ORCID Profile
0000-0002-6717-6436
Current Organisations
St. James Hospital and Tallaght University Hospital
,
Peter MacCallum Cancer Centre
,
University of Dublin Trinity College
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Publisher: Impact Journals, LLC
Date: 09-04-2016
Publisher: MDPI AG
Date: 22-02-2013
Publisher: Elsevier BV
Date: 2013
DOI: 10.1016/J.CANLET.2013.09.040
Abstract: Physiological processes such as the sleep-wake cycle, metabolism and hormone secretion are controlled by a circadian rhythm adapted to 24h day-night periodicity. This circadian synchronisation is in part controlled by ambient light decreasing melatonin secretion by the pineal gland and co-ordinated by the suprachiasmatic nucleus of the hypothalamus. Peripheral cell autonomous circadian clocks controlled by the suprachiasmatic nucleus, the master regulator, exist within every cell of the body and are comprised of at least twelve genes. These include the basic helix-loop-helix/PAS domain containing transcription factors Clock, BMal1 and Npas2 which activate transcription of the periodic genes (Per1 and Per2) and cryptochrome genes (Cry1 and Cry2). Points of coupling exist between the cellular clock and the cell cycle. Cell cycle genes which are affected by the molecular circadian clock include c-Myc, Wee1, cyclin D and p21. Therefore the rhythm of the circadian clock and cancer are interlinked. Molecular ex les exist including activation of Per2 leads to c-myc overexpression and an increased tumor incidence. Mice with mutations in Cryptochrome 1 and 2 are arrhythmic (lack a circadian rhythm) and arrhythmic mice have a faster rate of growth of implanted tumors. Epidemiological finding of relevance include 'The Nurses' Health Study' where it was established that women working rotational night shifts have an increased incidence of breast cancer. Compounds that affect circadian rhythm exist with attendant future therapeutic possibilities. These include casein kinase I inhibitors and a candidate small molecule KL001 that affects the degradation of cryptochrome. Theoretically the cell cycle and malignant disease may be targeted vicariously by selective alteration of the cellular molecular clock.
Publisher: Oxford University Press (OUP)
Date: 23-07-2013
Abstract: Fibroblast growth factors (FGF) are a family of ligands that bind to four different types of cell surface receptor entitled, FGFR1, FGFR2, FGFR3 and FGFR4. These receptors differ in their ligand binding affinity and tissue distribution. The prototypical receptor structure is that of an extracellular region comprising three immunoglobulin (Ig)-like domains, a hydrophobic transmembrane segment and a split intracellular tyrosine kinase domain. Alternative gene splicing affecting the extracellular third Ig loop also creates different receptor isoforms entitled FGFRIIIb and FGFRIIIc. Somatic fibroblast growth factor receptor (FGFR) mutations are implicated in different types of cancer and germline FGFR mutations occur in developmental syndromes particularly those in which craniosynostosis is a feature. The mutations found in both conditions are often identical. Many somatic FGFR mutations in cancer are gain-of-function mutations of established preclinical oncogenic potential. Gene lification can also occur with 19-22% of squamous cell lung cancers for ex le having lification of FGFR1. Ontologic comparators can be informative such as aberrant spermatogenesis being implicated in both spermatocytic seminomas and Apert syndrome. The former arises from somatic FGFR3 mutations and Apert syndrome arises from germline FGFR2 mutations. Finally, therapeutics directed at inhibiting the FGF/FGFR interaction are a promising subject for clinical trials.
Publisher: Informa UK Limited
Date: 2007
Publisher: Elsevier BV
Date: 06-2012
DOI: 10.1016/J.CLCC.2011.07.001
Abstract: The risk of recurrence of colon cancer after curative surgery can be estimated by using decision aids. These aids use pathologic and patient factors to predict recurrence risk after adjuvant chemotherapy and have been validated when using clinical trial populations however, the performance of 2 decision aids were compared by using a cohort of patients treated at a single center. Patient data were used to estimate the risk of recurrence when using both the Adjuvant! for colon cancer and Memorial Sloan Kettering Cancer Center (MSKCC) decision aids. A receiver operator characteristic (ROC) curve analyzed the predicted chance of being disease free at 5 years against the actual outcome for each patient. This curve was then used to define cutoff points at a chosen sensitivity and specificity to stratify patients into risk groups, and survival curves for each group calculated. Data on 134 patients were analyzed. The Pearson correlation between the 2 nomograms was 0.848 (P < .01). The ROC curve for the MSKCC nomogram had an area under the curve of 0.638. At a sensitivity and a specificity of 0.8, the MSKCC curve has a risk recurrence score of 69% and 84%, respectively. By using these cutoffs to stratify patients into 3 risk groups, a statistically significant difference in survival was found between high risk and low risk (P = .025). Tools to predict risk or recurrence and estimate benefit from therapy may be enhanced in the future by using genetic profiling, but use of existing tools can help deliver a personalized approach to adjuvant therapy.
