Clinical significance of gene polymorphisms for hereditary predisposition to breast and ovarian cancer (review of literature).

The review presents classical and modern views on the molecular genetic causes underlying hereditary predisposition to breast and ovarian cancer. A computerized literature search was carried out in the electronic databases MEDLINE, Scopus, and Web of Science, published between January 1994 and May 2021, using the keywords: «hereditary breast and ovarian cancer¼, «BRCA¼ and «DNA repair¼. Current views on the role of germline mutations in genes for susceptibility to breast cancer (BC): BRCA1, BRCA2, PALB2, TP53, CHEK2, PTEN, ATM, and PPM1D are presented. The role of a complex of genes involved in homologous DNA repair and causing other hereditary oncological diseases is considered. The role of the loss of heterozygosity in these genes, which increases the level of chromosomal instability and leads to an increased risk of malignant transformation, is considered. Germinal mutations in the genes under consideration in 90% of clinical cases are the cause of initiation of tissue malignancy and greatly increase the risk of developing hereditary breast cancer and OC. The review emphasizes the complex nature of pathogenesis and significant polymorphism of genetic targets for hereditary breast cancer and OC. It is concluded that it is necessary to use NGS panels for complex screening of genes of hereditary susceptibility to these oncological diseases. The review provides data on the clinical significance of each group of genes of hereditary predisposition in the pathogenesis of breast cancer and OC, and also demonstrates the possible role of methylation of the promoter regions of genes and the state of mitochondrial DNA in the development of these pathologies. The purpose of this review was to broaden the horizons of specialists in the field of oncology and clinical diagnostics in the context of the rapidly expanding spectrum of molecular genetic markers of hereditary breast and ovarian cancers.

SARS-CoV-2 will constantly sweep its tracks: a vaccine containing CpG motifs in 'lasso' for the multi-faced virus.

During the current COVID-19 pandemic, the global ratio between the dead and the survivors is approximately 1 to 10, which has put humanity on high alert and provided strong motivation for the intensive search for vaccines and drugs. It is already clear that if we follow the most likely scenario, which is similar to that used to create seasonal influenza vaccines, then we will need to develop improved vaccine formulas every year to control the spread of the new, highly mutable coronavirus SARS-CoV-2. In this article, using well-known RNA viruses (HIV, influenza viruses, HCV) as examples, we consider the main successes and failures in creating primarily highly effective vaccines. The experience accumulated dealing with the biology of zoonotic RNA viruses suggests that the fight against COVID-19 will be difficult and lengthy. The most effective vaccines against SARS-CoV-2 will be those able to form highly effective memory cells for both humoral (memory B cells) and cellular (cross-reactive antiviral memory T cells) immunity. Unfortunately, RNA viruses constantly sweep their tracks and perhaps one of the most promising solutions in the fight against the COVID-19 pandemic is the creation of 'universal' vaccines based on conservative SARS-CoV-2 genome sequences (antigen-presenting) and unmethylated CpG dinucleotides (adjuvant) in the composition of the phosphorothioate backbone of single-stranded DNA oligonucleotides (ODN), which can be effective for long periods of use. Here, we propose a SARS-CoV-2 vaccine based on a lasso-like phosphorothioate oligonucleotide construction containing CpG motifs and the antigen-presenting unique ACG-containing genome sequence of SARS-CoV-2. We found that CpG dinucleotides are the most rare dinucleotides in the genomes of SARS-CoV-2 and other known human coronaviruses, and hypothesized that their higher frequency could be responsible for the unwanted increased lethality to the host, causing a 'cytokine storm' in people who overexpress cytokines through the activation of specific Toll-like receptors in a manner similar to TLR9-CpG ODN interactions. Interestingly, the virus strains sequenced in China (Wuhan) in February 2020 contained on average one CpG dinucleotide more in their genome than the later strains from the USA (New York) sequenced in May 2020. Obviously, during the first steps of the microevolution of SARS-CoV-2 in the human population, natural selection tends to select viral genomes containing fewer CpG motifs that do not trigger a strong innate immune response, so the infected person has moderate symptoms and spreads SARS-CoV-2 more readily. However, in our opinion, unmethylated CpG dinucleotides are also capable of preparing the host immune system for the coronavirus infection and should be present in SARS-CoV-2 vaccines as strong adjuvants.

