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2. Genomic investigations of unexplained acute hepatitis in children

Author

Morfopoulou, Sofia, Buddle, Sarah, Torres Montaguth, Oscar Enrique, Atkinson, Laura, Guerra-Assunção, José Afonso, Moradi Marjaneh, Mahdi, Zennezini Chiozzi, Riccardo, Storey, Nathaniel, Campos, Luis, Hutchinson, J. Ciaran, Counsell, John R., Pollara, Gabriele, Roy, Sunando, Venturini, Cristina, Antinao Diaz, Juan F., Siam, Ala’a, Tappouni, Luke J., Asgarian, Zeinab, Ng, Joanne, Hanlon, Killian S., Lennon, Alexander, McArdle, Andrew, Czap, Agata, Rosenheim, Joshua, Andrade, Catarina, Anderson, Glenn, Lee, Jack C. D., Williams, Rachel, Williams, Charlotte A., Tutill, Helena, Bayzid, Nadua, Martin Bernal, Luz Marina, Macpherson, Hannah, Montgomery, Kylie-Ann, Moore, Catherine, Templeton, Kate, Neill, Claire, Holden, Matt, Gunson, Rory, Shepherd, Samantha J., Shah, Priyen, Cooray, Samantha, Voice, Marie, Steele, Michael, Fink, Colin, Whittaker, Thomas E., Santilli, Giorgia, Gissen, Paul, Kaufer, Benedikt B., Reich, Jana, Andreani, Julien, Simmonds, Peter, Alrabiah, Dimah K., Castellano, Sergi, Chikowore, Primrose, Odam, Miranda, Rampling, Tommy, Houlihan, Catherine, Hoschler, Katja, Talts, Tiina, Celma, Cristina, Gonzalez, Suam, Gallagher, Eileen, Simmons, Ruth, Watson, Conall, Mandal, Sema, Zambon, Maria, Chand, Meera, Hatcher, James, De, Surjo, Baillie, Kenneth, Semple, Malcolm Gracie, Martin, Joanne, Ushiro-Lumb, Ines, Noursadeghi, Mahdad, Deheragoda, Maesha, Hadzic, Nedim, Grammatikopoulos, Tassos, Brown, Rachel, Kelgeri, Chayarani, Thalassinos, Konstantinos, Waddington, Simon N., Jacques, Thomas S., Thomson, Emma, Levin, Michael, Brown, Julianne R., and Breuer, Judith

Published
2023
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4. Protective Effect of Nasal Colonisation with ∆cps/piaA and ∆cps/proABC Streptococcus pneumoniae Strains against Recolonisation and Invasive Infection

Author

Ramos-Sevillano, Elisa, Ercoli, Giuseppe, Guerra-Assunção, José Afonso, Felgner, Philip, de Assis, Rafael Ramiro, Nakajima, Rie, Goldblatt, David, Tetteh, Kevin Kweku Adjei, Heyderman, Robert Simon, Gordon, Stephen Brian, Ferreria, Daniela Mulari, and Brown, Jeremy Stuart

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Infectious Diseases, Pneumonia & Influenza, Pneumonia, Lung, Prevention, 2.1 Biological and endogenous factors, Aetiology, 2.2 Factors relating to the physical environment, Infection, Streptococcus pneumoniae, capsule, vaccine, psaA, proABC, colonisation, immunity, Clinical sciences, Immunology, Medical microbiology
Abstract

RationaleNasopharyngeal administration of live virulence-attenuated Streptococcus pneumoniae strains is a potential novel preventative strategy. One target for creating reduced virulence S. pneumoniae strains is the capsule, but loss of the capsule reduces the duration of S. pneumoniae colonisation in mice which could impair protective efficacy against subsequent infection.ObjectivesTo assess protective efficacy of nasopharyngeal administration of unencapsulated S. pneumoniae strains in murine infection models.MethodsStrains containing cps locus deletions combined with the S. pneumoniae virulence factors psaA (reduces colonisation) or proABC (no effect on colonisation) were constructed and their virulence phenotypes and ability to prevent recolonisation or invasive infection assessed using mouse infection models. Serological responses to colonisation were compared between strains using ELISAs, immunoblots and 254 S. pneumoniae protein antigen array.Measurements and main resultsThe ∆cps/piaA and ∆cps/proABC strains were strongly attenuated in virulence in both invasive infection models and had a reduced ability to colonise the nasopharynx. ELISAs, immunoblots and protein arrays showed colonisation with either strain stimulated weaker serological responses than the wild type strain. Mice previously colonised with these strains were protected against septicaemic pneumonia but, unlike mice colonised with the wild type strain, not against S. pneumoniae recolonisation.ConclusionsColonisation with the ∆cps/piaA and ∆cps/proABC strains prevented subsequent septicaemia, but in contrast, to published data for encapsulated double mutant strains they did not prevent recolonisation with S. pneumoniae. These data suggest targeting the cps locus is a less effective option for creating live attenuated strains that prevent S. pneumoniae infections.

Published
2021

5. Rapid synchronous type 1 IFN and virus-specific T cell responses characterize first wave non-severe SARS-CoV-2 infections

Author

Chandran, Aneesh, Rosenheim, Joshua, Nageswaran, Gayathri, Swadling, Leo, Pollara, Gabriele, Gupta, Rishi K., Burton, Alice R., Guerra-Assunção, José Afonso, Woolston, Annemarie, Ronel, Tahel, Pade, Corinna, Gibbons, Joseph M., Sanz-Magallon Duque De Estrada, Blanca, Robert de Massy, Marc, Whelan, Matthew, Semper, Amanda, Brooks, Tim, Altmann, Daniel M., Boyton, Rosemary J., McKnight, Áine, Captur, Gabriella, Manisty, Charlotte, Treibel, Thomas Alexander, Moon, James C., Tomlinson, Gillian S., Maini, Mala K., Chain, Benjamin M., and Noursadeghi, Mahdad

Published
2022
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7. Chemotherapy induces canalization of cell state in childhood B-cell precursor acute lymphoblastic leukemia

Author

Turati, Virginia A., Guerra-Assunção, José Afonso, Potter, Nicola E., Gupta, Rajeev, Ecker, Simone, Daneviciute, Agne, Tarabichi, Maxime, Webster, Amy P., Ding, Chuling, May, Gillian, James, Chela, Brown, John, Conde, Lucia, Russell, Lisa J., Ancliff, Phil, Inglott, Sarah, Cazzaniga, Giovanni, Biondi, Andrea, Hall, Georgina W., Lynch, Mark, Hubank, Mike, Macaulay, Iain, Beck, Stephan, Van Loo, Peter, Jacobsen, Sten E., Greaves, Mel, Herrero, Javier, and Enver, Tariq

Published
2021
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8. The T cell differentiation landscape is shaped by tumour mutations in lung cancer

Author

Ghorani, Ehsan, Reading, James L., Henry, Jake Y., Massy, Marc Robert de, Rosenthal, Rachel, Turati, Virginia, Joshi, Kroopa, Furness, Andrew J. S., Ben Aissa, Assma, Saini, Sunil Kumar, Ramskov, Sofie, Georgiou, Andrew, Sunderland, Mariana Werner, Wong, Yien Ning Sophia, Mucha, Maria Vila De, Day, William, Galvez-Cancino, Felipe, Becker, Pablo D., Uddin, Imran, Oakes, Theres, Ismail, Mazlina, Ronel, Tahel, Woolston, Annemarie, Jamal-Hanjani, Mariam, Veeriah, Selvaraju, Birkbak, Nicolai J., Wilson, Gareth A., Litchfield, Kevin, Conde, Lucia, Guerra-Assunção, José Afonso, Blighe, Kevin, Biswas, Dhruva, Salgado, Roberto, Lund, Tom, Bakir, Maise Al, Moore, David A., Hiley, Crispin T., Loi, Sherene, Sun, Yuxin, Yuan, Yinyin, AbdulJabbar, Khalid, Turajilic, Samra, Herrero, Javier, Enver, Tariq, Hadrup, Sine R., Hackshaw, Allan, Peggs, Karl S., McGranahan, Nicholas, Chain, Benny, Swanton, Charles, and Quezada, Sergio A.

