A5032255977- Multiple Myeloma Research and Treatments
- Chemokine receptors and signaling
- Cancer Mechanisms and Therapy
- Peptidase Inhibition and Analysis
- PI3K/AKT/mTOR signaling in cancer
- Cancer, Hypoxia, and Metabolism
- Bone health and treatments
- Hematopoietic Stem Cell Transplantation
- Metabolism, Diabetes, and Cancer
- Acute Myeloid Leukemia Research
- Neuroblastoma Research and Treatments
- Polyamine Metabolism and Applications
- Circular RNAs in diseases
- Cell Adhesion Molecules Research
- Obstructive Sleep Apnea Research
- Bone Metabolism and Diseases
- Glycosylation and Glycoproteins Research
- Adipose Tissue and Metabolism
- Cell death mechanisms and regulation
- Mast cells and histamine
- Prostate Cancer Diagnosis and Treatment
- Growth Hormone and Insulin-like Growth Factors
- Cognitive Functions and Memory
- Colorectal Cancer Screening and Detection
- Cancer-related gene regulation
The University of Adelaide
2007-2022
South Australian Health and Medical Research Institute
2015-2022
Freemasons Foundation Centre for Men's Health
2022
Institute for Stem Cell Biology and Regenerative Medicine
2020
South Australia Pathology
2004-2015
Hanson Institute
2006-2015
Centre for Cancer Biology
2010-2015
Case Western Reserve University
1996
University of Chicago
1994
Howard Hughes Medical Institute
1994
Proglucagon is processed differentially in the pancreatic alpha cells and intestinal L to yield either glucagon or glucagon-like peptide 1, respectively, structurally related hormones with opposing metabolic actions. Here, we have studied processing of proglucagon TC1-6 cells, an islet-cell line transformed by simian virus 40 large tumor (T) antigen, a model cell. We found that these process at certain dibasic cleavage sites release only small amounts as demonstrated both continuous...
Abstract Multiple myeloma (MM) is an incurable plasma cell (PC) malignancy able to mediate massive destruction of the axial and craniofacial skeleton. The aim this study was investigate role potent chemokine, stromal-derived factor-1α (SDF-1α) in recruitment osteoclast precursors bone marrow. Our studies show that MM PC produce significant levels SDF-1α protein exhibit elevated when compared with normal, age-matched subjects. level positively correlated presence multiple radiological lesions...
Abstract The cardiovascular therapeutic potential of bone marrow mesenchymal stromal/stem cells (MSC) is largely mediated by paracrine effects. Traditional preparation MSC has involved plastic adherence‐isolation. In contrast, prospective immunoselection aims to improve cell isolation enriching for precursor (MPC) at higher purity. This study compared the biological characteristics and trophic activity adherence‐isolated (PA‐MSC) MPC prepared from same human donors stromal antigen‐1...
Adipocytes (AdCs) and osteoblasts (OBs) are derived from mesenchymal stem cells (MSCs) differentiation toward either lineage is both mutually exclusive transcriptionally controlled. Recent studies implicate the mammalian target of rapamycin (mTOR) pathway as important in determining MSC fate, with inhibition mTOR promoting OB suppressing AdC differentiation. functions within two distinct multiprotein complexes, mTORC1 mTORC2, each which contains unique adaptor protein, raptor or rictor,...
The mammalian target of rapamycin complex 1 (mTORC1) is activated by extracellular factors that control bone accrual. However, the direct role this in osteoblast biology remains to be determined. To investigate question, we disrupted mTORC1 function preosteoblasts targeted deletion Raptor (Rptor) Osterix-expressing cells. Deletion Rptor resulted reduced limb length was associated with smaller epiphyseal growth plates postnatal skeleton. caused a marked reduction pre- and accrual, which...
Background Multiple myeloma is an incurable malignancy of bone marrow plasma cells. Progression multiple accompanied by increase in angiogenesis. Studies from our laboratory suggest a role for the CXCL12 chemokine this process, with circulating levels correlating angiogenesis patients myeloma. While mechanisms responsible aberrant cell expression remain to be determined, studies other systems hypoxia and hypoxia-inducible transcription factors.Design Methods The factor protein was examined...
