ORCID Profile
0000-0002-1033-849X
Current Organisation
University of Adelaide
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Publisher: Elsevier BV
Date: 12-2017
Publisher: Springer Science and Business Media LLC
Date: 06-01-2021
Publisher: Wiley
Date: 26-02-2013
DOI: 10.1111/BJH.12280
Abstract: N-cadherin (cadherin 2, type 1, N-cadherin (neuronal) CDN2) is a homotypic adhesion molecule that is upregulated in breast, prostate and bladder cancer. Here we investigated the prognostic significance of upregulated N-cadherin expression in multiple myeloma (MM). Our results indicate that N-cadherin protein and gene expression is abnormally increased in trephine biopsies and CD38(++) /CD138(+) plasma cells from MM patients, when compared with those of normal donors. In addition, levels of circulating N-cadherin were elevated in a subset of patients with MM (n = 81 mean: 14·50 ng/ml, range: 0-146·78 ng/ml), relative to age-matched controls (n = 27 mean: 2·66 ng/ml, range: 0-5·96 ng/ml), although this did not reach statistical significance. Notably, patients with abnormally high levels of N-cadherin (>6 ng/ml) had decreased progression-free survival (P = 0·036 hazard ratio: 1·94) and overall survival (P = 0·002 hazard ratio: 3·15), when compared with patients with normal N-cadherin levels (≤6 ng/ml). Furthermore, multivariate analyses revealed that the combination of N-cadherin levels and International Staging System (ISS) was a more powerful prognostic indicator than using ISS alone. Collectively, our studies demonstrate that circulating N-cadherin levels are a viable prognostic marker for high-risk MM patients.
Publisher: Bioscientifica
Date: 02-04-2012
DOI: 10.1530/JME-12-0003
Abstract: Improved glucose and lipid metabolism is a unique side effect of imatinib therapy in some chronic myeloid leukaemia (CML) patients. We recently reported that plasma levels of adiponectin, an important regulator of insulin sensitivity, are elevated following imatinib therapy in CML patients, which could account for these improved metabolic outcomes. Adiponectin is secreted exclusively from adipocytes, suggesting that imatinib modulates adiponectin levels directly, by transcriptional upregulation of adiponectin in pre-existing adipocytes, and/or indirectly, by stimulating adipogenesis. In this report, we have demonstrated that imatinib promotes adipogenic differentiation of human mesenchymal stromal cells (MSCs), which in turn secrete high-molecular-weight adiponectin. Conversely, imatinib does not stimulate adiponectin secretion from mature adipocytes. We hypothesise that inhibition of PDGFRα (PDGFRA) and PDGFRβ (PDGFRB) is the mechanism by which imatinib promotes adipogenesis. Supporting this, functional blocking antibodies to PDGFR promote adipogenesis and adiponectin secretion in MSC cultures. We have shown that imatinib is a potent inhibitor of PDGF-induced PI3 kinase activation and, using a PI3 kinase p110α-specific inhibitor (PIK-75), we have demonstrated that suppression of this pathway recapitulates the effects of imatinib on MSC differentiation. Furthermore, using mitogens that activate the PI3 kinase pathway, or MSCs expressing constitutively activated Akt, we have shown that activation of the PI3 kinase pathway negates the pro-adipogenic effects of imatinib. Taken together, our results suggest that imatinib increases plasma adiponectin levels by promoting adipogenesis through the suppression of PI3 kinase signalling downstream of PDGFR.
