1, CD29 and Ki-67. A direct relationship has been established between the presence of Ki-67 and CCND1, CII, between CCND1 and CD29 in NMBD. In patients with ICNT, a direct correlation was found between the HRG mRNA expression and the presence of CII, and an inverse correlation between the number of cells containing CII and CD29. It was found that in ICNT and NMBD with the presence of HRG mRNA expression, the CDH1 expression is less than in its absence. Conclusions. Indicators of HRG mRNA expression in NMBD, combined with the assessment of proliferation and EMT markers, can be useful in developing criteria for cell malignancy in benign breast diseases.

Resistance to tyrosine kinase inhibitors (TKIs) is currently an important clinical problem in the management of patients with chronic myeloid leukemia (CML). Recent studies suggested that aberrant cytokine secretion may be among the BCR/ABL-independent mechanisms of resistance, thus contributing to the persistence of leukemic stem cells in spite of continuous targeted therapy. The aim of the study was to evaluate concentration of cytokines in the serum of patients with CML depending on the efficiency of therapy.Quantitative determination of the cytokines (TNFα, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-17, IL-18, IFNα and VEGF) in blood serum of patients with chronic-phase CML (n = 84) and healthy subjects (n = 30) was performed using enzyme immunoassay (ELISA). The patients with CML were divided into 3 groups depending on the duration of therapy: group I, newly diagnosed patients (n = 10); group II, patients receiving therapy for < 12 months (n = 10); group III included patients receiving therapy for more than 12 months (n = 64).The results of our study showed that cytokine concentration among CML patients significantly differed, depending on the duration of therapy. Significantly higher concentration of IL-17, IL-6, IL-1β, IL-10, IL-18, IL-2 and TNFα was found in group I compared with control group. Group II patients also demonstrated significantly higher concentrations of TNFα, IL-6, IL-10, IL-18 and IFNα by comparison with control group, as well as higher concentration of IFNα compared with in groups I and III. In group III, concentrations of IL-17, IL-1β, TNFα, IL-6, IL-10, IL-18 were significantly higher than in control group. When compared with group I, it was found that concentrations of IL-1β, IL-2 and IL-18 were significantly lower. A direct correlation was found between expression levels of chimeric BCR/ABL gene, (a marker of CML malignancy), and concentrations of IL-1β and IL-17. ROC-analysis demonstrated high-quality models which showed an association between achievement of major molecular response (MMR) and low serum concentrations of IL-1β, IL-6 and IL-17.Hence, the results of our study have shown that determination of IL-1β, IL-6 and IL-17 concentrations may be a prognostic marker for assessing the efficiency of therapy and probability of achieving MMR in CML.

Breast tumors show a complex structure and are highly heterogeneous. The study of cytokines, which exert great influence on tumor cells, and microRNAs, which, along with their influence on the proliferation and migration of neoplastic cells, may affect the work of cytokines, will contribute to a deeper understanding of pathological processes occurring in breast cancer. The aim of our work was to analyze the relationship of cytokine production with expression of miR-181a and miR-25in patients with invasive breast carcinoma of a non-specific type (IBC NST) with various molecular subtypes.Patients with IBC NST were divided into five subgroups according to the molecular genetics subtype of the tumor classified by immunohistochemical analysis of estrogen receptor (ER), progesterone (PR), epidermal growth factor 2 (HER2) and proliferation marker Ki-67. Using enzyme immunoassay, the concentration of 14 cytokines was determined in the supernatants of immunocompetent blood cells and tumors: IL-2, IL-6, IL-8, IL-10, IL-17, IL-18, IL-1β, IL-1ra, TNFα, IFNγ, G-CSF, GM-CSF, VEGF and MCP-1. The expression of miR-181a and miR-25 microRNAs isolated from the patients’ blood serum was evaluated using digital droplet polymerase chain reaction (ddPCR).In the luminal A subtype, cytokine concentrations and expression of miR-181a and miR-25 are significantly lower compared to other subtypes. Patients with the luminal B HER2-negative subtype were characterized by significantly increased expression of both studied microRNAs, especially when compared with the luminal A subtype. At the same time, patients with a triple negative molecular subtype, on the contrary, were characterized by high concentrations of cytokines in the supernatants of tumor samples and blood cells compared to other subtypes. In the general group of patients with IBC NST, direct correlations were found between the expression of both studied microRNAs and the concentration of vascular endothelial growth factor (VEGF) in the supernatant of tumor samples, which may presume mutual interactions existing between miR-181a and miR-25, and the process of angiogenesis in the tumor.The levels of cytokines in blood supernatants and tumors in invasive breast carcinoma may vary, depending on distinct molecular subtypes of the tumor. Moreover, they also have direct links with the levels of miR-181a and miR-25 in blood serum. Particularly noteworthy were the results of measuring the cytokines and microRNAs concentrations in luminal A, luminal B HER2-negative and triple negative molecular subtypes.

