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1. Corrigendum to: 'An international genome-wide meta-analysis of primary biliary cholangitis: Novel risk loci and candidate drugs' [J Hepatol 75 (2021) 572-581]

Author: Heather J. Cordell, James J. Fryett, Kazuko Ueno, Rebecca Darlay, Yoshihiro Aiba, Yuki Hitomi, Minae Kawashima, Nao Nishida, Seik-Soon Khor, Olivier Gervais, Yosuke Kawai, Masao Nagasaki, Katsushi Tokunaga, Ruqi Tang, Yongyong Shi, Zhiqiang Li, Brian D. Juran, Elizabeth J. Atkinson, Alessio Gerussi, Marco Carbone, Rosanna Asselta, Angela Cheung, Mariza de Andrade, Aris Baras, Julie Horowitz, Manuel A.R. Ferreira, Dylan Sun, David E. Jones, Steven Flack, Ann Spicer, Victoria L. Mulcahy, Jinyoung Byan, Younghun Han, Richard N. Sandford, Konstantinos N. Lazaridis, Christopher I. Amos, Gideon M. Hirschfield, Michael F. Seldin, Pietro Invernizzi, Katherine A. Siminovitch, Xiong Ma, Minoru Nakamura, and George F. Mells
Subjects: Hepatology
Published: 2023
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2. Corrigendum to 'An international genome-wide meta-analysis of primary biliary cholangitis: Novel risk loci and candidate drugs' [J Hepatol 2021;75(3):572-581]

Author: Heather J, Cordell, James J, Fryett, Kazuko, Ueno, Rebecca, Darlay, Yoshihiro, Aiba, Yuki, Hitomi, Minae, Kawashima, Nao, Nishida, Seik-Soon, Khor, Olivier, Gervai, Yosuke, Kawai, Masao, Nagasaki, Katsushi, Tokunaga, Ruqi, Tang, Yongyong, Shi, Zhiqiang, Li, Brian D, Juran, Elizabeth J, Atkinson, Alessio, Gerussi, Marco, Carbone, Rosanna, Asselta, Angela, Cheung, Mariza, de Andrade, Aris, Bara, Julie, Horowitz, Manuel A R, Ferreira, Dylan, Sun, David E, Jone, Steven, Flack, Ann, Spicer, Victoria L, Mulcahy, Jinyoung, Byun, Younghun, Han, Richard N, Sandford, Konstantinos N, Lazaridi, Christopher I, Amo, Gideon M, Hirschfield, Michael F, Seldin, Pietro, Invernizzi, Katherine A, Siminovitch, Xiong, Ma, Minoru, Nakamura, George F, Mell, Siminovitch, Katherine A., Hirschfield, Gideon M., Mason, Andrew, Vincent, Catherine, Xie, Gang, Zhang, Jinyi, Tang, Ruqi, Ma, Xiong, Li, Zhiqiang, Shi, Yongyong, Affronti, Andrea, Almasio, Piero L., Alvaro, Domenico, Andreone, Pietro, Andriulli, Angelo, Azzaroli, Francesco, Battezzati, Pier Maria, Benedetti, Antonio, Bragazzi, Maria Consiglia, Brunetto, Maurizia, Bruno, Savino, Calvaruso, Vincenza, Cardinale, Vincenzo, Casella, Giovanni, Cazzagon, Nora, Ciaccio, Antonio, Coco, Barbara, Colli, Agostino, Colloredo, Guido, Colombo, Massimo, Colombo, Silvia, Cristoferi, Laura, Cursaro, Carmela, Saveria Crocè, Lory, Crosignani, Andrea, D’Amato, Daphne, Donato, Francesca, Elia, Gianfranco, Fabris, Luca, Fagiuoli, Stefano, Ferrari, Carlo, Floreani, Annarosa, Galli, Andrea, Giannini, Edoardo, Grattagliano, Ignazio, Lampertico, Pietro, Lleo, Ana, Malinverno, Federica, Mancuso, Clara, Marra, Fabio, Marzioni, Marco, Massironi, Sara, Mattalia, Alberto, Miele, Luca, Milani, Chiara, Morini, Lorenzo, Morisco, Filomena, Muratori, Luigi, Muratori, Paolo, Niro, Grazia A., O’Donnell, Sarah, Picciotto, Antonio, Portincasa, Piero, Rigamonti, Cristina, Ronca, Vincenzo, Rosina, Floriano, Spinzi, Giancarlo, Strazzabosco, Mario, Tarocchi, Mirko, Tiribelli, Claudio, Toniutto, Pierluigi, Valenti, Luca, Vinci, Maria, Zuin, Massimo, Consortium, Japan-PBC-GWAS, PBC Consortium, U, Consortium, UK-PBC, Luca, Miele (ORCID:0000-0003-3464-0068), Heather J, Cordell, James J, Fryett, Kazuko, Ueno, Rebecca, Darlay, Yoshihiro, Aiba, Yuki, Hitomi, Minae, Kawashima, Nao, Nishida, Seik-Soon, Khor, Olivier, Gervai, Yosuke, Kawai, Masao, Nagasaki, Katsushi, Tokunaga, Ruqi, Tang, Yongyong, Shi, Zhiqiang, Li, Brian D, Juran, Elizabeth J, Atkinson, Alessio, Gerussi, Marco, Carbone, Rosanna, Asselta, Angela, Cheung, Mariza, de Andrade, Aris, Bara, Julie, Horowitz, Manuel A R, Ferreira, Dylan, Sun, David E, Jone, Steven, Flack, Ann, Spicer, Victoria L, Mulcahy, Jinyoung, Byun, Younghun, Han, Richard N, Sandford, Konstantinos N, Lazaridi, Christopher I, Amo, Gideon M, Hirschfield, Michael F, Seldin, Pietro, Invernizzi, Katherine A, Siminovitch, Xiong, Ma, Minoru, Nakamura, George F, Mell, Siminovitch, Katherine A., Hirschfield, Gideon M., Mason, Andrew, Vincent, Catherine, Xie, Gang, Zhang, Jinyi, Tang, Ruqi, Ma, Xiong, Li, Zhiqiang, Shi, Yongyong, Affronti, Andrea, Almasio, Piero L., Alvaro, Domenico, Andreone, Pietro, Andriulli, Angelo, Azzaroli, Francesco, Battezzati, Pier Maria, Benedetti, Antonio, Bragazzi, Maria Consiglia, Brunetto, Maurizia, Bruno, Savino, Calvaruso, Vincenza, Cardinale, Vincenzo, Casella, Giovanni, Cazzagon, Nora, Ciaccio, Antonio, Coco, Barbara, Colli, Agostino, Colloredo, Guido, Colombo, Massimo, Colombo, Silvia, Cristoferi, Laura, Cursaro, Carmela, Saveria Crocè, Lory, Crosignani, Andrea, D’Amato, Daphne, Donato, Francesca, Elia, Gianfranco, Fabris, Luca, Fagiuoli, Stefano, Ferrari, Carlo, Floreani, Annarosa, Galli, Andrea, Giannini, Edoardo, Grattagliano, Ignazio, Lampertico, Pietro, Lleo, Ana, Malinverno, Federica, Mancuso, Clara, Marra, Fabio, Marzioni, Marco, Massironi, Sara, Mattalia, Alberto, Miele, Luca, Milani, Chiara, Morini, Lorenzo, Morisco, Filomena, Muratori, Luigi, Muratori, Paolo, Niro, Grazia A., O’Donnell, Sarah, Picciotto, Antonio, Portincasa, Piero, Rigamonti, Cristina, Ronca, Vincenzo, Rosina, Floriano, Spinzi, Giancarlo, Strazzabosco, Mario, Tarocchi, Mirko, Tiribelli, Claudio, Toniutto, Pierluigi, Valenti, Luca, Vinci, Maria, Zuin, Massimo, Consortium, Japan-PBC-GWAS, PBC Consortium, U, Consortium, UK-PBC, and Luca, Miele (ORCID:0000-0003-3464-0068)
Abstract: N/A
Published: 2022

3. Corrigendum to ‘An international genome-wide meta-analysis of primary biliary cholangitis: Novel risk loci and candidate drugs’ [J Hepatol 2021;75(3):572–581]

Author: Heather J. Cordell, James J. Fryett, Kazuko Ueno, Rebecca Darlay, Yoshihiro Aiba, Yuki Hitomi, Minae Kawashima, Nao Nishida, Seik-Soon Khor, Olivier Gervais, Yosuke Kawai, Masao Nagasaki, Katsushi Tokunaga, Ruqi Tang, Yongyong Shi, Zhiqiang Li, Brian D. Juran, Elizabeth J. Atkinson, Alessio Gerussi, Marco Carbone, Rosanna Asselta, Angela Cheung, Mariza de Andrade, Aris Baras, Julie Horowitz, Manuel A.R. Ferreira, Dylan Sun, David E. Jones, Steven Flack, Ann Spicer, Victoria L. Mulcahy, Jinyoung Byun, Younghun Han, Richard N. Sandford, Konstantinos N. Lazaridis, Christopher I. Amos, Gideon M. Hirschfield, Michael F. Seldin, Pietro Invernizzi, Katherine A. Siminovitch, Xiong Ma, Minoru Nakamura, George F. Mells, Andrew Mason, Catherine Vincent, Gang Xie, Jinyi Zhang, Andrea Affronti, Piero L. Almasio, Domenico Alvaro, Pietro Andreone, Angelo Andriulli, Francesco Azzaroli, Pier Maria Battezzati, Antonio Benedetti, Maria Consiglia Bragazzi, Maurizia Brunetto, Savino Bruno, Vincenza Calvaruso, Vincenzo Cardinale, Giovanni Casella, Nora Cazzagon, Antonio Ciaccio, Barbara Coco, Agostino Colli, Guido Colloredo, Massimo Colombo, Silvia Colombo, Laura Cristoferi, Carmela Cursaro, Lory Saveria Crocè, Andrea Crosignani, Daphne D’Amato, Francesca Donato, Gianfranco Elia, Luca Fabris, Stefano Fagiuoli, Carlo Ferrari, Annarosa Floreani, Andrea Galli, Edoardo Giannini, Ignazio Grattagliano, Pietro Lampertico, Ana Lleo, Federica Malinverno, Clara Mancuso, Fabio Marra, Marco Marzioni, Sara Massironi, Alberto Mattalia, Luca Miele, Chiara Milani, Lorenzo Morini, Filomena Morisco, Luigi Muratori, Paolo Muratori, Grazia A. Niro, Sarah O’Donnell, Antonio Picciotto, Piero Portincasa, Cristina Rigamonti, Vincenzo Ronca, Floriano Rosina, Giancarlo Spinzi, Mario Strazzabosco, Mirko Tarocchi, Claudio Tiribelli, Pierluigi Toniutto, Luca Valenti, Maria Vinci, Massimo Zuin, Hitomi Nakamura, Seigo Abiru, Shinya Nagaoka, Atsumasa Komori, Hiroshi Yatsuhashi, Hiromi Ishibashi, Masahiro Ito, Kiyoshi Migita, Hiromasa Ohira, Shinji Katsushima, Atsushi Naganuma, Kazuhiro Sugi, Tatsuji Komatsu, Tomohiko Mannami, Kouki Matsushita, Kaname Yoshizawa, Fujio Makita, Toshiki Nikami, Hideo Nishimura, Hiroshi Kouno, Hirotaka Kouno, Hajime Ota, Takuya Komura, Yoko Nakamura, Masaaki Shimada, Noboru Hirashima, Toshiki Komeda, Keisuke Ario, Makoto Nakamuta, Tsutomu Yamashita, Kiyoshi Furuta, Masahiro Kikuchi, Noriaki Naeshiro, Hironao Takahashi, Yutaka Mano, Seiji Tsunematsu, Iwao Yabuuchi, Yusuke Shimada, Kazuhiko Yamauchi, Rie Sugimoto, Hironori Sakai, Eiji Mita, Masaharu Koda, Satoru Tsuruta, Hiroshi Kamitsukasa, Takeaki Sato, Naohiko Masaki, Tatsuro Kobata, Nobuyoshi Fukushima, Yukio Ohara, Toyokichi Muro, Eiichi Takesaki, Hitoshi Takaki, Tetsuo Yamamoto, Michio Kato, Yuko Nagaoki, Shigeki Hayashi, Jinya Ishida, Yukio Watanabe, Masakazu Kobayashi, Michiaki Koga, Takeo Saoshiro, Michiyasu Yagura, Keisuke Hirata, Atsushu Tanaka, Hajime Takikawa, Mikio Zeniya, Masanori Abe, Morikazu Onji, Shuichi Kaneko, Masao Honda, Kuniaki Arai, Teruko Arinaga-Hino, Etsuko Hashimoto, Makiko Taniai, Takeji Umemura, Satoru Joshita, Kazuhiko Nakao, Tatsuki Ichikawa, Hidetaka Shibata, Satoshi Yamagiwa, Masataka Seike, Koichi Honda, Shotaro Sakisaka, Yasuaki Takeyama, Masaru Harada, Michio Senju, Osamu Yokosuka, Tatsuo Kanda, Yoshiyuki Ueno, Kentaro Kikuchi, Hirotoshi Ebinuma, Takashi Himoto, Michio Yasunami, Kazumoto Murata, Masashi Mizokami, Kazuhito Kawata, Shinji Shimoda, Yasuhiro Miyake, Akinobu Takaki, Kazuhide Yamamoto, Katsuji Hirano, Takafumi Ichida, Akio Ido, Hirohito Tsubouchi, Kazuaki Chayama, Kenichi Harada, Yasuni Nakanuma, Yoshihiko Maehara, Akinobu Taketomi, Ken Shirabe, Yuji Soejima, Akira Mori, Shintaro Yagi, Shinji Uemoto, Egawa H, Tomohiro Tanaka, Noriyo Yamashiki, Sumito Tamura, Yasuhiro Sugawara, Norihiro Kokudo, Naga Chalasani, Vel Luketic, Joseph Odin, Kapil Chopra, Goncalo Abecasis, Michael Cantor, Giovanni Coppola, Aris Economides, Luca A. Lotta, John D. Overton, Jeffrey G. Reid, Alan Shuldiner, Christina Beechert, Caitlin Forsythe, Erin D. Fuller, Zhenhua Gu, Michael Lattari, Alexander Lopez, Thomas D. Schleicher, Maria Sotiropoulos Padilla, Karina Toledo, Louis Widom, Sarah E. Wolf, Manasi Pradhan, Kia Manoochehri, Ricardo H. Ulloa, Xiaodong Bai, Suganthi Balasubramanian, Leland Barnard, Andrew Blumenfeld, Gisu Eom, Lukas Habegger, Alicia Hawes, Shareef Khalid, Evan K. Maxwell, William Salerno, Jeffrey C. Staples, Marcus B. Jones, Lyndon J. Mitnaul, Richard Sturgess, Christopher Healey, Andrew Yeoman, Anton V.J. Gunasekera, Paul Kooner, Kapil Kapur, V. Sathyanarayana, Yiannis Kallis, Javaid Subhani, Rory Harvey, Roger McCorry, Paul Rooney, David Ramanaden, Richard Evans, Thiriloganathan Mathialahan, Jaber Gasem, Christopher Shorrock, Mahesh Bhalme, Paul Southern, Jeremy A. Tibble, David A. Gorard, Susan Jones, George Mells, Victoria Mulcahy, Brijesh Srivastava, Matthew R. Foxton, Carole E. Collins, David Elphick, Mazn Karmo, Francisco Porras-Perez, Michael Mendall, Tom Yapp, Minesh Patel, Roland Ede, Joanne Sayer, James Jupp, Neil Fisher, Martyn J. Carter, Konrad Koss, Jayshri Shah, Andrzej Piotrowicz, Glyn Scott, Charles Grimley, Ian R. Gooding, Simon Williams, Judith Tidbury, Guan Lim, Kuldeep Cheent, Sass Levi, Dina Mansour, Matilda Beckley, Coral Hollywood, Terry Wong, Richard Marley, John Ramage, Harriet M. Gordon, Jo Ridpath, Theodore Ngatchu, Vijay Paul Bob Grover, Ray G. Shidrawi, George Abouda, L. Corless, Mark Narain, Ian Rees, Ashley Brown, Simon Taylor-Robinson, Joy Wilkins, Leonie Grellier, Paul Banim, Debasish Das, Michael A. Heneghan, Howard Curtis, Helen C. Matthews, Faiyaz Mohammed, Mark Aldersley, Raj Srirajaskanthan, Giles Walker, Alistair McNair, Amar Sharif, Sambit Sen, George Bird, Martin I. Prince, Geeta Prasad, Paul Kitchen, Adrian Barnardo, Chirag Oza, Nurani N. Sivaramakrishnan, Prakash Gupta, Amir Shah, Chris D.J. Evans, Subrata Saha, Katharine Pollock, Peter Bramley, Ashis Mukhopadhya, Stephen T. Barclay, Natasha McDonald, Andrew J. Bathgate, Kelvin Palmer, John F. Dillon, Simon M. Rushbrook, Robert Przemioslo, Chris McDonald, Andrew Millar, Cheh Tai, Stephen Mitchell, Jane Metcalf, Syed Shaukat, Mary Ninkovic, Udi Shmueli, Andrew Davis, Asifabbas Naqvi, Tom J.W. Lee, Stephen Ryder, Jane Collier, Howard Klass, Matthew E. Cramp, Nichols Sharer, Richard Aspinall, Deb Ghosh, Andrew C. Douds, Jonathan Booth, Earl Williams, Hyder Hussaini, John Christie, Steven Mann, Douglas Thorburn, Aileen Marshall, Imran Patanwala, Aftab Ala, Julia Maltby, Ray Matthew, Chris Corbett, Sam Vyas, Saket Singhal, Dermot Gleeson, Sharat Misra, Jeff Butterworth, Keith George, Tim Harding, Andrew Douglass, Harriet Mitchison, Simon Panter, Jeremy Shearman, Gary Bray, Michael Roberts, Graham Butcher, Daniel Forton, Zahid Mahmood, Matthew Cowan, Debashis Das, Chin Lye Ch'ng, Mesbah Rahman, Gregory C.A. Whatley, Emma Wesley, Aditya Mandal, Sanjiv Jain, Stephen P. Pereira, Mark Wright, Palak Trivedi, Fiona H. Gordon, Esther Unitt, Altaf Palejwala, Andrew Austin, Vishwaraj Vemala, Allister Grant, Andrew D. Higham, Alison Brind, Ray Mathew, Mark Cox, Subramaniam Ramakrishnan, Alistair King, Simon Whalley, Jocelyn Fraser, S.J. Thomson, Andrew Bell, Voi Shim Wong, Richard Kia, Ian Gee, Richard Keld, Rupert Ransford, James Gotto, and Charles Millson
Subjects: Science & Technology, Hepatology, Gastroenterology & Hepatology, Italian PBC Study Group, Japan-PBC-GWAS Consortium, UK-PBC Consortium, Chinese PBC Consortium, 1103 Clinical Sciences, US PBC Consortium, Canadian PBC Consortium, Life Sciences & Biomedicine, PBC Consortia, 1117 Public Health and Health Services
Published: 2021

