TY - JOUR A1 - Budich, Jan Carl A1 - Trauzettel, Björn T1 - Z(2) Green's function topology of Majorana wires JF - New Journal of Physics N2 - We represent the Z2 topological invariant characterizing a one-dimensional topological superconductor using a Wess–Zumino–Witten dimensional extension. The invariant is formulated in terms of the single-particle Green’s function which allows us to classify interacting systems. Employing a recently proposed generalized Berry curvature method, the topological invariant is represented independent of the extra dimension requiring only the single-particle Green’s function at zero frequency of the interacting system. Furthermore, a modified twisted boundary conditions approach is used to rigorously define the topological invariant for disordered interacting systems. KW - Green's function Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-129751 VL - 15 IS - 065006 ER - TY - JOUR A1 - Herbert, Cornelia A1 - Sfärlea, Anca A1 - Blumenthal, Terry T1 - Your emotion or mine: labeling feelings alters emotional face perception—an ERP study on automatic and intentional affect labeling JF - Frontiers in Human Neuroscience N2 - Empirical evidence suggests that words are powerful regulators of emotion processing. Although a number of studies have used words as contextual cues for emotion processing, the role of what is being labeled by the words (i.e., one's own emotion as compared to the emotion expressed by the sender) is poorly understood. The present study reports results from two experiments which used ERP methodology to evaluate the impact of emotional faces and self- vs. sender-related emotional pronoun-noun pairs (e.g., my fear vs. his fear) as cues for emotional face processing. The influence of self- and sender-related cues on the processing of fearful, angry and happy faces was investigated in two contexts: an automatic (experiment 1) and intentional affect labeling task (experiment 2), along with control conditions of passive face processing. ERP patterns varied as a function of the label's reference (self vs. sender) and the intentionality of the labeling task (experiment 1 vs. experiment 2). In experiment 1, self-related labels increased the motivational relevance of the emotional faces in the time-window of the EPN component. Processing of sender-related labels improved emotion recognition specifically for fearful faces in the N170 time-window. Spontaneous processing of affective labels modulated later stages of face processing as well. Amplitudes of the late positive potential (LPP) were reduced for fearful, happy, and angry faces relative to the control condition of passive viewing. During intentional regulation (experiment 2) amplitudes of the LPP were enhanced for emotional faces when subjects used the self-related emotion labels to label their own emotion during face processing, and they rated the faces as higher in arousal than the emotional faces that had been presented in the “label sender's emotion” condition or the passive viewing condition. The present results argue in favor of a differentiated view of language-as-context for emotion processing. KW - emotion regulation KW - language-as-context KW - affect labeling KW - face processing KW - event-related brain potentials KW - social context KW - social cognition KW - perspective taking Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-97065 ER - TY - JOUR A1 - Schwarz, Katharina A. A1 - Wieser, Matthias J. A1 - Gerdes, Antje B. M. A1 - Mühlberger, Andreas A1 - Pauli, Paul T1 - Why are you looking like that? How the context influences evaluation and processing of human faces JF - Social Cognitive and Affective Neuroscience N2 - Perception and evaluation of facial expressions are known to be heavily modulated by emotional features of contextual information. Such contextual effects, however, might also be driven by non-emotional aspects of contextual information, an interaction of emotional and non-emotional factors, and by the observers’ inherent traits. Therefore, we sought to assess whether contextual information about self-reference in addition to information about valence influences the evaluation and neural processing of neutral faces. Furthermore, we investigated whether social anxiety moderates these effects. In the present functional magnetic resonance imaging (fMRI) study, participants