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1. Progress and harmonization of gene editing to treat human diseases: Proceeding of COST Action CA21113 GenE-HumDi.

Author

Cavazza, A., Hendel, A., Bak, R.O., Rio, P., Güell, M., Lainšček, D., Arechavala-Gomeza, V., Peng, L., Hapil, F.Z., Harvey, J., Ortega, F.G., Gonzalez-Martinez, C., Lederer, C.W., Mikkelsen, K., Gasiunas, G., Kalter, N., Gonçalves, M.A.F.V., Petersen, J., Garanto, A., Montoliu, L., Maresca, M., Seemann, S.E., Gorodkin, J., Mazini, L., Sanchez, R., Rodriguez-Madoz, J.R., Maldonado-Pérez, N., Laura, T., Schmueck-Henneresse, M., Maccalli, C., Grünewald, J., Carmona, G., Kachamakova-Trojanowska, N., Miccio, A., Martin, F., Turchiano, G., Cathomen, T., Luo, Y, Tsai, S.Q., Benabdellah, K., Cavazza, A., Hendel, A., Bak, R.O., Rio, P., Güell, M., Lainšček, D., Arechavala-Gomeza, V., Peng, L., Hapil, F.Z., Harvey, J., Ortega, F.G., Gonzalez-Martinez, C., Lederer, C.W., Mikkelsen, K., Gasiunas, G., Kalter, N., Gonçalves, M.A.F.V., Petersen, J., Garanto, A., Montoliu, L., Maresca, M., Seemann, S.E., Gorodkin, J., Mazini, L., Sanchez, R., Rodriguez-Madoz, J.R., Maldonado-Pérez, N., Laura, T., Schmueck-Henneresse, M., Maccalli, C., Grünewald, J., Carmona, G., Kachamakova-Trojanowska, N., Miccio, A., Martin, F., Turchiano, G., Cathomen, T., Luo, Y, Tsai, S.Q., and Benabdellah, K.

Abstract

Item does not contain fulltext, The European Cooperation in Science and Technology (COST) is an intergovernmental organization dedicated to funding and coordinating scientific and technological research in Europe, fostering collaboration among researchers and institutions across countries. Recently, COST Action funded the "Genome Editing to treat Human Diseases" (GenE-HumDi) network, uniting various stakeholders such as pharmaceutical companies, academic institutions, regulatory agencies, biotech firms, and patient advocacy groups. GenE-HumDi's primary objective is to expedite the application of genome editing for therapeutic purposes in treating human diseases. To achieve this goal, GenE-HumDi is organized in several working groups, each focusing on specific aspects. These groups aim to enhance genome editing technologies, assess delivery systems, address safety concerns, promote clinical translation, and develop regulatory guidelines. The network seeks to establish standard procedures and guidelines for these areas to standardize scientific practices and facilitate knowledge sharing. Furthermore, GenE-HumDi aims to communicate its findings to the public in accessible yet rigorous language, emphasizing genome editing's potential to revolutionize the treatment of many human diseases. The inaugural GenE-HumDi meeting, held in Granada, Spain, in March 2023, featured presentations from experts in the field, discussing recent breakthroughs in delivery methods, safety measures, clinical translation, and regulatory aspects related to gene editing.

Published
2023

2. Nephrotisches Syndrom

Author

Huber, T. and Grünewald, J.

Abstract

Minimal-Change-Nephropathie („minimal change disease“, MCD) und fokal-segmentale Glomerulosklerose (FSGS) sind histopathologisch definierte Podozytopathien, die sich klinisch als nephrotisches Syndrom manifestieren. Während die MCD vor allem bei Kindern auftritt und meist benigne verläuft, zeigt die FSGS eine höhere Prävalenz bei Erwachsenen und oftmals einen gleichzeitigen Verlust der Nierenfunktion bis hin zur terminalen Niereninsuffizienz. Primäre und sekundäre FSGS sind hinsichtlich Ätiologie, Klinik und Therapieoptionen erheblich differierende Erkrankungen [1, 2]. Bezüglich der Pathogenese von MCD und FSGS haben sich in den letzten Jahren neue Hypothesen etabliert, welche in die klinische Diagnostik noch nicht Einzug gehalten haben, jedoch langfristig zu einem besseren Verständnis der Erkrankungen und möglicherweise zu neuen Therapieansätzen beitragen könnten. Minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are histopathologically defined podocytopathies which are clinically manifested as nephrotic syndrome. While MCD is most commonly seen in children and usually exhibits a benign clinical course, FSGS has a higher prevalence in adult patients and often leads to a deterioration of renal function possibly resulting in end-stage renal disease. Primary and secondary FSGS differ substantially concerning etiology, clinical presentation and therapy [1, 2]. New hypotheses have been established in recent years regarding the pathogenesis of MCD and FSGS but have not yet been incorporated into clinical diagnostics. However, these insights might translate into a better understanding of these diseases in the long run and possibly contribute to new therapeutic approaches.

Published
2024
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6. The occurrence of intersex in different populations of the marine amphipod Echinogammarus marinus in north-west Brittany – A longterm-study

Author

Oetken, M., Adler, M., Alt, K., Bachmann, J., Dombrowski, A., Duhme, F., Gabriel, A.-L., Grünewald, J., Jourdan, J., Lück, Maren, Mensch, C., Rösch, D., Ruthemann, A., Terres, S., Völker, M.L., Wilhelm, F., Oehlmann, J., Oetken, M., Adler, M., Alt, K., Bachmann, J., Dombrowski, A., Duhme, F., Gabriel, A.-L., Grünewald, J., Jourdan, J., Lück, Maren, Mensch, C., Rösch, D., Ruthemann, A., Terres, S., Völker, M.L., Wilhelm, F., and Oehlmann, J.

Abstract

In the past two decades, an increasing body of studies has been published on the intersex phenomenon in separate-sexed crustaceans from marine and freshwater ecosystems. Various causes are being considered that could have an influence on the occurrence of intersex. Besides genetic factors, environmental conditions such as photoperiodicity, temperature, salinity and parasitism, but also environmental pollution with endocrine disrupting chemicals (EDCs) are discussed. As part of a long-term monitoring (2012 – 2020) in north-west Brittany, we recorded the occurrence of intersex in the marine amphipod Echinogammarus marinus. We quantified the intersex incidence at marine and estuarine sites and analyzed the incidence in relation to the endocrine potential of the sediments. Intersex occurred with mean frequencies between 0.87% and 12%. It was striking that the incidence of intersex increased with increasing distance from the sea. Since the highest incidence was observed at the range boundary of this stenohaline species, we assume that intersex is triggered by endocrine potential and increasing stress due to increasing freshwater content − and thus an interplay of different environmental factors.

Published
2021

7. GFR estimation in lenalidomide treatment of multiple myeloma patients: a prospective cohort study

Author

Schmidts, A. Grünewald, J. Kleber, M. Terpos, E. Ihorst, G. Reinhardt, H. Walz, G. Wäsch, R. Engelhardt, M. Zschiedrich, S.

Subjects
urologic and male genital diseases, female genital diseases and pregnancy complications
Abstract

Background: The estimated glomerular filtration rate (eGFR) is clinically used to approximate renal function and adapt drug dosage. Multiple myeloma is a hematological disease; its prognosis is largely influenced by renal function. We evaluated two commonly used GFR estimations, CKD-EPI and MDRD (CKD Epidemiology Collaboration; Modification of Diet in Renal Disease) in myeloma patients undergoing treatment with lenalidomide, a renally excreted immunomodulatory drug. Methods: We prospectively studied 130 myeloma patients receiving lenalidomide treatment at our institution. At baseline and after 3 months, GFR estimations were performed based on the CKD-EPI and MDRD equations. We compared eGFR-dependent CKD staging and lenalidomide dosage assignments. Results: Initially, most patients were classified as CKD stage I/II, using both equations. Comparison of baseline renal function via CKD-EPI and MDRD induced concordance of CKD staging in 83% of patients, while CKD-EPI improved CKD staging in 16% of patients (p = 0.11). CKD-EPI assigned 3% of patients to higher lenalidomide dosing as opposed to MDRD. Both equations showed improved eGFR after 3 months of lenalidomide treatment. Conclusions: In our multiple myeloma patient cohort, CKD-EPI and MDRD led to similar CKD staging with minor differences in lenalidomide dosage assignment. Consistent with previous studies, eGFR improved under lenalidomide treatment. To standardize GFR estimation in myeloma patients, we suggest using the CKD-EPI equation. © 2018, Japanese Society of Nephrology.

Published
2019

14. Nephrotisches Syndrom.

Author

Huber, T. and Grünewald, J.

Abstract

Copyright of Der Nephrologe is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Published
2016
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24. Combination of Tevatron searches for the standard model Higgs boson in the W+W- decay mode

