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2,116 results on '"Johnston, Paul A."'

4. Risk loci involved in giant cell arteritis susceptibility: a genome-wide association study

Author

Callejas, José Luis, Caminal-Montero, Luis, Corbera-Bellalta, Marc, de Miguel, Eugenio, Díaz-López, J. Bernardino, García-Villanueva, María Jesús, Gómez-Vaquero, Carmen, Guijarro-Rojas, Mercedes, Hidalgo-Conde, Ana, Marí-Alfonso, Begoña, Martínez-Berriochoa, Agustín, Morado, Inmaculada C., Narváez, Javier, Ramentol-Sintas, Marc, Martínez-Zapico, Aleida, Martínez-Taboada, Víctor Manuel, Miranda-Filloy, José A., Monfort, Jordi, Pérez-Conesa, Mercedes, Prieto-González, Sergio, Raya, Enrique, Ríos-Fenández, Raquel, Sánchez-Martín, Julio, Sopeña, Bernardo, Tío, Laura, Unzurrunzaga, Ainhoa, Wordsworth, Oliver, Whitwell, Isobel, Brock, Jessica, Douglas, Victoria, Hettiarachchi, Chamila, Bartholomew, Jacqui, Jarrett, Stephen, Smithson, Gayle, Green, Michael, Brown, Pearl Clark, Lawson, Cathy, Gordon, Esther, Lane, Suzanne, Francis, Rebecca, Dasgupta, Bhaskar, Masunda, Bridgett, Calver, Jo, Patel, Yusuf, Thompson, Charlotte, Gregory, Louise, Levy, Sarah, Menon, Ajit, Thompson, Amy, Dyche, Lisa, Martin, Michael, Li, Charles, Laxminarayan, Ramasharan, Wilcox, Louise, de Guzman, Ralph, Isaacs, John, Lorenzi, Alice, Farley, Ross, Hinchcliffe-Hume, Helain, Bejarano, Victoria, Hope, Susan, Nandi, Pradip, Stockham, Lynne, Wilde, Catherine, Durrant, Donna, Lloyd, Mark, Ye, Chee-Seng, Stevens, Rob, Jilani, Amjad, Collins, David, Pegler, Suzannah, Rivett, Ali, Price, Liz, McHugh, Neil, Skeoch, Sarah, O'Kane, Diana, Kirkwood, Sue, Vadivelu, Saravanan, Pugmire, Susan, Sultan, Shabina, Dooks, Emma, Armstrong, Lisa, Sadik, Hala, Nandagudi, Anupama, Abioye, Tolu, Ramos, Angelo, Gumus, Steph, Sofat, Nidhi, Harrison, Abiola, Seward, Abi, Mollan, Susan, Rahan, Ray, Hawkins, Helen, Emsley, Hedley, Bhargava, Anna, Fleming, Vicki, Hare, Marianne, Raj, Sonia, George, Emmanuel, Allen, Nicola, Hunter, Karl, O'Sullivan, Eoin, Bird, Georgina, Magliano, Malgorzata, Manzo, Katarina, Sanghera, Bobbie, Hutchinson, David, Hammonds, Fiona, Sharma, Poonam, Cooper, Richard, McLintock, Graeme, Al-Saffar, Zaid S., Green, Mike, Elliott, Kerry, Neale, Tania, Mallinson, Janine, Lanyon, Peter, Pradere, Marie-Josephe, Jordan, Natasha, Htut, Ei Phyu, Mushapaidzi, Thelma, Abercrombie, Donna, Wright, Sam, Rowlands, Jane, Mukhtyar, Chetan, Kennedy, James, Makkuni, Damodar, Wilhelmsen, Elva, Kouroupis, Michael, John, Lily, Hughes, Rod, Walsh, Margaret, Buckley, Marie, Mackay, Kirsten, Camden-Woodley, Tracey, Redome, Joan, Pearce, Kirsty, Marianayagam, Thiraupathy, Cruz, Carina, Warner, Elizabeth, Atchia, Ishmael, Walker, Claire, Black, Karen, Duffy, Stacey, Fothergill, Lynda, Jefferey, Rebecca, Toomey, Jackie, Rhys-Dillon, Ceril, Pothecary, Carla, Green, Lauren, Toms, Tracey, Maher, Linda, Davis, Diana, Sayan, Amrinder, Thankachen, Mini, Abusalameh, Mahdi, Record, Jessica, Khan, Asad, Stafford, Sam, Hussein, Azza, Williams, Clare, Fletcher, Alison, Johson, Laura, Burnett, Richard, Moots, Robert, Frankland, Helen, Dale, James, Moar, Kirsten, Hollas, Carol, Parker, Ben, Ridings, Derek, Eapen, Sandhya, John, Sindhu, Robson, Jo, Guthrie, Lucy Belle, Fyfe, Rose, Tait, Moira, Marks, Jonathan, Gunter, Emma, Hernandez, Rochelle, Bhat, Smita, Johnston, Paul, Khurshid, Muhammad, Barclay, Charlotte, Kapur, Deepti, Jeffrey, Helen, Hughes, Anna, Slack, Lauren, Thomas, Eleri, Royon, Anna, Hall, Angela, King, Jon, Nyathi, Sindi, Morris, Vanessa, Castelino, Madhura, Hawkins, Ellie, Tomson, Linda, Singh, Animesh, Nunag, Annalyn, O'Connor, Stella, Rushby, Nathan, Hewitson, Nicola, O'Sunmboye, Kenny, Lewszuk, Adam, Boyles, Louise, Perry, Martin, Williams, Emma, Graver, Christine, Defever, Emmanuel, Kamanth, Sanjeet, Kay, Dominic, Ogor, Joe, Winter, Louise, Horton, Sarah, Welch, Gillian, Hollinshead, Kath, Peters, James, Labao, Julius, Dmello, Andrea, Dawson, Julie, Graham, Denise, De Lord, Denise, Deery, Jo, Hazelton, Tracy, Carette, Simon, Chung, Sharon, Cuthbertson, David, Forbess, Lindsy J., Gewurz-Singer, Ora, Hoffman, Gary S., Koening, Curry L., Maksimowicz-McKinnon, Kathleen M., McAlear, Carol A., Moreland, Larry W., Pagnoux, Christian, Seo, Philip, Specks, Ulrich, Spiera, Robert F., Sreih, Antoine, Warrington, Kenneth J., Monach, Paul A., Weisman, Michael, Borrego-Yaniz, Gonzalo, Ortiz-Fernández, Lourdes, Madrid-Paredes, Adela, Kerick, Martin, Hernández-Rodríguez, José, Mackie, Sarah L, Vaglio, Augusto, Castañeda, Santos, Solans, Roser, Mestre-Torres, Jaume, Khalidi, Nader, Langford, Carol A, Ytterberg, Steven, Beretta, Lorenzo, Govoni, Marcello, Emmi, Giacomo, Cimmino, Marco A, Witte, Torsten, Neumann, Thomas, Holle, Julia, Schönau, Verena, Pugnet, Gregory, Papo, Thomas, Haroche, Julien, Mahr, Alfred, Mouthon, Luc, Molberg, Øyvind, Diamantopoulos, Andreas P, Voskuyl, Alexandre, Daikeler, Thomas, Berger, Christoph T, Molloy, Eamonn S, Blockmans, Daniel, van Sleen, Yannick, Iles, Mark, Sorensen, Louise, Luqmani, Raashid, Reynolds, Gary, Bukhari, Marwan, Bhagat, Shweta, Ortego-Centeno, Norberto, Brouwer, Elisabeth, Lamprecht, Peter, Klapa, Sebastian, Salvarani, Carlo, Merkel, Peter A, Cid, María C, González-Gay, Miguel A, Morgan, Ann W, Martin, Javier, and Márquez, Ana

Published
2024
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10. Generative Mechanisms for Student Value Perceptions: An Exploratory Case Study

Author

Nicholson, Alex and Johnston, Paul

Abstract

Despite ever-strengthening political rhetoric to the contrary, there can be little doubt that the holistic value of an undergraduate degree is far greater than merely its potential for employability enhancement. However, what is less clear is the extent to which fee-paying students perceive broader aspects of value, and how such value perceptions are formed. This paper outlines findings from an exploratory case study comprising six life history interviews in which past and present law students from a post-92 university in the UK were asked to explore how they perceive the value of their degree, specifically focusing on how and when such value perceptions might have been shaped by their life experiences. Through analysis of the resultant data, a wide range of possible 'generative mechanisms' were identified which may influence student value perceptions in this context. Generative mechanisms are not direct causes but things which have the potential to have a real-world impact given the right conditions. By understanding such mechanisms, legal education providers -- and to a lesser extent also providers from other disciplines -- can more effectively design and market their programmes to ensure that they deliver maximum value that is perceived within their markets.