viewed neutral facial expressions preceded by a contextual sentence conveying either positive or negative evaluations about the participant or about somebody else. Contextual influences were reflected in rating and fMRI measures, with strong effects of self-reference on brain activity in the medial prefrontal cortex and right fusiform gyrus. Additionally, social anxiety strongly affected the response to faces conveying negative, self-related evaluations as revealed by the participants’ rating patterns and brain activity in cortical midline structures and regions of interest in the left and right middle frontal gyrus. These results suggest that face perception and processing are highly individual processes influenced by emotional and non-emotional aspects of contextual information and further modulated by individual personality traits. KW - social anxiety KW - facial expression KW - context KW - self-reference Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-132126 VL - 8 IS - 4 ER - TY - JOUR A1 - Gageik, Nils A1 - Strohmeier, Michael A1 - Montenegro, Sergio T1 - Waypoint flight parameter comparison of an autonomous UAV JF - International Journal of Artificial Intelligence & Applications (IJAIA) N2 - The present paper compares the effect of different waypoint parameters on the flight performance of a special autonomous indoor UAV (unmanned aerial vehicle) fusing ultrasonic, inertial, pressure and optical sensors for 3D positioning and controlling. The investigated parameters are the acceptance threshold for reaching a waypoint as well as the maximal waypoint step size or block size. The effect of these parameters on the flight time and accuracy of the flight path is investigated. Therefore the paper addresses how the acceptance threshold and step size influence the speed and accuracy of the autonomous flight and thus influence the performance of the presented autonomous quadrocopter under real indoor navigation circumstances. Furthermore the paper demonstrates a drawback of the standard potential field method for navigation of such autonomous quadrocopters and points to an improvement. KW - autonomous UAV KW - Quadrocopter KW - Quadrotor KW - waypoint parameter KW - navigation Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-96833 ER - TY - JOUR A1 - Camago-Molina, J.E. A1 - O'Leary, B. A1 - Porod, W. A1 - Staub, F. T1 - Vevacious: a tool for finding the global minima of one-loop effective potentials with many scalars JF - European Physical Journal C N2 - Several extensions of the Standard Model of particle physics contain additional scalars implying a more complex scalar potential compared to that of the Standard Model. In general these potentials allow for charge- and/or color-breaking minima besides the desired one with correctly broken SU(2) L ×U(1) Y . Even if one assumes that a metastable local minimum is realized, one has to ensure that its lifetime exceeds that of our universe. We introduce a new program called Vevacious which takes a generic expression for a one-loop effective potential energy function and finds all the tree-level extrema, which are then used as the starting points for gradient-based minimization of the one-loop effective potential. The tunneling time from a given input vacuum to the deepest minimum, if different from the input vacuum, can be calculated. The parameter points are given as files in the SLHA format (though is not restricted to supersymmetric models), and new model files can be easily generated automatically by the Mathematica package SARAH. This code uses HOM4PS2 to find all the minima of the tree-level potential, PyMinuit to follow gradients to the minima of the one-loop potential, and CosmoTransitions to calculate tunneling times. KW - True Vacuum KW - One-loop Effective Potential KW - Saddle Point KW - Minimal Surface Tension KW - CMSSM Point KW - SM Gauge Group KW - Renormalization Scale KW - Landau Gauge KW - Homotopy Continuation Method KW - Gauge-dependent Quantity KW - False Vacuum KW - Spectrum Generator KW - SLHA File KW - Tunneling Time KW - Charged Scalar Field Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-132110 VL - 73 IS - 2588 ER - TY - JOUR A1 - Matlach, Juliane A1 - Freiberg, Florentina J. A1 - Gadeholt, Ottar A1 - Göbel, Winfried T1 - Vasculitis-like hemorrhagic retinal angiopathy in Wegener’s granulomatosis