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1. STAR LIGHT Study: XBB.1.5 COVID-19 mRNA Vaccines Boost Systemic but Not Mucosal Immunity Against the SARS-CoV-2 JN.1 Variant in Patients with Chronic Liver Disease

Author

Simon Woelfel, Daniel Junker, Irina Bergamin, Pamela Meyer-Herbon, Roman Stillhard, Nicole Graf, Georg Leinenkugel, Joel Dütschler, Marius König, Livia Kammerlander, Rahel Häuptle, Sarah Zwyssig, Claudia Krieger, Samuel Truniger, Seraina Koller, Katline Metzger-Peter, Nicola Frei, STAR SIGN Study Investigators, Werner C. Albrich, Matthias Friedrich, Christine Bernsmeier, Jan Hendrik Niess, Wolfgang Korte, Justus J. Bürgi, Alex Dulovic, Nicole Schneiderhan-Marra, David Semela, and Stephan Brand

Subjects
COVID-19, SARS-CoV-2, mRNA vaccines, XBB.1.5 vaccines, chronic liver disease, liver transplantation, Medicine
Abstract

Background: Patients with chronic liver disease (CLD) have impaired vaccine immunogenicity and an excess risk of severe COVID-19. While variant-adapted COVID-19 mRNA vaccines are recommended for vulnerable individuals, their efficacy in patients with CLD has not been studied. Methods: We present the first evaluation of XBB.1.5 COVID-19 vaccine immunogenicity against the SARS-CoV-2 JN.1 variant in patients with CLD. Serum anti-receptor binding domain (RBD) IgG, neutralization, and saliva anti-RBD IgG and IgA against wild-type SARS-CoV-2 (WT) and the XBB.1.5, EG.5.1, BA.2.86, and JN.1 variants were quantified before and 2–4 weeks following a fourth dose of XBB.1.5 mRNA vaccines. Results: Vaccination boosted anti-RBD IgG and neutralization against all tested variants including JN.1 (each p < 0.001). Following immunization, neutralization was lower against JN.1 compared to WT, XBB.1.5, and EG.5.1 (p < 0.001, p < 0.001, and p < 0.01, respectively). Vaccination reduced neutralization failure rates against BA.2.86 and JN.1 (each p < 0.05). The evasion of vaccine-induced antibodies by the tested variants was low, indicated by the positive correlation between anti-RBD IgG and neutralization. At mucosal sites, vaccination boosted anti-RBD IgG (each p < 0.01) but failed to induce infection-blocking IgA (each p > 0.05). Conclusion: XBB.1.5 vaccines protect CLD patients against recent SARS-CoV-2 variants, but developing vaccines with optimized mucosal immunogenicity is required to prevent SARS-CoV-2 transmission and recurrent seasonal COVID-19 outbreaks.

Published
2024
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2. Systemic and Mucosal Immunogenicity of Monovalent XBB.1.5-Adapted COVID-19 mRNA Vaccines in Patients with Inflammatory Bowel Disease

Author

Simon Woelfel, Joel Dütschler, Daniel Junker, Marius König, Georg Leinenkugel, Nicole Graf, Claudia Krieger, Samuel Truniger, Annett Franke, Seraina Koller, Katline Metzger-Peter, Melanie Oberholzer, Nicola Frei, Nora Geissler, Peter Schaub, STAR SIGN Investigators, Werner C. Albrich, Matthias Friedrich, Jan Hendrik Niess, Nicole Schneiderhan-Marra, Alex Dulovic, Wolfgang Korte, Justus J. Bürgi, and Stephan Brand

Subjects
XBB.1.5-adapted COVID-19 vaccines, mRNA vaccines, inflammatory bowel disease, anti-TNF therapy, SARS-CoV-2, COVID-19, Medicine
Abstract

Recently updated COVID-19 mRNA vaccines encode the spike protein of the omicron subvariant XBB.1.5 and are recommended for patients with inflammatory bowel disease (IBD) on immunosuppressive treatment. Nonetheless, their immunogenicity in patients with IBD against rapidly expanding virus variants remains unknown. This prospective multicenter cohort study is the first study to investigate the immunogenicity of XBB.1.5-adapted vaccines in patients with IBD. Systemic and mucosal antibodies targeting the receptor-binding domains (RBDs) of the omicron subvariants XBB.1.5, EG.5.1, and BA.2.86, as well as their neutralization were quantified before and two to four weeks after vaccination with monovalent XBB.1.5-adapted mRNA vaccines. Vaccination increased levels of serum anti-RBD IgG targeting XBB.1.5, EG.5.1, and BA.2.86 (1.9-fold, 1.8-fold, and 2.6-fold, respectively) and enhanced corresponding neutralization responses (2.3-fold, 3.1-fold, and 3.5-fold, respectively). Following vaccination, anti-TNF-treated patients had reduced virus neutralization compared to patients on treatments with other cellular targets. 11.1% and 16.7% of patients lacked EG.5.1 and BA.2.86 neutralization, respectively; all these patients received anti-TNF treatment. At mucosal sites, vaccination induced variant-specific anti-RBD IgG but failed to induce RBD-targeting IgA. Our findings provide a basis for future vaccine recommendations while highlighting the importance of frequent booster vaccine adaptation and the need for mucosal vaccination strategies in patients with IBD.

Published
2024
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4. A conserved population of MHC II-restricted, innate-like, commensal-reactive T cells in the gut of humans and mice

Author

Carl-Philipp Hackstein, Dana Costigan, Linnea Drexhage, Claire Pearson, Samuel Bullers, Nicholas Ilott, Hossain Delowar Akther, Yisu Gu, Michael E. B. FitzPatrick, Oliver J. Harrison, Lucy C. Garner, Elizabeth H. Mann, Sumeet Pandey, Matthias Friedrich, Nicholas M. Provine, Holm H. Uhlig, Emanuele Marchi, Fiona Powrie, Paul Klenerman, and Emily E. Thornton

Subjects
Science
Abstract

Interactions between the host immune response and the commensal microbiota play essential roles in health and disease. Here the authors identify a population of MHC class II, innate like, commensal reactive cells in the gut of mice and humans.

Published
2022
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5. Simultaneous multi-parametric acquisition and reconstruction techniques in cardiac magnetic resonance imaging: Basic concepts and status of clinical development

Author

Katerina Eyre, Katherine Lindsay, Saad Razzaq, Michael Chetrit, and Matthias Friedrich

Subjects
cardiac MRI (CMR), undersampled acquisition, fast cardiac imaging, multiparametric cardiovascular magnetic resonance imaging, sub-Nyquist sampling, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Simultaneous multi-parametric acquisition and reconstruction techniques (SMART) are gaining attention for their potential to overcome some of cardiovascular magnetic resonance imaging’s (CMR) clinical limitations. The major advantages of SMART lie within their ability to simultaneously capture multiple “features” such as cardiac motion, respiratory motion, T1/T2 relaxation. This review aims to summarize the overarching theory of SMART, describing key concepts that many of these techniques share to produce co-registered, high quality CMR images in less time and with less requirements for specialized personnel. Further, this review provides an overview of the recent developments in the field of SMART by describing how they work, the parameters they can acquire, their status of clinical testing and validation, and by providing examples for how their use can improve the current state of clinical CMR workflows. Many of the SMART are in early phases of development and testing, thus larger scale, controlled trials are needed to evaluate their use in clinical setting and with different cardiac pathologies.

Published
2022
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6. Impact of COVID-19 Pandemic on Cardiovascular Testing in Asia

