Dupilumab: basic aspects and applications to T2-mediated diseases

The asthma, chronic rhinosinusitis with nasal polyps (CRSwNP), atopic dermatitis (AD), eosinophilic esophagitis and other diseases based on T2-inflammation are a widespread in the world. It has led to the development of genetically engineered drugs aimed at individual and specific components of inflammation. One of the leading positions in the pathogenesis of T2-mediated diseases is occupied by interleukin (IL)-4 and IL-13, which explains the prospects of studying these cytokines for the creation of anti-IL-4/IL-13 monoclonal antibodies. The first immunobiological drug was registered to directe against the α subunit of the IL-4 receptor (IL-4Ra), common to both IL-4 and IL-4/IL-13 receptor complexes is dupilumab which is a fully human monoclonal antibody. Dupilumab targets the IL-4 receptor alpha chain (IL-4Rα), common to both IL-4R complexes: type 1 (IL-4Rα/γc; IL-4 specific) and type 2 (IL-4Rα/IL-13Rα1; IL-4 and IL-13 specific). Because the IL-4/IL-13/STAT6 signaling pathway plays a significant role in T2 inflammation. IL-4 and IL-13 are secreted by several cells and, along with other T2 cytokines, as well as with the participation of IL-33, IL-25 and TSLP can stimulate cells to further secrete pro-inflammatory cytokines, contributing to the maintenance of the inflammatory process. Currently, dupilumab has been studied in at least 3,000 patients with asthma, AD, CRSwNP and eosinophilic esophagitis. The results of investigation show an acceptable safety profile in placebo-controlled studies worldwide. In this article, we have highlighted the results of numerous clinical studies and observations that have proven the effectiveness and safety of the use of dupilumab in asthma, AD, CRSwNP, prurigo, eosinophilic esophagitis and eosinophilic pneumonia

Genetic environment of the blaKPC-2 gene in a Klebsiella pneumoniae isolate that may have been imported to Russia from Southeast Asia

The nucleotide sequence of a blaKPC-2-harboring plasmid (pKPCAPSS) from Klebsiella pneumoniae ST273 isolated in Saint Petersburg, Russia, from a patient with history of recent travel to Vietnam is presented. This 127,970-bp plasmid possessed both IncFII and IncR replicons. blaKPC-2 was localized on a hypothetical mobile element. This element was flanked by 38-bp inverted Tn3 repeats and included a Tn3-specific transposase gene, macrolide resistance operon (mphA-mrx-mphR), and a fragment of blaTEM with unique polymorphisms. © 2017 American Society for Microbiology. All Rights Reserved

Glycyrrhetinic acid and its derivatives as inhibitors of poly(ADP-ribose)polymerases 1 and 2, apurinic/apyrimidinic endonuclease 1 and DNA polymerase β

Aim. For strengthening the efficiency of monofunctional alkylating antineoplastic drugs it is important to lower the capacity of base excision repair (BER) system which corrects the majority of DNA damages caused by these reagents. The objective was to create inhibitors of the key BER enzymes (PARP1, PARP2, DNA polymerase β, and APE1) by the directed modification of glycyrrhetinic acid (GA). Methods. Amides of GA were produced from the GA acetate by formation of the corresponding acyl chloride, amidation with the appropriate amine and subsequent deacylation. Small library of 2-cyano substituted derivatives of GA methyl esters was obtained by the structural modification of GA framework and carboxylic acid group. The inhibitory capacity of the compounds was estimated by comparison of the enzyme activities in specific tests in the presence of compounds versus their absence. Results. None of tested compounds inhibits PARP1 significantly. Unmodified GA and its morpholinic derivative were shown to be weak inhibitors of PARP2. The derivatives of GA containing keto-group in 11 triterpene framework were shown to be moderate inhibitors of pol β. Compound 3, containing 12-oxo-9(11)-en moiety in the ring C, was shown to be a single inhibitor of APE1 among all compounds studied. Conclusions. The class of GA derivatives, selective pol β inhibitors, was found out. The selective inhibitor of APE1 and weak selective inhibitor of PARP2 were also revealed