Published
2020
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9. The BioMart community portal: an innovative alternative to large, centralized data repositories.

Author

Smedley, Damian, Haider, Syed, Durinck, Steffen, Pandini, Luca, Provero, Paolo, Allen, James, Arnaiz, Olivier, Awedh, Mohammad Hamza, Baldock, Richard, Barbiera, Giulia, Bardou, Philippe, Beck, Tim, Blake, Andrew, Bonierbale, Merideth, Brookes, Anthony J, Bucci, Gabriele, Buetti, Iwan, Burge, Sarah, Cabau, Cédric, Carlson, Joseph W, Chelala, Claude, Chrysostomou, Charalambos, Cittaro, Davide, Collin, Olivier, Cordova, Raul, Cutts, Rosalind J, Dassi, Erik, Di Genova, Alex, Djari, Anis, Esposito, Anthony, Estrella, Heather, Eyras, Eduardo, Fernandez-Banet, Julio, Forbes, Simon, Free, Robert C, Fujisawa, Takatomo, Gadaleta, Emanuela, Garcia-Manteiga, Jose M, Goodstein, David, Gray, Kristian, Guerra-Assunção, José Afonso, Haggarty, Bernard, Han, Dong-Jin, Han, Byung Woo, Harris, Todd, Harshbarger, Jayson, Hastings, Robert K, Hayes, Richard D, Hoede, Claire, Hu, Shen, Hu, Zhi-Liang, Hutchins, Lucie, Kan, Zhengyan, Kawaji, Hideya, Keliet, Aminah, Kerhornou, Arnaud, Kim, Sunghoon, Kinsella, Rhoda, Klopp, Christophe, Kong, Lei, Lawson, Daniel, Lazarevic, Dejan, Lee, Ji-Hyun, Letellier, Thomas, Li, Chuan-Yun, Lio, Pietro, Liu, Chu-Jun, Luo, Jie, Maass, Alejandro, Mariette, Jerome, Maurel, Thomas, Merella, Stefania, Mohamed, Azza Mostafa, Moreews, Francois, Nabihoudine, Ibounyamine, Ndegwa, Nelson, Noirot, Céline, Perez-Llamas, Cristian, Primig, Michael, Quattrone, Alessandro, Quesneville, Hadi, Rambaldi, Davide, Reecy, James, Riba, Michela, Rosanoff, Steven, Saddiq, Amna Ali, Salas, Elisa, Sallou, Olivier, Shepherd, Rebecca, Simon, Reinhard, Sperling, Linda, Spooner, William, Staines, Daniel M, Steinbach, Delphine, Stone, Kevin, Stupka, Elia, Teague, Jon W, Dayem Ullah, Abu Z, Wang, Jun, and Ware, Doreen

Subjects
Humans, Neoplasms, Proteomics, Genomics, Internet, Database Management Systems, Developmental Biology, Environmental Sciences, Biological Sciences, Information and Computing Sciences
Abstract

The BioMart Community Portal (www.biomart.org) is a community-driven effort to provide a unified interface to biomedical databases that are distributed worldwide. The portal provides access to numerous database projects supported by 30 scientific organizations. It includes over 800 different biological datasets spanning genomics, proteomics, model organisms, cancer data, ontology information and more. All resources available through the portal are independently administered and funded by their host organizations. The BioMart data federation technology provides a unified interface to all the available data. The latest version of the portal comes with many new databases that have been created by our ever-growing community. It also comes with better support and extensibility for data analysis and visualization tools. A new addition to our toolbox, the enrichment analysis tool is now accessible through graphical and web service interface. The BioMart community portal averages over one million requests per day. Building on this level of service and the wealth of information that has become available, the BioMart Community Portal has introduced a new, more scalable and cheaper alternative to the large data stores maintained by specialized organizations.

Published
2015

10. Essential role of proline synthesis and the one-carbon metabolism pathways for systemic virulence ofStreptococcus pneumoniae

Author

Ramos-Sevillano, Elisa, primary, Ercoli, Giuseppe, additional, Guerra-Assunção, José Afonso, additional, Betts, Modupeh, additional, Partridge, Frederick, additional, Fernandes, Vitor E., additional, Wall, Emma, additional, Gordon, Stephen B., additional, Ferreira, Daniela M., additional, Heyderman, Rob, additional, and Brown, Jeremy S., additional

Published
2023
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12. Supplementary Table 3 from EZH2-Deficient T-cell Acute Lymphoblastic Leukemia Is Sensitized to CHK1 Inhibition through Enhanced Replication Stress

Author

León, Theresa E., primary, Rapoz-D'Silva, Tanya, primary, Bertoli, Cosetta, primary, Rahman, Sunniyat, primary, Magnussen, Michael, primary, Philip, Brian, primary, Farah, Nadine, primary, Richardson, Simon E., primary, Ahrabi, Sara, primary, Guerra-Assunção, José Afonso, primary, Gupta, Rajeev, primary, Nacheva, Elisabeth P., primary, Henderson, Stephen, primary, Herrero, Javier, primary, Linch, David C., primary, de Bruin, Robertus A.M., primary, and Mansour, Marc R., primary

Published
2023
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13. Supplementary Table 1 from EZH2-Deficient T-cell Acute Lymphoblastic Leukemia Is Sensitized to CHK1 Inhibition through Enhanced Replication Stress

Author

León, Theresa E., primary, Rapoz-D'Silva, Tanya, primary, Bertoli, Cosetta, primary, Rahman, Sunniyat, primary, Magnussen, Michael, primary, Philip, Brian, primary, Farah, Nadine, primary, Richardson, Simon E., primary, Ahrabi, Sara, primary, Guerra-Assunção, José Afonso, primary, Gupta, Rajeev, primary, Nacheva, Elisabeth P., primary, Henderson, Stephen, primary, Herrero, Javier, primary, Linch, David C., primary, de Bruin, Robertus A.M., primary, and Mansour, Marc R., primary

Published
2023
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14. Data from EZH2-Deficient T-cell Acute Lymphoblastic Leukemia Is Sensitized to CHK1 Inhibition through Enhanced Replication Stress

Author

León, Theresa E., primary, Rapoz-D'Silva, Tanya, primary, Bertoli, Cosetta, primary, Rahman, Sunniyat, primary, Magnussen, Michael, primary, Philip, Brian, primary, Farah, Nadine, primary, Richardson, Simon E., primary, Ahrabi, Sara, primary, Guerra-Assunção, José Afonso, primary, Gupta, Rajeev, primary, Nacheva, Elisabeth P., primary, Henderson, Stephen, primary, Herrero, Javier, primary, Linch, David C., primary, de Bruin, Robertus A.M., primary, and Mansour, Marc R., primary

