STUDY OF MINIMAL RESIDUAL DISEASE BY MULTICOLOR FLOW CYTOMETRY IN MULTIPLE MYELOMA AFTER AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION

The frequency of achieving complete remission, as well as overall and disease-free survival, in multiple myeloma (MM) had increased due to introduction in MM treatment regimens of high-dose chemotherapy with following autologous hematopoietic stem cell transplantation (ASCT). However the number of relapses remains high, caused by persistence of residual tumor cells, i.e., the presence of minimal residual disease (MRD). One of the methods for MRD study is multicolor flow cytometry (MFC) where abnormal expression of surface antigens on myeloma plasma cells (PC) is determined. The aim of our study was to investigate the MRD by MFC before and after ASCT, the frequency of MRD-negative status achievement in complete remission (CR) patients at +100 days after ASCT and the frequency of abnormal expressed antigens on myeloma plasma cells. The study included40 MMpatients in CR at +100 days after ASCT and showed that the most common aberrations of PC were: abnormal absence of CD19 and/or CD27, decreased expression of CD38 and abnormal presence of CD56. The proportion of myeloma PCs from all bone marrow cells decreased significantly after ASCT: 20 % of patients acquired MRD-negative status, 10 % had a decrease in the number of abnormal PCs by one fold. Analysis of probability of immunochemical relapse showed that the worst prognosis was in patients with MRD-positive status before and after ASCT. During the MRD monitoring within 3-18 months, MRD-relapses were detected with the subsequent development of immunochemical relapse. The detection MRD in the dynamics is more informative than the study at only one step of therapy. It may help to select more adequate treatment for patient with multiple myeloma in each specific case

