Lay summaries are provided below of the Research Grants given in 2018.
Endometriosis is an estrogen-dependent gynaecological disorder that affects up to 10% of reproductive-aged women. In endometriosis, tissue resembling the lining of the uterus (endometrium) is found outside the uterine cavity (endometriotic lesions) at various abdominal sites including the peritoneum, ovary and bowel. Symptoms associated with endometriosis include crippling pain (eg. period pain, painful intercourse and chronic pelvic pain) and infertility.
There is suggestion that women with endometriosis may represent a high-risk group for coronary heart disease. Adding to endometriosis disease burden, women with the disorder commonly have other co-morbidities related to metabolic dysfunction including abnormal glucose and liver metabolism, deficient thyroid function and altered body shape (body mass index [BMI]). Preliminary data from our research indicates that endometrial gene expression is not affected by BMI; this strongly suggests that factors beyond the endometrial gene expression need to be considered if we are to understand the hypothesised metabolic dysfunction in women with endometriosis.
If we are to better understand endometriosis disease processes, more attention needs to be paid to the site of disease, the lesion itself. No lesion, no endometriosis! The purpose of this project is to determine if lesions demonstrate novel and/or aberrant metabolic and lipidomic profiles relative to non-diseased tissues. Moreover, can small molecule metabolites and lipids measured in endometriotic lesions be detected systemically in patients with endometriosis? If these questions can be answered, we will improve our understanding of the lipidomic and metabolomic changes that occur in women with endometriosis and perhaps improve long term outcomes in these women.
Gestational diabetes mellitus (GDM) affects up to 20% of all pregnancies but have an impact that extends well beyond pregnancy and childbirth, with the potential for lifelong morbidity or mortality for both mother and baby.
Despite the enormous health-impact, little progress has been made with interventions aimed at prevention with the rate of GDM is increasing in parallel with the obesity epidemic. Thus, a safe and effective intervention that can reduce the burden of GDM would be a major public health initiative.
We have recently discovered a family of regulatory proteins – Bromodomain containing proteins (BRDs) -important in GDM. In this study, we will assess the potential of BRDs as a novel therapeutic target for the prevention of GDM. Using my unique biobank of human clinical samples, the role of BRDs in GDM will be thoroughly characterised. The successful completion of this program of work will identify BRD2, BRD3 and or BRD4 as novel putative sites for therapeutic intervention of GDM.
This study aims to determine how medications such as enoxaparin (‘Clexane’) that reduce the risk of blood clots, affect the release of DNA from the placenta. Measuring levels of placental DNA in the bloodstream of pregnant women is the basis of a noninvasive prenatal screening test that detects fetal chromosome abnormalities with high accuracy. Clinical studies of pregnant women on blood-thinning medication suggest that these women have less placental DNA in their blood, manifesting as test failures with cfDNA screening. cfDNA test failures are more than 37 times more likely in women on blood-thinning medication (up to ~18%), resulting in patient anxiety, stress and increased medical costs due the additional follow-up and testing require.
The reduction in placental DNA release in women on blood-thinning medications is speculated to be caused by improved cell survival in the placenta. Understanding the relationship between blood-thinning medications and placental DNA release may not only help avoid test failures on prenatal screening, but also suggest future avenues for clinical research into therapies for placenta-medicated pregnancy complications such as preeclampsia.
The day you are born is one of the most risky days in your life. Fetal distress during labour is a leading cause of seizures, cerebral palsy and death of newborns at team. It occurs due to the uterine contractions of labour limiting blood flow and oxygen delivery to the fetus. If fetal distress is identified early, then the baby can be swiftly delivered, avoiding these devastating complications.
Currently we use a heart rate monitor (cardiotocography CTG) to determine whether the baby is coping with labour. The CTG is often difficult to interpret and inaccurate. To improve our assessment of fetal distress we perform fetal scalp blood sampling. This is a very invasive procedure and is performed sparingly. Unfortunately it only tells us how the baby is coping at the moment it is taken and can miss the critical point when the baby needs delivery.
Using state of the art technology we have developed a novel sensor that continuously measures a direct marker of fetal distress. In this grant we will validate our sensor. We will ensure our sensor accurately detects this marker of distress in fetal blood. We will also ensure that it accurately detects this marker over a period of around 10 hours.