Publisher: SAGE Publications
Date: 13-01-2021
Abstract: Systemic anti-cancer treatment (SACT) can improve symptoms and survival in patients with incurable cancer but there may be harmful consequences. Information regarding the use of SACT at the end-of-life and its impact on patients has not been described in Ireland. The study aimed to quantify and describe the use of SACT at end-of-life. The primary outcome of interest was the number of patients who received treatment in the last 12, 4 and 2 weeks of life. Secondary outcomes included the frequency of admissions and procedures, location of death, and timing of specialist palliative care (SPC) referral. Retrospective review. Fisher exact testing was used for analyses. Patients were included if they died between January 2015 and July 2017 and received at least 1 dose of treatment for a solid tumor malignancy. Five hundred and eighty two patients were included. Three hundred and thirty eight (58%), 128 (22%) and 36 (6%) received treatment in the last 12, 4 and 2 weeks of life respectively. Patients who received chemotherapy in the last 12 weeks of life were more likely to be admitted to hospital, undergo a procedure, and die in hospital than those who did not (P 0.001 for all). Median time of SPC referral before death was shorter in those patients who received chemotherapy than those who did not (61 v129 days, p = 0.0001). Patients who received chemotherapy had a higher likelihood of hospital admission, invasive procedure, and in-hospital death. They were less likely to have been referred early to SPC services.
Publisher: Humana Press
Date: 2011
DOI: 10.1007/978-1-61779-289-2_13
Abstract: Exosomes are nano-sized, cell membrane surrounded structures that are released from many cell types. These exosomes are believed to transport a range of molecules, including mRNAs, miRNAs, and proteins the contents depending on their cell of origin. The physiological and pathological relevance of exosomes has yet to be fully elucidated. Exosomes have been implicated in cell-to-cell communication. For ex le, in relation to the immune system, such exosomes may enable exchange of antigen or major histocompatibility complex-peptide complexes between antigen-bearing cells and antigen-presenting cells in cancer, they may contain molecules that not only have relevance as biomarkers, but may also be taken up and cause adverse effects on secondary cells. Furthermore, exosomes have been proposed as autologous delivery systems that could be exploited for personalised delivery of therapeutics. In order to explore the contents and functional relevance of exosomes from medium conditioned by culture cells or from other biological fluids, prior to extensive molecular profiling, they must be isolated and purified. Here, we describe differential centrifugation methods suitable for isolating exosomes from conditioned medium and from other biological fluids, including serum, saliva, tumour ascites, and urine. We also detail Western blotting and transmission electron microscopy methods suitable for basic assessment of their presence, size, and purity, prior to progressing to global mRNA, miRNA, or protein profiling.
Publisher: Elsevier BV
Date: 09-2010
DOI: 10.1016/J.EJCA.2010.04.006
Abstract: The anaplastic lymphoma kinase gene (ALK) is a gene on chromosome 2p23 that has expression restricted to the brain, testis and small intestine but is not expressed in normal lymphoid tissue. It has similarity to the insulin receptor subfamily of kinases and is emerging as having increased pathologic and potential therapeutic importance in malignant disease. This gene was originally established as being implicated in the pathogenesis of rare diseases including inflammatory myofibroblastic tumour (IMT) and ALK-positive anaplastic large cell lymphoma, which is a subtype of non-Hodgkin's lymphoma. Recently the number of diseases in which ALK is implicated in their pathogenesis has increased. In 2007, an inversion of chromosome 2 involving ALK and a fusion partner gene in a subset of non-small cell lung cancer was discovered. In 2008, publications emerged implicating ALK in familial and sporadic cases of neuroblastoma, a childhood cancer of the sympatho-adrenal system. Chromosomal abnormalities involving ALK are translocations, lifications or mutations. Chromosomal translocations are the longest recognised ALK genetic abnormality. When translocations occur a fusion gene is created between ALK and a gene partner. This has been described in ALK-positive anaplastic large cell lymphoma in which ALK is fused to NPM (nucleolar protein gene) and in non-small cell lung cancer where ALK is fused to EML4 (Echinoderm microtubule-associated protein 4). The most frequently described partner genes in inflammatory myofibroblastic tumour are tropomyosin 3/4 (TMP3/4), however in IMTs a ersity of ALK fusion partners have been found, with the ability to homodimerise a common characteristic. Point mutations and lification of the ALK gene occur in the childhood cancer neuroblastoma. Therapeutic targeting of ALK fusion genes using tyrosine kinase inhibition, vaccination using an ALK specific antigen and treatment using viral vectors for RNAi are emerging potential therapeutic possibilities.
