THE MAIN PARAMETERS OF CELLULAR IMMUNITY IN PATIENTS WITH TRIPLE-NEGATIVE BREAST CANCER: RELATIONSHIP WITH EFFICIENCY OF CHEMOTHERAPY

Chemotherapy is among the primary methods of treating advanced breast cancer. It was shown that clinical efficacy of various chemotherapeutic agents in many cases depends not only on their direct cytostatic and/or cytotoxic effect upon tumor cells, but also on their ability to modulate phenotype of the tumor cells and to influence anti-tumor immune response. Initial state of the immune system and its response to treatment is crucial. Antitumor response involves cells of innate and adaptive immunity (NK, NKT, T cells). These populations are heterogeneous and contain, e.g., cells with antitumor activity and regulatory (suppressor) cells that suppress immune response and promote tumor progression. The aim of this work was to determine the relationship between the initial state of cellular immunity of patients suffering from locally advanced breast cancer with triple negative phenotype, and clinical effect of chemotherapy (cisplatin + doxorubicin/paclitaxel), and studying effects of the therapy upon subpopulation profiles of peripheral blood lymphocytes in the patients. We registered the terms of the disease progression as well as overall survival and progression-free survival. The disease progressed in 25 of 53 cases (47.2%) whereas 28 of 53 patients (52.8%) remained progression-free. The observation period was 35.5 months. Laboratory examination of the patients included immunophenotyping of peripheral blood lymphocytes and determination of NK cell cytotoxic activity before and after chemotherapy. Percentages of effectors and regulatory lymphocyte populations were determined. The results obtained showed that, for some lymphocyte subsets, the pre-treatment differences of cell percentage deviations from control were found between the progression-free groups and patients with progression of the disease. The differences in percentages of NKT cells and lymphocytes expressing CD25 activation marker proved to be most significant. Decreased number of NKT cells and activated CD25+ lymphocytes prior to chemotherapy was associated with increased probability of disease progression. Reduced percentage of NKT cells against control was observed in 56% of patients from the progression group (PD), and only 21.4% in the group free of disease progression (DF). [OR = 4.6 (95% CI 1.4 to 15.4)]. Percentage of CD25+ lymphocytes was decreased from 68.2% in the PD group, and 28.6% for DF patients [OR = 5.4 (95% CI 1.6-18.1)]. We studied relationships between the overall survival (OS) and percentage of perforin-containing NK, NKT, and T cells, and mean perforin fluorescence density (PFD) in these lymphocyte subsets in 26 of the 53 patients before treatment. A statistically significant positive correlation was revealed between OS and perforin PFD in all the three cell populations under study. Normalization of the parameters altered before treatment, and an increase of T cell numbers was observed in the disease-free patients

Влияние состава бинарного растворителя CH3CN-H2O на кинетику окисления циклогексена п-бензохиноном в растворах катионных комплексов палладия(II)

During the study of cyclohexene oxidation by p-benzoquinones into cyclohexanone in water-organic solutions of cationic complexes of palladium(II) it was demonstrated that the initial reaction rate R0 depends complicatedly on water molar fraction for three studied solvents: acetonitrile (AN), dimethylformamide, and dimethylsulfoxide. In order to explain the obtained bimodal dependence for the example of AN-water system, modeling of phase equilibrium in the studied system was performed. The existence of two- and three-phase immiscibility areas as well as a three-component heteroazeotrope was found. By UV spectroscopy it was stated that varying of water molar fraction in the binary solvent substantially changes the state of starting cationic complexes [Pd(АН)x(H2O)4-x]2+. For mathematical description of medium effect on R0 value three models were proposed taking into account different factors, such as: a) physico-chemical properties of binary solvent; b) composition of possible associates AN-water; c) composition of starting [Pd(АН)x(H2O)4-x]2+ complexes. The adequate description of bimodal dependency was obtained in the model considering the changes of [Pd(АН)x(H2O)4-x]2+ complexes composition with simultaneous presence of an associate of (АН)2(H2O) composition.В ходе изучения кинетики окисления циклогексена п-бензохиноном до циклогексанона в водно-органических растворах катионных комплексов палладия(II) показано, что начальная скорость реакции R0 сложным образом зависит от мольной доли воды для трех изученных растворителей: ацетонитрил (АН), диметилформамид и диметилсульфоксид. На примере системы ацетонитрил-вода проведено моделирование фазовых равновесий в исследуемой системе, позволившее выявить наличие областей двух- и трехфазного расслаивания, а также трехкомпонентного гетероазеотропа. Методом УФ-спектроскопии установлено, что изменение мольной доли воды в бинарном растворителе существенно меняет состояние исходных катионных комплексов [Pd(АН)x(H2O)4-x]2+. Для математического описания эффектов влияния среды на величину R0 предложены три модели, учитывающие такие факторы, как: а) физико-химические свойства бинарного растворителя, б) состав возможных ассоциатов ацетонитрил-вода, в) состав исходных комплексов Pd(II). Адекватное описание бимодальной зависимости получено в рамках модели, рассматривающей изменение состава комплексов [Pd(АН)x(H2O)4-x]2+ с одновременным присутствием ассоциата состава (АН)2(H2O)

