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3. Community assessment to advance computational prediction of cancer drug combinations in a pharmacogenomic screen

Author

Menden M, Wang D, Mason M, Szalai B, Bulusu K, Guan Y, Yu T, Kang J, Jeon M, Wolfinger R, Nguyen T, Zaslavskiy M, Jang I, Ghazoui Z, Ahsen M, Vogel R, Neto E, Norman T, Tang E, Garnett M, Di Veroli G, Fawell S, Stolovitzky G, Guinney J, Dry J, Saez-Rodriguez J, Abante J, Abecassis B, Aben N, Aghamirzaie D, Aittokallio T, Akhtari F, Al-lazikani B, Alam T, Allam A, Allen C, de Almeida M, Altarawy D, Alves V, Amadoz A, Anchang B, Antolin A, Ash J, Aznar V, Ba-alawi W, Bagheri M, Bajic V, Ball G, Ballester P, Baptista D, Bare C, Bateson M, Bender A, Bertrand D, Wijayawardena B, Boroevich K, Bosdriesz E, Bougouffa S, Bounova G, Brouwer T, Bryant B, Calaza M, Calderone A, Calza S, Capuzzi S, Carbonell-Caballero J, Carlin D, Carter H, Castagnoli L, Celebi R, Cesareni G, Chang H, Chen G, Chen H, Cheng L, Chernomoretz A, Chicco D, Cho K, Cho S, Choi D, Choi J, Choi K, Choi M, De Cock M, Coker E, Cortes-Ciriano I, Cserzo M, Cubuk C, Curtis C, Van Daele D, Dang C, Dijkstra T, Dopazo J, Draghici S, Drosou A, Dumontier M, Ehrhart F, Eid F, ElHefnawi M, Elmarakeby H, van Engelen B, Engin H, de Esch I, Evelo C, Falcao A, Farag S, Fernandez-Lozano C, Fisch K, Flobak A, Fornari C, Foroushani A, Fotso D, Fourches D, Friend S, Frigessi A, Gao F, Gao X, Gerold J, Gestraud P, Ghosh S, Gillberg J, Godoy-Lorite A, Godynyuk L, Godzik A, Goldenberg A, Gomez-Cabrero D, Gonen M, de Graaf C, Gray H, Grechkin M, Guimera R, Guney E, Haibe-Kains B, Han Y, Hase T, He D, He L, Heath L, Hellton K, Helmer-Citterich M, Hidalgo M, Hidru D, Hill S, Hochreiter S, Hong S, Hovig E, Hsueh Y, Hu Z, Huang J, Huang R, Hunyady L, Hwang J, Hwang T, Hwang W, Hwang Y, Isayev O, Walk O, Jack J, Jahandideh S, Ji J, Jo Y, Kamola P, Kanev G, Karacosta L, Karimi M, Kaski S, Kazanov M, Khamis A, Khan S, Kiani N, Kim A, Kim J, Kim K, Kim S, Kim Y, Kirk P, Kitano H, Klambauer G, Knowles D, Ko M, Kohn-Luque A, Kooistra A, Kuenemann M, Kuiper M, Kurz C, Kwon M, van Laarhoven T, Laegreid A, Lederer S, Lee H, Lee J, Lee Y, Leppaho E, Lewis R, Li J, Li L, Liley J, Lim W, Lin C, Liu Y, Lopez Y, Low J, Lysenko A, Machado D, Madhukar N, De Maeyer D, Malpartida A, Mamitsuka H, Marabita F, Marchal K, Marttinen P, Mason D, Mazaheri A, Mehmood A, Mehreen A, Michaut M, Miller R, Mitsopoulos C, Modos D, Van Moerbeke M, Moo K, Motsinger-Reif A, Movva R, Muraru S, Muratov E, Mushthofa M, Nagarajan N, Nakken S, Nath A, Neuvial P, Newton R, Ning Z, De Niz C, Oliva B, Olsen C, Palmeri A, Panesar B, Papadopoulos S, Park J, Park S, Pawitan Y, Peluso D, Pendyala S, Peng J, Perfetto L, Pirro S, Plevritis S, Politi R, Poon H, Porta E, Prellner I, Preuer K, Pujana M, Ramnarine R, Reid J, Reyal F, Richardson S, Ricketts C, Rieswijk L, Rocha M, Rodriguez-Gonzalvez C, Roell K, Rotroff D, de Ruiter J, Rukawa P, Sadacca B, Safikhani Z, Safitri F, Sales-Pardo M, Sauer S, Schlichting M, Seoane J, Serra J, Shang M, Sharma A, Sharma H, Shen Y, Shiga M, Shin M, Shkedy Z, Shopsowitz K, Sinai S, Skola D, Smirnov P, Soerensen I, Soerensen P, Song J, Song S, Soufan O, Spitzmueller A, Steipe B, Suphavilai C, Tamayo S, Tamborero D, Tang J, Tanoli Z, Tarres-Deulofeu M, Tegner J, Thommesen L, Tonekaboni S, Tran H, De Troyer E, Truong A, Tsunoda T, Turu G, Tzeng G, Verbeke L, Videla S, Vis D, Voronkov A, Votis K, Wang A, Wang H, Wang P, Wang S, Wang W, Wang X, Wennerberg K, Wernisch L, Wessels L, van Westen G, Westerman B, White S, Willighagen E, Wurdinger T, Xie L, Xie S, Xu H, Yadav B, Yau C, Yeerna H, Yin J, Yu M, Yun S, Zakharov A, Zamichos A, Zanin M, Zeng L, Zenil H, Zhang F, Zhang P, Zhang W, Zhao H, Zhao L, Zheng W, Zoufir A, Zucknick M, AstraZeneca-Sanger Drug Combinatio, Ege Üniversitesi, Gönen, Mehmet (ORCID 0000-0002-2483-075X & YÖK ID 237468), Menden, Michael P., Wang, Dennis, Mason, Mike J., Szalai, Bence, Bulusu, Krishna C., Guan, Yuanfang, Yu, Thomas, Kang, Jaewoo, Jeon, Minji, Wolfinger, Russ, Nguyen, Tin, Zaslavskiy, Mikhail, Jang, In Sock, Ghazoui, Zara, Ahsen, Mehmet Eren, Vogel, Robert, Neto, Elias Chaibub, Norman, Thea, Tang, Eric K. Y., Garnett, Mathew J., Di Veroli, Giovanni Y., Fawell, Stephen, Stolovitzky, Gustavo, Guinney, Justin, Dry, Jonathan R., Saez-Rodriguez, Julio, Abante, Jordi, Abecassis, Barbara Schmitz, Aben, Nanne, Aghamirzaie, Delasa, Aittokallio, Tero, Akhtari, Farida S., Al-lazikani, Bissan, Alam, Tanvir, Allam, Amin, Allen, Chad, de Almeida, Mariana Pelicano, Altarawy, Doaa, Alves, Vinicius, Amadoz, Alicia, Anchang, Benedict, Antolin, Albert A., Ash, Jeremy R., Romeo Aznar, Victoria, Ba-alawi, Wail, Bagheri, Moeen, Bajic, Vladimir, Ball, Gordon, Ballester, Pedro J., Baptista, Delora, Bare, Christopher, Bateson, Mathilde, Bender, Andreas, Bertrand, Denis, Wijayawardena, Bhagya, Boroevich, Keith A., Bosdriesz, Evert, Bougouffa, Salim, Bounova, Gergana, Brouwer, Thomas, Bryant, Barbara, Calaza, Manuel, Calderone, Alberto, Calza, Stefano, Capuzzi, Stephen, Carbonell-Caballero, Jose, Carlin, Daniel, Carter, Hannah, Castagnoli, Luisa, Celebi, Remzi, Cesareni, Gianni, Chang, Hyeokyoon, Chen, Guocai, Chen, Haoran, Chen, Huiyuan, Cheng, Lijun, Chernomoretz, Ariel, Chicco, Davide, Cho, Kwang-Hyun, Cho, Sunghwan, Choi, Daeseon, Choi, Jaejoon, Choi, Kwanghun, Choi, Minsoo, De Cock, Martine, Coker, Elizabeth, Cortes-Ciriano, Isidro, Cserzo, Miklos, Cubuk, Cankut, Curtis, Christina, Van Daele, Dries, Dang, Cuong C., Dijkstra, Tjeerd, Dopazo, Joaquin, Draghici, Sorin, Drosou, Anastasios, Dumontier, Michel, Ehrhart, Friederike, Eid, Fatma-Elzahraa, ElHefnawi, Mahmoud, Elmarakeby, Haitham, van Engelen, Bo, Engin, Hatice Billur, de Esch, Iwan, Evelo, Chris, Falcao, Andre O., Farag, Sherif, Fernandez-Lozano, Carlos, Fisch, Kathleen, Flobak, Asmund, Fornari, Chiara, Foroushani, Amir B. K., Fotso, Donatien Chedom, Fourches, Denis, Friend, Stephen, Frigessi, Arnoldo, Gao, Feng, Gao, Xiaoting, Gerold, Jeffrey M., Gestraud, Pierre, Ghosh, Samik, Gillberg, Jussi, Godoy-Lorite, Antonia, Godynyuk, Lizzy, Godzik, Adam, Goldenberg, Anna, Gomez-Cabrero, David, de Graaf, Chris, Gray, Harry, Grechkin, Maxim, Guimera, Roger, Guney, Emre, Haibe-Kains, Benjamin, Han, Younghyun, Hase, Takeshi, He, Di, He, Liye, Heath, Lenwood S., Hellton, Kristoffer H., Helmer-Citterich, Manuela, Hidalgo, Marta R., Hidru, Daniel, Hill, Steven M., Hochreiter, Sepp, Hong, Seungpyo, Hovig, Eivind, Hsueh, Ya-Chih, Hu, Zhiyuan, Huang, Justin K., Huang, R. Stephanie, Hunyady, Laszlo, Hwang, Jinseub, Hwang, Tae Hyun, Hwang, Woochang, Hwang, Yongdeuk, Isayev, Olexandr, Walk, Oliver Bear Don't, Jack, John, Jahandideh, Samad, Ji, Jiadong, Jo, Yousang, Kamola, Piotr J., Kanev, Georgi K., Karacosta, Loukia, Karimi, Mostafa, Kaski, Samuel, Kazanov, Marat, Khamis, Abdullah M., Khan, Suleiman Ali, Kiani, Narsis A., Kim, Allen, Kim, Jinhan, Kim, Juntae, Kim, Kiseong, Kim, Kyung, Kim, Sunkyu, Kim, Yongsoo, Kim, Yunseong, Kirk, Paul D. W., Kitano, Hiroaki, Klambauer, Gunter, Knowles, David, Ko, Melissa, Kohn-Luque, Alvaro, Kooistra, Albert J., Kuenemann, Melaine A., Kuiper, Martin, Kurz, Christoph, Kwon, Mijin, van Laarhoven, Twan, Laegreid, Astrid, Lederer, Simone, Lee, Heewon, Lee, Jeon, Lee, Yun Woo, Leppaho, Eemeli, Lewis, Richard, Li, Jing, Li, Lang, Liley, James, Lim, Weng Khong, Lin, Chieh, Liu, Yiyi, Lopez, Yosvany, Low, Joshua, Lysenko, Artem, Machado, Daniel, Madhukar, Neel, De Maeyer, Dries, Malpartida, Ana Belen, Mamitsuka, Hiroshi, Marabita, Francesco, Marchal, Kathleen, Marttinen, Pekka, Mason, Daniel, Mazaheri, Alireza, Mehmood, Arfa, Mehreen, Ali, Michaut, Magali, Miller, Ryan A., Mitsopoulos, Costas, Modos, Dezso, Van Moerbeke, Marijke, Moo, Keagan, Motsinger-Reif, Alison, Movva, Rajiv, Muraru, Sebastian, Muratov, Eugene, Mushthofa, Mushthofa, Nagarajan, Niranjan, Nakken, Sigve, Nath, Aritro, Neuvial, Pierre, Newton, Richard, Ning, Zheng, De Niz, Carlos, Oliva, Baldo, Olsen, Catharina, Palmeri, Antonio, Panesar, Bhawan, Papadopoulos, Stavros, Park, Jaesub, Park, Seonyeong, Park, Sungjoon, Pawitan, Yudi, Peluso, Daniele, Pendyala, Sriram, Peng, Jian, Perfetto, Livia, Pirro, Stefano, Plevritis, Sylvia, Politi, Regina, Poon, Hoifung, Porta, Eduard, Prellner, Isak, Preuer, Kristina, Angel Pujana, Miguel, Ramnarine, Ricardo, Reid, John E., Reyal, Fabien, Richardson, Sylvia, Ricketts, Camir, Rieswijk, Linda, Rocha, Miguel, Rodriguez-Gonzalvez, Carmen, Roell, Kyle, Rotroff, Daniel, de Ruiter, Julian R., Rukawa, Ploy, Sadacca, Benjamin, Safikhani, Zhaleh, Safitri, Fita, Sales-Pardo, Marta, Sauer, Sebastian, Schlichting, Moritz, Seoane, Jose A., Serra, Jordi, Shang, Ming-Mei, Sharma, Alok, Sharma, Hari, Shen, Yang, Shiga, Motoki, Shin, Moonshik, Shkedy, Ziv, Shopsowitz, Kevin, Sinai, Sam, Skola, Dylan, Smirnov, Petr, Soerensen, Izel Fourie, Soerensen, Peter, Song, Je-Hoon, Song, Sang Ok, Soufan, Othman, Spitzmueller, Andreas, Steipe, Boris, Suphavilai, Chayaporn, Tamayo, Sergio Pulido, Tamborero, David, Tang, Jing, Tanoli, Zia-ur-Rehman, Tarres-Deulofeu, Marc, Tegner, Jesper, Thommesen, Liv, Tonekaboni, Seyed Ali Madani, Tran, Hong, De Troyer, Ewoud, Truong, Amy, Tsunoda, Tatsuhiko, Turu, Gabor, Tzeng, Guang-Yo, Verbeke, Lieven, Videla, Santiago, Vis, Daniel, Voronkov, Andrey, Votis, Konstantinos, Wang, Ashley, Wang, Hong-Qiang Horace, Wang, Po-Wei, Wang, Sheng, Wang, Wei, Wang, Xiaochen, Wang, Xin, Wennerberg, Krister, Wernisch, Lorenz, Wessels, Lodewyk, van Westen, Gerard J. P., Westerman, Bart A., White, Simon Richard, Willighagen, Egon, Wurdinger, Tom, Xie, Lei, Xie, Shuilian, Xu, Hua, Yadav, Bhagwan, Yau, Christopher, Yeerna, Huwate, Yin, Jia Wei, Yu, Michael, Yu, MinHwan, Yun, So Jeong, Zakharov, Alexey, Zamichos, Alexandros, Zanin, Massimiliano, Zeng, Li, Zenil, Hector, Zhang, Frederick, Zhang, Pengyue, Zhang, Wei, Zhao, Hongyu, Zhao, Lan, Zheng, Wenjin, Zoufir, Azedine, Zucknick, Manuela, College of Engineering, Department of Industrial Engineering, Institute of Data Science, RS: FSE DACS IDS, Bioinformatica, RS: NUTRIM - R1 - Obesity, diabetes and cardiovascular health, RS: FHML MaCSBio, Promovendi NTM, Tero Aittokallio / Principal Investigator, Bioinformatics, Institute for Molecular Medicine Finland, Hu, Z, Fotso, DC, Menden, M, Wang, D, Mason, M, Szalai, B, Bulusu, K, Guan, Y, Yu, T, Kang, J, Jeon, M, Wolfinger, R, Nguyen, T, Zaslavskiy, M, Abante, J, Abecassis, B, Aben, N, Aghamirzaie, D, Aittokallio, T, Akhtari, F, Al-lazikani, B, Alam, T, Allam, A, Allen, C, de Almeida, M, Altarawy, D, Alves, V, Amadoz, A, Anchang, B, Antolin, A, Ash, J, Aznar, V, Ba-alawi, W, Bagheri, M, Bajic, V, Ball, G, Ballester, P, Baptista, D, Bare, C, Bateson, M, Bender, A, Bertrand, D, Wijayawardena, B, Boroevich, K, Bosdriesz, E, Bougouffa, S, Bounova, G, Brouwer, T, Bryant, B, Calaza, M, Calderone, A, Calza, S, Capuzzi, S, Carbonell-Caballero, J, Carlin, D, Carter, H, Castagnoli, L, Celebi, R, Cesareni, G, Chang, H, Chen, G, Chen, H, Cheng, L, Chernomoretz, A, Chicco, D, Cho, K, Cho, S, Choi, D, Choi, J, Choi, K, Choi, M, Cock, M, Coker, E, Cortes-Ciriano, I, Cserzo, M, Cubuk, C, Curtis, C, Daele, D, Dang, C, Dijkstra, T, Dopazo, J, Draghici, S, Drosou, A, Dumontier, M, Ehrhart, F, Eid, F, Elhefnawi, M, Elmarakeby, H, van Engelen, B, Engin, H, de Esch, I, Evelo, C, Falcao, A, Farag, S, Fernandez-Lozano, C, Fisch, K, Flobak, A, Fornari, C, Foroushani, A, Fotso, D, Fourches, D, Friend, S, Frigessi, A, Gao, F, Gao, X, Gerold, J, Gestraud, P, Ghosh, S, Gillberg, J, Godoy-Lorite, A, Godynyuk, L, Godzik, A, Goldenberg, A, Gomez-Cabrero, D, Gonen, M, de Graaf, C, Gray, H, Grechkin, M, Guimera, R, Guney, E, Haibe-Kains, B, Han, Y, Hase, T, He, D, He, L, Heath, L, Hellton, K, Helmer-Citterich, M, Hidalgo, M, Hidru, D, Hill, S, Hochreiter, S, Hong, S, Hovig, E, Hsueh, Y, Huang, J, Huang, R, Hunyady, L, Hwang, J, Hwang, T, Hwang, W, Hwang, Y, Isayev, O, Don't Walk, O, Jack, J, Jahandideh, S, Ji, J, Jo, Y, Kamola, P, Kanev, G, Karacosta, L, Karimi, M, Kaski, S, Kazanov, M, Khamis, A, Khan, S, Kiani, N, Kim, A, Kim, J, Kim, K, Kim, S, Kim, Y, Kirk, P, Kitano, H, Klambauer, G, Knowles, D, Ko, M, Kohn-Luque, A, Kooistra, A, Kuenemann, M, Kuiper, M, Kurz, C, Kwon, M, van Laarhoven, T, Laegreid, A, Lederer, S, Lee, H, Lee, J, Lee, Y, Lepp_aho, E, Lewis, R, Li, J, Li, L, Liley, J, Lim, W, Lin, C, Liu, Y, Lopez, Y, Low, J, Lysenko, A, Machado, D, Madhukar, N, Maeyer, D, Malpartida, A, Mamitsuka, H, Marabita, F, Marchal, K, Marttinen, P, Mason, D, Mazaheri, A, Mehmood, A, Mehreen, A, Michaut, M, Miller, R, Mitsopoulos, C, Modos, D, Moerbeke, M, Moo, K, Motsinger-Reif, A, Movva, R, Muraru, S, Muratov, E, Mushthofa, M, Nagarajan, N, Nakken, S, Nath, A, Neuvial, P, Newton, R, Ning, Z, Niz, C, Oliva, B, Olsen, C, Palmeri, A, Panesar, B, Papadopoulos, S, Park, J, Park, S, Pawitan, Y, Peluso, D, Pendyala, S, Peng, J, Perfetto, L, Pirro, S, Plevritis, S, Politi, R, Poon, H, Porta, E, Prellner, I, Preuer, K, Pujana, M, Ramnarine, R, Reid, J, Reyal, F, Richardson, S, Ricketts, C, Rieswijk, L, Rocha, M, Rodriguez-Gonzalvez, C, Roell, K, Rotroff, D, de Ruiter, J, Rukawa, P, Sadacca, B, Safikhani, Z, Safitri, F, Sales-Pardo, M, Sauer, S, Schlichting, M, Seoane, J, Serra, J, Shang, M, Sharma, A, Sharma, H, Shen, Y, Shiga, M, Shin, M, Shkedy, Z, Shopsowitz, K, Sinai, S, Skola, D, Smirnov, P, Soerensen, I, Soerensen, P, Song, J, Song, S, Soufan, O, Spitzmueller, A, Steipe, B, Suphavilai, C, Tamayo, S, Tamborero, D, Tang, J, Tanoli, Z, Tarres-Deulofeu, M, Tegner, J, Thommesen, L, Tonekaboni, S, Tran, H, Troyer, E, Truong, A, Tsunoda, T, Turu, G, Tzeng, G, Verbeke, L, Videla, S, Vis, D, Voronkov, A, Votis, K, Wang, A, Wang, H, Wang, P, Wang, S, Wang, W, Wang, X, Wennerberg, K, Wernisch, L, Wessels, L, van Westen, G, Westerman, B, White, S, Willighagen, E, Wurdinger, T, Xie, L, Xie, S, Xu, H, Yadav, B, Yau, C, Yeerna, H, Yin, J, Yu, M, Yun, S, Zakharov, A, Zamichos, A, Zanin, M, Zeng, L, Zenil, H, Zhang, F, Zhang, P, Zhang, W, Zhao, H, Zhao, L, Zheng, W, Zoufir, A, Zucknick, M, Jang, I, Ghazoui, Z, Ahsen, M, Vogel, R, Neto, E, Norman, T, Tang, E, Garnett, M, Veroli, G, Fawell, S, Stolovitzky, G, Guinney, J, Dry, J, Saez-Rodriguez, J, Menden, Michael P. [0000-0003-0267-5792], Mason, Mike J. [0000-0002-5652-7739], Yu, Thomas [0000-0002-5841-0198], Kang, Jaewoo [0000-0001-6798-9106], Nguyen, Tin [0000-0001-8001-9470], Ahsen, Mehmet Eren [0000-0002-4907-0427], Stolovitzky, Gustavo [0000-0002-9618-2819], Guinney, Justin [0000-0003-1477-1888], Saez-Rodriguez, Julio [0000-0002-8552-8976], Apollo - University of Cambridge Repository, Menden, Michael P [0000-0003-0267-5792], Mason, Mike J [0000-0002-5652-7739], Pathology, CCA - Cancer biology and immunology, Medical oncology laboratory, Neurosurgery, Chemistry and Pharmaceutical Sciences, AIMMS, Medicinal chemistry, Universidade do Minho, Department of Computer Science, Professorship Marttinen P., Aalto-yliopisto, and Aalto University

