@article{SchaeferWeibelDonatetal.2012,
  author    = {Sch{\"a}fer, Simon and Weibel, Stephanie and Donat, Ulrike and Zhang, Quian and Aguilar, Richard J. and Chen, Nanhai G. and Szalay, Aladar A.},
  title     = {Vaccinia virus-mediated intra-tumoral expression of matrix metalloproteinase 9 enhances oncolysis of PC-3 xenograft tumors},
  series = {BMC Cancer},
  volume    = {12},
  journal   = {BMC Cancer},
  number    = {366},
  doi       = {10.1186/1471-2407-12-366},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-140800},
  year      = {2012},
  abstract  = {Background Oncolytic viruses, including vaccinia virus (VACV), are a promising alternative to classical mono-cancer treatment methods such as surgery, chemo- or radiotherapy. However, combined therapeutic modalities may be more effective than mono-therapies. In this study, we enhanced the effectiveness of oncolytic virotherapy by matrix metalloproteinase (MMP-9)-mediated degradation of proteins of the tumoral extracellular matrix (ECM), leading to increased viral distribution within the tumors. Methods For this study, the oncolytic vaccinia virus GLV-1h255, containing the mmp-9 gene, was constructed and used to treat PC-3 tumor-bearing mice, achieving an intra-tumoral over-expression of MMP-9. The intra-tumoral MMP-9 content was quantified by immunohistochemistry in tumor sections. Therapeutic efficacy of GLV-1h255 was evaluated by monitoring tumor growth kinetics and intra-tumoral virus titers. Microenvironmental changes mediated by the intra-tumoral MMP-9 over-expression were investigated by microscopic quantification of the collagen IV content, the blood vessel density (BVD) and the analysis of lymph node metastasis formation. Results GLV-1h255-treatment of PC-3 tumors led to a significant over-expression of intra-tumoral MMP-9, accompanied by a marked decrease in collagen IV content in infected tumor areas, when compared to GLV-1h68-infected tumor areas. This led to considerably elevated virus titers in GLV-1h255 infected tumors, and to enhanced tumor regression. The analysis of the BVD, as well as the lumbar and renal lymph node volumes, revealed lower BVD and significantly smaller lymph nodes in both GLV-1h68- and GLV-1h255- injected mice compared to those injected with PBS, indicating that MMP-9 over-expression does not alter the metastasis-reducing effect of oncolytic VACV. Conclusions Taken together, these results indicate that a GLV-1h255-mediated intra-tumoral over-expression of MMP-9 leads to a degradation of collagen IV, facilitating intra-tumoral viral dissemination, and resulting in accelerated tumor regression. We propose that approaches which enhance the oncolytic effect by increasing the intra-tumoral viral load, may be an effective way to improve therapeutic outcome.},
  language  = {en}
}
@article{DonatRotherSchaeferetal.2014,
  author    = {Donat, Ulrike and Rother, Juliane and Sch{\"a}fer, Simon and Hess, Michael and H{\"a}rtl, Barbara and Kober, Christina and Langbein-Laugwitz, Johanna and Stritzker, Jochen and Chen, Nanhai G. and Aguilar, Richard J. and Weibel, Stephanie and Szalay, Alandar A.},
  title     = {Characterization of Metastasis Formation and Virotherapy in the Human C33A Cervical Cancer Model},
  series = {PLoS ONE},
  volume    = {9},
  journal   = {PLoS ONE},
  number    = {6},
  issn      = {1932-6203},
  doi       = {10.1371/journal.pone.0098533},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-119674},
  pages     = {e98533},
  year      = {2014},
