CSFP Research


Research areas pursued by MMI Clinician Scientist Fellows included cystic fibrosis, autism, diabetes, heart disease, disorders of pregnancy, lung fibrosis, myeloma, neuroimaging in psychiatric disorder, bleeding complications, HIV-associated metabolic toxicities and cancers of the breast and oesophagus.

 

Research Projects

Dr Aoife Lowery (NUI Galway) - Analysis of MicroRNA Expression and Function in Human Breast Cancer
Supervisors : Professor Michael J Kerin, Professor of Surgery, Department of Surgery Clinical Science Institute, National University of Ireland Galway
Dr Nicola Miller, Senior Scientist, Department of Surgery, Clinical Science Institute, National University of Ireland Galway
Thesis Abstract: Breast cancer is a heterogenous disease, representing a number of distinct phenotypes. The complex nature of breast cancer makes disease progression difficult to predict and challenging to manage, and the pursuit of improved diagnostic and prognostic tools to guide individualized therapy has been the focus of much scientific and translational research. Despite this, an understanding of the precise molecular mechanisms underlying breast cancer has remained largely elusive. The discovery that mi(cro)RNASs regulate the expression of multiple target genes and are frequently dysregulated in breast cancer has placed them at the forefront of molecular research into the origins of tumourigenesis. The use of highthroughput techniques such as microarray profiling is being increasingly used to identify differentially expressed microRNAs that may provide insight into the complex and diverse molecular mechanisms of breast cancer initiation and progression.

This study was undertaken to characterise miRNA expression in breast tumours, to examine relationships between miRNAs and clinicopathological parameters and to investigate the functional role of specific abberantly expressed microRNAs in breast cancer.

Expression profiling of 453 miRNAs was performed in 29 early-stage breast tumours. Stepwise artificial neural network (ANN) analysis identified predictive miRNA signatures corresponding with estrogen, progesterone and HER2/neu receptor status. Differentially expressed miRNAs were validated by RQ-PCR in an expanded cohort of 95 breast tumours and 18 tumour-associated normal tissues. RQ-PCR was also used to quantitate circulating miRNA levels in breast cancer patients compared to healthy controls.

Gain-of-function analysis in breast cancer cell lines was performed using miRNA precursors to assess the effect of specific miRNAs on cancer cell behaviour. Overexpression of miR-342 in triple negative breast cancer cells resulted in dysregulation of apoptotic genes and resultant increased apoptosis. Overexpression of miR-183 resulted in downregulation of VIL2 and was associated with decreased migration in breast cancer cells.

The data presented indicates that microarray technology and ANN analysis reliably identifies biologically relevant miRNAs associated with specific breast cancer phenotypes. The association of specific miRNAs with ER, PR and HER2/neu status indicates a role for these miRNAs in disease classification of breast cancer and their detection in the circulation of breast cancer patients implicates potential as novel minimally invasive breast cancer biomarkers. Futhermore, the functional analysis of miR-342 and miR-183 reveals that not only are these miRNAs dysregulated, but they also have potential tumour suppressor roles in breast cancer and represent attractive targets for therapeutic intervention.
Dr Aonghus O'Loughlin (NUI Galway) - Novel Cell-Based Approaches in the Treatment of Diabetic Foot Ulcers
Supervisors:
Professor Timothy O’Brien, Director Regenerative Medicine Centre, NCBES, NUI Galway
Dr. Sean Dinneen, Consultant Endocrinologist, Department of Medicine, Clinical, Science Institute, NUI Galway / UCH Galway
Thesis Abstract:

The focus of this research is on developing novel cell based therapies for the treatment of non-healing diabetic foot ulceration. The thesis begins with a concise review of the diabetic foot ulcers. The burden associated with non-healing diabetic foot ulceration in humans is presented. The biology of the diabetic ulcer is reviewed and the scientific rationale for pursuing the development of a stem and progenitor cell-based therapy is emphasised. Cell transplantation using biomaterials is reviewed.

The first cell type that is investigated is the early endothelial progenitor cell or circulating angiogenic cell. A cell-scaffold treatment was developed using collagen. A preclinical model of diabetic wound healing was validated. The model is the alloxan induced diabetic rabbit ear ulcer model. Subsequently autologous circulating angiogenic cells exposed to the matricellular protein osteopontin were applied to a full thickness cutaneous ulcer. The cells were delivered via a collagen scaffold and the percentage wound closure was assessed after one week. Circulating angiogenic cells exposed to osteopontin and seeded on a collagen scaffold displayed significantly increased percentage wound closure as compared to other groups. Stereological analysis of wounds demonstrated a superior vascular network in wounds treated with circulating angiogenic cells exposed to osteopontin. The secretome of human circulating angiogenic cells was assessed with diabetic CACs demonstrating less angiogenesis in vitro.

Topical treatment of ulcers with allogeneic non-diabetic mesenchymal stem cells was assessed in the same preclinical model. A dose escalation protocol was carried out. Wounds treated with 1,000,000 MSCs seeded in a collagen scaffold augmented wound healing as compared to untreated wounds. Stereological analysis demonstrated a superior neovasculature in wounds treated with 1,000,000 MSCs.

The outcome of this research is the demonstration of the therapeutic efficacy of topically applied circulating angiogenic cells and mesenchymal cells in diabetic cutaneous ulceration.

Dr Gerard Curley (NUI Galway) - Investigation of the Mechanisms of Repair Following Ventilator Induced Lung Injury and the Potential for Mesenchymal Stem Cells to Enhance the Repair Process
Supervisors : Professor John Laffey, Professor and Head, Department of Anaesthesia, National University of Ireland, Galway
Dr Leo Kevin, Consultant Anaesthetist and Clinical lecturer, Department of Anaesthesia, National University of Ireland, Galway.
Thesis Abstract:

Introduction: The time course and mechanisms of resolution and repair, and the potential for fibrosis following ventilation induced lung injury (VILI) are unclear. We sought to examine the pattern of inflammation, injury and repair, and fibrosis following VILI. In addition, recent pre-clinical experimental studies indicate that bone-marrow derived mesenchymal stem cells (MSCs) may reduce the severity of Acute Lung Injury (ALI). We wished to evaluate the role of MSCs in modulating inflammation and enhancing repair after Ventilator Induced Lung Injury (VILI).

