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- ItemInhibition of cardiac CaMKII to cure heart failure: step by step towards translation?(Heidelberg : Springer, 2016) Cuello, Friederike; Lorenz, Kristina[no abstract available]
- ItemAn experimental study on the influence of trace impurities on ionization of atmospheric noble gas dielectric barrier discharges(Cambridge : Royal Society of Chemistry, 2016) Klute, F.D.; Schütz, A.; Michels, A.; Vadla, C.; Veza, D.; Horvatic, V.; Franzke, J.While the influence of trace impurities in noble gas discharges is well established in theoretical work, experimental approaches are difficult. Particularly the effects of trace concentrations of N2 on He discharges are complicated to investigate due to the fact that for He 5.0 the purity of He is only 99.999%. This corresponds to a residual concentration of 10 ppm, thereof 3 ppm of N2, in He. Matters are made difficult by the fact that He DBD plasmajets are normally operated under an ambient atmosphere, which has a high abundance of N2. This work tackles these problems from two sides. The first approach is to operate a DBD plasmajet under a quasi-controlled He atmosphere, therefore diminishing the effect of atmospheric N2 and making a defined contamination with N2 possible. The second approach is using Ar as the operating gas and introducing propane (C3H8) as a suitable substitute impurity like N2 in He. As will be shown both discharges in either He or Ar, with their respective impurity show the same qualitative behaviour.
- ItemGene network activity in cultivated primary hepatocytes is highly similar to diseased mammalian liver tissue(Heidelberg : Springer, 2016) Godoy, Patricio; Widera, Agata; Schmidt-Heck, Wolfgang; Campos, Gisela; Meyer, Christoph; Cadenas, Cristina; Reif, Raymond; Stöber, Regina; Hammad, Seddik; Pütter, Larissa; Gianmoena, Kathrin; Marchan, Rosemarie; Ghallab, Ahmed; Edlund, Karolina; Nüssler, Andreas; Thasler, Wolfgang E.; Damm, Georg; Seehofer, Daniel; Weiss, Thomas S.; Dirsch, Olaf; Dahmen, Uta; Gebhardt, Rolf; Chaudhari, Umesh; Meganathan, Kesavan; Sachinidis , Agapios; Kelm, Jens; Hofmann, Ute; Zahedi, René P.; Guthke, Reinhard; Blüthgen, Nils; Dooley, Steven; Hengstler, Jan G.It is well known that isolation and cultivation of primary hepatocytes cause major gene expression alterations. In the present genome-wide, time-resolved study of cultivated human and mouse hepatocytes, we made the observation that expression changes in culture strongly resemble alterations in liver diseases. Hepatocytes of both species were cultivated in collagen sandwich and in monolayer conditions. Genome-wide data were also obtained from human NAFLD, cirrhosis, HCC and hepatitis B virus-infected tissue as well as mouse livers after partial hepatectomy, CCl4 intoxication, obesity, HCC and LPS. A strong similarity between cultivation and disease-induced expression alterations was observed. For example, expression changes in hepatocytes induced by 1-day cultivation and 1-day CCl4 exposure in vivo correlated with R = 0.615 (p < 0.001). Interspecies comparison identified predominantly similar responses in human and mouse hepatocytes but also a set of genes that responded differently. Unsupervised clustering of altered genes identified three main clusters: (1) downregulated genes corresponding to mature liver functions, (2) upregulation of an inflammation/RNA processing cluster and (3) upregulated migration/cell cycle-associated genes. Gene regulatory network analysis highlights overrepresented and deregulated HNF4 and CAR (Cluster 1), Krüppel-like factors MafF and ELK1 (Cluster 2) as well as ETF (Cluster 3) among the interspecies conserved key regulators of expression changes. Interventions ameliorating but not abrogating cultivation-induced responses include removal of non-parenchymal cells, generation of the hepatocytes’ own matrix in spheroids, supplementation with bile salts and siRNA-mediated suppression of key transcription factors. In conclusion, this study shows that gene regulatory network alterations of cultivated hepatocytes resemble those of inflammatory liver diseases and should therefore be considered and exploited as disease models.
- ItemEukaryotic elongation factor 2 is a prognostic marker and its kinase a potential therapeutic target in HCC(Orchard Park : Impact Journals, 2017) Pott, Leona L.; Hagemann, Sascha; Reis, Henning; Lorenz, Kristina; Bracht, Thilo; Herold, Thomas; Skryabin, Boris V.; Megger, Dominik A.; Kälsch, Julia; Weber, Frank; Sitek, Barbara; Baba, Hideo A.Hepatocellular carcinoma is a cancer with increasing incidence and largely refractory to current anticancer drugs. Since Sorafenib, a multikinase inhibitor has shown modest efficacy in advanced hepatocellular carcinoma additional treatments are highly needed. Protein phosphorylation via kinases is an important post-translational modification to regulate cell homeostasis including proliferation and apoptosis. Therefore kinases are valuable targets in cancer therapy. To this end we performed 2D differential gel electrophoresis and mass spectrometry analysis of phosphoprotein-enriched lysates of tumor and corresponding non-tumorous liver samples to detect differentially abundant phosphoproteins to screen for novel kinases as potential drug targets. We identified 34 differentially abundant proteins in phosphoprotein enriched lysates. Expression and distribution of the candidate protein eEF2 and its phosphorylated isoform was validated immunohistochemically on 78 hepatocellular carcinoma and non-tumorous tissue samples. Validation showed that total eEF2 and phosphorylated eEF2 at threonine 56 are prognostic markers for overall survival of HCC-patients. The activity of the regulating eEF2 kinase, compared between tumor and non-tumorous tissue lysates by in vitro kinase assays, is more than four times higher in tumor tissues. Functional analyzes regarding eEF2 kinase were performed in JHH5 cells with CRISPR/Cas9 mediated eEF2 kinase knock out. Proliferation and growth is decreased in eEF2 kinase knock out cells.