35 results on '"O'boyle G"'
Search Results
2. The role of tumour volume as a prognostic factor in non-small cell lung cancer (NSCLC) patients treated with definitive radiotherapy
- Author
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Joyce, R., primary, O’Boyle, G., additional, McDermott, R. L., additional, and Small, C., additional
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- 2019
- Full Text
- View/download PDF
3. Retrospective analysis of radium-223 treatment for adults with progressive castration-resistant metastatic prostate cancer with symptomatic bone metastasis
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Gaffney, J., primary, O’Boyle, G., additional, Gaffney, B., additional, Roshan, D., additional, Sullivan, F., additional, Ibrahim, N., additional, Martin, J., additional, and Small, C., additional
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- 2017
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- View/download PDF
4. The prognostic significance and impact of the CXCR4-CXCR7-CXCL12 axis in primary cutaneous melanoma
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McConnell, A.T., primary, Ellis, R., additional, Pathy, B., additional, Plummer, R., additional, Lovat, P.E., additional, and O'Boyle, G., additional
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- 2016
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5. 2188 - Retrospective analysis of radium-223 treatment for adults with progressive castration-resistant metastatic prostate cancer with symptomatic bone metastasis
- Author
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Gaffney, J., O’Boyle, G., Gaffney, B., Roshan, D., Sullivan, F., Ibrahim, N., Martin, J., and Small, C.
- Published
- 2017
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6. PTU-074 Ulcerative Colitis: The Alpha-e-beta-7 Integrin Is Associated With A High Frequency Of Th17, Th1 And Th17/th1 Cd4 Lymphocytes
- Author
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Lamb, CA, primary, Mansfield, JC, additional, Tew, GW, additional, Gibbons, D, additional, Long, AK, additional, Irving, PM, additional, Deihl, L, additional, Eastham Anderson, J, additional, O’Boyle, G, additional, Jones, DE, additional, Hayday, A, additional, Keir, M, additional, Egen, JG, additional, and Kirby, JA, additional
- Published
- 2014
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7. DOP009 Ulcerative colitis: The αEβ7 integrin is associated with a high frequency of Th17, Th1 and Th17/Th1 CD4 lymphocytes
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Lamb, C.A., primary, Mansfield, J.C., additional, Tew, G.W., additional, Gibbons, D.L., additional, Long, A.K., additional, Irving, P.M., additional, Diehl, L., additional, Eastham-Anderson, J., additional, O'Boyle, G., additional, Jones, D.E.J., additional, Hayday, A.C., additional, Keir, M.E., additional, Egen, J.G., additional, and Kirby, J.A., additional
- Published
- 2014
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8. EP-1940: Early outcome of salvage LDR brachytherapy for local failure after EBRT for prostate cancer - Irish Experience
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Khalid, J., primary, Jamaluddin, M.F., additional, Zuchora, A., additional, Cleary, S., additional, Fahy, L., additional, Moore, M., additional, O'Boyle, G., additional, Ibrahim, M.N., additional, and Sullivan, F.J., additional
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- 2014
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9. Inhibition of CXCR4–CXCL12 chemotaxis in melanoma by AMD11070
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O'Boyle, G, primary, Swidenbank, I, additional, Marshall, H, additional, Barker, C E, additional, Armstrong, J, additional, White, S A, additional, Fricker, S P, additional, Plummer, R, additional, Wright, M, additional, and Lovat, P E, additional
- Published
- 2013
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10. PMO-238 Blockade of the B7 integrin prevents adherence of t lymphocytes to MAdCAM-1 in an in vitro model of vascular microcirculation post-capillary shear flow
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Lamb, C A, primary, O'Boyle, G, additional, Jones, D E, additional, Mansfield, J C, additional, and Kirby, J A, additional
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- 2012
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11. Modulatory effects of heparin and short-length oligosaccharides of heparin on the metastasis and growth of LMD MDA-MB 231 breast cancer cells in vivo
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Mellor, P, primary, Harvey, J R, additional, Murphy, K J, additional, Pye, D, additional, O'Boyle, G, additional, Lennard, T W J, additional, Kirby, J A, additional, and Ali, S, additional
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- 2007
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12. [719] EFFECTS OF ETHANOL ON ENDOTOXIN-MEDIATED CYTOKINE RELEASE: SENSITISATION VIA TLR4 BUT NORMAL TOLERANCE
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Kendrick, S.F.W., primary, O'Boyle, G., additional, Jones, D.E.J., additional, and Day, C.P., additional
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- 2007
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13. Theories of Justification and Political Violence: Examples from Four Groups
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O'Boyle, G., primary
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- 2002
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14. CARDIAC ALLOGRAFT REJECTION: EXPRESSION AND REGULATION OF THE CHEMOKINE DEOCY RECEPTOR D6.
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O'boyle, G., Ali, S., Robertson, H., and Kirby, J. A.
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- 2010
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15. A STRATEGY TO INHIBIT EFFECTOR T CELL INFILTRATION OF ALLOGRAFT TISSUES BY STIMULATION OF THE CHEMOKINE RECEPTOR CXCR3.
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O'boyle, G., Newton, P., Jenkins, Y., Ali, S., and Kirby, J. A.
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- 2010
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16. A National Cyberattack Affecting Radiation Therapy: The Irish Experience.
