A5009276756- IL-33, ST2, and ILC Pathways
- Regulation of Appetite and Obesity
- RNA modifications and cancer
- HER2/EGFR in Cancer Research
- Radiomics and Machine Learning in Medical Imaging
- Advanced Fluorescence Microscopy Techniques
- Bioinformatics and Genomic Networks
- Extracellular vesicles in disease
- Monoclonal and Polyclonal Antibodies Research
- Breast Cancer Treatment Studies
- Biochemical Analysis and Sensing Techniques
- Medical Imaging Techniques and Applications
- Adipose Tissue and Metabolism
- Cancer Immunotherapy and Biomarkers
- Immunotherapy and Immune Responses
- Gene Regulatory Network Analysis
- Cell Adhesion Molecules Research
- Pancreatic function and diabetes
- Gastric Cancer Management and Outcomes
- Receptor Mechanisms and Signaling
- Adipokines, Inflammation, and Metabolic Diseases
- Neuroblastoma Research and Treatments
- Fungal and yeast genetics research
- Cancer Genomics and Diagnostics
- Cancer Research and Treatments
Addenbrooke's Hospital
2018-2025
University of Cambridge
2018-2025
NIHR Cambridge Biomedical Research Centre
2023-2025
MRC Epidemiology Unit
2025
Wellcome/MRC Institute of Metabolic Science
2019-2024
Cambridge Quantum Computing (United Kingdom)
2024
University of Tasmania
2023
Wellcome Trust
2013-2022
King's College London
2010-2019
Kings Health Partners
2017
Abstract Obesity is a major risk factor for many common diseases and has substantial heritable component. To identify new genetic determinants, we performed exome-sequence analyses adult body mass index (BMI) in up to 587,027 individuals. We identified rare loss-of-function variants two genes ( BSN APBA1 ) with effects substantially larger than those of well-established obesity such as MC4R . In contrast most other obesity-related genes, were not associated normal variation childhood...
The immunosuppressive transmembrane protein PD-L1 was shown to traffic via the multivesicular body (MVB) and be released on exosomes. A high-content siRNA screen identified endosomal sorting complexes required for transport (ESCRT)-associated ALIX as a regulator of both EGFR activity surface presentation in basal-like breast cancer (BLBC) cells. depletion results prolonged enhanced stimulation-induced well defective trafficking through MVB, reduced exosomal secretion, its redistribution cell...
Abstract Cancer cells tend to metastasize first tumor-draining lymph nodes, but the mechanisms mediating cancer cell invasion into lymphatic vasculature remain little understood. Here, we show that in human breast tumor microenvironment (TME), presence of increased numbers RORγt+ group 3 innate lymphoid (ILC3) correlates with an likelihood node metastasis. In a preclinical mouse model cancer, CCL21-mediated recruitment ILC3 tumors stimulated production CXCL13 by TME stromal cells, which turn...
Transcriptional analysis of brain tissue from people with molecularly defined causes obesity may highlight disease mechanisms and therapeutic targets. We performed RNA sequencing hypothalamus individuals Prader-Willi syndrome (PWS), a genetic characterized by severe hyperphagia. found that upregulated genes overlap the transcriptome mouse Agrp neurons signal hunger, while downregulated expression profile Pomc activated feeding. Downregulated are expressed mainly in neuronal cells contribute...
Radiotherapy is a major treatment modality for head and neck squamous cell carcinoma (HNSCC). Up to 50% of patients with locally advanced disease relapse after radical there therefore need develop predictive bomarkers clinical use that allow the selection who are likely respond. MicroRNA (miRNA) expression profiling panel HNSCC tumours without recurrent surgery radiotherapy detected miR‐196a as one highest upregulated miRNAs in poor prognostic group. To further study role miR‐196a, its was...
Abstract Hypothalamic neurons expressing the anorectic peptide Pro-opiomelanocortin (Pomc) regulate food intake and body weight. Here, we show that Steroid Receptor Coactivator-1 (SRC-1) interacts with a target of leptin receptor activation, phosphorylated STAT3, to potentiate Pomc transcription. Deletion SRC-1 in mice attenuates their depolarization by leptin, decreases expression increases leading high-fat diet-induced obesity. In humans, fifteen rare heterozygous variants found severely...
Abstract Serotonin reuptake inhibitors and receptor agonists are used to treat obesity, anxiety depression. Here we studied the role of serotonin 2C (5-HT R) in weight regulation behavior. Using exome sequencing 2,548 people with severe obesity 1,117 control individuals without identified 13 rare variants gene encoding 5-HT R ( HTR2C ) 19 unrelated (3 males 16 females). Eleven caused a loss function HEK293 cells. All who carried had hyperphagia some degree maladaptive Knock-in male mice...
New approaches are needed to treat people whose obesity and type 2 diabetes (T2D) driven by specific mechanisms. We investigate a deletion on chromosome 16p11.2 (breakpoint 2-3 [BP2-3]) encompassing SH2B1, mediator of leptin insulin signaling. Phenome-wide association scans in the UK (N = 502,399) Estonian 208,360) biobanks show that carriers have increased body mass index (BMI; p 1.3 × 10
Dimerization of EGFR with an ErbB4 receptor variant increases growth factor–induced migration breast cancer cells.
