We investigated the efficacy and safety of dual bronchodilation with QVA149 versus its monocomponents indacaterol and glycopyrronium， tiotropium and placebo in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD). This was a multicentre， randomised， double-blind， placebo- and active-controlled， 26-week trial. Patients (n = 2144) were randomised (2：2：2：2：1) to receive once-daily QVA149 (indacaterol 110 μg/glycopyrronium 50 μg)， indacaterol 150 μg， glycopyrronium 50 μg， open-label tiotropium 18 μg or placebo. The primary end-point was trough forced expiratory volume in 1 s (FEV1) at week 26 for QVA149 versus its monocomponents. Secondary end-points included dyspnoea， health status， rescue medication use and safety. Trough FEV1 at week 26 was significantly improved (p<0.001) with QVA149 compared with indacaterol and glycopyrronium (least squares mean (LSM) differences 0.07 L and 0.09 L， respectively)， tiotropium and placebo (LSM differences 0.08 L and 0.20 L， respectively); these beneficial effects were sustained throughout the 26-week study. QVA149 significantly improved dyspnoea and health status versus placebo (p<0.001 and p = 0.002， respectively) and tiotropium (p = 0.007 and p = 0.009， respectively) at week 26. All treatments were well tolerated. Dual bronchodilation with once-daily QVA149 demonstrated superior and clinically meaningful outcomes versus placebo and superiority versus treatment with a single bronchodilator， with a safety and tolerability profile similar to placebo， supporting the concept of fixed-dose long-acting muscarinic antagonist/long-acting β2-agonist combinations for the treatment of COPD.
Abstract The tumor suppressor p53 is activated in response to cellular stress to prevent malignant transformation by activation of the DNA repair machinery to preserve the cell， or by induction of apoptosis to eliminate the cell should the damage prove irrevocable. The gene encoding p53 frequently undergoes inactivating mutations in many human cancers， but WT p53 is often expressed at high levels in melanoma， which， as judged from the malignant nature of the disease， fails to act as an effective tumor suppressor. Here we show that p53 directly up-regulates microRNA-149* (miR-149*) that in turn targets glycogen synthase kinase-3α， resulting in increased expression of Mcl-1 and resistance to apoptosis in melanoma cells. Although deficiency in miR-149* undermined survival of melanoma cells and inhibited melanoma growth in a mouse xenograft model， elevated expression of miR-149* was found in fresh human metastatic melanoma isolates， which was associated with decreased glycogen synthase kinase-3α and increased Mcl-1. These results reveal a p53-dependent， miR-149*-mediated pathway that contributes to survival of melanoma cells， provides a rational explanation for the ineffectiveness of p53 to suppress melanoma， and identifies the expression of miR-149* as a mechanism involved in the increased expression of Mcl-1 in melanoma cells.
We evaluated the effect of QVA149， a dual combining indacaterol and glycopyrronium， on direct patient-reported dyspnoea in patients with moderate-to-. In this multicentre， blinded， double-dummy， three-period crossover study， 247 patients were randomised to once-daily QVA149 110/50 μg， placebo or tiotropium 18 μg. Superiority of QVA149 versus placebo (primary objective) and tiotropium (secondary objective) was assessed for improvement in dyspnoea via the self-administered computerised () version of the Baseline and Transition Dyspnoea Index after 6 weeks. Secondary end-points included lung function， rescue medication use and safety. After 6 weeks， the Transition Dyspnoea Index total score was significantly higher with QVA149 versus placebo (least squares mean (LSM) treatment difference 1.37， p<0.001) and tiotropium (LSM treatment difference 0.49， p=0.021). QVA149 provided significant improvements in lung function， with higher forced expiratory volume in 1 s area under the curve from 0-4 h post-dose versus placebo and tiotropium at day 1 and week 6 (all p<0.001). Rescue medication use was significantly lower with QVA149 versus placebo (p<0.001) and tiotropium (p=0.002). All treatments were well tolerated. Once-daily QVA149 provided superior improvements in patient-reported dyspnoea and lung function versus placebo and tiotropium. These benefits were associated with improvements in other symptoms and reduced use of rescue medication.
