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ID PMID Title PublicationDate abstract
29502187 Epidemiology and correlates of osteoporotic fractures among type 2 diabetic patients. 2018 Mar 3 This study analyzed data on 87,224 osteoporotic patients with up to 18 years of computerized medical history. Patients with osteoporosis and type 2 diabetes had higher bone density yet more fractures than non-diabetic osteoporotic patients. Fracture incidence among the diabetic patients was associated with retinopathy and cardiovascular disease, but not with diabetes duration. PURPOSE: Little is known about the association between type 2 diabetes mellitus (T2DM) and fragility fractures or the mechanism(s) involved. We examined fracture correlates among T2DM patients with osteoporosis. METHODS: We used electronic health records of an osteoporosis (OP) registry cross-linked with a diabetes registry of a large payer provider healthcare organization in Israel. A cross-sectional analysis compared osteoporosis patients with and without T2DM, and a longitudinal Cox proportional hazard regression was used to identify incident fracture correlates. RESULTS: As of December 2015 a total of 87,224 current OP patients were identified, of whom 15,700 (18%) had T2DM. The T2DM OP patients were characterized by older age (mean 74.6 vs. 69.5), more males (20.3 vs. 14.0%), and a higher rate of chronic comorbidities compared to OP without diabetes. All major OP fractures (hip, spine, humerus, and forearm) were significantly more prevalent among T2DM OP patients (44 vs. 32%), with an overall age-standardized ratio of 1.22 (95% CI 1.19 to 1.25) and 1.15 (95% CI 1.10 to 1.21) for females and males respectively. The average T-scores were higher (femur neck - 1.8 vs. - 1.9, total hip - 1.2 vs. - 1.6, and vertebrae - 1.3 vs. - 1.7) for the T2DM OP patients compared to the non-T2DM OP patients. Among women with coexisting T2DM and osteoporosis (n = 10,812), fracture incidence was significantly associated with retinopathy (HR = 1.24, 95% CI 1.05 to 1.47) and cardiovascular disease (HR = 1.22, 95% CI 1.10 to 1.36) after controlling for age, bone mineral density T-score, rheumatoid arthritis, glucocorticoids, alcohol, and smoking). CONCLUSION: This large population-based study confirms the higher fracture risk of osteoporotic patients with T2DM, as compared to osteoporotic patients without T2DM, despite higher bone mineral density levels. The presence of micro- and macrovascular disease appears to increase this risk.
29378554 Screening of Baccaurea ramiflora (Lour.) extracts for cytotoxic, analgesic, anti-inflammat 2018 Jan 30 BACKGROUND: It has been observed that the various part of Baccaurea ramiflora plant is used in rheumatoid arthritis, cellulitis, abscesses, constipation and injuries. This plant also has anticholinergic, hypolipidemic, hypoglycemic, antiviral, antioxidant, diuretic and cytotoxic activities. The present studyaimed to assess the cytotoxic, analgesic, anti-inflammatory, CNS depressant and antidiarrheal activities of methanol extract of Baccaurea ramiflora pulp and seeds in mice model. METHODS: The cytotoxic activity was determined by brine shrimp lethality bioassay; anti-nociceptive activity was determined by acetic acid-induced writhing, formalin- induced licking and biting, and tail immersion methods. The anti-inflammatory, CNS depressant and anti-diarrheal activities were assessed by carrageenan-induced hind paw edema, the open field and hole cross tests, and castor oil-induced diarrheal methods, respectively. The data were analyzed by one way ANOVA (analysis of variance) followed by Dunnett's test. RESULTS: In brine shrimp lethality bioassay, the LC(50) values of the methanol extracts of Baccaurea ramiflora pulp and seed were 40 μg/mL and 10 μg/mL, respectively. Our investigation showed that Baccaurea ramiflora pulp and seed extracts (200 mg/kg) inhibited acetic acid induced pain 67.51 and 66.08%, respectively (p < 0.05) that was strongly comparable with that of Ibuprofen (72%) (p < 0.05). The Baccaurea ramiflora pulp and seed extracts (200 mg/kg) significantly (p < 0.05) reduced 58.5 and 53.4 in early and 80.8%, 76.61% in late phase of formalin-induced licking and biting. At 60 and 90 min pulp and seed extracts (200 mg/kg) inhibited nociception of thermal stimulus 50.16 and 62.4%, respectively (p < 0.05) which was comparable with the standard (morphine, 75.9% inhibition). The pulp and seed extracts (200 mg/kg) significantly (p < 0.05) reduced inflammation (42.00 and 55.22%, respectively) in carrageenan-induced hind paw edema and defecations (59.7 and 63.03%, respectively) in castor oil induced diarrhea. Both the extracts showed high sedative activity at 30, 60, 90, and 120 min. CONCLUSION: Our investigation demonstrated significant cytotoxic, analgesic, anti-inflammatory, CNS depressant and antidiarrheal activities of methanol extract of Baccaurea ramiflora pulp and seeds (200 mg/kg).
