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- Nilsson, Magnus, et al.
(författare)
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Characterization of Selective and Potent JAK1 Inhibitors Intended for the Inhaled Treatment of Asthma
- 2022
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Ingår i: Drug Design, Development and Therapy. - : Informa Healthcare. - 1177-8881. ; 16, s. 2901-2917
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Janus kinase 1 (JAK1) is implicated in multiple inflammatory pathways that are critical for the pathogenesis of asthma, including the interleukin (IL)-4, IL-5, IL-13, and thymic stromal lymphopoietin cytokine signaling pathways, which have previously been targeted to treat allergic asthma. Here, we describe the development of AZD0449 and AZD4604, two novel and highly selective JAK1 inhibitors with promising properties for inhalation.Methods: The effects of AZD0449 and AZD4604 in JAK1 signaling pathways were assessed by measuring phosphorylation of signal transducer and activator of transcription (STAT) proteins and chemokine release using immunoassays of whole blood from healthy human volunteers and rats. Pharmacokinetic studies performed on rats evaluated AZD0449 at a lung deposited dose of 52 mu g/kg and AZD4604 at 30 mu g/kg. The efficacy of AZD0449 and AZD4604 was assessed by evaluating lung inflammation (cell count and cytokine levels) and the late asthmatic response (average enhanced pause [Penh]).Results: Both compounds inhibited JAK1-dependent cytokine signaling pathways in a dose-dependent manner in human and rat leukocytes. After intratracheal administration in rats, both compounds exhibited low systemic exposures and medium-to-long terminal lung half-lives (AZD0449, 34 hours; AZD4604, 5 hours). Both compounds inhibited STAT3 and STAT5 phosphorylation in lung tissue from ovalbumin (OVA)-challenged rats. AZD0449 and AZD4604 also inhibited eosinophilia in the lung and reduced the late asthmatic response, measured as Penh in the OVA rat model.Conclusion: AZD0449 and AZD4604 show potential as inhibitors of signaling pathways involved in asthmatic immune responses, with target engagement demonstrated locally in the lung. These findings support the clinical development of AZD0449 and AZD4604 for the treatment of patients with asthma.
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- Sjogren, Per, et al.
(författare)
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High plasma concentrations of autoantibodies against native peptide 210 of apoB-100 are related to less coronary atherosclerosis and lower risk of myocardial infarction
- 2008
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Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 1522-9645 .- 0195-668X. ; 29:18, s. 2218-2226
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Tidskriftsartikel (refereegranskat)abstract
- Aims We examined whether antibodies against peptides 45 and 210 of apoB-100 are related to myocardial infarction (MI) and severity of coronary atherosclerosis. Methods and results Three hundred and eighty-seven survivors of a first MI (aged < 60 years) and 387 sex- and age-matched controls were characterized in detail. IgG and IgM autoantibodies against native and malondialdehyde (MDA)-modified peptides 45 and 210 of apoB-100 (amino acids 661-680 and 3136-3155) were quantified in plasma and quantitative coronary angiography was performed in 243 patients. Post-infarction patients had significantly lower IgG against the native peptide 210 (IgG-p210(nat)) and higher IgM against the MDA-modified peptide 210 (IgM-p210(MDA)) compared with controls, whereas no differences were found for other antibodies. Plasma concentrations of IgG-p210(nat), but not IgM-p210(MDA), were independently and inversely related to the degree of coronary atherosclerosis in patients. In multiple logistic regression analysis (including established risk indicators), MI risk was 0.55 (95%CI: 0.37-0.81) for individuals in the IgG-p210(nat) upper quartile compared with the remaining individuals. Conclusion Circulating IgG antibodies against the native peptide 210 of apoB-100 are inversely related to the severity of coronary atherosclerosis and associated with lower risk of MI. Epitope 210 of apoB-100 emerges as a target for immunization against atherosclerosis in humans.
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TRANSP modelling of experimentally measured fast particle redistribution and losses on MAST
- 2013
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Proceedings (redaktörskap) (övrigt vetenskapligt/konstnärligt)abstract
- MAST is a mid-size spherical tokamak with BT = 0.3-0.6 T and two NBI systems delivering up to 3.5 MW of super-Alfvénic deuterons and therefore suitable for understanding the dynamics of fast particles in ITER-relevant scenarios. It is well known that MHD instabilities can cause redistribution and/or losses of fast ions as observed in many tokamaks (such as NSTX, TFTR, DIII-D, JET, ASDEX, NSTX and MAST). In particular, on MAST, the effect of fast particle driven instabilities, such as fishbones and long-lived modes upon the total neutron yield measured by fission chamber (FC) and the neutron count rates measured by Neutron Camera (NC) has been observed [1]. Fishbones are characterized by burst-like behaviour observed in magnetic and SXR diagnostics and by the sweeping of the mode frequency during a burst. The resonant interaction between the toroidal and poloidal motion of the fast ions in the plasma with the n = 1, m = 1 internal kink mode is the mechanism responsible for driving the fishbone instability [2].
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