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Flavin A, O'Toole E, Murphy L, Ryan R, McClean B, Faul C, McGibney C, Coyne S, O'Boyle G, Small C, Sims C, Kearney M, Coffey M, and O'Donovan A
- Abstract
On Friday, May 14, 2021, the Health Service Executive, the organization providing public health services in the Republic of Ireland, was the victim of a significant cyberattack on its information technology systems. All systems were subsequently shut down to prevent further damage and to allow cybersecurity experts to investigate the attack. As a result, oncology services were severely disrupted, with the cessation of radiation therapy treatments in all public radiation therapy departments. Ireland has 5 large public and 6 smaller private radiation therapy centers in total. Because of the widespread adoption of electronic medical records in radiation therapy departments, it wasn't possible to retrieve patient details of those who were undergoing radiation therapy at the time of the cyberattack. In total, 513 patients nationally had their radiation therapy interrupted. A national radiation therapy cyberattack response team was formed immediately to oversee the response to the attack. The immediate concerns were radiation therapy emergencies and category 1 patients where gaps in treatment would have an adverse effect on outcome. Communication with patients and the public was also established as a priority and agreements were reached with the private sector for the treatment of patients affected by the cyberattack. The national media was used to alert patients of the need to communicate with their radiation therapy department. Dedicated phone lines were established. Locally, radiation therapy departments held daily crisis meetings with key staff members, including information technology personnel. Individual centers employed different technologies for treatment planning and data storage, so local solutions to the cyberattack to reestablish radiation therapy for patients were developed. In addition, national documentation on prioritization of patients to resume treatment was produced and a national approach was made to compensate for gaps in treatment caused by the attack. All 5 centers had reestablished radiation therapy by May 30, although there has been a long aftermath to the cyberattack. In this article, we provide an overview of the effects of the cyberattack on our national radiation therapy service and our strategy to resume patient treatment in a timely fashion., (© 2022 The Authors.)
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- 2022
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17. Driving and Disabling Factors of Noncurative Oral Chemotherapy Adherence: A Qualitative Evidence Synthesis.
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Dowling M, Hunter A, Biesty L, Meskell P, Conway A, O'Boyle G, Morrissey E, and Houghton C
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- Administration, Oral, Adult, Aged, Aged, 80 and over, Antineoplastic Agents administration & dosage, Female, Humans, Male, Middle Aged, Antineoplastic Agents therapeutic use, Medication Adherence psychology, Medication Adherence statistics & numerical data, Mouth Neoplasms drug therapy, Mouth Neoplasms psychology
- Abstract
Problem Identification: Adherence to oral chemotherapy is influenced by many factors. This qualitative evidence synthesis aimed to contribute to an interpretive understanding of the factors that act as facilitators or barriers to adherence among people with cancer taking lifelong, noncurative oral chemotherapy., Literature Search: A systematic search strategy was developed, and searching was undertaken across several electronic databases (CINAHL®, Cochrane Library, EMBASE, EThOS, ProQuest, PsycINFO®, PubMed, Scopus, Web of Science including MEDLINE®)., Data Evaluation: 12 reports on 10 qualitative studies were included in the synthesis. A total of 206 patients were included, with 109 taking an oral tyrosine kinase inhibitor, along with a total of 57 healthcare professionals., Synthesis: Two principal analytic themes (driving adherence and disabling adherence) and seven subthemes were identified., Implications for Practice: A trusting relationship between healthcare professionals and patients is important to adherence. Open discussions concerning treatment side effects and patients' perceived quality of life should occur at each visit.
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- 2019
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18. Potential role of indoleamine 2,3-dioxygenase in primary biliary cirrhosis.
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Asghar K, Brain J, Palmer JM, Douglass S, Naemi FMA, O'Boyle G, Kirby J, and Ali S
- Abstract
Indoleamine 2,3-dioxygenase (IDO)-induced immunosuppression can be clinically beneficial for autoimmune diseases. Primary biliary cirrhosis (PBC) is characterized by autoimmune lesions of intrahepatic bile duct epithelial cells that may lead to irreversible cirrhosis or hepatocellular carcinoma. The present study assessed the expression and function of IDO in a cell culture model and in PBC patients. IDO expression was monitored in a human immortalized but non-malignant biliary epithelial cell (iBEC) line. Increased expression of IDO1/2 was observed in the iBECs following stimulation with interferon-γ (IFN-γ). The induction of IDO was IFN-γ-dependent, but was independent of the transforming growth factor-β (TGF-β) pathway. IDO enzymatic activity was observed in the supernatant of iBECs following stimulation with IFN-γ using colorimetric assays. A total of 47 serum samples from PBC patients were used to examine IDO activity by high-performance liquid chromatography, with samples from 24 healthy volunteers used as controls. Patients with PBC exhibited an increased rate of tryptophan to kynurenine conversion (P>0.01). Liver sections from patients with PBC (n=5) and those of healthy controls (n=5) were used for immunohistochemical studies. IDO expression was observed in biliary epithelial cells and in hepatocytes of PBC patients. Finally, the effect of tryptophan metabolites on human cluster of differentiation (CD) 4
+ T cells in inducing polarization towards a regulatory T cell phenotype was examined. 3-Hydroxykynurenine significantly upregulated the fraction of CD4+ cells expressing forkhead box p3 (Foxp3). The results of the present study suggest a therapeutic opportunity for the management of PBC and indicate that tryptophan catabolism could serve as a potential biomarker to monitor disease progression.- Published
- 2017
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19. αEβ7 Integrin Identifies Subsets of Pro-Inflammatory Colonic CD4+ T Lymphocytes in Ulcerative Colitis.
