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Huningue, France

Reich K.,Dermatologikum Hamburg and SCIderm Research Institute | Papp K.A.,Probity Inc. | Matheson R.T.,Oregon Medical Research Center | Tu J.H.,Skin Search of Rochester | And 20 more authors.
Experimental Dermatology | Year: 2015

The response of psoriasis to antibodies targeting the interleukin (IL)-23/IL-17A pathway suggests a prominent role of T-helper type-17 (Th17) cells in this disease. We examined the clinical and immunological response patterns of 100 subjects with moderate-to-severe psoriasis receiving 3 different intravenous dosing regimens of the anti-IL-17A antibody secukinumab (1 × 3 mg/kg or 1 × 10 mg/kg on Day 1, or 3 × 10 mg/kg on Days 1, 15 and 29) or placebo in a phase 2 trial. Baseline biopsies revealed typical features of active psoriasis, including epidermal accumulation of neutrophils and formation of microabscesses in >60% of cases. Neutrophils were the numerically largest fraction of infiltrating cells containing IL-17 and may store the cytokine preformed, as IL-17A mRNA was not detectable in neutrophils isolated from active plaques. Significant clinical responses to secukinumab were observed 2 weeks after a single infusion, associated with extensive clearance of cutaneous neutrophils parallel to the normalization of keratinocyte abnormalities and reduction of IL-17-inducible neutrophil chemoattractants (e.g. CXCL1, CXCL8); effects on numbers of T cells and CD11c-positive dendritic cells were more delayed. Histological and immunological improvements were generally dose dependent and not observed in the placebo group. In the lowest-dose group, a recurrence of neutrophils was seen in some subjects at Week 12; these subjects relapsed faster than those without microabscesses. Our findings are indicative of a neutrophil-keratinocyte axis in psoriasis that may involve neutrophil-derived IL-17 and is an early target of IL-17A-directed therapies such as secukinumab. © 2015 The Authors. Experimental Dermatology Published by John Wiley & Sons Ltd.

Kadakal F.,Yedikule Chest Disease and Surgery Education and Research Hospital | Aras G.,Yedikule Chest Disease and Surgery Education and Research Hospital | Kanmaz D.,Yedikule Chest Disease and Surgery Education and Research Hospital | Uzumcu M.,Taksim Education and Research Hospital | And 2 more authors.
Journal of the Pakistan Medical Association | Year: 2013

Objectives: To see if high-sensitivity C-reactive protein levels increase even in the early stages of asthma, and to evaluate if corticosteroid therapy affects the levels in asthma patients. Methods: The case-control pilot study was conducted at Yedikule Chest Disease and Surgery Education and Research Hospital, Turkey, from February to April 2011. Patients newly diagnosed with asthma who reported symptoms that occurred six months before diagnosis were included in the study. The protein levels were measured pre-treatment and one month post-treatment. In addition, pulmonary function test and total Immunoglobulin-E measurements were taken and the prick test was performed. Statistical analysis was done using SPSS 15. Results: There were 15 cases; 8 (53%) females and 7 (47%) males. Besides, there were 19 Controls; 9 (47%) females and 10 (53%) males. The mean age of the Cases was 29.13±10.30 years, while for the Controls it was 28.9±5.35 years. The difference was not statistically significant (p<0.54). The difference in protein levels pre and post-treatment was not significant. However, a higher level in the pre-treatment period was found compared to the Controls. Post-treatment levels in the Cases were not significantly different than the Controls. Conclusion: Elevated high-sensitivity C-reactive protein levels in asthmatic patients may indicate an increased risk for cardiovascular disease. Future studies in asthma patients should focus on this relationship.

Bendjama K.,Firalis SAS | Guionaud S.,Shire Inc | Aras G.,Firalis SAS | Arber N.,Integrated Cancer Prevention Center | And 21 more authors.
Toxicologic Pathology | Year: 2014

Drug-induced vascular injury (DIVI) is a common preclinical toxicity usually characterized by hemorrhage, vascular endothelial and smooth muscle damage, and inflammation. DIVI findings can cause delays or termination of drug candidates due to low safety margins. The situation is complicated by the absence of sensitive, noninvasive biomarkers for monitoring vascular injury and the uncertain relevance to humans. The Safer And Faster Evidence-based Translation (SAFE-T) consortium is a public-private partnership funded within the European Commission's Innovative Medicines Initiative (IMI) aiming to accelerate drug development by qualifying biomarkers for drug-induced organ injuries, including DIVI. The group is using patients with vascular diseases that have key histomorphologic features (endothelial damage, smooth muscle damage, and inflammation) in common with those observed in DIVI, and has selected candidate biomarkers associated with these features. Studied populations include healthy volunteers, patients with spontaneous vasculitides and other vascular disorders. Initial results from studies with healthy volunteers and patients with vasculitides show that a panel of biomarkers can successfully discriminate the population groups. The SAFE-T group plans to seek endorsement from health authorities (European Medicines Agency and Food and Drug Administration) to qualify the biomarkers for use in regulatory decision-making processes. © 2014 by The Author(s).