[Changes of Nonspecific Proteinases and Proinflammatory Cytokines in the Clinical Course of Acute Myocardial Infarction of Various Severity].

PURPOSE: to study changes of serum levels of nonspecific proteinases, their inhibitors, and proinflammatory cytokines during short term observation of patients with acute myocardial infarction (MI). MATERIALS AND METHODS: We included in this prospective short-term study 82 patients (27 with uncomplicated non-Q wave MI, 30 with Q-MI complicated by Killip class I-II acute left ventricular failure [ALVF], 17 with Q-MI complicated by Killip class III-IV ALVF, and 8 non-survivors due to development of cardiogenic shock) and 12 healthy controls. Serum levels of interleukin (IL) - 1ß, IL-6 and tumor necrosis factor (TNF)-α were measured by ELISA. Elastaselike (ELA) and trypsin-like (TLA) activities as well as characteristics of proteinase inhibitors (antitrypsin activity and acid-stable inhibitors) were also determined. Blood samples were taken at hospital admission within 24 hours after onset of symptoms. The GUSTO Score at admission was used for risk stratification. RESULTS: All cytokines levels were significantly elevated in MI patients in comparison to controls. Mean concentrations of IL-6 and TNF-α at baseline were higher among patients with MI complicated by ALVF than in the group with uncomplicated MI (27.45 vs 16.04 pikogram / mL, р.

THE IMPACT OF ALCOHOL ON PRO-METASTATIC N-GLYCOSYLATION IN PROSTATE CANCER.

Chronic alcohol abuse and alcoholism are considered risk factors for prostate cancer (PCa) progression, but the mechanism is unknown. Previously, we found that: (1) fragmentation of the Golgi complex correlates with the progression of PCa; (2) ethanol (EtOH) induces Golgi disorganization, which, in turn, alters intra-Golgi localization of some Golgi proteins. Also, progression of the prostate tumor is associated with activation of N-acetylglucosaminyltransferase-V (MGAT5)-mediated N-glycosylation of pro-metastatic proteins, including matriptase and integrins, followed by their enhanced retention at the cell surface. Here, using high-resolution microscopy, we found that alcohol effect on Golgi in low passage androgen-responsive LNCaP cells mimic the fragmented Golgi phenotype of androgen-refractory high passage LNCaP and PC-3 cells. Next, we detected that transition to androgen unresponsiveness is accompanied by downregulation of N-acetylglucosaminyltransferase-III (MGAT3), the enzyme that competes with MGAT5 for anti-metastatic N-glycan branching. Moreover, in low passage LNCaP cells, alcohol-induced Golgi fragmentation induced translocation of MGAT3 from the Golgi to the cytoplasm, while intra-Golgi localization of MGAT5 appeared unaffected. Then, the relationship between Golgi morphology, MGAT3 intracellular position, and clinicopathologic features was assessed in human PCa patient specimens with and without a history of alcohol dependence. We revealed that within the same clinical stage, the level of Golgi disorganization and the cytoplasmic shift of MGAT3 was more prominent in patients consuming alcohol. In vitro studies suggest that EtOH-induced downregulation of MGAT3 correlates with activation of MGAT5-mediated glycosylation and overexpression of both matriptase and integrins. In sum, we provide a novel insight into the alcohol-mediated tumor promotion.

[Efficiency of polyphenol-rich grape products for the prevention of metabolic disorders in the experiment].

