TY - JOUR A1 - Reisgen, Uwe A1 - Schleser, Markus A1 - Mokrov, Oleg A1 - Zabirov, Alexander A1 - Füssel, Uwe A1 - Schnick, Michael A1 - Hertel, Martin A1 - Jaeckel, Sebastian T1 - Modelling and visualisation of the GMA process JF - Welding and Cutting Y1 - 2012 SN - 1612-3433 VL - 11 IS - 4 SP - 242 EP - 249 PB - DVS Verlag CY - Düsseldorf ER - TY - JOUR A1 - Reisgen, Uwe A1 - Schleser, Markus A1 - Abdurakhmanov, Aydemir A1 - Turichin, Gleb A1 - Valdaitseva, Elena A1 - Bach, Friedrich-Wilhelm A1 - Hassel, Thomas A1 - Beniyashi, Alexander T1 - Investigation of factors influencing the formation of weld defects in non-vacuum electron beam welding JF - The Paton welding journal N2 - The influence of welding condition parameters and properties of material on formation of defects, such as humping and undercuts, in non-vacuum electron beam welding was investigated. The influence of separate welding parameters on the quality of welds was determined. Y1 - 2012 SN - 0957-798X VL - 2012 IS - 2 SP - 11 EP - 18 PB - Paton Publishing House CY - Kiev ER - TY - JOUR A1 - Borgmeier, Claudia A1 - Bongaerts, Johannes A1 - Meinhardt, Friedhelm T1 - Genetic analysis of the Bacillus licheniformis degSU operon and the impact of regulatory mutations on protease production JF - Journal of biotechnology N2 - Disruption experiments targeted at the Bacillus licheniformis degSU operon and GFP-reporter analysis provided evidence for promoter activity immediately upstream of degU. pMutin mediated concomitant introduction of the degU32 allele – known to cause hypersecretion in Bacillus subtilis – resulted in a marked increase in protease activity. Application of 5-fluorouracil based counterselection through establishment of a phosphoribosyltransferase deficient Δupp strain eventually facilitated the marker-free introduction of degU32 leading to further protease enhancement achieving levels as for hypersecreting wild strains in which degU was overexpressed. Surprisingly, deletion of rapG – known to interfere with DegU DNA-binding in B. subtilis – did not enhance protease production neither in the wild type nor in the degU32 strain. The combination of degU32 and Δupp counterselection in the type strain is not only equally effective as in hypersecreting wild strains with respect to protease production but furthermore facilitates genetic strain improvement aiming at biological containment and effectiveness of biotechnological processes. KW - Marker-free mutagenesis KW - Extracellular enzymes KW - Uracil-phosphoribosyltransferase KW - Hypersecretion Y1 - 2012 U6 - https://doi.org/10.1016/j.jbiotec.2012.02.011 SN - 1873-4863 (E-Journal); 0168-1656 (Print) VL - 159 IS - 1-2 SP - 12 EP - 20 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Hötter, Jan-Steffen A1 - Fateri, Miranda A1 - Gebhardt, Andreas T1 - Selective laser melting of metals: desktop machines open up new chances even for small companies JF - Advanced materials research N2 - Additive manufacturing (AM) of metal parts by using Selective Laser Melting (SLM) has become a powerful tool mostly in the area of automotive, aerospace engineering and others. Especially in the field of dentistry, jewelry and related branches that require individualized or even one-of-a-kind products, the direct digital manufacturing process opens up new ways of design and manufacturing. In these fields, mostly small and medium sized businesses (SME) are operating which do not have sufficient human and economic resources to invest in this technology. But to stay competitive, the application of AM can be regarded as a necessity. In this situation a new desktop machine (Realizer SLM 50) was introduced that cost about 1/3 of a shop floor SLM machine and promises small quality parts. To find out whether the machine really is an alternative for SMEs the University of Applied Science, Aachen, Germany, designed, build and optimized typical parts from the dentistry and the jewelry branches using CoCr and