| 1. |
- Bossart, Martin, et al.
(author)
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Effects on weight loss and glycemic control with SAR441255, a potent unimolecular peptide GLP-1/GIP/GCG receptor triagonist
- 2022
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In: Cell Metabolism. - : CELL PRESS. - 1550-4131 .- 1932-7420. ; 34:1, s. 59-
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Journal article (peer-reviewed)abstract
- Unimolecular triple incretins, combining the activity of glucagon-like peptide-1 (GLP-1), glucose -dependent insulinotropic polypeptide (GIP), and glucagon (GCG), have demonstrated reduction in body weight and improved glucose control in rodent models. We developed SAR441255, a synthetic peptide agonist of the GLP-1, GCG, and GIP receptors, structurally based on the exendin-4 sequence. SAR441255 displays high potency with balanced activation of all three target receptors. In animal models, metabolic outcomes were superior to results with a dual GLP-1/GCG receptor agonist. Preclinical in vivo positron emission tomography imaging demonstrated SAR441255 binding to GLP-1 and GCG receptors. In healthy subjects, SAR441255 improved glycemic control during a mixed-meal tolerance test and impacted biomarkers for GCG and GIP receptor activation. Single doses of SAR441255 were well tolerated. The results demonstrate that integrating GIP activity into dual GLP-1 and GCG receptor agonism provides improved effects on weight loss and glycemic control while buffering the diabetogenic risk of chronic GCG receptor agonism.
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| 2. |
- Eriksson, Olof, et al.
(author)
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Drug Occupancy Assessment at the Glucose-Dependent Insulinotropic Polypeptide Receptor by Positron Emission Tomography
- 2021
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In: Diabetes. - : AMER DIABETES ASSOC. - 0012-1797 .- 1939-327X. ; 70:4, s. 842-853
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Journal article (peer-reviewed)abstract
- Targeting of the glucose-dependent insulinotropic polypeptide receptor (GIPR) is an emerging strategy in antidiabetic drug development. The aim of this study was to develop a positron emission tomography (PET) radioligand for the GIPR to enable the assessment of target distribution and drug target engagement in vivo. The GIPR-selective peptide S02-GIP was radiolabeled with Ga-68. The resulting PET tracer [Ga-68]S02-GIP-T4 was evaluated for affinity and specificity to human GIPR (huGIPR). The in vivo GIPR binding of [Ga-68]S02-GIP-T4 as well as the occupancy of a drug candidate with GIPR activity were assessed in nonhuman primates (NHPs) by PET. [Ga-68]S02-GIP-T4 bound with nanomolar affinity and high selectivity to huGIPR in overexpressing cells. In vivo, pancreatic binding in NHPs could be dose-dependently inhibited by coinjection of unlabeled S02-GIP-T4. Finally, subcutaneous pretreatment with a high dose of a drug candidate with GIPR activity led to a decreased pancreatic binding of [Ga-68]S02-GIP-T4, corresponding to a GIPR drug occupancy of almost 90%. [Ga-68]S02-GIP-T4 demonstrated a safe dosimetric profile, allowing for repeated studies in humans. In conclusion, [Ga-68]S02-GIP-T4 is a novel PET biomarker for safe, noninvasive, and quantitative assessment of GIPR target distribution and drug occupancy.
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| 3. |
- Gualandro, Danielle M. M., et al.
(author)
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Acute heart failure after non-cardiac surgery: incidence, phenotypes, determinants and outcomes
- 2023
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In: European Journal of Heart Failure. - : WILEY. - 1388-9842 .- 1879-0844. ; 25:3, s. 347-357
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Journal article (peer-reviewed)abstract
- Aims Primary acute heart failure (AHF) is a common cause of hospitalization. AHF may also develop postoperatively (pAHF). The aim of this study was to assess the incidence, phenotypes, determinants and outcomes of pAHF following non-cardiac surgery.Methods and results A total of 9164 consecutive high-risk patients undergoing 11 262 non-cardiac inpatient surgeries were prospectively included. The incidence, phenotypes, determinants and outcome of pAHF, centrally adjudicated by independent cardiologists, were determined. The incidence of pAHF was 2.5% (95% confidence interval [CI] 2.2-2.8%); 51% of pAHF occurred in patients without known heart failure (de novo pAHF), and 49% in patients with chronic heart failure. Among patients with chronic heart failure, 10% developed pAHF, and among patients without a history of heart failure, 1.5% developed pAHF. Chronic heart failure, diabetes, urgent/emergent surgery, atrial fibrillation, cardiac troponin elevations above the 99th percentile, chronic obstructive pulmonary disease, anaemia, peripheral artery disease, coronary artery disease, and age, were independent predictors of pAHF in the logistic regression model. Patients with pAHF had significantly higher all-cause mortality (44% vs. 11%, p < 0.001) and AHF readmission (15% vs. 2%, p < 0.001) within 1 year than patients without pAHF. After Cox regression analysis, pAHF was an independent predictor of all-cause mortality (adjusted hazard ratio [aHR] 1.7 [95% CI 1.3-2.2]; p < 0.001) and AHF readmission (aHR 2.3 [95% CI 1.5-3.7]; p < 0.001). Findings were confirmed in an external validation cohort using a prospective multicentre cohort of 1250 patients (incidence of pAHF 2.4% [95% CI 1.6-3.3%]).Conclusions Postoperative AHF frequently developed following non-cardiac surgery, being de novo in half of cases, and associated with a very high mortality.
