Candidate antirheumatic genotherapeutic plasmid constructions have low immunogenicity

Rheumatoid arthritis (RA) is a serious systemic disease of connective tissue, mainly affecting joints but also with different extra-articular manifestations. In the course of RA the degenerative changes occur in cartilage surfaces of affected joints and also in subchondral bone tissue, joints get deformed and lose their mobility. RA affects about 1 % of the global human population. Biological therapy with recombinant protein inhibitors of inflammatory cytokines is an effective and well-accepted treatment of RA. TNF inhibitors such as recombinant receptors or monoclonal antibodies are the most widely used biotherapeutics in clinical practice. However, this treatment has some serious side effects. The patients treated with TNF inhibitors are more susceptible to infection diseases, they are also at higher risk of developing neoplastic or autoimmune disorders. Biotherapeutics become less effective or even lose their efficiency with evoking specific antidrug antibodies. These drawbacks are in general associated with repeated systemic injections of large amounts of recombinant protein required to achieve the therapeutic efficacy. Genetic therapy might provide a good and effective solution. Viral genes coding for immunomodulatory factors could be used to create new gene therapy products to treat RA and other human disease. Poxviruses, as compared to other viral families, have an unprecedentedly rich set of such immunomodulatory genes. In particular, they have genes encoding TNF-binding proteins. Previously in a variety of laboratory models we have shown that recombinant TNF-binding protein CrmB can effectively block TNF. In this work we demonstrated that candidate antirheumatic genotherapeutic plasmid constructions encoding poxviral TNF-binding proteins have low immunogenicity

Metabolic Risk Factors and Their Impact on Quality of Life in Patients with Pancreatic Cancer, Acute or Exacerbated Chronic Pancreatitis

Аim: to evaluate metabolic risk factors and their impact on quality of life in patients with pancreatic cancer (PC) and in patients with acute or exacerbated chronic pancreatitis.Materials and methods. Forty-five patients with PC (group 1) and 141 patients with acute pancreatitis or exacerbated chronic pancreatitis (group 2) in an observational multicenter clinical cross-sectional uncontrolled study were examined. Clinical, laboratory and instrumental examination of patients and assessment of risk factors (lipid profile, blood plasma glucose, obesity, arterial hypertension) were carried out in accordance with clinical recommendations. Patients completed the SF-36 questionnaire once to assess quality of life at hospital admission before treatment.Results. In group 1, indicators of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) in blood serum (3.7 ± 0.2; 2.2 ± 0.2 and 0.8 ± 0.1 mmol/L) were lower than in group 2 (5.1 ± 0.1; 3.1 ± 0.1 and 1.2 ± 0.1 mmol/L; p < 0.05). Arterial hypertension was more common in group 1 (55.6 %) than in group 2 (34.8 %; p = 0.013). The presence of arterial hypertension increases the chance of having PC by 2.7 times (p < 0.05). Body mass index parameters, including obesity, as well as parameters of triglycerides, and fasting plasma glucose, did not differ between the groups. Logistic regression analysis revealed a direct relationship with PC HDL hypocholesterolemia (Exp B = 4.976; p < 0.001) and arterial hypertension (Exp B = 2.742; p = 0.027) and an inverse relationship — with hypercholesterolemia (Exp B = 0.204; p = 0.002). The chance of having PC was not associated with age, fasting plasma glucose ³ 7.0 mmol/L, obesity. Quality of life indicators were higher in group 1 than in group 2 on four SF-36 scales: bodily pain (68.1 ± 5.1 and 36.8 ± 2.0; p < 0.001), general health (51.1 ± 2.5 and 38.0 ± 1.7 points; p < 0.001), social functioning (74.7 ± 3.0 and 64.5 ± 2.2 points; p = 0.007), role emotional functioning (28.2 ± 5.2 and 12.5 ± 3.1 points; p = 0.007) and in the general domain “physical component of health” (40.2 ± 1.0 and 33.6 ± 0.8 points; p < 0.001). In group 1 with HDL hypocholesterolemia compared with its absence, the indicators of role emotional functioning (22.2 ± 5.1 and 51.9 ± 13.7 points; p = 0.020) were lower, with arterial hypertension compared with its absence — role physical functioning (5.0 ± 4.0 and 25.5 ± 7.5 points; p = 0.036) and role emotional functioning (16.0 ± 5.1 and 43.3 ± 8.8 points; p = 0.007) were lower.Conclusions. In patients with PC arterial hypertension was more common and the levels of total cholesterol, LDL-C and HDL-C were lower than in patients with acute or exacerbated chronic pancreatitis. The chance of having PC is directly associated with HDL hypocholesterolemia, with arterial hypertension, inversely — with hypercholesterolemia, and is not associated with age, fasting plasma glucose ³ 7 mmol/L, or obesity. In patients with PC, quality of life indicators were higher on four SF-36 scales and on the general domain “physical component of health” than in the group with acute or exacerbated chronic pancreatitis. In patients with PC metabolic factors significantly worsened self-assessment of quality of life in terms of role functioning; in patients with acute or exacerbated chronic pancreatitis there was no such association