Published
2021
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12. Correction: Feasibility of conservative fluid administration and deresuscitation compared with usual care in critical illness: the Role of Active Deresuscitation Correction: After Resuscitation-2 (RADAR-2) randomised clinical trial

Author

Silversides, Jonathan A., McMullan, Ross, Emerson, Lydia M., Bradbury, Ian, Bannard-Smith, Jonathan, Szakmany, Tamas, Trinder, John, Rostron, Anthony J., Johnston, Paul, Ferguson, Andrew J., Boyle, Andrew J., Blackwood, Bronagh, Marshall, John C., and McAuley, Daniel F.

Published
2023
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19. Feasibility of conservative fluid administration and deresuscitation compared with usual care in critical illness: the Role of Active Deresuscitation After Resuscitation-2 (RADAR-2) randomised clinical trial

Author

Silversides, Jonathan A., McMullan, Ross, Emerson, Lydia M., Bradbury, Ian, Bannard-Smith, Jonathan, Szakmany, Tamas, Trinder, John, Rostron, Anthony J., Johnston, Paul, Ferguson, Andrew J., Boyle, Andrew J., Blackwood, Bronagh, Marshall, John C., and McAuley, Daniel F.

Published
2022
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21. Postoperative continuous positive airway pressure to prevent pneumonia, re-intubation, and death after major abdominal surgery (PRISM): a multicentre, open-label, randomised, phase 3 trial

