Background. Patients with acute myeloid leukemia (AML) are predisposed to infectious complications (IC). Single nucleotide polymorphisms in genes can affect the function and/or expression of the proteins they encode. Since the functioning of the innate immune system is under genetic control, identifying polymorphic variants that reduce the effectiveness of the immune response is a promising method for identifying patients at high risk of severe infections.Aim. To evaluate the relationship between presence of single nucleotide polymorphisms TLR3 C1234G and IL4 C589T with IC frequency in AML patients.Materials and methods. TLR3 C1234G and IL4 C589T polymorphisms were genotyped in 93 patients with AML, of which 77 (82.80 %) – de novo AML, 16 (17.20 %) – AML with previous myelodysplastic syndrome. Patients received 263 chemotherapy courses. Median age was 58 (Q1–Q3: 38–66) years, 50 (53.76 %) were men, 43 (46.24 %) were women. Sepsis and pneumonia were considered severe IC. Allele-specific polymerase chain reaction with detection of amplification products in a 3 % agarose gel was used to genotype single nucleotide polymorphisms in immune response genes.Results. Severe IC were developed in 57 (21.67 %) chemotherapy courses. It was found that in patients with the TLR3 1234GG genotype, compared with carriers of the TLR31234CC genotype, the frequency of severe IC is 4.8 times lower (odds ratio 0.21; p = 0.022). Severe IC occurred 2.3 times more often in heterozygous carriers of the IL4 C589T polymorphism than in homozygous carriers of the C allele (odds ratio 2.29; p = 0.025). In multivariate analysis, taking into account age, gender and severity of neutropenia, the TLR31234GG and IL4 589CT genotypes variants remained independent predictors of IC.Conclusion. The TLR3 1234CC and IL4589CT genotypes are associated with the risk of severe IC in AML patients.

Aim. To define the association of CDKN2A/B deletions in the 9p21 locus with survival of patients with diffuse large B-cell lymphoma. Materials and methods. The study included 105 patients with diffuse large B-cell lymphoma who received firstline therapy with R-CHOP. A deletion of 9p21 was detected by fluorescent in situ hybridization of tumor tissue biopsy samples. Deletions of CDKN2A and CDKN2B were determined by real-time quantitative polymerase chain reaction. The overall survival and the progression-free survival were calculated by the Kaplan – Meier method with plotting of survival curves (the log-rank test). The risk of event occurrence was determined by the Cox regression analysis with the calculation of the risk ratio (RR) and 95% confidence interval (CI). The differences between the variables were considered statistically significant at p < 0.05. Results. The deletion of the chromosomal region 9p21 was detected in the biopsy samples in 16.2% of patients. The CDKN2A deletions were detected in 23.8% of patients and CDKN2B loss – in 28.6% of patients. The progressionfree survival was significantly lower in patients with the 9p21 deletion than in those without this aberration: 29.4% vs. 62.5%, respectively ( p = 0.012; RR = 2.26; 95% CI = 1.17–4.38). The risk of disease progression at low and low-intermediate values of the International Prognostic Index was 5.9 times higher in patients with the CDKN2B deletion than in patients without this abnormality. Conclusion. Deletion of the chromosomal region 9p21 is associated with low progression-free survival in patients with diffuse large B-cell lymphoma. Loss of CDKN2B is associated with a high risk of disease progression in patients with low and low-intermediate risk according to the International Prognostic Index.

The use of mesenchymal stem cells (MSCs), which have a pronounced immunomodulatory activity, is a promising direction in the development of biomedical cell preparations (BMCPs). In oncohematology, the use of BMCPs containing MSCs is aimed at supporting hematopoiesis during cotransplantation with hematopoietic stem cells (HSCs) and suppressing immune conflicts during allogeneic unrelated transplantation and severe autoimmune processes. An obligatory stage of registration of BMCPs is confirmation of the identity of the MSC cell line (CL), which includes the establishment of morphological characteristics, evaluation of the expression of specific markers and proteins, and confirmation of the genetic stability of CL during cultivation. Determination of markers of genetic stability is possible using various methods, however, according to the recommendations of the American National Standardization Institute, the standard is the analysis of short tandem repeats (STR analysis). The purpose of the study is to develop an algorithm for determining the authenticity of BMCPs containing MSCs, including STR analysis. Material and methods. Identification of MSC cells in BMCP was performed according to the criteria of the International Society for Cell Therapy. Viable cells were counted in a Goryaev chamber. Immunophenotypic characteristics of MSCs were determined by flow cytometry. The level of production of specific proteins was assessed using enzyme immunoassay. Genetic stability markers were identified by STR analysis. Results and discussion. The methods were tested in triplicate for ten BMCP samples to confirm the reproducibility and reliability of the results. The developed algorithm for determining the authenticity of BMCP has a high accuracy, as it includes the STR analysis technique, which makes it possible to identify 19 polymorphic STR markers located on different alleles. Using the method will allow BMCP manufacturers to go through the procedure of state registration of drugs.

