TNF-α AND IONIZING RADIATION: THE ROLE IN THE PATHOGENESIS AND TREATMENT OF PLASMA CELL MYELOMA (review). / TNF-α ТА ІОНІЗУЮЧЕ ВИПРОМІНЮВАННЯ: РОЛЬ В ПАТОГЕНЕЗІ І ЛІКУВАННІ ПЛАЗМОКЛІТИННОЇ МІЄЛОМИ (огляд літератури).

The review presents data from the literature on the role of Tumor necrosis factor-α (TNF-α) and ionizing radiation (IR) in the pathogenesis and treatment of plasma cell myeloma (PCM). There was analyzed disturbance of regulation of functioning of this cytokine, which affects the interaction of the immune system with substrate plasma cells under the influence of negative external factors, including ionizing radiation IR. Modern directions of therapy of this disease using the latest technologies are presented, in particular CAR T-cell therapy, which will allow to optimize in the future treatment of this disease and, thus, improve the quality and life expectancy of PCM patients.

REVIEW OF THE NATURE OF ANTI/INFLAMMATORY AND PRO-INFLAMMATORY CYTOKINE REGULATION IN DIFFERENT PERIODS OF PLASMA CELL MYELOMA NATURAL HISTORY IN THE CHORNOBYL NPP ACCIDENT SURVIVORS. / АНАЛІЗ ХАРАКТЕРУ РЕГУЛЯЦІЇ ПРОТИЗАПАЛЬНИХ І ПРОЗАПАЛЬНИХ ЦИТОКІНІВ НА РІЗНИХ ЕТАПАХ ПЕРЕБІГУ ПЛАЗМОКЛІТИННОЇ МІЄЛОМИ У ХВОРИХ, ЯКІ ПОСТРАЖДАЛИ ВНАСЛІДОК АВАРІЇ НА ЧОРНОБИЛЬСЬКІЙ АЕС.

OBJECTIVE: identify the nature of anti-inflammatory and pro-inflammatory cytokine regulation in different periods of plasma cell myeloma (PCM) natural history with evaluation of its role as a prognostic criterion for the disease course in the Chornobyl NPP (ChNPP) accident survivors. MATERIALS AND METHODS: Levels of pro-inflammatory (IL-6, TNF-α) and anti-inflammatory (IL-10) cytokines both with their relationship were studied in the stage I-II and stage III PCM patients (n = 74) in different periods of the disease natural history i.e. remission/stabilization and progression. Study groups included the ChNPP accident survivors (n = 35) and non-irradiated subjects (n = 39). Immunoenzymatic method was applied using the Vector-Best CJSC commercial kits. RESULTS: There was a unidirectional increase in the levels of IL-6, TNF-α, and IL-10 in irradiated persons, and an elevation of IL-6 and TNF-α concentration but with a decreased level of IL-10 in non-irradiated subjects compared to control at the time of PCM diagnosis. Period of the disease remission/stabilization in PCM stage I-II patients featured a decrease in IL-6 concentration regardless of the exposure to ionizing radiation, while TNF-α content remained at the level of the control group. There was a significant increase in IL-6 concentration in both study groups during the disease relapse, while TNF-α level remained unchanged compared to stabilization phase of the disease. According to the obtained data a certain contribution of radiation exposure to the PCM pathogenesis as a possible predictor of the exacerbated disease course cannon be excluded. CONCLUSION: Determining the serum level of pro-inflammatory and anti-inflammatory cytokines (IL-6, TNF-α and IL-10 respectively) provides advancement in assessment of the PCM course and predict the effectiveness of administration of therapy protocols.

IONIZING RADIATION AND CYTOKINES: THE ROLE IN THE PATHOGENESIS OF PLASMA CELL MYELOMA (LITERATURE REVIEW). / IONIZUIuChE VYPROMINIuVANNIa I TsYTOKINY: ROL' V PATOGENEZI PLAZMOKLITYNNOÏ MIIeLOMY (OGLIaD LITERATURY).

The review presents literature data on the role of ionizing radiation as a negative environmental factor in the occurrence of plasma cell myeloma (PCM). The data of studies of various categories of irradiated persons regarding the incidence of PCM, in particular employees of nuclear enterprises and victims of the accident at the Chornobyl Nuclear Power Plant accident, are given. The effect of cytokines (interleukin-6 and interleukin-10) on PCM substrate cells was analyzed, including under conditions of combined action of IR and cytostatic agents in vitro.

