Pancreatic ductal adenocarcinoma (PDAC) is resistant to T-cell–mediated immunotherapy. We engineered T cells to transiently express a messenger RNA encoding a chimeric antigen receptor (CAR) specific ...for mesothelin, a protein that is overexpressed by PDAC cells. We performed a phase I study to evaluate the safety and efficacy of adoptive cell therapy with autologous mesothelin-specific CAR T cells (CARTmeso cells) in 6 patients with chemotherapy-refractory metastatic PDAC. Patients were given intravenous CARTmeso cells 3 times weekly for 3 weeks. None of the patients developed cytokine release syndrome or neurologic symptoms and there were no dose-limiting toxicities. Disease stabilized in 2 patients, with progression-free survival times of 3.8 and 5.4 months. We used 18F-2-fluoro-2-deoxy-D-glucose (FDG)-positron emission tomography/computed tomography imaging to monitor the metabolic active volume (MAV) of individual tumor lesions. The total MAV remained stable in 3 patients and decreased by 69.2% in 1 patient with biopsy-proven mesothelin expression; in this patient, all liver lesions had a complete reduction in FDG uptake at 1 month compared with baseline, although there was no effect on the primary PDAC. Transient CAR expression was detected in patients’ blood after infusion and led to expansion of new immunoglobulin G proteins. Our results provide evidence for the potential antitumor activity of messenger RNA CARTmeso cells, as well as PDAC resistance to the immune response.
HIV is adept at avoiding naturally generated T cell responses; therefore, there is a need to develop HIV-specific T cells with greater potency for use in HIV cure strategies. Starting with a ...CD4-based chimeric antigen receptor (CAR) that was previously used without toxicity in clinical trials, we optimized the vector backbone, promoter, HIV targeting moiety, and transmembrane and signaling domains to determine which components augmented the ability of T cells to control HIV replication. This re-engineered CAR was at least 50-fold more potent in vitro at controlling HIV replication than the original CD4 CAR, or a TCR-based approach, and substantially better than broadly neutralizing antibody-based CARs. A humanized mouse model of HIV infection demonstrated that T cells expressing optimized CARs were superior at expanding in response to antigen, protecting CD4 T cells from infection, and reducing viral loads compared to T cells expressing the original, clinical trial CAR. Moreover, in a humanized mouse model of HIV treatment, CD4 CAR T cells containing the 4-1BB costimulatory domain controlled HIV spread after ART removal better than analogous CAR T cells containing the CD28 costimulatory domain. Together, these data indicate that potent HIV-specific T cells can be generated using improved CAR design and that CAR T cells could be important components of an HIV cure strategy.
The paper reveals the concept of “the image of the professions of the future” and the relevance of its formation in modern life conditions. The factors influencing the formation of images of the ...future, as well as methods of studying the image of the professions of the future among high school students, have been determined. The image of the professions of the future, being one of the most important components of a holistic picture of the world, is a set of ideas about the profession, its value in society and about oneself as a possible representative of the professional community with the necessary competencies. The study of the process of shaping the image of the professions of the future in adolescents contributes to scientific ideas about the development of their worldview. The research in this area, which actualizes modern trends in the study of the characteristics of the younger generation, is presented. One of the important areas of interest for high school students is to study and plan options for their future profession. Scientists consider the image of the professions of the future as a connection between the current life situation of a student and the promising life aspirations of a high school student, which determine the possibility of their implementation in the future. According to the principles of career guidance, high school students are at the stage of studying professional growth, which includes crystallizing and clarifying their professional preferences, as well as making preliminary decisions about choosing a profession.
The epidermal growth factor receptor variant III (EGFRvIII) has been investigated as a therapeutic target for chimeric antigen receptor (CAR) T cell therapy in glioblastoma. Earlier research ...demonstrated that phenotypic and genotypic characteristics in T cells and CAR T product predicted therapeutic success in hematologic malignancies, to date no determinants for clinical response in solid tumors have been identified. We analyzed apheresis and infusion products from the first-in-human trial of EGFRvIII-directed CAR T for recurrent glioblastoma (NCT02209376) by flow cytometry. Clinical response was quantified
engraftment in peripheral circulation and progression-free survival (PFS), as determined by the time from CAR T infusion to first radiographic evidence of progression. The CD4
CAR T cell population in patient infusion products demonstrated PD1 expression which positively correlated with AUC engraftment and PFS. On immune checkpoint inhibitor analysis, CTLA-4, TIM3, and LAG3 did not exhibit significant associations with engraftment or PFS. The frequencies of PD1
GZMB
and PD1
HLA-DR
CAR T cells in the CD4
infusion products were directly proportional to AUC and PFS. No significant associations were observed within the apheresis products. In summary, PD1 in CAR T infusion products predicted peripheral engraftment and PFS in recurrent glioblastoma.
