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  • Analysis of 51 proposed hypertrophic cardiomyopathy genes from genome sequencing data in sarcomere negative cases has negligible diagnostic yield.

    16 January 2019

    PURPOSE: Increasing numbers of genes are being implicated in Mendelian disorders and incorporated into clinical test panels. However, lack of evidence supporting the gene-disease relationship can hinder interpretation. We explored the utility of testing 51 additional genes for hypertrophic cardiomyopathy (HCM), one of the most commonly tested Mendelian disorders. METHODS: Using genome sequencing data from 240 sarcomere gene negative HCM cases and 6229 controls, we undertook case-control and individual variant analyses to assess 51 genes that have been proposed for HCM testing. RESULTS: We found no evidence to suggest that rare variants in these genes are prevalent causes of HCM. One variant, in a single case, was categorized as likely to be pathogenic. Over 99% of variants were classified as a variant of uncertain significance (VUS) and 54% of cases had one or more VUS. CONCLUSION: For almost all genes, the gene-disease relationship could not be validated and lack of evidence precluded variant interpretation. Thus, the incremental diagnostic yield of extending testing was negligible, and would, we propose, be outweighed by problems that arise with a high rate of uninterpretable findings. These findings highlight the need for rigorous, evidence-based selection of genes for clinical test panels.

  • Reduction of Cardiovascular Risk and Improved Estimated Glomerular Filtration Rate by SGLT2 Inhibitors, Including Dapagliflozin, Is Consistent Across the Class: An Analysis of the Placebo Arm of EXSCEL.

    12 December 2018

    OBJECTIVE: The sodium-glucose cotransporter 2 inhibitors (SGLT2is) empagliflozin and canagliflozin reduce the incidence of major adverse cardiovascular events (MACE), all-cause mortality (ACM), and renal events in cardiovascular outcomes trials, with observational real-world evidence suggesting class effect benefits that include dapagliflozin. We examined the placebo arm of EXSCEL to determine whether the effects of drop-in open-label dapagliflozin on MACE, ACM, and estimated glomerular filtration rate (eGFR) were consistent with the SGLT2i class as a whole. RESEARCH DESIGN AND METHODS: SGLT2i drop-in therapy occurred in 10.6% of EXSCEL participants, with 5.2% taking dapagliflozin. Propensity-matched cohorts of SGLT2i users and nonusers (n = 709 per group) were generated on the basis of their characteristics before open-label SGLT2i drop-in or at baseline for participants taking SGLT2is at enrollment and an equivalent study visit for non-SGLT2i users. Time to first adjudicated MACE and ACM was analyzed using Cox regression. eGFR slopes were compared between matched cohorts using a mixed-model repeated-measures analysis. RESULTS: In adjusted analyses, SGLT2i users (compared with nonusers) had a numerically lower risk of MACE (adjusted hazard ratio 0.79 [95% CI 0.49-1.28]), as did dapagliflozin users (0.55 [0.26-1.15]). SGLT2i users had a significantly lower ACM risk (0.51 [0.27-0.95]; dapagliflozin: 0.66 [0.25-1.72]). Compared with nonusers, eGFR slope was significantly better for SGLT2i users overall (+1.78 [95% CI 0.87-2.69] mL/min/1.73 m2 per year) and for dapagliflozin users (+2.28 [1.01-3.54] mL/min/1.73 m2 per year). CONCLUSIONS: This post hoc analysis of the placebo arm of EXSCEL supports a beneficial class effect for all SGLT2i, including dapagliflozin, for reduced ACM and less eGFR decline.

  • Of mice and men: is there a future for metformin in the treatment of hepatic steatosis?

