Structure and significance of cytogenetic abnormalities in adult patients with Ph-negative acute lymphoblastic leukemia

Objective. To evaluate occurrence, variety, structural peculiarities and prognostic meaning of cytogenetic abnormalities in adult patients with Ph-negative acute lymphoblastic leukemia (ALL) receiving therapy according to ALL-2009 protocol. Materials and methods. The study included 115 adult patients with firstly diagnosed Ph-negative ALL: 58 male and 57 female aged from 15 to 61 years (mean age 26.5 years), who underwent treatment from September 2009 to September 2015 in National Medical Research Center for Hematology MH RF (n=101) and in hematology departments of regional hospitals (n=14). All patients received therapy of ALL-2009 protocol (ClinicalTrials.gov, NCT01193933). The median follow-up was 24.5 months (0.2-94.4 months). As a part of the study results of a standard cytogenetic assay (SCA) were analyzed and fluorescence hybridization in situ (FISH) with the use of DNA-probes was performed on archived biological material for structural changes in gene locuses MLL/t(11q23), с-MYC/t(8q24), TP53/ deletion 17p13, CDKN2A/ deletion 9p21, translocation t(1;19)/E2A-PBX1 и t(12;21)/ETV6-RUNX1; iAMP21 identification. Results. Karyotype was defined using SCA in 86% of patients. Normal karyotype was found in 48.5% of them, chromosome aberrations in 51.5% (structural changes were found in 19.2%, hyperploidy in 27.2%, and hypoploidy in 5.1%). In 17.2% of patients complex karyotype abnormalities were found. With the use of FISH technique aberrations were found in 67% of patients: 9p21/CDKN2A deletion in 24.3%, MLL/t(11q23) gene abnormalities in 7.8%, 17p13/TP53 deletion in 5.2%, abnormalities of c-MYC/t(8q24) in 1.7%, t(1;19)/E2A-PBX1 in 0.8%, and iAMP21 in 0.8%, other abnormalities (additional signals/absence of signals from gene locuses) in 26.4%, t(12;21)/ETV6-RUNX1 was not found. FISH technique use in addition to SCA allows to increase aberrant karyotype location from 51.5 to 67%. A statistically significant correlation of 9p21/CDKN2A deletion with high serum lactate dehydrogenase activity (p=0.02); MLL/t(11q23) gene abnormalities - with leucocytosis and high blast cells level in blood (p=0.0016), hyperploidy - with normal leukocyte count (p=0.02) was shown. In groups with different cytogenetic abnormalities no statistically significant differences of treatment with ALL-2009 protocol were found (in terms of complete remission, early mortality and treatment resistance). When connection of cytogenetic abnormalities and their combinations with long-term results were analyzed according to ALL-2009 protocol, only two characteristics - MLL/t(11q23) and c MYC/t(8q24) gene abnormalities had a statistically significant influence on disease-free survival (HR - 176.9;

Diagnostics and treatment challenges of Ph-like acute lymphoblastic leukemia: a description of 3 clinical cases

B-cell acute lymphoblastic leukemia (B-ALL) is a diverse group of malignant blood disorders both with regard to the biological properties of the tumor and to therapeutic approaches. Immunophenotyping, molecular genetic techniques, whole-genome sequencing characterize B-ALL as a very diverse group for sensitivity to chemotherapy and prognosis. We present three clinical cases of patients with B-ALL and expected good response to standard therapy, in whom standard protocol treatment failured: refractoriness, persistence of minimal residual disease (MRD), and progression (MRD increase). The remission in these patients was achieved after chemotherapy change to immunological targeted therapy. Nowadays a unified therapeutic approach to all primary patients of the B-ALL is considered generally outdated. Great efforts are carrying out to develop molecular genetic classifications. The molecular dissection of subtypes of B-ALL goes on, and new protocols for selective treatment with targeting are clearly outlined for each subtype of B-ALL

Results of program acute myeloid leukemia therapy use in National Medical Research Center for Hematology of the Ministry of Health of Russian Federation

