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3. Correction to: Toxicogenomics directory of chemically exposed human hepatocytes

Author

Grinberg, Marianna, Stöber, Regina M., Edlund, Karolina, Rempel, Eugen, Godoy, Patricio, Reif, Raymond, Widera, Agata, Madjar, Katrin, Schmidt-Heck, Wolfgang, Marchan, Rosemarie, Sachinidis, Agapios, Spitkovsky, Dimitry, Hescheler, Jürgen, Carmo, Helena, Arbo, Marcelo D., van de Water, Bob, Wink, Steven, Vinken, Mathieu, Rogiers, Vera, Escher, Sylvia, Hardy, Barry, Mitic, Dragana, Apic, Gordana, Myatt, Glenn, Waldmann, Tanja, Mardinoglu, Adil, Damm, Georg, Seehofer, Daniel, Nüssler, Andreas, Weiss, Thomas S., Oberemm, Axel, Lampen, ·Alfons, Schaap, Mirjam M., Luijten, Mirjam, van Steeg, Harry, Thasler, Wolfgang E., Kleinjans, Jos C. S., Stierum, Rob H., Leist, ·Marcel, Rahnenführer, Jörg, and Hengstler, Jan G.

Published
2022
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5. Emerging Trends in the Field of Inflammation and Proteinopathy in ALS/FTD Spectrum Disorder

Author

De Marchi, Fabiola, primary, Franjkic, Toni, additional, Schito, Paride, additional, Russo, Tommaso, additional, Nimac, Jerneja, additional, Chami, Anna A., additional, Mele, Angelica, additional, Vidatic, Lea, additional, Kriz, Jasna, additional, Julien, Jean-Pierre, additional, Apic, Gordana, additional, Russell, Robert B., additional, Rogelj, Boris, additional, Cannon, Jason R., additional, Baralle, Marco, additional, Agosta, Federica, additional, Hecimovic, Silva, additional, Mazzini, Letizia, additional, Buratti, Emanuele, additional, and Munitic, Ivana, additional

Published
2023
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6. The Precision Toxicology Initiative

Author

Busquet, François, primary, Laperrouze, Jeanne, additional, Jankovic, Katica, additional, Krsmanovic, Tamara, additional, Ignasiak, Tomasz, additional, Leoni, Benedetta, additional, Apic, Gordana, additional, Asole, Giovanni, additional, Guigó, Roderic, additional, Marangio, Paolo, additional, Palumbo, Emilio, additional, Perez-Lluch, Silvia, additional, Wucher, Valentin, additional, Vlot, Anna Hendrika, additional, Anholt, Robert, additional, Mackay, Trudy, additional, Escher, Beate I., additional, Grasse, Nico, additional, Huchthausen, Julia, additional, Massei, Riccardo, additional, Reemtsma, Thorsten, additional, Scholz, Stefan, additional, Schüürmann, Gerrit, additional, Bondesson, Maria, additional, Cherbas, Peter, additional, Freedman, Jonathan H., additional, Glaholt, Stephen, additional, Holsopple, Jessica, additional, Jacobson, Stephen C., additional, Kaufman, Thomas, additional, Popodi, Ellen, additional, Shaw, Joseph J., additional, Smoot, Shannon, additional, Tennessen, Jason M., additional, Churchill, Gary, additional, von Clausbruch, Christina Cramer, additional, Dickmeis, Thomas, additional, Hayot, Gaëlle, additional, Pace, Giuseppina, additional, Peravali, Ravindra, additional, Weiss, Carsten, additional, Cistjakova, Nadezda, additional, Liu, Xin, additional, Slaitas, Andis, additional, Brown, James (Ben), additional, Ayerbe, Rafael, additional, Cabellos, Joan, additional, Cerro-Gálvez, Elena, additional, Diez-Ortiz, María, additional, González, Verónica, additional, Martínez, Rubén, additional, Vives, Patricia Solórzano, additional, Barnett, Rosemary, additional, Lawson, Thomas, additional, Lee, Robert G., additional, Sostare, Elena, additional, Viant, Mark, additional, Grafström, Roland, additional, Hongisto, Vesa, additional, Kohonen, Pekka, additional, Patyra, Konrad, additional, Bhaskar, Pradeep Kumar, additional, Garmendia-Cedillos, Marcial, additional, Farooq, Ibraheem, additional, Oliver, Brian, additional, Pohida, Tom, additional, Salem, Ghadi, additional, Jacobson, Daniel, additional, Andrews, Elisabeth, additional, Barnard, Marianne, additional, Čavoški, Aleksandra, additional, Chaturvedi, Anurag, additional, Colbourne, John K., additional, Epps, David J.T., additional, Holden, Laura, additional, Jones, Martin R., additional, Li, Xiaojing, additional, Müller, Ferenc, additional, Ormanin-Lewandowska, Agata, additional, Orsini, Luisa, additional, Roberts, Ruth, additional, Weber, Ralf J.M., additional, Zhou, Jiarui, additional, Chung, Mu-En, additional, Sanchez, Juan Carlos Gonzalez, additional, Diwan, Gaurav D., additional, Singh, Gurdeep, additional, Strähle, Uwe, additional, Russell, Robert B., additional, Batista, Dominique, additional, Sansone, Susanna-Assunta, additional, Rocca-Serra, Philippe, additional, Du Pasquier, David, additional, Lemkine, Gregory, additional, Robin-Duchesne, Barbara, additional, and Tindall, Andrew, additional

