Beyond the marrow:insights from comprehensive next-generation sequencing of extramedullary multiple myeloma tumors

Extramedullary multiple myeloma (EMM) is an aggressive form of multiple myeloma (MM). This study represents the most comprehensive next-generation sequencing analysis of EMM tumors (N = 14) to date, uncovering key molecular features and describing the tumor microenvironment. We observed the co-occurrence of 1q21 gain/amplification and MAPK pathway mutations in 79% of EMM samples, suggesting that these are crucial mutational events in EMM development. We also demonstrated that patients with mutated KRAS and 1q21 gain/amplification at the time of diagnosis have a significantly higher risk of EMM development (HR = 2.4, p = 0.011) using data from a large CoMMpass dataset. We identified downregulation of CXCR4 and enhanced cell proliferation, along with reduced expression of therapeutic targets (CD38, SLAMF7, GPRC5D, FCRH5), potentially explaining diminished efficacy of immunotherapy. Conversely, we identified significantly upregulated EZH2 and CD70 as potential future therapeutic options. For the first time, we report on the tumor microenvironment of EMM, revealing CD8+ T cells and NK cells as predominant immune effector cells using single-cell sequencing. Finally, this is the first longitudinal study in EMM revealing the molecular changes from the time of diagnosis to EMM relapse.</p

Assessment of Seroprevalence to SARS-CoV-2 in Various Population Cohorts Using Logit Regression Models During Initial Period of Herd Immunity Formation

The aim of the study was to assess the dynamics of seroprevalence to SARS-CoV-2 in various population groups during the initial period of herd immunity formation based on multivariate analysis using logit regression models.Materials and methods. The study involved 1561 individuals divided into three population cohorts: people living with HIV/AIDS (PLHA), healthy blood donors, medical workers. The presence of antibodies to SARS-CoV-2 was determined in blood serum through ELISA using commercial reagent kits. Multivariate analysis of the dynamics of seroprevalence to SARS-CoV-2 was carried out using logistic regression models.Results and discussion. It has been revealed that probability of detecting IgG antibodies to SARS-CoV-2 significantly increased among the donors and medical workers in the spring-autumn 2020 series (p=0.005 и p&lt;0.001, respectively), which corresponds to seroprevalence shift in the general population. Groups of donors and medical workers can be considered as indicator groups that characterize the herd immunity in reference to SARS-CoV-2, as well as the intensity of COVID-19 epidemic process. Seroprevalence to SARS-CoV-2 in PLHA group was at a consistently high level throughout the observation period. The generated logistic regression models made it possible to determine the trends in the development of the epidemic situation based on multifactorial analysis of the dynamics of seroprevalence to SARS-CoV-2

HEMITSELLYULOZA AND THEIR NANOBIOCOMPOSITES - PERSPECTIVE NANOSTRUCTURED SINBIOTICS

Natural nanocomposites hemicellulose arabinogalactan and flavonoids isolated (from Siberian larch) and characterized. Additionally nitro- and sulfo-esters of arabinogalactan and its calcium salt are synthesized and. characterized. All of the derivatives of the beta-hemicellulose arabinogalactan. are water-soluble and are promising prebiotics on the example test-strain Bifidobacterium bifidum. (except for the nitrate esters of arabinogalactan)

Acute myocardial ischemia: changes of free circulating mtDNA level in blood after occlusion of the upper one-third left descending branch of the coronary artery

The aim of the present study is to analyze the dynamics of free circulating mtDNA level in blood after occlusion of the upper one-third left descending branch of the coronary artery. We showed that the concentration of free circulating mtDNA of blood tends to decrease 24 hours after ligation; it increased and reached values close to control samples 48 and 72 hours after ligation. These data define the need in further investigation of the dynamics of this parameter during later periods of myocardial infarction modeling that will contribute to objective evaluation of its significance for acute myocardial damage diagnostics and prognosis

Динамика Т- и В-лимфоцитов у больных ревматоидным артритом, получающих терапию генно-инженерными биологическими препаратами

