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4. SCIENCE AND SOCIETY: The RA-MAP Consortium: a working model for academia-industry collaboration

Author

Cope, Andrew P., Barnes, Michael R., Belson, Alexandra, Binks, Michael, Brockbank, Sarah, Bonachela-Capdevila, Francisco, Carini, Claudio, Fisher, Benjamin A., Goodyear, Carl S., Emery, Paul, Ehrenstein, Michael R., Gozzard, Neil, Harris, Ray, Hollis, Sally, Keidel, Sarah, Levesque, Marc, Lindholm, Catharina, McDermott, Michael F., McInnes, Iain B., Mela, Christopher M., Parker, Gerry, Read, Simon, Pedersen, Ayako Wakatsuki, Ponchel, Frederique, Porter, Duncan, Rao, Ravi, Rowe, Anthony, Schulze-Knappe, Peter, Sleeman, Matthew A., Symmons, Deborah, Taylor, Peter C., Tom, Brian, Tsuji, Wayne, Verbeeck, Denny, and Isaacs, John D.

Published
2018
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5. RA-MAP, molecular immunological landscapes in early rheumatoid arthritis and healthy vaccine recipients

Author

Isaacs, John D., Brockbank, Sarah, Pedersen, Ayako Wakatsuki, Hilkens, Catharien, Anderson, Amy, Stocks, Philip, Lendrem, Dennis, Tarn, Jessica, Smith, Graham R., Allen, Ben, Casement, John, Diboll, Julie, Harry, Rachel, Cooles, Faye A. H., Cope, Andrew P., Simpson, Gemma, Toward, Ruth, Noble, Hayley, Parke, Angela, Wu, Wing, Clarke, Fiona, Scott, David, Scott, Ian C., Galloway, James, Lempp, Heidi, Ibrahim, Fowzia, Schwank, Samana, Molyneux, Gemma, Lazarov, Tomi, Geissmann, Frederic, Goodyear, Carl S., McInnes, Iain B., Donnelly, Iona, Gilmour, Ashley, Virlan, Aysin Tulunay, Porter, Duncan, Ponchel, Frederique, Emery, Paul, El-Jawhari, Jehan, Parmar, Rekha, McDermott, Michael F., Fisher, Benjamin A., Young, Steve P., Jones, Philip, Raza, Karim, Filer, Andrew, Pitzalis, Costantino, Barnes, Michael R., Watson, David S., Henkin, Rafael, Thorborn, Georgina, Fossati-Jimack, Liliane, Kelly, Stephen, Humby, Frances, Bombardieri, Michele, Rana, Sharmila, Jia, Zhilong, Goldmann, Katriona, Lewis, Myles, Ng, Sandra, Barbosa-Silva, Adriano, Tzanis, Evan, Gallagher-Syed, Amaya, John, Christopher R., Ehrenstein, Michael R., Altobelli, Gioia, Martins, Sandra, Nguyen, Dao, Ali, Humayara, Ciurtin, Coziana, Buch, Maya, Symmons, Deborah, Worthington, Jane, Bruce, Ian N., Sergeant, Jamie C., Verstappen, Suzanne M. M., Stirling, Fiona, Hughes-Morley, Adwoa, Tom, Brian, Farewell, Vernon, Zhong, Yujie, Taylor, Peter C., Buckley, Christopher D., Keidel, Sarah, Cuff, Carolyn, Levesque, Marc, Long, Andrew, Liu, Zheng, Lipsky, Samantha, Harvey, Bohdan, Macoritto, Michael, Hong, Feng, Kaymakcalan, Sukru, Tsuji, Wayne, Sabin, Tony, Ward, Neil, Talbot, Susan, Padhji, Desmond, Sleeman, Matthew, Finch, Donna, Herath, Athula, Lindholm, Catharina, Jenkins, Martin, Ho, Meilien, Hollis, Sally, Marshall, Chris, Parker, Gerry, Page, Matt, Edwards, Hannah, Cuza, Alexandru, Gozzard, Neil, Pandis, Ioannis, Rowe, Anthony, Capdevila, Francisco Bonachela, Loza, Matthew J., Curran, Mark, Verbeeck, Denny, Dan Baker, Mela, Christopher M., Vranic, Ivana, Mela, Catherine T., Wright, Stephen, Rowell, Lucy, Vernon, Emma, Joseph, Nina, Payne, Neil, Rao, Ravi, Binks, Michael, Belson, Alexandra, Ludbrook, Valerie, Hicks, Kirsty, Tipney, Hannah, Ellis, Joanne, Hasan, Samiul, Didierlaurent, Arnaud, Burny, Wivine, Haynes, Andrea, Larminie, Chris, Harris, Ray, Dastros-Pitei, Daniela, Carini, Claudio, Kola, Blerina, Jelinsky, Scott, Hodge, Martin, Maciejewski, Mateusz, Ziemek, Daniel, Schulz-Knappe, Peter, Zucht, Hans-Dieter, Budde, Petra, Coles, Mark, Butler, James A., Read, Simon, and Consortium, The RA-MAP

