119 results on '"Maciewicz, Rose A."'
Search Results
102. Transmission densitometry of stained nitrocellulose paper
- Author
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Maciewicz, Rose A., primary and Knight, Peter J., additional
- Published
- 1988
- Full Text
- View/download PDF
103. Effects of shearing on chromatin structure
- Author
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Maciewicz, Rose A., primary and Li, Hsueh Jei, additional
- Published
- 1978
- Full Text
- View/download PDF
104. Studies on the activation mechanism for the precursor to cathepsin L
- Author
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MACIEWICZ, ROSE A., primary, WARDALE, R. JOHN, additional, and ETHERINGTON, DAVID J., additional
- Published
- 1988
- Full Text
- View/download PDF
105. Association of Beta-Blocker Use With Less Prevalent Joint Pain and Lower Opioid Requirement in People With Osteoarthritis.
- Author
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Valdes, Ana M, Abhishek, Abhishek, Muir, Kenneth, Zhang, Weiya, Maciewicz, Rose A, and Doherty, Michael
- Subjects
OSTEOARTHRITIS diagnosis ,HIP joint diseases diagnosis ,ADRENERGIC beta blockers ,ANALGESICS ,COMBINATION drug therapy ,HIP joint diseases ,KNEE diseases ,LONGITUDINAL method ,NARCOTICS ,OSTEOARTHRITIS ,RESEARCH funding ,PAIN measurement ,DISEASE prevalence ,CROSS-sectional method ,CASE-control method ,JOINT pain ,DIAGNOSIS - Abstract
Objective: Recent findings suggest that β-adrenergic blockers have antinociceptive properties. The aim of this study was to compare levels of large-joint pain between those taking adrenergic blockers and those taking other antihypertensive medications.Methods: Data from the Genetics of Osteoarthritis and Lifestyle (GOAL) study, a secondary-care cohort of osteoarthritis (OA) patients, were used. Joint pain was assessed using Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain scores in 873 individuals with symptomatic hip and/or knee OA and hypertension, who were taking ≥1 prescription antihypertensive medications. The association between adrenergic blocker prescription and at least moderate joint pain (WOMAC score <75) and use of prescription analgesics was examined using binary logistic regression. Analyses were adjusted for age, sex, body mass index, knee or hip OA, history of joint replacement (at other joints), anxiety, and depression.Results: The use of β-adrenergic blockers was associated with lower WOMAC pain scores and with a lower prevalence of joint pain after adjustment for demographic variables and comorbidity (adjusted odds ratio [ORadj ] for pain 0.68 [95% confidence interval (95% CI) 0.51, 0.92]; P < 0.011). No associations with pain were observed with use of alpha-blockers (ORadj for pain 0.94 [95% CI 0.55, 1.58]) or with any other class of antihypertensive medications. Prescription of beta-blockers was also associated negatively with opioid use (ORadj for opioids 0.73 [95% CI 0.54, 0.98]; P < 0.037) and with the use of prescription analgesics in general (ORadj for analgesics 0.74 [95% CI 0.56, 0.94]; P < 0.032).Conclusion: The use of beta-blockers is associated with less joint pain and a lower use of opioids and other analgesics in individuals with symptomatic large-joint OA. This observation needs to be confirmed by other studies. [ABSTRACT FROM AUTHOR]- Published
- 2016
- Full Text
- View/download PDF
106. The association between ANKHpromoter polymorphism and chondrocalcinosis is independent of age and osteoarthritis: results of a case?control study
- Author
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Abhishek, Abhishek, Doherty, Sally, Maciewicz, Rose, Muir, Kenneth, Zhang, Weiya, Doherty, Michael, and Valdes, Anna
- Abstract
Chondrocalcinosis (CC) most commonly results from calcium pyrophosphate crystal deposition (CPPD). The objective of this study is to examine the association between candidate single-nucleotide polymorphisms (SNPs) and radiographic CC.
- Published
- 2014
- Full Text
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107. Upper Airway Cell Transcriptomics Identify a Major New Immunological Phenotype with Strong Clinical Correlates in Young Children with Acute Wheezing.
