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Aims/hypothesis Recent reports indicate that B lymphocyte-induced maturation protein 1 (BLIMP-1), encoded by the Prdm1 gene, expands its control over T cells and is associated with susceptibility to colitis in mice with T cell-specific BLIMP-1 deficiency. In this study, we aimed to investigate the potential role of BLIMP-1 in regulating autoimmune diabetes and T helper type 17 (Th17) cells. Methods We generated T cell-specific Blimp1 (also known as Prdm1 ) transgenic (Tg) or conditional knockout (CKO) NOD mice, in which Blimp1 is overexpressed or deleted in T cells, respectively. By side-by-side analysing these Tg or CKO mice, we further dissected the potential mechanisms of BLIMP-1-mediated modulation on autoimmune diabetes. Results Overproduction of BLIMP-1 in T cells significantly attenuated insulitis and the incidence of diabetes in NOD mice. Consistent with these results, the diabetogenic effect of splenocytes was remarkably impaired in Blimp1 Tg mice. Moreover, overproduction of BLIMP-1 repressed the proliferation and activation of lymphocytes and enhanced the function of regulatory T cells (Tregs) in NOD mice. In contrast, mice lacking BLIMP-1 in T cells markedly increased Th1 and Th17 cells, and developed highly proliferative and activated lymphocytes. Strikingly, overexpansion of Th1 and Th17 cells in CKO mice was significantly reduced by introducing a Blimp1 transgene, reinforcing the emerging role of BLIMP-1 in autoimmunity. Conclusions/interpretation We conclude that BLIMP-1 orchestrates a T cell-specific modulation of autoimmunity by affecting lymphocyte proliferation and activation, Th1 and Th17 cell differentiation, and Treg function. Our results provide a theoretical basis for developing BLIMP-1-manipulated therapies for autoimmune diabetes.

Background:AR882 is a highly selective URAT1 inhibitor in development for the treatment of gout and tophaceous gout. It has demonstrated favorable pharmacokinetics (PK) and robust efficacy in clinical studies. In AR882 phase 2 studies in patients with gout, no drug interactions (DDIs) were observed between AR882 and the commonly prescribed drugs for comorbidities such as antihyperglycemics, antihypertensives, statins and diuretics. There was no dose adjustment needed for concomitant medications while the efficacy of AR882 was steady. The lack of DDIs with these transporter-mediated drugs is consistent with the results from in vitro modeling and animal studies.Objectives:Comprehensive evaluation of AR882’s DDI potential with key renal, hepatic, and intestinal transporters that are typically associated with drugs used for comorbidity usually seen in gout patients.Methods:In in vitro studies, AR882’s interactions with various transporters were assessed in HEK293 cells expressing MATE1, MATE2-K, OATP1B1, OATP1B3, OAT1, OAT3, OCT1 and OCT2, or Caco-2 cells/membrane vesicles (P-gp and BCRP, BSEP). Substrate and inhibition assays for relevant transporters were conducted with AR882 in concentrations exceeding clinical drug concentration (i.e., at least 100-fold the Imax,u of high clinical dose at 75 mg). The obtained accumulation ratio (substrate) and the IC50 (inhibition) using model-base methods were analyzed for DDI predication. Furthermore, AR882 potential as a substrate for P-gp and BCRP transporters was assessed using tissue distribution data in rat and renal excretion data from the human ADME study using [14C]AR882. In order to determine the clinical significance of AR882’s DDI potential with BCRP, a phase 1 clinical study dosed in 10 male healthy participants with sulfasalazine 500 mg on Day 1, followed by a second single dose of sulfasalazine 500 mg on Day 4 with multiple-dose