Genome-wide Epigenetic Analysis Of Childhood Acute Lymphoblastic Leukaemia
Funder
National Health and Medical Research Council
Funding Amount
$410,469.00
Summary
Of all cancers in children, Acute Lymphoblastic Leukaemia is the most common. To date, the causal mechanism(s) for leukaemia in children remain unclear. Although 5-year event-free survival rates are relatively high (up to 80%) it is still unclear why children expected to survive with a good prognosis, succumb to the disease. Therefore, there is still a need to further refine current diagnosis and prognosis parameters that will together lead to improved outcomes to children with leukaemia.
A Randomized Trial Of Idarubicin Dose Escalation In Consolidation Therapy For Adult Acute Myeloid Leukemia
Funder
National Health and Medical Research Council
Funding Amount
$425,000.00
Summary
This project is a clinical trial to test the value of giving a higher than usual dose of one of the most important anti-cancer drugs, called idarubicin, in the initial treatment of adults with newly diagnosed acute myeloid leukemia (AML). This disease is the most serious form of leukemia in adults, and is usually treated with strong anti-cancer drugs, including idarubicin. Research in Australia and overseas has shown that increasing the doses of the other major drug (called cytarabine) used to t ....This project is a clinical trial to test the value of giving a higher than usual dose of one of the most important anti-cancer drugs, called idarubicin, in the initial treatment of adults with newly diagnosed acute myeloid leukemia (AML). This disease is the most serious form of leukemia in adults, and is usually treated with strong anti-cancer drugs, including idarubicin. Research in Australia and overseas has shown that increasing the doses of the other major drug (called cytarabine) used to treat AML in adults results in a doubling of the number of people cured of this disease, given that they have achieved a remission. This project will examine whether there is a similar benefit of increasing the idarubicin dose beyond that which has been conventionally used up to date. People who have AML diagnosed at one of the Australian hospitals participating in this study will receive initial treatment with an established drug combination. Those patients achieving a good response to the first treatment will then be randomly allocated to receive 2 further courses of treatment, one with a conventional dose of idarubicin, and the other with double the idarubicin dose. All patients will then be assesed for side effects of the treatment, and followed for at least 3 years for any signs of recurrence of their leukemia.Read moreRead less
BIOLOGICAL STUDIES OF A NEW RECURRENT FUSION GENE FOUND IN T-CELL LEUKAEMIA
Funder
National Health and Medical Research Council
Funding Amount
$187,925.00
Summary
Chromosome translocation, in which breaks occur in two chromosomes and rejoin to form two new hybrid chromosomes, is a common genetic alteration in leukaemia. Translocations have been invaluable in identifying genes important in the development of leukaemia. The genetic consequence of translocation is either the deregulation of critical genes adjacent to the breakpoints or the formation of new hybrid genes with novel properties. We have identified the genes at the breakpoints of a T-cell leukaem ....Chromosome translocation, in which breaks occur in two chromosomes and rejoin to form two new hybrid chromosomes, is a common genetic alteration in leukaemia. Translocations have been invaluable in identifying genes important in the development of leukaemia. The genetic consequence of translocation is either the deregulation of critical genes adjacent to the breakpoints or the formation of new hybrid genes with novel properties. We have identified the genes at the breakpoints of a T-cell leukaemia translocation involving chromosomes 4 and 11. The chromosome 11 gene, NUP98, is known to be involved in two other translocations in acute myeloid leukaemia but not in T-cell leukaemia. The chromosome 4 gene RAP1GDS has not been previously shown to be involved in human cancer. This project seeks to understand how the fusion protein NUP98-RAP1GDS (NRG) plays a role in the origin of leukaemia.Read moreRead less
Childhood Precursors Of Adult Cardiovascular Disease, Obesity And Diabetes- 16 Year Follow Up Of A Longitudinal Cohort
Funder
National Health and Medical Research Council
Funding Amount
$835,631.00
Summary
There is a world wide 'epidemic' of obesity and diabetes with rates tripling in young adults in the last twenty years. This is likely to lead to an upsurge in heart attack and stroke and to reverse many of the gains seen in this area in Australia. This project aims to study the childhood and antenatal precursors for the risk of adult obesity, diabetes, heart disease and stroke. The study involves The Perth longitudinal childrens 'Raine' cohort, a unique group of just under 3000 children, first m ....There is a world wide 'epidemic' of obesity and diabetes with rates tripling in young adults in the last twenty years. This is likely to lead to an upsurge in heart attack and stroke and to reverse many of the gains seen in this area in Australia. This project aims to study the childhood and antenatal precursors for the risk of adult obesity, diabetes, heart disease and stroke. The study involves The Perth longitudinal childrens 'Raine' cohort, a unique group of just under 3000 children, first monitored in the womb before mid pregnancy and then repeatedly through to the age of 13 years. Every 2 to 3 years the study children have been carefully assessed for changes in fatness, blood pressure and more recently, nutrition, physical activity and fitness, blood cholesterol and tendency to diabetes. Families have also been carefully monitored for a range of social characteristics and mental health. We already have evidence that about a fifth of the children at age 8 are particularly at risk of obesity, diabetes and cholesterol problems and high blood pressure. We now plan to study the children after puberty at age 16, when they will be adopting a range of more adult behaviours which may profoundly affect these risks. This study will provide comprehensive information on the children from before birth to adolescence and help pinpoint ways in which growth in the womb, and subsequent childhood behaviour interacts with influences of family, social factors, environment and mental health to affect long term risk of obesity, premature diabetes or heart disease. The study will also provide a basis for future examination of the links between genes, environment and health.Read moreRead less
Obesity, Self Image, Eating Behaviour, Nutriton And Activity In Australian Preadolescent School Children.