The results of system studies of the environment and socio-economics of the White Sea and the catchment area (Belomorye), obtained mainly from the results of RFBR project No. 18-05-60296, as well as developments under State assignments, are presented. The changes in the economy, social sphere and the environment that have oc- curred during the years of reforms from 1991 to 2019 are determined. The current state of the White Sea watershed has been studied: forests, soils, hydrological features, climate changes, as well as the economy and social sphere. The state and changes of the White Sea ecosystems under possible climate warming are considered. To study the socio-ecological-economic system of the watershed, cognitive models of the White Sea have been developed, which are considered as a tool for synthesizing the heterogeneous information about a complex system. Prognostic estimates of possible changes in the complex system of the region under a different set of economic and natural conditions are obtained.

Введение. Синдром диссеминированного внутрисосудистого свертывания (ДВС-синдром) является частым осложнением онкогематологических заболеваний. Известно, что повреждение эндотелия сосудов играет одну из ключевых ролей в развитии коагулопатии потребления, особенно в условиях системного воспаления. Повышение концентрации синдекана-1, одного из основных протеогликанов эндотелиального гликокаликса, в плазме крови описано при различных патологических состояниях, включая острые лейкозы и ДВС-синдром. Определение его содержания у больных гемобластозами может способствовать ранней диагностике ДВС-синдрома и своевременному назначению патогенетической терапии. Цель исследования: оценить роль протеогликана синдекан-1 в диагностике ДВС-синдрома у больных гемобластозами с сепсисом. Материалы и методы. Проведен анализ гематологических и биохимических показателей периферической крови, коагулограммы, кислотно-основного состояния и сывороточного содержания синдекана-1 у 54 больных гемобластозами с признаками системного воспаления. Острый миелоидный лейкоз диагностирован у 19 (35%), острый лимфобластный лейкоз – у 10 (18%), неходжкинская лимфома – у 13 (24%), лимфома Ходжкина – у 9 (17%), множественная миелома – у 3 (6%). Концентрацию синдекана-1 сравнивали с таковой у здоровых доноров. Наличие ДВС-синдрома определяли по шкале DIC-score Международного общества по тромбозам и гемостазу (англ. International Society on Thrombosis and Hemostasis, ISTH), степень органных дисфункций – по шкале SOFA (англ. Sequential Organ Failure Assessment). Сепсис верифицировали по критериям консенсуса «Сепсис-3». Взаимосвязь уровня синдекана-1 с показателями гемограммы, коагулограммы, биохимическими параметрами и данными шкал DIC и SOFA оценивали с использованием критерия Спирмена. Диагностическую роль синдекана-1 определяли при помощи ROC-анализа. Результаты. У больных гемобластозами выявлено повышение уровня синдекана-1 по сравнению с таковым у здоровых доноров в 5,8 раз (р = 0,008). Сепсис диагностирован у 28 (52%) пациентов, явный ДВС-синдром выявлен у 14 (25%). Концентрация синдекана-1 в сыворотке крови коррелировала со значениями активированного парциального тромбопластинового времени и протромбинового времени, количеством тромбоцитов, активностью антитромбина III, показателями шкал DIC-score и SOFA. Определена диагностическая роль синдекана-1 при развитии явного ДВС-синдрома (точка отсечения – 5,48 нг/мл, чувствительность – 73%, специфичность – 90%). Заключение. Повышенный уровень синдекана-1 (более 5,48 нг/мл) может служить дополнительным критерием развития ДВС-синдрома у больных гемобластозами с сепсисом. Background. Disseminated intravascular coagulation (DIC) is a severe complication of hemoblastosis. The key role of the vascular endothelium in hemostasis regulation is well known. Its activation and damage are the most important factors of consumption coagulopathy during systemic inflammation. Increased blood level of one of the main proteoglycans of the endothelial glycocalyx – syndecan-1 has been described in various pathological conditions, including acute leukemia and DIC. Syndecan-1 level evaluation in patients with hemoblastosis can help early DIC diagnosis and improve therapy results. Objectives: to assess the role of syndecan-1 for DIC diagnosis in hemablastosis patients with sepsis. Patients/Methods. Hematological and biochemical data of peripheral blood, coagulogram, acid-base balance and serum level of syndecan-1 were analyzed in 54 patients with hemoblastosis with signs of systemic inflammation. Acute myeloid leukemia was diagnosed in 19 (35%) patients, acute lymphoblastic leukemia – in 10 (18%), non-Hodgkin’s lymphoma – in 13 (24%), Hodgkin’s lymphoma – in 9 (17%), multiple myeloma – in 3 (6%). Syndecan-1 concentration was compared with that of healthy donors. DIC was assessed by DIC-score (ISTH, International Society on Thrombosis and Hemostasis), organ dysfunction – by SOFA (Sequential Organ Failure Assessment) score. Sepsis was verified according to the third international consensus definitions for sepsis and septic shock. Relationship of syndecan-1 level with hematological, сoagulological, biochemical data and DIC or SOFA scores was assessed by Spearman rank correlation. The diagnostic value of syndecan-1 was determined by ROC-analysis. Results. Increased level of syndecan-1 in 5.8 times was revealed in patients with hemoblastosis in comparison to healthy donors (p = 0.008). Sepsis was diagnosed in 28 (52%) patients, overt DIC – in 14 (25%). Serum syndecan-1 level correlated with activated partial thromboplastin time, prothrombin time, platelet count, antithrombin III activity, DIC and SOFA scores. The diagnostic role of syndecan-1 was determined in overt DIC (cut-off – 5.48 ng/ml, sensitivity – 73%, specificity – 90%). Conclusions. Increased syndecan-1 level (more than 5.48 ng/ml) can be additional diagnostic criterion for DIC in patients with hematological malignancies and sepsis.

