TY - JOUR A1 - Albanna, W. A1 - Conzen, C. A1 - Weiss, M. A1 - Clusmann, H. A1 - Fuest, M. A1 - Mueller, M. A1 - Brockmann, M.A. A1 - Vilser, W. A1 - Schmidt-Trucksäss, A. A1 - Hoellig, A. A1 - Seiz, M. A1 - Thomé, C. A1 - Kotliar, Konstantin A1 - Schubert, G.A. T1 - Retinal Vessel Analysis (RVA) in the context of subarachnoid hemorrhage: A proof of concept study JF - PLoS ONE N2 - Background Timely detection of impending delayed cerebral ischemia after subarachnoid hemorrhage (SAH) is essential to improve outcome, but poses a diagnostic challenge. Retinal vessels as an embryological part of the intracranial vasculature are easily accessible for analysis and may hold the key to a new and non-invasive monitoring technique. This investigation aims to determine the feasibility of standardized retinal vessel analysis (RVA) in the context of SAH. Methods In a prospective pilot study, we performed RVA in six patients awake and cooperative with SAH in the acute phase (day 2–14) and eight patients at the time of follow-up (mean 4.6±1.7months after SAH), and included 33 age-matched healthy controls. Data was acquired using a manoeuvrable Dynamic Vessel Analyzer (Imedos Systems UG, Jena) for examination of retinal vessel dimension and neurovascular coupling. Results Image quality was satisfactory in the majority of cases (93.3%). In the acute phase after SAH, retinal arteries were significantly dilated when compared to the control group (124.2±4.3MU vs 110.9±11.4MU, p<0.01), a difference that persisted to a lesser extent in the later stage of the disease (122.7±17.2MU, p<0.05). Testing for neurovascular coupling showed a trend towards impaired primary vasodilation and secondary vasoconstriction (p = 0.08, p = 0.09 resp.) initially and partial recovery at the time of follow-up, indicating a relative improvement in a time-dependent fashion. Conclusion RVA is technically feasible in patients with SAH and can detect fluctuations in vessel diameter and autoregulation even in less severely affected patients. Preliminary data suggests potential for RVA as a new and non-invasive tool for advanced SAH monitoring, but clinical relevance and prognostic value will have to be determined in a larger cohort. Y1 - 2016 U6 - https://doi.org/10.1371/journal.pone.0158781 SN - 1932-6203 VL - 11 IS - 7 PB - PLOS CY - San Francisco ER - TY - JOUR A1 - Rieper, Harald A1 - Gebhardt, Andreas A1 - Stucker, Brent T1 - Selective Laser Melting of the Eutectic Silver-Copper Alloy Ag 28 wt % Cu JF - RTejournal - Forum für Rapid Technologie N2 - The aim of this work was to perform a detailed investigation of the use of Selective Laser Melting (SLM) technology to process eutectic silver-copper alloy Ag 28 wt. % Cu (also called AgCu28). The processing occurred with a Realizer SLM 50 desktop machine. The powder analysis (SEM-topography, EDX, particle distribution) was reported as well as the absorption rates for the near-infrared (NIR) spectrum. Microscope imaging showed the surface topography of the manufactured parts. Furthermore, microsections were conducted for the analysis of porosity. The Design of Experiments approach used the response surface method in order to model the statistical relationship between laser power, spot distance and pulse time. KW - SLM KW - Response Surface Method KW - Porositat KW - Eutectic Silver Copper alloy KW - Additive Manufacturing Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?nbn:de:0009-2-44141 SN - 1614-0923 VL - 13 ER - TY - JOUR A1 - Pinkenburg, Olaf A1 - Schiffels, Johannes A1 - Selmer, Thorsten T1 - Das CoLibry-Konzept – ein Werkzeugkasten für die Synthetische Biologie: Bioproduktion JF - BIOspektrum N2 - Regardless of size or destination, synthetic biology starts with com-parably small information units, which need to be combined and properly arranged in order to achieve a certain goal. This may be the de novo synthesis of individual genes from oligonucleotides, a shuffling of protein domains in order to create novel biocatalysts, the assembly of multiple enzyme encoding genes in metabolic pathway design, or strain development at the production stage. The CoLibry concept has been designed in order to close the gap between recombinant production