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30 results on '"Thomas, Huw B."'

1. Combining a prioritization strategy and functional studies nominates 5’UTR variants underlying inherited retinal disease

Author

Dueñas Rey, Alfredo, del Pozo Valero, Marta, Bouckaert, Manon, Wood, Katherine A, Van den Broeck, Filip, Daich Varela, Malena, Thomas, Huw B, Van Heetvelde, Mattias, De Bruyne, Marieke, Van de Sompele, Stijn, Bauwens, Miriam, Lenaerts, Hanne, Mahieu, Quinten, Josifova, Dragana, Rivolta, Carlo, O’Keefe, Raymond T, Ellingford, Jamie, Webster, Andrew R, Arno, Gavin, Ayuso, Carmen, De Zaeytijd, Julie, Leroy, Bart P, De Baere, Elfride, and Coppieters, Frauke

Published
2024
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2. Novel homozygous variants in PRORP expand the genotypic spectrum of combined oxidative phosphorylation deficiency 54

Author

Smith, Thomas B., Rea, Alessandro, Thomas, Huw B., Thompson, Kyle, Oláhová, Monika, Maroofian, Reza, Zamani, Mina, He, Langping, Sadeghian, Saeid, Galehdari, Hamid, Lotan, Nava Shaul, Gilboa, Tal, Herman, Kristin C., McCorvie, Thomas J., Yue, Wyatt W., Houlden, Henry, Taylor, Robert W., Newman, William G., and O’Keefe, Raymond T.

Published
2023
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4. Uncovering genetic mechanisms of hypertension through multi-omic analysis of the kidney

Author

Eales, James M., Jiang, Xiao, Xu, Xiaoguang, Saluja, Sushant, Akbarov, Artur, Cano-Gamez, Eddie, McNulty, Michelle T., Finan, Christopher, Guo, Hui, Wystrychowski, Wojciech, Szulinska, Monika, Thomas, Huw B., Pramanik, Sanjeev, Chopade, Sandesh, Prestes, Priscilla R., Wise, Ingrid, Evangelou, Evangelos, Salehi, Mahan, Shakanti, Yusif, Ekholm, Mikael, Denniff, Matthew, Nazgiewicz, Alicja, Eichinger, Felix, Godfrey, Bradley, Antczak, Andrzej, Glyda, Maciej, Król, Robert, Eyre, Stephen, Brown, Jason, Berzuini, Carlo, Bowes, John, Caulfield, Mark, Zukowska-Szczechowska, Ewa, Zywiec, Joanna, Bogdanski, Pawel, Kretzler, Matthias, Woolf, Adrian S., Talavera, David, Keavney, Bernard, Maffia, Pasquale, Guzik, Tomasz J., O’Keefe, Raymond T., Trynka, Gosia, Samani, Nilesh J., Hingorani, Aroon, Sampson, Matthew G., Morris, Andrew P., Charchar, Fadi J., and Tomaszewski, Maciej

Published
2021
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8. Novel homozygous variants in PRORPexpand the genotypic spectrum of combined oxidative phosphorylation deficiency 54

Author

Smith, Thomas B., Rea, Alessandro, Thomas, Huw B., Thompson, Kyle, Oláhová, Monika, Maroofian, Reza, Zamani, Mina, He, Langping, Sadeghian, Saeid, Galehdari, Hamid, Lotan, Nava Shaul, Gilboa, Tal, Herman, Kristin C., McCorvie, Thomas J., Yue, Wyatt W., Houlden, Henry, Taylor, Robert W., Newman, William G., and O’Keefe, Raymond T.

