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Institute
- Institut für Theoretische Physik und Astrophysik (3)
- Institut für Klinische Epidemiologie und Biometrie (2)
- Institut für Virologie und Immunbiologie (2)
- Kinderklinik und Poliklinik (2)
- Medizinische Klinik und Poliklinik II (2)
- Theodor-Boveri-Institut für Biowissenschaften (2)
- Frauenklinik und Poliklinik (1)
- Institut für Humangenetik (1)
- Klinik und Poliklinik für Dermatologie, Venerologie und Allergologie (1)
- Klinik und Poliklinik für Kinder- und Jugendpsychiatrie, Psychosomatik und Psychotherapie (1)
Bousquet, J. ; Farrell, J. ; Crooks, G. ; Hellings, P. ; Bel, E. H. ; Bewick, M. ; Chavannes, N. H. ; Correia de Sousa, J. ; Cruz, A. A. ; Haahtela, T. ; Joos, G. ; Khaltaev, N. ; Malva, J. ; Muraro, A. ; Nogues, M. ; Palkonen, S. ; Pedersen, S. ; Robalo-Cordeiro, C. ; Samolinski, B. ; Strandberg, T. ; Valiulis, A. ; Yorgancioglu, A. ; Zuberbier, T. ; Bedbrook, A. ; Aberer, W. ; Adachi, M. ; Agusti, A. ; Akdis, C. A. ; Akdis, M. ; Ankri, J. ; Alonso, A. ; Annesi-Maesano, I. ; Ansotegui, I. J. ; Anto, J. M. ; Arnavielhe, S. ; Arshad, H. ; Bai, C. ; Baiardini, I. ; Bachert, C. ; Baigenzhin, A. K. ; Barbara, C. ; Bateman, E. D. ; Beghé, B. ; Ben Kheder, A. ; Bennoor, K. S. ; Benson, M. ; Bergmann, K. C. ; Bieber, T. ; Bindslev-Jensen, C. ; Bjermer, L. ; Blain, H. ; Blasi, F. ; Boner, A. L. ; Bonini, M. ; Bonini, S. ; Bosnic-Anticevitch, S. ; Boulet, L. P. ; Bourret, R. ; Bousquet, P. J. ; Braido, F. ; Briggs, A. H. ; Brightling, C. E. ; Brozek, J. ; Buhl, R. ; Burney, P. G. ; Bush, A. ; Caballero-Fonseca, F. ; Caimmi, D. ; Calderon, M. A. ; Calverley, P. M. ; Camargos, P. A. M. ; Canonica, G. W. ; Camuzat, T. ; Carlsen, K. H. ; Carr, W. ; Carriazo, A. ; Casale, T. ; Cepeda Sarabia, A. M. ; Chatzi, L. ; Chen, Y. Z. ; Chiron, R. ; Chkhartishvili, E. ; Chuchalin, A. G. ; Chung, K. F. ; Ciprandi, G. ; Cirule, I. ; Cox, L. ; Costa, D. J. ; Custovic, A. ; Dahl, R. ; Dahlen, S. E. ; Darsow, U. ; De Carlo, G. ; De Blay, F. ; Dedeu, T. ; Deleanu, D. ; De Manuel Keenoy, E. ; Demoly, P. ; Denburg, J. A. ; Devillier, P. ; Didier, A. ; Dinh-Xuan, A. T. ; Djukanovic, R. ; Dokic, D. ; Douagui, H. ; Dray, G. ; Dubakiene, R. ; Durham, S. R. ; Dykewicz, M. S. ; El-Gamal, Y. ; Emuzyte, R. ; Fabbri, L. M. ; Fletcher, M. ; Fiocchi, A. ; Fink Wagner, A. ; Fonseca, J. ; Fokkens, W. J. ; Forastiere, F. ; Frith, P. ; Gaga, M. ; Gamkrelidze, A. ; Garces, J. ; Garcia-Aymerich, J. ; Gemicioğlu, B. ; Gereda, J. E. ; González Diaz, S. ; Gotua, M. ; Grisle, I. ; Grouse, L. ; Gutter, Z. ; Guzmán, M. A. ; Heaney, L. G. ; Hellquist-Dahl, B. ; Henderson, D. ; Hendry, A. ; Heinrich, J. ; Heve, D. ; Horak, F. ; Hourihane, J. O’. B. ; Howarth, P. ; Humbert, M. ; Hyland, M. E. ; Illario, M. ; Ivancevich, J. C. ; Jardim, J. R. ; Jares, E. J. ; Jeandel, C. ; Jenkins, C. ; Johnston, S. L. ; Jonquet, O. ; Julge, K. ; Jung, K. S. ; Just, J. ; Kaidashev, I. ; Kaitov, M. R. ; Kalayci, O. ; Kalyoncu, A. F. ; Keil, T. ; Keith, P. K. ; Klimek, L. ; Koffi N’Goran, B. ; Kolek, V. ; Koppelman, G. H. ; Kowalski, M. L. ; Kull, I. ; Kuna, P. ; Kvedariene, V. ; Lambrecht, B. ; Lau, S. ; Larenas‑Linnemann, D. ; Laune, D. ; Le, L. T. T. ; Lieberman, P. ; Lipworth, B. ; Li, J. ; Lodrup Carlsen, K. ; Louis, R. ; MacNee, W. ; Magard, Y. ; Magnan, A. ; Mahboub, B. ; Mair, A. ; Majer, I. ; Makela, M. J. ; Manning, P. ; Mara, S. ; Marshall, G. D. ; Masjedi, M. R. ; Matignon, P. ; Maurer, M. ; Mavale‑Manuel, S. ; Melén, E. ; Melo‑Gomes, E. ; Meltzer, E. O. ; Menzies‑Gow, A. ; Merk, H. ; Michel, J. P. ; Miculinic, N. ; Mihaltan, F. ; Milenkovic, B. ; Mohammad, G. M. Y. ; Molimard, M. ; Momas, I. ; Montilla‑Santana, A. ; Morais‑Almeida, M. ; Morgan, M. ; Mösges, R. ; Mullol, J. ; Nafti, S. ; Namazova‑Baranova, L. ; Naclerio, R. ; Neou, A. ; Neffen, H. ; Nekam, K. ; Niggemann, B. ; Ninot, G. ; Nyembue, T. D. ; O’Hehir, R. E. ; Ohta, K. ; Okamoto, Y. ; Okubo, K. ; Ouedraogo, S. ; Paggiaro, P. ; Pali‑Schöll, I. ; Panzner, P. ; Papadopoulos, N. ; Papi, A. ; Park, H. S. ; Passalacqua, G. ; Pavord, I. ; Pawankar, R. ; Pengelly, R. ; Pfaar, O. ; Picard, R. ; Pigearias, B. ; Pin, I. ; Plavec, D. ; Poethig, D. ; Pohl, W. ; Popov, T. A. ; Portejoie, F. ; Potter, P. ; Postma, D. ; Price, D. ; Rabe, K. F. ; Raciborski, F. ; Radier Pontal, F. ; Repka‑Ramirez, S. ; Reitamo, S. ; Rennard, S. ; Rodenas, F. ; Roberts, J. ; Roca, J. ; Rodriguez Mañas, L. ; et al