Author

Maxim Perfilov, B. Carls, V. Sorin, P. Lukens, Kevin Lannon, P. Verdier, Guenakh Mitselmakher, Guillelmo Gomez-Ceballos, Marcelo Vogel, V. A. Kuzmin, U. K. Yang, Chris Hays, W. T. Fedorko, Y. A. Yatsunenko, M. Mussini, Y. C. Yang, J. Keung, G. C. Blazey, D. Torretta, A. F. Barfuss, L. Bellantoni, Viatcheslav Stolin, Frank Würthwein, M. Shochet, C. Plager, F. Canelli, V. A. Bezzubov, A. Hocker, P. D. Grannis, Jun Guo, Q. Z. Li, Mark Kruse, Alison Lister, J. P. Fernandez, J. P. Negret, J. Nett, Stefano Giagu, Paul Tipton, G. L. Strycker, C. Mesropian, R. Yamada, D. N. Brown, P. Squillacioti, Kazuhiko Hara, J. Osta, Carlos Avila, L. E. Kirsch, Ricardo Eusebi, J. Galyardt, Alexei Safonov, R. Luna-Garcia, Raimund Ströhmer, V. Simak, D. Krop, Sabine Lammers, Jonas Rademacker, D. Amidei, J. M. Heuser, J. Sekaric, Michael A. Strauss, Jean-Francois Grivaz, K. Devaughan, A. T. Goshaw, P. Padley, Michael Hildreth, P. Skubic, A. Semenov, D. Clark, J. Boudreau, Wendy Taylor, M. Pangilinan, Jason Nielsen, G. Introzzi, B. Casal, Mitchell Wayne, N. Miladinovic, Y. Tu, H. Schellman, J. M. Kohli, K. Potamianos, Z. Gunay-Unalan, Darren Price, A. Sanchez-Hernandez, M. Wiok, Sergo Jindariani, Fedor Prokoshin, P. Jonsson, Thomas Hebbeker, Katsufumi Sato, A. J. Slaughter, Stefan Grünendahl, S. Cihangir, V. Zutshi, Yasuyoshi Nagai, Francesco Crescioli, S. Uzunyan, S. W. Lee, P. Ttito-Guzmán, T. Okusawa, B. Gómez, R. Madrak, Chong-Yu Xu, J. Naganoma, B. Tuchming, P. Wagner, V. Bunichev, Shinhong Kim, J. Budagov, Fabrice Couderc, K. Makhoul, Manfred Paulini, B. Tiller, Dmitri Tsybychev, R. L. McCarthy, Thomas LeCompte, Manuela Campanelli, I. Lazzizzera, Eva Halkiadakis, M. Gold, Tetsuo Arisawa, C. Neu, Amnon Harel, W. M. Lee, K. Kondo, Mary Beth Adams, D. Whiteson, I. Shreyber, K. Yamamoto, Malte Renz, Andrew Askew, R. L. Lander, G. De Lorenzo, A. Savoy-Navarro, Allan G Clark, Roger Moore, D. O. Litvintsev, S. Söldner-Rembold, A. Anastassov, G. Giurgiu, L. Sartori, Sooran Kim, O. Poukhov, A. Jonckheere, H. E. Fisk, P. Lebrun, M. N. Mondragon, I. Hall, A. Lobodenko, Wolfgang Wagner, Liang Li, J. C. Yun, J. Lueck, Stephen Wimpenny, S. Carrillo, J. Backusmayes, Martin Grunewald, Nicola D'Ascenzo, J. A. Appel, P. H. Beauchemin, M. Heck, D. Beecher, Peter McIntyre, G. Pauletta, M. Martínez, J. Patrick, E. Strauss, Guennadi Borissov, M. Jones, C. Pagliarone, D. Menezes, Intae Yu, Oliver Stelzer-Chilton, Th Muller, D. W. Jang, R. Van Kooten, B. Y. Han, I. Heredia-De La Cruz, Michael L. Norman, Yongsun Kim, Lev Dudko, Milos Lokajicek, D. Karmanov, M. M. Deninno, Markus Wobisch, R. Magaña-Villalba, S. W. Cho, G. Obrant, B. Whitehouse, S. Y. Jun, Julia Thom, W. C. Fisher, Adrian Buzatu, V. Boisvert, Daria Zieminska, Suneel Dutt, J. E. Kim, Aran Garcia-Bellido, M. D. Corcoran, S. Cabrera, D. E. Pellett, M. Binkley, R. D. Schamberger, M. Corbo, Y. C. Chen, F. Guo, A. J. Martin, C. Vellidis, Darien Wood, Y. Shon, D. K. Cho, T. R. Wyatt, E. Brubaker, Shabnam Jabeen, S. De Cecco, A. Dubey, G. Grenier, Hwi Dong Yoo, Zdenek Hubacek, L. Santi, A. Alton, Meng Wang, Neeti Parashar, L. Pondrom, E. Wicklund, Christoph Paus, C. P. Buszello, S. Hou, A. Das, M. Sosebee, A. Manousakis-Katsikakis, Emily Nurse, M. Merkin, L. Han, Giorgio Chiarelli, A. Rahaman, J. Huston, J. D. Lewis, Yuehong Xie, T. Scanlon, S. Kermiche, W. H. Chung, M. Rominsky, L. Brigliadori, V. M. Abazov, D. Buchholz, I. Ripp-Baudot, R. McNulty, M. Hare, M. Tecchio, A. Gessler, Helio Nogima, I. Razumov, S. Blessing, M. Zielinski, V. Rusu, A. Elagin, Vyacheslav Krutelyov, G. S. Muanza, Jay Dittmann, W. Ashmanskas, D. Hirschbuehl, H. C. Fang, Frederic Deliot, Michele Gallinaro, G. Savage, Peter Wittich, A. Napier, A. Meyer, Scott Snyder, J. Hays, S. Tokar, Suman Bala Beri, C.S. Johnson, G. Sajot, V. Hynek, Robert Hirosky, Alberto Annovi, P. Murat, Y. Hu, D. J. Cox, A. Di Canto, V. Khotilovich, Y. Seiya, O. Atramentov, Elizaveta Shabalina, M. Lancaster, G. Alkhazov, Y. Zheng, Jian Tang, L. Oakes, A. Gresele, Y. N. Kharzheev, A. Varganov, Sudhir Malik, E. G. Zverev, M. Vidal, Ia Iashvili, G. Manca, P. Roy, Raymond Brock, Robin Erbacher, M. Datta, R. Beuselinck, C. Cuenca Almenar, Javier Cuevas, Jean-Arcady Meyer, J. Mülmenstädt, D. V. Bandurin, S. Greder, Y. W. Liu, Iain Alexander Bertram, Virgil E Barnes, M. Padilla, L. Bagby, M. S. Rangel, Jahred Adelman, Jane Nachtman, Graham Wilson, Sergio F Novaes, S. Hossain, B. Jayatilaka, Kyung-Suk Cho, R. E. Hughes, P. Rich, T. Rodriguez, D. Gillberg, H. Wolfe, B. Sanghi, Suyong Choi, J. Parsons, G. Velev, J. M. Hauptman, Cecilia Elena Gerber, V. M. Podstavkov, G. Chlachidze, Michael Rijssenbeek, S. Zelitch, Jeannine Wagner-Kuhr, M. A. Strang, Brajesh C Choudhary, D. Lucchesi, Bernd Stelzer, S. Tkaczyk, F. Vázquez, P. Svoisky, C. Zeitnitz, J. Yamaoka, Arnulf Quadt, Petar Maksimovic, A. Juste, E. De La Cruz-Burelo, A. Attal, E. Pueschel, T. Wright, S. Grinstein, Todd Adams, K. M. Chan, A. S. Ito, A. Melnitchouk, T. Aaltonen, J. Antos, Thorsten Chwalek, Elemer Nagy, C. J. Lin, W. M. Van Leeuwen, M. Fortner, Sarah Catherine Eno, Horst Severini, Tiehui Liu, Rodolfo Carosi, A. Barbaro-Galtieri, R. G. Feild, J. S. Suh, K. Osterberg, D. Mietlicki, S. Richter, Michal Kreps, T. Nunnemann, B. Baldin, Corrinne Mills, G. P. Yeh, C. S. Moon, M. J. Kim, S. J. Park, A. Menzione, M. E. Convery, E. Palencia, J. C. Cully, Aron Soha, M. Cordelli, G. Busetto, Brian L Winer, G. Ginther, G. Bauer, G. Golovanov, M. J. Morello, F. D. Snider, J. Y. Han, N. Giokaris, Junjie Zhu, S. Wolbers, V. V. Tokmenin, L. S. Vertogradov, R. J. Miller, J. Martínez-Ortega, M. Weinberger, Bjoern Penning, G. Facini, M. Kurata, Andrea Castro, G. D. Alexeev, Flera Rizatdinova, M. Milnik, U. Husemann, B. Álvarez González, V. N. Evdokimov, A. Bridgeman, K. Sliwa, S. Klimenko, Evelyn Thomson, C. Deluca, Fabrizio Scuri, D. Wicke, Dennis Stephen Mackin, Andrew Brandt, Kirti Ranjan, Jianming Qian, J. L. Gimmell, V. V. Lipaev, J. Lellouch, H. A. Neal, Ivan-Kresimir Furic, Y. D. Oh, D. Bauer, M. C. Cousinou, V. A. Giakoumopoulou, Carsten Hensel, A. Mukherjee, C. Belanger-Champagne, B. S. Acharya, Nicola Turini, J. Pursley, H. Nilsen, R. G. Wagner, B. Spurlock, G. Piacentino, M. Buehler, A. T. Laasanen, Zeno Dixon Greenwood, Y. Arnoud, Richard B. Lipton, D. W. Gerdes, Pedro G Mercadante, Ph Gris, T. Kuhr, P. Houben, M. H. Kirby, H. Miyake, F. Happacher, Kristian Harder, Dario Bisello, G. Gutierrez, M. D'Errico, Joe Kroll, B. C.K. Casey, X. Wu, T. A. Schwarz, A. Bhatti, P. A. Kasper, Hugh Williams, M. P. Sanders, Ignacio Redondo, Hyun-Chul Kim, Yurii Maravin, Vladimir Gavrilov, A. Aurisano, Teresa Rodrigo, D. Boline, K. Chung, Peter Love, Pushpalatha C Bhat, W. Geng, N. Ranjan, R. Jesik, S. Carron, L. Demortier, S. Dube, S. H. Oh, M. A. Schmidt, Mark Richard James Williams, R. Bernhard, W. E. Cooper, P. N. Dong, D. Khatidze, Giovanni Bellettini, M. Rossi, J. Slaunwhite, D. Cutts, J. T. Linnemann, David T. Johnston, Gordon Watts, Daniela Bortoletto, O. Mundal, K. Yip, P. E. Karchin, P. Haefner, Roman Lysak, M. Iori, C. Bromberg, Duncan Carlsmith, K. A. Johns, Anna Goussiou, Elisabetta Pianori, A. V. Kotwal, Gregorio Bernardi, Andrea Bocci, D. Denisov, X. Zhang, A. Scribano, D. Onoprienko, T. J. Phillips, A. A. Paramanov, K. Ebina, G. Otero y Garzon, M. Trovato, M. Cavalli-Sforza, W. M. Yao, Aaron Dominguez, Jochen Jens Heinrich, W. Geist, Tiefu Zhao, S. Budd, G. A. Thompson, Je Jung, S. W. Youn, P. Polozov, Koji Nakamura, Arnaud Duperrin, S. Neubauer, S. Y. Tsai, Sharon Hagopian, S. Torre, S. Amerio, S. Zucchelli, A. K.A. Maciel, W. Johnson, K. T. Pitts, A. Simonenko, V. Sirotenko, S. Wilbur, J. K. Kraus, J. Weinelt, Greg Landsberg, I. Suslov, K. Herner, N. Khalatyan, S. Yacoob, A. Schmidt, B. Hoeneisen, Lee Sawyer, Maria Agnese Ciocci, A. Mitra, Michael Schmitt, N. Kimura, Hal Evans, Thomas Ferbel, M. Prewitt, Cristina Galea, M. Hartz, T. Wakisaka, Lars Sonnenschein, Zhanqiang Liu, M. Cooke, Tommaso Dorigo, S. Hewamanage, Sinead Farrington, M. P. Schmidt, P. L.M. Podesta-Lerma, D. H. Kim, V. Kaushik, J. F. Bartlett, J. Lys, Stephan Lammel, Lucio Cerrito, R. E. Blair, Jong-Sung Yu, F. Rimondi, Pavol Bartos, N. Ershaidat, E. E. Boos, E. E. Schmidt, Marco Verzocchi, Theodoros Christoudias, S. Lami, Emanuela Barberis, Avraham Yagil, Dean Hidas, Heriberto Castilla-Valdez, J. Morlock, S. Seidel, R. Unalan, L. Stutte, A. Canepa, C. Ferrazza, C. P. Marino, G. Flanagan, A. N. Sisakyan, E. Rogers, P. Totaro, R. Nayyar, Robert Kehoe, Maxwell Chertok, A. Patwa, W. Badgett, J. Clutter, Md. Naimuddin, V. Papadimitriou, M. Kirsch, A.S. Dyshkant, D. Smirnov, George Alverson, K. Tollefson, E. J. Jeon, A. Sukhanov, R. Vilar, N. Krumnack, P. K. Teng, K. S. McFarland, Federico Sforza, Mark Owen, S. Somalwar, Deepak Kar, R. Piegaia, V. V. Glagolev, MarioPaolo Giordani, S. J. De Jong, K. Soustruznik, Ashok Kumar, E. Carrera, I. Bizjak, J. Conway, E. Lee, M. Stanitzki, A. Papaikonomou, M. E. Mattson, M. Arov, Andre Sopczak, G. Hesketh, B. Brau, D. Hedin, Brad Abbott, P. Catastini, T. Tomura, A. Evdokimov, S. Pagan Griso, Robert Snihur, Marcia Begalli, Ulysses Grundler, C. I. Ciobanu, R. L. Wagner, Jiri Kvita, D. Gerbaudo, D. Lam, S. Z. Shalhout, Victoria Jane Martin, R. Martínez-Ballarín, Thomas Peiffer, Alexander Grohsjean, Phillip Gutierrez, Pierre Petroff, A. Golossanov, Shih-Fu Chang, Rainer Wallny, M. Demarteau, Andreas Warburton, Satoru Uozumi, U. Bassler, Andrew Beretvas, R. F. Harr, M. Mathis, Meenakshi Narain, A. Pronko, Arie Bodek, S. Moed, P. J. Van Den Berg, Lev Uvarov, Marc Besancon, D. Benjamin, K. Goulianos, J. Snow, M. Abolins, S. Rolli, Elliott Cheu, T. Schliephake, A. Taffard, Victor Daniel Elvira, Marvin Johnson, K. Peters, Sung Keun Park, Massimo Casarsa, Sergey Burdin, S. Robinson, J. Deng, Gregory R Snow, A. A. Shchukin, P. Movilla Fernandez, M. Shimojima, J. P. Chou, Heimo Saarikko, A. Sedov, M. A. Carrasco-Lizarraga, M. Feindt, M. Eads, Y. Takeuchi, Regina Demina, J. Strologas, C. Calancha, B. Di Ruzza, P. Sinervo, P. Schlabach, S. P. Denisov, V. Parihar, Frank Fiedler, A. L. Lyon, Philip Baringer, F. Garberson, H. W. Kim, N. K. Mondal, Mauro Dell'Orso, Tulika Bose, S. Pashapour, A. Apresyan, E. Kajfasz, Song-Ming Wang, A. V. Kozelov, Samuel Calvet, H. T. Diehl, T. A. Bolton, P. Neustroev, V. Saveliev, F. Azfar, R. Culbertson, C. Haber, O. Norniella, V. V. Shary, A. Boehnlein, M. Lindgren, J. Piper, S. Banerjee, E. Vataga, Dorothee Schaile, Michael Mulhearn, R. St. Denis, J. R. Smith, G. B. Yu, J. Ellison, W. Ketchum, D. Hare, G. Williams, D. Edmunds, Igor Volobouev, Jeroen Hegeman, J. Linacre, T. Moulik, P. de Barbaro, Avto Kharchilava, C. A. Cox, Fumihiko Ukegawa, Sa. Jain, A. Penzo, S. Fuess, K. K. Joo, T. Kurca, Marc Weber, B. Parks, James Russ, Kohei Yorita, T. Hoang, Franco Bedeschi, R. Otec, D. Glenzinski, Alexander Khanov, Jonas Strandberg, P. B. Renton, J. Orduna, S. S. Yu, Tomoko Yoshida, A. B. Wicklund, D. Jamin, Grigory Safronov, S. Chevalier-Théry, J. Thome, S. Chakrabarti, V. Cavaliere, D. Waters, M. Hohlfeld, P. N. Ratoff, D. Toback, Y. Peters, P. Vint, Zhenyu Ye, Maksym Titov, Yuri Gershtein, N. P. Kulkarni, Y. Zeng, P. Rubinov, Daniel Duggan, Ernest Aguilo, Tara Shears, Hua-Lei Yin, A. V. Popov, W. C. Wester, M. Campbell, D. Stentz, A. Loginov, S. Desai, T. Dorland, D. Dagenhart, M. Jaffré, Gustaaf Brooijmans, M. Rescigno, L. S. Ancu, Petr Vokac, Joseph Haley, J. Warchol, P. Lujan, P. Garosi, Christophe Royon, V. Ramakrishnan, Alexander Leflat, J. Asaadi, Y. S. Chung, E. Camacho-Pérez, C. Wolfe, P. Barria, E. James, B. Calpas, L. Lovas, Reinhard Schwienhorst, S. Behari, Luca Scodellaro, H. D. Wahl, Alexander Kupco, F. Badaud, K. L. Byrum, P. Giromini, Andrew White, Gilvan Alves, L. Sexton-Kennedy, R. Forrest, I. Katsanos, Anna Zanetti, G. Compostella, Maxim Goncharov, N. Huske, N. Parua, D. Vilanova, Randy Ruchti, Joe Incandela, L. Nodulman, J. N. Bellinger, M. D'onofrio, T. Miao, P. Mättig, X. B. Bu, D. Chokheli, R. Kephart, K. Gibson, M. M. Meijer, L. Ristori, N. S. Lockyer, Roberto Rossin, A. Boveia, Aidan Robson, Kevin Burkett, T. Yasuda, R. Illingworth, N. Moggi, D. Errede, S. Beale, Chuan-Ming Liu, G. Punzi, John Hobbs, Yuji Enari, Y. Kato, L. Zivkovic, J. Guimaraes Da Costa, J. Barreto, D. Tonelli, Alexey Ferapontov, M. Wetstein, I. V. Gorelov, H. S. Budd, M. A. Houlden, Andrew Mehta, Jacobo Konigsberg, L. Duflot, J. K. Lim, Stefano Camarda, Frank Chlebana, F. Ptohos, B. Åsman, L. Pinera, A. P. Heinson, S. Malde, M. A. Pleier, P. Renkel, P. Mehtala, M. Giunta, A. Artikov, S. Schlobohm, H. Greenlee, D. M. Strom, Matthew Herndon, E. Lipeles, M. K. Jha, A. Bross, Christopher George Tully, M. Hussein, Benjamin Kilminster, Serban Protopopescu, Barry Blumenfeld, M. Aoki, Andy