Abstract

Biallelic hypomorphic variants in PRORPhave been recently described as causing the autosomal recessive disorder combined oxidative phosphorylation deficiency type 54 (COXPD54). COXPD54 encompasses a phenotypic spectrum of sensorineural hearing loss and ovarian insufficiency (Perrault syndrome) to leukodystrophy. Here, we report three additional families with homozygous missense PRORPvariants with pleiotropic phenotypes. Each missense variant altered a highly conserved residue within the metallonuclease domain. In vitro mitochondrial tRNA processing assays with recombinant TRMT10C, SDR5C1 and PRORP indicated two COXPD54-associated PRORPvariants, c.1159A>G (p.Thr387Ala) and c.1241C>T (p.Ala414Val), decreased pre-tRNAIlecleavage, consistent with both variants impacting tRNA processing. No significant decrease in tRNA processing was observed with PRORPc.1093T>C (p.Tyr365His), which was identified in an individual with leukodystrophy. These data provide independent evidence that PRORPvariants are associated with COXPD54 and that the assessment of 5′ leader mitochondrial tRNA processing is a valuable assay for the functional analysis and clinical interpretation of novel PRORPvariants.

Published
2023
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10. Bi-allelic FRA10AC1 variants in a multisystem human syndrome

Author

Banka, Siddharth, primary, Shalev, Stavit, additional, Park, Soo-Mi, additional, Wood, Katherine A, additional, Thomas, Huw B, additional, Wright, Helen L, additional, Alyahya, Mohammed, additional, Bankier, Sean, additional, Alimi, Ola, additional, Chervinsky, Elena, additional, Zeef, Leo A H, additional, and O’Keefe, Raymond T, additional

Published
2022
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13. Comparison of in Silico Strategies to Prioritize Rare Genomic Variants Impacting RNA Splicing for the Diagnosis of Genomic Disorders

Author

Rowlands, Charlie, primary, Thomas, Huw B, additional, Lord, Jenny, additional, Wai, Htoo A, additional, Arno, Gavin, additional, Beaman, Glenda, additional, Sergouniotis, Panagiotis, additional, Gomes-Silva, Beatriz, additional, Campbell, Christopher, additional, Gossan, Nicole, additional, Hardcastle, Claire, additional, Webb, Kevin, additional, O’Callaghan, Christopher, additional, Hirst, Robert A, additional, Ramsden, Simon, additional, Jones, Elizabeth, additional, -Smith, Jill Clayton, additional, Webster, Andrew R, additional, Douglas, Andrew GL, additional, O’Keefe, Raymond T, additional, Newman, William G, additional, Baralle, Diana, additional, Black, Graeme CM, additional, and Ellingford, Jamie M, additional

Published
2021
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15. Expanding the genotypic spectrum of TXNL4A variants in Burn‐McKeown syndrome.

Author

Wood, Katherine A., Ellingford, Jamie M., Thomas, Huw B., Douzgou, Sofia, Beaman, Glenda M., Hobson, Emma, Prescott, Katrina, O'Keefe, Raymond T., and Newman, William G.

Subjects
RNA splicing, GENOTYPES, BINDING sites, TRANSCRIPTION factors, TELEOLOGY
Abstract

The developmental disorder Burn‐McKeown Syndrome (BMKS) is characterised by choanal atresia and specific craniofacial features. BMKS is caused by biallelic variants in the pre‐messenger RNA splicing factor TXNL4A. Most patients have a loss‐of‐function variant in trans with a 34‐base pair (bp) deletion (type 1 Δ34) in the promoter region. Here, we identified two patients with BMKS. One individual has a TXNL4A c.93_94delCC, p.His32Argfs *21 variant combined with a type 1 Δ34 promoter deletion. The other has an intronic TXNL4A splice site variant (c.258‐3C>G) and a type 1 Δ34 promoter deletion. We show the c.258‐3C>G variant and a previously reported c.258‐2A>G variant, cause skipping of the final exon of TXNL4A in a minigene splicing assay. Furthermore, we identify putative transcription factor binding sites within the 56 bp of the TXNL4A promoter affected by the type 1 and type 2 Δ34 and use dual luciferase assays to identify a 22 bp repeated motif essential for TXNL4A expression within this promoter region. We propose that additional variants affecting critical transcription factor binding nucleotides within the 22 bp repeated motif could be relevant to BMKS aetiology. Finally, our data emphasises the need to analyse the non‐coding sequence in individuals where a single likely pathogenic coding variant is identified in an autosomal recessive disorder consistent with the clinical presentation. [ABSTRACT FROM AUTHOR]

Published
2022
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17. EFTUD2 missense variants disrupt protein function and splicing in mandibulofacial dysostosis Guion‐Almeida type

Author

Thomas, Huw B., primary, Wood, Katherine A., additional, Buczek, Weronika A., additional, Gordon, Christopher T., additional, Pingault, Véronique, additional, Attié‐Bitach, Tania, additional, Hentges, Kathryn E., additional, Varghese, Vinod C., additional, Amiel, Jeanne, additional, Newman, William G., additional, and O'Keefe, Raymond T., additional

Published
2020
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18. Comparison of in silico strategies to prioritize rare genomic variants impacting RNA splicing for the diagnosis of genomic disorders.