Published
2023
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7. Focal structural variants revealed by whole genome sequencing disrupt the histone demethylase KDM4C in B-cell lymphomas

Author

López, Cristina, Schleussner, Nikolai, Bernhart, Stephan H., Kleinheinz, Kortine, Sungalee, Stephanie, Sczakiel, Henrike L., Kretzmer, Helene, Toprak, Umut H., Glaser, Selina, Wagener, Rabea, Ammerpohl, Ole, Bens, Susanne, Giefing, Maciej, González Sánchez, Juan C., Apic, Gordana, Hübschmann, Daniel, Janz, Martin, Kreuz, Markus, Mottok, Anja, Müller, Judith M., Seufert, Julian, Hoffmann, Steve, Korbel, Jan O., Russell, Robert B., Schüle, Roland, Trümper, Lorenz, Klapper, Wolfram, Radlwimmer, Bernhard, Lichter, Peter, Küppers, Ralf, Schlesner, Matthias, Mathas, Stephan, Siebert, Reiner, Sanchez, Juan C. Gonzalez, European Union (EU), and Horizon 2020

Subjects
Cancer Research, GENES, LANDSCAPE, MUTATIONS, BURKITT, PATHOGENESIS, Medizin, EXOME, Hematology, ddc:610, Histone methyltransferases, DDC 610 / Medicine & health
Abstract

Histone methylation-modifiers, such as EZH2 and KMT2D, are recurrently altered in B-cell lymphomas. To comprehensively describe the landscape of alterations affecting genes encoding histone methylation-modifiers in lymphomagenesis we investigated whole genome and transcriptome data of 186 mature B-cell lymphomas sequenced in the ICGC MMML-Seq project. Besides confirming common alterations of KMT2D (47% of cases), EZH2 (17%), SETD1B (5%), PRDM9 (4%), KMT2C (4%), and SETD2 (4%), also identified by prior exome or RNA-sequencing studies, we here found recurrent alterations to KDM4C in chromosome 9p24, encoding a histone demethylase. Focal structural variation was the main mechanism of KDM4C alterations, and was independent from 9p24 amplification. We also identified KDM4C alterations in lymphoma cell lines including a focal homozygous deletion in a classical Hodgkin lymphoma cell line. By integrating RNA-sequencing and genome sequencing data we predict that KDM4C structural variants result in loss-offunction. By functional reconstitution studies in cell lines, we provide evidence that KDM4C can act as a tumor suppressor. Thus, we show that identification of structural variants in whole genome sequencing data adds to the comprehensive description of the mutational landscape of lymphomas and, moreover, establish KDM4C as a putative tumor suppressive gene recurrently altered in subsets of B-cell derived lymphomas., publishedVersion

Published
2023

8. Toxicogenomics directory of chemically exposed human hepatocytes (vol 88, pg 2261, 2014)

Author

Grinberg, Marianna, Stoeber, Regina M., Edlund, Karolina, Rempel, Eugen, Godoy, Patricio, Reif, Raymond, Widera, Agata, Madjar, Katrin, Schmidt-Heck, Wolfgang, Marchan, Rosemarie, Sachinidis, Agapios, Spitkovsky, Dimitry, Hescheler, Juergen, Carmo, Helena, Arbo, Marcelo D., van de Water, Bob, Wink, Steven, Vinken, Mathieu, Rogiers, Vera, Escher, Sylvia, Hardy, Barry, Mitic, Dragana, Apic, Gordana, Myatt, Glenn, Waldmann, Tanja, Mardinoglu, Adil, Damm, Georg, Seehofer, Daniel, Nuessler, Andreas, Weiss, Thomas S., Oberemm, Axel, Lampen, Alfons, Schaap, Mirjam M., Luijten, Mirjam, van Steeg, Harry, Thasler, Wolfgang E., Kleinjans, Jos C. S., Stierum, Rob H., Leist, Marcel, Rahnenfuehrer, Joerg, Hengstler, Jan G., Grinberg, Marianna, Stoeber, Regina M., Edlund, Karolina, Rempel, Eugen, Godoy, Patricio, Reif, Raymond, Widera, Agata, Madjar, Katrin, Schmidt-Heck, Wolfgang, Marchan, Rosemarie, Sachinidis, Agapios, Spitkovsky, Dimitry, Hescheler, Juergen, Carmo, Helena, Arbo, Marcelo D., van de Water, Bob, Wink, Steven, Vinken, Mathieu, Rogiers, Vera, Escher, Sylvia, Hardy, Barry, Mitic, Dragana, Apic, Gordana, Myatt, Glenn, Waldmann, Tanja, Mardinoglu, Adil, Damm, Georg, Seehofer, Daniel, Nuessler, Andreas, Weiss, Thomas S., Oberemm, Axel, Lampen, Alfons, Schaap, Mirjam M., Luijten, Mirjam, van Steeg, Harry, Thasler, Wolfgang E., Kleinjans, Jos C. S., Stierum, Rob H., Leist, Marcel, Rahnenfuehrer, Joerg, and Hengstler, Jan G.

