[Oxytocin receptor expression is associated with estrogen receptor status in breast tumors]. / Ékspressiia oksitotsinovogo retseptora assotsiirovana so statusom éstrogenovogo retseptora v opukholiakh molochnoi zhelezy.

The oxytocin receptor (OXTR) plays an important role in childbirth, breastfeeding, and social interactions. There is emerging evidence that OXTR is associated with the breast cancer (BC) initiation and progression. However, the mechanisms leading to a change in its expression, the diagnostic or prognostic value of the receptor in BC are currently poorly understood. Here, we have evaluated the relative level of OXTR expression in BC samples (n=107), and also investigated the effect of estradiol on its expression in MCF-7 and MDA-MB-231 cells. The level of OXTR expression was significantly lower in breast tumor tissue than in normal tissue obtained from the same patient. The expression of OXTR was dependent on the status and expression of the estrogen receptor (ER): the level of OXTR mRNA was significantly lower in ER-negative BC samples compared to ER-positive BC samples. Moreover, OXTR expression was also lower in samples from patients with luminal subtype with a low value of ER expression (0-5 score according to the IHC assay, Allred scoring) compared with samples with high ER expression (6-8 score). In luminal BC, OXTR expression was associated with the HER2 expression level: the OXTR mRNA level was higher in tumors with a HER2 IHC score of 1+ as compared to cases with the HER2 expression score of 2+, 3+. We also showed that estradiol increased the level of OXTR mRNA in MCF-7 cells, but not in ER-negative MDA-MB-231 cells. These data indicate that changes in OXTR expression in BC tissues can be caused by increased ER expression. We found no association between OXTR and T or N stages and progesterone receptor expression.

[Influence of the HLDF differentiation factor on the production of cytokines by bio-tissues of breast tissue in its non-malignant diseases and in invasive carcinoma of a non-specific type]. / Vliianie faktora differentsirovki HLDF na produktsiiu tsitokinov bioptatami tkani molochnoi zhelezy pri ee nezlokachestvennykh zabolevaniiakh i pri invazivnoi kartsinome nespetsificheskogo tipa.

We studied the effect of the HLDF differentiation factor on production of cytokines by biopsy samples of nonmalignant breast diseases (ND) and invasive breast carcinoma of no special type (IBC-NST), in the absence and presence of lymphogenic metastasis: IBC-NST patients werw subdivided into groups on the prognostic protocol of the 8th edition of the AJCC committee. Group IA consisted of patients with T1-T2 tumor sizes, and predominantly with positive expression of estrogen and progesterone receptors (ER+/PR+/HER2-); it also included one patient with the HER2+ (ER-/PR-/HER2+) molecular subtype. The IB group was mainly composed of patients with T2 tumor size, with the presence of lymphogenic metastasis (in 8 out of 10) patients and with positive expression of estrogen and progesterone receptors (ER+/PR+/HER2-) and it also included three patients with the HER2+ (ER-/PR-/HER2+) molecular subtype. Group IIA consisted of patients with T1-T2 tumor sizes, mainly with no metastases in the lymph nodes (in 11 out of 12 patients) and with a triple negative molecular subtype. Group IIB included patients with T2 tumor size, the presence of nodal metastasis and the expression of markers of ER-/PR-/HER2 - and ER-/PR-/HER2+. Group IIIA consisted of patients with tumor size T1-T3, with the presence of nodal metastasis and the expression of markers of ER-/PR+/HER2+ and ER-/PR-/HER2+. Group IIIC consisted of patients with T3 tumor size, lymphogenic metastasis, and expression of ER-/PR-/HER2-markers (triple negative molecular subtype). Due to a limited number of patients in the groups IIB, IIIA and IIIC, as well as due to more severe clinical and pathological stages, according to the prognostic Protocol of the 8th edition of the AJCC Committee, they were pooled into group III. Concentrations of IL-2, IL-4, IL-6, IL-8, IL-10, IL-17, IL-18, IL-1ß, IL-1Ra, TNF-α, IFN-γ, G-CSF, GM-CSF, VEGF and MCP-1 were assayed in supernatants of biopsy specimens of breast tissue. Results have shown that with IBC-NST, a statistically significantly higher level of spontaneous production (SP) by biopsy specimens of IL-17, IL-18, IFN-γ and VEGF, and a lower level of SP IL-6 as compared with ND. Patients of all clinical and pathological groups showed a high VEGF spontaneous production as compared with ND, while statistically significant differences from patients with ND were not found in IL-17 spontaneous production in group IB patients, and IL-18 spontaneous production were absent in group IA. Only in patients with IA and IB, the IL-6 spontaneous production was lower as compared to ND, and the IL-8 spontaneous production was lower in the IA group. IFN-γ spontaneous production was higher in patients with IBC-NST group IIA as compared with ND. Under the influence of the HLDF differentiation factor, it was found that the parameters of IBC-NST patients were statistically significantly higher in the production of IL-1Ra, IL-17, IL-18 and VEGF, and statistically significantly lower in the production of IL-6 as compared to ND. HLDF had a higher impact on the content of IL-18 in IBC-NST patients than in ND. After HDLF sublimation IL-6 values were lower in patients of groups IA and IB, and HLDF-induced IL-17 production was higher only in patients of group IA. Statistically significant differences in the index of influence of HLDF (IVHLDF), representing ratio of the cytokine concentration in the supernatants of a biopsy specimen stimulated by HLDF to spontaneous cytokine production, were found between ND and IBC-NST in the case of on IFN-γ production, and also in the case of IL-4 production (between patients in the absence and presence of lymphogenic metastasis). IVHLDF for production of IL-6, IL-8 and TNF-α was lower in group IIA patients compared to group IA, and IVHLDF for production of GM-CSF and MCP-1 was lower in group IIA as compared to group III, in addition IVHLDF for MCP-1 products was lower in group IIA as compared to ND. The HLDF effect on the cytokine production by the tumor and its microenvironment was different in ND patients and IBC-NST patients. HDLF suppressed IFN-γ production in the pooled group of IBC-NST patients; HLDF mainly had a suppressive effect on the production of IL-6, IL-8, TNF-α, GM-CSF and MCP-1 in IBC-NST patients of group IIA.

