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1. Epigenomic alterations define lethal CIMP-positive ependymomas of infancy

Author

Mack, SC, Witt, H, Piro, RM, Gu, L, Zuyderduyn, S, Stütz, AM, Wang, X, Gallo, M, Garzia, L, Zayne, K, Zhang, X, Ramaswamy, V, Jäger, N, Jones, DTW, Sill, M, Pugh, TJ, Ryzhova, M, Wani, KM, Shih, DJH, Head, R, Remke, M, Bailey, SD, Zichner, T, Faria, CC, Barszczyk, M, Stark, S, Seker-Cin, H, Hutter, S, Johann, P, Bender, S, Hovestadt, V, Tzaridis, T, Dubuc, AM, Northcott, PA, Peacock, J, Bertrand, KC, Agnihotri, S, Cavalli, FMG, Clarke, I, Nethery-Brokx, K, Creasy, CL, Verma, SK, Koster, J, Wu, X, Yao, Y, Milde, T, Sin-Chan, P, Zuccaro, J, Lau, L, Pereira, S, Castelo-Branco, P, Hirst, M, Marra, MA, Roberts, SS, Fults, D, Massimi, L, Cho, YJ, Van Meter, T, Grajkowska, W, Lach, B, Kulozik, AE, von Deimling, A, Witt, O, Scherer, SW, Fan, X, Muraszko, KM, Kool, M, Pomeroy, SL, Gupta, N, Phillips, J, Huang, A, Tabori, U, Hawkins, C, Malkin, D, Kongkham, PN, Weiss, WA, Jabado, N, Rutka, JT, Bouffet, E, Korbel, JO, Lupien, M, Aldape, KD, Bader, GD, Eils, R, Lichter, P, Dirks, PB, Pfister, SM, Korshunov, A, and Taylor, MD

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Genetics, Pediatric, Human Genome, Rare Diseases, Animals, Brain Neoplasms, CpG Islands, DNA Methylation, Embryonic Stem Cells, Ependymoma, Epigenesis, Genetic, Epigenomics, Female, Gene Expression Regulation, Neoplastic, Gene Silencing, Histones, Humans, Infant, Mice, Mice, Inbred NOD, Mice, SCID, Mutation, Phenotype, Polycomb Repressive Complex 2, Prognosis, Rhombencephalon, Xenograft Model Antitumor Assays, General Science & Technology
Abstract

Ependymomas are common childhood brain tumours that occur throughout the nervous system, but are most common in the paediatric hindbrain. Current standard therapy comprises surgery and radiation, but not cytotoxic chemotherapy as it does not further increase survival. Whole-genome and whole-exome sequencing of 47 hindbrain ependymomas reveals an extremely low mutation rate, and zero significant recurrent somatic single nucleotide variants. Although devoid of recurrent single nucleotide variants and focal copy number aberrations, poor-prognosis hindbrain ependymomas exhibit a CpG island methylator phenotype. Transcriptional silencing driven by CpG methylation converges exclusively on targets of the Polycomb repressive complex 2 which represses expression of differentiation genes through trimethylation of H3K27. CpG island methylator phenotype-positive hindbrain ependymomas are responsive to clinical drugs that target either DNA or H3K27 methylation both in vitro and in vivo. We conclude that epigenetic modifiers are the first rational therapeutic candidates for this deadly malignancy, which is epigenetically deregulated but genetically bland.

Published
2014

5. A C19MC-LIN28A-MYCN Oncogenic Circuit Driven by Hijacked Super-enhancers Is a Distinct Therapeutic Vulnerability in ETMRs: A Lethal Brain Tumor

Author

Sin-Chan, P., Mumal, I., Suwal, T., Ho, B., Fan, X., Singh, I., Du, Y., Lu, M., Patel, N., Torchia, J., Popovski, D., Fouladi, M., Guilhamon, P., Hansford, J. R., Leary, S., Hoffman, L. M., Mulcahy Levy, J. M., Lassaletta, A., Solano-Paez, P., Rivas, E., Reddy, A., Gillespie, G. Y., Gupta, N., Van Meter, T. E., Nakamura, H., Wong, T. -T., Ra, Y. -S., Kim, S. -K., Massimi, Luca, Grundy, R. G., Fangusaro, J., Johnston, D., Chan, J., Lafay-Cousin, L., Hwang, E. I., Wang, Y., Catchpoole, D., Michaud, J., Ellezam, B., Ramanujachar, R., Lindsay, H., Taylor, M. D., Hawkins, C. E., Bouffet, E., Jabado, N., Singh, S. K., Kleinman, C. L., Barsyte-Lovejoy, D., Li, X. -N., Dirks, P. B., Lin, C. Y., Mack, S. C., Rich, J. N., Huang, A., Massimi L., Sin-Chan, P., Mumal, I., Suwal, T., Ho, B., Fan, X., Singh, I., Du, Y., Lu, M., Patel, N., Torchia, J., Popovski, D., Fouladi, M., Guilhamon, P., Hansford, J. R., Leary, S., Hoffman, L. M., Mulcahy Levy, J. M., Lassaletta, A., Solano-Paez, P., Rivas, E., Reddy, A., Gillespie, G. Y., Gupta, N., Van Meter, T. E., Nakamura, H., Wong, T. -T., Ra, Y. -S., Kim, S. -K., Massimi, Luca, Grundy, R. G., Fangusaro, J., Johnston, D., Chan, J., Lafay-Cousin, L., Hwang, E. I., Wang, Y., Catchpoole, D., Michaud, J., Ellezam, B., Ramanujachar, R., Lindsay, H., Taylor, M. D., Hawkins, C. E., Bouffet, E., Jabado, N., Singh, S. K., Kleinman, C. L., Barsyte-Lovejoy, D., Li, X. -N., Dirks, P. B., Lin, C. Y., Mack, S. C., Rich, J. N., Huang, A., and Massimi L.

Abstract

Embryonal tumors with multilayered rosettes (ETMRs) are highly lethal infant brain cancers with characteristic amplification of Chr19q13.41 miRNA cluster (C19MC) and enrichment of pluripotency factor LIN28A. Here we investigated C19MC oncogenic mechanisms and discovered a C19MC-LIN28A-MYCN circuit fueled by multiple complex regulatory loops including an MYCN core transcriptional network and super-enhancers resulting from long-range MYCN DNA interactions and C19MC gene fusions. Our data show that this powerful oncogenic circuit, which entraps an early neural lineage network, is potently abrogated by bromodomain inhibitor JQ1, leading to ETMR cell death. Sin-Chan et al. uncover a C19MC-LIN28A-MYCN super-enhancer-dependent oncogenic circuit in embryonal tumors with multilayered rosettes (ETMRs). The circuit entraps an early neural lineage network to sustain embryonic epigenetic programming and is vulnerable to bromodomain inhibition, which promotes ETMR cell death.

Published
2019

9. Epigenomic alterations define lethal CIMP-positive ependymomas of infancy.

Author

Mack, S, Mack, S, Witt, H, Piro, R, Gu, L, Zuyderduyn, S, Stütz, A, Wang, X, Gallo, M, Garzia, L, Zayne, K, Zhang, X, Ramaswamy, V, Jäger, N, Jones, D, Sill, M, Pugh, T, Ryzhova, M, Wani, K, Shih, D, Head, R, Remke, M, Bailey, S, Zichner, T, Faria, C, Barszczyk, M, Stark, S, Seker-Cin, H, Hutter, S, Johann, P, Bender, S, Hovestadt, V, Tzaridis, T, Dubuc, A, Northcott, P, Peacock, J, Bertrand, K, Agnihotri, S, Cavalli, F, Clarke, I, Nethery-Brokx, K, Creasy, C, Verma, S, Koster, J, Wu, X, Yao, Y, Milde, T, Sin-Chan, P, Zuccaro, J, Lau, L, Pereira, S, Castelo-Branco, P, Hirst, M, Marra, M, Roberts, S, Fults, D, Massimi, L, Cho, Y, Van Meter, T, Grajkowska, W, Lach, B, Kulozik, A, von Deimling, A, Witt, O, Scherer, S, Fan, X, Muraszko, K, Kool, M, Pomeroy, S, Jabado, N, Rutka, J, Bouffet, E, Korbel, J, Lupien, M, Aldape, K, Bader, G, Eils, R, Lichter, P, Dirks, P, Pfister, S, Korshunov, A, Taylor, M, Huang, A, Tabori, U, Hawkins, C, Malkin, D, Kongkham, P, Gupta, Nalin, Phillips, Joanna, Weiss, William, Mack, S, Mack, S, Witt, H, Piro, R, Gu, L, Zuyderduyn, S, Stütz, A, Wang, X, Gallo, M, Garzia, L, Zayne, K, Zhang, X, Ramaswamy, V, Jäger, N, Jones, D, Sill, M, Pugh, T, Ryzhova, M, Wani, K, Shih, D, Head, R, Remke, M, Bailey, S, Zichner, T, Faria, C, Barszczyk, M, Stark, S, Seker-Cin, H, Hutter, S, Johann, P, Bender, S, Hovestadt, V, Tzaridis, T, Dubuc, A, Northcott, P, Peacock, J, Bertrand, K, Agnihotri, S, Cavalli, F, Clarke, I, Nethery-Brokx, K, Creasy, C, Verma, S, Koster, J, Wu, X, Yao, Y, Milde, T, Sin-Chan, P, Zuccaro, J, Lau, L, Pereira, S, Castelo-Branco, P, Hirst, M, Marra, M, Roberts, S, Fults, D, Massimi, L, Cho, Y, Van Meter, T, Grajkowska, W, Lach, B, Kulozik, A, von Deimling, A, Witt, O, Scherer, S, Fan, X, Muraszko, K, Kool, M, Pomeroy, S, Jabado, N, Rutka, J, Bouffet, E, Korbel, J, Lupien, M, Aldape, K, Bader, G, Eils, R, Lichter, P, Dirks, P, Pfister, S, Korshunov, A, Taylor, M, Huang, A, Tabori, U, Hawkins, C, Malkin, D, Kongkham, P, Gupta, Nalin, Phillips, Joanna, and Weiss, William

Abstract

Ependymomas are common childhood brain tumours that occur throughout the nervous system, but are most common in the paediatric hindbrain. Current standard therapy comprises surgery and radiation, but not cytotoxic chemotherapy as it does not further increase survival. Whole-genome and whole-exome sequencing of 47 hindbrain ependymomas reveals an extremely low mutation rate, and zero significant recurrent somatic single nucleotide variants. Although devoid of recurrent single nucleotide variants and focal copy number aberrations, poor-prognosis hindbrain ependymomas exhibit a CpG island methylator phenotype. Transcriptional silencing driven by CpG methylation converges exclusively on targets of the Polycomb repressive complex 2 which represses expression of differentiation genes through trimethylation of H3K27. CpG island methylator phenotype-positive hindbrain ependymomas are responsive to clinical drugs that target either DNA or H3K27 methylation both in vitro and in vivo. We conclude that epigenetic modifiers are the first rational therapeutic candidates for this deadly malignancy, which is epigenetically deregulated but genetically bland.

