Enabling planetary science across light-years. Ariel Definition Study Report

Ariel, the Atmospheric Remote-sensing Infrared Exoplanet Large-survey, was adopted as the fourth medium-class mission in ESA's Cosmic Vision programme to be launched in 2029. During its 4-year mission, Ariel will study what exoplanets are made of, how they formed and how they evolve, by surveying a diverse sample of about 1000 extrasolar planets, simultaneously in visible and infrared wavelengths. It is the first mission dedicated to measuring the chemical composition and thermal structures of hundreds of transiting exoplanets, enabling planetary science far beyond the boundaries of the Solar System. The payload consists of an off-axis Cassegrain telescope (primary mirror 1100 mm x 730 mm ellipse) and two separate instruments (FGS and AIRS) covering simultaneously 0.5-7.8 micron spectral range. The satellite is best placed into an L2 orbit to maximise the thermal stability and the field of regard. The payload module is passively cooled via a series of V-Groove radiators; the detectors for the AIRS are the only items that require active cooling via an active Ne JT cooler. The Ariel payload is developed by a consortium of more than 50 institutes from 16 ESA countries, which include the UK, France, Italy, Belgium, Poland, Spain, Austria, Denmark, Ireland, Portugal, Czech Republic, Hungary, the Netherlands, Sweden, Norway, Estonia, and a NASA contribution

A New Bistable Switch Model of Alzheimer’s Disease Pathogenesis

We propose a model to explain the pathogenesis of Alzheimer’s disease (AD) based on the theory that any disease affecting a healthy organism originates from a bistable feedback loop that shifts the system from a physiological to a pathological condition. We focused on the known double inhibitory loop involving the cellular prion protein (PrPC) and the enzyme BACE1 that produces amyloid-beta (Aβ) peptides. BACE1 is inhibited by PrPC, but its inhibitory activity is lost when PrPC binds to Aβ oligomers (Aβo). Excessive Aβo formation would switch the loop to a pathogenic condition involving the Aβo-PrPC-mGluR5 complex, Fyn kinase activation, tau, and NMDAR phosphorylation, ultimately leading to neurodegeneration. Based on the emerging role of cyclic nucleotides in Aβ production, and thereby in synaptic plasticity and cognitive processes, cAMP and cGMP can be considered as modulatory factors capable of inducing the transition from a physiological steady state to a pathogenic one. This would imply that critical pharmacological targets for AD treatment lie within pathways that lead to an imbalance of cyclic nucleotides in neurons. If this hypothesis is confirmed, it will provide precise indications for the development of preventive or therapeutic treatments for the disease

Orphan medicinal products in Europe and United States to cover needs of patients with rare diseases: an increased common effort is to be foreseen

Abstract Background In the European Union (EU) and United States (US), specific regulations have been released to provide incentives to develop and sell orphan medicinal products. We analysed the status of orphan drugs designated that not yet received a marketing authorisation or already marketed for patients affected by rare diseases in the EU and US up to December 2015. For each drug, the following data were extracted: designation date, active substance(s), orphan condition and indication, trade name, approved therapeutic indication, approved ages, genetic nature of disease and if affects children. Results In the EU, 1264 Orphan Drug Designations have been granted and 133 medicinal products were approved covering a total of 179 indications and 122 rare conditions. Among these, 79 were approved under Regulation (EC)141/2000 (65 still listed in the Orphan Medicinal Products Register and 14 lost the orphan designation but still authorised) and 23 were approved centrally by the European Agency before the Orphan Regulation entered into force. On the other hand, in the US 3082 designations and 415 orphan products, covering a total of 521 indications and 300 rare conditions, were granted. As a result, the mean of designations per year is 79 in the EU and 93.4 in the US, while the mean of approved indications per year is 8.5 in the EU and 15.8 in the US. No orphan product is marketed in the EU for bone and connective tissue, ophthalmic, poisoning/overdose, renal, urinary and reproductive rare diseases. Among the marketed medicinal products, only 46.6% in the EU and 35.2% in the US are approved for children. If all the existing market approvals were merged, 362 additional therapeutic indications in the EU and 72 in the US would be covered. Conclusions Our data show that notwithstanding the incentives issued, the number of medicines for rare diseases is still limited, and this is more evident in certain therapeutic areas. However, by merging all the existing approvals, patients would benefit of substantial advantages in both geographic areas. Efforts and cooperation between EU and US seem the only way to speed up the development and marketing of drugs for rare diseases

Clinical management of drug-induced cardiotoxicity in patients with HER-2+ breast cancer: current recommendations and future outlook