Influence of Internal and External Factors on the Production of Cytokines by Peripheral Blood Cells in Breast Cancer.

The article focuses on the influence of human leukemia differentiation factor (HLDF), carcinoembryonic antigen (CEA), and polyclonal activators (PA) on cytokine production by peripheral blood cells in breast cancer and benign breast diseases. It was found that the influence of internal factors on the production of cytokines by the peripheral blood cells is associated with lymphatic metastasis (CEA: IL-10; HLDF: IL-6, IL-1ß, TNF-α, and G-CSF). One special circumstance was that there were no differences between the production of cytokines by peripheral blood cells in the patients with breast cancer compared to the patients with benign breast diseases with a high risk of malignant transformation. This is evidence of the functional similarity of peripheral blood cells in patients with these conditions. Cytokine production under the influence of PA was different only in case of TNF-α in all study groups.

Personalized Approach to Determination of Histidine-Rich Glycoprotein and E-Cadherin in Supernatants of Immunocompetent Blood Cells and Breast Biopsy Specimens in Breast Malignant and Non-Malignant Disease.

The material of patients with invasive carcinoma of no special type (ICNT) and nonmalignant diseases (ND) of the mammary gland was studied. When comparing the concentrations of histidine-rich glycoprotein (HRG) and E-cadherin (CDH1), statistically significant differences between ICNT and ND by HRG in the supernatant of blood cells and its spontaneous production by biopsies and by CDH1 at its induced production, as well as by influence indices of polyclonal activators on the production of CDH1 were found. When comparing the expression of immunohistochemical markers, no statistically significant differences between ICNT and ND were obtained.

[Analysis of prolactin receptor expression in breast cancer subtypes]. / Analiz ékspressii retseptora prolaktina v podtipakh raka molochnoi zhelezy.

