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Immune checkpoint inhibitors (ICIs) alone or in combination with chemotherapy have become one of the key approaches in the treatment of patients with advanced non-small cell lung cancer (NSCLC). Evaluation of level of PD-L1 (ligand of the programmed cell death receptor 1) expression on tumor cells using immunohistochemistry is the only approved option for determining the indications of ICIs in this group of patients. However, despite high level of PD-L1 expression, up to 80 % of patients do not respond to therapy due to the presence of primary or acquired resistance, which determines the limited effectiveness of ICI. In addition, 8–17 % of PD-L1-negative patients with NSCLC are also able to respond to ICIs. The limitation of this marker is that it does not allow assessing both intratumoral and systemic immune status. It is necessary to search for additional predictive markers to improve the accuracy of the selection of candidates for immunotherapy, which will avoid costs, wasted time, and a high risk of immune-related adverse events in potentially unresponsive patients. The attention of researchers is devoted to circulating markers in peripheral blood, as a non-invasive alternative to biopsy for predicting and monitoring the response. This review focuses on the most promising immunological markers in peripheral blood as potential predictors of response to ICIs in patients with advanced NSCLC.

Introduction. Epstein–Barr virus (EBV) is equally widespread in the endemic and non-endemic world regions for nasopharyngeal cancer (NPC). High incidence of NPC in endemic countries and low in non-endemic countries suggest there are different mechanisms and conditions for tumor occurrence and, possibly, different clinical significance of EBV-associated markers. However, significance of these markers for determining NPC in non-endemic regions is still poorly understood. Objective – to determine clinical significance of titers of IgG/IgA antibodies to EBV capsid antigen and concentrations of the viral DNA in patients’ blood plasma as diagnostic and monitoring markers for NPC in a non-endemic region of Russia. Materials and methods. Titers of EB-specific antibodies were determined by indirect immunofluorescence, and concentration of the viral DNA in plasma was measured using a quantitative polymerase chain reaction in real time. Study group included patients with NPC (n = 96), and control group – blood donors (n = 171) and patients with other head and neck tumors (n = 33).Results. Titers of IgG/IgA antibodies to EBV capsid antigen, being an important diagnostic marker of nasopharyngeal cancer, did not always correlate with patients’ clinical condition. Humoral response to emerging events often delayed due to inertia of the immune system. Concentration of EBV DNA in patients’ blood plasma clearly reflected the dynamics of the pathological process: it decreased to background values in remission and increased while the disease progressed. In contrast to endemic regions, we did not find any correlation between the studied EBV markers and clinical manifestations of the disease, evaluated in accordance with the TNM classification (Tumor, Nodus and Metastasis).Conclusion. In non-endemic countries, such as Russia, serological and molecular markers of EBV can be successfully used for the primary diagnosis of NPC. However, for the disease monitoring, it is preferable to use the value of the concentrations of circulating EBV DNA, which, in contrast to the values of IgG/IgA antibody titers to VCA EBV, more accurately reflect the patient’s clinical condition.

Introduction. There has been a recent trend toward a gradual increase in the incidence of rectal cancer and a decrease in the average age of patients. These changes interpret the need to personalize treatment in each case.Objective – to evaluate the association of polymorphic variants of some genes with the results of neoadjuvant chemoradiotherapy of rectal cancer.Materials and methods. We analyzed polymorphic variants of MTHFR, XPD, XRCC1, XRCC1, P53, VEGF, EGFR, TNF, CHEK2 and MMP1 genes in 76 patients with rectal cancer who underwent preoperative chemoradiation therapy followed by surgical treatment. Genotyping was performed by DNA isolation from venous blood leukocytes of the subjects followed by polymerase chain reaction with electrophoretic detection of the result.Results. Statistical analysis of the association of polymorphic variants of the studied genes with the treatment pathomorphosis revealed significance in relation to the MMP1-1607 gene (1G >2G) (p = 0.033). There was also an association of co-carrying polymorphic variants of TNF (G / A) + MMP1 (2G / 2G) genes with grade III–IV therapeutic pathomorphosis (p = 0.007).Conclusion. Carriage of recessive allele of MMP1 gene can be a predictor of favorable prognosis of preoperative chemoradiotherapy in patients with rectal cancer.

Introduction. Nitric oxide (NO) produced by NO synthases (NOS) is involved in the regulation of vital physiological functions. At the same time, NO and NOS are involved in events associated with the tumor process: mutagenesis, proliferation, apoptosis, angiogenesis, etc., exerting a multidirectional effect on the tumor.Objectives – analyze and summarize literature data concerning the role of NO and endothelial NOS (eNOS) in the initiation and progression of tumors, as well as in the inhibition of tumor growth.Materials and methods. In preparing the review, publications of information bases of biomedical literature were used: SciVerse Scopus (538), PubMed (1327), Web of Science (905), Russian Science Citation Index (125).Results. The molecular mechanisms of the action of NO and its derivatives on the initiation and progression of carcinogenesis have been explored. Numerous factors and conditions regulating the activity of eNOS in health and tumor growth have been analyzed. The molecular signaling pathways through which the pro-tumor effects of NO and eNOS, stimulating angiogenesis, lymphangiogenesis, are realized, including through the mobilization of stem cells, are considered.Conclusion. Nitric oxide produced by activated eNOS promotes tumor progression by increasing the proliferation of tumor cells, enhancing the action of pro-angiogenic factors, stimulating angiogenesis, lymphangiogenesis, and metastasis. Selective inhibition of increased eNOS activity may be a promising therapeutic approach aimed at reducing metastasis and tumor growth.

Osteopontin is an extracellular matrix protein which is produced by different types of cells and plays an important functional role in many biological processes. This review discusses the main functions of osteopontin, its role in the progression and chemoresistance of malignant neoplasms, in the regulation of epithelial-mesenchymal transition, angiogenesis, and the body’s immune response to the tumor. The article considers the currently known mechanisms by which osteopontin affects to the survival, mobility and invasion of tumor cells, to tumor sensitivity to drug treatment, as well as the prospects for a integrated study of the predictive significance of osteopontin, markers of hypoxia, angiogenesis, epithelial- mesenchymal transition, and immunological tolerance.

Background. Glioblastoma multiforme (GBM) develops in the hypoxic microenvironment, which plays an important role in the pathogenesis of the disease and is closely associated with tumor growth, development and poor prognosis. Hypoxia increases the resistance of tumor cells (TC) to radiation therapy and chemotherapy, promotes the appearance of an aggressive TC phenotype, leading to the disease recurrence. The molecular mechanism of hypoxic action on the secretome of GBM cells, which is involved in the formation of the tumor microenvironment, remains unclear. Also, markers of the aggressive hypoxia-associated phenotype of tumor cells have not been established. The purpose of research – to study the molecular mechanisms of the hypoxia-associated effect on the secretome of the U251 GBM cells.Materials and method. High resolution proteomic mass spectrometry, cell technologies.Results. A total of 1432 proteins were identified in the secretomes of two types of GBM cells (control and experiment). After the action of hypoxia, statistically significant changes in the expression of 390 proteins were registered. 11 proteins showed increase in expression over two orders of magnitude. The intracellular signaling pathways which are responsible for the hypoxia-associated effects on the U251 GMB cells have been identified.Conclusions. Hypoxia significantly affected the proteomic composition of the GBM cells secretome. Five overexpressed secretome proteins, S100A6, HEY1, ZIP3, S100A4, ZEB2, have been proposed as potential markers of the hypoxiaassociated phenotype of GBM, for which participation in the pathogenesis of glioblastoma multiforme has been previously showed.

Recently multiple data accumulated concerning mutations in the ESR1 gene coding estrogen receptor α (mutESR1) and in the LYN gene coding non receptor tyrosine kinase SRC family member (mutLYN) that are associated with endocrine therapy resistance and that could be considered as markers of endocrine therapy efficiency. In case of gynecologic cancers including ovarian cancer the most frequent mutESR1 are ESR1L536H/P/R/V , ESR1Y537S/N/C/H, ESR1D538G that emerge in the course of hormonotherapy especially using aromatase inhibitors. mutLYN including LYNE159K, LYND189Y, LYNK209N, LYNA370T, LYNG418R, LYNA503D are also identified. mutESR1 and mutLYN increase transcriptional activity of estrogen receptor α (ERα) coded with ESR1 gene and catalytic activity of LYN kinase inducing endocrine therapy resistance. Interdependence of ESR1 and LYN genes is revealed at the level of proteins that they code as the kinases of the SRC family including LYN activate ERα-dependent transcription due to the phosphorylation of ERα at Y537 amino-acid residue that is the most frequently mutated in tumors with endocrine therapy resistance. The aim of the review is revealing the clinical correlations of mutESR1 and mutLYN with the ovarian cancer endocrine therapy resistance that opens perspectives of mutESR1 and mutLYN use as new predictive markers of ovarian cancer and development of more efficient anti-tumor medicaments. In the review the information obtained from PubMed database for the last 20 years using the following key words: ESR1, LYN, mutation(s), estrogen receptor α (ERα), LYN kinase, SRC family kinases, ovarian cancer, gynecologic(al) cancer is discussed.

Background. Recent data show evidence that lipid rafts (LR) proteins could be involved in the formation of exosomes and the sorting of proteins that make up the exosomal cargo. Such data are available for flotillins, structural and functional components of flatted rafts. The presence of the main component of caveolar rafts, caveolin-1 (Cav-1), has been shown in exosomes produced by some cancer cells; however, its possible participation in the regulation of the protein composition of exosomes has not been studied previously.Materials and methods. Knockdown of Cav-1 by transduction of a lentiviral vector expressing precursors of short hairpin ribonucleic acid to Cav-1; isolation (by ultracentrifugation) and analysis (transmission electron microscopy, nanoparticle tracking analysis) of extracellular vesicles (EVs) from non-small cell lung cancer cells (NSCLC) H1299; analysis of proteins in cells and in EVs by immunoblotting.Results. Analysis of the effect of Cav-1 expression on the composition of EV proteins associated with exosome biogenesis revealed a decrease in the level of Alix and TSG101, an increase in the level of LR proteins and the absence of changes in the level of tetraspanin CD9. Conclusion. The obtained data demonstrate a Cav-1-dependent changes in the composition of EVs, indicating a change in the ratio of vesicles formed by the various molecular mechanisms.