Haas, G. Weber, D. Chakraborty, J. S. Lee, Don Lincoln, Erich Varnes, S. Shiraishi, S. Kwang, M. Hurwitz, S. R. Hahn, M. Vesterinen, N. Osman, A. Deisher, T. R. Junk, Patrick Slattery, A. Chandra, J. Yoh, D. A. Stoyanova, C. L. McGivern, Gervasio Gomez, Michael Begel, Andrey Korytov, Eduardo De Moraes Gregores, Luiz Mundim, R. Takashima, T. H. Burnett, Amitabh Lath, Anna Sfyrla, Paola Giannetti, B. A. Barnett, Giorgio Apollinari, J. A. Benitez, Teruki Kamon, P. Mazzanti, Craig Blocker, Ulrich Heintz, D. Cauz, Kaori Maeshima, P. K. Mal, H. S. Lee, Frank Filthaut, Paolo Mastrandrea, M. Diesburg, P. Wilson, J. E. Garcia, A. Tanasijczuk, T. Davies, C. S. Hill, Sandra Leone, S. Uvarov, B. Quinn, W. K. Sakumoto, C. Schwanenberger, Alice Bean, C. Grosso-Pilcher, I. Oksuzian, N. Goldschmidt, Volker Buescher, Peter Bussey, T. Gadfort, Maria Elena Pol, Kai Yi, C. M. Ginsburg, R. Roser, Ivan Vila, P. F. Shepard, B. Rutherford, Alexander Ivanov, N. Van Remortel, S. C. Hsu, Reisaburo Tanaka, Guido Volpi, Nikos Varelas, O. González, Bing Zhou, Luis Mendoza, R. K. Shivpuri, S. Donati, Kenichi Hatakeyama, M. Franklin, D. R. Claes, Gavin Davies, Philippe Calfayan, Itsuo Nakano, Harald Fox, S. M. Lietti, Y. Scheglov, J. C. Freeman, Kaushik De, A. Ruiz, Giuseppe Latino, Alan Garfinkel, Jan Stark, Fabrizio Margaroli, S. Errede, Maiko Takahashi, Henry Lubatti, J. Cammin, I. A. Vasilyev, Vipin Bhatnagar, A. Cerri, R. Partridge, Markus Frank, P. M. Tuts, D. MacQueen, H. Gerberich, Kenneth Bloom, V. L. Malyshev, Mark Neubauer, R. Orava, G. Lungu, R. D. Field, D. J. Kong, W. C. Yang, Department of Physics, Helsinki Institute of Physics, CDF Collaboration, D0 Collaboration, Laboratoire de Physique Subatomique et de Cosmologie (LPSC), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut Polytechnique de Grenoble - Grenoble Institute of Technology-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Physique Corpusculaire - Clermont-Ferrand (LPC), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Centre de Physique des Particules de Marseille (CPPM), Aix Marseille Université (AMU)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherches sur les lois Fondamentales de l'Univers (IRFU), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Laboratoire de Physique Nucléaire et de Hautes Énergies (LPNHE), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université Pierre et Marie Curie - Paris 6 (UPMC), Laboratoire de l'Accélérateur Linéaire (LAL), Centre National de la Recherche Scientifique (CNRS)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université Paris-Sud - Paris 11 (UP11), Institut de Physique Nucléaire de Lyon (IPNL), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3), CDF, D0, Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Institut Polytechnique de Grenoble - Grenoble Institute of Technology-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud - Paris 11 (UP11)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Universidad de Cantabria, T. 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MUANZA, A. MUKHERJEE, M. MULHEARN, TH. MULLER, J. MÜLMENSTÄDT, O. MUNDAL, L. MUNDIM, P. MURAT, M. MUSSINI, J. NACHTMAN,I, Y. NAGAI, J. NAGANOMA, E. NAGY, M. NAIMUDDIN, K. NAKAMURA, I. NAKANO, A. NAPIER, M. NARAIN, R. NAYYAR, H. A. NEAL, J. P. NEGRET, J. NETT, C. NEU, M. S. NEUBAUER, S. NEUBAUER, P. NEUSTROEV, J. NIELSEN, H. NILSEN, L. NODULMAN, H. NOGIMA, M. NORMAN, O. NORNIELLA, S. F. NOVAES, T. NUNNEMANN, E. NURSE, L. OAKES, G. OBRANT, S. H. OH, Y. D. OH, I. OKSUZIAN, T. OKUSAWA, D. ONOPRIENKO, R. ORAVA, J. ORDUNA, N. OSMAN, J. OSTA, K. OSTERBERG, R. OTEC, G. J. OTERO Y GARZÓN, M. OWEN, M. PADILLA, P. PADLEY, S. PAGAN GRISOB,A, C. PAGLIARONE, E. PALENCIA, M. PANGILINAN, V. PAPADIMITRIOU, A. PAPAIKONOMOU, A. A. PARAMANOV, N. PARASHAR, V. PARIHAR, S.-J. PARK, S. K. PARK, B. PARKS, J. PARSONS, R. PARTRIDGE, N. PARUA, S. PASHAPOUR, J. PATRICK, A. PATWA, G. PAULETTA, M. PAULINI, C. PAUS, T. PEIFFER, D. E. PELLETT, B. PENNING, A. PENZO, M. PERFILOV, K. PETERS, Y. PETERS, P. PÉTROFF, T. J. PHILLIPS, G. PIACENTINO, E. PIANORI, R. PIEGAIA, L. PINERA, J. PIPER, K. PITTS, C. PLAGER, M.-A. PLEIER, P. L. M. PODESTA-LERMA, V. M. PODSTAVKOV, M.-E. POL, P. POLOZOV, L. PONDROM, A. V. POPOV, K. POTAMIANOS, O. POUKHOV, M. PREWITT, D. PRICE, F. PROKOSHIN,U, A. PRONKO, S. PROTOPOPESCU, F. PTOHOS, E. PUESCHEL, G. PUNZI, J. PURSLEY, J. QIAN, A. QUADT, B. QUINN, J. RADEMACKER,§, A. RAHAMAN, V. RAMAKRISHNAN, M. S. RANGEL, K. RANJAN, N. RANJAN, P. N. RATOFF, I. RAZUMOV, I. REDONDO, P. RENKEL, P. RENTON, M. RENZ, M. RESCIGNO, P. RICH, S. RICHTER, M. RIJSSENBEEK, F. RIMONDI, I. RIPP-BAUDOT, L. RISTORIA, F. RIZATDINOVA, S. ROBINSON, A. ROBSON, T. RODRIGO, T. RODRIGUEZ, E. ROGERS, S. ROLLI, M. ROMINSKY, R. ROSER, M. ROSSIA, R. ROSSIN, P. ROY, C. ROYON, P. RUBINOV, R. RUCHTI, A. RUIZ, J. RUSS, V. RUSU, B. RUTHERFORD, H. SAARIKKO, A. SAFONOV, G. SAFRONOV, G. SAJOT, W. K. SAKUMOTO, A. SÁNCHEZ-HERNÁNDEZ, M. P. SANDERS, B. SANGHI, L. SANTI, L. SARTORIA, K. SATO, G. SAVAGE, V. SAVELIEV, A. SAVOY-NAVARRO, L. SAWYER, T. SCANLON, D. SCHAILE, R. D. SCHAMBERGER, Y. SCHEGLOV, H. SCHELLMAN, P. SCHLABACH, T. SCHLIEPHAKE, S. SCHLOBOHM, A. SCHMIDT, E. E. SCHMIDT, M. A. SCHMIDT, M. P. SCHMIDT, M. SCHMITT, C. SCHWANENBERGER, T. SCHWARZ, R. SCHWIENHORST, L. SCODELLARO, A. SCRIBANO, F. SCURIA, A. SEDOV, S. SEIDEL, Y. SEIYA, J. SEKARIC, A. SEMENOV, H. SEVERINI, L. SEXTON-KENNEDY, F. SFORZA, A. SFYRLA, E. SHABALINA, S. Z. SHALHOUT, V. SHARY, A. A. SHCHUKIN, T. SHEARS, P. F. SHEPARD, M. SHIMOJIMA,O, S. SHIRAISHI, R. K. SHIVPURI, M. SHOCHET, Y. SHON, I. SHREYBER, V. SIMAK, A. SIMONENKO, P. SINERVO, V. SIROTENKO, A. SISAKYAN, P. SKUBIC, P. SLATTERY, A. J. SLAUGHTER, J. SLAUNWHITE, K. SLIWA, D. SMIRNOV, J. R. SMITH, F. D. SNIDER, R. SNIHUR, G. R. SNOW, J. SNOW, S. SNYDER, A. SOHA, S. SÖLDNER-REMBOLD, S. SOMALWAR, L. SONNENSCHEIN, A. SOPCZAK, V. SORIN, M. SOSEBEE, K. SOUSTRUZNIK, B. SPURLOCK, P. SQUILLACIOTIC,A, M. STANITZKI, J. STARK, R. ST. DENIS, B. STELZER, O. STELZER-CHILTON, D. STENTZ, V. STOLIN, D. A. STOYANOVA, J. STRANDBERG, M. A. STRANG, E. STRAUSS, M. STRAUSS, R. STRÖHMER, J. STROLOGAS, D. STROM, G. L. STRYCKER, L. STUTTE, J. S. SUH, A. SUKHANOV, I. SUSLOV, P. SVOISKY, A. TAFFARD, M. TAKAHASHI, R. TAKASHIMA, Y. TAKEUCHI, R. TANAKA, A. TANASIJCZUK, J. TANG, W. TAYLOR, M. TECCHIO, P. K. TENG, J. THOM, J. THOME, G. A. THOMPSON, E. THOMSON, B. TILLER, P. TIPTON, M. TITOV, S. TKACZYK, D. TOBACK, S. TOKAR, V. V. TOKMENIN, K. TOLLEFSON, T. TOMURA, D. TONELLI, S. TORRE, D. TORRETTA, P. TOTARO, M. TROVATO, S.-Y. TSAI, D. TSYBYCHEV, P. TTITO-GUZMÁN, B. TUCHMING, Y. TU, C. TULLY, N. TURINI, P. M. TUTS, F. UKEGAWA, R. UNALAN, S. UOZUMI, L. UVAROV, S. UVAROV, S. UZUNYAN, P. J. VAN DEN BERG, R. VAN KOOTEN, W. M. VAN LEEUWEN, N. VAN REMORTEL, N. VARELAS, A. VARGANOV, E. W. VARNES, I. A. VASILYEV, E. VATAGAD,A, F. VÁZQUEZ,H, G. VELEV, C. VELLIDIS, P. VERDIER, L. S. VERTOGRADOV, M. VERZOCCHI, M. VESTERINEN, M. VIDAL, I. VILA, D. VILANOVA, R. VILAR, P. VINT, M. VOGEL, P. VOKAC, I. VOLOBOUEV,S, G. VOLPI, P. WAGNER, R. G. WAGNER, R. L. WAGNER, W. WAGNER,W, J. WAGNER-KUHR, H. D. WAHL, T. WAKISAKA, R. WALLNY, M. H. L. S. WANG, S. M. WANG, A. WARBURTON, J. WARCHOL, D. WATERS, G. WATTS, M. WAYNE, G. WEBER, M. WEBER, M. WEINBERGER, J. WEINELT, W. C. WESTER, III, M. WETSTEIN, A. WHITE, B. WHITEHOUSE, D. WHITESON, D. WICKE, A. B. WICKLUND, E. WICKLUND, S. WILBUR, G. WILLIAMS, H. H. WILLIAMS, M. R. J. WILLIAMS, G. W. WILSON, P. WILSON, S. J. WIMPENNY, B. L. WINER, P. WITTICH, M. WOBISCH, S. WOLBERS, C. WOLFE, H. WOLFE, D. R. WOOD, T. WRIGHT, X. WU, F. WÜRTHWEIN, T. R. WYATT, Y. XIE, C. XU, S. YACOOB, A. YAGIL, R. YAMADA, K. YAMAMOTO, J. YAMAOKA, U. K. YANG,M, W.-C. YANG, Y. C. YANG, W. M. YAO, T. YASUDA, Y. A. YATSUNENKO, Z. YE, G. P. YEH, K. YI,I, H. YIN, K. YIP, J. YOH, H. D. YOO, K. YORITA, T. YOSHIDA,F, S. W. YOUN, G. B. YU, I. YU, J. YU, S. S. YU, J. C. YUN, A. ZANETTIA, C. ZEITNITZ, S. ZELITCH, Y. ZENG, X. ZHANG, T. ZHAO, Y. ZHENG, B. ZHOU, J. ZHU, M. ZIELINSKI, D. ZIEMINSKA, L. ZIVKOVIC, S. ZUCCHELLI, V. ZUTSHI, E. G. ZVEREV, D0 (Tevatron, IHEF, IOP, FNWI), Universidad de Buenos Aires, Centro Brasileiro de Pesquisas Físicas, Universidade do Estado do Rio de Janeiro (UERJ), Universidade Federal do ABC (UFABC), Universidade Estadual Paulista (UNESP), McGill University, Simon Fraser University, University of Science and Technology of China, Academia Sinica, Universidad de los Andes, Faculty of Mathematics and Physics, Czech Technical University in Prague, Academy of Sciences, Universidad San Francisco de Quito, University of Helsinki, CNRS/IN2P3, Institut National Polytechnique de Grenoble, Irfu/SPP, RWTH Aachen University, Universität Bonn, Universität Freiburg, Georg-August-Universität Göttingen, Karlsruhe Institute of Technology, Universität Mainz, Ludwig-Maximilians-Universität München, University of Wuppertal, University of Athens, Panjab University, Delhi University, Tata Institute of Fundamental Research, University College Dublin, Istituto Nazionale di Fisica Nucleare Bologna, University of Bologna, Istituto Nazionale di Fisica Nucleare, Sezione di Padova-Trento, University of Padova, Istituto Nazionale di Fisica Nucleare Pisa, University of Pisa, University of Siena, Scuola Normale Superiore, Sezione di Roma 1, Sapienza Università di Roma, Istituto Nazionale di Fisica Nucleare Trieste/Udine, University of Trieste, Okayama University, Osaka City University, University of Tsukuba, Waseda University, Kyungpook National University, Korea University, SungKyunKwan University, CINVESTAV, NIKHEF, Radboud University Nijmegen/NIKHEF, Joint Institute for Nuclear Research, Institution for Theoretical and Experimental Physics, Moscow State University, Institute for High Energy Physics, Petersburg Nuclear Physics Institute, Comenius University, Universitat Autonoma de Barcelona, Medioambientales y Tecnologicas, University of Cantabria, Stockholm University, University of Geneva, Glasgow University, Lancaster University, University of Liverpool, Imperial College London, University College London, The University of Manchester, University of Oxford, University of Arizona, Ernest Orlando Lawrence Berkeley National Laboratory, University of California, Yale University, University of Florida, Florida State University, Argonne National Laboratory, Fermi National Accelerator Laboratory, University of Chicago, University of Illinois at Chicago, Northern Illinois University, Northwestern University, University of Illinois, Indiana University, Purdue University Calumet, University of Notre Dame, Purdue University, Iowa State University, University of Kansas, Kansas State University, Louisiana Tech University, The Johns Hopkins University, University of Maryland, Boston University, Northeastern University, Harvard University, Massachusetts Institute of Technology, Tufts University, Brandeis University, University of Michigan, Wayne State University, Michigan State University, University of Mississippi, University of Nebraska, Rutgers University, Princeton University, University of New Mexico, State University of New York, Columbia University, The Rockefeller University, University of Rochester, Brookhaven National Laboratory, Duke University, The Ohio State University, Langston University, University of Oklahoma, Oklahoma State University, University of Pennsylvania, Carnegie Mellon University, University of Pittsburgh, Brown University, University of Texas, Texas A and M University, Southern Methodist University, Rice University, Baylor University, University of Virginia, University of Washington, University of Wisconsin, Sezione di Cagliari, University of Toronto, TRIUMF, York University, Seoul National University, Sungkyunkwan University, Institute of Science and Technology Information, Chonnam National University, Chonbuk National University, Institute of Experimental Physics, University of Cyprus, University of Edinburgh, Fukui Prefecture, Kinki University, Universidad Iberoamericana, University of Iowa, University of California Irvine, Cornell University, University of London, University of Manchester, Inc., Nagasaki Institute of Applied Science, Obninsk State University, University de Oviedo, Texas Tech University, CSIC-Universitat de Valencia, Universidad Tecnica Federico Santa Maria, Bergische Universität Wuppertal, Yarmouk University, J. Stefan Institute, Augustana College, SLAC, ICREA/IFAE, Centro de Investigacion en Computacion-IPN, Universidad Autonoma de Sinaloa, Universiẗt Bern, University of Massachusetts Amherst, Universiteit Antwerpen, University of Bristol, University of California Santa Cruz, Chinese Academy of Sciences, Clark, Allan Geoffrey, Garcia Navarro, Jose Enrique, Lister, Alison, and Wu, Xin