Methods: Anesthetized rats were subject to: (1) high stretch; (2) low stretch; or (3) sham ventilation, and randomly allocated to undergo periods of recovery of 6, 24, 48, 96 hours, 7 days and 14 days. Animals were then re-anesthetized, and the extent of lung injury, inflammation and repair determined. We then used this unique animal model of repair to examine the potential for either local or systemic delivery of MSCs to enhance resolution after stretch induced lung injury. Subsequent experiments elucidated the mechanisms by which MSC’s enhance repair, by examining the potential for non-stem cells, and for MSC secreted products, to enhance repair in comparison to MSCs.

Results: No injury was seen following low stretch or sham ventilation. VILI caused severe lung injury, maximal at 24 hours, but largely resolved by 96 hours. Alveolar tumor necrosis factor-a, interleukin-1ß and transforming growth factor-ß1 concentrations peaked at 6 hours, and returned to baseline within 24 hours, while interleukin-10 remained elevated for 48 hours. VILI generated a marked but transient fibroproliferative response, which restored normal lung architecture. MSC therapy enhanced repair following VILI. MSCs enhanced restoration of systemic oxygenation and lung compliance, reduced total lung water, decreased lung inflammation and histologic lung injury, and restored lung structure. MSCs attenuated alveolar TNF-alpha and IL-6 levels, while increasing IL-10 concentrations. MSC secreted products also enhanced lung repair and attenuated the inflammatory response following VILI. The beneficial effect of the MSC secretome on repair of pulmonary epithelial wounds was attenuated by prior depletion of Ketatinocyte Growth Factor.

Conclusions: High stretch ventilation caused severe lung injury, activating a transient inflammatory and fibro-proliferative repair response, which restored normal lung architecture without evidence of fibrosis. Either systemic or local administration of MSCs enhanced repair, through a mechanism involving secretion of keratinocyte growth factor.

Dr Mark Coyne (NUI Galway) - Examining a new class of dual CDC7/CDK9 inhibitors, mechanisms of proliferation, and proliferation-based stratification in myeloma
Supervisors: Professor Kieran Murphy, Chairman, Department of Psychiatry, RCSI
Professor Hugh Garavan, Director of Functional Imaging, Trinity College Institute of Neuroscience, Dublin
Thesis Abstract:
Dr Damian McCartan (RCSI) - Identifying New Transcriptional Targets for SRC-1 in Breast Cancer
Supervisors: Dr. Leonie Young, Leader Of Surgical Research, Royal College of Surgeons in Ireland
Prof. Arnold Hill, Professor of Surgery, Beaumont Hospital, Royal College of Surgeons in Ireland
Thesis Abstract: SRC-1 is a p160 nuclear receptor co-activator protein that has been implicated as an important mediator of breast cancer metastasis. A small number of direct SRC-1 target genes have been identified to date. The aim of this work was to verify the recently discovered SRC-1 target S100B and to adopt a genome wide approach using modern, high throughput technologies to identify new SRC-1 transcriptional targets.

To identify novel SRC-1 target genes luminal B LY2 breast cancer cells were used to perform the first ChIP-sequencing experiment of SRC-1. Affymetrix whole genome expression arrays were used to analyse gene expression in LY2 cells treated with SRC-1 siRNA in comparison with those treated scrambled siRNA to complement the ChIP-seq experiment.

SRC-1 peaks within the genome were focused near transcription starts sites and often in close proximity to an estrogen response element. Three new putative SRC-1 target genes were selected for further validation. ADAM22 is a transmembrane disintegrin protein that has been shown to mediate cell migration but has yet to be implicated in tumourigenesis. Knockout, overexpression and ChIP studies confirm ADAM22 as an SRC-1 target gene.

Expression of ADAM22 was identified in 49% of patients with breast cancer and its expression was associated with an almost two fold increase in rate of disease relapse. Two other genes, namely BCAS3 and CUX1 were identified and validated as SRC-1 target genes and both of these have a known role in breast tumour progression. Elevated levels of S100B were detectable in the blood of 10% of patients with breast cancer.