The article presents the results of study of the effect of polyphenol-rich materials obtained from grapes on the clinical symptoms, activity of non-specific proteases, and parameters of lipid peroxidation (LPO) of blood of rats with fructose model of metabolic syndrome (MS). White male rats (n=54, with initial body weight of 190-210 g) were randomly divided into five groups: control and 4 experimental groups. Body weight, circumference of the abdomen, blood serum level of glucose, total cholesterol, triglycerides and high density (HDL) lipoproteins were monitored in all animals in dynamics. Also non-specific proteases and their inhibitors were evaluated in rat blood by enzymatic methods, lipid peroxidation profile (malondialdehyde and caeruloplasmin blood serum level, superoxide dismutase blood activity) - by spectrophotometric methods. Modeling of the MS (10% fructose in drinking water) within 8 weeks resulted in statistically significant increase in body mass, abdominal adipose tissue, the activity of elastase-like (ELA) and trypsin-like (TLA) proteinases (20 and 18% respectively), the level of secondary products of LPO (50%), and decrease in activity of superoxide dismutase (15%) compared with the parameters of intact animals. The use of polyphenol-rich materials obtained from grapes with a total content of 1; 1,1 and 4 mg of phenolic compounds (in 0.05 ml) at MS for 4 weeks contributed regression the key clinical signs of MS: significant decrease of glucose and triglyceride levels against the background of increasing the HDL cholesterol were observed. The polyphenol-rich materials obtained from grapes influenced positively on the proteolytic profile (decreased TLA and ELA by 20% at the maximum dosage), contributed to the increase of the level of acid-stable protease inhibitors (by 21%), and reduced the amount of secondary products of LPO (by 34%). The dose-dependent effect of the amount of polyphenol components contained in food concentrates has been revealed.

Endometrial hyperplasia-related inflammation: its role in the development and progression of endometrial hyperplasia.

BACKGROUND: Endometrial hyperplasia (EH) is one of the most common gynecologic diseases in the world. Different statistical categories implicate an imbalance of estrogens and progestogens in the etiology of this disease. We propose that inflammation also plays a key role in the progression of endometrial hyperplasia. OBJECTIVE: The aim of this study is to evaluate the role of inflammation in the transformation and progression of endometrial hyperplasia, using local inflammatory cytokines and nonspecific protease levels, CD 45(+) expression, and histological examination. DESIGN: The study included 107 patients (ages 29-49 years) with different forms of endometrial hyperplasia. The enrolled patients were randomized into one of the four groups: normal endometrium (n = 18) as the control group, simple hyperplasia (n = 41), complex hyperplasia without atypia (n = 36), complex atypical hyperplasia or endometrioid adenocarcinoma (n = 12). METHODS: The following were evaluated for patients with different forms of EH: steroid hormone levels in blood serum and uterine flushings, immunohistochemical estrogen and progesterone receptor expression patterns in the endometrial tissue, CD 45(+) (common leukocyte antigen) expression, the levels of the cytokines IL-1ß, IL-6, and TNF-α, and nonspecific proteases and their inhibitors. RESULTS: The level of estradiol in blood serum and especially in uterine flushings was elevated dramatically in simple EH as compared to that of controls, but there was no significant difference between estradiol levels among the different forms of EH. The estimation of CD 45(+), the levels of the cytokines IL-1ß, IL-6, and TNF-α, and the activity of proteases (elastase-like and trypsin-like activities) and their inhibitors showed that levels of nonspecific inflammatory markers increase with EH progression. CONCLUSIONS: We suggest that the initial responsibility for the development of simple endometrial hyperplasia belongs to systemic hyperestrogenemia and, in particular, local hyperestrogenia, but that the role of inflammatory processes increases in complex and atypical EH. Development of inflammatory changes in endometrial hyperplasia may be considered as a factor in the promotion and progression of pathology, as well as an attributed risk factor for malignancy in endometrial hyperplasia. In this study, we have established a role for CD 45(+) expression cells, non-specific proteases, and the inflammatory cytokines IL-1ß, IL-6, and TNF-α in endometrial hyperplasia-related inflammation.

[The antioxidant activity of the products of processing of red grape of Cabernet Sauvignon, Merlot, Saperavi].

Experimental data on the antioxidant activity of grape juice, grape concentrates and wine from grapes of Cabernet Sauvignon, Merlot and Saperavi from Crimea and Krasnodar regions was presented. Flavonoids are presented in the form of glycosides of such anthocyanins as delphinidin, malvidin, cyanidin, petunidin, peonidin and also by quercetin and its glycoside, (+)-D-catechin and (-)-epicatechin. Oligomeric procyanidins, which are condensed catechol units (2-6) soluble in water, are presented in significant amounts, and polymeric procyanidins with the amount catechin units greater than 7, insoluble in water, constituted the bulk of polyphenols od wine and concentrates from red grapes (no juice). Among non-flavonoid polyphenols hydroxybenzoic (gallic, syringic) and hydroxycinnamic (caftaric, cautaric) acids are identified, the relative content of which in the amount of polyphenols in the juice is maximum, and minimum is in concentrates. It was found that antioxidant activity for all products in standard Trolox method can be estimated by the equation: Y = 0.53627+0.1395X+0.080439X2-0.00064708X3, with a correlation coefficient r = 0.9952; where: Y--antioxidant activity, g/dm3 by Trolox method; X--mass concentration of phenolic substances on the Folin-Ciocalteu, g/dm3. The equation is valid for Y = 0.76-196.22; X = 1.0-82.67. The results of biological testing of wines Cabernet Sauvignon, Merlot, Saperavi and polyphenol concentrates from grape on the biological model of bioluminescent bacteria Photobacterium leiognathi Sh1 demonstrated the applicability of bioassay to assess the antioxidant activity, which correlates well with the polyphenols content and antioxidant activity by trolox method.