Complex 99mTc-PDA-DTPA for myocardial imaging

The 123I-labeled fatty acids such as 123I-Iodophenylpentadecanoic acid and 123I-Beta-methyliodophenylpentadecanoic acid are the agents used clinically for myocardial imaging. Fatty acids are the major source of energy for the normal myocardium. However, under ischemic conditions the myocardial cells switch to glucose metabolism for their energy needs. Fatty acids undergo prolonged metabolic stunning in patients with reversible ischemia, thereby helping in early diagnosis of coronary artery disease in highrisk patients. High cost andlimited availability of cyclotron-produced 123I, makes 99mTc-labeled fatty acids more desirable for the purpose. In diagnosis the dominant radionuclide is 99mTc. It is estimated that it is involved in about 85% of all imaging procedures in nuclear medicine. The method for preparation of new 99mTc-fatty chemical systems based on modified diethylene triamine pentaacetic acid (DTPA) molecule has been elaborated in this work . The main advantage using DTPA as chelate agent for radioactive label, is the molecule or it's derivative ability to form sufficiently stable complexes with different radioactive metals including technetium-99. Moiety of pentadecanoic acid addition gave the ability to prepare modified complex of DTPA. In a labeling procedure, freshly eluted Na99mTcO4 (20mCi) was added to a mixture of cysteine, stannous chloride, PDK-DTPA and ethanol in a vial. On keeping the reaction mixture at 90 0C for 30 min, [99mTc-PDK-DTPA] radiopharmaceutical was formed. Thereafter, the reaction mixture was cooled over ice and characterized by HPLC. The result of dynamic scintigraphic research showed, that after being injected, the substance is actively acumulated into myocardium. Eventually one can say that modified DTPA-moleculs are functionally suitable for myocardial imaging

Mentoring as a Form of Effective Cooperation of Teachers

В статье представлена практика наставничества как формы эффективного сотрудничества опытного педагога-наставника и молодого специалиста с целью повышения их профессиональной компетентности в педагогической деятельности.The article presents the practice of mentoring as a form of effective cooperation between an experienced teacher mentor and a young specialist in order to improve their professional competence in teaching

Friedreich's ataxia-associated childhood hypertrophic cardiomyopathy: a national cohort study

OBJECTIVE: Hypertrophic cardiomyopathy (HCM) is an important predictor of long-term outcomes in Friedreich's ataxia (FA), but the clinical spectrum and survival in childhood is poorly described. This study aimed to describe the clinical characteristics of children with FA-HCM. DESIGN AND SETTING: Retrospective, longitudinal cohort study of children with FA-HCM from the UK. PATIENTS: 78 children (<18 years) with FA-HCM diagnosed over four decades. INTERVENTION: Anonymised retrospective demographic and clinical data were collected from baseline evaluation and follow-up. MAIN OUTCOME MEASURES: The primary study end-point was all-cause mortality (sudden cardiac death, atrial arrhythmia-related death, heart failure-related death, non-cardiac death) or cardiac transplantation. RESULTS: The mean age at diagnosis of FA-HCM was 10.9 (±3.1) years. Diagnosis was within 1 year of cardiac referral in 34 (65.0%) patients, but preceded the diagnosis of FA in 4 (5.3%). At baseline, 65 (90.3%) had concentric left ventricular hypertrophy and 6 (12.5%) had systolic impairment. Over a median follow-up of 5.1 years (IQR 2.4-7.3), 8 (10.5%) had documented supraventricular arrhythmias and 8 (10.5%) died (atrial arrhythmia-related n=2; heart failure-related n=1; non-cardiac n=2; or unknown cause n=3), but there were no sudden cardiac deaths. Freedom from death or transplantation at 10 years was 80.8% (95% CI 62.5 to 90.8). CONCLUSIONS: This is the largest cohort of childhood FA-HCM reported to date and describes a high prevalence of atrial arrhythmias and impaired systolic function in childhood, suggesting early progression to end-stage disease. Overall mortality is similar to that reported in non-syndromic childhood HCM, but no patients died suddenly

A comprehensive evaluation of colonic mucosal isolates of Sutterella wadsworthensis from inflammatory bowel disease

Peer reviewedPublisher PD

Hormone therapy affecting interferon defense in children with infectious mononucleosis