Published
2022

9. Focal structural variants revealed by whole genome sequencing disrupt the histone demethylase KDM4C in B-cell lymphomas

Author

Lopez, Cristina, primary, Schleussner, Nikolai, additional, Bernhart, Stephan H., additional, Kleinheinz, Kortine, additional, Sungalee, Stephanie, additional, Sczakiel, Henrike L., additional, Kretzmer, Helene, additional, Toprak, Umut H., additional, Glaser, Selina, additional, Wagener, Rabea, additional, Ammerpohl, Ole, additional, Bens, Susanne, additional, Giefing, Maciej, additional, Sanchez, Juan C. Gonzalez, additional, Apic, Gordana, additional, Hubschmann, Daniel, additional, Janz, Martin, additional, Kreuz, Markus, additional, Mottok, Anja, additional, Muller, Judith M., additional, Seufert, Julian, additional, Hoffmann, Steve, additional, Korbel, Jan O., additional, Russell, Robert B., additional, Schule, Roland, additional, Trumper, Lorenz, additional, Klapper, Wolfram, additional, Radlwimmer, Bernhard, additional, Lichter, Peter, additional, Kuppers, Ralf, additional, Schlesner, Matthias, additional, Mathas, Stephan, additional, and Siebert, Reiner, additional

Published
2022
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19. An organelle-specific protein landscape identifies novel diseases and molecular mechanisms

