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4. Effects of Early Life Exposures to the Aryl Hydrocarbon Receptor Ligand TCDF on Gut Microbiota and Host Metabolic Homeostasis in C57BL/6J Mice

Author

Tian, Yuan, Rimal, Bipin, Bisanz, Jordan E., Gui, Wei, Wolfe, Trenton M., Koo, Imhoi, Murray, Iain A., Nettleford, Shaneice K., Yokoyama, Shigetoshi, Dong, Fangcong, Koshkin, Sergei, Prabhu, K. Sandeep, Turnbaugh, Peter J., Walk, Seth T., Perdew, Gary H., and Patterson, Andrew D.

Subjects
Physiological aspects, Environmental aspects, Health aspects, Homeostasis -- Environmental aspects, Microbiota (Symbiotic organisms) -- Physiological aspects -- Environmental aspects -- Health aspects, Hydrocarbons -- Physiological aspects -- Health aspects, Persistent organic pollutants -- Physiological aspects -- Health aspects, Metabolism -- Environmental aspects -- Health aspects
Abstract

Introduction Persistent organic pollutants (POPs) are a serious and global threat to human health owing to their persistence, prevalence, and bioaccumulative nature. Exposure to POPs is associated with various health [...], BACKGROUND: Exposure to persistent organic pollutants (POPs) and disruptions in the gastrointestinal microbiota have been positively correlated with a predisposition to factors such as obesity, metabolic syndrome, and type 2 diabetes; however, it is unclear how the microbiome contributes to this relationship. OBJECTIVE: This study aimed to explore the association between early life exposure to a potent aryl hydrocarbon receptor (AHR) agonist and persistent disruptions in the microbiota, leading to impaired metabolic homeostasis later in life. METHODS: This study used metagenomics, nuclear magnetic resonance (NMR)- and mass spectrometry (MS)-based metabolomics, and biochemical assays to analyze the gut microbiome composition and function, as well as the physiological and metabolic effects of early life exposure to 2,3,7,8-tetrachlorodibenzofuran (TCDF) in conventional, germ-free (GF), and Ahr-null mice. The impact of TCDF on Akkermansia muciniphila (A. muciniphila) in vitro was assessed using optical density (OD 600), flow cytometry, transcriptomics, and MS-based metabolomics. RESULTS: TCDF-exposed mice exhibited lower abundances of A. muciniphila, lower levels of cecal short-chain fatty acids (SCFAs) and indole-3-lactic acid (ILA), as well as lower levels of the gut hormones glucagon-like peptide 1 (GLP-1) and peptide YY (PYY), findings suggestive of disruption in the gut microbiome community structure and function. Importantly, microbial and metabolic phenotypes associated with early life POP exposure were transferable to GF recipients in the absence of POP carry-over. In addition, AHR-independent interactions between POPs and the microbiota were observed, and they were significantly associated with growth, physiology, gene expression, and metabolic activity outcomes of A. muciniphila, supporting suppressed activity along the ILA pathway. CONCLUSIONS: These data obtained in a mouse model point to the complex effects of POPs on the host and microbiota, providing strong evidence that early life, short-term, and self-limiting POP exposure can adversely impact the microbiome, with effects persisting into later life with associated health implications. https://doi.org/10.1289/EHP13356

Published
2024
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6. High Positive End-expiratory Pressure (PEEP) with Recruitment Maneuvers versus Low PEEP during General Anesthesia for Surgery: A Bayesian Individual Patient Data Meta-analysis of Three Randomized Clinical Trials

Author

Mazzinari, Guido, Zampieri, Fernando G., Ball, Lorenzo, Campos, Niklas S., Bluth, Thomas, Hemmes, Sabrine N. T., Ferrando, Carlos, Librero, Julian, Soro, Marina, Pelosi, Paolo, Gama de Abreu, Marcelo, Schultz, Marcus J., Serpa Neto, Ary, Campos, Niklas S., Bluth, Thomas, Hemmes, Sabrine N.T., Ferrando, Carlos, Pelosi, Paolo, de Abreu, Marcelo Gama, Schultz, Marcus J., Neto, Ary Serpa, Campos, Niklas S., Bluth, Thomas, Hemmes, Sabrine N.T., Librero, Julian, Pozo, Natividad, Ferrando, Carlos, Ball, Lorenzo, Mazzinari, Guido, Pelosi, Paolo, de Abreu, Marcelo Gama, Schultz, Marcus J., Neto, Ary Serpa, Hemmes, Sabrine N.T., Gama de Abreu, Marcelo, Severgnini, Paolo, Hollmann, Markus W., Binnekade, Jan M., Wrigge, Hermann, Canet, Jaume, Hiesmayr, Michael, Schmid, Werner, Tschernko, Edda, Jaber, Samir, Hedenstierna, Göran, Putensen, Christian, Pelosi, Paolo, Schultz, Marcus J., Marti, Agnes, Bacuzzi, Alessandro, Brodhun, Alexander, Molin, Alexandre, Merten, Alfred, Parera, Ana, Brunelli, Andrea, Cortegiani, Andrea, Güldner, Andreas, Reske, Andreas W., Gratarola, Angelo, Giarratano, Antonino, Bastin, Bea, Heyse, Bjorn, Mazul-Sunko, Branka, Amantea, Bruno, Barberis, Bruno, Putensen, Christian, Uhlig, Christopher, Minguez Marín, Conrado, Celentano, Cristian, La Bella, Daniela, D’Antini, David, Velghe, David, Sulemanji, Demet, De Robertis, Edoardo, Hartmann, Eric, Montalto, Francesca, Tropea, Francesco, Mills, Gary H., Cinnella, Gilda, Rocca, Giorgio Della, Caggianelli, Girolamo, Pellerano, Giulia, Mollica, Giuseppina, Bugedo, Guillermo, Wrigge, Hermann, Mulier, Jan-Paul, Vandenbrande, Jeroen, Geib, Johann, Yaqub, Jonathan, Florez, Jorge, Mayoral, Juan F., Sprung, Juraj, Van Limmen, Jurgen, Bos, Lieuwe D.J., de Baerdemaeker, Luc, Jamaer, Luc, Spagnolo, Luigi, Strys, Lydia, Granell Gil, Manuel, de Abreu, Marcelo Gama, Vidal Melo, Marcos F., Schultz, Marcus J., Unzueta, Maria Carmen, Moral, Maria Victoria, Ferner, Marion, Hollmann, Markus W., Weiss, Martin, Vanoni, Massimo, Schaefer, Maximilian S., Prieto, Mercè, Grio, Michele, Severgnini, Paolo, Spieth, Peter Markus, Simon, Philipp, Bodger, Phoebe, Sierra, Pilar, Laufenberg-Feldmann, Rita, Rusca, Roberta, Proietti, Rodolfo, Hemmes, Sabrine N.T., Raineri, Santi Maurizio, Caroleo, Santo, Sabaté, Sergi, De Hert, Stefan, Pezzato, Stefano, Treschan, Tanja A., Goranovic, Tatjana, Koch, Thea, Bluth, Thomas, Kiss, Thomas, Perilli, Valter, Cegarra, Virginia, Schmid, Werner, Ferrando, Carlos, Belda, Javier, Soro, Marina, Canet, Jaume, Unzueta, Carmen, Suarez-Sipmann, Fernando, Librero, Julián, Llombart, Alicia, Rovira, Lucas, Granell, Manuel, Aldecoa, César, Diaz-Cambronero, Oscar, Balust, Jaume, Garutti, Ignacio, Gonzalez, Rafael, Gallego, Lucia, del Valle, Santiago Garcia, Redondo, Javier, Pestaña, David, Rodríguez, Aurelio, García, Javier, de la Matta, Manuel, Ibáñez, Maite, Barrios, Francisco, Hernández, Samuel, Torres, Vicente, Peiró, Salvador, Pozo, Natividad, Villena, Abigail, Carramiñana, Albert, Gallego-Casilda, Alberto, Duca, Alejandro, Alcón, Amalia, Miñana, Amanda, Asensio, Ana, Colás, Ana, Isabel Galve, Ana, Izquierdo, Ana, Jurado, Ana, María Pérez, Ana, Mugarra, Ana, Parera, Ana, Brunelli, Andrea, Gutierrez, Andrea, De Miguel, Ángeles, Lozano, Angels, Katime, Antonio, Romero, Antonio, Garrigues, Beatriz, Ayas, Begoña, Arocas, Blanca, Delgado, Carlos, Fernández, Carmen, Romero, Carolina, Gallego, Clara, Garcés, Cristina, Lisbona, Cristina, Parrilla, Cristina, López-Herrera, Daniel, González, Domingo, Llamazares, Eduardo, Del Rio, Elena, Lozano, Elena, Pastor, Ernesto, Chamorro, Estefanía, Gracia, Estefanía, Sánchez, Ester, Romero, Esther, Díez, Fernando, Serralta, Ferran, Daviu, Francisco, Sandín, Francisco, Aguilar, Gerardo, Tusman, Gerardo, Azparren, Gonzalo, Martínez-Pallí, Graciela, Mazzinari, Guido, Benítez, Inmaculada, Hernandéz, Inmaculada, India, Inmaculada, León, Irene, Fuentes, Isabel, Ruiz, Isabel, Puig, Jaume, Ignacio Román, Javie, Acosta, Jesús, Rico, Jesús, Olmedo, Jonathan, Carbonell, Jose A., Alonso, Jose M., María Pérez, Jose, Miguel Marcos, Jose, Navarro, Jose, Valdivia, Jose, Carrizo, Juan, Piqueras, Laura, Soriano, Laura, Vaquero, Laura, Miguel, Lisset, Muñoz, Lorena, Valencia, Lucia, Olmedilla, Luis, Etulain, Ma Justina, Tisner, Manuel, Barrio, María, Dolores Alonso, María, García, María, Hernández, María J., José Alberola, María, Parra, María, Pilar Argente, María, Vila, María, De Fez, Mario, Agilaga, Marta, Gine, Marta, Ayuso, Mercedes, García, Mercedes, Bejarano, Natalia, Peña, Natalia, Ojeda, Nazario, Martínez, Nilda, García, Nuria, Padrón, Oto, García, Pablo, Valls, Paola, Cruz, Patricia, Piñeiro, Patricia, Charco, Pedro, Anaya, Rafael, López, Ramiro, Rodríguez, Rayco, Martínez, Rocío, Pujol, Roger, Dosdá, Rosa, Lardies, Rosa, Díaz, Ruben, Villazala, Rubén, Zapatero, Sara, Cabrera, Sergio, Sánchez, Sergio, Martin, Silvia, Diaz, Suzana, Franco, Tania, Moreno, Tania, Socorro, Tania, Gilabert, Vicente, Balandrón, Victor, Moral, Victoria, Cegarra, Virgina, Varón, Viviana, Bluth, Thomas, Serpa Neto, Ary, Bobek, Ilona, Canet, Jaume, Cinnella, Gilda, de Baerdemaeker, Luc, Gregoretti, Cesare, Hedenstierna, Göran, Hemmes, Sabrine N.T., Hiesmayr, Michael, Hollmann, Markus W., Jaber, Samir, Laffey, John, Licker, Marc-Joseph, Markstaller, Klaus, Matot, Idit, Mills, Gary H., Mulier, Jan Paul, Putensen, Christian, Rossaint, Rolf, Schmitt, Jochen, Senturk, Mert, Severgnini, Paolo, Sprung, Juraj, Vidal Melo, Marcos F., Wrigge, Hermann, Schultz, Marcus J., Pelosi, Paolo, de Abreu, Marcelo Gama, Abelha, Fernando, Abitağaoğlu, Sühayla, Achilles, Marc, Adebesin, Afeez, Adriaensens, Ine, Ahene, Charles, Akbar, Fatima, Al Harbi, Mohammed, Al Khoury al Kallab, Rita, Albanel, Xavier, Aldenkortt, Florence, Alfouzan, Rawan Abdullah Saleh, Alruqaie, Reef, Altermatt, Fernando, Araujo, Bruno Luís de Castro, Arbesú, Genaro, Artsi, Hanna, Aurilio, Caterina, Ayanoglu, Omer Hilmi, Bacuzzi, Alessandro, Baig, Harris, Baird, Yolanda, Balonov, Konstantin, Balust, Jaume, Banks, Samantha, Bao, Xiaodong, Baumgartner, Mélanie, Belda Tortosa, Isabel, Bergamaschi, Alice, Bergmann, Lars, Bigatello, Luca, Biosca Pérez, Elena, Birr, Katja, Bluth, Thomas, Bojaxhi, Elird, Bonenti, Chiara, Bonney, Iwona, Bos, Elke M.E., Bowman, Sara, Braz, Leandro Gobbo, Brugnoni, Elisa, Brull, Sorin J., Brunetti, Iole, Bruni, Andrea, Buenvenida, Shonie L., Busch, Cornelius Johannes, Camerini, Giovanni, Canet, Jaume, Capatti, Beatrice, Carmona, Javiera, Carungcong, Jaime, Carvalho, Marta, Cattan, Anat, Cavaleiro, Carla, Chiumello, Davide, Ciardo, Stefano, Coburn, Mark, Colella, Umberto, Contreras, Victor, Corman Dincer, Pelin, Cotter, Elizabeth, Crovetto, Marcia, Darrah, William, Davies, Simon, de Baerdemaeker, Luc, De Hert, Stefan, Del Cojo Peces, Enrique, Delphin, Ellise, Diaper, John, do Nascimento, Paulo, Jr., Donatiello, Valerio, Dong, Jing, Dourado, Maria do Socorro, Dullenkopf, Alexander, Ebner, Felix, Elgendy, Hamed, Ellenberger, Christoph, Erdoğan Ari, Dilek, Ermert, Thomas, Farah, Fadi, Fernandez-Bustamante, Ana, Ferreira, Cristina, Fiore, Marco, Fonte, Ana, Fortià Palahí, Christina, Galimberti, Andrea, Gama de Abreu, Marcelo, Garofano, Najia, Giaccari, Luca Gregorio, Gilsanz, Fernando, Girrbach, Felix, Gobbi, Luca, Godfried, Marc Bernard, Goettel, Nicolai, Goldstein, Peter A., Goren, Or, Gorlin, Andrew, Granell Gil, Manuel, Gratarola, Angelo, Graterol, Juan, Guyon, Pierre, Haire, Kevin, Harou, Philippe, Helf, Antonia, Hemmes, Sabrine N.T., Hempel, Gunther, Hernández Cádiz, María José, Heyse, Björn, Hollmann, Markus W., Huercio, Ivan, Ilievska, Jasmina, Jakus, Lien, Jeganath, Vijay, Jelting, Yvonne, Jung, Minoa, Kabon, Barbara, Kacha, Aalok, Karaman Ilić, Maja, Karuppiah, Arunthevaraja, Kavas, Ayse Duygu, Keli Barcelos, Gleicy, Kellogg, Todd A., Kemper, Johann, Kerbrat, Romain, Khodr, Suraya, Kienbaum, Peter, Kir, Bunyamin, Kiss, Thomas, Kivrak, Selin, Klarić, Vlasta, Koch, Thea, Köksal, Ceren, Kowark, Ana, Kranke, Peter, Kuvaki, Bahar, Kuzmanovska, Biljana, Laffey, John, Lange, Mirko, Lemos, Marília Freitas de, Licker, Marc-Joseph, López-Baamonde, Manuel, López-Hernández, Antonio, Lopez-Martinez, Mercedes, Luise, Stéphane, MacGregor, Mark, Machado, Humberto S., Magalhães, Danielle, Maillard, Julien, Malerbi, Patrizia, Manimekalai, Natesan, Margarson, Michael, Markstaller, Klaus, Martin, Archer K, Martin, David P., Martin, Yvette N., Martínez-Ocon, Julia, Martin-Loeches, Ignacio, Maseda, Emilio, Matot, Idit, McAuliffe, Niamh, McKenzie, Travis J., Medina, Paulina, Meersch, Melanie, Menzen, Angelika, Mertens, Els, Meurer, Bernd, Meyer-Treschan, Tanja, Miao, Changhong, Micalizzi, Camilla, Milić, Morena, Módolo, Norma Sueli Pinheiro, Moine, Pierre, Mölders, Patrick, Montero-Feijoo, Ana, Moret, Enrique, Muller, Markus K, Murphy, Zoe, Nalwaya, Pramod, Filip, Naumovski, Navalesi, Paolo, Navarro e Lima, Lais Helena, Nesek Adam, Višnja, Neumann, Claudia, Newell, Christopher, Nisnevitch, Zoulfira, Nizamuddin, Junaid, Novazzi, Cecilia, Nunes, Catarina S, O’Connor, Michael, Oprea, Günther, Orhan Sungur, Mukadder, Özbilgin, Şule, Pace, Maria Caterina, Pacheco, Marcos, Packianathaswamy, Balaji, Palma Gonzalez, Estefania, Papaspyros, Fotios, Paredes, Sebastián, Passavanti, Maria Beatrice, Pedemonte, Juan Cristobal, Pelosi, Paolo, Peremin, Sanja, Philipsenburg, Christoph, Pinho, Daniela, Pinho, Silvia, Posthuma, Linda M., Pota, Vincenzo, Preckel, Benedikt, Priani, Paolo, Putensen, Christian, Rached, Mohamed Aymen, Radoeshki, Aleksandar, Ragazzi, Riccardo, Rajamanickam, Tamilselvan, Rajamohan, Arthi, Ramakrishna, Harish, Rangarajan, Desikan, Reiterer, Christian, Renew, J. Ross, Reynaud, Thomas, Rhys, Rhidian, Rivas, Eva, Robitzky, Luisa, Rossaint, Rolf, Rubulotta, Francesca, Sabbatini, Giovanni, Samuels, Jon D, Sanahuja, Josep Martí, Sansone, Pasquale, Santos, Alice, Sayedalahl, Mohamed, Schaefer, Maximilian S., Scharffenberg, Martin, Schiffer, Eduardo, Schliewe, Nadja, Schorer, Raoul, Schultz, Marcus J., Schumann, Roman, Selmo, Gabriele, Sendra, Mar, Senturk, Mert, Severgnini, Paolo, Shaw, Kate, Shosholcheva, Mirjana, Sibai, Abdulrazak, Simon, Philipp, Simonassi, Francesca, Sinno, Claudia, Sivrikoz, Nukhet, Skandalou, Vasiliki, Smith, Neil, Soares, Maria, Socorro Artiles, Tania, Sousa Castro, Diogo, Sousa, Miguel, Spadaro, Savino, Sprung, Juraj, Stamatakis, Emmanouil, Steiner, Luzius A., Stevenazzi, Andrea, Suarez-de-la-Rica, Alejandro, Suppan, Mélanie, Teichmann, Robert, Tena Guerrero, José Maria, Thiel, Bram, Tolós, Raquel, Tucci, Michelle, Turnbull, Zachary A., Turudić, Žana, Unterberg, Matthias, Van Limmen, Jurgen, Van Nieuwenhove, Yves, Van Waesberghe, Julia, Vidal Melo, Marcos Francisco, Vitković, Bibiana, Vivona, Luigi, Vizcaychipi, Marcela, Volta, Carlo Alberto, Weber, Anne, Weingarten, Toby N., Wittenstein, Jakob, Wrigge, Hermann, Wyffels, Piet, Yagüe, Julio, Yates, David, Yavru, Ayşen, Zac, Lilach, and Zhong, Jing

