Biology subjects

Elliott, P.

Publications and source records attributed to Elliott, P..

4 recordsLinked to original sources

bioRxiv2018

Determinants of accelerated metabolomic and epigenetic ageing in a UK cohort

Markers of biological ageing have potential utility in primary care and public health. We developed an elastic net regression model of age based on untargeted metabolic profiling across multiple platforms, including nuclear magnetic resonance spectroscopy and liquid chromatography-mass spectrometry in urine and serum (almost 100,000 features assayed), within a large sample (N=2,239) from the UK occupational Airwave cohort. We investigated the determinants of accelerated ageing, including genetic, lifestyle and psychological risk factors for premature mortality. The metabolomic age model was well correlated with chronological age (r=0.85 in independent test set). Increased metabolomic age acceleration (mAA) was associated (p<0.0025) with overweight/obesity and depression and nominally associated (p<0.05) with high alcohol use and low income. DNA methylation age acceleration (N=1,102) was nominally associated (p<0.05) with high alcohol use, anxiety and post-traumatic stress disorder, but not correlated with mAA. Biological age acceleration may present an important mechanism linking psycho-social stress to age-related disease.

epidemiology↗

bioRxiv2018

CTC Marker CD117/c-kit Represents a Prostate Cancer Stem-Like Subpopulation Driving Progression, Migration, and TKI Resistance

Cancer stem-like cells (CSCs) are associated with cancer progression, metastasis, and recurrence, and may also represent a subset of circulating tumor cells (CTCs). In our prior study, CTCs in advanced prostate cancer patients were found to express CD117/c-kit in a liquid biopsy. Whether CD117 expression played an active or passive role in the aggressiveness and migration of these CTCs remained an open question. In this study, we show that CD117 expression in prostate cancer patients is associated with decreased overall and progression-free survival and that activation and phosphorylation of CD117 increases in prostate cancer patients with higher Gleason grades. To determine how CD117 expression and activation by its ligand stem cell factor (SCF, kit ligand, steel factor) alter prostate cancer aggressiveness, we used LNCaP-C4-2 and PC3-mm human prostate cancer cells, which contain a CD117+ subpopulation. We demonstrate that CD117+ cells display increased proliferation and migration. In prostaspheres, CD117 expression enhances sphere formation. In both 2D and 3D cultures, stemness marker gene expression is higher in CD117+ cells. Using xenograft limiting dilution assays and serial tumor initiation assays, we show that CD117+ cells represent a CSC population. Combined, these data indicate that CD117 expression potentially promotes tumor initiation and metastasis. Further, in cell lines, CD117 activation by SCF promotes faster proliferation and invasiveness, while blocking CD117 activation with tyrosine kinase inhibitors (TKIs) decreased progression in a context-dependent manner. We demonstrate that CD117 expression and activation drives prostate cancer aggressiveness through the CSC phenotype and TKI resistance.

cancer biology↗

bioRxiv2017

Genetic architecture of early childhood growth phenotypes gives insights into their link with later obesity

Early childhood growth patterns are associated with adult metabolic health, but the underlying mechanisms are unclear. We performed genome-wide meta-analyses and follow-up in up to 22,769 European children for six early growth phenotypes derived from longitudinal data: peak height and weight velocities, age and body mass index (BMI) at adiposity peak (AP ~9 months) and rebound (AR ~5-6 years). We identified four associated loci (P< 5x10-8): LEPR/LEPROT with BMI at AP, FTO and TFAP2B with Age at AR and GNPDA2 with BMI at AR. The observed AR-associated SNPs at FTO, TFAP2B and GNPDA2 represent known adult BMI-associated variants. The common BMI at AP associated variant at LEPR/LEPROT was not associated with adult BMI but was associated with LEPROT gene expression levels, especially in subcutaneous fat (P<2x10-51). We identify strong positive genetic correlations between early growth and later adiposity traits, and analysis of the full discovery stage results for Age at AR revealed enrichment for insulin-like growth factor 1 (IGF-1) signaling and apolipoprotein pathways. This genome-wide association study suggests mechanistic links between early childhood growth and adiposity in later childhood and adulthood, highlighting these early growth phenotypes as potential targets for the prevention of obesity.

genomics↗

bioRxiv2017

Novel Repolarisation Metric Predicts Arrhythmia Origin And Clinical Events In ARVC And Brugada Syndrome

Structured abstractO_ST_ABSBackgroundC_ST_ABSInitiation of re-entrant ventricular tachycardia (VT) involves complex interactions between activation (AT) and repolarization times (RT). The re-entry vulnerability index (RVI) is a recently proposed activation-repolarization metric designed to quantify tissue susceptibility to re-entry.\n\nObjectivesThe study aimed to test the feasibility of an RVI-based algorithm to predict the exit site of VT and occurrence of clinical events.\n\nMethodsPatients with Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) (n=11), Brugada Syndrome (BrS) (n=13) and focal RV outflow tract VT (n=9) underwent programmed stimulation with unipolar electrograms recorded from a non-contact array. The distance between region of lowest RVI and site of VT breakout (Dmin), and global minimum RVI (RVIG) were computed to assess prediction of site of VT breakout and occurrence of clinical events, respectively.\n\nResultsLowest values of RVI, representing sites of highest susceptibility to re-entry, co-localised with site of VT breakout in ARVC/BrS but not in focal VT and Dmin values were lower in ARVC/BrS. ARVC/BrS patients with inducible VT had lower RVIG than those who were non-inducible or those with focal VT. Patients were followed up for 112 {+/-} 19 months; those with clinical VT events had lower RVIg than those without VT or those with focal VT.\n\nConclusionsThe proposed methodology based on RVI localises the origin of re-entrant but not focal ventricular arrhythmias and predicts clinical events. This index could be applied to target ablation for arrhythmias which are difficult to induce or are haemodynamically unstable and also risk stratify patients for ICD prophylaxis.\n\nAbbreviations list

physiology↗