A Novel Study Design for the Comparison Between Once-Daily QVA149 and Twice-Daily Salmeterol/Fluticasone on the Reduction of COPD Exacerbations: The FLAME Study.
COPD QVA149 PostersSESSION TYPE： Poster PresentationsPRESENTED ON： Saturday， March 22， 2014 at 01：15 PM - 02：15 PMPURPOSE： Current COPD treatment guidelines recommend long-acting β2-agonist/inhaled corticosteroids (LABA/ICS) for severe COPD patients with a history of exacerbations. The 26-week ILLUMINATE study in moderate-to-severe COPD patients showed superiority of QVA149 versus the LABA/ICS salmeterol/fluticasone combination (SFC) in lung function. A novel study design to evaluate the effect of QVA149 versus SFC on COPD exacerbations in more severe patients with a history of exacerbations is presented.This multicenter， double-blind， active-controlled study will randomize ~3332 patients with moderate-to-very severe COPD (1：1) to once-daily QVA149 (110μg indacaterol/50μg glycopyrronium) or twice-daily SFC (50/500μg) for 52 weeks. The study will have a 1-week screening， a 4-week run-in where tiotropium rather than rescue therapy alone will be provided to all patients， a 52-week blinded treatment， and a 30-day follow-up period. Patients ≥40 years， history of ≥1 COPD exacerbations in the past 12 months requiring systemic glucocorticosteroids and/or antibiotics and post-bronchodilator forced expiratory volume in 1 second ≥25 and <60% predicted value will be included.Primary objective： to show that QVA149 is non-inferior to SFC for annual rate of all COPD exacerbations (mild/moderate/severe). Secondary outcomes： evaluating potential superiority of QVA149 versus SFC for annual rate of all exacerbations time to first COPD exacerbations， lung function， health status， safety and tolerability.This study should provide the first evidence about the long-term effect of QVA149 on reduction of COPD exacerbations when compared with LABA/ICS in patients with a history of exacerbations. In addition， the data from the study should provide more evidence on additional benefits of LABA/long-acting muscarinic antagonist (LAMA) QVA149 over LABA/ICS in terms of improvements in lung function， health status， rescue medication use and safety in patients with COPD.The results from this study should elucidate the potential place in therapy for dual bronchodilation with QVA149 versus LABA/ICS in a moderate-to-very severe COPD population with a history of exacerbations.Jadwiga Wedzicha： Consultant fee， speaker bureau， advisory committee， etc.： JW has received speaking fee and/or for advisory boards from GlaxoSmithKline， AstraZeneca， Novartis， Bayer， Boehringer Ingelheim， Nycomed. Chiesi and Respifor as well as travel reimbursements from Boehringer Ingelheim. JW has received research grants from GlaxoSmithKline， AstraZeneca， Chiesi and Novartis. Nicola Gallagher： Employee： Novartis employee Donald Banerji： Employee： Novartis employee The following authors have nothing to disclose： Jørgen VestboClinical trial results of QVA149， combination of two approved products indacaterol and glycopyrronium， will be presented， QVA is in the late stage phase 3 trials prior to approval.
Weighing up the cardiovascular benefits of thiazolidinedione therapy: the impact of increased risk of heart failure.
Type 2 diabetes and heart failure commonly occur together and this combination is associated with poor outcomes. The relationship is likely to be multifactorial and also may involve a specific， though ill-defined， diabetic cardiomyopathy. Glucose-lowering therapies may also be associated with an increased risk of heart failure. Data from recent large-scale clinical trials have drawn particular attention to the thiazolidinediones that appear to increase the risk of heart failure in patients with type 2 diabetes. Although pioglitazone therapy has been shown to decrease the risk of macrovascular events， the overall cardiovascular benefit needs to be addressed together with the apparent increase in heart failure risk. In this review， we provide appropriate context for assessing this balance from several perspectives. First， we consider the high underlying risk of heart failure already present in type 2 diabetes. Secondly， we highlight a potential distinction between genuine heart failure due to cardiac dysfunction and thiazolidinedione-associated oedema that may simply unmask previously undiagnosed cardiac dysfunction without itself having any direct impact on heart muscle. Most importantly， we emphasize the apparent lack of any long-term mortality consequences and a relative improvement in outcomes associated with thiazolidinedione-induced 'heart failure' and discuss the potential mechanisms underlying this apparent paradox. Finally， we review the current guidelines for thiazolidinedione use and heart failure and suggest potential future strategies for avoiding and/or minimizing this association.
