@article{DavisYuKeenanetal.2013, author = {Davis, Lea K. and Yu, Dongmei and Keenan, Clare L. and Gamazon, Eric R. and Konkashbaev, Anuar I. and Derks, Eske M. and Neale, Benjamin M. and Yang, Jian and Lee, S. Hong and Evans, Patrick and Barr, Cathy L. and Bellodi, Laura and Benarroch, Fortu and Berrio, Gabriel Bedoya and Bienvenu, Oscar J. and Bloch, Michael H. and Blom, Rianne M. and Bruun, Ruth D. and Budman, Cathy L. and Camarena, Beatriz and Campbell, Desmond and Cappi, Carolina and Cardona Silgado, Julio C. and Cath, Danielle C. and Cavallini, Maria C. and Chavira, Denise A. and Chouinard, Sylvian and Conti, David V. and Cook, Edwin H. and Coric, Vladimir and Cullen, Bernadette A. and Deforce, Dieter and Delorme, Richard and Dion, Yves and Edlund, Christopher K. and Egberts, Karin and Falkai, Peter and Fernandez, Thomas V. and Gallagher, Patience J. and Garrido, Helena and Geller, Daniel and Girard, Simon L. and Grabe, Hans J. and Grados, Marco A. and Greenberg, Benjamin D. and Gross-Tsur, Varda and Haddad, Stephen and Heiman, Gary A. and Hemmings, Sian M. J. and Hounie, Ana G. and Illmann, Cornelia and Jankovic, Joseph and Jenike, Micheal A. and Kennedy, James L. and King, Robert A. and Kremeyer, Barbara and Kurlan, Roger and Lanzagorta, Nuria and Leboyer, Marion and Leckman, James F. and Lennertz, Leonhard and Liu, Chunyu and Lochner, Christine and Lowe, Thomas L. and Macciardi, Fabio and McCracken, James T. and McGrath, Lauren M. and Restrepo, Sandra C. Mesa and Moessner, Rainald and Morgan, Jubel and Muller, Heike and Murphy, Dennis L. and Naarden, Allan L. and Ochoa, William Cornejo and Ophoff, Roel A. and Osiecki, Lisa and Pakstis, Andrew J. and Pato, Michele T. and Pato, Carlos N. and Piacentini, John and Pittenger, Christopher and Pollak, Yehunda and Rauch, Scott L. and Renner, Tobias J. and Reus, Victor I. and Richter, Margaret A. and Riddle, Mark A. and Robertson, Mary M. and Romero, Roxana and Ros{\`a}rio, Maria C. and Rosenberg, David and Rouleau, Guy A. and Ruhrmann, Stephan and Ruiz-Linares, Andreas and Sampaio, Aline S. and Samuels, Jack and Sandor, Paul and Sheppard, Broke and Singer, Harvey S. and Smit, Jan H. and Stein, Dan J. and Strengman, E. and Tischfield, Jay A. and Valencia Duarte, Ana V. and Vallada, Homero and Van Nieuwerburgh, Flip and Veenstra-VanderWeele, Jeremy and Walitza, Susanne and Wang, Ying and Wendland, Jens R. and Westenberg, Herman G. M. and Shugart, Yin Yao and Miguel, Euripedes C. and McMahon, William and Wagner, Michael and Nicolini, Humberto and Posthuma, Danielle and Hanna, Gregory L. and Heutink, Peter and Denys, Damiaan and Arnold, Paul D. and Oostra, Ben A. and Nestadt, Gerald and Freimer, Nelson B. and Pauls, David L. and Wray, Naomi R. and Stewart, S. Evelyn and Mathews, Carol A. and Knowles, James A. and Cox, Nancy J. and Scharf, Jeremiah M.}, title = {Partitioning the Heritability of Tourette Syndrome and Obsessive Compulsive Disorder Reveals Differences in Genetic Architecture}, series = {PLoS Genetics}, volume = {9}, journal = {PLoS Genetics}, number = {10}, issn = {1553-7390}, doi = {10.1371/journal.pgen.1003864}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-127377}, pages = {e1003864}, year = {2013}, abstract = {The direct estimation of heritability from genome-wide common variant data as implemented in the program Genome-wide Complex Trait Analysis (GCTA) has provided a means to quantify heritability attributable to all interrogated variants. We have quantified the variance in liability to disease explained by all SNPs for two phenotypically-related neurobehavioral disorders, obsessive-compulsive disorder (OCD) and Tourette Syndrome (TS), using GCTA. Our analysis yielded a heritability point estimate of 0.58 (se = 0.09, p = 5.64e-12) for TS, and 0.37 (se = 0.07, p = 1.5e-07) for OCD. In addition, we conducted multiple genomic partitioning analyses to identify genomic elements that concentrate this heritability. We examined genomic architectures of TS and OCD by chromosome, MAF bin, and functional annotations. In addition, we assessed heritability for early onset and adult onset OCD. Among other notable results, we found that SNPs with a minor allele frequency of less than 5\% accounted for 21\% of the TS heritability and 0\% of the OCD heritability. Additionally, we identified a significant contribution to TS and OCD heritability by variants significantly associated with gene expression in two regions of the brain (parietal cortex and cerebellum) for which we had available expression quantitative trait loci (eQTLs). Finally we analyzed the genetic correlation between TS and OCD, revealing a genetic correlation of 0.41 (se = 0.15, p = 0.002). These results are very close to previous heritability estimates for TS and OCD based on twin and family studies, suggesting that very little, if any, heritability is truly missing (i.e., unassayed) from TS and OCD GWAS studies of common variation. The results also indicate that there is some genetic overlap between these two phenotypically-related neuropsychiatric disorders, but suggest that the two disorders have distinct genetic architectures.}, language = {en} } @article{FerreiraGamazonAlEjehetal.2019, author = {Ferreira, Manuel A. and Gamazon, Eric R. and Al-Ejeh, Fares and Aittom{\"a}ki, Kristiina and Andrulis, Irene L. and Anton-Culver, Hoda and Arason, Adalgeir and Arndt, Volker and Aronson, Kristan J. and Arun, Banu K. and Asseryanis, Ella and Azzollini, Jacopo and Balma{\~n}a, Judith and Barnes, Daniel R. and Barrowdale, Daniel and Beckmann, Matthias W. and Behrens, Sabine and Benitez, Javier and Bermisheva, Marina and Bialkowska, Katarzyna and Blomqvist, Carl and Bogdanova, Natalia V. and Bojesen, Stig E. and Bolla, Manjeet K. and Borg, Ake and Brauch, Hiltrud and Brenner, Hermann and Broeks, Annegien and Burwinkel, Barbara and Cald{\´e}s, Trinidad and Caligo, Maria A. and Campa, Daniele and Campbell, Ian and Canzian, Federico and Carter, Jonathan and Carter, Brian D. and Castelao, Jose E. and Chang-Claude, Jenny and Chanock, Stephen J. and Christiansen, Hans and Chung, Wendy K. and Claes, Kathleen B. M. and Clarke, Christine L. and Couch, Fergus J. and Cox, Angela and Cross, Simon S. and Czene, Kamila