We studied the effect of a combination of three muramylpeptides from gram-negative bacteria (Polymuramyl) on hematological parameters, morphology of the spleen, and serum cytokine level in mice with B16 melanoma treated with cyclophosphamide. Intraperitoneal administration of cyclophosphamide to tumor-bearing animals sharply reduced the number of leukocytes, especially neutrophils, in the blood and depleted the cellular composition of the spleen white pulp. Subsequent three daily intramuscular injections of Polymuramyl in doses of 70 and 860 ng/mouse for 3 days, as well as subcutaneous injection of the reference drug filgrastim (granulocytic CSF) in a dose of 12 μg/mouse partially corrected hematopoietic disorders and restored the cellular composition of the spleen. Granulocytic CSF more effectively replenished the content of mature neutrophils in the blood, while Polymuramyl restored the content of stab neutrophils. In contrast to granulocytic CSF, administration of Polymuramyl was followed by an increase in the level of granulocyte-macrophage CSF and a tendency to an increase in the serum content of IL-6, which indicates the involvement of these cytokines in the hematopoietic activity of Polymuramyl.

Mesenchymal stem cells (MSC) are characterized by tolerogenic potential and therefore, are used in the treatment of autoimmune diseases such as graft-versus-host disease (GVHD) reactions after allogeneic hematopoietic cell transplantation to improve the transplant functions, as well as for the therapy and prevention of cytokine storm in COVID-19 patients and some other conditions. However, MSC can exhibit proinflammatory activity, which causes risks for their clinical use. We studied the cytokine profile of bone marrow MSC culture and demonstrate intensive production of IL-6, IL-8, and chemokine MCP-1, which participate in the pathogenesis of cytokine storm and GVHD. At the same time, no anti-inflammatory IL-4 and IL-10 were detected. To reduce the risks of MSC application in the GVHD therapeutic protocols, further studies of the conditions promoting generation of MSC with tolerogenic potential and approved clinical standards of MSC use are required.

After removal of the primary tumor node, tumor-specific activity appears in the serum that blocks tumor growth in mice. This activity is observed at the time interval when activity of the tumor growth-stimulating factor is not determined. Administration of blood serum (0.1 ml) from mice with removed tumor to mice with CaO1 adenocarcinoma for 14 days led first to a stop of its growth, and then to tumor regression. The animals cured of adenocarcinoma lived for at least one year without signs of relapse. The cured animals did not develop resistance to repeated tumor transplantation. Repeated transplantation led to the growth of the new tumor. No cellular immune response was observed on histological slides of the regressing tumor. It was concluded that a serum factor is required for the growth of a tumor in the body and the state of the serum with blocked activity of this tumor-stimulating factor can be used for tumor treatment in oncology patients. This is the first result in the syngeneic system, when the tumor was cured by syngeneic serum proteins.

Relevance: Interleukin-2 (IL-2) alone has been shown to induce tumor regression and approved to treat metastatic renal cancer and melanoma. Checkpoint inhibitors realize their therapeutic effect through stimulation of immune system effectors; one of such mechanisms is the enhancement of IL-2 production by T-helpers. The purpose of the study was to determine the effectiveness of IL-2 administration as a component of combined immunotherapy with immune checkpoint inhibitors and to suggest the mechanisms by which IL-2 can reduce the frequency and severity of side effects during checkpoint inhibitor therapy without reducing their effectiveness. Methods: The literature search was performed in the PubMed, SCOPUS, and Web of Science databases by the keywords in article titles: “immunotherapy,” “checkpoint inhibitors,” “interleukin-2,” and “combination therapy” for the period 2011-2021. A total of 248 relevant articles were found. The review’s inclusion criteria were: clinical cases; data of clinical research methods; data on humans/body fluids from humans; literature reviews and meta-analyses. The selected 24 articles met the search criteria and were included in the review. Results: The combined action of IL-2 and сheckpoint inhibitors increases the proliferative and killer activity of the antitumor immunity effectors compared to the action of the same drugs in mono-mode at a level exceeding the summation effect. Conclusion: The combination of IL-2 and сheckpoint inhibitors can increase the effectiveness of anticancer treatment and is a promising area of immunotherapy

Immune checkpoint inhibitors (ICT) therapy is a successful immunotherapy (IT) strategy that is quite effective in a number of patients with non-small cell lung cancer, melanoma, bladder cancer, breast cancer and others. Nevertheless, there is a need in predictive markers for ICT therapy for personalized IT as far as there is a large group of patients, the proportion of which varies depending on the tumor, who do not have a clinical response to such therapy. The review summarizes the theoretical aspects and results of clinical trials dedicated to various clinical efficiency predictor using modern databases. As a result of the analysis it is established that the main candidates for the role of such markers are tumor infiltrating lymphocytes and their subpopulations, peripheral blood lymphocytes (PBL) and their subpopulations. PD1 (programmed death receptor 1) and PDL1 (programmed death receptor ligand 1) expression in tumor tissue can also be important for predicting IT efficiency. The most promising predictive biomarker meaning the most clinically relevant is a combination of the PBL subpopulations study and PD1 and PDL1 expression on the tumor cells.PubMed, Scopus, Web of Science, eLibrary, Russian Science Citation Index databases were searched for the available appropriate literature reports. The authors included 82 in the given review.

