TY  - JOUR
A1  - Gattenloehner, Stefan
A1  - Joerissen, H.
A1  - Huhn, M.
A1  - Vincent, A.
A1  - Beeson, D.
A1  - Tzartos, S.
A1  - Mamalaki, A.
A1  - Etschmann, B.
A1  - Muller-Hermelink, H. K.
A1  - Koscielniak, E.
A1  - Barth, S.
A1  - Marx, A.
T1  - A Human Recombinant Autoantibody-Based Immunotoxin Specific for the Fetal Acetylcholine Receptor Inhibits Rhabdomyosarcoma Growth In Vitro and in a Murine Transplantation Model [Research Article]
N2  - Rhabdomyosarcoma (RMS) is the most common malignant soft tissue tumor in children and is highly resistant to all forms of treatment currently available once metastasis or relapse has commenced. As it has recently been determined that the acetylcholine receptor (AChR) γ-subunit, which defines the fetal AChR (fAChR) isoform, is almost exclusively expressed in RMS post partum, we recombinantly fused a single chain variable fragment (scFv) derived from a fully human anti-fAChR Fab-fragment to Pseudomonas exotoxin A to generate an anti-fAChR immunotoxin (scFv35-ETA).While scFv35-ETA had no damaging effect on fAChR-negative control cell lines, it killed human embryonic and alveolar RMS cell lines in vitro and delayed RMS development in a murine transplantation model. These results indicate that scFv35-ETA may be a valuable new therapeutic tool as well as a relevant step towards the development of a fully human immunotoxin directed against RMS. Moreover, as approximately 20% of metastatic malignant melanomas (MMs) display rhabdoid features including the expression of fAChR, the immunotoxin we developed may also prove to be of significant use in the treatment of these more common and most often fatal neoplasms.
KW  - Medizin
Y1  - 2010
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-68200
ER  - 
TY  - JOUR
A1  - Dammert, Marcel A.
A1  - Brägelmann, Johannes
A1  - Olsen, Rachelle R.
A1  - Böhm, Stefanie
A1  - Monhasery, Niloufar
A1  - Whitney, Christopher P.
A1  - Chalishazar, Milind D.
A1  - Tumbrink, Hannah L.
A1  - Guthrie, Matthew R.
A1  - Klein, Sebastian
A1  - Ireland, Abbie S.
A1  - Ryan, Jeremy
A1  - Schmitt, Anna
A1  - Marx, Annika
A1  - Ozretić, Luka
A1  - Castiglione, Roberta
A1  - Lorenz, Carina
A1  - Jachimowicz, Ron D.
A1  - Wolf, Elmar
A1  - Thomas, Roman K.
A1  - Poirier, John T.
A1  - Büttner, Reinhard
A1  - Sen, Triparna
A1  - Byers, Lauren A.
A1  - Reinhardt, H. Christian
A1  - Letai, Anthony
A1  - Oliver, Trudy G.
A1  - Sos, Martin L.
T1  - MYC paralog-dependent apoptotic priming orchestrates a spectrum of vulnerabilities in small cell lung cancer
JF  - Nature Communications
N2  - MYC paralogs are frequently activated in small cell lung cancer (SCLC) but represent poor drug targets. Thus, a detailed mapping of MYC-paralog-specific vulnerabilities may help to develop effective therapies for SCLC patients. Using a unique cellular CRISPR activation model, we uncover that, in contrast to MYCN and MYCL, MYC represses BCL2 transcription via interaction with MIZ1 and DNMT3a. The resulting lack of BCL2 expression promotes sensitivity to cell cycle control inhibition and dependency on MCL1. Furthermore, MYC activation leads to heightened apoptotic priming, intrinsic genotoxic stress and susceptibility to DNA damage checkpoint inhibitors. Finally, combined AURK and CHK1 inhibition substantially prolongs the survival of mice bearing MYC-driven SCLC beyond that of combination chemotherapy. These analyses uncover MYC-paralog-specific regulation of the apoptotic machinery with implications for genotype-based selection of targeted therapeutics in SCLC patients.
KW  - genetic engineering
KW  - oncogenes
KW  - small-cell lung cancer
KW  - targeted therapies
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-223569
VL  - 10
ER  - 
TY  - JOUR
A1  - Huang, Bei
A1  - Belharazem, Djeda
A1  - Li, Li
A1  - Kneitz, Susanne
A1  - Schnabel, Philipp A.
A1  - Rieker, Ralf J.
