C G Begley

Royal Melbourne Hospital, Melbourne, Victoria, Australia

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Publications (160)1105.61 Total impact

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    ABSTRACT: The basic helix-loop-helix (bHLH) transcription factor stem cell leukaemia (SCL) is a 'master regulator' of haematopoiesis, where SCL is pivotal in cell fate determination and differentiation. SCL has also been detected in CNS, where other members of the bHLH-family have been shown to be indispensable for neuronal development; however, no detailed expression pattern of SCL has so far been described. We have generated a map of SCL expression in the embryonic and adult mouse brain based on histochemical analysis of LacZ reporter gene expression in sequential sections of brain tissue derived from SCL-LacZ knockin mice. The expression of LacZ was confirmed to reflect SCL expression by in situ hybridisation. LacZ expression was found in a range of different diencephalic, mesencephalic and metencephalic brain nuclei in adult CNS. Co-localisation of LacZ with the neuronal marker NeuN indicated expression in post-mitotic neurons in adulthood. LacZ expression by neurons was confirmed in tissue culture analysis. The nature of the pretectal, midbrain and hindbrain regions expressing LacZ suggest that SCL in adult CNS is potentially involved in processing of visual, auditory and pain related information. During embryogenesis, LacZ expression was similarly confined to thalamus, midbrain and hindbrain. LacZ staining was also evident in parts of the intermediate and marginal zone of the aqueduct and ventricular zone of the fourth ventricle at E12.5 and E14. These cells may represent progenitor stages of differentiating neural cells. Given the presence of SCL in both the developing brain and in post-mitotic neurons, it seems likely that the function of SCL in neuronal differentiation may differ from its function in maintaining the differentiated state of the mature neuron.
    Neuroscience 02/2003; 122(2):421-36. · 3.12 Impact Factor
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    ABSTRACT: We have established a reliable, reproducible and objective growth assay to measure whether leukemia inhibitory factor (LIF) was able to protect tumour-derived cell lines from toxic effects of the chemotherapy agents, cisplatin and paclitaxel. Using this assay, we demonstrated that LIF did not alter the cytotoxic action of these drugs, on a panel of seven cancer cell lines. This was not because of the inactivity of the LIF or because the cell lines did not express components of the LIF receptor. These findings suggest that the potential clinical use of LIF, as a neuroprotective agent, in conjunction with chemotherapy will not interfere with the anti-tumour treatment.
    Growth Factors 10/2002; 20(3):141-5. · 2.20 Impact Factor
  • R L Basser, C G Begley
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    ABSTRACT: A number of hematopoietic growth factors have been identified that are active on megakaryocytes and platelets, but only 2, interleukin-11 (IL-11) and thrombopoietin, are being actively pursued clinically, with IL-11 approved for treatment of thrombocytopenia. The development of these agents in general has been disappointing, and in part this reflects the inherent biology of these factors with a failure to match clinical need with physiological function. The delayed action of these factors is also a consequence of the intrinsic biology of megakaryocytes and platelets, and thus is likely to be limiting regardless of which factor is employed. In addition, the development of these agents has occurred at a time when there is something of a decreasing demand for platelets, at least in the context of chemotherapy-induced thrombocytopenia. This decrease is the result of increased use of blood stem cells to support intensive chemotherapy procedures, reduced thresholds for platelet transfusion, and a decreasing role for intensive chemotherapy. These issues are discussed.