COMPLEX ANALYSIS OF THE ROLE OF CYTOKINE GENE POLYMORPHISMS AS PROGNOSTIC FACTOR OF THE RISK OF PLASMA CELL MYELOMA IN PERSONS SUFFERED AFTER THE CHORNOBYL NPP ACCIDENT. / KOMPLEKSNYI ANALIZ ROLI POLIMORFIZMU GENIV TsYTOKINIV IaK PROGNOSTYChNOGO ChYNNYKA RYZYKU PLAZMOKLITYNNOÏ MIIeLOMY U OSIB, POSTRAZhDALYKh VNASLIDOK AVARIÏ NA ChORNOBYL'S'KII AES.

OBJECTIVE: to provide a comparative characterization of the prevalence of polymorphic variants of cytokine genes in plasma cell myeloma (PCM) patients suffered after the Chornobyl disaster and patients who were in contact with ionizing radiation within the natural radiation background, based on comparison with population controls to determine their contribution as genetic markers of disease risk. MATERIALS AND METHODS: Molecular genetic studies of polymorphism of cytokine genes (TNF-α, TGF-ß1, IL-6, IL-10, IFN-γ) and complex frequency analysis of occurrence in three-, four-, and five-locus combinations of their allelic variants as prognostic markers of the risks of plasma cell myeloma was carried out in 102 patients - 56 victims of the Chornobyl nuclear power plant accident and 46 patients irradiated within the limits of the natural radiation background, in comparison with the control group (364 practically healthy people, residents of the Central geno-geographical region of Ukraine). RESULTS: The same probable increase in the prevalence of the TGF-ß genotype codon10 T/T of the TGF-ß1 gene was established in the groups of patients irradiated after the Chornobyl NPP accident and non-irradiated patients. In patients with plasma cell myeloma a protective effect for IL-10 -1082 A/G and an association with the risk of disease occurrence for IL-10 -1082 G/G were determined. CONCLUSION: Probable difference in the frequency of the TGF-ß1 genotype codon10 T/T of the TGF-ß1 gene in the observed groups relative to the control group provides grounds for considering this single-nucleotide polymorphism of the TGF-ß1 gene as an immunogenetic factor of predisposition to the development of PCM independent of exogenous factors. The study of the contribution of multigene combinations of «gene-gene¼ interaction indicates their role in the mechanisms of plasma cell myeloma occurrence and confirms the presence of an additive interaction.

ORAL HYGIENE IN CHILDREN WITH DISTURBANCES IN TOOTH FORMATION WHO WERE AFFECTED AS A CONSEQUENCE OF THE ChNPP ACCIDENT. / STAN GIGIIeNY POROZhNYNY ROTA U DITEI Z PORUShENNIaMY FORMUVANNIa ZUBIV, POSTRAZhDALYKh VNASLIDOK AVARIÏ NA ChAES.

OBJECTIVE: evaluation of oral hygiene to enhance the prophylaxis of complications specifically of dental caries inchildren with disturbances in tooth formation (DTF) who live on radiologically contaminated territories after theChornobyl NPP (ChNPP) accident. MATERIALS AND METHODS: Children aged 6-14 years (n = 1470) with DTF were the study subjects examined in 2012-2016. Among them there were (n = 528) residents of the zones III and IV of radiological contamination after theChNPP accident with 137Cs soil contamination density 1-15 Ci/km2. The effective radiation dose in them was notexceeding 1 mSv/year. The Green-Vermillion and Silness-Loe oral hygiene indices were assesses within clinicalexamination methods. RESULTS: The worth oral hygiene was revealed in children having got the DTF, compensated chronic diseases oforgans and systems, and in those with burdened radiation history. The Green-Vermilion and Silness-Loe indices were1.7 ± 0.51 and 1.65 ± 0.46 respectively. CONCLUSIONS: A significant deterioration in oral hygiene confirmed by the highest values of the Green-Vermillion index (1.7 ± 0.51; p < 0.001 - «unsatisfactory oral hygiene¼ criterion) and Silness-Loe index (1.65 ± 0.46; p < 0.001 -«poor oral hygiene¼ criterion) was found in children with DTF aged 6-14 years being residents of contaminated areasas a result of the Chernobyl accident. The revealed deterioration may be due to a set of negative factors, includingthe impact of ionizing radiation in low doses and peculiarities of social status. Results of the questioning of surveyed pediatric contingents both having got an DTF and with no defects of the hard tissues of teeth indicate aninsufficient level of knowledge and skills in hygienic care of oral cavity regardless of the area of residence.Development of a set of measures to prevent the DTF complications in children should be carried out taking intoaccount the state of oral hygiene, level of knowledge and skills in oral care, and include the use of hygiene products, namely toothpastes and anti-caries mouthwashes.