and Daly, Mary B. and de la Hoya, Miguel and Dennis, Joe and Devilee, Peter and Diez, Orland and D{\"o}rk, Thilo and Dunning, Alison M. and Dwek, Miriam and Eccles, Diana M. and Ejlertsen, Bent and Ellberg, Carolina and Engel, Christoph and Eriksson, Mikael and Fasching, Peter A. and Fletcher, Olivia and Flyger, Henrik and Friedman, Eitan and Frost, Debra and Gabrielson, Marike and Gago-Dominguez, Manuela and Ganz, Patricia A. and Gapstur, Susan M. and Garber, Judy and Garc{\´i}a-Closas, Montserrat and Garc{\´i}a-S{\´a}enz, Jos{\´e} A. and Gaudet, Mia M. and Giles, Graham G. and Glendon, Gord and Godwin, Andrew K. and Goldberg, Mark S. and Goldgar, David E. and Gonz{\´a}lez-Neira, Anna and Greene, Mark H. and Gronwald, Jacek and Guen{\´e}l, Pascal and Haimann, Christopher A. and Hall, Per and Hamann, Ute and He, Wei and Heyworth, Jane and Hogervorst, Frans B. L. and Hollestelle, Antoinette and Hoover, Robert N. and Hopper, John L. and Hulick, Peter J. and Humphreys, Keith and Imyanitov, Evgeny N. and Isaacs, Claudine and Jakimovska, Milena and Jakubowska, Anna and James, Paul A. and Janavicius, Ramunas and Jankowitz, Rachel C. and John, Esther M. and Johnson, Nichola and Joseph, Vijai and Karlan, Beth Y. and Khusnutdinova, Elza and Kiiski, Johanna I. and Ko, Yon-Dschun and Jones, Michael E. and Konstantopoulou, Irene and Kristensen, Vessela N. and Laitman, Yael and Lambrechts, Diether and Lazaro, Conxi and Leslie, Goska and Lester, Jenny and Lesueur, Fabienne and Lindstr{\"o}m, Sara and Long, Jirong and Loud, Jennifer T. and Lubiński, Jan and Makalic, Enes and Mannermaa, Arto and Manoochehri, Mehdi and Margolin, Sara and Maurer, Tabea and Mavroudis, Dimitrios and McGuffog, Lesley and Meindl, Alfons and Menon, Usha and Michailidou, Kyriaki and Miller, Austin and Montagna, Marco and Moreno, Fernando and Moserle, Lidia and Mulligan, Anna Marie and Nathanson, Katherine L. and Neuhausen, Susan L. and Nevanlinna, Heli and Nevelsteen, Ines and Nielsen, Finn C. and Nikitina-Zake, Liene and Nussbaum, Robert L. and Offit, Kenneth and Olah, Edith and Olopade, Olufunmilayo I. and Olsson, H{\aa}kan and Osorio, Ana and Papp, Janos and Park-Simon, Tjoung-Won and Parsons, Michael T. and Pedersen, Inge Sokilde and Peixoto, Ana and Peterlongo, Paolo and Pharaoh, Paul D. P. and Plaseska-Karanfilska, Dijana and Poppe, Bruce and Presneau, Nadege and Radice, Paolo and Rantala, Johanna and Rennert, Gad and Risch, Harvey A. and Saloustros, Emmanouil and Sanden, Kristin and Sawyer, Elinor J. and Schmidt, Marjanka K. and Schmutzler, Rita K. and Sharma, Priyanka and Shu, Xiao-Ou and Simard, Jaques and Singer, Christian F. and Soucy, Penny and Southey, Melissa C. and Spinelli, John J. and Spurdle, Amanda B. and Stone, Jennifer and Swerdlow, Anthony J. and Tapper, William J. and Taylor, Jack A. and Teixeira, Manuel R. and Terry, Mary Beth and Teul{\´e}, Alex and Thomassen, Mads and Th{\"o}ne, Kathrin and Thull, Darcy L. and Tischkowitz, Marc and Toland, Amanda E. and Torres, Diana and Truong, Th{\´e}r{\`e}se and Tung, Nadine and Vachon, Celine M. and van Asperen, Christi J. and van den Ouweland, Ans M. W. and van Rensburg, Elizabeth J. and Vega, Ana and Viel, Alexandra and Wang, Qin and Wappenschmidt, Barbara and Weitzel, Jeffrey N. and Wendt, Camilla and Winqvist, Robert and Yang, Xiaohong R. and Yannoukakos, Drakoulis and Ziogas, Argyrios and Kraft, Peter and Antoniou, Antonis C. and Zheng, Wei and Easton, Douglas F. and Milne, Roger L. and Beesley, Jonathan and Chenevix-Trench, Georgia}, title = {Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer}, series = {Nature Communications}, volume = {10}, journal = {Nature Communications}, organization = {EMBRACE Collaborators, GC-HBOC Study Collaborators, GEMO Study Collaborators, ABCTB Investigators, HEBON Investigators, BCFR Investigators}, doi = {10.1038/s41467-018-08053-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-228024}, year = {2019}, abstract = {Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.}, language = {en} } @article{MencacciIsaiasReichetal.2014, author = {Mencacci, Niccol{\´o} E. and Isaias, Ioannis U. and Reich, Martin M. and Ganos, Christos and Plagnol, Vincent and Polke, James M. and Bras, Jose and Hersheson, Joshua and Stamelou, Maria and Pittman, Alan M. and Noyce, Alastair J. and Mok, Kin Y. and Opladen, Thomas and Kunstmann, Erdmute and Hodecker, Sybille and M{\"u}nchau, Alexander and Volkmann, Jens and Samnick, Samuel and Sidle, Katie and Nanji, Tina and Sweeney, Mary G. and Houlden, Henry and Batla, Amit and Zecchinelli, Anna L. and Pezzoli, Gianni and Marotta, Giorgio and Lees, Andrew and Alegria, Paulo and Krack, Paul and Cormier-Dequaire, Florence and Lesage, Suzanne and Brice, Alexis and Heutink, Peter and Gasser, Thomas and Lubbe, Steven J. and Morris, Huw R. and Taba, Pille and Koks, Sulev and Majounie, Elisa and Gibbs, J. Raphael and Singleton, Andrew and Hardy, John and Klebe, Stephan and Bhatia, Kailash P. and Wood, Nicholas W.}, title = {Parkinson's disease in GTP cyclohydrolase 1 mutation carriers}, series = {Brain}, volume = {137}, journal = {Brain}, number = {9}, doi = {10.1093/brain/awu179}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-121268}, pages = {2480-92}, year = {2014}, abstract = {GTP cyclohydrolase 1, encoded by the GCH1 gene, is an essential enzyme for dopamine production in nigrostriatal cells. Loss-of-function mutations in GCH1 result in severe reduction of dopamine synthesis in nigrostriatal cells and are the most common cause of DOPA-responsive dystonia, a rare disease that classically presents in childhood with generalized dystonia and a dramatic long-lasting response to levodopa. We describe clinical, genetic and nigrostriatal dopaminergic imaging ([(123)I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl) tropane single photon computed tomography) findings of four unrelated pedigrees with DOPA-responsive dystonia in which pathogenic GCH1 variants were identified in family members with adult-onset parkinsonism. Dopamine transporter imaging was abnormal in all parkinsonian patients, indicating Parkinson's disease-like nigrostriatal dopaminergic denervation. We subsequently explored the possibility that pathogenic GCH1 