Subjects
Drug Resistance, 02 engineering and technology, 13, PATHWAY, Antineoplastic Combined Chemotherapy Protocols, Molecular Targeted Therapy, Càncer, lcsh:Science, media_common, Cancer, Tumor, Settore BIO/18, Settore BIO/11, Drug combinations, High-throughput screening, Drug Synergism, purl.org/becyt/ford/1.2 [https], Genomics, Machine Learning, predictions, 3. Good health, ddc, Technologie de l'environnement, contrôle de la pollution, Benchmarking, 5.1 Pharmaceuticals, Cancer treatment, Farmacogenètica, Science & Technology - Other Topics, Development of treatments and therapeutic interventions, 0210 nano-technology, Human, Drug, media_common.quotation_subject, Science, 49/23, ADAM17 Protein, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, SDG 3 - Good Health and Well-being, RESOURCE, Machine learning, Genetics, Chimie, Humans, BREAST-CANCER, CELL, 49/98, Science & Technology, Antineoplastic Combined Chemotherapy Protocol, 45, MUTATIONS, Computational Biology, Androgen receptor, Breast-cancer, Gene, Cell, Inhibition, Resistance, Pathway, Mutations, Landscape, Resource, 631/114/1305, medicine.disease, Drug synergy, 49, 030104 developmental biology, Pharmacogenetics, Mutation, Ciências Médicas::Biotecnologia Médica, lcsh:Q, 631/154/1435/2163, Biomarkers, RESISTANCE, 0301 basic medicine, ING-INF/06 - BIOINGEGNERIA ELETTRONICA E INFORMATICA, Statistical methods, Computer science, General Physics and Astronomy, Datasets as Topic, Drug resistance, purl.org/becyt/ford/1 [https], Phosphatidylinositol 3-Kinases, Biotecnologia Médica [Ciências Médicas], Neoplasms, Science and technology, Phosphoinositide-3 Kinase Inhibitors, Multidisciplinary, Biomarkers, Tumor, Cell Line, Tumor, Drug Antagonism, Drug Resistance, Neoplasm, Treatment Outcome, Pharmacogenetic, article, ANDROGEN RECEPTOR, 49/39, 631/114/2415, 021001 nanoscience & nanotechnology, 692/4028/67, Multidisciplinary Sciences, 317 Pharmacy, Patient Safety, Systems biology, 3122 Cancers, INHIBITION, Computational biology, Cell Line, medicine, LANDSCAPE, Physique, Human Genome, Data Science, General Chemistry, AstraZeneca-Sanger Drug Combination DREAM Consortium, Astronomie, GENE, Good Health and Well Being, Pharmacogenomics, Genomic, Neoplasm, 631/553, Phosphatidylinositol 3-Kinase
Abstract

PubMed: 31209238, The effectiveness of most cancer targeted therapies is short-lived. Tumors often develop resistance that might be overcome with drug combinations. However, the number of possible combinations is vast, necessitating data-driven approaches to find optimal patient-specific treatments. Here we report AstraZeneca’s large drug combination dataset, consisting of 11,576 experiments from 910 combinations across 85 molecularly characterized cancer cell lines, and results of a DREAM Challenge to evaluate computational strategies for predicting synergistic drug pairs and biomarkers. 160 teams participated to provide a comprehensive methodological development and benchmarking. Winning methods incorporate prior knowledge of drug-target interactions. Synergy is predicted with an accuracy matching biological replicates for >60% of combinations. However, 20% of drug combinations are poorly predicted by all methods. Genomic rationale for synergy predictions are identified, including ADAM17 inhibitor antagonism when combined with PIK3CB/D inhibition contrasting to synergy when combined with other PI3K-pathway inhibitors in PIK3CA mutant cells. © 2019, The Author(s)., National Institute for Health Research, NIHR Wellcome Trust, WT: 102696, 206194 Magyar Tudományos Akadémia, MTA Bayer 668858 PrECISE AstraZeneca, We thank the Genomics of Drug Sensitivity in Cancer and COSMIC teams at the Wellcome Trust Sanger Institute for help with the preparation of the molecular data, Denes Turei for help with Omnipath, and Katjusa Koler for help with matching drug names across combination screens. We thank AstraZeneca for funding and provision of data to the DREAM Consortium to run the challenge, and funding from the European Union Horizon 2020 research (under grant agreement No 668858 PrECISE to J.S.R.), the Joint Research Center for Computational Biomedicine (which is partially funded by Bayer AG) to J.S.R., National Institute for Health Research (NIHR) Sheffield Biomedical Research Center, Premium Postdoctoral Fellowship Program of the Hungarian Academy of Sciences. M.G lab is supported by Wellcome Trust (102696 and 206194)., Competing interests: K.C.B., Z.G., G.Y.D., E.K.Y.T., S.F., and J.R.D. are AstraZeneca employees. K.C.B., Z.G., E.K.Y.T., S.F., and J.R.D. are AstraZeneca shareholders. Y.G. receives personal compensation from Eli Lilly and Company, is a shareholder of Cleerly, Inc., and Ann Arbor Algorithms, Inc. M.G. receives research funding from AstraZeneca and has performed consultancy for Sanofi. The remaining authors declare no competing interests.