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Lamb CA, Mansfield JC, Tew GW, Gibbons D, Long AK, Irving P, Diehl L, Eastham-Anderson J, Price MB, O'Boyle G, Jones DEJ, O'Byrne S, Hayday A, Keir ME, Egen JG, and Kirby JA
- Subjects
- Adult, Aged, Case-Control Studies, Colitis, Ulcerative metabolism, Colon immunology, Cytokines metabolism, Female, Flow Cytometry, Humans, Male, Middle Aged, Real-Time Polymerase Chain Reaction, Young Adult, CD4-Positive T-Lymphocytes immunology, Colitis, Ulcerative immunology, Colon cytology, Integrins immunology
- Abstract
Background and Aims: The αEβ7 integrin is crucial for retention of T lymphocytes at mucosal surfaces through its interaction with E-cadherin. Pathogenic or protective functions of these cells during human intestinal inflammation, such as ulcerative colitis [UC], have not previously been defined, with understanding largely derived from animal model data. Defining this phenotype in human samples is important for understanding UC pathogenesis and is of translational importance for therapeutic targeting of αEβ7-E-cadherin interactions., Methods: αEβ7+ and αEβ7- colonic T cell localization, inflammatory cytokine production and expression of regulatory T cell-associated markers were evaluated in cohorts of control subjects and patients with active UC by immunohistochemistry, flow cytometry and real-time PCR of FACS-purified cell populations., Results: CD4+αEβ7+ T lymphocytes from both healthy controls and UC patients had lower expression of regulatory T cell-associated genes, including FOXP3, IL-10, CTLA-4 and ICOS in comparison with CD4+αEβ7- T lymphocytes. In UC, CD4+αEβ7+ lymphocytes expressed higher levels of IFNγ and TNFα in comparison with CD4+αEβ7- lymphocytes. Additionally the CD4+αEβ7+ subset was enriched for Th17 cells and the recently described Th17/Th1 subset co-expressing both IL-17A and IFNγ, both of which were found at higher frequencies in UC compared to control., Conclusion: αEβ7 integrin expression on human colonic CD4+ T cells was associated with increased production of pro-inflammatory Th1, Th17 and Th17/Th1 cytokines, with reduced expression of regulatory T cell-associated markers. These data suggest colonic CD4+αEβ7+ T cells are pro-inflammatory and may play a role in UC pathobiology., (© European Crohn’s and Colitis Organisation 2016.)
- Published
- 2017
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20. CCL2 nitration is a negative regulator of chemokine-mediated inflammation.
- Author
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Barker CE, Thompson S, O'Boyle G, Lortat-Jacob H, Sheerin NS, Ali S, and Kirby JA
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- Animals, Binding Sites, Cell Movement genetics, Chemokine CCL2 chemistry, Chemokines metabolism, Inflammation pathology, Leukocytes metabolism, Mice, Monocytes metabolism, Oxidative Stress genetics, Peroxynitrous Acid chemistry, Peroxynitrous Acid metabolism, Reactive Nitrogen Species chemistry, Receptors, CCR2 genetics, Tyrosine metabolism, Chemokine CCL2 metabolism, Inflammation metabolism, Reactive Nitrogen Species metabolism, Receptors, CCR2 metabolism
- Abstract
Chemokines promote leukocyte recruitment during inflammation. The oxidative burst is an important effector mechanism, this leads to the generation of reactive nitrogen species (RNS), including peroxynitrite (ONOO). The current study was performed to determine the potential for nitration to alter the chemical and biological properties of the prototypical CC chemokine, CCL2. Immunofluorescence was performed to assess the presence of RNS in kidney biopsies. Co-localisation was observed between RNS-modified tyrosine residues and the chemokine CCL2 in diseased kidneys. Nitration reduced the potential of CCL2 to stimulate monocyte migration in diffusion gradient chemotaxis assays (p < 0.05). This was consistent with a trend towards reduced affinity of the nitrated chemokine for its cognate receptor CCR2b. The nitrated chemokine was unable to induce transendothelial monocyte migration in vitro and failed to promote leukocyte recruitment when added to murine air pouches (p < 0.05). This could potentially be attributed to reduced glycosaminoglycan binding ability, as surface plasmon resonance spectroscopy showed that nitration reduced heparan sulphate binding by CCL2. Importantly, intravenous administration of nitrated CCL2 also inhibited the normal recruitment of leukocytes to murine air pouches filled with unmodified CCL2. Together these data suggest that nitration of CCL2 during inflammation provides a mechanism to limit and resolve acute inflammation.
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- 2017
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21. Erratum to: Defective Leukocyte Adhesion and Chemotaxis Contributes to Combined Immunodeficiency in Humans with Autosomal Recessive MST1 Deficiency.
- Author
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Dang TS, Willet JD, Griffin HR, Morgan NV, O'Boyle G, Arkwright PD, Hughes SM, Abinun M, Tee LJ, Barge D, Engelhardt KR, Jackson M, Cant AJ, Maher ER, Koref MS, Reynard LN, Ali S, and Hambleton S
- Published
- 2016
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22. Defective Leukocyte Adhesion and Chemotaxis Contributes to Combined Immunodeficiency in Humans with Autosomal Recessive MST1 Deficiency.