Published
2025
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7. Impact of COVID-19 in patients on active melanoma therapy and with history of melanoma.

Author

Johnson, Douglas B, Atkins, Michael B, Hennessy, Cassandra, Wise-Draper, Trisha, Heilman, Hannah, Awosika, Joy, Bakouny, Ziad, Labaki, Chris, Saliby, Renee Maria, Hwang, Clara, Singh, Sunny RK, Balanchivadze, Nino, Friese, Christopher R, Fecher, Leslie A, Yoon, James J, Hayes-Lattin, Brandon, Bilen, Mehmet A, Castellano, Cecilia A, Lyman, Gary H, Tachiki, Lisa, Shah, Sumit A, Glover, Michael J, Flora, Daniel B, Wulff-Burchfield, Elizabeth, Kasi, Anup, Abbasi, Saqib H, Farmakiotis, Dimitrios, Viera, Kendra, Klein, Elizabeth J, Weissman, Lisa B, Jani, Chinmay, Puc, Matthew, Fahey, Catherine C, Reuben, Daniel Y, Mishra, Sanjay, Beeghly-Fadiel, Alicia, French, Benjamin, Warner, Jeremy L, and COVID-19 and Cancer Consortium

Subjects
COVID-19 and Cancer Consortium, Humans, Melanoma, Multiple Organ Failure, Immunotherapy, COVID-19, Cancer, Immune therapy, Targeted therapy, Rehabilitation, Clinical Research, Lung, Rare Diseases, Good Health and Well Being, Oncology and Carcinogenesis, Public Health and Health Services, Oncology & Carcinogenesis
Abstract

IntroductionCOVID-19 particularly impacted patients with co-morbid conditions, including cancer. Patients with melanoma have not been specifically studied in large numbers. Here, we sought to identify factors that associated with COVID-19 severity among patients with melanoma, particularly assessing outcomes of patients on active targeted or immune therapy.MethodsUsing the COVID-19 and Cancer Consortium (CCC19) registry, we identified 307 patients with melanoma diagnosed with COVID-19. We used multivariable models to assess demographic, cancer-related, and treatment-related factors associated with COVID-19 severity on a 6-level ordinal severity scale. We assessed whether treatment was associated with increased cardiac or pulmonary dysfunction among hospitalized patients and assessed mortality among patients with a history of melanoma compared with other cancer survivors.ResultsOf 307 patients, 52 received immunotherapy (17%), and 32 targeted therapy (10%) in the previous 3 months. Using multivariable analyses, these treatments were not associated with COVID-19 severity (immunotherapy OR 0.51, 95% CI 0.19 - 1.39; targeted therapy OR 1.89, 95% CI 0.64 - 5.55). Among hospitalized patients, no signals of increased cardiac or pulmonary organ dysfunction, as measured by troponin, brain natriuretic peptide, and oxygenation were noted. Patients with a history of melanoma had similar 90-day mortality compared with other cancer survivors (OR 1.21, 95% CI 0.62 - 2.35).ConclusionsMelanoma therapies did not appear to be associated with increased severity of COVID-19 or worsening organ dysfunction. Patients with history of melanoma had similar 90-day survival following COVID-19 compared with other cancer survivors.