Published
2014

10. Epigenomic alterations define lethal CIMP-positive ependymomas of infancy

Author

Mack, S. C., Witt, H., Piro, R. M., Gu, L., Zuyderduyn, S., Stütz, A. M., Wang, X., Gallo, M., Garzia, L., Zayne, K., Zhang, X., Ramaswamy, V., Jäger, N., Jones, D. T. W., Sill, M., Pugh, T. J., Ryzhova, M., Wani, K. M., Shih, D. J. H., Head, R., Remke, M., Bailey, S. D., Zichner, T., Faria, C. C., Barszczyk, M., Stark, S., Seker-Cin, H., Hutter, S., Johann, P., Bender, S., Hovestadt, V., Tzaridis, T., Dubuc, A. M., Northcott, P. A., Peacock, J., Bertrand, K. C., Agnihotri, S., Cavalli, F. M. G., Clarke, I., Nethery-Brokx, K., Creasy, C. L., Verma, S. K., Koster, J., Wu, X., Yao, Y., Milde, T., Sin-Chan, P., Zuccaro, J., Lau, L., Pereira, S., Castelo-Branco, P., Hirst, M., Marra, M. A., Roberts, S. S., Fults, D., Massimi, Luca, Cho, Y. J., Van Meter, T., Grajkowska, W., Lach, B., Kulozik, A. E., Von Deimling, A., Witt, O., Scherer, S. W., Fan, X., Muraszko, K. M., Kool, M., Pomeroy, S. L., Gupta, N., Phillips, J., Huang, A., Tabori, U., Hawkins, C., Malkin, D., Kongkham, P. N., Weiss, W. A., Jabado, N., Rutka, J. T., Bouffet, E., Korbel, J. O., Lupien, M., Aldape, K. D., Bader, G. D., Eils, R., Lichter, P., Dirks, P. B., Pfister, S. M., Korshunov, A., Taylor, M. D., Massimi, L., Mack, S. C., Witt, H., Piro, R. M., Gu, L., Zuyderduyn, S., Stütz, A. M., Wang, X., Gallo, M., Garzia, L., Zayne, K., Zhang, X., Ramaswamy, V., Jäger, N., Jones, D. T. W., Sill, M., Pugh, T. J., Ryzhova, M., Wani, K. M., Shih, D. J. H., Head, R., Remke, M., Bailey, S. D., Zichner, T., Faria, C. C., Barszczyk, M., Stark, S., Seker-Cin, H., Hutter, S., Johann, P., Bender, S., Hovestadt, V., Tzaridis, T., Dubuc, A. M., Northcott, P. A., Peacock, J., Bertrand, K. C., Agnihotri, S., Cavalli, F. M. G., Clarke, I., Nethery-Brokx, K., Creasy, C. L., Verma, S. K., Koster, J., Wu, X., Yao, Y., Milde, T., Sin-Chan, P., Zuccaro, J., Lau, L., Pereira, S., Castelo-Branco, P., Hirst, M., Marra, M. A., Roberts, S. S., Fults, D., Massimi, Luca, Cho, Y. J., Van Meter, T., Grajkowska, W., Lach, B., Kulozik, A. E., Von Deimling, A., Witt, O., Scherer, S. W., Fan, X., Muraszko, K. M., Kool, M., Pomeroy, S. L., Gupta, N., Phillips, J., Huang, A., Tabori, U., Hawkins, C., Malkin, D., Kongkham, P. N., Weiss, W. A., Jabado, N., Rutka, J. T., Bouffet, E., Korbel, J. O., Lupien, M., Aldape, K. D., Bader, G. D., Eils, R., Lichter, P., Dirks, P. B., Pfister, S. M., Korshunov, A., Taylor, M. D., and Massimi, L.

Abstract

Ependymomas are common childhood brain tumours that occur throughout the nervous system, but are most common in the paediatric hindbrain. Current standard therapy comprises surgery and radiation, but not cytotoxic chemotherapy as it does not further increase survival. Whole-genome and whole-exome sequencing of 47 hindbrain ependymomas reveals an extremely low mutation rate, and zero significant recurrent somatic single nucleotide variants. Although devoid of recurrent single nucleotide variants and focal copy number aberrations, poor-prognosis hindbrain ependymomas exhibit a CpG island methylator phenotype. Transcriptional silencing driven by CpG methylation converges exclusively on targets of the Polycomb repressive complex 2 which represses expression of differentiation genes through trimethylation of H3K27. CpG island methylator phenotype-positive hindbrain ependymomas are responsive to clinical drugs that target either DNA or H3K27 methylation both in vitro and in vivo. We conclude that epigenetic modifiers are the first rational therapeutic candidates for this deadly malignancy, which is epigenetically deregulated but genetically bland. © 2014 Macmillan Publishers Limited.

Published
2014

14. GE-21 * DRASTIC GENOMIC DIVERGENCE OF RECURRENT MEDULLOBLASTOMA INVALIDATES TARGETED THERAPIES DISCOVERED AT DIAGNOSIS

Author

Morrissy, S., primary, Garzia, L., additional, Remke, M., additional, Ramaswamy, V., additional, Jorgensen, F., additional, Wu, X., additional, Shah, S., additional, Ma, Y., additional, Mungall, K., additional, Van Meter, T., additional, Cho, Y.-J., additional, Collins, P., additional, MacDonald, T., additional, Li, X.-N., additional, Moore, R., additional, Northcott, P., additional, Pfister, S., additional, Malkin, D., additional, Marra, M., additional, and Taylor, M., additional

Published
2014
Full Text
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15. MEDULLOBLASTOMA

Author

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

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2014
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17. Abstracts from the 2012 BNOS Conference

Author

Birks, S., primary, Altinkaya, M., additional, Altinkaya, A., additional, Pilkington, G., additional, Kurian, K. M., additional, Crosby, C., additional, Hopkins, K., additional, Williams, M., additional, Donovan, L., additional, Birks, S., additional, Eason, A., additional, Bosak, V., additional, Holliday, J., additional, Corbett, I., additional, Keeling, M., additional, Bambrough, J., additional, Simpson, J., additional, Higgins, S., additional, Dogra, H., additional, Zhang, Y., additional, Bradley, M., additional, Schmidberger, C., additional, Hafizi, S., additional, Noorani, I., additional, Price, S., additional, Dubocq, A., additional, Jaunky, T., additional, Chatelain, C., additional, Evans, L., additional, Gaissmaier, T., additional, Pilkington, G. J., additional, An, Q., additional, Hurwitz, V., additional, Logan, J., additional, Bhangoo, R., additional, Ashkan, K., additional, Gullan, A., additional, Beaney, R., additional, Brazil, L., additional, Kokkinos, S., additional, Blake, R., additional, Singleton, A., additional, Shaw, A., additional, Iyer, V., additional, Jeyapalan, J. N., additional, Morley, I. C., additional, Hill, A. A., additional, Mumin, M. A., additional, Tatevossian, R. G., additional, Qaddoumi, I., additional, Ellison, D. W., additional, Sheer, D., additional, Frary, A., additional, Jefferies, S., additional, Harris, F., additional, Burnet, N., additional, Jena, R., additional, Watts, C., additional, Haylock, B., additional, Leow-Dyke, S., additional, Rathi, N., additional, Wong, H., additional, Dunn, J., additional, Baborie, A., additional, Crooks, D., additional, Husband, D., additional, Shenoy, A., additional, Brodbelt, A., additional, Walker, C., additional, Bahl, A., additional, Larsen, J., additional, Craven, I., additional, Metherall, P., additional, McKevitt, F., additional, Romanowski, C., additional, Hoggard, N., additional, Jellinek, D. A., additional, Bell, S., additional, Murray, E., additional, Muirhead, R., additional, James, A., additional, Hanzely, Z., additional, Jackson, R., additional, Stewart, W., additional, O'Brien, A., additional, Young, A., additional, Shepherd, S., additional, Cavers, D., additional, Wallace, L., additional, Hacking, B., additional, Scott, S., additional, Bowyer, D., additional, Elmahdi, A., additional, Frary, A. J., additional, O'Donovan, D. G., additional, Price, S. J., additional, Kia, A., additional, Przystal, J. M., additional, Nianiaris, N., additional, Mazarakis, N. D., additional, Mintz, P. J., additional, Hajitou, A., additional, Karakoula, K., additional, Phipps, K., additional, Harkness, W., additional, Hayward, R., additional, Thompson, D., additional, Jacques, T., additional, Harding, B., additional, Darling, J., additional, Warr, T., additional, Jenkinson, M., additional, Zhou, L., additional, Ercolano, E., additional, Ammoun, S., additional, Schmid, M. C., additional, Barczyk, M., additional, Hanemann, C. O., additional, Rowther, F., additional, Dawson, T., additional, Ashton, K., additional, Maherally, Z., additional, Hatherell, K. E., additional, Kroese, K., additional, Singh, P., additional, McQuaid, S., additional, Al-Rashid, S., additional, Prise, K., additional, Herron, B., additional, Healy, E., additional, Shoakazemi, A., additional, Donnelly, M., additional, McConnell, R., additional, Harney, J., additional, Conkey, D., additional, McGrath, E., additional, Lunsford, L., additional, Kondziolka, D., additional, Niranjan, A., additional, Kano, H., additional, Hamilton, R., additional, Flannery, T., additional, Majani, Y., additional, Smith, S., additional, Grundy, R., additional, Rahman, R., additional, Saini, S., additional, Hall, G., additional, Davis, C., additional, Lawson, T., additional, Potter, N., additional, Goessl, E., additional, Wilkins, S., additional, Smith, T., additional, Petinou, V., additional, Nicholl, I., additional, Singh, J., additional, Lea, R., additional, Welsby, P., additional, Spiteri, I., additional, Sottoriva, A., additional, Marko, N., additional, Tavare, S., additional, Collins, P., additional, Su, Z., additional, Gerhard, A., additional, Hinz, R., additional, Roncaroli, F., additional, Coope, D., additional, Thompson, G., additional, Karabatsou, K., additional, Sofat, A., additional, Leggate, J., additional, du Plessis, D., additional, Turkheimer, F., additional, Jackson, A., additional, Das, K., additional, Herholz, K., additional, Whittle, I. R., additional, Grundy, P., additional, Cruickshank, G., additional, Berry, V., additional, Elder, D., additional, Cohen, N., additional, Tavare, J., additional, Zilidis, G., additional, Tibarewal, P., additional, Spinelli, L., additional, Leslie, N. R., additional, Coope, D. J., additional, Green, S., additional, Wall, G., additional, Brennan, P., additional, Baily, J., additional, Diaz, M., additional, Ironside, J., additional, Sansom, O., additional, Brunton, V., additional, Frame, M., additional, Thomas, O., additional, Mohsen, L., additional, Lupson, V., additional, McLean, M., additional, Arora, M., additional, Shaw, L., additional, Lawrence, C., additional, Alder, J., additional, Rada, L., additional, Chen, K., additional, Shivane, A., additional, Parkinson, D., additional, Hanemann, C., additional, Pangeni, R. P., additional, Warr, T. J., additional, Morris, M. R., additional, Mackinnon, M., additional, Williamson, A., additional, Chalmers, A., additional, Beckett, V., additional, Joannides, A., additional, Brock, R., additional, McCarthy, K., additional, Singh, A., additional, Kardooni, H., additional, Morris, M., additional, Syed, N., additional, Janczar, K., additional, O'Neil, K., additional, Nigro, C. L., additional, Lattanzio, L., additional, Coley, H., additional, Hatzimichael, E., additional, Bomalaski, J., additional, Szlosarek, P., additional, Crook, T., additional, Pullen, N. A., additional, Anand, M., additional, Van Meter, T., additional, Williams, S., additional, Boissinot, M., additional, Steele, L., additional, Chiocca, E. A., additional, Lawler, S., additional, Al Rashid, S. T., additional, Mashal, S., additional, Taggart, L., additional, Clarke, E., additional, and Prise, K. M., additional