A1  - Körner, Daniel
A1  - Nix, Wilfried
A1  - Schalke, Berthold
A1  - Müller-Hermelink, Hans Konrad
A1  - Ott, German
A1  - Rosenwald, Andreas
A1  - Ströbel, Philipp
A1  - Marx, Alexander
T1  - Anti-apoptotic signature in thymic squamous cell carcinomas – functional relevance of anti-apoptotic BIRC3 expression in the thymic carcinoma cell line 1889c
JF  - Frontiers in Oncology
N2  - The molecular pathogenesis of thymomas and thymic arcinomas (TCs) is poorly understood and results of adjuvant therapy are unsatisfactory in case of metastatic disease and tumor recurrence. For these clinical settings, novel therapeutic strategies are urgently needed. Recently, limited sequencing efforts revealed that a broad spectrum of genes that play key roles in various common cancers are rarely affected in thymomas and TCs, suggesting that other oncogenic principles might be important.This made us re-analyze historic expression data obtained in a spectrumof thymomas and thymic squamous cell carcinomas (TSCCs) with a custom-made cDNA microarray. By cluster analysis, different anti-apoptotic signatures were detected in type B3 thymoma and TSCC, including overexpression of BIRC3 in TSCCs. This was confirmed by qRT-PCR in the original and an independent validation set of tumors. In contrast to several other cancer cell lines, the BIRC3-positive TSCC cell line, 1889c showed spontaneous apoptosis after BIRC3 knock-down. Targeting apoptosis genes is worth testing as therapeutic principle in TSCC.
KW  - gene expression
KW  - MTCH2
KW  - targeted
KW  - myasthenia gravis
KW  - apoptosis
KW  - thymus
KW  - thymoma
KW  - thymic carcinoma
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-132214
VL  - 3
IS  - 316
ER  - 
TY  - JOUR
A1  - Gordon, Sarah
A1  - Daneshian, Mardas
A1  - Bouwstra, Joke
A1  - Caloni, Francesca
A1  - Constant, Samuel
A1  - Davies, Donna E.
A1  - Dandekar, Gudrun
A1  - Guzman, Carlos A.
A1  - Fabian, Eric
A1  - Haltner, Eleonore
A1  - Hartung, Thomas
A1  - Hasiwa, Nina
A1  - Hayden, Patrick
A1  - Kandarova, Helena
A1  - Khare, Sangeeta
A1  - Krug, Harald F.
A1  - Kneuer, Carsten
A1  - Leist, Marcel
A1  - Lian, Guoping
A1  - Marx, Uwe
A1  - Metzger, Marco
A1  - Ott, Katharina
A1  - Prieto, Pilar
A1  - Roberts, Michael S.
A1  - Roggen, Erwin L.
A1  - Tralau, Tewes
A1  - van den Braak, Claudia
A1  - Walles, Heike
A1  - Lehr, Claus-Michael
T1  - Non-animal models of epithelial barriers (skin, intestine and lung) in research, industrial applications and regulatory toxicology
JF  - ALTEX: Alternatives to Animal Experimentation
N2  - Models of the outer epithelia of the human body namely the skin, the intestine and the lung have found valid applications in both research and industrial settings as attractive alternatives to animal testing. A variety of approaches to model these barriers are currently employed in such fields, ranging from the utilization of ex vivo tissue to reconstructed in vitro models, and further to chip-based technologies, synthetic membrane systems and, of increasing current interest, in silico modeling approaches. An international group of experts in the field of epithelial barriers was convened from academia, industry and regulatory bodies to present both the current state of the art of non-animal models of the skin, intestinal and pulmonary barriers in their various fields of application, and to discuss research-based, industry-driven and regulatory-relevant future directions for both the development of new models and the refinement of existing test methods. Issues of model relevance and preference, validation and standardization, acceptance, and the need for simplicity versus complexity were focal themes of the discussions. The outcomes of workshop presentations and discussions, in relation to both current status and future directions in the utilization and development of epithelial barrier models, are presented by the attending experts in the current report.
KW  - on-a-chip
KW  - asthmatic bronchial epithelium
KW  - vesicle-based barrier
KW  - pulmonary drug-delivery
KW  - epithelial cell culture
KW  - cytotoxicity
KW  - transport studies
KW  - permeability
KW  - in vitro models
KW  - air-liquid interface
KW  - respiratory syncytial virus
KW  - reconstructed human epidermis
KW  - artificial membrane-permeability
KW  - embryonic stem cells
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-144275
VL  - 32
IS  - 4
ER  -