Search

Background We investigated the role of A2B-adenosine receptor (A2BAR) in regulating immunosuppressive metabolic stress in the tumor microenvironment (TME). Novel A2BAR antagonist PBF-1129 was tested for anti-tumor activity in animals and evaluated for safety and immunological efficacy in a phase-I clinical trial in non-small-cell lung cancer (NSCLC) patients. Methods Anti-tumor efficacy of A2BAR antagonists and impact on metabolic and immune TME was evaluated in lung, melanoma, colon, breast and EGFR-inducible transgenic cancer models. Employing Electron Paramagnetic Resonance, we assessed changes in TME metabolic parameters including pO2, pH, and inorganic phosphate (Pi) during tumor growth and evaluated the immunological effects of PBF-1129, including its pharmacokinetics, safety, and toxicity in NSCLC patients. Results Levels of metabolic stress correlated with tumor growth, metastasis, and immunosuppression. Tumor interstitial Pi emerged as a correlative and cumulative measure of TME stress and immunosuppression. A2BAR inhibition alleviated metabolic stress, downregulated expression of adenosine-generating ecto-nucleotidases, increased expression of adenosine deaminase (ADA), decreased tumor growth and metastasis, increased IFN-γ-production and enhanced the efficacy of anti-tumor therapies following combination regimens in animal models (anti-PD-1 vs. anti-PD-1 plus PBF-1129 treatment hazard ratio [HR] = 11.74, 95% CI = 3.35 to 41.13, n = 10, P Conclusions Data identify A2BAR as a valuable therapeutic target to modify metabolic and immune TME to reduce immunosuppression, enhance the efficacy of immunotherapies, and support clinical application of PBF-1129 in combination therapies.

Background Cumulative research show association of neutrophils and neutrophil extracellular traps (NETs) with poor outcomes in severe COVID-19. However, to date, there is no curative intent therapy able to block neutrophil/NETs-mediated progression of multi-organ dysfunction. Because of emerging neutrophil heterogeneity, the study of subsets of circulating NET-forming neutrophils [NET + Ns] as mediators of multi-organ failure progression among patients with COVID-19 is critical to identification of therapeutic targets. Methods We conducted a prospective observational study of circulating levels of CD11b + [NET + N] immunotyped for dual endothelin-1/signal peptide receptor (DEspR ±) expression by quantitative immunofluorescence-cytology and causal mediation analysis. In 36 consented adults hospitalized with mod-severe COVID-19, May to September 2020, we measured acute multi-organ failure via SOFA-scores and respiratory failure via SaO2/FiO2 (SF)-ratio at time points t1 (average 5.5 days from ICU/hospital admission) and t2 (the day before ICU-discharge or death), and ICU-free days at day28 (ICUFD). Circulating absolute neutrophil counts (ANC) and [NET + N] subset-specific counts were measured at t1. Spearman correlation and causal mediation analyses were conducted. Results Spearman correlation analyses showed correlations of t1-SOFA with t2-SOFA (rho rS = 0.80) and ICUFD (rS = -0.76); circulating DEspR + [NET + Ns] with t1-SOFA (rS = 0.71), t2-SOFA (rS = 0.62), and ICUFD (rS = -0.63), and ANC with t1-SOFA (rS = 0.71), and t2-SOFA (rS = 0.61). Causal mediation analysis identified DEspR + [NET + Ns] as mediator of 44.1% [95% CI:16.5,110.6] of the causal path between t1-SOFA (exposure) and t2-SOFA (outcome), with 46.9% [15.8,124.6] eliminated when DEspR + [NET + Ns] were theoretically reduced to zero. Concordantly, DEspR + [NET + Ns] mediated 47.1% [22.0,72.3%] of the t1-SOFA to ICUFD causal path, with 51.1% [22.8,80.4%] eliminated if DEspR + [NET + Ns] were reduced to zero. In patients with t1-SOFA > 1, the indirect effect of a hypothetical treatment eliminating DEspR + [NET + Ns] projected a reduction of t2-SOFA by 0.98 [0.29,2.06] points and ICUFD by 3.0 [0.85,7.09] days. In contrast, there was no significant mediation of SF-ratio through DEspR + [NET + Ns], and no significant mediation of SOFA-score through ANC. Conclusions Despite equivalent correlations, DEspR + [NET + Ns], but not ANC, mediated progression of multi-organ failure in acute COVID-19, and its hypothetical reduction is projected to improve ICUFD. These translational findings warrant further studies of DEspR + [NET + Ns] as potential patient-stratifier and actionable therapeutic target for multi-organ failure in COVID-19.