Elevated serum S100B at time of diagnosis is an independent predictor of disease progression in breast cancer.
An unbiased, genome wide approach has identified a variety of novel, direct SRC-1 target genes. A series of molecular and translational studies have validated S100B as a clinically important and detectable target of SRC-1 while ADAM22, as transmembrane protein may offer the first therapeutic target to disrupt the central role of SRC-1 in mediating breast cancer metastasis.
Dr Finian O'Brien (RCSI) - Neuroimaging of Psychiatric Disorder
Supervisors:
Professor Kieran Murphy, Chairman, Department of Psychiatry, RCSI
Professor Hugh Garavan, Director of Functional Imaging, Trinity College Institute of Neuroscience, DublinThesis Abstract:
Dr Mazen Al-Alawi (RCSI) - The Role of Lipoxin A4 in Regulating Ion Transport and Airway Surface Liquid Dynamics in Cystic Fibrosis
Supervisors: Professor Brian Harvey, Director of Research, Professor of Molecular Medicine, RCSI
Professor Richard Costello, Associate Professor of Medicine and Consultant Chest Physician, RCSI Education and Research Centre, Smurfit Building, Beaumont Hospital
Thesis Abstract: The thesis reports novel findings on the role of LXA4 in inodulating the airway surface liquid (ASL) layer height and in particular expanding the deficient ASL observed in CF as a novel means to augmenting existing therapy. Lipoxin A4 (LXA4) is produced at inflammatory sites, and exerts antiinflammatoiy effects and has been reported to be reduced in cystic fibrosis (CF) airways. The altered Cl- secretion and Na+ hyperabsorption in CF affects the ASL height and leads to a defective mucociliary clearance, chronic infection, inflammation and progressive lung destruction. The role of LXA4 in modulating ion transport and ASL height in CF and non-CF airway epithelia was investigated. CF (CuFi-1) and non-CF (NuLi-1) bronchial epithelial cell lines were grown into well-differentiated epithelia. LXA4 effects were explored using laser confocal inicroscopy to measure ASL height, short-circuit current to investigate ion transporters activity, and ATP assay to measure ATP release at the apical side of CF epithelia. LXA4 (1 nM) treatment for 15 minutes, increased ASL height in Nuli-1 and CuFi-1 epithelia. The stimulatory effect of LXA4 on ASL height was inhibited by the LXA4 receptor FPR2/ALX inhibitor, boc-2; in addition to bumetanide, reactive blue and extracellular hexolinase, while amiloride was showed an additive effect to LXA4. LXA4 was activated Cl- secretion and inhibited Na+ absorption in the CF epithelia. In addition, LXA4 stimulated an apical Boc-2 sensitive release of ATP in CF epithelia. This thesis provides evidence for a novel effect of LXA4 involving the FPR2/ALX receptor, apical ATP release and purinoreceptor activation, inhibition of Na+ absorption and stimulation of Cl+ secretion in CF and non-CF epithelia to finally increase ASL height. These effects open up a new therapeutic avenue in the treatment of CF.
Dr Sanjay Chotirmall (RCSI) - The role of Estrogen in Cystic Fibrosis
Supervisors: Prof. Noel G. McElvaney, Dept. Medicine, Respiratory Research Division, RCSI
Dr. Catherine M. Greene, Dept. Medicine, Respiratory Research Division, RCSI
Prof Brian Harvey, Dept. Molecular Medicine, RCSI
Thesis Abstract:
An unexplained gender dichotomy is observed in cystic fibrosis (CF). Females with disease have poorer lung function, decreased survival, earlier Pseudomonas colonization and mucoid conversion. We evaluated the effect of 17β-estradiol (E2) and its metabolite estriol (E3) on CF bronchial epithelial cells and P. aeruginosa in vitro and in vivo. We additionally determined the effect of E2 on female exacerbations. Upon exposure of CFBE41o- cultures to physiological concentrations of E2, there was a significant dose-dependent inhibition of IL-8 release induced by toll-like receptor agonists, CF bronchoalveolar lavage fluid (CF BALF) or Pseudomonas-conditioned media. Both estrogen receptor (ER)-α and -β were expressed in airway epithelium in vitro and in vivo, although ERβ expression was significantly higher in CF. Using ER isoform-specific agonists and antagonists, we established that ERβ mediates the inhibition of CF BALF induced IL-8 release. We also show that secretory leucoprotease inhibitor (SLPI) gene expression and protein localization to the nucleus increased in response to E2. SLPI knockdown abrogated the inhibitory effects of E2. E3 was detectable in E2-treated airway epithelial cultures and CF BALF. Levels are highest in female CF BALF during the follicular phase of the menstrual cycle. E2 and E3 induce alginate production in laboratory and clinical strains of P. aeruginosa. Testosterone had no effect on alginate production. Following prolonged E2 exposure, P. aeruginosa adopts early mucoid morphology on blue agar while acute exposure inhibits bacterial catalase activity and increases H2O2, a potential DNA damaging agent. Consequently, a frameshift mutation is identified in the mucA gene. In vivo E2 concentrations correlate with infective exacerbations in CF females (n=172) with the majority occurring during the follicular phase of the menstrual cycle. Our review of the Irish CF registry revealed that females acquire and convert to mucoid strains of P. aeruginosa in advance of males (n=1,009) and that use of oral contraception decreases the need for antibiotics. Predominantly non-mucoid P. aeruginosa is isolated from sputum during exacerbations occurring in the luteal phase (low E2). Enhanced proportions of mucoid bacteria are isolated during exacerbations occurring in the follicular phase (high E2) with a variable P. aeruginosa phenotype evident in vivo during the course of a menstrual cycle corresponding to fluctuating E2 concentrations.
In conclusion, E2 inhibits IL-8 release via ERβ in CF bronchial epithelial cells through up-regulation of SLPI, inhibition of NF-κB and IL-8 gene expression. Additionally, E2 induces mucoid conversion of P. aeruginosa in CF through a mutation of mucA in vitro and is associated with selectivity for mucoid isolation, increased exacerbations and mucoid conversion in vivo. These data implicate a novel anti-inflammatory mechanism and a milieu during high circulating E2 states in CF females which predisposes to infection and P. aeruginosa colonization and mucoid conversion. These factors in tandem at least in part, may account for the observed gender differences in CF disease.
Dr David Prichard (TCD) - Ursodeoxycholic Acid – a Molecular Modulator of the Inflammation-Cancer Sequence in the Oesophagus
Supervisors:
Professor Dermot Kelleher, Department of Clinical Medicine, Trinity College Dublin
Dr Aideen Long, Department of Clinical Medicine, Trinity College Dublin
Thesis Abstract:
The incidence of oesophageal adenocarcinoma (OAC) is rising at an alarming rate. The predominant risk factor for this cancer is gastro-oesophageal reflux disease (GORD). Highly effective acid suppression therapies have targeted the acid component of GORD without impacting on the increasing incidence of OAC. Bile acids (BAs) have been identified as a significant component of GORD and as pro-inflammatory and carcinogenic molecules in the oesophagus. Ursodeoxycholic acid (UDCA) has been shown to attenuate the inflammatory and carcinogenic effects of BAs. Thus, the aim of this research was to investigate whether UDCA could modulate BA-induced inflammation in the oesophagus.

