Sructural rearrangements of NTRK genes: characteristics, methods of detection and targeted therapy for cancer

Background. The first-generation trk inhibitors, larotrectinib and entrectinib, were approved by the u.s. Food and drug administration (Fda) for the treatment of advanced solid tumors harboring NTRK gene fusions in November 2018 and in august 2019, respectively. The purpose of the study was to present upto-date data on the structure and functions of ntrk genes, the frequency of occurrence of rearrangements with their participation, the consequences of their occurrence at the cellular level, methods of detecting such rearrangements, as well as targeted drugs used in the presence of chimeric NTRK genes. Material and methods. A systemic literature search was conducted in pubmed ncbi, Web of science, scopus databases. Results. The products of NTRK genes are receptors for neurotrophins, and their high expression is normally observed only in a narrow range of tissue types. Intrachromosomal or interchromosomal rearrangements lead to a significant increase in the level of expression of the chimeric gene regulated by the strong promoter of the partner gene. The high transcriptional activity of such a gene, along with the constant activation of the kinase activity of the protein product, leads to the activation of metabolic pathways responsible for cell escape from apoptosis and disruption of the regulation of the cell cycle. The occurrence of chimeric NTRK genes varies between different types of tumors, with the highest (up to 90 %) in rare cancers (secretory carcinoma of the breast, secretory carcinoma of the salivary glands, congenital mesoblastic nephroma, children’s fibrosarcoma). Larotrectinib and entrectinib are highly effective targeted drugs in suppressing the growth of a tumor carrying NTRK rearrangements, regardless of the type of tumor. In this regard, the introduction of new high-precision methods for the detection of chimeric NTRK genes, as well as the study of the mechanisms of the development of resistance with the assumption of ways to overcome it, seems relevant. Conclusion. Rearrangements of NTRK genes are quite common in various types of oncology and are an effective target for modern targeted drugs.

Genomics and predictive medicine

Progress in understanding of structural and functional human genome organization and deciphering primary DNA sequence in human cells allowed for hitherto unreachable new capabilities of medical genetics in identifying the causes and mechanisms of inherited and inborn pathology. Implementation of genetics into medicine is progressively advancing along with improvement of molecular analysis of genome. Knowledge of genome and its functions allows to provide more accurate diagnosis, predict, to a considerable extent, the presence of genetic predisposition of a person to pathology, and to assess the chances for developing one or another disease. This approach became the basis for a new area of medical genetics named predictive medicine. The progress of predictive medicine refl ects success in tremendous upgrowth of molecular genetic methods and new capabilities of studying structure and functions of genome. Within less than 15 years after deciphering genome, medical genetics has travelled a long way from a single gene analysis to whole genome studies, from screening of genetic associations to systems genetics of multifactorial diseases, from translational to high-precision genetics, and from genetic passport idea to electronic genetic health records. The development of a genetic passport, prognostic genetic testing, and genomic chart of reproductive health is especially relevant for current practical medicine.

Structure and Functions of the Non-profit Sector in the Context of Socialization of Economic Relations

Non-profit field in the national economy of Russia, which significance, functionality and specific role is rather problematic to formulate unambiguously, examined in the article. This is equally characteristic of other countries on our planet. The reason for this is the diversity of forms and purposes, and the richness of typology. It is customary to distinguish the basic functionality of NPOs – economic, social and institutional. Historically, the importance of NCOs in the formation of statehood cannot be overestimated, as the process is largely initiated thanks to NCOs, emanating from the masses of the people, changing established social relations, introducing new tools and trends of independent governance, focusing on specific spiritual and social values.

Molecular Characterization and Functional Analysis of the Nattectin-like Toxin from the Venomous Fish Thalassophryne maculosa

TmC4-47.2 is a toxin with myotoxic activity found in the venom of Thalassophryne maculosa, a venomous fish commonly found in Latin America whose envenomation produces an injury characterized by delayed neutrophil migration, production of major pro-inflammatory cytokines, and necrosis at the wound site, as well as a specific systemic immune response. However, there are few studies on the protein structure and functions associated with it. Here, the toxin was identified from the crude venom by chromatography and protein purification systems. TmC4-47.2 shows high homology with the Nattectin from Thalassophryne nattereri venom, with 6 cysteines and QPD domain for binding to galactose. We confirm its hemagglutinating and microbicide abilities independent of carbohydrate binding, supporting its classification as a nattectin-like lectin. After performing the characterization of TmC4-47.2, we verified its ability to induce an increase in the rolling and adherence of leukocytes in cremaster post-capillary venules dependent on the α5β1 integrin. Finally, we could observe the inflammatory activity of TmC4-47.2 through the production of IL-6 and eotaxin in the peritoneal cavity with sustained recruitment of eosinophils and neutrophils up to 24 h. Together, our study characterized a nattectin-like protein from T. maculosa, pointing to its role as a molecule involved in the carbohydrate-independent agglutination response and modulation of eosinophilic and neutrophilic inflammation.

BIOSURFACTANTS FROM MARINE MICROORGANISMS: I. STRUCTURE AND FUNCTIONS

Marine microorganisms have unique metabolic and physiological characteristics and are an important source of new biomolecules such as biosurfactants. Low molecular weight surfactants are glycolipids, phospholipids, fatty acids, lipopeptides and lipoproteins, and high molecular weight surfactants are mixtures of heteropolysaccharides, lipopolysaccharides, lipoproteins and proteins. The main general of bacteria that synthesize biosurfactants are Pseudomonas, Bacillus, Acinetobacter, Antarctobacter, Rhodococcus, Halomonas, Alcanivorax, Pseudoalteromonas and Marinobacter. This review examines the structure and function of biosurfactants isolated from marine microorganisms.

Structural and Functional Insights into the Role of Guard Cell Ion Channels in Abiotic Stress-Induced Stomatal Closure

A stomatal pore is formed by a pair of specialized guard cells and serves as a major gateway for water transpiration and atmospheric CO2 influx for photosynthesis in plants. These pores must be tightly controlled, as inadequate CO2 intake and excessive water loss are devastating for plants. When the plants are exposed to extreme weather conditions such as high CO2 levels, O3, low air humidity, and drought, the turgor pressure of the guard cells exhibits an appropriate response against these stresses, which leads to stomatal closure. This phenomenon involves a complex network of ion channels and their regulation. It is well-established that the turgor pressure of guard cells is regulated by ions transportation across the membrane, such as anions and potassium ions. In this review, the guard cell ion channels are discussed, highlighting the structure and functions of key ion channels; the SLAC1 anion channel and KAT1 potassium channel, and their regulatory components, emphasizing their significance in guard cell response to various stimuli.