    International Journal of Hematology 01/2002; 74(4):390-6. · 1.68 Impact Factor
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    ABSTRACT: mpl(-/-) mice have a profound defect in platelets and megakaryocytes and a defect in hematopoietic progenitor cells and stem cells. However, no specific subset of the progenitor/stem cell compartment has been shown to be particularly affected by this deficiency in mpl(-/-) mice. In this article, we identified a specific subset of bone marrow progenitor/stem cells that was altered in mpl(-/-) mice. In vitro and in vivo hematopoietic assays were utilized to examine the response to interleukin-11 in mice lacking the receptor for thrombopoietin (TPO) (mpl(-/-) mice). The interleukin (IL)-11-responsive subset of progenitor cells was not detected in clonal cultures of bone marrow cells from mpl(-/-) mice. However, mpl(-/-) mice responded to IL-11 in vivo as evidenced by a rise in platelet count and an increase in spleen weight. Experiments were performed to address this paradox: administration of 5-fluorouracil with consequent "expansion" of early hematopoietic cells resulted in the appearance of IL-11-responsive cells in mpl(-/-) mice when assayed in in vitro cultures. Thus, although mpl(-/-) mice have the capacity to produce IL-11-responsive progenitor cells, under steady state conditions their expansion is dependent on TPO. This is the first evidence that a specific subset of bone marrow progenitor/stem cells is altered in mpl(-/-) mice.
    Experimental Hematology 03/2001; 29(2):138-45. · 2.91 Impact Factor
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    ABSTRACT: We have previously reported the inhibitory effects of oncostatin M (OSM) and leukemia inhibitory factor (LIF) on the proliferation of breast cancer cell lines. In this study, we examined the action of OSM and LIF on normal, non-malignant human breast epithelial cells (HBECs). We demonstrated expression of three components of the OSM receptor; gp130, the leukemia inhibitory factor receptor (LIFRbeta) and the OSM specific receptor (OSMRbeta). Treatment of the normal HBECs with OSM and LIF resulted in inhibition of proliferation, even in the presence of the breast mitogen, epidermal growth factor (EGF), which is required for HBEC growth. The inhibition was associated with a reduction of cells in the S-phase of the cell cycle and an accumulation of cells in G0/G1. These results suggest a previously unrecognised physiological role for these growth factors in the regulation of normal breast epithelium.
    Growth Factors 02/2001; 19(3):153-62. · 2.20 Impact Factor
  • R L Basser, C G Begley
    Cancer Investigation 02/2001; 19(6):660-6. · 2.24 Impact Factor
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    ABSTRACT: We report the cloning and chromosomal localization of murine and human Mix genes, members of a subclass of paired-like homeobox genes of which the Xenopus laevis Mix.1 gene is the founding member. The murine Mix gene was mapped to the distal region of chromosome 1 and the human region to the syntenic region 1q41-42. Northern analysis and RT-PCR of murine adult and embryonic tissues demonstrated that Mix expression was restricted to the early embryo. Whole-mount in situ hybridization revealed patchy but symmetrical Mix expression in visceral endoderm of embryonic day (E)5.5 embryos. In slightly older embryos, the expression was skewed to one side of the embryo and by E6.5, at the onset of gastrulation, expression was seen in the epiblast, visceral endoderm, nascent mesoderm, and the primitive streak. This expression pattern was maintained in mid- and late-streak embryos. In early bud-stage embryos, expression was strongest in the proximal two thirds of the streak, extending to the base of the allantois. By the headfold-stage, expression was confined to the remnant of the primitive streak in the caudal region of the embryo and, after E8.0, in the caudal notochord and tail bud mesoderm. Mix transcripts were no longer detectable after embryonic day 9.5.
    Developmental Dynamics 01/2001; 219(4):497-504. · 2.59 Impact Factor
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    ABSTRACT: Activation of the SRC family of protein tyrosine kinases is an important component of intracellular signaling in hematopoiesis, but their critical substrates are less well understood. In this report, we describe the cloning and functional characterization of murine SKAP55R (mSKAP55R), an SRC family kinase substrate. Expression of mSKAP55R was examined by Northern blot. Phosphorylation of mSKAP55R was examined by transient transfection of COS cells. For overexpression studies, mSKAP55R was cloned into a bicistronic murine stem cell virus-based retrovirus. Transduced cells (FDC-P1 cell line and murine bone marrow) were FACS isolated by expression of the selectable marker green fluorescent protein.mSKAP55R showed 90% amino acid identity to the recently published human SKAP55R. mSKAP55R contained a central pleckstrin homology domain, a C-terminal SH3 domain, and a putative SRC kinase consensus substrate DEIY(260). mSKAP55R was expressed in all hematopoietic lineages, with relative mRNA levels greatest in cells of the myeloid and erythroid lineages. Induced myeloid differentiation of M1 and HL-60 cell lines was associated with an eight-fold increase in mSKAP55R mRNA. Transient expression of mSKAP55R in COS cells demonstrated that tyrosine 260 was the predominant site of phosphorylation by FYN kinase. Furthermore, this phosphotyrosine was essential for coimmunoprecipitation of FYN with mSKAP55R. Enforced expression of mSKAP55R inhibited in vitro growth of the myeloid FDC-P1 cell line and primary hematopoietic progenitors. In contrast, a tyrosine 260 mutant mSKAP55R had no effect on in vitro growth. These studies implicate mSKAP55R in the processes of myeloid differentiation and growth arrest.