Action Plan B3 of the European Innovation Partnership on Active and Healthy Ageing (EIP on AHA) focuses on the integrated care of chronic diseases. Area 5 (Care Pathways) was initiated using chronic respiratory diseases as a model. The chronic respiratory disease action plan includes (1) AIRWAYS integrated care pathways (ICPs), (2) the joint initiative between the Reference site MACVIA-LR (Contre les MAladies Chroniques pour un VIeillissement Actif) and ARIA (Allergic Rhinitis and its Impact on Asthma), (3) Commitments for Action to the European Innovation Partnership on Active and Healthy Ageing and the AIRWAYS ICPs network. It is deployed in collaboration with the World Health Organization Global Alliance against Chronic Respiratory Diseases (GARD). The European Innovation Partnership on Active and Healthy Ageing has proposed a 5-step framework for developing an individual scaling up strategy: (1) what to scale up: (1-a) databases of good practices, (1-b) assessment of viability of the scaling up of good practices, (1-c) classification of good practices for local replication and (2) how to scale up: (2-a) facilitating partnerships for scaling up, (2-b) implementation of key success factors and lessons learnt, including emerging technologies for individualised and predictive medicine. This strategy has already been applied to the chronic respiratory disease action plan of the European Innovation Partnership on Active and Healthy Ageing.
Galluzzi, L. ; Bravo-San Pedro, J. M. ; Vitale, I. ; Aaronson, S. A. ; Abrams, J. M. ; Adam, D. ; Alnemri, E. S. ; Altucci, L. ; Andrews, D. ; Annicchiarico-Petruzelli, M. ; Baehrecke, E. H. ; Bazan, N. G. ; Bertrand, M. J. ; Bianchi, K. ; Blagosklonny, M. V. ; Blomgren, K. ; Borner, C. ; Bredesen, D. E. ; Brenner, C. ; Campanella, M. ; Candi, E. ; Cecconi, F. ; Chan, F. K. ; Chandel, N. S. ; Cheng, E. H. ; Chipuk, J. E. ; Cidlowski, J. A. ; Ciechanover, A. ; Dawson, T. M. ; Dawson, V. L. ; De Laurenzi, V. ; De Maria, R. ; Debatin, K. M. ; Di Daniele, N. ; Dixit, V. M. ; Dynlacht, B. D. ; El-Deiry, W. S. ; Fimia, G. M. ; Flavell, R. A. ; Fulda, S. ; Garrido, C. ; Gougeon, M. L. ; Green, D. R. ; Gronemeyer, H. ; Hajnoczky, G. ; Hardwick, J. M. ; Hengartner, M. O. ; Ichijo, H. ; Joseph, B. ; Jost, P. J. ; Kaufmann, T. ; Kepp, O. ; Klionsky, D. J. ; Knight, R. A. ; Kumar, S. ; Lemasters, J. J. ; Levine, B. ; Linkermann, A. ; Lipton, S. A. ; Lockshin, R. A. ; López-Otín, C. ; Lugli, E. ; Madeo, F. ; Malorni, W. ; Marine, J. C. ; Martin, S. J. ; Martinou, J. C. ; Medema, J. P. ; Meier, P. ; Melino, S. ; Mizushima, N. ; Moll, U. ; Muñoz-Pinedo, C. ; Nuñez, G. ; Oberst, A. ; Panaretakis, T. ; Penninger, J. M. ; Peter, M. E. ; Piacentini, M. ; Pinton, P. ; Prehn, J. H. ; Puthalakath, H. ; Rabinovich, G. A. ; Ravichandran, K. S. ; Rizzuto, R. ; Rodrigues, C. M. ; Rubinsztein, D. C. ; Rudel, T. ; Shi, Y. ; Simon, H. U. ; Stockwell, B. R. ; Szabadkai, G. ; Tait, S. W. ; Tang, H. L. ; Tavernarakis, N. ; Tsujimoto, Y. ; Vanden Berghe, T. ; Vandenabeele, P. ; Villunger, A. ; Wagner, E. F. ; Walczak, H. ; White, E. ; Wood, W. G. ; Yuan, J. ; Zakeri, Z. ; Zhivotovsky, B. ; Melino, G. ; Kroemer, G.
Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is generally referred to as 'accidental cell death' (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. 'Regulated cell death' (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exert true cytoprotective effects in the mammalian system, but simply alters the kinetics of cellular demise as it shifts its morphologic and biochemical correlates. Conversely, bona fide cytoprotection can be achieved by inhibiting the transduction of lethal signals in the early phases of the process, when adaptive responses are still operational. Thus, the mechanisms that truly execute RCD may be less understood, less inhibitable and perhaps more homogeneous than previously thought. Here, the Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death.
