DNA Damage Repair in Brain Tumor Immunotherapy

With the gradual understanding of tumor development, many tumor therapies have been invented and applied in clinical work, and immunotherapy has been widely concerned as an emerging hot topic in the last decade. It is worth noting that immunotherapy is nowadays applied under too harsh conditions, and many tumors are defined as “cold tumors” that are not sensitive to immunotherapy, and brain tumors are typical of them. However, there is much evidence that suggests a link between DNA damage repair mechanisms and immunotherapy. This may be a breakthrough for the application of immunotherapy in brain tumors. Therefore, in this review, first, we will describe the common pathways of DNA damage repair. Second, we will focus on immunotherapy and analyze the mechanisms of DNA damage repair involved in the immune process. Third, we will review biomarkers that have been or may be used to evaluate immunotherapy for brain tumors, such as TAMs, RPA, and other molecules that may provide a precursor assessment for the rational implementation of immunotherapy for brain tumors. Finally, we will discuss the rational combination of immunotherapy with other therapeutic approaches that have an impact on the DNA damage repair process in order to open new pathways for the application of immunotherapy in brain tumors, to maximize the effect of immunotherapy on DNA damage repair mechanisms, and to provide ideas and guidance for immunotherapy in brain tumors.

Epigenetic, Metabolic, and Immune Crosstalk in Germinal-Center-Derived B-Cell Lymphomas: Unveiling New Vulnerabilities for Rational Combination Therapies

B-cell non-Hodgkin lymphomas (B-NHLs) are highly heterogenous by genetic, phenotypic, and clinical appearance. Next-generation sequencing technologies and multi-dimensional data analyses have further refined the way these diseases can be more precisely classified by specific genomic, epigenomic, and transcriptomic characteristics. The molecular and genetic heterogeneity of B-NHLs may contribute to the poor outcome of some of these diseases, suggesting that more personalized precision-medicine approaches are needed for improved therapeutic efficacy. The germinal center (GC) B-cell like diffuse large B-cell lymphomas (GCB-DLBCLs) and follicular lymphomas (FLs) share specific epigenetic programs. These diseases often remain difficult to treat and surprisingly do not respond advanced immunotherapies, despite arising in secondary lymphoid organs at sites of antigen recognition. Epigenetic dysregulation is a hallmark of GCB-DLBCLs and FLs, with gain-of-function (GOF) mutations in the histone methyltransferase EZH2, loss-of-function (LOF) mutations in histone acetyl transferases CREBBP and EP300, and the histone methyltransferase KMT2D representing the most prevalent genetic lesions driving these diseases. These mutations have the common effect to disrupt the interactions between lymphoma cells and the immune microenvironment, via decreased antigen presentation and responsiveness to IFN-γ and CD40 signaling pathways. This indicates that immune evasion is a key step in GC B-cell lymphomagenesis. EZH2 inhibitors are now approved for the treatment of FL and selective HDAC3 inhibitors counteracting the effects of CREBBP LOF mutations are under development. These treatments can help restore the immune control of GCB lymphomas, and may represent optimal candidate agents for more effective combination with immunotherapies. Here, we review recent progress in understanding the impact of mutant chromatin modifiers on immune evasion in GCB lymphomas. We provide new insights on how the epigenetic program of these diseases may be regulated at the level of metabolism, discussing the role of metabolic intermediates as cofactors of epigenetic enzymes. In addition, lymphoma metabolic adaptation can negatively influence the immune microenvironment, further contributing to the development of immune cold tumors, poorly infiltrated by effector immune cells. Based on these findings, we discuss relevant candidate epigenetic/metabolic/immune targets for rational combination therapies to investigate as more effective precision-medicine approaches for GCB lymphomas.

Therapeutic apheresis in the complex pathogenetic therapy of anti-NMDA encephalitis associated with ovarian teratoma at a late stage of the disease

Anti‑NMDA encephalitis is a rare autoimmune disease of the central nervous system caused by the synthesis of autoantibodies to the NR1/NR2 subunits of the NMDA receptor, characterized by the development of acute mental, cognitive, motor, autonomic disorders, epileptic syndrome and central hypoventilation.The article presents a three‑year observation of patient 34 years old with anti‑NMDA ncephalitis associated with late‑ stage ovarian teratoma, accompanied by an increase titer of antibodies to NMDA receptors in serum to 1:640.Based on a detailed analysis of clinical, neurological, neuropsychological (MMSE, MoСA, FAB, 10 words test A.R. Luria) and laboratory‑instrumental characteristics of the disease (titer anti‑NMDA, level of IgG, IgM, IgA, lymphocyte subpopulations, EEG, MRI of the brain, pelvis) suggested a combination scheme of first and second line therapy. The sequential use of two cycles of medium‑volume membrane plasmapheresis (25–30 % of the circulating plasma volume, No. 5 + 5) was carried out in combination with pulse therapy with methylprednisolone 1.0 (No. 4 + 3) and cyclophasphamide 1.0 (No. 2 + 1) on background of persistent ovarian teratoma. Symptom regression was achieved by the end of the first cycle, and full recovery to the initial level of cognitive functions occurred after the second cycle, while maintaining the anti‑NMDA antibody titer to 1:160. After removal of ovarian teratoma, the level of anti‑NMDA decreased in a month to 1:40, and after 7 months it reached normal values (<1:10) against the background of basic pill therapy with methotrexate 12.5 mg/week.Thus, a rational combination and sequence of first and second line therapy and therapeutic apheresis, taking into account the pathogenetic features of each phase of the disease, can quickly achieve complete stable remission in patient with anti‑NMDA encephalitis.