Published
2019

5. Community assessment to advance computational prediction of cancer drug combinations in a pharmacogenomic screen

Author

Menden, M, Wang, D, Mason, M, Szalai, B, Bulusu, K, Guan, Y, Yu, T, Kang, J, Jeon, M, Wolfinger, R, Nguyen, T, Zaslavskiy, M, Abante, J, Abecassis, B, Aben, N, Aghamirzaie, D, Aittokallio, T, Akhtari, F, Al-lazikani, B, Alam, T, Allam, A, Allen, C, de Almeida, M, Altarawy, D, Alves, V, Amadoz, A, Anchang, B, Antolin, A, Ash, J, Aznar, V, Ba-alawi, W, Bagheri, M, Bajic, V, Ball, G, Ballester, P, Baptista, D, Bare, C, Bateson, M, Bender, A, Bertrand, D, Wijayawardena, B, Boroevich, K, Bosdriesz, E, Bougouffa, S, Bounova, G, Brouwer, T, Bryant, B, Calaza, M, Calderone, A, Calza, S, Capuzzi, S, Carbonell-Caballero, J, Carlin, D, Carter, H, Castagnoli, L, Celebi, R, Cesareni, G, Chang, H, Chen, G, Chen, H, Cheng, L, Chernomoretz, A, Chicco, D, Cho, K, Cho, S, Choi, D, Choi, J, Choi, K, Choi, M, Cock, M, Coker, E, Cortes-Ciriano, I, Cserzo, M, Cubuk, C, Curtis, C, Daele, D, Dang, C, Dijkstra, T, Dopazo, J, Draghici, S, Drosou, A, Dumontier, M, Ehrhart, F, Eid, F, Elhefnawi, M, Elmarakeby, H, van Engelen, B, Engin, H, de Esch, I, Evelo, C, Falcao, A, Farag, S, Fernandez-Lozano, C, Fisch, K, Flobak, A, Fornari, C, Foroushani, A, Fotso, D, Fourches, D, Friend, S, Frigessi, A, Gao, F, Gao, X, Gerold, J, Gestraud, P, Ghosh, S, Gillberg, J, Godoy-Lorite, A, Godynyuk, L, Godzik, A, Goldenberg, A, Gomez-Cabrero, D, Gonen, M, de Graaf, C, Gray, H, Grechkin, M, Guimera, R, Guney, E, Haibe-Kains, B, Han, Y, Hase, T, He, D, He, L, Heath, L, Hellton, K, Helmer-Citterich, M, Hidalgo, M, Hidru, D, Hill, S, Hochreiter, S, Hong, S, Hovig, E, Hsueh, Y, Hu, Z, Huang, J, Huang, R, Hunyady, L, Hwang, J, Hwang, T, Hwang, W, Hwang, Y, Isayev, O, Don't Walk, O, Jack, J, Jahandideh, S, Ji, J, Jo, Y, Kamola, P, Kanev, G, Karacosta, L, Karimi, M, Kaski, S, Kazanov, M, Khamis, A, Khan, S, Kiani, N, Kim, A, Kim, J, Kim, K, Kim, S, Kim, Y, Kirk, P, Kitano, H, Klambauer, G, Knowles, D, Ko, M, Kohn-Luque, A, Kooistra, A, Kuenemann, M, Kuiper, M, Kurz, C, Kwon, M, van Laarhoven, T, Laegreid, A, Lederer, S, Lee, H, Lee, J, Lee, Y, Lepp_aho, E, Lewis, R, Li, J, Li, L, Liley, J, Lim, W, Lin, C, Liu, Y, Lopez, Y, Low, J, Lysenko, A, Machado, D, Madhukar, N, Maeyer, D, Malpartida, A, Mamitsuka, H, Marabita, F, Marchal, K, Marttinen, P, Mason, D, Mazaheri, A, Mehmood, A, Mehreen, A, Michaut, M, Miller, R, Mitsopoulos, C, Modos, D, Moerbeke, M, Moo, K, Motsinger-Reif, A, Movva, R, Muraru, S, Muratov, E, Mushthofa, M, Nagarajan, N, Nakken, S, Nath, A, Neuvial, P, Newton, R, Ning, Z, Niz, C, Oliva, B, Olsen, C, Palmeri, A, Panesar, B, Papadopoulos, S, Park, J, Park, S, Pawitan, Y, Peluso, D, Pendyala, S, Peng, J, Perfetto, L, Pirro, S, Plevritis, S, Politi, R, Poon, H, Porta, E, Prellner, I, Preuer, K, Pujana, M, Ramnarine, R, Reid, J, Reyal, F, Richardson, S, Ricketts, C, Rieswijk, L, Rocha, M, Rodriguez-Gonzalvez, C, Roell, K, Rotroff, D, de Ruiter, J, Rukawa, P, Sadacca, B, Safikhani, Z, Safitri, F, Sales-Pardo, M, Sauer, S, Schlichting, M, Seoane, J, Serra, J, Shang, M, Sharma, A, Sharma, H, Shen, Y, Shiga, M, Shin, M, Shkedy, Z, Shopsowitz, K, Sinai, S, Skola, D, Smirnov, P, Soerensen, I, Soerensen, P, Song, J, Song, S, Soufan, O, Spitzmueller, A, Steipe, B, Suphavilai, C, Tamayo, S, Tamborero, D, Tang, J, Tanoli, Z, Tarres-Deulofeu, M, Tegner, J, Thommesen, L, Tonekaboni, S, Tran, H, Troyer, E, Truong, A, Tsunoda, T, Turu, G, Tzeng, G, Verbeke, L, Videla, S, Vis, D, Voronkov, A, Votis, K, Wang, A, Wang, H, Wang, P, Wang, S, Wang, W, Wang, X, Wennerberg, K, Wernisch, L, Wessels, L, van Westen, G, Westerman, B, White, S, Willighagen, E, Wurdinger, T, Xie, L, Xie, S, Xu, H, Yadav, B, Yau, C, Yeerna, H, Yin, J, Yu, M, Yun, S, Zakharov, A, Zamichos, A, Zanin, M, Zeng, L, Zenil, H, Zhang, F, Zhang, P, Zhang, W, Zhao, H, Zhao, L, Zheng, W, Zoufir, A, Zucknick, M, Jang, I, Ghazoui, Z, Ahsen, M, Vogel, R, Neto, E, Norman, T, Tang, E, Garnett, M, Veroli, G, Fawell, S, Stolovitzky, G, Guinney, J, Dry, J, Saez-Rodriguez, J, Menden M. P., Wang D., Mason M. J., Szalai B., Bulusu K. C., Guan Y., Yu T., Kang J., Jeon M., Wolfinger R., Nguyen T., Zaslavskiy M., Abante J., Abecassis B. S., Aben N., Aghamirzaie D., Aittokallio T., Akhtari F. S., Al-lazikani B., Alam T., Allam A., Allen C., de Almeida M. P., Altarawy D., Alves V., Amadoz A., Anchang B., Antolin A. A., Ash J. R., Aznar V. R., Ba-alawi W., Bagheri M., Bajic V., Ball G., Ballester P. J., Baptista D., Bare C., Bateson M., Bender A., Bertrand D., Wijayawardena B., Boroevich K. A., Bosdriesz E., Bougouffa S., Bounova G., Brouwer T., Bryant B., Calaza M., Calderone A., Calza S., Capuzzi S., Carbonell-Caballero J., Carlin D., Carter H., Castagnoli L., Celebi R., Cesareni G., Chang H., Chen G., Chen H., Cheng L., Chernomoretz A., Chicco D., Cho K. -H., Cho S., Choi D., Choi J., Choi K., Choi M., Cock M. D., Coker E., Cortes-Ciriano I., Cserzo M., Cubuk C., Curtis C., Daele D. V., Dang C. C., Dijkstra T., Dopazo J., Draghici S., Drosou A., Dumontier M., Ehrhart F., Eid F. -E., ElHefnawi M., Elmarakeby H., van Engelen B., Engin H. B., de Esch I., Evelo C., Falcao A. O., Farag S., Fernandez-Lozano C., Fisch K., Flobak A., Fornari C., Foroushani A. B. K., Fotso D. C., Fourches D., Friend S., Frigessi A., Gao F., Gao X., Gerold J. M., Gestraud P., Ghosh S., Gillberg J., Godoy-Lorite A., Godynyuk L., Godzik A., Goldenberg A., Gomez-Cabrero D., Gonen M., de Graaf C., Gray H., Grechkin M., Guimera R., Guney E., Haibe-Kains B., Han Y., Hase T., He D., He L., Heath L. S., Hellton K. H., Helmer-Citterich M., Hidalgo M. R., Hidru D., Hill S. M., Hochreiter S., Hong S., Hovig E., Hsueh Y. -C., Hu Z., Huang J. K., Huang R. S., Hunyady L., Hwang J., Hwang T. H., Hwang W., Hwang Y., Isayev O., Don't Walk O. B., Jack J., Jahandideh S., Ji J., Jo Y., Kamola P. J., Kanev G. K., Karacosta L., Karimi M., Kaski S., Kazanov M., Khamis A. M., Khan S. A., Kiani N. A., Kim A., Kim J., Kim K., Kim S., Kim Y., Kirk P. D. W., Kitano H., Klambauer G., Knowles D., Ko M., Kohn-Luque A., Kooistra A. J., Kuenemann M. A., Kuiper M., Kurz C., Kwon M., van Laarhoven T., Laegreid A., Lederer S., Lee H., Lee J., Lee Y. W., Lepp_aho E., Lewis R., Li J., Li L., Liley J., Lim W. K., Lin C., Liu Y., Lopez Y., Low J., Lysenko A., Machado D., Madhukar N., Maeyer D. D., Malpartida A. B., Mamitsuka H., Marabita F., Marchal K., Marttinen P., Mason D., Mazaheri A., Mehmood A., Mehreen A., Michaut M., Miller R. A., Mitsopoulos C., Modos D., Moerbeke M. V., Moo K., Motsinger-Reif A., Movva R., Muraru S., Muratov E., Mushthofa M., Nagarajan N., Nakken S., Nath A., Neuvial P., Newton R., Ning Z., Niz C. D., Oliva B., Olsen C., Palmeri A., Panesar B., Papadopoulos S., Park J., Park S., Pawitan Y., Peluso D., Pendyala S., Peng J., Perfetto L., Pirro S., Plevritis S., Politi R., Poon H., Porta E., Prellner I., Preuer K., Pujana M. A., Ramnarine R., Reid J. E., Reyal F., Richardson S., Ricketts C., Rieswijk L., Rocha M., Rodriguez-Gonzalvez C., Roell K., Rotroff D., de Ruiter J. R., Rukawa P., Sadacca B., Safikhani Z., Safitri F., Sales-Pardo M., Sauer S., Schlichting M., Seoane J. A., Serra J., Shang M. -M., Sharma A., Sharma H., Shen Y., Shiga M., Shin M., Shkedy Z., Shopsowitz K., Sinai S., Skola D., Smirnov P., Soerensen I. F., Soerensen P., Song J. -H., Song S. O., Soufan O., Spitzmueller A., Steipe B., Suphavilai C., Tamayo S. P., Tamborero D., Tang J., Tanoli Z. -U. -R., Tarres-Deulofeu M., Tegner J., Thommesen L., Tonekaboni S. A. M., Tran H., Troyer E. D., Truong A., Tsunoda T., Turu G., Tzeng G. -Y., Verbeke L., Videla S., Vis D., Voronkov A., Votis K., Wang A., Wang H. -Q. H., Wang P. -W., Wang S., Wang W., Wang X., Wennerberg K., Wernisch L., Wessels L., van Westen G. J. P., Westerman B. A., White S. R., Willighagen E., Wurdinger T., Xie L., Xie S., Xu H., Yadav B., Yau C., Yeerna H., Yin J. W., Yu M., Yu M. H., Yun S. J., Zakharov A., Zamichos A., Zanin M., Zeng L., Zenil H., Zhang F., Zhang P., Zhang W., Zhao H., Zhao L., Zheng W., Zoufir A., Zucknick M., Jang I. S., Ghazoui Z., Ahsen M. E., Vogel R., Neto E. C., Norman T., Tang E. K. Y., Garnett M. J., Veroli G. Y. D., Fawell S., Stolovitzky G., Guinney J., Dry J. R., Saez-Rodriguez J., Menden, M, Wang, D, Mason, M, Szalai, B, Bulusu, K, Guan, Y, Yu, T, Kang, J, Jeon, M, Wolfinger, R, Nguyen, T, Zaslavskiy, M, Abante, J, Abecassis, B, Aben, N, Aghamirzaie, D, Aittokallio, T, Akhtari, F, Al-lazikani, B, Alam, T, Allam, A, Allen, C, de Almeida, M, Altarawy, D, Alves, V, Amadoz, A, Anchang, B, Antolin, A, Ash, J, Aznar, V, Ba-alawi, W, Bagheri, M, Bajic, V, Ball, G, Ballester, P, Baptista, D, Bare, C, Bateson, M, Bender, A, Bertrand, D, Wijayawardena, B, Boroevich, K, Bosdriesz, E, Bougouffa, S, Bounova, G, Brouwer, T, Bryant, B, Calaza, M, Calderone, A, Calza, S, Capuzzi, S, Carbonell-Caballero, J, Carlin, D, Carter, H, Castagnoli, L, Celebi, R, Cesareni, G, Chang, H, Chen, G, Chen, H, Cheng, L, Chernomoretz, A, Chicco, D, Cho, K, Cho, S, Choi, D, Choi, J, Choi, K, Choi, M, Cock, M, Coker, E, Cortes-Ciriano, I, Cserzo, M, Cubuk, C, Curtis, C, Daele, D, Dang, C, Dijkstra, T, Dopazo, J, Draghici, S, Drosou, A, Dumontier, M, Ehrhart, F, Eid, F, Elhefnawi, M, Elmarakeby, H, van Engelen, B, Engin, H, de Esch, I, Evelo, C, Falcao, A, Farag, S, Fernandez-Lozano, C, Fisch, K, Flobak, A, Fornari, C, Foroushani, A, Fotso, D, Fourches, D, Friend, S, Frigessi, A, Gao, F, Gao, X, Gerold, J, Gestraud, P, Ghosh, S, Gillberg, J, Godoy-Lorite, A, Godynyuk, L, Godzik, A, Goldenberg, A, Gomez-Cabrero, D, Gonen, M, de Graaf, C, Gray, H, Grechkin, M, Guimera, R, Guney, E, Haibe-Kains, B, Han, Y, Hase, T, He, D, He, L, Heath, L, Hellton, K, Helmer-Citterich, M, Hidalgo, M, Hidru, D, Hill, S, Hochreiter, S, Hong, S, Hovig, E, Hsueh, Y, Hu, Z, Huang, J, Huang, R, Hunyady, L, Hwang, J, Hwang, T, Hwang, W, Hwang, Y, Isayev, O, Don't Walk, O, Jack, J, Jahandideh, S, Ji, J, Jo, Y, Kamola, P, Kanev, G, Karacosta, L, Karimi, M, Kaski, S, Kazanov, M, Khamis, A, Khan, S, Kiani, N, Kim, A, Kim, J, Kim, K, Kim, S, Kim, Y, Kirk, P, Kitano, H, Klambauer, G, Knowles, D, Ko, M, Kohn-Luque, A, Kooistra, A, Kuenemann, M, Kuiper, M, Kurz, C, Kwon, M, van Laarhoven, T, Laegreid, A, Lederer, S, Lee, H, Lee, J, Lee, Y, Lepp_aho, E, Lewis, R, Li, J, Li, L, Liley, J, Lim, W, Lin, C, Liu, Y, Lopez, Y, Low, J, Lysenko, A, Machado, D, Madhukar, N, Maeyer, D, Malpartida, A, Mamitsuka, H, Marabita, F, Marchal, K, Marttinen, P, Mason, D, Mazaheri, A, Mehmood, A, Mehreen, A, Michaut, M, Miller, R, Mitsopoulos, C, Modos, D, Moerbeke, M, Moo, K, Motsinger-Reif, A, Movva, R, Muraru, S, Muratov, E, Mushthofa, M, Nagarajan, N, Nakken, S, Nath, A, Neuvial, P, Newton, R, Ning, Z, Niz, C, Oliva, B, Olsen, C, Palmeri, A, Panesar, B, Papadopoulos, S, Park, J, Park, S, Pawitan, Y, Peluso, D, Pendyala, S, Peng, J, Perfetto, L, Pirro, S, Plevritis, S, Politi, R, Poon, H, Porta, E, Prellner, I, Preuer, K, Pujana, M, Ramnarine, R, Reid, J, Reyal, F, Richardson, S, Ricketts, C, Rieswijk, L, Rocha, M, Rodriguez-Gonzalvez, C, Roell, K, Rotroff, D, de Ruiter, J, Rukawa, P, Sadacca, B, Safikhani, Z, Safitri, F, Sales-Pardo, M, Sauer, S, Schlichting, M, Seoane, J, Serra, J, Shang, M, Sharma, A, Sharma, H, Shen, Y, Shiga, M, Shin, M, Shkedy, Z, Shopsowitz, K, Sinai, S, Skola, D, Smirnov, P, Soerensen, I, Soerensen, P, Song, J, Song, S, Soufan, O, Spitzmueller, A, Steipe, B, Suphavilai, C, Tamayo, S, Tamborero, D, Tang, J, Tanoli, Z, Tarres-Deulofeu, M, Tegner, J, Thommesen, L, Tonekaboni, S, Tran, H, Troyer, E, Truong, A, Tsunoda, T, Turu, G, Tzeng, G, Verbeke, L, Videla, S, Vis, D, Voronkov, A, Votis, K, Wang, A, Wang, H, Wang, P, Wang, S, Wang, W, Wang, X, Wennerberg, K, Wernisch, L, Wessels, L, van Westen, G, Westerman, B, White, S, Willighagen, E, Wurdinger, T, Xie, L, Xie, S, Xu, H, Yadav, B, Yau, C, Yeerna, H, Yin, J, Yu, M, Yun, S, Zakharov, A, Zamichos, A, Zanin, M, Zeng, L, Zenil, H, Zhang, F, Zhang, P, Zhang, W, Zhao, H, Zhao, L, Zheng, W, Zoufir, A, Zucknick, M, Jang, I, Ghazoui, Z, Ahsen, M, Vogel, R, Neto, E, Norman, T, Tang, E, Garnett, M, Veroli, G, Fawell, S, Stolovitzky, G, Guinney, J, Dry, J, Saez-Rodriguez, J, Menden M. P., Wang D., Mason M. J., Szalai B., Bulusu K. C., Guan Y., Yu T., Kang J., Jeon M., Wolfinger R., Nguyen T., Zaslavskiy M., Abante J., Abecassis B. S., Aben N., Aghamirzaie D., Aittokallio T., Akhtari F. S., Al-lazikani B., Alam T., Allam A., Allen C., de Almeida M. P., Altarawy D., Alves V., Amadoz A., Anchang B., Antolin A. A., Ash J. R., Aznar V. R., Ba-alawi W., Bagheri M., Bajic V., Ball G., Ballester P. J., Baptista D., Bare C., Bateson M., Bender A., Bertrand D., Wijayawardena B., Boroevich K. A., Bosdriesz E., Bougouffa S., Bounova G., Brouwer T., Bryant B., Calaza M., Calderone A., Calza S., Capuzzi S., Carbonell-Caballero J., Carlin D., Carter H., Castagnoli L., Celebi R., Cesareni G., Chang H., Chen G., Chen H., Cheng L., Chernomoretz A., Chicco D., Cho K. -H., Cho S., Choi D., Choi J., Choi K., Choi M., Cock M. D., Coker E., Cortes-Ciriano I., Cserzo M., Cubuk C., Curtis C., Daele D. V., Dang C. C., Dijkstra T., Dopazo J., Draghici S., Drosou A., Dumontier M., Ehrhart F., Eid F. -E., ElHefnawi M., Elmarakeby H., van Engelen B., Engin H. B., de Esch I., Evelo C., Falcao A. O., Farag S., Fernandez-Lozano C., Fisch K., Flobak A., Fornari C., Foroushani A. B. K., Fotso D. C., Fourches D., Friend S., Frigessi A., Gao F., Gao X., Gerold J. M., Gestraud P., Ghosh S., Gillberg J., Godoy-Lorite A., Godynyuk L., Godzik A., Goldenberg A., Gomez-Cabrero D., Gonen M., de Graaf C., Gray H., Grechkin M., Guimera R., Guney E., Haibe-Kains B., Han Y., Hase T., He D., He L., Heath L. S., Hellton K. H., Helmer-Citterich M., Hidalgo M. R., Hidru D., Hill S. M., Hochreiter S., Hong S., Hovig E., Hsueh Y. -C., Hu Z., Huang J. K., Huang R. S., Hunyady L., Hwang J., Hwang T. H., Hwang W., Hwang Y., Isayev O., Don't Walk O. B., Jack J., Jahandideh S., Ji J., Jo Y., Kamola P. J., Kanev G. K., Karacosta L., Karimi M., Kaski S., Kazanov M., Khamis A. M., Khan S. A., Kiani N. A., Kim A., Kim J., Kim K., Kim S., Kim Y., Kirk P. D. W., Kitano H., Klambauer G., Knowles D., Ko M., Kohn-Luque A., Kooistra A. J., Kuenemann M. A., Kuiper M., Kurz C., Kwon M., van Laarhoven T., Laegreid A., Lederer S., Lee H., Lee J., Lee Y. W., Lepp_aho E., Lewis R., Li J., Li L., Liley J., Lim W. K., Lin C., Liu Y., Lopez Y., Low J., Lysenko A., Machado D., Madhukar N., Maeyer D. D., Malpartida A. B., Mamitsuka H., Marabita F., Marchal K., Marttinen P., Mason D., Mazaheri A., Mehmood A., Mehreen A., Michaut M., Miller R. A., Mitsopoulos C., Modos D., Moerbeke M. V., Moo K., Motsinger-Reif A., Movva R., Muraru S., Muratov E., Mushthofa M., Nagarajan N., Nakken S., Nath A., Neuvial P., Newton R., Ning Z., Niz C. D., Oliva B., Olsen C., Palmeri A., Panesar B., Papadopoulos S., Park J., Park S., Pawitan Y., Peluso D., Pendyala S., Peng J., Perfetto L., Pirro S., Plevritis S., Politi R., Poon H., Porta E., Prellner I., Preuer K., Pujana M. A., Ramnarine R., Reid J. E., Reyal F., Richardson S., Ricketts C., Rieswijk L., Rocha M., Rodriguez-Gonzalvez C., Roell K., Rotroff D., de Ruiter J. R., Rukawa P., Sadacca B., Safikhani Z., Safitri F., Sales-Pardo M., Sauer S., Schlichting M., Seoane J. A., Serra J., Shang M. -M., Sharma A., Sharma H., Shen Y., Shiga M., Shin M., Shkedy Z., Shopsowitz K., Sinai S., Skola D., Smirnov P., Soerensen I. F., Soerensen P., Song J. -H., Song S. O., Soufan O., Spitzmueller A., Steipe B., Suphavilai C., Tamayo S. P., Tamborero D., Tang J., Tanoli Z. -U. -R., Tarres-Deulofeu M., Tegner J., Thommesen L., Tonekaboni S. A. M., Tran H., Troyer E. D., Truong A., Tsunoda T., Turu G., Tzeng G. -Y., Verbeke L., Videla S., Vis D., Voronkov A., Votis K., Wang A., Wang H. -Q. H., Wang P. -W., Wang S., Wang W., Wang X., Wennerberg K., Wernisch L., Wessels L., van Westen G. J. P., Westerman B. A., White S. R., Willighagen E., Wurdinger T., Xie L., Xie S., Xu H., Yadav B., Yau C., Yeerna H., Yin J. W., Yu M., Yu M. H., Yun S. J., Zakharov A., Zamichos A., Zanin M., Zeng L., Zenil H., Zhang F., Zhang P., Zhang W., Zhao H., Zhao L., Zheng W., Zoufir A., Zucknick M., Jang I. S., Ghazoui Z., Ahsen M. E., Vogel R., Neto E. C., Norman T., Tang E. K. Y., Garnett M. J., Veroli G. Y. D., Fawell S., Stolovitzky G., Guinney J., Dry J. R., and Saez-Rodriguez J.

