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Abstract The development of CAR-T specific therapy made a revolution in modern oncology. Despite the pronounced therapeutic effects, this novel approach displayed several crucial limitations caused by the complications in pharmacokinetics and pharmacodynamics controls. The presence of the several severe medical complications of CAR-T therapy initiated a set of attempts aimed to regulate their activity in vivo. We propose to apply the barnase-barstar system to control the cytotoxic antitumor activity of CAR-T cells. To menage the regulation targeting effect of the system we propose to use barstar-modified CAR-T cells together with barnase-based molecules. Barnase was fused with designed ankyrin repeat proteins (DARPins) specific to tumor antigens HER2 (human epidermal growth factor receptor 2) The application of the system demonstrates the pronounced regulatory effects of CAR-T targeting.

The existing biological models of diffuse alveolar damage (DAD) in mice have many shortcomings. To offset these shortcomings, we have proposed a simple, nonsurgical, and reproducible method of unilateral total damage of the left lung in ICR mice. This model is based on the intrabronchial administration of a mixture of bacterial lipopolysaccharide (LPS) from the cell wall of S. enterica and α-galactosylceramide (inducing substances) to the left lung.Using computer tomography of the lungs with endobronchial administration of contrast material, we have been able to perform an operative intravital verification of the targeted delivery of the inducer. The model presented is characterized by more serious and homogeneous damage of the affected lung compared to the existing models of focal pneumonia; at the same time, our model is characterized by longer animal survival since the right lung remains intact.The model is also characterized by diffuse alveolar damage of the left lung, animal survival of 100%, abrupt increases in plasma levels of TNFa, INFg, and IL-6, and significant myocardial overload in the right heart. It can be used to assess the efficacy of innovative drugs for the treatment of DAD and ARDS as the clinical manifestations that are developed in patients infected with SARS-CoV-2. Morphological patterns of lungs in the noninfectious ("sterile") model of DAD induced by LPS simultaneously with α-galactosylceramide (presented here) and in the infectious model of DAD induced by SARS-CoV-2 have been compared.The DAD model we have proposed can be widely used for studying the efficacy of candidate molecules for the treatment of infectious respiratory diseases, such as viral pneumonias of different etiology, including SARS-CoV-2.

Introduction. The standard of 1st line treatment of HER2+ metastatic breast cancer (mBC) is double blockade with trastuzumab and pertuzumab + taxane, 2nd line – Trastuzumab-emtazine. There are no standards for further treatment, as well as the optimal drug sequence. Expansion of the arsenal of therapeutic possibilities and the use of new combinations will certainly improve the results of treatment of this category of patients and increase their life expectancy.Aim. We sought to describe treatment patterns of eribulin and clinical outcomes of metastatic HER2-positive breast cancer treated with eribulin plus trastuzumab combination in academic institutions and community oncology practices across the Russian Federation.Materials and methods. Patients treated with eribulin anytime between Jan, 2014 and Sep, 2019 with a diagnosis of MBC were identified by 23 providers from Russia. Providers retrospectively reviewed the health records and abstracted selected data points into an electronic case report form for each eligible patient.Results. 100 HER2-positive pts received eribulin in combination with trastuzumab. Median age was 55 (31–80) yrs and ECOG status 0–3. 67% pts had visceral metastases. Eribulin was administered as 1st and 2nd line to 23 (23%) pts, 3rd line to 31 (31%) pts, 4th line and later to 46 (46%). Median number of cycles was 5 (2–27). ORR was 12%, SD – 72%, SD > 6 months – 23%, PD – 16%. Clinical efficacy rate achieved in 35%. Median PFS was 5.07 months (95% CI 4.021–6.119). According to the ER-status the response to eribulin and trastuzumab was different. ORR was 18.8%, SD 72.9% in pts with ER-positive MBC (n = 48) and 5.8% and 71.2% respectively in ER-negative MBC (n = 52). Median PFS was 6.97 months (95% CI 3.924–10.016) in pts with ER-positive MBC and 4.67 months (95% CI 3.841–5.499) in ER-negative MBC (р = 0.3). The combination was well tolerated: dose reductions were required in 12% pts, withdrawal due to toxicity in 4% pts. The most common type of toxicity was hematological with neutropenia Gr III-IV in 14 (14%) pts. Peripheral neuropathy Gr III was observed in 5 (5%) pts. No cardiotoxicity was detected.Conclusions. This is the real-life data of clinical outcomes for patients receiving eribulin plus trastuzumab for HER2-positive MBC throughout the Russian Federation. Our experience with eribulin plus trastuzumab demonstrates that this combination may be a potential effective treatment option for HER-2 positive MBC patients.

