@misc{DrenckhahnBaumgartnerZonneveld2017, author = {Drenckhahn, Detlev and Baumgartner, Werner and Zonneveld, Ben}, title = {Forum Geobotanicum Vol. 7 (2016/2017)}, volume = {7(2016/2017)}, editor = {Meierott, Lenz and Drenckhahn, Detlev and Dunkel, Franz G. and Ewald, J{\"o}rg and Schuhwerk, Franz}, issn = {1867-9315}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-157381}, year = {2017}, abstract = {Forum Geobotanicum is an electronic journal devoted to disseminate information concerning geographical distribution, ecology, morphology, taxonomy and conservation of vascular plants in the European Union with a main focus on middle Europe. It covers from molecular biology to environmental aspects. The focus is to publish original papers, reviews and announcements for the educated generalist as well as the specialist in this broad field. Forum Geobotanicum does not aim to supplant existing paper journals, but will be much more flexible in format, publication time and world-wide distribution than paper journals. Many important studies are being currently published in local journals and booklets and some of them are published privately. Hence, these studies will become aware to only a limited readership. Forum Geobotanicum will encourage authors of such papers to submit them as special issues of the journal. Moreover, the journal is planning to build up an E-mail-address section to support communication between geobotanists in Europe. The editors are optimistic that this electronic journal will develop to a widely used communication forum that will help to stimulate activities in the entire field of geobotany in middle Europe. To overcome problems of long term archivation and effective taxonomic publication of articles published electronically in Forum Geobotanicum, print versions of each volume of the journal and appropriate digital storage devices will be delivered freely to selected university libraries and state libraries in middle Europe.}, language = {mul} } @phdthesis{Lutz2017, author = {Lutz, Mathias}, title = {T-Zell-Immunit{\"a}t gegen die tumorassoziierten Antigene HER2/neu, MUC1, PRAME und WT1 bei gesunden Blutspendern und Schwangeren als ein immuntherapeutisches Modell f{\"u}r die allogene Blutstammzelltransplantation}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-156587}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2017}, abstract = {Der Erfolg der allogenen h{\"a}matopoetischen Stammzelltransplantation (HSZT) als Immuntherapie basiert neben den Minorantigendifferenzen zwischen Spender und Empf{\"a}nger entscheidend auf einer spendervermittelten Immunit{\"a}t gegen tumorassoziierte Antigene (TAA), {\"u}ber deren Herkunft und Frequenz bei gesunden Blutspendern die derzeitige Studienlage kaum Informationen bietet. Da f{\"u}r viele klinisch relevante TAA eine Expression im fetalen und plazentaren Gewebe bekannt ist, wurde in dieser Arbeit die Schwangerschaft als m{\"o}glicher Ausl{\"o}ser dieser T-lymphozyt{\"a}ren Ged{\"a}chtnisimmunantworten im Sinne eines Tumor- und Transplantationsmodells untersucht. Hierf{\"u}r wurden insgesamt 114 gesunde Blutspender in drei Subgruppen aus 38 Frauen mit negativer Schwangerschaftsanamnese, 38 Frauen mit positiver Geburtenanamnese und 38 M{\"a}nnern in einer Querschnittsstudie betrachtet, daneben wurden 44 Frauen longitudinal w{\"a}hrend und nach ihrer ersten Schwangerschaft untersucht. Dabei wurden die CD8-positiven T-Lymphozyten der Probanden isoliert, mit Peptiden der vier klinisch relevanten TAA HER2/neu (human epidermal growth factor receptor 2), MUC1 (Mucin 1), PRAME (preferentially expressed antigen of melanoma) und WT1 (Wilms tumor protein 1) stimuliert und die Produktion von IFN-γ-mRNA mittels RT-qPCR gemessen. Daneben wurden zum Vergleich durchflusszytometrische und ELISPOT-basierte Verfahren durchgef{\"u}hrt. Bei den gesunden Blutspendern konnten CD8-positive Ged{\"a}chtnisimmunantworten von niedriger und/oder hoher funktioneller Avidit{\"a}t gegen alle vier untersuchten TAA gemessen werden: Die Frequenz der dabei als „positiv" definierten Immunantworten betrug bei HER2/neu 5 \%, bei MUC1 14 \%, bei PRAME 7 \% und bei WT1 15 \%. M{\"a}nner wiesen insgesamt h{\"o}here