ANTICANCER IMMUNOGENIC POTENTIAL OF ONCOLYTIC PEPTIDES: RECENT ADVANCES AND NEW PROSPECTS.

Oncolytic peptides are derived from natural host defense peptides/antimicrobial peptides produced in a wide variety of life forms. Over the past two decades, they have attracted much attention in both basic research and clinical applications. Oncolytic peptides were expected to act primarily on tumor cells and also trigger the immunogenic cell death. Their ability in the tumor microenvironment remodeling and potentiating the anticancer immunity has long been ignored. Despite the promising results, clinical application of oncolytic peptides is still hindered by their unsatisfactory bioactivity and toxicity to normal cells. To ensure safer therapy, various approaches are being developed. The idea of the Ukrainian research group was to equip peptide molecules with a "molecular photoswitch" - a diarylethene fragment capable of photoisomerization, allowing for the localized photoactivation of peptides within tumors reducing side effects. Such oncolytic peptides that may induce the membrane lysis-mediated cancer cell death and subsequent anticancer immune responses in combination with the low toxicity to normal cells have provided a new paradigm for cancer therapy. This review gives an overview of the broad effects and perspectives of oncolytic peptides in anticancer immunity highlighting the potential issues related to the use of oncolytic peptides in cancer immunotherapy. We summarize the current status of research on peptide-based tumor immunotherapy in combination with other therapies including immune checkpoint inhibitors, chemotherapy, and targeted therapy.

[Applying robust management approaches to transit to value-based healthcare].

Health systems require continuous improvement. Along with that, despite the pace of the society development, they face a number of global problems, which can be solved by the transition to value-based healthcare through robust management. The purpose of the study is to analyze the relationship between sustainable healthcare management and life expectancy in the regions of the Russian Federation, with a special focus on the impact of robust management factors on this indicator. The study used theoretical methods: observation, measurement, comparison, analysis, modeling, synthesis, study and generalization, as well as practical ones: modeling using Pandas, Numpy, Scipy, Geopandas, Sklearn, Matplotlib and Seaborn packages for the Python programming language. The study resulted in the construction of a tree-like model of the relationship of indicators, which made it possible to obtain a multi-level list with the mutual influence of factors and thresholds. By examining the dynamics in the relationship between health management strategies and life expectancy across regions, we sought to identify key control factors that can be used to improve health outcomes across the country and assess which ones have more and less impact. The result of the analysis was the determination of the threshold values of indicators, the change in which leads to a significant change in life expectancy.

HUMAN MICROBIOTA AND BREAST CANCER.

Breast cancer is the leading malignancy in women worldwide. To date, much is known about the molecular subtypes of these malignant neoplasms and the mechanisms of drug resistance. Significant success has been achieved in approaches to early diagnosis, which allows identifying the tumor process in the early stages of development. Recently, the study of the influence of the human body microbiota on cancer development and the effectiveness of treatment has become an actively developing field of research. This review presents an analysis of the literature data on this issue.

Human microbiota and effectiveness of cancer chemotherapy.

This review presents up-to-date information on the effects of microbiota on the individual chemotherapy sensitivity in cancer treatment. Recent studies have shown that a fine balance between the intestinal microbiota and the immune system is crucial for maintaining an efficacy of cancer chemotherapy. A number of antitumor drugs have complex mechanisms of action involving not only direct effects but also the activity of the intestinal microbiota and the immune system. A unique combination of these factors contributes to the individual chemotherapy sensitivity.

[POSSIBILITY OF ENHANCING OF THE TRANSPAPILLARY INTERVENTIONS EFFICACY, APPLYING OPTIMIZATION OF THEIR ANESTHESIOLOGICAL SUPPORT].

In 2015 yr еndoscopic transpapillary interventions (ЕТI), performed for diseases of the hepatopancreatoduodenal zone organs, were done in 697 patients. In 315 (45.2%) of them ЕТI were diagnostic, in 382 (54.8%) ­ performed with treatment objective. Меdicinal support for the ЕТI conduction in 631 (90.5%) patients have included conduction of superficial sedation and local anesthesia of pharynx. Аnesthesiological support was applied in 66 (9.5%) patients, including total intravenous anesthesia ­ in 11 (16.6%), еndotracheal narcosis ­ in 55 (83.4%). Using of general anesthesia in comparison to superficial sedation creates more favorable conditions for the ЕТI performance, what have permitted to reduce their duration and complications rate twice.

[COMBINED LAPAROSCOPICALLY AND RETROPERITONEOSCOPICALLY ASSISTED PANCREATONECRSEQUESTRECTOMY].

Combined method of laparoscopically and retroperitoneoscopically assisted necrsequestrectomy, consisting of staged application of miniinvasive methods with simultaneous laparoscopic and retroperitoneoscopic control of necrsequestrectomy, was elaborated with the objective to improve surgical treatment of an acute pancreatitits. The procedure has significant advantages over open operative intervention in purulent complications of necrotic purulent pancreatitis: reduction of the local and systemic operative treatment severity, minimization of microbial metabolites coming into the blood, total visual control of intervention, reduction of the vascular injuries risk, аdequate surgical sanation with saving of viable pancreatic parenchyma, absence of conditions for the purulent complications occurrence while the operative wound healing is going on, preservation of possibility for an adequate draining, using drains of a large diameter.

Remodulating effect of doxorubicin on the state of iron-containing proteins, and redox characteristics of tumor with allowance for its sensitivity to cytostatic agents.

