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14 results on '"M Kool"'

1. The ethics of embryo donation: what are the moral similarities and differences of surplus embryo donation and double gamete donation?

Author

E H Huele, Annelies M. E. Bos, Annelien L. Bredenoord, E M Kool, and Bart C.J.M. Fauser

Subjects
animal structures, media_common.quotation_subject, Social Welfare, Disclosure, Treatment results, Morals, 0603 philosophy, ethics and religion, Developmental psychology, 03 medical and health sciences, 0302 clinical medicine, Empirical research, Gamete donation, Humans, Embryo Disposition, Moral duty, Child, media_common, Ivf treatment, 030219 obstetrics & reproductive medicine, Oocyte Donation, Rehabilitation, Embryo donation, Obstetrics and Gynecology, 06 humanities and the arts, Tissue Donors, Germ Cells, Reproductive Medicine, embryonic structures, 060301 applied ethics, Psychology, Welfare
Abstract

Over the years, the demand for ART with donated embryos has increased. Treatment can be performed using donated ‘surplus embryos’ from IVF treatment or with embryos intentionally created through so-called ‘double gamete donation’. Embryo donation is particularly sensitive because treatment results in the absence of a genetic link between the parent(s) and the child, creating complex family structures, including full genetic siblings living in another family in the case of surplus embryo donation. In this paper, we explore the ethical acceptability of embryo donation in light of the similarities and differences between surplus embryo donation and double gamete donation. We will argue that no overriding objections to either form of embryo donation exist. First of all, ART with donated embryos respects patients’ reproductive autonomy by allowing them to experience gestational parenthood. It also respects IVF patients’ reproductive autonomy by providing an additional option to discarding or donating surplus embryos to research. Second, an extensive body of empirical research has shown that a genetic link between parent and child is not a condition for a loving caring relationship between parent(s) and child. Third, the low moral status of a pre-implantation embryo signifies no moral duty for clinics to first use available surplus embryos or to prevent the development of (more) surplus embryos through double gamete donation. Fourth, there is no reason to assume that knowledge of having (full or half) genetically related persons living elsewhere provides an unacceptable impact on the welfare of donor-conceived offspring, existing children of the donors, and their respective families. Thus, patients and clinicians should discuss which form of ART would be suitable in their specific situation. To guarantee ethically sound ART with donated embryos certain conditions have to be met. Counselling of IVF patients should involve a discussion on the destination of potential surplus embryos. When counselling donors and recipient(s) a discussion of the significance of early disclosure of the child’s mode of conception, the implications of having children raised in families with whom they share no genetic ties, expectations around information-exchange and contact between donor and recipient families or genetically related siblings is warranted. Importantly, conclusions are mainly drawn from results of empirical studies on single gamete donation families. To evaluate the welfare of families created through surplus embryo donation or double gamete donation additional empirical research on these particular families is warranted.

Published
2020
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2. ETMR-14. TREATMENT OF EMBRYONAL TUMOURS WITH MULTILAYERED ROSETTES (ETMR) WITH CARBOPLATIN-ETOPOSIDE INDUCTION AND TANDEM HIGH-DOSE CHEMOTHERAPY WITHIN THE PROSPECTIVE HIT-TRIALS AND REGISTRIES

Author

Nicolas U. Gerber, Monika Warmuth-Metz, Björn-Ole Juhnke, M Kool, Stefan Rutkowski, Ulrich Schüller, Christine Haberler, Brigitte Bison, Stefan M. Pfister, Torsten Pietsch, Katja von Hoff, Carsten Friedrich, Rolf-Dieter Kortmann, Martin Mynarek, and Marco Gessi

Subjects
Oncology, Cancer Research, medicine.medical_specialty, business.industry, medicine.medical_treatment, Chemotherapy regimen, Carboplatin, Radiation therapy, chemistry.chemical_compound, High dose chemotherapy, Innovative Therapies, chemistry, Internal medicine, medicine, AcademicSubjects/MED00300, AcademicSubjects/MED00310, ETMR and other Embryonal Tumors, Neurology (clinical), Progression-free survival, business, Carboplatin/etoposide, Etoposide, medicine.drug
Abstract

BACKGROUND Embryonal tumours with multilayered rosettes (ETMR) are highly aggressive tumors, mostly occurring in infants. Published clinical data refer to retrospective cohorts of inhomogeneously treated patients. Here, we describe the outcome of patients, who were prospectively treated within the P-HIT2000-trial, the subsequent HIT2000-interim-registry and earlier HIT-trials. PATIENTS AND METHODS Nineteen patients from the P-HIT2000-trial (2001–2011), 12 patients from the subsequent HIT2000-interim-registry (2012–2014) and 4 patients from earlier HIT-trials with centrally reviewed neuropathological and molecularly-confirmed diagnosis of ETMR were included. Outcome of 18 patients treated with carboplatin-etoposide-induction followed by tandem-high-dose chemotherapy (“CARBO-ETO+HDCT”) with stage-stratified radiotherapy administered in case of persistant disease, relapse or progression were compared to patients treated with HIT-SKK chemotherapy ± radiotherapy (n=9) or other regimens (n=8). RESULTS Median age at diagnosis was 2.9(1.0–5.3) years. Metastases at diagnosis were detected in 9 patients (26%). For the entire cohort of n=35, 5-year overall survival (OS) was 26.7%, and progression-free survival (PFS) was 18.5%. Five-year OS for patients with CARBO-ETO+HDCT, SKK chemotherapy or other regimens was 44.4%, 13.0% and 0%, respectively (p=0.006). Five-year PFS was 33.3%, 0% and 0%, respectively (p=0.119). Of 10 survivors, n=8 were treated with CARBO-ETO+HDCT; n=4 had craniospinal, n=2 local and n=4 no radiotherapy. Impact of initial gross-total-resection (p=0.231) and non-metastatic disease (p=0.097) was limited. CONCLUSIONS We show improved survival with carboplatin-etoposide-induction followed by tandem-high-dose chemotherapy, indicating that a cure is possible for some patients. However, despite intensive treatment, outcome is unsatisfactory and innovative therapies urgently need to be included in an upfront setting.

Published
2020
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3. MEDULLOBLASTOMA

