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3. 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, L., 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., and Taylor, M. D.

Published
2014
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6. FORETINIB IS EFFECTIVE THERAPY FOR METASTATIC SONIC HEDGEHOG MEDULLOBLASTOMA

Author

Smith, C., primary, Faria, C. C., additional, Dubuc, A. M., additional, Remke, M., additional, Golbourn, B. J., additional, Diaz, R. J., additional, Agnihotri, S., additional, Luck, A., additional, Sabha, N., additional, Olsen, S., additional, Wu, X., additional, Garzia, L., additional, Ramaswamy, V., additional, Mack, S. C., additional, Wang, X., additional, Leadley, M., additional, Reynaud, D., additional, Ermini, L., additional, Post, M., additional, Northcott, P. A., additional, Pfister, S. M., additional, Croul, S. E., additional, Kool, M., additional, Korshunov, A., additional, Taylor, M. D., additional, and Rutka, J. T., additional

Published
2014
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7. EPENDYMOMA

Author

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

Published
2014
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11. 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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16. Evasion of p53 and G2/M checkpoints are characteristic of Hh-driven basal cell carcinoma.

Author

Li, Z J, Mack, S C, Mak, T H, Angers, S, Taylor, M D, and Hui, C-C

Subjects
*P53 antioncogene, *BASAL cell carcinoma treatment, *HEDGEHOG signaling proteins, *GENETIC mutation, *CELL cycle regulation, *HOMEOSTASIS
Abstract

Basal cell carcinoma (BCC), the most common type of cancer, is characterized by aberrant Hedgehog (Hh) pathway activity. Mutations in pathway components, such as PATCHED1 (PTCH1), are commonly found in BCC. While the tumor suppressor role of PTCH1 in BCC is well established, how Hh pathway activation disrupts normal skin homeostasis to promote BCC formationremains poorly understood. Like Ptc1, Sufu is a major negative regulator of the Hh pathway. Previously, we showed that inactivation of Sufu in the skin does not result in BCC formation. Why loss of Ptc1, but not Sufu, in the epidermis induces BCC formation is unclear. In this report, we utilized gene expression profiling to identify biological pathways and processes that distinguish Sufu from Ptc1 mutants, and discovered a novel role for Sufu in cell cycle regulation. We demonstrated that the Hh pathway activation inSufu and Ptc1 mutant skin is associated with abnormal cell cycle entry, ectopic expression of D-type cyclins and increasedDNA damage. However, despite the presence of DNA damage, p53 stabilization was impaired in the mutant skin. Alternative mechanism to halt genomic instability is the activation of G2/M cell cycle checkpoint, which can occur independent of p53. We found that while Ptc1 mutant cells continue to cycle, which would favor genomic instability, loss of Sufu results in G2/M cell cycle arrest.This finding may explain why inactivation of Sufu is not sufficient to drive BCC formation. Taken together, these studies revealed a unique role for Sufu in G2/M phase progression, and uncovered the molecular and cellular features associated with Hh-driven BCC. [ABSTRACT FROM AUTHOR]

Published
2014
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19. Metabolic Regulation of the Epigenome Drives Lethal Infantile Ependymoma

Author

Samuel Weiss, Leo J.Y. Kim, Xiaochong Wu, Randy Van Ommeren, Yanqing Jiang, Kaitlin Kharas, Evgeny Kanshin, Moloud Ahmadi, Alberto Delaidelli, Geneviève Deblois, David Przelicki, Stephane Angers, Hiromichi Suzuki, Sameer Agnihotri, Bradly G. Wouters, Graham MacLeod, Ricky Tsai, Pasqualino De Antonellis, Michelle Ly, Stacey L. Krumholtz, Paul Guilhamon, James Loukides, Ravi N. Vellanki, Alex Rasnitsyn, Hamza Farooq, Daniel Schramek, Nada Jabado, María Sánchez-Osuna, Laura K. Donovan, Vijay Ramaswamy, Ibrahim El-Hamamy, Joonas Haapasalo, Jeremy N. Rich, Michael D. Taylor, Benjamin A. Garcia, Mike Tyers, Kyle Juraschka, Winnie Ong, Olivier Saulnier, Panagiotis Prinos, John J.Y. Lee, Borja L. Holgado, Olga Sirbu, Craig Daniels, Cheryl H. Arrowsmith, Cory Richman, Poul H. Sorensen, Kulandaimanuvel Antony Michealraj, Sheila K. Singh, Andrea Bajic, Polina Balin, Stephen C. Mack, Betty Luu, Fiona J. Coutinho, Dilakshan Srikanthan, Florence M.G. Cavalli, Sachin Kumar, Evan Y. Wang, Mathieu Lupien, Peter B. Dirks, Maria C. Vladoiu, Lincoln Stein, Livia Garzia, Ahmad Malik, John Wojcik, Avesta Rastan, Michealraj, K. A., Kumar, S. A., Kim, L. J. Y., Cavalli, F. M. G., Przelicki, D., Wojcik, J. B., Delaidelli, A., Bajic, A., Saulnier, O., Macleod, G., Vellanki, R. N., Vladoiu, M. C., Guilhamon, P., Ong, W., Lee, J. J. Y., Jiang, Y., Holgado, B. L., Rasnitsyn, A., Malik, A. A., Tsai, R., Richman, C. M., Juraschka, K., Haapasalo, J., Wang, E. Y., De Antonellis, P., Suzuki, H., Farooq, H., Balin, P., Kharas, K., Van Ommeren, R., Sirbu, O., Rastan, A., Krumholtz, S. L., Ly, M., Ahmadi, M., Deblois, G., Srikanthan, D., Luu, B., Loukides, J., Wu, X., Garzia, L., Ramaswamy, V., Kanshin, E., Sanchez-Osuna, M., El-Hamamy, I., Coutinho, F. J., Prinos, P., Singh, S., Donovan, L. K., Daniels, C., Schramek, D., Tyers, M., Weiss, S., Stein, L. D., Lupien, M., Wouters, B. G., Garcia, B. A., Arrowsmith, C. H., Sorensen, P. H., Angers, S., Jabado, N., Dirks, P. B., Mack, S. C., Agnihotri, S., Rich, J. N., and Taylor, M. D.