Subjects
Particle physics, Astrophysics::High Energy Astrophysical Phenomena, Tevatron, FOS: Physical sciences, General Physics and Astronomy, Elementary particle, ddc:500.2, PARTON DISTRIBUTIONS, HADRON COLLIDERS, QCD, NNLO, 7. Clean energy, 01 natural sciences, 114 Physical sciences, High Energy Physics - Experiment, Standard Model, Nuclear physics, High Energy Physics - Experiment (hep-ex), Particle decay, 0103 physical sciences, [PHYS.HEXP]Physics [physics]/High Energy Physics - Experiment [hep-ex], Grand Unified Theory, Fermilab, TEVATRON, Nuclear Experiment, 010306 general physics, Boson, Physics, HIGGS BOSON, 010308 nuclear & particles physics, High Energy Physics::Phenomenology, 3. Good health, Higgs boson, CDF, Physics::Accelerator Physics, High Energy Physics::Experiment, +W%2B+W-+|+W%3A+pair+production+|+W%3A+leptonic+decay+|+dilepton%3A+final+state+|+jet%3A+multiplicity+|+cross+section%3A+upper+limit+|+mass+dependence+|+Higgs+particle%3A+mass+|+background+|+DZERO+|+CDF+|+Batavia+TEVATRON+Coll+|+anti-p+p+-->+Higgs+particle+anything+|+anti-p+p+-->+Higgs+particle+anything+intermediate+boson+anything+|+anti-p+p+-->+Higgs+particle+anything+quark+antiquark+anything+|+1960+GeV-cms%22">Anti-p p: interaction | Higgs particle: search for | gluon gluon: fusion | intermediate boson: fusion | quark antiquark: annihilation | Higgs particle: decay | Higgs particle --> W+ W- | W: pair production | W: leptonic decay | dilepton: final state | jet: multiplicity | cross section: upper limit | mass dependence | Higgs particle: mass | background | DZERO | CDF | Batavia TEVATRON Coll | anti-p p --> Higgs particle anything | anti-p p --> Higgs particle anything intermediate boson anything | anti-p p --> Higgs particle anything quark antiquark anything | 1960 GeV-cms
Abstract