Author

Takashi Kudo, MD, PhD, Ryan Lahey, MD, PhD, Cole B. Hirschfeld, MD, Michelle C. Williams, MBChB, PhD, Bin Lu, MD, PhD, Mirvat Alasnag, MD, Mona Bhatia, MD, Hee-Seung Henry Bom, MD, PhD, Tairkhan Dautov, MD, Reza Fazel, MD, MSc, Ganesan Karthikeyan, MD, Felix Y.J. Keng, MBBS, Ronen Rubinshtein, MD, Nathan Better, MBBS, Rodrigo Julio Cerci, MD, Sharmila Dorbala, MD, MPH, Paolo Raggi, MD, Leslee J. Shaw, PhD, Todd C. Villines, MD, João V. Vitola, MD, PhD, Andrew D. Choi, MD, Eli Malkovskiy, Benjamin Goebel, BS, Yosef A. Cohen, BA, Michael Randazzo, MD, Thomas N.B. Pascual, MD, Yaroslav Pynda, MSc, Maurizio Dondi, MD, PhD, Diana Paez, MD, MEd, Andrew J. Einstein, MD, PhD, Andrew J. Einstein, Diana Paez, Maurizio Dondi, Nathan Better, Rodrigo Cerci, Sharmila Dorbala, Thomas N.B. Pascual, Paolo Raggi, Leslee J. Shaw, Todd C. Villines, Joao V. Vitola, Michelle C. Williams, Yaroslav Pynda, Gerd Hinterleitner, Yao Lu, Olga Morozova, Zhuoran Xu, Cole B. Hirschfeld, Yosef Cohen, Benjamin Goebel, Michael Randazzo, Andrew Choi, Juan Lopez-Mattei, Purvi Parwani, Mohammad Nawaz Nasery, Artan Goda, Ervina Shirka, Rabie Benlabgaa, Salah Bouyoucef, Abdelkader Medjahedi, Qais Nailli, Mariela Agolti, Roberto Nicolas Aguero, Maria del Carmen Alak, Lucia Graciela Alberguina, Guillermo Arroñada, Andrea Astesiano, Alfredo Astesiano, Carolina Bas Norton, Pablo Benteo, Juan Blanco, Juan Manuel Bonelli, Jose Javier Bustos, Raul Cabrejas, Jorge Cachero, Roxana Campisi, Alejandro Canderoli, Silvia Carames, Patrícia Carrascosa, Ricardo Castro, Oscar Cendoya, Luciano Martin Cognigni, Carlos Collaud, Claudia Cortes, Javier Courtis, Daniel Cragnolino, Mariana Daicz, Alejandro De La Vega, Silvia Teresa De Maria, Horacio Del Riego, Fernando Dettori, Alejandro Deviggiano, Laura Dragonetti, Mario Embon, Ruben Emilio Enriquez, Jorge Ensinas, Fernando Faccio, Adolfo Facello, Diego Garofalo, Ricardo Geronazzo, Natalia Gonza, Lucas Gutierrez, Miguel Angel Guzzo, Victor Hasbani, Melina Huerin, Victor Jäger, Julio Manuel Lewkowicz, Maria Nieves A. López De Munaín, Jose Maria Lotti, Alejandra Marquez, Osvaldo Masoli, Osvaldo Horacio Masoli, Edgardo Mastrovito, Matias Mayoraz, Graciela Eva Melado, Anibal Mele, Maria Fernanda Merani, Alejandro Horacio Meretta, Susana Molteni, Marcos Montecinos, Eduardo Noguera, Carlos Novoa, Claudio Pereyra Sueldo, Sebastian Perez Ascani, Pablo Pollono, Maria Paula Pujol, Alejandro Radzinschi, Gustavo Raimondi, Marcela Redruello, Marina Rodríguez, Matías Rodríguez, Romina Lorena Romero, Arturo Romero Acuña, Federico Rovaletti, Lucas San Miguel, Lucrecia Solari, Bruno Strada, Sonia Traverso, Sonia Simona Traverzo, Maria del Huerto Velazquez Espeche, Juan Sebastian Weihmuller, Juan Wolcan, Susana Zeffiro, Mari Sakanyan, Scott Beuzeville, Raef Boktor, Patrick Butler, Jennifer Calcott, Loretta Carr, Virgil Chan, Charles Chao, Woon Chong, Mark Dobson, D'Arne Downie, Girish Dwivedi, Barry Elison, Jean Engela, Roslyn Francis, Anand Gaikwad, Ashok Gangasandra Basavaraj, Bruce Goodwin, Robert Greenough, Christian Hamilton-Craig, Victar Hsieh, Subodh Joshi, Karin Lederer, Kenneth Lee, Joseph Lee, John Magnussen, Nghi Mai, Gordon Mander, Fiona Murton, Dee Nandurkar, Johanne Neill, Edward O'Rourke, Patricia O'Sullivan, George Pandos, Kunthi Pathmaraj, Alexander Pitman, Rohan Poulter, Manuja Premaratne, David Prior, Lloyd Ridley, Natalie Rutherford, Hamid Salehi, Connor Saunders, Luke Scarlett, Sujith Seneviratne, Deepa Shetty, Ganesh Shrestha, Jonathan Shulman, Vijay Solanki, Tony Stanton, Murch Stuart, Michael Stubbs, Ian Swainson, Kim Taubman, Andrew Taylor, Paul Thomas, Steven Unger, Anthony Upton, Shankar Vamadevan, William Van Gaal, Johan Verjans, Demetrius Voutnis, Victor Wayne, Peter Wilson, David Wong, Kirby Wong, John Younger, Gudrun Feuchtner, Siroos Mirzaei, Konrad Weiss, Natallia Maroz-Vadalazhskaya, Olivier Gheysens, Filip Homans, Rodrigo Moreno-Reyes, Agnès Pasquet, Veronique Roelants, Caroline M. Van De Heyning, Raúl Araujo Ríos, Valentina Soldat-Stankovic, Sinisa Stankovic, Maria Helena Albernaz Siqueira, Augusto Almeida, Paulo Henrique Alves Togni, Jose Henrique Andrade, Luciana Andrade, Carlos Anselmi, Roberta Araújo, Guilherme Azevedo, Sabbrina Bezerra, Rodrigo Biancardi, Gabriel Blacher Grossman, Simone Brandão, Diego Bromfman Pianta, Lara Carreira, Bruno Castro, Tien Chang, Fernando Cunali, Jr., Roberto Cury, Roberto Dantas, Fernando de Amorim Fernandes, Andrea De Lorenzo, Robson De Macedo Filho, Fernanda Erthal, Fabio Fernandes, Juliano Fernandes, Thiago Ferreira De Souza, Wilson Furlan Alves, Bruno Ghini, Luiz Goncalves, Ilan Gottlieb, Marcelo Hadlich, Vinícius Kameoka, Ronaldo Lima, Adna Lima, Rafael Willain Lopes, Ricardo Machado e Silva, Tiago Magalhães, Fábio Martins Silva, Luiz Eduardo Mastrocola, Fábio Medeiros, José Claudio Meneghetti, Vania Naue, Danilo Naves, Roberto Nolasco, Cesar Nomura, Joao Bruno Oliveira, Eduardo Paixao, Filipe Penna De Carvalho, Ibraim Pinto, Priscila Possetti, Mayra Quinta, Rodrigo Rizzo Nogueira Ramos, Ricardo Rocha, Alfredo Rodrigues, Carlos Rodrigues, Leila Romantini, Adelina Sanches, Sara Santana, Leonardo Sara da Silva, Paulo Schvartzman, Cristina Sebastião Matushita, Tiago Senra, Afonso Shiozaki, Maria Eduarda Menezes de Siqueira, Cristiano Siqueira, Paola Smanio, Carlos Eduardo Soares, José Soares Junior, Marcio Sommer Bittencourt, Bernardo Spiro, Cláudio Tinoco Mesquita, Jorge Torreao, Rafael Torres, Marly Uellendahl, Guilherme Urpia Monte, Otávia Veríssimo, Estevan Vieira Cabeda, Felipe Villela Pedras, Roberto Waltrick, Marcello Zapparoli, Hamid Naseer, Marina Garcheva-Tsacheva, Irena Kostadinova, Youdaline Theng, Gad Abikhzer, Rene Barette, Benjamin Chow, Dominique Dabreo, Matthias Friedrich, Ria Garg, Mohammed Nassoh Hafez, Chris Johnson, Marla Kiess, Jonathon Leipsic, Eugene Leung, Robert Miller, Anastasia Oikonomou, Stephan Probst, Idan Roifman, Gary Small, Vikas Tandon, Adwait Trivedi, James White, Katherine Zukotynski, Jose Canessa, Gabriel Castro Muñoz, Carmen Concha, Pablo Hidalgo, Cesar Lovera, Teresa Massardo, Luis Salazar Vargas, Pedro Abad, Harold Arturo, Sandra Ayala, Luis Benitez, Alberto Cadena, Carlos Caicedo, Antonio Calderón Moncayo, Sharon Gomez, Claudia T. Gutierrez Villamil, Claudia Jaimes, Juan Londoño, Juan Luis Londoño Blair, Luz Pabon, Mauricio Pineda, Juan Carlos Rojas, Diego Ruiz, Manuel Valencia Escobar, Andres Vasquez, Damiana Vergel, Alejandro Zuluaga, Isabel Berrocal Gamboa, Gabriel Castro, Ulises González, Ana Baric, Tonci Batinic, Maja Franceschi, Maja Hrabak Paar, Mladen Jukic, Petar Medakovic, Viktor Persic, Marina Prpic, Ante Punda, Juan Felipe Batista, Juan Manuel Gómez Lauchy, Yamile Marcos Gutierrez, Rayner Menéndez, Amalia Peix, Luis Rochela, Christoforos Panagidis, Ioannis Petrou, Vaclav Engelmann, Milan Kaminek, Vladimír Kincl, Otto Lang, Milan Simanek, Jawdat Abdulla, Morten Bøttcher, Mette Christensen, Lars Christian Gormsen, Philip Hasbak, Søren Hess, Paw Holdgaard, Allan Johansen, Kasper Kyhl, Bjarne Linde Norgaard, Kristian Altern Øvrehus, Niels Peter Rønnow Sand, Rolf Steffensen, Anders Thomassen, Bo Zerahn, Alfredo Perez, Giovanni Alejandro Escorza Velez, Mayra Sanchez Velez, Islam Shawky Abdel Aziz, Mahasen Abougabal, Taghreed Ahmed, Adel Allam, Ahmed Asfour, Mona Hassan, Alia Hassan, Ahmed Ibrahim, Sameh Kaffas, Ahmed Kandeel, Mohamed Mandour Ali, Ahmad Mansy, Hany Maurice, Sherif Nabil, Mahmoud Shaaban, Ana Camila Flores, Anne Poksi, Juhani Knuuti, Velipekka Kokkonen, Martti Larikka, Valtteri Uusitalo, Matthieu Bailly, Samuel Burg, Jean-François Deux, Vincent Habouzit, Fabien Hyafil, Olivier Lairez, Franck Proffit, Hamza Regaieg, Laure Sarda-Mantel, Vania Tacher, Roman P. Schneider, Harold Ayetey, George Angelidis, Aikaterini Archontaki, Sofia Chatziioannou, Ioannis Datseris, Christina Fragkaki, Panagiotis Georgoulias, Sophia Koukouraki, Maria Koutelou, Eleni Kyrozi, Evangelos Repasos, Petros Stavrou, Pipitsa Valsamaki, Carla Gonzalez, Goleat Gutierrez, Alejandro Maldonado, Klara Buga, Ildiko Garai, Pál Maurovich-Horvat, Erzsébet Schmidt, Balint Szilveszter, Edit Várady, Nilesh Banthia, Jinendra Kumar Bhagat, Rishi Bhargava, Vivek Bhat, Mona Bhatia, Partha Choudhury, Vijay Sai Chowdekar, Aparna Irodi, Shashank Jain, Elizabeth Joseph, Sukriti Kumar, Prof Dr Girijanandan Mahapatra, Deepanjan Mitra, Bhagwant Rai Mittal, Ahmad Ozair, Chetan Patel, Tapan Patel, Ravi Patel, Shivani Patel, Sudhir Saxena, Shantanu Sengupta, Santosh Singh, Bhanupriya Singh, Ashwani Sood, Atul Verma, Erwin Affandi, Padma Savenadia Alam, Edison Edison, Gani Gunawan, Habusari Hapkido, Basuki Hidayat, Aulia Huda, Anggoro Praja Mukti, Djoko Prawiro, Erwin Affandi Soeriadi, Hilman Syawaluddin, Amjed Albadr, Majid Assadi, Farshad Emami, Golnaz Houshmand, Majid Maleki, Maryam Tajik Rostami, Seyed Rasoul Zakavi, Eed Abu Zaid, Svetlana Agranovich, Yoav Arnson, Rachel Bar-Shalom, Alex Frenkel, Galit Knafo, Rachel Lugassi, Israel Shlomo Maor Moalem, Maya Mor, Noam Muskal, Sara Ranser, Aryeh Shalev, Domenico Albano, Pierpaolo Alongi, Gaspare Arnone, Elisa Bagatin, Sergio Baldari, Matteo Bauckneht, Paolo Bertelli, Francesco Bianco, Rachele Bonfiglioli, Roberto Boni, Andrea Bruno, Isabella Bruno, Elena Busnardo, Elena Califaretti, Luca Camoni, Aldo Carnevale, Roberta Casoni, Armando Ugo Cavallo, Giorgio Cavenaghi, Franca Chierichetti, Marcello Chiocchi, Corrado Cittanti, Mauro Colletta, Umberto Conti, Alberto Cossu, Alberto Cuocolo, Marco Cuzzocrea, Maria Luisa De Rimini, Giuseppe De Vincentis, Eleonora Del Giudice, Alberico Del Torto, Veronica Della Tommasina, Rexhep Durmo, Paola Anna Erba, Laura Evangelista, Riccardo Faletti, Evelina Faragasso, Mohsen Farsad, Paola Ferro, Luigia Florimonte, Viviana Frantellizzi, Fabio Massimo Fringuelli, Marco Gatti, Angela Gaudiano, Alessia Gimelli, Raffaele Giubbini, Francesca Giuffrida, Salvatore Ialuna, Riccardo Laudicella, Lucia Leccisotti, Lucia Leva, Riccardo Liga, Carlo Liguori, Giampiero Longo, Margherita Maffione, Maria Elisabetta Mancini, Claudio Marcassa, Elisa Milan, Barbara Nardi, Sara Pacella, Giovanna Pepe, Gianluca Pontone, Sabina Pulizzi, Natale Quartuccio, Lucia Rampin, Fabrizio Ricci, Pierluigi Rossini, Giuseppe Rubini, Vincenzo Russo, Gian Mauro Sacchetti, Gianmario Sambuceti, Massimo Scarano, Roberto Sciagrà, Massimiliano Sperandio, Antonella Stefanelli, Guido Ventroni, Stefania Zoboli, Dainia Baugh, Duane Chambers, Ernest Madu, Felix Nunura, Hiroshi Asano, Chimura Misato Chimura, Shinichiro Fujimoto, Koichiro Fujisue, Tomohisa Fukunaga, Yoshimitsu Fukushima, Kae Fukuyama, Jun Hashimoto, Yasutaka Ichikawa, Nobuo Iguchi, Masamichi Imai, Anri Inaki, Hayato Ishimura, Satoshi Isobe, Toshiaki Kadokami, Takao Kato, Takashi Kudo, Shinichiro Kumita, Hirotaka Maruno, Hiroyuki Mataki, Masao Miyagawa, Ryota Morimoto, Masao Moroi, Shigeki Nagamachi, Kenichi Nakajima, Tomoaki Nakata, Ryo Nakazato, Mamoru Nanasato, Masanao Naya, Takashi Norikane, Yasutoshi Ohta, Satoshi Okayama, Atsutaka Okizaki, Yoichi Otomi, Hideki Otsuka, Masaki Saito, Sakata Yasushi Sakata, Masayoshi Sarai, Daisuke Sato, Shinya Shiraishi, Yoshinobu Suwa, Kentaro Takanami, Kazuya Takehana, Junichi Taki, Nagara Tamaki, Yasuyo Taniguchi, Hiroki Teragawa, Nobuo Tomizawa, Kenichi Tsujita, Kyoko Umeji, Yasushi Wakabayashi, Shinichiro Yamada, Shinya Yamazaki, Tatsuya Yoneyama, Mohammad Rawashdeh, Daultai Batyrkhanov, Tairkhan Dautov, Khalid Makhdomi, Kevin Ombati, Faridah Alkandari, Masoud Garashi, Tchoyoson Lim Coie, Sonexay Rajvong, Artem Kalinin, Marika Kalnina, Mohamad Haidar, Renata Komiagiene, Giedre Kviecinskiene, Mindaugas Mataciunas, Donatas Vajauskas, Christian Picard, Noor Khairiah A. Karim, Luise Reichmuth, Anthony Samuel, Mohammad Aaftaab Allarakha, Ambedhkar Shantaram Naojee, Erick Alexanderson-Rosas, Erika Barragan, Alejandro Becerril González-Montecinos, Manuel Cabada, Daniel Calderon Rodriguez, Isabel Carvajal-Juarez, Violeta Cortés, Filiberto Cortés, Erasmo De La Peña, Manlio Gama-Moreno, Luis González, Nelsy Gonzalez Ramírez, Moisés Jiménez-Santos, Luis Matos, Edgar Monroy, Martha Morelos, Mario Ornelas, Jose Alberto Ortga Ramirez, Andrés Preciado-Anaya, Óscar Ulises Preciado-Gutiérrez, Adriana Puente Barragan, Sandra Graciela Rosales Uvera, Sigelinda Sandoval, Miguel Santaularia Tomas, Lilia M. Sierra-Galan, Silvia Siu, Enrique Vallejo, Mario Valles, Marc Faraggi, Erdenechimeg Sereegotov, Srdja Ilic, Nozha Ben-Rais, Nadia Ismaili Alaoui, Sara Taleb, Khin Pa Pa Myo, Phyo Si Thu, Ram Kumar Ghimire, Bijoy Rajbanshi, Peter Barneveld, Andor Glaudemans, Jesse Habets, Klaas Pieter Koopmans, Jeroen Manders, Stefan Pool, Arthur Scholte, Asbjørn Scholtens, Riemer Slart, Paul Thimister, Erik-Jan Van Asperen, Niels Veltman, Derk Verschure, Nils Wagenaar, John Edmond, Chris Ellis, Kerryanne Johnson, Ross Keenan, Shaw Hua (Anthony) Kueh, Christopher Occleshaw, Alexander Sasse, Andrew To, Niels Van Pelt, Calum Young, Teresa Cuadra, Hector Bladimir Roque Vanegas, Idrissa Adamou Soli, Djibrillou Moussa Issoufou, Tolulope Ayodele, Chibuzo Madu, Yetunde Onimode, Elen Efros-Monsen, Signe Helene Forsdahl, Jenni-Mari Hildre Dimmen, Arve Jørgensen, Isabel Krohn, Pål Løvhaugen, Anders Tjellaug Bråten, Humoud Al Dhuhli, Faiza Al Kindi, Naeema Al-Bulushi, Zabah Jawa, Naima Tag, Muhammad Shehzad Afzal, Shazia Fatima, Muhammad Numair Younis, Musab Riaz, Mohammad Saadullah, Yariela Herrera, Dora Lenturut-Katal, Manuel Castillo Vázquez, José Ortellado, Afroza Akhter, Dianbo Cao, Stephen Cheung, Xu Dai, Lianggeng Gong, Dan Han, Yang Hou, Caiying Li, Tao Li, Dong Li, Sijin Li, Jinkang Liu, Hui Liu, Bin Lu, Ming Yen Ng, Kai Sun, Gongshun Tang, Jian Wang, Ximing Wang, Zhao-Qian Wang, Yining Wang, Yifan Wang, Jiang Wu, Zhifang Wu, Liming Xia, Jiangxi Xiao, Lei Xu, Youyou Yang, Wu Yin, Jianqun Yu, Li Yuan, Tong Zhang, Longjiang Zhang, Yong-Gao Zhang, Xiaoli Zhang, Li Zhu, Ana Alfaro, Paz Abrihan, Asela Barroso, Eric Cruz, Marie Rhiamar Gomez, Vincent Peter Magboo, John Michael Medina, Jerry Obaldo, Davidson Pastrana, Christian Michael Pawhay, Alvin Quinon, Jeanelle Margareth Tang, Bettina Tecson, Kristine Joy Uson, Mila Uy, Magdalena Kostkiewicz, Jolanta Kunikowska, Nuno Bettencourt, Guilhermina Cantinho, Antonio Ferreira, Ghulam Syed, Samer Arnous, Said Atyani, Angela Byrne, Tadhg Gleeson, David Kerins, Conor Meehan, David Murphy, Mark Murphy, John Murray, Julie O'Brien, Ji-In Bang, Henry Bom, Sang-Geon Cho, Chae Moon Hong, Su Jin Jang, Yong Hyu Jeong, Won Jun Kang, Ji-Young Kim, Jaetae Lee, Chang Kyeong Namgung, Young So, Kyoung Sook Won, Venjamin Majstorov, Marija Vavlukis, Barbara Gužic Salobir, Monika Štalc, Theodora Benedek, Imre Benedek, Raluca Mititelu, Claudiu Adrian Stan, Alexey Ansheles, Olga Dariy, Olga Drozdova, Nina Gagarina, Vsevolod Milyevich Gulyaev, Irina Itskovich, Anatoly Karalkin, Alexander Kokov, Ekaterina Migunova, Viktor Pospelov, Daria Ryzhkova, Guzaliya Saifullina, Svetlana Sazonova, Vladimir Sergienko, Irina Shurupova, Tatjana Trifonova, Wladimir Yurievich Ussov, Margarita Vakhromeeva, Nailya Valiullina, Konstantin Zavadovsky, Kirill Zhuravlev, Mirvat Alasnag, Subhani Okarvi, Dragana Sobic Saranovic, Felix Keng, Jia Hao Jason See, Ramkumar Sekar, Min Sen Yew, Andrej Vondrak, Shereen Bejai, George Bennie, Ria Bester, Gerrit Engelbrecht, Osayande Evbuomwan, Harlem Gongxeka, Magritha Jv Vuuren, Mitchell Kaplan, Purbhoo Khushica, Hoosen Lakhi, Lizette Louw, Nico Malan, Katarina Milos, Moshe Modiselle, Stuart More, Mathava Naidoo, Leonie Scholtz, Mboyo Vangu, Santiago Aguadé-Bruix, Isabel Blanco, Antonio Cabrera, Alicia Camarero, Irene Casáns-Tormo, Hug Cuellar-Calabria, Albert Flotats, Maria Eugenia Fuentes Cañamero, María Elia García, Amelia Jimenez-Heffernan, Rubén Leta, Javier Lopez Diaz, Luis Lumbreras, Juan Javier Marquez-Cabeza, Francisco Martin, Anxo Martinez de Alegria, Francisco Medina, Maria Pedrera Canal, Virginia Peiro, Virginia Pubul-Nuñez, Juan Ignacio Rayo Madrid, Cristina Rodríguez Rey, Ricardo Ruano Perez, Joaquín Ruiz, Gertrudis Sabatel Hernández, Ana Sevilla, Nahla Zeidán, Damayanthi Nanayakkara, Chandraguptha Udugama, Magnus Simonsson, Hatem Alkadhi, Ronny Ralf Buechel, Peter Burger, Luca Ceriani, Bart De Boeck, Christoph Gräni, Alix Juillet de Saint Lager Lucas, Christel H. Kamani, Nadine Kawel-Boehm, Robert Manka, John O. Prior, Axel Rominger, Jean-Paul Vallée, Benjapa Khiewvan, Teerapon Premprabha, Tanyaluck Thientunyakit, Ali Sellem, Kemal Metin Kir, Haluk Sayman, Mugisha Julius Sebikali, Zerida Muyinda, Yaroslav Kmetyuk, Pavlo Korol, Olena Mykhalchenko, Volodymyr Pliatsek, Maryna Satyr, Batool Albalooshi, Mohamed Ismail Ahmed Hassan, Jill Anderson, Punit Bedi, Thomas Biggans, Anda Bularga, Russell Bull, Rajesh Burgul, John-Paul Carpenter, Duncan Coles, David Cusack, Aparna Deshpande, John Dougan, Timothy Fairbairn, Alexia Farrugia, Deepa Gopalan, Alistair Gummow, Prasad Guntur Ramkumar, Mark Hamilton, Mark Harbinson, Thomas Hartley, Benjamin Hudson, Nikhil Joshi, Michael Kay, Andrew Kelion, Azhar Khokhar, Jamie Kitt, Ken Lee, Chen Low, Sze Mun Mak, Ntouskou Marousa, Jon Martin, Elisa Mcalindon, Leon Menezes, Gareth Morgan-Hughes, Alastair Moss, Anthony Murray, Edward Nicol, Dilip Patel, Charles Peebles, Francesca Pugliese, Jonathan Carl Luis Rodrigues, Christopher Rofe, Nikant Sabharwal, Rebecca Schofield, Thomas Semple, Naveen Sharma, Peter Strouhal, Deepak Subedi, William Topping, Katharine Tweed, Jonathan Weir-Mccall, Suhny Abbara, Taimur Abbasi, Brian Abbott, Shady Abohashem, Sandra Abramson, Tarek Al-Abboud, Mouaz Al-Mallah, Omar Almousalli, Karthikeyan Ananthasubramaniam, Mohan Ashok Kumar, Jeffrey Askew, Lea Attanasio, Mallory Balmer-Swain, Richard R. Bayer, Adam Bernheim, Sabha Bhatti, Erik Bieging, Ron Blankstein, Stephen Bloom, Sean Blue, David Bluemke, Andressa Borges, Kelley Branch, Paco Bravo, Jessica Brothers, Matthew Budoff, Renée Bullock-Palmer, Angela Burandt, Floyd W. Burke, Kelvin Bush, Candace Candela, Elizabeth Capasso, Joao Cavalcante, Donald Chang, Saurav Chatterjee, Yiannis Chatzizisis, Michael Cheezum, Tiffany Chen, Jennifer Chen, Marcus Chen, James Clarcq, Ayreen Cordero, Matthew Crim, Sorin Danciu, Bruce Decter, Nimish Dhruva, Neil Doherty, Rami Doukky, Anjori Dunbar, William Duvall, Rachael Edwards, Kerry Esquitin, Husam Farah, Emilio Fentanes, Maros Ferencik, Daniel Fisher, Daniel Fitzpatrick, Cameron Foster, Tony Fuisz, Michael Gannon, Lori Gastner, Myron Gerson, Brian Ghoshhajra, Alan Goldberg, Brian Goldner, Jorge Gonzalez, Rosco Gore, Sandra Gracia-López, Fadi Hage, Agha Haider, Sofia Haider, Yasmin Hamirani, Karen Hassen, Mallory Hatfield, Carolyn Hawkins, Katie Hawthorne, Nicholas Heath, Robert Hendel, Phillip Hernandez, Gregory Hill, Stephen Horgan, Jeff Huffman, Lynne Hurwitz, Ami Iskandrian, Rajesh Janardhanan, Christine Jellis, Scott Jerome, Dinesh Kalra, Summanther Kaviratne, Fernando Kay, Faith Kelly, Omar Khalique, Mona Kinkhabwala, George Kinzfogl Iii, Jacqueline Kircher, Rachael Kirkbride, Michael Kontos, Anupama Kottam, Joseph Krepp, Jay Layer, Steven H. Lee, Jeffrey Leppo, John Lesser, Steve Leung, Howard Lewin, Diana Litmanovich, Yiyan Liu, Kathleen Magurany, Jeremy Markowitz, Amanda Marn, Stephen E. Matis, Michael Mckenna, Tony Mcrae, Fernando Mendoza, Michael Merhige, David Min, Chanan Moffitt, Karen Moncher, Warren Moore, Shamil Morayati, Michael Morris, Mahmud Mossa-Basha, Zorana Mrsic, Venkatesh Murthy, Prashant Nagpal, Kyle Napier, Katarina Nelson, Prabhjot Nijjar, Medhat Osman, Edward Passen, Amit Patel, Pravin Patil, Ryan Paul, Lawrence Phillips, Venkateshwar Polsani, Rajaram Poludasu, Brian Pomerantz, Thomas Porter, Ryan Prentice, Amit Pursnani, Mark Rabbat, Suresh Ramamurti, Florence Rich, Hiram Rivera Luna, Austin Robinson, Kim Robles, Cesar Rodríguez, Mark Rorie, John Rumberger, Raymond Russell, Philip Sabra, Diego Sadler, Mary Schemmer, U. Joseph Schoepf, Samir Shah, Nishant Shah, Sujata Shanbhag, Gaurav Sharma, Steven Shayani, Jamshid Shirani, Pushpa Shivaram, Steven Sigman, Mitch Simon, Ahmad Slim, David Smith, Alexandra Smith, Prem Soman, Aditya Sood, Monvadi Barbara Srichai-Parsia, James Streeter, Albert T, Ahmed Tawakol, Dustin Thomas, Randall Thompson, Tara Torbet, Desiree Trinidad, Shawn Ullery, Samuel Unzek, Seth Uretsky, Srikanth Vallurupalli, Vikas Verma, Alfonso Waller, Ellen Wang, Parker Ward, Gaby Weissman, George Wesbey, Kelly White, David Winchester, David Wolinsky, Sandra Yost, Michael Zgaljardic, Omar Alonso, Mario Beretta, Rodolfo Ferrando, Miguel Kapitan, Fernando Mut, Omoa Djuraev, Gulnora Rozikhodjaeva, Ha Le Ngoc, Son Hong Mai, and Xuan Canh Nguyen

Subjects
cardiac testing, cardiovascular disease, coronavirus, COVID-19, global health, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Background: The coronavirus disease-2019 (COVID-19) pandemic significantly affected management of cardiovascular disease around the world. The effect of the pandemic on volume of cardiovascular diagnostic procedures is not known. Objectives: This study sought to evaluate the effects of the early phase of the COVID-19 pandemic on cardiovascular diagnostic procedures and safety practices in Asia. Methods: The International Atomic Energy Agency conducted a worldwide survey to assess changes in cardiovascular procedure volume and safety practices caused by COVID-19. Testing volumes were reported for March 2020 and April 2020 and were compared to those from March 2019. Data from 180 centers across 33 Asian countries were grouped into 4 subregions for comparison. Results: Procedure volumes decreased by 47% from March 2019 to March 2020, showing recovery from March 2020 to April 2020 in Eastern Asia, particularly in China. The majority of centers cancelled outpatient activities and increased time per study. Practice changes included implementing physical distancing and restricting visitors. Although COVID testing was not commonly performed, it was conducted in one-third of facilities in Eastern Asia. The most severe reductions in procedure volumes were observed in lower-income countries, where volumes decreased 81% from March 2019 to April 2020. Conclusions: The COVID-19 pandemic in Asia caused significant reductions in cardiovascular diagnostic procedures, particularly in low-income countries. Further studies on effects of COVID-19 on cardiovascular outcomes and changes in care delivery are warranted.