Abstract Osteoblasts are bone-forming cells derived from mesenchymal stromal (MSCs) that reside within the bone marrow. In response to a variety of factors, MSCs proliferate and differentiate into mature, functional osteoblasts. Several studies have shown previously suppression PI3K mTOR signaling pathways in these strongly promotes osteogenic differentiation, which suggests inhibitors may be useful as anabolic agents. this study we examined effect BEZ235, newly developed dual inhibitor...
Disease progression and relapse in multiple myeloma is dependent on the ability of plasma cells (PC) to reenter circulation disseminate throughout bone marrow. Increased marrow hypoxia associated with increased recirculation PCs. Accordingly, we hypothesized that during chronic hypoxia, activation HIF-2α may overcome retention signal provided by stromal-derived CXCL12, thereby enabling dissemination Here demonstrate upregulates PC CXCL12 expression, decreasing migration toward reducing...
Sean Martin, Matthew Haren, Anne Taylor, Sue Middleton, Gary Wittert and Members of the Florey Adelaide Male Ageing Study (FAMAS)
Abstract The plasma cell malignancy multiple myeloma ( MM ) is unique among haematological malignancies in its capacity to cause osteoclast‐mediated skeletal destruction. PI3K/Akt/ mTOR pathway mediates proliferation, survival and drug resistance cells also involved regulating the formation activity of bone‐forming osteoblasts bone‐resorbing osteoclasts. NVP‐BEZ235 a dual pan class I PI3K inhibitor that currently undergoing clinical evaluation several tumour settings. In this study, we...
Abstract Purpose: Multiple myeloma is an incurable disease, for which the development of new therapeutic approaches required. Here, we report on efficacy recombinant soluble Apo2L/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to inhibit tumor progression and bone destruction in a xenogeneic model human multiple myeloma. Experimental Design: We established mouse myeloma, Apo2L/TRAIL-sensitive RPMI-8226 or KMS-11 cells, tagged with triple reporter gene construct...
Multiple myeloma is an incurable hematologic malignancy characterized by increased bone marrow angiogenesis and extensive lytic disease. We have previously shown that elevated levels of stromal-derived factor-1alpha (SDF-1alpha) in peripheral blood plasma are associated with osteolysis multiple patients. now examined whether SDF-1alpha also correlate angiogenesis.We the contribution cell-derived stimulation vitro using a tube formation assay. collected trephine samples from patients to...
Abstract Skeletal osteoblasts are important regulators of B-lymphopoiesis, serving as a rich source factors such CXCL12 and IL-7 which crucial for B-cell development. Recent studies from our laboratory others have shown that deletion Rptor , unique component the mTORC1 nutrient-sensing complex, early in osteoblast lineage development results defective bone mice. In this study, we now demonstrate signalling pre-osteoblasts is required normal B-lymphocyte Targeted osterix-expressing ( ob −/− )...
The classical concept holds that liver and kidneys are the main sinks of glycerol released by adipose tissue. However, rates appearance (Ra) exceed rate delivery to kidneys. We measured hepatic renal contributions production utilization in anesthetized dogs were fasted either overnight or for 24 h after 3 days on a carbohydrate-free diet. Dogs infused with [2H5]glycerol, concentration 2H enrichment across kidney. After baseline period, norepinephrine glucose plus insulin was alter...
Abstract Overnutrition causes hyperactivation of mTORC1-dependent negative feedback loops leading to the downregulation insulin signaling and development resistance. In osteoblasts (OBs), plays a crucial role in control systemic glucose homeostasis. We utilized mice with conditional deletion Rptor investigate how loss mTORC1 function OB affects metabolism under normal overnutrition dietary states. Compared controls, chow-fed ob −/− had substantially less fat mass exhibited adipocyte...
ABSTRACT The mammalian target of rapamycin complex 1 ( mTORC1) is the major nutrient sensor in cells that responds to amino acids, energy levels, growth factors, and hormones, such as insulin, control anabolic catabolic processes. We have recently shown suppression mTORC1 bone‐forming osteoblasts (OBs) improved glucose handling male mice fed a normal or obesogenic diet. Mechanistically, this occurs, at least part, by increasing OB insulin sensitivity leading upregulation uptake glycolysis....