4. Inhibition of the Cytolytic Protein Perforin Prevents Rejection of Transplanted Bone Marrow Stem Cells in Vivo

Author: William A. Denny, Stephen M. F. Jamieson, Christian K. Miller, Kate H. Gartlan, Julie Ann Spicer, Jiney Jose, Karshing Chang, Matthew Bull, Hedieh Akhlaghi, Joseph A. Trapani, Jagdish K. Jaiswal, Geoff R. Hill, Patrick D. O'Connor, and Anna C. Giddens
Subjects: Graft Rejection, Male, chemical and pharmacologic phenomena, Context (language use), 01 natural sciences, Cell Line, Bone Marrow Stem Cell Transplantation, Mice, 03 medical and health sciences, In vivo, Drug Discovery, Animals, Cytotoxic T cell, Bone Marrow Transplantation, 030304 developmental biology, Mice, Inbred BALB C, Sulfonamides, 0303 health sciences, biology, Perforin, Chemistry, 3. Good health, 0104 chemical sciences, Mice, Inbred C57BL, 010404 medicinal & biomolecular chemistry, Granzyme, Cell culture, biology.protein, Cancer research, Molecular Medicine, Stem cell, Stem Cell Transplantation
Abstract: Perforin is a key effector protein in the vertebrate immune system and is secreted by cytotoxic T lymphocytes and natural killer cells to help eliminate virus-infected and transformed target cells. The ability to modulate perforin activity in vivo could be extremely useful, especially in the context of bone marrow stem cell transplantation where early rejection of immunologically mismatched grafts is driven by the recipient's natural killer cells, which overwhelmingly use perforin to kill their targets. Bone marrow stem cell transplantation is a potentially curative treatment for both malignant and nonmalignant disorders, but when the body recognizes the graft as foreign, it is rejected by this process, often with fatal consequences. Here we report optimization of a previously identified series of benzenesulfonamide-based perforin inhibitors for their physicochemical and pharmacokinetic properties, resulting in the identification of 16, the first reported small molecule able to prevent rejection of transplanted bone marrow stem cells in vivo by blocking perforin function.
Published: 2019
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5. Synthesis and Evaluation of Imidazo[1,2‐a]pyridine Analogues of the ZSTK474 Class of Phosphatidylinositol 3‐Kinase Inhibitors

Author: James M. J. Dickson, Swarna A. Gamage, Julie Ann Spicer, Kit Yee Tsang, Woo-Jeong Lee, Gordon W. Rewcastle, William A. Denny, Patrick D. O'Connor, Peter R. Shepherd, and Jack U. Flanagan
Subjects: Benzimidazole, Pyridines, Stereochemistry, 010402 general chemistry, 01 natural sciences, Biochemistry, Phosphatidylinositol 3-Kinases, Structure-Activity Relationship, chemistry.chemical_compound, Heck reaction, Pyridine, Humans, Phosphatidylinositol, Enzyme Inhibitors, Phosphoinositide-3 Kinase Inhibitors, Dose-Response Relationship, Drug, Molecular Structure, 010405 organic chemistry, Kinase, Hydrogen bond, Organic Chemistry, Biological activity, General Chemistry, 0104 chemical sciences, chemistry, Selectivity
Abstract: Using a scaffold-hopping approach, imidazo[1,2-a]pyridine analogues of the ZSTK474 (benzimidazole) class of phosphatidylinositol 3-kinase (PI3K) inhibitors have been synthesized for biological evaluation. Compounds were prepared using a heteroaryl Heck reaction procedure, involving the palladium-catalysed coupling of 2-(difluoromethyl)imidazo[1,2-a]pyridines with chloro, iodo or trifluoromethanesulfonyloxy (trifloxy) substituted 1,3,5-triazines or pyrimidines, with the iodo intermediates being preferred in terms of higher yields and milder reaction conditions. The new compounds maintain the PI3K isoform selectivity of their benzimidazole analogues, but in general show less potency.
Published: 2019
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6. An international genome-wide meta-analysis of primary biliary cholangitis: Novel risk loci and candidate drugs