Introduction. Currently, there are conflicting data regarding the effect of the c.470T> C germline mutation in the CHEK2 gene on increasing the risk of breast cancer (BC), so it is necessary to conduct research on large samples of patients, including in the Russian population, in order to analyze the contribution of this mutation to the risk of cancer developing.The aim of the study was to determine the frequency of occurrence of the genetic variant c.470Т>С in the CHEK2 gene in the Russian population in patients with BC and patients with benign breast diseases (BBD) to assess the possible effect of this deoxyribonucleic acid damage on the likelihood of cancer occurrence.Materials and methods. The study included 2,787 patients with BC and 1,004 patients with BBD who underwent examination and treatment at the Russian Scientific Center of Roentgenoradiology of the Ministry of the Russian Federation from 2010 to 2018. Molecular genetic study was carried out by real-time polymerase chain reaction to determine the characteristic of the Russian population hereditary genetic variant c.470Т>С in the CHEK2 gene using a diagnostic panel that allows to determine three germline mutations: c.1100delC, c.444+1G>A and c.470Т>С in the CHEK2 gene.Results. In patients with BC the frequency of the mutation c.470T>C in the CHEK2 gene was 3.8 %, in patients with BBD this mutation was detected in 4.7 % of cases. The frequency of the genetic variant c.470T>C in high-risk groups was: 5.1 % – for BC patients with clinical signs of hereditary disease and 4.9 % – for patients with BBD with a family history of cancer. There were no statistically significant differences between the frequency of the mutation c.470T>C in the general groups of BC patients and patients with BBD and the corresponding frequency in the high-risk groups, as well as in the groups of BC patients and patients with BBD (p >0.05).Conclusion. The results of this study indicate the probable absence of a relationship between the presence of the mutation c.470Т>С in the CHEK2 gene and an increased risk of BC.

Background. The search and use of new molecular prognostic and predictive markers of efficacy detected by liquid biopsy are aimed at understanding the biology of Carcinomas of Unknown Primary (CUP) and improving results of patient treatment. The review is devoted to advances in scientific and clinical research on this issue.Materials and methods. In order to assess the current state of the problem, a search and analysis of relevant data of the scientific databases PubMed, Medline, RISC was carried out.Results. The scientific rationale for the use of liquid biopsy in clinical practice to improve the treatment of cancer patients with CUP is presented. The results of the use of modern approaches to the analysis of fluid biopsy samples in CUP are presented. In particular, the features of using circulating free DNA, circulating tumor DNA, circulating tumor cells in the analysis are considered. The modern possibilities of determining tissue specificity using liquid biopsy in CUP are discussed. The prospects for the development of liquid biopsy for improving diagnostics, determining the prognosis of the disease, and choosing a strategy for treating CUP and the treatment monitoring have been determined.Conclusion. A review of the literature confirms that modern methods of molecular profiling of tumor cells obtained both as a result of liquid biopsy and tissue biopsies will make a significant contribution to the determination of tissue specificity, molecular characteristics of CUP for a personalized approach in order to improve strategies and treatment outcomes for patients with CUP.

Background.Retinoic acid (RA), by modulation of the transcription of a number of retinoid-responsive genes, is involved in the regulation of cell differentiation and proliferation. The mechanisms by which the RA-binding proteins, molecular chaperones CRABP1 and CRABP2 (Cellular Retinoic Acid Proteins-1 and -2), participate in the realization of RA activity, as well as their precise role in tumor progression are still not fully understood. Recent data indicate that functional differences of CRABP proteins with respect to malignization of breast cancer cells could be determined by different sensitivity of tumor cells to RA and with the receptor status of the tumor.Materials and methods.The CRABP1 coding sequence was overexpressed in breast cancer cells without endogenous expression of this protein, with different levels of RA sensitivity and receptor status – SKBR3 (RA-sensitive, ER(–) / HER2(+) cells) and MDA-MB-231 (RA-resistant, triple negative status). The growth of CRABP1(+) derivatives and control cells was evaluated under standard culture conditions and in the presence of various concentrations of RA.Results.The effect of CRABP1 expression in RA-sensitive and RA-resistant breast cancer cells with different receptor status on the growth rate and sensitivity of cells to RA was studied. The expression of CRABP1 in RA-sensitive SKBR3 cells enhances proliferation in the absence of RA and decreases the antiproliferative effect of RA, while in RA-resistant triple-negative MDA-MB-231 cells, the expression of CRABP1 does not affect the studied characteristics.Conclusion.CRABP1 stimulates growth and suppresses the RA-sensitivity of HER2(+) RA-sensitive cells, but does not have a similar effect on highly aggressive triple-negative RA-resistant cells.

The VHL gene alterations are the early and characteristic feature of clear cell renal cell carcinoma (ccRCC). We have examined VHL mutations in sporadic 98 ccRCC cases to evaluate their localization in relation to functionally important motifs of the VHL protein. The DNA samples were obtained from snap-frozen carcinoma biopsies and used for Sanger sequencing, while 62 ccRCC DNA cases were studied by next generation sequencing (NGS) analysis in parallel. In 73 (74.4 %) оf 98 ccRCC cases the somatic non-silent VHL mutations were identified. Loss of function VHL mutations (nonsilent, frameshifts or in splicing sites) were detected in 40 (40.8 %) ccRCC, while missense mutations – in 35 (35.7 %) ccRCC. In total 76 mutations important for VHL functioning were detected in 72 (73 %) ccRCC samples, of them 15 mutations (deletion / insertion in-frame or frameshifts) were identified for the first time. Four ccRCC cases contained two mutations each. Most of missense mutations disturb the sites of VHL interactions with HIF, РКС or kinesin. The pathogenicity of p.P154P silent mutation and intronic mutations near mRNA VHL splicing sites was discussed. The obtained results are important for understanding the role of VHL mutations in ccRCC progression and prognosis.

Background.Currently, little is known about the specific microRNAs involved in the development of cervical intraepithelial neoplasia(CIN1, 2, 3) and the transition to cancer in situ (CIS). Our meta-analysis allowed us to isolate 8 microRNAs (hsa-miR-1246, hsa-miR-145-5p, hsa-miR-196b-5p, hsa-miR-34a-5p, hsa-miR-20a-5p, hsa-miR-21-5p, hsa-miR-375-5p, hsa-miR-96-5p) with potential significance in the progression of precancerous diseases to cervical cancer.Objective:to analyze the expression features of hsa-miR-1246, hsa-miR-145-5p, hsa-miR-196b-5p, hsa-miR-34a-5p, hsa-miR-20a-5p,hsa-miR-21-5p, hsa-miR-375-5p, hsa-miR-96-5p and their target genes, as well as genes associated with them in common signaling pathways in the tissues of the cervix in patients with CIN1–3 and CIS.Materials and methods.To assess the expression level of microRNA and matrixRNA, the quantitative polymerase chain reaction in real time method was used. Data analysis was carried out in the Python programming language using the SciPy library. Search for target genes was performed using the TarPmiR algorithm and the overrepresentation of microRNAs in signaling pathways (Over-Representation Analysis) was analyzed. To identify genes associated with target genes in common signaling pathways, GIANT (Genome-scale Integrated Analysis of gene Networks in Tissues) and network integration with several associations algorithms were used.Results.For microRNAs miR-145, miR-196b, miR-34a, miR-20a, miR-21, miR-375 and miR-96 a decrease in expression was found in the subgroup of patients with CIS, while for 4 microRNAs (miR-145, miR-34a, miR-20a and miR-375), an increase in the expression level was found for CIN1, 2. The detected features of microRNA expression in subgroups of patients with CIN1–3 and CIS also affected the expression of their target genes (CDKN2A, MKI67, TOP2A and CD82), as well as the genes associated with them in common signaling pathways (PGK1, THBS4 (TSP4) and ECM1).Conclusion.Thus, the study revealed that each degree of CIN is characterized by its own specific molecular profile – the differential expression of microRNAs, their target genes and the genes associated with them in the general signaling pathways.

Background. The search for molecular markers of colon diseases allowing highly specific and sensitive identification and differentiation of pathological processes is a clinically important problem. Expression levels of genes responsible for proliferation can reflect the changes in the affected tissues. The study objective is to perform comparative analysis of molecular and genetic markers of proliferative activity in benign and malignant neoplasms of the colon. Materials and methods. Analysis of the changes in proliferation markers (CCND1, с-MYC, Ki-67, HER2neu, TERT) in adenocarcinoma of the colon (n = 259), resection margin (about 15–20 cm from the tumor lesion) (n = 251), unchanged colon mucosa from healthy donors (n = 247), polyps (n = 28), unchanged colon mucosa intestinal polyposis (10–15 cm from the polyp) (n = 75) was performed using RT-PCR. Results and conclusion. It was shown that morphologically unchanged tissue of intestinal mucosa in malignant tumors has significant differences from normal tissue of healthy donors. Significant differences in the level of expression of genes responsible for the processes of proliferation, с-MYC, CCND1, TERT were found in benign hyperproliferative diseases (polyps). Moreover, these changes were specific to the type of pathological process, which allows us to consider these genes as the most promising candidates in the development of a differential method for diagnosing colon diseases.

Autophagy and epithelial-to-mesenchymal transition (EMT) are the main biological processes involved in tumor progression, and are closely linked. On the one hand, activation of autophagy provides energy and essential nutrients for EMT during the metastases spreading, which is required for tumor cells survival in adverse environmental conditions. On the other hand, autophagy, acting as a tumor suppressor, tends to inhibit metastasis by selectively suppressing the transcription factors of EMT in the early stages. Therefore, inhibition of EMT by inhibitors or inducers of autophagy may be a new strategy for antitumor therapy. Thus, the aim of this review is to highlight current knowledge about the crosstalk between autophagy and EMT processes in tumor progression and to summarize data supporting the necessity of parallel regulation of two processes through signaling pathways.

In the treatment of breast cancer, the neoadjuvant chemotherapy is vitally important and the evaluation of its effectiveness is crucial for determining the further therapy treatment, as well as the prognosis of the disease. This review provides current data of the physical, instrumental, morphological, molecular biology and genetics analysis used for the estimation of the neoadjuvant treatment effectiveness. Thus, review discusses the data concerning association of the disease peculiarities with the efficient therapeutic response to neoadjuvant chemotherapy including characteristics of patients (age, status of regional lymph nodes, presence of the lymphovascular invasion) and tumors (size, histological type, degree of differentiation, severity of the lymphoid tumor infiltration, molecular biological and genetic peculiarities). Particular attention is paid to such a promising predictive marker of the breast cancer response to chemotherapy as the level of tissue hypoxia. This section discusses the currently known mechanisms that might enable the effect of tissue hypoxia on the sensitivity of the tumor to drug treatment. The prospects for the use of a comprehensive analysis of predictive markers of the effectiveness of chemotherapeutic treatment are discussed.