EFFICIENCY OF BONE MARROW PRECURSOR CELL COLONY-FORMING AS A PREDICTOR OF DISEASE COURSE IN PLASMA CELL MYELOMA PATIENTS WITH A HISTORY OF RADIATION EXPOSURE. / EFEKTYVNIST' KOLONIIeUTVORENNIa KLITYN-POPEREDNYKIV KISTKOVOGO MOZKU, IaK PROGNOSTYChNYI FAKTOR PEREBIGU PLAZMOKLITYNNOÏ MIIeLOMY U OSIB Z RADIATsIINYM ANAMNEZOM.

OBJECTIVE: Assessment of role of the bone marrow colony-forming efficiency in plasma cell myeloma patients at different stages of treatment as a prognostic criterion for the disease course. MATERIALS AND METHODS: The colony forming efficiency (CFE) was assayed in stage I-II plasma cell myeloma (PCM)patients (n = 37) aged 42-73, namely in patients survived after the Chornobyl NPP accident (n = 21) and persons notexposed to ionizing radiation (n = 16). There were 11 males exposed to ionizing radiation and having got stage I PCM,9 males and 3 females exposed and having got stage II PCM, 3 males and 3 females not exposed and having got stageI PCM, 6 males and 2 females not exposed and having got stage II PCM. Healthy persons (n = 20) were included in thecontrol group. RESULTS: Number of the bone marrow (BM) granulocyte-macrophage colony-forming units (CFU-GM) in both exposedand not exposed PCM patients depended on a disease stage. CFU-GM was (16.7 ± 1.2) in the stage I PCM patients vs.(11.1 ± 1.1) in the stage II PCM ones both being lower (p < 0.05) compared to control (64.5 ± 2.2). Changes in cluster formation were similar, i.e. (37.7 ± 1.6) and (19.4 ± 1.3) correspondingly in the stage I and stage II PCM patients.Respective values in control were (89.8 ± 3.6). The CFE in stage I and stage II PCM patients at the time of diagnosiswas lower (5.7 ± 1.5 and 2.4 ± 1.1 respectively) vs. control (39.5 ± 1.51, p < 0.05), but has increased in remission upto (29. 6 ± 1.8) and (13.8 ± 1.2) respectively. There was no difference at that between the irradiated and non-irradiated patients. Number of the fibroblast colony-forming units (CFU-F) in the stage I and stage II PCM patients duringdiagnosis, namely (43.9 ± 5.4) and (22.5 ± 3.7), was lower (p < 0.05) vs. control (110.5 ± 4.9). Upon reaching remission the CFU-F value increased significantly (p < 0.05), reaching (87.4 ± 4.2) and (55.6 ± 2.7) correspondingly in thestage I and stage II PCM patients. CONCLUSION: Dependence of the BM cell CFE on the stage of PCM and presence or absence of remission was established. Prognostic value of the CFE of BM CFU-GM in terms of life span of patients was shown (Ro Spearm = 0.39,p < 0.02), namely in case of CFE > 20 before the polychemotherapy administration the life span of PCM patients wassignificantly longer vs. cases of CFE < 20.

IMMUNOGENETIC AND PHARMACOCHEMICAL CHARACTERIZATION OF THE ABO SYSTEM GLYCOPROTEIN PROPERTIES AS CRITERIA OF INDIVIDUAL SENSITIVITY TO ANTITUMOR AGENT BORTEZOMIB IN THE PLASMA CELL MYELOMA PATIENTS. / IMUNOGENETYChNYY̆ TA FARMAKOKhIMIChNYY̆ ANALIZ VLASTYVOSTEY̆ GLIKOPROTEÏNIV SYSTEMY AVO IaK KRYTERIÏV INDYVIDUAL'NOÏ ChUTLYVOSTI ShchODO PROTYPUKhLYNNOGO PREPARATU BORTEZOMIBU U KhVORYKh NA PLAZMOKLITYNNU MIIeLOMU.