In the first part of this research both UDCA and deoxycholic acid (DCA) were demonstrated to inhibit the proliferation of an oesophageal cell line. However, four hours pre-treatment with UDCA reduced markers of (DCA)-induced apoptosis. But this strategy did not reduce the magnitude of cell death induced by DCA. This suggests that apoptosis may be being switched to necrosis by UDCA pre-treatment.

In the second part of this research the ability of DCA to induce a loss of adhesion in oesophageal cells was investigated. DCA reversibly induced a detachment of adherent cells. This loss of adherence appears specific for a subset of extracellular matrix proteins and is mediated by a reversible reduction in the surface expression of a subset of integrins.

In the final part of this research, the ability of UDCA to modulate the glucocorticoid receptor (GR) was investigated. The GR is an endogenous anti-inflammatory transcription factor. Expression of the GR was identified in oesophageal tissues. UDCA treatment induced nuclear translocation of the GR. Using micro-array based technology the gene profile induced by UDCA was found to be as similar to Dexamethasone (a GR ligand) as it is to DCA. Pre-treatment of oesophageal cells with UDCA was capable of attenuating the DCA-induced upregulation of Interleukin 8, a pro-inflammatory chemokine.

These findings suggest that UDCA could potentially act as a therapeutic modulator of BA-induced inflammation in the oesophagus.
Dr Fionnuala Ni Ainle (TCD) - Generation and Characterisation of Activated Protein C variants with Altered Functional Properties and Enhanced Therapeutic Potential
Supervisors:
Dr James O’Donnell - Senior Lecturer and Director, Haemostasis Research Group, IMM, TCD
Dr Roger Preston – Senior Post-Doctoral Fellow, Haemostasis Research Group, IMM, TCD
Thesis Abstract:
Activated protein C (APC) is an anticoagulant glycoprotein that attenuates thrombin generation. Moreover, it has recently been demonstrated that APC possesses anti-inflammatory, anti-apoptotic and endothelial cell barrier stabilizing properties. The first goal of this thesis was to study the role of N-linked carbohydrates (glycans) in modulating APC anticoagulant function and endothelial cytoprotective signalling via the endothelial cell protein C receptor (EPCR) and protease activated receptor 1 (PAR1). It was determined that removal of APC N-linked glycans using the enzyme PNGase resulted in a ~6-fold reduction in the APC concentration required to achieve half-maximal inhibition of thrombin-induced endothelial cell barrier permeability. Furthermore, deglycosylation enhanced APC anti-apoptotic function on endothelial cells compared to untreated APC. Recombinant APC variants were generated in which each Asn-linked glycan attachment site was eliminated by amino acid substitution. The variant APC-N329Q displayed up to 5-fold enhanced protection of the endothelial barrier compared to wild type APC. Moreover, an APC variant (APC-L38D/N329Q) was generated which possessed minimal anticoagulant activity but 5-fold improved endothelial barrier protective function compared to wild type APC. These results have identified that APC N-linked glycosylation modulates EPCR-dependent, PAR1-mediated cytoprotective signaling. These data also suggest that β-protein C, a naturally occurring glycoform characterized by lack of N-linked glycosylation at Asn-329, may play a role in APC cytoprotective function in vivo. Protamine sulphate is used to reverse heparin-induced anticoagulation. Paradoxically, it is associated with unwanted anticoagulant properties which can be associated with bleeding complications in vivo. The molecular mechanisms underlying these anticoagulant properties have been poorly understood. The second goal of this project was to elucidate these mechanisms. Protamine sulphate was found to prolong plasma clotting times and to attenuate thrombin generation in vitro, reducing endogenous thrombin potential (ETP) by 41±7%. Protamine sulphate profoundly enhanced the anticoagulant properties of APC in thrombin generation and activated partial thromboplastin time (APTT) assays. In an assay of procoagulant factor V (FV) activation, protamine was found to greatly reduce the rate of FV activation both by thrombin and by factor Xa (FXa). Moreover, administration of pharmacological doses of protamine sulphate to BALB/c mice prolonged tail bleeding time in vivo. These novel findings represent the molecular mechanism underlying the anticoagulant properties of protamine sulphate in plasma.
Dr Jane McGrath (TCD) - Brain Structure, Function and Connectivity in Autism Spectrum Disorders
Supervisors:
Dr Louise Gallagher, PhD, MRCPsych, Consultant Child and Adolescent Psychiatrist, Clinical Senior Lecturer, School of Medicine, Department of Psychiatry, Trinity College Dublin
Professor Hugh Garavan, PhD, Associate Professor, Trinity College Institute of Neuroscience, Department of Psychology, Trinity College, Dublin.
Dr Katherine Johnson, PhD, Research Fellow, Trinity College Institute of Neuroscience, Department of Psychology, Trinity College, Dublin.
Thesis Abstract:
Introduction
Autism spectrum disorders (ASDs) are devastating neurodevelopmental disorders of childhood of unknown aetiology. Neuroimaging research has demonstrated numerous abnormalities in brain structure and function in ASDs, from which a theory of altered cortical connectivity has emerged. This holds that core social and cognitive deficits in ASD are underpinned by abnormal interregional brain connectivity. Functional and structural evidence for this theory is accumulating. There is, however, a striking lack of research attempting to relate disrupted functional connectivity to brain structural abnormalities. This approach is crucial in understanding of the pathogenesis of the condition.

Aims

  1. To examine neural connectivity in ASDs using two advanced neuroimaging modalities; functional magnetic resonance imaging (fMRI), which allows measurement of brain activity and functional connectivity, and diffusion tensor imaging (DTI), which measures micro-structural organisation of white matter (the connecting nerve fibres of the brain) and allows assessment of structural connectivity.
  2. To investigate links between functional connectivity, structural connectivity and behaviour, an approach that is hoped will provide novel insights into the underlying pathophysiology of ASD.

