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Glioblastoma (GBM) is the most malignant and the most common primary tumor of the central nervous system. During the last several years GBM has been classified and managed according to the World Health Organization (WHO) criteria which subdivide it into primary and secondary GBM. As it is suggested, GBM originates from glial cells and has a diffuse growth pattern, but its etiology and pathophysiology are poorly investigated up to date. Its rapid progression and anatomical location in the brain often limits the effectiveness of therapeutic interventions. Despite all scientific and technological advances, GBM remains an incurable disease with a median survival of approximately 18 months. Standard treatment options involving maximal safe resection of the tumor followed with radiotherapy and chemotherapy do not provide satisfactory Results.Better understanding of the molecular pathology of GBM and its associated signaling pathways has opened up possibilities for new treatments for newly diagnosed and relapsing tumors. A multitargeted therapeutic approach using compounds capable of inhibiting more than one specific molecular target is a promising alternative to conventional therapies.Currently, specialists study such innovative treatment options as small molecule inhibitors aimed at signaling pathway disruptions, immunotherapy, including checkpoint inhibitors, oncolytic vaccines, CAR T-cell therapy, and drug delivery systems. In terms of an innovative approach, the elaboration of targeted drug delivery systems is of particular interest, since this strategy looks the most promising due to its ability to increase the bioavailability and effectiveness of both standard and newly tested agents. This review discusses results of preclinical and clinical studies of innovative therapeutic approaches, their advantages and disadvantages. An interdisciplinary approach is expected to be able to combine the results of cutting-edge research in this area and to provide novel promising therapeutic strategies for patients with GBM.

Purpose of the study. Evaluation of the expression of immunohistochemical tumor markers Ki-67, b-catenin, Bcl-2, P53, connexin 32 and connexin 43 when using 2-(6,8-dimethyl-5-nitro-4-chloroquinoline-2-yl)-5,6,7-trichloro-1,3-tropolone in mice with xenographs of squamous cell lung cancer.Materials and methods. Subcutaneous PDX models of human squamous cell lung cancer were created in immunodeficient BALB/c Nude mice. A fragment of the patient’s tumor (3 × 3 × 3 mm) was implanted subcutaneously in the right thigh of a previously anesthetized mouse. 200 μl of 2-(6,8-dimethyl-5-nitro-4-chloroquinoline-2-yl)-5,6,7-trichloro-1,3-tropolone was administered orally using a probe in 12 doses once every 3 days. All animals were divided into groups depending on the tropolone doses: experimental groups 2–5 with doses of 0.0055, 0.055, 0.55 and 2.75 mg/g, respectively. The control group received 1 % starch gel which was tropolone carrier. The animals were euthanized 36 days after the start of the substance administration, and the tumor tissue was isolated and prepared for the IHC study according to the standard protocol. IHC reactions were performed using antibodies for Ki-67, b-catenin, Bcl-2, P53, connexin 32 and connexin 43.Results. Higher tropolone doses were associated with decreased expression of Ki-67, b-catenin, and the Bcl-2 protein, but increased expression of the P53 protein. The dosage of tropolone and expression of connexin 43 were directly proportional.Conclusion. Immunohistochemical analysis of expression of proteins in PDX models of human squamous cell lung cancer when using 2-(6,8-dimethyl-5-nitro-4-chloroquinoline-2-yl)-5,6,7-trichloro-1,3-tropolone showed the changes indicating its antitumor efficacy and suggesting a possible mechanism of action based on the activation of apoptosis.

Purpose of the study. Was to reveal the antitumor effect of 2‑(6,8‑dimethyl‑5‑nitro‑4‑chloroquinoline‑2‑yl)‑5,6,7‑trichloro‑1,3‑tropolone in subcutaneous PDX models of human lung cancer.Material and methods. The studied tropolone was synthesized using a method of expanding the o‑quinone cycle. Assess to it’s toxic effects was given by the survival and changes in the health status of female Balb/c Nude mice. Antitumor tropolone effects were studied in subcutaneous patient‑derived xenograft (PDX) models of human squamous cell lung cancer in Balb/c Nude mice. The average volumes of tumor nodes and tumor growth inhibition (TGI %) rate were taken into account. Biochemical blood tests and histological analysis of the tumor material were performed in recipient mice.Results. An analysis of acute tropolone toxic effects did not reveal the lethal dose. The maximal TGI was observed on day 36 of the experiment in group 5 which have received 2.75 mg/g tropolone and accounted 73.5 % for females and 74.4 % for males. The average tumor volumes in females of this group were 431.3 ± 1,1 mm3 on day 33 of the experiment, in males – 428.9 ± 1,7 mm3 on day 30, and then the tumor volumes declined. The biochemical analysis of blood and histological examination of the tumor tissue of recipient mice reflect the severity of the antitumor effect on the dose of the studied tropolone.Conclusion. The research demonstrated the antitumor activity of 2‑(6,8‑dimethyl‑5‑nitro‑4‑chloroquinoline‑2‑yl)‑5,6,7‑trichloro‑1,3‑tropolone against subcutaneous PDX models of human NSCLC. The revealed tendencies can be used to search for effective modes of the compound application in clinical practice.