Breast cancer (BC) is the most common cancer among women. It is known that the prolactin receptor (PRLR) may play a role in breast carcinogenesis, but the available data are often contradictory. To get a more complete picture of the relationship between the receptor and mammary gland carcinogenesis, we examined the association between changes in PRLR expression level and tumor subtype (and its main characteristics). To do this, using real-time PCR, we evaluated the level of PRLR mRNA in BC tissue samples and untransformed adjoining tissue samples (89 pairs). Since the androgen receptor (AR) has begun to be seen as a prognostic marker in breast cancer, we also evaluated the association between mRNA levels of AR and PRLR. We found a significant increase in PRLR expression in luminal subtypes; the highest level of PRLR mRNA was detected in luminal A subtype. In HER2-positive ER-, PR-negative BC, the PRLR mRNA level decreases in tumor tissues compared with untransformed tissues. High PRLR expression is also associated with smaller tumor size in luminal B HER2-negative subtype. In ER-, PR-negative tumors, PRLR expression is associated with AR expression: PRLR mRNA level is increased when AR mRNA level is reduced by more than 8 times in triple-negative tumors; in contrast, in HER2-positive subtype it decreases more significantly when AR expression is reduced by more than 3 times. A tendency towards an increase in PRLR expression with an increase in the AR mRNA level was also discovered in luminal subtypes. The level of PRLR expression depends on the age of patients. In luminal A, PRLR expression is higher in patients under 65 years. In contrast, in luminal B HER2-negative and triple-negative BC, reduced PRLR expression was observed in patients under the age of 40 years and under the age of 50 years, respectively. In this group of patients under the age of 40 years with luminal B HER2-negative BC, ER expression was also reduced (0-4 score according to the IHC assay). Thus, PRLR probably plays a different role in the development and progression of BC: in luminal A and luminal B HER2-positive subtypes PRLR may act as an oncogen, and in luminal B HER2-negative and ER-, PR-negative subtypes can play a tumor suppressor role.

[Assessment of the cytokine-producing resource of tumor biopsy samples from patients with invasive carcinoma of no special type and with non-malignant breast diseases]. / Otsenka tsitokinprodutsiruiushchego resursa bioptatov opukholei patsientov s invazivnoi kartsinomoi nespetsificheskogo tipa i s nezlokachestvennymi zabolevaniiami molochnoi zhelezy.

Breast cancer, in most cases, is a malignant neoplasm associated with infiltration of a tumor with the cells that form its microenvironment and produce various cytokines. The aim of the study was to evaluate the cytokine-producing function of tumor cells and their microenvironment in biopsy specimen of patients with invasive carcinoma of no special type and in patients with benign breast diseases. To assess the cytokine-producing activity of the tumor and its microenvironment, the index of polyclonal activators influence on cytokine production by biopsy specimens of patients with invasive carcinoma of no special type (group I) and in patients with benign breast tumors (group II) was calculated. Group II was further subdivided into group IIa, which included only patients with fibroadenoma, and group IIb, which included the patients with leaf-shaped fibroadenoma, fibroadenomatosis, fibrocystic mastopathy, intraductal papillomatosis, sclerosing adenosis and fibrocystic mastopathy with microcalcifications. The concentrations of IL-2, IL-6, IL-8, IL-10, IL-17, IL-18, IL-1ß, IL-1Ra, TNF-α, IFN-γ, G-CSF, GM-CSF, VEGF, and MCP-1 were measured in tumor biopsy supernatants. When comparing groups I and II, higher indices of the polyclonal activators influence on the production of IL-17, IL-18 and TNF-α were observed in patients with benign diseases. Higher indices of the polyclonal activators influence on the production of IL-18, TNF-α, and IL-1ß and the ratio of IL1ß/IL1Ra were observed in patients with fibroadenoma as compared to those with invasive carcinoma of no special type. There were no significant differences in the indices of the polyclonal activators influence between groups I and IIb. This suggests the existence of changes in the mammary gland in patients of group IIb similar to those present in patients with invasive carcinoma of no special type. Higher indices of polyclonal activators influence on the production of IL-1ß, as well as the ratio of IL1ß/IL1Ra were observed in the patients of group IIa compared to the patients of group IIb. The results of the study identify the features of the cytokine-producing resource of tumor biopsy specimens in patients with invasive carcinoma of no special type and with benign breast tumors.

[Cytokine production by blood immune cells, tumor and its microenvironment, characteristic of extracellular matrix in patients with invasive ductal carcinoma of no special type]. / Produktsiia tsitokinov immunokompetentnymi kletkami krovi, opukhol'iu i ee mikrookruzheniem, osobennosti sostoianiia vnekletochnogo matriksa u bol'nykh invazivnoi kartsinomoi molochnoi zhelezy nespetsificheskogo tipa.