OBJECTIVE: Experimental study of the effect profile of bortezomib in the plasma cell myeloma (PCM) patients depend- ing on a specific phenotype carrier state and a pharmacochemical characteristics of ABO system glycoproteins. MATERIALS AND METHODS: The research was conducted on the 104 PCM patients, including the Chornobyl NPP acci- dent survivors (n = 49) and 65 study subjects in the comparison group. Immunogenetic criteria for positive response to the applied treatment protocols were issued according to the duration of remission, absence of infectious com- plications, and evidence of chronic renal failure as a disease complication. RESULTS: Possibility of glycoproteins A and B participation in the formation of human biological individuality at a level of protein-protein interaction with antineoplastic drug bortezomib, which is widely used in cancer management prac- tice, in particular in the PCM treatment is considered. The glycoprotein B was shown being a selective target for borte- zomib, slowing down the recognition and interaction of antigen B with monoclonal anti-B antibody, while the agglu- tination period lengthens at that by 66 %. Assumption that the formation of bortezomib complex with glycoprotein B provides a background for interaction with the key reaction of proteasome 26S inhibition, which to some extent con- tributes to the drug effect retardation was confirmed through the quantum-chemical calculations. Equilibrium is shift- ed toward the main reaction leading to a higher drug efficacy in patients with blood groups O (I) and A (II). CONCLUSIONS: Since the complexation occurs predominantly in alkaline medium the administration of drugs with alkaline reaction should be restricted for at least round the clock after administration of bortezomib according to its half-life in plasma in patients with B (III) blood group and chronic renal failure.

Childhood leukemia in Ukraine after the Chornobyl accident.

This population-based ecological study analyzes the prevalence of childhood leukemia in Ukraine before and after the Chornobyl nuclear power plant accident, based on the contamination status of the territory, time period, gender, and age. Three regions-Zhytomyr, Kyiv (except Kyiv city), and Chernihiv were included as areas contaminated by radioactive 137Cs from 1 to 15 Ci/km2 with annual effective doses exceeding 1.0 mSv, and Sumy region as the control (non-contaminated) area with 137Cs contamination less than 1 Ci/km2 and effective doses less than 0.5 mSv per year. The integrated database of the National Research Centre for Radiation Medicine used in the present study included 1085 childhood leukemia cases. Two aggregated periods were used for analysis: 1980-1986 (pre-accident) and 1987-2000 (post-accident). ICD-9 codes for leukemia (204-208.9) were used to perform analyses according to the extent of leukemic cells maturity (acute, chronic, and maturity unspecified leukemia), leukemic cell lineage (lymphoid, myeloid and lineage unspecified leukemia) and all leukemia cases in different age subgroups (1-4, 5-9, 10-14, and 15-19 years). Standard methods of descriptive epidemiology were used to calculate the prevalence of disease and frequency ratio in regression models. A statistically significant increase in frequency ratio for acute leukemia (1.44; 95% confidence interval (CI), 1.22-1.71), myeloid leukemia (2.93; 95% CI, 1.71-5.40), cell lineage unspecified leukemia (II) (1.48; 95% CI, 1.18-1.87) and all forms of leukemia (1.59; 95% CI, 1.36-1.86) was found for the post-accident period in highly contaminated areas. The results indicate that the frequency of childhood leukemia (and of some of its types) increased in contaminated areas during the post-accident period, suggesting that radiation exposure after the Chornobyl accident might be the cause of the increase. However, further analytical studies, with individual or at least group dose estimates, are needed to confirm a link between childhood leukemia and the Chornobyl accident.

CLINICAL, HEMATOLOGICAL CHARACTERIZATION AND POLYMORPHISM OF ABO AND Rh BLOOD GROUP SYSTEMS IN PLASMA CELL MYELOMA PATIENTS. / KLINIKO-GEMATOLOGIChNA KhARAKTERYSTYKA TA POLIMORFIZM SYSTEM GRUP KROVI AVO TA Rh U KhVORYKh NA PLAZMOKLITYNNU MIIeLOMU.