    Experimental Hematology 12/2000; 28(11):1250-9. · 2.91 Impact Factor
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    ABSTRACT: Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been shown to play a protective role in leishmanial infection. Mice with a null mutation in the gene for the beta common (beta c) chain of the receptors for GM-CSF, interleukin(IL)-3 and IL-5 (beta c-null mice) display normal steady state hemopoiesis and develop lung disease similar to the human condition, alveolar proteinosis, due to a lack of signaling by GM-CSF. We therefore expected to observe a heightened sensitivity to Leishmania major in the beta c-null mice. Surprisingly, the beta c-null mice were more resistant to cutaneous infection than wild-type (wt) mice. Upon intradermal injection of L. major promastigotes, fewer beta c-null mice developed cutaneous lesions than wt mice and these lesions were smaller and healed more rapidly than in wt mice. This resistance to disease was associated with a reduced percentage of in vitro infected beta c-null macrophages. Macrophages from beta c-null mice displayed a more activated phenotype and produced increased amounts of nitric oxide following infection with L. major, both in vivo and in vitro. Paradoxically, however, the parasite burden in the draining lymph nodes was similar in both beta c-null and wt mice, suggesting that at least a subpopulation of cells was susceptible to the parasite. The mechanism preventing normal lesion development remains to be elucidated.
    Microbes and Infection 09/2000; 2(10):1131-8. · 2.92 Impact Factor
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    ABSTRACT: To examine the role of granulocyte-macrophage colony-stimulating factor (GM-CSF) in thrombopoiesis. Thrombopoietin-unresponsi ve mice (mpl null mice), which have a profound reduction in platelets and mature megakaryocytes, were interbred with mice that do not respond to GM-CSF or interleukin 5 (betac null mice), and hematopoiesis was examined. In initial experiments on a mixed genetic background, double mutant mice (betac/mpl null mice) showed an unexpected amelioration of the thrombocytopenia seen in mpl null mice. Platelet counts were elevated approximately twofold in betac/mpl null mice compared with mpl null mice (mpl null 73+/-31; betac/mpl null 164+/-70; n = 10 to 29 mice per genotype, p<0.00001). This was associated with lessening of the deficit of megakaryocytes, progenitor cells, and colony-forming units spleen seen in mpl null mice. This amelioration of the mpl null phenotype in betac/mpl null mice on a mixed genetic background was highly statistically significant. To determine whether this amelioration of phenotype was solely the consequence of loss of betac signaling, progeny of a second intercross on a C57BL/6 background (B6betac/mpl null mice) were examined. When the resulting B6betac/mpl null mice were analyzed and compared with B6mpl null littermates, the increase in platelet count, hematopoietic progenitor cell number, and colony-forming units spleen number was no longer observed. There was no additional effect seen as a result of loss of betac signaling. GM-CSF did not play a significant role in thrombopoiesis, even in combination with the absence of thrombopoietin signaling. These results highlight problems that can be encountered when studying introduced mutations in mice. They exemplify the importance of eliminating the influence of modifying genes when attributing biologic differences to specific introduced genetic alterations.