Dumont, Martine ; Weber-Lassalle, Nana ; Joly-Beauparlant, Charles ; Ernst, Corinna ; Droit, Arnaud ; Feng, Bing-Jian ; Dubois, Stéphane ; Collin-Deschesnes, Annie-Claude ; Soucy, Penny ; Vallée, Maxime ; Fournier, Frédéric ; Lemaçon, Audrey ; Adank, Muriel A. ; Allen, Jamie ; Altmüller, Janine ; Arnold, Norbert ; Ausems, Margreet G. E. M. ; Berutti, Riccardo ; Bolla, Manjeet K. ; Bull, Shelley ; Carvalho, Sara ; Cornelissen, Sten ; Dufault, Michael R. ; Dunning, Alison M. ; Engel, Christoph ; Gehrig, Andrea ; Geurts-Giele, Willemina R. R. ; Gieger, Christian ; Green, Jessica ; Hackmann, Karl ; Helmy, Mohamed ; Hentschel, Julia ; Hogervorst, Frans B. L. ; Hollestelle, Antoinette ; Hooning, Maartje J. ; Horváth, Judit ; Ikram, M. Arfan ; Kaulfuß, Silke ; Keeman, Renske ; Kuang, Da ; Luccarini, Craig ; Maier, Wolfgang ; Martens, John W. M. ; Niederacher, Dieter ; Nürnberg, Peter ; Ott, Claus-Eric ; Peters, Annette ; Pharoah, Paul D. P. ; Ramirez, Alfredo ; Ramser, Juliane ; Riedel-Heller, Steffi ; Schmidt, Gunnar ; Shah, Mitul ; Scherer, Martin ; Stäbler, Antje ; Strom, Tim M. ; Sutter, Christian ; Thiele, Holger ; van Asperen, Christi J. ; van der Kolk, Lizet ; van der Luijt, Rob B. ; Volk, Alexander E. ; Wagner, Michael ; Waisfisz, Quinten ; Wang, Qin ; Wang-Gohrke, Shan ; Weber, Bernhard H. F. ; Devilee, Peter ; Tavtigian, Sean ; Bader, Gary D. ; Meindl, Alfons ; Goldgar, David E. ; Andrulis, Irene L. ; Schmutzler, Rita K. ; Easton, Douglas F. ; Schmidt, Marjanka K. ; Hahnen, Eric ; Simard, Jacques
Rare variants in at least 10 genes, including BRCA1, BRCA2, PALB2, ATM, and CHEK2, are associated with increased risk of breast cancer; however, these variants, in combination with common variants identified through genome-wide association studies, explain only a fraction of the familial aggregation of the disease. To identify further susceptibility genes, we performed a two-stage whole-exome sequencing study. In the discovery stage, samples from 1528 breast cancer cases enriched for breast cancer susceptibility and 3733 geographically matched unaffected controls were sequenced. Using five different filtering and gene prioritization strategies, 198 genes were selected for further validation. These genes, and a panel of 32 known or suspected breast cancer susceptibility genes, were assessed in a validation set of 6211 cases and 6019 controls for their association with risk of breast cancer overall, and by estrogen receptor (ER) disease subtypes, using gene burden tests applied to loss-of-function and rare missense variants. Twenty genes showed nominal evidence of association (p-value < 0.05) with either overall or subtype-specific breast cancer. Our study had the statistical power to detect susceptibility genes with effect sizes similar to ATM, CHEK2, and PALB2, however, it was underpowered to identify genes in which susceptibility variants are rarer or confer smaller effect sizes. Larger sample sizes would be required in order to identify such genes.
Adrián-Martínez, S. ; Albert, A. ; André, M. ; Anghinolfi, M. ; Anton, G. ; Ardid, M. ; Aubert, J.-J. ; Avgitas, T. ; Baret, B. ; Barrios-Martí, J. ; Basa, S. ; Bertin, V. ; Biagi, S. ; Bormuth, R. ; Bouwhuis, M.C. ; Bruijn, R. ; Brunner, J. ; Busto, J. ; Capone, A. ; Caramete, L. ; Carr, J. ; Celli, S. ; Chiarusi, T. ; Circella, M. ; Coleiro, A. ; Coniglione, R. ; Constantini, H. ; Coyle, P. ; Creusot, A. ; Deschamps, A. ; De Bonis, G. ; Distefano, C. ; Donzaud, C. ; Dornic, D. ; Drouhin, D. ; Eberl, T. ; El Bojaddaini, I. ; Elsässer, D. ; Enzenhöfer, A. ; Fehn, K. ; Felis, I. ; Fusco, L.A. ; Galatà, S. ; Gay, P. ; Geißelsöder, S. ; Geyer, K. ; Giordano, V. ; Gleixner, A. ; Glotin, H. ; Gracia-Ruiz, R. ; Graf, K. ; Hallmann, S. ; van Haren, H. ; Heijboer, A.J. ; Hello, Y. ; Hernández-Rey, J.J. ; Hößl, J. ; Hofestädt, J. ; Hugon, C. ; Illuminati, G. ; James, C.W. ; de Jong, M. ; Kadler, M. ; Kalekin, O. ; Katz, U. ; Kießling, D. ; Kouchner, A. ; Kreter, M. ; Kreykenbohm, I. ; Kulikovskiy, V. ; Lachaud, C. ; Lahmann, R. ; Lefèvre, D. ; Leonora, E. ; Loucatos, S. ; Marcelin, M. ; Margiotta, A. ; Marinelli, A. ; Martínez-Mora, J.A. ; Mathieu, A. ; Michael, T. ; Migliozzi, P. ; Moussa, A. ; Mueller, C. ; Nezri, E. ; Pavalas, G.E. ; Pellegrino, C. ; Perrina, C. ; Piattelli, P. ; Popa, V. ; Pradier, T. ; Racca, C. ; Riccobene, G. ; Roensch, K. ; Saldaña, M. ; Samtleben, D.F.E. ; Sánchez-Losa, A. ; Sanguineti, M. ; Sapienza, P. ; Schnabel, J. ; Schüssler, F. ; Seitz, T. ; Sieger, C. ; Spurio, M. ; Stolarczyk, Th. ; Taiuti, M. ; Trovato, A. ; Tselengidou, M. ; Turpin, D. ; Tönnis, C. ; Vallage, B. ; Vallée, C. ; Van Elewyck, V. ; Visser, E. ; Vivolo, D. ; Wagner, S. ; Wilms, J. ; Zornoza, J.D. ; Zúñiga, J.