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Dang TS, Willet JD, Griffin HR, Morgan NV, O'Boyle G, Arkwright PD, Hughes SM, Abinun M, Tee LJ, Barge D, Engelhardt KR, Jackson M, Cant AJ, Maher ER, Koref MS, Reynard LN, Ali S, and Hambleton S
- Subjects
- Child, Preschool, Female, Humans, Immunologic Deficiency Syndromes metabolism, Immunophenotyping, Intercellular Adhesion Molecule-1 metabolism, Intracellular Signaling Peptides and Proteins, Lymphocytes immunology, Lymphocytes metabolism, Pedigree, Phenotype, Siblings, Cell Adhesion genetics, Chemotaxis, Leukocyte genetics, Genes, Recessive, Immunologic Deficiency Syndromes diagnosis, Immunologic Deficiency Syndromes genetics, Protein Serine-Threonine Kinases deficiency
- Abstract
Purpose: To investigate the clinical and functional aspects of MST1 (STK4) deficiency in a profoundly CD4-lymphopenic kindred with a novel homozygous nonsense mutation in STK4. Although recent studies have described the cellular effects of murine Mst1 deficiency, the phenotype of MST1-deficient human lymphocytes has yet to be fully explored. Patient lymphocytes were therefore investigated in the context of current knowledge of murine Mst1 deficiency., Methods: Genetic etiology was identified by whole exome sequencing of genomic DNA from two siblings, combined with linkage analysis in the wider family. MST1 protein expression was assessed by immunoblotting. The ability of patient lymphocytes to adhere to ICAM-1 under flow conditions was measured, and transwell assays were used to assess chemotaxis. Chemokine receptor expression was examined by flow cytometry and receptor signalling by immunoblotting., Results: A homozygous nonsense mutation in STK4 (c.442C > T, p.Arg148Stop) was found in the patients, leading to a lack of MST1 protein expression. Patient leukocytes exhibited deficient chemotaxis after stimulation with CXCL11, despite preserved expression of CXCR3. Patient lymphocytes were also unable to bind effectively to immobilised ICAM-1 under flow conditions, in keeping with a failure to develop high affinity binding., Conclusion: The observed abnormalities of adhesion and migration imply a profound trafficking defect among human MST1-deficient lymphocytes. By analogy with murine Mst1 deficiency and other defects of leucocyte trafficking, this is likely to contribute to immunodeficiency by impairing key aspects of T-cell development and function such as positive selection in the thymus, thymic egress and immune synapse formation in the periphery.
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- 2016
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23. Transplantation and inflammation: implications for the modification of chemokine function.
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Barker CE, Ali S, O'Boyle G, and Kirby JA
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- Animals, Biomarkers metabolism, Humans, Inflammation immunology, Oxidative Stress, Protein Processing, Post-Translational, Signal Transduction, Treatment Outcome, Chemokines metabolism, Inflammation metabolism, Inflammation Mediators metabolism, Organ Transplantation adverse effects
- Abstract
Oxidative stress is a major and recurring cause of damage during inflammation, especially following organ transplantation. Initial ischaemia-reperfusion injury causes the production of many reactive oxygen and nitrogen species, and subsequent recruitment and activation of inflammatory cells can lead to further oxidative stress. This stress is well known to cause damage at the cellular level, for example by induction of senescence leading to the production of a characteristic senescence-associated secretory phenotype. Chemokines are an important component of the senescence-associated secretory phenotype, recruiting further leucocytes and reinforcing the stress and senescence responses. As well as inducing the production of proteins, including chemokines, oxidative stress can alter proteins themselves, both directly and by induction of enzymes capable of modification. These alterations can lead to important modifications to their biological activity and also alter detection by some antibodies, potentially limiting the biological relevance of some immunochemical and proteomic biomarkers. Peroxynitrite, a reactive nitrogen species generated during inflammation and ischaemia, can cause such modifications by nitrating chemokines. Matrix metalloproteinases, released by many stressed cells, can cleave chemokines, altering function, while peptidylarginine deiminases can inactivate certain chemokines by citrullination. This review discusses the relationship between inflammation and post-translational modification, focusing on the functional modulation of transplant-relevant pro-inflammatory chemokines., (© 2014 The Authors. Immunology Published by John Wiley & Sons Ltd.)
- Published
- 2014
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24. Comment on "CXCL9 Causes heterologous desensitization of CXCL12-mediated memory T lymphocyte activation".
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O'Boyle G, Ali S, and Kirby JA
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- Animals, Humans, Chemokine CXCL12 metabolism, Chemokine CXCL9 metabolism, Immunologic Memory, Lymphocyte Activation immunology, T-Lymphocytes immunology, T-Lymphocytes metabolism
- Published
- 2013
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25. Regulatory T cells inhibit CD8(+) T-cell tissue invasion in human skin graft-versus-host reactions.