    Experimental Hematology 09/2000; 28(9):1001-7. · 2.91 Impact Factor
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    ABSTRACT: To explore the influence of dose and schedule on the ability of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) to abrogate thrombocytopenia after multiple cycles of chemotherapy and to mobilize peripheral-blood progenitor cells (PBPC). In this open-label study, 68 patients with advanced cancer were randomized to receive PEG-rHuMGDF subcutaneously at different doses and durations before administration of carboplatin 600 mg/m(2), cyclophosphamide 1,200 mg/m(2), and filgrastim 5 microgram/kg/d. PEG-rHuMGDF was not given after the first cycle of chemotherapy but was given after the second and subsequent cycles. Chemotherapy was given every 28 days for up to six cycles. In patients who received the same dose of chemotherapy for at least two cycles, the platelet nadir was significantly higher (47.5 x 10(9)/L v 35.5 x 10(9)/L; P =.003) and duration of grade 3 or 4 thrombocytopenia significantly shorter (0 v 3 days; P =.004) when PEG-rHuMGDF was administered after chemotherapy. There was no evidence of an effect of PEG-rHuMGDF when it was given before chemotherapy. Platelet recovery after the first cycle of chemotherapy was no different for different PEG-rHuMGDF regimens, and there was no difference between patients treated with PEG-rHuMGDF and historical controls treated with identical chemotherapy. There was a modest dose-related increase in progenitor cell levels after administration of PEG-rHuMGDF alone. Peak levels of PBPC occurred later in cycle 2 than in cycle 1 but were not different in magnitude. PEG-rHuMGDF abrogated severe thrombocytopenia after dose-intensive chemotherapy. However, it had only a modest effect on progenitor cell levels and did not enhance progenitor cell mobilization after chemotherapy and filgrastim.
    Journal of Clinical Oncology 09/2000; 18(15):2852-61. · 18.04 Impact Factor
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    ABSTRACT: Mice lacking both the gene encoding the shared receptor for granulocyte macrophage-colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and IL-5 common beta-chain (B(c)) and the gene for the IL-3 specific receptor (BIL3) were generated. This was achieved by targeting the B(c) locus in embryonic stem cells that were heterozygous for a null mutation of BIL3. Cells from mice generated with the doubly targeted embryonic stem cells were unresponsive to all 3 cytokines. Considerable previous data suggested a role for common beta-chain (beta(c)) in modulating signaling of cytokines including erythropoietin (EPO), G-CSF, and stem cell factor (SCF). However, bone marrow cells from mice lacking beta(c) and beta(IL3) showed normal responsiveness to these cytokines. Thus, there was no evidence for a biologically significant interaction between signaling via beta(c) or beta(IL3) and signaling by EPO, G-CSF, or SCF. Previously documented biochemical phenomena, including receptor transmodulation, receptor transphosphorylation, and even direct physical interaction, involving the beta(c)/beta IL-3 receptor systems do not reflect genuine interactions of physiological significance in primary hematopoietic cells. This study provided results that challenge conclusions previously established using a variety of biochemical assays. (Blood. 2000;96:1588-1590)
    Blood 09/2000; 96(4):1588-90. · 9.06 Impact Factor
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    ABSTRACT: Fifty-two patients with poor prognosis carcinoma of the breast underwent peripheral blood stem cell (PBSC) mobilization using five different regimens. The yields of primitive haemopoietic progenitors were quantified by a recently described pre-colony-forming unit (pre-CFU) assay using limiting dilution analysis (LDA). Results of days 14 and 35 pre-CFU were also correlated with conventional CD34+ cell enumeration, CFU-GM (granulocyte-macrophage) and long-term culture-initiating cell (LTCIC) assays. The yield of pre-CFUs with the combination of granulocyte colony-stimulating factor (G-CSF) and stem cell factor (SCF) was significantly higher than with G-CSF alone, cyclophosphamide (Cyclo) and granulocyte-monocyte colony-stimulating factor (GM-CSF), interleukin (IL)-3 and GM-CSF, or Cyclo alone. No significant correlation between neutrophil engraftment and pre-CFU could be demonstrated. Furthermore, CFU-GM was shown to bear a stronger correlation with pre-CFU and LTCIC than CD34+ cell measurement; thus, CFU-GM remains a useful biological tool for haemopoietic stem cell assay. We conclude that the combination of G-CSF and SCF mobilizes the highest number of pre-CFUs as measured by functional pre-CFU assay, which provides an alternative measurement of primitive haemopoietic progenitors to the LTCIC assay.