of AR882 75 mg administered once daily from Days 4 to 6. Plasma levels of sulfasalazine, as well as metabolites sulfapyridine and mesalamine were determined by LC/MS/MS analyses. PK parameters Cmax, and AUC were assessed to calculate geometric mean ratios.Results:In vitro assessments indicated that AR882 was not a substrate of any key renal and hepatic transporters. AR882 was determined to be a substrate of BCRP and P-gp; AR882 had no inhibitory effect on any transporters except for BCRP with an IC50 of 1.18 µM in animal studies, which warranted a clinical DDI study as an inhibitor of BCRP. Sulfasalazine, a clinical substrate of BCRP and a commonly used drug in autoimmune and rheumatic diseases was selected for the study. Co-administration of AR882 75 mg (maximum therapeutic dose) with sulfasalazine produced no clinically relevant alterations in pharmacokinetics (Cmax and AUC) of sulfasalazine with a geometric mean ratio of 1.09 (co-administration) verse 1.05 (sulfasalazine alone), suggesting no clinically significant BCRP-mediated DDI.Conclusion:AR882 has been comprehensively evaluated for transporter-mediated DDI potential in vitro and in clinical studies, and exhibited no DDI concerns. These findings demonstrated that AR882 can be safely given in gout patients with various comorbid conditions including diabetes, hypertension and hyperlipidemia and the concomitant medications that are primarily cleared via transporters.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of Interests:Zancong Shen Arthrosi Therapeutics Inc, Rongzi Yan Arthrosi Therapeutics Inc, Elizabeth Polvent Arthrosi Therapeutics Inc, Vijay Hingorani Arthrosi Therapeutics Inc, Shunqi Yan Arthrosi Therapeutics Inc, Robert Keenan Arthrosi Therapeutics Inc, Li-Tain Yeh Arthrosi Therapeutics Inc.

Background:AR882 is a novel and selective URAT1 inhibitor currently in clinical stage development for the treatment of gout and tophaceous gout. In the first 6-month period of a phase 2 proof-of-concept trial in patients with chronic gouty arthritis, AR882 has demonstrated significant reduction in serum urate (sUA) and marked reduction of clinically visible subcutaneous tophi and total urate crystal deposition by digital caliper measurement and Dual Energy Computer Tomography (DECT), respectively.Objectives:To evaluate the long-term effect of AR882 on the resolution of target subcutaneous tophi and reduction in urate crystal deposition volume using DECT in gout patients with subcutaneous tophi.Methods:The phase 2, randomized, open-label, global trial, recruited 42 patients with at least one subcutaneous tophus. The patients were randomized equally into three treatment groups to receive AR882 75 mg once daily (QD), AR882 50 mg + allopurinol QD, or allopurinol up to 300 mg QD. At 6 months all participants were eligible to enroll in a 6-month extension. Those in the allopurinol monotherapy group who opted in the 6-month extension had AR882 75 mg added to their current allopurinol regimen (AR882 75 mg + allopurinol QD), while patients in other groups continued their current regimen. Tophi measurements with calipers were completed every 4 weeks for the first 6 months followed by every 3 months in the extension phase. DECT imaging was conducted at baseline, Months 6 and 12. Efficacy endpoints included change in sUA change from baseline and change from baseline in target tophus area and crystal volume at Months 6 and 12. Safety assessments, including vital signs and electrocardiograms, were collected throughout the study.Results:The average baseline sUA level ranged between 9.1-9.6 mg/dL across groups. At Month 3, the median sUA levels were reduced to 4.5, 4.7, and 6.1 mg/dL for AR882 75 mg, AR882 50 mg+allopurinol