The study was aimed at determining the changes of metal-containing proteins in blood serum and tumor tissue of animals with parental and doxorubicin-resistant strains of Walker-256 carcinosarcoma before and after the cytostatic administration. It has been shown that upon doxorubicin action the levels of total iron and transferrin in the tissues from the both groups of animals decreased while that of ferritine simultaneously increased with more pronounced pattern in the group of animals with resistant tumor strain. It has been shown that upon the action of doxorubicin in tumor tissue of animals with different sensitivity to the cytostatic there could be observed oppositely directed changes in the redox state of these cells that in turn determined the content of " free iron" complexes, RO S generation and concentration of active forms of matrix metaloproteinase- 2 and matrix metaloproteinase-9, namely, the increase of these indexes in animals with parental strain and their decrease in animals with the resistant one. So, our study has demonstrated the remodulating effect of doxorubicin on the state of metal-containing proteins and redox characteristics of tumor dependent on its sensitivity to cytostatic, at the levels of the tumor and an organism. These data may serve as a criterion for the development of programs for the correction of malfunction of iron metabolism aimed at elevating tumor sensitivity to cytostatic agents.

METALLOPROTEINS DURING DEVELOPMENT OF WALKER-256 CARCINOSARCOMA RESISTANT PHENOTYPE.

The study was focused on the detection of changes in serum and tumor metal-containing proteins in animals during development ofdoxorubicin-resistant phenotype in malignant cells after 12 courses of chemotherapy. We found that on every stage of resistance development there was a significant increase in content of ferritin and transferrin proteins (which take part in iron traffick and storage) in Walker-256 carc'inosarcoma tissue. We observed decreased serumferritin levels at the beginning stage of the resistance development and significant elevation of this protein levels in the cases withfully developed resistance phenotype. Transferrin content showed changes opposite to that offerritin. During the development of resistance phenotype the tumor tissue also exhibited increased 'free iron' concentration that putatively correlate with elevation of ROS generation and levels of MMP-2 and MMP-9 active forms. The tumor non-protein thiol content increases gradually as well. The serum of animals with early stages of resistance phenotype development showed high ceruloplasmin activity and its significant reduction after loss of tumor sensitivity to doxorubicin. Therefore, the development of resistance phenotype in Walker-256 carcinosarcoma is accompanied by both the deregulation of metal-containing proteins in serum and tumor tissue and by the changes in activity of antioxidant defense system. Thus, the results of this study allow us to determine the spectrum of metal-containing proteins that are involved in the development of resistant tumor phenotype and that may be targeted for methods for doxorubicin sensitivity correction therapy.

Pharmacological effect of aminoferrocene in mice with L1210 leukemia.

AIM: To study the cytostatic and some biological effects of aminoferrocene using mice with L1210 lymphoid leukemia. MATERIALS AND METHODS: Experiments were performed on BDF1 male mice (DBA/2, female × C57Bl/6, male) with transplantable L1210 lymphoid leukemia. Determination of antitumor activity of Benzyl-Fc Boron (Bn), it was injected intraperitoneally 6 times daily, starting on day 2 after L1210 leukemia cell transplantation. Doses of Bn such as 26; 260 and 2600 µg/kg were used. The determination of intracellular content of cardiolipin, thiols, reactive oxygen species (ROS) and also analysis of Annexin V positivity and mitochondrial transmembrane potential (JC-1 staining) were performed with use of flow cytometry. The levels of "free iron" complexes, transferrin active forms and the rate of NO generation were measured by EPR-specroscopy. RESULTS: Six daily injections of Bn at a dose of 26 µg/kg resulted in an increased survival of mice with L1210 leukemia by 28% (p < 0.05). Bn led to an increase of apoptotic cells number and ROS amount in leukemia cells. Besides, Bn caused a decrease of cardiolipin and nonprotein thiol compounds content. The membrane electrochemical potential of cell mitochondria was decreased also after Bn administration. Studies using EPR-spectroscopy revealed a significant increase in a level of "free iron", content of transferrin active species and generation rate of NO by inducible NO-synthase in L1210 cells after aminoferrocene administration. CONCLUSION: Our data indicate that Benzyl-Fc Boron can be promising candidate for realizing a new strategy of anticancer therapy with the use of ROS-inducing agents.

Metabolic changes during development of Walker-256 carcinosarcoma resistance to doxorubicin.

AIM: To study indices of energy metabolism, content of K(+) and Mg(++) both in peripheral blood and in Walker-256 carcinosarcoma during development of resistance to doxorubicin. METHODS: Resistance of Walker-256 carcinosarcoma to doxorubicin has been developed through 12 subsequent transplantations of tumor after the chemotherapy. Parental strain was inhibited by drug by 65%, while transitional resistant substrains - by 30% and 2%, respectively. Determination of biochemical indices in blood serum and homogenates of tumor tissue, level of potassium, magnesium, lactate, glucose, activities of lactate dehydrogenase and glucose-6-phosphate dehydrogenase was performed with the help of biochemical and immune-enzyme analyzer GBG ChemWell 2990 (USA) using standard kits. Polarography was used to determine indices of mitochondrial oxidative phosphorylation. Study of mitochondrial membrane potential was carried out on flow cytometer Beckman Coulter Epics XL using dye JC-1. RESULTS: It has been determined that development of drug resistance causes the decrease of K(+), Mg(++), glucose content in blood serum and increase of these indices in tumor tissue. At the same time, gradual tumor's loss of sensitivity is characterized by decrease of glycolysis activity in it and activation of mitochondrial oxidative phosphorylation and pentose phosphate pathway of glucose degradation, which causes more intensive formation of NADPH. CONCLUSION: Development of drug resistance of tumor causes certain metabolic changes in organism and tumor. Further study of such changes will make possible to determine tumor and extratumor markers of resistance.