variants could contribute to the risk of developing Parkinson's disease, even in the absence of a family history for DOPA-responsive dystonia. The frequency of GCH1 variants was evaluated in whole-exome sequencing data of 1318 cases with Parkinson's disease and 5935 control subjects. Combining cases and controls, we identified a total of 11 different heterozygous GCH1 variants, all at low frequency. This list includes four pathogenic variants previously associated with DOPA-responsive dystonia (Q110X, V204I, K224R and M230I) and seven of undetermined clinical relevance (Q110E, T112A, A120S, D134G, I154V, R198Q and G217V). The frequency of GCH1 variants was significantly higher (Fisher's exact test P-value 0.0001) in cases (10/1318 = 0.75\%) than in controls (6/5935 = 0.1\%; odds ratio 7.5; 95\% confidence interval 2.4-25.3). Our results show that rare GCH1 variants are associated with an increased risk for Parkinson's disease. These findings expand the clinical and biological relevance of GTP cycloydrolase 1 deficiency, suggesting that it not only leads to biochemical striatal dopamine depletion and DOPA-responsive dystonia, but also predisposes to nigrostriatal cell loss. Further insight into GCH1-associated pathogenetic mechanisms will shed light on the role of dopamine metabolism in nigral degeneration and Parkinson's disease.}, language = {en} } @article{CouchWangMcGuffogetal.2013, author = {Couch, Fergus J. and Wang, Xianshu and McGuffog, Lesley and Lee, Andrew and Olswold, Curtis and Kuchenbaecker, Karoline B. and Soucy, Penny and Fredericksen, Zachary and Barrowdale, Daniel and Dennis, Joe and Gaudet, Mia M. and Dicks, Ed and Kosel, Matthew and Healey, Sue and Sinilnikova, Olga M. and Lee, Adam and Bacot, Fran{\c{c}}ios and Vincent, Daniel and Hogervorst, Frans B. L. and Peock, Susan and Stoppa-Lyonnet, Dominique and Jakubowska, Anna and Radice, Paolo and Schmutzler, Rita Katharina and Domchek, Susan M. and Piedmonte, Marion and Singer, Christian F. and Friedman, Eitan and Thomassen, Mads and Hansen, Thomas V. O. and Neuhausen, Susan L. and Szabo, Csilla I. and Blanco, Ingnacio and Greene, Mark H. and Karlan, Beth Y. and Garber, Judy and Phelan, Catherine M. and Weitzel, Jeffrey N. and Montagna, Marco and Olah, Edith and Andrulis, Irene L. and Godwin, Andrew K. and Yannoukakos, Drakoulis and Goldgar, David E. and Caldes, Trinidad and Nevanlinna, Heli and Osorio, Ana and Terry, Mary Beth and Daly, Mary B. and van Rensburg, Elisabeth J. and Hamann, Ute and Ramus, Susan J. and Toland, Amanda Ewart and Caligo, Maria A. and Olopade, Olufunmilayo I. and Tung, Nadine and Claes, Kathleen and Beattie, Mary S. and Southey, Melissa C. and Imyanitov, Evgeny N. and Tischkowitz, Marc and Janavicius, Ramunas and John, Esther M. and Kwong, Ava and Diez, Orland and Kwong, Ava and Balma{\~n}a, Judith and Barkardottir, Rosa B. and Arun, Banu K. and Rennert, Gad and Teo, Soo-Hwang and Ganz, Patricia A. and Campbell, Ian and van der Hout, Annemarie H. and van Deurzen, Carolien H. M. and Seynaeve, Caroline and Garcia, Encarna B. G{\´o}mez and van Leeuwen, Flora E. and Meijers-Heijboer, Hanne E. J. and Gille, Johannes J. P. and Ausems, Magreet G. E. M. and Blok, Marinus J. and Ligtenberg, Marjolinjin J. L. and Rookus, Matti A. and Devilee, Peter and Verhoef, Senno and van Os, Theo A. M. and Wijnen, Juul T. and Frost, Debra and Ellis, Steve and Fineberg, Elena and Platte, Radke and Evans, D. Gareth and Izatt, Luise and Eeles, Rosalind A. and Adlard, Julian and Eccles, Diana M. and Cook, Jackie and Brewer, Carole and Douglas, Fiona and Hodgson, Shirley and Morrison, Patrick J. and Side, Lucy E. and Donaldson, Alan and Houghton, Catherine and Rogers, Mark T. and Dorkins, Huw and Eason, Jacqueline and Gregory, Helen and McCann, Emma and Murray, Alex and Calender, Alain and Hardouin, Agn{\`e}s and Berthet, Pascaline and Delnatte, Capucine and Nogues, Catherine and Lasset, Christine and Houdayer, Claude and Leroux,, Dominique and Rouleau, Etienne and Prieur, Fabienne and Damiola, Francesca and Sobol, Hagay and Coupier, Isabelle and Venat-Bouvet, Laurence and Castera, Laurent and Gauthier-Villars, Marion and L{\´e}on{\´e}, M{\´e}lanie and Pujol, Pascal and Mazoyer, Sylvie and Bignon, Yves-Jean and Zlowocka-Perlowska, Elzbieta and Gronwald, Jacek and Lubinski,, Jan and Durda, Katarzyna and Jaworska, Katarzyna and Huzarski, Tomasz and Spurdle, Amanda B. and Viel, Alessandra and Peissel, Bernhard and Bonanni, Bernardo and Melloni, Guilia and Ottini, Laura and Papi, Laura and Varesco, Liliana and Tibiletti, Maria Grazia and Peterlongo, Paolo and Volorio, Sara and Manoukian, Siranoush and Pensotti, Valeria and Arnold, Norbert and Engel, Christoph and Deissler, Helmut and Gadzicki, Dorothea and Gehrig, Andrea and Kast, Karin and Rhiem, Kerstin and Meindl, Alfons and Niederacher, Dieter and Ditsch, Nina and Plendl, Hansjoerg and Preisler-Adams, Sabine and Engert, Stefanie and Sutter, Christian and Varon-Mateeva, Raymenda and Wappenschmidt, Barbara and Weber, Bernhard H. F. and Arver, Brita and Stenmark-Askmalm, Marie and Loman, Niklas and Rosenquist, Richard and Einbeigi, Zakaria and Nathanson, Katherine L. and Rebbeck, Timothy R. and Blank, Stephanie V. and Cohn, David E. and Rodriguez, Gustavo C. and Small, Laurie and Friedlander, Michael and Bae-Jump, Victoria L. and Fink-Retter, Anneliese and Rappaport, Christine and Gschwantler-Kaulich, Daphne and Pfeiler, Georg and Tea, Muy-Kheng and Lindor, Noralane M. and Kaufman, Bella and Paluch, Shani Shimon and Laitman, Yael and Skytte, Anne-Bine and Gerdes, Anne-Marie and Pedersen, Inge Sokilde and Moeller, Sanne Traasdahl and Kruse, Torben A. and Jensen, Uffe Birk and Vijai, Joseph and Sarrel, Kara and Robson, Mark and Kauff, Noah and Mulligan, Anna Marie and Glendon, Gord and Ozcelik, Hilmi and Ejlertsen, Bent and Nielsen, Finn C. and J{\o}nson, Lars and Andersen, Mette K. and Ding, Yuan Chun and Steele, Linda and Foretova, Lenka and Teul{\´e}, Alex and Lazaro, Conxi and Brunet, Joan and Pujana, Miquel Angel and Mai, Phuong L. and Loud, Jennifer T. and Walsh, Christine and Lester, Jenny and Orsulic, Sandra and Narod, Steven A. and Herzog, Josef and Sand, Sharon R. and Tognazzo, Silvia and Agata, Simona and Vaszko, Tibor and Weaver, Joellen and Stravropoulou, Alexandra V. and Buys, Saundra S. and Romero, Atocha and de la Hoya, Miguel and Aittom{\"a}ki, Kristiina and Muranen, Taru A. and Duran, Mercedes and Chung, Wendy K. and Lasa, Adriana and Dorfling, Cecilia M. and Miron, Alexander and Benitez, Javier and Senter, Leigha and Huo, Dezheng and Chan, Salina B. and Sokolenko, Anna P. and Chiquette, Jocelyne and Tihomirova, Laima and Friebel, Tara M. and Agnarsson, Bjarne A. and Lu, Karen H. and Lejbkowicz, Flavio and James, Paul A. and Hall, Per and Dunning, Alison M. and Tessier, Daniel and Cunningham, Julie and Slager, Susan L. and Chen, Wang and Hart, Steven and Stevens, Kristen and Simard, Jacques and Pastinen, Tomi and Pankratz, Vernon S. and Offit, Kenneth and Easton, Douglas F. and Chenevix-Trench, Georgia and Antoniou, Antonis C.