Author: Heather J. Cordell, James J. Fryett, Kazuko Ueno, Rebecca Darlay, Yoshihiro Aiba, Yuki Hitomi, Minae Kawashima, Nao Nishida, Seik-Soon Khor, Olivier Gervais, Yosuke Kawai, Masao Nagasaki, Katsushi Tokunaga, Ruqi Tang, Yongyong Shi, Zhiqiang Li, Brian D. Juran, Elizabeth J. Atkinson, Alessio Gerussi, Marco Carbone, Rosanna Asselta, Angela Cheung, Mariza de Andrade, Aris Baras, Julie Horowitz, Manuel A.R. Ferreira, Dylan Sun, David E. Jones, Steven Flack, Ann Spicer, Victoria L. Mulcahy, Jinyoung Byan, Younghun Han, Richard N. Sandford, Konstantinos N. Lazaridis, Christopher I. Amos, Gideon M. Hirschfield, Michael F. Seldin, Pietro Invernizzi, Katherine A. Siminovitch, Xiong Ma, Minoru Nakamura, George F. Mells, Andrew Mason, Catherine Vincent, Gang Xie, Jinyi Zhang, Andrea Affronti, Piero L. Almasio, Domenico Alvaro, Pietro Andreone, Angelo Andriulli, Francesco Azzaroli, Pier Maria Battezzati, Antonio Benedetti, MariaConsiglia Bragazzi, Maurizia Brunetto, Savino Bruno, Vincenza Calvaruso, Vincenzo Cardinale, Giovanni Casella, Nora Cazzagon, Antonio Ciaccio, Barbara Coco, Agostino Colli, Guido Colloredo, Massimo Colombo, Silvia Colombo, Laura Cristoferi, Carmela Cursaro, Lory Saveria Crocè, Andrea Crosignani, Daphne D’Amato, Francesca Donato, Gianfranco Elia, Luca Fabris, Stefano Fagiuoli, Carlo Ferrari, Annarosa Floreani, Andrea Galli, Edoardo Giannini, Ignazio Grattagliano, Pietro Lampertico, Ana Lleo, Federica Malinverno, Clara Mancuso, Fabio Marra, Marco Marzioni, Sara Massironi, Alberto Mattalia, Luca Miele, Chiara Milani, Lorenzo Morini, Filomena Morisco, Luigi Muratori, Paolo Muratori, Grazia A. Niro, Sarah O’Donnell, Antonio Picciotto, Piero Portincasa, Cristina Rigamonti, Vincenzo Ronca, Floriano Rosina, Giancarlo Spinzi, Mario Strazzabosco, Mirko Tarocchi, Claudio Tiribelli, Pierluigi Toniutto, Luca Valenti, Maria Vinci, Massimo Zuin, Hitomi Nakamura, Seigo Abiru, Shinya Nagaoka, Atsumasa Komori, Hiroshi Yatsuhashi, Hiromi Ishibashi, Masahiro Ito, Kiyoshi Migita, Hiromasa Ohira, Shinji Katsushima, Atsushi Naganuma, Kazuhiro Sugi, Tatsuji Komatsu, Tomohiko Mannami, Kouki Matsushita, Kaname Yoshizawa, Fujio Makita, Toshiki Nikami, Hideo Nishimura, Hiroshi Kouno, Hirotaka Kouno, Hajime Ota, Takuya Komura, Yoko Nakamura, Masaaki Shimada, Noboru Hirashima, Toshiki Komeda, Keisuke Ario, Makoto Nakamuta, Tsutomu Yamashita, Kiyoshi Furuta, Masahiro Kikuchi, Noriaki Naeshiro, Hironao Takahashi, Yutaka Mano, Seiji Tsunematsu, Iwao Yabuuchi, Yusuke Shimada, Kazuhiko Yamauchi, Rie Sugimoto, Hironori Sakai, Eiji Mita, Masaharu Koda, Satoru Tsuruta, Hiroshi Kamitsukasa, Takeaki Sato, Naohiko Masaki, Tatsuro Kobata, Nobuyoshi Fukushima, Yukio Ohara, Toyokichi Muro, Eiichi Takesaki, Hitoshi Takaki, Tetsuo Yamamoto, Michio Kato, Yuko Nagaoki, Shigeki Hayashi, Jinya Ishida, Yukio Watanabe, Masakazu Kobayashi, Michiaki Koga, Takeo Saoshiro, Michiyasu Yagura, Keisuke Hirata, Atsushu Tanaka, Hajime Takikawa, Mikio Zeniya, Masanori Abe, Morikazu Onji, Shuichi Kaneko, Masao Honda, Kuniaki Arai, Teruko Arinaga-Hino, Etsuko Hashimoto, Makiko Taniai, Takeji Umemura, Satoru Joshita, Kazuhiko Nakao, Tatsuki Ichikawa, Hidetaka Shibata, Satoshi Yamagiwa, Masataka Seike, Koichi Honda, Shotaro Sakisaka, Yasuaki Takeyama, Masaru Harada, Michio Senju, Osamu Yokosuka, Tatsuo Kanda, Yoshiyuki Ueno, Kentaro Kikuchi, Hirotoshi Ebinuma, Takashi Himoto, Michio Yasunami, Kazumoto Murata, Masashi Mizokami, Kazuhito Kawata, Shinji Shimoda, Yasuhiro Miyake, Akinobu Takaki, Kazuhide Yamamoto, Katsuji Hirano, Takafumi Ichida, Akio Ido, Hirohito Tsubouchi, Kazuaki Chayama, Kenichi Harada, Yasuni Nakanuma, Yoshihiko Maehara, Akinobu Taketomi, Ken Shirabe, Yuji Soejima, Akira Mori, Shintaro Yagi, Shinji Uemoto, Egawa H, Tomohiro Tanaka, Noriyo Yamashiki, Sumito Tamura, Yasuhiro Sugawara, Norihiro Kokudo, Naga Chalasani, Vel Luketic, Joseph Odin, Kapil Chopra, Goncalo Abecasis, Michael Cantor, Giovanni Coppola, Aris Economides, Luca A. Lotta, John D. Overton, Jeffrey G. Reid, Alan Shuldiner, Christina Beechert, Caitlin Forsythe, Erin D. Fuller, Zhenhua Gu, Michael Lattari, Alexander Lopez, Thomas D. Schleicher, Maria Sotiropoulos Padilla, Karina Toledo, Louis Widom, Sarah E. Wolf, Manasi Pradhan, Kia Manoochehri, Ricardo H. Ulloa, Xiaodong Bai, Suganthi Balasubramanian, Leland Barnard, Andrew Blumenfeld, Gisu Eom, Lukas Habegger, Alicia Hawes, Shareef Khalid, Evan K. Maxwell, William Salerno, Jeffrey C. Staples, Marcus B. Jones, Lyndon J. Mitnaul, Richard Sturgess, Christopher Healey, Andrew Yeoman, Anton VJ. Gunasekera, Paul Kooner, Kapil Kapur, V. Sathyanarayana, Yiannis Kallis, Javaid Subhani, Rory Harvey, Roger McCorry, Paul Rooney, David Ramanaden, Richard Evans, Thiriloganathan Mathialahan, Jaber Gasem, Christopher Shorrock, Mahesh Bhalme, Paul Southern, Jeremy A. Tibble, David A. Gorard, Susan Jones, George Mells, Victoria Mulcahy, Brijesh Srivastava, Matthew R. Foxton, Carole E. Collins, David Elphick, Mazn Karmo, Francisco Porras-Perez, Michael Mendall, Tom Yapp, Minesh Patel, Roland Ede, Joanne Sayer, James Jupp, Neil Fisher, Martyn J. Carter, Konrad Koss, Jayshri Shah, Andrzej Piotrowicz, Glyn Scott, Charles Grimley, Ian R. Gooding, Simon Williams, Judith Tidbury, Guan Lim, Kuldeep Cheent, Sass Levi, Dina Mansour, Matilda Beckley, Coral Hollywood, Terry Wong, Richard Marley, John Ramage, Harriet M. Gordon, Jo Ridpath, Theodore Ngatchu, Vijay Paul Bob Grover, Ray G. Shidrawi, George Abouda, L. Corless, Mark Narain, Ian Rees, Ashley Brown, Simon Taylor-Robinson, Joy Wilkins, Leonie Grellier, Paul Banim, Debasish Das, Michael A. Heneghan, Howard Curtis, Helen C. Matthews, Faiyaz Mohammed, Mark Aldersley, Raj Srirajaskanthan, Giles Walker, Alistair McNair, Amar Sharif, Sambit Sen, George Bird, Martin I. Prince, Geeta Prasad, Paul Kitchen, Adrian Barnardo, Chirag Oza, Nurani N. Sivaramakrishnan, Prakash Gupta, Amir Shah, Chris DJ. Evans, Subrata Saha, Katharine Pollock, Peter Bramley, Ashis Mukhopadhya, Stephen T. Barclay, Natasha McDonald, Andrew J. Bathgate, Kelvin Palmer, John F. Dillon, Simon M. Rushbrook, Robert Przemioslo, Chris McDonald, Andrew Millar, Cheh Tai, Stephen Mitchell, Jane Metcalf, Syed Shaukat, Mary Ninkovic, Udi Shmueli, Andrew Davis, Asifabbas Naqvi, Tom JW. Lee, Stephen Ryder, Jane Collier, Howard Klass, Matthew E. Cramp, Nichols Sharer, Richard Aspinall, Deb Ghosh, Andrew C. Douds, Jonathan Booth, Earl Williams, Hyder Hussaini, John Christie, Steven Mann, Douglas Thorburn, Aileen Marshall, Imran Patanwala, Aftab Ala, Julia Maltby, Ray Matthew, Chris Corbett, Sam Vyas, Saket Singhal, Dermot Gleeson, Sharat Misra, Jeff Butterworth, Keith George, Tim Harding, Andrew Douglass, Harriet Mitchison, Simon Panter, Jeremy Shearman, Gary Bray, Michael Roberts, Graham Butcher, Daniel Forton, Zahid Mahmood, Matthew Cowan, Debashis Das, Chin Lye Ch’ng, Mesbah Rahman, Gregory C.A. Whatley, Emma Wesley, Aditya Mandal, Sanjiv Jain, Stephen P. Pereira, Mark Wright, Palak Trivedi, Fiona H. Gordon, Esther Unitt, Altaf Palejwala, Andrew Austin, Vishwaraj Vemala, Allister Grant, Andrew D. Higham, Alison Brind, Ray Mathew, Mark Cox, Subramaniam Ramakrishnan, Alistair King, Simon Whalley, Jocelyn Fraser, S.J. Thomson, Andrew Bell, Voi Shim Wong, Richard Kia, Ian Gee, Richard Keld, Rupert Ransford, James Gotto, Charles Millson, Cordell, H. J., Fryett, J. J., Ueno, K., Darlay, R., Aiba, Y., Hitomi, Y., Kawashima, M., Nishida, N., Khor, S. -S., Gervais, O., Kawai, Y., Nagasaki, M., Tokunaga, K., Tang, R., Shi, Y., Li, Z., Juran, B. D., Atkinson, E. J., Gerussi, A., Carbone, M., Asselta, R., Cheung, A., de Andrade, M., Baras, A., Horowitz, J., Ferreira, M. A. R., Sun, D., Jones, D. E., Flack, S., Spicer, A., Mulcahy, V. L., Byan, J., Han, Y., Sandford, R. N., Lazaridis, K. N., Amos, C. I., Hirschfield, G. M., Seldin, M. F., Invernizzi, P., Siminovitch, K. A., Ma, X., Nakamura, M., Mells, G. F., Mason, A., Vincent, C., Xie, G., Zhang, J., Affronti, A., Almasio, P. L., Alvaro, D., Andreone, P., Andriulli, A., Azzaroli, F., Battezzati, P. M., Benedetti, A., Bragazzi, M., Brunetto, M., Bruno, S., Calvaruso, V., Cardinale, V., Casella, G., Cazzagon, N., Ciaccio, A., Coco, B., Colli, A., Colloredo, G., Colombo, M., Colombo, S., Cristoferi, L., Cursaro, C., Croce, L. S., Crosignani, A., D'Amato, D., Donato, F., Elia, G., Fabris, L., Fagiuoli, S., Ferrari, C., Floreani, A., Galli, A., Giannini, E., Grattagliano, I., Lampertico, P., Lleo, A., Malinverno, F., Mancuso, C., Marra, F., Marzioni, M., Massironi, S., Mattalia, A., Miele, L., Milani, C., Morini, L., Morisco, F., Muratori, L., Muratori, P., Niro, G. A., O'Donnell, S., Picciotto, A., Portincasa, P., Rigamonti, C., Ronca, V., Rosina, F., Spinzi, G., Strazzabosco, M., Tarocchi, M., Tiribelli, C., Toniutto, P., Valenti, L., Vinci, M., Zuin, M., Nakamura, H., Abiru, S., Nagaoka, S., Komori, A., Yatsuhashi, H., Ishibashi, H., Ito, M., Migita, K., Ohira, H., Katsushima, S., Naganuma, A., Sugi, K., Komatsu, T., Mannami, T., Matsushita, K., Yoshizawa, K., Makita, F., Nikami, T., Nishimura, H., Kouno, H., Ota, H., Komura, T., Nakamura, Y., Shimada, M., Hirashima, N., Komeda, T., Ario, K., Nakamuta, M., Yamashita, T., Furuta, K., Kikuchi, M., Naeshiro, N., Takahashi, H., Mano, Y., Tsunematsu, S., Yabuuchi, I., Shimada, Y., Yamauchi, K., Sugimoto, R., Sakai, H., Mita, E., Koda, M., Tsuruta, S., Kamitsukasa, H., Sato, T., Masaki, N., Kobata, T., Fukushima, N., Ohara, Y., Muro, T., Takesaki, E., Takaki, H., Yamamoto, T., Kato, M., Nagaoki, Y., Hayashi, S., Ishida, J., Watanabe, Y., Kobayashi, M., Koga, M., Saoshiro, T., Yagura, M., Hirata, K., Tanaka, A., Takikawa, H., Zeniya, M., Abe, M., Onji, M., Kaneko, S., Honda, M., Arai, K., Arinaga-Hino, T., Hashimoto, E., Taniai, M., Umemura, T., Joshita, S., Nakao, K., Ichikawa, T., Shibata, H., Yamagiwa, S., Seike, M., Honda, K., Sakisaka, S., Takeyama, Y., Harada, M., Senju, M., Yokosuka, O., Kanda, T., Ueno, Y., Kikuchi, K., Ebinuma, H., Himoto, T., Yasunami, M., Murata, K., Mizokami, M., Kawata, K., Shimoda, S., Miyake, Y., Takaki, A., Yamamoto, K., Hirano, K., Ichida, T., Ido, A., Tsubouchi, H., Chayama, K., Harada, K., Nakanuma, Y., Maehara, Y., Taketomi, A., Shirabe, K., Soejima, Y., Mori, A., Yagi, S., Uemoto, S., H, E., Tanaka, T., Yamashiki, N., Tamura, S., Sugawara, Y., Kokudo, N., Chalasani, N., Luketic, V., Odin, J., Chopra, K., Abecasis, G., Cantor, M., Coppola, G., Economides, A., Lotta, L. A., Overton, J. D., Reid, J. G., Shuldiner, A., Beechert, C., Forsythe, C., Fuller, E. D., Gu, Z., Lattari, M., Lopez, A., Schleicher, T. D., Padilla, M. S., Toledo, K., Widom, L., Wolf, S. E., Pradhan, M., Manoochehri, K., Ulloa, R. H., Bai, X., Balasubramanian, S., Barnard, L., Blumenfeld, A., Eom, G., Habegger, L., Hawes, A., Khalid, S., Maxwell, E. K., Salerno, W., Staples, J. C., Jones, M. B., Mitnaul, L. J., Sturgess, R., Healey, C., Yeoman, A., Gunasekera, A. V., Kooner, P., Kapur, K., Sathyanarayana, V., Kallis, Y., Subhani, J., Harvey, R., Mccorry, R., Rooney, P., Ramanaden, D., Evans, R., Mathialahan, T., Gasem, J., Shorrock, C., Bhalme, M., Southern, P., Tibble, J. A., Gorard, D. A., Jones, S., Mells, G., Mulcahy, V., Srivastava, B., Foxton, M. R., Collins, C. E., Elphick, D., Karmo, M., Porras-Perez, F., Mendall, M., Yapp, T., Patel, M., Ede, R., Sayer, J., Jupp, J., Fisher, N., Carter, M. J., Koss, K., Shah, J., Piotrowicz, A., Scott, G., Grimley, C., Gooding, I. R., Williams, S., Tidbury, J., Lim, G., Cheent, K., Levi, S., Mansour, D., Beckley, M., Hollywood, C., Wong, T., Marley, R., Ramage, J., Gordon, H. M., Ridpath, J., Ngatchu, T., Bob Grover, V. P., Shidrawi, R. G., Abouda, G., Corless, L., Narain, M., Rees, I., Brown, A., Taylor-Robinson, S., Wilkins, J., Grellier, L., Banim, P., Das, D., Heneghan, M. A., Curtis, H., Matthews, H. C., Mohammed, F., Aldersley, M., Srirajaskanthan, R., Walker, G., Mcnair, A., Sharif, A., Sen, S., Bird, G., Prince, M. I., Prasad, G., Kitchen, P., Barnardo, A., Oza, C., Sivaramakrishnan, N. N., Gupta, P., Shah, A., Evans, C. D., Saha, S., Pollock, K., Bramley, P., Mukhopadhya, A., Barclay, S. T., Mcdonald, N., Bathgate, A. J., Palmer, K., Dillon, J. F., Rushbrook, S. M., Przemioslo, R., Mcdonald, C., Millar, A., Tai, C., Mitchell, S., Metcalf, J., Shaukat, S., Ninkovic, M., Shmueli, U., Davis, A., Naqvi, A., Lee, T. J., Ryder, S., Collier, J., Klass, H., Cramp, M. E., Sharer, N., Aspinall, R., Ghosh, D., Douds, A. C., Booth, J., Williams, E., Hussaini, H., Christie, J., Mann, S., Thorburn, D., Marshall, A., Patanwala, I., Ala, A., Maltby, J., Matthew, R., Corbett, C., Vyas, S., Singhal, S., Gleeson, D., Misra, S., Butterworth, J., George, K., Harding, T., Douglass, A., Mitchison, H., Panter, S., Shearman, J., Bray, G., Roberts, M., Butcher, G., Forton, D., Mahmood, Z., Cowan, M., Ch'Ng, C. L., Rahman, M., Whatley, G. C. A., Wesley, E., Mandal, A., Jain, S., Pereira, S. P., Wright, M., Trivedi, P., Gordon, F. H., Unitt, E., Palejwala, A., Austin, A., Vemala, V., Grant, A., Higham, A. D., Brind, A., Mathew, R., Cox, M., Ramakrishnan, S., King, A., Whalley, S., Fraser, J., Thomson, S. J., Bell, A., Wong, V. S., Kia, R., Gee, I., Keld, R., Ransford, R., Gotto, J., Millson, C., Cordell H.J., Fryett J.J., Ueno K., Darlay R., Aiba Y., Hitomi Y., Kawashima M., Nishida N., Khor S.-S., Gervais O., Kawai Y., Nagasaki M., Tokunaga K., Tang R., Shi Y., Li Z., Juran B.D., Atkinson E.J., Gerussi A., Carbone M., Asselta R., Cheung A., de Andrade M., Baras A., Horowitz J., Ferreira M.A.R., Sun D., Jones D.E., Flack S., Spicer A., Mulcahy V.L., Byan J., Han Y., Sandford R.N., Lazaridis K.N., Amos C.I., Hirschfield G.M., Seldin M.F., Invernizzi P., Siminovitch K.A., Ma X., Nakamura M., Mells G.F., Mason A., Vincent C., Xie G., Zhang J., Affronti A., Almasio P.L., Alvaro D., Andreone P., Andriulli A., Azzaroli F., Battezzati P.M., Benedetti A., Bragazzi M., Brunetto M., Bruno S., Calvaruso V., Cardinale V., Casella G., Cazzagon N., Ciaccio A., Coco B., Colli A., Colloredo G., Colombo M., Colombo S., Cristoferi L., Cursaro C., Croce L.S., Crosignani A., D'Amato D., Donato F., Elia G., Fabris L., Fagiuoli S., Ferrari C., Floreani A., Galli A., Giannini E., Grattagliano I., Lampertico P., Lleo A., Malinverno F., Mancuso C., Marra F., Marzioni M., Massironi S., Mattalia A., Miele L., Milani C., Morini L., Morisco F., Muratori L., Muratori P., Niro G.A., O'Donnell S., Picciotto A., Portincasa P., Rigamonti C., Ronca V., Rosina F., Spinzi G., Strazzabosco M., Tarocchi M., Tiribelli C., Toniutto P., Valenti L., Vinci M., Zuin M., Nakamura H., Abiru S., Nagaoka S., Komori A., Yatsuhashi H., Ishibashi H., Ito M., Migita K., Ohira H., Katsushima S., Naganuma A., Sugi K., Komatsu T., Mannami T., Matsushita K., Yoshizawa K., Makita F., Nikami T., Nishimura H., Kouno H., Ota H., Komura T., Nakamura Y., Shimada M., Hirashima N., Komeda T., Ario K., Nakamuta M., Yamashita T., Furuta K., Kikuchi M., Naeshiro N., Takahashi H., Mano Y., Tsunematsu S., Yabuuchi I., Shimada Y., Yamauchi K., Sugimoto R., Sakai H., Mita E., Koda M., Tsuruta S., Kamitsukasa H., Sato T., Masaki N., Kobata T., Fukushima N., Ohara Y., Muro T., Takesaki E., Takaki H., Yamamoto T., Kato M., Nagaoki Y., Hayashi S., Ishida J., Watanabe Y., Kobayashi M., Koga M., Saoshiro T., Yagura M., Hirata K., Tanaka A., Takikawa H., Zeniya M., Abe M., Onji M., Kaneko S., Honda M., Arai K., Arinaga-Hino T., Hashimoto E., Taniai M., Umemura T., Joshita S., Nakao K., Ichikawa T., Shibata H., Yamagiwa S., Seike M., Honda K., Sakisaka S., Takeyama Y., Harada M., Senju M., Yokosuka O., Kanda T., Ueno Y., Kikuchi K., Ebinuma H., Himoto T., Yasunami M., Murata K., Mizokami M., Kawata K., Shimoda S., Miyake Y., Takaki A., Yamamoto K., Hirano K., Ichida T., Ido A., Tsubouchi H., Chayama K., Harada K., Nakanuma Y., Maehara Y., Taketomi A., Shirabe K., Soejima Y., Mori A., Yagi S., Uemoto S., H E., Tanaka T., Yamashiki N., Tamura S., Sugawara Y., Kokudo N., Chalasani N., Luketic V., Odin J., Chopra K., Abecasis G., Cantor M., Coppola G., Economides A., Lotta L.A., Overton J.D., Reid J.G., Shuldiner A., Beechert C., Forsythe C., Fuller E.D., Gu Z., Lattari M., Lopez A., Schleicher T.D., Padilla M.S., Toledo K., Widom L., Wolf S.E., Pradhan M., Manoochehri K., Ulloa R.H., Bai X., Balasubramanian S., Barnard L., Blumenfeld A., Eom G., Habegger L., Hawes A., Khalid S., Maxwell E.K., Salerno W., Staples J.C., Jones M.B., Mitnaul L.J., Sturgess R., Healey C., Yeoman A., Gunasekera A.V., Kooner P., Kapur K., Sathyanarayana V., Kallis Y., Subhani J., Harvey R., McCorry R., Rooney P., Ramanaden D., Evans R., Mathialahan T., Gasem J., Shorrock C., Bhalme M., Southern P., Tibble J.A., Gorard D.A., Jones S., Mells G., Mulcahy V., Srivastava B., Foxton M.R., Collins C.E., Elphick D., Karmo M., Porras-Perez F., Mendall M., Yapp T., Patel M., Ede R., Sayer J., Jupp J., Fisher N., Carter M.J., Koss K., Shah J., Piotrowicz A., Scott G., Grimley C., Gooding I.R., Williams S., Tidbury J., Lim G., Cheent K., Levi S., Mansour D., Beckley M., Hollywood C., Wong T., Marley R., Ramage J., Gordon H.M., Ridpath J., Ngatchu T., Bob Grover V.P., Shidrawi R.G., Abouda G., Corless L., Narain M., Rees I., Brown A., Taylor-Robinson S., Wilkins J., Grellier L., Banim P., Das D., Heneghan M.A., Curtis H., Matthews H.C., Mohammed F., Aldersley M., Srirajaskanthan R., Walker G., McNair A., Sharif A., Sen S., Bird G., Prince M.I., Prasad G., Kitchen P., Barnardo A., Oza C., Sivaramakrishnan N.N., Gupta P., Shah A., Evans C.D., Saha S., Pollock K., Bramley P., Mukhopadhya A., Barclay S.T., McDonald N., Bathgate A.J., Palmer K., Dillon J.F., Rushbrook S.M., Przemioslo R., McDonald C., Millar A., Tai C., Mitchell S., Metcalf J., Shaukat S., Ninkovic M., Shmueli U., Davis A., Naqvi A., Lee T.J., Ryder S., Collier J., Klass H., Cramp M.E., Sharer N., Aspinall R., Ghosh D., Douds A.C., Booth J., Williams E., Hussaini H., Christie J., Mann S., Thorburn D., Marshall A., Patanwala I., Ala A., Maltby J., Matthew R., Corbett C., Vyas S., Singhal S., Gleeson D., Misra S., Butterworth J., George K., Harding T., Douglass A., Mitchison H., Panter S., Shearman J., Bray G., Roberts M., Butcher G., Forton D., Mahmood Z., Cowan M., Ch'ng C.L., Rahman M., Whatley G.C.A., Wesley E., Mandal A., Jain S., Pereira S.P., Wright M., Trivedi P., Gordon F.H., Unitt E., Palejwala A., Austin A., Vemala V., Grant A., Higham A.D., Brind A., Mathew R., Cox M., Ramakrishnan S., King A., Whalley S., Fraser J., Thomson S.J., Bell A., Wong V.S., Kia R., Gee I., Keld R., Ransford R., Gotto J., Millson C., Medical Research Council (MRC), LiveR North, Cordell, H, Fryett, J, Ueno, K, Darlay, R, Aiba, Y, Hitomi, Y, Kawashima, M, Nishida, N, Khor, S, Gervais, O, Kawai, Y, Nagasaki, M, Tokunaga, K, Tang, R, Shi, Y, Li, Z, Juran, B, Atkinson, E, Gerussi, A, Carbone, M, Asselta, R, Cheung, A, de Andrade, M, Baras, A, Horowitz, J, Ferreira, M, Sun, D, Jones, D, Flack, S, Spicer, A, Mulcahy, V, Byan, J, Han, Y, Sandford, R, Lazaridis, K, Amos, C, Hirschfield, G, Seldin, M, Invernizzi, P, Siminovitch, K, Ma, X, Nakamura, M, Mells, G, Mason, A, Vincent, C, Xie, G, Zhang, J, Affronti, A, Almasio, P, Alvaro, D, Andreone, P, Andriulli, A, Azzaroli, F, Battezzati, P, Benedetti, A, Bragazzi, M, Brunetto, M, Bruno, S, Calvaruso, V, Cardinale, V, Casella, G, Cazzagon, N, Ciaccio, A, Coco, B, Colli, A, Colloredo, G, Colombo, M, Colombo, S, Cristoferi, L, Cursaro, C, Croce, L, Crosignani, A, D'Amato, D, Donato, F, Elia, G, Fabris, L, Fagiuoli, S, Ferrari, C, Floreani, A, Galli, A, Giannini, E, Grattagliano, I, Lampertico, P, Lleo, A, Malinverno, F, Mancuso, C, Marra, F, Marzioni, M, Massironi, S, Mattalia, A, Miele, L, Milani, C, Morini, L, Morisco, F, Muratori, L, Muratori, P, Niro, G, O'Donnell, S, Picciotto, A, Portincasa, P, Rigamonti, C, Ronca, V, Rosina, F, Spinzi, G, Strazzabosco, M, Tarocchi, M, Tiribelli, C, Toniutto, P, Valenti, L, Vinci, M, Zuin, M, Nakamura, H, Abiru, S, Nagaoka, S, Komori, A, Yatsuhashi, H, Ishibashi, H, Ito, M, Migita, K, Ohira, H, Katsushima, S, Naganuma, A, Sugi, K, Komatsu, T, Mannami, T, Matsushita, K, Yoshizawa, K, Makita, F, Nikami, T, Nishimura, H, Kouno, H, Ota, H, Komura, T, Nakamura, Y, Shimada, M, Hirashima, N, Komeda, T, Ario, K, Nakamuta, M, Yamashita, T, Furuta, K, Kikuchi, M, Naeshiro, N, Takahashi, H, Mano, Y, Tsunematsu, S, Yabuuchi, I, Shimada, Y, Yamauchi, K, Sugimoto, R, Sakai, H, Mita, E, Koda, M, Tsuruta, S, Kamitsukasa, H, Sato, T, Masaki, N, Kobata, T, Fukushima, N, Ohara, Y, Muro, T, Takesaki, E, Takaki, H, Yamamoto, T, Kato, M, Nagaoki, Y, Hayashi, S, Ishida, J, Watanabe, Y, Kobayashi, M, Koga, M, Saoshiro, T, Yagura, M, Hirata, K, Tanaka, A, Takikawa, H, Zeniya, M, Abe, M, Onji, M, Kaneko, S, Honda, M, Arai, K, Arinaga-Hino, T, Hashimoto, E, Taniai, M, Umemura, T, Joshita, S, Nakao, K, Ichikawa, T, Shibata, H, Yamagiwa, S, Seike, M, Honda, K, Sakisaka, S, Takeyama, Y, Harada, M, Senju, M, Yokosuka, O, Kanda, T, Ueno, Y, Kikuchi, K, Ebinuma, H, Himoto, T, Yasunami, M, Murata, K, Mizokami, M, Kawata, K, Shimoda, S, Miyake, Y, Takaki, A, Yamamoto, K, Hirano, K, Ichida, T, Ido, A, Tsubouchi, H, Chayama, K, Harada, K, Nakanuma, Y, Maehara, Y, Taketomi, A, Shirabe, K, Soejima, Y, Mori, A, Yagi, S, Uemoto, S, H, E, Tanaka, T, Yamashiki, N, Tamura, S, Sugawara, Y, Kokudo, N, Chalasani, N, Luketic, V, Odin, J, Chopra, K, Abecasis, G, Cantor, M, Coppola, G, Economides, A, Lotta, L, Overton, J, Reid, J, Shuldiner, A, Beechert, C, Forsythe, C, Fuller, E, Gu, Z, Lattari, M, Lopez, A, Schleicher, T, Padilla, M, Toledo, K, Widom, L, Wolf, S, Pradhan, M, Manoochehri, K, Ulloa, R, Bai, X, Balasubramanian, S, Barnard, L, Blumenfeld, A, Eom, G, Habegger, L, Hawes, A, Khalid, S, Maxwell, E, Salerno, W, Staples, J, Jones, M, Mitnaul, L, Sturgess, R, Healey, C, Yeoman, A, Gunasekera, A, Kooner, P, Kapur, K, Sathyanarayana, V, Kallis, Y, Subhani, J, Harvey, R, Mccorry, R, Rooney, P, Ramanaden, D, Evans, R, Mathialahan, T, Gasem, J, Shorrock, C, Bhalme, M, Southern, P, Tibble, J, Gorard, D, Jones, S, Srivastava, B, Foxton, M, Collins, C, Elphick, D, Karmo, M, Porras-Perez, F, Mendall, M, Yapp, T, Patel, M, Ede, R, Sayer, J, Jupp, J, Fisher, N, Carter, M, Koss, K, Shah, J, Piotrowicz, A, Scott, G, Grimley, C, Gooding, I, Williams, S, Tidbury, J, Lim, G, Cheent, K, Levi, S, Mansour, D, Beckley, M, Hollywood, C, Wong, T, Marley, R, Ramage, J, Gordon, H, Ridpath, J, Ngatchu, T, Bob Grover, V, Shidrawi, R, Abouda, G, Corless, L, Narain, M, Rees, I, Brown, A, Taylor-Robinson, S, Wilkins, J, Grellier, L, Banim, P, Das, D, Heneghan, M, Curtis, H, Matthews, H, Mohammed, F, Aldersley, M, Srirajaskanthan, R, Walker, G, Mcnair, A, Sharif, A, Sen, S, Bird, G, Prince, M, Prasad, G, Kitchen, P, Barnardo, A, Oza, C, Sivaramakrishnan, N, Gupta, P, Shah, A, Evans, C, Saha, S, Pollock, K, Bramley, P, Mukhopadhya, A, Barclay, S, Mcdonald, N, Bathgate, A, Palmer, K, Dillon, J, Rushbrook, S, Przemioslo, R, Mcdonald, C, Millar, A, Tai, C, Mitchell, S, Metcalf, J, Shaukat, S, Ninkovic, M, Shmueli, U, Davis, A, Naqvi, A, Lee, T, Ryder, S, Collier, J, Klass, H, Cramp, M, Sharer, N, Aspinall, R, Ghosh, D, Douds, A, Booth, J, Williams, E, Hussaini, H, Christie, J, Mann, S, Thorburn, D, Marshall, A, Patanwala, I, Ala, A, Maltby, J, Matthew, R, Corbett, C, Vyas, S, Singhal, S, Gleeson, D, Misra, S, Butterworth, J, George, K, Harding, T, Douglass, A, Mitchison, H, Panter, S, Shearman, J, Bray, G, Roberts, M, Butcher, G, Forton, D, Mahmood, Z, Cowan, M, Ch'Ng, C, Rahman, M, Whatley, G, Wesley, E, Mandal, A, Jain, S, Pereira, S, Wright, M, Trivedi, P, Gordon, F, Unitt, E, Palejwala, A, Austin, A, Vemala, V, Grant, A, Higham, A, Brind, A, Mathew, R, Cox, M, Ramakrishnan, S, King, A, Whalley, S, Fraser, J, Thomson, S, Bell, A, Wong, V, Kia, R, Gee, I, Keld, R, Ransford, R, Gotto, J, Millson, C, Cordell HJ, Fryett JJ, Ueno K, Darlay R, Aiba Y, Hitomi Y, Kawashima M, Nishida N, Khor SS, Gervais O, Kawai Y, Nagasaki M, Tokunaga K, Tang R, Shi Y, Li Z, Juran BD, Atkinson EJ, Gerussi A, Carbone M, Asselta R, Cheung A, de Andrade M, Baras A, Horowitz J, Ferreira MAR, Sun D, Jones DE, Flack S, Spicer A, Mulcahy VL, Byan J, Han Y, Sandford RN, Lazaridis KN, Amos CI, Hirschfield GM, Seldin MF, Invernizzi P, Siminovitch KA, Ma X, Nakamura M, Mells GF, PBC Consortia, Canadian PBC Consortium, Chinese PBC Consortium, Italian PBC Study Group, Japan-PBC-GWAS Consortium, US PBC Consortium, UK-PBC Consortium, and Calvaruso V. .
Subjects: Liver Cirrhosis, ALSPAC, ERN RARE-LIVER, Genomic co-localization, Network-based in silico drug efficacy screening, UK-PBC, 0301 basic medicine, Candidate gene, Genome-Wide Association Study, Humans, Liver Cirrhosis, Biliary, Italian PBC Study Group, LD SCORE REGRESSION, Japan-PBC-GWAS Consortium, Genome-wide association study, Locus (genetics), Disease, SUSCEPTIBILITY, PBC, Chronic liver disease, Bioinformatics, GENETIC ASSOCIATION, 1117 Public Health and Health Services, 03 medical and health sciences, 0302 clinical medicine, UK-PBC Consortium, Genotype, Medicine, Genetic association, Science & Technology, Gastroenterology & Hepatology, Hepatology, business.industry, Biliary, Chinese PBC Consortium, 1103 Clinical Sciences, medicine.disease, PBC Consortia, 030104 developmental biology, Meta-analysis, ERN RARE LIVER, 030211 gastroenterology & hepatology, US PBC Consortium, Canadian PBC Consortium, business, Life Sciences & Biomedicine, Human
Abstract: [BACKGROUND & AIMS] Primary biliary cholangitis (PBC) is a chronic liver disease in which autoimmune destruction of the small intra-hepatic bile ducts eventually leads to cirrhosis. Many patients have inadequate response to licensed medications, motivating the search for novel therapies. Previous genome-wide association studies (GWAS) and meta-analyses (GWMA) of PBC have identified numerous risk loci for this condition, providing insight into its aetiology. We undertook the largest GWMA of PBC to date, aiming to identify additional risk loci and prioritise candidate genes for in silico drug efficacy screening. [METHODS] We combined new and existing genotype data for 10, 516 cases and 20, 772 controls from five European and two East Asian cohorts. [RESULTS] We identified 56 genome-wide significant loci (20 novel) including 46 in European, 13 in Asian, and 41 in combined cohorts; and a 57th genome-wide significant locus (also novel) in conditional analysis of the European cohorts. Candidate genes at newly identified loci include FCRL3, INAVA, PRDM1, IRF7, CCR6, CD226, and IL12RB1, each having key roles in immunity. Pathway analysis reiterated the likely importance of pattern recognition receptor and TNF signalling, Jak-STAT signalling, and differentiation of TH1 and TH17 cells in the pathogenesis of this disease. Drug efficacy screening identified several medications predicted to be therapeutic in PBC, some well-established in the treatment of other autoimmune disorders. [CONCLUSIONS] This study has identified additional risk loci for PBC, provided a hierarchy of agents that could be trialled in this condition, and emphasised the value of genetic and genomic approaches to drug discovery in complex disorders. [Lay summary] Primary biliary cholangitis (PBC) is a chronic liver disease that eventually leads to cirrhosis. In this study, we analysed genetic information from 10, 516 people with PBC and 20, 772 healthy individuals recruited in Canada, China, Italy, Japan, UK, or USA. We identified several genetic regions associated with PBC. Each of these regions contains several genes. For each region, we used diverse sources of evidence to help us choose the gene most likely to be involved in causing PBC. We used these ‘candidate genes’ to help us identify medications that are currently used for treatment of other conditions, which might also be useful for treatment of PBC., 原発性胆汁性胆管炎のゲノムワイド関連解析 --国際メタ解析による新規疾患感受性遺伝子と治療薬候補の同定--. 京都大学プレスリリース. 2021-06-28.
Published: 2021

