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  • Funded Activity

    Integrating Conventional Mesothelioma Therapies With Immuno- And Gene-therapies

    Funder
    National Health and Medical Research Council
    Funding Amount
    $804,916.00
    Summary
    Asbestos-induces cancers are some of the most aggressive cancers know to medicine. Unfortunately, treatments are not very effective and it is unusual for these cancers to be cured, particularly mesothelioma. Because recent scientific studies have suggested that combinations of therapy which include immunotherapy, ie treatments aimed at stimulating the bodies anti-cancer immune responses to attack the cancer, can be effective, we plan to develop this work in order to determine exactly which combi .... Asbestos-induces cancers are some of the most aggressive cancers know to medicine. Unfortunately, treatments are not very effective and it is unusual for these cancers to be cured, particularly mesothelioma. Because recent scientific studies have suggested that combinations of therapy which include immunotherapy, ie treatments aimed at stimulating the bodies anti-cancer immune responses to attack the cancer, can be effective, we plan to develop this work in order to determine exactly which combinations are likely to be the most effective and therefore the most suitable for clinical trial in patients.
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    Funded Activity

    Epidemiology And Community Consequences Of Asbestos Exposure In WA

    Funder
    National Health and Medical Research Council
    Funding Amount
    $879,876.00
    Summary
    We aim to explore the impact of asbestos exposure on the health of individuals using the Wittenoom workers and residents cohort studies and the Australian community with the formation of a new community based cohort study. Using data from the Wittenoom workers and residents studies, we will examine the impact of asbestos exposure on women�s health which has not been looked at before. We will examine if asbestos exposure affects psychosocial health and determine if long term supplementation with .... We aim to explore the impact of asbestos exposure on the health of individuals using the Wittenoom workers and residents cohort studies and the Australian community with the formation of a new community based cohort study. Using data from the Wittenoom workers and residents studies, we will examine the impact of asbestos exposure on women�s health which has not been looked at before. We will examine if asbestos exposure affects psychosocial health and determine if long term supplementation with Vitamin A for cancer prevention results in an increased risk of bone fractures. We will also examine the genetic susceptibility of asbestos related diseases in these cohorts, and create and validate an algorithm to derive measures of fibre counts from occupational histories. Earlier projections of mesothelioma in the general community have been based on extrapolations from disease incidence in the past. We intend collecting data on a new community based cohort, to examine the distribution of asbestos in the community in order to predict future cases of asbestos related disease and the perception, beliefs and knowledge that exists in the community of its potential health effects. With this new knowledge we will devise an intervention program with the aim of preventing future cases of asbestos related disease. As part of this process we will use a multimedia website as an information hub. This will allow us to experiment with the use of creative media to present personal and community experiences of living with asbestos and present scientific research and public health messages.
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    Funded Activity

    Role Of FLT PET In Malignant Pleural Mesothelioma - Prediction Of Response To Chemotherapy

    Funder
    National Health and Medical Research Council
    Funding Amount
    $93,639.00
    Summary
    Mesothelioma is a cancer of the lining of the lung. Chemotherapy is often used to treat patients in order to reduce their symptoms and to improve quality and length of life. Not all patients however benefit from chemotherapy, and most patients will experience some side-effects. Currently CT scans are used to assess response to chemotherapy, however the way that mesothelioma grows makes measuring response difficult. CT scans also are not very sensitive in detecting response early - often 3 or 4 c .... Mesothelioma is a cancer of the lining of the lung. Chemotherapy is often used to treat patients in order to reduce their symptoms and to improve quality and length of life. Not all patients however benefit from chemotherapy, and most patients will experience some side-effects. Currently CT scans are used to assess response to chemotherapy, however the way that mesothelioma grows makes measuring response difficult. CT scans also are not very sensitive in detecting response early - often 3 or 4 cycles of treatment (3-4 months) are required before benefit is seen. A test that could predict which patients were benefiting after only 1 cycle (3-4 weeks) of chemotherapy would be a great advantage, and may spare some patients unnecessary and potentially toxic treatment. Fluorothymidine (FLT) is a radioactive tracer that, after injection into a vein, is taken up by dividing cells. Tumour cells usually divide more actively than surrounding normal cells, and therefore when a positron emission tomography (PET) scan is performed it will demonstrate the tumour as a 'hot spot'. The amount of FLT uptake into the tumour depends on how much DNA synthesis (active cell division) is occurring. After chemotherapy, if the tumour responds it would be expected that the amount of FLT in the tumour will reduce. This can be assessed by repeating the FLT PET scan after the first cycle of chemotherapy. This study aims to assess the ability of the change in FLT uptake in mesothelioma after 1 cycle of chemotherapy to predict response, as measured on CT scans, and patient outcomes such as quality of life and survival. It is hoped that if successful this type of scan may improve patient care by selecting those who are likely to benefit from chemotherapy early and avoid unnecessary toxicity to patients who will not benefit from the treatment.
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    Funded Activity