    12 December 2018

    Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of liver diseases, of which the first stage is steatosis. It is one of the most common liver diseases in developed countries and there is a clear association between type 2 diabetes (T2DM) and NAFLD. It is estimated that 70% of people with T2DM have NAFLD and yet there is currently no licenced pharmacological agent to treat NAFLD. Whilst lifestyle modification may ameliorate liver fat, it is often difficult to achieve or sustain, thus there is great interest in pharmacological treatments for NAFLD. Metformin is the first line medication in the management of T2DM and evidence from animal and human studies has suggested that it may be useful in reducing liver fat via inhibition of lipogenesis and increased fatty acid oxidation. Findings from the majority of studies undertaken in rodent models clearly suggest that metformin may be a powerful therapeutic agent to specifically reduce liver fat accumulation; data from human studies is less convincing. In this review we discuss the evidence for the specific effects of metformin treatment on liver fat accumulation in animal and human studies and the underlying proposed mechanisms to try and understand and reconcile the difference in findings from rodent and human work. This article is protected by copyright. All rights reserved.

  • MicroRNAs Regulate Sleep and Sleep Homeostasis in Drosophila.

    12 December 2018

    To discover microRNAs that regulate sleep, we performed a genetic screen using a library of miRNA sponge-expressing flies. We identified 25 miRNAs that regulate baseline sleep; 17 were sleep-promoting and 8 promoted wake. We identified one miRNA that is required for recovery sleep after deprivation and 8 miRNAs that limit the extent of recovery sleep. 65% of the hits belong to human-conserved families. Interestingly, the majority (75%), but not all, of the baseline sleep-regulating miRNAs are required in neurons. Sponges that target miRNAs in the same family, including the miR-92a/92b/310 family and the miR-263a/263b family, have similar effects. Finally, mutation of one of the screen's strongest hits, let-7, using CRISPR/Cas-9, phenocopies sponge-mediated let-7 inhibition. Cell-type-specific and temporally restricted let-7 sponge expression experiments suggest that let-7 is required in the mushroom body both during development and in adulthood. This screen sets the stage for understanding the role of miRNAs in sleep.

  • Precise tuning of gene expression output levels in mammalian cells

    12 December 2018

    Precise, analogue regulation of gene expression is critical for development, homeostasis and regeneration in mammals. In contrast, widely employed experimental and therapeutic approaches such as knock-in/out strategies are more suitable for binary control of gene activity, while RNA interference (RNAi) can lead to pervasive off-target effects and unpredictable levels of repression. Here we report on a method for the precise control of gene expression levels in mammalian cells based on engineered, synthetic microRNA response elements (MREs). To develop this system, we established a high-throughput sequencing approach for measuring the efficacy of thousands of miR-17 MRE variants. This allowed us to create a library of microRNA silencing-mediated fine-tuners (miSFITs) of varying strength that can be employed to control the expression of user specified genes. To demonstrate the value of this technology, we used a panel of miSFITs to tune the expression of a peptide antigen in a mouse melanoma model. This analysis revealed that antigen expression level is a key determinant of the anti-tumour immune response in vitro and in vivo. miSFITs are a powerful tool for modulating gene expression output levels with applications in research and cellular engineering.

  • Decoupling tRNA promoter and processing activities enables specific Pol-II Cas9 guide RNA expression

    12 December 2018

    Spatial/temporal control of Cas9 guide RNA expression could considerably expand the utility of CRISPR-based technologies. Current approaches based on tRNA processing offer a promising strategy but suffer from high background. Here we developed a variant screening platform to identify differential sequence determinants of human tRNA promoter and processing activities. Rational design based on the ensuing principles allowed us to engineer an improved tRNA scaffold that enabled highly specific guide RNA production from a Pol-II promoter.

  • Loss of ZnT8 function protects against diabetes by enhanced insulin secretion

    4 January 2019

    A rare loss-of-function variant p.Arg138* in SLC30A8 encoding the zinc transporter 8 (ZnT8) enriched in Western Finland protects against type 2 diabetes (T2D). We recruited relatives of the identified carriers and showed that protection was associated with better insulin secretion due to enhanced glucose responsiveness and proinsulin conversion, especially compared with individuals matched for the genotype of a common T2D risk variant in SLC30A8, p.Arg325. In genome-edited human IPS-derived β-like cells, we establish that the p.Arg138* variant results in reduced SLC30A8 expression due to haploinsufficiency. In human β-cells loss of SLC30A8 leads to increased glucose responsiveness and reduced KATP channel function, which was also seen in isolated islets from carriers of the T2D-protective allele p.Trp325. These data position ZnT8 as an appealing target for treatment aiming at maintaining insulin secretion capacity in T2D.