Vilahur G.,Cardiovascular Research Center | Cubedo J.,Cardiovascular Research Center | Padro T.,Cardiovascular Research Center | Casani L.,Cardiovascular Research Center | And 6 more authors.
Toxicologic Pathology | Year: 2015

Drug-induced vascular injury (DIVI) is commonly associated with phosphodiesterase (PDE) inhibitors. Despite histological characterization, qualified biomarkers for DIVI detection are lacking. We investigated whether a single administration of roflumilast (PDE-IV inhibitor) induces vascular damage and identified novel surrogate biomarkers of acute vascular injury. Pigs received postoperative 250, 375, or 500g of roflumilast or placebo/control. After 1.5 hr, coronary reactivity was determined by catheter-based administration of acetylcholine and sodium nitroprusside (SNP) in the coronary sinus. Immunohistochemical analysis of vessel integrity (von Willebrand factor [vWF]) and fibrin(ogen) deposition was performed in the coronary artery and aorta. Peripheral blood was collected for differential proteomics and microparticles analysis. Circulating interleukin (IL)-6 was analyzed. Roflumilast-treated animals displayed higher vasodilation to acetylcholine and SNP versus controls (p <.05). Roflumilast-treated animals showed a dose-dependent (p <.05) decrease in vessel integrity and dose-dependent increase in fibrin deposition forming a continuous layer at roflumilast-500g. Peripheral blood of roflumilast-500-g-treated animals showed increased levels of total and endothelial-derived microparticles and exhibited a coordinated change in proteins kininogen-1, endothelin-1, gelsolin, apolipoprotein A-I, and apolipoprotein-J associated with vascular injury (p <.05 vs. controls). IL-6 remained unaltered. Roflumilast-induced vascular injury can be detected by novel markers in peripheral blood. Validation of these surrogate markers in human samples seems required. © 2014 by The Author(s).

Atar D.,University of Oslo | Arheden H.,Skane University Hospital | Berdeaux A.,University Paris Est Creteil | Bonnet J.-L.,Assistance Publique Hopitaux de Marseille | And 25 more authors.
European Heart Journal | Year: 2015

Aim The MITOCARE study evaluated the efficacy and safety of TRO40303 for the reduction of reperfusion injury in patients undergoing revascularization for ST-elevation myocardial infarction (STEMI). Methods Patients presenting with STEMI within 6 h of the onset of pain randomly received TRO40303 (n = 83) or placebo (n = 80) via i.v. Bolus injection prior to balloon inflation during primary percutaneous coronary intervention in a double-blind manner. The primary endpoint was infarct size expressed as area under the curve (AUC) for creatine kinase (CK) and for troponin I (TnI) over 3 days. Secondary endpoints included measures of infarct size using cardiac magnetic resonance (CMR) and safety outcomes. Results The median pain-to-balloon time was 180 min for both groups, and the median (mean) door-to-balloon time was 60 (38) min for all sites. Infarct size, as measured by CK and TnI AUCs at 3 days, was not significantly different between treatment groups. There were no significant differences in the CMR-assessed myocardial salvage index (1-infarct size/myocardium at risk) (mean 52 vs. 58% with placebo, P = 0.1000), mean CMR-assessed infarct size (21.9 g vs. 20.0 g, or 17 vs. 15% of LV-mass) or left ventricular ejection fraction (LVEF) (46 vs. 48%), or in the mean 30-day echocardiographic LVEF (51.5 vs. 52.2%) between TRO40303 and placebo. A greater number of adjudicated safety events occurred in the TRO40303 group for unexplained reasons. Conclusion This study in STEMI patients treated with contemporary mechanical revascularization principles did not show any effect of TRO40303 in limiting reperfusion injury of the ischaemic myocardium. © 2014 Published on behalf of the European Society of Cardiology.

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