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ID PMID Title PublicationDate abstract
30666833 Tumor Necrosis Factor and Regulatory T Cells. 2019 Feb CD4⁺CD25⁺FoxP3⁺ regulatory T (Treg) cells play major roles in the maintenance of immune homeostasis. In this review, we comprehensively describe the relationship between tumor necrosis factor (TNF) and Treg cells, focusing on the effects of TNF on Treg cells and on TNF-producing Treg cells. Contradictory results have been reported for the effect of TNF on the suppressive activity of Treg cells. In patients with rheumatoid arthritis, TNF has been shown to reduce the suppressive activity of Treg cells. Meanwhile, however, TNF has also been reported to maintain the suppressive activity of Treg cells via a TNFR2-mediated mechanism. In addition, Treg cells have been found to acquire the ability to produce TNF under inflammatory conditions, such as acute viral hepatitis. These TNF-producing Treg cells exhibit T helper 17-like features and hold significance in various human diseases.
30639262 Anti-tumor effect of sulfasalazine in neuroblastoma. 2019 Apr Neuroblastoma (NB) is a tumor arising from the sympathetic nervous system during infancy and early childhood. High-risk patients who relapse often fail to respond to further therapy, which results in 5-year survival rate for this patient group below 5%. Therefore, there continues to be an urgent need for innovative treatments. Recently, we found that sulfasalazine (SSZ), an FDA-approved drug for the treatment of rheumatoid arthritis and ulcerative colitis induces anti-proliferative effects in NB tumor cells. SSZ was recently shown to inhibit sepiapterin reductase (SPR), a key enzyme that produces tetrahydrobiopterin (BH4) in the nitric oxide (NO) pathway. Here we tested SSZ against purified SPR in vitro, measured the anti-proliferative effect of SSZ on a panel of MYCN amplified and MYCN non-amplified NB cell lines, and assessed the anti-tumor effect of SSZ in NB tumor-xenografted mice. We found that the expression of both SPR mRNA and SPR protein was significantly higher in cell lines without MYCN amplification. SSZ inhibited SPR enzyme activity in vitro and exhibits anti-proliferative activity in a large number of NB cell lines derived from high-risk tumors. Importantly, oral/intraperitoneal (i.p.) SSZ co-administration resulted in measureable anti-tumor effects in vivo. The FDA-approved drug SSZ, a well-tolerated drug in clinical use, could be repositioned to inhibit tumor growth in NB.
30634065 Prevalent vertebral fracture on bone density lateral spine (VFA) images in routine clinica 2019 Apr PURPOSE: The predictive validity of vertebral fracture assessment (VFA) on bone density lateral spine images to identify prevalent vertebral fractures in routine clinical practice has not been established. Our objective was to estimate the associations of prevalent vertebral fracture identified on VFA images in routine practice with incident hip, all non-vertebral, major osteoporotic, and clinical vertebral fractures, using the Manitoba Bone Density database. METHODS: From 2010 onward, 9972 men and women (mean age [SD] 76 [6.9] years) had VFA images obtained at the time of bone densitometry that were interpreted for vertebral fracture by the clinicians reading the bone density tests. Definite and possible prevalent vertebral fractures, respectively, were identified in 1575 (15.8%) and 293 (2.9%) using a modified Algorithm Based Qualitative method. We ascertained incident fractures using Manitoba provincial health databases over a mean 2.8 (SD 1.7) years and used Cox proportional hazards models to estimate the associations of prevalent vertebral fractures with incident fractures. RESULTS: Compared to no prevalent vertebral fracture, those with definite prevalent vertebral fracture had higher hazard ratios for incident hip (HR 1.95, 95% C.I. 1.45 to 2.62), non-vertebral (HR 1.99, 95% C.I. 1.68 to 2.35), and clinical vertebral fracture (HR 2.68, 95% C.I. 1.69 to 4.23) adjusted for age, bone mineral density, body mass index, prior fracture, parental hip fracture, glucocorticoid use, alcohol use, smoking, and rheumatoid arthritis. These associations did not vary by FRAX fracture risk estimates or bone mineral density category. CONCLUSION: Prevalent vertebral fractures identified on densitometric VFA images in routine clinical practice are strongly associated with incident fractures, and this study is the first to show this using any lateral spine imaging modality outside of research settings. These findings are strong evidence supporting the targeted use of densitometric VFA imaging among post-menopausal women and older men referred for bone densitometry.