7. Effects of primary biliary cholangitis on quality of life and health care costs in the United Kingdom

Author: Steven Flack, Simon D. Taylor-Robinson, Dimitrios Minos, David Jones, Diarmuid Coughlan, George F. Mells, Jonathan Badrock, Mark D. F. Shirley, Stephen Rice, Richard Sandford, Luke Vale, Viviana Albani, Gulnar Fattakhova, Nikoletta Varvaropoulou, Gideon M. Hirschfield, Ann Spicer, Marco Carbone, Medical Research Council (MRC), Rice, S, Albani, V, Minos, D, Fattakhova, G, Mells, G, Carbone, M, Flack, S, Varvaropoulou, N, Badrock, J, Spicer, A, Sandford, R, Shirley, M, Coughlan, D, Hirschfield, G, Taylor-Robinson, S, Vale, L, and Jones, D
Subjects: medicine.medical_specialty, Cost estimate, Cost effectiveness, Economics, medicine.medical_treatment, Economic, Liver transplantation, State Medicine, UDCA, 03 medical and health sciences, 0302 clinical medicine, Quality of life, Cost of Illness, EQ-5D, Health care, UK-PBC Consortium, Humans, Medicine, Science & Technology, Hepatology, Gastroenterology & Hepatology, Liver Cirrhosis, Biliary, business.industry, Gastroenterology, 1103 Clinical Sciences, Health Care Costs, United Kingdom, Confidence interval, digestive system diseases, humanities, Management, Cost of Illne, 030220 oncology & carcinogenesis, Cohort, Emergency medicine, Quality of Life, 030211 gastroenterology & hepatology, business, Life Sciences & Biomedicine
Abstract: Background & Aims There have been few high-quality studies of the costs, preference-based health-related quality of life (HRQoL) and cost effectiveness of treatments for primary biliary cholangitis (PBC). We aimed to estimate the marginal effects of PBC complications and symptoms, accounting for treatment, on HRQoL and the annual cost of health care in the United Kingdom (UK). These are essential components for evaluation of cost effectiveness and this information will aid in evaluation of new treatments. Methods Questionnaires were mailed to 4583 participants in the UK-PBC research cohort and data were collected on HRQoL and use of the National Health Service (NHS) in the UK from 2015 through 2016. HRQoL was measured using the EQ-5D-5L instrument. The annual cost of resource use was calculated using unit costs obtained from NHS sources. We performed econometric analyses to determine the effects of treatment, symptoms, complications, liver transplantation status, and patient characteristics on HRQoL and annual costs. Results In an analysis of data from 2240 participants (over 10% of all UK PBC patients), we found that PBC symptoms have a considerable effect on HRQoL. Ursodeoxycholic acid therapy was associated with significantly higher HRQoL regardless of response status. Having had a liver transplant and ascites were also independently associated with reduced HRQoL. Having had a liver transplant (US$4294) and esophageal varices (US$3401) were the factors with the two greatest mean annual costs to the NHS. Symptoms were not independently associated with cost but were associated with reduction in HRQoL for patients, indicating the lack of effective treatments for PBC symptoms. Conclusions In an analysis of data from 2240 participants in the UK PBC, we found that HRQoL and cost estimates provide greater insight into the relative importance of PBC-related symptoms and complications. These findings provide estimates for health technology assessments of new treatments for PBC.
Published: 2020

8. Perforin inhibition protects from lethal endothelial damage during fulminant viral hepatitis

Author: Jonel Trebicka, Zeinab Abdullah, Sarah Eickhoff, Dietmar Zehn, K Manske, Meike Welz, Hedieh Akhlaghi, Percy A. Knolle, Anthony J. Demetris, Martina Anton, Joseph A. Trapani, Julie Ann Spicer, Kate H. Gartlan, Christian Kurts, Bernhard Nieswandt, Dirk Wohlleber, and Wolfgang Kastenmüller
Subjects: 0301 basic medicine, Fulminant, Gene Expression, General Physics and Astronomy, CD8-Positive T-Lymphocytes, Mice, Liver disease, 0302 clinical medicine, Genes, Reporter, Cytotoxic T cell, Luciferases, lcsh:Science, Mice, Knockout, Sulfonamides, Multidisciplinary, biology, food and beverages, 3. Good health, medicine.anatomical_structure, Liver, Hepatitis, Viral, Animal, Hepatocyte, 030211 gastroenterology & hepatology, Viral hepatitis, Pore Forming Cytotoxic Proteins, Ovalbumin, Science, Green Fluorescent Proteins, Protective Agents, Article, Antibodies, General Biochemistry, Genetics and Molecular Biology, Adenoviridae, 03 medical and health sciences, medicine, Animals, Humans, CD40 Antigens, Fulminant hepatitis, Hepatitis, business.industry, fungi, Endothelial Cells, General Chemistry, medicine.disease, Capillaries, Mice, Inbred C57BL, Disease Models, Animal, Poly I-C, 030104 developmental biology, Perforin, Hepatocytes, biology.protein, Cancer research, lcsh:Q, business
Abstract: CD8 T cells protect the liver against viral infection, but can also cause severe liver damage that may even lead to organ failure. Given the lack of mechanistic insights and specific treatment options in patients with acute fulminant hepatitis, we develop a mouse model reflecting a severe acute virus-induced CD8 T cell-mediated hepatitis. Here we show that antigen-specific CD8 T cells induce liver damage in a perforin-dependent manner, yet liver failure is not caused by effector responses targeting virus-infected hepatocytes alone. Additionally, CD8 T cell mediated elimination of cross-presenting liver sinusoidal endothelial cells causes endothelial damage that leads to a dramatically impaired sinusoidal perfusion and indirectly to hepatocyte death. With the identification of perforin-mediated killing as a critical pathophysiologic mechanism of liver failure and the protective function of a new class of perforin inhibitor, our study opens new potential therapeutic angles for fulminant viral hepatitis., CD8 T cells can protect the liver from viral infection, but can also result in severe liver damage and organ failure. Here, the authors develop a mouse model reflecting fulminant CD8 T cell mediated viral hepatitis, which occurs in a perforin-dependent manner that is protected by the use of perforin inhibitors.
Published: 2018
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9. Substituted arylsulphonamides as inhibitors of perforin-mediated lysis

Author: Joseph A. Trapani, Christian K. Miller, Jagdish K. Jaiswal, Kristiina M. Huttunen, Patrick D. O'Connor, Jiney Jose, William A. Denny, Hedieh Akhlaghi, Julie Ann Spicer, Kylie A. Browne, and School of Pharmacy, Activities
Subjects: 0301 basic medicine, Bioisostere, chemical and pharmacologic phenomena, Jurkat cells, Jurkat Cells, Structure-Activity Relationship, 03 medical and health sciences, 0302 clinical medicine, Immune system, Arylsulphonamide, Drug Discovery, medicine, Humans, Cytotoxicity, Immunosuppressant, Pharmacology, Sulfonamides, Dose-Response Relationship, Drug, Molecular Structure, biology, Perforin, Chemistry, Organic Chemistry, General Medicine, Perforin inhibitor, medicine.disease, 3. Good health, Transplant rejection, Killer Cells, Natural, Granzyme B, 030104 developmental biology, Graft-versus-host disease, Lytic cycle, 030220 oncology & carcinogenesis, Immunology, biology.protein, Cancer research, Research Paper
Abstract: The structure-activity relationships for a series of arylsulphonamide-based inhibitors of the pore-forming protein perforin have been explored. Perforin is a key component of the human immune response, however inappropriate activity has also been implicated in certain auto-immune and therapy-induced conditions such as allograft rejection and graft versus host disease. Since perforin is expressed exclusively by cells of the immune system, inhibition of this protein would be a highly selective strategy for the immunosuppressive treatment of these disorders. Compounds from this series were demonstrated to be potent inhibitors of the lytic action of both isolated recombinant perforin and perforin secreted by natural killer cells in vitro. Several potent and soluble examples were assessed for in vivo pharmacokinetic properties and found to be suitable for progression to an in vivo model of transplant rejection., final draft, peerReviewed
Published: 2017
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10. Benzenesulphonamide inhibitors of the cytolytic protein perforin

Author: William A. Denny, Patrick D. O'Connor, Christian K. Miller, Jagdish K. Jaiswal, Kristiina M. Huttunen, Joseph A. Trapani, Julie Ann Spicer, Kylie A. Browne, Hedieh Akhlaghi, Jiney Jose, and School of Pharmacy, Activities
Subjects: 0301 basic medicine, Bioisostere, Clinical Biochemistry, Pharmaceutical Science, chemical and pharmacologic phenomena, Biochemistry, Article, 03 medical and health sciences, Structure-Activity Relationship, 0302 clinical medicine, In vivo, Immunity, Cell Line, Tumor, Benzenesulphonamide, Drug Discovery, medicine, Structure–activity relationship, Humans, Secretion, Molecular Biology, ComputingMethodologies_COMPUTERGRAPHICS, Immunosuppressant, Sulfonamides, biology, Chemistry, Perforin, Organic Chemistry, medicine.disease, Perforin inhibitor, 3. Good health, Killer Cells, Natural, 030104 developmental biology, Graft-versus-host disease, Granzyme, Solubility, Cell culture, 030220 oncology & carcinogenesis, biology.protein, Cancer research, Molecular Medicine, Immunosuppressive Agents
Abstract: The pore-forming protein perforin is a key component of mammalian cell-mediated immunity and essential to the pathway that allows elimination of virus-infected and transformed cells. Perforin activity has also been implicated in certain auto-immune conditions and therapy-induced conditions such as allograft rejection and graft versus host disease. An inhibitor of perforin activity could be used as a highly specific immunosuppressive treatment for these conditions, with reduced side-effects compared to currently accepted therapies. Previously identified first-in-class inhibitors based on a 2-thioxoimidazolidin-4-one core show suboptimal physicochemical properties and toxicity toward the natural killer (NK) cells that secrete perforin in vivo. The current benzenesulphonamide-based series delivers a non-toxic bioisosteric replacement possessing improved solubility., published version, peerReviewed
Published: 2017
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11. Tyrosine Kinase Inhibitors. 20. Optimization of Substituted Quinazoline and Pyrido[3,4-d]pyrimidine Derivatives as Orally Active, Irreversible Inhibitors of the Epidermal Growth Factor Receptor Family