Author

Boldt, Karsten, van Reeuwijk, Jeroen, Dougherty, Gerard, Lamers, Ideke J C, Coene, Karlien L M, Arts, Heleen H, Betts, Matthew J, Beyer, Tina, Bolat, Emine, Gloeckner, Christian Johannes, Haidari, Khatera, Hetterschijt, Lisette, Lu, Qianhao, Iaconis, Daniela, Jenkins, Dagan, Klose, Franziska, Knapp, Barbara, Latour, Brooke, Letteboer, Stef J F, Marcelis, Carlo L, Mitic, Dragana, Morleo, Manuela, Oud, Machteld M, Koutroumpas, Konstantinos, Riemersma, Moniek, Rix, Susan, Terhal, Paulien A, Toedt, Grischa, van Dam, Teunis J P, de Vrieze, Erik, Wissinger, Yasmin, Wu, Ka Man, Apic, Gordana, Beales, Philip L, Nguyen, Thanh-Minh T, Blacque, Oliver E, Gibson, Toby J, Huynen, Martijn A, Katsanis, Nicholas, Kremer, Hannie, Omran, Heymut, van Wijk, Erwin, Wolfrum, Uwe, Kepes, François, Davis, Erica E, Texier, Yves, Franco, Brunella, Giles, Rachel H, Ueffing, Marius, Russell, Robert B, Roepman, Ronald, Group, UK10K Rare Diseases, Al-Turki, Saeed, Anderson, Carl, Antony, Dinu, Barroso, Inês, van Beersum, Sylvia E C, Bentham, Jamie, Bhattacharya, Shoumo, Carss, Keren, Chatterjee, Krishna, Cirak, Sebahattin, Cosgrove, Catherine, Danecek, Petr, Durbin, Richard, Fitzpatrick, David, Floyd, Jamie, Horn, Nicola, Reghan Foley, A., Franklin, Chris, Futema, Marta, Humphries, Steve E, Hurles, Matt, Joyce, Chris, McCarthy, Shane, Mitchison, Hannah M, Muddyman, Dawn, Muntoni, Francesco, Willer, Jason R, O'Rahilly, Stephen, Onoufriadis, Alexandros, Payne, Felicity, Plagnol, Vincent, Raymond, Lucy, Savage, David B, Scambler, Peter, Schmidts, Miriam, Schoenmakers, Nadia, Semple, Robert, Mans, Dorus A, Serra, Eva, Stalker, Jim, van Kogelenberg, Margriet, Vijayarangakannan, Parthiban, Walter, Klaudia, Whittall, Ros, Williamson, Kathy, Boldt, K, van Reeuwijk, J, Lu, Q, Koutroumpas, K, Nguyen, Tmt, Texier, Y, van Beersum, Sec, Horn, N, Willer, Jr, Mans, Da, Dougherty, G, Lamers, Ijc, Coene, Klm, Arts, Hh, Betts, Mj, Beyer, T, Bolat, E, Gloeckner, Cj, Haidari, K, Hetterschijt, L, Iaconis, D, Jenkins, D, Klose, F, Knapp, B, Latour, B, Letteboer, Sjf, Marcelis, Cl, Mitic, D, Morleo, M, Oud, Mm, Riemersma, M, Rix, S, Terhal, Pa, Toedt, G, van Dam, Tjp, de Vrieze, E, Wissinger, Y, Wu, Km, Apic, G, Beales, Pl, Blacque, Oe, Gibson, Tj, Huynen, Ma, Katsanis, N, Kremer, H, Omran, H, van Wijk, E, Wolfrum, U, Kepes, F, Davis, Ee, Franco, B, Giles, Rh, Ueffing, M, Russell, Rb, Roepman, R, Boldt, Karsten, Van Reeuwijk, Jeroen, Lu, Qianhao, Koutroumpas, Konstantino, Nguyen, Thanh Minh T., Texier, Yve, Van Beersum, Sylvia E. C., Horn, Nicola, Willer, Jason R., Mans, Dorus A., Dougherty, Gerard, Lamers, Ideke J. C., Coene, Karlien L. M., Arts, Heleen H., Betts, Matthew J., Beyer, Tina, Bolat, Emine, Gloeckner, Christian Johanne, Haidari, Khatera, Hetterschijt, Lisette, Iaconis, Daniela, Jenkins, Dagan, Klose, Franziska, Knapp, Barbara, Latour, Brooke, Letteboer, Stef J. F., Marcelis, Carlo L., Mitic, Dragana, Morleo, Manuela, Oud, Machteld M., Riemersma, Moniek, Rix, Susan, Terhal, Paulien A., Toedt, Grischa, Van Dam, Teunis J. P., De Vrieze, Erik, Wissinger, Yasmin, Wu, Ka Man, Al Turki, Saeed, Anderson, Carl, Antony, Dinu, Barroso, Inê, Bentham, Jamie, Bhattacharya, Shoumo, Carss, Keren, Chatterjee, Krishna, Cirak, Sebahattin, Cosgrove, Catherine, Danecek, Petr, Durbin, Richard, Fitzpatrick, David, Floyd, Jamie, Foley, A. Reghan, Franklin, Chri, Futema, Marta, Humphries, Steve E., Hurles, Matt, Joyce, Chri, Mccarthy, Shane, Mitchison, Hannah M., Muddyman, Dawn, Muntoni, Francesco, O'Rahilly, Stephen, Onoufriadis, Alexandro, Payne, Felicity, Plagnol, Vincent, Raymond, Lucy, Savage, David B., Scambler, Peter, Schmidts, Miriam, Schoenmakers, Nadia, Semple, Robert, Serra, Eva, Stalker, Jim, Van Kogelenberg, Margriet, Vijayarangakannan, Parthiban, Walter, Klaudia, Whittall, Ro, Williamson, Kathy, Apic, Gordana, Beales, Philip L., Blacque, Oliver E., Gibson, Toby J., Huynen, Martijn A., Katsanis, Nichola, Kremer, Hannie, Omran, Heymut, Van Wijk, Erwin, Wolfrum, Uwe, Kepes, Françoi, Davis, Erica E., Franco, Brunella, Giles, Rachel H., Ueffing, Mariu, Russell, Robert B., and Roepman, Ronald

Subjects
Proteomics, 0301 basic medicine, Systems Analysis, DNA Mutational Analysis, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], General Physics and Astronomy, Datasets as Topic, methods [Chromatography, Affinity], Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], Chromatography, Affinity, Mass Spectrometry, Protein Interaction Mapping, therapy [Ciliopathies], genetics [Ciliopathies], methods [Molecular Targeted Therapy], Molecular Targeted Therapy, Protein Interaction Maps, Multidisciplinary, Cilium, Chemistry (all), abnormalities [Spine], pathology [Ciliopathies], genetics [Muscle Hypotonia], therapy [Muscle Hypotonia], Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], metabolism [Proteins], isolation & purification [Proteins], physiology [Biological Transport], 3. Good health, Cell biology, Vesicular transport protein, pathology [Dwarfism], metabolism [Cilia], Muscle Hypotonia, ddc:500, pathology [Muscle Hypotonia], pathology [Spine], genetics [Dwarfism], Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], Science, Dwarfism, Exocyst, Biology, Article, General Biochemistry, Genetics and Molecular Biology, Physics and Astronomy (all), 03 medical and health sciences, Intraflagellar transport, Ciliogenesis, Organelle, Humans, Cilia, Biochemistry, Genetics and Molecular Biology (all), Proteins, Biological Transport, General Chemistry, therapy [Dwarfism], Fibroblasts, genetics [Proteins], Ciliopathies, Spine, methods [Protein Interaction Mapping], Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], 030104 developmental biology, Proteostasis, HEK293 Cells, methods [Proteomics]
Abstract

