Identification of genomic biomarkers for anthracycline-induced cardiotoxicity in human iPSC-derived cardiomyocytes: an in vitro repeated exposure toxicity approach for safety assessment.

The currently available techniques for the safety evaluation of candidate drugs are usually cost-intensive and time-consuming and are often insufficient to predict human relevant cardiotoxicity. The purpose of this study was to develop an in vitro repeated exposure toxicity methodology allowing the identification of predictive genomics biomarkers of functional relevance for drug-induced cardiotoxicity in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). The hiPSC-CMs were incubated with 156 nM doxorubicin, which is a well-characterized cardiotoxicant, for 2 or 6 days followed by washout of the test compound and further incubation in compound-free culture medium until day 14 after the onset of exposure. An xCELLigence Real-Time Cell Analyser was used to monitor doxorubicin-induced cytotoxicity while also monitoring functional alterations of cardiomyocytes by counting of the beating frequency of cardiomyocytes. Unlike single exposure, repeated doxorubicin exposure resulted in long-term arrhythmic beating in hiPSC-CMs accompanied by significant cytotoxicity. Global gene expression changes were studied using microarrays and bioinformatics tools. Analysis of the transcriptomic data revealed early expression signatures of genes involved in formation of sarcomeric structures, regulation of ion homeostasis and induction of apoptosis. Eighty-four significantly deregulated genes related to cardiac functions, stress and apoptosis were validated using real-time PCR. The expression of the 84 genes was further studied by real-time PCR in hiPSC-CMs incubated with daunorubicin and mitoxantrone, further anthracycline family members that are also known to induce cardiotoxicity. A panel of 35 genes was deregulated by all three anthracycline family members and can therefore be expected to predict the cardiotoxicity of compounds acting by similar mechanisms as doxorubicin, daunorubicin or mitoxantrone. The identified gene panel can be applied in the safety assessment of novel drug candidates as well as available therapeutics to identify compounds that may cause cardiotoxicity

Magnetohydrodynamic waves in the pulsar magnetosphere

MHD waves can be responsible for plasma fluctuations and short-term variations of the pulsar emission. We consider the properties of plane and cylindrical waves that can exist in the force-free magnetosphere. Waves are considered by means of a linear analysis of the force-free MHD equations. We argue that these particular types of waves can exist in the magnetosphere of pulsars. These waves are closely related to the Alfven waves of the standard magnetohydrodynamics but are modified by the force-free condition and non-zero charge density. We derive the dispersion relation for magnetospheric waves and show that the wave periods are likely within the range \sim 10^{-2}-10^(-4} s depending on the magnetospheric parameters.Comment: 4 pages; to appear in Astronomy and Astrophysic

A Model for Emission from Jets in X-ray Binaries: Consequences of a Single Acceleration Episode

There are strong evidence for powerful jets in the low/hard state of black-hole X-ray binaries (BHXRBs). Here, we present a model in which electrons are accelerated once at the base of the jet, and are cooled by synchrotron emission and possible adiabatic energy losses. The accelerated electrons assume a Maxwellian distribution at low energies and possible energetic power law tail. These assumptions yield to a wealth of spectra, which we study in details. We identify critical values of the magnetic field, and five transition frequencies in the spectra. In particular, we show that: (I) the decay of the magnetic field along the jet enables, for wide jets, production of flat radio spectra without the need for electrons re-acceleration along the jet. (II) An increase of the magnetic field above a critical value of ~10^5 G leads to a sharp decrease in the flux at the radio band, while the flux at higher frequencies saturates to a constant value. (III) For strong magnetic field, the flux decays in the optical/UV band as F_nu ~ nu^{-1/2}, irrespective of the electrons initial distribution. (IV) For B_0 ~ 10^4 G, the X-ray flux gradually steepens. (V) With adiabatic energy losses, flat spectrum can be obtained only at a limited frequency range, and under certain conditions (VI) For narrow jets, r(x) ~ x^{alpha} with alpha < 1/2, flat radio spectrum cannot be obtained. We provide full description of the spectrum in the different scenarios, and show that our model is consistent with the key observed properties of BHXRBs.Comment: Slightly shortened; references added; accepted for publication in Ap

X-ray Emission from Transient Jet Model in Black Hole Binaries

While the non-thermal radio through at least near-infrared emission in the hard state in X-ray binaries (XRBs) is known to originate in jets, the source of the non-thermal X-ray component is still uncertain. We introduce a new model for this emission, which takes into account the transient nature of outflows, and show that it can explain the observed properties of the X-ray spectrum. Rapid radiative cooling of the electrons naturally accounts for the break often seen below around 10 keV, and for the canonical spectral slope F_\nu ~ \nu^{-1/2} observed below the break. We derive the constraints set by the data for both synchrotron- and Compton-dominated models. We show that for the synchrotron-dominated case, the jet should be launched at radii comparable to the inner radius of the disk (~few 100 r_s for the 2000 outburst of XTE J1118+480), with typical magnetic field B >~ 10^{6} G. We discuss the consequences of our results on the possible connection between the inflow and outflow in the hard state of XRBs.Comment: Extended discussion on the consequences of different acceleration mechanisms. Figure added; Accepted for publication in the Astrophysical Journa

Identification of genomic biomarkers for anthracycline-induced cardiotoxicity in human iPSC-derived cardiomyocytes: an in vitro repeated exposure toxicity approach for safety assessment

The currently available techniques for the safety evaluation of candidate drugs are usually cost-intensive and time-consuming and are often insufficient to predict human relevant cardiotoxicity. The purpose of this study was to develop an in vitro repeated exposure toxicity methodology allowing the identification of predictive genomics biomarkers of functional relevance for drug-induced cardiotoxicity in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs).JRC.F.2-Consumer Products Safet

Identification of genomic biomarkers for anthracycline-induced cardiotoxicity in human iPSC-derived cardiomyocytes: an in vitro repeated exposure toxicity approach for safety assessment

The currently available techniques for the safety evaluation of candidate drugs are usually cost-intensive and time-consuming and are often insufficient to predict human relevant cardiotoxicity. The purpose of this study was to develop an in vitro repeated exposure toxicity methodology allowing the identification of predictive genomics biomarkers of functional relevance for drug-induced cardiotoxicity in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). The hiPSC-CMs were incubated with 156 nM doxorubicin, which is a well-characterized cardiotoxicant, for 2 or 6 days followed by washout of the test compound and further incubation in compound-free culture medium until day 14 after the onset of exposure. An xCELLigence Real-Time Cell Analyser was used to monitor doxorubicin-induced cytotoxicity while also monitoring functional alterations of cardiomyocytes by counting of the beating frequency of cardiomyocytes. Unlike single exposure, repeated doxorubicin exposure resulted in long-term arrhythmic beating in hiPSC-CMs accompanied by significant cytotoxicity. Global gene expression changes were studied using microarrays and bioinformatics tools. Analysis of the transcriptomic data revealed early expression signatures of genes involved in formation of sarcomeric structures, regulation of ion homeostasis and induction of apoptosis. Eighty-four significantly deregulated genes related to cardiac functions, stress and apoptosis were validated using real-time PCR. The expression of the 84 genes was further studied by real-time PCR in hiPSC-CMs incubated with daunorubicin and mitoxantrone, further anthracycline family members that are also known to induce cardiotoxicity. A panel of 35 genes was deregulated by all three anthracycline family members and can therefore be expected to predict the cardiotoxicity of compounds acting by similar mechanisms as doxorubicin, daunorubicin or mitoxantrone. The identified gene panel can be applied in the safety assessment of novel drug candidates as well as available therapeutics to identify compounds that may cause cardiotoxicity