Urbane Legenden - Kenntnisse und Empfänglichkeit bei Wiener Studenten

Diese Diplomarbeit beschäftigt sich mit unterschiedlichen Faktoren, welche die Empfänglichkeit für urbane Legenden beeinflussen könnten. Es werden mehrere soziale und psychologische Konstrukte, wie das Geschlecht, die Herkunft (urban oder ländlich), das zwischenmenschliche Vertrauen, die Studienrichtung, das Interesse für Spannung und Grusel und die Quelle der urbanen Legenden, dahingehend untersucht, in wie fern sie einen Einfluss auf die Empfänglichkeit von Studenten für diese Art von Erzählung haben. Diese Konstrukte werden mit einem Fragebogen erhoben und die Daten anschließend mit verschiedenen multivariaten Analyseverfahren untersucht. Diese Arbeit soll dabei helfen, einen Einblick in die Bedeutsamkeit urbaner Legenden in der heutigen Gesellschaft zu liefern.Aim of this diploma thesis is to clarify the impact of diverse parameters on the receptivity of viennese students for urban legends. To this end several constructs regarding the probant’s sociodemographic characteristics (sex, origin, course of study) and his/her psychological profil (interpersonal trust, interest in suspense an horror) were surveyed. These data as well as the source of the used urban legends will be statistically analysed using diverse multivariate methods. This approach will help to gain more insights into the role of urban legends in the modern society

Molecular mechanisms underlying the anticancer activity of the new lanthanum compound KP772

