Publications by authors named "Chris Chamberlain"

8 Publications

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Integrative Analysis Reveals a Molecular Stratification of Systemic Autoimmune Diseases.

Authors:
Guillermo Barturen Sepideh Babaei Francesc Català-Moll Manuel Martínez-Bueno Zuzanna Makowska Jordi Martorell-Marugán Pedro Carmona-Sáez Daniel Toro-Domínguez Elena Carnero-Montoro María Teruel Martin Kerick Marialbert Acosta-Herrera Lucas Le Lann Christophe Jamin Javier Rodríguez-Ubreva Antonio García-Gómez Jorge Kageyama Anne Buttgereit Sikander Hayat Joerg Mueller Ralf Lesche Maria Hernandez-Fuentes Maria Juarez Tania Rowley Ian White Concepción Marañón Tania Gomes Anjos Nieves Varela Rocío Aguilar-Quesada Francisco Javier Garrancho Antonio López-Berrio Manuel Rodriguez Maresca Héctor Navarro-Linares Isabel Almeida Nancy Azevedo Mariana Brandão Ana Campar Raquel Faria Fátima Farinha António Marinho Esmeralda Neves Ana Tavares Carlos Vasconcelos Elena Trombetta Gaia Montanelli Barbara Vigone Damiana Alvarez-Errico Tianlu Li Ricardo Blanco Alonso Alfonso Corrales Martínez Fernanda Genre Raquel López Mejías Miguel A Gonzalez-Gay Sara Remuzgo Begoña Ubilla Garcia Ricard Cervera Gerard Espinosa Ignasi Rodríguez-Pintó Ellen De Langhe Jonathan Cremer Rik Lories Doreen Belz Nicolas Hunzelmann Niklas Baerlecken Katja Kniesch Torsten Witte Michaela Lehner Georg Stummvoll Michael Zauner Maria Angeles Aguirre-Zamorano Nuria Barbarroja Maria Carmen Castro-Villegas Eduardo Collantes-Estevez Enrique de Ramon Isabel Díaz Quintero Alejandro Escudero-Contreras María Concepción Fernández Roldán Yolanda Jiménez Gómez Inmaculada Jiménez Moleón Rosario Lopez-Pedrera Rafaela Ortega-Castro Norberto Ortego Enrique Raya Carolina Artusi Maria Gerosa Pier Luigi Meroni Tommaso Schioppo Aurélie De Groof Julie Ducreux Bernard Lauwerys Anne-Lise Maudoux Divi Cornec Valérie Devauchelle-Pensec Sandrine Jousse-Joulin Pierre-Emmanuel Jouve Bénédicte Rouvière Alain Saraux Quentin Simon Montserrat Alvarez Carlo Chizzolini Aleksandra Dufour Donatienne Wynar Attila Balog Márta Bocskai Magdolna Deák Sonja Dulic Gabriella Kádár László Kovács Qingyu Cheng Velia Gerl Falk Hiepe Laleh Khodadadi Silvia Thiel Emanuele de Rinaldis Sambasiva Rao Robert J Benschop Chris Chamberlain Ernst R Dow Yiannis Ioannou Laurence Laigle Jacqueline Marovac Jerome Wojcik Yves Renaudineau Maria Orietta Borghi Johan Frostegård Javier Martín Lorenzo Beretta Esteban Ballestar Fiona McDonald Jacques-Olivier Pers Marta E Alarcón-Riquelme

Arthritis Rheumatol 2020 Dec 8. Epub 2020 Dec 8.

Department of Medical Genomics, Center for Genomics and Oncological Research (GENYO), Granada, Spain.

Objective: Clinical heterogeneity, a hallmark of systemic autoimmune diseases (SADs) impedes early diagnosis and effective treatment, issues that may be addressed if patients could be grouped into a molecular defined stratification.

Methods: With the aim of reclassifying SADs independently of the clinical diagnoses, unsupervised clustering of integrated whole blood transcriptome and methylome cross-sectional data of 955 patients with 7 SADs and 267 healthy controls was undertaken. In addition, an inception cohort was prospectively followed for 6 and 14 months to validate the results and analyze if cluster assignment changed or not with time.

Results: Four clusters were identified and validated. Three were pathological representing 'inflammatory', 'lymphoid', and 'interferon' patterns each including all diagnoses and defined by genetic, clinical, serological, and cellular features. A fourth cluster with no specific molecular pattern associated with low activity, and accumulated also healthy controls. A longitudinal and independent inception cohort showed a relapse-remission pattern, where patients remained in their pathological cluster, moving only to the healthy one, thus showing that with time, the molecular clusters remain stable and that single pathogenic molecular signatures characterize each individual patient.

