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1.  ESICM LIVES 2016: part two 
Sivakumar, S. | Taccone, F. S. | Desai, K. A. | Lazaridis, C. | Skarzynski, M. | Sekhon, M. | Henderson, W. | Griesdale, D. | Chapple, L. | Deane, A. | Williams, L. | Strickland, R. | Lange, K. | Heyland, D. | Chapman, M. | Rowland, M. J. | Garry, P. | Westbrook, J. | Corkill, R. | Antoniades, C. A. | Pattinson, K. T. | Fatania, G. | Strong, A. J. | Myers, R. B. | Lazaridis, C. | Jermaine, C. M. | Robertson, C. S. | Rusin, C. G. | Hofmeijer, J. | Sondag, L. | Tjepkema-Cloostermans, M. C. | Beishuizen, A. | Bosch, F. H. | van Putten, M. J. A. M. | Carteron, L. | Patet, C. | Solari, D. | Oddo, M. | Ali, M. A. | Dias, C. | Almeida, R. | Vaz-Ferreira, A. | Silva, J. | Monteiro, E. | Cerejo, A. | Rocha, A. P. | Elsayed, A. A. | Abougabal, A. M. | Beshey, B. N. | Alzahaby, K. M. | Pozzebon, S. | Ortiz, A. Blandino | Cristallini, S. | Lheureux, O. | Brasseur, A. | Vincent, J. L. | Creteur, J. | Taccone, F. S. | Hravnak, M. | Yousef, K. | Chang, Y. | Crago, E. | Friedlander, R. M. | Abdelmonem, S. A. | Tahon, S. A. | Helmy, T. A. | Meligy, H. S. | Puig, F. | Dunn-Siegrist, I. | Pugin, J. | Gupta, S. | Govil, D. | Srinivasan, S. | Patel, S. J. | N, J. K. | Gupta, A. | Tomar, D. S. | Shafi, M. | Harne, R. | Arora, D. P. | Talwar, N. | Mazumdar, S. | Papakrivou, E. E. | Makris, D. | Manoulakas, E. | Tsolaki, B. | Karadodas, B. | Zakynthinos, E. | Garcia, I. Palacios | Martin, A. Diaz | Encinares, V. Sanchez | Ibañez, M. Pachón | Montero, J. Garnacho | Labrador, G. | Cangueiro, T. Cebrero | Poulose, V. | Koh, J. | Kam, J. W. | Yeter, H. | Kara, A. | Aktepe, O. | Topeli, A. | Tsolakoglou, I. | Intas, G. | Stergiannis, P. | Kolaros, A. A. | Chalari, E. | Athanasiadou, E. | Martika, A. | Fildisis, G. | Faivre, V. | Mengelle, C. | Favier, B. | Payen, D. | Poppe, A. | Winkler, M. S. | Mudersbach, E. | Schreiber, J. | Wruck, M. L. | Schwedhelm, E. | Kluge, S. | Zöllner, C. | Tavladaki, T. | Spanaki, A. M. | Dimitriou, H. | Kondili, E. | Choulaki, C. | Meleti, E. | Kafetzopoulos, D. | Georgopoulos, D. | Briassoulis, G. | la Torre, A. García-de | de la Torre-Prados, M. V. | Tsvetanova-Spasova, T. | Nuevo-Ortega, P. | Rueda-Molina, C. | Fernández-Porcel, A. | Camara-Sola, E. | Salido-Díaz, L. | García-Alcántara, A. | Tavladaki, T. | Spanaki, A. M. | Dimitriou, H. | Kondili, E. | Choulaki, C. | Meleti, D. E. | Kafetzopoulos, D. | Georgopoulos, D. | Briassoulis, G. | Suberviola, B. | Riera, J. | Rellan, L. | Sanchez, M. | Robles, J. C. | Lopez, E. | Vicente, R. | Miñambres, E. | Santibañez, M. | Le Guen, M. | Moore, J. | Mason, N. | Windpassinger, M. | Plattner, O. | Mascha, E. | Sessler, D. I. | Research, Outcomes | Melia, U. | Fontanet, J. | van den Berg, J. P. | Struys, M. M. R. F. | Vereecke, H. E. M. | Jensen, E. W. | Rood, P. J. T. | van de Schoor, F. | van Tertholen, K. | Pickkers, P. | van den Boogaard, M. | Beardow, Z. J. | Redhead, H. | Paramasivam, K. | Numan, T. | van den Boogaard, M. | Kamper, A. M. | Rood, P. | Peelen, L. M. | Zeman, P. M. | Slooter, A. J. | van Ewijk, C. E. | Jacobs, G. E. | Girbes, A. R. J. | Myatra, S. N. | Harish, M. M. | Prabu, N. R. | Siddiqui, S. | Kulkarni, A. P. | Divatia, J. V. | Murbach, L. D. | Leite, M. A. | Osaku, E. F. | Costa, C. R. L. M. | Pelenz, M. | Neitzke, N. M. | Moraes, M. M. | Jaskowiak, J. L. | Silva, M. M. M. | Zaponi, R. S. | Abentroth, L. R. L. | Ogasawara, S. M. | Jorge, A. C. | Duarte, P. A. D. | Hernández-Sánchez, N. | Sánchez-Hurtado, L. A. | García-Guillen, F. J. | Ñamendys-Silva, S. A. | Maghsoudi, B. | Emami, M. | Khosravi, M. B. | Zand, F. | Tabatabaie, H. R. | Masjedi, M. | Sabetiyan, G. | Mokri, A. | Troubleyn, J. | Diltoer, M. | Jacobs, R. | Nguyen, D. N. | De Waele, E. | De Regt, J. | Honoré, P. M. | Van Gorp, V. | Spapen, H. D. | Contreras, R. S. | Toapanta, N. D. | Moreno, G. | Sabater, J. | Torrado, H. | Gonzalez, M. | Marin, M. | Farigola, E. | Gonzalez, A. | Fernandez, J. | Vera, A. | Gisbert, X. | Juliá, C. | Uya, J. | Corral, L. | Elias-Jones, I. | Gemmell, L. | MacKay, A. | Randall, D. | Adwaney, A. | Blunden, M. | Prowle, J. R. | Kirwan, C. J. | Thomas, N. | Martin, A. | Owen, H. | Darwin, L. | Conway, D. | Atkinson, D. | Sharman, M. | Moore, J. | Barbanti, C. | Amour, J. | Gaudard, P. | Rozec, B. | Mauriat, P. | M’rini, M. | Leger, P. L. | Cambonie, G. | Liet, J. M. | Girard, C. | Laroche, S. | Damas, P. | Assaf, Z. | Loron, G. | Lecourt, L. | Pouard, P. | Randall, D. | Adwaney, A. | Blunden, M. | Prowle, J.R. | Kirwan, C. J. | Kim, S. H. | Na, S. | Kim, J. | Oh, S. Y. | Jung, C. W. | Yoo, S. H. | Min, S. H. | Chung, E. J. | Lee, H. | Lee, N. J. | Lee, K. W. | Suh, K. S. | Ryu, H. G. | Marshall, D. C. | Goodson, R. J. | Salciccioli, J. D. | Shalhoub, J. | Potter, E. K. | Kirk-Bayley, J. | Karanjia, N. D. | Forni, L. G. | Creagh-Brown, B. C. | Bossy, M. | Nyman, M. | Tailor, A. | Creagh-Brown, B. | D’Antini, D. | Spadaro, S. | Valentino, F. | Sollitto, F. | Cinnella, G. | Mirabella, L. | Calvo, F. J. Redondo | Bejarano, N. | Padilla, D. | Baladron, V. | Villajero, P. | Villazala, R. | Redondo, J. | Yuste, A. S. | Liu, J. | Shen, F. | Teboul, J. L. | Anguel, N. | Beurton, A. | Bezaz, N. | Richard, C. | Monnet, X. | Fossali, T. | Colombo, R. | Ottolina, D. | Rossetti, M. | Mazzucco, C. | Marchi, A. | Porta, A. | Catena, E. | Tollisen, K. H. | Andersen, G. Ø. | Heyerdahl, F. | Jacobsen, D. | de