Objective to study the peculiarities of clinical characteristics and polymorphism of ABO and Rh blood group systemsin relation to the natural history of plasma cell myeloma in the ChNPP accident survivors. MATERIALS AND METHODS: Peculiarities of the disease natural history were reviewed in the 111 plasma cell myeloma(PCM) patients receiving medical management at the Department of Radiation Oncohematology of the NRCRM dur-ing 2010-2017. Principal clinical and laboratory characteristics of PCM, namely the values/levels of LDH, ß2-mic-roglobulin, albumin, serum calcium, urea, creatinine and hemoglobin were assessed, taking into account the gender,radiation history (ChNPP accident clean-up workers, evacuees from areas of obligatory resettlement, inhabitants ofcontaminated territories, and the comparison group) and the PCM stage codenamed by Durie-Salmon et al. (1975)and the ISS (1985) classifications. Distribution of polymorphic variants on ABO and Rh blood systems was studiedin the 106 PCM patients. RESULTS: It was found that the level of ß2-micro-globulin and calcium was increased significantly in male (p = 0.02and p = 0.04, respectively), whereas serum urea content was elevated in female (p = 0.04) PCM patients featuring acompromised radiation anamnesis in comparison to non-irradiated patients. Some probable differences were foundfor urea level (F = 3.58, p = 0.05) and serum albumin (F = 4.00, p = 0.05) in the examined group of PCM patients.Probable (p < 0.05) incidence increase of the B phenotype was established as a predictor of complicated natural his-tory of PCM with abnormal genetic equilibrium resulted from the increased incidence of IB allele in chronic renal fail-ure (CRF) patients. Significant (p < 0.05) prolongation of the remission period upon a standard PCT application wasfound in PCM patients being the A phenotype carriers having a preserved gene and phenotypic equilibrium comparedwith carriers of O and B phenotypes. CONCLUSIONS: Clinical and hematological parameters are different in PCM patients survived after the ChNPP accidentand those with favorable radiation history. Distribution of polymorphic variants of ABO antigenic structures inpatients with complicated natural history of the disease is also different, that can be a background for predictingthe effectiveness of treatment. Further research is required in this field.

State of oral cavity hygiene, sIgA level, mineral content of oral fluid, and optimization of preventive intervention in children with enamel hypoplasia and underlying comorbidity. / GIGIIeNIChNYY STAN POROZhNYNY ROTA, RIVEN' sIgA, MINERAL'NI SKLADOVI ROTOVOI RIDYNY TA OPTYMIZATsIIa PROFILAKTYChNYKh ZAKhODIV U DITEY Z GIPOPLAZIIeIu EMALI ZUBIV NA TLI KOMORBIDNOI PATOLOGII.

OBJECTIVE: To advance the efficiency of tooth caries prevention in children with enamel hypoplasia through a com plex intervention focused at amelioration of oral hygiene, secretory immunoglobulin A (sIgA) level, and mineral con tent of oral fluid. MATERIALS AND METHODS: Hypoplasia of permanent teeth enamel was the target of research. State of oral cavity hygiene, sIgA, total calcium and orthophosphate content in oral fluid were the research subject. Enamel vital stain ing, transillumination, immunoenzymometric and photometric techniques were applied. Indices of oral cavity hygiene: simplified oral hygiene index (OHI S) by Green and Vermillion (1964) and Silness Loe (1964, 1967) plaque index were the assayed. Assessment of oral cavity hygiene and assay of sIgA, calcium and orthophosphate content in oral fluid were held in 43 children 6-14 years old (n=21, Group 1; n=22, Group 2) with a systemic enamel hypoplasia and underlying diffuse non toxic (euthyroid) goiter. All children were born from the ChNPP accident clean up work ers and evacuees from territories of mandatory resettlement. Children in the Group 1 were prescribed a set of preven tive interventions including recommendations on choice of the oral care tools and teaching the standard dental cleaning skills. Children in the Group 2 additionally used the remineralizing gel with calcium, phosphorus, magnesium and xylitol (Sanction of the State Sanitary and Epidemiological Service of Ukraine # 05.03.02 03/9351 from 07.02.2014). RESULTS: State of oral cavity hygiene in children of the both study groups was assayed by a "dissatisfactory" criteri on according to the OHI S by Green and Vermillion and by a "poor" criterion according to the Silness Loe plaque index. Upon application of preventive intervrntions the state of oral cavity hygiene improved in children of Group 1 and Group 2: there was a significant decrease of OHI S by Green and Vermillion (p=0.0001) and Silness Loe plaque index (p=0.0003). Administration of remineralizing gel resulted in a significant increase of calcium (р = 0.0008) and orthophosphate (р = 0.001) content in oral fluid. No substantial change in sIgA concentration was found in both groups. CONCLUSION: Implementation of the preventive intervention tools including preparation with remineralizing effect promoted the amelioration of oral hygiene, increased content of mineral constituents in oral fluid, however with no effect on sIgA level.