    British Journal of Haematology 07/2000; 109(4):751-8. · 4.94 Impact Factor
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    ABSTRACT: Pulmonary alveolar proteinosis (PAP) is caused by inactivation of either granulocyte-macrophage colony-stimulating factor (GM-CSF) or GM receptor common beta-chain (beta(c)) genes in mice [GM(-/-), beta(c)(-/-)], demonstrating a critical role of GM-CSF signaling in surfactant homeostasis. To distinguish possible phenotypic differences in GM(-/-) and beta(c)(-/-) mice, surfactant metabolism was compared in beta(c)(-/-), GM(-/-), and wild-type mice. Although lung histology in beta(c)(-/-) and GM(-/-) mice was indistinguishable, distinct differences were observed in surfactant phospholipid and surfactant protein concentrations and clearance from lungs of beta(c)(-/-) and GM(-/-) mice. At 1-2 days of age, lung saturated phosphatidylcholine (Sat PC) pool sizes were higher in wild-type, beta(c)(-/-), and GM(-/-) mice compared with wild-type adult mice. In wild-type mice, Sat PC pool sizes decreased to adult levels by 7 days of age; however, Sat PC increased with advancing age in beta(c)(-/-) and GM(-/-) mice. Postnatal changes in Sat PC pool sizes were different in GM(-/-) compared with beta(c)(-/-) mice. After 7 days of age, the increased lung Sat PC pool sizes remained constant in beta(c)(-/-) mice but continued to increase in GM(-/-) mice, so that by 56 days of age, lung Sat PC pools were increased three- and sixfold, respectively, compared with wild-type controls. After intratracheal injection, the percent recovery of [(3)H]dipalmitoylphosphatidylcholine and (125)I-recombinant surfactant protein (SP) C was higher in beta(c)(-/-) compared with wild-type mice, reflecting decreased clearance in the receptor-deficient mice. The defect in clearance was significantly more severe in GM(-/-) than in beta(c)(-/-) mice. The ratio of SP Sat PC to SP-A, -B, and -C was similar in bronchoalveolar lavage fluid (BALF) from adult mice of all genotypes, but the ratio of SP-D to Sat PC was markedly increased in beta(c)(-/-) and GM(-/-) mice (10- and 5-fold, respectively) compared with wild-type mice. GM-CSF concentrations were increased in BALF but not in serum of beta(c)(-/-) mice, consistent with a pulmonary response to the lack of GM-CSF signaling. The observed differences in surfactant metabolism suggest the presence of alternative clearance mechanisms regulating surfactant homeostasis in beta(c)(-/-) and GM(-/-) mice and may provide a molecular basis for the range in severity of PAP symptoms. surfactant metabolism; alveolar macrophage; granulocyte-macrophage colony-stimulating factor
    AJP Lung Cellular and Molecular Physiology 07/2000; 278(6):L1164-71. · 3.52 Impact Factor
  • C G Begley, R L Basser
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    ABSTRACT: The search for a thrombopoietic agent has resulted in the identification of numerous cytokines and growth factors with thrombopoietic activity. However, with the exception of interleukin (IL)-11 and thrombopoietin (TPO), the megakaryopoietic activity of most of these molecules has not produced clearly identifiable clinical benefits. Despite the relatively modest effect of IL-11 on megakaryocyte and platelet production in vitro and in vivo, it does reduce the need for platelet transfusions in specialized clinical settings. In contrast, the c-Mpl ligand TPO has been shown to be a potent stimulator of megakaryocyte and platelet production both in vitro and in vivo. Clinical studies are being conducted with two different preparations of the c-Mpl ligand: recombinant human thrombopoietin (rhTPO) and pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF). A recombinant form of the complete human molecule, rhTPO is glycosylated and produced in mammalian cells. PEG-rHuMGDF consists of only the receptor-binding domain linked to a polyethylene glycol (PEG) moiety and is generated in Escherichia coil. Although c-Mpl ligands are still being evaluated, preliminary evidence indicates that these molecules can elevate platelet counts and may be useful in a range of clinical contexts. This report discusses aspects of the biology behind the clinical actions of IL-11 and the c-Mpl ligands.