Subjects
Arthritis, Rheumatoid, Proteomics, Statistics and Probability, Vaccines, Humans, Library and Information Sciences, Statistics, Probability and Uncertainty, Monocytes, Autoantibodies, Biological Specimen Banks, Computer Science Applications, Education, Information Systems
Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory disorder with poorly defined aetiology characterised by synovial inflammation with variable disease severity and drug responsiveness. To investigate the peripheral blood immune cell landscape of early, drug naive RA, we performed comprehensive clinical and molecular profiling of 267 RA patients and 52 healthy vaccine recipients for up to 18 months to establish a high quality sample biobank including plasma, serum, peripheral blood cells, urine, genomic DNA, RNA from whole blood, lymphocyte and monocyte subsets. We have performed extensive multi-omic immune phenotyping, including genomic, metabolomic, proteomic, transcriptomic and autoantibody profiling. We anticipate that these detailed clinical and molecular data will serve as a fundamental resource offering insights into immune-mediated disease pathogenesis, progression and therapeutic response, ultimately contributing to the development and application of targeted therapies for RA.

Published
2022
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7. Additional file 1 of Prolonged Scar-in-a-Jar: an in vitro screening tool for anti-fibrotic therapies using biomarkers of extracellular matrix synthesis

Author

Rønnow, Sarah Rank, Dabbagh, Rand Qais, Genovese, Federica, Nanthakumar, Carmel B., Barrett, Vikki J., Good, Robert B., Brockbank, Sarah, Cruwys, Simon, Jessen, Henrik, Sorensen, Grith Lykke, Karsdal, Morten Asser, Leeming, Diana Julie, and Sand, Jannie Marie Bülow

Abstract

Additional file 1:Figure S1. Effect of pirfenidone shown by day. Lung fibroblasts were stimulated with TGF-β1 and treated with 3 × 101, 1 × 102, 3 × 102 or 1 × 103 μM pirfenidone or corresponding vehicle (0.03, 0.1, 0.3 or 1% DMSO). Biomarkers of ECM synthesis (type I (PRO-C1), III (PRO-C3) and VI (PRO-C6) collagen and fibronectin (FBN-C)) and fibroblast activation (α-SMA) were measured in the supernatant at day 4, 8 and 12. Data are shown as dose-response curves for pirfenidone and its vehicle for the different timepoints and are presented as percentage of the TGF-β1 control over time. All data are shown as mean ± SD of 3 separate experiments each with 4 replicates/treatment and analyzed by two-way ANOVA with Sidak’s multiple comparisons test comparing pirfenidone to vehicle. ns non-significant; *P

Published
2020
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9. RA-MAP, molecular immunological landscapes in early rheumatoid arthritis and healthy vaccine recipients.

Author

The RA-MAP Consortium, Isaacs, John D., Brockbank, Sarah, Pedersen, Ayako Wakatsuki, Hilkens, Catharien, Anderson, Amy, Stocks, Philip, Lendrem, Dennis, Tarn, Jessica, Smith, Graham R., Allen, Ben, Casement, John, Diboll, Julie, Harry, Rachel, Cooles, Faye A. H., Cope, Andrew P., Simpson, Gemma, Toward, Ruth, Noble, Hayley, and Parke, Angela