  abstract  = {More than 90\% of cancer mortalities are due to cancer that has metastasized. Therefore, it is crucial to intensify research on metastasis formation and therapy. Here, we describe for the first time the metastasizing ability of the human cervical cancer cell line C33A in athymic nude mice after subcutaneous implantation of tumor cells. In this model, we demonstrated a steady progression of lumbar and renal lymph node metastases during tumor development. Besides predominantly occurring lymphatic metastases, we visualized the formation of hematogenous metastases utilizing red fluorescent protein (RFP) expressing C33A-RFP cells. RFP positive cancer cells were found migrating in blood vessels and forming micrometastases in lungs of tumor-bearing mice. Next, we set out to analyze the influence of oncolytic virotherapy in the C33A-RFP model and demonstrated an efficient virus-mediated reduction of tumor size and metastatic burden. These results suggest the C33A-RFP cervical cancer model as a new platform to analyze cancer metastases as well as to test novel treatment options to combat metastases.},
  language  = {en}
}
@article{AntoniouKuchenbaeckerSoucyetal.2012,
  author    = {Antoniou, Antonis C. and Kuchenbaecker, Karoline B. and Soucy, Penny and Beesley, Jonathan and Chen, Xiaoqing and McGuffog, Lesley and Lee, Andrew and Barrowdale, Daniel and Healey, Sue and Sinilnikova, Olga M. and Caligo, Maria A. and Loman, Niklas and Harbst, Katja and Lindblom, Annika and Arver, Brita and Rosenquist, Richard and Karlsson, Per and Nathanson, Kate and Domchek, Susan and Rebbeck, Tim and Jakubowska, Anna and Lubinski, Jan and Jaworska, Katarzyna and Durda, Katarzyna and Zlowowcka-Perłowska, Elżbieta and Osorio, Ana and Dur{\´a}n, Mercedes and Andr{\´e}s, Raquel and Ben{\´i}tez, Javier and Hamann, Ute and Hogervorst, Frans B. and van Os, Theo A. and Verhoef, Senno and Meijers-Heijboer, Hanne E. J. and Wijnen, Juul and Garcia, Encarna B. G{\´o}mez and Ligtenberg, Marjolijn J. and Kriege, Mieke and Coll{\´e}e, Margriet and Ausems, Margreet G. E. M. and Oosterwijk, Jan C. and Peock, Susan and Frost, Debra and Ellis, Steve D. and Platte, Radka and Fineberg, Elena and Evans, D. Gareth and Lalloo, Fiona and Jacobs, Chris and Eeles, Ros and Adlard, Julian and Davidson, Rosemarie and Cole, Trevor and Cook, Jackie and Paterson, Joan and Douglas, Fiona and Brewer, Carole and Hodgson, Shirley and Morrison, Patrick J. and Walker, Lisa and Rogers, Mark T. and Donaldson, Alan and Dorkins, Huw and Godwin, Andrew K. and Bove, Betsy and Stoppa-Lyonnet, Dominique and Houdayer, Claude and Buecher, Bruno and de Pauw, Antoine and Mazoyer, Sylvie and Calender, Alain and L{\´e}on{\´e}, M{\´e}lanie and Bressac-de Paillerets, Brigitte and Caron, Olivier and Sobol, Hagay and Frenay, Marc and Prieur, Fabienne and Ferrer, Sandra Fert and Mortemousque, Isabelle and Buys, Saundra and Daly, Mary and Miron, Alexander and Terry, Mary Beth and Hopper, John L. and John, Esther M. and Southey, Melissa and Goldgar, David and Singer, Christian F. and Fink-Retter, Anneliese and Muy-Kheng, Tea and Geschwantler Kaulich, Daphne and Hansen, Thomas V. O. and Nielsen, Finn C. and Barkardottir, Rosa B. and Gaudet, Mia and Kirchhoff, Tomas and Joseph, Vijai and Dutra-Clarke, Ana and Offit, Kenneth and Piedmonte, Marion and Kirk, Judy and Cohn, David and Hurteau, Jean and Byron, John and Fiorica, James and Toland, Amanda E. and Montagna, Marco and Oliani, Cristina and Imyanitov, Evgeny and Isaacs, Claudine and Tihomirova, Laima and Blanco, Ignacio and Lazaro, Conxi and Teul{\´e}, Alex and Del Valle, J. and Gayther, Simon A. and Odunsi, Kunle and Gross, Jenny and Karlan, Beth Y. and Olah, Edith and Teo, Soo-Hwang and Ganz, Patricia A. and Beattie, Mary S. and Dorfling, Cecelia M. and Jansen van Rensburg, Elizabeth and Diez, Orland and Kwong, Ava and Schmutzler, Rita K. and Wappenschmidt, Barbara and Engel, Christoph and Meindl, Alfons and Ditsch, Nina and Arnold, Norbert and Heidemann, Simone and Niederacher, Dieter and Preisler-Adams, Sabine and Gadzicki, Dorothea and Varon-Mateeva, Raymonda and Deissler, Helmut and Gehrig, Andrea and Sutter, Christian and Kast, Karin and Fiebig, Britta and Sch{\"a}fer, Dieter and Caldes, Trinidad and de la Hoya, Miguel and