11 páginas, 4 figuras, 1 tabla.-- CDF Collaboration: et al., We combine searches by the CDF and D0 Collaborations for a Higgs boson decaying to W+W-. The data correspond to an integrated total luminosity of 4.8 (CDF) and 5.4 (D0) fb(-1) of p (p) over bar collisions at root s = 1.96 TeV at the Fermilab Tevatron collider. No excess is observed above background expectation, and resulting limits on Higgs boson production exclude a standard model Higgs boson in the mass range 162-166 GeV at the 95% C.L., We thank the Fermilab staff and the technical staffs of the participating institutions for their vital contributions. This work was supported by DOE and NSF (USA), CONICET and UBACyT (Argentina), CNPq, FAPERJ, FAPESP and FUNDUNESP (Brazil), CRC Program, CFI, NSERC and WestGrid Project (Canada), CAS and CNSF (China), Colciencias (Colombia), MSMT and GACR (Czech Republic), Academy of Finland (Finland), CEA and CNRS/IN2P3 (France), BMBF and DFG (Germany), Ministry of Education, Culture, Sports, Science and Technology (Japan), World Class University Program, National Research Foundation (Korea), KRF and KOSEF (Korea), DAE and DST (India), SFI (Ireland),INFN (Italy), CONACyT (Mexico), NSC(Republic of China), FASI, Rosatom and RFBR (Russia), Slovak R&D Agency (Slovakia), Ministerio de Ciencia e Innovación, and Programa Consolider-Ingenio 2010 (Spain), The Swedish Research Council (Sweden), Swiss National Science Foundation (Switzerland), FOM (The Netherlands), STFC and the Royal Society (UK), and the A.P. Sloan Foundation (USA).

Published
2010

25. Progress and harmonization of gene editing to treat human diseases: Proceeding of COST Action CA21113 GenE-HumDi.

Author

Cavazza A, Hendel A, Bak RO, Rio P, Güell M, Lainšček D, Arechavala-Gomeza V, Peng L, Hapil FZ, Harvey J, Ortega FG, Gonzalez-Martinez C, Lederer CW, Mikkelsen K, Gasiunas G, Kalter N, Gonçalves MAFV, Petersen J, Garanto A, Montoliu L, Maresca M, Seemann SE, Gorodkin J, Mazini L, Sanchez R, Rodriguez-Madoz JR, Maldonado-Pérez N, Laura T, Schmueck-Henneresse M, Maccalli C, Grünewald J, Carmona G, Kachamakova-Trojanowska N, Miccio A, Martin F, Turchiano G, Cathomen T, Luo Y, Tsai SQ, and Benabdellah K

Abstract

The European Cooperation in Science and Technology (COST) is an intergovernmental organization dedicated to funding and coordinating scientific and technological research in Europe, fostering collaboration among researchers and institutions across countries. Recently, COST Action funded the "Genome Editing to treat Human Diseases" (GenE-HumDi) network, uniting various stakeholders such as pharmaceutical companies, academic institutions, regulatory agencies, biotech firms, and patient advocacy groups. GenE-HumDi's primary objective is to expedite the application of genome editing for therapeutic purposes in treating human diseases. To achieve this goal, GenE-HumDi is organized in several working groups, each focusing on specific aspects. These groups aim to enhance genome editing technologies, assess delivery systems, address safety concerns, promote clinical translation, and develop regulatory guidelines. The network seeks to establish standard procedures and guidelines for these areas to standardize scientific practices and facilitate knowledge sharing. Furthermore, GenE-HumDi aims to communicate its findings to the public in accessible yet rigorous language, emphasizing genome editing's potential to revolutionize the treatment of many human diseases. The inaugural GenE-HumDi meeting, held in Granada, Spain, in March 2023, featured presentations from experts in the field, discussing recent breakthroughs in delivery methods, safety measures, clinical translation, and regulatory aspects related to gene editing., Competing Interests: P.R. has licensed the PGK:FANCAWpre∗ LV medicinal product and receives funding and equity from Rocket Pharmaceuticals, Inc., patents and royalties, research & consulting funding. D.L. is an inventor on a patent National Institute of Chemistry filed (WO/2021/032759 patent application, European patent application EP 3783104, China patent application CN 114269930 with National Phase entry EP2020756868). R.O.B. holds patents related to CRISPR-Cas genome editing and has equity in Graphite Bio and is consultant for UNIKUM Tx. G.G. holds patents related to CRISPR-Cas genome editing, is an employee of CasZyme, and has equity in CasZyme. S.Q.T. is a co-inventor on patents for GUIDE-seq, CHANGE-seq, and other genome editing technologies and a member of the scientific advisory boards of Prime Medicine and Ensoma. T.C. is a co-inventor on patents for CAST-seq, Abnoba-Seq, and other genome editing technologies, and a member of the scientific advisory boards of Cimeo Therapeutics, Excision BioTherapeutics, and GenCC. A.C. and G.T. are inventors on a patent for MEGA (WO/2023/079285), G.T. is also co-inventor on a patent for CAST-seq., (© 2023 The Author(s).)

Published
2023
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27. Engineered CRISPR prime editors with compact, untethered reverse transcriptases.

Author

Grünewald J, Miller BR, Szalay RN, Cabeceiras PK, Woodilla CJ, Holtz EJB, Petri K, and Joung JK

Subjects
Animals, Humans, Mice, Deoxyribonuclease I genetics, CRISPR-Cas Systems genetics, Gene Editing methods, Moloney murine leukemia virus genetics, RNA-Directed DNA Polymerase genetics, Streptococcus pyogenes genetics
Abstract

The CRISPR prime editor PE2 consists of a Streptococcus pyogenes Cas9 nickase (nSpCas9) fused at its C-terminus to a Moloney murine leukemia virus reverse transcriptase (MMLV-RT). Here we show that separated nSpCas9 and MMLV-RT proteins function as efficiently as intact PE2 in human cells. We use this Split-PE system to rapidly identify and engineer more compact prime editor architectures that also broaden the types of RTs used for prime editing., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Published
2023
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28. Aldosterone secretion during the day: Salivary aldosterone awakening response and daytime levels.

Author

Gideon A, Sauter C, Deuber J, Grünewald J, and Wirtz PH

Subjects
Circadian Rhythm physiology, Humans, Hydrocortisone analysis, Male, Sleep physiology, Wakefulness physiology, Aldosterone, Saliva chemistry
Abstract

Background: The mineralocorticoid hormone aldosterone is a key regulator of the sodium-potassium balance and blood pressure. In excess, aldosterone relates to hypertension and cardiovascular disease (CVD). Here, we systematically investigated aldosterone secretion during the day in terms of salivary aldosterone awakening response (AldAR) and salivary aldosterone daytime levels (AldDay) under controlled conditions in participants' natural environment including assessment of potential confounding variables., Methods: In 40 healthy young men, saliva samples for AldAR were collected immediately after awakening and 15, 30, 45, and 60 min thereafter. AldDay levels were measured in 1 h intervals from 9:00-22:00 h. Analyses were complemented by salivary cortisol assessment. Fluid and food intake was standardized and as potential confounders, we assessed awakening time and sleep duration, age, BMI and MAP, as well as chronic stress., Results: Awakening was followed by significant increases in salivary aldosterone (p = .004, f= 0.31), returning to baseline levels > 60 min later. Longer sleep duration was associated with lower AldAR (p < .001, f= 0.36). Over the course of the day we observed a continuous decrease of AldDay (p < .001, f= 0.45). Longer sleep duration (p = .097, f= .21), later time of awakening (p < .001, f= .29), and higher chronic stress (p = .041, f= .23) were associated with AldDay characteristics. Circadian aldosterone secretion was positively associated with most cortisol measures., Conclusions: We observed an awakening response in salivary aldosterone and could confirm a decrease in aldosterone levels during the day, comparable to cortisol. Significant confounders were sleep-related variables and chronic stress. Clinical implications of circadian aldosterone secretion with respect to CVD risk remain to be elucidated., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Published
2022
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29. Exploration of an Alarm Sensor to Detect Infusion Failure Administered by Syringe Pumps.

Author

Wieduwilt F, Grünewald J, Ctistis G, Lenth C, Perl T, and Wackerbarth H

Abstract

Incorrect medication administration causes millions of undesirable complications worldwide every year. The problem is severe and there are many control systems in the market, yet the exact molecular composition of the solution is not monitored. Here, we propose an alarm sensor based on UV-Vis spectroscopy and refractometry. Both methods are non-invasive and non-destructive as they utilize visible light for the analysis. Moreover, they can be used for on-site or point-of-care diagnosis. UV-Vis-spectrometer detect the absorption of light caused by an electronic transition in an atom or molecule. In contrast a refractometer measures the extent of light refraction as part of a refractive index of transparent substances. Both methods can be used for quantification of dissolved analytes in transparent substances. We show that a sensor combining both methods is capable to discern most standard medications that are used in intensive care medicine. Furthermore, an integration of the alarm sensor in already existing monitoring systems is possible.

