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Differential Drug Survival of Biologic Therapies for the Treatment of Psoriasis: A Prospective Observational Cohort Study from the British Association of Dermatologists Biologic Interventions Register (BADBIR).
No full textDrug survival reflects a drug's effectiveness, safety, and tolerability. We assessed the drug survival of biologics used to treat psoriasis in a prospective national pharmacovigilance cohort (British Association of Dermatologists Biologic Interventions Register (BADBIR)). The survival rates of the first course of biologics for 3,523 biologic-naive patients with chronic plaque psoriasis were compared using survival analysis techniques and predictors of discontinuation analyzed using a multivariate Cox proportional hazards model. Data for patients on adalimumab (n=1,879), etanercept (n=1,098), infliximab (n=96), and ustekinumab (n=450) were available. The overall survival rate in the first year was 77%, falling to 53% in the third year. Multivariate analysis showed that female gender (hazard ratio (HR) 1.22; 95% confidence interval (CI): 1.09-1.37), being a current smoker (HR 1.19; 95% CI: 1.03-1.38), and a higher baseline dermatology life quality index (HR 1.01; 95% CI: 1.00-1.02) were predictors of discontinuation. Presence of psoriatic arthritis (HR 0.82; 95% CI: 0.71-0.96) was a predictor for drug survival. As compared with adalimumab, patients on etanercept (HR 1.63; 95% CI: 1.45-1.84) or infliximab (HR 1.56; 95% CI: 1.16-2.09) were more likely to discontinue therapy, whereas patients on ustekinumab were more likely to persist (HR 0.48; 95% CI: 0.37-0.62). After accounting for relevant covariates, ustekinumab had the highest first-course drug survival. The results of this study will aid clinical decision making when choosing biologic therapy for psoriasis patients
Covariation Is a Poor Measure of Molecular Coevolution.
No full textRecent developments in the analysis of amino acid covariation are leading to breakthroughs in protein structure prediction, protein design, and prediction of the interactome. It is assumed that observed patterns of covariation are caused by molecular coevolution, where substitutions at one site affect the evolutionary forces acting at neighboring sites. Our theoretical and empirical results cast doubt on this assumption. We demonstrate that the strongest coevolutionary signal is a decrease in evolutionary rate and that unfeasibly long times are required to produce coordinated substitutions. We find that covarying substitutions are mostly found on different branches of the phylogenetic tree, indicating that they are independent events that may or may not be attributable to coevolution. These observations undermine the hypothesis that molecular coevolution is the primary cause of the covariation signal. In contrast, we find that the pairs of residues with the strongest covariation signal tend to have low evolutionary rates, and that it is this low rate that gives rise to the covariation signal. Slowly evolving residue pairs are disproportionately located in the protein's core, which explains covariation methods' ability to detect pairs of residues that are close in three dimensions. These observations lead us to propose the "coevolution paradox": The strength of coevolution required to cause coordinated changes means the evolutionary rate is so low that such changes are highly unlikely to occur. As modern covariation methods may lead to breakthroughs in structural genomics, it is critical to recognize their biases and limitations
Rethinking 'academic' drug discovery:the Manchester Institute perspective
No full textThe contraction in research within pharma has seen a renaissance in drug discovery within the academic setting. Often, groups grow organically from academic research laboratories, exploiting a particular area of novel biology or new technology. However, increasingly, new groups driven by industrial staff are emerging with demonstrable expertise in the delivery of medicines. As part of a strategic review by Cancer Research UK (CR-UK), the drug discovery team at the Manchester Institute was established to translate novel research from the Manchester cancer research community into drug discovery programmes. From a standing start, we have taken innovative approaches to solve key issues faced by similar groups, such as hit finding and target identification. Herein, we share our lessons learnt and successful strategies.</p
RM-ly work in progress: some current whats and hows from our interdisciplinary, collaborative work to date
No full textA caveolin-dependent and PI3K/AKT-independent role of PTEN in β-catenin transcriptional activity.
No full textLoss of the tumour suppressor PTEN is frequent in human melanoma, results in MAPK activation, suppresses senescence and mediates metastatic behaviour. How PTEN loss mediates these effects is unknown. Here we show that loss of PTEN in epithelial and melanocytic cell lines induces the nuclear localization and transcriptional activation of β-catenin independent of the PI3K-AKT-GSK3β axis. The absence of PTEN leads to caveolin-1 (CAV1)-dependent β-catenin transcriptional modulation in vitro, cooperates with NRAS(Q61K) to initiate melanomagenesis in vivo and induces efficient metastasis formation associated with E-cadherin internalization. The CAV1-β-catenin axis is mediated by a feedback loop in which β-catenin represses transcription of miR-199a-5p and miR-203, which suppress the levels of CAV1 mRNA in melanoma cells. These data reveal a mechanism by which loss of PTEN increases CAV1-mediated dissociation of β-catenin from membranous E-cadherin, which may promote senescence bypass and metastasis
Evaluating the impacts of re-vegetation of bare peat on blanket peat water tables
No full textStudies of the hydrological impacts of peat restoration in blanket peat systems have focused on the impacts of drain and gully blocking on water tables. However, in the South Pennines of the UK large areas of previously bare blanket peat have been restored by re-vegetation. The effects of this restoration treatment on water table behaviour have not been fully evaluated. Preliminary data from space-for-time studies indicate that re-vegetation leads to significant rises in water tables and decreases in water table variability. Here we present additional data from a before-after-control-intervention (BACI) study to validate these preliminary observations. We also present meteorological, net radiation and evapotranspiration data to test the hypothesis that water table changes associated with re-vegetation are driven by changing evapotranspiration rates as bare peat surfaces re-vegetate. The wider ecosystem service benefits of water table increases associated with re-vegetation of bare peat are discussed
A real-time fast radio burst: polarization detection and multiwavelength follow-up
No full textFast radio bursts (FRBs) are one of the most tantalizing mysteries of the radio sky; their progenitors and origins remain unknown and until now no rapid multiwavelength follow-up of an FRB has been possible. New instrumentation has decreased the time between observation and discovery from years to seconds, and enables polarimetry to be performed on FRBs for the first time. We have discovered an FRB (FRB 140514) in real-time on 2014 May 14 at 17:14:11.06 UTC at the Parkes radio telescope and triggered follow-up at other wavelengths within hours of the event. FRB 140514 was found with a dispersion measure (DM) of 562.7(6) cm-3 pc, giving an upper limit on source redshift of z ≲ 0.5. FRB 140514 was found to be 21 ± 7 per cent (3σ) circularly polarized on the leading edge with a 1σ upper limit on linear polarizatio
Interim Report 2: WP2-Part A "ENWL area demand response quantification: Methodology and first results"
No full textThis document presents the progress of WP2 Task 1.2. In particular, the methodology developed to estimate the demand response (DR) of primary substations for which no network models are available is illustrated adopting Egremont as case study. Thereafter, by applying this methodology to the whole ENWL fleet of primary substations, the aggregated DR that can be provide to National Grid is estimated at half hour resolution for two typical days. Both simulated-based (i.e., from WP2 Part A) and measurement-based load models (i.e., from WP1) were adopted