silver material, the latter being new with this application. The paper describes the SLM procedure and how to find and optimize the most important parameters. The test is accompanied by digital simulation in order to verify the build parameters and to plan future builds. The procedure is shown as well as the resulting parts made from CoCr and silver material. Y1 - 2012 U6 - https://doi.org/10.4028/www.scientific.net/AMR.622-623.461 SN - 1662-8985 (E-Journal); 1022-6680 (Print) VL - 622-623 SP - 461 EP - 465 PB - Trans Tech Publ. CY - Baech ER - TY - JOUR A1 - Boettcher, Martin A1 - Haselhuhn, Angelika A1 - Jakse, Gerhard A1 - Brehmer, Bernhard A1 - Kirschner-Hermanns, Ruth T1 - Overactive bladder syndrome: an underestimated long-term problem after treatment of patients with localized prostate cancer? JF - BJU international N2 - In this study we observed courses of micturition symptoms and differentiated degrees of symptoms for each point in time while also considering the impact of bothersomeness. Our data show that not only significantly more patients who have undergone BT suffer from OAB than those who have undergone RP, but also that those affected show significantly higher values for severity of OAB symptoms throughout the whole observation period of 36 months. Our data analysis further shows that variability of OAB symptoms as well as fluctuation of severity of OAB symptoms vary to a significantly higher degree after BT than after RP. Looking only at mean figures at a given point in time clearly underestimates the underlying problem. This fact is not reflected in the literature. KW - quality of life KW - prostate cancer KW - prostatectomy KW - incontinence KW - brachytherapy Y1 - 2012 U6 - https://doi.org/10.1111/j.1464-410X.2011.10623.x SN - 1365-2176 (E-Journal); 1464-410X (E-Journal); 0007-1331 (Print); 1464-4096 (Print) VL - 109 IS - 12 SP - 1824 EP - 1830 PB - Wiley-Blackwell CY - Oxford ER - TY - JOUR A1 - Oertel, Mario A1 - Bung, Daniel Bernhard T1 - Initial stage of two-dimensional dam-break waves: laboratory versus VOF JF - Journal of hydraulic research N2 - Since several decades, dam-break waves have been of main research interest. Mathematical approaches have been developed by analytical, physical and numerical models within the past 120 years. During the past 10 years, the number of research investigations has increased due to improved measurement techniques as well as significantly increased computer memories and performances. In this context, the present research deals with the initial stage of two-dimensional dam-break waves by comparing physical and numerical model results as well as analytical approaches. High-speed images and resulting particle image velocimetry calculations are thereby compared with the numerical volume-of-fluid (VOF) method, included in the commercial code FLOW-3D. Wave profiles and drag forces on placed obstacles are analysed in detail. Generally, a good agreement between the laboratory and VOF results is found. KW - VOF KW - PIV KW - physical model KW - numerical model KW - drag force KW - dam-break Y1 - 2012 U6 - https://doi.org/10.1080/00221686.2011.639981 SN - 1814-2079 (E-Journal); 0022-1686 (Print) VL - 50 IS - 1 SP - 89 EP - 97 PB - Taylor & Francis CY - London ER - TY - JOUR A1 - Ribitsch, D. A1 - Heumann, S. A1 - Karl, W. A1 - Gerlach, J. A1 - Leber, R. A1 - Birner-Gruenberger, R. A1 - Gruber, K. A1 - Eiteljoerg, I. A1 - Remler, P. A1 - Siegert, Petra A1 - Lange, J. A1 - Maurer, Karl-Heinz A1 - Berg, G. A1 - Guebitz, G. M. A1 - Schwab, H. T1 - Extracellular serine proteases from Stenotrophomonas maltophilia: Screening, isolation and heterologous expression in E. coli JF - Journal of biotechnology N2 - A large strain collection comprising antagonistic bacteria was screened for novel detergent proteases. Several strains displayed protease activity on agar plates containing skim milk but were inactive in liquid media. Encapsulation of cells in