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Activation of the sympathetic nervous system plays an important role in arterial hypertension (AH) development. Antihypertensive drugs of central action contribute to the elimination of sympathetic activation. The selective imidazoline receptor agonist moxonidine has been successfully used in the treatment of patients with hypertension. The review article presents data on the antihypertensive efficacy of moxonidine, the possibility of its use in combination therapy to reduce elevated blood pressure (BP). The effectiveness of moxonidine in overweight patients, metabolic syndrome, diabetes mellitus, and postmenopausal women is shown. In addition to lowering blood pressure in obese patients, moxonidine reduces plasma leptin levels and weakens sympathetic overactivity, which contributes to weight loss. In patients with metabolic syndrome — obesity, type 2 diabetes mellitus, the use of moxonidine, along with the antihypertensive effect, was accompanied by an additional positive effect on increased variability in blood pressure levels, contributing to the normalization of the daily blood pressure profile, eliminating the morning rise in blood pressure levels. The beneficial effect of moxonidine on carbohydrate metabolism and tissue sensitivity to insulin was noted. The administration of moxonidine to patients with hypertension and menopausal syndrome in peri- and postmenopause, along with effective level control, was accompanied by a significant improvement in the quality of life. In patients with hypertension and osteopenia during menopause, moxonidine led to increased bone formation processes, which helps reduce the risk of developing or progressing osteopenia and osteoporosis. The article focuses on additional indications for the use of moxonidine. In the presence of concomitant pathology — chronic obstructive pulmonary disease, chronic kidney disease, dementia in elderly patients, the use of moxonidine, along with antihypertensive action, led to an improvement in the quality of life.

Background. Vascular endothelial growth factor A (VEGFA) is one of the most important factors for regulation of hematopoietic stem cells differentiation. It is involved in leukemogenesis and central nervous system (CNS) damage in acute leukemia. According to the literature, the VEGFA production by blast cells is increased, but the values of serum concentration and the associations with CNS involvement are contradictory.Aim. evaluate the VEGFA, VEGFR1, VEGFR2 concentration in serum and cerebrospinal fluid of patient with different types of acute leukemia in disease onset and during treatment.Materials and methods. The concentration of VEGFA in serum and cerebrospinal fluid was studied in 74 primary patients with acute leukemia. The comparison group consisted of 67 healthy donors. VEGFR1, VEGFR2 were studied in serum and cerebrospinal fluid in 34 patients at the onset of the disease. The comparison group consisted of 10 healthy donors. For the analysis, an enzyme immunoassay was used on a semi-automatic Personal Lab analyzer (Adaltis) and Affymetrix eBioscience human VEGF-A Platinum ELISA reagents.Results. Serum VEGFA concentration was statistically significantly lower in acute leukemia patients than that of donors (median 149.78 and 432.19 pg/ml respectively; p

Aim. To establish the features of the influence of anxiety and depressive disorders on treatment adherence, as well as to clarify the factors associated with it in hematologic malignancies patients. Materials and methods. The study included 117 patients: 51 men and 66 women, aged 19 to 67 years, with Hodgkin's lymphoma 88, acute lymphoblastic leukemia 16 and aplastic anemia 13 patients. Patients were examined by psychiatrist using the Brief Psychiatric Rating Scale, as well as some psychometric methods. Results. Anxiety-depressive spectrum disorders were detected in 36 (40.9%) patients with Hodgkin's lymphoma and 8 (50%) with acute lymphoblastic leukemia, in the aplastic anemia group there were three (23.1%) of such patients. It was found that the average adherence to treatment was in 2/3 of patients, low and high in the remaining 1/3 of patients. With medium and low adherence to treatment, the risk of adverse events increases by an average of 1.7 times. The adherence to treatment it is significantly higher in patients older than 45 years. Signs of depression that negatively correlated with adherence to treatment were pessimism and disruption of social ties. Adherence to treatment significantly positively correlates with the following types of attitudes towards the disease: anosognosic, hypochondriac and egocentric, and significantly negatively correlates with the following types of attitudes towards the disease: anxious, melancholic and dysphoric. Conclusion. Anxiety/depressive disorders contribute to reduced adherence of hematologic malignancies patients to treatment. Their correction and increased adherence should be carried out jointly by hematologists and mental health professionals.