Published
2022
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30. The Occurrence of Intersex in Different Populations of the Marine Amphipod Echinogammarus marinus in North-West Brittany - A Longterm-Study.

Author

Oetken M, Adler M, Alt K, Bachmann J, Dombrowski A, Duhme F, Gabriel AL, Grünewald J, Jourdan J, Lück M, Mensch C, Rösch D, Ruthemann A, Terres S, Völker ML, Wilhelm F, and Oehlmann J

Subjects
Amphipoda, Animals, Disorders of Sex Development chemically induced, Endocrine Disruptors toxicity, France, Osmotic Pressure drug effects, Time Factors, Biological Monitoring methods, Disorders of Sex Development physiopathology, Ecosystem, Osmotic Pressure physiology, Water Pollutants, Chemical toxicity
Abstract

In the past two decades, an increasing body of studies has been published on the intersex phenomenon in separate-sexed crustaceans from marine and freshwater ecosystems. Various causes are being considered that could have an influence on the occurrence of intersex. Besides genetic factors, environmental conditions such as photoperiodicity, temperature, salinity and parasitism, but also environmental pollution with endocrine disrupting chemicals (EDCs) are discussed. As part of a long-term monitoring (2012 - 2020) in north-west Brittany, we recorded the occurrence of intersex in the marine amphipod Echinogammarus marinus . We quantified the intersex incidence at marine and estuarine sites and analyzed the incidence in relation to the endocrine potential of the sediments. Intersex occurred with mean frequencies between 0.87% and 12%. It was striking that the incidence of intersex increased with increasing distance from the sea. Since the highest incidence was observed at the range boundary of this stenohaline species, we assume that intersex is triggered by endocrine potential and increasing stress due to increasing freshwater content - and thus an interplay of different environmental factors., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Oetken, Adler, Alt, Bachmann, Dombrowski, Duhme, Gabriel, Grünewald, Jourdan, Lück, Mensch, Rösch, Ruthemann, Terres, Völker, Wilhelm and Oehlmann.)

Published
2021
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31. Heat Perception and Coping Strategies: A Structured Interview-Based Study of Elderly People in Cologne, Germany.

Author

Kemen J, Schäffer-Gemein S, Grünewald J, and Kistemann T

Subjects
Aged, Female, Germany, Humans, Perception, Surveys and Questionnaires, Adaptation, Psychological, Hot Temperature
Abstract

The transdisciplinary project "Heat-Health Action Plan for Elderly People in Cologne" addresses the most heat-vulnerable risk group, people over 65 years of age. A quantitative study aimed to better understand heat perception and coping strategies of elderly people during heat waves to inform heat-health action plans. We conducted a representative quantitative survey via structured interviews with 258 randomly chosen people over 65 years old, living in their own homes in four areas of Cologne, Germany. These areas varied, both in terms of social status and heat strain. Data regarding demographics, health status, coping strategies, and heat perception were collected in personal interviews from August to October 2019. The majority of the participants perceived heat strain as moderate to very challenging. Women, people with a lower monthly income, and those with a lower health status found the heat more challenging. We found that participants adapted to heat with a number of body-related, home-protective, and activity-related coping strategies. The number of coping strategies was associated with perceived personal heat strain. There is a definite underuse of water-related heat adaption strategies among the elderly. This is of increasing relevance, as rising heat impact will lead to more heat-related geriatric morbidity. Our results are seminal to inform elderly-specific, socio-adapted local heat-health action plans.

Published
2021
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32. PrimeDesign software for rapid and simplified design of prime editing guide RNAs.

Author

Hsu JY, Grünewald J, Szalay R, Shih J, Anzalone AV, Lam KC, Shen MW, Petri K, Liu DR, Joung JK, and Pinello L

Subjects
Base Pairing, Base Sequence, CRISPR-Associated Protein 9 genetics, CRISPR-Associated Protein 9 metabolism, Clustered Regularly Interspaced Short Palindromic Repeats, Databases, Genetic, Fabry Disease genetics, Fabry Disease metabolism, Fabry Disease pathology, Green Fluorescent Proteins genetics, Green Fluorescent Proteins metabolism, HEK293 Cells, Hemophilia A genetics, Hemophilia A metabolism, Hemophilia A pathology, Humans, Models, Biological, Muscular Dystrophy, Duchenne genetics, Muscular Dystrophy, Duchenne metabolism, Muscular Dystrophy, Duchenne pathology, Mutation, Nucleic Acid Conformation, Plasmids chemistry, Plasmids metabolism, RNA, Guide, CRISPR-Cas Systems metabolism, Recombinant Fusion Proteins genetics, Recombinant Fusion Proteins metabolism, CRISPR-Cas Systems, Gene Editing methods, Genome, Human, RNA, Guide, CRISPR-Cas Systems genetics
Abstract

Prime editing (PE) is a versatile genome editing technology, but design of the required guide RNAs is more complex than for standard CRISPR-based nucleases or base editors. Here we describe PrimeDesign, a user-friendly, end-to-end web application and command-line tool for the design of PE experiments. PrimeDesign can be used for single and combination editing applications, as well as genome-wide and saturation mutagenesis screens. Using PrimeDesign, we construct PrimeVar, a comprehensive and searchable database that includes candidate prime editing guide RNA (pegRNA) and nicking sgRNA (ngRNA) combinations for installing or correcting >68,500 pathogenic human genetic variants from the ClinVar database. Finally, we use PrimeDesign to design pegRNAs/ngRNAs to install a variety of human pathogenic variants in human cells.

Published
2021
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33. A Code of Ethics for Gene Drive Research.

Author

Annas GJ, Beisel CL, Clement K, Crisanti A, Francis S, Galardini M, Galizi R, Grünewald J, Immobile G, Khalil AS, Müller R, Pattanayak V, Petri K, Paul L, Pinello L, Simoni A, Taxiarchi C, and Joung JK

Subjects
Ecosystem, Gene Editing, Humans, Introduced Species, Morals, Public Health, Codes of Ethics, Gene Drive Technology
Abstract

Gene drives hold promise for use in controlling insect vectors of diseases, agricultural pests, and for conservation of ecosystems against invasive species. At the same time, this technology comes with potential risks that include unknown downstream effects on entire ecosystems as well as the accidental or nefarious spread of organisms that carry the gene drive machinery. A code of ethics can be a useful tool for all parties involved in the development and regulation of gene drives and can be used to help ensure that a balanced analysis of risks, benefits, and values is taken into consideration in the interest of society and humanity. We have developed a code of ethics for gene drive research with the hope that this code will encourage the development of an international framework that includes ethical guidance of gene drive research and is incorporated into scientific practice by gaining broad agreement and adherence.

Published
2021
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34. CRISPR C-to-G base editors for inducing targeted DNA transversions in human cells.

Author

Kurt IC, Zhou R, Iyer S, Garcia SP, Miller BR, Langner LM, Grünewald J, and Joung JK

Subjects
Cytidine Deaminase metabolism, DNA genetics, DNA metabolism, Guanine metabolism, HEK293 Cells, Humans, CRISPR-Cas Systems genetics, Cytosine metabolism, Gene Editing methods
Abstract

CRISPR-guided DNA cytosine and adenine base editors are widely used for many applications 1-4 but primarily create DNA base transitions (that is, pyrimidine-to-pyrimidine or purine-to-purine). Here we describe the engineering of two base editor architectures that can efficiently induce targeted C-to-G base transversions, with reduced levels of unwanted C-to-W (W = A or T) and indel mutations. One of these C-to-G base editors (CGBE1), consists of an RNA-guided Cas9 nickase, an Escherichia coli-derived uracil DNA N-glycosylase (eUNG) and a rat APOBEC1 cytidine deaminase variant (R33A) previously shown to have reduced off-target RNA and DNA editing activities 5,6 . We show that CGBE1 can efficiently induce C-to-G edits, particularly in AT-rich sequence contexts in human cells. We also removed the eUNG domain to yield miniCGBE1, which reduced indel frequencies but only modestly decreased editing efficiency. CGBE1 and miniCGBE1 enable C-to-G edits and will serve as a basis for optimizing C-to-G base editors for research and therapeutic applications.

Published
2021
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35. A dual-deaminase CRISPR base editor enables concurrent adenine and cytosine editing.

Author

Grünewald J, Zhou R, Lareau CA, Garcia SP, Iyer S, Miller BR, Langner LM, Hsu JY, Aryee MJ, and Joung JK

Subjects
Adenine chemistry, Cytosine chemistry, HEK293 Cells, Humans, Mutation genetics, RNA genetics, CRISPR-Associated Protein 9 genetics, CRISPR-Cas Systems genetics, Cytosine Deaminase genetics, Gene Editing
Abstract

Existing adenine and cytosine base editors induce only a single type of modification, limiting the range of DNA alterations that can be created. Here we describe a CRISPR-Cas9-based synchronous programmable adenine and cytosine editor (SPACE) that can concurrently introduce A-to-G and C-to-T substitutions with minimal RNA off-target edits. SPACE expands the range of possible DNA sequence alterations, broadening the research applications of CRISPR base editors.

Published
2020
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36. CRISPR DNA base editors with reduced RNA off-target and self-editing activities.

Author

Grünewald J, Zhou R, Iyer S, Lareau CA, Garcia SP, Aryee MJ, and Joung JK

Subjects
APOBEC Deaminases genetics, APOBEC Deaminases metabolism, Animals, Cloning, Molecular, Flow Cytometry, Gene Expression Regulation, Enzymologic, Gene Targeting, HEK293 Cells, Humans, Petromyzon, Protein Conformation, RNA, RNA, Guide, CRISPR-Cas Systems genetics, Streptococcus pyogenes, Transcriptome, CRISPR-Cas Systems, Gene Editing methods
Abstract

Cytosine or adenine base editors (CBEs or ABEs) can introduce specific DNA C-to-T or A-to-G alterations 1-4 . However, we recently demonstrated that they can also induce transcriptome-wide guide-RNA-independent editing of RNA bases 5 , and created selective curbing of unwanted RNA editing (SECURE)-BE3 variants that have reduced unwanted RNA-editing activity 5 . Here we describe structure-guided engineering of SECURE-ABE variants with reduced off-target RNA-editing activity and comparable on-target DNA-editing activity that are also among the smallest Streptococcus pyogenes Cas9 base editors described to date. We also tested CBEs with cytidine deaminases other than APOBEC1 and found that the human APOBEC3A-based CBE induces substantial editing of RNA bases, whereas an enhanced APOBEC3A-based CBE 6 , human activation-induced cytidine deaminase-based CBE 7 , and the Petromyzon marinus cytidine deaminase-based CBE Target-AID 4 induce less editing of RNA. Finally, we found that CBEs and ABEs that exhibit RNA off-target editing activity can also self-edit their own transcripts, thereby leading to heterogeneity in base-editor coding sequences.