Early application of an implantable loop recorder allows effective specific therapy in patients with recurrent suspected neurally mediated syncope.
AIMS： This prospective multicentre observational study assessed the efficacy of specific therapy based on implantable loop recorder (ILR) diagnostic observations in patients with recurrent suspected ().： Patients with three or more clinically severe syncopal episodes in the last 2 years without significant electrocardiographic and cardiac abnormalities were included. Orthostatic hypotension and were excluded. After ILR implantation， patients were followed until the first documented syncope (Phase I). The ILR documentation of this episode determined the subsequent therapy and commenced Phase II follow-up. Among 392 patients， the 1-year recurrence rate of syncope during Phase I was 33%. One hundred and three patients had a documented episode and entered Phase II： 53 patients received specific therapy [47 a pacemaker because of asystole of a median 11.5 s duration and six anti-tachyarrhythmia therapy (catheter ablation： four， implantable defibrillator： one， anti-arrhythmic drug： one)] and the remaining 50 patients did not receive specific therapy. The 1-year recurrence rate in 53 patients assigned to a specific therapy was 10% (burden 0.07 +/- 0.2 episodes per patient/year) compared with 41% (burden 0.83 +/- 1.57 episodes per patient/year) in the patients without specific therapy (80% relative risk reduction for patients， P = 0.002， and 92% for burden， P = 0.002). The 1-year recurrence rate in patients with pacemakers was 5% (burden 0.05 +/- 0.15 episodes per patient/year). Severe trauma secondary to syncope relapse occurred in 2% and mild trauma in 4% of the patients.： A strategy based on early diagnostic ILR application， with therapy delayed until documentation of syncope allows a safe， specific， and effective therapy in patients with .
Endovascular Stent-Graft Treatment of Aortic Dissection: Determinants of Post-interventional Outcome
To investigate the results of endovascular stent-graft placement for the treatment of patients with type B aortic dissection (B-AD).A total of 38 patients (62+/-10 years， 32 male) with acute (n=10) and chronic (n=28) type B-AD were treated with endovascular stent-grafts. The implantation procedure was successful in all patients. Peri-procedural non-fatal complications occurred in four (11%) patients. Overall， 4/38 (11%) patients died during the in-hospital period. Patients undergoing stent-graft placement for acute AD had a significantly higher in-hospital mortality than patients with chronic AD (40 vs. 0%， P=0.001). During a median follow-up of 18 (1-57) months， there were six additional deaths. Overall survival rates were 97.4+/-2.6% at 30 days， 80.4+/-6.7% at 1 year， 73.2+/-7.8% at 2 years， and 54.9+/-16.9% at 4 years. Patients with a poor clinical health status (ASA class > 3) had a significantly reduced life expectancy compared with patients with only moderate co-morbidities (ASA class = 3) (1-year survival rate 28.6+/-17.1 vs. 92.6+/-6.7%， P=0.0001). Multivariable analysis revealed that a poor clinical health status (ASA 3) pre-operatively (HR=29.5， 95% CI 1.5-581.9， P=0.026) and increased age (HR=1.1， 95% CI 0.9-1.2， P=0.084) were independent determinants of post-interventional mortality.Endovascular stent-graft treatment is a safe alternative for patients with AD. The pre-operative clinical health status of the patient is the most important determinant of post-interventional outcome. Careful patient selection is thus of particular importance.
