Australian Centre for Blood Diseases€¦ · The Australian Centre for Blood Diseases (ACBD) brings together the skills and facilities of separate yet complimentary organisations

Australian Centre for Blood Diseases

Research Report 2007 – 2008

www.acbd.monash.org 1

Research report 2007-2008

The Australian Centre for Blood Diseases (ACBD) brings together the skills and facilities of separate yet complimentary organisations in order to enhance understanding of blood and its diseases. Level 6, Burnet Tower 89 Commercial Road Melbourne, Victoria 3004

Melway Map 58,2L,B9 Telephone: +61 3 9903 0122 Fax: +61 3 9903 0228 Website: www.acbd.monash.org

2 www.acbd.monash.org

Contents

Foreword…………………………………………………………………………………….. 3

Highlights 2007- 008 ………………………………………………………………………. 4

Director‟s report ……………………………………………………………………………. 5

Research report ……………………………………………………………………………. 7

Serpin Biology Unit ……………………………………………………………….. 7

Vascular Biology Laboratory ……………………………………………………… 8

Fibrinolysis and Gene Regulation Unit …………………………………………. 10

Thrombosis Research Unit ……………………………………………………… 13

Malignant Haematology & Stem Cell Transplantation Service ………………. 17

-Myeloma Research Group ……………………………………………… 17

-Immunotherapy Research Group ………………………………………. 18

-Stem Cell Transplantation Research Group .…………………………. 19

-Clinical Research Group ………………………………………………… 19

Eastern Clinical Research Unit (ECRU) ………………………………………... 20

- Biotechnology Research Division ……………………………………… 20

- Clinical Research – Trials division …………………………………….. 22

Haematology Consortium ………………………………………………………… 23

State-of-the-art facilities …………………………………………………………………. 24

Academic news …………………………………………………………………………… 27

ACBD prizes and awards ………………………………………………………… 27

Arrivals to the ACBD ……………………………………………………………… 29

Departures ………………………………………………………………………… 30

Postgraduate education …………………………………………………………………. 31

Ph.D. program ……………………………………………………………………. 31

Honours Degree Program……………………………………………………….. 32

Undergraduate Teaching Program …………………………………………….. 34

ACBD Summer Scholarship Program …………………………………………. 34

Student information nights at the ACBD ………………………………………. 35

Grant funding 2007-2008 ……………………………………………………………….. 36

Publications 2007-2008 …………………………………………………………………. 37

Professional activities …………………………………………………………………… 42

ACBD personnel ………………………………………………………………………….. 44


Foreword

The Australian Centre for Blood Diseases (ACBD) was established to further knowledge

about blood diseases. This would be carried out through research, through education of

doctors and patients, and by providing up to date care for sufferers of different difficult

blood diseases. I am proud of the progress the Centre has made since its establishment

and particularly since its relocation to its new facilities at the Alfred Medical Research

and Education Precinct.

The research focus of the Centre has evolved to encompass benign and malignant blood

conditions. The clinical programs of the Centre have witnessed considerable expansion

with care delivered to more than half of Victoria‟s population. It is my view that a

seamless relation between clinical care, basic and applied research is essential to allow

prompt and meaningful application of research advances to patients with blood diseases.

I also see the Centre playing an increasing role in disseminating latest advances in the

diagnoses and treatment of blood conditions to other clinicians in the country. This

education is required to ensure that all Australians suffering from blood diseases are

offered the latest treatments available world wide and to be certain patients and their

families are well informed on the diseases.

While the ACBD has made steady and considerable progress, I see more challenges

facing us in the future. Continuing to attract the brightest minds to opportunities in the

Centre is fundamental to the long term contribution of the ACBD to the health of

Australians. The growth of the Centre will inevitably mean the need for more space and

equipment for our world class staff. This will in turn require additional funding.

The reality of the task which the ACBD is embarked upon is so large we need partners.

Our next challenge is how best to work with, engage with, and collaborate with other

players in the blood field particularly the Australian Red Cross Blood Service. Building

sound long term relationships will prove critical in the long term success and productivity

of the ACBD. This long term success will in turn spell further improvement in clinical

outcomes to all patients.

Sir Roderick Carnegie, Patron



Highlights 2007-2008

Dr Sascha Hughan

Dr Sascha Hughan

Dr Simone Schoenwaelder

Elizabeth Gardiner receiving the 2008 ASTH Medal from society

President, Chris Ward (photo: ASTH)

Dr Justin Hamilton

2008 NHMRC Career Development Award (Biomedical), Level 1. In December 2008, Dr Sascha Hughan was awarded a Career Development Award (Biomedical), by the National Health and Medical Research Council. These CDAs are available for early career researchers and are designed to foster Australia‟s health and

medical research community, with a strong emphasis being placed on population and clinical health, as well as health industry research. Dr Hughan received this award for her recent work uncovering a novel, shear-dependent role for a platelet adapter protein in haemostasis and thrombosis. Australian Society for Thrombosis and Haemostasis (ASTH) Scientific Medal The Australian Society for Thrombosis and Haemostasis (ASTH) Scientific Medal is an annual award, instituted in 1996, for clinical and laboratory research in the field of thrombosis and haemostasis. The award is presented at the annual combined meeting of the ASTH, the Haematology Society of Australia and New Zealand (HSANZ) and the Australia and New Zealand Society of Blood Transfusion (ANZSBT). In both 2007 and 2008, the ASTH Scientific Medal was awarded to ACBD researchers. In 2007, Dr Simone Schoenwaelder received this award for her work uncovering a novel contractile mechanism regulating blood clot stability. In 2008, Dr Elizabeth Gardiner received the award for her work uncovering a shear-dependent mechanism for regulating platelet glycoprotein VI (GPVI) expression, a key receptor in arterial thrombosis and immune dysfunction. National Heart Foundation Career Development Fellowship In 2007, Dr Justin Hamilton received one of three Career Development Fellowships awarded from the National Heart Foundation of Australia (NHFA). The five year Fellowship (2008-2012) is the NHFA‟s most prestigious award and will allow Justin to

continue his work at the ACBD investigating novel approaches to prevent blood clot formation for the treatment of heart attacks and occlusive strokes.


Director‟s report Professor Hatem Salem

Professor Hatem Salem, Director, Australian Centre for Blood Diseases

Director‟s report Professor Hatem Salem

The preceding two years have witnessed considerable expansion of our activities and significant progress towards achieving our aims. Today we have more PhD students than we ever did. Although we did have a slow start, there is little doubt that we have come a long way with 15 PhD students and several Honours students training in blood diseases in the Centre. In 2008, a generous donation by Mr. Gordon Wheaton has enabled the establishment of the Wheaton PhD Scholarship in Blood Diseases. In 2009, we are hoping to offer this Scholarship to an outstanding graduate who will enrol in a PhD program in the Centre. Success in securing competitive grants has been a highlight of the Centre over the preceding two years and the number of post-doctoral fellows from Australia and overseas working in the Centre continues to grow. These achievements could not be any more pleasing. The hard work and diligence of all members of the Centre is deeply acknowledged. The research program in the ACBD has continued to evolve and grow. The Platelet Research group has continued to grow in size and achievements. Without any doubt it is the largest group in the country in this field of research. The group has been further strengthened by the relocation of Professor Michael Berndt and his group from the Department of Immunology. Michael is well known nationally and internationally for his work in the field of thrombosis. Following the group‟s relocation to the ACBD, Michael resigned from Monash University to take up a new appointment as Dean of Medicine at the University of Cork in Ireland. Michael has maintained his relationship with ACBD and is now an Honorary Professor in the Centre and has a close liaison with Dr Robert Andrews who has assumed the leadership of the group. We wish Robert and Michael the very best. The Fibrinolysis Research group, under the leadership of Robert Medcalf, has continued to make impressive progress on the role of fibrinolytic proteins in the functioning of the brain. The work is a wonderful demonstration of the fact that science knows no boundaries. Proteins that we considered to be specifically involved in blood clotting have now been documented to have a very important role in knowledge acquisition, memory and other functions of the brain. Given that many of these proteins are used to treat patients with acute thrombosis, and that bleeding in the brain is their most feared side effect gives the work carried out by the Medcalf group more importance and relevance. A better understanding of the effects of these proteins on the brain will undoubtedly help in identifying ways to avoid these side effects. The Centre was established with the aim of bringing together clinical care, research and education in blood diseases under the one umbrella. Ultimately we see the Centre as a major resource for the medical community. We also believe the Centre will play a useful role in informing the general public about the importance of blood diseases and how they can get help, particularly in conditions where it is difficult to find reliable information. Today more than ever patients and their families seek to be better informed about the natural history of the disease and treatment options. For most, the Internet is the primary source of such information. Unfortunately, more often than not the information available on the net can be misleading and may not be directly relevant and applicable. In this regard, it is interesting to note that the American Society of Hematology carried out a national survey to determine the general public‟s knowledge and understanding of blood diseases. Very much similar to our experience in Australia, the survey revealed very limited knowledge and understanding of what constitutes blood diseases and what hematologists do. This survey confirmed the public‟s need for an easy to access and understand resource on blood disease. As I mentioned, this knowledge gap is not unique to the USA, and I suspect it is a common finding in most countries. It is certainly our experience in Australia and was one of the reasons that we embarked on establishing a Centre that could fill that void. The American Society of Hematology‟s response to the survey was far more dramatic and impressive. The Society launched Blood: the Vital Connection, a public education campaign that provides credible information on many different blood diseases as well as risk factors, prevention strategies, and treatment options. This website also allows clinicians and patients to identify a hematologist by location or specialty. Again this is one of our ultimate aims to ensure that appropriate referrals are made and that patients


Jennie Saravanamuttu Personal Assistant to Professor Hatem Salem

obtain an opinion from appropriately credentialed and trained individuals. While we still have a long way to achieve our aims, it is comforting to know that our experience and direction are shared by others. The path taken by the American Society of Hematology will undoubtedly help us in our way forward. Since the last report, the clinical program of the Centre has witnessed considerable changes. A review of the Bone Marrow Transplantation activity was undertaken and confirmed the strong support by our Health Service of this activity. Following the review, the position of Director of Malignant Haematology and Stem Cell Transplantation was advertised and Andrew Spencer was appointed. Since his appointment Andrew has been busy organizing his clinical service, and has continued to expand his Multiple Myeloma Research activity. The program established by Andrew has attracted several researchers and postgraduate students and is a wonderful model of translational research. Our relationship with Southern Health continues to grow and is far more solid than ever before. We have just signed a new three year clinical service agreement that sees our haematologists continue to deliver care for patients with blood disease at all Southern Health hospitals. In addition, we have, for the first time, commenced a comprehensive training program for our advanced trainees with terms at both Alfred and Southern Health. This is a unique model, and offers the trainees a program that covers most aspects of blood diseases. As a result, our clinical positions are highly sought after and many talented scientists compete for them. This, I believe, is a wonderful outcome for haematology at large. Our commitment to teaching continues to develop with significant expansion of both undergraduate and postgraduate education programs. In this regard, I am very indebted to all the hard work and dedication shown by Simone Schoenwaelder in ensuring that the Centre evolves as the main provider of education in blood diseases. Without Simone‟s contributions and hard work we could not have achieved what we have to date. We continue to produce our reports biennially. Two years between reports is a relatively long time and we have seen many staff members depart and welcomed many others; this information will appear elsewhere in the report. I will however welcome Robert Andrews and his group to the Centre and wish them all the best in their new facilities. I am very excited that they have relocated to the Centre and see considerable synergies in their work and that of other members of the Centre. I am very excited about the future of the Centre. I believe we are still in the early stages of our journey and all the indicators are that we are heading in the right direction. In this regard I am deeply indebted to Sir Roderick Carnegie, the Chairman of our Advisory Board, who continues to be a huge factor in our overall success. His personal support and interest are greatly appreciated. I wish to extend my gratitude to all my colleagues in the Centre. It is difficult to single out individuals, as everyone worked to the best of their ability and potential to help us achieve our aims. We have a long way to go, but we are well on the road. Professor Hatem Salem, Director, Australian Centre for Blood Diseases


Research report Serpin Biology Unit

Associate Professor Paul Coughlin

Ms Trifina Sofian, PhD Candidate

Overview

The prevention and treatment of blood clots is a delicate act: too much anti-platelet or anti-coagulation therapy can lead to unwanted bleeding which can have catastrophic consequences (such as haemorrhagic stroke), while fibrinolysis therapy can cause brain damage. But is there another way of treating and preventing blood clots that can avoid these complications? The Serpin Biology Laboratory focuses on the serpin (serine protease inhibitors) super family of proteins. We are developing ways of treating thrombosis patients by manipulating antiplasmin, the natural inhibitor of the clot dissolving enzyme, plasmin. In addition, our laboratory examines the role serpins play in many diseases such as lymphoma and lung disease. Of great interest is our recent research related to antitrypsin and antichymotrypsin activation. This research could ultimately lead to an effective treatment for the severe emphysema seen in the many Australians with α1antitrypsin deficiency.

Current areas of research focus during 2007-2008

The evolutionary success of serpins marks them as a very special group of proteins. Their name is an acronym derived from the best known feature of the family, serine protease inhibitor. Over 800 serpin genes are present in sequence databases from prokaryotes, plants, simple multicellular animals and mammals. The human genome alone contains 35 serpin genes. Centerin: a serpin expressed in lymphoma

Another member of the „A‟ clade serpin cluster is the germinal centre cell-specific protein, centerin. Preliminary investigations by other investigators have shown that this is not expressed in any other tissues but it is markedly upregulated in B-cell lymphomas. We have cloned the gene for this protein and have produced a recombinant protein. Ongoing studies are evaluating the role of centerin in normal B-cell development and investigating its usefulness in the diagnosis and management of lymphomas. Antiplasmin: a key regulator of clot dissolution

A major problem in the management of patients with deep vein thrombosis is long-term pain, swelling and ulceration in the legs. The standard approach to treatment of these disorders is the use of anticoagulants because clot dissolving agents often cause an unacceptable risk of serious bleeding.

There is a need for therapeutic agents which promote clot dissolution without significantly increasing the risk of haemorrhage. A member of the serpin family, antiplasmin is the major inhibitor of the clot dissolving enzyme, plasmin. Although this protein has been known for a long time remarkably little is known about its precise mechanism of action or regulation. In 2008 we published the X-ray crystallographic structure of antiplasmin. Further structural studies of antiplasmin in complex with its target enzyme plasmin are ongoing. In addition, we are examining the relationship between the structure and function of antiplasmin by producing domain-specific antibodies. These will provide models for new therapeutic agents which will allow modulation of the fibrinolytic system.

Research in the Serpin Biology Group is complemented by active collaborations with members of Monash University Department of Biochemistry and Molecular Biology.

