Lung cancer is the leading cause of cancer related deaths worldwide. Unfortunately, current methods like CT scans have limitations in detecting lung cancer early and evaluating treatment response promptly, causing delays in diagnosis/therapy. To address this, I will investigate the potential of a technology called fluorescent lifetime imaging (FLIM). FLIM can detect emitted light from cells in the body, and I have shown that the light emitted from cells within a cancer differs from that of non-cancerous cells. Although the reason for this discrepancy is unknown, my findings suggest a correlation with how cells regulate their metabolism, through a chemical called adenosine. The FLIM technology is state-of-the-art and designed for use during bronchoscopy (where a camera is inserted into the lungs to examine suspected cancers). Here, using specialised fibres that can reach lesions/tumours we can obtain real-time metabolic profiles of the cancerous tissue, enabling immediate cancer diagnosis. I will also use small chemical compounds that detect the overactivity of two cell types crucial in the response to treatments: fibroblasts and T cells. This approach may provide early indications of treatment effectiveness, such as chemotherapy, before changes are visible on CT scans. Aims: 1) Define FLIM signals in lung cancer at both the cellular and whole cancer levels. 2) To investigate the relationship between FLIM signals and the activity of the adenosine pathway in lung cancer, linked to drug treatments. Objectives: Objective 1. Determine the cell specific FLIM signal in lung cancer and relate this to both the cells level of activation and function. Using surgically resected cancers, I will breakdown these into their individual cell component and measure the cell specific FLIM signal in each cell type. Parallel confirmatory experiments will tell us the cell activation and function levels. Then, using advanced culture methods that mimic cancer conditions I will understand what changes occur with drug treatments as we would use in the clinic, and relate this to how efficiently the cancer cells are killed. Finally, using an established large pathology set of lung cancers, I will make a unique atlas of all the cell types in cancer and their FLIM signal. This will be made into a shared community resource for other researchers. Objective 2. I will use a small device to allow us to understand how multiple combinations of drugs work in lung cancer, linked to FLIM. Using a device capable of delivering 20 drug combinations to small, confined areas of the cancer (less than 1 mm distance), I will study multiple combinations of drugs that target the adenosine pathway in lung cancer patients who have had their cancer removed. Using multiple laboratory techniques, including FLIM, I will measure how well the drug combinations have performed. The optimal combinations will be delivered (without the device) to patients a few days before their surgery for confirmation. Ultimately, we will aim to do the whole device experiments in patients' cancers before surgery, but this will be done with further research funding and on completion of the above stages of research. Objective 3. Assess FLIM signals in patients and combine this with small chemical compounds that report activity of fibroblasts and T cells. I will use an existing trial infrastructure in Edinburgh and will recruit patients with i) suspected cancer, ii) undergoing surgery, iii) planned for drug-based cancer treatment. Each group will have FLIM imaging combined with the chemical probes that can identify activated fibroblasts and signatures of cell death caused by T cells. This will gain valuable insights into the behaviour of the cancer and its response to therapy by FLIM. Together, this will determine if FLIM can be used as a tool for immediate diagnosis and early assessment of treatment response in lung cancer, ultimately enhancing outcomes for patients.

Preeclampsia, a multisystem disorder characterised by hypertension and organ dysfunction, remains a leading cause of maternal and fetal morbidity and mortality worldwide, complicating 3-5% of all pregnancies1. There are two types of preeclampsia based on when symptoms arise: early-onset (before 34 weeks of pregnancy) and late-onset (after 34 weeks)2. Early-onset preeclampsia, though less common (about 12% of cases), poses a much higher risk of severe health problems and fetal mortality3. Early detection of women at risk of early-onset preeclampsia is crucial to enable timely interventions like low-dose aspirin treatment, ideally before 16 weeks of pregnancy4,5. Unfortunately, current methods for identifying preeclampsiarisk during this time frame based solely on clinical risk factors are not very sensitive6. More advanced risk prediction models are available, including biomarker and ultrasound assessment of placental blood flow, but these are costly and labour-intensive, and not widely available. Additionally, even the advanced clinical models do not fully capture the entirety of preeclampsia risk. Therefore, there is a need to explore additional ways of screening for preeclampsia to enable timely, individualised preventive strategies aimed at improving outcomes for pregnant women and their babies. This project aims to evaluate, improve and further understand how genomics can help improve preeclampsia prediction. Initial experiments will evaluate available polygenic risk scores for preeclampsia in a cohort of approximately 6,000 women of multi-ethnic background from the Fetal Medicine Foundation (FMF) cohort. This will involve evaluating the improvement in prediction achieved by addition of polygenic scores to 'traditional' clinical models as well as the 'advanced' prediction model including biomarker and ultrasound assessment of placental blood flow. Subsequently the performance of the scores in women of African ancestry will be explored, and will be facilitated by the fact that the FMF cohort includes a higher number of women of African ancestry compared to any previous genetic study of preeclampsia. Specifically investigating genetic risk in this cohort is important because it is recognised that preeclampsia risk is higher among women of African ancestry7, but this cohort remains remain strongly underrepresented in genetic studies8. Thus, I will then aim to recalibrate available polygenic scores to make prediction more accurate for this ethnic group. Third, we will perform genotyping on a set of previously collected fetal chorionic villous samples that are paired to mothers in the biobank, with the aim of further understanding the contributions of both maternal and fetal genome in determining preeclampsia risk. We aim to then perform genome-wide association studies on both maternal and fetal genomes and meta-analyse these with all currently available data sources to create the largest up to date resource exploring both maternal and fetal genetic determinants of preeclampsia. Finally, a proteome- and transcriptome-wide Mendelian randomization analysis will be used to understand causal biological pathways.