Supplemental Figure 1: No clear interaction of molecular subtype with change in TIL score dureing NAC. Supplemental Figure 2: No clear relationship between pre-NAC TILs or change in TILs with RFS or OS. Supplemental Figure 3: No clear association between pre-NAC or post-NAC TILs and total number of targeted alterations identified by targeted NGS. Supplemental Figure 4: A) Percent of high expressers of PD-L1 (>1 standard deviation from the mean) in each molecular subtype in the TCGA breast cancer dataset. Supplemental Figure 5: MEK inhibition down-regulates downstream ERK signalling and inhibits proliferation of TNBC murine breast cancer lines AT3ova and 4T1.9 in vitro. Supplemental Figure 6: Efficacy of selumetinib and anti-PD-L1 therapy in MMTV-Neu models. Supplemental Figure 7: Pharmacodynamic activity of trametinib and selumetinib in vivo.

Purpose: Tumor-infiltrating lymphocytes (TIL) in the residual disease (RD) of triple-negative breast cancers (TNBC) after neoadjuvant chemotherapy (NAC) are associated with improved survival, but insight into tumor cell-autonomous molecular pathways affecting these features are lacking.Experimental Design: We analyzed TILs in the RD of clinically and molecularly characterized TNBCs after NAC and explored therapeutic strategies targeting combinations of MEK inhibitors with PD-1/PD-L1–targeted immunotherapy in mouse models of breast cancer.Results: Presence of TILs in the RD was significantly associated with improved prognosis. Genetic or transcriptomic alterations in Ras–MAPK signaling were significantly correlated with lower TILs. MEK inhibition upregulated cell surface MHC expression and PD-L1 in TNBC cells both in vivo and in vitro. Moreover, combined MEK and PD-L1/PD-1 inhibition enhanced antitumor immune responses in mouse models of breast cancer.Conclusions: These data suggest the possibility that Ras–MAPK pathway activation promotes immune-evasion in TNBC, and support clinical trials combining MEK- and PD-L1–targeted therapies. Furthermore, Ras/MAPK activation and MHC expression may be predictive biomarkers of response to immune checkpoint inhibitors. Clin Cancer Res; 22(6); 1499–509. ©2015 AACR.

Supplementary figure legend

For almost 30 years since the end of the civil war in Lebanon, signing of the Taif agreements in 1989 and the dissolution of the USSR in 1991 with the emergence of new Russia, the bilateral Russian-Lebanese relations remained partnership and friendly. They have reflected the trend of strengthening mutually beneficial cooperation. Nevertheless, Russian-Lebanese relations at the present stage (21st century) have remained partially unexplored. The article is devoted to a comprehensive study of Russian-Lebanese relations in the political, diplomatic, economic and cultural spheres; the focus is made on the 2000s. The research contains a quantitative analysis of Russian-Lebanese official contacts (2006-2020), as well as a review of the commodity structure of the countries turnover.

The sequence of sediment accumulation of the first and second terraces of the Tarbagataika River and changes in the stages of incision and filling, as well as sedimentation and soil formation over the last 14 kyr in the river valley were revealed. The dynamics of the sedimentation stages and of the phases of their stabilization and pedogenesis was determined by landscape-climatic changes in the study area. The period of geomorphologic formation of above-floodplain terraces was determined. The floodplain sedimentation regime was changed by the subaerial regime on the second terrace of the Tarbagataika River approximately 8 kyr BP. The accumulation of cover deposits on the first terrace began approximately 3.4 kyr BP. Deposits of the second terrace of the Tarbagataika River were formed during the Late Glacial and the Holocene during the last 14 kyr. They are composed of alluvial sediments that accumulated 14.0–8.0 kyr BP and of cover deposits, which accumulated 8.0–0 kyr BP. The first terrace of the Tarbagataika River of the Holocene age is composed of alluvial deposits, which were accumulated 7.0–3.4 kyr BP, and of deposits of the covering complex, which were formed over the last 3.4 kyr. The phases of intensification of erosion-accumulative processes related to increased water discharge were identified. The main stages of soil formation in the study area were determined. The data we obtained are in good agreement with the previously identified stages of pedogenesis in the Selenga middle mountains and adjacent regions of South-Eastern Siberia and Mongolia.