Laboratory Members

Head: Assoc Prof Paul Coughlin

Dr Anita Horvath

Ms Trifina Sofian

Ms Bernardine Lu


Research report Vascular Biology Laboratory

Dr Robert Andrews

Overview Glycoprotein (GP) Ib-IX-V, that binds von Willebrand factor and other ligands, and GPVI that binds collagen, form a unique adhesion-signaling complex on the platelet surface, and initiate thrombus formation at arterial shear rates relevant to thrombotic diseases such as heart attack and stroke. Research in the Vascular Biology laboratory focuses on the ligand binding, signaling and proteolytic regulation of GPIb-IX-V, GPVI and other platelet receptors. Recent research findings include the identification of proteolytic pathways regulating platelet GPIb-IX-V, GPVI, and the platelet Fc receptor, Fc RIIa, relevant to thrombotic abnormalities associated with autoimmune disease or immune dysfunction. Areas of research focus during 2007-2008 Identifying binding sites for GPIb-IX-V ligands, and how these interactions regulate cell adhesion and coagulation.

The platelet receptor glycoprotein (GP)Ib-IX-V of the leucine-rich repeat (LRR) family, plays a central role in mediating platelet adhesion to the vessel wall at high shear stress, and controls procoagulant activity on activated platelets by binding thrombin, coagulation factor XI (FXI) and factor XII (FXII), and kininogen. GPIb (the major ligand-binding subunit of GPIb-IX-V) mediates adhesion of circulating platelets to subendothelial matrix by binding von Willebrand factor (VWF), or to intact endothelium by binding P-selectin on activated endothelial cells, or P-selectin-associated VWF multimers. The major ligand-binding domain of GPIb is the extracellular N-terminal sequence His1-Glu282, consisting of seven LRR (Leu36-Ala200), N- and C-terminal flanking sequences (His1-Ile35 and Phe201-Gly268), and an anionic sequence Asp269-Glu282. The ligand-binding domain of GPIb is conformationally-sensitive, and not amenable to analysis by short peptides or random scanning-mutagenesis. However, our previous studies analysing cross-species human/canine chimeras of GPIb expressed on CHO cells have mapped binding sites for VWF and inhibitory anti-GPIb mAbs to specific structural regions. This approach is based on specificity of human VWF and murine mAbs for human (not canine) GPIb , and identified LRR2-4 spanning an electronegative patch in Leu60-Glu128 as crucial for GPIb -dependent adhesion to VWF. We have expanded these approaches to investigate other ligands including procoagulant FXI or FXII, localized to platelets via binding to GPIb . Deficiency of FXII of the intrinsic coagulation pathway has a major impact on arterial thrombosis, but minimal effect on normal haemostasis (bleeding time) in humans or mice. To analyse binding of these ligands to GPIb , we have established assays for measuring platelet/GPIb -dependent FXI/FXII mediated thrombin generation in human plasma, and have shown that selective depletion of GPIb from human platelets inhibits FXII-dependent coagulation. New studies aim to investigate the potential of targeting ligand binding to GPIb-IX-V for inhibiting thrombosis using experimental approaches and analysis of clinical samples.

Laboratory Members

Head: Dr Robert Andrews

Dr Jane Arthur

Dr Elizabeth Gardiner

Dr Fi-tjen Mu

Dr Yang Shen

Ms Cheryl Berndt

Ms Jing Jing

Dr Mohammad Al-Tamimi

International Society of Thrombosis and Haemostasis conference, Geneva 2007.


Examining the physiological and pathological significance of receptor shedding from platelets, and assess plasma soluble GPVI as a biomarker of thrombotic or immune abnormalities.

One of our major aims is to understand the molecular mechanisms integral to platelet activation processes initiated by receptor/ligand engagement. In normal haemostasis and in situations leading to pathological thrombosis, platelet receptors orchestrate platelet activation in turn leading to platelet adhesion, aggregation and thrombus formation. The primary signalling receptors that trigger these molecular events include GPIb-IX-V and GPVI (the platelet receptors for von Willebrand factor and collagen respectively). Recently we have uncovered molecular mechanisms leading to shedding (removal) of these specific receptors from the platelet surface. By shedding these receptors, platelets can „self-regulate‟ their ability to activate, and to adhere and spread on a blood vessel wall. We have projects examining the role of receptor shedding in formation and dissolution of a thrombus. Clinically, excessive shedding of platelet receptors may indicate a prothrombotic or inflammatory situation and may indicate aberrant platelet activation leading to coronary vessel occlusion and stroke. We have designed assays to measure the extent of receptor shedding and will examine populations of people at risk of stroke and myocardial infarction for plasma levels of shed receptor protein. The control of platelet receptor shedding also represents a novel target for therapeutic intervention. Planned studies will address how shedding of receptors from platelets exposed to shear force occurs, and assess plasma levels of soluble GPVI as a clinical marker of platelet activation and inflammation and in patients at risk of stroke. To dissect the molecular interactions and assembly of platelet receptor signalling complexes and initiation of thrombus formation The capacity of platelets to rapidly adhere to exposed vascular matrix at arterial and pathological shear rates is dependent on two adhesion receptor complexes unique to platelets, the glycoprotein (GP)VI/FcR -chain complex that binds collagen and the GPIb-IX-V complex that binds von Willebrand Factor (VWF). In recent years, it has become clear that reactive oxygen species (ROS) generated by NADPH oxidase play a role in regulating platelet function: increased oxidative stress promotes platelet aggregation, while antioxidants such as quercetin (found in onions, tea and wine) inhibit platelet aggregation. The precise signaling pathways remain to be fully defined. The overall objective of this research is to define whether early signaling events involving GPVI/FcR -chain and GPIb-IX-V are redox regulated, by measuring intracellular and extracelluar ROS production by human platelets, assessment of temporal changes in platelet function following activation, and investigation of platelet function in NADPH oxidase-knockout mice.


Research report Fibrinolysis and Gene Regulation Unit

Associate Professor Robert Medcalf

Overview The removal of blood clots from the circulation and the turnover of extracellular matrix proteins is facilitated by specialised enzymes. One of the most important enzymes in this setting is plasmin. Plasmin performs many functions, but it is generally accepted that its primary role is to degrade fibrin, the structural scaffold of a blood clot.

The generation of plasmin from its inactive precursor plasminogen is mediated by enzymes known as tissue-type plasminogen activator (t-PA) and urokinase (u-PA). The proteolytic activity of t-PA and u-PA is in turn regulated by specific enzymes: plasminogen activator inhibitor (PAI)-1 and PAI-2. A specific cell surface receptor for u-PA also exists which not only provides a means of generating localised proteolytic activity in the pericellular environment, but, with the help of adjacent transmembrane proteins, can transmit signals to the cell nucleus and influence the expression pattern of other genes. The plasminogen activating system also actively participates in cell movement, wound healing and the metastatic spread of cancer.

Finally, there is now clear evidence that the plasminogen activating system plays a role in the central nervous system. For example, t-PA has been shown to influence a role in cognitive memory, visual processing, and can promote neurodegeneration. Therefore, our research impacts directly into the areas of neurobiology and neuro-pathophysiology, including stroke and traumatic brain injury. Figure 1 provides a schematic overview of the plasminogen activating system.

Our laboratory is interested in the molecular and cellular biology of this enzyme system. We have a strong interest in gene regulation, notably at the transcriptional and post-transcriptional levels, in various cell types. We also have devoted much effort to understand the biology and pathophysiology of the plasminogen activator system in the central nervous system, particularly in relation to ischaemic stroke and neurotrauma and modulation of the blood brain barrier.

Current areas of research focus during 2007-2008 Regulation of tissue-type plasminogen activator gene expression in vitro:

The activation of plasminogen by t-PA is the principle means by which plasmin is

generated in the circulation. Many agents influence the transcriptional control of the t-PA gene, most notably cytokines and growth factors. We have been interested in determining how cytokines regulate t-PA gene expression. One important cytokine in this setting is the inflammatory mediator, tumour necrosis factor (TNF). High levels of TNF in the blood are associated with the development of thrombosis and in this context, addition of TNF to endothelial cells results in a marked suppression of t-PA production. Hence it follows that the means by which TNF can promote thrombosis occurs, at least in part, by switching off the t-PA gene, thereby reducing the ability of the host to remove blood clots. One project we are undertaking addresses the molecular mechanism behind TNF-mediated suppression of t-PA transcription in endothelial cells. We are examining the regulatory domains within the t-PA promoter to identify the control sequences that are needed to convey TNF-mediated suppression to the t-PA gene promoter. In addition to these approaches, we are exploring post-transcriptional regulation of the t-PA gene by TNF and other agents. More recently we have been investigating the means by which the t-PA gene is regulated in neuronal cells. One important modulator of neuronal function that also regulates t-PA expression in the brain is known as “Brain Derived Neurotropic Factor (BDNF). We are therefore interested in learning how BDNF influences t-PA expression in the brain, particularly at the level of t-PA gene transcription.

Laboratory Members

Head: Assoc Prof Robert Medcalf

Dr Stan Stasinopoulos

Dr Simone Beckham

Dr Andre Samson

Dr Maithili Sashindranath

Mr Adam Galle

Mr. Be‟Eri Niego

Ms Rachael Borg

Mr Darren Karadimos

Ms Roxanne Freeman


t-PA gene regulation in vivo

Transgenic mice provide a means to assess the in vivo expression pattern directed by defined sequences of gene promoters. Transgenic mice and rats expressing 9.5 kb of the human t-PA promoter fused to a reporter gene (9.5 tPALacZ) have been used to visualise t-PA promoter-directed expression in vivo. We previously showed that the 9.5 kb human t-PA promoter directs high level reporter gene expression in discrete areas of the brain including the limbic region, hippocampus, the superior colliculis and cerebellum. The expression pattern in the brain was reproducible and consistent with the expression pattern of the endogenous mouse t-PA gene. These mice give us the opportunity to look more closely at how the t-PA gene is regulated in neuronal cells following ischaemia treatment and following treatment with agents that promote neurodegeneration. Figure 1 shows the pattern of expression directed by the human t-PA gene promoter in the mouse brain. Panels i and ii show Dorsal ventral views, respectively of transgenic mice expressing the LacZ reporter gene controlled by 9.5 kb of the human t-PA gene promoter. Blue-green colouration indicates regions of reporter gene expression on the brain surface. For comparative purposes, panel iii shows a dorsal view of a transgenic line expressing the LacZ reporter gene driven by only 1.4 kb of the human t-PA promoter that does not show reporter gene expression. Coronal sections of the brains of transgenic mice expressing 9.5 kb of the t-PA promoter were cut and stained for reporter gene expression (Figure 2, panel iii). As shown, LacZ staining is directed to discrete regions of the brain. Panel iv shows a magnified region of the area outlined in panel iv showing more clearly the areas expressing the reporter gene: H (hippocampus); DG (dentate gyrus); MH (medial habenula). Scale bar in panel i = 5 mm; Scale bar in panel v = 2.5 mm.

The Role of t-PA in the central nervous system

As mentioned above, t-PA is highly expressed in the brain. In this compartment, t-PA plays a positive role under normal conditions as it participates in neuronal plasticity and memory formation and also plays a role in stress-induced anxiety. Under conditions of neuronal injury, the presence of t-PA intensifies the degree of cell death indicating a negative effect of t-PA under these conditions. We are presently attempting to determine the means by which t-PA is neurotoxic. We have been able to show that t-PA does not necessarily need to generate plasmin to stimulate neurons. We have also identified a receptor that is present on neurons and other cells in the brain, that is necessary for t-PA to stimulate neurons. This receptor is a member of the LDL receptor family, more commonly associated with the clearance of cholesterol but also known as a receptor that binds t-PA. The ability of t-PA to potentiate neuronal stimulation has implications is various paradigms of neuronal injury. Indeed, we have established a number of animal models that allow us to explore the role of t-PA in neurotrauma and ischaemic stroke. Our neurotrauma project is designed to address the relationship between endogenous t-PA levels with outcome following brain injury and we have unique mouse models to allow us to address this question directly with suport from the Victorian Neurotrauma Initiative. Our interest in t-PA has potential ramifications in the area of ischaemic stroke. Previously, we demonstrated the lack of neurotoxicity of a plasminogen activator derived from the saliva of the common vampire bat (Desmodus rotundus). This substance, known as DSPA (Desmodus rotundus salivary plasminogen activator) is far more fibrin-selective than t-PA (hence more clot-specific) and this molecule is being trialled in patients with ischaemic stroke. Overall, many of the detrimental effects of t-PA are tied in with its effect on the blood brain barrier (BBB). Indeed, numerous studies have shown that t-PA can promote BBB leakiness in vitro and in vivo. We have also commenced a study to further understand the mechanisms by which t-PA modulats the BBB using an in vitro model. This model is shown schematically in Figure 2 and is comprised of a transwell insert that contains a porous membrane. The inner surface of this membrane contains endothelial cells, while the outer side of the membrane contains astrocytes, (cells which are integral to the BBB). The porous membrane allows these cells to communicate with each other. We

Figure 1

Figure 2


have shown that the integrity this membrane “sandwich” is compromised in the presence of t-PA and we are now in a position to understand more of the underlying mechanisms that are necessary for t-PA to modulate the BBB. Regulation of the plasminogen activator inhibitor type 2 gene

Post transcriptional regulation of PAI-2 gene expression

We have devoted much effort to elucidate the molecular mechanisms underlying the regulation of the PAI-2 gene. We have been particularly interested in the biology and regulation of PAI-2 for a number of reasons. Firstly, PAI-2 is an unusual protease inhibitor since it resides intracellularly, yet its targets are located extracellularly. This suggests that PAI-2 may have an intracellular function independent of the inhibition of u-PA. In fact, much evidence suggests a role for PAI-2 as an inhibitor of apoptosis and in the innate immune response. The PAI-2 gene is also one of the most responsive genes known: for example, the PAI-2 gene is the most prominently induced gene in fibroblasts treated with the inflammatory mediator, tumour necrosis factor (TNF).

Our laboratory has shown that PAI-2 gene expression is modulated at the level of PAI-2

mRNA stability. We have identified sequences within the PAI-2 3‟-UTR as well as in the coding region that provide binding sites for cellular factors that appear to influence the decay rate of PAI-2 mRNA. Some of these binding proteins have been identified and work is underway to define the role of these and other factors in the control of PAI-2 mRNA metabolism. We are also using a proteomics approach to identify other novel mRNA binding proteins. To this end we have extablished a collaboration with Dr Yoshikuni Nagamine in Basel, Switzerland to further explore this question.


