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Objective The problem of drug resistance to BRAF-targeted therapy often occurs in melanoma treatment. Activation of PI3K/AKT/mTOR signaling pathway is one of the mechanisms of acquired resistance and a potential target for treatment. In the current research, we investigated that dual inhibition of mTOR and MEK synergistically reduced the viability of melanoma cells in vitro. Methods A combination of rapamycin (a macrolide immunosuppressant, mTOR inhibitor) and binimetinib (an anti-cancer small molecule, selective inhibitor of MEK) was studied using a panel of melanoma cell lines, including patient-derived cells. Results It was found, that combinatorial therapy of rapamycin (250 nM) and binimetinib (2 μM) resulted in 25% of cell viability compared to either rapamycin (85%) or binimetinib alone (50%) for A375 and vemurafenib-resistant Mel IL/R cells. The suppressed activation of mTOR and MEK by combined rapamycin and binimetinib treatment was confirmed using Western blot assay. Cell death occured via the apoptosis pathway; however, the combination treatment significantly increased the apoptosis only for Mel IL/R cells. The enhanced cytotoxic effect was also associated with enhanced cell cycle arrest in the G0/G1 phase. Conclusion In general, we provide the evidence that dual inhibition of mTOR and MEK could be promising for further preclinical investigations.

We consider a gas-dynamic model of a one-dimensional flow of non-viscous perfect gas in the absence of heat conduction when a high-power localized heat source is switched on. Within the framework of this model, it is possible to thoroughly analyze the problem of the gas-flow regimes, which occur as a result of switch-on of such a source, in a wide range of values of the energy-deposition power and initial gas-dynamic characteristics of the flow. Eventually, we obtain a sufficiently general insight into the character of the resulting flows and the conditions of their realizations.

We consider a gas-dynamic model describing the formation of a plasma with multiply ionized ions under the conditions of resonant heating of the electron component. Based on the isothermal approximation, possible regimes of the plasma flow are classified, the influence of the geometric divergence of the flow on the formation of the ion charge distribution is studied, and optimal regimes for the achievement of the maximum ion charge are identified. The model can be used for optimization and interpretation of modern experiments on generation of the extreme ultraviolet radiation due to the excitation of lines of multiply ionized atoms in a gas flow heated by strong millimeter or submillimeter waves.

Results obtained when investigating the possibility of using an Ardenne duoplasmatron as a generator of a highly ionized plasma beam containing ions of dielectric materials for depositing resistive films in a vacuum are presented. The constructional features of the duoplasmatron are considered, and information on the parameters of the plasma reactor of the evaporator is presented. The rate of deposition of films is investigated experimentally as a function of the modes of operation of the duoplasmatron. The properties of the films obtained are discussed. Methods of controlling the parameters of the highly ionized plasma fluxes which ensure a change in the velocity vector of the flux, its density, and the percentage content of the drop phase in it are considered.