Nevanlinna, Heli and Muranen, Taru A. and Lesp{\´e}rance, Bernard and Spurdle, Amanda B. and Neuhausen, Susan L. and Ding, Yuan C. and Wang, Xianshu and Fredericksen, Zachary and Pankratz, Vernon S. and Lindor, Noralane M. and Peterlongo, Paulo and Manoukian, Siranoush and Peissel, Bernard and Zaffaroni, Daniela and Bonanni, Bernardo and Bernard, Loris and Dolcetti, Riccardo and Papi, Laura and Ottini, Laura and Radice, Paolo and Greene, Mark H. and Loud, Jennifer T. and Andrulis, Irene L. and Ozcelik, Hilmi and Mulligan, Anna Marie and Glendon, Gord and Thomassen, Mads and Gerdes, Anne-Marie and Jensen, Uffe B. and Skytte, Anne-Bine and Kruse, Torben A. and Chenevix-Trench, Georgia and Couch, Fergus J. and Simard, Jacques and Easton, Douglas F.},
  title     = {Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers},
  series = {Breast Cancer Research},
  volume    = {14},
  journal   = {Breast Cancer Research},
  number    = {R33},
  organization    = {CIMBA; SWE-BRCA; HEBON; EMBRACE; GEMO Study Collaborators; kConFab Investigators},
  doi       = {10.1186/bcr3121},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130449},
  year      = {2012},
  abstract  = {Introduction: Several common alleles have been shown to be associated with breast and/or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Recent genome-wide association studies of breast cancer have identified eight additional breast cancer susceptibility loci: rs1011970 (9p21, CDKN2A/B), rs10995190 (ZNF365), rs704010 (ZMIZ1), rs2380205 (10p15), rs614367 (11q13), rs1292011 (12q24), rs10771399 (12p11 near PTHLH) and rs865686 (9q31.2). Methods: To evaluate whether these single nucleotide polymorphisms (SNPs) are associated with breast cancer risk for BRCA1 and BRCA2 carriers, we genotyped these SNPs in 12,599 BRCA1 and 7,132 BRCA2 mutation carriers and analysed the associations with breast cancer risk within a retrospective likelihood framework. Results: Only SNP rs10771399 near PTHLH was associated with breast cancer risk for BRCA1 mutation carriers (per-allele hazard ratio (HR) = 0.87, 95\% CI: 0.81 to 0.94, P-trend = 3 x 10\(^{-4}\)). The association was restricted to mutations proven or predicted to lead to absence of protein expression (HR = 0.82, 95\% CI: 0.74 to 0.90, P-trend = 3.1 x 10\(^{-5}\), P-difference = 0.03). Four SNPs were associated with the risk of breast cancer for BRCA2 mutation carriers: rs10995190, P-trend = 0.015; rs1011970, P-trend = 0.048; rs865686, 2df P = 0.007; rs1292011 2df P = 0.03. rs10771399 (PTHLH) was predominantly associated with estrogen receptor (ER)-negative breast cancer for BRCA1 mutation carriers (HR = 0.81, 95\% CI: 0.74 to 0.90, P-trend = 4 x 10\(^{-5}\)) and there was marginal evidence of association with ER- negative breast cancer for BRCA2 mutation carriers (HR = 0.78, 95\% CI: 0.62 to 1.00, P-trend = 0.049). Conclusions: The present findings, in combination with previously identified modifiers of risk, will ultimately lead to more accurate risk prediction and an improved understanding of the disease etiology in BRCA1 and BRCA2 mutation carriers.},
  language  = {en}
}
@article{SchaeferWeibelDonatetal.2012,
  author    = {Sch{\"a}fer, Simon and Weibel, Stephanie and Donat, Ulrike and Zhang, Qian and Aguilar, Richard J. and Chen, Nanhai G. and Szalay, Aladar A.},
  title     = {Vaccinia virus-mediated intra-tumoral expression of matrix metalloproteinase 9 enhances oncolysis of PC-3 xenograft tumors},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-78220},
  year      = {2012},