Background. One of the main reasons of the ineffectiveness of chemotherapy is still considered to be the formation of the multidrug resistance phenotype of the tumor due to the expression of energy-dependent proteins of ABC transporters. Our previous studies for some ABC genes have established that the expression of these genes correlates with the effectiveness of neoadjuvant chemotherapy (NAC). Some of the clinical studies indicate that ABC transporters can influence not only the formation of chemoresistance in the tumor, but also the progression, invasion and metastasis of the tumor node. Objective: to evaluate the level of transcription of all 49 known ABC genes in a breast tumor before and after treatment and their prognostic significance. Materials and methods. The study included 31 patients with a diagnosis of stage IIA – IIIB breast cancer. RNA was isolated from paired samples of tumor tissue before and after NAC. A microarray study of all tumor samples was performed on ClariomТМ S Assay, human microarrays. Using microarray studies, the expression of 49 genes of the ABC transporter family was studied. Analysis of the microchip data was carried out using the program Transcriptome Analysis Console (TAC) software 4.0. Results. It was found that changes in the expression (increase/decrease during NAC) of the ABCA5, ABCA7, ABCB1, ABCB4, ABCB11, ABCC1, ABCC10, ABCC11, ABCG1, ABCG2, ABCG4, ABCG5, ABCG8 genes are statistically significantly associated with the response to NAC. In addition, the prognostic significance of ABCB1 and ABCB4 gene expression was established. Survival analysis showed that 5-year survival rates in patients with high gene expression of ABCB1 and ABCB4 are lower compared to patients with low expression of these genes (log-rank-test p = 0.001 and 0.04 respectively). Conclusion. Data were obtained on the relationship of gene expression of the ABC transporter family with the effect of NAC in patients with breast cancer and the outcome of the disease. The prognostic potential of the ABCB1 and ABCB4 genes in patients with breast cancer has been established.

Glioblastoma multiforme (GBM), a grade IV astrocytoma, is the most common and deadly type of primary malignant brain tumor, with a patien’s median survival rate ranging from 12 to 15 months. Over the last fifteen years, the treatment for GBM has included maximal safe surgical resection with combination radiotherapy and adjuvant temozolomide chemotherapy. The low efficacy of mentioned therapies has forced researchers to explore an appropriate alternative or complementary treatment for GBM. It has been shown that curcumin has therapeutic potentials to fight against GBM via affecting on cell proliferation, apoptosis, cell cycle, invasion and angiogenesis pathways. In addition, curcumin possess a synergistic impact with chemotherapeutic agents. Herein, we summarized the current findings on curcumin as potential therapeutic agent in the treatment of GBM.

The current estimates of the contribution of the environmental contamination to cancer mortality range from 1 to 20 %, being a function of the ecological conditions, the density of industrial enterprises, occupational composition of the population, and others. Assessment of the impact of environmental contamination on cancer risk includes: •setting research priorities on the local, regional, and on the all-Russian levels; •the selection of the research that may be maximally socially profitable; •the choice of the research method that the most adequately meets the research objectives; •systemic analysis of the planed research to determine the availability of the resources, personnel, and information; •monitoring of atmospheric pollutions with analysis of the fraction composition of the particulate matters; •coordination of available data basis on environment and the population health conditions; •the implementation of the of molecular biology to determine prenosological manifestation of carcinogenesis and development of fine and diverse research methods on relationships between the environment and cancer risk.For effective implementation of the research objectives aimed to decrease the impact of hazard factors with special reference on cancer risk in the Russian population, it is necessary: to create training personnel capable of providing epidemiologic studies, using up-to day methods, publication of methodological materials, text books, and sufficient funding of studies.

Objective: to study the state of cellular immunity in patients with gastric adenocarcinoma.Materials and methods. From 2017 to 2018, 45 previously untreated patients with gastric adenocarcinoma (25 with stage I–III, 20 with stage IV) received surgical / combined treatment or independent chemotherapy, respectively, at the N. N. Blokhin National Medical ResearchCenter of Oncology. Peripheral blood sampling was carried out before starting treatment. We studied the cellular composition of peripheral blood, as well as systemic immunity parameters determined by flow cytometry (CD3+CD4+; CD3+CD8+; CD4+CD8+; CD4+/CD8+; CD3–CD16+CD56+; CD3–CD19+), and their prognostic significance in relation to overall survival and progression-free survival.Results. The prognostic value of the relative indicator of platelet lymphocytic index was determined: progression-free survival in patients with a high level of platelet-lymphocytic index (>208.7) was higher: 8.1 months versus 4.5 months (p = 0.0027). A favorable prognosis for overall survival was an increase in the number of CD3–CD19+ lymphocytes (hazard ratio (HR) 0.91; 95 % confidence interval (CI) 0.85–0.97; p = 0.007), and an unfavorable prognosis was an increase in the number of neutrophils (HR 1.26; 95 % CI 1.05–1.50; p = 0.012), platelet count (HR 1.01; 95 % CI 1.0–1.01; p = 0.043), as well as an increase in the number of NK cells (HR 1.04, 95 % CI 1.0–1.09; p = 0.029).Conclusion. Indicators of the cellular composition of peripheral blood, characterizing a systemic inflammatory reaction, as well as indicators of systemic immunity, can serve as additional prognostic factors for gastric cancer.

Background. Curaxin CBL0137 is a novel non-genotoxic compound with anti-cancer activity based on CBL0137 ability of non-covalent interaction with DNA causing histone chaperone FACT relocation. Anti-cancer activity of this drug was demonstrated previously on the wide panel of solid cancer models in vitro and in vivo.Objectives. Estimation of anticancer effects of CBL0137 on the acute myeloblastic leukemia cells (THP-1) and acute lymphoblastic leukemia (CCRF-CEM).Materials and methods. CBL0137 cytotoxicity was analyzed using the MTT test, the effects on the cell cycle and the induction of apoptosis was assessed by flow cytometry, the activity of signaling pathways in cells treated with CBL0137 was determined by real-time polymerase chain reaction.Results. Cell treatment with CBL0137 led to cell cycle arrest and apoptosis induction. In the study of CBL0137 effect on target gene clusters of 10 signal transduction pathways involved in the pathogenesis of acute leukemia we have showed that CBL0137 inhibited the expression of down-stream genes of WNT and Hedgehog signaling in both cell lines. In THP-1 cells we also observed the inhibition of the expression of PPARγ target and hypoxia-activated genes. In CCRF-CEM cells CBL0137 also induced the expression of Notch signaling target genes.Conclusion. The antitumor activity of CBL0137 was demonstrated on acute leukemia cell cultures, the drug possesses cytotoxicity, causes cell cycle arrest and activation of apoptosis. Significant changes in the expression of efferent gene clusters of several signaling pathways were observed in the cells treated with CBL0137.

Lynch syndrome is the most common cancer-prone syndrome associated with a high risk of colorectal cancer (CRC), neoplasms of the upper gastrointestinal system, the urinary tract, the female reproductive system, brain tumours and others. The only known form of hereditary endometrial cancer is also diagnosed as part of Lynch syndrome. One or more pathogenic germline mutations in one of the mismatch repair (MMR) genes are the cause of Lynch syndrome. Mapping of MMR genes and the discovery of microsatellite instability (MSI) have given rise to the possibility of using these clue characteristics of the pathogenic process for the elaboration of a screening test for Lynch syndrome. Being highly accurate and superior to all previously developed clinical criteria and guidelines, MSI-testing along with the assessment of the expression patterns of MMR proteins by immunohistochemistry has taken the leading role in the early diagnosis of Lynch syndrome. This article focuses on a brief review about the main evolutionary stages of clinical, anamnestic, molecular and genetic criteria for Lynch syndrome together with the results of our own research on the accuracy of the Amsterdam criteria, the Bethesda guidelines and MSI-diagnostics in the determination of the indications for MMR-genotyping in colorectal cancer patients suspected for Lynch syndrome.

Introduction. Cancer of the esophagus ranks sixth in mortality among malignant neoplastic diseases. To understand the molecular mechanisms of its progression, it is necessary to study not only tumor cells directly, but also cells of the microenvironment. In this work, we studied tumor-associated macrophages and their different phenotypes using membrane protein, indoleamine 2,3‑dioxygenase-1 (IDO1) as a marker for type 1 macrophages and macrophage scavenger receptor (CD204) as a marker for type 2 macrophages.The objective of this work was to study the expression of IDO1 and CD204 in tumors of squamous cell carcinoma of the esophagus and to assess its prognostic value.Materials and methods. The study included tumor samples obtained from 48 patients with squamous cell carcinoma of the esophagus. The expression of CD204 and IDO1 was assessed by immunohistochemistry. Survival analysis was carried out by constructing survival curves using the Kaplan–Meier method. Comparison of the significance of differences was performed using the logarithmic rank test. Differences were considered statistically significant at p Results. We analyzed the expression of CD204 and IDO1 in esophageal squamous cell carcinoma tumors. Expression of CD204 was detected in stromal macrophages in 100 % of cases and was not detected in tumor cells. We have shown that in esophageal cancer, IDO1 is expressed in both stromal and tumor cells. In tumor cells, the expression of IDO1 was found in 44 % of the samples, in stromal cells, IDO1 was expressed in 92 % of cases. No association with clinical and morphological characteristics was observed for CD204 in stromal cells and IDO1 in tumor cells. For IDO1 expressed in stromal cells, an association with the stage of the disease (p = 0.0450) and the presence of regional metastases (p = 0.0279) was observed. Survival analysis showed that CD204 is a marker of a favorable prognosis for esophageal cancer (hazard ratio 0.455, p = 0.0419).Conclusion. This study has shown that the expression of IDO1 in the tumor stroma is associated with more favorable clinical characteristics. It has also been shown that an increased content of CD204+ macrophages is a marker of a good prognosis for esophageal cancer.

Background. Leiomyosarcoma is one of the most common types of soft tissue sarcomas. Radical surgical resection with subsequent adjuvant chemotherapy remain the most effective treatment approach. Immunotherapy based on inhibition of PD-L1 (programmed death ligand 1) or its receptor PD1 (programmed death 1) is considered a promising treatment option. Level of PD-L1 expression in tumor cells and presence of microsatellite instability (МSI) could be considered prognostic and predictive markers of disease progression and effectiveness of immunotherapy.The study objective is to determine PD-L1 expression level and МSI status in patients with retroperitoneal leiomyosarcomas and evaluate their effect on overall and recurrence-free survival.Materials and methods. The study included 57 patients with retroperitoneal leiomyosarcomas who underwent surgical or combination treatment. Analysis of clinical and morphological characteristics was performed; results of surgical treatment were researched. Evaluation of PD-L1 expression and MSI status was performed using immunohistochemical and molecular genetic analysis.Results. PD-L1 expression and MSI status were evaluated in 41 patients of 57. In 10 (24 %) of 41 cases, positive PD-L1 expression was observed (expression level 3–50 %). In 1 (2.4 %) patient, the primary tumor and metastatic lesion had low MSI level (MSI-low, MSI-L). Median follow-up was 31 months. In patients with positive PD-L1 expression, higher Ki-67 proliferative index was observed compared to patients with PD-L1 negative tumors (58.8 and 47.8 % respectively; р = 0.02), as well as significantly lower median overall survival for grade II tumors (30 and 105 months; p = 0.043). In grade III leiomyosarcomas, a trend towards lower median overall survival in patients with PD-L1‑negative tumors (31.0 months) compared to patients with PD-L1 expression (61.2 months) (р = 0.11) was observed.Conclusion. Among patients with retroperitoneal leiomyosarcomas, positive expression of PD-L1 was observed in 24 % (10 / 41) of cases and MSI-low status was found in 2.4 % (1 / 41) of cases. In patients with grade 2 tumors, positive PD-L1 expression is associated with significantly lower overall survival. PD-L1 expression in patients with retroperitoneal leiomyosarcomas could be considered a prognostic marker and a potential therapeutic target.