Author

Rowlands, Charlie, Thomas, Huw B., Lord, Jenny, Wai, Htoo A., Arno, Gavin, Beaman, Glenda, Sergouniotis, Panagiotis, Gomes-Silva, Beatriz, Campbell, Christopher, Gossan, Nicole, Hardcastle, Claire, Webb, Kevin, O'Callaghan, Christopher, Hirst, Robert A., Ramsden, Simon, Jones, Elizabeth, Clayton-Smith, Jill, Webster, Andrew R., Genomics England Research Consortium, and Ambrose, J. C.

Subjects
*RNA splicing, *DIAGNOSIS, *DIAGNOSIS methods, *FUNCTIONAL analysis
Abstract

The development of computational methods to assess pathogenicity of pre-messenger RNA splicing variants is critical for diagnosis of human disease. We assessed the capability of eight algorithms, and a consensus approach, to prioritize 249 variants of uncertain significance (VUSs) that underwent splicing functional analyses. The capability of algorithms to differentiate VUSs away from the immediate splice site as being 'pathogenic' or 'benign' is likely to have substantial impact on diagnostic testing. We show that SpliceAI is the best single strategy in this regard, but that combined usage of tools using a weighted approach can increase accuracy further. We incorporated prioritization strategies alongside diagnostic testing for rare disorders. We show that 15% of 2783 referred individuals carry rare variants expected to impact splicing that were not initially identified as 'pathogenic' or 'likely pathogenic'; one in five of these cases could lead to new or refined diagnoses. [ABSTRACT FROM AUTHOR]

Published
2021
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19. A homozygous missense variant in CHRM3 associated with familial urinary bladder disease

Author

Beaman, Glenda M., primary, Galatà, Gabriella, additional, Teik, Keng W., additional, Urquhart, Jill E., additional, Aishah, Ali, additional, O'Sullivan, James, additional, Bhaskar, Sanjeev S., additional, Wood, Katherine A., additional, Thomas, Huw B., additional, O'Keefe, Raymond T., additional, Woolf, Adrian S., additional, Stuart, Helen M., additional, and Newman, William G., additional

Published
2019
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20. Disease modeling of core pre-mRNA splicing factor haploinsufficiency

Author

Wood, Katherine A, primary, Rowlands, Charlie F, additional, Qureshi, Wasay Mohiuddin Shaikh, additional, Thomas, Huw B, additional, Buczek, Weronika A, additional, Briggs, Tracy A, additional, Hubbard, Simon J, additional, Hentges, Kathryn E, additional, Newman, William G, additional, and O’Keefe, Raymond T, additional

Published
2019
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21. Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Author