A highly significant excess of high-energy astrophysical neutrinos has been reported by the IceCube Collaboration. Some features of the energy and declination distributions of IceCube events hint at a North/South asymmetry of the neutrino flux. This could be due to the presence of the bulk of our Galaxy in the Southern hemisphere. The ANTARES neutrino telescope, located in the Mediterranean Sea, has been taking data since 2007. It offers the best sensitivity to muon neutrinos produced by galactic cosmic ray interactions in this region of the sky. In this letter a search for an extended neutrino flux from the Galactic Ridge region is presented. Different models of neutrino production by cosmic ray propagation are tested. No excess of events is observed and upper limits for different neutrino flux spectral indices Γ are set. For Γ=2.4 the 90% confidence level flux upper limit at 100 TeV for one neutrino flavour corresponds to Φ\(^{1f}_{0}\) (100 TeV) = 2.0 · 10\(^{−17}\) GeV\(^{−1}\) cm\(^{−2}\)s\(^{−1}\)sr\(^{−1}\). Under this assumption, at most two events of the IceCube cosmic candidates can originate from the Galactic Ridge. A simple power-law extrapolation of the Fermi-LAT flux to account for IceCube High Energy Starting Events is excluded at 90% confidence level.
Adrián-Martínez, S. ; Albert, A. ; André, M. ; Anton, G. ; Ardid, M. ; Aubert, J.-J. ; Avgitas, T. ; Baret, B. ; Barrios-Martí, J. ; Basa, S. ; Bertin, V. ; Biagi, S. ; Bormuth, R. ; Bou-Cabo, M. ; Bouwhuis, M.C. ; Bruijn, R. ; Brunner, J. ; Busto, J. ; Capone, A. ; Caramete, L. ; Carr, J. ; Celli, S. ; Chiarusi, T. ; Circella, M. ; Coleiro, A. ; Coniglione, R. ; Costantini, H. ; Coyle, P. ; Creusot, A. ; Deschamps, A. ; De Bonis, G. ; Distefano, C. ; Donzaud, C. ; Dornic, D. ; Drouhin, D. ; Eberl, T. ; El Bojaddaini, I. ; Elsässer, D. ; Enzenhöfer, A. ; Fehn, K. ; Felis, I. ; Fusco, L.A. ; Galatà, S. ; Gay, P. ; Geißelsöder, S. ; Geyer, K. ; Giordano, V. ; Gleixner, A. ; Glotin, H. ; Gracia-Ruiz, R. ; Graf, K. ; Hallmann, S. ; van Haren, H. ; Heijboer, A.J. ; Hello, Y. ; Hernández-Rey, J.-J. ; Hößl, J. ; Hofestädt, J. ; Hugon, C. ; Illuminati, G. ; James, C.W. ; de Jong, M. ; Kadler, M. ; Kalekin, O. ; Katz, U. ; Kießling, D. ; Kouchner, A. ; Kreter, M. ; Kreykenbohm, I. ; Kulikovskiy, V. ; Lachaud, C. ; Lahmann, R. ; Lefèvre, D. ; Leonora, E. ; Loucatos, S. ; Marcelin, M. ; Margiotta, A. ; Marinelli, A. ; Martínez-Mora, J.A. ; Mathieu, A. ; Michael, T. ; Migliozzi, P. ; Moussa, A. ; Mueller, C. ; Nezri, E. ; Păvălaș, G.E. ; Pellegrino, C. ; Perrina, C. ; Piattelli, P. ; Popa, V. ; Pradier, T. ; Racca, C. ; Riccobene, G. ; Roensch, K. ; Saldaña, M. ; Samtleben, D.F.E. ; Sanguineti, M. ; Sapienza, P. ; Schnabel, J. ; Schüssler, F. ; Seitz, T. ; Sieger, C. ; Spurio, M. ; Stolarczyk, Th. ; Sánchez-Losa, A. ; Taiuti, M. ; Trovato, A. ; Tselengidou, M. ; Turpin, D. ; Tönnis, C. ; Vallage, B. ; Vallée, C. ; Van Elewyck, V. ; Vivolo, D. ; Wagner, S. ; Wilms, J. ; Zornoza, J.D. ; Zúñiga, J.
A search for Secluded Dark Matter annihilation in the Sun using 2007-2012 data of the ANTARES neutrino telescope is presented. Three different cases are considered: a) detection of dimuons that result from the decay of the mediator, or neutrino detection from: b) mediator that decays into a dimuon and, in turn, into neutrinos, and c) mediator that decays directly into neutrinos. As no significant excess over background is observed, constraints are derived on the dark matter mass and the lifetime of the mediator.
Adrián-Martínez, S. ; Albert, A. ; André, M. ; Anton, G. ; Ardid, M. ; Aubert, J.-J. ; Avgitas, T. ; Baret, B. ; Barrios-Martí, J. ; Basa, S. ; Bertin, V. ; Biagi, S. ; Bormuth, R. ; Bouwhuis, M.C. ; Bruijn, R. ; Brunner, J. ; Busto, J. ; Capone, A. ; Caramete, L. ; Carr, J. ; Celli, S. ; Chiarusi, T. ; Circella, M. ; Coleiro, A. ; Coniglione, R. ; Costantini, H. ; Coyle, P. ; Creusot, A. ; Deschamps, A. ; De Bonis, G. ; Distefano, C. ; Donzaud, C. ; Dornic, D. ; Drouhin, D. ; Eberl, T. ; El Bojaddaini, I. ; Elsässer, D. ; Enzenhöfer, A. ; Fehn, K. ; Felis, I. ; Fusco, L.A. ; Galatà, S. ; Gay, P. ; Geißelsöder, S. ; Geyer, K. ; Giordano, V. ; Gleixner, A. ; Glotin, H. ; Gracia-Ruiz, R. ; Graf, K. ; Hallmann, S. ; van Haren, H. ; Heijboer, A.J. ; Hello, Y. ; Hernández-Rey, J.J. ; Hößl, J. ; Hofestädt, J. ; Hugon, C. ; Illuminati, G. ; James, C.W. ; de Jong, M. ; Jongen, M. ; Kadler, M. ; Kalekin, O. ; Katz, U. ; Kießling, D. ; Kouchner, A. ; Kreter, M. ; Kreykenbohm, I. ; Kulikovskiy, V. ; Lachaud, C. ; Lahmann, R. ; Lefèvre, D. ; Leonora, E. ; Loucatos, S. ; Marcelin, M. ; Margiotta, A. ; Marinelli, A. ; Martínez-Mora, J.A. ; Mathieu, A. ; Melis, K. ; Michael, T. ; Migliozzi, P. ; Moussa, A. ; Mueller, C. ; Nezri, E. ; Pavalas, G.E. ; Pellegrino, C. ; Perrina, C. ; Piattelli, P. ; Popa, V. ; Pradier, T. ; Racca, C. ; Riccobene, G. ; Roensch, K. ; Saldaña, M. ; Samtleben, D.F.E. ; Sánchez-Losa, A. ; Sanguineti, M. ; Sapienza, P. ; Schnabel, J. ; Schüssler, F. ; Seitz, T. ; Sieger, C. ; Spurio, M. ; Stolarczyk, Th. ; Taiuti, M. ; Tönnis, C. ; Trovato, A. ; Tselengidou, M. ; Turpin, D. ; Vallage, B. ; Vallée, C. ; Van Elewyck, V. ; Vivolo, D. ; Wagner, S. ; Wilms, J. ; Zornoza, J.D. ; Zúñiga, J.