Experimental induction of reparative morphogenesis and adaptive reserves in the ischemic myocardium using multipotent mesenchymal bone marrow-derived stem cells.

INTRODUCTION: Current experimental research has proven the efficacy of transplantation bone marrow-derived mesenchymal stem cells (MSC) in the treatment of myocardial infarction (MI). The one of the main purposes of research was to evaluate the comparative data of the MSC transplantation with (5-azacytidine) and without commitment and to assess the post transplantation effects. METHODS: The efficiency of intravenous cardiomyoplasty by infusion of MSC was evaluated in female Wistar-Kyoto rats with myocardial infarction model using echocardiography, morphological study, morphometry, immunohistostaining, data from in situ hybridization, and by measurement of blood serum levels of nitric oxide, endothelin-1, vascular endothelial growth factor (VEGF), and fibroblast growth factor 2 (FGF2). RESULTS: The transplanted MSC were detected in all layers of the myocardium; MCS actively participate in the formation of blood vessels and connective tissue in the scar zone. There was no observable differentiation of male MSC into cardiomyocytes in female rats with MI. However, MSC transplantation leads to significant improvement in vascularization in the area of MI, elevation blood serum levels of nitric oxide, VEGF, and FGF2. No significant differences were identified morphologically between the two groups of animals after transplantation with unmodified MSC or commited MSC (5-azaC). CONCLUSION: Intravenous transplantation of MSC without commitment in rats with MI improves the contractile function of the heart, the morphology of the myocardium, and should be recommended for further clinical investigation as an alternative approach to deal with heart diseases.

[Effect of proteinase inhibitors on efficiency of suppression of proteolytic activation in pneumonia].

We studied the influence of a way of introduction proteinase inhibitors on efficiency of suppression of proteolysis activation during pneumonia. Comparative study of efficiency of proteases inhibition in experimental pneumonia has shown higher efficacy of local introduction of drugs. Intravenous and intraperitoneal introduction of proteinase inhibitors exhibited inhibitory effect of a smaller degree on local and systemic proteases activation, did not decrease an acute phase of response of alpha-1-protease inhibitor in comparison with endotracheal instillation of Contrycal and Ingiprol. The study has established that endotracheal introduction of proteinase inhibitors is the most effective for correction of the proteinase-inhibitor balance. It also helps to promote the activity proteinase-inhibitor, suppresses elastolytic activity, decreases cellular infiltration, reduces the concentration of proteins in bronco-alveolar lavage fluid that is connected with address delivery of drugs to the target organ creating a maximal concentration of drugs in affected area.

[Elastolytic activity of bronchoalveolar lavage fluid in acute lung inflammatory injury].

Elastolytic activity in bronchoalveolar lavage fluid in the lung with acute inflammatory injury and properties of different proteinase inhibitors for its correction was established. It was determined, that 4/5 of elastolytic activities are submitted to neutrophile serine proteinase (EC 3.4.21.37) and 1/5 of elastolytic activities - metalloenzymes macrophages origin (EC 3.4.24.65). Inhibition of elastase-like activity with the use of three proteinase inhibitors: contrycal, ingiprol and thermo- and acid-stable proteinase inhibitor from rabbit blood showed more intensive ability of thermo- and acid-stable proteinase inhibitor to inhibit pancreatic elastase and pull of neutrophil and macrophage elastase. Preventive use and treatment of proteinase inhibitors effectively suppressed activation of proteinases in the acute lung inflammatory injury.