29279329 Purine nucleotide metabolism regulates expression of the human immune ligand MICA. 2018 Mar 16 Expression of the cell-surface glycoprotein MHC class I polypeptide-related sequence A (MICA) is induced in dangerous, abnormal, or "stressed" cells, including cancer cells, virus-infected cells, and rapidly proliferating cells. MICA is recognized by the activating immune cell receptor natural killer group 2D (NKG2D), providing a mechanism by which immune cells can identify and potentially eliminate pathological cells. Immune recognition through NKG2D is implicated in cancer, atherosclerosis, transplant rejection, and inflammatory diseases, such as rheumatoid arthritis. Despite the wide range of potential therapeutic applications of MICA manipulation, the factors that control MICA expression are unclear. Here we use metabolic interventions and metabolomic analyses to show that the transition from quiescent cellular metabolism to a "Warburg" or biosynthetic metabolic state induces MICA expression. Specifically, we show that glucose transport into the cell and active glycolytic metabolism are necessary to up-regulate MICA expression. Active purine synthesis is necessary to support this effect of glucose, and increases in purine nucleotide levels are sufficient to induce MICA expression. Metabolic induction of MICA expression directly influences NKG2D-dependent cytotoxicity by immune cells. These findings support a model of MICA regulation whereby the purine metabolic activity of individual cells is reflected by cell-surface MICA expression and is the subject of surveillance by NKG2D receptor-expressing immune cells.
29134648 Pharmacokinetics, Pharmacodynamics, and Proposed Dosing of the Oral JAK1 and JAK2 Inhibito 2018 Aug Population pharmacokinetic (popPK) modeling was used to characterize the PK profile of the oral Janus kinase (JAK)1/JAK2 inhibitor, baricitinib, in 18 patients with Mendelian interferonopathies who are enrolled in a compassionate use program. Patients received doses between 0.1 to 17 mg per day. Covariates of weight and renal function significantly influenced volume-of-distribution and clearance, respectively. The half-life of baricitinib in patients less than 40 kg was substantially shorter than in adult populations, requiring the need for dosing up to 4 times daily. On therapeutic doses, the mean area-under-the-concentration-vs.-time curve was 2,388 nM*hr, which is 1.83-fold higher than mean baricitinib exposures in adult patients with rheumatoid arthritis receiving doses of 4 mg once-daily. Dose-dependent decreases in interferon (IFN) biomarkers confirmed an in vivo effect of baricitinib on type-1 IFN signaling. PopPK and pharmacodynamic data support a proposal for a weight- and estimated glomerular filtration rate-based dosing regimen in guiding baricitinib dosing in patients with rare interferonopathies.
30073580 Persistence with Biological Disease-modifying Antirheumatic Drugs and Its Associated Resou 2018 Sep OBJECTIVE: The study assessed persistence rates of biological disease-modifying antirheumatic drugs (bDMARDs) for the treatment of rheumatoid arthritis in Japan and compared resource utilization and treatment costs between persistence and non-persistence groups. METHODS: Data were extracted from a Japanese claims database between 2009 and 2015. bDMARD-naïve patients were identified and included in the final analysis. Survival analysis was used to estimate 1-year persistence rates for current bDMARDs. Propensity score matching was applied to control for potential treatment selection bias. Resource utilization and healthcare costs were calculated 1 year before and after initiation of bDMARDs and compared between persistence and non-persistence groups. RESULTS: A total of 6153 bDMARD-naïve patients were identified and the overall 1-year persistence rate was 85% (95% CI 84-86). Overall, 1-year outpatient visits increased from 10 at baseline to 16 after bDMARD treatment, while the number of hospital admissions declined from 3.3 to 1.6. The non-persistence group had a larger increase in outpatient visits after bDMARD initiation compared with the persistence group (8-16 vs. 10-16, respectively) and a smaller decrease in hospital admissions (3.1-1.9 vs. 3.5-1.4, respectively). Persistence was associated with a reduction in total healthcare costs of US$760. CONCLUSIONS: Japanese bDMARD-naïve patients with RA have a high persistence rate with those treatments. The reduction in medication costs in non-persistent patients is offset by higher hospitalization costs, making non-persistence more expensive.
