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Jährlich erkranken etwa 425 000 Menschen in Deutschland an Krebs. Die Tendenz ist steigend: Experten gehen davon aus, dass die Zahl der Neuerkrankungen bis zum Jahr 2030 um 50 Prozent zunehmen wird. Doch zu dieser schlechten Nachricht gibt es auch eine gute: Körperliche Aktivität und Sport können das allgemeine Risiko, an bestimmten Krebsformen zu erkranken, vermindern. Dazu zählen vor allem Darmkrebs sowie der nach den Wechseljahren auftretende Brust- und Gebärmutterschleimhautkrebs. Aber auch wer schon erkrankt ist, kann sein Wohlbefinden und Selbstvertrauen durch spezielle Bewegungsprogramme, wie sie an der Goethe-Universität entwickelt werden, steigern. Selbst die Leiden von Patienten mit fortgeschrittenen Krebserkrankungen lassen sich auf diese Weise lindern. Denn Bewegung beeinflusst nicht nur die unmittelbar tumorbedingten Symptome, sondern auch therapiebedingte Nebenwirkungen, insbesondere die der Chemotherapie.
Die britische Autorin Caryl Churchill hat ein Stück gegen den israelischen Einmarsch in Gaza geschrieben – und sich den Vorwurf des Antisemitismus eingehandelt. Doch tatsächlich stellt dieses brutal-offene Stück einen mutigen Versuch der Einfühlung dar und zeigt so, was Politisches Theater sein kann.
Bensheim: Wie sind Fabriken, Unternehmer, Fabrikantenvillen, Arbeitersiedlungen immer auch Bestandteil der Ortsgeschichte? Wie wirken Unternehmen und Unternehmer hinein in das Leben und Zusammenleben der Menschen in Ort und Region? Wie sind Unternehmen, die nach 150 Jahren des Bestehens - epochal von der deutschen Hochindustrialisierung bis zur aktuellen Globalisierung - geschlossen werden, verankert im sog. kolektiven Gedächtnis eines Ortes und mit welcher Relevanz?
Acute myeloid leukemia (AML) is a hematopoietic cell disorder characterized by a block in differentiation and increased proliferation and survival of malignant blasts. Expansion of the malignant cell clone effects the normal production of blood cells and – if left untreated – leads to death. Receptor tyrosine kinases (RTKs) play an important role in the pathogenesis of AML, as they are either often mutated or overexpressed. In normal hematopoiesis, RTK signal termination is tightly controlled, and involves ubiquitination, internalization, endocytosis and degradation. Cbl proteins are E3 ligases and have been shown to ubiquitinate several activated RTKs, including Flt3 and Kit, targeting them for degradation. Recently, several Cbl mutations have been identified: Cbl-R420Q was identified in an AML patient and Cbl-70Z was identified in a mouse lymphoma model. In this thesis work, the role of these Cbl mutants in Kit signaling and in a mouse transplantation model was studied. Cbl mutants (Cbl-R420Q, Cbl-70Z) have the ability to transform the myeloid 32D cell line in cooperation with Kit WT. Cbl mutants along with Kit promoted interleukin-3 (IL3)-independent proliferation and enhanced the cell survival of 32D cells. In contrast, expression of the Cbl mutants alone did not confer IL3-independent growth. Stem cell factor (SCF, the Kit ligand) dependent growth was enhanced in the presence of Cbl mutants and Cbl mutants promoted colonogenic growth in the presence of Kit. Furthermore, Cbl mutants inhibited the ubiquitination of the activated Kit receptor. In addition, Cbl mutants inhibited the endocytosis of the activated Kit receptor. Retroviral expression of Cbl mutants in transplanted bone marrow induced a generalized mastocytosis, a myeloproliferative disease and, in rare care cases, myeloid leukemia. Splenomegaly was observed in the presence of Cbl mutants. Furthermore, mast cells with variable range of infiltration were noticed in all the vital organs (spleen, liver, bone marrow, lung, kidney, heart) of Cbl (mutant) transplanted mice. Almost all recipients of bone marrow cells transduced with Cbl