The process of transferring the technology for obtaining a drug from the laboratory to production and, then, to the clinical practice is always a very complicated and time-consuming way, requiring many adaptation solutions. Regarding biomedical cell products (BMCP), this is even a more complex process, requiring large-scale expansion of procedures to obtain clinically significant numbers of cells, adaptation to reagents and equipment, and establishment of safety parameters for reagents, equipment and the final product. Nevertheless, cell therapy has become an integral part of treatment regimens for malignant neoplasms. Today, thousands of studies of BMCP are being conducted around the world, both in mono-regimen and in various regimen combinations.

Natural killer cells (NK) are part of the innate immune system of the body and play an important role in the immune surveillance of foreign cells and the body’s own altered cells, including the transformed ones. The NK cells, without prior stimulation, can eliminate target cells which do not express their own MHC class I molecules or express stress-induced molecules. These basic, natural functions of the NK cells as a tool in the fight against malignant tumors have attracted particular attention. For this purpose, various approaches are used to increase the number and/or enhance the functional activity of the NK cells. One approach uses cytokines to selectively increase both the number and effectiveness of the NK cell antitumor function. Another approach focuses on checkpoint inhibitors targeting the NK cell receptor. Bispecific and trispecific activators have been developed to enhance the specific immune response by cross-linking specific tumor antigens with effector cells. In addition, methods of adoptive transfer of the NK cells have shown promising results, however, a fairly large volume of cell mass is required there.

Gangliosides are complex glycosphingolipids which contain ceramide and various oligosaccharides usually bearing sialic acids. An interesting feature of gangliosides is that their quantitative and qualitative composition changes during oncogenesis. This process is specific and depends on the histological type of a tumor and its functional status even within one neoplasm. On the other hand, latest advances in understanding structural and functional organization of glycosphingolipids, and primarily insights into lipid raft formation, showed that gangliosides may take part in the regulation of the activity of kinases mediating the modulation of signaling pathways involved in the malignant potential of cells. This article describes basic concepts of gangliosides and their biological role in signaling pathways involved in tumor development. We focused on experimental studies revealing both inhibitory and activating effects on important protein receptors responsible for cell proliferation, differentiation and death.

Neuroblastoma (NB) is a rare malignant tumor characterized by highly variable biological behavior, including spontaneous and induced regression, maturation, and progression. To assess the prognosis and response to therapy in NB, the determination of a number of oncological markers is used, such as neuron-specific enolase, lactate dehydrogenase, ferritin. Nevertheless, the models for assessing the prognosis developed so far do not fully predict the specificity of the course of the disease. In this regard, the creation of methods for monitoring tumor status in real time, based on the analysis of circulating tumor biomarkers, seems to be extremely urgent. A characteristic feature of NB is the expression of various gangliosides on the surface of tumor cells. In particular, the content of disialoganglioside GD2 reaches up to 30 % of all gangliosides. At the same time, the level of GD2 expression depends on the differentiation of neurogenic tumors: the highest concentrations are determined on NB cells, the lowest – on ganglioneuroblastoma and ganglioneuroma. The phenomenon of “shedding”, the so-called flushing, of GD2 from the NB cell membrane made it possible to estimate its concentration in the peripheral bloodstream. The article discusses the evolutionary path of the methodology for detecting GD2 in blood serum, with an emphasis on the recently introduced liquid chromatography/ tandem mass spectrometry technique, which can be used as a starting point for the emergence of GD2 as a soluble biomarker of the tumor process, which is undoubtedly a powerful application in the clinical practice that offers hope for improved diagnosis, prognosis and riskadapted therapy strategies based on well-defined, measurable determinants in accordance with the concept of evidence-based medicine.

Neuroblastoma is one of the most common solid tumors in children, characterized by high clinical heterogeneity and low predictability of the progression course. To assess the prognosis and response to therapy, protein tumor markers are often used, such as neuron-specific enolase, lactate dehydrogenase, ferritin as well as catecholamine metabolites: homovanillic acid, vanillylmandelic acid, 3-methoxytyramine, meta- and normetanephrine. Immunocytochemical studies have shown that many neuroblastomas are characterized by high surface expression of disialogangliaside GD2.