Heathfield, Sarah, Parker, Ben, Zeef, Leo, Bruce, Ian, Alexander, Yvonne, Collins, Fraser, Stone, Michael, Wang, Edward, Williams, Anwen S., Wright, Helen L., Thomas, Huw B., Moots, Robert J., Edwards, Steven W., Bullock, Craig, Chapman, Victoria, Walsh, David A., Mobasheri, Ali, Kendall, David, Kelly, Sara, Bayley, Rachel, Buckley, Chris D., Young, Stephen P., Rump-Goodrich, Lisa, Middleton, Jim, Chen, Liye, Fisher, Roman, Kollnberger, Simon, Shastri, Nilabh, Kessler, Benedikt M., Bowness, Paul, Nazeer Moideen, Abdul, Evans, Laura, Osgood, Louise, Jones, Simon A., Nowell, Mari A., Mahadik, Younis, Young, Stephen, Morgan, Matthew, Gordon, Caroline, Harper, Lorraine, Giles, Joanna L., Paul Morgan, B., Harris, Claire L., Rysnik, Oliwia J., McHugh, Kirsty, Payeli, Sravan, Marroquin, Osiris, Shaw, Jacqueline, Renner, Christoph, Nayar, Saba, Cloake, Tom, Bombardieri, Michele, Pitzalis, Costantino, Buckley, Chris, Barone, Francesca, Lane, Peter, Coles, Mark, Williams, Emma L., Edwards, Christopher J., Cooper, Cyrus, Oreffo, Richard O., Dunn, Sara, Crawford, Aileen, Wilkinson, Mark, Le Maitre, Christine, Bunning, Rowena, Daniels, Jodie, Phillips, Kate L. E., Chiverton, Neil, Le Maitre, Christine L., Shaw, Jackie, Ridley, Anna, Wong-Baeza, Isabel, Keidel, Sarah, Chan, Antoni, Gullick, Nicola J., Abozaid, Hanan S., Jayaraj, David M., Evans, Hayley G., Scott, David L., Choy, Ernest H., Taams, Leonie S., Hickling, M., Golor, G., Jullion, A., Shaw, S., Kretsos, K., Bari, Syed F., Rhys-Dillon, Brian, Amos, Nicholson, Siebert, Stefan, Bunning, Rowena D., Haddock, Gail, Cross, Alison K., Kate, I., Phillips, E., Cross, Alison, Bunning, Rowena A. D., Ceeraz, Sabrina, Spencer, Jo, Choy, Ernest, Corrigall, Valerie, Crilly, Anne, Palmer, Helen, Lockhart, John, Plevin, Robin, Ferrell, William R., McInnes, Iain, Hutchinson, David, Perry, Liz, DiCicco, Maria, Humby, Frances, Kelly, Stephen, Hands, Rebecca, McInnes, Ian, Taylor, Peter, Mehta, Puja, Mitchell, Adam, Tysoe, Carolyn, Caswell, Richard, Owens, Martina, Vincent, Tonia, Hashmi, Tahir M., Price-Forbes, Alec, Sharp, Charlotte A., Murphy, Helen, Wood, Elizabeth F., Doherty, Teresa, Sheldon, Jo, Sofat, Nidhi, Goff, Iain, Platt, Philip N., Abdulkader, Rita, Clunie, Gavin, Ismajli, Mediola, Nikiphorou, Elena, Young, Adam, Tugnet, Nicola, Dixey, Josh, Banik, Snehashish, Alcorn, Desmond, Hunter, John, Win Maw, Win, Patil, Pravin, Hayes, Fiona, Main Wong, Way, Borg, Frances A., Dasgupta, Bhaskar, Malaviya, Anshuman P., Ostor, Andrew J., Chana, Jasroop K., Ahmed, Azeem A., Edmonds, Sally, Coward, Lucy, Borg, Frances, Heaney, Jonathan, Amft, Nicole, Simpson, John, Dhillon, Veena, Ayalew, Yezenash, Khattak, Fazlihakim, Gayed, Mary, Amarasena, Roshan