and allopurinol groups, respectively. At Month 12, sUA levels were 4.3 mg/dL, 3.7 mg/dL and 2.9 mg/dL for AR882 75 mg, AR882 50 mg+allopurinol and AR882 75 mg+allopurinol groups, respectively. At Month 6, complete tophus resolution of at least 1 target tophus measured by digital caliper was seen with 4 patients (29%) in the AR882 75 mg group, 1 patient (8%) in allopurinol and 1 patient (8%) in AR882 50 mg + allopurinol group. During the 6 months extension phase, complete tophus resolution was seen in 5 patients (50.0%) and 4 patients (36.4%) in the AR882 75 mg and AR882 75 mg+allopurinol groups, respectively (Table 1). The AR882 75 mg alone or combined with allopurinol showed reduction of total urate crystal volume from baseline to Month 6 with sustained crystal volume reduction through Months 6 to 12. AR882 was well tolerated throughout 12-month chronic treatment as monotherapy or in combination with allopurinol. The most frequently reported adverse event was gout flare, mild or moderate adverse events including diarrhea, headache, and upper respiratory infection. Gout flare rate appeared continued to decline following AR882 treatment.Conclusion:The 12-month treatment of AR882 in patients with tophaceous gout demonstrated safe and efficacious sUA lowering, continued tophus resolution and total crystal volume dissolution from initial 6-month treatment. AR882 may offer improved efficacy and better safety compared to existing therapies in the treatment of patients with gout, including those with both clinically visible and subclinical crystal deposition.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of Interests:Robert Keenan Arthrosi Therapeutics Inc, James Cheng-Chung Wei Arthrosi Therapeutics Inc, Nicola Dalbeth AstraZeneca, Novartis, Horizon, Selecta, Arthrosi, JW Pharmaceutical Corporation, PK Med, LG Chem, JPI, PTC Therapeutics, Protalix, Unlocked Labs, Hikma, and Dexcel Pharma., AstraZeneca, Novartis, Horizon, Selecta, Arthrosi, JW Pharmaceutical Corporation, PK Med, LG Chem, JPI, PTC Therapeutics, Protalix, Unlocked Labs, Hikma, and Dexcel Pharma., AstraZeneca, Novartis, Horizon, Selecta, Arthrosi, JW Pharmaceutical Corporation, PK Med, LG Chem, JPI, PTC Therapeutics, Protalix, Unlocked Labs, Hikma, and Dexcel Pharma., Sarah Morris Arthrosi Therapeutics Inc, Pamela Mundell Arthrosi Therapeutics Inc, Wen Wei Arthrosi Therapeutics Inc, Zancong Shen Arthrosi Therapeutics Inc, Vijay Hingorani Arthrosi Therapeutics Inc, Shunqi Yan Arthrosi Therapeutics Inc, Bahram Kiani: None declared, Li-Tain Yeh Arthrosi Therapeutics Inc.

Published studies of prevalence of depression in old age in Taiwan have yielded equivocal results. To study the prevalence of depressive disorders among community-dwelling elderly; further, to assess socio-demographic correlates and life events in relation to depression. A randomised sample of 1500 subjects aged 65 and over was selected from three communities. Research psychiatrists conducted all assessments using the Geriatric Mental State Schedule. The diagnosis of depression was made with the GMS-AGECAT (Automated Geriatric Examination for Computerised Assisted Taxonomy); data on life events were collected with the Taiwanese version of the Life Events and Difficulties Schedule. One-month prevalence of psychiatric disorders was 37.7%, with 15.3% depressive neurosis and 5.9% major depression. A high risk of depressive disorders was found among widows with a low educational level living in the urban community, and among those with physical illnesses. Contrary to most previous reports, we found that the prevalence of depressive disorders among the elderly in the community in Taiwan is high and comparable to rates reported in some studies of UK samples.