Publisher: Springer Science and Business Media LLC
Date: 07-09-2017
DOI: 10.1038/BJC.2017.306
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2017
Publisher: Oxford University Press (OUP)
Date: 24-12-2010
Abstract: To conduct a systematic review of the role that the hedgehog signaling pathway has in pancreatic cancer tumorigenesis. PubMed search (2000-2010) and literature based references. 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. 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.
Publisher: Elsevier BV
Date: 12-2019
DOI: 10.1016/J.JPAINSYMMAN.2019.06.030
Abstract: Dysphagia is usually associated with malignancies of the head, neck, and upper gastrointestinal tract but also occurs in those with tumors outside anatomic swallow regions. It can lead to aspiration pneumonia, malnutrition, reduced quality of life, and psychosocial distress. No studies have yet reliably described dysphagia prevalence in those with malignancies outside anatomic swallow regions. The objective of this study was to establish the prevalence and predictors of dysphagia in adults with solid malignancies outside the head, neck, and upper gastrointestinal tract. A cross-sectional, observational study using consecutive s ling was conducted. There were 385 participants (mean age 66 ± 12 years) with 21 different primary cancer sites from two acute hospitals and one hospice. Locoregional disease was present in 33%, metastatic in 67%. Dysphagia was screened by empirical questionnaire and confirmed through swallow evaluation. Demographic and clinical predictors were determined by univariate and multivariate binary regression. Dysphagia occurred in 19% of those with malignancies outside anatomic swallow regions. Prevalence was 30% in palliative care and 32% in hospice care. Dysphagia was most strongly associated with cough, nausea, and worse performance status. It was also associated with lower quality of life and nutritional difficulties. Dysphagia was common and usually undiagnosed before study participation. It occurred at all disease stages but coincided with functional decline. It may therefore represent a cancer frailty marker. Oncology and palliative care services should routinely screen for this symptom. Timely dysphagia identification and management may improve patient well-being and prevent adverse effects like aspiration pneumonia and weight loss.
Publisher: Oxford University Press (OUP)
Date: 02-12-2018
Abstract: It has been historically uncertain if extra centrosomes are a cause or consequence of tumorigenesis. Experiments have recently established that overexpression of polo-like kinase 4 (PLK4) promotes centrosome lification with consequential promotion of cellular aneuploidy. Furthermore, centrosome lification drives spontaneous tumorigenesis in mice. Tissues lacking normal functional p53 tolerate extra centrosomes, whereas p53 proficient tissues initiate proliferative arrest in this circumstance. Extra centrosomes trigger activation of the multi-protein PIDDosome complex, with Caspase-2 effecting cleavage of the p53-negative regulator mouse double minute 2, consequent stabilization of p53 and p21-dependent arrest of the cell cycle. The co-occurrence of cellular aneuploidy, complex chromosomal rearrangements and p53 dysfunction is a striking feature of some osteosarcomas. It is postulated that small-molecule PLK4 inhibitors such as CFI-400945, which are in development, may have utility in osteosarcoma given these findings.
Publisher: Elsevier BV
Date: 12-2005
DOI: 10.1016/J.CLON.2005.07.017
Abstract: The treatment of prostate cancer is frequently influenced by the Partin Tables. This predictive model has been internally and externally validated since it was conceived, and has proved to be remarkably reliable and consistent. This paper proposes that, by using the statistical programme for the social sciences (SPSS) and receiver-operator characteristic curves, it is possible to detect institutions that apply this model sub-optimally. This theory was supported by a PUBMED search using relevant search words. This is a novel technique with the potential to allow retrospective and prospective accrual of results. A systematic institutional review of how accurately a hospital assesses the clinical stage, Gleason score and PSA has the potential to increase an institution's predictive accuracy when it uses the Partin Tables. The proposed method allows for quantitation of the level of error and comparison of predictive accuracy between institutions. It also may be used as an internal outcome measure to assess improvement in a hospital's investigative procedures over time.