Published
2023
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15. Supplementary Table 2 from EZH2-Deficient T-cell Acute Lymphoblastic Leukemia Is Sensitized to CHK1 Inhibition through Enhanced Replication Stress

Author

León, Theresa E., primary, Rapoz-D'Silva, Tanya, primary, Bertoli, Cosetta, primary, Rahman, Sunniyat, primary, Magnussen, Michael, primary, Philip, Brian, primary, Farah, Nadine, primary, Richardson, Simon E., primary, Ahrabi, Sara, primary, Guerra-Assunção, José Afonso, primary, Gupta, Rajeev, primary, Nacheva, Elisabeth P., primary, Henderson, Stephen, primary, Herrero, Javier, primary, Linch, David C., primary, de Bruin, Robertus A.M., primary, and Mansour, Marc R., primary

Published
2023
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16. Supplementary information from EZH2-Deficient T-cell Acute Lymphoblastic Leukemia Is Sensitized to CHK1 Inhibition through Enhanced Replication Stress

Author

León, Theresa E., primary, Rapoz-D'Silva, Tanya, primary, Bertoli, Cosetta, primary, Rahman, Sunniyat, primary, Magnussen, Michael, primary, Philip, Brian, primary, Farah, Nadine, primary, Richardson, Simon E., primary, Ahrabi, Sara, primary, Guerra-Assunção, José Afonso, primary, Gupta, Rajeev, primary, Nacheva, Elisabeth P., primary, Henderson, Stephen, primary, Herrero, Javier, primary, Linch, David C., primary, de Bruin, Robertus A.M., primary, and Mansour, Marc R., primary

Published
2023
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17. Supplementary Figures and Legends from EZH2-Deficient T-cell Acute Lymphoblastic Leukemia Is Sensitized to CHK1 Inhibition through Enhanced Replication Stress

Author

León, Theresa E., primary, Rapoz-D'Silva, Tanya, primary, Bertoli, Cosetta, primary, Rahman, Sunniyat, primary, Magnussen, Michael, primary, Philip, Brian, primary, Farah, Nadine, primary, Richardson, Simon E., primary, Ahrabi, Sara, primary, Guerra-Assunção, José Afonso, primary, Gupta, Rajeev, primary, Nacheva, Elisabeth P., primary, Henderson, Stephen, primary, Herrero, Javier, primary, Linch, David C., primary, de Bruin, Robertus A.M., primary, and Mansour, Marc R., primary

Published
2023
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18. Genomic investigations of unexplained acute hepatitis in children

Author

Morfopoulou, Sofia; https://orcid.org/0000-0001-8181-4548, Buddle, Sarah; https://orcid.org/0000-0002-4738-9469, Montaguth, Oscar Enrique Torres, Atkinson, Laura, Guerra-Assunção, José Afonso; https://orcid.org/0000-0001-6593-403X, Marjaneh, Mahdi Moradi; https://orcid.org/0000-0002-9412-9029, Chiozzi, Riccardo Zenezini, Storey, Nathaniel; https://orcid.org/0000-0001-5942-4674, Campos, Luis; https://orcid.org/0000-0002-4317-0013, Hutchinson, J Ciaran, Counsell, John R; https://orcid.org/0000-0001-9208-101X, Pollara, Gabriele; https://orcid.org/0000-0001-5772-0322, Roy, Sunando, Venturini, Cristina, Antinao Diaz, Juan F, Siam, Ala'a, Tappouni, Luke J; https://orcid.org/0000-0003-2397-0512, Asgarian, Zeinab, Ng, Joanne, Hanlon, Killian S, Lennon, Alexander; https://orcid.org/0000-0002-3363-0637, McArdle, Andrew; https://orcid.org/0000-0001-7448-0869, Czap, Agata, Rosenheim, Joshua; https://orcid.org/0000-0003-0171-2053, Andrade, Catarina, Anderson, Glenn, Lee, Jack C D; https://orcid.org/0000-0002-9866-2808, Williams, Rachel, Williams, Charlotte A, Tutill, Helena; https://orcid.org/0000-0002-9977-9012, et al, Morfopoulou, Sofia; https://orcid.org/0000-0001-8181-4548, Buddle, Sarah; https://orcid.org/0000-0002-4738-9469, Montaguth, Oscar Enrique Torres, Atkinson, Laura, Guerra-Assunção, José Afonso; https://orcid.org/0000-0001-6593-403X, Marjaneh, Mahdi Moradi; https://orcid.org/0000-0002-9412-9029, Chiozzi, Riccardo Zenezini, Storey, Nathaniel; https://orcid.org/0000-0001-5942-4674, Campos, Luis; https://orcid.org/0000-0002-4317-0013, Hutchinson, J Ciaran, Counsell, John R; https://orcid.org/0000-0001-9208-101X, Pollara, Gabriele; https://orcid.org/0000-0001-5772-0322, Roy, Sunando, Venturini, Cristina, Antinao Diaz, Juan F, Siam, Ala'a, Tappouni, Luke J; https://orcid.org/0000-0003-2397-0512, Asgarian, Zeinab, Ng, Joanne, Hanlon, Killian S, Lennon, Alexander; https://orcid.org/0000-0002-3363-0637, McArdle, Andrew; https://orcid.org/0000-0001-7448-0869, Czap, Agata, Rosenheim, Joshua; https://orcid.org/0000-0003-0171-2053, Andrade, Catarina, Anderson, Glenn, Lee, Jack C D; https://orcid.org/0000-0002-9866-2808, Williams, Rachel, Williams, Charlotte A, Tutill, Helena; https://orcid.org/0000-0002-9977-9012, and et al

Abstract

Since its first identification in Scotland, over 1000 cases of unexplained pediatric hepatitis in children have been reported worldwide, including 278 cases in the UK. Here we report investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator subjects, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in liver, blood, plasma or stool from 27/28 cases. We found low levels of Adenovirus (HAdV) and Human Herpesvirus 6B (HHV-6B), in 23/31 and 16/23 respectively of the cases tested. In contrast, AAV2 was infrequently detected at low titre in blood or liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T-cells and B-lineage cells. Proteomic comparison of liver tissue from cases and healthy controls, identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and in severe cases HHV-6B, may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children.

Published
2023

21. Recurrence due to Relapse or Reinfection With Mycobacterium tuberculosis: A Whole-Genome Sequencing Approach in a Large, Population-Based Cohort With a High HIV Infection Prevalence and Active Follow-up

Author

Guerra-Assunção, José Afonso, Houben, Rein M. G. J., Crampin, Amelia C., Mzembe, Themba, Mallard, Kim, Coll, Francesc, Khan, Palwasha, Banda, Louis, Chiwaya, Arthur, Pereira, Rui P. A., McNerney, Ruth, Harris, David, Parkhill, Julian, Clark, Taane G., and Glynn, Judith R.