JF - BMC Research Notes N2 - Background: Granulomatosis with polyangiitis, also known as Wegener’s granulomatosis, is a chronic systemic inflammatory disease that can also involve the eyes. We report a case of massive retinal and preretinal hemorrhages with perivascular changes as the initial signs in granulomatosis with polyangiitis (Wegener’s granulomatosis). Case presentation: A 39-year-old Caucasian male presented with blurred vision in his right eye, myalgia and arthralgia, recurrent nose bleeds and anosmia. Fundus image of his right eye showed massive retinal hemorrhages and vasculitis-like angiopathy, although no fluorescein extravasation was present in fluorescein angiography. Laboratory investigations revealed an inflammation with increased C-reactive protein, elevated erythrocyte sedimentation rate and neutrophil count. Tests for antineutrophil cytoplasmic antibodies (ANCA) were positive for c-ANCA (cytoplasmatic ANCA) and PR3-ANCA (proteinase 3-ANCA). Renal biopsy demonstrated a focal segmental necrotizing glomerulonephritis. Granulomatosis with polyangiitis (Wegener’s granulomatosis) was diagnosed and a combined systemic therapy of cyclophosphamide and corticosteroids was initiated. During 3 months of follow-up, complete resorption of retinal hemorrhages was seen and general complaints as well as visual acuity improved during therapy. Conclusion: Vasculitis-like retinal changes can occur in Wegener’s granulomatosis. Despite massive retinal and preretinal hemorrhages that cause visual impairment, immunosuppressive therapy can improve ocular symptoms. KW - cyclophosphamide KW - Wegener’s granulomatosis KW - granulomatosis with polyangiitis KW - retinal vasculitis KW - hemorrhages Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-128744 VL - 6 IS - 364 ER - TY - JOUR A1 - Streng, Andrea A1 - Grote, Veit A1 - Carr, David A1 - Hagemann, Christine A1 - Liese, Johannes G. T1 - Varicella routine vaccination and the effects on varicella epidemiology – results from the Bavarian Varicella Surveillance Project (BaVariPro), 2006-2011 JF - BMC Infectious Diseases N2 - Background In 2004, routine varicella vaccination was recommended in Germany for children 11-14 months of age with one dose, and since 2009, with a second dose at 15-23 months of age. The effects on varicella epidemiology were investigated. Methods Data on varicella vaccinations, cases and complications were collected from annual parent surveys (2006-2011), monthly paediatric practice surveillance (Oct 2006 - Sep 2011; five varicella seasons) and paediatric hospital databases (2005-2009) in the area of Munich (about 238,000 paediatric inhabitants); annual incidences of cases and hospitalisations were estimated. Results Varicella vaccination coverage (1st dose) in children 18-36 months of age increased in two steps (38%, 51%, 53%, 53%, 66% and 68%); second-dose coverage reached 59% in the 2011 survey. A monthly mean of 82 (62%) practices participated; they applied a total of 50,059 first-dose and 40,541 second-dose varicella vaccinations, with preferential use of combined MMR-varicella vaccine after recommendation of two doses, and reported a total of 16,054 varicella cases <17 years of age. The mean number of cases decreased by 67% in two steps, from 6.6 (95%CI 6.1-7.0) per 1,000 patient contacts in season 2006/07 to 4.2 (95%CI 3.9-4.6) in 2007/08 and 4.0 (95%CI 3.6-4.3) in 2008/09, and further to 2.3 (95%CI 2.0-2.6) in 2009/10 and 2.2 (95%CI 1.9-2.5) in 2010/11. The decrease occurred in all paediatric age groups, indicating herd protection effects. Incidence of varicella was estimated as 78/1,000 children <17 years of age in 2006/07, and 19/1,000 in 2010/11. Vaccinated cases increased from 0.3 (95%0.2-0.3) per 1,000 patient contacts in 2006/07 to 0.4 (95%CI 0.3-0.5) until 2008/09 and decreased to 0.2 (95%CI 0.2-0.3) until 2010/11. The practices treated a total of 134 complicated cases, mainly with skin complications. The paediatric hospitals recorded a total of 178 varicella patients, including 40 (22.5%) with neurological complications and one (0.6%) fatality due to varicella pneumonia. Incidence of hospitalisations decreased from 7.6 per 100,000 children <17 years of age in 2005 to 4.3 in 2009, and from 21.0 to 4.7 in children <5 years of age. Conclusions Overall, the results show increasing acceptance and a