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In the midst of the centennial anniversary of the First World War, there has been an explosion of scholarship on the war and its legacy in the Middle East. Scholars have reassessed – or taken up for the first time – questions of the Ottoman Empire’s motivations for joining the war, military history, social history, the environmental impact of the war, and the war’s aftermath in the region, among other topics. Together, historians have reconstructed the importance of the war and its legacy as ...

Malignant gliomas are one of the most devastating cancers in humans. One characteristic hallmark of malignant gliomas is their cellular heterogeneity with frequent genetic lesions and disturbed gene expression levels conferring selective growth advantage. Here, we report on the neuronal-associated growth promoting gene PRG3 executing oncogenic cooperation in gliomas. We have identified perturbed PRG3 levels in human malignant brain tumors displaying either elevated or down-regulated PRG3 levels compared to non-transformed specimens. Further, imbalanced PRG3 levels in gliomas foster Ras-driven oncogenic amplification with increased proliferation and cell migration although angiogenesis was unaffected. Hence, PRG3 interacts with RasGEF1 (RasGRF1/CDC25), undergoes Ras-induced challenges, whereas deletion of the C-terminal domain of PRG3 (PRG3ΔCT) inhibits Ras. Moreover PRG3 silencing makes gliomas resistant to Ras inhibition. In vivo disequilibrated PRG3 gliomas show aggravated proliferation, invasion, and deteriorate clinical outcome. Thus, our data show that the interference with PRG3 homeostasis amplifies oncogenic properties and foster the malignancy potential in gliomas.

Hintergrund und Ziele Das Glioblastoma multiforme ist auch heute noch der bösartigste, hirneigene Tumor, der trotz modernster Medizin und zahlreicher Fortschritte in der Wissenschaft eine schlechte Prognose aufweist. Die mediane Überlebenszeit beträgt momentan 14 Monate. Neben einer chirurgischen Therapie durch Resektion des Tumorgewebes und einer adjuvanten Radiochemotherapie rücken mittlerweile verschiedene Medikamente aus der experimentellen Forschung in den klinischen Alltag. Die aktuelle medikamentöse Therapie bietet unterschiedliche Ansätze: Die Normalisierung der Tumor-spezifischen Gefäße, antitumorale Wirkstoffe und die Aufhebung des tumoralen Einflusses auf die peritumorale Ödemzone. Das Anliegen dieser Arbeit war es, ein organotypisches Hirnschnittmodell zu präsentieren, in welchem die Erforschung des Tumor-Mikromilieus und der Interaktionen von Glioblastomen und dem umliegenden Gewebe und Gefäßen möglich ist. Methoden Es wurden organotypische Hirnschnitte aus postnatal sechs bis neun Tagen alten Ratten hergestellt, die bis zu einer Woche in Kultur gehalten werden konnten. In diesem ex vivo Modell wurden dann Tumorprogressions-Analysen, medikamentöse Behandlungen mit Sunitinib einem Tyrosinkinase-Rezeptor-Blocker sowie angiogenetische Untersuchungen in Bezug auf die peritumorale Invasionszone und direkte Live-Zell-Färbung der Hirngefäße durchgeführt. Im vaskulären organotypischen Gliom-Invasions-Modell konnten zudem unterschiedliche Zonen, ähnlich dem Tumorzonen-Modell nachgewiesen werden. Ergebnisse Im organotypischen Hirnschnitt-Modell zeigte sich dass im Hirnschnitt implantierte Glioblastomzellen solide Tumormassen formen und diese um eine Fläche von 50% innerhalb einer Woche wachsen. Unter medikamentöser Behandlung konnte das Wachstum deutlich verlangsamt werden; in hohen Konzentrationen beobachtete man gliomtoxische Effekte. Nach dem Fixieren und Färben der Hirnschnitte wurden die Gefäße untersucht. So herrschte in der peritumoralen Zone stets eine höhere Gefäßdichte. Eine medikamentöse Behandlung mit Sunitinib zeigte hierbei eine geringere Gefäßdichte im Vergleich zu den Kontrollen. Weiterhin konnten unterschiedliche Zonen im Hirnschnitt definiert werden. Um den Tumor herum zeichnete sich eine Ödemzone mit hoher Zelldichte ab. Des Weiteren war es möglich über eine Live-Zell-Färbung mit Hilfe des Isolectins IB-4 Gefäße im lebenden Hirnschnitt sichtbar zu machen. Schlussfolgerungen und Ausblick Diese Arbeit konnte zeigen, dass das VOGIM eine Ergänzung als Brücken-Modell zwischen in vivo und in vitro Studien darstellt. Das ex vivo Modell ermöglicht die Erforschung von Interaktionen zwischen malignen Gliomen und Astrozyten, Neuronen und Gefäßen in einem lebenden abgeschlossenen System, das der in vivo Situation so nah als nur möglich kommt. So kann eine medikamentöse Behandlung von malignen Gliomen in kurzer Zeit getestet werden, um unterschiedliche Wirkungen wie Gliomtoxizität, Antiangiogenese und Neuroprotektion zu erforschen. Zudem kann die Arbeit einen Ausblick auf künftige Möglichkeiten von organotypischen Hirnschnittmodellen liefern: Durch Live-Zell-Färbung gelang es uns Gefäße im lebenden Hirnschnitt sichtbar zu machen. Durch Erweiterungen der Methoden, im Speziellen der Live-Zell-Färbung könnten zelluläre Interaktionen auf mikroskopischer Ebene, das Tumor-Mikromilieu und die Entstehung der Tumorzonen in Echtzeit beobachtet werden. Aim and background of the study The glioblastoma multiforme remains to be the most devastating primary brain tumour, despite the modern medical treatment and numerous advances in science with a survival rate of 14 months after diagnosis. Alongside the surgical therapy by resection of the cancer tissue and additional adjuvant radio- and chemotherapy, there are various agents, which made the transition from bench to bedside. The current medical treatment regimen offers multiple approaches: The antiangiogenic approach with normalization of pathological vessels, antitumoral agents and the blockage of the tumours’ influence on the peritumoral edema zone in which tyrosine kinase inhibitors like sunitinib might play a crucial role. The aim of this study was to present an organotypical brain slice culture to study the tumour microenvironment and interaction between glioblastomas and the surrounding tissue and vessels. Methods Organotypical brain slices have been prepared from six to nine day old rats to be kept in culture to up to one week. Analysis of tumour progression, treatment with sunitinib, a tyrosine kinase receptor blocker as well as angiogenetic studies have then been performed. Angiogenesis was mainly studied in context to the peritumoural zone. In addition, a live-cell-staining for vessels has been performed. Moreover, we detected various zones in the organotypical brain slice, which may resemble closely the tumour zone model. Results After implantation on the organotypical brain slice, malignant glioma cells form a solid tumour mass. Over a course of one week, the area of the tumour mass grows by 50%. When medicated, the tumours grow significantly slower and when treated with high concentrations gliomatoxic effects occur. After fixation and staining of the slice cultures, brain vessels have been examined. The peritumoural zone is dominated by high vessel density. When treated with sunitinib the vessel density in the peritumoural zone was significantly lower compared to controls. Moreover, different zones have been defined. The tumour mass is surrounded by an edema with high cell density. In addition, it was possible to perform a live-cell-imaging of vessels in the living brain slice with isolectin IB-4. Conclusion and outlook To put it in a nutshell, this study was able to demonstrate the VOGIM as a bridging method to in vivo and in vitro studies. The ex vivo design enables to study interactions of malignant gliomas with astrocytes, neurons and vessels in a self-contained system, which resembles the living as close as possible. Medication of malignant gliomas can be tested in no time to study different aspects like gliomatoxicity, antiangiogenesis and neuroprotection. Moreover, this work provides an outlook on various possibilities of the brain slice model like live-cell-imaging. Improvement of live-cell-imaging may lead to studies of cellular interactions, of the tumour microenvironment and the formation of the tumour zones in real time.