Abstract

The effectiveness of most cancer targeted therapies is short-lived. Tumors often develop resistance that might be overcome with drug combinations. However, the number of possible combinations is vast, necessitating data-driven approaches to find optimal patient-specific treatments. Here we report AstraZeneca’s large drug combination dataset, consisting of 11,576 experiments from 910 combinations across 85 molecularly characterized cancer cell lines, and results of a DREAM Challenge to evaluate computational strategies for predicting synergistic drug pairs and biomarkers. 160 teams participated to provide a comprehensive methodological development and benchmarking. Winning methods incorporate prior knowledge of drug-target interactions. Synergy is predicted with an accuracy matching biological replicates for >60% of combinations. However, 20% of drug combinations are poorly predicted by all methods. Genomic rationale for synergy predictions are identified, including ADAM17 inhibitor antagonism when combined with PIK3CB/D inhibition contrasting to synergy when combined with other PI3K-pathway inhibitors in PIK3CA mutant cells.

Published
2019

6. COVID-19 Disease Map, a computational knowledge repository of virus-host interaction mechanisms (vol 17, e10387, 2021)

Author

Ostaszewski, M, Niarakis, A, Mazein, A, Kuperstein, I, Phair, R, Orta-Resendiz, A, Singh, V, Aghamiri, S, Acencio, M, Glaab, E, Ruepp, A, Fobo, G, Montrone, C, Brauner, B, Frishman, G, Gomez, L, Somers, J, Hoch, M, Gupta, S, Scheel, J, Borlinghaus, H, Czauderna, T, Schreiber, F, Montagud, A, de Leon, M, Funahashi, A, Hiki, Y, Hiroi, N, Yamada, T, Drager, A, Renz, A, Naveez, M, Bocskei, Z, Messina, F, Bornigen, D, Fergusson, L, Conti, M, Rameil, M, Nakonecnij, V, Vanhoefer, J, Schmiester, L, Wang, M, Ackerman, E, Shoemaker, J, Zucker, J, Oxford, K, Teuton, J, Kocakaya, E, Summak, G, Hanspers, K, Kutmon, M, Coort, S, Eijssen, L, Ehrhart, F, Rex, D, Slenter, D, Martens, M, Pham, N, Haw, R, Jassal, B, Matthews, L, Orlic-Milacic, M, Senff-Ribeiro, A, Rothfels, K, Shamovsky, V, Stephan, R, Sevilla, C, Varusai, T, Ravel, J, Fraser, R, Ortseifen, V, Marchesi, S, Gawron, P, Smula, E, Heirendt, L, Satagopam, V, Gm, W, Riutta, A, Golebiewski, M, Owen, S, Goble, C, Xm, H, Overall, R, Maier, D, Bauch, A, Gyori, B, Bachman, J, Vega, C, Groues, V, Vazquez, M, Porras, P, Licata, L, Iannuccelli, M, Sacco, F, Nesterova, A, Yuryev, A, de Waard, A, Turei, D, Luna, A, Babur, O, Soliman, S, Valdeolivas, A, Esteban-Medina, M, Pena-Chilet, M, Rian, K, Helikar, T, Puniya, B, Modos, D, Treveil, A, Olbei, M, De Meulder, B, Ballereau, S, Dugourd, A, Naldi, A, Noel, V, Calzone, L, Sander, C, Demir, E, Korcsmaros, T, Freeman, T, Auge, F, Beckmann, J, Hasenauer, J, Wolkenhauer, O, Willighagen, E, Pico, A, Evelo, C, Gillespie, M, Stein, L, Hermjakob, H, D'Eustachio, P, Saez-Rodriguez, J, Dopazo, J, Valencia, A, Kitano, H, Barillot, E, Auffray, C, Balling, R, and Schneider, R

Subjects
Settore BIO/18, Settore BIO/11
Published
2021

8. The molecular processes in the trabecular meshwork after exposure to corticosteroids and in corticosteroid response

Author

Liesenborghs, I., Eijssen, L. M. T., Kutmon, M., Gorgels, T. G. M. F., Evelo, C. T., Beckers, H. J. M., Webers, C. A. B., Schouten, J. S. A. G., Maastricht Centre for Systems Biology, MUMC+: MA AIOS Oogheelkunde (9), RS: FSE MaCSBio, RS: FPN MaCSBio, Psychiatrie & Neuropsychologie, Bioinformatica, RS: MHeNs - R3 - Neuroscience, RS: FHML MaCSBio, RS: NUTRIM - R1 - Obesity, diabetes and cardiovascular health, MUMC+: AB Onderzoekers (9), Oogheelkunde, MUMC+: MA Oogheelkunde (9), MUMC+: MA Oogheelkunde (3), and MUMC+: Centrum voor Oogheelkunde (3)