Purpose of the study. Evaluation of the effect of the benzimidazole derivative dihydrobromide‑2-(3,4‑dihydroxyphenyl)- 9‑diethylamino-ethylimidazo-[ 1,2‑a] benzimidazole (RU‑185) on the growth of Lewis lung epidermoid carcinoma and B16-F10 melanoma when administered intragastrically.Materials and methods. For the experiment, we used female C57Bl/6j mice, which were inoculated subcutaneously with syngeneic tumors: Lewis lung carcinoma (LLC) and B16-F10 melanoma. RU‑185 was administered intragastrically to animals in a volume of 0.3 ml for 10 days, 1 time per day. For both tumors, depending on single doses of the substance for administration, groups were divided: 1st and 4th – 50 mg/kg, 2nd and 5th – 220 and 3rd and 6th – 500 mg/kg. The control groups were injected intragastrically with physiological saline in the same volumes and according to the same scheme. The following parameters were assessed: tumor volume, increase in life expectancy (T/S, %) and tumor growth inhibition index (TGI, %).Results. For animals with LLC in the 2nd group there is an increase in the indicator of life expectancy (T/S 162.3 %), and in the 3rd group there is a tendency to an increase in the T/S indicator. On the 1st day after the end of treatment in the 2nd and 3rd groups TGI was 73.0 % and 30.1 %, respectively (р < 0.05). On the 7th and 14th days after the end of the use of RU‑185 in the 2nd and 3rd groups the volume of tumors is 3.5 and 1.4 times less (on the 7th day) and 2.3 and 1.3 times (on the 14th day), respectively than in the control group (р < 0.05). At a dose of 220 mg/kg, complete regression of LLC tumors was shown in 20 % of animals.With the growth of B16-F10, the life expectancy of all groups did not differ. Intergroup differences in the dynamics of tumor growth are provided. Highlighted changes were found in the 5th group (on the 14th day after the end of the administration of RU‑185, TGI was 48.7 %).Conclusion. The investigated chemical substance dihydrobromide‑2-(3,4‑dihydroxyphenyl)-9‑diethylamino-ethylimidazo- [1,2‑a] benzimidazole showed antitumor efficacy against syngeneic tumors: Lewis lung epidermoid carcinoma and B16-F10 melanoma when administered intragastrically which leads to further testing of RU‑185 as a potential drug for the treatment of malignant neoplasms.

Purpose of the study. Was to analyze antitumor efficacy of the XAV 939 Wnt signaling pathway inhibitor and its combination with 5 fluorouracil in subcutaneous xenografts derived from patients with colorectal cancer.Materials and methods. Antitumor efficacy of the agents and their combination was studied in xenografts derived from patients with colorectal cancer and subcutaneously implanted in immunodeficient Balb/c Nude mice. All animals with tumors were divided into 4 groups (n = 5): group 1 received 5 fluorouracil 25 mg/kg, group 2 – XAV 939 25 mg/kg, group 3–5 fluorouracil and XAV 939 combination at the same dosages, group 4 was control. Criteria for the efficacy of the tested agents and their combination included tumor growth rate and tumor growth inhibition rate (TGI %).Results. The mean volumes of xenografts and tumor growth rate in the group receiving a combination of 5 fluorouracil and XAV 939 were 335.2 ± 40.7 mm3 , being lower than the averages of xenografts in controls – 609.3 ± 69.5 mm3 (p < 0.05). The mean volumes of xenografts in the group receiving 5 fluorouracil monotherapy were 601.9 ± 45.5 mm3 , in the group with the XAV 939 monotherapy – 527.9 ± 258.6 mm3 . The highest TGI (44.99 %) was registered in the group receiving a combination of 5 fluorouracil and XAV 939.Conclusion. The study revealed the ability of combined XAV 939 Wnt signaling pathway inhibitor and 5 fluorouracil to inhibit the growth of subcutaneous xenografts derived from patients with colorectal cancer.

