PGRMC1 phosphorylation affects cell shape, motility, glycolysis, mitochondrial form and function, and tumor growth.

BackgroundProgesterone Receptor Membrane Component 1 (PGRMC1) is expressed in many cancer cells, where it is associated with detrimental patient outcomes. It contains phosphorylated tyrosines which evolutionarily preceded deuterostome gastrulation and tissue differentiation mechanisms.ResultsWe demonstrate that manipulating PGRMC1 phosphorylation status in MIA PaCa-2 (MP) cells imposes broad pleiotropic effects. Relative to parental cells over-expressing hemagglutinin-tagged wild-type (WT) PGRMC1-HA, cells expressing a PGRMC1-HA-S57A/S181A double mutant (DM) exhibited reduced levels of proteins involved in energy metabolism and mitochondrial function, and altered glucose metabolism suggesting modulation of the Warburg effect. This was associated with increased PI3K/AKT activity, altered cell shape, actin cytoskeleton, motility, and mitochondrial properties. An S57A/Y180F/S181A triple mutant (TM) indicated the involvement of Y180 in PI3K/AKT activation. Mutation of Y180F strongly attenuated subcutaneous xenograft tumor growth in NOD-SCID gamma mice. Elsewhere we demonstrate altered metabolism, mutation incidence, and epigenetic status in these cells.ConclusionsAltogether, these results indicate that mutational manipulation of PGRMC1 phosphorylation status exerts broad pleiotropic effects relevant to cancer and other cell biology

Long-term nitrogen dioxide exposure assessment using back-extrapolation of satellite-based land-use regression models for Australia

Hewson, MG ORCiD: 0000-0002-5212-3921Assessing historical exposure to air pollution in epidemiological studies is often problematic because of limited spatial and temporal measurement coverage. Several methods for modelling historical exposures have been described, including land-use regression (LUR). Satellite-based LUR is a recent technique that seeks to improve predictive ability and spatial coverage of traditional LUR models by using satellite observations of pollutants as inputs to LUR. Few studies have explored its validity for assessing historical exposures, reflecting the absence of historical observations from popular satellite platforms like Aura (launched mid-2004). We investigated whether contemporary satellite-based LUR models for Australia, developed longitudinally for 2006–2011, could capture nitrogen dioxide (NO2) concentrations during 1990–2005 at 89 sites around the country. We assessed three methods to back-extrapolate year-2006 NO2 predictions: (1) ‘do nothing’ (i.e., use the year-2006 estimates directly, for prior years); (2) change the independent variable ‘year’ in our LUR models to match the years of interest (i.e., assume a linear trend prior to year-2006, following national average patterns in 2006–2011), and; (3) adjust year-2006 predictions using selected historical measurements. We evaluated prediction error and bias, and the correlation and absolute agreement of measurements and predictions using R2 and mean-square error R2 (MSE-R2), respectively. We found that changing the year variable led to best performance; predictions captured between 41% (1991; MSE-R2 = 31%) and 80% (2003; MSE-R2 = 78%) of spatial variability in NO2 in a given year, and 76% (MSE-R2 = 72%) averaged over 1990–2005. We conclude that simple methods for back-extrapolating prior to year-2006 yield valid historical NO2 estimates for Australia during 1990–2005. These results suggest that for the time scales considered here, satellite-based LUR has a potential role to play in long-term exposure assessment, even in the absence of historical predictor data. © 2018 Elsevier Inc

Long-term nitrogen dioxide exposure assessment using back-extrapolation of satellite-based land-use regression models for Australia