Research report Thrombosis Research Unit

Professor Shaun Jackson

Overview

Platelets are small, specialised blood cells designed to stop bleeding following an injury to a blood vessel (haemostasis). Haemostasis is initiated by adhesion of circulating blood platelets to damaged vessel walls culminating in the formation of a platelet plug. Ironically, when triggered within diseased blood vessels, this normally protective cascade of events results in an abnormal platelet plug that blocks blood flow through the vessel (arterial thrombosis). Platelets represent a key ingredient in the development of blood clots (thrombosis) that lead to devastating diseases such as heart attacks and strokes. No other single cell type is responsible for as much death and disability as the platelet and, as a consequence, it represents a major target for therapeutic intervention. The growing awareness of the importance of platelets in cardiovascular disease is reflected in the increasing number of patients receiving anti-platelet therapy (e.g. aspirin) to prevent cardiovascular disease. There are, however, significant drawbacks with existing therapies in many people. In some patients, anti-platelet medicine doesn‟t provide protection against cardiovascular disease, and in many others, complications such as unwanted bleeding occurs. Despite intense investigation over the last 40 years into the discovery and development of more effective antithrombotic drugs, the impact of these therapies on patient mortality rates has remained disappointingly low, with less than 1 in 6 patients taking antithrombotic therapies avoiding a fatal thrombotic event. This situation is likely to worsen in the future due to the rapidly growing incidence of obesity, diabetes and the metabolic syndrome. These diseases are typically more resistant to the benefits of antithrombotic therapy, thus there is a pressing need for the identification and development of more effective approaches to prevent thrombosis. Research undertaken within the Thrombosis Research Unit aims to further our understanding of the basic principles surrounding normal haemostasis, with the ultimate goal to discover a „magic bullet‟ that selectively targets pathological thrombus formation without causing bleeding complications. One such recent discovery from the Thrombosis Research Unit has identified a new contractile process used by platelets to stablise blood clots, a process which holds potential to be manipulated therapeutically to assist in removing unwanted blood clots in patients with cardiovascular disease. These and other developing studies from our laboratory will unravel new molecular events regulating thrombosis, thereby providing promising new avenues to solving this long-standing problem. Areas of research focus during 2007-2008

Novel insights into platelet function and thrombus formation

i. Identification of a novel thrombus contraction process

Fundamental to the haemostatic function of platelets is their ability to transmit contractile forces to their extracellular environment, a process that is essential for retraction of fibrin blood clots to minimise size and secure anchorage to the vessel wall during wound healing. We have found a new platelet contraction process that causes tight packing of platelets in a blood clot, enabling the clot to avoid detachment under blood flow. We have identified the enzyme responsible for this novel process as Rho kinase. We are currently exploring the possibility that inhibition of Rho kinase-mediated thrombus contraction may provide a new way in which to loosen clots, promoting their removal in patients suffering occlusive blood clots leading to heart attack and stroke. These studies will provide new insight into clot stability, and may provide major clinical benefit in the delivery of thrombolytic therapy.

Associated Publications and Patents:

Akiko Ono, Erik Westein, Sarah Hsiao, Warwick S Nesbitt, Shaun P Jackson* and Simone M Schoenwaelder*, [*Equal senior author]. Blood, 112(1):90-99, 2008.

Laboratory Members

Head: Prof Shaun Jackson

Dr Simone Schoenwaelder

Dr Yuping Yuan

Dr Warwick Nesbitt

Dr Sue Cranmer

Dr Sascha Hughan

Dr Justin Hamilton

Dr Sharelle Sturgeon

Dr Anna Calkin

Ms Yu (Joy) Yao

Ms Akiko Ono

Mr Erik Westein

Mr Mehran Ghasemzadeh

Dr Michelle Gordon

Ms Jessica Mountford

Mr Patrick Leung

Ms Abbey Willcox

Ms My Hua

Ms Hannah Lee

Ms Kim Nguyen

Ms Katrina Ashworth

Ms Gabrielle VanderKraan


Ono A, Schoenwaelder SM and Jackson SP. Provisional Specification #2008900430, Filed January 31st, 2008.

ii. Platelet Apoptosis?

Evasion of apoptosis is a hallmark of cancer. Bcl-2 inhibitors are currently being developed to induce apoptosis and kill cancerous cell types overexpressing these proteins. However these inhibitors cause a rapid loss of circulating platelets, suggesting that the Bcl-2 family of proteins plays an important role in regulating platelet survival. These findings have raised the possibility that Bcl-2 inhibitors may not only be useful for the treatment of cancers, but may also be used to reduce platelet counts in patients with thrombocytosis (a common disorder which leads to increased numbers of platelets in the circulation and an increased blood clotting tendency). Ongoing studies in our laboratory are focussing on the importance of the Bcl-2 family of proteins in regulating platelet survival and function. Associated publications:

Wei A, Jackson SP. Nat Med. 2008 Sep;14(9):917-8.

iii. Platelets and Diabetes

Diabetes is a significant risk factor for cardiovascular disease. Evidence suggests that changes in platelet function, leading to pathological blood clots, is a major diabetes-associated complication, predisposing diabetics to cardiovascular disease. It has been reported that platelets from diabetic patients are more readily activated, and do not respond as well to current anti-platelet medications. Our laboratory is investigating the mechanisms underlying platelet hyperactivity in the setting of diabetes. Associated publications:

Jackson SP, Calkin AC. Nat Med. 2007 Sep;13(9):1015-6. iv. A role for platelets in inflammation

Platelets and leukocytes act in a co-operative manner to promote thrombotic and inflammatory responses, with platelet-leukocyte interactions causally linked to the onset and propagation of atherosclerosis. Our laboratory is investigating the mechanisms whereby platelets enhance leukocyte function, and promote inflammatory processes. Associated publications:

Kulkarni S, Woollard KJ, Thomas S, Oxley D, Jackson SP. Blood. 2007 Sep 15;110(6):1879-86. Woollard KJ, Suhartoyo A, Harris EE, Eisenhardt SU, Jackson SP, Peter K, Dart

AM, Hickey MJ, Chin-Dusting JP. Circ Res. 2008 Nov 7;103(10):1128-38. Biochemical and physical factors regulating platelet function i. PI 3-kinase – a new target for antithrombotic therapy

Many of the anti-platelet therapies currently in use in the clinic target processes that not only control disease forming blood clots (thrombosis), but they also affect normal blood clotting processes (haemostasis). Hence, their use is associated with significant bleeding side-effects. In a major breakthrough published in Nature Medicine in 2005, our research team developed a novel class of antithrombotic agents that are more effective than aspirin at preventing arterial thrombosis without increasing bleeding risk. The unique ability of these drugs to differentiate between pathological thrombosis and haemostasis was based on their ability to inhibit a specific enzyme required for shear-activation of platelets, necessary for arterial thrombus formation. This enzyme PI 3-kinase p110 was not previously known to play an important role in platelet function, nor was it appreciated to be involved in thrombus development. Our studies uncovered the molecular basis by which PI 3-kinase p110 regulates platelet adhesive function and have demonstrated that inhibition of this enzyme provides a complimentary


antithrombotic approach to all existing antiplatelet agents. In studies undertaken during 2007 and 2008, we have continued to characterise the role of PI 3-kinase p110 in platelet function. We have demonstrated not only a role for this enzyme in sustaining platelet adhesive function, but also in regulating the ability of platelets to facilitate thrombin generation – a function known as their procoagulant function. Our new antithrombotic compounds have been patented world-wide and have been extensively tested in preclinical toxicology programs and Phase I human trials. The results to date have been extremely encouraging as these compounds are well tolerated and do not cause bleeding side-effects. The further clinical and commercial development of these compounds is currently underway. Associated publications:

Schoenwaelder SM, et al, J Biol Chem. 2007 Sep 28;282(39):28648-58. Fjellstrom O, Gustafsson D, Lindberg J and Jackson SP. International Patent Application.

Serial No: 61/023498; PCT/103026 1 USA CV. Filed 25th January 2008. Frazzetto M, Suphioglu C, Zhu J, Schmidt-Kittler O, Jennings IG, Cranmer SL, Jackson

SP, Kinzler KW, Vogelstein B, Thompson PE. Biochem J. 2008 Sep 15;414(3):383-90. van der Meijden PE, Schoenwaelder SM, et al, FEBS J. 2008 Jan;275(2):371-85. Epub

2007 Dec 13. Erratum in: FEBS J. 2008 Feb;275(4):811 Straub A, et al, Thromb Haemost. 2008 Mar;99(3):609-15. Kim S, et al, Blood. 2007 Dec 15;110(13):4206-13. Kendall JD, et al, Bioorg Med Chem. 2007 Dec 15;15(24):7677-87.

ii. A role for Dok2 proteins in regulating haemostasis and thrombosis

A critical receptor on the surface of platelets responsible for their adhesive function is integrin IIb 3. Clinically, inhibitors of integrin IIb 3 are used to treat patients with cardiovascular disease. Conversely, deficiency of this receptor triggers a severe bleeding disorder, Glanzmann thrombasthenia. While much is known about the mechanisms that activate this receptor, much less is known about the negative regulators of integrin IIb 3 function. Over recent years, a family of proteins known as „Downstream of Kinase‟ (Dok) has been shown to negatively regulate cellular events in a variety of cell types. Studies in our laboratory have identified Dok proteins in platelets, and have shown that they associate with integrin IIb 3 in activated platelets. Our most recent studies have been focussed on investigating the functional importance of Dok2 in platelet function, using mice that no longer express this protein (Dok2 knockout mice). Using this model, we have shown that mice lacking Dok2 have hyperactive platelets, and demonstrate increased blood clot formation, suggesting that Dok2 is important for negatively regulating platelet function. We are currently performing studies to understand the mechanisms used by Dok2 to regulate platelets. Associated publications:

Hughan SC, Hughes CE, McCarty OJ, Schweighoffer E, Soultanova I, Ware J, Tybulewicz VL, Watson SP. Arterioscler Thromb Vasc Biol. 2007 Feb;27(2):422-9.

Hughan SC, Watson SP. J Thromb Haemost. 2007 Feb;5(2):387-94.

iii. The effects of disturbed blood flow on blood clot formation One of the reasons for the occurrence of thrombosis in diseased vessels is the disturbance of normal blood flow, producing complex and rapid changes in the shear environment (shear gradients). The contribution of disturbed blood flow to the development of arterial thrombi remains relatively poorly defined. Our laboratory has defined an unexpected central role for disturbed blood flow in promoting platelet aggregation and blood clot development. Strikingly, this new prothrombotic mechanism is not inhibited by currently employed antithrombotic drugs, such as aspirin, clopidogrel or warfarin, defining an important new mechanism underlying antithrombotic drug resistance. This discovery has established an entirely new field of investigation that is likely to have major implications for the understanding and treatment of cardiovascular diseases. Ongoing studies in the laboratory are aimed at characterising this novel mechanism in order to identify new ways in which to inhibit thrombosis.


Associated publications: Jackson SP. Blood. 2007 Jun 15;109(12):5087-95. Review. Maxwell MJ, Westein E, Nesbitt WS, Giuliano S, Dopheide SM, Jackson SP. Blood. 2007

Jan 15;109(2):566-76.

Platelet receptors and their roles in haemostasis & thrombosis

i. The vWf receptor – GPIb/V/IX

The platelet glycoprotein (GP)Ib/V/IX receptor complex plays a major role in promoting platelet adhesion and thrombosis, and as such, has become a major target for the development of novel anti-clotting drugs. The importance of GPIb/V/IX in the clotting process is highlighted by the congenital bleeding disorder, Bernard-Soulier syndrome. Over the last several years, a focus of the Thrombosis Research Unit has been to investigate the association between GPIb/V/IX and the platelet membrane scaffolding (cytoskeleton). Our previous findings have demonstrated that the interaction between GPIb/V/IX and the cytoskeletal-associated protein, filamin-A, regulates the ability of platelets to maintain adhesion to blood vessels under high shear conditions. We believe this may be an important mechanism that regulates platelet adhesion and normal blood clotting. We have generated transgenic mice with a disruption of this exact region, to further understand the implications of this interaction for haemostasis and thrombosis in vivo. Associated publications:

Jackson SP, Cranmer S, Mangin P, Yuan Y. Blood. 2007 Jan 15;109(2):846-7; discussion 847-8. No abstract available.

Mu FT, Andrews RK, Arthur JF, Munday AD, Cranmer SL, Jackson SP, Stomski FC, Lopez AF, Berndt MC. Blood. 2008 May 1;111(9):4580-7. Epub 2008 Feb 25.

ii. Thrombin and the protease activated receptors

Thrombin represents one of the most potent activators of platelets, acting via protease-activated receptors (PARs) located on the platelet surface. Using both murine and human models, our laboratory is investigating the role of thrombin induced platelet activation in thrombus formation. Our recent studies have shown that mice which are genetically deficient in PARs are protected against thrombosis, yet they do not exhibit spontaneous bleeding, indicating the potential of these receptors as targets for safe antithrombotic therapy in humans. Our ongoing studies will continue to define the roles of PARs in thrombus growth and stability and to incorporate fundamental studies on the importance of PARs in human thrombus formation. Associated publications:

Vandendries ER, Hamilton JR, Coughlin SR, Furie B, Furie BC. Proc Natl Acad Sci U S A. 2007 Jan 2;104(1):288-92. Epub 2006 Dec 26.

Hamilton JR. Blood Rev. 2008 Jul 19. [Epub ahead of print] doi:10.1016/j.blre.2008.06.002.

Hamilton, J.R., Cornelissen, I., Mountford, J.K. and Coughlin, S.R. (2008). Atherosclerosis. 10.1016 j.atherosclerosis.2008.12.018.

Hamilton JR, Kaplan Z, Jackson SP and Opat S. Exp. Opin. Drug Dev. 2:1035-1040, 2007


Research report Malignant Haematology & Stem Cell Transplantation Service

Associate Professor Andrew Spencer

Myeloma research Group Overview The Myeloma Research Group is a translational research team focusing on 1. identification and characterisation of novel therapeutic agents for multiple myeloma

and related haematological cancers, in particular, acute myeloid leukaemia 2. development of strategies to overcome drug resistance mechanisms in these

disorders, and 3. development and implementation of correlative laboratory studies undertaken in

parallel with clinical trials. Areas of research focus during 2007-2008 Epigenetic targeting of haematological malignancies.

The modulation of cellular epigenetic mechanisms is assuming increasing importance as a potential area for cancer therapeutics. We have been evaluating agents that inhibit both DNA methyltransferase and histone deacetylation thus leading to chromatin re-modelling and changes in gene expression. Furthermore, „off-target‟ non-epigenetic targeting with these agents is also actively under investigation. Small molecule development programme.

During 2007-2008 a number of ongoing and new collaborative projects examined the therapeutic potential of novel small molecules and monoclonal antibodies for the treatment of multiple myeloma and acute myeloid leukaemia. Cell adhesion mediated drug resistance (CAM-DR).

Work continued on the development and characterisation of models for the study of CAM-DR in haematological cancers. Complementary parallel studies are evaluating the impact on CAM-DR of the constitutive phosphorylation of Focal Adhesion Kinase (FAK) that the group has recently described in multiple myeloma. Tissue array as a predictive tool in multiple myeloma drug response. The group in collaboration with the Alfred anatomical pathology department has established and validated a tissue array methodology examining primary myeloma cell protein expression and it‟s correlation with drug responsiveness.

Group Members:

A/Prof Andrew Spencer

Dr Andrew Wei

Dr Tiffany Khong

Dr Alex Rizzitelli

Dr Mae-Xhum Wong

Dr Tonged Das

Mr Sung Lin Yeh

Ms Adele Baker

Ms Katherine Monaghan


Associate Professo r Anthony Schwarer

Immunotherapy Research Group

Overview

The Immunotherapy Research Group undertakes translational research with the goal of improving the understanding of the haemopoietic stem cell transplantation (SCT) related graft-versus-leukaemia phenomenon and the development of laboratory techniques that attempt to harness this phenomenon to increase the chance of curing patients with leukaemia while at the same time, potentially decreasing the side-effects and risks of SCT, in particular graft-versus-host-disease.