Published
2015

24. Genomic Investigations of Acute Hepatitis of Unknown Aetiology in Children

Author

Breuer, Judith, primary, Morfopoulou, Sofia, additional, Buddle, Sarah, additional, Montaguth, Oscar Torres, additional, Atkinson, Laura, additional, Guerra-Assunção, José Afonso, additional, Storey, Nathaniel, additional, Roy, Sunando, additional, Lennon, Alexander, additional, Lee, Jack, additional, Williams, Rachel, additional, Williams, Charlotte, additional, Tutill, Helena, additional, Bayzid, Nadua, additional, Bernal, Luz Marina Martin, additional, Moore, Catherine, additional, Templeton, Kate, additional, Holden, Matthew, additional, Shah, Priyen, additional, Cooray, Samantha, additional, Voice, Marie, additional, Steele, Michael, additional, Fink, Colin, additional, Whittaker, Thomas, additional, Santilli, Giorgia, additional, Gissen, Paul, additional, Brown, Rachel, additional, Kaufer, Benedikt, additional, Reich, Jana, additional, Andreani, Julien, additional, Simmonds, Peter, additional, Alrabiah, Dimah, additional, Hereza, Sergi Castellano, additional, Andrade, Catarina, additional, Anderson, Glenn, additional, Kelgeri, Chayarani, additional, Waddington, Simon, additional, Diaz, Juan Antinao, additional, Hatcher, James, additional, De, Surjo, additional, Chiozzi, Riccardo, additional, Thalassinos, Konstantinos, additional, Jacques, Thomas, additional, Hoschler, Katja, additional, Talts, Tiina, additional, Celma, Cristina, additional, Gonzalez, Suam, additional, Gallagher, Eileen, additional, Simmons, Ruth, additional, Watson, Conall, additional, Mandal, Sema, additional, Zambon, Maria, additional, Chand, Meera, additional, Campos, Luis, additional, Martin, Joanne, additional, Thomson, Emma, additional, Ushiro-Lumb, Ines, additional, Levin, Michael, additional, Brown, Julianne, additional, and Breuer, Judith, additional

Published
2022
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25. HIV-1 Vpr drives a tissue residency-like phenotype during selective infection of resting memory T cells

Author

Reuschl, Ann-Kathrin, primary, Mesner, Dejan, additional, Shivkumar, Maitreyi, additional, Whelan, Matthew V.X., additional, Pallett, Laura J., additional, Guerra-Assunção, José Afonso, additional, Madansein, Rajhmun, additional, Dullabh, Kaylesh J., additional, Sigal, Alex, additional, Thornhill, John P., additional, Herrera, Carolina, additional, Fidler, Sarah, additional, Noursadeghi, Mahdad, additional, Maini, Mala K., additional, and Jolly, Clare, additional

Published
2022
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26. The Alpha variant was not associated with excess nosocomial SARS-CoV-2 infection in a multi-centre UK hospital study

Author

Boshier, Florencia A.T., Venturini, Cristina, Stirrup, Oliver, Guerra-Assunção, José Afonso, Alcolea-Medina, Adela, Becket, Angela H., Byott, Matthew, Charalampous, Themoula, Filipe, Ana da Silva, Frampton, Dan, Glaysher, Sharon, Khan, Tabassum, Kulasegara-Shylini, Raghavendran, Kele, Beatrix, Monahan, Irene M., Mollett, Guy, Parker, Matthew, Pelosi, Emanuela, Randell, Paul, Roy, Sunando, Taylor, Joshua F., Weller, Sophie J., Wilson-Davies, Eleri, Wade, Phillip, Williams, Rachel, Copas, Andrew J., Cutino-Moguel, Teresa, Freemantle, Nick, Hayward, Andrew C., Holmes, Alison, Hughes, Joseph, Mahungu, Tabitha W., Nebbia, Gaia, Nastouli, Eleni, Partridge, David G., Pope, Cassie F., Price, James R., Robson, Samuel C., Saeed, Kordo, Shin, Gee Yen, de Silva, Thushan I., Snell, Luke B., Thomson, Emma C., Witney, Adam A., Breuer, Judith, COG-UK HOCI Variant Substudy consortium, The COVID-19 Genomics UK (COG-UK) consortium, Bashton, Matthew, Nelson, Andrew, McCann, Clare, Smith, Darren, and Young, Greg

Subjects
Microbiology (medical), medicine.medical_specialty, lineage B.1.1.7, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), B100, Alpha (ethology), variants of concern, Logistic regression, Article, Internal medicine, Epidemiology, medicine, Humans, transmissibility, Infection control, nosocomial outbreaks, Cross Infection, Nosocomial outbreak, SARS-CoV-2, business.industry, Transmission (medicine), COVID-19, Outbreak, C500, C700, Hospitals, United Kingdom, Infectious Diseases, Alpha variant, business
Abstract

Objectives : Recently emerging SARS-CoV-2 variants have been associated with an increased rate of transmission within the community. We sought to determine whether this also resulted in increased transmission within hospitals. Methods : We collected viral sequences and epidemiological data of patients with community and healthcare associated SARS-CoV-2 infections, sampled from 16th November 2020 to 10th January 2021, from nine hospitals participating in the COG-UK HOCI study. Outbreaks were identified using ward information, lineage and pairwise genetic differences between viral sequences. Results : Mixed effects logistic regression analysis of 4184 sequences showed healthcare-acquired infections were no more likely to be identified as the Alpha variant than community acquired infections. Nosocomial outbreaks were investigated based on overlapping ward stay and SARS-CoV-2 genome sequence similarity. There was no significant difference in the number of patients involved in outbreaks caused by the Alpha variant compared to outbreaks caused by other lineages. Conclusions : We find no evidence to support it causing more nosocomial transmission than previous lineages. This suggests that the stringent infection prevention measures already in place in UK hospitals contained the spread of the Alpha variant as effectively as other less transmissible lineages, providing reassurance of their efficacy against emerging variants of concern. 40 word summary: This UK multicentre study found no evidence to support the Alpha variant as having caused more nosocomial transmission that previous SARS-CoV-2 variants. This provides some reassurance that currently implemented IPC measures may be as effective against more transmissible variants.

Published
2021

27. The Alpha variant was not associated with excess nosocomial SARS-CoV-2 infection in a multi-centre UK hospital study

Author

Boshier, Florencia AT, Venturini, Cristina, Stirrup, Oliver, Guerra-Assunção, José Afonso, Alcolea-Medina, Adela, Becket, Angela H, Byott, Matthew, Charalampous, Themoula, Filipe, Ana Da Silva, Frampton, Dan, Glaysher, Sharon, Khan, Tabassum, Kulasegara-Shylini, Raghavendran, Kele, Beatrix, Monahan, Irene M, Mollett, Guy, Parker, Matthew, Pelosi, Emanuela, Randell, Paul, Roy, Sunando, Taylor, Joshua F, Weller, Sophie J, Wilson-Davies, Eleri, Wade, Phillip, Williams, Rachel, Copas, Andrew J, Cutino-Moguel, Teresa, Freemantle, Nick, Hayward, Andrew C, Holmes, Alison, Hughes, Joseph, Mahungu, Tabitha W, Nebbia, Gaia, Nastouli, Eleni, Partridge, David G, Pope, Cassie F, Price, James R, Robson, Samuel C, Saeed, Kordo, Shin, Gee Yen, De Silva, Thushan I, Snell, Luke B, Thomson, Emma C, Witney, Adam A, Breuer, Judith, COG-UK HOCI Variant Substudy Consortium*, The COVID-19 Genomics UK (COG-UK) Consortium, Venturini, Cristina [0000-0002-4769-7912], Copas, Andrew J [0000-0001-8968-5963], Robson, Samuel C [0000-0001-5702-9160], Breuer, Judith [0000-0001-8246-0534], and Apollo - University of Cambridge Repository