of individual genes and genome editing. Y1 - 2016 U6 - https://doi.org/10.1007/s12268-016-0734-8 VL - 22 IS - 6 SP - 593 EP - 595 PB - Springer CY - Berlin ER - TY - JOUR A1 - König, Johannes Alexander A1 - Völker, Veronika A1 - Wolf, Martin A1 - Schuba, Marko T1 - Gamified Hacking Offence Simulation-based Training (GHOST) JF - Crisis Prevention Y1 - 2016 VL - 2016 IS - 3 SP - 44 EP - 46 PB - Beta CY - Bonn ER - TY - JOUR A1 - Kern, Alexander T1 - Blitz- und Überspannungsschutz von Kernkraftwerken - Nachweisführung der ausreichenden Sicherheit für leittechnische Einrichtungen auch bei Blitzeinschlägen mit extremen Parametern JF - Atw. International Journal for Nuclear Power N2 - Für das Auftreten extremer Wetterereignisse werden für Kernkraftwerke Eintrittshäufigkeiten für nicht mehr beherrschbare Zustände von unter 10⁻⁴/a gefordert. Dies gilt auch für die Einwirkung von Blitzeinschlägen. Die bisherige Nachweisführung zu Blitz- und Überspannungsschutz eines KKW in Deutschland ist deterministisch. In diesem Bericht werden das Vorgehen für einen entsprechenden Nachweis für leittechnische Einrichtungen der Sicherheitstechnik von KKW, der zur geforderten Zielgröße der Eintrittshäufigkeit führt. Die Ergebnisse werden zusammenfassend bewertet. Y1 - 2016 SN - 1431-5254 VL - 61 IS - 8/9 SP - 534 EP - 543 PB - Inforum CY - Berlin ER - TY - JOUR A1 - Wagner, Torsten A1 - Vornholt, Wolfgang A1 - Werner, Frederik A1 - Yoshinobu, Tatsuo A1 - Miyamoto, Ko-Ichiro A1 - Keusgen, Michael A1 - Schöning, Michael Josef T1 - Light-addressable potentiometric sensor (LAPS) combined with magnetic beads for pharmaceutical screening JF - Physics in medicine N2 - The light-addressable potentiometric sensor (LAPS) has the unique feature to address different regions of a sensor surface without the need of complex structures. Measurements at different locations on the sensor surface can be performed in a common analyte solution, which distinctly simplifies the fluidic set-up. However, the measurement in a single analyte chamber prevents the application of different drugs or different concentrations of a drug to each measurement spot at the same time as in the case of multi-reservoir-based set-ups. In this work, the authors designed a LAPS-based set-up for cell culture screening that utilises magnetic beads loaded with the endotoxin (lipopolysaccharides, LPS), to generate a spatially distributed gradient of analyte concentration. Different external magnetic fields can be adjusted to move the magnetic beads loaded with a specific drug within the measurement cell. By recording the metabolic activities of a cell layer cultured on top of the LAPS surface, this work shows the possibility to apply different concentrations of a sample along the LAPS measurement spots within a common analyte solution. Y1 - 2016 U6 - https://doi.org/10.1016/j.phmed.2016.03.001 SN - 2352-4510 VL - 2016 IS - 1 SP - 2 EP - 7 ER - TY - JOUR A1 - Doll, Theodor A1 - Wagner, Torsten A1 - Wagner, Patrick A1 - Schöning, Michael Josef T1 - Engineering of functional interfaces / Theodor Doll ; Torsten Wagner ; Patrick Wagner ; Michael J. Schöning (eds.) JF - Physica status solidi (a) Y1 - 2016 U6 - https://doi.org/10.1002/pssa.201670641 SN - 1862-6319 VL - 213 IS - 6 SP - 1393 EP - 1394 PB - Wiley-VCH CY - Weinheim ER - TY - JOUR A1 - Knobe, M. A1 - Giesen, M. A1 - Plate, S. A1 - Gradl-Dietsch, G. A1 - Buecking, B. A1 - Eschbach, D. A1 - Laack, Walter van A1 - Pape, H.-C. T1 - The Aachen mobility and balance index to measure physiological falls risk: a comparison with the Tinetti POMA scale JF - European Journal Of Trauma And Emergency Surgery N2 - Purpose The most commonly used mobility assessments for screening risk of falls among older adults are rating scales such as the Tinetti performance oriented mobility assessment (POMA). However, its correlation with falls is not always predictable and disadvantages of the scale include difficulty to assess many of the items on a 3-point scale and poor specificity. The purpose of this study was to describe the ability of the new Aachen Mobility and Balance Index (AMBI) to discriminate between subjects with a fall history and subjects without such events in comparison