Subjects
RHEUMATOID arthritis, BLOOD cells, RHEUMATOID factor, LYMPHOCYTE subsets, NON-coding RNA, RNA sequencing, AUTOANTIBODIES, METABOLOMICS
Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory disorder with poorly defined aetiology characterised by synovial inflammation with variable disease severity and drug responsiveness. To investigate the peripheral blood immune cell landscape of early, drug naive RA, we performed comprehensive clinical and molecular profiling of 267 RA patients and 52 healthy vaccine recipients for up to 18 months to establish a high quality sample biobank including plasma, serum, peripheral blood cells, urine, genomic DNA, RNA from whole blood, lymphocyte and monocyte subsets. We have performed extensive multi-omic immune phenotyping, including genomic, metabolomic, proteomic, transcriptomic and autoantibody profiling. We anticipate that these detailed clinical and molecular data will serve as a fundamental resource offering insights into immune-mediated disease pathogenesis, progression and therapeutic response, ultimately contributing to the development and application of targeted therapies for RA. Measurement(s) Transcriptomics, small RNA, proteomics, autoantibodies, metabolomics, genotype, blood, urine Technology Type(s) microarray, RNA sequencing, somascan, NMR metabolomics, luminex autoantibody array, exome array Sample Characteristic - Organism Homo sapiens [ABSTRACT FROM AUTHOR]

Published
2022
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11. Prolonged Scar-in-a-Jar: an in vitro screening tool for anti-fibrotic therapies using biomarkers of extracellular matrix synthesis

Author

Rønnow, Sarah Rank, primary, Dabbagh, Rand Qais, additional, Genovese, Federica, additional, Nanthakumar, Carmel B., additional, Barrett, Vikki J., additional, Good, Robert B., additional, Brockbank, Sarah, additional, Cruwys, Simon, additional, Jessen, Henrik, additional, Sorensen, Grith Lykke, additional, Karsdal, Morten Asser, additional, Leeming, Diana Julie, additional, and Sand, Jannie Marie Bülow, additional

Published
2020
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12. Addition of trans fat and alcohol has divergent effects on atherogenic diet-induced liver injury in rodent models of steatohepatitis

Author

Daniels, Samuel J., primary, Leeming, Diana J., additional, Detlefsen, Sönke, additional, Bruun, Maria F., additional, Hjuler, Sara T., additional, Henriksen, Kim, additional, Hein, Peter, additional, Krag, Aleksander, additional, Karsdal, Morten A., additional, Nielsen, Mette Juul, additional, Brockbank, Sarah, additional, and Cruwys, Simon, additional

Published
2020
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17. Characterization of disease course and remission in early seropositive rheumatoid arthritis: results from the TACERA longitudinal cohort study.

Author

Barnes, Michael, Brockbank, Sarah, Bruce, Ian N, Ciurtin, Coziana, Cop, Andrew P., Ehrenstein, Michael R., Emery, Paul, Fisher, Benjamin A., Isaacs, John, Matthews, Ruth, McInnes, Iain B., Noble, Hayley, Wakatsuki Pedersen, Ayako, Pitzalis, Costantino, Raza, Karim, Rowe, Anthony, Simpson, Gemma, Stringer, Dominic, Taylor, Peter C., and Tom, Brian

Abstract

Background: To characterise disease course and remission in a longitudinal observational study of newly diagnosed, initially treatment-naïve patients with seropositive rheumatoid arthritis (RA). Methods: Patients with early untreated seropositive RA were recruited from 28 UK centres. Multiple clinical and laboratory measures were collected every 3 months for up to 18 months. Disease activity was measured using the 28-joint Disease Activity Score with C-reactive protein (DAS28-CRP) and Simplified Disease Activity Index (SDAI). Logistic regression models examined clinical predictors of 6-month remission and latent class mixed models characterised disease course. Results: We enrolled 275 patients of whom 267 met full eligibility and provided baseline data. According to SDAI definition, 24.3% attained 6-month remission. Lower baseline Health Assessment Questionnaire (HAQ) and SDAI predicted 6-month remission (p = 0.013 and 0.011). Alcohol intake and baseline prescribing of methotrexate with a second disease-modifying antirheumatic drug (DMARD; vs monotherapy without glucocorticoids) were also predictive. Three distinct SDAI trajectory subpopulations emerged; corresponding to an inadequate responder group (6.5%), and higher and lower baseline activity responder groups (22.4% and 71.1%). Baseline HAQ and Short Form-36 Health Survey – Mental Component Score (SF-36 MCS) distinguished these groups. In addition, a number of baseline clinical predictors correlated with disease activity severity within subpopulations. Beneficial effects of alcohol intake were found across subpopulations. Conclusion: Three distinct disease trajectory subpopulations were identified. Differential effects of functional and mental well-being, alcohol consumption, and baseline RA medication prescribing on disease activity severity were found across subpopulations. Heterogeneity across trajectories cannot be fully explained by baseline clinical predictors. We hypothesise that biological markers collected early in disease course (within 6 months) may help patient management and better targeting of existing and novel therapies. [ABSTRACT FROM AUTHOR]

Published
2021
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20. Cloning, sequencing, and expression of the DNA gyrase genes from Staphylococcus aures

Author

Brockbank, Sarah M.V. and Barth, Peter T.

