ORCID Profile
0000-0002-3968-6551
Current Organisations
University of Adelaide
,
University of South Australia
,
University of Melbourne
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Publisher: Springer Science and Business Media LLC
Date: 10-04-2018
DOI: 10.1038/S41467-018-03640-Y
Abstract: Despite anti-TNF therapy advancements for inflammatory diseases such as rheumatoid arthritis, the burden of diseases remains high. An 11-mer TNF peptide, TNF 70–80 , is known to stimulate selective functional responses compared to the parent TNF molecule. Here, we show that TNF 70–80 binds to the TNF receptor, activating p38 MAP kinase through TNF receptor-associated factor 2. Using truncated TNFR mutants, we identify the sequence in TNFRI which enables p38 activation by TNF 70–80 . Peptides with this TNFRI sequence, such as TNFRI 206–211 bind to TNF and inhibit TNF-induced p38 activation, respiratory burst, cytokine production and adhesion receptor expression but not F-Met-Leu-Phe-induced respiratory burst in neutrophils. TNFRI 206–211 does not prevent TNF binding to TNFRI or TNF-induced stimulation of ERK, JNK and NF-κB. TNFRI 206–211 inhibits bacterial lipopolysaccharide-induced peritonitis, carrageenan-induced and antigen-induced paw inflammation, and respiratory syncytial virus-induced lung inflammation in mice. Our findings suggest a way of targeting TNF-p38 pathway to treat chronic inflammatory disorders.
Publisher: Springer Science and Business Media LLC
Date: 18-02-2021
DOI: 10.1038/S41598-021-82481-0
Abstract: In chronic obstructive pulmonary disease (COPD) apoptotic bronchial epithelial cells are increased, and their phagocytosis by alveolar macrophages (AM) is decreased alongside bacterial phagocytosis. Epithelial cellular lipids, including those exposed on uncleared apoptotic bodies, can become oxidized, and may be recognized and presented as non-self by antigen presenting cells. CD1b is a lipid-presenting protein, previously only described in dendritic cells. We investigated whether CD1b is upregulated in COPD AM, and whether lipid oxidation products are found in the airways of cigarette smoke (CS) exposed mice. We also characterise CD1b for the first time in a range of macrophages and assess CD1b expression and phagocytic function in response to oxidised lipid. Bronchoalveolar lavage and exhaled breath condensate were collected from never-smoker, current-smoker, and COPD patients and AM CD1b expression and airway 8-isoprostane levels assessed. Malondialdehyde was measured in CS-exposed mouse airways by confocal/immunofluorescence. Oxidation of lipids produced from CS-exposed 16HBE14o- (HBE) bronchial epithelial cells was assessed by spectrophotometry and changes in lipid classes assessed by mass spectrometry. 16HBE cell toxicity was measured by flow cytometry as was phagocytosis, CD1b expression, HLA class I/II, and mannose receptor (MR) in monocyte derived macrophages (MDM). AM CD1b was significantly increased in COPD smokers (4.5 fold), COPD ex-smokers (4.3 fold), and smokers (3.9 fold), and AM CD1b significantly correlated with disease severity (FEV 1 ) and smoking pack years. Airway 8-isoprostane also increased in smokers and COPD smokers and ex-smokers. Malondialdehyde was significantly increased in the bronchial epithelium of CS-exposed mice (MFI of 18.18 vs 23.50 for control). Oxidised lipid was produced from CS-exposed bronchial epithelial cells (9.8-fold of control) and showed a different overall lipid makeup to that of control total cellular lipid. This oxidised epithelial lipid significantly upregulated MDM CD1b, caused bronchial epithelial cell toxicity, and reduced MDM phagocytic capacity and MR in a dose dependent manner. Increased levels of oxidised lipids in the airways of COPD patients may be responsible for reduced phagocytosis and may become a self-antigen to be presented by CD1b on macrophages to perpetuate disease progression despite smoking cessation.