  abstract  = {Background: Oncolytic viruses, including vaccinia virus (VACV), are a promising alternative to classical mono-cancer treatment methods such as surgery, chemo- or radiotherapy. However, combined therapeutic modalities may be more effective than mono-therapies. In this study, we enhanced the effectiveness of oncolytic virotherapy by matrix metalloproteinase (MMP-9)-mediated degradation of proteins of the tumoral extracellular matrix (ECM), leading to increased viral distribution within the tumors. Methods: For this study, the oncolytic vaccinia virus GLV-1h255, containing the mmp-9 gene, was constructed and used to treat PC-3 tumor-bearing mice, achieving an intra-tumoral over-expression of MMP-9. The intra-tumoral MMP-9 content was quantified by immunohistochemistry in tumor sections. Therapeutic efficacy of GLV-1h255 was evaluated by monitoring tumor growth kinetics and intra-tumoral virus titers. Microenvironmental changes mediated by the intra-tumoral MMP-9 over-expression were investigated by microscopic quantification of the collagen IV content, the blood vessel density (BVD) and the analysis of lymph node metastasis formation. Results: GLV-1h255-treatment of PC-3 tumors led to a significant over-expression of intra-tumoral MMP-9, accompanied by a marked decrease in collagen IV content in infected tumor areas, when compared to GLV-1h68-infected tumor areas. This led to considerably elevated virus titers in GLV-1h255 infected tumors, and to enhanced tumor regression. The analysis of the BVD, as well as the lumbar and renal lymph node volumes, revealed lower BVD and significantly smaller lymph nodes in both GLV-1h68- and GLV-1h255- injected mice compared to those injected with PBS, indicating that MMP-9 over-expression does not alter the metastasis-reducing effect of oncolytic VACV. Conclusions: Taken together, these results indicate that a GLV-1h255-mediated intra-tumoral over-expression of MMP-9 leads to a degradation of collagen IV, facilitating intra-tumoral viral dissemination, and resulting in accelerated tumor regression. We propose that approaches which enhance the oncolytic effect by increasing the intra-tumoral viral load, may be an effective way to improve therapeutic outcome.},
  subject      = {Biochemie},
  language  = {en}
}
@article{EckardtStasikKrameretal.2021,
  author    = {Eckardt, Jan-Niklas and Stasik, Sebastian and Kramer, Michael and R{\"o}llig, Christoph and Kr{\"a}mer, Alwin and Scholl, Sebastian and Hochhaus, Andreas and Crysandt, Martina and Br{\"u}mmendorf, Tim H. and Naumann, Ralph and Steffen, Bj{\"o}rn and Kunzmann, Volker and Einsele, Hermann and Schaich, Markus and Burchert, Andreas and Neubauer, Andreas and Sch{\"a}fer-Eckart, Kerstin and Schliemann, Christoph and Krause, Stefan W. and Herbst, Regina and H{\"a}nel, Mathias and Frickhofen, Norbert and Noppeney, Richard and Kaiser, Ulrich and Baldus, Claudia D. and Kaufmann, Martin and R{\´a}cil, Zdenek and Platzbecker, Uwe and Berdel, Wolfgang E. and Mayer, Jiř{\´i} and Serve, Hubert and M{\"u}ller-Tidow, Carsten and Ehninger, Gerhard and St{\"o}lzel, Friedrich and Kroschinsky, Frank and Schetelig, Johannes and Bornh{\"a}user, Martin and Thiede, Christian and Middeke, Jan Moritz},
  title     = {Loss-of-function mutations of BCOR are an independent marker of adverse outcomes in intensively treated patients with acute myeloid leukemia},
  series = {Cancers},
  volume    = {13},
  journal   = {Cancers},
  number    = {9},
  issn      = {2072-6694},
  doi       = {10.3390/cancers13092095},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-236735},
  year      = {2021},
  abstract  = {Acute myeloid leukemia (AML) is characterized by recurrent genetic events. The BCL6 corepressor (BCOR) and its homolog, the BCL6 corepressor-like 1 (BCORL1), have been reported to be rare but recurrent mutations in AML. Previously, smaller studies have reported conflicting results regarding impacts on outcomes. Here, we retrospectively analyzed a large cohort of 1529 patients with newly diagnosed and intensively treated AML. BCOR and BCORL1 mutations were found in 71 (4.6\%) and 53 patients (3.5\%), respectively. Frequently co-mutated genes were DNTM3A, TET2 and RUNX1. Mutated BCORL1 and loss-of-function