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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.

Kennedy A.,St. Vincents Institute | Ng C.T.,St. Vincents Institute | Biniecka M.,St. Vincents Institute | Saber T.,St. Vincents 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.

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.

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.

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