Kraus V.,Division for Bioinformatics and Translational Research |
Dehmer M.,Division for Bioinformatics and Translational Research |
Dehmer M.,University of Federal Defense Munich |
Emmert-Streib F.,Center for Cancer Research and Cell Biology
Information Sciences | Year: 2014
Proving interrelations between structural graph measures analytically has been intricate. Generally, relations between structural graph measures describe the interplay between measures which turned out to be useful for better understanding the properties of such quantities. The results which have been achieved so far are restricted to simple measures or special graph classes such as trees. In this paper, we introduce a probabilistic approach for establishing inequalities between quantitative network measures on random networks. Those inequalities between different graph measures lead to a deeper understanding of the mathematical apparatus and, in particular, to a discussion of quality aspects of structural graph measures, which is a major contribution of this paper. © 2014 Elsevier Inc. All rights reserved.
Ahmad J.,Queen's University of Belfast |
Arthur K.,Queen's University of Belfast |
Maxwell P.,Center for Cancer Research and Cell Biology |
Kennedy A.,Royal Victoria Hospital |
And 3 more authors.
Diseases of the Esophagus | Year: 2015
Summary: The incidence of esophageal adenocarcinoma has increased dramatically over recent years and Barrett's esophagus is considered the most established risk factor for its development. Endoscopic surveillance of Barrett's esophagus is therefore recommended but hinges on histological interpretation of randomly taken biopsies which is poorly reproducible. The use of biomarkers presents an opportunity to improve our ability to risk-stratify these patients.We examined three biomarkers namely p504s, CD133, and Twist in the setting of Barrett's esophagus, low-grade dysplasia, and esophageal adenocarcinoma to evaluate differential expression between benign, dysplastic, and malignant Barrett's tissue in an exploratory cross-sectional study. Twenty-five cases each of Barrett's esophagus, low-grade dysplasia, and esophageal adenocarcinoma were included along-with 25 cases of esophagectomy resections for Barrett's adenocarcinoma. The biomarkers were immunostained on automated Ventana® immunostainer. The biopsies were assessed for biomarker expression by two independent observers. Granular cytoplasmic staining of p504s was observed in dysplastic Barrett's biopsies and esophageal adenocarcinoma but not in Barrett's esophagus. Apical and membranous CD133 expression was also observed in dysplastic Barrett's and esophageal adenocarcinoma. Nuclear Twist expression was seen predominantly in stromal cells. There was increased p504s expression in dysplastic Barrett's esophagus and esophageal adenocarcinoma compared with controls. CD133 expression was detected for the first time in esophageal adenocarcinoma and dysplastic Barrett's esophagus. Twist expression was not convincing enough to be labeled as Barrett's biomarker. p504s and CD133 have the potential to differentiate benign from malignant Barrett's tissue in this exploratory study. Their validity should be established in prospective longitudinal studies. © 2014 International Society for Diseases of the Esophagus.
McDade S.S.,Center for Cancer Research and Cell Biology |
Patel D.,Center for Cancer Research and Cell Biology |
McCance D.J.,Center for Cancer Research and Cell Biology
Journal of Cell Science | Year: 2011
p63 is a master regulator of proliferation and differentiation in stratifying epithelia, and its expression is frequently altered in carcinogenesis. However, its role in maintaining proliferative capacity remains unclear. Here, we demonstrate that hypoproliferation and loss of differentiation in organotypic raft cultures of primary neonatal human foreskin keratinocytes (HFKs) depleted of the α and β isoforms of p63 result from p53-p21-mediated accumulation of retinoblastoma (Rb) family member p130. Hypoproliferation in p63-depleted HFKs can be rescued by depletion of p53, p21CIP1 or p130. Furthermore, we identified the gene encoding S-phase kinaseassociated protein 2 (Skp2), the recognition component of the SCFSkp2 E3 ubiquitin ligase, as a novel target of p63, potentially influencing p130 levels. Expression of Skp2 is maintained by p63 binding to a site in intron 2 and mRNA levels are downregulated in p63-depleted cells. Hypoproliferation in p63-depleted cells can be restored by re-expression of Skp2. Taken together, these results indicate that p63 plays a multifaceted role in maintaining proliferation in the mature regenerating epidermis, in addition to being required for differentiation. © 2011. Published by The Company of Biologists Ltd.
