Browse

Search for: rheumatoid arthritis    methotrexate    autoimmune disease    biomarker    gene expression    GWAS    HLA genes    non-HLA genes   

ID PMID Title PublicationDate abstract
31084231 Development and exacerbation of pulmonary nontuberculous mycobacterial infection in patien 2020 May Objectives: To examine the development and exacerbation of pulmonary nontuberculous mycobacterial (NTM) infection in patients with systemic autoimmune rheumatic diseases (SARD).Methods: We conducted a case-control study. Seventeen of 7013 patients with SARD fulfilling the criteria for pulmonary NTM infection were enrolled in the NTM group. The control group was matched for age, sex, and SARD at a ratio of 2:1.Results: Eight patients with rheumatoid arthritis, four with systemic vasculitis, three with Sjögren's syndrome, and one each with dermatomyositis and systemic lupus erythematosus were included in the NTM group. Mycobacterium avium was detected in 12 (71%) patients, M. chelonae in 2, and M. intracellulare, M. abscessus, and M. kansasii in 1 patient each. Preexisting lung disease was more common in the NTM group than in the control group (88% versus 38%, p = .0009), particularly bronchiectasis (65% versus 29%, p = .033). The body mass index and serum albumin level were significantly lower in the NTM group than in the control group. Six patients (35%) experienced NTM exacerbation during observation. Clinical immune status at the time of NTM diagnosis, as indicated by the peripheral blood leukocyte/lymphocyte count and serum immunoglobulin G level, was unremarkable and comparable between patients with and without exacerbation, as were the treatments for SARD.Conclusions: In patients with SARD, pulmonary NTM infection may develop and exacerbate without clinically apparent immunosuppression.
30954362 The potential use of l-sulforaphane for the treatment of chronic inflammatory diseases: A 2020 Mar According to the World Health Organisation, 70% of all deaths globally can be attributed to chronic inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, respiratory conditions, cardiovascular diseases, diabetes and cancer. Chronic inflammation has a significant impact on the quality of life of affected individuals with an increased risk of developing other chronic inflammatory diseases. Given the limitations of current pharmaceuticals, there is an intense research interest in identifying novel dietary interventions that can regulate and alleviate inflammation. A diet rich in cruciferous vegetables has been extensively studied for its immediate and long-term health benefits, particularly in the context of cardiovascular disease and cancer. Cruciferous vegetables contain the precursor glucoraphanin, which is hydrolysed upon consumption to form l-sulforaphane (LSF), the primary active compound that mediates potential cardio-protective and anti-carcinogenic effects. LSF has been shown to have beneficial effects in vitro and in animal studies through its classical antioxidant and anti-inflammatory properties, and more recently its chromatin modifying effects. This review discusses the clinical evidence to date in relation to the use of LSF in the context of chronic inflammatory diseases as well as provide key mechanistic insights for these effects.
30895813 Trends in Primary Proximal Interphalangeal Joint System and Revisions for Osteoarthritis o 2020 Nov Background: Proximal interphalangeal arthroplasty (PIPA) has been indicated for patients suffering from osteoarthritis (OA) or rheumatoid arthritis of the hand. Although there is extensive literature showing the outcomes of PIPA, there is paucity in the literature regarding trends of PIPA in patients with OA of the hand. The purpose of this study was to determine annual primary utilization and revision PIPA trends within the Medicare population with the use of an administrative database. Methods: A retrospective query was performed using the Medicare Standard Analytical Files from the PearlDiver database. Patients undergoing primary and revision PIPA with hand OA were queried using International Classification of Disease, Ninth Revision, and Current Procedural Terminology coding. Primary outcomes analyzed included annual and revision utilization of PIPA and demographic comparison of age, gender, and geographic location. Statistical analysis was primarily descriptive. An α value less than 0.05 was considered statistically significant. Results: The query returned 10 191 patients who underwent primary and revision PIPA between 2005 and 2013. Calculated annual growth rate for primary and revision PIPA was 2.40% and -0.03%, respectively (P < .001). Patients between the ages of 70 and 74 years represented most of the patients undergoing a primary PIPA, whereas patients between 65 and 69 years most commonly underwent a revision procedure. Regionally, primary and revision PIPA were most commonly performed in the South. Conclusion: The data demonstrate an increased use of primary PIPA utilization for patients with OA, whereas revision PIPA decreased. The increased use indicates the increasing demand for PIPA in the United States.