Применение различных схем противовирусной терапии ОРВИ у детей

To optimize selection of antiviral agents for children in routine practice of ARVI management, a double-center, prospective, open-label, randomized study of efficacy and tolerability of schemes including Ergoferon, Cagocel, Arbidol in children > 3 years was performed throughout two epidemic seasons (fall 2012 — spring 2014). In total 152 children with ARVI symptoms lasting for no more than 48 hours were randomized into 3 groups, i.e. Ergoferon (group E, n = 67), Cagocel (group C, n = 40), Arbidol (group A, n = 45). At visits 2 and 3 proportion of children with normalized body temperature (primary criterion) and intensity of intoxication and catarrhal syndrome were evaluated. At visit 3 the following parameters were measured: efficacy index (efficacy and tolerability assessment by the doctor using CGI scale) and evaluation of safety and tolerability of the study drug by parents/representatives of the child; incidence of medical product prescriptions was recorded, i.e. the total number of prescriptions per group, incidence and duration of administration of individual groups of agents. To analyze and evaluate the data obtained, conventional methods of parametric and non-parametric statistics were applied. Groups C and A were not statistically different in baseline characteristics and throughout efficacy criteria assessment. A new group 2 (n=85) was generated out of these groups for further analysis. At visit 2 group 1 and group 2 showed normalization in morning and evening body temperature in 76% and 79% in group 1, respectively, vs. 73% and 79% — in group 2 (2, p > 0.05). 100% subjects in group 1 and 98% — in group 2 did not have intoxication signs, or the rank value of mild intoxication did not exceed 1 (mild). Proportion of subjects with mild catarrhal syndrome at rank 2—3 in group 1 vs. baseline reduced from 15% to 3%, in group 2 — from 18% to 8%. At visit 3, 94% subjects in group 1 and 95% — in group did not show clinical intoxication signs. Almost every one in three children in both groups had catarrhal signs completely resolved by the end of the treatment, in 70% and 65% cases in groups 1 and 2 severity of catarrhal syndrome did not exceed rank 1 (2, p > 0.05). No adverse effects associated with the study scheme components have been reported during the study. Efficacy and tolerability evaluation by the doctors using CGI in group 1 was 3.37 ± 0.65 (M ± SD, 95% CI 3.22-3.53) vs. 3.23 ± 0.77 (M ± SD, 95%CI 3.08—3.39) in group 2 (Т-test, p = 0.38). In group 1 maximum rating (4 scores) was assigned by the doctors in 46%, minimum one (2 scores) — in 9%, while in group 2 the equivalent proportions were 40% and 16%, respectively (p = 0.44 for maximum score and p = 0.17 for minimum score). Therapeutic efficacy evaluation by  parents in group 1 was 3.73 ± 0.57 (M ± SD, 95% CI 3.59-3.87) vs. 3.35 ± 0.72 (M ± SD, 95%CI 3.20—3.50) in group 2; Т-test, p = 0.04. According to frequency assessment, positive scoring (4-5 scores) was more prevalent among parents in group 1: 71% vs. 44% (group 2), 2 test, p = 0.001, minimum scoring (2 scores) was less common in group 1: 1.5% vs. 12% (group 2),?2 test, p = 0.02. Evaluation of therapeutic tolerability by parents in group 1 (4.04 ± 0.53, 95%CI 3.91—4.18) was higher as compared to group 2 (3.82 ± 0.53, 95%CI 3.71—3.93); Т-test, p = 0.01. Maximum scoring (5 scores) was obtained in group 1 in 16% cases, in group 2 — 6% (2 test, p = 0.03). Analysis of additional drug prescriptions revealed that 3.6 ± 1.2 prescriptions have been made on average in group 1 vs. 5.0 ± 1.2 in group 2 (Т-test, р = 0.01). Proportion of children receiving more than 5 drugs was 18% in group 1 vs. 32% in group 2 (2 test, p = 0.05). Seven drugs were given to 3% children in group 1 and 12% — in group 2 (exact Fisher’s test, p = 0.067). Duration of therapy with H1-histamine blockers in group 1 was 5 days (Me: 5.0 (5.0; 6.0) vs. 8.5 days (Me: 8.5 (7.5; 10.0) in group 2 (U-test, р = 0.006). Therefore, comparable clinical efficacy and tolerability of anti-ARVI therapeutic schemes were revealed in children using Ergoferon, Cagocel and Arbidol. At that Ergoferon group showed higher therapeutic quality scoring (efficacy and tolerability), both according to the doctors (CGI scale) and parents. Reduced number of prescriptions and duration of drug therapy in Ergoferon group for ARVI management were revealed.С целью оптимизации выбора противовирусных средств у детей в рутинной практике лечения ОРВИ было проведено двухцентровое проспективное открытое рандомизированное исследование эффективности и переносимости схем терапии с применением Эргоферона, Кагоцела, Арбидола у детей в возрасте старше 3 лет на протяжении двух эпидсезонов (осень 2012 — весна 2014 гг.). 