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Kelleher F.C.,St Vincents University Hospital | Kelleher F.C.,Peter MacCallum Cancer Center
Carcinogenesis | Year: 2011

Objective: To conduct a systematic review of the role that the hedgehog signaling pathway has in pancreatic cancer tumorigenesis. Method. PubMed search (2000-2010) and literature based references. Results: Firstly, in 2009 a genetic analysis of pancreatic cancers found that a core set of 12 cellular signaling pathways including hedgehog were genetically altered in 67-100% of cases. Secondly, in vitro and in vivo studies of treatment with cyclopamine (a naturally occurring antagonist of the hedgehog signaling pathway component; Smoothened) has shown that inhibition of hedgehog can abrogate pancreatic cancer metastasis. Thirdly, experimental evidence has demonstrated that sonic hedgehog (Shh) is correlated with desmoplasia in pancreatic cancer. This is important because targeting the Shh pathway potentially may facilitate chemotherapeutic drug delivery as pancreatic cancers tend to have a dense fibrotic stroma that extrinsically compresses the tumor vasculature leading to a hypoperfusing intratumoral circulation. It is probable that patients with locally advanced pancreatic cancer will derive the greatest benefit from treatment with Smoothened antagonists. Fourthly, it has been found that ligand dependent activation by hedgehog occurs in the tumor stromal microenvironment in pancreatic cancer, a paracrine effect on tumorigenesis. Finally, in pancreatic cancer, cells with the CD44+CD24+ESA+ immunophenotype select a population enriched for cancer initiating stem cells. Shh is increased 46-fold in CD44+CD24+ESA+ cells compared with normal pancreatic epithelial cells. Medications that destruct pancreatic cancer initiating stem cells are a potentially novel strategy in cancer treatment. Conclusions: Aberrant hedgehog signaling occurs in pancreatic cancer tumorigenesis and therapeutics that target the transmembrane receptor Smoothened abrogate hedgehog signaling and may improve the outcomes of patients with pancreatic cancer. © The Author 2010. Published by Oxford University Press. All rights reserved. Source

Mohd M.S.N.,Beaumont Hospital | Crown J.,St Vincents University Hospital | Hennessy B.T.,Beaumont Hospital
Annals of Oncology | Year: 2012

Background: Approximately 15%-23% of breast cancers overexpress human epidermal growth factor receptor 2 (HER2), which leads to the activation of signaling pathways that stimulate cell proliferation and survival. HER2-targeted therapy has substantially improved outcomes in patients with HER2-positive breast cancer. However, both de novo and acquired resistance are observed. Design: A literature search was performed to identify proposed mechanisms of resistance to HER2-targeted therapy and identified novel targets in clinical development for treating HER2-resistant disease. Results: Proposed HER2-resistance mechanisms include impediments to HER2-inhibitor binding, signaling through alternative pathways, upregulation of signaling pathways downstream of HER2, and failure to elicit an appropriate immune response. Although continuing HER2 inhibition beyond progression may provide an additional clinical benefit, the availability of novel therapies targeting different mechanisms of action could improve outcomes. The developmental strategy with the most available data is targeting the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (mTOR) pathway. The oral mTOR inhibitor everolimus has shown promising activity in combination with chemotherapy and trastuzumab in trastuzumab-refractory, advanced breast cancer. Conclusions: Non-HER2-targeted therapy is a promising means of overcoming resistance to HER2-targeted treatment. Ongoing clinical studies will provide additional information on the efficacy and safety of novel targeted therapies in HER2-resistant advanced breast cancer.. © The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. Source

Kennelly S.,Trinity College Dublin | Collins O.,St Vincents University Hospital
Journal of Alzheimer's Disease | Year: 2012