The construction of a thermal model of a fully air cooled turbine generator stator with taking into account gas dynamics is considered. The complete mathematical model includes various physical subsystems with multiphysical relationships. The study is based on accurate 3D models with the use of the modern and proven COMSOL Multiphysics software, in which the finite element method is used for calculation. The equivalent thermal conductivity of the gap between the winding bar copper conductors and stator iron is studied. The gap in question consists of the winding bar main insulation and a gap filled with additional semiconducting gaskets or similar materials. The above-mentioned physical parameter has a strong influence on the temperature distribution, because the main part of the heat releasing in the bar is transferred to the stator core through these elements. The optimal minimum equivalent thermal conductivity coefficient is analyzed and selected. A model of a turbine generator stator symmetric element together with a turbulent cooling air flow is developed and analyzed. The development of such integrated models will make it possible not only to simplify the design process, but also to analyze various insulation systems. For example, air-cooled turbine generators initially use the Global VPI insulation system; however, after replacing---for economic reasons---the stator winding, another insulation system is used, namely, the Resin Rich system. For correctly making a transition to another insulation system, integrated calculations, including thermal ones, should be carried out. In practice, after changing the insulation system, which may entail certain thermal limitations, it may be necessary to decrease the turbine generator rated power output for its further operation without overheating the stator winding, which can be obtained on the basis of simulation. In this regard, the equivalent thermal conductivity coefficient also plays an important role; its value can be preliminarily analyzed to select the necessary materials in terms of their thermal properties, and their filling factor to retain the turbine generator nominal parameters after its rewinding.

Results of studies of the explosive expansion of a set of shrapnel discs of natural crushing are described in the article. Set consisted of two disks of different thickness, but of a fixed total mass. The studies were carried out by computer simulation of shock-wave processes in a continuous formulation using the ANSYS/LS-DYNA program. The program of computer design foresees development of three-dimensional certainly-element model including, in accordance with symmetry of the examined system fourth part of the examined explosive system of casting block, with imposed on its knots of the proper scopes terms concerted with taken mixed Lagrangian-Eulerian approach within the framework of the continuum model. The effect of the order of installing disks of different thickness on the distribution of their mass and its velocity in the middle of the meridional angle of expansion is established. The analysis of the computer simulation presented on the basis of numerical studies on the distribution of the mass of the disks and its velocity of motion suggests that to create a narrow high-speed uniformly filled fragmentary mass of the axial flow, it is necessary to change the geometric shape of the disc so that in the central angular zones of the disks. This allows the velocity of the fragment mass to be aligned along the radius of the discs and to fill the first angular zones with the required mass of fragments.

The geometrical and electronic structures of iron and cobalt metal complexes of porphyrazine and tetra(1,2,5-thiadiazole)porphyrazine in ground and low-lying excited electronic states were determined by DFT calculations and the complete active space (CASSCF) method with following accounting dynamic correlation by multiconfigurational quasidegenerate second-order perturbation theory (MCQDPT2). A geometrical structure of D[Formula: see text] symmetry has been obtained for all four complexes. According to data obtained by the MCQDPT2 method, the complexes of cobalt and iron possess the ground states 2A[Formula: see text] and 3A[Formula: see text], respectively, and wave functions of the ground states have the form of a single determinant. It is shown that the crystal field theory (CFT) can be used to describe the sequence of electronic states of the investigated complexes. The nature of the bonds between metal atoms and nitrogen atoms has been described using the analysis of the electron density distribution in the frame of Bader’s quantum theory of atoms in molecule (QTAIM).