This device has the potential to transform monitoring in labour and reduce brain injury and death of babies at term.
It has been demonstrated that the sensor accurately detects a direct murmur of fetal distress and a prototype has been built. The prototype is now ready to manufacture for use in animal studies. It is hoped that the device will better detect fetuses in distress and ultimately reduce cerebral palsy and seizures and developmental delay resulting from birth.
Fetal growth restriction (FGR) is the failure of a fetus to reach its genetically pre-determined growth potential. The major contributor to FGR is placental insufficiency where the placenta fails to provide adequate nutrition and oxygen to the growing fetus. It is the leading cause of stillbirth, a tragedy impacting 1:130 pregnancies in Australia. Our ability to reduce the burden of stillbirth is limited by the poor sensitivity and specificity of current screening tools available to detect small babies during pregnancy.
The Fetal Longitudinal Assessment of Growth (FLAG) study is a study involving over 2000 women who had blood samples taken at 28 and 36 weeks’ gestation. The aim of the FLAG study was to examine the predictive ability of genetic markers (mRNA) released from the placenta into the maternal blood to predict small babies at term. Of the 2000 women, 10.5% subsequently delivered a small baby, with birthweight <10th centile. Utilising blood samples already collected as part of the FLAG study, we have identified promising ‘genetic signatures’ that appear to perform well at predicting the small baby.
This research proposal aims to validate these novel placenta-specific genes using a technique which is more advanced, more sensitive, and clinically useful known as digital PCR. In addition, we will further continue our discovery for other mRNA biomarkers. If successful, this project will have validated these ‘genetic signatures’ in the blood of pregnant women destined to deliver a growth restricted baby. This will form the basis of a larger funding application to develop a clinically useful test that could measure placenta- specific genes and proteins to predict women at risk of fetal growth restriction.
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Endometrial cancer, or cancer of the uterus, is the fifth most common cancer affecting Australian women. It is the commonest cancer of female reproductive organs, with approximately 2500 cases diagnosed each year. This rate is increasing, and we know that certain factors increase the risk. these factors include obesity, infertility, genetics and increasing age. Many different types of endometrial cancer (EC) are recognised. The majority are known as ‘type 1’ cancers and begin with a precancerous condition called ‘atypical endometrial hyperplasia (AH) . In most cases hysterectomy (removal of the uterus) is the recommended treatment for these problems. A hysterectomy makes a woman infertile and is a major operation, so for particular patients it may not always be appropriate or safe.
We know that obesity, genetics, infertility and increasing age can all contribute to an increased risk of endometrial cancer. But equally importantly, they can also contribute to increased risks, or problems, with hysterectomy. In our daily practice we are seeing AH and EC in young, obese women with infertility problems. These women want to avoid a hysterectomy so that they can preserve their option to have children. On the other hand, we are seeing AH and EC in an ageing population of obese women (with many other medical problems) who may be too sick to survive a hysterectomy. For women in both of these groups, hysterectomy may not be an acceptable option.
There are other options that we have for these women. Hormonal therapy with progesterone (either taken in tablet form, or inserted in to the uterus) is one of these alternatives. Studies of hormone therapies to treat AH and EC have shown success in 75-90%, and 70-75% of cases respectively. Whilst these studies do support hormonal therapy as an effective option, we also know that not all patients will respond to the treatment. What we need to work out is: who are the patients who will respond, and who are the ones who won’t? This matters because if hormonal therapy isn’t working, or was never going to, the patient should be recommended to have a hysterectomy instead. There are some studies which have looked at addressing this dilemma, or predicting the success rate of progesterone therapy, but they are limited by small patient numbers, and assessment of only select factors (known as prognostic variables).
At Mercy Hospital for Women, we have been using progesterone therapy to treat AH and EC for over 10 years. We propose a pilot study to identify factors, which alone or in combination, could be used to predict response to treatment. Our results could then be used to design a much larger study whose aim would be to develop a new predictive tool enabling doctors to select which patients are most likely to have success with hormonal therapy. Not only would patients then be able to receive more individualised care, they would also have greater ability to make their own informed choices about their treatment options.