Author

G. Vaidyanathan, S. Gururangan, D. Bigner, M. Zalutsky, M. Morfouace, A. Shelat, J. Megan, B. B. Freeman, S. Robinson, S. Throm, J. M. Olson, X.-N. Li, K. R. Guy, G. Robinson, C. Stewart, A. Gajjar, M. Roussel, N. Sirachainan, S. Pakakasama, U. Anurathapan, A. Hansasuta, M. Dhanachai, C. Khongkhatithum, S. Hongeng, A. Feroze, K.-S. Lee, S. Gholamin, Z. Wu, B. Lu, S. Mitra, S. Cheshier, P. Northcott, C. Lee, T. Zichner, P. Lichter, J. Korbel, R. Wechsler-Reya, S. Pfister, I. P. T. Project, K. K.-W. Li, T. Xia, F. M. T. Ma, R. Zhang, L. Zhou, K.-M. Lau, H.-K. Ng, L. Lafay-Cousin, S. Chi, J. Madden, A. Smith, E. Wells, E. Owens, D. Strother, N. Foreman, R. Packer, E. Bouffet, T. Wataya, J. Peacock, M. D. Taylor, D. Ivanov, M. Garnett, T. Parker, C. Alexander, L. Meijer, R. Grundy, P. Gellert, M. Ashford, D. Walker, J. Brent, F. Z. Cader, D. Ford, A. Kay, R. Walsh, G. Solanki, A. Peet, M. English, T. Shalaby, G. Fiaschetti, S. Baulande, N. Gerber, M. Baumgartner, M. Grotzer, T. Hayase, Y. Kawahara, M. Yagi, T. Minami, N. Kanai, T. Yamaguchi, A. Gomi, A. Morimoto, R. Hill, S. Kuijper, J. Lindsey, E. Schwalbe, K. Barker, J. Boult, D. Williamson, Z. Ahmad, A. Hallsworth, S. Ryan, E. Poon, R. Ruddle, F. Raynaud, L. Howell, C. Kwok, A. Joshi, S. L. Nicholson, S. Crosier, S. Wharton, K. Robson, A. Michalski, D. Hargrave, T. Jacques, B. Pizer, S. Bailey, F. Swartling, K. Petrie, W. Weiss, L. Chesler, S. Clifford, L. Kitanovski, T. Prelog, B. F. Kotnik, M. Debeljak, M. A. Grotzer, A. Gevorgian, E. Morozova, I. Kazantsev, T. Iukhta, S. Safonova, E. Kumirova, Y. Punanov, B. Afanasyev, O. Zheludkova, W. Grajkowska, M. Pronicki, B. Cukrowska, B. Dembowska-Baginska, M. Lastowska, A. Murase, S. Nobusawa, Y. Gemma, F. Yamazaki, A. Masuzawa, T. Uno, T. Osumi, Y. Shioda, C. Kiyotani, T. Mori, K. Matsumoto, H. Ogiwara, N. Morota, J. Hirato, A. Nakazawa, K. Terashima, T. Fay-McClymont, K. Walsh, D. Mabbott, D. Sturm, P. A. Northcott, D. T. W. Jones, A. Korshunov, S. M. Pfister, M. Kool, C. Hooper, S. Hawes, U. Kees, N. Gottardo, P. Dallas, A. Siegfried, A. I. Bertozzi, A. Sevely, N. Loukh, C. Munzer, C. Miquel, F. Bourdeaut, T. Pietsch, C. Dufour, M. B. Delisle, D. Kawauchi, J. Rehg, D. Finkelstein, F. Zindy, T. Phoenix, R. Gilbertson, J. Trubicka, M. Borucka-Mankiewicz, E. Ciara, K. Chrzanowska, M. Perek-Polnik, D. Abramczuk-Piekutowska, D. Jurkiewicz, S. Luczak, P. Kowalski, M. Krajewska-Walasek, C. Sheila, S. Lee, C. Foster, B. Manoranjan, M. Pambit, R. Berns, A. Fotovati, C. Venugopal, K. O'Halloran, A. Narendran, C. Hawkins, V. Ramaswamy, M. Taylor, A. Singhal, J. Hukin, R. Rassekh, S. Yip, S. Singh, C. Duhman, S. Dunn, T. Chen, S. Rush, H. Fuji, Y. Ishida, T. Onoe, T. Kanda, Y. Kase, H. Yamashita, S. Murayama, Y. Nakasu, T. Kurimoto, A. Kondo, S. Sakaguchi, J. Fujimura, M. Saito, T. Arakawa, H. Arai, T. Shimizu, E. Jurkiewicz, P. Daszkiewicz, M. Drogosiewicz, V. Hovestadt, I. Buchhalter, N. N. Jager, A. Stuetz, P. Johann, C. Schmidt, M. Ryzhova, P. Landgraf, M. Hasselblatt, U. Schuller, M.-L. Yaspo, A. von Deimling, R. Eils, A. Modi, M. Patel, M. Berk, L.-x. Wang, G. Plautz, H. Camara-Costa, A. Resch, C. Lalande, V. Kieffer, G. Poggi, C. Kennedy, K. Bull, G. Calaminus, J. Grill, F. Doz, S. Rutkowski, M. Massimino, R.-D. Kortmann, B. Lannering, G. Dellatolas, M. Chevignard, D. Solecki, P. McKinnon, J. Olson, J. Hayden, D. Ellison, M. Buss, M. Remke, J. Lee, T. Caspary, R. Castellino, M. Sabel, G. Gustafsson, G. Fleischhack, M. Benesch, A. Navajas, R. Reddingius, M.-B. Delisle, D. Lafon, N. Sevenet, G. Pierron, O. Delattre, J. Ecker, I. Oehme, R. Mazitschek, M. Lodrini, H. E. Deubzer, A. E. Kulozik, O. Witt, T. Milde, D. Patmore, N. Boulos, K. Wright, S. Boop, T. Janicki, S. Burzynski, G. Burzynski, A. Marszalek, J. Triscott, M. Green, S. R. Rassekh, B. Toyota, C. Dunham, S. E. Dunn, K.-W. Liu, Y. Pei, L. Genovesi, P. Ji, M. Davis, C. G. Ng, Y.-J. Cho, N. Jenkins, N. Copeland, B. Wainwright, Y. Tang, S. Schubert, B. Nguyen, S. Masoud, A. Lee, M. Willardson, P. Bandopadhayay, G. Bergthold, S. Atwood, R. Whitson, J. Qi, R. Beroukhim, J. Tang, A. Oro, B. Link, J. Bradner, S. G. Vallero, D. Bertin, M. E. Basso, C. Milanaccio, P. Peretta, A. Cama, A. Mussano, S. Barra, G. Morana, I. Morra, P. Nozza, F. Fagioli, M. L. Garre, A. Darabi, E. Sanden, E. Visse, N. Stahl, P. Siesjo, D. Vaka, F. Vasquez, B. Weir, G. Cowley, C. Keller, W. Hahn, I. C. Gibbs, S. Partap, K. Yeom, M. Martinez, H. Vogel, S. S. Donaldson, P. Fisher, S. Perreault, L. Guerrini-Rousseau, S. Pujet, V. Kieffer-Renaux, M. A. Raquin, P. Varlet, A. Longaud, C. Sainte-Rose, D. Valteau-Couanet, J. Staal, L. S. Lau, H. Zhang, W. J. Ingram, Y. J. Cho, Y. Hathout, K. Brown, B. R. Rood, M. Handler, T. Hankinson, B. K. Kleinschmidt-Demasters, S. Hutter, D. T. Jones, N. Kagawa, R. Hirayama, N. Kijima, Y. Chiba, M. Kinoshita, K. Takano, D. Eino, S. Fukuya, F. Yamamoto, K. Nakanishi, N. Hashimoto, Y. Hashii, J. Hara, T. Yoshimine, J. Wang, C. Guo, Q. Yang, Z. Chen, I. Filipek, E. Swieszkowska, M. Tarasinska, D. Perek, R. Kebudi, B. Koc, O. Gorgun, F. Y. Agaoglu, J. Wolff, E. Darendeliler, K. Kerl, J. Gronych, J. McGlade, R. Endersby, H. Hii, T. Johns, J. Sastry, D. Murphy, M. Ronghe, C. Cunningham, F. Cowie, R. Jones, A. Calisto, M. Sangra, C. Mathieson, J. Brown, K. Phuakpet, V. Larouche, U. Bartels, T. Ishida, D. Hasegawa, K. Miyata, S. Ochi, A. Saito, A. Kozaki, T. Yanai, K. Kawasaki, K. Yamamoto, A. Kawamura, T. Nagashima, Y. Akasaka, T. Soejima, M. Yoshida, Y. Kosaka, A. von Bueren, T. Goschzik, R. Kortmann, K. von Hoff, C. Friedrich, A. z. Muehlen, M. Warmuth-Metz, N. Soerensen, F. Deinlein, I. Zwiener, A. Faldum, J. Kuehl, K. KRAMER, N. P. -Taskar, P. Zanzonico, J. L. Humm, S. L. Wolden, N.-K. V. Cheung, S. Venkataraman, I. Alimova, P. Harris, D. Birks, I. Balakrishnan, A. Griesinger, N. K. Foreman, R. Vibhakar, A. Margol, N. Robison, J. Gnanachandran, L. Hung, R. Kennedy, M. Vali, G. Dhall, J. Finlay, A. Erdrich-Epstein, M. Krieger, R. Drissi, M. Fouladi, F. Gilles, A. Judkins, R. Sposto, S. Asgharzadeh, A. Peyrl, M. Chocholous, S. Holm, P. Grillner, K. Blomgren, A. Azizi, T. Czech, B. Gustafsson, K. Dieckmann, U. Leiss, I. Slavc, S. Babelyan, I. Dolgopolov, R. Pimenov, G. Mentkevich, S. Gorelishev, M. Laskov, A. O. von Bueren, J. Nowak, R. D. Kortmann, M. Mynarek, K. Muller, N. U. Gerber, H. Ottensmeier, R. Kwiecien, M. Yankelevich, V. Boyarshinov, I. Glekov, S. Ozerov, S. Gorelyshev, A. Popa, N. Subbotina, A. M. Martin, C. Nirschl, M. Polanczyk, R. Bell, D. Martinez, L. M. Sullivan, M. Santi, P. C. Burger, J. M. Taube, C. G. Drake, D. M. Pardoll, M. Lim, L. Li, W.-G. Wang, J.-X. Pu, H.-D. Sun, R. Ruggieri, M. H. Symons, M. I. Vanan, S. Bolin, S. Schumacher, R. Zeid, F. Yu, N. Vue, W. Gibson, B. Paolella, F. J. Swartling, M. W. Kieran, J. E. Bradner, O. Maher, S. Khatua, N. Tarek, W. Zaky, T. Gupta, S. Mohanty, S. Kannan, R. Jalali, E. Kapitza, D. Denkhaus, A. z. Muhlen, D. G. van Vuurden, M. Garami, J. Fangusaro, T. B. Davidson, M. J. G. da Costa, J. Sterba, S. C. Clifford, J. L. Finlay, R. Schmidt, J. Felsberg, H. Skladny, F. Cremer, G. Reifenberger, R. Kunder, E. Sridhar, A. A. Moiyadi, A. Goel, N. Goel, N. Shirsat, R. Othman, L. Storer, I. Kerr, B. Coyle, N. Law, M. L. Smith, M. Greenberg, S. Laughlin, D. Malkin, F. Liu, I. Moxon-Emre, N. Scantlebury, A. Nasir, D. Onion, A. Lourdusamy, A. Grabowska, Y. Cai, T. Bradshaw, R. S. S. de Medeiros, A. Beaugrand, S. Soares, S. Epelman, W. Wang, M. Sultan, R. J. Wechsler-Reya, M. Zapatka, B. Radlwimmer, D. Alderete, L. Baroni, F. Lubinieki, F. Auad, M. L. Gonzalez, W. Puya, P. Pacheco, O. Aurtenetxe, A. Gaffar, L. Gros, O. Cruz, C. Calvo, N. Shinojima, H. Nakamura, J.-i. Kuratsu, A. Hanaford, C. Eberhart, T. Archer, P. Tamayo, S. Pomeroy, E. Raabe, K. De Braganca, S. Gilheeney, Y. Khakoo, K. Kramer, S. Wolden, I. Dunkel, R. R. Lulla, J. Laskowski, S. Goldman, V. Gopalakrishnan, D. Shih, X. Wang, C. Faria, C. Raybaud, U. Tabori, J. Rutka, S. Jacobs, F. De Vathaire, I. Diallo, D. Llanas, C. Verez, F. Diop, A. Kahlouche, S. Puget, E. Thompson, E. Prince, V. Amani, P. Sin-Chan, M. Lu, C. Kleinman, T. Spence, D. Picard, K. C. Ho, J. Chan, J. Majewski, N. Jabado, P. Dirks, A. Huang, J. R. Madden, A. M. Donson, D. M. Mirsky, A. Dubuc, S. Mack, D. Gendoo, B. Luu, T. MacDonald, T. Van Meter, S. Croul, A. Laureano, W. Brugmann, C. Denman, H. Singh, H. Huls, J. Moyes, D. Sandberg, L. Silla, L. Cooper, and D. Lee

