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- Abteilung für Funktionswerkstoffe der Medizin und der Zahnheilkunde (1)
Sonstige beteiligte Institutionen
Osorio, Ana ; Milne, Roger L. ; Kuchenbaecker, Karoline ; Vaclová, Tereza ; Pita, Guillermo ; Alonso, Rosario ; Peterlongo, Paolo ; Blanco, Ignacio ; de la Hoya, Miguel ; Duran, Mercedes ; Diez, Orland ; Ramón y Cajal, Teresa ; Konstantopoulou, Irene ; Martínez-Bouzas, Christina ; Conejero, Raquel Andrés ; Soucy, Penny ; McGuffog, Lesley ; Barrowdale, Daniel ; Lee, Andrew ; Arver, Brita ; Rantala, Johanna ; Loman, Niklas ; Ehrencrona, Hans ; Olopade, Olufunmilayo I. ; Beattie, Mary S. ; Domchek, Susan M. ; Nathanson, Katherine ; Rebbeck, Timothy R. ; Arun, Banu K. ; Karlan, Beth Y. ; Walsh, Christine ; Lester, Jenny ; John, Esther M. ; Whittemore, Alice S. ; Daly, Mary B. ; Southey, Melissa ; Hopper, John ; Terry, Mary B. ; Buys, Saundra S. ; Janavicius, Ramunas ; Dorfling, Cecilia M. ; van Rensburg, Elizabeth J. ; Steele, Linda ; Neuhausen, Susan L. ; Ding, Yuan Chun ; Hansen, Thomas V. O. ; Jønson, Lars ; Ejlertsen, Bent ; Gerdes, Anne-Marie ; Infante, Mar ; Herráez, Belén ; Moreno, Leticia Thais ; Weitzel, Jeffrey N. ; Herzog, Josef ; Weeman, Kisa ; Manoukian, Siranoush ; Peissel, Bernard ; Zaffaroni, Daniela ; Scuvera, Guilietta ; Bonanni, Bernardo ; Mariette, Frederique ; Volorio, Sara ; Viel, Alessandra ; Varesco, Liliana ; Papi, Laura ; Ottini, Laura ; Tibiletti, Maria Grazia ; Radice, Paolo ; Yannoukakos, Drakoulis ; Garber, Judy ; Ellis, Steve ; Frost, Debra ; Platte, Radka ; Fineberg, Elena ; Evans, Gareth ; Lalloo, Fiona ; Izatt, Louise ; Eeles, Ros ; Adlard, Julian ; Davidson, Rosemarie ; Cole, Trevor ; Eccles, Diana ; Cook, Jackie ; Hodgson, Shirley ; Brewer, Carole ; Tischkowitz, Marc ; Douglas, Fiona ; Porteous, Mary ; Side, Lucy ; Walker, Lisa ; Morrison, Patrick ; Donaldson, Alan ; Kennedy, John ; Foo, Claire ; Godwin, Andrew K. ; Schmutzler, Rita Katharina ; Wappenschmidt, Barbara ; Rhiem, Kerstin ; Engel, Christoph ; Meindl, Alftons ; Ditsch, Nina ; Arnold, Norbert ; Plendl, Hans Jörg ; Niederacher, Dieter ; Sutter, Christian ; Wang-Gohrke, Shan ; Steinemann, Doris ; Preisler-Adams, Sabine ; Kast, Karin ; Varon-Mateeva, Raymonda ; Gehrig, Andrea ; Stoppa-Lyonnet, Dominique ; Sinilnikova, Olga M. ; Mazoyer, Sylvie ; Damiola, Francesca ; Poppe, Bruce ; Claes, Kathleen ; Piedmonte, Marion ; Tucker, Kathy ; Backes, Floor ; Rodríguez, Gustavo ; Brewster, Wendy ; Wakeley, Katie ; Rutherford, Thomas ; Caldés, Trinidad ; Nevanlinna, Heli ; Aittomäki, Kristiina ; Rookus, Matti A. ; van Os, Theo A. M. ; van der Kolk, Lizet ; de Lange, J. L. ; Meijers-Heijboer, Hanne E. J. ; van der Hout, A. H. ; van Asperen, Christi J. ; Goméz Garcia, Encarna B. ; Encarna, B. ; Hoogerbrugge, Nicoline ; Collée, J. Margriet ; van Deurzen, Carolien H. M. ; van der Luijt, Rob B. ; Devilee, Peter ; Olah, Edith ; Lázaro, Conxi ; Teulé, Alex ; Menéndez, Mireia ; Jakubowska, Anna ; Cybulski, Cezary ; Gronwald, Jecek ; Lubinski, Jan ; Durda, Katarzyna ; Jaworska-Bieniek, Katarzyna ; Johannsson, Oskar Th. ; Maugard, Christine ; Montagna, Marco ; Tognazzo, Silvia ; Teixeira, Manuel R. ; Healey, Sue ; Olswold, Curtis ; Guidugli, Lucia ; Lindor, Noralane ; Slager, Susan ; Szabo, Csilla I. ; Vijai, Joseph ; Robson, Mark ; Kauff, Noah ; Zhang, Liying ; Rau-Murthy, Rohini ; Fink-Retter, Anneliese ; Singer, Christine F. ; Rappaport, Christine ; Kaulich, Daphne Geschwantler ; Pfeiler, Georg ; Tea, Muy-Kheng ; Berger, Andreas ; Phelan, Catherine M. ; Greene, Mark H. ; Mai, Phuong L. ; Lejbkowicz, Flavio ; Andrulis, Irene ; Mulligan, Anna Marie ; Glendon, Gord ; Toland, Amanda Ewart ; Bojesen, Anders ; Pedersen, Inge Sokilde ; Sunde, Lone ; Thomassen, Mads ; Kruse, Torben A. ; Jensen, Uffe Birk ; Friedman, Eitan ; Laitman, Yeal ; Shimon, Shanie Paluch ; Simard, Jaques ; Easton, Douglas F. ; Offit, Kenneth ; Couch, Fergus J. ; Chenevix-Trench, Georgia ; Antoniou, Antonis C. ; Benitez, Javier