Cellular organelles provide opportunities to relate biological mechanisms to disease. Here we use affinity proteomics, genetics and cell biology to interrogate cilia: poorly understood organelles, where defects cause genetic diseases. Two hundred and seventeen tagged human ciliary proteins create a final landscape of 1,319 proteins, 4,905 interactions and 52 complexes. Reverse tagging, repetition of purifications and statistical analyses, produce a high-resolution network that reveals organelle-specific interactions and complexes not apparent in larger studies, and links vesicle transport, the cytoskeleton, signalling and ubiquitination to ciliary signalling and proteostasis. We observe sub-complexes in exocyst and intraflagellar transport complexes, which we validate biochemically, and by probing structurally predicted, disruptive, genetic variants from ciliary disease patients. The landscape suggests other genetic diseases could be ciliary including 3M syndrome. We show that 3M genes are involved in ciliogenesis, and that patient fibroblasts lack cilia. Overall, this organelle-specific targeting strategy shows considerable promise for Systems Medicine., Mutations in proteins that localize to primary cilia cause devastating diseases, yet the primary cilium is a poorly understood organelle. Here the authors use interaction proteomics to identify a network of human ciliary proteins that provides new insights into several biological processes and diseases.

Published
2016
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20. Corrigendum: Insights into cancer severity from biomolecular interaction mechanisms

Author

Raimondi, Francesco, Singh, Gurdeep, Betts, Matthew J., Apic, Gordana, Vukotic, Ranka, Andreone, Pietro, Stein, Lincoln, Russell, Robert B., Raimondi, F., Singh, G., Betts, M. J., Apic, G., Vukotic, R., Andreone, P., Stein, L., and Russell, R. B.

Subjects
Neoplasms, Mutation, Humans, Corrigenda, Models, Biological, Neoplasm Proteins
Abstract

To attain a deeper understanding of diseases like cancer, it is critical to couple genetics with biomolecular mechanisms. High-throughput sequencing has identified thousands of somatic mutations across dozens of cancers, and there is a pressing need to identify the few that are pathologically relevant. Here we use protein structure and interaction data to interrogate nonsynonymous somatic cancer mutations, identifying a set of 213 molecular interfaces (protein-protein, -small molecule or -nucleic acid) most often perturbed in cancer, highlighting several potentially novel cancer genes. Over half of these interfaces involve protein-small-molecule interactions highlighting their overall importance in cancer. We found distinct differences in the predominance of perturbed interfaces between cancers and histological subtypes and presence or absence of certain interfaces appears to correlate with cancer severity.

Published
2017

26. Mechismo: predicting the mechanistic impact of mutations and modifications on molecular interactions

Author

Betts, Matthew J., primary, Lu, Qianhao, additional, Jiang, YingYing, additional, Drusko, Armin, additional, Wichmann, Oliver, additional, Utz, Mathias, additional, Valtierra-Gutiérrez, Ilse A., additional, Schlesner, Matthias, additional, Jaeger, Natalie, additional, Jones, David T., additional, Pfister, Stefan, additional, Lichter, Peter, additional, Eils, Roland, additional, Siebert, Reiner, additional, Bork, Peer, additional, Apic, Gordana, additional, Gavin, Anne-Claude, additional, and Russell, Robert B., additional

Published
2014
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29. Toxicology Ontology Perspectives

Author

Hardy, Barry, Apic, Gordana, Carthew, Philip, Clark, Dominic, Cook, David, Dix, Ian, Escher, Sylvia, Hastings, Janna, Heard, David J, Jeliazkova, Nina, Judson, Philip, Matis-Mitchell, Sherri, Mitic, Dragana, Myatt, Glenn, Shah, Imran, Spjuth, Ola, Tcheremenskaia, Olga, Toldo, Luca, Watson, David, White, Andrew, Yang, Chihae, Hardy, Barry, Apic, Gordana, Carthew, Philip, Clark, Dominic, Cook, David, Dix, Ian, Escher, Sylvia, Hastings, Janna, Heard, David J, Jeliazkova, Nina, Judson, Philip, Matis-Mitchell, Sherri, Mitic, Dragana, Myatt, Glenn, Shah, Imran, Spjuth, Ola, Tcheremenskaia, Olga, Toldo, Luca, Watson, David, White, Andrew, and Yang, Chihae

