ORCID Profile
0000-0002-4623-9098
Current Organisation
The University of Queensland: Brisbane, Qld, AU
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Publisher: Springer Science and Business Media LLC
Date: 02-11-2014
DOI: 10.1038/NM.3705
Abstract: In type 2 diabetes, hyperglycemia is present when an increased demand for insulin, typically due to insulin resistance, is not met as a result of progressive pancreatic beta cell dysfunction. This defect in beta cell activity is typically characterized by impaired insulin biosynthesis and secretion, usually accompanied by oxidative and endoplasmic reticulum (ER) stress. We demonstrate that multiple inflammatory cytokines elevated in diabetic pancreatic islets induce beta cell oxidative and ER stress, with interleukin-23 (IL-23), IL-24 and IL-33 being the most potent. Conversely, we show that islet-endogenous and exogenous IL-22, by regulating oxidative stress pathways, suppresses oxidative and ER stress caused by cytokines or glucolipotoxicity in mouse and human beta cells. In obese mice, antibody neutralization of IL-23 or IL-24 partially reduced beta cell ER stress and improved glucose tolerance, whereas IL-22 administration modulated oxidative stress regulatory genes in islets, suppressed ER stress and inflammation, promoted secretion of high-quality efficacious insulin and fully restored glucose homeostasis followed by restitution of insulin sensitivity. Thus, therapeutic manipulation of immune regulators of beta cell stress reverses the hyperglycemia central to diabetes pathology.
Publisher: Frontiers Media SA
Date: 14-06-2022
DOI: 10.3389/FCIMB.2022.856962
Abstract: The mucosal surfaces that form the boundary between the external environment and the underlying tissue are protected by a mucus barrier. Mucin glycoproteins, both secreted and cell surface mucins, are the major components of the barrier. They can exclude pathogens and toxins while hosting the commensal bacteria. In this review, we highlight the dynamic function of the mucins and mucus during infection, how this mucosal barrier is regulated, and how pathogens have evolved mechanisms to evade this defence system.
Publisher: SAGE Publications
Date: 10-1996
DOI: 10.1177/096120339600500509
Abstract: ‘Antiphospholipid’ (aPL) antibodies are of important clinical significance because of their association with thrombosis both arterial and venous, recurrent foetal loss, specific neurological sequelae like seizures and chorea, cardiac valvular abnormalities and thrombocytopenia. 1 Traditionally these autoantibodies have been assayed using phospholipid (PL) dependent tests and are classified as lupus anticoagulants (LA) and anticardiolipin (aCL) antibodies based on the method of detection. 2 The antibodies thus, had been thought to bind PLs but it has now become clear that the true antigens are PL-binding proteins. The major protein consistently found as the target antigen for these autoantibodies is β 2 -glycoprotein I (β 2 -GPI). 3 Other candidate PL-binding proteins have also been investigated including prothrombin, protein C and protein S 4 but thus far appear to play less important roles in the binding of these antibodies.
Publisher: Elsevier BV
Date: 04-2001
Publisher: Elsevier BV
Date: 2002
Publisher: Springer Science and Business Media LLC
Date: 30-08-2019
DOI: 10.1038/S41388-019-0983-3
Abstract: Elevated CUB-domain containing protein 1 (CDCP1) is predictive of colorectal cancer (CRC) recurrence and poor patient survival. While CDCP1 expression identifies stem cell populations that mediate lung metastasis, mechanisms underlying the role of this cell surface receptor in CRC have not been defined. We sought to identify CDCP1 regulated processes in CRC using stem cell populations, enriched from primary cells and cell lines, in extensive in vitro and in vivo assays. These experiments, demonstrating that CDCP1 is functionally important in CRC tumor initiation, growth and metastasis, identified CDCP1 as a positive regulator of Wnt signaling. Detailed cell fractionation, immunoprecipitation, microscopy, and immunohistochemical analyses demonstrated that CDCP1 promotes translocation of the key regulators of Wnt signaling, β-catenin, and E-cadherin, to the nucleus. Of functional importance, disruption of CDCP1 reduces nuclear localized, chromatin-associated β-catenin and nuclear localized E-cadherin, increases sequestration of these proteins in cell membranes, disrupts regulation of CRC promoting genes, and reduces CRC tumor burden. Thus, disruption of CDCP1 perturbs pro-cancerous Wnt signaling including nuclear localization of β-catenin and E-cadherin.