Publisher: MDPI AG
Date: 10-04-2012
DOI: 10.3390/JPM2020035
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2012
Publisher: Informa UK Limited
Date: 2006
DOI: 10.1080/02841860600602946
Abstract: Cancer may arise because the developmental programs that create the dramatic alterations in form and structure in embryonic development are potentially corrupted. The cells in our bodies retain memories of these processes and cancer can occur later in life if imperfections occur in the fidelity of these pathways. This article is particularly interested in the phenomenon of epithelial to mesenchymal transition, which occurs in embryogenesis. Also reviewed are the small molecules and pathways that are involved both in homeostasis in adult epithelium and embryogenesis in utero. There are five such pathways in particular selected for review in this article: the Wnt pathway, Hedgehog, Notch, PAR and Bone morphogenetic peptide/TGF beta. These are usually conserved throughout mammalian evolution. Though they have been arbitrarily separated in this article they are not exclusive from one another. Their pathologically altered expression is found especially frequently in childhood tumours where they may recapitulate their developmental role, and in tumours that resemble primitive precursor cells. These pathways are important for selecting cell fates, cellular rearrangements, cytological context and morphologic design in embryology as well as participating in epithelial function in adults.
Publisher: Elsevier BV
Date: 12-2021
DOI: 10.1016/J.CURRPROBLCANCER.2021.100736
Abstract: Basal cell carcinomas occur in up to 39% of Caucasian men and 28% of women. Rarely it can present a management dilemma in patients with neglected locally advanced disease of large dimension or involvement of critical structures. The Hedgehog pathway is constitutively active in almost all basal cell carcinomas and patients with Naevoid Basal Cell Carcinoma Syndrome have germline mutations in the Patched tumor suppressor gene, a Hedgehog pathway component, on chromosome 9q. This case describes an elderly patient with an untreated sporadic Basal cell carcinoma whose dimensions precluded local management approaches. The Hedgehog pathway inhibitor Vismodegib had a dramatic response allowing definitive treatment to be pursued.
Publisher: Mary Ann Liebert Inc
Date: 09-2017
Abstract: Macrophages appear to have a fundamental role in the pathogenesis of osteosarcoma. These highly erse plastic cells are sub ided into classical or inflammatory macrophages known as M1 and alternative macrophages, which decrease inflammation and are reparative, called M2. Although primary and metastatic osteosarcomas are infiltrated with M2 macrophages, targeting the M1 macrophages with the immune adjuvant muramyl tripeptide phosphatidyl ethanolamine (MTP-PE) has been the greatest recent therapeutic advance in osteosarcoma. This discrepancy between the presence of M2 and activation of M1 macrophages is intriguing and is likely explained either by the plasticity of M1 and M2 macrophages or nonclassical patrolling monocytes (PMos). To date, MTP-PE has been approved in combination with chemotherapy for nonmetastatic osteosarcoma, but its use in metastatic tumors has not been investigated. In this review, we focus on macrophages, monocytes, and osteoclasts, their role in osteosarcoma, and the potential for targeting these cells in this disease.
Publisher: Informa Healthcare
Date: 14-07-2015
Publisher: Elsevier BV
Date: 11-2012
DOI: 10.1016/J.PHARMTHERA.2012.08.004
Abstract: The hedgehog signaling pathway is important in embryogenesis and post natal development. Constitutive activation of the pathway due to mutation of pathway components occurs in ~25% of medulloblastomas and also in basal cell carcinomas. In many other malignancies the therapeutic role for hedgehog inhibition though intriguing, based on preclinical data, is far from assured. Hedgehog inhibition is not an established part of the treatment paradigm of sarcoma but the scientific rationale for a possible benefit is compelling. In chondrosarcoma there is evidence of hedgehog pathway activation and an ontologic comparison between growth plate chondrocyte differentiation and different chondrosarcoma subtypes. Immunostaining epiphyseal growth plate for Indian hedgehog is particularly positive in the zone of pre-hypertrophic chondrocytes which correlates ontologically with conventional chondrosarcoma. In Ewing sarcoma/PNET tumors the Gli1 transcription factor is a direct target of the EWS-FLI1 oncoprotein present in 85% of cases. In many cases of rhabdomyosarcomas there is increased expression of Gli1 (Ragazzini et al., 2004). Additionally, a third of embryonal rhabdomyosarcomas have loss of Chr.9q22 that encompasses the patched locus (Bridge et al., 2000). The potential to treat osteosarcoma by inhibition of Gli2 and the role of the pathway in ovarian fibromas and other connective tissue tumors is also discussed (Nagao et al., 2011 Hirotsu et al., 2010). Emergence of acquired secondary resistance to targeted therapeutics is an important issue that is also relevant to hedgehog inhibition. In this context secondary resistance of medulloblastomas to treatment with a smoothened antagonist in two tumor mouse models is examined.
