@misc{TippkoetterUlber2012, author = {Tippk{\"o}tter, Nils and Ulber, Roland}, title = {Rezension zu: Encyclopedia of Industrial Biotechnology, Vol. 1-7. By MC Flickinger.}, series = {Chemie Ingenieur Technik}, volume = {6}, journal = {Chemie Ingenieur Technik}, number = {84}, publisher = {Wiley-VCH}, address = {Weinheim}, issn = {0009-286X}, doi = {10.1002/cite.201290052}, pages = {936}, year = {2012}, language = {en} } @misc{GraesslRenzHezeletal.2012, author = {Gr{\"a}ßl, Andreas and Renz, Wolfgang and Hezel, Fabian and Frauenrath, Tobias and Pfeiffer, Harald and Hoffmann, Werner and Kellmann, Peter and Martin, Conrad and Niendorf, Thoralf}, title = {Design, evaluation and application of a modular 32 channel transmit/receive surface coil array for cardiac MRI at 7T}, series = {2012 ISMRM Annual Meeting Proceedings}, journal = {2012 ISMRM Annual Meeting Proceedings}, issn = {1545-4428}, year = {2012}, abstract = {Cardiac MR (CMR) at ultrahigh (≥7.0 T) fields is regarded as one of the most challenging MRI applications. At 7.0 T image quality is not always exclusively defined by signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR). Detrimental effects bear the potential to spoil the signal-to-noise (SNR) and contrast-to-noise (CNR) benefits of cardiac MR (CMR) at 7.0 T. B₁⁺-inhomogeneities and signal voids represent the main challenges. Various pioneering coil concepts have been proposed to tackle these issues, enabling cardiac MRI at 7.0 T. This includes a trend towards an ever larger number of transmit and receive channels. This approach affords multi-dimensional B₁⁺ modulations to improve B₁⁺ shimming performance and to enhance RF efficiency. Also, parallel imaging benefits from a high number of receive channels enabling two-dimensional acceleration. Realizing the limitations of existing coil designs tailored for UHF CMR and recognizing the opportunities of a many element TX/RX channel architecture this work proposes a modular, two dimensional 32-channel transmit and receive array using loop elements and examines its efficacy for enhanced B¹+ homogeneity and improved parallel imaging performance.}, language = {en} } @misc{TkachenkovonKnobelsdorffBrenkenhoffKleindienstetal.2012, author = {Tkachenko, Valeriy and von Knobelsdorff-Brenkenhoff, Florian and Kleindienst, Denise and Winter, Lukas and Rieger, Jan and Frauenrath, Tobias and Dieringer, Matthias A. and Santoro, Davide and Niendorf, Thoralf and Schulz-Menger, Jeanette}, title = {Cardiovasular MR at 7Tesla: assessment of the right ventricle}, series = {2012 ISMRM Annual Meeting Proceedings}, journal = {2012 ISMRM Annual Meeting Proceedings}, issn = {1545-4428}, year = {2012}, abstract = {The assessment of the right ventricle (RV) is a challenge in today's cardiology, but of growing clinical impact regarding patient prognosis in different cardiac diseases. The detection and differentiation of small wall motion abnormalities may help to enhance the differentiation of cardiomyopathies including Arrhythmogenic Rightventricular Cardiomyopathy. Cardiovascular magnetic resonance (CMR) at 1.5T is the accepted gold standard for RV quantification. The higher spatial resolution achievable at ultrahigh field strength (UHF) offers the potential to gain new insights into the structure and function of the RV. To approach this goal accurate RV chamber quantification at 7T has to be proven. Consequently this study examines the feasibility of assessment of RV dimensions and function at 7T using improved spatial resolution enabled by the intrinsic sensitivity gain of UHF CMR. For this purpose, a dedicated 16 channel TX/RX RF coil array is used together with 2D CINE fast gradient echo (FGRE) imaging. For comparison RV chamber quantification is conducted at 1.5T using a SSFP based state of the art clinical protocol.