A5071077684- Ovarian cancer diagnosis and treatment
- PARP inhibition in cancer therapy
- Cancer Mechanisms and Therapy
- RNA modifications and cancer
- Cancer Genomics and Diagnostics
- HER2/EGFR in Cancer Research
- Virus-based gene therapy research
- CRISPR and Genetic Engineering
- Renal cell carcinoma treatment
- Chromatin Remodeling and Cancer
- Digestive system and related health
- Wnt/β-catenin signaling in development and cancer
- Diet and metabolism studies
- Renal and related cancers
- Endometrial and Cervical Cancer Treatments
- Endometriosis Research and Treatment
- Cancer-related Molecular Pathways
- Lung Cancer Treatments and Mutations
- Cancer-related gene regulation
- Genetic factors in colorectal cancer
- Ferroptosis and cancer prognosis
- Diet, Metabolism, and Disease
- Kruppel-like factors research
- Amino Acid Enzymes and Metabolism
- Epigenetics and DNA Methylation
Imperial College London
2016-2025
Hammersmith Hospital
2014-2024
Alexandria University
2012-2024
Center for Human Reproduction
2023
Imperial College Healthcare NHS Trust
2015-2022
Queen Charlotte's and Chelsea Hospital
2021
The London College
2018-2020
Johns Hopkins University
2016
Royal Marsden Hospital
2010-2016
National Cancer Institute
2016
The Krebs cycle enzyme fumarate hydratase (FH) is a human tumor suppressor whose inactivation associated with the development of leiomyomata, renal cysts, and tumors. It has been proposed that activation hypoxia inducible factor (HIF) by fumarate-mediated inhibition HIF prolyl hydroxylases drives oncogenesis. Using mouse model, we provide genetic evidence Fh1-associated cyst formation Hif independent, as striking upregulation antioxidant signaling pathways revealed gene expression profiling....
Germline mutations in the FH gene encoding Krebs cycle enzyme fumarate hydratase predispose to hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome. FH-deficient cells tissues accumulate high levels of fumarate, which may act as an oncometabolite contribute tumourigenesis. A recently proposed role for covalent modification cysteine residues S-(2-succinyl) (2SC) (termed protein succination) prompted us assess 2SC our existing models HLRCC. Herein, using a previously characterized...
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is known for specifically killing cancer cells, whereas in resistant cancers, TRAIL/TRAIL-R can promote metastasis via Rac1 and PI3K. It remains unknown, however, whether to what extent signaling cells affect the immune microenvironment. Here we show that TRAIL-triggered cytokine secretion from TRAIL-resistant FADD dependent identify TRAIL-induced secretome drive monocyte polarization myeloid-derived suppressor (MDSCs)...
To identify therapeutic targets in ovarian clear cell carcinomas, a chemoresistant and aggressive type of cancer.Twelve carcinoma lines were subjected to tiling path microarray comparative genomic hybridization genome-wide expression profiling analysis. Regions high-level amplification defined genes whose levels determined by copy number correlated with gene identified. The effects inhibition PPM1D assessed using short hairpin RNA constructs small-molecule inhibitor (CCT007093). prevalence...
Survival from ovarian cancer (OC) is improved with surgery, but surgery can be complex and tumour identification, especially for borderline tumours (BOT), challenging. The Rapid Evaporative Ionisation Mass Spectrometric (REIMS) technique reports tissue histology in real-time by analysing aerosolised during electrosurgical dissection. Aerosol produced diathermy of tissues was sampled the REIMS interface. Histological diagnosis mass spectra featuring lipid species populated a reference...
Abstract Purpose: Ovarian clear cell carcinomas (OCCC) are a drug-resistant and aggressive type of epithelial ovarian cancer. We analyzed the molecular genetic profiles OCCCs to determine whether distinct genomic subgroups exist. Experimental design: Fifty pure primary were subjected high-resolution microarray-based comparative hybridization (aCGH). Unsupervised hierarchical clustering using Ward's linkage analysis was performed identify OCCCs. Survival Kaplan–Meier method log-rank test....
RNA-binding proteins (RBPs) are increasingly identified as post-transcriptional drivers of cancer progression. The RBP LARP1 is an mRNA stability regulator, and elevated expression the protein in hepatocellular lung cancers correlated with adverse prognosis. associates interactome that enriched for oncogenic transcripts. Here we explore role epithelial ovarian cancer, a disease characterized by rapid acquisition resistance to chemotherapy through induction pro-survival signalling. We show,...
Pulmonary arterial hypertension (PAH) is a disease of progressive vascular remodeling, characterized by dysregulated growth pulmonary cells and inflammation. A prevailing view that abnormal cellular metabolism, notably aerobic glycolysis increases glucose demand, underlies the pathogenesis PAH. Increased lung uptake has been reported in animal models. Few data exist from patients with PAH.Dynamic positron emission tomography imaging fluorine-18-labeled 2-fluoro-2-deoxyglucose ((18)FDG)...
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can induce apoptosis in many cancer cells without causing toxicity vivo. However, to date, TRAIL-receptor agonists have only shown limited therapeutic benefit clinical trials. This can, most likely, be attributed the fact that 50% of all cell lines and primary human cancers are TRAIL resistant. Consequently, future TRAIL-based therapies will require addition sensitizing agents remove crucial blocks pathway. Here, we identify...