- Author
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Siew-Kim Khoo, Read, James, Franks, Kimberley, Guicheng Zhang, Bizzintino, Joelene, Coleman, Laura, McCrae, Christopher, Öberg, Lisa, Troy, Niamh M., Prastanti, Franciska, Everard, Janet, Oo, Stephen, Borland, Meredith L., Maciewicz, Rose A., Souëf, Peter N. Le, Laing, Ingrid A., and Bosco, Anthony
- Subjects
- *
WHEEZE , *COUGH , *COMMON cold , *ASTHMA in children , *PHENOTYPES , *AIRWAY (Anatomy) , *GENE regulatory networks - Abstract
Asthma exacerbations are triggered by rhinovirus infections. We employed a systems biology approach to delineate upper-airway gene network patterns underlying asthma exacerbation phenotypes in children. Cluster analysis unveiled distinct IRF7hi versus IRF7lo molecular phenotypes, the former exhibiting robust upregulation of Th1/type I IFN responses and the latter an alternative signature marked by upregulation of cytokine and growth factor signaling and downregulation of IFN-γ. The two phenotypes also produced distinct clinical phenotypes. For IRF7lo children, symptom duration prior to hospital presentation was more than twice as long from initial symptoms (p = 0.011) and nearly three times as long for cough (p < 0.001), the odds ratio of admission to hospital was increased more than 4-fold (p = 0.018), and time to recurrence was shorter (p = 0.015). In summary, our findings demonstrate that asthma exacerbations in children can be divided into IRF7hi versus IRF7lo phenotypes with associated differences in clinical phenotypes. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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- View/download PDF
108. Integrin α5β1 and ADAM-17 Interact in Vitro and Co-localize in Migrating HeLa Cells.
- Author
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Bax, Daniel V., Messent, Anthea J., Tart, Jonathan, van Hoang, Mien, Kott, Jan, Maciewicz, Rose A., and Humphries, Martin J.
- Subjects
- *
TUMOR necrosis factors , *CELL membranes , *PROTEOLYTIC enzymes , *PROTEOLYSIS , *ANTI-inflammatory agents , *LIGAND binding (Biochemistry) - Abstract
Tumor necrosis factor (TNF) α-converting enzyme (TACE/ADAM-17) has diverse roles in the proteolytic processing of cell surface molecules and, due to its ability to process TNFα is a validated therapeutic target for anti-inflammatory therapies. Unlike a number of other ADAM proteins, which interact with integrin receptors via their disintegrin domains, there is currently no evidence for an ADAM-17-integrin association. By analyzing the adhesion of a series of cell lines with recombinant fragments of the extracellular domain of ADAM-17, we now demonstrate a functional interaction between ADAM-17 and α5β3 integrin in a trans orientation. Because ADAM-17-mediated adhesion was sensitive to RGD peptides and EDTA, and the integrin-binding site within ADAM-17 was narrowed down to the disintegrin/ cysteine-rich region, the two molecules appear to have a ligand-receptor relationship mediated by the α5β1 ligand binding pocket. Intriguingly, ADAM-17 and α5β1 were found to co-localize in both membrane ruffles and focal adhesions in HeLa cells. When confluent HeLa cell monolayers were wounded, ADAM-17 and α5β1 redistributed to the leading edge and co-localized, which is suggestive of a cis orientation. We postulate that the interaction of ADAM-17 with α5β1 may target or modulate its metalloproteolytic activity. [ABSTRACT FROM AUTHOR]
- Published
- 2004
- Full Text
- View/download PDF
109. MEK inhibition drives anti-viral defence in RV but not RSV challenged human airway epithelial cells through AKT/p70S6K/4E-BP1 signalling.