Funder
National Health and Medical Research Council
Funding Amount
$167,328.00
Summary
Obesity in children is increasing, but there is a great deal of concern about whether education about diet and obesity will produce eating disorders. While there is a lot of information about the eating practices, body image worries and self esteem in teenagers, there is no information really available about what primary school children in this country know about eating, about whether they diet or not, where they get their information about dieting and about their self esteem and body image part ....Obesity in children is increasing, but there is a great deal of concern about whether education about diet and obesity will produce eating disorders. While there is a lot of information about the eating practices, body image worries and self esteem in teenagers, there is no information really available about what primary school children in this country know about eating, about whether they diet or not, where they get their information about dieting and about their self esteem and body image particularly if they are overweight or very thin. It is important to gather this information as it is in the teen years that problems about eating and body image really emerge. These concerns must be starting in primary school children, This study aims to gather this information and more from 2442 primary school children across NSW. This information will enable proper education programs about eating, body image and obesity to be developed so no harm is caused by trying to reduce obesity. This study will also gather important information about how many children are obese or have eating disorders and will see what part their physical activity plays in their weight and the way they go about controlling it. To have healthy adults in the next generation, with less obesity and eating problems, it is important to gather information about nutrition and eating beliefs, dieting, body image and self esteem in children now.Read moreRead less
Novel Artemisinin-based Combination Therapies For Children Exposed To High Transmission Of Multiple Plasmodium Species
Funder
National Health and Medical Research Council
Funding Amount
$1,378,408.00
Summary
We recently found that the WHO-recommended combination antimalarial therapy artemether-lumefantrine and the candidate regimen dihydroartemisinin-piperaquine were not fully effective for both falciparum and vivax malaria in young PNG children, a group at risk of complications and death. We plan to study two new combinations (artesunate-pyronaridine and artemisinin-naphthoquine) and hypothesise that at least one will prove superior and be used as first-line treatment in PNG and similar countries.
Is Insulin Sensitivity In Children And Their Mothers Programmed By Maternal Blood Glucose?
Funder
National Health and Medical Research Council
Funding Amount
$169,630.00
Summary
Glucose intolerance in pregnancy is associated with the birth of large-for-dates and macrosomic (>4000g) babies. The risk of type 2 diabetes is greater in babies who are small or large at birth compared to those with normal birth weight. This study will determine if treatment of mothers with glucose intolerance in pregnancy (which is intermediate between normal glucose tolerance and diabetes) alters the regulation of glucose tolerance in their children. The mothers were randomised to receive ....Glucose intolerance in pregnancy is associated with the birth of large-for-dates and macrosomic (>4000g) babies. The risk of type 2 diabetes is greater in babies who are small or large at birth compared to those with normal birth weight. This study will determine if treatment of mothers with glucose intolerance in pregnancy (which is intermediate between normal glucose tolerance and diabetes) alters the regulation of glucose tolerance in their children. The mothers were randomised to receive normal antenatal care or to have their blood sugar measured and controlled by diet and insulin as for diabetics. We will measure the insulin sensitivity of the children to a glucose load. We will also measure blood pressure and lipids in these children. Treatment of the mother during pregnancy may alter the deposition of fat in the fetus the effect of which will continue into childhood. Thus the offspring of treated mothers may remain thinner throughout childhood. Each pregnancy increases a woman's chance of developing type 2 diabetes in later life. This risk is further increased by abnormal glucose tolerance during pregnancy. This study will test the long-term benefits of treatment during pregnancy of women with impaired glucose tolerance on the subsequent regulation of glucose tolerance. We shall invite women who took part in the Australian Carbohydrate Study in Pregnancy (ACHOIS) to return and have an intravenous glucose tolerance test. Insulin sensitivity and glucose tolerance will be determined and related to treatment of the impaired glucose tolerance in pregnancy. This study will be the first follow-up of a large randomised trial of treatments of impaired glucose tolerance in pregnancy. The potential long-term benefits are strategies to reduce the future chance of developing risk factors for type 2 diabetes, obesity and abnormal blood lipids in childhood and adult life. The study will establish the benefits or otherwise of tight control of blood glucose in pregnancy.Read moreRead less
Developing Novel Molecules To Down-Regulate Src Family Tyrosine Kinases
Funder
National Health and Medical Research Council
Funding Amount
$201,261.00
Summary