Subjects
Variants of concern, Cross Infection, Alpha variant, SARS-CoV-2, Transmissibility, COVID-19, Humans, Lineage B.1.1.7, Nosocomial outbreaks, Hospitals, United Kingdom
Abstract

OBJECTIVES: Recently emerging SARS-CoV-2 variants have been associated with an increased rate of transmission within the community. We sought to determine whether this also resulted in increased transmission within hospitals. METHODS: We collected viral sequences and epidemiological data of patients with community and healthcare associated SARS-CoV-2 infections, sampled from 16th November 2020 to 10th January 2021, from nine hospitals participating in the COG-UK HOCI study. Outbreaks were identified using ward information, lineage and pairwise genetic differences between viral sequences. RESULTS: Mixed effects logistic regression analysis of 4184 sequences showed healthcare-acquired infections were no more likely to be identified as the Alpha variant than community acquired infections. Nosocomial outbreaks were investigated based on overlapping ward stay and SARS-CoV-2 genome sequence similarity. There was no significant difference in the number of patients involved in outbreaks caused by the Alpha variant compared to outbreaks caused by other lineages. CONCLUSIONS: We find no evidence to support it causing more nosocomial transmission than previous lineages. This suggests that the stringent infection prevention measures already in place in UK hospitals contained the spread of the Alpha variant as effectively as other less transmissible lineages, providing reassurance of their efficacy against emerging variants of concern.

Published
2021

28. SARS-CoV-2 lineage B.1.1.7 is associated with greater disease severity among hospitalised women but not men: multicentre cohort study

Author

Stirrup, Oliver, Boshier, Florencia, Venturini, Cristina, Guerra-Assunção, José Afonso, Alcolea-Medina, Adela, Beckett, Angela, Charalampous, Themoula, Da Silva Filipe, Ana, Glaysher, Sharon, Khan, Tabassum, Kulasegaran Shylini, Raghavendran, Kele, Beatrix, Monahan, Irene, Mollett, Guy, Parker, Matthew, Pelosi, Emanuela, Randell, Paul, Roy, Sunando, Taylor, Joshua, Weller, Sophie, Wilson-Davies, Eleri, Wade, Phillip, Williams, Rachel, COG-UK-HOCI Variant Substudy Consortium, COVID-19 Genomics UK (COG-UK) Consortium, Copas, Andrew, Cutino-Moguel, Maria-Teresa, Freemantle, Nick, Hayward, Andrew C, Holmes, Alison, Hughes, Joseph, Mahungu, Tabitha, Nebbia, Gaia, Partridge, David, Pope, Cassie, Price, James, Robson, Samuel, Saeed, Kordo, De Silva, Thushan, Snell, Luke, Thomson, Emma, Witney, Adam A, Breuer, Judith, Stirrup, Oliver [0000-0002-8705-3281], Kulasegaran Shylini, Raghavendran [0000-0003-4303-5716], Price, James [0000-0003-2541-8545], and Apollo - University of Cambridge Repository

Subjects
Adult, Aged, 80 and over, Male, Adolescent, SARS-CoV-2, Infant, Newborn, COVID-19, Infant, Middle Aged, Severity of Illness Index, United Kingdom, Cohort Studies, Young Adult, COVID-19 Testing, Child, Preschool, Humans, Female, viral infection, Child, Aged
Abstract

BACKGROUND: SARS-CoV-2 lineage B.1.1.7 has been associated with an increased rate of transmission and disease severity among subjects testing positive in the community. Its impact on hospitalised patients is less well documented. METHODS: We collected viral sequences and clinical data of patients admitted with SARS-CoV-2 and hospital-onset COVID-19 infections (HOCIs), sampled 16 November 2020 to 10 January 2021, from eight hospitals participating in the COG-UK-HOCI study. Associations between the variant and the outcomes of all-cause mortality and intensive therapy unit (ITU) admission were evaluated using mixed effects Cox models adjusted by age, sex, comorbidities, care home residence, pregnancy and ethnicity. FINDINGS: Sequences were obtained from 2341 inpatients (HOCI cases=786) and analysis of clinical outcomes was carried out in 2147 inpatients with all data available. The HR for mortality of B.1.1.7 compared with other lineages was 1.01 (95% CI 0.79 to 1.28, p=0.94) and for ITU admission was 1.01 (95% CI 0.75 to 1.37, p=0.96). Analysis of sex-specific effects of B.1.1.7 identified increased risk of mortality (HR 1.30, 95% CI 0.95 to 1.78, p=0.096) and ITU admission (HR 1.82, 95% CI 1.15 to 2.90, p=0.011) in females infected with the variant but not males (mortality HR 0.82, 95% CI 0.61 to 1.10, p=0.177; ITU HR 0.74, 95% CI 0.52 to 1.04, p=0.086). INTERPRETATION: In common with smaller studies of patients hospitalised with SARS-CoV-2, we did not find an overall increase in mortality or ITU admission associated with B.1.1.7 compared with other lineages. However, women with B.1.1.7 may be at an increased risk of admission to intensive care and at modestly increased risk of mortality.

Published
2021
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29. Post-vaccination COVID-19: A case-control study and genomic analysis of 119 breakthrough infections in partially vaccinated individuals

Author

Baltas, Ioannis, Boshier, Florencia A T, Williams, Charlotte A, Bayzid, Nadua, Cotic, Marius, Guerra-Assunção, José Afonso, Irish-Tavares, Dianne, Haque, Tanzina, Hart, Jennifer, Roy, Sunando, Williams, Rachel, Breuer, Judith, and Mahungu, Tabitha W

Subjects
AcademicSubjects/MED00290, SARS-CoV-2, Case-Control Studies, ChAdOx1 nCoV-19, Mutation, Vaccination, Major Article, Humans, COVID-19, Genomics, Mortality, BNT162 Vaccine, Phylogeny
Abstract

Background Post-vaccination infections challenge the control of the COVID-19 pandemic. Methods We matched 119 cases of post-vaccination SARS-CoV-2 infection with BNT162b2 mRNA, or ChAdOx1 nCOV-19, to 476 unvaccinated patients with COVID-19 (Sept 2020-March 2021), according to age and sex. Differences in 60-day all-cause mortality, hospital admission, and hospital length of stay were evaluated. Phylogenetic, single nucleotide polymorphism (SNP) and minority variant allele (MVA) full genome sequencing analysis was performed. Results 116/119 cases developed COVID-19 post first vaccination dose (median 14 days, IQR 9 – 24 days). Overall, 13/119 (10∙9%) cases and 158/476 (33∙2%) controls died (p

Published
2021

31. Protective Effect of Nasal Colonisation with ∆cps/piaA and ∆cps/proABCStreptococcus pneumoniae Strains against Recolonisation and Invasive Infection.

