The Design and Application of Target-Focused Compound Libraries

Target-focused compound libraries are collections of compounds which are designed to interact with an individual protein target or, frequently, a family of related targets (such as kinases, voltage-gated ion channels, serine/cysteine proteases). They are used for screening against therapeutic targets in order to find hit compounds that might be further developed into drugs. The design of such libraries generally utilizes structural information about the target or family of interest. In the absence of such structural information, a chemogenomic model that incorporates sequence and mutagenesis data to predict the properties of the binding site can be employed. A third option, usually pursued when no structural data are available, utilizes knowledge of the ligands of the target from which focused libraries can be developed via scaffold hopping. Consequently, the methods used for the design of target-focused libraries vary according to the quantity and quality of structural or ligand data that is available for each target family. This article describes examples of each of these design approaches and illustrates them with case studies, which highlight some of the issues and successes observed when screening target-focused libraries

Measurement of D* Meson Cross Sections at HERA and Determination of the Gluon Density in the Proton using NLO QCD

With the H1 detector at the ep collider HERA, D* meson production cross sections have been measured in deep inelastic scattering with four-momentum transfers Q^2>2 GeV2 and in photoproduction at energies around W(gamma p)~ 88 GeV and 194 GeV. Next-to-Leading Order QCD calculations are found to describe the differential cross sections within theoretical and experimental uncertainties. Using these calculations, the NLO gluon momentum distribution in the proton, x_g g(x_g), has been extracted in the momentum fraction range 7.5x10^{-4}< x_g <4x10^{-2} at average scales mu^2 =25 to 50 GeV2. The gluon momentum fraction x_g has been obtained from the measured kinematics of the scattered electron and the D* meson in the final state. The results compare well with the gluon distribution obtained from the analysis of scaling violations of the proton structure function F_2.Comment: 27 pages, 9 figures, 2 tables, submitted to Nucl. Phys.

Characterization of optical properties and surface roughness profiles: The Casimir force between real materials

The Lifshitz theory provides a method to calculate the Casimir force between two flat plates if the frequency dependent dielectric function of the plates is known. In reality any plate is rough and its optical properties are known only to some degree. For high precision experiments the plates must be carefully characterized otherwise the experimental result cannot be compared with the theory or with other experiments. In this chapter we explain why optical properties of interacting materials are important for the Casimir force, how they can be measured, and how one can calculate the force using these properties. The surface roughness can be characterized, for example, with the atomic force microscope images. We introduce the main characteristics of a rough surface that can be extracted from these images, and explain how one can use them to calculate the roughness correction to the force. At small separations this correction becomes large as our experiments show. Finally we discuss the distance upon contact separating two rough surfaces, and explain the importance of this parameter for determination of the absolute separation between bodies.}Comment: 33 pages, 14 figures, to appear in Springer Lecture Notes in Physics, Volume on Casimir Physics, edited by Diego Dalvit, Peter Milonni, David Roberts, and Felipe da Ros

Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation

We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 &times; 10-11 to 5.0 &times; 10-21). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 &times; 10-6). Our results provide new evidence for the role of DNA methylation in blood pressure regulation

Use of SMS texts for facilitating access to online alcohol interventions: a feasibility study

A41 Use of SMS texts for facilitating access to online alcohol interventions: a feasibility study In: Addiction Science & Clinical Practice 2017, 12(Suppl 1): A4

Dynamic contrast-enhanced CT compared with positron emission tomography CT to characterise solitary pulmonary nodules : the SPUtNIk diagnostic accuracy study and economic modelling

