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Frampton A.E.,HPB Surgical Unit | Gall T.M.,HPB Surgical Unit | Castellano L.,Imperial College London | Stebbing J.,Hammersmith Hospital Campus | And 2 more authors.
Expert Review of Molecular Diagnostics | Year: 2013

Evaluation of: Ali S, Saleh H, Sethi S, Sarkar FH, Philip PA. MicroRNA profiling of diagnostic needle aspirates from patients with pancreatic cancer. Br. J. Cancer 107(8), 1354-1360 (2012). Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease, despite advances in imaging, surgery and a greater understanding of its molecular biology. Patient outcomes remain poor due to an inability to detect disease early and resistance to anticancer treatments. miRNAs are promised to become ideal cancer biomarkers, as they are tumor and tissue specific and also incredibly stable molecules. So far, large profiling studies of the PDAC miRNome have identified the 'usual suspects' known to be deregulated in solid tumors, such as oncomiR-21, as well as others that could be more robust for differentiating malignant from benign pancreatic disease. However, many of these are yet to be validated clinically. The paper under evaluation provides further evidence for the use of miRNAs as diagnostic biomarkers for PDAC. We have reviewed the use of miRNAs as diagnostic analytes for detecting PDAC in biopsies. © 2013 Expert Reviews Ltd.

Malerba A.,Royal Holloway, University of London | Sharp P.S.,Hammersmith Hospital Campus | Graham I.R.,Royal Holloway, University of London | Arechavala-Gomeza V.,University College London | And 5 more authors.
Molecular Therapy | Year: 2011

The administration of antisense oligonucleotides (AOs) to skip one or more exons in mutated forms of the DMD gene and so restore the reading frame of the transcript is one of the most promising approaches to treat Duchenne muscular dystrophy (DMD). At present, preclinical studies demonstrating the efficacy and safety of long-term AO administration have not been conducted. Furthermore, it is essential to determine the minimal effective dose and frequency of administration. In this study, two different low doses (LDs) of phosphorodiamidate morpholino oligomer (PMO) designed to skip the mutated exon 23 in the mdx dystrophic mouse were administered for up to 12 months. Mice treated for 50 weeks showed a substantial dose-related amelioration of the pathology, particularly in the diaphragm. Moreover, the generalized physical activity was profoundly enhanced compared to untreated mdx mice showing that widespread, albeit partial, dystrophin expression restores the normal activity in mdx mice. Our results show for the first time that a chronic long-term administration of LDs of unmodified PMO, equivalent to doses in use in DMD boys, is safe, significantly ameliorates the muscular dystrophic phenotype and improves the activity of dystrophin-deficient mice, thus encouraging the further clinical translation of this approach in humans. © The American Society of Gene & Cell Therapy.

Sharp D.J.,Hammersmith Hospital Campus | Sharp D.J.,Imperial College London | Turkheimer F.E.,Hammersmith Hospital Campus | Turkheimer F.E.,Imperial College London | And 4 more authors.
Annals of Neurology | Year: 2010

The neural mechanism by which patients spontaneously recover cognitive function after brain injury is not understood. Here we demonstrate for the first time that aphasic patients, who have largely recovered language function, show increased frontoparietal integration. A similar change in functional connectivity is also observed when normal subjects are exposed to adverse listening conditions. Thus, compensation for inefficient language processing is associated with increased integration between parts of the language network critical to language control. This change reflects greater top-down control of speech comprehension and provides a mechanism by which language impairments after stroke may be compensated for. © 2010 American Neurological Association.

Pellegrino L.,Hammersmith Hospital Campus | Jacob J.,Hammersmith Hospital Campus | Roca-Alonso L.,Hammersmith Hospital Campus | Krell J.,Hammersmith Hospital Campus | And 2 more authors.
Expert Review of Anticancer Therapy | Year: 2013

Several studies have implicated miRNAs in the initiation and progression of human cancers. Examining the biogenesis pathways that generate these important regulatory molecules has revealed new mechanisms for tumor development. Altered expression of the endoribonuclease Dicer in many tumors has given new hope to unraveling the complex relationship between miRNA processing and cancer. This may provide further insight into mechanisms for targeting multiple genes that are critical for the malignant phenotype of several cancers. The evaluated article demonstrates that Dicer is transcriptionally regulated by Sox4 and reduced levels of this transcription factor consequently leads to a reduction in expression, and therefore deregulation of cancer-related miRNAs in melanoma. Reduced Dicer expression in malignant melanoma is an independent predictor of poor survival. In this review, we assess the prognostic significance of Dicer expression in different tumor types. © 2013 2013 Expert Reviews Ltd.

Zhang H.,Hammersmith Hospital Campus | Xu Y.,Hammersmith Hospital Campus | Filipovic A.,Hammersmith Hospital Campus | Lit L.C.,Hammersmith Hospital Campus | And 4 more authors.
British Journal of Cancer | Year: 2013

Background:We have previously identified kinase suppressor of ras-1 (KSR1) as a potential regulatory gene in breast cancer. KSR1, originally described as a novel protein kinase, has a role in activation of mitogen-activated protein kinases. Emerging evidence has shown that KSR1 may have dual functions as an active kinase as well as a scaffold facilitating multiprotein complex assembly. Although efforts have been made to study the role of KSR1 in certain tumour types, its involvement in breast cancer remains unknown.Methods:A quantitative mass spectrometry analysis using stable isotope labelling of amino acids in cell culture (SILAC) was implemented to identify KSR1-regulated phosphoproteins in breast cancer. In vitro luciferase assays, co-immunoprecipitation as well as western blotting experiments were performed to further study the function of KSR1 in breast cancer.Results:Of significance, proteomic analysis reveals that KSR1 overexpression decreases deleted in breast cancer-1 (DBC1) phosphorylation. Furthermore, we show that KSR1 decreases the transcriptional activity of p53 by reducing the phosphorylation of DBC1, which leads to a reduced interaction of DBC1 with sirtuin-1 (SIRT1); this in turn enables SIRT1 to deacetylate p53.Conclusion:Our findings integrate KSR1 into a network involving DBC1 and SIRT1, which results in the regulation of p53 acetylation and its transcriptional activity. © 2013 Cancer Research UK. All rights reserved.

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