Introduction: Human epidermal growth factor receptor two (HER2) target therapies have drastically revolutionized the treatment of HER2-positive breast cancer. Starting with trastuzumab, early phase III trials have already highlighted its significant cardiotoxicity, which is also present, albeit to a lesser extent, in the new generation drugs. Also given the growing population of patients with cardiovascular diseases, it is vital to set up proper long-term follow-up to prevent morbidity related to the development of cardiotoxicity. Areas covered: This review discusses the mechanisms of action underlying the cardiotoxicity of HER2 targeted therapies and the main clinical evidence on the toxicity of these drugs. In addition, the patterns of patient assessment prior to the initiation of therapy with HER2 targeted therapies are discussed, as well as the main evidence concerning the follow-up and management of cardiotoxicity. Expert opinion: The mechanisms of cardiotoxicity of new HER2 drugs need further study and, likewise, methods to prevent, monitor and identify HER-2-induced cardiotoxicity need to be implemented. Although some studies highlight the validity of cardiac biomarkers as predictive factors for cardiotoxicity, their actual usefulness and timing is still debated. Further studies are needed to assess the effectiveness of possible pharmacological primary prevention

A phase II trial of the FGFR inhibitor pemigatinib in patients with metastatic esophageal-gastric junction/gastric cancer trastuzumab resistant: the FiGhTeR trial

Background: Prognosis of patients affected by metastatic esophageal-gastric junction (EGJ) or gastric cancer (GC) remains dismal. Trastuzumab, an anti-HER2 monoclonal antibody, is the only targeted agent approved for the first-line treatment of patients with HER2-overexpressing advanced EGJ or GC in combination with chemotherapy. However, patients invariably become resistant during this treatment. We recently identified the overexpression of fibroblast growth factor (FGF) receptor 3 (FGFR3) as a molecular mechanism responsible for trastuzumab resistance in GC models, providing the rationale for the inhibition of this receptor as a potential second-line strategy in this disease. Pemigatinib is a selective, potent, oral inhibitor of FGFR1, 2, and 3. Methods: The FiGhTeR trial is a phase II, single-arm, open-label study to assess safety and activity of the FGFR inhibitor pemigatinib as second-line treatment strategy in metastatic EGJ/GC patients progressing under trastuzumab-containing therapies. The primary endpoint is the 12-week progression-free survival rate. Plasma and tumor tissue samples will be collected for translational research analyses at baseline, during treatment, and at progression on pemigatinib. Discussion: Co-alterations in genes coding for different tyrosine-kinase receptors are emerging as relevant mechanisms of acquired resistance to anti-HER2 therapeutic strategies in GC. In particular, our group has recently identified that in GC models the overexpression of FGFR3 sustains the acquired resistance to trastuzumab. This trial aims to assess the safety, tolerability and activity of the FGFR inhibitor pemigatinib as a second-line treatment in metastatic EGJ/GC patients refractory to first-line trastuzumab-containing therapies. Furthermore, this study offers the opportunity to prospectively study mechanisms and pathways involved in trastuzumab resistance. Protocol number: CRC2017_02 EudraCT Number: 2017-004522-1

Plasma adrenomedullin and endothelin-1 concentration during low-dose dobutamine infusion: Relationship between pulmonary uptake and pulmonary vascular pressure/flow characteristics

Aim: To study the role of endothelin (ET-1) and adrenomedullin (AM) on pulmonary vascular pressure/flow characteristic (pulmonary arterial pressure/cardiac output (Pap/CO)) during low-dose dobutamine infusion. Methods: Case control study of 14 patients (12 men, 2 women) with severe lung disease (chronic obstructive pulmonary disease, COPD n=5; cystic fibrosis, CF n=9) and 5 control subjects (CTRL, 4 men, 1 woman). ET-1 and AM plasma levels in pulmonary artery (mixed venous blood, ven) and aorta or femoral artery (arterial, art), were measured at baseline and during dobutamine infusion (5-10-15 mcg kg(-1) min(-1)). The Ppa/ CO coordinates obtained at baseline and during dobutamina infusion for each patients were used to calculate the Slope and Intercept by linear regression analysis. Results: Baseline hemodynamics measurements were similar in the three groups with a trend towards a mild elevation in Ppa in CF group (Ppa min Hg: CTRL 19 +/- 3.5, COPD 19.4 +/- 5.5, CF 22.7 +/- 7.5). Baseline plasma ET-1(ET-1ven pg ml(-1): CTRL 13.9 +/- 6.7, COPD 20.1 +/- 14, CIF 20.4 +/- 7.1; ET-1art pg ml(-1): CTRL 16.7 +/- 6.4, COPD 20.1 +/- 11.7, CIF 18.1 +/- 3.9) and AM (AMven pg ml(-1): CTRL 15.8 +/- 5, COPD 31.8 +/- 17.6, CF 27.7 +/- 7.6; AMart pg ml(-1): CTRL 15.9 +/- 1.4, COPD 21.4 +/- 3.8, CIF 27 +/- 7.6) showed a trend towards higher value among patients' groups compared to the controls. Baseline ET-1 pulmonary gradient did not show significant difference among the three groups as well AM pulmonary gradient. Dobutamine infusion caused a comparable increase of heart rate and CO in the three groups. Mean pulmonary pressure had a trend towards a greater increase in COPD and CF than in controls, consequently, pulmonary Pap/CO relationship showed a steeper slope in patients' groups (Slope min Hg L-1 min(-1): CTRL 0.9 +/- 0.3, COPD 2.1 +/- 0.8 p < 0.02 vs. CTRL, CF 1.9 +/- 0.9 p < 0.03 vs CTRL). During dobutamine plasma ET-1 and AM showed a great individual variability resulting in no significant difference among groups. ET-1 pulmonary gradient showed a trend towards pulmonary uptake in patients' groups (ET-1art-ven pg min(-1): CTRL 2.7 +/- 12.9, COPD-6.1 7.8, CF 4 +/- 4.8) while AM pulmonary gradient did not show any particular pattern. During dobutamine ET-1 was significantly correlated to Pap/CO characteristics (Slope and ET-lven, r=-0.59,p < 0.05; Slope and ET-lartven, r=-0.60, p < 0.05; Intercept and ET-lart-ven, r=0.63, p < 0.004), and ET-lart-ven was the only independent variable related to Slope and Intercept. Conclusions: In patients with moderate pulmonary vascular impairment, ET-1 pulmonary gradient, but not AM pulmonary gradient, is inversely correlated with pulmonary incremental resistance, suggesting a role of ET-1 in the regulation of pulmonary vascular resistance. (c) 2006 Elsevier B.V. All rights reserved