}, language = {en} } @misc{FrauenrathFuchsHezeletal.2012, author = {Frauenrath, Tobias and Fuchs, Katharina and Hezel, Fabian and Dieringer, Matthias A. and Rieger, Jan and Niendorf, Thoralf}, title = {Improved cardiac triggering by combining multiple physiological signals: a cardiac MR feasibility study at 7.0 T}, series = {2012 ISMRM Annual Meeting Proceedings}, journal = {2012 ISMRM Annual Meeting Proceedings}, issn = {1545-4428}, year = {2012}, abstract = {In current clinical cardiovascular MR (CMR) practice cardiac motion is commonly dealt with using ECG based synchronization. However, ECG is corrupted by magneto-hydrodynamic (MHD) effects in magnetic fields. This leads to artifacts in the ECG trace and evokes severe T-wave elevations, which might be misinterpreted as R-waves resulting in erroneous triggering. At (ultra)high field strengths, the propensity of ECG recordings to MHD effects is further pronounced. Pulse oximetry (POX) being inherently sensitive to blood oxygenation provides an alternative approach for cardiac gating. However, due to the travel time of the blood the peak of maximum oxygenation and hence the trigger is delayed by approx. 300 ms with respect to the ECG's R-wave. Also the peak of maximum oxygenation shows a jitter of up to 65 ms. Alternative triggering approaches include acoustic cardiac triggering (ACT). In current clinical practice cardiac gating / triggering commonly relies on using single physiological signals only. Realizing this limitation this study proposes a combined triggering approach which exploits multiple physiological signals including ECG, POX or ACT to track cardiac activity. The feasibility of the coupled approach is examined for LV function assessment at 7.0 T. For this purpose, breath-held 2D-CINE imaging in conjunction with cardiac synchronization was performed paralleled by real time logging of physiological waveforms to track (mis)synchronization between the cardiac cycle and data acquisition. Combinations of the ECG, POX and ACT signals were evaluated and processed in real time to facilitate reliable trigger information.}, language = {en} } @misc{FrauenrathPfeifferHezeletal.2012, author = {Frauenrath, Tobias and Pfeiffer, Harald and Hezel, Fabian and Dieringer, Matthias A. and Winter, Lukas and Gr{\"a}ßl, Andreas and Santoro, Davide and {\"O}zerdem, Celal and Renz, Wolfgang and Greiser, Andreas and Niendorf, Thoralf}, title = {Lessons learned from cardiac MRI at 7.0 T: LV function assessment at 3.0 T using local multi-channel transceiver coil arrays}, series = {2012 ISMRM Annual Meeting Proceedings}, journal = {2012 ISMRM Annual Meeting Proceedings}, issn = {1545-4428}, year = {2012}, abstract = {Cardiac MR (CMR) is of proven clinical value but also an area of vigorous ongoing research since image quality is not always exclusively defined by signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR). Recent developments of CMR at 7.0 T have been driven by pioneering explorations into novel multichannel transmit and receive coil array technology to tackle the challenges B1+-field inhomogeneities, to offset specific-absorption rate (SAR) constraints and to reduce banding artifacts in SSFP imaging. For this study, recognition of the benefits and performance of local surface Tx/Rx-array structures recently established at 7.0 T inspired migration to 3.0 T, where RF inhomogeneities and SAR limitations encountered in routine clinical CMR, though somewhat reduced versus the 7.0 T situation, remain significant. For all these reasons, this study was designed to build and examine the feasibility of a local four channel Tx/Rx cardiac coil array for anatomical and functional cardiac imaging at 3.0 T. For comparison, a homebuilt 4 channel Rx cardiac coil array exhibiting the same geometry as the Tx/Rx coil and a Rx surface coil array were used.