НОВЫЕ ВОЗМОЖНОСТИ РЕГУЛЯЦИИ ПРОТИВООПУХОЛЕВОГО ИММУННОГО ОТВЕТА

The tumor has different mechanisms capable of destroying the immunological protection. Population of regulatory cells, along with other factors provide “escape” of the tumor from immune surveillance. In our laboratory, we studied the features of quantitative changes of some subpopulations of peripheral blood lymphocytes in primary operable breast cancer (BC) and melanoma at different stages of tumor growth and in the process of tumor therapy. In 94.5% of patients with breast cancer were found to increase compared to the control amount of NKT-cells with the phenotype CD45+CD3+ CD16+CD56+, 78% increase in number of CD8+CD28– T-cells, and 20.5% increase in the number of patients Regulatory CD4+CD25+FOXP3+ T cells. Was found to depend on changes in the number of these cells from the stage of the disease. Patients with stage I and II disease there was a statistically significant increase in the percentage of CD8+CD28– T–cells and CD45+CD3+ CD16+CD56+ NKT-cells compared to the donor. At the same time in patients with stage III the number of cells of both populations declined and did not differ from the norm. Such dynamics of quantitative changes were typical for the main populations of effector cells antitumor immunity. In the evaluation of patients with disseminated melanoma was found that no increase in the number of cytotoxic CD45+CD8+CD11b+ T cells in the treatment dendritic cell vaccine (DCV) appears to be an indication to stop vaccine therapy, initially increased amount of CD3+CD8+CD16+. NKT-cells may serve as grounds for refusal of DCV. A brief description of the major co-receptor inhibitor of T-cells, and monoclonal antibodies that block the inhibitory molecule on immune and tumor cells in order to increase the efficiency of anti-tumor immune response. Encouraging clinical results have been obtained by using anti-CTLA-4 (ipilimumab), and anti-PD-1 (nivolumab) monoclonal antibodies.Опухоль обладает различными механизмами, способными разрушать иммунологическую защиту. Популяции регуляторных клеток наряду с другими факторами обеспечивают «ускользание» опухоли от иммунологического надзора. В нашей лаборатории было проведено изучение особенностей количественных изменений некоторых субпопуляций лимфоцитов периферической крови у первично-операбельных больных раком молочной железы (РМЖ) и диссеминированной меланомой на разных этапах опухолевого роста и в процессе противоопухолевой терапии. У 94,5% больных РМЖ было обнаружено повышение по сравнению с контролем количества NKT-клеток с фенотипом CD45+CD3+CD16+CD56+, у 78% повышение количества CD8+CD28- Т-клеток, и у 20,5% больных повышение количества регуляторных CD4+CD25+FOXP3+ Т-клеток. Выявлена зависимость изменений количества этих клеток от стадии заболевания: у пациенток с I и II стадиями заболевания отмечалось статистически значимое повышение процента CD8+CD28- Т-клеток и CD45+CD3+CD16+CD56+ NKT-клеток по сравнению с донорами. В то же время у пациенток с III стадией количество клеток обеих популяций снижалось и практически не отличалось от нормы. Подобная динамика количественных изменений была характерна и для основных популяций клеток-эффекторов противоопухолевого иммунитета. При обследовании больных диссеминированной меланомой было обнаружено, что отсутствие повышения количества цитотоксических CD45+CD8+CD11b+ Т-клеток в процессе лечения дендритноклеточной вакциной (ДКВ), по-видимому, является показанием к прекращению вакцинотерапии, а исходно повышенное количество CD3+CD8+CD16+ NKT-клеток может служить основанием для отказа от ДКВ. Приводится краткое описание основных ко-ингибиторных рецепторов Т-клеток и моноклональных антител, блокирующих ингибиторные молекулы на иммунокомпетентных и опухолевых клетках, с целью повышения эффективности противоопухолевого иммунного ответа. Обнадеживающие клинические результаты были получены при применении анти-CTLA-4 (ипилимумаб) и анти-PD-1 (ниволумаб) моноклональных антител