Publisher: Wiley
Date: 02-06-2016
DOI: 10.1002/JCB.25596
Abstract: MSC-like populations derived from induced pluripotent stem cells (iPSC-MSC) serve as an alternative stem cell source due to their high proliferative capacity. In this study, we assessed the immunomodulatory potential of iPSC-MSC generated from periodontal ligament (PDL) and gingival (GF) tissue. The iPSC-MSC lines exhibited a similar level of suppression of mitogen-stimulated peripheral blood mononuclear cells (PBMNC) proliferation compared to their respective parental fibroblast populations in vitro. Moreover, iPSC-MSC demonstrated the ability to suppress T-cells effector cells, Th1/Th2/Th17 populations, and increase levels of Treg cells. In order to investigate the mechanisms involved, expression of common MSC-derived soluble factors known to supress lymphocyte proliferation were assessed in iPSC-MSC cultured with PBMNC with direct cell-cell contact or separated in transwells. Real-time PCR analysis of factors known to be involved in MSC mediated immune regulation, found a general trend of elevated IDO1 and IL6 transcript levels in iPSC-MSC lines and their respective primary cells co-cultured with activated PBMNC, with a wide range of gene expression levels between the different mesenchymal cell types. The results suggest that different iPSC-MSC may be useful as a potential alternative source of cells for future clinical use in therapeutic applications because of their potent immunosuppressive properties. J. Cell. Biochem. 117: 2844-2853, 2016. © 2016 Wiley Periodicals, Inc.
Publisher: Public Library of Science (PLoS)
Date: 29-01-2020
Publisher: Springer Science and Business Media LLC
Date: 06-10-2015
Publisher: MDPI AG
Date: 03-08-2020
Abstract: In most instances, multiple myeloma (MM) plasma cells (PCs) are reliant on factors made by cells of the bone marrow (BM) stroma for their survival and growth. To date, the nature and cellular composition of the BM tumor microenvironment and the critical factors which drive tumor progression remain imprecisely defined. Our studies show that Gremlin1 (Grem1), a highly conserved protein, which is abundantly secreted by a subset of BM mesenchymal stromal cells, plays a critical role in MM disease development. Analysis of human and mouse BM stromal s les by quantitative PCR showed that GREM1/Grem1 expression was significantly higher in the MM tumor-bearing cohorts compared to healthy controls (p 0.05, Mann–Whitney test). Additionally, BM-stromal cells cultured with 5TGM1 MM PC line expressed significantly higher levels of Grem1, compared to stromal cells alone (p 0.01, t-test), suggesting that MM PCs promote increased Grem1 expression in stromal cells. Furthermore, the proliferation of 5TGM1 MM PCs was found to be significantly increased when co-cultured with Grem1-overexpressing stromal cells (p 0.01, t-test). To examine the role of Grem1 in MM disease in vivo, we utilized the 5TGM1/KaLwRij mouse model of MM. Our studies showed that, compared to immunoglobulin G (IgG) control antibody-treated mice, mice treated with an anti-Grem1 neutralizing antibody had a decrease in MM tumor burden of up to 81.2% (p 0.05, two-way ANOVA). The studies presented here demonstrate, for the first time, a novel positive feedback loop between MM PCs and BM stroma, and that inhibiting this vicious cycle with a neutralizing antibody can dramatically reduce tumor burden in a preclinical mouse model of MM.
Publisher: The Endocrine Society
Date: 08-2010
DOI: 10.1210/JC.2010-0086
Abstract: The mechanism(s) by which imatinib improves glycemic control in chronic myeloid leukemia (CML) patients with type 2 diabetes remains unclear. Adiponectin is an important regulator of insulin sensitivity that is secreted exclusively by adipocytes. We previously reported that imatinib promotes adipocytic differentiation of mesenchymal stromal cells. We therefore hypothesized that imatinib therapy would be associated with an increase in peripheral and intramedullary adiposity and elevated plasma adiponectin levels. Adiponectin levels in CML patient plasma, at diagnosis and then during imatinib mesylate therapy, was measured using an ELISA. Adiponectin multimers in plasma were analyzed using nondenaturing PAGE and immunoblotting. Intramedullary adiposity and adipose tissue mass was determined using histomorphometry and dual-energy X-ray absorptiometry, respectively. In CML patients, an increase in intramedullary and peripheral adiposity was observed after 6 months of imatinib therapy and plasma adiponectin levels, in the form of high- and low-molecular-weight complexes, were elevated 3-fold, compared with pretreatment levels, after 3, 6, and 12 months of therapy. Elevated adiponectin levels in imatinib-treated CML patients provide a possible mechanism for improved glucose and lipid metabolism reported for some imatinib-treated patients.