Single Nucleotide Polymorphisms (SNPs) in genes involved in the DNA Base Excision Repair (BER) pathway could be associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of the components of the BER pathway, PARP1 (poly ADP ribose polymerase), and both BRCA1 and BRCA2. In the present study, we have performed a comprehensive analysis of 18 genes involved in BER using a tagging SNP approach in a large series of BRCA1 and BRCA2 mutation carriers. 144 SNPs were analyzed in a two stage study involving 23,463 carriers from the CIMBA consortium (the Consortium of Investigators of Modifiers of BRCA1 and BRCA2). Eleven SNPs showed evidence of association with breast and/or ovarian cancer at p<0.05 in the combined analysis. Four of the five genes for which strongest evidence of association was observed were DNA glycosylases. The strongest evidence was for rs1466785 in the NEIL2 (endonuclease VIII-like 2) gene (HR: 1.09, 95% CI (1.03-1.16), p = 2.7x10(-3)) for association with breast cancer risk in BRCA2 mutation carriers, and rs2304277 in the OGG1 (8-guanine DNA glycosylase) gene, with ovarian cancer risk in BRCA1 mutation carriers (HR: 1.12 95% CI: 1.03-1.21, p = 4.8x10(-3)). DNA glycosylases involved in the first steps of the BER pathway may be associated with cancer risk in BRCA1/2 mutation carriers and should be more comprehensively studied.
Antoniou, Antonis C. ; Kuchenbaecker, Karoline B. ; Soucy, Penny ; Beesley, Jonathan ; Chen, Xiaoqing ; McGuffog, Lesley ; Lee, Andrew ; Barrowdale, Daniel ; Healey, Sue ; Sinilnikova, Olga M. ; Caligo, Maria A. ; Loman, Niklas ; Harbst, Katja ; Lindblom, Annika ; Arver, Brita ; Rosenquist, Richard ; Karlsson, Per ; Nathanson, Kate ; Domchek, Susan ; Rebbeck, Tim ; Jakubowska, Anna ; Lubinski, Jan ; Jaworska, Katarzyna ; Durda, Katarzyna ; Zlowowcka-Perłowska, Elżbieta ; Osorio, Ana ; Durán, Mercedes ; Andrés, Raquel ; Benítez, Javier ; Hamann, Ute ; Hogervorst, Frans B. ; van Os, Theo A. ; Verhoef, Senno ; Meijers-Heijboer, Hanne E. J. ; Wijnen, Juul ; Garcia, Encarna B. Gómez ; Ligtenberg, Marjolijn J. ; Kriege, Mieke ; Collée, Margriet ; Ausems, Margreet G. E. M. ; Oosterwijk, Jan C. ; Peock, Susan ; Frost, Debra ; Ellis, Steve D. ; Platte, Radka ; Fineberg, Elena ; Evans, D. Gareth ; Lalloo, Fiona ; Jacobs, Chris ; Eeles, Ros ; Adlard, Julian ; Davidson, Rosemarie ; Cole, Trevor ; Cook, Jackie ; Paterson, Joan ; Douglas, Fiona ; Brewer, Carole ; Hodgson, Shirley ; Morrison, Patrick J. ; Walker, Lisa ; Rogers, Mark T. ; Donaldson, Alan ; Dorkins, Huw ; Godwin, Andrew K. ; Bove, Betsy ; Stoppa-Lyonnet, Dominique ; Houdayer, Claude ; Buecher, Bruno ; de Pauw, Antoine ; Mazoyer, Sylvie ; Calender, Alain ; Léoné, Mélanie ; Bressac-de Paillerets, Brigitte ; Caron, Olivier ; Sobol, Hagay ; Frenay, Marc ; Prieur, Fabienne ; Ferrer, Sandra Fert ; Mortemousque, Isabelle ; Buys, Saundra ; Daly, Mary ; Miron, Alexander ; Terry, Mary Beth ; Hopper, John L. ; John, Esther M. ; Southey, Melissa ; Goldgar, David ; Singer, Christian F. ; Fink-Retter, Anneliese ; Muy-Kheng, Tea ; Geschwantler Kaulich, Daphne ; Hansen, Thomas V. O. ; Nielsen, Finn C. ; Barkardottir, Rosa