to the Tinetti POMA Scale. Methods For this prospective cohort study, 24 participants in the study group and 10 in the control group were selected from a population of patients in our hospital who had met the stringent inclusion criteria. Both groups completed the Tinetti POMA Scale (gait and balance component) and the AMBI (tandem stance, tandem walk, ten-meter-walk-test, sit-to-stand with five repetitions, 360° turns, timed-up-and-go-test and measurement of the dominant hand grip strength). A history of falls and hospitalization in the past year were evaluated retrospectively. The relationships among the mobility tests were examined with Bland–Altmananalysis. Receiver-operated characteristics curves, sensitivity and specificity were calculated. Results The study showed a strong negative correlation between the AMBI (17 points max., highest fall risk) and Tinetti POMA Scale (28 points max., lowest fall risk; r = −0.78, p < 0.001) with an excellent discrimination between community-dwelling older people and a younger control group. However, there were no differences in any of the mobility and balance measurements between participants with and without a fall history with equal characteristics in test comparison (AMBI vs. Tinetti POMA Scale: AUC 0.570 vs. 0.598; p = 0.762). The Tinetti POMA Scale (cut-off <20 points) showed a sensitivity of 0.45 and a specificity of 0.69, the AMBI a sensitivity of 0.64 and a specificity of 0.46 (cut-off >5 points). Conclusion The AMBI comprises mobility and balance tasks with increasing difficulty as well as a measurement of the dominant hand-grip strength. Its ability to identify fallers was comparable to the Tinetti POMA Scale. However, both measurement sets showed shortcomings in discrimination between fallers and non-fallers based on a self-reported retrospective falls-status. KW - Tinetti test KW - Mobility KW - Mobility tests KW - Ground-level falls KW - Elderly KW - Fall prevention KW - Co-managed care KW - Balance Y1 - 2016 U6 - https://doi.org/10.1007/s00068-016-0693-2 SN - 1863-9941 VL - 42 IS - 5 SP - 537 EP - 545 PB - Springer CY - Berlin ER - TY - JOUR A1 - Molinnus, Denise A1 - Sorich, Maren A1 - Bartz, Alexander A1 - Siegert, Petra A1 - Willenberg, Holger S. A1 - Lisdat, Fred A1 - Poghossian, Arshak A1 - Keusgen, Michael A1 - Schöning, Michael Josef T1 - Towards an adrenaline biosensor based on substrate recycling amplification in combination with an enzyme logic gate JF - Sensors and Actuators B: Chemical N2 - An amperometric biosensor using a substrate recycling principle was realized for the detection of low adrenaline concentrations (1 nM) by measurements in phosphate buffer and Ringer’s solution at pH 6.5 and pH 7.4, respectively. In proof-of-concept experiments, a Boolean logic-gate principle has been applied to develop a digital adrenaline biosensor based on an enzyme AND logic gate. The obtained results demonstrate that the developed digital biosensor is capable for a rapid qualitative determination of the presence/absence of adrenaline in a YES/NO statement. Such digital biosensor could be used in clinical diagnostics for the control of a correct insertion of a catheter in the adrenal veins during adrenal venous-sampling procedure. Y1 - 2016 U6 - https://doi.org/10.1016/j.snb.2016.06.064 SN - 0925-4005 VL - 237 SP - 190 EP - 195 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Valero, Daniel A1 - Bung, Daniel Bernhard T1 - Development of the interfacial air layer in the non-aerated region of high-velocity spillway flows: Instabilities growth, entrapped air and influence on the self-aeration onset JF - International Journal of Multiphase Flow N2 - Self-aeration is traditionally explained by the water turbulent boundary layer outer edge intersection with the free surface. This paper presents a discussion on the commonly accepted hypothesis behind the computation of the critical point of self-aeration in spillway flows and a new formulation is proposed based on the existence of a developing air flow over the free surface. Upstream of the inception point of self-aeration, some surface roughening has been often reported in previous studies which consequently implies some entrapped air transport