The development of chimeric antigen receptor (CAR) T cell therapy has become a critical milestone in modern oncotherapy. Despite the remarkable in vitro effectiveness, the problem of safety and efficacy of CAR T cell therapy against solid tumors is challenged by the lack of tumor-specific antigens required to avoid on-target off-tumor effects. Spatially separating the cytotoxic function of CAR T cells from tumor antigen recognition provided by protein mediators allows for the precise control of CAR T cell cytotoxicity. Here, the high affinity and capability of the bacterial toxin-antitoxin barnase-barstar system were adopted to guide CAR T cells to solid tumors. The complementary modules based on ( 1 ) ankyrin repeat (DARPin)-barnase proteins and ( 2 ) barstar-based CAR (BsCAR) were designed to provide switchable targeting to tumor cells. The alteration of the DARPin-barnase switches enabled the targeting of different tumor antigens with a single BsCAR. A gradual increase in cytokine release and tunable BsCAR T cell cytotoxicity was achieved by varying DARPin-barnase loads. Switchable BsCAR T cell therapy was able to eradicate the HER2 + ductal carcinoma in vivo. Guiding BsCAR T cells by DARPin-barnase switches provides a universal approach for a controlled multitargeted adoptive immunotherapy.

The pathogenesis of autoimmune arthritis is a hot topic in current research. The main focus of this work was to study cytokines released in CFA-induced arthritis in ICR mice as well as the regulation of blood levels of cytokines by two peptides of the innate immunity protein Tag7 (PGLYRP1) capable of blocking the activation of the TNFR1 receptor. Arthritis was induced by local periarticular single-dose injections of 40 µL of complete Freund’s adjuvant (CFA) into the left ankle joints of mice. The levels of chemokines and cytokines in plasma were measured using a Bio-Plex Pro Mouse Cytokine Kit at 3, 10, and 21 days after arthritis induction. Tag7 peptides were shown to decrease the blood levels of the pro-inflammatory cytokines IL-6, TNF, and IL-1β. Administration of peptides also decreased the levels of chemokines MGSA/CXCL1, MIP-2α/CXCL2, ENA78/CXCL5, MIG/CXCL9, IP-10/CXCL10, MCP-1/CCL2, and RANTES/CCL5. Furthermore, a decrease in the levels of cytokines IL7, G-CSF, and M-CSF was demonstrated. Addition of the studied peptides strongly affected IFN-γ concentration. We believe that a decrease in the levels of cytokine IFN-γ was associated with a therapeutic effect of Tag7 peptides manifested in alleviation of the destruction of cartilage and bone tissues in the CFA-induced arthritis.

The effectiveness of destruction of air objects (AO) largely depends on the excellence of radar devices, which are called radar homing heads (RHH) of the guided weapons systems (GWS). In the process of GWS AO development, several generations of RHHs were created: semi-active RHHs with a pulsed or continuous target illumination signal; RHHs providing combined guidance; RHHs, providing realization of inertial guidance with radio correction from the weapon control system of the GWS carrier, active guidance, a combination of semi-active and active modes, combined guidance, in which inertial guidance with radio correction, passive and active homing are consistently implemented. Currently, there is a need for an analytical generalization of information about the GHHs, published in various open scientific and technical sources of information. In the course of the analysis, it was found that the main directions for improving the RHHs are: the development of new, more flexible non-stationary homing methods and their information support, which provide the ability to intercept new types of AO in complex signal-jamming multipurpose situations. This predetermines the need to achieve a high level of RHHs protection from natural and intentional interference, the use of trajectory control of observation when aiming at radio-emitting and group objects, improvement of situational awareness, RHHs intellectualization and digitalization, improvement of RHH antenna systems.