alginate beads induced protease production. Stenotrophomonas maltophilia emerged as best performer under washing conditions. For identification of wash-active proteases, four extracellular serine proteases called StmPr1, StmPr2, StmPr3 and StmPr4 were cloned. StmPr2 and StmPr4 were sufficiently overexpressed in E. coli. Expression of StmPr1 and StmPr3 resulted in unprocessed, insoluble protein. Truncation of most of the C-terminal domain which has been identified by enzyme modeling succeeded in expression of soluble, active StmPr1 but failed in case of StmPr3. From laundry application tests StmPr2 turned out to be a highly wash-active protease at 45 °C. Specific activity of StmPr2 determined with suc-l-Ala-l-Ala-l-Pro-l-Phe-p-nitroanilide as the substrate was 17 ± 2 U/mg. In addition we determined the kinetic parameters and cleavage preferences of protease StmPr2. KW - Alginate beads KW - Stenotrophomonas maltophilia KW - Detergent protease Y1 - 2012 U6 - https://doi.org/10.1016/j.jbiotec.2011.09.025 SN - 1873-4863 (E-Journal); 0168-1656 (Print) VL - 157 IS - 1 SP - 140 EP - 147 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Schmitz, Philipp A1 - Weber, Martin T1 - Buying and selling behavior of individual investors in option-like securities JF - Die Betriebswirtschaft : DBW N2 - We analyze the trading behavior of individual investors in option-like securities, namely bankissued warrants, and thus expand the growing literature of investors behavior to a new kind of securities. A unique data set from a large German discount broker gives us the opportunity to analyze the trading behavior of 1,454 investors, making 89,958 transactions in 6,724 warrants on 397 underlyings. In different logit regression, we make use of the facts that investors can speculate on rising and falling prices of the underlying with call and put warrants and that we also have information about the stock portfolios of the investors. We report several facts about the trading behavior of individual investors in warrants that are consistent with the literature on the behavior of individual investors in the stock market. The warrant investors buy calls and sell puts if the price of the underlying has decreased over the past trading days and they sell calls and buy puts if the price of the underlying has increased. That means, the investors follow negative feedback trading strategies in all four trading categories observed. In addition, we find strong evidence for the disposition effect for call as well as put warrants, which is reversed in December. The trading behavior is also influenced if the underlying reaches some exceptionally prices, e.g. highs, lows or the strike price. We show that hedging, as one natural candidate to buy puts, does not play an important role in the market for bank-issued warrants. KW - Bank-issued Warrants KW - Disposition Effect KW - Negative Feedback Trading KW - Trading Behavior KW - Individual Investors Y1 - 2012 U6 - https://doi.org/10.2139/ssrn.2055088 SN - 0342-7064 VL - 72 IS - 5 SP - 409 EP - 426 PB - Schäffer-Poeschel CY - Stuttgart ER - TY - JOUR A1 - Leidinger, Rafael A1 - Noisten, Thomas A1 - Wollert, Jörg T1 - Realtime automation networks in moVing industrial environments JF - Journal of systemics, cybernetics and informatics N2 - The radio-based wireless data communication has made the realization of new technical solutions possible in many fields of the automation technology (AT). For about ten years, a constant disproportionate growth of wireless technologies can be observed in the automation technology. However, it shows that especially for the AT, conventional technologies of office automation are unsuitable and/or not manageable. The employment of mobile services in the industrial automation technology has the potential of significant cost and time savings. This leads to an increased productivity in various fields of the AT, for example in the factory and process automation or in