Author

Ramos-Sevillano, Elisa, Ramos-Sevillano, Elisa, Ercoli, Giuseppe, Guerra-Assunção, José Afonso, Felgner, Philip, Ramiro de Assis, Rafael, Nakajima, Rie, Goldblatt, David, Tetteh, Kevin Kweku Adjei, Heyderman, Robert Simon, Gordon, Stephen Brian, Ferreria, Daniela Mulari, Brown, Jeremy Stuart, Ramos-Sevillano, Elisa, Ramos-Sevillano, Elisa, Ercoli, Giuseppe, Guerra-Assunção, José Afonso, Felgner, Philip, Ramiro de Assis, Rafael, Nakajima, Rie, Goldblatt, David, Tetteh, Kevin Kweku Adjei, Heyderman, Robert Simon, Gordon, Stephen Brian, Ferreria, Daniela Mulari, and Brown, Jeremy Stuart

Abstract

RationaleNasopharyngeal administration of live virulence-attenuated Streptococcus pneumoniae strains is a potential novel preventative strategy. One target for creating reduced virulence S. pneumoniae strains is the capsule, but loss of the capsule reduces the duration of S. pneumoniae colonisation in mice which could impair protective efficacy against subsequent infection.ObjectivesTo assess protective efficacy of nasopharyngeal administration of unencapsulated S. pneumoniae strains in murine infection models.MethodsStrains containing cps locus deletions combined with the S. pneumoniae virulence factors psaA (reduces colonisation) or proABC (no effect on colonisation) were constructed and their virulence phenotypes and ability to prevent recolonisation or invasive infection assessed using mouse infection models. Serological responses to colonisation were compared between strains using ELISAs, immunoblots and 254 S. pneumoniae protein antigen array.Measurements and main resultsThe ∆cps/piaA and ∆cps/proABC strains were strongly attenuated in virulence in both invasive infection models and had a reduced ability to colonise the nasopharynx. ELISAs, immunoblots and protein arrays showed colonisation with either strain stimulated weaker serological responses than the wild type strain. Mice previously colonised with these strains were protected against septicaemic pneumonia but, unlike mice colonised with the wild type strain, not against S. pneumoniae recolonisation.ConclusionsColonisation with the ∆cps/piaA and ∆cps/proABC strains prevented subsequent septicaemia, but in contrast, to published data for encapsulated double mutant strains they did not prevent recolonisation with S. pneumoniae. These data suggest targeting the cps locus is a less effective option for creating live attenuated strains that prevent S. pneumoniae infections.

Published
2021

32. Meta-analysis of tumor- and T cell-intrinsic mechanisms of sensitization to checkpoint inhibition

Author

Litchfield, Kevin, Reading, James L., Puttick, Clare, Thakkar, Krupa, Abbosh, Chris, Bentham, Robert, Watkins, Thomas B.K., Rosenthal, Rachel, Biswas, Dhruva, Rowan, Andrew, Lim, Emilia, Al Bakir, Maise, Turati, Virginia, Guerra-Assunção, José Afonso, Conde, Lucia, Furness, Andrew J.S., Saini, Sunil Kumar, Hadrup, Sine R., Herrero, Javier, Lee, Se Hoon, Van Loo, Peter, Enver, Tariq, Larkin, James, Hellmann, Matthew D., Turajlic, Samra, Quezada, Sergio A., McGranahan, Nicholas, Swanton, Charles, Litchfield, Kevin, Reading, James L., Puttick, Clare, Thakkar, Krupa, Abbosh, Chris, Bentham, Robert, Watkins, Thomas B.K., Rosenthal, Rachel, Biswas, Dhruva, Rowan, Andrew, Lim, Emilia, Al Bakir, Maise, Turati, Virginia, Guerra-Assunção, José Afonso, Conde, Lucia, Furness, Andrew J.S., Saini, Sunil Kumar, Hadrup, Sine R., Herrero, Javier, Lee, Se Hoon, Van Loo, Peter, Enver, Tariq, Larkin, James, Hellmann, Matthew D., Turajlic, Samra, Quezada, Sergio A., McGranahan, Nicholas, and Swanton, Charles

Abstract

Checkpoint inhibitors (CPIs) augment adaptive immunity. Systematic pan-tumor analyses may reveal the relative importance of tumor-cell-intrinsic and microenvironmental features underpinning CPI sensitization. Here, we collated whole-exome and transcriptomic data for >1,000 CPI-treated patients across seven tumor types, utilizing standardized bioinformatics workflows and clinical outcome criteria to validate multivariable predictors of CPI sensitization. Clonal tumor mutation burden (TMB) was the strongest predictor of CPI response, followed by total TMB and CXCL9 expression. Subclonal TMB, somatic copy alteration burden, and histocompatibility leukocyte antigen (HLA) evolutionary divergence failed to attain pan-cancer significance. Dinucleotide variants were identified as a source of immunogenic epitopes associated with radical amino acid substitutions and enhanced peptide hydrophobicity/immunogenicity. Copy-number analysis revealed two additional determinants of CPI outcome supported by prior functional evidence: 9q34 (TRAF2) loss associated with response and CCND1 amplification associated with resistance. Finally, single-cell RNA sequencing (RNA-seq) of clonal neoantigen-reactive CD8 tumor-infiltrating lymphocytes (TILs), combined with bulk RNA-seq analysis of CPI-responding tumors, identified CCR5 and CXCL13 as T-cell-intrinsic markers of CPI sensitivity.

Published
2021

34. Post-Vaccination Coronavirus Disease 2019: A Case-Control Study and Genomic Analysis of 119 Breakthrough Infections in Partially Vaccinated Individuals.

Author

Baltas, Ioannis, Boshier, Florencia A T, Williams, Charlotte A, Bayzid, Nadua, Cotic, Marius, Guerra-Assunção, José Afonso, Irish-Tavares, Dianne, Haque, Tanzina, Hart, Jennifer, Roy, Sunando, Williams, Rachel, Breuer, Judith, and Mahungu, Tabitha W

Subjects
BREAKTHROUGH infections, RELATIVE medical risk, LENGTH of stay in hospitals, IMMUNIZATION, COVID-19, CONFIDENCE intervals, COVID-19 vaccines, CASE-control method, GENOMICS, DESCRIPTIVE statistics, ODDS ratio
Abstract

Background Post-vaccination infections challenge the control of the coronavirus disease 2019 (COVID-19) pandemic. Methods We matched 119 cases of post-vaccination severe acute respiratory syndrome coronavirus 2 infection with BNT162b2 mRNA or ChAdOx1 nCOV-19 to 476 unvaccinated patients with COVID-19 (September 2020–March 2021) according to age and sex. Differences in 60-day all-cause mortality, hospital admission, and hospital length of stay were evaluated. Phylogenetic, single-nucleotide polymorphism (SNP), and minority variant allele (MVA) full-genome sequencing analysis was performed. Results Overall, 116 of 119 cases developed COVID-19 post–first vaccination dose (median, 14 days). Thirteen of 119 (10.9%) cases and 158 of 476 (33.2%) controls died (P  < .001), corresponding to the 4.5 number needed to treat (NNT). Multivariably, vaccination was associated with a 69.3% (95% confidence interval [CI]: 45.8 to 82.6) relative risk (RR) reduction in mortality. Similar results were seen in subgroup analysis for patients with infection onset ≥14 days after first vaccination and across vaccine subgroups. Hospital admissions (odds ratio, 0.80; 95% CI:.51 to 1.28) and length of stay (–1.89 days; 95% CI: –4.57 to 0.78) were lower for cases, while cycle threshold values were higher (30.8 vs 28.8, P  = .053). B.1.1.7 was the predominant lineage in cases (100 of 108, 92.6%) and controls (341 of 446, 76.5%). Genomic analysis identified 1 post-vaccination case that harbored the E484K vaccine-escape mutation (B.1.525 lineage). Conclusions Previous vaccination reduces mortality when B.1.1.7 is the predominant lineage. No significant lineage-specific genomic changes during phylogenetic, SNP, and MVA analysis were detected. [ABSTRACT FROM AUTHOR]

