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Despite the high number of individuals infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) who develop coronavirus disease 2019 (COVID-19) symptoms worldwide, many exposed individuals remain asymptomatic and/or uninfected and seronegative. This could be explained by a combination of environmental (exposure), immunological (previous infection), epigenetic, and genetic factors. Aiming to identify genetic factors involved in immune response in symptomatic COVID-19 as compared to asymptomatic exposed individuals, we analyzed 83 Brazilian couples where one individual was infected and symptomatic while the partner remained asymptomatic and serum-negative for at least 6 months despite sharing the same bedroom during the infection. We refer to these as “discordant couples”. We performed whole-exome sequencing followed by a state-of-the-art method to call genotypes and haplotypes across the highly polymorphic major histocompatibility complex (MHC) region. The discordant partners had comparable ages and genetic ancestry, but women were overrepresented (65%) in the asymptomatic group. In the antigen-presentation pathway, we observed an association between HLA-DRB1 alleles encoding Lys at residue 71 (mostly DRB1*03:01 and DRB1*04:01) and DOB*01:02 with symptomatic infections and HLA-A alleles encoding 144Q/151R with asymptomatic seronegative women. Among the genes related to immune modulation, we detected variants in MICA and MICB associated with symptomatic infections. These variants are related to higher expression of soluble MICA and low expression of MICB. Thus, quantitative differences in these molecules that modulate natural killer (NK) activity could contribute to susceptibility to COVID-19 by downregulating NK cell cytotoxic activity in infected individuals but not in the asymptomatic partners.
Despite the high number of individuals infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) who develop coronavirus disease 2019 (COVID-19) symptoms worldwide, many exposed individuals remain asymptomatic and/or uninfected and seronegative. This could be explained by a combination of environmental (exposure), immunological (previous infection), epigenetic, and genetic factors. Aiming to identify genetic factors involved in immune response in symptomatic COVID-19 as compared to asymptomatic exposed individuals, we analyzed 83 Brazilian couples where one individual was infected and symptomatic while the partner remained asymptomatic and serum-negative for at least 6 months despite sharing the same bedroom during the infection. We refer to these as “discordant couples”. We performed whole-exome sequencing followed by a state-of-the-art method to call genotypes and haplotypes across the highly polymorphic major histocompatibility complex (MHC) region. The discordant partners had comparable ages and genetic ancestry, but women were overrepresented (65%) in the asymptomatic group. In the antigen-presentation pathway, we observed an association between HLA-DRB1 alleles encoding Lys at residue 71 (mostly DRB1*03:01 and DRB1*04:01) and DOB*01:02 with symptomatic infections and HLA-A alleles encoding 144Q/151R with asymptomatic seronegative women. Among the genes related to immune modulation, we detected variants in MICA and MICB associated with symptomatic infections. These variants are related to higher expression of soluble MICA and low expression of MICB. Thus, quantitative differences in these molecules that modulate natural killer (NK) activity could contribute to susceptibility to COVID-19 by downregulating NK cell cytotoxic activity in infected individuals but not in the asymptomatic partners.
The monograph is devoted to the analysis of the theoretical and methodological foundations of the innovative development of the health care system in the national, European and global contexts, as well as the mechanisms for ensuring and managing human health in the multidisciplinary context of the sustainable development of modern society. Since the international community recognizes that it is the balanced development of society that is a priority in matters of international cooperation and interaction, then it is the issues of Human health, as the main component of the health of a developed society, that are the publicly understandable integrative goal that can combine diverse components and priority components of global social processes. . In modern conditions of European integration both in Ukraine and in Europe and in the world, the issues of multidisciplinary, complex and multi-level development of a physically, emotionally and spiritually healthy Person, as a structural unit of a healthy society, are topical. The reason is that the innovative development of the health care system is possible only in the conditions of sustainable development of human society as a whole. And the development of modern society is the cause and effect of providing favorable conditions for the constant and purposeful development of all components of human health, in the context of achieving complete physical, psychological, social, economic well-being, and not just overcoming some of the most threatening pathological conditions, wars, traumatization, violation of ecological mechanisms, destructive tendencies emanating from individual powers, the state structure of which is experiencing stagnation and artificially maintained through violence and aggression on the part of government circles and weapons. It is widely accepted to understand health as the result of a harmonious combination of the physical, psychological and social components of development. Only achieving a balance between them will make it possible to move on to social development that develops natural and human resources, and therefore can last long enough for the quality and safety of life of the next generations to be higher than the quality and safety of life of our contemporaries. Ensuring sustainable innovative development of the health care system in the national, European and global world context is not a purely technical task requiring new technical means or technologies. This is a matter of adjusting the goals and objectives of society, in the direction