The aim of this research was to study cytokine production by blood immune cells, tumor, and its microenvironment, and characterize extracellular matrix of patients with invasive ductal carcinoma of no special type and lymphatic metastases. Spontaneous and polyclonal activators stimulated production of cytokines by blood immune cells, tumor and its microenvironment were studied in 95 patients with invasive ductal carcinoma of no special type. The concentration of IL-2, IL-4, IL-6, IL-8, IL-10, IL-17, IL-18, IL-1ß, IL-1Ra, TNF-α, IFN-γ, G-CSF, GM-CSF, VEGF and MCP-1 was determined by the solid-phase enzyme-linked immunosorbent assay. The condition of fibrous component and presence of neutral glycoproteins and sulfated glycosaminoglycans were evaluated during the research of extracellular matrix. Regional lymphatic metastases were detected in 35 of 95 patients. It was shown that in the presence or absence of lymphatic metastases index of polyclonal activators influence on the production of cytokines by blood immune cells was different for IL-6, IL-8, and IL-1ß; while in the case of cytokine production by tumor and its microenvironment the index of influence was different for IL-2 and IL-17. The presence of lymphatic metastases corresponded with the rise of cytokines spontaneous production, while the absence of lymphatic metastases corresponded with the rise of cytokines production stimulated by polyclonal activators. The value of indices of polyclonal activators influence on the production of cytokines by blood immune cells pointed to the highly stimulating effect of polyclonal activators while the value of indices of polyclonal activators influence on cytokines production by tumor and its microenvironments pointed to the low and sometimes even absent effect of polyclonal activators. Basing on these data we propose a ratio of indices of polyclonal activators influence for the better evaluation of the probability of lymphatic metastases during preoperative period. After characterizing extracellular matrix we found out a point threshold, which, in 100% of cases, predicted the presence of lymphatic metastases basing on the condition of extracellular matrix. Using the data acquired, we are proposing a risk group for metastasis among women with no lymphatic metastases in the moment of check-up.

Personalized Approach to Assessing mRNA Expression of Histidine-Rich Glycoprotein and Immunohistochemical Markers in Diseases of the Breast.

Biopsy material of patients with malignant and benign breast diseases was examined. HRG mRNA expression was detected in 70% of cases in biopsy material obtained from patients with nonspecific invasive carcinoma and in 66.7% of cases in biopsy material of patients with benign breast diseases. Immunohistochemical analysis revealed expression of collagen II, the beta-1 integrin, and E-cadherin-markers of epithelial-mesenchymal transition. The use of RT-qPCR combined with immunohistochemical study made it possible to identify atypical cells, which can be regarded as precancerous changes, in individual patients.

Phenotypic and functional characteristics of dendritic cells and contents of suppressor cell populations in peripheral blood of breast cancer patients.

The progression or the appearance of distant metastases in breast cancer (BC) is influenced by a variety of antitumor immune response suppression mechanisms. In this paper we study circulating dendritic cells (DC) and the suppressor cell populations in peripheral blood of breast cancer patients. The study of phenotypic and functional properties of DCs was performed in the samples of intact and TLR-stimulated whole blood from breast cancer patients and healthy women by multicolor flow cytometry. To determine the suppressor cell population among lymphocytes multicolor panel comprising markers CD 4, CD 25, CD 127, FoxP3 was used. It is showed that the formation of secondary foci of tumor growth in patients was accompanied by disturbances of the functional activity plasmocytoid DC and accumulation of cells with immunosuppressive functions.

[The structure of the rat lymph nodes draining purulent inflammation region after interleukin-2 treatment].

The structure of rat lymph nodes regional to the purulent wound under the conditions of interleukin (IL-2) treatment was investigated by the methods of light microscopy. In the lymph nodes from intact animals, the cortical plateau was found to become diminished with the simultaneous paracortical zone expansion. In the regional lymph nodes from rats with an untreated purulent wound, the relative dimensions of cortical plateau were decreased because of expansion of the medullary structures. Lymphoid parenchyma and the sinuses of lymph nodes contained erythrocytes, the numbers of immuno- and plasmoblasts, macrophages and neutrophilic granulocytes were increased. IL-2 treatment in animals with a purulent inflammatory reaction secured the greater integrity of structure of these organs and of cytoarchitecture of their various zones. However, the administration of this cytokine resulted in increased vascular permeability and enhanced the probability of allergic reaction development, which requires the development and application of prophylactic measures of the specified side effects and complications.

Expression of different proteoglycans in human breast tumors.

The composition of proteoglycans and their changes during malignant transformation are important factors influencing adhesive properties and mitotic activity of tumor cells. In this study, expression level of different proteoglycans (decorin, syndecan-1, lumican, glypican-1, and aggrecan) in tumors and normal human breast tissue was investigated. Multiplex RT-PCR data revealed different expression changes for different proteoglycans in human breast tumors--syndecan expression was activated compared to almost no expression in normal breast tissue, expression of decorin and lumican decreased 2-5- and 2-3-fold, respectively, and aggrecan transcription seems to be unaffected. A change of expression level of decorin correlated with expression of D-glucuronyl-C5-epimerase, a key enzyme responsible for the biosynthesis of idurone-containing glycosaminoglycans, possessing antimitotic activity. The results suggest that changes in decorin, lumican, and syndecan-1 expression in tumor tissue could induce a distortion of proteoglycan composition and mitotic activity of cells in human breast tumor.

