Defining mechanisms directing YAP/TAZ-mediated tumorigenesis

Dysregulated Hippo pathway signaling promotes the onset of aggressive cancers through the induced nuclear activity of yes-associated protein (YAP) and transcriptional co-activator with PDZ binding motif (TAZ) (YAP/TAZ). Uncontrolled nuclear YAP/TAZ activity evokes tumor-initiating properties in a range of epithelial-derived cancers, including oral and breast cancers, but their downstream targets and mechanisms of action are unclear. Recent studies have suggested that the pro-tumorigenic roles for YAP/TAZ relate to their convergence with growth factor signaling pathways. Based on these previous studies, I hypothesized that YAP/TAZ driven transcription contributes to carcinoma progression, and that cooperation with transforming growth factor β (TGFβ)-induced signals promotes aggressive oncogenic traits. In this thesis I show that dysregulated YAP localization precedes oral squamous cell carcinoma (OSCC) development, and that nuclear YAP/TAZ activity drives cell proliferation, survival, and migration in vitro, and is required for tumor growth and metastasis in vivo. Global gene expression studies in OSCC cells revealed that YAP/TAZ-mediated gene expression correlates with expression changes that occur in human OSCCs identified by “The Cancer Genome Atlas” (TCGA), many of which encode cell cycle and survival regulators. By exploring the relationship with growth factor signaling, I found that YAP/TAZ induce pro-tumorigenic events by converging with TGFβ-induced signals, particularly in breast cancer cells where TGFβ is known to promote metastatic properties. My observations indicated that YAP/TAZ are necessary for maintaining and promoting TGFβ-induced tumorigenic phenotypes in breast cancer cells, and that these phenotypes result from the cooperative activity of YAP/TAZ, the TEA domain family of transcription factors (TEADs), and TGFβ-activated SMAD2/3 in the nucleus. Genome-wide expression analyses indicated that YAP/TAZ, TEADs, and TGFβ-induced signals coordinate a specific pro-tumorigenic transcriptional program. Importantly, genes cooperatively regulated by these complexes, such as the novel targets neuronal growth regulator 1 (NEGR1) and urothelial cancer associated 1 (UCA1), are necessary to maintain tumorigenic activity in metastatic breast cancer cells. Nuclear YAP/TAZ also cooperate with TGFβ signaling to promote phenotypic and transcriptional changes in non-tumorigenic cells to overcome TGFβ-mediated growth inhibition. This work thus defines novel roles for YAP/TAZ in cancer, offering molecular mechanisms that may be useful for identifying and targeting YAP/TAZ-driven cancers

Patterns in the Acoustic Presence and Vocal Behaviour of Bowhead Whales Balaena mysticetus in Eastern Fram Strait

Fram Strait, located between Greenland and Svalbard, provides a critical habitat to seasonally migrant and endemic cetaceans, including bowhead whales Balaena mysticetus of the Spitsbergen population. This population has been depleted close to the point of extinction by commercial whaling and still is considered as endangered. Due to its low abundance and the remoteness of its habitat, baseline knowledge on spatio-temporal distribution patterns and behavioural aspects are scarce, yet crucial for the conservation of this population. Long-term passive acoustic recordings were collected at different locations in eastern Fram Strait (78-79°N, 0-7°E), contributing to the Ocean Observing System FRAM (Frontiers in Arctic Marine Monitoring). Data recorded during two sampling periods between 2012 and 2017 were analysed for the occurrence of bowhead whales using the Low-Frequency Detection and Classification System (LFDCS). Seasonal changes in their acoustic repertoire were investigated using recordings from a single year and location. Bowhead whales were acoustically present from autumn throughout winter (October/November-February) and occasionally in spring (March-June), suggesting that Fram Strait is used as an overwintering area. Given that peak levels of acoustic presence coincided with the presumed mating period of bowhead whales, Fram Strait may also serve as a mating area. No bowhead whales were recorded in summer (July-September), indicating that they either were vocally inactive or had migrated to summering areas. Eight distinct song types of bowhead whales were identified comprising simple songs and call sequences. Even though more than one song type was recorded at a given time, there was an overall trend that songs occurred in temporal succession. It remains speculative why songs appeared and subsequently disappeared with the progressing season, but the temporal succession possibly is related to the song types being used in different behavioural contexts. One song type formed an exception as it was recorded throughout almost the entire season and may hence serve a communicative function common to all individuals, or at a least a large part of the population. In contrast to previous studies on bowhead whales in western Fram Strait, the recorded bowhead whale detections were less frequent and, in addition, less complex. Bowhead whales appear to preferentially occupy the western part of Fram Strait where sea ice concentrations are generally higher. Due to the observed regional differences in the acoustic behaviour between eastern and western Fram Strait, eastern Fram Strait may represent the easterly distribution range boundary of the bowhead whale overwintering area. The findings of this study further highlight the importance of Fram Strait as a habitat for the endangered Spitsbergen bowhead whale population. In the light of rapid changes in the Arctic region, an improved understanding of distribution patterns and the acoustic behaviour is of particular relevance for developing effective conservation and management strategies, but also for assessing potential effects on the bowhead whale population resulting from climate-induced environmental changes