Published
2023

10. Stratified analyses refine association between TLR7 rare variants and severe COVID-19

Author

Jannik Boos, Caspar I. van der Made, Gayatri Ramakrishnan, Eamon Coughlan, Rosanna Asselta, Britt-Sabina Löscher, Luca V.C. Valenti, Rafael de Cid, Luis Bujanda, Antonio Julià, Erola Pairo-Castineira, J. Kenneth Baillie, Sandra May, Berina Zametica, Julia Heggemann, Agustín Albillos, Jesus M. Banales, Jordi Barretina, Natalia Blay, Paolo Bonfanti, Maria Buti, Javier Fernandez, Sara Marsal, Daniele Prati, Luisa Ronzoni, Nicoletta Sacchi, Joachim L. Schultze, Olaf Riess, Andre Franke, Konrad Rawlik, David Ellinghaus, Alexander Hoischen, Axel Schmidt, Kerstin U. Ludwig, Valeria Rimoldi, Elvezia M. Paraboschi, Alessandra Bandera, Flora Peyvandi, Giacomo Grasselli, Francesco Blasi, Francesco Malvestiti, Serena Pelusi, Cristiana Bianco, Lorenzo Miano, Angela Lombardi, Pietro Invernizzi, Alessio Gerussi, Giuseppe Citerio, Andrea Biondi, Maria Grazia Valsecchi, Marina Elena Cazzaniga, Giuseppe Foti, Ilaria Beretta, Mariella D'Angiò, Laura Rachele Bettini, Xavier Farré, Susana Iraola-Guzmán, Manolis Kogevinas, Gemma Castaño-Vinyals, Koldo Garcia-Etxebarria, Beatriz Nafria, Mauro D'Amato, Adriana Palom, Colin Begg, Sara Clohisey, Charles Hinds, Peter Horby, Julian Knight, Lowell Ling, David Maslove, Danny McAuley, Johnny Millar, Hugh Montgomery, Alistair Nichol, Peter J.M. Openshaw, Alexandre C. Pereira, Chris P. Ponting, Kathy Rowan, Malcolm G. Semple, Manu Shankar-Hari, Charlotte Summers, Timothy Walsh, Latha Aravindan, Ruth Armstrong, Heather Biggs, Ceilia Boz, Adam Brown, Richard Clark, Audrey Coutts, Judy Coyle, Louise Cullum, Sukamal Das, Nicky Day, Lorna Donnelly, Esther Duncan, Angie Fawkes, Paul Fineran, Max Head Fourman, Anita Furlong, James Furniss, Bernadette Gallagher, Tammy Gilchrist, Ailsa Golightly, Fiona Griffiths, Katarzyna Hafezi, Debbie Hamilton, Ross Hendry, Andy Law, Dawn Law, Rachel Law, Sarah Law, Rebecca Lidstone-Scott, Louise Macgillivray, Alan Maclean, Hanning Mal, Sarah McCafferty, Ellie Mcmaster, Jen Meikle, Shona C. Moore, Kirstie Morrice, Lee Murphy, Sheena Murphy, Mybaya Hellen, Wilna Oosthuyzen, Chenqing Zheng, Jiantao Chen, Nick Parkinson, Trevor Paterson, Katherine Schon, Andrew Stenhouse, Mihaela Das, Maaike Swets, Helen Szoor-McElhinney, Filip Taneski, Lance Turtle, Tony Wackett, Mairi Ward, Jane Weaver, Nicola Wrobel, Marie Zechner, Gill Arbane, Aneta Bociek, Sara Campos, Neus Grau, Tim Owen Jones, Rosario Lim, Martina Marotti, Marlies Ostermann, Christopher Whitton, Zoe Alldis, Raine Astin-Chamberlain, Fatima Bibi, Jack Biddle, Sarah Blow, Matthew Bolton, Catherine Borra, Ruth Bowles, Maudrian Burton, Yasmin Choudhury, David Collier, Amber Cox, Amy Easthope, Patrizia Ebano, Stavros Fotiadis, Jana Gurasashvili, Rosslyn Halls, Pippa Hartridge, Delordson Kallon, Jamila Kassam, Ivone Lancoma-Malcolm, Maninderpal Matharu, Peter May, Oliver Mitchelmore, Tabitha Newman, Mital Patel, Jane Pheby, Irene Pinzuti, Zoe Prime, Oleksandra Prysyazhna, Julian Shiel, Melanie Taylor, Carey Tierney, Suzanne Wood, Anne Zak, Olivier Zongo, Stephen Bonner, Keith Hugill, Jessica Jones, Steven Liggett, Evie Headlam, Nageswar Bandla, Minnie Gellamucho, Michelle Davies, Christopher Thompson, Marwa Abdelrazik, Dhanalakshmi Bakthavatsalam, Munzir Elhassan, Arunkumar Ganesan, Anne Haldeos, Jeronimo Moreno-Cuesta, Dharam Purohit, Rachel Vincent, Kugan Xavier, Kumar Rohit, Frater Alasdair, Malik Saleem, Carter David, Jenkins Samuel, Zoe Lamond, Wall Alanna, Jaime Fernandez-Roman, David O. Hamilton, Emily Johnson, Brian Johnston, Maria Lopez Martinez, Suleman Mulla, David Shaw, Alicia A.C. Waite, Victoria Waugh, Ingeborg D. Welters, Karen Williams, Anna Cavazza, Maeve Cockrell, Eleanor Corcoran, Maria Depante, Clare Finney, Ellen Jerome, Mark McPhail, Monalisa Nayak, Harriet Noble, Kevin O'Reilly, Evita Pappa, Rohit Saha, Sian Saha, John Smith, Abigail Knighton, David Antcliffe, Dorota Banach, Stephen Brett, Phoebe Coghlan, Ziortza Fernandez, Anthony Gordon, Roceld Rojo, Sonia Sousa Arias, Maie Templeton, Megan Meredith, Lucy Morris, Lucy Ryan, Amy Clark, Julia Sampson, Cecilia Peters, Martin Dent, Margaret Langley, Saima Ashraf, Shuying Wei, Angela Andrew, Archana Bashyal, Neil Davidson, Paula Hutton, Stuart McKechnie, Jean Wilson, David Baptista, Rebecca Crowe, Rita Fernandes, Rosaleen Herdman-Grant, Anna Joseph, Denise O'Connor, Meryem Allen, Adam Loveridge, India McKenley, Eriko Morino, Andres Naranjo, Richard Simms, Kathryn Sollesta, Andrew Swain, Harish Venkatesh, Jacyntha Khera, Jonathan Fox, Gillian Andrew, Lucy Barclay, Marie Callaghan, Rachael Campbell, Sarah Clark, Dave Hope, Lucy Marshall, Corrienne McCulloch, Kate Briton, Jo Singleton, Sohphie Birch, Lutece Brimfield, Zoe Daly, David Pogson, Steve Rose, Ceri Battle, Elaine Brinkworth, Rachel Harford, Carl Murphy, Luke Newey, Tabitha Rees, Marie Williams, Sophie Arnold, Petra Polgarova, Katerina Stroud, Eoghan Meaney, Megan Jones, Anthony Ng, Shruti Agrawal, Nazima Pathan, Deborah White, Esther Daubney, Kay Elston, Lina Grauslyte, Musarat Hussain, Mandeep Phull, Tatiana Pogreban, Lace Rosaroso, Erika Salciute, George Franke, Joanna Wong, Aparna George, Laura Ortiz-Ruiz de Gordoa, Emily Peasgood, Claire Phillips, Michelle Bates, Jo Dasgin, Jaspret Gill, Annette Nilsson, James Scriven, Carlos Castro Delgado, Deborah Dawson, Lijun Ding, Georgia Durrant, Obiageri Ezeobu, Sarah Farnell-Ward, Abiola Harrison, Rebecca Kanu, Susannah Leaver, Elena Maccacari, Soumendu Manna, Romina Pepermans Saluzzio, Joana Queiroz, Tinashe Samakomva, Christine Sicat, Joana Texeira, Edna Fernandes Da Gloria, Ana Lisboa, John Rawlins, Jisha Mathew, Ashley Kinch, William James Hurt, Nirav Shah, Victoria Clark, Maria Thanasi, Nikki Yun, Kamal Patel, Sara Bennett, Emma Goodwin, Matthew Jackson, Alissa Kent, Clare Tibke, Wiesia Woodyatt, Ahmed Zaki, Azmerelda Abraheem, Peter Bamford, Kathryn Cawley, Charlie Dunmore, Maria Faulkner, Rumanah Girach, Helen Jeffrey, Rhianna Jones, Emily London, Imrun Nagra, Farah Nasir, Hannah Sainsbury, Clare Smedley, Tahera Patel, Matthew Smith, Srikanth Chukkambotla, Aayesha Kazi, Janice Hartley, Joseph Dykes, Muhammad Hijazi, Sarah Keith, Meherunnisa Khan, Janet Ryan-Smith, Philippa Springle, Jacqueline Thomas, Nick Truman, Samuel Saad, Dabheoc Coleman, Christopher Fine, Roseanna Matt, Bethan Gay, Jack Dalziel, Syamlan Ali, Drew Goodchild, Rhiannan Harling, Ravi Bhatterjee, Wendy Goddard, Chloe Davison, Stephen Duberly, Jeanette Hargreaves, Rachel Bolton, Miriam Davey, David Golden, Rebecca Seaman, Shiney Cherian, Sean Cutler, Anne Emma Heron, Anna Roynon-Reed, Tamas Szakmany, Gemma Williams, Owen Richards, Yusuf Cheema, Hollie Brooke, Sarah Buckley, Jose Cebrian Suarez, Ruth Charlesworth, Karen Hansson, John Norris, Alice Poole, Alastair Rose, Rajdeep Sandhu, Brendan Sloan, Elizabeth Smithson, Muthu Thirumaran, Veronica Wagstaff, Alexandra Metcalfe, Mark Brunton, Jess Caterson, Holly Coles, Matthew Frise, Sabi Gurung Rai, Nicola Jacques, Liza Keating, Emma Tilney, Shauna Bartley, Parminder Bhuie, Sian Gibson, Amanda Lyle, Fiona McNeela, Jayachandran Radhakrishnan, Alistair Hughes, Bryan Yates, Jessica Reynolds, Helen Campbell, Maria Thompsom, Steve Dodds, Stacey Duffy, Sandra Greer, Karen Shuker, Ascanio Tridente, Reena Khade, Ashok Sundar, George Tsinaslanidis, Isobel Birkinshaw, Joseph Carter, Kate Howard, Joanne Ingham, Rosie Joy, Harriet Pearson, Samantha Roche, Zoe Scott, Hollie Bancroft, Mary Bellamy, Margaret Carmody, Jacqueline Daglish, Faye Moore, Joanne Rhodes, Mirriam Sangombe, Salma Kadiri, Maria Croft, Ian White, Victoria Frost, Maia Aquino, Rajeev Jha, Vinodh Krishnamurthy, Lai Lim, Li Lim, Edward Combes, Teishel Joefield, Sonja Monnery, Valerie Beech, Sallyanne Trotman, Christine Almaden-Boyle, Pauline Austin, Louise Cabrelli, Stephen Cole, Matt Casey, Susan Chapman, Clare Whyte, Yolanda Baird, Aaron Butler, Indra Chadbourn, Linda Folkes, Heather Fox, Amy Gardner, Raquel Gomez, Gillian Hobden, Luke Hodgson, Kirsten King, Michael Margarson, Tim Martindale, Emma Meadows, Dana Raynard, Yvette Thirlwall, David Helm, Jordi Margalef, Kristine Criste, Rebecca Cusack, Kim Golder, Hannah Golding, Oliver Jones, Samantha Leggett, Michelle Male, Martyna Marani, Kirsty Prager, Toran Williams, Belinda Roberts, Karen Salmon, Peter Anderson, Katie Archer, Karen Austin, Caroline Davis, Alison Durie, Olivia Kelsall, Jessica Thrush, Charlie Vigurs, Laura Wild, Hannah-Louise Wood, Helen Tranter, Alison Harrison, Nicholas Cowley, Michael McAlindon, Andrew Burtenshaw, Stephen Digby, Emma Low, Aled Morgan, Naiara Cother, Tobias Rankin, Sarah Clayton, Alex McCurdy, Cecilia Ahmed, Balvinder Baines, Sarah Clamp, Julie Colley, Risna Haq, Anne Hayes, Jonathan Hulme, Samia Hussain, Sibet Joseph, Rita Kumar, Zahira Maqsood, Manjit Purewal, Leonie Benham, Zena Bradshaw, Joanna Brown, Melanie Caswell, Jason Cupitt, Sarah Melling, Stephen Preston, Nicola Slawson, Emma Stoddard, Scott Warden, Bethan Deacon, Ceri Lynch, Carla Pothecary, Lisa Roche, Gwenllian Sera Howe, Jayaprakash Singh, Keri Turner, Hannah Ellis, Natalie Stroud, Jodie Hunt, Joy Dearden, Emma Dobson, Andy Drummond, Michelle Mulcahy, Sheila Munt, Grainne O'Connor, Jennifer Philbin, Chloe Rishton, Redmond Tully, Sarah Winnard, Susanne Cathcart, Katharine Duffy, Alex Puxty, Kathryn Puxty, Lynne Turner, Jane Ireland, Gary Semple, Kate Long, Simon Whiteley, Elizabeth Wilby, Bethan Ogg, Amanda Cowton, Andrea Kay, Melanie Kent, Kathryn Potts, Ami Wilkinson, Suzanne Campbell, Ellen Brown, Julie Melville, Jay Naisbitt, Rosane Joseph, Maria Lazo, Olivia Walton, Alan Neal, Peter Alexander, Schvearn Allen, Joanne Bradley-Potts, Craig Brantwood, Jasmine Egan, Timothy Felton, Grace Padden, Luke Ward, Stuart Moss, Susannah Glasgow, Lynn Abel, Michael Brett, Brian Digby, Lisa Gemmell, James Hornsby, Patrick MacGoey, Pauline O'Neil, Richard Price, Natalie Rodden, Kevin Rooney, Radha Sundaram, Nicola Thomson, Bridget Hopkins, Laura Thrasyvoulou, Heather Willis, Martyn Clark, Martina Coulding, Edward Jude, Jacqueline McCormick, Oliver Mercer, Darsh Potla, Hafiz Rehman, Heather Savill, Victoria Turner, Charlotte Downes, Kathleen Holding, Katie Riches, Mary Hilton, Mel Hayman, Deepak Subramanian, Priya Daniel, Oluronke Adanini, Nikhil Bhatia, Maines Msiska, Rebecca Collins, Ian Clement, Bijal Patel, A. Gulati, Carole Hays, K. Webster, Anne Hudson, Andrea Webster, Elaine Stephenson, Louise McCormack, Victoria Slater, Rachel Nixon, Helen Hanson, Maggie Fearby, Sinead Kelly, Victoria Bridgett, Philip Robinson, Julie Camsooksai, Charlotte Humphrey, Sarah Jenkins, Henrik Reschreiter, Beverley Wadams, Yasmin Death, Victoria Bastion, Daphene Clarke, Beena David, Harriet Kent, Rachel Lorusso, Gamu Lubimbi, Sophie Murdoch, Melchizedek Penacerrada, Alastair Thomas, Jennifer Valentine, Ana Vochin, Retno Wulandari, Brice Djeugam, Gillian Bell, Katy English, Amro Katary, Louise Wilcox, Michelle Bruce, Karen Connolly, Tracy Duncan, Helen T-Michael, Gabriella Lindergard, Samuel Hey, Claire Fox, Jordan Alfonso, Laura Jayne Durrans, Jacinta Guerin, Bethan Blackledge, Jade Harris, Martin Hruska, Ayaa Eltayeb, Thomas Lamb, Tracey Hodgkiss, Lisa Cooper, Joanne Rothwell, Angela Allan, Felicity Anderson, Callum Kaye, Jade Liew, Jasmine Medhora, Teresa Scott, Erin Trumper, Adriana Botello, Liana Lankester, Nikitas Nikitas, Colin Wells, Bethan Stowe, Kayleigh Spencer, Craig Brandwood, Lara Smith, Katie Birchall, Laurel Kolakaluri, Deborah Baines, Anila Sukumaran, Elena Apetri, Cathrine Basikolo, Laura Catlow, Bethan Charles, Paul Dark, Reece Doonan, Alice Harvey, Daniel Horner, Karen Knowles, Stephanie Lee, Diane Lomas, Chloe Lyons, Tracy Marsden, Danielle McLaughlan, Liam McMorrow, Jessica Pendlebury, Jane Perez, Maria Poulaka, Nicola Proudfoot, Melanie Slaughter, Kathryn Slevin, Vicky Thomas, Danielle Walker, Angiy Michael, Matthew Collis, Tracey Cosier, Gemma Millen, Neil Richardson, Natasha Schumacher, Heather Weston, James Rand, Nicola Baxter, Steven Henderson, Sophie Kennedy-Hay, Christopher McParland, Laura Rooney, Malcolm Sim, Gordan McCreath, Louise Akeroyd, Shereen Bano, Matt Bromley, Lucy Gurr, Tom Lawton, James Morgan, Kirsten Sellick, Deborah Warren, Brian Wilkinson, Janet McGowan, Camilla Ledgard, Amelia Stacey, Kate Pye, Ruth Bellwood, Michael Bentley, Jeremy Bewley, Zoe Garland, Lisa Grimmer, Bethany Gumbrill, Rebekah Johnson, Katie Sweet, Denise Webster, Georgia Efford, Karen Convery, Deirdre Fottrell-Gould, Lisa Hudig, Jocelyn Keshet-Price, Georgina Randell, Katie Stammers, Maria Bokhari, Vanessa Linnett, Rachael Lucas, Wendy McCormick, Jenny Ritzema, Amanda Sanderson, Helen Wild, Anthony Rostron, Alistair Roy, Lindsey Woods, Sarah Cornell, Fiona Wakinshaw, Kimberley Rogerson, Jordan Jarmain, Robert Parker, Amie Reddy, Ian Turner-Bone, Laura Wilding, Peter Harding, Caroline Abernathy, Louise Foster, Andrew Gratrix, Vicky Martinson, Priyai Parkinson, Elizabeth Stones, Llucia Carbral-Ortega, Georgia Bercades, David Brealey, Ingrid Hass, Niall MacCallum, Gladys Martir, Eamon Raith, Anna Reyes, Deborah Smyth, Letizia Zitter, Sarah Benyon, Suzie Marriott, Linda Park, Samantha Keenan, Elizabeth Gordon, Helen Quinn, Kizzy Baines, Lenka Cagova, Adama Fofano, Lucie Garner, Helen Holcombe, Sue Mepham, Alice Michael Mitchell, Lucy Mwaura, Krithivasan Praman, Alain Vuylsteke, Julie Zamikula, Bally Purewal, Vanessa Rivers, Stephanie Bell, Hayley Blakemore, Borislava Borislavova, Beverley Faulkner, Emma Gendall, Elizabeth Goff, Kati Hayes, Matt Thomas, Ruth Worner, Kerry Smith, Deanna Stephens, Louise Mew, Esther Mwaura, Richard Stewart, Felicity Williams, Lynn Wren, Sara-Beth Sutherland, Emily Bevan, Jane Martin, Dawn Trodd, Geoff Watson, Caroline Wrey Brown, Amy Collins, Waqas Khaliq, Estefania Treus Gude, Olugbenga Akinkugbe, Alasdair Bamford, Emily Beech, Holly Belfield, Michael Bell, Charlene Davies, Gareth A.L. Jones, Tara McHugh, Hamza Meghari, Lauran O'Neill, Mark J. Peters, Samiran Ray, Ana Luisa Tomas, Iona Burn, Geraldine Hambrook, Katarina Manso, Ruth Penn, Pradeep Shanmugasundaram, Julie Tebbutt, Danielle Thornton, Jade Cole, Rhys Davies, Donna Duffin, Helen Hill, Ben Player, Emma Thomas, Angharad Williams, Denise Griffin, Nycola Muchenje, Mcdonald Mupudzi, Richard Partridge, Jo-Anna Conyngham, Rachel Thomas, Mary Wright, Maria Alvarez Corral, Reni Jacob, Cathy Jones, Craig Denmade, Sarah Beavis, Katie Dale, Rachel Gascoyne, Joanne Hawes, Kelly Pritchard, Lesley Stevenson, Amanda Whileman, Patricia Doble, Joanne Hutter, Corinne Pawley, Charmaine Shovelton, Marius Vaida, Deborah Butcher, Susie O'Sullivan, Nicola Butterworth-Cowin, Norfaizan Ahmad, Joann Barker, Kris Bauchmuller, Sarah Bird, Kay Cawthron, Kate Harrington, Yvonne Jackson, Faith Kibutu, Becky Lenagh, Shamiso Masuko, Gary H. Mills, Ajay Raithatha, Matthew Wiles, Jayne Willson, Helen Newell, Alison Lye, Lorenza Nwafor, Claire Jarman, Sarah Rowland-Jones, David Foote, Joby Cole, Roger Thompson, James Watson, Lisa Hesseldon, Irene Macharia, Luke Chetam, Jacqui Smith, Amber Ford, Samantha Anderson, Kathryn Birchall, Kay Housley, Sara Walker, Leanne Milner, Helena Hanratty, Helen Trower, Patrick Phillips, Simon Oxspring, Ben Donne, Catherine Jardine, Dewi Williams, Alasdair Hay, Rebecca Flanagan, Gareth Hughes, Scott Latham, Emma McKenna, Jennifer Anderson, Robert Hull, Kat Rhead, Carina Cruz, Natalie Pattison, Rob Charnock, Denise McFarland, Denise Cosgrove, Ashar Ahmed, Anna Morris, Srinivas Jakkula, Asifa Ali, Megan Brady, Sam Dale, Annalisa Dance, Lisa Gledhill, Jill Greig, Kathryn Hanson, Kelly Holdroyd, Marie Home, Diane Kelly, Ross Kitson, Lear Matapure, Deborah Melia, Samantha Mellor, Tonicha Nortcliffe, Jez Pinnell, Matthew Robinson, Lisa Shaw, Ryan Shaw, Lesley Thomis, Alison Wilson, Tracy Wood, Lee-Ann Bayo, Ekta Merwaha, Tahira Ishaq, Sarah Hanley, Meg Hibbert, Dariusz Tetla, Chrsitopher Woodford, Latha Durga, Gareth Kennard-Holden, Debbie Branney, Jordan Frankham, Sally Pitts, Nigel White, Shondipon Laha, Mark Verlander, Alexandra Williams, Abdelhakim Altabaibeh, Ana Alvaro, Kayleigh Gilbert, Louise Ma, Loreta Mostoles, Chetan Parmar, Kathryn Simpson, Champa Jetha, Lauren Booker, Anezka Pratley, Colene Adams, Anita Agasou, Tracie Arden, Amy Bowes, Pauline Boyle, Mandy Beekes, Heather Button, Nigel Capps, Mandy Carnahan, Anne Carter, Danielle Childs, Denise Donaldson, Kelly Hard, Fran Hurford, Yasmin Hussain, Ayesha Javaid, James Jones, Sanal Jose, Michael Leigh, Terry Martin, Helen Millward, Nichola Motherwell, Rachel Rikunenko, Jo Stickley, Julie Summers, Louise Ting, Helen Tivenan, Louise Tonks, Rebecca Wilcox, Maureen Holland, Natalie Keenan, Marc Lyons, Helen Wassall, Chris Marsh, Mervin Mahenthran, Emma Carter, Thomas Kong, Helen Blackman, Ben Creagh-Brown, Sinead Donlon, Natalia Michalak-Glinska, Sheila Mtuwa, Veronika Pristopan, Armorel Salberg, Eleanor Smith, Sarah Stone, Charles Piercy, Jerik Verula, Dorota Burda, Rugia Montaser, Lesley Harden, Irving Mayangao, Cheryl Marriott, Paul Bradley, Celia Harris, Susan Anderson, Eleanor Andrews, Janine Birch, Emma Collins, Kate Hammerton, Ryan O'Leary, Michele Clark, Sarah Purvis, Russell Barber, Claire Hewitt, Annette Hilldrith, Karen Jackson-Lawrence, Sarah Shepardson, Maryanne Wills, Susan Butler, Silvia Tavares, Amy Cunningham, Julia Hindale, Sarwat Arif, Sarah Bean, Karen Burt, Michael Spivey, Carrie Demetriou, Charlotte Eckbad, Sarah Hierons, Lucy Howie, Sarah Mitchard, Lidia Ramos, Alfredo Serrano-Ruiz, Katie White, Fiona Kelly, Daniele Cristiano, Natalie Dormand, Zohreh Farzad, Mahitha Gummadi, Kamal Liyanage, Brijesh Patel, Sara Salmi, Geraldine Sloane, Vicky Thwaites, Mathew Varghese, Anelise C. Zborowski, John Allan, Tim Geary, Gordon Houston, Alistair Meikle, Peter O'Brien, Miranda Forsey, Agilan Kaliappan, Anne Nicholson, Joanne Riches, Mark Vertue, Elizabeth Allan, Kate Darlington, Ffyon Davies, Jack Easton, Sumit Kumar, Richard Lean, Daniel Menzies, Richard Pugh, Xinyi Qiu, Llinos Davies, Hannah Williams, Jeremy Scanlon, Gwyneth Davies, Callum Mackay, Joannne Lewis, Stephanie Rees, Metod Oblak, Monica Popescu, Mini Thankachen, Andrew Higham, Kerry Simpson, Jayne Craig, Rosie Baruah, Sheila Morris, Susie Ferguson, Amy Shepherd, Luke Stephen Prockter Moore, Marcela Paola Vizcaychipi, Laura Gomes de Almeida Martins, Jaime Carungcong, Inthakab Ali Mohamed Ali, Karen Beaumont, Mark Blunt, Zoe Coton, Hollie Curgenven, Mohamed Elsaadany, Kay Fernandes, Sameena Mohamed Ally, Harini Rangarajan, Varun Sarathy, Sivarupan Selvanayagam, Dave Vedage, Matthew White, Mandy Gill, Paul Paul, Valli Ratnam, Sarah Shelton, Inez Wynter, Siobhain Carmody, Valerie Joan Page, Claire Marie Beith, Karen Black, Suzanne Clements, Alan Morrison, Dominic Strachan, Margaret Taylor, Michelle Clarkson, Stuart D'Sylva, Kathryn Norman, Fiona Auld, Joanne Donnachie, Ian Edmond, Lynn Prentice, Nikole Runciman, Dario Salutous, Lesley Symon, Anne Todd, Patricia Turner, Abigail Short, Laura Sweeney, Euan Murdoch, Dhaneesha Senaratne, Michaela Hill, Thogulava Kannan, Wild Laura, Rikki Crawley, Abigail Crew, Mishell Cunningham, Allison Daniels, Laura Harrison, Susan Hope, Ken Inweregbu, Sian Jones, Nicola Lancaster, Jamie Matthews, Alice Nicholson, Gemma Wray, Helen Langton, Rachel Prout, Malcolm Watters, Catherine Novis, Anthony Barron, Ciara Collins, Sundeep Kaul, Heather Passmore, Claire Prendergast, Anna Reed, Paula Rogers, Rajvinder Shokkar, Meriel Woodruff, Hayley Middleton, Oliver Polgar, Claire Nolan, Kanta Mahay, Dawn Collier, Anil Hormis, Victoria Maynard, Cheryl Graham, Rachel Walker, Ellen Knights, Alicia Price, Alice Thomas, Chris Thorpe, Teresa Behan, Caroline Burnett, Jonathan Hatton, Elaine Heeney, Atideb Mitra, Maria Newton, Rachel Pollard, Rachael Stead, Vishal Amin, Elena Anastasescu, Vikram Anumakonda, Komala Karthik, Rizwana Kausar, Karen Reid, Jacqueline Smith, Janet Imeson-Wood, Denise Skinner, Jane Gaylard, Dee Mullan, Julie Newman, Alison Brown, Vikki Crickmore, Gabor Debreceni, Joy Wilkins, Liz Nicol, Rosie Reece-Anthony, Mark Birt, Alison Ghosh, Emma Williams, Louise Allen, Eva Beranova, Nikki Crisp, Joanne Deery, Tracy Hazelton, Alicia Knight, Carly Price, Sorrell Tilbey, Salah Turki, Sharon Turney, Joshua Cooper, Cheryl Finch, Sarah Liderth, Alison Quinn, Natalia Waddington, Tina Coventry, Susan Fowler, Michael MacMahon, Amanda McGregor, Anne Cowley, Judith Highgate, Jane Gregory, Susan O'Connell, Tim Smith, Luigi Barberis, Shameer Gopal, Nichola Harris, Victoria Lake, Stella Metherell, Elizabeth Radford, Amelia Daniel, Joanne Finn, Rajnish Saha, Nikki White, Phil Donnison, Fiona Trim, Beena Eapen, Jenny Birch, Laura Bough, Josie Goodsell, Rebecca Tutton, Patricia Williams, Sarah Williams, Barbara Winter-Goodwin, Ailstair Nichol, Kathy Brickell, Michelle Smyth, Lorna Murphy, Samantha Coetzee, Alistair Gales, Igor Otahal, Meena Raj, Craig Sell, Paula Hilltout, Jayne Evitts, Amanda Tyler, Joanne Waldron, Kate Beesley, Sarah Board, Agnieszka Kubisz-Pudelko, Alison Lewis, Jess Perry, Lucy Pippard, Di Wood, Clare Buckley, Peter Barry, Neil Flint, Patel Rekha, Dawn Hales, Lara Bunni, Claire Jennings, Monica Latif, Rebecca Marshall, Gayathri Subramanian, Peter J. McGuigan, Christopher Wasson, Stephanie Finn, Jackie Green, Erin Collins, Bernadette King, Andy Campbell, Sara Smuts, Joseph Duffield, Oliver Smith, Lewis Mallon, Watkins Claire, Liam Botfield, Joanna Butler, Catherine Dexter, Jo Fletcher, Atul Garg, Aditya Kuravi, Poonam Ranga, Emma Virgilio, Zakaula Belagodu, Bridget Fuller, Anca Gherman, Olumide Olufuwa, Remi Paramsothy, Carmel Stuart, Naomi Oakley, Charlotte Kamundi, David Tyl, Katy Collins, Pedro Silva, June Taylor, Laura King, Charlotte Coates, Maria Crowley, Phillipa Wakefield, Jane Beadle, Laura Johnson, Janet Sargeant, Madeleine Anderson, Ailbhe Brady, Rebekah Chan, Jeff Little, Shane McIvor, Helena Prady, Helen Whittle, Bijoy Mathew, Ben Attwood, Penny Parsons, Geraldine Ward, Pamela Bremmer, West Joe, Baird Tracy, Ruddy Jim, Ellie Davies, Sonia Sathe, Catherine Dennis, Alastair McGregor, Victoria Parris, Sinduya Srikaran, Anisha Sukha, Noreen Clarke, Jonathan Whiteside, Mairi Mascarenhas, Avril Donaldson, Joanna Matheson, Fiona Barrett, Marianne O'Hara, Laura Okeefe, Clare Bradley, Christine Eastgate-Jackson, Helder Filipe, Daniel Martin, Amitaa Maharajh, Sara Mingo Garcia, Glykeria Pakou, Mark De Neef, Kathy Dent, Elizabeth Horsley, Muhmmad Nauman Akhtar, Sandra Pearson, Dorota Potoczna, Sue Spencer, Melanie Clapham, Rosemary Harper, Una Poultney, Polly Rice, Rachel Mutch, Lisa Armstrong, Hayley Bates, Emma Dooks, Fiona Farquhar, Brigid Hairsine, Chantal McParland, Sophie Packham, Rehana Bi, Barney Scholefield, Lydia Ashton, Linsha George, Sophie Twiss, David Wright, Manish Chablani, Amy Kirkby, Kimberley Netherton, Kim Davies, Linda O'Brien, Zohra Omar, Emma Perkins, Tracy Lewis, Isobel Sutherland, Karen Burns, Dr Ben Chandler, Kerry Elliott, Janine Mallinson, Alison Turnbull, Prisca Gondo, Bernard Hadebe, Abdul Kayani, Bridgett Masunda, Taya Anderson, Dan Hawcutt, Laura O'Malley, Laura Rad, Naomi Rogers, Paula Saunderson, Kathryn Sian Allison, Deborah Afolabi, Jennifer Whitbread, Dawn Jones, Rachael Dore, Matthew Halkes, Pauline Mercer, Lorraine Thornton, Joy Dawson, Sweyn Garrioch, Melanie Tolson, Jonathan Aldridge, Ritoo Kapoor, David Loader, Karen Castle, Sally Humphreys, Ruth Tampsett, Katherine Mackintosh, Amanda Ayers, Wendy Harrison, Julie North, Suzanne Allibone, Roman Genetu, Vidya Kasipandian, Amit Patel, Ainhi Mac, Anthony Murphy, Parisa Mahjoob, Roonak Nazari, Lucy Worsley, Andrew Fagan, Thomas Bemand, Ethel Black, Arnold Dela Rosa, Ryan Howle, Shaman Jhanji, Ravishankar Rao Baikady, Kate Colette Tatham, Benjamin Thomas, Dina Bell, Rosalind Boyle, Katie Douglas, Lynn Glass, Emma Lee, Liz Lennon, Austin Rattray, Abigail Taylor, Rachel Anne Hughes, Helen Thomas, Alun Rees, Michaela Duskova, Janet Phipps, Suzanne Brooks, Michelle Edwards, Sheena Quaid, Ekaterina Watson, Adam Brayne, Emma Fisher, Jane Hunt, Peter Jackson, Duncan Kaye, Nicholas Love, Juliet Parkin, Victoria Tuckey, Lynne Van Koutrik, Sasha Carter, Benedict Andrew, Louise Findlay, Katie Adams, Jen Service, Alison Williams, Claire Cheyne, Anne Saunderson, Sam Moultrie, Miranda Odam, Kathryn Hall, Isheunesu Mapfunde, Charlotte Willis, Alex Lyon, Chunda Sri-Chandana, Joslan Scherewode, Lorraine Stephenson, Sarah Marsh, John Hardy, Henry Houlden, Eleanor Moncur, Ambreen Tariq, Arianna Tucci, Maria Hobrok, Ronda Loosley, Heather McGuinness, Helen Tench, Rebecca Wolf-Roberts, Val Irvine, Benjamin Shelley, Claire Gorman, Abhinav Gupta, Elizabeth Timlick, Rebecca Brady, Barry Milligan, Arianna Bellini, Jade Bryant, Anton Mayer, Amy Pickard, Nicholas Roe, Jason Sowter, Alex Howlett, Katy Fidler, Emma Tagliavini, and Kevin Donnelly