}, title = {Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk}, series = {PLOS Genetics}, volume = {9}, journal = {PLOS Genetics}, number = {3}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1003212}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-127947}, pages = {e1003212}, year = {2013}, abstract = {BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7 x 10(-8), HR = 1.14, 95\% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4 x 10(-8), HR = 1.27, 95\% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4 x 10(-8), HR = 1.20, 95\% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2 x 10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5\% of BRCA1 carriers at lowest risk are 28\%-50\% compared to 81\%-100\% for the 5\% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5\% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28\% or lower, whereas the 5\% at highest risk will have a risk of 63\% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.}, language = {en} } @article{LandoEndesfelderBergeretal.2012, author = {Lando, David and Endesfelder, Ulrike and Berger, Harald and Subramanian, Lakxmi and Dunne, Paul D. and McColl, James and Klenerman, David and Carr, Antony M. and Sauer, Markus and Allshire, Robin C. and Heilemann, Mike and Laue, Ernest D.}, title = {Quantitative single-molecule microscopy reveals that CENP-A\(^{Cnp1}\) deposition occurs during G2 in fission yeast}, series = {Open Biology}, volume = {2}, journal = {Open Biology}, number = {120078}, doi = {10.1098/rsob.120078}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-134682}, year = {2012}, abstract = {The inheritance of the histone H3 variant CENP-A in nucleosomes at centromeres following DNA replication is mediated by an epigenetic mechanism. To understand the process of epigenetic inheritance, or propagation of histones and histone variants, as nucleosomes are disassembled and reassembled in living eukaryotic cells, we have explored the feasibility of exploiting photo-activated localization microscopy (PALM). PALM of single molecules in living cells has the potential to reveal new concepts in cell biology, providing insights into stochastic variation in cellular states. However, thus far, its use has been limited to studies in bacteria or to processes occurring near the surface of eukaryotic cells. With PALM, one literally observes and 'counts' individual molecules in cells one-by-one and this allows the recording of images with a resolution higher than that determined by the diffraction of light (the so-called super-resolution microscopy). Here, we investigate the use of different fluorophores and develop procedures to count the centromere-specific histone H3 variant CENP-A\(^{Cnp1}\) with single-molecule sensitivity in fission yeast (Schizosaccharomyces pombe). The results obtained are validated by and compared with ChIP-seq analyses. Using this approach, CENP-A\(^{Cnp1}\) levels at fission yeast (S. pombe) centromeres were followed as they change during the cell cycle. Our measurements show that CENP-A(Cnp1) is deposited solely during the G2 phase of the cell cycle.}, language = {en} } @article{ManchiaAdliAkulaetal.2013, author = {Manchia, Mirko and Adli, Mazda and Akula, Nirmala and Arda, Raffaella and Aubry, Jean-Michel and Backlund, Lena and Banzato, Claudio E. M. and Baune, Bernhard T. and Bellivier, Frank and Bengesser, Susanne and Biernacka, Joanna M. and Brichant-Petitjean, Clara and Bui, Elise and Calkin, Cynthia V. and Cheng, Andrew Tai Ann and Chillotti, Caterina and Cichon, Sven and Clark, Scott and Czerski, Piotr M. and Dantas, Clarissa and Del Zompo, Maria and DePaulo, J. Raymond and Detera-Wadleigh, Sevilla D. and Etain, Bruno and Falkai, Peter and Fris{\´e}n, Louise and Frye, Mark A. and Fullerton, Jan and Gard, S{\´e}bastien and Garnham, Julie and Goes, Fernando S. and Grof, Paul and Gruber, Oliver and Hashimoto, Ryota and Hauser, Joanna and Heilbronner, Urs and Hoban, Rebecca and Hou, Liping and Jamain, St{\´e}phane and Kahn, Jean-Pierre and Kassem, Layla and Kato, Tadafumi and Kelsoe, John R. and Kittel-Schneider, Sarah and Kliwicki, Sebastian and Kuo, Po-Hsiu and Kusumi, Ichiro and Laje, Gonzalo and Lavebratt, Catharina and Leboyer, Marion and Leckband, Susan G. and L{\´o}pez Jaramillo, Carlos A. and Maj, Mario and Malafosse, Alain and Martinsson, Lina and Masui, Takuya and Mitchell, Philip B. and Mondimore, Frank and Monteleone, Palmiero and Nallet, Audrey and Neuner, Maria and Nov{\´a}k, Tom{\´a}s and O'Donovan, Claire and {\"O}sby, Urban and Ozaki, Norio and Perlis, Roy H. and Pfennig, Andrea and Potash, James B. and Reich-Erkelenz, Daniela and Reif, Andreas and Reininghaus, Eva and Richardson, Sara and Rouleau, Guy A. and Rybakowski, Janusz K. and Schalling, Martin and Schofield, Peter R. and Schubert, Oliver K. and Schweizer, Barbara and Seem{\"u}ller, Florian and Grigoroiu-Serbanescu, Maria and Severino, Giovanni and Seymour, Lisa R. and Slaney, Claire and Smoller, Jordan W. and Squassina, Alessio and Stamm, Thomas and Steele, Jo and Stopkova, Pavla and Tighe, Sarah K. and Tortorella, Alfonso and Turecki, Gustavo and Wray, Naomi R. and Wright, Adam and Zandi, Peter P. and Zilles, David and Bauer, Michael and Rietschel, Marcella and McMahon, Francis J. and Schulze, Thomas G. and Alda, Martin}, title = {Assessment of Response to Lithium Maintenance Treatment