A5033882151- Estrogen and related hormone effects
- Advanced Breast Cancer Therapies
- Cancer, Lipids, and Metabolism
- Lung Cancer Research Studies
- Cancer, Hypoxia, and Metabolism
- Cancer Cells and Metastasis
- Cancer Mechanisms and Therapy
- PI3K/AKT/mTOR signaling in cancer
- Neural Networks and Applications
- Renal and related cancers
- Prostate Cancer Treatment and Research
- Infant Nutrition and Health
- Hepatocellular Carcinoma Treatment and Prognosis
- Cancer Genomics and Diagnostics
- Protein Degradation and Inhibitors
- Angiogenesis and VEGF in Cancer
- Pluripotent Stem Cells Research
- Epigenetics and DNA Methylation
- Lung Cancer Treatments and Mutations
- Prostate Cancer Diagnosis and Treatment
- Enzyme function and inhibition
- Tissue Engineering and Regenerative Medicine
- Breastfeeding Practices and Influences
- Computational Drug Discovery Methods
- Receptor Mechanisms and Signaling
AstraZeneca (United Kingdom)
2021-2024
Cancer Research UK Manchester Institute
2016-2023
Cancer Research UK
2022-2023
CRUK Lung Cancer Centre of Excellence
2022-2023
University of Manchester
2016-2022
Stanford University
2020
Newcastle University
2011-2014
Newcastle upon Tyne Hospital
2014
King's College London
2012
University Hospitals of Leicester NHS Trust
2012
Abstract Small cell lung cancer (SCLC) is characterized by prevalent circulating tumour cells (CTCs), early metastasis and poor prognosis. We show that SCLC patients (37/38) have rare CTC subpopulations co-expressing vascular endothelial-cadherin (VE-cadherin) cytokeratins consistent with vasculogenic mimicry (VM), a process whereby form ‘endothelial-like’ vessels. Single-cell genomic analysis reveals characteristic changes in both VE-cadherin-positive -negative CTCs. Higher levels of VM are...
Seven very low birthweight (less than 1.3 kg) preterm infants, aged between 3 and 6 weeks were fed raw, pasteurised, boiled human milk for consecutive weeks. Serial metabolic balance techniques used to assess the absorption retention of calcium, phosphorous, sodium, nitrogen, fat. Fat was reduced by approximately one-third when raw heated. It is suggested that improved fat from may be related preservation lipases. A reduction in amount N retained also noted infants milk. There no obvious...
BackgroundOver the past decade, numerous reports describe generation and increasing utility of non-small-cell lung cancer (NSCLC) patient-derived xenografts (PDX) from tissue biopsies. While PDX have proven useful for genetic profiling preclinical drug testing, requirement a biopsy limits available patient population, particularly those with advanced oligometastatic disease. Conversely, 'liquid biopsies' such as circulating tumour cells (CTCs) are minimally invasive easier to obtain. Here,...
Abstract Oral selective estrogen receptor degraders (SERD) could become the backbone of endocrine therapy (ET) for receptor–positive (ER+) breast cancer, as they achieve greater inhibition ER-driven cancers than current ETs and overcome key resistance mechanisms. In this study, we evaluated preclinical pharmacology efficacy next-generation oral SERD camizestrant (AZD9833) assessed ER–co-targeting strategies by combining with CDK4/6 inhibitors (CDK4/6i) PI3K/AKT/mTOR-targeted in models...
Primary culture and animal cell-line models of prostate bladder development have limitations in describing human biology, novel strategies that describe the full spectrum differentiation from foetal through to ageing tissue are required. Recent advances biology demonstrate direct reprogramming somatic cells into pluripotent embryonic stem cell (ESC)-like is possible. These cells, termed induced (iPSCs), could theoretically generate adult tissue, providing an alternative strategy study...
Sporadic mitochondrial DNA mutations serve as clonal marks providing access to the identity and lineage potential of stem cells within human tissues. By combining quantitative mapping with 3D reconstruction adult prostates, we show that multipotent basal cells, confined discrete niches in juxta-urethral ducts, generate bipotent progenitors directed epithelial migration streams. Basal are then dispersed throughout entire glandular network, dividing differentiating replenish loss apoptotic...
Abstract Small-cell lung cancer (SCLC) is an aggressive form of with dismal survival rates. While kinases often play key roles driving tumorigenesis, there are strikingly few known to promote the development SCLC. Here, we investigated contribution MAPK module MEK5–ERK5 SCLC growth. MEK5 and ERK5 were required for optimal expansion cell lines in vitro vivo. Transcriptomics analyses identified a role axis metabolism cells, including lipid metabolism. In-depth lipidomics showed that loss...
Abstract Background/objective To explore the anti-tumour activity of combining AKT inhibition and docetaxel in PTEN protein null WT prostate tumours. Methods Mechanisms associated with capivasertib treatment cancer were examined using a panel vivo tumour models cell lines. Results Combining had increased vivo. In vitro short-term caused cycle arrest majority cells. However, sub-population docetaxel-persister cells did not undergo G2/M but upregulated phosphorylation PI3K/AKT pathway...
More than 50% of human tumors display hyperactivation the serine/threonine kinase AKT. Despite evidence clinical efficacy, therapeutic window current generation AKT inhibitors could be improved. Here, we report development a second-generation degrader, INY-05-040, which outperformed catalytic inhibition with respect to cellular suppression AKT-dependent phenotypes in breast cancer cell lines. A growth screen 288 lines confirmed that INY-05-040 had substantially higher potency our...