Author

Pearse, Rupert, Ranieri, Marco, Abbott, Tom, Pakats, Mari-Liis, Piervincenzi, Edoardo, Patel, Akshaykumar, Kahan, Brennan, Rhodes, Andrew, Dias, Priyanthi, Hewson, Russell, Jammer, Ib, Chew, Michelle, Aldecoa, Cesar, Rodseth, Reitze, Biccard, Bruce, Stephens, Tim, Payne, Sara, Hepworth, David, Pischke, Soeren, Asvall, Joerund, Hausken, John, Jhanji, Shaman, Rooms, Martin, Flint, Neil, Hales, Dawn, Szakmany, Tamas, Leitch, Andrew, Spadaro, Savino, Chiumello, Davide, Johnston, Paul, Yeung, Joyce, Tellan, Guglielmo, Veenith, Tonny, Macmillan, Josep, Terragni, Pierpaolo, Sander, Caroline, Kasipandian, Vidya, Ahmad, Tahania, Lee, Aaron, Tammaro, Marcello, McAuley, Danny, Skene, Simon, Vohra, Ravinder, Wilson, Matt, Edwards, Mark, Griffiths, Ewen, Pritchard, Naomi, Filippini, Claudia, Aasmundstad, Tor, Aksnes, Einar, Alpers, Lise-Merete, Barratt-Due, Andreas, Dahl, Anita, Feldt, Linda, Figari, Elisa, Flåten, Eva, Granheim, Karen, Hagring, Minna, Haugaa, Håkon, Kjoesen, Gisle, Klaevahaugen, Inge, Lenz, Harald, Myhre, Marianne, Orrem, Hilde, Stitt, Emily, Toennessen, Tor Inge, Al-Kadhimi, Samuel, Anker, Robert, Balint, Mihaela, Barraclough, Lauren, Black, Ethel, Clayton, Matt, Conneely, Leonora, Edwards, Zara, Eeles, Alex, Evans, Matthew, Gerstman, Michelle, Greenshields, Nicole, Harvey, Eleanor, Hegarty, Aoife, Hester, Natalie, Hutchinson, Jenna, Kasivisvanathan, Ramanathan, Lawrence, Helen, Marsh, Veronica, Matthews, Laura, Mazzola, Francesca, McCanny, Jamie, Morrison, Ben, O'Mahony, Michelle, Pang, Ching Ling, Parkinson, David, Pirie, Katrina, Rao Baikady, Ravishankar, Shovel, Louisa, Smith, Lorna, Tatham, Kate, Thomas, Peter, Uren, Sophie, Walker, Susanna, Wills, Alasdair, Andreou, Prematie, Howson, Alex, Kaur, Jasmin, Lewszuk, Adam, Molina, Esther, Ramsamy, Nirmalabaye, Roberts, Emma, Amaral, Vanessa, Begum, Salma, Bekele, Soliana, Cashmore, Richard, Correia, Carmen, Dunkley, Steven, Fernandez, Maria, Fowler, Alexander, Garcia, Amaia, Della Giovampaola, Maria, Greaves, Kathryn, Griffiths, Bethan, Haines, Ryan, Haslop, Richard, Hu, Ying, Hui, Sarah, Januszewska, Marta, Manon, Vasi, Martin, Tim, May, Shaun, Minicozzi, Annamaria, Niebrzegowska, Edyta, Oliveira, Monica, Pates, Katherine, Santos, Filipa, Shahid, Tasnin, Simili, Paolo, Somerville, Alastair, Subhedar, Emily, Uddin, Ruzena, Walker, Sophie, Wan, Yize, Whalley, Jan, Zolfaghari, Parjam, Gunter, Una, Hodkinson, Gemma, Howe, Gwenllian, Baratozzi, Valentina, Casotto, Giulia, Darai, Giulia, Ferrari, Erica, Mistraletti, Giovanni, Palmaverdi, Valentina, Furlani, Stefano, Priani, Paolo, Ragazzi, Riccardo, Salmaso, Marco, Verri, Marco, Volta, Carlo, Nutt, Chris, McKay, Emma, O'Neill, Orla, Patel, Jaimin, Atterbury, Katie, Ballinger, Sarah, Carling, Natalie, Ellis, Kaytie, Gresty, Jo, Melody, Teresa, Monk, Jade, Norman, Chloe, Reeves, Eleanor, Sampson, Julia, Sutton, Peter, Thomas, Marie, Bamford, Amy, Bergin, Colin, Carrera, Ronald, Cooper, Lauren, Despy, Liesl, Ellis, Karen, Fellows, Emma, Goundry, Stephanie, Harkett, Samantha, Ip, Peter, Mason, Tracy, McGhee, Christopher, McLaughlin, Aisling, Neal, Aoife, Pope, Martin, Porter, Stephanie, Smith, Hazel, Snelson, Catherine, Spruce, Elaine, Vigo, Ylenia, Whitehouse, Arlo, Whitehouse, Tony, Donatiello, Maria, Gazzanelli, Sergio, Mezzapesa, Mario, Savino, Martina, Settesoldi, Giacomo, Kunst, Gudrun, Birch, Sian, Greig, Louise, Noble, Harriet, Pappa, Evita, Penhaligon, Bethany, Cossu, Andrea, Floris, Leda, Piredda, Davide, Racca, Alberto, Brattstrom, Olof, Heggelund, Bente, Flodberg, Magnus, Månsson, Sandra, Ahmed, Mamoona, Allen, Jonathan, Bell, Paula, Genetu, Roman, Glennon, Julia, Hanley, Janice, Jenner, Katy, Jogi, Summayyah, Mahjoob, Parisa, McGovern, Clare, Murphy, Anthony, Nazari, Roonak, Routledge, Jacki, Uttamlal, Trishna, Ward, Sinead, Iotti, Giorgio, Picchioni, Raffaella, Poma, Silvia, Navalesi, Paolo, Bruni, Andrea, De Leonardis, Brunella, Garofalo, Eugenio, Patel, Panna, McArthur, Carol, Burns, Karen, Peters, Steven, Foti, Giuseppe, Calcinati, Serena, Grassi, Alice, Villa, Silvia, Berridge, John, Kanakaraj, Muthuraj, Cahill, Hazel, Forshaw, Greg, Gibson, Andy, Grainger, Lia, Howard, Kate, James, Katherine, Murphy, Zoe, Sweeting, Helen, Tait, Rebecca, Wilcock, Danielle, Yates, David, Cope, Sean, Allan, Ashley, Betts, Rebecca, Cornell, Sarah, Sheriff, Julie, Woods, Lindsey, Grasselli, Giacomo, Brioni, Matteo, Castagna, Luigi, von Rahden, Richard, Farina, Zane, Green, Samantha, Gumede, Simphiwe, Rajah, Chantal, Ramkillawan, Arisha, Moug, Susan, Alcorn, David, Dalton, Carol, Dickinson, Natalie, Edwards, Jennifer, Henderson, Steven, McIlveen, Erin, Ramsaran, Richard, Bell, Joanne, Fleming, Lorna, Monks, Kathleen, Parker, Jane, Stamper, Sean, Stokes-Denson, Jo, Elías, Elisa, Guerra, Yessica, Rico-Feijoo, Jesus, Kidel, Carlos, Filipe, Helder, Asis, Gretchelle, Gleeson, Yvonne, Harvey, Alice, Jackson, Christine, McNeil, Margaret, Mingo, Sara, Pakou, Glykeria, Pinto, Manuel, Wright, Stephen, Babio-Galan, Maite, Buckley, David, Calder, Verity, Chishti, Ahmad, Cosgrove, Joseph, Cullen, Katherine, Dunn, Leigh, Faulds, Matthew, Fortune, Jonathan, Gardner, Matthew, Harrison, Abigail, Hays, Carole, Jones, Gerry, Macfie, Caroline, Mccullagh, Iain, Nesbitt, Ian, O'Neil, Suzanne, Phoenix, Catherine, Rangaswamy, Girish, Samson, Craig, Scott, Carmen, Shrestha, Tara, Singh, Rita, Soulsby, Graham, Walton, Jon, Zwiggelaar, Kimberley, Lynch, Ceri, Clarke, Heidi, Deacon, Bethan, Ivatt, Helen, Jones, Leanne, Latif, Ahmed, Oram, Shaun, Perman, Chris, Roche, Lisa, Duys, Rowan, Flint, Margot, Bhagwan, Kamal, Coetzee, Ettienne, Joubert, Ivan, Montoya-Pelaez, Felipe, Navsaria, Pradeep, Picken, Guy, Porrill, Owen, Strathie, Grant, Zungu, Thembinkosi, Aluri, Sireesha, Chau, Simon, Cooper, Deborah, Cunningham, Mishell, Daniels, Allison, Hope, Susan, Nicholson, Alice, Walker, Laura, Giarratano, Antonino, Accurso, Giuseppe, Raineri, Santi, Tricoli, Giuseppe, Innes, Richard, Doble, Patricia, Hutter, Joanne, Pawley, Corinne, Tait, Moira, Hamilton, Mark, Andrade, Edward, Barnes, Veronica, Dalton, Claire, Delgado, Carlos, Farnell-Ward, Sarah, Farrah, Helen, Gray, Geraldine, Howlett, Luisa, Joseph, Gipsy, Krupa, Monika, Leaver, Susannah, Macedo, Joao, Maher, Karen, Mellinghoff, Johannes, Oguntimehin, Rachel, Pereira, Joel, Robinson, Frances, Ryan, Christine, Shah, Nirav, Shirley, Paula, Torborg, Alexandra, Biyase, Thuli, Drummond, Leanne, Kusel, Belinda, Mbuyisa, Mbalenhle, Solala, Sivuyisiwe, Taylor, Jenna, Ezihe-Ejiofor, Adanma, Aduse-Poku, Maame, Colville, Gary, Davies, Louise, Kang, Soo, Phillips, Alex, Kirk-Bayley, Justin, Kelliher, Leigh, Carvelli, Paula, Daysal, Gokce, Dickinson, Matthew, Doyle, Nancileigh, Hughes, Christina, Montague, Laura, Potter, Elizabeth, Salberg, Armorel, Sibug, Sheena, Sivarajan, Sinduja, Thomson, Milo, Wakeford, Nichola, Rocco, Monica, Alampi, Daniela, Conway, Daniel, Clark, Richard, Maria, Jashmin, Pomeroy, Fiona, Quraishi, Tanviha, Williams, Abigail, Chukkambotla, Srikanth, Aherne, Caroline, Harrison-Briggs, Donna, Fitchett, Jill, Duberley, Stephen, Zanoni, Andrea, Cardinale, Daniela, Righi, Claudia, Blunt, Mark, Fuller, Tracy, Hodgson, Ruth, Rosbergen, Melissa, Brennan, Andrew, Akeroyd, Louise, Boardman, Victoria, Bull, Christopher, Carrick, Mike, Chadderton, Ian, Cooper, Sarah, Goellner, Sarah, Graham, Laura, Ilyas, Carl, King, James, Laklouk, Muhammad, Lawton, Tom, Macrow, Christopher, Munro, Michael, Neep, Adam, Northey, Martin, Peacock, Victoria, Pye, Kate, Radley, Lydia, Sira, James, Smithson, Beth, Syddall, Stuart, Tooth, David, White, Thomas, Hoel, Sindre, Aakre, Elin, Bakke, Monica, Hoivik, Tone, Makowski, Arystarch, Alcock, Harry, Cardoso, Sean, Coetzee, Samantha, Everett, Mary, Ibrahim, Mohamed, Kouridaki, Christina, Ogbeide, Vongayi, Bertellini, Elisabetta, Bertolotti, Valentina, Buono, Antonio, Fanigliulo, Maria, Kumar, Ram, Richards, Nicole, Allana, Alisha, Bacciarelli, Samantha, Barker, Helen, De Bois, Jessica, Bradley, Isabel, Crooks, Jennifer, Daum, Peter, Feben, Alex, Gannon, Lizzie, Kipling, Sarah, Peetamsingh, Andrew, Quamina, Charlotte, Sethi, Sahiba, Sivadhas, Harry, Sollesta, Kathryn, Swain, Andrew, Tan, Evalyn, Willis, Joan, Zou, Maggie, Cranshaw, Julius, Barratt, Nina, Bowman, Katie, Branney, Debbie, Letts, Maria, Pitts, Sally, Day, Christopher, Benyon, Sarah, Eddy, Sara, Green, Adam, Grice, Anna, Kelly, Sinéad, Mackle, Daisy, Mariano, Victor, Park, Linda, Sibley, Pauline, Spencer, William, Bignami, Elena, Bellini, Valentina, Forfori, Francesco, Curci, Maria, Leo, Alessandra, Jackson, Matthew, Awolesi, Jennifer, Hodgkinson, Sheila, Kent, Alissa, Leonard, Dee, Stapleton, Claire, Tibke, Clare, Alexander-Sefre, Farhad, Campey, Lorraine, Hall, Kathryn, Spimpolo, Jennifer, Nilsson, Malin, Didriksson, Helen, Hamilton, Emma, Carnahan, Mandy, Mowatt, Chris, Stickley, Jo, Corcione, Antonio, Rossi, Giuseppe, Fladby, Hege, Andersen, Nina, Bjoernå, Gunhild, Reite, Mads, Roertveit, Linda, Seidel, Philipp, Arnold, Glenn, Benavente, Melissa, Chattersingh, Anjalee, Chironga, Nyasha, Hornzee, Gillian, Kibaru, Joyce, Malik, Ihtisham, McLeavy, Laura, Pathmanathan, Byiravey, Prior, Florence, Strudwick, Rhea, Vezyrgiannis, Marios, Sinha, Aneeta, Babu, Sheeba, Batuwitage, Bisanth, Daly, Zoe, Ellinor, Katharine, Hawes, Elizabeth, Holmes, Ann, Hudson, Karen, Nightingale, Jeremy, Le Poidevin, Alison, Roberts, Lindsey, Kubisz-Pudelko, Agnieszka, Allison, Joanna, Pippard, Lucy, Hamlyn, Vincent, Organ, Angie, Prabhahar, Thaventhran, Bridger, Hayley, Dvorkin, Lee, Manhas, Vitul, Vincent, Rachel, Laha, Shondipon, Cromie, Terri-Louise, Doyle, Donna, Howarth, Rachel, Verlander, Mark, Watt, Ailsa, Williams, Alexandra, Antonelli, Massimo, Cutuli, Salvatore, Montini, Luca, Graterol, Juan, Adams, Benita, Bean, Sarah, Burt, Karen, Hammonds, Fiona, Jigajinni, Suyogi, Fulton, Laura, Kinghorn, Stephen, Mullenheim, Jost, Baillie, Kirsty, Cain, Martyn, Colling, Kerry, Hannaway, Carol, Corso, Ruggero, Calli, Morena, Ferrando, Carlos, Romero, Esther, Jorge-Monjas, Pablo, Soria-García, María, Gómez-Herreras, José, Rodríguez-Jiménez, Rita, and De Prada-Martín, Blanca