Background Current pathways recommend positron emission tomography–computerised tomography for the characterisation of solitary pulmonary nodules. Dynamic contrast-enhanced computerised tomography may be a more cost-effective approach. Objectives To determine the diagnostic performances of dynamic contrast-enhanced computerised tomography and positron emission tomography–computerised tomography in the NHS for solitary pulmonary nodules. Systematic reviews and a health economic evaluation contributed to the decision-analytic modelling to assess the likely costs and health outcomes resulting from incorporation of dynamic contrast-enhanced computerised tomography into management strategies. Design Multicentre comparative accuracy trial. Setting Secondary or tertiary outpatient settings at 16 hospitals in the UK. Participants Participants with solitary pulmonary nodules of ≥ 8 mm and of ≤ 30 mm in size with no malignancy in the previous 2 years were included. Interventions Baseline positron emission tomography–computerised tomography and dynamic contrast-enhanced computer tomography with 2 years’ follow-up. Main outcome measures Primary outcome measures were sensitivity, specificity and diagnostic accuracy for positron emission tomography–computerised tomography and dynamic contrast-enhanced computerised tomography. Incremental cost-effectiveness ratios compared management strategies that used dynamic contrast-enhanced computerised tomography with management strategies that did not use dynamic contrast-enhanced computerised tomography. Results A total of 380 patients were recruited (median age 69 years). Of 312 patients with matched dynamic contrast-enhanced computer tomography and positron emission tomography–computerised tomography examinations, 191 (61%) were cancer patients. The sensitivity, specificity and diagnostic accuracy for positron emission tomography–computerised tomography and dynamic contrast-enhanced computer tomography were 72.8% (95% confidence interval 66.1% to 78.6%), 81.8% (95% confidence interval 74.0% to 87.7%), 76.3% (95% confidence interval 71.3% to 80.7%) and 95.3% (95% confidence interval 91.3% to 97.5%), 29.8% (95% confidence interval 22.3% to 38.4%) and 69.9% (95% confidence interval 64.6% to 74.7%), respectively. Exploratory modelling showed that maximum standardised uptake values had the best diagnostic accuracy, with an area under the curve of 0.87, which increased to 0.90 if combined with dynamic contrast-enhanced computerised tomography peak enhancement. The economic analysis showed that, over 24 months, dynamic contrast-enhanced computerised tomography was less costly (£3305, 95% confidence interval £2952 to £3746) than positron emission tomography–computerised tomography (£4013, 95% confidence interval £3673 to £4498) or a strategy combining the two tests (£4058, 95% confidence interval £3702 to £4547). Positron emission tomography–computerised tomography led to more patients with malignant nodules being correctly managed, 0.44 on average (95% confidence interval 0.39 to 0.49), compared with 0.40 (95% confidence interval 0.35 to 0.45); using both tests further increased this (0.47, 95% confidence interval 0.42 to 0.51). Limitations The high prevalence of malignancy in nodules observed in this trial, compared with that observed in nodules identified within screening programmes, limits the generalisation of the current results to nodules identified by screening. Conclusions Findings from this research indicate that positron emission tomography–computerised tomography is more accurate than dynamic contrast-enhanced computerised tomography for the characterisation of solitary pulmonary nodules. A combination of maximum standardised uptake value and peak enhancement had the highest accuracy with a small increase in costs. Findings from this research also indicate that a combined positron emission tomography–dynamic contrast-enhanced computerised tomography approach with a slightly higher willingness to pay to avoid missing small cancers or to avoid a ‘watch and wait’ policy may be an approach to consider. Future work Integration of the dynamic contrast-enhanced component into the positron emission tomography–computerised tomography examination and the feasibility of dynamic contrast-enhanced computerised tomography at lung screening for the characterisation of solitary pulmonary nodules should be explored, together with a lower radiation dose protocol. Study registration This study is registered as PROSPERO CRD42018112215 and CRD42019124299, and the trial is registered as ISRCTN30784948 and ClinicalTrials.gov NCT02013063

Comparative Accuracy and Cost-Effectiveness of Dynamic Contrast Enhanced Computed Tomography and Positron Emission Tomography in the Characterisation of Solitary Pulmonary Nodules

Abstract Introduction: Dynamic contrast-enhanced computed tomography (DCE-CT) and Positron Emission Tomography/Computed Tomography (PET/CT) have a high reported accuracy for the diagnosis of malignancy in solitary pulmonary nodules. The aim of this study was to compare the accuracy and cost-effectiveness of these. Methods: In this prospective multicentre trial, 380 participants with a solitary pulmonary nodule (8-30mm) and no recent history of malignancy underwent DCE-CT and PET/CT. All patients underwent either biopsy with histological diagnosis or completed CT follow-up. Primary outcome measures were sensitivity, specificity, and overall diagnostic accuracy for PET/CT and DCE-CT. Costs and cost-effectiveness were estimated from a healthcare provider perspective using a decision-model. Results: 312 participants (47% female, 68.1±9.0 years) completed the study, with 61% rate of malignancy at 2 years. The sensitivity, specificity, positive predictive value and negative predictive values for DCE-CT were 95.3% [95% CI 91.3;97.5], 29.8% [95% CI 22.3;38.4], 68.2% [95% CI 62.4%;73.5%] and 80.0% [95% CI 66.2;89.1] respectively, and for PET/CT were 79.1% [95% CI 72.7;84.2], 81.8% [95% CI 74.0;87.7], 87.3%[95% CI 81.5;91.5) and 71·2% [95% CI 63.2;78.1]. The area under the receiver operator characteristic curve (AUROC) for DCE-CT and PET/CT was 0.62 [95%CI 0.58;0.67] and 0.80 [95%CI 0.76;0.85] respectively (p<0.001). Combined results significantly increased diagnostic accuracy over PET/CT alone (AUROC=0.90 [95%CI 0.86;0.93], p<0.001). DCE-CT was preferred when the willingness to pay per incremental cost per correctly treated malignancy was below £9000. Above £15500 a combined approach was preferred. Conclusions: PET/CT has a superior diagnostic accuracy to DCE-CT for the diagnosis of solitary pulmonary nodules. Combining both techniques improves the diagnostic accuracy over either test alone and could be cost-effective. (Clinical trials.gov - NCT02013063)