30617613 Clinical results of revision total elbow arthroplasty: comparison of infected and non-infe 2019 Jun BACKGROUND: Total elbow arthroplasty (TEA) is considered a successful treatment for several conditions, including rheumatoid arthritis and comminuted fractures. However, failure rates as high as 62% have been reported, with many patients requiring surgical revision. Causes of failure requiring revision can be classified as infected or non-infected. This study evaluated the clinical and radiologic outcomes of TEA revision surgery according to causes of failure. METHODS: Twenty patients undergoing revision TEAs in 2010-2015 were retrospectively evaluated. Mean follow-up was 52.7 months. Patients were categorized into infected and non-infected groups based on radiologic and serologic tests. Clinical outcomes included range of motion (ROM) and Mayo Elbow Performance Score (MEPS), and radiological outcomes included loosening signs on anteroposterior (AP) and lateral plain radiographs at final follow-up. Complications were assessed in both groups. RESULTS: Overall, mean MEPS was 79.7, and mean ROM arc was 97.9° at final follow-up. Nine patients underwent revision due to infection, and 11 due to non-infectious causes. Mean MEPS in these two groups was 75.6 and 83.5, respectively, and mean ROM arc for flexion-extension was 89.4° and 108°, respectively. Two (22%) of the nine patients in the infection group required second revision surgery due to recurrent infection. No patient in the non-infected group underwent second revision surgery. The most frequent complication in the infected group was osteolysis, observed in five patients, including four with symptomatic aseptic loosening and one with non-symptomatic osteolysis. Two patients in the non-infected group demonstrated a non-progressive radiolucent line, which was asymptomatic at final follow-up. CONCLUSION: Revision TEA provided clinical improvement in elbow function and resulted in satisfactory outcomes. Outcomes were worse in the infected than in the non-infected groups. Comorbidities and older age were apparent risk factors for infected TEA.
30146381 Increased risk of symptomatic progression of instability following decompression for lumba 2019 Jan BACKGROUND: Lumbar decompression surgery is a commonly used treatment for degenerative lumbar spinal stenosis; however, some patients develop symptomatic spinal instability following decompression surgery. The objective of this study was to reveal risk factors for delayed instability following decompression surgery for lumbar spinal stenosis. METHODS: One hundred ten patients who underwent single-level lumbar decompression between 2008 and 2014 were retrospectively reviewed. Surgical indication for decompression surgery was symptomatic lumbar canal stenosis without spondylolisthesis or with minimum spondylolisthesis (less than 4 mm translation). Patients with gross segmental motion (>10° in disc angle, >2 mm translation) on flexion-extension lumbar radiographs were excluded. Age, sex, body mass index, smoking history, diabetes mellitus, autoimmune connective tissue diseases including rheumatoid arthritis, and the use of glucocorticoids were investigated. Radiographic measurements included disc angle, disc height, slippage, facet angle, segmental motion (flexion-extension), lumbar alignment, facet effusion, and disc degeneration. Data were analyzed using multivariate forward selection stepwise logistic regression, chi-square tests, and Student t-test. RESULTS: Six of 110 patients (5.5%) developed symptomatic spinal instability at the operative level and underwent spinal fusion surgery at an average of 2.1 years postoperatively. Autoimmune connective tissue disorders and chronic use of glucocorticoids were associated with the occurrence of symptomatic spinal instability requiring spine fusion surgery, while there was no significant difference in radiographic parameters and demographic factors excluding autoimmune connective tissue diseases between reoperation and non-reoperation groups. CONCLUSIONS: Patients with autoimmune connective tissue disorders receiving chronic glucocorticoid therapy are more likely to develop symptomatic spinal instability following decompression surgery for lumbar canal stenosis without or with minimal spondylolisthesis.