I., McKenna, Frank, Mc Laughlin, Maeve, Baburaj, Krishnan, Fattah, Zozik, Ng, Nora, Wilson, Jo, Colaco, Bernard, Williams, Mark R., Adizie, Tochukwu, Casey, Matthew, Lip, Stefanie, Tan, Shaun, Anderson, David, Robertson, Calum, Devanny, Ian, Field, Max, Walker, David, Robinson, Sandra, Ryan, Sarah, Hassell, Andrew, Bateman, James, Allen, Maggie, Davies, David, Crouch, Carina, Walker-Bone, Karen, Gainsborough, Nicola, Lutalo, Pamela M., Davies, Ursula M., Mckew, Jennifer R., Millar, Auleen M., Wright, Stephen A., Bell, Aubrey L., Thapper, Muryum, Roussou, Thalia, Cumming, Jo, Hull, Richard G., McKeogh, John, O'Connor, Mortimer B., Hassan, Ahmed I., Bond, Ursula, Swan, Joan, Phelan, Mark J., Coady, David, Kumar, Namita, Farrow, Luke, Bukhari, Marwan, Oldroyd, Alexander G., Greenbank, Cathi, McBeth, John, Duncan, Rosie, Brown, Deborah, Horan, Michael, Pendleton, Neil, Littlewood, Alison, Cordingley, Lis, Mulvey, Matthew, Curtis, Elizabeth M., Cole, Zoe A., Crozier, Sarah R., Georgia, Ntani, Robinson, Siân M., Godfrey, Keith M., Sayer, Avan A., Inskip, Hazel M., Harvey, Nicholas C., Davies, Rebecca, Mercer, Louise, Galloway, James, Low, Audrey, Watson, Kath, Lunt, Mark, Symmons, Deborah, Hyrich, Kimme, Chitale, Sarang, Estrach, Cristina, Goodson, Nicola J., Rankin, Elizabeth, Jiang, C. Q., Cheng, K. K., Lam, T. H., Adab, Peymané, Ling, Stephanie, Humphreys, Jennifer, Ellis, Corrinne, Bunn, Diane, Verstappen, Suzanne M., Fluess, Elisa, Macfarlane, Gary J., Bond, Christine, Jones, Gareth T., Scott, Ian C., Steer, Sophia, Lewis, Cathryn M., Cope, Andrew, Mulvey, Matthew R., Lovell, Karina, Keeley, Philip, Woby, Steve, Beasley, Marcus, Viatte, Sebastien, Plant, Darren, Fu, Bo, Solymossy, Csilla, Worthington, Jane, Barton, Anne, Williams, Frances M., Osei-Bordom, Daniel-Clement, Popham, Maria, MacGregor, Alex, Spector, Tim, Little, Jayne, Herrick, Ariane, Pushpakom, S., Ennis, H., McBurney, H., Worthington, J., Newman, W., Ibrahim, Ibrahim, Morgan, Anne, Wilson, Anthony, Isaacs, John, Sanderson, Tessa, Hewlett, Sarah, Calnan, Michael, Morris, Marianne, Raza, Karim, Kumar, Kanta, Cardy, Caroline M., Pauling, John D., Jenkins, Jessica, Brown, Sue J., McHugh, Neil, Mugford, Miranda, Davies, Charlotte, Cooper, Nicola, Brooksby, Alan, Dures, Emma, Ambler, Nick, Fletcher, Debbie, Pope, Denise, Robinson, Frances, Rooke, Royston, Gorman, Claire L., Reynolds, Piero, Hakim, Alan J., Bosworth, Ailsa, Weaver, Dan, Kiely, Patrick