Published
2021
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7. Digital Development Process for the Drive System of a Balanced Two-Wheel Scooter

Author

Kevin Holder, Sven Schumacher, Matthias Friedrich, Markus Till, Ralf Stetter, Walter Fichter, and Stephan Rudolph

Subjects
digital design process, urban vehicles, balanced two-wheel scooter, Mechanical engineering and machinery, TJ1-1570, Machine design and drawing, TJ227-240, Motor vehicles. Aeronautics. Astronautics, TL1-4050
Abstract

Graph-based design languages have received increasing attention in the research community, because they offer a promising approach to address several major issues in engineering, e.g., the frequent manual data transfer between computer-aided design (CAD) and computer-aided engineering (CAE) systems. Currently, these issues prevent the realization of machine executable digital design processes of complex systems such as vehicles. Promising scenarios for urban transportation include an interconnection of mass transportation systems such as buses and subways with individual vehicles for the so-called “last mile” transport. For several reasons, these vehicles should be as small and light as possible. A considerable reduction in weight and size can be achieved, if such vehicles are tailored to the individual size, weight and proportion of the individual user. However, tailoring vehicles for the individual characteristics of each user go beyond a simple building set and require a continuous digital design process. Consequently, the topic of this paper is a digital design process of a self-balanced scooter, which can be used as an individual last-mile means of transport. This process is based on graph-based design languages, because in these languages, a digital system model is generated, which contains all relevant information about a design and can be fed into any simulation tool which is needed to evaluate the impact of a possible design variation on the resulting product performance. As this process can be automated by digital compilers, it is possible to perform systematic design variations for an almost infinite amount of parameters and topological variants. Consequently, these kinds of graph-based languages are a powerful means to generate viable design alternatives and thus permit fast evaluations. The paper demonstrates the design process, focusing on the drive system of the respective balanced two-wheel scooter and highlights the advantages (data integration and possibility for machine execution).

Published
2021
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8. The Canadian Alliance for Healthy Hearts and Minds: How Well Does It Reflect the Canadian Population?

Author

Ruth E. Hall, PhD, Natasa Tusevljak, MSc, C. Fangyun Wu, MSc, Quazi Ibrahim, MSc, Karleen Schulze, MMath, Anam M. Khan, MPH, Dipika Desai, MSc, Philip Awadalla, PhD, Philippe Broet, PhD, Trevor J.B. Dummer, PhD, Jason Hicks, MSc, Jean-Claude Tardif, PhD, Koon K. Teo, MD, PhD, Jennifer Vena, PhD, Douglas Lee, MD, PhD, Matthias Friedrich, MD, Sonia S. Anand, MD, PhD, and Jack V. Tu, MD, PhD

Subjects
Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Background: The intent of the Canadian Alliance for Healthy Hearts and Minds (CAHHM) cohort is to understand the early determinants of subclinical cardiac and vascular disease and progression in adults selected from existing cohorts—the Canadian Partnership for Tomorrow’s Health, the Prospective Urban and Rural Evaluation (PURE) cohort, and the Montreal Heart Institute Biobank. We evaluated how well the CAHHM-Health Services Research (CAHHM-HSR) subcohort reflects the Canadian population. Methods: A cross-sectional design was used among a prospective cohort of community-dwelling adults aged 35-69 years who met the CAHHM inclusion criteria, and a cohort of adults aged 35-69 years who responded to the 2015 Canadian Community Health Survey-Rapid Response module. The INTERHEART risk score was calculated at the individual level with means and proportions reported at the overall and provincial level. Results: There are modest differences between CAHHM-HSR study participants and the 2015 Canadian Community Health Survey-Rapid Response respondents in age (56.3 vs 51.7 mean years), proportion of men (44.9% vs 49.3%), and mean INTERHEART risk score (9.7 vs 10.1). Larger differences were observed in postsecondary education (86.8% vs 70.2%), Chinese ethnicity (11.0% vs 3.3%), obesity (23.2% vs 29.3%), current smoker status (6.1% vs 18.4%), and having no cardiac testing (30.4% vs 55.9%). Conclusions: CAHHM-HSR participants are older, of higher socioeconomic status, and have a similar mean INTERHEART risk score, compared with participants in the Canadian Community Health Survey. Differing sampling strategies and missing data may explain some differences between the CAHHM-HSR cohort and Canadian community-dwelling adults and should be considered when using the CAHHM-HSR for scientific research. Résumé: Contexte: L’étude Alliance canadienne cœurs et cerveaux sains (CAHHM) vise à mieux comprendre les facteurs déterminants précoces et la progression de l’atteinte cardiovasculaire subclinique chez des adultes sélectionnés au sein de cohortes existantes – soit celles de l’étude menée par le Partenariat canadien pour la santé de demain, de l’étude PURE (Prospective Urban and Rural Evaluation) et de la biobanque de l’Institut de cardiologie de Montréal. Nous avons évalué la mesure dans laquelle la sous-cohorte du volet de recherche sur l’utilisation des services de santé de la CAHHM (CAHHM-HSR) représente la population canadienne. Méthodologie: Nous avons adopté une approche transversale pour étudier une cohorte prospective d’adultes vivant dans la communauté âgés de 35 à 69 ans et répondant aux critères d’inclusion de l’étude CAHHM, ainsi qu’une cohorte d’adultes âgés de 35 à 69 ans ayant participé au volet de réponse rapide de l’Enquête sur la santé dans les collectivités canadiennes (ESCC) de 2015. Le score de risque INTERHEART individuel des participants a été calculé à partir des moyennes et des proportions rapportées à l’échelle globale et à l’échelle provinciale. Résultats: Les différences entre les participants du volet CAHHM-HSR et ceux du volet de réponse rapide de l’ESCC de 2015 étaient minimes quant à l’âge (56,3 ans vs 51,7 ans en moyenne), à la proportion d’hommes (44,9 % vs 49,3 %) et au score de risque INTERHEART moyen (9,7 vs 10,1). On a toutefois noté des différences plus importantes en ce qui concerne les caractéristiques suivantes : éducation postsecondaire (86,8 % vs 70,2 %), origine ethnique chinoise (11,0 % vs 3,3 %), obésité (23,2 % vs 29,3 %), tabagisme actuel (6,1 % vs 18,4 %) et absence d’antécédents d’examen cardiaque (30,4 % vs 55,9 %). Conclusions: Les participants du volet CAHHM-HSR sont plus âgés et ont un statut socioéconomique plus élevé que ceux du volet de réponse rapide de l’ESCC, mais ont un score de risque INTERHEART moyen comparable. Les différences quant aux stratégies d’échantillonnage et des données manquantes pourraient expliquer certains des écarts observés entre la cohorte CAHHM-HSR et celle des adultes canadiens vivant dans la communauté; il conviendrait d’en tenir compte lorsqu’on utilise les données du volet CAHHM-HSR à des fins de recherche scientifique.

Published
2020
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9. CARDEA study protocol: investigating early markers of cardiovascular disease and their association with lifestyle habits, inflammation and oxidative stress in adolescence using a cross-sectional comparison of adolescents with type 1 diabetes and healthy controls

Author

Andrea Benedetti, Marie-Eve Mathieu, Melanie Henderson, Emile Levy, Tracie A Barnett, Jean-Claude Lavoie, Matthias Friedrich, Andraea Van Hulst, Catherine Pelletier, Jean-Luc Bigras, Vicky Drapeau, and Anne-Monique Nuyt

Subjects
Medicine
Abstract

Introduction Little is known regarding associations between potentially modifiable lifestyle habits and early markers of cardiovascular disease (CVD) in pediatric type 1 diabetes (T1D), hindering early prevention efforts. Specific objectives are: (1) compare established risk factors (dyslipidemia, hypertension) with novel early markers for CVD (cardiac phenotype, aortic distensibility, endothelial function) in adolescents with T1D and healthy age-matched and sex-matched controls; (2) examine associations between these novel early markers with: (i) lifestyle habits; (ii) adipokines and measures of inflammation; and (iii) markers of oxidative stress among adolescents with T1D and controls, and determine group differences in these associations; (3) explore, across both groups, associations between CVD markers and residential neighbourhood features.Methods and analyses Using a cross-sectional design, we will compare 100 participants aged 14–18 years with T1D to 100 healthy controls. Measures include: anthropometrics; stage of sexual maturity (Tanner stages); physical activity (7-day accelerometry); sleep and sedentary behaviour (self-report and accelerometry); fitness (peak oxygen consumption); and dietary intake (three non-consecutive 24- hour dietary recalls). Repeated measures of blood pressure will be obtained. Lipid profiles will be determined after a 12- hour fast. Cardiac structure/function: non-contrast cardiac magnetic resonance imaging (CMR) images will evaluate volume, mass, systolic and diastolic function and myocardial fibrosis. Aortic distensibility will be determined by pulse wave velocity with elasticity and resistance studies at the central aorta. Endothelial function will be determined by flow-mediated dilation. Inflammatory markers include plasma leptin, adiponectin, tumour necrosis factor alpha (TNF-α), type I and type II TNF-α soluble receptors and interleukin-6 concentrations. Measures of endogenous antioxidants include manganese superoxide dismutase, glutathione peroxidase and glutathione in blood. Neighbourhood features include built and social environment indicators and air quality.Ethics and dissemination This study was approved by the Sainte-Justine Hospital Research Ethics Board. Written informed assent and consent will be obtained from participants and their parents.Trial registration number NCT04304729.

Published
2021
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10. Development of a uniform, very aggressive disease phenotype in all homozygous carriers of the NOD2 mutation p.Leu1007fsX1008 with Crohn's disease and active smoking status resulting in ileal stenosis requiring surgery.

Author

Fabian Schnitzler, Matthias Friedrich, Marianne Angelberger, Julia Diegelmann, Johannes Stallhofer, Christiane Wolf, Joel Dütschler, Samuel Truniger, Torsten Olszak, Florian Beigel, Cornelia Tillack, Peter Lohse, and Stephan Brand

Subjects
Medicine, Science
Abstract

BackgroundNOD2 variants are the strongest genetic predictors for susceptibility to Crohn's disease (CD). However, the clinical value of NOD2 on an individual patient level remains controversial. We aimed to define the predictive power of the major NOD2 mutations regarding complicated CD in a large single center cohort.Methods1076 CD patients were prospectively genotyped for the three common CD-associated NOD2 mutations rs2066844, rs2066845, and rs2066847, followed by detailed genotype-phenotype analyses.ResultsOverall, 434 CD patients (40.3%) carried at least one of the three main NOD2 mutations. A significantly higher minor allele frequency (15.6%) of the NOD2 frameshift mutation p.Leu1007fsX1008 (rs2066847) was seen in patients with aggressive disease compared to 8.2% in patients with mild disease (p = 2.6 x 10-5). Moreover, a total of 54 CD patients (5.0%) were homozygous for this NOD2 frameshift mutation. 100% of these patients had ileal disease compared to 82% of NOD2 wild-type carriers (pConclusionHomozygosity for Leu1007fsX1008 is an excellent biomarker for predicting complicated CD on an individual patient level. Active smoking and homozygosity for this mutation is associated with a 100% risk for developing ileal stenosis requiring CD-related surgery. In these patients, smoking cessation and early initiation of immunosuppressive strategies may be beneficial.

Published
2020
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11. TCR and Inflammatory Signals Tune Human MAIT Cells to Exert Specific Tissue Repair and Effector Functions

Author

Tianqi Leng, Hossain Delowar Akther, Carl-Philipp Hackstein, Kate Powell, Thomas King, Matthias Friedrich, Zoe Christoforidou, Sarah McCuaig, Mastura Neyazi, Carolina V. Arancibia-Cárcamo, Joachim Hagel, Fiona Powrie, Raphael Sanches Peres, Val Millar, Daniel Ebner, Rajesh Lamichhane, James Ussher, Timothy S.C. Hinks, Emanuele Marchi, Chris Willberg, and Paul Klenerman

Subjects
Biology (General), QH301-705.5
Abstract

Summary: MAIT cells are an unconventional T cell population that can be activated through both TCR-dependent and TCR-independent mechanisms. Here, we examined the impact of combinations of TCR-dependent and TCR-independent signals in human CD8+ MAIT cells. TCR-independent activation of these MAIT cells from blood and gut was maximized by extending the panel of cytokines to include TNF-superfamily member TL1A. RNA-seq experiments revealed that TCR-dependent and TCR-independent signals drive MAIT cells to exert overlapping and specific effector functions, affecting both host defense and tissue homeostasis. Although TCR triggering alone is insufficient to drive sustained activation, TCR-triggered MAIT cells showed specific enrichment of tissue-repair functions at the gene and protein levels and in in vitro assays. Altogether, these data indicate the blend of TCR-dependent and TCR-independent signaling to CD8+ MAIT cells may play a role in controlling the balance between healthy and pathological processes of tissue inflammation and repair. : Leng et al. explore the consequences of activation of human MAIT cells via their TCR and/or cytokines, including the gut-associated TNF-superfamily member TL1A. TCR triggering reveals a transcriptional program linked to tissue-repair functions seen in vivo, consistent with a homeostatic role for these cells in epithelia. Keywords: MAIT cells, effector functions, TCR signaling, cytokines, tissue repair

Published
2019
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12. Possibilities and Challenges of Different Experimental Techniques for Airflow Characterisation in the Air Cavities of Façades

Author

Emanuela Giancola, M. Nuria Sánchez, Matthias Friedrich, Olena Kalyanova Larsen, Alessandro Nocente, Stefano Avesani, Francesco Babich, and Francesco Goia

Subjects
façade characterisation, experimental techniques, airflow monitoring, tracer gas, velocity profile, ultrasound, Architecture, NA1-9428, Building construction, TH1-9745
Abstract

Ventilated façades are applied in both new and existing buildings. It has been claimed that these components help to reduce energy use in buildings and improve occupant comfort. However, their performance strongly depends on the airflow passing through the cavity. In order to characterise and to model the behaviour of the ventilation and its effectiveness, the components need to be tested in the laboratory, as well as under real dynamic weather conditions. Despite the steadily growing research in this area, there are few studies with conclusive results about the reliability of existing experimental procedures for characterisation of airflow in the ventilated cavities. The aim of this paper is to describe and review recent state of the art experimental assessments for the airflow characterisation in ventilated cavities. The paper starts with a short introduction on the potentialities and limitations of different experimental methodologies, and continues with a detailed classification and description of the most relevant monitoring techniques for airflow in air cavities of façades that have been developed in recent years.

Published
2018
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13. A multicenter phase 1 study of solitomab (MT110, AMG 110), a bispecific EpCAM/CD3 T-cell engager (BiTE®) antibody construct, in patients with refractory solid tumors

Author

Maxim Kebenko, Marie-Elisabeth Goebeler, Martin Wolf, Annette Hasenburg, Ruth Seggewiss-Bernhardt, Barbara Ritter, Beate Rautenberg, Djordje Atanackovic, Andrea Kratzer, James B. Rottman, Matthias Friedrich, Eva Vieser, Stefanie Elm, Ingrid Patzak, Dorothea Wessiepe, Sabine Stienen, and Walter Fiedler

Subjects
amg 110, solitomab, mt110, immunotherapy, bispecific, bite®, epcam, phase 1, solid tumor, cd3, Immunologic diseases. Allergy, RC581-607, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

We assessed the tolerability and antitumor activity of solitomab, a bispecific T-cell engager (BiTE®) antibody construct targeting epithelial cell adhesion molecule (EpCAM). Patients with relapsed/refractory solid tumors not amenable to standard therapy received solitomab as continuous IV infusion in a phase 1 dose-escalation study with six different dosing schedules. The primary endpoint was frequency and severity of adverse events (AEs). Secondary endpoints included pharmacokinetics, pharmacodynamics, immunogenicity, and antitumor activity. Sixty-five patients received solitomab at doses between 1 and 96 µg/day for ≥28 days. Fifteen patients had dose-limiting toxicities (DLTs): eight had transient abnormal liver parameters shortly after infusion start or dose escalation (grade 3, n = 4; grade 4, n = 4), and one had supraventricular tachycardia (grade 3); all events resolved with solitomab discontinuation. Six patients had a DLT of diarrhea: four events resolved (grade 3, n = 3; grade 4, n = 1), one (grade 3) was ongoing at the time of treatment-unrelated death, and one (grade 3) progressed to grade 5 after solitomab discontinuation. The maximum tolerated dose was 24 µg/day. Overall, 95% of patients had grade ≥3 treatment-related AEs, primarily diarrhea, elevated liver parameters, and elevated lipase. Solitomab half-life was 4.5 hours; serum levels plateaued within 24 hours. One unconfirmed partial response was observed. In this study of a BiTE® antibody construct targeting solid tumors, treatment of relapsed/refractory EpCAM-positive solid tumors with solitomab was associated with DLTs, including severe diarrhea and increased liver enzymes, which precluded dose escalation to potentially therapeutic levels.

Published
2018
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14. The NOD2 Single Nucleotide Polymorphism rs72796353 (IVS4+10 A>C) Is a Predictor for Perianal Fistulas in Patients with Crohn's Disease in the Absence of Other NOD2 Mutations.

Author

Fabian Schnitzler, Matthias Friedrich, Christiane Wolf, Johannes Stallhofer, Marianne Angelberger, Julia Diegelmann, Torsten Olszak, Cornelia Tillack, Florian Beigel, Burkhard Göke, Jürgen Glas, Peter Lohse, and Stephan Brand

Subjects
Medicine, Science
Abstract

A previous study suggested an association of the single nucleotide polymorphism (SNP) rs72796353 (IVS4+10 A>C) in the NOD2 gene with susceptibility to Crohn's disease (CD). However, this finding has not been confirmed. Given that NOD2 variants still represent the most important predictors for CD susceptibility and phenotype, we evaluated the association of rs72796353 with inflammatory bowel disease (IBD) susceptibility and the IBD phenotype.Genomic DNA from 2256 Caucasians, including 1073 CD patients, 464 patients with ulcerative colitis (UC), and 719 healthy controls, was genotyped for the NOD2 SNP rs72796353 and the three main CD-associated NOD2 mutations rs2066844, rs2066845, and rs2066847. Subsequently, IBD association and genotype-phenotype analyses were conducted.In contrast to the strong associations of the NOD2 SNPs rs2066844 (p=3.51 x 10(-3)), rs2066845 (p=1.54 x 10(-2)), and rs2066847 (p=1.61 x 10(-20)) with CD susceptibility, no significant association of rs72796353 with CD or UC susceptibility was found. However, in CD patients without the three main CD-associated NOD2 mutations, rs72796353 was significantly associated with the development of perianal fistulas (p=2.78 x 10(-7), OR 5.27, [95% CI 2.75-10.12] vs. NOD2 wild-type carriers).Currently, this study represents the largest genotype-phenotype analysis of the impact of the NOD2 variant rs72796353 on the disease phenotype in IBD. Our data demonstrate that in CD patients the IVS4+10 A>C variant is strongly associated with the development of perianal fistulas. This association is particularly pronounced in patients who are not carriers of the three main CD-associated NOD2 mutations, suggesting rs72796353 as additional genetic marker for the CD disease behaviour.

Published
2015
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15. Solid Organ Transplantation in Patients with Inflammatory Bowel Diseases (IBD): Analysis of Transplantation Outcome and IBD Activity in a Large Single Center Cohort.