Abstract Differentiation is critical for cell fate decisions, but the signals involved remain unclear. The kidney proximal tubule (PT) cells reabsorb disulphide-rich proteins through endocytosis, generating cystine via lysosomal proteolysis. Here we report that defective cystine mobilization from lysosomes through cystinosin (CTNS), which is mutated in cystinosis, diverts PT cells towards growth and proliferation, disrupting their functions. Mechanistically, cystine storage stimulates Ragulator-Rag GTPase-dependent recruitment of mechanistic target of rapamycin complex 1 (mTORC1) and its constitutive activation. Re-introduction of CTNS restores nutrient-dependent regulation of mTORC1 in knockout cells, whereas cell-permeant analogues of L-cystine, accumulating within lysosomes, render wild-type cells resistant to nutrient withdrawal. Therapeutic mTORC1 inhibition corrects lysosome and differentiation downstream of cystine storage, and phenotypes in preclinical models of cystinosis. Thus, cystine serves as a lysosomal signal that tailors mTORC1 and metabolism to direct epithelial cell fate decisions. These results identify mechanisms and therapeutic targets for dysregulated homeostasis in cystinosis.

Neutrophils play a primary role in protecting our body from pathogens. When confronted with invading bacteria, neutrophils begin to produce leukotriene B4, a potent chemoattractant that, in cooperation with the primary bacterial chemoattractant fMLP, stimulates the formation of swarms of neutrophils surrounding pathogens. Here we describe a complex redox regulation that either stimulates or inhibits fMLP-induced leukotriene synthesis in an experimental model of neutrophils interacting with Salmonella typhimurium. The scavenging of mitochondrial reactive oxygen species by mitochondria-targeted antioxidants MitoQ and SkQ1, as well as inhibition of their production by mitochondrial inhibitors, inhibit the synthesis of leukotrienes regardless of the cessation of oxidative phosphorylation. On the contrary, antioxidants N-acetylcysteine and sodium hydrosulfide promoting reductive shift in the reversible thiol-disulfide system stimulate the synthesis of leukotrienes. Diamide that oxidizes glutathione at high concentrations inhibits leukotriene synthesis, and the glutathione precursor S-adenosyl-L-methionine prevents this inhibition. Diamide-dependent inhibition is also prevented by diphenyleneiodonium, presumably through inhibition of NADPH oxidase and NADPH accumulation. Thus, during bacterial infection, maintaining the reduced state of glutathione in neutrophils plays a decisive role in the synthesis of leukotriene B4. Suppression of excess leukotriene synthesis is an effective strategy for treating various inflammatory pathologies. Our data suggest that the use of mitochondria-targeted antioxidants may be promising for this purpose, whereas known thiol-based antioxidants, such as N-acetylcysteine, may dangerously stimulate leukotriene synthesis by neutrophils during severe pathogenic infection.

The analysis of the influence of the parameters of electrospark alloying with an aluminium electrode on the quality (roughness, microstructure of the coating, its continuity, phase composition, and microhardness) of the aluminized layer is presented. The effect of finishing methods after aluminizing is evaluated. The heat resistance of the obtained coatings is studied. Metallographic analysis shows that the coating consists of three sections: a ‘white’ layer, a diffusion zone, and the base metal. With an increase in the discharge energy, such quality parameters of the surface layer as thickness, microhardness of both a ‘white’ layer and a transition zone, and roughness are increased. The continuity of a ‘white’ layer at the discharge energy Wp = 0.52 J is low (of 50–60%); with a subsequent increase in the discharge energy, it increases and, at Wp = 6.8 J, it is of 100%. An increase in the discharge energy during electric-spark alloying (ESA) leads to a change in the chemical and phase compositions of the layer: at low discharge energies, a layer is formed, consisting mainly of α-Fe and aluminium oxides. As Wp increases, the layer consists of iron and aluminium intermetallic compounds, as well as free aluminium, that is confirmed by the data of local x-ray microanalysis. For practical application, it is possible to recommend the process of aluminizing by the ESA method, using the modes (discharge energy in the range of 4.6–6.8 J and productivity of 2.0–3.0 cm2/min). Such process provides the formation of a ‘white’ layer with a thickness of 70–130 µm, microhardness of 5000–7500 MPa, roughness (Ra) of 6–9 µm, and continuity of 95–100%. In order to increase the thickness of the aluminized layer, it is recommended to preliminarily apply grease containing aluminium powder to the steel surface and, without waiting for it to dry, carry out ESA with an aluminium electrode. In this case, the coating continuity is of 100%, the layer thickness is of up to 200 µm, and the microhardness is of 4500 MPa. The paper presents the results of a study of the quality parameters of multicomponent aluminium-containing coatings of Al–S, Al–C–S, and Al–C–B systems. Replacing the aluminium electrode with graphite one leads to a decrease in the thickness and continuity of a ‘white’ layer, respectively, to 50 µm and 30%. In turn, the microhardness on the surface increases to 9000 MPa. The addition of 0.7 boron to the consistency substance leads to an increase in the thickness and continuity of a ‘white’ layer, respectively, up to 60 µm and 70%. The microhardness on the surface rises to 12000 MPa. In order to reduce the roughness of the surface layer and to obtain continuous coatings, it is recommended to carry out ESA with an aluminium electrode, but at lower modes.