We study theoretically the nonlinear optical response of a monolayer of regularly arranged three-level identical quantum emitters with a doublet in the excited state to the action of a monochromatic electromagnetic field quasi-resonant to optical transitions in the emitter. The total retarded dipole–dipole interaction of the emitters is accounted for in the mean-field approximation. This interaction plays the role of a positive feedback, which (in combination with the immanent nonlinearity of emitters themselves) leads to multistability of the monolayer response. The stability of different response branches is analyzed using the Lyapunov exponents method. It is found that the instability type depends on the doublet splitting and changes from self-oscillations to chaos upon increasing the splitting. Another important property of the monolayer is its high (almost 100%) reflectance in a certain frequency range; i.e., within this range, the monolayer operates as a perfect nanometer mirror; moreover, reflection can be switched to transmission changing slightly the incident field amplitude (bistability). The possibility of application of the above mentioned monolayer optical properties in nanophotonics is discussed.

The article reviews the literature devoted to modern methods of treating children with flat-valgus deformity of the feet. The basic concept, etiology, pathogenesis of the disease, methods of conservative and surgical treatment of feet deformities in children are given, conclusions on the topic are presented, special emphasis has been placed on minimally invasive intervention. Currently one of the most popular methods of surgical correction of flat-valgus deformity of the feet in children is subtalar arthroeresis.

We propose an algorithm for the fusion of partial images collected from the visual and infrared cameras such that the visual and infrared images are the real and imaginary parts of a complex function. The proposed image fusion algorithm of the complex function is a generalization for the algorithm of conventional image addition in the same way as the addition of complex numbers is the generalization for the addition of real numbers. The proposed algorithm of the complex function is simple in use and non-demanding in computer power. The complex form of the fused image opens a possibility to form the fused image either as the amplitude image or as a phase image, which in turn can be in several forms. We show theoretically that the local contrast of the fused phase images is higher than those of the partial images as well as in comparison with the images obtained by the algorithm of the simple or weighted addition. Experimental image quality assessment of the fused phase images performed using the histograms, entropy shows the higher quality of the phase images in comparison with those of the input partial images as well as those obtained with different fusion methods reported in the literature.

Object and purpose of research. This paper discusses vibroacoustic parameters of engineering structures in a wide frequency band. The purpose of the study is to select a numerical method in terms of the maximum convergence between analytical and experimental data for both higher and lower frequencies. Materials and methods. The paper discusses numerical simulation methods (FEM, SEA, hybrid) for vibroacoustic parameters of engineering structures. Experimental vibroacoustic measurements were performed in a small-size tank on a full-scale model of a double-hulled structure. Main results. The study concludes that hybrid method is the most suitable in terms of sufficient calculation speed and accuracy of results for vibroacoustic parameters in a wide frequency band. Conclusion. Application of hybrid simulation method to vibroacoustic parameters pointed out the possibility of studies on large models in a restricted space of small-size tank for medium and low frequencies.

Electronic and geometric structures of metal-free, Al, Ga and In complexes with tetrapyrazinoporphyrazine (TPyzPA) and octachlorotetrapyrazinoporphyrazine (TPyzPACl8) were investigated by density functional theory (DFT) calculations and compared in order to study the effect of chlorination on the structure and properties of these macrocycles. The nature of the bonds between metal atoms and nitrogen atoms was described using the NBO-analysis. Simulation and interpretation of electronic spectra were performed with the use of time-dependent density functional theory (TDDFT). A description of calculated IR spectra was carried out based on the analysis of the distribution of the potential energy of normal vibrational coordinates.