Areas of research focus during 2007-2008 Generation of CMV-specific T cells for prevention of CMV disease following SCT. Investigating the possibility of a broadly applicable treatment for CMV disease using a multi-epitope T cell response applicable to a wide variety of HLA types using a recombinant chimeric CMV protein containing IE1 and pp65, rather than CMV peptides. Generation of minor histocompatibility antigen specific-T cells for use in

immunotherapy as a potential treatment for leukaemia patients.

Minor histocompatibility polymorphic leukaemia antigens such as HB1 and tumour associated antigens such as hTERT are being purified using the Baculovirus Expression System Role of NK cells and HLA-E in the recovery of patients after SCT. Investigation of the potential role of NK cells and HLA-E in the recovery of patients after SCT. The expression of the calcitonin receptor on leukaemia cells and its role in the disease process. Evaluation of the expression of the calcitonin receptor on leukaemia cells, its role in the disease process and thus it‟s potential as a therapeutic target. Modulation of immune function by anti-fungal drugs.

A study evaluating the effect of amphotericin B on the immune function of T cells and NK cells

Group Members:

A/Prof Anthony Schwarer

Dr Ann Stewart

Ms Oanh Nguyen

Ms Alison Hamlett

Ms Ehteramolsadat

Housseini


Stem Cell Transplantation Research Group

Overview For the first time in 2008 a specific programme systematically evaluating critical short and long-term sequelae of SCT was initiated within the Malignant Haematology & Stem Cell Transplantation Service. Late Effects Clinic.

A specific clinic evaluating long-term survivors of SCT commenced in 2008. As well as providing critical patient medical follow-up the clinic provides a focus for studies relating to the long-term impact of SCT on organ function, quality of life and the sequential banking of peripheral blood cells for clonality studies as a predictor of secondary malignancy. Immune reconstitution following novel reduced intensity conditioned (RIC) SCT.

This is a longitudinal study of immune recovery following 2 novel RIC SCT strategies correlating quantitative and functional analyses of immune cells with SCT complications and recovery. Longitudinal audit of invasive fungal infections (IFI) in SCT and acute leukaemia

induction.

IFI is one of the most ominous events complicating SCT and leukaemic induction therapy. This study is a prospective analysis of IFI incidence and anti-fungal drug usage including intermittent comparison with historical data preceding the introduction in early 2008 of modified strategies for the prevention of IFI. Clinical Research Group During 2007-2008 the clinical trials group went from strength to strength with an increased number of members and a continued rise in clinical trial activity. By the end of 2008 the group was co-ordinating over 40 investigator initiated (ITT) and sponsored clinical trails with a major focus on multiple myeloma, chronic myeloid leukaemia and acute myeloid leukaemia. Of particular note was the increasing proportion of Phase I and first-time-in-human studies being undertaken, the expansion in trials evaluating epigenetic modifiers and the expanding portfolio of ITT in acute myeloid leukaemia. The group continued to be one of the highest recruiters to international myeloma trials and enrolled more than 40 patients on the pivotal Phase I trial of the novel histone deacetylase inhibitor LBH589. Pleasingly 2008 saw the final analysis of the multicentre ALLG MM6 trial that had been co-ordinated by Ms Nola Kennedy and it‟s acceptance for

publication in the Journal of Clinical Oncology. Importantly in 2008 funding was obtained to enable the development of the Haematology Early Phase Clinical Unit (HEPCRU), a dedicated clinical treatment area for patients on Phase I and first-time-in-human studies planned to open in early 2009.

Group Members:

Dr Sharon Avery

Dr Sushrut Patil

Dr Patricia Walker

Dr Tongted Das

Ms Sally Mongta

Group Members:

Ms Nola Kennedy

Ms Kate Reed

Ms Jennifer Muirhead

Ms Christine Mazis

Ms Lisa Di Maio

Ms Desleigh Gilbert

Ms Julia Farr

Ms Katie Boast

Ms Sarah Palliser

Ms Yamna Taouk

Ms Emma Jane Furphy


Research report Eastern Clinical Research Unit (ECRU) Biotechnology Research Division

Dr Anthony Dear

Dr Yunshan Hu

Overview The 2007-2008 period has continued to see the expansion and diversification of basic and translational research activities carried out by the Unit. ECRU clinical disciplines continue to initiate and support a range of research projects with application to relevant clinical conditions. Professor Richard Simpson from the Endocrinology Unit continues to champion research into novel treatments for Type 2 Diabetes with recent, news worthy success, in the acquisition of $196,000 in funding from a large multinational pharmaceutical company to investigate the potential beneficial effects of a novel agent to treat Type 2 Diabetes on vascular disease in this patient population. Professor Christopher Bladin from the Neurology Unit continues to undertake research into the potential beneficial effects of a novel class of agents, the thiazolidinediones, on stroke severity whilst Professor Joe McKendrick from the Oncology Unit supports research into the investigation of the effects of a novel class of anti-cancer agents, the histone deacetylase inhibitors (HDACi), in myelodysplasia, in collaboration with the pharmaceutical company Celgene. As an extension of research undertaken in collaboration with Melbourne based biotechnology company AVEXA and Professor Sharon Lewin of the Burnet Institute into the effects of novel HDACi on human immunodeficiency virus (HIV) latency the Unit has identified potential new intellectual property currently being evaluated by Monash university. The Unit, through its support of PhD students at Monash University Departments of Chemistry and Pharmacology, has successfully developed and tested several novel small molecule treatments in disease states ranging from breast cancer to vascular disease. Dr Penny Mayes (Chemistry) and Dr Antony Vinh (Pharmacology), previously PhD students supported by the Unit, have both successfully completed and been awarded their PhD for work, in-part, relating to novel small molecule synthesis and testing undertaken by the Unit. The Unit continues to maintain several National and International research collaborations to facilitate its broad research base and actively promotes its research findings with presentation of material at National and International scientific meetings. Recent meetings at which the Unit has presented its research findings include the American Diabetes Association 68th Scientific Sessions, San Francisco, CA, USA June (2008) and the 44rth European Association for the Study of Diabetes (EASD), Rome, Italy, September (2008). The Unit continues to publish recent findings in relation to novel observations and promote an atmosphere of academic enquiry though support of PhD students engaged in research activities.

Laboratory Members

Head: Dr Anthony Dear

Dr Hong Bin Liu

Dr Yunshan Hu

Assoc Prof Richard Simpson


Dr Hong Bin Liu

Active collaborations –

1. Associate Professor Robert Widdop (Department of Pharmacology, Monash University, Melbourne, Australia). “Assessment of Novel Small Molecule Treatments in In vivo Models of, Abdominal Aortic Aneurysm, Atherosclerosis and Neointimal hyperplasia”.

2. Dr Lotte Knudsen (New Antidiabetic Agents Discovery Management Programme,

Novo Nordisk A/S, Bagsværd Denmark). “Effects of Liraglutide on Vascular Endothelial Peptide Expression in In vitro and In vivo Models of Vascular Disease”.

3. Professor Alan Daugherty (Professor of Medicine and Physiology, University of

Kentucky, Lexington Kentucky, USA). “Effects of Novel Histone Deacetylase Inhibitors in Models of Abdominal Aortic Aneurism”.

4. Associate Professor Patrick Perlmutter (Department of Chemistry, Monash

University, Melbourne, Australia) “Synthesis of Novel Histone deacetylase Inhibitors for Assessment in In vivo Models of Metastatic Cancer and Vascular Disease”.

5. Assoc Professor Robin Anderson (Peter MacCallum Research Institute, Melbourne

Victoria, Australia). “In vivo Characterisation of Novel Histone deacetylase Inhibitors in Breast Carcinomal”.

6. Assoc Professor Ricky Johnstone (Peter MacCallum Research Institute,

Melbourne Victoria, Australia). “Assessment of Novel Histone Deacetylase Inhibitors in the Treatment of Lymphoma”.

7. Dr David Rhodes (AVEXA Pty Ltd, Melbourne, Australia). “Effects of Novel Histone

Deacetylase Inhibitors on Latent HIV Expression”). 8. Professor Sharon Lewin (Department of Infectious Diseases, Burnet Institute,

Melbourne). “Effects of Novel HDAC Inhibitors on HIV Latency”. 9. Associate Professor Joe McKendrick (Department of Oncology, Box Hill Hospital,

Melbourne). “Effects of Novel HDAC Inhibitors and Azacytidine in the Myelodysplastic Syndrome”.

10. Professor Giuseppe Leone/Dr Maria Teresa Voso (Catholic University, Gemmelli,

Rome, Italy). “Effects of Novel HDAC Inhibitors in Myelodysplastic Syndrome”. 11. Dr Kevin Lynch (Celgene Corporation) “Effects of Novel HDAC Inhibitors alone

and in combination with Azacytidine in In vitro Models of Myelodysplasia”. 12. Professor Christopher Bladin (Department of Neurology, Box Hill Hospital,

Melbourne). “Effects of Thiazolidinediones on Severity of Acute Thromboembolic Cerebrovascular Accident”.


Research report Eastern Clinical Research Unit (ECRU) Clinical research – Trial division HAEMATOLOGY

The Eastern Clinical Research Unit (ECRU), an initiative of the Monash University Department of Medicine, is based at Box Hill and Maroondah Hospitals. Founded in 1996 , ECRU currently employs over 50 medical/nursing and support staff. ECRU manages over 150 clinical trials in haematology, oncology, endocrinology, respiratory, gastroenterology in both acute hospital patients and outpatients.

The ECRU Haematology Unit is the most active and successful of the ECRU units. In the last two years 220 patients have been randomised into 31 protocols at Box Hill Hospital. Maroondah has randomised 86 patients into 14 prtocols. The principle area of research is the treatment and prevention of thrombosis with a smaller number of studies exploring new treatment modalities for Idiopathic Thrombocytopaenia.

There are several novel anti-coagulants currently under investigation targeting discreet points of the clotting cascade. These new drugs either directly or indirectly inhibit factor Xa or interfere with the production of thrombin thereby producing an anti coagulant effect. The most exciting aspect of these new anti-coagulants is that they require coagulation monitoring . The majority of the new agents are oral and short acting however there is one very promising long-acting and reversible weekly injectable which may prove to be beneficial in select situations.

Rivaroxaban, one of the new oral anti-Xa inhibitors, has recently been approved by the Federal Government for use in the prevention of venous thromboembolism following total hip or kneereplacement surgery. ECRU Haematolgy contributed to this approval by participating in two of the studies which endorsed the use of Rivoxaban as an effective and safe oral anti-coagulant in the prevention of Venous Thromboembolism following Total Hip Surgery.

The field of ITP research for ECRU Haematology is small in comparison to Thrombosis research. Two new agents are currently under invesitgation. Both are novel thrombopoietin receptor agonists in phase three studies.

Whilst we are still predominently Thrombosis focused prospective studies in Chronic Lymphocytic Leukaemia and Multiple Myeloma are currently being reviewed by the Ethics Committee.

The unit continues to grow, we have welcomed a number of new appointees including Claire Gollogly, Rosemary Petrie, Bronwen Williamson and Robyn Batrouney. Sadly some people had to leave including Cheryl Gillzan, Keiren Walsh, Heather Coughlin and Rita Broner.

ECRU personnel

Principal Investigators

Box Hill

Professor Hatem Salem

Assoc/Professor Paul Coughlin

Maroondah

Assoc/Professor Michael Leyden

Box Hill Hospital Staff

Lesley Poulton (Manager) Brenda Niessner

Claire Gollogly Rosemary Petrie

Maria di Stasso Belinda Davis

Bronwen Williamson

Robyn Batrouney

Maroondah Hospital Staff

Melissa Fitzpatrick Dominique Leyden

Caroline Sturtz Kayte Robinson

Vichy Walkerden


Research report Haematology Clinical Research Unit

The clinical trial group continued to expand during 2007-8 with a continued increase in clinical trial activity and number of staff. By the end of 2008, the group was co-ordinating 27 sponsored and investigator-initiated clinical trials involving patients with venous thromboembolism (VTE), immune thrombocytopenic purpura (ITP), non-hodgkin lymphoma (NHL), multiple myeloma (MM), myelodysplasia (MDS) and Gaucher disease. The group continued to be among the highest recruiters to all international VTE clinical trials, and was in fact the highest recruiter to the phase III RE-COVER trial evaluating the efficacy and safety of a novel oral direct thrombin inhibitor, dabigatran vs. warfarin, enrolling over 65 patients. Members of group have expanded their interest into the roll of fibrinolysis in VTE and begun collaborative studies with the Obstetrics group to evaluate the utility of D-dimer and fibrinolysis in pregnancy-related complications, while continuing to publish widely with more than 20 manuscript accepted in peer-reviewed medical journals. Members of the group also participated in Murray to Moyne 24-hour bicycle relay charity event, successfully raising awareness for haematological diseases, as well as more than $10,000 for the ACBD to go towards further research.

Haematology Clinical Research members

A/Prof Eng Gan

A/Prof Stephen Opat

Dr Huyen Tran

Dr Susan Brown

Dr Hang Quach

Dr Zane Kaplan

MS Cheryl Coleman

MS Lynnette Stafford

Mr Matthew Van Dam

MS Jannette Gamgee

Ms Anita Cummins

MS Linda Hunter


State-of-the-art facilities

At the ACBD, the research we perform is greatly facilitated by a plethora of specialised research facilities. While some of these have been developed in-house, others are located either on the AMREP precinct or within the research environment of Monash University. These facilities include: Facilities within the ACBD Imaging at the ACBD

The ACBD under the auspices of Monash Micro-Imaging (MMI) has established a state-of-the-art micro-imaging and biorheology laboratory with the purpose of developing novel imaging modalities and applications aimed at investigating the cellular and molecular mechanisms of platelet thrombosis and cardiovascular disease. The overarching aim of the laboratory is to develop an international reputation in the development and application of cutting edge imaging modalities applied to both live cell and intra-vital techniques, with a particular focus on cardiovascular biology and related areas. The great strength of this facility is the integration of basic biology with the development of new imaging techniques. This boutique approach to imaging development is unlike the traditional „Turnkey‟ centralised approach used by many imaging facilities, which tend to operate at a distance from the day-to-day requirements of the biological researcher.

The current ACBD imaging laboratory consists of:

• Three dedicated biorheology imaging workstations comprised of inverted wide-field instruments with a range of both long working distance and short working distance high numerical aperture objectives, MTI-DAGE analogue CCD cameras, analogue video acquisition and an integrated MCID digital acquisition/analysis workstation.

• Confocal suite, consisting of a Leica TCS-SP and both invert(DM-IRBE) and upright dedicated microscopes.

• Two offline imaging workstation for analysis along with a range of software applications.

• Analogue -MTI-Gen-II-Sys image intensifier

• Leica MPV-Combi

• A range of specialist incubation chambers, platforms and hoods for both live cell and intravital microscopy applications.


The ACBD continues to extend upon our existing micro-imaging facilities with the development a novel multi-mode imaging system that combines recent advances in objective-type Total Internal Reflection Fluorescence Microscopy (TIRFM) and high speed epi-fluorescence techniques. This system is being developed by Dr Warwick Nesbitt, a research officer within the Thrombosis Research unit, in association with Olympus Australia and SDR Clinical Services. Significant progress has been made in the development of this system, which will allow us to examine many aspects of cell membrane adhesion and signalling processes that would otherwise be beyond the resolution of existing techniques.