production logistics. In this paper technologies and solutions for an automation-suited supply of mobile wireless services will be introduced under the criteria of real time suitability, IT-security and service orientation. Emphasis will be put on the investigation and development of wireless convergence layers for different radio technologies, on the central provision of support services for an easy-to-use, central, backup enabled management of combined wired / wireless networks and on the study on integrability in a Profinet real-time Ethernet network. KW - PROFINET KW - Distributed Control Systems, KW - Industrial Automation Technology, KW - 802.15.4 KW - Bluetooth KW - Wireless Networks Y1 - 2012 SN - 1690-4532 VL - Vol. 10 IS - Iss. 2 SP - 52 EP - 56 PB - IIIC CY - Orlando ER - TY - JOUR A1 - Mottaghy, Darius A1 - Dijkshoorn, Lydia T1 - Implementing an effective finite difference formulation for borehole heat exchangers into a heat and mass transport code JF - Renewable Energy N2 - We present an effective finite difference formulation for implementing and modeling multiple borehole heat exchangers (BHE) in the general 3-D coupled heat and flow transport code SHEMAT. The BHE with arbitrary length can be either coaxial or double U-shaped. It is particularly suitable for modeling deep BHEs which contain varying pipe diameters and materials. Usually, in numerical simulations, a fine discretization of the BHE assemblage is required, due to the large geometric aspect ratios involved. This yields large models and long simulation times. The approach avoids this problem by considering heat transport between fluid and the soil through pipes and grout via thermal resistances. Therefore, the simulation time can be significantly reduced. The coupling with SHEMAT is realized by introducing an effective heat generation. Due to this connection, it is possible to consider heterogeneous geological models, as well as the influence of groundwater flow. This is particularly interesting when studying the long term behavior of a single BHE or a BHE field. Heating and cooling loads can enter the model with an arbitrary interval, e.g. from hourly to monthly values. When dealing with large BHE fields, computing times can be further significantly reduced by focusing on the temperature field around the BHEs, without explicitly modeling inlet and outlet temperatures. This allows to determine the possible migration of cold and warm plumes due to groundwater flow, which is of particular importance in urban areas with a high BHE installation density. The model is validated against the existing BHE modeling codes EWS and EED. A comparison with monitoring data from a deep BHE in Switzerland shows a good agreement. Synthetic examples demonstrate the field of application of this model. KW - Borehole heat exchanger KW - Finite differences KW - Heat transport Y1 - 2012 U6 - https://doi.org/10.1016/j.renene.2012.02.013 SN - 0960-1481 VL - 45 SP - 59 EP - 71 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Bragard, Michael A1 - van Hoek, H. A1 - De Doncker, R. W. T1 - A major design step in IETO concept realization that allows overcurrent protection and pushes limits of switching performance JF - IEEE transactions on power electronics N2 - This paper presents the latest prototype of the integrated emitter turn-off thyristor concept, which potentially ranks among thyristor high-power devices like the gate turn-off thyristor and the integrated gate-commutated thyristor (IGCT). Due to modifications of the external driver stage and mechanical press-pack design optimization, this prototype allows for full device characterization. The turn-off capability was increased to 1600 A with an active silicon area of 823mm2 . This leads to a transient peak power of 672.1kW/cm² . Within this paper, measurements and concept assessment are presented and a comparison to state-of-the-art IGCT devices is provided. Y1 - 2012 U6 - https://doi.org/10.1109/TPEL.2012.2189136 SN - 0885-8993 VL - 27 IS - 9 SP - 4163 EP - 4171 PB - IEEE CY - New York ER - TY - JOUR A1 - Eilmann, Britta A1 - Rigling, Andreas ED - Abrams, Marc T1 - Tree-growth analyses to estimate tree species' drought tolerance JF - Tree Physiology N2 - Climate change is challenging forestry management and practices. Among other things, tree species with the ability to cope with more extreme climate conditions have to be identified. However, while environmental factors may severely limit tree growth or even cause tree death, assessing a tree species' potential for surviving future aggravated environmental conditions is rather demanding. The aim of this study was to find a tree-ring-based method suitable for identifying very drought-tolerant species, particularly potential substitute species for Scots pine (Pinus sylvestris L.) in Valais. In this inner-Alpine valley, Scots pine used to be the dominating species for dry forests, but today it suffers from high drought-induced mortality. We investigate the growth response of two native tree species, Scots pine and European larch (Larix decidua Mill.), and two non-native species, black pine (Pinus nigra Arnold) and Douglas fir (Pseudotsuga menziesii Mirb. var. menziesii), to drought. This involved analysing how the radial increment of these species responded to increasing water shortage (abandonment of irrigation) and to increasingly frequent drought years. Black pine and Douglas fir are able to cope with drought better than Scots pine and larch, as they show relatively high radial growth even after irrigation has been stopped and a plastic growth response to drought years. European larch does not seem to be able to cope with these dry conditions as it lacks the ability to recover from drought years. The analysis of trees' short-term response to extreme climate events seems to be the most promising and suitable method for detecting how tolerant a tree species is towards drought. However, combining all the methods used in this study provides a complete picture of how water shortage could limit species. Y1 - 2012 U6 - https://doi.org/10.1093/treephys/tps004 SN - 0829-318X (Print) SN - 1758-4469 (Online) VL - 32 IS - 2 SP - 178 EP - 187 PB - Oxford University Press CY - Oxford ER - TY - JOUR A1 - Rigling, Andreas A1 - Bigler, Christof A1 - Eilmann, Britta A1 - Feldmeyer-Christe, Elisabeth A1 - Gimmi, Urs A1 - Ginzler, Christian A1 - Graf, Ulrich A1 - Mayer, Phillip A1 - Vacchiano, Giorgio A1 - Weber, Pascal A1 - Wohlgemuth, Thomas A1 - zweifel, Roman A1 - Dobbertin, Matthias T1 - Driving factors of a vegetation shift from Scots pine to pubescent oak in dry Alpine forests JF - Global Change Biology N2 - An increasing number of studies have reported on forest declines and vegetation shifts triggered by drought. In the Swiss Rhone valley (Valais), one of the driest inner-Alpine regions, the species composition in low elevation forests is changing: The sub-boreal Scots pine (Pinus sylvestris L.) dominating the dry forests is showing high mortality rates. Concurrently the sub-Mediterranean pubescent oak (Quercus pubescens Willd.) has locally increased in abundance. However, it remains unclear whether this local change in species composition is part of a larger-scale vegetation shift. To study variability in mortality and regeneration in these dry forests we analysed data from the Swiss national forest inventory (NFI) on a regular grid between 1983 and 2003, and combined it with annual mortality data from a monitoring site. Pine mortality was found to be highest at low elevation (below 1000 m a.s.l.). Annual variation in pine mortality was correlated with a drought index computed for the summer months prior to observed tree death. A generalized linear mixed-effects model indicated for the NFI data increased pine mortality on dryer sites with high stand competition, particularly for small-diameter trees. Pine regeneration was low in comparison to