- Author
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Baturcam, Engin, Vollmer, Stefan, Schlüter, Holger, Maciewicz, Rose A., Kurian, Nisha, Vaarala, Outi, Ludwig, Stephan, and Cunoosamy, Danen Mootoosamy
- Subjects
- *
EPITHELIAL cells , *MITOGEN-activated protein kinases , *TYPE I interferons , *RESPIRATORY syncytial virus , *VIRAL load , *RESPIRATORY infections - Abstract
Background: The airway epithelium is a major target tissue in respiratory infections, and its antiviral response is mainly orchestrated by the interferon regulatory factor-3 (IRF3), which subsequently induces type I (β) and III (λ) interferon (IFN) signalling. Dual specificity mitogen-activated protein kinase kinase (MEK) pathway contributes to epithelial defence, but its role in the regulation of IFN response in human primary airway epithelial cells (AECs) is not fully understood. Here, we studied the impact of a small-molecule inhibitor (MEKi) on the IFN response following challenge with two major respiratory viruses rhinovirus (RV2) and respiratory syncytial virus (RSVA2) and a TLR3 agonist, poly(I:C). Methods: The impact of MEKi on viral load and IFN response was evaluated in primary AECs with or without a neutralising antibody against IFN-β. Quantification of viral load was determined by live virus assay and absolute quantification using qRT-PCR. Secretion of cytokines was determined by AlphaLISA/ELISA and expression of interferon-stimulated genes (ISGs) was examined by qRT-PCR and immunoblotting. A poly(I:C) model was also used to further understand the molecular mechanism by which MEK controls IFN response. AlphaLISA, siRNA-interference, immunoblotting, and confocal microscopy was used to investigate the effect of MEKi on IRF3 activation and signalling. The impact of MEKi on ERK and AKT signalling was evaluated by immunoblotting and AlphaLISA. Results: Here, we report that pharmacological inhibition of MEK pathway augments IRF3-driven type I and III IFN response in primary human AECs. MEKi induced activation of PI3K-AKT pathway, which was associated with phosphorylation/inactivation of the translational repressor 4E-BP1 and activation of the protein synthesis regulator p70 S6 kinase, two critical translational effectors. Elevated IFN-β response due to MEKi was also attributed to decreased STAT3 activation, which consequently dampened expression of the transcriptional repressor of IFNB1 gene, PRDI-BF1. Augmented IFN response translated into inhibition of rhinovirus 2 replication in primary AECs but not respiratory syncytial virus A2. Conclusions: Our findings unveil MEK as a key molecular mechanism by which rhinovirus dampens the epithelial cell's antiviral response. Our study provides a better understanding of the role of signalling pathways in shaping the antiviral response and suggests the use of MEK inhibitors in anti-viral therapy against RV. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
110. Selective IL-27 production by intestinal regulatory T cells permits gut-specific regulation of T H 17 cell immunity.
- Author
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Lin CH, Wu CJ, Cho S, Patkar R, Huth WJ, Lin LL, Chen MC, Israelsson E, Betts J, Niedzielska M, Patel SA, Duong HG, Gerner RR, Hsu CY, Catley M, Maciewicz RA, Chu H, Raffatellu M, Chang JT, and Lu LF
- Subjects
- Mice, Animals, T-Lymphocytes, Helper-Inducer, Immune Tolerance, Immunity, Cellular, Th17 Cells, T-Lymphocytes, Regulatory, Interleukin-27
- Abstract
Regulatory T cells (T
reg cells) are instrumental in establishing immunological tolerance. However, the precise effector mechanisms by which Treg cells control a specific type of immune response in a given tissue remains unresolved. By simultaneously studying Treg cells from different tissue origins under systemic autoimmunity, in the present study we show that interleukin (IL)-27 is specifically produced by intestinal Treg cells to regulate helper T17 cell (TH 17 cell) immunity. Selectively increased intestinal TH 17 cell responses in mice with Treg cell-specific IL-27 ablation led to exacerbated intestinal inflammation and colitis-associated cancer, but also helped protect against enteric bacterial infection. Furthermore, single-cell transcriptomic analysis has identified a CD83+ CD62Llo Treg cell subset that is distinct from previously characterized intestinal Treg cell populations as the main IL-27 producers. Collectively, our study uncovers a new Treg cell suppression mechanism crucial for controlling a specific type of immune response in a particular tissue and provides further mechanistic insights into tissue-specific Treg cell-mediated immune regulation., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)- Published
