@article{MederKoenigOzretićetal.2016,
  author    = {Meder, Lydia and K{\"o}nig, Katharina and Ozretić, Luka and Schultheis, Anne M. and Ueckeroth, Frank and Ade, Carsten P. and Albus, Kerstin and Boehm, Diana and Rommerscheidt-Fuss, Ursula and Florin, Alexandra and Buhl, Theresa and Hartmann, Wolfgang and Wolf, J{\"u}rgen and Merkelbach-Bruse, Sabine and Eilers, Martin and Perner, Sven and Heukamp, Lukas C. and Buettner, Reinhard},
  title     = {NOTCH, ASCL1, p53 and RB alterations define an alternative pathway driving neuroendocrine and small cell lung carcinomas},
  series = {International Journal of Cancer},
  volume    = {138},
  journal   = {International Journal of Cancer},
  number    = {4},
  doi       = {10.1002/ijc.29835},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-190853},
  pages     = {927-938},
  year      = {2016},
  abstract  = {Small cell lung cancers (SCLCs) and extrapulmonary small cell cancers (SCCs) are very aggressive tumors arising de novo as primary small cell cancer with characteristic genetic lesions in RB1 and TP53. Based on murine models, neuroendocrine stem cells of the terminal bronchioli have been postulated as the cellular origin of primary SCLC. However, both in lung and many other organs, combined small cell/non-small cell tumors and secondary transitions from non-small cell carcinomas upon cancer therapy to neuroendocrine and small cell tumors occur. We define features of "small cell-ness" based on neuroendocrine markers, characteristic RB1 and TP53 mutations and small cell morphology. Furthermore, here we identify a pathway driving the pathogenesis of secondary SCLC involving inactivating NOTCH mutations, activation of the NOTCH target ASCL1 and canonical WNT-signaling in the context of mutual bi-allelic RB1 and TP53 lesions. Additionaly, we explored ASCL1 dependent RB inactivation by phosphorylation, which is reversible by CDK5 inhibition. We experimentally verify the NOTCH-ASCL1-RB-p53 signaling axis in vitro and validate its activation by genetic alterations in vivo. We analyzed clinical tumor samples including SCLC, SCC and pulmonary large cell neuroendocrine carcinomas and adenocarcinomas using amplicon-based Next Generation Sequencing, immunohistochemistry and fluorescence in situ hybridization. In conclusion, we identified a novel pathway underlying rare secondary SCLC which may drive small cell carcinomas in organs other than lung, as well.},
  language  = {en}
}
@phdthesis{Wolf2005,
  author    = {Wolf, J{\"u}rgen},
  title     = {H{\"a}modynamische Auswirkungen synthetischer, pflanzlicher und endogener Cannabinoide im Modell der isolierten Kaninchenlunge},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-15858},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2005},
  abstract  = {Cannabinoide zeigen komplexe kardiovaskul{\"a}re Effekte. Das endogene Cannabinoid Anandamid (Arachidonylethanolamid) induziert in verschiedenen Organsystemen eine haupts{\"a}chlich {\"u}ber periphere CB1-Rezeptoren vermittelte Vasodilatation. Der Einfluss von Cannabinoiden auf die pulmonale Strombahn ist jedoch unklar. Am Modell einer isolierten, perfundierten und ventilierten Kaninchenlunge konnte gezeigt werden, dass die endogenen Cannabinoide Anandamid und 2-Arachidonylglycerol (2-AG) dosisabh{\"a}ngig den pulmonalarteriellen Druck erh{\"o}hen. Cannabinoide, die abweichend zu Anandamid und 2-AG keine Arachidons{\"a}urestruktur haben, z.B. das synthetische HU-210 oder das pflanzliche \&\#916;9-THC, erh{\"o}hen den pulmonalarteriellen Druck nicht. Im Gegensatz zu Anandamid und 2-AG f{\"u}hren die stoffwechselstabilen, gegen enzymatischen Abbau gesch{\"u}tzten Analoga von Anandamid und 2-AG, R-Methanandamid und Noladin{\"a}ther, zu keinem Anstieg des pulmonalarteriellen Druckes. Blockade des CB1-Rezeptors durch den spezifischen Antagonisten AM-251 verhindert die pulmonalarterielle Druckerh{\"o}hung nach Anandamidgabe nicht. Wir folgern daraus, dass Abbauprodukte von Anandamid und 2-AG f{\"u}r die Druckerh{\"o}hung verantwortlich sind. Erstmalig konnten wir quantitativ Anandamid und 2-AG mittels Fl{\"u}ssigkeitschromatographie / Massenspektrometrie in der Kaninchenlunge nachweisen. Dies legt eine physiologische Relevanz der beiden Endocannabinoide bei der Tonus-Regulation des Lungenkreislaufes nahe.},
  language  = {de}
}