Subjects
Staphylococcus aureus -- Genetic aspects, DNA topoisomerase II -- Genetic aspects, Biological sciences
Abstract

The Staphylococcus aureus genes encoding DNA gyrase were isolated by screening a chromosomal library using previously characterized sequences from other species. The screen identified two genes, gyrA and gyrB, which encodes the subunits of DNA gyrase. Sequence analysis indicated that gyrA and gyrB codes for proteins of 886 and 644 amino acid residues, respectively. The genes were expressed, and protein sequence analysis showed that gyrB undergoes a five residue cleavage. The protein sequence also confirmed the DNA sequence data.

Published
1993

21. Novel methodology to discern predictors of remission and patterns of disease activity over time using rheumatoid arthritis clinical trials data

Author

Brockbank, Sarah, Carini, Claudio, Pope, Andrew, Ehrenstein, Michael R., Fisher, Benjamin, Goodyear, Carl S., Gozzard, Neil, Harris, Ray, Hicks, Kirsty, Hollis, Sally, Hughes Morley, Adwoa, Isaacs, John D., Kola, Blerina, McInnes, Iain B, Mela, Christopher M., Parker, Gerry, Wakatsuki Pedersen, Ayako, Ponchel, Frederique, Sabin, Tony, Scott, David L, Scott, Ian C., Sleeman, Matthew A., Symmons, Deborah, Taylor, Peter C., Tom, Brian, Tsuji, Wayne, and Zhong, Yujie

Subjects
musculoskeletal diseases, immune system diseases, skin and connective tissue diseases
Abstract

Objectives To identify predictors of remission and disease activity patterns in patients with rheumatoid arthritis (RA) using individual participant data (IPD) from clinical trials. Methods Phase II and III clinical trials completed between 2002 and 2012 were identified by systematic literature review and contact with UK market authorisation holders. Anonymised baseline and follow-up IPD from nonbiological arms were amalgamated. Multiple imputation was used to handle missing outcome and covariate information. Random effects logistic regression was used to identify predictors of remission, measured by the Disease Activity Score 28 (DAS28) at 6 months. Novel latent class mixed models characterised DAS28 over time. Results IPD of 3290 participants from 18 trials were included. Of these participants, 92% received methotrexate (MTX). Remission rates were estimated at 8.4%(95%CI 7.4%to9.5%) overall, 17%(95%CI 14.8%to19.4%) for MTX-naïve patients with early RA and 3.2% (95% CI 2.4% to 4.3%) for those with prior MTX exposure at entry. In prior MTX-exposed patients, lower baseline DAS28 and MTX reinitiation were associated with remission. In MTX-naïve patients, being young, white, male, with better functional and mental health, lower baseline DAS28 and receiving concomitant glucocorticoids were associated with remission. Three DAS28 trajectory subpopulations were identified in MTX-naïve and MTX-exposed patients. A number of variables were associated with subpopulation membership and DAS28 levels within subpopulations. Conclusions Predictors of remission differed between MTX-naïve and prior MTX-exposed patients at entry. Latent class mixed models supported differential non-biological therapy response, with three distinct trajectories observed in both MTX-naïve and MTX-exposed patients. Findings should be useful when designing future RA trials and interpreting results of biomarker studies.

Published
2018

24. Clinically validated markers of the extracellular matrix remodelling are altered by potential anti-fibrotic compounds in a human lung fibrosis ex vivo model

Author

Leeming, Diana Julie, primary, Sand, Jannie M.B, additional, Hesse, Christina, additional, Konzok, Sebastian, additional, Sewald, Katherina, additional, Rønnow, Sarah, additional, Braun, Armin, additional, Karsdal, Morten A, additional, Brockbank, Sarah, additional, and Cruwys, Simon, additional

Published
2018
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28. The RA-MAP Consortium: a working model for academia–industry collaboration