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2012
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18. EPENDYMOMA

Author

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

Published
2012
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24. Integrated (epi)-Genomic Analyses Identify Subgroup-Specific Therapeutic Targets in CNS Rhabdoid Tumors

Author

Constanze Zeller, Joseph D. Norman, Man Yu, Jian Qiang Lu, Doug Strother, Miklós Garami, C. Jane McGlade, Seung-Ki Kim, Misko Dzamba, Ronald Grant, David D. Eisenstat, Beverly Wilson, Anat Erdreich-Epstein, Almos Klekner, A. Sorana Morrissy, Richard Grundy, Young Shin Ra, Joanna J. Phillips, Alexandre Montpetit, Takafumi Wataya, Alexander R. Judkins, Shayna Zelcer, Nicholas K. Foreman, Rishi Lulla, Aline Cristiane Planello, Marc Remke, Harriet Druker, Annie Huang, Torsten Pietsch, José Pimentel, Jordan R. Hansford, Lindsey M. Hoffman, Mark Barszczyk, Tarik Tihan, Eugene Hwang, Vivek Mehta, László Bognár, Louis Letourneau, Donna L. Johnston, Stephen Yip, Lucie Lafay-Cousin, Mei Lu, Pasqualino De Antonellis, Katrin Scheinemann, Deena M.A. Gendoo, Shengrui Feng, James T. Rutka, G. Yancey Gillespie, Ho Keung Ng, Robert Hammond, David Malkin, Lúcia Roque, Anne Sophie Carret, King Ching Ho, Helen Toledano, Jennifer A. Chan, Monika Warmuth-Metz, Jacek Majewski, Jonathon Torchia, Livia Garzia, Stefan Rutkowski, Gino R. Somers, Tibor Hortobágyi, Ute Bartels, Peter Hauser, Ulrich Schüller, Cynthia Hawkins, Shih Hwa Chiou, Eric Bouffet, Adam Fleming, Alexandra N. Riemenschneider, Timothy E. Van Meter, Vijay Ramaswamy, Hideo Nakamura, Tiago Medina, Alexandre Vasiljevic, Noppadol Larbcharoensub, Patrick Sin-Chan, Christopher Dunham, Theodore Nicolaides, Iris Fried, Daniel Picard, Maryam Fouladi, Chris Fryer, Brian Golbourn, Mathieu Bourgey, Jean Michaud, Claudia C. Faria, Gary D. Bader, Mathieu Lupien, Amar Gajjar, Guillaume Bourque, Peter B. Dirks, Steffen Albrecht, Suradej Hongeng, Cheryl H. Arrowsmith, Uri Tabori, David A. Ramsay, Dalia Barsyte-Lovejoy, Paul Guilhamon, Michael Brudno, Nada Jabado, Juliette Hukin, Dong Anh Khuong-Quang, Michael D. Taylor, Tiffany Chan, Natalia R. Agamez, Daniel D. De Carvalho, Nongnuch Sirachainan, Samina Afzal, Seung Ah Choi, Diane K. Birks, Daniel W. Fults, Andrew S. Moore, Alyssa Reddy, Jason Fangusaro, Daniel Catchpoole, Yin Wang, Torchia, J., Golbourn, B., Feng, S., Ho, K. C., Sin-Chan, P., Vasiljevic, A., Norman, J. D., Guilhamon, P., Garzia, L., Agamez, N. R., Lu, M., Chan, T. S., Picard, D., de Antonellis, P., Khuong-Quang, D. -A., Planello, A. C., Zeller, C., Barsyte-Lovejoy, D., Lafay-Cousin, L., Letourneau, L., Bourgey, M., Yu, M., Gendoo, D. M. A., Dzamba, M., Barszczyk, M., Medina, T., Riemenschneider, A. N., Morrissy, A. S., Ra, Y. -S., Ramaswamy, V., Remke, M., Dunham, C. P., Yip, S., Ng, H. -K., Lu, J. -Q., Mehta, V., Albrecht, S., Pimentel, J., Chan, J. A., Somers, G. R., Faria, C. C., Roque, L., Fouladi, M., Hoffman, L. M., Moore, A. S., Wang, Y., Choi, S. A., Hansford, J. R., Catchpoole, D., Birks, D. K., Foreman, N. K., Strother, D., Klekner, A., Bognar, L., Garami, M., Hauser, P., Hortobagyi, T., Wilson, B., Hukin, J., Carret, A. -S., Van Meter, T. E., Hwang, E. I., Gajjar, A., Chiou, S. -H., Nakamura, H., Toledano, H., Fried, I., Fults, D., Wataya, T., Fryer, C., Eisenstat, D. D., Scheinemann, K., Fleming, A. J., Johnston, D. L., Michaud, J., Zelcer, S., Hammond, R., Afzal, S., Ramsay, D. A., Sirachainan, N., Hongeng, S., Larbcharoensub, N., Grundy, R. G., Lulla, R. R., Fangusaro, J. R., Druker, H., Bartels, U., Grant, R., Malkin, D., Mcglade, C. J., Nicolaides, T., Tihan, T., Phillips, J., Majewski, J., Montpetit, A., Bourque, G., Bader, G. D., Reddy, A. T., Gillespie, G. Y., Warmuth-Metz, M., Rutkowski, S., Tabori, U., Lupien, M., Brudno, M., Schuller, U., Pietsch, T., Judkins, A. R., Hawkins, C. E., Bouffet, E., Kim, S. -K., Dirks, P. B., Taylor, M. D., Erdreich-Epstein, A., Arrowsmith, C. H., De Carvalho, D. D., Rutka, J. T., Jabado, N., and Huang, A.

Subjects
Epigenomics, 0301 basic medicine, Cancer Research, Dasatinib, 1109 Neurosciences, 1112 Oncology and Carcinogenesis, ATRT, Epigenesis, Genetic, Central Nervous System Neoplasms, genomic, SMARCB1, Epigenesis, Central Nervous System Neoplasm, Teratoma, SMARCB1 Protein, Orvostudományok, Chromatin, 3. Good health, Oncology, DNA methylation, subgroup-specific therapeutic, Human, medicine.drug, Epigenomic, Cell Survival, Protein Kinase Inhibitor, Biology, Klinikai orvostudományok, Article, Receptor, Platelet-Derived Growth Factor beta, 03 medical and health sciences, Cell Line, Tumor, medicine, Humans, Oncology & Carcinogenesis, Epigenetics, Protein Kinase Inhibitors, rhabdoid tumor, Rhabdoid Tumor, Cell Proliferation, Cancer, DNA Methylation, medicine.disease, Pyrimidines, 030104 developmental biology, Pyrimidine, Mutation, Cancer research, enhancer
Abstract

We recently reported that atypical teratoid rhabdoid tumors (ATRTs) comprise at least two transcriptional subtypes with different clinical outcomes; however, the mechanisms underlying therapeutic heterogeneity remained unclear. In this study, we analyzed 191 primary ATRTs and 10 ATRT cell lines to define the genomic and epigenomic landscape of ATRTs and identify subgroup-specific therapeutic targets. We found ATRTs segregated into three epigenetic subgroups with distinct genomic profiles, SMARCB1 genotypes, and chromatin landscape that correlated with differential cellular responses to a panel of signaling and epigenetic inhibitors. Significantly, we discovered that differential methylation of a PDGFRB-associated enhancer confers specific sensitivity of group 2 ATRT cells to dasatinib and nilotinib, and suggest that these are promising therapies for this highly lethal ATRT subtype.

