Репозиторий Университета

To date, two chimeric antigen receptors (CAR)-T cell products from autologous T cells have been approved by The United States Food and Drug Administration (FDA). The case-by-case autologous T cell generation setting is largely considered as a pivotal restraining cause for its large-scale clinical use because of the costly and prolonged manufacturing procedure. Further, activated CAR-T cells mainly express immune checkpoint molecules, including CTLA4, PD1, LAG3, abrogating CAR-T anti-tumor activity. In addition, CAR-T cell therapy potently results in some toxicity, such as cytokine releases syndrome (CRS). Therefore, the development of the universal allogeneic T cells with higher anti-tumor effects is of paramount importance. Thus, genome-editing technologies, in particular, clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9 are currently being used to establish “off-the-shelf” CAR-T cells with robust resistance to immune cell-suppressive molecules. In fact, that simultaneous ablation of PD-1, T cell receptor alpha constant (TRAC or TCR), and also β-2 microglobulin (B2M) by CRISPR-Cas9 technique can support the manufacture of universal CAR-T cells with robust resistance to PD-L1. Indeed, the ablation of β2M or TARC can severely hinder swift elimination of allogeneic T cells those express foreign HLA-I molecules, and thereby enables the generation of CAR-T cells from allogeneic healthy donors T cells with higher persistence in vivo. Herein, we will deliver a brief overview of the CAR-T cell application in the context of tumor immunotherapy. More importantly, we will discuss recent finding concerning the application of genome editing technologies for preparing universal CAR-T cells or cells that can effectively counter tumor escape, with a special focus on CRISPR-Cas9 technology.

Intratumoral heterogeneity in lung cancer is essential for evasion of immune surveillance by tumor cells and establishment of immunosuppression. Gathering data reveal that circular RNAs (circRNAs), play a role in the pathogenesis and progression of lung cancer. Particularly Kras-driven circRNA signaling triggers infiltration of myeloid-associated tumor macrophages in lung tumor microenvironment thus establishing immune deregulation, and immunosuppression but the exact pathogenic mechanism is still unknown. In this study, we investigate the role of oncogenic Kras signaling in circRNA-related immunosuppression and its involvement in tumoral chemoresistance. The expression pattern of circRNAs HIPK3 and PTK2 was determined using quantitative polymerase chain reaction (qPCR) in lung cancer patient samples and cell lines. Apoptosis was analyzed by Annexin V/PI staining and FACS detection. M2 macrophage polarization and MDSC subset analysis (Gr1−/CD11b−, Gr1−/CD11b+) were determined by flow cytometry. Tumor growth and metastatic potential were determined in vivo in C57BL/6 mice. Findings reveal intra-epithelial CD163+/CD206+ M2 macrophages to drive Kras immunosuppressive chemoresistance through myeloid differentiation. In particular, monocytic MDSC subsets Gr1−/CD11b−, Gr1−/CD11b+ triggered an M2-dependent immune response, creating an immunosuppressive tumor-promoting network via circHIPK3/PTK2 enrichment. Specifically, upregulation of exosomal cicHIPK3/PTK2 expression prompted Kras-driven intratumoral heterogeneity and guided lymph node metastasis in C57BL/6 mice. Consequent co-inhibition of circPTK2/M2 macrophage signaling suppressed lung tumor growth along with metastatic potential and prolonged survival in vivo. Taken together, these results demonstrate the key role of myeloid-associated macrophages in sustaining lung immunosuppressive neoplasia through circRNA regulation and represent a potential therapeutic target for clinical intervention in metastatic lung cancer.