Subjects
Epigenomics, Ependymoma, Male, ependymoma, Epigenomic, Somatic cell, cancer metabolism, Infratentorial Neoplasms, Biology, General Biochemistry, Genetics and Molecular Biology, Cell Line, Histones, Brain Neoplasm, 03 medical and health sciences, Epigenome, 0302 clinical medicine, Histone demethylation, Histone methylation, medicine, Animals, Humans, Epigenetics, 030304 developmental biology, hindbrain development, Cell Proliferation, Infratentorial Neoplasm, 0303 health sciences, Brain Neoplasms, Animal, Lysine, Infant, DNA Methylation, medicine.disease, microenvironment, Mice, Inbred C57BL, Histone, Acetylation, paediatric cancer, Mutation, biology.protein, Cancer research, 030217 neurology & neurosurgery, epigenetic, Human
Abstract

Posterior fossa A (PFA) ependymomas are lethal malignancies of the hindbrain in infants and toddlers. Lacking highly recurrent somatic mutations, PFA ependymomas are proposed to be epigenetically driven tumors for which model systems are lacking. Here we demonstrate that PFA ependymomas are maintained under hypoxia, associated with restricted availability of specific metabolites to diminish histone methylation, and increase histone demethylation and acetylation at histone 3 lysine 27 (H3K27). PFA ependymomas initiate from a cell lineage in the first trimester of human development that resides in restricted oxygen. Unlike other ependymomas, transient exposure of PFA cells to ambient oxygen induces irreversible cellular toxicity. PFA tumors exhibit a low basal level of H3K27me3, and, paradoxically, inhibition of H3K27 methylation specifically disrupts PFA tumor growth. Targeting metabolism and/or the epigenome presents a unique opportunity for rational therapy for infants with PFA ependymoma. Hypoxia reprograms the cellular metabolome and epigenome to promote growth of the most lethal ependymomas.

Published
2020

20. Locoregional delivery of CAR T cells to the cerebrospinal fluid for treatment of metastatic medulloblastoma and ependymoma

Author

Carolina Nor, Martin Komosa, Olga Sirbu, Nabil Ahmed, Joonas Haapasalo, Kristen Fousek, Jonelle G. Pallota, Betty Luu, Cynthia Hawkins, Kenneth Aldape, Uri Tabori, David Przelicki, Srinidhi Varadharajan, Liam D. Hendrikse, Meenakshi Hegde, Claudia M. Kuzan-Fischer, Ana Guerreiro Stucklin, Tajana Douglas, Ahmed Z. Gad, Xiaochong Wu, Randy Van Ommeren, Polina Balin, Alex Manno, Sachin Kumar, Raul Suarez, Avesta Rastan, Craig Daniels, Mads Daugaard, Maria C. Vladoiu, Stephen Yip, Cory Richman, Michelle Ly, Matthew L. Baker, Kaitlin Kharas, Laura K. Donovan, Stephen C. Mack, Claudia C. Faria, Pasqualino De Antonellis, Ning Huang, Poul H. Sorensen, Zied Abdullaev, Lei Qin, Livia Garzia, Alyssa C. M. Joynt, A. Sorana Morrissy, Michael D. Taylor, Sujith K. Joseph, Antony Michealraj, Dilakshan Srikanthan, Florence M.G. Cavalli, Borja L. Holgado, John M. Maris, Alberto Delaidelli, Vijay Ramaswamy, Kevin Bielamowicz, Juliette Hukin, Donovan, L. K., Delaidelli, A., Joseph, S. K., Bielamowicz, K., Fousek, K., Holgado, B. L., Manno, A., Srikanthan, D., Gad, A. Z., Van Ommeren, R., Przelicki, D., Richman, C., Ramaswamy, V., Daniels, C., Pallota, J. G., Douglas, T., Joynt, A. C. M., Haapasalo, J., Nor, C., Vladoiu, M. C., Kuzan-Fischer, C. M., Garzia, L., Mack, S. C., Varadharajan, S., Baker, M. L., Hendrikse, L., Ly, M., Kharas, K., Balin, P., Wu, X., Qin, L., Huang, N., Stucklin, A. G., Morrissy, A. S., Cavalli, F. M. G., Luu, B., Suarez, R., De Antonellis, P., Michealraj, A., Rastan, A., Hegde, M., Komosa, M., Sirbu, O., Kumar, S. A., Abdullaev, Z., Faria, C. C., Yip, S., Hukin, J., Tabori, U., Hawkins, C., Aldape, K., Daugaard, M., Maris, J. M., Sorensen, P. H., Ahmed, N., and Taylor, M. D.