in Bipolar Disorder: A Consortium on Lithium Genetics (ConLiGen) Report}, series = {PLoS ONE}, volume = {8}, journal = {PLoS ONE}, number = {6}, doi = {10.1371/journal.pone.0065636}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130938}, pages = {e65636}, year = {2013}, abstract = {Objective: The assessment of response to lithium maintenance treatment in bipolar disorder (BD) is complicated by variable length of treatment, unpredictable clinical course, and often inconsistent compliance. Prospective and retrospective methods of assessment of lithium response have been proposed in the literature. In this study we report the key phenotypic measures of the "Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder" scale currently used in the Consortium on Lithium Genetics (ConLiGen) study. Materials and Methods: Twenty-nine ConLiGen sites took part in a two-stage case-vignette rating procedure to examine inter-rater agreement [Kappa (\(\kappa\))] and reliability [intra-class correlation coefficient (ICC)] of lithium response. Annotated first-round vignettes and rating guidelines were circulated to expert research clinicians for training purposes between the two stages. Further, we analyzed the distributional properties of the treatment response scores available for 1,308 patients using mixture modeling. Results: Substantial and moderate agreement was shown across sites in the first and second sets of vignettes (\(\kappa\) = 0.66 and \(\kappa\) = 0.54, respectively), without significant improvement from training. However, definition of response using the A score as a quantitative trait and selecting cases with B criteria of 4 or less showed an improvement between the two stages (\(ICC_1 = 0.71\) and \(ICC_2 = 0.75\), respectively). Mixture modeling of score distribution indicated three subpopulations (full responders, partial responders, non responders). Conclusions: We identified two definitions of lithium response, one dichotomous and the other continuous, with moderate to substantial inter-rater agreement and reliability. Accurate phenotypic measurement of lithium response is crucial for the ongoing ConLiGen pharmacogenomic study.}, language = {en} } @article{ColvillBoothNilletal.2016, author = {Colvill, Emma and Booth, Jeremy and Nill, Simeon and Fast, Martin and Bedford, James and Oelfke, Uwe and Nakamura, Mitsuhiro and Poulsen, Per and Worm, Esben and Hansen, Rune and Ravkilde, Thomas and Rydh{\"o}g, Jonas Scherman and Pommer, Tobias and af Rosenschold, Per Munck and Lang, Stephanie and Guckenberger, Matthias and Groh, Christian and Herrmann, Christian and Verellen, Dirk and Poels, Kenneth and Wang, Lei and Hadsell, Michael and Sothmann, Thilo and Blanck, Oliver and Keall, Paul}, title = {A dosimetric comparison of real-time adaptive and non-adaptive radiotherapy: a multi-institutional study encompassing robotic, gimbaled, multileaf collimator and couch tracking}, series = {Radiotherapy and Oncology}, volume = {119}, journal = {Radiotherapy and Oncology}, number = {1}, doi = {10.1016/j.radonc.2016.03.006}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-189605}, pages = {159-165}, year = {2016}, abstract = {Purpose: A study of real-time adaptive radiotherapy systems was performed to test the hypothesis that, across delivery systems and institutions, the dosimetric accuracy is improved with adaptive treatments over non-adaptive radiotherapy in the presence of patient-measured tumor motion. Methods and materials: Ten institutions with robotic(2), gimbaled(2), MLC(4) or couch tracking(2) used common materials including CT and structure sets, motion traces and planning protocols to create a lung and a prostate plan. For each motion trace, the plan was delivered twice to a moving dosimeter; with and without real-time adaptation. Each measurement was compared to a static measurement and the percentage of failed points for gamma-tests recorded. Results: For all lung traces all measurement sets show improved dose accuracy with a mean 2\%/2 mm gamma-fail rate of 1.6\% with adaptation and 15.2\% without adaptation (p < 0.001). For all prostate the mean 2\%/2 mm gamma-fail rate was 1.4\% with adaptation and 17.3\% without adaptation (p < 0.001). The difference between the four systems was small with an average 2\%/2 mm gamma-fail rate of <3\% for all systems with adaptation for lung and prostate. Conclusions: The investigated systems all accounted for realistic tumor motion accurately and performed to a similar high standard, with real-time adaptation significantly outperforming non-adaptive delivery methods.}, language = {en} } @article{SilvestriBarrowdaleMulliganetal.2016, author = {Silvestri, Valentina and Barrowdale, Daniel and Mulligan, Anna Marie and Neuhausen, Susan L. and Fox, Stephen and Karlan, Beth Y. and Mitchell, Gillian and James, Paul and Thull, Darcy L. and Zorn, Kristin K. and Carter, Natalie J. and Nathanson, Katherine L. and Domchek, Susan M. and Rebbeck, Timothy R. and Ramus, Susan J. and Nussbaum, Robert L. and Olopade, Olufunmilayo I. and Rantala, Johanna and Yoon, Sook-Yee and Caligo, Maria A. and Spugnesi, Laura and Bojesen, Anders and Pedersen, Inge Sokilde and Thomassen, Mads and Jensen, Uffe Birk and Toland, Amanda Ewart and Senter, Leigha and Andrulis, Irene L. and Glendon, Gord and Hulick, Peter J. and Imyanitov, Evgeny N. and Greene, Mark H. and Mai, Phuong L. and Singer, Christian F. and Rappaport-Fuerhauser, Christine and Kramer, Gero and Vijai, Joseph and Offit, Kenneth and Robson, Mark and Lincoln, Anne and Jacobs, Lauren and Machackova, Eva and Foretova, Lenka and Navratilova, Marie and Vasickova, Petra and Couch, Fergus J. and Hallberg, Emily and Ruddy, Kathryn J. and Sharma, Priyanka and Kim, Sung-Won and Teixeira, Manuel R. and Pinto, Pedro and Montagna, Marco and Matricardi, Laura and Arason, Adalgeir and Johannsson, Oskar Th and Barkardottir, Rosa B. and Jakubowska, Anna and Lubinski, Jan and Izquierdo, Angel and Pujana, Miguel Angel and Balma{\~n}a, Judith and Diez, Orland and Ivady, Gabriella and Papp, Janos and Olah, Edith and Kwong, Ava and Nevanlinna, Heli and Aittom{\"a}ki, Kristiina and Segura, Pedro Perez and Caldes, Trinidad and Van Maerken, Tom and Poppe, Bruce and