B. ; Gaudet, Mia ; Kirchhoff, Tomas ; Joseph, Vijai ; Dutra-Clarke, Ana ; Offit, Kenneth ; Piedmonte, Marion ; Kirk, Judy ; Cohn, David ; Hurteau, Jean ; Byron, John ; Fiorica, James ; Toland, Amanda E. ; Montagna, Marco ; Oliani, Cristina ; Imyanitov, Evgeny ; Isaacs, Claudine ; Tihomirova, Laima ; Blanco, Ignacio ; Lazaro, Conxi ; Teulé, Alex ; Del Valle, J. ; Gayther, Simon A. ; Odunsi, Kunle ; Gross, Jenny ; Karlan, Beth Y. ; Olah, Edith ; Teo, Soo-Hwang ; Ganz, Patricia A. ; Beattie, Mary S. ; Dorfling, Cecelia M. ; Jansen van Rensburg, Elizabeth ; Diez, Orland ; Kwong, Ava ; Schmutzler, Rita K. ; Wappenschmidt, Barbara ; Engel, Christoph ; Meindl, Alfons ; Ditsch, Nina ; Arnold, Norbert ; Heidemann, Simone ; Niederacher, Dieter ; Preisler-Adams, Sabine ; Gadzicki, Dorothea ; Varon-Mateeva, Raymonda ; Deissler, Helmut ; Gehrig, Andrea ; Sutter, Christian ; Kast, Karin ; Fiebig, Britta ; Schäfer, Dieter ; Caldes, Trinidad ; de la Hoya, Miguel ; Nevanlinna, Heli ; Muranen, Taru A. ; Lespérance, Bernard ; Spurdle, Amanda B. ; Neuhausen, Susan L. ; Ding, Yuan C. ; Wang, Xianshu ; Fredericksen, Zachary ; Pankratz, Vernon S. ; Lindor, Noralane M. ; Peterlongo, Paulo ; Manoukian, Siranoush ; Peissel, Bernard ; Zaffaroni, Daniela ; Bonanni, Bernardo ; Bernard, Loris ; Dolcetti, Riccardo ; Papi, Laura ; Ottini, Laura ; Radice, Paolo ; Greene, Mark H. ; Loud, Jennifer T. ; Andrulis, Irene L. ; Ozcelik, Hilmi ; Mulligan, Anna Marie ; Glendon, Gord ; Thomassen, Mads ; Gerdes, Anne-Marie ; Jensen, Uffe B. ; Skytte, Anne-Bine ; Kruse, Torben A. ; Chenevix-Trench, Georgia ; Couch, Fergus J. ; Simard, Jacques ; Easton, Douglas F.
Introduction: Several common alleles have been shown to be associated with breast and/or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Recent genome-wide association studies of breast cancer have identified eight additional breast cancer susceptibility loci: rs1011970 (9p21, CDKN2A/B), rs10995190 (ZNF365), rs704010 (ZMIZ1), rs2380205 (10p15), rs614367 (11q13), rs1292011 (12q24), rs10771399 (12p11 near PTHLH) and rs865686 (9q31.2).
Methods: To evaluate whether these single nucleotide polymorphisms (SNPs) are associated with breast cancer risk for BRCA1 and BRCA2 carriers, we genotyped these SNPs in 12,599 BRCA1 and 7,132 BRCA2 mutation carriers and analysed the associations with breast cancer risk within a retrospective likelihood framework.
Results: Only SNP rs10771399 near PTHLH was associated with breast cancer risk for BRCA1 mutation carriers (per-allele hazard ratio (HR) = 0.87, 95% CI: 0.81 to 0.94, P-trend = 3 x 10\(^{-4}\)). The association was restricted to mutations proven or predicted to lead to absence of protein expression (HR = 0.82, 95% CI: 0.74 to 0.90, P-trend = 3.1 x 10\(^{-5}\), P-difference = 0.03). Four SNPs were associated with the risk of breast cancer for BRCA2 mutation carriers: rs10995190, P-trend = 0.015; rs1011970, P-trend = 0.048; rs865686, 2df P = 0.007; rs1292011 2df P = 0.03. rs10771399 (PTHLH) was predominantly associated with estrogen receptor (ER)-negative breast cancer for BRCA1 mutation carriers (HR = 0.81, 95% CI: 0.74 to 0.90, P-trend = 4 x 10\(^{-5}\)) and there was marginal evidence of association with ER- negative breast cancer for BRCA2 mutation carriers (HR = 0.78, 95% CI: 0.62 to 1.00, P-trend = 0.049).
Conclusions: The present findings, in combination with previously identified modifiers of risk, will ultimately lead to more accurate risk prediction and an improved understanding of the disease etiology in BRCA1 and BRCA2 mutation carriers.