Leukaemia and cancer cells have altered biochemical properties resulting in their high rate of growth compared to normal cells. One of the common biochemical characteristics of cancer-leukaemia cells is augmented activity levels of enzymes called tyrosine kinases. A major group of tyrosine kinase involved in several cancer-leukaemia types is called the Src family of tyrosine kinases. One member of this family called Lyn has been our focus of study for several years, investigating the signalling ....Leukaemia and cancer cells have altered biochemical properties resulting in their high rate of growth compared to normal cells. One of the common biochemical characteristics of cancer-leukaemia cells is augmented activity levels of enzymes called tyrosine kinases. A major group of tyrosine kinase involved in several cancer-leukaemia types is called the Src family of tyrosine kinases. One member of this family called Lyn has been our focus of study for several years, investigating the signalling pathways that it is involved in. This molecule has also been implicated in several specific leukaemia (Chronic Myeloid Leukaemia and Acute Myeloid Leukaemia) as well as cancer (Prostate, Colon, Breast) in recent years. We have identified a novel mechanism of down-regulation of this enzyme mediated by an adapter molecule called Cbp, which recruits the Lyn inactivating molecules Csk-Ctk as well as SOCS-1; together they inhibit the activity of Lyn and degrade the enzyme. Using our knowledge of the essential interaction elements of Cbp we will design and test various mini-Cbp molecules for their ability to inactivate and degrade Lyn in leukemic and cancer cells. These molecules may allow us to develop novel therapeutics capable of inactivating-degrading specific tyrosine kinases in cancer and leukaemia.Read moreRead less
The Regulation Of 14-3-3 Protein Function By Post-translational Modification
Funder
National Health and Medical Research Council
Funding Amount
$212,036.00
Summary
The cells of our body have control mechanisms that prevent them from growing abnormally. However, when cells become cancerous they escape the normal checks and controls and are able to survive, divide and grow uncontrollably. In the last decade the molecular basis of several of the control mechanisms involved in preventing cancerous growth have been uncovered. However, our understanding is far from complete and recent research reports suggest that we have thus far overlooked a whole level of reg ....The cells of our body have control mechanisms that prevent them from growing abnormally. However, when cells become cancerous they escape the normal checks and controls and are able to survive, divide and grow uncontrollably. In the last decade the molecular basis of several of the control mechanisms involved in preventing cancerous growth have been uncovered. However, our understanding is far from complete and recent research reports suggest that we have thus far overlooked a whole level of regulation of cell growth control. Signals that instruct a normal cell to divide are propogated by pathways of interacting molecules within the cell. These pathways are regulated by switch mechanisms that either modify the interacting molecules, thereby inactivating their activity or by controlling when and where the molecules are allowed to interact. This spatial and temporal control mechanism is mediated by a family of specialised molecules, called 14-3-3 proteins. Recent research indicates that the function of these 14-3-3 proteins is also tightly controlled, although as yet we don't understand how. This research proposal attempts to discover the molecular mechanism of regulation of 14-3-3 function. An understanding of this process may provide new molecular targets for the development of therapeutics against cancer.Read moreRead less
Does Women's Nutrition During Pregnancy Influence Metabolic Health Of Their Children?
Funder
National Health and Medical Research Council
Funding Amount
$255,752.00
Summary
The occurrence of type 2 diabetes is increasing around the world, with the rising incidence among children and adolescents especially worrying. Widespread obesity has clearly contributed to this epidemic, but does not fully explain it. Diabetes develops over many years and obesity appears to exacerbate a pre-existing susceptibility. Our work focuses on understanding and preventing this initial susceptibility. Metabolic changes in the way the body produces and disposes of insulin, and responds to ....The occurrence of type 2 diabetes is increasing around the world, with the rising incidence among children and adolescents especially worrying. Widespread obesity has clearly contributed to this epidemic, but does not fully explain it. Diabetes develops over many years and obesity appears to exacerbate a pre-existing susceptibility. Our work focuses on understanding and preventing this initial susceptibility. Metabolic changes in the way the body produces and disposes of insulin, and responds to glucose, are seen much earlier in individuals who become diabetic. These metabolic defects are thought to be due, in part, to sub-optimal growth and development before birth (affecting the way the pancreas and liver function, for example). Poor nutrition before birth may be an important underlying cause. Animal studies reliably demonstrate that a poor quality diet of the pregnant mother can result in offspring that have impaired glucose tolerance and related metabolic problems. We now need to determine whether this occurs in humans. A limited amount of community-based research suggests this is possible. The balance between carbohydrate and protein in the mother's diet may be a key factor, and possibly the type of carbohydrate (high or low glycaemic). Weight before and during pregnancy could also be influential. We have been following a cohort of 500 children from before birth, through childhood. We collected detailed information on the mothers' diets during pregnancy. In this project, we plan to assess the glucose-insulin metabolism of the children at 8 years of age. We will then investigate whether diet of the mothers during pregnancy affects the metabolism of the children later on. Improving nutrition of pregnant women could lead to life-long improvement in metabolic health of the children. This study will contribute to the evidence-base about whether maternal diet is important, and give specific details about what kinds of changes are needed.Read moreRead less