Claes, Kathleen B. M. and Isaacs, Claudine and Elan, Camille and Lasset, Christine and Stoppa-Lyonnet, Dominique and Barjhoux, Laure and Belotti, Muriel and Meindl, Alfons and Gehrig, Andrea and Sutter, Christian and Engel, Christoph and Niederacher, Dieter and Steinemann, Doris and Hahnen, Eric and Kast, Karin and Arnold, Norbert and Varon-Mateeva, Raymonda and Wand, Dorothea and Godwin, Andrew K. and Evans, D. Gareth and Frost, Debra and Perkins, Jo and Adlard, Julian and Izatt, Louise and Platte, Radka and Eeles, Ros and Ellis, Steve and Hamann, Ute and Garber, Judy and Fostira, Florentia and Fountzilas, George and Pasini, Barbara and Giannini, Giuseppe and Rizzolo, Piera and Russo, Antonio and Cortesi, Laura and Papi, Laura and Varesco, Liliana and Palli, Domenico and Zanna, Ines and Savarese, Antonella and Radice, Paolo and Manoukian, Siranoush and Peissel, Bernard and Barile, Monica and Bonanni, Bernardo and Viel, Alessandra and Pensotti, Valeria and Tommasi, Stefania and Peterlongo, Paolo and Weitzel, Jeffrey N. and Osorio, Ana and Benitez, Javier and McGuffog, Lesley and Healey, Sue and Gerdes, Anne-Marie and Ejlertsen, Bent and Hansen, Thomas V. O. and Steele, Linda and Ding, Yuan Chun and Tung, Nadine and Janavicius, Ramunas and Goldgar, David E. and Buys, Saundra S. and Daly, Mary B. and Bane, Anita and Terry, Mary Beth and John, Esther M. and Southey, Melissa and Easton, Douglas F. and Chenevix-Trench, Georgia and Antoniou, Antonis C. and Ottini, Laura}, title = {Male breast cancer in BRCA1 and BRCA2 mutation carriers: pathology data from the Consortium of Investigators of Modifiers of BRCA1/2}, series = {Breast Cancer Research}, volume = {18}, journal = {Breast Cancer Research}, number = {15}, doi = {10.1186/s13058-016-0671-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-164769}, year = {2016}, abstract = {Background BRCA1 and, more commonly, BRCA2 mutations are associated with increased risk of male breast cancer (MBC). However, only a paucity of data exists on the pathology of breast cancers (BCs) in men with BRCA1/2 mutations. Using the largest available dataset, we determined whether MBCs arising in BRCA1/2 mutation carriers display specific pathologic features and whether these features differ from those of BRCA1/2 female BCs (FBCs). Methods We characterised the pathologic features of 419 BRCA1/2 MBCs and, using logistic regression analysis, contrasted those with data from 9675 BRCA1/2 FBCs and with population-based data from 6351 MBCs in the Surveillance, Epidemiology, and End Results (SEER) database. Results Among BRCA2 MBCs, grade significantly decreased with increasing age at diagnosis (P = 0.005). Compared with BRCA2 FBCs, BRCA2 MBCs were of significantly higher stage (P for trend = 2 × 10-5) and higher grade (P for trend = 0.005) and were more likely to be oestrogen receptor-positive [odds ratio (OR) 10.59; 95 \% confidence interval (CI) 5.15-21.80] and progesterone receptor-positive (OR 5.04; 95 \% CI 3.17-8.04). With the exception of grade, similar patterns of associations emerged when we compared BRCA1 MBCs and FBCs. BRCA2 MBCs also presented with higher grade than MBCs from the SEER database (P for trend = 4 × 10-12). Conclusions On the basis of the largest series analysed to date, our results show that BRCA1/2 MBCs display distinct pathologic characteristics compared with BRCA1/2 FBCs, and we identified a specific BRCA2-associated MBC phenotype characterised by a variable suggesting greater biological aggressiveness (i.e., high histologic grade). These findings could lead to the development of gender-specific risk prediction models and guide clinical strategies appropriate for MBC management.}, language = {en} } @article{RietjensDussortGuentheretal.2018, author = {Rietjens, Ivonne M. C. M. and Dussort, P. and G{\"u}nther, Helmut and Hanlon, Paul and Honda, Hiroshi and Mally, Angela and O'Hagan, Sue and Scholz, Gabriele and Seidel, Albrecht and Swenberg, James and Teeguarden, Justin and Eisenbrand, Gerhard}, title = {Exposure assessment of process-related contaminants in food by biomarker monitoring}, series = {Archives of Toxicology}, volume = {92}, journal = {Archives of Toxicology}, number = {1}, doi = {10.1007/s00204-017-2143-2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-226268}, pages = {15-40}, year = {2018}, abstract = {Exposure assessment is a fundamental part of the risk assessment paradigm, but can often present a number of challenges and uncertainties. This is especially the case for process contaminants formed during the processing, e.g. heating of food, since they are in part highly reactive and/or volatile, thus making exposure assessment by analysing contents in food unreliable. New approaches are therefore required to accurately assess consumer exposure and thus better inform the risk assessment. Such novel approaches may include the use of biomarkers, physiologically based kinetic (PBK) modelling-facilitated reverse dosimetry, and/or duplicate diet studies. This review focuses on the state of the art with respect to the use of biomarkers of exposure for the process contaminants acrylamide, 3-MCPD esters, glycidyl esters, furan and acrolein. From the overview presented, it becomes clear that the field of assessing human exposure to process-related contaminants in food by biomarker monitoring is promising and strongly developing. The current state of the art as well as the existing data gaps and challenges for the future were defined. They include (1) using PBK modelling and duplicate diet studies to establish, preferably in humans, correlations between external exposure and biomarkers; (2) elucidation of the possible endogenous formation of the process-related contaminants and the resulting biomarker levels; (3) the influence of inter-individual variations and how to include that in the biomarker-based exposure predictions; (4) the correction for confounding factors; (5) the value of the different biomarkers in relation to exposure scenario's and risk assessment, and (6) the possibilities of novel methodologies. In spite of these challenges it can be concluded that biomarker-based exposure assessment provides a unique opportunity to more accurately assess consumer exposure to process-related contaminants in food and thus to better inform risk assessment.