Author: Patricia J. Harvey, Gonzales Andrea, Shannon Leigh Black, Jeff B. Smaill, Ken Hook, Florence O. McCarthy, Stephen Fakhoury, Adrian Blaser, Haile Tecle, Freddy Rivault, Tong Zhu, Brian D. Palmer, Kevin Matthew Schlosser, Jessica Elizabeth Reed, Karen Elaine Sexton, William A. Denny, Irene W. Althaus, R. Thomas Winters, Teresa Ellis, Helen Tsenwhei Lee, Andrew M. Thompson, Erin Trachet, Alexander James Bridges, Julie Ann Spicer, and Paul A. Ellis
Subjects: Male, 0301 basic medicine, Pyrimidine, Pyridines, Stereochemistry, Morpholines, Administration, Oral, Mice, Nude, Antineoplastic Agents, Stereoisomerism, Rats, Sprague-Dawley, Structure-Activity Relationship, 03 medical and health sciences, chemistry.chemical_compound, Dogs, 0302 clinical medicine, In vivo, Drug Discovery, Quinazoline, Animals, Humans, Structure–activity relationship, Phosphorylation, skin and connective tissue diseases, Quinazolinones, Canertinib, Chemistry, Autophosphorylation, ErbB Receptors, Macaca fascicularis, Pyrimidines, 030104 developmental biology, 030220 oncology & carcinogenesis, Injections, Intravenous, Quinazolines, Heterografts, Molecular Medicine, Tyrosine kinase, Neoplasm Transplantation
Abstract: Structure-activity relationships for inhibition of erbB1, erbB2, and erbB4 were determined for a series of quinazoline- and pyrido[3,4-d]pyrimidine-based analogues of the irreversible pan-erbB inhibitor, canertinib. Cyclic amine bearing crotonamides were determined to provide rapid inhibition of cellular erbB1 autophosphorylation and good metabolic stability in liver microsome and hepatocyte assays. The influence of 4-anilino substitution on pan-erbB inhibitory potency was investigated. Several anilines were identified as providing potent, reversible pan-erbB inhibition. Optimum 4- and 6-substituents with known 7-substituents provided preferred irreversible inhibitors for pharmacodynamic testing in vivo. Quinazoline 54 and pyrido[3,4-d]pyrimidine 71 were identified as clearly superior to canertinib. Both compounds possess a piperidinyl crotonamide Michael acceptor and a 3-chloro-4-fluoroaniline, indicating these as optimized 6- and 4-substituents, respectively. Pharmacokinetic comparison of compounds 54 and 71 across three species selected compound 54 as the preferred candidate. Compound 54 (PF-00299804) has been assigned the nomenclature of dacomitinib and is currently under clinical evaluation.
Published: 2016
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12. Systemic and Brain Pharmacokinetics of Perforin Inhibitor Prodrugs

Author: Julie Ann Spicer, William A. Denny, Kristiina M. Huttunen, Darryl S. Pickering, and Mikko Gynther
Subjects: Male, Xylazine, 0301 basic medicine, Pharmaceutical Science, Pharmacology, Blood–brain barrier, Mass Spectrometry, Mice, 03 medical and health sciences, Pharmacokinetics, Pregnancy, In vivo, Drug Discovery, medicine, Animals, Prodrugs, Cells, Cultured, Chromatography, High Pressure Liquid, Neurons, biology, Perforin, Chemistry, Brain, Biological Transport, Transporter, Prodrug, 3. Good health, Probenecid, 030104 developmental biology, medicine.anatomical_structure, Blood-Brain Barrier, Astrocytes, biology.protein, Molecular Medicine, Female, Ketamine, Chromatography, Liquid, medicine.drug, Organic anion
Abstract: We have recently reported that by converting a perforin inhibitor into an l-type amino acid transporter 1 (LAT1)-utilizing prodrug its cellular uptake can be greatly increased. The aim of the present study was to determine the in vivo and brain pharmacokinetics of two perforin inhibitors and their LAT1-utilizing prodrugs 1 and 2. In addition, the brain uptake mechanism and entry into primary mouse cortical neurons and astrocytes were evaluated. After 23 μmol/kg i.p. bolus injection, the prodrugs' unbound area under the concentration curve in brain was 0.3 nmol/g × min, whereas the parent drugs could not reach the brain. The unbound brain concentrations of the prodrugs after 100 μM in situ mouse brain perfusion were 521.4 ± 46.9 and 126.9 ± 19.9 pmol/g for prodrugs 1 and 2, respectively. The combination of competing transporter substrates for LAT1, l-tryptophan, and for organic anion transporting polypeptides, probenecid, decreased the brain concentrations to 352.4 ± 44.5 and 70.9 ± 7.0 pmol/g, respectively. In addition, in vitro uptake studies showed that at 100 μM prodrug 1 had 3.4-fold and 4.5-fold higher uptake rate into neurons and astrocytes, respectively, compared to its parent drug. Thus, the prodrugs enhance significantly the therapeutic potential of the parent drugs for the treatment of disorders of central nervous system in which neuroinflammation is involved.
Published: 2016
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13. A Selective and Slowly Reversible Inhibitor of <scp>l</scp>-Type Amino Acid Transporter 1 (LAT1) Potentiates Antiproliferative Drug Efficacy in Cancer Cells

Author: Kristiina M. Huttunen, Elena Puris, William A. Denny, Julie Ann Spicer, Johanna Huttunen, and Mikko Gynther
Subjects: Male, 0301 basic medicine, Cell Survival, Pyridines, medicine.medical_treatment, Intraperitoneal injection, Cell, Antineoplastic Agents, Large Neutral Amino Acid-Transporter 1, Pharmacology, Mice, Structure-Activity Relationship, 03 medical and health sciences, 0302 clinical medicine, Drug Discovery, medicine, Animals, Humans, Structure–activity relationship, Cell Proliferation, Cisplatin, Dose-Response Relationship, Drug, Molecular Structure, Cell growth, Chemistry, Imidazoles, Prostatic Neoplasms, Transporter, 030104 developmental biology, medicine.anatomical_structure, Biochemistry, 030220 oncology & carcinogenesis, Cancer cell, MCF-7 Cells, Molecular Medicine, Drug Screening Assays, Antitumor, medicine.drug
Abstract: The l-type amino acid transporter 1 (LAT1) is a transmembrane protein carrying bulky and neutral amino acids into cells. LAT1 is overexpressed in several types of tumors, and its inhibition can result in reduced cancer cell growth. However, known LAT1 inhibitors lack selectivity over other transporters. In the present study, we designed and synthesized a novel selective LAT1 inhibitor (1), which inhibited the uptake of LAT1 substrate, l-leucin as well as cell growth. It also significantly potentiated the efficacy of bestatin and cisplatin even at low concentrations (25 μM). Inhibition was slowly reversible, as the inhibitor was able to be detached from the cell surface and blood-brain barrier. Moreover, the inhibitor was metabolically stable and selective toward LAT1. Since the inhibitor was readily accumulated into the prostate after intraperitoneal injection to the healthy mice, this compound may be a promising agent or adjuvant especially for the treatment of prostate cancer.
Published: 2016
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14. l -Type amino acid transporter 1 (lat1)-mediated targeted delivery of perforin inhibitors

Author: William A. Denny, Mikko Gynther, Kristiina M. Huttunen, Imke Aufderhaar, Johanna Huttunen, and Julie Ann Spicer
Subjects: 0301 basic medicine, Pharmaceutical Science, chemical and pharmacologic phenomena, Biology, Large Neutral Amino Acid-Transporter 1, 03 medical and health sciences, Drug Delivery Systems, 0302 clinical medicine, Immune system, Animals, Humans, Cytotoxic T cell, Prodrugs, Amino acid transporter, Dose-Response Relationship, Drug, Perforin, Effector, Prodrug, Rats, Cell biology, Cytolysis, 030104 developmental biology, Biochemistry, Targeted drug delivery, 030220 oncology & carcinogenesis, MCF-7 Cells, biology.protein
Abstract: Perforin is a cytolytic pore-forming glycoprotein secreted by cytotoxic effector cells. It is a key component of the immune response against virus-infected and transformed cells and has been implicated in a number of human diseases. Perforin activity can be inhibited by small-molecular-weight compounds, although less is known about their delivery to the site of action. Therefore, in the present study, it was explored if perforin inhibitors could be efficiently and site-selectively delivered firstly into the cytotoxic effector cells and secondly into lytic granules, in which perforin is stored. This was accomplished by designing and synthesizing four prodrugs of perforin inhibitors that could utilize l-type amino acid transporter (LAT1), since activated immune cells are known to over-express LAT1. The results demonstrate that cellular uptake of perforin inhibitors can be increased by LAT1-utilizing prodrugs (into human breast adenocarcinoma cells (MCF-7)). Furthermore, these prodrugs were also able to deliver perforin inhibitors into the cell organelles having lower pH (rat liver lysosomes). Therefore, by using these prodrugs, intracellular mechanisms of perforin inhibitory activity can be studied more thoroughly in future. Moreover, this prodrug approach can be applied for other drugs that would benefit from targeted delivery into cells expressing LAT1, such as cancer.
Published: 2016
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15. Diarylthiophenes as inhibitors of the pore-forming protein perforin

Author: Joseph A. Trapani, Christian K. Miller, Jagdish K. Jaiswal, Kristiina M. Huttunen, Annette Ciccone, Kylie A. Browne, Julie Ann Spicer, and William A. Denny
Subjects: 0301 basic medicine, Bioisostere, Clinical Biochemistry, Pharmaceutical Science, Carboxamide, DMSO, dimethyl sulfoxide, Biochemistry, Pore forming protein, chemistry.chemical_compound, DCC, N,N′-dicyclohexylcarbodiimide, Drug Discovery, Immunosuppressant, biology, SAR, structure–activity relationships, PFP, pentafluorophenyl, HTS, high-throughput screen, EDCI, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, 3. Good health, Killer Cells, Natural, PAINS, pan-assay interference compounds, Lytic cycle, Molecular Medicine, DMF, dimethylformamide, THF, tetrahydrofuran, PRF, perforin, medicine.drug_class, Thiophenes, CTL, cytotoxic T lymphocytes, Article, NK, natural killer cells, 03 medical and health sciences, Structure-Activity Relationship, KF, potassium fluoride, medicine, AgNO3, silver(I) nitrate, Structure–activity relationship, Humans, KOAc, potassium acetate, Molecular Biology, ComputingMethodologies_COMPUTERGRAPHICS, Benzofurans, Perforin, Organic Chemistry, Perforin inhibitor, Diarylthiophene, In vitro, CTL, 030104 developmental biology, chemistry, biology.protein, HOBt, hydroxybenzotriazole
Abstract: Graphical abstract, Evolution from a furan-containing high-throughput screen (HTS) hit (1) resulted in isobenzofuran-1(3H)-one (2) as a potent inhibitor of the function of both isolated perforin protein and perforin delivered in situ by intact KHYG-1 NK cells. In the current study, structure–activity relationship (SAR) development towards a novel series of diarylthiophene analogues has continued through the use of substituted-benzene and -pyridyl moieties as bioisosteres for 2-thioxoimidazolidin-4-one (A) on a thiophene (B) -isobenzofuranone (C) scaffold. The resulting compounds were tested for their ability to inhibit perforin lytic activity in vitro. Carboxamide (23) shows a 4-fold increase over (2) in lytic activity against isolated perforin and provides good rationale for continued development within this class.
Published: 2016

16. Pretreatment prediction of response to ursodeoxycholic acid in primary biliary cholangitis: development and validation of the UDCA Response Score