    Seminars in Hematology 05/2000; 37(2 Suppl 4):19-27. · 3.36 Impact Factor
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    ABSTRACT: Mice lacking thrombopoietin (TPO) or its receptor c-Mpl are severely thrombocytopenic, consistent with a dominant physiological role for this cytokine in megakaryocytopoiesis. However, these mice remain healthy and show no signs of spontaneous hemorrhage, implying that TPO-independent mechanisms for platelet production exist and are sufficient for hemostasis. To investigate the roles of cytokines that act through the gp130 signaling chain in the residual platelet production of mpl (-/-) mice, mpl (-/-)IL-6(-/-), mpl(-/-)LIF(-/-), and mpl(-/-)IL-11Ralpha(-/-) double-mutant mice were generated. In each of these compound mutants, the number of circulating platelets was no lower than that observed in mice lacking only the c-mpl gene. Moreover, the deficits in the numbers of megakaryocytes and megakaryocyte progenitor cells in the bone marrow and spleen were no further exacerbated in mpl(-/-)IL-6(-/-), mpl(-/-)LIF(-/-), or mpl(-/-)IL-11Ralpha(-/-) double-mutant mice compared with those in Mpl-deficient animals. In single IL-6(-/-), LIF(-/-), and IL-11Ralpha(-/-) mutant mice, platelet production was normal. These data establish that, as single regulators, IL-6, IL-11, and LIF have no essential role in normal steady-state megakaryocytopoiesis, and are not required for the residual megakaryocyte and platelet production seen in the c-mpl(-/-) mouse. (Blood. 2000;95:528-534)
    Blood 02/2000; 95(2):528-34. · 9.06 Impact Factor
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    ABSTRACT: Human acute myeloid leukemia (AML) cells can proliferate in vitro in the absence of added growth factors when cultured at high cell density. Autocrine growth factor production is a postulated mechanism of autonomous growth. We sought to examine this using murine AML cells. We have utilized a Moloney murine leukemia virus (M-MuLV) model of AML to investigate the nature of autonomous in vitro growth of myeloid leukemic cells. Like human AML, M-MuLV-induced myeloid leukemic cells displayed autonomous growth in unstimulated high cell density cultures. However, replating of individual, primary, growth factor autonomous colonies of leukemic cells demonstrated the presence of clonogenic cells capable of autonomous growth when cultured at low cell density. In addition, there was heterogeneity in the progeny of these cells: both factor-dependent leukemic cells and cells autonomous of exogenous factor were observed. We propose that clonogenic cells capable of autonomous growth at low cell density represent leukemic progenitors while the majority of leukemic cells derived from these "autonomous" leukemic cells are factor-dependent.
    Experimental Hematology 02/2000; 28(1):36-45. · 2.91 Impact Factor
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    ABSTRACT: Phase I studies with pegylated megakaryocyte growth and development factor (PEG-rHuMGDF), a c-Mpl ligand that stimulates megakaryopoiesis, have demonstrated that PEG-rHuMGDF is biologically active alone and causes a dose-related enhancement of platelet recovery when administered after chemotherapy. Here we report the dose-ranging pharmacokinetics of PEG-rHuMGDF. Pre-injection blood samples were drawn daily for pharmacokinetic studies on 43 patients. An ELISA, established using PEG-rHuMGDF as the standard, was able to quantitate Mpl ligand at concentrations > 0.02 ng/mL. Over the dose range 0.03 to 5.0 microg/kg/day, subcutaneous administration produced linear increases in steady-state serum levels. Maximum levels of PEG-rHuMGDF attained after 5.0 microg/kg/day were 5.88 to 10.9 ng/mL. After discontinuation of PEG-rHuMGDF, concentrations of Mpl ligand returned to baseline within 5 days. The pharmacokinetics were best described by a one-compartment model with first-order absorption, an absorption delay, and non linear clearance over the first 48 hours. The mean terminal half-life was 33.3 + 16.7 hours, and the average apparent at steady state was 27.7 + 14.0 mL/h/kg; both were independent of administered dose. The apparent clearance of PEG-rHuMGDF was not predicted by platelet count. Administration of chemotherapy and Filgrastim did not alter the pharmacokinetics of PEG-rHuMGDF.