BackgroundDespite gout being the most common inflammatory arthritis, there remains an unmet need for more effective treatment. AR882 is a novel, potent, and selective uric acid transporter 1 (URAT1) inhibitor in development for the treatment of gout and tophaceous gout. AR882 was well tolerated, including patients with various degrees of renal insufficiency, and has consistently demonstrated robust sUA lowering in multiple clinical trials.ObjectivesThis global phase 2b trial is a randomized, double-blinded, placebo-controlled, 12-week study to evaluate the safety, tolerability, and efficacy of AR882 versus placebo in patients with gout.MethodsThe trial recruited patients 18 to 75 years of age with eGFR >30 mL/min across 20 sites in the US, Australia, and Taiwan, who met the ACR/EULAR Gout Classification Criteria. Following gout flare prophylaxis for 10 days, patients received either once-daily AR882 50 mg, AR882 75 mg, or matching placebo for 12 weeks. Blood samples were collected every two weeks through Week 12 for laboratory tests, sUA and pharmacokinetic measurements. Efficacy endpoint was the percent of patients who reached sUA below 6, 5, 4, and 3 mg/dL. Safety including vital signs and electrocardiograms were collected throughout the study.ResultsA total of 140 patients were enrolled in this study. The majority of patients were male (93.6%) and white (58%), followed by Asian (28%) and Black or African (15%). The baseline sUA level was 8.6 (±1.3) mg/dL; mean age 54.3 (24-73) years; mean body weight 96.4 (±17.8) kg. Major comorbidities seen in patients included hypertension (47%), hyperlipidemia (35%), renal insufficiency (34%), arthritis (23%), diabetes (19%), cardiovascular disease (15%), lung disease (11%), and liver disease (5%). Following 12 weeks of treatment, median sUA levels were reduced from baseline 8.6 mg/dL to 3.5 mg/dL with 75 mg and 5.0 mg/dL with 50 mg. No change was observed in the placebo group. At Week 12, 89%, 82%, 63% and 29% of patients achieved < 6, <5, <4 and <3 mg/dL, respectively, in the 75 mg group. In the 50 mg group, 78%, 50%, 8% of patients achieved < 6, <5 and <4 mg/dL, respectively. The sUA lowering effect was similar for three consecutive measurements between Week 8 and 12. There were no serious adverse events in AR882 treated patients. Mild or moderate adverse events including diarrhea, headache, and upper respiratory infection were observed in this study. A total of 65 gout flare incidents were observed and evenly distributed across groups during the 12-week treatment.ConclusionThe majority of patients receiving AR882 had achieved sUA levels below 5 or 4 mg/dL, which are two key thresholds for more efficient flare and tophi reductions[1][2]. AR882 was well tolerated over the 12-week treatment period and patients with comorbidities did not require any adjustments in management of the diseases while treated with AR882. This study suggests AR882 may offer improved efficacy with acceptable safety compared to existing therapies for gout and may have utility in the treatment of patients across the spectrum of gout including those with severe or refractory disease.Figure 1.Percent of Patients with sUA at Targets following 12-week Treatment of AR882 or Placebo.References[1]Perez-Ruiz F, Calabozo M, Pijoan JI, et al. Arthritis Rheum. 2002;47(4):356-60[2]Richette P, Doherty M, Pascual E, et al. Ann Rheum Dis. 2017;76:29-42.Acknowledgements:NIL.Disclosure of InterestsJames Cheng-Chung Wei: None declared, Roy M. Fleischmann Speakers bureau: AbbVie, Pfizer Inc, Consultant of: AbbVie, Amgen Inc., Biogen, Bristol Myers Squibb, Eli Lilly and Company, Galapagos, Galvani, Gilead, GSK plc, Janssen Pharmaceuticals, Novartis AG, Union Chimique Belge (UCB), Grant/research support from: AbbVie, Amgen Inc., Biogen, Bristol Myers Squibb, Eli Lilly and Company, Flexion, Galapagos, Galvani, Genentech, Gilead, GSK plc, Horizon, Janssen Pharmaceuticals, Novartis AG, UCB, Viela, Sarah Morris Shareholder of: Arthrosi therapeutics, Employee of: Arthrosi therapeutics, Elizabeth Polvent Shareholder of: Arthrosi therapeutics, Employee of: Arthrosi therapeutics, Zancong Shen Shareholder of: Arthrosi therapeutics, Employee of: Arthrosi therapeutics, Andrea Clouser Roche Shareholder of: Arthrosi therapeutics, Employee of: Arthrosi therapeutics, Vijay Hingorani Consultant of: Arthrosi therapeutics, Shunqi Yan Shareholder of: Arthrosi therapeutics, Employee of: Arthrosi therapeutics, Li-Tain Yeh Shareholder of: Arthrosi therapeutics, Employee of: Arthrosi therapeutics, Robert Keenan Shareholder of: Arthrosi therapeutics, Employee of: Arthrosi therapeutics.