The review provides information on the mechanisms of the antitumor action of natural and synthetic compounds of the tropolone series, obtained over the past 30 years in studies on cell cultures and, to a lesser extent, in in vivo experiments. Interest in this group of substances is due to the urgent need of clinical oncology for drugs that effectively damage malignant cells and, at the same time, are safe for healthy tissues. The processes that realize the effects of colchicine, hinokithiol (ß-tuyaplicin) and some of their derivatives (derivatives of bistropolone, α-substituted tropolones, etc.) have been studied most fully. Herewith, more numerous mechanisms of realization of the antitumor effect of hinokithiol and its derivatives were revealed in comparison with colchicine. In addition to the disruption in the formation of the cell division spindle, shown for colchicine and colchamine, such phenomena as caspase-dependent apoptosis and some other types of apoptosis, autophagy, limitation of mitochondrial metabolism, DNA damage and demethylation, and accelerated aging of malignant cells etc. have been described. The promising properties of 2‑quinolyl 1,3‑tropolone derivatives have been shown, and the relationship of their antitumor effect with the induction of apoptosis and changes in the activity of the ERK signaling pathway in some types of malignant cells have been revealed. The results indicate a multiplicity of possible ways of the influence of tropolones on the state of malignant cells, the conditions for the implementation of ones need to be clarified, especially with a lack of information about in vivo processes.The review includes information from the literature presented in the Scopus, WoS, Pubmed databases. 35 % of articles have been published in the last 5 years.

The tribe Triticeae includes important agricultural crops, such as bread wheat, durum wheat, barley, rye, and triticale. Research in the field of reverse genetics and genetic engineering of Triticeae received a new impetus as the CRISPR/Cas genome editing system came into broad use. The review describes and analyzes the data on recent advances in genomic editing of cultivated plants of the tribe Triticeae and tools used in the field. The tools most commonly used for genome editing in Triticeae include the codon-optimized Cas9 gene under the control of the maize ubiquitin gene promoter and guide RNAs under the control of Pol III promoters U6 and U3 in one or more binary vectors. Phosphinothricin and hygromycin resistance genes are used as selectable genes. Agrobacterium-mediated transformation and biolistics are performed to obtain genome-edited plants, and immature embryos are used as explants. Approaches developed to overcome the problem of low regenerative capacity of Triticeae include in planta transformation of shoot apical meristems, transformation of microspores and pollen grains, and the use of haploinductors. Bread wheat and barley were subject to genomic editing in the majority of studies published to date, and durum wheat and triticale were recently used in CRISPR/Cas knockout studies of target genes. Further progress in the development of genome editing of cultivated plants of the tribe Triticeae should be aimed at expanding the range of species and varieties involved and overcoming the problems of low regenerative capacity. This will allow genetic modification of elite varieties, which will be in demand in agricultural production.

The expression profile of transcription factor genes was studied in varieties of common wheat in the pre-Ural steppe zone in response to drought and hypothermia. Increased transcriptional activity under stress is indicated for the TabZIP1, TabZIP60, TaDREB1, and TaNAC 69 genes.

Mutagenesis of Triticum sinskajae was performed using sodium azide. The optimal concentration was 0.1 mM. Changes were observed in the length of the spike and stem in the experimental plants as compared with the control ones.

The allelic states of waxy genes in genomes A, B and D were studied by genome-specific primers in cultivars and lines of common wheat of the pre-Ural steppe. The studied cultivars and lines revealed differences in genotypes for genome A.