For decades, scientists have believed that women were born with all the eggs they would ever have and that no new ones could ever be made. Recently a group of researchers in the USA isolated a primitive "stem" like cell from the ovaries of adult women. These cells were shown to be capable of forming what appeared to be new eggs (oocytes) when they were injected back into ovarian tissue. The implications of this are potentially enormous, but at the moment we know very little about what these cells may or may not be capable of. If we could make new eggs we could eventually help restore fertility in women who have become infertile for a variety of reasons, including chemotherapy, early menopause or just normal ageing. However, these findings have led to controversy and many questions remain as to whether these new eggs can develop normally. This project will determine whether these cells can be isolated from the ovaries of healthy women from a range of ages. Then using a system which we have developed where we can grow eggs outside the body (culture system), we will determine whether these cells can form new eggs and whether they are normal. The ultimate end point of this work would be to determine whether these cells were capable of forming eggs that could be fertilised and form embryos.

Most interventions to improve education in developing countries require spending significant amounts of money on improving the quality of the inputs to the education system. While this is often a useful approach, in countries with weak governments and low tax collection, little resources are available to invest in schools. In these settings, such as in Pakistan, private schools have provided an alternative to the low quality public schools, and parents are willing to pay for the improved quality, and so even in many remote rural areas, parents can pick from sending their child to the public school or one of several private schools in the village. This variety of schools has prompted us to study education markets instead of the inputs to the production of learning, applying theories from studying Small and Medium Enterprises (SMEs) to private schools. Instead of going to schools and telling them which inputs they should focus on, we tend to ask them what prevents them from expanding in quality and quantity. Over the past decade, our research team led by Tahir Andrabi (Pomona College), Jishnu Das (World Bank), and Asim Ijaz Khwaja (Harvard University) has studied the education markets in Pakistan. Despite the tremendous growth in the low cost private school (LCPS) sector (rising from 3,300 schools in 1983 to over 70,000 in 2011) and relatively better quality than the public sector (LCPS are 1.5 years ahead in learning outcomes relative to government schools), there is also evidence of substantial untapped innovation potential in this sector. The team has gathered both primary data and implemented randomized controlled trials (RCTs) that reveal constraints to growth and quality improvement for LCPS. Two factors that contribute to this innovation constraint are the lack of financing (a financial market failure) and access to affordable educational support services (ESS) (an input market failure), which together create a very challenging context for school owners. The current project is a RCT that seeks to explain how alleviating these constraints one at a time or simultaneously would affect learning outcomes, enrolment and school profitability. The randomized component means that schools are randomly allocated to either receiving offers of a loan product or an equity product to alleviate financial constraints, and/or receive access to buying ESS such as teacher training, improved curricula or student testing services. The controlled component of the trial means that some - randomly chosen - schools do not get any of these treatments, which allows us to compare the treatment outcomes with the counterfactual. The two financial products were developed together with one of Pakistan's largest microfinance banks. The equity product represents an innovation in the type of financial product offered to SMEs, and it is particularly relevant to LCPS since its revenue-contingent interest rate (if the school earns more, it will pay a higher interest rate) effectively shifts some of the risk of an investment over to the bank, and LCPS tend to have to make more lumpy investments than other SMEs. Our theory is that a less risky financial product would allow schools to take on more risky investments, such as investments in quality-improving ESS services. Our earlier studies have shown that schools are, under most circumstances, more prone to undertake capacity-improving investments such as buying more chairs when they get access to finance, perhaps because the school owner can more accurately predict and advertise the result from buying new chairs than from buying teacher training services. This results in a stagnant quality development of learning outcomes, which are already very poor in rural Pakistan. In conclusion, the present study will broaden the knowledge about what policy makers and providers of financial and ESS products can do to facilitate the improvement of learning outcomes in challenging rural contexts where LCPS are present.

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