}, language = {en} } @misc{LindelGreiserWaxmanetal.2012, author = {Lindel, Tomasz Dawid and Greiser, Andreas and Waxman, Patrick and Dietterle, Martin and Seifert, Frank and Fontius, Ulrich and Renz, Wolfgang and Dieringer, Matthias A. and Frauenrath, Tobias and Schulz-Menger, Jeanette and Niendorf, Thoralf and Ittermann, Bernd}, title = {Cardiac CINE MRI at 7 T using a transmit array}, series = {2012 ISMRM Annual Meeting Proceedings}, journal = {2012 ISMRM Annual Meeting Proceedings}, issn = {1545-4428}, year = {2012}, abstract = {With its need for high SNR and short acquisition times, Cardiac MRI (CMR) is an intriguing target application for ultrahigh field MRI. Due to the sheer size of the upper torso, however, the known RF issues of 7T MRI are also most prominent in CMR. Recent years brought substantial progress but the full potential of the ultrahigh field for CMR is yet to be exploited. Parallel transmission (pTx) is a promising approach in this context and several groups have already reported B1 shimming for 7T CMR. In such a static pTx application amplitudes and phases of all Tx channels are adjusted individually but otherwise imaging techniques established in current clinical practice 1.5 T and 3 T are applied. More advanced forms of pTx as spatially selective excitation (SSE) using Transmit SENSE promise additional benefits like faster imaging with reduced fields of view or improved SAR control. SSE requires the full dynamic capabilities of pTx, however, and for the majority of today's implemented pTx hardware the internal synchronization of the Tx array does not easily permit external triggering as needed for CMR. Here we report a software solution to this problem and demonstrate the feasibility of CINE CMR at 7 T using a Tx array.}, language = {en} } @incollection{NiendorfWinterFrauenrath2012, author = {Niendorf, Thoralf and Winter, Lukas and Frauenrath, Tobias}, title = {Electrocardiogram in an MRI environment: Clinical needs, practical considerations, safety implications, technical solutions and fFuture directions}, series = {Advances in Electrocardiograms - Methods and Analysis}, booktitle = {Advances in Electrocardiograms - Methods and Analysis}, editor = {Millis, Richard}, publisher = {IntechOpen}, address = {London}, isbn = {978-953-307-923-3 (print)}, doi = {10.5772/24340}, pages = {309 -- 324}, year = {2012}, language = {en} } @article{GrandeMeffertSchoenbergeretal.2012, author = {Grande, Marion and Meffert, Elisabeth and Schoenberger, Eva and Jung, Stefanie and Frauenrath, Tobias and Huber, Walter and Hussmann, Katja and Moormann, Mareike and Heim, Stefan}, title = {From a concept to a word in a syntactically complete sentence: An fMRI study on spontaneous language production in an overt picture description task}, series = {NeuroImage}, volume = {61}, journal = {NeuroImage}, number = {3}, publisher = {Elsevier}, address = {Amsterdam}, issn = {1522-2586}, doi = {10.1016/j.neuroimage.2012.03.087}, pages = {702 -- 714}, year = {2012}, abstract = {Spontaneous language has rarely been subjected to neuroimaging studies. This study therefore introduces a newly developed method for the analysis of linguistic phenomena observed in continuous language production during fMRI. Most neuroimaging studies investigating language have so far focussed on single word or — to a smaller extent — sentence processing, mostly due to methodological considerations. Natural language production, however, is far more than the mere combination of words to larger units. Therefore, the present study aimed at relating brain activation to linguistic phenomena like word-finding difficulties or syntactic completeness in a continuous language fMRI paradigm. A picture description task with special constraints was used to provoke hesitation phenomena and speech errors. The transcribed speech sample was segmented into events of one second and each event was assigned to one category of a complex schema especially developed for this purpose. The main results were: conceptual planning engages bilateral activation of the precuneus. Successful lexical retrieval is accompanied - particularly in comparison to unsolved word-finding difficulties - by the left middle and superior temporal gyrus. Syntactic completeness is reflected in activation of the left inferior frontal gyrus (IFG) (area 44). In sum, the method has proven to be useful for investigating the neural correlates of lexical and syntactic phenomena in an overt picture description task. This opens up new prospects for the analysis of spontaneous language production during fMRI.