To date, two chimeric antigen receptors (CAR)-T cell products from autologous T cells have been approved by The United States Food and Drug Administration (FDA). The case-by-case autologous T cell generation setting is largely considered as a pivotal restraining cause for its large-scale clinical use because of the costly and prolonged manufacturing procedure. Further, activated CAR-T cells mainly express immune checkpoint molecules, including CTLA4, PD1, LAG3, abrogating CAR-T anti-tumor activity. In addition, CAR-T cell therapy potently results in some toxicity, such as cytokine releases syndrome (CRS). Therefore, the development of the universal allogeneic T cells with higher anti-tumor effects is of paramount importance. Thus, genome-editing technologies, in particular, clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9 are currently being used to establish “off-the-shelf” CAR-T cells with robust resistance to immune cell-suppressive molecules. In fact, that simultaneous ablation of PD-1, T cell receptor alpha constant (TRAC or TCR), and also β-2 microglobulin (B2M) by CRISPR-Cas9 technique can support the manufacture of universal CAR-T cells with robust resistance to PD-L1. Indeed, the ablation of β2M or TARC can severely hinder swift elimination of allogeneic T cells those express foreign HLA-I molecules, and thereby enables the generation of CAR-T cells from allogeneic healthy donors T cells with higher persistence in vivo. Herein, we will deliver a brief overview of the CAR-T cell application in the context of tumor immunotherapy. More importantly, we will discuss recent finding concerning the application of genome editing technologies for preparing universal CAR-T cells or cells that can effectively counter tumor escape, with a special focus on CRISPR-Cas9 technology.

Intratumoral heterogeneity in lung cancer is essential for evasion of immune surveillance by tumor cells and establishment of immunosuppression. Gathering data reveal that circular RNAs (circRNAs), play a role in the pathogenesis and progression of lung cancer. Particularly Kras-driven circRNA signaling triggers infiltration of myeloid-associated tumor macrophages in lung tumor microenvironment thus establishing immune deregulation, and immunosuppression but the exact pathogenic mechanism is still unknown. In this study, we investigate the role of oncogenic Kras signaling in circRNA-related immunosuppression and its involvement in tumoral chemoresistance. The expression pattern of circRNAs HIPK3 and PTK2 was determined using quantitative polymerase chain reaction (qPCR) in lung cancer patient samples and cell lines. Apoptosis was analyzed by Annexin V/PI staining and FACS detection. M2 macrophage polarization and MDSC subset analysis (Gr1−/CD11b−, Gr1−/CD11b+) were determined by flow cytometry. Tumor growth and metastatic potential were determined in vivo in C57BL/6 mice. Findings reveal intra-epithelial CD163+/CD206+ M2 macrophages to drive Kras immunosuppressive chemoresistance through myeloid differentiation. In particular, monocytic MDSC subsets Gr1−/CD11b−, Gr1−/CD11b+ triggered an M2-dependent immune response, creating an immunosuppressive tumor-promoting network via circHIPK3/PTK2 enrichment. Specifically, upregulation of exosomal cicHIPK3/PTK2 expression prompted Kras-driven intratumoral heterogeneity and guided lymph node metastasis in C57BL/6 mice. Consequent co-inhibition of circPTK2/M2 macrophage signaling suppressed lung tumor growth along with metastatic potential and prolonged survival in vivo. Taken together, these results demonstrate the key role of myeloid-associated macrophages in sustaining lung immunosuppressive neoplasia through circRNA regulation and represent a potential therapeutic target for clinical intervention in metastatic lung cancer.

To date, two chimeric antigen receptors (CAR)-T cell products from autologous T cells have been approved by The United States Food and Drug Administration (FDA). The case-by-case autologous T cell generation setting is largely considered as a pivotal restraining cause for its large-scale clinical use because of the costly and prolonged manufacturing procedure. Further, activated CAR-T cells mainly express immune checkpoint molecules, including CTLA4, PD1, LAG3, abrogating CAR-T anti-tumor activity. In addition, CAR-T cell therapy potently results in some toxicity, such as cytokine releases syndrome (CRS). Therefore, the development of the universal allogeneic T cells with higher anti-tumor effects is of paramount importance. Thus, genome-editing technologies, in particular, clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9 are currently being used to establish “off-the-shelf” CAR-T cells with robust resistance to immune cell-suppressive molecules. In fact, that simultaneous ablation of PD-1, T cell receptor alpha constant (TRAC or TCR), and also β-2 microglobulin (B2M) by CRISPR-Cas9 technique can support the manufacture of universal CAR-T cells with robust resistance to PD-L1. Indeed, the ablation of β2M or TARC can severely hinder swift elimination of allogeneic T cells those express foreign HLA-I molecules, and thereby enables the generation of CAR-T cells from allogeneic healthy donors T cells with higher persistence in vivo. Herein, we will deliver a brief overview of the CAR-T cell application in the context of tumor immunotherapy. More importantly, we will discuss recent finding concerning the application of genome editing technologies for preparing universal CAR-T cells or cells that can effectively counter tumor escape, with a special focus on CRISPR-Cas9 technology.