and air–water flows coupling. Such air flow is proven in this study by presenting measured air velocities and computing the air boundary layer thickness for a 1V:2H smooth chute flow. Additionally, the growth rate of free surface waves has been analysed by means of Ultrasonic Sensors measurements, obtaining also the entrapped air concentration. High-speed camera imaging has been used for qualitative study of the flow perturbations. Y1 - 2016 U6 - https://doi.org/10.1016/j.ijmultiphaseflow.2016.04.012 SN - 0301-9322 VL - 84 SP - 66 EP - 74 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Ghosch, S. A1 - Baier, M. A1 - Schütz, J. A1 - Schneider, Felix A1 - Scherer, Ulrich W. T1 - Analysis of electronic autoradiographs by mathematical post-processing JF - Radiation Effects and Defects in Solids: Incorporating plasma science and plasma technology N2 - Autoradiography is a well-established method of nuclear imaging. When different radionuclides are present simultaneously, additional processing is needed to distinguish distributions of radionuclides. In this work, a method is presented where aluminium absorbers of different thickness are used to produce images with different cut-off energies. By subtracting images pixel-by-pixel one can generate images representing certain ranges of β-particle energies. The method is applied to the measurement of irradiated reactor graphite samples containing several radionuclides to determine the spatial distribution of these radionuclides within pre-defined energy windows. The process was repeated under fixed parameters after thermal treatment of the samples. The greyscale images of the distribution after treatment were subtracted from the corresponding pre-treatment images. Significant changes in the intensity and distribution of radionuclides could be observed in some samples. Due to the thermal treatment parameters the most significant differences were observed in the ³H and ¹⁴C inventory and distribution. Y1 - 2016 U6 - https://doi.org/10.1080/10420150.2016.1155587 SN - 1029-4953 VL - 171 IS - 1-2 SP - 161 EP - 172 PB - Taylor & Francis CY - London ER - TY - JOUR A1 - Kolditz, Melanie A1 - Albin, Thivaharan A1 - Abel, Dirk A1 - Fasse, Alessandro A1 - Brüggemann, Gert-Peter A1 - Albracht, Kirsten T1 - Evaluation of foot position and orientation as manipulated variables to control external knee adduction moments in leg extension training JF - Computer methods and programs in biomedicine N2 - Background and Objective Effective leg extension training at a leg press requires high forces, which need to be controlled to avoid training-induced damage. In order to avoid high external knee adduction moments, which are one reason for unphysiological loadings on knee joint structures, both training movements and the whole reaction force vector need to be observed. In this study, the applicability of lateral and medial changes in foot orientation and position as possible manipulated variables to control external knee adduction moments is investigated. As secondary parameters both the medio-lateral position of the center of pressure and the frontal-plane orientation of the reaction force vector are analyzed. Methods Knee adduction moments are estimated using a dynamic model of the musculoskeletal system together with the measured reaction force vector and the motion of the subject by solving the inverse kinematic and dynamic problem. Six different foot conditions with varying positions and orientations of the foot in a static leg press are evaluated and compared to a neutral foot position. Results Both lateral and medial wedges under the foot and medial and lateral shifts of the foot can influence external knee adduction moments in the presented study with six healthy subjects. Different effects are observed with the varying conditions: the pose of the leg is changed and the direction and center of pressure of the reaction force vector is influenced. Each effect results in a different direction or center of pressure of the reaction force vector. Conclusions The results allow the conclusion that foot position and orientation can be used as manipulated variables in a control loop to actively control knee adduction moments in