}, language = {en} } @article{FrauenrathFuchsDieringeretal.2012, author = {Frauenrath, Tobias and Fuchs, Katharina and Dieringer, Matthias A. and {\"O}zerdem, Celal and Patel, Nishan and Renz, Wolfgang and Greiser, Andreas and Elgeti, Thomas and Niendorf, Thoralf}, title = {Detailing the use of magnetohydrodynamic effects for synchronization of MRI with the cardiac cycle: A feasibility study}, series = {Journal of Magnetic Resonance Imaging}, volume = {36}, journal = {Journal of Magnetic Resonance Imaging}, number = {2}, publisher = {Wiley-Liss}, address = {New York}, issn = {1522-2586}, doi = {10.1002/jmri.23634}, pages = {364 -- 372}, year = {2012}, abstract = {Purpose: To investigate the feasibility of using magnetohydrodynamic (MHD) effects for synchronization of magnetic resonance imaging (MRI) with the cardiac cycle. Materials and Methods: The MHD effect was scrutinized using a pulsatile flow phantom at B0 = 7.0 T. MHD effects were examined in vivo in healthy volunteers (n = 10) for B0 ranging from 0.05-7.0 T. Noncontrast-enhanced MR angiography (MRA) of the carotids was performed using a gated steady-state free-precession (SSFP) imaging technique in conjunction with electrocardiogram (ECG) and MHD synchronization. Results: The MHD potential correlates with flow velocities derived from phase contrast MRI. MHD voltages depend on the orientation between B0 and the flow of a conductive fluid. An increase in the interelectrode spacing along the flow increases the MHD potential. In vivo measurement of the MHD effect provides peak voltages of 1.5 mV for surface areas close to the common carotid artery at B0 = 7.0 T. Synchronization of MRI with the cardiac cycle using MHD triggering is feasible. MHD triggered MRA of the carotids at 3.0 T showed an overall image quality and richness of anatomic detail, which is comparable to ECG-triggered MRAs. Conclusion: This feasibility study demonstrates the use of MHD effects for synchronization of MR acquisitions with the cardiac cycle. J. Magn. Reson. Imaging 2012;36:364-372. © 2012 Wiley Periodicals, Inc.}, language = {en} } @article{HerzwurmKramsPietschetal.2012, author = {Herzwurm, Georg and Krams, Benedikt and Pietsch, Wolfram and Schockert, Sixten}, title = {Report from the 3rd international workshop on requirements prioritization for customer oriented software development (RePriCo'12)}, series = {ACM SIGSOFT Software Engineering Notes}, volume = {37}, journal = {ACM SIGSOFT Software Engineering Notes}, number = {4}, publisher = {Association for Computing Machinery}, address = {New York}, issn = {0163-5948}, doi = {10.1145/2237796.2237817}, pages = {32 -- 34}, year = {2012}, abstract = {Prioritization is an essential task within requirements engineering to cope with complexity and to establish focus properly. The 3rd Workshop on Requirements Prioritization for customer oriented Software Development (RePriCo'12) focused on requirements prioritization and adjacent themes in the context of customer oriented development of bespoke and standard software. Five submissions have been accepted for the proceedings and for presentation. The report summarizes and points out key findings.}, language = {en} } @article{CzarneckiSpiliopoulou2012, author = {Czarnecki, Christian and Spiliopoulou, Myra}, title = {A holistic framework for the implementation of a next generation network}, series = {International Journal of Business Information Systems}, volume = {9}, journal = {International Journal of Business Information Systems}, number = {4}, publisher = {Inderscience Enterprises}, address = {Olney, Bucks}, issn = {1746-0972}, doi = {10.1504/IJBIS.2012.046291}, pages = {385 -- 401}, year = {2012}, abstract = {As the potential of a next generation network (NGN) is recognised, telecommunication companies consider switching to it. Although the implementation of an NGN seems to be merely a modification of the network infrastructure, it may trigger or require changes in the whole company, because it builds upon the separation between service and transport, a flexible bundling of services to products and the streamlining of the IT infrastructure. We propose a holistic framework, structured into the layers 'strategy', 'processes' and 'information systems' and incorporate into each layer all concepts necessary for the implementation of an NGN, as well as the alignment of these concepts. As a first proof-of-concept for our framework we have performed a case study on the introduction of NGN in a large telecommunication company; we show that our framework captures all topics that are affected by an NGN implementation.