Validating And Optimising The Analysis Of Magnetic Resonance Physiology Data
Funder
National Health and Medical Research Council
Funding Amount
$91,725.00
Summary
Combined electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) is used to detect the anatomical areas in the brain that show electrical activity. Several centres worldwide use this technique to localise the seizure focus in patients with epilepsy. However, there is a lack of validation of the currently applied techniques. Current analysis methods have been developed and validated for other fMRI paradigms, such as motor tasks. It is not known whether the same principles ar ....Combined electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) is used to detect the anatomical areas in the brain that show electrical activity. Several centres worldwide use this technique to localise the seizure focus in patients with epilepsy. However, there is a lack of validation of the currently applied techniques. Current analysis methods have been developed and validated for other fMRI paradigms, such as motor tasks. It is not known whether the same principles are applicable and optimal for fMRI-EEG data. The proposed project aims at validating and optimising the analysis strategies for fMRI-EEG data.Read moreRead less
The 3-dimensional Structure Of Anticancer Drug-DNA Complexes Determined By X-ray Crystallography
Funder
National Health and Medical Research Council
Funding Amount
$264,358.00
Summary
Our main objective is to discover the molecular details of how cancer drugs interact with DNA and how these interactions differ from those of inactive chemically related compounds. We propose to use X-ray crystallography together with the successful methods we have developed for determining the 3-dimensional structures of the DNA complexes of a class of antitumour active drugs to study the complexes of other clinically or scientifically important DNA intercalating anticancer drugs. These agents ....Our main objective is to discover the molecular details of how cancer drugs interact with DNA and how these interactions differ from those of inactive chemically related compounds. We propose to use X-ray crystallography together with the successful methods we have developed for determining the 3-dimensional structures of the DNA complexes of a class of antitumour active drugs to study the complexes of other clinically or scientifically important DNA intercalating anticancer drugs. These agents act by poisoning the DNA binding enzyme topoisomerase. Crystallographic analysis will give us unequivocal answers at the atomic level as to the exact way in which the drug binds to DNA and how this binding differs between antitumour active and inactive compounds. We believe that a knowledge of the DNA binding mode of a class of intercalating anticancer drugs at the atomic level is valuable in guiding drug design within that class.Read moreRead less
The Clinical Value Of Serology And Molecular Tests For Diagnosing Invasive Aspergillosis In At-risk Hematology Patients
Funder
National Health and Medical Research Council
Funding Amount
$1,095,500.00
Summary
Aspergillus is a fungus found in soil, on farms and on construction sites. In those whose immune system is impaired it causes severe infection. The people who are particularly at high-risk of Aspergillus infection (called Invasive Aspergillosis) are those with acute leukaemia on chemotherapy or post bone marrow transplantation. Currently 15% of those at high-risk get Invasive Aspergillosis and 58-93% of those infected die. The main reason for this high death rate is that our current diagnostic t ....Aspergillus is a fungus found in soil, on farms and on construction sites. In those whose immune system is impaired it causes severe infection. The people who are particularly at high-risk of Aspergillus infection (called Invasive Aspergillosis) are those with acute leukaemia on chemotherapy or post bone marrow transplantation. Currently 15% of those at high-risk get Invasive Aspergillosis and 58-93% of those infected die. The main reason for this high death rate is that our current diagnostic tests are not good at detecting infection or often only detect the infection at advanced stages when treatment is ineffective. Because of the limitations of current diagnostic tests the current practice is to give empiric antifungal therapy (EAFT) early to treat Invasive Aspergillosis. However studies have demonstrated that this therapy has only resulted in a minor reduction in the mortality rates and it causes significant drug toxicity. It is a suboptimal treatment modality. New tests have been developed to diagnose Invasive Aspergillosis. These tests are for the detection of an Aspergillus protein in blood and for the detection of Aspergillus DNA in the blood. Available data suggests that these new tests are sensitive in the detection of Invasive Aspergillosis. Also other studies suggest that these new tests make an early diagnosis and seem to be able to monitor responses to treatment. However no study has been performed to date which demonstrates that the use of these tests can impact on important patient outcomes. This trial is designed to determine whether the use of the new tests to guide therapy will help improve treatment of Invasive Aspergillosis, reduce drug toxicity and reduce the death rate in the high-risk patients as compared with the current standard method of diagnosis and treatment with EAFT. If the trial is successful then this represents a significant advancement in the treatment and survival of leukaemic and bone marrow transplantation patients.Read moreRead less