Platinhältige Chemotherapeutika gehören zu den am häufigsten in der Krebstherapie eingesetzten Medikamenten. Leider ist ihr Einsatz auf Grund hoher Nebenwirkungen und dem Auftreten von Chemotherapieresistenzen nicht immer erfolgreich. Deswegen ist die Entwicklung von neuen, verbesserten metallhältigen Medikamenten weiterhin ein aktuelles Thema. In den letzten Jahrzehnten wurden zu diesem Zweck tausende neue Metallverbindungen entwickelt, von denen es aber nur ein Bruchteil bis zur klinischen Anwendung geschafft hat. Außerdem ist trotz der Menge neuer Substanzen das Wissen über ihre chemischen und biologischen Wirkungsmechanismen im Körper und im Tumor immer noch begrenzt. Besonders der Einfluss und die Entwicklung von Resistenzmechanismen gegen diese Verbindungen sind weitgehend unerforscht (Manuskript 1). [Tris(1,10-phenanthroline)lanthanum(III)]trithiocyanate (KP772) ist eine neue Lanthanverbindung mit vielversprechender Wirksamkeit gegen ein großes Spektrum von Tumorzelllinien in vitro und ein Dickdarmkrebsmodell in vivo. Ziel der hier präsentierten Arbeit war es die molekularen und zellbiologischen Mechanismen zu erforschen, die der Wirksamkeit dieser neuen Substanz gegen Krebszellen zugrunde liegen. Schon in einer frühen Phase des Projekts wurde entdeckt, dass die Behandlung mit KP772 die DNS-Synthese in Tumorzellen blockiert und die Zellteilung in der G0/G1-Phase stoppt. Dieser Zellzyklusarrest, der nicht durch DNS-Schäden hervorgerufen wurde, wurde von apoptotischem Absterben der Zellen begleitet (Manuskript 2, Manuskript 3). Zusätzlich wurde die Zytotoxizität von KP772 gegen 60 Zelllinien am National Cancer Institute (NCI) getestet und das Ergebnis in einer Datenbankanalyse mit anderen Chemotherapeutika verglichen. Dieses Screening zeigte, dass die Wirksamkeit von KP772 nur schwach mit der von anderen Substanzen korrelierte. Interessanterweise waren mehrere Antimetaboliten (z.B. Hydroxyharnstoff) unter jenen Zytostatika, die die höchsten Korrelationswerte erreichten. Da der Hydroxyharnstoff ein allgemein bekannter Ribonukleotidreduktase (RR)-Hemmstoff ist, wurde als nächstes die Hemmwirkung von KP772 auf dieses Enzym untersucht. Die Behandlung mit KP772 führte zu einer signifikanten Reduktion des Cytidineinbaus und dem Abfall der zellulären dNTP-Level. Außerdem zeigten die in diesem Projekt durchgeführten Experimente, dass KP772 die R2 Untereinheit der RR durch Eisenchelatierung und Störung des Tyrosylradikals hemmt (Manuskript 4).Zusätzlich wurde in diesem Projekt der Einfluss von resistenzvermittelnden Transportproteinen auf die Wirksamkeit von KP772 untersucht (Manuskript 5). Interessanterweise stellte sich heraus, dass die Expression dieser Resistenzproteine mit einer erhöhten Sensitivität gegen KP772 einhergingen. Außerdem führte eine längere Behandlung mit subtoxischen KP772 Konzentrationen zum kompletten Verlust der Transportpumpen, was zu einer Wiederherstellung der Sensitivität gegen Chemotherapie führt. Schließlich wurde das mögliche Auftreten von Resistenz gegen KP772 nach mehreren Behandlungszyklen untersucht. Im Gegensatz zu herkömmlichen Medikamenten konnten Krebszellen keine Resistenz gegen KP772 entwickeln. Zusammenfassend deuten die hier präsentierten Untersuchungen daraufhin, dass KP772 besonders vielversprechend für die Behandlung von PatientInnen sein könnte, die an chemotherapieresistenten Tumortypen leiden. Darüber hinaus könnte es sogar ein Wiederansprechen dieser Tumorerkrankungen auf herkömmliche Chemotherapie bewirken.Platinum drugs are essential components of modern cancer chemotherapy. However, their success is limited due to severe adverse effects and/or drug resistance. Thus, several research groups focus on the synthesis of novel metal drugs with reduced adverse side effects and less propensity to induce drug resistance (Manuscript 1). Although a large number of new metal compounds has been developed, in many cases the knowledge on their actual chemical and biological interactions within the human body, especial with regard to mechanisms which lead to resistance of tumor cells is still limited. [Tris(1,10-phenanthroline)lanthanum(III)] trithiocyanate (KP772) is a new compound exerting potent activity against a wide range of tumor cell lines in vitro and a colon carcinoma xenograft model in vivo. Aim of the here presented thesis was the investigation of the molecular and cell biological mechanisms underlying the anticancer activity of KP772. Treatment with KP772 was found to block DNA synthesis and cell cycle progression in G0/G1 phase which was not based on radical- or intercalation-induced DNA damage. This was accompanied by apoptotic cell death via the mitochondrial pathway. Additionally, KP772 was evaluated against a panel of 60 cell lines as part of the in vitro anticancer-screening services provided by the NCI (Manuscript 2, Manuscript 3). When this NCI profile was compared to that of other drugs, only moderate correlations with other known chemotherapeutics were observed. Notably, several antimetabolic drugs including hydroxyurea (HU) were amongthose reaching significant correlations. Since HU is a known ribonucleotide reductase (RR) inhibitor, the next step was the investigation of the RR inhibitory potential of KP772. The respective experiments revealed that KP772 treatment led to significant reduction of cytidine incorporation and decrease of all dNTP pools. Moreover, the iron center of the R2 subunit of RR might be targeted by due to the iron chelating and radical scavenging properties of KP772 (Manuscript 4). With regard to the impact of common resistance mechanisms, overexpression of resistancemediating efflux pumps (ABC-transporter) was found to significantly sensitise against KP772. This hypersensitivity was demonstrated to be based on stronger apoptosis induction and/or cell cycle arrest at unaltered cellular drug accumulation. Moreover, long-term KP772 treatment of transporter-overexpressing cells at subtoxic concentrations led within 20 passages to a complete loss of drug resistance. Additionally, when exposing chemosensitive cells to stepwise increasing KP772 concentrations, we observed, in contrast to several other metal drugs, no acquisition of resistance (Manuscript 5). Taken together, these data indicated that KP772 might be especially promising for treatment of patients suffering from chemotherapy-resistant tumors based on ABC transporter-mediated resistance or as second line treatment after standard chemotherapy failure

Identifying new topoisomerase II poison scaffolds by combining publicly available toxicity data and 2D/3D-based virtual screening

Molecular descriptor (2D) and three dimensional (3D) shape based similarity methods are widely used in ligand based virtual drug design. In the present study pairwise structure comparisons among a set of 4858 DTP compounds tested in the NCI60 tumor cell line anticancer drug screen were computed using chemical hashed fingerprints and 3D molecule shapes to calculate 2D and 3D similarities, respectively. Additionally, pairwise biological activity similarities were calculated by correlating the 60 element vectors of pGI50 values corresponding to the cytotoxicity of the compounds across the NCI60 panel. Subsequently, we compared the power of 2D and 3D structural similarity metrics to predict the toxicity pattern of compounds. We found that while the positive predictive value and sensitivity of 3D and molecular descriptor based approaches to predict biological activity are similar, a subset of molecule pairs yielded contradictory results. By simultaneously requiring similarity of biological activities and 3D shapes, and dissimilarity of molecular descriptor based comparisons, we identify pairs of scaffold hopping candidates displaying characteristic core structural changes such as heteroatom/heterocycle change and ring closure. Attempts to discover scaffold hopping candidates of mitoxantrone recovered known Topoisomerase II (Top2) inhibitors, and also predicted new, previously unknown chemotypes possessing in vitro Top2 inhibitory activity