Diversification as a strategic direction for sustainable development of enterprises in the agricultural sector of the economy

The diversification of the activities of agricultural enterprises is considered as a process of mastering the production of new or expanding the range of traditional types of products, which makes it possible to more fully realize the existing natural, biological, resource, production potential and helps to strengthen financial, economic and environmental safety, increases the competitiveness and efficiency of economic entities. Today, the need to diversify the activities of domestic agricultural enterprises is determined by a set of prerequisites, both general economic and specific. In modern realities, the overwhelming majority of farmers are focused on the production of the most liquid and least capital- and labor-intensive types of products with a short payback period. The economic results of agricultural enterprises in most cases directly depend on the efficiency of production of grain and oilseeds. Narrow specialization, and sometimes practically monoculture, increases the threats of agrobiological, ecological, and economic nature Diversification of their activities allows minimizing the risks of agricultural enterprises from unfavorable phenomena of agrotechnical and weather-climatic nature and unforeseen changes in market conditions. Optimization of the sectoral structure on the basis of a rational combination of the main, additional, and subsidiary industries ensures more efficient use of land and means of production, leads to the leveling of seasonality, and creates conditions for an enterprise to receive a guaranteed stable income. The priority for the diversification of large-scale agricultural production is its investment and innovative development with a rational combination of crop and livestock industries, the revival of the traditional for Ukraine industries of beet growing, vegetable growing, horticulture, cattle breeding, pig breeding, sheep breeding. Diversification of the activities of small and medium-sized producers provides for an orientation towards the production of products with a high level of labor intensity, environmentally friendly organic products, niche agriculture, the production of non-traditional agricultural products, green, agritourism, etc. The need to change the raw material nature of the agricultural sector of the Ukrainian economy determines the need to increase the industrial processing of agricultural raw materials. This will not only make it possible to obtain greater added value, but will also ensure the creation of additional jobs, will contribute to the growth of incomes of the population, and an increase in the revenues of budgets of all levels. The development of diversification processes guarantees a stable income and an increase in the profitability of agricultural producers and will also contribute to the implementation of national priorities for ensuring the country's food security, increasing employment, and solving social and material problems of peasants.

Heat-insulating porous material based on glauconite-containing sands and aleurites of the Novodvorskoye deposit of the Republic of Belarus

The results on the research of heat-insulating porous ceramic materials produced using overburden rocks of the Novodvorsk deposit of Pinsk district of the Brest region as the main component of raw materials are presented in the study and the use of bulk rock consisting of glauconite sands and aleurites is recommended. Low-melting clay, basalt and a blowing agent are used as additional components, rational combination of which would ensure the forming ability of ceramic masses and the required set of the physicochemical properties of the material. The dependence of the bulk density, swelling coefficient, coefficient of thermal conductivity on the chemical and mineral composition of the used and raw materials is established, wich is the criteria for choosing composition with the maximum use of overburden and the necessary plasticity of the ceramic mass required for the molding process of raw granules. The obtained results can serve as a basis for the large-scale use of not only the minerals of the Novodvorsk deposit (basalts and tuffs), but also associated – glauconite-containing overburden. This will make a significant contribution to the expanding the mineral resource base of the Republic of Belarus.

Cancer cell membrane-coated nanoparticles for bimodal imaging-guided photothermal therapy and docetaxel-enhanced immunotherapy against cancer

