TY  - JOUR
A1  - Adrián-Martínez, S.
A1  - Ageron, M.
A1  - Aharonian, F.
A1  - Aiello, S.
A1  - Albert, A.
A1  - Ameli, F.
A1  - Annasontzis, E.
A1  - Andre, M.
A1  - Androulakis, G.
A1  - Anghinolfi, M.
A1  - Anton, G.
A1  - Ardid, M.
A1  - Avgitas, T.
A1  - Barbarino, G.
A1  - Baret, B.
A1  - Barrios-Martí, J.
A1  - Belhorma, B.
A1  - Belias, A.
A1  - Berbee, A.
A1  - van den Berg, A.
A1  - Bertin, V.
A1  - Beurthey, S.
A1  - van Beeveren, V.
A1  - Beverini, N.
A1  - Biagi, S.
A1  - Biagioni, A.
A1  - Billault, M.
A1  - Bondì, M.
A1  - Bormuth, R.
A1  - Bouhadef, B.
A1  - Bourlis, G.
A1  - Bourret, S.
A1  - Boutonnet, C.
A1  - Bouwhuis, M.
A1  - Bozza, C.
A1  - Bruijn, R.
A1  - Brunner, J.
A1  - Buis, E.
A1  - Busto, J.
A1  - Cacopardo, G.
A1  - Caillat, L.
A1  - Calmai, M.
A1  - Calvo, D.
A1  - Capone, A.
A1  - Caramete, L.
A1  - Cecchini, S.
A1  - Celli, S.
A1  - Champion, C.
A1  - Cherkaoui El Moursli, R.
A1  - Cherubini, S.
A1  - Chiarusi, T.
A1  - Circella, M.
A1  - Classen, L.
A1  - Cocimano, R.
A1  - Coelho, J. A. B.
A1  - Coleiro, A.
A1  - Colonges, S.
A1  - Coniglione, R.
A1  - Cordelli, M.
A1  - Cosquer, A.
A1  - Coyle, P.
A1  - Creusot, A.
A1  - Cuttone, G.
A1  - D'Amico, A.
A1  - De Bonis, G.
A1  - De Rosa, G.
A1  - De Sio, C.
A1  - Di Capua, F.
A1  - Di Palma, I.
A1  - Díaz García, A. F.
A1  - Distefano, C.
A1  - Donzaud, C.
A1  - Dornic, D.
A1  - Dorosti-Hasankiadeh, Q.
A1  - Drakopoulou, E.
A1  - Drouhin, D.
A1  - Drury, L.
A1  - Durocher, M.
A1  - Eberl, T.
A1  - Eichie, S.
A1  - van Eijk, D.
A1  - El Bojaddaini, I.
A1  - El Khayati, N.
A1  - Elsaesser, D.
A1  - Enzenhöfer, A.
A1  - Fassi, F.
A1  - Favali, P.
A1  - Fermani, P.
A1  - Ferrara, G.
A1  - Filippidis, C.
A1  - Frascadore, G.
A1  - Fusco, L. A.
A1  - Gal, T.
A1  - Galatà, S.
A1  - Garufi, F.
A1  - Gay, P.
A1  - Gebyehu, M.
A1  - Giordano, V.
A1  - Gizani, N.
A1  - Gracia, R.
A1  - Graf, K.
A1  - Grégoire, T.
A1  - Grella, G.
A1  - Habel, R.
A1  - Hallmann, S.
A1  - van Haren, H.
A1  - Harissopulos, S.
A1  - Heid, T.
A1  - Heijboer, A.
A1  - Heine, E.
A1  - Henry, S.
A1  - Hernández-Rey, J. J.
A1  - Hevinga, M.
A1  - Hofestädt, J.
A1  - Hugon, C. M. F.
A1  - Illuminati, G.
A1  - James, C. W.
A1  - Jansweijer, P.
A1  - Jongen, M.
A1  - de Jong, M.
A1  - Kadler, M.
A1  - Kalekin, O.
A1  - Kappes, A.
A1  - Katz, U. F.
A1  - Keller, P.
A1  - Kieft, G.
A1  - Kießling, D.
A1  - Koffeman, E. N.
A1  - Kooijman, P.
A1  - Kouchner, A.
A1  - Kulikovskiy, V.
A1  - Lahmann, R.
A1  - Lamare, P.
A1  - Leisos, A.
A1  - Leonora, E.
A1  - Lindsey Clark, M.
A1  - Liolios, A.
A1  - Llorenz Alvarez, C. D.
A1  - Lo Presti, D.
A1  - Löhner, H.
A1  - Lonardo, A.
A1  - Lotze, M.
A1  - Loucatos, S.
A1  - Maccioni, E.
A1  - Mannheim, K.
A1  - Margiotta, A.
A1  - Marinelli, A.
A1  - Mariş, O.
A1  - Markou, C.
A1  - Martínez-Mora, J. A.
A1  - Martini, A.
A1  - Mele, R.
A1  - Melis, K. W.
A1  - Michael, T.
A1  - Migliozzi, P.
A1  - Migneco, E.
A1  - Mijakowski, P.
A1  - Miraglia, A.
A1  - Mollo, C. M.
A1  - Mongelli, M.
A1  - Morganti, M.
A1  - Moussa, A.
A1  - Musico, P.
A1  - Musumeci, M.
A1  - Navas, S.
A1  - Nicoleau, C. A.
A1  - Olcina, I.
A1  - Olivetto, C.
A1  - Orlando, A.
A1  - Papaikonomou, A.
A1  - Papaleo, R.
A1  - Păvălaş, G. E.
A1  - Peek, H.
A1  - Pellegrino, C.
A1  - Perrina, C.
A1  - Pfutzner, M.
A1  - Piattelli, P.
A1  - Pikounis, K.
A1  - Poma, G. E.
A1  - Popa, V.
A1  - Pradier, T.
A1  - Pratolongo, F.
A1  - Pühlhofer, G.
A1  - Pulvirenti, S.
A1  - Quinn, L.
A1  - Racca, C.
A1  - Raffaelli, F.
A1  - Randazzo, N.
A1  - Rapidis, P.
A1  - Razis, P.
A1  - Real, D.
A1  - Resvanis, L.
A1  - Reubelt, J.
A1  - Riccobene, G.
A1  - Rossi, C.
A1  - Rovelli, A.
A1  - Saldaña, M.
A1  - Salvadori, I.
A1  - Samtleben, D. F. E.
A1  - Sánchez García, A.
A1  - Sánchez Losa, A.
A1  - Sanguineti, M.
A1  - Santangelo, A.
A1  - Santonocito, D.
A1  - Sapienza, P.
A1  - Schimmel, F.
A1  - Schmelling, J.
A1  - Sciacca, V.
A1  - Sedita, M.
A1  - Seitz, T.
A1  - Sgura, I.
A1  - Simeone, F.
A1  - Siotis, I.
A1  - Sipala, V.
A1  - Spisso, B.
A1  - Spurio, M.
A1  - Stavropoulos, G.
A1  - Steijger, J.
A1  - Stellacci, S. M.
A1  - Stransky, D.
A1  - Taiuti, M.
A1  - Tayalati, Y.
A1  - Tézier, D.
A1  - Theraube, S.
A1  - Thompson, L.
A1  - Timmer, P.
A1  - Tönnis, C.
A1  - Trasatti, L.
A1  - Trovato, A.
A1  - Tsirigotis, A.
A1  - Tzamarias, S.
A1  - Tzamariudaki, E.
A1  - Vallage, B.
A1  - Van Elewyk, V.
A1  - Vermeulen, J.
A1  - Vicini, P.
A1  - Viola, S.
A1  - Vivolo, D.
A1  - Volkert, M.
A1  - Voulgaris, G.
A1  - Wiggers, L.
A1  - Wilms, J.
A1  - de Wolf, E.
A1  - Zachariadou, K.
A1  - Zornoza, J. D.
A1  - Zúñiga, J.
T1  - Letter of intent for KM3NeT 2.0
JF  - Journal of Physics G-Nuclear and Particle Physics
N2  - The main objectives of the KM3NeT Collaboration are (i) the discovery and subsequent observation of high-energy neutrino sources in the Universe and (ii) the determination of the mass hierarchy of neutrinos. These objectives are strongly motivated by two recent important discoveries, namely: (1) the high-energy astrophysical neutrino signal reported by IceCube and (2) the sizable contribution of electron neutrinos to the third neutrino mass eigenstate as reported by Daya Bay, Reno and others. To meet these objectives, the KM3NeT Collaboration plans to build a new Research Infrastructure consisting of a network of deep-sea neutrino telescopes in the Mediterranean Sea. A phased and distributed implementation is pursued which maximises the access to regional funds, the availability of human resources and the synergistic opportunities for the Earth and sea sciences community. Three suitable deep-sea sites are selected, namely off-shore Toulon (France), Capo Passero (Sicily, Italy) and Pylos (Peloponnese, Greece). The infrastructure will consist of three so-called building blocks. A building block comprises 115 strings, each string comprises 18 optical modules and each optical module comprises 31 photo-multiplier tubes. Each building block thus constitutes a three-dimensional array of photo sensors that can be used to detect the Cherenkov light produced by relativistic particles emerging from neutrino interactions. Two building blocks will be sparsely configured to fully explore the IceCube signal with similar instrumented volume, different methodology, improved resolution and
KW  - neutrino astronomy
KW  - eutrino physics
KW  - deep sea neutrino telescope
KW  - neutrino mass hierarchy
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-188050
VL  - 43
IS  - 8
ER  - 
TY  - JOUR
A1  - Djakovic, Lara
A1  - Hennig, Thomas
A1  - Reinisch, Katharina
A1  - Milić, Andrea
A1  - Whisnant, Adam W.