Intratumoral heterogeneity in lung cancer is essential for evasion of immune surveillance by tumor cells and establishment of immunosuppression. Gathering data reveal that circular RNAs (circRNAs), play a role in the pathogenesis and progression of lung cancer. Particularly Kras-driven circRNA signaling triggers infiltration of myeloid-associated tumor macrophages in lung tumor microenvironment thus establishing immune deregulation, and immunosuppression but the exact pathogenic mechanism is still unknown. In this study, we investigate the role of oncogenic Kras signaling in circRNA-related immunosuppression and its involvement in tumoral chemoresistance. The expression pattern of circRNAs HIPK3 and PTK2 was determined using quantitative polymerase chain reaction (qPCR) in lung cancer patient samples and cell lines. Apoptosis was analyzed by Annexin V/PI staining and FACS detection. M2 macrophage polarization and MDSC subset analysis (Gr1−/CD11b−, Gr1−/CD11b+) were determined by flow cytometry. Tumor growth and metastatic potential were determined in vivo in C57BL/6 mice. Findings reveal intra-epithelial CD163+/CD206+ M2 macrophages to drive Kras immunosuppressive chemoresistance through myeloid differentiation. In particular, monocytic MDSC subsets Gr1−/CD11b−, Gr1−/CD11b+ triggered an M2-dependent immune response, creating an immunosuppressive tumor-promoting network via circHIPK3/PTK2 enrichment. Specifically, upregulation of exosomal cicHIPK3/PTK2 expression prompted Kras-driven intratumoral heterogeneity and guided lymph node metastasis in C57BL/6 mice. Consequent co-inhibition of circPTK2/M2 macrophage signaling suppressed lung tumor growth along with metastatic potential and prolonged survival in vivo. Taken together, these results demonstrate the key role of myeloid-associated macrophages in sustaining lung immunosuppressive neoplasia through circRNA regulation and represent a potential therapeutic target for clinical intervention in metastatic lung cancer.

Vaccination against Streptococcus pneumoniae is among the most effective measures for preventing pneumonia and reducing the rate of chronic obstructive pulmonary disease (COPD) exacerbations. The objective of this work was to evaluate the long-term effectiveness of PCV13 and PPV23 for preventing pneumonia and COPD exacerbations. The open-label, prospective, observational cohort study involved 302 male patients aged ≥ 45 years: PCV13 group (n = 123); PPV23 group (n = 32); and vaccine-naïve group (n = 147). The primary endpoint included the frequency of pneumonia episodes and COPD exacerbations per year over a 5-year follow-up period. The secondary endpoints included the dynamics of dyspnea severity (MMRC), the BODE index, FEV1, the CAT index, the SGRQ score, and the results of 6-min walk test. Vaccination with PCV13 and PPV23 significantly reduces the total rate of pneumonia during the first year after vaccination. Starting with the second year, clinical effectiveness in PPV23 group decreases compared with both PCV13 group and vaccine-naïve patients. Pneumonia by year 5 after vaccination was registered in 47% of patients in the PPV23 group, versus 3.3% of patients in the PCV13 group (p < 0.001); COPD exacerbations—in 81.3% versus 23.6%, respectively (p < 0.001). Vaccination with PCV13 significantly reduced and maintained the BODE index over the 5-year follow-up period. Although both vaccines have comparable clinical effects during the first year after vaccination, only PCV13 is characterized by persistent clinical effectiveness during the 5-year follow-up period. Patients older than 55 years who received PPV23 have significantly higher risks of having pneumonia episodes more frequently during the long-term follow-up.

