Binding Affinity and Specificity of SH2 Domain Interactions in Receptor Tyrosine Kinase Signaling Networks

Receptor tyrosine kinase (RTK) signaling mechanisms play a central role in intracellular signaling and control development of multicellular organisms, cell growth, cell migration, and programmed cell death. Dysregulation of these signaling mechanisms results in defects of development and diseases such as cancer. Control of this network relies on the specificity and selectivity of Src Homology 2 (SH2) domain interactions with phosphorylated target peptides. In this work, we review and identify the limitations of current quantitative understanding of SH2 domain interactions, and identify severe limitations in accuracy and availability of SH2 domain interaction data. We propose a framework to address some of these limitations and present new results which improve the quality and accuracy of currently available data. Furthermore, we supplement published results with a large body of negative interactions of high-confidence extracted from rejected data, allowing for improved modeling and prediction of SH2 interactions. We present and analyze new experimental results for the dynamic response of downstream signaling proteins in response to RTK signaling. Our data identify differences in downstream response depending on the character and dose of the receptor stimulus, which has implications for previous studies using high-dose stimulation. We review some of the methods used in this work, focusing on pitfalls of clustering biological data, and address the high-dimensional nature of biological data from high-throughput experiments, the failure to consider more than one clustering method for a given problem, and the difficulty in determining whether clustering has produced meaningful results

3D Monte Carlo radiation transfer modelling of photodynamic therapy

We acknowledge the support of the UK Engineering and Physics Sciences Research Council (EPSRC) for funding through a studentship for C L Campbell as well as the Alfred Stewart Trust.The effects of ageing and skin type on Photodynamic Therapy (PDT) for different treatment methods have been theoretically investigated. A multilayered Monte Carlo Radiation Transfer model is presented where both daylight activated PDT and conventional PDT are compared. It was found that light penetrates deeper through older skin with a lighter complexion, which translates into a deeper effective treatment depth. The effect of ageing was found to be larger for darker skin types. The investigation further strengthens the usage of daylight as a potential light source for PDT where effective treatment depths of about 2 mm can be achieved.Publisher PD

The epidemiology of UK autoimmune liver disease varies with geographic latitude

BACKGROUND & AIMS: The epidemiology of autoimmune liver disease (AILD) is challenging to study because of the diseases’ rarity and because of cohort selection bias. Increased incidence farther from the Equator has been reported for multiple sclerosis, another autoimmune disease. We assessed the incidence of primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and autoimmune hepatitis (AIH) in relation to latitude. METHODS: We performed a retrospective cohort study using anonymized UK primary care records from January 1, 2002, to May 10, 2016. All adults without a baseline diagnosis of AILD were included and followed up until the first occurrence of an AILD diagnosis, death, or they left the database. Latitude was measured as registered general practice rounded down to whole degrees. RESULTS: The cohort included 8,590,421 records with 53.3 × 10(7) years of follow-up evaluation from 694 practices. There were 1314 incident cases of PBC, 396 of PSC, and 1034 of AIH. Crude incidences were as follows: PBC, 2.47 (95% CI, 2.34–2.60); PSC, 0.74 (95% CI, 0.67–0.82); and AIH, 1.94 (95% CI, 1.83–2.06) per 100,000 per year. PBC incidence correlated with female sex, smoking, and deprivation; PSC incidence correlated with male sex and non-smoking; AIH incidence correlated with female sex and deprivation. A more northerly latitude was associated strongly with incidence of PBC: 2.16 (95% CI, 1.79–2.60) to 4.86 (95% CI, 3.93–6.00) from 50°N to 57°N (P = .002) and incidence of AIH: 2.00 (95% CI, 1.65–2.43) to 3.28 (95% CI, 2.53–4.24) (P = .003), but not incidence of PSC: 0.82 (95% CI, 0.60–1.11) to 1.02 (95% CI, 0.64–1.61) (P = .473). Incidence after adjustment for age, sex, smoking, and deprivation status showed similar positive correlations for PBC and AIH with latitude, but not PSC. Incident AIH cases were younger at more northerly latitude. CONCLUSIONS: We describe an association in the United Kingdom between more northerly latitude and the incidence of PBC and AIH that requires both confirmation and explanation

A Continuous Improvement Journey in the Higher Education Sector: A Case Study of a University in Ireland

The paper’s purpose is to contribute to a developing literature in relation to Continuous Improvement (CI), incorporating Lean Six Sigma (LSS) in Higher Education Institutions (HEIs). This paper follows on from a previous study which focused on the initial steps taken by an Irish university on its CI journey by discussing the next steps, detailing the findings from these

The role of contraindications in prescribing anticoagulants to patients with atrial fibrillation::a cross-sectional analysis of primary care data in the UK