Uncontrolled cell proliferation and cytoskeletal remodeling are responsible for tumor development ultimately metastasis. A number of studies have implicated microRNAs in the regulation cancer invasion migration. Here, we show that miR-23b regulates focal adhesion, spreading, cell-cell junctions formation lamellipodia breast (BC), implicating a central role it dynamics. Inhibition miR-23b, using specific sponge construct, leads to an increase migration metastatic spread vivo, indicating as...
The current study evaluated three biomarkers [homologous recombination deficiency (HRD), tumor BRCA1/2 (tBRCA) mutations, and CCNE1 copy-number variation (CNV)] in ovarian tumors from patients enrolled on the SCOTROC4 clinical trial for associations with outcome following carboplatin monotherapy. Ovarian (n = 250), high-grade serous (HGSOC) subgroup analysis 179) were classified as HRD positive (HRD score ≥42 or tBRCA mutation) amplification (CCNE1 CNV >2.4). Seventy-four (30%) positive,...
Abstract Context: Activation of the hypoxia-inducible transcription factors HIF-1 and HIF-2 a HIF-independent defect in developmental apoptosis have been implicated pathogenesis pheochromocytoma (PCC) associated with VHL, SDHB, SDHD mutations. Objective: Our objective was to compare protein (HIF-1α, EPAS1, JunB, CCND1, CD34, CLU) gene (VEGF, BNIP3) expression patterns VHL SDHB/D tumors. Results: Overexpression relatively more common than PCC (12 13 vs. 14 20, P = 0.02), whereas nuclear...
Leydig cell tumors (LCTs) are the most common non-germ-cell neoplasms of testis. LCTs often hormonally active and can result in precocious virilization or adult feminization. We identified an LCT affected individual from a kindred with hereditary leiomyomatosis renal cancer (HLRCC) germline fumarate hydratase (FH) mutation (N64T).Our objective was to investigate role FH mutations predisposition LCTs.We tested for pathogenic effects N64T screened additional 29 unselected alterations. also...
The identification of mutated metabolic enzymes in hereditary cancer syndromes has established a direct link between dysregulation and cancer. Mutations the Krebs cycle enzyme, fumarate hydratase (FH), predispose affected individuals to leiomyomas, renal cysts, cancers, though respective pathogenic roles mitochondrial cytosolic FH isoforms remain undefined. On basis comprehensive metabolomic analyses, we demonstrate that FH1-deficient cells tissues exhibit defects urea cycle/arginine...
Abstract We aimed to validate the prognostic association of p16 expression in ovarian high‐grade serous carcinomas (HGSC) and explore it other carcinoma histotypes. protein was assessed by clinical‐grade immunohistochemistry 6525 including 4334 HGSC using tissue microarrays from 24 studies participating Ovarian Tumor Tissue Analysis consortium. patterns were interpreted as abnormal (either overexpression referred block or absence) normal (heterogeneous). CDKN2A (which encodes p16) mRNA also...
Abstract Targeted inhibition of the ERK-MAPK pathway, upregulated in a majority human cancers, has been hindered clinic by drug resistance and toxicity. The MRAS-SHOC2-PP1 (SHOC2 phosphatase) complex plays key role RAF-ERK pathway activation dephosphorylating critical inhibitory site on RAF kinases. Here we show that genetic SHOC2 suppresses tumorigenic growth subset KRAS-mutant NSCLC cell lines prominently inhibits tumour development autochthonous murine KRAS-driven lung cancer models. On...
Recommendations are graded as per the Royal College of Obstetricians and Gynaecologists document, Clinical Governance Advice No. 1: Guidance for Development RCOG Green-top Guidelines, available on website at (see Supplementary Tables 1 2 below www.rcog.org.uk/rcog). Definitions certainty evidence based formal GRADE assessment within systematic reviews given in Table 3 [682GRADE Handbook.: Working Group; 2013. Available from:...
Solid pseudopapillary tumor (SPT) of the pancreas is an uncommon neoplasm uncertain lineage. They have been shown to express nuclear beta-catenin believed be due mutations gene. The aim this study was investigate status E-cadherin/catenin complex in SPTs. We studied expression 4 principal members using immunohistochemistry and E-cadherin gene by screening all exons for mutations, 6 cases SPT. In addition localization beta-catenin, we found tumors with complete absence membranous cytoplasmic...
Methods for lineage tracing of stem cell progeny in human tissues are currently not available. We describe a technique detecting the expansion single cell's that contain clonal mitochondrial DNA (mtDNA) mutations affecting expression mtDNA-encoded cytochrome c oxidase (COX). Because such take up to 40 years become phenotypically apparent, we believe these patches originate cells. Dual-color enzyme histochemistry was used identify COX-deficient cells, and were confirmed by microdissection...
Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is caused by mutations in the Krebs cycle enzyme fumarate hydratase (FH). It has been proposed that "pseudohypoxic" stabilization of hypoxia-inducible factor-α (HIF-α) accumulation contributes to tumorigenesis HLRCC. We hypothesized an additional direct consequence FH deficiency establishment a biosynthetic milieu. To investigate this hypothesis, we isolated primary mouse embryonic fibroblast (MEF) lines from Fh1-deficient mice. As...