Background. The regimens of therapy with bortezomib have significantly improved the survival among patients with multiple myeloma (MM). However, the development of peripheral polyneuropathy (PP) resulting from treatment using proteasome inhibitors is still an undesirable event. Risk factors for PP in MM patients include old age, previous neuropathy and use of neurotoxic drugs. Recent studies have established the presence of a genetic component in the mechanism of developing bortezomib-induced neurotoxicity. However, there are conflicting opinions on the role of genetic characteristics in predicting the risk of treatment-induced neuropathy development.Aim. To identify the risk group of bortezomib-induced PP based on the analysis of gene polymorphism of the immune response in patients with newly-diagnosed MM.Materials and methods. A study of the association of 20 polymorphic loci of 14 immune response genes in 46 MM patients was conducted using a candidate gene identification approach. All the patietns were receiving VCD therapy with bortezomib.Results. The distribution of single nucleotide polymorphisms was compared in groups of patients with the presence and absence of PP. It is found that homozygous carriers of the wild type allele of the genes TLR6 (Ser249Pro) (p = 0.006), IL1β (G-1473C) (p = 0.04), IL4 (C-589T) (p = 0.04), as well as haplotype carriers with the mutant allele of the gene IL10 (G-1082A) (p = 0.04) and with the wild type allele gene IL2 (T-330G) (p = 0.01) were significantly more frequent among PP patients.Сonclusion. Our results have confirmed the contribution of the genetic component to the risk of developing bortezomibinduced neuropathy. These findings can be used for individualization of therapeutic approaches to the treatment of MM patients.