In vivo physiology at the ACBD

Researchers at the ACBD have established several in vivo models to investigate normal and abnormal blood clotting (haemostasis and thrombosis), as well as models to investigate the neurological effects associated with stroke and trauma. Some of these models include:

Models to examine arterial thrombosis - Despite great advances in treatment, cardiovascular disease continues to be the leading cause of death in the world today. Heart attack and stroke, caused by plaque rupture and occlusive thrombi (blood clots) in the major blood vessels supplying the heart and brain, contribute to the majority of deaths. Thus research into the mechanisms by which thrombi form, and ultimately the development of novel treatments, is ongoing. The advent of genetically modified mice has contributed greatly to such research in recent years. By being able to remove a protein from the animal‟s genome, we can then investigate how important that protein is in the formation of thrombi in disease states. To investigate the role of such proteins, we must be able to mimic these diseases states in animals.

To this end, the Thrombosis research unit have successfully developed a number of models of arterial thrombosis.

The folts and electrolytic models are two of the most common and well characterised animal models of arterial thrombosis in cardiovascular research, both of which we have developed for application in murine and rodent arteries. The Folts model is a high shear model which mimics conditions of turbulent flow surrounding thrombi forming at sites of atherosclerotic plaques in human vessels. The thrombus formed in this model is platelet-rich making it an ideal model for studies involving anti-platelet therapies. The electrolytic model is a relatively low shear model producing thrombi that are both platelet- and fibrin-rich, making it an ideal model for studies involving both the aggregation and fibrinolytic pathways. Models to investigate the neurological effects associated with stroke and trauma-

o Stereotactic microinjection procedures developed to study the role of fibrinolytic enzymes during neuronal degeneration in the murine brain.

o Transgenic models to allow us to study the expression pattern and regulation of these fibrinolytic enzymes under normal and pathological conditions.


AMREP-wide facilities AMREP AS Pty Ltd (AAS) – internally known as Precinct Animal Centre (PAC)

AMREP AS (AAS) is a purpose-built facility for breeding and housing animals to be used in medical research, and as such, plays a vital role in research at the AMREP precinct. Jointly owned by the BakerIDI and Burnet Intitute incorporating agovernance structure embracing all AMREP partners. AAS provides colocated animal and support facilities within the AMREP precinct. The facility and its operations conform to high standards of animal welfare and relevant codes of practice and legislation. Research projects involving animals require approval by the National Health and Medical Research Council and the AMREP AnimalEethics Committee. Core service areas include surgical suites for conducting sterile recovery procedures, procedural areas for non-invasive procedures, autopsy of animals and recovery of tissues. Combined with all this is a skilled team of technical staff headed by Debra Ramsey who can assist researchers in animal ethics applications, animal handling, technical procedures and animal care. Monash University facilities Monash mouseworks This Monash-based facility provides services for the generation, housing and phenotyping of genetically modified mice. The ACBD has utilised the services of Monash mouseworks within the Thrombosis Research unit. http://www.med.monash.edu.au/mouseworks/ The protein crystallography unit Located within Department of Biochemistry at Clayton Campus, protein crystallography is the major tool for solving the 3-D structure of proteins and as such provides unparalleled detailed information on the structure and function of proteins, as well as a platform for rationally designing therapeutics. The ACBD has strong collaborative links to the crystallography unit, particularly within the Serpin Biology Unit. http://www.med.monash.edu.au/biochem/staff/rossjohn.html Biomedical Proteomics Facility

Proteomics describes the analysis of the protein content of the genome, known as the proteome, which embodies the characterisation of the entire protein complement expressed by a cell. This Monash-based facility is accessible to any academic investigators from any institution as well as industrial clients. http://www.med.monash.edu.au/biochem/facilities/proteomics/index.html Monash Microimaging A microscopy and imaging resource facility located at Monash University, providing consultation, equipment, services and training, collaborative research, project development and contract work for all aspects of imaging inclusive of Live cell imaging, Multiphoton microscopy, Transmission electron microscopy, Scanning electron microscopy and Cryo methods for tissue preparation. http://microimaging.monash.org/ Enquiries: [email protected]

http://www.med.monash.edu.au/mouseworks/

http://www.med.monash.edu.au/biochem/staff/rossjohn.html

http://www.med.monash.edu.au/biochem/facilities/proteomics/index.html

http://microimaging.monash.org/

mailto:[email protected]


Academic news

Akiko Ono

Associate Professor Robert Medcalf

Dr Justin Hamilton

Awards and Prizes NHMRC Senior Research Fellowship Associate Professor Robert Medcalf had his NH&MRC Senior Research Fellowship renewed in 2008 for a 5 year term. These fellowships are highly prestigious awards and he will use this award to further his research interests in the field of plasminogen activation research.

National Heart Foundation Career Development Fellowship In 2007, Dr Justin Hamilton received one of three Career Development Fellowships awarded from the National Heart Foundation of Australia (NHFA). The five year Fellowship (2008-2012) is the NHFA‟s most prestigious award and will allow Justin to continue his work at the ACBD investigating novel approaches to prevent blood clot formation for the treatment of heart attacks and occlusive strokes.

NHMRC Career Development Award

In December 2008, Dr Sascha Hughan was awarded a Career Development Award by the National Health and Medical Research Council. This award, designed to foster promising early career researchers, will allow Dr Hughan to continue her work examining a novel protein involved in the response of platelets to changing blood flow conditions during haemostasis and thrombosis.

Australian Society for Thrombosis and Haemostasis (ASTH) Scientific Medal The Australian Society for Thrombosis and Haemostasis (ASTH) Scientific Medal presented at the annual combined meeting of the ASTH and the HSANZ and ANZSBT, was awarded in 2007 to Dr Simone Schoenwaelder for her work uncovering a novel contractile mechanism regulating blood clot stability; and in 2008 to Dr Elizabeth Gardiner, for her work uncovering a shear-dependent mechanism for regulating platelet glycoprotein VI (GPVI) expression, a key receptor in arterial thrombosis and immune dysfunction.

AVBS/ANZMS Michael Perry Young Investigator Award PhD candidate Akiko Ono was awarded the ANZMS Young Investigator Award at the Australian Vascular Biology Society / Australian New Zealand Microcirculation Society Joint Symposium 2007 held in Victoria, 2007. Ms Ono was also awarded an AVBS Young Investigator award to support her attendance and presentation at the International Vascular Biology Meeting (IVBM) in Sydney 2008.


Erik Westein

Young Investigator Awards Asia Pacific Society on Thrombosis and Haemostasis In 2007, Ms Akiko Ono received a Young Investigator Award at the Japanese Society of Thrombosis and Haemostasis (JSTH) / Asia Pacific Society of Thrombosis and Haemostasis (APSTH) Joint Symposium in Japan. In 2008, ACBD PhD candidate Erik Westein also received this award, allowing him to present his research findings at the APSTH, held in Osaka, Japan. Alfred Medical Research and Eductaion Precinct (AMREP) Postgraduate Research Symposium In 2008, Mr Erik Westein was awarded first prize for his presentation at the inaugural AMREP Post Graduate Research Symposium.


Dr Andrew Wei

Dr Mae-Xhum Wong

Maithili Sashindranath

Dr Yang Shen and Ms Jing Jing

Arrivals to the ACBD Vascular Biology Laboratory relocated to the Australian Centre for Blood Diseases in mid-2008, from the Monash Department of Immunology (since 2006). The laboratory currently consists of Robert Andrews, Elizabeth Gardiner, Jane Arthur, Cheryl Berndt, Fi-tjen Mu, Mohammad al Tamimi, Yang Shen and Jing Jing. Current research including collaborations with other ACBD laboratories, the AMREP precinct, as well as national and international research groups, involves experimental and clinical investigations of platelet receptors that regulate thrombus formation relevant to heart attack or stroke, and thrombotic disorders associated with immune dysfunction.

Dr Andrew Wei is a medical graduate from Melbourne University and staff specialist in Haematology at the Alfred Hospital. He completed a PhD at WEHI investigating apoptosis in haematological malignancies. His research activities are currently focussed on translational aspects of malignant blood disorders.

Dr Trish Walker Dr Trish Walker (MBBS, BMed Sci, FRACP, RCPA) is Haematologist working in full time clinical and basic research for the Malignant Haematology and Stem Cell Transplantation Service at the ACBD. She is currently enrolled in a PhD at Monash University working on a project in stem cell transplantation patients that encompasses immune reconstitution, viral immunity, quality of life and health resource utilisation. As well as her laboratory activities Trish continues her clinical duties with Clinical Trial and Stem Cell Transplantation patients. She kindly supported by the Anderson Bone Marrow Transplant Fellowship (The Alfred) and the Pfizer Cancer Research Grants.

Dr Mae-Xhum Wong completed a PhD at the Austin Research Institute, Melbourne, majoring in the studies of immune cell receptor functions in normal and pathological immunity. Currently employed as a clinical scientist for Immune Systems Therapeutics Ltd. (Sydney), she works in collaboration with Professor Andrew Spencer's laboratory in divulging the mechanisms of drug action for potential multiple myeloma therapy.

Ms Maithili Sashindranath joined the ACBD in June 2008 after completing a PhD at the University of Melbourne, where she investigated Seizure-induced Oxidative Stress and Kinase Signalling in the Kindling Model of Epilepsy. She completed her BSc. Hons degree from the University of Cape Town in South Africa. Her post-doctoral research at the ACBD is focussed on the role of tissue-type plasminogen activator in the pathophysiology of traumatic brain injury.

Dr Ziad Touat completet a PhD in Denis Diderot University (INSERM U698, Paris VII, France), with Dr Jean-Baptiste MICHEL. He investigated the role of blood, and platelets in particular in different forms of aneurysms in human. Ziad accepted a postdoctoral postion with Dr Shaun Jackson at ACBD to work on platelet activation.


Maya Fujihara

Ms Nerine Twigg joined the ACBD as the Business Manager for the Haematology Consortium. Nerine has a degree in Bachelor of Nursing and is studying a Graduate Diploma in Management at Monash University. Nerine‟s employment background is in

Nurse Management. Nerine commenced in April 2008 and departed in November 2008.

Ms Maya Fujihara joined the department in 2008 as an Administration Officer. She provides financial reporting to each lab heads, website updating and student activities management. She has a Bachelor degree in Art and Humanities from Ritsumeikan University in Kyoto, Japan.

There were also many Research Staff joined ACBD in 2007-2008. The ACBD welcomed Dr Fu Jia, Dr Alexandra Rizzitelli, Dr Simone Beckham, Mr Chris Spring, Ms Roxanne Freeman, Ms Adele Baker, Mr Adam Galle, Mr Darren Karadimos and Ms Sarah Xiao.

Departures In 2007-2008, the ACBD bid farewell to a number of staff members, including: Fu Jia, Simone Beckham, Declan Green, Chris Spring, Sarah Xiao, Bree Latta, Adam Galle, Alexandra Rizzitelli, Melinda Missen, Mark Frazzetto, Mei Chan, Michelle Gordon, Kevin Woollard, Joanna Lim, Sung-Lin Yeh, Jane Duong, Mellissa Brauer, Corinne Hitchen, Nerine Twigg and Juliet Sagar, who left to pursue their respective careers. We wish them all the very best with their future endeavours.


Katherine Monaghan

Mehran Ghasemzadeh

Mohammad Al-tamimi

Rachael Borg

Our scientists of the future

The ACBD encourages the development of science at both the undergraduate and postgraduate level. The centre hosts dynamic postgraduate PhD and honours programs, as well as fostering undergraduate science talent. PhD Program

The ACBD is currently responsible for the supervision of 6 PhD students: Akiko Ono

Project title: Investigation mechanisms underlying thrombus stability. Supervisors: Professor Shaun Jackson, Drs Simone Schoenwaelder and Justin Hamilton Erik Westein

Project title: Spatial and temporal regulation of signalling events leading to αIIbβ3 activation Supervisors: Professor Shaun Jackson and Dr Warwick Nesbitt Katherine Monaghan

Project title: The Role of the Bone Marrow Microenvironment in Multiple Myeloma Supervisor: Associate Profs Andrew Spencer Mehran Ghasemzadeh

Project title: Examining the signalling mechanisms regulating platelet activation and in particular the role of PI3-kinases in this process. Supervisors: Professor Shaun Jackson and Dr Yuping Yuan Trifina Sofian

Project title: Characterisation of the interaction between Plasmin and Antiplasmin. Supervisors: Associate Profs Paul Coughlin and Robert Medcalf Jessica Mountford

Project title: Investigating Class II Phosphoinositide 3-Kinase Function in Murine Megakaryocytes Supervisors: Dr Justin Hamilton Rachael Borg

Project title: Investigation into the interaction between tissue-type plasminogen activator and injured cells Supervisors: Associate Profs Robert Medcalf and Dr Andre Samson Patrick Leung

Project title: Investigation of the cross talk between haemostasis and inflammation Supervisors: Professor Shaun Jackson and Dr Yuping Yuan Mohammad Al-tamimi

Project title: Platelet receptor shedding (platelet specific collagen receptor glycopprotein VI) Supervisors: Dr Robert Andrews and Dr Elizabeth Gardiner We congratulate the following students who were successfully awarded their doctorate during the 2007-2008:

Penelope Anne Mayes Title: Towards a New Steroid Synthesis; Conformational Analogues of Oxamflatin as Histone Deacetylase Inhibitors

Postgraduate education


Melinda Paterson Title: Characterisation of centerin, a germinal cell serpin

Anthony Vinh Title: Angiotensin IV-Evoked Modulation of Vascular Function and Atherogenesis in ApoE-Deficient Mice

Firkin PhD Scholarship Students that are interested in pursuing doctorate studies in cardiovascular disciplines, and who have the appropriate graduate qualifications, are encouraged to apply for the Firkin PhD. Award to undertake a PhD program at the ACBD or affiliated institutes comprising AMREP. Further information on these scholarships can be obtained by contacting Dr Robert Medcalf. Up to four scholarships of three years duration will be awarded with an annual tax-free stipend of $22,500.

Honours Degree Program

Over the last few years, the honours program at the ACBD has been conducted under the umbrella of several Monash University Departments; Immunology, Anatomy, and Biochemistry. The program is heavily devoted to the student‟s research project, and thereby emphasizes the importance of experimental design, data collection and analysis, literature reviews and trouble shooting.

The ACBD has supported a large number of honours students in the past, and the period 2007-2008 was no exception. We congratulate the following students who successfully completed their honours year with us.