Methods
Twenty-five individuals with an ASD and 25 age- and IQ-matched controls participated in this study. All participants completed a mental rotation task during fMRI scanning, and DTI data was obtained on all participants using a High Angular Resolution Diffusion Imaging (HARDI) acquisition protocol. Functional MRI and functional connectivity analysis were performed on the fMRI data. DTI data were analysed using two advanced techniques; Tract Based Spatial Statistics (TBSS) and Constrained Spherical Deconvolution (CSD)-based tractography.

Main Results

  1. Behavioural results from the mental rotation task revealed a previously unreported dissociation between ASD and control groups in response times during mental rotation whereby neurotypical controls slowed significantly on the more cognitively demanding trials but the ASD group did not show this slowing. This may reflect a relative superiority of visuospatial processing in ASD.
  2. Results from the functional connectivity analyses provided novel insight into the neural underpinnings of the behavioural results, and, on a wider scale, into the neural mechanisms of atypical visuospatial processing in ASD. Functional connectivity between multiple brain regions was abnormal in the ASD group. Atypical visuospatial processing in ASD appears to be associated with both quantitative and qualitative differences in functional connectivity, which may result in a combination of enhanced low-level perceptual processing and a reduction of higher-level cortical control.
  3. At the whole brain level, TBSS analysis of DTI data revealed significant disruption of white matter microstructural organization in small regions of seven major association, projection and commissural tracts in the ASD group.
  4. Results from CSD-based tractography analysis revealed that there was disruption of white matter in major inter- and intra-hemispheric white matter tracts in ASD, which was associated with both autism severity and visuospatial processing performance.
  5. Integration of functional and structural connectivity data revealed that microstructural organisation is disrupted in some tracts that link regions showing abnormal functional connectivity. In addition, there are strong correlations between measures of white matter microstructure, functional connectivity and behaviour, which provide a fascinating insight into the relationships between brain structure, brain function and information processing in both neurotypical controls and individuals with ASD.

Conclusion
This novel multimodal imaging study reports, for the first time, direct associations between abnormal functional connectivity and disrupted white matter structure in ASD. It reveals that there are significant correlations between the microstructural integrity of white matter, functional connectivity, visuospatial processing speed and autism severity.

Dr Niall Conlon (TCD) - The association of variations in the immune response with the development of idiopathic bronchiectasis.
Supervisors:
Dr. John Jackson FRCPath, Chief Scientist, Department of Immunology, St. James’s Hospital Dublin
Dr. Mary Therese Keogan, MD. FRCPI, FRCPath, FFPath(RCPI), Consultant Immunologist, Beaumont Hospital, Medical Director of the National Histocompatibility and Immunogenetics Service for Solid Organ Transplantation, Hon. Senior Lecturer, Royal College of Surgeons in Ireland
Prof. Con Feighery FRCPI, Consultant Immunologist, St. James’s Hospital, Director of Department of Clinical Immunology Supporting Collaboration: Prof. Luke O’ Neill, School of Biochemistry and Immunology
Thesis Abstract:
Dr James Ryan (UCC) - Cellular mechanisms of insulin resistance due to the r482w mutation of the lmna gene in familial partial lipodystrophy, Dunnigan variety (fpld)
Supervisors:
Rosemary O'Connor, Ph.D., Professor of Cell Biology, Department of Biochemistry, BioSciences Institute, University College Cork
Dr. Domhnall J. O’Halloran, Consultant in Endocrinology & Diabetes Mellitus, Cork University Hospital
Thesis Abstract:
Dr John O'Sullivan (UCC) - Cardiovascular Biology
Supervisors:
Professor Noel M Caplice MD PhD, Director, Centre for Research in Vascular Biology, Biosciences Institute, UCC; Professor of Cardiovascular Sciences UCC; Consultant Physician/ Cardiologist Cork University Hospital
Thesis Abstract:
Dr Fergus McCarthy (UCC) - The Role of Peroxisome Proliferator Activated Receptor Gamma in Normal Rat Pregnancy and an Animal Model of Pre-eclampsia
Supervisors:
Dr Louise Kenny, Anu Research Center, Department of Obstetrics and Gynaecology, UCC
Dr Sarah Walsh, Postdoctoral Fellow, Department of Obstetrics and Gynaecology, UCC
Thesis Abstract:
Introduction: Pre-eclampsia is a multisystemic disorder of pregnancy characterised by hypertension, proteinuria and maternal endothelial dysfunction, which is thought to be due, in part, to inadequate trophoblast invasion. Peroxisome proliferator activated receptors (PPARs) are ligand activated transcription factors expressed in trophoblasts, which regulate both cell differentiation and proliferation. In addition, PPAR-γ is expressed in the vasculature and activation of this receptor has been shown to improve endothelium dependent vasodilatation, suggesting a seminal role for this receptor in the maintenance of normal vascular function. Taken together, these findings may suggest an important role for PPAR-γ both in the progression of a healthy pregnancy and as a possible therapeutic target for pre-eclampsia, a pregnancy specific hypertensive condition which complicates 2% to 8% of pregnancies and remains a major cause of maternal and perinatal mortality and morbidity worldwide.

Aims:

  • To investigate the effect of PPAR-γ antagonism during uncomplicated pregnancy in rats
  • To investigate the role of PPAR-γ activation during complicated pregnancy using the reduced uterine
  • To investigate the effect of the PPAR-γ agonist, rosiglitazone, on the human placental explant production of angiogenic factors

Methods: Using an intraperitoneal miniosmotic pump, healthy pregnant rats were administered either vehicle or the PPAR-γ specific antagonist, T0070907 (1mg/kg/day from gestational days 11-15). In a separate study, the effect of administration of a PPAR-γ agonist to the reduced uterine perfusion pressure (RUPP) rat model of pre-eclampsia was investigated. The selective PPAR-γ agonist, rosiglitazone, was administered to pregnant rats that had undergone RUPP surgery. To investigate whether any observed beneficial effects of PPAR-γ activation were mediated via the antioxidant enzyme, heme oxygenase 1 (HO-1), rosiglitazone was administered alone and in combination with the HO-1 inhibitor, SnPP. Finally, using the PPAR-γ agonist rosiglitazone, human placental tissue was incubated with varying doses of rosiglitazone and the secretion of angiogenic factors and the cytoprotective enzyme, HO-1, were measured in the media.