A1  - Wolf, Katharina
A1  - Weiß, Elena
A1  - Haas, Tobias
A1  - Grothey, Arnhild
A1  - Jürges, Christopher S.
A1  - Kluge, Michael
A1  - Wolf, Elmar
A1  - Erhard, Florian
A1  - Friedel, Caroline C.
A1  - Dölken, Lars
T1  - The HSV-1 ICP22 protein selectively impairs histone repositioning upon Pol II transcription downstream of genes
JF  - Nature Communications
N2  - Herpes simplex virus 1 (HSV-1) infection and stress responses disrupt transcription termination by RNA Polymerase II (Pol II). In HSV-1 infection, but not upon salt or heat stress, this is accompanied by a dramatic increase in chromatin accessibility downstream of genes. Here, we show that the HSV-1 immediate-early protein ICP22 is both necessary and sufficient to induce downstream open chromatin regions (dOCRs) when transcription termination is disrupted by the viral ICP27 protein. This is accompanied by a marked ICP22-dependent loss of histones downstream of affected genes consistent with impaired histone repositioning in the wake of Pol II. Efficient knock-down of the ICP22-interacting histone chaperone FACT is not sufficient to induce dOCRs in ΔICP22 infection but increases dOCR induction in wild-type HSV-1 infection. Interestingly, this is accompanied by a marked increase in chromatin accessibility within gene bodies. We propose a model in which allosteric changes in Pol II composition downstream of genes and ICP22-mediated interference with FACT activity explain the differential impairment of histone repositioning downstream of genes in the wake of Pol II in HSV-1 infection.
KW  - herpes virus
KW  - transcription
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-358161
VL  - 14
ER  - 
TY  - JOUR
A1  - Hudson, Lawrence N.
A1  - Newbold, Tim
A1  - Contu, Sara
A1  - Hill, Samantha L. L.
A1  - Lysenko, Igor
A1  - De Palma, Adriana
A1  - Phillips, Helen R. P.
A1  - Senior, Rebecca A.
A1  - Bennett, Dominic J.
A1  - Booth, Hollie
A1  - Choimes, Argyrios
A1  - Correia, David L. P.
A1  - Day, Julie
A1  - Echeverria-Londono, Susy
A1  - Garon, Morgan
A1  - Harrison, Michelle L. K.
A1  - Ingram, Daniel J.
A1  - Jung, Martin
A1  - Kemp, Victoria
A1  - Kirkpatrick, Lucinda
A1  - Martin, Callum D.
A1  - Pan, Yuan
A1  - White, Hannah J.
A1  - Aben, Job
A1  - Abrahamczyk, Stefan
A1  - Adum, Gilbert B.
A1  - Aguilar-Barquero, Virginia
A1  - Aizen, Marcelo
A1  - Ancrenaz, Marc
A1  - Arbelaez-Cortes, Enrique
A1  - Armbrecht, Inge
A1  - Azhar, Badrul
A1  - Azpiroz, Adrian B.
A1  - Baeten, Lander
A1  - Báldi, András
A1  - Banks, John E.
A1  - Barlow, Jos
A1  - Batáry, Péter
A1  - Bates, Adam J.
A1  - Bayne, Erin M.
A1  - Beja, Pedro
A1  - Berg, Ake
A1  - Berry, Nicholas J.
A1  - Bicknell, Jake E.
A1  - Bihn, Jochen H.
A1  - Böhning-Gaese, Katrin
A1  - Boekhout, Teun
A1  - Boutin, Celine
A1  - Bouyer, Jeremy
A1  - Brearley, Francis Q.
A1  - Brito, Isabel
A1  - Brunet, Jörg
A1  - Buczkowski, Grzegorz
A1  - Buscardo, Erika
A1  - Cabra-Garcia, Jimmy
A1  - Calvino-Cancela, Maria
A1  - Cameron, Sydney A.
A1  - Cancello, Eliana M.
A1  - Carrijo, Tiago F.
A1  - Carvalho, Anelena L.
A1  - Castro, Helena
A1  - Castro-Luna, Alejandro A.
A1  - Cerda, Rolando
A1  - Cerezo, Alexis
A1  - Chauvat, Matthieu
A1  - Clarke, Frank M.
A1  - Cleary, Daniel F. R.
A1  - Connop, Stuart P.
A1  - D'Aniello, Biagio
A1  - da Silva, Pedro Giovani
A1  - Darvill, Ben
A1  - Dauber, Jens
A1  - Dejean, Alain
A1  - Diekötter, Tim
A1  - Dominguez-Haydar, Yamileth
A1  - Dormann, Carsten F.
A1  - Dumont, Bertrand
A1  - Dures, Simon G.
A1  - Dynesius, Mats
A1  - Edenius, Lars
A1  - Elek, Zoltán
A1  - Entling, Martin H.
A1  - Farwig, Nina
A1  - Fayle, Tom M.
A1  - Felicioli, Antonio
A1  - Felton, Annika M.
A1  - Ficetola, Gentile F.
A1  - Filgueiras, Bruno K. C.
A1  - Fonte, Steve J.
A1  - Fraser, Lauchlan H.
A1  - Fukuda, Daisuke
A1  - Furlani, Dario
A1  - Ganzhorn, Jörg U.
A1  - Garden, Jenni G.
A1  - Gheler-Costa, Carla
A1  - Giordani, Paolo
A1  - Giordano, Simonetta
A1  - Gottschalk, Marco S.
A1  - Goulson, Dave
A1  - Gove, Aaron D.
A1  - Grogan, James
A1  - Hanley, Mick E.
A1  - Hanson, Thor
A1  - Hashim, Nor R.
A1  - Hawes, Joseph E.
A1  - Hébert, Christian
A1  - Helden, Alvin J.
A1  - Henden, John-André
A1  - Hernández, Lionel
A1  - Herzog, Felix
A1  - Higuera-Diaz, Diego
A1  - Hilje, Branko
A1  - Horgan, Finbarr G.
A1  - Horváth, Roland
A1  - Hylander, Kristoffer
A1  - Horváth, Roland
A1  - Isaacs-Cubides, Paola
A1  - Ishitani, Mashiro
A1  - Jacobs, Carmen T.
A1  - Jaramillo, Victor J.
A1  - Jauker, Birgit
A1  - Jonsell, Matts
A1  - Jung, Thomas S.
A1  - Kapoor, Vena
A1  - Kati, Vassiliki
A1  - Katovai, Eric
A1  - Kessler, Michael
A1  - Knop, Eva
A1  - Kolb, Annette
A1  - Körösi, Àdám
A1  - Lachat, Thibault
A1  - Lantschner, Victoria
A1  - Le Féon, Violette
A1  - LeBuhn, Gretchen
A1  - Légaré, Jean-Philippe
A1  - Letcher, Susan G.
A1  - Littlewood, Nick A.
A1  - López-Quintero, Carlos A.
A1  - Louhaichi, Mounir
A1  - Lövei, Gabor L.
A1  - Lucas-Borja, Manuel Esteban
A1  - Luja, Victor H.
A1  - Maeto, Kaoru
A1  - Magura, Tibor
A1  - Mallari, Neil Aldrin
A1  - Marin-Spiotta, Erika
A1  - Marhall, E. J. P.
A1  - Martínez, Eliana
A1  - Mayfield, Margaret M.
A1  - Mikusinski, Gregorz
A1  - Milder, Jeffery C.
A1  - Miller, James R.
A1  - Morales, Carolina L.
A1  - Muchane, Mary N.
A1  - Muchane, Muchai
A1  - Naidoo, Robin
A1  - Nakamura, Akihiro
A1  - Naoe, Shoji
A1  - Nates-Parra, Guiomar
A1  - Navarerete Gutierrez, Dario A.
A1  - Neuschulz, Eike L.
A1  - Noreika, Norbertas
A1  - Norfolk, Olivia
A1  - Noriega, Jorge Ari
A1  - Nöske, Nicole M.
A1  - O'Dea, Niall
A1  - Oduro, William
A1  - Ofori-Boateng, Caleb
A1  - Oke, Chris O.
A1  - Osgathorpe, Lynne M.
A1  - Paritsis, Juan
A1  - Parrah, Alejandro
A1  - Pelegrin, Nicolás
A1  - Peres, Carlos A.
A1  - Persson, Anna S.
A1  - Petanidou, Theodora
A1  - Phalan, Ben
A1  - Philips, T. Keith
A1  - Poveda, Katja
A1  - Power, Eileen F.
A1  - Presley, Steven J.
A1  - Proença, Vânia
A1  - Quaranta, Marino
A1  - Quintero, Carolina
A1  - Redpath-Downing, Nicola A.
A1  - Reid, J. Leighton
A1  - Reis, Yana T.
A1  - Ribeiro, Danilo B.
A1  - Richardson, Barbara A.
A1  - Richardson, Michael J.
A1  - Robles, Carolina A.
A1  - Römbke, Jörg
A1  - Romero-Duque, Luz Piedad
A1  - Rosselli, Loreta
A1  - Rossiter, Stephen J.
A1  - Roulston, T'ai H.
A1  - Rousseau, Laurent
A1  - Sadler, Jonathan P.
A1  - Sáfián, Szbolcs
A1  - Saldaña-Vásquez, Romeo A.
A1  - Samnegård, Ulrika
A1  - Schüepp, Christof
A1  - Schweiger, Oliver
A1  - Sedlock, Jodi L.
A1  - Shahabuddin, Ghazala
A1  - Sheil, Douglas
A1  - Silva, Fernando A. B.
A1  - Slade, Eleanor
A1  - Smith-Pardo, Allan H.
A1  - Sodhi, Navjot S.
A1  - Somarriba, Eduardo J.
A1  - Sosa, Ramón A.
A1  - Stout, Jane C.
A1  - Struebig, Matthew J.
A1  - Sung, Yik-Hei
A1  - Threlfall, Caragh G.