The Structural Basis For The Action Of Anticancer DNA-intercalating Topoisomerase Poisons
Funder
National Health and Medical Research Council
Funding Amount
$459,750.00
Summary
Cancer kills one in four people in the Western world and half of those afflicted will die from the disease. If the malignancy is detected early, surgery and radiotherapy will often effect a cure but if the disease is disseminated at presentation then treatment requires chemotherapy. Chemotherapy can be curative for some tumour types but it is generally only palliative for the overwhelming majority of solid cancers. Consequently, there is an urgent need to improve the efficacy of anticancer drugs ....Cancer kills one in four people in the Western world and half of those afflicted will die from the disease. If the malignancy is detected early, surgery and radiotherapy will often effect a cure but if the disease is disseminated at presentation then treatment requires chemotherapy. Chemotherapy can be curative for some tumour types but it is generally only palliative for the overwhelming majority of solid cancers. Consequently, there is an urgent need to improve the efficacy of anticancer drugs. Many of these drugs work by binding directly to DNA and poisoning the DNA-manipulating enzyme, topoisomerase. Our objective is to discover the molecular basis of how anticancer drugs act through their interaction with DNA and topoisomerase. We propose to use the successful X-ray crystallography methods we have developed for determining the 3-dimensional structures of the DNA complexes of a class of anti-tumour active drugs, to study the complexes of other clinically or scientifically important DNA intercalating anticancer drugs. Crystallographic analysis provides unequivocal data, at near atomic resolution, of the nature of the molecular interactions which provide specificity and selectivity in drug-DNA complexes. This information will be a valuable guide in the further development of this important class of topoisomerase poisons as anticancer drugs. We will initiate structural studies of ternary complexes between the topoisomerase enzyme, DNA and anticancer drugs. The solution of the X-ray crystal structures of these ternary complexes will allow the design of new antitumour topoisomerase poisons to be put on a completely rational basis.Read moreRead less
Translating Bacterial Molecular Epidemiology Into Information To Improve Infectious Disease Risk Assessment And Control
Funder
National Health and Medical Research Council
Funding Amount
$494,500.00
Summary
Streptococcus pneumoniae (pneumococcus) and group B streptococcus (GBS) are important pathogenic bacteria, which cause septicaemia and meningitis in young infants, the elderly and people with certain chronic diseases. Both consist of a number of different types, some of which are more likely to cause disease than others. Pneumococcal vaccines that protect against the commonest pathogenic types are used in Australia in people most at risk.Antibiotic resistance is an increasing problem, which shou ....Streptococcus pneumoniae (pneumococcus) and group B streptococcus (GBS) are important pathogenic bacteria, which cause septicaemia and meningitis in young infants, the elderly and people with certain chronic diseases. Both consist of a number of different types, some of which are more likely to cause disease than others. Pneumococcal vaccines that protect against the commonest pathogenic types are used in Australia in people most at risk.Antibiotic resistance is an increasing problem, which should be partly off-set by immunisation. Giving antibiotics during labour, to women colonised with GBS, can reduce infection rates in newborns, but there are many disadvantages of this approach, including the risk of increased antibiotic resistance. Vaccines against GBS are mpt yet available. We have developed methods to identify detailed fingerprints of these bacteria which allow us to identify types, antibiotic resistance and, for GBS, other characteristics which can distinguish highly pathogenic strains from the majority that are carried harmlessly and unlikely to cause disease. The methods are still quite slow and expensive and produce complex patterns,which are difficult to interpret rapidly. We plan to develop a new, rapid and relatively inexpensive, fingerprinting system for these bacteria and computer programs to analyse and interpret the results. They will allow us to check the strains of pneumococci that cause disease to make sure that new ones, not covered by the vaccine, do not become more common and reduce the effectiveness of vaccine and that antibiotic resistance does not increase further. The methods will also allow us to study differences between the small proportion of GBS strains that cause neonatal infection and the majority that are carried harmlessly by pregnant women and are of little risk to their babies. Eventually this should allow doctors to identify women whose babies are most at risk, reduce unnecessary antibiotic use.Read moreRead less