D., Skeoch, Sarah, Jani, Meghna, Amarasena, Roshan, Rao, Chandini, Macphie, Elizabeth, McLoughlin, Yokemei, Shah, Preeti, Else, Sara, Semenova, Olga, Thompson, Helen, Ogunbambi, Olabambo, Kallankara, Sathish, Patel, Yusuf, Baguley, Elaine, Halsey, John, Severn, Andrew, Selvan, Shilpa, Price, Elizabeth, Husain, Muhammad J., Brophy, Sinead, Phillips, Ceri J., Cooksey, Roxanne, Irvine, Elizabeth, Lendrem, Dennis, Mitchell, Sheryl, Bowman, Simon, Pease, Colin T., Emery, Paul, Andrews, Jacqueline, Sutcliffe, Nurhan, Lanyon, Peter, Gupta, Monica, McLaren, John, Regan, Marian, Cooper, Annie, Giles, Ian, Isenberg, David, Griffiths, Bridget, Foggo, Heather, Edgar, Suzanne, Vadivelu, Saravanan, Ng, Wan-Fai, Iqbal, Itrat, Heron, Louise, Pilling, Claire, Marks, Jonathan, Hull, Richard, Ledingham, Jo, Han, Chenglong, Gathany, Tim, Tandon, Neeta, Hsia, Elizabeth, Taylor, P., Strand, V., Sensky, T., Harta, N., Fleming, S., Kay, Lesley, Rutherford, Michelle, Nicholl, Karl, Eyre, Tracey, Wilson, Gillian, Johnson, Phil, Russell, M., Timoshanko, J., Duncan, G., Spandley, A., Roskell, S., West, Louise, Adshead, Rebecca, Donnelly, Simon P., Ashton, Simon, Tahir, Hasan, Patel, Dipti, Darroch, James, Boulton, John, Ellis, Benjamin, Finlay, Ron, Murray-Brown, William, Priori, R., Tappuni, T., Vartoukian, S., Seoudi, N., Picarelli, G., Fortune, F., Valesini, G., Pitzalis, C., Bombardieri, M., Ball, Elisabeth, Rooney, Madeleine, Bell, Aubrey, Mérida, Angeles Acosta, Tarelli, Edward, Axford, John, Pericleous, Charis, Pierangeli, Silvia S., Ioannou, John, Rahman, Anisur, Alavi, Azita, Hughes, Michael, Evans, Bronwen, Zaki, Awal, Hui, Michelle, Garner, Rozeena, Rees, Frances, Bavakunji, Riaz, Daniel, Priya, Varughese, Sneha, Srikanth, Asha, Andres, Mariano, Pearce, Fiona, Leung, Jansen, Lim, Ken, Oomatia, Amin, Petri, Michelle, Fang, Hong, Birnbaum, Julius, Amissah-Arthur, Maame, Stewart, Kirsty, Jennens, Hannah, Braude, Simon, Sutton, Emily J., Watson, Kath D., Yee, Chee-Seng, Jayne, David, Akil, Mohammed, Ahmad, Yasmeen, D'Cruz, David, Khamashta, Munther, Teh, Lee-Suan, Zoma, Asad, Dey, Ida D., Kenu, Ernest, Garza-Garcia, Acely, Murfitt, Lucy, Driscoll, Paul C., Pierangeli, Silvia, Ioannou, Yiannis, Reynolds, John A., Ray, David W., O'Neill, Terence, Segeda, Iuliia, Shevchuk, Sergii, Kuvikova, Inna, Brown, Nina, Venning, Michael, Dhanjal, Mandish, Mason, Justin, Nelson-Piercy, Catherine, Basu, Neil, Paudyal, Priya, Stockton, Marie, Lawton, Sally, Dent, Caroline, Kindness, Kathy, Meldrum, Gillian, John, Elizabeth, Arthur, Catherine, West, Lucy, Macfarlane, Matthew V., Reid, David M., Yates, Max, Loke, Yoon, Watts, Richard, Christidis, Dimitrios, Williams, Mark, Sivakumar, Rajappa, Misra, Ramnath, Danda, Debashish, Mahendranath, K. M., Bacon, Paul A., and Mackie, Sarah L.