absolute Level der Immunantworten gegen die untersuchten TAA auf, was auf eine testikul{\"a}re Expression dieser Antigene zur{\"u}ckzuf{\"u}hren sein k{\"o}nnte. In der Longitudinalanalyse bei den erstschwangeren Frauen ließen sich die st{\"a}rksten Immunantworten zu Beginn der Schwangerschaft nachweisen, so dass es hier zu einem „Boost" pr{\"a}existenter TAA-spezifischer Autoimmunit{\"a}t zu kommen scheint. Durch das immunsuppressive hormonelle Milieu im Verlauf der Schwangerschaft und den Verlust der Zielantigene der feto-plazentaren Einheit durch die Geburt und Nachgeburt scheint diese Immunit{\"a}t aber nicht zu persistieren. Dadurch erkl{\"a}rt sich auch die Beobachtung, dass Frauen mit einer positiven Geburtenanamnese keine st{\"a}rkeren Immunantworten gegen die untersuchten TAA aufwiesen als Frauen mit einer negativen Schwangerschaftsanamnese. Die Schwangerschaft hinterl{\"a}sst diesbez{\"u}glich also ohne die Anwesenheit der vermittelnden Antigene keinen regelhaft bleibenden Effekt. Diese Resultate decken sich mit Beobachtungen aus der Tumorimmuntherapie, bei denen Vakzinierungen gegen TAA zwar eine kurzfristige Immunit{\"a}t generieren konnten, die aber nicht persistierte. Im Rahmen der HSZT kann eine solche TAA-spezifische Immunit{\"a}t vom Spender auf den Empf{\"a}nger transferiert werden und vermag dann aufgrund des proinflammatorischen Immunmilieus sehr wohl zu expandieren und in einem begrenzten Ausmaß auch zu persistieren. Dementsprechend ergeben sich aus den in dieser Arbeit gewonnenen Resultaten relevante Implikationen f{\"u}r die allogene und in geringerem Ausmaß die autologe HSZT, daneben aber auch f{\"u}r innovative Tumortherapien wie die Immuncheckpoint-Blockade, da die Persistenz von tumorspezifischer Immunit{\"a}t letztendlich hochrelevant f{\"u}r eine langfristige Tumorkontrolle und damit f{\"u}r ein tumorfreies {\"U}berleben ist. Das vorliegende Modell tr{\"a}gt somit zum Verst{\"a}ndnis der komplexen immunregulatorischen Vorg{\"a}nge bei der Tumorkontrolle bei. Ob die hierbei aufgezeigten Immunantworten generell zu einer verbesserten TAA-spezifischen Immunrekonstitution und konsekutiv zu einem besseren klinischen Ergebnis beitragen, bleibt offen und wird in klinischen Studien gekl{\"a}rt werden m{\"u}ssen.}, subject = {Immuntherapie}, language = {de} } @phdthesis{Simin2017, author = {Simin, Dmitrij}, title = {Quantum Sensing with Highly Coherent Spin Centers in Silicon Carbide}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-156199}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2017}, abstract = {In the present work, the energetic structure and coherence properties of the silicon vacancy point defect in the technologically important material silicon carbide are extensively studied by the optically detected magnetic resonance (ODMR) technique in order to verify its high potential for various quantum applications. In the spin vacancy, unique attributes are arising from the C3v symmetry and the spin-3/2 state, which are not fully described by the standard Hamiltonian of the uniaxial model. Therefore, an advanced Hamiltonian, describing well the appearing phenomena is established and the relevant parameters are experimentally determined. Utilizing these new accomplishments, several quantum metrology techniques are proposed. First, a vector magnetometry scheme, utilizing the appearance of four ODMR lines, allows for simultaneous detection of the magnetic field strength and the tilting angle of the magnetic field from the symmetry axis of the crystal. The second magnetometry protocol utilizes the appearance of energetic level anticrossings (LAC) in the ground state (GS) energy levels. Relying only on the change in photoluminescence in the vicinity of this GSLACs, this all-optical method does not require any radio waves and hence provides a much easier operation with less error sources as for the common magnetometry schemes utilizing quantum points. A similar all-optical method is applied for temperature sensing, utilizing the thermal shift of the zero field splitting and consequently the anticrossing in the excited state (ES). Since the GSLACs show no dependence on temperature, the all-optical magnetometry and