Objective. To analyze treatment results of 172 patients with acute myeloid leukemia (AML) aged 18-60 years in National Medical Research Center for Hematology of MHRF. Materials and methods. Inductive and consolidation program for 139 (80%) patients was based on a standardized protocol: 4 courses “7+3” with different anthracycline use (2 courses of daunorubicin, idarubicin, mitoxantrone) and continuous use of cytarabine on the second inductive course. In 20% of patients cytarabine courses at the dose of 1 g/m2 2 times a day for 1-3 days combined with idarubicin and mitoxantrone were used as two consolidation courses. Allogenic bone marrow transplantation was performed in the first complete remission (CR) period in 40% of patients. Results. The frequency of CR achievement in all patients was 78.6%, refractory forms were observed in 13.9% of patients, early mortality - in 7.5% of patients. Seven-year overall survival (OS) rate was 40.7%, relapse free survival (RFS) - 43.2%. When estimating effectiveness depending on cytogenetic risk group it was demonstrated that 5-year OS and RFS in patients with translocation (8; 21) cannot be considered as satisfying, it accounted for 50 and 34%, respectively. At the same time in patients with 16th chromosome inversion (inv16) these characteristics accounted for 68.6 and 63.5%. Acquired results forced reconsidering of the consolidation program in AML patients of this subgroup. The median time to allogenic blood stem cells transplantation (allo-BSCT) in patients with first CR was 6.5 months that was taken as a reference point in landmark analysis of patients in whom allo-BSCT was not performed. Landmark analysis showed that in AML patients of favorable prognosis group allo-BSCT does not significantly reduce the probability of relapse (0 and 36%) and does not influence RFS (33 and 64%). In patients of border-line and poor prognosis allo-BSCT significantly reduces relapse probability (26 and 66%; 20 and 100%) and significantly increases a 7-year RFS (68.7 and 30%; 45.6 and 0%). Allo-BSCT also results in significant RFS increase and reduces the probability of relapse (25 and 78%) in patients in whom CR was achieved only after the second induction course. At the same time allo-BSCT does not influence patients who achieved CR after the first treatment course: 55 and 50%. Conclusion. Multivariate analysis showed that cytogenetic risk group (HR=2.3), time of CR achievement (HR=2.9), and allo-BSCT transplantation (HR=0.16) are independent factors for disease relapse prognosis after achieving CR

Modeling Spinal Muscular Atrophy in Drosophila

Spinal Muscular Atrophy (SMA), a recessive hereditary neurodegenerative disease in humans, has been linked to mutations in the survival motor neuron (SMN) gene. SMA patients display early onset lethality coupled with motor neuron loss and skeletal muscle atrophy. We used Drosophila, which encodes a single SMN ortholog, survival motor neuron (Smn), to model SMA, since reduction of Smn function leads to defects that mimic the SMA pathology in humans. Here we show that a normal neuromuscular junction (NMJ) structure depends on SMN expression and that SMN concentrates in the post-synaptic NMJ regions. We conducted a screen for genetic modifiers of an Smn phenotype using the Exelixis collection of transposon-induced mutations, which affects approximately 50% of the Drosophila genome. This screen resulted in the recovery of 27 modifiers, thereby expanding the genetic circuitry of Smn to include several genes not previously known to be associated with this locus. Among the identified modifiers was wishful thinking (wit), a type II BMP receptor, which was shown to alter the Smn NMJ phenotype. Further characterization of two additional members of the BMP signaling pathway, Mothers against dpp (Mad) and Daughters against dpp (Dad), also modify the Smn NMJ phenotype. The NMJ defects caused by loss of Smn function can be ameliorated by increasing BMP signals, suggesting that increased BMP activity in SMA patients may help to alleviate symptoms of the disease. These results confirm that our genetic approach is likely to identify bona fide modulators of SMN activity, especially regarding its role at the neuromuscular junction, and as a consequence, may identify putative SMA therapeutic targets

Experience of haematological observatory ward during COVID-10 pandemic

Introduction . The SARS-CoV-2 infection (COronaVIrus Disease 2019, COVID-19) usually progresses uncomplicated in an acute respiratory form but causes frequent severe illness in oncohaematological patients. Aim  — analysis of the management and efficacy of medical aid at a haematology clinic during the COVID-19 pandemic. Patients . The clinic admitted 2,130 patients in April 20 — November 20, 2020, with 920 of them triaged into observatory wards. At the time of admission, 907 (98.5 %) patients were SARS-CoV-2 RNA-negative, with 13 hospitalised without nasopharyngeal swab tests. Patient nosology: 235 (25.5 %) lymphoma, 152 (16.5 %) multiple myeloma, 131 (14.2 %) acute leucaemia, 86 (9.3 %) haemophilia, 35 (4 %) Gaucher’s disease, 17 (1.8 %) Waldenstrom macroglobulinemia, 16 (1.7 %) aplastic anaemia, 153 (16.6 %) various surgical diseases, 81 (8.8 %) other haematological diseases and 14 (1.6 %) were bone marrow donors. Results . Among the 920 patients admitted to the observatory, 139 (15 %) were severe and 653 (71 %) had a moderate condition. Fever was reported in 124 (13.5  %) patients at admission. Chest computed tomography (CT) was performed in 809 patients, with recent lung inflammation detected in 121 (15 %) cases. Twenty four (2.6 %) patients were revealed SARS-CoV-2-positive, with 20 diagnoses PCR-verified and four — in chest CT. Ten patients were diagnosed positive in routine examination or at a specialty unit as fever aggravated. Thus, a two-staged SARS-CoV-2 screening with PCR and chest CT allowed an extra 2.6 % detection of COVID-19 cases despite negative tests at admission. Conclusion . The observatory management has reduced the likelihood of nosocomial COVID-19 and ensured a continued supply of specialty medical aid