2007 Abbey Wilcox

Project title: Platelet Apoptosis: The role of Bcl-2 family proteins in platelet lifespan and function Supervisor: Dr Simone Schoenwaelder

Jessica Mountford

Project title: Determining the role of Class II Phosphoinositide 3-Kinase in platelet function Supervisor: Dr Justin Hamilton

Jonathon Teoh

Project Title: The role of endogenous tissue-type plasminogen activator in neurotrauma Supervisor: Associate Profs Robert Medcalf

For enquiries into our Firkin PhD Scholarship, contact:

Assoc Prof Robert Medcalf Australian Centre for Blood Diseases Monash University 6th Floor, Burnet Building, AMREP 89 Commercial Road Melbourne, Victoria 3004 Australia

Email: [email protected]




Patrick Leung

Project title: Investigation of the cross talk between haemostasis and inflammation Supervisors: Professor Shaun Jackson and Dr Yuping Yuan 2008

Amanda Au Project Title: Investigation into the effects of stroke-related therapeutic agents and soluble blood-born agents on neuronal injury. Supervisors: A/Prof. Robert Medcalf and Dr. Andre Samson Bernadine Lu Project Title: Investigation of the plasmin and antiplasmin interaction by mutagenesis of the antiplasmin C-terminus. Supervisors: A/Prof. Paul Coughlin and Dr. Anita Horvath Cindy Lin Project Title: Investigation of the plasmin and antiplasmin interaction by mutagenesis of the antiplasmin C-terminus. Supervisors: A/Prof. Paul Coughlin and Dr. Anita Horvath Gabrielle Van der Kraan

Project Title: The role of GPIb-V-IX in the negative regulation of integrin aIIbb 3 adhesive function. Supervisor: Dr. Sue Cranmer Hannah Lee Project Title: Defining the role of thromb-induced platelet activation in thrombosis. Supervisor: Dr. Justin Hamilton Katrina Ashworth Project Title: The interaction of GPIb-alpha and filamin A in platelet adhesion and thrombus formation Supervisor: Dr. Sue Cranmer Linda Nguyen Project Title: The production and characterisation of primary human megakaryocytes. Supervisor: Dr. Justin Hamilton My Van Hua Project Title: Live and let die - regulation of platelet reactivity. Supervisor: Dr. Simone Schoenwaelder and Prof. Shaun Jackson

Honours students 2008: Amanda Au, Cindy Lin, Bernadine Lu, Katrina Ashworth, Gabrielle Van der Kraan, Hannah Lee, My Van Hua, Linda Nguyen


Undergraduate teaching

The undergraduate years represent a critical time in the development of our future scientists and medical researchers. For most, lectures and practical sessions will provide many students with their first encounter into the world of medical research. The ACBD is committed to providing undergraduate students with a basic understanding into haematology and blood diseases, and is currently expanding its contribution to undergraduate teaching at Monash University. In 2007, the ACBD took on the coordination of the undergraduate teaching units Human Pathology 1 „Understanding Disease processes‟ and Human Pathology 2 „Pathology of Human Diseases‟ (HUP3011, HUP3022). Together, these 3rd year Science units explore how disruption of normal molecular mechanisms in cells, tissues and organs, impacts the human body during disease. They also describe the causes of disease, and current methods for diagnosis and treatment. Both units are available to 3rd year Science and Biomedical Science undergraduates. In addition, staff at the ACBD continue to participate in the delivery of lectures, practical classes and tutorials for several other Science, Biomedical science and MBBS subjects including: CEL2012: Cell Biology IMM3042: Clinical immunopatholgy MBBS: 2nd and 3rd year haematology tutes

Molecular Medicine and Biotechnology Research Laboratory miniprojects

In addition to formal lecturing, the ACBD continues to play an active role in the Bachelor of Biomedical Sciences (BMS) – Molecular Medicine and Biotechnology Research Laboratory Miniprojects scheme. This teaching initiative involves groups of third year students being assigned a miniproject within the Centre, to be undertaken as part of their university contact hours. Students visiting the laboratories were required to participate in laboratory work, prepare a formal presentation and critically review some of the relevant literature. This scheme took the students beyond the bounds of the university environment and into some of the research Institutes affiliated with Monash University. ACBD summer scholarship program

Each year the ACBD invites currently enrolled Science, Biomedical Science and Medicine undergraduates to apply for a B.G. Firkin Summer Scholarship. The scholarships recognise the enormous contribution of the late Professor B.G. Firkin to the fields of thrombosis and cardiovascular disease. The scholarships, available to both both second and third year students, are designed to encourage high-achieving undergraduates who wish to pursue a career in biomedical research by giving them the opportunity to participate in a research project supervised by senior research staff for six to ten weeks during their university holidays. The „hands on‟ involvement of the students in these projects provides them with a unique chance to enhance their practical skills and to challenge them with the intellectual rigors inherent in good research. In many cases, the summer scholarships also serve as a springboard for students to undertake an Honours year within the department.

Further Opportunities for Undergraduates to gain working experience at the ACBD

In addition to offering summer scholarships and opening up our research laboratories to host miniprojects for BMS undergraduates, the ACBD also offers the opportunity for second and third-year undergraduates to apply for a part-time position to gain valuable working experience in our research laboratories. These positions are designed to allow undergraduates to experience the research lab environment, and gain a better

If you would like more information on honours at the ACBD, contact:

Dr Simone M Schoenwaelder Australian Centre for Blood Diseases Monash University 6th Floor, Burnet Building, AMREP Commercial Road Melbourne, Victoria 3004 Australia

Email:[email protected]

Bernadine Lu

The ACBD vacation scholarship program allowed me to explore

various aspects to biomedical research during my undergraduate years. My experience enabled me to gain a better understanding and appreciation for medical research and contributed to my decision to

undertake honours and subsequently commence my PhD

candidature.





Dr Sue Cranmer

understanding of what it means to be a „scientist‟ before they delve into their honours and PhD years. This program has been on offer for a number of years now, and has proven to be very effective in assisting undergraduates in their career decision making, and also providing them with that all important „first experience‟ that is required for many job applications. Student information nights at the ACBD

In order to provide prospective students, and the wider community, with a better understanding of what we do at the ACBD, we have participated in several information sessions as well as hosting our own information nights. ACBD Information Nights

The ACBD hosted two information nights in August 2007 and 2008. Mail-outs with information with regard to laboratories and projects were sent out to Science and Biomedical Science students. The information nights were very successful with 85 students participating, generating a significant amount of interest in the areas of blood diseases and haematology. Future Open Days are planned in July/August ‟09. For more information on these sessions, or to find out about our information nights at the ACBD, please refer to our website or contact Ms. Maya Fujihara [99030130, [email protected]] AMREP information night (2007/2008) and Monash Post-graduate Information Sessions :

ACBD also participated in the AMREP Information nights and the Monash Post-graduate information sessions held in 2007/08. Our researchers were on hand to answer queries from interested students. These information sessions are also held each year, and further information on proposed dates for future information sessions can be obtained either from our website, or by contacting us directly.

For enquiries into our Summer scholarship program or research opportunities at the ACBD, contact:

Ms Maya Fujihara Australian Centre for Blood Diseases Email: [email protected]

Dr Yuping Yuan with students at the ACBD student information night




Grant funding 2007-2008

Scholarships/Fellowships

2003-2007 R.L. Medcalf, NH&MRC, Senior Research Fellowship 2004-2008 S.P. Jackson, NH&MRC, Principal Research Fellowship 2005-2007 J.R. Hamilton, NH&MRC, CJ Martin Training Fellowship 2004-2008 S.C. Hughan, NH&MRC, CJ Martin Training Fellowship 2008-2012 R.L. Medcalf, NH&MRC, Senior Research Fellowship 2008-2012 Hamilton, NHF, Career Development Fellowship 2008-ongoing A. Spencer, Anderson Trust Fellowship 2006-2008 A. Ono, Joint NHF/NHMRC Postgraduate Scholarship 2006-2009 E. Westein, NHF Postgraduate Scholarship 2007-2008 M. Hua, NHF Summer Vacation Scholarship

Competitive project grants

2005-2007 NHMRC Project Grant, No. 334080, S.P. Jackson ($240,000) 2006-2008 ARC Project Grant, No. DP0663904, S.P. Jackson ($294,000) 2006-2008 NHMRC Project Grant, No. 384249, S.P. Jackson ($495,000) 2006-2008 NHMRC Project Grant, M.Berndt, HH Salem, SL Cranmer ($506,000) 2007 NHMRC Development Grant, S.P. Jackson, D. Duncan ($184,000) 2007-2008 NHF Project Grant, S.P. Jackson ($123,000) 2007-2008 NHF Project Grant, S.M. Schoenwaelder, H.H. Salem ($123,000) 2007-2009 NHMRC Project Grant, No. 436879, R.K. Andrews ($349,500) 2007 NHMRC Project Grant, No. 436784, A.I. Smith, R.A. Lew, R.K. Andrews ($466,500) 2008-2010 NHMRC Project Grant, S.P. Jackson ($515,500) 2008-2010 NHMRC Project Grant, S.P. Jackson ($515,500) 2008-2010 NHMRC Project Grant, B.T. Kile, S.P. Jackson, A. Roberts ($521,000) 2008 Victorian Neurotrauma Initiative, R.L. Medcalf, C. Morganti-Kossmann, HHHW Schmidt ($578,064) 2008-2010 NHMRC Project Grant, R.L. Medcalf ($488,250) 2008-2010 NHMRC Project Grant, R.L. Medcalf ($483,750) 2008-2009 NHF Project Grant, R.L. Medcalf ($129,000) 2008-2010 NHMRC Project Grant, S.C. Hughan, W.S. Nesbitt ($428,750) 2008-2010 NHMRC Project Grant, J.R. Hamilton, H.H. Salem ($317,250)

Commercial funding

2008 Cerylid Patent: S.P. Jackson ($299,210) 2008 Paion: R.L. Medcalf ($12,000) 2006-2008 Forest Research Institute: R.L.Medcalf ($20,184) 2008 Cytopia: A. Spencer ($65,000) 2008 Novartis: A. Spencer ($50,000) 2008-ongoing Novartis: A. Spencer ($115,000 +ongoing)

Other funding

2006-2008 Monash University Support Funds, S.C. Hughan ($100,000) 2008 Equity Trustee Limited-Harold and Cora Brennen Benevolent Trust Research Grant, S.P. Jackson, S.L.

Cranmer ($14,000)


Publications 2007-2008

2007 Arcaro A, Doepfner KT, Boller D, Guerreiro AS, Shalaby T, Jackson SP, Schoenwaelder SM, Delattre O, Grotzer MA, Fischer B. Novel role for insulin as an autocrine growth factor for malignant brain tumor cells. Biochem. J., 406(1):57-66,2007. Baker M, Allen P, Shortt J, Lewin SR, Spencer A. Immune recovery uveitis in HIV-infected and HIV-negative immunosuppressed individuals in Australia: Clinical Case notes. Clinical and Experimental Opthalmology 2007: 189-190. Bassler N, Loeffler C, Mangin P, Yuan Y, Schwarz M, Eisenhardt S, Ahrens I, Bode C, Jackson SP and Peter K. A Mechanistic Model for Paradoxical Platelet Activation by Ligand-mimetic IIb 3 (GPIIb/IIIa) Antagonists. Art. Thromb. Vasc. Biol. 27(3):e9-15, 2007. Baulch-Brown C, Molloy TJ, Yeh SL, Ma D, Spencer A. Inhibitors of the mevalonate pathway as potential therapeutic agents in multiple myeloma. Leukemia Research 2007; 31: 341-352. Busso, N., Frasnelli, M., Feifel, R., Cenni, B., Steinhoff, M., Hamilton, J.R. and So, A. (2007) Evaluation of protease-activated receptor 2 (PAR2) in murine models of arthritis. Arthritis Rheum. 56, 101-107. Chaussade C, Rewcastle GW, Kendall JA, Denny WA, Cho K, GrØnning LM, Chong ML, Anagnostou SH, Jackson SP, Daniele N and Shepherd PR. Evidence for Functional Redundancy of Class-Ia PI 3-kinase Isoforms in Insulin Signaling. Biochem. J. 404:449-458, 2007. Daniel PB, Lux W, Samson AL, Schleuning WD, Niego B, Weiss TW, Tjärnlund-Wolf A, Medcalf RL. Two conserved regions within the tissue-type plasminogen activator gene promoter mediate regulation by brain-derived neurotrophic factor. FEBS J. 2007 May;274(9):2411-23. Dawson M, Patil S, Spencer A. Extramedullary relapse of multiple myeloma associated with a shift in secretion from intact immunoglobulin to light chains. Haematologica 2007; 92: 143-144. Dear AE and Byron K. Letter: “Genotype and Adverse Drug Reactions”. Med J Aust 2007 187:61-2. Dimopoulos M, Spencer A, Attal M, Prince HM, Harousseau JL, Dmoszynska A, San Miguel J, Hellman A, Facon T, Foa R, Lazzarino M, Masliak Z, Olesnyckyj M, Yu Z, Patin J, Zeldis JB, Knight RD. Oral lenalidomide and dexamethasone versus placebo and dexamethasone in patients with relapsed or refractory multiple myeloma. New England Journal of Medicine 2007; 357: 2123-2132. Ferguson JG, Milne L, Kulkarni S, Sasaki T, Walker S, Andrews S, Crabbe T, Finan P, Jones G, Jackson S, Camps M, Rommel C, Wymann M, Hirsch E, Hawkins PT & Stephens LR. In neutrophils PI3K plays an important, context-dependent role in chemokinesis but not in gradient-biased migration. Nat. Cell Biol. 9:86-91, 2007 Golledge J, Muller J, Shephard N, Clancy P, Smallwood L, Moran C, Dear AE, Palmer L, Normal P. “Association Between Osteopontin and Human Abdominal Aortic Aneurysm”. Art Throm Vasc Biol 2007 27:655-60. Hamilton, J.R., Kaplan, Z., Jackson, S.P. and Opat, S. (2007) Antiplatelet Therapy: Current Status and Future Prospects. Expert Opinion on Drug Discovery. 2, 1035-1040. Hughan SC, Watson SP. Differential regulation of adapter proteins Dok2 and Dok1 in platelets, leading to an association of Dok2 with integrin alphaIIbbeta3. J Thromb Haemost. 2007 Feb;5(2):387-94. Hughan SC, Hughes CE, McCarty OJ, Schweighoffer E, Soultanova I, Ware J, Tybulewicz VL, Watson SP. GPVI potentiation of platelet activation by thrombin and adhesion molecules independent of Src kinases and Syk. Arterioscler Thromb Vasc Biol. 2007 Feb;27(2):422-9. Jackson SP. The Growing Complexity of Platelet Aggregation. Blood 109:5087-5095, 2007. Jackson SP, Cranmer SL, Mangin P and Yuan Y. Are Erk, Btk and PECAM1 major players in GPIb signaling? The challenge of unravelling signaling events downstream of platelet GPIb. Blood (Perspective) 109:846-847, 2007. Jackson SP and Calkin A. The Clot Thickens – Oxidized Lipids and Thrombosis. Nature Med. (News & Views) 13(9):1015-1016, 2007.