Published
2021
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22. A genome-wide association study suggests correlations of common genetic variants with peritoneal solute transfer rates in patients with kidney failure receiving peritoneal dialysis

Author

Pisoni, Ronald, Robinson, Bruce, Johnson, David, Cho, Yeoungjee, Wong, Muh Geot, Mather, Amanda, Cooper, Bruce, Devuyst, Olivier, Morelle, Johann, Goffin, Eric, Bammens, Bert, Bovy, Philippe, Margetts, Peter, Perl, Jeffrey, Taylor, Paul, Jain, Arsh, Jassal, Vanita, Stenvinkel, Peter, Heimburger, Olof, Kuan, Ying, Harron, Camille, Dasgupta, Indranil, Stoves, John, Akbani, Habib, Abeygunasekara, Sumith, Sharples, Edward, Mead, Paul, Hayat, Amer, Morgan, Neal, Cramp, Hilary, Robertson, Susan, Fielding, Richard, Brown, Edwina, Collinson, Helen, Ande, Pravene, Doulton, Tim, MacDougall, Iain, Cairns, Hugh, Vilar, Enric, Vardhan, Anand, Chess, James, Sandhu, Kanwaljit, Wilkie, Martin, McHaffie, Gavin, Lewis, Robert, Kamesh, Lavanya, Buck, Kate, Peel, Robert, Taylor, Jo, Johnston, Paul, Leung, Janson, Bingham, Coralie, Anijeet, Hameed, Asghar, Ramzana, Ranakrishna, Satish, Nair, Sunita, Iggo, Neil, Lewis, David, Udayaraj, Uday, Dawson, Susan, Woordrow, Graham, Chandrasekar, Thangavelu, Hamer, Rizwan, Barratt, Jonathan, Baines, Richard, Davies, Simon, Donovan, Kieron, Jones, Colin, Ynares, Christina, Dukes, Carl, Imam, Talha H., Corapi, Kristin, Nigwekar, Sagar, Khawar, Osman, Weiner, Daniel, Lau, Wei Ling, Harley, Kevin, Ghaffari, Arshia, Saxena, Ramesh, Abraham, Josephine, Mehrotra, Rajnish, Himmelfarb, Jonathan, Cavanaugh, Kerri L., Golper, Thomas A., Burkart, John M., Pirkle, James L., Miller, Brent, Jang, Judy, Turner, Jeffrey, Stanaway, Ian B., Jarvik, Gail P., Lambie, Mark, Johnson, David W., and Davies, Simon J.

Published
2021
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23. High Content Imaging Assays for IL-6-Induced STAT3 Pathway Activation in Head and Neck Cancer Cell Lines

Author

Johnston, Paul A, Sen, Malabika, Hua, Yun, Camarco, Daniel P, Shun, Tong Ying, Lazo, John S, and Grandis, Jennifer R

Subjects
Biochemistry and Cell Biology, Biological Sciences, Biotechnology, Cancer, Genetics, Rare Diseases, Animals, Cell Line, Tumor, Head and Neck Neoplasms, High-Throughput Screening Assays, Humans, Image Processing, Computer-Assisted, Interleukin-6, Molecular Imaging, Protein Binding, STAT3 Transcription Factor, Signal Transduction, STAT3 pathway activation, Head and neck cancer, High content screening, Imaging, Image analysis, Other Chemical Sciences, Developmental Biology, Biochemistry and cell biology, Medicinal and biomolecular chemistry
Abstract

In the canonical STAT3 signaling pathway, IL-6 receptor engagement leads to the recruitment of latent STAT3 to the activated IL-6 complex and the associated Janus kinase (JAK) phosphorylates STAT3 at Y705. pSTAT3-Y705 dimers traffic into the nucleus and bind to specific DNA response elements in the promoters of target genes to regulate their transcription. However, IL-6 receptor activation induces the phosphorylation of both the Y705 and S727 residues of STAT3, and S727 phosphorylation is required to achieve maximal STAT3 transcriptional activity. STAT3 continuously shuttles between the nucleus and cytoplasm and maintains a prominent nuclear presence that is independent of Y705 phosphorylation. The constitutive nuclear entry of un-phosphorylated STAT3 (U-STAT3) drives expression of a second round of genes by a mechanism distinct from that used by pSTAT3-Y705 dimers. The abnormally elevated levels of U-STAT3 produced by the constitutive activation of pSTAT3-Y705 observed in many tumors drive the expression of an additional set of pSTAT3-independent genes that contribute to tumorigenesis. In this chapter, we describe the HCS assay methods to measure IL-6-induced STAT3 signaling pathway activation in head and neck tumor cell lines as revealed by the expression and subcellular distribution of pSTAT3-Y705, pSTAT3-S727, and U-STAT3. Only the larger dynamic range provided by the pSTAT3-Y705 antibody would be robust and reproducible enough for screening.

Published
2018

25. Mechanism of action of selective inhibitors of IL-6 induced STAT3 pathway in head and neck cancer cell lines

Author

Sen, Malabika, Johnston, Paul A, Pollock, Netanya I, DeGrave, Kara, Joyce, Sonali C, Freilino, Maria L, Hua, Yun, Camarco, Daniel P, Close, David A, Huryn, Donna M, Wipf, Peter, and Grandis, Jennifer R

Subjects
Chemical Sciences, Dental/Oral and Craniofacial Disease, Cancer, Rare Diseases, Biotechnology, 2.1 Biological and endogenous factors, 5.1 Pharmaceuticals, Head and neck cancer, Interleukin-6, STAT3 inhibitors, STAT3 pathway, Biological Sciences, Biological sciences, Chemical sciences
Abstract

Studies indicate that elevated interleukin-6 (IL-6) levels engage IL6Rα-gp130 receptor complexes to activate signal transducer and activator of transcription 3 (STAT3) that is hyperactivated in many cancers including head and neck squamous cell carcinoma (HNSCC). Our previous HCS campaign identified several hits that selectively blocked IL-6-induced STAT3 activation. This study describes our investigation of the mechanism(s) of action of three of the four chemical series that progressed to lead activities: a triazolothiadiazine (864669), amino alcohol (856350), and an oxazole-piperazine (4248543). We demonstrated that all three blocked IL-6-induced upregulation of the cyclin D1 and Bcl-XL STAT3 target genes. None of the compounds exhibited direct binding interactions with STAT3 in surface plasmon resonance (SPR) binding assays; neither did they inhibit the recruitment and binding of a phospho-tyrosine-gp130 peptide to STAT3 in a fluorescence polarization assay. Furthermore, they exhibited little or no inhibition in a panel of 83 cancer-associated in vitro kinase profiling assays, including lack of inhibition of IL-6-induced Janus kinase (JAK 1, 2, and 3) activation. Further, 864669 and 4248543 selectively inhibited IL-6-induced STAT3 activation but not that induced by oncostatin M (OSM). The compounds 864669 and 4248543 abrogated IL-6-induced phosphorylation of the gp130 signaling subunit (phospho-gp130Y905) of the IL-6-receptor complex in HNSCC cell lines which generate docking sites for the SH2 domains of STAT3. Our data indicate that 864669 and 4248543 block IL-6-induced STAT activation by interfering with the recruitment, assembly, or activation of the hexamer-activated IL-6/IL-6Rα/gp130 signaling complex that occurs after IL-6 binding to IL-6Rα subunits.

Published
2017

26. Reconnecting society with its ecological roots

Author

Everard, Mark, Kass, Gary, Longhurst, James, zu Ermgassen, Sophus, Girardet, Herbert, Stewart-Evans, James, Wentworth, Jonathan, Austin, Kevin, Dwyer, Ciara, Fish, Robert, Johnston, Paul, Mantle, Gary, Staddon, Chad, Tickner, Dave, Spode, Steve, Vale, Jackie, Jarvis, Rhianna, Digby, Mathilda, Wren, Gwilym, Sunderland, Tim, and Craig, Amanda

Published
2021
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30. Morphology and systematic position of Shaninopsis Isberg, 1934 (Bivalvia: Cryptodonta), from the Boda Limestone (Upper Ordovician), Sweden.