Hardware/software co-design is an interesting topic for most embedded system architects. However, designers find integrating hardware and software communications interface challenging. A framework for integrating the software and hardware communication interface, for computing in reconfigurable embedded systems, called IRES, is proposed. The framework supports reconfigurable computing architectures, based on traditional central processing unit and the reconfigurable field programmable gate array, and composed of the integration linker, the boot loader, small task-oriented operating objects and the hardware management unit. The integration linker enables the IRES to link hardware net-list files and tasks into one execution file, called the executor, constructed with the boot loader, the task-oriented operating kernel, the application tasks and the accelerating hardware functions. When the executor operates on the target-embedded environment, the implicit hardwire-call will be supported to invoke hardware functions in the task codes. The IRES successfully implements in the realised hardware platform, and this work verifies communication effectiveness between hardware and software through video compression applications.

Background Lesinurad is a novel URAT1 inhibitor that has been well tolerated in humans, with dose-dependent reductions of serum urate (sUA). In vitro experiments and in vivo human absorption, metabolism, and mass balance (AME) studies indicated that hepatic metabolism, renal excretion, and biliary uptake all contributed to the elimination of lesinurad. Drug-drug interaction (DDI) studies with drugs commonly used by gout patients have been conducted. Projections of DDI potential with drugs in different therapeutic areas have also been generated using established preclinical models. Objectives To evaluate the potential inhibitory effect of lesinurad upon initiation of lesinurad once daily dosing or the potential induction effect of lesinurad following multiple doses of lesinurad on pharmacokinetic (PK) of commonly used drugs such as atorvastatin (OATP1B1 and CYP3A), tolbutamide (CYP2C9 and CYP3A), repaglinide (CYP2C8 and CYP3A), or amlodipine (CYP3A) in healthy subjects, as well as PK and sUA lowering of febuxostat (FBX; CYP2C9) or oxypurinol (URAT1), the active metabolite of allopurinol (ALLO), following once daily (qd) dosing of lesinurad in gout patients with hyperuricemia. Methods A total of 70 healthy subject volunteers were enrolled across 4 DDI studies with drugs commonly used by gout patients including atorvastatin (N=28), tolbutamide (N=14), repaglinide (N=14), and amlodipine (N=14), given with concurrent administration of first dose or qd doses of lesinurad ranging between 200 and 400 mg. Full PK profiles of these drugs were obtained without coadministration with lesinurad, following first dose, or following at least 10 days of qd doses of lesinurad. A total of 41 gout patients were enrolled across 2 multiple-dose DDI studies with FBX and ALLO. In the ALLO DDI study, patients were administered ALLO 300 mg qd in week 1, a combination of ALLO and lesinurad 400 or 600 mg in week 2, then lesinurad alone in week 3. In the FBX DDI study, patients received FBX 40 or 80 mg qd in week 1, a combination of FBX and lesinurad 400 mg and 600 mg in week 2 and week 3, respectively. Results In healthy subjects, lesinurad showed minimal inhibitory effects (10-30%) on plasma exposure of atorvastatin, tolbutamide and repaglinide upon first dose of 400 mg lesinurad, the highest dose planned for Phase 3 evaluations. Following 400 mg qd doses of lesinurad, plasma exposure of tolbutamide and repaglinide were unaffected, while plasma exposure of atorvastatin, and amlodipine were minimally decreased. In gout patients, although co-administration of lesinurad 400 mg resulted in 26% decrease in oxypurinol plasma exposure, additive reduction in sUA was observed. Coadminstration of lesinurad 400 mg resulted in minimal (<20%) increases in FBX plasma exposure, and synergistic reductions in sUA. Neither allopurinol nor FBX had any effect on the PK of lesinurad. Preclinical DDI modeling of the most commonly used drugs by gout patients identified few potential interactions Conclusions Potential drug-drug interactions are limited to mild reductions in oxypurinol (expected due to URAT1 activity) and mild induction of CYP3A4 at the doses being evaluated in Phase 3. No clinically meaningful drug interactions are anticipated with lesinurad Disclosure of Interest L.-T. Yeh Employee of: Ardea Biosciences, Z. Shen Employee of: Ardea Biosciences, B. Kerr Consultant for: Ardea Biosciences, D. Wilson Employee of: Ardea Biosciences, C. Yang Employee of: Ardea Biosciences, S. Squier Consultant for: Ardea Biosciences, V. Hingorani Consultant for: Ardea Biosciences, D. Hagerty Employee of: Ardea Biosciences, K. Manhard Employee of: Ardea Biosciences, B. Quart Employee of: Ardea Biosciences