- 2023
- Full Text
- View/download PDF
111. Selective IL-27 production by intestinal regulatory T cells permits gut-specific regulation of Th17 immunity.
- Author
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Lin CH, Wu CJ, Cho S, Patkar R, Lin LL, Chen MC, Israelsson E, Betts J, Niedzielska M, Patel SA, Duong HG, Gerner RR, Hsu CY, Catley M, Maciewicz RA, Chu H, Raffatellu M, Chang JT, and Lu LF
- Abstract
Regulatory T (Treg) cells are instrumental in establishing immunological tolerance. However, the precise effector mechanisms by which Treg cells control a specific type of immune response in a given tissue remains unresolved. By simultaneously studying Treg cells from different tissue origins under systemic autoimmunity, here we show that IL-27 is specifically produced by intestinal Treg cells to regulate Th17 immunity. Selectively increased intestinal Th17 responses in mice with Treg cell-specific IL-27 ablation led to exacerbated intestinal inflammation and colitis-associated cancer, but also helped protect against enteric bacterial infection. Furthermore, single-cell transcriptomic analysis has identified a CD83
+ TCF1+ Treg cell subset that is distinct from previously characterized intestinal Treg cell populations as the main IL-27 producers. Collectively, our study uncovers a novel Treg cell suppression mechanism crucial for controlling a specific type of immune response in a particular tissue, and provides further mechanistic insights into tissue-specific Treg cell-mediated immune regulation., Competing Interests: Declaration of interests E.I., J.B., M.N., M.C., and R.A.M are or were employees of AstraZeneca and may own stock or stock options.- Published
- 2023
- Full Text
- View/download PDF
112. Searchlight: automated bulk RNA-seq exploration and visualisation using dynamically generated R scripts.
- Author
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Cole JJ, Faydaci BA, McGuinness D, Shaw R, Maciewicz RA, Robertson NA, and Goodyear CS
- Subjects
- RNA-Seq, Exome Sequencing, Workflow, Publications, Software
- Abstract
Background: Once bulk RNA-seq data has been processed, i.e. aligned and then expression and differential tables generated, there remains the essential process where the biology is explored, visualized and interpreted. Without the use of a visualisation and interpretation pipeline this step can be time consuming and laborious, and is often completed using R. Though commercial visualisation and interpretation pipelines are comprehensive, freely available pipelines are currently more limited., Results: Here we demonstrate Searchlight, a freely available bulk RNA-seq visualisation and interpretation pipeline. Searchlight provides: a comprehensive statistical and visual analysis, focusing on the global, pathway and single gene levels; compatibility with most differential experimental designs irrespective of organism or experimental complexity, via three workflows; reports; and support for downstream user modification of plots via user-friendly R-scripts and a Shiny app. We show that Searchlight offers greater automation than current best tools (VIPER and BioJupies). We demonstrate in a timed re-analysis study, that alongside a standard bulk RNA-seq processing pipeline, Searchlight can be used to complete bulk RNA-seq projects up to the point of manuscript quality figures, in under 3 h., Conclusions: Compared to a manual R based analysis or current best freely available pipelines (VIPER and BioJupies), Searchlight can reduce the time and effort needed to complete bulk RNA-seq projects to manuscript level. Searchlight is suitable for bioinformaticians, service providers and bench scientists. https://github.com/Searchlight2/Searchlight2 ., (© 2021. The Author(s).)
- Published
- 2021
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113. Phenotypic screening identifies Axl kinase as a negative regulator of an alveolar epithelial cell phenotype.