32063718 Comparison Of Methods To Estimate Disease-Related Cost And Healthcare Resource Utilization 2019 BACKGROUND: Establishing disease-related cost and/or healthcare resource utilization (HCRU) is an important aspect of health outcomes research, particularly when considering the cost offset of novel treatments. However, few studies have compared methodologies used to assess disease-related cost/HCRU. METHODS: Data from the United States IBM(®) MarketScan(®) Research Databases were used to compare four different methods of calculating disease-related cost and HCRU in patients with rheumatoid arthritis (RA). The analysis was repeated, in part, for patients with ulcerative colitis (UC) to explore the generalizability of findings to a second autoimmune disease. Four methods of disease-related cost/HCRU attribution were selected following a literature search for potential methods: Method 1, claim-wide cost/HCRU attribution based on claim-listed diagnosis codes and a predetermined disease-related medication list (pharmacy claims only); Method 2, line-item cost/HCRU attribution based on procedures/medications more likely to occur in disease cases than in matched controls at two likelihood ratio cutoffs (1.5× and 3.5×); Method 3, disease-related cost/HCRU calculated as the difference in total average cost/HCRU between cases and matched controls; Method 4, line-item cost/HCRU attribution based on clinician manual determination of procedures/medications related to the disease. RESULTS AND CONCLUSION: Overall, 24,373 patients with RA and 9665 with UC were included. Average total cost during 2015 was $US28,750 per patient with RA and $US20,480 per patient with UC. Disease-related cost and HCRU for RA calculated using Method 4 were most closely approximated by Methods 1 and 2 (3.5×), with Method 2 (3.5×) the closest approximation. However, in certain research scenarios, the simplest method compared in this analysis, Method 1, may provide an adequate approximation of disease-related cost and HCRU. Although Method 4 was not executed in the UC analysis because of its labor-intensive nature, similar patterns of disease-related cost and HCRU were observed for Methods 1-3 in patients with UC and RA.
31829761 Amyloidosis and Ocular Involvement: an Overview. 2020 Jan 2 Purpose: To describe the ophthalmic manifestations of amyloidosis and the corresponding therapeutic measures.Methods: The 178 patients included in the study had different types of amyloidosis, diagnosed at a single internal medicine institution (Bari, Italy). To provide a comprehensive review of the types of amyloidosis that can be associated with ocular involvement, the images and clinical descriptions of patients with amyloidosis structurally related to gelsolin, keratoepithelin and lactoferrin were obtained in collaborations with the ophthalmology departments of hospitals in Mainz (Germany) and Helsinki (Finland).Results: Overall, ocular morbidity was detected in 41 of the 178 patients with amyloidosis (23%). AL amyloidosis was diagnosed in 18 patients with systemic disease, 3 with multiple myeloma, and 11 with localized amyloidosis. AA amyloidosis was detected in 2 patients with rheumatoid arthritis and 3 with Behçet syndrome, and transthyretin amyloidosis in 4 patients. The treatment of AL amyloidosis is based on chemotherapy to suppress the production of amyloidogenic L-chains and on surgical excision of orbital or conjunctival masses. AA amyloidosis is managed by targeting the underlying condition. Vitreous opacities and additional findings of ocular involvement in patients with transthyretin amyloidosis indicate the need for pars plana vitrectomy. Gelsolin amyloidosis, characterized by lattice corneal amyloidosis and polyneuropathy, results in recurrent keratitis and corneal scarring, such that keratoplasty is inevitable. In patients with lattice corneal dystrophies associated with amyloid deposits of keratoepithelin fragments, corneal transparency is compromised by deposits of congophilic material in the subepithelial layer and deep corneal stroma. Patients with established corneal opacities are treated by corneal transplantation, but the prognosis is poor because recurrent corneal deposits are possible after surgery. In patients with gelatinous drop-like dystrophy, the amyloid fibrils that accumulate beneath the corneal epithelium consist of lactoferrin and can severely impair visual acuity. Keratoplasty and its variants are performed for visual rehabilitation.Conclusion: A routine ophthalmic follow-up is recommended for all patients with established or suspected amyloidosis, independent of the biochemical type of the amyloid. Close collaboration between the ophthalmologist and the internist will facilitate a more precise diagnosis of ocular involvement in amyloidosis and allow the multidisciplinary management of these patients.Abbreviations: CD: corneal dystrophy; CLA: corneal lattice amyloidosis; CNS: central nervous system; CT: computed tomography; FAP: familial amyloidotic polyneuropathy; GDLCD: gelatinous drop-like corneal dystrophy; GLN: gelsolin; LCD: lattice corneal dystrophy; MRI: magnetic resonance imaging; OLT: orthotopic liver transplantation; TEM: transmission electron microscopy; TGFBI: transforming growth factor β induced; TTR: transthyretin.