Bousquet, Jean ; Anto, Josep M. ; Bachert, Claus ; Haahtela, Tari ; Zuberbier, Torsten ; Czarlewski, Wienczyslawa ; Bedbrook, Anna ; Bosnic‐Anticevich, Sinthia ; Walter Canonica, G. ; Cardona, Victoria ; Costa, Elisio ; Cruz, Alvaro A. ; Erhola, Marina ; Fokkens, Wytske J. ; Fonseca, Joao A. ; Illario, Maddalena ; Ivancevich, Juan‐Carlos ; Jutel, Marek ; Klimek, Ludger ; Kuna, Piotr ; Kvedariene, Violeta ; Le, LTT ; Larenas‐Linnemann, Désirée E. ; Laune, Daniel ; Lourenço, Olga M. ; Melén, Erik ; Mullol, Joaquim ; Niedoszytko, Marek ; Odemyr, Mikaëla ; Okamoto, Yoshitaka ; Papadopoulos, Nikos G. ; Patella, Vincenzo ; Pfaar, Oliver ; Pham‐Thi, Nhân ; Rolland, Christine ; Samolinski, Boleslaw ; Sheikh, Aziz ; Sofiev, Mikhail ; Suppli Ulrik, Charlotte ; Todo‐Bom, Ana ; Tomazic, Peter‐Valentin ; Toppila‐Salmi, Sanna ; Tsiligianni, Ioanna ; Valiulis, Arunas ; Valovirta, Erkka ; Ventura, Maria‐Teresa ; Walker, Samantha ; Williams, Sian ; Yorgancioglu, Arzu ; Agache, Ioana ; Akdis, Cezmi A. ; Almeida, Rute ; Ansotegui, Ignacio J. ; Annesi‐Maesano, Isabella ; Arnavielhe, Sylvie ; Basagaña, Xavier ; D. Bateman, Eric ; Bédard, Annabelle ; Bedolla‐Barajas, Martin ; Becker, Sven ; Bennoor, Kazi S. ; Benveniste, Samuel ; Bergmann, Karl C. ; Bewick, Michael ; Bialek, Slawomir ; E. Billo, Nils ; Bindslev‐Jensen, Carsten ; Bjermer, Leif ; Blain, Hubert ; Bonini, Matteo ; Bonniaud, Philippe ; Bosse, Isabelle ; Bouchard, Jacques ; Boulet, Louis‐Philippe ; Bourret, Rodolphe ; Boussery, Koen ; Braido, Fluvio ; Briedis, Vitalis ; Briggs, Andrew ; Brightling, Christopher E. ; Brozek, Jan ; Brusselle, Guy ; Brussino, Luisa ; Buhl, Roland ; Buonaiuto, Roland ; Calderon, Moises A. ; Camargos, Paulo ; Camuzat, Thierry ; Caraballo, Luis ; Carriazo, Ana‐Maria ; Carr, Warner ; Cartier, Christine ; Casale, Thomas ; Cecchi, Lorenzo ; Cepeda Sarabia, Alfonso M. ; H. Chavannes, Niels ; Chkhartishvili, Ekaterine ; Chu, Derek K. ; Cingi, Cemal ; Correia de Sousa, Jaime ; Costa, David J. ; Courbis, Anne‐Lise ; Custovic, Adnan ; Cvetkosvki, Biljana ; D'Amato, Gennaro ; da Silva, Jane ; Dantas, Carina ; Dokic, Dejan ; Dauvilliers, Yves ; De Feo, Giulia ; De Vries, Govert ; Devillier, Philippe ; Di Capua, Stefania ; Dray, Gerard ; Dubakiene, Ruta ; Durham, Stephen R. ; Dykewicz, Mark ; Ebisawa, Motohiro ; Gaga, Mina ; El‐Gamal, Yehia ; Heffler, Enrico ; Emuzyte, Regina ; Farrell, John ; Fauquert, Jean‐Luc ; Fiocchi, Alessandro ; Fink‐Wagner, Antje ; Fontaine, Jean‐François ; Fuentes Perez, José M. ; Gemicioğlu, Bilun ; Gamkrelidze, Amiran ; Garcia‐Aymerich, Judith ; Gevaert, Philippe ; Gomez, René Maximiliano ; González Diaz, Sandra ; Gotua, Maia ; Guldemond, Nick A. ; Guzmán, Maria‐Antonieta ; Hajjam, Jawad ; Huerta Villalobos, Yunuen R. ; Humbert, Marc ; Iaccarino, Guido ; Ierodiakonou, Despo ; Iinuma, Tomohisa ; Jassem, Ewa ; Joos, Guy ; Jung, Ki‐Suck ; Kaidashev, Igor ; Kalayci, Omer ; Kardas, Przemyslaw ; Keil, Thomas ; Khaitov, Musa ; Khaltaev, Nikolai ; Kleine‐Tebbe, Jorg ; Kouznetsov, Rostislav ; Kowalski, Marek L. ; Kritikos, Vicky ; Kull, Inger ; La Grutta, Stefania ; Leonardini, Lisa ; Ljungberg, Henrik ; Lieberman, Philip ; Lipworth, Brian ; Lodrup Carlsen, Karin C. ; Lopes‐Pereira, Catarina ; Loureiro, Claudia C. ; Louis, Renaud ; Mair, Alpana ; Mahboub, Bassam ; Makris, Michaël ; Malva, Joao ; Manning, Patrick ; Marshall, Gailen D. ; Masjedi, Mohamed R. ; Maspero, Jorge F. ; Carreiro‐Martins, Pedro ; Makela, Mika ; Mathieu‐Dupas, Eve ; Maurer, Marcus ; De Manuel Keenoy, Esteban ; Melo‐Gomes, Elisabete ; Meltzer, Eli O. ; Menditto, Enrica ; Mercier, Jacques ; Micheli, Yann ; Miculinic, Neven ; Mihaltan, Florin ; Milenkovic, Branislava ; Mitsias, Dimitirios I. ; Moda, Giuliana ; Mogica‐Martinez, Maria‐Dolores ; Mohammad, Yousser ; Montefort, Steve ; Monti, Ricardo ; Morais‐Almeida, Mario ; Mösges, Ralph ; Münter, Lars ; Muraro, Antonella ; Murray, Ruth ; Naclerio, Robert ; Napoli, Luigi ; Namazova‐Baranova, Leyla ; Neffen, Hugo ; Nekam, Kristoff ; Neou, Angelo ; Nordlund, Björn ; Novellino, Ettore ; Nyembue, Dieudonné ; O'Hehir, Robyn ; Ohta, Ken ; Okubo, Kimi ; Onorato, Gabrielle L. ; Orlando, Valentina ; Ouedraogo, Solange ; Palamarchuk, Julia ; Pali‐Schöll, Isabella ; Panzner, Peter ; Park, Hae‐Sim ; Passalacqua, Gianni ; Pépin, Jean‐Louis ; Paulino, Ema ; Pawankar, Ruby ; Phillips, Jim ; Picard, Robert ; Pinnock, Hilary ; Plavec, Davor ; Popov, Todor A. ; Portejoie, Fabienne ; Price, David ; Prokopakis, Emmanuel P. ; Psarros, Fotis ; Pugin, Benoit ; Puggioni, Francesca ; Quinones‐Delgado, Pablo ; Raciborski, Filip ; Rajabian‐Söderlund, Rojin ; Regateiro, Frederico S. ; Reitsma, Sietze ; Rivero‐Yeverino, Daniela ; Roberts, Graham ; Roche, Nicolas ; Rodriguez‐Zagal, Erendira ; Rolland, Christine ; Roller‐Wirnsberger, Regina E. ; Rosario, Nelson ; Romano, Antonino ; Rottem, Menachem ; Ryan, Dermot ; Salimäki, Johanna ; Sanchez‐Borges, Mario M. ; Sastre, Joaquin ; Scadding, Glenis K. ; Scheire, Sophie ; Schmid‐Grendelmeier, Peter ; Schünemann, Holger J. ; Sarquis Serpa, Faradiba ; Shamji, Mohamed ; Sisul, Juan‐Carlos ; Sofiev, Mikhail ; Solé, Dirceu ; Somekh, David ; Sooronbaev, Talant ; Sova, Milan ; Spertini, François ; Spranger, Otto ; Stellato, Cristiana ; Stelmach, Rafael ; Thibaudon, Michel ; To, Teresa ; Toumi, Mondher ; Usmani, Omar ; Valero, Antonio A. ; Valenta, Rudolph ; Valentin‐Rostan, Marylin ; Pereira, Marilyn Urrutia ; van der Kleij, Rianne ; Van Eerd, Michiel ; Vandenplas, Olivier ; Vasankari, Tuula ; Vaz Carneiro, Antonio ; Vezzani, Giorgio ; Viart, Frédéric ; Viegi, Giovanni ; Wallace, Dana ; Wagenmann, Martin ; Wang, De Yun ; Waserman, Susan ; Wickman, Magnus ; Williams, Dennis M. ; Wong, Gary ; Wroczynski, Piotr ; Yiallouros, Panayiotis K. ; Yusuf, Osman M. ; Zar, Heather J. ; Zeng, Stéphane ; Zernotti, Mario E. ; Zhang, Luo ; Shan Zhong, Nan ; Zidarn, Mihaela
Digital anamorphosis is used to define a distorted image of health and care that may be viewed correctly using digital tools and strategies. MASK digital anamorphosis represents the process used by MASK to develop the digital transformation of health and care in rhinitis. It strengthens the ARIA change management strategy in the prevention and management of airway disease. The MASK strategy is based on validated digital tools. Using the MASK digital tool and the CARAT online enhanced clinical framework, solutions for practical steps of digital enhancement of care are proposed.
