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Simple Summary The major obstacle for the long-term success of targeted therapies in melanoma is the occurrence of resistance. Here, we present a new mechanism of targeted therapy resistance in melanoma where the treatment with the BRAF inhibitor vemurafenib causes an increased activation of HER3 via shed ligands. This is followed by an activation of STAT3 via HER3 and results in the expression of the STAT3 target gene SOX2. Pharmacological inhibition of HERs sensitizes melanoma cells toward vemurafenib treatment. Thus, blocking HER family members and especially HER3 in addition to targeted therapy treatment might prevent the occurrence of resistance. Abstract Melanoma is an aggressive form of skin cancer that is often characterized by activating mutations in the Mitogen-Activated Protein (MAP) kinase pathway, causing hyperproliferation of the cancer cells. Thus, inhibitors targeting this pathway were developed. These inhibitors are initially very effective, but the occurrence of resistance eventually leads to a failure of the therapy and is the major obstacle for clinical success. Therefore, investigating the mechanisms causing resistance and discovering ways to overcome them is essential for the success of therapy. Here, we observed that treatment of melanoma cells with the B-Raf Proto-Oncogene, Serine/Threonine Kinase (BRAF) inhibitor vemurafenib caused an increased cell surface expression and activation of human epidermal growth factor receptor 3 (HER3) by shed ligands. HER3 promoted the activation of signal transducer and activator of transcription 3 (STAT3) resulting in upregulation of the STAT3 target gene SRY-Box Transcription Factor 2 (SOX2) and survival of the cancer cells. Pharmacological blocking of HER led to a diminished STAT3 activation and increased sensitivity toward vemurafenib. Moreover, HER blocking sensitized vemurafenib-resistant cells to drug treatment. We conclude that the inhibition of the STAT3 upstream regulator HER might help to overcome melanoma therapy resistance toward targeted therapies.

Although melanoma is one of the most immunogenic tumors, it has an ability to evade anti-tumor immune responses by exploiting tolerance mechanisms, including negative immune checkpoint molecules. The most extensively studied checkpoints represent cytotoxic T lymphocyte-associated protein-4 (CTLA-4) and programmed cell death protein 1 (PD-1). Immune checkpoint inhibitors (ICI), which were broadly applied for melanoma treatment in the past decade, can unleash anti-tumor immune responses and result in melanoma regression. Patients responding to the ICI treatment showed long-lasting remission or disease control status. However, a large group of patients failed to respond to this therapy, indicating the development of resistance mechanisms. Among them are intrinsic tumor properties, the dysfunction of effector cells, and the generation of immunosuppressive tumor microenvironment (TME). This review discusses achievements of ICI treatment in melanoma, reasons for its failure, and promising approaches for overcoming the resistance. These methods include combinations of different ICI with each other, strategies for neutralizing the immunosuppressive TME and combining ICI with other anti-cancer therapies such as radiation, oncolytic viral, or targeted therapy. New therapeutic approaches targeting other immune checkpoint molecules are also discussed.