23 children diagnosed with acute infectious mononucleosis were hospitalized and examined after a short prednisolone treatment course. Related interferon status during infection was compared with that in 38 patients with acute infectious mononucleosis receiving no hormone therapy. Interferon status was investigated by Ershov method, allowing to estimate amount of interferon in the blood serum samples or patient blood cell culture by assessing interferon biological activity. Along with measuring IFNα or IFNγ biological activity, their level was quantified by using enzyme immunoassay. Immunological examination conducted on the next day after the end of hormone therapy revealed sharply decreased potential of patient blood cells to produce both IFNα and IFNγ. The multiplicity of IFNα and IFNγ titer reduction in various patients varied by 4–5 and 3–4-fold, respectively. The concentration of IFNα, determined by ELISA, decreased by 4–6-fold, whereas for IFNγ — by 1.5–2-fold. A follow-up examination 1 month after discharge from the clinic showed that mean IFNα titer in children aged 3–6 years and treated with prednisolone was significantly reduced compared to the baseline, whereas most patients receiving no hormone therapy had normal IFNα production. The change in the level of IFNα 1 month after hormone therapy in 7–14-year age group was similar. IFNγ production quickly recovered, and 1 month after discharge from the clinic, its concentration in culture supernatants from patients reached 10–15 ng/ml, exceeding normal values more than twice. The biological activity of IFNγ in these culture supernatants was significantly higher than those immediately after hormone therapy, whereas in 3–6-year-old group of patients it was also higher than baseline level. These results can serve as a laboratory justification for including recombinant IFNα-2b drugs in the therapy of such patients, presumably immediately after the end of hormone course. Overall, laboratory justified administration of interferon preparations seems to be necessary to determine optimal timepoint for applying such drugs to increase effectiveness for achieving a durable patient recovery

Myeloid-derived suppressor cells as biomarkers of the effectiveness of therapy with new biological agents in axial spondyloarthritis

Innate immune cells, including myeloid cells — myeloid derived suppressor cells (MDSCs) — are supposed to play an important role in the pathogenesis of axial spondyloarthritis (AxSp). Myeloid derived suppressor cells represent a heterogeneous population of immature cells capable of suppressing innate and adaptive immune responses with the most pronounced suppressor activity against T cells. Biological disease-modifying antirheumatic drugs (bDMARDs) can reduce the clinical and laboratory disease activity, but their effectiveness varies widely in different patients with AxSp. The present study is aimed at studying MDSCs subpopulations and their suppressive function depending on the response to bDMARD therapy in AxSp. The study included AxSp patients with a disease duration of 16.5 years (median); HLA-B27 (+) status was detected in 79% of cases. All patients received bDMARDs at least the past 12 weeks, including TNF inhibitors (etanercept, certolizumab pegol, adalimumab, or golimumab) or IL-17 inhibitors (secukinumab, ixekizumab, or netakimab). Percentage of granulocytic MDSCs (G-MDSCs, Lin-HLA-DR-CD33+CD66b+), monocytic MDSCs (M-MDSCs, HLA-DRlow/-CD14+), MDSCs of early stage differentiation (E-MDSCs, Lin-HLA-DR- CD33+CD66b-), as well as intracellular expression of arginase-1 was assessed by flow cytometry. Frequency of circulating MDSC subpopulations of patients with a stable response to bDMARDs (responders) did not differ significantly compared to healthy donors. Patients not responding to bDMARDs therapy showed increased relative and absolute number of E-MDSCs compared to healthy donors (pU = 0.01 and pU = 0.02, respectively) and the responders (pU = 0.03 and pU = 0.07, respectively). Increased percentage of E-MDSCs was positively correlated to disease activity — ESR (Rs = 0.821; p = 0.023), CRP (Rs = 0.714; p = 0.07) and ASDASCRP (Rs = 0.829; p = 0.042) in the non-responder group. Responder patients exhibited no correlation between disease activity and circulating MDSCs. The suppressor potential of MDSCs was analyzed by the intracellular expression of arginase-1 molecule which is involved in the inhibition of T cell response. Patients with the stable response were characterized by increased expression of arginase-1 in E-MDSCs compared to donors (pU = 0.02). Non-responders did not demonstrate significant changes in Arg-1 expression, however, the percentage of arginase-1-expressing G-MDSCs was positively correlated to indexes ASDASESR (Rs = 0.857; p = 0.014) and BASDAI (Rs = 0.785; p = 0.036). Thus, E-MDSCs as well as arginase-1 expression in MDSCs may serve as biomarkers of effectiveness bDMARD therapy, and act as potential candidate predictors of response to therapy in AxSp