of changing social relations and the formation of such a health care system that will be aimed at preventing and rehabilitating the occurrence and development of diseases in the first place, in a newly formed society that will not destroy, but support and develop environment of its existence. The main principles of the innovative development of the modern health care system are: the formation of the correct spiritual principles of Human development, which create the goal of the individual in the development of the Spirit, Soul and Mind, mutual respect and support for each other, the correct emotional education of awareness and responsibility and psychological support from an early childhood, the education of the right habits of physical development and emotional response, which will contribute to the harmonious development and individual. and public health, combination of nature conservation and social development; the development of basic human needs and their transfer to the field of ecological, natural trends, instead of the development of consumerism and technocracy; development of the health care system towards providing affordable, high-quality medical care for all citizens on the basis of equality and social justice; close interaction and innovative development of all healthcare systems of the world on the basis of comprehensive friendly support, as well as taking into account the resources, knowledge and skills that came to us from the works of our ancient ancestors, incl. remaining in national cultures and trends, taking into account social self-determination and cultural diversity; maintaining the integrity of the ecosystem. If the goal of the world is a spiritually, mentally, physically and socially healthy and mature Person, then harmony, peace, justice and awareness, environmental friendliness will triumph in this world, which will provide a really huge resource for the innovative development of health care systems already in the present and will lead to a halt in development. existing pandemics and global pathological trends, such as oncology, diabetes mellitus, heart disease, depression, pain syndromes, obesity and others To achieve a balance, the principle of preserving cultural and natural heritage in health care systems at all levels must be harmoniously combined with the principle of innovation and creativity. Identification of the mechanisms for implementing this approach is the content of this publication. The monographic study presents the scientific developments of a team of authors, revealing various aspects of the innovative development of human health and society, mechanisms of psychological support for sustainable human development, including in times of crisis and war, pathogenetic and etiological aspects of the development of pathological conditions common in human society, diagnostic and terminological aspects of managing patients with various types of pathologies, characteristics of innovative therapeutic and surgical technologies, introduced in Ukraine in wartime for the effective treatment of wounded by firearms and patients suffering from chronic pathological processes of various origins and localization, the etio-pathogenesis, diagnosis and management of patients of the most complex clinical profiles in dermatology, ophthalmology, neurology, surgery, hematology, gastroenterology, rehabilitation medicine, including the use of innovative technologies, methods and techniques, a description of the unique experience of Ukrainian practicing doctors and world-class scientists. The monograph is composed of 21 sections, which are written by medical researchers of various medical specializations, completed in alphabetical order of their names. This decision was made at the general meeting of the authors, based on the fact that multidisciplinarity is the main characteristic of today's realities of practical healthcare in Ukraine and the structural formation of a monograph, based on the artificial division of the human body into systems, is not absolutely correct within the framework of the above approach. As part of the presented monograph, 6 chapters (the first three, sixth, seventh and 21st) are devoted to the most relevant aspects of physical rehabilitation medicine, namely the issues of etio-pathogenesis, diagnosis and effectiveness of the use of physical therapy and reshaped physical factors to restore and improve the standard of living of patients with fibromyalgia (Tatiana Asaulyuk), dorsalgia (Professor Lidia Butskaya), obesity (Professor Vladimir Bulda), type 2 diabetes mellitus (Professor Nikolay Chukhraev), post-covid syndrome (Professor Yuri Zabulonov), these diseases today top ten chronic pathologies that affect most of the chronic patients in highly developed countries and their prevalence allows them to be classified as pandemics, which makes the study and development of rehabilitation methods for patients of these groups particularly relevant, also because they are predictors of the further spread of pathological processes to the cardiovascular, nervous systems і, which leads both to a significant decrease in the quality of life of patients, as we see in people with chronic fibromyalgia and dorsadgia, and to early death, if we talk about patients with diabetes mellitus, obesity, post-COVID syndrome. Also, the work of professor, vascular surgeon, director of the University Clinic of KNU Viktor Chernyak is devoted to works demonstrating the effectiveness of the use of preformed physical factors in the treatment and rehabilitation of patients, namely the innovative therapeutic multi-laser complex. Four sections of the monograph, namely the fifth, eighth, thirteenth and sixteenth, are devoted to diagnostic aspects, prevention and solution of psychological problems of people of all ages, including those who suffered in Ukraine from the hostilities of Russian troops. So, in the work of Professor Drevitskaya, the problems of borderline psychological disorders in children 7-10 years old are considered, the work of Professor Olga Pletka is devoted to the issues of psychoemotional support and psychoeducation in people with post-traumatic syndromes, Professor Elena Malina reveals the features of an individual style of