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Jansen C.,VU University Amsterdam | Wang H.,University of North Carolina at Chapel Hill | Kooistra A.J.,VU University Amsterdam | De Graaf C.,VU University Amsterdam | And 7 more authors.
Journal of Medicinal Chemistry | Year: 2013

Trypanosoma brucei cyclic nucleotide phosphodiesterase B1 (TbrPDEB1) and TbrPDEB2 have recently been validated as new therapeutic targets for human African trypanosomiasis by both genetic and pharmacological means. In this study we report the crystal structure of the catalytic domain of the unliganded TbrPDEB1 and its use for the in silico screening for new TbrPDEB1 inhibitors with novel scaffolds. The TbrPDEB1 crystal structure shows the characteristic folds of human PDE enzymes but also contains the parasite-specific P-pocket found in the structures of Leishmania major PDEB1 and Trypanosoma cruzi PDEC. The unliganded TbrPDEB1 X-ray structure was subjected to a structure-based in silico screening approach that combines molecular docking simulations with a protein-ligand interaction fingerprint (IFP) scoring method. This approach identified six novel TbrPDEB1 inhibitors with IC50 values of 10-80 μM, which may be further optimized as potential selective TbrPDEB inhibitors. © 2013 American Chemical Society.


Duenas J.A.,Technical University of Madrid | Mora J.M.,Technical University of Madrid | Traeger M.,Helmholtz Center for Heavy Ion Research | Galbiati A.,St Johns Innovation Center | And 2 more authors.
Diamond and Related Materials | Year: 2015

Short current pulses of width around 1 ns are generated by 50 μm thickness single crystal diamond detectors, which makes them very attractive for fast timing nuclear experiments. The shape of the pulse is greatly affected by the applied electric field that influences both the pulse rise time and its width. An exponential behaviour is found for the rise time and pulse width vs electric field. Measurements performed with high bandwidth electronics yield rise time down to 300 ps. It is also shown that for pulse duration in the nanosecond range, alternative electronic systems to the bulky and costly digital oscilloscopes, are commercially available. © 2015 Elsevier B.V. All rights reserved.


Moffat J.G.,Genentech | Rudolph J.,Genentech | Bailey D.,St Johns Innovation Center
Nature Reviews Drug Discovery | Year: 2014

There has been a resurgence of interest in the use of phenotypic screens in drug discovery as an alternative to target-focused approaches. Given that oncology is currently the most active therapeutic area, and also one in which target-focused approaches have been particularly prominent in the past two decades, we investigated the contribution of phenotypic assays to oncology drug discovery by analysing the origins of all new small-molecule cancer drugs approved by the US Food and Drug Administration (FDA) over the past 15 years and those currently in clinical development. Although the majority of these drugs originated from target-based discovery, we identified a significant number whose discovery depended on phenotypic screening approaches. We postulate that the contribution of phenotypic screening to cancer drug discovery has been hampered by a reliance on 'classical' nonspecific drug effects such as cytotoxicity and mitotic arrest, exacerbated by a paucity of mechanistically defined cellular models for therapeutically translatable cancer phenotypes. However, technical and biological advances that enable such mechanistically informed phenotypic models have the potential to empower phenotypic drug discovery in oncology. © 2014 Macmillan Publishers Limited. All rights reserved.


Apic G.,St Johns Innovation Center | Apic G.,University of Heidelberg | Russell R.B.,University of Heidelberg
Science Signaling | Year: 2010

Although the combination of modular domains within proteins has been proposed as a determining feature of evolutionary innovation and flexibility, direct evidence for this mechanism of evolution has been sketchy. Two papers, one creating new domain combinations in the yeast mating pathway and another involving a comprehensive analysis of protein function and domain architecture across major organisms, have provided firm evidence that the recombining of domains can lead to evolutionary innovation. The results will guide future studies in synthetic and evolutionary biology.


PubMed | Clinical Pharmacology Modeling & Simulation, Medimmune, GSK Clinical Unit, Medicines Research Center and 5 more.
Type: Journal Article | Journal: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology | Year: 2016

The A118G single-nucleotide polymorphism (SNP rs1799971) in the -opioid receptor gene, OPRM1, has been much studied in relation to alcohol use disorders. The reported effects of allelic variation at this SNP on alcohol-related behaviors, and on opioid receptor antagonist treatments, have been inconsistent. We investigated the pharmacogenetic interaction between A118G variation and the effects of two -opioid receptor antagonists in a clinical lab setting. Fifty-six overweight and moderate-heavy drinkers were prospectively stratified by genotype (29 AA homozygotes, 27 carriers of at least 1 G allele) in a double-blind placebo-controlled, three-period crossover design with naltrexone (NTX; 25mg OD for 2 days, then 50mg OD for 3 days) and GSK1521498 (10mg OD for 5 days). The primary end point was regional brain activation by the contrast between alcohol and neutral tastes measured using functional magnetic resonance imaging (fMRI). Secondary end points included other fMRI contrasts, subjective responses to intravenous alcohol challenge, and food intake. GSK1521498 (but not NTX) significantly attenuated fMRI activation by appetitive tastes in the midbrain and amygdala. GSK1521498 (and NTX to a lesser extent) significantly affected self-reported responses to alcohol infusion. Both drugs reduced food intake. Across all end points, there was less robust evidence for significant effects of OPRM1 allelic variation, or for pharmacogenetic interactions between genotype and drug treatment. These results do not support strong modulatory effects of OPRM1 genetic variation on opioid receptor antagonist attenuation of alcohol- and food-related behaviors. However, they do support further investigation of GSK1521498 as a potential therapeutic for alcohol use and eating disorders.