Publisher: Springer Science and Business Media LLC
Date: 19-08-2016
DOI: 10.1038/LEU.2015.231
Abstract: Current immunosuppressive/anti-inflammatory agents target the responding effector arm of the immune response and their nonspecific action increases the risk of infection and malignancy. These effects impact on their use in allogeneic haematopoietic cell transplantation and other forms of transplantation. Interventions that target activated dendritic cells (DCs) have the potential to suppress the induction of undesired immune responses (for ex le, graft versus host disease (GVHD) or transplant rejection) and to leave protective T-cell immune responses intact (for ex le, cytomegalovirus (CMV) immunity). We developed a human IgG1 monoclonal antibody (mAb), 3C12, specific for CD83, which is expressed on activated but not resting DC. The 3C12 mAb and an affinity improved version, 3C12C, depleted CD83(+) cells by CD16(+) NK cell-mediated antibody-dependent cellular cytotoxicity, and inhibited allogeneic T-cell proliferation in vitro. A single dose of 3C12C prevented human peripheral blood mononuclear cell-induced acute GVHD in SCID mouse recipients. The mAb 3C12C depleted CMRF-44(+)CD83(bright) activated DC but spared CD83(dim/-) DC in vivo. It reduced human T-cell activation in vivo and maintained the proportion of CD4(+) FoxP3(+) CD25(+) Treg cells and also viral-specific CD8(+) T cells. The anti-CD83 mAb, 3C12C, merits further evaluation as a new immunosuppressive agent in transplantation.
Publisher: SAGE Publications
Date: 04-1996
DOI: 10.1177/096120339600500211
Abstract: Antiphospholipid antibodies were originally thought to bind negatively-charged (aniomic) phospholipids. Current evidence suggests that the target antigen is considerably more complex and includes β 2 -glycoprotein I, a phospholipid-binding plasma protein. Our under standing of the pathophysiology of the antiphospholipid syndrome has increased exponen tially with a number of studies into the interactions of antiphospholipid antibodies and β 2 -glycoprotein I.
Publisher: Wiley
Date: 21-12-2012
DOI: 10.1111/J.1440-1746.2011.06909.X
Abstract: The gastrointestinal tract is protected by a mucus barrier with both secreted and cell-surface mucins contributing to the exclusion of luminal microbes and toxins. Alterations in the structure and/or quantity of mucins alter the barrier function of mucus and could play roles in initiating and maintaining mucosal inflammation in inflammatory bowel diseases (IBD), and in driving cancer development in the intestine. The aim of this review is to focus on the roles of the mucins in IBD. The polymorphisms of mucin genes that have been associated with susceptibility to IBD, and alterations in mucin expression as well as factors that regulate production of the mucins in IBD, are summarized. Data from animal models of intestinal inflammation, which support the importance of mucins in IBD and cancer development, are also discussed.