thermometry (utilizing the ESLACs) can be conducted subsequently on the same defect. In order to quantify the achievable sensitivity of quantum metrology, as well as to prove the potential of the Si-vacancy in SiC for quantum processing, the coherence properties are investigated by the pulsed ODMR technique. The spin-lattice relaxation time T1 and the spin-spin relaxation time T2 are thoroughly analyzed for their dependence on the external magnetic field and temperature. For actual sensing implementations, it is crucial to obtain the best signal-to-noise ratio without loss in coherence time. Therefore, the irradiation process, by which the defects are created in the crystal, plays a decisive role in the device performance. In the present work, samples irradiated with electrons or neutrons with different fluences and energies, producing different defect densities, are analyzed in regard to their T1 and T2 times at room temperature. Last but not least, a scheme to substantially prolong the T2 coherence time by locking the spin polarization with the dynamic decoupling Carr-Purcell-Meiboom-Gill (CPMG) pulse sequence is applied.}, subject = {Siliciumcarbid}, language = {en} } @article{DrenckhahnZonneveld2017, author = {Drenckhahn, Detlev and Zonneveld, Ben}, title = {Rubus viridilucidus Drenckhahn, eine neue Brombeerart aus der Sektion Corylifolii, Serie Subcanescentes}, series = {Forum Geobotanicum}, volume = {7}, journal = {Forum Geobotanicum}, issn = {1867-9315}, doi = {10.3264/FG.2017.1221}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-156257}, pages = {34-42}, year = {2017}, abstract = {Rubus viridilucidus Drenckhahn ist eine tetraploide Brombeerart (2n=28) aus der Sektion Corylifolii, Serie Subcanescentes mit einem Genomgewicht (2C-Wert) von 1,49 pg, das dem Genomgewicht verwandter Sippen der Serie Subcanescentes wie R. scabrosus, R. fasciculatiformis und R. fasciculatus (1,52-1,54 pg) aus Unterfranken entspricht. Charakteristische Merkmale sind 3-4(5)-z{\"a}hlige Bl{\"a}tter mit herab gekr{\"u}mmten rundlichen bis breit obovaten Endbl{\"a}ttchen und breitovalen Seitenbl{\"a}ttchen, die eine v{\"o}llig unbehaarte, lichtgr{\"u}ne, mattgl{\"a}nzende Blattoberfl{\"a}che besitzen mit kontrastierender hell gr{\"u}nlich-grauer, samtig behaarter Blattunterseite. Die {\"u}berwiegend rundlichen bis stumpf kantigen, lichtgr{\"u}nen bis r{\"o}tlich {\"u}berlaufenen Sch{\"o}sslinge sind unbehaart und sp{\"a}rlich mit kurzen (<4mm) nadelf{\"o}rmigen Stacheln und wenigen Stieldr{\"u}sen besetzt. R. viridilucidus entwickelt zus{\"a}tzlich zu den Bl{\"u}tenzweigen der zweij{\"a}hrigen Sch{\"o}sslinge (Ausbreitungssch{\"o}sslinge) einen besonderen bl{\"u}henden 0,8 bis 1,6 m langen Sch{\"o}sslingstyp aus, den Rispensch{\"o}ssling, der direkt aus dem Wurzelstock entspringt und terminal in eine Bl{\"u}tenrispe ausl{\"a}uft. Bei R. viridilucidus sind zwei verschiedene Typen von Rispensch{\"o}sslingen ausgebildet. Die Sippe w{\"a}chst bevorzugt auf gest{\"o}rten Fl{\"a}chen wie Brachen, Straßenr{\"a}ndern, Lagerpl{\"a}tzen, Weinbergr{\"a}ndern und kann sich mit 1-2 m j{\"a}hrlichem Zuwachs (Satellitenbildauswertung, Vermessungen vor Ort) schnell ausbreiten. Die bekannt gewordenen Fundstellen erstrecken sich vom n{\"o}rdlichen Baden-W{\"u}rttemberg bis in den n{\"o}rdlichsten Teil von Bayern (Rh{\"o}n).}, subject = {Brombeere}, language = {de} } @phdthesis{ObermeierProbst2017, author = {Obermeier-Probst, Marielle}, title = {Modulierung der Emotionsverarbeitung durch transkranielle Gleichstromstimulation (tDCS)}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-155898}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2017}, abstract = {Die Idee dieser Studie war es, die Modulation der Emotionsverarbeitung mittels transkranieller Gleichstrom-Stimulation nachzuweisen. Dieser Effekt wurde in anderen Studien bereits gezeigt. In diesem Versuch wurde der emotionsabh{\"a}ngige acoustic-Startle-Reflex als Messindikator f{\"u}r modulierte Emotionsverarbeitung eingesetzt. Wir konnten den Effekt der emotionsabh{\"a}ngigen Startle-Reflex Modulierung replizieren und unsere Messmethodik validieren. Entgegen der Hypothese dieser Studie, konnten - bezogen auf die