Author

Fabian Schnitzler, Matthias Friedrich, Johannes Stallhofer, Ulf Schönermarck, Michael Fischereder, Antje Habicht, Nazanin Karbalai, Christiane Wolf, Marianne Angelberger, Torsten Olszak, Florian Beigel, Cornelia Tillack, Burkhard Göke, Reinhart Zachoval, Gerald Denk, Markus Guba, Christian Rust, Norbert Grüner, and Stephan Brand

Subjects
Medicine, Science
Abstract

Currently, limited data of the outcome of inflammatory bowel disease (IBD) in patients after solid organ transplantation (SOT) are available. We aimed to analyze effects of SOT on the IBD course in a large IBD patient cohort.Clinical data from 1537 IBD patients were analyzed for patients who underwent SOT (n = 31) between July 2002 and May 2014. Sub-analyses included SOT outcome parameters, IBD activity before and after SOT, and efficacy of IBD treatment.4.74% of patients with ulcerative colitis (UC) and 0.84% of patients with Crohn's disease (CD) underwent SOT (p = 2.69 x 10(-6), UC vs. CD). 77.4% of patients with SOT underwent liver transplantation (LTx) with tacrolimus-based immunosuppressive therapy after SOT. All LTx were due to primary sclerosing cholangitis (PSC) or PSC overlap syndromes. Six patients (19.4%) required renal transplantation and one patient (3.2%) heart transplantation. A survival rate of 83.9% after a median follow-up period of 103 months was observed. Before SOT, 65.0% of patients were in clinical remission and 5 patients received immunosuppressive therapy (16.1%). After SOT, 61.0% of patients were in remission (p = 1.00 vs. before SOT) and 29.0% required IBD-specific immunosuppressive or anti-TNF therapy (p = 0.54 vs. before SOT). 42.9% of patients with worsening of IBD after SOT were at higher risk of needing steroid therapy for increased IBD activity (p = 0.03; relative risk (RR): 10.29; 95% CI 1.26-84.06). Four patients (13.0%) needed anti-TNF therapy after SOT (response rate 75%).SOT was more common in UC patients due to the higher prevalence of PSC-related liver cirrhosis in UC. Despite mainly tacrolimus-based immunosuppressive regimens, outcome of SOT and IBD was excellent in this cohort. In this SOT cohort, concomitant immunosuppressive therapy due to IBD was well tolerated.

Published
2015
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16. Oncostatin M mediates STAT3-dependent intestinal epithelial restitution via increased cell proliferation, decreased apoptosis and upregulation of SERPIN family members.

Author

Florian Beigel, Matthias Friedrich, Corina Probst, Karl Sotlar, Burkhard Göke, Julia Diegelmann, and Stephan Brand

Subjects
Medicine, Science
Abstract

OBJECTIVE: Oncostatin M (OSM) is produced by activated T cells, monocytes, and dendritic cells and signals through two distinct receptor complexes consisting of gp130 and LIFR (I) or OSMR-β and gp130 (II), respectively. Aim of this study was to analyze the role of OSM in intestinal epithelial cells (IEC) and intestinal inflammation. METHODS: OSM expression and OSM receptor distribution was analyzed by PCR and immunohistochemistry experiments, signal transduction by immunoblotting. Gene expression studies were performed by microarray analysis and RT-PCR. Apoptosis was measured by caspases-3/7 activity. IEC migration and proliferation was studied in wounding and water soluble tetrazolium assays. RESULTS: The IEC lines Caco-2, DLD-1, SW480, HCT116 and HT-29 express mRNA for the OSM receptor subunits gp130 and OSMR-β, while only HCT116, HT-29 and DLD-1 cells express LIFR mRNA. OSM binding to its receptor complex activates STAT1, STAT3, ERK-1/2, SAPK/JNK-1/2, and Akt. Microarray analysis revealed 79 genes that were significantly up-regulated (adj.-p ≤ 0.05) by OSM in IEC. Most up-regulated genes belong to the functional categories "immunity and defense" (p = 2.1 × 10(-7)), "apoptosis" (p = 3.7 × 10(-4)) and "JAK/STAT cascade" (p = 3.4 × 10(-6)). Members of the SERPIN gene family were among the most strongly up-regulated genes. OSM significantly increased STAT3- and MEK1-dependent IEC cell proliferation (p

Published
2014
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17. The NOD2 p.Leu1007fsX1008 mutation (rs2066847) is a stronger predictor of the clinical course of Crohn's disease than the FOXO3A intron variant rs12212067.

Author

Fabian Schnitzler, Matthias Friedrich, Christiane Wolf, Marianne Angelberger, Julia Diegelmann, Torsten Olszak, Florian Beigel, Cornelia Tillack, Johannes Stallhofer, Burkhard Göke, Jürgen Glas, Peter Lohse, and Stephan Brand

Subjects
Medicine, Science
Abstract

Very recently, a sub-analysis of genome-wide association scans revealed that the non-coding single nucleotide polymorphism (SNP) rs12212067 in the FOXO3A gene is associated with a milder course of Crohn's disease (CD) (Cell 2013;155:57-69). The aim of our study was to evaluate the clinical value of the SNP rs12212067 in predicting the severity of CD by correlating CD patient genotype status with the most relevant complications of CD such as stenoses, fistulas, and CD-related surgery.We genotyped 550 CD patients for rs12212067 (FOXO3A) and the three common CD-associated NOD2 mutations rs2066844, rs2066847, and rs2066847 and performed genotype-phenotype analyses.No significant phenotypic differences were found between the wild-type genotype TT of the FOXO3A SNP rs12212067 and the minor genotypes TG and GG independently from NOD2 variants. The allele frequency of the minor G allele was 12.7%. Age at diagnosis, disease duration, body mass index, surgery rate, stenoses, fistula, need for immunosuppressive therapy, and disease course were not significantly different. In contrast, the NOD2 mutant p.Leu1007fsX1008 (rs2066847) was highly associated with penetrating CD (p = 0.01), the development of fistulas (p = 0.01) and stenoses (p = 0.01), and ileal disease localization (p = 0.03). Importantly, the NOD2 SNP rs2066847 was a strong separator between an aggressive and a mild course of CD (p = 2.99×10(-5)), while the FOXO3A SNP rs12212067 did not separate between mild and aggressive CD behavior in our cohort (p = 0.35). 96.2% of the homozygous NOD2 p.Leu1007fsX1008 carriers had an aggressive disease behavior compared to 69.3% of the patients with the NOD2 wild-type genotype (p = 0.007).In clinical practice, the NOD2 variant p.Leu1007fsX1008 (rs2066847), in particular in homozygous form, is a much stronger marker for a severe clinical phenotype than the FOXO3A rs12212067 SNP for a mild disease course on an individual patient level despite its important impact on the inflammatory response of monocytes.

Published
2014
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18. Further development of the urban bioclimate model UBIKLIM, taking local wind systems into account

Author

Matthias Friedrich, Angelika Grätz, and Gerd Jendritzky

Subjects
Meteorology. Climatology, QC851-999
Abstract

The urban bioclimate model UBIKLIM is an application model providing an assessment on the influence of urban climate on human beings. On a calm summer's day with fair weather conditions it calculates the meteorological parameters air temperature, humidity, wind velocity and short and long wave radiation based on a digital height model and appropriate land use information. These meteorological parameters determine the heat exchange conditions of human beings and thus can be analyzed with the help of the Klima-Michel model into physiologically significant terms. The result is a bioclimate map on a scale that is appropriate for climate-related planning in an urban environment. In urban areas lying in a distinct relief, a superimposed wind regime, such as a down valley wind, can modify the bioclimate considerably. Up to now it was not possible for UBIKLIM to take this situation into account. In this point UBIKLIM has been developed further, but its easily applicable character has been preserved. This has been realized, firstly by combining an orographically induced wind field with the one calculated in UBIKLIM as a function of land use esp. of urban structure, and secondly by introducing an algorithm by working out conveyance processes in the direction of the superposed wind field. UBIKLIM fills the gap between meso and micro scale models. Results of the further developed model are shown in the example of the city of Freiburg im Breisgau which is influenced by the distinct relief at the southern edge of the Black Forest. Das Stadtbioklimamodell UBIKLIM ist ein Anwendungsmodell, das eine auf den Menschen bezogene Bewertung von Klima in StÄdten liefert. FÜr einen windschwachen sommerlichen Strahlungstag werden darin die physiologisch relevanten meteorologischen Größen Lufttemperatur, Feuchte, Windgeschwindigkeit sowie lang- und kurzwellige Strahlung auf der Basis digitaler Höhen- und Landnutzungsdaten berechnet. Die Analyse dieser Felder mit dem Klima-Michel Modell fÜhrt zur Bioklimakarte, aus der sich planungsrelevante Aussagen ableiten lassen. Lokale Windsysteme, wie sie in StÄdten in orographisch gegliedertem GelÄnde bedeutend sein können, konnten bislang nicht berÜcksichtigt werden. An diesem Punkt wurde UBIKLIM erweitert, wobei weiterhin das Prinzip einer leichten und schnellen Anwendbarkeit des Verfahrens gewÄhrleistet sein sollte. Dazu werden erstens ein topographisch induziertes, nutzungsunabhÄngiges Windfeld und das durch die Stadtstruktur gegebene UBIKLIM-Windfeld gekoppelt, was flÄchendeckend zu einer Änderung der AbkÜhlungsgröße Wind fÜhrt. Zweitens wird ein Algorithmus eingefÜhrt, der in Richtung des Überlagerten Windfeldes Transportprozesse berÜcksichtigt. Ergebnisse werden am Beispiel der Stadt Freiburg im Breisgau vorgestellt.

Published
2001
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19. IRGM variants and susceptibility to inflammatory bowel disease in the German population.

Author

Jürgen Glas, Julia Seiderer, Stephanie Bues, Johannes Stallhofer, Christoph Fries, Torsten Olszak, Eleni Tsekeri, Martin Wetzke, Florian Beigel, Christian Steib, Matthias Friedrich, Burkhard Göke, Julia Diegelmann, Darina Czamara, and Stephan Brand

Subjects
Medicine, Science
Abstract

Genome-wide association studies identified the autophagy gene IRGM to be strongly associated with Crohn's disease (CD) but its impact in ulcerative colitis (UC), its phenotypic effects and potential epistatic interactions with other IBD susceptibility genes are less clear which we therefore analyzed in this study.Genomic DNA from 2060 individuals including 817 CD patients, 283 UC patients, and 961 healthy, unrelated controls (all of Caucasian origin) was analyzed for six IRGM single nucleotide polymorphisms (SNPs) (rs13371189, rs10065172 = p.Leu105Leu, rs4958847, rs1000113, rs11747270, rs931058). In all patients, a detailed genotype-phenotype analysis and testing for epistasis with the three major CD susceptibility genes NOD2, IL23R and ATG16L1 were performed. Our analysis revealed an association of the IRGM SNPs rs13371189 (p = 0.02, OR 1.31 [95% CI 1.05-1.65]), rs10065172 = p.Leu105Leu (p = 0.016, OR 1.33 [95% CI 1.06-1.66]) and rs1000113 (p = 0.047, OR 1.27 [95% CI 1.01-1.61]) with CD susceptibility. There was linkage disequilibrium between these three IRGM SNPs. In UC, several IRGM haplotypes were weakly associated with UC susceptibility (p

Published
2013
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20. PTPN2 gene variants are associated with susceptibility to both Crohn's disease and ulcerative colitis supporting a common genetic disease background.

Author

Jürgen Glas, Johanna Wagner, Julia Seiderer, Torsten Olszak, Martin Wetzke, Florian Beigel, Cornelia Tillack, Johannes Stallhofer, Matthias Friedrich, Christian Steib, Burkhard Göke, Thomas Ochsenkühn, Nazanin Karbalai, Julia Diegelmann, Darina Czamara, and Stephan Brand

Subjects
Medicine, Science
Abstract

BACKGROUND: Genome-wide association studies identified PTPN2 (protein tyrosine phosphatase, non-receptor type 2) as susceptibility gene for inflammatory bowel diseases (IBD). However, the exact role of PTPN2 in Crohn's disease (CD) and ulcerative colitis (UC) and its phenotypic effect are unclear. We therefore performed a detailed genotype-phenotype and epistasis analysis of PTPN2 gene variants. METHODOLOGY/PRINCIPAL FINDINGS: Genomic DNA from 2131 individuals of Caucasian origin (905 patients with CD, 318 patients with UC, and 908 healthy, unrelated controls) was analyzed for two SNPs in the PTPN2 region (rs2542151, rs7234029) for which associations with IBD were found in previous studies in other cohorts. Our analysis revealed a significant association of PTPN2 SNP rs2542151 with both susceptibility to CD (p = 1.95×10⁻⁵; OR 1.49 [1.34-1.79]) and UC (p = 3.87×10⁻², OR 1.31 [1.02-1.68]). Moreover, PTPN2 SNP rs7234029 demonstrated a significant association with susceptibility to CD (p = 1.30×10⁻³; OR 1.35 [1.13-1.62]) and a trend towards association with UC (p = 7.53×10⁻²; OR 1.26 [0.98-1.62]). Genotype-phenotype analysis revealed an association of PTPN2 SNP rs7234029 with a stricturing disease phenotype (B2) in CD patients (p = 6.62×10⁻³). Epistasis analysis showed weak epistasis between the ATG16L1 SNP rs2241879 and PTPN2 SNP rs2542151 (p = 0.024) in CD and between ATG16L1 SNP rs4663396 and PTPN2 SNP rs7234029 (p = 4.68×10⁻³) in UC. There was no evidence of epistasis between PTPN2 and NOD2 and PTPN2 and IL23R. In silico analysis revealed that the SNP rs7234029 modulates potentially the binding sites of several transcription factors involved in inflammation including GATA-3, NF-κB, C/EBP, and E4BP4. CONCLUSIONS/SIGNIFICANCE: Our data confirm the association of PTPN2 variants with susceptibility to both CD and UC, suggesting a common disease pathomechanism for these diseases. Given recent evidence that PTPN2 regulates autophagosome formation in intestinal epithelial cells, the potential link between PTPN2 and ATG16L1 should be further investigated.

Published
2012
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21. Analysis of IL12B gene variants in inflammatory bowel disease.

Author

Jürgen Glas, Julia Seiderer, Johanna Wagner, Torsten Olszak, Christoph Fries, Cornelia Tillack, Matthias Friedrich, Florian Beigel, Johannes Stallhofer, Christian Steib, Martin Wetzke, Burkhard Göke, Thomas Ochsenkühn, Julia Diegelmann, Darina Czamara, and Stephan Brand

Subjects
Medicine, Science
Abstract

BACKGROUND: IL12B encodes the p40 subunit of IL-12, which is also part of IL-23. Recent genome-wide association studies identified IL12B and IL23R as susceptibility genes for inflammatory bowel disease (IBD). However, the phenotypic effects and potential gene-gene interactions of IL12B variants are largely unknown. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed IL12B gene variants regarding association with Crohn's disease (CD) and ulcerative colitis (UC). Genomic DNA from 2196 individuals including 913 CD patients, 318 UC patients and 965 healthy, unrelated controls was analyzed for four SNPs in the IL12B gene region (rs3212227, rs17860508, rs10045431, rs6887695). Our analysis revealed an association of the IL12B SNP rs6887695 with susceptibility to IBD (p = 0.035; OR 1.15 [95% CI 1.01-1.31] including a trend for rs6887695 for association with CD (OR 1.41; [0.99-1.31], p = 0.066) and UC (OR 1.18 [0.97-1.43], p = 0.092). CD patients, who were homozygous C/C carriers of this SNP, had significantly more often non-stricturing, non-penetrating disease than carriers of the G allele (p = 6.8×10(-5); OR = 2.84, 95% CI 1.66-4.84), while C/C homozygous UC patients had less often extensive colitis than G allele carriers (p = 0.029; OR = 0.36, 95% CI 0.14-0.92). In silico analysis predicted stronger binding of the minor C allele of rs6887695 to the transcription factor RORα which is involved in Th17 differentiation. Differences regarding the binding to the major and minor allele sequence of rs6887695 were also predicted for the transcription factors HSF1, HSF2, MZF1 and Oct-1. Epistasis analysis revealed weak epistasis of the IL12B SNP rs6887695 with several SNPs (rs11889341, rs7574865, rs7568275, rs8179673, rs10181656, rs7582694) in the STAT4 gene which encodes the major IL-12 downstream transcription factor STAT4 (p

Published
2012
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22. The role of osteopontin (OPN/SPP1) haplotypes in the susceptibility to Crohn's disease.

Author

Jürgen Glas, Julia Seiderer, Corinna Bayrle, Martin Wetzke, Christoph Fries, Cornelia Tillack, Torsten Olszak, Florian Beigel, Christian Steib, Matthias Friedrich, Julia Diegelmann, Darina Czamara, and Stephan Brand

Subjects
Medicine, Science
Abstract

BACKGROUND: Osteopontin represents a multifunctional molecule playing a pivotal role in chronic inflammatory and autoimmune diseases. Its expression is increased in inflammatory bowel disease (IBD). The aim of our study was to analyze the association of osteopontin (OPN/SPP1) gene variants in a large cohort of IBD patients. METHODOLOGY/PRINCIPAL FINDINGS: Genomic DNA from 2819 Caucasian individuals (n = 841 patients with Crohn's disease (CD), n = 473 patients with ulcerative colitis (UC), and n = 1505 healthy unrelated controls) was analyzed for nine OPN SNPs (rs2728127, rs2853744, rs11730582, rs11739060, rs28357094, rs4754 = p.Asp80Asp, rs1126616 = p.Ala236Ala, rs1126772 and rs9138). Considering the important role of osteopontin in Th17-mediated diseases, we performed analysis for epistasis with IBD-associated IL23R variants and analyzed serum levels of the Th17 cytokine IL-22. For four OPN SNPs (rs4754, rs1126616, rs1126772 and rs9138), we observed significantly different distributions between male and female CD patients. rs4754 was protective in male CD patients (p = 0.0004, OR = 0.69). None of the other investigated OPN SNPs was associated with CD or UC susceptibility. However, several OPN haplotypes showed significant associations with CD susceptibility. The strongest association was found for a haplotype consisting of the 8 OPN SNPs rs2728127-rs2853744-rs11730582-rs11439060-rs28357094-rs112661-rs1126772-rs9138 (omnibus p-value = 2.07×10⁻⁸). Overall, the mean IL-22 secretion in the combined group of OPN minor allele carriers with CD was significantly lower than that of CD patients with OPN wildtype alleles (p = 3.66×10⁻⁵). There was evidence for weak epistasis between the OPN SNP rs28357094 with the IL23R SNP rs10489629 (p = 4.18×10⁻²) and between OPN SNP rs1126616 and IL23R SNP rs2201841 (p = 4.18×10⁻²) but none of these associations remained significant after Bonferroni correction. CONCLUSIONS/SIGNIFICANCE: Our study identified OPN haplotypes as modifiers of CD susceptibility, while the combined effects of certain OPN variants may modulate IL-22 secretion.

Published
2011
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23. Highly efficient elimination of colorectal tumor-initiating cells by an EpCAM/CD3-bispecific antibody engaging human T cells.