strong impact of the varicella vaccination program, even with still suboptimal vaccination coverage. KW - Varicella KW - Surveillance KW - Coverage KW - Vaccination KW - Hospitalisation KW - Paediatric KW - Incidence Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-96297 UR - http://www.biomedcentral.com/1471-2334/13/303 ER - TY - THES A1 - Christ, Thomas T1 - Value-distribution of the Riemann zeta-function and related functions near the critical line T1 - Werteverteilung der Riemannschen Zetafunktion und verwandter Funktionen nahe der kritischen Geraden N2 - The Riemann zeta-function forms a central object in multiplicative number theory; its value-distribution encodes deep arithmetic properties of the prime numbers. Here, a crucial role is assigned to the analytic behavior of the zeta-function on the so called critical line. In this thesis we study the value-distribution of the Riemann zeta-function near and on the critical line. Amongst others we focus on the following. PART I: A modified concept of universality, a-points near the critical line and a denseness conjecture attributed to Ramachandra. The critical line is a natural boundary of the Voronin-type universality property of the Riemann zeta-function. We modify Voronin's concept by adding a scaling factor to the vertical shifts that appear in Voronin's universality theorem and investigate whether this modified concept is appropriate to keep up a certain universality property of the Riemann zeta-function near and on the critical line. It turns out that it is mainly the functional equation of the Riemann zeta-function that restricts the set of functions which can be approximated by this modified concept around the critical line. Levinson showed that almost all a-points of the Riemann zeta-function lie in a certain funnel-shaped region around the critical line. We complement Levinson's result: Relying on arguments of the theory of normal families and the notion of filling discs, we detect a-points in this region which are very close to the critical line. According to a folklore conjecture (often attributed to Ramachandra) one expects that the values of the Riemann zeta-function on the critical line lie dense in the complex numbers. We show that there are certain curves which approach the critical line asymptotically and have the property that the values of the zeta-function on these curves are dense in the complex numbers. Many of our results in part I are independent of the Euler product representation of the Riemann zeta-function and apply for meromorphic functions that satisfy a Riemann-type functional equation in general. PART II: Discrete and continuous moments. The Lindelöf hypothesis deals with the growth behavior of the Riemann zeta-function on the critical line. Due to classical works by Hardy and Littlewood, the Lindelöf hypothesis can be reformulated in terms of power moments to the right of the critical line. Tanaka showed recently that the expected asymptotic formulas for these power moments are true in a certain measure-theoretical sense; roughly speaking he omits a set of Banach density zero from the path of integration of these moments. We provide a discrete and integrated version of Tanaka's result and extend it to a large class of Dirichlet series connected to the Riemann zeta-function. N2 - Die Riemannsche Zetafunktion ist ein zentraler Gegenstand der multiplikativen Zahlentheorie; in ihrer Werteverteilung liegen wichtige arithmetische Eigenschaften der Primzahlen kodiert. Besondere Bedeutung kommt hierbei dem analytischen Verhalten der Zetafunktion auf der sog. kritischen Geraden zu. Wir untersuchen in dieser Arbeit die Werteverteilung der Riemannschen Zetafunktion auf und nahe der kritischen Geraden. Wir fokusieren wir uns dabei u.a. auf folgende Punkte. TEIL I: Ein modifiziertes Universalitätskonzept, a-Stellen nahe der kritischen Geraden und eine Dichtheitsvermutung nach Ramachandra. Die kritische Gerade fungiert als natürliche Grenze für die Voroninsche Universalitätseigenschaft der Riemannschen Zetafunktion. Wir modifizieren Voronins Universalitätskonzept dahingehend, dass wir die vertikalen Translationen aus Voronins Universalitätssatz mit einer zusätzlichen Skalierung versehen. Wir untersuchen, ob durch dieses modifizierte Konzept eine abgeschwächte Universalitätseigenschaft der Riemannschen