Multiple Mechanisms Mediate Resistance to Sorafenib in Urothelial Cancer

Genetic and epigenetic changes in the mitogen activated protein kinase (MAPK) signaling render urothelial cancer a potential target for tyrosine kinase inhibitor (TKI) treatment. However, clinical trials of several TKIs failed to prove efficacy. In this context, we investigated changes in MAPK signaling activity, downstream apoptotic regulators and changes in cell cycle distribution in different urothelial cancer cell lines (UCCs) upon treatment with the multikinase inhibitor sorafenib. None of the classical sorafenib targets (vascular endothelial growth factor receptor 1/-receptor 2, VEGFR1/-R2; platelet-derived growth factor receptor α/-receptor β, PDGFR-α/-β; c-KIT) was expressed at significant levels leaving RAF proteins as its likely molecular target. Low sorafenib concentrations paradoxically increased cell viability, whereas higher concentrations induced G1 arrest and eventually apoptosis. MAPK signaling remained partly active after sorafenib treatment, especially in T24 cells with an oncogenic HRAS mutation. AKT phosphorylation was increased, suggesting compensatory activation of the phosphatidylinositol-3-kinase (PI3K) pathway. Sorafenib regularly down regulated the anti-apoptotic myeloid cell leukemia 1 (Mcl-1) protein, but combinatorial treatment with ABT-737 targeting other B-cell lymphoma 2 (Bcl-2) family proteins did not result in synergistic effects. In summary, efficacy of sorafenib in urothelial cancer cell lines appears hampered by limited effects on MAPK signaling, crosstalk with further cancer pathways and an anti-apoptotic state of UCCs. These observations may account for the lack of efficacy of sorafenib in clinical trials and should be considered more broadly in the development of signaling pathway inhibitors for drug therapy in urothelial carcinoma.     

A new concept for glycosyltransferase inhibitors: nonionic mimics of the nucleotide donor of the human blood group B galactosyltransferase

Glycosyltransferases play an important role in the formation of oligosaccharides and glycoconjugates. To find suitable and selective inhibitors for this class of enzymes is still challenging. Here, we describe a novel concept that allows the design of inhibitors based on the structure of the donor substrate binding pocket. As a first step we describe the design, synthesis and analysis of inhibitors of the human blood group B galactosyltransferase (GTB). This enzyme served as a model system to study the concept, which can be used for easy access of glycosyltransferase inhibitors in general. In silico docking of bicyclic heteroaromatic ligands to GTB and experimental verification of binding affinities by saturation transfer difference NMR (STD NMR) spectroscopy gave 9-N-pentityl uric acid derivatives as non-ionic mimics of UDP. Two derivatives were synthesized and showed inhibitory activity for GTB as determined by competitive STD NMR experiments and by a radiolabeled enzyme assay.     

Trichloromethyl compounds--natural background concentrations and fates within and below coniferous forests

Pollution with organochlorines has received major attention due to various environmental effects, but it is now increasingly recognized, that they also take part in biogeochemical cycles and that natural background concentrations exist for several chlorinated compounds. We here report the natural occurrence and cycling of organic compounds with a trichloromethyl moiety in common. The study areas are temperate coniferous forests. Trichloromethyl compounds can be found in all compartments of the forests (groundwater, soil, vegetation and throughfall), but not all compounds in all compartments. The atmospheric input of trichloromethyl compounds is found to be minor, with significant contributions for trichloroacetic acid (TCAA), only.In top soil, where the formation of the compounds is expected to occur, there is a clear positive relationship between chloroform and trichloroacetyl containing compounds. Other positive relations occur, which in combination with chlorination experiments performed in the laboratory, point to the fact that all the trichloromethyl compounds may be formed concurrently in the soil, and their subsequent fates then differ due to different physical, chemical and biological properties. TCAA cannot be detected in soil and groundwater, but sorption and mineralization experiments performed in the laboratory in combination with analyses of vegetation, show that TCAA is probably formed in the top soil and then partly taken up by the vegetation and partly mineralized in the soil. Based on this and previous studies, a conceptual model for the natural cycling of trichloromethyl compounds in forests is proposed.     

Modellierung einer Einscheibentrockenkupplung mithilfe des C&C2-Ansatzes zur Identifikation von kritischen Gestalt-Funktion-Zusammenhängen bezüglich des Schwingungsphänomens zwangserregtes Kupplungsrupfen

Forschung im Ingenieurwesen - In diesem Beitrag wird ein systematisches Vorgehen zur Identifikation von kritischen Gestalt-Funktion-Zusammenhängen mit Einfluss auf zwangserregtes...     

Einfluss von Betriebsgrößen auf die Schwingungsreduzierungswirkung im nasslaufenden Kupplungssystem: Empirische Modellbildung – Kennfelder und Skalierbarkeit

Forschung im Ingenieurwesen - Nasslaufende Kupplungssysteme werden, mitunter durch die zunehmende Hybridisierung sowie die Automatisierung von Getrieben, auch in Zukunft in vielen...     

Aufbau eines Vorgehensmodells zur Analyse von Haft-Gleit-Übergängen trockenlaufender Friktionspaarungen

Forschung im Ingenieurwesen - Die Auslegung des Kraftschlusses und der entsprechenden Haftreibung ist für die Funktionserfüllung trockenlaufender Kupplungen und Bremsen von grundlegender...     

Nutzung von KI-Methoden für die Kupplungsentwicklung in automobilen Antriebssträngen

Forschung im Ingenieurwesen - Im Spannungsfeld steigender Erwartungen an Fahrkomfort und Energieeffizienz stoßen aktuelle Entwicklungsmethoden der Modellbildung und Optimierung für...