- Author
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Fujino N, Kubo H, and Maciewicz RA
- Subjects
- Animals, Cells, Cultured, Down-Regulation, Humans, Lung Diseases, Mice, Phenotype, Phosphorylation, Axl Receptor Tyrosine Kinase, Alveolar Epithelial Cells metabolism, Multipotent Stem Cells metabolism, Proto-Oncogene Proteins metabolism, Receptor Protein-Tyrosine Kinases metabolism, Transcription Factors metabolism
- Abstract
Loss of epithelial barrier integrity is implicated in a number of human lung diseases. However, the molecular pathways underlying this process are poorly understood. In a phenotypic screen, we identified Axl kinase as a negative regulator of epithelial phenotype and function. Furthermore, suppression of Axl activity by a small molecule kinase inhibitor or downregulation of Axl expression by small interfering RNA led to: (1) the increase in epithelial surfactant protein expression; (2) a cell morphology transition from front-rear polarity to cuboidal shape; (3) the cytoskeletal re-organization resulting in decreased cell mobility; and (4) the acquisition of epithelial junctions. Loss of Axl activity reduced activation of the Axl canonical pathway members, Akt and extracellular signal-regulated kinase-1/2 and resulted in the loss of gene expression of a unique profile of epithelial-to-mesenchymal transition transcription factors including SNAI2, HOXA5, TBX2 or TBX3. Finally, we observed that Axl was activated in hyperplasia of epithelial cells in idiopathic pulmonary fibrosis where epithelial barrier integrity was lost. These results suggest that the Axl kinase signaling pathway is associated with the loss integrity of alveolar epithelium in pathological remodeling of human lung diseases.
- Published
- 2017
- Full Text
- View/download PDF
114. Novel Genetic Variants for Cartilage Thickness and Hip Osteoarthritis.
- Author
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Castaño-Betancourt MC, Evans DS, Ramos YF, Boer CG, Metrustry S, Liu Y, den Hollander W, van Rooij J, Kraus VB, Yau MS, Mitchell BD, Muir K, Hofman A, Doherty M, Doherty S, Zhang W, Kraaij R, Rivadeneira F, Barrett-Connor E, Maciewicz RA, Arden N, Nelissen RG, Kloppenburg M, Jordan JM, Nevitt MC, Slagboom EP, Hart DJ, Lafeber F, Styrkarsdottir U, Zeggini E, Evangelou E, Spector TD, Uitterlinden AG, Lane NE, Meulenbelt I, Valdes AM, and van Meurs JB
- Subjects
- Aged, Aged, 80 and over, Cartilage pathology, Class Ia Phosphatidylinositol 3-Kinase, Female, Genetic Heterogeneity, Genetic Predisposition to Disease, Genome-Wide Association Study, Hip Joint physiopathology, Humans, Male, Middle Aged, Osteoarthritis, Hip pathology, Polymorphism, Single Nucleotide, Regulatory Sequences, Nucleic Acid genetics, Osteoarthritis, Hip genetics, Phosphatidylinositol 3-Kinases genetics, Receptor, Fibroblast Growth Factor, Type 3 genetics, Transforming Growth Factor alpha genetics, Trehalase genetics
- Abstract
Osteoarthritis is one of the most frequent and disabling diseases of the elderly. Only few genetic variants have been identified for osteoarthritis, which is partly due to large phenotype heterogeneity. To reduce heterogeneity, we here examined cartilage thickness, one of the structural components of joint health. We conducted a genome-wide association study of minimal joint space width (mJSW), a proxy for cartilage thickness, in a discovery set of 13,013 participants from five different cohorts and replication in 8,227 individuals from seven independent cohorts. We identified five genome-wide significant (GWS, P≤5·0×10-8) SNPs annotated to four distinct loci. In addition, we found two additional loci that were significantly replicated, but results of combined meta-analysis fell just below the genome wide significance threshold. The four novel associated genetic loci were located in/near TGFA (rs2862851), PIK3R1 (rs10471753), SLBP/FGFR3 (rs2236995), and TREH/DDX6 (rs496547), while the other two (DOT1L and SUPT3H/RUNX2) were previously identified. A systematic prioritization for underlying causal genes was performed using diverse lines of evidence. Exome sequencing data (n = 2,050 individuals) indicated that there were no rare exonic variants that could explain the identified associations. In addition, TGFA, FGFR3 and PIK3R1 were differentially expressed in OA cartilage lesions versus non-lesioned cartilage in the same individuals. In conclusion, we identified four novel loci (TGFA, PIK3R1, FGFR3 and TREH) and confirmed two loci known to be associated with cartilage thickness.The identified associations were not caused by rare exonic variants. This is the first report linking TGFA to human OA, which may serve as a new target for future therapies., Competing Interests: The collection of GOAL samples was funded by Astra Zeneca UK. Dr R. Maciewicz has ownership of stocks or shares in AstraZeneca and has paid employment in AstraZeneca. Dr J. Jordan was funded for genotyping by Algynomics, Inc. and had, but no longer has, stock options in Algynomics. Dr. U. Styrkarsdottir is an employee of deCODE, a biotechnology company that provides genetic testing services. The set-up of the GARP study was partially funded by Pfzer. The GoGo study was funded by GlaxoSmithKline. The rest of the authors have declared that they have no competing interests.