Published
2016

25. Corresponding ctDNA and tumor burden dynamics in metastatic melanoma patients on systemic treatment.

Author

Egger ME, Alexander E, Van Meter T, Kong M, Maung AA, Valdes R Jr, Hall MB, and Linder MW

Abstract

Radiographic imaging is the current standard for monitoring progression of tumor-burden and therapeutic resistance in patients with metastatic melanoma. Plasma circulating tumor DNA (ctDNA) has shown promise as a survelience tool, but longitudinal data on the dynamics between plasma ctDNA concentrations and radiographic imaging is lacking. We evaluated the relationship between longitudinal radiographic measures of tumor burden and ctDNA concentrations in plasma on 30 patients with metastatic melanoma on systemic treatment. In 9 patients with no radiographic evidence of disease over a total of 15 time points, ctDNA concentrations were undetectable. In 21 patients with radiographic tumor burden, ctDNA was detected in 81 % of 58 time points. Plasma ctDNA concentrations demonstrated a modest positive correlation with total tumor burden (TTB) measurements (R 2 = 0.49, p < 0.001), with the greatest degree of correlation observed under conditions of progressive disease (PD) (R 2 = 0.91, p = 0.032). Plasma ctDNA concentrations were significantly greater at times of RECIST v1.1 progression (PD; 22.1 % ± 5.7 %) when compared to samples collected during stable disease (SD; 4.99 % ± 3.0 %) (p = 0.012); this difference was independent of total tumor burden (p = 0.997). Changes in plasma ctDNA showed a strong correlation with changes in TTB (R 2 = 0.88, p<0.001). These data suggest that measurements of plasma ctDNA during therapy are a better surrogate for responding versus non-responding disease compared to absolute tumor burden., Competing Interests: Declaration of competing interest The authors of the manuscript Corresponding ctDNA and tumor burden dynamics in metastatic melanoma patients on systemic treatment by Michael E. Egger(2), Evan Alexander(1), Tracy Van Meter(3), Maiying Kong(4,6), Aye Maung (4,6) Roland Valdes Jr.(1,7), Melissa Barousse Hall(5,8), and Mark W. Linder(1) declare no competing interest., (Copyright © 2024. Published by Elsevier Inc.)

Published
2024
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26. Longitudinal Relationship between Idylla Plasma ctBRAF V600 Mutation Detection and Tumor Burden in Patients with Metastatic Melanoma.

Author

Linder MW, Egger ME, Van Meter T, Rai SN, Valdes R Jr, Hall MB, Wu X, Alghamdi N, and Chesney JA

Subjects
Circulating Tumor DNA genetics, Cross-Sectional Studies, Feasibility Studies, Humans, Longitudinal Studies, Male, Melanoma blood, Melanoma genetics, Neoplasm Metastasis, Pilot Projects, Proto-Oncogene Proteins B-raf genetics, Sensitivity and Specificity, Standard of Care, Tomography, X-Ray Computed, Tumor Burden, Melanoma diagnostic imaging, Melanoma pathology, Mutation, Proto-Oncogene Proteins B-raf blood
Abstract

Background: Circulating tumor DNA (ctDNA) may complement radiography for interim assessment of patients with cancer., Objective: Our objective was to explore the relationship between changes in plasma ctDNA versus radiographic imaging among patients with metastatic melanoma., Methods: Using the Idylla system, we measured B-Raf proto-oncogene (BRAF) V600 ctDNA in plasma from 15 patients with BRAF V600E/K-positive primary tumors undergoing standard-of-care monitoring, including cross-sectional computed tomography (CT) imaging. BRAF V600 mutant allele frequency (%MAF) was calculated from the Idylla Cq values and directly measured using droplet digital polymerase chain reaction (ddPCR)., Results: The Idylla ctDNA assay demonstrated 91% sensitivity, 96% specificity, 91% positive predictive value, and 96% negative predictive value for the presence of > 93 mm metastatic disease. Qualitative ctDNA results corresponded to changes in RECIST (Response Evaluation Criteria in Solid Tumors) 1.1 status determined by CT imaging in 11 of 15 subjects (73%). Calculated %MAF results correlated with ddPCR (R 2 = 0.94) and provided evidence of progressive disease 55 and 97 days in advance of CT imaging for two subjects with persistently positive qualitative results., Conclusions: Overall, interim ctDNA results provided evidence of partial response or progressive disease an average of 82 days before radiography. This pilot study supports the feasibility of using the Idylla plasma BRAF V600 ctDNA assay as a complement to CT scanning for routine monitoring of therapeutic response. Somatic mutation quantification based on Cq values shows promise for identifying disease progression and warrants further validation.

Published
2021
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27. Loss of Consciousness and Altered Mental State as Predictors of Functional Recovery Within 6 Months Following Mild Traumatic Brain Injury.

Author

Roy D, Peters ME, Everett AD, Leoutsakos JS, Yan H, Rao V, T Bechtold K, Sair HI, Van Meter T, Falk H, Vassila A, Hall A, Ofoche U, Akbari F, Lyketsos C, and Korley F

Subjects
Adult, Aged, Behavioral Symptoms etiology, Behavioral Symptoms therapy, Brain Concussion complications, Brain Concussion therapy, Female, Humans, Male, Middle Aged, Prognosis, Prospective Studies, Unconsciousness etiology, Unconsciousness therapy, Young Adult, Behavioral Symptoms physiopathology, Brain Concussion physiopathology, Recovery of Function physiology, Unconsciousness physiopathology
Abstract

Objective: The authors tested the hypothesis that a combination of loss of consciousness (LOC) and altered mental state (AMS) predicts the highest risk of incomplete functional recovery within 6 months after mild traumatic brain injury (mTBI), compared with either condition alone, and that LOC alone is more strongly associated with incomplete recovery, compared with AMS alone., Methods: Data were analyzed from 407 patients with mTBI from Head injury S erum M arkers for A ssessing R esponse to T rauma (HeadSMART), a prospective cohort study of TBI patients presenting to two urban emergency departments. Four patient subgroups were constructed based on information documented at the time of injury: neither LOC nor AMS, LOC only, AMS only, and both. Logistic regression models assessed LOC and AMS as predictors of functional recovery at 1, 3, and 6 months., Results: A gradient of risk of incomplete functional recovery at 1, 3, and 6 months postinjury was noted, moving from neither LOC nor AMS, to LOC or AMS alone, to both. LOC was associated with incomplete functional recovery at 1 and 3 months (odds ratio=2.17, SE=0.46, p<0.001; and odds ratio=1.80, SE=0.40, p=0.008, respectively). AMS was associated with incomplete functional recovery at 1 month only (odds ratio=1.77, SE=0.37 p=0.007). No association was found between AMS and functional recovery in patients with no LOC. Neither LOC nor AMS was predictive of functional recovery at later times., Conclusions: These findings highlight the need to include symptom-focused clinical variables that pertain to the injury itself when assessing who might be at highest risk of incomplete functional recovery post-mTBI.

Published
2020
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28. Iliocaval fistula with high output cardiac failure.

Author

Ismail MA and Van Meter T

Abstract

Fistulous communications between the common iliac arteries and inferior vena cava are very uncommon and usually occur as a result of trauma, aneurysmal rupture, or endovascular repair. They can present with signs of high output cardiac failure including hypotension, venous congestion, and pulmonary hypertension. This case outlines the utility of CTA in diagnosing iliocaval fistulas and the importance of considering this diagnosis in a patient with signs of right heart strain and high output cardiac failure.

Published
2019
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29. Early nontumorous CT findings after irreversible electroporation of locally advanced pancreatic cancer.

Author

Schulz B, Ou J, Van Meter T, and Martin RC

Subjects
Adenocarcinoma pathology, Adult, Aged, Female, Humans, Male, Middle Aged, Pancreatic Neoplasms pathology, Registries, Retrospective Studies, Treatment Outcome, Adenocarcinoma diagnostic imaging, Adenocarcinoma therapy, Electroporation, Pancreas diagnostic imaging, Pancreas pathology, Pancreatic Neoplasms diagnostic imaging, Pancreatic Neoplasms therapy, Tomography, X-Ray Computed
Abstract

Purpose: The use of irreversible electroporation (IRE) has been a relatively recent development in the palliative treatment of locally advanced pancreatic cancer. With CT as a key modality in patient follow-up, recognition of nontumorous imaging findings is paramount after IRE., Methods: A retrospective review of patients having undergone IRE for locally advanced pancreatic adenocarcinoma was performed. A total of 36 patients met inclusion criteria and their imaging studies were reviewed by two radiologists. Nontumorous abnormalities identified in the peri-electroporation bed on Computed Tomography (CT) during the early postoperative period (within 30 days) were characterized and classified into categories., Results: Our results indicate that the most common nontumorous findings in the peri-electroporation bed were vascular, followed by changes involving the gastrointestinal tract, peritoneal cavity, and, infrequently, the biliary tree., Conclusions: Interpretation of CT imaging of the postoperative peri-electroporation bed is challenging. This review of CT findings allows the radiologist to recognize and anticipate significant nontumorous findings in the peri-electroporation bed during early follow-up after IRE.

Published
2016
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30. New Brain Tumor Entities Emerge from Molecular Classification of CNS-PNETs.

Author

Sturm D, Orr BA, Toprak UH, Hovestadt V, Jones DTW, Capper D, Sill M, Buchhalter I, Northcott PA, Leis I, Ryzhova M, Koelsche C, Pfaff E, Allen SJ, Balasubramanian G, Worst BC, Pajtler KW, Brabetz S, Johann PD, Sahm F, Reimand J, Mackay A, Carvalho DM, Remke M, Phillips JJ, Perry A, Cowdrey C, Drissi R, Fouladi M, Giangaspero F, Łastowska M, Grajkowska W, Scheurlen W, Pietsch T, Hagel C, Gojo J, Lötsch D, Berger W, Slavc I, Haberler C, Jouvet A, Holm S, Hofer S, Prinz M, Keohane C, Fried I, Mawrin C, Scheie D, Mobley BC, Schniederjan MJ, Santi M, Buccoliero AM, Dahiya S, Kramm CM, von Bueren AO, von Hoff K, Rutkowski S, Herold-Mende C, Frühwald MC, Milde T, Hasselblatt M, Wesseling P, Rößler J, Schüller U, Ebinger M, Schittenhelm J, Frank S, Grobholz R, Vajtai I, Hans V, Schneppenheim R, Zitterbart K, Collins VP, Aronica E, Varlet P, Puget S, Dufour C, Grill J, Figarella-Branger D, Wolter M, Schuhmann MU, Shalaby T, Grotzer M, van Meter T, Monoranu CM, Felsberg J, Reifenberger G, Snuderl M, Forrester LA, Koster J, Versteeg R, Volckmann R, van Sluis P, Wolf S, Mikkelsen T, Gajjar A, Aldape K, Moore AS, Taylor MD, Jones C, Jabado N, Karajannis MA, Eils R, Schlesner M, Lichter P, von Deimling A, Pfister SM, Ellison DW, Korshunov A, and Kool M

