The article is aimed to consider phenomenological aspects of the recently discovered the general biological phenomenon, caused as the “rescue effect”. It means that irradiated cells or organisms show a biopositive response as a result of feedback signals from non-irradiated cells or organisms contacted with them. The analysis of the results presented in the world literature and obtained with various experimental models using primary human fibroblasts (NHFL), normal human dermal fibroblasts (NHDF), Danio Rerio embryonic fibroblasts (ZF4), normal human lung fibroblasts (W138), human macrophage and hepatocyte cell lines (U9347 and HL-7702 respectively), as well as cells of the "immortal" HeLa lineage, human melanoma (Me45), and lung adenocarcinoma (A549) was carried out. It is shown that the induction of the "rescue effect" depends on the combination of cell lines used as irradiated targets and bystander cells. The effects obtained in the Danio Rerio embryo model of (in vivo studies) are also discussed. The mechanisms associated with the induction of the "rescue effect" and soluble signaling factors (chemical messengers) that cells/organisms receive as biological "help" in the form of feedback signals sent by non-irradiated cells/individuals are considered. The ways of implementing the two identified types of the "rescue effect" are discussed. The type of ionizing radiation used, its dose range, the spectrum of irradiated and non-irradiated cells, and the various biological endpoints are crucial in order to differentiate or combine the two phenomena into a single phenomenon. In the future, this will not only be fundamental, but also of great practical importance related to drug development, optimization of radiotherapy methods and improvement of treatment outcomes for cancer patients.

Radiation-induced “bystander effects” were studied at the inter-organismal level. The experiment used mice irradiated at a dose of 3 Gy and nonirradiated bystander mice, kept together for 90 days. An analysis of the state of the bone marrow, spleen, and thymus in the experimental animals was carried out, which included an assessment of the mass of the spleen and thymus, as well as the number of nuclear cells in the bone marrow, spleen, and thymus in mice. The results of this study indicate the presence of a “bystander effect” in the nucleated cells of the bone marrow of mice. In unirradiated animals that were kept with irradiated mice in a cage without a septum, the number of nucleated cells is reduced statistically significantly ( t = 2.58; p = 0.02) compared to the control. There is an effect of increasing the number of nucleated cells in the bone marrow in the group of irradiated mice in a cage with a septum, statistically significant by 15% more than in the gamma control group ( t = 2.36; p = 0.03), i.e., the “rescue effect.” Obviously, in all organs of the hematopoietic system—bone marrow, thymus, and spleen—there are violations associated with the factor of contact of animals. It is possible that the observed radiation-induced “nontargeted effects” are realized at the level of induced changes in the DNA.

The task of studying radiation “bystander effects” at the organism level was set in the work. Irradiated and nonirradiated mice that were kept together were used in the experiment. Mice were irradiated at a dose of 3 Gy in a research radiobiological gamma installation with the sources of 137Cs. The number of leukocytes and relative number of lymphocytes in the peripheral blood of mice were estimated 3, 7, 14, 30, 60, and 90 days after the beginning of the experiment. In nonirradiated “bystander” mice kept with irradiated mice both in the cages without a partition and with a partition, there is a possible trend towards a decrease in the number of leukocytes as compared with indices in the biocontrol. During the analysis of relative number of lymphocytes, a trend towards a decrease in the index in “bystander” mice was demonstrated both when keeping without a partition and with a partition. In nonirradiated “bystander” animals when keeping with irradiated animals in the cage with a partition, a statistically significant decrease in the relative number of lymphocytes in the peripheral blood was registered on days 3 (t = 2.13; p = 0.047), 30 (t = 2.94; p = 0.01), and 90 (t = 3.07; p = 0.01) after irradiation as well as when keeping in the same cage with irradiated mice without a partition on day 60 (t = 2.24; p = 0.038) after the beginning of the experiment. A “bystander effect” in nonirradiated animals is one of possible explanations for the detected changes. In irradiated animals that were kept in the same cage with a partition together with nonirradiated animals, a statistically significant increase in the relative number of lymphocytes was registered on days 3 (t = 2.6; p = 0.02), 14 (t = 2.61; p = 0.018), and 60 (t = 2.38; p = 0.03) (“rescue effect”). Based on data obtained in the present experiment, it is assumed that the radiation “bystander effect” can have the opposite nature; that is, nonirradiated organisms are able to reduce the radiation effects in irradiated individuals (“rescue effect”).