Brown D.,St Johns Innovation Center
Nature Reviews Drug Discovery | Year: 2015

Concern over antibiotic resistance is growing, and new classes of antibiotics, particularly against Gram-negative bacteria, are needed. However, even if the scientific hurdles can be overcome, it could take decades for sufficient numbers of such antibiotics to become available. As an interim solution, antibiotic resistance could be 'broken' by co-administering appropriate non-antibiotic drugs with failing antibiotics. Several marketed drugs that do not currently have antibacterial indications can either directly kill bacteria, reduce the antibiotic minimum inhibitory concentration when used in combination with existing antibiotics and/or modulate host defence through effects on host innate immunity, in particular by altering inflammation and autophagy. This article discusses how such 'antibiotic resistance breakers' could contribute to reducing the antibiotic resistance problem, and analyses a priority list of candidates for further investigation. © 2015 Macmillan Publishers Limited.


Lafferty-Whyte K.,University of Glasgow | Bilsland A.,University of Glasgow | Cairney C.J.,University of Glasgow | Hanley L.,University of Glasgow | And 7 more authors.
BMC Genomics | Year: 2010

Background: Cellular senescence is a major barrier to tumour progression, though its role in pathogenesis of cancer and other diseases is poorly understood in vivo. Improved understanding of the degree to which latent senescence signalling persists in tumours might identify intervention strategies to provoke "accelerated senescence" responses as a therapeutic outcome. Senescence involves convergence of multiple pathways and requires ongoing dynamic signalling throughout its establishment and maintenance. Recent discovery of several new markers allows for an expression profiling approach to study specific senescence phenotypes in relevant tissue samples. We adopted a "senescence scoring" methodology based on expression profiles of multiple senescence markers to examine the degree to which signals of damage-associated or secretory senescence persist in various human tumours.Results: We first show that scoring captures differential induction of damage or inflammatory pathways in a series of public datasets involving radiotherapy of colon adenocarcinoma, chemotherapy of breast cancer cells, replicative senescence of mesenchymal stem cells, and progression of melanoma. We extended these results to investigate correlations between senescence score and growth inhibition in response to ~1500 compounds in the NCI60 panel. Scoring of our own mesenchymal tumour dataset highlighted differential expression of secretory signalling pathways between distinct subgroups of MPNST, liposarcomas and peritoneal mesothelioma. Furthermore, a pro-inflammatory signature yielded by hierarchical clustering of secretory markers showed prognostic significance in mesothelioma.Conclusions: We find that "senescence scoring" accurately reports senescence signalling in a variety of situations where senescence would be expected to occur and highlights differential expression of damage associated and secretory senescence pathways in a context-dependent manner. © 2010 Lafferty-Whyte et al; licensee BioMed Central Ltd.


Lang U.,ObjectSecurity | Lang U.,St Johns Innovation Center
Proceedings - 2nd IEEE International Conference on Cloud Computing Technology and Science, CloudCom 2010 | Year: 2010

This paper introduces the concept of moving security and compliance policy automation for Cloud applications and mashups into the Cloud. The policy automation aspects covered in this paper include policy configuration, technical policy generation using model-driven security, application authorization management, and incident reporting. Policy configuration is provided as a subscription-based Cloud service to application development tools, and technical policy generation, enforcement and monitoring is embedded into Cloud application development and runtime platforms. OpenPMF Security & Compliance as a Service ("ScaaS"), a reference implementation using ObjectSecurity OpenPMF, is also presented. © 2010 IEEE.


PubMed | St Johns Innovation Center
Type: Journal Article | Journal: Nature reviews. Drug discovery | Year: 2015

Concern over antibiotic resistance is growing, and new classes of antibiotics, particularly against Gram-negative bacteria, are needed. However, even if the scientific hurdles can be overcome, it could take decades for sufficient numbers of such antibiotics to become available. As an interim solution, antibiotic resistance could be broken by co-administering appropriate non-antibiotic drugs with failing antibiotics. Several marketed drugs that do not currently have antibacterial indications can either directly kill bacteria, reduce the antibiotic minimum inhibitory concentration when used in combination with existing antibiotics and/or modulate host defence through effects on host innate immunity, in particular by altering inflammation and autophagy. This article discusses how such antibiotic resistance breakers could contribute to reducing the antibiotic resistance problem, and analyses a priority list of candidates for further investigation.


PubMed | Animal Health Trust, St Johns Innovation Center and Queen's University
Type: Journal Article | Journal: The Veterinary record | Year: 2015

Although ultrasound and MRI are the imaging modalities of choice for the investigation of ocular diseases, the eyes are included in routine CT examinations of the head and should be examined as part of the complete evaluation. This report describes the dimensions, volumes and densities of the normal canine globe in CT. Forty-four eyes were studied. The mean axial length of the globe was 2.09 cm and its mean volume was 4.65 cm(3). The mean anteroposterior distance of the anterior chamber was 0.4 cm and of the vitreous chamber was 0.96 cm. There was a statistically significant difference between the mean aqueous humour density, 14.76 Hounsfield units (HU), and the mean vitreous humour density, 11.20 HU (P=0.0009). Statistically significant differences were also seen in both humours in precontrast and postcontrast studies. The mean anteroposterior dimension of the lens was 0.74 cm; its mean equatorial distance was 1.15 cm. The mean volume was 0.43 cm(3) and its mean density was 131.9 HU. There was contrast enhancement of the ciliary body, iris and retina/sclera/choroid complex. This study provides reference values to help in the interpretation of ocular structures on CT scans of the head, where incidental findings can change the medical management of specific cases.

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