Author

Cope, Andrew P., Barnes, Michael R., Belson, Alexandra, Binks, Michael, Brockbank, Sarah, Bonachela-Capdevila, Francisco, Carini, Claudio, Fisher, Benjamin A., Goodyear, Carl S., Emery, Paul, Ehrenstein, Michael R., Gozzard, Neil, Harris, Ray, Hollis, Sally, Keidel, Sarah, Levesque, Marc, Lindholm, Catharina, McDermott, Michael F., McInnes, Iain B., Mela, Christopher M., Parker, Gerry, Read, Simon, Pedersen, Ayako Wakatsuki, Ponchel, Frederique, Porter, Duncan, Rao, Ravi, Rowe, Anthony, Schulze-Knappe, Peter, Sleeman, Matthew A., Symmons, Deborah, Taylor, Peter C., Tom, Brian, Tsuji, Wayne, Verbeeck, Denny, and Isaacs, John D.

Abstract

Collaboration can be challenging; nevertheless, the emerging successes of large, multi-partner, multi-national cooperatives and research networks in the biomedical sector have sustained the appetite of academics and industry partners for developing and fostering new research consortia. This model has percolated down to national funding agencies across the globe, leading to funding for projects that aim to realise the true potential of genomic medicine in the 21st century and to reap the rewards of 'big data'. In this Perspectives article, the experiences of the RA-MAP consortium, a group of more than 140 individuals affiliated with 21 academic and industry organizations that are focused on making genomic medicine in rheumatoid arthritis a reality are described. The challenges of multi-partner collaboration in the UK are highlighted and wide-ranging solutions are offered that might benefit large research consortia around the world.

Published
2018
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31. PredictingTemperature-Dependent Aqueous Henry’sLaw Constants Using Group Contribution Methods.

Author

Brockbank, Sarah A., Giles, Neil F., Rowley, Richard L., and Wilding, Wade Vincent

Subjects
*AQUEOUS solutions, *HENRY'S law, *PREDICTION theory, *HYDROCARBONS, *BENZENE, *FUNCTIONAL groups
Abstract

A first-ordertemperature-dependent group contribution method wasdeveloped to predict Henry’s law constants of hydrocarbons,alcohols, ketones, and formates in which none of the functional groupsare attached directly to a benzene ring. Efforts to expand this methodto include ester and ether groups were unsuccessful. Second-ordergroups were developed at a reference condition of 298.15 K and 100kPa. A second-order temperature-dependent group contribution methodwas then developed for hydrocarbons, ketones, esters, ethers, andalcohols. These methods were compared to existing literature predictionmethods. [ABSTRACT FROM AUTHOR]

Published
2014
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32. Corrigendum: The RA-MAP Consortium: a working model for academia–industry collaboration

Author

Cope, Andrew P., Barnes, Michael R., Belson, Alexandra, Binks, Michael, Brockbank, Sarah, Bonachela-Capdevila, Francisco, Carini, Claudio, Fisher, Benjamin A., Goodyear, Carl S., Emery, Paul, Ehrenstein, Michael R., Gozzard, Neil, Harris, Ray, Hollis, Sally, Keidel, Sarah, Levesque, Marc, Lindholm, Catharina, McDermott, Michael F., McInnes, Iain B., Mela, Christopher M., Parker, Gerry, Read, Simon, Pedersen, Ayako Wakatsuki, Ponchel, Frederique, Porter, Duncan, Rao, Ravi, Rowe, Anthony, Schulze-Knappe, Peter, Sleeman, Matthew A., Symmons, Deborah, Taylor, Peter C., Tom, Brian, Tsuji, Wayne, Verbeeck, Denny, and Isaacs, John D.

Abstract

This corrects the article DOI: 10.1038/nrrheum.2017.200

Published
2018
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33. Interferon-α-mediated therapeutic resistance in early rheumatoid arthritis implicates epigenetic reprogramming