Published
2020

9. SBML Level 3: an extensible format for the exchange and reuse of biological models

Author

Keating, S, Waltemath, D, König, M, Zhang, F, Dräger, A, Chaouiya, C, Bergmann, F, Finney, A, Gillespie, C, Helikar, T, Hoops, S, Malik-Sheriff, R, Moodie, S, Moraru, I, Myers, C, Naldi, A, Olivier, B, Sahle, S, Schaff, J, Smith, L, Swat, M, Thieffry, D, Watanabe, L, Wilkinson, D, Blinov, M, Begley, K, Faeder, J, Gómez, H, Hamm, T, Inagaki, Y, Liebermeister, W, Lister, A, Lucio, D, Mjolsness, E, Proctor, C, Raman, K, Rodriguez, N, Shaffer, C, Shapiro, B, Stelling, J, Swainston, N, Tanimura, N, Wagner, J, Meier-Schellersheim, M, Sauro, H, Palsson, B, Bolouri, H, Kitano, H, Funahashi, A, Hermjakob, H, Doyle, J, Hucka, M, Adams, R, Allen, N, Angermann, B, Antoniotti, M, Bader, G, Červený, J, Courtot, M, Cox, C, Dalle Pezze, P, Demir, E, Denney, W, Dharuri, H, Dorier, J, Drasdo, D, Ebrahim, A, Eichner, J, Elf, J, Endler, L, Evelo, C, Flamm, C, Fleming, R, Fröhlich, M, Glont, M, Gonçalves, E, Golebiewski, M, Grabski, H, Gutteridge, A, Hachmeister, D, Harris, L, Heavner, B, Henkel, R, Hlavacek, W, Hu, B, Hyduke, D, Jong, H, Juty, N, Karp, P, Karr, J, Kell, D, Keller, R, Kiselev, I, Klamt, S, Klipp, E, Knüpfer, C, Kolpakov, F, Krause, F, Kutmon, M, Laibe, C, Lawless, C, Li, L, Loew, L, Machne, R, Matsuoka, Y, Mendes, P, Mi, H, Mittag, F, Monteiro, P, Natarajan, K, Nielsen, P, Nguyen, T, Palmisano, A, Jean-Baptiste, P, Pfau, T, Phair, R, Radivoyevitch, T, Rohwer, J, Ruebenacker, O, Saez-Rodriguez, J, Scharm, M, Schmidt, H, Schreiber, F, Schubert, M, Schulte, R, Sealfon, S, Smallbone, K, Soliman, S, Stefan, M, Sullivan, D, Takahashi, K, Teusink, B, Tolnay, D, Vazirabad, I, Kamp, A, Wittig, U, Wrzodek, C, Wrzodek, F, Xenarios, I, Zhukova, A, Zucker, J, Keating, SM, Bergmann, FT, Gillespie, CS, Malik-Sheriff, RS, Moodie, SL, Moraru, II, Myers, CJ, Olivier, BG, Schaff, JC, Smith, LP, Swat, MJ, Wilkinson, DJ, Blinov, ML, Faeder, JR, Gómez, HF, Hamm, TM, Lister, AL, Proctor, CJ, Shaffer, CA, Shapiro, BE, Sauro, HM, Doyle, JC, Adams, RR, Allen, NA, Angermann, BR, Bader, GD, Cox, CD, Denney, WS, Evelo, CT, Fleming, RM, Harris, LA, Heavner, BD, Hlavacek, WS, Hyduke, DR, Karp, PD, Karr, JR, Kell, DB, Loew, LM, Monteiro, PT, Natarajan, KN, Nielsen, PM, Phair, RD, Rohwer, JM, Ruebenacker, OA, Sealfon, SC, Stefan, MI, Sullivan, DP, Keating, S, Waltemath, D, König, M, Zhang, F, Dräger, A, Chaouiya, C, Bergmann, F, Finney, A, Gillespie, C, Helikar, T, Hoops, S, Malik-Sheriff, R, Moodie, S, Moraru, I, Myers, C, Naldi, A, Olivier, B, Sahle, S, Schaff, J, Smith, L, Swat, M, Thieffry, D, Watanabe, L, Wilkinson, D, Blinov, M, Begley, K, Faeder, J, Gómez, H, Hamm, T, Inagaki, Y, Liebermeister, W, Lister, A, Lucio, D, Mjolsness, E, Proctor, C, Raman, K, Rodriguez, N, Shaffer, C, Shapiro, B, Stelling, J, Swainston, N, Tanimura, N, Wagner, J, Meier-Schellersheim, M, Sauro, H, Palsson, B, Bolouri, H, Kitano, H, Funahashi, A, Hermjakob, H, Doyle, J, Hucka, M, Adams, R, Allen, N, Angermann, B, Antoniotti, M, Bader, G, Červený, J, Courtot, M, Cox, C, Dalle Pezze, P, Demir, E, Denney, W, Dharuri, H, Dorier, J, Drasdo, D, Ebrahim, A, Eichner, J, Elf, J, Endler, L, Evelo, C, Flamm, C, Fleming, R, Fröhlich, M, Glont, M, Gonçalves, E, Golebiewski, M, Grabski, H, Gutteridge, A, Hachmeister, D, Harris, L, Heavner, B, Henkel, R, Hlavacek, W, Hu, B, Hyduke, D, Jong, H, Juty, N, Karp, P, Karr, J, Kell, D, Keller, R, Kiselev, I, Klamt, S, Klipp, E, Knüpfer, C, Kolpakov, F, Krause, F, Kutmon, M, Laibe, C, Lawless, C, Li, L, Loew, L, Machne, R, Matsuoka, Y, Mendes, P, Mi, H, Mittag, F, Monteiro, P, Natarajan, K, Nielsen, P, Nguyen, T, Palmisano, A, Jean-Baptiste, P, Pfau, T, Phair, R, Radivoyevitch, T, Rohwer, J, Ruebenacker, O, Saez-Rodriguez, J, Scharm, M, Schmidt, H, Schreiber, F, Schubert, M, Schulte, R, Sealfon, S, Smallbone, K, Soliman, S, Stefan, M, Sullivan, D, Takahashi, K, Teusink, B, Tolnay, D, Vazirabad, I, Kamp, A, Wittig, U, Wrzodek, C, Wrzodek, F, Xenarios, I, Zhukova, A, Zucker, J, Keating, SM, Bergmann, FT, Gillespie, CS, Malik-Sheriff, RS, Moodie, SL, Moraru, II, Myers, CJ, Olivier, BG, Schaff, JC, Smith, LP, Swat, MJ, Wilkinson, DJ, Blinov, ML, Faeder, JR, Gómez, HF, Hamm, TM, Lister, AL, Proctor, CJ, Shaffer, CA, Shapiro, BE, Sauro, HM, Doyle, JC, Adams, RR, Allen, NA, Angermann, BR, Bader, GD, Cox, CD, Denney, WS, Evelo, CT, Fleming, RM, Harris, LA, Heavner, BD, Hlavacek, WS, Hyduke, DR, Karp, PD, Karr, JR, Kell, DB, Loew, LM, Monteiro, PT, Natarajan, KN, Nielsen, PM, Phair, RD, Rohwer, JM, Ruebenacker, OA, Sealfon, SC, Stefan, MI, and Sullivan, DP

Abstract

Systems biology has experienced dramatic growth in the number, size, and complexity of computational models. To reproduce simulation results and reuse models, researchers must exchange unambiguous model descriptions. We review the latest edition of the Systems Biology Markup Language (SBML), a format designed for this purpose. A community of modelers and software authors developed SBML Level 3 over the past decade. Its modular form consists of a core suited to representing reaction-based models and packages that extend the core with features suited to other model types including constraint-based models, reaction-diffusion models, logical network models, and rule-based models. The format leverages two decades of SBML and a rich software ecosystem that transformed how systems biologists build and interact with models. More recently, the rise of multiscale models of whole cells and organs, and new data sources such as single-cell measurements and live imaging, has precipitated new ways of integrating data with models. We provide our perspectives on the challenges presented by these developments and how SBML Level 3 provides the foundation needed to support this evolution.

Published
2020

11. The signature of the healthy trabecular meshwork

Author

Liesenborghs, I., Eijssen, L. M. T., Kutmon, M., Evelo, C. T., Gorgels, T. G. M. F., Hubens, W. H. G., Beckers, H. J. M., Webers, C. A. B., Schouten, J. S. A. G., Maastricht Centre for Systems Biology, RS: FSE MaCSBio, RS: FPN MaCSBio, RS: MHeNs - R3 - Neuroscience, Bioinformatica, RS: FHML MaCSBio, RS: NUTRIM - R1 - Obesity, diabetes and cardiovascular health, MUMC+: *AB Onderzoekers (9), Oogheelkunde, Promovendi MHN, MUMC+: MA UECM AIOS (9), MUMC+: MA UECM Oogartsen MUMC (9), and MUMC+: *MA Oogheelkunde (3)

Published
2019

16. Open PHACTS computational protocols for in silico target validation of cellular phenotypic screens: knowing the knowns† †The authors declare no competing interests. ‡ ‡Electronic supplementary information (ESI) available: Pipeline Pilot protocols, xls file with the output of the Pipeline Pilot protocols, KNIME workflows, and supplementary figures showing the Pipeline Pilot protocols. See DOI: 10.1039/c6md00065g Click here for additional data file

Author

Digles, D., Zdrazil, B., Neefs, J.-M., Van Vlijmen, H., Herhaus, C., Caracoti, A., Brea, J., Roibás, B., Loza, M. I., Queralt-Rosinach, N., Furlong, L. I., Gaulton, A., Bartek, L., Senger, S., Chichester, C., Engkvist, O., Evelo, C. T., Franklin, N. I., Marren, D., Ecker, G. F., and Jacoby, E.

Subjects
Chemistry, TheoryofComputation_COMPUTATIONBYABSTRACTDEVICES, ComputingMethodologies_PATTERNRECOGNITION, ComputingMethodologies_ARTIFICIALINTELLIGENCE
Abstract

Six computational protocols to annotate phenotypic screens., Phenotypic screening is in a renaissance phase and is expected by many academic and industry leaders to accelerate the discovery of new drugs for new biology. Given that phenotypic screening is per definition target agnostic, the emphasis of in silico and in vitro follow-up work is on the exploration of possible molecular mechanisms and efficacy targets underlying the biological processes interrogated by the phenotypic screening experiments. Herein, we present six exemplar computational protocols for the interpretation of cellular phenotypic screens based on the integration of compound, target, pathway, and disease data established by the IMI Open PHACTS project. The protocols annotate phenotypic hit lists and allow follow-up experiments and mechanistic conclusions. The annotations included are from ChEMBL, ChEBI, GO, WikiPathways and DisGeNET. Also provided are protocols which select from the IUPHAR/BPS Guide to PHARMACOLOGY interaction file selective compounds to probe potential targets and a correlation robot which systematically aims to identify an overlap of active compounds in both the phenotypic as well as any kinase assay. The protocols are applied to a phenotypic pre-lamin A/C splicing assay selected from the ChEMBL database to illustrate the process. The computational protocols make use of the Open PHACTS API and data and are built within the Pipeline Pilot and KNIME workflow tools.

Published
2016

18. Bioinformatical pathway analyses to discover the molecular pathogenesis of primary open angle glaucoma

Author

Liesenborghs, I., Kutmon, M., Eijssen, L. M. T., Gorgels, T. G. M. F., Evelo, C. T., Beckers, H. J. M., Webers, C. A. B., Schouten, J. S. A. G., Maastricht Centre for Systems Biology, RS: FSE MaCSBio, RS: FPN MaCSBio, RS: FHML MaCSBio, RS: NUTRIM - R1 - Obesity, diabetes and cardiovascular health, Bioinformatica, Psychiatrie & Neuropsychologie, RS: MHeNs - R3 - Neuroscience, MUMC+: *AB Onderzoekers (9), Oogheelkunde, MUMC+: MA UECM AIOS (9), MUMC+: MA UECM Oogartsen MUMC (9), and MUMC+: *MA Oogheelkunde (3)

Published
2018

19. OpenRiskNet, an open e-infrastructure to support data sharing, knowledge integration and in silico analysis and modelling in risk assessment

Author

Exner, T. E., Dokler, J., Bachler, D., Farcal, L. R., Evelo, C. T., Willighagen, E., Jennen, D. G. J., Jabocs, M., Doganis, P., Sarimveis, H., Lynch, I., Gkoutos, G., Kramer, S., Notredame, C., Spjuth, Ola, Jennings, P., Dudgeon, T., Bols, F., Hardy, B., Exner, T. E., Dokler, J., Bachler, D., Farcal, L. R., Evelo, C. T., Willighagen, E., Jennen, D. G. J., Jabocs, M., Doganis, P., Sarimveis, H., Lynch, I., Gkoutos, G., Kramer, S., Notredame, C., Spjuth, Ola, Jennings, P., Dudgeon, T., Bols, F., and Hardy, B.

Published
2018
Full Text
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20. Expression profiling of selenium deficiency in mouse colon and splenic leukocytes

Author

Kipp, A., Banning, A., van Schothorst, E.M., Meplan, C., Schomburg, L., Evelo, C., Coort, S.L., Gaj, S., Keijer, J., Hesketh, J., Brigelius, R., Kipp, A., Banning, A., van Schothorst, E.M., Meplan, C., Schomburg, L., Evelo, C., Coort, S.L., Gaj, S., Keijer, J., Hesketh, J., and Brigelius, R.