31787000 Primary reverse shoulder arthroplasty in patients older than 80 years of age: survival and 2019 Dec AIMS: Reverse shoulder arthroplasty (RSA) reliably improves shoulder pain and function for a variety of indications. However, the safety and efficacy of RSA in elderly patients is largely unknown. The purpose of this study was to report the mortality, morbidity, complications, reoperations, and outcomes of primary RSA in patients aged > 80 years. PATIENTS AND METHODS: Between 2004 and 2013, 242 consecutive primary RSAs were performed in patients aged > 80 years (mean 83.3 years (sd 3.1)). Of these, 53 were lost to follow-up before two years and ten had died within two years of surgery, leaving 179 for analysis of survivorship, pain, motion, and strength at a minimum of two years or until revision surgery. All 242 patients were considered for the analysis of 90-day, one-year, and overall mortality, medical complications (90-day and overall), surgical complications, and reoperations. The indications for surgery included rotator cuff arthropathy, osteoarthritis, fracture, the sequela of trauma, avascular necrosis, and rheumatoid arthritis. A retrospective review of the medical records was performed to collect all variables. Survivorship free of revision surgery was calculated at two and five years. RESULTS: One patient (0.4%) died within the first 90 days. A total of 45 patients (19%) were known to have died at the time of the final follow-up, with a median time to death of 67.7 months (interquartile range 40.4 to 94.7) postoperatively. Medical complications occurred in six patients (3%) and surgical complications occurred in 21/179 patients (12%). Survivorship free from revision was 98.9% at two years and 98.3% at five years; survivorship free from loosening was 99.5% at final follow-up. The presence of peripheral vascular disease correlated with a higher complication rate. CONCLUSION: Primary RSA was safe and effective in patients aged > 80 years, with a relatively low rate of medical and surgical complications. Thus, age alone should not be a contraindication to primary RSA in patients aged > 80 years. However, a careful evaluation of comorbidities is required in this age group when considering primary RSA. Cite this article: Bone Joint J 2019;101-B:1520-1525.
31602911 [Study on difference of liver toxicity and its molecular mechanisms caused by Tripterygium 2019 Aug Tripterygium wilfordii multiglycoside( GTW),an extract derived from T. wilfordii,has been used for rheumatoid arthritis and other immune diseases in China. However its potential hepatotoxicity has not been investigated completely. Firstly,the content of triptolid( TP) in GTW was 0. 008% confirmed by a LC method. Then after oral administration of GTW( 100,150 mg·kg-1) and TP( 12 μg·kg-1) in female Wistar rats for 24 h,it was found that 150 mg·kg-1 GTW showed more serious acute liver injury than 12 μg·kg-1 TP,with the significantly increased lever of serum ALT,AST,TBA,TBi L,TG and bile duct hyperplasia even hepatocyte apoptosis. The expression of mRNA and proteins of liver bile acid transporters such as BSEP,MRP2,NTCP and OATP were down-regulated significantly by GTW to inhibit bile acid excretion and absorption,resulting in cholestatic liver injury. Moreover,GTW was considered to be involved in hepatic oxidative stress injury,although it down-regulated SOD1 and GPX-1 mRNA expression without significant difference in MDA and GSH levels. In vitro,we found that TP was the main toxic component in GTW,which could inhibit cell viability up to 80% in Hep G2 and LO2 cells at the dose of 0. 1 μmol·L-1. Next a LC-MS/MS method was used to detect the concentration of triptolid in plasma from rats,interestingly,we found that the content of TP in GTW was always higher than in the same amount of TP,suggesting the other components in GTW may affect the TP metabolism. Finally,we screened the substrate of p-glycoprotein( p-gp) in Caco-2 cells treated with components except TP extrated from GTW,finding that wilforgine,wilforine and wilfordine was the substrate of p-gp. Thus,we speculated that wilforgine,wilforine and wilfordine may competitively inhibit the excretion of TP to bile through p-gp,leading to the enhanced hepatotoxity caused by GTW than the same amount of TP.
31482044 Outcomes and Predictors of Mortality in Hospitalized Frail Patients Undergoing Percutaneou 2019 Aug 16 Objective To study the impact of frailty on inpatient outcomes among patients undergoing percutaneous coronary intervention (PCI). Methods The National Inpatient Sample data of all PCI-related hospitalizations throughout the United States (US) from 2010 through 2014 was utilized. Patients were divided into two groups: frailty and no-frailty. International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes were used to stratify groups and outcomes. In order to address the substantial difference in the total number of valid observations between the two groups, a propensity-matched analysis was performed at a 1:1 ratio and caliper width of 0.01. Results A total of 2,612,661 PCI-related hospitalizations throughout the US from 2010 through 2014 were identified, out of which 16,517 admissions (0.6%) had coexisting frailty. Only 1:1 propensity-matched data was utilized for the study. Propensity-matched frailty group (n=14,717) as compared to no-frailty (n=14,755) was frequently older, white, and Medicare enrollee (p<0.05). The frailty group had significantly higher rates of comorbidities and complications (p<0.05). All-cause in-hospital mortality was higher in the no-frailty group (p<0.05). Age, white race, non-elective admission, urban hospitals, and comorbidities predicted in-hospital mortality in frailty group (p<0.05). Rheumatoid arthritis, depression, hypertension, obesity, dyslipidemia, and history of previous PCI decreased odds of in-hospital mortality in frailty group (p<0.05). Frailty group had prolonged hospital stay and higher hospital charges (p<0.05). Conclusions Frailty has a significant effect on PCI-related outcomes. We present a previously unknown protective effect of cardiovascular disease risk factors and other health risk factors on frail patients undergoing PCI. Frailty's inclusion in risk stratification will help in predicting the post-procedure complications and improve resource utilization.