Role of N-terminal brain natriuretic peptide(NTproBNP) in scleroderma-associated pulmonary arterial hypertension
The aims of this study were to evaluate the diagnostic value and to explore the prognostic value of N-terminal brain natriuretic peptide (N-TproBNP) in patients with systemic sclerosis (SSc) both with and without pulmonary arterial hypertension (PAH).N-TproBNP， six-minute walk distance (SMWD)， haemodynamics (at right heart catheterization) or tricuspid gradient (by echocardiography)， and survival were assessed in 109 patients with SSc. The study population included 68 individuals with PAH [mean pulmonary artery pressure (PAP) >25 mmHg and pulmonary capillary wedge pressure <15 mmHg] and 41 individuals without PAH. In patients with PAH， the prognostic value of baseline and change in WHO functional class， N-TproBNP levels， and SMWD were compared using Kaplan-Meier survival curves and Cox proportional hazard analysis. The mean duration of follow-up was 10 months (range 1-18 months). One year survival in patients with normal PAP was 100% when compared with 83.5% in those with SSc-PAH (P < 0.05). The patients without PAH had a mean N-TproBNP level of 139 pg/mL (SD 151); those with SSc-PAH had a significantly higher mean N-TproBNP level of 1474 pg/mL (SD 2642) (P = 0.0002). Among patients with PAH for every order of magnitude increase in N-TproBNP level there was a four-fold increased risk of death (P = 0.002 for baseline level and P = 0.006 for follow-up level). Baseline N-TproBNP levels were correlated positively with mean PAP (r = 0.62; P < 0.0001)， pulmonary vascular resistance (PVR) (r = 0.81; P < 0.0001)， and inversely with SMWD (r = -0.46; P < 0.0001). Among patients with SSc-PAH， 13 patients (19%) were in WHO functional classes II and had mean N-TproBNP levels of 325 pg/mL (SD 388). Fifty-three patients (78%) were in WHO classes III and IV and had significantly higher mean N-TproBNP levels of 1677 pg/mL (SD 2835) (P = 0.02). At an N-TproBNP level of 395 pg/mL， the sensitivity and specificity for predicting the presence of SSc-PAH were 56 and 95% respectively.Raised N-TproBNP levels are directly related to the severity of PAH. In screening programs， SSc patients with an N-TproBNP in excess of 395 pg/mL have a very high probability of having pulmonary hypertension. Baseline and serial changes in N-TproBNP levels are highly predictive of survival. A 10-fold increase in N-TproBNP level on therapy is associated with a greater than three-fold increase in mortality， and may indicate therapeutic failure.
miR149 functions as a tumor suppressor by controlling breast epithelial cell migration and invasion.
Deregulated molecular signaling pathways are responsible for the altered adhesive， migratory， and invasive properties of cancer cells. The different breast cancer subtypes are characterized by the expression of distinct miRNAs， short non-coding RNAs that posttranscriptionally modulate the expression of entire gene networks. Profiling studies have revealed downregulation of miR149 in basal breast cancer. Here， we show that miR149 expression severely impairs cell spreading， migration， and invasion of basal-like breast cancer cells. We identify signaling molecules， including the small GTPases Rap1a and Rap1b， downstream of integrin receptors as miR149 targets， providing an explanation for the defective Src and Rac activation during cell adhesion and spreading upon miR149 expression. Suppression of cell spreading by miR149 could be rescued， at least in part， by expression of constitutively active Rac. Finally， we demonstrate that increased miR149 levels block lung colonization in vivo. On the basis of our findings， we propose that miR149 downregulation in basal breast cancer facilitates the metastatic dissemination of tumor cells by supporting aberrant Rac activation. Cancer Res; 74(18); 5256-65. ©2014 AACR. ©2014 American Association for Cancer Research.
摘 要： 目的：探讨miR-149在鼻咽癌中的功能和机制。方法：Real-time PCR和2-△△Ct计算方法验证miR-149在鼻咽癌细胞系中的表达，分别应用MTT实验、划痕实验和transwell迁移实验分析miR-149对鼻咽癌细胞的增殖、迁移和侵袭功能的影响。Western印迹检测E-cadherin的变化。结果：相对于正常鼻咽上皮细胞NP69，miR-149在5-8F和6-10B鼻咽癌细胞系中表达增高。MTT实验、划痕实验和transwell实验显示miR-149能够促进鼻咽癌细胞的增殖、迁移和侵袭。Western印迹证实miR-149能够降低E-cadherin的表达;反之，抑制miR-149能抑制鼻咽癌细胞的增殖、迁移和侵袭转移能力。结论：miR-149通过调节细胞上皮-间质转变在鼻咽癌的侵袭转移中发挥重要作用。