Author

Ines Herrmann, Patrick A Baeuerle, Matthias Friedrich, Alexander Murr, Susanne Filusch, Dominik Rüttinger, Mariam W Majdoub, Sherven Sharma, Peter Kufer, Tobias Raum, and Markus Münz

Subjects
Medicine, Science
Abstract

With their resistance to genotoxic and anti-proliferative drugs and potential to grow tumors and metastases from very few cells, cancer stem or tumor-initiating cells (TICs) are a severe limitation for the treatment of cancer by conventional therapies. Here, we explored whether human T cells that are redirected via an EpCAM/CD3-bispecific antibody called MT110 can lyse colorectal TICs and prevent tumor growth from TICs. MT110 recognizes EpCAM, a cell adhesion molecule expressed on TICs from diverse human carcinoma, which was recently shown to promote tumor growth through engagement of elements of the wnt pathway. MT110 was highly potent in mediating complete redirected lysis of KRAS-, PI3 kinase- and BRAF-mutated colorectal TICs, as demonstrated in a soft agar assay. In immunodeficient mice, MT110 prevented growth of tumors from a 5,000-fold excess of a minimally tumorigenic TIC dose. T cells engaged by MT110 may provide a potent therapeutic means to eradicate TICs and bulk tumor cells derived thereof.

Published
2010
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24. Mechanical Properties of Diagonal Laminated Timber (DLT) with Respect to Point-Supported Mass Timber Slabs

Author

Winter, Stefan (Prof. Dr.), Winter, Stefan (Prof. Dr.);Dietsch, Philipp (Prof. Dr.);Serrano, Erik (Prof. Dr.), Arnold, Matthias Friedrich, Winter, Stefan (Prof. Dr.), Winter, Stefan (Prof. Dr.);Dietsch, Philipp (Prof. Dr.);Serrano, Erik (Prof. Dr.), and Arnold, Matthias Friedrich

Abstract

This thesis makes a contribution to the development of diagonal laminated timber (DLT), a composite timber product consisting of individual layers which are rotated to each other at a certain angle to optimize its stiffness properties for specific design situations and applications, such as biaxial bending due to point-supports. Therefore, DLT represents an application-optimized further development of cross laminated timber (CLT)., Diese Thesis befasst sich mit der Entwicklung von diagonal verklebtem Brettsperrholz (Diagonallagenholz - DLH), einem Laminat aus Massivholzlamellen, welche zur Anpassung der Steifigkeitseigenschaften in einem bestimmten Winkel zueinander angeordnet werden. DLH stellt eine anwendungsoptimierte Weiterentwicklung von Brettsperrholz (BSP) dar und erreicht bei gleichem Materialeinsatz verbesserte mechanische Eigenschaften.

Published
2024

25. Hermansky-Pudlak syndrome type 1 causes impaired anti-microbial immunity and inflammation due to dysregulated immunometabolism

Author

Athena Cavounidis, Sumeet Pandey, Melania Capitani, Matthias Friedrich, Amy Cross, Lisa Gartner, Dominik Aschenbrenner, Seunghee Kim-Schulze, Ying Ka Lam, Georgina Berridge, Dermot P.B. McGovern, Benedikt Kessler, Roman Fischer, Paul Klenerman, Joanna Hester, Fadi Issa, Esther A. Torres, Fiona Powrie, Bernadette R. Gochuico, William A. Gahl, Louis Cohen, and Holm H. Uhlig

Subjects
Proteomics, Inflammation, Hermanski-Pudlak Syndrome, TOR Serine-Threonine Kinases, Immunology, Humans, Immunology and Allergy, Lipids
Abstract

Hermansky-Pudlak syndrome (HPS) types 1 and 4 are caused by defective vesicle trafficking. The mechanism for Crohn's disease-like inflammation, lung fibrosis, and macrophage lipid accumulation in these patients remains enigmatic. The aim of this study is to understand the cellular basis of inflammation in HPS-1. We performed mass cytometry, proteomic and transcriptomic analyses to investigate peripheral blood cells and serum of HPS-1 patients. Using spatial transcriptomics, granuloma-associated signatures in the tissue of an HPS-1 patient with granulomatous colitis were dissected. In vitro studies were conducted to investigate anti-microbial responses of HPS-1 patient macrophages and cell lines. Monocytes of HPS-1 patients exhibit an inflammatory phenotype associated with dysregulated TNF, IL-1α, OSM in serum, and monocyte-derived macrophages. Inflammatory macrophages accumulate in the intestine and granuloma-associated macrophages in HPS-1 show transcriptional signatures suggestive of a lipid storage and metabolic defect. We show that HPS1 deficiency leads to an altered metabolic program and Rab32-dependent amplified mTOR signaling, facilitated by the accumulation of mTOR on lysosomes. This pathogenic mechanism translates into aberrant bacterial clearance, which can be rescued with mTORC1 inhibition. Rab32-mediated mTOR signaling acts as an immuno-metabolic checkpoint, adding to the evidence that defective bioenergetics can drive hampered anti-microbial activity and contribute to inflammation.

Published
2022
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28. Supplementary Figure 1 from Preclinical Characterization of AMG 330, a CD3/CD33-Bispecific T-Cell–Engaging Antibody with Potential for Treatment of Acute Myelogenous Leukemia

Author

Benno Rattel, Peter Kufer, Patrick A. Baeuerle, Jerry W. Slootstra, Majk Kvesic, Roman Kischel, Patrick Hoffmann, Joachim Wahl, Larissa Hendrich, Katja Matthes, Monika Bajtus, Tobias Raum, Anja Henn, and Matthias Friedrich

Abstract

PDF file - 83KB, Supplementary Figure S1. Characteristics of purified AMG 330.

Published
2023
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29. Supplementary File from AMG 757, a Half-Life Extended, DLL3-Targeted Bispecific T-Cell Engager, Shows High Potency and Sensitivity in Preclinical Models of Small-Cell Lung Cancer

Author

Paul E. Hughes, Julie M. Bailis, Angela Coxon, Jude Canon, Pedro J. Beltran, Jennitte Stevens, Sean Caenepeel, Yajing Yang, Tobias Raum, Joshua T. Pearson, Matthias Friedrich, Oliver Homann, Fei Lee, Siyuan Liu, Jonathan Werner, Christopher M. Murawsky, Melissa Thomas, Petra Deegen, Jinghui Zhan, Juan Estrada, Edward K. Lobenhofer, Keegan Cooke, and Michael J. Giffin

Abstract

Tissue expression datasets

Published
2023
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30. Supplementary Figure S2 from The PSMA-targeting Half-life Extended BiTE Therapy AMG 160 has Potent Antitumor Activity in Preclinical Models of Metastatic Castration-resistant Prostate Cancer

Author

Julie M. Bailis, Angela Coxon, Peter Kufer, Tobias Raum, Benno Rattel, Doris Rau, Katja Matthes, Michael Z. Liao, Matthias Friedrich, Famke Aeffner, Pamela Bogner, Joachim Wahl, Shyun Li, Olivier Nolan-Stevaux, Oliver Thomas, and Petra Deegen

Abstract

Figure S2. Enzalutamide increases PSMA expression levels and may enhance AMG 160-dependent cytotoxicity.

Published
2023
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31. Data from Molecular Imaging of Radiolabeled Bispecific T-Cell Engager 89Zr-AMG211 Targeting CEA-Positive Tumors

Author

Marjolijn N. Lub-de Hooge, Elisabeth G.E. de Vries, Carolien P. Schröder, Anton G.T. Terwisscha van Scheltinga, H. Kam Cheung, Alexander Sternjak, Matthias Friedrich, Sabine Stienen, Frank J. Warnders, and Stijn J.H. Waaijer

Abstract

Purpose: AMG 211, a bispecific T-cell engager (BiTE) antibody construct, targets carcinoembryonic antigen (CEA) and the CD3 epsilon subunit of the human T-cell receptor. AMG 211 was labeled with zirconium-89 (89Zr) or fluorescent dye to evaluate the tumor-targeting properties.Experimental Design: 89Zr-AMG211 was administered to mice bearing CEA-positive xenograft tumors of LS174T colorectal adenocarcinoma or BT474 breast cancer cells, as well as CEA-negative HL-60 promyelocytic leukemia xenografts. Biodistribution studies with 2- to 10-μg 89Zr-AMG211 supplemented with unlabeled AMG 211 up to 500-μg protein dose were performed. A BiTE that does not bind CEA, 89Zr-Mec14, served as a negative control. 89Zr-AMG211 integrity was determined in tumor lysates ex vivo. Intratumoral distribution was studied with IRDye800CW-AMG211. Moreover, 89Zr-AMG211 was manufactured according to Good Manufacturing Practice (GMP) guidelines for clinical trial NCT02760199.Results: 89Zr-AMG211 demonstrated dose-dependent tumor uptake at 6 hours. The highest tumor uptake was observed with a 2-μg dose, and the lowest tumor uptake was observed with a 500-μg dose. After 24 hours, higher uptake of 10-μg 89Zr-AMG211 occurred in CEA-positive xenografts, compared with CEA-negative xenografts. Although the blood half-life of 89Zr-AMG211 was approximately 1 hour, tumor retention persisted for at least 24 hours. 89Zr-Mec14 showed no tumor accumulation beyond background level. Ex vivo autoradiography revealed time-dependent disintegration of 89Zr-AMG211. 800CW-AMG211 was specifically localized in CEA-expressing viable tumor tissue. GMP-manufactured 89Zr-AMG211 fulfilled release specifications.Conclusions: 89Zr-AMG211 showed dose-dependent CEA-specific tumor targeting and localization in viable tumor tissue. Our data enabled its use to clinically evaluate AMG 211 in vivo behavior. Clin Cancer Res; 24(20); 4988–96. ©2018 AACR.

Published
2023
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32. Data from The PSMA-targeting Half-life Extended BiTE Therapy AMG 160 has Potent Antitumor Activity in Preclinical Models of Metastatic Castration-resistant Prostate Cancer

Author

Julie M. Bailis, Angela Coxon, Peter Kufer, Tobias Raum, Benno Rattel, Doris Rau, Katja Matthes, Michael Z. Liao, Matthias Friedrich, Famke Aeffner, Pamela Bogner, Joachim Wahl, Shyun Li, Olivier Nolan-Stevaux, Oliver Thomas, and Petra Deegen

Abstract

Purpose:Metastatic castration-resistant prostate cancer (mCRPC) remains a disease with high unmet medical need, as most patients do not achieve durable response with available treatments. Prostate-specific membrane antigen (PSMA) is a compelling target for mCRPC. It is highly expressed by primary and metastatic prostate cancer cells, with increased expression after progression on androgen deprivation therapy.Experimental Design:We developed AMG 160, a half-life extended, bispecific T-cell engager immuno-oncology therapy that binds PSMA on prostate cancer cells and cluster of differentiation 3 on T cells for treatment of mCRPC. AMG 160 was evaluated in vitro and in mCRPC xenograft models. AMG 160 tolerability was assessed in nonhuman primates (NHP). AMG 160 activity as monotherapy and in combination with a PSMA-imaging agent, novel hormonal therapy, and immune checkpoint blockade was evaluated.Results:AMG 160 induces potent, specific killing of PSMA-expressing prostate cancer cell lines in vitro, with half-maximal lysis of 6–42 pmol/L. In vivo, AMG 160 administered weekly at 0.2 mg/kg engages T cells administered systemically and promotes regression of established 22Rv-1 mCRPC xenograft tumors. AMG 160 is compatible with the imaging agent gallium 68–labeled PSMA-11, and shows enhanced cytotoxic activity when combined with enzalutamide or an anti-programmed death-1 antibody. AMG 160 exhibits an extended half-life and has an acceptable safety profile in NHPs.Conclusions:The preclinical characterization of AMG 160 highlights its potent antitumor activity in vitro and in vivo, and its potential for use with known diagnostic or therapeutic agents in mCRPC. These data support the ongoing clinical evaluation of AMG 160 in patients with mCRPC.See related commentary by Kamat et al., p. 2675

Published
2023
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33. Supplementary Methods from AMG 757, a Half-Life Extended, DLL3-Targeted Bispecific T-Cell Engager, Shows High Potency and Sensitivity in Preclinical Models of Small-Cell Lung Cancer

Author

Paul E. Hughes, Julie M. Bailis, Angela Coxon, Jude Canon, Pedro J. Beltran, Jennitte Stevens, Sean Caenepeel, Yajing Yang, Tobias Raum, Joshua T. Pearson, Matthias Friedrich, Oliver Homann, Fei Lee, Siyuan Liu, Jonathan Werner, Christopher M. Murawsky, Melissa Thomas, Petra Deegen, Jinghui Zhan, Juan Estrada, Edward K. Lobenhofer, Keegan Cooke, and Michael J. Giffin

Abstract

File contains Supplementary Methods

Published
2023
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34. Supplementary Figure 3 from AMG 757, a Half-Life Extended, DLL3-Targeted Bispecific T-Cell Engager, Shows High Potency and Sensitivity in Preclinical Models of Small-Cell Lung Cancer

Author

Paul E. Hughes, Julie M. Bailis, Angela Coxon, Jude Canon, Pedro J. Beltran, Jennitte Stevens, Sean Caenepeel, Yajing Yang, Tobias Raum, Joshua T. Pearson, Matthias Friedrich, Oliver Homann, Fei Lee, Siyuan Liu, Jonathan Werner, Christopher M. Murawsky, Melissa Thomas, Petra Deegen, Jinghui Zhan, Juan Estrada, Edward K. Lobenhofer, Keegan Cooke, and Michael J. Giffin

Abstract

Supplementary Figure 3 Evaluation of DLL3 expression in tumor types other than SCLC.

Published
2023
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36. Supplementary Figure 6 from AMG 757, a Half-Life Extended, DLL3-Targeted Bispecific T-Cell Engager, Shows High Potency and Sensitivity in Preclinical Models of Small-Cell Lung Cancer

Author

Paul E. Hughes, Julie M. Bailis, Angela Coxon, Jude Canon, Pedro J. Beltran, Jennitte Stevens, Sean Caenepeel, Yajing Yang, Tobias Raum, Joshua T. Pearson, Matthias Friedrich, Oliver Homann, Fei Lee, Siyuan Liu, Jonathan Werner, Christopher M. Murawsky, Melissa Thomas, Petra Deegen, Jinghui Zhan, Juan Estrada, Edward K. Lobenhofer, Keegan Cooke, and Michael J. Giffin

Abstract

Supplementary Figure 6 A, Expression of human CD25, CD69, PD-1, and 4-1BB on human CD4+ T cells isolated from mouse lungs harboring SHP-77 tumors 168 hours after treatment with AMG 757 or a control HLE BiTE® molecule. B, Expression of human CD25, CD69, PD-1, and 4-1BB on human CD8+ T cells isolated from mouse lungs harboring SHP-77 tumors 168 hours after treatment with either AMG 757 or a control HLE BiTE® molecule. *P < 0.05; **P < 0.01; *** P< 0.001

Published
2023
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37. Data from AMG 757, a Half-Life Extended, DLL3-Targeted Bispecific T-Cell Engager, Shows High Potency and Sensitivity in Preclinical Models of Small-Cell Lung Cancer

Author

Paul E. Hughes, Julie M. Bailis, Angela Coxon, Jude Canon, Pedro J. Beltran, Jennitte Stevens, Sean Caenepeel, Yajing Yang, Tobias Raum, Joshua T. Pearson, Matthias Friedrich, Oliver Homann, Fei Lee, Siyuan Liu, Jonathan Werner, Christopher M. Murawsky, Melissa Thomas, Petra Deegen, Jinghui Zhan, Juan Estrada, Edward K. Lobenhofer, Keegan Cooke, and Michael J. Giffin

Abstract

Purpose:Small-cell lung cancer (SCLC) is an aggressive neuroendocrine tumor with a high relapse rate, limited therapeutic options, and poor prognosis. We investigated the antitumor activity of AMG 757, a half-life extended bispecific T-cell engager molecule targeting delta-like ligand 3 (DLL3)—a target that is selectively expressed in SCLC tumors, but with minimal normal tissue expression.Experimental Design:AMG 757 efficacy was evaluated in SCLC cell lines and in orthotopic and patient-derived xenograft (PDX) mouse SCLC models. Following AMG 757 administration, changes in tumor volume, pharmacodynamic changes in tumor-infiltrating T cells (TILs), and the spatial relationship between the appearance of TILs and tumor histology were examined. Tolerability was assessed in nonhuman primates (NHPs).Results:AMG 757 showed potent and specific killing of even those SCLC cell lines with very low DLL3 expression (Conclusions:AMG 757 has a compelling safety and efficacy profile in preclinical studies making it a viable option for targeting DLL3-expressing SCLC tumors in the clinical setting.

Published
2023
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38. Supplementary Tables from AMG 757, a Half-Life Extended, DLL3-Targeted Bispecific T-Cell Engager, Shows High Potency and Sensitivity in Preclinical Models of Small-Cell Lung Cancer

Author

Paul E. Hughes, Julie M. Bailis, Angela Coxon, Jude Canon, Pedro J. Beltran, Jennitte Stevens, Sean Caenepeel, Yajing Yang, Tobias Raum, Joshua T. Pearson, Matthias Friedrich, Oliver Homann, Fei Lee, Siyuan Liu, Jonathan Werner, Christopher M. Murawsky, Melissa Thomas, Petra Deegen, Jinghui Zhan, Juan Estrada, Edward K. Lobenhofer, Keegan Cooke, and Michael J. Giffin

Abstract

This file contains Supplementary Tables 1-5

Published
2023
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39. Figures S1-S4 Table S1 from Molecular Imaging of Radiolabeled Bispecific T-Cell Engager 89Zr-AMG211 Targeting CEA-Positive Tumors

Author

Marjolijn N. Lub-de Hooge, Elisabeth G.E. de Vries, Carolien P. Schröder, Anton G.T. Terwisscha van Scheltinga, H. Kam Cheung, Alexander Sternjak, Matthias Friedrich, Sabine Stienen, Frank J. Warnders, and Stijn J.H. Waaijer

Abstract

Supplementary Figures S1-S4 and Supplementary Table S1 including Supplementary Figure legend and Supplementary Table caption Figure S1. Flow chart of the drug substance (N-sucDf-AMG211) manufacturing process and drug product (89Zr-AMG211) formulation and filling process. Figure S2. Quality control of 89Zr AMG211. Representative size exclusion high performance liquid chromatography chromatogram of 89Zr AMG211 with 280 nm signal (top panel), radiochemical signal (middle panel) and the overlay (lower panel). Figure S3. Immunoreactivity of 89Zr AMG211. A) Representative competition assay using an effective N sucDf:AMG 211 ratio of 2:1. Curve fit with 95% confidence interval is visualized. B) Immunoreactivity towards CEA of different ratios N sucDf:AMG 211. Data are mean {plus minus} SD. Figure S4. Membrane binding and internalization of 89Zr AMG211 after CEA binding on LS174T cells (n = 3). Membrane bound and internalized 89Zr-AMG211 are expressed as percentage of initial cell associated activity. Data are mean {plus minus} SD. Figure S5. Expression of CEA on LS174T, BT474 and HL 60 cell lines (n = 3). Membrane expression is expressed as percentage of LS174T signal. Data are mean {plus minus} SD Table S1. GMP manufacturing of N sucDf AMG211 and 89Zr AMG211. Release criteria are fulfilled for batch 1, 2, and 3. In addition stability are shown for N sucDf AMG211 stored at 80{degree sign}C for 6 months, all quality criteria are still met.