We aim to investigate the childhood outcomes of children in whom the pregnancy was complicated by diabetes. The short term implications of diabetes in pregnancy are well known, including stillbirth, macrosomia, special care nursery admission and preterm birth, but there is very little documented about outcomes outside the newborn period, apart from cardiovascular disease.
We plan to link a number of high quality data sets including the Victorian Perinatal Data Collection (VPDC), Australian Early Developmental Census (AEDC), National Diabetes Services Scheme (NDSS) and National Assessment Program – Literacy and Numeracy (Naplan) to examine a broad range of outcomes. This will enable us to compare children of women with type 1, type 2 and gestational diabetes with children of women without diabetes. We will examine the areas of physical health and wellbeing, social competence, emotional maturity, language and cognitive skills, communication skills and general knowledge. We will be able to describe the proportion of children developmentally on track, developmentally at risk or developmentally vulnerable in each group.
Understanding of the outcomes for infants of diabetic mothers may help us to target care more appropriately during pregnancy, focus early intervention programs, and provide more understanding to women about the importance of maintaining healthy lifestyle choices during pregnancy and the early childhood years.
Preeclampsia (PE) is a hypertensive disorder of pregnancy that is a major cause of both maternal and fetal morbidity and mortality throughout the world. It is characterised by poor placental implantation and release of placental factors into the maternal circulation. These placental factors cause dysfunction of the cells that line maternal blood vessels leading to end organ damage and the clinical complications of preeclampsia. At present, there is no way to predict who will develop preeclampsia. A predictive test would allow safe triage of antenatal surveillance strategies, implementation of closer monitoring where needed, and treatment to help alleviate the tragic impact of the disease.
MicroRNAs (miRs) are small (~20 nucleotides) non-coding RNAs that are highly stable in the circulation as they are not readily broken down. They regulate gene expression and distant cell signalling. There is growing interest in the use of miRs as predictive biomarkers of disease, particularly in the cancer field. We hope their potential might also be realised as predictive biomarkers of preeclampsia.
The Fetal Longitudinal of Growth Study (FLAG) involved prospectively taking blood samples from ~2000 women at 28 and 36 weeks’ gestation. These pregnancies were retrospectively characterised and some of these women were found to develop PE later in their pregnancies. Therefore, we have a cohort of blood samples from patients who are destined to develop PE which allows us to evaluate the predictive value of miRNA biomarkers.
In recent laboratory work funded by the Norman Beischer Medical Research Foundation, we identified GATA2 as a potential biomarker of preeclampsia. We have recently extended our findings to demonstrate that a pro-angiogenic miR closely associated with GATA2, miR126, is also a potential biomarker for disease; it is significantly reduced preceding PE diagnosis. This finding led us down the path to considering miRs as potential biomarkers of preeclampsia.
The aim of this proposal is to run a microarray containing 48 miRs in a case control cohort from the FLAG samples and to then validate any differentially expressed miRs in the first 1000 FLAG samples in order to formulate a diagnostic test to identify women at risk of preeclampsia.
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Necrotising Enterocolitis (NEC), a complex condition affecting up to 10% of premature babies, is thought to stem from the interaction between the neonatal gut microbiome and the baby’s immature immune system.
NEC causes inflammation and swelling of the wall of the gut which can progress to the necrosis of sections of the bowel that will need to be surgically removed. Unsurprisingly, babies with NEC become very sick with changes in blood pressure and effects that eventually extend to all body systems. Moreover, as a majority of the babies affected by NEC are usually premature, they are therefore, already weaker and more susceptible to the ravages of NEC. In fact, around 30% of babies suffering from NEC will die.
In the initial stages, NEC can be managed with antibiotic therapy. However, it is the case that surgery to remove dead and diseased bowel becomes necessary for many babies. All the treatments for NEC are associated with side effects. Antibiotic therapy leads to delays in feeding and poor growth and surgery may lead to short-gut syndrome as well as predictable complications of surgery, like poor wound healing, wound infections and prolonged need for opioid painkillers, among others. As NEC affects all body systems it is also associated with a worsening of the babies’ respiratory status and with poorer neurological outcomes that may affect these babies for life.