Aim. To determine the value of polymorphisms of the immune response genes for the treatment efficacy in MM patients receiving high-dose chemotherapy and autologous hematopoietic stem cell transplantation (autoHSCT). Methods. The overall of 20 ММ patients (8 men and 12 women) were included in the study. The median age was 51.5 years (range 32-67). Clinical laboratory tests had been performed before melphalan high-dose (200 mg/m2) conditioning therapy. In accordance with the achieved anticancer response to induction treatment the patients were divided into 3 groups: patients with partial remission (group 1; n = 7); patients with very good partial remission (group 2; n = 9); patients with complete remission (group 3; n = 4). Genotyping of 20 polymorphic loci of 14 immune response genes was performed using PCR. Results. The study showed that group 2 had no AA mutant homozygotes of IL10 in the G-1082A polymorphic locus compared to group 3 and no TT mutant homozygotes of TLR6 (Ser249Pro) compared to group 1. The patients with more pronounced mucositis (grade 2/3) compared to patients with minor mucositis (grade 0/1) had no CC mutant homozygotes of IL1ß in the G-1473C position and a smaller number of (CT+TT) heterozygous and homozygous haplotype carriers of IL10 with the T mutant allele in the C-819T mutation point. The multivariate analysis showed that the genetic marker statistically effecting the progression-free survival rates in MM patients after high-dose chemotherapy and autoHSCT was the polymorphous status of the IL10 (G-1082A), TNF (G-308A), TLR4 (Thr399Ile), and TLR9 in the T-1237C and A2848 polymorphic loci. Progression-free survival rates correlated with the mutation status of IL1ß (T-511C), IL2 (T-330G), IL6 (C-174G), CD14 (C-159T), TLR3 (Phe421Leu), and TLR4 (Asp299Gly). Conclusion. The obtained data show the correlation of 14 polymorphisms of 10 immune response genes with the immediate results of the induction treatment, and also with the severity of mucositis during the early post-transplant period, as well as overall and progression-free survival rates in MM patients. Due to a small sample volume further studies will be planned with the aim to verify the identified trends. The suggested hypothesis for immune response gene polymorphism effecting a disease prognosis can substantially contribute to developing of individualized approach to MM treatment.

Aim. To assess the prognostic value of clinical and hematological parameters used by hematologists for risk stratification in diffuse large B-cell lymphoma (DLBCL), and to justify the need for discovering new prognostic factors. Methods. The trial included 101 patients (48 men and 53 women) with newly diagnosed DLBCL at the age of 18-80 years (median age 58 years). The patients received R-CHOP as first-line therapy. Depending on their response all patients were stratified into 4 groups: with complete response (CR; n = 58), partial response (PR; n = 15), resistance to first-line therapy (n = 19), and early relapses (ER; n = 9). Median follow-up was 22 months (range 2-120 months). Results. In terms of age influence on the efficacy of R-СНОР as first-line therapy no significant differences were established in regard to response in patients younger and older than 65 years. Statistically significant differences were observed while analyzing two parameters of International Prognostic Index (IPI; disease stage and extranodal lesions) and B-symptoms in the CR and therapy-resistant groups. With respect to the same parameters no significant differences were found in the CR and ER groups. Median 2-year disease-free survival was not achieved in patients with CR. In patients with PR it was 12 months. Median 2-year overall survival in patients with CR, PR, and ER was not achieved, and in patients with therapy-resistant DLBCL it was 10 months. Conclusion. Results of the trial confirm prognostic value of factors applied for risk stratification in DLBCL. However, variability of clinical course of the disease, especially with a low IPI score, suggests the need for new prognostic parameters associated with the course of DLBCL.