A1  - Tonietto, Rebecca
A1  - Tóthmérész, Béla
A1  - Tscharntke, Teja
A1  - Turner, Edgar C.
A1  - Tylianakis, Jason M.
A1  - Vanbergen, Adam J.
A1  - Vassilev, Kiril
A1  - Verboven, Hans A. F.
A1  - Vergara, Carlos H.
A1  - Vergara, Pablo M.
A1  - Verhulst, Jort
A1  - Walker, Tony R.
A1  - Wang, Yanping
A1  - Watling, James I.
A1  - Wells, Konstans
A1  - Williams, Christopher D.
A1  - Willig, Michael R.
A1  - Woinarski, John C. Z.
A1  - Wolf, Jan H. D.
A1  - Woodcock, Ben A.
A1  - Yu, Douglas W.
A1  - Zailsev, Andreys
A1  - Collen, Ben
A1  - Ewers, Rob M.
A1  - Mace, Georgina M.
A1  - Purves, Drew W.
A1  - Scharlemann, Jörn P. W.
A1  - Pervis, Andy
T1  - The PREDICTS database: a global database of how local terrestrial biodiversity responds to human impacts
JF  - Ecology and Evolution
N2  - Biodiversity continues to decline in the face of increasing anthropogenic pressures such as habitat destruction, exploitation, pollution and introduction of alien species. Existing global databases of species' threat status or population time series are dominated by charismatic species. The collation of datasets with broad taxonomic and biogeographic extents, and that support computation of a range of biodiversity indicators, is necessary to enable better understanding of historical declines and to project - and avert - future declines. We describe and assess a new database of more than 1.6 million samples from 78 countries representing over 28,000 species, collated from existing spatial comparisons of local-scale biodiversity exposed to different intensities and types of anthropogenic pressures, from terrestrial sites around the world. The database contains measurements taken in 208 (of 814) ecoregions, 13 (of 14) biomes, 25 (of 35) biodiversity hotspots and 16 (of 17) megadiverse countries. The database contains more than 1% of the total number of all species described, and more than 1% of the described species within many taxonomic groups - including flowering plants, gymnosperms, birds, mammals, reptiles, amphibians, beetles, lepidopterans and hymenopterans. The dataset, which is still being added to, is therefore already considerably larger and more representative than those used by previous quantitative models of biodiversity trends and responses. The database is being assembled as part of the PREDICTS project (Projecting Responses of Ecological Diversity In Changing Terrestrial Systems - ). We make site-level summary data available alongside this article. The full database will be publicly available in 2015.
KW  - urban-rural gradient
KW  - instensively managed farmland
KW  - Mexican coffee plantations
KW  - Bombus Spp. Hymenoptera
KW  - bumblebee nest density
KW  - data sharing
KW  - land use
KW  - habitat destruction
KW  - global change
KW  - land-use change
KW  - plant community composition
KW  - Northeastern Costa Rica
KW  - dung beetle coleoptera
KW  - bird species richness
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-114425
VL  - 4
IS  - 24
ER  - 
TY  - JOUR
A1  - Hommers, L. G.
A1  - Richter, J.
A1  - Yang, Y.
A1  - Raab, A.
A1  - Baumann, C.
A1  - Lang, K.
A1  - Schiele, M. A.
A1  - Weber, H.
A1  - Wittmann, A.
A1  - Wolf, C.
A1  - Alpers, G. W.
A1  - Arolt, V.
A1  - Domschke, K.
A1  - Fehm, L.
A1  - Fydrich, T.
A1  - Gerlach, A.
A1  - Gloster, A. T.
A1  - Hamm, A. O.
A1  - Helbig-Lang, S.
A1  - Kircher, T.
A1  - Lang, T.
A1  - Pané-Farré, C. A.
A1  - Pauli, P.
A1  - Pfleiderer, B.
A1  - Reif, A.
A1  - Romanos, M.
A1  - Straube, B.
A1  - Ströhle, A.
A1  - Wittchen, H.-U.
A1  - Frantz, S.
A1  - Ertl, G.
A1  - Lohse, M. J.
A1  - Lueken, U.
A1  - Deckert, J.
T1  - A functional genetic variation of SLC6A2 repressor hsa-miR-579-3p upregulates sympathetic noradrenergic processes of fear and anxiety
JF  - Translational Psychiatry
N2  - Increased sympathetic noradrenergic signaling is crucially involved in fear and anxiety as defensive states. MicroRNAs regulate dynamic gene expression during synaptic plasticity and genetic variation of microRNAs modulating noradrenaline transporter gene (SLC6A2) expression may thus lead to altered central and peripheral processing of fear and anxiety. In silico prediction of microRNA regulation of SLC6A2 was confirmed by luciferase reporter assays and identified hsa-miR-579-3p as a regulating microRNA. The minor (T)-allele of rs2910931 (MAFcases = 0.431, MAFcontrols = 0.368) upstream of MIR579 was associated with panic disorder in patients (pallelic = 0.004, ncases = 506, ncontrols = 506) and with higher trait anxiety in healthy individuals (pASI = 0.029, pACQ = 0.047, n = 3112). Compared to the major (A)-allele, increased promoter activity was observed in luciferase reporter assays in vitro suggesting more effective MIR579 expression and SLC6A2 repression in vivo (p = 0.041). Healthy individuals carrying at least one (T)-allele showed a brain activation pattern suggesting increased defensive responding and sympathetic noradrenergic activation in midbrain and limbic areas during the extinction of conditioned fear. Panic disorder patients carrying two (T)-alleles showed elevated heart rates in an anxiety-provoking behavioral avoidance test (F(2, 270) = 5.47, p = 0.005). Fine-tuning of noradrenaline homeostasis by a MIR579 genetic variation modulated central and peripheral sympathetic noradrenergic activation during fear processing and anxiety. This study opens new perspectives on the role of microRNAs in the etiopathogenesis of anxiety disorders, particularly their cardiovascular symptoms and comorbidities.
KW  - clinical genetics
KW  - psychiatric disorders
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-322497
VL  - 8
ER  - 
TY  - JOUR
A1  - Gratwohl, A
A1  - Pfirrmann, M
A1  - Zander, A
A1  - Kröger, N
A1  - Beelen, D
A1  - Novotny, J
A1  - Nerl, C
A1  - Scheid, C
A1  - Spiekermann, K
A1  - Mayer, J
A1  - Sayer, HG
A1  - Falge, C
A1  - Bunjes, D
A1  - Döhner, H
A1  - Ganser, A
A1  - Schmidt-Wolf, I
A1  - Schwerdtfeger, R
A1  - Baurmann, H
A1  - Kuse, R
A1  - Schmitz, N
A1  - Wehmeier, A
A1  - Fischer, J Th
A1  - Ho, AD
A1  - Wilhelm, M
A1  - Goebeler, M-E
A1  - Lindemann, HW
A1  - Bormann, M
A1  - Hertenstein, B
A1  - Schlimok, G
A1  - Baerlocher, GM
A1  - Aul, C
A1  - Pfreundschuh, M
A1  - Fabian, M
A1  - Staib, P
A1  - Edinger, M
A1  - Schatz, M
A1  - Fauser, A
A1  - Arnold, R
A1  - Kindler, T
A1  - Wulf, G
A1  - Rosselet, A
A1  - Hellmann, A
A1  - Schäfer, E
A1  - Prümmer, O
A1  - Schenk, M
A1  - Hasford, J
A1  - Heimpel, H
A1  - Hossfeld, DK
A1  - Kolb, H-J
A1  - Büsche, G
A1  - Haferlach, C
A1  - Schnittger, S
A1  - Müller, MC
A1  - Reiter, A
A1  - Berger, U
A1  - Saußele, S
A1  - Hochhaus, A
A1  - Hehlmann, R
T1  - Long-term outcome of patients with newly diagnosed chronic myeloid leukemia: a randomized comparison of stem cell transplantation with drug treatment
JF  - Leukemia
N2  - Tyrosine kinase inhibitors represent today's treatment of choice in chronic myeloid leukemia (CML). Allogeneic hematopoietic stem cell transplantation (HSCT) is regarded as salvage therapy. This prospective randomized CML-study IIIA recruited 669 patients with newly diagnosed CML between July 1997 and January 2004 from 143 centers. Of these, 427 patients were considered eligible for HSCT and were randomized by availability of a matched family donor between primary HSCT (group A; N=166 patients) and best available drug treatment (group B; N=261). Primary end point was long-term survival. Survival probabilities were not different between groups A and B (10-year survival: 0.76 (95% confidence interval (CI): 0.69–0.82) vs 0.69 (95% CI: 0.61–0.76)), but influenced by disease and transplant risk. Patients with a low transplant risk showed superior survival compared with patients with high- (P<0.001) and non-high-risk disease (P=0.047) in group B; after entering blast crisis, survival was not different with or without HSCT. Significantly more patients in group A were in molecular remission (56% vs 39%; P = 0.005) and free of drug treatment (56% vs 6%; P<0.001). Differences in symptoms and Karnofsky score were not significant. In the era of tyrosine kinase inhibitors, HSCT remains a valid option when both disease and transplant risk are considered.
KW  - chronic myeloid leukemia
KW  - stem cell transplantation
KW  - drug treatment
KW  - CML
KW  - tyrosine kinase inhibitors
KW  - allogeneic hematopoietic stem cell transplantation
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-150368
VL  - 30
ER  - 
TY  - JOUR
A1  - Otto, C.
A1  - Schmidt, S.
A1  - Kastner, C.
A1  - Denk, S.
A1  - Kettler, J.
A1  - Müller, N.
A1  - Germer, C.T.
A1  - Wolf, E.
A1  - Gallant, P.
A1  - Wiegering, A.