Publisher: Public Library of Science (PLoS)
Date: 18-02-2013
Publisher: Elsevier BV
Date: 07-2012
DOI: 10.1016/J.LUNGCAN.2012.01.017
Abstract: Cytotoxic CD8(+) T-cells mount immune responses to cancer via cytotoxic pathways including granzyme B. Cancer cells are also known to develop immune evasion mechanisms. We hypothesised that lung cancer cells would over-express the granzyme B-inhibitor, proteinase inhibitor-9 (PI-9) and down-regulate granzyme B expression by neighbouring CD8(+) T-cells. We investigated PI-9 expression in lung cancer cell lines, and primary lung cancer cells obtained at curative lung resection from cancer patients with/without chronic obstructive pulmonary disease (COPD). Granzyme B and PI-9 expression was also determined in CD8(+) T-cells from the cancer and non-cancer areas of resected lung tissue and from bronchoalveolar lavage (BAL). We then evaluated the effects of conditioned media from lung cancer cell lines on granzyme B expression and the cytotoxic activity of CD8(+) T-cells. PI-9 was highly expressed in lung cancer cell lines. Increased PI-9 expression was also observed in primary cancer cells vs. epithelial cells from non-cancer tissue or bronchial brushing-derived normal primary large airway epithelial cells. Expression significantly correlated with cancer stage. Significantly reduced granzyme B was noted in CD8(+) T-cells from cancer vs. non-cancer tissue. Granzyme B production by CD8(+) T-cells was reduced in the presence of conditioned media from lung cancer cell lines. Our data suggest that lung cancer cells utilise their increased PI-9 expression to protect from granzyme B-mediated cytotoxicity as an immune evasion mechanism, a function that increases with lung cancer stage.
Publisher: Oxford University Press (OUP)
Date: 12-09-2011
DOI: 10.1111/J.1365-2249.2011.04455.X
Abstract: Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease it is a leading cause of death and existing treatments have no proven disease-modifying effect. The mechanisms underlying this resistance are largely unknown, but suggest the presence of some self-maintaining pathogenic process, possibly initiated by cigarette smoking, that prevents the normal resolution of inflammation. We have previously reported increased production of proinflammatory cytokines and granzyme b by CD8+ T cells in COPD costimulatory receptor/ligand interactions required include CD80:86/CD28, B7-1/CTLA4, 4-1BB/1BBL and OX40/OX40L. We hypothesized that a dysregulated expression/function of these molecules may play a role in inflammatory/autoimmune components of COPD. We analysed T cell co-stimulatory molecules in blood from 34 controls, 15 smokers and 48 COPD subjects. We assessed the potential functional relevance of CD8/CD28null cells in COPD by measuring their production of proinflammatory cytokines, co-stimulatory molecules, granzyme and perforin. A smoke-exposed murine model was applied to investigate the relative expression of CD8/CD28null T cells in blood, lung tissue and airway. CD8/CD28null cells were increased in both current- and ex-smoker COPD groups these cells expressed significantly more interferon (IFN)-γ, OX40, 4-1BB, CTLA4, granzyme and perforin when stimulated than CD8/CD28+ T cells. There were no changes in CD4/CD28null T cells. In mice exposed to cigarette smoke for 12 weeks, CD8/CD28null T cells were significantly increased in the airway with a trend for an increase in lung tissue and blood. Increased production of proinflammatory cytokines and expression of alternative co-stimulatory molecules by CD8/CD28null T cells may play a role in inflammatory or autoimmune responses in COPD and identify therapeutic targets.