Kendall JD, Rewcastle GW, Frederick R, Mawson C, Denny WA, Marshall ES, Baguley BC, Chaussade C, Jackson SP and Shepherd PR. Synthesis, biological evaluation and molecular modeling of sulfonohydrazides as selective PI3K p110α inhibitors. Bioorg. Med. Chem. 15(24):7677-87, 2007. Kim S, Garcia A, Jackson SP and Kunapuli SP. Insulin-like growth factor-1 regulates platelet activation through PI 3- Kalpha isoform. Blood 110:4206-13, 2007. Kulkarni S, Woollard KJ, Thomas S and Jackson SP. Conversion of Platelets from a Pro-Aggregatory to a Pro-Inflammatory Adhesive Phenotype. A Role for PAF in Spatially Regulating Neutrophil Adhesion and Spreading. Blood 110:1879-1886,2007. Law RH, Sofian T, Kan WT, Horvath AJ, Hitchen CR, Langendorf CG, Buckle AM, Whisstock JC, Coughlin PB. The X-ray crystal structure of the fibrinolysis inhibitor {alpha}2-antiplasmin. Blood. 2007 Dec 6; [Epub ahead of print] PMID: 18063751 Lindemann, R.K., A. Newbold, A., Whitecross, K.F., Cluse, L.A., Frew, A.J., Ellis, L., Williams S., Wiegmans, A., Dear, A.E., Scott, C.L., Pellegrini, M. Wei, A., Marks, P.A., Richon, V.M., Lowe, S.W., Smyth, M.J., and Johnstone, R.W. “Mechanistic analysis of the apoptotic and therapeutic activities of histone deacetylase inhibitors using a genetically tractable mouse model of B cell lymphoma”. Pro Nat Acad Sci USA 2007 104:8071-6 Maxwell MJ, Westein E, Nesbitt WS, Giuliano S, Dopheide SM and Jackson SP. Identification of a Two-Stage Platelet Aggregation Process Mediating Shear-Dependent Thrombus Formation. Blood 109:566-576, 2007 Medcalf RL. Fibrinolysis, inflammation, and regulation of the plasminogen activating system. J Thromb Haemost. 2007 Jul;5 Suppl 1:132-42. Review. Morschhauser F, Seymour JF, Kluin-Nelemans HC, Grigg A, Wolf M, Pfreundschuh M, Tilly H, Raemaekers J, van‟t Veer MB, Milpied N, Carton G, Pezzuto A, Spencer A, Reyes F, Dreyling M. A Phase II study of enzastaurin, a protein kinase C beta inhibitor, in patients with relapsed or refractory mantle cell lymphoma. Annals of Oncology 2007 (in press). Orlowski RZ, Nagler A, Sonneveld P, Bladé J, Hajek R, Spencer A, San Miguel J, Robak T, Dmoszynska A, Horvath N, Ivan Spicka I, Sutherland HJ, Suvorov AN, Zhuang SH, Parekh T, Xiu L, Yuan Z, Rackoff W, Harousseau JL. The combination of pegylated liposomal Doxorubicin and Bortezomib significantly improves time to progression of patients with relapsed/refractory Multiple Myeloma compared with Bortezomib alone: Results from a randomized Phase III study. Journal of Clinical Oncology 2007; 25: 3892-3901. Paterson MA, Horvath AJ, Pike RN, Coughlin PB. Molecular characterization of centerin, a germinal centre cell serpin. Biochem J. 2007 Aug 1;405(3):489-94. Schoenwaelder SM, Ono A, Sturgeon S, Chan SM, Mangin P, Maxwell MJ, Turnbull S, Mulchandani M, Anderson K, Kauffenstein G, Rewcastle GW, Kendall J, Gachet C, Salem HH and Jackson SP (2007). Identification of a unique co-operative PI 3-kinase signaling mechanism regulating integrin IIb 3 adhesive function in platelets. J Biol Chem., 282(39):28648-58 Sharkey J, Khong T, Spencer A. PKC412 demonstrates JNK-dependent activity against human multiple myeloma cells. Blood 2007; 109: 1712-1719. Slavin MA, Grigg AP, Schwarer AP, Szer J, Spencer A, Sainani A, Thursky KA, Roberts A. A randomized comparison of empiric or pre-emptive antibiotic therapy after hematopoietic stem cell transplantation. Bone Marrow Transplantation 2007; 40: 157-163. Spencer A, Reed K, Arthur C. A pilot study of an outpatient-based approach for advanced lymphoma using vinorelbine, gemcitabine and filgrastim (VGF). Internal Medicine Journal 2007; 37: 760-766. Vandendries, E.R., Hamilton, J.R., Coughlin, S.R., Furie, B. and Furie, B.C. (2007) PAR4 is required for platelet thrombus propagation but not fibrin generation in a mouse model of thrombosis. Proc. Nat. Acad. Sci. USA. 104, 288-292. Vinh A, Gaspari T, Widdop R, Liu HB, Dousha L and Dear AE. “A Novel Histone Deacetylase Inhibitor Reduces Abdominal Aortic Aneurism Formation in Angiotensin-II Infused APOE Deficient Mice”. J Vasc Res 2007 45:143-152.


2008

Andrews, RK, Berndt, MC. Microparticles facilitate neutrophil/platelet crosstalk at the inflammation/thrombosis interface. Blood 2008;112:2174-2175. Andrews, RK, Berndt, MC. Platelet adhesion: A game of catch and release. J Clin Invest 2008;118:3009-3011. Andrews, RK, Berndt, MC. Thrombosis@AMREP International Review of Thrombosis 2008;3:44-51. Arthur, JF, Gardiner, EE, Kenny, D, Andrews, RK, Berndt, MC. Platelet receptor redox regulation. Platelets 2008;19:1-8. Berndt, MC, Andrews, RK. Systems biology meets platelet biology. Blood 2008; 112:3920-3921. Berndt, MC, Andrews, RK. Molecular regulation of platelet adhesion. Japanese J Thromb Hemostas 2008;19:77-84. Berndt, MC, Andrews, RK. NEW direction for WE thrombin. Arterioscler Thromb Vasc Biol 2008;28:205-207. Blade J, Sonneveld P, San Miguel JF, Sutherland HJ, Hajek R, Nagler A, Spencer A, Robak T, Cibeira MT, Zhuang SH, Harousseau JL, Orlowski RZ, For The Doxil-Mmy-3001 Study Investigators. Pegylated Liposomal Doxorubicin plus Bortezomib in Relapsed or Refractory Multiple Myeloma: Efficacy and Safety in Patients with Renal Function Impaiment. Clinical Lymphoma Myeloma. 2008;8(6):352-355. Buzza, MS, Dyson, JM, Hiuwan Choi, H, Gardiner, EE, Andrews, RK, Kaiserman, D, Mitchell, CA, Berndt, MC, Dong, J-F, Bird PI. Anti-hemostatic activity of human granzyme B mediated by cleavage of von Willebrand factor. J Biol Chem 2008;283:22498-22504. Busso N, Chobaz-Peclat V, Hamilton JR, Spee P, Wagtmann N and So A. Essential role of platelet activation via PAR-4 in tissue factor-initiated inflammation. Arthritis Res. Ther 2008; 10: R42. Frazzetto M, Suphioglu C, Zhu J, Schmidt-KittlervO, Jennings IG, Cranmer SL, Jackson SP, Kinzler KW, Vogelstein B and Thompson PE. Dissecting isoform selectivity of P13K inhibitors: the role of non-conserved residues in the catalytic pocket. Biochemical Journal 2008;414(3):383-390. Gardiner, EE, Karunakaran, D, Arthur, JF, Mu, F-T, Powell, MS, Baker, RI, Hogarth, M, Kahn, ML, Andrews, RK, Berndt, MC. Dual ITAM-mediated proteolytic pathways for irreversible inactivation of platelet receptors: De-ITAM-ising Fc RIIa. Blood 2008;111:165-174. Gardiner, EE, Al-Tamimi, M, Mu, F-T, Karunakaran, D, Thom, JY, Moroi, M, Andrews, RK, Berndt, MC, Baker, RI. Compromised ITAM-based platelet receptor function in a patient with immune thrombocytopenic purpure. J Thromb Haemostas 2008;6:1175-1182. Gardiner, EE, Andrews, RK. The cut of the clot(h): snake venom fibrinogenases as therapeutic agents. J Thromb Haemostas 2008; 6:1360-1362 Hamilton JR, Mountford JK, Cornelissen I and Coughlin SR. Atherosclerotic lesioning of mouse aorta occurs independently of thrombin-induced platelet activation: evidence from protease-activated receptor 4 deficient mice. Atherosclerosis. 2008. Hamilton JR. Protease-activated receptors as targets for anti-platelet therapy. Blood Reviews 2008. Heller R, Chang Q, Ehrlich G, Hsieh SN, Schoenwaelder SM, Kuhlencordt PJ, Preissner KT, Hirsch E, and Wetzker R. Overlapping and distinct roles for P13K and isoforms in S1P-induced migration of human and mouse endothelial cells. Cardiovascular Research 2008;80(1):96-105. Hiwase DK, Hiwase S, Bailey M, Bollard G, Schwarer AP. The role of stem cell mobilization regimen on lymphocyte collection yield in patients with multiple myeloma. Cytotherapy 2008; 00: 1-11. Hiwase DK, Hiwase S, Bailey M, Bollard G, Schwarer AP. Higher infused lymphocyte dose predicts higher lymphocyte recovery, which in turn, predicts superior overall survival following autologous hematopoietic stem cell transplantation for multiple myeloma. Biol Blood Marrow Transplant 2008; 14: 116-24.


Hughes TP, Branford S, White DL, Reynolds J, Koelmeyer R, Seymour JF, Taylor K, Arthur C, Schwarer A, Morton J, Cooney J, Leahy MF, Rowlings P, Catalano J, Hertzberg M, Filshie R, Mills AK, Fay K, Durrant S, Januszewicz H, Joske D, Underhill C, Dunkley S, Lynch K, Grigg A. Impact of early dose intensity on cytogenetic and molecular responses in chronic phase CML patients receiving 600 mg/day of imatinib as initial therapy. Blood 2008 Sep 3; [Epub ahead of print]. Guerreiro AS, Fattet S, Fischer B, Shalaby T, Jackson SP, Schoenwaelder SM, Grotzer MA, Delattre O, and Arcaro A. Targeting the P13K p110 isoform inhibits medulloblastoma proliferation, chemoresistance, and migration. Clinical Cancer Research 2008 Nov;14(21):6761-6769. Jackson SP and Calkin AC. The Clot thickens- oxidized lipids and thrombosis. Nature Medicine2008 Sep;13(9):1015-1016. Kalff A, Shortt J, Farr J, McLennan R, Lui A, Scott J, Spencer A. Laboratory tumour lysis syndrome complicating LBH589 therapy in a patient with acute myeloid leukaemia. Haematologica 2008; 93: e16-17. Khong T, Sharkey J, Spencer A. The effect of azacitidine on interleukin-6 signaling and nuclear factor-kappaB activation and its in vitro and in vivo activity against multiple myeloma. Haematologica 2008; 93(6): 860-869. Liu H, Hu Y, Simpson RW and Dear AE. Glucagon-like peptide-1 attenuates tumour necrosis factor- mediated induction of plasminogen activator inhibitor-1 expression. Journal of Endocrinology 2008;196(1):57-65. Mason KD, Vandenberg CJ, Scott CL, Wei AH, Cory S, Huang DC, Roberts AW. In vivo efficacy of the Bcl-2 antagonist ABT-737 against aggressive Myc-driven lymphomas. Proceedings of the National Academy of Sciences of the United States of America. 2008;105(46):17961-6 Mu FT, Andrews RK, Arthur JF, Munday AD, Cranmer SL, Jackson SP, Stomski FC, Lopez AF and Berndt MC. A functional 14-3-3{zeta}-independent association of P13-Kinase with glycoprotein lb{alpha}, the major ligand-binding subunit of the platelet glycoprotein lb-IX-V complex. Blood 2008;111(9):4580-4587. Mullighan CG, Heatley SL, Danner S, Dean MM, Doherty K, Hahn U, Bradstock KF, Minchinton R, Schwarer AP, Szer J, Bardy PG. Mannose-binding lectin status is associated with risk of major injection following myeloablative sibling allogeneic hematopoietic stem cell transplantation. Blood 2008; 112: 2120-2128. Newbold A, Lindemann RK, Cluse LA, Whitecross KF, Dear AE, Johnstone RW. Characterisation of the novel apoptotic and therapeutic activities of the histone deacetylase inhibitor romidepsin. Molecular Cancer Therapeutics 2008;7(5):1066-1079. Nguyen TH, Mifsud NA, Stewart LA, Rose MJ, Etto TL, Williamson NA, Purcell AW, Kotsimbos T, Schwarer AP. Refinement in the production and purification of recombinant HCMV IE1-pp65 protein for the generation of epiltope-specific T cell immunity. Protein Expr Purif 2008; 61: 22-30. Niego B, Horvath A, Coughlin PB, Pugsley MK and Medcalf RL. Desmoteplase-mediated plasminogen activation and clot lysis are inhibited by the lysine analogue tranexamic acid. Blood Coagulation and Fibrinolysis 2008;19(4):322-324. Ono A, Westein E, Hsiao S, Nesbitt WS, Hamilton JR, Schoenwaelder SM and Jackson SP. Identification of a fibrin-independent platelet contractile mechanism regulating primary hemostasis and thrombus growth. Blood 2008;112:90-99. Palumbo A, Facon T, Sonneveld P, Blade J, Offidani M, Gay F, Moreau P, Waage A, Spencer A, Ludwig H, Boccadoro M, Haousseau JL. Thalidomide for treatment of multiple myeloma: 10 years later. Blood. 2008; 111(8):3968-77. Pasricha SR, Grigg A, Catalano J, Leahy M, Underhill C, Arthur C, D‟Rozario J, Lowenthal R, Reed K, Spencer A. A multicenter phase 2 study of risk-adjusted salvage chemotherapy incorporating vinorelbine and gemcitabine for relapsed and refractory lymphoma. Cancer 2008; 113(11): 3192-3198. Paterson MA, Hosking PS, Coughlin PB. Expression of the serpin centerin a geminal center phenotype in B-cell lymphomas. American Journal of Clinical Pathology. 2008;130(1):117-26. Patil S, Schwarer A, McLean C. Urinary cytology in multiple myeloma. Cytopathology 2008; 19: 130-1. Polizzotto MN, Shortt J, Opat SS, Cole-Sinclair MF. A drop of vitriol: microspherocytosis following sulphuric acid exposure. British Journal of Haematology. 2008;140(6):596.


Samson AL, Nevin ST and Medcalf RL. Low molecular weight contaminants in commercial preparations of plasmin and t-PA activate neurons. Journal of Thrombosis and Haemostasis 2008;6(12):2218-2220. Samson AL, Nevin ST, Croucher D, Niego B, Daniel PB, Weiss TW, Moreno E, Monard D, Lawrence DA and Medcalf RL. Tissue-type plasminogen activator requires a co-receptor to enhance NMDA receptor function. Journal of Neurochemistry 2008;107(4):1091-1101. Sant-Rayn P, Grigg A, Catalano J, Leahy M, Underhill C, Arthur C, D‟Rozario JD, Lowenthal R, Taylor K, Reed K, Spencer A. A multi-centre Phase II study of risk-adapted salvage therapy incorporating vinorelbine and gemcitabine in an ambulatory care setting for relapsed and refractory lymphoma. Cancer 2008;113(11); 3192-3198.