Zetafunktion um die kritschen Gerade aufrecht erhalten werden kann. Es stellt sich heraus, dass die Gestalt der Funktionen, die sich auf diese Weise durch die Zetafunktion approximieren lassen, stark von der Funktionalgleichung und der Wahl des skalierenden Faktors abhängt. Nach einem Resultat von Levinson liegen fast alle a-Stellen der Riemannschen Zetafunktion in einem trichterförmigen Bereich um die kritische Gerade. Gewisse Normalitätsargumenten sowie das Konzept der 'filling discs' erlauben uns Levinsons Resultat zu ergänzen und a-Stellen in diesem trichterförmigen Bereich aufzuspüren, die sehr nahe an der kritischen Geraden liegen. Man vermutet, dass die Werte der Riemannschen Zetafunktion auf der kritischen Geraden dicht in den komplexen Zahlen liegen. Wir nähern uns dieser Vermutung (die man oft Ramachandra zuschreibt), indem wir die Existenz gewisser Kurven nachweisen, die sich asymptotisch an die kritische Gerade anschmiegen und die Eigenschaft besitzen, dass die Werte der Zetafunktion auf diesen Kurven dicht in den komplexen Zahlen liegen. Viele unserer Ergebnisse in Teil I sind unabhängig von der Eulerproduktdarstellung der Zetafunktion und gelten allgemein für beliebige meromorphe Funktionen, die einer Funktionalgleichung vom Riemann-Typ genügen. TEIL II: Diskrete und kontinuierliche Momente. Die Lindelöf Vermutung trifft eine Aussage über das Wachstumsverhalten der Zetafunktion auf der kritischen Geraden. Nach klassischen Arbeiten von Hardy und Littlewood lässt sie sich mittels Potenzmomente der Zetafunktion rechts von der kritischen Geraden umformulieren. Tanaka konnte kürzlich nachweisen, dass die asymptotischen Formeln, die man für diese Potenzmomente erwartet in einem gewissen maßtheoretischem Sinne Gülitgkeit besitzen: grob gesprochen wird heibei eine Menge mit Banachdichte null vom Integrationsweg der Potenzmomente ausgespart. Wir stellen eine diskrete und eine integrierte Version von Tanakas Resultat zur Verfügung. Zudem verallgemeinern wir Tanakas Ergebnis auf eine große Klasse von Dirichletreihen. KW - Riemannsche Zetafunktion KW - Riemann zeta-function KW - universality KW - a-point distribution Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-97763 ER - TY - THES A1 - Huang, Ting T1 - Vaccinia Virus-mediated Therapy of Solid Tumor Xenografts: Intra-tumoral Delivery of Therapeutic Antibodies T1 - Vaccini-Virus-vermittelte Therapie solider Tumoren: Intra-tumoraler Transport therapeutischer Antikörper N2 - Over the past 30 years, much effort and financial support have been invested in the fight against cancer, yet cancer still represents the leading cause of death in the world. Conventional therapies for treatment of cancer are predominantly directed against tumor cells. Recently however, new treatments options have paid more attention to exploiting the advantage of targeting the tumor stroma instead. Vaccinia virus (VACV) has played an important role in human medicine since the 18th century as a vaccination against smallpox. In our laboratory, the recombinant, replication-competent vaccinia virus, GLV-1h68, was shown to enter, colonize and destroy cancer cells both in cell culture, and in vivo, in xenograft models (Zhang, Yu et al. 2007). In addition, combined therapy of GLV-1h68 and anti-VEGF immunotherapy significantly enhanced antitumor therapy in vivo (Frentzen, Yu et al. 2009). In this study, we constructed several new recombinant VACVs carrying genes encoding different antibodies against fibroblast activation protein (FAP) in stroma (GLV-1h282), nanobody against the extracellular domain of epidermal growth factor receptor (EGFR, GLV-1h442) or antibodies targeting both vascular endothelial growth factor (VEGF) and EGFR (GLV-1h444) or targeting both VEGF and FAP (GLV-1h446). The expression of the recombinant proteins was first verified using protein analytical methods, SDS-gel electrophoresis, Western blot analysis, immunoprecipitation (IP) assays and ELISA assays. The proteins were detected after infection of the cells with the different VACVs and the recombinant proteins purified by affinity adsorption. The purified antibodies were shown to specifically bind to their respective antigens. Secondly, the infection and replication capability of all the virus strains was analyzed in cell culture using several human tumor cell lines (A549, FaDu or DU145), revealing