Conclusions: Patients with SADs can be jointly stratified into three stable disease clusters with specific molecular patterns differentiating different molecular disease mechanisms. These results have important implications for future clinical trials and the study of therapy non-responsiveness marking a paradigm shift in our view of SADs.
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http://dx.doi.org/10.1002/art.41610DOI Listing
December 2020

Repeated administration of dapirolizumab pegol in a randomised phase I study is well tolerated and accompanied by improvements in several composite measures of systemic lupus erythematosus disease activity and changes in whole blood transcriptomic profiles.

Ann Rheum Dis 2017 Nov 5;76(11):1837-1844. Epub 2017 Aug 5.

Department of Rheumatology and Clinical Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany.

Objectives: Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease associated with diffuse immune cell dysfunction. CD40-CD40 ligand (CD40L) interaction activates B cells, antigen-presenting cells and platelets. CD40L blockade might provide an innovative treatment for systemic autoimmune disorders. We investigated the safety and clinical activity of dapirolizumab pegol, a polyethylene glycol conjugated anti-CD40L Fab' fragment, in patients with SLE.

Methods: This 32-week randomised, double-blind, multicentre study (NCT01764594) evaluated repeated intravenous administration of dapirolizumab pegol in patients with SLE who were positive for/had history of antidouble stranded DNA/antinuclear antibodies and were on stable doses of immunomodulatory therapies (if applicable). Sixteen patients were randomised to 30 mg/kg dapirolizumab pegol followed by 15 mg/kg every 2 weeks for 10 weeks; eight patients received a matched placebo regimen. Randomisation was stratified by evidence of antiphospholipid antibodies. Patients were followed for 18 weeks after the final dose.

Results: No serious treatment-emergent adverse events, thromboembolic events or deaths occurred. Adverse events were mild or moderate, transient and resolved without intervention. One patient withdrew due to infection.Efficacy assessments were conducted only in patients with high disease activity at baseline. Five of 11 (46%) dapirolizumab pegol-treated patients achieved British Isles Lupus Assessment Group-based Composite Lupus Assessment response (vs 1/7; 14% placebo) and 5/12 (42%) evaluable for SLE Responder Index-4 responded by week 12 (vs 1/7; 14% placebo). Mechanism-related gene expression changes were observed in blood RNA samples.

Conclusions: Dapirolizumab pegol could be an effective biological treatment for SLE. Further studies are required to address efficacy and safety.

Trial Registration Number: NCT01764594.
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http://dx.doi.org/10.1136/annrheumdis-2017-211388DOI Listing
November 2017

Omics studies: their use in diagnosis and reclassification of SLE and other systemic autoimmune diseases.

Rheumatology (Oxford) 2017 04;56(suppl_1):i78-i87

Parque Tecnológico de la Salud, Medical Genomics, Centre Pfizer, University of Granada, Andalusian Regional Government for Genomics and Oncological Research, Granada, Spain.

Omics studies of systemic autoimmune diseases (SADs) in general, and SLE in particular, have delivered isolated information from transcriptome, epigenome, genome, cytokine and metabolome analyses. Such analyses have resulted in the identification of disease susceptibility genes and the description of IFN expression signatures, allowing extensive insight into the mechanisms of disease and the development of new therapies. Access to such technologies allows the recognition of patterns of disease at a pathway level, thereby, to reclassify SLE and other SADs and to develop new therapeutics from a personalized perspective. The use of omic information allows the discovery of correlative patterns involving drugs not currently suspected to be of value in SADs. In this review, we summarize the omics findings for SLE and propose ways of using the data for the identification of new biomarkers, finding new drugs and reclassifying patients not only with SLE, but also with other SADs.
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http://dx.doi.org/10.1093/rheumatology/kew339DOI Listing
April 2017

Towards the taxonomy of human disease.

Nat Rev Drug Discov 2015 02;14(2):75-6

New Medicines, UCB, 208 Bath Road, Slough, SL1 4EN, UK.

Consortia have begun to establish 'mechanism-based taxonomies' for inflammatory and neurodegenerative diseases that could aid drug development and personalized therapy.
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http://dx.doi.org/10.1038/nrd4537DOI Listing
February 2015

Patient Characteristics are not Associated with Clinically Important Differential Response to Dapagliflozin: a Staged Analysis of Phase 3 Data.

Diabetes Ther 2014 Dec 12;5(2):471-82. Epub 2014 Dec 12.

AstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TF, UK.

Introduction: This study aimed to determine if data mining methodologies could identify reproducible predictors of dapagliflozin-specific treatment response in the phase 3 clinical program dataset.

Methods: Baseline and early treatment response variables were selected and data mining used to identify/rank all variables associated with reduction in glycated hemoglobin (HbA1c) at week 26. Generalized linear modeling was then employed using an independent dataset to identify which (if any) variables were predictive of dapagliflozin-specific treatment response as compared with treatment response in the study's control arm. The most parsimonious (i.e., simplest) model was validated by meta-analysis of nine other trials. This staged approach was used to minimize risk of type I errors.