Highlights•β4 integrin-expressing macrophages release TGF-β1 near breast cancer lymphovasculature•TGF-β1 drives β4 integrin clustering on macrophages, enhancing macrophage adhesion•TGF-β1 signals through RhoA to drive lymphatic endothelial cell contraction•Lymphatic remodeling signaling cascade facilitates metastasisSummaryLymphatic vasculature is crucial for metastasis in triple-negative (TNBC); however, cellular and molecular drivers controlling lymphovascular are poorly understood. We...
Over the past decade, immunotherapy delivered novel treatments for many cancer types. However, lung still leads mortality, and non-small-cell carcinoma patients with mutant EGFR cannot benefit from checkpoint inhibitors due to toxicity, relying only on palliative chemotherapy third-generation tyrosine kinase inhibitor (TKI) osimertinib. This new drug extends lifespan by 9-months vs. second-generation TKIs, but unfortunately, cancers relapse resistance mechanisms lack of antitumor immune...
Overexpression of HER2 is an important prognostic marker, and the only predictive biomarker response to HER2-targeted therapies in invasive breast cancer. HER2-HER3 dimer has been shown drive proliferation tumor progression, targeting this with pertuzumab alongside chemotherapy trastuzumab, significant clinical utility. The purpose study was accurately quantify dimerisation formalin fixed paraffin embedded (FFPE) cancer tissue as a novel biomarker.FFPE tissues were obtained from patients...
Abstract Context While severe obesity due to congenital leptin deficiency is rare, studies in patients before and after treatment with can provide unique insights into the role that plays metabolic endocrine function. Objective The aim of this study was characterize changes peripheral metabolism people undergoing replacement therapy, investigate extent which these are explained by reduced caloric intake. Design Ultrahigh performance liquid chromatography-tandem mass spectroscopy (UPLC-MS/MS)...
Abstract Disruption of brain-expressed G protein-coupled receptor-10 (GPR10) causes obesity in animals. Here, we identify multiple rare variants GPR10 people with severe and normal weight controls. These impair ligand binding protein-dependent signalling cells. Transgenic mice harbouring a loss function variant found an individual obesity, gain excessive due to decreased energy expenditure rather than increased food intake. This evidence supports role for human homeostasis. Therapeutic...
Disruption of hypothalamic melanocortin 4 receptors (MC4Rs) causes obesity in mice and humans. Here, we investigated the transcriptional regulation MC4R hypothalamus. In mice, show that homeodomain transcription factor Orthopedia (OTP) is enriched neurons paraventricular nucleus (PVN) hypothalamus directly regulates Mc4r transcription. Deletion Otp PVN during development or adulthood reduced expression, causing increased food intake obesity. humans, four five carriers rare predicted...
The cooperation of transcriptional and post-transcriptional levels control to shape gene regulation is only partially understood. Here we show that a combination two simple non-invasive genomic techniques, coupled with kinetic mathematical modeling, affords insight into the intricate dynamics RNA in response oxidative stress fission yeast Schizosaccharomyces pombe. This study reveals dominant role stress, but also points first minutes after induction as critical time when coordinated mRNA...
Declined memory is a hallmark of Alzheimer’s disease (AD). Experiments in rodents and human postmortem studies suggest that serotonin (5-hydroxytryptamine, 5-HT) plays role memory, but the underlying mechanisms are unknown. Here, we investigate 5-HT 2C receptor (5-HT R) regulating memory. Transgenic mice expressing humanized HTR2C mutation exhibit impaired plasticity hippocampal ventral CA1 (vCA1) neurons reduced Further, project to synapse onto vCA1 neurons. Disruption synthesis...
Abstract Context Genetic variants affecting the nuclear hormone receptor coactivator steroid coactivator, SRC-1, have been identified in people with severe obesity and impair melanocortin signaling cells mice. As a result, obese patients SRC-1 deficiency are being treated 4 agonist clinical trials. Objective Here, our aim was to comprehensively describe characterize phenotype of variant carriers facilitate diagnosis management. Methods In genetic studies 2462 obesity, we 23 rare heterozygous...
Abstract Background Inferring molecular pathway activity is an important step towards reducing the complexity of genomic data, understanding heterogeneity in clinical outcome, and obtaining correlates cancer imaging traits. Increasingly, approaches inference combine profiles (e.g gene or protein expression) with independent highly curated structural interaction data networks) more generally prior knowledge databases. However, it unclear how best to use information context any given study....
Genes for the production of a broad range fungal secondary metabolites are frequently colinear. The prevalence such gene clusters was systematically examined across genome cereal pathogen Fusarium graminearum. topological structure transcriptional networks also to investigate control mechanisms mycotoxin biosynthesis and other processes. genes associated with processes were identified, genomic location transcription-associated proteins (TAPs) analyzed in conjunction locations exhibiting...
The discovery of human obesity-associated genes can reveal new mechanisms to target for weight loss therapy. Genetic studies obese individuals and the analysis rare genetic variants identify novel genes. However, establishing a functional relationship between these candidate adiposity remains significant challenge. We uncovered large number homozygous gene by exome sequencing severely children, including those from consanguineous families. By assessing function in vivo Drosophila , we...
Hypoxia imaging is a promising tool for targeted therapy but the links between features and underlying molecular characteristics of tumour have not been investigated. The aim this study was to compare hypoxia biomarkers gene expression in oropharyngeal squamous cell carcinoma (OPSCC) diagnostic biopsies with imaged 64Cu-ATSM PET/CT. imaging, clinical data were obtained 15 patients. Primary SUVmax, muscle ratio (TMR) hypoxic volume tested association reported signatures biopsies. A putative...