Publisher: Public Library of Science (PLoS)
Date: 09-10-2009
Publisher: Frontiers Media SA
Date: 24-07-2020
Publisher: Wiley
Date: 2021
DOI: 10.1002/CTI2.1330
Abstract: Tumor‐associated autoantibodies (AAbs) in in iduals with cancer can precede clinical diagnosis by several months to years. The objective of this study was to determine whether the primary immune response in form of IgM and gut mucosa‐associated IgA can aid IgG AAbs in the detection of early‐stage colorectal cancer (CRC). We developed a novel protein array comprising 492 antigens seropositive in CRC. The array was used to profile IgG, IgM and IgA antibody signatures in 99 CRC patients and 99 sex‐ and age‐matched non‐cancer controls. A receiver operating curve (ROC), Kaplan–Meier survival analysis and univariate and multivariate Cox regression analyses were conducted. We identified a panel of 16 multi‐isotype AAbs with a cumulative sensitivity of 91% and specificity of 74% (AUC 0.90, 95% CI: 0.850–0.940) across all CRC stages. IgM and IgG isotypes were conversely associated with disease stage with IgM contributing significantly to improved stage I and II sensitivity of 96% at 78% specificity (AUC 0.928, 95% CI: 0.884–0.973). A single identified IgA AAb reached an overall sensitivity of 5% at 99% specificity (AUC 0.520, 95% CI: 0.440–0.601) balanced across all CRC stages. Kaplan–Meier analysis revealed that se33‐1 (ZNF638) IgG AAbs were associated with reduced 5‐year overall survival (log‐rank test, P = 0.012), whereas cumulative IgM isotype signatures were associated with improved 5‐year overall survival (log‐rank test, P = 0.024). IgM AAbs are associated with early‐stage colorectal cancer. Combining IgG, IgM and IgA AAbs is a novel strategy to improve early diagnosis of cancers.
Publisher: Elsevier BV
Date: 2023
Publisher: American Thoracic Society
Date: 15-03-2020
Publisher: Oxford University Press (OUP)
Date: 06-2001
DOI: 10.1046/J.1365-2249.2001.01555.X
Abstract: The diagnosis of the antiphospholipid syndrome (APS) requires both a typical clinical event plus a persistently positive test in an assay for either anticardiolipin (aCL) antibodies or a lupus anticoagulant (LA). Enzyme linked immunosorbent assays (ELISA) specific for autoantibodies against β2-glycoprotein I (β2GPI) or prothrombin are also used, but none of the tests are adequately sensitive or specific. A chromogenic assay was developed that measures the effect of test antibody or plasma s les on in vitro thrombin formation. It is able to detect both LA and β2GPI-dependent aCL antibodies and may have greater specificity for APS than currently available tests. Using this method various monoclonal antibodies (MoAbs) were examined, from mice immunized with β2GPI, mice with a spontaneous animal model of APS, and from three humans with APS. Plasma and affinity purified antibodies from patients with APS and control groups were also examined. Thrombin inhibition was more sensitive to perturbation by MoAbs than a combination of tests for LA (P & 0·05) and at lower antibody concentrations (12·5 µg/ml versus 100 µg/ml). There was a significant correlation between inhibition of thrombin generation and the level of MoAb reactivity to β2GPI (r = 0·90 P & 0·001) but not to CL (r = 0·06 P = 0·76). Plasma and affinity purified antibodies from patients with APS also inhibited thrombin generation, and significantly more so than patients with aPL from causes other than APS. APS patient s les showed thrombin inhibition in the presence of anti-β2GPI or antiprothrombin antibodies. All MoAbs binding β2GPI showed inhibition of thrombin generation, while MoAbs binding domain I of β2GPI had more LA effect.
Publisher: Research Square Platform LLC
Date: 26-07-2023
DOI: 10.21203/RS.3.RS-3183670/V1
Abstract: Chronic Lymphocytic Leukemia (CLL) is the most common leukemia in adults, characterized by the expansion of CD19 + CD5 + B cells. The origin of CLL remains debated, with one model suggesting that CLL cells carrying mutations in the variable regions of immunoglobulin are derived from post-germinal center B cells, whereas unmutated CLL cells originate from CD5 + mature B cell precursors. The cytokines BAFF and APRIL each play a significant role in CLL cell survival and accumulation, but their involvement in disease initiation is unclear. Using the TCL1-transgenic (Tg) model, we have demonstrated that BAFF, but not, APRIL is needed for the initiation and dissemination of CLL. In the absence of BAFF or its receptor BAFF-R, expression of the TCL1 transgene increases CLL cell numbers in the peritoneal cavity but does not allow dissemination into the periphery. BAFF binding to BAFF-R is not required for the survival of peritoneal CLL cells but for the expression of tumor-promoting genes, likely allowing peritoneal CLL cells to disseminate to other sites to drive CLL. Our findings unveil BAFF as an unrecognized tumor-promoting cytokine in CLL. Combining current CLL therapies with BAFF inhibition may offer dual benefits: reducing peripheral tumor burden and suppressing transformed CLL cell output.