Subjects
Oncology, Abstracts, Cancer Research, medicine.medical_specialty, Cns pnet, business.industry, Internal medicine, Meta-analysis, medicine, Neurology (clinical), business
Published
2014
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4. EPENDYMOMA

Author

L. M. Hoffman, A. M. Donson, I. Nakachi, A. M. Griesinger, D. K. Birks, V. Amani, M. S. Hemenway, A. K. Liu, M. Wang, T. C. Hankinson, M. H. Handler, N. K. Foreman, M. Zakrzewska, K. Zakrzewski, W. Fendler, L. Stefanczyk, P. P. Liberski, M. Massimino, L. Gandola, P. Ferroli, L. Valentini, V. Biassoni, M. L. Garre, I. Sardi, L. Genitori, C. Giussani, L. Massimi, D. Bertin, A. Mussano, E. Viscardi, P. Modena, A. Mastronuzzi, S. Barra, G. Scarzello, G. Cinalli, P. Peretta, F. Giangaspero, L. Boschetti, E. Schiavello, G. Calareso, M. Antonelli, E. Pecori, F. Di Meco, R. Migliorati, A. Taborelli, H. Witt, M. Sill, K. Wani, S. C. Mack, D. Capper, K. Pajtler, S. Lambert, T. Tzaridis, T. Milde, P. A. Northcott, A. E. Kulozik, O. Witt, V. P. Collins, D. W. Ellison, M. D. Taylor, M. Kool, D. T. W. Jones, A. Korshunov, A. Ken, S. M. Pfister, K. Makino, H. Nakamura, J.-i. Kuroda, J.-i. Kuratsu, H. Toledano, Y. Margolin, A. Ohali, S. Michowiz, P. Johann, U. Tabori, E. Walker, C. Hawkins, M. Taylor, I. Yaniv, S. Avigad, L. Hoffman, S. R. Plimpton, N. V. Stence, R. Vibhakar, A. Lourdusamy, R. Rahman, J. Ward, H. Rogers, R. Grundy, C. Punchihewa, R. Lee, T. Lin, W. Orisme, J. Dalton, E. Aronica, A. Smith, A. Gajjar, A. Onar, S. Pounds, R. Tatevossian, T. Merchant, D. Ellison, M. Parker, K. Mohankumar, R. Weinlich, T. Phoenix, R. Thiruvenkatam, E. White, K. Gupta, F. Boop, L. Ding, E. Mardis, R. Wilson, J. Downing, R. Gilbertson, D. Speed, T. Gould, t. I. E. Consortium, A. Griesinger, A. Donson, D. Birks, N. Ohe, H. Yano, N. Nakayama, T. Iwama, K. Wright, T. Hassall, D. C. Bowers, J. Crawford, A. Bendel, P. G. Fisher, P. Klimo, G. Armstrong, I. Qaddoumi, G. Robinson, C. Wetmore, A. Broniscer, R. Chapman, C. Mayne, H. Duane, J.-P. Kilday, B. Coyle, A. Graul-Conroy, W. Hartsell, T. Bragg, S. Goldman, S. Rebsamen, D. Puccetti, S. Salamat, N. J. Patel, A. Gomi, H. Oguma, T. Hayase, Y. Kawahara, M. Yagi, A. Morimoto, C. Wilbur, C. Dunham, D. Mabbott, A.-S. Carret, L. Lafay-Cousin, P. D. McNeely, D. Eisenstat, B. Wilson, D. Johnston, J. Hukin, M. Mynarek, R. D. Kortmann, P. Kaatsch, T. Pietsch, B. Timmermann, G. Fleischhack, M. Benesch, C. Friedrich, A. O. von Bueren, N. U. Gerber, K. Muller, S. Tippelt, M. Warmuth-Metz, S. Rutkowski, K. von Hoff, M. K. Murugesan, H. Poppleton, S. Currle, T. Kranenburg, C. Eden, N. Boulos, J. Dapper, Y. Patel, B. Freeman, A. Shelat, C. Stewart, R. Guy, J. Adamski, A. Huang, U. Bartels, V. Ramaswamy, R. Krishnatry, N. Laperriere, E. Bouffet, A. Araki, M. Chocholous, J. Gojo, C. Dorfer, T. Czech, K. Dieckmann, I. Slavc, C. Haberler, E. Doerner, A. z. Muehlen, R. Kortmann, A. von Buehren, H. Ottensmeier, A. Resch, R. Kwiecien, A. Faldum, J. Kuehl, D. Sabnis, L. Storer, L. Simmonds, S. Blackburn, J. Lowe, I. Kerr, I. Wohlers, T. Goschzik, V. Dreschmann, D. Denkhaus, S. Rahmann, L. Klein-Hitpass, M. J. L. Iglesias, F. G. Riet, F. D. Dhermain, S. Canale, C. Dufour, C. S. Rose, S. Puget, J. Grill, S. Bolle, J. Parkes, A. Davidson, A. Figaji, K. Pillay, T. Kilborn, L. Padayachy, M. Hendricks, A. Van Eyssen, E. Piccinin, E. Lorenzetto, M. Brenca, K. Aldape, Y.-J. Cho, W. Weiss, J. Phillips, N. Jabado, J. Mora, X. Fan, S. Jung, J. Y. Lee, K. Zitterbart, P. French, J. M. Kros, P. Hauser, C. Faria, and S. Pfister

