A Review of the Use of Extracellular Vesicles in the Treatment of Neonatal Diseases: Current State and Problems with Translation to the Clinic.

Neonatal disorders, particularly those resulting from prematurity, pose a major challenge in health care and have a significant impact on infant mortality and long-term child health. The limitations of current therapeutic strategies emphasize the need for innovative treatments. New cell-free technologies utilizing extracellular vesicles (EVs) offer a compelling opportunity for neonatal therapy by harnessing the inherent regenerative capabilities of EVs. These nanoscale particles, secreted by a variety of organisms including animals, bacteria, fungi and plants, contain a repertoire of bioactive molecules with therapeutic potential. This review aims to provide a comprehensive assessment of the therapeutic effects of EVs and mechanistic insights into EVs from stem cells, biological fluids and non-animal sources, with a focus on common neonatal conditions such as hypoxic-ischemic encephalopathy, respiratory distress syndrome, bronchopulmonary dysplasia and necrotizing enterocolitis. This review summarizes evidence for the therapeutic potential of EVs, analyzes evidence of their mechanisms of action and discusses the challenges associated with the implementation of EV-based therapies in neonatal clinical practice.

Optimal assessment share structured of Pharmacoeconomics for medical drugs according to minimax criterion

Objective: To develop a comprehensive methodology for the optimal assessment of the share of the use of medicines, based on the procedure for ranking drugs according to the pharmacoeconomic point scale and the minimax criterion was applied. Methods: The author’s approach is based on the minimax principle and allows solving the problem of optimizing the pharma drug portfolio based on available data, without the need to obtain the parameters of the Markowitz model associated with correlation analysis of data. Results: The authors obtained the optimal distribution of medicines in group A, B: 37% to 63%, which the authors consider a promising recommendation for a pharmaceutical company. The use of a similar approach, which does not contradict the Markowitz methodology, but allows us to reasonably accept the parameters of the model and give the optimal solution for the share distribution of drugs in medical practice. Conclusion: These mathematical tools, justified and equipped with an alternative confirmation, the minimax task can and should take a significant place in the complex pharma-analytical methodology of the management of large companies supplying concomitant drugs to the Russian and foreign market. (AU)

Preclinical Characterization of a Novel Anti-Cancer PD-L1 Inhibitor RPH-120.

RPH-120 is a novel fully human anti-PD-L1 IgG1 monoclonal antibody with specifically designed Asn300Ala mutation in Fc fragment. Surface plasmon resonance assay showed that affinity of the RPH-120 to the dimeric form of human PD-L1-Fc fusion protein was much higher than affinity to the monomeric His-tagged PD-L1. Further binding studies demonstrated that RPH-120 is able to bind to human and monkey but not mouse PD-L1. Tissue cross-reactivity study showed good comparability of human and Cynomolgus monkeys tissue staining. Bioactivity was assessed using mixed lymphocyte reaction assay. This study revealed that RPH-120 was able to activate T cells preventing PD1/PD-L1 interaction. Antitumor efficacy was analyzed in HCC-827 lung cancer xenografts in humanized CD34+ mice at three dosage levels: 20, 80, and 200 mg/kg. RPH-120 demonstrated significant tumor growth inhibition, and this inhibition was comparable to that of atezolizumab. In a single dose toxicity, toxicokinetic and dose range finding study performed in Cynomolgus monkeys, RPH-120 was administered via intravenous (IV) bolus or 60-min IV infusion, followed by 8-weeks recovery period. An acceptable toxicokinetic profile was demonstrated and administration at doses of up to 200 mg/kg was well tolerated by all animals. In conclusion, RPH-120 revealed promising in vitro and in vivo activity and safety. RPH-120 is a potent anti-PD-L1 drug candidate for cancer immunotherapy.

Patient Flows, Patient Distribution Computations and Medicines Accounting in the Pharmacoeconomic Models Through Procurement Perspective.