that all the new recombinant VACVs were able to infect cancer cells with comparable efficiency to the parental viruses from which they were derived. Thirdly, the antitumor efficacy of the new recombinant VACVs was evaluated in vivo using several human cancer xenograft models in mice. In A549 and DU145 xenografts, the new recombinant VACVs exhibited an enhanced therapeutic efficacy compared to GLV-1h68 with no change in toxicity in mice. In the FaDu xenograft, treatment with GLV-1h282 (anti-FAP) significantly slowed down the speed of tumor growth compared to GLV-1h68. Additionally, treatment with the recombinant VACVs expressed the various antibodies achieved comparable or superior therapeutic effects compared to treatment with a combination of GLV-1h68 and the commercial therapeutic antibodies, Avastin, Erbitux or both. Next, the virus distribution in tumors and organs of treated mice was evaluated. For most of the viruses, the virus titer in tumors was not signficantly diffferent than GLV-1h68. However, for animals treated with GLV-1h282, the virus titer in tumors was significantly higher than with GLV-1h68. This may be the reason for enhanced antitumor efficacy of GLV-1h282 in vivo. Lastly, the underlying mechanisms of therapeutic antibody-enhanced antitumor effects were investigated by immunohistochemistry. Blood vessels density and cell proliferation in tumors were suppressed after treatment with the antibody-encoded VACVs. The results indicated that the suppression of angiogenesis or cell proliferation in tumors may cause the observed therapeutic effect. In conclusion, the results of the studies presented here support the hypothesis that the treatment of solid tumors with a combination of oncolytic virotherapy and immunotherapy has an additive effect over each treatment alone. Moreover, expression of the immunotherapeutic antibody by the oncolytic VACV locally in the tumor enhances the antitumor effect over systemic treatment with the same antibody. Combined, these results indicate that therapy with oncolytic VACVs expressing-therapeutic antibodies may be a promising approach for the treatment of cancer. N2 - In den letzten 30 Jahren wurde viel Aufwand und finanzielle Unterstützung in den Kampf gegen Krebs investiert, doch das Resultat ist limitiert, da Krebs immer noch die zweithöchste Todesursache in der Welt darstellt. Zusätzlich zu gegenwärtig verwendeten Therapien, die vorwiegend gegen Tumorzellen gerichtet sind, wird neuen Therapien mehr Aufmerksamkeit gewidmet, die stattdessen direkt auf das Tumorstroma zielen. Onkolytische Vaccinia Viren haben seit dem 18ten Jahrhundert als Impfstoff gegen Pocken in der Humanmedizin eine wichtige Rolle gespielt. In unserem Labor hat das rekombinante, replikationskompetente Vaccinia Virus GLV-1h68 gezeigt, dass es in Zellkultur und in Xenograft Modellen in Krebszellen eindringen sowie diese kolonisieren und zerstören kann (Zhang, Yu et al. 2007). Zusätzlich verbessert die kombinierte Therapie von GLV-1h68 und anti-VEGF Immunotherapy signifikant die Antitumortherapie in vivo (Frentzen, Yu et al. 2009). In dieser Studie haben wir mehrere neue rekombinante VACVs konstruiert, die die Gene für verschiedene Antikörper gegen das Fibroblasten Aktivierungs Protein (FAP) im Stroma (GLV-1h282) oder einen Nanobody gegen die extrazelluläre Domäne des Epidermalen Wachstumsfaktor (EGFR; GLV-1h442) kodieren. Ausserdem wurden Viren konstruiert, die eine Ko-Expression von Antikörpern gegen sowohl vaskulären Endothelwachstumsfaktor (VEGF) als auch EGFR (GLV-1h444) oder gegen sowohl VEGF als auch FAP (GLV-1h446) erlauben. Zunächst wurden SDS-Gelelektrophorese, Western Blot Analyse, Immunprezipitation (IP) und ELISA Assays durchgeführt, um die Expression der rekombinanten Proteine in Zellen mit proteinanalytischen Methoden zu untersuchen. Die Proteine waren nach Infektion der Zellen mit den verschiedenen VACVs nachweisbar und wurden mittles des FLAG Tags mit einem IP Kit aufgereinigt. Es konnte gezeigt werden, dass die aufgereinigten Antikörper spezifisch an ihr jeweiliges Antigen binden. Zweitens wurde die Infektion und Replikationsfähigkeit aller Virusstämme in Zellkultur untersucht (A549, FaDu oder DU145) und mit ihrem jeweiligen Ausgangsstamm GLV-1h68, GLV-1h164, GLV-1h282 oder GLV-1h442 verglichen. Die Ergebnisse zeigten, dass alle neuen rekombinanten