33469518 Comparison of Blood Bacterial Communities in Periodontal Health and Periodontal Disease. 2020 The use of Next Generation Sequencing (NGS) techniques has generated a wide variety of blood microbiome data. Due to the large variation in bacterial DNA profiles between studies and the likely high concentrations of cell-free bacterial DNA in the blood, it is still not clear how such microbiome data relates to viable microbiota. For these reasons much remains to be understood about the true nature of any possible healthy blood microbiota and of bacteraemic events associated with disease. The gut, reproductive tracts, skin, and oral cavity are all likely sources of blood-borne bacteria. Oral bacteria, especially those associated with periodontal diseases, are also commonly associated with cardiovascular diseases such as infective endocarditis, and also have been linked to rheumatoid arthritis and Alzheimer's disease. Periodontal treatment, dental probing, and toothbrushing have been shown to cause transient bacteraemia and oral bacteria from the phyla Firmicutes (e.g. Streptococci) and Bacteroidetes (e.g. Porphyromonas) are found in cardiovascular lesions (CVD). Many studies of blood bacterial DNA content however, find Proteobacteria DNA to be the dominant microbiome component, suggesting a gut origin. Most studies of this type use total DNA extracted from either whole blood or blood fractions, such as buffy coat. Here, using a method that purifies DNA from intact bacterial cells only, we examined blood donated by those with active, severe periodontitis and periodontally healthy controls and show that 43-52% of bacterial species in blood are classified as oral. Firmicutes, consisting largely of members of the Streptococcus mitis group and Staphylococcus epidermidis, were predominant at 63.5% of all bacterial sequences detected in periodontal health and, little changed at 66.7% in periodontitis. Compared to studies using total DNA Proteobacteria were found here at relatively low levels in blood at 13.3% in periodontitis and 17.6% in health. This study reveals significant phylogenetic differences in blood bacterial population profiles when comparing periodontal health to periodontal disease cohorts.
35517169 Random acceleration and steered molecular dynamics simulations reveal the (un)binding tunn 2020 Dec 9 Adenosine deaminase (ADA) is an important enzyme related to purine nucleoside metabolism in human serum and various tissues. Abnormal ADA levels are related to a wide variety of diseases such as rheumatoid arthritis, AIDS, anemia, lymphoma, and leukemia and ADA is considered as a useful target for various diseases. Currently, ADA can be divided into open conformation and closed conformation according to the inhibitors of binding. As a consequence, we chose two inhibitors, namely, 6-hydroxy-1,6-dihydro purine nucleoside (PRH) and N-[4,5-bis(4-hydroxyphenyl)-1,3-thiazol-2-yl]hexanamide (FRK) to bind to ADA in the closed conformation or open conformation respectively. In this study, we performed the random acceleration molecular dynamics (RAMD) method, steered molecular dynamics (SMD) simulations and adaptive basing force (ABF) simulation to explore the unbinding tunnels and tunnel characteristics of the two inhibitors in ADA. Our results showed that PRH and FRK escaped from ADA using three main tunnels (namely, T1, T2, and T3). Inhibitors (PRH and FRK) escape through T3 more frequently and more easily. The results from ABF simulations confirm that the free energy barrier in T1 or T2 is larger than that in T3 when inhibitors dissociate from the ADA and have potential mean of force (PMF) depth. Moreover, in the complexes (ADA-PRH, ADA-FRK), we also found that the most active residue that remarkably contributed to the binding affinity is W117 in T3, and the residue played an important role in the unbinding tunnel for inhibitor leaving. Our theoretical study provided insight into the ADA inhibitor passway mechanism and may be a clue for potent ADA inhibitor design.