T1  - Targeting bromodomain-containing protein 4 (BRD4) inhibits MYC expression in colorectal cancer cells
JF  - Neoplasia
N2  - The transcriptional regulator BRD4 has been shown to be important for the expression of several oncogenes including MYC. Inhibiting of BRD4 has broad antiproliferative activity in different cancer cell types. The small molecule JQ1 blocks the interaction of BRD4 with acetylated histones leading to transcriptional modulation. Depleting BRD4 via engineered bifunctional small molecules named PROTACs (proteolysis targeting chimeras) represents the next-generation approach to JQ1-mediated BRD4 inhibition. PROTACs trigger BRD4 for proteasomale degradation by recruiting E3 ligases. The aim of this study was therefore to validate the importance of BRD4 as a relevant target in colorectal cancer (CRC) cells and to compare the efficacy of BRD4 inhibition with BRD4 degradation on downregulating MYC expression. JQ1 induced a downregulation of both MYC mRNA and MYC protein associated with an antiproliferative phenotype in CRC cells. dBET1 and MZ1 induced degradation of BRD4 followed by a reduction in MYC expression and CRC cell proliferation. In SW480 cells, where dBET1 failed, we found significantly lower levels of the E3 ligase cereblon, which is essential for dBET1-induced BRD4 degradation. To gain mechanistic insight into the unresponsiveness to dBET1, we generated dBET1-resistant LS174t cells and found a strong downregulation of cereblon protein. These findings suggest that inhibition of BRD4 by JQ1 and degradation of BRD4 by dBET1 and MZ1 are powerful tools for reducing MYC expression and CRC cell proliferation. In addition, downregulation of cereblon may be an important mechanism for developing dBET1 resistance, which can be evaded by incubating dBET1-resistant cells with JQ1 or MZ1.
KW  - Cancer
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202451
VL  - 21
IS  - 11
ER  - 
TY  - JOUR
A1  - Gröbner, Susanne N.
A1  - Worst, Barbara C.
A1  - Weischenfeldt, Joachim
A1  - Buchhalter, Ivo
A1  - Kleinheinz, Kortine
A1  - Rudneva, Vasilisa A.
A1  - Johann, Pascal D.
A1  - Balasubramanian, Gnana Prakash
A1  - Segura-Wang, Maia
A1  - Brabetz, Sebastian
A1  - Bender, Sebastian
A1  - Hutter, Barbara
A1  - Sturm, Dominik
A1  - Pfaff, Elke
A1  - Hübschmann, Daniel
A1  - Zipprich, Gideon
A1  - Heinold, Michael
A1  - Eils, Jürgen
A1  - Lawerenz, Christian
A1  - Erkek, Serap
A1  - Lambo, Sander
A1  - Waszak, Sebastian
A1  - Blattmann, Claudia
A1  - Borkhardt, Arndt
A1  - Kuhlen, Michaela
A1  - Eggert, Angelika
A1  - Fulda, Simone
A1  - Gessler, Manfred
A1  - Wegert, Jenny
A1  - Kappler, Roland
A1  - Baumhoer, Daniel
A1  - Stefan, Burdach
A1  - Kirschner-Schwabe, Renate
A1  - Kontny, Udo
A1  - Kulozik, Andreas E.
A1  - Lohmann, Dietmar
A1  - Hettmer, Simone
A1  - Eckert, Cornelia
A1  - Bielack, Stefan
A1  - Nathrath, Michaela
A1  - Niemeyer, Charlotte
A1  - Richter, Günther H.
A1  - Schulte, Johannes
A1  - Siebert, Reiner
A1  - Westermann, Frank
A1  - Molenaar, Jan J.
A1  - Vassal, Gilles
A1  - Witt, Hendrik
A1  - Burkhardt, Birgit
A1  - Kratz, Christian P.
A1  - Witt, Olaf
A1  - van Tilburg, Cornelis M.
A1  - Kramm, Christof M.
A1  - Fleischhack, Gudrun
A1  - Dirksen, Uta
A1  - Rutkowski, Stefan
A1  - Frühwald, Michael
A1  - Hoff, Katja von
A1  - Wolf, Stephan
A1  - Klingebeil, Thomas
A1  - Koscielniak, Ewa
A1  - Landgraf, Pablo
A1  - Koster, Jan
A1  - Resnick, Adam C.
A1  - Zhang, Jinghui
A1  - Liu, Yanling
A1  - Zhou, Xin
A1  - Waanders, Angela J.
A1  - Zwijnenburg, Danny A.
A1  - Raman, Pichai
A1  - Brors, Benedikt
A1  - Weber, Ursula D.
A1  - Northcott, Paul A.
A1  - Pajtler, Kristian W.
A1  - Kool, Marcel
A1  - Piro, Rosario M.
A1  - Korbel, Jan O.
A1  - Schlesner, Matthias
A1  - Eils, Roland
A1  - Jones, David T. W.
A1  - Lichter, Peter
A1  - Chavez, Lukas
A1  - Zapatka, Marc
A1  - Pfister, Stefan M.
T1  - The landscape of genomic alterations across childhood cancers
JF  - Nature
N2  - Pan-cancer analyses that examine commonalities and differences among various cancer types have emerged as a powerful way to obtain novel insights into cancer biology. Here we present a comprehensive analysis of genetic alterations in a pan-cancer cohort including 961 tumours from children, adolescents, and young adults, comprising 24 distinct molecular types of cancer. Using a standardized workflow, we identified marked differences in terms of mutation frequency and significantly mutated genes in comparison to previously analysed adult cancers. Genetic alterations in 149 putative cancer driver genes separate the tumours into two classes: small mutation and structural/copy-number variant (correlating with germline variants). Structural variants, hyperdiploidy, and chromothripsis are linked to TP53 mutation status and mutational signatures. Our data suggest that 7–8% of the children in this cohort carry an unambiguous predisposing germline variant and that nearly 50% of paediatric neoplasms harbour a potentially druggable event, which is highly relevant for the design of future clinical trials.
KW  - cancer genomics
KW  - oncogenesis
KW  - paediatric cancer
KW  - predictive markers
KW  - translational research
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-229579
VL  - 555
ER  - 
TY  - JOUR
A1  - Proetel, Ulrike
A1  - Pletsch, Nadine
A1  - Lauseker, Michael
A1  - Müller, Martin C.
A1  - Hanfstein, Benjamin
A1  - Krause, Stefan W.
A1  - Kalmanti, Lida
A1  - Schreiber, Annette
A1  - Heim, Dominik
A1  - Baerlocher, Gabriela M.
A1  - Hofmann, Wolf-Karsten
A1  - Lange, Elisabeth
A1  - Einsele, Hermann
A1  - Wernli, Martin
A1  - Kremers, Stephan
A1  - Schlag, Rudolf
A1  - Müller, Lothar
A1  - Hänel, Mathias
A1  - Link, Hartmut
A1  - Hertenstein, Bernd
A1  - Pfirrmann, Markus
A1  - Hochhaus, Andreas
A1  - Hasford, Joerg
A1  - Hehlmann, Rüdiger
A1  - Saußele, Susanne
T1  - Older patients with chronic myeloid leukemia (≥65 years) profit more from higher imatinib doses than younger patients: a subanalysis of the randomized CML-Study IV
JF  - Annals of Hematology
N2  - The impact of imatinib dose on response rates and survival in older patients with chronic myeloid leukemia in chronic phase has not been studied well. We analyzed data from the German CML-Study IV, a randomized five-arm treatment optimization study in newly diagnosed BCR-ABL-positive chronic myeloid leukemia in chronic phase. Patients randomized to imatinib 400 mg/day (IM400) or imatinib 800 mg/day (IM800) and stratified according to age (≥65 years vs. <65 years) were compared regarding dose, response, adverse events, rates of progression, and survival. The full 800 mg dose was given after a 6-week run-in period with imatinib 400 mg/day. The dose could then be reduced according to tolerability. A total of 828 patients were randomized to IM400 or IM800. Seven hundred eighty-four patients were evaluable (IM400, 382; IM800, 402). One hundred ten patients (29 %) on IM400 and 83 (21 %) on IM800 were ≥65 years. The median dose per day was lower for patients ≥65 years on IM800, with the highest median dose in the first year (466 mg/day for patients ≥65 years vs. 630 mg/day for patients <65 years). Older patients on IM800 achieved major molecular remission and deep molecular remission as fast as younger patients, in contrast to standard dose imatinib with which older patients achieved remissions much later than younger patients. Grades 3 and 4 adverse events were similar in both age groups. Five-year relative survival for older patients was comparable to that of younger patients. We suggest that the optimal dose for older patients is higher than 400 mg/day. ClinicalTrials.gov identifier: NCT00055874
KW  - chronic myeloid leukemia
KW  - older patients
KW  - different imatinib dose regimens
KW  - early applied higher imatinib dosages
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-121574
SN  - 0939-5555
VL  - 93
IS  - 7
ER  - 
TY  - JOUR
A1  - Otto, Wolfgang
A1  - Rubenwolf, Peter C.
A1  - Burger, Maximilian
A1  - Fritsche, Hans-Martin
A1  - Rößler, Wolfgang
A1  - May, Matthias
A1  - Hartmann, Arndt
A1  - Hofstädter, Ferdinand
A1  - Wieland, Wolf F.
A1  - Denzinger, Stefan
T1  - Loss of aquaporin 3 protein expression constitutes an independent prognostic factor for progression-free survival: an immunohistochemical study on stage pT1 urothelial bladder cancer
JF  - BMC Cancer
N2  - Background: Treatment of patients with stage pT1 urothelial bladder cancer (UBC) continues to be a challenge due to its unpredictable clinical course. Reliable molecular markers that help to determine appropriate individual treatment are still lacking. Loss of aquaporin (AQP) 3 protein expression has previously been shown in muscle-invasive UBC. The aim of the present study was to investigate the prognostic value of AQP3 protein expression with regard to the prognosis of stage pT1 UBC. 
