It is anticipated that biomarkers support rheumatologists to judge a group of patients that can improve the diagnosis and prognosis, and further facilitate appropriate and precise treatment with ...targeted therapy. In particular, biomarkers for predicting and monitoring response to biological disease modifying anti-rheumatic drugs (DMARDs) are demanding. Given the mechanism action of biological DMARDs is much more simple than the conventional synthetic DMARDs, a variety of approaches to find such biomarkers has been taken recent years. In this article, I will summarize the background for biomarker research and introduce recent topics in the research and the possible clinical applications of biomarkers to guide treatment in rheumatoid arthritis (RA).
•The background and issues for biomarker research are introduced.•Recent topics focusing on predicting and monitoring of response to biologics in RA are summarized.•Baseline target level and response to biologics are discussed.•Biologics drug level for monitoring of response is discussed.
Recent advances in our understanding in the immune-mediated inflammatory diseases (IMID) are explored and promoted by the targeted treatment. Among these targets, cytokines and cytokine receptors ...have become the good candidates for the drug development. In this review, the cytokine and cytokine receptors, which are approved in IMID, are overviewed, and modalities of the treatment, the role of cytokines and cytokine receptors in each disease, and the updated molecular information by modern technologies in rheumatoid arthritis as a role model are shown and discussed for the future perspectives.
In 1973, IL-6 was identified as a soluble factor that is secreted by T cells and is important for antibody production by B cells. Since its discovery more than 40 years ago, the IL-6 pathway has ...emerged as a pivotal pathway involved in immune regulation in health and dysregulation in many diseases. Targeting of the IL-6 pathway has led to innovative therapeutic approaches for various rheumatic diseases, such as rheumatoid arthritis, juvenile idiopathic arthritis, adult-onset Still's disease, giant cell arteritis and Takayasu arteritis, as well as other conditions such as Castleman disease and cytokine release syndrome. Targeting this pathway has also identified avenues for potential expansion into several other indications, such as uveitis, neuromyelitis optica and, most recently, COVID-19 pneumonia. To mark the tenth anniversary of anti-IL-6 receptor therapy worldwide, we discuss the history of research into IL-6 biology and the development of therapies that target IL-6 signalling, including the successes and challenges and with an emphasis on rheumatic diseases.
Neutrophils form neutrophil extracellular traps (NETs), which are involved in the pathogenesis of ANCA-associated vasculitis (AAV). Recent reports suggest that platelets stimulated via toll-like ...receptor (TLR) pathways can induce NETs formation. However, the mechanism underlying the involvement of platelets in NETs formation in AAV is unknown. We investigated the role of platelets in the pathogenesis of AAV. Platelets from AAV patients and healthy controls (HCs) were co-cultured with peripheral neutrophils, and NETs formation was visualized and quantified. The expression levels of TLRs on platelets were examined by flow cytometry. Platelets were treated with a TLR agonist, platelet-derived humoral factor, CXCL4 (platelet factor 4: PF4), and/or anti-CXCL4 antibody to investigate the effects of TLR-CXCL4 signaling on NETs formation. Platelets from AAV significantly upregulated NETs formation in vitro. Flow cytometric analysis revealed that the proportion of TLR9 positive platelets was significantly higher in AAV than HCs. CXCL4 released from TLR9 agonist-stimulated platelets was significantly enhanced in AAV, which subsequently increased NETs formation. Further, neutralizing anti-CXCL4 antibody significantly inhibited NETs formation enhanced by platelets from AAV. TLR9 signaling and CXCL4 release underlie the key role that platelets play in NETs formation in the pathogenesis of AAV.
Abstract
We compared the molecular clouds in the western part of SS 433 with near-ultraviolet radiation data obtained from GALEX. Near-ultraviolet radiation is prominently confirmed toward only N4, ...while no near-ultraviolet radiation is detected toward N1, N2, or N3. The radiative region of near-ultraviolet radiation is nearly the same as the CO-emitting region in N4, and does not extend beyond the jet seen in X-ray radiation. Near-ultraviolet radiation cannot be explained solely by broad-band continuous radiation and may originate from line emissions. The intensity of near-ultraviolet radiation exhibits an anti-correlation with that of 13CO(J = 3–2) emission. This anti-correlation, along with strong far-infrared radiation in the region with weaker near-ultraviolet radiation intensity compared to its surroundings, suggests that near-ultraviolet radiation originates from behind the molecular cloud, heating up the interstellar dust in N4. Subsequently, the dust in N4 reradiates in the far-infrared band. In the same region, a high peak TMB ratio of 12CO(J = 3–2)$/$12CO(J = 1–0) of ∼0.9, and a high kinetic temperature of Tk ∼ 56 K in the molecular cloud, indicate that CO molecules are highly excited, and the molecular cloud is heated through photoelectric heating. This heating results from electrons released due to the photoelectric effect caused by the phenomenon where interstellar dust absorbs near-ultraviolet radiation. In terms of the timescale of near-ultraviolet radiation originating from line emissions, near-ultraviolet radiation towards N4 cannot be explained by the shock of the blast wave from a supernova that created W 50. These findings also suggest that N4 directly interacts with the jet from SS 433. As a result of this direct interaction, near-ultraviolet radiation is emitted from an interacting layer between the jet and N4.
Immunoglobulin G4 (IgG4)-related disease is a systemic chronic fibroinflammatory disease that can affect almost every organ of the body. IgG4-related periaortitis/periarteritis is a newly recognized ...subset of IgG4-related disease, and its characteristics and prognosis remain unclear. We investigated the clinical characteristics and prognosis of IgG4-related periaortitis/periarteritis.