Abstract

The field of predictive toxicology requires the development of open, public, computable, standardized toxicology vocabularies and ontologies to support the applications required by in silico, in vitro, and in vivo toxicology methods and related analysis and reporting activities. In this article we review ontology developments based on a set of perspectives showing how ontologies are being used in predictive toxicology initiatives and applications. Perspectives on resources and initiatives reviewed include OpenTox, eTOX, Pistoia Alliance, ToxWiz, Virtual Liver, EU-ADR, BEL, ToxML, and Bioclipse. We also review existing ontology developments in neighboring fields that can contribute to establishing an ontological framework for predictive toxicology. A significant set of resources is already available to provide a foundation for an ontological framework for 21st century mechanistic-based toxicology research. Ontologies such as ToxWiz provide a basis for application to toxicology investigations, whereas other ontologies under development in the biological, chemical, and biomedical communities could be incorporated in an extended future framework. OpenTox has provided a semantic web framework for the implementation of such ontologies into software applications and linked data resources. Bioclipse developers have shown the benefit of interoperability obtained through ontology by being able to link their workbench application with remote OpenTox web services. Although these developments are promising, an increased international coordination of efforts is greatly needed to develop a more unified, standardized, and open toxicology ontology framework.

Published
2012

30. Food for thought... : A toxicology ontology roadmap

Author

Harry, Barry, Apic, Gordana, Carthew, Philip, Clark, Dominic, Cook, David, Dix, Ian, Escher, Sylvia, Hastings, Janna, Heard, David J, Jeliazkova, Nina, Judson, Philip, Matis-Mitchell, Sherri, Mitic, Dragana, Myatt, Glenn, Shah, Imran, Spjuth, Ola, Tcheremenskaia, Olga, Toldo, Luca, Watson, David, White, Andrew, Yang, Chihae, Harry, Barry, Apic, Gordana, Carthew, Philip, Clark, Dominic, Cook, David, Dix, Ian, Escher, Sylvia, Hastings, Janna, Heard, David J, Jeliazkova, Nina, Judson, Philip, Matis-Mitchell, Sherri, Mitic, Dragana, Myatt, Glenn, Shah, Imran, Spjuth, Ola, Tcheremenskaia, Olga, Toldo, Luca, Watson, David, White, Andrew, and Yang, Chihae

Abstract

Foreign substances can have a dramatic and unpredictable adverse effect on human health. In the development of new therapeutic agents, it is essential that the potential adverse effects of all candidates be identified as early as possible. The field of predictive toxicology strives to profile the potential for adverse effects of novel chemical substances before they occur, both with traditional in vivo experimental approaches and increasingly through the development of in vitro and computational methods which can supplement and reduce the need for animal testing. To be maximally effective, the field needs access to the largest possible knowledge base of previous toxicology findings, and such results need to be made available in such a fashion so as to be interoperable, comparable, and compatible with standard toolkits. This necessitates the development of open, public, computable, and standardized toxicology vocabularies and ontologies so as to support the applications required by in silico, in vitro, and in vivo toxicology methods and related analysis and reporting activities. Such ontology development will support data management, model building, integrated analysis, validation and reporting, including regulatory reporting and alternative testing submission requirements as required by guidelines such as the REACH legislation, leading to new scientific advances in a mechanistically-based predictive toxicology. Numerous existing ontology and standards initiatives can contribute to the creation of a toxicology ontology supporting the needs of predictive toxicology and risk assessment. Additionally, new ontologies are needed to satisfy practical use cases and scenarios where gaps currently exist. Developing and integrating these resources will require a well-coordinated and sustained effort across numerous stakeholders engaged in a public-private partnership. In this communication, we set out a roadmap for the development of an integrated toxicology ontology, harnessi

Published
2012

36. Recurrent mutation of the ID3 gene in Burkitt lymphoma identified by integrated genome, exome and transcriptome sequencing.

Author

Richter, Julia, Schlesner, Matthias, Hoffmann, Steve, Kreuz, Markus, Leich, Ellen, Burkhardt, Birgit, Rosolowski, Maciej, Ammerpohl, Ole, Wagener, Rabea, Bernhart, Stephan H, Lenze, Dido, Szczepanowski, Monika, Paulsen, Maren, Lipinski, Simone, Russell, Robert B, Adam-Klages, Sabine, Apic, Gordana, Claviez, Alexander, Hasenclever, Dirk, and Hovestadt, Volker

Subjects
CANCER relapse, GENETIC mutation, BURKITT'S lymphoma, NUCLEOTIDE sequence, CYTOGENETICS, ONCOGENES, GENETIC regulation, IMMUNOGLOBULIN genes
Abstract