Publisher: Wiley
Date: 14-09-2020
DOI: 10.1111/INM.12779
Publisher: Elsevier BV
Date: 11-2004
Publisher: Elsevier BV
Date: 10-2008
Publisher: Public Library of Science (PLoS)
Date: 26-04-2013
Publisher: Springer Science and Business Media LLC
Date: 2008
DOI: 10.1186/AR2426
Publisher: Elsevier BV
Date: 09-2011
Publisher: Wiley
Date: 02-02-2016
DOI: 10.1111/AJR.12280
Abstract: Patients diagnosed with cancer in the Emergency Department (ED) have more advanced disease at diagnosis and poorer outcomes. High rates of initial presentation to ED suggest potential problems with access to care. The aim of this project was to interpret findings in regional/rural Victoria and explore implications for practice. Cross-sectional study linking two independent data sets. Regional city of Geelong and surrounding rural areas in south-west Victoria. All newly diagnosed cancer patients in 2009. Number of cancer patients diagnosed in the ED. One in five newly diagnosed cancer patients present to ED 6 months prior to cancer diagnosis. One in 10 is diagnosed as a result of their ED visit. Patients presenting to ED were older, more often men and from disadvantaged areas. Symptoms on presentation included chest complaints, bowel obstruction, abdominal pain, anaemia and generalised weakness. Cancer diagnosed in the ED is associated with advanced stage and shorter survival. Reasons for presentation to ED would be multifactorial and include complex cases with coexisting symptoms making diagnosis difficult. The general public appear to have a low level of awareness of alternative primary care services or difficulty accessing such information. Some of the changes towards reducing the number of patients presenting to ED will include patient education.
Publisher: American Thoracic Society
Date: 05-2011
Publisher: Wiley
Date: 06-2018
DOI: 10.1111/IMJ.13617
Abstract: Magnetic resonance imaging (MRI) accuracy after neoadjuvant systemic therapy (NST) for breast cancer varies according to hormone receptor (HR), human epidermal growth factor receptor type-2 (HER2) subtype and Ki-67 proliferation index. Whether MRI accuracy varies by genomic signatures is unknown. We examined the accuracy of MRI in the NEONAB trial (Clinicaltrials.gov #: NCT01830244). To examine the accuracy of MRI to predict pathological response to neoadjuvant therapy for breast cancer in the NEONAB trial. Patients with stages II-III breast cancer received sequential epirubicin, cyclophosphamide and nab-paclitaxel and trastuzumab if they were HER2+. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated to assess the utility of preoperative MRI to predict pathological complete response (pCR). Bland-Altman plots were used to assess agreement between MRI and pathological assessment of residual disease. MRI correctly predicted pCR in 64.1% of the cohort. Sensitivity and specificity were 52% and 78%, respectively PPV 73% and NPV 58%. MRI predicted pCR most accurately in HER2-positive patients sensitivity 58%, specificity 100%, PPV 100% and NPV 38%. MRI had higher PPV and NPV in tumours with Ki-67 ≥ 15% than tumours with Ki-67 < 15%, 75% versus 50% and 57.5% versus 50%, respectively. In this study, MRI underestimated residual tumour size by 1.65 mm (limits of agreement: 43.07-39.77 mm). MRI appears more accurate for predicting pCR in HER2+ disease than other subtypes and in cancers with Ki-67 ≥ 15% compared to those with Ki-67 < 15%. Accuracy of MRI in our HR+, RS ≥ 25 cohort is comparable to previous reports of unselected HR+ disease. MRI post-NST should be interpreted in conjunction with HER2 status and Ki-67 index of the primary.
Publisher: Wiley
Date: 25-01-2013
DOI: 10.1111/J.1440-1843.2012.02287.X
Abstract: Natural killer (NK) and natural killer T (NKT)-like cells represent a small but important proportion of effector lymphocytes that we have previously shown to be major sources of pro-inflammatory cytokines and granzymes. We hypothesized that these cells would be increased in the airway in chronic obstructive pulmonary disease (COPD), accompanied by reduced expression of the inhibitory receptor CD94 (Kp43) and increased expression of cytotoxic mediators granzyme B and perforin. We measured NK and NKT-like cells and their expression of CD94 in the blood of COPD patients (n = 71 30 current and 41 ex-smokers), smokers (16) and healthy controls (25), and bronchoalveolar lavage fluid (BALF) from a cohort of subjects (19 controls, 12 smokers, 33 COPD). Activation was assessed by measuring CD69 in blood and the cytotoxic potential of NK cells by measuring granzymes A and B, and using a cytotoxicity assay in blood and BALF. In blood in COPD, there were no significant changes in the proportion of NK or NKT-like cells or expression of granzyme A or NK cytotoxic potential versus controls. There was, however, increased expression of granzyme B and decreased expression of CD94 by both cell types versus controls. The proportion of NK and NKT-like cells were increased in BALF in COPD, associated with increased NK cytotoxicity, increased expression of granzyme B and decreased expression of the inhibitory receptor CD94 by both cell types. Treatment strategies that target NK and NKT-like cells, their cytotoxicity and production of inflammatory mediators in the airway may improve COPD morbidity.