    Improving Care Of The Dying With Chronic Heart Failure

    Funder
    National Health and Medical Research Council
    Funding Amount
    $130,000.00
    Summary
    Chronic heart failure is increasing in prevalence and is primarily a condition of ageing. Although chronic heart failure has worse outcomes than many cancers, patients are often denied the benefits of palliative care with its emphasis on symptom management, spirituality, emotional health and focus on family issues. This project seeks to assess the state of knowledge in Australia related to palliative care in chronic heart failure. Guidelines and care maps appropriate to Australian conditions wil .... Chronic heart failure is increasing in prevalence and is primarily a condition of ageing. Although chronic heart failure has worse outcomes than many cancers, patients are often denied the benefits of palliative care with its emphasis on symptom management, spirituality, emotional health and focus on family issues. This project seeks to assess the state of knowledge in Australia related to palliative care in chronic heart failure. Guidelines and care maps appropriate to Australian conditions will be developed and their usefulness assessed in improving care of patients and their families.
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    Sensitive Serum Markers For Improved Diagnosis, Monitoring And Screening For Early Detection Of Mesothelioma

    Funder
    National Health and Medical Research Council
    Funding Amount
    $410,880.00
    Summary
    The deadly asbestos-induced cancer mesothelioma is continuing to kill tens of thousands of individuals per year and its incidence is increasing. Mesothelioma is predicted to cost communities hundreds of billions of dollars in compensation. This disease is unusually difficult to diagnose and tends to be already quite advanced by the time patients present to the doctor with symptoms. Unfortunately, treatment options for the majority of patients are limited and most die within a year of diagnosis. .... The deadly asbestos-induced cancer mesothelioma is continuing to kill tens of thousands of individuals per year and its incidence is increasing. Mesothelioma is predicted to cost communities hundreds of billions of dollars in compensation. This disease is unusually difficult to diagnose and tends to be already quite advanced by the time patients present to the doctor with symptoms. Unfortunately, treatment options for the majority of patients are limited and most die within a year of diagnosis. In different forms of cancer, levels of certain proteins in the blood can be measured and have been shown to indicate the presence of tumour and in some cases the extent of tumour. These proteins are collectively known as tumour markers. Tumour markers for ovarian, prostate, breast and other cancers are used by doctors to help with the diagnosis of specific cancers, to monitor the patients response to treatment and to give a valuable early warning of remission or relapse. There is no tumour marker currently used for patients with mesothelioma. We have shown in early studies published in the prestigious journal The Lancet that soluble mesothelin related protein (SMRP) is actually elevated in more than 75% of mesothelioma patients and in less than 2% of patients with other cancer and non-cancer lung diseases. In this current project we plan to extend our studies looking at blood levels of SMRP to see if they will help in the care of patients with mesothelioma. So far we have done most of the work in a particular group of patients, but it is vital that the work be extended to other groups with different types and durations of exposure to asbestos and to different areas of the country. As part of that we need to test how stable the molecule is in blood samples, because if it is not very stable it wont be a very pratical test. We also plan to look at some other markers that have been clinically useful in other forms of cancer and we will try to identify new, novel mesothelioma specific markers. This work has the potential to impact on patient care in many centres of the world.
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    Funded Activity