30069001 History of autoimmune conditions and lymphoma prognosis. 2018 Aug 1 Autoimmune conditions are strong risk factors for developing lymphoma, but their role in lymphoma prognosis is less clear. In a prospective cohort study, we evaluated self-reported history of eight autoimmune conditions with outcomes in 736 diffuse large B-cell, 703 follicular, 302 marginal zone (MZL), 193 mantle cell (MCL), 297 Hodgkin lymphoma (HL), and 186 T-cell lymphomas. We calculated event-free survival (EFS) and overall survival (OS), and estimated hazard ratios (HRs) and 95% confidence intervals (CIs), adjusting for sex, prognostic score, and treatment. History of any of the eight autoimmune conditions ranged from 7.4% in HL to 18.2% in MZL, and was not associated with EFS or OS for any lymphoma subtype. However, there was a positive association of autoimmune conditions primarily mediated by B-cell responses with inferior EFS in MCL (HR = 2.23, CI: 1.15-4.34) and HL (HR = 2.63, CI: 1.04-6.63), which was largely driven by rheumatoid arthritis. Autoimmune conditions primarily mediated by T-cell responses were not found to be associated with EFS or OS in any lymphoma subtype, although there were few events for this exposure. Our results indicate that distinguishing autoimmune conditions primarily mediated by B-cell/T-cell responses may yield insight regarding the impact of this comorbid disease, affecting ~10% of lymphoma patients, on survival.
29976222 Assessing patients' acceptance of their medication to reveal unmet needs: results from a l 2018 Jul 6 BACKGROUND: Patients with chronic conditions are required to take long-term treatments for their disease itself or to prevent any potential health risks. Measuring patient acceptance of their medication should help to better understand and predict patients' behavior toward treatment. This study aimed to describe the level of patient acceptance toward various long-term treatments in real life using an online patient community. METHODS: This was an observational, cross-sectional study conducted through the French Carenity platform. All Carenity patient members were invited to complete an online questionnaire including the 25-item ACCEptance by the Patients of their Treatment (ACCEPT©) questionnaire. ACCEPT© measures patient acceptance toward their medication and includes one general acceptance dimension (Acceptance/General) and six treatment-attribute specific dimensions (scores 0-100; lowest to highest acceptance): Acceptance/Medication Inconvenience, Acceptance/Long-term Treatment, Acceptance/Regimen Constraints, Acceptance/Side effects, Acceptance/Effectiveness, and Acceptance/Numerous Medications. Patients included in the analysis were treated adults experiencing any chronic diseases and who responded to at least one ACCEPT© item. RESULTS: Among the 4193 patients included in the analysis, more than 270 chronic diseases were represented, amidst which 19 included more than 30 patients. Mean ACCEPT© Acceptance/General score for those 19 diseases were 61.2 (SD = 31.9) for type 1 diabetes, 59.8 (SD = 32.3) for asthma, 56.3 (SD = 34.3) for hypertension, 52.0 (SD = 32.2) for chronic obstructive pulmonary disease, 51.7 (SD = 27.0) for epilepsy, 50.1 (SD = 33.1) for bipolar disorder, 49.9 (SD = 33.1) for type 2 diabetes, 48.6 (SD = 31.6) for multiple sclerosis, 46.1 (SD = 34.5) for Crohn's disease/ulcerative colitis, 44.3 (SD = 31.5) for depression, 42.8 (SD = 31.5) for lupus, 42.3 (SD = 33.0) for arthrosis, 41.8 (SD = 32.6) for Parkinson's disease, 40.5 (SD = 32.2) for rheumatoid arthritis, 38.6 (SD = 31.7) for breast cancer, 36.4 (SD = 36.4) for myocardial infarction, 35.8 (SD = 32.0) for ankylosing spondylitis, 34.1 (SD = 32.3) for psoriasis, and 33.7 (SD = 31.7) for fibromyalgia. CONCLUSIONS: This first of its kind study enabled ACCEPT© data to be collected in real life for a variety of chronic diseases. These data may help in evaluating and interpreting levels of acceptance in future studies and provide valuable insights about patient priorities and current unmet needs.
29879465 Bayesian synthesis using prior information on fracture risk from randomized trials to anal 2018 Sep OBJECTIVE: To conduct a Bayesian evidence synthesis using commonly available statistical procedures to estimate fracture risk for postmenopausal women undergoing hormonal therapy for breast cancer. STUDY DESIGN AND SETTING: Using linked administrative data, we conducted a retrospective cohort study of women aged 66 years or older diagnosed with stage I to III breast cancer in Ontario, Canada, between April 1, 2003, and February 28, 2010. We used data augmentation to perform Bayesian Cox regression of the hazard of a hip, spine, or wrist/forearm fracture, adjusting for age, history of fragility fracture, corticosteroid use, osteoporosis, rheumatoid arthritis, dementia, or diabetes diagnoses. RESULTS: Of 10,259 included in the sample, 3,733 initiated on tamoxifen and 6,526 on an aromatase inhibitor. Posterior probabilities that the hazard ratio (HR) exceeded 1 for aromatase inhibitor compared with tamoxifen were 46% (HR = 0.99, 95% credible interval [CrI] 0.71, 1.25), 35% (HR = 0.94, 95% CrI 0.78, 1.26), and 76% (HR = 1.08, 95% CrI 0.88, 1.32) with an uninformative prior, and 63% (HR = 1.04, 95% CrI 0.83, 1.3), 84% (HR = 1.12, 95% CrI 0.89, 1.4), and 89% (HR = 1.13, 95% CrI 0.93, 1.36) with an informative prior, for hip, spine, and wrist/forearm fractures, respectively. CONCLUSIONS: Prior information resulted in higher posterior probabilities. The strength of evidence for increased risk varied by fracture site.