Author

Cooles, Faye, Tarn, Jessica, Lendrem, Dennis, Naamane, Najib, Lin, Chung Ma, Millar, Ben, Maney, Nicola, Anderson, Amy, Thalayasingam, Nishanthi, Diboll, Julie, Bondet, Vincent, Duffy, Darragh, Barnes, Michael, Smith, Graham, Ng, Sandra, Watson, David, Henkin, Rafael, Cope, Andrew, Reynard, Louise, Pratt, Arthur, Isaacs, John, Newcastle University [Newcastle], Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), William Harvey Research Institute, Barts and the London Medical School, University College of London [London] (UCL), King‘s College London, RA-MAP Consortium: Adwoa Hughes-Morley, Alexandra Walker, Alexandru Cuza, Amaya Gallagher-Syed, Amy Anderson, Andrea Haynes, Andrew Filer, Andrew Long, Andrew P Cope, Angela Parke, Anthony Rowe, Arnaud Didierlaurent, Ashley Gilmour, Athula Herath, Ayako Wakatsuki, Pedersen Aysin, Tulunay Virlan, Ben Allen, Benjamin A Fisher, Blerina Kola, Bohdan Harvey, Brian Tom, Carl S Goodyear, Carolyn Cuff, Catharien Hilkens, Catharina Lindholm, Catherine T Mela, Christopher D Buckley, Chris Larminie, Chris Marshall, Christopher John, Christopher M Mela, Claudio Carini, Costantino Pitzalis, Coziana Ciurtin, Dan Baker, Daniel Ziemek, Daniela Dastros-Pitei, Dao Nguyen, David L Scott, David S Watson, Deborah Symmons, Dennis Lendrem, Denny Verbeeck, Desmond Padhji, Donna Finch, Duncan Porter, Emma Vernon, Faye Cooles, Feng Hong, Fiona Clarke, Fiona Stirling, Fowzia Ibrahim, Frances Humby, Francisco Bonachela Capdevila, Frederic Geissmann, Frederique Ponchel, Gemma Molyneux, Gemma Simpson, Georgina Thorborn, Gerry Parker, Gioia Altobelli, Graham R Smith, Hannah Edwards, Hannah Tipney, Hans-Dieter Zucht, Hayley Noble, Heidi Lempp, Humayara AliIain B McInnes, Ian C Scott, Ian N BruceIona Donnelly, Ivana Vranic, James A Butler, James Galloway, Jamie C Sergeant, Jane Worthington, Jehan El-Jawhari, Jessica Tarn, Joanne Ellis, John Casement, John Isaacs, Julie Diboll, Karim Raza, Katriona Goldmann, Kirsty Hicks, Liliane Fossati-Jimack, Lucy Rowell, Marc Levesque, Mark C Coles, Mark Coles, Mark Curran, Martin Hodge, Martin Jenkins, Mateusz Maciejewski, Matt Page, Matthew A Sleeman, Matthew J Loza, Maya Buch, Meilien Ho, Michael Binks, Michael F McDermott, Michael Macoritto, Michael R Barnes, Michael R Ehrenstein, Michele Bombardieri, Myles Lewis, Neil Gozzard, Neil Payne, Neil Ward, Nina Joseph, Paul Emery, Peter C Taylor, Peter Schulz-Knappe, Petra Budde, Philip Jones, Philip Stocks, Rachel Harry, Rafael Henkin, Ravi Rao, Ray Harris, Rekha Parmar, Ruth Toward, Sally Hollis, Samana Schwank, Samantha Lipsky, Samiul Hasan, Sandra Martins, Sandra Ng, Sarah Brockbank, Sarah Keidel, Scott Jelinsky, Sharmila Rana, Simon Read, Stephen Kelly, Stephen Wright, Steve P Young, Sukru Kaymakcalan, Susan Talbot, Suzanne Mm Verstappen, Tomi Lazarov, Tony Sabin, Valerie Ludbrook, Vernon Farewell, Wayne Tsuji, Wing Wu, Wivine Burny, Yujie Zhong, Zheng Liu, Zhilong Jia, and Vougny, Marie-Christine

Subjects
[SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, antirheumatic agents, Rheumatology, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, inflammation, [SDV.IMM.IA] Life Sciences [q-bio]/Immunology/Adaptive immunology, immune system diseases, Immunology, arthritis, rheumatoid, Immunology and Allergy, General Biochemistry, Genetics and Molecular Biology
Abstract

