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To L.B.,Royal Adelaide Hospital | To L.B.,University of Adelaide | Levesque J.-P.,Materials Medical Research Institute | Levesque J.-P.,University of Queensland | Herbert K.E.,Peter MacCallum Cancer Center
Blood | Year: 2011

Transplantation with 2-5 × 10 6 mobilized CD34 +cells/kg body weight lowers transplantation costs and mortality. Mobilization is most commonly performed with recombinant human G-CSF with or without chemotherapy, but a proportion of patients/donors fail to mobilize sufficient cells. BM disease, prior treatment, and age are factors influencing mobilization, but genetics also contributes. Mobilization may fail because of the changes affecting the HSC/progenitor cell/BM niche integrity and chemotaxis. Poor mobilization affects patient outcome and increases resource use. Until recently increasing G-CSF dose and adding SCF have been used in poor mobilizers with limited success. However, plerixafor through its rapid direct blockage of the CXCR4/CXCL12 chemotaxis pathway and synergy with G-CSF and chemotherapy has become a new and important agent for mobilization. Its efficacy in upfront and failed mobilizers is well established. To maximize HSC harvest in poor mobilizers the clinician needs to optimize current mobilization protocols and to integrate novel agents such as plerixafor. These include when to mobilize in relation to chemotherapy, how to schedule and perform apheresis, how to identify poor mobilizers, and what are the criteria for preemptive and immediate salvage use of plerixafor. © 2011 by The American Society of Hematology.


Forbes J.M.,Baker IDI Heart and Diabetes Institute | Forbes J.M.,Monash University | Forbes J.M.,Materials Medical Research Institute | Cooper M.E.,Baker IDI Heart and Diabetes Institute | And 2 more authors.
Physiological Reviews | Year: 2013

It is increasingly apparent that not only is a cure for the current worldwide diabetes epidemic required, but also for its major complications, affecting both small and large blood vessels. These complications occur in the majority of individuals with both type 1 and type 2 diabetes. Among the most prevalent microvascular complications are kidney disease, blindness, and amputations, with current therapies only slowing disease progression. Impaired kidney function, exhibited as a reduced glomerular filtration rate, is also a major risk factor for macrovascular complications, such as heart attacks and strokes. There have been a large number of new therapies tested in clinical trials for diabetic complications, with, in general, rather disappointing results. Indeed, it remains to be fully defined as to which pathways in diabetic complications are essentially protective rather than pathological, in terms of their effects on the underlying disease process. Furthermore, seemingly independent pathways are also showing significant interactions with each other to exacerbate pathology. Interestingly, some of these pathways may not only play key roles in complications but also in the development of diabetes per se. This review aims to comprehensively discuss the well validated, as well as putative mechanisms involved in the development of diabetic complications. In addition, new fields of research, which warrant targets of the future, will be highlighted. © 2013 the American Physiological Society.


Burdon-Jones D.,Materials Adult Hospital | Gibbons K.,Materials Medical Research Institute
Journal of the European Academy of Dermatology and Venereology | Year: 2013

Background Quality of life (QOL) issues in patients with non-metastatic skin cancer are not satisfactorily demonstrated when using existing QOL questionnaires. Objective To construct and validate a 10 item disease-specific QOL questionnaire, the Skin Cancer Quality of Life Impact Tool (SCQOLIT), for use in patients following treatment of non-metastatic skin cancer. Methods The SCQOLIT was constructed and administered initially to 120 patients with non-metastatic skin cancer, 60 with malignant melanoma (MM) and 60 with non-melanoma skin cancer (NMSC) following treatment, then repeated in half this cohort at seven days, and the other half at three months. Data was collected on age, gender, skin cancer type and Breslow thickness. Statistical validation was undertaken. Results There were 113 valid SCQOLIT responses at initial completion (54 in the MM group, and 59 in the NMSC group). Initial SCQOLIT median scores (interquartile range [IQR], range) for the two groups were 10 (12, 0-28) MM, and 4 (5, 0-19) NMSC. Amongst the cohort readministered the SCQOLIT at three months (23 in the MM group, 25 in the NMSC group) median scores (IQR, range) were 6 (6, 0-26) MM and 3 (4, 0-20) NMSC. Conclusions The SCQOLIT is a validated disease-specific QOL questionnaire for use in patients following treatment of non-metastatic skin cancer. Higher SCQOLIT scores are observed in MM patients than NMSC patients, but diminish with time in the MM group. Patients with persistently elevated SCQOLIT scores merit additional attention. © 2012 European Academy of Dermatology and Venereology.