[Carcinogenic aspects of indeterministic effects of ionizing radiation].

The results of clinical and epidemiological investigations on cancer diseases with different localization in irradiated persons are reviewed in the paper. The data on mechanisms of morbidity of mamma, thyroid, broncho-pulmonary, blood cancer in exposed to different doses of ionizing radiation persons are analyzed.

[Genetic aspects of indeterministic effects of ionizing radiation].

The theoretical and practical data on damage of cell genome using modern investigating methods in persons exposed to ionizing radiation are revealed. The mechanisms of cell genome damage as a basis of cancerogenesis in exposed to different doses of ionizing radiation persons are analyzed.

[Periferal blood subpopulation and apoptosis indices in the treatment of chronic myelogenous leukemia with Imatinib].

The results of immunophenotyping investigations of periferal blood granulocyte and lymphocyte population, number of p53+ and Bcl-2+ in 57 patients (among them 18 persons suffered after the Chernobyl NPP accident) with chronic phase of chronic myelogenic leukemia were presented in the article. The reduction of CD34+ granulocytes number, normalization of CD95 cells, negative correlation between the number of CD95 and p53, Bcl-2 granulocytes in Imatinib treated patients in comparison with a control group was determined. The results of the investigation confirmed the efficiency of using BCR/ABL tyrosin kinase inhibitor Imatinib in the treatment of chronic phase of CML.

[The experience of FISH technique application for reconstruction of individual radiation doses in Chernobyl liquidators in the framework of Ukrainian-American project "Leukemia"].

The results of proper investigations received under the cytogenetic examination of 225 persons (control groups, Chernobyl liquidators exposed to different radiation doses, oncogematology patients) had been summarized and analyzed. The conclusion concerning possibilities and limitations of FISH technique usage for retrospective biodosimetry of human radiation exposure has been presented.

[The characteristics of the pre- and leukemic stages of chronic myeloproliferative diseases in persons suffering as a result of the Chernobyl catastrophe]. / Kharakteristika pre- i leikemicheskoi stadii khronicheskikh mieloproliferativnykh zabolevanii u lits, postradavshikh vsledstvie chernobyl'skoi katastrofy.

Clinical, morphological and cytogenetic investigations were done in those patients with leukocytosis having become victims of the Chernobyl catastrophe. Of these (n = 10), six patients demonstrated chromosomal abnormalities. In the study made at a later date in six patients with cytogenetic abnormalities, five patients were found to have chronic myeloproliferative disorders, with four cases presenting with chronic myeloid leukemia and one patient having osteomyelofibrosis.

[Current treatment methods in myelodysplastic syndromes]. / Sovremennye metody lecheniia mielodisplaticheskikh sindromov.

Modern literary data about the treatment of myelodysplastic syndromes are reviewed. There have been analysed traditional methods and recent scientific achievements, such as using of the colony-stimulating growth factors and bone marrow transplantation.

[The blood kinin system of persons with a history of 1st-degree acute radiation sickness]. / Kininovaia sistema krovi u lits, perenesshikh ostruiu luchevuiu bolezn' I stepeni.

There tends to be an activation of blood kinin system in individuals with a prior acute grade I radiation sickness in the period of remote sequelae (six yr after irradiation). It is suggested that changes in the proteolytic processes may play a role in the natural course of the diseases in the individuals with a history of acute radiation sickness (pathology of the gastrointestinal tract, vegetovascular dystonia etc.). The disturbances revealed are of pathological nature and require therapeutic measures to be taken aimed at clearing them up.