ObjectivesAn interferon (IFN) gene signature (IGS) is present in approximately 50% of early, treatment naive rheumatoid arthritis (eRA) patients where it has been shown to negatively impact initial response to treatment. We wished to validate this effect and explore potential mechanisms of action.MethodsIn a multicentre inception cohort of eRA patients (n=191), we examined the whole blood IGS (MxA, IFI44L, OAS1, IFI6, ISG15) with reference to circulating IFN proteins, clinical outcomes and epigenetic influences on circulating CD19+ B and CD4+ T lymphocytes.ResultsWe reproduced our previous findings demonstrating a raised baseline IGS. We additionally showed, for the first time, that the IGS in eRA reflects circulating IFN-α protein. Paired longitudinal analysis demonstrated a significant reduction between baseline and 6-month IGS and IFN-α levels (pPARP9, STAT1,andEPSTI1, associated with baseline IGS/IFNα levels. Differentially methylated CPG sites implicated altered transcription factor binding in B cells (GATA3, ETSI, NFATC2, EZH2) and T cells (p300, HIF1α).ConclusionsOur data suggest that, in eRA, IFN-α can cause a sustained, epigenetically mediated, pathogenic increase in lymphocyte activation and proliferation, and that the IGS is, therefore, a robust prognostic biomarker. Its persistent harmful effects provide a rationale for the initial therapeutic targeting of IFN-α in selected patients with eRA.

Published
2022
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34. Addition of trans fat and alcohol has divergent effects on atherogenic diet-induced liver injury in rodent models of steatohepatitis.

Author

Daniels SJ, Leeming DJ, Detlefsen S, Bruun MF, Hjuler ST, Henriksen K, Hein P, Krag A, Karsdal MA, Nielsen MJ, Brockbank S, and Cruwys S

Subjects
Alanine Transaminase blood, Animals, Aspartate Aminotransferases blood, Biomarkers blood, Disease Models, Animal, Dyslipidemias etiology, Dyslipidemias metabolism, Dyslipidemias pathology, Fatty Liver, Alcoholic metabolism, Fatty Liver, Alcoholic pathology, Hepatomegaly etiology, Hepatomegaly metabolism, Hepatomegaly pathology, Lipid Metabolism, Liver metabolism, Liver Cirrhosis, Alcoholic etiology, Liver Cirrhosis, Alcoholic metabolism, Liver Cirrhosis, Alcoholic pathology, Male, Non-alcoholic Fatty Liver Disease metabolism, Non-alcoholic Fatty Liver Disease pathology, Obesity etiology, Obesity metabolism, Obesity pathology, Oxidative Stress, Peptide Fragments metabolism, Procollagen metabolism, Rats, Sprague-Dawley, Binge Drinking complications, Diet, Atherogenic, Fatty Liver, Alcoholic etiology, Liver pathology, Non-alcoholic Fatty Liver Disease etiology, Trans Fatty Acids
Abstract

Nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) are common causes of chronic liver disease. The overlap between ALD and NAFLD suggests the existence of metabolic steatohepatitis. Development of in vivo models that reflect various aspects of human steatohepatitis is essential for drug discovery. We aimed to characterize several models of steatohepatitis (SH) and to investigate whether the pathology could be modulated. Sprague-Dawley rats were fed a high-fat diet (HFD) for 9 wk, followed by either a high-fat, high-cholesterol and cholate diet (HFC) or a HFC diet containing 13% trans fat (HFC-TF). A subset received 15% ethanol-water twice a week for 12 wk. Serum triglycerides, cholesterol, LDL, HDL, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and rodent NH 2 -terminal propeptide of type III collagen (rPRO-C3) were assessed. The liver was weighed and evaluated using modified Nonalcoholic Steatohepatitis Clinical Research Network histological score system criteria. All diets induced hepatomegaly, but only HFC-TF increased the size of visceral adipose tissue. Trans fat augmented HFC-induced dyslipidemia, and cholesterol was higher and HDL was lower in the HFC-TF groups. Alcohol lowered triglycerides in both dietary groups. HFC elevated ALT and AST, which were lowered by trans fat. All diets induced histological SH, addition of trans fat induced more steatosis but less inflammation. Inclusion of alcohol augmented the HFC-induced inflammation. All diets induced mild fibrosis. Inclusion of trans fat and alcohol significantly increased rPRO-C3. The addition of trans fat reduced the HFC-induced inflammation but augmented steatosis and dyslipidemia. Inclusion of alcohol induced a more inflammatory and fibrogenic phenotype. NEW & NOTEWORTHY Alcoholic liver disease and nonalcoholic liver disease share significant overlap, which suggests the existence of metabolic steatohepatitis. Trans fat has been implicated in steatohepatitis development. Here, we show that the addition of trans fat to an atherogenic diet results in a more steatotic but less inflammatory phenotype, whereas the addition of alcohol to an atherogenic diet augments the inflammatory and fibrogenic properties of the diet.

Published
2020
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