Published
2019
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37. Transcriptome-wide off-target RNA editing induced by CRISPR-guided DNA base editors.

Author

Grünewald J, Zhou R, Garcia SP, Iyer S, Lareau CA, Aryee MJ, and Joung JK

Subjects
APOBEC-1 Deaminase chemistry, APOBEC-1 Deaminase genetics, APOBEC-1 Deaminase metabolism, Animals, Base Sequence, Cytosine metabolism, Deamination, HEK293 Cells, Hep G2 Cells, Humans, Mutation, RNA chemistry, RNA metabolism, Rats, CRISPR-Cas Systems genetics, Gene Editing, RNA Editing, Substrate Specificity genetics, Transcriptome genetics
Abstract

CRISPR-Cas base-editor technology enables targeted nucleotide alterations, and is being increasingly used for research and potential therapeutic applications 1,2 . The most widely used cytosine base editors (CBEs) induce deamination of DNA cytosines using the rat APOBEC1 enzyme, which is targeted by a linked Cas protein-guide RNA complex 3,4 . Previous studies of the specificity of CBEs have identified off-target DNA edits in mammalian cells 5,6 . Here we show that a CBE with rat APOBEC1 can cause extensive transcriptome-wide deamination of RNA cytosines in human cells, inducing tens of thousands of C-to-U edits with frequencies ranging from 0.07% to 100% in 38-58% of expressed genes. CBE-induced RNA edits occur in both protein-coding and non-protein-coding sequences and generate missense, nonsense, splice site, and 5' and 3' untranslated region mutations. We engineered two CBE variants bearing mutations in rat APOBEC1 that substantially decreased the number of RNA edits (by more than 390-fold and more than 3,800-fold) in human cells. These variants also showed more precise on-target DNA editing than the wild-type CBE and, for most guide RNAs tested, no substantial reduction in editing efficiency. Finally, we show that an adenine base editor 7 can also induce transcriptome-wide RNA edits. These results have implications for the use of base editors in both research and clinical settings, illustrate the feasibility of engineering improved variants with reduced RNA editing activities, and suggest the need to more fully define and characterize the RNA off-target effects of deaminase enzymes in base editor platforms.

Published
2019
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38. GFR estimation in lenalidomide treatment of multiple myeloma patients: a prospective cohort study.

Author

Schmidts A, Grünewald J, Kleber M, Terpos E, Ihorst G, Reinhardt H, Walz G, Wäsch R, Engelhardt M, and Zschiedrich S

Subjects
Adult, Aged, Aged, 80 and over, Biomarkers blood, Creatinine blood, Drug Dosage Calculations, Female, Humans, Male, Middle Aged, Models, Biological, Multiple Myeloma complications, Multiple Myeloma diagnosis, Prospective Studies, Renal Insufficiency, Chronic etiology, Renal Insufficiency, Chronic physiopathology, Time Factors, Treatment Outcome, Antineoplastic Agents administration & dosage, Glomerular Filtration Rate, Kidney physiopathology, Lenalidomide administration & dosage, Multiple Myeloma drug therapy, Renal Insufficiency, Chronic diagnosis
Abstract

Background: The estimated glomerular filtration rate (eGFR) is clinically used to approximate renal function and adapt drug dosage. Multiple myeloma is a hematological disease; its prognosis is largely influenced by renal function. We evaluated two commonly used GFR estimations, CKD-EPI and MDRD (CKD Epidemiology Collaboration; Modification of Diet in Renal Disease) in myeloma patients undergoing treatment with lenalidomide, a renally excreted immunomodulatory drug., Methods: We prospectively studied 130 myeloma patients receiving lenalidomide treatment at our institution. At baseline and after 3 months, GFR estimations were performed based on the CKD-EPI and MDRD equations. We compared eGFR-dependent CKD staging and lenalidomide dosage assignments., Results: Initially, most patients were classified as CKD stage I/II, using both equations. Comparison of baseline renal function via CKD-EPI and MDRD induced concordance of CKD staging in 83% of patients, while CKD-EPI improved CKD staging in 16% of patients (p = 0.11). CKD-EPI assigned 3% of patients to higher lenalidomide dosing as opposed to MDRD. Both equations showed improved eGFR after 3 months of lenalidomide treatment., Conclusions: In our multiple myeloma patient cohort, CKD-EPI and MDRD led to similar CKD staging with minor differences in lenalidomide dosage assignment. Consistent with previous studies, eGFR improved under lenalidomide treatment. To standardize GFR estimation in myeloma patients, we suggest using the CKD-EPI equation.

Published
2019
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39. Site-Specific Antibody Labeling Using Phosphopantetheinyl Transferase-Catalyzed Ligation.

Author

Grünewald J, Brock A, and Geierstanger BH

Subjects
Antineoplastic Agents chemistry, Catalysis, Molecular Structure, Recombinant Proteins, Structure-Activity Relationship, Antibodies chemistry, Bacterial Proteins chemistry, Immunoconjugates chemistry, Transferases (Other Substituted Phosphate Groups) chemistry
Abstract

4'-Phosphopantetheinyl transferases (PPTases) have been employed by researchers as versatile biocatalysts for the site-specific modification of numerous protein targets with structurally diverse molecules. Here we describe the use of these enzymes for the production of homogeneous antibody-drug conjugates (ADCs), which have garnered much attention as innovative anticancer drugs. The exceptionally broad substrate tolerance of PPTases allows for one-step and two-step conjugation strategies for site-specific ADC synthesis. While one-step conjugation involves direct coupling of a drug molecule to an antibody, two-step conjugation provides increased flexibility and efficiency of the conjugation process by first attaching a bioorthogonal chemical handle that is then used for drug molecule attachment in a second step. The aim of this chapter is to outline detailed protocols for both labeling procedures, as well as to provide guidance on enzyme and substrate preparation.

Published
2019
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40. Optimization of an Enzymatic Antibody-Drug Conjugation Approach Based on Coenzyme A Analogs.

Author

Grünewald J, Jin Y, Vance J, Read J, Wang X, Wan Y, Zhou H, Ou W, Klock HE, Peters EC, Uno T, Brock A, and Geierstanger BH

Subjects
Aminobenzoates administration & dosage, Aminobenzoates chemistry, Animals, Cytotoxins administration & dosage, Drug Stability, Mice, Oligopeptides administration & dosage, Oligopeptides chemistry, Structure-Activity Relationship, Antibodies, Monoclonal chemistry, Coenzyme A chemistry, Cytotoxins chemistry, Immunoconjugates chemistry
Abstract

Phosphopantetheine transferases (PPTases) can be used to efficiently prepare site-specific antibody-drug conjugates (ADCs) by enzymatically coupling coenzyme A (CoA)-linker payloads to 11-12 amino acid peptide substrates inserted into antibodies. Here, a two-step strategy is established wherein in a first step, CoA analogs with various bioorthogonal reactivities are enzymatically installed on the antibody for chemical conjugation with a cytotoxic payload in a second step. Because of the high structural similarity of these CoA analogs to the natural PPTase substrate CoA-SH, the first step proceeds very efficiently and enables the use of peptide tags as short as 6 amino acids compared to the 11-12 amino acids required for efficient one-step coupling of the payload molecule. Furthermore, two-step conjugation provides access to diverse linker chemistries and spacers of varying lengths. The potency of the ADCs was largely independent of linker architecture. In mice, proteolytic cleavage was observed for some C-terminally linked auristatin payloads. The in vivo stability of these ADCs was significantly improved by reduction of the linker length. In addition, linker stability was found to be modulated by attachment site, and this, together with linker length, provides an opportunity for maximizing ADC stability without sacrificing potency.

Published
2017
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42. Efficient Preparation of Site-Specific Antibody-Drug Conjugates Using Phosphopantetheinyl Transferases.

Author

Grünewald J, Klock HE, Cellitti SE, Bursulaya B, McMullan D, Jones DH, Chiu HP, Wang X, Patterson P, Zhou H, Vance J, Nigoghossian E, Tong H, Daniel D, Mallet W, Ou W, Uno T, Brock A, Lesley SA, and Geierstanger BH

Subjects
Aminobenzoates chemistry, Aminobenzoates therapeutic use, Animals, Antineoplastic Agents chemistry, Antineoplastic Agents therapeutic use, Humans, Immunoconjugates chemistry, Immunoconjugates therapeutic use, Mice, Mice, Nude, Neoplasms metabolism, Oligopeptides chemistry, Oligopeptides therapeutic use, Peptides chemistry, Peptides metabolism, Substrate Specificity, Trastuzumab chemistry, Trastuzumab therapeutic use, Aminobenzoates metabolism, Antineoplastic Agents metabolism, Bacterial Proteins metabolism, Immunoconjugates metabolism, Neoplasms drug therapy, Oligopeptides metabolism, Transferases (Other Substituted Phosphate Groups) metabolism, Trastuzumab metabolism
Abstract

Post-translational modification catalyzed by phosphopantetheinyl transferases (PPTases) has previously been used to site-specifically label proteins with structurally diverse molecules. PPTase catalysis results in covalent modification of a serine residue in acyl/peptidyl carrier proteins and their surrogate substrates which are typically fused to the N- or C-terminus. To test the utility of PPTases for preparing antibody-drug conjugates (ADCs), we inserted 11 and 12-mer PPTase substrate sequences at 110 constant region loop positions of trastuzumab. Using Sfp-PPTase, 63 sites could be efficiently labeled with an auristatin toxin, resulting in 95 homogeneous ADCs. ADCs labeled in the CH1 domain displayed in general excellent pharmacokinetic profiles and negligible drug loss. A subset of CH2 domain conjugates underwent rapid clearance in mouse pharmacokinetic studies. Rapid clearance correlated with lower thermal stability of the particular antibodies. Independent of conjugation site, almost all ADCs exhibited subnanomolar in vitro cytotoxicity against HER2-positive cell lines. One selected ADC was shown to induce tumor regression in a xenograft model at a single dose of 3 mg/kg, demonstrating that PPTase-mediated conjugation is suitable for the production of highly efficacious and homogeneous ADCs.

Published
2015
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43. Spontaneous and electric field-controlled front-rear polarization of human keratinocytes.

Author

Saltukoglu D, Grünewald J, Strohmeyer N, Bensch R, Ulbrich MH, Ronneberger O, and Simons M

Subjects
Actin-Related Protein 2-3 Complex antagonists & inhibitors, Actin-Related Protein 2-3 Complex metabolism, Cell Line, Transformed, Cell Movement drug effects, Cell Movement physiology, Cell Polarity drug effects, Cytoskeleton drug effects, Cytoskeleton metabolism, Electric Stimulation, Electricity, Humans, Hydrogen-Ion Concentration, Indoles pharmacology, Keratinocytes drug effects, Keratinocytes metabolism, Signal Transduction, Cell Polarity physiology, Keratinocytes cytology
Abstract

It has long been known that electrical fields (EFs) are able to influence the direction of migrating cells, a process commonly referred to as electrotaxis or galvanotaxis. Most studies have focused on migrating cells equipped with an existing polarity before EF application, making it difficult to delineate EF-specific pathways. Here we study the initial events in front-rear organization of spreading keratinocytes to dissect the molecular requirements for random and EF-controlled polarization. We find that Arp2/3-dependent protrusive forces and Rac1/Cdc42 activity were generally required for both forms of polarization but were dispensable for controlling the direction of EF-controlled polarization. By contrast, we found a crucial role for extracellular pH as well as G protein coupled-receptor (GPCR) or purinergic signaling in the control of directionality. The normal direction of polarization toward the cathode was reverted by lowering extracellular pH. Polarization toward the anode was also seen at neutral pH when GPCR or purinergic signaling was inhibited. However, the stepwise increase of extracellular pH in this scenario led to restoration of cathodal polarization. Overall our work puts forward a model in which the EF uses distinct polarization pathways. The cathodal pathway involves GPCR/purinergic signaling and is dominant over the anodal pathway at neutral pH., (© 2015 Saltukoglu et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).)