Simple Summary Myeloid-derived suppressor cells (MDSC) represent a heterogeneous myeloid cell population that is expanded in tumor bearing hosts and substantially contributes to immunosuppression, representing thereby a valuable therapeutic target. Our study analyzes polymorphonuclear (PMN) and monocytic (M) MDSC subsets regarding their immunosuppressive capacity and recruitment mechanisms in murine melanoma. The immunosuppressive activity of both subsets was comparable. We identified the C-X-C Motif Chemokine Receptor (CXCR) 2/chemokine C-X-C motif ligand (CXCL) 1 axis as an important mediator of PMN-MDSC recruitment. Inhibition of CXCR2 resulted in a decreased infiltration of tumors with PMN-MDSC and increased survival of melanoma bearing mice. Furthermore, adjuvant treatment of mice with resected tumors reduced the infiltration of pre-metastatic sites with PMN-MDSC and the occurrence of distant metastasis. The decrease in PMN-MDSC infiltration was accompanied by an increase in natural killer (NK) cell frequency, suggesting an important role of PMN-MDSC in suppressing the NK cell-mediated anti-tumor response. Abstract Background: Despite recent improvement in the treatment of malignant melanoma by immune-checkpoint inhibitors, the disease can progress due to an immunosuppressive tumor microenvironment (TME) mainly represented by myeloid-derived suppressor cells (MDSC). However, the relative contribution of the polymorphonuclear (PMN) and monocytic (M) MDSC subsets to melanoma progression is not clear. Here, we compared both subsets regarding their immunosuppressive capacity and recruitment mechanisms. Furthermore, we inhibited PMN-MDSC migration in vivo to determine its effect on tumor progression. Methods: Using the RET transgenic melanoma mouse model, we investigated the immunosuppressive function of MDSC subsets and chemokine receptor expression on these cells. The effect of CXCR2 inhibition on PMN-MDSC migration and tumor progression was studied in RET transgenic mice and in C57BL/6 mice after surgical resection of primary melanomas. Results: Immunosuppressive capacity of intratumoral M- and PMN-MDSC was comparable in melanoma bearing mice. Anti-CXCR2 therapy prolonged survival of these mice and decreased the occurrence of distant metastasis. Furthermore, this therapy reduced the infiltration of melanoma lesions and pre-metastatic sites with PMN-MDSC that was associated with the accumulation of natural killer (NK) cells. Conclusions: We provide evidence for the tumor−promoting properties of PMN-MDSC as well as for the anti-tumor effects upon their targeting in melanoma bearing mice.

The article deals with legal documents in the field of information security, methods of the information risk assessment including economic cost models for identifying probabilistic parameters and structure of information risks and application of these models to the analysis of investments in information security projects. An adequate assessment of information risk and optimization of investments amount in the information security projects are based on approaches and procedures contained in the international standards for managing information security risks. Unfortunately, these standards are largely conceptual and advisory without taking into account of many factors that significantly affect the accuracy and objectivity of risk assessment. Economic approach to the analysis of risks including the known Gordon-Loeb model is focused mainly on the optimal risk management in general without tailoring to the real object producing risks. We offer models that use heuristic motivational and cost mechanisms to determine the parameters and the structure of risks. These models set links between international standards of the analysis and risk assessment and approaches to the risk optimization presented in the Gordon-Loeb model. To ensure a greater compatibility of these models and practical requirements that must be met through their structure, we introduced the information about the psycho-social characteristics of the intruder.

We propose a new method for the electrochemical impulse monitoring of corrosion-mechanical failures of technological objects operating in liquid electrolytes in the chemical and petrochemical industries and, in particular, for the monitoring of the technical state of equipment and prediction of its residual life according to the changes in the potential difference and the rate of generation of electric fracture pulses as functions of time.

The purpose of this study was to determine pedagogical conditions for effective swimming training of students of pedagogical educational institutions . Materials and methods. The experimental group (EG) consisted of 45 first-year female students of the schools of foreign philology, physics and mathematics education, natural geography and ecology (special medical group) who had a sufficient physical fitness level and could not swim. The control group (CG) was composed of 40 first-year female students of the schools of foreign philology, physics and mathematics education, natural geography and ecology (special medical group) who had a sufficient physical fitness level, could float, swim short distances (3-5 meters). Results. After the experiment, there was a significant improvement in the test results. Specifically, the experimental group students showed increase in all parameters of the cardiorespiratory system functional state – an increase in breath-holding time in the Stange’s test and the Genci’s test ( р = 0.001) and, accordingly, in the Harvard step test ( р = 0.001). The results of the experimental group students improved in the Harvard step test by 13.56%; in the Stange’s test – by 9.26%; in the Genci’s test – by 13.15% ( р = 0.001). The experimental group students showed a statistically significant improvement in the test results of physical fitness. Specifically, in the tests: “Standing long jump”, the result increased by 4.70%; “ Sit-ups in 30 seconds ” – by 10.59%; “Jumping rope” – by 6.91%; “Push-ups” – by 17.62% ( p = 0.001). Conclusions. The study revealed a statistically significant effectiveness of the suggested methods of teaching swimming to special medical group students. On the basis of discriminant analysis, the researchers ascertained a statistically significant influence of the experimental methods on the dynamics of the students’ physical and functional fitness. Positive dynamics of change was found in the indicators of high level of anxiety during swimming training.

