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Duffy D.J.,University College Dublin | Krstic A.,University College Dublin | Schwarzl T.,University College Dublin | Higgins D.G.,University College Dublin | And 3 more authors.
Molecular Cancer Therapeutics | Year: 2014

Neuroblastoma is an embryonal tumor accounting for approximately 15% of childhood cancer deaths. There exists a clinical need to identify novel therapeutic targets, particularly for treatment-resistant forms of neuroblastoma. Therefore, we investigated the role of the neuronal master regulator GSK3 in controlling neuroblastoma cell fate. We identified novel GSK3-mediated regulation of MYC (c-MYC and MYCN) mRNA levels, which may have implications for numerous MYC-driven cancers. In addition, we showed that certain GSK3 inhibitors induced large-scale cell death in neuroblastoma cells, primarily through activating apoptosis. mRNA-seq of GSK3 inhibitor-treated cells was performed and subsequent pathway analysis revealed that multiple signaling pathways contributed to the loss of neuroblastoma cell viability. The contribution of two of the signaling pathways highlighted by the mRNA-seq analysis was functionally validated. Inhibition of the p53 tumor suppressor partly rescued the cell death phenotype, whereas activation of canonical Wnt signaling contributed to the loss of viability, in a p53-independent manner. Two GSK3 inhibitors (BIO-acetoxime and LiCl) and one small-molecule Wnt agonist (Wnt Agonist 1) demonstrated therapeutic potential for neuroblastoma treatment. These inhibitors reduced the viability of numerous neuroblastoma cell lines, even those derived from high-risk MYCN-amplified metastatic tumors, for which effective therapeutics are currently lacking. Furthermore, although LiCl was lethal to neuroblastoma cells, it did not reduce the viability of differentiated neurons. Taken together our data suggest that these small molecules may hold potential as effective therapeutic agents for the treatment of neuroblastoma and other MYC-driven cancers. Mol Cancer Ther; 13(2); 454-67. © 2013 American Association for Cancer Research.


Kenny O.,Teagasc | Kenny O.,Conway Institute of Biomolecular and Biomedical Research | Smyth T.J.,Teagasc | Hewage C.M.,Conway Institute of Biomolecular and Biomedical Research | Brunton N.P.,Teagasc
Food Chemistry | Year: 2013

Freeze-dried fenugreek (Trigonella foenum-graecum) seeds and bitter melon (Momordica charantia) fruit were extracted sequentially using non-polar to polar solvents, with further separation carried out on polar extracts by molecular weight cut off dialysis. The fenugreek ethyl acetate crude extract (FGE3) demonstrated the highest antioxidant activity, in terms of Trolox Equivalents (TE), for both the DPPH (35.338 ± 0.908 mg TE/g) and FRAP (77.352 ± 0.627 mg TE/g) assays. This extract also contained the highest phenolic content, in terms of Gallic Acid Equivalents (GAE) (106.316 ± 0.377 mg GAE/g). Despite having considerably lower antioxidant activity than fenugreek, the highest antioxidant activities for bitter fruit were observed in the hexane (BME1) and methanol hydrophilic < 3.5 kDa dialysed (BME4 < 3.5 kDa) extracts, while the highest phenolic content was found in the methanol hydrophilic > 3.5 kDa (BME4 > 3.5 kDa) dialysed extract. UPLC-MS was used to quantify 18 phenolic compounds from fenugreek and 13 from bitter melon in active crude extracts. The flavonoids apigenin- 7-O-glycoside (1955.55 ng/mg) and luteolin-7-O-glycoside (725.50 ng/mg) were the most abundant compounds in FGE3, while bitter melon extracts contained only small amounts of mainly phenolic acids. A further 5 fenugreek and 1 bitter melon compounds were identified in trace amounts from the same extracts, respectively. © 2013 Elsevier Ltd. All rights reserved.


Fizazi K.,Institut Universitaire de France | Sternberg C.N.,San Camillo and Forlanini Hospitals | Fitzpatrick J.M.,University College Dublin | Watson R.W.,Conway Institute of Biomolecular and Biomedical Research | Tabesh M.,Pfizer
BJU International | Year: 2010

Over the past decade, the treatment of advanced prostate cancer has developed significantly, and perhaps the most dramatic shift came in 2004 with the demonstration that docetaxel-based chemotherapy significantly improved overall survival in patients with castration-resistant prostate cancer. This led to a significant expansion of the role of chemotherapy in the management of prostate cancer. In addition, there is now considerable progress being made in the development of more effective antiandrogens, cytochrome P17 inhibitors, novel chemotherapy regimens, targeted therapies, and immunotherapies that can complement existing therapies and may soon become integrated into the treatment paradigm. Progress in our understanding of molecular signalling pathways that play an important role in prostate cancer has stimulated the investigation of targeted therapies, including antiangiogenic agents, bone-targeted agents, and specific inhibitors of key signalling molecules and chaperone proteins. For the most part, targeted agents are being combined with chemotherapy, similar to the approach taken in other solid tumours. Various therapeutic vaccine strategies also appear to have potential in the treatment of advanced prostate cancer. However, the development of new approaches to the treatment of prostate cancer presents many challenges that will demand collaboration and consensus building with respect to biomarkers for patient selection, clinical endpoints, and trial designs. © 2010 BJU International.