31342642 Performance of the revised 2016 fibromyalgia diagnostic criteria in Korean patients with f 2019 Sep AIM: Recently, the revised 2016 version of the 2010/2011 fibromyalgia (FM) criteria was released. No study has yet assessed whether the 2016 criteria perform better than the previous criteria. Therefore, we validated a Korean version of the revised FM criteria and explored whether they were better than the previous criteria in terms of diagnostic accuracy. METHODS: We enrolled 86 FM patients and 89 patients with various rheumatological disorders, including rheumatoid arthritis, systemic lupus erythematosus, osteoarthritis, and myofascial pain syndrome. All patients were invited to complete a questionnaire that included the revised Fibromyalgia Impact Questionnaire (FIQ), the EuroQol five-dimensional questionnaire (EQ-5D), and the Multidimensional Health Assessment Questionnaire (MD-HAQ). RESULTS: The test-retest reliability of the revised criteria was assessed in 30 patients after 2 weeks; the Spearman coefficient ranged from 0.616 to 0.910 and the Cronbach's alpha was 0.942 (95% CI: 0.930-0.964). The revised criteria correlated significantly with the revised FIQ score (P < .001), the EQ-5D score (P < .001), and the MD-HAQ score (P < .001). Using the revised criteria, FM was diagnosed in 94.2% of patients with a prior diagnosis of FM, and in 10.1% of those with other rheumatological disorders. The sensitivity and specificity of the revised criteria were 93.1% and 90.7%, respectively. The area under the receiver operating characteristic curve of the revised criteria was 0.966, higher than those of the 1990, 2010, and 2011 criteria. CONCLUSION: The revised criteria are reliable and valid when used to diagnose patients with FM, and are better than the previous criteria.
31258663 Identification of differentially expressed genes, associated functional terms pathways, an 2019 Jul Inflammatory bowel diseases (IBDs), including ulcerative colitis (UC) and Crohn's disease (CD), are chronic inflammatory disorders caused by genetic influences, the immune system and environmental factors. However, the underlying pathogenesis of IBDs and the pivotal molecular interactions remain to be fully elucidated. The aim of the present study was to identify genetic signatures in patients with IBDs and elucidate the potential molecular mechanisms underlying IBD subtypes. The gene expression profiles of the GSE75214 datasets were obtained from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were identified in UC and CD patients compared with controls using the GEO2R tool. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses of DEGs were performed using DAVID. Furthermore, protein-protein interaction (PPI) networks of the DEGs were constructed using Cytoscape software. Subsequently, significant modules were selected and the hub genes were identified. In the GO and KEGG pathway analysis, the top enriched pathways in UC and CD included Staphylococcus aureus infection, rheumatoid arthritis, complement and coagulation cascades, PI3K/Akt signaling pathway and osteoclast differentiation. In addition, the GO terms in the category biological process significantly enriched by these genes were inflammatory response, immune response, leukocyte migration, cell adhesion, response to molecules of bacterial origin and extracellular matrix (ECM) organization. However, several other biological processes (GO terms) and pathways (e.g., 'chemotaxis', 'collagen catabolic process' and 'ECM-receptor interaction') exhibited significant differences between the two subtypes of IBD. The top 10 hub genes were identified from the PPI network using respective DEGs. Of note, the hub genes G protein subunit gamma 11 (GNG11), G protein subunit beta 4 (GNB4), Angiotensinogen (AGT), Phosphoinositide-3-kinase regulatory subunit 3 (PIK3R3) and C-C motif chemokine receptor 7 (CCR7) are disease-specific and may be used as biomarkers for differentiating UC from CD. Furthermore, module analysis further confirmed that common significant pathways involved in the pathogenesis of IBD subtypes were associated with chemokine-induced inflammation, innate immunity, adapted immunity and infectious microbes. In conclusion, the present study identified DEGs, key target genes, functional pathways and enrichment analysis of IBDs, enhancing the understanding of the pathogenesis of IBDs and also advancing the clarification of the underlying molecular mechanisms of UC and CD. Furthermore, these results may provide potential molecular targets and diagnostic biomarkers for UC and CD.