Results: Rats treated with T0070907 developed key features of pre-eclampsia including hypertension, proteinuria, endothelial dysfunction, reduced pup weight and increased platelet aggregation. Pregnant rats administered T0070907, had reduced plasma levels of the pro-angiogenic VEGF and increased anti-angiogenic sFlt-1. Increases in total placental sFlt-1 mRNA and Flt-1 protein were also demonstrated, suggesting the placenta as the main contributor to the increased circulating levels of sFlt-1. The labyrinthine trophoblast in the placentas of T0070907 treated rats were less differentiated, had increased cellular proliferation and were strongly immunopositive for CD-31 staining indicating adaptive angiogenesis. These data demonstrate the pivotal role PPAR-γ plays in the progression of a healthy pregnancy, as antagonism of this receptor lead to the development of a pre-eclamptic-like condition.
Rats subjected to RUPP surgery were characterised by hypertension, endothelial dysfunction and elevated microalbumin creatinine ratios (MCR). Rosiglitazone administration ameliorated hypertension, improved vascular function, and reduced the elevated MCR in RUPP rats. With the exception of MCR, these beneficial effects were abrogated in the presence of SnPP. In summary, administration of a PPAR-γ agonist prevented the development of several of the pathophysiological characteristics associated with the RUPP model of pre-eclampsia, via a HO-1 dependent pathway. Incubation of first trimester placental tissue with rosiglitazone reduced media levels of anti-angiogenic sFlt-1. Furthermore, incubation of first trimester placental explants with rosiglitazone induced an elevation in HO-1 production, a cytoprotective enzyme. These data may suggest that rosiglitazone could be used to pharmacologically manipulate placental PPAR-γ.

Conclusion:
The present study suggests that PPAR-γ may play a pivotal role in the progression of a healthy pregnancy and may critically regulate the risk of pre-eclampsia. These findings have important implications regarding the underlying aetiology of pre-eclampsia and potential therapeutic targets in the prevention and treatment of pre-eclampsia.

Dr Daniel Schmidt (UCC) - Short interval change in Hepatitis C Hypervariable Region 1 in chronic infection Are there treatment windows in the envelope?
Supervisors:
Dr Liam Fanning, Director, Molecular Virology Diagnostic & Research Laboratory, Senior Lecturer and Research Scientist, Department of Medicine, Cork University Hospital
Dr Orla Crosbie, Consultant Hepatologist, Department of Medicine, Cork University Hospital
Thesis Abstract:
Dr Aidan Ryan (UCD) - The Therapeutic Potential of Lipoxins in Tubulointerstitial Fibrosis
Supervisors:
Professor Catherine Godson, Diabetes Research Centre, Conway Institute, School of Medicine and Medical Sciences, UCD
Dr. Denise Sadlier, Consultant Nephrologist and Senior Lecturer, Mater Misericordiae University Hospital and Clinician Investigator , Diabetes Research Centre, Conway Institute, School of Medicine and Medical Sciences, UCD
Thesis Abstract:
Lipoxin A4 (LAX4) is a pro-resoluttion eicosanoid that has previously been shown to attenuate pro-fibrotic responsesof mesangial cells, tubular epithelial cells and renal fibroblasts to a variety of cytokines including PGDF , CTGF and TGF-β1.TGF-β1 is a prototypic profibrotic cytokine and has been implicated in a variey of fibrotic responses, including fibroblast activation and extra-cellular matrix stabilisation. To date treatment for tubulointerstitial fibrosis (TIF) has been somewhat limited , however one of the most effective treatments for limiting progression of CKD, in particular proteinuria has been antagonising RAAS, namely ACEi and ARB. However use of these drugs maybe associated with aldostene excape which may continue to promote fibrotic responses. The exact mechanism by which aldostene promotes TIF remain to be fully explored but may involve TGF-β1.

In this work we show that LAX4 attenuates both TGF-β and aldostene induced fibroblast activation and aldostene induced epithelial activation. In addition pre-treatment with LX attenuated aldostene induced collagen and osteopontin induction, which has been shown to be an important chemokine in promoting TIF. We show that aldosterone induced fibroblast activation nd epithelial activation may involve Smad, Erk activation, in part driven by CTGF and TGF-β1 induction.

Previous work has shown that LAX4 promotes inflammatory resolution in a variety of acute inflammatory models, including dorsal air pouch, zymosan induced peritionitis. A key mechanism involved in promoting this response is a change in MФ to a resolutionary phenotype, promoting non-phlogistic phagocytosis of PMNs, dampening the inflammatory response and encouraging tissue repair. Fibrosis represents at the extreme end an impaired wound healing response and we hypothesize that part of the potential anti-fibrotic effect of LX rests on promoting inflammatory resolution. Therefore initially we undertook a dose response experiment in a dorsal air pouch model to determine effective dosing in promoting such effects. We show that LAX4 and benzo-LAX4 analogue (ta39) limit neutrophil infiltration in a murine dorsal air puch model when given both locally and systemically.

UUO is an established model of TIF with many of the factors driving fibrosis and injury in this model being correlated with human fibrotic kidney disease. Pre-treatment with both LAX4 and ta39 promoted the devlopment of Ly6C hi phenotype MФ, with mixed cytokine profile, which included an increase in IL-10, consistent with previous work on LX, but unexpectedly was also associated with an increase in TNF-α , IL-1β/ We discuss the significance of these findings, including previous work on LX discussing how new data has outlined the plasticity of the MФ particularly in TIF and how the classical M1/M2 classification may be inadequate to describe in vivo responses.