Changes in the structure and phase composition of the hydroxyapatite (HA) plasma coating were established during deposition at the initial temperatures of 20 and 550°C of the titanium substrate and a deposition distance of 95 and 150 mm. The structure of HA coatings was analyzed by SEM and optical microscopy. DSC analysis established the transition temperatures of HA coatings to the equilibrium state. When deposited on a substrate with an initial temperature of 20°C at a deposition distance of 95 mm, a nanostructure with a crystallite size of 21 nm is recorded in the HA coating. When the deposition distance increases to 150 mm, the nonequilibrium phase composition increases, the crystallite size decreases to 12 nm, the HA content decreases from 72 to 61%, the TTCP content decreases from 10 to 5%, and the α-TCP content increases from 17 to 30%. A nonequilibrium nanostructural state passes into a more equilibrium state with the release of heat at temperatures of 615–727°C in DSC studies. The high-temperature α-TCP phase is not recorded when the coating is deposited onto a substrate with an initial temperature of 550°C at a deposition distance of 95 mm, the TTCP content increases by two times, the size of the HA phase crystallites reaches 36 nm, and their size in the sprayed powder is 75 nm. The HA coating has a dendritic microstructure and has no thermal effect during DSC heating at an initial substrate temperature of 550°C.

Physical review / B 106(12), 125137 (2022). doi:10.1103/PhysRevB.106.125137, Novel two-dimensional electron systems at the interfaces and surfaces of transition-metal oxides recently have attracted much attention as they display tunable, intriguing properties that can be exploited in future electronic devices. Here we show that a high-mobility quasi-two-dimensional electron system with strong spin-orbit coupling can be induced at the surface of a KTaO$_3$ (001) crystal by pulsed laser deposition of a disordered LaAlO$_3$ film. The momentum-resolved electronic structure of the buried electron system is mapped out by hard x-ray angle-resolved photoelectron spectroscopy. From a comparison to calculations, it is found that the band structure deviates from that of electron-doped bulk KTaO$_3$ due to the confinement to the interface. Fermi surface mapping shows a three-dimensional, periodic intensity pattern consistent with electron pockets of quantum well states centered around the Γ points and the expectations from a Fourier analysis-based description of photoemission on confined electron systems. From the k broadening of the Fermi surface and core-level depth profiling, we estimate the extension of the electron system to be at least 1 nm but not much larger than 2 nm, respectively., Published by Inst., Woodbury, NY

Traumatic injury of the spinal cord is still one of the most challenging problems in the neurosurgical practice. Despite a long history of implementation of translational medicine in the field of spinal cord injury (SCI), it remains one of the most frequent causes of human disability and a critical situation for world healthcare systems. Here, we used our rat model of the of unilateral controlled SCI induced by a cryoinjury, which consistently reproduces glial scarring and posttraumatic cyst formation, and specifically evaluated histological, bioimaging and cytokine data. We propose a 10-grade scoring scale, which can objectively estimate the extent of damage of the experimental SCI according to the magnetic resonance imaging (MRI) results. It provides a homogeneous and reliable visual control of the dynamics of the posttraumatic processes, which makes it possible to clearly distinguish the extent of early damage, the formation of glial scars and the development of posttraumatic syringomyelic cysts. The concentration of cytokines and chemokines in the plasma following the experimental SCI increased up to two orders of magnitude in comparison with intact animals, suggesting that a traumatic injury of the spinal cord was accompanied by a remarkable cytokine storm. Our data suggested that the levels of IL-1α, IL-1β, TNFα, GRO/KC, G-CSF, IFNγ and IL-13 may be considered as a reliable prognostic index for SCI. Finally, we demonstrated that MRI together with plasma cytokines level directly correlated and reliably predicted the clinical outcome following SCI. The present study brings novel noninvasive and intravital methods for the evaluation of the therapeutic efficacy of SCI treatment protocols, which may be easily translated into the clinical practice.