Method: AQP 3 protein expression was investigated by immunohistochemistry in specimens of 87 stage T1 UBC patients, who were diagnosed by transurethral resection of the bladder (TURB) and subsequent second resection at a high-volume urological centre between 2002 and 2009. Patients underwent adjuvant instillation therapy with Bacillus Calmette-Guerin (BCG). Loss of AQP3 protein expression was defined as complete absence of the protein within the whole tumour. Expression status was correlated retrospectively with clinicopathological and follow-up data (median: 31 months). Multivariate Cox regression analysis was used to assess the value of AQP3 tumour expression with regard to recurrence-free (RFS), progression-free (PFS) and cancer-specific survival (CSS). RFS, PFS and CSS were calculated by Kaplan-Meier analysis and Log rank test. 
Results: 59% of patients were shown to exhibit AQP3-positive tumours, whereas 41% of tumours did not express the marker. Loss of AQP3 protein expression was associated with a statistically significantly worse PFS (20% vs. 72%, p=0.020). This finding was confirmed by multivariate Cox regression analysis (HR 7.58, CI 1.29 - 44.68; p=0.025). 
Conclusions: Loss of AQP3 protein expression in pT1 UBC appears to play a key role in disease progression and is associated with worse PFS. Considering its potential prognostic value, assessment of AQP3 protein expression could be used to help stratify the behavior of patients with pT1 UBC.
KW  - urothelial bladder carcinoma
KW  - progression
KW  - transitional cell carcinoma
KW  - bacillus calmette guerin
KW  - water channels
KW  - follow up
KW  - in vitro
KW  - recurrence
KW  - growth
KW  - T1
KW  - tumor
KW  - proliferation
KW  - stage pT1
KW  - aquaporin 3 protein
KW  - immunohistochemistry
Y1  - 2012
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-135679
VL  - 12
IS  - 459
ER  - 
TY  - JOUR
A1  - Hanfstein, Benjamin
A1  - Lauseker, Michael
A1  - Hehlmann, Rüdiger
A1  - Saussele, Susanne
A1  - Erben, Philipp
A1  - Dietz, Christian
A1  - Fabarius, Alice
A1  - Proetel, Ulrike
A1  - Schnittger, Susanne
A1  - Haferlach, Claudia
A1  - Krause, Stefan W.
A1  - Schubert, Jörg
A1  - Einsele, Hermann
A1  - Hänel, Mathias
A1  - Dengler, Jolanta
A1  - Falge, Christiane
A1  - Kanz, Lothar
A1  - Neubauer, Andreas
A1  - Kneba, Michael
A1  - Stengelmann, Frank
A1  - Pfreundschuh, Michael
A1  - Waller, Cornelius F.
A1  - Spiekerman, Karsten
A1  - Baerlocher, Gabriela M.
A1  - Pfirrmann, Markus
A1  - Hasford, Joerg
A1  - Hofmann, Wolf-Karsten
A1  - Hochhaus, Andreas
A1  - Müller, Martin C.
T1  - Distinct characteristics of e13a2 versus e14a2 BCR-ABL1 driven chronic myeloid leukemia under first-line therapy with imatinib
JF  - Haematologica
N2  - The vast majority of chronic myeloid leukemia patients express a BCR-ABL1 fusion gene mRNA encoding a 210 kDa tyrosine kinase which promotes leukemic transformation. A possible differential impact of the corresponding BCR-ABL1 transcript variants e13a2 ("b2a2") and e14a2 ("b3a2") on disease phenotype and outcome is still a subject of debate. A total of 1105 newly diagnosed imatinib-treated patients were analyzed according to transcript type at diagnosis (e13a2, n=451; e14a2, n=496; e13a2+e14a2, n=158). No differences regarding age, sex, or Euro risk score were observed. A significant difference was found between e13a2 and e14a2 when comparing white blood cells (88 vs. 65 x 10(9)/L, respectively; P<0.001) and platelets (296 vs. 430 x 109/L, respectively; P<0.001) at diagnosis, indicating a distinct disease phenotype. No significant difference was observed regarding other hematologic features, including spleen size and hematologic adverse events, during imatinib-based therapies. Cumulative molecular response was inferior in e13a2 patients (P=0.002 for major molecular response; P<0.001 for MR4). No difference was observed with regard to cytogenetic response and overall survival. In conclusion, e13a2 and e14a2 chronic myeloid leukemia seem to represent distinct biological entities. However, clinical outcome under imatinib treatment was comparable and no risk prediction can be made according to e13a2 versus e14a2 BCR-ABL1 transcript type at diagnosis. (clinicaltrials.gov identifier: 00055874)
KW  - chronic myelogenous leukemia
KW  - polymerase-chain-reaktion
KW  - hybrid messenger RNA
KW  - chronic phase
KW  - cytogenetic response
KW  - no correlation
KW  - ABL gene
KW  - transcripts
KW  - breakpoint
KW  - survival
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-115476
SN  - 1592-8721
VL  - 99
IS  - 9
ER  - 
TY  - JOUR
A1  - Wolf-Brandstetter, C
A1  - Beutner, R
A1  - Hess, R
A1  - Bierbaum, S
A1  - Wagner, K
A1  - Scharnweber, D
A1  - Gbureck, U
A1  - Moseke, C
T1  - Multifunctional calcium phosphate based coatings on titanium implants with integrated trace elements
JF  - Biomedical Materials
N2  - For decades, the main focus of titanium implants developed to restore bone functionality was on improved osseointegration. Additional antimicrobial properties have now become desirable, due to the risk that rising antibiotic resistance poses for implant-associated infections. To this end, the trace elements of copper and zinc were integrated into calcium phosphate based coatings by electrochemically assisted deposition. In addition to their antimicrobial activity, zinc is reported to attract bone progenitor cells through chemotaxis and thus increase osteogenic differentiation, and copper to stimulate angiogenesis. Quantities of up to 68.9 ± 0.1 μg cm\(^{-2}\) of copper and 56.6 ± 0.4 μg cm\(^{-2}\) of zinc were deposited; co-deposition of both ions did not influence the amount of zinc but slightly increased the amount of copper in the coatings. The release of deposited copper and zinc species was negligible in serum-free simulated body fluid. In protein-containing solutions, a burst release of up to 10 μg ml\(^{-1}\) was observed for copper, while zinc was released continuously for up to 14 days. The presence of zinc was beneficial for adhesion and growth of human mesenchymal stromal cells in a concentration-dependent manner, but cytotoxic effects were already visible for coatings with an intermediate copper content. However, co-deposited zinc could somewhat alleviate the adverse effects of copper. Antimicrobial tests with E. coli revealed a decrease in adherent bacteria on brushite without copper or zinc of 60%, but if the coating contained both ions there was almost no bacterial adhesion after 12 h. Coatings with high zinc content and intermediate copper content had the overall best multifunctional properties.
KW  - coating
KW  - titanium
KW  - implant
KW  - pro-angiogenic
KW  - osteogenic
KW  - antimicrobial
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-254085
VL  - 15
IS  - 2
ER  - 
TY  - JOUR
A1  - Rayner, Christopher
A1  - Coleman, Jonathan R. I.
A1  - Purves, Kirstin L.
A1  - Hodsoll, John
A1  - Goldsmith, Kimberley
A1  - Alpers, Georg W.
A1  - Andersson, Evelyn
A1  - Arolt, Volker
A1  - Boberg, Julia
A1  - Bögels, Susan
A1  - Creswell, Cathy
A1  - Cooper, Peter
A1  - Curtis, Charles
A1  - Deckert, Jürgen
A1  - Domschke, Katharina
A1  - El Alaoui, Samir
A1  - Fehm, Lydia
A1  - Fydrich, Thomas
A1  - Gerlach, Alexander L.
A1  - Grocholewski, Anja
A1  - Hahlweg, Kurt
A1  - Hamm, Alfons
A1  - Hedman, Erik
A1  - Heiervang, Einar R.
A1  - Hudson, Jennifer L.
A1  - Jöhren, Peter
A1  - Keers, Robert
A1  - Kircher, Tilo
A1  - Lang, Thomas
A1  - Lavebratt, Catharina
A1  - Lee, Sang-hyuck
A1  - Lester, Kathryn J.
A1  - Lindefors, Nils
A1  - Margraf, Jürgen
A1  - Nauta, Maaike
A1  - Pané-Farré, Christiane A.
A1  - Pauli, Paul
A1  - Rapee, Ronald M.
A1  - Reif, Andreas
A1  - Rief, Winfried
A1  - Roberts, Susanna
A1  - Schalling, Martin
A1  - Schneider, Silvia
A1  - Silverman, Wendy K.
A1  - Ströhle, Andreas
A1  - Teismann, Tobias
A1  - Thastum, Mikael
A1  - Wannemüller, Andre
A1  - Weber, Heike
A1  - Wittchen, Hans-Ulrich
A1  - Wolf, Christiane
A1  - Rück, Christian
A1  - Breen, Gerome
A1  - Eley, Thalia C.
T1  - A genome-wide association meta-analysis of prognostic outcomes following cognitive behavioural therapy in individuals with anxiety and depressive disorders
JF  - Translational Psychiatry
N2  - Major depressive disorder and the anxiety disorders are highly prevalent, disabling and moderately heritable. Depression and anxiety are also highly comorbid and have a strong genetic correlation (r(g) approximate to 1). Cognitive behavioural therapy is a leading evidence-based treatment but has variable outcomes. Currently, there are no strong predictors of outcome. Therapygenetics research aims to identify genetic predictors of prognosis following therapy. We performed genome-wide association meta-analyses of symptoms following cognitive behavioural therapy in adults with anxiety disorders (n = 972), adults with major depressive disorder (n = 832) and children with anxiety disorders (n = 920; meta-analysis n = 2724). We (h(SNP)(2)) and polygenic scoring was used to examine genetic associations between therapy outcomes and psychopathology, personality and estimated the variance in therapy outcomes that could be explained by common genetic variants learning. No single nucleotide polymorphisms were strongly associated with treatment outcomes. No significant estimate of h(SNP)(2) could be obtained, suggesting the heritability of therapy outcome is smaller than our analysis was powered to detect. Polygenic scoring failed to detect genetic overlap between therapy outcome and psychopathology, personality or learning. This study is the largest therapygenetics study to date. Results are consistent with previous, similarly powered genome-wide association studies of complex traits.