Lynch syndrome was synonymous with hereditary non-polyposis colorectal cancer for a long time, however, mapping of the DNA mismatch repair (MMR) genes has led to distinguish Lynch syndrome as an independent syndromic unit from a number of Lynch-like syndromes that phenotypically mimic with the most frequent hereditary variant of colon cancer but genetically representing quite a heterogeneous group. This article presents up to date clinical and genetic characteristics of Lynch syndrome and Lynch-like conditions.

Low grade gliomas are the most common brain tumors in children. Total resection for operable lesion helps to achieve local and system control. Nevertheless, for inaccessible tumors are required more effective treatment both to overcome the refractory course of the disease, and to mi nimize toxicity with conventional adjuvant chemotherapy and various types of radiation therapy. In recent years, there has been an accelerated understanding of the molecular pathogenesis of some tumors in children, including low grade gliomas. Given the fact that the basis of the molecular pathogenesis of the low grade gliomas is the activation of signaling pathways MARK (mitogen activated protein kinase) and mTOR (mammalian target of rapamycin), the most promising targeted agents are BRAF, MEK and mTOR inhibitors. Nevertheless, a number of other agents have been studied to find promising targeted therapy for this tumors type. This article summarizes the latest literature evaluating new drugs in low grade glioma.

Background. Nowadays, BRCA-associated breast cancer occupies a special position in the choice of treatment strategy. Although, the drug treatment of such patients was almost the same as the treatment of sporadic disease. Of particular interest is the assessment of the deficit of homologous recombination, which may include various dysfunctions of the BRCA1 gene. Moreover, it has been shown that a decrease in the functional activity of BRCA1 is reflected in the sensitivity of the tumor to DNA damaging agents, and the prognosis of the disease becomes more favorable.Objective: assessment of the association of BRCA1 gene expression in a breast tumor with the prognosis of the disease.Materials and methods. The study included 111 patients with breast cancer T1–4N0–3M0 (stage IIA–IIIB), with a morphologically verified diagnosis. Initial and postoperative expression of BRCA1 in tumor material was evaluated. RNA was isolated from the tumor material before treatment and after neoadjuvant chemotherapy. The level of BRCA1 expression was assessed using reverse transcriptase quantitative real-time polymerase chain reaction.Results. As a result of the study, long-term results of treatment of patients were evaluated depending on the level of BRCA1 gene expression. The presence of BRCA1 hypoexpression (level less than 1) in tumor tissue after neoadjuvant chemotherapy was found to be a favorable prognostic factor and is associated with high rates of metastasis-free survival (p = 0.0002). In addition, a similar result is shown for patients treated with the FAC (fluorouracil, doxorubicin, cyclophosphamide) neoadjuvant chemotherapy regimen (p = 0.005). Despite the absence of statistically significant differences, in 8 patients who underwent chemotherapy with the inclusion of platinum drugs, there was a low level of BRCA1 expression in a residual tumor and 100 % non-metastatic and overall survival.Conclusion. Based on the data obtained, it can be assumed that the aberrant state of the BRCA1 gene (low expression) in a breast tumor may also be a promising marker for the prognosis of the disease, which confirms the undoubted relevance of the study, but also requires further detailed study.

Background. The correct genome replication is essential for normal cell division to guarantee that genetic information comes changeless through the next cells generations. DNA replication is a strictly regulated and synchronous process and its disturbances could result to mutations appearances. Aberrant time of DNA replication affects on gene expression causes changes of epigenetic modifications and influences on increasing the structural rearrangements leading to enhanced genome disbalance. Replication time failure as asynchronous replication is common for cancerogeneses. The objective of our study was the assessment of asynchronous replication levels in patients with gastric cancer and patients with multiple tumors.Materials and methods. Fluorescence in situ hybridization (FISH) was used for the asynchronous replication of AURKA and TP53 genes analyses. Interphase FISH on lymphocytes of peripheral blood of 37 healthy donors, 19 patients with non-cancer gastrointestinal pathologies, 68 patients with solitary gastric cancer and 39 patients with multiple tumors having gastric cancer and other second synchronous or metachronous tumor was carried out.Results. Values of lymphocytes with asynchronous replication for AURKA were 19.8 ± 0.5 % for control group, 24.7 ± 0.4 % for non-cancer patients, 32.5 ± 0.5 % for gastric cancer patients, 39.5 ± 0.6 % for patients with multiple tumors and 17.3 ± 0.5, 19.5 ± 0.7, 26.1 ± 0.7 and 32.5 ± 0.6 % for TP53 respectively. Differences between cell populations of examined groups had statistical significance with p Conclusion. High lymphocytes with asynchronous replication level in oncological patients could serve as potential marker of second tumor or possible metastatic process including the earliest stage of it.

The review analyzes literature data and the results of our own research on the role of reactive nitrogen species (NO, NO 2 , N 2 O 3 ) in the initiation and progression of tumors. The possibility of modulating the activity of inducible NO synthase by the biologically active components of plant products and their effect on carcinogenesis is analyzed. Possible mechanisms of the ambiguous action of NO and its metabolic products in the mechanisms of carcinogenesis are discussed. The generalization and analysis of these data allowed us to formulate some principles for the use of substances that modulate the activity of inducible NO synthase and affect the formation of NO and its metabolic products in inhibiting carcinogenesis.

The modern concept of therapy for intrahepatic cholangiocarcinoma including surgical treatment, must take into account the achievements of molecular biology and modern staging principles. A detailed understanding of the molecular genetic (genetic and epigenetic) disorders underlying the pathogenesis of cholangiocarcinoma is important, which will improve the results of surgical treatment and expand the possibilities of personalized (targeted) therapy. Based on new data on cholangiocarcinogenesis, molecular profiling of bile duct tumors may be most appropriate for the selection of treatment in cases refractory to standard therapy. Current potential target therapy targets include endothelial growth factor receptors, fibroblast growth factor, MET tyrosine kinase, PI3K/Akt/mTOR signaling pathway and isocitrate dehydrogenase mutation. The review considers the molecular-genetic aspects underlying the pathogenesis and modern principles of staging intrahepatic cholangiocarcinoma.

Background . Worldwide, more than 300,000 women are diagnosed with uterine cancer each year. Currently, the problem of finding highly specific molecular tumor markers for this disease remains relevant. Screening for gene expression of transcription factors responsible for controlling the differentiation of cells of endometrial tissues may allow the formation of a tumor markers panel and explore the fundamental mechanisms of oncotransformation. Objective of our study was to analyze changes in the expression of transcription factors OCT4, SOX2 and C-MYC in the tissues of the uterus (corpus uteri) during the process of their malignancy. Materials and methods . Uterus tissue biopsy specimens of 45 patients (tumor and non-tumor) were used for the study. To determine the relative expression of 3 genetic loci encoding the transcription factors OCT4, SOX2 and C-MYC the real-time polymerase chain reaction method, ACTB was used as the reference gene. Results . A change of OCT4, SOX2 and C-MYC genes transcriptional activity in uterus tumor cells is found as the tumor develops. By reducing the tumor cells differentiation degree expression of OCT4 gene increases most significantly, that confirmsits status of undifferentiated cellsmarker. As the differentiation degree of tumor cells decreases, OCT4, SOX2 and C-MYC genes expression change affects the adjacent conditionally normal tissue of the uterus, but with less intensity, especially in the later stages of malignancy. Conclusion . The obtained data makes it possible to use the OCT4, SOX2 and C-MYC genes as differential markers of the tumor process development, and the SOX2 gene expression as a predictive marker of malignancy.

The expected effect of androgen-deprivation therapy is one of the important criteria when choosing therapy in patients with prostate cancer. No less significant factor is the time of its implementation. The study showed that high expression of androgen receptors (AR) in the tumor tissue against the background of low estrogen receptor α (ER α ) expression is characteristic of patients in whom the effect of androgen-deprivation therapy was observed for 12 months. A set of parameters has been identified that makes it possible to predict the duration of response to androgen-deprivation therapy in patients with prostate cancer, which include the patient’s age, testosterone level, prostate specific antigen, expression level of AR, ER α . These data allow us to consider these parameters as additional informative markers, to predict not only the expected effect, but also its duration.

Background . In our work, we investigated the role of ABC transporters and the transcription factor YB-1 protein in the formation of drug resistance to the proteasome inhibitor bortezomib in multiple myeloma. Materials and methods . We used the RPMI8226 and NCI-H929 cultures and their bortezomib-resistant sublines as models. Results . Two major ABC transporter proteins, P-glycoprotein and MRP1, are not involved in the emergence of resistance to bortezomib, moreover, bortezomib contributed to decrease of these genes expression. Expression of the MVP gene was increased only in the resistant RPMI8226/btz-6 variant, but not in H929/btz-6. The localization of the YB-1 protein, a transcription factor for the MDR1, MRP1 and MVP genes, changed only in RPMI8226/btz-6 cells, as well, it became diffuse in 20 % of the cells as compared to 7 % of the cells in the RPMI8226 parent line. The only ABC transporter gene, activated in both RPMI8226/btz-6 and H929/btz-6 sublines, was BCRP. С ross-resistance to doxorubicin is also shown for these sublines. Conclusion . Thus, the activation of ABC transporters is not a key mechanism for the formation of bortezomib drug resistance. MVP protein may play certain role, and an increase in the BCRP expression explains the emergence of resistance to doxorubicin, but not to bortezomib, since the latter is not a substrate of BCRP.

Тhe protein TRIM16 is involved in key intracellular processes, such as proliferation, cell differentiation and programmed death, including intrinsic and extrinsic apoptosis, autophagy-dependent cell death and immunogenic cell death. The TRIM16 protein acts the proteins TPD43, Gli-1, RARβ, Snail components and MAPK signaling pathway, cadherins, caspases and is also associated with the regulation of the immune system via direct and indirect mechanisms. The influence of TRIM16 protein on the pathogenesis of hormone-dependent tumors is well-known. Further study of the TRIM16 role in the development and progression of malignant neoplasms will form the basis for the development of new methods for predicting the course of the malignant process.