29751165 No Association Between Consumption of Sweetened Beverages and Risk of Later-Onset Crohn's 2019 Jan BACKGROUND & AIMS: Consumption of sweetened beverages has been associated with inflammation based on measurements of C-reactive protein and tumor necrosis factor, as well as immune-mediated disorders including rheumatoid arthritis. We investigated associations with Crohn's disease (CD) or ulcerative colitis (UC). METHODS: We conducted a prospective cohort study of 83,042 participants (age, 44-83 y) enrolled in the Cohort of Swedish Men or the Swedish Mammography Study. Dietary and lifestyle data were collected using a validated food frequency questionnaire at baseline in 1997. Diagnoses of CD and UC were ascertained from the Swedish Patient Register. We used Cox proportional hazards modeling to calculate hazard ratios and 95% CIs. RESULTS: Through December of 2014, we confirmed 143 incident cases of CD (incidence rate, 11 cases/100,000 person-years) and 349 incident cases of UC (incidence rate, 28 cases/100,000 person-years) over 1,264,345 person-years of follow-up evaluation. Consumption of sweetened beverages was not associated with increased risk of CD (Ptrend = .34) or UC (Ptrend = .40). Compared with participants who reported no consumption of sweetened beverages, the multivariable-adjusted hazard ratios for 1 or more servings per day were 1.02 for CD (95% CI, 0.60-1.73) and 1.14 for UC (95% CI, 0.83-1.57). The association between consumption of sugar-sweetened beverages and risk of CD or UC were not modified by age, sex (cohort), body mass index, or smoking (all Pinteraction ≥ .12). CONCLUSIONS: In analyses of data from 2 large prospective cohort studies from Sweden, we observed no evidence for associations between consumption of sweetened beverages and later risk of CD or UC.
29416058 Divergent roles for antigenic drive in the aetiology of primary versus dasatinib-associate 2018 Feb 7 CD8(+) T-cell expansions are the primary manifestation of T-cell large granular lymphocytic leukemia (T-LGLL), which is frequently accompanied by neutropenia and rheumatoid arthritis, and also occur as a secondary phenomenon in leukemia patients treated with dasatinib, notably in association with various drug-induced side-effects. However, the mechanisms that underlie the genesis and maintenance of expanded CD8(+) T-cell receptor (TCR)-Vβ(+) populations in these patient groups have yet to be fully defined. In this study, we performed a comprehensive phenotypic and clonotypic assessment of expanded (TCR-Vβ(+)) and residual (TCR-Vβ(-)) CD8(+) T-cell populations in T-LGLL and dasatinib-treated chronic myelogenous leukemia (CML) patients. The dominant CD8(+) TCR-Vβ(+) expansions in T-LGLL patients were largely monoclonal and highly differentiated, whereas the dominant CD8(+) TCR-Vβ(+) expansions in dasatinib-treated CML patients were oligoclonal or polyclonal, and displayed a broad range of memory phenotypes. These contrasting features suggest divergent roles for antigenic drive in the immunopathogenesis of primary versus dasatinib-associated CD8(+) TCR-Vβ(+) expansions.