Author

Johnston, Paul A, Collom, Christopher J, and Ebbestad, Jan Ove R

Subjects
*CHEMOSYNTHESIS (Biochemistry), *LIGAMENTS, *BIVALVES, *CALCITE, *LIMESTONE
Abstract

In a classic study of bivalves from the Upper Ordovician (Katian) Boda Limestone, Sweden, Isberg (1934) named and described 18 species of the unusual bivalve Shaninopsis , all from the same locality. Our study of the type material indicates that only three species at most are present: Shaninopsis prona Isberg, 1934, Shaninopsis radiata Isberg, 1934, and an unnamed species. Shaninopsis features a thick, prosocline, tear-drop-shaped shell with an opisthogyrous larval shell. Anterodorsally, the shell outline appears truncated to strongly concave owing to an inset sical surface that frames a conspicuous pedal gape. Above the gape, the lunule accreted posteriorly (retrusive growth—new term) and abuts the anterior part of the ligament area, perhaps compensating for anterior splitting of the ligament during growth. The hinge plate is edentulous, with a broad, opisthodetic, monovincular ligament. Muscle scars visible include only the posterior adductor, which is set near the posteroventral shell margin. Relict calcite prismatic texture preserved on the ligament area indicates the external prismatic calcite shell layer underlaid the ligament as in cardiolid praecardioids and some inoceramiformians. Evidence for a retractable non-biomineralized sheath-like structure extending from the pedal gape is presented. Shaninopsis is reconstructed as an orthothetic, epifaunal or shallow semi-infaunal bivalve capable of deeply probing underlying sediment for H2S uptake for chemosynthesis. Shaninopsis is assigned to a new subfamily Shaninopsiinae in the family Lunulacardiidae (infraclass Cryptodonta), a group otherwise unknown in pre-upper Silurian rocks. Remarkable similarities of Shaninopsis with the Permian bivalve Eurydesma suggest a mutual though geochronologically distant phylogenetic relationship. [ABSTRACT FROM AUTHOR]

Published
2024
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31. Yunfuconcha new genus, a possible stem-archiheterodont bivalve from the Ordovician of Guangdong, South China.

Author

Zhang, Ren-jie, Johnston, Paul A, Niu, Zhi-jun, Li, Chu-an, Wang, Zhi-hong, Hu, Kun, Song, Fang, He, Yao-yan, He, Jin-lan, Lin, Xiao-ming, and Yang, Wen-qiang

Subjects
*CONCAVE surfaces, *DENTITION, *HINGES, *BIVALVES, *LIGAMENTS
Abstract

Yunfuconcha bimenta , a new genus and species of bivalve from the Ordovician of western Guangdong, China, is described. Its unusual hinge consists of a palaeotaxodont-like dentition anteriorly and a heteroconch-like dentition posteriorly. The posterior hinge area exhibits a remarkable, broad, deeply inset, concave ligament area, which is reminiscent of the ventrally expanded ligament of some Recent and fossil lucinoids and the triangular resilifer in late Palaeozoic crassatellid heteroconchs. Lamellar posterior teeth and sockets complete the posterior dentition. The unusual combination of features, normally associated with either the Order Cardiolariatida (used here in place of Order 'Afghanodesmatida'—the type genus Afghanodesma , is known only from wax impressions rendering it and its nominal higher taxa invalid) or various crassatelloids and lucinoids, make systematic placement of Yunfuconcha n. gen. uncertain below subclass rank. In view of presumed derived heteroconch-like characters of the posterior hinge, we place Yunfuconcha n. gen. in the Subclass Autobranchia, possibly as a stem archiheterodont or a stem heteroconch. [ABSTRACT FROM AUTHOR]

Published
2024
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32. Subcutaneous administration of a novel TRPM8 antagonist reverses cold hypersensitivity while attenuating the drop in core body temperature.

Author

Gold, Michael S., Pineda‐Farias, Jorge B., Close, David, Patel, Smith, Johnston, Paul A., Stocker, Sean D., and Journigan, V. Blair

Subjects
CANCER chemotherapy, NEURALGIA, BODY temperature, TREATMENT effectiveness, TRPV cation channels
Abstract

Background and Purpose: We extend the characterization of the TRPM8 antagonist VBJ103 with tests of selectivity, specificity and distribution, therapeutic efficacy of systemic administration against oxaliplatin‐induced cold hyperalgesia and the impact of systemic administration on core body temperature (CBT). Experimental Approach: Selectivity at human TRPA1 and TRPV1 as well as in vitro safety profiling was determined. Effects of systemic administration of VBJ103 were evaluated in a model of oxaliplatin‐induced cold hyperalgesia. Both peripheral and centrally mediated effects of VBJ103 on CBT were assessed with radiotelemetry. Key Results: VBJ103 had no antagonist activity at TRPV1 and TRPA1, but low potency TRPA1 activation. The only safety liability detected was partial inhibition of the dopamine transporter (DAT). VBJ103 delivered subcutaneously dose‐dependently attenuated cold hypersensitivity in oxaliplatin‐treated mice at 3, 10 and 30 mg·kg−1 (n = 7, P < 0.05). VBJ103 (30 mg·kg−1) antinociception was influenced by neither the TRPA1 antagonist HC‐030031 nor the DAT antagonist GBR12909. Subcutaneous administration of VBJ103 (3, 10 and 30 mg·kg−1, but not 100 or 300 mg·kg−1, n = 7) decreased CBT (2°C). Intraperitoneal (i.p.) administration of VBJ103 (3, 10 and 30 mg·kg−1) dose‐dependently decreased CBT to an extent larger than that detected with subcutaneous administration. Intracerebroventricular (i.c.v.) administration (306 nmol/1 μL; n = 5) did not alter CBT. Conclusions and Implications: We achieve therapeutic efficacy with subcutaneous administration of a novel TRPM8 antagonist that attenuates deleterious influences on CBT, a side effect that has largely prevented the translation of TRPM8 as a target. [ABSTRACT FROM AUTHOR]

Published
2024
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38. Risk loci involved in giant cell arteritis susceptibility: a genome-wide association study