Assessing historical exposure to air pollution in epidemiological studies is often problematic because of limited spatial and temporal measurement coverage. Several methods for modelling historical exposures have been described, including land-use regression (LUR). Satellite-based LUR is a recent technique that seeks to improve predictive ability and spatial coverage of traditional LUR models by using satellite observations of pollutants as inputs to LUR. Few studies have explored its validity for assessing historical exposures, reflecting the absence of historical observations from popular satellite platforms like Aura (launched mid-2004). We investigated whether contemporary satellite-based LUR models for Australia, developed longitudinally for 2006–2011, could capture nitrogen dioxide (NO2) concentrations during 1990–2005 at 89 sites around the country. We assessed three methods to back-extrapolate year-2006 NO2 predictions: (1) ‘do nothing’ (i.e., use the year-2006 estimates directly, for prior years); (2) change the independent variable ‘year’ in our LUR models to match the years of interest (i.e., assume a linear trend prior to year-2006, following national average patterns in 2006–2011), and; (3) adjust year-2006 predictions using selected historical measurements. We evaluated prediction error and bias, and the correlation and absolute agreement of measurements and predictions using R2 and mean-square error R2 (MSE-R2), respectively. We found that changing the year variable led to best performance; predictions captured between 41% (1991; MSE-R2 = 31%) and 80% (2003; MSE-R2 = 78%) of spatial variability in NO2 in a given year, and 76% (MSE-R2 = 72%) averaged over 1990–2005. We conclude that simple methods for back-extrapolating prior to year-2006 yield valid historical NO2 estimates for Australia during 1990–2005. These results suggest that for the time scales considered here, satellite-based LUR has a potential role to play in long-term exposure assessment, even in the absence of historical predictor data. © 2018 Elsevier Inc

Independent validation of national satellite-based land-use regression models for nitrogen dioxide using passive samplers

Including satellite observations of nitrogen dioxide (NO2) in land-use regression (LUR) models can improve their predictive ability, but requires rigorous evaluation. We used 123 passive NO2 samplers sited to capture within-city and near-road variability in two Australian cities (Sydney and Perth) to assess the validity of annual mean NO2 estimates from existing national satellite-based LUR models (developed with 68 regulatory monitors). The samplers spanned roadside, urban near traffic (≤100 m to a major road), and urban background (>100 m to a major road) locations. We evaluated model performance using R2 (predicted NO2 regressed on independent measurements of NO2), mean-square-error R2 (MSE-R2), RMSE, and bias. Our models captured up to 69% of spatial variability in NO2 at urban near-traffic and urban background locations, and up to 58% of variability at all validation sites, including roadside locations. The absolute agreement of measurements and predictions (measured by MSE-R2) was similar to their correlation (measured by R2). Few previous studies have performed independent evaluations of national satellite-based LUR models, and there is little information on the performance of models developed with a small number of NO2 monitors. We have demonstrated that such models are a valid approach for estimating NO2 exposures in Australian cities

LobSig is a multigene predictor of outcome in invasive lobular carcinoma

Invasive lobular carcinoma (ILC) is the most common special type of breast cancer, and is characterized by functional loss of E-cadherin, resulting in cellular adhesion defects. ILC typically present as estrogen receptor positive, grade 2 breast cancers, with a good short-term prognosis. Several large-scale molecular profiling studies have now dissected the unique genomics of ILC. We have undertaken an integrative analysis of gene expression and DNA copy number to identify novel drivers and prognostic biomarkers, using in-house (n = 25), METABRIC (n = 125) and TCGA (n = 146) samples. Using in silico integrative analyses, a 194-gene set was derived that is highly prognostic in ILC (P = 1.20 × 10-5)-we named this metagene 'LobSig'. Assessing a 10-year follow-up period, LobSig outperformed the Nottingham Prognostic Index, PAM50 risk-of-recurrence (Prosigna), OncotypeDx, and Genomic Grade Index (MapQuantDx) in a stepwise, multivariate Cox proportional hazards model, particularly in grade 2 ILC cases (χ 2, P = 9.0 × 10-6), which are difficult to prognosticate clinically. Importantly, LobSig status predicted outcome with 94.6% accuracy amongst cases classified as 'moderate-risk' according to Nottingham Prognostic Index in the METABRIC cohort. Network analysis identified few candidate pathways, though genesets related to proliferation were identified, and a LobSig-high phenotype was associated with the TCGA proliferative subtype (χ 2, P < 8.86 × 10-4). ILC with a poor outcome as predicted by LobSig were enriched with mutations in ERBB2, ERBB3, TP53, AKT1 and ROS1. LobSig has the potential to be a clinically relevant prognostic signature and warrants further development