Published
2022
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36. Protective Effect of Nasal Colonisation with ∆cps/piaA and ∆cps/proABCStreptococcus pneumoniae Strains against Recolonisation and Invasive Infection

Author

Ramos-Sevillano, Elisa, primary, Ercoli, Giuseppe, additional, Guerra-Assunção, José Afonso, additional, Felgner, Philip, additional, Ramiro de Assis, Rafael, additional, Nakajima, Rie, additional, Goldblatt, David, additional, Tetteh, Kevin Kweku Adjei, additional, Heyderman, Robert Simon, additional, Gordon, Stephen Brian, additional, Ferreria, Daniela Mulari, additional, and Brown, Jeremy Stuart, additional

Published
2021
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37. Meta-analysis of tumor- and T cell-intrinsic mechanisms of sensitization to checkpoint inhibition

Author

Litchfield, Kevin, primary, Reading, James L., additional, Puttick, Clare, additional, Thakkar, Krupa, additional, Abbosh, Chris, additional, Bentham, Robert, additional, Watkins, Thomas B.K., additional, Rosenthal, Rachel, additional, Biswas, Dhruva, additional, Rowan, Andrew, additional, Lim, Emilia, additional, Al Bakir, Maise, additional, Turati, Virginia, additional, Guerra-Assunção, José Afonso, additional, Conde, Lucia, additional, Furness, Andrew J.S., additional, Saini, Sunil Kumar, additional, Hadrup, Sine R., additional, Herrero, Javier, additional, Lee, Se-Hoon, additional, Van Loo, Peter, additional, Enver, Tariq, additional, Larkin, James, additional, Hellmann, Matthew D., additional, Turajlic, Samra, additional, Quezada, Sergio A., additional, McGranahan, Nicholas, additional, and Swanton, Charles, additional

Published
2021
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38. HIV-1 Vpr drives a tissue residency-like phenotype during selective infection of resting memory T cells

Author

Reuschl, Ann-Kathrin, primary, Shivkumar, Maitreyi, additional, Mesner, Dejan, additional, Pallett, Laura J., additional, Guerra-Assunção, José Afonso, additional, Madansein, Rajhmun, additional, Dullabh, Kaylesh J, additional, Sigal, Alex, additional, Thornhill, John P., additional, Herrera, Carolina, additional, Fidler, Sarah, additional, Noursadeghi, Mahdad, additional, Maini, Mala K., additional, and Jolly, Clare, additional

Published
2021
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39. Identification of Recurrent Mutations in the microRNA-Binding Sites of B-Cell Lymphoma-Associated Genes in Follicular Lymphoma

Author

Larrea, Erika, primary, Fernandez-Mercado, Marta, additional, Guerra-Assunção, José Afonso, additional, Wang, Jun, additional, Goicoechea, Ibai, additional, Gaafar, Ayman, additional, Ceberio, Izaskun, additional, Lobo, Carmen, additional, Okosun, Jessica, additional, Enright, Anton J., additional, Fitzgibbon, Jude, additional, and Lawrie, Charles H., additional

Published
2020
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40. Mouse genomic variation and its effect on phenotypes and gene regulation

Author

Keane, Thomas M., Goodstadt, Leo, Danecek, Petr, White, Michael A., Wong, Kim, Yalcin, Binnaz, Heger, Andreas, Agam, Avigail, Slater, Guy, Goodson, Martin, Furlotte, Nicholas A., Eskin, Eleazar, Nellåker, Christoffer, Whitley, Helen, Cleak, James, Janowitz, Deborah, Hernandez-Pliego, Polinka, Edwards, Andrew, Belgard, Grant T., Oliver, Peter L., McIntyre, Rebecca E., Bhomra, Amarjit, Nicod, Jérôme, Gan, Xiangchao, Yuan, Wei, van der Weyden, Louise, Steward, Charles A., Bala, Sendu, Stalker, Jim, Mott, Richard, Durbin, Richard, Jackson, Ian J., Czechanski, Anne, Guerra-Assunção, José Afonso, Donahue, Leah Rae, Reinholdt, Laura G., Payseur, Bret A., Ponting, Chris P., Birney, Ewan, Flint, Jonathan, and Adams, David J.

Published
2011
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42. Meta-analysis of tumor and T cell intrinsic mechanisms of sensitization to checkpoint inhibition

Author

Litchfield, Kevin, primary, Reading, James L., additional, Puttick, Clare, additional, Abbosh, Chris, additional, Bentham, Robert, additional, Watkins, Thomas B. K., additional, Rosenthal, Rachel, additional, Biswas, Dhruva, additional, Lim, Emilia, additional, AL-Bakir, Maise, additional, Turati, Virginia, additional, Guerra-Assunção, José Afonso, additional, Conde, Lucia, additional, Furness, Andrew J.S., additional, Saini, Sunil Kumar, additional, Hadrup, Sine R, additional, Herrero, Javier, additional, Rowan, Andrew, additional, Enver, Tariq, additional, Hellmann, Matthew D., additional, Larkin, James, additional, Turajlic, Samra, additional, Quezada, Sergio, additional, McGranahan, Nicholas, additional, and Swanton, Charles, additional

Published
2020
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43. EZH2-Deficient T-cell Acute Lymphoblastic Leukemia Is Sensitized to CHK1 Inhibition through Enhanced Replication Stress

Author

León, Theresa E., primary, Rapoz-D'Silva, Tanya, additional, Bertoli, Cosetta, additional, Rahman, Sunniyat, additional, Magnussen, Michael, additional, Philip, Brian, additional, Farah, Nadine, additional, Richardson, Simon E., additional, Ahrabi, Sara, additional, Guerra-Assunção, José Afonso, additional, Gupta, Rajeev, additional, Nacheva, Elisabeth P., additional, Henderson, Stephen, additional, Herrero, Javier, additional, Linch, David C., additional, de Bruin, Robertus A.M., additional, and Mansour, Marc R., additional

Published
2020
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44. Spatial heterogeneity of the T cell receptor repertoire reflects the mutational landscape in lung cancer