The future of German chemical sites: Potential pathways and organizational readiness:Introduction of a study design

Chemical sites are an integral part of the chemical industry in Germany. Therefore, it is obvious that the development from diversified to more specialized chemical companies will also lead to rising challenges for the chemical siting sector. Furthermore, chemical sites need to react to changes in the environment of chemical companies, such as the relocation of supply chains or intensifying EU regulations. As changes in the chemical industry require the adaptation of chemical sites, this article presents a study design to assess the status quo and the future challenges chemical sites will need to confront

Model based detection and reconstruction of road traffic accidents

This thesis describes the detection and reconstruction of traffic accidents with event data recorders. The underlying idea is to describe the vehicle motion and dynamics up to the stability limit by means of linear and non-linear vehicle models. These models are used to categorize the driving behavior and to freeze the recorded data in a memory if an accident occurs. Based on these data, among others the vehicle trajectory is reconstructed with fuzzy data fusion. The side slip angle which is a crucial quantity describing the vehicle stability is estimated with non-linear state observers and Kalman-Filters. The methodologies presented may lead from accident reconstruction considered here to accident avoidance

Hat die Art der Operation einen Einfluss auf die Inzidenz von postoperativer Übelkeit und Erbrechen?

Das Auftreten von postoperativer Übelkeit und Erbrechen ist eine vergleichsweise häufige narkosebedingte Komplikation, die sowohl im Hinblick auf die Patientenzufriedenheit als auch auf körperliche und ökonomische Konsequenzen nicht zu vernachlässigen ist. Zur Optimierung der antiemetischen Prophylaxe ist die Identifizierung des patientenspezifischen Risikoprofils unabdingbar. In der vorliegenden Arbeit wurden 2347 Patient*innen auf die Abhängigkeit des PONV-Auftretens von der Operationsart unter möglichst exakter Elimination weiterer Einflussfaktoren untersucht. Zur Berechnung einer PONV-Prognose wurde zunächst anhand von Apfel- und Koivuranta-Score auf ein durchschnittliches PONV-Risiko innerhalb der Eingriffsgruppen geschlussfolgert. In diese Risiken wurde die medikamentöse Prophylaxe mittels additiver relativer Risikoreduktion einkalkuliert. Es wurden also für beide PONV-Angaben der Risikoscores je drei Rechnungen mit Risikoreduktionen von jeweils 30%, 25% bzw. 20% pro verabreichtem Antiemetikum durchgeführt. Somit resultierten für jede Operationsgruppe PONV-Prognosen, die sowohl Risikofaktoren als auch die protektive Wirkung der antiemetischen Prophylaxe enthielten. Die postoperativ erhobene PONV- Inzidenz wurde dann anhand von Konfidenzintervallen im Hinblick auf Abweichungen von diesen PONV-Prognosewerten und von der PONV-Inzidenz im Gesamtkollektiv untersucht. Eine Übereinstimmung von PONV-Prognose und tatsächlicher Inzidenz im Gesamtkollektiv als Referenzgruppe zeigte sich bei der Kalkulation mit einer relativen Risikoreduktion von 30% anhand der Risikoangaben beider Scores sowie mit einer relativen Risikoreduktion von 25% anhand des Koivuranta- Scores. Hier bestanden signifikante Abweichungen in den Kollektiven der Cholezystektomien und der gesamten sowie offen operierten Hysterektomien, deren PONV-Häufigkeit höher als prognostiziert ausfiel. Bei abdominalen Eingriffen zeigte sich nur bei der Kalkulation einer Prognose mit einer relativen Risikoreduktion von 30% eine höhere PONV-Inzidenz als das kalkulierte Risiko. Bei den gesamten und laparoskopisch operierten gynäkologischen Patient*innen sowie bei der laparoskopischen Vorgehensweise insgesamt war die Inzidenz ausschließlich höher als die anhand des Koivuranta-Scores mit einer Risikoreduktion von 30% kalkulierte PONV-Prognose. Bei dem Vergleich der tatsächlichen Inzidenzen mit der des Gesamtkollektivs (23.7%) bestanden niedrigere PONV-Häufigkeiten in den Gruppen der urologischen Patient*innen (13.9%), der Mamma-Operationen (17.0%) sowie bei den HNO-Eingriffen (17.4%). Höher waren die Inzidenzen bei orthopädischen (29.0%) und gynäkologischen (27.5%) Eingriffen, Cholezystektomien (35.9%), Hysterektomien (42.6%), abdominalen Eingriffen (34.0%) sowie Laparoskopien insgesamt (28.8%) und im gynäkologischen Kollektiv (32.1%). Die laparoskopische Eingriffsweise war insgesamt mit einem höheren PONV-Auftreten assoziiert als das offene Vorgehen; bei den Hysterektomien und den gynäkologischen Eingriffen bestand jedoch zwischen den beiden Vorgehensweisen keine Abweichung. Trotz dieser Erkenntnisse sollte die Intensivierung einer antiemetischen Prophylaxe bei den als risikoassoziiert identifizierten Eingriffen aufgrund der nicht zu eliminierenden Störfaktoren nicht grundsätzlich erwogen werden. Als einige dieser Einflussfaktoren lassen sich eine jüngerer Altersstruktur insbesondere bei laparoskopischen Eingriffen, eine variierende Operationsdauer, die Dosisabhängigkeit der PONV-Steigerung von Opioiden und volatilen Anästhetika, die begrenzte Aussagekraft der Risikoscores sowie die Ungenauigkeit der verallgemeinert gleichen und additiv betrachteten Wirksamkeit aller antiemetischen Methoden anführen. Weiterhin zeigte sich eine Heterogenität der in die einzelnen Subgruppen inkludierten Operationen sowie der unterschiedlichen perioperativen Settings bei variierenden Eingriffsspektren in den beteiligten Kliniken, wodurch Rückschlüsse auf das Risikoprofil spezifischer Operationsarten erschwert waren. Dennoch bestanden bei Hysterektomien und Cholezystektomien eine ausreichend robuste Abweichung der Inzidenz von der niedriger kalkulierten Prognose sowie eine im Vergleich zum Gesamtkollektiv häufiger benötigte antiemetische Therapie. In Zusammenschau mit anderen risikosteigernden Faktoren sollte hier eine Anpassung der Prophylaxe erwogen werden

First tracks of individual Blackcaps suggest a complex migration pattern

The Blackcap Sylvia atricapilla is a model species for the evolution of bird migration in a time of global change. However, many assumptions about putative changes to their migratory paths have not been verified because, until recently, it has not been possible to track individual small passerines throughout the entire migration cycle. With the recent development of miniaturised light-level geolocators, it is now possible to track passerines throughout the migration cycle and test these latter assumptions. We deployed 100 geolocators on Blackcaps breeding in southern Germany in 2015, and recaptured three of these birds in 2016. We used a new analytical tool implemented in the R package GeoLight to identify stopover sites during migration. One bird migrated due west to winter in southern England or possibly northwestern France, whereas two birds migrated south towards North Africa via Italy. Although none of the retrieved geolocators collected data throughout the entire migration cycle, the data suggest that migration patterns of the species are more complex than previously thought

The Second World War in Polish Cinema. Recent Filmic Approaches and the Reception in Poland and Germany

The article deals with the representations of history in contemporary Polish cinema. On the occasion of the 70th anniversary of the Warsaw Uprising, Jan Komasa released two fundamentally different films within one year. By an analysis focusing the context, the artistic product and the reception, the author intends to decode the different messages and reception offers. The intended reception is then contrasted to the real reception referring to the reactions in Polish and (in the case of Miasto 44) in German media.The article deals with the representations of history in contemporary Polish cinema. On the occasion of the 70th anniversary of the Warsaw Uprising, Jan Komasa released two fundamentally different films within one year. By an analysis focusing the context, the artistic product and the reception, the author intends to decode the different messages and reception offers. The intended reception is then contrasted to the real reception referring to the reactions in Polish and (in the case of Miasto 44) in German media