Waard, M. C. | Girbes, A. R. J. | van IJzendoorn, M. C. O. | Buter, H. | Kingma, W. P. | Navis, G. J. | Boerma, E. C. | Rulisek, J. | Balik, M. | Zacharov, S. | Kim, H. S. | Jeon, S. J. | Namgung, H. | Lee, E. | Lee, E. | Cho, Y. J. | Lee, Y. J. | Huang, A. | Cioccari, L. | Luethi, N. | Mårtensson, J. | Bellomo, R. | Forsberg, M. | Edman, G. | Höjer, J. | Forsberg, S. | Freile, M. T. Chiquito | Hidalgo, F. N. | Molina, J. A. Martinez | Lecumberri, R. | Rosselló, A. Figuerola | Travieso, P. Medrano | Leon, G. Tuero | Sanchez, J. Gonzalez | Frias, L. Sahuquillo | Rosello, D. Balsells | Verdejo, J. A. Garcia | Serrano, J. A. Noria | Winterwerp, D. | van Galen, T. | Vazin, A. | Karimzade, I. | Zand, A. | Ozen, E. | Ekemen, S. | Akcan, A. | Sen, E. | Yelken, B. Buyukkidan | Kureshi, N. | Fenerty, L. | Thibault-Halman, G. | Erdogan, M. | Walling, S. | Green, R. S. | Clarke, D. B. | Briassoulis, P. | Kalimeris, K. | Ntzouvani, A. | Nomikos, T. | Papaparaskeva, K. | Politi, E. | Kostopanagiotou, G. | Crewdson, K. | Rehn, M. | Weaver, A. | Brohi, K. | Lockey, D. | Wright, S. | Thomas, K. | Baker, C. | Mansfield, L. | Stafford, V. | Wade, C. | Watson, G. | Bryant, A. | Chadwick, T. | Shen, J. | Wilkinson, J. | Furneval, J. | Henderson, A. | Hugill, K. | Howard, P. | Roy, A. | Bonner, S. | Baudouin, S. | Ramírez, C. Sánchez | Escalada, S. Hípola | Viera, M. A. Hernández | Santana, M. Cabrera | Balcázar, L. Caipe | Monroy, N. Sangil | Campelo, F. Artiles | Vázquez, C. F. Lübbe | Santana, P. Saavedra | Santana, S. Ruiz | Carteron, L. | Patet, C. | Quintard, H. | Solari, D. | Bouzat, P. | Oddo, M. | Wollersheim, T. | Malleike, J. | Haas, K. | Carbon, N. | Schneider, J. | Birchmeier, C. | Fielitz, J. | Spuler, S. | Weber-Carstens, S. | Enseñat, L. | Pérez-Madrigal, A. | Saludes, P. | Proença, L. | Gruartmoner, G. | Espinal, C. | Mesquida, J. | Huber, W. | Eckmann, M. | Elkmann, F. | Gruber, A. | Lahmer, T. | Mayr, U. | Herner, A. | Schellnegger, R. | Schneider, J. | Schmid, R. M. | Ayoub, W. | Samy, W. | Esmat, A. | Battah, A. | Mukhtar, S. | Mongkolpun, W. | Cortés, D. Orbegozo | Cordeiro, C. P. R. | Vincent, J. L. | Creteur, J. | Funcke, S. | Groesdonk, H. | Saugel, B. | Wagenpfeil, G. | Wagenpfeil, S. | Reuter, D. A. | Fernandez, M. M. | Fernandez, R. | Magret, M. | González-Castro, A. | Bouza, M. T. | Ibañez, M. | García, C. | Balerdi, B. | Mas, A. | Arauzo, V. | Añón, J. M. | Ruiz, F. | Ferreres, J. | Tomás, R. | Alabert, M. | Tizón, A. I. | Altaba, S. | Llamas, N. | Goligher, E C. | Fan, E. | Herridge, M. | Vorona, S. | Sklar, M. | Dres, M. | Rittayamai, N. | Lanys, A. | Urrea, C. | Tomlinson, G. | Reid, W. D. | Rubenfeld, G. D. | Kavanagh, B. P. | Brochard, L. J. | Ferguson, N. D. | Neto, A. Serpa | de Abreu, M. Gama | Pelosi, P. | Schultz, M. J. | Guérin, C. | Papazian, L. | Reignier, J. | Ayzac, L. | Loundou, A. | Forel, J. M. | Rolland-Debord, C. | Bureau, C. | Poitou, T. | Clavel, M. | Perbet, S. | Terzi, N. | Kouatchet, A. | Similowski, T. | Demoule, A. | Hunfeld, N. | Trogrlic, Z. | Ladage, S. | Osse, R. J. | Koch, B. | Rietdijk, W. | Devlin, J. | van der Jagt, M. | Picetti, E. | Ceccarelli, P. | Mensi, F. | Malchiodi, L. | Risolo, S. | Rossi, I. | Antonini, M. V. | Servadei, F. | Caspani, M. L. | Roquilly, A. | Lasocki, S. | Seguin, P. | Geeraerts, T. | Perrigault, P. F. | Dahyot-Fizelier, C. | Paugam-Burtz, C. | Cook, F. | Cinotti, R. | dit Latte, D. Demeure | Mahe, P. J. | Fortuit, C. | Feuillet, F. | Asehnoune, K. | Marzorati, C. | Spina, S. | Scaravilli, V. | Vargiolu, A. | Riva, M. | Giussani, C. | Sganzerla, E. | Citerio, G. | Barbadillo, S. | de Molina, F. J. González | Álvarez-Lerma, F. | Rodríguez, A. | Zakharkina, T. | Martin-Loeches, I. | Matamoros, S. | Povoa, P. | Torres, A. | Kastelijn, J. | Hofstra, J. J. | de Jong, M. | Schultz, M. | Sterk, P. | Artigas, A. | Bos, L. J. | Moreau, A. S. | Martin-Loeches, I. | Povoa, P. | Salluh, J. | Rodriguez, A. | Nseir, S. | de Jong, E. | van Oers, J. A. | Beishuizen, A. | Girbes, A. R. J. | Nijsten, M. W. N. | de Lange, D. W. | Bonvicini, D. | Labate, D. | Benacchio, L. | Olivieri, A. | Pizzirani, E. | Lopez-Delgado, J. C. | Gonzalez-Romero, M. | Fuentes-Mila, V. | Berbel-Franco, D. | Romera-Peregrina, I. | Martinez-Pascual, A. | Perez-Sanchez, J. | Abellan-Lencina, R. | Ávila-Espinoza, R. E. | Moreno-Gonzalez, G. | Sbraga, F. | Griffiths, S. | Grocott, M. P. W. | Creagh-Brown, B. | Doyle, J. | Wilkerson, P. | Soon, Y. | Huddart, S. | Dickinson, M. | Riga, A. | Zuleika, A. | Miyamoto, K. | Kawazoe, Y. | Morimoto, T. | Yamamoto, T. | Fuke, A. | Hashimoto, A. | Koami, H. | Beppu, S. | Katayama, Y. | Ito, M. | Ohta, Y. | Yamamura, H. | Rygård, S. L. | Holst, L B. | Wetterslev, J. | Johansson, P. I. | Perner, A. | Soliman, I. W. | de Lange, D. W. | van Dijk, D. | van Delden, J. J. M. | Cremer, O. L. | Slooter, A. J. C. | Peelen, L. M. | McWilliams, D. | Snelson, C. | Neves, A. Das | Loudet, C. I. | Busico, M. | Vazquez, D. | Villalba, D. | Veronesi, M. | Lischinsky, A. | López, F. J. L. | Mori, L. Benito | Plotnikow, G. | Díaz, A. | Giannasi, S. | Hernandez, R. | Krzisnik, L. | Cecotti, C. | Viola, L. | Lopez, R. | Sottile, J. P. | Benavent, G. | Estenssoro, E. | Chen, C. M. | Lai, C. C. | Cheng, K. C. | Chou, W. | Chan, K. S. | Roeker, L. E. | Horkan, C. M. | Gibbons, F. K. | Christopher, K. B. | Weijs, P. J. M. | Mogensen, K. M. | Rawn, J. D. | Robinson, M. K. | Christopher, K. B. | Tang, Z. | Qiu, C. | Ouyang, B. | Cai, C. | Guan, X. | Regueira, T. | Cea, L. | Carlos, S. Juan | Elisa, B. | Puebla, C. | Vargas, A. | Poulsen, M. K. | Thomsen, L. P. | Kjærgaard, S. | Rees, S. E. | Karbing, D. S. | Wollersheim, T. | Frank, S. | Müller, M. C. | Carbon, N. M. | Skrypnikov, V. | Pickerodt, P. A. | Falk, R. | Mahlau, A. | Weber-Carstens, S. | Lee, A. | Inglis, R. | Morgan, R. | Barker, G. | Kamata, K. | Abe, T. | Saitoh, D. | Tokuda, Y. | Green, R. S. | Butler, M. B. | Erdogan, M. | Hwa, H. Tae | Gil, L. Jae | Vaquero, R. Hernández | Rodriguez-Ruiz, E. | Lago, A. Lopez | Allut, J. L. Garcia | Gestal, A. Estany | Gonzalez, M. A. Garcia | Thomas-Rüddel, D. O. | Schwarzkopf, D. | Fleischmann, C. | Reinhart, K. | Suwanpasu, S. | Sattayasomboon, Y. | Filho, N. M. Filgueiras | Oliveira, J. C. A. | Ballalai, C. S. | De Lucia, C. V. | Araponga, G. P. | Veiga, L. N. | Silva, C. S. | Garrido, M. E. | Ramos, B. B. | Ricaldi, E. F. | Gomes, S. S. | Gemmell, L. | MacKay, A. | Wright, C. | Docking, R. I. | Doherty, P. | Black, E. | Stenhouse, P. | Plummer, M. P. | Finnis, M. E. | Phillips, L. K. | Kar, P. | Bihari, S. | Biradar, V. | Moodie, S. | Horowitz, M. | Shaw, J. E. | Deane, A. M. | Yatabe, T. | Inoue, S. | Sakaguchi, M. | Egi, M. | Abdelhamid, Y. Ali | Plummer, M. P. | Finnis, M. E. | Phillips, L. K. | Kar, P. | Bihari, S. | Biradar, V. | Moodie, S. | Horowitz, M. | Shaw, J. E. | Deane, A. M. | Hokka, M. | Egi, M. | Mizobuchi, S. | Kar, P. | Plummer, M. | Abdelhamid, Y. Ali | Giersch, E. | Summers, M. | Hatzinikolas, S. | Heller, S. | Chapman, M. | Jones, K. | Horowitz, M. | Deane, A. | Schweizer, R. | Jacquet-Lagreze, M. | Portran, P. | Junot, S. | Allaouchiche, B. | Fellahi, J. L. | Guerci, P. | Ergin, B. | Kapucu, A. | Ince, C. | Cioccari, L. | Luethi, N. | Crisman, M. | Bellomo, R. | Mårtensson, J. | Shinotsuka, C. Righy | Fagnoul, D. | Brasseur, A. | Orbegozo, D. | Vincent, J. L. | Preiser, J. C. | Preiser, J. C. | Lheureux, O. | Thooft, A. | Brimioulle, S. | Vincent, J. L. | Iwasaka, H. | Tahara, S. | Nagamine, M. | Ichigatani, A. | Cabrera, A. Rugerio | Zepeda, E. Monares | Granillo, J. Franco | Sánchez, J. S. Aguirre | Montoya, A. A. Tanaka | Montenegro, A. Pedraza | Blanco, G. A. Gálvez | Robles, C. M. Coronado | Drolz, A. | Horvatits, T. | Roedl, K. | Rutter, K. | Kluge, S. | Funk, G. C. | Schneeweiss, B. | Fuhrmann, V. | Sabetian, G. | Pooresmaeel, F. | Zand, F. | Ghaffaripour, S. | Farbod, A. | Tabei, H. | Taheri, L. | Anandanadesan, R. | Metaxa, V. | Teixeira, C. | Pereira, S. M. | Hernández-Marrero, P. | Carvalho, A. S. | Beckmann, M. | Hartog, C. S. | Schwarzkopf, D. | Raadts, A. | Robertsen, A. | Førde, R. | Skaga, N. O. | Helseth, E. | Honeybul, S. | Ho, K. | Lopez, P. Martinez | Gonzalez, M. Nieto | Ortega, P. Nuevo | Sola, E. Camara | Spasova, T. | de la Torre-Prados, M. V. | Kopecky, O. | Rusinova, K. | Waldauf, P. | Cepeplikova, Z. | Balik, M. | Domínguez, J. Palamidessi | Almudevar, P. Matia | Carmona, S. Alcántara | Muñoz, J. J. Rubio | Castañeda, D. Palacios | Abellán, A. Naharro | Villamizar, P. Rodríguez | Ramos, J. Veganzones | Pérez, L. Pérez | Lucendo, A. Pérez | Ejarque, M. Camós | Estella, A. | Camps, V. Lopez | Martín, M. C. | Masnou, N. | Barbosa, S. | Varela, A. | Palma, I. | Cristina, L. | Nunes, E. | Pereira, I. | Campello, G. | Granja, C. | Pande, R. | Pandey, M. | Varghese, S. | Chanu, M. | Van Dam, M. J. | Ter Braak, E. W. M. T. | Estella, A. | Gracia, M. | Viciana, R. | Recuerda, M. | Fontaiña, L. Perez | Tharmalingam, B. | Kovari, F. | Rose, L. | Mcginlay, M. | Amin, R. | Burns, K. | Connolly, B. | Hart, N. | Jouvet, P. | Katz, S. | Leasa, D. | Mawdsley, C. | Mcauley, D. | Schultz, M. | Blackwood, B. | Denham, S. | Worrall, R. | Arshad, M. | Isherwood, P. | Khadjibaev, A. | Sabirov, D. | Rosstalnaya, A. | Parpibaev, F. | Sharipova, V. | Blanco, G. A. Galvez | Guzman, C. I. Olvera | Sánchez, J. S. Aguirre | Granillo, J. Franco | Gupta, S. | Govil, D. | Srinivasan, S. | Patel, S. J. | N, J. K. | Gupta, A. | Shafi, M. | Tomar, D. S. | Harne, R. | Arora, D. P. | Talwar, N. | Mazumdar, S. | Cha, Y. S. | Lee, S. J. | Tyagi, N. | Rajput, R. K. | Taneja, S. | Singh, V. K. | Sharma, S. C. | Mittal, S. | Rao, B. K. | Ayachi, J. | Fraj, N. | Romdhani, S. | Khedher, A. | Meddeb, K. | Sma, N. | Azouzi, A. | Bouneb, R. | Chouchene, I. | El Ghardallou, M. | Boussarsar, M. | Jennings, R. | Walter, E. | Ribeiro, J. M. | Moniz, I. | Marçal, R. | Santos, A. C. | Candeias, C. | e Silva, Z. Costa | Gomez, S. E. Zamora | Nieto, O. R. Perez | Gonzalez, J. A. Castanon | Cuellar, A. I. Vasquez | Mildh, H. | Pettilä, V. | Korhonen, A. M. | Karlsson, S. | Ala-Kokko, T. | Reinikainen, M. | Vaara, S. T. | Zaleska-Kociecka, M. | Grabowski, M. | Dąbrowski, M. | Wozniak, S. | Piotrowska, K. | Banaszewski, M. | Imiela, J. | Stepinska, J. | Pérez, A. González
doi:10.1186/s40635-016-0099-9
PMCID: PMC5042923
2.  PML/RARα-regulated miR-181a/b-cluster targets the tumor suppressor RASSF1A in Acute Promyelocytic Leukemia 
Cancer research  2015;75(16):3411-3424.