29080226 Temporal expression of interleukin-22, interleukin-22 receptor 1 and interleukin-22-bindin 2018 Apr BACKGROUND AND OBJECTIVE: Interleukin-22 (IL-22), mainly produced by CD4+ T-helper subtypes and innate lymphoid cells at barrier surfaces, is found to involve in several diseases, including diabetes, rheumatoid arthritis, peri-implantitis and chronic rhinosinusitis with nasal polyps. The purpose of this study was to investigate histological changes and the levels of interleukin-22, interleukin-22 receptor 1 (IL-22R1) and interleukin-22-binding protein (IL-22BP) in experimental periodontitis. MATERIAL AND METHODS: Sixty male 8-week-old Sprague Dawley rats were randomly allocated to six groups of 10 rats each. In the periodontitis groups, experimental periodontitis was established and the rats were killed on days 3, 5, 7, 11 and 15 after ligation, while the rats without ligation were killed on day 0, representing the healthy control group (day 0 group). Histopathologic changes were detected by hematoxylin and eosin (H&E) staining, and alveolar bone loss was determined by micro-computed tomography (micro-CT). Tartrate-resistant acid phosphatase (TRAP) staining was used to investigate osteoclast formation. Real-time quantitative PCR (qPCR) and immunohistochemistry were used to investigate the expression and location of IL-22, IL-22R1 and IL-22BP in gingival tissues. RESULTS: H&E staining showed increasingly severe destruction of the epithelial layer between day 3 and day 7, and the hyperplasia of pocket epithelium and the formation of periodontal pockets could be detected from day 11 to day 15. Micro-CT indicated an exponential increase in alveolar bone loss from day 3 to day 11 (P < .01). Bone resorption tended to be stationary after this period. TRAP staining showed that the number of multinucleate osteoclasts peaked at day 3 (P < .001, compared with day 0) and decreased at subsequent time points between day 5 and day 15. IL-22BP was expressed strongly under steady-state conditions in epithelial cells. IL-22-positive cells could be clearly observed both in the epithelial layer and around the lamina propria, whereas IL-22R1 was mainly localized in the epithelial layer of the damage period. Real-time qPCR revealed up-regulation of IL-22 and IL-22R1, as well as down-regulation of IL-22BP in gingival tissues during the destructive phase of periodontitis. CONCLUSION: This study shows the expression and localization of IL-22, IL-22R1 and IL-22BP, as well as the relevant histopathological alterations during the development of experimental periodontitis.
28962889 A new clerodane furano diterpene glycoside from Tinospora cordifolia triggers autophagy an 2018 Jan 30 ETHNOPHARMACOLOGICAL RELEVANCE: Tinospora cordifolia is a miraculous ayurvedic herb used in the treatment of innumerable diseases such as diabetes, gonorrhea, secondary syphilis, anaemia, rheumatoid arthritis, dermatological diseases, cancer, gout, jaundice, asthma, leprosy, in the treatment of bone fractures, liver & intestinal disorders, purifies the blood, gives new life to the whole body; (rejuvenating herb) and many more. Recent studies have revealed the anticancer potential of this plant but not much work has been done on the anticancer chemical constituents actually responsible for its amazing anticancer effects. This prompted us to investigate this plant further for new potent anticancer molecules. AIM OF THE STUDY: The present study was designed to isolate and identify new promising anticancer candidates from the aqueous alcoholic extract of T. cordifolia using bioassay-guided fractionation. MATERIALS AND METHODS: The structures of the isolated compounds were determined on the basis of spectroscopic data interpretation and that of new potent anticancer molecule, TC-2 was confirmed by a single-crystal X-ray crystallographic analysis of its corresponding acetate. The in vitro anti-cancer activity of TC-2 was evaluated by SRB assay and the autophagic activity was investigated by immunofluorescence microscopy. Annexin-V FITC and PI dual staining was applied for the detection of apoptosis. The studies on Mitochondrial Membrane potential and ROS (Reactive oxygen species) production were also done. RESULTS: Bioassay guided fractionation and purification of the aqueous alcoholic stem extract of Tinospora cordifolia led to the isolation of a new clerodane furano diterpene glycoside (TC-2) along with five known compounds i.e. cordifolioside A (β-D-Glucopyranoside,4-(3-hydroxy-1-propenyl)- 2,6-dimethoxyphenyl 3-O-D-apio-β-D-furanosyl) (TC-1), β-Sitosterol(TC-3), 2β,3β:15,16-Diepoxy- 4α, 6β-dihydroxy-13(16),14-clerodadiene-17,12:18,1-diolide (TC-4), ecdysterone(TC-5) and tinosporoside(TC-6). TC-2 emerged as a potential candidate for the treatment of colon cancer. CONCLUSION: The overall study on the bioassay guided isolation of T.cordifolia identified and isolated a new clerodane furano diterpenoid that exhibited anticancer activity via induction of mitochondria mediated apoptosis and autophagy in HCT116 cells. We have reported a promising future candidate for treating colon cancer.