leg extension training. KW - External knee adduction moments KW - Manipulated variables KW - Inverse dynamic problem KW - Inverse kinematic problem KW - Musculoskeletal model Y1 - 2016 U6 - https://doi.org/10.1016/j.cmpb.2016.09.005 SN - 0169-2607 N1 - Part of special issue: "SI: Personalised Models and System Identification" VL - 171 SP - 81 EP - 86 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Belavy, Daniel L. A1 - Albracht, Kirsten A1 - Bruggemann, Gert-Peter A1 - Vergroesen, Pieter-Paul A. A1 - Dieen, Jaap H. van T1 - Can exercise positively influence the intervertebral disc? JF - Sports Medicine N2 - To better understand what kinds of sports and exercise could be beneficial for the intervertebral disc (IVD), we performed a review to synthesise the literature on IVD adaptation with loading and exercise. The state of the literature did not permit a systematic review; therefore, we performed a narrative review. The majority of the available data come from cell or whole-disc loading models and animal exercise models. However, some studies have examined the impact of specific sports on IVD degeneration in humans and acute exercise on disc size. Based on the data available in the literature, loading types that are likely beneficial to the IVD are dynamic, axial, at slow to moderate movement speeds, and of a magnitude experienced in walking and jogging. Static loading, torsional loading, flexion with compression, rapid loading, high-impact loading and explosive tasks are likely detrimental for the IVD. Reduced physical activity and disuse appear to be detrimental for the IVD. We also consider the impact of genetics and the likelihood of a ‘critical period’ for the effect of exercise in IVD development. The current review summarises the literature to increase awareness amongst exercise, rehabilitation and ergonomic professionals regarding IVD health and provides recommendations on future directions in research. KW - Intradiscal Pressure KW - Annulus Fibrosus KW - Disc Degeneration KW - Nucleus Pulposus KW - Intervertebral Disc Y1 - 2016 U6 - https://doi.org/10.1007/s40279-015-0444-2 SN - 1179-2035 VL - 46 IS - 4 SP - 473 EP - 485 PB - Springer CY - Berlin ER - TY - JOUR A1 - Ferrein, Alexander A1 - Schiffer, Stefan A1 - Booysen, T. A1 - Stopforth, R. T1 - Why it is harder to run RoboCup in South Africa: Experiences from German South African collaborations JF - International Journal of Advanced Robotic Systems N2 - Robots are widely used as a vehicle to spark interest in science and technology in learners. A number of initiatives focus on this issue, for instance, the Roberta Initiative, the FIRST Lego League, the World Robot Olympiad and RoboCup Junior. Robotic competitions are valuable not only for school learners but also for university students, as the RoboCup initiative shows. Besides technical skills, the students get some project exposure and experience what it means to finish their tasks on time. But qualifying students for future high-tech areas should not only be for students from developed countries. In this article, we present our experiences with research and education in robotics within the RoboCup initiative, in Germany and South Africa; we report on our experiences with trying to get the RoboCup initiative in South Africa going. RoboCup has a huge support base of academic institutions in Germany; this is not the case in South Africa. We present our ‘north–south’ collaboration initiatives in RoboCup between Germany and South Africa and discuss some of the reasons why we think it is harder to run RoboCup in South Africa. Y1 - 2016 U6 - https://doi.org/10.1177/1729881416662789 SN - 1729-8806 VL - 13 IS - 5 SP - 1 EP - 13 ER - TY - JOUR A1 - Miyamoto, Ko-Ichiro A1 - Sato, Takuya A1 - Abe, Minami A1 - Wagner, Torsten A1 - Schöning, Michael Josef A1 - Yoshinobu, Tatsuo T1 - Light-addressable potentiometric sensor as a sensing element in plug-based microfluidic devices JF - Micromachines N2 - A plug-based microfluidic system based on the principle of the light-addressable potentiometric sensor (LAPS) is proposed. The LAPS is a semiconductor-based chemical sensor, which has a free addressability of the measurement point on the sensing