Publications (8)74.94 Total impact
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Article: In vivo modulation of angiogenesis by beta 2 glycoprotein I.
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ABSTRACT: Beta 2 glycoprotein I (β2GPI) is the major auto antigen in the antiphospholipid syndrome but also interacts with fibrinolytic and angiogenic proteins. The aim of this study was to examine the angiogenic potential of β2GPI in vivo in β2GPI deficient mice utilizing angiogenic assays. β2GPI deficient mice show increased microvessel formation in comparison to β2GPI replete controls when injected with growth factor free-matrigel implants. However, microvessel formation in matrigel plugs of β2GPI deficient mice was less than in β2GPI replete mice when basic fibroblast growth factor (bFGF) was included in the matrigel. Hemoglobin content was higher in vascular endothelial growth factor (VEGF) containing-matrigel plugs in the β2GPI deficient mouse demonstrating that the lack of β2GPI led to increased extravasation by VEGF. Melanoma B16F10 tumour growth was enhanced in β2GPI deficient mice. Melanoma microvessel density was increased in β2GPI deficient mice but the proliferation rate of tumour cells (determined by Ki67 immunohistochemistry) was unaffected by the presence or absence of β2GPI. Subcutaneous delivery of native human β2GPI by the ALZET osmotic pump did not affect melanoma tumour growth in β2GPI deficient mice. We conclude that the in vivo unopposed action of β2GPI is anti-angiogenic however this function is modified in the presence of a strong angiogenic stimulus into stabilization of vessel formation. Although the presence of β2GPI attenuates vessel sprouting in certain tumours, no survival benefit is conferred to tumour bearing animals. This does not preclude the potential benefit of modified or fragments of β2GPI in anti-angiogenesis research.Journal of Autoimmunity 11/2010; 35(3):232-40. · 7.37 Impact Factor -
Article: Redox control of β2-glycoprotein I-von Willebrand factor interaction by thioredoxin-1.
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ABSTRACT: β(2) -Glycoprotein I (β(2) GPI) is an abundant plasma protein that is closely linked to blood clotting, as it interacts with various protein and cellular components of the coagulation system. However, the role of β(2) GPI in thrombus formation is unknown. We have recently shown that β(2) GPI is susceptible to reduction by the thiol oxidoreductases thioredoxin-1 and protein disulfide isomerase, and that reduction of β(2) GPI can take place on the platelet surface. β(2) GPI, reduced by thioredoxin-1, was labeled with the selective sulfhydryl probe N(a)-(3-maleimidylpropionyl)biocytin and subjected to mass spectrometry to identify the specific cysteines involved in the thiol exchange reaction. Binding assays were used to examine the affinity of reduced β(2) GPI for von Willebrand factor (VWF) and the effect of reduced β2GPI on glycoprotein (GP)Ibα binding to VWF. Platelet adhesion to ristocetin-activated VWF was studied in the presence of reduced β(2) GPI. We demonstrate that the Cys288-Cys326 disulfide in domain V of β(2) GPI is the predominant disulfide reduced by thioredoxin-1. Reduced β(2) GPI in vitro displays increased binding to VWF that is dependent on disulfide bond formation. β(2) GPI reduced by thioredoxin-1, in comparison with non-reduced β(2) GPI, leads to increased binding of GPIbα to VWF and increased platelet adhesion to activated VWF. Given the importance of thiol oxidoreductases in thrombus formation, we provide preliminary evidence that the thiol-dependent interaction of β(2) GPI with VWF may contribute to the redox regulation of platelet adhesion.Journal of Thrombosis and Haemostasis 08/2010; 8(8):1754-62. · 5.73 Impact Factor -
Article: Mast cells/basophils in the peripheral blood of allergic individuals who are HIV-1 susceptible due to their surface expression of CD4 and the chemokine receptors CCR3, CCR5, and CXCR4.
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ABSTRACT: A population of metachromatic cells with mast cell (MC) and basophil features was identified recently in the peripheral blood of patients with several allergic disorders. This study now shows that these metachromatic cells express on their surface the high-affinity IgE receptor (FcepsilonRI), CD4, and the chemokine receptors CCR3, CCR5, and CXCR4, but not the T-cell surface protein CD3 and the monocyte/macrophage surface protein CD68. This population of MCs/basophils can be maintained ex vivo for at least 2 weeks, and a comparable population of cells can be generated in vitro from nongranulated hematopoietic CD3(-)/CD4(+)/CD117(-) progenitors. Both populations of MCs/basophils are susceptible to an M-tropic strain of human immunodeficiency virus 1 (HIV-1). Finally, many patients with acquired immunodeficiency syndrome have HIV-1-infected MCs/basophils in their peripheral blood. Although it is well known that HIV-1 can infect CD4(+) T cells and monocytes, this finding is the first example of a human MC or basophil shown to be susceptible to the retrovirus. (Blood. 2001;97:3484-3490)Blood 07/2001; 97(11):3484-90. · 9.90 Impact Factor -
Article: Identification of a novel population of mast cells/basophils in human periphal blood of allergic patients which is HIV-1 susceptible due to its surface expression of CD4, CCR5, and CXCR4.
