Expositionsbasierte kognitive Therapie bei Depressionen

Depressionen können erfolgreich behandelt werden, doch die Nachhaltigkeit psychotherapeutischer Effekte ist weiterhin eine Herausforderung. Expositionsbasierte Kognitive Therapie (EBCT) versucht, gleichzeitig Symptomatik und Depressionsvulnerabilität durch verstärkte kognitiv-emotionale Verarbeitung zu verändern. Die EBCT umfasst drei Behandlungsphasen: Aufbauphase zur Stabilisierung und Stärkung inklusive Achtsamkeitsübungen, Expositionsphase zur Bearbeitung depressionsrelevanter Selbstanteile mit emotionsfokussierten Methoden und Konsolidierungsphase zum Transfer erworbener Fertigkeiten und Erkenntnisse in den Alltag. In empirischen Studien konnten Belege für die Umsetzbarkeit der Methodenintegration sowie Akzeptabilität der Behandlung erbracht werden. In einer Vergleichsstudie zeigten sich große und der kognitiven Verhaltenstherapie (KVT) vergleichbare Prä-Post-Effekte der EBCT. Die kognitiv-emotionale Verarbeitung erfolgte hauptsächlich in der Expositionsphase und sagte das Therapieergebnis vorher. Die EBCT ist ein Beispiel für die erfolgreiche Integration ursprünglich theoriefremder Interventionen in die KVT. Zukünftige Entwicklungen der Depressionstherapie werden diskutiert.

Evolutionary conservation of the U7 small nuclear ribonucleoprotein in Drosophila melanogaster.

The U7 snRNP involved in histone RNA 3' end processing is related to but biochemically distinct from spliceosomal snRNPs. In vertebrates, the Sm core structure assembling around the noncanonical Sm-binding sequence of U7 snRNA contains only five of the seven standard Sm proteins. The missing Sm D1 and D2 subunits are replaced by U7-specific Sm-like proteins Lsm10 and Lsm11, at least the latter of which is important for histone RNA processing. So far, it was unknown if this special U7 snRNP composition is conserved in invertebrates. Here we describe several putative invertebrate Lsm10 and Lsm11 orthologs that display low but clear sequence similarity to their vertebrate counterparts. Immunoprecipitation studies in Drosophila S2 cells indicate that the Drosophila Lsm10 and Lsm11 orthologs (dLsm10 and dLsm11) associate with each other and with Sm B, but not with Sm D1 and D2. Moreover, dLsm11 associates with the recently characterized Drosophila U7 snRNA and, indirectly, with histone H3 pre-mRNA. Furthermore, dLsm10 and dLsm11 can assemble into U7 snRNPs in mammalian cells. These experiments demonstrate a strong evolutionary conservation of the unique U7 snRNP composition, despite a high degree of primary sequence divergence of its constituents. Therefore, Drosophila appears to be a suitable system for further genetic studies of the cell biology of U7 snRNPs.

Impact of p53 Status on Radiosensitization of Tumor Cells by MET Inhibition-Associated Checkpoint Abrogation

Signaling via the MET receptor tyrosine kinase has been implicated in crosstalk with cellular responses to DNA damage. Our group previously demonstrated that MET inhibition in tumor cells with deregulated MET activity results in radiosensitization via downregulation of the ATR-CHK1-CDC25 pathway, a major signaling cascade responsible for intra-S and G2/M cell cycle arrest following DNA damage. Here we aimed at studying the potential therapeutic application of ionizing radiation in combination with a MET inhibitor, EMD-1214063, in p53-deficient cancer cells that harbor impaired G1/S checkpoint regulation upon DNA damage. We hypothesized that upon MET inhibition, p53-deficient cells would bypass both G1/S and G2/M checkpoints, promoting premature mitotic entry with substantial DNA lesions and cell death in a greater extent than p53-proficient cells. Our data suggest that p53-deficient cells are more susceptible to EMD-1214063 and combined treatment with irradiation than wildtype p53 lines as inferred from elevated γH2AX expression and increased cytotoxicity. Furthermore, cell cycle distribution profiling indicates constantly lower G1 and higher G2/M population as well as higher expression of a mitotic marker p-histone H3 following the dual treatment in p53 knockdown isogenic variant, compared to the parental counterpart. IMPLICATIONS The concept of MET inhibition-mediated radiosensitization enhanced by p53 deficiency is of high clinical relevance, since p53 is frequently mutated in numerous types of human cancer. The current data point for a therapeutic advantage for an approach combining MET targeting along with DNA damaging agents for MET positive/p53 negative tumors.