Background: Risky sexual behaviour (RSB) is regarded as a major health problem during adolescence. Russia has one of the highest rates of teenage pregnancy, abortion and newly diagnosed HIV infections in the world, but research on RSB in Russian youth has been limited. To address this deficit, this study examined the role of several factors, including internalizing and externalizing symptoms, in RSB among Russian adolescents. Methods: Self-reported data were collected from 2573 Russian adolescents aged 13–17 years old (59.4 % girls; Mean age = 14.89) regarding RSB (unprotected sex, early pregnancy, multiple sexual partners and substance use during sexual encounters). Information was also obtained on externalizing (conduct problems and delinquent behaviour) and internalizing (depression, anxiety and posttraumatic stress) symptoms, as well as interpersonal risk and protective factors (affiliation with delinquent peers, parental involvement and teacher support). Hierarchical multiple binary logistic regression analysis was used to examine the associations between these variables and RSB. Results: Boys reported engaging in more RSB than girls. Externalizing symptoms and affiliation with delinquent peers were most strongly associated with RSB, whereas symptoms of anxiety were negatively associated with RSB. There was an interaction effect for sex and affiliation with delinquent peers on RSB with boys reporting RSB when having more delinquent peers. Neither parental involvement nor teacher support were protective against RSB. Conclusions: Early detection of and interventions for RSB and associated externalizing symptoms may be important for adolescent physical and mental wellbeing. Affiliation with delinquent peers should, especially among boys, be regarded as a risk marker for RSB.

Background: Risky sexual behaviour (RSB) is regarded as a major health problem during adolescence. Russia has one of the highest rates of teenage pregnancy, abortion and newly diagnosed HIV infections in the world, but research on RSB in Russian youth has been limited. To address this deficit, this study examined the role of several factors, including internalizing and externalizing symptoms, in RSB among Russian adolescents. Methods: Self-reported data were collected from 2573 Russian adolescents aged 13–17 years old (59.4 % girls; Mean age = 14.89) regarding RSB (unprotected sex, early pregnancy, multiple sexual partners and substance use during sexual encounters). Information was also obtained on externalizing (conduct problems and delinquent behaviour) and internalizing (depression, anxiety and posttraumatic stress) symptoms, as well as interpersonal risk and protective factors (affiliation with delinquent peers, parental involvement and teacher support). Hierarchical multiple binary logistic regression analysis was used to examine the associations between these variables and RSB. Results: Boys reported engaging in more RSB than girls. Externalizing symptoms and affiliation with delinquent peers were most strongly associated with RSB, whereas symptoms of anxiety were negatively associated with RSB. There was an interaction effect for sex and affiliation with delinquent peers on RSB with boys reporting RSB when having more delinquent peers. Neither parental involvement nor teacher support were protective against RSB. Conclusions: Early detection of and interventions for RSB and associated externalizing symptoms may be important for adolescent physical and mental wellbeing. Affiliation with delinquent peers should, especially among boys, be regarded as a risk marker for RSB.

The ovarian reserve is one of the most important indicators of female fertility. It allows for the evaluation of the number of viable oocytes. This parameter is actively used in pregnancy planning and in assisted reproductive technology application, as it determines chances of successful fertilization and healthy pregnancy. Due to increased attention towards diagnostic tests evaluating the ovarian reserve, there has been a growing interest in factors that influence the state of the ovarian reserve. True reasons for pathological changes in the ovarian reserve and volume have not yet been explored in depth, and current diagnostic screening methods often fall short in efficacy. In the following review we analyze existing data relating to the study of the ovarian reserve through genetic testing, determining specific characteristics of the ovarian reserve through genetic profiling. We explore existing studies dedicated to finding specific genetic targets influencing the state of the ovarian reserve.