Subjects
Amino Acid Sequence, Central Nervous System Neoplasms classification, Central Nervous System Neoplasms diagnosis, Child, Forkhead Transcription Factors genetics, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Molecular Sequence Data, Neuroectodermal Tumors classification, Neuroectodermal Tumors diagnosis, Proto-Oncogene Proteins chemistry, Proto-Oncogene Proteins genetics, Repressor Proteins chemistry, Repressor Proteins genetics, Signal Transduction, Trans-Activators, Tumor Suppressor Proteins genetics, Central Nervous System Neoplasms genetics, Central Nervous System Neoplasms pathology, DNA Methylation, Neuroectodermal Tumors genetics, Neuroectodermal Tumors pathology
Abstract

Primitive neuroectodermal tumors of the central nervous system (CNS-PNETs) are highly aggressive, poorly differentiated embryonal tumors occurring predominantly in young children but also affecting adolescents and adults. Herein, we demonstrate that a significant proportion of institutionally diagnosed CNS-PNETs display molecular profiles indistinguishable from those of various other well-defined CNS tumor entities, facilitating diagnosis and appropriate therapy for patients with these tumors. From the remaining fraction of CNS-PNETs, we identify four new CNS tumor entities, each associated with a recurrent genetic alteration and distinct histopathological and clinical features. These new molecular entities, designated "CNS neuroblastoma with FOXR2 activation (CNS NB-FOXR2)," "CNS Ewing sarcoma family tumor with CIC alteration (CNS EFT-CIC)," "CNS high-grade neuroepithelial tumor with MN1 alteration (CNS HGNET-MN1)," and "CNS high-grade neuroepithelial tumor with BCOR alteration (CNS HGNET-BCOR)," will enable meaningful clinical trials and the development of therapeutic strategies for patients affected by poorly differentiated CNS tumors., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Published
2016
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31. Medulloblastoma subgroups remain stable across primary and metastatic compartments.

Author

Wang X, Dubuc AM, Ramaswamy V, Mack S, Gendoo DM, Remke M, Wu X, Garzia L, Luu B, Cavalli F, Peacock J, López B, Skowron P, Zagzag D, Lyden D, Hoffman C, Cho YJ, Eberhart C, MacDonald T, Li XN, Van Meter T, Northcott PA, Haibe-Kains B, Hawkins C, Rutka JT, Bouffet E, Pfister SM, Korshunov A, and Taylor MD

Subjects
Adolescent, Child, Child, Preschool, Cluster Analysis, Female, Humans, Male, Oligonucleotide Array Sequence Analysis, Transcriptome, Cerebellar Neoplasms genetics, Cerebellar Neoplasms pathology, Medulloblastoma genetics, Medulloblastoma pathology, Neoplasm Metastasis genetics
Abstract

Medulloblastoma comprises four distinct molecular variants with distinct genetics, transcriptomes, and outcomes. Subgroup affiliation has been previously shown to remain stable at the time of recurrence, which likely reflects their distinct cells of origin. However, a therapeutically relevant question that remains unanswered is subgroup stability in the metastatic compartment. We assembled a cohort of 12-paired primary-metastatic tumors collected in the MAGIC consortium, and established their molecular subgroup affiliation by performing integrative gene expression and DNA methylation analysis. Frozen tissues were collected and profiled using Affymetrix gene expression arrays and Illumina methylation arrays. Class prediction and hierarchical clustering were performed using existing published datasets. Our molecular analysis, using consensus integrative genomic data, establishes the unequivocal maintenance of molecular subgroup affiliation in metastatic medulloblastoma. We further validated these findings by interrogating a non-overlapping cohort of 19 pairs of primary-metastatic tumors from the Burdenko Neurosurgical Institute using an orthogonal technique of immunohistochemical staining. This investigation represents the largest reported primary-metastatic paired cohort profiled to date and provides a unique opportunity to evaluate subgroup-specific molecular aberrations within the metastatic compartment. Our findings further support the hypothesis that medulloblastoma subgroups arise from distinct cells of origin, which are carried forward from ontogeny to oncology.

Published
2015
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32. CT Findings of Patients Treated with Irreversible Electroporation for Locally Advanced Pancreatic Cancer.

Author

Akinwande O, Ahmad SS, Van Meter T, Schulz B, and Martin RC

Abstract

Introduction. In patients with locally advanced pancreatic cancer (LAPC), IRE has been shown to be safe for local disease control and palliation. As IRE continues to gain acceptance it is important to characterize the expected imaging findings. Materials and Methods. A review of our prospective soft tissue ablation registry from July 2010 to June 2013 was performed on patients who had undergone IRE for LAPC. Five masses treated with intraoperative IRE ablation for pancreatic tumors that underwent CT imaging before and after ablation were reviewed. Results and Discussion. Following IRE, the postablation bed is larger than the original ablated tumor. This ablation zone may get smaller in size (due to decreased edema and hyperemia) in the following months and more importantly remains stable provided there is no recurrence. In cases of recurrent disease there is increased size of the ablation bed, mass effect, and new or worsening vascular encasement or occlusion. Conclusion. CT imaging remains the best current imaging modality to assess post-IRE ablation changes. Serial imaging over at least 2-6 months must be employed to detect recurrence by comparing with prior studies in conjunction with clinical and serum studies. Larger imaging studies are underway to evaluate a more ideal imaging modality for this unique patient population.

Published
2015
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33. Telomerase inhibition abolishes the tumorigenicity of pediatric ependymoma tumor-initiating cells.

Author

Barszczyk M, Buczkowicz P, Castelo-Branco P, Mack SC, Ramaswamy V, Mangerel J, Agnihotri S, Remke M, Golbourn B, Pajovic S, Elizabeth C, Yu M, Luu B, Morrison A, Adamski J, Nethery-Brokx K, Li XN, Van Meter T, Dirks PB, Rutka JT, Taylor MD, Tabori U, and Hawkins C

Subjects
Animals, Brain Neoplasms diagnosis, Brain Neoplasms enzymology, Carcinogenesis drug effects, Carcinogenesis metabolism, Cell Line, Tumor, Cell Proliferation drug effects, Cell Proliferation physiology, Child, Preschool, Cohort Studies, Disease-Free Survival, Ependymoma diagnosis, Ependymoma enzymology, Female, Humans, Mice, Neoplasm Recurrence, Local diagnosis, Neoplasm Recurrence, Local enzymology, Neoplasm Transplantation, Neoplastic Stem Cells enzymology, Niacinamide pharmacology, Oligonucleotides, Telomerase metabolism, Telomere drug effects, Telomere metabolism, Brain Neoplasms drug therapy, Enzyme Inhibitors pharmacology, Ependymoma drug therapy, Indoles pharmacology, Neoplastic Stem Cells drug effects, Niacinamide analogs & derivatives, Telomerase antagonists & inhibitors
Abstract

Pediatric ependymomas are highly recurrent tumors resistant to conventional chemotherapy. Telomerase, a ribonucleoprotein critical in permitting limitless replication, has been found to be critically important for the maintenance of tumor-initiating cells (TICs). These TICs are chemoresistant, repopulate the tumor from which they are identified, and are drivers of recurrence in numerous cancers. In this study, telomerase enzymatic activity was directly measured and inhibited to assess the therapeutic potential of targeting telomerase. Telomerase repeat amplification protocol (TRAP) (n = 36) and C-circle assay/telomere FISH/ATRX staining (n = 76) were performed on primary ependymomas to determine the prevalence and prognostic potential of telomerase activity or alternative lengthening of telomeres (ALT) as telomere maintenance mechanisms, respectively. Imetelstat, a phase 2 telomerase inhibitor, was used to elucidate the effect of telomerase inhibition on proliferation and tumorigenicity in established cell lines (BXD-1425EPN, R254), a primary TIC line (E520) and xenograft models of pediatric ependymoma. Over 60 % of pediatric ependymomas were found to rely on telomerase activity to maintain telomeres, while no ependymomas showed evidence of ALT. Children with telomerase-active tumors had reduced 5-year progression-free survival (29 ± 11 vs 64 ± 18 %; p = 0.03) and overall survival (58 ± 12 vs 83 ± 15 %; p = 0.05) rates compared to those with tumors lacking telomerase activity. Imetelstat inhibited proliferation and self-renewal by shortening telomeres and inducing senescence in vitro. In vivo, Imetelstat significantly reduced subcutaneous xenograft growth by 40 % (p = 0.03) and completely abolished the tumorigenicity of pediatric ependymoma TICs in an orthotopic xenograft model. Telomerase inhibition represents a promising therapeutic approach for telomerase-active pediatric ependymomas found to characterize high-risk ependymomas.

Published
2014
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34. CNS-PNETs with C19MC amplification and/or LIN28 expression comprise a distinct histogenetic diagnostic and therapeutic entity.

Author

Spence T, Sin-Chan P, Picard D, Barszczyk M, Hoss K, Lu M, Kim SK, Ra YS, Nakamura H, Fangusaro J, Hwang E, Kiehna E, Toledano H, Wang Y, Shi Q, Johnston D, Michaud J, La Spina M, Buccoliero AM, Adamek D, Camelo-Piragua S, Peter Collins V, Jones C, Kabbara N, Jurdi N, Varlet P, Perry A, Scharnhorst D, Fan X, Muraszko KM, Eberhart CG, Ng HK, Gururangan S, Van Meter T, Remke M, Lafay-Cousin L, Chan JA, Sirachainan N, Pomeroy SL, Clifford SC, Gajjar A, Shago M, Halliday W, Taylor MD, Grundy R, Lau CC, Phillips J, Bouffet E, Dirks PB, Hawkins CE, and Huang A

Subjects
Adolescent, Age of Onset, Brain Neoplasms diagnosis, Brain Neoplasms therapy, Cell Line, Tumor, Child, Child, Preschool, DNA (Cytosine-5-)-Methyltransferases metabolism, DNA Methylation, Diagnosis, Differential, Female, Gene Expression Regulation, Neoplastic, Humans, Infant, Male, Multigene Family, Neuroectodermal Tumors, Primitive diagnosis, Neuroectodermal Tumors, Primitive therapy, DNA Methyltransferase 3B, Brain Neoplasms genetics, Brain Neoplasms metabolism, MicroRNAs genetics, Neuroectodermal Tumors, Primitive genetics, Neuroectodermal Tumors, Primitive metabolism, RNA-Binding Proteins metabolism
Abstract