}, language = {en} } @incollection{BorggrafeOhndorfDachwaldetal.2012, author = {Borggrafe, Andreas and Ohndorf, Andreas and Dachwald, Bernd and Seboldt, Wolfgang}, title = {Analysis of interplanetary solar sail trajectories with attitude dynamics}, series = {Dynamics and Control of Space Systems 2012}, booktitle = {Dynamics and Control of Space Systems 2012}, publisher = {Univelt Inc}, address = {San Diego}, isbn = {978-0-87703-587-9}, pages = {1553 -- 1569}, year = {2012}, abstract = {We present a new approach to the problem of optimal control of solar sails for low-thrust trajectory optimization. The objective was to find the required control torque magnitudes in order to steer a solar sail in interplanetary space. A new steering strategy, controlling the solar sail with generic torques applied about the spacecraft body axes, is integrated into the existing low-thrust trajectory optimization software InTrance. This software combines artificial neural networks and evolutionary algorithms to find steering strategies close to the global optimum without an initial guess. Furthermore, we implement a three rotational degree-of-freedom rigid-body attitude dynamics model to represent the solar sail in space. Two interplanetary transfers to Mars and Neptune are chosen to represent typical future solar sail mission scenarios. The results found with the new steering strategy are compared to the existing reference trajectories without attitude dynamics. The resulting control torques required to accomplish the missions are investigated, as they pose the primary requirements to a real on-board attitude control system.}, language = {en} } @article{LoebSchartnerDachwaldetal.2012, author = {Loeb, Horst Wolfgang and Schartner, Karl-Heinz and Dachwald, Bernd and Ohndorf, Andreas and Seboldt, Wolfgang}, title = {Interstellar heliopause probe}, series = {Труды МАИ}, journal = {Труды МАИ}, number = {60}, publisher = {Moskauer Staatliches Luftfahrtinstitut (МАИ)}, address = {Moskau}, pages = {2 -- 2}, year = {2012}, abstract = {There is common agreement within the scientific community that in order to understand our local galactic environment it will be necessary to send a spacecraft into the region beyond the solar wind termination shock. Considering distances of 200 AU for a new mission, one needs a spacecraft traveling at a speed of close to 10 AU/yr in order to keep the mission duration in the range of less than 25 yrs, a transfer time postulated by European Space Agency (ESA). Two propulsion options for the mission have been proposed and discussed so far: the solar sail propulsion and the ballistic/radioisotope-electric propulsion (REP). As a further alternative, we here investigate a combination of solar-electric propulsion (SEP) and REP. The SEP stage consists of six 22-cms diameter RIT-22 ion thrusters working with a high specific impulse of 7377 s corresponding to a positive grid voltage of 5 kV. Solar power of 53 kW at begin of mission (BOM) is provided by a lightweight solar array.}, language = {en} } @book{Gell2012, author = {Gell, Sebastian}, title = {Determinants of earnings forecast error, earnings forecast revision and earnings forecast accuracy}, publisher = {Springer Gabler}, address = {Wiesbaden}, isbn = {978-3-8349-3936-4}, doi = {10.1007/978-3-8349-3937-1}, pages = {XXIV, 125 Seiten}, year = {2012}, abstract = {​Earnings forecasts are ubiquitous in today's financial markets. They are essential indicators of future firm performance and a starting point for firm valuation. Extremely inaccurate and overoptimistic forecasts during the most recent financial crisis have raised serious doubts regarding the reliability of such forecasts. This thesis therefore investigates new determinants of forecast errors and accuracy. In addition, new determinants of forecast revisions are examined. More specifically, the thesis answers the following questions: 1) How do analyst incentives lead to forecast errors? 