Author: Marco Carbone, Alessandra Nardi, Steve Flack, Guido Carpino, Nikoletta Varvaropoulou, Caius Gavrila, Ann Spicer, Jonathan Badrock, Francesca Bernuzzi, Vincenzo Cardinale, Holly F Ainsworth, Michael A Heneghan, Douglas Thorburn, Andrew Bathgate, Rebecca Jones, James M Neuberger, Pier Maria Battezzati, Massimo Zuin, Simon Taylor-Robinson, Maria F Donato, John Kirby, Robert Mitchell-Thain, Annarosa Floreani, Fotios Sampaziotis, Luigi Muratori, Domenico Alvaro, Marco Marzioni, Luca Miele, Fabio Marra, Edoardo Giannini, Eugenio Gaudio, Vincenzo Ronca, Giulia Bonato, Laura Cristoferi, Federica Malinverno, Alessio Gerussi, Deborah D Stocken, Heather J Cordell, Gideon M Hirschfield, Graeme J Alexander, Richard N Sandford, David E Jones, Pietro Invernizzi, George F Mells, Caradog Thomas, Meshbah Rahman, Tom Yapp, Chin Lye Ch'ng, Melanie Harrison, Richard Sturgess, Roman Galaska, Chris Healey, Jessica Whiteman, Marek Czaijkowski, Catherine Gray, Anton Gunasekera, Pranab Gyawli, Purushothaman Premchand, Steven Mann, Keith Elliott, Kapil Kapur, Alan Watson, Graham Foster, Paul Trembling, Javaid Subhani, Rory Harvey, Roger McCorry, Carolyn Adgey, Lucie Hobson, Caroline Mulvaney-Jones, Richard Evans, Thiriloganathan Mathialahan, David Ramanaden, Jaber Gasem, Greta Van Duyvenvoorde, Christopher Shorrock, Katie Seward, Paul Southern, Jeremy Tibble, Ruth Penn, David Gorard, Jane Maiden, Rose Damant, Altaf Palegwala, Susan Jones, Graeme Alexander, George Mells, Richard Sandford, Sunil Dolwani, Martin Prince, Valeria Silvestre, Matthew Foxton, Eleanor Dungca, Harriet Mitchison, Natalie Wheatley, Ian Gooding, Helen Doyle, Mazn Karmo, Melanie Kent, Sushma Saksena, Delyth Braim, Minesh Patel, Susan Lord, Roland Ede, Alison Paton, Andrew Austin, Nicola Lancaster, Joanna Sayer, Andrew Gibbins, Karen Hogben, Chris Hovell, Neil Fisher, Martyn Carter, Konrad Koss, Janine Musselwhite, Florin Muscariu, Andrzej Piotreowicz, Alexandra McKay, Charles Grimley, David Neal, Lai Ting Tan, Guan Lim, Jacqueline Brighton, Carole Foale, Aftab Ala, Athar Saeed, Kerry Flahive, Gordon Wood, Paula Townshend, Chris Ford, Jonathan Brown, Jean Kordula, Jane Bowles, Mark Wilkinson, Caroline Palmer, John Ramage, Harriet Gordon, James Featherstone, Jo Ridpath, Theodore Ngatchu, Sass Levi, Syed Shaukat, Joy Sadeghian, Ray Shidrawi, Bronwen Williams, George Abouda, Sarah Jones, Claire Duggan, Abigail Hynes, Mark Narain, Ian Rees, Imroz Salam, Mary Crossey, Ashley Brown, Carolyn MacNicol, Simon Williams, Elva Wilhelmsen, Paul Banim, Parizade Raymode, Andrew Chilton, Debasish Das, Hye-Jeong Lee, Howard Curtis, Michael Heneghan, Markus Gess, Emma Durant, IM Drake, Rebecca Bishop, Mervyn Davies, Mark Aldersley, Noma Ncube, Alistair McNair, Raj Srirajaskanthan, Sambit Sen, Rebecca Casey, George Bird, Mike Mendall, Caroline Cowley, Adrian Barnardo, Paul Kitchen, Kevin Yoong, Kelly Amore, Dawn Sirdefield, Jacky Orpe, Ray Mathew, George MacFaul, Aruna Wrigth, Amir Shah, Chris Evans, Janie Keggans, Bridget Bird, Gwen Baxter, Subrata Saha, Katharine Pollock, Maggie Hughes, Peter Bramley, Emma Grieve, Karin Young, Andrew Fraser, Ashis Mukhopadhya, Kate Ocker, Peter Mills, Francis Hines, Chris Shallcross, Joy Wilkins, Leonie Grellier, Stewart Campbell, Kirsty Martin, Caron Innes, Alan Shepherd, Simon Rushbrook, Talal Valliani, Robert Przemioslo, Helen Fairlamb, Chris Macdonald, Anne Eastick, Jane Metcalf, Elizabeth Tanqueray, Udi Shmueli, Becky Holbrook, Andrew Davis, Julie Browning, Asifabbas Naqvi, Kirsten Walker, Tom Lee, Juliette Verheyden, Susan Slininger, Stephen D Ryder, Roger Chapman, Jane Collier, Denise O'Donnell, Lizzie Stafford, Kate Williamson, Linda Kent, Howard Klass, Mary Ninkovic, Linda March, Matthew Cramp, Diane Simpson, Christine Dickson, Nicholas Sharer, Maria Hayes, Patrick Goggin, Mary Quinne, Sallyanne Pearson, Barbara Hoeroldt, Linda Jones, Alice Wright, Jonathan Booth, Alison Loftus, George Lipscomb, Hannah Dewhurst, Emma Gunter, Earl Williams, Anna Fouracres, Liz Farrington, Lyn Graves, Hyder Hussaini, Bill Stableforth, Suzie Marriott, Reuben Ayres, Marina Leoni, Andrew Burroughs, Eileen Marshall, David Tyrer, Kate Martin, Martin Lombard, Imran Patanwala, Lola Dali-Kemmery, Victoria Lambourne, Julia Maltby, Samir Vyas, Julie Colley, Bal Shinder, Saket Singhal, Jayne Jones, Marisa Mills, Dermot Gleeson, Mandy Carnahan, Jeff Butterworth, Kerenza Boulton, Natalie Taylor, Keith George, Tim Harding, Julie Tregonning, Andrew Douglass, Carly Brown, Gayle Clifford, Simon Panter, Denise Gocher, Jeremy Shearman, Gary Bray, Maria Hamilton, Graham Butcher, Daniel Forton, John Mclindon, Janette Curtis, Debashis Das, Tracey Shewan, Matthew Cowan, Gregory Whatley, Mariam Nasseri, Bob Grover, Nurani Sivaramakrishnan, Samantha Ducker, Kathryn Houghton, David Jones, Laura Griffiths, Sherill Tripoli, Maxton Pitcher, Ervin Shpuza, Nikki White, Deb Ghosh, Andrew Douds, Marie Green, Matthew Brookes, Lourdes Cumlat, Voi Shim Wong, Karen Warner, Kimberley Netherton, Adtya Mandal, Snjiv Jain, Hemant Gupta, Pradeep Sanghi, Steve Pereira, James Neuberger, Bridget Gunson, Gideon Hirschfield, Reina Teegan Lim, Susan Gallagher, Darren Clement, Alison Brind, Gill Watts, Mcdonald Mupudzi, Mark Wright, Jane Gitahi, Fiona Gordon, Denis Gocher, Esther Unitt, Hilary Pateman, Sally Batham, Toby Delahooke, Allister Grant, Jill Conder, Andrew Higham, Mark Cox, Lynn O'Donohoe, Lynn Currie, Alistair King, Metod Oblak, Carole Collins, Simon Whalley, Marie Quinn, Yolanda Baird, Isobel Amey, Jocelyn Fraser, Andy Li, Donna Cotterill, Andrew Bell, Amit Singhal, Ian Gee, Sandra Greer, Yeng Ang, Rupert Ransford, Joanna Allison, James Gotto, Simon Dyer, Helen Sweeting, Charles Millson, Giancarlo Labbadia, Maria Consiglia Bragazzi, Pietro Andreone, Francesco Azzaroli, Andrea Galli, Mirko Tarocchi, Antonio Gasbarrini, Antonio Grieco, Giuseppe Marrone, Maria Francesca Donato, Luca Valenti, Luca Maroni, Cristina Rigamonti, Antonino Picciotto, Carbone, M, Nardi, A, Flack, S, Carpino, G, Varvaropoulou, N, Gavrila, C, Spicer, A, Badrock, J, Bernuzzi, F, Cardinale, V, Ainsworth, H, Heneghan, M, Thorburn, D, Bathgate, A, Jones, R, Neuberger, J, Battezzati, P, Zuin, M, Taylor-Robinson, S, Donato, M, Kirby, J, Mitchell-Thain, R, Floreani, A, Sampaziotis, F, Muratori, L, Alvaro, D, Marzioni, M, Miele, L, Marra, F, Giannini, E, Gaudio, E, Ronca, V, Bonato, G, Cristoferi, L, Malinverno, F, Gerussi, A, Stocken, D, Cordell, H, Hirschfield, G, Alexander, G, Sandford, R, Jones, D, Invernizzi, P, Mells, G, Thomas, C, Rahman, M, Yapp, T, Lye Ch'ng, C, Harrison, M, Sturgess, R, Galaska, R, Healey, C, Whiteman, J, Czaijkowski, M, Gray, C, Gunasekera, A, Gyawli, P, Premchand, P, Mann, S, Elliott, K, Kapur, K, Watson, A, Foster, G, Trembling, P, Subhani, J, Harvey, R, Mccorry, R, Adgey, C, Hobson, L, Mulvaney-Jones, C, Evans, R, Mathialahan, T, Ramanaden, D, Gasem, J, Van Duyvenvoorde, G, Shorrock, C, Seward, K, Southern, P, Tibble, J, Penn, R, Gorard, D, Maiden, J, Damant, R, Palegwala, A, Jones, S, Dolwani, S, Prince, M, Silvestre, V, Foxton, M, Dungca, E, Mitchison, H, Wheatley, N, Gooding, I, Doyle, H, Karmo, M, Kent, M, Saksena, S, Braim, D, Patel, M, Lord, S, Ede, R, Paton, A, Austin, A, Lancaster, N, Sayer, J, Gibbins, A, Hogben, K, Hovell, C, Fisher, N, Carter, M, Koss, K, Musselwhite, J, Muscariu, F, Piotreowicz, A, Mckay, A, Grimley, C, Neal, D, Ting Tan, L, Lim, G, Brighton, J, Foale, C, Ala, A, Saeed, A, Flahive, K, Wood, G, Townshend, P, Ford, C, Brown, J, Kordula, J, Bowles, J, Wilkinson, M, Palmer, C, Ramage, J, Gordon, H, Featherstone, J, Ridpath, J, Ngatchu, T, Levi, S, Shaukat, S, Sadeghian, J, Shidrawi, R, Williams, B, Abouda, G, Duggan, C, Hynes, A, Narain, M, Rees, I, Salam, I, Crossey, M, Brown, A, Macnicol, C, Williams, S, Wilhelmsen, E, Banim, P, Raymode, P, Chilton, A, Das, D, Lee, H, Curtis, H, Gess, M, Durant, E, Drake, I, Bishop, R, Davies, M, Aldersley, M, Ncube, N, Mcnair, A, Srirajaskanthan, R, Sen, S, Casey, R, Bird, G, Mendall, M, Cowley, C, Barnardo, A, Kitchen, P, Yoong, K, Amore, K, Sirdefield, D, Orpe, J, Mathew, R, Macfaul, G, Wrigth, A, Shah, A, Evans, C, Keggans, J, Bird, B, Baxter, G, Saha, S, Pollock, K, Hughes, M, Bramley, P, Grieve, E, Young, K, Fraser, A, Mukhopadhya, A, Ocker, K, Mills, P, Hines, F, Shallcross, C, Wilkins, J, Grellier, L, Campbell, S, Martin, K, Innes, C, Shepherd, A, Rushbrook, S, Valliani, T, Przemioslo, R, Fairlamb, H, Macdonald, C, Eastick, A, Metcalf, J, Tanqueray, E, Shmueli, U, Holbrook, B, Davis, A, Browning, J, Naqvi, A, Walker, K, Lee, T, Verheyden, J, Slininger, S, Ryder, S, Chapman, R, Collier, J, O'Donnell, D, Stafford, L, Williamson, K, Kent, L, Klass, H, Ninkovic, M, March, L, Cramp, M, Simpson, D, Dickson, C, Sharer, N, Hayes, M, Goggin, P, Quinne, M, Pearson, S, Hoeroldt, B, Jones, L, Wright, A, Booth, J, Loftus, A, Lipscomb, G, Dewhurst, H, Gunter, E, Williams, E, Fouracres, A, Farrington, L, Graves, L, Hussaini, H, Stableforth, B, Marriott, S, Ayres, R, Leoni, M, Burroughs, A, Marshall, E, Tyrer, D, Lombard, M, Patanwala, I, Dali-Kemmery, L, Lambourne, V, Maltby, J, Vyas, S, Colley, J, Shinder, B, Singhal, S, Jones, J, Mills, M, Gleeson, D, Carnahan, M, Butterworth, J, Boulton, K, Taylor, N, George, K, Harding, T, Tregonning, J, Douglass, A, Brown, C, Clifford, G, Panter, S, Gocher, D, Shearman, J, Bray, G, Hamilton, M, Butcher, G, Forton, D, Mclindon, J, Curtis, J, Shewan, T, Cowan, M, Whatley, G, Nasseri, M, Grover, B, Sivaramakrishnan, N, Ducker, S, Houghton, K, Griffiths, L, Tripoli, S, Pitcher, M, Shpuza, E, White, N, Ghosh, D, Douds, A, Green, M, Brookes, M, Cumlat, L, Wong, V, Warner, K, Netherton, K, Mandal, A, Jain, S, Gupta, H, Sanghi, P, Pereira, S, Gunson, B, Lim, R, Gallagher, S, Clement, D, Brind, A, Watts, G, Mupudzi, M, Wright, M, Gitahi, J, Gordon, F, Unitt, E, Pateman, H, Batham, S, Delahooke, T, Grant, A, Conder, J, Higham, A, Cox, M, O'Donohoe, L, Currie, L, King, A, Oblak, M, Collins, C, Whalley, S, Quinn, M, Baird, Y, Amey, I, Fraser, J, Li, A, Cotterill, D, Bell, A, Singhal, A, Gee, I, Greer, S, Ang, Y, Ransford, R, Allison, J, Gotto, J, Dyer, S, Sweeting, H, Millson, C, Labbadia, G, Bragazzi, M, Andreone, P, Azzaroli, F, Galli, A, Tarocchi, M, Gasbarrini, A, Grieco, A, Marrone, G, Valenti, L, Maroni, L, Rigamonti, C, Picciotto, A, Sampaziotis, Fotios [0000-0003-0812-7586], Sandford, Richard [0000-0002-7437-0560], Apollo - University of Cambridge Repository, Carbone, Marco, Nardi, Alessandra, Flack, Steve, Carpino, Guido, Varvaropoulou, Nikoletta, Gavrila, Caiu, Spicer, Ann, Badrock, Jonathan, Bernuzzi, Francesca, Cardinale, Vincenzo, Ainsworth, Holly F, Heneghan, Michael A, Thorburn, Dougla, Bathgate, Andrew, Jones, Rebecca, Neuberger, James M, Battezzati, Pier Maria, Zuin, Massimo, Taylor-Robinson, Simon, Donato, Maria F, Kirby, John, Mitchell-Thain, Robert, Floreani, Annarosa, Sampaziotis, Fotio, Muratori, Luigi, Alvaro, Domenico, Marzioni, Marco, Miele, Luca, Marra, Fabio, Giannini, Edoardo, Gaudio, Eugenio, Ronca, Vincenzo, Bonato, Giulia, Cristoferi, Laura, Malinverno, Federica, Gerussi, Alessio, Stocken, Deborah D, Cordell, Heather J, Hirschfield, Gideon M, Alexander, Graeme J, Sandford, Richard N, Jones, David E, Invernizzi, Pietro, Mells, George F, Thomas, Caradog, Rahman, Meshbah, Yapp, Tom, Lye Ch'ng, Chin, Harrison, Melanie, Sturgess, Richard, Galaska, Roman, Healey, Chri, Whiteman, Jessica, Czaijkowski, Marek, Gray, Catherine, Gunasekera, Anton, Gyawli, Pranab, Premchand, Purushothaman, Mann, Steven, Elliott, Keith, Kapur, Kapil, Watson, Alan, Foster, Graham, Trembling, Paul, Subhani, Javaid, Harvey, Rory, McCorry, Roger, Adgey, Carolyn, Hobson, Lucie, Mulvaney-Jones, Caroline, Evans, Richard, Mathialahan, Thiriloganathan, Ramanaden, David, Gasem, Jaber, Van Duyvenvoorde, Greta, Shorrock, Christopher, Seward, Katie, Southern, Paul, Tibble, Jeremy, Penn, Ruth, Gorard, David, Maiden, Jane, Damant, Rose, Palegwala, Altaf, Jones, Susan, Alexander, Graeme, Mells, George, Sandford, Richard, Dolwani, Sunil, Prince, Martin, Silvestre, Valeria, Foxton, Matthew, Dungca, Eleanor, Mitchison, Harriet, Wheatley, Natalie, Gooding, Ian, Doyle, Helen, Karmo, Mazn, Kent, Melanie, Saksena, Sushma, Braim, Delyth, Patel, Minesh, Lord, Susan, Ede, Roland, Paton, Alison, Austin, Andrew, Lancaster, Nicola, Sayer, Joanna, Gibbins, Andrew, Hogben, Karen, Hovell, Chri, Fisher, Neil, Carter, Martyn, Koss, Konrad, Musselwhite, Janine, Muscariu, Florin, Piotreowicz, Andrzej, McKay, Alexandra, Grimley, Charle, Neal, David, Ting Tan, Lai, Lim, Guan, Brighton, Jacqueline, Foale, Carole, Ala, Aftab, Saeed, Athar, Flahive, Kerry, Wood, Gordon, Townshend, Paula, Ford, Chri, Brown, Jonathan, Kordula, Jean, Bowles, Jane, Wilkinson, Mark, Palmer, Caroline, Ramage, John, Gordon, Harriet, Featherstone, Jame, Ridpath, Jo, Ngatchu, Theodore, Levi, Sa, Shaukat, Syed, Sadeghian, Joy, Shidrawi, Ray, Williams, Bronwen, Abouda, George, Jones, Sarah, Duggan, Claire, Hynes, Abigail, Narain, Mark, Rees, Ian, Salam, Imroz, Crossey, Mary, Brown, Ashley, MacNicol, Carolyn, Williams, Simon, Wilhelmsen, Elva, Banim, Paul, Raymode, Parizade, Chilton, Andrew, Das, Debasish, Lee, Hye-Jeong, Curtis, Howard, Heneghan, Michael, Gess, Marku, Durant, Emma, Drake, I.M., Bishop, Rebecca, Davies, Mervyn, Aldersley, Mark, Ncube, Noma, McNair, Alistair, Srirajaskanthan, Raj, Sen, Sambit, Casey, Rebecca, Bird, George, Mendall, Mike, Cowley, Caroline, Barnardo, Adrian, Kitchen, Paul, Yoong, Kevin, Amore, Kelly, Sirdefield, Dawn, Orpe, Jacky, Mathew, Ray, MacFaul, George, Wrigth, Aruna, Shah, Amir, Evans, Chri, Keggans, Janie, Bird, Bridget, Baxter, Gwen, Saha, Subrata, Pollock, Katharine, Hughes, Maggie, Bramley, Peter, Grieve, Emma, Young, Karin, Fraser, Andrew, Mukhopadhya, Ashi, Ocker, Kate, Mills, Peter, Hines, Franci, Shallcross, Chri, Wilkins, Joy, Grellier, Leonie, Campbell, Stewart, Martin, Kirsty, Innes, Caron, Shepherd, Alan, Rushbrook, Simon, Valliani, Talal, Przemioslo, Robert, Fairlamb, Helen, Macdonald, Chri, Eastick, Anne, Metcalf, Jane, Tanqueray, Elizabeth, Shmueli, Udi, Holbrook, Becky, Davis, Andrew, Browning, Julie, Naqvi, Asifabba, Walker, Kirsten, Lee, Tom, Verheyden, Juliette, Slininger, Susan, Ryder, Stephen D, Chapman, Roger, Collier, Jane, O'Donnell, Denise, Stafford, Lizzie, Williamson, Kate, Kent, Linda, Klass, Howard, Ninkovic, Mary, March, Linda, Cramp, Matthew, Simpson, Diane, Dickson, Christine, Sharer, Nichola, Hayes, Maria, Goggin, Patrick, Quinne, Mary, Pearson, Sallyanne, Hoeroldt, Barbara, Jones, Linda, Wright, Alice, Booth, Jonathan, Loftus, Alison, Lipscomb, George, Dewhurst, Hannah, Gunter, Emma, Williams, Earl, Fouracres, Anna, Farrington, Liz, Graves, Lyn, Hussaini, Hyder, Stableforth, Bill, Marriott, Suzie, Ayres, Reuben, Leoni, Marina, Burroughs, Andrew, Marshall, Eileen, Tyrer, David, Martin, Kate, Lombard, Martin, Patanwala, Imran, Dali-Kemmery, Lola, Lambourne, Victoria, Maltby, Julia, Vyas, Samir, Colley, Julie, Shinder, Bal, Singhal, Saket, Jones, Jayne, Mills, Marisa, Gleeson, Dermot, Carnahan, Mandy, Butterworth, Jeff, Boulton, Kerenza, Taylor, Natalie, George, Keith, Harding, Tim, Tregonning, Julie, Douglass, Andrew, Brown, Carly, Clifford, Gayle, Panter, Simon, Gocher, Denise, Shearman, Jeremy, Bray, Gary, Hamilton, Maria, Butcher, Graham, Forton, Daniel, Mclindon, John, Curtis, Janette, Das, Debashi, Shewan, Tracey, Cowan, Matthew, Whatley, Gregory, Nasseri, Mariam, Grover, Bob, Sivaramakrishnan, Nurani, Ducker, Samantha, Houghton, Kathryn, Jones, David, Griffiths, Laura, Tripoli, Sherill, Pitcher, Maxton, Shpuza, Ervin, White, Nikki, Ghosh, Deb, Douds, Andrew, Green, Marie, Brookes, Matthew, Cumlat, Lourde, Wong, Voi Shim, Warner, Karen, Netherton, Kimberley, Mandal, Adtya, Jain, Snjiv, Gupta, Hemant, Sanghi, Pradeep, Pereira, Steve, Neuberger, Jame, Gunson, Bridget, Hirschfield, Gideon, Lim, Reina Teegan, Gallagher, Susan, Clement, Darren, Brind, Alison, Watts, Gill, Mupudzi, Mcdonald, Wright, Mark, Gitahi, Jane, Gordon, Fiona, Gocher, Deni, Unitt, Esther, Pateman, Hilary, Batham, Sally, Delahooke, Toby, Grant, Allister, Conder, Jill, Higham, Andrew, Cox, Mark, O'Donohoe, Lynn, Currie, Lynn, King, Alistair, Oblak, Metod, Collins, Carole, Whalley, Simon, Quinn, Marie, Baird, Yolanda, Amey, Isobel, Fraser, Jocelyn, Li, Andy, Cotterill, Donna, Bell, Andrew, Singhal, Amit, Gee, Ian, Greer, Sandra, Ang, Yeng, Ransford, Rupert, Allison, Joanna, Gotto, Jame, Dyer, Simon, Sweeting, Helen, Millson, Charle, Labbadia, Giancarlo, Bragazzi, Maria Consiglia, Andreone, Pietro, Azzaroli, Francesco, Galli, Andrea, Tarocchi, Mirko, Gasbarrini, Antonio, Grieco, Antonio, Marrone, Giuseppe, Donato, Maria Francesca, Valenti, Luca, Maroni, Luca, Rigamonti, Cristina, Picciotto, Antonino, and Medical Research Council (MRC)
Subjects: Male, Cholagogues and Choleretics, Cirrhosis, medicine.medical_treatment, PROGRESSION, Liver transplantation, PHENOTYPE, Gastroenterology, UDCA, 0302 clinical medicine, Primary biliary cirrhosis, Risk Factors, Medicine, Age of Onset, CIRRHOSIS, TREE, OUTCOMES, Settore MED/12 - Gastroenterologia, medicine.diagnostic_test, Liver Cirrhosis, Biliary, Ursodeoxycholic Acid, Area under the curve, URSODIOL, Middle Aged, Ursodeoxycholic acid, Treatment Outcome, Primary biliary cholangitis, ursodeoxycholic acid, 030220 oncology & carcinogenesis, Liver biopsy, Area Under Curve, 030211 gastroenterology & hepatology, Female, Life Sciences & Biomedicine, medicine.drug, medicine.medical_specialty, CONTROLLED-TRIAL, Hepatology, Decision Support Techniques, Time-to-Treatment, Biliary injury, 03 medical and health sciences, Internal medicine, Humans, Transaminases, Science & Technology, Gastroenterology & Hepatology, Italian PBC Study Group and the UK–PBC Consortium, business.industry, Bilirubin, medicine.disease, Alkaline Phosphatase, ROC Curve, CELLS, Linear Models, business
Abstract: Background: Treatment guidelines recommend a stepwise approach to primary biliary cholangitis: all patients begin treatment with ursodeoxycholic acid (UDCA) monotherapy and those with an inadequate biochemical response after 12 months are subsequently considered for second-line therapies. However, as a result, patients at the highest risk can wait the longest for effective treatment. We determined whether UDCA response can be accurately predicted using pretreatment clinical parameters. Methods: We did logistic regression analysis of pretreatment variables in a discovery cohort of patients in the UK with primary biliary cholangitis to derive the best-fitting model of UDCA response, defined as alkaline phosphatase less than 1Â·67 times the upper limit of normal (ULN), measured after 12 months of treatment with UDCA. We validated the model in an external cohort of patients with primary biliary cholangitis and treated with UDCA in Italy. Additionally, we assessed correlations between model predictions and key histological features, such as biliary injury and fibrosis, on liver biopsy samples. Findings: 2703 participants diagnosed with primary biliary cholangitis between Jan 1, 1998, and May 31, 2015, were included in the UK-PBC cohort for derivation of the model. The following pretreatment parameters were associated with lower probability of UDCA response: higher alkaline phosphatase concentration (p
Published: 2018
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17. The preclinical pharmacokinetic disposition of a series of perforin-inhibitors as potential immunosuppressive agents