In acute promyelocytic leukemia (APL), all-trans-retinoic acid (ATRA) treatment induces granulocytic maturation and complete remission of leukemia. MicroRNAs are known to be critical players in the formation of the leukemic phenotype. In this study, we report downregulation of the miR-181a/b gene cluster in APL blasts and NB4 leukemia cells upon ATRA treatment as key event in the drug response. We found that miR-181a/b expression was activated by the PML/RARα oncogene in cells and transgenic knock-in mice, an observation confirmed and extended by evidence of enhanced expression of miR-181a/b in APL patient specimens. RNAi-mediated attenuation of miR-181a/b expression in NB4 cells was sufficient to reduce colony forming capacity, proliferation and survival. Mechanistic investigations revealed that miR-181a/b targets the ATRA-regulated tumor suppressor gene RASSF1A by direct binding to its 3′UTR. Enforced expression of miR-181a/b or RNAi-mediated attenuation of RASSF1A inhibited ATRA-induced granulocytic differentiation via regulation of the cell cycle regulator cyclin D1. Conversely, RASSF1A overexpression enhanced apoptosis. Lastly, RASSF1A levels were reduced in PML/RARα knock-in mice and APL patient samples. Taken together, our results define miR-181a and miR-181b as oncomiRs in PML/RARα-associated APL, and they reveal RASSF1A as a pivotal element in the granulocytic differentiation program induced by ATRA in APL.
doi:10.1158/0008-5472.CAN-14-3521
PMCID: PMC4537849  PMID: 26041820
3.  Single-shot diffraction data from the Mimivirus particle using an X-ray free-electron laser 
Scientific Data  2016;3:160060.
Free-electron lasers (FEL) hold the potential to revolutionize structural biology by producing X-ray pules short enough to outrun radiation damage, thus allowing imaging of biological samples without the limitation from radiation damage. Thus, a major part of the scientific case for the first FELs was three-dimensional (3D) reconstruction of non-crystalline biological objects. In a recent publication we demonstrated the first 3D reconstruction of a biological object from an X-ray FEL using this technique. The sample was the giant Mimivirus, which is one of the largest known viruses with a diameter of 450 nm. Here we present the dataset used for this successful reconstruction. Data-analysis methods for single-particle imaging at FELs are undergoing heavy development but data collection relies on very limited time available through a highly competitive proposal process. This dataset provides experimental data to the entire community and could boost algorithm development and provide a benchmark dataset for new algorithms.
doi:10.1038/sdata.2016.60
PMCID: PMC4968188  PMID: 27479754
Biological physics; Virus structures; X-rays
4.  NF-κB/STAT5/miR-155 network targets PU.1 in FLT3-ITD-driven acute myeloid leukemia 
Leukemia  2014;29(3):535-547.
Almost 30% of all acute myeloid leukemias (AML) are associated with an internal tandem duplication (ITD) in the juxtamembrane domain of FMS-like tyrosine kinase 3 receptor (FLT3). Patients with FLT3-ITD mutations tend to have a poor prognosis. MicroRNAs (miRNAs) have a pivotal role in myeloid differentiation and leukemia. MiRNA-155 (MiR-155) was found to be upregulated in FLT3-ITD-associated AMLs. In this study, we discovered that FLT3-ITD signaling induces the oncogenic miR-155. We show in vitro and in vivo that miR-155 expression is regulated by FLT3-ITD downstream targets nuclear factor-κB (p65) and signal transducer and activator of transcription 5 (STAT5). Further, we demonstrate that miR-155 targets the myeloid transcription factor PU.1. Knockdown of miR-155 or overexpression of PU.1 blocks proliferation and induces apoptosis of FLT3-ITD-associated leukemic cells. Our data demonstrate a novel network in which FLT3-ITD signaling induces oncogenic miR-155 by p65 and STAT5 in AML, thereby targeting transcription factor PU.1.
doi:10.1038/leu.2014.231
PMCID: PMC4490787  PMID: 25092144
5.  The Effect of UV-C Pasteurization on Bacteriostatic Properties and Immunological Proteins of Donor Human Milk 
PLoS ONE  2013;8(12):e85867.
Background
Human milk possesses bacteriostatic properties, largely due to the presence of immunological proteins. Heat treatments such as Holder pasteurization reduce the concentration of immunological proteins in human milk and consequently increase the bacterial growth rate. This study investigated the bacterial growth rate and the immunological protein concentration of ultraviolet (UV-C) irradiated, Holder pasteurized and untreated human milk.
Methods
Samples (n=10) of untreated, Holder pasteurized and UV-C irradiated human milk were inoculated with E. coli and S. aureus and the growth rate over 2 hours incubation time at 37°C was observed. Additionally, the concentration of sIgA, lactoferrin and lysozyme of untreated and treated human milk was analyzed.
Results
The bacterial growth rate of untreated and UV-C irradiated human milk was not significantly different. The bacterial growth rate of Holder pasteurized human milk was double compared to untreated human milk (p<0.001). The retention of sIgA, lactoferrin and lysozyme after UV-C irradiation was 89%, 87%, and 75% respectively, which were higher than Holder treated with 49%, 9%, and 41% respectively.
Conclusion
UV-C irradiation of human milk preserves significantly higher levels of immunological proteins than Holder pasteurization, resulting in bacteriostatic properties similar to those of untreated human milk.
doi:10.1371/journal.pone.0085867
PMCID: PMC3871660  PMID: 24376898
6.  Radiation damage in protein serial femtosecond crystallography using an x-ray free-electron laser 
X-ray free-electron lasers deliver intense femtosecond pulses that promise to yield high resolution diffraction data of nanocrystals before the destruction of the sample by radiation damage. Diffraction intensities of lysozyme nanocrystals collected at the Linac Coherent Light Source using 2 keV photons were used for structure determination by molecular replacement and analyzed for radiation damage as a function of pulse length and fluence. Signatures of radiation damage are observed for pulses as short as 70 fs. Parametric scaling used in conventional crystallography does not account for the observed effects.
doi:10.1103/PhysRevB.84.214111
PMCID: PMC3786679  PMID: 24089594
7.  Self-terminating diffraction gates femtosecond X-ray nanocrystallography measurements 
Nature photonics  2011;6:35-40.
