A5056622062- Cancer Genomics and Diagnostics
- Genetic factors in colorectal cancer
- Advanced Proteomics Techniques and Applications
- vaccines and immunoinformatics approaches
- CRISPR and Genetic Engineering
- DNA Repair Mechanisms
- Genomics and Rare Diseases
- Bioinformatics and Genomic Networks
- Lung Cancer Treatments and Mutations
- Molecular Biology Techniques and Applications
- Mass Spectrometry Techniques and Applications
- Gene expression and cancer classification
- Peptidase Inhibition and Analysis
- Viral Infections and Immunology Research
- Multiple Myeloma Research and Treatments
- Ubiquitin and proteasome pathways
- Renal and related cancers
- Advanced Biosensing Techniques and Applications
- Cancer Diagnosis and Treatment
- Ear and Head Tumors
- Malaria Research and Control
- Metabolomics and Mass Spectrometry Studies
- Pluripotent Stem Cells Research
- Monoclonal and Polyclonal Antibodies Research
- Pancreatic and Hepatic Oncology Research
University of Cambridge
2020-2024
Wellcome Sanger Institute
2019-2024
National Institute for Health Research
2024
Cancer Research UK Cambridge Center
2022-2024
Hutchison/MRC Research Centre
2020-2024
Medical Genetics Center
2023
MRC Cancer Unit
2020-2021
Addenbrooke's Hospital
2020
ETH Zurich
2014-2019
Heidelberg University
2014
Abstract Mass spectrometry is the method of choice for deep and reliable exploration (human) proteome. Targeted mass reliably detects quantifies pre-determined sets proteins in a complex biological matrix used studies that rely on quantitatively accurate reproducible measurement across multiple samples. It requires one-time, priori generation specific assay each targeted protein. SWATH-MS spectrometric combines data-independent acquisition (DIA) data analysis vastly extends throughput can be...
Whole-genome sequencing (WGS) permits comprehensive cancer genome analyses, revealing mutational signatures, imprints of DNA damage and repair processes that have arisen in each patient's cancer. We performed signature analyses on 12,222 WGS tumor-normal matched pairs, from patients recruited via the UK National Health Service. contrasted our results to two independent datasets, International Cancer Genome Consortium (ICGC) Hartwig Foundation, involving 18,640 cancers total. Our add 40...
We present a novel mass spectrometry-based high-throughput workflow and an open-source computational data resource to reproducibly identify quantify HLA-associated peptides. Collectively, the resources support generation of HLA allele-specific peptide assay libraries consisting consensus fragment ion spectra, analysis quantitative digital maps peptidomes generated from range biological sources by SWATH spectrometry (MS). This study represents first community-based effort develop robust...
Abstract The chemotherapeutic agent CX-5461, or pidnarulex, has been fast-tracked by the United States Food and Drug Administration for early-stage clinical studies of BRCA1- , BRCA2- PALB2 -mutated cancers. It is under investigation in phase I II trials. Here, we find that, although CX-5461 exhibits synthetic lethality BRCA1-/BRCA2 -deficient cells, it also causes extensive, nonselective, collateral mutagenesis all three cell lines tested, to magnitudes that exceed known environmental carcinogens.
Here we describe a proteomic data resource for the NCI-60 cell lines generated by pressure cycling technology and SWATH mass spectrometry. We developed DIA-expert software to curate visualize data, leading reproducible detection of over 3,100 SwissProt proteotypic proteins systematic quantification pathway activities. Stoichiometric relationships interacting DNA replication, repair, chromatin remodeling NuRD complex, β-catenin, RNA metabolism, prefoldins are more evident than that at mRNA...
Abstract Identifying potential protein-ligand interactions is central to the field of drug discovery as it facilitates identification novel leads, contributes advancement from hits predicts off-target explanations for side effects approved drugs or candidates, well de-orphans phenotypic hits. For rapid interactions, we here present a chemogenomics algorithm prediction using new machine learning approach and class descriptor. The applies Bayesian Additive Regression Trees (BART) on newly...
The reproducible and efficient extraction of proteins from biopsy samples for quantitative analysis is a critical step in biomarker translational research. Recently, we described method consisting pressure-cycling technology (PCT) sequential windowed acquisition all theoretical fragment ions-mass spectrometry (SWATH-MS) the rapid quantification thousands biopsy-size tissue samples. As an improvement method, have incorporated PCT-MicroPestle into PCT-SWATH workflow. novel, miniaturized,...
Abstract The mechanisms that underpin how insertions or deletions (indels) become fixed in DNA have primarily been ascribed to replication-related and/or double-strand break (DSB)-related processes. Here, we introduce a method evaluate indels, orientating them relative gene transcription. In so doing, reveal number of surprising findings: First, there is transcriptional strand asymmetry the distribution mononucleotide repeat tracts reference human genome. Second, strong indels across 2,575...
Xeroderma pigmentosum (XP) is caused by defective nucleotide excision repair of DNA damage. This results in hypersensitivity to ultraviolet light and increased skin cancer risk, as sunlight-induced photoproducts remain unrepaired. However, many XP patients also display early-onset neurodegeneration, which leads premature death. The mechanism neurodegeneration unknown. Here, we investigate using pluripotent stem cells derived from healthy relatives, performing functional multi-omics on...
Abstract Pairwise perturbation of gene function using the CRISPR/Cas9 system has huge potential in screening for genetic interactions and synthetic lethal pairs to identify novel combination therapies cancer. However, existing dual guide expression systems are cumbersome clone, often result a large proportion undesired have imbalance from two positions. Here, we demonstrate next-generation delivery based around tRNA spacer that allows single step cloning strategy, as little 2% pairs, highly...
Summary We describe the rapid and reproducible acquisition of quantitative proteome maps for NCI-60 cancer cell lines their use to reveal biology drug response determinants. Proteome datasets 60 were acquired in duplicate within 30 working days using pressure cycling technology SWATH mass spectrometry. consistently quantified 3,171 SwissProt proteotypic proteins across all lines, generating a data matrix with 0.1% missing values, allowing analyses protein complexes pathway activities cells....
Summary Human Induced Pluripotent Stem Cells (hiPSC) are an established patient-specific model system where opportunities emerging for cell-based therapies. We contrast hiPSCs derived from different tissues, skin and blood, in the same individual. show extensive single-nucleotide mutagenesis all hiPSC lines, although fibroblast-derived (F-hiPSCs) particularly heavily mutagenized by ultraviolet(UV)-related damage. utilize genome sequencing data on 454 F-hiPSCs 44 blood-derived (B-hiPSCs) to...
Abstract Metastatic malignant cylindroma (MC) is a rare skin appendageal cancer for which there are no licensed chemotherapeutic interventions and has poor clinical outcomes. MC arising in CYLD cutaneous syndrome (CCS) been shown to carry pathogenic variants additional driver mutations TP53. Here we present whole-genome sequencing (WGS) data from 29-year-old man, revealing novel clinically targetable somatic mutation. The proband presented with growing, ulcerated on the scalp at 28 years of...