30472018 The Influence of Naproxen on Biological Factors in Leukocyte-Rich Platelet-Rich Plasma: A 2019 Jan PURPOSE: To quantify and compare normative catabolic and anabolic factor concentrations in leukocyte-rich platelet-rich plasma (LR-PRP) at various time points, including baseline, 1 week after initiating naproxen use, and after a 1-week washout period. METHODS: Asymptomatic healthy donors aged between 18 and 70 years were recruited (average age, 36.6 years; range, 25-64 years). Subjects were excluded from the study if they were actively taking any prescribed medications or nonsteroidal anti-inflammatory drugs (NSAIDs) or if they had any of the following at present or previously: blood or immunosuppression disorders, cancer, osteonecrosis, rheumatoid arthritis, avascular necrosis, NSAID intolerance, gastrointestinal or peptic ulcer disease, or kidney dysfunction. The anabolic factors vascular endothelial growth factor, fibroblast growth factor 2, platelet-derived growth factor AB (PDGF-AB), and platelet-derived growth factor AA (PDGF-AA) and the catabolic factors interleukin (IL) 1β, IL-6, IL-8, and tumor necrosis factor α in LR-PRP were measured. Peripheral blood was drawn at 3 time points: baseline, after 1 week of naproxen use, and after a 1-week washout period. RESULTS: The angiogenic factors PDGF-AA (44% decrease in median) and PDGF-AB (47% decrease) significantly declined from baseline (P < .05) after 1 week of naproxen use. There was a significant recovery (P < .05) of PDGF-AA (94% increase) and PDGF-AB (153% increase) levels after the 1-week washout period, with a return to baseline levels. The catabolic factor IL-6 also had a significant decline from baseline (77% decrease in median, P < .05) after 1 week of naproxen use. After a 1-week washout period, the IL-6 level was similar to the baseline level (130% increase, P < .05). CONCLUSIONS: Naproxen use diminished several biological factors in LR-PRP; however, a 1-week washout period was sufficient for the recovery of PDGF-AA, PDGF-AB, and IL-6 to return to baseline levels. Tumor necrosis factor α, IL-1β, IL-8, vascular endothelial growth factor, and fibroblast growth factor 2 did not show differences between the 3 time points of data collection. Discontinuing NSAIDs for a minimum of 1 week before LR-PRP treatment may improve certain biological factor levels. LEVEL OF EVIDENCE: Level II, prospective comparative study.
30429478 Colorectal cancer liver metastatic growth depends on PAD4-driven citrullination of the ext 2018 Nov 14 Citrullination of proteins, a post-translational conversion of arginine residues to citrulline, is recognized in rheumatoid arthritis, but largely undocumented in cancer. Here we show that citrullination of the extracellular matrix by cancer cell derived peptidylarginine deiminase 4 (PAD4) is essential for the growth of liver metastases from colorectal cancer (CRC). Using proteomics, we demonstrate that liver metastases exhibit higher levels of citrullination and PAD4 than unaffected liver, primary CRC or adjacent colonic mucosa. Functional significance for citrullination in metastatic growth is evident in murine models where inhibition of citrullination substantially reduces liver metastatic burden. Additionally, citrullination of a key matrix component collagen type I promotes greater adhesion and decreased migration of CRC cells along with increased expression of characteristic epithelial markers, suggesting a role for citrullination in promoting mesenchymal-to-epithelial transition and liver metastasis. Overall, our study reveals the potential for PAD4-dependant citrullination to drive the progression of CRC liver metastasis.
30415492 Regulation of osteoblasts by alkaline phosphatase in ankylosing spondylitis. 2019 Feb AIM: Ankylosing spondylitis (AS) is characterized by excessive spinal ankylosis and bone formation. Alkaline phosphatase (ALP) activity is reported to be high in AS, but little is known about the molecular relationship between ALP and AS. The aims of this study were to investigate the relevance of ALP to AS and the role of ALP in the regulation of osteoblast differentiation in AS. METHODS: High-throughput data with accession numbers GSE73754 and GSE41038 were downloaded from the Gene Expression Omnibus. We retrospectively collected and compared the ALP levels of male patients with AS to those of sex- and age-matched healthy controls (HC) and rheumatoid arthritis (RA) patients. Total serum ALP and ALP activity were measured in the AS and RA groups. ALP gene expression and intracellular ALP activity were analyzed in microarray data from primary diseases control (Ct) and AS-bone-derived cells (BdCs) and in vitro experiments. Furthermore, the effect of ALP inhibitor was examined in both primary Ct- and AS-BdCs under osteoblast differentiation. Regulation of runt-related transcription factor 2 (RUNX2) by ALP was also analyzed. RESULTS: Alkaline phosphatase level was higher in AS compared with RA and HC and was associated with radiograph progression. ALP expression was also enriched in the bone tissue of AS patients. Furthermore, AS-BdCs exhibited increasing ALP activity, leading to accelerated osteoblastic activity and differentiation. Intriguingly, inhibition of ALP reduced RUNX2 expression, a master transcriptional factor in osteoblasts, and differentiation status of both primary Ct- and AS-BdCs. Treatment of ALP activator or inhibitor modulated RUNX2 protein level and RUNX2 regulated ALP promoter activity, indicating a reciprocal ALP-RUNX2 positive feedback to regulate osteoblast differentiation. CONCLUSION: Alkaline phosphatase was highly expressed in AS patients, may be involved in the ankylosis of AS, and represents a possible therapeutic target for ankylosis.