Developing And Applying Biologically Plausible Statistical Models For Normal And Non-normal Family Data
Funder
National Health and Medical Research Council
Funding Amount
$339,700.00
Summary
Although molecular and computing advances have enabled more detailed investigations of inherited diseases and the ability to fit realistic statistical models to these data, limitations still exist when analysing family data. Often only basic statistical analyses are performed, due to the lack of understanding of complexities within the data and-or inability of researchers to fit appropriate statistical models. These factors have hampered the search for genes and environmental factors influencing ....Although molecular and computing advances have enabled more detailed investigations of inherited diseases and the ability to fit realistic statistical models to these data, limitations still exist when analysing family data. Often only basic statistical analyses are performed, due to the lack of understanding of complexities within the data and-or inability of researchers to fit appropriate statistical models. These factors have hampered the search for genes and environmental factors influencing common diseases. This project aims to develop novel, biologically realistic statistical models for investigation of common, complex diseases, such as heart disease and cancer, in families. These models will incorporate both measured and unmeasured genetic and environmental factors, and will be applicable to both normally distributed and non-normally distributed traits. Model fitting will use computer-intensive simulation techniques. Application of the models to data from two large pre-existing studies of international renown, the Victorian Family Heart Study and the Australian Prostate Cancer Family Study, will enable a better understanding of the genetic and environmental factors influencing heart disease and cancer. The models will also be applicable to many other studies of diseases which use data from families, and allow more accurate and useful information to be obtained from data. Software will also be made freely available to other researchers. This will ultimately translate into better outcomes from familial genetic research, and eventually, better prevention, detection, and treatment of the diseases.Read moreRead less
Strategies For Handling Missing Data In The Development, Validation And Implementation Of Clinical Risk Prediction Tools
Funder
National Health and Medical Research Council
Funding Amount
$451,692.00
Summary
Tools that predict the future outcome of disease are common. Missing data is a problem in studies that develop and validate such tools and affects their validity because simple approaches to dealing with missing data are biased. We will develop statistical methodology in this area and compare the performance of this and other methodologies. Alongside this methodological work we will re-assess existing prediction tools and develop new tools in the areas of cardiac surgery and kidney disease.
Magnetic Resonance Methods For Automated, Non-invasive Diagnosis Of Focal Brain Infections
Funder
National Health and Medical Research Council
Funding Amount
$483,564.00
Summary
Brain lesions caused by infections, tumours and some other diseases, often cannot be distinguished from each other clinically or by neuro-radiology examinations. A brain biopsy is usually needed to make a definite diagnosis and may cause sequelae or not be possible if the lesion is in certain areas of the brain. Magnetic resonance imaging (MRI) has increased our ability to detect brain lesions but cannot unequivocally diagnose the disease process. Magnetic resonance spectroscopic (MRS) methods r ....Brain lesions caused by infections, tumours and some other diseases, often cannot be distinguished from each other clinically or by neuro-radiology examinations. A brain biopsy is usually needed to make a definite diagnosis and may cause sequelae or not be possible if the lesion is in certain areas of the brain. Magnetic resonance imaging (MRI) has increased our ability to detect brain lesions but cannot unequivocally diagnose the disease process. Magnetic resonance spectroscopic (MRS) methods report on the chemical composition of lesions and can provide a simultaneous picture of the location of the lesion and the pathology of the disease process. Brain biopsies may therefore be avoided in a significant number of cases where drainage or decompression of lesions are not needed as part of therapy. Identification of specific fingerprints for the different diseases will provide a rapid, robust, automated diagnosis, which will expedite management decisions and improve patient outcomes. It should also be possible to monitor the efficacy of drug treatments using MRS methods. Each of these outcomes would constitute a major medical advance.Read moreRead less