Amplification of the C19MC oncogenic miRNA cluster and high LIN28 expression has been linked to a distinctly aggressive group of cerebral CNS-PNETs (group 1 CNS-PNETs) arising in young children. In this study, we sought to evaluate the diagnostic specificity of C19MC and LIN28, and the clinical and biological spectra of C19MC amplified and/or LIN28+ CNS-PNETs. We interrogated 450 pediatric brain tumors using FISH and IHC analyses and demonstrate that C19MC alteration is restricted to a sub-group of CNS-PNETs with high LIN28 expression; however, LIN28 immunopositivity was not exclusive to CNS-PNETs but was also detected in a proportion of other malignant pediatric brain tumors including rhabdoid brain tumors and malignant gliomas. C19MC amplified/LIN28+ group 1 CNS-PNETs arose predominantly in children <4 years old; a majority arose in the cerebrum but 24 % (13/54) of tumors had extra-cerebral origins. Notably, group 1 CNS-PNETs encompassed several histologic classes including embryonal tumor with abundant neuropil and true rosettes (ETANTR), medulloepithelioma, ependymoblastoma and CNS-PNETs with variable differentiation. Strikingly, gene expression and methylation profiling analyses revealed a common molecular signature enriched for primitive neural features, high LIN28/LIN28B and DNMT3B expression for all group 1 CNS-PNETs regardless of location or tumor histology. Our collective findings suggest that current known histologic categories of CNS-PNETs which include ETANTRs, medulloepitheliomas, ependymoblastomas in various CNS locations, comprise a common molecular and diagnostic entity and identify inhibitors of the LIN28/let7/PI3K/mTOR axis and DNMT3B as promising therapeutics for this distinct histogenetic entity.

Published
2014
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35. Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma.

Author

Sturm D, Witt H, Hovestadt V, Khuong-Quang DA, Jones DT, Konermann C, Pfaff E, Tönjes M, Sill M, Bender S, Kool M, Zapatka M, Becker N, Zucknick M, Hielscher T, Liu XY, Fontebasso AM, Ryzhova M, Albrecht S, Jacob K, Wolter M, Ebinger M, Schuhmann MU, van Meter T, Frühwald MC, Hauch H, Pekrun A, Radlwimmer B, Niehues T, von Komorowski G, Dürken M, Kulozik AE, Madden J, Donson A, Foreman NK, Drissi R, Fouladi M, Scheurlen W, von Deimling A, Monoranu C, Roggendorf W, Herold-Mende C, Unterberg A, Kramm CM, Felsberg J, Hartmann C, Wiestler B, Wick W, Milde T, Witt O, Lindroth AM, Schwartzentruber J, Faury D, Fleming A, Zakrzewska M, Liberski PP, Zakrzewski K, Hauser P, Garami M, Klekner A, Bognar L, Morrissy S, Cavalli F, Taylor MD, van Sluis P, Koster J, Versteeg R, Volckmann R, Mikkelsen T, Aldape K, Reifenberger G, Collins VP, Majewski J, Korshunov A, Lichter P, Plass C, Jabado N, and Pfister SM

Subjects
Adult, Brain Neoplasms pathology, Child, DNA Methylation, Glioblastoma pathology, Humans, Receptor, Platelet-Derived Growth Factor alpha genetics, Transcriptome, Brain Neoplasms genetics, Epigenesis, Genetic, Glioblastoma genetics, Histones genetics, Isocitrate Dehydrogenase genetics, Mutation
Abstract

Glioblastoma (GBM) is a brain tumor that carries a dismal prognosis and displays considerable heterogeneity. We have recently identified recurrent H3F3A mutations affecting two critical amino acids (K27 and G34) of histone H3.3 in one-third of pediatric GBM. Here, we show that each H3F3A mutation defines an epigenetic subgroup of GBM with a distinct global methylation pattern, and that they are mutually exclusive with IDH1 mutations, which characterize a third mutation-defined subgroup. Three further epigenetic subgroups were enriched for hallmark genetic events of adult GBM and/or established transcriptomic signatures. We also demonstrate that the two H3F3A mutations give rise to GBMs in separate anatomic compartments, with differential regulation of transcription factors OLIG1, OLIG2, and FOXG1, possibly reflecting different cellular origins., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Published
2012
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36. Markers of survival and metastatic potential in childhood CNS primitive neuro-ectodermal brain tumours: an integrative genomic analysis.

Author

Picard D, Miller S, Hawkins CE, Bouffet E, Rogers HA, Chan TS, Kim SK, Ra YS, Fangusaro J, Korshunov A, Toledano H, Nakamura H, Hayden JT, Chan J, Lafay-Cousin L, Hu P, Fan X, Muraszko KM, Pomeroy SL, Lau CC, Ng HK, Jones C, Van Meter T, Clifford SC, Eberhart C, Gajjar A, Pfister SM, Grundy RG, and Huang A

Subjects
Brain Neoplasms mortality, Brain Neoplasms pathology, Cell Lineage genetics, Chi-Square Distribution, Child, Child, Preschool, Cluster Analysis, Europe, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Immunohistochemistry, Japan, Kaplan-Meier Estimate, Male, Neuroectodermal Tumors, Primitive mortality, Neuroectodermal Tumors, Primitive secondary, North America, Oligodendrocyte Transcription Factor 2, Principal Component Analysis, Prognosis, Reproducibility of Results, Republic of Korea, Retrospective Studies, Risk Assessment, Risk Factors, Basic Helix-Loop-Helix Transcription Factors genetics, Biomarkers, Tumor genetics, Brain Neoplasms genetics, Genomics methods, Nerve Tissue Proteins genetics, Neuroectodermal Tumors, Primitive genetics, RNA-Binding Proteins genetics
Abstract

Background: Childhood CNS primitive neuro-ectodermal brain tumours (PNETs) are very aggressive brain tumours for which the molecular features and best treatment approaches are unknown. We assessed a large cohort of these rare tumours to identify molecular markers to enhance clinical management of this disease., Methods: We obtained 142 primary hemispheric CNS PNET samples from 20 institutions in nine countries and examined transcriptional profiles for a subset of 51 samples and copy number profiles for a subset of 77 samples. We used clustering, gene, and pathway enrichment analyses to identify tumour subgroups and group-specific molecular markers, and applied immunohistochemical and gene-expression analyses to validate and assess the clinical significance of the subgroup markers., Findings: We identified three molecular subgroups of CNS PNETs that were distinguished by primitive neural (group 1), oligoneural (group 2), and mesenchymal lineage (group 3) gene-expression signatures with differential expression of cell-lineage markers LIN28 and OLIG2. Patients with group 1 tumours were most often female (male:female ratio 0·61 for group 1 vs 1·25 for group 2 and 1·63 for group 3; p=0·043 [group 1 vs groups 2 and 3]), youngest (median age at diagnosis 2·9 years [95% CI 2·4-5·2] for group 1 vs 7·9 years [6·0-9·7] for group 2 and 5·9 years [4·9-7·8] for group 3; p=0·005), and had poorest survival (median survival 0·8 years [95% CI 0·5-1·2] in group 1, 1·8 years [1·4-2·3] in group 2 and 4·3 years [0·8-7·8] in group 3; p=0·019). Patients with group 3 tumours had the highest incidence of metastases at diagnosis (no distant metastasis:metastasis ratio 0·90 for group 3 vs 2·80 for group 1 and 5·67 for group 2; p=0·037)., Interpretation: LIN28 and OLIG2 are promising diagnostic and prognostic molecular markers for CNS PNET that warrant further assessment in prospective clinical trials., Funding: Canadian Institute of Health Research, Brainchild/SickKids Foundation, and the Samantha Dickson Brain Tumour Trust., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Published
2012
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37. Bortezomib induces apoptosis and growth suppression in human medulloblastoma cells, associated with inhibition of AKT and NF-ĸB signaling, and synergizes with an ERK inhibitor.

Author

Yang F, Jove V, Chang S, Hedvat M, Liu L, Buettner R, Tian Y, Scuto A, Wen W, Yip ML, Van Meter T, Yen Y, and Jove R

Subjects
Amino Acid Chloromethyl Ketones pharmacology, Apoptosis drug effects, Bortezomib, Caspase 3 metabolism, Caspase 9 metabolism, Cerebellar Neoplasms metabolism, Cerebellar Neoplasms pathology, Cyclin-Dependent Kinase Inhibitor p21 metabolism, Cyclin-Dependent Kinase Inhibitor p27 metabolism, Cytochromes c metabolism, Drug Synergism, Humans, Medulloblastoma metabolism, Medulloblastoma pathology, Niacinamide pharmacology, Protein Kinase Inhibitors pharmacology, Sorafenib, Tumor Cells, Cultured, bcl-2 Homologous Antagonist-Killer Protein metabolism, bcl-Associated Death Protein metabolism, Antineoplastic Agents pharmacology, Boronic Acids pharmacology, Cerebellar Neoplasms drug therapy, Extracellular Signal-Regulated MAP Kinases antagonists & inhibitors, Medulloblastoma drug therapy, NF-kappa B metabolism, Niacinamide analogs & derivatives, Phenylurea Compounds pharmacology, Proto-Oncogene Proteins c-akt metabolism, Pyrazines pharmacology
Abstract

Medulloblastoma is the most common brain tumor in children. Here, we report that bortezomib, a proteasome inhibitor, induced apoptosis and inhibited cell proliferation in two established cell lines and a primary culture of human medulloblastomas. Bortezomib increased the release of cytochrome c to cytosol and activated caspase-9 and caspase-3, resulting in cleavage of PARP. Caspase inhibitor (Z-VAD-FMK) could rescue medulloblastoma cells from the cytotoxicity of bortezomib. Phosphorylation of AKT and its upstream regulator mTOR were reduced by bortezomib treatment in medulloblastoma cells. Bortezomib increased the expression of Bad and Bak, pro-apoptotic proteins, and p21Cip1 and p27Kip1, negative regulators of cell cycle progression, which are associated with the growth suppression and induction of apoptosis in these tumor cells. Bortezomib also increased the accumulation of phosphorylated IĸBα, and decreased nuclear translocation of NF-ĸB. Thus, NF-ĸB signaling and activation of its downstream targets are suppressed. Moreover, ERK inhibitors or downregulating ERK with ERK siRNA synergized with bortezomib on anticancer effects in medulloblastoma cells. Bortezomib also inhibited the growth of human medulloblastoma cells in a mouse xenograft model. These findings suggest that proteasome inhibitors are potentially promising drugs for treatment of pediatric medulloblastomas.