Objective: assessment of the dynamics of T- and B-lymphocytes subpopulations in rheumatoid arthritis (RA) during therapy with synthetic disease-modifying antirheumatic drugs (sDMARDs) and biological disease-modifying antirheumatic drugs (bDMARDs): inhibitors of tumor necrosis factor α (iTNFα) and an inhibitor of interleukin 6 receptors (iIL6R ).Patients and methods. The study included 77 patients with RA who met the 2010 ACR/EULAR criteria (mean age 56 [44; 62] years). Group 1 included 30 (27 women and 3 men) patients with early RA who had not previously received therapy. Group 2 included 20 (14 women and 6 men) patients on sDMARD therapy who were prescribed iTNFα for the first time. The 3rd group is represented by retrospective data of 27 (23 women and 4 men) patients who previously used sDMARDs (MT – 85%, leflunomide – LEF – 15%), in whom iIL6R therapy was initiated for the first time. All study participants initially and 6 months later underwent immunophenotyping of T- and B-lymphocytes by flow cytofluorometry according to the standard method.Results and discussion. In all groups, there were no significant changes in the studied T-lymphocyte profile during 6 months of follow-up. When comparing the immunogram data of patients treated with sDMARDs and iTNFα, no significant differences in subpopulations of B-lymphocytes were found. At baseline, the iIL6R group had higher levels of naive B-lymphocytes and plasmablasts and low concentrations of «switched» B-cells. For all methods of treatment, the number of «switched» B-cells decreased, while plasmablasts and plasma cells increased.Conclusion. From the data obtained, it follows that the simultaneous decrease in the levels of memory B-cells and their «switched» forms, plasmablasts and plasma cells can be used as a marker for the early administration of drugs that disrupt the differentiation of B-lymphocytes, in particular, iIL6R.Цель исследования – оценка динамики субпопуляций Т- и В-лимфоцитов при ревматоидном артрите (РА) на фоне терапии синтетическими базисными противовоспалительными препаратами (сБПВП) и генно-инженерными биологическими препаратами (ГИБП): ингибиторами фактора некроза опухоли α (иФНОα) и ингибитором рецепторов интерлейкина 6 (иИЛ6Р).Пациенты и методы. В исследование включено 77 пациентов с РА, удовлетворявших критериям ACR/EULAR 2010 г. (средний возраст 56 [44; 62] лет). В 1-ю группу вошли 30 больных (27 женщин и 3 мужчин) с ранним РА, ранее не получавших терапию. 2-ю группу составили 20 пациентов (14 женщин и 6 мужчин), находящихся на терапии сБПВП, которым впервые назначены иФНОα. 3-я группа представлена ретроспективными данными 27 больных (23 женщины и 4 мужчин), ранее применявших сБПВП (МТ – 85%, лефлуномид – ЛЕФ – 15%), которым впервые инициирована терапия иИЛ6Р. У всех участников исследования исходно и через 6 мес проведено иммунофенотипирование Т- и В-лимфоцитов методом проточной цитофлюорометрии по стандартной методике.Результаты и обсуждение. Во всех группах значимых изменений исследуемого профиля Т-лимфоцитов в течение 6 мес наблюдения не выявлено. При сравнении данных иммунограмм пациентов, получавших сБПВП и иФНОα, значимых различий в субпопуляциях В-лимфоцитов не установлено. Исходно больные группы иИЛ6Р имели более высокие уровни наивных В-лимфоцитов и плазмобластов и низкие концентрации «переключенных» В-клеток. При всех методах лечения количество «переключенных» В-клеток сокращалось, а плазмобластов и плазмоцитов нарастало.Заключение. Из полученных данных следует, что одновременное снижение уровней В-клеток памяти и их «переключенных» форм, плазмобластов и плазмоцитов можно использовать как маркер для раннего назначения препаратов, нарушающих дифференцировку В-лимфоцитов, в частности иИЛ6Р

Economic Ideas and Institutional Change: Evidence from Soviet Economic Discourse 1987-1991

In recent years, institutional and evolutionary economists have become increasingly aware that ideas play an important role in economic development. In the current literature, the problem is usually elaborated upon in purely theoretical terms. In the present paper it is argued that ideas are always also shaped by historical and cultural factors. Due to this historical and cultural specificity theoretical research must be supplemented by historical case studies. The paper analyses the shift in ideas that took place in Soviet economic thought between 1987 and 1991. This case study, it is argued, may contribute to our understanding of the links between ideas and institutions. More specifically, it sheds new light on the issue of whether the evolution of economic ideas is pathdependent, so that they change only incrementally, or whether their development takes place in a discontinuous way that can best be compared with revolutions