Abstract

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q < 0.00005). This was supported by qPCR analysis at 6 hrs (E-selectin and VCAM-1; 208.5 fold and 40.5, respectively above control) and also at 1, 3 and 24 hrs (E-selectin; 25.6, 93.5, 12.7 fold, respectively) (VCAM-1; 4.7, 47.2, 17.6 fold) (n = 3; p < 0.05). In contrast, HAoECs treated with TNF in combination with CZP exhibited control levels of E-selectin and VCAM-1 transcript (p > 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interest

Published
2017

22. Oral Abstracts 7: RA Clinical * O37. Long-Term Outcomes of Early RA Patients Initiated with Adalimumab Plus Methotrexate Compared with Methotrexate Alone Following a Targeted Treatment Approach

Author

Fleischmann, Roy, van Vollenhoven, Ronald F., Smolen, Josef, Emery, Paul, Florentinus, Stefan, Rathmann, Suchitrita, Kupper, Hartmut, Kavanaugh, Arthur, Taylor, Peter, Genovese, Mark, Keystone, Edward C., Drescher, Edit, Berclaz, Pierre-Yves, Lee, Chin, Fidelus-Gort, Rosalind, Schlichting, Douglas, Beattie, Scott, Luchi, Monica, Macias, William, Dikranian, Ara H., Alten, Rieke, Klearman, Micki, Musselman, David, Agarwal, Sunil, Green, Jennifer, Gabay, Cem, Weinblatt, Michael E., Schiff, Michael H., Valente, Robert, van der Heijde, Desiree, Citera, Gustavo, Zhao, Cathy, Maldonado, Michael A., Rakieh, Chadi, Nam, Jacqueline L., Hunt, Laura, Villeneuve, Edith, Bissell, Lesley-Anne, Das, Sudipto, Conaghan, Philip, McGonagle, Dennis, Wakefield, Richard J., Wright, Helen L., Thomas, Huw B., Moots, Robert, Edwards, Steven W., Hamann, Philip, Heward, James, McHugh, Neil, Lindsay, Mark A., Haroon, Muhammad, Giles, Jon T., Winchester, Robert, FitzGerald, Oliver, Karaderi, Tugce, Cohen, Carla J., Keidel, Sarah, Appleton, Louise H., Macfarlane, Gary J., Siebert, Stefan, Evans, David, Paul Wordsworth, B., Plant, Darren, Bowes, John, Orozco, Gisela, Morgan, Ann W., Wilson, Anthony G., Isaacs, John, Barton, Anne, Williams, Frances M., Livshits, Gregory, Spector, Tim, MacGregor, Alexander, Scollen, Serena, Cao, Dandan, Memari, Yasin, Hyde, Craig L., Zhang, Baohong, Sidders, Benjamin, Ziemek, Daniel, Shi, Yujian, Harris, Juliette, Harrow, Ian, Dougherty, Brian, Malarstig, Anders, McEwen, Robert, Stephens, Joel L., Patel, Ketan, Shin, So-Youn, Surdulescu, Gabriela, He, Wen, Jin, Xin, McMahon, Stephen B., Soranzo, Nicole, John, Sally, Wang, Jun, Spector, Tim D., Baker, Jonathan, Litherland, Gary J., Rowan, Andrew D., Kite, Kerry A., Bayley, Rachel, Yang, Peiming, Smith, Jacqueline P., Williams, Julie, Harper, Lorraine, Kitas, George D., Buckley, Christopher, Young, Stephen P., Fitzpatrick, Martin A., McGettrick, Helen M., Filer, Andrew, Raza, Karim, Nash, Gerard, Muthana, Munitta, Davies, Holly, Khetan, Sachin, Adeleke, Gbadebo, Hawtree, Sarah, Tazzyman, Simon, Morrow, Fiona, Ciani, Barbara, Wilson, Gerry, Quirke, Anne-Marie, Lugli, Elena, Wegner, Natalia, Charles, Peter, Hamilton, Bart, Chowdhury, Muslima, Ytterberg, Jimmy, Potempa, Jan, Fisher, Benjamin, Thiele, Geoffrey, Mikuls, Ted, Venables, Patrick, Adebajo, Adewale O., Mease, Philip, Gomez-Reino, Juan J., Wollenhaupt, Jurgen, Hu, ChiaChi, Stevens, Randall, Sieper, Joachim, Dougados, Maxime, Van den Bosch, Filip, Goupille, Philippe, Rathmann, Suchitrita S., Pangan, Aileen L., Maksymowych, Walter P., Brown, Matthew A., Elewaut, Dirk, Anderson, Jaclyn, Ramasamy, Pathma, O'Rourke, Michael, Murphy, Conor, Fitzgerald, Oliver, Jani, Meghna, Moore, Sarah, Mirjafari, Hoda, Macphie, Elizabeth, Chinoy, Hector, Rao, Chan, McLoughlin, Yokemei, and Preeti, Shah

Subjects
medicine.medical_specialty, Rheumatology, business.industry, Radiography, medicine, Pharmacology (medical), Inflammation, In patient, Radiology, medicine.symptom, Axial spondyloarthritis, business, Joint (geology)
Abstract

Background: This analysis assessed, on a group level, whether there is a long-term advantage for early RA patients treated with adalimumab (ADA) + MTX vs those initially treated with placebo (PBO) + MTX who either responded to therapy or added ADA following inadequate response (IR). Methods: OPTIMA was a 78- week, randomized, controlled trial of ADA + MTX vs PBO + MTX in MTX-naïve early (