33356722 Immunomodulatory cytokine interleukin-35 and immune thrombocytopaenia. 2020 Dec Considerable attention has been paid to interleukin (IL)-35 because of its immunosuppressive effects in a variety of autoimmune diseases. IL-35, a recently identified cytokine of the IL-12 family, is a negative regulatory factor secreted by IL-35-inducible regulatory T cells (iTr35 cells) and the recently reported regulatory B cells (B(reg) cells). Four biological effects of IL-35 have been discovered in vitro and in vivo: (i) suppression of T cell proliferation; (ii) conversion of naive T cells into iTr35 cells; (iii) downregulation of type 17 helper T (T(h)17) cells; and (iv) conversion of B(reg) cells into a B(reg) subset that produces IL-35 and IL-10. IL-35 plays an important role in a variety of autoimmune diseases, such as rheumatoid arthritis, allergic asthma and systemic lupus erythematosus. Primary immune thrombocytopaenia (ITP), which is characterized by isolated thrombocytopaenia and mild mucocutaneous to life-threatening bleeding, is an autoimmune disease with complex dysregulation of the immune system. Both antibody-mediated and/or T cell-mediated platelet destruction are key processes. In addition, impairment of T cells and cytokine imbalances have now been recognized to be important. This review summarizes the immunomodulatory effects of IL-35 and its role in the pathogenesis of ITP as mediated by T and B cells.
33330676 The Role of iRhom2 in Metabolic and Cardiovascular-Related Disorders. 2020 Chronic obesity is associated with metabolic imbalance leading to diabetes, dyslipidemia, and cardiovascular diseases (CVDs), in which inflammation is caused by exposure to inflammatory stimuli, such as accumulating sphingolipid ceramides or intracellular stress. This inflammatory response is likely to be prolonged by the effects of dietary and blood cholesterol, thereby leading to chronic low-grade inflammation and endothelial dysfunction. Elevated levels of pro-inflammatory cytokines such as tumor necrosis factor (TNF) are predictive of CVDs and have been widely studied for potential therapeutic strategies. The release of TNF is controlled by a disintegrin and metalloprotease (ADAM) 17 and both are positively associated with CVDs. ADAM17 also cleaves most of the ligands of the epidermal growth factor receptor (EGFR) which have been associated with hypertension, atherogenesis, vascular dysfunction, and cardiac remodeling. The inactive rhomboid protein 2 (iRhom2) regulates the ADAM17-dependent shedding of TNF in immune cells. In addition, iRhom2 also regulates the ADAM17-mediated cleavage of EGFR ligands such as amphiregulin and heparin-binding EGF-like growth factor. Targeting iRhom2 has recently become a possible alternative therapeutic strategy in chronic inflammatory diseases such as lupus nephritis and rheumatoid arthritis. However, what role this intriguing interacting partner of ADAM17 plays in the vasculature and how it functions in the pathologies of obesity and associated CVDs, are exciting questions that are only beginning to be elucidated. In this review, we discuss the role of iRhom2 in cardiovascular-related pathologies such as atherogenesis and obesity by providing an evaluation of known iRhom2-dependent cellular and inflammatory pathways.
33329585 Tonsillectomy Improved Therapeutic Response in Anti-SRP Myopathy With Chronic Tonsillitis. 2020 Chronic tonsillitis has been attracted attention as a source of abnormal immune responses and a possible trigger of autoimmune diseases such as IgA nephritis, IgA vasculitis, palmoplantar pustulosis, psoriasis, rheumatoid arthritis, Behçet's disease, and myositis. Here we present the first report of anti-signal recognition particle antibody-associated necrotizing myopathy (anti-SRP myopathy) with IgA nephropathy and chronic tonsillitis in which the therapeutic response to intravenous immunoglobulin (IVIG) treatment was dramatically improved after tonsillectomy and accompanied by a rapid increase in ΔIgG, defined as the change in serum IgG levels 2 weeks after the start of IVIG treatment relative to pre-treatment levels. Moreover, serum anti-SRP antibody titers became undetectable after tonsillectomy even though the resected tonsils did not produce anti-SRP antibodies. Tonsillectomy should be considered when chronic tonsillitis is observed in patients with autoimmune diseases showing poor response to treatment, including anti-SRP myopathy.