THE RELATIONSHIP OF FoxP3+ T REGULATORY CELLS TO DISEASE ACTIVITY AND ANTIBODY LEVELS IN EARLY RHEUMATOID ARTHRITIS

Objective: to analyze the relationship of the count of FoxP3+ T regulatory cells (Tregs) to the clinical and laboratory parameters of disease activity and the levels of antibodies in a group of patients with early rheumatoid arthritis (RA).Subjects and methods. The investigation enrolled 45 patients with early RA (2010 ACR/EULAR criteria) who had not previously received treatment with methotrexate, including 39 women; median age was 52.0 [32.5; 57.5] years; disease duration, 5 [4; 6] months, DAS28 5.01 [4.18; 5.8]; 71.1% of the patients were rheumatoid factor (RF) positive and 88.9% were anti-cyclic citrullinated peptide positive. The relative and absolute counts of Treg (FoxP3+CD25+; CD152+surface; CD152+intracellular; FoxP3+CD127-; CD25+CD127-; FoxP3+ICOS+; FoxP3+CD154+; FoxP3+CD274+) were measured by immunofluorescence staining and multicolor flow cytometry. A control group consisted of 20 healthy donors who were matched for sex and age with the examined patients.Results and discussion. DАS28 was high, moderate, and low in 22 (48.9%), 20 (44.4%), and 3 (6.7%) patients, respectively. As compared with the healthy donors, the patients with early RA were observed to have lower values in the percentage of FoxP3+CD25+ cells, in the percentage and absolute count of FoxP3+ICOS+ cells, in the percentage and absolute count of FoxP3+CD154+ and FoxP3+ CD274+ T cells; p&lt;0.05 in all cases. Negative correlation was recorded between the percentage of FoxP3+CD25+ and C-reactive protein (CRP) (r=-0.4); that of CD152+intracellular and DAS28 (r=-0.35), ESR (r=-0.46), CRP (r=-0.54); that of FoxP3+CD127 and CRP (r=-0.42); that of CD25+CD127 and DAS28 (r=-0.38), SDAI (r=-0.41), CDAI (r=-0.36), ESR (r=-0.39), CRP (r=-0.47); p&lt;0.05 in all cases.The patients who were seronegative for RF were found to have higher values in the percentage of CD25+CD127, in the percentage and absolute count of Foxp3+CD154+ and Foxp3+CD274+ T lymphocytes.Conclusion. The given data may indicate that the count and functional activity of Treg were decreased in early RA, which is associated with higher disease activity, the systemic manifestations of the disease and which is also accompanied by antibody hyperproduction

CHANGES IN THE LEVEL OF FoxP3+ REGULATORY T LYMPHOCYTES IN PATIENTS WITH EARLY RHEUMATOID ARTHRITIS DURING METHOTREXATE THERAPY

Objective: to analyze the impact of methotrexate (MTX) therapy on percentage and absolute content of FoxP3+ regulatory T lymphocytes (Treg) in the peripheral blood of patients with early rheumatoid arthritis (RA) who had not previously received MTX.Subjects and methods. The investigation included 45 patients with early RA (2010 ACR/EULAR criteria) who had not previously received MTX, including 39 women; median age was 52.0 [32.5; 57.5] years; disease duration, 5 [4; 6] months, DAS28, 5.01 [4.18; 5.8]; 71.1% of the patients were positive for rheumatoid factor and 88.9% – for anticyclic citrullinated peptide antibodies. As the first disease-modifying antirheumatic drug, all the patients were assigned to receive subcutaneous MTX at an initial dose of 10 mg/week with its rapid escalation up to 20–25 mg/week. The percentage and absolute count of Treg (FoxP3+CD25+; CD152+surface; CD152+intracellular; FoxP3+CD127-; CD25+CD127-; FoxP3+ICOS+; FoxP3+CD154+; and FoxP3+CD274+) were measured by immunofluorescence staining and multicolor flow cytometry.Results and discussion. At 24 weeks after starting the therapy, median DAS28, SDAI, and CDAI were 3.1 [2.7; 3.62], 7.4 [4.2; 11.4], and 7.0 [4.0; 11.0], respectively; DAS28 and SDAI remission/low disease activity was reached by 22 (56.4%) and 25 (64.1%) patients, respectively; 4 (10.3%) patients had no MTX treatment effect according to the EULAR criteria. After a 6-month course of MTX therapy, the whole group had increases in the percentage of CD4+cells (from 45.0 [38.0; 49.2] to 46.8 [39.9; 53.2]%) and in the percentage and absolute number of CD152+surface from 0.65 [0.22; 1.67] to 2.07 [1.11; 3.81]% and from 0.0002 [0.0001; 0.0008]•109 to 0.0007 [0.0004; 0.002]•109, and a moderate decrease in the percentage and absolute content of FoxP3+ICOS+ cells from 5.3 [2.1; 11.3] to 4.07 [1.6;6.6]% and from 0.002 [0.001-0.006]•109 to 0.0015 [0.0006-0.003]•109 (p&lt;0.05 in all cases).Conclusion. The use of MTX in early RA is accompanied by an increase in the proportion and number of Treg with a high level of activation markers, which may indicate their enhanced suppressor activity that is more pronounced among the patients who have achieved remission/low disease activity during the treatment