Here, we demonstrate that human neutrophil interaction with the bacterium Salmonella typhimurium fuels leukotriene B4 synthesis induced by the chemoattractant fMLP. In this work, we found that extracellular ATP (eATP), the amount of which increases sharply during tissue damage, can effectively regulate fMLP-induced leukotriene B4 synthesis. The vector of influence strongly depends on the particular stage of sequential stimulation of neutrophils by bacteria and on the stage at which fMLP purinergic signaling occurs. Activation of 5-lipoxygenase (5-LOX), key enzyme of leukotriene biosynthesis, depends on an increase in the cytosolic concentration of Ca2+. We demonstrate that eATP treatment prior to fMLP, by markedly reducing the amplitude of the fMLP-induced Ca2+ transient jump, inhibits leukotriene synthesis. At the same time, when added with or shortly after fMLP, eATP effectively potentiates arachidonic acid metabolism, including by Ca2+ fluxes stimulation. Flufenamic acid, glibenclamide, and calmodulin antagonist R24571, all of which block calcium signaling in different ways, all suppressed 5-LOX product synthesis in our experimental model, indicating the dominance of calcium-mediated mechanisms in eATP regulatory potential. Investigation into the adhesive properties of neutrophils revealed the formation of cell clusters when adding fMLP to neutrophils exposed to the bacterium Salmonella typhimurium. eATP added simultaneously with fMLP supported neutrophil polarization and clustering. A cell-derived chemoattractant such as leukotriene B4 plays a crucial role in the recruitment of additional neutrophils to the foci of tissue damage or pathogen invasion, and eATP, through the dynamics of changes in [Ca2+]i, plays an important decisive role in fMLP-induced leukotrienes synthesis during neutrophil interactions with the bacterium Salmonella typhimurium.

Tumor-associated genes (PRAME, WT1 and XIAP) expression study is conducted in 34 patients with multiple myeloma (MM) in disease onset and after chemotherapy (VAD, 20 pts) and proteosom inhibitor therapy (10 pts). PRAME, WT1 и XIAP gene expression in bone marrow cells detected by polymerase chain reaction (PCR) method. PRAME gene expression in 62% primary patients was revealed, thus expression median was 0.3% that almost in 100 times greater than in bone marrow donors (0.0035%). WT1 gene expression in 20% patients was detected, and it was determined only in PRAMEpositive patients. At diagnosis XIAP gene expression was revealed in all MM patients, thus expression median was more 10 times greater than in the control groups (28% versus 2%). In patients with PRAME hyperexpression partial response was achieved only in 25% of cases, while in patients with low or absence of PRAME expression VAD therapy was effective in 75% of cases (р=0,06). After bortezomib treatment XIAP gene expression level was significantly decreased with complete and partial remission achievement: from 11-325% (median – 66%) to 1-123% (median – 20%). In cases of tumor resistance to bortezomib treatment XIAP expression increased from 16-127% (median – 36%) to 22-528% (median – 121%).