Published
2023
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40. Supplementary Figure 1 from AMG 757, a Half-Life Extended, DLL3-Targeted Bispecific T-Cell Engager, Shows High Potency and Sensitivity in Preclinical Models of Small-Cell Lung Cancer

Author

Paul E. Hughes, Julie M. Bailis, Angela Coxon, Jude Canon, Pedro J. Beltran, Jennitte Stevens, Sean Caenepeel, Yajing Yang, Tobias Raum, Joshua T. Pearson, Matthias Friedrich, Oliver Homann, Fei Lee, Siyuan Liu, Jonathan Werner, Christopher M. Murawsky, Melissa Thomas, Petra Deegen, Jinghui Zhan, Juan Estrada, Edward K. Lobenhofer, Keegan Cooke, and Michael J. Giffin

Abstract

Supplementary Figure 1 DLL3 is differentially expressed in SCLC tumors and cell lines compared with normal tissues.

Published
2023
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41. Data from The Interleukin 22 Pathway Interacts with Mutant KRAS to Promote Poor Prognosis in Colon Cancer

Author

Fiona Powrie, Nathaniel R. West, Timothy S. Maughan, Sabine Tejpar, Mauro Delorenzi, Viktor Hendrik Koelzer, Enric Domingo, Lucy C. Garner, Alina Janney, Samuel J. Bullers, Matthias Friedrich, Elizabeth H. Mann, David Barras, and Sarah McCuaig

Abstract

Purpose:The cytokine IL22 promotes tumor progression in murine models of colorectal cancer. However, the clinical significance of IL22 in human colorectal cancer remains unclear. We sought to determine whether the IL22 pathway is associated with prognosis in human colorectal cancer, and to identify mechanisms by which IL22 can influence disease progression.Experimental Design:Transcriptomic data from stage II/III colon cancers in independent discovery (GSE39582 population-based cohort, N = 566) and verification (PETACC3 clinical trial, N = 752) datasets were used to investigate the association between IL22 receptor expression (encoded by the genes IL22RA1 and IL10RB), tumor mutation status, and clinical outcome using Cox proportional hazard models. Functional interactions between IL22 and mutant KRAS were elucidated using human colorectal cancer cell lines and primary tumor organoids.Results:Transcriptomic analysis revealed a poor-prognosis subset of tumors characterized by high expression of IL22RA1, the alpha subunit of the heterodimeric IL22 receptor, and KRAS mutation [relapse-free survival (RFS): HR = 2.93, P = 0.0006; overall survival (OS): HR = 2.45, P = 0.0023]. KRAS mutations showed a similar interaction with IL10RB and conferred the worst prognosis in tumors with high expression of both IL22RA1 and IL10RB (RFS: HR = 3.81, P = 0.0036; OS: HR = 3.90, P = 0.0050). Analysis of human colorectal cancer cell lines and primary tumor organoids, including an isogenic cell line pair that differed only in KRAS mutation status, showed that IL22 and mutant KRAS cooperatively enhance cancer cell proliferation, in part through augmentation of the Myc pathway.Conclusions:Interactions between KRAS and IL22 signaling may underlie a previously unrecognized subset of clinically aggressive colorectal cancer that could benefit from therapeutic modulation of the IL22 pathway.

Published
2023
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42. Supplementary Figure 2 from AMG 757, a Half-Life Extended, DLL3-Targeted Bispecific T-Cell Engager, Shows High Potency and Sensitivity in Preclinical Models of Small-Cell Lung Cancer

Author

Paul E. Hughes, Julie M. Bailis, Angela Coxon, Jude Canon, Pedro J. Beltran, Jennitte Stevens, Sean Caenepeel, Yajing Yang, Tobias Raum, Joshua T. Pearson, Matthias Friedrich, Oliver Homann, Fei Lee, Siyuan Liu, Jonathan Werner, Christopher M. Murawsky, Melissa Thomas, Petra Deegen, Jinghui Zhan, Juan Estrada, Edward K. Lobenhofer, Keegan Cooke, and Michael J. Giffin

Abstract

Supplementary Figure 2 Representative photomicrographs of DLL3 immunostaining (brown color) in normal human tissues using immunohistochemistry.

Published
2023
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43. Supplementary Figure 5 from AMG 757, a Half-Life Extended, DLL3-Targeted Bispecific T-Cell Engager, Shows High Potency and Sensitivity in Preclinical Models of Small-Cell Lung Cancer

Author

Paul E. Hughes, Julie M. Bailis, Angela Coxon, Jude Canon, Pedro J. Beltran, Jennitte Stevens, Sean Caenepeel, Yajing Yang, Tobias Raum, Joshua T. Pearson, Matthias Friedrich, Oliver Homann, Fei Lee, Siyuan Liu, Jonathan Werner, Christopher M. Murawsky, Melissa Thomas, Petra Deegen, Jinghui Zhan, Juan Estrada, Edward K. Lobenhofer, Keegan Cooke, and Michael J. Giffin

Abstract

Supplementary Figure 5 A, DLL3 RNA expression levels in a panel of SCLC patient-derived xenograft (PDX) models compared with positive (NCI-H82) and negative (NCI-H460) control SCLC cell lines. Data are reported as relative quantification normalized to NCI-H460 cell line expression. B, DLL3 protein expression levels in a panel of SCLC PDX models compared with positive (NCI-H82) and negative (NCI-H460) control SCLC cell lines. GAPDH, glyceraldehyde 3-phosphate dehydrogenase.

Published
2023
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44. Supplementary Methods and Tables from The PSMA-targeting Half-life Extended BiTE Therapy AMG 160 has Potent Antitumor Activity in Preclinical Models of Metastatic Castration-resistant Prostate Cancer

Author

Julie M. Bailis, Angela Coxon, Peter Kufer, Tobias Raum, Benno Rattel, Doris Rau, Katja Matthes, Michael Z. Liao, Matthias Friedrich, Famke Aeffner, Pamela Bogner, Joachim Wahl, Shyun Li, Olivier Nolan-Stevaux, Oliver Thomas, and Petra Deegen

Abstract

Supplementary methods, tables, and references.

Published
2023
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45. Supplementary Figure 4 from AMG 757, a Half-Life Extended, DLL3-Targeted Bispecific T-Cell Engager, Shows High Potency and Sensitivity in Preclinical Models of Small-Cell Lung Cancer

Author

Paul E. Hughes, Julie M. Bailis, Angela Coxon, Jude Canon, Pedro J. Beltran, Jennitte Stevens, Sean Caenepeel, Yajing Yang, Tobias Raum, Joshua T. Pearson, Matthias Friedrich, Oliver Homann, Fei Lee, Siyuan Liu, Jonathan Werner, Christopher M. Murawsky, Melissa Thomas, Petra Deegen, Jinghui Zhan, Juan Estrada, Edward K. Lobenhofer, Keegan Cooke, and Michael J. Giffin

Abstract

Supplementary FIgure 4 AMG 757 demonstrated antitumor activity in the WM266-4 melanoma xenograft model.

Published
2023
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46. Abstract P134: Dietary Intake and Vascular Function and Myocardial Structure in Canadian Youth With and Without Type 1 Diabetes: The Cardea Study

Author

Soren Harnois-Leblanc, Vicky Drapeau, Andraea Van Hulst, Tracie A Barnett, Vanessa McNealis, Matthias Friedrich, Jean-Luc Bigras, Anne Monique Nuyt, Andrea Benedetti, Marie-Ève Mathieu, and Melanie Henderson

Subjects
Physiology (medical), Cardiology and Cardiovascular Medicine
Abstract

Introduction: People living with T1D are disproportionally more affected by CVD than the general population. As emerging evidence points to direct effects of diet on vascular function and cardiac structure, dietary interventions may be effective strategies to mitigate CVD risk early on. Hypothesis: We tested the hypothesis that specific dietary components and diet quality are associated with early markers of vascular and cardiac structure and function in youth with T1D. We compared these to associations in healthy controls. Methods: Cross-sectional study of 100 youth with T1D aged 14-18 yrs recruited at the Diabetes Clinic at Sainte-Justine Hospital University Center (Montreal, Canada) and 97 age and sex-matched healthy controls. Pulse-wave velocity (PWV) estimated arterial stiffness; velocity time integral (VTI) and acceleration during a flow-mediated dilation test assessed endothelial function. We measured left ventricular mass/height (LVMH), papillary mass, and wall thickness with cardiac MRI. Diet was measured with 3 x 24-h dietary recalls. Nutrients and foods were analyzed with the CANDAT software based on the Canadian Nutrient File. We assessed daily consumption of fruits, vegetables, fish, red meat, sugar-sweetened beverages and juices (SBJs), and sweets and chips. Food groups were all adjusted for total energy intake. We used the Diet Quality Index-International (DQI-I) to assess overall diet quality. We estimated linear regression models for each diet variable/outcome combination separately in youth with T1D and healthy controls adjusting for age, sex, ethnicity, parental education, physical activity and sedentary time (by accelerometer), and heart rate. Results: Girls comprised 48% of the sample; the mean age was 16.3 yrs (SD=1.3). The T1D group included more youth having overweight or obesity (43% vs. 20%), and was more ethnically diverse (White: 60% vs. 72%), compared to controls. Average glycated hemoglobin was 8.5% (SD=1.4) and median diabetes duration 6 yrs (IQR=3-10) in youth with T1D. In youth with T1D : Consuming more fruits was associated with lower PWV (beta [95% CI] per serving: -0.21 [-0.40; -0.02] m/s). Greater SBJ intake was paradoxically associated with higher VTI (per % total energy intake: 0.34 [0.04; 0.65] cm). DQI-I was related to a higher LVMH (per unit: 0.5 [0.1; 0.9] g/m). In controls : Eating more fruit was associated with a greater LVMH (per serving: 2.5 [0.1; 4.7] g/m). Higher SBJ intake was associated with a lower wall thickness (per % total energy intake: -0.10 [-0.20; -0.01] mm). Conclusions: Findings suggest that consuming more fruit could prevent arterial stiffening in youth with T1D. We previously reported that youth with T1D had lower LVMH than controls, and findings herein suggest that better diet quality could help compensate for this deficit. Overall, our results provide evidence on diet as a potential strategy to lower CVD risk in youth with T1D.

Published
2023
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47. IL-1-driven stromal–neutrophil interactions define a subset of patients with inflammatory bowel disease that does not respond to therapies

Author

Kevin Rue-Albrecht, Hannah Sharpe, Matthew A. Jackson, E Collantes, A P Frei, Alistair Easton, Fiona Powrie, M Coles, Christopher D. Buckley, Watts Gfm., Holm H. Uhlig, Simon Travis, Sarah McCuaig, M Brenner, Stephen N. Sansom, R Ravindran, Matthias Friedrich, R Tandon, Moustafa Attar, Ilya Korsunsky, Kevin Wei, T Thomas, F Barone, L Thomas, R S Peres, Samuel J. Bullers, Z Christoforidou, K G Lassen, Alessandra Geremia, Elizabeth H. Mann, Soumya Raychaudhuri, Mathilde Pohin, and D Sathananthan

Subjects
Adult, Male, Stromal cell, Neutrophils, Disease, Vascular Remodeling, Inflammatory bowel disease, General Biochemistry, Genetics and Molecular Biology, Article, Transcriptome, medicine, Humans, Fibroblast, Aged, business.industry, Receptors, Interleukin-1, General Medicine, Fibroblasts, Middle Aged, medicine.disease, Colitis, Inflammatory Bowel Diseases, digestive system diseases, Blockade, medicine.anatomical_structure, Neutrophil Infiltration, Pharmaceutical Preparations, Immunology, Mucosal immunology, Cytokines, Female, Tumor necrosis factor alpha, Stromal Cells, Chemokines, business, Infiltration (medical), Interleukin-1, Signal Transduction
Abstract

Current inflammatory bowel disease (IBD) therapies are ineffective in a high proportion of patients. Combining bulk and single-cell transcriptomics, quantitative histopathology and in situ localization across three cohorts of patients with IBD (total n = 376), we identify coexpressed gene modules within the heterogeneous tissular inflammatory response in IBD that map to distinct histopathological and cellular features (pathotypes). One of these pathotypes is defined by high neutrophil infiltration, activation of fibroblasts and vascular remodeling at sites of deep ulceration. Activated fibroblasts in the ulcer bed display neutrophil-chemoattractant properties that are IL-1R, but not TNF, dependent. Pathotype-associated neutrophil and fibroblast signatures are increased in nonresponders to several therapies across four independent cohorts (total n = 343). The identification of distinct, localized, tissular pathotypes will aid precision targeting of current therapeutics and provides a biological rationale for IL-1 signaling blockade in ulcerating disease., Transcriptomic and histological profiling of gut biopsies from multiple independent cohorts of patients with inflammatory bowel disease identifies distinct histopathological, molecular and cellular features associated with treatment response, providing insights for patient stratification and precision therapy.