Due to the cost efficiency and environmentally friendly surfactant features in enhanced oil recovery techniques, the appropriate designation of surfactant flooding should be considered. It is essential to evaluate the crucial factors that affect surfactant adsorption on rock surfaces to eliminate the total economic losses of surfactant retention and adsorption in porous media. In this paper, the considerable influence of temperature, different surfactant concentrations, and polymer addition were experimentally investigated for dolomite minerals extracted from Pabdeh formation. According to this study, higher adsorption density has occurred at lower temperatures, which implies lower kinetic energy between the surfactant molecules. For 25 ℃, the adsorption density is about 41 mg/g, and it has the lowest value of 100 ℃. It is about 17 mg/g. By the increase of surfactant concentration for different time steps, adsorption density has been increased. For the surfactant concentration of 5 Wt. %, the adsorption density is about 42 mg/g; however, it is for 0.15 Wt. % of surfactant concentration, the adsorption density is about 1 mg/g. Moreover, due to the higher stability of polymers, adsorption density has been decreased by the addition of polymer. The stopping time for each surfactant concentration is about 6.5 h for the surfactant concentration of 5 Wt. %. Consequently, the critical micelle concentration point is about 3.5 Wt. %, 4 Wt. %, and 5 Wt. % for linear alkylbenzene sulfonic acid, cetyl trimethyl ammonium bromide, and Triton X-100, respectively. This change in the conductivity is related to the start of the micelling process by increasing surfactant concentration.

In the search for anti-SARS-CoV-2 drugs, much attention is given to safe and widely available native compounds. The green tea component epigallocatechin 3 gallate (EGCG) is particularly promising because it reportedly inhibits viral replication and viral entry in vitro. However, conclusive evidence for its predominant activity is needed. We tested EGCG effects on the native virus isolated from COVID-19 patients in two independent series of experiments using VERO cells and two different treatment schemes in each series. The results confirmed modest cytotoxicity of EGCG and its substantial antiviral activity. The preincubation scheme aimed at infection prevention has proven particularly beneficial. We complemented that finding with a detailed investigation of EGCG interactions with viral S-protein subunits, including S2, RBD, and the RBD mutant harboring the N501Y mutation. Molecular modeling experiments revealed N501Y-specific stacking interactions in the RBD-ACE2 complex and provided insight into EGCG interference with the complex formation. Together, these findings provide a molecular basis for the observed EGCG effects and reinforce its prospects in COVID-19 prevention therapy.

The original article contained an error whereby Affiliation #5 was presented incorrectly. This has since been corrected.

The original version of this Article contained an error in the spelling of the author Anastasia I. Shpichka which was incorrectly given as Anastasia A. Shpichka. The original Article and accompanying Supplementary Information file have been corrected.

The original article contained an error whereby Affiliation #5 was presented incorrectly. This has since been corrected.

The original version of this Article contained an error in the spelling of the author Anastasia I. Shpichka which was incorrectly given as Anastasia A. Shpichka. The original Article and accompanying Supplementary Information file have been corrected.

To evaluate the shear bond strength (SBS) of different attachment materials used for lingual bonding, the influence of artificial aging and the radii of curvature of the enamel surface on SBS, 192 third molars were photographed to determine the radius of curvature of the oral surface. After phosphoric acid etching a cylindrical test piece was bonded to the oral enamel using a mold that was filled with a chemically curing (Maximum Cure, Transbond IDB Premix) or a dual-curing (Nexus NX3, RelyX Unicem2) attachment material. SBS was tested after 24 h, 500 thermal cycles or 90 days at 37 °C with a universal testing machine. Computed tomography scans were performed to determine the bonded surface and calculate SBS. Values ranged from 8.3 to 20.9 MPa. RelyX Unicem2 showed the highest SBS values at baseline, 500 thermal cycles and after 90 days (p < 0.001). Ninety days of wet storage significantly reduced SBS of Maximum Cure (p = 0.028). The radius of curvature correlated positively with SBS (rs = 0.204, p = 0.005). The SBS of all attachment materials was sufficient for clinical use, even after artificial aging. RelyX Unicem2 showed almost twice as high SBS values as the other attachment materials.