Perspective directions of blockchain technology usage in digital marketing

The article outlines the key directions for usage of the blockchain technology in digital marketing, describes the new business models of digital enterprises. The article characterizes the dynamics of changes in IT budgets of new business models of digital enterprises. Authors define the relationship of new business models in the digital economy. Authors suggest classification of enterprises based on approaches to the use of operational efficiency and customer experience. The directions ofdevelopment ofdigital enterprises are determined. Conclusions made on the structural changes ofdigital marketing

Training of Competitive Graduates Based on the Educational Standard of the ITMO University

The paper presents the concept, structure and features ofITMOUniversity’s independently established educational standard of a new generation. The standard has been developed on the basis of Federal State Educational Standard of Higher Education 3++, professional and international standards of engineering education, foresight forecasts of world scientific and technological development. The harmonious intellectual, cultural and moral development, as well as the formation of a professionally competitive personality is ensured by the implementation in the educational programs of the ITMO Code. TheITMOUniversityhas created mechanisms for the formation of actual requirements for the preparation of competitive professionals demanded at an international level. The authors propose the design and implementation system of the educational programs based on integration of the fundamental classical technical education, enhanced development of the universal, common and professional competencies, and extended implementation of the modern theoretical and applied practice-oriented researches, which are supported an active participation of industrial companies and research organizations in educational activities. An interdisciplinary content of educational programs together with orientation to individualization of education and introduction of advanced educational technologies including design, digital, network etc. provides a stable technology platform to achieve the standard requirements for learning outcomes

Prenatal morphogenesis of compartments of the parenchyma of the lymph nodes of domestic cattle (Bos taurus)

The article analyzes the regularities of the formation and development of the lymphoid lobules of the parenchyma of the somatic (Limphonodi cervicales superficiales) and visceral (L. jejunales) lymph nodes in domestic cattle in the fetal period of ontogenesis. We used routine histological techniques and author's modification of the impregnation of total median sections with silver nitrate. Visualization of various zones of lymphoid lobules was carried out taking into account the specific for different cell zones architectonics of reticular fibers. It has been established that signs of morphological heterogeneity of parenchyma of lymph nodes are first found in three month-old fetuses, which is associated with the concentration of lymphoid tissue along the marginal sinus. Separation of lymphoid lobules and their structural and functional differentiation are first detected in five month fetuses. In the lymphoid lobules of five month-old fetuses all structural and functional cell zones are observable, among which the regions of clonal proliferation of T and B lymphocytes are the least developed, and regions of the transit corridors for lymphocytes migrating medullary and the cords (zone of potential accumulation of plasmocytes and antibody formation) are the most developed. Structural and functional transformations of compartments in the prenatal period of ontogenesis are accompanied by a predominantly moderate increase of the relative volume of specialized T- and B-dependent zones of lobules, against a background of a gradual decrease of the volume of transit corridors for lymphocytes migrating and zone of potential accumulation of plasmocytes and antibody formation. Due to the small volume and relatively low rates of development of the lymphocytes clonal proliferation zones, the quantitative ratios of the cellular zones in lymphoid lobules of the lymph nodes of domestic cattle in prenatal ontogenesis remain relatively stable, while maintaining the maximum indices of the development of transit corridors for lymphocytes migration and medullary cords. Among the zones of lymphocytes clonal proliferation throughout the fetal period, T-dependent zones predominate, the relative volume of which is 5.0–7.5 times greater than the volume of B-dependent zones. Lymphoid lobules in the lymph nodes of the domestic cattle fetuses of all age groups are arranged along the marginal sinus in one row and have a polar structure due to the formation of lymph nodes at one pole of the lobules in the interfollicular zone. In the visceral lymph nodes (L. jejunum) of 8–9 month-old fetuses, individual lymph nodes can form in paracortical strands, on the border with the interfollicular zone