Involvement of COX-2/PGE2 Pathway in the Upregulation of MMP-9 Expression in Pancreatic Cancer

COX-2 and MMP-9 have been reported to show an overexpression in pancreatic cancer, and thus an attempt to explore the correlation between them has become a target of this study. Besides, PGE2, a product of COX-2, was also under research as to whether it is involved in the upregulation of MMP-9 expression by COX-2. Expression of COX-2 and MMP-9 mRNA varied in pancreatic adenocarcinomas, and the mRNA level of COX-2 was correlated positively with MMP-9. Both BxPC-3 and Capan-1 cells had strong expression of COX-2 and MMP-9. MMP-9 expression was downregulated significantly in BxPC-3 and Capan-1 cells after treatment with COX-2 inhibitors or COX-2 siRNA plasmids, and upregulated in BxPC-3 significantly by exogenous TNF-α, LPS or PGE2. The upregulation of MMP-9 by TNF-α or LPS was inhibited by COX-2 inhibitor NS398. There was a significant increase in the migration of BxPC-3 cells with TNF-α, LPS, or PGE2 treatment; however, the increase caused by TNF-α or LPS was also inhibited remarkably by NS398. Our findings demonstrated that COX-2 upregulates MMP-9 expression in pancreatic cancer, and PGE2 may be involved in it

D-optimal Designs for Multinomial Logistic Models

Multinomial logistic models have been widely used for categorical responses. There exist four types of logit models, that is, baseline-category logit model for nominal responses, cumulative logit model for ordinal responses, adjacent-categories logit model for ordinal responses, and continuation-ratio logit model for hierarchical responses. There also exist three model assumptions, including proportional odds (PO), non-proportional odds (NPO) and partial proportional odds (PPO). In order to construct a general framework towards D-optimal designs for these models, we unified all the models into a common form and derived three types of Fisher information matrix expressions. Based on them, we discussed positive definiteness of Fisher information matrix and obtained the number of minimally supported points for different models. Furthermore, we derived the general formula for Fisher information matrix's determinant, which applies to all types of multinomial logistic models. In some special cases, the determinant can be expressed explicitly (in a closed form) so D-optimal designs can be obtained directly. Two real experiments are used to illustrate locally and non-locally D-optimal design's efficiency improvement, which provides us a benchmark and criterion. The D-optimal designs recommended in these examples are minimally supported. Generally the uniform design is not D-optimal design for multinomial logistic models

POS0849 Long-term safety and efficacy of Upadacitinib or adalimumab in patients with rheumatoid arthritis: 5-year data from the select-compare study

BACKGROUND: Upadacitinib (UPA) is an oral reversible Janus kinase inhibitor. In patients (pts) with RA, UPA 15mg once daily (QD) demonstrated better clinical responses at 12 weeks (wks) vs adalimumab (ADA) 40mg every other week (EOW) in the phase 3 SELECT-COMPARE study; these were maintained through 3 years (yrs) in the ongoing long-term extension (LTE), along with an acceptable safety profile.[1,2] OBJECTIVES: To assess the safety and efficacy of UPA vs ADA through 5 yrs in the SELECT-COMPARE LTE. […

Efficacy and safety of upadacitinib in patients with ankylosing spondylitis refractory to biologic therapy: 1-year results from the open-label extension of a phase III study

Abstract Background Upadacitinib, a Janus kinase inhibitor, has demonstrated efficacy and an acceptable safety profile in patients with ankylosing spondylitis (AS) in the phase III SELECT-AXIS programs. We report the 1-year efficacy and safety in patients with AS and an inadequate response to biologic disease-modifying antirheumatic drugs (bDMARD-IR) from the SELECT-AXIS 2 study. Methods Patients ≥ 18 years with active AS who met the modified New York criteria for AS and were bDMARD-IR received double-blind upadacitinib 15 mg once daily (QD) or placebo for 14 weeks. Patients who completed 14 weeks could enter an open-label extension and receive upadacitinib 15 mg QD for up to 2 years. Efficacy endpoints included the percentage of patients achieving ≥ 40% improvement in Assessment of SpondyloArthritis international Society response (ASAS40), Ankylosing Spondylitis Disease Activity Score (ASDAS) low disease activity (LDA), and ASDAS inactive disease (ID); and change from baseline in total and nocturnal back pain, and Bath Ankylosing Spondylitis Functional Index (BASFI). Subgroup analyses (bDMARD lack of efficacy versus intolerance, and prior tumor necrosis factor inhibitor [TNFi] versus interleukin-17 inhibitor [IL-17i] exposure) were conducted. Binary and continuous efficacy endpoints were assessed using non-responder imputation with multiple imputation (NRI-MI) and as observed (AO) analyses; and mixed-effects model repeated measures (MMRM) and AO, respectively. Safety was assessed based on adverse events. Data through week 52 are reported. Results Of 420 randomized patients, 366 (continuous upadacitinib: n = 181; placebo to upadacitinib: n = 185) completed 52 weeks of treatment. At week 52, in the continuous upadacitinib and placebo to upadacitinib groups, ASAS40, ASDAS LDA, and ASDAS ID were achieved by 66% and 65%, 57% and 55%, and 26% and 25% (all NRI-MI); and change from baseline in total back pain, nocturnal back pain, and BASFI was -4.5 and -4.3, -4.6 and -4.4, and -3.6 and -3.5 (all MMRM), respectively. No new safety risks were identified. Subgroup analyses were consistent with the overall study population. Conclusions Upadacitinib 15 mg QD demonstrated sustained improvement up to 52 weeks in bDMARD-IR patients with AS. Efficacy was generally similar in patients with lack of efficacy versus intolerance to bDMARDs and prior TNFi versus IL-17i exposure. Trial registration NCT02049138