Author: Joseph A. Trapani, Nuala A. Helsby, Matthew Bull, William A. Denny, Julie Ann Spicer, Kylie A. Browne, Kristiina M. Huttunen, and Annette Ciccone
Subjects: Male, Pharmacology, biology, Perforin, Chemistry, Drug Evaluation, Preclinical, Oxidative phosphorylation, In vitro, Mice, Immune system, Biotransformation, Pharmacokinetics, Microsomes, Liver, biology.protein, Microsome, Animals, Distribution (pharmacology), Pharmacology (medical), Immunosuppressive Agents
Abstract: The cytolytic protein perforin is a key component of the immune response and is implicated in a number of human pathologies and therapy-induced conditions. A novel series of small molecule inhibitors of perforin function have been developed as potential immunosuppressive agents. The pharmacokinetics and metabolic stability of a series of 16 inhibitors of perforin was evaluated in male CD1 mice following intravenous administration. The compounds were well tolerated 6 h after dosing. After intravenous administration at 5 mg/kg, maximum plasma concentrations ranged from 532 ± 200 to 10,061 ± 12 ng/mL across the series. Plasma concentrations were greater than the concentrations required for in vitro inhibitory activity for 11 of the compounds. Following an initial rapid distribution phase, the elimination half-life values for the series ranged from 0.82 ± 0.25 to 4.38 ± 4.48 h. All compounds in the series were susceptible to oxidative biotransformation. Following incubations with microsomal preparations, a tenfold range in in vitro half-life was observed across the series. The data suggests that oxidative biotransformation was not singularly responsible for clearance of the compounds and no direct relationship between microsomal clearance and plasma clearance was observed. Structural modifications however, do provide some information as to the relative microsomal stability of the compounds, which may be useful for further drug development.
Published: 2014
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18. Exploration of a Series of 5-Arylidene-2-thioxoimidazolidin-4-ones as Inhibitors of the Cytolytic Protein Perforin

Author: Gersande Lena, Julie Ann Spicer, Dani Michelle Lyons, Annette Ciccone, Joseph A. Trapani, Kristiina M. Huttunen, Jesse A Rudd-Schmidt, Christian K. Miller, Jamie A. Lopez, Nuala A. Helsby, Kylie A. Browne, Stephen M. F. Jamieson, Matthew J. Bull, William A. Denny, Ilia Voskoboinik, and Patrick D. O'Connor
Subjects: Pore Forming Cytotoxic Proteins, Programmed cell death, Lactams, Protein subunit, Cell, Imidazolidines, 01 natural sciences, Jurkat cells, Article, 03 medical and health sciences, Inhibitory Concentration 50, Jurkat Cells, Mice, Structure-Activity Relationship, Drug Discovery, medicine, Structure–activity relationship, Animals, Humans, 030304 developmental biology, 0303 health sciences, biology, 010405 organic chemistry, Chemistry, Perforin, 0104 chemical sciences, 3. Good health, medicine.anatomical_structure, Granzyme, Lytic cycle, Biochemistry, biology.protein, Molecular Medicine
Abstract: A series of novel 5-arylidene-2-thioxoimidazolidin-4-ones were investigated as inhibitors of the lymphocyte-expressed pore-forming protein perforin. Structure-activity relationships were explored through variation of an isoindolinone or 3,4-dihydroisoquinolinone subunit on a fixed 2-thioxoimidazolidin-4-one/thiophene core. The ability of the resulting compounds to inhibit the lytic activity of both isolated perforin protein and perforin delivered in situ by natural killer cells was determined. A number of compounds showed excellent activity at concentrations that were nontoxic to the killer cells, and several were a significant improvement on previous classes of inhibitors, being substantially more potent and soluble. Representative examples showed rapid and reversible binding to immobilized mouse perforin at low concentrations (≤2.5 μM) by surface plasmon resonance and prevented formation of perforin pores in target cells despite effective target cell engagement, as determined by calcium influx studies. Mouse PK studies of two analogues showed T1/2 values of 1.1-1.2 h (dose of 5 mg/kg i.v.) and MTDs of 60-80 mg/kg (i.p.).
Published: 2013

19. Inhibition of the pore-forming protein perforin by a series of aryl-substituted isobenzofuran-1(3H)-ones

Author: Kylie A. Browne, Julie Ann Spicer, Christian K. Miller, Kristiina M. Huttunen, Joseph A. Trapani, William A. Denny, and Annette Ciccone
Subjects: Isobenzofuran, Lymphocyte, Clinical Biochemistry, Pharmaceutical Science, Biochemistry, Pore forming protein, Cell Line, chemistry.chemical_compound, Drug Discovery, medicine, Humans, Cytotoxicity, Molecular Biology, Benzofurans, biology, Perforin, Effector, Chemistry, Organic Chemistry, Killer Cells, Natural, medicine.anatomical_structure, Cell culture, biology.protein, Molecular Medicine, Lead compound, Immunosuppressive Agents
Abstract: An aryl-substituted isobenzofuran-1(3H)-one lead compound was identified from a high throughput screen designed to find inhibitors of the lymphocyte pore-forming protein perforin. A series of analogs were then designed and prepared, exploring structure-activity relationships through variation of 2-thioxoimidazolidin-4-one and furan subunits on an isobenzofuranone core. The ability of the resulting compounds to inhibit the lytic activity of both isolated perforin protein and perforin delivered in situ by intact KHYG-1 natural killer effector cells was determined. Several compounds showed excellent activity at concentrations that were non-toxic to the killer cells. This series represents a significant improvement on previous classes of compounds, being substantially more potent and largely retaining activity in the presence of serum.
Published: 2012
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20. Inhibition of the cellular function of perforin by 1-amino-2,4-dicyanopyrido[1,2-a]benzimidazoles

Author: Annette Ciccone, William A. Denny, Dani Michelle Lyons, Kylie A. Browne, Joseph A. Trapani, Julie Ann Spicer, and Kristiina M. Huttunen
Subjects: Benzimidazole, Clinical Biochemistry, Pharmaceutical Science, Biochemistry, Chemical synthesis, Cell Line, Natural killer cell, Structure-Activity Relationship, chemistry.chemical_compound, Drug Discovery, medicine, Humans, Moiety, Molecular Biology, biology, Perforin, Organic Chemistry, In vitro, Killer Cells, Natural, medicine.anatomical_structure, chemistry, Lytic cycle, Cell culture, biology.protein, Molecular Medicine, Benzimidazoles
Abstract: A high throughput screen showed the ability of a 1-amino-2,4-dicyanopyrido[1,2-a]benzimidazole analogue to directly inhibit the lytic activity of the pore-forming protein perforin. A series of analogues were prepared to study structure-activity relationships (SAR) for the this activity, either directly added to cells or released in situ by KHYG-1 NK cells, at non-toxic concentrations. These studies showed that the pyridobenzimidazole moiety was required for effective activity, with strongly basic centres disfavoured. This class of compounds was relatively unaffected by the addition of serum, which was not the case for a previous class of direct inhibitors.
Published: 2011
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21. Activation of a PAK-MEK signalling pathway in malaria parasite-infected erythrocytes

Author: Jean-Phillipe Semblat, Julie Ann Spicer, Silke Retzlaff, Dominique Dorin-Semblat, Andrew P. Waters, Audrey Sicard, Christian Doerig, Marc Moniatte, Romain Hamelin, Caroline Doerig, Anubhav Srivastava, and Volker Heussler
Subjects: 0303 health sciences, biology, Immunology, Plasmodium falciparum, biology.organism_classification, medicine.disease, Microbiology, Plasmodium, 3. Good health, Cell biology, Schizogony, 03 medical and health sciences, 0302 clinical medicine, PAK1, 030220 oncology & carcinogenesis, Virology, parasitic diseases, medicine, Kinome, Plasmodium berghei, p21-activated kinases, Malaria, 030304 developmental biology
Abstract: Merozoites of malaria parasites invade red blood cells (RBCs), where they multiply by schizogony, undergoing development through ring, trophozoite and schizont stages that are responsible for malaria pathogenesis. Here, we report that a protein kinase-mediated signalling pathway involving host RBC PAK1 and MEK1, which do not have orthologues in the Plasmodium kinome, is selectively stimulated in Plasmodium falciparum-infected (versus uninfected) RBCs, as determined by the use of phospho-specific antibodies directed against the activated forms of these enzymes. Pharmacological interference with host MEK and PAK function using highly specific allosteric inhibitors in their known cellular IC50 ranges results in parasite death. Furthermore, MEK inhibitors have parasiticidal effects in vitro on hepatocyte and erythrocyte stages of the rodent malaria parasite Plasmodium berghei, indicating conservation of this subversive strategy in malaria parasites. These findings have profound implications for the development of novel strategies for antimalarial chemotherapy.
Published: 2011
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22. 4-Anilino-5-carboxamido-2-pyridone Derivatives as Noncompetitive Inhibitors of Mitogen-Activated Protein Kinase Kinase

Author: Daniel F. Ortwine, Nadia Esmaeil, Haile Tecle, John Quin, Joseph S. Warmus, Michael Kaufman, William A. Denny, Jeffrey F. Ohren, and Alexander G. Pavlovsky, Ronald L. Merriman, Jared B. J. Milbank, Aurash B. Shahripour, Shannon Leigh Black, Judith Sebolt-Leopold, Christopher Whitehead, Julie Ann Spicer, Cathlin Marie Flamme, Heidi S. Camp, Kelley Moore, Richard Gowan, Charles Omer, Mark Stephen Plummer, Sally Pryzbranowski, Gordon W. Rewcastle, and Stephen Douglas Barrett
Subjects: Male, Models, Molecular, Pyridones, medicine.drug_class, Stereochemistry, MAP Kinase Kinase 2, MAP Kinase Kinase 1, Antineoplastic Agents, Carboxamide, Mitogen-activated protein kinase kinase, Chemical synthesis, Mice, Structure-Activity Relationship, Non-competitive inhibition, In vivo, Cell Line, Tumor, Drug Discovery, medicine, Animals, Transferase, Phosphorylation, Extracellular Signal-Regulated MAP Kinases, chemistry.chemical_classification, Aniline Compounds, Amides, In vitro, Rats, Enzyme, chemistry, Biochemistry, Benzamides, Molecular Medicine, Drug Screening Assays, Antitumor, Neoplasm Transplantation
Abstract: A new series of MEK1 inhibitors, the 4-anilino-5-carboxamido-2-pyridones, were designed and synthesized using a combination of medicinal chemistry, computational chemistry, and structural elucidation. The effect of variation in the carboxamide side chain, substitution on the pyridone nitrogen, and replacement of the 4'-iodide were all investigated. This study afforded several compounds which were either equipotent or more potent than the clinical candidate CI-1040 (1) in an isolated enzyme assay, as well as murine colon carcinoma (C26) cells, as measured by suppression of phosphorylated ERK substrate. Most notably, pyridone 27 was found to be more potent than 1 in vitro and produced a 100% response rate at a lower dose than 1, when tested for in vivo efficacy in animals bearing C26 tumors.
Published: 2007
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23. Structure−Activity Relationships for Pyrido-, Imidazo-, Pyrazolo-, Pyrazino-, and Pyrrolophenazinecarboxamides as Topoisomerase-Targeted Anticancer Agents

Author: Sukhjit Sohal, Gordon W. Rewcastle, Swarna A. Gamage, Nigel Vicker, Peter Charlton, William A. Denny, Prakash Mistry, Julie Ann Spicer, Wendy Dangerfield, and John Milton
Subjects: Stereochemistry, Transplantation, Heterologous, Phenazine, Antineoplastic Agents, Heterocyclic Compounds, 4 or More Rings, Chemical synthesis, Mice, Structure-Activity Relationship, chemistry.chemical_compound, Drug Discovery, Tumor Cells, Cultured, medicine, Animals, Humans, Topoisomerase II Inhibitors, ATP Binding Cassette Transporter, Subfamily B, Member 1, Enzyme Inhibitors, Cytotoxicity, biology, Topoisomerase, Amides, Drug Resistance, Multiple, Intercalating Agents, In vitro, Multiple drug resistance, chemistry, Mechanism of action, Drug Resistance, Neoplasm, Cell culture, biology.protein, Phenazines, Molecular Medicine, Drug Screening Assays, Antitumor, medicine.symptom, Neoplasm Transplantation
Abstract: Heterocyclic phenazinecarboxamides were prepared by condensation of aminoheterocycles and 2-halo-3-nitrobenzoic acids, followed by reductive ring closure and amidation. They showed similar inhibition of paired cell lines that underexpressed topo II or overexpressed P-glycoprotein, indicating a non topo II mechanism of cytotoxicity and indifference to P-glycoprotein mediated multidrug resistance. Compounds with a fused five-membered heterocyclic ring were generally less potent than the pyrido[4,3-a]phenazines. A 4-methoxypyrido[4,3-a]phenazine (IC(50)s 2.5-26 nM) gave modest (ca. 5 day) growth delays in H69/P xenografts with oral dosing.
Published: 2002
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24. Dicationic Bis(9-methylphenazine-1-carboxamides): Relationships between Biological Activity and Linker Chain Structure for a Series of Potent Topoisomerase Targeted Anticancer Drugs

Author: William A. Denny, Swarna A. Gamage, Bruce C. Baguley, Peter Charlton, Graeme J. Finlay, Julie Ann Spicer, and Alistair J. Stewart
Subjects: Cations, Divalent, Stereochemistry, medicine.drug_class, Transplantation, Heterologous, Mice, Nude, Antineoplastic Agents, Carboxamide, Chemical synthesis, Inhibitory Concentration 50, Mice, Structure-Activity Relationship, chemistry.chemical_compound, Diamine, Drug Discovery, Tumor Cells, Cultured, medicine, Animals, Humans, Topoisomerase II Inhibitors, Enzyme Inhibitors, Cytotoxicity, biology, DNA, Superhelical, Topoisomerase, Biological activity, Amides, Mice, Inbred C57BL, DNA Topoisomerases, Type II, DNA Topoisomerases, Type I, chemistry, Enzyme inhibitor, biology.protein, Phenazines, Molecular Medicine, Drug Screening Assays, Antitumor, Topoisomerase I Inhibitors, Linker
Abstract: Bis(9-methylphenazine-1-carboxamides) joined by a variety of dicationic (CH(2))(n)()NR(CH(2))(m)NR(CH(2))(n) linkers of varying length (carboxamide N-N distances from 11.0 to 18.4 A) and rigidity were prepared by reaction of 9-methylphenazine-1-carboxylic acid imidazolide with the appropriate polyamines. The compounds were evaluated for growth inhibitory properties in P388 leukemia, Lewis lung carcinoma, and wild-type (JL(C)) and mutant (JL(A) and JL(D)) forms of human Jurkat leukemia with low levels of topoisomerase II (topo II). The compounds all had IC(50) ratios of1 in the resistant Jurkat lines, consistent with topo II inhibition not being the primary mechanism of action. Analogues joined by an (CH(2))(2)NR(CH(2))(2)NR(CH(2))(2) linker were extremely potent cytotoxins, with selectivity toward the human cell lines, but absolute potencies declined sharply from R = H through R = Me to R = Pr and Bu. In contrast, (CH(2))(2)NR(CH(2))(3)NR(CH(2))(2) compounds showed reverse effects, with the R = Me analogue being more potent than the R = H one as well as being the most potent in the series [IC(50) in JL(C) cells 0.08 nM; superior to that for the clinical bis(naphthalimide) LU 79553]. Overall, the IC(50)s of analogues with linker chains (CH(2))(n)NH(CH(2))(m)NH(CH(2))(n) were inversely proportional to linker length. Constraining the rigidity of the linker chain by incorporating a piperazine ring did not decrease potency significantly. A representative compound bound tightly to DNA with high selectivity for GC sites, compatible with recent work suggesting that compounds of this type place their side chains in the major groove, making specific contacts with guanine bases. Representative compounds were susceptible to transport mediated resistance, being much less effective in cells that overexpressed P-glycoprotein. Overall the results suggest these compounds have a similar mode of action, mediated primarily by poisoning of topo I (possibly with some involvement of topo II). The bis(9-methylphenazine-1-carboxamides) show very high in vitro growth inhibitory potencies compared to their monomeric analogues. Two compounds showed in vivo activity in murine colon 38 syngeneic and HT29 human colon tumor xenograft models using intraperitoneal dosing.
Published: 2001
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25. Bis(phenazine-1-carboxamides): Structure−Activity Relationships for a New Class of Dual Topoisomerase I/II-Directed Anticancer Drugs