Despite their widespread clinical implementation, chimeric antigen receptor T-cell (CAR-T) therapy products, including those manufactured by industrial processes, are still not legally available or used in the Russian Federation.The aim of the study was to describe the current challenges associated with specific aspects of CAR-T manufacturing in the Russian Federation and the potential ways to overcome them.This article discusses the regulatory, legal, organisational, and methodological challenges of CAR-T manufacturing. It analyses differences in the interpretation of CAR-T therapy products under national and supranational law. According to Russian Federal Law No. 180-FZ “On Biomedical Cell Products” of 23 June 2016, CAR-T therapy products are considered biomedical cell products. However, according to Decision No. 78 of the Council of the Eurasian Economic Commission “On the Rules of Marketing Authorisation and Assessment of Medicinal Products for Human Use” of 3 November 2016, CAR-T therapy products are considered advanced therapy medicinal products (ATMPs). This article provides a detailed overview of the difficulties in obtaining starting biological materials (i.e. the inability to consider the patient as a donor) and transferring the materials for CAR-T manufacturing (i.e. the inapplicability of national law). In addition, this article describes export aspects specific to biological materials. The authors reckon that CAR-T therapy products should be categorised as ATMPs and that the corresponding active pharmaceutical ingredients, genetically modified autologous lymphocytes, should be defined as starting materials. Therefore, genetically modified autologous lymphocytes should be regulated under the requirements for starting materials for the manufacturing of active pharmaceutical ingredients that are set forth in Decision No. 77 of the Council of the Eurasian Economic Commission “On the Adoption of the Rules of Good Manufacturing Practice of the Eurasian Economic Union” of 3 November 2016. In conclusion, the authors recognise the need for national and supranational law harmonisation. For this task, it is necessary to establish expert groups that will include clinicians, legal experts, and representatives from the relevant authorities and the pharmaceutical industry.

In this paper, the authors discuss the method of deformations compensation (resulting from the impact of variable temperatures and pressure) in pipelines intended for fluids transport (liquids and gases). Classical methods of compensation through the so-called "natural compensation" and using special devices called expansion joints. In this paper authors present research work on a new type of the metal expansion joints, called bellow-lens expansion joints. The mechanically assisted laser forming method, which was used to manufacture the bellow-lens expansion joints, was presented. The method uses CO2 laser radiation to heat the element from which the expansion joint will be made and the proprietary system consists of an actuator and swivel handle.

The article reviews and analyses the current scientific research in the field of surface treatment of metal surfaces with concentrated energy fluxes (CEF) — the electric-spark (in the literature, known also as electrospark) alloying (ESA), which makes it possible to obtain surface structures with unique physical, mechanical and tribological properties at the nanoscale. The ESA method with a graphite electrode (electrospark carburizing — EC) is based on the process of diffusion (saturation of the surface layer of a part with carbon), and it is not accompanied by an increase in the size of the part. In this article, the influence of the EC parameters on the quality of the carburized layer is investigated. The microstructural analysis shows that the three characteristic zones could be distinguished in the structure: the carburized (‘white’) layer, the finely dispersed transition zone with fine grain, and the base metal zone. The analysis of the results of the durometric studies of the coatings is carried out. To achieve the required parameters of dimensional accuracy and roughness of the working surface of the part after the EC process, it is necessary to use the method of non-abrasive ultrasonic finishing (NAUF). In addition, because of applying the NAUF method, the surface roughness is decreased, the tensile stresses are changed to the compressive ones, and the fatigue strength is increased too. In addition, to reduce the roughness of the treated surface, it is proposed to apply the EC technology in stages, reducing the energy of the spark discharge at each subsequent stage. In order to increase the quality of the carburized layer obtained by the EC process, it is proposed to use a graphite powder, which is applied to the treated surface before alloying. The comparative analysis shows that, after the traditional EC process at Wp = 4.6 J, the surface roughness of steel 20 is Ra = 8.3–9.0 μm, and after the proposed technology, Ra = 3.2–4.8 μm. In this case, the continuity of the alloyed layer increases up to 100%; there increases the depth of the diffusion zone of carbon up to 80 μm as well as the microhardness of the ‘white’ layer and its thickness, which increase up to 9932 MPa and up to 230 μm, respectively. The local micro-x-ray spectral analysis of the obtained coatings shows that, at the EC process carried out in a traditional way, the applying Wp = 0.9, 2.6, 4.6 J provides the formation of the surface layers with high-carbon content depths of 70, 100, 120 μm, respectively, and with the use of a graphite powder, they are of 80, 120, 170 μm. While deepening, the amount of carbon is decreasing from 0.72–0.86% to the carbon content in the base metal — 0.17–0.24%. In the near-surface layer formed with the use of the new technology, the pores are filled with free graphite, which could be used as a solid lubricant to improve the operating characteristics of the friction-pairs parts processed thereby.