2) How do changes in analyst incentives lead to forecast revisions?, and 3) What factors drive differences in forecast accuracy?}, language = {en} } @article{MansurovDigelBiisenbaevetal.2012, author = {Mansurov, Z. and Digel, Ilya and Biisenbaev, M. and Savistkaya, I. and Kistaubaeva, A. and Akimbekov, Nuraly S. and Zhubanova, A.}, title = {Bio-composite material on the basis of carbonized rice husk in biomedicine and environmental applications}, series = {Eurasian Chemico-Technological Journal}, volume = {14}, journal = {Eurasian Chemico-Technological Journal}, number = {2}, publisher = {Institute of Combustion Problems}, address = {Almaty}, issn = {2522-4867}, doi = {10.18321/ectj105}, pages = {115 -- 131}, year = {2012}, language = {en} } @phdthesis{KurulganDemirci2012, author = {Kurulgan Demirci, Eylem}, title = {The effect of rhAPC on contractile tension : an in-vitro sepsis model of cardiomyocytes and endothelial cells}, year = {2012}, language = {en} } @phdthesis{Oflaz2012, author = {Oflaz, Hakan}, title = {Entwicklung eines Prototypen zur Prognose von Fr{\"u}hgeburten : ein biomedizintechnischer Ansatz}, publisher = {Deutsche Zentralbibliothek f{\"u}r Medizin}, address = {K{\"o}ln}, doi = {10.4126/38m-004639208}, year = {2012}, language = {en} } @article{LempiaeinenCouttetBolognanietal.2012, author = {Lempi{\"a}inen, Harri and Couttet, Philippe and Bolognani, Federico and M{\"u}ller, Arne and Dubost, Val{\´e}rie and Luisier, Rapha{\"e}lle and Rio-Espinola, Alberto del and Vitry, Veronique and Unterberger, Elif B. and Thomson, John P. and Treindl, Fridolin and Metzger, Ute and Wrzodek, Clemens and Hahne, Florian and Zollinger, Tulipan and Brasa, Sarah and Kalteis, Magdalena and Marcellin, Magali and Giudicelli, Fanny and Braeuning, Albert and Morawiec, Laurent and Zamurovic, Natasa and L{\"a}ngle, Ulrich and Scheer, Nico and Sch{\"u}beler, Dirk and Goodman, Jay and Chibout, Salah-Dine and Marlowe, Jennifer and Theil, Dietlinde and Heard, David J. and Grenet, Olivier and Zell, Andreas and Templin, Markus F. and Meehan, Richard R. and Wolf, Roland C. and Elcombe, Clifford R. and Schwarz, Michael and Moulin, Pierre and Terranova, R{\´e}mi and Moggs, Jonathan G.}, title = {Identification of Dlk1-Dio3 imprinted gene cluster non-coding RNAs as novel candidate biomarkers for liver tumor promotion}, series = {Toxicological Sciences}, volume = {131}, journal = {Toxicological Sciences}, number = {2}, publisher = {Oxford University Press}, address = {Oxford}, issn = {1094-2025}, doi = {10.1093/toxsci/kfs303}, pages = {375 -- 386}, year = {2012}, abstract = {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.}, language = {en} } @article{ScheerKapelyukhMcEwanetal.2012, author = {Scheer, Nico and Kapelyukh, Yury and McEwan, Jillian and Beuger, Vincent and Stanley, Lesley A. and Rode, Anja and Wolf, C. Roland}, title = {Modeling Human Cytochrome P450 2D6 Metabolism and Drug-drug Interaction by a Novel Panel of Knockout and Humanized Mouse Lines}, series = {Molecular Pharmacology}, volume = {81}, journal = {Molecular Pharmacology}, number = {1}, publisher = {ASPET}, address = {Bethesda, Md.}, issn = {1521-0111}, doi = {10.1124/mol.111.075192}, pages = {63 -- 72}, year = {2012}, abstract = {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.}, language = {en} } @article{ScheerKapelyukhRodeetal.2012, author = {Scheer, Nico and Kapelyukh, Yury and Rode, Anja and Buechel, Sandra and Wolf, C. Roland}, title = {Generation and characterization of novel cytochrome P450 Cyp2c gene cluster knockout and CYP2C9 humanized mouse lines}, series = {Molecular Pharmacology}, volume = {82}, journal = {Molecular Pharmacology}, number = {6}, publisher = {ASPET}, address = {Bethesda, Md.}, issn = {1521-0111}, doi = {10.1124/mol.112.080036}, pages = {1022 -- 1029}, year = {2012}, abstract = {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.}, language = {en} }