Dysregulation of the immune system undoubtedly plays an important and, perhaps, determining role in the COVID-19 pathogenesis. While the main treatment of the COVID-19 intoxication is focused on neutralizing the excessive inflammatory response, it is worth considering an equally significant problem of the immunosuppressive conditions including immuno-paralysis, which lead to the secondary infection. Therefore, choosing a treatment strategy for the immune-mediated complications of coronavirus infection, one has to pass between Scylla and Charybdis, so that, in the fight against the "cytokine storm," it is vital not to miss the point of the immune silence that turns into immuno-paralysis.

Non-degradable steel and titanium implants used to replace defects of the locomotor system or fabricate vascular stents provide maximum stability but have too many drawbacks. Currently, biodegradable magnesium alloys are considered as promising materials for creation of fixation devices in orthopedics and cardiovascular surgery. First attempts of using magnesium-based implants for bone fixation were made as early as at the beginning of the 20th century, however, due to a high corrosion rate and gas formation they turned out to be unsuccessful. Magnesium-based alloys developed recently demonstrate improved anti-corrosion and mechanical properties and are promising for manufacturing of biodegradable, biocompatible metal implants. The microstructure of magnesium implants, their mechanical properties, electrochemical behavior, and kinetics of degradation are affected by alloying elements, methods of surface coating, and thermomechanical treatment of implants. All these factors determine the rate of alloy degradation in physiological environment and the level of gas formation. Although preclinical studies and even singular pilot clinical trials of the medical devices based on magnesium alloys have been carried out recently, there remain many unsolved issues preventing the introduction of biodegradable magnesium alloys in clinical practice. This review discusses the most promising directions in the development of biomedical materials based on magnesium alloys, existing limitations, and challenges of their use. The possibility of employing biodegradable magnesium alloys in oncology is also shown.

We have studied the effect of a combination of three natural muramylpeptides containing a meso-diaminopimelic acid residue (polyramyl) on the subpopulations of circulating T cells, spleen morphology, and leukocyte level in the blood of C57Bl/6 mice with cyclophosphamideinduced immunosuppression. Intraperitoneal injections of cyclophosphamide in a dose of 100 mg/kg on days 1, 3, 5, and 7 of the experiment reduced leukocyte count and the relative number of CD4+ T cells in the blood, and also depleted the cellular composition of splenic white pulp on day 10. Subcutaneous injections of polyramyl in a dose of 200 μg/mouse on days 8 and 9 practically completely restored blood leukocytes count and morphology of the splenic white pulp. Moreover, administration of polyramyl induced marked tendency to increase in the relative number of CD4+ T cells and CD4/CD8 ratio in mice with cyclophosphamideinduced immunosuppression.

We studied antibacterial activity of a hybrid polymeric construction consisting of continuous and porous layers of ultrahigh-molecular-weight polyethylene reinforced by titanium. Experimental samples were impregnated with amoxycillin in subcritical Freon R22. The contact of bacterial culture with hybrid polymeric constructions saturated with amoxycillin suppressed the growth of microorganisms and the formation of their colonies. These results attest to the presence of a bactericidal effect of hybrid scaffold samples impregnated with an antibacterial component.

Introduction.Phyto-anti-estrogen secoisolariciresinol (SECO) has similar effectiveness to that of Tamoxifen (TAM), a member of selection estrogen receptor modulators, in estrogen-positive models of murine mammary adenocarcinoma and human breast cancer in vivo. Due to its antagonistic and agonistic functions Tamoxifen may enhance risk of development of uterine adenocarcinoma while providing effective prophylactics of breast cancer metastases. SECO effect on proliferative activity of circulating or disseminating tumor cells (occult metastases) is still unclear. We used epithelial cell marker – intracellular cytokeratin 19 (CK19) to study SECO function in terms of possible metastatic process, since prognostic significance of CK19 is well established for identifying occult metastases and breast cancer dissemination.Objective.To evaluate risk of tumor cell dissemination in mice with transplanted mammary adenocarcinoma after exposure to SECO and TAM.Materials and methods.Mice BDF 1 [C57Bl6j × DBA2] bearing Са755 of the 3rd passage were used for the experiments. CK19 expression was evaluated 24 hours after 10-day course of SECO in the effective single doses of 250 mg/kg or ТАM 50 mg/kg. Flow cytometry, immunofluorescence with light and luminescence microscopy were performed to evaluate CK19 expression.Results.Parameter GMFI ± SD (geometric mean fluorescence intensity ± SD) for CK19 expression in SECO and TAM groups in blood accounted for 28.87 ± 13.70 and 28.02 ± 9.50 and in control tumor growth (CTG) group GMFI ± SD was 31.94 ± 5.02; while in bone marrow it was 30.14 ± 2.33, 39.07 ± 2.30 and 32.48 ± 3.75, respectively.Conclusion.The results of the study showed similar expression of epithelial intracellular marker CK19 in blood in the studied groups of mice bearing mammary adenocarcinoma Ca755 sensitive to SECO and TAM exposure. GMFI for CK19 expression in bone marrow was lower in SECO group than in TAM (р = 0.0003). The data obtained in the murine model demonstrated no enhanced risk of tumor cell dissemination while performing treatment by phyto-anti-estrogen SECO in therapeutic regimen.