The article presents results of an empirical study of professional conceptions. Understanding the mechanism underlying the development of professional conceptions is an important factor in building the educational environment in a modern university. At the same time, the accumulated scientific knowledge does not allow us to determine all the factors affecting its development. The purpose of the study is to identify factors that impede the development of professional conceptions in students. Our hypothesis is that among the factors that significantly slow down the development of professional conceptions in students are negative emotional states that arise through educational and professional activities. The study was conducted on the basis of the Nizhny Novgorod State University named after Kozma Minin. The sample included 93 students aged from 18 to 26 years, 73 females and 20 males, including 67 second-year students and 26 fourth-year students. As a technique for determining professional conceptions we used a questionnaire of professional conceptions by E.I. Rogov. To estimate the level of development of professional conceptions, the repertory grids technique by D. Kelly was used. The individual style of activity was evaluated using the questionnaire “Behaviour self-regulation style” by V.I. Morosanova. Self-concepts of the subjects as representatives of the certain profession were measured using the technique by M. Kuhn and T. McPartland “Who am I” (adapted by T.V. Rumyantseva). The results showed significant differences in terms of clarity and evaluation (p

The objective of this study was to characterize and compare antigenic and genetic characteristics of Streptococcus pneumoniae strains isolated from patients with invasive and non-invasive pneumococcal infections (PIs) by using the data of high-throughput sequencing.Materials and methods. A total of 158 S. pneumoniae strains were studied. All of them were isolated during different stages of the PEHASus multicenter study performed in 2015-2020. The data analysis was based on the information about whole-genome sequences of 46 strains isolated during the above study. Real-time PCR methods and high-throughput sequencing (the Illumina platform) were used for identification of serotypes. The SeroBA, PneumoCaT software and PubMLST.org website resources were used in the data processing.Results and discussion. The serotypes of all the studied strains were identified. A number of discrepancies among serotypes in serogroup 6 and one discordant result were revealed by the analysis of whole-genome sequences using 2 programs. The PCR methods were effectively used to characterize serotypes in 87% and 69% of the pathogens of invasive and non-invasive PIs, respectively. The serotypes contained in PCV13 accounted for 59% and 37%, while PPV23 serotypes accounted for 78% and 53% of the strains isolated from patients with invasive and non-invasive PIs, respectively. The data analysis was unable to identify either the dominant sequence type (a total of 81 sequence types have been identified) or clonal complexes, except for serotype 3 strains, thus demonstrating consistency with the data from previous studies suggesting the absence of a well-represented clonal structure of S. pneumoniae associated with pneumococcal meningitis in Russia.Conclusion. The obtained data made it possible to identify the distribution of the circulating serotypes and genetic characteristics of the strains isolated from PI patients, thus being instrumental for assessment of the effectiveness of the existing polyvalent vaccines and providing information for improvement of the PCR-based methods of serotyping.

Leukotrienes are among the most potent mediators of inflammation, and inhibition of their biosynthesis, is becoming increasingly important in the treatment of many pathologies. In this work, we demonstrated that preincubation of human neutrophils with the mitochondria targeted antioxidant SkQ1 (100 nM) strongly inhibits leukotriene synthesis induced by three different stimuli: the Ca2+ ionophore A23187, the chemotactic formyl-peptide fMLP in combination with cytocholasin B, and opsonized zymosan. The SkQ1 analogue lacking the antioxidant quinone moiety (C12TPP) was ineffective, suggesting that mitochondrial production of reactive oxygen species (ROS) is critical for activating of leukotriene synthesis in human neutrophils. The uncoupler of oxidative phosphorylation FCCP also inhibits leukotriene synthesis, indicating that a high membrane potential is a prerequisite for stimulating leukotriene synthesis in neutrophils. Our data show that activation of mitogen-activated protein kinases p38 and ERK1/2, which is important for leukotriene synthesis in neutrophils is a target for SkQ1: 1) the selective p38 inhibitor SB203580 inhibited fMLP-induced leukotriene synthesis, while the ERK1/2 activation inhibitor U0126 suppressed leukotriene synthesis induced by any of the three stimuli; 2) SkQ1 effectively prevents p38 and ERK1/2 activation (accumulation of phosphorylated forms) induced by all three stimuli. This is the first study pointing to the involvement of mitochondrial reactive oxygen species in the activation of leukotriene synthesis in human neutrophils. The use of mitochondria-targeted antioxidants can be considered as a promising strategy for inhibiting leukotriene synthesis and treating various inflammatory pathologies.