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Mavin E, Ahmed SS, O'Boyle G, Turner B, Douglass S, Norden J, Collin M, Ali S, Dickinson A, and Wang XN
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- Antigens, Ly metabolism, Cell Adhesion, Cells, Cultured, Chemokine CXCL10 metabolism, Chemokine CXCL11 metabolism, Chemokine CXCL9 metabolism, Coculture Techniques, Flow Cytometry, Graft vs Host Disease genetics, Graft vs Host Disease immunology, Graft vs Host Disease pathology, Humans, Immunohistochemistry, Interferon-gamma metabolism, Real-Time Polymerase Chain Reaction, Receptors, CXCR3 metabolism, Skin pathology, Tissue Culture Techniques, Chemotaxis, Leukocyte, Graft vs Host Disease prevention & control, Graft vs Host Reaction immunology, Skin immunology, T-Lymphocytes, Regulatory immunology
- Abstract
Background: Regulatory T cells (Tregs) effectively ameliorate graft-versus-host disease (GVHD). The mechanisms underlying Treg therapeutic effect on GVHD are not fully elucidated. This study investigates whether Treg prevention of GVH tissue damage is associated with blocking CD8 effector T-cell tissue invasion, a question not yet addressed in humans., Method: Tissue-infiltrating T cells and histopathology scores were detected using an in vitro human GVHD skin explant model, together with immunohistochemistry, cytometric bead array, functional adhesion and migration assays, flow cytometry, and quantitative real-time polymerase chain reaction., Results: Treg intervention during priming significantly decreased effector T-cell infiltration into target tissue (P<0.01) resulting in a striking reduction in the histopathology score of tissue injury (P<0.0001). These results were coupled with reduced CXCR3 and cutaneous lymphocyte antigen expression by effector T cells, together with decreased CXCL10 and CXCL11 expression in target tissue. Treg intervention also impaired the functional interaction of CXCR3 and cutaneous lymphocyte antigen with their specific ligands (P<0.01) and suppressed the secretion of CXCL9, CXCL10, and interferon-γ (P<0.01, P<0.05, and P<0.001, respectively). Late addition of Tregs into the effector phase abolished their ability to suppress effector T-cell tissue invasion, resulting in a total loss of their ability to ameliorate GVH tissue damage., Conclusion: Preventing effector T-cell tissue invasion is a critical mechanistic event leading to Treg attenuation of GVH tissue damage. This therapeutic effect is associated with a failure of CD8 T cells to increase tissue homing receptors after allo-stimulation, together with a breakdown of interferon-γ-induced chemoattractant expression in the target tissue.
- Published
- 2012
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26. The yin and yang of chemokine receptor activation.
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O'Boyle G
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- Animals, Humans, Chemokine CXCL10 metabolism, Chemokine CXCL11 metabolism, Isoquinolines pharmacology, Receptors, CXCR3 agonists, Small Molecule Libraries pharmacology
- Abstract
Chemokines represent a class of cytokines that control the migration of leucocytes. The human chemokine system comprises 44 ligands and 21 receptors that have evolved to control leucocyte migration. Although chemokines are an attractive therapeutic target for anti-inflammatory intervention, clinical trials of small molecule receptor antagonists have failed to demonstrate efficacy. One often cited explanation for this is the apparent redundancy within the chemokine system, wherein several ligands bind and activate each receptor. The work of Scholten et al. and Nedjai et al. reported in this issue of the British Journal of Pharmacology demonstrates that this redundancy does not exist at the molecular level and provides a powerful insight into the complex nature of chemokine receptor activation., (© 2011 The Author. British Journal of Pharmacology © 2011 The British Pharmacological Society.)
- Published
- 2012
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27. Chemokine receptor CXCR3 agonist prevents human T-cell migration in a humanized model of arthritic inflammation.
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O'Boyle G, Fox CR, Walden HR, Willet JD, Mavin ER, Hine DW, Palmer JM, Barker CE, Lamb CA, Ali S, and Kirby JA
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- Animals, Arthritis metabolism, Autoimmunity, Chemokines metabolism, Female, Flow Cytometry methods, Humans, Inflammation pathology, Leukocytes, Mononuclear cytology, Mice, Mice, Inbred NOD, Phosphorylation, Receptors, CCR5 metabolism, T-Lymphocytes cytology, Receptors, CXCR3 metabolism, T-Lymphocytes metabolism
- Abstract
The recruitment of T lymphocytes during diseases such as rheumatoid arthritis is regulated by stimulation of the chemokine receptors expressed by these cells. This study was designed to assess the potential of a CXCR3-specific small-molecule agonist to inhibit the migration of activated human T cells toward multiple chemokines. Further experiments defined the molecular mechanism for this anti-inflammatory activity. Analysis in vitro demonstrated agonist induced internalization of both CXCR3 and other chemokine receptors coexpressed by CXCR3(+) T cells. Unlike chemokine receptor-specific antagonists, the CXCR3 agonist inhibited migration of activated T cells toward the chemokine mixture in synovial fluid from patients with active rheumatoid arthritis. A humanized mouse air-pouch model showed that intravenous treatment with the CXCR3 agonist prevented inflammatory migration of activated human T cells toward this synovial fluid. A potential mechanism for this action was defined by demonstration that the CXCR3 agonist induces receptor cross-phosphorylation within CXCR3-CCR5 heterodimers on the surface of activated T cells. This study shows that generalized chemokine receptor desensitization can be induced by specific stimulation of a single chemokine receptor on the surface of activated human T cells. A humanized mouse model was used to demonstrate that this receptor desensitization inhibits the inflammatory response that is normally produced by the chemokines present in synovial fluid from patients with active rheumatoid arthritis.