152 ребенка с симптомами ОРВИ, продолжительностью не более 48 часов, были рандомизированы в 3 группы, в которых для лечения ОРВИ применялись Эргоферон (группа Э, 67 пациентов), Кагоцел (группа К, 40 пациентов), Арбидол (группа А, 45 пациентов). На 2-м и 3-м визитах оценивалась доля пациентов с нормализацией температуры тела (первичный критерий), выраженность интоксикационного и катарального синдромов. На 3-м визите регистрировались: индекс эффективности (оценка врачом эффективности и переносимости терапии по шкале CGI) и оценки эффективности и переносимости исследуемого препарата со слов родителей/представителей ребенка; анализировалась частота назначения медикаментов — общее число назначений в группе, частота и продолжительность применения отдельных групп препаратов. Для анализа и оценки полученных данных применялись стандартные методы параметрической и непараметрической статистики. Группы К и А не имели статистически значимых различий в исходных характеристиках и в динамике оцениваемых критериев эффективности и для дальнейшего анализа из них была сформирована новая группа 2 (85 пациентов). На 2-м визите отмечалась нормализация утренней и вечерней температуры тела в 76 и 79% соответственно, в 1-й группе, против 73 и 79% — во 2-й группе (2, p > 0,05). 100% пациентов из 1-й группы и 98% пациентов — из 2-й группы не имели признаков интоксикации или ранговый показатель синдрома интоксикации был не выше 1 (слабо выражен). Доля пациентов с выраженностью катарального синдрома на уровне 2-3 рангов в 1-й группе по сравнению с исходными данными сократилась с 15 до 3%, во 2-й группе — с 18 до 8%. На 3-м визите 94% пациентов в 1-й группе и 95% во — 2-й группе не имели клинических проявлений интоксикации, практически, каждый третий ребенок из обеих групп полностью избавился от катаральных явлений к окончанию лечения, в 70 и в 65% случаев в 1-й и 2-й группах выраженность катарального синдрома не превышала 1 ранга (2, p > 0,05). В ходе проведения исследования не было зарегистрировано побочных эффектов, связанных с приемом тех или иных компонентов исследуемых схем терапии. Оценка эффективности и переносимости, данная врачами по шкале CGI в 1-й группе составила 3,37 ± 0,65 (M ± SD, 95%CI 3,22—3,53), против 3,23 ± 0,77 (M ± SD, 95%CI 3,08-3,39) во 2-й группе (Т-критерий, p = 0,38). В 1-й группе максимальную оценку (4 балла) врачи поставили в 46%, а минимальную (2 балла) — в 9%, в то время, как во 2-й группе аналогичные доли составили 40 и 16% соответственно (p = 0,44 для максимальной оценки и p = 0,17 для минимальной оценки). Оценка эффективности терапии родителями в 1-й группе составила 3,73 ± 0,57 (M ± SD, 95%CI 3,59-3,87) против 3,35 ± ± 0,72 (M ± SD, 95%CI 3,20—3,50) в 2-й группе; Т-критерий, p = 0,04. По данным частотного анализа балльных оценок, положительные оценки (4—5 баллов) чаще ставили родители детей из 1-й группы: 71% против 44% (2-я группа), критерий 2, p = = 0,001, минимальные оценки (2 балла) реже встречались во 1-й группе: 1,5% против 12% (2-я группа), критерий 2, p = 0,02. Оценка переносимости терапии, данная родителями в 1-й группе (4,04 ± 0,53, 95%CI 3,91-4,18) была более высокой, чем в 2-й группе (3,82 ± 0,53, 95%CI 3,71—3,93); Т-критерий, p = 0,01. Максимальная оценка в 5 баллов получена в 1-й группе в 16% случаев, а в 2-й группе — 6% (критерий 2, p = 0,03). В ходе анализа дополнительных медикаментозных назначений было выявлено, что в среднем в 1-й группе осуществлялось 3,6 ± ± 1,2 назначений, против 5,0 ± 1,2 во 2-й группе (Т-критерий, р = 0,01). Доля детей, получавших более 5 медикаментов, в 1-й группе составила 18%, тогда как во 2-й группе доля таких назначений была выше — 32% (критерий 2, p = 0,05). 7 препаратов получало 3% детей в 1-й группе и 12% пациентов во 2-й группе (точный критерий Фишера, p = 0,067). Продолжительности терапии H1 гистамино-блокаторами 1-й группе составила 5 дней (Me: 5,0 (5,0; 6,0) против 8,5 дней (Me: 8,5 (7,5; 10,0) их использования во 2-й группе (U-критерий, р = 0,006). Таким образом, выявлена сопоставимая клиническая эффективность и переносимость применения схем терапии ОРВИ у детей с использованием Эргоферона, Кагоцела и Арбидола. При этом в группе детей, получавших Эргоферон, чаще регистрировались более высокие оценки качества терапии (эффективность и переносимость), как со стороны врачей (по шкале CGI), так и со стороны родителей. Выявлено уменьшение числа назначаемых препаратов и снижение продолжительности применения препаратов в группе детей, получавших Эргоферон для лечения ОРВИ