Author

Joshi, Kroopa, Robert de Massy, Marc, Ismail, Mazlina, Reading, James L., Uddin, Imran, Woolston, Annemarie, Hatipoglu, Emine, Oakes, Theres, Rosenthal, Rachel, Peacock, Thomas, Ronel, Tahel, Noursadeghi, Mahdad, Turati, Virginia, Georgiou, Andrew, Furness, Andrew J. S., Wong, Yien Ning Sophia, Ben Aissa, Assma, Werner Sunderland, Mariana, Jamal-Hanjani, Mariam, Veeriah, Selvaraju, Birkbak, Nicolai Juul, Wilson, Gareth A., Hiley, Crispin T, Ghorani, Ehsan, Guerra-Assunção, José Afonso, Herrero, Javier, Enver, Tariq, Hadrup, Sine R., Hackshaw, Allan, Peggs, Karl S, McGranahan, Nicholas, Swanton, Charles, Quezada, Sergio A., Chain, Benny, Joshi, Kroopa, Robert de Massy, Marc, Ismail, Mazlina, Reading, James L., Uddin, Imran, Woolston, Annemarie, Hatipoglu, Emine, Oakes, Theres, Rosenthal, Rachel, Peacock, Thomas, Ronel, Tahel, Noursadeghi, Mahdad, Turati, Virginia, Georgiou, Andrew, Furness, Andrew J. S., Wong, Yien Ning Sophia, Ben Aissa, Assma, Werner Sunderland, Mariana, Jamal-Hanjani, Mariam, Veeriah, Selvaraju, Birkbak, Nicolai Juul, Wilson, Gareth A., Hiley, Crispin T, Ghorani, Ehsan, Guerra-Assunção, José Afonso, Herrero, Javier, Enver, Tariq, Hadrup, Sine R., Hackshaw, Allan, Peggs, Karl S, McGranahan, Nicholas, Swanton, Charles, Quezada, Sergio A., and Chain, Benny

Abstract

Somatic mutations together with immunoediting drive extensive heterogeneity within non-small-cell lung cancer (NSCLC). Herein we examine heterogeneity of the T cell antigen receptor (TCR) repertoire. The number of TCR sequences selectively expanded in tumors varies within and between tumors and correlates with the number of nonsynonymous mutations. Expanded TCRs can be subdivided into TCRs found in all tumor regions (ubiquitous) and those present in a subset of regions (regional). The number of ubiquitous and regional TCRs correlates with the number of ubiquitous and regional nonsynonymous mutations, respectively. Expanded TCRs form part of clusters of TCRs of similar sequence, suggestive of a spatially constrained antigen-driven process. CD8+ tumor-infiltrating lymphocytes harboring ubiquitous TCRs display a dysfunctional tissue-resident phenotype. Ubiquitous TCRs are preferentially detected in the blood at the time of tumor resection as compared to routine follow-up. These findings highlight a noninvasive method to identify and track relevant tumor-reactive TCRs for use in adoptive T cell immunotherapy.

Published
2019

45. Three‐Dimensional Model of Human Nicotinamide Nucleotide Transhydrogenase (NNT) and Sequence‐Structure Analysis of its Disease‐Causing Variations

Author

Metherell, Louise A, Guerra‐Assunção, José Afonso, Sternberg, Michael J, and David, Alessia

Subjects
Models, Molecular, Binding Sites, Mitochondrial Diseases, Protein Conformation, familial glucocorticoid deficiency, NAD, NADP Transhydrogenase, AB-Specific, NNT, Mitochondrial Proteins, mitochondrial disease, Protein Domains, health services administration, Mutation, Humans, Genetic Predisposition to Disease, Amino Acid Sequence, variations, protein structure, Research Articles, Research Article, Protein Binding
Abstract

Defective mitochondrial proteins are emerging as major contributors to human disease. Nicotinamide nucleotide transhydrogenase (NNT), a widely expressed mitochondrial protein, has a crucial role in the defence against oxidative stress. NNT variations have recently been reported in patients with familial glucocorticoid deficiency (FGD) and in patients with heart failure. Moreover, knockout animal models suggest that NNT has a major role in diabetes mellitus and obesity. In this study, we used experimental structures of bacterial transhydrogenases to generate a structural model of human NNT (H‐NNT). Structure‐based analysis allowed the identification of H‐NNT residues forming the NAD binding site, the proton canal and the large interaction site on the H‐NNT dimer. In addition, we were able to identify key motifs that allow conformational changes adopted by domain III in relation to its functional status, such as the flexible linker between domains II and III and the salt bridge formed by H‐NNT Arg882 and Asp830. Moreover, integration of sequence and structure data allowed us to study the structural and functional effect of deleterious amino acid substitutions causing FGD and left ventricular non‐compaction cardiomyopathy. In conclusion, interpretation of the function–structure relationship of H‐NNT contributes to our understanding of mitochondrial disorders.

Published
2016

46. The Personal Genome Project-UK: an open access resource of human multi-omics data

Author

Chervova, Olga, primary, Conde, Lucia, additional, Guerra-Assunção, José Afonso, additional, Moghul, Ismail, additional, Webster, Amy P., additional, Berner, Alison, additional, Cadieux, Elizabeth Larose, additional, Tian, Yuan, additional, Voloshin, Vitaly, additional, Hamoudi, Rifat, additional, Herrero, Javier, additional, and Beck, Stephan, additional

Published
2019
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47. Both the inflammatory response and clinical outcome differ markedly between adults with pneumococcal and meningococcal meningitis in a high HIV-1 prevalent setting in sub-Saharan Africa

Author

Wall, Emma C, primary, Guerra-Assunção, José Afonso, additional, Denis, Brigitte, additional, Scarborough, Matthew, additional, Ajdukiewicz, Katherine, additional, Cartwright, Katharine, additional, Mukaka, Mavuto, additional, Mlozowa, Veronica S, additional, Venturini, Cristina, additional, Allain, Theresa J, additional, Lalloo, David G, additional, Brown, Jeremy S, additional, Gordon, Stephen B, additional, and Heyderman, Robert S, additional

Published
2019
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48. Cerebrospinal fluid transcriptional analyses reveals upregulation of IL-17, Type 1 interferon transcriptional pathways and neutrophil persistence genes associated with increased mortality from pneumococcal meningitis in adults

Author

Wall, Emma C, primary, Guerra-Assunção, José Afonso, additional, Pollara, Gabriele, additional, Venturini, Cristina, additional, Mlozowa, Veronica S, additional, Allain, Theresa J, additional, Lalloo, David G, additional, Noursadeghi, Mahdad, additional, Brown, Jeremy S, additional, and Heyderman, Robert S, additional

Published
2018
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49. Cerebrospinal Fluid Transcriptional Analyses Reveals Upregulation of IL-17, Type 1 Interferon Transcriptional Pathways and Neutrophil Persistence Genes Associated with Increased Mortality from Pneumococcal Meningitis in Adults

Author

Wall, Emma, primary, Guerra-Assunção, José Afonso, additional, Pollara, Gabriele, additional, Venturini, Cristina, additional, Mlozowa, Veronica S., additional, Allain, Theresa J., additional, Lalloo, David G., additional, Noursadeghi, Mahdad, additional, Brown, Jeremy S., additional, and Heyderman, Robert S., additional

Published
2018
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50. Single-Cell Analysis of Clonal Dynamics in Childhood ALL Reveals a Key Role for Transcriptional Intratumor Heterogeneity in Driving Resistance to Chemotherapy

Author

Turati, Virginia A, primary, Guerra-Assunção, José Afonso, additional, Ambrose, John C, additional, Brown, John, additional, Hubank, Mike, additional, Hobbs, Alex, additional, Lynch, Mark, additional, Gaal, Bernadett, additional, Inglott, Sarah, additional, Conde, Lucia, additional, Richardson, Simon, additional, Herrero, Javier, additional, Jacobsen, Sten Eirik, additional, and Enver, Tariq, additional

Published
2016
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