Author

Borrego-Yaniz, Gonzalo, primary, Ortiz-Fernández, Lourdes, additional, Madrid-Paredes, Adela, additional, Kerick, Martin, additional, Hernández-Rodríguez, José, additional, Mackie, Sarah L, additional, Vaglio, Augusto, additional, Castañeda, Santos, additional, Solans, Roser, additional, Mestre-Torres, Jaume, additional, Khalidi, Nader, additional, Langford, Carol A, additional, Ytterberg, Steven, additional, Beretta, Lorenzo, additional, Govoni, Marcello, additional, Emmi, Giacomo, additional, Cimmino, Marco A, additional, Witte, Torsten, additional, Neumann, Thomas, additional, Holle, Julia, additional, Schönau, Verena, additional, Pugnet, Gregory, additional, Papo, Thomas, additional, Haroche, Julien, additional, Mahr, Alfred, additional, Mouthon, Luc, additional, Molberg, Øyvind, additional, Diamantopoulos, Andreas P, additional, Voskuyl, Alexandre, additional, Daikeler, Thomas, additional, Berger, Christoph T, additional, Molloy, Eamonn S, additional, Blockmans, Daniel, additional, van Sleen, Yannick, additional, Iles, Mark, additional, Sorensen, Louise, additional, Luqmani, Raashid, additional, Reynolds, Gary, additional, Bukhari, Marwan, additional, Bhagat, Shweta, additional, Ortego-Centeno, Norberto, additional, Brouwer, Elisabeth, additional, Lamprecht, Peter, additional, Klapa, Sebastian, additional, Salvarani, Carlo, additional, Merkel, Peter A, additional, Cid, María C, additional, González-Gay, Miguel A, additional, Morgan, Ann W, additional, Martin, Javier, additional, Márquez, Ana, additional, Callejas, José Luis, additional, Caminal-Montero, Luis, additional, Corbera-Bellalta, Marc, additional, de Miguel, Eugenio, additional, Díaz-López, J. Bernardino, additional, García-Villanueva, María Jesús, additional, Gómez-Vaquero, Carmen, additional, Guijarro-Rojas, Mercedes, additional, Hidalgo-Conde, Ana, additional, Marí-Alfonso, Begoña, additional, Martínez-Berriochoa, Agustín, additional, Morado, Inmaculada C., additional, Narváez, Javier, additional, Ramentol-Sintas, Marc, additional, Martínez-Zapico, Aleida, additional, Martínez-Taboada, Víctor Manuel, additional, Miranda-Filloy, José A., additional, Monfort, Jordi, additional, Pérez-Conesa, Mercedes, additional, Prieto-González, Sergio, additional, Raya, Enrique, additional, Ríos-Fenández, Raquel, additional, Sánchez-Martín, Julio, additional, Sopeña, Bernardo, additional, Tío, Laura, additional, Unzurrunzaga, Ainhoa, additional, Wordsworth, Oliver, additional, Whitwell, Isobel, additional, Brock, Jessica, additional, Douglas, Victoria, additional, Hettiarachchi, Chamila, additional, Bartholomew, Jacqui, additional, Jarrett, Stephen, additional, Smithson, Gayle, additional, Green, Michael, additional, Brown, Pearl Clark, additional, Lawson, Cathy, additional, Gordon, Esther, additional, Lane, Suzanne, additional, Francis, Rebecca, additional, Dasgupta, Bhaskar, additional, Masunda, Bridgett, additional, Calver, Jo, additional, Patel, Yusuf, additional, Thompson, Charlotte, additional, Gregory, Louise, additional, Levy, Sarah, additional, Menon, Ajit, additional, Thompson, Amy, additional, Dyche, Lisa, additional, Martin, Michael, additional, Li, Charles, additional, Laxminarayan, Ramasharan, additional, Wilcox, Louise, additional, de Guzman, Ralph, additional, Isaacs, John, additional, Lorenzi, Alice, additional, Farley, Ross, additional, Hinchcliffe-Hume, Helain, additional, Bejarano, Victoria, additional, Hope, Susan, additional, Nandi, Pradip, additional, Stockham, Lynne, additional, Wilde, Catherine, additional, Durrant, Donna, additional, Lloyd, Mark, additional, Ye, Chee-Seng, additional, Stevens, Rob, additional, Jilani, Amjad, additional, Collins, David, additional, Pegler, Suzannah, additional, Rivett, Ali, additional, Price, Liz, additional, McHugh, Neil, additional, Skeoch, Sarah, additional, O'Kane, Diana, additional, Kirkwood, Sue, additional, Vadivelu, Saravanan, additional, Pugmire, Susan, additional, Sultan, Shabina, additional, Dooks, Emma, additional, Armstrong, Lisa, additional, Sadik, Hala, additional, Nandagudi, Anupama, additional, Abioye, Tolu, additional, Ramos, Angelo, additional, Gumus, Steph, additional, Sofat, Nidhi, additional, Harrison, Abiola, additional, Seward, Abi, additional, Mollan, Susan, additional, Rahan, Ray, additional, Hawkins, Helen, additional, Emsley, Hedley, additional, Bhargava, Anna, additional, Fleming, Vicki, additional, Hare, Marianne, additional, Raj, Sonia, additional, George, Emmanuel, additional, Allen, Nicola, additional, Hunter, Karl, additional, O'Sullivan, Eoin, additional, Bird, Georgina, additional, Magliano, Malgorzata, additional, Manzo, Katarina, additional, Sanghera, Bobbie, additional, Hutchinson, David, additional, Hammonds, Fiona, additional, Sharma, Poonam, additional, Cooper, Richard, additional, McLintock, Graeme, additional, Al-Saffar, Zaid S., additional, Green, Mike, additional, Elliott, Kerry, additional, Neale, Tania, additional, Mallinson, Janine, additional, Lanyon, Peter, additional, Pradere, Marie-Josephe, additional, Jordan, Natasha, additional, Htut, Ei Phyu, additional, Mushapaidzi, Thelma, additional, Abercrombie, Donna, additional, Wright, Sam, additional, Rowlands, Jane, additional, Mukhtyar, Chetan, additional, Kennedy, James, additional, Makkuni, Damodar, additional, Wilhelmsen, Elva, additional, Kouroupis, Michael, additional, John, Lily, additional, Hughes, Rod, additional, Walsh, Margaret, additional, Buckley, Marie, additional, Mackay, Kirsten, additional, Camden-Woodley, Tracey, additional, Redome, Joan, additional, Pearce, Kirsty, additional, Marianayagam, Thiraupathy, additional, Cruz, Carina, additional, Warner, Elizabeth, additional, Atchia, Ishmael, additional, Walker, Claire, additional, Black, Karen, additional, Duffy, Stacey, additional, Fothergill, Lynda, additional, Jefferey, Rebecca, additional, Toomey, Jackie, additional, Rhys-Dillon, Ceril, additional, Pothecary, Carla, additional, Green, Lauren, additional, Toms, Tracey, additional, Maher, Linda, additional, Davis, Diana, additional, Sayan, Amrinder, additional, Thankachen, Mini, additional, Abusalameh, Mahdi, additional, Record, Jessica, additional, Khan, Asad, additional, Stafford, Sam, additional, Hussein, Azza, additional, Williams, Clare, additional, Fletcher, Alison, additional, Johson, Laura, additional, Burnett, Richard, additional, Moots, Robert, additional, Frankland, Helen, additional, Dale, James, additional, Moar, Kirsten, additional, Hollas, Carol, additional, Parker, Ben, additional, Ridings, Derek, additional, Eapen, Sandhya, additional, John, Sindhu, additional, Robson, Jo, additional, Guthrie, Lucy Belle, additional, Fyfe, Rose, additional, Tait, Moira, additional, Marks, Jonathan, additional, Gunter, Emma, additional, Hernandez, Rochelle, additional, Bhat, Smita, additional, Johnston, Paul, additional, Khurshid, Muhammad, additional, Barclay, Charlotte, additional, Kapur, Deepti, additional, Jeffrey, Helen, additional, Hughes, Anna, additional, Slack, Lauren, additional, Thomas, Eleri, additional, Royon, Anna, additional, Hall, Angela, additional, King, Jon, additional, Nyathi, Sindi, additional, Morris, Vanessa, additional, Castelino, Madhura, additional, Hawkins, Ellie, additional, Tomson, Linda, additional, Singh, Animesh, additional, Nunag, Annalyn, additional, O'Connor, Stella, additional, Rushby, Nathan, additional, Hewitson, Nicola, additional, O'Sunmboye, Kenny, additional, Lewszuk, Adam, additional, Boyles, Louise, additional, Perry, Martin, additional, Williams, Emma, additional, Graver, Christine, additional, Defever, Emmanuel, additional, Kamanth, Sanjeet, additional, Kay, Dominic, additional, Ogor, Joe, additional, Winter, Louise, additional, Horton, Sarah, additional, Welch, Gillian, additional, Hollinshead, Kath, additional, Peters, James, additional, Labao, Julius, additional, Dmello, Andrea, additional, Dawson, Julie, additional, Graham, Denise, additional, De Lord, Denise, additional, Deery, Jo, additional, Hazelton, Tracy, additional, Carette, Simon, additional, Chung, Sharon, additional, Cuthbertson, David, additional, Forbess, Lindsy J., additional, Gewurz-Singer, Ora, additional, Hoffman, Gary S., additional, Koening, Curry L., additional, Maksimowicz-McKinnon, Kathleen M., additional, McAlear, Carol A., additional, Moreland, Larry W., additional, Pagnoux, Christian, additional, Seo, Philip, additional, Specks, Ulrich, additional, Spiera, Robert F., additional, Sreih, Antoine, additional, Warrington, Kenneth J., additional, Monach, Paul A., additional, and Weisman, Michael, additional

Published
2024
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41. Toxicity, pharmacokinetics and metabolism of a novel inhibitor of IL-6-induced STAT3 activation

Author

Kiesel, Brian F, Parise, Robert A, Guo, Jianxia, Huryn, Donna M, Johnston, Paul A, Colombo, Raffaele, Sen, Malabika, Grandis, Jennifer R, Beumer, Jan H, and Eiseman, Julie L