}, language = {en} } @article{DeebGiordanoRossietal.2016, author = {Deeb, Wissam and Giordano, James J. and Rossi, Peter J. and Mogilner, Alon Y. and Gunduz, Aysegul and Judy, Jack W. and Klassen, Bryan T. and Butson, Christopher R. and Van Horne, Craig and Deny, Damiaan and Dougherty, Darin D. and Rowell, David and Gerhardt, Greg A. and Smith, Gwenn S. and Ponce, Francisco A. and Walker, Harrison C. and Bronte-Stewart, Helen M. and Mayberg, Helen S. and Chizeck, Howard J. and Langevin, Jean-Philippe and Volkmann, Jens and Ostrem, Jill L. and Shute, Jonathan B. and Jimenez-Shahed, Joohi and Foote, Kelly D. and Wagle Shukla, Aparna and Rossi, Marvin A. and Oh, Michael and Pourfar, Michael and Rosenberg, Paul B. and Silburn, Peter A. and de Hemptine, Coralie and Starr, Philip A. and Denison, Timothy and Akbar, Umer and Grill, Warren M. and Okun, Michael S.}, title = {Proceedings of the Fourth Annual Deep Brain Stimulation Think Tank: A Review of Emerging Issues and Technologies}, series = {Frontiers in Integrative Neuroscience}, volume = {10}, journal = {Frontiers in Integrative Neuroscience}, number = {38}, doi = {10.3389/fnint.2016.00038}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-168493}, year = {2016}, abstract = {This paper provides an overview of current progress in the technological advances and the use of deep brain stimulation (DBS) to treat neurological and neuropsychiatric disorders, as presented by participants of the Fourth Annual DBS Think Tank, which was convened in March 2016 in conjunction with the Center for Movement Disorders and Neurorestoration at the University of Florida, Gainesveille FL, USA. The Think Tank discussions first focused on policy and advocacy in DBS research and clinical practice, formation of registries, and issues involving the use of DBS in the treatment of Tourette Syndrome. Next, advances in the use of neuroimaging and electrochemical markers to enhance DBS specificity were addressed. Updates on ongoing use and developments of DBS for the treatment of Parkinson's disease, essential tremor, Alzheimer's disease, depression, post-traumatic stress disorder, obesity, addiction were presented, and progress toward innovation(s) in closed-loop applications were discussed. Each section of these proceedings provides updates and highlights of new information as presented at this year's international Think Tank, with a view toward current and near future advancement of the field.}, language = {en} } @article{WangSarwatWangetal.2020, author = {Wang, Shuang and Sarwat, Mariah and Wang, Peng and Surrao, Denver C. and Harkin, Damien G. and St John, James A. and Bolle, Eleonore C. L. and Forget, Aurelien and Dalton, Paul D. and Dargaville, Tim R.}, title = {Hydrogels with Cell Adhesion Peptide-Decorated Channel Walls for Cell Guidance}, series = {Macromolecular Rapid Communications}, volume = {41}, journal = {Macromolecular Rapid Communications}, number = {15}, doi = {10.1002/marc.202000295}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-218031}, year = {2020}, abstract = {A method is reported for making hollow channels within hydrogels decorated with cell-adhesion peptides exclusively at the channel surface. Sacrificial fibers of different diameters are used to introduce channels within poly(ethylene glycol) hydrogels crosslinked with maleimide-thiol chemistry, which are backfilled with a cysteine-containing peptide solution which is conjugated to the lumen with good spatial efficiency. This allows for peptide patterning in only the areas of the hydrogel where they are needed when used as cell-guides, reducing the amount of required peptide 20-fold when compared to bulk functionalization. The power of this approach is highlighted by successfully using these patterned hydrogels without active perfusion to guide fibroblasts and olfactory ensheathing cells—the latter having unique potential in neural repair therapies.}, language = {en} } @article{RhodesChenWilliamsonetal.2018, author = {Rhodes, David A. and Chen, Hung-Chang and Williamson, James C. and Hill, Alfred and Yuan, Jack and Smith, Sam and Rhodes, Harriet and Trowsdale, John and Lehner, Paul J. and Herrmann, Thomas and Eberl, Matthias}, title = {Regulation of Human γδ T Cells by BTN3A1 Protein Stability and ATP-Binding Cassette Transporters}, series = {Frontiers in Immunology}, volume = {9}, journal = {Frontiers in Immunology}, number = {662}, issn = {1664-3224}, doi = {10.3389/fimmu.2018.00662}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-197054}, year = {2018}, abstract = {Activation of human Vγ9/Vδ2 T cells by "phosphoantigens" (pAg), the microbial metabolite (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP) and the endogenous isoprenoid intermediate isopentenyl pyrophosphate, requires expression of butyrophilin BTN3A molecules by presenting cells. However, the precise mechanism of activation of Vγ9/Vδ2 T cells by BTN3A molecules remains elusive. It is not clear what conformation of the three BTN3A isoforms transmits activation signals nor how externally delivered pAg accesses the cytosolic B30.2 domain of BTN3A1. To approach these problems, we studied two HLA haplo-identical HeLa cell lines, termed HeLa-L and HeLa-M, which showed marked differences in pAg-dependent stimulation of Vγ9/Vδ2 T cells. Levels of IFN-γ secretion by Vγ9/Vδ2 T cells were profoundly increased by pAg loading, or by binding of the pan-BTN3A specific agonist antibody CD277 20.1, in HeLa-M compared to HeLa-L cells. IL-2 production from a murine hybridoma T cell line expressing human Vγ9/Vδ2 T cell receptor (TCR) transgenes confirmed that the differential responsiveness to HeLa-L and HeLa-M was TCR dependent. By tissue typing, both HeLa lines were shown to be genetically identical and full-length transcripts of the three BTN3A isoforms were detected in equal abundance with no sequence variation. Expression of BTN3A and interacting molecules, such as periplakin or RhoB, did not account for the functional variation between HeLa-L and HeLa-M cells. Instead, the data implicate a checkpoint controlling BTN3A1 stability and protein trafficking, acting at an early time point in its maturation. In addition, plasma membrane profiling was used to identify proteins upregulated in HMB-PP-treated HeLa-M. ABCG2, a member of the ATP-binding cassette (ABC) transporter family was the most significant candidate, which crucially showed reduced expression in HeLa-L. Expression of a subset of ABC transporters, including ABCA1 and ABCG1, correlated with efficiency of T cell activation by cytokine secretion, although direct evidence of a functional role was not obtained by knockdown experiments. Our findings indicate a link between members of the ABC protein superfamily and the BTN3A-dependent activation of γδ T cells by endogenous and exogenous pAg.