Introduction: ErbB signaling contributes to the regulation of vascular function through endothelial cell differentiation, proliferation, survival, and regulation of barrier integrity. Patients with diabetes (DM) are at an increased risk for endothelial dysfunction and worse outcomes after CABG. We investigated the level of ErbB expression on CD31 endothelial cells and CD105+ cells in DM and non-DM patients undergoing CABG. Methods: With IRB approval, left ventricular (LV) epicardial biopsies and blood samples from 25 patients (non-DM=9, DM=16), were obtained during surgery. Flow cytometry was used to determine the cell surface expression of ErbB receptors on cardiac endothelial and CD105+ cells isolated from the LV. Subpopulations of white blood cells were determined in blood samples. Plasma levels of IL-6, IL-8, and TNFα were measured. Results: Lower levels of ErbB1 and ErbB2 receptors expression on endothelial cells isolated from LV biopsies were found in patients with DM compared to non-DM control, and the expression of ErbB receptors negatively correlated with HgbA1c level. There were fewer CD105+ cells in DM patients (122 vs 153 cell/mg tissue, P=.021). Trends toward a negative association were found between the expression of ErbB2 in CD105+ cells and the number of neutrophils, as well as, HgbA1c level. No differences were found between DM and non-DM patients in the number of white blood cell subsets or plasma levels of IL-6, IL-8 and TNFα. Conclusions: We demonstrated that DM and high glucose blood levels are associated with reduced expression of ErbB1 and ErbB2 on endothelial cells and decreased number of CD105+ cells in the LV. Cardiac CD105+ are endothelial progenitor cells that differentiate in response to ErbB ligands. A decreased pool of CD105 endothelial progenitors in combination with down-regulation of ErbB1 and ErbB2 receptors in endothelial cells represent a novel mechanism for vascular dysfunction and adverse remodeling seen in diabetic patients.

Road dust is a composite substance formed due to wear of different components of transport infrastructure and motor vehicles. In 2017, 214 road dust samples were collected in Moscow to analyze pH, electrical conductivity (EC), and organic carbon (Cоrg) content that controls the ability of dust to fix pollutants. The road dust was dominated by sand and silt size particles (the share of PM10 particles varies from 2.3% to 39%) and had alkaline pH (6.4–8.1), high EC (33–712 μS/cm) and Cоrg (0.17–6.7%). The road dust is alkalinized by detergents and particles formed by abrasion of roadways and blown out from construction sites. A three-fold excess of the EC over the background values (dust in parks) is mainly due to the use of the de-icing agents and roadway maintenance. But the concentration of Cоrg in the Moscow’s road dust is on average 2 times lower compared to the background values; the increased content of Cоrg in the courtyards is associated with the application of organic fertilizers. The most significant factor that determines the physicochemical properties of the dust was the type of a road. The dust on large roads including the Third Ring Road had higher pH (7.0–8.0) and EC (98–712 μS/ cm); it contained higher proportions of the fine particle-size fractions compared to other roads. The Cоrg content in the road dust was minimum on Moscow’s major radial highways due to the insignificant contribution of soil particles. The spatial trends in variability of the physicochemical properties of the dust in Moscow were not evident as they were to a large extent masked by other factors: proximity to industrial zones and large forest parks, differences in the de-icing agents used, unequal frequencies of road cleaning, and the various contribution of soil particles that vary in composition and genesis in different parts of Moscow.

The article proposes a method of redistribution of time between stages of diagnostics and complete elimination of defects of radio-electronic means in the conditions of the repairing service. The method minimizes the average recovery time in the process of elimination of multiple defects which result from accidental or combat damage. It consists in a comprehensive consideration of the components of the repair process after preliminary identification of defects at the location of damage and in the estimation of the expected multiplicity of defects. A block diagram of the algorithm for solving of this problem is proposed. The algorithm differs from the known analogs by the account for the probability of correct diagnosis and the metrological reliability of the used measuring equipment. The application of the method at given conditions allows us to quantify the time of implementation of each stage of recovery and to reasonably recommend a redistribution of efforts to minimize the average recovery time of electronic devices with multiple defects. An example of the application of method, illustrating the influence of managed variables on the efficiency of the method, is presented. The use of the obtained results allows one to increase the capability of military repairing service in the recovery of equipment with weak and medium combat damages, either in the field conditions, or at the points of maintenance and repair service. The proposed method is recommended for implementation in the software for maintenance of the REMs of modular type.