Dr Eoin Feeney (UCD) - Molecular Mechansims of HIV-associated Metabolic Toxicities
Supervisors:
Dr Patrick Mallon, MB BCh FRACP PhD; Lecturer in Medicine and Consultant Infectious Diseases Physician, UCD School of Medicine and Medical Sciences, Catherine McAuley Education and Research Centre, Mater Misericordiae University Hospital, Dublin
Dr Peter Doran, BSc PhD, Scientific Director, UCD Clinical Research Centre, Genome Resource Unit, UCD School of Medicine and Medical Sciences, Mater Misericordiae Hospital, Dublin
Thesis Abstract:
Human immunodeficiency virus (HIV) infection and antiretroviral treatment may lead to a variety of metabolic changes, many of which can cause significant morbidity and mortality. In this thesis I examine the molecular mechanisms behind three significant areas of HIV-associated metabolic toxicity; nucleoside reverse transcriptase inhibitor (NRTI)-induced hyperlactataemia, mitochondrial toxicity in adipose tissue, and HIV-associated dyslipidaemia. In my first results chapter I examine the predictors (both clinical and molecular) of mitochondrial toxicity in the form of symptomatic hyperlactatemia and lactic acidosis in a large clinical trial, and demonstrate that only body mass index is a significant clinical predictor, while peripheral blood mononuclear cell (PBMC) mitochondrial DNA (mtDNA) and RNA (mtRNA) are not. In the subsequent three chapters I examine mitochondrial toxicity in subcutaneous adipose tissue (SAT), which is associated with the development of lipoatrophy and HIV-associated lipodystrophy.

I demonstrate that a) use of the thymidine NRTI analogue AZT (zidovudine) with the protease inhibitor lopinavir/ritonavir (LPVr) is associated with reduction in limb fat and SAT mtDNA while use of the nonnucleoside reverse transcriptor inhibitor (NNRTI) nevirapine and LPVr is not, b) in SAT the use of a dual protease inhibitor regimen leads to an increase in mtDNA without significantly affecting genes or proteins involved in adipose tissue differentiation and lipid metabolism, and c) in subjects on stable, AZT-containing regimens, switching away from AZT leads to a significant increase in SAT mtDNA content and increase in limb fat. In my last chapter I examine the effects of HIV and antiretrovirals on the expression of genes involved in intracellular cholesterol metabolism in monocytes. I demonstrate that HIV infection is associated with differences in the expression of genes involved in cholesterol efflux and downregulation of cholesterol metabolism genes within monocytes when compared to HIV negative controls, suggestive of intracellular cholesterol accumulation. Furthermore I demonstrate in HIV-infected subjects on antiretroviral therapy that expression of cholesterol efflux genes is similar to HIV-negative controls, but the gene expression pattern for intracellular cholesterol control pathways is suggestive of continuous intracellular cholesterol accumulation.

These data could help explain the elevated risk of cardiovascular disease in treated and untreated HIV infection.
Dr Patrick Collier (UCD) - Myocardial Interstitial Disease in Patients at Risk for Heart Failure: Role in Diastolic Dysfunction, Cardiac Remodelling and Disease Progression
Supervisors:
Dr. John Baugh, Principal Investigator & College Lecturer, UCD School of Medicine & Medical Science
Dr. Ken McDonald, Consultant Cardiologist, St. Vincent’s University Hospital
Thesis Abstract:
The heart failure syndrome has reached epidemic levels worldwide and as there are limited effective treatment options, early identification and intervention is of paramount importance. Adverse cardiac remodelling encompassing morphometric maladaptive responses of the myocardium in response to a wide range of insults is seen in all patients with heart failure and is considered by many to underlie disease progression. A critical contributor to such remodelling is persistent tissue inflammation and pathological reactive myocardial fibrosis which together have been coined “myocardial interstitial disease”. We hypothesized that serum markers of tissue inflammation and fibrosis secreted by the heart may aid earlier identification of myocardial remodelling and diastolic dysfunction and in particular identify those at highest risk of disease progression.

Firstly, we demonstrated that biomarkers indicative of myocardial interstitial disease show a rising trend with increasing left atrial volume indices and can aid detection of patients with subclinical remodelling changes. This is of particular relevance given that the echocardiographical assessment of atrial remodelling is increasingly being used as a pivotal index of significant diastolic dysfunction that can help to risk stratify asymptomatic patients.
Next, we illustrate that even prior to the development of heart failure, at-risk patients may manifest advanced degrees of quantifiable diffuse remodelling changes within atrial tissue for which underlying mechanisms may include reduced collagen breakdown as well as increased collagen synthesis. Having examined relationships between serum and tissue levels of fibro-inflammatory indicators, the results emphasized that serum biomarkers are more likely reflective of remodelling changes within the entire cardio-vasculature and that chamber specific differences in rates of remodelling may exist. Furthermore, our findings of strong correlations between serum markers of inflammation and fibrosis particularly in pre-heart failure patients compared to patients with more established heart failure are supportive of animal model data describing the importance of inflammation as an initial driver for the subsequent development of cardiac fibrosis.

Prompted by the result that the collagen III synthesis biomarker PIIINP (but not the collagen I synthesis marker PICP) was elevated in heart failure with preserved ejection fraction patients as compared to those with asymptomatic hypertension, we then applied a novel methodology to search for a biomechanical explanation of collagen subtype differences within human cardiac tissue. We showed for the first time that human myocardial collagen fibres are organised in a subtype-specific manner and that discrete biomechanical differences do indeed exist between subtypes, namely that collagen III fibres were less stiff, more prone to plastic change and less energy efficient compared to collagen I fibres. In addition, we demonstrated significant differences in fibre stiffness in atrial fibrillation compared to sinus rhythm.

Finally, having demonstrated that atrial tissue is particularly prone to pronounced remodelling changes, we serially followed at risk-patients with careful echocardiographical assessment of left atrial dimensions to identify cohorts of patients with and without evidence of disease progression and found that serum fibro-inflammatory biomarkers were also capable of acting as early warning indicators for at-risk patients.