Abstract

This SuperSeries is composed of the SubSeries listed below. Overall design: Refer to individual Series, This SuperSeries is composed of the SubSeries listed below. Overall design: Refer to individual Series

Published
2018

21. A bioinformatics approach to identify molecular pathways that characterize the trabecular meshwork

Author

Liesenborghs, I., Schouten, J. S. A. G., Eijssen, L. M. T., Kutmon, M., Gorgels, T. G. M. F., Hubens, W. H. G., Evelo, C. T., Beckers, H. J. M., Webers, C. A. B., Maastricht Centre for Systems Biology, RS: FSE MaCSBio, RS: FPN MaCSBio, Oogheelkunde, MUMC+: MA Oogheelkunde (9), Bioinformatica, RS: MHeNs - R3 - Neuroscience, RS: NUTRIM - R1 - Obesity, diabetes and cardiovascular health, Psychiatrie & Neuropsychologie, RS: NUTRIM - R4 - Gene-environment interaction, RS: FHML MaCSBio, MUMC+: AB Onderzoekers (9), Promovendi MHN, MUMC+: MA AIOS Oogheelkunde (9), and MUMC+: MA Oogheelkunde (3)

Published
2017

24. The NuGO proof of principle study package: a collaborative research effort of the European Nutrigenomics Organisation

Author

Baccini, M, Bachmaier, EM, Biggeri, A, Boekschoten, MV, Bouwman, FG, Brennan, L, Caesar, R, Cinti, S, Coort, SL, Crosley, K, Daniel, H, Drevon, CA, Duthie, S, Eijssen, L, Elliott, RM, van Erk, M, Evelo, C, Gibney, M, Heim, C, Horgan, GW, Johnson, IT, Kelder, T, Kleemann, R, Kooistra, T, van Iersel, MP, Mariman, EC, Mayer, C, McLoughlin, G, Müller, M, Mulholland, F, van Ommen, B, Polley, AC, Pujos-Guillot, E, Rubio-Aliaga, I, Roche, HM, de Roos, B, Sailer, M, Tonini, G, Williams, LM, de Wit, N, For the NuGO PPS Team, Università degli Studi di Firenze = University of Florence (UniFI), University of Aberdeen, Division of Human Nutrition, Wageningen University and Research [Wageningen] (WUR), Top Institute Food and Nutrition (TIFN), Maastricht University [Maastricht], School of Agriculture, Food Science and Veterinary Medicine, University College Dublin [Dublin] (UCD), University of Oslo (UiO), Università Politecnica delle Marche, Partenaires INRAE, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Institute of Food Research [Norwich], Biotechnology and Biological Sciences Research Council (BBSRC), Department of Physiological Genomics, Munich University, University College Dublin (UCD), Netherlands Organisation for Applied Scientific Research, Unité de Nutrition Humaine (UNH), Institut National de la Recherche Agronomique (INRA)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Clermont Université, TNO Kwaliteit van Leven, Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Humane Biologie, Bioinformatica, RS: CARIM School for Cardiovascular Diseases, and RS: NUTRIM - R4 - Gene-environment interaction

Subjects
Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], MEDLINE, 030209 endocrinology & metabolism, Physiological Sciences, Bioinformatics, 03 medical and health sciences, Voeding, Metabolisme en Genomica, 0302 clinical medicine, Voeding, Genetics, Network of excellence, Medicine, 030304 developmental biology, Nutrition, VLAG, 0303 health sciences, business.industry, Metabolism and Genomics, Nutrigenomics, immune-system, Proof of concept, Metabolisme en Genomica, Commentary, Engineering ethics, Nutrition, Metabolism and Genomics, business
Abstract

Acknowledgments This project is funded by the Nutrigenomics Organisation, EC funded Network of Excellence, grant nr.FOOD- 2004-506360.

Published
2008

25. Open PHACTS computational protocols for in silico target validation of cellular phenotypic screens: knowing the knowns

Author

Digles, D., Digles, D., Zdrazil, B., Neefs, J. -M., Van Vlijmen, H., Herhaus, C., Caracoti, A., Brea, J., Roibas, B., Loza, M. I., Queralt-Rosinach, N., Furlong, L. I., Gaulton, A., Bartek, L., Senger, S., Chichester, C., Engkvist, O., Evelo, C. T., Franklin, N. I., Marren, D., Ecker, G. F., Jacoby, E., Digles, D., Digles, D., Zdrazil, B., Neefs, J. -M., Van Vlijmen, H., Herhaus, C., Caracoti, A., Brea, J., Roibas, B., Loza, M. I., Queralt-Rosinach, N., Furlong, L. I., Gaulton, A., Bartek, L., Senger, S., Chichester, C., Engkvist, O., Evelo, C. T., Franklin, N. I., Marren, D., Ecker, G. F., and Jacoby, E.

Abstract

Phenotypic screening is in a renaissance phase and is expected by many academic and industry leaders to accelerate the discovery of new drugs for new biology. Given that phenotypic screening is per definition target agnostic, the emphasis of in silico and in vitro follow-up work is on the exploration of possible molecular mechanisms and efficacy targets underlying the biological processes interrogated by the phenotypic screening experiments. Herein, we present six exemplar computational protocols for the interpretation of cellular phenotypic screens based on the integration of compound, target, pathway, and disease data established by the IMI Open PHACTS project. The protocols annotate phenotypic hit lists and allow follow-up experiments and mechanistic conclusions. The annotations included are from ChEMBL, ChEBI, GO, WikiPathways and DisGeNET. Also provided are protocols which select from the IUPHAR/BPS Guide to PHARMACOLOGY interaction file selective compounds to probe potential targets and a correlation robot which systematically aims to identify an overlap of active compounds in both the phenotypic as well as any kinase assay. The protocols are applied to a phenotypic pre-lamin A/C splicing assay selected from the ChEMBL database to illustrate the process. The computational protocols make use of the Open PHACTS API and data and are built within the Pipeline Pilot and KNIME workflow tools.

Published
2016

26. Comment: The FAIR Guiding Principles for scientific data management and stewardship

Author

Wilkinson, M D, Dumontier, M, Aalbersberg, I J, Appleton, G, Axton, M, Baak, A, Blomberg, N, Boiten, J W, Santos, L B D, Bourne, P E, Bouwman, J, Brookes, AJ, Clark, T, Crosas, M, Dillo, I, Dumon, O, Edmunds, S, Evelo, C T, Finkers, R, Gonzalez-Beltran, A, Gray, A J G, Groth, P, Goble, C, Grethe, J S, Heringa, J, 't Hoen, PAC, Hooft, R, Kuhn, T, Kok, R, Kok, J, Lusher, SJ, Martone, M E, Mons, A, Packer, A L, Persson, B, Rocca-Serra, P, Roos, M, van Schaik, R, Sansone, S A, Schultes, E, Sengstag, T, Slater, T, Strawn, G, Swertz, MA, Thompson, M, Lei, Johan, van Mulligen, Erik, Velterop, J, Waagmeester, A, Wittenburg, P, Wolstencroft, K, Zhao, J, Mons, B, Wilkinson, M D, Dumontier, M, Aalbersberg, I J, Appleton, G, Axton, M, Baak, A, Blomberg, N, Boiten, J W, Santos, L B D, Bourne, P E, Bouwman, J, Brookes, AJ, Clark, T, Crosas, M, Dillo, I, Dumon, O, Edmunds, S, Evelo, C T, Finkers, R, Gonzalez-Beltran, A, Gray, A J G, Groth, P, Goble, C, Grethe, J S, Heringa, J, 't Hoen, PAC, Hooft, R, Kuhn, T, Kok, R, Kok, J, Lusher, SJ, Martone, M E, Mons, A, Packer, A L, Persson, B, Rocca-Serra, P, Roos, M, van Schaik, R, Sansone, S A, Schultes, E, Sengstag, T, Slater, T, Strawn, G, Swertz, MA, Thompson, M, Lei, Johan, van Mulligen, Erik, Velterop, J, Waagmeester, A, Wittenburg, P, Wolstencroft, K, Zhao, J, and Mons, B

Published
2016

27. Scientific Lenses to Support Multiple Views over Linked Chemistry Data

Author

Batchelor, C., Brenninkmeijer, C.A., Chichester, C., Davies, M., Digles, D., Dunlop, I., Evelo, C., Gaulton, A., Goble, C., Gray, A.G., Groth, P., Harland, L., Karapetyan, K., Loizou, A., Overington, J., Pettifer, S., Steele, J., Stevens, R, Tkachenko, V., Waagmeester, A., Williams, A., Willighagen, E., Mika, P., Tudorache, T., Bernstein, A., Welty, C., Knoblock, C., Vrandečić, D., Noy, N., Janowicz, K., Business Web and Media, Artificial intelligence, Network Institute, Knowledge Representation and Reasoning, Intelligent Information Systems, Bioinformatica, and RS: NUTRIM - R4 - Gene-environment interaction

Subjects
Computer science, Use case, Linked data, Data mining, Equivalence (formal languages), Multiple view, computer.software_genre, computer, Equivalence (measure theory), Data integration
Abstract

When are two entries about a small molecule in different datasets the same? If they have the same drug name, chemical structure, or some other criteria? The choice depends upon the application to which the data will be put. However, existing Linked Data approaches provide a single global view over the data with no way of varying the notion of equivalence to be applied. In this paper, we present an approach to enable applications to choose the equivalence criteria to apply between datasets. Thus, supporting multiple dynamic views over the Linked Data. For chemical data, we show that multiple sets of links can be automatically generated according to different equivalence criteria and published with semantic descriptions capturing their context and interpretation. This approach has been applied within a large scale public-private data integration platform for drug discovery. To cater for different use cases, the platform allows the application of different lenses which vary the equivalence rules to be applied based on the context and interpretation of the links.

Published
2014

30. Abstracts of papers Toxicological meeting

Author

Breukink, H. J., Baars, A. J., Vroomen, L. H. M., Jager, L. P., Korstanje, C., Witkamp, R. J., van Leeuwen, F. X. R., Boogaard, P. J., Zoeteweij, J. P., Mulder, G. J., Nagelkerke, J. F., Bos, R. P., Kromhout, H., Ikink, H., Theuws, J. L. G., Dentener, M. A., Maessen, J. G., Buurman, W. A., de Vries, H., Bojarski, J., van Henegouwen, G. M. J. Beijersbergen, de Wolff, F. A., van Welsum, R. A., Marani, E., van Keep, J. P., van der Voet, G. B., den Besten, P. J., Livingstone, D. R., Dogterom, P., Evelo, C. T. A., Fijneman, P. H. S., Pötgens, A. J. G., Furnée, Carina, Verhagen, Hans, Schutte, Bert, Reynders, Michèle M. J., Blijham, Geert H., ten Hoor, Foppe, Kieinjans, Jos C. S., Haenen, G. R. M. M., Bast, A., Hageman, Geja, Kjkken, Rene, Kleinjans, Jos, Welle, Irene, Hajee, C. A. J., Rietveld, E. C., Seutter-Berlage, F., Hoogenboom, L. A. P., van Vliet, T., Kuiper, H. A., Canssen, Y., Hageman, G., van Agen, B., Schreurs, J., Jongeneelen, F. J., van Schooten, F. J., Kriek, E., van Leeuwen, F., Kelder, P. P., Dubbeling, M., de Mol, N. J., Janssen, L. H. M., Koymans, Luc, van Lenthe, Joop H., van de Straat, Ronald, den Kelder, Gabriëlle M. Donn-Op, Vermeulen, Nico P. E., Luyckx, Niels B. Lucas, Mennes, Wim C., van Pelt, Frank N. A. M., Noordhoek, Jan, Blaauboer, Bas J., Lusthof, K. J., Richter, W., Mannes, Wim C., van Holsteijn, Ineke W. M., Spierenburg, Th. J., van der Molen, E. J., de Graaf, G. J., Jager, L. P., Spierenburo, Th. J., Jager, L. P., Brus, D. H. J., Tielen, M. J. M., Arts, B. J., Stijntjes, G. J., Vermeulen, N. P. E., ten Hoor, F., ten Kate, J., Moerkerk, P., Bosman, F., Kleinjans, J., van Benthem, J., Wilmer, J. W. G. M., Leeman, U. R., Winterwerp, H. H. K., den Engelse, L., Scherer, E., van Bree, L., Rietjens, I. M. C. M., Verhoef, M. A., de Boer, R., Muller, J. J. A., Dormans, J. A. M. A., Rombout, P. J. A., van de Poll, M. L. M., van der Hulst, O. A. M., Tates, A. D., Meerman, J. H. N., van de Wiel, J. A. G., Duyf, C. M. P., Bos, P. P., Verweij, P. E., Sips, A., van Erp, Yvette H. H., Heirbaut, Petra R. C. M., Koopmans, Marion J. E., Weterings, Peter J. J. M., van Ginkel, M. F., van der Voet, E. V., van Loveren, H., Blommaert, F. A., Krajnc, E. I., Vos, J. G., van Ommen, Ben, Bogaards, Jan, van Bladeren, Peter J., van der Heijden, Ruud M., Hassing, Ine G. A. M., van Welie, R. T. H., van Duyn, P., Beckers, Rico H. G., Kleinjans, Jos C. S., and Maas, Lou M.

Published
1989
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31. Abstracts of papers toxicological meeting

Author

Beynen, A. C., Meijer, G. W., Joosten, H. F. P., van Kolfschoten, A. A., Koëter, H. B. W. M., Leegwater, P. C., Hermens, J. L. M., Rauws, A. G., Lumley, C. E., Walker, S. R., Bodar, C. W. M., Voogt, P. A., Wijnne, H., v. d. Zee, A., Zandee, D. I., Boogaard, P. J., Mulder, G. J., Nagelkerke, J. F., Boot, J. H., van Holsteijn, C. W. M., Blaauboer, B. J., Bos, R. P., Theuws, J. L. G., Jongeneelen, F. J., Brouwer, E. J., de Wolff, F. A., Busker, Ruud W., Commandeur, J. N. M., Vermeulen, N. P. E., Coosen, R., Schenk, E., van Leeuwen, F. X. R., Vos, J. G., Peereboom-Stegeman, J. H. J. Copius, van Veen, H., Pertijs, J., Danse, L. H. J. C., de Jong, K., Speijers, G. J. A., de Kom, J. F. M., Edelbroek, P. M., de Jong, E. G., Maes, R. A. A., de Vries, H., van Henegouwen, G. M. J. Beyersbergen, Berkhuysen, M. H. J., Kalloe, P., de Zwaan, A., de Kock, W. Chr, den Besten, P. J., Dogterom, P., Dormans, J. A. M. A., Boere, A. J. F., van Bree, L., Rombout, P. J. A., Evelo, C. T. A., Fijneman, P. H. S., Henderson, P. Th., Goeptar, A. R., Haenen, G. R. M. M., Bast, A., Tai Tin Tsoi, J. N. L., Timmerman, H., Hageman, G., Hermans, R., Kleinjans, J., Herweijer, M. A., Bootsman, T. C., van der Meer, S. G., Planta, R. J., Kappers, Frederike I., Wondergem-van Eijk, Jacqueline A. A. M., Kelder, P. P., de Mol, N. J., Janssen, L. H. M., Kroese, E. D., van de Poll, M. L. M, Meerman, J. H. N., Lock, R. A. C., Verbost, P. M., Flik, G., Bonga, S. E. Wendelaar, Lusthof, K. J., Hennes, W. C., den Hartogh, R., Kietjens, I., Dornans, J., Rombout, P., Schoonderwoerd, S. A., Luijendijk, J. J., van Henegouwen, G. M. J. Beijersbergen, te Koppele, J. M., Coles, B., Ketterer, B., van Ginkel, M. F., van der Voet, G. B., van Pelt, F. N. A. M., olde Meierink, Y. J. M., Weterings, P. J. J. H, van Os, C. H., Verhagen, H., Schutte, B., Reynders, M. M. J., Blijham, G. H., ten Hoor, F., Kleinjans, J. C. S., Wetzer, A. M., Weetink, H., Rietveld, E. C, Seutter-Berlage, F., and van Henegouwen, Gerard M. J. Beijersbergen