In the study conducted on outbred female mice, the radiation-induced “bystander effect” and the “rescue effect“ were found to be formed at an inter-organismic level. Unirradiated and gamma-irradiated (3 Gy) outbred white female mice were placed in one cage. The effect of co-residing was registered with the use of hemopoietic cells of peripheral blood by comparing to the population of hemopoietic cells in irradiated and unirradiated mice placed in different cages. The “bystander effect“ was observed in the monocytes subpopulation on the 3rd, 7th and 60th days. The effect was also observed in the neutrophils subpopulation on the 7th and 90th days. The “rescue effect” was observed in irradiated cells. The 5.8-fold (increase in eosinophils was registered on the 30th day (t=2.85; p=0.01), the 1.6-fold increase in eosinophils was observed on the 60th day, the 3-fold increase in eosinophils was registered on the 90th day (t=2.28; p=0.04). The effect of neutrophils subpopulation is slightly expressed, it can be considered as a tendency to increase the number of neutrophils on the 14th and 30th days. When the “rescue effect“ on irradiated mice was estimated with the use of monocytes the 5.7-fold increase was registered on the 30th day (t=2.94; p=0.01), the 7.3-fold increase was registered on the 90th day (t=2.41; p=0.03). According to the data obtained the “bystander effect” and the “rescue effect” are observed in all studied hemopoietic cells subpopulations, however they respond differently. The findings demonstrate the manifestation of the “bystander effect” and the “rescue effect” at the inter-organismic level. However, their intensity and trend depend to a large extent on the time period after irradiation, the contact type (tactile or olfactory) and a cellular subpopulation.

In an experiment to study radiation "bystander effects" (BEs) at the interorganismic (systemic) level, we use mice irradiated at a dose of 3 Gy and mice that are not irradiated, bystanders, kept together. In the irradiated animals, on the 3rd and 60th days, when kept without a partition, and on the 14th day when kept in cells with and without a partition, a statistically significant decrease in the frequency of normal chromatophilic (oxyphilic) erythrocytes (NCEs) with micronuclei is revealed when compared with the gamma control. In the nonirradiated bystander-mice, kept with the irradiated mice in a cage with a partition on the 14th day and in a cage without a partition on the 60th day, a tendency to exceed the micronucleus (MN) frequency of the erythrocytes' values in the biocontrol is revealed. Based on the data obtained in this experiment, it is assumed that the radiation BE has the opposite character; i.e., nonirradiated organisms are able to reduce the radiation effects in irradiated individuals: the "rescue effect."

Most studies of radioadaptive response (RAR) in vivo have revealed its effective induction both by chronic and single irradiation of a human organism with low doses. The classical way of the for-mation of RAR on the human peripheral blood lymphocytes (PBL) was noted as in occupationally irradiated personnel as in residents of areas with increased natural or man-made accidental high background radiation. In some studies, the liquidators of the Chernobyl accident and children liv-ing in the Chernobyl pollution zone showed the phenomenon of increasing the radiosensitivity of PBL. A comparative analysis of the influence of two types of radiation (gamma and betta) with close RBE showed comparable effectiveness to induce an adaptive response in human PBL in the mode of chronic exposure in the long term. Evidence of RAR in vivo was also obtained in the study of DNA end-points and chromosomal damage. In an experiment with the effect on neutrophils of peripheral blood of the elderly people (age 63-84 years) induced by acute gamma-rays in a wide range of doses (0.1; 0.25; 1; 4 and 10 Gy) the greatest radioresistance of their phagocytic and lysosomal activity is shown. Gamma-rays at low doses (0.1 Gy) stimulated the formation of extracellular traps by neutrophils in vitro using activated pyrogen (Pyrogernalum). The article presents some mechanisms of RAR in vivo. The study of radioadaptive response should be considered as an indispensable factor for assessing and controlling individual human radiosensitivity.

The paper summarizes results of medical examination of two groups of patients, the public members resided in high natural background radiation areas and occupationally irradiated nu-clear and health workers. Adaptive response to chronic exposure to radiation was found to last much time and, thus, its impact on the development of late health effects, including cancer, may be great. In vitro studies demonstrate that induction of adaptive response is the multistep process including the excision reparation of nucleotides, nonhomologous DNA ends joining, antioxidative system and cell cycle control factors. The review presents data on effects of low doses radiation of high or low relative radiation effectiveness(RBE). Some damaged peripheral blood lympho-cytes demonstrated increased radioresistance to high radiation doses, results of examinations of both the public members and professionals.