Опыт применения комбинированной иммунотерапии в 1-й линии у больных метастатическим почечно-клеточным раком

The study objective is to evaluate effectiveness and tolerability of 1st line combination immuno-oncological therapy with nivolumab and ipilimumab in patients with metastatic renal cell carcinoma (mRCC) in clinical practice.Materials and methods. The study included 38 patients with mRCC who received combination immunotherapy between July of 2019 and September of 2021. Median follow-up duration was 8 (2-25) months. Mean age of the patients was 58.3 (20-85) years. Previously 22 (57.9 %) patients underwent surgical treatment. Unfavorable physical status 2-3 per the ECOG scale was observed in 10 (26.3 %) patients. Clear-cell type of renal cell carcinoma was diagnosed in 34 (89.6 %) patients, non-clear-cell types in 4 (10.4 %). Sarcomatoid component in the tumor was detected in 8 (21.0 %) patients. G3-4 mRCC variant was verified in 16 (42.1 %) patients. Poor prognosis per the IMDC (International Metastatic Renal Cell Carcinoma Database Consortium) scale was identified in 16 (42.1 %) patients, intermediate -in 20 (52.6 %) patients. All 4 administrations of combination immunotherapy were received by 29 (76.3 %) patients.Results. For median follow-up duration of 8 (2-25) months, 23 (60.5 %) patients continue treatment, 15 (39.5 %) completed therapy with nivolumab and ipilimumab due to various reasons including progression in 11 (28.9 %), death in 2 (5.3 %), intolerable toxicity in 2 (5.3 %) cases. Median duration of combination immunotherapy was 9 (2-24) months. Subsequent antitumor therapy was administered to 3 (7.9 %) patients. During induction course immune-mediated adverse event (grade III-IV hepatitis) developed in 3 (7.9 %) patients. Adverse events were observed in 81.6 % of patients, including grade III-IV in 23.7 % of patients. Objective response was observed in 44.8 % of cases, complete response in 5.3 % of cases, partial response in 39.5 % of cases; controlled disease was achieved in 84.3 % of patients. Median progression-free survival and overall survival were 8 months.Conclusion. In our study despite large number of patients with poor prognosis and poorly differentiated tumors, 64.0 % of patients are alive and 60.5 % of patients continue treatment without disease progression after 18 months of combination immunotherapy. Progression-free survival was significantly affected by sarcomatoid component in the tumor, number of unfavorable factors per the IMDC scale, best response per RECIST 1.1; overall survival was significantly affected by sarcomatoid component in the tumor, sum of measurable lesions, number of unfavorable factors per the IMDC scale, best response per RECIST 1.1, and presence of symptomatic metastases in the brain.Цель исследования - оценка эффективности и переносимости терапии 1-й линии у больных метастатическим почечно-клеточным раком (мПКР) комбинацией иммуноонкологических препаратов ниволумаб с ипилимумабом в реальной клинической практике.Материалы и методы. В исследование были включены 38 больных мПКР, получивших комбинированную иммунотерапию в период с июля 2019 г. по сентябрь 2021 г. Медиана времени наблюдения составила 8 (2-25) мес. Средний возраст пациентов - 58,3 (20-85) года. Хирургическое лечение ранее выполнили 22 (57,9 %) пациентам. Неблагоприятный соматический статус по шкале ECOG PS 2-3 отмечен у 10 (26,3 %) пациентов. Светлоклеточный вариант почечно-клеточного рака диагностировали у 34 (89,6 %) пациентов, несветлоклеточные варианты - у 4 (10,4 %). Саркоматоидный компонент в опухоли выявлен у 8 (21,0 %) больных. Вариант мПКР G3-4 верифицировали у 16 (42,1 %) больных. Неблагоприятный прогноз мПКР по шкале IMDC (International Metastatic Renal Cell Carcinoma Database Consortium) зарегистрировали у 16 (42,1 %) больных, промежуточный - у 20 (52,6 %). Все 4 введения комбинированной иммунотерапии получили 29 (76,3 %) пациентов.Результаты. При медиане времени наблюдения 8 (2-25) мес 23 (60,5 %) пациента продолжают лечение, 15 (39,5 %) больных завершили терапию ниволумабом с ипилимумабом по разным причинам, среди которых прогрессирование -в 11 (28,9 %), смерть - в 2 (5,3 %), непереносимая токсичность - в 2 (5,3 %) случаях. Медиана продолжительности комбинированной иммунотерапии составила 9 (2-24) мес. Последующую противоопухолевую терапию получили 3 (7,9 %) больных. На фоне индукционного курса иммуноопосредованное нежелательное явление (гепатит III-IV степеней тяжести) развилось у 3 (7,9 %) пациентов. Нежелательные явления зарегистрировали у 81,6 % пациентов, в том числе III-IV степеней тяжести - у 23,7 %. Частота объективного ответа составила 44,8 %, полный ответ зарегистрировали у 5,3 % пациентов, частичный - у 39,5 %, контроля над заболеванием удалось достичь у 84,3 % больных. Медиана выживаемости без прогрессирования и общей выживаемости составила 8 мес.Заключение. В нашем исследовании, несмотря на большое число больных группы неблагоприятного прогноза с низкодифференцированными опухолями, через 18 мес комбинированной иммунотерапии живы 64,0 % пациентов и 60,5 % пациентов продолжают лечение без прогрессирования заболевания. На выживаемость без прогрессирования достоверное влияние оказывали саркоматоидный компонент в опухоли, количество неблагоприятных факторов по шкале IMDC, наилучший ответ по критериям RECIST 1.1, на общую выживаемость - саркоматоидный компонент в опухоли, сумма измеряемых очагов, количество неблагоприятных факторов по шкале IMDC, наилучший ответ по критериям RECIST 1.1 и наличие симптомных метастазов в головном мозге