self-regulation, which makes it possible to provide more effective assistance to victims . The works of our neurologists – professor Elena Myalovitskaya (Peculiarities of neuropsychological disorders in patients with acute isolated cerebellar infarction) and her student, professor Irina Rozhelyuk (Peculiarities of ApoE gene polymorphism and the effectiveness of treatment with drugs of the neurotransmitter mechanism of action in elderly patients with dementia syndrome of Alzheimer's and vascular types) reveal the results of their own studies and provide evidence-based protocols for the management of patients with these pathologies, and the work of gastroenterologist Inna Berdnik and Oleg Dynnik is devoted to topical issues in the diagnosis and treatment of patients with pathologies of the liver and stomach. I would also like to note the novelty and fundamental nature of the research presented by professor cardiologist Olga Rasputnyak, the study of inflammation processes in ischemic cardiomyopathy patients with maladaptive left ventricular remodeling, professor, dermatologist Elena Oshivalova, dedicated to the secondary prevention of actinic keratosis, and professor ophthalmologist Oksana Vitovskaya, dedicated to the study of evidence-based protocols for diagnosing and treating patients with glaucoma), professor of hematology Irina Rodionova devoted to the description of modern clinical and laboratory methods for studying the pathology of the hemostasis system. Works of surgeons – Professor Sergey Dibkalyuk “Degenerative-dystrophic lesions of the spine with compression syndrome of the spinal artery. Diagnosis and treatment” and military doctor, surgeon Konstantin Karpenko “Mini-invasive surgery for post-thrombotic disease of the lower extremities”, are serious, fundamental scientific and practical research in the field of effective diagnosis, treatment of patients with this pathology, the papers also describe in detail the features of recommended surgical interventions and the features of their implementation. The chapter by Professor Mikhail Dzeman describes the life story, scientific and medical activities of the outstanding Ukrainian doctor and researcher, the founder of the Warsaw Medical and Surgical Academy Fedir S. Tsytsurin. The multidisciplinary approach proposed by us is very relevant for modern medicine and health care, because it provides an opportunity for doctors and scientists of various medical specialties to see a person and his health from different angles and to understand and apply the opportunities that multidisciplinary cooperation provides to our patients from the point of view raising the level and restoration of their health, preventing possible complications, improving the quality of life. We thank our Polish colleagues for the opportunity to create such a monograph in the European space and to show our foreign friends the achievements of Ukrainian doctors and scientists. We hope for further development and invite European doctors to such cooperation. Therefore, we congratulate our Ukrainian and Polish colleagues on their fruitful work on the creation of an international multidisciplinary monograph and wish all of us further success in this noble field.
Aim. To study antitumor cytotoxic effect of CAR-T NKG2D and CAR-T anti-CD19 in vitro and in vivo in order to compare antitumor activity of chimeric antigen receptors (CAR) with different structural and functional properties. Materials & Methods. CAR constructions were produced by molecular cloning. CAR-T cell populations were obtained by transduction of healthy donor T-lymphocytes with recombinant lentiviral particles coding CAR NKG2D or CD19 target antigen CAR sequences. CAR-T cell proportion was assessed by FusionRed fluorescence and EGFR membrane receptor imaging. Specific in vitro cytotoxic activity of CAR-T effector cells was analyzed by Real-Time Cytotoxicity Assay (RTCA) during co-cultivation with HeLa_CD19 target cell line using xCELLigence. Interferon-Y (IFN-y) synthesis in vitro and in vivo along with the degree of cytotoxic effect were analyzed by immunoassay of culture medium of co-cultivated effector cells and target cells as well as isolated auto-plasma from the peripheral blood of mice. To assess the in vivo functional activity, CAR-T cell populations were infused into immunodeficient NSG-SGM3 mice (10 000 000 cells/mouse) 12 days after HeLa_CD19 cell injection and confirmation of engraftment and tumor growth. Upon euthanasia, tumors were removed and fixed in paraffin to prepare histological sections. CAR-T cell tumor infiltration was assessed by CD3 antigen immunohistochemical staining. Results. The highest ligand (molecules MICA, ULBP1/2/3/4/5/6) expression levels were detected in HeLa cell line. The obtained NKG2D CAR-T cells showed a considerable cytotoxic activity against HeLa_CD19 target line (cell index [CI] = 1.27), which was, however, twice as low as that of CAR-T anti-CD19 (CI = 0.60) (p = 0.0038). IFN-y level during co-cultivation of CAR-T anti-CD19 with HeLa_CD19 at the ratio of Е/Т = 1:1 was 64,852 pcg/mL, which was 3.5 times higher than IFN-y level during co-cultivation of CAR-T NKG2D with HeLa_CD19 (18,635 pcg/mL) (p = 0.0360). The degree of tumor infiltration by CAR-T anti-CD19 cells was higher than that by CAR-T NKG2D. The absence of NKG2D proliferating CAR-T cells in mice peripheral blood confirms their low persistence. IFN-y concentration in mice auto-plasma was 11.89 pcg/mL after CAR-T anti-CD19 infusion and 0.57 pcg/mL after CAR-T NKG2D infusion (p = 0.0079). The mean weight of tumor xenografts in experimental groups 10 days after CAR-T anti-CD19 injection was 0.72 g (p = 0.0142), after Т-lymphocyte and NKG2D CAR-T cell infusions it was 2.12 g and 1.2 g, respectively. Conclusion. CAR-T anti-CD19 cells are characterized by more pronounced cytotoxic effect under both in vitro and in vivo experimental conditions compared with CAR-T NKG2D cells. The degree of CAR-T anti-CD19 proliferation and their infiltration in mice xenograft models is considerably higher than the levels reached with NKG2D CAR-T cell injections. A single CAR-T NKG2D injection results only in short-term tumor reduction.
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