Publisher: Springer Science and Business Media LLC
Date: 10-2018
Publisher: Wiley
Date: 12-2016
Publisher: Elsevier BV
Date: 07-2014
Publisher: Wiley
Date: 12-09-2023
DOI: 10.1111/BJH.19102
Publisher: American Society of Hematology
Date: 28-01-2010
DOI: 10.1182/BLOOD-2009-08-237404
Abstract: Imatinib mesylate is a rationally designed tyrosine kinase inhibitor that has revolutionized the treatment of chronic myeloid leukemia and gastrointestinal stromal tumors. Although the efficacy and tolerability of imatinib are a vast improvement over conventional chemotherapies, the drug exhibits off-target effects. An unanticipated side effect of imatinib therapy is hypophosphatemia and hypocalcemia, which in part has been attributed to drug-mediated changes to renal and gastrointestinal handling of phosphate and calcium. However, emerging data suggest that imatinib also targets cells of the skeleton, stimulating the retention and sequestration of calcium and phosphate to bone, leading to decreased circulating levels of these minerals. The aim of this review is to highlight our current understanding of the mechanisms surrounding the effects of imatinib on the skeleton. In particular, it examines recent studies suggesting that imatinib has direct effects on bone-resorbing osteoclasts and bone-forming osteoblasts through inhibition of c-fms, c-kit, carbonic anhydrase II, and the platelet-derived growth factor receptor. The potential application of imatinib in the treatment of cancer-induced osteolysis will also be discussed.
Publisher: Springer Science and Business Media LLC
Date: 26-12-2007
Abstract: Osteoprotegerin (OPG), a key regulator of bone resorption, is hypothesized to have a role in prostate cancer (CaP) bone metastasis. As advanced CaP is treated by androgen ablation, we examined if androgen modulates OPG expression by CaP cell lines in vitro. Basal levels of secreted OPG protein were significantly greater in androgen-independent PC-3 cells compared with androgen-responsive LNCaP-FGC cells (P<0.001) OPG was not detected in the androgen-responsive CaP cell lines LAPC-4 or DuCaP. Treatment with 5alpha-dihydrotestosterone (5alpha-DHT) significantly decreased OPG protein levels in both PC-3 and LNCaP-FGC, with maximal suppression using 10(-9)-10(-7) M 5alpha-DHT in PC-3 (P<0.01 day 3), and using 10(-10)-10(-9) M 5alpha-DHT in LNCaP-FGC cells (P<0.01 day 6). OPG messenger RNA levels were not significantly altered by this 5alpha-DHT treatment. Co-treatment with 10(-6) M flutamide blocked 5alpha-DHT inhibition of OPG protein expression in LNCaP-FGC cells. These data suggest that androgen may modulate OPG protein levels in CaP cell lines in vitro using a post-transcriptional mechanism.