A search for muon neutrinos originating from dark matter annihilations in the Sun is performed using the data recorded by the ANTARES neutrino telescope from 2007 to 2012. In order to obtain the best possible sensitivities to dark matter signals, an optimisation of the event selection criteria is performed taking into account the background of atmospheric muons, atmospheric neutrinos and the energy spectra of the expected neutrino signals. No significant excess over the background is observed and 90% C.L. upper limits on the neutrino flux, the spin-dependent and spin-independent WIMP-nucleon cross-sections are derived for WIMP masses ranging from 50 GeV to 5 TeV for the annihilation channels WIMP + WIMP→ b\(\overline{b}\), W\(^{+}\)W\(^{−}\) and τ\(^{+}\)τ\(^{−}\).
Bousquet, Jean ; Anto, Josep M. ; Bachert, Claus ; Haahtela, Tari ; Zuberbier, Torsten ; Czarlewski, Wienczyslawa ; Bedbrook, Anna ; Bosnic‐Anticevich, Sinthia ; Walter Canonica, G. ; Cardona, Victoria ; Costa, Elisio ; Cruz, Alvaro A. ; Erhola, Marina ; Fokkens, Wytske J. ; Fonseca, Joao A. ; Illario, Maddalena ; Ivancevich, Juan‐Carlos ; Jutel, Marek ; Klimek, Ludger ; Kuna, Piotr ; Kvedariene, Violeta ; Le, LTT ; Larenas‐Linnemann, Désirée E. ; Laune, Daniel ; Lourenço, Olga M. ; Melén, Erik ; Mullol, Joaquim ; Niedoszytko, Marek ; Odemyr, Mikaëla ; Okamoto, Yoshitaka ; Papadopoulos, Nikos G. ; Patella, Vincenzo ; Pfaar, Oliver ; Pham‐Thi, Nhân ; Rolland, Christine ; Samolinski, Boleslaw ; Sheikh, Aziz ; Sofiev, Mikhail ; Suppli Ulrik, Charlotte ; Todo‐Bom, Ana ; Tomazic, Peter‐Valentin ; Toppila‐Salmi, Sanna ; Tsiligianni, Ioanna ; Valiulis, Arunas ; Valovirta, Erkka ; Ventura, Maria‐Teresa ; Walker, Samantha ; Williams, Sian ; Yorgancioglu, Arzu ; Agache, Ioana ; Akdis, Cezmi A. ; Almeida, Rute ; Ansotegui, Ignacio J. ; Annesi‐Maesano, Isabella ; Arnavielhe, Sylvie ; Basagaña, Xavier ; D. Bateman, Eric ; Bédard, Annabelle ; Bedolla‐Barajas, Martin ; Becker, Sven ; Bennoor, Kazi S. ; Benveniste, Samuel ; Bergmann, Karl C. ; Bewick, Michael ; Bialek, Slawomir ; E. Billo, Nils ; Bindslev‐Jensen, Carsten ; Bjermer, Leif ; Blain, Hubert ; Bonini, Matteo ; Bonniaud, Philippe ; Bosse, Isabelle ; Bouchard, Jacques ; Boulet, Louis‐Philippe ; Bourret, Rodolphe ; Boussery, Koen ; Braido, Fluvio ; Briedis, Vitalis ; Briggs, Andrew ; Brightling, Christopher E. ; Brozek, Jan ; Brusselle, Guy ; Brussino, Luisa ; Buhl, Roland ; Buonaiuto, Roland ; Calderon, Moises A. ; Camargos, Paulo ; Camuzat, Thierry ; Caraballo, Luis ; Carriazo, Ana‐Maria ; Carr, Warner ; Cartier, Christine ; Casale, Thomas ; Cecchi, Lorenzo ; Cepeda Sarabia, Alfonso M. ; H. Chavannes, Niels ; Chkhartishvili, Ekaterine ; Chu, Derek K. ; Cingi, Cemal ; Correia de Sousa, Jaime ; Costa, David J. ; Courbis, Anne‐Lise ; Custovic, Adnan ; Cvetkosvki, Biljana ; D'Amato, Gennaro ; da Silva, Jane ; Dantas, Carina ; Dokic, Dejan ; Dauvilliers, Yves ; De Feo, Giulia ; De Vries, Govert ; Devillier, Philippe ; Di Capua, Stefania ; Dray, Gerard ; Dubakiene, Ruta ; Durham, Stephen R. ; Dykewicz, Mark ; Ebisawa, Motohiro ; Gaga, Mina ; El‐Gamal, Yehia ; Heffler, Enrico ; Emuzyte, Regina ; Farrell, John ; Fauquert, Jean‐Luc ; Fiocchi, Alessandro ; Fink‐Wagner, Antje ; Fontaine, Jean‐François ; Fuentes Perez, José M. ; Gemicioğlu, Bilun ; Gamkrelidze, Amiran ; Garcia‐Aymerich, Judith ; Gevaert, Philippe ; Gomez, René Maximiliano ; González Diaz, Sandra ; Gotua, Maia ; Guldemond, Nick A. ; Guzmán, Maria‐Antonieta ; Hajjam, Jawad ; Huerta Villalobos, Yunuen R. ; Humbert, Marc ; Iaccarino, Guido ; Ierodiakonou, Despo ; Iinuma, Tomohisa ; Jassem, Ewa ; Joos, Guy ; Jung, Ki‐Suck ; Kaidashev, Igor ; Kalayci, Omer ; Kardas, Przemyslaw ; Keil, Thomas ; Khaitov, Musa ; Khaltaev, Nikolai ; Kleine‐Tebbe, Jorg ; Kouznetsov, Rostislav ; Kowalski, Marek L. ; Kritikos, Vicky ; Kull, Inger ; La Grutta, Stefania ; Leonardini, Lisa ; Ljungberg, Henrik ; Lieberman, Philip ; Lipworth, Brian ; Lodrup Carlsen, Karin C. ; Lopes‐Pereira, Catarina ; Loureiro, Claudia C. ; Louis, Renaud ; Mair, Alpana ; Mahboub, Bassam ; Makris, Michaël ; Malva, Joao ; Manning, Patrick ; Marshall, Gailen D. ; Masjedi, Mohamed R. ; Maspero, Jorge F. ; Carreiro‐Martins, Pedro ; Makela, Mika ; Mathieu‐Dupas, Eve ; Maurer, Marcus ; De Manuel Keenoy, Esteban ; Melo‐Gomes, Elisabete ; Meltzer, Eli O. ; Menditto, Enrica ; Mercier, Jacques ; Micheli, Yann ; Miculinic, Neven ; Mihaltan, Florin ; Milenkovic, Branislava ; Mitsias, Dimitirios I. ; Moda, Giuliana ; Mogica‐Martinez, Maria‐Dolores ; Mohammad, Yousser ; Montefort, Steve ; Monti, Ricardo ; Morais‐Almeida, Mario ; Mösges, Ralph ; Münter, Lars ; Muraro, Antonella ; Murray, Ruth ; Naclerio, Robert ; Napoli, Luigi ; Namazova‐Baranova, Leyla ; Neffen, Hugo ; Nekam, Kristoff ; Neou, Angelo ; Nordlund, Björn ; Novellino, Ettore ; Nyembue, Dieudonné ; O'Hehir, Robyn ; Ohta, Ken ; Okubo, Kimi ; Onorato, Gabrielle L. ; Orlando, Valentina ; Ouedraogo, Solange ; Palamarchuk, Julia ; Pali‐Schöll, Isabella ; Panzner, Peter ; Park, Hae‐Sim ; Passalacqua, Gianni ; Pépin, Jean‐Louis ; Paulino, Ema ; Pawankar, Ruby ; Phillips, Jim ; Picard, Robert ; Pinnock, Hilary ; Plavec, Davor ; Popov, Todor A. ; Portejoie, Fabienne ; Price, David ; Prokopakis, Emmanuel P. ; Psarros, Fotis ; Pugin, Benoit ; Puggioni, Francesca ; Quinones‐Delgado, Pablo ; Raciborski, Filip ; Rajabian‐Söderlund, Rojin ; Regateiro, Frederico S. ; Reitsma, Sietze ; Rivero‐Yeverino, Daniela ; Roberts, Graham ; Roche, Nicolas ; Rodriguez‐Zagal, Erendira ; Rolland, Christine ; Roller‐Wirnsberger, Regina E. ; Rosario, Nelson ; Romano, Antonino ; Rottem, Menachem ; Ryan, Dermot ; Salimäki, Johanna ; Sanchez‐Borges, Mario M. ; Sastre, Joaquin ; Scadding, Glenis K. ; Scheire, Sophie ; Schmid‐Grendelmeier, Peter ; Schünemann, Holger J. ; Sarquis Serpa, Faradiba ; Shamji, Mohamed ; Sisul, Juan‐Carlos ; Sofiev, Mikhail ; Solé, Dirceu ; Somekh, David ; Sooronbaev, Talant ; Sova, Milan ; Spertini, François ; Spranger, Otto ; Stellato, Cristiana ; Stelmach, Rafael ; Thibaudon, Michel ; To, Teresa ; Toumi, Mondher ; Usmani, Omar ; Valero, Antonio A. ; Valenta, Rudolph ; Valentin‐Rostan, Marylin ; Pereira, Marilyn Urrutia ; van der Kleij, Rianne ; Van Eerd, Michiel ; Vandenplas, Olivier ; Vasankari, Tuula ; Vaz Carneiro, Antonio ; Vezzani, Giorgio ; Viart, Frédéric ; Viegi, Giovanni ; Wallace, Dana ; Wagenmann, Martin ; Wang, De Yun ; Waserman, Susan ; Wickman, Magnus ; Williams, Dennis M. ; Wong, Gary ; Wroczynski, Piotr ; Yiallouros, Panayiotis K. ; Yusuf, Osman M. ; Zar, Heather J. ; Zeng, Stéphane ; Zernotti, Mario E. ; Zhang, Luo ; Shan Zhong, Nan ; Zidarn, Mihaela
Digital anamorphosis is used to define a distorted image of health and care that may be viewed correctly using digital tools and strategies. MASK digital anamorphosis represents the process used by MASK to develop the digital transformation of health and care in rhinitis. It strengthens the ARIA change management strategy in the prevention and management of airway disease. The MASK strategy is based on validated digital tools. Using the MASK digital tool and the CARAT online enhanced clinical framework, solutions for practical steps of digital enhancement of care are proposed.