Published
1987
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32. Dutch Pharmacological Meeting 1984

Author

Timmerman, H., Koeman, J. H., den Tonkelaar, E. H., Merkus, F. W. H. M., Struyker-Boudier, H. A. J., Bolt, G. R., Saxena, P. R., Bos, R. P., Breed, A. S. P. M., Theuws, J. L. G., Henderson, P. Th., de Brauw, L. M., de Bruijn, E. A., van de Velde, C. J. H., Tjaden, U. R., Kothuis, B. J. L., van Oosterom, A. T., Reeuwijk, H. J. E. M., Pinedo, H. M., van der Hoeven, R., Bultsma, T., Linschoten, M. R., Peter, J., Burbach, H., de Kloet, E. Ronald, Castelein, O., Verbeke, N., Leuven, K. U., Conings, L., Doods, H. N., Kalkman, H. O., de Jonge, A., Wilffert, B., Thoolen, M. J. M. C., Timmermans, P. B. M. W. M., van Zwieten, P. A., van Driel, J. B. M., Klaassen, A. B. M., Kuypers, W., Beld, A. J., Rodrigues de Miranda, J. F., Driessen, O., van der Velde, E. A., Engels, F., Oosting, R. S., Nijkamp, F. P., Evelo, C. T. A., Neis, J. M., Peters, J. G. P., ten Broeke, M. A. M., Vulders, C. A. J. M., Franssen, M. J. A. M., van Herwaarden, C. L. A., van de Putte, L. B. A., Gribnau, F. W. J., van der Graaff, M., Vermeulen, N. P. E., Hofman, P. H., Breimer, D. D., 't Hart, B. J., Wilting, J., de Gier, J. J., Hazelhoff, Bernard, de Vries, Jan B., Oijkstra, Durk, Mulder, Theo, Wynberg, Hans, Horn, Alan, van Doorn, R., Leijdekkers, Ch. -M., Anzion, R., Hengstum, M. v., Festen, J., Buijs, W., Broek, W. v. d., Groothedde, R., Corstens, F., van Heuven-Nolsen, P., de Wildt, D. J., Hillen, F. C., van Noordwijk, J., Janssen, Lambert H. M., Jansen, P. A. F., Meyboom, R. H. B., Vree, T. B., Jelinek, J., Schönbaum, E., Lomax, P., de Jong, W., Sandor, P., Cox van Put, J. J., Jongeneelen, F. J., Leijdekkers, Ch. M., Kerklaan, P. R. M., Zoetemelk, C. E. M., Mohn, G. R., Grote, J. J., Kuijpers, W., Kleinbloesem, C. H., van Brummelen, P., van Harten, J., Koopmans, P. P., Kateman, W., Tan, Y., van Ginneken, C. A. M., van Koppen, C. J., van der Beek, E. M., Lammers, J. W. J., Krielaart, M. J., Laban, E., Charbon, G. A., Folgering, H. Th. M., Lenders, J. W. M., Sluiter, H. E., Willemsen, J., Thien, Th., Mooy, J., Schols, M., Baak, M. v., Hooff, M. v., Rahn, K. H., Mulder, Theo B. A., Grol, Cor J., Dijkstra, Durk, Horn, Alan S., Neef, C., Meijer, D. K. F., van Gemert, P. J. L., Roelofs, H. M. J., Osterhuis, B. O, ten Berge, R. J. M., Schellekens, P. T. A., van Boxtel, C. J., Peeters, P. A. M., Raghoebar, M., Tiemessen, H. L. G. H., Raaijmakers, J. A. M., van Rozen, A. J., Terpstra, G. K., Wassink, G. A., Kreukniet, J., Remeyer, L. R., Reeuwijk, H. J. E., Touw, D. J., Rollema, Hans, Mastebroex, Dora, Russel, F. G. M., Wouterse, A. C., Rijk, M. C. M., Salden, H. J. M., De Schaepdryver, A. F., Lefebvre, R. A., Bogaert, M. G., Scheres, H. M. E., Salden, H. J. H., Siero, H. L. M., Slee, P. H. Th. J., van den Berg, L., Huysmans, F. Th. M., Koene, R. A. P., Smits, J. F. M., Nievelstein, H. M. N., Struyker Boudier, H. A. J., Raaijmakers, J. A. H., Huidekoper, H. J., Thljssen, H. H. W., Baars, L. C. M., Mathy, M. J., Veldhoven, C. M. M., AriËns, E. J., Ruland, C. M., de Vos, Cor, de Graaf, Joop, van Aalst, Gerard, Steenbergen, Hans, Hekster, Y. A., Tijhuis, M. W., Nouws, J. F. M., Wollersheim, H., Fennis, J., van 't Laar, A., Wijnands, W. J., van der Gen, A., Jzerman, A. P. I., Aué, G., Dorlas, R., Krajnc, E. I., Loeber, J. G., van Leeuwen, F. X. R., Wester, P. W., Vos, J. G., Vaessen, H. A. M. G., Heijden, C. A. v. d., Canton, J. H., de Klerk, A., Krajc, E. I., Kruizinga, W., van Ommen, B., Rozing, J., van der Heijden, C. A., van der Voet, G. B., de Wolff, F. A., Edelbroek, Peter M., de Reus, Margot J. H., van den Berg, Tjeerd, and de Wolff, Frederik A.

Published
1984
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33. Abstract of papers

Author

Konings, A. W. T., Joenje, H., Bast, A., Julicher, R., Van Iersel, A. A. J., Blaauboer, B. J., Balfoort, H. W., Ronbout, P. J. A., Borm, P. J. A., Engelen, J. J. M., Wouters, E. F. M., Swaen, C. M. H., de Boorder, Tj., Bos, R. P., Prinsen, W. J. C., Jongeneelen, F. J., Theuws, J. L. G., Henderson, P. Th., Cervantes, A., Schuurhuis, G. J., Pinedo, H. M., Lankelma, J., Commandeur, J. N. M., Oostendorp, R. A. J., Schoofs, P. R., Xu, B., Vermeulen, N. P. E., Coosen, R., van Leeuwen, F. X. R., Vos, J. G., Thijssen, J. H. H., Loeber, J. G., de Mol, N. J., Becht, A. B. C., Koenen, J., Lodder, G., de Wolff, F. A., van Ginkel, M. F., van der Voet, G. B., Dogterom, P., Nagelkerke, J. F., Mulder, G. J., Edelbroek, P. M., Zitman, F. G., Evelo, C. T. A., Niessen, H. J. J. M., Roelofs, H. M. J., Falke, H. E., De Groot, A. P., Willems, M. I., Franken, M. A. M., Kapteijn, R., Krajnc, E. I., Haenen, G. R. M. M., Plug, J. P. M., Timmerman, H., Hageman, G. J., Verhagen, H., Kleinjans, J. C. S., Herweijer, M. A., Bootsman, T. C., Scholte, B. J., Planta, R. J., Kroese, E. D., Tijdens, R. B., Meerman, J. H. N., Lusthof, K. J., Decuyper, J. G. A., Groothuis-Pielage, I. L., de Mol, N. J., Rietjens, I. M. C. M., Vos, R. M. E., Alink, G. M., van Bladeren, P. J., Rietveld, E. C., Ketels, H. H. T. M., Wetzer, A. M. A. C., Seutter-Berlage, F., Rombout, P., Dormans, J., van Bree, L., Marra, M., Til, H. P., Woutersen, R. A., Feron, V. J., Clary, J. J., Brandsma, A. E., de Wofff, F. A., van de Straat, R., de Vries, J., Boere, A. J. F., Rombout, P. J. A., Rietjens, I., Alink, G., van Erp, Yvette H. M., Heirbaut, Petra R. C. M., Koopmans, Marion J. E., Weterings, Peter J. J. M., van Loveren, H., de Klerk, A., Hakkert, B., Vertagen, H., Thijssen, H. H. W., Wester, P. W., Canton, J. H., Weterings, Peter J. J. M., and van Erp, Yvette H. M.

Published
1987
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34. Alterations in hepatic one-carbon metabolism and related pathways following a high-fat dietary intervention

Author

Rubio-Aliaga, I., Roos, B., Sailer, M., McLoughlin, G., van Schothorst, E.M., van Erk, M.J., Keijer, J., Müller, M.R., Boekschoten, M.V., Bachmair, E.M., Coort, S.L., Evelo, C., Gibney, M.J., Daniel, H., Muller, M., Kleemann, R., Brennan, L., Bioinformatica, RS: NUTRIM - R4 - Gene-environment interaction, and RS: CARIM School for Cardiovascular Diseases

Subjects
Blood Glucose, Very low-density lipoprotein, High-fat feeding, obesity, Physiology, induced insulin-resistance, medicine.disease_cause, chemistry.chemical_compound, Mice, Voeding, Metabolisme en Genomica, Methionine, Life, Choline, Insulin, oxidative stress, homocysteine s-methyltransferase, Fatty liver, deficient mice, MHR - Metabolic Health Research MSB - Microbiology and Systems Biology, Metabolism and Genomics, Cholesterol, Metabolisme en Genomica, Human and Animal Physiology, Kennedy pathway, Nutrition, Metabolism and Genomics, EELS - Earth, Environmental and Life Sciences, ikk-beta, medicine.medical_specialty, Biology, liver, Insulin resistance, Voeding, choline, Internal medicine, Genetics, medicine, Animals, Obesity, Triglycerides, plasma, Nutrition, VLAG, disease, Metabolism, medicine.disease, Dietary Fats, Carbon, Fatty Liver, Mice, Inbred C57BL, Endocrinology, chemistry, Hyperglycemia, WIAS, Fysiologie van Mens en Dier, Steatosis, Insulin Resistance, Oxidative stress
Abstract

Obesity frequently leads to insulin resistance and the development of hepatic steatosis. to characterize the molecular changes that promote hepatic steatosis, transcriptomics, proteomics, and metabolomics technologies were applied to liver samples from c57bl/6j mice obtained from two independent intervention trials. after 12 wk of high-fat feeding the animals became obese, hyperglycemic, and insulin resistant, had elevated levels of blood cholesterol and vldl, and developed hepatic steatosis. nutrigenomic analysis revealed alterations of key metabolites and enzyme transcript levels of hepatic one-carbon metabolism and related pathways. the hepatic oxidative capacity and the lipid milieu were significantly altered, which may play a key role in the development of insulin resistance. additionally, high choline levels were observed after the high-fat diet. previous studies have linked choline levels with insulin resistance and hepatic steatosis in conjunction with changes of certain metabolites and enzyme levels of onecarbon metabolism. the present results suggest that the coupling of high levels of choline and low levels of methionine plays an important role in the development of insulin resistance and liver steatosis. in conclusion, the complexities of the alterations induced by high-fat feeding are multifactorial, indicating that the interplay between several metabolic pathways is responsible for the pathological consequences. © 2011 the American Physiological Society.

Published
2011

35. The Micronutrient Genomics Project: A community-driven knowledge base for micronutrient research

Author

van Ommen, B, El-Sohemy, A, Hesketh, J, Kaput, J, Fenech, M, Evelo, C, McArdle, H, Bouwman, J, Lietz, G, Mathers, J, Fairweather-Tait, S, van Kranen, H, Elliott, R, Wopereis, S, Ferguson, LR, Meplan, C, Perozzi, G, Allen, L, Revero, D, The Micronutrient Genomics Project Working Group, TNO Kwaliteit van Leven, Bioinformatica, and RS: NUTRIM - R4 - Gene-environment interaction

Subjects
030309 nutrition & dietetics, Computer science, Bioinformatics, Systems biology, Endocrinology, Diabetes and Metabolism, BIOLOGY, Context (language use), Genomics, Review, Physiological Sciences, METABOLISM, RIBOFLAVIN, DISEASE, Database, 03 medical and health sciences, STABLE-ISOTOPES, Genetics, Micronutrient, 030304 developmental biology, 2. Zero hunger, 0303 health sciences, VITAMIN-A, business.industry, BETA-CAROTENE, Data science, Toolbox, Human genetics, 3. Good health, Biotechnology, DEFICIENCY, Knowledge base, business, Biological network, FOLATE
Abstract

Micronutrients influence multiple metabolic pathways including oxidative and inflammatory processes. Optimum micronutrient supply is important for the maintenance of homeostasis in metabolism and, ultimately, for maintaining good health. With advances in systems biology and genomics technologies, it is becoming feasible to assess the activity of single and multiple micronutrients in their complete biological context. Existing research collects fragments of information, which are not stored systematically and are thus not optimally disseminated. The Micronutrient Genomics Project (MGP) was established as a community-driven project to facilitate the development of systematic capture, storage, management, analyses, and dissemination of data and knowledge generated by biological studies focused on micronutrient-genome interactions. Specifically, the MGP creates a public portal and open-source bioinformatics toolbox for all "omics" information and evaluation of micronutrient and health studies. The core of the project focuses on access to, and visualization of, genetic/genomic, transcriptomic, proteomic and metabolomic information related to micronutrients. For each micronutrient, an expert group is or will be established combining the various relevant areas (including genetics, nutrition, biochemistry, and epidemiology). Each expert group will (1) collect all available knowledge, (2) collaborate with bioinformatics teams towards constructing the pathways and biological networks, and (3) publish their findings on a regular basis. The project is coordinated in a transparent manner, regular meetings are organized and dissemination is arranged through tools, a toolbox web portal, a communications website and dedicated publications. © 2010 The Author(s).

Published
2010

36. Transcriptome analysis of peripheral blood mononuclear cells in human subjects following a 36 h fast provides evidence of effects on genes regulating inflammation, apoptosis and energy metabolism

Author

Elliott, R. M., primary, de Roos, B., additional, Duthie, S. J., additional, Bouwman, F. G., additional, Rubio-Aliaga, I., additional, Crosley, L. K., additional, Mayer, C., additional, Polley, A. C., additional, Heim, C., additional, Coort, S. L., additional, Evelo, C. T., additional, Mulholland, F., additional, Daniel, H., additional, Mariman, E. C., additional, and Johnson, I. T., additional

Published
2014
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37. Time-resolved and tissue-specific systems analysis of the pathogenesis of insulin resistance.