X-ray free-electron lasers have enabled new approaches to the structural determination of protein crystals that are too small or radiation-sensitive for conventional analysis1. For sufficiently short pulses, diffraction is collected before significant changes occur to the sample, and it has been predicted that pulses as short as 10 fs may be required to acquire atomic-resolution structural information1–4. Here, we describe a mechanism unique to ultrafast, ultra-intense X-ray experiments that allows structural information to be collected from crystalline samples using high radiation doses without the requirement for the pulse to terminate before the onset of sample damage. Instead, the diffracted X-rays are gated by a rapid loss of crystalline periodicity, producing apparent pulse lengths significantly shorter than the duration of the incident pulse. The shortest apparent pulse lengths occur at the highest resolution, and our measurements indicate that current X-ray free-electron laser technology5 should enable structural determination from submicrometre protein crystals with atomic resolution.
doi:10.1038/nphoton.2011.297
PMCID: PMC3783007  PMID: 24078834
8.  Ultraviolet-C Irradiation: A Novel Pasteurization Method for Donor Human Milk 
PLoS ONE  2013;8(6):e68120.
Background
Holder pasteurization (milk held at 62.5°C for 30 minutes) is the standard treatment method for donor human milk. Although this method of pasteurization is able to inactivate most bacteria, it also inactivates important bioactive components. Therefore, the objective of this study was to investigate ultraviolet irradiation as an alternative treatment method for donor human milk.
Methods
Human milk samples were inoculated with five species of bacteria and then UV-C irradiated. Untreated and treated samples were analysed for bacterial content, bile salt stimulated lipase (BSSL) activity, alkaline phosphatase (ALP) activity, and fatty acid profile.
Results
All five species of bacteria reacted similarly to UV-C irradiation, with higher dosages being required with increasing concentrations of total solids in the human milk sample. The decimal reduction dosage was 289±17 and 945±164 J/l for total solids of 107 and 146 g/l, respectively. No significant changes in the fatty acid profile, BSSL activity or ALP activity were observed up to the dosage required for a 5-log10 reduction of the five species of bacteria.
Conclusion
UV-C irradiation is capable of reducing vegetative bacteria in human milk to the requirements of milk bank guidelines with no loss of BSSL and ALP activity and no change of FA.
doi:10.1371/journal.pone.0068120
PMCID: PMC3694044  PMID: 23840820
9.  Analysis of Transcriptional Regulation of the Human miR-17-92 Cluster; Evidence for Involvement of Pim-1 
The human polycistronic miRNA cluster miR-17-92 is frequently overexpressed in hematopoietic malignancies and cancers. Its transcription is in part controlled by an E2F-regulated host gene promoter. An intronic A/T-rich region directly upstream of the miRNA coding region also contributes to cluster expression. Our deletion analysis of the A/T-rich region revealed a strong dependence on c-Myc binding to the functional E3 site. Yet, constructs lacking the 5′-proximal ~1.3 kb or 3′-distal ~0.1 kb of the 1.5 kb A/T-rich region still retained residual specific promoter activity, suggesting multiple transcription start sites (TSS) in this region. Furthermore, the protooncogenic kinase, Pim-1, its phosphorylation target HP1γ and c-Myc colocalize to the E3 region, as inferred from chromatin immunoprecipitation. Analysis of pri-miR-17-92 expression levels in K562 and HeLa cells revealed that silencing of E2F3, c-Myc or Pim-1 negatively affects cluster expression, with a synergistic effect caused by c-Myc/Pim-1 double knockdown in HeLa cells. Thus, we show, for the first time, that the protooncogene Pim-1 is part of the network that regulates transcription of the human miR-17-92 cluster.
doi:10.3390/ijms140612273
PMCID: PMC3709785  PMID: 23749113
miRNA; miR-17-92 cluster; Pim-1; miRNA promoter; c-Myc; HP1γ; RNAi
10.  Time-resolved protein nanocrystallography using an X-ray free-electron laser 
Aquila, Andrew | Hunter, Mark S. | Doak, R. Bruce | Kirian, Richard A. | Fromme, Petra | White, Thomas A. | Andreasson, Jakob | Arnlund, David | Bajt, Saša | Barends, Thomas R. M. | Barthelmess, Miriam | Bogan, Michael J. | Bostedt, Christoph | Bottin, Hervé | Bozek, John D. | Caleman, Carl | Coppola, Nicola | Davidsson, Jan | DePonte, Daniel P. | Elser, Veit | Epp, Sascha W. | Erk, Benjamin | Fleckenstein, Holger | Foucar, Lutz | Frank, Matthias | Fromme, Raimund | Graafsma, Heinz | Grotjohann, Ingo | Gumprecht, Lars | Hajdu, Janos | Hampton, Christina Y. | Hartmann, Andreas | Hartmann, Robert | Hau-Riege, Stefan | Hauser, Günter | Hirsemann, Helmut | Holl, Peter | Holton, James M. | Hömke, André | Johansson, Linda | Kimmel, Nils | Kassemeyer, Stephan | Krasniqi, Faton | Kühnel, Kai-Uwe | Liang, Mengning | Lomb, Lukas | Malmerberg, Erik | Marchesini, Stefano | Martin, Andrew V. | Maia, Filipe R.N.C. | Messerschmidt, Marc | Nass, Karol | Reich, Christian | Neutze, Richard | Rolles, Daniel | Rudek, Benedikt | Rudenko, Artem | Schlichting, Ilme | Schmidt, Carlo | Schmidt, Kevin E. | Schulz, Joachim | Seibert, M. Marvin | Shoeman, Robert L. | Sierra, Raymond | Soltau, Heike | Starodub, Dmitri | Stellato, Francesco | Stern, Stephan | Strüder, Lothar | Timneanu, Nicusor | Ullrich, Joachim | Wang, Xiaoyu | Williams, Garth J. | Weidenspointner, Georg | Weierstall, Uwe | Wunderer, Cornelia | Barty, Anton | Spence, John C. H. | Chapman, Henry N.
Optics Express  2012;20(3):2706-2716.
We demonstrate the use of an X-ray free electron laser synchronized with an optical pump laser to obtain X-ray diffraction snapshots from the photoactivated states of large membrane protein complexes in the form of nanocrystals flowing in a liquid jet. Light-induced changes of Photosystem I-Ferredoxin co-crystals were observed at time delays of 5 to 10 µs after excitation. The result correlates with the microsecond kinetics of electron transfer from Photosystem I to ferredoxin. The undocking process that follows the electron transfer leads to large rearrangements in the crystals that will terminally lead to the disintegration of the crystals. We describe the experimental setup and obtain the first time-resolved femtosecond serial X-ray crystallography results from an irreversible photo-chemical reaction at the Linac Coherent Light Source. This technique opens the door to time-resolved structural studies of reaction dynamics in biological systems.
doi:10.1364/OE.20.002706
PMCID: PMC3413412  PMID: 22330507
(170.7160) Ultrafast technology; (170.7440) X-ray imaging; (140.3450) Laser-induced chemistry; (140.7090) Ultrafast lasers; (170.0170) Medical optics and biotechnology
11.  Lipidic phase membrane protein serial femtosecond crystallography 
Nature methods  2012;9(3):263-265.