An expanded evaluation of protein function prediction methods shows an improvement in accuracy
(2016)
Jiang, Yuxiang ; Oron, Tal Ronnen ; Clark, Wyatt T. ; Bankapur, Asma R. ; D'Andrea, Daniel ; Lepore, Rosalba ; Funk, Christopher S. ; Kahanda, Indika ; Verspoor, Karin M. ; Ben-Hur, Asa ; Koo, Da Chen Emily ; Penfold-Brown, Duncan ; Shasha, Dennis ; Youngs, Noah ; Bonneau, Richard ; Lin, Alexandra ; Sahraeian, Sayed M. E. ; Martelli, Pier Luigi ; Profiti, Giuseppe ; Casadio, Rita ; Cao, Renzhi ; Zhong, Zhaolong ; Cheng, Jianlin ; Altenhoff, Adrian ; Skunca, Nives ; Dessimoz, Christophe ; Dogan, Tunca ; Hakala, Kai ; Kaewphan, Suwisa ; Mehryary, Farrokh ; Salakoski, Tapio ; Ginter, Filip ; Fang, Hai ; Smithers, Ben ; Oates, Matt ; Gough, Julian ; Törönen, Petri ; Koskinen, Patrik ; Holm, Liisa ; Chen, Ching-Tai ; Hsu, Wen-Lian ; Bryson, Kevin ; Cozzetto, Domenico ; Minneci, Federico ; Jones, David T. ; Chapman, Samuel ; BKC, Dukka ; Khan, Ishita K. ; Kihara, Daisuke ; Ofer, Dan ; Rappoport, Nadav ; Stern, Amos ; Cibrian-Uhalte, Elena ; Denny, Paul ; Foulger, Rebecca E. ; Hieta, Reija ; Legge, Duncan ; Lovering, Ruth C. ; Magrane, Michele ; Melidoni, Anna N. ; Mutowo-Meullenet, Prudence ; Pichler, Klemens ; Shypitsyna, Aleksandra ; Li, Biao ; Zakeri, Pooya ; ElShal, Sarah ; Tranchevent, Léon-Charles ; Das, Sayoni ; Dawson, Natalie L. ; Lee, David ; Lees, Jonathan G. ; Sillitoe, Ian ; Bhat, Prajwal ; Nepusz, Tamás ; Romero, Alfonso E. ; Sasidharan, Rajkumar ; Yang, Haixuan ; Paccanaro, Alberto ; Gillis, Jesse ; Sedeño-Cortés, Adriana E. ; Pavlidis, Paul ; Feng, Shou ; Cejuela, Juan M. ; Goldberg, Tatyana ; Hamp, Tobias ; Richter, Lothar ; Salamov, Asaf ; Gabaldon, Toni ; Marcet-Houben, Marina ; Supek, Fran ; Gong, Qingtian ; Ning, Wei ; Zhou, Yuanpeng ; Tian, Weidong ; Falda, Marco ; Fontana, Paolo ; Lavezzo, Enrico ; Toppo, Stefano ; Ferrari, Carlo ; Giollo, Manuel ; Piovesan, Damiano ; Tosatto, Silvio C. E. ; del Pozo, Angela ; Fernández, José M. ; Maietta, Paolo ; Valencia, Alfonso ; Tress, Michael L. ; Benso, Alfredo ; Di Carlo, Stefano ; Politano, Gianfranco ; Savino, Alessandro ; Rehman, Hafeez Ur ; Re, Matteo ; Mesiti, Marco ; Valentini, Giorgio ; Bargsten, Joachim W. ; van Dijk, Aalt D. J. ; Gemovic, Branislava ; Glisic, Sanja ; Perovic, Vladmir ; Veljkovic, Veljko ; Almeida-e-Silva, Danillo C. ; Vencio, Ricardo Z. N. ; Sharan, Malvika ; Vogel, Jörg ; Kansakar, Lakesh ; Zhang, Shanshan ; Vucetic, Slobodan ; Wang, Zheng ; Sternberg, Michael J. E. ; Wass, Mark N. ; Huntley, Rachael P. ; Martin, Maria J. ; O'Donovan, Claire ; Robinson, Peter N. ; Moreau, Yves ; Tramontano, Anna ; Babbitt, Patricia C. ; Brenner, Steven E. ; Linial, Michal ; Orengo, Christine A. ; Rost, Burkhard ; Greene, Casey S. ; Mooney, Sean D. ; Friedberg, Iddo ; Radivojac, Predrag ; Veljkovic, Nevena
Background
A major bottleneck in our understanding of the molecular underpinnings of life is the assignment of function to proteins. While molecular experiments provide the most reliable annotation of proteins, their relatively low throughput and restricted purview have led to an increasing role for computational function prediction. However, assessing methods for protein function prediction and tracking progress in the field remain challenging.
Results
We conducted the second critical assessment of functional annotation (CAFA), a timed challenge to assess computational methods that automatically assign protein function. We evaluated 126 methods from 56 research groups for their ability to predict biological functions using Gene Ontology and gene-disease associations using Human Phenotype Ontology on a set of 3681 proteins from 18 species. CAFA2 featured expanded analysis compared with CAFA1, with regards to data set size, variety, and assessment metrics. To review progress in the field, the analysis compared the best methods from CAFA1 to those of CAFA2.
Conclusions
The top-performing methods in CAFA2 outperformed those from CAFA1. This increased accuracy can be attributed to a combination of the growing number of experimental annotations and improved methods for function prediction. The assessment also revealed that the definition of top-performing algorithms is ontology specific, that different performance metrics can be used to probe the nature of accurate predictions, and the relative diversity of predictions in the biological process and human phenotype ontologies. While there was methodological improvement between CAFA1 and CAFA2, the interpretation of results and usefulness of individual methods remain context-dependent.