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- 2012
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28. Chemokines in transplantation: what can atypical receptors teach us about anti-inflammatory therapy?
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O'Boyle G, Ali S, and Kirby JA
- Subjects
- Animals, Anti-Inflammatory Agents immunology, Graft Rejection immunology, Humans, Leukocytes immunology, Signal Transduction, Transplantation, Homologous immunology, Chemokines immunology, Organ Transplantation, Receptors, Chemokine immunology
- Abstract
More than 45 members of the family of chemotactic cytokines have been described. These chemokines control the migration of leukocytes throughout the whole alloimmune response from initial ischemic damage to acute inflammation and eventual resolution. Several chemokines have been strongly linked to allograft rejection. Recent studies have described powerful endogenous mechanisms that regulate chemokine biology. This review will describe a new class of chemokine receptor that bind ligands with high affinity but lack the capacity for signaling. Atypical receptors represent a new paradigm in chemokine biology and may hold the key to our eventual manipulation of chemokine-driven allograft inflammation., (Copyright © 2011 Elsevier Inc. All rights reserved.)
- Published
- 2011
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29. Lung transplantation: the Yin and Yang of mesenchymal stem cells.
- Author
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Kirby JA and O'boyle G
- Subjects
- Bronchiolitis Obliterans pathology, Bronchoalveolar Lavage, Cell Differentiation physiology, Cell Movement physiology, Cell Proliferation, Humans, Lung Transplantation pathology, Mesenchymal Stem Cells pathology, Bronchiolitis Obliterans physiopathology, Endothelin-1 physiology, Lung Transplantation physiology, Mesenchymal Stem Cells physiology, Yin-Yang
- Published
- 2011
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30. Cardiac allograft rejection: examination of the expression and function of the decoy chemokine receptor D6.
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Bradford L, Marshall H, Robertson H, Kirby JA, Graham G, Ali S, and O'Boyle G
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- Animals, Biopsy, Cell Line, Cytokines immunology, Cytokines physiology, Graft Rejection pathology, Graft Survival immunology, Heart Transplantation pathology, Humans, Leukocytes physiology, Models, Animal, Monocytes physiology, Rats, Receptors, CCR10 immunology, Receptors, CCR10 physiology, Receptors, Chemokine physiology, Transplantation, Homologous immunology, Chemokine Receptor D6, Graft Rejection immunology, Heart Transplantation immunology, Receptors, CCR10 genetics
- Abstract
Background: Inflammatory cell recruitment during allograft rejection is driven by a group of inflammatory cytokines termed chemokines. Chemokines are presented on the surface of the vascular endothelium where they ligate specific receptors expressed on the surface of leukocytes. Recently, a group of nonsignaling chemokine receptors have been described. These bind and internalize chemokines but do not drive leukocyte migration. It is believed that these compete with classical signaling receptors to modulate inflammation., Methods: This study describes the first examination of the human decoy chemokine receptor D6 during rejection; D6 binds at least 12 potent proinflammatory chemokines. The expression of D6 by graft infiltrating leukocytes was examined in cardiac allografts by confocal microscopy on biopsy sections (n=19). Cytokine regulation of D6 was examined in vitro, and a chemokine scavenging assay was performed using the prototypical transplant-associated chemokine CCL5/RANTES., Results: D6 expression was found to be higher in the biopsies taken from more severe cardiac allograft rejection (P<0.01) and was predominantly localized to graft infiltrating CD45(+)CD68(+) leukocytes. In vitro studies demonstrated that the transforming growth factor-beta strongly increased the expression of D6 by monocytes, which significantly enhanced D6-mediated chemokine scavenging (by 85%, P<0.05)., Conclusions: We present the first examination of the biology of D6 during rejection and identify a transplant-associated cytokine that is able to regulate its expression. These data suggest an exciting new mechanism for the antiinflammatory actions of transforming growth factor-beta. Understanding the expression patterns of D6 may provide important insight into the regulation and control of inflammatory cell recruitment during allograft rejection.
- Published
- 2010
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31. Acetate, the key modulator of inflammatory responses in acute alcoholic hepatitis.