mutants developed a lethal hematologic disorder with a mean latency of 341 days in the Cbl-R420Q group and 395 days in the Cbl-70Z group. This is the first published report on a hematological disease with Cbl mutants in a mouse model. Co-immunoprecipitation studies indicated that Cbl-70Z binds to Kit, even in the absence of Kit ligand. Cbl-R420Q also bound to Kit in the absence of SCF, albeit to a lesser extent. Association of Cbl mutants to Kit was enhanced in the presence of SCF. Signaling studies demonstrated the constitutive activation of Akt and Erk in the presence of Cbl mutants and Kit. In addition, Cbl mutants enhanced the SCF-dependent Kit, Akt and Erk activation. Cbl-70Z, in association with kinase-dead Kit (Kit-KD) or kinase-dead Flt3 (Flt3-KD), conferred IL3-independent growth and survival to the myeloid 32D cell line. Cbl-R420Q provided only a slight growth advantage in the presence of Kit-KD. As demonstrated by pharmacological inhibition studies, Akt activation was necessary for the transformation mediated by Cbl-70Z and Kit-KD / Flt3-KD. Cbl mutants enhanced the Src family kinases (SFKs) activity. The pharmacological inhibition of SFK activity inhibited the proliferation and colonogenic growth. Interaction was found between Cbl-70Z, SFKs and Kit-KD. The SFK member Fyn was identified to bind to Cbl. In addition, kinase activity of SFKs was necessary for binding to Cbl, since SFKs inhibition by PP-2 abolished the binding between the complex-binding partners. Dasatinib and PP-2, both SFK inhibitors, inhibited the Cbl and Akt phosphorylation indicating that Fyn acts upstream of Akt. Inhibition of Kit with imatinib reduced the proliferation of cells overexpressing Kit WT and Cbl-70Z much stronger compared with cells expressing Kit-KD and Cbl-70Z, but much less than the dual KIT/SFK inhibitor dasatinib. This indicated that Kit kinase activity was required but not essential. The data presented in this thesis work implies that both RTK and SFK inhibition may have to be targeted, in order to effectively prevent transformation. In summary, the present thesis work indicates an important role of Cbl, Kit and SFKs in myeloid transformation and deregulated signal transduction.
Untersuchung hochmolekularer Proteinkomplexe in menschlichen Leukämien mittels Proteomics-Werkzeugen
(2009)
Funktionelle Multiproteinkomplexe stellen im Sinne von Proteomics das kleinste isolierbare Proteom dar. Die Untersuchung von Proteinkomplexen gibt uns die Möglichkeit, Funktionen innerhalb der Zelle oder des Zellkompartiments genauer zu verstehen. Erst durch das Verständnis der einzelnen kleinen Zusammenspiele innerhalb einer Zelle, können wir die Auswirkungen auf ein betreffendes Organ und damit auf den Körper betrachten. Wir erhalten dadurch auch Informationen über die Funktion von spezifischen Genen und können so Erklärungsansätze für Gendefekte finden und über mögliche Therapieansätze nachdenken. Neben den Hefe-Zwei-Hybrid-Analysen und dem Nachweis von Protein-Interaktionen mittels Immunopräzipitationsexperimenten stellt die Massenspektrometrie seit den 90er Jahren ein essentielles Werkzeug der Proteom-Forschung dar. Sie entwickelte sich zu einem etablierten Verfahren für die Charakterisierung von Biomolekülen und ermöglicht die Identifizierung unbekannter Proteine eines Komplexes. Das MLL-Gen auf Chromosom 11 Bande q23 ist in zahlreiche, reziproke chromosomale Translokationen verwickelt, die mit der Entstehung von akuten Leukämien assoziiert sind. Chromosomale Translokationen des MLL-Gens werden aufgrund ihrer sehr schlechten Prognose und Therapierbarkeit als Hochrisiko-Leukämien eingestuft. Bis heute konnten 64 Translokations-Partnergene identifiziert werden, wobei das AF4-Gen mit 42% bei allen untersuchten Leukämien und mit ca. 66% bei ALL (akute lymphatische Leukämie) den größten Prozentsatz ausmacht. Bei der Translokation t(4;11) sind das