This paper presents the first results of research and observations within the framework of the Integrated Project for the assessment of radiation-induced nontargeted effects. The remote bystander effect, related to nontargeted effects, is one of the least studied phenomena in terms of manifestations and mechanisms. The international laboratory practice with respect to this phenomenon commenced with demonstration of the bystander effect in fish and other aquacultures. Our studies have revealed changes similar to radiation-induced pathologies in nonirradiated mice kept for three months in contact with the irradiated species (exposed to a 3 Gy γ-ray dose). Changes in behavioral responses, a statistically significant trend for decreasing spleen weight ( r = –0.416; p = 0.048), an expanding area of alopecia ( r = –0.631; p = 0.001), and other anomalies are noted. Discussions on possible mechanisms of the phenomena refer to both A.M. Kuzin’s theory of radiotoxins (1966) and the interpretation of the hypotheses investigated by C. Mothersill (2010–2019). An assumption is made on the important role of derivatives of lipid peroxides in the formation of this effect. The results of these studies indicate the need for further investigation of the radiation-induced bystander effect by using the molecular and cellular methodological approaches.

Goals: an evaluation of effectiveness of Fludarabine, Cyclophosphomide and Rituximab (FCR therapy) for patients with newly diagnosed Chronic Lymphocytic Leukemia (CLL) for validation of results from multi-centered clinical trials in real clinical practice. Materials and methods: sixty six (66) patients with newly diagnosis of CLL were included to this prospective study with average age of 58 years old (39-73 years old). Stage I - II according to Rai staging system was found in 76% of patients; Stage III-IV – in 24 % of patients. All patients received 6-8 cycles of inductive FCR therapy: Rituximab 375 mg/m2, iv – first cycle, followed by 500 mg/m2, iv; Fludarabine – 25 mg/m2, iv – days 2,3 and 4 of a cycle; Cyclophosphamide – 250 mg/m2,iv– days 2,3 and 4 of a cycle). Patients were divided into two groups based on duration of induction cycles (IC). Group 1 had average IC of 36 days; Group 2 - 49 days. Evaluation of immunochemotherapy effectiveness was determined by presence of remissions (IWCLL-2008), progression-free survival (PFS) and overall survival (OS) (Kaplan – Meier method). Results: Complete Remission (CR) was observed more often in Group 1 (FCR-36) than in Group 2 (FCR-49) - 56.6% and 37.9% of patients, respectively (p > 0.05). Median PFS was 36 months in all patients; 45 months – in Group 1 (FCR-36) and was not achieved in Group 2 (FCR-49). Median OS was 45 months in Group 1 (FCR-36) and was not achieved in Group 2 (FCR-49). Conclusions: confirmation of FCR therapy effectiveness for newly diagnosed CLL patients was established in real clinical practice characterized by non-selective patient groups and prolonged induction therapy cycles. Results of this study provide validation for results from multi-centered clinical trials and could be reproduced on a greater scale in clinical practice. Keywords: Chronic Lymphocytic Leukemia (CLL), Chemotherapy, Immunotherapy No conflicts of interests pertinent to the abstract.

The article presents results of study of delayed effects of occupational exposure to alpha and gamma radiation on human genome. The group of 23 former Mayak employees at the city of Ozersk was involved in the study. During their work at the enterprise for plutonium processing they had been exposed to internal and external radiation. Average internal alpha radiation dose to lungs was 0.120.024 Gy, to the bone marrow – 0.0450.0087 Gy. Average individualized ex-ternal gamma radiation doses to the bone marrow and to the lungs were 1.60.1Gy, 1.80.12 Gy, respectively. Impacts of ionizing radiation and alpha particles on frequency of micronuclear cells and the components of adaptive response were assessed. Adaptive potential of lymphocytes cor-relates with doses in internal and external radiation. Results of the analysis indicate that sponta-neous DNA damage to the lymphocytes genome is related to the level of internal rather than ex-ternal damage to irradiation, of human lungs (r=0.51; p=0.015) and the bone marrow (r=0.47; p=0.026), it depends also on the duration of wok with alpha and gamma emitters (r=0.43; p=0.046). Results of the study may be useful for estimating risk of delayed effects on health sta-tus of workers dealing with radionuclides processing.

Monoclonal gammopathy (MG) is not only the state preceding of hematological neoplasms, but also associated with non - hematological diseases, in particular kidney damage. Aim. To assess the diagnostic value of “Freelite” methods in addition to electrophoresis (EF) and immunofixation (IF) of serum and urine proteins for detecting MG in patients with kidney diseases. Materials and methods. 87 patients with kidney damage, in which MG was established using the method of electrophoresis of serum proteins (EF), immunofixation (IF) and the method of free light chains determination - FLC “Freelite” were selected. The diagnostic value of three - component serum panel was compared with EF and IF. Results and discussion. AL-amyloidosis with kidney involvement was diagnosed in 41% patients, cryoglobulinemic glomerulonephritis (cryo GN) - in 18%, chronic glomerulonephritis (CGN) - in 35%, also there was small number of patients with light chain disease and cast - nephropathy. Determination of MG using EP was possible only in 38 (44%). Adding to the serum electrophoretic methods instead of the “Freelite” method, the urine EF and IF reduced the number of missed patients with monoclonal gammopathy from 24 (27%) to 11 (13%), including in the subgroup of patients with AL-amyloidosis but did not reach the sensitivity of the three - component serum screening panel. In 10 (11.5%) MG was represented only by intact mIg with one type of light chain, either κ or λ. Most often - in 25% of patients, intact monoclonal gammopathy was observed in HCV (+) cryo GN. A combination of intact mIgM, mIgG or mIgA with mFLC, was detected in 37 (42.5%). In almost half (46%) of the patients, only mFLC was detected - an abnormal κ/λ ratio. Conclusion: The serum screening panel EF + IF + “Freelite” spreads the low - grade monoclonal gammopathy recognition (MGUS) and should be included in the algorithm of examining patients with kidney disease.