- Author
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Kendrick SF, O'Boyle G, Mann J, Zeybel M, Palmer J, Jones DE, and Day CP
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- Acetate-CoA Ligase metabolism, Acetyl Coenzyme A metabolism, Acetylation, Cell Line, Ethanol adverse effects, Gene Knockdown Techniques, Hepatitis, Alcoholic etiology, Histone Acetyltransferases metabolism, Histone Deacetylases metabolism, Histones metabolism, Humans, Promoter Regions, Genetic, Acetates metabolism, Cytokines metabolism, Ethanol metabolism, Gene Expression Regulation, Hepatitis, Alcoholic metabolism, Macrophages metabolism
- Abstract
Unlabelled: Acute alcoholic hepatitis is characterized by disproportionate macrophage inflammatory cytokine responses to bacterial lipopolysaccharide. Lack of knowledge of the underlying mechanism has limited progress toward effective therapy. We postulated a novel mechanism by which ethanol increases histone acetylation, increasing proinflammatory gene transcription and cytokine synthesis. Cytokine responses to lipopolysaccharide in a human macrophage cell line cultured in 86 mM ethanol, 1 mM acetate, and normal media were measured by multiplex immunoassay. Changes in histone acetylation were determined by immunofluorescence microscopy and chromatin immunoprecipitation on presentation. The effect of ethanol and acetate on acetyl-coenzyme A (acetyl-coA) synthetases, which convert acetate to acetyl-coA, the substrate for histone acetylation, was determined by quantitative reverse-transcription polymerase chain reaction and immunoblotting. Knockdown of acetyl-coA synthetases by short hairpin RNA (shRNA) was used to determine their role in ethanol's enhancement of the inflammatory cytokine response. Ethanol-exposed macrophages developed enhanced interleukin 6 (IL6), IL8, and tumor necrosis factor alpha responses to lipopolysaccharide with time-dependent increases in histone acetylation that could be prevented by inhibition of ethanol metabolism. Chromatin immunoprecipitation confirmed increased histone acetylation at promoter regions of specific cytokine genes. The effect of ethanol was reproduced by incubation with acetate, the principal hepatic metabolite of ethanol, and both ethanol and acetate reduced histone deacetylase activity and up-regulated acetyl-coA synthetases. Knockdown of the acetyl-coA synthetases abrogated the effect of ethanol on cytokine production., Conclusion: Synthesis of metabolically available acetyl-coA from acetate is critical to the increased acetylation of proinflammatory gene histones and consequent enhancement of the inflammatory response in ethanol-exposed macrophages. This mechanism is a potential therapeutic target in acute alcoholic hepatitis.
- Published
- 2010
- Full Text
- View/download PDF
32. T cell extravasation: demonstration of synergy between activation of CXCR3 and the T cell receptor.
- Author
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Newton P, O'Boyle G, Jenkins Y, Ali S, and Kirby JA
- Subjects
- Adult, CD3 Complex immunology, Cell Line, Cell Proliferation drug effects, Chemotaxis drug effects, Cross-Linking Reagents pharmacology, Endothelial Cells cytology, Endothelial Cells drug effects, Endothelial Cells immunology, Fluorescence Resonance Energy Transfer, Humans, Lymphocyte Activation drug effects, Models, Immunological, Reproducibility of Results, T-Lymphocytes cytology, T-Lymphocytes drug effects, Lymphocyte Activation immunology, Receptors, Antigen, T-Cell immunology, Receptors, CXCR3 immunology, T-Lymphocytes immunology
- Abstract
Endothelial cells present chemokines to T cells and can also stimulate the T cell antigen receptor by presentation of peptide-MHC antigen complexes. This study was designed to investigate the potential synergy between stimulation of the chemokine receptor CXCR3 and the human T cell receptor complex. Transendothelial T cell migration towards CXCL10 was modified by crosslinking CD3 immediately before addition to the endothelium. When resting endothelium was used, T cells which had been activated by crosslinking CD3 for only 1 min showed a significant reduction (p<0.0001) in migration when compared with untreated T cells. By contrast, endothelial cells which had been activated by stimulation with interferon-gamma and tumour necrosis factor-alpha supported a specific increase in the migration of activated T cells; this was most apparent after CD3 had been activated for 90 min (p<0.0001). The molecular basis for synergy between CXCR3 and the T cell receptor complex was investigated by measurement of fluorescence resonance energy transfer. This showed that CXCL10 induced a close (<10 nm) spatial association between CXCR3 and the CD3epsilon subunit on the cell-surface. These data demonstrate that stimulation of both CXCR3 and the T cell receptor has the potential to enhance specifically both the proliferation and extravasation of specific T cells during episodes of local inflammation.
- Published
- 2009
- Full Text
- View/download PDF
33. Anti-inflammatory therapy by intravenous delivery of non-heparan sulfate-binding CXCL12.
- Author
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O'Boyle G, Mellor P, Kirby JA, and Ali S
- Subjects
- Amino Acid Sequence, Amino Acid Substitution, Animals, CHO Cells, Chemokine CXCL12 administration & dosage, Chemokine CXCL12 pharmacology, Chemotaxis, Leukocyte immunology, Cricetinae, Cricetulus, Endothelium metabolism, Female, Heparitin Sulfate metabolism, Humans, Injections, Intravenous, Integrin alpha4beta1 immunology, Mice, Mice, Inbred BALB C, Molecular Sequence Data, Receptors, CXCR4 agonists, Signal Transduction drug effects, Anti-Inflammatory Agents pharmacology, Chemokine CXCL12 genetics, Receptors, CXCR4 metabolism
- Abstract
Interaction between chemokines and heparan sulfate (HS) is essential for leukocyte recruitment during inflammation. Previous studies have shown that a non-HS-binding mutant form of the inflammatory chemokine CCL7 can block inflammation produced by wild-type chemokines. This study examined the anti-inflammatory mechanism of a non-HS-binding mutant of the homeostatic chemokine CXCL12. Initial experiments demonstrated that mutant CXCL12 was an effective CXCR4 agonist. However, this mutant chemokine failed to promote transendothelial migration in vitro and inhibited the haptotactic response to wild-type CCL7, CXCL12, and CXCL8, and naturally occurring chemoattractants in synovial fluid from the rheumatoid synovium, including CCL2, CCL7, and CXCL8. Notably, intravenous administration of mutant CXCL12 also inhibited the recruitment of leukocytes to murine air pouches filled with wild-type CXCL12. Following intravenous administration, wild-type CXCL12 was cleared from the circulation rapidly, while the mutant chemokine persisted for >24 h. Chronic exposure to mutant CXCL12 in the circulation reduced leukocyte-surface expression of CXCR4, reduced the chemotactic response of these cells to CXCL12, and inhibited normal chemokine-mediated induction of adhesion between the alpha4beta1 integrin, VLA-4, and VCAM-1. These data demonstrate that systemic administration of non-HS-binding variants of CXCL12 can mediate a powerful anti-inflammatory effect through chemokine receptor desensitization.