Upadacitinib in patients with psoriatic arthritis and inadequate response to biologics : 56-week data from the randomized controlled phase 3 SELECT-PsA 2 study

Introduction Upadacitinib is a Janus kinase inhibitor under investigation in patients with psoriatic arthritis (PsA). This study assessed the 56-week efficacy and safety of upadacitinib in patients with PsA and an inadequate response or intolerance to biologic therapy. Methods In the phase 3 SELECT-PsA 2 study, patients were randomized to 56 weeks of blinded treatment with oral upadacitinib 15 or 30 mg once daily, or placebo switched to upadacitinib 15 or 30 mg once daily at week 24. Efficacy endpoints included the proportion of patients achieving 20/50/70% improvement in American College of Rheumatology criteria (ACR20/50/70), 75/90/100% improvement in Psoriasis Area and Severity Index (PASI75/90/100), and minimal disease activity. Safety was assessed throughout the study. Results Of 641 patients who received >= 1 dose of study drug, 479 (74.7%) completed 56 weeks of treatment. Improvements in the proportion of patients achieving ACR20/50/70, PASI75/90/100, and minimal disease activity were maintained with both doses of upadacitinib through 56 weeks. Week 56 results for patients who switched from placebo to upadacitinib at week 24 were similar to those for patients originally randomized to the upadacitinib groups. The exposure-adjusted event rate for serious infections was 2.6 and 6.1 events/100 patient-years in the upadacitinib 15 and 30 mg groups, respectively. Herpes zoster occurred more frequently with upadacitinib 30 versus 15 mg; most cases were non-serious. Conclusion In patients with PsA who had an inadequate response or intolerance to biologic therapy, the efficacy of upadacitinib was maintained over 56 weeks with no new significant safety signals observed

Upadacitinib in Patients with Psoriatic Arthritis and Inadequate Response to Biologics: 56-Week Data from the Randomized Controlled Phase 3 SELECT-PsA 2 Study.

INTRODUCTION: Upadacitinib is a Janus kinase inhibitor under investigation in patients with psoriatic arthritis (PsA). This study assessed the 56-week efficacy and safety of upadacitinib in patients with PsA and an inadequate response or intolerance to biologic therapy. METHODS: In the phase 3 SELECT-PsA 2 study, patients were randomized to 56 weeks of blinded treatment with oral upadacitinib 15 or 30 mg once daily, or placebo switched to upadacitinib 15 or 30 mg once daily at week 24. Efficacy endpoints included the proportion of patients achieving 20/50/70% improvement in American College of Rheumatology criteria (ACR20/50/70), 75/90/100% improvement in Psoriasis Area and Severity Index (PASI75/90/100), and minimal disease activity. Safety was assessed throughout the study. RESULTS: Of 641 patients who received ≥ 1 dose of study drug, 479 (74.7%) completed 56 weeks of treatment. Improvements in the proportion of patients achieving ACR20/50/70, PASI75/90/100, and minimal disease activity were maintained with both doses of upadacitinib through 56 weeks. Week 56 results for patients who switched from placebo to upadacitinib at week 24 were similar to those for patients originally randomized to the upadacitinib groups. The exposure-adjusted event rate for serious infections was 2.6 and 6.1 events/100 patient-years in the upadacitinib 15 and 30 mg groups, respectively. Herpes zoster occurred more frequently with upadacitinib 30 versus 15 mg; most cases were non-serious. CONCLUSION: In patients with PsA who had an inadequate response or intolerance to biologic therapy, the efficacy of upadacitinib was maintained over 56 weeks with no new significant safety signals observed. TRIAL REGISTRATION: NCT03104374

Prevalence and burden of chronic cough in China: a national cross-sectional study

Background Chronic cough is a common complaint, but there are no population-based data on its burden in China. We determined the prevalence of chronic cough and its impact on health status in adults stratified by sex, age and the diagnosis of COPD or the presence of small airway dysfunction (SAD). Methods A representative sample of 57 779 Chinese adults aged 20 years or older was recruited and pulmonary function test was measured. Chronic cough was defined as cough lasting for >3 months in each year. Quality of life was assessed by the 12-item Short Form Health Survey (SF-12), and self-reported history of hospital visits was recorded. Results Chronic cough was found in 3.6% (95% CI 3.1–4.1) of Chinese adults, 2.4% (95% CI 1.9–3.1) of those aged 20–49 years and 6.0% (95% CI 5.3–6.8) of those aged 50 years or older. Individuals with chronic cough had an impaired physical component summary (PCS) score of the SF-12 (p<0.0001) and more emergency visits (p=0.0042) and hospital admissions (p=0.0002). Furthermore, the impact of chronic cough on PCS score was more significant in those aged 50 years or older, or with COPD (p=0.0018 or 0.0002, respectively), with the impact on hospital admission being more significant in those with COPD or with SAD (p=0.0026 or 0.0065, respectively). Conclusions Chronic cough is prevalent in China and is associated with a poorer health status, especially in individuals aged 50 years or older and those with the diagnosis of COPD or SAD