KW  - Human behaviour
KW  - Personalized medicine
KW  - Prognostic markers
KW  - Psychiatric disorders
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-225048
VL  - 9
IS  - 150
ER  - 
TY  - JOUR
A1  - Jessen, Christina
A1  - Kreß, Julia K. C.
A1  - Baluapuri, Apoorva
A1  - Hufnagel, Anita
A1  - Schmitz, Werner
A1  - Kneitz, Susanne
A1  - Roth, Sabine
A1  - Marquardt, André
A1  - Appenzeller, Silke
A1  - Ade, Casten P.
A1  - Glutsch, Valerie
A1  - Wobser, Marion
A1  - Friedmann-Angeli, José Pedro
A1  - Mosteo, Laura
A1  - Goding, Colin R.
A1  - Schilling, Bastian
A1  - Geissinger, Eva
A1  - Wolf, Elmar
A1  - Meierjohann, Svenja
T1  - The transcription factor NRF2 enhances melanoma malignancy by blocking differentiation and inducing COX2 expression
JF  - Oncogene
N2  - The transcription factor NRF2 is the major mediator of oxidative stress responses and is closely connected to therapy resistance in tumors harboring activating mutations in the NRF2 pathway. In melanoma, such mutations are rare, and it is unclear to what extent melanomas rely on NRF2. Here we show that NRF2 suppresses the activity of the melanocyte lineage marker MITF in melanoma, thereby reducing the expression of pigmentation markers. Intriguingly, we furthermore identified NRF2 as key regulator of immune-modulating genes, linking oxidative stress with the induction of cyclooxygenase 2 (COX2) in an ATF4-dependent manner. COX2 is critical for the secretion of prostaglandin E2 and was strongly induced by H\(_2\)O\(_2\) or TNFα only in presence of NRF2. Induction of MITF and depletion of COX2 and PGE2 were also observed in NRF2-deleted melanoma cells in vivo. Furthermore, genes corresponding to the innate immune response such as RSAD2 and IFIH1 were strongly elevated in absence of NRF2 and coincided with immune evasion parameters in human melanoma datasets. Even in vitro, NRF2 activation or prostaglandin E2 supplementation blunted the induction of the innate immune response in melanoma cells. Transcriptome analyses from lung adenocarcinomas indicate that the observed link between NRF2 and the innate immune response is not restricted to melanoma.
KW  - NRF2
KW  - melanoma malignancy
KW  - COX2 expression
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-235064
SN  - 0950-9232
VL  - 39
ER  - 
TY  - JOUR
A1  - Murakawa, Yasuhiro
A1  - Hinz, Michael
A1  - Mothes, Janina
A1  - Schuetz, Anja
A1  - Uhl, Michael
A1  - Wyler, Emanuel
A1  - Yasuda, Tomoharu
A1  - Mastrobuoni, Guido
A1  - Friedel, Caroline C.
A1  - Dölken, Lars
A1  - Kempa, Stefan
A1  - Schmidt-Supprian, Marc
A1  - Blüthgen, Nils
A1  - Backofen, Rolf
A1  - Heinemann, Udo
A1  - Wolf, Jana
A1  - Scheidereit, Claus
A1  - Landthaler, Markus
T1  - RC3H1 post-transcriptionally regulates A20 mRNA and modulates the activity of the IKK/NF-\(\kappa\)B pathway
JF  - Nature Communications
N2  - The RNA-binding protein RC3H1 (also known as ROQUIN) promotes TNF\(\alpha\) mRNA decay via a 3'UTR constitutive decay element (CDE). Here we applied PAR-CLIP to human RC3H1 to identify ~3,800 mRNA targets with >16,000 binding sites. A large number of sites are distinct from the consensus CDE and revealed a structure-sequence motif with U-rich sequences embedded in hairpins. RC3H1 binds preferentially short-lived and DNA damage-induced mRNAs, indicating a role of this RNA-binding protein in the post-transcriptional regulation of the DNA damage response. Intriguingly, RC3H1 affects expression of the NF-\(\kappa\)B pathway regulators such as I\(\kappa\)B\(\alpha\) and A20. RC3H1 uses ROQ and Zn-finger domains to contact a binding site in the A20 3'UTR, demonstrating a not yet recognized mode of RC3H1 binding. Knockdown of RC3H1 resulted in increased A20 protein expression, thereby interfering with I\(\kappa\)B kinase and NF-\(\kappa\)B activities, demonstrating that RC3H1 can modulate the activity of the IKK/NF-\(\kappa\)B pathway.
KW  - large gene lists
KW  - decay
KW  - identification
KW  - stress
KW  - binding protein
KW  - RQQ domain
KW  - autoimmunity
KW  - complex
KW  - degradation
KW  - motifs
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-151596
VL  - 6
IS  - 7367
ER  - 
TY  - JOUR
A1  - Saussele, Susanne
A1  - Hehlmann, Ruediger
A1  - Fabarius, Alice
A1  - Jeromin, Sabine
A1  - Proetel, Ulrike
A1  - Rinaldetti, Sebastien
A1  - Kohlbrenner, Katharina
A1  - Einsele, Hermann
A1  - Falge, Christine
A1  - Kanz, Lothar
A1  - Neubauer, Andreas
A1  - Kneba, Michael
A1  - Stegelmann, Frank
A1  - Pfreundschuh, Michael
A1  - Waller, Cornelius F.
A1  - Oppliger Leibundgut, Elisabeth
A1  - Heim, Dominik
A1  - Krause, Stefan W.
A1  - Hofmann, Wolf-Karsten
A1  - Hasford, Joerg
A1  - Pfirrmann, Markus
A1  - Müller, Martin C.
A1  - Hochhaus, Andreas
A1  - Lauseker, Michael
T1  - Defining therapy goals for major molecular remission in chronic myeloid leukemia: results of the randomized CML Study IV
JF  - Leukemia
N2  - Major molecular remission (MMR) is an important therapy goal in chronic myeloid leukemia (CML). So far, MMR is not a failure criterion according to ELN management recommendation leading to uncertainties when to change therapy in CML patients not reaching MMR after 12 months. At monthly landmarks, for different molecular remission status Hazard ratios (HR) were estimated for patients registered to CML study IV who were divided in a learning and a validation sample. The minimum HR for MMR was found at 2.5 years with 0.28 (compared to patients without remission). In the validation sample, a significant advantage for progression-free survival (PFS) for patients in MMR could be detected (p-value 0.007). The optimal time to predict PFS in patients with MMR could be validated in an independent sample at 2.5 years. With our model we provide a suggestion when to define lack of MMR as therapy failure and thus treatment change should be considered. The optimal response time for 1% BCR-ABL at about 12-15 months was confirmed and for deep molecular remission no specific time point was detected. Nevertheless, it was demonstrated that the earlier the MMR is achieved the higher is the chance to attain deep molecular response later.
KW  - Chronic myeloid leukaemia
KW  - Molecularly targeted therapy
KW  - Risk factors
KW  - Risk factors
KW  - Translational research
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227528
VL  - 32
IS  - 5
ER  - 
TY  - JOUR
A1  - Meder, Lydia
A1  - König, Katharina
A1  - Ozretić, Luka
A1  - Schultheis, Anne M.
A1  - Ueckeroth, Frank
A1  - Ade, Carsten P.
A1  - Albus, Kerstin
A1  - Boehm, Diana
A1  - Rommerscheidt-Fuss, Ursula
A1  - Florin, Alexandra
A1  - Buhl, Theresa
A1  - Hartmann, Wolfgang
A1  - Wolf, Jürgen
A1  - Merkelbach-Bruse, Sabine
A1  - Eilers, Martin
A1  - Perner, Sven
A1  - Heukamp, Lukas C.
A1  - Buettner, Reinhard
T1  - NOTCH, ASCL1, p53 and RB alterations define an alternative pathway driving neuroendocrine and small cell lung carcinomas
JF  - International Journal of Cancer
N2  - Small cell lung cancers (SCLCs) and extrapulmonary small cell cancers (SCCs) are very aggressive tumors arising de novo as primary small cell cancer with characteristic genetic lesions in RB1 and TP53. Based on murine models, neuroendocrine stem cells of the terminal bronchioli have been postulated as the cellular origin of primary SCLC. However, both in lung and many other organs, combined small cell/non-small cell tumors and secondary transitions from non-small cell carcinomas upon cancer therapy to neuroendocrine and small cell tumors occur. We define features of "small cell-ness" based on neuroendocrine markers, characteristic RB1 and TP53 mutations and small cell morphology. Furthermore, here we identify a pathway driving the pathogenesis of secondary SCLC involving inactivating NOTCH mutations, activation of the NOTCH target ASCL1 and canonical WNT-signaling in the context of mutual bi-allelic RB1 and TP53 lesions. Additionaly, we explored ASCL1 dependent RB inactivation by phosphorylation, which is reversible by CDK5 inhibition. We experimentally verify the NOTCH-ASCL1-RB-p53 signaling axis in vitro and validate its activation by genetic alterations in vivo. We analyzed clinical tumor samples including SCLC, SCC and pulmonary large cell neuroendocrine carcinomas and adenocarcinomas using amplicon-based Next Generation Sequencing, immunohistochemistry and fluorescence in situ hybridization. In conclusion, we identified a novel pathway underlying rare secondary SCLC which may drive small cell carcinomas in organs other than lung, as well.