Sequence-Specific Binding of Recombinant Zbed4 to DNA: Insights into Zbed4 Participation in Gene Transcription and Its Association with Other Proteins

Zbed4, a member of the BED subclass of Zinc-finger proteins, is expressed in cone photoreceptors and glial Müller cells of human retina whereas it is only present in Müller cells of mouse retina. To characterize structural and functional properties of Zbed4, enough amounts of purified protein were needed. Thus, recombinant Zbed4 was expressed in E. coli and its refolding conditions optimized for the production of homogenous and functionally active protein. Zbed4’s secondary structure, determined by circular dichroism spectroscopy, showed that this protein contains 32% α-helices, 18% β-sheets, 20% turns and 30% unordered structures. CASTing was used to identify the target sites of Zbed4 in DNA. The majority of the DNA fragments obtained contained poly-Gs and some of them had, in addition, the core signature of GC boxes; a few clones had only GC-boxes. With electrophoretic mobility shift assays we demonstrated that Zbed4 binds both not only to DNA and but also to RNA oligonucleotides with very high affinity, interacting with poly-G tracts that have a minimum of 5 Gs; its binding to and GC-box consensus sequences. However, the latter binding depends on the GC-box flanking nucleotides. We also found that Zbed4 interacts in Y79 retinoblastoma cells with nuclear and cytoplasmic proteins Scaffold Attachment Factor B1 (SAFB1), estrogen receptor alpha (ERα), and cellular myosin 9 (MYH9), as shown with immunoprecipitation and mass spectrometry studies as well as gel overlay assays. In addition, immunostaining corroborated the co-localization of Zbed4 with these proteins. Most importantly, in vitro experiments using constructs containing promoters of genes directing expression of the luciferase gene, showed that Zbed4 transactivates the transcription of those promoters with poly-G tracts

ВАРИАЦИИ СИЛЫ ТЯЖЕСТИ И СОВРЕМЕННАЯ ГЕОДИНАМИКА ЮГОЗАПАДНОЙ ЧАСТИ БАЙКАЛЬСКОГО РЕГИОНА

Modern methods for determination of gravity values make it possible to obtain measurements with the accuracy up to 10–9 from g0 of the normal value (up to 1 microgal = 10 m/sec2). While all the systematic and periodic effects are excluded, a question is raised about stability of the gravity field of the Earth over time. Changes of the altitude (the Earth’s radius) with time can be estimated with an accuracy of 0.1 mm by modern space geodetic techniques, such as VLBI method. Our experiments for evaluation of stability of the gravity values over the past decades are based on the data obtained by Russian and foreign observatories using absolute ballistic laser gravimeters. The results put a limit of 10–10 per year to changes of the Earth’s radius. These estimations can be useful for testing hypotheses in tectonics.Measurements of non-tidal variations of gravity (Δg), which were obtained from 1992 to 2012 at the Talaya seismic station (located in the south-western part of the Baikal region), are interpreted together with GPS observation data. At the Talaya seismic station, the linear component of gravity variations corresponds to changes in the elevation of this site. The correlation coefficient is close to the normal value of the vertical gradient of gravity. At this site, coseismic gravity variations at the time of the Kultuk earthquake (27 August 2008, Mw=6.3) were caused by a combined effect of the change of the site’s elevation and deformation of the crust. Our estimations of the coseismic effects are consistent with results obtained by modeling based on the available seismic data.Современные методы определения значения силы тяжести позволяют проводить измерения с точностью до 10–9 от g0 нормального значения (до 1 микрогала = 10 нм/с2). При этом исключаются все систематические и периодические эффекты и возникает вопрос о стабильности поля силы тяжести Земли во времени. Оценить изменения высоты (радиуса Земли) во времени с точностью до 0.1 мм позволяют современные методы космической геодезии (VLBI метод). Экспериментальные оценки стабильности значения силы тяжести за последние десятилетия сделаны по материалам отечественных и зарубежных обсерваторий, использующих абсолютные лазерные баллистические гравиметры. Полученные результаты ограничивают изменение радиуса Земли значением 10–10 в год. Эти оценки можно использовать для тестирования тектонических гипотез.Результаты измерений неприливных вариаций ускорения силы тяжести Δg, проведенных в 1992–2012 гг. на сейсмостанции «Талая» (юго-западная часть Байкальского региона), интерпретируются совместно с данными GPS-наблюдений. Линейная составляющая вариации силы тяжести на станции Талая соответствует изменениям высоты пункта. Коэффициент корреляции близок к нормальному значению вертикального градиента силы тяжести. Косейсмические вариации силы тяжести на этом пункте в эпоху Култукского землетрясения (27.08.2008 г., Мw=6.3) вызваны комплексным эффектом изменения высоты пункта и деформации земной коры. Оценки косейсмических эффектов соответствуют результатам моделирования на основе сейсмологических данных