Therapy in acute myeloid leukemia (AML) usually begins with a course of induction chemotherapy using anthracyclines and cytarabine to eliminate blast cells. Chemotherapy is a necessary step in preparing a patient for transplantation of donor hematopoietic stem cells (HSCs). However, leukemia stem cells often show their chemoresistance and initiate the AML recurrence. Specific elimination of the leukemic stem cells during the preparation of a patient for HSC transplantation may reduce the probability of recurrence. For this purpose, an active development of chimeric antigen receptors (CAR) to address various markers of AML is being in progress.

Cutaneous T-cell lymphomas are a heterogeneous group of T-cell lymphoproliferative diseases affecting the skin. Mycosis fungoides and Sezary syndrome are the most studied variants of them. The literature review includes the latest published data on the pathological processes development in mycosis fungoides and Sezary syndrome and the diagnosis of these diseases. The genomic instability features in cutaneous T-cell lymphomas are described, the existing hypotheses of the origin of these diseases are considered based on the results of T-cell receptor repertoire studying.

The article presents the results of a prospective on e-c enter observational clinical study. The level of therapeutic drug monitoring antibiotics was studied in patients with sepsis. The objective: to assess the impact of pharmacokinetics and pharmacodynamics parameters of the main classes of antibacterial drugs using specific indices to improve the effectiveness of ongoing antimicrobial therapy in patients with sepsis asscoaited with the infectious process with pa n-r esistant nosocomial microflora. Subjects and Methods. A total of 8 patients with sepsis meetiing the criteria of Sepsi s-3 were included. Carbapenems, oxazolidinones, and aminoglycosides were used in the treatment. Concentrations of drugs in blood plasma were studied by hig h-p erformance liquid chromatography with mass spectrometry. Analysis of the effectiveness of treatment was performed on the third day of therapy. Results. The T > MIC index reached 40% of the time interval between the two administrations for MIC for Pseudomonas aeruginosa in only two cases for group II carbapenems. In both cases, high peak concentrations of the drug (19.5 and 35.4 m g/L , respectively) were observed, a low static volume of antibiotic distribution (0.06 l/k g and 0,09 l/k g) and reduced total clearance of the drug (7.18 and 4.11 m l/h r) were noted. The peak concentration of amikacin was low (3.35 m g/l ), while the time to achieve it and the level of static volume distribution (356.5 liters) increased. The peak concentration of linezolid was reduced in all observations and amounted to 4.04 and 3.35 m g/l . The time of its achievement was increased (3.27 and 6.6 hours), the ratio of AU C / M IC was low and made 76.8 and 59.2. The resolution of organ dysfunction and reduction of manifestations of infectious intoxication were noted only in three patients on the third day of observation. Conclusion. Static pharmacokineti c/p harmacodynamic criteria may serve as a guideline for antimicrobial therapy. Limitations in changing the tactics of antimicrobial therapy based on the use instruction nevertheless allow optimizing treatment by controlling the volume of distribution of the drug, presence of renal or hepatic insufficiency that, however, does not guarantee treatment success. The volume of therapeutic drug monitoring of antibiotics sufficient for compilation of static pharmakinetic models, does not meet the requirements of modern intensive care.

This study presents the clinical and laboratory data of 50 patients with ataxia-telangioectasia syndrome (AT) (Louis-Bar syndrome) treated at the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology (Moscow, Russia) between 2012 and 2021. The study was approved by the Independent Ethics Committee and the Scientific Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthcare of the Russian Federation. We found that the patients experienced a significant diagnostic delay (the median delay in diagnosis was 4.5 years), although the first typical symptoms of AT were present at an earlier age (the median age was 1.5 years). The majority of patients showed laboratory signs of immunodeficiency, yet only 24% of the children developed severe infections. However, lung infections resulted in bronchiectasis in 16% of the patients and were the cause of death in 4/10 cases. Fifty-two percent of the patients had autoimmune complications, including interstitial lung disease and skin granulomas, and 24% of the patients developed malignant neoplasms. Of patients who underwent testing, 85% had KREC and/or TREC levels below the cutoff values used for neonatal screening of primary immunodeficiency disorders in Russia, which suggests that the majority of AT cases could be diagnosed by neonatal screening. Early diagnosis, multidisciplinary approach and high clinical suspicion for neoplastic manifestations are crucial for the successful management of AT.