31185702 Fucoidan Prevents RANKL-Stimulated Osteoclastogenesis and LPS-Induced Inflammatory Bone Lo 2019 Jun 10 Excessive osteoclast differentiation and/or function plays a pivotal role in the pathogenesis of bone diseases such as osteoporosis and rheumatoid arthritis. Here, we examined whether fucoidan, a sulfated polysaccharide present in brown algae, attenuates receptor activator of nuclear factor-κB ligand (RANKL)-stimulated osteoclastogenesis in vitro and lipopolysaccharide (LPS)-induced bone resorption in vivo, and investigated the molecular mechanisms involved. Our results indicated that fucoidan significantly inhibited osteoclast differentiation in RANKL-stimulated macrophages and the bone resorbing activity of osteoclasts. The effects of fucoidan may be mediated by regulation of Akt/GSK3β/PTEN signaling and suppression of the increase in intracellular Ca(2+) level and calcineurin activity, thereby inhibiting the translocation of nuclear factor-activated T cells c1 (NFATc1) into the nucleus. However, fucoidan-mediated NFATc1 inactivation was greatly reversed by kenpaullone, a GSK3β inhibitor. In addition, using microcomputer tomography (micro-CT) scanning and bone histomorphometry, we found that fucoidan treatment markedly prevented LPS-induced bone erosion in mice. Collectively, we demonstrated that fucoidan was capable of inhibiting osteoclast differentiation and inflammatory bone loss, which may be modulated by regulation of Akt/GSK3β/PTEN/NFATc1 and Ca(2+)/calcineurin signaling cascades. These findings suggest that fucoidan may be a potential agent for the treatment of osteoclast-related bone diseases.
31172362 Pharmacophore modeling and virtual screening in search of novel Bruton's tyrosine kinase i 2019 Jun 6 Bruton's tyrosine kinase (BTK) is a known drug target for B cell malignancies and autoimmune diseases like rheumatoid arthritis. Consequently, efforts to develop BTK inhibitors have gained momentum in the last decade, resulting in a number of potential inhibitory molecules. However, to date, there are only two FDA approved drugs for B cell malignancies (Ibrutinib and Acalabrutinib), thus continued efforts are warranted. A large number of molecular scaffolds with potential BTK inhibitory activity are already available from these studies, and therefore we employed a ligand-based approach towards computer-aided drug design to develop a pharmacophore model for BTK inhibitors. Using over 400 molecules with known half maximal inhibitory concentrations (IC(50)) for BTK, a four-point pharmacophore hypothesis was derived, with two aromatic rings (R), one hydrogen bond acceptor (A) and one hydrogen bond donor (D). Screening of two small-molecule databases against this pharmacophore returned 620 hits with matching chemical features. Docking these against the ATP-binding site of the BTK kinase domain through a virtual screening workflow yielded 30 hits from which ultimately two natural compounds (two best scoring poses for each) were prioritized. Molecular dynamics simulations of these four docked complexes confirmed the stability of protein-ligand binding over a 200 ns time period, and thus their suitability for lead molecule development with further optimization and experimental testing. Of note, the pharmacophore model developed in this study would also be further useful for de novo drug design and virtual screening efforts on a larger scale. Graphical abstract Pharmacophore modeling and virtual screening in search of novel Bruton's tyrosine kinase inhibitors.
31115673 Impact of autoimmune comorbidity on fatigue, sleepiness and mood in myasthenia gravis. 2019 Aug BACKGROUND: Disease burden in myasthenia gravis (MG) and in other autoimmune disorders is often determined by common accompanying symptoms such as fatigue, sleepiness and mood disturbances. Many MG patients have a second autoimmune disease, but it is unclear whether autoimmune comorbidities add to the severity of fatigue, sleepiness and mood disturbances. METHODS: We ascertained the presence of autoimmune comorbidities in 69 well-characterized MG patients. To assess fatigue, sleepiness and mood disturbances, we applied the Fatigue Severity Scale (FSS), the Fatigue Impact Scale (FIS), the Epworth Sleepiness Scale (ESS), as well as the Beck Depression Inventory (BDI) and State-Trait Anxiety Inventory (STAI) to all patients. RESULTS: Thirteen MG patients had concomitant autoimmune thyroid disease (AITD), including 1 patient with rheumatoid arthritis as third autoimmune disease. Fatigue (68.1%), excessive daytime sleepiness (14.5%), moderate-severe depression (20.3%) and anxiety (26.1%) were common, but MG patients with and without autoimmune comorbidities had similar FSS, FIS, ESS, BDI and STAI scores. The presence of autoimmune comorbidities was not associated with altered clinical and immunological MG characteristics, but MG patients with autoimmune comorbidities have more often been treated with corticosteroids than patients without autoimmune comorbidities (92.3% vs. 60.7%; p = 0.03). CONCLUSIONS: While many MG patients were affected by fatigue, sleepiness, depression and anxiety, the present study does not suggest that coexisting autoimmune diseases substantially contribute to the magnitude of these cumbersome comorbid symptoms. However, the higher frequency of steroid treatment may have counterbalanced the effects of the autoimmune comorbidity.