Control reconstruction in hyperbolic systems

We consider an inverse dynamics problem which is to reconstruct a priori unknown distributed controls in a hyperbolic system given the results of approximate observations of the movements of this system. To solve this ill-posed problem, we propose to use the Tikhonov's method with a regularizer containing the sum of mean squared norm and the total variation over the time of an admissible control. Using such a regularizer lets one get, in a number of cases, better results than just approximating the control in question in Lebesgue spaces. In particular, along these lines we can establish pointwise and piecewise uniform convergence for regularized approximations, which opens up new opportunities for numerical reconstruction of the fine structure of the control. We give numerical modeling results. © 2012 Pleiades Publishing, Ltd

RENIN-ANGIOTENSIN SYSTEM IN REGULATION OF HEMATOPOIESIS

The renin-angiotensin system (RAS) has long been known as the endocrine system involved in the regulation of arterial pressure and waterelectrolyte balance. Local (tissue) RAS can influence cellular activity, tissue damage and regeneration. In the bone marrow there are active ligands of peptides, mediators, receptors and signaling pathways of the RAS. Local RAS can influence the growth, production, proliferation and differentiation of hematopoietic cells and participate in the regulation of both normal and pathological hematopoiesis. Angiotensin-converting enzyme (ACE) CD143 plays a key role in the classical RAS. After differentiation from hemangioblast, hematopoietic progenitor cells constantly express ACE in human embryonic, fetal and adult hematopoietic tissues, as well as at all stages of hematopoietic ontogeny. The ACE cleaves the C-terminal dipeptide and thus forms the octapeptide Angiotensin II. In addition to angiotensin II, ACE also regulates a group of biologically active peptides, such as substance P, ac-SDKP and angiotensin 1–7. Local RAS is also one of the most important components in the tumor microenvironment, affecting tumor growth and metastasis by autocrine and paracrine pathways, modulating numerous carcinogenic events such as angiogenesis, apoptosis, cell proliferation, immune responses, and extracellular matrix formation.The purpose of this review is to describe the known functions of local RAS in the hematopoiesis regulation. More detailed study of the RAS components mechanisms of action will expand therapy approaches in the neoplastic diseases and in bone marrow transplantation

The use of Different Schemes of Antiviral Therapy of Acute Respiratory Viral Infection in Children