  • Funding Opportunities

    17 July 2018

    OCH Training Grants for Allied Healthcare Professionals and Special Study Modules

  • Defence and Counter-defence: The interplay between Zika virus and the immune system

    Virus infection triggers a multitude of immune responses. Detection of virus presence by the innate immune system is a crucial event mediated by germ-line encoded receptors inside cells. These sensors of virus presence signal for the induction of innate immune response genes, such as those encoding type I interferons. Many of these receptors sense viral nucleic acids. For example, RIG-I recognizes the RNA genomes of viruses such as influenza A virus (Rehwinkel et al., Cell 2010). Viruses in turn have developed strategies to counteract and evade detection by innate immune receptors. As such, cells and viruses are in a dynamic arms race in which host defence mechanisms and viral counter-measures rapidly co-evolve. One of our aims is to understand the molecular basis of host pathogen interactions.

  • Investigating innate immune signalling with CRISPR-Cas9 screens

    Genome editing using CRISPR-Cas9 is a powerful system to study gene function and can be used in genome-wide screens. This project will make use of this transformative technique to identify novel regulators of innate immune responses. Our group is interested in signalling pathways that allow cells to detect invading viruses. Indeed, detection of virus presence by the innate immune system is a crucial event mediated by germ-line encoded receptors inside cells. These sensors of virus presence signal for the induction of innate immune response genes, such as those encoding type I interferons. Many of these receptors sense viral nucleic acids. For example, RIG-I recognizes the RNA genomes of viruses such as influenza A virus (Rehwinkel et al., Cell 2010) and cGAS detects viral DNA. In addition to their roles in virus infection, these sensors are also important in some autoinflammatory diseases and in cancer.

  • Funding Options

    17 May 2017

    Most of our students, whether basic scientists or clinical fellows, are fully funded. The department is able to offer full funding at a generous level for basic scientists and our Principal Investigators have considerable experience in supporting clinicians in their applications for Clinical Research Fellowships (CRF).

  • How to apply

    31 August 2017

  • Graduate Studies

    16 August 2017

    The Radcliffe Department of Medicine provides graduate students with exceptional teaching, training and career development in a broad spectrum of sciences related to medicine. With around 150 graduate students currently in the Department, most of whom are studying for a four year DPhil, the Department is committed to training the next generation of researchers in biological and clinical sciences.

  • WIMM Prize Studentships

    18 May 2017

    The MRC Weatherall Institute of Molecular Medicine (WIMM) is an internationally renowned Institute that aims to unravel the mechanisms of disease and build on these findings to improve human health. For those who would like to work at the WIMM, the Institute offers a number of four year Prize Studentships to outstanding students of any nationality.

  • Identification of the atrial transcriptional signature of patients who develop atrial fibrillation

    Microarray expression analyses have identified differences in the expression of gene sets related to ion channel function and transcription factors in atrial tissue from patients with paroxysmal or persistent atrial fibrillation (AF) versus normal sinus rhythm (SR) and differential expression of miRs involved in the regulation of ion channel subunits have been identified between similar patient groups. However, it is unclear whether these changes are a cause or a consequence of AF.

  • RDM Governance

    16 August 2017

  • Research

    30 November 2018

  • Novo Nordisk - Oxford Fellowships

    31 August 2017

    The Novo Nordisk – Oxford Fellowship Programme aims to support the development of a new generation of exceptional young diabetes researchers, who will become future leaders in the field.

  • Graduate Studies

    16 August 2017

  • Supervisor Profiles

    16 October 2018

    Below are outlines of potential DPhil (PhD) research opportunities in each of our research groups interested in recruiting students for October 2019 entry. Applicants are strongly encouraged to contact supervisors in advance of application to discuss potential projects or directions for research they may be able to take. This is to ensure that there is a good fit between the student and the lab and is considered an integral part of our admissions process. Applications for funded places through the RDM Scholars Programme are now closed. Some supervisors may still be able to consider applications from students who have alternative means of funding (for example, charitable funding, clinical fellows or applicants with funding from a foreign government or equivalent). Prospective applicants are strongly advised to contact their prospective supervisor in advance of making an application. Please note that any applications received after the main funding deadline will not be assessed until all applications that were received by the deadline have been processed. This may affect supervisor availability. If you are considering making an application after the funding deadline, we advise you to submit your application as soon as possible. This allows more time to complete all admissions processes and makes it easier to find a college place. The latest date you can apply for a place for October 2019 entry in Friday 26 July 2019.