Vascular risk factors are implicated in the pathogenesis of Alzheimer's disease (AD). There is an age-dependent relationship between blood pressure and the risk of AD. Given the potential temporal lag that can exist between the two conditions, longitudinal population studies offer the best opportunity to identify a causal relationship. Midlife hypertension increases the risk for AD, yet later-life hypertension does not appear to confer the same risk and may in fact be protective. Low diastolic blood pressure, especially in later-life, is associated with an increased risk of AD. Orthostatic hypotension and other neurocardiovascular syndromes may increase the risk for cognitive impairment and AD. Several physiopathological mechanisms may contribute to this increased risk. Dynamic blood pressure changes and impaired cerebrovascular autoregulation may result in cerebral hypoperfusion. Hypertensive patients also develop cerebral infarcts, resulting in diminished perfusion. Subsequent hypoxia driven pathways result in increased cerebral amyloid-β and phosphorylated tau protein accumulation. Treatment of elevated blood pressure with antihypertensive medications attenuates the risk of AD attributable to elevated midlife hypertension. Certain antihypertensive compounds have neuroprotective properties that may reduce the risk of AD, independent of their effects on blood pressure. © 2012 - IOS Press and the authors. All rights reserved. Source

Duffy M.J.,St Vincents University Hospital | Duffy M.J.,University College Dublin
Tumor Biology | Year: 2013

Of all the diseases affecting humankind, cancer is one of the most difficult to treat and cure. One of the main reasons for this difficulty relates to the fact that cancer is not a single disease but consists of hundreds of different types. Furthermore, cancers exhibit considerable genetic complexity with more than 400 different genes implicated in their development. In addition, cancers display major inter- and intratumor heterogeneity. Despite these complexities, several successes have been achieved in recent years. Most of these successes relate to the specific targeting of driver genes involved in cancer development. These successes include imatinib for the treatment of chronic myeloid leukemia, anti-HER2 therapies (trastuzumab, pertuzumab, and lapatinib) to treat breast cancer, anti-EGFR tyrosine kinase inhibitors (gefitinib and erlotinib) to treat non-small cell lung cancer, and anti-BRAF agents (vemurafenib and dabrafenib) to treat melanoma. Although the war on cancer has not yet been won, neither has it been lost. With continued basic and clinical research, cancer is being transformed into a chronic disease in which patients have increased survival rates and better quality of life. © 2013 International Society of Oncology and BioMarkers (ISOBM). Source

Haroon M.,Park University | Kirby B.,St Vincents University Hospital | FitzGerald O.,Park University
Annals of the Rheumatic Diseases | Year: 2013

Objectives The objectives of this study were to: (1) assess the prevalence of psoriatic arthritis (PsA) among Psoriasis (Ps) patients attending dermatology clinics; (2) identify clinical predictors of the development of PsA; and (3) compare the performance of three PsA screening questionnaires: Psoriatic Arthritis Screening and Evaluation (PASE), Psoriasis Epidemiology Screening Tool (PEST) and Toronto Psoriatic Arthritis Screening (ToPAS). Methods Patients were divided into two groups: Group-1, consecutive psoriasis patients attending dermatology clinics with no known diagnosis of inflammatory arthritis and Group-2, consecutive patients attending rheumatology clinics with a confirmed diagnosis of PsA. In Group-1, patients completed the screening questionnaires, followed by a full rheumatological evaluation whether or not they reported musculoskeletal symptoms. Results 200 patients were recruited with 100 in each group. In all, 84% of patients in dermatology group were using systemic therapy for their skin disease, and 99% of patients in rheumatology group were on systemic immunosuppressives. In Group-1, 29% of patients were diagnosed with PsA after rheumatological evaluation. On univariate and multivariate analyses, there was a significant positive association between Psoriasis Area and Severity Index and a new diagnosis of PsA (p=0.046). Different patterns of joint involvement were noted in patients with newly diagnosed PsA versus patients with established PsA with fewer polyarticular disease presentations (p=0.0001). In Group-1, the PEST, PASE and ToPAS assessments had sensitivities of 27.5%, 24% and 41%, and specificities of 98%, 94% and 90%, respectively. In Group-2, the sensitivities were 86%, 62% and 83%, respectively. Conclusions 29% of Ps patients attending dermatology clinics had undiagnosed PsA. Psoriasis severity was associated with a new diagnosis of PsA. Poor sensitivities for the screening questionnaires were noted due to inadequate detection of patterns of arthritis other than polyarticular disease. Source

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