Project description:Cardiotoxicity remains a major cause of drug withdrawal, partially due to lacking predictability of animal models. Additionally, risk of cardiotoxicity following treatment of cancer patients is treatment limiting. It is unclear which patients will develop heart failure following therapy. Human pluripotent stem cell (hPSC)-derived cardiomyocytes present an unlimited cell source and may offer individualized solutions to this problem. We developed a platform to predict molecular and functional aspects of cardiotoxicity. Our platform can discriminate between the different cardiotoxic mechanisms of existing and novel anthracyclines Doxorubicin (DOXO), Aclarubicin (ACLA) and Amrubicin (AMR). DOXO and ACLA unlike AMR substantially affected the transcriptome, mitochondrial membrane integrity, contractile force and transcription factor availability. Cardiomyocytes recovered fully within two or three weeks, corresponding to the intermittent clinical treatment regimen. Our system permits the study of hPSC-cardiomyocyte recovery and the effects of accumulated dose after multiple dosing, allowing individualized cardiotoxicity evaluation, which effects millions of cancer patients treated with anthracyclines annually.
Project description:Purpose: To explore the effects of Wnt inhibitor Sfrp2 and to clarify the changes that in situ c-Kit(+) cells undergo in the infarcted heart we performed transcript profiling (RNA-seq)
Project description:To further investigate the role of hyaluronan and the regulation of its synthesis in cardiac hypertrophy, quantitative measurements of myocardial hyaluronan was correlated to gene transcription in hypertrophic cardiac tissue. Factor analysis was used to study correlation over time. Abdominal aorta was ligated in Wistar rats. Heart was excised 1 day, 6 days and 42 days after operation. Aorta ligated animals was compared to sham operated animals. N=6 in each time group, except aorta ligated after six days where n=5.
Project description:In atherosclerosis, macrophage accumulation is directly linked to destabilization and rupture of plaque, causing acute atherothrombotic events. Circulating monocytes enter the plaque and differentiate into macrophages, where they are activated by CD4+ T-lymphocytes through CD40-CD40 ligand signaling. Here we show that interruption of this signaling pathway in monocyte / macrophage exerts rapid anti-inflammatory effects in an Apoe-/- mouse model of atherosclerosis. For this purpose we developed an infusible recombinant high-density lipoprotein nanoparticle carrying small molecule inhibitor of the interaction of CD40s and tumor necrosis factor receptor-associated factor 6. We show monocyte / macrophage specific targeting of our nanoimmunotherapy, which impairs their migratory capacity. Rapid induction of plaque inflammation by this therapy represents a novel strategy in the treatment of atherosclerosis, with high potential for clinical translation, as illustrated by the favorable toxicity profile in non-human primates.
Project description:Purpose: To evaluate whether administration of the oral DNA hypomethylating agent (HMA) CC-486 enhances the poor response rate of immunologically ‘cold’ solid tumors to immune checkpoint inhibitor durvalumab.
Project description:Purpose: In this study, we used RNA-Seq to characterize differences in the Left ventricle expression profiles rats with 62-week old submited to gestational protein restricion (LP) compared to normal protein (NP) offspring during de gestacional. Methods: Total RNA was extracted from left heart (rats with 62-week old submited to gestational protein restricion (LP) (n=5) compared to normal protein (NP) offspring during de gestacional) (n=5) using the Trizol methods. RNA concentration was quantitated using the NanoDrop. A library was built for each sample, using the TruSeq Stranded mRNA kit (illumina) and submitted to sequencing. Results: By genomic sequencing analysis, we verified changes in the expression of 137 genes; After gene to gene biological evaluation and relevance, the present study demonstrated significant differences in genes linked to inflammatory activity, oxidative stress, apoptosis process, autophagy and, in hypertrophy and fibrosis pathways resulting heart function disorders. Conclusion: The present study suggests that maternal protein restriction may lead to early heart disorders in the LP offspring compared to the NP group. We may hypothesize that rapid heart dysfunction is associated with heart fibrosis, myocardial cell hypertrophy and multiple gene expression abnormalities in the LP offspring.
Project description:Food safety evaluation of new, genetically modified (GM) plant varieties has led to basic questions regarding the safety assessment of new plant varieties and whole foods derived thereof. An important part of the hazard identification in the European approach is a targeted compositional analysis of new GM plant varieties compared to one or more conventional reference varieties. Comparative analysis will become much more informative with unbiased analytical approaches, such as omics profiling. Analysis tools that estimate the similarity of new varieties to the reference would in turn greatly facilitate hazard identification. Further in-depth biological, functional and eventually toxicological analysis of the data would then only be necessary for varieties that fall outside the scale of those with a history of safe human consumption. For this purpose, the use of a one-class classifier tool was explored in this study to assess and classify transcriptome profiles of potato varieties. Five potato varieties were grown in the Netherlands during the same year (NL samples) and included four biological replicates for four varieties or two biological replicates for the fifth one. They were all analysed in 2011. A sixth variety was grown in the UK in a previous study and a previous year, for which the data are submitted in E-MTAB-605. The two UK samples were analysed in the original study in 2008 and again together with the NL samples in the present study, resulting in four profiles for two samples.