Macrophages are the key cells of the innate immune system. One of the main functions of macrophages is the regulation of inflammation. Being common in all tissues and organs of the human body, tissue macrophages control their condition and guarantee a timely and effective response to damage, pathogen penetration or cell transformation. After eliminating the cause of inflammation, macrophages initiate the processes of healing and restoration of tissue homeostasis. At the end of the 20thcentury, the concept of macrophage activation dichotomy was proposed, which divided them into classically (M1) and alternatively (M2) activated ones. The development of this concept has led to the description of a wide variety of macrophage phenotypes. At the same time, M2 continues to be considered a prototype of tumor associated macrophages (TAM).TAM represent one of the most important cell types in the tumor microenvironment. Like all macrophages, they have a certain level of heterogeneity and plasticity, which develop under the influence of cytokines and growth factors produced by tumor cells. TAM, in turn, produces growth factors, cytokines and extracellular matrix components that support the progression of the tumor and increase its malignant potential. Numerous clinical studies have shown that the amount of TAM is often correlated with a poor prognosis of the disease. TAM perform a large number of functions necessary to maintain tumor progression. They are capable of stimulating angiogenesis and reorganization of the vascular system. Since the role of TAM in tumor development has become apparent, various attempts have been made to use them in the clinic. It can be confidently asserted that various TAM markers are very attractive as diagnostic and prognostic markers of various tumors, and also as promising targets for the development of new targeted therapeutic agents.

The objectiveis to evaluate the level of ADAM10 and ADAM17 (a disintegrin and metalloproteinase) proteases, as well as 20S-proteasomes in blood plasma exosomes of patients with colorectal cancer.Materials and methods. The study included 60 patients with colorectal cancer (T2–4N0–2M0–1) and 10 control patients. The material for the study was EDTA blood plasma. Exosomes of blood plasma were isolated by ultrafiltration with ultracentrifugation. The level of tetraspanin-associated (ADAM10 and ADAM17) and tetraspanin-non-associated (20S-proteasome) proteases was evaluated by flow cytometry and Western blotting.Results.A twice negative subpopulation (ADAM10–/ADAM17–) predominated in blood plasma exosomes of colorectal cancer patients and control patients. The level of ADAM10+/ADAM17– exosomes was significantly higher in the exosomes of the plasma of control patients. There were no significant differences between the ADAM10/ADAM17 subpopulations and the 20S-proteasome level, depending on sex, age and tumor grade. A decrease in the ADAM10+/ADAM17– subpopulation was found in patients with metastatic colorectal cancer with hematogenous metastases compared with patients with T2–4N1–2M0 and 20S-proteasome compared to T2–4N0M0. A decrease in ADAM10–/ ADAM17+ exosomes and 20S-proteasomes level was found in exosomes of patients with colorectal cancer with a metabolic syndrome in comparison with patients without metabolic disorders.

Background.Overexpression of the human papillomavirus oncogenes E6 and E7 is a major factor in initiation and progression of HPV-induced tumors. Inactivation of negative regulatory function of E2 protein – the main viral transcription and replication regulator – is considered to be an important mechanism leading to the viral oncogenes overexpression. It is known that the loss of E2 functions occurs due to disruption of E2 open reading frame during the viral DNA integration into a cell genome in a part of HPV-positive tumors. An alternative mechanism of E2 function blocking in tumors retained its expression can be methylation of the HPV regulatory region, since it is known that E2 is incapable to bind its methylated binding sites.The study objectiveis to analyze methylation of the HPV16 regulatory region and expression of the viral E6 and E7 oncogenes in E2 expressing or non-expressing clinical samples of cervical cancer.Results.It has been demonstrated that the level of the HPV16 URR methylation in E2-expressing lesions is significantly higher than that in non-expressing cervical cancer lesions. Demethylation of the HPV16 promoter in cervical cell line Caski is followed by decrease of the viral E6 и E7 oncogenes mRNA levels, supporting the hypothesis that methylation is necessary for effective E6 and E7 transcription and indicates on restitution of E2 regulatory function in E2-expressing cervical cancer cells.Conclusion.These data suggest that methylation of E2 binding sites in HPV16 regulatory region blocking E2 protein binding represents an important mechanism ensuring high level of the viral E6 and E7 oncogenes expression.

Neuroendocrine neoplasms (NENs) are a heterogeneous group of rare epithelial tumors that arise from cells with a neuroendocrine phenotype. NENs are found in the gastrointestinal tract and pancreas – 60 % of all localities. The incidence of gastric NENs is about 9 % of all neuroendocrine tumors of the gastrointestinal tract and 0.3 % of all stomach tumors. Stomach neuroendocrine tumors (NETs) are classified into three clinico-pathological types, based on etiology, pathogenesis and morphology. There are also separate neuroendocrine cancers: small- and large-cell. The prognosis and approach to treatment of various types of gastric NENs differs significantly. Modern methods of instrumental diagnostics, immunohistochemical methods of morphological research, along with light microscopy, do not always allow us to accurately assess the malignant potential of a tumor and individualize the treatment process. One of the promising directions in the study of NETs is to determine the molecular mechanism underlying their development, in particular the role of microRNAs. This direction can open a new vector of understanding the pathogenesis, determining the prognosis of the disease, as well as finding new application points for the drug treatment of NETs. MicroRNAs are a class of short non-coding RNA molecules (18–25 nucleotides). MicroRNAs can be involved in the regulation of all major cellular processes, including proliferation and differentiation, metabolism, signaling pathways, and apoptosis. A study of microRNA expression in tissues revealed tumor-specific microRNAs. In contrast to a number of other malignant tumors, microRNA expression in patients diagnosed with NENs is poorly understood. MicroRNA-222 and microRNA-202 are among the few microRNAs that have been demonstrated in the NETs of the stomach.

Цель исследования: изучение влияния донора газотрансмиттера (ГТ) сероводорода (NaНS) и активатора его внутриклеточного синтеза (Lцистеина) на микрореологические характеристики эритроцитов в норме и при сахарном диабете 2-го типа (СД2). Материалы и методы. Эритроциты 16 здоровых лиц и 16 больных СД2 инкубировали с донором сероводорода гидросульфидом натрия (NaHS) в концентрации 10, 50 и 100 мкмоль и стимулятором его эндогенного синтеза Lцистеином в концентрации 10, 50 и 100 мкмоль. Блокировали АТФзависимые калиевые каналы глибенкламидом (50 мкмоль). Ингибировали растворимую гуанилатциклазу с помощью 0,5 мкмоль ODQ (1H-1,2,4-oxadiazolo4,3-a quinoxalin-l-one). Регистрировали деформируемость (ИУЭ) и агрегацию эритроцитов. Результаты. Под влиянием NaHS наблюдали дозозависимые положительные изменения микрореологии эритроцитов. Микрореологические ответы эритроцитов на NaHS были более выраженными у здоровых лиц, чем у больных СД2. Сходную картину наблюдали и при воздействии на эритроциты Lцистеином. Прединкубация с глибенкламидом не устраняла положительного влияния донора ГТ на микрореологию эритроцитов, тогда как ингибирование растворимой гуанилатциклазы с помощью ODQ полностью устраняло положительные изменения ИУЭ под действием ГТ и существенно уменьшало его влияние на агрегацию клеток. Заключение. Таким образом, сероводород как газотрансмиттер улучшает микрореологию эритроцитов. При одинаковой концентрации донора сероводорода (NaHS) и стимулятора его синтеза (Lцистеина) более выраженные сдвиги микрореологических параметров эритроцитов наблюдаются у здоровых лиц по сравнению с больными СД2., Aim: to study the effect of donor gasotransmitter (GT) hydrogen sulphide (NaHS) and the activator of its intracellular synthesis (Lcysteine) on the red blood cells (RBCs) microrheological characteristics in normal and diabetes mellitus type 2 (DM2). Materials and methods. RBCs of 16 healthy individuals and 16 patients with DM2 were incubated with hydrogen sulfide donor sodium hydrosulfide (NaHS) in concentrations of 10, 50 and 100 mol and a stimulator of its endogenous synthesis Lcysteine (10, 50 and 100 mol). ATPdependent potassium channels were blocked by glibenclamide (50 mol). Soluble guanylate cyclase was inhibited using 0.5 mol ODQ (1H-1,2,4-oxadiazolo4,3-a quinoxalin-l-one). Deformability (RBCD) and RBCs aggregation were recorded. Results. Under the influence of NaHS, dose-dependent positive changes in RBCs microrheology were observed. Cellular microrheological responses to GT donor were more pronounced in healthy individuals than in patients with DM2. A similar pattern was observed when RBCs were exposed to Lcysteine. Preincubation with glibenclamide did not eliminate the positive effect of GT donor on RBCs microrheology. Whereas inhibition of soluble guanylate cyclase with the help of ODQ completely eliminated positive changes in RBCD under the action of GT and significantly reduced its effect on aggregation. Conclusion. Thus, hydrogen sulfide as a gasotransmitter improves RBCs microrheology. With the same concentration of hydrogen sulphide donor (NaHS) and its synthesis stimulator (Lcysteine), more pronounced shifts in the microrheological parameters of erythrocytes are observed in healthy individuals as compared with DM2 patients., №1(81) (2020)

Введение. Ранее, по данным теста генерации тромбина (ТГТ), нами было показано, что группа больных остеоартрозом (ОА) крупных суставов неоднородна по реакции адаптации системы гемокоагуляции. Учитывая, что ОА сопряжен с воспалением, интерес представляет взаимосвязь активности воспалительной реакции с характером адаптационного ответа системы гемокоагуляции. Цель исследования: выявить корреляционные связи между параметрами ТГТ, показателями коагулограммы и маркерами воспаления у пациентов с ОА тазобедренных и коленных суставов с отсутствием или наличием клинически манифестирующего воспаления. Материалы и методы. Состояние системы гемостаза исследовали у 141 пациента с ОА крупных суставов. По результатам ТГТ больные были разделены на 2 группы: 1я группа пациенты с адекватной реакцией адаптации 2я группа пациенты с напряженной реакцией адаптации. О состоянии системы гемокоагуляции судили по локальным тестам скрининговой коагулограммы и интегральному тесту ТГТ. Активность воспалительного процесса оценивали по содержанию фибриногена и С-реактивного белка (СРБ). Результаты. Методом корреляционного анализа показано наличие связей между параметрами ТГТ и продуктами деградации фибрина у больных ОА в 1й группе, а во 2й группе между показателями ТГТ и воспалительными маркерами. При распределении пациентов 2й группы на 2 подгруппы по клиническому признаку оказалось, что в 2а подгруппе (больные ОА), также как и в 1й группе больных, большое число корреляций отражает связь между параметрами ТГТ и Д-димерами, а в подгруппе 2б (больные с перипротезной инфекцией) между параметрами ТГТ и СРБ, что указывает на различный механизм формирования адаптационной реакции. Заключение. Полученные данные свидетельствуют о различных механизмах процесса адаптации системы гемостаза в зависимости от активности воспалительного процесса., Introduction. Earlier we run thrombin generation assay (TGA) and proved that the group of patients with osteoarthritis (OA) of large joints is heterogeneous by their coagulation adaptation response. OA is associated with inflammation so the relationship between inflammatory activity and hemocoagulation adaptive response is of interest. Aim: to identify correlations between TGA parameters, coagulogram parameters and inflammation markers in patients with OA of hip and knee joints with absence or presence of clinically manifesting inflammation. Materials and methods. We studied hemostasis in 141 patients with OA of large joints. According to TGA results the patients were divided into 2 groups: 1st group patients with adequate adaptation reaction 2nd group with a strained adaptation reaction. Hemocoagulation was evaluated using local screening coagulogram tests and TGA. The activity of inflammatory process was assessed by fibrinogen and C-reactive protein (CRP). Results. Correlation analysis showed links between TGA parameters and fibrin degradation products in patients with OA in the 1st group (adequate adaptation response), and between TGA parameters and inflammatory markers in the 2nd group (stress adaptation reaction). Patients of the 2nd group were divided into 2 subgroups according to clinical signs. In subgroup 2a (patients with OA) as well as in the 1st group, a lot of correlations reflect the relationships between parameters of TGT and D-dimers, and in subgroup 2b (patients with periprosthetic infection) between parameters of TGT and CRP. This points to a different mechanism for the formation of adaptive reaction. Conclusion. The obtained data indicate about different hemostatic adaptation mechanisms depending on the inflammatory activity., №1(81) (2020)