33249704 Does interleukin-33 level correlate with the activity of Pemphigus vulgaris?: A case-contr 2021 Jan Pemphigus is a group of immune-mediated blistering diseases of skin and mucus membrane caused by destruction of the intercellular junction (desmosomes) by autoantibodies. Pemphigus vulgaris (PV) is considered the most common type of all pemphigus family. Various cytokines play a major role in pemphigus pathogenesis. Interleukin-33 (IL-33) role has been studied in various autoimmune diseases as; psoriasis and rheumatoid arthritis, yet it has not been studied in Egyptian patients with PV. The study aimed to evaluate the possible role of IL-33 in PV by assessing its level in the serum using ELISA and to detect its correlation with activity score using Pemphigus Disease Area Index (PDAI). Forty-four patients with PV and 36 age and sex-matched healthy controls were enrolled in the study. After full history taking and complete dermatological examination, the severity score was calculated using PDAI, then serum samples were taken from each patient and control subjects and subjected to quantitative measurement of serum IL-33 using ELISA. Serum level of IL-33 is significantly raised in PV patients compared to control subjects (P-value = .007). The level of IL-33 was found to be strongly correlated with the activity of the disease measured by PDAI. IL-33 might have a role in PV pathogenesis as shown by its rising level in PV patients. In addition, serum level of IL-33 is strongly correlated with the activity of PV. Thus, we suspect that IL-33 can be used as marker for monitoring PV severity and measuring treatment efficacy.
33228426 Transcultural adaptation and validation of the Spanish-French versions of the Self-reporte 2020 Nov 24 OBJECTIVE: The study aim was to cross-culturally adapt the Self-reported Foot and Ankle Score (SEFAS) into Spanish and French-language versions, to validate them and to evaluate their psychometric properties. METHODS: The cross-cultural translation from the original SEFAS into French and Spanish was performed in accordance with the guidelines of the ISPOR. The participants were recruited from some private healthcare institutions in France and Sapin, from June to August 2019. The following inclusion criteria were applied: aged at least 18 years, with foot and/or ankle deformity, had a history of subtalar and/or ankle and/or talonavicular or hindfoot pain, did not make daily use of walking aids, and were able to achieve the normal range of motions in the ankle, subtalar and midtarsal joints. All patients gave signed informed consent and completed the SF-36 and SEFAS questionnaires in the Spanish or French version. RESULTS: The analysis was based on 319 participants. Internal consistency was excellent (Cronbach's alpha values of 0.94 for the Spanish version and 0.88 for the French version). No floor/ceiling effect was observed in any item, in either version. CONCLUSION: The Spanish and French versions of SEFAS are valid, reliable instruments for evaluating foot and ankle pain and function.IMPLICATIONS FOR REHABILITATIONSelf-report questionnaires specific to patients with rheumatoid arthritis are needed to assess the degree of pain, disability, and disability caused by foot problems.The Spanish and French versions of SEFAS show the necessary psychometric characteristics.Each version provides a valid, reliable tool ensuring the correct evaluation of pain, function and limitation of function in the foot and/or ankle in the target population.
32994772 In silico analysis of CpG islands and miRNAs potentially regulating the JAK-STAT signallin 2020 Aug INTRODUCTION: Searching for new therapeutic possibilities constitutes a challenge for modern medicine and an answer to better understanding of molecular mechanisms of pro-inflammatory diseases. The JAK-STAT pathway plays an important role in the inflammatory processes, which is supported by the fact that its inhibitors are used to treat, for instance, psoriasis and rheumatoid arthritis. AIM: To determine whether the epigenetic mechanisms - methylation of gene promotion regions and miRNAs may serve as a new therapeutic strategy for JAK-STAT pathway inhibition. MATERIAL AND METHODS: Basing on MethPrimer (plus CpG Island Prediction) program and microrna.org database of the said mechanism in the regulation of the JAK-STAT signalling pathway, the gene expression was performed, indicating or excluding the possibility of their use as new potential therapeutic strategies. RESULTS: A different number of CpG islands (CGI) for each gene (JAK1-4 CGI; JAK2-2 CGI; JAK3-5 CGI, TYK2-6 CGI; STAT1-2 CGI; STAT2-1 CGI; STAT3-3 CGI; STAT5A-4 CGI; STAT5B-3 CGI) might be a new therapeutic goal. What is more, our results show that genes associated with JAK-STAT signalling pathways can be regulated by miRNAs (JAK1-42 miRNAs; JAK2-47 miRNAs; JAK3-15 miRNAs, TYK2-4 miRNAs; STAT1-17 miRNAs; STAT2-30 miRNAs, STAT3-36 miRNAs, STAT4-15 miRNAs; STAT5A-10 miRNAs; STAT5B-23 miRNAs). CONCLUSIONS: The epigenetic mechanisms of the regulation of the JAK-STAT signalling pathway gene expression constitute a promising new therapeutic strategy for treatment of those diseases, during which disorders are observed in gene expression models of the analysed signalling pathway.