PURPOSE: Stimulating cost reduction of pharmaceutical companies to optimize the structure of distribution of patients by the level of treatment costs in various programs. PATIENTS AND METHODS: In this article, we rise up the issues of pharmacoeconomic modeling related to the description of the patient flows in the pharmacoeconomic model and methods to determining the course dose of drugs under the restriction of integer computations. We established two possible ways of distributing patients through treatment regimens in pharmacoeconomic models, also analyzed the effects of simultaneous and uniform entry of patients into the model. Also, we considered the limitations and possibilities of calculations based on the active substance and packaging, as well as the transition factor of the remainder of the drug in the next time period. RESULTS: A mathematical model of the analysis of the system assessment of patients by the level of risk of abandoning a healthy lifestyle in connection with the growing problems of the difficult-to-control process is developed. The use of a rational data convolution mode allowed us to obtain a criterion for the optimality of the process and a logical point of stability of the pharmaceutical company by rationally applying treatment methods according to established standards (percentage base). This approach makes it possible to influence the management of private clinics through clear ideas on the algorithms for prescribing drugs in each group of patients and their zoning in the vector recovery mode. CONCLUSION: Initial data and sample size: 552 measurements of the intervals of changes in the subject's indicators in seconds (smoothing and scaling the data to the level of the base (analytical) period or the final (barrier) period). Regular use of this approach makes it possible to reserve the resources of the body of a healthy and physically active person in a timely manner for a very reliable functioning of all body systems, taking into account the dosed intake of prescribed drugs and the conditions of comfortable (decent) maintenance of patients during the course of treatment according to the method chosen by the doctor.

Involvement of mitophagy in cisplatin-induced cell death regulation.

Mitophagy, the selective degradation of mitochondria via the autophagic pathway, is a vital mechanism of mitochondrial quality control in cells. The removal of malfunctioning or damaged mitochondria is essential for normal cellular physiology and tissue development. Stimulation of mitochondrial permeabilization and release of proapoptotic factors from the intermembrane space is an essential step in triggering the mitochondrial pathway of cell death. In this study, we analyzed the extent to which mitophagy interferes with cell death, attenuating the efficiency of cancer therapy. We show that stimulation of mitophagy suppressed cisplatin-induced apoptosis, while mitophagy inhibition stimulates apoptosis and autophagy. Suppression of mitophagy involved production of reactive oxygen species, and the fate of cell was dependent on the interplay between endoplasmic reticulum stress and autophagy.

Concept of Combining Cost-Effectiveness Analysis and Budget Impact Analysis in Health Care Decision-Making.

OBJECTIVES: The objective of this study is to cover the ways of solving the problem of understanding the results of two key methods of pharmacoeconomic analysis - budget impact and cost-effectiveness. It is important to note that pharmacoeconomic assessment based on this evidence often has controversial character. The results of one type of analysis can characterize assessed health technology favorably, and the results of other critically. Pharmacoeconomic evidence is often a crucial part of decision-making in healthcare, that's why clear understanding of combination of this two types of analysis is highly in demand. METHODS: Authors propose methodological solution of the stated problem. This model is a useful tool in making unified pharmacoeconomic report based on cost-effectiveness analysis and budget impact analysis results. Use of this model preserves the meaning and significance of each type of pharmacoeconomic analysis. RESULTS: Three-dimensional pharmacoeconomic model proposes full account of both types of pharmacoeconomic analyses during conclusion preparation, the formation of a single consistent pharmacoeconomic conclusion. Though further validation of a tool is needed, presented model can be interesting for the professional community. CONCLUSIONS: The proposed model of combining budget impact and cost-effectiveness analysis can be used by healthcare decision-makers for obtaining reliable and transparent pharmacoeconomic data.

Mitophagy: Link to cancer development and therapy.

Mitophagy, the selective degradation of mitochondria via the autophagic pathway, is a vital mechanism of mitochondrial quality control in cells. Mitophagy is responsible for the removal of malfunctioning or damaged mitochondria, which is essential for normal cellular physiology and tissue development. Pathways involved in the regulation of mitophagy, tumorigenesis, and cell death are overlapping in many cases and may be triggered by common upstream signals, which converge at the mitochondria. The failure to properly modulate mitochondrial turnover in response to oncogenic stresses can either stimulate or suppress tumorigenesis. Thus, the analysis of crosstalk among the processes of mitophagy, cell death and tumorigenesis is important for the identification of targets responsible for the stimulation of cell death and selective elimination of cancer cells. In the present review, we analyze the mechanisms of mitophagy regulation, the pathways underlying the utilization of damaged mitochondria, and how intervention with mitophagy can affect tumor cell resistance to treatment.