Subjects
SARS-CoV-2, host genetics, toll-like receptor 7, targeted sequencing, rare variants, variant collapsing analysis, Genetics, QH426-470
Abstract

Summary: Despite extensive global research into genetic predisposition for severe COVID-19, knowledge on the role of rare host genetic variants and their relation to other risk factors remains limited. Here, 52 genes with prior etiological evidence were sequenced in 1,772 severe COVID-19 cases and 5,347 population-based controls from Spain/Italy. Rare deleterious TLR7 variants were present in 2.4% of young (

Published
2024
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11. Sphingosine Kinase 2 Regulates Aryl Hydrocarbon Receptor Nuclear Translocation and Target Gene Activation

Author

Shigetoshi Yokoyama, Imhoi Koo, Daisuke Aibara, Yuan Tian, Iain A. Murray, Stephanie L. Collins, Denise M. Coslo, Mari Kono, Jeffrey M. Peters, Richard L. Proia, Frank J. Gonzalez, Gary H. Perdew, and Andrew D. Patterson

Subjects
AHR, ceramide, sphingolipid, SPHK2, Science
Abstract

Abstract Sphingolipids play vital roles in metabolism and regulation. Previously, the aryl hydrocarbon receptor (AHR), a ligand‐activated transcription factor, was reported to directly regulate ceramide synthesis genes by binding to their promoters. Herein, sphingosine kinase 2 (SPHK2), responsible for producing sphingosine‐1‐phosphate (S1P), was found to interact with AHR through LXXLL motifs, influencing AHR nuclear localization. Through mutagenesis and co‐transfection studies, AHR activation and subsequent nuclear translocation was hindered by SPHK2 LXXLL mutants or SPHK2 lacking a nuclear localization signal (NLS). Similarly, an NLS‐deficient AHR mutant impaired SPHK2 nuclear translocation. Silencing SPHK2 reduced AHR expression and its target gene CYP1A1, while SPHK2 overexpression enhanced AHR activity. SPHK2 was found enriched on the CYP1A1 promoter, underscoring its role in AHR target gene activation. Additionally, S1P rapidly increased AHR expression at both the mRNA and protein levels and promoted AHR recruitment to the CYP1A1 promoter. Using mouse models, AHR deficiency compromised SPHK2 nuclear translocation, illustrating a critical interaction where SPHK2 facilitates AHR nuclear localization and supports a positive feedback loop between AHR and sphingolipid enzyme activity in the nucleus. These findings highlight a novel function of SPHK2 in regulating AHR activity and gene expression.

Published
2024
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12. Mouse genomic associations with in vitro sensitivity to simulated space radiation

Author

Cekanaviciute, Egle, Tran, Duc, Nguyen, Hung, Lopez Macha, Alejandra, Pariset, Eloise, Langley, Sasha, Babbi, Giulia, Malkani, Sherina, Penninckx, Sébastien, Schisler, Jonathan C, Nguyen, Tin, Karpen, Gary H, and Costes, Sylvain V

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Human Genome, Cancer, 2.1 Biological and endogenous factors, Humans, Mice, Animals, DNA Damage, DNA Repair, Radiation, Ionizing, Neoplasms, Genomics, Space radiation, DNA damage, Radiosensitivity, GWAS, Mouse models, Genome-wide association study, ionizing radiation, space radiation, space biology, mouse genetics
Abstract

Exposure to ionizing radiation is considered by NASA to be a major health hazard for deep space exploration missions. Ionizing radiation sensitivity is modulated by both genomic and environmental factors. Understanding their contributions is crucial for designing experiments in model organisms, evaluating the risk of deep space (i.e. high-linear energy transfer, or LET, particle) radiation exposure in astronauts, and also selecting therapeutic irradiation regimes for cancer patients. We identified single nucleotide polymorphisms in 15 strains of mice, including 10 collaborative cross model strains and 5 founder strains, associated with spontaneous and ionizing radiation-induced in vitro DNA damage quantified based on immunofluorescent tumor protein p53 binding protein (53BP1) positive nuclear foci. Statistical analysis suggested an association with pathways primarily related to cellular signaling, metabolism, tumorigenesis and nervous system damage. We observed different genomic associations in early (4 and 8 h) responses to different LET radiation, while later (24 hour) DNA damage responses showed a stronger overlap across all LETs. Furthermore, a subset of pathways was associated with spontaneous DNA damage, suggesting 53BP1 positive foci as a potential biomarker for DNA integrity in mouse models. Our results suggest several mouse strains as new models to further study the impact of ionizing radiation and validate the identified genetic loci. We also highlight the importance of future human in vitro studies to refine the association of genes and pathways with the DNA damage response to ionizing radiation and identify targets for space travel countermeasures.

Published
2023

13. Clinical characteristics, racial inequities, and outcomes in patients with breast cancer and COVID-19: A COVID-19 and cancer consortium (CCC19) cohort study

Author

Nagaraj, Gayathri, Vinayak, Shaveta, Khaki, Ali Raza, Sun, Tianyi, Kuderer, Nicole M, Aboulafia, David M, Acoba, Jared D, Awosika, Joy, Bakouny, Ziad, Balmaceda, Nicole B, Bao, Ting, Bashir, Babar, Berg, Stephanie, Bilen, Mehmet A, Bindal, Poorva, Blau, Sibel, Bodin, Brianne E, Borno, Hala T, Castellano, Cecilia, Choi, Horyun, Deeken, John, Desai, Aakash, Edwin, Natasha, Feldman, Lawrence E, Flora, Daniel B, Friese, Christopher R, Galsky, Matthew D, Gonzalez, Cyndi J, Grivas, Petros, Gupta, Shilpa, Haynam, Marcy, Heilman, Hannah, Hershman, Dawn L, Hwang, Clara, Jani, Chinmay, Jhawar, Sachin R, Joshi, Monika, Kaklamani, Virginia, Klein, Elizabeth J, Knox, Natalie, Koshkin, Vadim S, Kulkarni, Amit A, Kwon, Daniel H, Labaki, Chris, Lammers, Philip E, Lathrop, Kate I, Lewis, Mark A, Li, Xuanyi, de Lima Lopes, Gilbert, Lyman, Gary H, Makower, Della F, Mansoor, Abdul-Hai, Markham, Merry-Jennifer, Mashru, Sandeep H, McKay, Rana R, Messing, Ian, Mico, Vasil, Nadkarni, Rajani, Namburi, Swathi, Nguyen, Ryan H, Nonato, Taylor Kristian, O'Connor, Tracey Lynn, Panagiotou, Orestis A, Park, Kyu, Patel, Jaymin M, Patel, Kanishka GopikaBimal, Peppercorn, Jeffrey, Polimera, Hyma, Puc, Matthew, Rao, Yuan James, Razavi, Pedram, Reid, Sonya A, Riess, Jonathan W, Rivera, Donna R, Robson, Mark, Rose, Suzanne J, Russ, Atlantis D, Schapira, Lidia, Shah, Pankil K, Shanahan, M Kelly, Shapiro, Lauren C, Smits, Melissa, Stover, Daniel G, Streckfuss, Mitrianna, Tachiki, Lisa, Thompson, Michael A, Tolaney, Sara M, Weissmann, Lisa B, Wilson, Grace, Wotman, Michael T, Wulff-Burchfield, Elizabeth M, Mishra, Sanjay, French, Benjamin, Warner, Jeremy L, Lustberg, Maryam B, Accordino, Melissa K, and Shah, Dimpy P

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Emerging Infectious Diseases, Cancer, Infectious Diseases, Lung, Breast Cancer, Coronaviruses, Clinical Research, Women's Health, Good Health and Well Being, United States, Humans, Female, Middle Aged, COVID-19, SARS-CoV-2, Cohort Studies, Breast Neoplasms, Retrospective Studies, COVID-19 and Cancer Consortium, breast cancer, epidemiology, global health, human, oncology, pandemic, racial inequities, Biochemistry and Cell Biology, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

BackgroundLimited information is available for patients with breast cancer (BC) and coronavirus disease 2019 (COVID-19), especially among underrepresented racial/ethnic populations.MethodsThis is a COVID-19 and Cancer Consortium (CCC19) registry-based retrospective cohort study of females with active or history of BC and laboratory-confirmed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection diagnosed between March 2020 and June 2021 in the US. Primary outcome was COVID-19 severity measured on a five-level ordinal scale, including none of the following complications, hospitalization, intensive care unit admission, mechanical ventilation, and all-cause mortality. Multivariable ordinal logistic regression model identified characteristics associated with COVID-19 severity.Results1383 female patient records with BC and COVID-19 were included in the analysis, the median age was 61 years, and median follow-up was 90 days. Multivariable analysis revealed higher odds of COVID-19 severity for older age (aOR per decade, 1.48 [95% CI, 1.32-1.67]); Black patients (aOR 1.74; 95 CI 1.24-2.45), Asian Americans and Pacific Islander patients (aOR 3.40; 95 CI 1.70-6.79) and Other (aOR 2.97; 95 CI 1.71-5.17) racial/ethnic groups; worse ECOG performance status (ECOG PS ≥2: aOR, 7.78 [95% CI, 4.83-12.5]); pre-existing cardiovascular (aOR, 2.26 [95% CI, 1.63-3.15])/pulmonary comorbidities (aOR, 1.65 [95% CI, 1.20-2.29]); diabetes mellitus (aOR, 2.25 [95% CI, 1.66-3.04]); and active and progressing cancer (aOR, 12.5 [95% CI, 6.89-22.6]). Hispanic ethnicity, timing, and type of anti-cancer therapy modalities were not significantly associated with worse COVID-19 outcomes. The total all-cause mortality and hospitalization rate for the entire cohort was 9% and 37%, respectively however, it varied according to the BC disease status.ConclusionsUsing one of the largest registries on cancer and COVID-19, we identified patient and BC-related factors associated with worse COVID-19 outcomes. After adjusting for baseline characteristics, underrepresented racial/ethnic patients experienced worse outcomes compared to non-Hispanic White patients.FundingThis study was partly supported by National Cancer Institute grant number P30 CA068485 to Tianyi Sun, Sanjay Mishra, Benjamin French, Jeremy L Warner; P30-CA046592 to Christopher R Friese; P30 CA023100 for Rana R McKay; P30-CA054174 for Pankil K Shah and Dimpy P Shah; KL2 TR002646 for Pankil Shah and the American Cancer Society and Hope Foundation for Cancer Research (MRSG-16-152-01-CCE) and P30-CA054174 for Dimpy P Shah. REDCap is developed and supported by Vanderbilt Institute for Clinical and Translational Research grant support (UL1 TR000445 from NCATS/NIH). The funding sources had no role in the writing of the manuscript or the decision to submit it for publication.Clinical trial numberCCC19 registry is registered on ClinicalTrials.gov, NCT04354701.

