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Sivakumar S.,University of Cambridge | de Santiago I.,University of Cambridge | Chlon L.,University of Cambridge | Chlon L.,& Cancer Imaging Center in Cambridge and Manchester | And 2 more authors.
PLoS Medicine | Year: 2017

Background: KRAS is the most frequently mutated gene in pancreatic ductal adenocarcinoma (PDAC), but the mechanisms underlying the transcriptional response to oncogenic KRAS are still not fully understood. We aimed to uncover transcription factors that regulate the transcriptional response of oncogenic KRAS in pancreatic cancer and to understand their clinical relevance. Methods and Findings: We applied a well-established network biology approach (master regulator analysis) to combine a transcriptional signature for oncogenic KRAS derived from a murine isogenic cell line with a coexpression network derived by integrating 560 human pancreatic cancer cases across seven studies. The datasets included the ICGC cohort (n = 242), the TCGA cohort (n = 178), and five smaller studies (n = 17, 25, 26, 36, and 36). 55 transcription factors were coexpressed with a significant number of genes in the transcriptional signature (gene set enrichment analysis [GSEA] p < 0.01). Community detection in the coexpression network identified 27 of the 55 transcription factors contributing to three major biological processes: Notch pathway, down-regulated Hedgehog/Wnt pathway, and cell cycle. The activities of these processes define three distinct subtypes of PDAC, which demonstrate differences in survival and mutational load as well as stromal and immune cell composition. The Hedgehog subgroup showed worst survival (hazard ratio 1.73, 95% CI 1.1 to 2.72, coxPH test p = 0.018) and the Notch subgroup the best (hazard ratio 0.62, 95% CI 0.42 to 0.93, coxPH test p = 0.019). The cell cycle subtype showed highest mutational burden (ANOVA p < 0.01) and the smallest amount of stromal admixture (ANOVA p < 2.2e–16). This study is limited by the information provided in published datasets, not all of which provide mutational profiles, survival data, or the specifics of treatment history. Conclusions: Our results characterize the regulatory mechanisms underlying the transcriptional response to oncogenic KRAS and provide a framework to develop strategies for specific subtypes of this disease using current therapeutics and by identifying targets for new groups. © 2017 Sivakumar et al.


Offerman S.C.,University of Manchester | Kadirvel M.,Cancer Imaging Center in Cambridge and Manchester | Abusara O.H.,University of Manchester | Bryant J.L.,University of Manchester | And 7 more authors.
MedChemComm | Year: 2017

Natural prenylated indoles have been proposed as potential anticancer agents. To exploit this discovery for developing new peptide therapeutics, we report the first studies whereby incorporation of prenylated indoles into primary sequences has been achieved. We developed a route to synthesise Nα-Fmoc-protected tryptophan derivatives in which the prenyl group is linked to the N-indole core, using Pd(ii)-mediated C-H functionalisation of 2-methyl-2-butene. Based on the Substance P antagonist G (SPG), a well-known Small Cell Lung Cancer (SCLC) anticancer agent, we designed a new penta-peptide sequence to include a prenyl moiety on one of the tryptophan residues. The N-tert-prenylated tryptophan analogue was assembled into the pentameric peptide using standard solid phase peptide synthesis or liquid phase synthesis by fragment coupling. In vitro screening showed that the N-tert-prenylation of the indole ring on the tryptophan residue located near the C-terminal of the penta-peptide enhanced the cytotoxicity against H69 (IC50 = 2.84 ± 0.14 μM) and DMS79 (IC50 = 4.37 ± 0.44 μM) SCLC cell lines when compared with the unmodified penta-peptide (H69, IC50 = 30.74 ± 0.30 μM and DMS79, IC50 = 23.00 ± 2.07 μM) or the parent SPG sequence (IC50 > 30 μM, both cell lines). SCLC almost invariably relapses with therapy-resistant disease. The DMS79 cell line was established from a patient following treatment with a number of chemotherapeutics (cytoxan, vincristine and methotrexate) and radiation therapy. Treating DMS79 tumour-bearing nude mice provided a human xenograft model of drug resistance to test the efficacy of the prenylated peptide. A low dose (1.5 mg kg−1) of the prenylated peptide was found to reduce tumour growth by ∼30% (P < 0.05) at day 7, relative to the control group receiving vehicle only. We conclude that the availability of the Fmoc-Trp(N-tert-prenyl)-OH amino acid facilitates the synthesis of prenylated-tryptophan-containing peptides to explore their therapeutic potential. © The Royal Society of Chemistry.