KW  - lung cancer
KW  - small cell lung cancer
KW  - achaete-scute homolog 1
KW  - neurogenic locus notch homolog
KW  - retinoblastoma protein
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-190853
VL  - 138
IS  - 4
ER  - 
TY  - JOUR
A1  - Schischlevskij, Pavel
A1  - Cordts, Isabell
A1  - Günther, René
A1  - Stolte, Benjamin
A1  - Zeller, Daniel
A1  - Schröter, Carsten
A1  - Weyen, Ute
A1  - Regensburger, Martin
A1  - Wolf, Joachim
A1  - Schneider, Ilka
A1  - Hermann, Andreas
A1  - Metelmann, Moritz
A1  - Kohl, Zacharias
A1  - Linker, Ralf A.
A1  - Koch, Jan Christoph
A1  - Stendel, Claudia
A1  - Müschen, Lars H.
A1  - Osmanovic, Alma
A1  - Binz, Camilla
A1  - Klopstock, Thomas
A1  - Dorst, Johannes
A1  - Ludolph, Albert C.
A1  - Boentert, Matthias
A1  - Hagenacker, Tim
A1  - Deschauer, Marcus
A1  - Lingor, Paul
A1  - Petri, Susanne
A1  - Schreiber-Katz, Olivia
T1  - Informal caregiving in amyotrophic lateral sclerosis (ALS): a high caregiver burden and drastic consequences on caregivers' lives
JF  - Brain Sciences
N2  - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that causes progressive autonomy loss and need for care. This does not only affect patients themselves, but also the patients’ informal caregivers (CGs) in their health, personal and professional lives. The big efforts of this multi-center study were not only to evaluate the caregivers' burden and to identify its predictors, but it also should provide a specific understanding of the needs of ALS patients' CGs and fill the gap of knowledge on their personal and work lives. Using standardized questionnaires, primary data from patients and their main informal CGs (n = 249) were collected. Patients' functional status and disease severity were evaluated using the Barthel Index, the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) and the King’s Stages for ALS. The caregivers' burden was recorded by the Zarit Burden Interview (ZBI). Comorbid anxiety and depression of caregivers were assessed by the Hospital Anxiety and Depression Scale. Additionally, the EuroQol Five Dimension Five Level Scale evaluated their health-related quality of life. The caregivers' burden was high (mean ZBI = 26/88, 0 = no burden, ≥24 = highly burdened) and correlated with patients' functional status (r\(_p\) = −0.555, p < 0.001, n = 242). It was influenced by the CGs' own mental health issues due to caregiving (+11.36, 95% CI [6.84; 15.87], p < 0.001), patients' wheelchair dependency (+9.30, 95% CI [5.94; 12.66], p < 0.001) and was interrelated with the CGs' depression (r\(_p\) = 0.627, p < 0.001, n = 234), anxiety (r\(_p\) = 0.550, p < 0.001, n = 234), and poorer physical condition (r\(_p\) = −0.362, p < 0.001, n = 237). Moreover, female CGs showed symptoms of anxiety more often, which also correlated with the patients' impairment in daily routine (r\(_s\) = −0.280, p < 0.001, n = 169). As increasing disease severity, along with decreasing autonomy, was the main predictor of caregiver burden and showed to create relevant (negative) implications on CGs' lives, patient care and supportive therapies should address this issue. Moreover, in order to preserve the mental and physical health of the CGs, new concepts of care have to focus on both, on not only patients but also their CGs and gender-associated specific issues. As caregiving in ALS also significantly influences the socioeconomic status by restrictions in CGs' work lives and income, and the main reported needs being lack of psychological support and a high bureaucracy, the situation of CGs needs more attention. Apart from their own multi-disciplinary medical and psychological care, more support in care and patient management issues is required.
KW  - amyotrophic lateral sclerosis (ALS)
KW  - informal caregiving
KW  - caregiver burden
KW  - functional status
KW  - decreasing autonomy
KW  - depression
KW  - anxiety
KW  - health-related quality of life
KW  - socioeconomic status
KW  - psychological support
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-240981
SN  - 2076-3425
VL  - 11
IS  - 6
ER  - 
TY  - JOUR
A1  - Hartmann, Oliver
A1  - Reissland, Michaela
A1  - Maier, Carina R.
A1  - Fischer, Thomas
A1  - Prieto-Garcia, Cristian
A1  - Baluapuri, Apoorva
A1  - Schwarz, Jessica
A1  - Schmitz, Werner
A1  - Garrido-Rodriguez, Martin
A1  - Pahor, Nikolett
A1  - Davies, Clare C.
A1  - Bassermann, Florian
A1  - Orian, Amir
A1  - Wolf, Elmar
A1  - Schulze, Almut
A1  - Calzado, Marco A.
A1  - Rosenfeldt, Mathias T.
A1  - Diefenbacher, Markus E.
T1  - Implementation of CRISPR/Cas9 Genome Editing to Generate Murine Lung Cancer Models That Depict the Mutational Landscape of Human Disease
JF  - Frontiers in Cell and Developmental Biology
N2  - Lung cancer is the most common cancer worldwide and the leading cause of cancer-related deaths in both men and women. Despite the development of novel therapeutic interventions, the 5-year survival rate for non-small cell lung cancer (NSCLC) patients remains low, demonstrating the necessity for novel treatments. One strategy to improve translational research is the development of surrogate models reflecting somatic mutations identified in lung cancer patients as these impact treatment responses. With the advent of CRISPR-mediated genome editing, gene deletion as well as site-directed integration of point mutations enabled us to model human malignancies in more detail than ever before. Here, we report that by using CRISPR/Cas9-mediated targeting of Trp53 and KRas, we recapitulated the classic murine NSCLC model Trp53fl/fl:lsl-KRasG12D/wt. Developing tumors were indistinguishable from Trp53fl/fl:lsl-KRasG12D/wt-derived tumors with regard to morphology, marker expression, and transcriptional profiles. We demonstrate the applicability of CRISPR for tumor modeling in vivo and ameliorating the need to use conventional genetically engineered mouse models. Furthermore, tumor onset was not only achieved in constitutive Cas9 expression but also in wild-type animals via infection of lung epithelial cells with two discrete AAVs encoding different parts of the CRISPR machinery. While conventional mouse models require extensive husbandry to integrate new genetic features allowing for gene targeting, basic molecular methods suffice to inflict the desired genetic alterations in vivo. Utilizing the CRISPR toolbox, in vivo cancer research and modeling is rapidly evolving and enables researchers to swiftly develop new, clinically relevant surrogate models for translational research.
KW  - non-small cell lung cancer
KW  - CRISPR-Cas9
KW  - mouse model
KW  - lung cancer
KW  - MYC
KW  - JUN
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-230949
SN  - 2296-634X
VL  - 9
ER  - 
TY  - JOUR
A1  - Peseschkian, Tara
A1  - Cordts, Isabell
A1  - Günther, René
A1  - Stolte, Benjamin
A1  - Zeller, Daniel
A1  - Schröter, Carsten
A1  - Weyen, Ute
A1  - Regensburger, Martin
A1  - Wolf, Joachim
A1  - Schneider, Ilka
A1  - Hermann, Andreas
A1  - Metelmann, Moritz
A1  - Kohl, Zacharias
A1  - Linker, Ralf A.
A1  - Koch, Jan Christoph
A1  - Büchner, Boriana
A1  - Weiland, Ulrike
A1  - Schönfelder, Erik
A1  - Heinrich, Felix
A1  - Osmanovic, Alma
A1  - Klopstock, Thomas
A1  - Dorst, Johannes
A1  - Ludolph, Albert C.
A1  - Boentert, Matthias
A1  - Hagenacker, Tim
A1  - Deschauer, Marcus
A1  - Lingor, Paul
A1  - Petri, Susanne
A1  - Schreiber-Katz, Olivia
T1  - A nation-wide, multi-center study on the quality of life of ALS patients in Germany
JF  - Brain Sciences
N2  - Improving quality of life (QoL) is central to amyotrophic lateral sclerosis (ALS) treatment. This Germany-wide, multicenter cross-sectional study analyses the impact of different symptom-specific treatments and ALS variants on QoL. Health-related QoL (HRQoL) in 325 ALS patients was assessed using the Amyotrophic Lateral Sclerosis Assessment Questionnaire 5 (ALSAQ-5) and EuroQol Five Dimension Five Level Scale (EQ-5D-5L), together with disease severity (captured by the revised ALS Functional Rating Scale (ALSFRS-R)) and the current care and therapies used by our cohort. At inclusion, the mean ALSAQ-5 total score was 56.93 (max. 100, best = 0) with a better QoL associated with a less severe disease status (β = −1.96 per increase of one point in the ALSFRS-R score, p < 0.001). “Limb-onset” ALS (lALS) was associated with a better QoL than “bulbar-onset” ALS (bALS) (mean ALSAQ-5 total score 55.46 versus 60.99, p = 0.040). Moreover, with the ALSFRS-R as a covariate, using a mobility aid (β = −7.60, p = 0.001), being tracheostomized (β = −14.80, p = 0.004) and using non-invasive ventilation (β = −5.71, p = 0.030) were associated with an improved QoL, compared to those at the same disease stage who did not use these aids. In contrast, antidepressant intake (β = 5.95, p = 0.007), and increasing age (β = 0.18, p = 0.023) were predictors of worse QoL. Our results showed that the ALSAQ-5 was better-suited for ALS patients than the EQ-5D-5L. Further, the early and symptom-specific clinical management and supply of assistive devices can significantly improve the individual HRQoL of ALS patients. Appropriate QoL questionnaires are needed to monitor the impact of treatment to provide the best possible and individualized care.