Results: From the large dataset, 22 variables were selected for model generation as potentially predictive for dapagliflozin-specific reduction in HbA1c. Although baseline HbA1c was the variable most strongly associated with reduction in HbA1c at study end (i.e., the best prognostic variable), baseline fasting plasma glucose (FPG) was the only predictive dapagliflozin-specific variable in the model. Placebo-adjusted treatment effect of dapagliflozin plus metformin vs. metformin alone for change in HbA1c from baseline was -0.65% at the average baseline FPG of 192.3 mg/dL (10.7 mmol/L). This response changed by -0.32% for every SD [57.2 mg/dL (3.2 mmol/L)] increase in baseline FPG. Effect of baseline FPG was confirmed in the meta-analysis of nine studies, but the magnitude was smaller. No other variable was independently predictive of a dapagliflozin-specific reduction in HbA1c.

Conclusions: This methodology successfully identified a reproducible baseline predictor of differential response to dapagliflozin. Although baseline FPG was shown to be a predictor, the effect size was not of sufficient magnitude to suggest clinical usefulness in identifying patients who would uniquely benefit from dapagliflozin treatment. The findings do support potential benefit for dapagliflozin treatment that is consistent with current recommended use.
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http://dx.doi.org/10.1007/s13300-014-0090-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4269640PMC
December 2014

Rheumatoid arthritis: a case for personalized health care?

Arthritis Care Res (Hoboken) 2014 Sep;66(9):1273-80

Nordic Bioscience, Herlev, Denmark.

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http://dx.doi.org/10.1002/acr.22289DOI Listing
September 2014

Rad21 is required for centrosome integrity in human cells independently of its role in chromosome cohesion.

Cell Cycle 2010 May 15;9(9):1774-80. Epub 2010 May 15.

Department of Genetics, Cell Biology & Development, University of Minnesota Medical School, Minneapolis, MN, USA.

Classically, chromosomal functions in DNA repair and sister chromatid association have been assigned to the cohesin proteins. More recent studies have provided evidence that cohesins also localize to the centrosomes, which organize the bipolar spindle during mitosis. Depletion of cohesin proteins is associated with multi-polar mitosis in which spindle pole integrity is compromised. However, the spindle pole defects after cohesin depletion could be an indirect consequence of a chromosomal cohesion defect which might impact centrosome integrity via alterations to the spindle microtubule network. Here we show that the cohesin Rad21 is required for centrosome integrity independently of its role as a chromosomal cohesin. Thus, Rad21 may promote accurate chromosome transmission not only by virtue of its function as a chromosomal cohesin, but also because it is required for centrosome function.
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http://dx.doi.org/10.4161/cc.9.9.11524DOI Listing
May 2010

Nurse discharge planning in the emergency department: a Toowoomba, Australia, study.

J Clin Nurs 2006 Aug;15(8):1033-44

University of Queensland, University of Southern Queensland and Toowoomba Health Service, Toowoomba, Qld, Australia.

Aim: This study aimed to ascertain whether a model of risk screening carried out by an experienced community nurse was effective in decreasing re-presentations and readmissions and the length of stay of older people presenting to an Australian emergency department.

Objectives: The objectives of the study were to (i) identify all older people who presented to the emergency department of an Australian regional hospital; (ii) identify the proportion of re-presentations and readmissions within this cohort of patients; and (iii) risk-screen all older patients and provide referrals when necessary to community services.

Design: The study involved the application of a risk screening tool to 2,139 men and women over 70 years of age from October 2002 to June 2003. Of these, 1,102 (51.5%) were admitted and 246 (11.5%) were re-presentations with the same illness. Patients presenting from Monday to Friday from 08:00 to 16:00 hours were risk-screened face to face in the emergency department. Outside of these hours, but within 72 hours of presentation, risk screening was carried out by telephone if the patient was discharged or within the ward if the patient had been admitted.

Results: There was a 16% decrease in the re-presentation rate of people over 70 years of age to the emergency department. Additionally during this time there was a 5.5% decrease in the readmission rate (this decrease did not reach significance). There was a decrease in the average length of stay in hospital from 6.17 days per patient in October 2002 to 5.37 days per patient in June 2003. An unexpected finding was the decrease in re-presentations in people who represented to the emergency department three or more times per month (known as 'frequent flyers').

Conclusions: Risk screening of older people in the emergency department by a specialist community nurse resulted in a decrease of re-presentations to the emergency department. There was some evidence of a decreased length of stay. It is suggested that the decrease in re-presentations was the result of increased referral and use of community services. It appears that the use of a specialist community nurse to undertake risk screening rather than the triage nurse may impact on service utilization.

Relevance To Clinical Practice: It is apparent that older people presenting to the emergency department have complex care needs. Undertaking risk screening using an experienced community nurse to ascertain the correct level of community assistance required and ensuring speedy referral to appropriate community services has positive outcomes for both the hospital and the patient.
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http://dx.doi.org/10.1111/j.1365-2702.2006.01405.xDOI Listing
August 2006