To optimize selection of antiviral agents for children in routine practice of ARVI management, a double-center, prospective, open-label, randomized study of efficacy and tolerability of schemes including Ergoferon, Cagocel, Arbidol in children > 3 years was performed throughout two epidemic seasons (fall 2012 — spring 2014). In total 152 children with ARVI symptoms lasting for no more than 48 hours were randomized into 3 groups, i.e. Ergoferon (group E, n = 67), Cagocel (group C, n = 40), Arbidol (group A, n = 45). At visits 2 and 3 proportion of children with normalized body temperature (primary criterion) and intensity of intoxication and catarrhal syndrome were evaluated. At visit 3 the following parameters were measured: efficacy index (efficacy and tolerability assessment by the doctor using CGI scale) and evaluation of safety and tolerability of the study drug by parents/representatives of the child; incidence of medical product prescriptions was recorded, i.e. the total number of prescriptions per group, incidence and duration of administration of individual groups of agents. To analyze and evaluate the data obtained, conventional methods of parametric and non-parametric statistics were applied. Groups C and A were not statistically different in baseline characteristics and throughout efficacy criteria assessment. A new group 2 (n=85) was generated out of these groups for further analysis. At visit 2 group 1 and group 2 showed normalization in morning and evening body temperature in 76% and 79% in group 1, respectively, vs. 73% and 79% — in group 2 (2, p > 0.05). 100% subjects in group 1 and 98% — in group 2 did not have intoxication signs, or the rank value of mild intoxication did not exceed 1 (mild). Proportion of subjects with mild catarrhal syndrome at rank 2—3 in group 1 vs. baseline reduced from 15% to 3%, in group 2 — from 18% to 8%. At visit 3, 94% subjects in group 1 and 95% — in group did not show clinical intoxication signs. Almost every one in three children in both groups had catarrhal signs completely resolved by the end of the treatment, in 70% and 65% cases in groups 1 and 2 severity of catarrhal syndrome did not exceed rank 1 (2, p > 0.05). No adverse effects associated with the study scheme components have been reported during the study. Efficacy and tolerability evaluation by the doctors using CGI in group 1 was 3.37 ± 0.65 (M ± SD, 95% CI 3.22-3.53) vs. 3.23 ± 0.77 (M ± SD, 95%CI 3.08—3.39) in group 2 (Т-test, p = 0.38). In group 1 maximum rating (4 scores) was assigned by the doctors in 46%, minimum one (2 scores) — in 9%, while in group 2 the equivalent proportions were 40% and 16%, respectively (p = 0.44 for maximum score and p = 0.17 for minimum score). Therapeutic efficacy evaluation by  parents in group 1 was 3.73 ± 0.57 (M ± SD, 95% CI 3.59-3.87) vs. 3.35 ± 0.72 (M ± SD, 95%CI 3.20—3.50) in group 2; Т-test, p = 0.04. According to frequency assessment, positive scoring (4-5 scores) was more prevalent among parents in group 1: 71% vs. 44% (group 2), 2 test, p = 0.001, minimum scoring (2 scores) was less common in group 1: 1.5% vs. 12% (group 2),?2 test, p = 0.02. Evaluation of therapeutic tolerability by parents in group 1 (4.04 ± 0.53, 95%CI 3.91—4.18) was higher as compared to group 2 (3.82 ± 0.53, 95%CI 3.71—3.93); Т-test, p = 0.01. Maximum scoring (5 scores) was obtained in group 1 in 16% cases, in group 2 — 6% (2 test, p = 0.03). Analysis of additional drug prescriptions revealed that 3.6 ± 1.2 prescriptions have been made on average in group 1 vs. 5.0 ± 1.2 in group 2 (Т-test, р = 0.01). Proportion of children receiving more than 5 drugs was 18% in group 1 vs. 32% in group 2 (2 test, p = 0.05). Seven drugs were given to 3% children in group 1 and 12% — in group 2 (exact Fisher’s test, p = 0.067). Duration of therapy with H1-histamine blockers in group 1 was 5 days (Me: 5.0 (5.0; 6.0) vs. 8.5 days (Me: 8.5 (7.5; 10.0) in group 2 (U-test, р = 0.006). Therefore, comparable clinical efficacy and tolerability of anti-ARVI therapeutic schemes were revealed in children using Ergoferon, Cagocel and Arbidol. At that Ergoferon group showed higher therapeutic quality scoring (efficacy and tolerability), both according to the doctors (CGI scale) and parents. Reduced number of prescriptions and duration of drug therapy in Ergoferon group for ARVI management were revealed