Subjects
Abstracts, Cancer Research, Tumor grade, Oncology, Expression pattern, business.industry, microRNA, Cancer research, Medicine, Neurology (clinical), business
Published
2014
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6. TB-06 MOLECULAR MECHANISM OF BRAIN TUMOUR FORMATION DRIVEN BY SUPRATENTORIAL EPENDYMOMA-SPECIFIC YAP1 FUSION GENES

Author

Mikio Hoshino, Stefan Pfister, Patricia Benites Goncalves da Silva, M Kool, Daisuke Kawauchi, Yiju Wei, Kristian W. Pajtler, Wei Li, Konstantin Okonechnikov, and David T. W. Jones

Subjects
Ependymoma, YAP1, Biology, medicine.disease, medicine.disease_cause, Fusion protein, Tumor formation, Malignant transformation, Fusion gene, Abstracts, Tumor Biology/Models (Tb), Cancer research, medicine, Carcinogenesis, Transcription factor
Abstract

YAP1 fusion-positive supratentorial ependymomas predominantly occur in infants, but the molecular mechanisms of oncogenesis are unknown. Here we show YAP1-MAMLD1 fusions but not YAP1 wildtype are sufficient to drive malignant transformation of neural progenitors in the developing cerebral cortex in mice, and the resulting tumours share histo-molecular characteristics of human ependymomas. Nuclear localization of YAP1-MAMLD1 protein is associated with its oncogenicity and is mediated by the nuclear localization signal of MAMLD1 in a YAP1-Ser127 phosphorylation-independent manner. Chromatin immunoprecipitation-sequencing analyses of human YAP1-MAMLD1-positive ependymoma reveal enrichment of NFI and TEAD transcription factor binding site motifs in YAP1-bound regulatory elements, hypothesizing the important role of these transcription factors in YAP1-MAMLD1-driven tumourigenesis. Indeed, co-immunoprecipitation assays revealed physical interactions of TEADs and NFIA/B with the YAP1 and MAMLD1 domains of the fusion protein, respectively. Mutation of the TEAD binding site in the YAP1 fusion or repression of NFI targets prevents tumour induction in mice. Together, these results demonstrate that the YAP1-MAMLD1 fusion functions as an oncogenic driver of ependymoma through recruitment of TEADs and NFIs, indicating a rationale for preclinical studies to block the interaction between YAP1 fusions and NFI and TEAD transcription factors.

Published
2019
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7. ATRT-07. TARGETING PRIMARY CILIOGENESIS IN ATYPICAL TERATOID/RHABDOID TUMORS

Author

Serap Erkek, Lena Blümel, Frauke-Dorothee Meyer, Claudia C. Faria, Johannes Berlandi, Stefan M. Pfister, Eunice Paisana, Michael C. Frühwald, Max C. Liebau, Daniel Picard, Carlos Custódia, Pascal Johann, Nan Qin, Kornelius Kerl, Bastian Malzkorn, Astrid Jeibmann, Martin Hasselblatt, M Kool, Isabel Tegeder, Katharina Thiel, Kai Stühler, Maike Langini, Arndt Borkhardt, Guido Reifenberger, and Marc Remke

Subjects
Cancer Research, Cell growth, Cilium, Biology, Phenotype, Atypical Teratoid Rhabdoid Tumor (ATRT), Oncology, Cell culture, Ciliogenesis, Cancer research, Neurology (clinical), Stem cell, Signal transduction, Gene
Abstract

Atypical teratoid/rhabdoid tumors (AT/RT) are among the most common malignant brain tumors in infants. Comprehensive genomic studies revealed three distinct molecular subgroups (AT/RT-TYR, -MYC and -SHH). As primary cilia (PC) have already been shown to play a pivotal role in other tumor entities, we aimed to characterize the distribution of PC across AT/RT subgroups and to target primary ciliogenesis in these tumors with dismal prognosis. We performed immunofluorescence to detect PC in AT/RT primary tumor sections and cell lines. The functional role of PC was investigated in vitro by knockdown of KIF3A. The relevance of primary ciliogenesis in AT/RT biology was further elucidated in vivo using a fly model of SMARCB1 deficiency and an orthotopic mouse model. We detected PC in all AT/RT primary tumor sections and cell lines investigated in this study. Notably, we observed a significant subgroup-specific difference in the proportion of PC-positive cells. Specifically, AT/RT-TYR demonstrated the highest percentage of ciliated cells. Knockdown of KIF3A significantly reduced cell proliferation and stem cell properties. Additionally, apoptosis was significantly increased via upregulation of JAK1/STAT1 signaling. In a fly model of SMARCB1 deficiency, concomitant knockdown of several cilia-associated genes resulted in a substantial shift of the lethal phenotype with >20% of flies reaching adulthood. Finally, we demonstrated a significantly prolonged survival in an orthotopic xenograft model upon knockdown of KIF3A. In conclusion, our results implicate PC as a key feature of AT/RT biology and suggest primary ciliogenesis as a potential therapeutic target, especially in AT/RT-TYR.

Published
2019
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8. OMICS AND PROGNSTIC MARKERS