HIV-1 epidemic in Russia is one of the fastest growing in the world reaching 1.14 million people living with HIV-1 (PLWH) in 2021. Since mid-1990s, the HIV-1 epidemic in Russia has started to grow substantially due to the multiple HIV-1 outbreaks among persons who inject drugs (PWID) leading to expansion of the HIV-1 sub-subtype A6 (former Soviet Union (FSU) subtype A). In 2006, a local HIV-1 sub-epidemic caused by the distribution of novel genetic lineage CRF63_02A6 was identified in Siberia. In this study, we used a comprehensive dataset of CRF63_02A6 pol gene sequences to investigate the spatiotemporal dynamic of the HIV-1 CRF63_02A6 sub-epidemic. This study includes all the available CRF63_02A6 HIV-1 pol gene sequences from Los Alamos National Laboratory (LANL) HIV Sequence Database. The HIV-1 subtypes of those sequences were conferred using phylogenetic analysis, and two automated HIV-1 subtyping tools Stanford HIVdb Program and COMET. Ancestral state reconstruction and origin date were estimated using Nextstrain. Evolutionary rate and phylodynamic analysis were estimated using BEAST v 1.10.4. CRF63_02A6 was assigned for 872 pol gene sequences using phylogenetic analysis approach. Predominant number (n = 832; 95.4%) of those sequences were from Russia; the remaining 40 (4.6%) sequences were from countries of Central Asia. Out of 872 CRF63_02A6 sequences, the corresponding genetic variant was assigned for 75.7 and 79.8% of sequences by Stanford and COMET subtyping tools, respectively. Dated phylogenetic analysis of the CRF63_02A6 sequences showed that the virus most likely originated in Novosibirsk, Russia, in 2005. Over the last two decades CRF63_02A6 has been widely distributed across Russia and has been sporadically detected in countries of Central Asia. Introduction of new genetic variant into mature sub-subtype A6 and CRF02_AGFSU epidemics could promote the increase of viral genetic diversity and emergence of new recombinant forms. Further HIV-1 studies are needed due to a continuing rapid virus distribution. Also, the implementation of HIV-1 prevention programs is required to reduce HIV-1 transmission. This study also highlights the discrepancies in HIV-1 subtyping approaches. The reference lists of HIV-1 sequences implemented in widely used HIV-1 automated subtyping tools need to be updated to provide reliable results.

Porous coatings are actively used in engineering practice. The porous coating determines the reliability of the operation of the intricostal implant, the heat transfer process when the aggregate state of the refrigerant is changed. The choice of method for quantitative analysis of porosity is determined by the structure of the coating. In this study, plasma coatings sprayed from powders were analyzed. A porosity of 10.3% inside the alumina coating was analyzed by mercury porosimetry. The main volume of the porosity of the coating is formed by pores ranging in size from 0.13 to 0.36 μm; their share in the total volume is 68.29%. The remaining volume is distributed in sizes of 0.04-0.12 mm, 0.58-4.66 mm, and 5.66-18.2 mm. Micro tomography allows you to get a more complete general idea of the macro- and microstructure of coatings, establishing the mechanisms of its formation, and allows you to obtain data on the real shape of the pores. A quantitative description of the visible pores of three-dimensional capillary-porous 3CaO·Al2O3 coatings in the form of ridges and depressions was determined by raster image analysis using special STIMAN programs. The porosity of this coating is 39.7% of the distribution over four pore groups: 0.74-3.56, 4.34-11.57, 14.08-55.65, 67.73-267.71 mm.

An analysis of the surface of a plasma three-dimensional capillary-porous (TCP) Ti coating with an additional bioactive hydroxyapatite coating formed by microplasma oxidation (MPO) has been performed. Scanning electron microscopy (SEM) analyzed the open porosity of these composite coatings. The surface of the TCP Ti coating consists of ridges and depressions. The porosity of the TCP Ti coating of the depressions reaches 43 %. The presence of macro- and micropores with a size of 0.08 – 600 µm makes the TCP Ti coatings promising for use in a number of areas, including on the surface of intraosseous implants.

