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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. Source


Krell J.,Hammersmith Hospital | Frampton A.E.,HPB Surgical Unit | Mirnezami R.,Imperial College London | Harding V.,Hammersmith Hospital | And 10 more authors.
PLoS ONE | Year: 2014

Background: The growth arrest-specific transcript 5 gene (GAS5) encodes a long noncoding RNA (lncRNA) and hosts a number of small nucleolar RNAs (snoRNAs) that have recently been implicated in multiple cellular processes and cancer. Here, we investigate the relationship between DNA damage, p53, and the GAS5 snoRNAs to gain further insight into the potential role of this locus in cell survival and oncogenesis both in vivo and in vitro. Methods: We used quantitative techniques to analyse the effect of DNA damage on GAS5 snoRNA expression and to assess the relationship between p53 and the GAS5 snoRNAs in cancer cell lines and in normal, pre-malignant, and malignant human colorectal tissue and used biological techniques to suggest potential roles for these snoRNAs in the DNA damage response. Results: GAS5-derived snoRNA expression was induced by DNA damage in a p53-dependent manner in colorectal cancer cell lines and their levels were not affected by DICER. Furthermore, p53 levels strongly correlated with GAS5-derived snoRNA expression in colorectal tissue. Conclusions: In aggregate, these data suggest that the GAS5-derived snoRNAs are under control of p53 and that they have an important role in mediating the p53 response to DNA damage, which may not relate to their function in the ribosome. We suggest that these snoRNAs are not processed by DICER to form smaller snoRNA-derived RNAs with microRNA (miRNA)-like functions, but their precise role requires further evaluation. Furthermore, since GAS5 host snoRNAs are often used as endogenous controls in qPCR quantifications we show that their use as housekeeping genes in DNA damage experiments can lead to inaccurate results. © 2014 Krell et al. Source


Spampinato M.G.,HPB Surgical Unit | Coratti A.,Misericordia Hospital | Bianco L.,Misericordia Hospital | Caniglia F.,University of Pisa | And 4 more authors.
Surgical Endoscopy and Other Interventional Techniques | Year: 2014

Background: Laparoscopic major hepatectomy (LMH), although safely feasible in experienced hands and in selected patients, is a formidable challenge because of the technical demands of controlling hemorrhage, sealing bile ducts, avoiding gas embolism, and maintaining oncologic surgical principles. The enhanced surgical dexterity offered by robotic assistance could improve feasibility and/or safety of minimally invasive major hepatectomy. The aim of this study was to compare perioperative outcomes of LMH and robotic-assisted major hepatectomy (RMH).Methods: Pooled data from four Italian hepatobiliary centers were analyzed retrospectively. Demographic data, operative, and postoperative outcomes were collected from prospectively maintained databases and compared.Results: Between January 2009 and December 2012, 25 patients underwent LMH and 25 RMH. The two groups were comparable for all baseline characteristics including type of resection and underlying pathology. Conversion to open surgery was required in one patient in each group (4 %). No difference was noted in operative time, estimated blood, and need for allogenic blood transfusions. Intermittent pedicle occlusion was required only in LMH (32 % vs. 0; p = 0.004). Length of hospital stay, including time spent in intensive care unit, was similar between the two groups, but patients undergoing LMH showed quicker recovery of bowel activity, with shorter time to first flatus (1 vs. 3 days; p = 0.023) and earlier tolerance to oral liquid diet (1 vs. 2 days; p = 0.001). No difference was noted in complication rate, 90-day mortality, and readmission rate.Conclusions: This retrospective multi-institution study confirms that selected patients can safely undergo minimally invasive major hepatectomy, either LMH or RMH. The fact that intermittent pedicle occlusion could be avoided in RMH suggests improved surgical ability to deal with bleeding during liver transection, but further studies are needed before any final conclusion can be drawn. © 2014, Springer Science+Business Media New York. Source


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. Source


Krell J.,Imperial College London | Frampton A.E.,HPB Surgical Unit | Colombo T.,University of Rome La Sapienza | Gall T.M.,HPB Surgical Unit | And 4 more authors.
Epigenomics | Year: 2013

p53 is one of the most frequently mutated tumor suppressors. It regulates protein-coding genes and noncoding RNAs involved in many cellular processes, functioning predominantly at the transcriptional level but also through nontranscriptional processes. miRNAs have recently been identified as key mediators of the p53 stress-response pathway. p53 regulates miRNA transcription and processing, and miRNAs regulate p53 activity and expression and, accordingly, various feedback/feed-forward loops have been identified. Many chemotherapeutic agents induce cancer cell death or senescence via DNA damage and the subsequent activation of p53. Resistance to chemotherapy can occur due to the mutation of components in p53 signaling networks. A better understanding of the role of the various components within these pathways and their interactions with each other may allow the modification and improvement of current treatments, and the design of novel therapies. Improving our knowledge of the role of miRNAs in such p53 signaling networks may be crucial to achieving this. © 2013 Future Medicine Ltd. Source

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