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Infectious Diseases, Rare Diseases, Orphan Drug, Animals, Female, Interleukin-6, Mice, Microsomes, Liver, STAT3 Transcription Factor, Thiadiazines, Triazoles, Pharmacokinetics, Small molecule inhibitor of STAT3, IL-6, LC-MS, Pharmacology and Pharmaceutical Sciences, Oncology & Carcinogenesis, Oncology and carcinogenesis, Pharmacology and pharmaceutical sciences
Abstract

PurposeThe oncogenic transcription factor signal transducer and activator of transcription 3 (STAT3) promotes gene transcription involved in cancer, and its activation by IL-6 is found in head and neck squamous cell carcinoma. Four triazolothiadizine STAT3 pathway inhibitors were evaluated to prioritize a single compound for in vivo examination.MethodsMetabolic stability in mouse liver microsome incubation was used to evaluate four triazolothiadizine analogues, and UPCDC-10205 was administered to mice IV as single or multiple doses to evaluate toxicity. Single-dose pharmacokinetics (PK), bioavailability and metabolism were studied after IV 4 mg/kg, PO 4 mg/kg, or PO 30 mg/kg suspension in 1% carboxymethyl cellulose. Mice were euthanized between 5 min to 24 h after dosing, and plasma and tissues were analyzed by LC-MS. Non-compartmental PK parameters were determined.ResultsOf the four triazolothiadizine analogues evaluated, UPCDC-10205 was metabolically most stable. The maximum soluble dose of 4 mg/kg in 10% Solutol™ was not toxic to mice after single and multiple doses. PK analysis showed extensive tissue distribution and rapid plasma clearance. Bioavailability was ~5%. A direct glucuronide conjugate was identified as the major metabolite which was recapitulated in vitro.ConclusionsRapid clearance of UPCDC-10205 was thought to be the result of phase II metabolism despite its favorable stability in a phase I in vitro metabolic stability assay. The direct glucuronidation explains why microsomal stability (reflective of phase I metabolism) did not translate to in vivo metabolic stability. UPCDC-10205 did not demonstrate appropriate exposure to support efficacy studies in the current formulation.

Published
2016

42. Optimization of pyrazole-containing 1,2,4-triazolo-[3,4-b]thiadiazines, a new class of STAT3 pathway inhibitors

Author

LaPorte, Matthew G, Wang, Zhuzhu, Colombo, Raffaele, Garzan, Atefeh, Peshkov, Vsevolod A, Liang, Mary, Johnston, Paul A, Schurdak, Mark E, Sen, Malabika, Camarco, Daniel P, Hua, Yun, Pollock, Netanya I, Lazo, John S, Grandis, Jennifer R, Wipf, Peter, and Huryn, Donna M

Subjects
Medicinal and Biomolecular Chemistry, Chemical Sciences, Biotechnology, Antineoplastic Agents, Cell Line, Tumor, Cell Proliferation, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Humans, Molecular Structure, Pyrazoles, STAT3 Transcription Factor, Structure-Activity Relationship, Thiadiazines, Triazoles, STAT3 inhibitor, Triazolo-thiadiazines, Anti-cancer agents, STAT1, Organic Chemistry, Pharmacology and Pharmaceutical Sciences, Medicinal & Biomolecular Chemistry, Medicinal and biomolecular chemistry, Organic chemistry
Abstract

Structure-activity relationship studies of a 1,2,4-triazolo-[3,4-b]thiadiazine scaffold, identified in an HTS campaign for selective STAT3 pathway inhibitors, determined that a pyrazole group and specific aryl substitution on the thiadiazine were necessary for activity. Improvements in potency and metabolic stability were accomplished by the introduction of an α-methyl group on the thiadiazine. Optimized compounds exhibited anti-proliferative activity, reduction of phosphorylated STAT3 levels and effects on STAT3 target genes. These compounds represent a starting point for further drug discovery efforts targeting the STAT3 pathway.

Published
2016

47. Unique features of a global human ectoparasite identified through sequencing of the bed bug genome.

Author

Benoit, Joshua B, Adelman, Zach N, Reinhardt, Klaus, Dolan, Amanda, Poelchau, Monica, Jennings, Emily C, Szuter, Elise M, Hagan, Richard W, Gujar, Hemant, Shukla, Jayendra Nath, Zhu, Fang, Mohan, M, Nelson, David R, Rosendale, Andrew J, Derst, Christian, Resnik, Valentina, Wernig, Sebastian, Menegazzi, Pamela, Wegener, Christian, Peschel, Nicolai, Hendershot, Jacob M, Blenau, Wolfgang, Predel, Reinhard, Johnston, Paul R, Ioannidis, Panagiotis, Waterhouse, Robert M, Nauen, Ralf, Schorn, Corinna, Ott, Mark-Christoph, Maiwald, Frank, Johnston, J Spencer, Gondhalekar, Ameya D, Scharf, Michael E, Peterson, Brittany F, Raje, Kapil R, Hottel, Benjamin A, Armisén, David, Crumière, Antonin Jean Johan, Refki, Peter Nagui, Santos, Maria Emilia, Sghaier, Essia, Viala, Sèverine, Khila, Abderrahman, Ahn, Seung-Joon, Childers, Christopher, Lee, Chien-Yueh, Lin, Han, Hughes, Daniel ST, Duncan, Elizabeth J, Murali, Shwetha C, Qu, Jiaxin, Dugan, Shannon, Lee, Sandra L, Chao, Hsu, Dinh, Huyen, Han, Yi, Doddapaneni, Harshavardhan, Worley, Kim C, Muzny, Donna M, Wheeler, David, Panfilio, Kristen A, Vargas Jentzsch, Iris M, Vargo, Edward L, Booth, Warren, Friedrich, Markus, Weirauch, Matthew T, Anderson, Michelle AE, Jones, Jeffery W, Mittapalli, Omprakash, Zhao, Chaoyang, Zhou, Jing-Jiang, Evans, Jay D, Attardo, Geoffrey M, Robertson, Hugh M, Zdobnov, Evgeny M, Ribeiro, Jose MC, Gibbs, Richard A, Werren, John H, Palli, Subba R, Schal, Coby, and Richards, Stephen

Subjects
Animals, Humans, Bedbugs, Ectoparasitic Infestations, Insecticides, Sequence Analysis, DNA, Feeding Behavior, Gene Transfer, Horizontal, Insecticide Resistance, Genome, Host-Parasite Interactions, Gene Transfer, Horizontal, Sequence Analysis, DNA
Abstract

The bed bug, Cimex lectularius, has re-established itself as a ubiquitous human ectoparasite throughout much of the world during the past two decades. This global resurgence is likely linked to increased international travel and commerce in addition to widespread insecticide resistance. Analyses of the C. lectularius sequenced genome (650 Mb) and 14,220 predicted protein-coding genes provide a comprehensive representation of genes that are linked to traumatic insemination, a reduced chemosensory repertoire of genes related to obligate hematophagy, host-symbiont interactions, and several mechanisms of insecticide resistance. In addition, we document the presence of multiple putative lateral gene transfer events. Genome sequencing and annotation establish a solid foundation for future research on mechanisms of insecticide resistance, human-bed bug and symbiont-bed bug associations, and unique features of bed bug biology that contribute to the unprecedented success of C. lectularius as a human ectoparasite.

Published
2016

48. Morphology and systematic position of Shaninopsis Isberg, 1934 (Bivalvia : Cryptodonta), from the Boda Limestone (Upper Ordovician), Sweden

Author

Johnston, Paul A., Collom, Christopher J., Ebbestad, Jan Ove R., Johnston, Paul A., Collom, Christopher J., and Ebbestad, Jan Ove R.