Contrasting effects of cardiac glycosides on cisplatin- and etoposide-induced cell death.

Cardiac glycosides (CGs) or cardiotonic steroids, which constitute a group of naturally occurring compounds with a steroid-like structure, can act on Na+/K+-ATPase as a receptor and activate intracellular signaling messengers leading to a variety of cellular responses. Epidemiological studies have revealed that CGs, used for the treatment of cardiac disorders, may also be beneficial as anti-cancer agents. CGs, acting in combination with other chemotherapeutic agents, may significantly alter their efficiency in relation to cancer cell elimination, causing both sensitization and an increase in cancer cell death, and in some cases resistance to chemotherapy. Here we show the ability of CGs to modulate apoptotic response to conventionally used anti-cancer drugs. In combination with etoposide, CGs digoxin may enhance cytotoxic potential, thereby allowing the chemotherapeutic dose to be decreased and minimizing toxicity and adverse reactions. Mechanisms behind this event are discussed.

Targeting mitochondria by α-tocopheryl succinate overcomes hypoxia-mediated tumor cell resistance to treatment.

Rapidly proliferating tumor cells easily become hypoxic. This results in acquired stability towards treatment with anticancer drugs. Here, we show that cells grown at 0.1 % oxygen are more resistant towards treatment with the conventionally used anticancer drugs doxorubicin and cisplatin. The stimulation of apoptosis, as assessed by the number of cells in the SubG1 fraction of the cell cycle, release of cytochrome c into the cytosol, activation of caspase-3, and cleavage of PARP, was markedly suppressed under low oxygen content or when hypoxia was mimicked by deferoxamine. Hypoxia or deferoxamine treatment was accompanied by stabilization of the hypoxia-inducible factor (HIF-1). The downregulation of HIF-1 using siRNA technique restored cell sensitivity to treatment under hypoxic conditions to the levels detected under normoxic conditions. In contrast to cisplatin or doxorubicin, α-tocopheryl succinate (α-TOS), a compound that targets mitochondria, stimulated cell death irrespective of the oxygen concentration. Moreover, under hypoxic condition cell death induced by α-TOS was even enhanced. Thus, α-TOS can successfully overcome resistance to treatment caused by hypoxia, which makes α-TOS an attractive candidate for antitumor therapy via mitochondrial targeting.

Ouabain activates signaling pathways associated with cell death in human neuroblastoma.

Cardiotonic steroids (CTS) like ouabain are not only specific inhibitors of the sodium pump (Na(+),K(+)-ATPase), they also can influence various cytosolic signaling events in a hormone-like manner. In the neuroblastoma cell line SH-SY5Y ouabain triggers multiple signaling pathways. Within 30 min of incubation with 1 or 10 microM ouabain, SH-SY5Y cells generate reactive oxygen species to a level approximately 50% above control and show a modest but significant elevation in cytosolic [Ca(2+)] of about 25%. After 6 h of exposure, ouabain stimulates a series of anti-apoptotic actions in SH-SY5Y cells, including concentration-dependent phosphorylation of Erk1/2, Akt, and Bad. Nevertheless, at the same time this CTS also induces a series of events that inhibit retinoic acid-induced neuritogenesis and promote cell death. Both of these latter phenomena are possibly associated with the observed ouabain-induced reduction in the abundance of the anti-apoptotic proteins Bcl-XL and Bcl-2. In addition, ouabain treatment results in cytochrome c release into the cytosol and induces activation of caspase 3, events that point towards the stimulation of apoptotic pathways that are probably enhanced by the stimulation of p53 phosphorylation at Ser15 also observed in this study. These pathways may eventually lead to cell death: treatment with 10 nM ouabain results in a 20% decrease in cell number after 4 days of incubation and treatment with 1 microM ouabain decreases cells number by about 75%. The results obtained here emphasize the importance of further research in order to elucidate the various signalling cascades triggered by ouabain and possibly other CTS that are used in the treatment of heart failure and to identify their primary receptor(s).