The paper reviews the issue of the creation of a fundamentally new innovative model of negotiation process focused on settling the Israeli-Palestinian conflict. In the author’s opinion, political leadership factor that is typical for the Arab-Israeli world is instrumental in providing a conceptual framework for peace talks between Israel and Palestine in the context of globalization. The article focuses on the peculiarities of the Islamic model of political or, to be more precise, religious and political leadership and how it can be implemented to give a new impetus to the currently bogged down Israeli-Palestinian peace talks. The author argues that is impossible to achieve any tangible regional treaty because not all the arrangements concerning Palestine have a legitimate character from the point of view of both the Palestinians and the people of other Muslim countries in the world. Therefore, in the author’s opinion, without using such an innovative model of the negotiation process it will be principally impossible to achieve a final settlement of the Israeli-Palestinian conflict.

The aim of the study: was to improve the results of treatment in children with recurrent severe patellar dislocation, through the development of a differentiated approach to preoperative planning. Material and Methods. In SLLP Clinics Samara state medical University from 2014 to 2018 was observed 54 patients with this disease. In 37 patients recurrent severe dislocation. The average age of patients is 14.2 years. The patients underwent postural radiography of the lower extremities, radiography of the knee joint in the lateral projection, computed tomography of the knee joints, computed tomography of the hip joints. Research patients measured parameters, confirming mnohopocetny dysplastic changes of the joint angle Q, the index InsallSalvati, the congruence angle on Merchant and anticarsia of the femoral head. Because of the severe degree of the disease, bone plastic surgery is indicated. Patients underwent corrective supracondylar derotationdialysisa osteotomy of the femur in combination with medialization and distalization of the tibial tuberosity. During this operation, it is possible to perform a correction in all three planes. Results. In the postoperative period,32 patients have no complications,1 patient has relapse,4 patients have contracture. In the long-term postoperative period 86.5% of positive results and 13.5% of unsatisfactory results, which is much lower than 36.1% the percentage of complications according to the medical literature. Conclusion. The proposed personalized approach in preoperative planning for recurrent dislocation of the patella of severe degree, allows you to choose the best option for surgery

Expressions for calculation of optimal criteria for highest information and sensitivity indices and lowest mean square error in test signals for radio-electronic systems (RES), working under influence of the additive Gaussian noise, are derived. In this framework, the technical state of a RES is determined via measurement of its dynamic characteristics. Because at negligible electromagnetic noise, all test signals are equivalently optimal, the test signal of the RES, which is optimal for a high-level noise, is considered to be optimal for the noise of lower level. It is proven, that at high levels of noise these three criteria (maximums of informative and sensitivity indices and minimum of mean square error) reduce into a single criterion. This universal criterion can be used to synthesize test signals with optimal parameters for determination of the technical state of any radio electronic device at any level of an additive Gaussian noise and can be applied in situ of RES operation.

The article first proposed an approach to improving the accuracy of quantitative assessment of reliability indicators of radio-electronic means with a variable structure, operating in different modes of operation using separate sets of elements in each of them. In the well-known works, this circumstance is not taken into account and there liability indicators of the product are estimated under the assumption that all elements operate simultaneously, which leads to a decrease in the calculated value of mean time to failure. The problem is solved by the introduction of the utilization rate of each structural element of the product in all possible modes of operation. An example of using the obtained results for the quantitative assessment of the time to failure of a radio station is given, and the effect of clarifying the calculations is shown.Reliability of radio-electronic means is quantitatively evaluated by indicators, the main ones being the time between products failure and the average time of its recovery. They define a comprehensive measure of reliability - availability. Reducing the calculated value of time between failures requires, to ensure its desired value, the use of more reliable components, which leads to an increase in the value of the product as a whole.The article for the first time obtained a mathematical model for assessing reliability indicators, taking into account the product operation time in each of the possible modes, and when calculating the maintainability index, metrological reliability of measuring equipment tools that are used in the process of diagnostics during radio repair is taken into account.The proposed model for estimating the values of reliability indicators of objects with variable structure is advisable to use at the design stage of modern radio electronic equipment. The effect of its implementation is to provide the specified values of reliability indicators of multi-mode electronic means at their minimum cost.