Author

K. Adachi, H. Sasaki, S. Nagahisa, K. Yoshida, N. Hattori, Y. Nishiyama, T. Kawase, M. Hasegawa, M. Abe, Y. Hirose, A. Alentorn, Y. Marie, S. Poggioli, H. Alshehhi, B. Boisselier, C. Carpentier, K. Mokhtari, L. Capelle, D. Figarella-Branger, K. Hoang-Xuan, M. Sanson, J.-Y. Delattre, A. Idbaih, S. Yust-Katz, M. Anderson, A. Olar, A. Eterovic, N. Ezzeddine, K. Chen, H. Zhao, G. Fuller, K. Aldape, J. de Groot, N. Andor, J. Harness, S. G. Lopez, T. L. Fung, H. W. Mewes, C. Petritsch, A. Arivazhagan, K. Somasundaram, K. Thennarasu, P. Pandey, B. Anandh, V. Santosh, B. Chandramouli, A. Hegde, P. Kondaiah, M. Rao, R. Bell, R. Kang, C. Hong, J. Song, J. Costello, R. Nagarajan, B. Zhang, A. Diaz, T. Wang, L. Bie, Y. Li, H. Liu, W. F. C. Luyo, M. H. Carnero, M. E. P. Iruegas, A. R. Morell, M. C. Figueiras, R. L. Lopez, C. F. Valverde, A. K.-Y. Chan, J. C.-S. Pang, N. Y.-F. Chung, K. K.-W. Li, W. S. Poon, D. T.-M. Chan, Y. Wang, H.-a. K. Ng, M. Chaumeil, P. Larson, H. Yoshihara, D. Vigneron, S. Nelson, R. Pieper, J. Phillips, S. Ronen, V. Clark, Z. E. Omay, A. Serin, J. Gunel, B. Omay, C. Grady, M. Youngblood, K. Bilguvar, J. Baehring, J. Piepmeier, P. Gutin, A. Vortmeyer, C. Brennan, M. N. Pamir, T. Kilic, B. Krischek, M. Simon, K. Yasuno, M. Gunel, A. L. Cohen, M. Sato, K. D. Aldape, C. Mason, K. Diefes, L. Heathcock, L. Abegglen, D. Shrieve, W. Couldwell, J. D. Schiffman, H. Colman, Q. G. D'Alessandris, T. Cenci, M. Martini, L. Ricci-Vitiani, R. De Maria, L. M. Larocca, R. Pallini, B. Theeler, F. Lang, G. Rao, M. Gilbert, E. Sulman, R. Luthra, K. Eterovic, M. Routbort, R. Verhaak, G. Mills, J. Mendelsohn, F. Meric-Bernstam, A. Yung, K. MacArthur, S. Hahn, G. Kao, R. Lustig, M. Alonso-Basanta, S. Chandrasekaran, E. P. Wileyto, E. Reyes, J. Dorsey, K. Fujii, K. Kurozumi, T. Ichikawa, M. Onishi, J. Ishida, Y. Shimazu, B. Kaur, E. A. Chiocca, I. Date, C. Geisenberger, A. Mock, R. Warta, C. Schwager, C. Hartmann, A. von Deimling, A. Abdollahi, C. Herold-Mende, O. Gevaert, A. Achrol, S. Gholamin, S. Mitra, E. Westbroek, J. Loya, L. Mitchell, S. Chang, G. Steinberg, S. Plevritis, S. Cheshier, J. Xu, S. Napel, G. Zaharchuk, G. Harsh, D. Gutman, C. Holder, R. Colen, W. Dunn, R. Jain, L. Cooper, S. Hwang, A. Flanders, D. Brat, J. Hayes, A. Droop, H. Thygesen, M. Boissinot, D. Westhead, S. Short, S. Lawler, P. Bady, S. Kurscheid, M. Delorenzi, M. E. Hegi, C. Crosby, C. Faulkner, T. Smye-Rumsby, K. Kurian, M. Williams, K. Hopkins, A. Palmer, H. Williams, C. Wragg, H. R. Haynes, K. M. Kurian, P. White, T. Oka, L. Jalbert, A. Elkhaled, R. Jensen, K. Salzman, M. Schabel, D. Gillespie, M. Mumert, B. Johnson, T. Mazor, M. Barnes, S. Yamamoto, H. Ueda, K. Tatsuno, K. Aihara, A. Bollen, M. Hirst, M. Marra, A. Mukasa, N. Saito, H. Aburatani, M. Berger, B. Taylor, S. Popov, A. Mackay, W. Ingram, A. Burford, A. Jury, M. Vinci, C. Jones, D. T. W. Jones, V. Hovestadt, S. Picelli, W. Wang, P. A. Northcott, M. Kool, G. Reifenberger, T. Pietsch, M. Sultan, H. Lehrach, M.-L. Yaspo, A. Borkhardt, P. Landgraf, R. Eils, A. Korshunov, M. Zapatka, B. Radlwimmer, S. M. Pfister, P. Lichter, A. Joy, I. Smirnov, M. Reiser, W. Shapiro, S. Kim, B. Feuerstein, C. Jungk, S. Friauf, A. Unterberg, T. A. Juratli, J. McElroy, W. Meng, A. Huebner, K. D. Geiger, D. Krex, G. Schackert, A. Chakravarti, T. Lautenschlaeger, B. Y. Kim, W. Jiang, J. Beiko, S. Prabhu, F. DeMonte, R. Sawaya, D. Cahill, I. McCutcheon, C. Lau, L. Wang, K. Terashima, S. Yamaguchi, M. Burstein, J. Sun, T. Suzuki, R. Nishikawa, H. Nakamura, A. Natsume, S. Terasaka, H.-K. Ng, D. Muzny, R. Gibbs, D. Wheeler, X.-q. Zhang, S. Sun, K.-f. Lam, K. M. Y. Kiang, J. K. S. Pu, A. S. W. Ho, G. K. K. Leung, F. Loebel, W. T. Curry, F. G. Barker, N. Lelic, A. S. Chi, D. P. Cahill, D. Lu, J. Yin, C. Teo, K. McDonald, A. Madhankumar, C. Weston, B. Slagle-Webb, J. Sheehan, A. Patel, M. Glantz, J. Connor, C. Maire, J. Francis, C.-Z. Zhang, J. Jung, V. Manzo, V. Adalsteinsson, H. Homer, B. Blumenstiel, C. S. Pedamallu, E. Nickerson, A. Ligon, C. Love, M. Meyerson, K. Ligon, L. E. Jalbert, S. J. Nelson, A. W. Bollen, I. V. Smirnov, J. S. Song, A. B. Olshen, M. S. Berger, S. M. Chang, B. S. Taylor, J. F. Costello, S. Mehta, B. Armstrong, S. Peng, A. Bapat, M. Berens, B. Melendez, M. Mollejo, P. Mur, T. Hernandez-Iglesias, C. Fiano, J. Ruiz, J. A. Rey, V. Stadler, A. Schulte, K. Lamszus, C. Schichor, M. Westphal, J.-C. Tonn, O. Morozova, S. Katzman, M. Grifford, S. Salama, D. Haussler, A. Olshen, S. Fouse, S. Nakamizo, T. Sasayama, H. Tanaka, K. Tanaka, K. Mizukawa, M. Yoshida, E. Kohmura, P. Northcott, D. Jones, S. Pfister, R. Otani, S. Takayanagi, K. Saito, S. Tanaka, M. Shin, T. Ozawa, M. Riester, Y.-K. Cheng, J. Huse, K. Helmy, N. Charles, M. Squatrito, F. Michor, E. Holland, M. Perrech, L. Dreher, G. Rohn, R. Goldbrunner, M. Timmer, B. Pollo, V. Palumbo, C. Calatozzolo, M. Patane, R. Nunziata, M. Farinotti, A. Silvani, S. Lodrini, G. Finocchiaro, E. Lopez, A. Rioscovian, R. Ruiz, G. Siordia, A. P. de Leon, C. Rostomily, R. Rostomily, D. Silbergeld, D. Kolstoe, M. Chamberlain, J. Silber, P. Roth, A. Keller, J. Hoheisel, P. Codo, A. Bauer, C. Backes, P. Leidinger, E. Meese, E. Thiel, A. Korfel, M. Weller, G. Nagae, M. Nagane, J. Z. Sanborn, T. Mikkelsen, S. Jhanwar, L. Chin, M. Nishihara, M. Schliesser, C. Grimm, E. Weiss, R. Claus, D. Weichenhan, M. Weiler, T. Hielscher, F. Sahm, B. Wiestler, A.-C. Klein, J. Blaes, C. Plass, W. Wick, G. Stragliotto, A. Rahbar, C. Soderberg-Naucler, M. Won, R. Ezhilarasan, P. Sun, D. Blumenthal, M. Vogelbaum, R. Jenkins, R. Jeraj, P. Brown, K. Jaeckle, D. Schiff, J. Dignam, J. Atkins, D. Brachman, M. Werner-Wasik, M. Mehta, J. Shen, J. Luan, A. Yu, M. Matsutani, Y. Liang, T.-K. Man, A. Trister, M. Tokita, S. Mikheeva, A. Mikheev, S. Friend, M. van den Bent, L. Erdem, T. Gorlia, M. Taphoorn, J. Kros, P. Wesseling, H. Dubbink, A. Ibdaih, P. French, H. van Thuijl, J. Heimans, B. Ylstra, J. Reijneveld, A. Prabowo, I. Scheinin, H. van Essen, W. Spliet, C. Ferrier, P. van Rijen, T. Veersema, M. Thom, A. S.-v. Meeteren, E. Aronica, H. Kim, S. Zheng, D. J. Brat, S. Virk, S. Amini, C. Sougnez, J. Barnholtz-Sloan, R. G. W. Verhaak, C. Watts, A. Sottoriva, I. Spiteri, S. Piccirillo, A. Touloumis, P. Collins, J. Marioni, C. Curtis, S. Tavare, B. Tews, T. P. C. Yeung, B. Al-Khazraji, L. Morrison, L. Hoffman, D. Jackson, T.-Y. Lee, S. Yartsev, G. Bauman, J. Fu, R. Vegesna, Y. Mao, L. E. Heathcock, W. Torres-Garcia, S. Wang, A. McKenna, C. W. Brennan, W. K. A. Yung, J. N. Weinstein, E. P. Sulman, and D. Koul

Subjects
Abstracts, Cancer Research, Text mining, Oncology, business.industry, Neurology (clinical), Computational biology, Biology, Omics, business
Published
2013
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9. HIGH GRADE GLIOMAS