X-ray free electron laser (X-feL)-based serial femtosecond crystallography is an emerging method with potential to rapidly advance the challenging field of membrane protein structural biology. here we recorded interpretable diffraction data from micrometer-sized lipidic sponge phase crystals of the Blastochloris viridis photosynthetic reaction center delivered into an X-feL beam using a sponge phase micro-jet.
doi:10.1038/nmeth.1867
PMCID: PMC3438231  PMID: 22286383
12.  In vivo protein crystallization opens new routes in structural biology 
Nature methods  2012;9(3):259-262.
Protein crystallization in cells has been observed several times in nature. However, owing to their small size these crystals have not yet been used for X-ray crystallographic analysis. We prepared nano-sized in vivo–grown crystals of Trypanosoma brucei enzymes and applied the emerging method of free-electron laser-based serial femtosecond crystallography to record interpretable diffraction data. This combined approach will open new opportunities in structural systems biology.
doi:10.1038/nmeth.1859
PMCID: PMC3429599  PMID: 22286384
13.  Time-resolved protein nanocrystallography using an X-ray free-electron laser 
Aquila, Andrew | Hunter, Mark S | Bruce Doak, R. | Kirian, Richard A. | Fromme, Petra | White, Thomas A. | Andreasson, Jakob | Arnlund, David | Bajt, Saša | Barends, Thomas R. M. | Barthelmess, Miriam | Bogan, Michael J. | Bostedt, Christoph | Bottin, Hervé | Bozek, John D. | Caleman, Carl | Coppola, Nicola | Davidsson, Jan | DePonte, Daniel P. | Elser, Veit | Epp, Sascha W. | Erk, Benjamin | Fleckenstein, Holger | Foucar, Lutz | Frank, Matthias | Fromme, Raimund | Graafsma, Heinz | Grotjohann, Ingo | Gumprecht, Lars | Hajdu, Janos | Hampton, Christina Y. | Hartmann, Andreas | Hartmann, Robert | Hau-Riege, Stefan | Hauser, Günter | Hirsemann, Helmut | Holl, Peter | Holton, James M. | Hömke, André | Johansson, Linda | Kimmel, Nils | Kassemeyer, Stephan | Krasniqi, Faton | Kühnel, Kai-Uwe | Liang, Mengning | Lomb, Lukas | Malmerberg, Erik | Marchesini, Stefano | Martin, Andrew V. | Maia, Filipe R.N.C. | Messerschmidt, Marc | Nass, Karol | Reich, Christian | Neutze, Richard | Rolles, Daniel | Rudek, Benedikt | Rudenko, Artem | Schlichting, Ilme | Schmidt, Carlo | Schmidt, Kevin E. | Schulz, Joachim | Seibert, M. Marvin | Shoeman, Robert L. | Sierra, Raymond | Soltau, Heike | Starodub, Dmitri | Stellato, Francesco | Stern, Stephan | Strüder, Lothar | Timneanu, Nicusor | Ullrich, Joachim | Wang, Xiaoyu | Williams, Garth J. | Weidenspointner, Georg | Weierstall, Uwe | Wunderer, Cornelia | Barty, Anton | Spence, John C. H | Chapman, Henry N.
Optics express  2012;20(3):2706-2716.
We demonstrate the use of an X-ray free electron laser synchronized with an optical pump laser to obtain X-ray diffraction snapshots from the photoactivated states of large membrane protein complexes in the form of nanocrystals flowing in a liquid jet. Light-induced changes of Photosystem I-Ferredoxin co-crystals were observed at time delays of 5 to 10 μs after excitation. The result correlates with the microsecond kinetics of electron transfer from Photosystem I to ferredoxin. The undocking process that follows the electron transfer leads to large rearrangements in the crystals that will terminally lead to the disintegration of the crystals. We describe the experimental setup and obtain the first time-resolved femtosecond serial X-ray crystallography results from an irreversible photo-chemical reaction at the Linac Coherent Light Source. This technique opens the door to time-resolved structural studies of reaction dynamics in biological systems.
PMCID: PMC3413412  PMID: 22330507
14.  Automatic retrieval of single microchimeric cells and verification of identity by on-chip multiplex PCR 
Abstract
The analysis of rare cells is not an easy task. This is especially true when cells representing a fetal microchimerism are to be utilized for the purpose of non-invasive prenatal diagnosis because it is both imperative and difficult to avoid contaminating the minority of fetal cells with maternal ones. Under these conditions, even highly specific biochemical markers are not perfectly reliable. We have developed a method to verify the genomic identity of rare cells that combines automatic screening for enriched target cells (based on immunofluorescence labelling) with isolation of single candidate microchimeric cells (by laser microdissection and subsequent laser catapulting) and low-volume on-chip multiplex PCR for DNA fingerprint analysis. The power of the method was tested using samples containing mixed cells of related and non-related individuals. Single-cell DNA fingerprinting was successful in 74% of the cells analysed (55/74), with a PCR efficiency of 59.2% (860/1452) for heterozygous loci. The identification of cells by means of DNA profiling was achieved in 100% (12/12) of non-related cells in artificial mixtures and in 86% (37/43) of cells sharing a haploid set of chromosomes and was performed on cells enriched from blood and cells isolated from tissue. We suggest DNA profiling as a standard for the identification of microchimerism on a single-cell basis.
doi:10.1111/j.1582-4934.2009.00784.x
PMCID: PMC3823127  PMID: 19453769
microchimerism; prenatal diagnosis; rare cell analysis; single-cell PCR
15.  Analysis of Plasmacytoid and Myeloid Dendritic Cells in Nasal Epithelium▿  
Clinical and Vaccine Immunology  2006;13(11):1278-1286.
The role of plasmacytoid dendritic cells (PDC), the major producers of alpha interferon upon viral infection, in the nasal mucosa is largely unknown. Here we examined the presence of PDC together with myeloid dendritic cells (MDC) in the nasal epithelia of healthy individuals, of asymptomatic patients with chronic nasal allergy, of patients undergoing steroid therapy, and of patients with infectious rhinitis or rhinosinusitis. Considerable numbers of PDC and MDC could be detected in the nasal epithelium. Furthermore, we demonstrate the expression of SDF-1, the major chemoattractant for PDC, in the nasal epithelium. PDC levels were significantly lower for patients with allergies than for healthy individuals. Interestingly, PDC and MDC were almost absent from patients who received treatment with glucocorticoids, while very high numbers of PDC were found for patients with recent upper respiratory tract infections. Our results demonstrate for the first time a quantitative analysis of PDC and MDC in the healthy nasal epithelium and in nasal epithelia from patients with different pathological conditions. With the identification of PDC, the major target cell for CpG DNA or immunostimulatory RNA, in the nasal epithelium, this study forms the basis for a local nasal application of such oligonucleotides for the treatment of viral infection and allergy.
doi:10.1128/CVI.00172-06
PMCID: PMC1656540  PMID: 16928885
17.  Active syphilis in HIV infection: a multicentre retrospective survey. The German AIDS Study Group (GASG). 
Genitourinary Medicine  1996;72(3):176-181.