Burkitt lymphoma is a mature aggressive B-cell lymphoma derived from germinal center B cells. Its cytogenetic hallmark is the Burkitt translocation t(8;14)(q24;q32) and its variants, which juxtapose the MYC oncogene with one of the three immunoglobulin loci. Consequently, MYC is deregulated, resulting in massive perturbation of gene expression. Nevertheless, MYC deregulation alone seems not to be sufficient to drive Burkitt lymphomagenesis. By whole-genome, whole-exome and transcriptome sequencing of four prototypical Burkitt lymphomas with immunoglobulin gene (IG)-MYC translocation, we identified seven recurrently mutated genes. One of these genes, ID3, mapped to a region of focal homozygous loss in Burkitt lymphoma. In an extended cohort, 36 of 53 molecularly defined Burkitt lymphomas (68%) carried potentially damaging mutations of ID3. These were strongly enriched at somatic hypermutation motifs. Only 6 of 47 other B-cell lymphomas with the IG-MYC translocation (13%) carried ID3 mutations. These findings suggest that cooperation between ID3 inactivation and IG-MYC translocation is a hallmark of Burkitt lymphomagenesis. [ABSTRACT FROM AUTHOR]

Published
2012
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37. A Toxicology Ontology Roadmap.

Author

Hardy, Barry, Apic, Gordana, Carthew, Philip, Clark, Dominic, Cook, David, Dix, Ian, Escher, Sylvia, Hastings, Janna, Heard, David J., Jeliazkova, Nina, Judson, Philip, Matis-Mitchell, Sherri, Mitic, Dragana, Myatt, Glenn, Shah, Imran, Spjuth, Ola, Tcheremenskaia, Olga, Toldo, Luca, Watson, David, and White, Andrew

Abstract

Foreign substances can have a dramatic and unpredictable adverse effect on human health. In the development of new therapeutic agents, it is essential that the potential adverse effects of all candidates be identified as early as possible. The field of predictive toxicology strives to profile the potential for adverse effects of novel chemical substances before they occur, both with traditional in vivo experimental approaches and increasingly through the development of in vitro and computational methods which can supplement and reduce the need for animal testing. To be maximally effective, the field needs access to the largest possible knowledge base of previous toxicology findings, and such results need to be made available in such a fashion so as to be interoperable, comparable, and compatible with standard toolkits. This necessitates the development of open, public, computable, and standardized toxicology vocabularies and ontologies so as to support the applications required by in silico, in vitro, and in vivo toxicology methods and related analysis and reporting activities. Such ontology development will support data management, model building, integrated analysis, validation and reporting, including regulatory reporting and alternative testing submission requirements as required by guidelines such as the REACH legislation, leading to new scientific advances in a mechanistically-based predictive toxicology. Numerous existing ontology and standards initiatives can contribute to the creation of a toxicology ontology supporting the needs of predictive toxicology and risk assessment. Additionally, new ontologies are needed to satisfy practical use cases and scenarios where gaps currently exist. Developing and integrating these resources will require a well-coordinated and sustained effort across numerous stakeholders engaged in a public-private partnership. In this communication, we set out a roadmap for the development of an integrated toxicology ontology, harnessing existing resources where applicable. We describe the stakeholders' requirements analysis from the academic and industry perspectives, timelines, and expected benefits of this initiative, with a view to engagement with the wider community. [ABSTRACT FROM AUTHOR]

Published
2012
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38. Insights into cancer severity from biomolecular interaction mechanisms

Author

Matthew J. Betts, Pietro Andreone, Lincoln Stein, Robert B. Russell, Ranka Vukotic, Gordana Apic, Francesco Raimondi, Gurdeep Singh, Raimondi, F., Singh, G., Betts, M. J., Apic, G., Vukotic, R., Andreone, P., Stein, L., Russell, R. B., Raimondi, Francesco, Singh, Gurdeep, Betts, Matthew J., Apic, Gordana, Vukotic, Ranka, Andreone, Pietro, Stein, Lincoln, and Russell, Robert B.

Subjects
0301 basic medicine, Genetics, Nonsynonymous substitution, Mutation, Multidisciplinary, Somatic cell, Cancer, Biology, medicine.disease, medicine.disease_cause, Small molecule, Article, Protein–protein interaction, oncogenic proteins, protein interactions, genetic variations, 03 medical and health sciences, 030104 developmental biology, Protein structure, Cancer, oncogenic proteins, protein interactions, genetic variations, medicine, Cancer gene
Abstract

To attain a deeper understanding of diseases like cancer, it is critical to couple genetics with biomolecular mechanisms. High-throughput sequencing has identified thousands of somatic mutations across dozens of cancers, and there is a pressing need to identify the few that are pathologically relevant. Here we use protein structure and interaction data to interrogate nonsynonymous somatic cancer mutations, identifying a set of 213 molecular interfaces (protein-protein, -small molecule or –nucleic acid) most often perturbed in cancer, highlighting several potentially novel cancer genes. Over half of these interfaces involve protein-small-molecule interactions highlighting their overall importance in cancer. We found distinct differences in the predominance of perturbed interfaces between cancers and histological subtypes and presence or absence of certain interfaces appears to correlate with cancer severity.