Publisher: Bentham Science Publishers Ltd.
Date: 04-2011
DOI: 10.2174/138945011794751609
Abstract: Apoptosis of bronchial epithelial cells and the phagocytic clearance of these cells by alveolar macrophages (a process termed efferocytosis) are integral processes leading to repair of airway epithelial injury. Efferocytosis allows for the removal of apoptotic material with minimal inflammation and prevents the development of secondary necrosis and ongoing inflammation. Defective efferocytosis and the increased presence of apoptotic cells have been identified in the airways of subjects with chronic obstructive pulmonary disease (COPD). There are three major potential causes for this accumulation of apoptotic cells: (i) increased apoptosis per se as a result of an increase in apoptotic mediators, (ii) defects in the recognition of apoptotic cells by AM and (iii) failure to clear the unwanted cells by the process of efferocytosis. The implications of these processes in COPD and novel treatment strategies aimed at improving clearance of apoptotic cells form the focus of the present review.
Publisher: MDPI AG
Date: 12-07-2021
Abstract: Despite recent reviews of best practice for the treatment of Australian venomous bites and stings, there is controversy about some aspects of care, particularly the use of antivenom. Our aim was to understand current attitudes and practice in the management of suspected snake envenoming. A single-stage, cross-sectional survey of Australian emergency care physicians who had treated snake envenomation in the previous 36 months was conducted. Hospital pharmacists were also invited to complete a survey about antivenom availability, usage, and wastage in Australian hospitals. The survey was available between 5 March and 16 June 2019. A total of 121 snake envenoming cases were reported, and more than a third (44.6%) of patients were not treated with antivenom. For those treated with antivenom (n = 67), 29 patients (43%) received more than one oule. Nearly a quarter of respondents (21%) identified that antivenom availability was, or could be, a barrier to manage snake envenoming, while cost was identified as the least important factor. Adverse reactions following antivenom use were described in 11.9% of cases (n = 8). The majority of patients with suspected envenoming did not receive antivenom. We noted variation in dosage, sources of information, beliefs, and approaches to the care of the envenomed patient.
Publisher: Oxford University Press (OUP)
Date: 22-01-2010
DOI: 10.1189/JLB.0609399
Abstract: JNK is identified as a key MAP kinase which regulates neutrophil bactericidal activity and chemotaxis. The role of JNK in neutrophil chemotaxis and killing of microbial pathogens remains unclear. Using a recently described cell-permeable peptide inhibitor of the JNK pathway, based on the JBD of JIP-1, coupled to the protein transduction domain of HIV-TAT (TAT-JIP), in association with control peptides, we demonstrate that the JNK pathway plays a major role in regulating human neutrophil chemotaxis and killing of microbial pathogens. Serum-opsonized Staphylococcus aureus elicited JNK activation and c-jun phosphorylation. The activation of the JNK pathway and bactericidal activity were inhibited by the TAT-JIP peptide. The stimulation of oxygen radical generation by S. aureus was dependent on the JNK signaling pathway, as was the phagocytosis of serum-opsonized bacteria. Chemotaxis to activated serum complement but not random migration was inhibited by the TAT-JIP peptide. The findings demonstrate a major role for the JNK signaling pathway in neutrophil-mediated defense against microbial pathogens.
Publisher: Public Library of Science (PLoS)
Date: 14-02-2019
No related grants have been discovered for Violet Mukaro.