MLL-Gen auf Chromosom 11 und das AF4-Gen auf Chromosom 4 beteiligt. Akute Leukämien mit einer t(4;11)-Translokation treten häufig bei Säuglingen und Kleinkindern auf und betreffen vorwiegend den lymphatischen Zweig des blutbildenden Systems. Durch die Translokation entstehen zwei neue Derivatchromosomen – Derivat 11 (MLL•AF4, der11) und Derivat 4 (AF4•MLL, der4). Beide Fusionsgene verfügen über einen intakten Leserahmen und führen zur Expression der zwei Fusionsproteine MLL•AF4 (der11) und AF4•MLL (der4). Der pathomolekulare Mechanismus der t(4;11)-vermittelten ALL ist bis heute noch nicht hinreichend geklärt. Funktionen des der11-Fusionsproteins werden zwar schon intensiv erforscht, aber es gibt noch keine Erkenntnisse über die Funktion des der4-Fusionsproteins. Ähnlich sah die Situation zu Beginn dieser Arbeit für das AF4-Protein aus. Während schon einige Daten zur Funktion des MLL-Multiproteinkomplexes vorlagen, gab es nur wenige Informationen über die Funktion von AF4. Im Zuge dieser Arbeit wurden der AF4- und der der4-Multiproteinkomplex mittels affinitätschromatographischer Methoden aus transient transfizierten 293T-Zellen erfolgreich isoliert. Eine Größenbestimmung der Komplexe über eine Größenausschlusschromatographiesäule ergab für beide Komplexe eine Größe von ca. 2 MDa. Die Charakterisierung der beteiligten Interaktionspartner erfolgte mittels nLC-MALDI-MS/MS, Western Blot Analyse und Immunopräzipitation. Es konnte gezeigt werden, dass AF4 zusammen mit den Proteinen ENL/AF9, CDK9, CCNT1, AF10, DOT1L und der RNA-Polymerase II in einem Komplex vorliegt. Bereits 2007 konnte dieser Komplex in einem Mausmodell isoliert werden. Damit fungiert der AF4-Komplex auch in humanen Zellen als Stimulator der RNA-Polymerase-II-abhängigen transkriptionellen Elongation und vermittelt eine DOT1L-abhängige H3K79-Methylierung, die einen aktiven Transkriptionsstatus aufrechterhält. Zusätzlich konnten 6 neue Interaktionspartner identifiziert werden (AF5q31, BDR4, DDX6, HEXIM1, NFkB1/RELA und NPM1). Die Anwesenheit von BRD4 und HEXIM1 lässt vermuten, dass der AF4-Komplex in einem aktiven und einem inaktiven Zustand vorliegen kann. Außerdem wird der AF4-Komplex möglicherweise über den NFkB-Signalweg reguliert bzw. durch die Anwesenheit von NFkB1 an dessen Zielgene rekrutiert. Die Untersuchung des der4-Komplexes zeigte, dass er sich aus Mitgliedern der beiden Wildtyp-Proteinkomplexe zusammensetzt. So wurden die Proteine P-TEFb, HEXIM1, NFkB1, NPM1, DDX6 und das AF4 selbst aus dem AF4-Komplex sowie ASH2L, RBBP5, WDR5, DPY-30, CBP, HCF-1 und HCF-2 aus dem MLL-Komplex identifiziert. Der der4-Komplex weist somit partielle Eigenschaften des AF4- und MLL-Wildtyp-Proteins auf. Diese Eigenschaften sind ausreichend für eine kompetitive Situation zwischen dem der4-Komplex und den beiden AF4- und MLL-Wildtyp-Komplexen. Die Gleichgewichte dieser Wildtyp-Komplexe werden vermutlich gestört. Für beide Komplexe wurde mit Hilfe eines in vitro Histon-Methyltransferase-Assays eine Histon-Methyltransferase-Aktivität nachgewiesen. Für den AF4-Komplex muss zusätzlich eine bisher noch unbekannte Methyltransferase-Aktivität angenommen werden, da eine Methylierung des Histons H3 in den ersten 46 Aminosäuren gezeigt werden konnte, die sich nicht auf die Methyltransferase-Aktivität des DOT1L-Proteins im AF4-Komplex zurückführen lässt. Die H3K4-Methyltransferase-Aktivität des der4-Komplexes wird auf die Anwesenheit des SET-Domänen-Komplexes (ASH2L, WDR5, RBBP5 und DPY-30) zurückgeführt. Im Zusammenhang mit dem AF4-Protein wurde auch der ENL-Komplex untersucht. Mittels Western Blot konnten die Interaktionspartner AF4, CDK9, CCNT1, RNA-Polymerase II, NFkB1 und RING1 identifiziert werden. Damit ist auch das ENL mit dem globalen positiven transkriptionellen Elongationsfaktor P-TEFb assoziiert und beeinflusst die RNA-Polymerase-II-abhängige transkriptionelle Elongation.
