8 results on '"Ann Spicer"'
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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]
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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
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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
3. Substituted arylsulphonamides as inhibitors of perforin-mediated lysis
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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
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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
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- 2017
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4. Benzenesulphonamide inhibitors of the cytolytic protein perforin
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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
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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
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- 2017
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5. l -Type amino acid transporter 1 (lat1)-mediated targeted delivery of perforin inhibitors
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William A. Denny, Mikko Gynther, Kristiina M. Huttunen, Imke Aufderhaar, Johanna Huttunen, and Julie Ann Spicer
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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.
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- 2016
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6. Inhibition of the pore-forming protein perforin by a series of aryl-substituted isobenzofuran-1(3H)-ones
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Kylie A. Browne, Julie Ann Spicer, Christian K. Miller, Kristiina M. Huttunen, Joseph A. Trapani, William A. Denny, and Annette Ciccone
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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.
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- 2012
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7. Inhibition of the cellular function of perforin by 1-amino-2,4-dicyanopyrido[1,2-a]benzimidazoles
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Annette Ciccone, William A. Denny, Dani Michelle Lyons, Kylie A. Browne, Joseph A. Trapani, Julie Ann Spicer, and Kristiina M. Huttunen
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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.
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- 2011
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8. A new synthesis of substituted acridine-4-carboxylic acids and the anticancer drug N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA)
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Swarna A. Gamage, Julie Ann Spicer, Gordon W. Rewcastle, and William A. Denny
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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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