OBJECTIVE: To study syphilis in HIV infection focusing on immunocompromised patients with an atypical or aggressive clinical course of syphilis, inappropriate serological reactions or an unreliable response to therapy. STUDY DESIGN: A multicentre retrospective chart review using a standardised questionnaire for all patients with active syphilis. SETTINGS: Thirteen dermatological and medical centres throughout Germany, all members of the German AIDS Study Group (GASG). PATIENTS: Clinical data of 11,368 HIV infected patients have been analysed for cases of active syphilis requiring treatment. Asymptotic patients with reactive serological parameters indicating latent syphilis without a need for treatment were excluded. RESULTS: Active syphilis was reported in 151 of 11,368 HIV infected patients (1.33%, range per centre 0.3%-5.1%). Most of the 151 syphilis patients were male (93%) and belonged to the homosexual or bisexual exposure category for HIV infection (79%); another 6% were iv drug users. Among the 151 syphilis patients primary syphilis was diagnosed in 17.2%, maculopapular secondary syphilis in 29.1%, ulcerating secondary syphilis in 7.3%, neurosyphilis in 16.6% and latent seropositive syphilis without clinical symptoms but serological abnormalities indicating active syphilis in 25.2%. A history of prior treatments for syphilis was reported in 50%. At the time of syphilis diagnosis 26.5% of the patients were in CDC stage II, 33.8% in stage III and 24.5% in stage IV of HIV disease (CDC classification 1987). CD4 cell count was lowest in those with ulcerating secondary syphilis (mean 307, SD 140/microliters) and neurosyphilis (351, SD 235/ microliters). The highest CD4 count was found in patients with early primary and early secondary syphilis (444, SD 163/microliters and 470, SD 355/microliters). Inappropriate serological response to syphilis infection was found in 81 of 151 patients (54%). Remarkable findings were false negative VDRL titres (11 patients with non primary syphilis), false negative TPHA (1) or 19S-IgM-FTA-ABS-tests (16), and strongly reactive VDRL (> or = 512, 8) or TPHA titres (> or = 10 240, 47). Treatment failures were reported in at least 6 of 151 cases (4%). CONCLUSIONS: Atypical clinical and serological courses of syphilis were observed in HIV infected patients. Ulcerating secondary syphilis with general symptoms ("malignant syphilis") was 60 times more frequent than in historic syphilis series. Neurosyphilis was found in one sixth of those with active syphilis. Therefore lumbar puncture should be considered a routine in coinfections with HIV and syphilis. Treatment efficacy should be monitored carefully.
Images
PMCID: PMC1195645  PMID: 8707318
19.  N‐terminally and C‐terminally truncated forms of glucose‐dependent insulinotropic polypeptide are high‐affinity competitive antagonists of the human GIP receptor 
British Journal of Pharmacology  2016;173(5):826-838.
Background and Purpose
Glucose‐dependent insulinotropic polypeptide (GIP) affects lipid, bone and glucose homeostasis. High‐affinity ligands for the GIP receptor are needed to elucidate the physiological functions and pharmacological potential of GIP in vivo. GIP(1–30)NH2 is a naturally occurring truncation of GIP(1–42). Here, we have characterized eight N‐terminal truncations of human GIP(1–30)NH2.
Experimental Approach
COS‐7 cells were transiently transfected with human GIP receptors and assessed for cAMP accumulation upon ligand stimulation or competition binding with 125I‐labelled GIP(1–42), GIP(1–30)NH2, GIP(2–30)NH2 or GIP(3–30)NH2.
Key Results
GIP(1–30)NH2 displaced 125I‐GIP(1–42) as effectively as GIP(1–42) (Ki 0.75 nM), whereas the eight truncations displayed lower affinities (Ki 2.3–347 nM) with highest affinities for GIP(3–30)NH2 and GIP(5–30)NH2 (5–30)NH2. Only GIP(1–30)NH2 (Emax 100% of GIP(1–42)) and GIP(2–30)NH2 (Emax 20%) were agonists. GIP(2‐ to 9–30)NH2 displayed antagonism (IC50 12–450 nM) and Schild plot analyses identified GIP(3–30)NH2 and GIP(5–30)NH2 as competitive antagonists (Ki 15 nM). GIP(3–30) NH2 was a 26‐fold more potent antagonist than GIP(3–42). Binding studies with agonist (125I‐GIP(1–30)NH2), partial agonist (125I‐GIP(2–30)NH2) and competitive antagonist (125I‐GIP(3–30)NH2) revealed distinct receptor conformations for these three ligand classes.
Conclusions and Implications
The N‐terminus is crucial for GIP agonist activity. Removal of the C‐terminus of the endogenous GIP(3–42) creates another naturally occurring, more potent, antagonist GIP(3–30)NH2, which like GIP(5–30)NH2, was a high‐affinity competitive antagonist. These peptides may be suitable tools for basic GIP research and future pharmacological interventions.
doi:10.1111/bph.13384
PMCID: PMC4761099  PMID: 26572091
20.  Neurodevelopmental outcome at two years of age after general and awake-regional anaesthesia in infancy: a randomised controlled trial 
Lancet (London, England)  2015;387(10015):239-250.
Summary
Background
There is pre-clinical evidence that general anaesthetics affect brain development. There is mixed evidence from cohort studies that young children exposed to anaesthesia may have an increased risk of poorer neurodevelopmental outcome. This trial aims to determine if GA in infancy has any impact on neurodevelopmental outcome. The primary outcome for the trial is neurodevelopmental outcome at 5 years of age. The secondary outcome is neurodevelopmental outcome at two years of age and is reported here.
Methods
We performed an international assessor-masked randomised controlled equivalence trial in infants less than 60 weeks post-menstrual age, born at greater than 26 weeks gestational age having inguinal herniorrhaphy. Infants were excluded if they had existing risk factors for neurologic injury. Infants were randomly assigned to awake-regional (RA) or sevoflurane-based general anaesthesia (GA). Web-based randomisation was performed in blocks of two or four and stratified by site and gestational age at birth. The outcome for analysis was the composite cognitive score of the Bayley Scales of Infant and Toddler Development, Third Edition. The analysis was as-per-protocol adjusted for gestational age at birth. A difference in means of five points (1/3 SD) was predefined as the clinical equivalence margin. The trial was registered at ANZCTR, ACTRN12606000441516 and ClinicalTrials.gov, NCT00756600.
Findings
Between February 2007, and January 2013, 363 infants were randomised to RA and 359 to GA. Outcome data were available for 238 in the RA and 294 in the GA arms. The median duration of anaesthesia in the GA arm was 54 minutes. For the cognitive composite score there was equivalence in means between arms (RA-GA: +0·169, 95% CI −2·30 to +2·64).
Interpretation
For this secondary outcome we found no evidence that just under an hour of sevoflurane anaesthesia in infancy increases the risk of adverse neurodevelopmental outcome at two years of age compared to RA.
doi:10.1016/S0140-6736(15)00608-X
PMCID: PMC5023520  PMID: 26507180
21.  PD-1 blunts the function of ovarian tumor-infiltrating dendritic cells by inactivating NF-κB 
Cancer research  2015;76(2):239-250.
The PD-1:PD-L1 immune signaling axis mediates suppression of T cell-dependent tumor immunity. PD-1 expression was recently found to be upregulated on tumor-infiltrating murine (CD11c+CD11b+CD8−CD209a+) and human (CD1c+CD19−) myeloid dendritic cells (TIDC), an innate immune cell type also implicated in immune escape. However, there is little knowledge concerning how PD-1 regulates innate immune cells. In the present study, we examined the role of PD-1 in TIDC derived from mice bearing ovarian tumors. Similar to lymphocytes, TIDC expression of pd-1 was associated with expression of the adapter protein SHP-2, which signals to NF-κB, however, in contrast to its role in lymphocytes, we found that expression of PD-1 in TIDC tonically paralyzed NF-kB activation. Further mechanistic investigations showed that PD-1 blocked NF-kB-dependent cytokine release in a SHP-2-dependent manner. Conversely, inhibition of NF-kB-mediated antigen presentation by PD-1 occurred independently of SHP-2. Collectively, our findings revealed that PD-1 acts in a distinct manner in innate immune cells compared to adaptive immune cells, prompting further investigations of the signaling pathways controlled by this central mediator of immune escape in cancer.
doi:10.1158/0008-5472.CAN-15-0748
PMCID: PMC4715980  PMID: 26567141
Tolerance; tumor microenvironment; myeloid cells; MDSCs; immunity
22.  Should patients older than 65 years be offered a second kidney transplant? 
BMC Nephrology  2017;18:13.
