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Cardiff, United Kingdom

Thomas N.,Maynard Center
Journal of Biomolecular Screening | Year: 2010

In the past decade, high-content screening has become a highly developed approach to obtaining richly descriptive quantitative phenotypic data using automated microscopy. From early use in drug screening, the technique has evolved to embrace a diverse range of applications in both academic and industrial sectors and is now widely recognized as providing an efficient and effective approach to large-scale programs investigating cell biology in situ and in context. © 2010 Society for Biomolecular Sciences.

Since human embryonic stem cells (hESCs) were first isolated and cultured nearly 15 years ago, stem cell biology has been a promising and fast-moving area of research. Improved clinical predictivity in drug development, use in assays to personalise medicine effectively and as the foundation for cell-based therapies are all areas where stem cells can play an important role. But with opportunities come challenges and it is vital that the field of stem cells continues to progress to achieve its potential. This article outlines the measures the Cell Technologies group at GE Healthcare Life Sciences are taking, along with its collaborators in academia, industry and the clinic, to advance stem cell tools and technologies, as well as identifying some future challenges for stem cell research, drug discovery, cell therapy and regenerative medicine. © 2013 Elsevier B.V.

Hoffman E.,Institute of Pharmaceutical Science | Hoffman E.,Medical University of Lodz | Kumar A.,Institute of Pharmaceutical Science | Kanabar V.,Institute of Pharmaceutical Science | And 10 more authors.
Molecular Pharmaceutics | Year: 2015

Although foamy macrophages (FMΦ) are commonly observed during nonclinical development of medicines for inhalation, there are no accepted criteria to differentiate adaptive from adverse FMΦ responses in drug safety studies. The purpose of this study was to develop a multiparameter in vitro assay strategy to differentiate and characterize different mechanisms of drug-induced FMΦ. Amiodarone, staurosporine, and poly(vinyl acetate) nanoparticles were used to induce distinct FMΦ phenotypes in J774A.1 cells, which were then compared with negative controls. Treated macrophages were evaluated for morphometry, lipid accumulation, gene expression, apoptosis, cell activation, and phagocytosis. Analysis of vacuolization (number/area vacuoles per cell) and phospholipid content revealed inducer-dependent distinctive patterns, which were confirmed by electron microscopy. In contrast to the other inducers, amiodarone increased vacuole size rather than number and resulted in phospholipid accumulation. No pronounced dysregulation of transcriptional activity or apoptosis was observed in response to sublethal concentrations of all inducers. Functionally, FMΦ induction did not affect macrophage activation by lipopolysaccharide, but it reduced phagocytic capacity, with different patterns of induction, severity, and resolution observed with the different inducers. An in vitro multiparameter assay strategy is reported that successfully differentiates and characterizes mechanisms leading to FMΦ induction by different types of agents. © 2015 American Chemical Society.

Ekonomou A.,Kings College London | Johnson M.,Vitality | Perry R.H.,Vitality | Perry E.K.,Vitality | And 4 more authors.
Neuropathology and Applied Neurobiology | Year: 2012

Aims: Recent work has highlighted a significant increase of neural stem/progenitor cells after stroke in humans. In this study, we examined neurogenesis in small vessel disease, a key concurrent pathology in Alzheimer's disease. Methods: We assayed autopsy tissue from 13 vascular dementia patients with small vessel disease and 12 age-matched subjects without cerebrovascular pathology, undertaking immunohistochemistry in the affected brain area and the subventricular zone with a well-characterized battery of antibodies to detect neural stem cells/progenitors and immature neurones, as well as choline acetyltransferase immunoreactivity. Results: We showed significant increases ranging from 33% to 92% (P<0.05) in neural progenitor cells around the areas of microvascular pathology and in the subventricular zone in patients with small vessel disease compared to individuals without cerebrovascular changes, even in patients with severe cerebrovascular disease, as defined by neuropathological assessment. Some of the progenitor cells give rise to immature neurones in the affected areas. These alterations were associated with vascular changes, but were unrelated to the cholinergic deficit observed in the cortex and subventricular zone in these patients, in contrast to other dementias examined such as dementia with Lewy bodies. Conclusions: This study provides evidence for neurogenesis in small vessel disease and may have important implications for the development of new therapies for neurodegenerative diseases. © 2011 The Authors. Neuropathology and Applied Neurobiology © 2011 British Neuropathological Society.

McCormack E.,University of Bergen | Silden E.,University of Bergen | Pavlin T.,University of Bergen | Micklem D.R.,University of Bergen | And 4 more authors.
Cancer Research | Year: 2013

The ability to visualize reporter gene expression in vivo has revolutionized all facets of biologic investigation and none more so than imaging applications in oncology. Near-infrared reporter gene imaging may facilitate more accurate evaluation of chemotherapeutic response in preclinical models of orthotopic and metastatic cancers.We report the development of a cell permeable, quenched squarine probe (CytoCy5S), which is reduced by Escherichia coli nitroreductase (NTR), resulting in a near-infrared fluorescent product. Time-domain molecular imaging of NTR/CytoCy5S reporter platform permitted noninvasive monitoring of disease progression in orthotopic xenografts of disseminated leukemia, lung, and metastatic breast cancer. This methodology facilitated therapeutic evaluation of NTR gene-directed enzymatic prodrug therapy with conventional metronidazole antibiotics. These studies show NTR/CytoCy5S as a near-infrared gene reporter system with broad preclinical and prospective clinical applications within imaging, and gene therapy, of cancer. © 2012 AACR.

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