- Published
- 2016
- Full Text
- View/download PDF
115. The Axl receptor tyrosine kinase is a discriminator of macrophage function in the inflamed lung.
- Author
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Fujimori T, Grabiec AM, Kaur M, Bell TJ, Fujino N, Cook PC, Svedberg FR, MacDonald AS, Maciewicz RA, Singh D, and Hussell T
- Subjects
- Animals, Female, Humans, Intercellular Signaling Peptides and Proteins genetics, Intercellular Signaling Peptides and Proteins immunology, Lung pathology, Macrophages pathology, Mice, Mice, Knockout, Organ Specificity, Orthomyxoviridae Infections genetics, Orthomyxoviridae Infections pathology, Pneumonia genetics, Pneumonia pathology, Protein S genetics, Protein S immunology, Proto-Oncogene Proteins genetics, Receptor Protein-Tyrosine Kinases genetics, Axl Receptor Tyrosine Kinase, Lung immunology, Macrophages immunology, Orthomyxoviridae Infections immunology, Pneumonia immunology, Proto-Oncogene Proteins immunology, Receptor Protein-Tyrosine Kinases immunology
- Abstract
Much of the biology surrounding macrophage functional specificity has arisen through examining inflammation-induced polarizing signals, but this also occurs in homeostasis, requiring tissue-specific environmental triggers that influence macrophage phenotype and function. The TAM receptor family of receptor tyrosine kinases (Tyro3, Axl and MerTK) mediates the non-inflammatory removal of apoptotic cells by phagocytes through the bridging phosphatidylserine-binding molecules growth arrest-specific 6 (Gas6) or Protein S. We show that one such TAM receptor (Axl) is exclusively expressed on mouse airway macrophages, but not interstitial macrophages and other lung leukocytes, under homeostatic conditions and is constitutively ligated to Gas6. Axl expression is potently induced by granulocyte-macrophage colony-stimulating factor expressed in the healthy and inflamed airway, and by type I interferon or Toll-like receptor-3 stimulation on human and mouse macrophages, indicating potential involvement of Axl in apoptotic cell removal under inflammatory conditions. Indeed, an absence of Axl does not cause sterile inflammation in health, but leads to exaggerated lung inflammatory disease upon influenza infection. These data imply that Axl allows specific identification of airway macrophages, and that its expression is critical for macrophage functional compartmentalization in the airspaces or lung interstitium. We propose that this may be a critical feature to prevent excessive inflammation because of secondary necrosis of apoptotic cells that have not been cleared by efferocytosis.
- Published
- 2015
- Full Text
- View/download PDF
116. Gene-environment interaction between body mass index and transforming growth factor beta 1 (TGFβ1) gene in knee and hip osteoarthritis.