Published
2023

15. Sex dependence of postoperative pulmonary complications – A post hoc unmatched and matched analysis of LAS VEGAS

Author

Kroell, Wolfgang, Metzler, Helfried, Struber, Gerd, Wegscheider, Thomas, Gombotz, Hans, Hiesmayr, Michael, Schmid, Werner, Urbanek, Bernhard, Kahn, David, Momeni, Mona, Pospiech, Audrey, Lois, Fernande, Forget, Patrice, Grosu, Irina, Poelaert, Jan, van Mossevelde, Veerle, van Malderen, Marie-Claire, Dylst, Dimitri, van Melkebeek, Jeroen, Beran, Maud, de Hert, Stefan, De Baerdemaeker, Luc, Heyse, Bjorn, Van Limmen, Jurgen, Wyffels, Piet, Jacobs, Tom, Roels, Nathalie, De Bruyne, Ann, van de Velde, Stijn, Leva, Brigitte, Damster, Sandrine, Plichon, Benoit, Juros-Zovko, Marina, Djonoviċ-Omanoviċ, Dejana, Pernar, Selma, Zunic, Josip, Miskovic, Petar, Zilic, Antonio, Kvolik, Slavica, Ivic, Dubravka, Azenic-Venzera, Darija, Skiljic, Sonja, Vinkovic, Hrvoje, Oputric, Ivana, Juricic, Kazimir, Frkovic, Vedran, Kopic, Jasminka, Mirkovic, Ivan, Karanovic, Nenad, Carev, Mladen, Dropulic, Natasa, Saric, Jadranka Pavicic, Erceg, Gorjana, Dvorscak, Matea Bogdanovic, Mazul-Sunko, Branka, Pavicic, Anna Marija, Goranovic, Tanja, Maldini, Branka, Radocaj, Tomislav, Gavranovic, Zeljka, Mladic-Batinica, Inga, Sehovic, Mirna, Stourac, Petr, Harazim, Hana, Smekalova, Olga, Kosinova, Martina, Kolacek, Tomas, Hudacek, Kamil, Drab, Michal, Brujevic, Jan, Vitkova, Katerina, Jirmanova, Katerina, Volfova, Ivana, Dzurnakova, Paula, Liskova, Katarina, Dudas, Radovan, Filipsky, Radek, el Kafrawy, Samir, Abdelwahab, Hisham Hosny, Metwally, Tarek, Abdel-Razek, Ahmed, El-Shaarawy, Ahmed Mostafa, Hasan, Wael Fathy, Ahmed, Ahmed Gouda, Yassin, Hany, Magdy, Mohamed, Abdelhady, Mahdy, Mahran, Mohamed, Herodes, Eiko, Kivik, Peeter, Oganjan, Juri, Aun, Annika, Sormus, Alar, Sarapuu, Kaili, Mall, Merilin, Karjagin, Juri, Futier, Emmanuel, Petit, Antoine, Gerard, Adeline, Marret, Emmanuel, Solier, Marc, Jaber, Samir, Prades, Albert, Krassler, Jens, Merzky, Simone, de Abreu, Marcel Gama, Uhlig, Christopher, Kiss, Thomas, Bundy, Anette, Bluth, Thomas, Gueldner, Andreas, Spieth, Peter, Scharffenberg, Martin, Thiem, Denny Tran, Koch, Thea, Treschan, Tanja, Schaefer, Maximilian, Bastin, Bea, Geib, Johann, Weiss, Martin, Kienbaum, Peter, Pannen, Benedikt, Gottschalk, Andre, Konrad, Mirja, Westerheide, Diana, Schwerdtfeger, Ben, Wrigge, Hermann, Simon, Philipp, Reske, Andreas, Nestler, Christian, Valsamidis, Dimitrios, Stroumpoulis, Konstantinos, Antholopoulos, Georgios, Andreou, Antonis, Karapanos, Dimitris, Theodoraki, Kassiani, Gkiokas, Georgios, Tasoulis, Marios-Konstantinos, Sidiropoulou, Tatiana, Zafeiropoulou, Foteini, Florou, Panagiota, Pandazi, Aggeliki, Tsaousi, Georgia, Nouris, Christos, Pourzitaki, Chryssa, Bystritski, Dmitri, Pizov, Reuven, Eden, Arieh, Pesce, Caterina Valeria, Campanile, Annamaria, Marrella, Antonella, Grasso, Salvatore, De Michele, Michele, Bona, Francesco, Giacoletto, Gianmarco, Sardo, Elena, Sottosanti, Luigi Giancarlo Vicari, Solca, Maurizio, Volta, Carlo Alberto, Spadaro, Savino, Verri, Marco, Ragazzi, Riccardo, Zoppellari, Roberto, Cinnella, Gilda, Raimondo, Pasquale, La Bella, Daniela, Mirabella, Lucia, D'antini, Davide, Pelosi, Paolo, Molin, Alexandre, Brunetti, Iole, Gratarola, Angelo, Pellerano, Giulia, Sileo, Rosanna, Pezzatto, Stefano, Montagnani, Luca, Pasin, Laura, Landoni, Giovanni, Zangrillo, Alberto, Beretta, Luigi, Di Parma, Ambra Licia, Tarzia, Valentina, Dossi, Roberto, Sassone, Marta Eugenia, Sances, Daniele, Tredici, Stefano, Spano, Gianluca, Castellani, Gianluca, Delunas, Luigi, Peradze, Sopio, Venturino, Marco, Arpino, Ines, Sher, Sara, Tommasino, Concezione, Rapido, Francesca, Morelli, Paola, Vargas, Maria, Servillo, Giuseppe, Cortegiani, Andrea, Raineri, Santi Maurizio, Montalto, Francesca, Russotto, Vincenzo, Giarratano, Antonino, Baciarello, Marco, Generali, Michela, Cerati, Giorgia, Leykin, Yigal, Bressan, Filippo, Bartolini, Vittoria, Zamidei, Lucia, Brazzi, Luca, Liperi, Corrado, Sales, Gabriele, Pistidda, Laura, Severgnini, Paolo, Brugnoni, Elisa, Musella, Giuseppe, Bacuzzi, Alessandro, Muhardri, Dalip, Gecaj-Gashi, Agreta, Sada, Fatos, Bytyqi, Adem, Karbonskiene, Aurika, Aukstakalniene, Ruta, Teberaite, Zivile, Salciute, Erika, Tikuisis, Renatas, Miliauskas, Povilas, Jurate, Sipylaite, Kontrimaviciute, Egle, Tomkute, Gabija, Xuereb, John, Bezzina, Maureen, Borg, Francis Joseph, Hemmes, Sabrine, Schultz, Marcus, Hollmann, Markus, Wiersma, Irene, Binnekade, Jan, Bos, Lieuwe, Nijbroek, Sunny, Boer, Christa, Duvekot, Anne, ’t Veld, Bas in, Werger, Alice, Dennesen, Paul, Severijns, Charlotte, De Jong, Jasper, Hering, Jens, van Beek, Rienk, Ivars, Stefan, Jammer, Ib, Breidablik, Alena, Hodt, Katharina Skirstad, Fjellanger, Frode, Avalos, Manuel Vico, Mellin-Olsen, Jannicke, Andersson, Elisabeth, Shafi-Kabiri, Amir, Molina, Ruby, Wutai, Stanley, Morais, Erick, Tareco, Glória, Ferreira, Daniel, Amaral, Joana, de Lurdes Goncalves Castro, Maria, Cadilha, Susana, Appleton, Sofia, Parente, Suzana, Correia, Mariana, Martins, Diogo, Monteirosa, Angela, Ricardo, Ana, Rodrigues, Sara, Horhota, Lucian, Grintescu, Ioana Marina, Mirea, Liliana, Grintescu, Ioana Cristina, Corneci, Dan, Negoita, Silvius, Dutu, Madalina, Garotescu, Ioana Popescu, Filipescu, Daniela, Prodan, Alexandru Bogdan, Droc, Gabriela, Fota, Ruxandra, Popescu, Mihai, Tomescu, Dana, Petcu, Ana Maria, Tudoroiu, Marian Irinel, Moise, Alida, Guran, Catalin-Traian, Gherghina, Iorel, Costea, Dan, Cindea, Iulia, Copotoiu, Sanda-Maria, Copotoiu, Ruxandra, Barsan, Victoria, Tolcser, Zsolt, Riciu, Magda, Moldovan, Septimiu Gheorghe, Veres, Mihaly, Gritsan, Alexey, Kapkan, Tatyana, Gritsan, Galina, Korolkov, Oleg, Kulikov, Alexander, Lubnin, Andrey, Ovezov, Alexey, Prokoshev, Pavel, Lugovoy, Alexander, Anipchenko, Natalia, Babayants, Andrey, Komissarova, Irina, Zalina, Karginova, Likhvantsev, Valery, Fedorov, Sergei, Lazukic, Aleksandra, Pejakovic, Jasmina, Mihajlovic, Dunja, Kusnierikova, Zuzana, Zelinkova, Maria, Bruncakova, Katarina, Polakovicova, Lenka, Sobona, Villiam, Novak-Supe, Barbka, Pekle-Golez, Ana, Jovanov, Miroljub, Strazisar, Branka, Markovic-Bozic, Jasmina, Novak-Jankovic, Vesna, Voje, Minca, Grynyuk, Andriy, Kostadinov, Ivan, Spindler-Vesel, Alenka, Moral, Victoria, Unzueta, Mari Carmen, Puigbo, Carlos, Fava, Josep, Canet, Jaume, Moret, Enrique, Nunez, Mónica Rodriguez, Sendra, Mar, Brunelli, Andrea, Rodenas, Frederic, Monedero, Pablo, Martinezv, Francisco Hidalgo, Temino, Maria Jose Yepes, Simon, Antonio Martínez, de Abajo Larriba, Ana, Lisi, Alberto, Perez, Gisela, Martinez, Raquel, Granell, Manuel, Vivo, Jose Tatay, Ruiz, Cristina Saiz, de Andrés Ibañez, Jose Antonio, Pastor, Ernesto, Soro, Marina, Ferrando, Carlos, Defez, Mario, Alvares-Santullano, Cesar Aldecoa, Perez, Rocio, Rico, Jesus, Jawad, Monir, Saeed, Yousif, Gillberg, Lars, Hedenstierma, Göran, Bengisun, Zuleyha Kazak, Kazbek, Baturay Kansu, Coskunfirat, Nesil, Boztug, Neval, Sanli, Suat, Yilmaz, Murat, Hadimioglu, Necmiye, Senturk, Nuzhet Mert, Camci, Emre, Kucukgoncu, Semra, Sungur, Zerrin, Sivrikoz, Nukhet, Ozgen, Serpil Ustalar, Toraman, Fevzi, Selvi, Onur, Senturk, Ozgur, Yildiz, Mine, Kuvaki, Bahar, Gunenc, Ferim, Kucukguclu, Semih, Ozbilgin, Şule, Maral, Jale, Canli, Seyda, Arun, Oguzhan, Saltali, Ali, Aydogan, Eyup, Akgun, Fatma Nur, Sanlikarip, Ceren, Karaman, Fatma Mine, Mazur, Andriy, Vorotyntsev, Sergiy, Rousseau, Guy, Barrett, Colin, Stancombe, Lucia, Shelley, Ben, Scholes, Helen, Limb, James, Rafi, Amir, Wayman, Lisa, Deane, Jill, Rogerson, David, Williams, John, Yates, Susan, Rogers, Elaine, Pulletz, Mark, Moreton, Sarah, Jones, Stephanie, Venkatesh, Suresh, Burton, Maudrian, Brown, Lucy, Goodall, Cait, Rucklidge, Matthew, Fuller, Debbie, Nadolski, Maria, Kusre, Sandeep, Lundberg, Michael, Everett, Lynn, Nutt, Helen, Zuleika, Maka, Carvalho, Peter, Clements, Deborah, Creagh-Brown, Ben, Watt, Philip, Raymode, Parizade, Pearse, Rupert, Mohr, Otto, Raj, Ashok, Creary, Thais, Chishti, Ahmed, Bell, Andrea, Higham, Charley, Cain, Alistair, Gibb, Sarah, Mowat, Stephen, Franklin, Danielle, West, Claire, Minto, Gary, Boyd, Nicholas, Mills, Gary, Calton, Emily, Walker, Rachel, Mackenzie, Felicity, Ellison, Branwen, Roberts, Helen, Chikungwa, Moses, Jackson, Clare, Donovan, Andrew, Foot, Jayne, Homan, Elizabeth, Montgomery, Jane, Portch, David, Mercer, Pauline, Palmer, Janet, Paddle, Jonathan, Fouracres, Anna, Datson, Amanda, Andrew, Alyson, Welch, Leanne, Rose, Alastair, Varma, Sandeep, Simeson, Karen, Rambhatla, Mrutyunjaya, Susarla, Jaysimha, Marri, Sudhakar, Kodaganallur, Krishnan, Das, Ashok, Algarsamy, Shivarajan, Colley, Julie, Davies, Simon, Szewczyk, Margaret, Smith, Thomas, Fernandez-Bustamante, Ana, Luzier, Elizabeth, Almagro, Angela, Melo, Marcos Vidal, Fernando, Luiz, Sulemanji, Demet, Sprung, Juraj, Weingarten, Toby, Kor, Daryl, Scavonetto, Federica, Tze, Yeo, Vermeulen, Tom D., Hol, Liselotte, Swart, Pien, Mills, Gary H., Putensen, Christian, Serpa Neto, Ary, Vidal Melo, Marcos F., Hollmann, Markus W., Gama de Abreu, Marcelo, Schultz, Marcus J., Hemmes, Sabrine N., and van Meenen, David M.

Published
2024
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16. The All of Us Research Program is an opportunity to enhance the diversity of US biomedical research

Author

Bianchi, Diana W., Brennan, Patricia Flatley, Chiang, Michael F., Criswell, Lindsey A., D’Souza, Rena N., Gibbons, Gary H., Gilman, James K., Gordon, Joshua A., Green, Eric D., Gregurick, Susan, Hodes, Richard J., Kilmarx, Peter H., Koob, George F., Koroshetz, Walter J., Langevin, Helene M., Lorsch, Jon R., Marrazzo, Jeanne M., Pérez-Stable, Eliseo J., Rathmell, W. Kimryn, Rodgers, Griffin P., Rutter, Joni L., Simoni, Jane M., Tromberg, Bruce J., Tucci, Debara L., Volkow, Nora D., Woychik, Rick, Zenk, Shannon N., Kozlowski, Elyse, Peterson, Rachele S., Ginsburg, Geoffrey S., and Denny, Joshua C.