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| 4. |
- Pingen, Katrin, et al.
(author)
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High growth rate magnetron sputter epitaxy of GaN using a solid Ga target
- 2024
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In: Vacuum. - : PERGAMON-ELSEVIER SCIENCE LTD. - 0042-207X .- 1879-2715. ; 220
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Journal article (peer-reviewed)abstract
- Magnetron sputter epitaxy (MSE) is a promising processing route for group-III nitride semiconductors, with the potential to enable high-quality and low cost GaN growth for widespread use. However, fundamental techno-logical hurdles must be overcome to enable the adoption of MSE in industrial production. Here, we present a new UHV-compatible magnetron design with high-performance cooling, enabling high GaN growth rates at high growth temperatures using a solid Ga target. The magnetron is tested with a wide range of process parameters and a stable process is feasible while maintaining the solid state of the Ga target. High GaN growth rates of up to 5 mu m/h are achieved at room temperature and a growth rate of 4 mu m/h at high temperature, which is one order of magnitude higher compared to MSE with a liquid target. We grow GaN on c-plane sapphire substrates and show the impact of partial pressure ratio and target-to-substrate distance (TSD) on growth rate, film morphology and crystal quality of GaN films with scanning electron microscopy and X-ray diffraction. While the growth rate and film morphology are strongly impacted by the process parameter variation, the crystal quality is further impacted by the overall film thickness. For a 2 mu m thick GaN film a full width at half maximum of X-ray rocking curve (omega-FWHM) of GaN 10 1 1 reflection of 0.32 degrees is achieved. We demonstrate a process window for growth of dense and smooth GaN films with high crystal quality using low N2 flow rates and high TSD. By introducing a 20 nm AlN nucleation layer prior to the growth of 390 nm GaN, the omega-FWHM of GaN 0002 reflection of 0.19 degrees is achieved. The epitaxially grown crystalline structure is precisely examined by transmission electron microscopy.
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| 5. |
- Rodriguez, Sébastien, et al.
(author)
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Science goals and new mission concepts for future exploration of Titan's atmosphere, geology and habitability : titan POlar scout/orbitEr and in situ lake lander and DrONe explorer (POSEIDON)
- 2022
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In: Experimental astronomy. - : Springer Science and Business Media LLC. - 0922-6435 .- 1572-9508. ; 54:2-3, s. 911-973
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Journal article (peer-reviewed)abstract
- In response to ESA’s “Voyage 2050” announcement of opportunity, we propose an ambitious L-class mission to explore one of the most exciting bodies in the Solar System, Saturn’s largest moon Titan. Titan, a “world with two oceans”, is an organic-rich body with interior-surface-atmosphere interactions that are comparable in complexity to the Earth. Titan is also one of the few places in the Solar System with habitability potential. Titan’s remarkable nature was only partly revealed by the Cassini-Huygens mission and still holds mysteries requiring a complete exploration using a variety of vehicles and instruments. The proposed mission concept POSEIDON (Titan POlar Scout/orbitEr and In situ lake lander DrONe explorer) would perform joint orbital and in situ investigations of Titan. It is designed to build on and exceed the scope and scientific/technological accomplishments of Cassini-Huygens, exploring Titan in ways that were not previously possible, in particular through full close-up and in situ coverage over long periods of time. In the proposed mission architecture, POSEIDON consists of two major elements: a spacecraft with a large set of instruments that would orbit Titan, preferably in a low-eccentricity polar orbit, and a suite of in situ investigation components, i.e. a lake lander, a “heavy” drone (possibly amphibious) and/or a fleet of mini-drones, dedicated to the exploration of the polar regions. The ideal arrival time at Titan would be slightly before the next northern Spring equinox (2039), as equinoxes are the most active periods to monitor still largely unknown atmospheric and surface seasonal changes. The exploration of Titan’s northern latitudes with an orbiter and in situ element(s) would be highly complementary in terms of timing (with possible mission timing overlap), locations, and science goals with the upcoming NASA New Frontiers Dragonfly mission that will provide in situ exploration of Titan’s equatorial regions, in the mid-2030s.
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