Publisher: Elsevier BV
Date: 09-2000
Publisher: Elsevier BV
Date: 05-2013
DOI: 10.1038/MI.2012.98
Abstract: The MUC1 cell-surface mucin is highly expressed on the gastric mucosal surface, while MUC13 is highly expressed on the intestinal mucosal surface. Polymorphisms in both MUC1 and MUC13 have been linked to inflammatory bowel diseases. MUC1 can act as a decoy molecule on the apical cell surface of epithelial cells and thereby limit bacterial adherence, infection, and inflammation. In this study, we examined whether and how MUC1 and MUC13 modulate infectious and inflammatory signaling. Using gastrointestinal tissue from Muc1- or Muc13-deficient mice in ex vivo culture, MUC1 small interfering RNA (siRNA) silencing in MKN7 gastric epithelial cells, and MUC13 siRNA silencing in LS513 intestinal epithelial cells, we showed that loss of MUC1 increased chemokine secretion, whereas loss of MUC13 decreased chemokine secretion in response to tumor necrosis factor-α. Anti-inflammatory activity of MUC1 and pro-inflammatory activity of MUC13 were also seen after exposure to pathogens, NOD1 (nucleotide-binding oligomerisation domain-containing protein-1), and Toll-like receptor ligands. MUC1 and MUC13 both regulate chemokine secretion in gastrointestinal epithelial cells through a nuclear factor-κB-dependent pathway, although MUC13 modulation could also involve other pathways. Our studies demonstrate that MUC1 and MUC13 are important components of gastrointestinal homeostasis and that disruption or inappropriate expression of these mucins could predispose to infectious and inflammatory disease and inflammation-induced cancer.
Publisher: Springer Science and Business Media LLC
Date: 19-08-2019
DOI: 10.1038/S41388-019-0951-Y
Abstract: Many adenocarcinomas, including colorectal cancer (CRC), overexpress the MUC13 cell surface mucin, but the functional significance and mechanisms are unknown. Here, we report the roles of MUC13 in colonic tumorigenesis and tumor progression. High-MUC13 expression is associated with poor survival in two independent patient cohorts. In a comprehensive series of in vivo experiments, we identified a critical role for MUC13 in the development of this malignancy, by promoting survival and proliferation of tumor-initiating cells and driving an immunosuppressive environment that protects tumors from checkpoint inhibitor immunotherapy. In Muc13-deficient mice, fewer tumors are generated after exposure to carcinogens and inflammation, they have markedly reduced β-catenin signaling, have more tumor-infiltrating CD103
Publisher: Wiley
Date: 04-1997
Publisher: Elsevier BV
Date: 08-2016
DOI: 10.1016/J.COLSURFB.2016.03.076
Abstract: The naturally occurring polyphenol resveratrol (RES) has attracted increasing attention in recent years due to its antioxidant, anti-inflammatory, and anticancer activity. However, resveratrol's promising potential as a nutraceutical is hindered by its poor aqueous solubility, which limits its biological activity. Here we show that encapsulating resveratrol in colloidal mesoporous silica nanoparticles (MCM-48-RES) enhances its saturated solubility by ∼95% and increases its in vitro release kinetics compared to pure resveratrol. MCM-48-RES showed high loading capacity (20% w/w) and excellent encapsulation efficiency (100%). When tested against HT-29 and LS147T colon cancer cell lines, MCM-48-RES-mediated in vitro cell death was higher than that of pure resveratrol, mediated via the PARP and cIAP1 pathways. Finally, MCM-48-RES treatment also inhibited lipopolysaccharide-induced NF-κB activation in RAW264.7 cells, demonstrating improved anti-inflammatory activity. More broadly, our observations demonstrate the potential of colloidal mesoporous silica nanoparticles as next generation delivery carriers for hydrophobic nutraceuticals.