mutations of BCOR were significantly more common in the ELN2017 intermediate-risk group. Patients harboring loss-of-function mutations of BCOR had a significantly reduced median event-free survival (HR = 1.464 (95\%-Confidence Interval (CI): 1.005-2.134), p = 0.047), relapse-free survival (HR = 1.904 (95\%-CI: 1.163-3.117), p = 0.01), and trend for reduced overall survival (HR = 1.495 (95\%-CI: 0.990-2.258), p = 0.056) in multivariable analysis. Our study establishes a novel role for loss-of-function mutations of BCOR regarding risk stratification in AML, which may influence treatment allocation.},
  language  = {en}
}
@article{BonigKuciKucietal.2019,
  author    = {Bonig, Halvard and Ku{\c{c}}i, Zyrafete and Ku{\c{c}}i, Selim and Bakhtiar, Shahrzad and Basu, Oliver and Bug, Gesine and Dennis, Mike and Greil, Johann and Barta, Aniko and K{\´a}llay, Kriszti{\´a}n M. and Lang, Peter and Lucchini, Giovanna and Pol, Raj and Schulz, Ansgar and Sykora, Karl-Walter and Teichert von Luettichau, Irene and Herter-Sprie, Grit and Ashab Uddin, Mohammad and Jenkin, Phil and Alsultan, Abdulrahman and Buechner, Jochen and Stein, Jerry and Kelemen, Agnes and Jarisch, Andrea and Soerensen, Jan and Salzmann-Manrique, Emilia and Hutter, Martin and Sch{\"a}fer, Richard and Seifried, Erhard and Paneesha, Shankara and Novitzky-Basso, Igor and Gefen, Aharon and Nevo, Neta and Beutel, Gernot and Schlegel, Paul-Gerhardt and Klingebiel, Thomas and Bader, Peter},
  title     = {Children and adults with Refractory acute Graft-versus-Host Disease respond to treatment with the Mesenchymal Stromal cell preparation "MSC-FFM"—Outcome report of 92 patients},
  series = {Cells},
  volume    = {8},
  journal   = {Cells},
  number    = {12},
  issn      = {2073-4409},
  doi       = {10.3390/cells8121577},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-193878},
  pages     = {1577},
  year      = {2019},
  abstract  = {(1) Background: Refractory acute graft-versus-host disease (R-aGvHD) remains a leading cause of death after allogeneic stem cell transplantation. Survival rates of 15\% after four years are currently achieved; deaths are only in part due to aGvHD itself, but mostly due to adverse effects of R-aGvHD treatment with immunosuppressive agents as these predispose patients to opportunistic infections and loss of graft-versus-leukemia surveillance resulting in relapse. Mesenchymal stromal cells (MSC) from different tissues and those generated by various protocols have been proposed as a remedy for R-aGvHD but the enthusiasm raised by initial reports has not been ubiquitously reproduced. (2) Methods: We previously reported on a unique MSC product, which was generated from pooled bone marrow mononuclear cells of multiple third-party donors. The products showed dose-to-dose equipotency and greater immunosuppressive capacity than individually expanded MSCs from the same donors. This product, MSC-FFM, has entered clinical routine in Germany where it is licensed with a national hospital exemption authorization. We previously reported satisfying initial clinical outcomes, which we are now updating. The data were collected in our post-approval pharmacovigilance program, i.e., this is not a clinical study and the data is high-level and non-monitored. (3) Results: Follow-up for 92 recipients of MSC-FFM was reported, 88 with GvHD ≥°III, one-third only steroid-refractory and two-thirds therapy resistant (refractory to steroids plus ≥2 additional lines of treatment). A median of three doses of MSC-FFM was administered without apparent toxicity. Overall response rates were 82\% and 81\% at the first and last evaluation, respectively. At six months, the estimated overall survival was 64\%, while the cumulative incidence of death from underlying disease was 3\%. (4) Conclusions: MSC-FFM promises to be a safe and efficient treatment for severe R-aGvHD.},
  language  = {en}
}