Published
2024
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18. Ruminative reflection is associated with anticorrelations between the orbitofrontal cortex and the default mode network in depression: implications for repetitive transcranial magnetic stimulation

Author

Ehrlich, Tobin J, Bhat, Jyoti, Horwege, Andrea M, Mathalon, Daniel H, Glover, Gary H, Roach, Brian J, Badran, Bashar W, Forman, Steven D, George, Mark S, Scott, J Cobb, Thase, Michael E, Yesavage, Jerome A, Yurgelun-Todd, Deborah A, and Rosen, Allyson C

Subjects
Biological Psychology, Psychology, Depression, Brain Disorders, Neurosciences, Mental Health, Clinical Research, Aetiology, 2.1 Biological and endogenous factors, Mental health, Default Mode Network, Depressive Disorder, Major, Humans, Magnetic Resonance Imaging, Prefrontal Cortex, Transcranial Magnetic Stimulation, Rumination, Reflection, Treatment-resistant depression, Default mode network, Repetitive transcranial magnetic stimulation, Medical and Health Sciences, Psychology and Cognitive Sciences, Experimental Psychology, Biomedical and clinical sciences, Health sciences
Abstract

Patients with depression who ruminate repeatedly focus on depressive thoughts; however, there are two cognitive subtypes of rumination, reflection and brooding, each associated with different prognoses. Reflection involves problem-solving and is associated with positive outcomes, whereas brooding involves passive, negative, comparison with other people and is associated with poor outcomes. Rumination has also been related to atypical functional hyperconnectivity between the default mode network and subgenual prefrontal cortex. Repetitive pulse transcranial magnetic stimulation of the prefrontal cortex has been shown to alter functional connectivity, suggesting that the abnormal connectivity associated with rumination could potentially be altered. This study examined potential repetitive pulse transcranial magnetic stimulation prefrontal cortical targets that could modulate one or both of these rumination subtypes. Forty-three patients who took part in a trial of repetitive pulse transcranial magnetic stimulation completed the Rumination Response Scale questionnaire and resting-state functional magnetic resonance imaging. Seed to voxel functional connectivity analyses identified an anticorrelation between the left lateral orbitofrontal cortex (-44, 26, -8; k = 172) with the default mode network-subgenual region in relation to higher levels of reflection. Parallel analyses were not significant for brooding or the RRS total score. These findings extend previous studies of rumination and identify a potential mechanistic model for symptom-based neuromodulation of rumination.

Published
2022

19. Patients recently treated for B-lymphoid malignancies show increased risk of severe COVID-19: a CCC19 registry analysisImpact of B-cell malignancy therapy on COVID-19 outcomes

Author

Rubinstein, Samuel M, Bhutani, Divaya, Lynch, Ryan C, Hsu, Chih-Yuan, Shyr, Yu, Advani, Shailesh, Mesa, Ruben A, Mishra, Sanjay, Mundt, Daniel P, Shah, Dimpy P, Sica, R Alejandro, Stockerl-Goldstein, Keith E, Stratton, Catherine, Weiss, Matthias, Beeghly-Fadiel, Alicia, Accordino, Melissa, Assouline, Sarit E, Awosika, Joy, Bakouny, Ziad, Bashir, Babar, Berg, Stephanie, Bilen, Mehmet Asim, Castellano, Cecilia A, Cogan, Jacob C, Kc, Devendra, Friese, Christopher R, Gupta, Shilpa, Hausrath, Daniel, Hwang, Clara, Johnson, Nathalie A, Joshi, Monika, Kasi, Anup, Klein, Elizabeth J, Koshkin, Vadim S, Kuderer, Nicole M, Kwon, Daniel H, Labaki, Chris, Latif, Tahir, Lau, Eric, Li, Xuanyi, Lyman, Gary H, McKay, Rana R, Nagaraj, Gayathri, Nizam, Amanda, Nonato, Taylor K, Olszewski, Adam J, Polimera, Hyma V, Portuguese, Andrew J, Puc, Matthew M, Razavi, Pedram, Rosovski, Rachel, Schmidt, Andrew, Shah, Sumit A, Shastri, Aditi, Su, Christopher, Torka, Pallawi, Wise-Draper, Trisha M, Zubiri, Leyre, Warner, Jeremy L, and Thompson, Michael A

Subjects
Rare Diseases, Clinical Research, Prevention, Cancer, Aetiology, 2.1 Biological and endogenous factors, COVID-19, COVID-19 Testing, Humans, Lymphatic Diseases, Neoplasms, Risk Factors, SARS-CoV-2, COVID-19 and Cancer Consortium
Abstract

Patients with B-lymphoid malignancies have been consistently identified as a population at high risk of severe COVID-19. Whether this is exclusively due to cancer-related deficits in humoral and cellular immunity, or whether risk of severe COVID-19 is increased by anticancer therapy, is uncertain. Using data derived from the COVID-19 and Cancer Consortium (CCC19), we show that patients treated for B-lymphoid malignancies have an increased risk of severe COVID-19 compared with control populations of patients with non-B-lymphoid malignancies. Among patients with B-lymphoid malignancies, those who received anticancer therapy within 12 months of COVID-19 diagnosis experienced increased COVID-19 severity compared with patients with non-recently treated B-lymphoid malignancies, after adjustment for cancer status and several other prognostic factors. Our findings suggest that patients recently treated for a B-lymphoid malignancy are at uniquely high risk for severe COVID-19.SignificanceOur study suggests that recent therapy for a B-lymphoid malignancy is an independent risk factor for COVID-19 severity. These findings provide rationale to develop mitigation strategies targeted at the uniquely high-risk population of patients with recently treated B-lymphoid malignancies. This article is highlighted in the In This Issue feature, p. 171.

Published
2022

20. Gestational Insulin Resistance Is Mediated by the Gut Microbiome–Indoleamine 2,3-Dioxygenase Axis

Author

Priyadarshini, Medha, Navarro, Guadalupe, Reiman, Derek J, Sharma, Anukriti, Xu, Kai, Lednovich, Kristen, Manzella, Christopher R, Khan, Md Wasim, Garcia, Mariana Salas, Allard, Sarah, Wicksteed, Barton, Chlipala, George E, Szynal, Barbara, Bernabe, Beatriz Penalver, Maki, Pauline M, Gill, Ravinder K, Perdew, Gary H, Gilbert, Jack, Dai, Yang, and Layden, Brian T

Subjects
Medical Biochemistry and Metabolomics, Biomedical and Clinical Sciences, Diabetes, Genetics, Aetiology, 2.1 Biological and endogenous factors, Reproductive health and childbirth, Animals, Female, Gastrointestinal Microbiome, Humans, Indoleamine-Pyrrole 2, 3, -Dioxygenase, Inflammation, Insulin Resistance, Kynurenine, Mice, Pregnancy, RNA, Ribosomal, 16S, Gut Microbiome, IDO1, Clinical Sciences, Neurosciences, Paediatrics and Reproductive Medicine, Gastroenterology & Hepatology, Clinical sciences, Nutrition and dietetics
Abstract

Background & aimsNormal gestation involves a reprogramming of the maternal gut microbiome (GM) that contributes to maternal metabolic changes by unclear mechanisms. This study aimed to understand the mechanistic underpinnings of the GM-maternal metabolism interaction.MethodsThe GM and plasma metabolome of CD1, NIH-Swiss, and C57 mice were analyzed with the use of 16S rRNA sequencing and untargeted liquid chromatography-mass spectrometry throughout gestation. Pharmacologic and genetic knockout mouse models were used to identify the role of indoleamine 2,3-dioxygenase (IDO1) in pregnancy-associated insulin resistance (IR). Involvement of gestational GM was studied with the use of fecal microbial transplants (FMTs).ResultsSignificant variation in GM alpha diversity occurred throughout pregnancy. Enrichment in gut bacterial taxa was mouse strain and pregnancy time point specific, with the species enriched at gestation day 15/19 (G15/19), a point of heightened IR, being distinct from those enriched before or after pregnancy. Metabolomics revealed elevated plasma kynurenine at G15/19 in all 3 mouse strains. IDO1, the rate-limiting enzyme for kynurenine production, had increased intestinal expression at G15, which was associated with mild systemic and gut inflammation. Pharmacologic and genetic inhibition of IDO1 inhibited kynurenine levels and reversed pregnancy-associated IR. FMT revealed that IDO1 induction and local kynurenine level effects on IR derive from the GM in both mouse and human pregnancy.ConclusionsGM changes accompanying pregnancy shift IDO1-dependent tryptophan metabolism toward kynurenine production, intestinal inflammation, and gestational IR, a phenotype reversed by genetic deletion or inhibition of IDO1. (Gestational Gut Microbiome-IDO1 Axis Mediates Pregnancy Insulin Resistance; EMBL-ENA ID: PRJEB45047. MetaboLights ID: MTBLS3598).

Published
2022

21. Complete genomic and epigenetic maps of human centromeres

Author

Altemose, Nicolas, Logsdon, Glennis A, Bzikadze, Andrey V, Sidhwani, Pragya, Langley, Sasha A, Caldas, Gina V, Hoyt, Savannah J, Uralsky, Lev, Ryabov, Fedor D, Shew, Colin J, Sauria, Michael EG, Borchers, Matthew, Gershman, Ariel, Mikheenko, Alla, Shepelev, Valery A, Dvorkina, Tatiana, Kunyavskaya, Olga, Vollger, Mitchell R, Rhie, Arang, McCartney, Ann M, Asri, Mobin, Lorig-Roach, Ryan, Shafin, Kishwar, Lucas, Julian K, Aganezov, Sergey, Olson, Daniel, de Lima, Leonardo Gomes, Potapova, Tamara, Hartley, Gabrielle A, Haukness, Marina, Kerpedjiev, Peter, Gusev, Fedor, Tigyi, Kristof, Brooks, Shelise, Young, Alice, Nurk, Sergey, Koren, Sergey, Salama, Sofie R, Paten, Benedict, Rogaev, Evgeny I, Streets, Aaron, Karpen, Gary H, Dernburg, Abby F, Sullivan, Beth A, Straight, Aaron F, Wheeler, Travis J, Gerton, Jennifer L, Eichler, Evan E, Phillippy, Adam M, Timp, Winston, Dennis, Megan Y, O'Neill, Rachel J, Zook, Justin M, Schatz, Michael C, Pevzner, Pavel A, Diekhans, Mark, Langley, Charles H, Alexandrov, Ivan A, and Miga, Karen H

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Human Genome, Generic health relevance, Centromere, Chromosome Mapping, Epigenesis, Genetic, Evolution, Molecular, Genome, Human, Genomics, Humans, Repetitive Sequences, Nucleic Acid, General Science & Technology
Abstract

Existing human genome assemblies have almost entirely excluded repetitive sequences within and near centromeres, limiting our understanding of their organization, evolution, and functions, which include facilitating proper chromosome segregation. Now, a complete, telomere-to-telomere human genome assembly (T2T-CHM13) has enabled us to comprehensively characterize pericentromeric and centromeric repeats, which constitute 6.2% of the genome (189.9 megabases). Detailed maps of these regions revealed multimegabase structural rearrangements, including in active centromeric repeat arrays. Analysis of centromere-associated sequences uncovered a strong relationship between the position of the centromere and the evolution of the surrounding DNA through layered repeat expansions. Furthermore, comparisons of chromosome X centromeres across a diverse panel of individuals illuminated high degrees of structural, epigenetic, and sequence variation in these complex and rapidly evolving regions.

Published
2022

23. AHR is a master regulator of diverse pathways in endogenous metabolism

Author

Granados, Jeffry C, Falah, Kian, Koo, Imhoi, Morgan, Ethan W, Perdew, Gary H, Patterson, Andrew D, Jamshidi, Neema, and Nigam, Sanjay K

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Biological Sciences, Chemical Sciences, Medical Biochemistry and Metabolomics, Digestive Diseases, Genetics, 2.1 Biological and endogenous factors, Aetiology, Animals, Antioxidants, Basic Helix-Loop-Helix Transcription Factors, Bile Acids and Salts, Choline, Humans, Ligands, Mice, Receptors, Aryl Hydrocarbon
Abstract

The aryl hydrocarbon receptor (AHR) is a transcription factor with roles in detoxification, development, immune response, chronic kidney disease and other syndromes. It regulates the expression of drug transporters and drug metabolizing enzymes in a proposed Remote Sensing and Signaling Network involved in inter-organ communication via metabolites and signaling molecules. Here, we use integrated omics approaches to analyze its contributions to metabolism across multiple scales from the organ to the organelle. Global metabolomics analysis of Ahr-/- mice revealed the role of AHR in the regulation of 290 metabolites involved in many biochemical pathways affecting fatty acids, bile acids, gut microbiome products, antioxidants, choline derivatives, and uremic toxins. Chemoinformatics analysis suggest that AHR plays a role in determining the hydrophobicity of metabolites and perhaps their transporter-mediated movement into and out of tissues. Of known AHR ligands, indolepropionate was the only significantly altered molecule, and it activated AHR in both human and murine cells. To gain a deeper biological understanding of AHR, we employed genome scale metabolic reconstruction to integrate knockout transcriptomics and metabolomics data, which indicated a role for AHR in regulation of organic acids and redox state. Together, the results indicate a central role of AHR in metabolism and signaling between multiple organs and across multiple scales.

Published
2022

24. Coinfections in Patients With Cancer and COVID-19: A COVID-19 and Cancer Consortium (CCC19) Study

Author

Satyanarayana, Gowri, Enriquez, Kyle T, Sun, Tianyi, Klein, Elizabeth J, Abidi, Maheen, Advani, Shailesh M, Awosika, Joy, Bakouny, Ziad, Bashir, Babar, Berg, Stephanie, Bernardes, Marilia, Egan, Pamela C, Elkrief, Arielle, Feldman, Lawrence E, Friese, Christopher R, Goel, Shipra, Gomez, Cyndi Gonzalez, Grant, Keith L, Griffiths, Elizabeth A, Gulati, Shuchi, Gupta, Shilpa, Hwang, Clara, Jain, Jayanshu, Jani, Chinmay, Kaltsas, Anna, Kasi, Anup, Khan, Hina, Knox, Natalie, Koshkin, Vadim S, Kwon, Daniel H, Labaki, Chris, Lyman, Gary H, McKay, Rana R, McNair, Christopher, Nagaraj, Gayathri, Nakasone, Elizabeth S, Nguyen, Ryan, Nonato, Taylor K, Olszewski, Adam J, Panagiotou, Orestis A, Puc, Matthew, Razavi, Pedram, Robilotti, Elizabeth V, Santos-Dutra, Miriam, Schmidt, Andrew L, Shah, Dimpy P, Shah, Sumit A, Vieira, Kendra, Weissmann, Lisa B, Wise-Draper, Trisha M, Wu, Ulysses, Wu, Julie Tsu-Yu, Choueiri, Toni K, Mishra, Sanjay, Warner, Jeremy L, French, Benjamin, and Farmakiotis, Dimitrios

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Infectious Diseases, Prevention, Lung, Clinical Research, Emerging Infectious Diseases, 2.2 Factors relating to the physical environment, Aetiology, Infection, Good Health and Well Being, bacterial infections, CAPA, COVID-19, mucormycoses, viral infections, Clinical sciences, Medical microbiology
Abstract

BackgroundThe frequency of coinfections and their association with outcomes have not been adequately studied among patients with cancer and coronavirus disease 2019 (COVID-19), a high-risk group for coinfection.MethodsWe included adult (≥18 years) patients with active or prior hematologic or invasive solid malignancies and laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) infection, using data from the COVID-19 and Cancer Consortium (CCC19, NCT04354701). We captured coinfections within ±2 weeks from diagnosis of COVID-19, identified factors cross-sectionally associated with risk of coinfection, and quantified the association of coinfections with 30-day mortality.ResultsAmong 8765 patients (hospitalized or not; median age, 65 years; 47.4% male), 16.6% developed coinfections: 12.1% bacterial, 2.1% viral, 0.9% fungal. An additional 6.4% only had clinical diagnosis of a coinfection. The adjusted risk of any coinfection was positively associated with age >50 years, male sex, cardiovascular, pulmonary, and renal comorbidities, diabetes, hematologic malignancy, multiple malignancies, Eastern Cooperative Oncology Group Performance Status, progressing cancer, recent cytotoxic chemotherapy, and baseline corticosteroids; the adjusted risk of superinfection was positively associated with tocilizumab administration. Among hospitalized patients, high neutrophil count and C-reactive protein were positively associated with bacterial coinfection risk, and high or low neutrophil count with fungal coinfection risk. Adjusted mortality rates were significantly higher among patients with bacterial (odds ratio [OR], 1.61; 95% CI, 1.33-1.95) and fungal (OR, 2.20; 95% CI, 1.28-3.76) coinfections.ConclusionsViral and fungal coinfections are infrequent among patients with cancer and COVID-19, with the latter associated with very high mortality rates. Clinical and laboratory parameters can be used to guide early empiric antimicrobial therapy, which may improve clinical outcomes.