The features of primary seed production of winter bread wheat

The current paper has presented the features of primary seed production of winter bread wheat in the Rostov region and highlighted the main methods of varietal renewal, which make it possible to obtain high-quality seed material with strict preservation of their purity, biological and productive traits, in the amounts that meet the needs of the farms. The purpose of the research was to organize primary seed production of new and commercial varieties of winter bread wheat, which allows maintaining varietal purity and providing the required number of seeds of higher reproductions. There have been conducted the field trials to identify the best indicators of seed productivity, varietal and sowing qualities in the primary links of seed production. Seed production is based on individual-family selection with a two-year assessment of the progeny. The main percentage of variety rejection in the laboratory conditions was made according to such indicators as 1000 seed weight, family productivity, uniformity and plump condition of kernels within the family. In PIP-1 the rejection among the varieties ‘Volnitsa', ‘Volny Don', ‘Zhavoronok', ‘Polina', ‘Ambar', ‘Donskaya Stepp', ‘Yubiley Dona' was carried out for all indicators from 16 to 32%. The variety ‘Zhavoronok' was found the best according to the indicators and its rejection rate was 7%. In PIP-2 over the years of variety trials, the studied varieties of winter bread wheat were rejected in the field for all indicators from 2 to 7%. In the laboratory conditions, the rejection rate was slightly different and ranged from 1 to 8%. The highest seed productivity was formed by the varieties ‘Zernogradka 11' (11.2 t/ha), ‘Ermak' (10.8 t/ha), ‘Marafon' (11.5 t/ha) and ‘Krasa Dona' (11.5 t/ha). The percentage of seed productivity of the studied varieties varied from 67.4% to 93.3%. The maximum 1000 seed weight was identified in the varieties ‘Krasa Dona' (52.7 g), ‘Volny Don' (49.8 g), ‘Volnitsa' (49.1 g). The indicators of the main varietal and sowing qualities of winter wheat seeds corresponded to GOST R 52325-2005