Gieling R.G.,University of Manchester | Gieling R.G.,Cancer Imaging Center in Cambridge and Manchester | Fitzmaurice R.J.,Royal Infirmary | Telfer B.A.,University of Manchester | And 3 more authors.
Clinical and Experimental Metastasis | Year: 2015

Complications associated with the development of lung metastases have a detrimental effect on the overall survival rate of many cancer patients. Preclinical models that mimic the clinical aspects of lung metastases are an important tool in developing new therapy options for these patients. The commonly used intravenous models only recapitulate dissemination of cancer cells to the lungs via the haematological route. Here we compared spontaneous and intravenous lung metastases of the highly metastatic KHT mouse fibrosarcoma cells after injecting KHT cells into the subcutaneous layer of the skin or directly into the tail vein. In contrast to the intravenous model, metastases spontaneously arising from the subcutaneous tumours disseminated most consistent with the lymph nodes/lymphatics route and were more hypoxic than the metastases observed following tail-vein administration and haematological spread. To ascertain whether this impacted on drug response, we tested the effectiveness of the hypoxia-sensitive cytotoxin AQ4N (Banoxantrone) in both models. AQ4N was more effective as an anti-metastatic drug in mice with subcutaneous KHT tumours, significantly reducing the metastatic score. Complementing the KHT studies, pathology studies in additional models of spontaneous lung metastases showed haematological (HCT116 intrasplenic implant) or mixed haematological/lymphatic (B16 intradermal implant) spread. These data suggest that preclinical models can demonstrate differing, clinically relevant dissemination patterns, and that careful selection of preclinical models is required when evaluating new strategies for targeting metastatic disease. © 2015, Springer Science+Business Media Dordrecht.


Fleming I.N.,Biomedical Imaging Center | Manavaki R.,University of Cambridge | Blower P.J.,King's College London | West C.,University of Manchester | And 8 more authors.
British Journal of Cancer | Year: 2015

Hypoxia, a hallmark of most solid tumours, is a negative prognostic factor due to its association with an aggressive tumour phenotype and therapeutic resistance. Given its prominent role in oncology, accurate detection of hypoxia is important, as it impacts on prognosis and could influence treatment planning. A variety of approaches have been explored over the years for detecting and monitoring changes in hypoxia in tumours, including biological markers and noninvasive imaging techniques. Positron emission tomography (PET) is the preferred method for imaging tumour hypoxia due to its high specificity and sensitivity to probe physiological processes in vivo, as well as the ability to provide information about intracellular oxygenation levels. This review provides an overview of imaging hypoxia with PET, with an emphasis on the advantages and limitations of the currently available hypoxia radiotracers. © 2015 Cancer Research UK. All rights reserved.


Zhou F.-L.,University of Manchester | Zhou F.-L.,Cancer Imaging Center in Cambridge and Manchester | Hubbard Cristinacce P.L.,University of Manchester | Eichhorn S.J.,University of Exeter | And 2 more authors.
NanoScience and Technology | Year: 2015

Diffusion magnetic resonance imaging (dMRI) provides a non-invasive tool to explore biological tissues, including brain with its highly organised hierarchical fibrous structures. An MR phantom is a test object with known size and material for the calibration of MR scanners and the validation of image processing algorithms. Despite extensive research on the development of brain-mimicking phantoms, there are significant problems with using the existing phantoms for dMRI. This chapter is designed to lead the reader through the development of brain-mimetic phantoms for application in dMRI. Our starting point is a brief introduction to the dMRI technique and phantoms previously developed to mimic brain tissues. The second section focuses on the preparation and characterization of novel physical phantoms composed of co-electrospun hollow microfibres. Finally, the evaluation of the developed co-electrospun phantoms is presented in the third section. © Springer International Publishing Switzerland 2015.


Alnabulsi S.,University of Manchester | Santina E.,University of Manchester | Russo I.,University of Manchester | Hussein B.,University of Manchester | And 9 more authors.
European Journal of Medicinal Chemistry | Year: 2016

NRH:quinone oxidoreductase 2 enzyme (NQO2) is a potential therapeutic target in cancer and neurodegenerative diseases, with roles in either chemoprevention or chemotherapy. Here we report the design, synthesis and evaluation of non-symmetrical furan-amidines and their analogues as novel selective NQO2 inhibitors with reduced adverse off-target effects, such as binding to DNA. A pathway for the synthesis of the non-symmetrical furan-amidines was established from the corresponding 1,4-diketones. The synthesized non-symmetrical furan-amidines and their analogues showed potent NQO2 inhibition activity with nano-molar IC50 values. The most active compounds were non-symmetrical furan-amidines with meta- and para-nitro substitution on the aromatic ring, with IC50 values of 15 nM. In contrast to the symmetric furan-amidines, which showed potent intercalation in the minor grooves of DNA, the synthesized non-symmetrical furan-amidines showed no affinity towards DNA, as demonstrated by DNA melting temperature experiments. In addition, Plasmodium parasites, which possess their own quinone oxidoreductase PfNDH2, were inhibited by the non-symmetrical furan-amidines, the most active possessing a para-fluoro substituent (IC50 9.6 nM). The high NQO2 inhibition activity and nanomolar antimalarial effect of some of these analogues suggest the lead compounds are worthy of further development and optimization as potential drugs for novel anti-cancer and antimalarial strategies. © 2016 Elsevier Masson SAS.