Genetically modified T cells expressing chimeric receptors (CAR-T) have become an important tool for the treatment of the CD19+ hematological tumors. Due to a single-chain variable fragment of the antibody as a part of the CAR receptor, the cells acquire their specificity against selected tumorassociated antigens. The 3rd generation CAR also includes transmembrane, co-stimulatory domains, and tyrosine activation motifs derived from CD3z.

Снижение риска развития жизнеугрожающих кровотечений и улучшение качества жизни пациентов с синдромом Вискотта–Олдрича (СВО) до проведения трансплантации гемопоэтических стволовых клеток является одной из главных задач ведения этих больных. Основной целью данной работы явилась оценка эффективности и безопасности терапии пациентов с СВО с использованием агониста рецептора тромбопоэтина ромиплостима, направленной на достижение нормального уровня тромбоцитов и снижение риска развития тяжелых кровотечений. Данное исследование одобрено независимым этическим комитетом и утверждено решением ученого совета ФГБУ «НМИЦ ДГОИ им. Дмитрия Рогачева» Минздрава России. В исследование были включены 67 пациентов с генетически верифицированным диагнозом СВО, получавших терапию ромиплостимом в дозе 9 мкг/кг еженедельно в НМИЦ ДГОИ им. Дмитрия Рогачева в период с 2012 по 2019 г. Медиана длительности лечения составила 8 (1–12) мес. Полный ответ достигнут у 22 (33%) пациентов и частичный ответ – у 18 (27%). Тяжелых нежелательных явлений на фоне терапии ромиплостимом не отмечено. Единственным нежелательным явлением, возникшим на фоне проводимого лечения и, возможно, не связанным с ним, было развитие артериального тромбоза у пациента с системным васкулитом и аневризмой аорты в анамнезе. Применение ромиплостима у детей с СВО показало безопасность и высокую эффективность в коррекции тромбоцитопении и кровотечений у большинства пациентов. Ключевые слова: синдром Вискотта–Олдрича, ромиплостим, тромбоцитопения, геморрагический синдром

Рентгенология — это огромная и наиболее интеллектуально емкая область медицины. Применение искусственного интеллекта (ИИ) пока далеко от полноценного анализа снимков, успешно решаются только базовые, рутинные задачи. В данной обзорной статье представлены современные возможности машинного зрения, основанного на искусственных нейронных сетях (ИНС), в лучевой диагностике, в частности в стоматологии и в челюстно-лицевой хирургии. Результат поиска статей по ключевым словам (от 12.04.2020) демонстрирует увеличение количества публикаций на порядок: с 58 статей в среднем в год в 2000—2015 гг. до 945 в 2019 г. Основное применение нейросети нашли в распознавании анатомических объектов на рентгеновских снимках: кортикального и губчатого слоя челюстных костей, канала нижней челюсти, верхнечелюстного синуса, зубов, корневых каналов; патологических образований и процессов: периапикальных воспалительных изменений, в том числе кист, опухолей, костной резорбции при пародонтите, переломов корней зубов и др. Современные нейросети обучаются и работают как с двухмерными снимками: ортопантомограмма, телерентгенограммы в прямой и боковой проекциях, изображения ультразвукового исследования, так и с трехмерными данными компьютерной и магниторезонансной томографии. Отдельное внимание уделено цефалометрическому анализу. В статье, кроме анализа теоретических изысканий, рассматриваются механизмы интеграции нейросети в лечебный процесс и оценка их реальной пользы для практикующих врачей, а также перспективы развития нейросетевых подходов. Заключение. Внедрение технологий машинного зрения на основе глубоких сверточных нейронных сетей для рентгенологической диагностики в стоматологии (и в медицине в целом) является перспективным направлением, позволяющим автоматизировать и ускорить обработку и распознавание исходных данных, и, возможно, уменьшить количество ошибок, связанных с человеческим фактором. Тем не менее сейчас ИНС не могут и не должны заменять узкоспециализированных врачей при постановке диагноза и составлении плана лечения, рекомендуется использовать их в качестве независимых экспертных систем.