29496905 Control of hyperglycemia in male mice by leflunomide: mechanisms of action. 2018 Apr p70 S6 kinase (S6K1) is a serine/threonine kinase that phosphorylates the insulin receptor substrate-1 (IRS-1) at serine 1101 and desensitizes insulin receptor signaling. S6K1 hyperactivation due to overnutrition leads to hyperglycemia and type 2 diabetes. Our recent study showed that A77 1726, the active metabolite of the anti-rheumatoid arthritis (RA) drug leflunomide, is an inhibitor of S6K1. Whether leflunomide can control hyperglycemia and sensitize the insulin receptor has not been tested. Here we report that A77 1726 increased AKT(S473/T308) and S6K1(T389) phosphorylation but decreased S6(S235/236) and IRS-1(S1101) phosphorylation in 3T3-L1 adipocytes, C2C12 and L6 myotubes. A77 1726 increased insulin receptor tyrosine phosphorylation and binding of the p85 subunit of the PI-3 kinase to IRS-1. A77 1726 enhanced insulin-stimulated glucose uptake in L6 myotubes and 3T3-L1 adipocytes, and enhanced insulin-stimulated glucose transporter type 4 (GLUT4) translocation to the plasma membrane of L6 cells. Finally, we investigated the anti-hyperglycemic effect of leflunomide on ob/ob and high-fat diet (HFD)-induced diabetes mouse models. Leflunomide treatment normalized blood glucose levels and overcame insulin resistance in glucose and insulin tolerance tests in ob/ob and HFD-fed mice but had no effect on mice fed a normal chow diet (NCD). Leflunomide treatment increased AKT(S473/T308) phosphorylation in the fat and muscle of ob/ob mice but not in normal mice. Our results suggest that leflunomide sensitizes the insulin receptor by inhibiting S6K1 activity in vitro, and that leflunomide could be potentially useful for treating patients with both RA and diabetes.
29314261 Future Osteoporotic Fracture Risk Related to Lumbar Vertebral Trabecular Attenuation Measu 2018 May We sought to determine if vertebral trabecular attenuation values measured on routine body computed tomography (CT) scans obtained for a variety of unrelated indications can predict future osteoporotic fractures at multiple skeletal sites. For this Health Insurance Portability and Accountability Act (HIPAA)-compliant and Institutional Review Board (IRB)-approved retrospective cohort study, trabecular attenuation of the first lumbar vertebra was measured in 1966 consecutive older adults who underwent chest and/or abdominal CT at a single institution over the course of 1 year. New pathologic fragility fractures that occurred after a patient's CT study date were identified through an electronic health record database query using International Classification of Diseases (ICD)-9 codes for vertebral, hip, and extremity fractures. Univariate and multivariate Cox proportional hazards regression were performed to determine the effect of L(1) trabecular attenuation on fracture-free survival. Age at CT, sex, and presence of a prior fragility fracture were included as confounders in multivariate survival analysis. Model discriminative capability was assessed through calculation of an optimism-corrected concordance index. A total of 507 patients (mean age 73.4 ± 6.3 years; 277 women, 230 men) were included in the final analysis. The median post-CT follow-up interval was 5.8 years (interquartile range 2.1-11.0 years). Univariate analysis showed that L(1) attenuation values ≤90 Hounsfield units (HU) are significantly associated with decreased fracture-free survival (p < 0.001 by log-rank test). After adjusting for age, sex, prior fracture, glucocorticoid use, bisphosphonate use, chronic kidney disease, tobacco use, ethanol abuse, cancer history, and rheumatoid arthritis history, multivariate analysis demonstrated a persistent modest effect of L(1) attenuation on fracture-free survival (hazard ratio [HR] = 0.63 per 10-unit increase; 95% confidence interval [CI] 0.47-0.85). The model concordance index was 0.700. Ten-year probabilities for major osteoporosis-related fractures straddled the treatment threshold for most subcohorts over the observed L(1) HU range. In conclusion, for patients undergoing body CT scanning for any indication, L(1) vertebral trabecular attenuation is a simple measure that, when ≤90 HU, identifies patients with a significant decrease in fracture-free survival. © 2018 American Society for Bone and Mineral Research.