Zhou F.-L.,University of Manchester | Zhou F.-L.,Cancer Imaging Center in Cambridge and Manchester | Parker G.J.M.,University of Manchester | Parker G.J.M.,Cancer Imaging Center in Cambridge and Manchester | And 2 more authors.
Materials Characterization | Year: 2015

The development of co-electrospun (co-ES) hollow microfibrous assemblies of an appreciable thickness is critical for many practical applications, including filtration membranes and tissue-mimicking scaffolds. In this study, thick uniaxially aligned hollow microfibrous assemblies forming fiber bundles and strips were prepared by co-ES of polycaprolactone (PCL) and polyethylene oxide (PEO) as shell and core materials, respectively. Hollow microfiber bundles were deposited on a fixed rotating disc, which resulted in non-controllable cross-sectional shapes on a macroscopic scale. In comparison, fiber strips were produced with tuneable thickness and width by additionally employing an x-y translation stage in co-ES. Scanning electron microscopy (SEM) images of cross-sections of fiber assemblies were analyzed to investigate the effects of production time (from 0.5 h to 12 h), core flow rate (from 0.8 mL/h to 2.0 mL/h) and/or translation speed (from 0.2 mm/s to 5 mm/s) on the pores and porosity. We observed significant changes in pore size and shape with core flow rate but the influence of production time varied; five strips produced under the same conditions had reasonably good size and porosity reproducibility; pore sizes didn't vary significantly from strip bottom to surface, although the porosity gradually decreased and then returned to the initial level. © 2015 The Authors. Published by Elsevier Inc.


Jeanmaire D.,University of Manchester | Timco G.A.,University of Manchester | Gennari A.,University of Manchester | Sproules S.,University of Manchester | And 5 more authors.
Chemical Communications | Year: 2015

A new nano contrast agent has been prepared incorporating a molecular magnet in oxidation-responsive nanoparticles; this system has shown a remarkable sensitivity to hydrogen peroxide (detection down to at least 40 μM), which was used as a model reactive oxygen species. Surprisingly, the response had a binary (off/on) character, due to a non-linear cascade relation between extent of oxidation and water permeability in the particles. © The Royal Society of Chemistry 2015.


Brochu F.M.,University of Cambridge | Joseph J.,University of Cambridge | Joseph J.,Cancer Imaging Center in Cambridge and Manchester | Tomaszewski M.,University of Cambridge | And 4 more authors.
Progress in Biomedical Optics and Imaging - Proceedings of SPIE | Year: 2015

MultiSpectral Optoacoustic Tomography (MSOT) is a fast developing imaging modality, combining the high resolution and penetration depth of ultrasound with the excellent contrast from optical imaging of tissue. Absorption and scattering of the near infrared excitation light modulates the spectral profile of light as it propagates deep into biological tissue, meaning the images obtained provide only qualitative insight into the distribution of tissue chromophores. The goal of this work is to accurately recover the spectral profile of excitation light by modelling light fluence in the data reconstruction, to enable quantitative imaging. We worked with a commercial small animal MSOT scanner and developed our light fluence correction for its' cylindrical geometry. Optoacoustic image reconstruction pinpoints the sources of acoustic waves detected by the transducers and returns the initial pressure amplitude at these points. This pressure is the product of the dimensionless Grüneisen parameter, the absorption coefficient and the light fluence. Under the condition of constant Grüneisen parameter and well modelled light fluence, there is a linear relationship between the initial pressure amplitude measured in the optoacoustic image and the absorption coefficient. We were able to reproduce this linear relationship in different physical regions of an agarose gel phantom containing targets of known optical absorption coefficient, demonstrating that our light fluence model was working. We also demonstrate promising results of light fluence correction effects on in vivo data. © 2015 SPIE.


Gordon G.S.D.,University of Cambridge | Joseph J.,University of Cambridge | Joseph J.,Cancer Imaging Center in Cambridge and Manchester | Bohndiek S.E.,University of Cambridge | And 2 more authors.
Journal of Lightwave Technology | Year: 2015

In this paper, a novel single-pixel method for coherent imaging through an endoscopic fiber bundle is presented. The use of a single-pixel detector allows greater sensitivity over a wider range of wavelengths, which could have significant applications in an endoscopic fluorescence microscopy. First, the principle of lensless focussing at the distal end of a coherent fiber bundle is simulated to examine the impact of pixelation at microscopic scales. Next, an experimental optical correlator system using spatial light modulators is presented. A simple contrast imaging method of characterizing and compensating phase aberrations introduced by fiber bundles is described. Experimental results are then presented showing that our phase compensation method enables characterization of the optical phase profile of individual fiberlets. After applying this correction, early results demonstrating the ability of the system to electronically adjust the focal plane at the distal end of the fiber bundle are presented. The structural similarity index between the simulated image and the experimental focus-adjusted image increases noticeably when the phase correction is applied and the retrieved image is visually recognizable. Strategies to improve image quality are discussed. © 1983-2012 IEEE.

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