VACVs Zellen mit vergleichbarer Effizienz infizieren konnten wie ihre Ausgangsstämme. Drittens, um die Antitumoreffizienz der neuen rekombinanten Stämme in vivo zu testen, wurden verschiedene humane Tumor Xenotransplantat-tragende Nacktmäuse mit verschiedenen VACVs behandelt. In A549 und DU145 Xenotransplantaten zeigten die neuen rekombinanten VACVs erhöhte therapeutische Effizienz verglichen mit dem Ausgangsstamm GLV-1h68, ohne Veränderung der Toxizität in Mäusen. Im FaDu Xenotransplantat verursachte die Behandlung mit GLV-1h68 keine Tumorregression, wohingegen die Behandlung mit GLV-1h282 (anti-FAP) die Geschwindigkeit des Tumorwachstums signifikant verlangsamte sowie das Überleben verlängerte. Zusätzlich haben wir herausgefunden, dass die Behandlung mit Antikörpern, die mittels Virus geliefert wurden, einen identischen oder sogar erhöhten inhibitorischen Effekt erzielen können, wie in einer Kombinationstherapie von GLV-1h68 und kommerziell erhältlichen Antikörpern, wie Avastin, Erbitux oder beidem. Um die virale Verteilung in vivo zu untersuchen, wurden Tumore und Organe von Mäusen seziert und homogenisiert, gefolgt von Titration der Virusmenge. Die Virus-Titer in Tumoren waren signifikant höher in Tieren, die mit GLV-1h282 behandelt wurden als solche, die mit GLV-1h68 behandelt wurden. Dies mag den Grund für die erhöhte Antitumoreffizienz von GLV-1h282 in vivo darstellen. Die Virus-Titer in allen anderen Gruppen zeigten keinen signifikanten Unterschied. Um den Mechanismus der durch therapeutische Antikörper erhöhten Antitumortherapie zu untersuchen, wurde Immunohistochemie durchgeführt. Nach Behandlung mit den Antikörper-kodierenden VACVs waren die Blutgefäβdichte und Zellproliferation in Tumoren reduziert, nachgewiesen durch die jeweilige CD31 and Ki67 Färbung. Die Resultate deuteten an, dass die Suppression der Angiogenese oder der Zellproliferation in Tumoren den beobachteten Effekt verursachen könnte. Zusammenfassend zeigen die hier präsentierten Daten dass die Kombination der Behandlung von onkolytischer Virotherapie mit Immunotherapie durch Virus-gelieferte Antikörper einen vielversprechenden Ansatz für Krebstherapie darstellt. KW - Vaccinia-Virus KW - therapeutic antibody KW - oncolytic virus KW - Krebs KW - Therapie KW - Antikörper KW - Tumor Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-91327 ER - TY - THES A1 - Heß, Michael T1 - Vaccinia virus-encoded bacterial beta-glucuronidase as a diagnostic biomarker for oncolytic virotherapy T1 - Vaccinia Virus-codierte bakterielle Beta-Glucuronidase als diagnostischer Biomarker in der onkolytischen Virotherapie N2 - Oncolytic virotherapy represents a promising approach to revolutionize cancer therapy. Several preclinical and clinical trials display the safety of oncolytic viruses as wells as their efficiency against solid tumors. The development of complementary diagnosis and monitoring concepts as well as the optimization of anti-tumor activity are key points of current virotherapy research. Within the framework of this thesis, the diagnostic and therapeutic prospects of beta-glucuronidase expressed by the oncolytic vaccinia virus strain GLV-1h68 were evaluated. In this regard, a beta-glucuronidase-based, therapy-accompanying biomarker test was established which is currently under clinical validation. By using fluorescent substrates, the activity of virally expressed beta-glucuronidase could be detected and quantified. Thereby conclusions about the replication kinetics of oncolytic viruses in animal models and virus-induced cancer cell lysis could be drawn. These findings finally led to the elaboration and establishment of a versatile biomarker assay which allows statements regarding the replication of oncolytic viruses in mice based on serum samples. Besides the analysis of retrospective conditions, this test is able to serve as therapy-accompanying monitoring tool for virotherapy approaches with beta-glucuronidase-expressing viruses. The newly developed assay also served as complement to routinely used plaque assays as well as reference for virally expressed anti-angiogenic antibodies in additional preclinical studies. Further validation of this biomarker test is currently taking place in the context of clinical trials with GL-ONC1 (clinical grade GLV-1h68) and has already shown promising preliminary results. It was