Published
2022

27. Drug development for major chronic health conditions—aligning with growing public health needs: Proceedings from a multistakeholder think tank

Author

Krychtiuk, Konstantin A., Andersson, Tomas LG, Bodesheim, Ulrike, Butler, Javed, Curtis, Lesley H., Elkind, Mitchell, Hernandez, Adrian F., Hornik, Christoph, Lyman, Gary H., Khatri, Pooja, Mbagwu, Michael, Murakami, Masahiro, Nichols, Gwen, Roessig, Lothar, Young, Anne Quinn, Schilsky, Richard L., and Pagidipati, Neha

Published
2024
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29. Cellugyrin (synaptogyrin-2) dependent pathways are used by bacterial cytolethal distending toxin and SARS-CoV-2 virus to gain cell entry

Author

Kathleen Boesze-Battaglia, Gary H. Cohen, Paul F. Bates, Lisa M. Walker, Ali Zekavat, and Bruce J. Shenker

Subjects
cellugyrin, synaptogyrin-2, cytolethal distending toxin, SARS-CoV-2, pathogen, cell entry, Microbiology, QR1-502
Abstract

Aggregatibacter actinomycetemcomitans cytolethal distending toxin (Cdt) is capable of intoxicating lymphocytes macrophages, mast cells and epithelial cells. Following Cdt binding to cholesterol, in the region of membrane lipid rafts, the CdtB and CdtC subunits are internalized and traffic to intracellular compartments. These events are dependent upon, cellugyrin, a critical component of synaptic like microvesicles (SLMVCg+). Target cells, such as Jurkat cells, rendered unable to express cellugyrin are resistant to Cdt-induced toxicity. Similar to Cdt, SARS-CoV-2 entry into host cells is initiated by binding to cell surface receptors, ACE-2, also associated with cholesterol-rich lipid rafts; this association leads to fusion and/or endocytosis of viral and host cell membranes and intracellular trafficking. The similarity in internalization pathways for both Cdt and SARS-CoV-2 led us to consider the possibility that cellugyrin was a critical component in both processes. Cellugyrin deficient Calu-3 cells (Calu-3Cg-) were prepared using Lentiviral particles containing shRNA; these cells were resistant to infection by VSV/SARS-CoV-2-spike pseudotype virus and partially resistant to VSV/VSV-G pseudotype virus. Synthetic peptides representing various regions of the cellugyrin protein were prepared and assessed for their ability to bind to Cdt subunits using surface plasmon resonance. Cdt was capable of binding to a region designated the middle outer loop (MOL) which corresponds to a region extending into the cytoplasmic surface of the SLMVCg+. SARS-CoV-2 spike proteins were assessed for their ability to bind to cellugyrin peptides; SARS-CoV-2 full length spike protein preferentially binds to a region within the SLMVCg+ lumen, designated intraluminal loop 1A. SARS-CoV-2-spike protein domain S1, which contains the receptor binding domains, binds to cellugyrin N-terminus which extends out from the cytoplasmic surface of SLMV. Binding specificity was further analyzed using cellugyrin scrambled peptide mutants. We propose that SLMVCg+ represent a component of a common pathway that facilitates pathogen and/or pathogen-derived toxins to gain host cell entry.

Published
2024
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30. Variables associated with admission rates among cancer patients presenting to emergency departments: a CONCERN group study

Author

Rico, Juan Felipe, Caterino, Jeffrey M., Stephens, Julie A., Abar, Beau, Adler, David, Bastani, Aveh, Bernstein, Steven L., Bischof, Jason J., Coyne, Christopher J., Grudzen, Corita R., Henning, Daniel J., Hudson, Matthew F., Klotz, Adam D., Lyman, Gary H., Madsen, Troy E., Reyes, Cielito C., Ryan, Richard J., Shapiro, Nathan I., Swor, Robert, Thomas, Jr., Charles R., Venkat, Arvind, Wilson, Jason, Yeung, Sai-Ching Jim, Yilmaz, Sule, and Baugh, Christopher W.

Published
2023
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31. The CoVID‐TE risk assessment model for venous thromboembolism in hospitalized patients with cancer and COVID‐19

Author

Li, Ang, Kuderer, Nicole M, Hsu, Chih‐Yuan, Shyr, Yu, Warner, Jeremy L, Shah, Dimpy P, Kumar, Vaibhav, Shah, Surbhi, Kulkarni, Amit A, Fu, Julie, Gulati, Shuchi, Zon, Rebecca L, Li, Monica, Desai, Aakash, Egan, Pamela C, Bakouny, Ziad, Devendra, KC, Hwang, Clara, Akpan, Imo J, McKay, Rana R, Girard, Jennifer, Schmidt, Andrew L, Halmos, Balazs, Thompson, Michael A, Patel, Jaymin M, Pennell, Nathan A, Peters, Solange, Elshoury, Amro, de Lima Lopes, Gilbero, Stover, Daniel G, Grivas, Petros, Rini, Brian I, Painter, Corrie A, Mishra, Sanjay, Connors, Jean M, Lyman, Gary H, Rosovsky, Rachel P, and consortium, the CCC19

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Clinical Research, Prevention, Hematology, Cancer, COVID-19, Cohort Studies, Humans, Neoplasms, Risk Assessment, SARS-CoV-2, Venous Thromboembolism, clinical decision rules, thrombosis, venous thromboembolism, CCC19 consortium, Cardiorespiratory Medicine and Haematology, Clinical Sciences, Cardiovascular System & Hematology, Cardiovascular medicine and haematology, Clinical sciences
Abstract

BackgroundHospitalized patients with COVID-19 have increased risks of venous (VTE) and arterial thromboembolism (ATE). Active cancer diagnosis and treatment are well-known risk factors; however, a risk assessment model (RAM) for VTE in patients with both cancer and COVID-19 is lacking.ObjectivesTo assess the incidence of and risk factors for thrombosis in hospitalized patients with cancer and COVID-19.MethodsAmong patients with cancer in the COVID-19 and Cancer Consortium registry (CCC19) cohort study, we assessed the incidence of VTE and ATE within 90 days of COVID-19-associated hospitalization. A multivariable logistic regression model specifically for VTE was built using a priori determined clinical risk factors. A simplified RAM was derived and internally validated using bootstrap.ResultsFrom March 17, 2020 to November 30, 2020, 2804 hospitalized patients were analyzed. The incidence of VTE and ATE was 7.6% and 3.9%, respectively. The incidence of VTE, but not ATE, was higher in patients receiving recent anti-cancer therapy. A simplified RAM for VTE was derived and named CoVID-TE (Cancer subtype high to very-high risk by original Khorana score +1, VTE history +2, ICU admission +2, D-dimer elevation +1, recent systemic anti-cancer Therapy +1, and non-Hispanic Ethnicity +1). The RAM stratified patients into two cohorts (low-risk, 0-2 points, n = 1423 vs. high-risk, 3+ points, n = 1034) where VTE occurred in 4.1% low-risk and 11.3% high-risk patients (c statistic 0.67, 95% confidence interval 0.63-0.71). The RAM performed similarly well in subgroups of patients not on anticoagulant prior to admission and moderately ill patients not requiring direct ICU admission.ConclusionsHospitalized patients with cancer and COVID-19 have elevated thrombotic risks. The CoVID-TE RAM for VTE prediction may help real-time data-driven decisions in this vulnerable population.

Published
2021

32. Hindlimb Somatosensory Information Influences Trunk Sensory and Motor Cortices to Support Trunk Stabilization.

Author

Nandakumar, Bharadwaj, Blumenthal, Gary H, Pauzin, Francois Philippe, and Moxon, Karen A

Subjects
Neurosciences, Neurological, Animals, Hindlimb, Motor Cortex, Rats, Somatosensory Cortex, Thalamus, Wakefulness, dermatome, dorsal root ganglion, mapping, motor cortex, sensory cortex, Psychology, Cognitive Sciences, Experimental Psychology
Abstract

Sensorimotor integration in the trunk system is poorly understood despite its importance for functional recovery after neurological injury. To address this, a series of mapping studies were performed in the rat. First, the receptive fields (RFs) of cells recorded from thoracic dorsal root ganglia were identified. Second, the RFs of cells recorded from trunk primary sensory cortex (S1) were used to assess the extent and internal organization of trunk S1. Finally, the trunk motor cortex (M1) was mapped using intracortical microstimulation to assess coactivation of trunk muscles with hindlimb and forelimb muscles, and integration with S1. Projections from trunk S1 to trunk M1 were not anatomically organized, with relatively weak sensorimotor integration between trunk S1 and M1 compared to extensive integration between hindlimb S1/M1 and trunk M1. Assessment of response latency and anatomical tracing suggest that trunk M1 is abundantly guided by hindlimb somatosensory information that is derived primarily from the thalamus. Finally, neural recordings from awake animals during unexpected postural perturbations support sensorimotor integration between hindlimb S1 and trunk M1, providing insight into the role of the trunk system in postural control that is useful when studying recovery after injury.

Published
2021

33. A New Prognostic Model in Patients with Advanced Urothelial Carcinoma Treated with First-line Immune Checkpoint Inhibitors

Author

Khaki, Ali Raza, Li, Ang, Diamantopoulos, Leonidas N, Miller, Natalie J, Carril-Ajuria, Lucia, Castellano, Daniel, De Kouchkovsky, Ivan, Koshkin, Vadim, Park, Joseph, Alva, Ajjai, Bilen, Mehmet A, Stewart, Tyler, Santos, Victor, Agarwal, Neeraj, Jain, Jayanshu, Zakharia, Yousef, Morales-Barrera, Rafael, Devitt, Michael, Nelson, Ariel, Hoimes, Christopher J, Shreck, Evan, Gartrell, Benjamin A, Sankin, Alex, Tripathi, Abhishek, Zakopoulou, Roubini, Bamias, Aristotelis, Rodriguez-Vida, Alejo, Drakaki, Alexandra, Liu, Sandy, Kumar, Vivek, Lythgoe, Mark P, Pinato, David J, Murgic, Jure, Fröbe, Ana, Joshi, Monika, Isaacsson Velho, Pedro, Hahn, Noah, Alonso Buznego, Lucia, Duran, Ignacio, Moses, Marcus, Barata, Pedro, Galsky, Matthew D, Sonpavde, Guru, Yu, Evan Y, Shankaran, Veena, Lyman, Gary H, and Grivas, Petros

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Clinical Research, Patient Safety, Cancer, Digestive Diseases, Prevention, Liver Disease, Aged, Carcinoma, Transitional Cell, Cohort Studies, Female, Humans, Immune Checkpoint Inhibitors, Prognosis, Retrospective Studies, Urinary Bladder Neoplasms, Bladder cancer, Immunotherapy, Outcome research, Prognostic model, Urothelial carcinoma, Clinical sciences, Oncology and carcinogenesis
Abstract

BackgroundWhile immune checkpoint inhibitors (ICIs) are approved in the first-line (1L) setting for cisplatin-unfit patients with programmed death-ligand 1 (PD-L1)-high tumors or for platinum (cisplatin/carboplatin)-unfit patients, response rates remain modest and outcomes vary with no clinically useful biomarkers (except for PD-L1).ObjectiveWe aimed to develop a prognostic model for overall survival (OS) in patients receiving 1L ICIs for advanced urothelial cancer (aUC) in a multicenter cohort study.Design, setting, and participantsPatients treated with 1L ICIs for aUC across 24 institutions and five countries (in the USA and Europe) outside clinical trials were included in this study.Outcome measurements and statistical analysisWe used a stepwise, hypothesis-driven approach using clinician-selected covariates to develop a new risk score for patients receiving ICIs in the 1L setting. Demographics, clinicopathologic data, treatment patterns, and OS were collected uniformly. Univariate Cox regression was performed on 18 covariates hypothesized to be associated with OS based on published data. Variables were retained for multivariate analysis (MVA) if they correlated with OS (p < 0.2) and were included in the final model if p < 0.05 on MVA. Retained covariates were assigned points based on the beta coefficient to create a risk score. Stratified median OS and C-statistic were calculated.Results and limitationsAmong 984 patients, 357 with a mean age of 71 yr were included in the analysis, 27% were female, 68% had pure UC, and 13% had upper tract UC. Eastern Cooperative Oncology Group performance status ≥2, albumin 5, and liver metastases were significant prognostic factors on MVA and were included in the risk score. C index for new 1L risk score was 0.68 (95% confidence interval 0.65-0.71). Limitations include retrospective nature and lack of external validation.ConclusionsWe developed a new 1L ICI risk score for OS based on data from patients with aUC treated with ICIs in the USA and Europe outside of clinical trials. The score components highlight readily available factors related to tumor biology and treatment response. External validation is being pursued.Patient summaryWith multiple new treatments under development and approved for advanced urothelial carcinoma, it can be difficult to identify the best treatment sequence for each patient. The risk score may help inform treatment discussions and estimate outcomes in patients treated with first-line immune checkpoint inhibitors, while it can also impact clinical trial design and endpoints. TAKE  HOME MESSAGE: A new risk score was developed for advanced urothelial carcinoma treated with first-line immune checkpoint inhibitors. The score assigned Eastern Cooperative Oncology Group performance status ≥2, albumin 5, and liver metastases each one point, with a higher score being associated with worse overall survival.

Published
2021

35. Adverse events among chronic myelogenous leukemia patients treated with tyrosine kinase inhibitors: a real-world analysis of health plan enrollees

Author

Chow, Eric J, Doody, David R, Wilkes, Jennifer J, Becker, Laura K, Chennupati, Shasank, Morin, Pamela E, Winestone, Lena E, Henk, Henry J, and Lyman, Gary H

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Clinical Research, Rare Diseases, Cancer, Hematology, Chronic Disease, Cohort Studies, Humans, Imatinib Mesylate, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Protein Kinase Inhibitors, Chronic myelogenous leukemia, tyrosine kinase inhibitor, complications, epidemiology, insurance, Immunology, Cardiovascular medicine and haematology
Abstract

With tyrosine kinase inhibitor (TKI) therapy, chronic myelogenous leukemia (CML) is now a chronic disease. CML patients treated with TKIs (n = 1200) were identified from the OptumLabs® Data Warehouse (de-identified claims and electronic health records) between 2000 and 2016 and compared with a non-cancer cohort (n = 7635). The 5-year cumulative incidence of all organ system outcomes was significantly greater for the TKI versus non-cancer group. In the first year, compared with imatinib, later generation TKIs were associated with primary infections (hazard ratios [HR] 1.43, 95% CI 1.02-2.00), circulatory events (HR 1.15, 95% CI 1.01-1.31), and skin issues (HR 1.43, 95% CI 1.13-1.80); musculoskeletal and nervous system/sensory issues were less common (HRs 0.83-0.84, p

Published
2021

36. Modelling at‐level allodynia after mid‐thoracic contusion in the rat

Author

Blumenthal, Gary H, Nandakumar, Bharadwaj, Schnider, Ashley K, Detloff, Megan R, Ricard, Jerome, Bethea, John R, and Moxon, Karen A

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Spinal Cord Injury, Traumatic Head and Spine Injury, Pain Research, Neurodegenerative, Physical Injury - Accidents and Adverse Effects, Chronic Pain, 2.1 Biological and endogenous factors, Aetiology, Neurological, Animals, Contusions, Disease Models, Animal, Hyperalgesia, Rats, Rats, Sprague-Dawley, Spinal Cord Injuries, Pharmacology and Pharmaceutical Sciences, Anesthesiology, Clinical sciences, Pharmacology and pharmaceutical sciences
Abstract

BackgroundThe rat mid-thoracic contusion model has been used to study at-level tactile allodynia, a common type of pain that develops after spinal cord injury (SCI). An important advantage of this model is that not all animals develop hypersensitivity. Therefore, it can be used to examine mechanisms that are strictly related to the development of pain-like behaviour separately from mechanisms related to the injury itself. However, how to separate animals that develop hypersensitivity from those that do not is unclear.MethodsThe aims of the current study were to identify where hypersensitivity and spasticity develop and use this information to identify metrics to separate animals that develop hypersensitivity from those that do not to study differences in their behaviour. To accomplish these aims, a grid was used to localize hypersensitivity on the dorsal trunk relative to thoracic dermatomes and supraspinal responses to tactile stimulation were tallied. These supraspinal responses were used to develop a hypersensitivity score to separate animals that develop hypersensitivity, or pain-like response to nonpainful stimuli.ResultsSimilar to humans, the development of hypersensitivity could occur with the development of spasticity or hyperreflexia. Moreover, the time course and prevalence of hypersensitivity phenotypes (at-, above-, or below level) produced by this model were similar to that observed in humans with SCI.ConclusionHowever, the amount of spared spinal matter in the cord did not explain the development of hypersensitivity, as previously reported. This approach can be used to study the mechanisms underlying the development of hypersensitivity separately from mechanisms related to injury alone.

Published
2021

37. Health Care Cost Associated With Contemporary Chronic Myelogenous Leukemia Therapy Compared With That of Other Hematologic Malignancies.