its occurrence in the overstorey, whereas oak regeneration was comparably abundant. Although both species regenerated well at dry sites, pine regeneration was favoured at cooler sites at higher altitude and oak regeneration was more frequent at warmer sites, indicating a higher adaptation potential of oaks under future warming. Our results thus suggest that an extended shift in species composition is actually occurring in the pine forests in the Valais. The main driving factors are found to be climatic variability, particularly drought, and variability in stand structure and topography. Thus, pine forests at low elevations are developing into oak forests with unknown consequences for these ecosystems and their goods and services. Y1 - 2012 U6 - https://doi.org/10.1111/gcb.12038 SN - 1354-1013 (Print) SN - 1365-2486 (Online) VL - 19 IS - 1 SP - 229 EP - 240 PB - Wiley-Blackwell CY - Oxford ER - TY - JOUR A1 - Henken, F. E. A1 - Oosterhuis, K. A1 - Öhlschläger, Peter A1 - Bosch, L. A1 - Hooijberg, E. A1 - Haanen, J. B. A. G. A1 - Steenbergen, R. D. M. T1 - Preclinical safety evaluation of DNA vaccines encoding modified HPV16 E6 and E7 JF - Vaccine N2 - Persistent infection with high-risk human papillomaviruses (hrHPV) can result in the formation of anogenital cancers. As hrHPV proteins E6 and E7 are required for cancer initiation and maintenance, they are ideal targets for immunotherapeutic interventions. Previously, we have described the development of DNA vaccines for the induction of HPV16 E6 and E7 specific T cell immunity. These vaccines consist of ‘gene-shuffled’ (SH) versions of HPV16 E6 and E7 that were fused to Tetanus Toxin Fragment C domain 1 (TTFC) and were named TTFC-E6SH and TTFC-E7SH. Gene-shuffling was performed to avoid the risk of inducing malignant transformation at the vaccination site. Here, we describe the preclinical safety evaluation of these candidate vaccines by analysis of their transforming capacity in vitro using established murine fibroblasts (NIH 3T3 cells) and primary human foreskin keratinocytes (HFKs). We demonstrate that neither ectopic expression of TTFC-E6SH and TTFC-E7SH alone or in combination enabled NIH 3T3 cells to form colonies in soft agar. In contrast, expression of HPV16 E6WT and E7WT alone or in combination resulted in effective transformation. Similarly, retroviral transduction of HFKs from three independent donors with both TTFC-E6SH and TTFC-E7SH alone or in combination did not show any signs of immortalization. In contrast, the combined expression of E6WT and E7WT induced immortalization in HFKs from all donors. Based on these results we consider it justified to proceed to clinical evaluation of DNA vaccines encoding TTFC-E6SH and TTFC-E7SH in patients with HPV16 associated (pre)malignancies. Y1 - 2012 U6 - https://doi.org/10.1016/j.vaccine.2012.04.013 SN - 0264-410X VL - 30 IS - 28 SP - 4259 EP - 4266 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Immel, Timo A1 - Grützke, Martin A1 - Späte, Anne-Katrin A1 - Groth, Ulrich A1 - Öhlschläger, Peter A1 - Huhn, Thomas T1 - Synthesis and X-ray structure analysis of a heptacoordinate titanium(IV)-bis-chelate with enhanced in vivo antitumor efficacy JF - Chemical Communications N2 - Chelate stabilization of a titanium(IV)–salan alkoxide by ligand exchange with 2,6-pyridinedicarboxylic acid (dipic) resulted in heptacoordinate complex 3 which is not redox-active, stable on silica gel and has increased aqueous stability. 