32815838 Reoperation Risk After Total Elbow Arthroplasty Versus Open Reduction Internal Fixation fo 2020 Sep OBJECTIVE: To compare reoperation risk after total elbow arthroplasty (TEA) and open reduction internal fixation (ORIF) for intra-articular distal humerus fractures in elderly patients. DESIGN: Retrospective comparative. SETTING: Five percent Medicare Part B claims database. PATIENTS: Patients older than 65 years of age with closed distal humerus fractures undergoing TEA or ORIF from 1996 to 2016. INTERVENTION: TEA and ORIF. MAIN OUTCOME MEASURE: Reoperation risk based on multivariate Cox proportional hazards modeling. RESULTS: A total of 142 TEA and 522 ORIF cases were identified. TEA patients had a greater age and Charlson Comorbidity Index , as well as a higher prevalence of rheumatoid arthritis and osteoporosis than ORIF patients (P < 0.05). Although reoperation risk was lower for TEA than that for ORIF within the entire cohort (11.3% vs. 25.1%; hazard ratio = 0.49; P = 0.014), no significant difference was found for TEA and ORIF performed between 2006 and 2016 (12.6% vs. 18.4%; hazard ratio = 0.73; P = 0.380). The death rate was 65.5% in the TEA group at 3.6 years and 55.7% in the ORIF group at 4.9 years. CONCLUSIONS: TEA was associated with a decreased reoperation risk compared with ORIF, although this difference did not exist for more recent procedures after popularization of the locking plate technology and half of the reoperations after ORIF were for instrumentation removal. The high death rate within several years of the index procedure may contribute to the low TEA revision rate beyond the short-term when following patients into the medium and long term. Further study comparing TEA and locked plating using prospective, randomized data with long-term follow-up and functional outcomes is warranted. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.
32812686 GPR91, a critical signaling mechanism in modulating pathophysiologic processes in chronic 2020 Oct Succinate receptor GPR91 is one of G protein-coupled receptors (GPCRs), and is expressed in a variety of cell types and tissues. Succinate is its natural ligand, and its activation represents that an intrinsic metabolic intermediate exerts a regulatory role on many critical life processes involving pathophysiologic mechanisms, such as innate immunity, inflammation, tissue repair, and oncogenesis. With the illustration of 3-dimensional crystal structure of the receptor and discovery of its antagonists, it is possible to dissect the succinate-GPR91-G protein signaling pathways in different cell types under pathophysiological conditions. Deep understanding of the GPR91-ligand binding mode with various agonists and antagonists would aid in elucidating the molecular basis of a spectrum of chronic illnesses, such as hypertension, diabetes, and their renal and retina complications, metabolic-associated fatty liver diseases, such as nonalcoholic steatohepatitis and its fibrotic progression, inflammatory bowel diseases (Crohn's disease and ulcerative colitis), age-related macular degeneration, rheumatoid arthritis, and progressive behaviors of malignancies. With better delineation of critical regulatory role of the succinate-GPR91 axis in these illnesses, therapeutic intervention may be developed by specifically targeting this signaling pathway with small molecular antagonists or other strategies.
32598194 Effect of lipid and edge activator concentration on development of aceclofenac-loaded tran 2020 Aug The present investigation focused mainly on the development of aceclofenac (AF) loaded transfersomal gel (AF-TG) to minimize the frequency of oral dosing during the treatment of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis. AF-loaded transfersomes (AF-TS) were prepared by using the film hydration method. The effect of drug loading, pH of hydration medium, edge activator (EA) and lipid concentration on the properties of the AF-TS were studied and optimized. Optimized AF-TS converted into AF-TG by the addition of carbopol 934. Morphology and compatibility studies of AF-TS were observed with scanning electron microscopy (SEM) and differential scanning calorimetry (DSC). AT-TG formulation was evaluated further for ex vivo skin permeation studies compared with marketed Hifenac 30 g gel. Optimized AF-TS showed vesicle size, PDI, and zeta potential of 111.1 ± 3.2 nm, 0.19 ± 0.02, and -29.6 ± 1.2 mV, respectively. Entrapment efficiency of 74.1 ± 1.8% with pH 5.8 phosphate buffer as a hydration medium and 17.1 ± 0.9 elasticity at 0.15%w/v EA and 1%w/v lipid concentration were observed. SEM and DSC studies revealed the spherical shape and no incompatibilities in the AF-TS formulation. The permeability of the AF from AF-TG was enhanced by 14-folds with similar rheological properties compared with marketed gel. Overall, TG containing AF was superior to marketed AF gel formulation for enhanced skin delivery. Therefore, TS and TG formulation could be considered as an alternative delivery approach for the enhanced transdermal application of AF.