Metastasis is the leading cause of death in patients with breast cancer (BC). It is known that the lesion of regional lymph nodes by tumor cells is more common in tumors with higher proliferative activity. Moreover, there is literature evidence on effects of cytokines and proteins upon the migration potential of the tumor. The aim of our work was to study the correlation between the concentrations of cytokines, proteins, and expression of Ki-67 proliferation marker in breast cancer with histology of non-specific invasive carcinoma.On the basis of pathological findings, 16 patients had metastases in regional lymph nodes (group I), and 18 patients had no detectable metastases (group II). Solid-phase enzyme immunoassay was used to determine concentrations of 14 cytokines in the supernatants of immunocompetent blood cells, i.e., IL-2, IL-6, IL-8, IL-10, IL-17, IL-18, IL-1β, IL-1ra, TNFα, IFNγ, G-CSF, GM-CSF, VEGF and MCP-1, and concentrations of 6 proteins were determined in blood serum: estrogen and progesterone receptors, cadherin-E (CDH1), plasminogen activator type 1 (PAI-1), mucin 1 (MUC1), heat shock protein 90αA1 (HSP90αA1). Immunohistochemical study of Ki-67 expression was performed in paraffin sections of tumors using monoclonal antibodies.The study showed that Ki-67 expression in tumor tissues and blood concentrations of IL-6, IL-8, IL-1β and TNFα were higher in group I patients. On the contrary, blood concentrations of CDH1 and PAI-1 were higher in group II patients. It was found that Ki-67 showed both inverse correlations with CDH1 and PAI1, and direct correlations with IL-8 and TNFα. CDH1 had a direct correlation with PAI1, and inverse correlations with IL-6, IL-1β and TNFα. The studied cytokines showed direct correlations with each other. The analysis of ROC curves showed good quality and optimal values of the cut-off points for Ki-67 expression, cytokine and protein concentrations, thus allowing best prediction for detectable lymphatic metastasis.On the basis of these results, a quotient was proposed, which represents a ratio of CDH1 contents to the sum of IL-1β and TNFα concentrations in blood samples, which can help identification of the patients with breast cancer at risk for lymphatic metastasis.

The article focuses on cerebral allergy (CA), described in the middle of 20th century. The evolution of subsequent notions about CA and some relevant definitions are provided. Mechanisms of CA are outlined along with the data concerning pyrroles and pyroluria. Main neurologic and psychiatric manifestations of CA and pyroluria are described, along with treatment approaches.

The legal regulation of environmental policy in the Russian Federation is carried out by a number of institutions and organisations, the management process of which in practice proves to be fragmented and uncoordinated. The functioning of this system, which lacks internal unity, leads to larger crises at the social, economic, and international levels. In today's increasingly globalised environment, environmental law seeks new ways of consolidation and international cooperation, which can only be achieved through the internal integration of legal institutions. Examining the shortcomings of the existing legal system, identifying ways to address them, and identifying mechanisms for integration will lead to positive effects in addressing environmental issues, both nationally and internationally.

This article is devoted to the methodology of the interdisciplinary problem of "lawyer's professional competence". The authors proceed from the importance of finding scientific and practical approaches to the formation of a new quality of an essential part of professional legal culture, professional competence of a lawyer both by the Teacher in the system of educational process coordinates and by the student himself in the mode of self-reflection.

The authors consider the main theoretical approaches and practical recommendations related to the perception and application of the principle of uniformity of judicial practice in the field of ecology as the basis of justice. The publication proposes a model of positioning judicial practice in its two forms of being: as an instrument and a source of law in their dialectical unity.

The aim of the study was to identify patterns of distribution of the magnitude of the the equivalent dose rate of gamma radiation in an open area of urban space, depending on the functional purpose of the inner-city territory and the type of artificial coating. Materials and methods. Measurements of the equivalent dose rate of gamma radiation (gamma background) in the city of Voronezh were carried out at 70 points, conventionally classified by functional use (industrial area, transport area, residential area, recreational area), as well as the type of coverage in open areas (granite stone blocks , asphalt pavement, paving slabs, open ground) For carrying out radiation monitoring, a highly sensitive portable search device was used – a search measuring gauge microprocessor ICP-PM1401MA. To assess the reliability of differences in the average values of the indicator by functional inner-city zones and types of artificial turf, the methods of parametric statistics (Student’s criterion) are used. Parametric methods of statistics in comparison with nonparametric methods allow statistically unambiguous interpretation of the results. There is no need to use other statistical tools in this regard. Results. The results of the evaluation of the radiation background show that the equivalent dose rate of gamma radiation (gamma background) in the city of Voronezh is from 0.06 to 0.14 µSv / h and it does not exceed the permissible value (0.3 µSv / h). Significant differences in the average values of indicators in the industrial, transport, residential functional areas in relation to the recreational area were not found (tcalc. < ttabl., P < 0.05). The maximum levels of gamma background (0.09-0.14 µSv / h) in the territory of the city of Voronezh were found in those places where processed natural stones (granite) were used for the improvement of the territory. When solving the problem of identifying the dependence of the indicator of the equivalent dose rate of gamma radiation in an open area of an inner-city space on the type of coating, in order to reduce uncertainties in the future, it is necessary to take into account the formulation of materials, especially the fraction of granite chips.