IL-18, a recently identified member of IL-1 family, is now recognized as an important regulator of innate and acquired immune responses. Therefore, the antitumor activities of IL-18 have been investigated. IL-18 has been shown to induce IFN-γ production by T, B, and NK cells, enhances NK cell activity, activates Fas ligandmediated apoptosis of the tumor cells, and improves the overall antitumor immunity. KG-1 cells were derived from a patient with acute myeloid leukemia (AML). IL-18 has been shown to induce IFN-γ production in those leukemic cells. TLR-3, in addition to its ability to recognize viral double stranded RNA, also can recognize the synthetic analogue poly(I:C) and induces type I IFN, inflammatory cytokine production, e.g TNF-α, and maturation of denderitic cells. In the present work the potential modulatory effect of PIC on IFN-γ and TNF-α production by KG-1 cells treated with IL-18 was investigated. Indeed, PIC strongly amplified the production of IFN-γ induced by IL-18 on mRNA and protein levels via NF-κB as well as p38 and JNK MAPK activation. Compared to IFN-γ, TNF-α showed different behaviour in KG-1 cells. On mRNA level I found only weak induction of TNF-α by IL-18 which was potentiated in the presence of PIC. Similarly, the release of TNF-α by IL-18 plus PIC required NF-κB as well as p38 and JNK MAPK activation. Furthermore, in the present work I found that TLR-3 is required for IFN-γ and TNF-α production. In addition, it is demonstrated by immunofluoresence that TLR-3 is localized in cytoplasm but not on the cell surface in KG-1 cells. Recently, it has been demonstrated that IFN-γ shows therapeutic potential as detected in AML blasts, specifically via inhibition of proliferation and induction of apoptosis. Thus our data could serve as a rationale for the clinical use of PIC and IL-18 in combination therapy. In search for new cytokines potentially modulated by the combination IL-18 plus PIC in KG-1 cells, cytokine antibody array analysis was performed. I found an upregulation of expected genes like IP-10 but most interestingly unexpected upregulation of PDGF-AA. Searching for detailed mechanisms of PDGF-AA induction, I found that neither p38 nor JNK is involved in PDGF-AA production but NF-κB is essential for the expression of PDGF-AA. Furthermore, I found that PDGF-AA is not able to increase the proliferation of KG-1 cells. PDGF and TGF-β are examples of signaling molecules which control the growth, survival, motility, and differentiation of cells. Therefore, the release of TGF-β by IL-18 plus PIC was monitored by ELISA. The level of TGF-β in cellular supernatants revealed that neither PIC nor IL-18 was able to significantly mediate release of TGF-β indicating that only PDGF-AA but not TGF-β is induced by PIC and IL-18 in KG-1 cells. To the best of our knowledge this is the first time that IL-18 or PIC is shown to induce the expression of PDGF-AA in KG-1 cells.
Algorithms and data structures constitute the theoretical foundations of computer science and are an integral part of any classical computer science curriculum. Due to their high level of abstraction, the understanding of algorithms is of crucial concern to the vast majority of novice students. To facilitate the understanding and teaching of algorithms, a new research field termed "algorithm visualisation" evolved in the early 1980's. This field is concerned with innovating techniques and concepts for the development of effective algorithm visualisations for teaching, study, and research purposes. Due to the large number of requirements that high-quality algorithm visualisations need to meet, developing and deploying effective algorithm visualisations from scratch is often deemed to be an arduous, time-consuming task, which necessitates high-level skills in didactics, design, programming and evaluation. A substantial part of this thesis is devoted to the problems and solutions related to the automation of three-dimensional visual simulation of algorithms. The scientific contribution of the research presented in this work lies in addressing three concerns: - Identifying and investigating the issues related to the full automation of visual simulations. - Developing an automation-based approach to minimising the effort required for creating effective visual simulations. - Designing and implementing a rich environment for the visualisation of arbitrary algorithms and data structures in 3D. The presented research in this thesis is of considerable interest to (1) researchers anxious to facilitate the development process of algorithm visualisations, (2) educators concerned with adopting algorithm visualisations as a teaching aid and (3) students interested in developing their own algorithm animations.