furthermore demonstrated that fluorogenic substrates in combination with beta-glucuronidase expressed by oncolytic viruses facilitated the optical detection of solid tumors in preclinical models. In addition to diagnostic purposes, virus-encoded enzymes could also be combined with prodrugs resulting in an improved therapeutic outcome of oncolytic virotherapy. In further studies, the visualization of virus-induced immune reactions as well as the establishment of innovative concepts to improve the therapeutic outcome of oncolytic virotherapy could be accomplished. In conclusion, the results of this thesis provide crucial findings about the influence of virally expressed beta-glucuronidase on various diagnostic concepts in the context of oncolytic virotherapy. In addition, innovative monitoring and therapeutic strategies could be established. Our preclinical findings have important clinical influence, particularly by the development of a therapy-associated biomarker assay which is currently used in different clinical trials. N2 - Onkolytische Viren stellen einen vielversprechenden Therapieansatz dar, der die Behandlung von Krebserkrankungen revolutionieren könnte. Intensive präklinische und klinische Studien zeigen sowohl die körperliche Verträglichkeit von onkolytischen Viren, als auch deren Wirksamkeit gegenüber soliden Tumoren. Die Entwicklung von therapiebegleitenden Diagnose- und Monitoringkonzepten sowie eine Optimierung der Antitumorwirkung onkolytischer Viren stellen Eckpunkte der aktuellen Forschung auf dem Gebiet der Virotherapie dar. Im Rahmen dieser Arbeit wurde untersucht, welche diagnostischen und therapeutischen Möglichkeiten die virale Expression von beta-Glucuronidase durch den onkolytischen Vaccinia-Virus-Stamm GLV-1h68 eröffnet. In diesem Zusammenhang wurde ein, auf beta-Glucuronidase basierender, therapiebegleitender Biomarkertest entwickelt, dessen klinische Validierung derzeit stattfindet. Mit Hilfe von fluorogenen Substraten konnte die Aktivität viral exprimierter beta-Glucuronidase detektiert und quantifiziert werden. Dies lies direkte Rückschlüsse auf das Replikationsverhalten von onkolytischen Viren im Tiermodell zu und ermöglichte zudem Aussagen über die Zelllyse Virus-infizierter Krebszellen. Diese Erkenntnisse führten letztendlich zur Ausarbeitung und Etablierung eines vielseitig anwendbaren Biomarker-Assays, der es ermöglicht anhand von Blutproben Aussagen über das Replikationsverhalten onkolytischer Viren in Mäusen zu machen. Neben retrospektiven Analysen erlaubt dieser Test auch ein therapiebegleitendes Monitoring der onkolytischen Virotherapie mit beta-Glucuronidase-exprimierenden Viren. In weiteren präklinischen Untersuchungen diente der entwickelte Assay zudem als Ergänzung zum viralen Plaque Assays sowie als Referenz für Virus-exprimierte anti-angiogene Antikörper. Eine fortführende Validierung dieses neuartigen Biomarkertests findet derzeit im Rahmen humaner Studien mit der klinischen Formulierung von GLV-1h68, GL-ONC1, statt und zeigte bereits erste positive Resultate. Weiterhin konnte im Rahmen dieser Arbeit gezeigt werden, dass die Expression von beta-Glucuronidase durch onkolytische Viren in Verbindung mit fluoreszierenden Substraten eine optische Detektion von Karzinomen im präklinischen Tiermodell ermöglicht. Neben diagnostischen Zwecken, konnten Virus-kodierte Enzyme in Kombination mit Prodrugs genutzt werden, um den Therapieerfolg der onkolytischen Virotherapie zu verbessern. In zusätzlichen Studien konnten zudem Methoden zur Visualisierung der Virus-induzierten Immunantwort sowie neuartige Konzepte zur Therapieverbesserung etabliert werden. Zusammenfassend liefern die Ergebnisse der vorliegenden Arbeit wichtige Erkenntnisse über den Einfluss Virus-exprimierter beta-Glucuronidase auf unterschiedliche Diagnosekonzepte im Rahmen der onkolytischen Virotherapie. Daneben konnten entscheidende Erkenntnisse über den möglichen Einsatz neuer Monitoring- und Therapieansätze erzielt werden. Insbesondere durch die Entwicklung eines therapiebegleitenden Biomarkertests haben diese Resultate erheblichen Einfluss auf die weitere klinische Anwendung von onkolytischen Vaccinia-Viren. KW - Vaccinia-Virus KW - Glucuronidase KW - Krebs KW - cancer KW - oncolytic virus KW - biomarker KW - beta-glucuronidase Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-86789 ER -