Altay G.,Center for Cancer Research and Cell Biology |
Emmert-Streib F.,Center for Cancer Research and Cell Biology
Bioinformatics | Year: 2010
Motivation: The inference of regulatory networks from large-scale expression data holds great promise because of the potentially causal interpretation of these networks. However, due to the difficulty to establish reliable methods based on observational data there is so far only incomplete knowledge about possibilities and limitations of such inference methods in this context. Results: In this article, we conduct a statistical analysis investigating differences and similarities of four network inference algorithms, ARACNE, CLR, MRNET and RN, with respect to local network-based measures. We employ ensemble methods allowing to assess the inferability down to the level of individual edges. Our analysis reveals the bias of these inference methods with respect to the inference of various network components and, hence, provides guidance in the interpretation of inferred regulatory networks from expression data. Further, as application we predict the total number of regulatory interactions in human B cells and hypothesize about the role of Myc and its targets regarding molecular information processing. © The Author 2010.
Coulter J.A.,ay Research Center |
Jain S.,Center for Cancer Research and Cell Biology |
Butterworth K.T.,Center for Cancer Research and Cell Biology |
Taggart L.E.,Center for Cancer Research and Cell Biology |
And 13 more authors.
International Journal of Nanomedicine | Year: 2012
Background: This follow-up study aims to determine the physical parameters which govern the differential radiosensitization capacity of two tumor cell lines and one immortalized normal cell line to 1.9 nm gold nanoparticles. In addition to comparing the uptake potential, localization, and cytotoxicity of 1.9 nm gold nanoparticles, the current study also draws on comparisons between nanoparticle size and total nanoparticle uptake based on previously published data. Methods: We quantified gold nanoparticle uptake using atomic emission spectroscopy and imaged intracellular localization by transmission electron microscopy. Cell growth delay and clonogenic assays were used to determine cytotoxicity and radiosensitization potential, respectively. Mechanistic data were obtained by Western blot, flow cytometry, and assays for reactive oxygen species. Results: Gold nanoparticle uptake was preferentially observed in tumor cells, resulting in an increased expression of cleaved caspase proteins and an accumulation of cells in sub G1 phase. Despite this, gold nanoparticle cytotoxicity remained low, with immortalized normal cells exhibiting an LD50 concentration approximately 14 times higher than tumor cells. The surviving fraction for gold nanoparticle-treated cells at 3 Gy compared with that of untreated control cells indicated a strong dependence on cell type in respect to radiosensitization potential. Conclusion: Gold nanoparticles were most avidly endocytosed and localized within cytoplasmic vesicles during the first 6 hours of exposure. The lack of significant cytotoxicity in the absence of radiation, and the generation of gold nanoparticle-induced reactive oxygen species provide a potential mechanism for previously reported radiosensitization at megavoltage energies. © 2012 Coulter et al, publisher and licensee Dove Medical Press Ltd.
Emmert-Streib F.,Center for Cancer Research and Cell Biology |
Glazko G.V.,University of Rochester
Wiley Interdisciplinary Reviews: Systems Biology and Medicine | Year: 2011
In this paper we discuss the dualism of gene networks and their role in systems biology. We argue that gene networks (1) can serve as a conceptual framework, forming a fundamental level of a phenomenological description, and (2) are a means to represent and analyze data. The latter point does not only allow a systems analysis but is even amenable for a direct approach to study biological function. Here we focus on the clarity of our main arguments and conceptual meaning of gene networks, rather than the causal inference of gene networks from data. © 2010 John Wiley & Sons, Inc.