El-Helou, Sabine M. ; Biegner, Anika-Kerstin ; Bode, Sebastian ; Ehl, Stephan R. ; Heeg, Maximilian ; Maccari, Maria E. ; Ritterbusch, Henrike ; Speckmann, Carsten ; Rusch, Stephan ; Scheible, Raphael ; Warnatz, Klaus ; Atschekzei, Faranaz ; Beider, Renata ; Ernst, Diana ; Gerschmann, Stev ; Jablonka, Alexandra ; Mielke, Gudrun ; Schmidt, Reinhold E. ; Schürmann, Gesine ; Sogkas, Georgios ; Baumann, Ulrich H. ; Klemann, Christian ; Viemann, Dorothee ; Bernuth, Horst von ; Krüger, Renate ; Hanitsch, Leif G. ; Scheibenbogen, Carmen M. ; Wittke, Kirsten ; Albert, Michael H. ; Eichinger, Anna ; Hauck, Fabian ; Klein, Christoph ; Rack-Hoch, Anita ; Sollinger, Franz M. ; Avila, Anne ; Borte, Michael ; Borte, Stephan ; Fasshauer, Maria ; Hauenherm, Anja ; Kellner, Nils ; Müller, Anna H. ; Ülzen, Anett ; Bader, Peter ; Bakhtiar, Shahrzad ; Lee, Jae-Yun ; Heß, Ursula ; Schubert, Ralf ; Wölke, Sandra ; Zielen, Stefan ; Ghosh, Sujal ; Laws, Hans-Juergen ; Neubert, Jennifer ; Oommen, Prasad T. ; Hönig, Manfred ; Schulz, Ansgar ; Steinmann, Sandra ; Klaus, Schwarz ; Dückers, Gregor ; Lamers, Beate ; Langemeyer, Vanessa ; Niehues, Tim ; Shai, Sonu ; Graf, Dagmar ; Müglich, Carmen ; Schmalzing, Marc T. ; Schwaneck, Eva C. ; Tony, Hans-Peter ; Dirks, Johannes ; Haase, Gabriele ; Liese, Johannes G. ; Morbach, Henner ; Foell, Dirk ; Hellige, Antje ; Wittkowski, Helmut ; Masjosthusmann, Katja ; Mohr, Michael ; Geberzahn, Linda ; Hedrich, Christian M. ; Müller, Christiane ; Rösen-Wolff, Angela ; Roesler, Joachim ; Zimmermann, Antje ; Behrends, Uta ; Rieber, Nikolaus ; Schauer, Uwe ; Handgretinger, Rupert ; Holzer, Ursula ; Henes, Jörg ; Kanz, Lothar ; Boesecke, Christoph ; Rockstroh, Jürgen K. ; Schwarze-Zander, Carolynne ; Wasmuth, Jan-Christian ; Dilloo, Dagmar ; Hülsmann, Brigitte ; Schönberger, Stefan ; Schreiber, Stefan ; Zeuner, Rainald ; Ankermann, Tobias ; Bismarck, Philipp von ; Huppertz, Hans-Iko ; Kaiser-Labusch, Petra ; Greil, Johann ; Jakoby, Donate ; Kulozik, Andreas E. ; Metzler, Markus ; Naumann-Bartsch, Nora ; Sobik, Bettina ; Graf, Norbert ; Heine, Sabine ; Kobbe, Robin ; Lehmberg, Kai ; Müller, Ingo ; Herrmann, Friedrich ; Horneff, Gerd ; Klein, Ariane ; Peitz, Joachim ; Schmidt, Nadine ; Bielack, Stefan ; Groß-Wieltsch, Ute ; Classen, Carl F. ; Klasen, Jessica ; Deutz, Peter ; Kamitz, Dirk ; Lassy, Lisa ; Tenbrock, Klaus ; Wagner, Norbert ; Bernbeck, Benedikt ; Brummel, Bastian ; Lara-Villacanas, Eusebia ; Münstermann, Esther ; Schneider, Dominik T. ; Tietsch, Nadine ; Westkemper, Marco ; Weiß, Michael ; Kramm, Christof ; Kühnle, Ingrid ; Kullmann, Silke ; Girschick, Hermann ; Specker, Christof ; Vinnemeier-Laubenthal, Elisabeth ; Haenicke, Henriette ; Schulz, Claudia ; Schweigerer, Lothar ; Müller, Thomas G. ; Stiefel, Martina ; Belohradsky, Bernd H. ; Soetedjo, Veronika ; Kindle, Gerhard ; Grimbacher, Bodo
Introduction: The German PID-NET registry was founded in 2009, serving as the first national registry of patients with primary immunodeficiencies (PID) in Germany. It is part of the European Society for Immunodeficiencies (ESID) registry. The primary purpose of the registry is to gather data on the epidemiology, diagnostic delay, diagnosis, and treatment of PIDs.
Methods: Clinical and laboratory data was collected from 2,453 patients from 36 German PID centres in an online registry. Data was analysed with the software Stata® and Excel.
Results: The minimum prevalence of PID in Germany is 2.72 per 100,000 inhabitants. Among patients aged 1-25, there was a clear predominance of males. The median age of living patients ranged between 7 and 40 years, depending on the respective PID. Predominantly antibody disorders were the most prevalent group with 57% of all 2,453 PID patients (including 728 CVID patients). A gene defect was identified in 36% of patients. Familial cases were observed in 21% of patients. The age of onset for presenting symptoms ranged from birth to late adulthood (range 0-88 years). Presenting symptoms comprised infections (74%) and immune dysregulation (22%). Ninety-three patients were diagnosed without prior clinical symptoms. Regarding the general and clinical diagnostic delay, no PID had undergone a slight decrease within the last decade. However, both, SCID and hyper IgE-syndrome showed a substantial improvement in shortening the time between onset of symptoms and genetic diagnosis. Regarding treatment, 49% of all patients received immunoglobulin G (IgG) substitution (70%-subcutaneous; 29%-intravenous; 1%-unknown). Three-hundred patients underwent at least one hematopoietic stem cell transplantation (HSCT). Five patients had gene therapy.
Conclusion: The German PID-NET registry is a precious tool for physicians, researchers, the pharmaceutical industry, politicians, and ultimately the patients, for whom the outcomes will eventually lead to a more timely diagnosis and better treatment.