Quantification of ferritin-bound iron in murine samples for Alzheimer's disease studies using species-specific isotope dilution mass spectrometry

Acknowledgments The project ReMiND 15HLT02 has received funding from the EMPIR programme co-financed by the Participating States and from the European Union's Horizon 2020 research and innovation programme. The authors gratefully thank Christoph Baumgartinger for his support with sample preparation as well as one independent referee for highly constructive comments.Peer reviewedPublisher PD

Aggressiveness of human melanoma xenograft models is promoted by aneuploidy-driven gene expression deregulation.

Melanoma is a devastating skin cancer characterized by distinct biological subtypes. Besides frequent mutations in growth- and survival-promoting genes like BRAF and NRAS, melanomas additionally harbor complex non-random genomic alterations. Using an integrative approach, we have analysed genomic and gene expression changes in human melanoma cell lines (N=32) derived from primary tumors and various metastatic sites and investigated the relation to local growth aggressiveness as xenografts in immuno-compromised mice (N=22). Although the vast majority >90% of melanoma models harbored mutations in either BRAF or NRAS, significant differences in subcutaneous growth aggressiveness became obvious. Unsupervised clustering revealed that genomic alterations rather than gene expression data reflected this aggressive phenotype, while no association with histology, stage or metastatic site of the original melanoma was found. Genomic clustering allowed separation of melanoma models into two subgroups with differing local growth aggressiveness in vivo. Regarding genes expressed at significantly altered levels between these subgroups, a surprising correlation with the respective gene doses (>85% accordance) was found. Genes deregulated at the DNA and mRNA level included well-known cancer genes partly already linked to melanoma (RAS genes, PTEN, AURKA, MAPK inhibitors Sprouty/Spred), but also novel candidates like SIPA1 (a Rap1GAP). Pathway mining further supported deregulation of Rap1 signaling in the aggressive subgroup e.g. by additional repression of two Rap1GEFs. Accordingly, siRNA-mediated down-regulation of SIPA1 exerted significant effects on clonogenicity, adherence and migration in aggressive melanoma models. Together our data suggest that an aneuploidy-driven gene expression deregulation drives local aggressiveness in human melanoma

Maleimide-functionalised platinum(IV) complexes as synthetic platform for targeted drug delivery

Maleimide-functionalised Pt(IV) complexes with highly selective binding properties to thiol groups were synthesised as precursors for binding of thiol-containing tumour targeting molecules like human serum albumi

Solution Equilibrium Studies of Anticancer Ruthenium(II)-η6-p-cymene Complexes of Pyridinecarboxylic Acids

Stoichiometry and stability of antitumor ruthenium(II)-η6-p-cymene complexes of picolinic acid and its 6-methyl and 6-carboxylic acid derivatives were determined by pH-potentiometry, 1H NMR spectroscopy and UV–Vis spectrophotometry in aqueous solution in the presence or absence of coordinating chloride ions. The picolinates form exclusively mono-ligand complexes in which they can coordinate via the bidentate (O,N) mode and a chloride or a water molecule is found at the third binding site of the ruthenium(II)-η6-p-cymene moiety depending on the conditions. [Ru(η6-p-cymene)(L)(H2O/Cl)] species are predominant at physiological pH in all studied cases. Hydrolysis of the aqua complex or the chlorido/hydroxido co-ligand exchange results in the formation of the mixed-hydroxido species [Ru(η6-p-cymene)(L)(OH)] in the basic pH range. There is no indication for the decomposition of the mono-ligand complexes during 24 h in the ruthenium(II)-η6-p-cymene-picolinic acid system between pH 3 and 11; however, a slight dissociation with a low reaction rate was found in the other two systems leading to the appearance of the dinuclear trihydroxido-bridged species [Ru2(η6-p-cymene)2(OH)3]+ and free ligands at pH > 10. The replacement of the chlorido by an aqua ligand in [Ru(η6-p-cymene)(L)Cl] was also monitored and equilibrium constants for the exchange process were determined