In 1976 a human-milk bank was established at King's College Hospital to serve the neonatal intensive care unit. The is staffed by two part-time nurses, who interview prospective donors, organise collections, prepare samples for bacteriological screening, and process milk. On average 25 litres month may be collected from about 15 of which least two-thirds free enough bacteria fed raw (unheated) sick low-birth-weight infants. Most remainder used after holder pasteurisation. provides an...
Abstract Stem cells accumulate mitochondrial DNA (mtDNA) mutations resulting in an observable respiratory chain defect their progeny, allowing the mapping of stem cell fate. There is considerable uncertainty prostate epithelial biology where both basal and luminal have been described, this study clonal relationships within human layers were explored by tracing Fresh‐frozen formalin‐fixed histologically‐benign samples from 35 patients studied using sequential cytochrome c oxidase...
Vasculogenic mimicry (VM), the process of tumor cell transdifferentiation to endow endothelial-like characteristics supporting de novo vessel formation, is associated with poor prognosis in several types, including SCLC. In genetically engineered mouse models (GEMMs) SCLC, NOTCH, and MYC co-operate drive a neuroendocrine (NE) non-NE phenotypic switch, co-operation between NE cells required for metastasis. Here, we define phenotype VM-competent molecular mechanisms underpinning SCLC VM using...
Combining the selective AKT inhibitor, capivasertib, and SERD, fulvestrant improved PFS in a Phase III clinical trial (CAPItello-291), treating HR+ breast cancer patients following aromatase inhibitors, with or without CDK4/6 inhibitors. However, data suggests treatment may reduce response to subsequent monotherapy endocrine treatment. To support understanding of trials such as CAPItello-291 gain insight into this emerging population patients, we explored how inhibitor influences ER+ tumour...
Side population (SP) and ABC transporter expression enrich for stem cells in numerous tissues. We explored if this phenotype characterised human bladder cancer (CSCs) attempted to identify regulatory mechanisms. Focusing on non-muscle invasive (NMIBC), multiple cell lines were used characterise SP expression. In vitro vivo phenotypic functional assessments of CSC behaviour undertaken. Expression putative marker ABCG2 was assessed clinical NMIBC samples (n = 148), a role MAPK signalling,...
The lysine methyltransferase SETD6 modifies the histone variant H2AZ, a key component of nuclear receptor-dependent transcription. Herein, we report identification several factors that associate with and are implicated in hormone receptor signaling. Specifically, associates estrogen α (ERα), deacetylase HDAC1, metastasis protein MTA2, transcriptional co-activator TRRAP. Luciferase reporter assays identify as repressor, agreement its association HDAC1 MTA2. However, behaves...
Stem cells are thought to be the cell of origin in malignant transformation many tissues, but their role human prostate carcinogenesis continues debated. One conflicts with this model is that cancer stem have been described lack androgen receptor (AR) expression, which established importance initiation and progression. We re-examined expression patterns AR within adult epithelial differentiation using an optimised sensitive specific approach examining transcript, protein regulated gene...
Abstract BACKGROUND This study investigated whether the increase in serum prostate specific antigen (PSA) typically seen during male urinary tract infection (UTI) is incidental or reflects an innate defence mechanism of prostate. The protective roles whey‐acid‐motif‐4‐disulphide core (WFDC) proteins, secretory leukoproteinase inhibitor (SLPI) and WFDC2, were also examined. METHODS UTI recurrence was assessed retrospectively men following initial by patient interview. PSA, SLPI, WFDC2 gene...
There is considerable interest in the use of multi-potent stem cells kidney tissue regeneration. We studied if spermatogonial have ability to undergo differentiation. Spermatogonial cell differentiation was induced using vitro and ex vivo co-culture techniques. Conditioned media from human fibroblasts expression epithelial endothelial lineages cells, consistent with nephrogenesis. Furthermore, we showed that these up-regulated renal tubular-specific markers alkaline phosphatase,...
Functional networks play an important role in the analysis of biological processes and systems. The inference these from high-throughput (-omics) data is area intense research. So far, similarity-based paradigm (e.g. gene co-expression) has been most popular approach. It assumes a functional relationship between genes which are expressed at similar levels across different samples. An alternative to this relationships structure machine learning models. These models able capture complex...
<div>Abstract<p>Oral selective estrogen receptor degraders (SERD) could become the backbone of endocrine therapy (ET) for receptor–positive (ER<sup>+</sup>) breast cancer, as they achieve greater inhibition ER-driven cancers than current ETs and overcome key resistance mechanisms. In this study, we evaluated preclinical pharmacology efficacy next-generation oral SERD camizestrant (AZD9833) assessed ER–co-targeting strategies by combining with CDK4/6 inhibitors...
<p>Camizestrant has superior <i>in vivo</i> activity to fulvestrant in <i>ESR1</i>wt and <i>ESR1</i>m PDX models (<a href="#bib1" target="_blank">1</a>). <b>A,</b> Waterfall plot representing the growth of 28 ER<sup>+</sup> breast cancer treated with camizestrant 10 mg/kg daily; bars are colored according <i>ESR1</i> mutational status other genomic characteristics annotated at top. The percentage change...