    Growth Factors 02/2000; 18(3):215-26. · 2.20 Impact Factor
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    ABSTRACT: The helix-loop-helix transcription factor SCL (TAL1) is indispensable for blood cell formation in the mouse embryo. We have explored the localization and developmental potential of cells fated to express SCL during murine development using SCL-lacZ mutant mice in which the Escherichia coli lacZ reporter gene was 'knocked in' to the SCL locus. In addition to the hematopoietic defect associated with SCL deficiency, the yolk sac blood vessels in SCL(lacZ/lacZ) embryos formed an abnormal primary vascular plexus, which failed to undergo subsequent remodeling and formation of large branching vessels. Intraembryonic vasculogenesis in precirculation SCL(lacZ/lacZ) embryos appeared normal but, in embryos older than embryonic day (E) 8.5 to E9, absolute anemia leading to severe hypoxia precluded an accurate assessment of further vascular development. In heterozygous SCL(lacZ/w) embryos, lacZ was expressed in the central nervous system, vascular endothelia, and primitive and definitive hematopoietic cells in the blood, aortic wall, and fetal liver. Culture of fetal liver cells sorted for high and low levels of beta galactosidase activity from SCL(lacZ/w) heterozygous embryos indicated that there was a correlation between the level of SCL expression and the frequency of hematopoietic progenitor cells.
    Blood 01/2000; 94(11):3754-63. · 9.06 Impact Factor
  • C L Scott, C G Begley
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    ABSTRACT: The hematopoietic cytokines granulocyte-macrophage colony-stimulating factor (GM-CSF), Interleukin (IL)-5 and IL-3 utilise a common receptor signalling molecule, the beta common chain (beta c). This shared receptor component explains, in part the overlapping actions of these cytokines. Mice lacking beta c have a low circulating eosinophil level, have impaired eosinophilic responses to parasitic infection and develop lung disease analogous to human pulmonary alveolar proteinosis (PAP). Surprisingly however, mature hematopoietic cell function is relatively intact, although all GM-CSF-mediated mature cell responses, including glucose transport are absent. Intriguing observations suggesting altered susceptibility to some infectious agents and amelioration of responses to inflammatory stimuli, require further clarification.
    The International Journal of Biochemistry & Cell Biology 11/1999; 31(10):1011-5. · 4.15 Impact Factor

Publication Stats

6k Citations
1,105.61 Total Impact Points


  • 1985–2002
    • Royal Melbourne Hospital
      Melbourne, Victoria, Australia
  • 2001
    • Melbourne Health
      Melbourne, Victoria, Australia
  • 1995–2000
    • The Walter and Eliza Hall Institute of Medical Research
      • Division of Cancer and Haematology
      Melbourne, Victoria, Australia
  • 1999
    • Ludwig Institute for Cancer Research Australia
      Melbourne, Victoria, Australia
  • 1995–1999
    • University of Cambridge
      • Department of Haematology
      Cambridge, ENG, United Kingdom
  • 1986–1997
    • Walter And Eliza Hall Institute For Medical Research
      Melbourne, Victoria, Australia
  • 1996
    • The Royal Children's Hospital
      Melbourne, Victoria, Australia
  • 1989–1991
    • National Cancer Institute (USA)
      Maryland, United States
  • 1990
    • Duke University
      Durham, North Carolina, United States
    • National Institutes of Health
      • Branch of Metabolism
      Bethesda, MD, United States