Author

A. Leonard, J. Wolff, R. Sengupta, J. Marassa, D. Piwnica-Worms, J. Rubin, I. Pollack, R. Jakacki, L. Butterfield, H. Okada, J. Fangusaro, K. E. Warren, C. Mullins, P. Jurgen, S. Julia, C. C. Friedrich, S. Keir, J. Saling, M. Roskoski, H. Friedman, D. Bigner, C. Moertel, M. Olin, T. Dahlheimer, M. Gustafson, D. Sumstad, D. McKenna, W. Low, D. Nascene, A. Dietz, J. Ohlfest, D. Sturm, H. Witt, V. Hovestadt, D. A. K. Quan, D. T. W. Jones, C. Konermann, E. Pfaff, A. Korshunov, M. Rizhova, T. Milde, O. Witt, M. Zapatka, V. P. Collins, M. Kool, G. Reifenberger, P. Lichter, A. M. Lindroth, C. Plass, N. Jabado, S. M. Pfister, B. Pizer, A. Salehzadeh, A. Brodbelt, C. Mallucci, M. Brassesco, J. Pezuk, A. Morales, J. de Oliveira, G. Roberto, K. Umezawa, E. Valera, E. Rego, C. Scrideli, L. Tone, S. J. E. Veringa, D. G. Van Vuurden, P. Wesseling, W. P. Vandertop, D. P. Noske, T. Wurdinger, G. J. L. Kaspers, E. Hulleman, K. Wright, A. Broniscer, A. Bendel, D. Bowers, J. Crawford, P. Fisher, T. Hassall, G. Armstrong, J. Baker, I. Qaddoumi, G. Robinson, C. Wetmore, P. Klimo, F. Boop, A. Onar-Thomas, D. Ellison, A. Gajjar, O. Cruz, C. de Torres, M. Sunol, E. Rodriguez, L. Alonso, A. Parareda, T. Cardesa, H. Salvador, V. Celis, A. Guillen, G. Garcia, J. Muchart, C. Trampal, M. L. Martin, M. Rebollo, J. Mora, A. Piotrowski, A. Kowalska, P. Coyle, S. Smith, H. Rogers, D. Macarthur, R. Grundy, D. Puccetti, S. Salamat, T. Kennedy, N. Patel, K. Bradley, K. Casey, B. Iskandar, Y. Nakano, K. Okada, Y. Osugi, K. Yamasaki, H. Fujisaki, H. Fukushima, T. Inoue, Y. Matsusaka, H. Sakamoto, J. Hara, S. De Vleeschouwer, H. Ardon, F. Van Calenbergh, R. Sciot, G. Wilms, J. Van Loon, J. Goffin, S. Van Gool, D. Rusinak, P. Knight, K. Onel, D. Wargowski, A. Stettner, A. Al-Ghafari, W. Punjaruk, B. Coyle, I. Kerr, E. Xipell, M. Rodriguez, M. Gonzalez-Huarriz, M. T. Tunon, I. Zazpe, S. Tejada-Solis, R. Diez-Valle, J. Fueyo, C. Gomez-Manzano, M. M. Alonso, D. Pastakia, C. McCully, R. Murphy, J. Bacher, M. Thomas, E. Steffen-Smith, K. Saleem, S. Waldbridge, B. Widemann, K. Warren, E. Miele, F. Buttarelli, A. Arcella, F. Begalli, A. Po, C. Baldi, G. Carissimo, M. Antonelli, V. Donofrio, I. Morra, P. Nozza, A. Gulino, F. Giangaspero, E. Ferretti, I. Elens, F. Pauwels, S. Fritzell, S. Eberstal, E. Sanden, E. Visse, A. Darabi, P. Siesjo, P. McDonald, J. Wrogemann, S. Krawitz, M. Del Bigio, D. Eisenstat, R. Kwiecien, T. Pietsch, A. Faldum, R.-D. Kortmann, M. Warmuth-Metz, S. Rutkowski, I. Slavc, C. M. Kramm, U. Uparkar, R. Geyer, R. Ermoian, R. Ellenbogen, S. Leary, J. Triscott, K. Hu, A. Fotovati, S. Yip, R. Kast, B. Toyota, S. Dunn, M. Hegde, A. Corder, K. Chow, M. Mukherjee, A. Ashoori, V. Brawley, H. Heslop, S. Gottschalk, E. Yvon, N. Ahmed, T.-T. Wong, F.-Y. Yang, M. Lu, H.-F. Liang, H.-E. Wang, R.-S. Liu, M.-C. Teng, C.-C. Yen, S. Agnihotri, C. Ternamian, C. Jones, G. Zadeh, J. Rutka, C. Hawkins, I. Filipek, M. Drogosiewicz, M. Perek-Polnik, E. Swieszkowska, B. D. Baginska, E. Jurkiewicz, D. Perek, A. Kuehn, F. Falkenstein, A. Gnekow, C. Kramm, M. D. Brooks, E. Jackson, R. D. Mitra, J. B. Rubin, X.-Y. Liu, J. Schwartzentruber, A. M. Fontebasso, D.-A. K. Quang, S. Albrecht, Z. Dong, P. Siegel, A. Von Diemling, D. Faury, U. Tabori, J. Majewski, R. Lulla, M. Echevarria, T. Alden, A. DiPatri, T. Tomita, S. Goldman, T. Lin, T. E. Merchant, M. Kocak, A. P. Panandiker, G. T. Armstrong, G. H. Gielen, A. z. Muehlen, C. Hubert, Y. Ding, C. Toledo, P. Paddison, J. Olson, M. Nandhabalan, L. Bjerke, D. Bax, D. Carvalho, I. Bajrami, A. Ashworth, C. Lord, D. Hargrave, R. Reis, P. Workman, S. Little, S. Popov, A. Jury, A. Burford, L. Doey, S. Al-Sarraj, J. Jurgensmeier, L. Chen, I. Kozarewa, S. Baker, L. Perryman, G. Box, F. Raynaud, S. Eccles, M. Viana-Pereira, M. Pereira, T. Forshew, R. Tatevossian, D. Sheer, J. Pimental, M. Pires, C. Sarkar, P. Jha, I. R. P. Patrick, K. Somasundaram, P. Pathak, M. C. Sharma, V. Suri, A. Suri, N. Gerges, T. Haque, A. Nantel, C. Lee, J. Chen, C. Venugopal, A. Singhal, C. Dunham, J. Kerr, M. Verreault, H. Wakimoto, A. Jayanthan, A. Narendran, S. Singh, G. Giraud, S. Holm, B. Gustavsson, R. Kizyma, Z. Kizyma, L. Dvornyak, B. Kotsay, S. Epari, P. Sharma, M. Gurav, T. Gupta, P. Shetty, A. Moiyadi, S. Kane, and R. Jalali

Subjects
Abstracts, 03 medical and health sciences, Cancer Research, 0302 clinical medicine, Oncology, business.industry, 030220 oncology & carcinogenesis, Medicine, Neurology (clinical), business, 030217 neurology & neurosurgery
Published
2012
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10. EPENDYMOMA