Indications of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with primary myelofibrosis are intermediate-2 and high-risk group of DIPSS (Dynamic International Prognostic Scoring System), beginning of the disease in childhood. The other adverse factors affect engraftment and survival after allo-HSCT, example partialy matched donor. But the result of allo-HSCT from matched related donors and result of allo-HSCT from haploidentical donors are comparable. The method for haploidentical hematopoietic stem cell transplantation is T-cell-depletion. This is clinical case of T-cell-depleted haploidentical hematopoietic stem cell transplantation in patient with primary myelofibrosis, the diagnosis was established in childhood.

Next generation sequencing is used to determine full-length sequences of HLA genes at the 4-field (allelic) resolution. The study was aimed at determining frequency and diversity of HLA alleles in a cohort of blood donors from the Registry of the National Research Center for Hematology who design ated themselves as Russians (including some not routinely typed variations in HLA gene regions). The studied population consisted of 1510 donors. HLA typing was performed by next generation sequencing. Libraries were performed with AllType NGS Amplification Kits (One Lambda, USA) and sequenced using MiSeq (Illumina, USA). Data analysis used the TypeStream Visual Software V2.0.0.68 (One Lambda, USA) and IPD-IMGT/HLA database 3.40.0.1. Arlequin 3.5 software was used for estimation of allele and haplotype frequencies, deviation from Hardy-Weinberg equilibrium. 82 HLA-A, 156 HLA-В and 85 HLA-С alleles were identified with four-field resolution. 45 HLA-DRB1 and 18 HLA-DQB1 alleles were identified with 2-3-field resolution. Considerable HLA diversity was found among the donors self-designated as Russians: the population had large numbers of distinct alleles at each HLA gene, high percentage of alleles (25-32% of HLA class I) were revealed only once. Sufficient numbers of new alleles were registered which are absent in the IPD-IMGT/HLA database. Considerable allelic diversity in Russian population is due to low-incidence alleles. Despite this diversity, the majority of HLA alleles detected at each locus were common. Significant HLA diversity of the donors was connected with a large number of alleles with rare occurrence. The novel alleles identified in our study differed from the known alleles by single nucleotide substitutions. The most common alleles at the four-field level were as follows: A*02:01:01:01 (27.1%), C*07:02:01:03 (13.1%), A*03:01:01:01 (13.0%), B*07:02:01:01 (13.0%), A*01:01:01:01 (11.6%) and C*07:01:01:01/16 (10.4%). The HLA alleles, which are common for Russian populations, are not always common or well-documented alleles in present catalogues. The data obtained in this study may be used as a reference sample for estimation of HLA allele frequencies in Russian population, for proper frequency evaluation of specific alleles when searching donors for allogeneic hematopoietic stem cell transplantation, as well as for association studies between HLA alleles and different diseases, and for research in population genetics.

Research aim: to investigate the proliferative status of endometrium in the different morphotypes of endometrial hyperplasia based upon the identification of key molecular markers of the cell cycle. Materials and methods. Endometrial samples taken from 137 women were investigated: 40 – normal endometrium (NE), 61 – non-atypical endometrial hyperplasia (ЕH), 36 – atypical hyperplasia (AHE). Expression of gene cyclin D1, nuclear antigen Кі-67, glycoproteins Е-cadherin and β-catenin, estradiol receptors (ER) and progesterone receptors (PGR) were investigated. Results. ER expression of NE was high in the proliferative phase and decreased significantly in the secretory phase. PGR expression was high in both phases. ER expression of EH in glandular (180 ± 8.3) and in stromal cells (170.5 ± 4.1) exceed the indicators of the secretory phase. PGR expression in the stromal cells of EH (197.5 ± 9.3) exceed significantly indicators of NE. ER and PGR expression significantly and reliably decreased if there was AHE. ER expression of glandular cells was 2.6 times lower (74.6 ± 3.9) compere to proliferative NE (p