The Journal of allergy and clinical immunology 01/2000; Vol. 105(Issue 1):pp. S86-S87. · 9.17 Impact Factor -
Article: Genetic influences on type I collagen synthesis and degradation: further evidence for genetic regulation of bone turnover.
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ABSTRACT: Circulating osteocalcin, a marker of bone formation, is under strong genetic influence, and this effect is related to the genetic influence on bone density. To examine genetic influences on bone turnover further, other markers of bone formation (serum carboxyterminal propeptide of type I procollagen, PICP), bone resorption (serum pyridinoline cross-linked carboxyterminal telopeptide of type I collagen, ICTP), and nonosseous connective tissue synthesis (serum aminoterminal propeptide of type III procollagen, PIIINP) were studied in 82 female twin pairs: 42 monozygotic (MZ) and 40 dizygotic (DZ) twin pairs (mean age, MZ; 48.4 yr; DZ; 45.6 yr). The intraclass correlation coefficients of MZ twin pairs, rMZ, for serum PICP (0.78) and serum ICTP (0.68) were significantly greater than the corresponding rDZ (0.31 and 0.36, respectively), but a genetic effect on serum PIIINP was not demonstrable. Within DZ twin pair differences in serum PICP predicted differences in lumbar spine bone density (r = -0.37); higher serum PICP levels indicating the twin with the lower lumbar spine bone density. Also within pair differences in serum ICTP and PICP predicted differences in bone density at the lumbar spine independent of serum osteocalcin. These data indicate that both synthesis and degradation of type I collagen are genetically determined and that this phenomenon is related to the genetic regulation of bone density.Journal of Clinical Endocrinology & Metabolism 07/1994; 78(6):1461-6. · 6.50 Impact Factor -
Article: Prediction of bone density from vitamin D receptor alleles.
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ABSTRACT: Bone density achieved in early adulthood is the major determinant of risk of osteoporotic fracture. Up to 60% of women suffer osteoporotic fractures as a result of low bone density, which is under strong genetic control acting through effects on bone turnover. Here we show that common allelic variants in the gene encoding the vitamin D receptor can be used to predict differences in bone density, accounting for up to 75% of the total genetic effect on bone density in healthy individuals. The genotype associated with lower bone density was overrepresented in postmenopausal women with bone densities more than 2 standard deviations below values in young normal women. The molecular mechanisms by which bone density is regulated by the vitamin D receptor gene are not certain, although allelic differences in the 3' untranslated region may alter messenger RNA levels. These findings could open new avenues to the development and targeting of prophylactic interventions. It follows that other pathophysiological processes considered to be subject to complex multifactorial genetic regulation may also be modulated by a single gene with pleiotropic transcriptional actions.Nature 02/1994; 367(6460):284-7. · 36.28 Impact Factor -
Article: Beta 2 glycoprotein I is a substrate of thiol oxidoreductases.
Blood. IN PRESS, 25th Feb 2010. -
Article: In vivo modulation of angiogenesis by beta 2 glycoprotein I
[show abstract] [hide abstract]
ABSTRACT: Beta 2 glycoprotein I (β2GPI) is the major auto antigen in the antiphospholipid syndrome but also interacts with fibrinolytic and angiogenic proteins. The aim of this study was to examine the angiogenic potential of β2GPI in vivo in β2GPI deficient mice utilizing angiogenic assays. β2GPI deficient mice show increased microvessel formation in comparison to β2GPI replete controls when injected with growth factor free-matrigel implants. However, microvessel formation in matrigel plugs of β2GPI deficient mice was less than in β2GPI replete mice when basic fibroblast growth factor (bFGF) was included in the matrigel. Hemoglobin content was higher in vascular endothelial growth factor (VEGF) containing-matrigel plugs in the β2GPI deficient mouse demonstrating that the lack of β2GPI led to increased extravasation by VEGF. Melanoma B16F10 tumour growth was enhanced in β2GPI deficient mice. Melanoma microvessel density was increased in β2GPI deficient mice but the proliferation rate of tumour cells (determined by Ki67 immunohistochemistry) was unaffected by the presence or absence of β2GPI. Subcutaneous delivery of native human β2GPI by the ALZET osmotic pump did not affect melanoma tumour growth in β2GPI deficient mice. We conclude that the in vivo unopposed action of β2GPI is anti-angiogenic however this function is modified in the presence of a strong angiogenic stimulus into stabilization of vessel formation. Although the presence of β2GPI attenuates vessel sprouting in certain tumours, no survival benefit is conferred to tumour bearing animals. This does not preclude the potential benefit of modified or fragments of β2GPI in anti-angiogenesis research.Journal of Autoimmunity.
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2010
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St George Hospital
Sydney, New South Wales, Australia
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