Введение. Тромбоз остается одной из ведущих причин летальности населения. В связи с этим остро стоит вопрос своевременной диагностики причин и анализа провоцирующих факторов возникновения тромботических событий, в особенности у детей с генетически детерминированной тромбофилией. Цель описания клинического случая: демонстрация роли мультифакторности генеза тромбоза в сочетании с патологическими состояниями, усиливающими гемостатическую активность крови в детском возрасте, для дальнейшего прогнозирования развития ребенка и определения методов профилактики рецидивов тромботических осложнений во взрослом возрасте. Результаты. Мальчик А., в возрасте 7 лет перенес острое нарушение мозгового кровообращения по ишемическому типу от 25.08.16, которому предшествовала ревакцинация корь-паротит-краснуха , острый гастроэнтерит с эксикозом II степени, токсикозом и длительным периодом иммобилизации в течение 2 нед. На момент тромботического события установлена гипергомоцистеинемия (10 мкмоль/л при референсных значениях возрастной нормы 3,05,0 мкмоль/л). При выполнении молекулярно-генетического исследования выявлено 5 гетерозиготных полиморфизмов минорного риска тромбоза (MTHFR, MTRR, PAI1, FGB, ITGA22). На момент последней госпитализации (февраль 2019 г.) обнаружено снижение эффективности работы системы естественных антикоагулянтов по результатам теста генерации тромбина, а также умеренное снижение активности антикоагулянта протеина С до 74 (при нижней границе нормы 75). Заключение. Мультифакторность тромбоза у детей предусматривает комплексный подход к диагностике и лечению, а также профилактике рецидивов тромботического события с обязательным контролем в динамике состояния системы гемостаза, уровня естественных антикоагулянтов и гомоцистеина., Introduction. Thrombosis remains one of the leading causes of mortality in the population. Thereby the timely diagnosis and analysis of the triggering factors of thrombotic events, especially in cases of genetically determined thrombophilia in children is acute question. Aim: to demonstrate the role of the multifactor genesis of thrombosis in combination with pathological conditions that enhanced blood hemostatic activity in childhood, for further prediction and prophylaxis of recurrence of thrombotic events in adulthood. Results. Patient A. had an ischemic stroke when he was 7 years old. It was preceded by rubeola-parotitis-rubella revaccination, acute gastroenteritis with degree II excision, toxicosis and a long period of immobilization for 2 weeks. Hyperhomocysteinemia was revealed (10 mol/L, reference values of the age norm are 3.05.0 mol/L) at the time of the thrombotic event. Molecular genetics study identified 5 heterozygous polymorphisms of a minor risk of thrombosis (MTHFR, MTRR, PAI1, FGB, ITGA22). At the date of last hospitalization (February 2019) decreased efficiency of anticoagulant system (according to the results of the thrombin generation assay) and moderate decreasing of protein C activity to 74 (with a lower normal limit of 75) were found. Conclusion. The multifactorial nature of thrombosis in children provides an integrated approach to the diagnosis, treatment and prophylaxis of recurrence of thrombotic events with monitoring of hemostasis, levels of natural anticoagulants and homocysteine., №1(81) (2020)

Введение. Эндовенозная термическая абляция (ЭТА) поверхностных вен, включая лазерную абляцию или радиочастотную абляцию, широко применяется в лечении варикозной болезни нижних конечностей. Учитывая высокую частоту встречаемости варикозной болезни, частоту венозных тромбоэмболических осложнений (ВТЭО) после данного вмешательства, логично предположить, что выполнение ЭТА увеличит риск возникновения послеоперационного венозного тромбоза у онкологических больных. Существует недостаток данных о частоте ВТЭО в онкохирургии при ЭТА в анамнезе. Цель исследования: оценить влияние ранее проведенной ЭТА поверхностных вен нижних конечностей на послеоперационные ВТЭО в онкохирургии. Материалы и методы. Одноцентровое исследование с ретроспективным анализом онкологических больных на хирургическом этапе лечения злокачественных опухолей абдоминальной, гинекологической или урологической локализации проведено с мая 2013 г. по ноябрь 2018 г. В исследование были включены 36 пациентов, перенесших ЭТА более 3 мес назад (319 мес). Ультразвуковое дуплексное исследование вен нижних конечностей проводили перед операцией (за 110 дней) по поводу онкологического заболевания всем пациентам. Полная облитерация ствола большой подкожной вены (БПкВ) обнаружена в 66,7 случаев (n 24), реканализация в 33,3 (n 12). Все пациенты получали стандартную антикоагулянтную профилактику (надропарин по 0,4 мл/сут подкожно). Проведен морфологический анализ 3 случаев послеоперационного венозного тромбоза. Результаты. ВТЭО возникли в 20,8 (n 5) случаев при полной облитерации БПкВ, в 66,7 (n 8) с реканализацией ствола (95 ДИ 1,37,7) в послеоперационном периоде. Реканализация вены увеличила частоту развития послеоперационного венозного тромбоза в 3,2 раза. Заключение. ВТЭО часто возникают после неполной облитерации при ЭТА в отдаленном периоде при наличии дополнительных факторов риска. Учитывая широкое распространение данного типа операций во флебологии и возможность серьезных осложнений, необходимы дальнейшие исследования частоты венозного тромбоза при ЭТА в анамнезе у онкологических больных и определение стратегии профилактики ВТЭО., Introduction. Endovenous thermal ablation of saphenous vein (EVTA SV) including laser ablation or radiofrequency ablation widely used in varicose veins treatment of the lower extremities. EVTA SV can increase the risk of postoperative venous thrombosis in cancer patients. There is a deficiency of data examining rates of thrombotic events (VTE) in oncological patients. Aim: to assess influence of previously performed EVTA SV on postoperative VTE in oncosurgery. Materials and methods. This was a single centre study with retrospective analysis of consecutive oncological patients who underwent abdominal, gynecological or urological surgery from May 2013 to November 2018. 36 patients were included who underwent EVTA SV more than 3 month ago (319 months). Duplex ultrasound (DUS) was performed before oncological surgery (110 days). Complete SV obliteration was found in 66.7 of cases (n 24), recanalization in 33.3 (n 12). All patients had standard anticoagulant prophylaxis nadroparin 0.4 ml per day. We performed a morphologic analysis of 3 VTE cases. Results. Thrombotic complications occurred in 20.8 (n 5) of cases with complete SV obliteration, in 66.7 (n 8) with recanalization (95 CI 1.37.7). Recanalization of SV increased rate of postoperative cancer-associated VTE in 3.2 times. Conclusion. Thrombotic events occur frequently following incomplete obliteration after procedures EVTA SV. Taken account of the high rate of this procedures and the potential for serious consequences, further research is needed on VTE сomplications in oncology and their management., №1(81) (2020)

Нарастающая распространенность ишемического инсульта (ИИ) ставит перед исследователями новые задачи в обеспечении прогнозирования и диагностики. Одной из альтернатив традиционным методам диагностики ИИ является гемореология. Это относительно недорогие методы в применении, не требующие дорогостоящих расходных материалов. В русскоязычной литературе методам гемореологии уделено мало внимания. В статье представлен подробный обзор публикаций по гемореологии ИИ. Освещены работы по характеристике реологических нарушений, встречающихся у пациентов с це- ребральной ишемией, с рентгенологическими признаками патологии церебральных сосудов. Приведены данные о показателях ухудшения текучести крови, включающие повышение вязкости плазмы, нарушение деформируемости и агрегации эритроцитов, которые наблюдается задолго до манифестации ИИ, а также являются факторами риска развития стойкого неврологического ухудшения во время госпитализации после острого ИИ и увеличения срока госпитализации. Очерчен круг клинических ситуаций ИИ, в которых реологические методы получили применение при оценке эффективности терапевтических стратегий (тромболизиса, гемодилюции, афереза, медикаментозной коррекции)., The increasing prevalence of ischemic stroke (IS) poses new challenges for researchers in providing prognosis and diagnosis. Hemorheological methods is one of the alternatives to the traditional methods for IS diagnosis they are relatively inexpensive and do not require expensive consumables. In Russian-language literature little attention is paid to hemorheological methods. The article presents a detailed review about hemorheology in IS, characteristics of rheological disorders that occur in patients with cerebral ischemia, with radiological signs of cerebral vascular pathology. The data are presented about disturbances of blood fluidity, including increased plasma viscosity, impaired deformability and aggregation of red blood cells that are observed long before IS manifestation, and are the risk factors for persistent neurological aggravation during hospitalization after acute IS and increase the period of hospitalization. Clinical IS situations are described, in which rheological methods have been used for assessing the effectiveness of therapeutic strategies (thrombolysis, hemodilution, apheresis, drug correction)., №1(81) (2020)