The development of geothermal sites for electricity production, direct utilization, or tourist destinations has increased in recent decades worldwide. Such development requires investigation of the engineering geological setting, including an assessment of the physical-mechanical properties of rocks. Geothermal regions in the Kuril-Kamchatka arc are composed of Neogene-Quaternary volcanic formations with relatively high strength and deformation properties. Thermal fluids circulating within rocks change their compositions, porosities, and physical-mechanical properties. The most intense alterations occurring in the thermal fields are due to argillization. This study investigates the effects of hydrothermal alteration on the physical-mechanical properties of tuffites in the Upper Pauzhetsky thermal field located in South Kamchatka. The aims are to consider the entire range of hydrothermal argillization and to analyze the relationships between physical-mechanical properties and degrees of alteration. The variations in mineralogy, microstructure, particle size distribution, consistency, and rock properties along the section of the thermal field are studied. The results show that argillic alteration gradually decomposes tuffites to weak clay-rich soils, forming a cover several meters thick. The alteration is accompanied by decreases in strength and rock weakening; minor variations are observed between fresh and altered tuffites, whereas a dramatic reduction in strength occurs when tuffites disintegrate and are converted into clays. The heterogeneity of the clayey layer and the presence of secondary siliceous minerals and residual components of parent rocks are the factors that distinguish hydrothermal clays from sedimentary deposits.

The purpose of the article is to substantiate the peculiarities of ensuring environmental safety of products of the food industry. The problems of ensuring environmental safety of the food industry have been identified and the current state and the trends of food industry development in Ukraine have been analyzed. For increasing the leadership positions of the food industry of Ukraine in order to ensure its environmental safety, it has been proposed to strengthen the effective interaction of all interested parties - the state, food industry enterprises, agricultural producers and research institutions.

Research is devoted to the problem of recycling waste of the Baikal Pulp and Paper Mill, whose activity has caused serious damage to the ecological environment of Lake Baikal and its environs. Grouting waste production is currently the most effective possible decision to the problem of pollutants, such as sludge-lignin and ash, in water objects and groundwater. The results on the grouting of liquid and solid waste from the Baikal Pulp and Paper Mill, represented by sludge lignin and ash, are presented. Cement, liquid glass, colloidal silica, ammonium persulfate, hydrogen peroxide were used as the main hardeners. Samples were formed by mixing the original waste with astringent. The strength in time, shrinkage, resistance to water were studied. Samples formed on the basis of colloidal silica solution have a maximum uniaxial compressive strength of 0.4 - 0.5 MPa, on the basis of liquid glass—0.2 - 0.3 MPa. Adding fine sand increases the strength by 1.5 - 1.7 times. Samples based on ammonium persulfate and hydrogen peroxide do not have sufficient strength. Adding fine quartz sand increases the strength up to 1.0 - 1.2 MPa.

This study reviews the findings of recent experiments designed to investigate the cytokine profile after a spinal cord injury. The role played by key cytokines in eliciting the cellular response to trauma was assessed. The results of the specific immunopathogenetic interaction between the nervous and immune systems in the immediate and chronic post-traumatic periods are summarized. It was demonstrated that it is reasonable to use the step-by-step approach to the assessment of the cytokine profile after a spinal cord injury and take into account the combination of the pathogenetic and protective components in implementing the regulatory effects of individual cytokines and their integration into the regenerative processes in the injured spinal cord. This allows one to rationally organize treatment and develop novel drugs.

Photon rings near the edge of a black hole shadow is supposed to be a unique tool to validate general relativity and provide reliable measurements of principal black hole parameters: spin and mass. Such measurements are possible though only for nearby supermassive black holes (SMBH) with Space-Earth Very Long Baseline Interferometry (S-VLBI) in the submillimeter wavelength range. For subrings to be distinguished S-EVLBI observations with long baselines at the Lagrangian Sun-Earth L2 libration point are needed. However, the average fluxes of nearby SMBH: Sagittarius A$^\ast$ (Sgr A$^\ast$) and M87$^\ast$ -- $F_\nu\sim 1$ Jy, are still insufficient to detect the signal from the photon rings with even such long baselines. We argue that only manifestations of flares in the submillimeter waveband in their accretion disks can reveal observable signals from the photon rings with the S-EVLBI at L2. Such observations will become possible within the planned join program of the {\it Event Horizon Telescope} (EHT) and {\it Millimetron Space Observatory} (MSO), and within the planned {\it next generation EHT} (ngEHT) project. Two different observational tests for photons rings are discussed. The first one involves observations of a time series of responds from subsequent subrings as can be seen in a 1D visibility function within the join EHT-MSO configuration, the second one -- measurements of an increase of the angle between subsequent subrings in the 2D VLBI image which can be obtained within the ngEHT project., Comment: Accepted to publish in Physical Review D