Increased plasma levels of adrenomedullin, a vasoactive peptide, in patients with end-stage pulmonary disease

Aim: To study adrenomedullin (AM) plasma levels in patients with severe lung disease and to analyze the relationship between AM and heart changes, hemodynamics and blood gases. Methods: Case control study of 56 patients (36 men, 20 women) with severe lung disease and 9 control subjects (7 men, 2 women). Patients with end-stage pulmonary disease, including chronic obstructive pulmonary disease (COPD, n=11), cystic fibrosis (CF, 26), idiopatic pulmonary fibrosis (1LD, n=9), and idiopatic pulmonary arterial hypertension (PAH, n=10), who were evaluated for lung trasplantation between January 1997 and September 2000, and nine patients who underwent lung surgery for a solitary benign nodule. AM plasma levels in pulmonary artery (mixed venous blood, vein) and aorta or femoral artery (arterial, art), art and vein blood gases, pulmonary hemodynamics, systemic hemodynamics, two-dimensional transthoracic echocardiography and echo-Doppler study. Result: Plasma AM (art and ven) levels were higher among patients' group compared to the controls (AMartp<0.02 and AMven p<0.04) for CF, ILD, PAH (AMart, pg ml(-1) Controls 13.7 +/- 3.6, COPD 22.8 +/- 6.2, CF 28.1 +/- 11.4, ILD 34.1 +/- 14.3, PAH 35.1 +/- 18.9; AMven, pg ml(-1) Controls 14.2 +/- 4.8, COPD 28.1 +/- 12.6, CF 31.7 +/- 14. 1, ILD 38.7 +/- 16.5, PAH 40.1 +/- 4.4). We found with a trend towards higher concentration in ILD and PAH patients compared to COPD and CF but no statistical significant differences. Mixed-venous AM was higher than arterial AM in all groups resulting in AM uptake (AMPulmUp pg min(-1) Controls 4.8 +/- 22.6, COPD 21.1 +/- 44.9, CF 20.6 +/- 45.1, ILD 23.7 +/- 38.5, PAH 29.9 +/- 49.7). The univariate analysis showed a weak but significant correlation between AMart and mean systemic arterial pressure, heart rate, mean pulmonary arterial pressure and systemic vascular resistance. In the multivariate analysis, four variables emerged as independent factors of AMart including mean pulmonary arterial pressure, heart rate, mean systemic arterial pressure and left ventricular diastolic diameter (F=8.6, p<0.00001, r=0.60, r(2)=0.32). A similar weak correlation was apparent between AMven, systemic vascular resistance, and mean pulmonary arterial pressure. The results of multivariate analysis identify right atrial enlargement, mean right atrial pressure, heart rate and left ventricular dimensions as the only independent variables related to AMven (F=4.3, p<0.0004 r=0.56, r(2)=0.26). AM pulmonary uptake was significantly correlated with AMven (r=0.65), but not with hemodynamic, blood gas and echocardiographic variables. Conclusions: AM plasma levels are elevated in patients with severe lung disease in face of a preserved pulmonary uptake. These results suggest that the high AM plasma levels in patients with severe lung disease are not caused by a reduced pulmonary clearance, instead suggesting a systemic production. (C) 2004 Elsevier B.V. All rights reserved