Humanfoamy virus (HFV) is a retrovirus encoding structural genes and, like human immunodeficiency virus and human T ceU leukemia virus I, several anciUary reading frames collectively termed the belgenes. We have previously shown that HFV transgenic mice develop an encephalopathy with neuronal loss in hippocampus and cerebral cortex. We have now raised and characterized rabbit antisera to various recombinant portions of gag, pot, env, and bel-I, the viraltransactivator. Immunoreactivity for gag and bel-I was observed in nuclei and processes of hippocampal and cortical neurons before the onset of morphological lesions and correlated with the appearance of HFV mRNA. Astrocyte-derived multinucleated giant ceUs containing HFV proteins were present in the brain oftransgenic mice coexpressingfuU- length HFV genes but not in mice expressing truncated gag and env, suggesting that these genes contain afusogenic domain. Expression of fuU-length structural genes decreased the life expectancy oftransgenic mice, implying an a4Juvant rolefor these proteins in HFV-induced brain damage. (Am] Pathol 1993, 142:1061-1072)
Davis, Lea K. ; Yu, Dongmei ; Keenan, Clare L. ; Gamazon, Eric R. ; Konkashbaev, Anuar I. ; Derks, Eske M. ; Neale, Benjamin M. ; Yang, Jian ; Lee, S. Hong ; Evans, Patrick ; Barr, Cathy L. ; Bellodi, Laura ; Benarroch, Fortu ; Berrio, Gabriel Bedoya ; Bienvenu, Oscar J. ; Bloch, Michael H. ; Blom, Rianne M. ; Bruun, Ruth D. ; Budman, Cathy L. ; Camarena, Beatriz ; Campbell, Desmond ; Cappi, Carolina ; Cardona Silgado, Julio C. ; Cath, Danielle C. ; Cavallini, Maria C. ; Chavira, Denise A. ; Chouinard, Sylvian ; Conti, David V. ; Cook, Edwin H. ; Coric, Vladimir ; Cullen, Bernadette A. ; Deforce, Dieter ; Delorme, Richard ; Dion, Yves ; Edlund, Christopher K. ; Egberts, Karin ; Falkai, Peter ; Fernandez, Thomas V. ; Gallagher, Patience J. ; Garrido, Helena ; Geller, Daniel ; Girard, Simon L. ; Grabe, Hans J. ; Grados, Marco A. ; Greenberg, Benjamin D. ; Gross-Tsur, Varda ; Haddad, Stephen ; Heiman, Gary A. ; Hemmings, Sian M. J. ; Hounie, Ana G. ; Illmann, Cornelia ; Jankovic, Joseph ; Jenike, Micheal A. ; Kennedy, James L. ; King, Robert A. ; Kremeyer, Barbara ; Kurlan, Roger ; Lanzagorta, Nuria ; Leboyer, Marion ; Leckman, James F. ; Lennertz, Leonhard ; Liu, Chunyu ; Lochner, Christine ; Lowe, Thomas L. ; Macciardi, Fabio ; McCracken, James T. ; McGrath, Lauren M. ; Restrepo, Sandra C. Mesa ; Moessner, Rainald ; Morgan, Jubel ; Muller, Heike ; Murphy, Dennis L. ; Naarden, Allan L. ; Ochoa, William Cornejo ; Ophoff, Roel A. ; Osiecki, Lisa ; Pakstis, Andrew J. ; Pato, Michele T. ; Pato, Carlos N. ; Piacentini, John ; Pittenger, Christopher ; Pollak, Yehunda ; Rauch, Scott L. ; Renner, Tobias J. ; Reus, Victor I. ; Richter, Margaret A. ; Riddle, Mark A. ; Robertson, Mary M. ; Romero, Roxana ; Rosàrio, Maria C. ; Rosenberg, David ; Rouleau, Guy A. ; Ruhrmann, Stephan ; Ruiz-Linares, Andreas ; Sampaio, Aline S. ; Samuels, Jack ; Sandor, Paul ; Sheppard, Broke ; Singer, Harvey S. ; Smit, Jan H. ; Stein, Dan J. ; Strengman, E. ; Tischfield, Jay A. ; Valencia Duarte, Ana V. ; Vallada, Homero ; Van Nieuwerburgh, Flip ; Veenstra-VanderWeele, Jeremy ; Walitza, Susanne ; Wang, Ying ; Wendland, Jens R. ; Westenberg, Herman G. M. ; Shugart, Yin Yao ; Miguel, Euripedes C. ; McMahon, William ; Wagner, Michael ; Nicolini, Humberto ; Posthuma, Danielle ; Hanna, Gregory L. ; Heutink, Peter ; Denys, Damiaan ; Arnold, Paul D. ; Oostra, Ben A. ; Nestadt, Gerald ; Freimer, Nelson B. ; Pauls, David L. ; Wray, Naomi R. ; Stewart, S. Evelyn ; Mathews, Carol A. ; Knowles, James A. ; Cox, Nancy J. ; Scharf, Jeremiah M.
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.
Haake, Markus ; Haack, Beatrice ; Schäfer, Tina ; Harter, Patrick N. ; Mattavelli, Greta ; Eiring, Patrick ; Vashist, Neha ; Wedekink, Florian ; Genssler, Sabrina ; Fischer, Birgitt ; Dahlhoff, Julia ; Mokhtari, Fatemeh ; Kuzkina, Anastasia ; Welters, Marij J. P. ; Benz, Tamara M. ; Sorger, Lena ; Thiemann, Vincent ; Almanzar, Giovanni ; Selle, Martina ; Thein, Klara ; Späth, Jacob ; Gonzalez, Maria Cecilia ; Reitinger, Carmen ; Ipsen-Escobedo, Andrea ; Wistuba-Hamprecht, Kilian ; Eichler, Kristin ; Filipski, Katharina ; Zeiner, Pia S. ; Beschorner, Rudi ; Goedemans, Renske ; Gogolla, Falk Hagen ; Hackl, Hubert ; Rooswinkel, Rogier W. ; Thiem, Alexander ; Romer Roche, Paula ; Joshi, Hemant ; Pühringer, Dirk ; Wöckel, Achim ; Diessner, Joachim E. ; Rüdiger, Manfred ; Leo, Eugen ; Cheng, Phil F. ; Levesque, Mitchell P. ; Goebeler, Matthias ; Sauer, Markus ; Nimmerjahn, Falk ; Schuberth-Wagner, Christine ; Felten, Stefanie von ; Mittelbronn, Michel ; Mehling, Matthias ; Beilhack, Andreas ; van der Burg, Sjoerd H. ; Riedel, Angela ; Weide, Benjamin ; Dummer, Reinhard ; Wischhusen, Jörg
Immune checkpoint blockade therapy is beneficial and even curative for some cancer patients. However, the majority don’t respond to immune therapy. Across different tumor types, pre-existing T cell infiltrates predict response to checkpoint-based immunotherapy. Based on in vitro pharmacological studies, mouse models and analyses of human melanoma patients, we show that the cytokine GDF-15 impairs LFA-1/β2-integrin-mediated adhesion of T cells to activated endothelial cells, which is a pre-requisite of T cell extravasation. In melanoma patients, GDF-15 serum levels strongly correlate with failure of PD-1-based immune checkpoint blockade therapy. Neutralization of GDF-15 improves both T cell trafficking and therapy efficiency in murine tumor models. Thus GDF-15, beside its known role in cancer-related anorexia and cachexia, emerges as a regulator of T cell extravasation into the tumor microenvironment, which provides an even stronger rationale for therapeutic anti-GDF-15 antibody development.
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