Publisher: Oxford University Press (OUP)
Date: 25-03-2004
Publisher: Elsevier BV
Date: 2020
Publisher: Elsevier BV
Date: 04-1997
Abstract: beta 2-Glycoprotein I, a serum protein with in vitro anticoagulant properties, plays a vital role in the binding of "anticardiolipin" antibodies purified from patients with autoimmune disease in a cardiolipin ELISA. The gene (ApoH) encoding the mouse beta 2-glycoprotein I, including 5' and 3' flanking sequences, has been isolated and characterized. The gene covers approximately 18 kb and consists of eight exons. We demonstrate that the gene is present in a single copy in the mouse genome. The exon/intron structure was elucidated by nucleotide sequencing and restriction enzyme mapping. The exon/intron splice junction sites follow the gt/ag consensus sequence rule. The transcription start site was identified by primer extension 44 nucleotides upstream of the initiator AUG codon. beta 2-Glycoprotein I consists of repeated domains that correspond well to the exon/intron structure of the gene.
Publisher: Humana Press
Date: 16-12-2012
DOI: 10.1007/978-1-61779-513-8_18
Abstract: Most mammalian pathogens and parasites infect their hosts via the mucosal surfaces. The first barrier they encounter in all mucosal tissues is a layer of viscous mucus which can be modulated by immune responses to the pathogen or parasite. The major macromolecular constituents of mucus are secreted mucin glycoproteins which give mucus its viscous properties. Underneath the mucus layer, the mucosal epithelial cells have a cell surface glycocalyx that is rich in transmembrane mucin glycoproteins. Both the cell surface and secreted mucins present a vast array of potential binding sites for pathogens and parasites and both forms of mucins are involved in protecting the host from infection. However, many pathogens and parasites have evolved mechanisms to subvert the mucin barrier. Thus, studying mucin interactions with pathogens and parasites is critical to understanding host-pathogen interactions at the mucosal surfaces. In this chapter, we describe methods for studying the interactions between mucins and pathogens and parasites, methods for studying the degradation of mucins by pathogens and parasites, and in vitro and in vivo methods for exploring the functional significance of the mucins in host defence from infection.
Publisher: SAGE Publications
Date: 02-1998
DOI: 10.1177/096120339800700202
Abstract: It has become clear that β2-glycoprotein I (β2GPI) is the most common and best-characterised antigenic target for ‘antiphospholipid’ (aPL) autoantibodies. These antibodies preferentially bind β2GPI that has been immobilised on anionic phospholipid membranes or certain synthetic surfaces. These surfaces appear to act by increasing antigen density to allow binding of intrinsically low-affinity anti-β2GPI autoantibodies. Binding of β2GPI in fluid phase is weak and requires high concentrations of β2GPI. Our understanding of the pathophysiology of the ‘Antiphospholipid’ Syndrome (APS) has increased exponentially with the number of studies into the interactions of aPL antibodies and β2GPI.
Publisher: Elsevier BV
Date: 2022
Start Date: 2011
End Date: 2012
Funder: Cancer Council Queensland
View Funded ActivityStart Date: 2021
End Date: 2022
Funder: Gastroenterological Society of Australia
View Funded ActivityStart Date: 2021
End Date: 2022
Funder: Gastroenterological Society of Australia
View Funded ActivityStart Date: 2014
End Date: 2016
Funder: National Health and Medical Research Council
View Funded Activity