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Cronin J.,University of Swansea | McAdam E.,University of Swansea | Danikas A.,Grove Center | Tselepis C.,University of Birmingham | And 5 more authors.
American Journal of Gastroenterology | Year: 2011

Objectives: The assessment of cancer risk in patients with Barrett's esophagus (BE) is currently fraught with difficulty. The current gold standard method of assessing cancer risk is histological assessment, with the appearance of high-grade dysplasia (HGD) as the key event monitored. Sampling error during endoscopy limits the usefulness of this approach, and there has been much recent interest in supplementing histological assessment with molecular markers, which may aid in patient stratification. Methods: No molecular marker has been yet validated to accurately correlate with esophageal histological progression. Here, we assessed the suitability of several membranous proteins as biomarkers by correlating their abundance with histological progression. In all, 107 patient samples, from 100 patients, were arranged on a tissue microarray (TMA) and represented the various stages of histological progression in BE. This TMA was probed with antibodies for eight receptor proteins (mostly membranous). Results: Epidermal growth factor receptor (EGFR) staining was found to be the most promising biomarker identified with clear increases in staining accompanying histological progression. Further, immunohistochemistry was performed using the full-tissue sections from BE, HGD, and adenocarcinoma tissues, which confirmed the stepwise increase in EGFR abundance. Using a robust H-score analysis, EGFR abundance was shown to increase 13-fold in the adenocarcinoma tissues compared to the BE tissues. EGFR was overexpressed in 35% of HGD specimens and 80% of adenocarcinoma specimens when using the H-score of the BE patients (plus 3 s.d.) as the threshold to define overexpression. EGFR staining was also noted to be higher in BE tissues adjacent to HGD/adenocarcinoma. Western blotting, although showing more EGFR protein in the adenocarcinomas compared to the BE tissue, was highly variable. EGFR overexpression was accompanied by aneuploidy (gain) of chromosome 7, plus amplification of the EGFR locus. Finally, the bile acid deoxycholic acid (DCA) (at neutral and acidic pH) and acid alone was capable of upregulating EGFR mRNA in vitro, and in the case of neutral pH DCA, this was NF-B dependent. Conclusions: EGFR is overexpressed during the histological progression in BE tissues and hence may be useful as a biomarker of histological progression. Furthermore, as EGFR is a membranous protein expressed on the luminal surface of the esophageal mucosa, it may also be a useful target for biopsy guidance during endoscopy. © 2011 by the American College of Gastroenterology. Source


Cant A.A.,University of Glasgow | Champion S.,University of Glasgow | Bhalla R.,Grove Center | Pimlott S.L.,University of Glasgow | Sutherland A.,University of Glasgow
Angewandte Chemie - International Edition | Year: 2013

Rapid and efficient radioiodination of aryl and heteroaryl bromides has been achieved using a nickel(0)-mediated halogen-exchange reaction. This transformation gives direct access to [123I]- and [ 125I]-imaging agents for single photon emission computed tomography (SPECT), such as 5-[123I]-A85380 (see scheme, Boc=tert- butyloxycarbonyl, cod=1,5-cyclooctadiene, TFA=trifluoroacetic acid). Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. Source


Cant A.A.,University of Glasgow | Bhalla R.,Grove Center | Pimlott S.L.,West of Scotland Radionuclide Dispensary | Sutherland A.,University of Glasgow
Chemical Communications | Year: 2012

A fast and efficient nickel-catalysed iodination reaction of aryl and heteroaryl bromides has been developed. The transformation was found to be general for a wide range of substrates and was used for the synthesis of iodo-PK11195, an imaging agent of Alzheimer's disease and iniparib, a compound used in the treatment of breast cancer. © 2012 The Royal Society of Chemistry. Source


Macholl S.,Free University of Berlin | Macholl S.,Grove Center | Tietze D.,TU Darmstadt | Buntkowsky G.,TU Darmstadt
CrystEngComm | Year: 2013

NMR crystallography, the combination of solid-state NMR techniques, chemical modelling, quantum chemical calculations and other characterization techniques, allows the determination of molecular and supramolecular structures which are not amenable to standard X-ray crystallography. The method is demonstrated on a set of application examples. First the principles and practical considerations of NMR crystallography based on dipolar NMR spectroscopy are outlined in conformational studies of polymorphs of N-octyl-gluconamide and of methoxycarbonyl urea. Then structural studies of two substrate-inhibitor complexes, human manganese superoxide dismutase with azide and nickel superoxide dismutase with cyanide, are reviewed. Finally an example of ongoing developments in the related field of EPR crystallography is reported. © 2013 The Royal Society of Chemistry. Source


MacHoll S.,Grove Center | Morrison M.S.,Grove Center | Iveson P.,Grove Center | Arbo B.E.,General Electric | And 3 more authors.
Molecular Imaging and Biology | Year: 2012

Purpose: A novel molecular imaging agent has been developed recently, which stains tissues of low extracellular pH [pH (low) insertion peptide, pHLIP®]. A pH-dependent process of peptide folding and insertion into cell membranes has been found in vitro. Targeting of acidic solid tumours has been demonstrated in vivo using fluorescence and PET labels. Here, we present proof of feasibility studies of pHLIP with a single-photon emission computed tomography (SPECT) label, 99mTc-AH114567, with focus on preclinical efficacy and imageability. Procedures: Lewis lung carcinoma, lymph node carcinoma of the prostate and prostate adenocarcinoma tumour xenografts were grown in mice and characterised by the angiogenesis marker 99mTc- NC100692 and by extracellular pH measurements with 31P-MRS of 3-aminopropyl phosphonate. Biodistribution was assessed and CT/SPECT imaging performed. Oral administration of bicarbonate served as control. Results and Conclusion: Tc-AH114567 can be obtained via a robust synthesis with good radiolabelling profile and improved formulation. The tracer retains the pH-dependent ability to insert into membranes and to target tumours with similar pharmacokinetics and efficacy that had been demonstrated earlier for pHLIP with optical or 64Cu PET labels. Despite the inherent challenges of SPECT compared to optical and PET imaging, e.g., in terms of lower sensitivity, 99mTc-AH114567 shows adequate image quality and contrast. The main development need for transitioning SPECT labelled pHLIP into the clinic is more rapid background signal reduction, which will be the focus of a subsequent optimisation study. © World Molecular Imaging Society, 2011. Source

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