Введение. Влияние стандартной и альтернативных схем антикоагулянтной терапии на степень и скорость реканализации глубоких вен привлекает внимание современных исследователей. Цель исследования: сравнение эффективности терапии тромбоза глубоких вен (ТГВ) нижних конечностей варфарином и ривароксабаном в отдаленном периоде. Материалы и методы. В исследование включено 94 пациента с ТГВ нижних конечностей, которые были разделены на 2 группы в зависимости от назначенной схемы лечения. Средний возраст 50 пациентов группы 1 составил 44,0 12,6 лет, 44 больных группы 2 39,5 11,7 лет. Пациентам группы 1 был назначен варфарин, группы 2 ривароксабан в течение 6 мес после выписки. Конечная точка наблюдения 4 года. Результаты. Прием антикоагулянта ранее установленного срока прекратили 18 (36) пациентов из группы 1 и 2 (4,5) пациента из группы 2. Режим эластической компрессии в обеих группах пациенты соблюдали нерегулярно. Рецидив венозных тромбоэмболических осложнений в группе 1 отмечен в 11 (22) случаях, в группе 2 у 7 (15,9) пациентов. Отрицательная динамика ультразвукового обследования складывалась у пациентов обеих групп: у 16 пациентов группы 1 и у 9,1 группы 2 появились признаки поражения ранее неизмененных вен или окклюзия ранее проходимой вены после перенесенного тромбоза без клиники острого венозного тромбоза в анамнезе. Трофические расстройства отмечены у одного пациента группы 2 и у 1/3 пациентов группы 1 к четвертому году наблюдения. Значимые отличия между группами были получены по таким параметрам, как приверженность к лечению и степень тяжести венозной недостаточности, оцениваемая клинически, в пользу ривароксабана. Заключение. Неудовлетворительные результаты лечения при использовании стандартной схемы терапии ТГВ требуют назначения препаратов из группы новых оральных антикоагулянтов с возможным внедрением схемы профилактического приема., Introduction. Effect of standard and alternative anticoagulant therapy regimens on the degree and rapidity of deep vein recanalization attracts the attention of modern researchers. Aim: to compare the treatment effectiveness of deep vein thrombosis (DVT) of lower limbs with warfarin and rivaroxaban in the long-term period. Materials and methods. The study included 94 patients with DVT of lower limbs they were divided into 2 groups depending on the prescribed treatment regimen. The average age of 50 patients of group 1 was 44.0 12.6 years, 44 patients of group 2 39.5 11.7 years. Warfarin was prescribed to patients of group 1, rivaroxaban to patients of group 2 treatment was prescribed for 6 months after discharge. The endpoint of observation was 4 years. Results. 18 (36) patients from group 1 and 2 (4.5) patients from group 2 stopped taking the anticoagulant earlier than target date. Elastic compression treatment patients in both groups kept irregularly. Recurrence of venous thromboembolic complications in group 1 was noted in 11 (22) cases, in group 2 in 7 (15.9) patients. The negative ultrasound dynamics was observed in patients of both groups: 16 of patients in group 1 and 9.1 in group 2 had lesion signs of previously unchanged veins or occlusion of a previously passable vein after thrombosis without clinic of acute venous thrombosis. Trophic disorders were identified in 1 patient in group 2 and in 1/3 of patients in group 1 by the 4th year of observation. Significant differences between the groups were obtained in favor of rivaroxaban according to such parameters as adherence to treatment and the severity of venous insufficiency. Conclusion. Unsatisfactory results of DVT treatment with standard therapy regimen require the administration of new oral anticoagulants with the possible introduction of prophylactic regimen., №1(81) (2020)

Введение. Тромбоз глубоких вен (ТГВ) является жизнеугрожающим заболеванием и осложнением, имеющим большое количество этиологических факторов. В современной литературе основным предрасполагающим фактором развития ТГВ в пожилом и старческом возрасте принято считать онкологические заболевания. Цель исследования: оптимизировать скрининговую диагностику и тактику антикоагулянтной терапии у пациентов пожилого и старческого возраста с ТГВ в зависимости от этиологического фактора. Материалы и методы. В рамках исследования проводили лечение 40 больных c ТГВ из них 29 пациентов находились на амбулаторном лечении, 11 на стационарном. Среди них было 18 (45) мужчин и 22 (55) женщины в возрасте от 61 года до 87 лет, средний возраст составил 72 года. Диагноз ТГВ устанавливали на основании клинического обследования и данных ультразвукового дуплексного сканирования (УЗДС) вен нижних конечностей. Амбулаторно обследовались и получали лечение пациенты с низким риском развития тромбоэмболии легочной артерии по шкале Geneva. Все пациенты сдавали анализы крови на наличие наследственных тромбофилий. Наблюдение осуществляли в течение 1 года, что включало визиты в клинику и телефонные звонки, а также регулярные УЗДС нижних конечностей и лабораторный контроль пациента через 3, 14 дней, 1, 3, 6 мес и 1 год. Результаты. У 26 (65) человек тромботический процесс локализовался в подвздошно-бедренном сегменте, изолированный дистальный тромбоз обнаружен у 8 (20) пациентов. Новообразования найдены у 16 (40) обследованных, причем в органах малого таза в 33 случаев. По классификации ТNM (tumor, nodus, metastasis) выявленные онкологические патологии были представлены IIII стадиями. У 6 (9) пациентов обнаружена мутация V фактора (Лейденская мутация) свертывания крови (у 5 гетерозиготная, у 1 гомозиготная), 3 (3) пациента имели мутацию гена протромбина (у всех гетерозиготная). Заключение. Генетические тромбофилии очень скромный предиктор развития ТГВ у пациентов пожилого и старческого возраста. Онкологическая патология является более сильным драйвером тромбоза глубоких вен, чем генетическая предрасположенность., Introduction. Deep vein thrombosis (DVT) is a life-threatening disease and complication, and has a large number of etiological factors. In modern literature cancer is considered to be the main predisposing factor for DVT development in elderly and senile age. Aim: to optimize the screening diagnostics and tactics of anticoagulant therapy in elderly and senile patients with DVT depending from etiological factor. Materials and methods. We treated 40 patients with DVT 29 of them were outpatient and 11 inpatient. Among them were 18 (45) men and 22 (55) women aged 6187 years, the average age was 72 years. DVT was diagnosed on the basis of clinical examination and ultrasound duplex scanning (USDS) of the veins of lower extremities. Patients with a low risk of pulmonary embolism according to the Geneva scale were examined and received treatment on an outpatient basis. All patients were examined for hereditary thrombophilia. The observation was carried out for 1 year: visits to the clinic and phone calls, as well as regular USDS of the lower extremities and laboratory monitoring after 3, 14 days, 1, 3, 6 months and 1 year. Results. In 26 (65) patients the thrombotic process was localized in the ileo-femoral segment isolated distal thrombosis was found in 8 (20) patients. Neoplasms were found in 16 (40) patients, and in pelvic organs in 33 of cases. According to the TNM classification (tumor, nodus, metastasis), the identified oncological pathologies were represented by stages IIII. In 6 (9) patients factor V mutation (Leiden mutation) of blood coagulation was detected (in 5 heterozygous, in 1 homozygous), 3 (3) patients had a prothrombin gene mutation (all heterozygous). Conclusion. Genetic thrombophilia is a very modest predictor of DVT development in elderly and senile patients. Oncological pathology is a stronger driver of DVT than a genetic predisposition., №1(81) (2020)

Впервые описанное в 1926 г. Эриком фон Виллебрандом нарушение коагуляции, названное им наследственная псевдогемофилия , а затем получившее название болезнь Виллебранда в честь своего открывателя, является самой распространенной наследственный коагулопатией, поражающей от 1 до 3 населения планеты. Данная статья рассматривает вопросы этиологии, патогенеза, диагностики и лечения данного заболевания., In 1926 by Erik von Willebrand first described coagulation disturbance and called it hereditary pseudohemophilia . Later it was named von Willebrand disease in honor of its discoverer. This disease is the most common hereditary coagulopathy that affects 13 of the worlds population. This article analyzes the etiology, pathogenesis, diagnosis, and treatment of this disease., №1(81) (2020)

Введение: В последнее время стали востребованы интегральные тесты оценки системы гемостаза у женщин во время беременности, а также во время акушерских операций, связанных с кровотечением. В нашей стране отсутствуют работы по определению популяционных норм ротационной тромбоэластометрии (РОТЕМ) у беременных, рожениц и родильниц. Цель исследования: определить пределы референсных интервалов показателей РОТЕМ во время физиологически протекающей беременности и в раннем послеродовом периоде и провести корреляционный анализ со стандартными показателями коагулограммы. Материалы и методы: Обследовано 229 женщин Красноярского края, которые были поделены на 5 групп: небеременные (контроль), беременные II и III триместров, женщины раннего послеродового периода после операции кесарева сечения и естественных родов. Все женщины были сопоставимы по возрасту, индексу массы тела, сопутствующей патологии. Референсные интервалы рассчитывали либо через среднее и стандартное отклонение (для нормального распределения), либо через медиану и 2,5 и 97,5% перцентили (для ненормального распределения). Результаты: В процессе исследования подтвердилось, что во время беременности и в раннем послеродовом периоде происходят изменения в системе гемостаза в сторону гиперкоагуляции. Показатели ROTЕM у женщин в III триместре беременности и раннем послеродовом периоде существенно отличаются от показателей небеременных в популяции. У женщин после родов вне зависимости от способа родоразрешения различий между параметрами ROTЕM не установлено. Корреляция между параметрами ROTЕM и традиционными лабораторными тестами коагуляции выявила взаимосвязь между амплитудой плотности сгустка в тесте FIBTEM и уровнем фибриногена по Клаусу. Заключение: Представлены референсные интервалы параметров РОТЕМ у женщин Красноярского края. Найдена корреляция между параметрами РОТЭМ и уровнем фибриногена., Background: Recently, integral tests for hemostasis assessment in pregnant women as well as during obstetric surgery associated with bleeding have become popular. In our country, there are no studies of population norms for rotational thromboelastometry (ROTEM) in pregnant women, parturients and puerperants. Objectives: to identify reference intervals limits for ROTEM parameters during physiological pregnancy and in early postpartum period and to carry out correlation analysis with standard coagulogram parameters. Patients/Methods: We examined 229 women in Krasnoyarsk region; they were divided into 5 groups: nonpregnant (control), pregnant women in II and III trimesters, women in early postpartum period after cesarean section and after vaginal delivery. All women were comparable in age, body mass index, and concomitant pathology. Reference intervals were calculated either as the mean and standard deviation (for normal distribution), or as the median and 2.5 and 97.5% percentiles (for abnormal distribution). Results: The study confirmed hemostasis hypercoagulation changes during pregnancy and in early postpartum period. ROTEM parameters in women in III trimester of pregnancy and in early postpartum period differ significantly from those in non-pregnant women. Differences between ROTEM parameters in puerperants, regardless of the delivery method, not found. The correlation between ROTEM parameters and traditional laboratory coagulation tests revealed a relationship between clot density amplitude in FIBTEM test and Klaus fi brinogen level. Conclusions: Reference intervals of ROTEM parameters in women of Krasnoyarsk region are presented. A correlation was found between ROTEM parameters and fibrinogen level, Тромбоз, гемостаз и реология, Выпуск 3 2020