29663342 Associations of chronic urticaria with atopic and autoimmune comorbidities: a nationwide p 2018 Jul BACKGROUND: Most cases of chronic urticaria (CU) are idiopathic. Circumstantial evidence suggests that some CU cases have an autoimmune pathogenesis. Previous research indicates that a substantial percentage of patients with CU have an atopic background. OBJECTIVES: This study aims to examine the association between CU, and atopic and autoimmune diseases. METHODS: This population-based retrospective cohort study identified 9,332 patients with CU and 37,328 controls matched for age, sex, and number of dermatological clinic visits from the Taiwan National Health Insurance Research Database for 2004-2009. Using multiple logistic regression, we estimated odds ratios (OR) and 95% confidence intervals (CI) for associations of CU with atopic and autoimmune diseases. RESULTS: CU was most strongly associated with Kawasaki disease (modified OR, 2.76; 95% CI 1.15-6.63), followed by Henoch-Schönlein purpura (HSP), atopic dermatitis (AD), systemic lupus erythematosus (SLE), allergic rhinitis (AR), autoimmune thyroid diseases, Sjögren syndrome, inflammatory bowel disease (IBD), and asthma, which had the lowest adjusted OR (1.11; 95% CI 1.01-1.22) among comorbidities significantly associated with CU. The associations varied in relation to age, group, and sex. Among women, CU was significantly associated with AD, AR, autoimmune thyroid diseases, SLE, vitiligo, and HSP. Among men, CU was significantly associated with AD, AR, autoimmune thyroid diseases, Kawasaki disease, and IBD. CONCLUSION: CU is associated with atopic/autoimmune diseases. Increased awareness of atopic and autoimmune comorbidities may be warranted for patients with CU.
29297959 P2Y(2) R deletion ameliorates sialadenitis in IL-14α-transgenic mice. 2018 Jul OBJECTIVE: Interleukin-14α-transgenic (IL-14αTG) mice develop an autoimmune exocrinopathy with characteristics similar to Sjögren's syndrome, including sialadenitis and hyposalivation. The P2Y(2) receptor (P2Y(2) R) for extracellular ATP and UTP is upregulated during salivary gland inflammation (i.e., sialadenitis) where it regulates numerous inflammatory responses. This study investigated the role of P2Y(2) Rs in autoimmune sialadenitis in the IL-14αTG mouse model of Sjögren's syndrome. MATERIALS AND METHODS: IL-14αTG mice were bred with P2Y(2) R(-/-) mice to generate IL-14αTG × P2Y(2) R(-/-) mice. P2Y(2) R expression, lymphocytic focus scores, B- and T-cell accumulation, and lymphotoxin-α expression were evaluated in the submandibular glands (SMG) along with carbachol-stimulated saliva secretion in IL-14αTG, IL-14αTG × P2Y(2) R(-/-) , and C57BL/6 control mice at 9 and 12 months of age. RESULTS: Genetic ablation of P2Y(2) Rs in IL-14αTG mice significantly reduced B and T lymphocyte infiltration of SMGs. However, reduced sialadenitis did not restore saliva secretion in IL-14αTG × P2Y(2) R(-/-) mice. Decreased sialadenitis in IL-14αTG × P2Y(2) R(-/-) mice correlated with decreased lymphotoxin-α levels, a critical proinflammatory cytokine associated with autoimmune pathology in IL-14αTG mice. CONCLUSIONS: The results of this study suggest that P2Y(2) Rs contribute to the development of salivary gland inflammation in IL-14αTG mice and may also contribute to autoimmune sialadenitis in humans.
30519241 Ly9 (CD229) Antibody Targeting Depletes Marginal Zone and Germinal Center B Cells in Lymph 2018 Sjögren's Syndrome (SjS) is a common chronic autoimmune disease characterized by the B cell hyperactivation, lymphocyte infiltration, and tissue damage of exocrine glands. It can also present life-threatening extraglandular manifestations, such as pulmonary and hepatic involvement, renal inflammation and marginal zone (MZ) B cell lymphoma. Several biologic agents have been tested in SjS but none has shown significant efficacy. Here, we report the effects of Ly9 (CD229) antibody targeting, a cell surface molecule that belongs to the SLAM family of immunomodulatory receptors, using NOD.H-2(h4) mice as a model of SjS-like disease. Female mice were treated with anti-Ly9 antibody or isotype control at week 24, when all mice present SjS related autoantibodies, salivary gland infiltrates, and marginal zone (MZ) B cell pool enlargement. Antibody injection depleted key lymphocyte subsets involved in SjS pathology such as MZ, B1, and germinal center B cells in spleen and draining lymph nodes without inducing a general immunosuppression. Importantly, mice receiving anti-Ly9 mAb showed a reduced lymphocyte infiltrate within salivary glands. This reduction may be, in part, explained by the down-regulation of L-selectin and alfa4/beta7 integrin induced by the anti-Ly9 antibody. Furthermore, levels of anti-nuclear autoantibodies were reduced after anti-Ly9 treatment. These data indicate that Ly9 is a potential therapeutic target for the treatment of SjS.