By now, a whole number of pathogenic antibiotic-resistant or tolerant microorganisms has been progressively increased. Hence, efficient fight against them requires to change the class of antibiotics, increase their dose, or develop new antimicrobial drugs. On the contrary, another option could rely on augmenting innate immunity. During coevolution, eukaryotes have developed several ways for their protection against microorganisms. Innate immunity conserved in all multicellular organisms. The essential principles of innate immunity include recognition of a foreign structures and their subsequent destruction. A set of specific receptors recognize conserved pathogen-derived structures. Elimination occurs due to phagocytosis and cleavage, e.g. via oxidative burst in phagocytic cells, compliment system or antimicrobial peptides. Recognition system in innate immunity is based on the pattern recognition receptors. Due to the pathogen diversity, multiple conserved structures typical to pathogens (e.g. lipopolysaccharide, peptidoglycan, flagellin etc.) are sensed by numerous receptors. The family of peptidoglycan recognition proteins is among such receptors, which were first isolated in 1996 from the silkworm Bombyx mori and mice. Later, it was demonstrated that this family is conserved and its members are found in insects, fish and mammals. Here, functions of insect peptidoglycan recognition proteins in Drosophila melanogaster as well as mammals are discussed. Such proteins are expressed mainly in liver cells (insects — in adipose tissue cells as analogue of mammalian liver), intestinal cells, and epidermis. Numerous studies demonstrate that peptidoglycan-recognition proteins moderate immune response, and may act as antimicrobial proteins, or to regulate microbiota as well as prevent enterocyte activation and restrict inflammatory response. Due to evolutionary conservatism observed for such proteins and inability for bacteria to evade their protective effects, it seems promising to use peptidoglycan recognition proteins in a combination therapeutic approach against antibiotic-resistant and antibiotic-tolerant forms of microorganisms.

ALK-positive anaplastic large cell lymphoma is a heterogeneous group of mature T-cell non-Hodgkin lymphoma, and is characterized by CD30/Ki-1 expression. Recently, value of various prognostic factors is investigated. These include clinical, histological and molecular genetic changes associated with different signaling pathways activation. Some features of the mechanism of action of anaplastic lymphoma kinases and targeted therapies possibilities addressed in this review.

FN-y is a cytokine of great clinical significance. The excessive or insufficient function of the signalling pathway triggered by IFN-y is a cause of various pathological states of the immune system and the body in general. At present, clinical practice uses quantitative methods of detection of this protein without taking into account its functional activity. Traditional tests for assessment of the biological activity of IFN-y are technologically complex and their results are poorly quantified. In the course of this work a model system was created representing a cell line with a reporter construct stably integrated into the genome controlled by a STAT-dependent promotor. Processing of the cells of this model system by IFN-y activates the STAT-1-signalling pathway, which causes expression of FFly luciferase gene. Luciferase activity is quantitatively assessed by detection of bioluminescence. Working concentration values (2.5 ng/ml) and time of performing the assay (8 h) were chosen. The effectiveness of using the model system for testing IFN-y bioactivity has been shown.

Nanoantibodies (single-domain antibodies, nanobodies) derived from noncanonical single-chain immunoglobulins provide an attractive tool for in vitro and in vivo diagnostics as well as for development of targeted drugs for clinical use. Nanoantibodies against several clinically important targets have been developed and are actively investigated. However, no development of nanoantibodies against vascular endothelial growth factor VEGF-A(165) has been reported. We describe here the generation of nanoantibodies derived from single-chain Bactrian camel immunoglobulins directed against VEGF-A(165). We demonstrate that these nanoantibodies are suitable for enzyme-linked immunoassay to quantify human VEGF-A(165) as well as for blocking its activity. Our results provide a basis for diagnostic kit development for quantification of VEGF-A(165), which emerges as a biomarker useful in various pathological conditions. In addition, the nanoantibodies might be used for development of therapeutic molecules targeting VEGF-A(165)-dependent pathological neoangiogenesis.