Background Mono-therapeutic modality has limitations in combating metastatic lesions with complications. Although emerging immunotherapy exhibits preliminary success, solid tumors are usually immunosuppressive, leading to ineffective antitumor immune responses and immunotherapeutic resistance. The rational combination of several therapeutic modalities may potentially become a new therapeutic strategy to effectively combat cancer. Results Poly lactic-co-glycolic acid (PLGA, 50 mg) nanospheres were constructed with photothermal transduction agents (PTAs)-Prussian blue (PB, 2.98 mg) encapsulated in the core and chemotherapeutic docetaxel (DTX, 4.18 mg)/ immune adjuvant-imiquimod (R837, 1.57 mg) loaded in the shell. Tumor cell membranes were further coated outside PLGA nanospheres (designated “M@P-PDR”), which acted as “Nano-targeted cells” to actively accumulate in tumor sites, and were guided/monitored by photoacoustic (PA)/ magnetic resonance (MR) imaging. Upon laser irradiation, photothermal effects were triggered. Combined with DTX, PTT induced in situ tumor eradication. Assisted by the immune adjuvant R837, the maturation rate of DCs increased by 4.34-fold compared with that of the control. In addition, DTX polarized M2-phenotype tumor-associated macrophages (TAMs) to M1-phenotype, relieving the immunosuppressive TME. The proportion of M2-TAMs decreased from 68.57% to 32.80%, and the proportion of M1-TAMs increased from 37.02% to 70.81%. Integrating the above processes, the infiltration of cytotoxic T lymphocytes (CTLs) increased from 17.33% (control) to 35.5%. Primary tumors and metastasis were significantly inhibited when treated with “Nano-targeted cells”-based cocktail therapy. Conclusion “Nano-targeted cells”-based therapeutic cocktail therapy is a promising approach to promote tumor regression and counter metastasis/recurrence. Graphical Abstract

Reliability in mechanical systems projects

Sufficient safety of the parts, which determines the safety of the system specified by the technical assignment, is the necessary quality of the project, the subject of the design engineer’s attention and the customer’s requirement. An extensive task is the collection of data for iterative refinement of the resource for project details in a probabilistic aspect. It can be significantly reduced when using approximate methods for estimating the resource at intermediate stages of refining the project to the required resource with a calculated probability of failure-free operation. Thus, by the analysis of dimensionless relations of parameters of models of fatigue damage development, it is possible to obtain tools of numerical estimation of technological and constructive techniques of increase of a resource of details and their rational combination. The paper deals with the numerical measures of various directions of upgrading the fatigue life of the parts, derived from the dimensionless relations of the parameters of fatigue damage development models.

PROBLEMS OF COMBINING ENTREPRENEURSHIP AND PLANNING IN A POST-INDUSTRIAL ECONOMY

From the standpoint of a comparative analysis, the author considers the problems of combining entrepreneurship and planning inherent in the industrial and post-industrial economies. It is shown that the level of importance of planning in entrepreneurial activity is significantly influenced not only by the dominant position of the buyer or manufacturer (and seller) in the market, but also by the phase of the cycle of economic activity. It has been demonstrated that without the proper attitude of entrepreneurs to planning and a stake on instant success, it is impossible to achieve sustainable development and stable profitability in the medium and long term. Recommendations are formulated to ensure a rational combination of entrepreneurship and planning in a post-industrial economy.

Substantiation of the composition of a semi-solid dosage form with a probiotic component for use in dermatology

One of the important issues in the pharmaceutical development of a semisolid preparation for dermal use is the scientific and experimental justification for choosing the base-carrier of active substances. The aim of this study was to experimentally substantiate the choice of rational combination of excipients in the development of a semisolid dosage form with a probiotic component for use in dermatology. Materials and methods. Hydrophilic gelling agents were used as excipients in the study: Sepiplus 400, Aristoflex AVC, Carbopol 934, hydroxyethylcellulose HEC, sodium alginate. Physical and chemical, pharmaco-technological and microbiological methods were used to select the optimal basis. Colloidal stability was determined using a laboratory centrifuge at a speed of 6000 rpm for 5 min, an electronic thermometer and a water bath laboratory. Thermostability was determined in the thermostat at (40±2) °C for 24 hours. Investigation of the rheological properties of the samples was performed using a Rheolab QC (Anton Paar, Austria) rheoviscometer using a system of coaxial cylinders C-CC27/SS. The kinetics of water absorption of the samples were studied by dialysis through a semipermeable Cuprophan membrane, Type 150 pm at a temperature of (34±2) °C. The number of viable lactobacilli cells was determined by surface seeding on Petri dishes with dense MRS medium. Research results. The results of the study of the number of viable lactobacilli cells showed that the lowest number of viable cells was in sample based on HEC. Tests for thermostability and colloidal stability showed that for sample No. 5 based on sodium alginate, stratification was observed in the experiment, which indicates its instability. These samples were excluded. Samples on Sepiplus 400 and Aristoflex AVC on a set of rheological features have advantages both consumer and technological; and sample on t Aristoflex AVC has the best indicators of osmotic activity and the viability of cells in the dynamics for this study. Conclusions. As a result of physical and chemical (organoleptic, colloidal and thermostability), pharmaco-technological (osmotic and structural and mechanical properties) and microbiological studies (number of viable lactobacilli cells) studies it was found that further work should be carried out with a sample based on gelling agent Aristoflex AVC, which has the most optimal performance in this development for a semisolid dosage form with a probiotic component for use in dermatology