The study objective is to investigate gender and age structure of multiple chronic conditions (MCC) among patients seeking medical help from a primary care physician. Materials and methods . In total, 1940 patients under the care of primary care physicians in several polyclinics of Ryazan and the Ryazan Region were examined: 646 men and 1294 women aged 18–99. The list of conditions included cardiovascular disorders, lung, gastrointestinal, kidney diseases, oncological diseases, diabetes mellitus, etc. All diagnoses were made per the generally accepted criteria. The patients were divided into 5 age groups; age and gender structure of MCC, as well as polymorbidity index (total number of conditions per 1 patient), were determined. Results. Among all patients with MCC in all age groups, the number of women was larger than men. In the structure of MCC, predominance of cardiovascular disorders, diseases of the kidneys and joints was observed. With age, the fraction of patients in whom the majority of organs and systems was affected increased. However, in older patients, peptic ulcer disease, diabetes mellitus, oncological and autoimmune diseases were comparatively rare. In men, the mean number of diseases per 1 patient was higher, but after 75 years of age the number of conditions in women exceeded the number in men. In obese patients, age increase led to quicker polymorbidity increase than in normal patients. The gender differences consisted of the prevalence of stomach/duodenal peptic ulcer, non-specific lung diseases, obliterating atherosclerosis of the lower extremities in men, and kidney diseases, diabetes mellitus type 2 in women. Conclusion. The main causes of polymorbidity are old age and obesity. In the structure of MCC, cardiovascular diseases, kidney and joint disorders are the most common. A gender difference in the incidence of some diseases is observed.

Important role in treatment and prophylaxis for vibration disease due to local vibration is played by physical factors. If high frequency components prevalent in occupational vibration, treatment with electric therapy, laser, magnetic fields, lymphatic drainage, hydrotherapy provides influence on leading chains of systemic microangiopathies pathogenesis - dysbalance of regulation influences by vegetative nervous system, vasoconstriction and intravascular changes, vascular permeability and microcirculation disorders. If low frequency coomponents prevalent in occupational vibration, treatment of polyneuropathies and locomotory disorders incorporates trophic processes activation: transcranial electroanalgesia, surface application of mineral waters, manual and subwater massage, ozone therapy, local spark discharges, peloids. Complex use of physical methods also increases human adaptational resources.

Influence of mediators of the signal systems of salicylic (SA) and jasmonic (JA) acids and their mixture on reactive oxygen species’ (ROS) (superoxide radical and O2·− H2O2) generation and activity of oxidoreductases (oxalate oxidase, peroxidase and catalase) in leaves of wheat Triticum aestivum L. infected by Septoria leaf blotch pathogen Septoria nodorum Berk has been studied. Presowing treatment of seeds by SA and JA decreased the development rate of fungus on wheat leaves. SA provided earlier inductive effect on production of O2·− and H2O2 compared with JA. The protective effect of the salicylic and jasmonic acids against Septoria leaf blotch pathogen was caused by activation of oxalate oxidase, induction of anion and cation peroxidases, and decrease of catalase activity. Ability of compounds to stimulate ROS in the plant tissues can be used as criteria for evaluation of immune-modulating activity of new substances for protection of the plants.

Influence of mediators of the signal systems of salicylic (SA) and jasmonic (JA) acids and their mixture on reactive oxygen species' (ROS) (superoxide radical O2*- and H2O2) generation and activity of oxidoreductases (oxalate oxidase, peroxidase and catalase) in leaves of wheat Triticum aestivum L. infected by Septoria leaf blotch pathogen Septoria nodorum Berk. has been studied. Presowing treatment of seeds by SA and JA decreased the development rate of fungus on wheat leaves. SA provided earlier inductive effect on production of O2*- and H2O2 compared with JA. The protective effect of the salicylic and jasmonic acids against Septoria leaf blotch pathogen was caused by activation of oxalate oxidase, induction of anion and cation peroxidases, and decrease of catalase activity. Ability of compounds to stimulate ROS in the plant tissues can be used as criteria for evaluation of immune-modulating activity of new substances for protection of the plants.

A comparative study of hydrogen peroxide (H2O2) generation, the character of a fungal catalase SNOG_03173.1 gene expression, and the catalase activity in wheat plants, infected with Septoria nodorum Berk. strains differing in their aggressiveness, has been carried out. The decreased intensity of H2O2 accumulation in infected tissues, influenced by an aggressive S. nodorum strain and caused by the enhanced transcriptional activity of the fungal catalase gene and the heightened synthesis of its product, has been revealed to be more expressed compared to a similar decrease influenced by a less aggressive strain. An assumption was made that the transcriptional activity of the fungi catalase gene and, therefore, the activity of catalase involved in the regulation of the H2O2 content in the infected zone of wheat plants represent important factors providing high aggressiveness and pathogenicity of S. nodorum.