Productivity and sowing qualities of spring barley seeds when using biostimulants in the primary seed production

The current paper has presented the study results of 2017–2019 on estimating the indices of productivity and sowing seed qualities of the spring barley varieties ‘Gris’ and ‘Leon’. Ther was conducted pre-sowing treatment of seed material, depending on the fractional composition of grain and plants during the growing season. There were used the growth biostimulants based on algae Ruter and Stimax Start in the conditions of the southern part of the Rostov region. There has been found out that seed and plant treatment with biostimulants had an effect on the sowing qualities and yield properties of seeds. There has been established that the seeds isolated on sieves with a hole diameter of 2.4 × 20 mm, when using the biological product Ruter, had the highest germination energy (93–94%) and laboratory germination (97%), as well as the highest yield in the studied spring barley varieties ‘Gris’ (8.8 t/ha) and ‘Leon’ (8.3 t/ha). The largest grain size was obtained from the 2.4 × 20 fraction using the biological product Ruter (the variety ‘Leon’ produced 43.1 g and the variety ‘Gris’ produced 50.1 g). The maximum seed yield in the studied varieties after treatment (86.4 and 90.1%, respectively) was also identified in the 2.4 × 20 mm fraction when using the biostimulator Ruter. On the control without biostimulants, the seed yield of the variety ‘Leon’ in the 2.4 × 20 fraction was 80.3%, and that of the variety ‘Gris’ was 81.4%. There has been shown an economic efficiency of the biological products depending on the fraction of sowing material in the cultivation technology of spring barley. The largest productivity increase (the variety ‘Leon’ 1.2 t/ha (2.4 × 20 mm fraction) and ‘Gris’ 0.9 t/ha (2.2 × 20 mm fraction)) was obtained in the variants when using the bioproduct Ruter with the maximum (195.8%) profitability of the variety ‘Gris’. The results of the trials have shown that the use of biostimulants based on algae in general had a positive effect on the development of spring barley varieties and the production of high-quality seed material in the Rostov region

Seed production and variety changing periods of spring barley in the FSBSI “ARC “Donskoy”

The current paper has presented the stages of variety changing and the results of four-year study (2016-2019) of spring barley varieties bred in different years by the farmers of the Center. The area occupied by spring barley in the Rostov region in 2016-2019 ranged from 315.12 to 406.41 thousand hectares, which was from 6.7 to 8.9% of the total arable land. The average productivity in the region for all the years studied was 2.3 t/ha, varying from year to year from 1.7 t/ha in the dry 2018 year to 2.8 t/ha in the most favorable 2017 year. The 2018 year was unfavorable in terms of climatic conditions, where the area under spring barley was almost 354 thousand hectares, and the gross yield was 601.8 thousand tons. The purpose of the work was to consider the periods of spring barley variety changing in primary seed production. The study was carried out on blackearth (chernozem) soils of the southern zone of the Rostov region at the FSBSI “Agricultural Research Center “Donskoy”. The varieties were sown in the spring at the time optimal for spring crops. The maximum productivity of many spring barley varieties in breeding plots exceeded 5.0 t/ha. In 2016-2019 in seed plots, there were sown such spring barley varieties as “Gris”, “Ratnik”, “Leon”, “Schedry”. The year of 2018 was unfavorable for these varieties, both in scientific departments and among agricultural producers in the Rostov region. The variety “Schedry” showed the lowest productivity (4.8 t/ha and 3.9 t/ha) and 1000 grain weight (45.0 g and 42.2 g) in both PIP-2 and OS-1. In the favorable year of 2017, the variety “Gris” showed the best results, namely 8.0 t/ha of productivity and 50.6 g of 1000 grain weight. The variety “Gris” was characterized with a stable high 1000 grain weight (on average 50 g) through all years. In different years the varieties “Ratnik” and “Leon” produced the best yields