Publisher: Wiley
Date: 30-07-2010
DOI: 10.1002/JBMR.85
Abstract: Dasatinib is a potent tyrosine kinase inhibitor that is used to treat chronic myeloid leukemia in patients resistant or intolerant to imatinib mesylate. While designed to inhibit Abl and Src kinases, dasatinib shows multitarget effects, including inhibition of the macrophage colony-stimulating factor (M-CSF) receptor c-fms. We have shown previously that dasatinib abrogates osteoclast formation and activity in vitro owing, in part, to its specificity for c-fms. In this study we examined whether dasatinib could significantly alter bone volume in a model of physiologic bone turnover. Sprague-Dawley rats were administered dasatinib (5 mg/kg/day) or vehicle by gavage or zoledronic acid (ZOL 100 microg/kg/6 weeks) subcutaneously. Following 4, 8, and 12 weeks of treatment, serum biochemical, bone morphometric, and histologic analyses were performed. Whole-body bone mineral density and tibial cortical thickness where unchanged in the dasatinib- or ZOL-treated animals relative to controls. However, micro-computed tomographic (microCT) analysis of cancellous bone at the proximal tibias showed that trabecular volume (BV/TV) and thickness (Tb.Th) were increased in dasatinib-treated animals at levels comparable with those of the ZOL-treated group. These changes were associated with a decrease in osteoclast numbers (N.Oc/B.Pm) and surface (Oc.S/BS) and decreased serum levels of the osteoclast marker c-terminal collagen crosslinks (CTX-1). Mineral apposition rate (MAR), bone-formation rate (BFR), and levels of the serum osteoblast markers osteocalcin and N-terminal propeptide of type I procollagen (P1NP) were not altered significantly in the dasatinib-treated animals relative to controls. These studies show that dasatinib increases trabecular bone volume at least in part by inhibiting osteoclast activity, suggesting that dasatinib therapy may result in dysregulated bone remodeling.
Publisher: American Society of Hematology
Date: 29-04-2021
Publisher: The Endocrine Society
Date: 2013
DOI: 10.1210/JC.2012-2426
Abstract: Imatinib is a tyrosine kinase inhibitor that has been successfully used to treat Philadelphia chromosome-positive chronic myeloid leukemia (CML) and Kit+ gastrointestinal stromal tumors. We have previously shown that imatinib therapy is associated with an increase in trabecular bone volume. In the present study, we performed a prospective analysis of bone indices in imatinib-treated CML patients to determine the mechanism responsible for this altered bone remodeling. This study assessed the effects of high-dose (600 mg/d) imatinib on bone parameters in newly diagnosed chronic-phase Philadelphia chromosome-positive CML patients (n = 11) enrolled in the TIDEL II study. At baseline and after 6, 12, and 24 months of treatment, serum markers of bone remodeling were quantitated, dual-energy x-ray absorptiometry analysis of bone mineral density (BMD) was carried out, and a bone biopsy was collected for histological and micro-computed tomography analysis. Our studies show that the increase in trabecular bone volume and trabecular thickness after imatinib treatment was associated with a significant decrease in osteoclast numbers, accompanied by a significant decrease in serum levels of a marker of osteoclast activity. In contrast, osteoblast numbers were not altered by up to 24 months of imatinib treatment. Notably, we also found that imatinib caused a site-specific decrease in BMD at the femoral neck. These data suggest that imatinib therapy dysregulates bone remodeling, causing a generalized decrease in osteoclast number and activity that is not counterbalanced by a decrease in osteoblast activity, leading to increased trabecular bone volume. Further long-term investigations are required to determine the causes and consequences of the site-specific decrease in BMD at the femoral neck.
Publisher: Springer Science and Business Media LLC
Date: 09-01-2023
Publisher: Springer Science and Business Media LLC
Date: 18-12-2008
DOI: 10.1038/LEU.2008.356
Publisher: American Chemical Society (ACS)
Date: 13-03-2014
DOI: 10.1021/BM401825C
Abstract: The aim of this investigation was to understand and engineer the interactions between endothelial cells and the electrospun (ES) polyvinylidene fluoride-co-hexafluoropropylene (PVDF-HFP) nanofiber surfaces and evaluate their potential for endothelialization. Elastomeric PVDF-HFP s les were electrospun to evaluate their potential use as small diameter artificial vascular graft scaffold (SDAVG) and compared with solvent cast (SC) PVDF-HFP films. We examined the consequences of fibrinogen adsorption onto the ES and SC s les for endothelialisation. Bone marrow derived endothelial cells (BMEC) of human origin were incubated with the test and control s les and their attachment, proliferation, and viability were examined. The nature of interaction of fibrinogen with SC and ES s les was investigated in detail using ELISA, XPS, and FTIR techniques. The pristine SC and ES PVDF-HFP s les displayed hydrophobic and ultrahydrophobic behavior and accordingly, exhibited minimal BMEC growth. Fibrinogen adsorbed SC s les did not significantly enhance endothelial cell binding or proliferation. In contrast, the fibrinogen adsorbed electrospun surfaces showed a clear ability to modulate endothelial cell behavior. This system also represents an ideal model system that enables us to understand the natural interaction between cells and their extracellular environment. The research reported shows potential of ES surfaces for artificial vascular graft applications.