  • Internal Communications

    17 January 2019

  • WIMM

    31 August 2017

  • Where to Find Us

    7 September 2017

  • Diabetes, Metabolism and Endocrinology

    28 March 2017

    Our focus is on finding the causes of metabolic and endocrine disease and capitalising on these discoveries to yield new treatments. We are world leaders in both large-scale genetic studies and global clinical trials, taking an international approach to advance our understanding and treatment of type 1 and type 2 diabetes. From target discovery for type 2 diabetes and probing the biochemistry of fat, through to understanding islet physiology and transplantation, investigating liver disease and unravelling the mechanisms behind rare endocrine tumours, our research truly spans the bed to bedside journey.

  • Cardiovascular Science

    28 March 2017

    We aim to better understand, diagnose and treat heart and vascular disease through our extensive cutting edge research programmes. We have a particular focus on understanding disease mechanisms and on new approaches to stratifying patients. Our expertise encompasses genetic studies to identify causative and risk genes, cardiovascular physiology and cellular biology to understand health and disease, the development and application of advanced imaging, experimental medicine and clinical trials.

  • Haematology and Pathology

    28 March 2017

    We seek to understand the causes of diseases of the blood and other malignancies, from a molecular to systems level, with a focus on blood cancers, rare inherited conditions and the tumour microenvironment. We use and develop innovative techniques to drive research in this area, and are committed to bringing about change in clinical diagnosis and practice. Our pathologists discovered many of the biomarkers now used routinely in clinical practice, translate laboratory findings into clinical tests and are developing digital pathology initiatives.

  • Experimental Therapeutics

    28 March 2017

    Building on critical findings from our research streams, we are initiating new drug discovery programmes. Many of our researchers are engaged in target discovery and target validation research – elucidating molecular pathways that can be manipulated for disease modification.

  • Geratology

    28 March 2017

    With an ageing population, it’s critical that we better understand diseases associated with old age. We have particular strengths in acute stroke research, with a two pronged approach encompassing molecular and clinical aspects to better understand the factors influencing stroke recovery.

  • Clinical Imaging

    28 March 2017

    We have world-class clinical imaging facilities aimed at better understanding, diagnosing and treating disease. Our clinical studies feedback into molecular research, taking learnings from the clinical setting to ask further questions in model systems. We have particular strengths in cardiovascular imaging and our facilities integrate clinical care with the latest research.

  • Cellular and Preclinical Imaging

    28 March 2017

    Using a range of imaging modalities, our researchers can probe – at the molecular level – the events that underpin cellular health and dysfunction.

  • Clinical Studies and Trials

    28 March 2017

    We are committed to translating our innovative research into clinical benefit. From new methods of diagnosing chronic conditions, to finding the latest treatments for diabetes, cancer, heart disease, stroke and rare diseases, our department is involved in hundreds of clinical studies every year.

  • Genetics, Genomics and Genome Biology

    28 March 2017

    Employing a range of genetic techniques, we probe the fundamental causes of disease. Our expertise spans identification of causative genes in rare inherited diseases, through to elucidating complex gene regulatory pathways and exploration of susceptibility to common disease through genome-wide association studies. We use cutting edge techniques to manipulate the genome to determine how particular genes work and study how variants in regulatory DNA may contribute to common disease. An important overall aim is to improve the management of human genetic diseases.

  • The slimy jelly that helps us respond to infection

    26 June 2017

    A fully functioning immune system is dependent on good communication between many different types of cell. We know that one set of cells detects damage and infection, while another leaps into action to defend the body. But we weren’t entirely clear how the two ‘talked’ to each other. New research by the Jackson lab suggests that a special type of carbohydrate acts as the broker between the two.

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    28 March 2017

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