Gray S.M.,Center for Cancer Research and Cell Biology |
McGeown J.G.,Center for Cancer Research and Cell Biology |
McMurray G.,Pfizer |
McCloskey K.D.,Center for Cancer Research and Cell Biology
PLoS ONE | Year: 2013
Several populations of interstitial cells of Cajal (ICC) exist in the bladder, associated with intramural nerves. Although ICC respond to exogenous agonists, there is currently no evidence of their functional innervation. The objective was to determine whether bladder ICC are functionally innervated. Guinea-pig bladder tissues, loaded with fluo-4AM were imaged with fluorescent microscopy and challenged with neurogenic electrical field stimulation (EFS). All subtypes of ICC and smooth muscle cells (SMC) displayed spontaneous Ca2+-oscillations. EFS (0.5 Hz, 2 Hz, 10 Hz) evoked tetrodotoxin (1 μM)-sensitive Ca2+-transients in lamina propria ICC (ICC-LP), detrusor ICC and perivascular ICC (PICC) associated with mucosal microvessels. EFS responses in ICC-LP were significantly reduced by atropine or suramin. SMC and vascular SMC (VSM) also responded to EFS. Spontaneous Ca2+-oscillations in individual ICC-LP within networks occurred asynchronously whereas EFS evoked coordinated Ca2+-transients in all ICC-LP within a field of view. Non-correlated Ca2+-oscillations in detrusor ICC and adjacent SMC pre-EFS, contrasted with simultaneous neurogenic Ca2+ transients evoked by EFS. Spontaneous Ca2+-oscillations in PICC were little affected by EFS, whereas large Ca2+-transients were evoked in pre-EFS quiescent PICC. EFS also increased the frequency of VSM Ca2+-oscillations. In conclusion, ICC-LP, detrusor ICC and PICC are functionally innervated. Interestingly, Ca2+-activity within ICC-LP networks and between detrusor ICC and their adjacent SMC were synchronous under neural control. VSM and PICC Ca2+-activity was regulated by bladder nerves. These novel findings demonstrate functional neural control of bladder ICC. Similar studies should now be carried out on neurogenic bladder to elucidate the contribution of impaired nerve-ICC communication to bladder pathophysiology. © 2013 Gray et al.
Hamilton P.W.,Center for Cancer Research and Cell Biology
Diagnostic Histopathology | Year: 2010
The ability to take and process digital images is important in histopathology, cytopathology and pathology-centric research. In particular publishers demand that digital images are presented in a certain format. Since taking, processing and preparing digital images are often in the hands of the researcher, we should know how to handle digital images and prepare them for publication. This paper outlines the basic principles of digital imaging, what defines image resolution and how to prepare digital images for publication. Common pitfalls in preparing digital illustrations are reviewed together with the ethical constraints around the processing of scientific images. © 2010.
Jeganathan R.,Royal Victoria Hospital |
McGuigan J.,Royal Victoria Hospital |
Campbell F.,Center for Cancer Research and Cell Biology |
Lynch T.,Belfast City Hospital
European Journal of Nuclear Medicine and Molecular Imaging | Year: 2011
Purpose: The aim of the study was to compare the pre-operative metabolic tumour length on FDG PET/CT with the resected pathological specimen in patients with oesophageal cancer. Methods: All patients diagnosed with oesophageal carcinoma who had undergone staging PET/CT imaging between the period of June 2002 and May 2008 who were then suitable for curative surgery, either with or without neo-adjuvant chemotherapy, were included in this study. Metabolic tumour length was assessed using both visual analysis and a maximum standardised uptake value (SUVmax) cutoff of 2.5. Results: Thirty-nine patients proceeded directly to curative surgical resection, whereas 48 patients received neo-adjuvant chemotherapy, followed by curative surgery. The 95% limits of agreement in the surgical arm were more accurate when the metabolic tumour length was visually assessed with a mean difference of -0.05 cm (SD 2.16 cm) compared to a mean difference of +2.42 cm (SD 3.46 cm) when assessed with an SUVmax cutoff of 2.5. In the neo-adjuvant group, the 95% limits of agreement were once again more accurate when assessed visually with a mean difference of -0.6 cm (SD 1.84 cm) compared to a mean difference of +1.58 cm (SD 3.1 cm) when assessed with an SUVmax cutoff of 2.5. Conclusion: This study confirms the high accuracy of PET/CT in measuring gross target volume (GTV) length. A visual method for GTV length measurement was demonstrated to be superior and more accurate than when using an SUVmax cutoff of 2.5. This has the potential of reducing the planning target volume with dose escalation to the tumour with a corresponding reduction in normal tissue complication probability. © 2010 Springer-Verlag.
PubMed | Poole Hospital NHS Foundation Trust, University of Liverpool, Royal Marsden NHS Foundation Trust, University of Edinburgh and 14 more.
Type: | Journal: Cancer research | Year: 2016
A rising incidence of oropharyngeal squamous cell carcinoma (OPSCC) incidence has occurred throughout the developed world, where it has been attributed to an increasing impact of human papillomavirus (HPV) on disease etiology. This report presents the findings of a multicenter cross-sectional retrospective study aimed at determining the proportion of HPV-positive and HPV-negative OPSCC within the United Kingdom. Archival tumor tissue blocks from 1,602 patients previously diagnosed with OPSCC (2002-2011) were collated from 11 centers. HPV status was determined with three validated commercial tests to provide valid data for 1,474 cases in total. Corresponding national incidence data from the same decade were obtained from UK Cancer registries. The overall proportion of HPV