31054506 Colony-stimulating factor 1 receptor inhibition prevents against lipopolysaccharide -induc 2019 Jul Lipopolysaccharide (LPS) can induce bone loss by stimulating osteoclast formation. Colony-stimulating factor 1 receptor (CSF 1R) inhibitors have great potential for the treatment of rheumatoid arthritis and tumor-related bone erosion. However, its role in LPS-induced bone loss is still not clarified. In this study, we observed the effects of CSF 1R inhibitor, PLX3397, on LPS-induced bone damage in an animal model. The models were established by LPS administration in male Sprague-Dawley rats. PLX3397 (30 mg/kg body weight) was given by oral gavage. MicroCT analysis, biomechanical properties, biomarker assay, histological examination, and mRNA expression of osteoclast differentiation-related genes (Traf6, Fra1, c-fos and NFATc1) were performed on the 8th week. LPS induced bone loss was shown as the decrease in bone volume fraction and trabecular number and increase in trabecular separation (p < 0.05). LPS exposure also markedly decreased the bone biomechanical properties. PLX3397 significantly abolished the LPS-induced bone microstructure damage (p < 0.05) and loss of biomechanical properties. PLX3397 also inhibited the increases of serum tartrate-resistant acid phosphatase 5b level enhanced by LPS (p < 0.05). PLX3397 attenuated the high expression of Traf6, Fra1, c-fos and NFATc1 stimulated by LPS. Our data demonstrated that PLX3397, a type of CSF 1R inhibitor, can suppress LPS-induced bone loss via the inhibition osteoclast formation.
30968694 Reversal of Osteoporotic Activity by Endothelial Cell-Secreted Bone Targeting and Biocompa 2019 May 8 Exosomes, also known as extracellular vesicles, are naturally occurring, biocompatible, and bioacive nanoparticles ranging from 40 to 150 nm in diameter. Bone-secreted exosomes play important roles in bone homeostasis, the interruption of which can lead to diseases such as osteoporosis, rheumatoid arthritis, and osteopetrosis. Though the relationship between vascular and bone homeostasis has been recognized recently, the role of vascular endothelial cell (EC)-secreted exosomes (EC-Exos) in bone homeostasis is not well understood. Herein, we found that EC-Exos show more efficient bone targeting than osteoblast-derived exosomes or bone marrow mesenchymal stem cell-derived exosomes. We also found that EC-Exos can be internalized by bone marrow-derived macrophages (BMMs) to alter their morphology. EC-Exos can inhibit osteoclast activity in vitro and inhibit osteoporosis in an ovariectomized mouse model. Sequencing of exosome miRNA revealed that miR-155 was highly expressed in EC-Exos-treated BMMs. The miR-155 level in EC-Exos was much higher than that in BMMs and ECs, indicating that miR-155 was endogenous cargo of EC-derived vesicles. Blockage of BMMs miR-155 levels reversed the suppression by EC-Exos of osteoclast induction, confirming that exosomal miR-155 may have therapeutic potential against osteoporosis. Taken together, our findings suggest that EC-Exos may be utilized as a bone targeting and nontoxic nanomedicine for the treatment of bone resorption disorders.