BackgroundUnderuse of anticoagulants in atrial fibrillation (AF) is an international problem, which has often been attributed to the presence of contraindications to treatment. No studies have assessed the influence of contraindications on anticoagulant prescribing in the UK.AimTo determine the influence of contraindications on anticoagulant prescribing in patients with AF in the UK.Design and settingCross-sectional analysis of primary care data from 645 general practices contributing to The Health Improvement Network, a large UK database of electronic primary care records.MethodTwelve sequential cross-sectional analyses were carried out from 2004 to 2015. Patients with a diagnosis of AF aged ≥35 years and registered for at least 1 year were included. Outcome measure was prescription of anticoagulant medication.ResultsOver the 12 study years, the proportion of eligible patients with AF with contraindications who were prescribed anticoagulants increased from 40.1% (95% confidence interval [CI] = 38.3 to 41.9) to 67.2% (95% CI = 65.6 to 68.8), and the proportion of those without contraindications prescribed anticoagulants increased from 42.1% (95% CI = 41.6 to 42.6) to 67.7% (95% CI = 67.2 to 68.1). In patients with a recent history of major bleeding or aneurysm, prescribing rates increased from 44.3% (95% CI = 42.2 to 46.5) and 34.8% (95% CI = 29.4 to 40.6) in 2004 to 71.7% (95% CI = 69.9 to 73.5) and 63.2% (95% CI = 58.3 to 67.8) in 2015, respectively, comparable with rates in patients without contraindications.ConclusionThe presence or absence of recorded contraindications has little influence on the decision to prescribe anticoagulants for the prevention of stroke in patients with AF. The study analysis suggests that, nationally, 38 000 patients with AF with contraindications are treated with anticoagulants. This has implications for patient safety.</jats:sec

Cohort study investigating the relationship between cholesterol, cardiovascular risk score and the prescribing of statins in UK primary care: study protocol

INTRODUCTION: Risk scoring is an integral part of the prevention of cardiovascular disease (CVD) and should form the basis for the decision to offer medication to reduce cholesterol (statins). However, there is a suggestion in the literature that many patients are still initiated on statins based on raised cholesterol rather than a raised CVD risk. It is important, therefore, to investigate the role that lipid levels and CVD risks have in the decision to prescribe. This research will establish how cholesterol levels and CVD risk independently influence the prescribing of statins for the primary prevention of CVD in primary care. METHODS AND ANALYSIS: The Health Improvement Network (THIN) is a database of coded primary care electronic patient records from over 500 UK general practices. From this resource, a historical cohort will be created of patients without a diagnosis of CVD, not currently receiving a prescription for statins and who had a lipid profile measured. A post hoc QRISK2 score will be calculated for these patients and they will be followed up for 60 days to establish whether they were subsequently prescribed a statin. Primary analysis will consist of predictive modelling using multivariate logistic regression with potential predictors including cholesterol level, calculated QRISK2 score, sociodemographic characteristic and comorbidities. Descriptive statistics will be used to identify trends in prescribing and further secondary analysis will explore what other factors may have influenced the prescribing of statins and the degree of interprescriber variability. ETHICS AND DISSEMINATION: The THIN Data Collection Scheme was approved by the South-East Multicentre Research Ethics Committee in 2003. Individual studies using THIN require Scientific Review Committee approval. The original protocol for this study and a subsequent amendment have been approved (16THIN009A1). The results will be published in a peer review journal and presented at national and international conferences

Statin initiations and QRISK2 scoring in UK general practice:a THIN database study

BackgroundStatin prescribing should be based on cardiovascular disease (CVD) risk, but evidence suggests overtreatment of low-risk groups and undertreatment of high-risk groups.AimTo investigate the relationship between CVD risk scoring in primary care and initiation of statins for the primary prevention of CVD, and the effect of changes to the National Institute for Health and Care Excellence (NICE) guidance in 2014.Design and settingHistorical cohort study using UK electronic primary care records.MethodA cohort was created of statin-naïve patients without CVD between 1 January 2000 and 31 December 2015. CVD risk scores (calculated using QRISK2 available from 2012) and statin initiations were identified. Rates of CVD risk score recording were calculated and relationships between CVD risk category (low-, intermediate-, and high-risk: &lt;10%, 10–19.9%, and ≥20% 10-year CVD risk) and statin initiation were analysed.ResultsA total of 1.4 million patients were identified from 248 practices. Of these, 151 788 had a recorded CVD risk score since 2012 (10.67%) and 217 860 were initiated on a statin (15.31%). Among patients initiated on a statin after 2012, 27.1% had a documented QRISK2 score: 2.7% of low-risk, 13.8% of intermediate-risk, and 35.0% of high-risk patients were initiated on statins. Statin initiation rates halved from a peak in 2006. After the 2014 NICE guidelines, statin initiation rates declined in high-risk patients but increased in intermediate-risk patients.ConclusionMost patients initiated on statins had no QRISK2 score recorded. Most patients at high risk of CVD were not initiated on statins. One in six statin initiations were to low-risk patients indicating significant overtreatment. Initiations of statins in intermediate-risk patients rose after NICE guidelines were updated in 2014.</jats:sec