Crowe L.,Materials Medical Research Institute
Cochrane database of systematic reviews (Online) | Year: 2012

One of the most challenging milestones for preterm infants is the acquisition of safe and efficient feeding skills. The majority of healthy full term infants are born with skills to coordinate their suck, swallow and respiration. However, this is not the case for preterm infants who develop these skills gradually as they transition from tube feeding to suck feeds. For preterm infants the ability to engage in oral feeding behaviour is dependent on many factors. The complexity of factors influencing feeding readiness has led some researchers to investigate the use of an individualised assessment of an infant's abilities. A limited number of instruments that aim to indicate an individual infant's readiness to commence either breast or bottle feeding have been developed. To determine the effects of using a feeding readiness instrument when compared to no instrument or another instrument on the outcomes of time to establish full oral feeding and duration of hospitalisation. We used the standard methods of the Cochrane Neonatal Review Group, including a search of the Cochrane Central Register of Controlled Trials (The Cochrane Library 2010, Issue 2), MEDLINE via EBSCO (1966 to July 2010), EMBASE (1980 to July 2010), CINAHL via EBSCO (1982 to July 2010), Web of Science via EBSCO (1980 to July 2010) and Health Source (1980 to July 2010). Other sources such as cited references from retrieved articles and databases of clinical trials were also searched. We did not apply any language restriction. We updated this search in March 2012. Randomised and quasi-randomised trials comparing a formal instrument to assess a preterm infant's readiness to commence suck feeds with either no instrument (usual practice) or another feeding readiness instrument. The standard methods of the Cochrane Neonatal Review Group were used. Two authors independently screened potential studies for inclusion. No studies were found that met our inclusion criteria. No studies met the inclusion criteria. There is currently no evidence to inform clinical practice, with no studies meeting the inclusion criteria for this review. Research is needed in this area to establish an evidence base for the clinical utility of implementing the use of an instrument to assess feeding readiness in the preterm infant population.


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 example, graft versus host disease (GVHD) or transplant rejection) and to leave protective T-cell immune responses intact (for example, 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+CD83bright activated DC but spared CD83dim/- 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.Leukemia advance online publication, 2 October 2015; doi:10.1038/leu.2015.231. © 2015 Macmillan Publishers Limited


Carreira P.E.,Materials Medical Research Institute | Richardson S.R.,Materials Medical Research Institute | Faulkner G.J.,Materials Medical Research Institute | Faulkner G.J.,University of Queensland
FEBS Journal | Year: 2014

Retrotransposons have played a central role in human genome evolution. The accumulation of heritable L1, Alu and SVA retrotransposon insertions continues to generate structural variation within and between populations, and can result in spontaneous genetic disease. Recent works have reported somatic L1 retrotransposition in tumours, which in some cases may contribute to oncogenesis. Intriguingly, L1 mobilization appears to occur almost exclusively in cancers of epithelial cell origin. In this review, we discuss how L1 retrotransposition could potentially trigger neoplastic transformation, based on the established correlation between L1 activity and cellular plasticity, and the proven capacity of L1-mediated insertional mutagenesis to decisively alter gene expression and functional output. © 2013 The Authors.