Naciri M.,Conway Institute of Biomolecular and Biomedical Research | Dowling D.,University College Dublin | Al-Rubeai M.,Conway Institute of Biomolecular and Biomedical Research
Plasma Processes and Polymers | Year: 2014

In vitro experiments demonstrated a differential sensitivity to non-thermal atmospheric plasma among three mammalian cell lines. The highest proliferation rates, osteoblast cells (MG63) were the most sensitive; Chinese hamster ovary cells (CHO), with the lowest proliferation rate, were the least sensitive; and colon cancer cells (SW480) were in between. Apoptosis was found to increase in all cell lines and at all levels of exposure in comparison to the controls. Cells grown in batch cultures, following plasma exposure, demonstrated similar trends of decreasing proliferation rates and ATP concentrations as exposure time increased. The investigation demonstrated that plasma exposure increases the propensity of surviving cells to adhere to surfaces. SEM and fluorescence studies showed that plasma-exposed cells exhibited better cell spreading and cell adhesion. Non-thermal plasma rapidly inactivated cells by permeabilizing the cell surface, resulting in loss of membrane integrity. Interestingly, plasma exposure enhanced cell adhesion to surfaces, possibly by increasing lamellipodia and various long filopodia and elicited a marked dose-dependent inhibition of the proliferation of cultured cells. The data support the hypothesis that plasma sensitivity closely correlates with proliferation rates. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


O'Shea L.C.,Conway Institute of Biomolecular and Biomedical Research | Mehta J.,University College Dublin | Lonergan P.,University College Dublin | Hensey C.,Conway Institute of Biomolecular and Biomedical Research | Fair T.,University College Dublin
Systems Biology in Reproductive Medicine | Year: 2012

Common aspects of infertility can be seen across several species. In humans, dairy cows, and mares there is only a 25-35% chance of producing a live offspring after a single insemination, whether natural or artificial. Oocyte quality and subsequent embryo development can be affected by factors such as nutrition, hormonal regulation, and environmental influence. The objective of this study was to identify genes expressed in oocytes and/or cumulus cells, across a diverse range of species, which may be linked to the ability an oocyte has to develop following fertilization. Performing a meta-analysis on previously published microarray data on various models of oocyte and embryo quality allowed for the identification of 56 candidate genes associated with oocyte quality across several species, 4 of which were identified in the cumulus cells that surround the oocyte. Twenty-one potential biomarkers were associated with increased competence and 35 potential biomarkers were associated with decreased competence. The upregulation of Metap2, and the decrease of multiple genes linked to mRNA and protein synthesis in models of competence, highlights the importance of de novo protein synthesis and its regulation for successful oocyte maturation and subsequent development. The negative regulation of Wnt signaling has emerged in human, monkey, bovine, and mouse models of oocyte competence. Atrx expression was linked to decreased competence in both oocytes and cumulus cells. Biological networks and transcription factor regulation associated with increased and decreased competence were also identified. These genes could potentially act as biomarkers of oocyte quality or as pharmacological targets for manipulation in order to improve oocyte developmental potential. Copyright © 2012 Informa Healthcare USA, Inc.


Yang S.,National University of Ireland, Maynooth | Wang B.,National University of Ireland, Maynooth | Tang L.S.,National University of Ireland, Maynooth | Siednienko J.,National University of Ireland, Maynooth | And 2 more authors.
Nature Communications | Year: 2013

Tumour necrosis factor-α (TNF) can activate NF-κB to induce pro-inflammatory genes but can also stimulate the caspase cascade to promote apoptosis. Here we show that deficiency of the ubiquitin E3 ligase, Pellino3, sensitizes cells to TNF-induced apoptosis without inhibiting the NF-κB pathway. Suppressed expression of Pellino3 leads to enhanced formation of the death-induced signalling complex, complex II, in response to TNF. We show that Pellino3 targets RIP1, in a TNF-dependent manner, to inhibit TNF-induced complex II formation and caspase 8-mediated cleavage of RIP1 in response to TNF/cycloheximide co-stimulation. Pellino3-deficient mice also show increased sensitivity to TNF-induced apoptosis and greatly increased lethality in response to TNF administration. These findings define Pellino3 as a novel regulator of TNF signalling and an important determining factor in dictating whether TNF induces cell survival or death.