Published
2015
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44. Isotope-Coded Labeling for Accelerated Protein Interaction Profiling Using MS.

Author

Venable JD, Steckler C, Ou W, Grünewald J, Agarwalla S, and Brock A

Subjects
Binding Sites, Isotope Labeling, Models, Molecular, Protein Structure, Secondary, Gas Chromatography-Mass Spectrometry, Protein Interaction Mapping methods, Proteins chemistry
Abstract

Protein interaction surface mapping using MS is widely applied but comparatively resource-intensive. Here, a workflow adaptation for use of isotope-coded tandem mass tags for the purpose is reported. The key benefit of improved throughput derived from sample acquisition multiplexing and automated analysis is shown to be maintained in the new application. Mapping of the epitopes of two monoclonal antibodies on their respective targets serves to illustrate the novel approach. We conclude that the approach enables mapping of interactions by MS at significantly larger scales than hereto possible.

Published
2015
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45. Site-specific dual labeling of proteins by using small orthogonal tags at neutral pH.

Author

Grünewald J, Jones DH, Brock A, Chiu HP, Bursulaya B, Ng K, Vo T, Patterson P, Uno T, Hunt J, Spraggon G, and Geierstanger BH

Subjects
Biosensing Techniques, Fluorescence Resonance Energy Transfer, Hydrogen-Ion Concentration, Lysine chemistry, Molecular Structure, Fluorescent Dyes chemistry, Lysine analogs & derivatives, Peptides chemistry, Proteins chemistry, Staining and Labeling methods
Abstract

To expand the utility of proteinaceous FRET biosensors, we have developed a dual-labeling approach based on two small bio-orthogonal tags: pyrroline-carboxy-lysine (Pcl) and the S6 peptide. The lack of cross-reactivity between those tags enables site-specific two-color protein conjugation in a one-pot reaction. Moreover, Pcl/S6 dual-tagged proteins can be produced in both bacterial and mammalian expression systems, as demonstrated for Z domain and IgE-Fc, respectively. Both proteins could be efficiently dual-labeled with FRET-compatible fluorescent dyes at neutral pH. In the case of IgE-Fc, the resulting conjugate enabled the monitoring of IgE binding to its high-affinity receptor FcεRI, which is a key event in allergic disease., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Published
2014
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46. Simultaneous purification and site-specific modification of pyrroline-carboxy-lysine proteins.

Author

Chiu HP, Grünewald J, Hao X, Brock A, Okach L, Uno T, and Geierstanger BH

Subjects
Benzaldehydes chemistry, Binding Sites, Lysine chemistry, Lysine metabolism, Molecular Structure, Lysine analogs & derivatives, Proteins chemistry, Proteins isolation & purification
Abstract

Sticky residue: Pyrroline-carboxy-lysine (Pcl) can be readily incorporated into proteins expressed in E. coli and mammalian cells by using the pyrrolysyl tRNA/tRNA synthetase pair. Pcl can be used as a single amino acid purification tag and can be site-specifically modified with functional probes during the elution process., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Published
2012
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47. Loss of CD4 T-cell-dependent tolerance to proteins with modified amino acids.

Author

Gauba V, Grünewald J, Gorney V, Deaton LM, Kang M, Bursulaya B, Ou W, Lerner RA, Schmedt C, Geierstanger BH, Schultz PG, and Ramirez-Montagut T

Subjects
Amino Acid Substitution, Amino Acids genetics, Animals, Autoantibodies immunology, CD4-Positive T-Lymphocytes metabolism, Electrophoresis, Polyacrylamide Gel, Enzyme-Linked Immunosorbent Assay, Epidermal Growth Factor genetics, Epidermal Growth Factor immunology, Epidermal Growth Factor metabolism, Epitopes immunology, Epitopes metabolism, Female, Immunization methods, Male, Mice, Mice, Inbred BALB C, Mice, Inbred C3H, Mice, Inbred C57BL, Mutant Proteins genetics, Mutant Proteins immunology, Phenylalanine analogs & derivatives, Phenylalanine genetics, Phenylalanine immunology, Time Factors, Tumor Necrosis Factor-alpha genetics, Tumor Necrosis Factor-alpha metabolism, Tyrosine analogs & derivatives, Tyrosine genetics, Tyrosine immunology, Amino Acids immunology, CD4-Positive T-Lymphocytes immunology, Immune Tolerance immunology, Tumor Necrosis Factor-alpha immunology
Abstract

The site-specific incorporation of the unnatural amino acid p-nitrophenylalanine (pNO(2)Phe) into autologous proteins overcomes self-tolerance and induces a long-lasting polyclonal IgG antibody response. To determine the molecular mechanism by which such simple modifications to amino acids are able to induce autoantibodies, we incorporated pNO(2)Phe, sulfotyrosine (SO(3)Tyr), and 3-nitrotyrosine (3NO(2)Tyr) at specific sites in murine TNF-α and EGF. A subset of TNF-α and EGF mutants with these nitrated or sulfated residues is highly immunogenic and induces antibodies against the unaltered native protein. Analysis of the immune response to the TNF-α mutants in different strains of mice that are congenic for the H-2 locus indicates that CD4 T-cell recognition is necessary for autoantibody production. IFN-γ ELISPOT analysis of CD4 T cells isolated from vaccinated mice demonstrates that peptides with mutated residues, but not the wild-type residues, are recognized. Immunization of these peptides revealed that a CD4 repertoire exists for the mutated peptides but is lacking for the wild-type peptides and that the mutated residues are processed, loaded, and presented on the I-A(b) molecule. Overall, our results illustrate that, although autoantibodies are generated against the endogenous protein, CD4 cells are activated through a neo-epitope recognition mechanism. Therefore, tolerance is maintained at a CD4 level but is broken at the level of antibody production. Finally, these results suggest that naturally occurring posttranslational modifications such as nitration may play a role in antibody-mediated autoimmune disorders.

Published
2011
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48. Site-specific protein modifications through pyrroline-carboxy-lysine residues.

Author

Ou W, Uno T, Chiu HP, Grünewald J, Cellitti SE, Crossgrove T, Hao X, Fan Q, Quinn LL, Patterson P, Okach L, Jones DH, Lesley SA, Brock A, and Geierstanger BH

Subjects
Culture Media, Escherichia coli genetics, Nuclear Magnetic Resonance, Biomolecular, Lysine chemistry, Proteins chemistry, Pyrroles chemistry
Abstract

Pyrroline-carboxy-lysine (Pcl) is a demethylated form of pyrrolysine that is generated by the pyrrolysine biosynthetic enzymes when the growth media is supplemented with D-ornithine. Pcl is readily incorporated by the unmodified pyrrolysyl-tRNA/tRNA synthetase pair into proteins expressed in Escherichia coli and in mammalian cells. Here, we describe a broadly applicable conjugation chemistry that is specific for Pcl and orthogonal to all other reactive groups on proteins. The reaction of Pcl with 2-amino-benzaldehyde or 2-amino-acetophenone reagents proceeds to near completion at neutral pH with high efficiency. We illustrate the versatility of the chemistry by conjugating Pcl proteins with poly(ethylene glycol)s, peptides, oligosaccharides, oligonucleotides, fluorescence, and biotin labels and other small molecules. Because Pcl is genetically encoded by TAG codons, this conjugation chemistry enables enhancements of the pharmacology and functionality of proteins through site-specific conjugation.

Published
2011
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49. D-Ornithine coopts pyrrolysine biosynthesis to make and insert pyrroline-carboxy-lysine.

Author

Cellitti SE, Ou W, Chiu HP, Grünewald J, Jones DH, Hao X, Fan Q, Quinn LL, Ng K, Anfora AT, Lesley SA, Uno T, Brock A, and Geierstanger BH

Subjects
Amino Acid Sequence, Escherichia coli, Gene Expression Regulation physiology, HEK293 Cells, Humans, Lysine biosynthesis, Lysine chemistry, Methanosarcina genetics, Methanosarcina metabolism, Molecular Structure, Ornithine chemistry, Ornithine metabolism, Plasmids, Promoter Regions, Genetic, Lysine analogs & derivatives, Ornithine pharmacology
Abstract

D-ornithine has previously been suggested to enhance the expression of pyrrolysine-containing proteins. We unexpectedly discovered that uptake of D-ornithine results in the insertion of a new amino acid, pyrroline-carboxy-lysine (Pcl) instead of the anticipated pyrrolysine (Pyl). Our feeding and biochemical studies point to specific roles of the poorly understood Pyl biosynthetic enzymes PylC and PylD in converting L-lysine and D-ornithine to Pcl and confirm intermediates in the biosynthesis of Pyl.

Published
2011
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50. Regulation of Frizzled-dependent planar polarity signaling by a V-ATPase subunit.

Author

Hermle T, Saltukoglu D, Grünewald J, Walz G, and Simons M

Subjects
Animals, Drosophila genetics, Immunohistochemistry, Immunoprecipitation, Wings, Animal growth & development, Wings, Animal metabolism, Cell Polarity physiology, Drosophila physiology, Drosophila Proteins metabolism, Frizzled Receptors metabolism, Membrane Proteins metabolism, Receptors, G-Protein-Coupled metabolism, Signal Transduction physiology, Vacuolar Proton-Translocating ATPases metabolism
Abstract

Frizzled (Fz) is a seven-pass transmembrane receptor that acts in both Wingless (Wg) and planar cell polarity (PCP) pathways. A prerequisite for PCP signaling is the asymmetric subcellular distribution of Fz. However, the regulation of Fz asymmetry is currently not well understood. Here we describe that the transmembrane protein CG8444 (here termed VhaPRR) is needed for PCP signaling in Drosophila. VhaPRR is an accessory subunit of the vacuolar (V)-ATPase proton pump, but it also functions as a receptor for (pro)renin (PRR) in mammals. We show that VhaPRR function is tightly linked with Fz but not other PCP core proteins. Fz fails to localize asymmetrically in the absence of VhaPRR, and this is accompanied by prehair mispolarization of pupal wing cells. In addition, VhaPRR forms a protein complex with Fz receptors and interacts genetically with Fz in the Drosophila eye. VhaPRR also acts as a modulator of canonical Wnt signaling in larval and adult wing tissue. Its loss leads to an expansion of the Wg morphogen gradient and a reduction of Wg target gene expression. The requirement for additional V-ATPase subunits suggests that proton fluxes contribute to normal Fz receptor function and signaling., (2010 Elsevier Ltd. All rights reserved.)

Published
2010
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