Because the very presence of NEC is linked to a plethora of adverse effects and even the treatments for it are not without their own risks, much work focuses on reducing the risk of NEC. It is well established and accepted that breastmilk is protective for babies. This protective effect is improved if milk feeds are introduced slowly with small, controlled increments. The use of probiotics is now also widely accepted as another preventive strategy reducing the risk of NEC. Despite these and other measures improving the individual‘s risk of contracting NEC and probably ameliorating any disease that might develop, the global incidence of NEC has remained relatively constant.
The effectiveness of the treatments and risk reduction therapies already mentioned make sense as more has been understood about the neonatal microbiome. The term microbiome encompass the total bacterial population specifically related to each human being. It is used to describe both the total population of bacteria living in and on a human, although it can also be narrowed down to the totality of bacteria belonging to a particular organ or system. Thus, we talk about the skin microbiome, respiratory microbiome, uterine microbiome and gut microbiome.
The microbiome is composed of many different species of bacteria in balance. A change in the majority species can be associated with disease, both acute and chronic; these changes are sometimes termed a dysbiosis.
Good evidence exists that premature babies may have a broadly different gut microbiome than their full term counterparts. It has also been shown that babies who develop NEC undergo specific changes in their gut microbiome before developing NEC. If NEC may be thought of, at least partly, as due to a dysbiosis it then makes sense that interventions which might correct this dysbiosis may consequently help reduce the risk of developing NEC.
This study aims to prospectively monitor changes in the microbiome of premature infants while recording medical interventions, like ventilation, antibiotic therapy etc., together with some physiological parameters, as oxygen saturations, type and volume of feed etc. This investigation should help in bringing into sharp contrast existing patterns of microbiome change in response to certain situations, should these exist with reference to NEC.
To summarise, the best interventions we currently have do not completely eliminate the risk of NEC. Since our understanding of the neonatal microbiome is still growing and developing, it may be that a more thorough appreciation of this complex interplay between the human organism and its bacteria may lead to identify thresholds and to advance our knowledge of relevant changes, perhaps pointing to possible further interventions and to more specific recommendations.
Endometrial Cancer (EC) is a cancer that affects the lining of the uterus and is the most common Gynaecological cancer. Between 1982 and 2008, the number of new endometrial cancers per year more than doubled. ECs are very diverse in behaviour and although many early stage cancers are cured, if recurrence occurs the prognosis is poor, with a median survival of approximately 12 months. EC has traditionally been divided into two types; Type 1 and Type 22. Type 1 ECs are the most common form of EC and are associated with high oestrogen levels from internal causes such as obesity, early menarche and late menopause, and external causes such as unopposed synthetic oestrogen. Type 1 ECs often present at early stage, are less likely to spread to other tissues quickly and are associated with a more favourable prognosis. In contrast, Type 2 ECs are less common accounting for only 20 percent of presentations 2•3, but are an aggressive subtype and often present at advanced stages and are responsible for 40% of deaths 2•4.
Despite progress in other areas of oncology, the outcomes for women with endometrial cancer have failed to improve, which in part is due to tumour biology, significant variability amongst patients with the same histological type and the current approaches to treatment. New biomarkers are urgently required to help select treatment and provide a more personalised management approach.
Circulating tumour DNA (ctDNA) known as a ‘liquid biopsy’, is a new technology being explored in many areas of oncology and has the capacity to be the biomarker needed to guide prognosis and management for women with EC. The capturing of ctDNA in the blood following primary surgery may help to define the women most and least at risk of cancer recurrence and could therefore
guide therapy. In addition, ctDNA is a non-invasive biopsy which has the potential to provide critical information on the genes driving the cancer to guide personalised treatment, and to track treatment response and resistance.
The aim of this study is to assess the utility of circulating tumour DNA (ctDNA) as a prognostic biomarker endometrial cancer. Tissue samples will be collected from patients’ primary tumours to undertake genomic profiling and this will be matched to the ctDNA in the blood. This project has the potential to answer a number of important research questions and provide feasibility to take this technology forward into future clinical trials with the hope of improving the outcome for patients with EC.
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