30875084 Anti-C1q autoantibodies are frequently detected in patients with systemic sclerosis associ 2019 Jul BACKGROUND: Anti-C1q autoantibodies (autoAbs) are associated with systemic lupus erythematosus (SLE), but their presence in other rheumatic diseases has not been adequately investigated. OBJECTIVES: We aimed to assess anti-C1q autoAbs and circulating immune complexes (CICs) in systemic sclerosis (SSc). METHODS: In total 124 patients with SSc were studied; 106 were female and the median age was 59·4 years (range 25-81·4). Overall 75 (60·5%) had limited cutaneous SSc and 49 (39·5%) had diffuse cutaneous SSc. Also included were 25 patients with Sjögren syndrome (SjS), 29 with rheumatoid arthritis (RA), 38 with SLE and 53 healthy controls. Enzyme-linked immunosorbent assays with high- and low-salt buffers were used to measure anti-C1q antibodies and CICs. The former allows only anti-C1q antibody binding to C1q and the latter also allows IgG Fc to bind to C1q. RESULTS: Anti-C1q antibodies were present in 20 of 124 (16·1%) patients with SSc: five had high levels (> 80 RU mL(-1) ) and 10 (50%) had moderate levels (40-80 RU mL(-1) ). Anti-C1q antibodies were also present in one of 25 (4%) patients with SjS, one of 29 (3%) with RA (P < 0·05 for both) and three of 53 (6%) healthy controls (P < 0·01). Anti-C1q antibodies were detected in 13 of 38 (34%) patients with SLEs. Anti-C1q antibodies were more frequent in male than female patients with SSc (P = 0·005); this association remained after multivariate regression analysis. Anti-C1q antibody level was the most important factor in predicting the presence of pulmonary fibrosis, and the second most important in predicting pulmonary arterial hypertension. Fourteen patients with SSc (11·3%) had CICs. CONCLUSIONS: Anti-C1q autoAbs were frequently detected in patients with SSc, and their high levels predict the co-occurrence of pulmonary fibrosis or pulmonary arterial hypertension.
30854088 The association between infection incidence and autoimmune diseases in breast cancer patie 2019 Purpose: To evaluate the infection incidence in breast cancer patients whether they have a major autoimmune disease or not. Methods: This retrospective cohort study compared the infection incidence of 174 breast cancer patients with an autoimmune disease, including Sjogren's Syndrome (SS), Rheumatoid Arthritis (RA), and Systemic Lupus Erythematosus (SLE), along with 4429 patients without an autoimmune disease, for the period 2000 to 2016. Six-hundred and ninety six, age-, stage-, and diagnosis era-matched patients without any autoimmune disease were analyzed to eliminate the effects of these confounding factors may have on the results. Results: After adjusting for age, stage and diagnosis era, breast cancer patients with an autoimmune disease had a higher Infection Incidence Ratio (IRR: 2.62) than the patients without any autoimmune disease. In the univariate analysis, patients who had an autoimmune disease (p<0.001), underwent chemotherapy (p<0.001), radiotherapy (p=0.004), and monoclonal antibody therapy (p<0.001) had a higher infection rate. In the multivariate analysis, autoimmune disease was shown to be an independent factor for infection incidence. Conclusion: Autoimmune disease was a potential predictor of infection incidence in breast cancer patients post-treatment after adjusting for clinical confounding factors.
30673842 High-level expression of β-N-Acetylglucosaminidase BsNagZ in Pichia pastoris to obtain Gl 2019 Apr β-N-Acetylglucosaminidases (NAGase) can remove N-acetylglucosamine (GlcNAc) from the non-reducing end of chitin or chitosan. GlcNAc has many important physiological functions in organism, which can be used for the treatment of rheumatoid arthritis clinically and be used as food antioxidant, infant food additive and diabetic sweetener. Thus, it is very important to develop genetic-engineering strains with high-yield NAGase to hydrolyze chitin into GlcNAc. Here, the NAGase gene of Bacillus subtilis 168 (BsnagZ) was synthesized according to the codon bias of Pichia pastoris and expressed in P. pastoris. The expression level of BsNagZ in P. pastoris increased over the induced time and the highest activity reached 0.76 U/mL at the 7th day. The recombinant BsNagZ was purified for characterization. The optimal temperature and pH are 60 °C and 6.0, respectively. It can both keep over 80% activities after pre-incubation at 55 °C for one hour and at 4 °C for 12 h from pH 4.5 to 10.0. To further improve the expression level of BsNagZ, a recombinant strain with four copy BsnagZs was screened using a high concentration of zeocin. The highest BsNagZ activity reached 3.2 U/mL at the 12th day, which was fourfold higher than that of single-copy strain. Combined with commercial chitinase CtnSg, GlcNAc can be produced by recombinant BsNagZ when used colloidal chitin as the substrate. Our study highlights that the NAGase was first successfully expressed in P. pastoris and GlcNAc can be produced via NAGase hydrolyzing the colloidal chitin.