    Environmental Influences In The Establishment Of The Epigenetic Landscape In Children

    Funder
    National Health and Medical Research Council
    Funding Amount
    $695,097.00
    Summary
    The DNA in each of our cells does not exist alone, it is packaged into complex structures called chromosomes, through association with many different proteins. The distribution of these proteins varies along the length of a chromosome depending on the type of cell and this phenomenon is called 'epigenetics', literally meaning 'above the DNA'. Epigenetic analysis is the study of how proteins and other molecules can change the activity of a gene without changing the DNA sequence. All of our cells .... The DNA in each of our cells does not exist alone, it is packaged into complex structures called chromosomes, through association with many different proteins. The distribution of these proteins varies along the length of a chromosome depending on the type of cell and this phenomenon is called 'epigenetics', literally meaning 'above the DNA'. Epigenetic analysis is the study of how proteins and other molecules can change the activity of a gene without changing the DNA sequence. All of our cells use epigenetic changes to help control how they grow and develop. Evidence suggests a direct link between diet and environmental influences on our epigenetic profile. Recent research has traced the origins of many of the health problems of adult life back to the earliest periods of development _ to the time spent in the womb and the first few years of life. If we are born with a low birth weight, we are more likely to get sick later in life. Overwhelming evidence exists that the environment in the womb is critical for a healthy birth weight (and health in later life) and it is thought that epigenetics may be the missing link between this environment, low birth weight, and therefore health in later life. In addition, mounting evidence supports a general link between epigenetic de-regulation and predisposition to disease. However, the timing and the overall contribution of environmental- genetic influences to the establishment of faulty epigenetic markings remain largely unknown. Twins are the best model to study this link as they share similar (but not identical environments) and some share identical genetic makeup. Using twins, Dr Jeffrey Craig and his team will investigate the factors in the prenatal environment that modify specific cells, leading to low birth weight and increase disease risk later in life. They predict that this occurs via specific changes in gene activity caused by epigenetic disruption.
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    Funded Activity

    Novel Strategies For The Early Identification Provention And Treatment Of The Microvascular Complications Of Diabetes

    Funder
    National Health and Medical Research Council
    Funding Amount
    $4,715,000.00
    Summary
    Despite recent advances, approximately one third of subjects with type 1 diabetes develop kidney disease and similar proportion develop vision-threatening eye disease. Indeed, in many instances eye and kidney disease occur in the same individual. The central aim of this proposed Special Program is the exploration of mechanisms that lead to the development and progression of these devastating complications of type 1 diabetes with a particular focus on novel strategies, directly applicable to man, .... Despite recent advances, approximately one third of subjects with type 1 diabetes develop kidney disease and similar proportion develop vision-threatening eye disease. Indeed, in many instances eye and kidney disease occur in the same individual. The central aim of this proposed Special Program is the exploration of mechanisms that lead to the development and progression of these devastating complications of type 1 diabetes with a particular focus on novel strategies, directly applicable to man, for their prevention and treatment. Participants in Special Program include both established diabetes researchers and investigators from other areas of academia (blood vessel biology and applied genetics). Strong interrelationships between the various investigators and their departments already exist and will be further consolidated with continued collaboration, sharing a combination of models, novel interventions and complex genetic techniques that would not be possible outside of a large collaborative framework. In addition to academic collaboration, interactions with industry-based drug discovery programs is also an important component in developing new treatment strategies for diabetic kidney and eye disease. The Special Program will thus consist of a range of studies of direct relevance to diabetic kidney and diabetic eye disease in humans. It is expected that these studies will lead to new strategies for the prevention, treatment and even the reversal of long term complications of diabetes.
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    Funded Activity

    Transforming Growth Factor Beta Signalling In Malignant Mesothelioma Growth And Collagen Production