- Author
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Muthuri SG, Doherty S, Zhang W, Maciewicz RA, Muir KR, and Doherty M
- Subjects
- Aged, Aged, 80 and over, Case-Control Studies, Female, Genetic Predisposition to Disease genetics, Genotype, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Body Mass Index, Gene-Environment Interaction, Osteoarthritis, Hip genetics, Osteoarthritis, Knee genetics, Transforming Growth Factor beta1 genetics
- Abstract
Introduction: The objective was to investigate potential gene-environment interaction between body mass index (BMI) and each of eight TGFβ1 polymorphisms in knee and hip osteoarthritis (OA)., Methods: We conducted a case-control study of Caucasian men and women aged 45 to 86 years from Nottingham, United Kingdom (Genetics of OA and Lifestyle (GOAL) study). Cases had clinically severe symptoms and radiographic knee or hip OA; controls had no symptoms and no radiographic knee/hip OA. We used logistic regression to investigate the association of TGFβ1 polymorphisms and OA when stratifying by BMI. Knee and hip OA were analyzed separately with adjustment for potential confounders. Additive and multiplicative interactions were examined., Results: 2,048 cases (1,042 knee OA, 1,006 hip OA) and 967 controls were studied. For hip OA, the highest risk was in overweight (BMI ≥ 25 kg/m2) individuals with the variant allele of single-nucleotide polymorphism (SNP) rs1800468 (odds ratio (OR) 2.21, 95% confidence interval (CI) 1.55, 3.15). Evaluation of gene-environment interaction indicated significant synergetic interaction (relative excess risk due to interaction (RERI) = 0.93, synergy index (SI) = 4.33) with an attributable proportion due to interaction (AP) of 42% (AP = 0.42; 95% CI 0.16, 0.68). Multiplicative interaction was also significant (OR for interaction (ORINT) = 2.27, P = 0.015). For knee OA, the highest risk was in overweight individuals with homozygous genotype 11 of SNP rs2278422 (OR = 6.95, P <0.001). In contrast, the variant allele indicated slightly lower risks (OR = 4.72, P <0.001), a significant antagonistic interaction (RERI = -2.66, SI = 0.59), AP = -0.56 (95%CI -0.94, -0.17) and a significant multiplicative interaction (ORINT = 0.47, P = 0.013)., Conclusion: TGFβ1 gene polymorphisms interact with being overweight to influence the risk of large joint OA.
- Published
- 2013
- Full Text
- View/download PDF
117. Genome-wide association and functional studies identify the DOT1L gene to be involved in cartilage thickness and hip osteoarthritis.
- Author
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Castaño Betancourt MC, Cailotto F, Kerkhof HJ, Cornelis FM, Doherty SA, Hart DJ, Hofman A, Luyten FP, Maciewicz RA, Mangino M, Metrustry S, Muir K, Peters MJ, Rivadeneira F, Wheeler M, Zhang W, Arden N, Spector TD, Uitterlinden AG, Doherty M, Lories RJ, Valdes AM, and van Meurs JB
- Subjects
- Age Factors, Animals, Cartilage, Articular pathology, Cartilage, Articular physiology, Cell Line, Chondrocytes cytology, Genetic Variation, Hepatocyte Nuclear Factor 1-alpha metabolism, Histone-Lysine N-Methyltransferase, Humans, Methyltransferases metabolism, Mice, Osteoarthritis, Hip epidemiology, Osteoarthritis, Hip pathology, Risk Factors, Wnt Signaling Pathway physiology, Chondrocytes physiology, Chondrogenesis genetics, Genome-Wide Association Study, Methyltransferases genetics, Osteoarthritis, Hip genetics
- Abstract
Hip osteoarthritis (HOA) is one of the most disabling and common joint disorders with a large genetic component that is, however, still ill-defined. To date, genome-wide association studies (GWAS) in osteoarthritis (OA) and specifically in HOA have yielded only few loci, which is partly explained by heterogeneity in the OA definition. Therefore, we here focused on radiographically measured joint-space width (JSW), a proxy for cartilage thickness and an important underlying intermediate trait for HOA. In a GWAS of 6,523 individuals on hip-JSW, we identified the G allele of rs12982744 on chromosome 19p13.3 to be associated with a 5% larger JSW (P = 4.8 × 10(-10)). The association was replicated in 4,442 individuals from three United Kingdom cohorts with an overall meta-analysis P value of 1.1 × 10(-11). The SNP was also strongly associated with a 12% reduced risk for HOA (P = 1 × 10(-4)). The SNP is located in the DOT1L gene, which is an evolutionarily conserved histone methyltransferase, recently identified as a potentially dedicated enzyme for Wnt target-gene activation in leukemia. Immunohistochemical staining of the DOT1L protein in mouse limbs supports a role for DOT1L in chondrogenic differentiation and adult articular cartilage. DOT1L is also expressed in OA articular chondrocytes. Silencing of Dot1l inhibited chondrogenesis in vitro. Dot1l knockdown reduces proteoglycan and collagen content, and mineralization during chondrogenesis. In the ATDC5 chondrogenesis model system, DOT1L interacts with TCF and Wnt signaling. These data are a further step to better understand the role of Wnt-signaling during chondrogenesis and cartilage homeostasis. DOT1L may represent a therapeutic target for OA.