Published
2021

48. Initial Invasive or Conservative Strategy for Stable Coronary Disease

Author

Maron D. J., Hochman J. S., Reynolds H. R., Bangalore S., O'Brien S. M., Boden W. E., Chaitman B. R., Senior R., Lopez-Sendon J., Alexander K. P., Lopes R. D., Shaw L. J., Berger J. S., Newman J. D., Sidhu M. S., Goodman S. G., Ruzyllo W., Gosselin G., Maggioni A. P., White H. D., Bhargava B., Min J. K., John Mancini G. B., Berman D. S., Picard M. H., Kwong R. Y., Ali Z. A., Mark D. B., Spertus J. A., Krishnan M. N., Elghamaz A., Moorthy N., Hueb W. A., Demkow M., Mavromatis K., Bockeria O., Peteiro J., Miller T. D., Szwed H., Doerr R., Keltai M., Selvanayagam J. B., Gabriel Steg P., Held C., Kohsaka S., Mavromichalis S., Kirby R., Jeffries N. O., Harrell F. E., Rockhold F. W., Broderick S., Bruce Ferguson T., Williams D. O., Harrington R. A., Stone G. W., Rosenberg Y, ISCHEMIA Research Group: Joseph Ricci, A Tello Montoliu, A I Robero Aniorte, Abbey Mulder, Abhay A Laddu, Abhinav Goyal, Abhishek Dubey, Abhishek Goyal, Abigail Knighton, Abraham Oomman, Adam J Jaskowiak, Adam Kolodziej, Adam Witkowski, Adnan Hameed, Adriana Anesini, Afshan Hussain, Agne Juceviciene, Agne Urboniene, Agnes Jakal, Agnieszka Szramowska, Ahmad Khairuddin, Ahmed Abdel-Latif, Ahmed Adel, Ahmed Aljzeeri, Ahmed Kamal, Ahmed Talaat, Aimee Mann, Aira Contreras, Ajit Kumar, V K Kumar, Akemi Furukawa, Akshay Bagai, Akvile Smigelskaite, Alain Furber, Alain Rheault, Alaine Melanie Loehr, Alan Rosen, Albert Varga, Albertina Qelaj, Alberto Barioli, Aldo Russo, Alec Moorman, Alejandro Gisbert, Aleksandra Fratczak, Aleksandras Laucevicius, Alena Kuleshova, Alessandro Sionis, Alexander A Sirker, Alexander M Chernyavskiy, Alexandra Craft, Alexandra Vazquez, Alexandre Ciappina Hueb, Alexandre S Colafranseschi, Alexandre Schaan de Quadros, Alexandre Tognon, Ali Alghamdi, Alice Manica Muller, Aline Nogueira Rabaça, Aline Peixoto Deiro, Alison Hallam, Allegra Stone, Allison Schley, Almudena Castro, Alvaro Rabelo Ales, Amanda Germann, Amanda O'Malley, Amar Uxa, Amarachi Ojajuni, Amarino C Oliveira Jr, Amber B Hull, Ambuj Roy, Amer Zarka, Amir Janmohamed, Ammani Brown, Ammy Malinay, Amparo Martinez Monzonis, Amy J Richards, Amy Iskandrian, Amy Ollinger, Ana D Djordjevic-Dikic, Ana Fernández Martínez, Ana Gomes Almeida, Ana Paula Batista, Ana Rita Francisco, Ana S Mladenovic, Ana Santana, Anam Siddiqui, Anastasia M Kuzmina-Krutetskaya, Andras Vertes, Andre S Sousa, Andre Gabriel, André Schmidt, Andrea M Lundeen, Andrea Bartykowszki, Andrea Lorimer, Andrea Mortara, Andrea Pascual, Andreia Coelho, Andreia Rocha, Andrés García-Rincón, Andrew G Howarth, Andrew J Moriarty, Andrew Docherty, Andrew Starovoytov, Andrew Zurick, Andrzej Łabyk, Andrzej Swiatkowski, Andy Lam, Anelise Kawakami, Angela Hoye, Angela Kim, Angelique Smit, Angelo Nobre, Anil V Shah, Anja Ljubez, Anjali Anand, Ankush Sachdeva, Ann Greenberg, Ann Luyten, Ann Ostrander, Anna Di Donato, Anna Cichocka-Radwan, Anna Fojt, Anna Plachcinska, Anna Proietti, Anna Teresinska, Anne Marie Webb, Anne Cartwright, Anne Heath, Anne Mackin, Anong Amaritakomol, Anong Chaiyasri, Anoop Chauhan, Anoop Mathew, Anthony Gemignani, Anto Luigi Andres, Antonia Vega, Antonietta Hansen, Antonino Ginel Iglesias, Antonio Carlos Carvalho, Antonio Di Chiara, Antonio Serra Peñaranda, Antonio Carvalho, Antonio Colombo, Antonio Fiarresga, Anupama Rao, Aquiles Valdespino-Estrada, Araceli Boan, Areef Ishani, Ariel Diaz, Arijit Ghosh, Arintaya Prommintikul, Arline Roberts, Arnold H Seto, Arnold P Good, Arshed Quyyumi, Arthur J Labovitz, Arthur Kerner, Arturo S Campos-Santaolalla, Arunima Misra, Ashok Mukherjee, Ashok Seth, Ashraf Seedhom, Asim N Cheema, Asker Ahmed, Atul Mathur, Atul Verma, Audrey W Leong, Axel Åkerblom, Axelle Fuentes, Aynun Naher, Badhma Valaiyapathi, Baljeet Kaur, Bandula Guruge, Barbara Brzezińska, Barbara Nardi, Bartosz Czarniak, Bebek Singh, Begoña Igual, Bela Merkely, Belen Cid Alvarez, Benjamin J Spooner, Benjamin J W Chow, Benjamin Cheong, Benoy N Shah, Bernard de Bruyne, Bernardas Valecka, Bernhard Jäger, Beth A Archer, Beth Abramson, Beth Jorgenson, Bethany Harvey, Betsy O'Neal, Bev Atkinson, Bev Bozek, Bevin Lang, Bijulal Sasidharan, Bin Yang, Bin Zhang, Binoy Mannekkattukudy Kurian, Bjoern Goebel, Bob Hu, Bogdan A Popescu, Bogdan Crnokrak, Bolin Zhu, Bonnie J Kirby, Brandi D Zimbelman, Brandy Starks, Branko D Beleslin, Brenda Hart, Brian P Shapiro, Brian McCandless, Brianna Wisniewski, Brigham R Smith, Brooks Mirrer, Bruce McManus, Bruce Rutkin, Bruna Edilena Paulino, Bruna Maria Ascoli, Bryn Smith, Byron J Allen, C Michael Gibson, C Noel Bairey Merz, Calin Pop, Cameron Hague, Camila Thais de Ormundo, Candace Gopaul, Candice P Edillo, Carísi A Polanczyk, Carita Krannila, Carla Vicente, Carl-Éric Gagné, Carlo Briguori, Carlos Peña Gil, Carlos Alvarez, Carly Ohmart, Carmen C Beladan, Carmen Ginghina, Carol M Kartje, Caroline Alsweiler, Caroline Brown, Caroline Callison, Caroline Pinheiro, Caroline Rodgers, Caroline Spindler, Carolyn Corbett, Carrie Drum, Casey Riedberger, Catherine Bone, Catherine Fleming, Catherine Gordon, Catherine Jahrsdorfer, Catherine Lemay, Catherine Weick, Cathrine Patten, Cecilia Goletto, Cezary Kepka, Chandini Suvarna, Chang Xu, Chantale Mercure, Charle A Viljoen, Charlene Wiyarand, Charles Jia-Yin Hou, Charles Y Lui, Charles Cannan, Charles Cornet, Charlotte Pirro, Chataroon Rimsukcharoenchai, Chen Wang, Cheng-Ting Tsai, Chen-Yen Chien, Cheryl A Allardyce, Chester M Hedgepeth, Chetan Patel, Chiara Attanasio, Chih-Hsuan Yen, Chi-Ming Chow, Ching Min Er, Ching-Ching Ong, Cholenahally Nanjappa Manjunath, Chris Beck, Chris Buller, Christel Vassaliere, Christian Hamm, Christiano Caldeira, Christie Ballantyne, Christina Björklund, Christine R Hinton, Christine Bergeron, Christine Masson, Christine Roraff, Christine Shelley, Christophe Laure, Christophe Thuaire, Christopher Kinsey, Christopher McFarren, Christopher Spizzieri, Christopher Travill, Chun-Chieh Liu, Chung-Lieh Hung, Chunguang Li, Chun-Ho Yun, Chunli Xia, Ciarra Heard, Cidney Schultz, Clare Venn-Edmonds, Claudia P Hochberg, Claudia Wegmayr, Claudia Cortés, Claudia Escobar, Cláudia Freixo, Claudio T Mesquita, Clemens T Kadalie, Colin Berry, Constance Philander, Corine Thobois, Costantino Costantini, Courtney Page, Craig Atkinson, Craig Barr, Craig Paterson, Cristina Bare, Cynthia Baumann, Cynthia Burman, Dalisa Espinosa, Damien Collison, Dan Deleanu, Dan Elian, Dan Gao, Dana Oliver, Daniel P Vezina, Daniel O'Rourke, Daniele Komar, Danielle Schade, Darrel P Francis, Dastan Malaev, David A Bull, David E Winchester, David P Faxon, David Booth, David Cohen, David DeMets, David Foo, David Schlichting, David Taggart, David Waters, David Wohns, Davis Vo, Dawid Teodorczyk, Dawn Shelstad, Dawn Turnbull, Dayuan Li, Dean Kereiakes, Deborah O'Neill, Deborah Yip, Debra K Johnson, Debra Dees, Deepak L Bhatt, Deepika Gopal, Deepti Kumar, Deirdre Mattina, Deirdre Murphy, Delano R Small, Delsa K Rose, Dengke Jiang, Denis Carl Phaneuf, Denise Braganza, Denise Fine, Derek Cyr, Desiree Tobin, Diana Cukali, Diana Parra, Diane Camara, Diane Minshall Liu, Diego Adrián Vences, Diego Franca de Cunha, Dimitrios Stournaras, Dipti Patel, Dongze Li, Donna Exley, Dorit Grahl, Dragana Stanojevic, Duarte Cacela, Dwayne S G Conway, E Pinar Bermudez, Eapen Punnoose, Edgar L Tay, Edgar Karanjah, Edoardo Verna, Eduardo Hernandez-Rangel, Edward D Nicol, Edward O McFalls, Edward T Martin, Edyta Kaczmarska, Ekaterina I Lubinskaya, Elena A Demchenko, Elena Refoyo Salicio, Eli Feen, Elihú Durán-Cortés, Elisabeth M Janzen, Elise L Hannemann, Elise van Dongen, Elissa Restelli Piloto, Eliza Kaplan, Elizabeta Srbinovska Kostovska, Elizabeth Capasso-Gulve, Elizabeth Congdon, Elizabeth Ferguson, Elizaveta V Zbyshevskaya, Ellen Magedanz, Ellie Fridell, Ellis W Lader, Elvin Kedhi, Emanuela Racca, Emilie Tachot, Emily DeRosa, Encarnación Alonso-Álvarez, Eric Nicollet, Eric Peterson, Erick Alexánderson Rosas, Erick Donato Morales, Erin Orvis, Ermina Moga, Estelle Montpetit, Estevao Figueiredo, Eugene Passamani, Eugenia Nikolsky, Eunice Yeoh, Evgeniy I Kretov, Ewa Szczerba, Ewelina Wojtala, Expedito Eustáquio Ribeiro Silva, F Marin Ortuño, Fabio R Farias, Fabio Fimiani, Fabrizio Rolfo, Fa-Chang Yu, Fadi Hage, Fadi Matar, Fahim Haider Jafary, Fang Feng, Fang Liu, Fatima Ranjbaran, Fatima Rodriguez, Fausto J Pinto, Fauzia Rashid, Federica Ramani, Fei Wang, Fernanda Igansi, Filipa Silva, Filippo Ottani, Fiona Haines, Firas Al Solaiman, Flávia Egydio, Flavio Lyra, Florian Egger, Fran Farquharson, Frances Laube, Francesc Carreras Costa, Francesca de Micco, Francesca Bianchini, Francesca Pezzetta, Francesca Pietrucci, Francesco Orso, Francesco Pisano, Francis Burt, Francisca Patuleia Figueiras, Francisco Fernandez-Aviles, Francois Pierre Mongeon, Frans Van de Werf, Franziska Guenther, Fraser N Witherow, Fred Mohr, Frederico Dall'Orto, Fumiyuki Otsuka, G De La Morena, G Karthikeyan, Gabor Dekany, Gabor Kerecsen, Gabriel Galeote, Gabriel Grossmann, Gabriel Vorobiof, Gabriela Sanchez de Souza, Gabriela Guzman, Gabriela Zeballos, Gabriele Gabrielli, Gabriele Jakl-Kotauschek, Gail A Shammas, Gail Brandt, Gang Chen, Gary E Lane, Gary J Luckasen, Gautam Sharma, Gelmina Mikolaitiene, Gennie Yee, Georg Nickenig, George E Revtyak, George J Juang, Gerald Fletcher, Gerald Leonard, Gerard Patrick Devlin, Gerard Esposito, Gergely Ágoston, Gervasio Lamas, Geza Fontos, Ghada Mikhail, Gia Cobb, Gian Piero Perna, Gianpiero Leone, Giles Roditi, Gilles Barone-Rochette, Girish Mishra, Giuseppe Tarantini, Glenda Wong, Glenn S Hamroff, Glenn Rayos, Gong Cheng, Gonzalo Barge-Caballero, Goran Davidović, Goran Stankovic, Gordana Stevanovic, Grace Jingyan Wang, Grace M Young, Graceanne Wayser, Graciela Scaro, Graham S Hillis, Graham Wong, Grazyna Anna Szulczyk, Gregor Simonis, Gregory Kumkumian, Gretchen Ann Peichel, Grzegorz Gajos, Gudrun Steinmaurer, Guilherme G Rucatti, Guilherme Portugal, Guilhermina Cantinho Lopes, Guillem Pons Lladó, Gunnar Frostfelt, Gurpreet S Wander, Gurpreet Gulati, Gustavo Pucci, Hafidz Abd Hadi, Haibo Zhang, Haitao Wang, Halina Marciniak, Han Chen, Hanan Kerr, Hani Najm, Hanna Douglas, Hannah Phillips, Hao Dai, Haojian Dong, Haqeel Jamil, Harikrishnan Sivadasanpillai, Harry Suryapranata, Hassan Reda, Hayley Pomeroy, Heather Barrentine, Heather Golden, Heather Hurlburt, Heidi Wilson, Helen C Tucker, Helene Abergel, Hemalata Siddaram, Hermine Osseni, Herwig Schuchlenz, Hesong Zeng, Hicham Skali, Hilda Solomon, Hollie Horton, Holly Hetrick, Holly Little, Holly Park, Hongjie Chi, Hossam Mahrous, Howard A Levite, Hristo Pejkov, Huajun Li, Hugo Bloise-Adames, Hugo Marques, Hui Zhong, Hui-Min Zhang, Humayrah Hashim, Hung-I Yeh, Hussien El Fishawy, Ian Webb, Iftikhar Kullo, Igor O Grazhdankin, Ihab Hamzeh, Ikraam Hassan, Ikuko Ueda, Ileana L Pina, Ilona Tamasauskiene, Ilse Bouwhuis, Imran Arif, Ina Wenzelburger, Inês Zimbarra Cabrita, Ines Rodrigues, Inga H Robbins, Inga Soveri, Ingela Schnittger, Iqbal Karimullah, Ira M Dauber, Iram Rehman, Irena Peovska Mitevska, Irene Marthe Lang, Irina Subbotina, Irma Kalibataite-Rutkauskiene, Irni Yusnida, Isabel Estela Carvajal, Isabella C Palazzo, Isabelle Hogan, Isabelle Roy, Ishba Syed, Ishita Tejani, Ivan A Naryshkin, Ivana Jankovic, Iwona Niedzwiecka, J David Knight, Jacek Kusmierek, Jackie M White, Jackie Chow, Jacob Udell, Jacqueline E Tamis-Holland, Jacqueline Fannon, Jacquelyn A Quin, Jacquelyn Do, Jaekyeong Heo, Jakub Maksym, James E Davies, James H O'Keefe Jr, James J Jang, James Cha, James Harrison, James Hirsch, James Stafford, James Tatoulis, Jamie Rankin, Jan Henzel, Jan Orga, Jana Tancredi, Janaina Oliveira, Jane Burton, Jane Eckstein, Jane Marucci, Janet P Knight, Janet Blount, Janet Halliday, Janetta Kourzenkova, Janitha Raj, Jan-Malte Sinning, Jaqueline Pozzibon, Jaroslaw Drozdz, Jaroslaw Karwowski, Jason D Glover, Jason Loh Kwok, Jason T Call, Jason Linefsky, Jassira Gomes, Jati Anumpa, Javier J Garcia, Javier Courtis, Jay Meisner, K Jayakumar, Jayne Scales, Jean E Denaro, Jean Michel Juliard, Jean Ho, Jeanette K Stansborough, Jean-Michel Juliard, Jeanne Russo, Jeannette J M Schoep, Jeet Thambyrajah, Jeff Leimberger, Jeffery A Breall, Jeffrey A Kohn, Jeffrey C Milliken, Jeffrey Anderson, Jeffrey Blume, Jeffrey Kanters, Jeffrey Lorin, Jeffrey Moses, Jelena J Stepanovic, Jelena Celutkiene, Jelena Djokic, Jelena Stojkovic, Jenne M Jose, Jenne Manchery, Jennifer A Mull, Jennifer H Czerniak, Jennifer L Stanford, Jennifer Gillis, Jennifer Horst, Jennifer Isaacs, Jennifer Langdon, Jennifer Thomson, Jennifer Tomfohr, Jennifer White, Jen-Yuan Kuo, Jeremy Rautureau, Jerome Fleg, Jessica Berg, Jessica Rodriguez, Jessica Waldron, Jhina Patro, Jia Li, Jiajia Mao, Jiamin Liu, Jian'an Wang, Jianhua Li, Jianxin Zhang, Jie Qi, Jihyun Lyo, Jill Marcus, Jim Blankenship, Jing Zhang, Jingjing Liu, Jing-Yao Fan, Jiun-Yi Li, Jiwan Pradhan, Jiyan Chen, J M Rivera Caravaca, Jo Evans, Joan Garcia Picart, Joan Hecht, Joanna Jaroch, Joanna Zalewska, Joanne Kelly, Joanne Taaffe, João Reynaldo Abbud, João V Vitola, Joaquín V Peñafiel, Jocelyne Benatar, Jody Bindeman, Joe Sabik, Joel Klitch, Johann Christopher, Johannes Aspberg, John D Friedman, John F Beltrame, John F Heitner, John Joseph Graham, John R Davies, John Doan, John Kotter, John Kurian, John Mukai, John Pownall, Jolanta Sobolewska, Jon Kobashigawa, Jonathan L Goldberg, Jonathan W Bazeley, Jonathan Byrne, Jonathan Himmelfarb, Jonathan Leipsic, Jonean Thorsen, Jorge F Trejo Gutierrez, Jorge Escobedo, Jorik Timmer, José A Ortega-Ramírez, José Antonio Marin-Neto, Jose D Salas, Jose Enrique Castillo, Jose Francisco Saraiva, José J Cuenca-Castillo, Jose L Diez, José Luis Narro Villanueva, José Luiz da Vieira, José M Flores-Palacios, Jose Ramon Gonzalez, Jose Seijas Amigo, Jose Fragata, Josep Maria Padró, Josheph F X McGarvey Jr, Joseph Hannan, Joseph Sacco, Joseph Sweeny, Joseph Wiesel, Josephine D Abraham, Joshua P Loh, Joy Burkhardt, Joyce R White, Joyce Riestenberg-Smith, Judit Sebo, Judith L Meadows, Judith Wright, Judy Mae Foltz, Judy Hung, Judy Otis, Juergen Stumpf, Jui-Peng Tsai, Julia S Dionne, Julia de Aveiro Morata, Julie Bunke, Julie Morrow, Julio César Figal, Jun Fujita, Jun Jiang, Junhua Li, Junqing Yang, Juntima Euathrongchit, Jyotsna Garg, K Manjula Rani, K Preethi, Kaatje Goetschalckx, Kai Eggers, Kamalakar Surineni, Kanae Hirase, T R Kapilamoorthy, Karen Calfas, Karen Gratrix, Karen Hallett, Karen Hultberg, Karen Nugent, Karen Petrosyan, Karen Swan, Karolina Kryczka, Karolina Wojtczak-Soska, Karolina Wojtera, Karsten Lenk, Karthik Ramasamy, Katarzyna Łuczak, Katarzyna Malinowska, Kate Pointon, Kate Robb, Katherine Martin, Kathleen Claes, Kathryn Carruthers, Kathy E Siegel, Katia Drouin, Katie Fowler-Lehman, Kavita Rawat, Kay Rowe, Keiichi Fukuda, Keith A A Fox, Ken Mahaffey, Kendra Unterbrink, Kenneth Giedd, Kerrie Van Loo, Kerry Lee, Kerstin Bonin, Kevin R Bainey, Kevin T Harley, Kevin Anstrom, Kevin Chan, Kevin Croce, Kevin Landolfo, Kevin Marzo, Keyur Patel, Khaled Abdul-Nour, Khaled Alfakih, Khaled Dajani, Khaled Ziada, Khaula Baloch, Khrystyna Kushniriuk, Kian-Keong Poh, Kim F Ireland, Kim Holland, Kimberly Ann Byrne, Kimberly E Halverson, Kimberly Elmore, Kimberly Miller-Cox, Kiran Reddy, Kirsten J Quiles, Kirsty Abercrombie, Klaus Matschke, Konrad Szymczyk, Koo Hui Chan, Kotiboinna Preethi, Kozhaya Sokhon, Krissada Meemuk, Kristian Thygesen, Kristin M Salmi, Kristin Newby, Kristina Wippler, Kristine Arges, Kristine Teoh, Krystal Etherington, Krystyna Łoboz-Grudzień, Krzysztof W Reczuch, Krzysztof Bury, Krzysztof Drzymalski, Krzysztof Kukuła, Kuo-Tzu Sung, Kurt Huber, Ladda Douangvila, Lance Sullenberger, Larissa Miranda Trama, Laszlone Matics, Laura Drew, Laura Flint, Laura Keinaite, Laura Sarti, Laurel Kolakaluri, Lawrence M Phillips, Lawrence Friedman, Lawrence Phillips, Lazar Velicki, Leah Howell, Leandro C Maranan, Leanne Cox, Ledjalem Daba, Lei Zhang, Lekshmi Dharmarajan, Leo Bockeria, Leonardo Pizzol Caetano, Leonardo Bridi, Leonid L Bershtein, Leszek Sokalski, Li Hai Yan, Li Li, Lia Nijmeijer, Lidia Sousa, Lihong Xu, Lihua Zhang, Lili Zhang, Lilia Schiavi, Lilian Mazza Barbosa, Lillian L Khor, Lina Felix-Stern, Linda L Hall, Linda M Hollenweger, Linda Arcand, Linda Davidson-Ray, Linda Schwarz, Lindsey N Sikora, Lingping Chi, Lino Patricio, Liping Zhang, Lisa Chaytor, Lisa Hatch, Lisa McCloy, Lisa Wong, Liselotte Persson, Lixin Jiang, Liz Low, Ljiljana Pupic, Loïc Bière, Lorenzo Monti, Lori Christensen, Lori Pritchard, Loriane Black, Lori-Ann Desimone, Lori-Ann Larmand, Lorraine McGregor, Louise Morby, Louise Thomson, Luc Harvey, Luciana de Pádua Baptista, Lucilla Garcia, Ludivine Eliahou, Ludmila Helmer, Luis F Smidt, Luis Bernanrdes, Luis Guzman, Luiz A Carvalho, Luyang Xiong, Lynette L Teo, Lynn M Neeson, Lynne Winstanley, M Barbara Srichai-Parsia, M Quintana Giner, M Sowjanya Reddy, M Valdés Chávarri, M Grazia Rossi, Maarten Simoons, Maayan Konigstein, Maciej Lesiak, Maciej Olsowka, Mafalda Selas, Magalie Corfias, Magdalena Madero Rovalo, Magdalena Łanocha, Magdalena Miller, Magdalena Misztal-Teodorczyk, Magdalena Rantinella, Magdy Abdelhamid, Magnolia Jimenez, Mahboob Alam, Mahevamma Mylarappa, Mahfouz El Shahawy, Mahmoud Mohamed, Mahmud Al-Bustami, Majo X Joseph, Malgorzata Frach, Małgorzta Celińska-Spodar, Malte Helm, Manas Chacko, Mandy Murphy, Manitha Vinod, Manjula Rani, Manu Dhawan, Manuela Mombelli, Marcel Weber, Marcello Galvani, Marcelo Jamus Rodrigues, Marcia F Dubin, Marcia F Werner Bayer, Marcin Szkopiak, Marco Antonio Monsalve, Marco Bizzaro Santos, Marco Magnoni, Marco Marini, Marco Sicuro, Marco Zenati, Marcos Valério Coimbra Resende, Marek Roik, Margalit Bentzvi, Margaret Gilsenan, Margaret Iraola, Margot C 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Jr, Matthew Budoff, Matthew Jezior, Matthew Luckie, Matthias Friedrich, Mauren P Haeffner, Maximilian Tscharre, Max-Paul Winter, Mayana Almeida, Mayil S Krishnam, Mayuri Patel, Meenakshi Mishra, Megan Manocchia, Meghana Kakade, Melanie J Munro, Melissa D Chaplin, Melissa LeFevre, Mervyn Andiapen, Michael A Gibson, Michael B Rubens, Michael C Turner, Michael D Shapiro, Michael W Lee, Michael Berlowitz, Michael Davidson, Michael Mack, Michael McDaniel, Michael Mumma, Michal Wlodarczyk, Michel G Khouri, Michel S Slama, Michele Rawlins, Michelle M Bonner, Michelle M Seib, Michelle Chang, Michelle Crowder, Michelle Dixon, Michelle Mayon, Michelle McEvoy, Michelle Yee, Miguel M Fernandes, Miguel Nobre Menezes, Miguel Souto Bayarri, Miguel Barrero, Mikhail T Torosoff, Milan R Dobric, Milan Dobric, Milica Nikola Dekleva, Milind Avdhoot Gadkari, Millie Gomez, Min Tun Kyaw, Miriam Brooks, Miroslav Stevo Martinovic, Mitchel B Lustre, Mohammad Tariq Vakani, Mohammad El-Hajjar, Mohammed Al-Amoodi, 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Riezebos, Robert M Donnino, Robert Bojar, Robert Chilton, Robert Guyton, Robert Henderson, Robert Kornberg, Robert Leber, Robert Mao, Robert Stenberg, Roberta P Santos, Roberto René Favaloro, Roberto Amati, Rodolfo G S D Lima, Rodrigo J Cerci, Rogerio Tumelero, Rohit Tandon, Roma Tewari, Romalisa Miranda-Peats, Ron Wald, Ronald A Mastouri, Ronald G Morford, Ronald G Schwartz, Ronald P Pedalino, Rongrong Hu, Ronnell A Hansen, Ronny A Cohen, Rory Hachamovitch, Rosa Homem, Rosa Sandonato, Rosane Laimer, Rosann Gans, Roxanne Yost, Roy Mathew, Rubén Baleón-Espinosa, Ruben Ramos, Rubine Gevorgyan, Rui Ferreira, Rui Jing, Ruth Pérez-Fernández, S K Dwivedi, S Ramakrishnan, Saadat Khan, Sabahat Bokhari, Sabu Thomas, Sadath Lubna, Sajeeda Parveen Khan, Sajeev Chakanalil Govindan, Saket Girotra, Saleem Kassam, Sallie Canada, Salvador Cruz-Flores, Samaa Mohamed, Samantha Ly, Sameh El Kaffas, Samia Massalha, Sampoornima Setty, Samuel Nwosu, Sandeep Seth, Sandeep Singh, Sander R Niehe, Sandra M 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C Wong, Raymond W Little, Raymundo Ocaranza Sanchez, Rebecca J Wimmer, Rebecca Bariciano, Rebecca Otis, Rebekah R Herrmann, Reem Yunis, Reinette Hampson, Renato Abdala Karam, Renee C Hessian, Renee Kaneshiro, Reshma Ravindran, Reto Andreas Gamma, Reyna Bhandari, Reza Arsanjani, Ricardo L Lopes, Ricardo Mendes Oliveira, Ricardo Costa, Richa Bhatt, Richard F Davies, Richard H J Trimlett, Richard Goldweit, Rik Hermanides, Rine Nakanishi, Rinu R Sidh, Risha Patel, Rita Coram, Rizwan A Siddiqui, Rob S Beanlands, Robert J Hamburger, Robert K Riezebos, Robert M Donnino, Robert Bojar, Robert Chilton, Robert Guyton, Robert Henderson, Robert Kornberg, Robert Leber, Robert Mao, Robert Stenberg, Roberta P Santos, Roberto René Favaloro, Roberto Amati, Rodolfo G S D Lima, Rodrigo J Cerci, Rogerio Tumelero, Rohit Tandon, Roma Tewari, Romalisa Miranda-Peats, Ron Wald, Ronald A Mastouri, Ronald G Morford, Ronald G Schwartz, Ronald P Pedalino, Rongrong Hu, Ronnell A Hansen, Ronny A Cohen, Rory Hachamovitch, Rosa Homem, Rosa Sandonato, Rosane Laimer, Rosann Gans, Roxanne Yost, Roy Mathew, Rubén Baleón-Espinosa, Ruben Ramos, Rubine Gevorgyan, Rui Ferreira, Rui Jing, Ruth Pérez-Fernández, S K Dwivedi, S Ramakrishnan, Saadat Khan, Sabahat Bokhari, Sabu Thomas, Sadath Lubna, Sajeeda Parveen Khan, Sajeev Chakanalil Govindan, Saket Girotra, Saleem Kassam, Sallie Canada, Salvador Cruz-Flores, Samaa Mohamed, Samantha Ly, Sameh El Kaffas, Samia Massalha, Sampoornima Setty, Samuel Nwosu, Sandeep Seth, Sandeep Singh, Sander R Niehe, Sandra M Rivest, Sandra S Zier, Sandra Ahoud, Sandy Carr, Sanjay Ganapathi, Sanjay Shetty, Sanjeev Sharma, Santa Jimenez, Santhosh Satheesh, Santiago A Garcia, Sara Fernandez, Sara Karlsson, Sara Salkind, Sara Temiyasathit, Sarah Medina Rodriguez, Sarah Beaudry, Sarah Hadjih, Sarah Williams, Sarah Zahrani, Sarju Ralhan, Sasa Hinic, Sasko Kedev, Satinder Singh, Satoshi Yasuda, Satvic Cholenahally Manjunath, Sau Lee, Scott M Kaczkowski, Scott Kinlay, Sean W Hayes, Sebastian Sobczak, Senait Asier, Sergey A Sayganov, Seth I Sokol, Shaheen Pandie, Shaiful Azmi Yahaya, Shamir Mehta, Shao-Ping Nie, Sharad Chandra, Sharder Islam, Sharon Tai, Sheetal Rupesh Karwa, Sheri Ussery, Sheromani Bajaj, Sherron C Crook, Shigeyuki Nishimura, Shintaro Nakano, Shirin Heydari, Shiv Kumar Choudhary, Shivali Patel, Shobana Ganesan, Shruti Pandey, Shuyang Zhang, Shweta Hande, Siddharth Gadage, Sik-Yin V Tan, Silvia Zottis Poletti, Silvia Riera, Silvia Valbuena, Simon Walsh, Simona Maspoli, Simone Savaris, Si-Ting Feng, So Yang Cho, Solomon Yakubov, Songlin Zhu, Songtao Wang, Sonia Guerrero, Sonika Gupta, Sonja Salinger Martinovic, Sonya Brons, Sorin Brener, Sothinathan Gurunathan, Souheil Saba, Soundarya Nayak, Sowjanya Reddy, Srinivasa Potluri, Sriram Sudarshan, Srun Kuanprasert, Stacie Van Oosterhout, Stamatios Lerakis, Stanley E Cobos, Stefan C Bertog, Stefan M Simović, Stefan Weikl, Stefano Di Marco, Stefano Provasoli, Stephanie A Tirado, Stephanie C Boer, Stephanie M Lane, Stephanie Ferket, Stephanie Kelly, Stephanie Wasmiller, Stephen H McKellar, Stephen P Hoole, Stephen Fremes, Stephen Preston, Steve Leung, Steven A Fein, Steven J Lindsay, Steven P Sedlis, Steven Giovannone, Steven Michael, Steven Weitz, Stijn van Vugt, Subhash Banerjee, Sudhir Naik, Suellen Hosino, Sukie Desire, Sukit Yamwong, Suku T Thambar, Sulagna Mookherjee, Suman Singh, Sundeep Mishra, Sunil Kumar Verma, Supap Kulthawong, Supatchara Khwakhong, Surendra Naik, Suresh Babu, Surin Woragidpoonpol, Suryaprakash Narayanappa, Susan Derbyshire, Susan Gent, Susan Mathus, Susan Milbrandt, Susan Moore, Susan Regan, Susan Stinson, Susan Webber, Susana Silva, Susanna Stevens, Susanne Gruensfelder, Suthara Aramcharoen, Suvarna Kolhe, Suzana Tavares, Suzanne Arnold, Suzanne Welsh, Svetlana Apostolovic, Swapna Kunhunny, Ta-Chuan Hung, Taissa Zappernick, Tali Sharir, Talita Silva, Tamara Colaiácovo Soares, Tapan Umesh Pillay, Tarun K Mittal, Tatiana Trifonova, Tauane Bello Duarte, Tauqir Huk, Téodora Dutoiu, Terrance Chua, Terry Weyand, Thabitha Charles, Theodoros Kofidis, Theresa McCreary, Thierry Lefevre, Thippeekaa Arumairajah, Thitipong Tepsuwan, Thomas J Mulhearn, Thomas M Meyer, Thomas P Rocco, Thomas R Downes, Thomas Crain, Thomas Haldis, Thomas Mathew, Thomas Redick, Thounaojam Indira Devi, Thuraia Nageh, Tia Cauthren, Tiago Silva, Tiffany Little, Tijana Andric, Tina Harding, Titus Lau, Tiziana Formisano, Tiziano Moccetti, Tomasz Ciurus, Tomasz Mazurek, Tomasz Tarchalski, Toshiyuki Nagai, Tri Tran, Tricia Youn, Trish Tucker, Trudie Milner, Tuhina Bose, Tushar Kotecha, Udo Sechtem, Uma S Valeti, Umberto Cucchini, Umesh Badami, Upendra Kaul, V K Bahl, V S Narain, Valentina Casali, Valeria Godoy, Valerie Robesyn, Vamshi P Priya, Vandana Yadav, Vera McKinney, Veronica De Lenges, Veronica Tinnirello, Vicente Miro, Victor Navarro, Victoria Gumerova, Victoria Hernandez, Vidya Seeratan, Vijay Kumar, Vikentiy Y Kozulin, Viktoria Bulkley, Vilmar Veiga Jr, Vincent Setang, C P Vineeth, Virginai Pubull Nuñez, Virginia Fernández-Figares, Vitor Gomes, Viviana Gabriel, Viviane Dos Santos, Viviane Almeida, Vlad A Iliescu, Vladan Mudrenovic, Vladimir Dzavik, Vojislav L Giga, Walter Enrique Mogrovejo, Wan Xian Chan, Wanda C Marfori, Wanda Parker, Warangkana Mekara, Wassim Nona, Wayne Old, Wayne Pennachi, Weerachai Nawarawong, Wei Chen, Wei Su, Weibing Xing, Wei-Ren Lan, Wenda Crawford, Wendy L Stewart, Wendy Drewes, Wenhua Lin, William B Abernethy, William D Salerno, William F Fearon, William Vergoni, William Weintraub, Winnie C Sia, Wlodzimierz J Musial, Xacobe Flores-Ríos, Xavier Garcia-Moll Marimon, Xi Su, Xiang Ma, Xiangqiong Gu, Xiao Wang, Xiaomei Li, Xiaowei Yao, Xin Fu, Xin Su, Xin Zeng, Xinchun Yang, Xiuhong Li, Xuehua Fang, Xutong Wang, Yaming Geng, Yan Yan, Yanek Pépin-Dubois, Yanfu Wang, Yang Wang, Yanmeng Tian, Yaping Huang, Yechen Han, Yesenia Zambrano, Yi-Hsuan Yang, Ying Tung Sia, Yining Yang, Yitong Ma, Yolayfi Peralta, Yongjian Wu, Yu Kunwu, Yu Zhao, Yudong Peng, Yueh-Hung Lin, Yulan Zhao, Yumei Dong, Yunhai Zhao, Yutthaphan Wannasopha, Yvonne Taul, Zakir Sahul, Zalina Kudzoeva, Zbigniew Kalarus, Zeljko Z Markovic, Zhen Huang, Zheng Ji, Zhenyu Liu, Zhou Yue, Zhulin Zhang, Zhuxi Li, Zile Singh Meharwal, Ziliang Bai, Zixiang Yu, Zohra Huda, Zoltan Davidovits

