Cholangiocarcinoma (CCA) is a rare, but devastating disease arising from the epithelium of intrahepatic and extrahepatic bile ducts. There are neither effective systemic therapies nor satisfying treatment options for inoperable CCA. Histopathological and biochemical studies of CCA show frequent dysregulation of the phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (mTOR) pathway. Therefore, we investigated the efficacy of the mTOR inhibitor RAD001 and the impact of AKT signaling following mTOR inhibition in the treatment of CCA. RAD001 significantly inhibits proliferation of CCA cell lines, however, a concentration-dependent and isoform specific feedback activation of the three AKT isoforms (AKT1, AKT2 and AKT3) was observed after mTOR inhibition. As activation of AKT might limit the RAD001-mediated anti-tumor effect, the efficacy of combined mTOR and AKT inhibition was investigated using the allosteric AKT inhibitor MK-2206. Our results show that inhibition of AKT potentiates the efficacy of mTOR inhibition both in vitro and in a xenograft mouse model in vivo. Mechanistically, the antiproliferative effect of the pan-AKT inhibitor MK2206 in the CCA cell line TFK-1 was due to inhibition of AKT1 and AKT2, because knockdown of either AKT1 or AKT2, but not AKT3, showed a synergistic reduction of cell proliferation in combination with mTOR treatment. Finally, using an AKT isoform specific in vitro kinase assay, enzymatic activity of each of the three AKT isoforms was detected in all tissue samples from CCA patients, analyzed. In summary, our preclinical data suggest that combined targeting of mTOR and AKT using RAD001 and MK-2206 might be a new, effective strategy for the treatment of CCA.Cholangiocarcinoma (CCA) is a devastating disease that arises from the epithelium of intrahepatic and extrahepatic biliary ducts. Although CCA account for only 3% of all gastrointestinal cancers, CCA represent the second most frequent primary hepatic malignancy after hepatocellular carcinoma, and a progressively increasing incidence was observed worldwide in the last decades. 1,2 Surgical resection is the only chance for cure, but even after careful resection, local recurrence is frequent. 3 Yet, no systemic therapy was shown to be effective. Therefore, prognosis of patients with CCA is extremely dismal, with less than 5% of all patients, and only 22-36% of patients undergoing surgical resection surviving 5 years. 1,4 Thus, new and effective treatment options are urgently needed.The phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway plays a central role in regulation of tumor cell proliferation, migration, survival and angiogenesis. 5 A frequent dysregulation of AKT and mammalian target of rapamycin (mTOR) in up to 60% of intrahepatic and 80% of extrahepatic CCA has been reported, and a correlation between poor survival and phosphorylated AKT in patients with extrahepatic CCA was shown. 6,7 Therefore, the PI3K/AKT/mTOR pathway represents a promising target for new treatment strategies.

Fernsehsender, Start-Ups und Hardware-Hersteller setzen in zunehmendem Umfang auf soziale Interaktion während des Fernsehens – und erhoffen sich mit „Social TV“ einen Weg zur ‚Rettung‘ des linearen Fernsehens und der Erschließung neuer Geschäftsfelder. Auf der Grundlage von 34 leitfadengestützten Experteninterviews mit Marktteilnehmern diskutiert der Beitrag das Marktumfeld von Social TV und seine Perspektiven in Deutschland. Der Fokus liegt auf Nutzerinnen und Nutzern, spezifischen Fernsehformaten sowie auf technologischen Entwicklungen, zukünftigen Geschäftsmodellen sowie den damit verbundenen Chancen und Risiken von Social TV.

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Social TV ist kein Phänomen, das von kapitalstarken Organisationen in Innovationsprozessen strategisch entwickelt wurde. Es entstand vielmehr in der Alltagspraxis von Nutzern, die neue Möglichkeitsräume in digitalen Medien erschlossen haben. Der Beitrag stellt Ergebnisse einer Befragung dieser Lead User vor und gibt Auskunft über ihre Nutzungsgewohnheiten, ihre technologische Ausstattung, genutzte Plattformen und Genrepräferenzen. Vergleichend werden Ergebnisse einer Untersuchung von Nichtnutzern herangezogen. Auf Basis der empirischen Erkenntnisse können Handlungsoptionen für die Marktteilnehmer, insbesondere für Fernsehunternehmen, abgeleitet werden.