Author

Kleemann, R., Erk, M. van, Verschuren, L., Hoek, A.M. van den, Koek, M., Wielinga, P.Y., Jie, A., Pellis, L., Bobeldijk-Pastorova, I., Kelder, T., Toet, K., Wopereis, S., Cnubben, N., Evelo, C., Ommen, B. van, Kooistra, T., Kleemann, R., Erk, M. van, Verschuren, L., Hoek, A.M. van den, Koek, M., Wielinga, P.Y., Jie, A., Pellis, L., Bobeldijk-Pastorova, I., Kelder, T., Toet, K., Wopereis, S., Cnubben, N., Evelo, C., Ommen, B. van, and Kooistra, T.

Abstract

BACKGROUND: The sequence of events leading to the development of insulin resistance (IR) as well as the underlying pathophysiological mechanisms are incompletely understood. As reductionist approaches have been largely unsuccessful in providing an understanding of the pathogenesis of IR, there is a need for an integrative, time-resolved approach to elucidate the development of the disease. METHODOLOGY/PRINCIPAL FINDINGS: Male ApoE3Leiden transgenic mice exhibiting a humanized lipid metabolism were fed a high-fat diet (HFD) for 0, 1, 6, 9, or 12 weeks. Development of IR was monitored in individual mice over time by performing glucose tolerance tests and measuring specific biomarkers in plasma, and hyperinsulinemic-euglycemic clamp analysis to assess IR in a tissue-specific manner. To elucidate the dynamics and tissue-specificity of metabolic and inflammatory processes key to IR development, a time-resolved systems analysis of gene expression and metabolite levels in liver, white adipose tissue (WAT), and muscle was performed. During HFD feeding, the mice became increasingly obese and showed a gradual increase in glucose intolerance. IR became first manifest in liver (week 6) and then in WAT (week 12), while skeletal muscle remained insulin-sensitive. Microarray analysis showed rapid upregulation of carbohydrate (only liver) and lipid metabolism genes (liver, WAT). Metabolomics revealed significant changes in the ratio of saturated to polyunsaturated fatty acids (liver, WAT, plasma) and in the concentrations of glucose, gluconeogenesis and Krebs cycle metabolites, and branched amino acids (liver). HFD evoked an early hepatic inflammatory response which then gradually declined to near baseline. By contrast, inflammation in WAT increased over time, reaching highest values in week 12. In skeletal muscle, carbohydrate metabolism, lipid metabolism, and inflammation was gradually suppressed with HFD. CONCLUSIONS/SIGNIFICANCE: HFD-induced IR is a time- and tissue-dependent p

Published
2010

38. Identification of novel ER-alpha target genes in breast cancer cells: Gene- and cell-selective co-regulator recruitment at target promoters determines the response to 17beta-estradiol and tamoxifen

Author

Romano, A., Romano, A., Michiel Adriaens, M.E., Kuenen, S., Delvoux, B., Dunselman, G., Evelo, C., Groothuis, P., Romano, A., Romano, A., Michiel Adriaens, M.E., Kuenen, S., Delvoux, B., Dunselman, G., Evelo, C., and Groothuis, P.

Abstract

Tamoxifen and 17beta-estradiol are capable of up-regulating the expression of some genes and down-regulate the expression of others simultaneously in the same cell. In addition, tamoxifen shows distinct transcriptional activities in different target tissues. To elucidate whether these events are determined by differences in the recruitment of co-regulators by activated estrogen receptor-alpha (ER-alpha) at target promoters, we applied chromatin immunoprecipitation (ChIP) with promoter microarray hybridisation in breast cancer T47D cells and identified 904 ER-alpha targets genome-wide. On a selection of newly identified targets, we show that 17beta-estradiol and tamoxifen stimulated up- or down-regulation of transcription correlates with the selective recruitment of co-activators or co-repressors, respectively. This is shown for both breast (T47D) and endometrial carcinoma cells (ECC1). Moreover, differential co-regulator recruitment also explains that tamoxifen regulates a number of genes in opposite direction in breast and endometrial cancer cells. Over-expression of co-activator SRC-1 or co-repressor SMRT is sufficient to alter the transcriptional action of tamoxifen on a number of targets. Our findings support the notion that recruitment of co-regulator at target gene promoters and their expression levels determine the effect of ER-alpha on gene expression to a large extent.

Published
2010

39. A Combined Transcriptomics and Lipidomics Analysis of Subcutaneous, Epididymal and Mesenteric Adipose Tissue Reveals Marked Functional Differences

Author

Caesar, R., Manieri, M., Kelder, T., Boekschoten, M.V., Evelo, C., Müller, M.R., Kooistra, T., Cinti, S., Kleemann, R., Drevon, C.A., Caesar, R., Manieri, M., Kelder, T., Boekschoten, M.V., Evelo, C., Müller, M.R., Kooistra, T., Cinti, S., Kleemann, R., and Drevon, C.A.

Abstract

Depot-dependent differences in adipose tissue physiology may reflect specialized functions and local interactions between adipocytes and surrounding tissues. We combined time-resolved microarray analyses of mesenteric- (MWAT), subcutaneous- (SWAT) and epididymal adipose tissue (EWAT) during high-fat feeding of male transgenic ApoE3Leiden mice with histology, targeted lipidomics and biochemical analyses of metabolic pathways to identify differentially regulated processes and site-specific functions. EWAT was found to exhibit physiological zonation. De novo lipogenesis in fat proximal to epididymis was stably low, whereas de novo lipogenesis distal to epididymis and at other locations was down-regulated in response to high-fat diet. The contents of linoleic acid and a-linolenic acid in EWAT were increased compared to other depots. Expression of the androgen receptor (Ar) was higher in EWAT than in MWAT and SWAT. We suggest that Ar may mediate depot-dependent differences in de novo lipogenesis rate and propose that accumulation of linoleic acid and a-linolenic acid in EWAT is favored by testosterone-mediated inhibition of de novo lipogenesis and may promote further elongation and desaturation of these polyunsaturated fatty acids during spermatogenesis

Published
2010

40. Challenges of molecular nutrition research 6: the nutritional phenotype database to store, share and evaluate nutritional systems biology studies

Author

van Ommen, B., Bouwman, J.H., Dragsted, L.O., Drevon, C.A., Elliott, R., de Groot, P.J., Kaput, J., Mathers, J.C., Müller, M.R., Pepping, F., Saito, J., Scalbert, A., Radonjic, M., Rocca-Serra, P., Travis, A., Wopereis, S., Evelo, C., van Ommen, B., Bouwman, J.H., Dragsted, L.O., Drevon, C.A., Elliott, R., de Groot, P.J., Kaput, J., Mathers, J.C., Müller, M.R., Pepping, F., Saito, J., Scalbert, A., Radonjic, M., Rocca-Serra, P., Travis, A., Wopereis, S., and Evelo, C.

Abstract

The challenge of modern nutrition and health research is to identify food-based strategies promoting life-long optimal health and well-being. This research is complex because it exploits a multitude of bioactive compounds acting on an extensive network of interacting processes. Whereas nutrition research can profit enormously from the revolution in ‘omics’ technologies, it has discipline-specific requirements for analytical and bioinformatic procedures. In addition to measurements of the parameters of interest (measures of health), extensive description of the subjects of study and foods or diets consumed is central for describing the nutritional phenotype. We propose and pursue an infrastructural activity of constructing the “Nutritional Phenotype database” (dbNP). When fully developed, dbNP will be a research and collaboration tool and a publicly available data and knowledge repository. Creation and implementation of the dbNP will maximize benefits to the research community by enabling integration and interrogation of data from multiple studies, from different research groups, different countries and different-omics levels. The dbNP is designed to facilitate storage of biologically relevant, pre-processed-omics data, as well as study descriptive and study participant phenotype data. It is also important to enable the combination of this information at different levels (e.g. to facilitate linkage of data describing participant phenotype, genotype and food intake with information on study design and-omics measurements, and to combine all of this with existing knowledge). The biological information stored in the database (i.e. genetics, transcriptomics, proteomics, biomarkers, metabolomics, functional assays, food intake and food composition) is tailored to nutrition research and embedded in an environment of standard procedures and protocols, annotations, modular data-basing, networking and integrated bioinformatics. The dbNP is an evolving enterprise, which is only

Published
2010

41. Four selenoproteins, protein biosynthesis, and Wnt signalling are particularly sensitive to limited selenium intake in mouse colon

Author

Kipp, A., Kipp, A., Banning, A., van Schothorst, E.M., Meplan, C., Schomburg, L., Evelo, C., Coort, S., Gaj, S., Keijer, J., Hesketh, J., Brigelius Flohe, R., Kipp, A., Kipp, A., Banning, A., van Schothorst, E.M., Meplan, C., Schomburg, L., Evelo, C., Coort, S., Gaj, S., Keijer, J., Hesketh, J., and Brigelius Flohe, R.

Abstract

Selenium is an essential micronutrient. Its recommended daily allowance is not attained by a significant proportion of the population in many countries and its intake has been suggested to affect colorectal carcinogenesis. Therefore, microarrays were used to determine how both selenoprotein and global gene expression patterns in the mouse colon were affected by marginal selenium deficiency comparable to variations in human dietary intakes. Two groups of 12 mice each were fed a selenium-deficient (0.086 mg Se/kg) or a selenium-adequate (0.15 mg Se/kg) diet. After 6 wk, plasma selenium level, liver, and colon glutathione peroxidase (GPx) activity in the deficient group was 12, 34, and 50%, respectively, of that of the adequate group. Differential gene expression was analysed with mouse 44K whole genome microarrays. Pathway analysis by GenMAPP identified the protein biosynthesis pathway as most significantly affected, followed by inflammation, Delta-Notch and Wnt pathways. Selected gene expression changes were confirmed by quantitative real-time PCR. GPx1 and the selenoproteins W, H, and M, responded significantly to selenium intake making them candidates as biomarkers for selenium status. Thus, feeding a marginal selenium-deficient diet resulted in distinct changes in global gene expression in the mouse colon. Modulation of cancer-related pathways may contribute to the higher susceptibility to colon carcinogenesis in low selenium status.

Published
2009

42. Reduction of colonic inflammation in HLA-B27 transgenic rats by feeding Marie Ménard apples, rich in polyphenols

Author

Castagnini, C., Luceri, C., Toti, S., Bigagli, E., Caderni, G., Femia, A.P., Giovannelli, L., Lodovici, M., Pitozzi, V., Salvadori, M., Messerini, L., Martin, R., Zoetendal, E.G., Gaj, S., Eijssen, L., Evelo, C., Renard, C.M., Baron, A., Dolara, P., Castagnini, C., Luceri, C., Toti, S., Bigagli, E., Caderni, G., Femia, A.P., Giovannelli, L., Lodovici, M., Pitozzi, V., Salvadori, M., Messerini, L., Martin, R., Zoetendal, E.G., Gaj, S., Eijssen, L., Evelo, C., Renard, C.M., Baron, A., and Dolara, P.

Abstract

Inflammatory bowel diseases (IBD) are immunomediated ailments affecting millions of individuals. Although diet is regarded as an important factor influencing IBD, there are no accepted dietary recommendations presently available. We administered 7.6 % lyophilised apples obtained from two cultivars (Golden Delicious and Marie Ménard, low and high in polyphenols, respectively) to HLA-B27 transgenic rats which develop spontaneous IBD. After 3 months feeding, rats fed Marie Ménard apples had reduced myeloperoxidase activity (3.6 (sem 0.3) v. 2.2 (sem 0.2) U/g tissue; P <0.05) and reduced cyclo-oxygenase-2 (P <0.05) and inducible NO synthase gene expression (P <0.01) in the colon mucosa and significantly less diarrhoea (P <0.05), compared with control rats. Cell proliferation in the colon mucosa was reduced significantly by feeding Golden Delicious apples, with a borderline effect of Marie Ménard apples. Gene expression profiling of the colon mucosa, analysed using the Whole Rat Genome 4 x 44 K Agilent Arrays, revealed a down-regulation of the pathways of PG synthesis, mitogen-activated protein kinase (MAPK) signalling and TNFalpha-NF-kappaB in Marie Ménard-fed rats. In the stools of the animals of this group we also measured a significant reduction of bacteria of the Bacteriodes fragilis group. In conclusion, the administration of Marie Ménard apples, rich in polyphenols and used at present only in the manufacturing of cider, ameliorates colon inflammation in transgenic rats developing spontaneous intestinal inflammation, suggesting the possible use of these and other apple varieties to control inflammation in IBD patients

Published
2009

43. The NuGO proof of principle study package: a collaborative research effort of the European Nutrigenomics Oganisation

Author

Baccini, M., Bachmaier, E.M., Biggeri, A., Boekschoten, M.V., Bouwman, F.G., Brennan, L., Caesar, R., Cinti, S., Coort, S.L., Crosley, K., Daniel, H., Drevon, C.A., Duthie, S., Eijssen, L., Elliott, R., van Erk, M.J., Evelo, C., Gibney, M.J., Heim, C., Horgan, G., Johnson, I.T., Kelder, T., Kleemann, R., Kooistra, T., van Iersel, M.P., Mariman, E.C.M., Mayer, C., McLoughlin, G., Müller, M.R., Mulholland, F., van Ommen, B., Polley, A.C., Pujos-Guillot, E., Rubio-Aliaga, I., Roche, H., de Roos, B., Sailer, M., Tonini, G., Williams, L.M., de Wit, N.J.W., Baccini, M., Bachmaier, E.M., Biggeri, A., Boekschoten, M.V., Bouwman, F.G., Brennan, L., Caesar, R., Cinti, S., Coort, S.L., Crosley, K., Daniel, H., Drevon, C.A., Duthie, S., Eijssen, L., Elliott, R., van Erk, M.J., Evelo, C., Gibney, M.J., Heim, C., Horgan, G., Johnson, I.T., Kelder, T., Kleemann, R., Kooistra, T., van Iersel, M.P., Mariman, E.C.M., Mayer, C., McLoughlin, G., Müller, M.R., Mulholland, F., van Ommen, B., Polley, A.C., Pujos-Guillot, E., Rubio-Aliaga, I., Roche, H., de Roos, B., Sailer, M., Tonini, G., Williams, L.M., and de Wit, N.J.W.

Published
2008

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