Gesamtpopulation - keine Effekte der tDCS auf die Verarbeitung emotionalrelevanter Bilder gezeigt werden. Da Emotionsverarbeitung stattgefunden hat, wie durch die emotionsabh{\"a}ngige Modulierung des acoustic-Startle-Reflexes gezeigt wurde, kann der fehlende Effekt nicht auf fehlende emotionale Triggerkraft der Bilder zur{\"u}ckgef{\"u}hrt werden. Umso interessanter ist die Beobachtung, dass die Versuchspersonen mit erh{\"o}hter Angstsensitivit{\"a}t signifikant anders auf die tDCS reagierten, als diejenigen mit niedriger Angstsensitivit{\"a}t. Sie zeigten signifikant verringerte acoustic-Startle-Reflex Amplituden, was gem{\"a}ß dem sog. Motivational Priming bedeutet, dass sie eine herabgesetzte aversive Grundstimmung, bzw. eine gehobene Befindlichkeit versp{\"u}rt haben k{\"o}nnten. Der Effekt schien durch die bilaterale, links-kathodale/rechts-anodale Stimulation des DLPFC bedingt zu sein. Angstsensitivit{\"a}t umschreibt die Auspr{\"a}gung der Angst vor Ver{\"a}nderungen (k{\"o}rperlich, sozial, kognitiv), welche mit dem realen Erleben der Emotion Angst einhergehen k{\"o}nnen und wird als Risikofaktor f{\"u}r das Entstehen vieler Angsterkrankungen, speziell der Panikst{\"o}rungen verstanden. In mehreren Studien wurden mediale Anteile des Pr{\"a}frontalen Cortex, im Besonderen der dorsomediale Pr{\"a}frontale Cortex (DMPFC) und der anteriore cingul{\"a}re Cortex (ACC) als u.a. f{\"u}r Angstsensitivit{\"a}t kodierende neuronale Korrelate isoliert. Als in Frage kommende Ursache f{\"u}r den tDCS-Effekt wird die Modulierung des DMPFC und des benachbarten ACC diskutiert. Unterst{\"u}tzung f{\"u}r die vermutlich {\"u}ber das eigentlich anvisierte Areal des DLPFC hinausgehenden tDCS-induzierten Effekte, geben Bildgebungsstudien, in welchen bei bilateraler Stimulierung des DLPFC Aktivit{\"a}tsver{\"a}nderungen in weiter medial gelegenen Teilen des PFC nachgewiesen werden konnten. Das Ergebnis, welches mit einer relativ kleinen Stichprobe klinisch gesunder Personen gewonnen wurde, l{\"a}dt dazu ein, die gleiche Untersuchung mit einem gr{\"o}ßeren Kollektiv von Angstsensitiven durchzuf{\"u}hren. Eine begleitend durchzuf{\"u}hrende funktionelle Bildgebung k{\"o}nnte Aufschluss {\"u}ber die bei bilateraler tDCS des DLPFC tats{\"a}chlich stimulierten Hirnareale geben.}, subject = {Emotionen}, language = {de} } @phdthesis{Hoffmann2017, author = {Hoffmann, Helene}, title = {Identifying regulators of tumor vascular morphology}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-142348}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2017}, abstract = {In contrast to normal vessels, tumor vasculature is structurally and functionally abnormal. Tumor vessels are highly disorganized, tortuous and dilated, with uneven diameter and excessive branching. Consequently, tumor blood flow is chaotic, which leads to hypoxic and acidic regions in tumors. These conditions lower the therapeutic effectiveness and select for cancer cells that are more malignant and metastatic. The therapeutic outcome could be improved by increasing the functionality and density of the tumor vasculature. Tumor angiogenesis also shows parallels to epithelial to mesenchymal transition (EMT), a process enabling metastasis. Metastasis is a multi-step process, during which tumor cells have to invade the surrounding host tissue to reach the circulation and to be transported to distant sites. We hypothesize that the variability in the phenotype of the tumor vasculature is controlled by the differential expression of key transcription factors. Inhibiting these transcription factors might be a promising way for angiogenic intervention and vascular re-engineering. Therefore, we investigated the interdependence of tumor-, stroma- and immune cell-derived angiogenic factors, transcription factors and resulting vessel phenotypes. Additionally, we evaluated whether transcription factors that regulate EMT are promising targets for vascular remodeling. We used formalin fixed paraffin embedded samples from breast cancer patients, classified according to estrogen-, progesterone- and human epidermal growth factor receptor (HER) 2 status. Establishing various techniques (CD34 staining, laser microdissection, RNA