Published
2012
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38. Subgroup-specific alternative splicing in medulloblastoma.

Author

Dubuc AM, Morrissy AS, Kloosterhof NK, Northcott PA, Yu EP, Shih D, Peacock J, Grajkowska W, van Meter T, Eberhart CG, Pfister S, Marra MA, Weiss WA, Scherer SW, Rutka JT, French PJ, and Taylor MD

Subjects
Adult, Cluster Analysis, Computational Biology, Fetus, Gene Expression Profiling, Hedgehog Proteins genetics, Humans, Kv1.1 Potassium Channel genetics, Microarray Analysis, Receptors, Atrial Natriuretic Factor genetics, Reproducibility of Results, Wnt Proteins genetics, Alternative Splicing genetics, Cerebellar Neoplasms classification, Cerebellar Neoplasms genetics, Medulloblastoma classification, Medulloblastoma genetics
Abstract

Medulloblastoma comprises four distinct molecular variants: WNT, SHH, Group 3, and Group 4. We analyzed alternative splicing usage in 14 normal cerebellar samples and 103 medulloblastomas of known subgroup. Medulloblastoma samples have a statistically significant increase in alternative splicing as compared to normal fetal cerebella (2.3-times; P < 6.47E-8). Splicing patterns are distinct and specific between molecular subgroups. Unsupervised hierarchical clustering of alternative splicing events accurately assigns medulloblastomas to their correct subgroup. Subgroup-specific splicing and alternative promoter usage was most prevalent in Group 3 (19.4%) and SHH (16.2%) medulloblastomas, while observed less frequently in WNT (3.2%), and Group 4 (9.3%) tumors. Functional annotation of alternatively spliced genes reveals overrepresentation of genes important for neuronal development. Alternative splicing events in medulloblastoma may be regulated in part by the correlative expression of antisense transcripts, suggesting a possible mechanism affecting subgroup-specific alternative splicing. Our results identify additional candidate markers for medulloblastoma subgroup affiliation, further support the existence of distinct subgroups of the disease, and demonstrate an additional level of transcriptional heterogeneity between medulloblastoma subgroups.

Published
2012
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39. Clonal selection drives genetic divergence of metastatic medulloblastoma.

Author

Wu X, Northcott PA, Dubuc A, Dupuy AJ, Shih DJ, Witt H, Croul S, Bouffet E, Fults DW, Eberhart CG, Garzia L, Van Meter T, Zagzag D, Jabado N, Schwartzentruber J, Majewski J, Scheetz TE, Pfister SM, Korshunov A, Li XN, Scherer SW, Cho YJ, Akagi K, MacDonald TJ, Koster J, McCabe MG, Sarver AL, Collins VP, Weiss WA, Largaespada DA, Collier LS, and Taylor MD

Subjects
Animals, CpG Islands genetics, DNA Methylation, DNA Transposable Elements genetics, Disease Models, Animal, Genes, p53 genetics, Germ-Line Mutation genetics, Humans, Li-Fraumeni Syndrome complications, Li-Fraumeni Syndrome genetics, Medulloblastoma complications, Mice, Mutagenesis, Insertional, Survival Rate, Clonal Evolution genetics, Medulloblastoma genetics, Medulloblastoma pathology, Neoplasm Metastasis genetics, Neoplasm Metastasis pathology
Abstract

Medulloblastoma, the most common malignant paediatric brain tumour, arises in the cerebellum and disseminates through the cerebrospinal fluid in the leptomeningeal space to coat the brain and spinal cord. Dissemination, a marker of poor prognosis, is found in up to 40% of children at diagnosis and in most children at the time of recurrence. Affected children therefore are treated with radiation to the entire developing brain and spinal cord, followed by high-dose chemotherapy, with the ensuing deleterious effects on the developing nervous system. The mechanisms of dissemination through the cerebrospinal fluid are poorly studied, and medulloblastoma metastases have been assumed to be biologically similar to the primary tumour. Here we show that in both mouse and human medulloblastoma, the metastases from an individual are extremely similar to each other but are divergent from the matched primary tumour. Clonal genetic events in the metastases can be demonstrated in a restricted subclone of the primary tumour, suggesting that only rare cells within the primary tumour have the ability to metastasize. Failure to account for the bicompartmental nature of metastatic medulloblastoma could be a major barrier to the development of effective targeted therapies.

Published
2012
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40. Delineation of two clinically and molecularly distinct subgroups of posterior fossa ependymoma.

Author

Witt H, Mack SC, Ryzhova M, Bender S, Sill M, Isserlin R, Benner A, Hielscher T, Milde T, Remke M, Jones DT, Northcott PA, Garzia L, Bertrand KC, Wittmann A, Yao Y, Roberts SS, Massimi L, Van Meter T, Weiss WA, Gupta N, Grajkowska W, Lach B, Cho YJ, von Deimling A, Kulozik AE, Witt O, Bader GD, Hawkins CE, Tabori U, Guha A, Rutka JT, Lichter P, Korshunov A, Taylor MD, and Pfister SM

Subjects
Adult, Brain Neoplasms genetics, Chromosome Aberrations, Ependymoma genetics, Female, Gene Expression Profiling, Humans, Male, Middle Aged, Brain Neoplasms classification, Cranial Fossa, Posterior pathology, Ependymoma classification
Abstract

Despite the histological similarity of ependymomas from throughout the neuroaxis, the disease likely comprises multiple independent entities, each with a distinct molecular pathogenesis. Transcriptional profiling of two large independent cohorts of ependymoma reveals the existence of two demographically, transcriptionally, genetically, and clinically distinct groups of posterior fossa (PF) ependymomas. Group A patients are younger, have laterally located tumors with a balanced genome, and are much more likely to exhibit recurrence, metastasis at recurrence, and death compared with Group B patients. Identification and optimization of immunohistochemical (IHC) markers for PF ependymoma subgroups allowed validation of our findings on a third independent cohort, using a human ependymoma tissue microarray, and provides a tool for prospective prognostication and stratification of PF ependymoma patients., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Published
2011
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41. Genetic and epigenetic inactivation of Kruppel-like factor 4 in medulloblastoma.

Author

Nakahara Y, Northcott PA, Li M, Kongkham PN, Smith C, Yan H, Croul S, Ra YS, Eberhart C, Huang A, Bigner D, Grajkowska W, Van Meter T, Rutka JT, and Taylor MD

Subjects
Adult, Animals, Antimetabolites, Antineoplastic pharmacology, Azacitidine pharmacology, Cell Line, Tumor, Cerebellar Neoplasms pathology, CpG Islands genetics, DNA Methylation drug effects, Gene Expression Regulation, Neoplastic drug effects, Gene Expression Regulation, Neoplastic genetics, Humans, Kaplan-Meier Estimate, Kruppel-Like Factor 4, Loss of Heterozygosity, Medulloblastoma pathology, Mice, Mice, Nude, Neoplasms, Experimental genetics, Neoplasms, Experimental pathology, Oligonucleotide Array Sequence Analysis, Polymorphism, Single Nucleotide, Promoter Regions, Genetic genetics, Reverse Transcriptase Polymerase Chain Reaction, Transplantation, Heterologous, Cerebellar Neoplasms genetics, Epigenesis, Genetic, Kruppel-Like Transcription Factors genetics, Medulloblastoma genetics
Abstract

Although medulloblastoma is the most common pediatric malignant brain tumor, its molecular underpinnings are largely unknown. We have identified rare, recurrent homozygous deletions of Kruppel-like Factor 4 (KLF4) in medulloblastoma using high-resolution single nucleotide polymorphism arrays, digital karyotyping, and genomic real-time polymerase chain reaction (PCR). Furthermore, we show that there is loss of physiological KLF4 expression in more than 40% of primary medulloblastomas both at the RNA and protein levels. Medulloblastoma cell lines drastically increase the expression of KLF4 in response to the demethylating agent 5-azacytidine and demonstrate dense methylation of the promoter CpG island by bisulfite sequencing. Methylation-specific PCR targeting the KLF4 promoter demonstrates CpG methylation in approximately 16% of primary medulloblastomas. Reexpression of KLF4 in the D283 medulloblastoma cell line results in significant growth suppression both in vitro and in vivo. We conclude that KLF4 is inactivated by either genetic or epigenetic mechanisms in a large subset of medulloblastomas and that it likely functions as a tumor suppressor gene in the pathogenesis of medulloblastoma.

Published
2010
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42. Frequent amplification of a chr19q13.41 microRNA polycistron in aggressive primitive neuroectodermal brain tumors.

Author

Li M, Lee KF, Lu Y, Clarke I, Shih D, Eberhart C, Collins VP, Van Meter T, Picard D, Zhou L, Boutros PC, Modena P, Liang ML, Scherer SW, Bouffet E, Rutka JT, Pomeroy SL, Lau CC, Taylor MD, Gajjar A, Dirks PB, Hawkins CE, and Huang A

Subjects
Animals, Brain Neoplasms pathology, Cell Differentiation, Humans, Mice, Neuroectodermal Tumors, Primitive pathology, Signal Transduction, Stem Cells, Wnt Proteins metabolism, Brain Neoplasms genetics, Chromosomes, Human, Pair 19, Gene Amplification, MicroRNAs genetics, Neuroectodermal Tumors, Primitive genetics
Abstract

We discovered a high-level amplicon involving the chr19q13.41 microRNA (miRNA) cluster (C19MC) in 11/45 ( approximately 25%) primary CNS-PNET, which results in striking overexpression of miR-517c and 520g. Constitutive expression of miR-517c or 520g promotes in vitro and in vivo oncogenicity, modulates cell survival, and robustly enhances growth of untransformed human neural stem cells (hNSCs) in part by upregulating WNT pathway signaling and restricting differentiation of hNSCs. Remarkably, the C19MC amplicon, which is very rare in other brain tumors (1/263), identifies an aggressive subgroup of CNS-PNET with distinct gene-expression profiles, characteristic histology, and dismal survival. Our data implicate miR-517c and 520g as oncogenes and promising biological markers for CNS-PNET and provide important insights into oncogenic properties of the C19MC locus.