Aim. To evaluate the concentration of immunoglobulin free light chains (FLC) in comparison with that of intact measurable paraproteins (PIg) in patients with relapsed/resistant multiple myeloma (RR MM) undergoing treatment with bortezomib.Materials and methods. A retrospective study included 15 patients with RR MM with intact measurable PIg. Following 6 cycles of bortezomib treatment, an evaluation of the treatment efficacy was performed using standard criteria and by analysing serum FLC of immunoglobulins (sFLC).Results. A partial response (PR) and small response was achieved in 4 and 5 patients, respectively. The stabilization of the disease was observed in 6 patients. No cases of complete response (CR) or stringent complete response (SCR) were recorded. On the basis of the data on the concentration of sFLC after treatment, all patients were divided into 2 groups: those with an abnormal (clonal) and normal κ/λ ratio. In 11 patients with a response lower than PR, sFLC κ/λ ratio was of a clonal nature, which corresponded to changes in the concentrations of intact PIg during treatment. In 4 cases with PR, the residual tumour was determined by the presence of intact PIg within the 32–45 % range under, however, a normal sFLC κ/λ ratio.Conclusion. Treatment with bortezomib affects all processes in MM with intact PIg, such as synthesis of FLC by tumour plasma cells, a decrease in the amount of circulating sFLC in blood and in the concentration of intact PIg. Normalization of sFLC κ/λ ratio under the achievement of PR could be considered as a prognostic factor in a favourable clinical outcome.

Presence of Serum-Free Immunoglobulin Light Chains (sFLC) was analyzed for 15 patients with newly diagnosed Chronic Lymphocytic Leukemia (CLL). All patients were also characterized by peripheral blood lymphocytes' immunotype (including k/lambda), presence of absolute lymphocytosis and clinical data. Of the 15 patients 11 had elevated concentrations of monoclonal sFLC: 7 patients had elevated K sFLC (K/lambda ratio > 1,65); 4 patients had elevated) sFLC (K/lambda ratio < 0,26). The type of elevated clone for sFLC was the same as the isotype of clonal lymphocytosis. The remaining 4 of 15 patients did not have elevated concentrations of sFLC whereas clonal lymphocytosis (lambda type for all 4 patients) and absolute lymphocytosis were observed. 10 of 15 patients received 6 courses of RFC-therapy. For those patients sFLC concentration was measured before and after the therapy. In 6 of 10 patients tumor clone of sFLC was detected. After RFC-therapy, 4 of those patients demonstrated a reduction in concentrations of elevated sFLC on average for 63,1% and a normal K/lambda ratio that corresponded with the absence of clonal and absolute lymphosytosis. The remaining 2 patients did not have a decrease in sFLC concentrations and had abnormal k/lambda ratio, however, tumor clone lymphocytes and absolute lymphocytosis were not detected, that was presented with better overall clinical outcome. In 4 out of 10 patients that demonstrated no initial elevation in clonal sFLC, measured sFLC concentrations varied within the normal range. Conclusions: 73,7% of CLL patients in our study showed elevated concentrations of clonal sFLC. Serum-Free Light Chains concentration could serve as an integral criterion for evaluation of tumor mass and therapy effectiveness.

The article deals with the so-called monoclonal gammopathy of undetermined significance (MGUS), which is being actively explored in the world and has been recently investigated in Russia. It indicates the principles of identifying the phenotypes of MGUS and criteria for assessing the risk of its progression to cancer. There is an update on the possible involvement of monoclonal proteins in the pathogenesis of certain non-neoplastic kidney diseases, renal injuries in particular. The paper gives their classification and enumerates differential diagnostic techniques, including the Freelite method, a highly sensitive one to determine free light chains (FLC), prognostic criteria, and approaches to treating each separate form in relation to the phenotype of a monoclonal protein. The authors present their own data on detection rates for MGUS at a multidisciplinary hospital and a clinical case of MGUS-associated membranoproliferative glomerulonephritis, by justifying a treatment regimen containing bortezomib (velcade).