Biernacka, J. M. ; Sangkuhl, K. ; Jenkins, G. ; Whaley, R. M. ; Barman, P. ; Batzler, A. ; Altman, R. B. ; Arolt, V. ; Brockmöller, J. ; Chen, C. H. ; Domschke, K. ; Hall-Flavin, D. K. ; Hong, C. J. ; Illi, A. ; Ji, Y. ; Kampman, O. ; Kinoshita, T. ; Leinonen, E. ; Liou, Y. J. ; Mushiroda, T. ; Nonen, S. ; Skime, M. K. ; Wang, L. ; Baune, B. T. ; Kato, M. ; Liu, Y. L. ; Praphanphoj, V. ; Stingl, J. C. ; Tsai, S. J. ; Kubo, M. ; Klein, T. E. ; Weinshilboum, R.
Response to treatment with selective serotonin reuptake inhibitors (SSRIs) varies considerably between patients. The International SSRI Pharmacogenomics Consortium (ISPC) was formed with the primary goal of identifying genetic variation that may contribute to response to SSRI treatment of major depressive disorder. A genome-wide association study of 4-week treatment outcomes, measured using the 17-item Hamilton Rating Scale for Depression (HRSD-17), was performed using data from 865 subjects from seven sites. The primary outcomes were percent change in HRSD-17 score and response, defined as at least 50% reduction in HRSD-17. Data from two prior studies, the Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomics Study (PGRN-AMPS) and the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, were used for replication, and a meta-analysis of the three studies was performed (N = 2394). Although many top association signals in the ISPC analysis map to interesting candidate genes, none were significant at the genome-wide level and the associations were not replicated using PGRN-AMPS and STAR*D data. Top association results in the meta-analysis of response included single-nucleotide polymorphisms (SNPs) in the HPRTP4 (hypoxanthine phosphoribosyltransferase pseudogene 4)/VSTM5 (V-set and transmembrane domain containing 5) region, which approached genome-wide significance (P = 5.03E - 08) and SNPs 5' upstream of the neuregulin-1 gene, NRG1 (P = 1.20E - 06). NRG1 is involved in many aspects of brain development, including neuronal maturation and variations in this gene have been shown to be associated with increased risk for mental disorders, particularly schizophrenia. Replication and functional studies of these findings are warranted.
Pollitt, Alice Y. ; Poulter, Natalie S. ; Gitz, Eelo ; Navarro-Nuñez, Leyre ; Wang, Ying-Jie ; Hughes, Craig E. ; Thomas, Steven G. ; Nieswandt, Bernhard ; Douglas, Michael R. ; Owen, Dylan M. ; Jackson, David G. ; Dustin, Michael L. ; Watson, Steve P.
The interaction of CLEC-2 on platelets with Podoplanin on lymphatic endothelial cells initiates platelet signalling events that are necessary for prevention of blood-lymph mixing during development. In the present study, we show that CLEC-2 signalling via Src family and Syk tyrosine kinases promotes platelet adhesion to primary mouse lymphatic endothelial cells at low shear. Using supported lipid bilayers containing mobile Podoplanin, we further show that activation of Src and Syk in platelets promotes clustering of CLEC-2 and Podoplanin. Clusters of CLEC-2-bound Podoplanin migrate rapidly to the centre of the platelet to form a single structure. Fluorescence life-time imaging demonstrates that molecules within these clusters are within 10 nm of one another and that the clusters are disrupted by inhibition of Src and Syk family kinases. CLEC-2 clusters are also seen in platelets adhered to immobilised Podoplanin using direct stochastic optical reconstruction microscopy (dSTORM). These findings provide mechanistic insight by which CLEC-2 signalling promotes adhesion to Podoplanin and regulation of Podoplanin signalling thereby contributing to lymphatic vasculature development.
van Koolwijk, Leonieke M. E. ; Ramdas, Wishal D. ; Ikram, M. Kamran ; Jansonius, Nomdo M. ; Pasutto, Francesca ; Hys, Pirro G. ; Macgregor, Stuart ; Janssen, Sarah F. ; Hewitt, Alex W. ; Viswanathan, Ananth C. ; ten Brink, Jacoline B. ; Hosseini, S. Mohsen ; Amin, Najaf ; Despriet, Dominiek D. G. ; Willemse-Assink, Jacqueline J. M. ; Kramer, Rogier ; Rivadeneira, Fernando ; Struchalin, Maksim ; Aulchenko, Yurii S. ; Weisschuh, Nicole ; Zenkel, Matthias ; Mardin, Christian Y. ; Gramer, Eugen ; Welge-Lüssen, Ulrich ; Montgomery, Grant W. ; Carbonaro, Francis ; Young, Terri L. ; Bellenguez, Céline ; McGuffin, Peter ; Foster, Paul J. ; Topouzis, Fotis ; Mitchell, Paul ; Wang, Jie Jin ; Wong, Tien Y. ; Czudowska, Monika A. ; Hofman, Albert ; Uitterlinden, Andre G. ; Wolfs, Roger C. W. ; de Jong, Paulus T. V. M. ; Oostra, Ben A. ; Paterson, Andrew D. ; Mackey, David A. ; Bergen, Arthur A. B. ; Reis, Andre ; Hammond, Christopher J. ; Vingerling, Johannes R. ; Lemij, Hans G. ; Klaver, Caroline C. W. ; van Duijn, Cornelia M.