We performed a systematic literature review of IgG4-related periaortitis/periarteritis. Additionally, we have summarized the characteristics and prognosis of IgG4-related coronary arteritis.
We investigated 248 patients with IgG4-related periaortitis/periarteritis. All studies reported the condition in elderly patients, and male predominance was observed. The infra-renal abdominal aorta and iliac arteries were the most commonly affected sites. Most reports showed the serum C-reactive protein elevation in this disease entity, in contrast to non-vascular IgG4-related disease. Based on radiological findings observed in 27 patients with IgG4-related coronary arteritis, vasculitic lesions were classified into 3 types: stenotic (67% of patients), aneurysmal (42%), and diffuse wall thickening type (92%). Serum IgG4 level, but not C-reactive protein level, was associated with the number of affected organs in IgG4-related coronary arteritis. Corticosteroid treatment with or without cardiac surgery or percutaneous coronary intervention was effective in most patients with IgG4-related coronary arteritis; however, 33% of patients showed an unfavorable clinical course including disease progression, relapse, or death. Pre-treatment stenosis and/or aneurysms were associated with progression of stenosis or aneurysm after corticosteroid treatment.
Most clinical characteristics were similar between the IgG4-related periaortitis/periarteritis and the non-vascular IgG4-related disease groups; however, serum C-reactive protein level elevation was observed only in the former. Although corticosteroid treatment was effective, this disease can be life-threatening secondary to myocardial infarction, aortic dissection, and aneurysmal rupture. Pre-treatment evaluation of stenosis or aneurysms is important for predicting progression of stenosis or aneurysm after corticosteroid treatment.
Dust in galaxies forms and evolves by various processes, and these dust processes change the grain size distribution and amount of dust in the interstellar medium (ISM). We construct a dust evolution ...model taking into account the grain size distribution, and investigate what kind of dust processes determine the grain size distribution at each stage of galaxy evolution. In addition to the dust production by Type II supernovae (SNe II) and asymptotic giant branch (AGB) stars, we consider three processes in the ISM: (i) dust destruction by SN shocks, (ii) metal accretion on to the surface of pre-existing grains in the cold neutral medium (CNM; called grain growth) and (iii) grain-grain collisions (shattering and coagulation) in the warm neutral medium and CNM. We found that the grain size distribution in galaxies is controlled by stellar sources in the early stage of galaxy evolution, and that afterwards the main processes that govern the size distribution changes to those in the ISM, and this change occurs at earlier stage of galaxy evolution for a shorter star formation time-scale (for star formation time-scales = 0.5, 5 and 50 Gyr, the change occurs about galactic age t ∼ 0.6, 2 and 5 Gyr, respectively). If we only take into account the processes which directly affect the total dust mass (dust production by SNe II and AGB stars, dust destruction by SN shocks and grain growth), the grain size distribution is biased to large grains (a ∼ 0.2-0.5 μm, where a is the grain radius). Therefore, shattering is crucial to produce small (a 0.01 μm) grains. Since shattering produces a large abundance of small grains (consequently, the surface-to-volume ratio of grains increases), it enhances the efficiency of grain growth, contributing to the significant increase of the total dust mass. Grain growth creates a large bump in the grain size distribution around a ∼ 0.01 μm. Coagulation occurs effectively after the number of small grains is enhanced by shattering, and the grain size distribution is deformed to have a bump at a ∼ 0.03-0.05 μm at t ∼ 10 Gyr. We conclude that the evolutions of the total dust mass and the grain size distribution in galaxies are closely related to each other, and the grain size distribution changes considerably through the galaxy evolution because the dominant dust processes which regulate the grain size distribution change.
This paper investigates the main driver of dust mass growth in the interstellar medium (ISM) by using a chemical evolution model of a galaxy with metals (elements heavier than helium) in the dust ...phase, in addition to the total amount of metals. We consider asymptotic giant branch (AGB) stars, type II supernovae (SNe II), and dust mass growth in the ISM, as the sources of dust, and SN shocks as the destruction mechanism of dust. Furthermore, to describe the dust evolution precisely, our model takes into account the age and metallicity (the ratio of metal mass to ISM mass) dependence of the sources of dust. We have particularly focused on the dust mass growth, and found that in the ISM this is regulated by the metallicity. To quantify this aspect, we introduce a “critical metallicity”, which is the metallicity at which the contribution of stars (AGB stars and SNe II) equals that of the dust mass growth in the ISM. If the star-formation timescale is shorter, the value of the critical metallicity is higher, but the galactic age at which the metallicity reaches the critical metallicity is shorter. From observations, it was expected that the dust mass growth was the dominant source of dust in the Milky Way and dusty QSOs at high redshifts. By introducing a critical metallicity, it is clearly shown that the dust mass growth is the main source of dust in such galaxies with various star-formation timescales and ages. The dust mass growth in the ISM is regulated by metallicity, and we emphasize that the critical metallicity serves as an indicator to judge whether the grain growth in the ISM is the dominant source of dust in a galaxy, especially because of the strong, and nonlinear, dependence on the metallicity.
Molecules involved in the disease process facilitated our understanding of pathogenesis of the disease with unknown etiology such as immune-mediated and inflammatory diseases. Moreover, the targeted ...therapies against the proposed molecular targets by biological agents provide enormous benefits to the patients and societies. Here, I will review recent progress of the biological treatment in the immune-inflammatory diseases by focusing on the rheumatoid arthritis, the disease characterized by persistent polyarthritis leading to joint destruction and disability with autoimmune features, as a role model.
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