Введение: В 2019 г. опубликованы полученные в модели артериального сдвига доказательства более слабой связи с фактором Виллебранда тромбоцитов группы О: у не-О тромбоцитов кинетика этой связи на 40% выше. Высказано предположение о меньшей гемостатической эффективности переливания этих тромбоцитов. Цель исследования: сопоставить клиническую эффективность переливания тромбоцитов группы О и других фенотипов системы группы крови АВО (не-О). Материалы и методы: У 310 пациентов проведено 674 переливания тромбоцитов. Анализировали и оценивали клиническую эффективность переливания двух групп тромбоцитов различных фенотипов системы группы крови АВО: О (n = 290) и не-О (n = 384). Результаты: При переливании О-тромбоцитов реципиентам реже требовались последующие трансфузии, а интервал до следующей трансфузии в среднем был на 21,7% больше, чем при переливании не-О тромбоцитов. После переливания О-тромбоцитов и не-О тромбоцитов не выявлено различий в концентрации тромбоцитов в крови реципиентов до переливания и спустя 20 ч. При переливании О-тромбоцитов наблюдали более высокий абсолютный прирост тромбоцитов в крови реципиентов, однако скорректированный прирост тромбоцитов после переливания О и не-О тромбоцитов не различался. Заключение: Таким образом, гипотеза о сниженной гемостатической активности тромбоцитов группы О не подтверждена., Background: In 2019 on arterial shift model the evidence was obtained of a weaker connection of von Willebrand factor and group O-platelets: in non-O platelets the kinetics of this connection was higher by 40%. A hypothesis was suggested that the O-platelet transfusion is hemostatically less effective. Objectives: to compare the clinical effectiveness of O-platelets transfusion and other phenotypes of ABO blood group (non-O). Patients/Methods: In 310 patients, 674 platelet transfusions were performed. Clinical effectiveness of transfusion of two platelet groups with different phenotypes of ABO blood group was analyzed and assessed: O (n = 290) and non-O (n = 384). Results: After O-platelets transfusion, recipients rarely required next transfusions, and the interval until next transfusion was on average 21.7% longer than after non-O platelets transfusion. After transfusion of O-platelets and non-O platelets, there were no differences between platelets concentration in recipient’s blood before transfusion and after 20 hours. After O-platelets transfusion, a higher absolute increment of platelets in recipient’s blood was observed, but the corrected increment of platelets after transfusion of O and non-O platelets did not differ. Conclusions: So, the hypothesis of reduced hemostatic activity of O-platelets is not confirmed., Тромбоз, гемостаз и реология, Выпуск 3 2020

Введение: Задержка роста плода (ЗРП) занимает второе место в структуре причин перинатальной смертности, а ее наличие имеет длительное неблагоприятное влияние на здоровье ребенка. Оценка степени активации системы гемостаза при ЗРП в сопоставлении с клиническими исходами имеет важное значение в понимании патогенеза, улучшении прогнозирования и профилактики этого патологического состояния. Цель исследования: оценить состояние гемостаза у беременных с ЗРП в сравнении с женщинами с физиологическим течением беременности. Материалы и методы: Тип исследования: поперечный срез на базе когортного. В исследование включено 52 беременных. Основная группа — 32 пациентки с ЗРП, выявленной при ультразвуковой фетометрии; контрольная группа — 20 практически здоровых женщин без отягощенного акушерско-гинекологического анамнеза, с физиологически протекавшей беременностью, завершившейся неосложненными родами. Оценку состояния системы гемостаза проводили на сроке 24–32 нед гестации. Результаты: Среди факторов тромботического риска у беременных с ЗРП чаще выявлялось табакокурение во время беременности. Наличие ЗРП было значимо связано с маловодием, генитальной и внутриматочной инфекцией, преэклампсией, нарушениями маточно-плацентарно-плодового кровотока. У женщин с ЗРП обнаружен более высокий уровень фибриногена, а также повышение скорости роста сгустка, больший размер сгустка, более частое формирование спонтанных сгустков в сравнении с контрольной группой. Заключение: У беременных с ЗРП имеется протромботическая готовность плазмы, что может служить основанием для дальнейшей разработки антитромботической коррекции с целью улучшения перинатальных исходов., Background: Fetal growth retardation (FGR) is the second leading cause of perinatal mortality, has a long-term adverse effect on child health. Assessment of hemostasis activation in FGR in comparison with clinical outcomes is important for understanding pathogenesis, improving the prognosis and prevention of this pathological state. Objectives: to assess hemostasis state in pregnant women with FGR compared to women with physiological pregnancy. Patients/Methods: Type of study: crosssectional based on cohort. The study included 52 pregnant women. The main group consisted of 32 patients with FGR diagnosed by ultrasound fetometry; the control group consisted of 20 practically healthy women without burdened obstetric-gynecological history, with physiological pregnancy that ended in uncomplicated childbirth. Hemostasis assessment was carried out at 24–32 weeks of gestation. Results: Smoking during pregnancy as a factor of thrombotic risk was more common in pregnant women with FGR. FGR was significantly associated with oligohydramnios, genital and intrauterine infection, preeclampsia, and placental insufficiency. Women with FGR showed a higher level of fibrinogen, as well as an increased rate of clot growth, clot larger size, and more frequent formation of spontaneous clots in comparison with the control group. Conclusions: Pregnant women with FGR are characterized by prothrombotic state that may be the basis for further development of antithrombotic correction for improving perinatal outcomes., Тромбоз, гемостаз и реология, Выпуск 3 2020

Низкомолекулярные гепарины (НМГ) рекомендованы всем госпитализированным пациентам с COVID-19. Однако эффективная доза НМГ неизвестна, и эскалация дозы НМГ представляется уместной для лечения COVID-19-ассоциированной коагулопатии. Цель исследования: анализ дозирования НМГ для лечения COVID-19-ассоциированной коагулопатии, а также индикаторов, указывающих на необходимость коррекции доз этих препаратов. Материалы и методы. В период апрель-июнь 2020 г. обследовано 49 человек с диагнозом COVID-19. НМГ получили 43 пациента: 25 человек — эноксапарин натрия, 18 — далтепарин натрия. При лабораторном обследовании определяли С-реактивный белок, количество тромбоцитов, активированное частичное тромбопластиновое время, тромбиновое время, концентрацию фибриногена, активность антитромбина III, протромбиновое время, концентрацию Д-димера и анти-фактор Ха активность (анти- Ха активность). Данные были представлены как медиана (Me), нижний (LQ) и верхний (UQ) квартили. Статистический анализ включал в себя проверку на нормальность распределения по критерию Шапиро–Уилка, сравнение независимых групп по критерию Манна–Уитни при уровне значимости < 0,05, корреляционный анализ с применением критерия Спирмена, регрессионный анализ с использованием F-критерия. Многомерный поэтапный анализ результатов исследования проводили методами кластерного, дискриминантного и ROC-анализа. Результаты. Установлено, что воспалительный ответ у мужчин и у женщин протекает с различающимися акцентами в рамках системы гемостаза. Если анти- Ха активность была ниже 0,4 МЕ / мл, то выбранная доза НМГ никак не влияла ни на процессы тромбообразования и воспаления, ни на течение заболевания в целом. При анти- Ха активности в диапазоне 0,4–0,6 МЕ / мл воспалительный ответ также преодолевал эффект НМГ. Только при анти- Ха активности > 0,6 МЕ / мл была выявлена достоверная корреляция между анти- Ха активностью и суточной дозой НМГ (r = 0,493; p = 0,031). Выявление в этой группе такой связи означает, что часть поступившего в организм НМГ уже была «потрачена» на противовоспалительные цели, а оставшаяся проявила эффект, направленный на другую цель назначения НМГ, т. е. собственно антитромботический. При этом ROC-анализ не подтвердил значимость концентрации фибриногена в прогнозе достижения антитромботической эффективности НМГ. Кластерный анализ достоверно разделил исходную выборку в точке анти- Ха активность = 0,6 ЕД / мл. Из 43 пациентов, получивших НМГ, только у 15 (34,9%) выбранная доза НМГ анти- Ха активность > 0,6 ЕД / мл, тогда как у оставшихся анти- Ха активность оказалась ниже данного значения, несмотря на большую вариацию полученного НМГ: AUC = 0,482 (95% ДИ = 0,298–0,665) со статистической значимостью p = 0,848. Дискриминантный анализ показал, а ROC-анализ подтвердил, что для до- стижения антитромботического эффекта требуется коррекция дозы с учетом веса тела пациента, а целевым значением анти- Ха активности является 0,65 ME / мл. Заключение. Антитромботический эффект как искомый результат применения НМГ достижим только при дозировании с учетом массы тела пациента, независимо от того, снижена она, нормальная или повышена. Развитие антитромботического эффекта должно выявляться, а его стабильность подтверждаться на основе определения анти- Ха активности, которая должна быть не менее 0,65 МЕ/мл. Анти- Ха активность ниже данного значения может служить указанием на необходимость коррекции дозы НМГ у пациентов с COVID-19-ассоциированной коагулопатией., Background. Low molecular weight heparins (LMWH) are guided for all in-hospital patients with COVID-19. However LMWH effective dose is still unknown. Escalating the LMWH dose seems appropriate for the treatment of COVID-19-associated coagulopathy. Objectives: to explore the LMWHs doses effects in the treatment of COVID-19-associated coagulopathy, and to fi nd indicators signaling the need to adjust the LMWH dose. Patients / Methods. From April to June 2020, 49 patients with COVID-19 were examined. LMWH were given to 43 patients: 25 of them received enoxaparin sodium, 18 — dalteparin sodium. Lab testing included C-reactive protein, platelet count, activated partial thromboplastin time, thrombin time, fibrinogen, antithrombin III, prothrombin time, D-dimer, and anti-factor Xa activity (anti- Xa activity). The data were presented as median (Me), lower (LQ) and upper (UQ) quartiles. Statistical analysis included the check of the distribution normality by Shapiro–Wilk test, comparing independent groups with Mann- Whitney test for p < 0.05, correlation analysis with Spearman test, and regression analysis with the F-test. Multivariate step-by-step analysis of data was performed using cluster analysis, discriminant analysis and ROC-analysis. Results. It was found that the inflammatory response reflects differently for hemostatic system in men and women. When anti-Xa activity was < 0.4 IU / ml, the LMWH selected dose did not affect either the processes of thrombosis and inflammation, or the course of the disease as a whole. When anti- Xa activity was within 0.4–0.6 IU / ml, the inflammation overcame the LMWH effect as well. A significant correlation between anti- Xa activity and the LMWH daily dose (r = 0.493; p = 0.031) was found only for anti-Xa activity > 0.6 IU / ml. That does mean that part of the administered LMWH was already “spent” for anti-inflammatory purposes, and the remaining part was enough to develop an antithrombotic effect. Other result was that ROC-analysis did not confirm the fibrinogen value for the forecast of LMWH antithrombotic effectiveness. Cluster analysis divided significantly the initial sample at the point with anti- Xa activity = 0.6 IU / ml. Of the 43 patients received LMWH, the selected LMWH dose provided anti- Xa activity > 0.6 IU / ml in 15 (34.9%) only, while in other patients the anti- Xa activity was lower despite a wide variation in the LMWH doses: AUC = 0.482 (95% CI = 0.298–0.665; p = 0.848). Discriminant analysis showed, and then ROC-analysis confirmed, that to an antithrombotic effect, LMWH dose adjustment is required taking into account the patient’s body weight, and the target value of anti- Xa activity is 0.65 IU / ml. Conclusions. The antithrombotic effect as the desired result of the LMWH use is achievable only under dosing with the patient’s body weight regardless of whether it is reduced, normal or increased. The LMWH antithrombotic effect should be detected and then its stability confirmed by testing the anti- Xa activity which should be at least 0.65 IU / ml. Lower anti- Xa activity may indicate the need for LMWH dose adjustment in patients with COVID-19-associated coagulopathy., Тромбоз, гемостаз и реология, Выпуск 4 2020