We demonstrate the possibility of application of the polarization-current method to the corrosion monitoring of the operating equipment and present the numerical results showing that the indicated method enables one to estimate the degree of damage to the equipment at distances from the electrochemical probe not smaller than 5 m. The sensitivity of the method depends on the resistance of the electrolyte and the sizes of the tested object.

The paper deals with one of the acute for the nuclear energy problem of accident regimes of NPPs recognition diagnostics using noise signal diagnostics methodology. The methodology intends transformation of the random noise signals of the main technological parameters at the exit of a nuclear facility (neutron flow, dynamic pressure etc.) which contain the important information about the technical status of the equipment. The effective algorithms for identification of random processes wore developed. After proper transformation its were considered as multidimensional random vectors. Automatic classification of these vectors in the developed algorithms is realized on the basis of the probability function in particular Bayes classifier and decision functions. Till now there no mathematical models for thermalhydraulic regimes of fuel assemblies recognition on the acoustic and neutron noises parameters in the core of nuclear facilities. The two mathematical models for analysis of the random processes submitted to the automatic classification is proposed, i.e. statistical (using Bayes classifier of acoustic spectral density diagnosis signals) and geometrical (on the basis of formation in the featured space of dividing hyperplane). The theoretical basis of the bubble boiling regimes in the fuel assemblies is formulated as identification of these regimes on the basis of random parameters of auto spectral density of acoustic noise (ASD) measured in the fuel assemblies (dynamic pressure in the upper plenum in the paper). The elaborated algorithms allow recognize realistic status of the fuel assemblies. For verification of the proposed mathematical models the analysis of experimental measurements was carried out. The research of the boiling onset and definition of the local values of the flow parameters in the seven-beam fuel assembly (length of 1.3 m, diameter of 6 mm) have shown the correct identification of the bubble boiling regimes. The experimental measurements on real WWER core assemblies were analysed as well. On the basis of model of Bayes classifier for bubble structure of two-phase flow in fuel assemblies of WWBR-440 (intends usage of 28 dimensional accidental realizations of ASD of neutron noise) the reliable identification of the pointed regimes of fuel assemblies in WWERs up to 98% was obtained. On the basis of geometrical mathematical model of identification at essentially more limited volume of teaching sampling the recognition of ASD realizations of the neutron noise of the same both dimensions and quantity of the reliability of correct identification of these parameters was up to 92%. The recognition of the pointed thermalhydraulic parameters was carried out on the basis of experimental research of ASD of acoustic noise parameters of the experimental fuel assembly with electrically heated imitators using the two recognition models — statistical and geometrical. It confirmed high efficiency of the algorithms developed. The average reliability of identification of the first vapor bubbles activation regime at the heat transfer surface was not low then 90%.Copyright © 2002 by ASME

Inflammatory process is not limited only local effects but could affect other organs and tissues. In this study, we investigated the influence of experimental tibial osteomyelitis on skin cells in dynamics. Although the skin located at the distance from the infection nidus it supposed to manifest intensive proliferation, reparation and apoptosis under adverse factors. Immunohistochemical assay of apoptotic regulators and proliferation-related proteins was carried out in fibroblasts of stratum reticulare in Wistar rats. Proliferating fibroblasts pool decrease confirmed by Ki67 expression decrease was revealed, overexpression of p53 and Bax was accompanied by Bcl-2 expression decrease. Findings suggest depressed regeneratory potential of fibroblasts, high probability of apoptosis in the skin cells at the persisting osteomyelitis that should be considered in dermatological practice.