Author

Wilkes, Jennifer J, Lyman, Gary H, Doody, David R, Chennupati, Shasank, Becker, Laura K, Morin, Pamela E, Winestone, Lena E, Henk, Henry J, and Chow, Eric J

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Hematology, Rare Diseases, Clinical Research, Health Services, Cancer, Health Care Costs, Hematologic Neoplasms, Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Protein Kinase Inhibitors, Retrospective Studies, Oncology and carcinogenesis
Abstract

PurposeGiven the widespread introduction of tyrosine kinase inhibitors (TKIs), we evaluated the cost associated with chronic myelogenous leukemia (CML) care compared with the cost of care for patients with hematologic malignancies (HEM) and for patients without cancer (GEN), to aid with resource allocation and clinical decision making.MethodsA retrospective cohort was constructed from the OptumLabs Data Warehouse using claims from 2000 to 2016. Eligible patients had ≥ 2 CML claims and were enrolled continuously for ≥ 6 months before diagnosis and ≥ 1 year afterward (n = 1,909). Patients with CML were frequency matched 4:1 with HEM and GEN cohorts and were observed through October 2017. We used generalized linear models to assess the variation in total mean annualized health care costs in the 3 cohorts and to examine the influence of factors associated with costs.ResultsMean annualized costs for CML were $82,054 (ie, $25,471 [95% CI, $20,808 to $30,133] more than those for HEM and $74,993 [95% CI, $70,818 to $79,167] more than those for GEN); these differences were driven by pharmacy costs in the CML group. The cost of CML care exceeded that for HEM and GEN for all index years in this study and increased over each diagnostic interval until 2015, peaking at $91,990. The mean annual cost of all TKIs increased. Imatinib's mean annualized cost was $41,546 in the period 2000-2004 but increased to $105,069 in the period 2015-2017. In multivariable analysis, percent days on TKIs had the greatest influence on cost: ≥ 75% of the time versus none showed a difference in cost of $108,716 (95% CI, $99,193 to $118,239).ConclusionContemporary CML costs exceeded the cost of treatment of other hematologic malignancies. Cost was primarily driven by TKIs, whose cost continued to increase over time.

Published
2021

38. Comparative Assessment of Shell Structural, Mechanical, and Elemental Properties in Adult Acorn Barnacles

Author

Jazmine Shaw, Yeram Kang, Callie Triano, Corin J. Hoppe, Nick Aldred, Rebecca A. Metzler, and Gary H. Dickinson

Subjects
biomineralization, shell formation, crustacean, Amphibalanus, exoskeleton, calcite, Biology (General), QH301-705.5
Abstract

Balanomorph (acorn) barnacles are found throughout the world’s coastal oceans, and their success is dependent on a hard, mineralized, outer shell. Although macro-scale morphology of barnacle shells has been studied extensively, relatively little is known about shell properties at the micron-scale and if such properties vary among species. We assessed shell structure, mechanics, and composition in seven species of balanomorph barnacles from five genera. Three species, Amphibalanus amphitrite, Amphibalanus improvisus, and Austrominius modestus, were laboratory-reared, enabling direct comparison of shell properties of barnacles grown under the same conditions for the same duration. Four other species, Semibalanus balanoides, Amphibalanus eburneus, Chthamalus stellatus, and Tetraclita rubescens, were field-collected. At the macro- and meso-scales, shell properties varied markedly among species, with differences in the number of shell plates, the presence of canals within the plates, mineralization of the base, and shell plate thickness. At the micron-scale, however, structure was remarkably similar among species. Plates of all species were constructed of irregular micron-scale crystallites, with a broad range of crystallite dimensions observed within the same shell. Similarly, micromechanical properties did not vary among species, regardless of testing orientation. Calcium carbonate was identified as calcite in all species assessed with no other mineral phases present, and calcium content did not vary among species. Hence, despite variation in the overall macro- and meso-scale morphology of barnacles, all appear to be built using the same, evolutionarily conserved, mineralization pathway.

Published
2024
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39. Recent developments and future avenues for human corticospinal neuroimaging

Author

Merve Kaptan, Dario Pfyffer, Christiane G. Konstantopoulos, Christine S.W. Law, Kenneth A. Weber II, Gary H. Glover, and Sean Mackey

Subjects
corticospinal imaging, corticospinal fMRI, combined brain and spinal cord fMRI, fMRI data analysis, resting-state fMRI, pain processing, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Non-invasive neuroimaging serves as a valuable tool for investigating the mechanisms within the central nervous system (CNS) related to somatosensory and motor processing, emotions, memory, cognition, and other functions. Despite the extensive use of brain imaging, spinal cord imaging has received relatively less attention, regardless of its potential to study peripheral communications with the brain and the descending corticospinal systems. To comprehensively understand the neural mechanisms underlying human sensory and motor functions, particularly in pathological conditions, simultaneous examination of neuronal activity in both the brain and spinal cord becomes imperative. Although technically demanding in terms of data acquisition and analysis, a growing but limited number of studies have successfully utilized specialized acquisition protocols for corticospinal imaging. These studies have effectively assessed sensorimotor, autonomic, and interneuronal signaling within the spinal cord, revealing interactions with cortical processes in the brain. In this mini-review, we aim to examine the expanding body of literature that employs cutting-edge corticospinal imaging to investigate the flow of sensorimotor information between the brain and spinal cord. Additionally, we will provide a concise overview of recent advancements in functional magnetic resonance imaging (fMRI) techniques. Furthermore, we will discuss potential future perspectives aimed at enhancing our comprehension of large-scale neuronal networks in the CNS and their disruptions in clinical disorders. This collective knowledge will aid in refining combined corticospinal fMRI methodologies, leading to the development of clinically relevant biomarkers for conditions affecting sensorimotor processing in the CNS.

Published
2024
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42. Longitudinal Lung Function Assessment of Patients Hospitalized With COVID-19 Using 1H and 129Xe Lung MRI

Author

Saunders, Laura C., Collier, Guilhem J., Chan, Ho-Fung, Hughes, Paul J.C., Smith, Laurie J., Watson, J.G.R., Meiring, James E., Gabriel, Zoë, Newman, Thomas, Plowright, Megan, Wade, Phillip, Eaden, James A., Thomas, Siby, Strickland, Scarlett, Gustafsson, Lotta, Bray, Jody, BSc, Marshall, Helen, Capener, David A., Armstrong, Leanne, Rodgers, Jennifer, Brook, Martin, Biancardi, Alberto M., Rao, Madhwesha R., Norquay, Graham, Rodgers, Oliver, Munro, Ryan, Ball, James E., Stewart, Neil J., Lawrie, Allan, Jenkins, R. Gisli, Grist, James T., Gleeson, Fergus, Schulte, Rolf F., Johnson, Kevin M., Wilson, Frederick J., Cahn, Anthony, Swift, Andrew J., Rajaram, Smitha, Mills, Gary H., Watson, Lisa, Collini, Paul J., Lawson, Rod, Thompson, A.A. Roger, and Wild, Jim M.

Published
2023
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44. Innovation of heterochromatin functions drives rapid evolution of essential ZAD-ZNF genes in Drosophila.

Author

Kasinathan, Bhavatharini, Colmenares, Serafin U, McConnell, Hannah, Young, Janet M, Karpen, Gary H, and Malik, Harmit S

Subjects
D. melanogaster, chromatin, evolutionary biology, gene essentiality, gene turnover, genetics, genomics, heterochromatin, krab-zinc finger, positive selection, Biochemistry and Cell Biology
Abstract

Contrary to dogma, evolutionarily young and dynamic genes can encode essential functions. We find that evolutionarily dynamic ZAD-ZNF genes, which encode the most abundant class of insect transcription factors, are more likely to encode essential functions in Drosophila melanogaster than ancient, conserved ZAD-ZNF genes. We focus on the Nicknack ZAD-ZNF gene, which is evolutionarily young, poorly retained in Drosophila species, and evolves under strong positive selection. Yet we find that it is necessary for larval development in D. melanogaster. We show that Nicknack encodes a heterochromatin-localizing protein like its paralog Oddjob, also an evolutionarily dynamic yet essential ZAD-ZNF gene. We find that the divergent D. simulans Nicknack protein can still localize to D. melanogaster heterochromatin and rescue viability of female but not male Nicknack-null D. melanogaster. Our findings suggest that innovation for rapidly changing heterochromatin functions might generally explain the essentiality of many evolutionarily dynamic ZAD-ZNF genes in insects.

Published
2020

45. Clinical impact of COVID-19 on patients with cancer (CCC19): a cohort study

Author

Kuderer, Nicole M, Choueiri, Toni K, Shah, Dimpy P, Shyr, Yu, Rubinstein, Samuel M, Rivera, Donna R, Shete, Sanjay, Hsu, Chih-Yuan, Desai, Aakash, de Lima Lopes, Gilberto, Grivas, Petros, Painter, Corrie A, Peters, Solange, Thompson, Michael A, Bakouny, Ziad, Batist, Gerald, Bekaii-Saab, Tanios, Bilen, Mehmet A, Bouganim, Nathaniel, Larroya, Mateo Bover, Castellano, Daniel, Del Prete, Salvatore A, Doroshow, Deborah B, Egan, Pamela C, Elkrief, Arielle, Farmakiotis, Dimitrios, Flora, Daniel, Galsky, Matthew D, Glover, Michael J, Griffiths, Elizabeth A, Gulati, Anthony P, Gupta, Shilpa, Hafez, Navid, Halfdanarson, Thorvardur R, Hawley, Jessica E, Hsu, Emily, Kasi, Anup, Khaki, Ali R, Lemmon, Christopher A, Lewis, Colleen, Logan, Barbara, Masters, Tyler, McKay, Rana R, Mesa, Ruben A, Morgans, Alicia K, Mulcahy, Mary F, Panagiotou, Orestis A, Peddi, Prakash, Pennell, Nathan A, Reynolds, Kerry, Rosen, Lane R, Rosovsky, Rachel, Salazar, Mary, Schmidt, Andrew, Shah, Sumit A, Shaya, Justin A, Steinharter, John, Stockerl-Goldstein, Keith E, Subbiah, Suki, Vinh, Donald C, Wehbe, Firas H, Weissmann, Lisa B, Wu, Julie Tsu-Yu, Wulff-Burchfield, Elizabeth, Xie, Zhuoer, Yeh, Albert, Yu, Peter P, Zhou, Alice Y, Zubiri, Leyre, Mishra, Sanjay, Lyman, Gary H, Rini, Brian I, Warner, Jeremy L, Consortium, COVID-19 and Cancer, Abidi, Maheen, Acoba, Jared D, Agarwal, Neeraj, Ahmad, Syed, Ajmera, Archana, Altman, Jessica, Angevine, Anne H, Azad, Nilo, Bar, Michael H, Bardia, Aditya, Barnholtz-Sloan, Jill, Barrow, Briana, Bashir, Babar, Belenkaya, Rimma, Berg, Stephanie, Bernicker, Eric H, Bestvina, Christine, Bishnoi, Rohit, Boland, Genevieve, Bonnen, Mark, Bouchard, Gabrielle, Bowles, Daniel W, Busser, Fiona, Cabal, Angelo, Caimi, Paolo, and Carducci, Theresa

Subjects
Biomedical and Clinical Sciences, Health Sciences, Clinical Sciences, Oncology and Carcinogenesis, Infectious Diseases, Prevention, Lung, Coronaviruses, Cancer, Emerging Infectious Diseases, Good Health and Well Being, Aged, Antiviral Agents, Azithromycin, Betacoronavirus, COVID-19, Cause of Death, Comorbidity, Coronavirus Infections, Databases, Factual, Female, Humans, Hydroxychloroquine, Male, Middle Aged, Neoplasms, Pandemics, Pneumonia, Viral, Prognosis, Risk Factors, SARS-CoV-2, COVID-19 Drug Treatment, COVID-19 and Cancer Consortium, Medical and Health Sciences, General & Internal Medicine, Biomedical and clinical sciences, Health sciences
Abstract

BackgroundData on patients with COVID-19 who have cancer are lacking. Here we characterise the outcomes of a cohort of patients with cancer and COVID-19 and identify potential prognostic factors for mortality and severe illness.MethodsIn this cohort study, we collected de-identified data on patients with active or previous malignancy, aged 18 years and older, with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection from the USA, Canada, and Spain from the COVID-19 and Cancer Consortium (CCC19) database for whom baseline data were added between March 17 and April 16, 2020. We collected data on baseline clinical conditions, medications, cancer diagnosis and treatment, and COVID-19 disease course. The primary endpoint was all-cause mortality within 30 days of diagnosis of COVID-19. We assessed the association between the outcome and potential prognostic variables using logistic regression analyses, partially adjusted for age, sex, smoking status, and obesity. This study is registered with ClinicalTrials.gov, NCT04354701, and is ongoing.FindingsOf 1035 records entered into the CCC19 database during the study period, 928 patients met inclusion criteria for our analysis. Median age was 66 years (IQR 57-76), 279 (30%) were aged 75 years or older, and 468 (50%) patients were male. The most prevalent malignancies were breast (191 [21%]) and prostate (152 [16%]). 366 (39%) patients were on active anticancer treatment, and 396 (43%) had active (measurable) cancer. At analysis (May 7, 2020), 121 (13%) patients had died. In logistic regression analysis, independent factors associated with increased 30-day mortality, after partial adjustment, were: increased age (per 10 years; partially adjusted odds ratio 1·84, 95% CI 1·53-2·21), male sex (1·63, 1·07-2·48), smoking status (former smoker vs never smoked: 1·60, 1·03-2·47), number of comorbidities (two vs none: 4·50, 1·33-15·28), Eastern Cooperative Oncology Group performance status of 2 or higher (status of 2 vs 0 or 1: 3·89, 2·11-7·18), active cancer (progressing vs remission: 5·20, 2·77-9·77), and receipt of azithromycin plus hydroxychloroquine (vs treatment with neither: 2·93, 1·79-4·79; confounding by indication cannot be excluded). Compared with residence in the US-Northeast, residence in Canada (0·24, 0·07-0·84) or the US-Midwest (0·50, 0·28-0·90) were associated with decreased 30-day all-cause mortality. Race and ethnicity, obesity status, cancer type, type of anticancer therapy, and recent surgery were not associated with mortality.InterpretationAmong patients with cancer and COVID-19, 30-day all-cause mortality was high and associated with general risk factors and risk factors unique to patients with cancer. Longer follow-up is needed to better understand the effect of COVID-19 on outcomes in patients with cancer, including the ability to continue specific cancer treatments.FundingAmerican Cancer Society, National Institutes of Health, and Hope Foundation for Cancer Research.

Published
2020

46. Pericentromeric heterochromatin is hierarchically organized and spatially contacts H3K9me2 islands in euchromatin.

Author

Lee, Yuh, Ogiyama, Yuki, Martins, Nuno, Beliveau, Brian, Acevedo, David, Wu, C-Ting, Cavalli, Giacomo, and KARPEN, Gary H.

Abstract

Membraneless pericentromeric heterochromatin (PCH) domains play vital roles in chromosome dynamics and genome stability. However, our current understanding of 3D genome organization does not include PCH domains because of technical challenges associated with repetitive sequences enriched in PCH genomic regions. We investigated the 3D architecture of Drosophila melanogaster PCH domains and their spatial associations with the euchromatic genome by developing a novel analysis method that incorporates genome-wide Hi-C reads originating from PCH DNA. Combined with cytogenetic analysis, we reveal a hierarchical organization of the PCH domains into distinct territories. Strikingly, H3K9me2-enriched regions embedded in the euchromatic genome show prevalent 3D interactions with the PCH domain. These spatial contacts require H3K9me2 enrichment, are likely mediated by liquid-liquid phase separation, and may influence organismal fitness. Our findings have important implications for how PCH architecture influences the function and evolution of both repetitive heterochromatin and the gene-rich euchromatin.

Published
2020

48. CARD 2023: expanded curation, support for machine learning, and resistome prediction at the Comprehensive Antibiotic Resistance Database.

Author

Brian P. Alcock, William Huynh, Romeo Chalil, Keaton W. Smith, Amogelang R. Raphenya, Mateusz A. Wlodarski, Arman Edalatmand, Aaron J. Petkau, Sohaib A. Syed, Kara K. Tsang, Sheridan J. C. Baker, Mugdha Dave, Madeline C. McCarthy, Karyn M. Mukiri, Jalees A. Nasir, Bahar Golbon, Hamna Imtiaz, Xingjian Jiang, Komal Kaur, Megan Kwong, Zi Cheng Liang, Keyu C. Niu, Prabakar Shan, Jasmine Y. J. Yang, Kristen L. Gray, Gemma Hoad, Baofeng Jia, Timsy Bhando, Lindsey A. Carfrae, Maya A. Farha, Shawn French, Rodion Gordzevich, Kenneth Rachwalski, Megan M. Tu, Emily Bordeleau, Damion M. Dooley, Emma J. Griffiths, Haley L. Zubyk, Eric D. Brown, Finlay Maguire, Robert G. Beiko, William W. L. Hsiao, Fiona S. L. Brinkman, Gary H. Van Domselaar, and Andrew G. McArthur

Published
2023
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