- Published
- 2012
- Full Text
- View/download PDF
118. Can increased understanding of the role of lung development and aging drive new advances in chronic obstructive pulmonary disease?
- Author
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Maciewicz RA, Warburton D, and Rennard SI
- Subjects
- Humans, Aging physiology, Lung embryology, Pulmonary Disease, Chronic Obstructive physiopathology
- Abstract
To advance our ability to effect earlier diagnosis, prevent, and possibly restore healthy lung function in patients with chronic obstructive pulmonary disease (COPD) may require novel thinking. One avenue to explore is the concept of COPD as a trans-generational disease. Early development and COPD may be related first by failure of normal growth development leading to an increased risk of disease, and second by recapitulation of some developmental pathways that may be key to lung repair after injury. While we should be mindful that "aging" may not be only thought of as "late" development in a COPD context, the aging process in the lung is probably fundamentally different from emphysema. However, injury of the aging lung may result in emphysema. Finally, taking a more holistic view of COPD, aging and development in extrapulmonary contexts (e.g., musculoskeletal or immune systems) may also impact on COPD initiation and progression. Addressing the impact of development and the aging process on the natural history of the disease, both in men and in women, may open up research avenues that will drive new advances in disease classification, diagnosis, prognosis, and therapy for this chronic debilitating lung disease.
- Published
- 2009
- Full Text
- View/download PDF
119. Integrin alpha5beta1 and ADAM-17 interact in vitro and co-localize in migrating HeLa cells.
- Author
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Bax DV, Messent AJ, Tart J, van Hoang M, Kott J, Maciewicz RA, and Humphries MJ
- Subjects
- ADAM Proteins, ADAM17 Protein, Animals, Antibodies, Monoclonal chemistry, Binding Sites, Blotting, Western, COS Cells, Cations, Cell Adhesion, Cell Line, Cell Movement, Cell Separation, DNA, Complementary metabolism, Dose-Response Relationship, Drug, Edetic Acid chemistry, Fibroblasts metabolism, Flow Cytometry, HeLa Cells, Humans, Inflammation, Ligands, Microscopy, Fluorescence, Peptides chemistry, Protein Binding, Protein Structure, Tertiary, Recombinant Proteins metabolism, Skin cytology, Wound Healing, Integrin alpha5beta1 metabolism, Metalloendopeptidases metabolism
- Abstract
Tumor necrosis factor (TNF) alpha-converting enzyme (TACE/ADAM-17) has diverse roles in the proteolytic processing of cell surface molecules and, due to its ability to process TNFalpha, is a validated therapeutic target for anti-inflammatory therapies. Unlike a number of other ADAM proteins, which interact with integrin receptors via their disintegrin domains, there is currently no evidence for an ADAM-17-integrin association. By analyzing the adhesion of a series of cell lines with recombinant fragments of the extracellular domain of ADAM-17, we now demonstrate a functional interaction between ADAM-17 and alpha(5)beta(1) integrin in a trans orientation. Because ADAM-17-mediated adhesion was sensitive to RGD peptides and EDTA, and the integrin-binding site within ADAM-17 was narrowed down to the disintegrin/cysteine-rich region, the two molecules appear to have a ligand-receptor relationship mediated by the alpha(5)beta(1) ligand binding pocket. Intriguingly, ADAM-17 and alpha(5)beta(1) were found to co-localize in both membrane ruffles and focal adhesions in HeLa cells. When confluent HeLa cell monolayers were wounded, ADAM-17 and alpha(5)beta(1) redistributed to the leading edge and co-localized, which is suggestive of a cis orientation. We postulate that the interaction of ADAM-17 with alpha(5)beta(1) may target or modulate its metalloproteolytic activity.
- Published
- 2004
- Full Text
- View/download PDF
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