Subjects
0301 basic medicine, Ependymoma, Male, medicine.medical_treatment, T-Lymphocytes, Immunotherapy, Adoptive, Mice, 0302 clinical medicine, Cerebrospinal fluid, Drug Delivery Systems, HEK293 Cell, Cancer immunotherapy, Tumor Cells, Cultured, Neoplasm Metastasis, Child, Cerebrospinal Fluid, Receptors, Chimeric Antigen, Brain Neoplasms, General Medicine, Neoplasm Metastasi, Treatment Outcome, 030220 oncology & carcinogenesis, Child, Preschool, Female, Cancer Vaccine, Human, Cancer Vaccines, General Biochemistry, Genetics and Molecular Biology, Brain Neoplasm, 03 medical and health sciences, medicine, Animals, Humans, Cerebellar Neoplasms, neoplasms, Injections, Intraventricular, Medulloblastoma, Animal, business.industry, Cerebellar Neoplasm, Infant, Immunotherapy, Recurrent Medulloblastoma, medicine.disease, Interleukin-13 receptor, Xenograft Model Antitumor Assays, Chimeric antigen receptor, 030104 developmental biology, HEK293 Cells, T-Lymphocyte, Cancer research, business, Drug Delivery System
Abstract

Recurrent medulloblastoma and ependymoma are universally lethal, with no approved targeted therapies and few candidates presently under clinical evaluation. Nearly all recurrent medulloblastomas and posterior fossa group A (PFA) ependymomas are located adjacent to and bathed by the cerebrospinal fluid, presenting an opportunity for locoregional therapy, bypassing the blood–brain barrier. We identify three cell-surface targets, EPHA2, HER2 and interleukin 13 receptor α2, expressed on medulloblastomas and ependymomas, but not expressed in the normal developing brain. We validate intrathecal delivery of EPHA2, HER2 and interleukin 13 receptor α2 chimeric antigen receptor T cells as an effective treatment for primary, metastatic and recurrent group 3 medulloblastoma and PFA ependymoma xenografts in mouse models. Finally, we demonstrate that administration of these chimeric antigen receptor T cells into the cerebrospinal fluid, alone or in combination with azacytidine, is a highly effective therapy for multiple metastatic mouse models of group 3 medulloblastoma and PFA ependymoma, thereby providing a rationale for clinical trials of these approaches in humans.

Published
2019

21. Splenic function after splenectomy for trauma. Role of autotransplantation and splenosis.

Author

Lüdtke FE, Mack SC, Schuff-Werner P, and Voth E

Subjects
Adolescent, Adult, Aged, Child, Evaluation Studies as Topic, Female, Follow-Up Studies, Humans, Immunity, Cellular, Leukocyte Count, Liver diagnostic imaging, Male, Middle Aged, Platelet Count, Postoperative Complications, Radionuclide Imaging, Skin immunology, Spleen diagnostic imaging, Spleen transplantation, Transplantation, Autologous, Spleen immunology, Splenectomy, Splenic Rupture surgery
Abstract

Follow-up of patients treated for severe trauma to the spleen, with autotransplantation (20 cases) or splenectomy (21 cases) included hepatic and splenic scintigraphy, intracutaneous skin testing with seven recall antigens and hematologic studies (red and white blood count, Howell-Jolly bodies, erythrocyte morphology, immunoglobulins, complements). In all reimplantation cases splenic tissue was scintigraphically demonstrated. After removal of the spleen due to severe traumatic ruptures the incidence of splenosis was 66%. Good clearance function in all reimplantation and splenosis cases was demonstrated by Howell-Jolly bodies and erythrocyte morphology. Autotransplantation of splenic tissue is a simple and safe procedure, without serious complications. As yet, however, there is no proof that it provides adequate resistance to infections. Reimplantation, therefore, should be performed only if spleen-preserving procedures are not feasible.

Published
1989

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