Acute myeloid leukemia (AML) is a serious, life-threatening, and hardly curable hematological malignancy that affects the myeloid cell progenies and challenges patients of all ages but mostly occurs in adults. Although several therapies are available including chemotherapy, allogeneic hematopoietic stem cell transplantation (alloHSCT), and receptor-antagonist drugs, the 5-year survival of patients is quietly disappointing, less than 30%. alloHSCT is the major curative approach for AML with promising results but the treatment has severe adverse effects such as graft-versus-host disease (GVHD). Therefore, as an alternative, more efficient and less harmful immunotherapy-based approaches such as the adoptive transferring T cell therapy are in development for the treatment of AML. As such, chimeric antigen receptor (CAR) T cells are engineered T cells which have been developed in recent years as a breakthrough in cancer therapy. Interestingly, CAR T cells are effective against both solid tumors and hematological cancers such as AML. Gradually, CAR T cell therapy found its way into cancer therapy and was widely used for the treatment of hematologic malignancies with successful results particularly with somewhat better results in hematological cancer in comparison to solid tumors. The AML is generally fatal, therapy-resistant, and sometimes refractory disease with a disappointing low survival rate and weak prognosis. The 5-year survival rate for AML is only about 30%. However, the survival rate seems to be age-dependent. Novel CAR T cell therapy is a light at the end of the tunnel. The CD19 is an important target antigen in AML and lymphoma and the CAR T cells are engineered to target the CD19. In addition, a lot of research goes on the discovery of novel target antigens with therapeutic efficacy and utilizable for generating CAR T cells against various types of cancers. In recent years, many pieces of research on screening and identification of novel AML antigen targets with the goal of generation of effective anti-cancer CAR T cells have led to new therapies with strong cytotoxicity against cancerous cells and impressive clinical outcomes. Also, more recently, an improved version of CAR T cells which were called modified or smartly reprogrammed CAR T cells has been designed with less unwelcome effects, less toxicity against normal cells, more safety, more specificity, longer persistence, and proliferation capability. The purpose of this review is to discuss and explain the most recent advances in CAR T cell-based therapies targeting AML antigens and review the results of preclinical and clinical trials. Moreover, we will criticize the clinical challenges, side effects, and the different strategies for CAR T cell therapy.

A correlation between the crystal structure and magnetic properties of system (1-x)BiFeO3 – (x)BaTiO3 with compounds across the morphotropic phase boundary was studied using X-ray and neutron diffraction, magnetometry, and Mössbauer spectroscopy measurements. Increase in the dopants content leads to the structural transition from the rhombohedral phase to the cubic phase via a formation of the two-phase region (0.2 < x < 0.33), wherein the magnetic structure changes from the modulated G-type antiferromagnetic to the collinear antiferromagnetic via a stabilization of the non-collinear antiferromagnetic phase with non-zero remanent magnetization. The value of magnetic moment calculated per iron ion based on the Mössbauer and neutron diffraction data decreases from m ≈ 4.4 μB for the compound with x = 0.25 to m = 3.2 μB for the compound with x = 0.35 testifying a dominance of 3 + oxidation state of the iron ions. Increase in the amount of the cubic phase leads to a reduction in the remanent magnetization from 0.02 emu/g for the compounds with the dominant rhombohedral phase (x < 0.27) down to about 0.001 emu/g for the compounds with dominant cubic structure (x ≥ 0.27). Rapid decrease in the remanent magnetization observed in the compounds across the phase coexistence region points at no direct correlation between the type of structural distortion and non-zero remanent magnetization, while the oxygen octahedra tilting is the key factor determining the presence of non-zero remanent magnetization.

© 1995-2012 IEEE. In this review, we discuss the crucial role of cranial and the extracranial lymphatics in keeping the central nervous system (CNS) health. We talk about the important lymphatic mechanism of removal of metabolites and toxins from the brain, which orchestrates the regenerative processes in CNS. We debate a novel knowledge about the lymphatic mechanism responsible for maintaining the balance between the exit and the entrance of molecules and cells from and into CNS. Finally, we highlight the pioneering technologies of biophotonic stimulation of lymphatic drainage function that can open a new era for the development of novel bedside, readily applicable and commercially viable technologies for the treatment of brain diseases.