surface. By combining a microfluidic device and LAPS, ion sensing can be performed anywhere inside the microfluidic channel. In this study, the sample solution to be measured was introduced into the channel in a form of a plug with a volume in the range of microliters. Taking advantage of the light-addressability, the position of the plug could be monitored and pneumatically controlled. With the developed system, the pH value of a plug with a volume down to 400 nL could be measured. As an example of plug-based operation, two plugs were merged in the channel, and the pH change was detected by differential measurement. KW - light-addressable potentiometric sensor KW - plug-based microfluidic device KW - chemical sensor Y1 - 2016 U6 - https://doi.org/10.3390/mi7070111 SN - 2072-666X N1 - This article belongs to the Special Issue "Micro/Nano Devices for Chemical Analysis" VL - 7 IS - 7 SP - 111 PB - MDPI CY - Basel ER - TY - JOUR A1 - Lind, Thorsten Patric T1 - Zurechenbarkeit des als Mitglied des Aufsichtsrats einer Aktiengesellschaft erlangten Wissens des Prokuristen einer Bank : BGH, Urteil vom 26.04.2016 - XI ZR 108/15 (OLG München) JF - LMK : kommentierte BGH-Rechtsprechung ; in Zsarb. mit der Neuen Juristischen Wochenschrift / Lindenmaier-Möhring N2 - Mit der vorliegenden, parallel entsprechend in 10 weiteren Verfahren ergangenen Entscheidung behandelte der BGH zum wiederholten Male das Geschäftsmodell der Accessio Wertpapierhandelshaus AG („A AG“, früher: Wertpapierhandelshaus Driver & Bengsch AG). Die klagenden Anleger, zunächst nur akquiriert durch ein Tagesgeldkonto mit besonders attraktiven Zinsen, schlossen im Weiteren mit dieser einen Vermögensverwaltungsvertrag ab. Zur Abwicklung der Wertpapiergeschäfte eröffneten sie über die A AG zugleich ein Depotkonto bei der beklagten Discount-Brokerin. Für dieses erhielt die A AG eine Transaktionsvollmacht. Die Discount-Brokerin schuldete nach den Vertragsdokumenten über die gesetzlichen Aufklärungs- und Erkundigungspflichten bei Auftragsausführung hinaus keine Anlageberatung („execution-only-business“). Durch nach ihrer Behauptung fehlerhafte Anlageberatung der A AG erlitten die Anleger einen Schaden. In dem Rechtsstreit verlangten sie dessen Ersatz von der Discount-Brokerin, da die A AG zwischenzeitlich insolvent wurde. Y1 - 2016 SN - 1611-1095 SP - 380532 PB - Beck CY - München ER - TY - JOUR A1 - Chwallek, Constanze A1 - Frohn, Sandra T1 - Den Mitarbeitern den Rücken stärken JF - Personalwirtschaft N2 - Ein Drittel der Mitarbeiter der Saint-Gobain Glass Deutschland GmbH hat drei Jahre lang regelmäßig seinen Rücken trainiert. Mit Erfolg, wie eine abschließende Evaluation in Zusammenarbeit mit der FH Aachen zeigt. Die Fehltage der Trainingsteilnehmer sind enorm zurückgegangen, während die untrainierten Kollegen weiterhin unter Rückenbeschwerden leiden. Y1 - 2016 SN - 0341-4698 IS - 5 SP - 46 EP - 48 PB - F.A.Z. Business Media CY - Frankfurt a.M. ER - TY - JOUR A1 - Zhang, Jin A1 - Heimbach, Tycho A1 - Scheer, Nico A1 - Barve, Avantika A1 - Li, Wenkui A1 - Lin, Wen A1 - He, Handan T1 - Clinical Exposure Boost Predictions by Integrating Cytochrome P450 3A4–Humanized Mouse Studies With PBPK Modeling JF - Journal of Pharmaceutical Sciences N2 - NVS123 is a poorly water-soluble protease 56 inhibitor in clinical development. Data from in vitro hepatocyte studies suggested that NVS123 is mainly metabolized by CYP3A4. As a consequence of limited solubility, NVS123 therapeutic plasma exposures could not be achieved even with high doses and optimized formulations. One approach to overcome NVS123 developability issues was to increase plasma exposure by coadministrating it with an inhibitor of CYP3A4 such as ritonavir. A clinical boost effect was predicted by using physiologically based pharmacokinetic (PBPK) modeling. However, initial boost predictions lacked sufficient confidence because a key parameter, fraction of drug metabolized by CYP3A4 (ƒₘCYP3A4), could not be estimated with accuracy on account of disconnects between in vitro and in vivo preclinical data. To accurately estimate ƒₘCYP3A4 in human, an in vivo boost effect study was conducted using CYP3A4-humanized mouse model which showed a 33- to 