KW  - Amyotrophic Lateral Sclerosis (ALS)
KW  - Amyotrophic Lateral Sclerosis Assessment Questionnaire 5 (ALSAQ-5)
KW  - ALS treatment
KW  - “bulbar-onset” ALS (bALS)
KW  - “limb-onset” ALS (lALS)
KW  - EuroQol Five Dimension Five Level Scale (EQ-5D-5L)
KW  - health-related quality of life (HRQoL)
KW  - quality of life (QoL)
KW  - symptom-specific treatment
KW  - assistive devices
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-234147
SN  - 2076-3425
VL  - 11
IS  - 3
ER  - 
TY  - JOUR
A1  - Rieger, C. T.
A1  - Liss, B.
A1  - Mellinghoff, S.
A1  - Buchheidt, D.
A1  - Cornely, O. A.
A1  - Egerer, G.
A1  - Heinz, W. J.
A1  - Hentrich, M.
A1  - Maschmeyer, G.
A1  - Mayer, K.
A1  - Sandherr, M.
A1  - Silling, G.
A1  - Ullmann, A.
A1  - Vehreschild, M. J. G. T.
A1  - von Lilienfeld-Toal, M.
A1  - Wolf, H. H.
A1  - Lehners, N.
T1  - Anti-infective vaccination strategies in patients with hematologic malignancies or solid tumors-Guideline of the Infectious Diseases Working Party (AGIHO) of the German Society for Hematology and Medical Oncology (DGHO)
JF  - Annals of Oncology
N2  - Infectious complications are a significant cause of morbidity and mortality in patients with malignancies specifically when receiving anticancer treatments. Prevention of infection through vaccines is an important aspect of clinical care of cancer patients. Immunocompromising effects of the underlying disease as well as of antineoplastic therapies need to be considered when devising vaccination strategies. This guideline provides clinical recommendations on vaccine use in cancer patients including autologous stem cell transplant recipients, while allogeneic stem cell transplantation is subject of a separate guideline. The document was prepared by the Infectious Diseases Working Party (AGIHO) of the German Society for Hematology and Medical Oncology (DGHO) by reviewing currently available data and applying evidence-based medicine criteria.
KW  - infection
KW  - anti-infective vaccination
KW  - cancer
KW  - immunosuppression
KW  - autologous stem cell transplantation
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226196
VL  - 29
IS  - 6
ER  - 
TY  - JOUR
A1  - Häder, Antje
A1  - Schäuble, Sascha
A1  - Gehlen, Jan
A1  - Thielemann, Nadja
A1  - Buerfent, Benedikt C.
A1  - Schüller, Vitalia
A1  - Hess, Timo
A1  - Wolf, Thomas
A1  - Schröder, Julia
A1  - Weber, Michael
A1  - Hünniger, Kerstin
A1  - Löffler, Jürgen
A1  - Vylkova, Slavena
A1  - Panagiotou, Gianni
A1  - Schumacher, Johannes
A1  - Kurzai, Oliver
T1  - Pathogen-specific innate immune response patterns are distinctly affected by genetic diversity
JF  - Nature Communications
N2  - Innate immune responses vary by pathogen and host genetics. We analyze quantitative trait loci (eQTLs) and transcriptomes of monocytes from 215 individuals stimulated by fungal, Gram-negative or Gram-positive bacterial pathogens. We identify conserved monocyte responses to bacterial pathogens and a distinct antifungal response. These include 745 response eQTLs (reQTLs) and corresponding genes with pathogen-specific effects, which we find first in samples of male donors and subsequently confirm for selected reQTLs in females. reQTLs affect predominantly upregulated genes that regulate immune response via e.g., NOD-like, C-type lectin, Toll-like and complement receptor-signaling pathways. Hence, reQTLs provide a functional explanation for individual differences in innate response patterns. Our identified reQTLs are also associated with cancer, autoimmunity, inflammatory and infectious diseases as shown by external genome-wide association studies. Thus, reQTLs help to explain interindividual variation in immune response to infection and provide candidate genes for variants associated with a range of diseases.
KW  - antimicrobial responses
KW  - immunogenetics
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357441
VL  - 14
ER  - 
TY  - JOUR
A1  - Moris, Victoria C.
A1  - Christmann, Katharina
A1  - Wirtgen, Aline
A1  - Belokobylskij, Sergey A.
A1  - Berg, Alexander
A1  - Liebig, Wolf-Harald
A1  - Soon, Villu
A1  - Baur, Hannes
A1  - Schmitt, Thomas
A1  - Niehuis, Oliver
T1  - Cuticular hydrocarbons on old museum specimens of the spiny mason wasp, Odynerus spinipes (Hymenoptera: Vespidae: Eumeninae), shed light on the distribution and on regional frequencies of distinct chemotypes
JF  - Chemoecology
N2  - The mason wasp Odynerus spinipes shows an exceptional case of intrasexual cuticular hydrocarbon (CHC) profile dimorphism. Females of this species display one of two CHC profiles (chemotypes) that differ qualitatively and quantitatively from each other. The ratio of the two chemotypes was previously shown to be close to 1:1 at three sites in Southern Germany, which might not be representative given the Palearctic distribution of the species. To infer the frequency of the two chemotypes across the entire distributional range of the species, we analyzed with GC–MS the CHC profile of 1042 dry-mounted specimens stored in private and museum collections. We complemented our sampling by including 324 samples collected and preserved specifically for studying their CHCs. We were capable of reliably identifying the chemotypes in 91% of dry-mounted samples, some of which collected almost 200 years ago. We found both chemotypes to occur in the Far East, the presumed glacial refuge of the species, and their frequency to differ considerably between sites and geographic regions. The geographic structure in the chemotype frequencies could be the result of differential selection regimes and/or different dispersal routes during the colonization of the Western Palearctic. The presented data pave the route for disentangling these factors by providing information where to geographically sample O. spinipes for population genetic analyses. They also form the much-needed basis for future studies aiming to understand the evolutionary and geographic origin as well as the genetics of the astounding CHC profile dimorphism that O. spinipes females exhibit.
KW  - cuticular hydrocarbons
KW  - chemotypes
KW  - dry-mounted samples
KW  - collections
KW  - distribution
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-306999
SN  - 0937-7409
SN  - 1423-0445
VL  - 31
IS  - 5
ER  - 
TY  - JOUR
A1  - Annunziata, Ida
A1  - van de Vlekkert, Diantha
A1  - Wolf, Elmar
A1  - Finkelstein, David
A1  - Neale, Geoffrey
A1  - Machado, Eda
A1  - Mosca, Rosario
A1  - Campos, Yvan
A1  - Tillman, Heather
A1  - Roussel, Martine F.
A1  - Weesner, Jason Andrew
A1  - Fremuth, Leigh Ellen
A1  - Qiu, Xiaohui
A1  - Han, Min-Joon
A1  - Grosveld, Gerard C.
A1  - d'Azzo, Alessandra
T1  - MYC competes with MiT/TFE in regulating lysosomal biogenesis and autophagy through an epigenetic rheostat
JF  - Nature Communications
N2  - Coordinated regulation of the lysosomal and autophagic systems ensures basal catabolism and normal cell physiology, and failure of either system causes disease. Here we describe an epigenetic rheostat orchestrated by c-MYC and histone deacetylases that inhibits lysosomal and autophagic biogenesis by concomitantly repressing the expression of the transcription factors MiT/TFE and FOXH1, and that of lysosomal and autophagy genes. Inhibition of histone deacetylases abates c-MYC binding to the promoters of lysosomal and autophagy genes, granting promoter occupancy to the MiT/TFE members, TFEB and TFE3, and/or the autophagy regulator FOXH1. In pluripotent stem cells and cancer, suppression of lysosomal and autophagic function is directly downstream of c-MYC overexpression and may represent a hallmark of malignant transformation. We propose that, by determining the fate of these catabolic systems, this hierarchical switch regulates the adaptive response of cells to pathological and physiological cues that could be exploited therapeutically.
KW  - autophagy
KW  - cancer
KW  - cancer metabolism
KW  - cell biology
KW  - mechanisms of disease
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-221189
VL  - 10
ER  - 
TY  - JOUR
A1  - Elkon, Ran
A1  - Loayza-Puch, Fabricio
A1  - Korkmaz, Gozde
A1  - Lopes, Rui
A1  - van Breugel, Pieter C
A1  - Bleijerveld, Onno B
A1  - Altelaar, AF Maarten
A1  - Wolf, Elmar
A1  - Lorenzin, Francesca
A1  - Eilers, Martin
A1  - Agami, Reuven
T1  - Myc coordinates transcription and translation to enhance transformation and suppress invasiveness
JF  - EMBO reports
N2  - c‐Myc is one of the major human proto‐oncogenes and is often associated with tumor aggression and poor clinical outcome. Paradoxically, Myc was also reported as a suppressor of cell motility, invasiveness, and metastasis. Among the direct targets of Myc are many components of the protein synthesis machinery whose induction results in an overall increase in protein synthesis that empowers tumor cell growth. At present, it is largely unknown whether beyond the global enhancement of protein synthesis, Myc activation results in translation modulation of specific genes. Here, we measured Myc‐induced global changes in gene expression at the transcription, translation, and protein levels and uncovered extensive transcript‐specific regulation of protein translation. Particularly, we detected a broad coordination between regulation of transcription and translation upon modulation of Myc activity and showed the connection of these responses to mTOR signaling to enhance oncogenic transformation and to the TGFβ pathway to modulate cell migration and invasiveness. Our results elucidate novel facets of Myc‐induced cellular responses and provide a more comprehensive view of the consequences of its activation in cancer cells.
KW  - c‐Myc
KW  - transcriptional responses
KW  - translational regulation
KW  - transcription
KW  - transformation
KW  - metastasis
KW  - cancer
KW  - protein biosynthesis & quality control
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-150373
VL  - 16
IS  - 12
ER  -