32596609 Identification of Sphingosine Kinase-1 Inhibitors from Bioactive Natural Products Targetin 2020 Jun 23 Sphingosine kinase 1 (SphK1) is an oncogenic lipid kinase that catalyzes the formation of sphingosine-1-phosphate via phosphorylation of sphingosine and known to play a crucial role in angiogenesis, lymphocyte trafficking, signal transduction pathways, and response to apoptotic stimuli. SphK1 has received attention because of its involvement in varying types of cancer and inflammatory diseases such as rheumatoid arthritis, diabetes, renal fibrosis, pulmonary fibrosis, asthma, and neurodegenerative disorders. In the malignancies of breast, lung, uterus, ovary, kidney, and leukemia, overexpression of SphK1 has been reported and thus considered as a potential drug target. In this study, we have performed virtual high-throughput screening of ∼90,000 natural products from the ZINC database to find potential SphK1-inhibitors. Initially, the hits were selected by applying absorption, distribution, metabolism, excretion, and toxicity properties, Lipinski's rule, and PAINS filters. Further, docking analysis was performed to estimate the binding affinities and specificity to find safe and effective preclinical leads against SphK1. Two compounds, ZINC05434006 and ZINC04260971, bearing appreciable binding affinity and SphK1 selectivity were selected for 100 ns molecular dynamics (MD) simulations under explicit water conditions. The all-atom MD simulation results suggested that the ZINC05434006 and ZINC04260971 binding induces a slight structural change and stabilizes the SphK1 structure. In conclusion, we propose natural compounds, ZINC05434006 and ZINC04260971, as potential inhibitors of SphK1, which may be further exploited as potential leads to develop effective therapeutics against SphK1-associated diseases including cancer after in vitro and in vivo validations.
32414117 Multimorbidity among Two Million Adults in China. 2020 May 13 To explore the multimorbidity prevalence and patterns among middle-aged and older adults from China. Data on thirteen chronic diseases were collected from 2,097,150 participants aged over 45 years between January 1st 2011 and December 31st 2015 from Beijing Medical Claim Data for Employees. Association rule mining and hierarchical cluster analysis were applied to assess multimorbidity patterns. Multimorbidity prevalence was 51.6% and 81.3% in the middle-aged and older groups, respectively. The most prevalent disease pair was that of osteoarthritis and rheumatoid arthritis (OARA) with hypertension (HT) (middle-aged: 22.5%; older: 41.8%). Ischaemic heart disease (IHD), HT, and OARA constituted the most common triad combination (middle-aged: 11.0%; older: 31.2%). Among the middle-aged group, the strongest associations were found in a combination of cerebrovascular disease (CBD), OARA, and HT with IHD in males (lift = 3.49), and CBD, OARA, and COPD with IHD in females (lift = 3.24). Among older patients, glaucoma and cataracts in females (lift = 2.95), and IHD, OARA, and glaucoma combined with cataracts in males (lift = 2.45) were observed. Visual impairment clusters, a mixed cluster of OARA, IHD, COPD, and cardiometabolic clusters were detected. Multimorbidity is prevalent among middle-aged and older Chinese individuals. The observations of multimorbidity patterns have implications for improving preventive care and developing appropriate guidelines for morbidity treatment.
32268821 Repurposing leflunomide for relapsed/refractory multiple myeloma: a phase 1 study. 2020 Jul The inexpensive, well-tolerated, immunomodulatory agent leflunomide, used extensively for the treatment of rheumatoid arthritis, has been shown to produce significant activity against multiple myeloma (MM) in pre-clinical studies. We conducted a phase 1 study (clinicaltrials.gov: NCT02509052) of single agent leflunomide in patients with relapsed/refractory MM (≥3 prior therapies). At dose levels 1 and 2 (20 and 40 mg), no dose-limiting toxicities (DLTs) were observed. At dose level 3 (60 mg), one patient experienced elevated alanine aminotransferase; an additional three patients were enrolled at this dose level without further DLTs. Overall, toxicities were infrequent and manageable. Nine out of 11 patients achieved stable disease (SD), two subjects experiencing SD for nearly one year or longer. The tolerable safety profile of leflunomide, combined with a potential disease stabilization, is motivating future studies of leflunomide, in combination with other MM drugs, or as an approach to delay progression of smoldering MM.