Publisher: Elsevier BV
Date: 04-2020
Publisher: Springer Science and Business Media LLC
Date: 23-07-2009
DOI: 10.1038/LEU.2009.150
Publisher: Impact Journals, LLC
Date: 14-04-2017
Publisher: MDPI AG
Date: 04-12-2020
Abstract: Multiple myeloma (MM) is a plasma cell (PC) malignancy characterised by the presence of MM PCs at multiple sites throughout the bone marrow. Increased numbers of peripheral blood MM PCs are associated with rapid disease progression, shorter time to relapse and are a feature of advanced disease. In this review, the current understanding of the process of MM PC dissemination and the extrinsic and intrinsic factors potentially driving it are addressed through analysis of patient-derived MM PCs and MM cell lines as well as mouse models of homing and dissemination. In addition, we discuss how patient cytogenetic subgroups that present with highly disseminated disease, such as t(4 ), t(14 ) and t(14 ), suggest that intrinsic properties of MM PC influence their ability to disseminate. Finally, we discuss the possibility of using therapeutic targeting of tumour dissemination to slow disease progression and prevent overt relapse.
Publisher: Mary Ann Liebert Inc
Date: 15-06-2016
Publisher: Wiley
Date: 06-2020
Publisher: Elsevier BV
Date: 08-2019
Publisher: Wiley
Date: 20-07-2015
DOI: 10.1111/BJH.13596
Abstract: Elevated expression of the cell adhesion molecule N-cadherin (cadherin 2, type 1, N-cadherin (neuronal) CDH2) is associated with poor prognosis in newly-diagnosed multiple myeloma (MM) patients. In this study, we investigated whether targeting of N-cadherin represents a potential treatment for the ~50% of MM patients with elevated N-cadherin. Initially, we stably knocked-down N-cadherin in the mouse MM plasma cell (PC) line 5TGM1 to assess the functional role of N-cadherin in MM pathogenesis. When compared with 5TGM1-scramble-shRNA cells, 5TGM1-Cdh2-shRNA cells had significantly reduced adhesion to bone marrow endothelial cells. However, N-cadherin knock-down did not affect 5TGM1 cell proliferation or adhesion to bone marrow stromal cells. In the C57BL/KaLwRij murine MM model, mice intravenously inoculated with 5TGM1-Cdh2-shRNA cells showed significantly decreased tumour burden after 4 weeks, compared with animals bearing 5TGM1-scramble-shRNA cells. Finally, the N-cadherin antagonist ADH-1 had no effect on tumour burden in the established disease setting, whereas up-front ADH-1 treatment resulted in significantly reduced tumour burden after 4 weeks. Our findings demonstrate that N-cadherin may play a key role in the extravasation of circulating MM PCs promoting bone marrow homing. Moreover, these studies suggest that N-cadherin may represent a viable therapeutic target to prevent the dissemination of MM PCs and delay MM disease progression.