}, language = {en} } @article{KimpelSchindlerSchmidtPenningtonetal.2023, author = {Kimpel, Otilia and Schindler, Paul and Schmidt-Pennington, Laura and Altieri, Barbara and Megerle, Felix and Haak, Harm and Pittaway, James and Dischinger, Ulrich and Quinkler, Marcus and Mai, Knut and Kroiss, Matthias and Polat, B{\"u}lent and Fassnacht, Martin}, title = {Efficacy and safety of radiation therapy in advanced adrenocortical carcinoma}, series = {British Journal of Cancer}, volume = {128}, journal = {British Journal of Cancer}, number = {4}, doi = {10.1038/s41416-022-02082-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-324411}, pages = {586-593}, year = {2023}, abstract = {Background International guidelines emphasise the role of radiotherapy (RT) for the management of advanced adrenocortical carcinoma (ACC). However, the evidence for this recommendation is very low. Methods We retrospectively analysed all patients who received RT for advanced ACC in five European centres since 2000. Primary endpoint: time to progression of the treated lesion (tTTP). Secondary endpoints: best objective response, progression-free survival (PFS), overall survival (OS), adverse events, and the establishment of predictive factors by Cox analyses. Results In total, 132 tumoural lesions of 80 patients were treated with conventional RT (cRT) of 50-60 Gy (n = 20) or 20-49 Gy (n = 69), stereotactic body RT of 35-50 Gy (SBRT) (n = 36), or brachytherapy of 12-25 Gy (BT) (n = 7). Best objective lesional response was complete (n = 6), partial (n = 52), stable disease (n = 60), progressive disease (n = 14). Median tTTP was 7.6 months (1.0-148.6). In comparison to cRT\(_{20-49Gy}\), tTTP was significantly longer for cRT\(_{50-60Gy}\) (multivariate adjusted HR 0.10; 95\% CI 0.03-0.33; p < 0.001) and SBRT (HR 0.31; 95\% CI 0.12-0.80; p = 0.016), but not for BT (HR 0.66; 95\% CI 0.22-1.99; p = 0.46). Toxicity was generally mild and moderate with three grade 3 events. No convincing predictive factors could be established. Conclusions This largest published study on RT in advanced ACC provides clear evidence that RT is effective in ACC.}, language = {en} } @article{BreuerMattheisenFranketal.2018, author = {Breuer, Ren{\´e} and Mattheisen, Manuel and Frank, Josef and Krumm, Bertram and Treutlein, Jens and Kassem, Layla and Strohmaier, Jana and Herms, Stefan and M{\"u}hleisen, Thomas W. and Degenhardt, Franziska and Cichon, Sven and N{\"o}then, Markus M. and Karypis, George and Kelsoe, John and Greenwood, Tiffany and Nievergelt, Caroline and Shilling, Paul and Shekhtman, Tatyana and Edenberg, Howard and Craig, David and Szelinger, Szabolcs and Nurnberger, John and Gershon, Elliot and Alliey-Rodriguez, Ney and Zandi, Peter and Goes, Fernando and Schork, Nicholas and Smith, Erin and Koller, Daniel and Zhang, Peng and Badner, Judith and Berrettini, Wade and Bloss, Cinnamon and Byerley, William and Coryell, William and Foroud, Tatiana and Guo, Yirin and Hipolito, Maria and Keating, Brendan and Lawson, William and Liu, Chunyu and Mahon, Pamela and McInnis, Melvin and Murray, Sarah and Nwulia, Evaristus and Potash, James and Rice, John and Scheftner, William and Z{\"o}llner, Sebastian and McMahon, Francis J. and Rietschel, Marcella and Schulze, Thomas G.}, title = {Detecting significant genotype-phenotype association rules in bipolar disorder: market research meets complex genetics}, series = {International Journal of Bipolar Disorders}, volume = {6}, journal = {International Journal of Bipolar Disorders}, doi = {10.1186/s40345-018-0132-x}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-220509}, year = {2018}, abstract = {Background Disentangling the etiology of common, complex diseases is a major challenge in genetic research. For bipolar disorder (BD), several genome-wide association studies (GWAS) have been performed. Similar to other complex disorders, major breakthroughs in explaining the high heritability of BD through GWAS have remained elusive. To overcome this dilemma, genetic research into BD, has embraced a variety of strategies such as the formation of large consortia to increase sample size and sequencing approaches. Here we advocate a complementary approach making use of already existing GWAS data: a novel data mining procedure to identify yet undetected genotype-phenotype relationships. We adapted association rule mining, a data mining technique traditionally used in retail market research, to identify frequent and characteristic genotype patterns showing strong associations to phenotype clusters. We applied this strategy to three independent GWAS datasets from 2835 phenotypically characterized patients with BD. In a discovery step, 20,882 candidate association rules were extracted. Results Two of these rules—one associated with eating disorder and the other with anxiety—remained significant in an independent dataset after robust correction for multiple testing. Both showed considerable effect sizes (odds ratio ~ 3.4 and 3.0, respectively) and support previously reported molecular biological findings. Conclusion Our approach detected novel specific genotype-phenotype relationships in BD that were missed by standard analyses like GWAS. While we developed and applied our method within the context of BD gene discovery, it may facilitate identifying highly specific genotype-phenotype relationships in subsets of genome-wide data sets of other complex phenotype with similar epidemiological properties and challenges to gene discovery efforts.}, language = {en} }