    Funder
    National Health and Medical Research Council
    Funding Amount
    $509,917.00
    Summary
    Many cancers contain abundant connective tissue molecules called extracellular matrix (ECM) and data show that interaction of ECM with cells are important in the growth of cancers (1). Changes in expression of ECM and their receptors (integrins) have been associated with malignant changes in cells, enhanced tumour growth and resistance to chemotherapy (2,3). We have recently shown that inhibition of collagen, the most abundant ECM molecule produced by malignant mesothelioma (MM) cells, reduced M .... Many cancers contain abundant connective tissue molecules called extracellular matrix (ECM) and data show that interaction of ECM with cells are important in the growth of cancers (1). Changes in expression of ECM and their receptors (integrins) have been associated with malignant changes in cells, enhanced tumour growth and resistance to chemotherapy (2,3). We have recently shown that inhibition of collagen, the most abundant ECM molecule produced by malignant mesothelioma (MM) cells, reduced MM growth. How cancer cells regulate ECM production and control their growth is unclear but strong evidence suggests the growth factor transforming growth factor-beta (TGFB) plays an important role. We and others showed that MM cells secrete all forms (1-3) of TGFB, and TGFB1,2-like activity has been reported in pleural effusions from MM (4,5). All TGFB forms stimulate MM cells to grow and make ECM (6,7). We showed that high levels of collagen produced by MM are enhanced by TGFB. Small molecules called antisense oligonucleotides (AO) which blocked production of TGFB2 by cells, reduced MM cell growth in soft agar, a characteristic of cancer, and partially blocked MM growth in animal models (4,6). This was supported by studies using soluble TGFB type II receptors, which blocks TGFB1,3 (8), and our studies using TGFB2 specific antibodies, as both studies reduced tumour growth. These findings support a role for TGFB in MM growth. However, all TGFB forms can promote cell grow and collagen synthesis and therefore ways to block all TGFB forms are required to ensure maximal effect. This study will examine the effect of blocking common downstream signalling pathways of all three TGFB isoforms on MM collagen production and tumour growth. These pathways are activated when TGFB binds to its receptors sending messages to the nucleus of the cell to make collagen or grow. By identifying which TGFB signalling pathway is important, we may be able to design novel therapeutic approaches to help treat patients with this disease.
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    Funded Activity

    Creating B-cells To Cure Type 1 Diabetes

    Funder
    National Health and Medical Research Council
    Funding Amount
    $4,260,000.00
    Summary
    They aim to create insulin-secreting B cells by identifying their progenitor cells and the moleculaes normally required for their development, in order to restore B-cell function in the people with type 1 diabetes. Mouse and human multipotent embryonic stem (ES) cells and fetal mouse panceas and adult pancreas duct cells will be used as sources of progenitor B cells. Comparative studies will provide a more complete picture of human B-cell ontogeny. Culture systems developed for ES cells-embryoid .... They aim to create insulin-secreting B cells by identifying their progenitor cells and the moleculaes normally required for their development, in order to restore B-cell function in the people with type 1 diabetes. Mouse and human multipotent embryonic stem (ES) cells and fetal mouse panceas and adult pancreas duct cells will be used as sources of progenitor B cells. Comparative studies will provide a more complete picture of human B-cell ontogeny. Culture systems developed for ES cells-embryoid bodies (EB) - EB-derived cells, fetal pancreas and adult pancreas duct cells, will be employed to screen for and identify novel growth-differentiation factors and to optimise parameters for creating B cells in vitro or (re) generating B cells in vivo. Genetic constructs allowing regulated expression of fluorescently-tagged marker genes and growth-transcription factors will be introduced into cultured cells or transgenic mice to enable progenitor B cells to be tracked and isolated. Progenitor B cells will be typed with panels of known novel markers molecules at the gene and protein level, and gene expression profiles of tissue yielding B cells will be analysed across time to reveal further candidate markers. Molecules and methods effective in mouse systems will be applied to human ES cell-derived or pancreatic duct cells. The capacity to progenitor cells or insulin-secreting cells to ameliorate diabetes when transplanted into the testis, under the kidney capsule or into the pancreas of mouse models would represent proof-of-concept. Functional B cells derived from human ERS cells or pancreas duct cells, or growth factors that regenerate B cells in vivo, could together with appropriate immunotherapy restore B-cell function in people with type 1 diabetes.
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