Publisher: Elsevier BV
Date: 04-2007
DOI: 10.1593/NEO.06775
Abstract: Few treatment options exist for metastatic prostate cancer (PC) that becomes hormone refractory (HRPC). In vitro, plant-derived MINA-05 caused dose-dependent decreases in cell numbers in HRPC cell lines LNCaP-C4-2B and PC-3, and in androgen-sensitive LNCaP-FGC, DuCaP, and LAPC-4, by WST-1 assay. MINA-05 pretreatment significantly decreased clonogenic survival in agar and on plastic at 1 x and 2 x IC50 for PC-3 (P < .05 and P < .001, respectively), and at 1/2 x, 1 x, and 2 x IC50 for LNCaP-FGC cells (P < .001). MINA-05 also induced G2M arrest of LNCaP-FGC and PC-3 cells (by flow cytometry) and caused some apoptosis in LNCaP-FGC (sub-G1 peak on flow, expression of activated caspase-3) but not in PC-3 cells. Western blotting indicated that these cell cycle changes were associated with decreased levels of regulatory proteins cyclin B1 and cdc25C. MINA-05 given daily by gavage for 39 days did not diminish primary orthotopic PC-3 growth in nude mice, but decreased the extent of lymph node invasion at higher doses. We conclude that MINA-05 induces G2M arrest, inhibits cell growth, reduces PC cell regrowth in vitro, and reduces lymph node invasion after orthotopic PC-3 cell implantation in vivo. It has potential as an adjuvant treatment for patients with PC.
Publisher: Springer Science and Business Media LLC
Date: 04-02-2011
DOI: 10.1038/BCJ.2011.1
Publisher: Wiley
Date: 18-03-2013
DOI: 10.1002/JBMR.1821
Abstract: Previous reports have identified a role for the tyrosine kinase receptor EphB4 and its ligand, ephrinB2, as potential mediators of both bone formation by osteoblasts and bone resorption by osteoclasts. In the present study, we examined the role of EphB4 during bone repair after traumatic injury. We performed femoral fractures with internal fixation in transgenic mice that overexpress EphB4 under the collagen type 1 promoter (Col1-EphB4) and investigated the bone repair process up to 12 weeks postfracture. The data indicated that Col1-EphB4 mice exhibited stiffer and stronger bones after fracture compared with wild-type mice. The fractured bones of Col1-EphB4 transgenic mice displayed significantly greater tissue and bone volume 2 weeks postfracture compared with that of wild-type mice. These findings correlated with increased chondrogenesis and mineral formation within the callus site at 2 weeks postfracture, as demonstrated by increased safranin O and von Kossa staining, respectively. Interestingly, Col1-EphB4 mice were found to possess significantly greater numbers of clonogenic mesenchymal stromal progenitor cells (CFU-F), with an increased capacity to form mineralized nodules in vitro under osteogenic conditions, when compared with those of the wild-type control mice. Furthermore, Col1-EphB4 mice had significantly lower numbers of TRAP-positive multinucleated osteoclasts within the callus site. Taken together, these observations suggest that EphB4 promotes endochondral ossification while inhibiting osteoclast development during callus formation and may represent a novel drug target for the repair of fractured bones.
Publisher: American Society of Hematology
Date: 04-07-2019
Abstract: The era of targeted therapies has seen significant improvements in depth of response, progression-free survival, and overall survival for patients with multiple myeloma. Despite these improvements in clinical outcome, patients inevitably relapse and require further treatment. Drug-resistant dormant myeloma cells that reside in specific niches within the skeleton are considered a basis of disease relapse but remain elusive and difficult to study. Here, we developed a method to sequence the transcriptome of in idual dormant myeloma cells from the bones of tumor-bearing mice. Our analyses show that dormant myeloma cells express a distinct transcriptome signature enriched for immune genes and, unexpectedly, genes associated with myeloid cell differentiation. These genes were switched on by coculture with osteoblastic cells. Targeting AXL, a gene highly expressed by dormant cells, using small-molecule inhibitors released cells from dormancy and promoted their proliferation. Analysis of the expression of AXL and coregulated genes in human cohorts showed that healthy human controls and patients with monoclonal gammopathy of uncertain significance expressed higher levels of the dormancy signature genes than patients with multiple myeloma. Furthermore, in patients with multiple myeloma, the expression of this myeloid transcriptome signature translated into a twofold increase in overall survival, indicating that this dormancy signature may be a marker of disease progression. Thus, engagement of myeloma cells with the osteoblastic niche induces expression of a suite of myeloid genes that predicts disease progression and that comprises potential drug targets to eradicate dormant myeloma cells.
No related grants have been discovered for Kate Vandyke.