A number of studies have shown that distinct common variants of the genes controlling immune/inflammatory response may affect efficiency of chronic lymphocytic leukemia (CLL) treatment. In a recently published paper, we reported polymorphic variants of some immune response genes in CLL patients to be associated with different rates of disease progression. Correlations between the distribution of gene modification profiles in indolent and agressive forms of CLL have been established. The present study describes results of pharmacogenetic studies aimed for identifying associations between the immune response genes polymorphism, and efficacy of FCR treatment regimen in CLL patients. 19 polymorphic loci of 14 immune response genes were studied in 33 patients with CLL who received FCR therapy. The TLR2, TLR3, TLR4, TLR6, TLR9, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-17A, CD14, TNFα, FCGR2A genotypes were determined by polymerase chain reaction with allele-specific primers. CLL patients were divided into several groups depending on the terms of response to FCR treatment, i.e., achieving partial/complete remission after two, four, six courses of treatment, and those who did not respond to the therapy. Statistically significant differences in the distribution of haplotype frequencies were detected for the following genes: IL-1β (C-3953T, p = 0.02-0.009); IL-10 (C-819T, p = 0.04); IL-10 (G-1082A, p = 0.04-0.002-0.006), FCGR2A (His166Arg, p = 0.006); TLR4 (Thr399Ile, p = 0.02); TLR6 (Ser249Pro, p = 0.04); TLR9 (A2848G, p = 0.04-0.007); CD14 (C-159T, p = 0.03). When testing the significance hypothesis by multiple comparisons, the difference for the detected events was confirmed only for IL-10 gene (G-1082A, p < 0.01; χ2 = 20,082). The results show a relationship between the allelic status of the IL-10-1082 gene and the timing of response to FCR therapy, as well as predict a group of patients with primary-resistant CLL before treatment. The role of the relationship between IL-10 gene polymorphism and IL-10 production is discussed in connection with occurrence risk and clinical course of mature B-cell lymphoid malignancies. IL-10 is thought to be a growth factor for normal and transformed human B-lymphocytes, it controls a balance between cellular and humoral immune responses while exerting a pronounced immunosuppressive activity, along with ability to stimulate tumor cell proliferation. A rationale for conducting pharmacogenomic studies in CLL is provided, in order to predict efficiency of a specific drug or their combination in a distinct patient, thus representing chances to detect a factor which may influence success of the therapy since its earlier stage.

Most hematological malignancies are characterized with aberrant functioning of the immune system. The conducted studies indicate an important role in the development of malignant hematopoietic diseases arising from genetic factors, including the genes of intracellular signalling pathways, especially those involved in the implementation of an antitumor immune response. The review presents aggregated data on polymorphism studies of the toll-like receptors signalling pathway molecules of genes whose role in the development and course of various types of hematological malignancies is considered to be proven.

Lake Onego, as one of the largest water bodies in a humid zone, is the recipient of terrestrial carbon and plays an important role in the global balance of this element. Due to heterotrophic metabolism in the Lake Onego ecosystem, substantial emissions of carbon dioxide from this lake into the atmosphere can be assumed. However, the extent of this phenomenon is still poorly known. As a climate change has led to an increase in water and organic matter flow into the northern water bodies, the carbon balance study of aquatic ecosystems is of particular relevance. The elements of the water balance for the Lake Onego catchment area in the current climate conditions are assessed. Based on satellite images the model of Lake Onego watershed terrestrial ecosystems is used to simulate the flow of organic matter into the lake with different types of vegetation and topography consideration. The assessment of the benthic communities habitat is carried out taking into account the accumulation of organic matter in various parts of Lake Onego.

The complex interaction between environmental factors and human genes makes a significant contribution to the development of chronic lymphoproliferative diseases (CLPD) in individuals with mutations in various genes, including the innate immune response genes. We examined 51 patients with chronic lymphocytic leukemia (CLL) and 70 multiple myeloma (MM) patients. The control group consisted of 47 healthy persons without hematological malignancies. The patients from control group were matched for gender and age characteristics of CLPD patients. In observed persons there was determined the prevalence of genetic polymorphisms (single-nucleotide polymorphism SNP) in the innate immune response genes including 20 genetic polymorphisms (single-nucleotide polymorphism SNP) in 14 genes of the innate immune response. In patients with CLL haplotype AA for the TLR3 gene in -421 position was revealed to occur significantly more often than in the control group (OR: 18.56; p = 0.005). In MM patients there was noted the relation between the risk of the development of the disease and gene polymorphism for IL-10-1082,TLR2-753 and TLR3-421. There were found genetic markers for rapidly progressing forms of CLL and MM (CG + GG haplotype of the gene IL-6 and haplotypes GG + GA gene IL-17A, respectively). It is possible to assume a probable link of gene polymorphisms for IL-6, IL-10, IL-17A,TLR2 and TLR3 with the development of the CLPD and recommend these markers as early additional diagnostic and prognostic criteria.