56-fold exposure boost effect. Using a top-down approach, human ƒₘCYP3A4 for NVS123 was estimated to be very high and included in the human PBPK modeling to support subsequent clinical study design. The combined use of the in vivo boost study in CYP3A4-humanized mouse model mice along with PBPK modeling accurately predicted the clinical outcome and identified a significant NVS123 exposure boost (∼42-fold increase) with ritonavir. Y1 - 2016 U6 - https://doi.org/doi.org/10.1016/j.xphs.2016.01.021 SN - 0022-3549 VL - Volume 105 IS - Issue 4 SP - 1398 EP - 1404 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Dallas, Shannon A1 - Salphati, Laurent A1 - Gomez-Zepeda, David A1 - Wanek, Thomas A1 - Chen, Liangfu A1 - Chu, Xiaoyan A1 - Kunta, Jeevan A1 - Mezler, Mario A1 - Menet, Marie-Claude A1 - Chasseigneaux, Stephanie A1 - Declèves, Xavier A1 - Langer, Oliver A1 - Pierre, Esaie A1 - DiLoreto, Karen A1 - Hoft, Carolin A1 - Laplanche, Loic A1 - Pang, Jodie A1 - Pereira, Tony A1 - Andonian, Clara A1 - Simic, Damir A1 - Rode, Anja A1 - Yabut, Jocelyn A1 - Zhang, Xiaolin A1 - Scheer, Nico T1 - Generation and Characterization of a Breast Cancer Resistance Protein Humanized Mouse Model JF - Molecular Pharmacology N2 - Breast cancer resistance protein (BCRP) is expressed in various tissues, such as the gut, liver, kidney and blood brain barrier (BBB), where it mediates the unidirectional transport of substrates to the apical/luminal side of polarized cells. Thereby BCRP acts as an efflux pump, mediating the elimination or restricting the entry of endogenous compounds or xenobiotics into tissues and it plays important roles in drug disposition, efficacy and safety. Bcrp knockout mice (Bcrp−/−) have been used widely to study the role of this transporter in limiting intestinal absorption and brain penetration of substrate compounds. Here we describe the first generation and characterization of a mouse line humanized for BCRP (hBCRP), in which the mouse coding sequence from the start to stop codon was replaced with the corresponding human genomic region, such that the human transporter is expressed under control of the murine Bcrp promoter. We demonstrate robust human and loss of mouse BCRP/Bcrp mRNA and protein expression in the hBCRP mice and the absence of major compensatory changes in the expression of other genes involved in drug metabolism and disposition. Pharmacokinetic and brain distribution studies with several BCRP probe substrates confirmed the functional activity of the human transporter in these mice. Furthermore, we provide practical examples for the use of hBCRP mice to study drug-drug interactions (DDIs). The hBCRP mouse is a promising model to study the in vivo role of human BCRP in limiting absorption and BBB penetration of substrate compounds and to investigate clinically relevant DDIs involving BCRP. Y1 - 2016 U6 - https://doi.org/10.1124/mol.115.102079 SN - 1521-0111 VL - 89 IS - 5 SP - 492 EP - 504 PB - ASPET CY - Bethesda, Md. ER - TY - JOUR A1 - Scheer, Nico A1 - Wilson, Ian D. T1 - A comparison between genetically humanized and chimeric liver humanized mouse models for studies in drug metabolism and toxicity JF - Drug Discovery Today N2 - Mice that have been genetically humanized for proteins involved in drug metabolism and toxicity and mice engrafted with human hepatocytes are emerging and promising in vivo models for an improved prediction of the pharmacokinetic, drug–drug interaction and safety characteristics of compounds in humans. The specific advantages and disadvantages of these models should be carefully considered when using them for studies in drug discovery and development. Here, an overview on the corresponding genetically humanized and chimeric liver humanized mouse models described to date is provided and illustrated with examples of their utility in drug metabolism and toxicity studies. We compare the strength and weaknesses of the two different approaches, give guidance for the selection of the appropriate model for various applications and discuss future trends and perspectives. Y1 - 2016 U6 - https://doi.org/10.1016/j.drudis.2015.09.002 SN - 1359-6446 VL - 21 IS - 2 SP - 250 EP - 263 PB - Elsevier CY - Amsterdam ER -