PSYCHOPHYSIOLOGIC AND IMMUNOLOGIC CHARACTERISTICS IN PATIENTS WITH BRONCHIAL ASTHMA AND IN HEALTHY MEN WITH DIFFERENT FUNCTIONAL ASYMMETRY OF THE HEMISPHERES OF THE BRAIN

On the basis of the analysis of own and literary data, proved the interaction psychophysiologic and immunologic parameters in healthy people and in patients with bronchial asthma. The main accent was made on the investigation of the role of the functional asymmetry of a brain, as the base phenomenon defining features of mental, vegetative and immunologic activity

SHORT OVERVIEW OF CLINICAL TRIALS WITH CURRENT IMMUNOTHERAPEUTIC TOOLS FOR CANCER TREATMENT

Over last decade, a substantial progress has been made, with respect to understanding of cancer biology and its interplay with the host immune system. Different immunotherapeutic drugs based on recombinant cytokines and monoclonal antibodies are widely used in cancer therapy, and a large number of experimental cancer treatments have been developed, many of which are currently undergoing various stages of clinical trials. Recent endorsement of a recombinant oncolytic herpesvirus T-VEC for the treatment of melanoma was an important step towards a more safe and efficient anticancer therapeutics. In this review, we shall mention only some of the most promising cancer immunotherapy strategies, namely, immune checkpoint inhibitors, cellular therapy and oncolytic viruses

SELECTED ASPECTS OF ALLO- AND XENOGRAFT MODEL APPLICATIONS FOR DEVELOPING NOVEL ANTI-CANCER VACCINES AND ONCOLYTIC VIRUSES

To date, cancer diseases are one of the leading causes of mortality and morbidity in the world. Recent advances in understanding the molecular genetic mechanisms of oncogenesis and anti-cancer immune responses open new opportunities for the development of novel effective therapeutic strategies against cancer diseases; the strategies that would be more specific to tumor cells and less toxic to the host. Immunotherapeutic anti-cancer vaccines and oncolytic viruses are among the most promising approaches of this kind. For rapid and reliable screening and preclinical testing of new therapeutic approaches the relevant animal models are of critical importance. Such models provide the ability to partially reproduce tumor microenvironment and vascularization, as well as to reproduce at some extent the immune system reactions. Allograft and xenograft tumor models are the most common in cancer research. Allogenic transplantation involves the cancer cells or tumor fragments transfer between the organisms of the same species. Xenoplastic transplantation involves the transfer of tumor cells or tissues between the organisms of distinct species. Both tumor cell lines and patient-derived tumor cells and fragments obtained with biopsy can be used for xenotransplantation. Over the past decades the researchers developed numerous strains of immunodeficient mice and rats, suitable for xenografting human tumors. However, despite the widespread of immunodeficient laboratory animals as in vivo models in experimental oncology, these models do also have significant limitations associated with inability to fairly reproduce the tumor microenvironment and human immune system functions in mice, and also with the development of graft versus host reactions. Thus, when planning the experiments, it is necessary to carefully analyze all the advantages and disadvantages of animal strains, supposed to be used in experimental oncology studies

Lipids, liver and pancreas at the crossroads of metabolic syndrome and obesity epidemics

The prevalence of metabolic syndrome (MS), non-alcoholic fatty liver disease (NAFLD) and non-alcoholic fatty pancreatic disease (NAFPD) is 1/4–1/3 of the planet population. It has been proven that the main links in their pathogenesis are disorders of lipid and carbohydrate metabolism. A high comorbidity of NAFLD and NAFPD was shown: in 67,9 % of patients with NAFPD, fatty liver was revealed, and in 96,8 % of patients with NAFLD, pancreatic steatosis was diagnosed. The prevalence of MC among NAFPD patients is 59,2–76,9 %. A meta-analysis revealed that NAFPD is associated with an increased risk of MS (relative risk (RR) = 2,25; 95 % CI 2,00–2,53; p < 0,0001), arterial hypertension (RR = 1,43; 95 % CI 1,08–1,90; p = 0,013), NAFLD (RR = 2,49; 95 % CI 2,06–3,02; p < 0,0001), diabetes mellitus 2 type (RR = 1,99; 95 % CI 1,18–3,35; p = 0,01), and obesity (RR = 1,91; 95 % CI 1,67–2,19; p < 0,0001). Concomitant MS negatively affects the clinical course of acute and chronic pancreatitis, for example, moderately severe acute pancreatitis is observed 3 times more often with MS than without MS, partly due to that I, IV and V types of hyperlipidemia are associated with acute pancreatitis. Dyslipidemia in NAFLD occurs in 60–70 % of cases and is characterized by hypertriglyceridemia, elevated level of free fatty acids and low density lipoprotein cholesterol, decreased content of high density lipoprotein cholesterol. Therefore, strategies aimed at the primary prevention of dyslipidemia can help reduce morbidity and mortality in liver and pancreatic pathology associated with MS