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

Structural, optical, thermal, mechanical, morphological & radiation shielding parameters of Pr3+ doped ZAIFB glass systems

Authors have investigated a series of newly developed Pr3+ doped 10ZnF(2) - (5-y) Al-2 O-3-30LiF - 55B(2)O(3) - yPr(6)O(11) (y = 0-0.5 mol %) glasses synthesized through melt quench technique with an objective to analyse its optical, structural, thermal, morphological, mechanical and radiation shielding capabilities. The structural evolution was systematically investigated by density, X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FTIR) and Energy dispersive analysis (EDAX). The overlaid absorbance (H-3(4) -> D-1(2)) and emission (D-1(2) -> H-3(4)) bands of 0.05 mol% of Pr3+-doped ZAlFB glass indicated the cross-relaxation channel for energy transfer between Rare-Earth (RE) ions. The ZAlFB:Pr3+ glasses excited at 445 nm exhibited intense reddish orange emission with D-1(2) -> H-3(4) transition at 605 nm. This proves its suitability in reddish orange LEDs. Luminescence quenching was observed past 0.05 mol% of Pr3+ concentration in ZAlFB glass. The D-1(2) -> H-3(4) transition exhibited maximum branching ratio (beta(r) = 0.8601) in Pr0.5 glass. All the Pr3+ doped glasses revealed strong thermal stability with Delta T > 100 degrees C. Pr0.5 glass sample showed maximum thermal strength and mechanical hardness (Vicker's Microhardness tester). Hence, compromise over the hardness or the optical properties of the samples were studied in the ZAlFB:Pr3+ glasses. Radiation shielding properties indicated 0.5 mol% Pr3+ doped sample as a superior gamma rays shielder among the investigated ZnF2-Al2O3-LiF-B2O3-Pr6O11 glass system with favourable luminescent and radiation shielding properties, these Pr3+ doped ZAlFB glasses can be used as photonic/lasing devices in radiation zones as well