Abstract

In a classic study of bivalves from the Upper Ordovician (Katian) Boda Limestone, Sweden, Isberg (1934) named and described 18 species of the unusual bivalve Shaninopsis, all from the same locality. Our study of the type material indicates that only three species at most are present: Shaninopsis prona Isberg, 1934, Shaninopsis radiata Isberg, 1934, and an unnamed species. Shaninopsis features a thick, prosocline, tear-drop-shaped shell with an opisthogyrous larval shell. Anterodorsally, the shell outline appears truncated to strongly concave owing to an inset sical surface that frames a conspicuous pedal gape. Above the gape, the lunule accreted posteriorly (retrusive growth-new term) and abuts the anterior part of the ligament area, perhaps compensating for anterior splitting of the ligament during growth. The hinge plate is edentulous, with a broad, opisthodetic, monovincular ligament. Muscle scars visible include only the posterior adductor, which is set near the posteroventral shell margin. Relict calcite prismatic texture preserved on the ligament area indicates the external prismatic calcite shell layer underlaid the ligament as in cardiolid praecardioids and some inoceramiformians. Evidence for a retractable non-biomineralized sheath-like structure extending from the pedal gape is presented. Shaninopsis is reconstructed as an orthothetic, epifaunal or shallow semi-infaunal bivalve capable of deeply probing underlying sediment for H2S uptake for chemosynthesis. Shaninopsis is assigned to a new subfamily Shaninopsiinae in the family Lunulacardiidae (infraclass Cryptodonta), a group otherwise unknown in pre-upper Silurian rocks. Remarkable similarities of Shaninopsis with the Permian bivalve Eurydesma suggest a mutual though geochronologically distant phylogenetic relationship.

Published
2024
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49. HCS Campaign to Identify Selective Inhibitors of IL-6-Induced STAT3 Pathway Activation in Head and Neck Cancer Cell Lines

Author

Johnston, Paul A, Sen, Malabika, Hua, Yun, Camarco, Daniel P, Shun, Tong Ying, Lazo, John S, Wilson, Gabriela Mustata, Resnick, Lynn O, LaPorte, Matthew G, Wipf, Peter, Huryn, Donna M, and Grandis, Jennifer R

Subjects
Biomedical and Clinical Sciences, Medicinal and Biomolecular Chemistry, Chemical Sciences, Oncology and Carcinogenesis, Cancer, Dental/Oral and Craniofacial Disease, Rare Diseases, 5.1 Pharmaceuticals, Carcinoma, Squamous Cell, Cell Line, Tumor, Head and Neck Neoplasms, High-Throughput Screening Assays, Humans, Interferon-gamma, Interleukin-6, STAT1 Transcription Factor, STAT3 Transcription Factor, Signal Transduction, Squamous Cell Carcinoma of Head and Neck, Physical Chemistry (incl. Structural), Pharmacology and Pharmaceutical Sciences, Medicinal & Biomolecular Chemistry, Pharmacology and pharmaceutical sciences, Medicinal and biomolecular chemistry
Abstract

Signal transducer and activator of transcription factor 3 (STAT3) is hyperactivated in head and neck squamous cell carcinomas (HNSCC). Cumulative evidence indicates that IL-6 production by HNSCC cells and/or stromal cells in the tumor microenvironment activates STAT3 and contributes to tumor progression and drug resistance. A library of 94,491 compounds from the Molecular Library Screening Center Network (MLSCN) was screened for the ability to inhibit interleukin-6 (IL-6)-induced pSTAT3 activation. For contractual reasons, the primary high-content screening (HCS) campaign was conducted over several months in 3 distinct phases; 1,068 (1.1%) primary HCS actives remained after cytotoxic or fluorescent outliers were eliminated. One thousand one hundred eighty-seven compounds were cherry-picked for confirmation; actives identified in the primary HCS and compounds selected by a structural similarity search of the remaining MLSCN library using hits identified in phases I and II of the screen. Actives were confirmed in pSTAT3 IC50 assays, and an IFNγ-induced pSTAT1 activation assay was used to prioritize selective inhibitors of STAT3 activation that would not inhibit STAT1 tumor suppressor functions. Two hundred three concentration-dependent inhibitors of IL-6-induced pSTAT3 activation were identified and 89 of these also produced IC50s against IFN-γ-induced pSTAT1 activation. Forty-nine compounds met our hit criteria: they reproducibly inhibited IL-6-induced pSTAT3 activation by ≥70% at 20 μM; their pSTAT3 activation IC50s were ≤25 μM; they were ≥2-fold selective for pSTAT3 inhibition over pSTAT1 inhibition; a cross target query of PubChem indicated that they were not biologically promiscuous; and they were ≥90% pure. Twenty-six chemically tractable hits that passed filters for nuisance compounds and had acceptable drug-like and ADME-Tox properties by computational evaluation were purchased for characterization. The hit structures were distributed among 5 clusters and 8 singletons. Twenty-four compounds inhibited IL-6-induced pSTAT3 activation with IC50s ≤20 μM and 13 were ≥3-fold selective versus inhibition of pSTAT1 activation. Eighteen hits inhibited the growth of HNSCC cell lines with average IC50s ≤ 20 μM. Four chemical series were progressed into lead optimization: the guanidinoquinazolines, the triazolothiadiazines, the amino alcohols, and an oxazole-piperazine singleton.

Published
2015

50. Genomic Correlate of Exceptional Erlotinib Response in Head and Neck Squamous Cell Carcinoma

Author

Van Allen, Eliezer M, Lui, Vivian WY, Egloff, Ann Marie, Goetz, Eva M, Li, Hua, Johnson, Jonas T, Duvvuri, Umamaheswar, Bauman, Julie E, Stransky, Nicolas, Zeng, Yan, Gilbert, Breean R, Pendleton, Kelsey P, Wang, Lin, Chiosea, Simion, Sougnez, Carrie, Wagle, Nikhil, Zhang, Fan, Du, Yu, Close, David, Johnston, Paul A, McKenna, Aaron, Carter, Scott L, Golub, Todd R, Getz, Gad, Mills, Gordon B, Garraway, Levi A, and Grandis, Jennifer R

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Genetics, Dental/Oral and Craniofacial Disease, Cancer, Clinical Research, Cancer Genomics, Human Genome, Lung, Orphan Drug, Clinical Trials and Supportive Activities, Rare Diseases, Lung Cancer, Adult, Antineoplastic Agents, Biomarkers, Tumor, Biopsy, Carcinoma, Squamous Cell, Chemotherapy, Adjuvant, DNA Mutational Analysis, Drug Administration Schedule, ErbB Receptors, Erlotinib Hydrochloride, Genetic Predisposition to Disease, Head and Neck Neoplasms, Humans, Male, Mitogen-Activated Protein Kinase 1, Molecular Targeted Therapy, Mutation, Neoadjuvant Therapy, Neoplasm Staging, Phenotype, Phosphorylation, Predictive Value of Tests, Protein Kinase Inhibitors, Randomized Controlled Trials as Topic, Remission Induction, Squamous Cell Carcinoma of Head and Neck, Time Factors, Tongue Neoplasms, Treatment Outcome, Public Health and Health Services, Oncology and carcinogenesis
Abstract

ImportanceRandomized clinical trials demonstrate no benefit for epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in unselected patients with head and neck squamous cell carcinoma (HNSCC). However, a patient with stage IVA HNSCC received 13 days of neoadjuvant erlotinib and experienced a near-complete histologic response.ObjectiveTo determine a mechanism of exceptional response to erlotinib therapy in HNSCC.Design, setting, and participantsSingle patient with locally advanced HNSCC who received erlotinib monotherapy in a window-of-opportunity clinical trial (patients scheduled to undergo primary cancer surgery are treated briefly with an investigational agent). Whole-exome sequencing of pretreatment tumor and germline patient samples was performed at a quaternary care academic medical center, and a candidate somatic variant was experimentally investigated for mediating erlotinib response.InterventionA brief course of erlotinib monotherapy followed by surgical resection.Main outcomes and measuresIdentification of pretreatment tumor somatic alterations that may contribute to the exceptional response to erlotinib. Hypotheses were formulated regarding enhanced erlotinib response in preclinical models harboring the patient tumor somatic variant MAPK1 E322K following the identification of tumor somatic variants.ResultsNo EGFR alterations were observed in the pretreatment tumor DNA. Paradoxically, the tumor harbored an activating MAPK1 E322K mutation (allelic fraction 0.13), which predicts ERK activation and erlotinib resistance in EGFR-mutant lung cancer. The HNSCC cells with MAPK1 E322K exhibited enhanced EGFR phosphorylation and erlotinib sensitivity compared with wild-type MAPK1 cells.Conclusions and relevanceSelective erlotinib use in HNSCC may be informed by precision oncology approaches.

Published
2015

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