Author: Gordon W. Rewcastle, Bruce C. Baguley, David J. A. Bridewell, William A. Denny, Julie Ann Spicer, Swarna A. Gamage, and Graeme J. Finlay
Subjects: Tertiary amine, Stereochemistry, medicine.drug_class, Mutant, Antineoplastic Agents, Carboxamide, Jurkat cells, Chemical synthesis, Mice, Structure-Activity Relationship, Drug Discovery, Tumor Cells, Cultured, medicine, Animals, Humans, Topoisomerase II Inhibitors, Enzyme Inhibitors, chemistry.chemical_classification, biology, Chemistry, Topoisomerase, Lewis lung carcinoma, Amides, Enzyme, biology.protein, Phenazines, Molecular Medicine, Drug Screening Assays, Antitumor, Topoisomerase I Inhibitors, Neoplasm Transplantation
Abstract: Ring-substituted bis(phenazine-1-carboxamides), linked by a -(CH(2))(3)NMe(CH(2))(3)- chain, were prepared from the corresponding substituted phenazine-1-carboxylic acids by reaction of the intermediate imidazolides with bis(3-aminopropyl)methylamine. The compounds were evaluated for growth inhibitory activity in a panel of tumor cell lines, including P388 leukemia, Lewis lung carcinoma, and wild-type (JL(C)) and mutant (JL(A) and JL(D)) forms of human Jurkat leukemia. The latter mutant lines are resistant to topoisomerase (topo) II targeted agents because of lower levels of the enzyme. Analogues with small, lipophilic substituents (e.g., Me, Cl) at the 9-position were the most potent inhibitors, superior to the corresponding dimeric bis(acridine-4-carboxamides) (bis-DACA analogues). Several of the compounds were preferentially (up to 2-fold) more cytotoxic toward the mutant Jurkat lines than the wild-type. To test whether this selectivity was related to topoisomerase action, the most potent of the compounds (9-methyl) was evaluated in a cell-free system. It poisoned topo I at drug concentrations of 0.25 and 0.5 microM and inhibited the catalytic activity of both topo I and topo II at concentrations of 1 and 5 microM, respectively. Results from the NCI human tumor cell line panel showed the compounds had preferential activity toward colon tumor lines (on average 9.5-fold more active in the HT29 line than in the cell line panel as a whole). Several analogues produced significant growth delays in the relatively refractory subcutaneous colon 38 tumor model in vivo. In particular, the 9-methyl compound was substantially more potent in this tumor model than the clinical dual topo I/II poison DACA (total dose 90 versus 400 mg/kg) with comparable activity. The bis(phenazine-1-carboxamides) are a new and interesting class of dual topo I/II-directed anticancer drugs.
Published: 2000
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26. Structure−Activity Relationships for Acridine-Substituted Analogues of the Mixed Topoisomerase I/II Inhibitor N-[2-(Dimethylamino)ethyl]acridine-4-carboxamide

Author: Bruce C. Baguley, Julie Ann Spicer, Swarna A. Gamage, Graeme J. Finlay, Graham J. Atwell, and William A. Denny
Subjects: Steric effects, Lung Neoplasms, medicine.drug_class, Stereochemistry, Antineoplastic Agents, Carboxamide, Chemical synthesis, Mice, Structure-Activity Relationship, chemistry.chemical_compound, Drug Discovery, Tumor Cells, Cultured, medicine, Animals, Enzyme Inhibitors, Cytotoxicity, Leukemia, Molecular Structure, biology, Leukemia P388, Topoisomerase, Diphenylamine, Rats, chemistry, Enzyme inhibitor, Colonic Neoplasms, Acridine, biology.protein, Acridines, Molecular Medicine, Topoisomerase I Inhibitors, Cell Division, Neoplasm Transplantation
Abstract: The mixed topoisomerase I/II inhibitor N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA) is currently in clinical trial as an anticancer drug. A series of acridine-substituted analogues were prepared, using a new synthetic route to substituted acridine-4-carboxylic acids (conversion of substituted diphenylamine diacid monoesters to the corresponding aldehydes and mild acid-catalyzed ring closure to form the acridines directly). The analogues were evaluated in a panel of cell lines which included wild-type (JLC) and mutant (JLA and JLD) forms of the human Jurkat leukemia line. The latter mutant lines are resistant to topoisomerase II targeted agents due to lower levels of the enzyme. Structure-activity studies suggest that the electronic properties of the substituents do not markedly affect cytotoxicity, but steric bulk is important, with larger groups leading to loss of activity. The compounds fell broadly into two categories. The majority had cytotoxicities similar to (or lower than) that of DACA itself and were equitoxic in all the Jurkat lines, suggesting a relatively greater effect on topoisomerase I compared with topoisomerase II. Most of the 5-substituted derivatives and the 7-Ph compound were more cytotoxic than DACA, but were less effective against JLA and JLD cell lines than in the wild-type JLC, suggesting a mode of cytotoxicity largely mediated by effects on topoisomerase II. Both DACA and selected acridine-substituted analogues were active in the relatively refractory subcutaneous colon 38 tumor model in vivo.
Published: 1997
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27. A new synthesis of substituted acridine-4-carboxylic acids and the anticancer drug N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA)

Author: Swarna A. Gamage, Julie Ann Spicer, Gordon W. Rewcastle, and William A. Denny
Subjects: chemistry.chemical_compound, Hydrolysis, Chemistry, Organic Chemistry, Drug Discovery, Acridine, Trifluoroacetic acid, Organic chemistry, N-(2'-(dimethylamino)ethyl)acridine-4-carboxamide, Biochemistry, Medicinal chemistry, Anticancer drug, Benzoates
Abstract: A new synthesis of substituted acridine-4-carboxylic acids 2 from methyl 2-[ N -(2-carboxyphenyl)amino]benzoates ( 4 ) is reported, via NaBH 4 reduction of the corresponding imidazolides ( 5 ), oxidation of the resulting alcohols 6 to aldehydes 7 , and cyclisation of these with trifluoroacetic acid to the methyl acridine-4-carboxylates ( 8 ), followed by base hydrolysis. Direct amidation of 8a provides a new route to the clinical anticancer drug DACA ( 3 ) which avoids use of the irritant acid 2a .
Published: 1997
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28. ChemInform Abstract: A New Synthesis of Substituted Acridine-4-carboxylic Acids and the Anticancer Drug N-(2-(Dimethylamino)ethyl)acridine-4-carboxamide (DACA)

Author: Gordon W. Rewcastle, William A. Denny, Julie Ann Spicer, and Swarna A. Gamage
Subjects: chemistry.chemical_compound, Hydrolysis, Chemistry, Acridine, Acridine derivatives, Trifluoroacetic acid, N-(2'-(dimethylamino)ethyl)acridine-4-carboxamide, General Medicine, Medicinal chemistry, Anticancer drug, Benzoates
Abstract: A new synthesis of substituted acridine-4-carboxylic acids 2 from methyl 2-[ N -(2-carboxyphenyl)amino]benzoates ( 4 ) is reported, via NaBH 4 reduction of the corresponding imidazolides ( 5 ), oxidation of the resulting alcohols 6 to aldehydes 7 , and cyclisation of these with trifluoroacetic acid to the methyl acridine-4-carboxylates ( 8 ), followed by base hydrolysis. Direct amidation of 8a provides a new route to the clinical anticancer drug DACA ( 3 ) which avoids use of the irritant acid 2a .
Published: 2010
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29. Dihydrofuro[3,4-c]pyridinones as inhibitors of the cytolytic effects of the pore-forming glycoprotein perforin

Author: Kylie A. Browne, Mark J. Smyth, Vivien R. Sutton, Gersande Lena, Joseph A. Trapani, Annette Ciccone, William A. Denny, and Julie Ann Spicer
Subjects: Lysis, Erythrocytes, Stereochemistry, Pyridones, Apoptosis, Jurkat cells, Natural killer cell, Jurkat Cells, Structure-Activity Relationship, Drug Discovery, medicine, Cytotoxic T cell, Animals, Humans, Furans, Sheep, biology, Bicyclic molecule, Dose-Response Relationship, Drug, Molecular Structure, Chemistry, Perforin, Thiones, Stereoisomerism, Small molecule, In vitro, Killer Cells, Natural, medicine.anatomical_structure, Biochemistry, Drug Design, biology.protein, Molecular Medicine
Abstract: Dihydrofuro[3,4-c]pyridinones are the first class of small molecules reported to inhibit the cytolytic effects of the lymphocyte toxin perforin. A lead structure was identified from a high throughput screen, and a series of analogues were designed and prepared to explore structure-activity relationships around the core bicyclic thioxofuropyridinone and pendant furan ring. This resulted in the identification of a submicromolar inhibitor of the perforin-induced lysis of Jurkat T-lymphoma cells.
Published: 2008

30. Synthesis and evaluation of unsymmetrical bis(arylcarboxamides) designed as topoisomerase-targeted anticancer drugs

Author: William A. Denny, Julie Ann Spicer, Swarna A. Gamage, and Graeme J. Finlay
Subjects: Magnetic Resonance Spectroscopy, medicine.drug_class, Stereochemistry, Clinical Biochemistry, Drug Evaluation, Preclinical, Pharmaceutical Science, Carboxamide, Antineoplastic Agents, Biochemistry, Chemical synthesis, chemistry.chemical_compound, Diamine, Drug Discovery, medicine, Tumor Cells, Cultured, Animals, Humans, Imide, Molecular Biology, Organic Chemistry, Nuclear magnetic resonance spectroscopy, Chromophore, Amides, Naphthalimides, chemistry, DNA Topoisomerases, Type I, Molecular Medicine, Drug Screening Assays, Antitumor, Linker
Abstract: Symmetrical dimers of lipophilic intercalating chromophores linked by cation-containing chains have recently been shown to have broad-spectrum in vivo anticancer activity. We report the preparation and evaluation of a series of both symmetric and unsymmetric dimers of a variety of intercalating chromophores of varied DNA binding strength, including naphthalimides, acridines, phenazines, oxanthrenes and 2-phenylquinolines. The unsymmetrical dimers were prepared by sequential coupling of the chromophores to linkers with selectively protected primary terminal amines to ensure high yields and unequivocal product. Protection of the internal (secondary) amines as BOC derivatives was used to ensure complete structural specificity, and was also an aid to the purification of these very polar compounds. The growth inhibitory abilities (as IC(50) values) of the compounds in a range of cell lines showed that the nature of the linker chain was important, and independent of the nature of the chromophore, with compounds containing the dicationic linker [-(CH2)2NH(CH2)2NH(CH2)2-] being on average 30-fold more potent than the corresponding compounds containing the monocationic linker [-(CH2)3NMe(CH2)3-]. However, the chromophores also play a role in determining biological activity, with the cytotoxicities of symmetric and unsymmetric dicationic dimers correlating with the overall DNA binding abilities of the chromophores.
Published: 2001

31. Structure-activity relationships for substituted bis(acridine-4-carboxamides): a new class of anticancer agents

Author: Julie Ann Spicer, Graham J. Atwell, William A. Denny, Swarna A. Gamage, Graeme J. Finlay, and Bruce C. Baguley
Subjects: Tertiary amine, medicine.drug_class, Stereochemistry, Carboxamide, Antineoplastic Agents, Topoisomerase-I Inhibitor, chemistry.chemical_compound, Mice, Structure-Activity Relationship, Drug Discovery, medicine, Tumor Cells, Cultured, Structure–activity relationship, Animals, Humans, Topoisomerase II Inhibitors, Enzyme Inhibitors, biology, Chemistry, Topoisomerase, Drug Resistance, Neoplasm, Acridine, Colonic Neoplasms, Mutation, biology.protein, Molecular Medicine, Acridines, Topoisomerase-II Inhibitor, Drug Screening Assays, Antitumor, Topoisomerase I Inhibitors, Topoisomerase inhibitor, Neoplasm Transplantation
Abstract: A series of acridine-substituted bis(acridine-4-carboxamides) linked by a (CH2)3N(Me)(CH2)3 chain have been prepared by reaction of the isolated imidazolides of the substituted acridine-4-carboxylic acids with N,N-bis(3-aminopropyl)methylamine. These dimeric analogues of the mixed topoisomerase I/II inhibitor N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA), currently in clinical trial, show superior potencies to the corresponding monomeric DACA analogues in a panel of cell lines, including wild-type (JLC) and mutant (JLA and JLD) forms of human Jurkat leukemia. The latter mutant lines are resistant to topoisomerase II targeted agents because of lower levels of the enzyme. Analogues with small substituents (e.g., Me, Cl) at the acridine 5-position were clearly superior, with IC50's as low as 2 nM against the Lewis lung carcinoma and 11 nM against JLC. Larger substituents at any position caused a steady decrease in potency, likely due to lowering of DNA binding affinity. A small series of analogues of the most potent bis(5-methylDACA) compound, with second substituents (Me and Cl) in the 1- or 8- position had broadly similar potencies to the 5-Me compound, indicating that, while the 1- and 8-substituents are acceptable, they add little to the enhancing effect of the 5-methyl group. All of the compounds were at least equitoxic (some up to 4-fold more cytotoxic) against the mutant Jurkat lines than in the wild-type, consistent with a relatively greater effect on topoisomerase I compared with topoisomerase II. The bis(5-methylDACA) compound was found to inhibit the action of purified topoisomerase I in a cell-free assay. Compounds were on average 10-fold less cytotoxic in an MCF7 breast cancer line overexpressing P-glycoprotein than in the wild-type line and showed some selectivity for colon tumor lines in the NCI human tumor cell line panel. Several analogues produced significant growth delays in the relatively refractory subcutaneous colon 38 tumor model in vivo at substantially lower doses than DACA. The bis(acridine-4-carboxamides) represent a new and interesting class of potent topoisomerase inhibitors.
Published: 1999

32. Ethyl 4-hydroxymethyl-2-methylpyridine-5-carboxylate

Author: Peter D. W. Boyd, Gersande Lena, and Julie Ann Spicer
Subjects: Crystallography, Chemistry, Hydrogen bond, General Chemistry, Crystal structure, Condensed Matter Physics, Bioinformatics, Ring (chemistry), Medicinal chemistry, Organic Papers, chemistry.chemical_compound, Group (periodic table), QD901-999, Pyridine, General Materials Science
Abstract: The title compound, C10H13NO3, was obtained as a by-product of the aldolization reaction of furo[3,4-c]pyridin-3(1H)-one with thiophene-2-carboxaldehyde. The substituents on the pyridine ring are nearly coplanar, with an 8.1 (2)° rotation of the hydroxmethyl group from this plane. The molecules assemble in the crystal structure as chains via O—H...N hydrogen bonding between the pyridine N atom and a neighbouring hydroxymethyl OH group.
Published: 2008

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32 results on '"Ann, Spicer"'

1. Corrigendum to: 'An international genome-wide meta-analysis of primary biliary cholangitis: Novel risk loci and candidate drugs' [J Hepatol 75 (2021) 572-581]

2. Corrigendum to 'An international genome-wide meta-analysis of primary biliary cholangitis: Novel risk loci and candidate drugs' [J Hepatol 2021;75(3):572-581]

3. Corrigendum to ‘An international genome-wide meta-analysis of primary biliary cholangitis: Novel risk loci and candidate drugs’ [J Hepatol 2021;75(3):572–581]

4. Inhibition of the Cytolytic Protein Perforin Prevents Rejection of Transplanted Bone Marrow Stem Cells in Vivo

5. Synthesis and Evaluation of Imidazo[1,2‐a]pyridine Analogues of the ZSTK474 Class of Phosphatidylinositol 3‐Kinase Inhibitors

6. An international genome-wide meta-analysis of primary biliary cholangitis: Novel risk loci and candidate drugs

7. Effects of primary biliary cholangitis on quality of life and health care costs in the United Kingdom

8. Perforin inhibition protects from lethal endothelial damage during fulminant viral hepatitis

9. Substituted arylsulphonamides as inhibitors of perforin-mediated lysis

10. Benzenesulphonamide inhibitors of the cytolytic protein perforin

11. Tyrosine Kinase Inhibitors. 20. Optimization of Substituted Quinazoline and Pyrido[3,4-d]pyrimidine Derivatives as Orally Active, Irreversible Inhibitors of the Epidermal Growth Factor Receptor Family

12. Systemic and Brain Pharmacokinetics of Perforin Inhibitor Prodrugs

13. A Selective and Slowly Reversible Inhibitor of <scp>l</scp>-Type Amino Acid Transporter 1 (LAT1) Potentiates Antiproliferative Drug Efficacy in Cancer Cells

14. l -Type amino acid transporter 1 (lat1)-mediated targeted delivery of perforin inhibitors

15. Diarylthiophenes as inhibitors of the pore-forming protein perforin

16. Pretreatment prediction of response to ursodeoxycholic acid in primary biliary cholangitis: development and validation of the UDCA Response Score

17. The preclinical pharmacokinetic disposition of a series of perforin-inhibitors as potential immunosuppressive agents

18. Exploration of a Series of 5-Arylidene-2-thioxoimidazolidin-4-ones as Inhibitors of the Cytolytic Protein Perforin

19. Inhibition of the pore-forming protein perforin by a series of aryl-substituted isobenzofuran-1(3H)-ones

20. Inhibition of the cellular function of perforin by 1-amino-2,4-dicyanopyrido[1,2-a]benzimidazoles

21. Activation of a PAK-MEK signalling pathway in malaria parasite-infected erythrocytes

22. 4-Anilino-5-carboxamido-2-pyridone Derivatives as Noncompetitive Inhibitors of Mitogen-Activated Protein Kinase Kinase

23. Structure−Activity Relationships for Pyrido-, Imidazo-, Pyrazolo-, Pyrazino-, and Pyrrolophenazinecarboxamides as Topoisomerase-Targeted Anticancer Agents

24. Dicationic Bis(9-methylphenazine-1-carboxamides): Relationships between Biological Activity and Linker Chain Structure for a Series of Potent Topoisomerase Targeted Anticancer Drugs

25. Bis(phenazine-1-carboxamides): Structure−Activity Relationships for a New Class of Dual Topoisomerase I/II-Directed Anticancer Drugs

26. Structure−Activity Relationships for Acridine-Substituted Analogues of the Mixed Topoisomerase I/II Inhibitor N-[2-(Dimethylamino)ethyl]acridine-4-carboxamide

27. A new synthesis of substituted acridine-4-carboxylic acids and the anticancer drug N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA)

28. ChemInform Abstract: A New Synthesis of Substituted Acridine-4-carboxylic Acids and the Anticancer Drug N-(2-(Dimethylamino)ethyl)acridine-4-carboxamide (DACA)

29. Dihydrofuro[3,4-c]pyridinones as inhibitors of the cytolytic effects of the pore-forming glycoprotein perforin

30. Synthesis and evaluation of unsymmetrical bis(arylcarboxamides) designed as topoisomerase-targeted anticancer drugs

31. Structure-activity relationships for substituted bis(acridine-4-carboxamides): a new class of anticancer agents

32. Ethyl 4-hydroxymethyl-2-methylpyridine-5-carboxylate

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32 results on '"Ann, Spicer"'

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