Background
Age and number of recipients in need of kidney re-transplantation are increasing. Re-transplantation practices and outcomes in elderly recipients are not previously explored. We aimed to retrospectively evaluate the outcomes of recipients 65 years and older receiving their second deceased donor allograft.
Methods
The study was designed as a retrospective registry based study. All recipients 65 years or older who received a deceased donor kidney transplant at Oslo University Hospital between 2000 and 2014 were included in the study. Survival outcomes were compared between recipients of first (TX1) and second (TX2) allograft. Survival analyses were performed using the Kaplan–Meier method and Cox proportional hazard models with patient survival, uncensored graft survival and death-censored graft survival as outcomes in the analyses.
Results
Seven hundred and thirty-tree recipients > 65 years received a first (n = 687) or second (n = 46) deceased donor kidney transplant. Five years uncensored graft survival rates were 64% in TX 2 and 67% in TX 1 (P= 0.789). Estimated five years graft survival rates censored for death with functioning graft were 88% in TX2 and 90% in TX1 (P=0.475). Adjusted hazard ratio for uncensored graft loss (TX2 vs. TX1) was 1.24 (95% CI 0.77 – 2.00). Adjusted hazard ratio for graft loss censored for death with functioning graft (TX2 vs. TX1) was 1.70 (0.72-4.02).
Conclusions
Older recipients of second transplants have outcomes that are comparable to the outcomes of age-matched first transplant recipients, and far better than previously documented for older transplant candidates remaining on dialysis treatment. Advanced age by itself should not be a contraindication for re-transplantation. Best results are achieved with short time on dialysis before re-transplantation.
doi:10.1186/s12882-016-0426-0
PMCID: PMC5225523  PMID: 28077080
Kidney transplantation; Elderly; Epidemiology; Graft survival; Chronic renal failure
23.  Deficits in reinforcement learning but no link to apathy in patients with schizophrenia 
Scientific Reports  2017;7:40352.
Negative symptoms in schizophrenia have been linked to selective reinforcement learning deficits in the context of gains combined with intact loss-avoidance learning. Fundamental mechanisms of reinforcement learning and choice are prediction error signaling and the precise representation of reward value for future decisions. It is unclear which of these mechanisms contribute to the impairments in learning from positive outcomes observed in schizophrenia. A recent study suggested that patients with severe apathy symptoms show deficits in the representation of expected value. Considering the fundamental relevance for the understanding of these symptoms, we aimed to assess the stability of these findings across studies. Sixty-four patients with schizophrenia and 19 healthy control participants performed a probabilistic reward learning task. They had to associate stimuli with gain or loss-avoidance. In a transfer phase participants indicated valuation of the previously learned stimuli by choosing among them. Patients demonstrated an overall impairment in learning compared to healthy controls. No effects of apathy symptoms on task indices were observed. However, patients with schizophrenia learned better in the context of loss-avoidance than in the context of gain. Earlier findings were thus partially replicated. Further studies are needed to clarify the mechanistic link between negative symptoms and reinforcement learning.
doi:10.1038/srep40352
PMCID: PMC5223142  PMID: 28071747
24.  Intraperitoneal cisplatin and doxorubicin as maintenance chemotherapy for unresectable ovarian cancer: a case report 
BMC Cancer  2017;17:26.
Background
Primary advanced, unresectable ovarian cancer (OC) is treated with palliative systemic chemotherapy. Intraperitoneal chemotherapy may be an alternative local maintenance therapy.
Case presentation
A 75 year old woman with laparoscopically and histologically confirmed unresectable OC was treated with 13 cycles of intraperitoneal cisplatin 7.5 mg/m2 and doxorubicin 1.5 mg/m2 over 2 years using laparoscopic pressurized intraperitoneal aerosol chemotherapy (PIPAC). Objective tumor response (tumor regression on histology, stable disease on repeated video-laparoscopy and peritoneal carcinomatosis index) was noted. No Common Terminology Criteria for Adverse Events (CTCAE) > grade 3 were observed. EORTC QLQ-C30 quality of life measurements were stable throughout the therapy.
Conclusions
Repeated intraperitoneal chemotherapy with cisplatin and doxorubicin applied as PIPAC may be an effective maintenance treatment in women with primary advanced, unresectable OC.
Electronic supplementary material
The online version of this article (doi:10.1186/s12885-016-3004-8) contains supplementary material, which is available to authorized users.
doi:10.1186/s12885-016-3004-8
PMCID: PMC5216537  PMID: 28061769
Ovarian cancer; Intraperitoneal chemotherapy; Maintenance; Peritoneal carcinomatosis; PIPAC; Quality of life; Antineoplastic agents; Adverse effects
25.  Adrenomedullin: a marker of impaired hemodynamics, organ dysfunction, and poor prognosis in cardiogenic shock 
Background
The clinical CardShock risk score, including baseline lactate levels, was recently shown to facilitate risk stratification in patients with cardiogenic shock (CS). As based on baseline parameters, however, it may not reflect the change in mortality risk in response to initial therapies. Adrenomedullin is a prognostic biomarker in several cardiovascular diseases and was recently shown to associate with hemodynamic instability in patients with septic shock. The aim of our study was to evaluate the prognostic value and association with hemodynamic parameters of bioactive adrenomedullin (bio-ADM) in patients with CS.
Methods
CardShock was a prospective, observational, European multinational cohort study of CS. In this sub-analysis, serial plasma bio-ADM and arterial blood lactate measurements were collected from 178 patients during the first 10 days after detection of CS.
Results
Both bio-ADM and lactate were higher in 90-day non-survivors compared to survivors at all time points (P < 0.05 for all). Lactate showed good prognostic value during the initial 24 h (AUC 0.78 at admission and 0.76 at 24 h). Subsequently, lactate returned normal (≤2 mmol/L) in most patients regardless of later outcome with lower prognostic value. By contrast, bio-ADM showed increasing prognostic value from 48 h and beyond (AUC 0.71 at 48 h and 0.80 at 5–10 days). Serial measurements of either bio-ADM or lactate were independent of and provided added value to CardShock risk score (P < 0.001 for both). Ninety-day mortality was more than double higher in patients with high levels of bio-ADM (>55.7 pg/mL) at 48 h compared to those with low bio-ADM levels (49.1 vs. 22.6%, P = 0.001). High levels of bio-ADM were associated with impaired cardiac index, mean arterial pressure, central venous pressure, and systolic pulmonary artery pressure during the study period. Furthermore, high levels of bio-ADM at 48 to 96 h were related to persistently impaired cardiac and end-organ function.
Conclusions
Bio-ADM is a valuable prognosticator and marker of impaired hemodynamics in CS patients. High levels of bio-ADM may show shock refractoriness and developing end-organ dysfunction and thus help to guide therapeutic approach in patients with CS.
Study identifier of CardShock study NCT01374867 at clinicaltrials.gov
Electronic supplementary material
The online version of this article (doi:10.1186/s13613-016-0229-2) contains supplementary material, which is available to authorized users.
doi:10.1186/s13613-016-0229-2
PMCID: PMC5209311  PMID: 28050899
Adrenomedullin; Cardiogenic shock; Biomarkers; Lactate; Hemodynamics; Mortality

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