Literature review is devoted to immunosuppression in sepsis and possibilities of its correction.

Введение.Разработка новых ортотопических моделей опухолевого роста (surgical orthotopic implantation, SOI) открывает возможность доклинического изучения потенциального антиметастатического действия препаратов, в том числе направленных на лечение диссеминированного светлоклеточного рака почки, с использованием в качестве имплантата фрагмента опухоли или метастаза от пациента.Использование подкожного (п/к) ксенографта открывает возможность оптимизации SOI с расширением возможностей применения в эксперименте.Наличие п/к ксенографта РПоч1, охарактеризованного трансплантационно, морфологически, иммунологически и по чувствительности к классическим противоопухолевым цитостатикам в коллекции опухолевых штаммов ФГБУ «Российский онкологический научный центр им.Н. Н. Блохина» Минздрава России, позволяет получить ортотопическую модель для полифункционального применения при доклиническом изучении новых специфических лекарств

Multipotent mesenchymal stromal/stem cells (MSCs) are regarded as a stable, safe and easily available source of precursor cells for purposes of regenerative medicine. However, under repeated replication in tissue reparation processes and action of inflammatory mediators, aged MSCs may be transformed and obtain certain tumor-cell characteristics. The present review deals with the MSCs role in pathogenesis of rheumatoid arthritis. High proliferation speed, lack of contact inhibition and invasive growth of transformed MSCs is an important mechanism of cartilage destruction in rheumatoid arthritis.

Введение. В рамках конструирования молекул с патогенетической направленностью к опухолевой клетке создан ряд химерных пептидов, включающих функциональный фрагмент с аминокислотной последовательностью из группы SEQ ID NO: 1 – SEQ ID NO: 17 и транспортную последовательность. Эти пептиды при целевой доставке в клетку способны обнаруживать короткие функциональные домены в белках-регуляторах различных функций. Среди них ММ-D37K, блокирующий фазу G1 и индуцирующий апоптоз в клетках опухолей человека, в том числе колоректального рака HCT-116. Этот пептид рассматривается как потенциальный противоопухолевый агент с соответствующими этапами изучения. Цель исследования – изучение дозовых характеристик MM-D37K при парентеральном введении на подкожных (п / к) ксенографтах колоректального рака человека in vivo. Задачи. 1. Изучение эффективности ММ-D37K в диапазоне доз при многократном п / к или внутривенном (в / в) введении мышам Balb / c nude c п / к ксенографтами колоректального рака человека HCT-116. 2. Оценка переносимости ММ-D37K при многократном парентеральном введении мышам с HCТ-116. Материалы и методы. Исследования химерного пептида MM-D37K (ингибитор циклинзависимых киназ 4 / 6) проведены на п / к ксенографтах колоректального рака человека HCT-116 у имммунодефицитных мышей Balb / c nude при использовании стандартных критериев оценка эффективности и переносимости и адекватной статистической обработке результатов с использованием непараметрического U-критерия Манна–Уитни. Результаты. Показано, что MM-D37K в разовых дозах 5 или 10 мг / кг при п / к или в / в 5-кратном введении через 48 ч (суммарные дозы 25 или 50 мг / кг соответственно) значимо и достоверно ингибирует рост опухоли в течение 9 дней после окончания лечения на уровне Т / С = 27–43 % (p <0,05) (стандартный критерий Т / С ≤42 %) при удовлетворительной переносимости. При обоих путях введения выявлена слабая дозовая зависимость как по Т / С, так и по сроку достижения максимального эффекта при индивидуальной чувствительности к пептиду (вариабельность размеров опухолевых узлов при в / в введении большей дозы). Заключение. Полученные данные свидетельствуют о достаточной широте терапевтического действия химерного пептида MM-D37K на модели колоректального рака человека HCT-116, позволяющей получить значимый достоверный противоопухолевый эффект при парентеральном многократном применении в 2-кратном диапазоне действующих доз.