Published
2013

23. Differential changes in gene expression in human neutrophils following TNF-α stimulation: Up-regulation of anti-apoptotic proteins and down-regulation of proteins involved in death receptor signaling

Author

Chiewchengchol, Direkrit, Wright, Helen L, Thomas, Huw B, Lam, Connie W, Roberts, Kate J, Hirankarn, Nattiya, Beresford, Michael W, Moots, Robert J, and Edwards, Steven W

Abstract

Responses of human neutrophils to TNF-α are complex and multifactorial. Exposure of human neutrophils to TNF-α in vitro primes the respiratory burst, delays apoptosis and induces the expression of several genes including chemokines, and TNF-α itself. This study aimed to determine the impact of TNF-α exposure on the expression of neutrophil genes and proteins that regulate apoptosis. Quantitative PCR and RNA-Seq, identified changes in expression of several apoptosis regulating genes in response to TNF-α exposure. Up-regulated genes included TNF-α itself, and several anti-apoptotic genes, including BCL2A1, CFLAR (cFLIP) and TNFAIP3, whose mRNA levels increased above control values by between 4-20 fold (n = 3, P

Published
2016

24. Differential changes in gene expression in human neutrophils following TNF-α stimulation: Up-regulation of anti-apoptotic proteins and down-regulation of proteins involved in death receptor signaling

Author

Chiewchengchol, Direkrit, primary, Wright, Helen L., additional, Thomas, Huw B., additional, Lam, Connie W., additional, Roberts, Kate J., additional, Hirankarn, Nattiya, additional, Beresford, Michael W., additional, Moots, Robert J., additional, and Edwards, Steven W., additional

Published
2015
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29. A basement membrane discovery pipeline uncovers network complexity, regulators, and human disease associations.

Author

Jayadev, Ranjay, Morais, Mychel R. P. T., Ellingford, Jamie M., Srinivasan, Sandhya, Naylor, Richard W., Lawless, Craig, Li, Anna S., Ingham, Jack F., Hastie, Eric, Qiuyi Chi, Fresquet, Maryline, Koudis, Nikki-Maria, Thomas, Huw B., O'Keefe, Raymond T., Williams, Emily, Adamson, Antony, Stuart, Helen M., Banka, Siddharth, Smedley, Damian, and Sherwood, David R.

Subjects
*GONADS, *BASAL lamina, *SALIVARY glands, *RECESSIVE genes, *EXTRACELLULAR matrix proteins, *HUMAN biology, *LIFE sciences, *DEVELOPMENTAL biology
Abstract

The article discusses a 2022 study on the complexity of basement membranes (BM) and their impact on human health. Topics covered include the definition of a network of 22 human proteins and their animal orthologs localized to BMs, the uncovering of BM regulators like ADAMTS, ROBO, and TGFß, and the link of more than 100 BM network genes to human phenotypes. Also noted are findings of loss-of-function variants and their regulation of BM composition and function.

Published
2022
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30. Advanced Methods for the Analysis of Altered Pre-mRNA Splicing in Yeast and Disease.

Author

Thomas HB and O'Keefe RT

Subjects
Animals, Humans, RNA Precursors genetics, RNA Splicing genetics, Saccharomyces cerevisiae genetics, Saccharomyces cerevisiae metabolism, Spliceosomes genetics, Spliceosomes metabolism
Abstract

Splicing of pre-messenger RNA (pre-mRNA) transcripts is a fundamental process in all eukaryotes that provides a mechanism of increasing the proteomic diversity within a cell that can be tightly regulated in a dynamic manner. While constitutive and alternative splicing are necessary for the correct development and regulation of cells/organisms, aberrant splicing is now associated with an increasingly varied number of human diseases, such as neurological and developmental diseases, and cancer. Studies of splicing mechanisms and regulation are often achieved in nonhuman model organisms such as yeast. Yeasts possess homologs to many of the core spliceosome components of higher organisms, including humans, and as such yeast species are now a well-established model organism for understanding how differential splicing of transcripts can alter the phenotype of a cell or organism. Here we describe methods to investigate pre-mRNA splicing in yeast cells using modern RNA-Seq technology and bioinformatics software. Details of traditional validation methods are also described.

Published
2019
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