The relevance of the issue under study lies in meeting global, national and regional challenges of modern time in the course of vocational preparation of Master’s degree students. The purpose of ...article is to define psychological and pedagogical conditions that have an impact on the process of teaching Masters of Education in the context of social challenges and the created portrait of a student of Southern Federal University as a consumer of educational services. As for these psychological and pedagogical conditions, we would like to refer to the concept of pedagogical education development approved at Southern Federal University; the strategy of preparing Masters in the direction "Pedagogical Education"; the stakeholder-focused model of Masters’ preparation. The devised psychological and pedagogical conditions were step by step discussed by the professional community of Southern Federal University and invited employers. Research findings define its practical importance: in the course of the conducted research, the authors have worked out, systemically described, put into practice and presented the results to the professional community for independent assessment at a conference, a round table and a pedagogical forum.
The article covers current trends in the worldwide experience of quality assessment in preschool education. The authors have analyzed the world's best practices in assessing the quality of preschool ...education. One of the tools recognized in the world community is the ECERS-R scale. The authors share understanding of the ways to apply these scales to quality assessment in accord with the requirements of the Federal State Educational Standard for preschool education and make it possible to assess the quality of conditions for development, moral instruction and education of preschool children. The ECERS-R scores make it possible to reveal the development vector of a preschool educational organization. When using ECERS-R scales for a comprehensive assessment of the quality of education in preschool educational organizations, the assessment becomes the key to the development of the preschool establishment. Identifying and bridging the gap between the norm of the standard and activities of the institution, i.e. the goal and the reality, shape the key directions in work. On the basis of this assessment, a program for development of a preschool organization should be defined. The authors conducted a research on introducing the ECERS-R scales into activities of the teaching staff to improve the quality of interaction between employees. The researchers worked out and implemented a plan for improving staff interaction and collaboration based on the ECERS-R scales. The work carried out showed a significant qualitative improvement in the interaction between employees, which consequently affects the education quality.
The article describes the global processes that are transforming the world (migration and integration processes, inclusive education, digitalization of education, socio-psychological gap between ...generations, etc.). Global tendencies have changed the social space of people's life - “cultural gaps”, “social bottom”, “spiritual crisis of parent-child relations and intergenerational ties”, etc. have appeared, as modern challenges of society, affecting the social reproduction of generations. The problem of social reproduction, the significance of which is associated with the need for the development of sociality, the construction of the social world in the event chronotope, has been actualized; preservation of the social and historical memory of the people, the self-identity of the national community, the “core” of the spiritual image of the nation, etc. A powerful challenge in modern society is digitalization, which has changed the forms of communication and social roles, created a new virtual space for self-presentation, self-expression, while the risk is the loss of cultural identity, blurring the lines between generations, etc. The article presents the mechanisms of integration of traditional and digital technologies of social reproduction of generations, the difference of which lies in the actualization of children's interest in the historical and cultural values of the people, in the organization of joint activities to create virtual historical museums, etc. Social reproduction of generations is a complex and long-term process, the success of which depends on the unity of activities in the professional, parenting and children's community.
In this article, dealing with robotics is defined as a factor driving the development of preschool children. What was created by science fiction writers has become a natural space for the child. ...Children do not know a world where there are no drones, smart phones, and computers. Robotics is becoming one of the leading activities for children, which determines the development of creativity, initiative, and independence. Joint design acts as a team work environment where children learn to agree on a project topic, discuss problems in its implementation, look for information from different sources, and use digital technologies. However, immersing a child into the world of robotics can isolate him from the society; immerse him into the virtual world. “Digital flashing” of a child‟s brain can affect its cognitive methods, affecting the neural mechanisms responsible for communicating with other people. This problem is being studied by scientists from around the world. Today the world is doubling - life in two spaces - material, objective and virtual, ideal. That is why the determination of the common ground for these worlds determines the harmonization of the children development in modern space. One of this common ground could be robotics classes. In preschool education, the development of technical creativity occurs through the designers of LegoEdu. The logic of designing cognitive-research activities of children is presented.
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