Published
2009
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43. Improved ATM kinase inhibitor KU-60019 radiosensitizes glioma cells, compromises insulin, AKT and ERK prosurvival signaling, and inhibits migration and invasion.

Author

Golding SE, Rosenberg E, Valerie N, Hussaini I, Frigerio M, Cockcroft XF, Chong WY, Hummersone M, Rigoreau L, Menear KA, O'Connor MJ, Povirk LF, van Meter T, and Valerie K

Subjects
Ataxia Telangiectasia enzymology, Ataxia Telangiectasia pathology, Ataxia Telangiectasia Mutated Proteins, Cell Cycle Proteins antagonists & inhibitors, Cell Cycle Proteins metabolism, Cell Survival drug effects, Cell Survival radiation effects, DNA-Binding Proteins antagonists & inhibitors, DNA-Binding Proteins metabolism, Fibroblasts drug effects, Fibroblasts enzymology, Fibroblasts radiation effects, Gamma Rays, Glioma pathology, Humans, Insulin pharmacology, MAP Kinase Signaling System drug effects, MAP Kinase Signaling System radiation effects, Morpholines chemistry, Morpholines pharmacology, Neoplasm Invasiveness, Phosphoserine metabolism, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors pharmacology, Protein Serine-Threonine Kinases antagonists & inhibitors, Protein Serine-Threonine Kinases metabolism, Pyrones chemistry, Pyrones pharmacology, Radiation-Sensitizing Agents pharmacology, Radiation-Sensitizing Agents therapeutic use, Thioxanthenes chemistry, Thioxanthenes pharmacology, Tumor Suppressor Proteins antagonists & inhibitors, Tumor Suppressor Proteins metabolism, Cell Movement drug effects, Cell Movement radiation effects, Extracellular Signal-Regulated MAP Kinases metabolism, Glioma drug therapy, Glioma enzymology, Insulin metabolism, Morpholines therapeutic use, Protein Kinase Inhibitors therapeutic use, Proto-Oncogene Proteins c-akt metabolism, Thioxanthenes therapeutic use
Abstract

Ataxia telangiectasia (A-T) mutated (ATM) is critical for cell cycle checkpoints and DNA repair. Thus, specific small molecule inhibitors targeting ATM could perhaps be developed into efficient radiosensitizers. Recently, a specific inhibitor of the ATM kinase, KU-55933, was shown to radiosensitize human cancer cells. Herein, we report on an improved analogue of KU-55933 (KU-60019) with K(i) and IC(50) values half of those of KU-55933. KU-60019 is 10-fold more effective than KU-55933 at blocking radiation-induced phosphorylation of key ATM targets in human glioma cells. As expected, KU-60019 is a highly effective radiosensitizer of human glioma cells. A-T fibroblasts were not radiosensitized by KU-60019, strongly suggesting that the ATM kinase is specifically targeted. Furthermore, KU-60019 reduced basal S473 AKT phosphorylation, suggesting that the ATM kinase might regulate a protein phosphatase acting on AKT. In line with this finding, the effect of KU-60019 on AKT phosphorylation was countered by low levels of okadaic acid, a phosphatase inhibitor, and A-T cells were impaired in S473 AKT phosphorylation in response to radiation and insulin and unresponsive to KU-60019. We also show that KU-60019 inhibits glioma cell migration and invasion in vitro, suggesting that glioma growth and motility might be controlled by ATM via AKT. Inhibitors of MEK and AKT did not further radiosensitize cells treated with KU-60019, supporting the idea that KU-60019 interferes with prosurvival signaling separate from its radiosensitizing properties. Altogether, KU-60019 inhibits the DNA damage response, reduces AKT phosphorylation and prosurvival signaling, inhibits migration and invasion, and effectively radiosensitizes human glioma cells.

Published
2009
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44. The miR-17/92 polycistron is up-regulated in sonic hedgehog-driven medulloblastomas and induced by N-myc in sonic hedgehog-treated cerebellar neural precursors.

Author

Northcott PA, Fernandez-L A, Hagan JP, Ellison DW, Grajkowska W, Gillespie Y, Grundy R, Van Meter T, Rutka JT, Croce CM, Kenney AM, and Taylor MD

Subjects
Adult, Animals, Cell Growth Processes genetics, Cerebellar Neoplasms metabolism, Cerebellar Neoplasms pathology, Gene Amplification, Hedgehog Proteins genetics, Hedgehog Proteins pharmacology, Humans, Medulloblastoma metabolism, Medulloblastoma pathology, Mice, MicroRNAs biosynthesis, Multigene Family, Neurons drug effects, Neurons pathology, Proto-Oncogene Mas, Proto-Oncogene Proteins c-myc biosynthesis, Signal Transduction, Stem Cells drug effects, Stem Cells pathology, Up-Regulation, Cerebellar Neoplasms genetics, Hedgehog Proteins metabolism, Medulloblastoma genetics, MicroRNAs genetics, Proto-Oncogene Proteins c-myc genetics
Abstract

Medulloblastoma is the most common malignant pediatric brain tumor, and mechanisms underlying its development are poorly understood. We identified recurrent amplification of the miR-17/92 polycistron proto-oncogene in 6% of pediatric medulloblastomas by high-resolution single-nucleotide polymorphism genotyping arrays and subsequent interphase fluorescence in situ hybridization on a human medulloblastoma tissue microarray. Profiling the expression of 427 mature microRNAs (miRNA) in a series of 90 primary human medulloblastomas revealed that components of the miR-17/92 polycistron are the most highly up-regulated miRNAs in medulloblastoma. Expression of miR-17/92 was highest in the subgroup of medulloblastomas associated with activation of the sonic hedgehog (Shh) signaling pathway compared with other subgroups of medulloblastoma. Medulloblastomas in which miR-17/92 was up-regulated also had elevated levels of MYC/MYCN expression. Consistent with its regulation by Shh, we observed that Shh treatment of primary cerebellar granule neuron precursors (CGNP), proposed cells of origin for the Shh-associated medulloblastomas, resulted in increased miR-17/92 expression. In CGNPs, the Shh effector N-myc, but not Gli1, induced miR-17/92 expression. Ectopic miR-17/92 expression in CGNPs synergized with exogenous Shh to increase proliferation and also enabled them to proliferate in the absence of Shh. We conclude that miR-17/92 is a positive effector of Shh-mediated proliferation and that aberrant expression/amplification of this miR confers a growth advantage to medulloblastomas.

Published
2009
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45. Multiple recurrent genetic events converge on control of histone lysine methylation in medulloblastoma.

Author

Northcott PA, Nakahara Y, Wu X, Feuk L, Ellison DW, Croul S, Mack S, Kongkham PN, Peacock J, Dubuc A, Ra YS, Zilberberg K, McLeod J, Scherer SW, Sunil Rao J, Eberhart CG, Grajkowska W, Gillespie Y, Lach B, Grundy R, Pollack IF, Hamilton RL, Van Meter T, Carlotti CG, Boop F, Bigner D, Gilbertson RJ, Rutka JT, and Taylor MD

Subjects
Cerebellar Neoplasms enzymology, Gene Amplification, Gene Deletion, Genes, Tumor Suppressor, Genome, Human, Histone-Lysine N-Methyltransferase genetics, Histones metabolism, Humans, Lysine metabolism, Medulloblastoma enzymology, Polymorphism, Single Nucleotide, Protein Processing, Post-Translational genetics, Sequence Deletion, Cerebellar Neoplasms genetics, Medulloblastoma genetics
Abstract

We used high-resolution SNP genotyping to identify regions of genomic gain and loss in the genomes of 212 medulloblastomas, malignant pediatric brain tumors. We found focal amplifications of 15 known oncogenes and focal deletions of 20 known tumor suppressor genes (TSG), most not previously implicated in medulloblastoma. Notably, we identified previously unknown amplifications and homozygous deletions, including recurrent, mutually exclusive, highly focal genetic events in genes targeting histone lysine methylation, particularly that of histone 3, lysine 9 (H3K9). Post-translational modification of histone proteins is critical for regulation of gene expression, can participate in determination of stem cell fates and has been implicated in carcinogenesis. Consistent with our genetic data, restoration of expression of genes controlling H3K9 methylation greatly diminishes proliferation of medulloblastoma in vitro. Copy number aberrations of genes with critical roles in writing, reading, removing and blocking the state of histone lysine methylation, particularly at H3K9, suggest that defective control of the histone code contributes to the pathogenesis of medulloblastoma.

Published
2009
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46. Microarray analysis of MRI-defined tissue samples in glioblastoma reveals differences in regional expression of therapeutic targets.

Author

Van Meter T, Dumur C, Hafez N, Garrett C, Fillmore H, and Broaddus WC

Subjects
Algorithms, Biopsy, Blotting, Western, Cluster Analysis, Humans, Prospective Studies, RNA analysis, Reproducibility of Results, Reverse Transcriptase Polymerase Chain Reaction, Stereotaxic Techniques, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Glioblastoma genetics, Glioblastoma pathology, Magnetic Resonance Imaging, Interventional, Oligonucleotide Array Sequence Analysis
Abstract

Microarray technologies have come into prominence for the assessment of molecular diagnostic profiles in cancer tissue biopsies. To better understand the effect of sampling bias, we paired image-guided stereotactic biopsy and microarray technology to study regional intratumoral differences in tumor periphery and core regions of untreated glioblastoma. RNA was extracted from serial frozen sections using an integral histopathologic scoring approach. Gene expression analysis was performed using high-density oligonucleotide microarrays (22,283 probe sets). A consensus list of 643 genes (784 probe sets) with greater than 2-fold difference between intratumoral periphery and core samples was obtained using Microarray Suite 5.0, model-based expression indexes, and robust multiarray analysis algorithms. Results were validated using quantitative polymerase chain reaction and Western blotting analyses. Reproducible profiles emerged, in which multiple therapeutic targets significant to glioblastoma [matrix metalloproteinases, AKT1 (v-akt murine thymoma viral oncogene homolog 1), epidermal growth factor receptor, vascular endothelial growth factor] showed significant differences in regional expression that may affect treatment response. This study suggests important intratumoral regional differences in the molecular phenotype of glioblastoma.

Published
2006
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47. Concerns about the genetics of pre-eclampsia.

Author

Van Meter TD and Weaver DD

Subjects
Chromosome Mapping methods, Female, Gene Frequency, Genetic Linkage, Humans, Pedigree, Pregnancy, Pre-Eclampsia genetics
Published
1993

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