Published
2016

39. Focal structural variants revealed by whole genome sequencing disrupt the histone demethylase KDM4C in B-cell lymphomas.

Author

Lopez C, Schleussner N, Bernhart SH, Kleinheinz K, Sungalee S, Sczakiel HL, Kretzmer H, Toprak UH, Glaser S, Wagener R, Ammerpohl O, Bens S, Giefing M, Sanchez JCG, Apic G, Hubschmann D, Janz M, Kreuz M, Mottok A, Muller JM, Seufert J, Hoffmann S, Korbel JO, Russell RB, Schule R, Trumper L, Klapper W, Radlwimmer B, Lichter P, Kuppers R, Schlesner M, Mathas S, and Siebert R

Subjects
Humans, Histones metabolism, Histone Demethylases genetics, Homozygote, Sequence Deletion, Whole Genome Sequencing, RNA, Jumonji Domain-Containing Histone Demethylases genetics, Jumonji Domain-Containing Histone Demethylases chemistry, Jumonji Domain-Containing Histone Demethylases metabolism, Histone-Lysine N-Methyltransferase genetics, Lymphoma genetics, Lymphoma, B-Cell genetics
Abstract

Histone methylation-modifiers, such as EZH2 and KMT2D, are recurrently altered in B-cell lymphomas. To comprehensively describe the landscape of alterations affecting genes encoding histone methylation-modifiers in lymphomagenesis we investigated whole genome and transcriptome data of 186 mature B-cell lymphomas sequenced in the ICGC MMML-Seq project. Besides confirming common alterations of KMT2D (47% of cases), EZH2 (17%), SETD1B (5%), PRDM9 (4%), KMT2C (4%), and SETD2 (4%), also identified by prior exome or RNA-sequencing studies, we here found recurrent alterations to KDM4C in chromosome 9p24, encoding a histone demethylase. Focal structural variation was the main mechanism of KDM4C alterations, and was independent from 9p24 amplification. We also identified KDM4C alterations in lymphoma cell lines including a focal homozygous deletion in a classical Hodgkin lymphoma cell line. By integrating RNA-sequencing and genome sequencing data we predict that KDM4C structural variants result in loss-offunction. By functional reconstitution studies in cell lines, we provide evidence that KDM4C can act as a tumor suppressor. Thus, we show that identification of structural variants in whole genome sequencing data adds to the comprehensive description of the mutational landscape of lymphomas and, moreover, establish KDM4C as a putative tumor suppressive gene recurrently altered in subsets of B-cell derived lymphomas.

Published
2023
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40. Toxicology ontology perspectives.

Author

Hardy B, Apic G, Carthew P, Clark D, Cook D, Dix I, Escher S, Hastings J, Heard DJ, Jeliazkova N, Judson P, Matis-Mitchell S, Mitic D, Myatt G, Shah I, Spjuth O, Tcheremenskaia O, Toldo L, Watson D, White A, and Yang C

Subjects
Animals, Databases, Factual, Gene Expression Regulation drug effects, Humans, Toxicology methods, Vocabulary, Controlled
Abstract

The field of predictive toxicology requires the development of open, public, computable, standardized toxicology vocabularies and ontologies to support the applications required by in silico, in vitro, and in vivo toxicology methods and related analysis and reporting activities. In this article we review ontology developments based on a set of perspectives showing how ontologies are being used in predictive toxicology initiatives and applications. Perspectives on resources and initiatives reviewed include OpenTox, eTOX, Pistoia Alliance, ToxWiz, Virtual Liver, EU-ADR, BEL, ToxML, and Bioclipse. We also review existing ontology developments in neighboring fields that can contribute to establishing an ontological framework for predictive toxicology. A significant set of resources is already available to provide a foundation for an ontological framework for 21st century mechanistic-based toxicology research. Ontologies such as ToxWiz provide a basis for application to toxicology investigations, whereas other ontologies under development in the biological, chemical, and biomedical communities could be incorporated in an extended future framework. OpenTox has provided a semantic web framework for the implementation of such ontologies into software applications and linked data resources. Bioclipse developers have shown the benefit of interoperability obtained through ontology by being able to link their workbench application with remote OpenTox web services. Although these developments are promising, an increased international coordination of efforts is greatly needed to develop a more unified, standardized, and open toxicology ontology framework.

Published
2012
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