Author

M. Zaghloul, M. Elbeltagy, A. Mousa, E. Eldebawy, A. Amin, Z. Pavelka, V. Vranova, I. Valaskova, L. Tomasikova, A. Oltova, J. Ventruba, Z. Mackerle, L. Kren, J. Skotakova, K. Zitterbart, J. Sterba, T. Milde, S. Kleber, A. Korshunov, H. Witt, T. Hielscher, P. Koch, H.-G. Koch, M. Jugold, H. E. Deubzer, I. Oehme, M. Lodrini, H.-J. Grone, A. Benner, O. Brustle, R. J. Gilbertson, A. von Deimling, A. E. Kulozik, S. M. Pfister, M.-V. Ana, O. Witt, M. Kool, S. C. Mack, M. D. Taylor, F. Fouyssac, E. Schmitt, L. Mansuy, J.-C. Marchal, L. Coffinet, V. Bernier, P. Chastagner, D. Sperl, S. Zacharoulis, M. Massimino, E. Schiavello, B. Pizer, C. Piette, L. Kitanovski, K. von Hoff, F. Quehenberger, S. Rutkowski, M. Benesch, T.-D. Tzaridis, S. Bender, E. Pfaff, S. Barbus, J. Bageritz, D.-T.-W. Jones, A. Kulozik, P. Lichter, S.-M. Pfister, S.-H. Song, C.-W. Kang, S.-H. Kim, P. Bandopadhayay, N. Ullrich, L. Goumnerova, R. M. Scott, V. M. Silvera, K. L. Ligon, K. J. Marcus, N. Robison, P. E. Manley, S. Chi, M. W. Kieran, V. Biassoni, P. Pierani, S. Cesaro, M. Maura, S. Mack, N. Jager, D. T. W. Jones, A. Stutz, P. A. Northcott, D. W. Fults, N. Gupta, M. Karajannis, J. T. Rutka, J. Korbel, A. C. P. de Rezende, M. J. Chen, N. S. da Silva, A. Cappellano, S. Cavalheiro, E. Weltman, S. Currle, R. Thiruvenkatam, M. Murugesan, T. Kranenburg, T. Phoenix, K. Gupta, R. Gilbertson, H. Rogers, J.-P. Kilday, C. Mayne, J. Ward, M. Adamowicz-Brice, E. Schwalbe, S. Clifford, B. Coyle, R. Grundy, B. Mitra, C. Domerg, F. Andreiuolo, T. Osteso-Ibanez, A. Mauguen, P. Varlet, M.-C. Le Deley, J. Lowe, D. W. Ellison, J. Grill, R. G. Grundy, G. Fleischhack, K. Pajtler, M. Zimmermann, M. Warmuth-Metz, R.-D. Kortmann, T. Pietsch, A. Faldum, U. Bode, L. Gandola, E. Pecori, G. Scarzello, S. Barra, M. Mascarin, S. Scoccianti, A. Mussano, M. L. Garre, S. Jacopo, E. Viscardi, R. Balter, D. Bertin, F. Giangaspero, M. Pearlman, S. Khatua, T. Van Meter, D. Koul, A. Yung, A. Paulino, J. Su, R. Dauser, W. Whitehead, B. Teh, M. Chintagumpala, D. Perek, M. Drogosiewicz, I. Filipek, M. P. Polnik, B. D. Baginska, J. Wachowiak, B. Kazmierczak, G. Sobol, K. Musiol, J. Kowalczyk, H. W. Slusarz, J. Peregud-Pogorzelski, W. Grajkowska, M. Roszkowski, W.-Y. Teo, F. Okcu, A. Mahajan, A. Adesina, A. Jea, R. Bollo, A. C. Paulino, N. Velez-Char, E. Doerner, A. z. Muehlen, V. Vladimirova, R. Kortmann, C. Friedrich, A. O. von Bueren, M. Barszczyk, P. Buczkowicz, A. Morrison, U. Tabori, C. Hawkins, K. Krajewski, G. Kammler, A. von Bueren, J. Krauss, C. Ferreira, G. Dieffenbach, C. Barbosa, P. Cuny, E. Piccinin, M. Brenca, E. Lorenzetto, I. Sardi, L. Genitori, B. Pollo, R. Maestro, P. Modena, S. MacDonald, D. Ebb, B. Lavally, B. Yeap, K. Marcus, N. Tarbell, T. Yock, S. Schittone, A. Donson, D. Birks, V. Amani, A. Griesinger, M. Handler, M. Madey, T. Merchant, N. Foreman, J. Hukin, T. Ailon, C. Dunham, A.-S. Carret, P. D. McNeely, S. Zelcer, B. Wilson, L. Lafay-Cousin, D. Johnston, D. Eisenstat, M. Silva, N. Jabado, S. Yip, K. Goddard, C. Fryer, G. Hendson, S. Dunn, A. Singhal, Y. Lassen-Ramshad, A. Vestergaard, K. Seiersen, H. P. Schultz, M. Hoeyer, J. B. Petersen, L. Moreno, S. Popov, A. Jury, S. Al Sarraj, C. Jones, D. Bowers, L. Gargan, C. J. Horton, D. Rakheja, L. Margraf, J. Yeung, R. Hamilton, H. Okada, R. Jakacki, I. Pollack, A. Fleming, C. Saint-Martin, C. Freeman, S. Albrecht, and J.-L. Montes

Subjects
Abstracts, Cancer Research, Oncology, Neurology (clinical)
Published
2012
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11. BIOLOGY

Author

J. H. Kim, H. B. Song, D. H. Kim, K. D. Park, B. J. Lee, S. Khatua, E. Kalkan, R. Brown, M. Pearlman, T. Vats, L. Abela, G. Fiaschetti, T. Shalaby, E. Grunder, M. Ma, J. Grahlert, M. Baumgartner, U. Siler, N. Nonoguchi, H. Ohgaki, M. Grotzer, J.-i. Adachi, T. Suzuki, K. Fukuoka, T. Yanagisawa, K. Mishima, T. Koga, M. Matsutani, R. Nishikawa, I. Sardi, L. Giunti, C. Bresci, S. Cardellicchio, M. Da Ros, A. M. Buccoliero, S. Farina, M. Arico, L. Genitori, M. Massimino, L. Filippi, A. Erdreich-Epstein, H. Zhou, X. Ren, M. Schur, T. B. Davidson, L. Ji, R. Sposto, S. Asgharzadeh, Y. Tong, E. White, M. Murugesan, B. Nimmervoll, M. Wang, D. Marino, D. Ellison, D. Finkelstein, S. Pounds, D. Malkin, R. Gilbertson, C. Eden, B. Ju, T. Phoenix, H. Poppleton, C. Lessman, M. Taylor, G. la Marca, S. Malvagia, V. Fratoni, M. G. Giovannini, F. Giangaspero, M. Badiali, V. Gleize, S. Paris, L. Moi, S. Elhouadani, A. Arcella, R. Morace, M. Antonelli, F. Buttarelli, K. Mokhtari, M. Sanson, S. Smith, J. Ward, M. Wilson, C. Rahman, F. Rose, A. Peet, D. Macarthur, R. Grundy, R. Rahman, S. Venkatraman, D. Birks, I. Balakrishnan, I. Alimova, P. Harris, P. Patel, N. Foreman, R. Vibhakar, H. Wu, Q. Zhou, D. Wang, G. Wang, D. Dang, E. Pencreach, A. Nguyen, E. Guerin, C. Lasthaus, D. Guenot, N. Entz-Werle, R. Unland, S. Schlosser, N. Farwick, T. Plagemann, G. Richter, H. Juergens, M. Fruehwald, C.-L. Chien, Y.-H. Lee, C.-I. Lin, J.-Y. Hsieh, S.-C. Lin, T.-T. Wong, D. M.-T. Ho, H.-W. Wang, S. Lagah, I.-L. Tan, S. Malcolm, Y. Majani, D. G. van Vuurden, E. Aronica, L. E. Wedekind, E. Hulleman, D. Biesmans, M. Bugiani, W. P. Vandertop, G. J. L. Kaspers, T. Wurdinger, D. P. Noske, P. M. Van der Stoop, S. Shukla, G. K. Kuipers, B. J. Slotman, J. Cloos, T. Sun, N. Warrington, J. Luo, S. Ganzhorn, U. Tabori, T. Druley, D. Gutmann, J. Rubin, P. Castelo-Branco, S. Choufani, S. Mack, D. Galagher, C. Zhang, T. Lipman, N. Zhukova, D. Martin, D. Merino, J. Wasserman, C. Samuel, N. Alon, J. Hitzler, J. C. Y. Wang, G. Keller, P. B. Dirks, S. Pfister, M. D. Taylor, R. Weksberg, P. Leblond, S. Meignan, A. Dewitte, F. Le Tinier, N. Wattez, E. Lartigau, A. Lansiaux, R. Hanson, I. Gordon, S. Zhao, K. Camphausen, K. Warren, N. M. Warrington, D. H. Gutmann, J. B. Rubin, M. Jaillet, Z. Kovacs, E. Martin-Fiori, M. Bernasconi, B. Werner, C. Dyberg, N. Baryawno, J. Milosevic, M. Wickstrom, P. A. Northcott, M. Kool, P. Kogner, J. I. Johnsen, G. Reynolds, N. Davies, T. Arvanitis, A. Zoghbi, M. Meisterernst, M. C. Fruehwald, K. Kerl, B. Orr, M. Haffner, W. Nelson, S. Yegnasubramanian, C. Eberhart, A. Fotovati, S. Abu-Ali, P.-S. Wang, L. Deleyrolle, C. Lee, J. Triscott, J. Chen, S. Franciosi, Y. Nakamura, Y. Sugita, T. Uchiumi, M. Kuwano, B. Leavitt, S. Singh, A. Jury, C. Jones, H. Wakimoto, B. Reynolds, C. Pallen, S. Dunn, S. Fletcher, J. Levine, M. Li, N. Kagawa, R. Hirayama, Y. Chiba, N. Kijima, H. Arita, M. Kinoshita, N. Hashimoto, S. Izumoto, M. Maruno, and T. Yoshimine