Long R.,Conway Institute of Biomolecular and Biomedical Research | English N.J.,Conway Institute of Biomolecular and Biomedical Research | Mooney D.A.,Conway Institute of Biomolecular and Biomedical Research
Physics Letters, Section A: General, Atomic and Solid State Physics | Year: 2010

The large intrinsic band gap of NiO has hindered severely its potential application under visible-light irradiation. In this Letter, we have performed first-principles calculations on the electronic properties of N- and C-doped NiO to ascertain if its band gap may be narrowed theoretically. It was found that impurity bands driven by N 2p or C 2p states appear in the band gap of NiO and that some of these locate at the conduction band minimum, which leads to a significant band gap narrowing. Our results show that N-doped NiO may serve as a potential photocatalyst relative to C-doped NiO, due to the presence of some recombination centres in C-doped NiO. © 2009 Elsevier B.V. All rights reserved.


Kennedy A.,St. Vincent's Institute | Ng C.T.,St. Vincent's Institute | Biniecka M.,St. Vincent's Institute | Saber T.,St. Vincent's Institute | And 4 more authors.
Arthritis and Rheumatism | Year: 2010

Objective. To assess blood vessel stability in inflammatory synovial tissue (ST) and to examine neural cell adhesion molecule (NCAM), oxidative DNA damage, and hypoxia in vivo. Methods. Macroscopic vascularity and ST oxygen levels were determined in vivo in patients with inflammatory arthritis who were undergoing arthroscopy. Vessel maturity/stability was quantified in matched ST samples by dual immunofluorescence staining for factor VIII (FVIII)/α-smooth muscle actin (α-SMA). NCAM and 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) were examined by immunohistochemistry. Angiogenesis was assessed in vitro, using human dermal endothelial cells (HDECs) in a Matrigel tube formation assay. Results. A significant number of immature vessels (showing no pericyte recruitment) was observed in tissue from patients with inflammatory arthritis (P < 0.001), in contrast to osteoarthritic and normal tissue, which showed complete recruitment of pericytes. Low in vivo PO2 levels in the inflamed joint (median [range] 22.8 [3.2-54.1] mm Hg) were inversely related to increased macroscopic vascularity (P < 0.04) and increased microscopic expression of FVIII and α-SMA (P < 0.04 and P < 0.03, respectively). A significant proportion of vessels showed focal expression of NCAM and strong nuclear 8-oxodG expression, implicating a loss of EC-pericyte contact and increased DNA damage, levels of which were inversely associated with low in vivo PO2 (P = 0.04 for each comparison). Circulating cells were completely negative for 8-oxodG. Exposure of HDEC to 3% O2 (reflecting mean ST in vivo measurements) significantly increased EC tube formation (P < 0.05). Conclusion. Our findings indicate the presence of unstable vessels in inflamed joints associated with hypoxia, incomplete EC-pericyte interactions, and increased DNA damage. These changes may further contribute to persistent hypoxia in the inflamed joint to further drive this unstable microenvironment. © 2010, American College of Rheumatology.


Mourad J.-J.,Hopital Avicenne | O'Brien E.,Conway Institute of Biomolecular and Biomedical Research
Current Hypertension Reports | Year: 2010

Ambulatory blood pressure (BP) monitoring is increasingly used in the evaluation of hypertensive patients. The ability to monitor BP throughout the day and night allows the detection of abnormal nocturnal BP patterns, the most common being a "nondipping" pattern, which is associated with increased cardiovascular risk; its correction appears to have a positive impact on cardiovascular outcome. Antihypertensive treatment should be individually adjusted to control BP during both daytime and nighttime. However, drug-induced lowering of nocturnal BP, if excessive, could amplify the morning BP surge in patients with daytime BP elevation, increasing the risk of developing a cardiovascular event. Ambulatory BP monitoring therefore represents a unique tool to establish the most appropriate antihypertensive drug regimen for the individual patient. © 2010 Springer Science+Business Media, LLC.


Duffy C.D.,Conway Institute of Biomolecular and Biomedical Research | Guiry P.J.,Conway Institute of Biomolecular and Biomedical Research
MedChemComm | Year: 2010

Lipoxins are naturally occurring signalling molecules which play an integral role in the resolution of inflammation. In this review, we highlight the synthetic and biological developments of novel stable Lipoxin analogues, which show resistance to enzymatic metabolism. This article aims to illustrate the major and noteworthy synthetic obstacles and achievements which have dominated this active area of research over the past twenty five years. We examine the synthetic routes to stable Lipoxin analogues and the evaluation of their biological potency in an ongoing effort to provide novel therapeutic agents to combat an array of inflammatory diseases. © 2011 The Royal Society of Chemistry.

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