isolation and expression profiling) we systematically analyzed tumor and stroma-derived growths factors. In addition, vascular parameters such as microvessel size, area, circularity and density were assessed. Finally the established expression profiles were correlated with the observed vessel phenotype. As the SNAI1 transcriptional repressor is a key regulator of EMT, we examined the effect of vascular knockdown of Snai1 in murine cancer models (E0771, B16-F10 and lewis lung carcinoma). Among individual mammary carcinomas, but not among subtypes, strong differences of vascular parameters were observed. Also, little difference between lobular carcinomas and ductal carcinomas was found. Vessel phenotype of Her2 enriched carcinomas was similar to that of lobular carcinomas. Vessel morphology of luminal A and B and basal-like tumors resembled each other. Expression of angiogenic factors was variable across subtypes. We discovered an inverse correlation of PDGF-B and VEGF-A with vessel area in luminal A tumors. In these tumors expression of IL12A, an inhibitor of angiogenesis, was also correlated with vessel size. Treatment of endothelial cells with growth factors revealed an increased expression of transcription factors involved in the regulation of EMT. Knockdown of Snai1 in endothelial cells of mice increased tumor growth and decreased hypoxia in the E0771 and the B16-F10 models. In the lewis lung carcinomas, tumor vascularity and biodistribution of doxorubicin were improved. Here, doxorubicin treatment in combination with the endothelial cell-specific knockdown did slow tumor growth. This shows that SNAI1 is important for a tumor's vascularization, with the significance of its role depending on the tumor model. The methods established in this work open the way for the analysis of the expression of key transcription factors in vessels of formalin fixed paraffin embedded tumors. This research enables us to find novel targets for vascular intervention and to eventually design novel targeted drugs to inhibit these targets.}, subject = {Antiangiogenese}, language = {en} } @phdthesis{Danner2017, author = {Danner, Nadja}, title = {Honey bee foraging in agricultural landscapes}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-139322}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2017}, abstract = {1. Today honey bee colonies face a wide range of challenges in modern agricultural landscapes which entails the need for a comprehensive investigation of honey bees in a landscape context and the assessment of environmental risks. Within this dissertation the pollen foraging of honey bee colonies is studied in different agricultural landscapes to gain insight into the use of pollen resources and the influence of landscape structure across the season. General suggestions for landscape management to support honey bees and other pollinators are derived. 2. Decoding of waggle dances and a subsequent spatial foraging analysis are used as methods in Chapters 4 and 5 to study honey bee colonies in agricultural landscapes. The recently developed metabarcoding of mixed pollen samples was applied for the first time in honey bee foraging ecology and allowed for a detailed analysis of pollen, that was trapped from honey bees in front hive entrances (Chapter 6). 3. Pollen identification through molecular sequencing and DNA barcoding has been proposed as an alternative approach to light microscopy, which still is a tedious and error-prone task. In this study we assessed mixed pollen probes through next-generation sequencing and developed a bioinformatic workflow to analyse these high-throughput data with a newly created reference database. To evaluate the feasibility, we compared results from classical identification based on light microscopy from the same samples with our sequencing results. Abundance estimations from sequencing data were significantly correlated with counted abundances through light microscopy. Next-generation sequencing thus presents a useful and efficient workflow to identify pollen at the genus and species level without requiring specialized palynological expert knowledge. 