Subjects
Abstracts, Cancer Research, Oncology, Neurology (clinical)
Published
2012
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12. ATRT-34. TARGETING PRIMARY CILIOGENESIS IN ATYPICAL TERATOID/RHABDOID TUMORS

Author

Max C. Liebau, Michael C. Frühwald, Guido Reifenberger, Kai Stühler, Nan Qin, Marc Remke, Arndt Borkhardt, Pascal Johann, Astrid Jeibmann, Kornelius Kerl, Bastian Malzkorn, Lena Blümel, M Kool, Serap Erkek, Johannes Berlandi, Isabel Tegeder, Martin Hasselblatt, Frauke-Dorothee Meyer, Katharina Thiel, Stefan M. Pfister, Maike Langini, and Daniel Picard

Subjects
Abstracts, Cancer Research, Oncology, Cell growth, Ciliogenesis, Rhabdoid tumors, SMARCB1 Protein, Cancer research, Neurology (clinical), Stem cell, Biology, Gene, Genome
Abstract

Atypical teratoid/rhabdoid tumors (AT/RT) are among the most common malignant brain tumors in infants. Comprehensive genomic studies revealed three distinct molecular subgroups (AT/RT-TYR, -MYC and -SHH). As primary cilia (PC) have already been shown to play a central role in other tumor entities, we aimed to characterize the distribution of PC across AT/RT subgroups and to target primary ciliogenesis in these tumors with dismal prognosis. We performed immunofluorescence to detect PC in AT/RT cell lines (n=2) and primary tumor sections (n=13). The functional role of PC was investigated by knockdown of KIF3A and pharmacological inhibition with Ciliobrevin D in vitro. The relevance of primary ciliogenesis in AT/RT biology was further elucidated using a fly model of SMARCB1 deficiency. We detected PC in both AT/RT cell lines and all primary tumors investigated in this study. Notably, we observed a significant subgroup-specific difference in the proportion of PC-positive cells. Specifically, AT/RT-TYR demonstrated the highest percentage of ciliated cells. Knockdown of KIF3A significantly reduced cell proliferation and stem cell properties. Additionally, death receptor 5 signaling was significantly up-regulated. Pharmacological inhibition by Ciliobrevin D phenocopied these results, specifically after induction of primary ciliogenesis through serum starvation. In a fly model of SMARCB1 deficiency, concomitant knockdown of several cilia-associated genes resulted in a substantial shift of the lethal phenotype with >20% of flies reaching adulthood. In conclusion, these results implicate PC as a key feature of AT/RT biology and suggest primary ciliogenesis as a potential therapeutic target, especially in AT/RT-TYR.

Published
2018
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13. ATRT-24. CHROMATIN SEGMENTATION IN ATRT REVEALS AN IMPORTANT ROLE FOR RESIDUAL SWI/SNF MEMBERS

Author

Martina Finetti, Stefan M. Pfister, M Kool, Serap Erkek, Martin Hasselblatt, Pascal Johann, and Daniel Williamson

Subjects
Cancer Research, macromolecular substances, Epigenome, Computational biology, Biology, SWI/SNF, Chromatin, Abstracts, Histone, Oncology, SMARCA4, biology.protein, Neurology (clinical), Epigenetics, SMARCB1, Enhancer
Abstract

Although SMARCB1 mutations represent the only recurrent genetic aberration in atypical teratoid/rhabdoid tumors (ATRT), a comprehensive assessment of the epigenetic effect of SMARCB1 loss has not been attempted so far. To achieve this, we performed ChIP-sequencing for six histone marks (H3K4me1, H3K4me3, H3K27me3, H3K27Ac, H3K9me3, H3K36me3) and EZH2 in 11 primary ATRTs, encompassing all three molecular subgroups of ATRT. Chromatin segmentation analyses revealed that across all three subgroups a high percentage of ATRT epigenomes resides in a quiescent state and active enhancer states are significantly underrepresented as compared to non-neoplastic brain. We validated these findings in a SMARCB1-reexpressing ATRT cell line and also found an overall deincrease of H3K27Ac and H3K27me3 upon SMARCB1 reexpression. Interestingly, by comparing the genome wide distribution of EZH2 and H3K27me3, we also identified classes of ATRT-specific active genes bound by EZH2, but lackingH3K27me3, pointing at a non-canonical role of EZH2 in gene activation. ChIP-Sequencing of SMARCA4 in these samples revealed that many of these „EZH2 only” genes display a high signal of of this protein. Many of these genes (such as e.g. CCND2) were downregulated upon knock-down of SMARCA4 in ATRT cell lines. Adding to the overall characterization of the epigenome, we have shown that a number of genes - despite being bound by EZH2- are maintained in an active state by residual SWI/SNF complex binding. This sheds new light on the role of residual SWI/SNFSMARCA4 still being present in AT/RT and elucidates a mechanism by which AT/RT keep important tumor-genes in an active state.

Published
2018
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14. TMOD-05. MOLECULAR CHARACTERIZATION OF ORTHOTOPIC PATIENT-DERIVED XENOGRAFT MODELS OF PEDIATRIC BRAIN TUMORS AND THEIR USE IN PRECLINICAL EXPERIMENTS

Author

Lukas Chavez, Till Milde, Jones Dtw, Susanne N. Groebner, Olaf Witt, Xiao-Nan Li, Robert J. Wechsler-Reya, M Kool, Huriye Seker-Cin, Sebastian Brabetz, Sarah Leary, James Olson, Norman Mack, S Pfister, and Christin Schmidt

Subjects
Abstracts, Cancer Research, Text mining, Oncology, business.industry, Pediatric brain, Cancer research, Medicine, Neurology (clinical), business, Tumor xenograft
Abstract

Genomic studies have shown that multiple molecular subtypes of pediatric brain tumors exist that are biologically and clinically highly distinct. These findings ask for novel subtype specific treatments. To develop these we need more and better preclinical models that correctly reflect the proper tumor (sub)type. Orthotopic patient-derived xenograft (PDX) models generated by intracranial injection of primary patient material into the brain of NSG mice offer the unique possibility to test novel substances in primary patient tissue in an in vivo environment. Prior to drug selection and testing, extensive molecular characterizations of PDX and matching primary tumor/blood (DNA methylation, DNA sequencing, and gene expression) are needed to see how the PDX represents the original disease and to learn about targetable oncogenic drivers in each model. In collaboration with several groups around the world we have generated and fully characterized thus far 75 PDX models reflecting 15 distinct subtypes of pediatric brain cancer. PDX models always retain their molecular subtype and in the vast majority of cases also mutations and copy number alterations compared to matching primary tumors. Most aggressive tumors, harboring MYC(N) amplifications, are overrepresented in the cohort, but also subtypes which have not been available for preclinical testing before due to lack of genetically engineered mouse models or suitable cell lines, such as Group 4 medulloblastoma, are included. All models and corresponding molecular data will become available for the community for preclinical research. Examples of such preclinical experiments will be presented. PDX models of pediatric brain tumors are still quite rare. Our repertoire of PDX models and corresponding molecular characterizations allow researchers all over the world to find the right models for their specific scientific questions. It will provide an unprecedented resource to study tumor biology and pave the way for improving treatment strategies for children with malignant brain tumors.

Published
2017
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