Publisher: American Association for Cancer Research (AACR)
Date: 02-2014
DOI: 10.1158/1078-0432.CCR-13-2010
Abstract: Peto's paradox is the counterintuitive finding that increasing body mass and thereby cell number does not correlate with an increase in cancer incidence across different species. The Hippo signaling pathway is an evolutionarily conserved system that determines organ size by regulating apoptosis and cell proliferation. It also affects cell growth by microRNA-29 (miR-29)–mediated cross-talk to the mTOR signaling pathway. Whether these pathways that decide organ size could explain this paradox merits consideration. Inactivation of most genes of the Hippo pathway in Drosophila melanogaster genetic screens causes excessive tissue-specific growth of developing tissues. Altered Hippo pathway activity is frequently found in erse tumor types, but mutations of component pathway genes are rare. Most Hippo pathway components are encoded by tumor suppressor genes (TSG), but an exception is the downstream effector gene called YAP. Activity of the Hippo pathway causes deactivating phosphorylation of YES-associated protein (YAP) with nuclear exclusion. YAP can also be phosphorylated at a second site, S127, by AKT. YAP induces the expression of genes responsible for proliferation and suppression of apoptosis. Resolving Peto's paradox may serendipitously provide new insights into the biology and treatment of cancer. This article considers Hippo signaling and Peto's paradox in the context of TSG–oncogene computed models. Interspecies differences in dietary composition, metabolic rates, and anabolic processes are also discussed in the context of Hippo–mTOR signaling. The metabolically important LKB1-AMPK (liver kinase B1-AMP activated protein kinase) signaling axis that suppresses the mTOR pathway is also considered. Clin Cancer Res 20(3) 557–64. ©2013 AACR.
Publisher: Baishideng Publishing Group Inc.
Date: 2017
Publisher: Springer Science and Business Media LLC
Date: 28-11-2020
DOI: 10.1186/S13569-020-00147-3
Abstract: Encephalopathy is an established side effect of the chemotherapeutic agent, ifosfamide, occurring in 10–30% of cases. The EEG commonly shows non-specific features of encephalopathy, and rarely shows frontal intermittent rhythmic delta activity (FIRDA). This is a case report of a 71 year old woman with pleomorphic sarcoma, who developed ifosfamide-induced encephalopathy with her second dose of ifosfamide. It shows the characteristic EEG findings that have been described previously with ifosfamide-induced encephalopathy and additionally the unusual and rare finding of FIRDA. This was followed up by a further EEG showing resolution of the encephalopathy, after administration of methylene blue, coinciding with rapid and complete resolution of her symptoms. The rapid resolution of the encephalopathy on the EEG after administration of methylene blue adds further evidence to its effectiveness as a treatment for the disorder.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 03-2018
Publisher: Springer Science and Business Media LLC
Date: 02-2012
Publisher: American College of Physicians
Date: 04-2008
Publisher: Springer Science and Business Media LLC
Date: 22-02-2020
DOI: 10.1186/S12967-020-02273-4
Abstract: An increasing number of anti-cancer therapeutic agents target specific mutant proteins that are expressed by many different tumor types. Successful use of these therapies is dependent on the presence or absence of somatic mutations within the patient’s tumor that can confer clinical efficacy or drug resistance. The aim of our study was to determine the type, frequency, overlap and functional proteomic effects of potentially targetable recurrent somatic hotspot mutations in 47 cancer-related genes in multiple disease sites that could be potential therapeutic targets using currently available agents or agents in clinical development. Using MassArray technology, of the 1300 patient tumors analysed 571 (43.9%) had at least one somatic mutation. Mutations were identified in 30 different genes. KRAS (16.5%), PIK3CA (13.6%) and BRAF (3.8%) were the most frequently mutated genes. Prostate (10.8%) had the lowest number of somatic mutations identified, while no mutations were identified in sarcoma. Ocular melanoma (90.6%), endometrial (72.4%) and colorectal (66.4%) tumors had the highest number of mutations. We noted high concordance between mutations in different parts of the tumor (94%) and matched primary and metastatic s les (90%). KRAS and BRAF mutations were mutually exclusive. Mutation co-occurrence involved mainly PIK3CA and PTPN11 , and PTPN11 and APC . Reverse Phase Protein Array (RPPA) analysis demonstrated that PI3K and MAPK signalling pathways were more altered in tumors with mutations compared to wild type tumors. Hotspot mutational profiling is a sensitive, high-throughput approach for identifying mutations of clinical relevance to molecular based therapeutics for treatment of cancer, and could potentially be of use in identifying novel opportunities for genotype-driven clinical trials.
Publisher: Elsevier BV
Date: 2007
DOI: 10.4065/82.1.134
Publisher: Elsevier
Date: 2012
Location: Ireland
No related grants have been discovered for Fergal Kelleher.