Investigation of the cytokine expression dynamics as well as the cytokine-producing potential of immune-competent cells allows extensive studies of their functional characteristics. mRNAs encoding a number of cytokine genes are relatively stable, thus their level may be used as a marker for assessing the levels of activation and proliferation of immunocompetent cells as well as for evaluating the cytokine-producing potential of immunocompetent cells.In our work, we assessed correlations between the levels of mRNA expression specific for IL-10, TNF-α, GM-CSF cytokines determined in a culture of differentiated macrophage U937 cells, and protein concentrations of the same cytokines as measured in supernates of U937 cell cultures, without and after exposure to polyclonal activators. The IL-10, TNF-α, GM-CSF mRNA expression was determined by real-time quantitative polymerase chain reaction. Protein concentrations of IL-10, TNF-α, GM-CSF cytokines in the culture supernatant of U937 cells were measured by an enzyme immunoassay. The use of an initially homogeneous cell culture in the study is convenient due to the identical conditions in all experimental variants.The most pronounced effect of polyclonal activators is exerted upon production of GM-CSF mRNA, as well as protein concentration of this cytokine in the cell culture supernatants, thus actually coinciding with RT-qPCR results. The TNF-α mRNA level decreased under the influence of polyclonal activators, whereas concentration of this cytokine was decreased in the cell supernate. The TNF-α protein in a culture medium did not reflect temporal changes in the cellular TNF-α mRNA expression, probably, due to potential decrease of cellular mRNA occurring by the feedback inhibitory mechanism. While the cytokines can accumulate and remain in the supernatant, the mRNA-related events leading to cytokine formation may be completed earlier. Therefore, the signalling pathways and cytokine release kinetics should be studied after establishing the time dependence at short time intervals, which may be individual for each cytokine.Thus, the results of a study using polyclonal activators suggest that polyclonal activators applied as mitogens, have a significant effect upon the concentration of secreted IL-10, TNFα and GM-CSF. In this case, polyclonal activators affect the levels of mRNA encoded by cytokine genes, thus indicating transcriptional mechanisms of its action. But, in view of the fact that the data are ambiguous, in order to achieve greater correspondence between the changes in the studied proteins and specific mRNAs, a detailed description of the time dependence is required for the changes in mRNA contents.

At present, only ductal carcinoma in situ is included into the group of precancerous lesions of mammary ducts, according to International Agency for the Study of Cancer. However, based on recent publications, in addition to ductal carcinoma in situ, sclerosing adenosis, intraductal proliferative lesions and radial scar may be also attributed to precancerous changes. A variety of both benign and malignant events in mammary gland, the features of neoplastic growth and age of the patients require new approaches to study of carcinogenic events in mammary gland. As based on the known role of cytokines in genesis of malignancies, the aim of the study was to evaluate the cytokine-producing resource of immunocompetent blood cells in malignant, benign and precancerous mammary disorders. To assess the cytokine-producing resource of immunocompetent blood cells in the patients, we studied quantitative effects of polyclonal activators upon production of cytokines by immunocompetent blood cells of patients with invasive ductal cancer representing a histological type of adenocarcinoma (group I), and patients with non-malignant breast neoplasias (group II). At subsequent step, the patients with non-malignant neoplasms of the breast were divided into a subgroup of patients with only fibroadenoma and mastopathy (group III), and a group which included patients with precancerous diseases, i.e., sclerosing adenosis and interductal proliferates (group IV). Concentrations of IL-2, IL-6, IL-8, IL-10, IL-17, IL-18, IL-1β, IL-1ra, TNFα, IFNγ, G-CSF, GM-CSF, VEGF, and MCP-1 were determined by solid-phase enzyme immunoassay. When comparing groups I and II, we revealed higher influence of polyclonal activators upon production of G-CSF and GM-CSF in patients with invasive ductal cancer. When comparing the influence of polyclonal activation for cytokine production in patients of I and III groups, higher values were registered in patients with invasive ductal cancer (production of IL-2, G-CSF, and GM-CSF), and in patients with fibroadenoma and mastopathy (IL-18, and TNFαproduction). When comparing patients of groups I and IV, higher indexes of the polyclonal activator effects were found only for IL-1ra, G-CSF, and VEGF production in invasive ductal cancer. When comparing the indexes of polyclonal activator influence upon cytokine production of groups III and IV, higher values were obtained in patients with benign changes for the following cytokines: IL-8, IL-18, IL-1β, IL-1ra and TNFα, in contrast to patients with sclerosing adenosis and proliferates. The lower indexes of polyclonal activating effects upon the production of a number of cytokines in patients with precancerous changes, as compared to patients with malignant and benign breast tumors, do not indicate a decreased functional activity of immunocompetent blood cells. However, those may be due to high level of spontaneous cytokine production in sclerosing adenosis and interductal proliferates.