[One stage skin-sparing breast repair after mastectomy]. / Odnomementnaia rekonstruktsiia molochnoi zhelezy posle mastéktomii s sokhraneniem kozhi.

Breast-conserving therapy has become very popular in the past 20 years. This treatment is beneficial only for early stages of breast cancer. When breast-conserving therapy is not indicated, skin-sparing mastectomy with immediate breast reconstruction using silicone implants or autogenous tissue is the surgical method of choice. The authors have analyzed the results obtained at three hospitals of Moscow, Novosibirsk, and Tula. A total of 58 breast repairs, including 23 with silicone expanders, 35 with TRAM-flaps were performed by February 2000. They accomplished different designs of skin incisions in relation to the size and site of a tumor and to the shape of the breast. These groups comprised patients with breast cancer T1-2No-1Mo. The follow-up averaged 25.8 months (range 5-52 months). All the patients underwent combined and complex treatments. The median of overall survival was not not achieved. One patient died from dissemination. Two-year acturial survival was 86.8% (one local recurrence). The incidence of postoperative complications was 34.7% in the implant group and 14.2% in the TRAM-flap group.

[Regulation of nitrate metabolism through anion polycompartmentation in plant roots]. / Reguliatsiia metabolizma nitrata s uchastiem sistemy polikompartmentatsii aniona v korniakh rastenii.

A new concept illustrated by a corresponding mathematical model of nitrate metabolism regulation is proposed. The model is based on root nitrate compartmentation in several functional pools: storage, metabolic and a mobile pool which is intended for translocation to shoots. Data on nitrate uptake, compartmentation, reduction in intact roots and translocation to shoots were obtained on steady-state wheat seedlings grown at 25 and 12 degrees C in the root zone. The net uptake, influx/efflux ratio, mobile pool size and translocation changed depending on the medium temperature. The oscillations of the net uptake rate, nitrate tissue concentration were revealed and the effect of temperature on these changes was demonstrated. The scheme of regulation is based on the idea that net uptake through nitrate influx/efflux is under the control of the nitrate the mobile pool whose size was dependent on the nitrate translocation into shoots. The mathematical model is represented by a system of ordinary differential equations simplified according to the time hierarchy of reactions. It has a limit cycle at definite values of the parameters. The model postulates the mechanism of a positive feed-back regulation of the transfer of newly absorbed nitrate into translocated pool formed in the root cortex. Theoretical results are verified experimentally.

[The effect of single maximal physical loading on the emotional behavior of rats]. / Vliianie odnokratnoi maksimal'noi fizicheskoi nagruzki na émotsional'noe povedenie krys.

In experiments on 250 Wistar female rats the influence was studied of a single maximum and submaximum physical loads on the emotional behaviour and the state of conditioned activity. It has been established, that as a result of maximum possible run of the animals depression takes place of orienting investigatory activity in conditions of the "open field" and disturbance of elaboration and reproduction of the conditioned reflex of two-way avoidance. Normalization of these parameters took place in 48 hours after the maximum load action. Analogous effect was observed in the period of aftereffect of the submaximum physical load, characterized by lowering of the level of behavioural activity in the "open field", disturbance of the elaboration of two-way avoidance as a result of presumable increase of functional tonus of the brain inhibitory systems.

[Functional state of the frontal cortex and ventromedial hypothalamus during physical overexertion and experimental neurosis in the rabbit]. / Funktsional'noe sostoianie frontal'noi kory i ventromedial'nogo gipotalamusa pri fizicheskom perenapriazhenii i éksperimental'nom nevroze u krolikov.

A change of excitability, pO2 and local cortical blood flow under a long-term maximum physical load and in conditions of experimental neurosis, was investigated in rabbits with electrodes implanted in the frontal cortex and ventromedial hypothalamus. It was found that functional activity of these structures under physical orverstrain rises as the blood flow and pO2 increase, and the excitability also increases. In experimental neurosis, a discoordination in functioning of the cortex and hypothalamus is observed. Relative stabilization of the functional state of tested structures, observed during physical overstrain, is absent in conditions of experimental neurosis.