3 is highly toxic in HeLa S3 and Hep G2 and has enhanced antitumor efficacy in a mouse cervical-cancer model. Y1 - 2012 U6 - https://doi.org/10.1039/C2CC31624B SN - 1364-548X VL - 48 IS - 46 SP - 5790 EP - 5792 PB - Royal Society of Chemistry CY - Cambridge ER - TY - JOUR A1 - Staat, Manfred T1 - Limit and shakedown analysis under uncertainty JF - Tap chi Khoa hoc & ung dung - Dai hoc Ton Duc Thang Y1 - 2012 N1 - = Journal of Applied Sciences - Ton Duc Thang University VL - 19 SP - 45 EP - 47 ER - TY - JOUR A1 - Scheer, Nico A1 - Balimane, Praveen A1 - Hayward, Michael D. A1 - Buechel, Sandra A1 - Kauselmann, Gunther A1 - Wolf, C. Roland T1 - Generation and Characterization of a Novel Multidrug Resistance Protein 2 Humanized Mouse Line JF - Drug Metabolism and Disposition N2 - The multidrug resistance protein (MRP) 2 is predominantly expressed in liver, intestine, and kidney, where it plays an important role in the excretion of a range of drugs and their metabolites or endogenous compounds into bile, feces, and urine. Mrp knockout [Mrp2(−/−)] mice have been used recently to study the role of MRP2 in drug disposition. Here, we describe the first generation and initial characterization of a mouse line humanized for MRP2 (huMRP2), which is nulled for the mouse Mrp2 gene and expresses the human transporter in the organs and cell types where MRP2 is normally expressed. Analysis of the mRNA expression for selected cytochrome P450 and transporter genes revealed no major changes in huMRP2 mice compared with wild-type controls. We show that human MRP2 is able to compensate functionally for the loss of the mouse transporter as demonstrated by comparable bilirubin levels in the humanized mice and wild-type controls, in contrast to the hyperbilirubinemia phenotype that is observed in MRP2(−/−) mice. The huMRP2 mouse provides a model to study the role of the human transporter in drug disposition and in assessing the in vivo consequences of inhibiting this transporter by compounds interacting with human MRP2. Y1 - 2012 U6 - https://doi.org/10.1124/dmd.112.047605 SN - 1521-0111 VL - 40 IS - 11 SP - 2212 EP - 2218 PB - ASPET CY - Bethesda, Md. ER - TY - JOUR A1 - Scheer, Nico A1 - Kapelyukh, Yury A1 - Rode, Anja A1 - Buechel, Sandra A1 - Wolf, C. Roland T1 - Generation and characterization of novel cytochrome P450 Cyp2c gene cluster knockout and CYP2C9 humanized mouse lines JF - Molecular Pharmacology N2 - Compared with rodents and many other animal species, the human cytochrome P450 (P450) Cyp2c gene cluster varies significantly in the multiplicity of functional genes and in the substrate specificity of its enzymes. As a consequence, the use of wild-type animal models to predict the role of human CYP2C enzymes in drug metabolism and drug-drug interactions is limited. Within the human CYP2C cluster CYP2C9 is of particular importance, because it is one of the most abundant P450 enzymes in human liver, and it is involved in the metabolism of a wide variety of important drugs and environmental chemicals. To investigate the in vivo functions of cytochrome P450 Cyp2c genes and to establish a model for studying the functions of CYP2C9 in vivo, we have generated a mouse model with a deletion of the murine Cyp2c gene cluster and a corresponding humanized model expressing CYP2C9 specifically in the liver. Despite the high number of functional genes in the mouse Cyp2c cluster and the reported roles of some of these proteins in different biological processes, mice deleted for Cyp2c genes were viable and fertile but showed certain phenotypic alterations in the liver. The expression of CYP2C9 in the liver also resulted in viable animals active in the metabolism and disposition of a number of CYP2C9 substrates. These mouse lines provide a powerful tool for studying the role of Cyp2c genes and of CYP2C9 in particular in drug disposition and as a factor in drug-drug interaction. Y1 - 2012 U6 - https://doi.org/10.1124/mol.112.080036 SN - 1521-0111 VL - 82 IS - 6 SP - 1022 EP - 1029 PB - ASPET CY - Bethesda, Md. ER - TY - JOUR A1 - Lempiäinen, Harri A1 - Couttet, Philippe A1 - Bolognani, Federico A1 - Müller, Arne A1 - Dubost, Valérie A1 - Luisier, Raphaëlle A1 - Rio-Espinola, Alberto del A1 - Vitry, Veronique A1 - Unterberger, Elif B. A1 - Thomson, John P. A1 - Treindl, Fridolin A1 - Metzger, Ute A1 - Wrzodek, Clemens A1 - Hahne, Florian A1 - Zollinger, Tulipan A1 - Brasa, Sarah A1 - Kalteis, Magdalena A1 - Marcellin, Magali A1 - Giudicelli, Fanny A1 - Braeuning, Albert A1 - Morawiec, Laurent A1 - Zamurovic, Natasa A1 - Längle, Ulrich A1 - Scheer, Nico A1 - Schübeler, Dirk A1 - Goodman, Jay A1 - Chibout, Salah-Dine A1 - Marlowe, Jennifer A1 - Theil, Dietlinde A1 - Heard, David J. A1 - Grenet, Olivier A1 - Zell, Andreas A1 - Templin, Markus F. A1 - Meehan, Richard R. A1 - Wolf, Roland C. A1 - Elcombe, Clifford R. A1 - Schwarz, Michael A1 - Moulin, Pierre A1 - Terranova, Rémi A1 - Moggs, Jonathan G. T1 - Identification of Dlk1-Dio3 imprinted gene cluster non-coding RNAs as novel candidate biomarkers for liver tumor promotion JF - Toxicological Sciences N2 - The molecular events during nongenotoxic carcinogenesis and their temporal order are poorly understood but thought to include long-lasting perturbations of gene expression. Here, we have investigated the temporal sequence of molecular and pathological perturbations at early stages of phenobarbital (PB) mediated liver tumor promotion in vivo. Molecular profiling (mRNA, microRNA [miRNA], DNA methylation, and proteins) of mouse liver during 13 weeks of PB treatment revealed progressive increases in hepatic expression of long noncoding RNAs and miRNAs originating from the Dlk1-Dio3 imprinted gene cluster, a locus that has recently been associated with stem cell pluripotency in mice and various neoplasms in humans. PB induction of the Dlk1-Dio3 cluster noncoding RNA (ncRNA) Meg3 was localized to glutamine synthetase-positive hypertrophic perivenous hepatocytes, sug- gesting a role for β-catenin signaling in the dysregulation of Dlk1-Dio3 ncRNAs. The carcinogenic relevance of Dlk1-Dio3 locus ncRNA induction was further supported by in vivo genetic dependence on constitutive androstane receptor and β-catenin pathways. Our data identify Dlk1-Dio3 ncRNAs as novel candidate early biomarkers for mouse liver tumor promotion and provide new opportunities for assessing the carcinogenic potential of novel compounds. Y1 - 2012 U6 - https://doi.org/10.1093/toxsci/kfs303 SN - 1094-2025 VL - 131 IS - 2 SP - 375 EP - 386 PB - Oxford University Press CY - Oxford ER - TY - JOUR A1 - Scheer, Nico A1 - Kapelyukh, Yury A1 - McEwan, Jillian A1 - Beuger, Vincent A1 - Stanley, Lesley A. A1 - Rode, Anja A1 - Wolf, C. Roland T1 - Modeling Human Cytochrome P450 2D6 Metabolism and Drug-drug Interaction by a Novel Panel of Knockout and Humanized Mouse Lines JF - Molecular Pharmacology N2 - The highly polymorphic human cytochrome P450 2D6 enzyme is involved in the metabolism of up to 25% of all marketed drugs and accounts for significant individual differences in response to CYP2D6 substrates. Because of the differences in the multiplicity and substrate specificity of CYP2D family members among species, it is difficult to predict pathways of human CYP2D6-dependent drug metabolism on the basis of animal studies. To create animal models that reflect the human situation more closely and that allow an in vivo assessment of the consequences of differential CYP2D6 drug metabolism, we have developed a novel straightforward approach to delete the entire murine Cyp2d gene cluster and replace it with allelic variants of human CYP2D6. By using this approach, we have generated mouse lines expressing the two frequent human protein isoforms CYP2D6.1 and CYP2D6.2 and an as yet undescribed variant of this enzyme, as well as a Cyp2d cluster knockout mouse. We demonstrate that the various transgenic mouse lines cover a wide spectrum of different human CYP2D6 metabolizer phenotypes. The novel humanization strategy described here provides a robust approach for the expression of different CYP2D6 allelic variants in transgenic mice and thus can help to evaluate potential CYP2D6-dependent interindividual differences in drug response in the context of personalized medicine. Y1 - 2012 U6 - https://doi.org/10.1124/mol.111.075192 SN - 1521-0111 VL - 81 IS - 1 SP - 63 EP - 72 PB - ASPET CY - Bethesda, Md. ER -