Intraocular pressure (IOP) is a highly heritable risk factor for primary open-angle glaucoma and is the only target for current glaucoma therapy. The genetic factors which determine IOP are largely unknown. We performed a genome-wide association study for IOP in 11,972 participants from 4 independent population-based studies in The Netherlands. We replicated our findings in 7,482 participants from 4 additional cohorts from the UK, Australia, Canada, and the Wellcome Trust Case-Control Consortium 2/Blue Mountains Eye Study. IOP was significantly associated with rs11656696, located in GAS7 at 17p13.1 (p = 1.4 x 10\(^{-8}\)), and with rs7555523, located in TMCO1 at 1q24.1 (p = 1.6 x 10\(^{-8}\)). In a meta-analysis of 4 case-control studies (total N = 1,432 glaucoma cases), both variants also showed evidence for association with glaucoma (p = 2.4 x 10\(^{-2}\) for rs11656696 and p = 9.1 x 10\(^{-4}\) for rs7555523). GAS7 and TMCO1 are highly expressed in the ciliary body and trabecular meshwork as well as in the lamina cribrosa, optic nerve, and retina. Both genes functionally interact with known glaucoma disease genes. These data suggest that we have identified two clinically relevant genes involved in IOP regulation.
Spivey, Tara L. ; De Giorgi, Valeria ; Zhao, Yingdong ; Bedognetti, Davide ; Pos, Zoltan ; Liu, Qiuzhen ; Tomei, Sara ; Ascierto, Maria Libera ; Uccellini, Lorenzo ; Reinboth, Jennifer ; Chouchane, Lotfi ; Stroncek, David F. ; Wang, Ena ; Marincola, Francesco M.
Background: The weight that gene copy number plays in transcription remains controversial; although in specific cases gene expression correlates with copy number, the relationship cannot be inferred at the global level. We hypothesized that genes steadily expressed by 15 melanoma cell lines (CMs) and their parental tissues (TMs) should be critical for oncogenesis and their expression most frequently influenced by their respective copy number.
Results: Functional interpretation of 3,030 transcripts concordantly expressed (Pearson's correlation coefficient p-value < 0.05) by CMs and TMs confirmed an enrichment of functions crucial to oncogenesis. Among them, 968 were expressed according to the transcriptional efficiency predicted by copy number analysis (Pearson's correlation coefficient p-value < 0.05). We named these genes, "genomic delegates" as they represent at the transcriptional level the genetic footprint of individual cancers. We then tested whether the genes could categorize 112 melanoma metastases. Two divergent phenotypes were observed: one with prevalent expression of cancer testis antigens, enhanced cyclin activity, WNT signaling, and a Th17 immune phenotype (Class A). This phenotype expressed, therefore, transcripts previously associated to more aggressive cancer. The second class (B) prevalently expressed genes associated with melanoma signaling including MITF, melanoma differentiation antigens, and displayed a Th1 immune phenotype associated with better prognosis and likelihood to respond to immunotherapy. An intermediate third class (C) was further identified. The three phenotypes were confirmed by unsupervised principal component analysis.
Conclusions: This study suggests that clinically relevant phenotypes of melanoma can be retraced to stable oncogenic properties of cancer cells linked to their genetic back bone, and offers a roadmap for uncovering novel targets for tailored anti-cancer therapy.
CXCL10 Controls Inflammatory Pain via Opioid Peptide- Containing Macrophages in Electroacupuncture
(2014)
Rittner, Heike L. ; Wang, Ying ; Gehringer, Rebekka ; Mousa, Shaaban A. ; Hackel, Dagmar ; Brack, Alexander
Acupuncture is widely used for pain treatment in patients with osteoarthritis or low back pain, but molecular mechanisms remain largely enigmatic. In the early phase of inflammation neutrophilic chemokines direct opioid-containing neutrophils in the inflamed tissue and stimulate opioid peptide release and antinociception. In this study the molecular pathway and neuroimmune connections in complete Freund's adjuvant (CFA)-induced hind paw inflammation and electroacupuncture for peripheral pain control were analyzed. Free moving Wistar rats with hind paw inflammation were treated twice with electroacupuncture at GB30 (Huan Tiao - gall bladder meridian) (day 0 and 1) and analyzed for mechanical and thermal nociceptive thresholds. The cytokine profiles as well as the expression of opioid peptides were quantified in the inflamed paw. Electroacupuncture elicited long-term antinociception blocked by local injection of anti-opioid peptide antibodies (beta-endorphin, met-enkephalin, dynorphin A). The treatment altered the cytokine profile towards an anti-inflammatory pattern but augmented interferon (IFN)-gamma and the chemokine CXCL10 (IP-10: interferon gamma-inducible protein) protein and mRNA expression with concomitant increased numbers of opioid peptide-containing CXCR3+ macrophages. In rats with CFA hind paw inflammation without acupuncture repeated injection of CXCL10 triggered opioid-mediated antinociception and increase opioid-containing macrophages. Conversely, neutralization of CXCL10 time-dependently decreased electroacupuncture-induced antinociception and the number of infiltrating opioid peptide-expressing CXCR3+ macrophages. In summary, we describe a novel function of the chemokine CXCL10 - as a regulator for an increase of opioid-containing macrophages and antinociceptive mediator in inflammatory pain and as a key chemokine regulated by electroacupuncture.