- Published
- 2009
- Full Text
- View/download PDF
34. Chemokine-mediated inflammation: Identification of a possible regulatory role for CCR2.
- Author
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O'Boyle G, Brain JG, Kirby JA, and Ali S
- Subjects
- Cell Line, Chemotaxis drug effects, Chemotaxis genetics, Enzyme Activation drug effects, Enzyme Activation genetics, Enzyme Activation physiology, Gene Expression Regulation drug effects, Gene Expression Regulation genetics, Humans, Inflammation genetics, Inflammation immunology, Mitogen-Activated Protein Kinase 3 genetics, Mitogen-Activated Protein Kinase 3 immunology, Monocyte Chemoattractant Proteins pharmacology, Oncogene Protein p21(ras) genetics, Oncogene Protein p21(ras) immunology, Proto-Oncogene Proteins c-akt genetics, Proto-Oncogene Proteins c-akt immunology, Proto-Oncogene Proteins c-myc genetics, Proto-Oncogene Proteins c-myc immunology, Receptors, CCR2, Receptors, Chemokine genetics, Signal Transduction drug effects, Signal Transduction genetics, Chemotaxis immunology, Gene Expression Regulation immunology, Monocyte Chemoattractant Proteins immunology, Receptors, Chemokine immunology, Signal Transduction immunology
- Abstract
The chemokine receptor CCR2 binds four pro-inflammatory monocyte chemoattractant proteins, designated MCP1/CCL2, MCP2/CCL8, MCP3/CCL7 and MCP4/CCL13. This study demonstrates the important biology of this receptor during the response to the chemokine milieu. Competitive chemotaxis and calcium flux assays were performed utilising mixtures of chemokines to assess a hierarchal arrangement of chemokine prepotency; these demonstrated that the MCP2-CCR2 interaction is able to supersede signals generated by RANTES, another pro-inflammatory chemokine, or the homeostatic chemokine SDF1. These observations were validated using three physiologically relevant monocytic cell lines. Having identified the importance of CCR2, experiments were then performed to examine the signal transduction processes coupled to this receptor. G protein coupling was initially examined; Cholera toxin reduced the chemotactic response to MCP2 (p<0.001), whilst the response to the other MCP chemokines remained normal. The response to MCP2 was uniquely inhibited by elevated concentrations of cAMP and, unlike MCP1, 3 and 4 (p<0.05), MCP2 failed to inhibit adenylate cyclase. Expression of dominant negative H-ras demonstrated that each MCP chemokine required active ras in order to elicit ERK activation and a chemotactic response. Unlike MCP1, MCP2 failed to induce nuclear translocation of activated ERK1 or subsequent induction of c-Myc expression. Akt activation also showed ligand-specific differences, with MCP2 producing a delayed response compared to the other MCP chemokines. Together these data highlight the importance of CCR2 and suggest that it is a powerful tool for fine tuning the immune response.
- Published
- 2007
- Full Text
- View/download PDF
35. An apparent paradox: chemokine receptor agonists can be used for anti-inflammatory therapy.
- Author
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Ali S, O'Boyle G, Mellor P, and Kirby JA
- Subjects
- Anti-Inflammatory Agents pharmacology, Drug Design, Humans, Receptors, Chemokine physiology, Anti-Inflammatory Agents therapeutic use, Inflammation drug therapy, Receptors, Chemokine agonists
- Abstract
Inflammation plays an important role in a wide range of human diseases. Chemokines are a group of proteins which control the migration and activation of the immune cells involved in all aspects of the inflammatory response. Chemokines bind to specific receptors of the seven-transmembrane spanning type on target leukocytes and also bind to cell-surface glycosaminoglycans (GAG). Leukocytes express a range of chemokine receptors which can cross-desensitise each other, potentially allowing a single chemokine receptor agonist to desensitise all the chemokine receptors on a cell. If an appropriate single receptor agonist is engineered to be non-chemotactic itself, then a treated cell will lose the potential to migrate in response to chemokines towards any developing site of inflammation. A non-GAG-binding but receptor agonistic form of the chemokine CCL7 can inhibit leukocyte recruitment in response to a diverse range of chemokines in vitro and in vivo. We hypothesise that this modified chemokine mediates its effect by inducing homologous and heterologous receptor desensitisation and further propose that other suitable candidates could include agonistic chemokine receptor-specific antibodies or small molecule chemokine receptor agonists. Hence, an appropriate chemokine receptor agonist could be used to inhibit multiple chemokine receptors, thereby producing a powerful and robust anti-inflammatory effect. This review considers the mechanisms leading to chemokine receptor desensitisation and discusses the potential to develop a new class of anti-inflammatory agents based on targeted stimulation of chemokine receptors.
- Published
- 2007
- Full Text
- View/download PDF
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