Scientific Publications

Peer Reviewed Articles, Conference Posters, Publications on Technology

The selexipag active metabolite ACT-333679 displays strong anti-contractile and anti- remodeling effects, but low β-arrestin recruitment and desensitization potential

The Journal of Pharmacology and Experimental Therapeutics, 2017

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John Gatfield, Katalin Menyhart, Daniel Wanner, Carmela Gnerre, Lucile Monnier, Keith Morrison, Patrick Hess, Marc Iglarz, Martine Clozel and Oliver Nayler.

Abstract

Prostacyclin (PGI2) receptor (IP receptor) agonists, which are indicated for the treatment of pulmonary arterial hypertension (PAH), increase cytosolic cAMP levels and thereby inhibit pulmonary vasoconstriction, pulmonary arterial smooth muscle cell (PASMC) proliferation and extracellular matrix synthesis. Selexipag (Uptravi®) is the first non-prostanoid IP receptor agonist, it is available orally and was recently approved for the treatment of PAH. In this study we show that the active metabolite of selexipag and the main contributor to clinical efficacy, ACT-333679 (previously known as MRE-269), behaved as full agonist in multiple PAH-relevant receptor-distal – or downstream – cellular readouts with a maximal efficacy comparable to that of the prototypic PGI2analog iloprost: In PASMC, ACT-333679 potently induced cellular relaxation (EC50=4.3 nM), inhibited cell proliferation (IC50=4.0 nM) as well as extracellular matrix synthesis (IC50=8.3 nM). In contrast, ACT-333679 displayed partial agonism in receptor-proximal – or upstream – cAMP accumulation assays (Emax=56%) when compared to iloprost (Emax=100%) and the PGI2 analogs beraprost and treprostinil. Partial agonism of ACT-333679 also resulted in limited β-arrestin recruitment (Emax=40%) and lack of sustained IP receptor internalization, whereas all tested PGI2analogs behaved as full agonists in these desensitization-related assays. In line with these in vitro findings, selexipag, but not treprostinil, displayed sustained efficacy in rat models of pulmonary and systemic hypertension. Thus, the partial agonism of ACT-333679 allows for full efficacy in amplified receptor-distal PAH-relevant readouts while causing limited activity in desensitization-related receptor-proximal readouts.

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Live Single-cell Mass Spectrometry with Spatial Quantitation by Three-Dimensional Holographic and Tomographic Laser Microscopy

Analytical Sciences as Rapid Communication, 2016

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Ali A, Abouleila Y, Amer S, Furushima R, Emara S, Equis S, Cotte Y, Masujima T

Abstract

The locations and volumes of the contents of a single HepG2 cell were visualized under three-dimensional (3D) holographic and tomographic (HT) laser microscopy, colored by refractive index, not staining. After trapping the specific area of a target cell in a nanospray tip, quantification was performed by live single-cell mass spectrometry. Comparison of the HepG2 cells’ before and after 3D-HT images allowed the inference of the precise volume and original location of the trapped cell contents. The total amount of a trapped molecule was estimated. The images also revealed morphological changes in the cell structure caused by the manipulation.

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Tomographic Holographic Microscopy for Nano-Scale Dose Calculation and Assessing Gold Nanoparticle Uptake in Live Cells

ASTRO 2016

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Grassberger C, Dinkelborg P, McNamara A, Schuemann J, McMahon S*, Willers H, Paganetti H, Wang M

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Nanomicroscopy for Live Cell tomography

The Handbook of Nanomedicine, Third Edition, 2017

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„Nanolive‘s Cell Explorer‘s technology enables determination of how light propagets through the cell [… ] Applications of this technology, which is commercially available, will enable discoveries on living cells and study of diseases as well as effects of drugs at cell level. It will be useful for recording celular uptake as well as localization of metal nanoparticles and assessments of cell exposure to nanoparticles.“

Characterising live cell behaviour: Traditional label-free and quantitative phase imaging approaches

The International Journal of Biochemistry & Cell Biology, 2017

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“2.2. Quantitative phase imaging:  Commercially-available QPI systems can be broadly classified according to the phase retrieval method utilised: (i) off-axis digital holography (PhiAB, Nanolive, Lyncee Tec, Tescan,1 Ovizio); (ii) wavefront sensing (Phasics); (iii) spatial light interference (Phi Optics); (iv) ptychography (Phasefocus).”