Representations of the unknown and the foreign can be found in every culture. Paralleling the method of constructing identity in relation to the Other, all cultures create myths about the ‘foreign’ in order to discern what the ‘native’ is, and thus often essentialize them as either good or bad, ultimately to vindicate one’s own actions and values. The nature of myths has it as such that they lend themselves to images, which are easily transformed into representations. Representations of the foreign in the United States follow the same purpose; they are propagated to define the nation’s identity and set it into political and cultural relation to other nations and civilizations. In this thesis’ context, then, representations of Asian Americans in American culture strengthen the imaginative bonds of American national identity manifesto. However, the interdependency of the Self and the Other clarifies and further entangles the subjects that constitute American national identity and in turn legitimizes the belated claim of Asian Americans to be included into it. Asian American literature is primarily concerned with these myths and (mis)representations that are influenced by Orientalist images in Western culture. Thus, Orientalism – a constructed myth about the Orient, which exists in art, books, and armchair theories of all kinds in the Western world – becomes the main motif for Asian American literature. If we construe this theory a little further then Asian American identity is formed in relation to Orientalist representations that need to be deconstructed first. From the outset, if Orientalism is considered as a produce of imperialism, it seems that time is a defining factor in Orientalism, both as an agent of change and as a factor of perspective. In reality, however, Orientalism seems resilient to time and change; the creation of the Madame Butterfly myth exemplifies what was created in 1887 had been perfected by 1900 and since then enjoys frequent comebacks until today. Thus, for Asian American artists and writers to dismantle Orientalist stereotypes begins a literally archaeological process: excavating the leftovers of American Orientalism, evaluating those finds, and re-relating them with their own cultural and historical actuality. Rather than producing a neat line of argumentation, the approaches on defining Asian American identity within the American national identity manifesto fall into unwieldy clusters and even get tangled up into self-contradictions. The methods of dismantling Orientalist stereotypes are manifold and range from total rejection over evocation and appropriation to reflection. In order to wrestle such disparate issues Orientalism produces in Asian American Literature into an organic whole, it was important to focus consistently on the over arching theme of American national identity. As this thesis aims to show, Orientalist issues that are dealt with in Asian American literature all point toward the greater aim of national inclusion. This thesis is grouped into two parts. PART I provides historical and theoretical background information necessary to understand Orientalist issues in contemporary Asian American literature. Analogous to Asian American writers that feel the necessity to bed their work into the correct historical frame in order to prevent misunderstanding, chapters two and three serve to couch my argument into the correct frame. The theoretical base work is laid with Edward Said’s Orientalism and its implementation on the American and Asian American context. PART II examines literary examples, applying the theorems discussed in PART I. Chapter four is a close analysis of the submissive Butterfly stereotype that has, since its appearance in late nineteenth century, moved, inspired and even outraged writers. Beginning with the literary development of Madame Butterfly, D. H. Hwang’s deconstructivist M. Butterfly gives new perspectives on Orientalism by redefining gender and racial roles. To complement my analysis, in chapter five, I try to trace current Asian American reactions to Orientalism. Texts by comedian Margaret Cho and poet Beau Sia serve as examples of analysis. As a result of the disparate narrative forms of the analyzed works and the unevenness of scholarship on twenty-first century, the analyses vary greatly in scope and detail. In choosing fairly young narrative forms like stand-up comedy and spoken word poetry I want to emphasize how Orientalism pertains to the question of Asian American identity. To close the circle of my discourse I will go back to where I start my thesis: Asian Americans and their position within America’s national identity discourse. It is noteworthy that until today, Asian American identity remains a hostage of these Orientalist stereotypes that mark the boundaries of their American identity.