Subjects
Male, Cardiac Catheterization, Computed Tomography Angiography, medicine.medical_treatment, Myocardial Ischemia, Coronary Disease, Coronary Artery Disease, Kaplan-Meier Estimate, 030204 cardiovascular system & hematology, Coronary Angiography, ISCHEMIA Research Group, law.invention, Angina, Coronary artery disease, 0302 clinical medicine, Randomized controlled trial, law, Cardiovascular Disease, Myocardial Revascularization, 030212 general & internal medicine, Coronary Artery Bypass, 11 Medical and Health Sciences, Cardiac catheterization, General Medicine, Middle Aged, humanities, Cardiovascular Diseases, Cardiology, Female, Human, medicine.medical_specialty, Ischemia, Article, 03 medical and health sciences, Geriatric cardiology, Percutaneous Coronary Intervention, General & Internal Medicine, Internal medicine, medicine, Humans, Angina, Unstable, Aged, business.industry, Coronary Artery Bypa, Percutaneous coronary intervention, Bayes Theorem, medicine.disease, Heart failure, Quality of Life, business
Abstract

BACKGROUND: Among patients with stable coronary disease and moderate or severe ischemia, whether clinical outcomes are better in those who receive an invasive intervention plus medical therapy than in those who receive medical therapy alone is uncertain. METHODS: We randomly assigned 5179 patients with moderate or severe ischemia to an initial invasive strategy (angiography and revascularization when feasible) and medical therapy or to an initial conservative strategy of medical therapy alone and angiography if medical therapy failed. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. A key secondary outcome was death from cardiovascular causes or myocardial infarction. RESULTS: Over a median of 3.2 years, 318 primary outcome events occurred in the invasive-strategy group and 352 occurred in the conservative-strategy group. At 6 months, the cumulative event rate was 5.3% in the invasive-strategy group and 3.4% in the conservative-strategy group (difference, 1.9 percentage points; 95% confidence interval [CI], 0.8 to 3.0); at 5 years, the cumulative event rate was 16.4% and 18.2%, respectively (difference, -1.8 percentage points; 95% CI, -4.7 to 1.0). Results were similar with respect to the key secondary outcome. The incidence of the primary outcome was sensitive to the definition of myocardial infarction; a secondary analysis yielded more procedural myocardial infarctions of uncertain clinical importance. There were 145 deaths in the invasive-strategy group and 144 deaths in the conservative-strategy group (hazard ratio, 1.05; 95% CI, 0.83 to 1.32). CONCLUSIONS: Among patients with stable coronary disease and moderate or severe ischemia, we did not find evidence that an initial invasive strategy, as compared with an initial conservative strategy, reduced the risk of ischemic cardiovascular events or death from any cause over a median of 3.2 years. The trial findings were sensitive to the definition of myocardial infarction that was used. (Funded by the National Heart, Lung, and Blood Institute and others; ISCHEMIA ClinicalTrials.gov number, NCT01471522.).

Published
2020
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49. AMG 757, a Half-Life Extended, DLL3-Targeted Bispecific T-Cell Engager, Shows High Potency and Sensitivity in Preclinical Models of Small-Cell Lung Cancer

Author

Jinghui Zhan, Christopher Murawsky, Petra Deegen, Jonathan Werner, Oliver Homann, Siyuan Liu, Melissa Thomas, Angela Coxon, Keegan Cooke, Pedro J. Beltran, Joshua T. Pearson, Juan Estrada, Fei Lee, Tobias Raum, Julie M. Bailis, Matthias Friedrich, Jude Canon, Jennitte Stevens, Giffin Michael John, Sean Caenepeel, Yajing Yang, Paul E. Hughes, and Edward K. Lobenhofer

Subjects
0301 basic medicine, Cancer Research, Lung Neoplasms, T-Lymphocytes, T cell, Antineoplastic Agents, Apoptosis, Mice, SCID, Mice, 03 medical and health sciences, 0302 clinical medicine, Mice, Inbred NOD, Antibodies, Bispecific, Tumor Cells, Cultured, Animals, Humans, Medicine, Potency, Lung cancer, Cell Proliferation, business.industry, Intracellular Signaling Peptides and Proteins, Antibodies, Monoclonal, Membrane Proteins, Half-life, medicine.disease, Small Cell Lung Carcinoma, Xenograft Model Antitumor Assays, respiratory tract diseases, Gene Expression Regulation, Neoplastic, 030104 developmental biology, medicine.anatomical_structure, Oncology, Tolerability, Cell culture, 030220 oncology & carcinogenesis, Pharmacodynamics, Cancer research, Female, Non small cell, business
Abstract

Purpose: Small-cell lung cancer (SCLC) is an aggressive neuroendocrine tumor with a high relapse rate, limited therapeutic options, and poor prognosis. We investigated the antitumor activity of AMG 757, a half-life extended bispecific T-cell engager molecule targeting delta-like ligand 3 (DLL3)—a target that is selectively expressed in SCLC tumors, but with minimal normal tissue expression. Experimental Design: AMG 757 efficacy was evaluated in SCLC cell lines and in orthotopic and patient-derived xenograft (PDX) mouse SCLC models. Following AMG 757 administration, changes in tumor volume, pharmacodynamic changes in tumor-infiltrating T cells (TILs), and the spatial relationship between the appearance of TILs and tumor histology were examined. Tolerability was assessed in nonhuman primates (NHPs). Results: AMG 757 showed potent and specific killing of even those SCLC cell lines with very low DLL3 expression ( Conclusions: AMG 757 has a compelling safety and efficacy profile in preclinical studies making it a viable option for targeting DLL3-expressing SCLC tumors in the clinical setting.

Published
2021
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50. Digital Development Process for the Drive System of a Balanced Two-Wheel Scooter

Author

Sven Schumacher, Ralf Stetter, Matthias Friedrich, Stephan Rudolph, Walter Fichter, Kevin Holder, and Markus Till

Subjects
0209 industrial biotechnology, lcsh:Machine design and drawing, Process (engineering), Computer science, urban vehicles, lcsh:Mechanical engineering and machinery, lcsh:Motor vehicles. Aeronautics. Astronautics, Distributed computing, balanced two-wheel scooter, 02 engineering and technology, computer.software_genre, digital design process, System model, 020901 industrial engineering & automation, 0202 electrical engineering, electronic engineering, information engineering, lcsh:TJ1-1570, 020207 software engineering, computer.file_format, lcsh:TJ227-240, Design process, Graph (abstract data type), Last mile, Executable, lcsh:TL1-4050, Engineering design process, computer, Data integration
Abstract

Graph-based design languages have received increasing attention in the research community, because they offer a promising approach to address several major issues in engineering, e.g., the frequent manual data transfer between computer-aided design (CAD) and computer-aided engineering (CAE) systems. Currently, these issues prevent the realization of machine executable digital design processes of complex systems such as vehicles. Promising scenarios for urban transportation include an interconnection of mass transportation systems such as buses and subways with individual vehicles for the so-called &ldquo, last mile&rdquo, transport. For several reasons, these vehicles should be as small and light as possible. A considerable reduction in weight and size can be achieved, if such vehicles are tailored to the individual size, weight and proportion of the individual user. However, tailoring vehicles for the individual characteristics of each user go beyond a simple building set and require a continuous digital design process. Consequently, the topic of this paper is a digital design process of a self-balanced scooter, which can be used as an individual last-mile means of transport. This process is based on graph-based design languages, because in these languages, a digital system model is generated, which contains all relevant information about a design and can be fed into any simulation tool which is needed to evaluate the impact of a possible design variation on the resulting product performance. As this process can be automated by digital compilers, it is possible to perform systematic design variations for an almost infinite amount of parameters and topological variants. Consequently, these kinds of graph-based languages are a powerful means to generate viable design alternatives and thus permit fast evaluations. The paper demonstrates the design process, focusing on the drive system of the respective balanced two-wheel scooter and highlights the advantages (data integration and possibility for machine execution).

Published
2021
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