4. During maize flowering, four observation hives were placed in and rotated between 11 landscapes covering a gradient in maize acreage. A higher foraging frequency on maize fields compared to other landuse types showed that maize is an intensively used pollen resource for honey bee colonies. Mean foraging distances were significantly shorter for maize pollen than for other pollen origins, indicating that effort is put into collecting a diverse pollen diet. The percentage of maize pollen foragers did not increase with maize acreage in the landscape and was not reduced by grassland area as an alternative pollen resource. Our findings allow estimating the distance-related exposure risk of honey bee colonies to pollen from surrounding maize fields treated with systemic insecticides. 5. It is unknown how an increasing area of mass-flowering crops like oilseed rape (OSR) or a decrease of semi-natural habitats (SNH) change the temporal and spatial availability of pollen resources for honey bee colonies, and thus foraging distances and frequency in different habitat types. Sixteen observation hives were placed in and rotated between 16 agricultural landscapes with independent gradients of OSR and SNH area within 2 km to analyze foraging distances and frequencies. SNH and OSR reduced foraging distance at different spatial scales and depending on season, with possible benefits for the performance of honey bee colonies. Frequency of pollen foragers per habitat type was equally high for SNH, grassland and OSR fields, but lower for other crops and forest. In landscapes with a small proportion of SNH a significantly higher density of pollen foragers on SNH was observed, indicating the limitation of pollen resources in simple agricultural landscapes and the importance of SNH. 6. Quantity and diversity of collected pollen can influence the growth and health of honey bee colonies, but little is known about the influence of landscape structure on pollen diet. In a field experiment we rotated 16 honey bee colonies across 16 agricultural landscapes (see also Chapter 5), used traps to get samples of collected pollen and observed the intra-colonial dance communication to gain information about foraging distances. Neither the amount of collected pollen nor pollen diversity were related to landscape diversity. The revealed increase of foraging distances with decreasing landscape diversity suggests that honey bees compensate for a lower landscape diversity by increasing their pollen foraging range in order to maintain pollen amount and diversity. 7. Our results show the importance of diverse pollen resources for honey bee colonies in agricultural landscapes. Beside the risk of exposure to pesticides honey bees face the risk of nutritional deficiency with implications for their health. By modifying landscape composition and therefore availability of resources we are able to contribute to the wellbeing of honey bees. Agri-environmental schemes aiming to support pollinators should focus on possible spatial and temporal gaps in pollen availability and diversity in agricultural landscapes.}, subject = {Apis mellifera}, language = {en} } @phdthesis{Schlag2017, author = {Schlag, Stephanie}, title = {Mikrobiologie, Klinik und Antibiotika-Therapie invasiver bakterieller Infektionen an der W{\"u}rzburger Universit{\"a}ts-Kinderklinik zwischen 2006 und 2012}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-156236}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2017}, abstract = {In einem Zeitraum von sieben Jahren untersuchten wir invasive bakterielle Infektionen bei Kindern durch die wichtigsten Erreger von Blutstrombahninfektionen an der W{\"u}rzburger Universit{\"a}ts-Kinderklinik.