Dawson P.A.,Materials Medical Research Institute
Seminars in Cell and Developmental Biology | Year: 2011

Sulfate (SO 4 2-) is an important nutrient for human growth and development, and is obtained from the diet and the intra-cellular metabolism of sulfur-containing amino acids, including methionine and cysteine. During pregnancy, fetal tissues have a limited capacity to produce sulfate, and rely on sulfate obtained from the maternal circulation. Sulfate enters and exits placental and fetal cells via transporters on the plasma membrane, which maintain a sufficient intracellular supply of sulfate and its universal sulfonate donor 3'-phosphoadenosine 5'-phosphosulfate (PAPS) for sulfate conjugation (sulfonation) reactions to function effectively. Sulfotransferases mediate sulfonation of numerous endogenous compounds, including proteins and steroids, which biotransforms their biological activities. In addition, sulfonation of proteoglycans is important for maintaining normal structure and development of tissues, as shown for reduced sulfonation of cartilage proteoglycans that leads to developmental dwarfism disorders and four different osteochondrodysplasias (diastrophic dysplasia, atelosteogenesis type II, achondrogenesis type IB and multiple epiphyseal dysplasia). The removal of sulfate via sulfatases is an important step in proteoglycan degradation, and defects in several sulfatases are linked to perturbed fetal bone development, including mesomelia-synostoses syndrome and chondrodysplasia punctata 1. In recent years, interest in sulfate and its role in developmental biology has expanded following the characterisation of sulfate transporters, sulfotransferases and sulfatases and their involvement in fetal growth. This review will focus on the physiological roles of sulfate in fetal development, with links to human and animal pathophysiologies. © 2011 Elsevier Ltd.


Barbier V.,Materials Medical Research Institute
Methods in molecular biology (Clifton, N.J.) | Year: 2012

An important factor contributing to hematopoietic stem cell (HSC) mobilization is the ability of mobilizing cytokines and chemotherapy to disturb the cellular components of HSC niches, particularly osteoblasts and their progenitors, and to inhibit the production of HSC supportive cytokines and chemokines. Although the mechanisms by which niche cells are inhibited by mobilizing treatments is still incompletely understood, it has recently emerged that bone marrow macrophages play a critical role in maintaining osteoblasts, bone formation, and the expression of CXCL12, KIT ligand, and angiopoietin-1 necessary to HSC maintenance. In this chapter, we describe how to mobilize HSC into the blood in mice by depleting macrophages with clodronate-loaded liposomes and compare this mode of mobilization to mobilization induced by granulocyte colony-stimulating factor and cyclophosphamide. Detailed methods to analyze mobilization of phenotypic and functional reconstituting HSC are described with examples.


Levesque J.-P.,Materials Medical Research Institute | Levesque J.-P.,University of Queensland | Helwani F.M.,Materials Medical Research Institute | Winkler I.G.,Materials Medical Research Institute
Leukemia | Year: 2010

The concept of hematopoietic stem cell (HSC) niche was formulated in 1978, but HSC niches remained unidentified for the following two decades largely owing to technical limitations. Sophisticated live microscopy techniques and genetic manipulations have identified the endosteal region of the bone marrow (BM) as a preferential site of residence for the most potent HSC- able to reconstitute in serial transplants- with osteoblasts and their progenitors as critical cellular elements of these endosteal niches. This article reviews the path to the discovery of these endosteal niches (often called osteoblastic niches) for HSC, what cell types contribute to these niches with their known physical and biochemical features. In the past decade, a first wave of research uncovered many mechanisms responsible for HSC homing to, and mobilization from, the whole BM tissue. However, the recent discovery of endosteal HSC niches has initiated a second wave of research focusing on the mechanisms by which most primitive HSC lodge into and migrate out of their endosteal niches. The second part of this article reviews the current knowledge of the mechanisms of HSC lodgment into, retention in and mobilization from osteoblastic niches. © 2010 Macmillan Publishers Limited All rights reserved.


Patent
Materials Medical Research Institute | Date: 2015-09-09

This invention discloses the use of an E-selectin antagonist and a mobilizer of hematopoietic stem cells or progenitor cells in methods and compositions for treating or preventing immunocompromised conditions resulting from medical treatment. The present invention is particular relevant for prophylaxis and/or treatment of hematopoietic disorders including neutropenia, agranulocytosis, anemia and thrombocytopenia in individuals receiving or proposed to receive treatments that target rapidly dividing cells or that disrupt the cell cycle or cell division.

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