Background Excess body burden of uric acid promotes gout. Diminished renal clearance of uric acid causes hyperuricemia in most patients with gout, and the renal urate transporter (URAT)1 is important for regulation of serum uric acid (sUA) levels. The URAT1 inhibitors probenecid and benzbromarone are used as gout therapies; however, their use is limited by drug–drug interactions and off-target toxicity, respectively. Here, we define the mechanism of action of lesinurad (Zurampic®; RDEA594), a novel URAT1 inhibitor, recently approved in the USA and Europe for treatment of chronic gout. Methods sUA levels, fractional excretion of uric acid (FE UA ), lesinurad plasma levels, and urinary excretion of lesinurad were measured in healthy volunteers treated with lesinurad. In addition, lesinurad, probenecid, and benzbromarone were compared in vitro for effects on urate transporters and the organic anion transporters (OAT)1 and OAT3, changes in mitochondrial membrane potential, and human peroxisome proliferator-activated receptor gamma (PPARγ) activity. Results After 6 hours, a single 200-mg dose of lesinurad elevated FE UA 3.6-fold ( p  < 0.001) and reduced sUA levels by 33 % ( p  < 0.001). At concentrations achieved in the clinic, lesinurad inhibited activity of URAT1 and OAT4 in vitro, did not inhibit GLUT9, and had no effect on ABCG2. Lesinurad also showed a low risk for mitochondrial toxicity and PPARγ induction compared to benzbromarone. Unlike probenecid, lesinurad did not inhibit OAT1 or OAT3 in the clinical setting. Conclusion The pharmacodynamic effects and in vitro activity of lesinurad are consistent with inhibition of URAT1 and OAT4, major apical transporters for uric acid. Lesinurad also has a favorable selectivity and safety profile, consistent with an important role in sUA-lowering therapy for patients with gout.

Purpose There have been few studies using mindfulness-based stress reduction (MBSR) to improve sexual function in Asian women with breast cancer. This study aimed to evaluate the impact of mindfulness intervention on female sexual function, mental health, and quality of life in patients with breast cancer. Methods Fifty-one women with breast cancer were allocated into 6-week MBSR ( n =26) sessions or usual care ( n =25), without differences in group characteristics. The research tools included the Female Sexual Function Index (FSFI), the Depression Anxiety Stress Scales-21 (DASS-21), and the EuroQol instrument (EQ-5D). The Greene Climacteric Scale (GCS) was used to verify the foregoing scale. The effects of MBSR were evaluated by the differences between the post- and pre-intervention scores in each scale. Statistical analyses consisted of the descriptive dataset and Mann-Whitney ranked-pairs test. Results Although MBSR did not significantly improve sexual desire and depression in patients with breast cancer, MBSR could improve parts of female sexual function [i.e., Δarousal: 5.73 vs. -5.96, Δlubrication: 3.35 vs. -3.48, and Δsatisfaction: 8.48 vs. 1.76; all p <.005], with a range from small to medium effect sizes. A significantly benefits were found on mental health [Δanxiety: -10.92 vs.11.36 and Δstress: -10.96 vs.11.40; both p <.001], with large effect sizes, ranging from 0.75 to 0.87. Conclusion Our study revealed that MBSR can improve female sexual function and mental health except for sexual desire and depression in women with breast cancer. Medical staff can incorporate MBSR into clinical health education for patients with breast cancer to promote their overall quality of life.

[...]the advantages of the DSS are threefold: (a) DSS helps the organizer to reduce erroneous scoring; (b) DSS helps the referee to make the best possible decision by means of replaying the missed motion; and (c) DSS improves timing control.