Nowadays, about one fourth of all prime time commercials in the United States feature celebrity endorsers. Previous research has identified numerous benefits of this powerful marketing strategy. Unfortunately, celebrities have been increasingly involved in negative publicity in the recent past. Using event study methodology, I examine the influence of negative celebrity endorser publicity on immediate and subsequent stock returns, covering 59 events during a 25 year period from 1988 to 2012. My research shows that firms do not have to take losses for granted. By choosing proactive versus reactive/passive strategies, firms can successfully counteract the subsequent negative stock returns. Thus, it is not the negative event itself that drives the subsequent financial performance, but rather the immediate response of firms. Although immediate firm reactions increase the salience of the event and cause stock prices to drop initially, they also build up investors' trust and confidence again, ultimately leading to increased stock returns in the subsequent weeks. On the flipside, a reactive/passive strategy shows a lack of control and leadership, which can lead to substantial financial losses in the subsequent weeks. I show that this main effect is attenuated for subsidiary (vs. corporate) brands. Further, the appropriateness of the reaction (match between expected and actual firm reaction) is also crucial. Overall, this dissertation helps to advance the knowledge regarding the financial risk of negative celebrity endorser publicity and provides firms with advice to best manage the situation. Ph. D.

The contribution compares the abrasion and erosion resistance of twohigh-alloy tool steels, X153CrMoV12-1 and Böhler K390 Micro Clean, coated with multilayer coatings TiN/TiCN and TiN/Ti-B-N. Multilayer coatings were applied to hardened and tempered samples by pulsed direct current (DC) plasma-assisted chemical-vapour deposition (PACVD) process in the Rübig PC 70/90 industrial vacuum furnace. The mechanical properties of the coating were tested by calottest, Rockwell-C indentation and the micro hardness tests. Abrasion resistance was tested by the “Dry sand/Rubber wheel” and micro abrasion method. Erosion resistance was tested by exposing the surface of the samples to a jet of fine sand particles at an angle of incidence of 90 degrees for 60min. Worn surfaces were analysed with a light and scanning electron microscope. It was found that increased resistance to abrasion and erosion wear is achieved on samples with higher substrate hardness and higher hardness, and better adhesion of the coating.