Shortt J, Opat SS, Gorniak MB. Aumann HA, Collecutt MF, Street AM. A retrospective study of the utility of desmopressin (1-deamino-8-D-arginine vasopressin) trials in the management of patients with von Willebrand disorder. International Journal of Laboratory Haematology. 2008 Oct: Epub ahead of print. Shortt J, Polizzotto MN, Opat SS, Cole-Sinclair MF. Oxidative haemolysis due to 'poppers'. British Journal of Haematology. 2008 May: Epub ahead of print. Sonneveld P, Hajek R, Nagler A, Spencer A, Blade J, Robak T, Zhuang SH, Harousseau JL, Orlowski RZ, DOXIL-MMY-3001 Study Investigators. Combined pegylated liposomal doxorubicin and bortezomib is highly effective in patients with recurrent or refractory multiple myeloma who received prior thalidomide/lenalidomide therapy. Cancer. 2008; 112(7): 1529-37. Spelman D, Buttery J, Daley A, Isaacs D, Jennens I, Kakakios A, Lawrence R, Roberts S, Torda A, Watson DS, Wooley I, Anderson T, Street A; Australasian Society for Infectious Diseases. Guidelines for the prevention of sepsis in asplenic and hyposplenic patients. Internal Medicine Journal. 2008: 38; 349-356. Spencer A, Roberts A, Kennedy N, Ravera C, Cremers S, Bilic S, Neeman T, Copeman M, Schran H, Lynch K. Renal safety of zoledronic acid with thalidomide in patients with myeloma: a pharmacokinetic and safety sub-study. BMC Clin Pharmacol. 2008; 8: 2. Straub A, Wendel HP, Dietz K, Schiebold D, Peter K, Schoenwaelder SM, Ziemer G. Selective inhibition of the platelet phosphoinositide 3-kinase p110 as promising new strategy for platelet protection during extracorporeal circulation. Thrombosis and Haemostasis 2008;99(3):609-615. Sutherland JS, Spyroglou L, Muirhead JL, Heng TS, Prieto-Hinojosa A, Prince HM, Chidgey AP, Schwarer AP, Boyd RL. Enhanced immune system regeneration in humans following allogeneic or autologous hemopoietic stem cell transplantation by temporary sex steroid blockage. Clin Cancer Res 2008; 14: 1138-1149. van der Meijden PE, Schoenwaelder SM, Feijge MAH, Cosemans JMEM, Munnix ICA, Wetzker R, Heller R, Jackson SP and Heemskerk JWM. Dual P2Y 12 receptor signalling in thrombin-stimulated platelets- involvement of phosphoinositide 3-kinase beta but not gamma isoform in Ca2+ mobilization and procoagulant activity. FEBS Journal 2008;275(4):371-385. Wang M, Dimopoulos MA, Chen C, Cibeira MT, Attal M, Spencer A, Rajkumar SV, Yu Z, Olesnyckyj M, Zeldis JB, Knight RD, Weber DM. Lenalidomide plus dexamethasone is more effective than dexamethasone alone in patients with relapsed or refractory multiple myeloma regardless of prior thalidomide exposure. Blood 2008; 112(12): 4445-4451. Wei A and Jackson SP. Boosting platelet production. Nature Medicine 2008;14(9):917-918. Wei AH, Roberts AW. Bortezomib: putting mantle cell lymphoma on death row. Leukemia and Lymphoma. 2008;49(4):657-658. Wei A, Alison J, Goldstein J, Tippett C, Coughlan PB. Prosthetic pulmonary valve thrombosis in pregnancy successfully treated with thrombolysis. Internal Medicine Journal. 2008;38(2):142-3. Wei A, Prosthetic pulmonary valve thrombosis in pregnancy successfully treated with thrombolysis. Internal Medicine Journal 2008;38: 142-143. Woollard KJ, Suhartoyo A, Harris EE, Eisenhardt SU, Jackson SP, Peter K, Dart AM, Hickey MJ and Chin-Dusting JPF. Pathophysiological levels of soluble P-selectin mediate adhesion of leukocytes to the endothelium through Mac-1 activation. Circulation Research 2008 Sep;103(10):1128-1138. Vinh A, Gaspari TA, Liu H, Dousha LF, Widdop RE, Dear AE. A novel histone deacetylase inhibitor reduces abdominal aortic aneurysm formation in angiotensin II-infused apolipoprotein E-deficient mice. Journal of Vascular Research 2008;45:143-152.


Professional activities

Vascular Biology Laboratory Invited presentations RK Andrews

Australasian Society of Thrombosis and Haemostasis, HAA conference, Perth; October 2008

EG Gardiner

Australasian Society of Thrombosis and Haemostasis, HAA conference, Perth; October 2008

5th Congress, Asian-Pacific Society of Thrombosis and Haemostasis, Singapore; 2008 15th International Vascular Biology Meeting, Sydney; 2008 JF Arthur

International Society of Thrombosis and Haemostasis, XXIst Congress, Geneva; July 2007 RMIT Department of Biological Medicine Seminar series, hosted by Prof. Owen Woodman; October 2008 Conference session chair RK Andrews

American Society of Hematology (ASH), 50th Annual Meeting, San Francisco, USA; 2008 Australasian Society of Thrombosis and Haemostasis, HAA conference, Perth; 2008 UK-Japan platelet meeting, 5th Congress, APSTH, Singapore; 2008 Atherothrombosis meeting, Satellite Meeting of the 15th IVBM, Melbourne; 2008 1st Australia–China Biomedical Research Conference, Melbourne; 2007

Fibrinolysis and Gene Regulation Unit RL Medcalf State of the Art lecture: International Society on Thrombosis and Haemostasis, XXIst

Congress, Geneva, Switzerland; July 2007 Thrombosis Research Unit Symposia/State-of-the-art/Plenary presentations SP Jackson

Symposium Presentation, The International Society on Thrombosis & Hemostasis, XXIst Congress, Geneva, Switzerland; July 2007 Symposium, Joint Australian Vascular Biology & Australian New Zealand Microcirculation Society Meeting, Hepburn Springs, Victoria; Sept 2007 Symposium, Haematology Society of Australia, Annual Scientific Meeting, Brisbane; October 2007 Symposium, Garvan Signalling Symposium, Garvan Institute, Sydney; October 2007 Symposum, 3rd Barossa Signalling Meeting, Barossa Valley, Sth Australia; Nov 2007 Plenary Lecture, International Society of Laboratory Haematology Meeting, Sydney, Australia; April 2008 Plenary Lecture, XVth International Vascular Biology Meeting, Sydney, Australia; June 2008 Atherothrombosis Symposium, Satellite Symposium to IVBM Meeting, Melbourne, 2008 Symposium Presentation, SSC/ISTH Scientific Meeting, Vienna, Austria (Invited, but unable to attend); July 2008 Plenary Lecture, 42nd Lake Kawaguchi Conference of Cardiology, Chiba, Japan; July 2008 Symposium, Amgen Australia Haematology Symposium, Sydney; July 2008 Symposium, Australian Diabetes Society Annual Scientific Meeting, Melbourne; July 2008 Symposium, ComBio Annual Scientific Meeting, Canberra (Invited, but unable to attend); Sept 2008 Symposium Presentation, Platelets 2008 International Symposium, Massachusetts, USA; October 2008 Symposium Presentation, Amercian Heart Association Meeting, New Orleans, USA; Nov 2008 Other invited presentations SP Jackson The International Society on Thrombosis & Hemostasis, XXIst Congress, Geneva, Switzerland; 2007 Joint Australian Vascular Biology & Australian New Zealand Microcirculation Society Meeting, Hepburn Springs, Victoria; 2007 SSC Biorheology Meeting, Geneva, Switzerland; 2007 Portola Pharmaceuticals Inc., San Francisco, USA; March 2007 IMVS, Royal Adelaide Hospital, Adelaide; July 2007 Gran WEHI, Institute Seminar, Melbourne; May 2008


SC Hughan National Scientific meeting of the Australian Institute of Medical Scientists (AIMS); October 2008, 13-17 October, Melbourne, Australia. Dr Justin Hamilton

HAA 2008 Congress, invited on behalf of ASTH, Perth, 2008. Haematology Update – Novo Nordisk, invited speaker, Werribee, 2008. Department of Pharmacology, University of Melbourne, 2007. Department of Pharmacology, Monash University, 2007. Centre for Inflammatory Diseases/Department of Medicine, Monash University, 2007.

SM Schoenwaelder HAA2007 Congress, Gold Coast, QLD [Selected for ASTH/HSANZ Presidential Symposium]; October 2007 AVBS/ANZMS joint symposium, Hepburn Springs, Victoria; Sept 2007 Department of Cell and Developmental biology, University of North Carolina at Chapel Hill, NC, USA. Invited Departmental Seminar Speaker, Host: Professor Keith Burridge; October 2008. Platelets 2008 5th International Symposium, Woods Hole, MA, USA; October 2008

Malignant Haematology & Stem Cell Transplantation Service

Invited National/International Presentations/Lectures A. Spencer

Satellite Symposioum, 33rd Annual Meeting of the European Group for Blood and Marrow Transplantation (EBMT). Lyon, France, April 2007. Novartis Oncology Australia – Research and Development Symposium. Melbourne, August 2007. Satellite Symposium, Annual Meeting of the European Group for Blood and Marrow Transplantation (EBMT). Florence, Italy, March 2008. Asia Pacific Translational Medicine Workshop, Shanghai, China, March 2008. M3 Symposium: Managing Multiple Myeloma. Sydney, March 2008. Fully financed by organisers. ALLG Transplantation Symposium. Melbourne, May 2008. Australia & Asia Pacific Clinical Oncology Research Development Workshop (ACORD). Sunshine Coast, Australia, September 2008. Nereus pharmaceuticals NPI-0052-102 Trial investigators meeting, 50th American Society of Hematology (ASH) Annual Meeting and Exposition. San Francisco, USA, December 2008. Costs already covered. Lunch-time Symposium, 50th American Society of Hematology (ASH) Annual Meeting and Exposition. San Francisco, USA, December 2008. Fully financed by organisers. A. Wei

Educational DVD Leukaemia Foundation of Australia. 2007 30th Annual Meeting of the Australasian Flow Cytometry Group. Melbourne, September 2007 HOTT Meeting. Sydney, March 2008. Leukaemia Foundation Inaugural Annual Meeting. Melbourne, December 2008.

ECRU Biotechnology INVITED SEMINARS National

Prince of Wales Private Hospital, Randwick Sydney, March 5th 2008. Epworth Private Hospital Department of Cardiology Seminar, Richmond, Melbourne, November 12th 2008. International

43rd European Association for the Study of Diabetes (EASD), Amsterdam, The Netherlands, September 17-21st (2007). 44th European Association for the Study of Diabetes (EASD), Rome, Italy, September 7th-11th (2008).


ACBD Personnel


Professor Hatem Salem, Head of Department Administrative Staff Dr Declan Green, Operations Manager Ms Melissa Brauer, Business Manager for Haematology Consortium 2007 Ms Nerine Twigg, Business Manager for Haematology Consortium 2008 Mrs Jennie Saravanamuttu, Personal Assistant to Head of the Department Mrs Kathy Lago, Administrative Officer Mrs Juliet Sagar, Administrative Officer Ms Maya Fujihara, Administrative Officer Mrs Maree Borland, Administrative Officer Thrombosis Research Unit

Professor Shaun Jackson (Head) Dr Simone M Schoenwaelder Dr Sue Cranmer Dr Yuping Yuan Dr Warwick Nesbitt Dr Sharelle Sturgeon Dr Sascha Hughan Dr Justin Hamilton Dr Kevin Woollard Dr Anna Calkin Dr Michelle Gordon Dr Ziad Touat Dr Fu Jia Ms Mei Chan Mr Mark Frazzetto Mr Chris Spring Mrs Yu (Joy) Yao Ms Sarah Xiao Mr Erik Westein Ms Akiko Ono Mr Mehran Ghazemzadeh Ms Joanna Lim Dr Michelle Gordon

Ms Jessica Mountford Mr Patrick Leung Ms Abby Willcox Ms My Hua Ms Hannah Lee Ms Kim Nguyen Ms Katrina Ashworth Ms Gabrielle VanderKraan Fibrinolysis Laboratory

Assoc Prof Robert Medcalf (Head) Dr Stan Stasinopoulos Dr Simone Beckham Dr Andre Samson Dr Maithili Sashindranath Mr Adam Galle Mr Be‟Eri Niego Ms Rachael Borg Mr Darren Karadimos Ms Roxanne Freeman Serpin Biology Laboratory

Assoc Prof Paul Coughlin (Head) Dr Anita Horvath Ms Mellinda Missen Ms Trifina Sofian Ms Bernadine Liu

Vascular Biology Laboratory

Dr Robert Andrews (Head) Dr Jane Arthur Dr Elizabeth Gardiner Dr Fi-tjen Mu Dr Yang Shen Ms Cheryl Berndt Ms Jing Jing Dr Mohammad Al-Tamimi


MH&SCTS Group

A/Prof Andrew Spencer Dr Andrew Wei Dr Tiffany Khong Dr Alex Rizzitelli Dr Mae-Xhum Wong Dr Tonged Das Mr Sung Lin Yeh Ms Adele Baker Ms Katherine Monaghan A/Prof Anthony Schwarer Dr Ann Stewart Ms Oanh Nguyen Ms Alison Hamlett Ms Ehteramolsadat Housseini Dr Sharon Avery Dr Sushrut Patil Dr Patricia Walker Dr Tongted Das Ms Sally Mongta Ms Nola Kennedy Ms Kate Reed Ms Jennifer Muirhead Ms Christine Mazis Ms Lisa Di Maio Ms Desleigh Gilbert Ms Julia Farr Ms Katie Boast Ms Sarah Palliser Ms Yamna Taouk Ms Emma Jane Furphy Eastern Clinical Research Unit (ECRU) Biotechnology Research Division

Dr Anthony Dear (Head) Dr Hong Bin Liu Dr Yunshan Hu Assoc Prof Richard Simpson

ECRU – Clinical Trials Division (Haematology) Maroondah

Assoc/Professor Michael Leyden Box Hill Hospital Staff

Lesley Poulton (Manager) Brenda Niessner Claire Gollogly Rosemary Petrie Maria di Stasso Belinda Davis Bronwen Williamson Robyn Batrouney Maroondah Hospital Staff

Melissa Fitzpatrick Dominique Leyden Caroline Sturtz Kayte Robinson Vichy Walkerden Haematology Consortium

A/Prof Eng Gan A/Prof Stephen Opat Dr Huyen Tran Dr Susan Brown Dr Hang Quach Dr Zane Kaplan MS Cheryl Coleman MS Lynnette Stafford Mr Matthew Van Dam MS Jannette Gamgee Ms Anita Cummins MS Linda Hunter

Disclaimer: The information in this report was correct at the time of publication. Monash University reserves the right to alter this information should the need arise. CRICOS provider: Monash University 00008C. June 2009. TSG217829

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Australian Centre for Blood Diseases€¦ · The Australian Centre for Blood Diseases (ACBD) brings together the skills and facilities of separate yet complimentary organisations