The purpose of the study was to estimate the doses to the Voronezh region population from natural sources of ionizing radiation and the technologically altered background in the territory of Voronezh Region. The data of forms of state statistical observation No. 4-DOZ “Information on the doses of population exposure due to natural and technologically altered background” for 20102017 and the radiation and hygienic passport of the territory of the Voronezh Region were used. The average annual per caput effective dose due to all types of ionizing radiation remains stable with a slight upward trend and lies in the range from 2.925 (2010) to 3.656 mSv (2017). Natural sources are the main dose-forming factors for the population. Their annual contribution to the annual effective dose ranges from 74.96 to 83.65%. The leading contribution to the total dose from natural sources is the exposure due to the inhalation of radon isotopes: it ranges from 37.6 to 51.1%. In second place,there is the share of external exposure from sources of terrigenous origin, which ranges from 21.2 to 28.9% of the total dose. The average annual effective dose of natural exposure to humans varies from 2,355 to 2,980 mSv / year, the exposure from radon – from 0,83 to 1,65 mSv / year. The dose from technogenic-altered radiation background, including global radioactive fallout due to atmospheric nuclear tests and due to past radiation accidents are insignificant (0,062 mSv / year). Its annual contribution to the total dose is less than 2%. Based on the results of the assessment of the indicators characterizing the level of exposure of sources of ionizing radiation to natural and technogenic-altered radiation background, no excess of radiation safety standards has been recorded. The situation associated with exposure to ionizing radiation sources in the Voronezh region has been described as safe for the last 8 years.

Розглянуто деякi властивостi iнтегровних на сегментi функцiй. Отримано оцiнки для наближень.

The purpose of this work is to establish and determine, on the basis of a systematic analysis, the factors influencing the state of food security of the Russian Federation, the problems of legal support of national priorities related to food independence. Qualitative and quantitative characteristics of the current state of food security in the Russian Federation are closely related to the criteria for the development of the socio-economic system of the state. An important condition for the effective implementation of national priorities is the normative regulation of the toolkit of state management impact on the threats and risks of food independence. To understand the essence of these problems and minimize their consequences, the authors substantiate the need to study the indicated problem within the framework of the concept of legal dementia. Legal dementia is a state of compliance by subjects of law with the provisions of the law, which is characterized by non-fulfillment to one degree or another by state bodies not only of their functions, but also by the inability to respond, due to a low level of competence and professionalism, to factors that weaken the effectiveness of legal guarantees.

The proposed article is designed to prove the importance of forming a national economy based on the domestic experience of state and legal regulation, taking into account the realities of the development of international relations, as well as threats arising at the interstate and national levels. At the same time, each state has its own economic system associated with the categories of "economic sovereignty" and "state sovereignty". For that reason, the comparative methodology is reflected in the consideration of the problems stated in the proposed article. The authors proved the importance of financial and economic support of Russia as a social state in order to develop its demographic potential-the most important segment of the national economy construction. In conclusion, the opinion was expressed that ensuring the economic sovereignty of the Russian Federation through the construction of the national economy will have a positive impact on the level of national security.

The children born to parents irradiation-exposed in childhood due to the Chernobyl accident were found to have mainly the upper gastrointestinal pathology, namely chronic gastroduodenitis, usually concomitant, and several areas of the alimentary canal being involved into the pathological process. The children with the syndrome of heart connective tissue dysplasia have earlier manifestation of the upper gastrointestinal diseases (from pre-school age) and with age systemic damage of various organs and systems is noted, as evidenced by such indicators as a number of clinical entities per child (among the children of the I group — 6.8; II group — 4.9). The analysis of biomedical risk factors and index of burdened familial history on gastrointestinal pathology in I–II degree relatives did not demonstrate a significant difference between the groups. The clinical manifestations of chronic upper gastroduodenal diseases in children with the syndrome of heart connective tissue dysplasia typically have more frequent exacerbations due to the psycho-emotional and physical exhaustion. These children more often have moderate periodic pain; higher occurence of gastric dyspepsia symptoms, intestinal motor dysfunction and concomitant nervous system disorders (80.0 %) and chronic foci of infection (62.2 %).