}, subject = {Antibiotikum}, language = {de} } @phdthesis{PreussWiedenhoff2017, author = {Preuß-Wiedenhoff, Andrea}, title = {Therapeutisches Drug Monitoring bei an Schizophrenie erkrankten Kindern und Jugendlichen unter Pharmakotherapie mit Risperidon}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-156176}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2017}, abstract = {Ziel: Das Ziel dieser retrospektiven, naturalistischen Studie ist zum einen die Untersuchung der Zusammenh{\"a}nge von Dosierung und Serumkonzentration, Serumkonzentration und Therapieeffekt sowie von Serumkonzentration und unerw{\"u}nschten Arzneimittel-Wirkungen (UAW) bei an Schizophrenie erkrankten Kindern und Jugendlichen unter Risperidon-Therapie. Zum anderen soll die Anwendbarkeit des therapeutischen Serumkonzentrations-Referenzbereichs von Erwachsenen f{\"u}r Kinder und Jugendliche untersucht werden. Methode: Die von mehreren Kliniken in den Jahren 2005 - 2009 erhobenen Daten von 40 Kindern und Jugendlichen, die mittels des Therapeutischen Drug Monitorings {\"u}berwacht wurden, wurden retrospektiv ausgewertet. Die gemessenen Serumkonzentrationen erfolgten im Steady State und beziehen sich auf die Summe von Risperidon und 9-hydroxy-Risperidon (aktive Menge). Die Beurteilung der Therapieeffekte erfolgte mittels der CGI-C-Unterskala (Clinical Global Impression of Change), die der UAW mithilfe der UKU-Skala (Udvalg for Kliniske Unders{\o}gelser). Ergebnis und Fazit: Es zeigt sich eine signifikante, positive Korrelation zwischen der Tagesdosierung und der Serumkonzentration und keine signifikante Korrelation zwischen der Serumkonzentration und dem Therapieeffekt bzw. den UAW. Die Ergebnisse dieser Arbeit liefern erste Hinweise f{\"u}r einen m{\"o}glicherweise niedrigeren therapeutischen Referenzbereich f{\"u}r an Schizophrenie erkrankten Kindern und Jugendlichen unter Risperidon-Behandlung. Aufgrund der Limitationen des naturalistischen Studiendesigns ist der vorgeschlagene Referenzbereich eine richtungsweisende Empfehlung. Weitere Studien mit gr{\"o}ßeren Stichprobenzahlen sind n{\"o}tig um diese Ergebnisse zu validieren.}, subject = {Arzneimittel{\"u}berwachung}, language = {de} } @phdthesis{Kuen2017, author = {Kuen, Janina}, title = {Influence of 3D tumor cell/fibroblast co-culture on monocyte differentiation and tumor progression in pancreatic cancer}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-156226}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2017}, abstract = {Pancreatic cancer (PC) remains one of the most challenging solid tumors to treat with a high unmet medical need as patients poorly respond to standard-of-care-therapies. Prominent desmoplastic reaction involving cancer-associated fibroblasts (CAFs) and the immune cells in the tumor microenvironment (TME) and their cross-talk play a significant role in tumor immune escape and progression. To identify the key cellular mechanisms induce an immunosuppressive tumor microenvironment, we established 3D co-culture model with pancreatic cancer cells, CAFs, monocyte as well as T cells. Using this model, we analysed the influence of tumor cells and fibroblasts on monocytes and their immune suppressive phenotype. Phenotypic characterization of the monocytes after 3D co-culture with tumor/fibroblast spheroids was performed by analysing the expression of defined cell surface markers and soluble factors. Functionality of these monocytes and their ability to influence T cell phenotype and proliferation was investigated. 3D co-culture of monocytes with pancreatic cancer cells and fibroblasts induced the production of immunosuppressive cytokines which are known to promote polarization of M2 like macrophages and myeloid derived suppressive cells (MDSCs). These co-culture spheroid polarized monocyte derived macrophages (MDMs) were poorly differentiated and had an M2 phenotype. The immunosuppressive function of these co-culture spheroids polarized MDMs was demonstrated by their ability to inhibit autologous CD4+ and CD8+ T cell activation and proliferation in vitro, which we could partially reverse by 3D co-culture spheroid treatment with therapeutic molecules that are able to re-activate spheroid polarized MDMs or block immune suppressive factors such as Arginase-I. In conclusion, we generated a physiologically relevant 3D co-culture model, which can be used as a promising tool to study complex cell-cell interactions between different cell types within the tumor microenvironment and to support drug screening and development. In future, research focused on better understanding of resistance mechanisms to existing cancer immunotherapies will help to develop new therapeutic strategies in order to combat cancer.}, subject = {monocyte}, language = {en} }