32233366 Rationally Designed Small-Molecule Inhibitors Targeting an Unconventional Pocket on the TL 2020 Apr 23 Rational designs of small-molecule inhibitors targeting protein-protein interfaces have met little success. Herein, we have designed a series of triazole derivatives with a novel scaffold to specifically intervene with the interaction of TLR8 homomerization. In multiple assays, TH1027 was identified as a highly potent and specific inhibitor of TLR8. A successful solution of the X-ray crystal structure of TLR8 in complex with TH1027 provided an in-depth mechanistic insight into its binding mode, validating that TH1027 was located between two TLR8 monomers and recognized as an unconventional pocket, thereby preventing TLR8 from activation. Further biological evaluations showed that TH1027 dose-dependently suppressed the TLR8-mediated inflammatory responses in both human monocyte cell lines, peripheral blood mononuclear cells, and rheumatoid arthritis patient specimens, suggesting a strong therapeutic potential against autoimmune diseases.
31078323 The association of pain locus of control with pain outcomes among older adults. 2020 Sep Our primary objective was to 1) determine the prevalence of pain locus of control (LOC) subscales in a population of older adults with pain conditions, and 2) estimate their associated protective effects on pain outcomes. A mailed survey was sent to a stratified sample of older adults age≥65 with diagnosed back pain, osteoarthritis and/or rheumatoid arthritis. Multivariate logistic regression modeling was used to determine the relative protective associations of positive resources, including LOC, resilience and social networks, on pain outcomes. Among respondents (N = 3,824), 31% were identified as internal; 34% as powerful others; and 35% as chance. In adjusted models, internal was associated with outcomes of lower pain severity, reduced chronic opioid use and increased physical functionality. Powerful others was partially protective; chance was associated with the poorest outcomes. Multidimensional pain programs should incorporate the enhancement of positive resources, including LOC, to maximize the effectiveness of pain management strategies.
33520995 Modeling Inflammation in Zebrafish for the Development of Anti-inflammatory Drugs. 2020 Dysregulation of the inflammatory response in humans can lead to various inflammatory diseases, like asthma and rheumatoid arthritis. The innate branch of the immune system, including macrophage and neutrophil functions, plays a critical role in all inflammatory diseases. This part of the immune system is well-conserved between humans and the zebrafish, which has emerged as a powerful animal model for inflammation, because it offers the possibility to image and study inflammatory responses in vivo at the early life stages. This review focuses on different inflammation models established in zebrafish, and how they are being used for the development of novel anti-inflammatory drugs. The most commonly used model is the tail fin amputation model, in which part of the tail fin of a zebrafish larva is clipped. This model has been used to study fundamental aspects of the inflammatory response, like the role of specific signaling pathways, the migration of leukocytes, and the interaction between different immune cells, and has also been used to screen libraries of natural compounds, approved drugs, and well-characterized pathway inhibitors. In other models the inflammation is induced by chemical treatment, such as lipopolysaccharide (LPS), leukotriene B4 (LTB4), and copper, and some chemical-induced models, such as treatment with trinitrobenzene sulfonic acid (TNBS), specifically model inflammation in the gastro-intestinal tract. Two mutant zebrafish lines, carrying a mutation in the hepatocyte growth factor activator inhibitor 1a gene (hai1a) and the cdp-diacylglycerolinositol 3-phosphatidyltransferase (cdipt) gene, show an inflammatory phenotype, and they provide interesting model systems for studying inflammation. These zebrafish inflammation models are often used to study the anti-inflammatory effects of glucocorticoids, to increase our understanding of the mechanism of action of this class of drugs and to develop novel glucocorticoid drugs. In this review, an overview is provided of the available inflammation models in zebrafish, and how they are used to unravel molecular mechanisms underlying the inflammatory response and to screen for novel anti-inflammatory drugs.