In conclusion, this thesis supports the utility of serum markers of inflammation and fibrosis as markers of early and ongoing myocardial injury albeit with clear limitations. The quest for novel biomarkers with more optimal characteristics will continue.
Dr Brian Walsh (UCC) - Early Biomarkers to Predict Grade of Encephalopathy following Hypoxic Ischaemic Injury
Supervisors:
Dr Deirdre Murray, Senior Lecturer, Department of Paediatrics and Child Health, UCC
Dr Geraldine Boylan, Senior Lecturer, School of Medicine, UCC
Dr Louise Kenny, Senior Lecturer, Department of Obstetrics and Gynaecology, UCC
Dr Eugene Dempsey, Consultant Neonatologist, Cork University Maternity Hospital, Cork
Thesis Abstract:
Hypoxic ischaemic encephalopathy (HIE) occurs in 2 per 1000 deliveries, and causes 1 million neonatal deaths globally per year. Therapeutic hypothermia is the first treatment available that is proven to reduce both the morbidity and mortality among these infants. It requires that the severity of injury is rapidly determined, such that treatment is initiated within 6 hours of birth. While clinical scoring will distinguish most who would benefit, there is a sizeable minority who will be missed, with the severity of injury only determined beyond the time window to initiate treatment. Alternate techniques to clinical scoring in the first hours of life are limited, with amplitude integrated-EEG (aEEG) being one of the few in common use. Despite this, the exact correlation between aEEG and conventional EEG background grade remains unclear. Similarly while aEEG is reported to be a user-friendly tool, many clinicians report that they are unsure of their own interpretive abilities. Therefore I would advocate that an alternate, objective, and importantly, an early, measure of injury severity is required.
In this study, my aim was to obtain early biological samples, in a well defined, prospectively recruited cohort of infants at risk for, and with HIE. To ensure accuracy of HIE grade I decided to characterise the degree of encephalopathy using both standard clinical neurological assessment, and continuous EEG recordings. From this data, I wished to examine the ability of potential biomarkers within these samples to predict which infants would develop moderate or severe HIE, and therefore become candidates for therapeutic hypothermia.

Methods:
The study was set in a large maternity service, with 9000 deliveries per year. Infants with asphyxia and HIE were identified, and recruited following delivery. Continuous multi-channel video-electroencephalograph (cEEG) and simultaneous aEEG, was commenced on all infants following recruitment and continued for up to 72 hours. Clinical markers including pH, base deficit, lactate, nucleated red blood cell (NRBC) count, Apgar scores and neonatal course were recorded in each case. Modified Sarnat grade was assigned clinically at 24 hours, and serial neurological examination was performed.
The study utilised cohorts from two time epochs, a historic prospectively recruited cohort of infants with exclusively HIE (recruited before the era of hypothermia), and a current prospectively recruited cohort of infants with both HIE and asphyxia without encephalopathy. The historical prospective cohort was utilised for comparison of the background grade of cEEG with simultaneously recorded aEEG, and when contrasting the NRBC count in normothermic encephalopathic infants with those undergoing hypothermia (current cohort).
All infants in the current prospectively recruited cohort had umbilical cord blood drawn, processed, and biobanked at -80 Celsius within 3 hours of birth. This cohort was used for all umbilical cord blood analysis. A matched control population, with umbilical cord blood samples, was recruited over the same period as part of an ongoing birth cohort study (The BASELINE Study www.baselinestudy.net). Following recruitment, the biobanked samples from both cases and matched controls were analysed for multiple potential biomarkers. Specifically; inflammatory proteins were studied using luminex multiplex assay; the metabolomic profile was analysed using mass spectrometry; and the miRNA profile using microarray.

Results:
Eighty five infants at risk of asphyxia were recruited in the current prospective cohort, having had both blood samples biobanked, and cEEG recorded within the first 24 hours following delivery. Of these infants 39 had HIE, and 47 had asphyxia without encephalopathy. Within the independent historical cohort, 46 normothermic infants with HIE were included.
To compare the cEEG and aEEG background grades, 127 simultaneous recordings were analysed. There was moderate agreement between cEEG and aEEG grades assigned, using both standard methods of aEEG background assessment (cEEG vs aEEG Amplitude method κ=0.450, vs aEEG Pattern method κ=0.436). The best agreement existed at the extremes (mild and severe/isoelectric grades), with only 46% agreement between moderate cEEG grade and both the moderate grade using the Amplitude method and DNV in the Pattern method of aEEG assessment.
We had previously determined that the post-natal NRBC count could accurately differentiate mild from moderate/severely encephalopathic EEG backgrounds in infants not undergoing hypothermia. In the current cohort we found that the NRBC count could no longer differentiate mild vs. moderate/severely encephalopathic infants undergoing hypothermia (p=0.38). Comparing the two cohorts we found that the difference in these results was due to a decrease in the NRBC count among moderately encephalopathic infants undergoing hypothermia (p=0.04). All further analysis was confined to umbilical cord blood samples (from the current cohort).
For analysis of inflammatory proteins, exploratory analysis of 37 analytes was conducted on a sub-population of 30 infants (HIE=10, asphyxia=10, controls=10). Three analytes, Matrix Metalloproteinase-9 (MMP-9), Interleuken-16 (IL-16), and Interleuken-6 (IL-6) differed significantly in infants with a moderate/severely abnormal EEG compared to both a normal-mildly abnormal EEG (IL-16 p=0.005: IL-6 p=0.016; MMP-9 p=0.001), and controls (IL-16 p=0.014: IL-6 p=0.003; MMP-9 p=0.005), demonstrating a positive correlation with worsening EEG (IL-16 r=0.639, p=0.002; IL-6 r=0.561, p=0.01; MMP-9 r=0.706, p=0.001). Validation of these results was conducted in a separate sample of 100 infants (HIE=20, asphyxia=29, controls=51). A significant difference existed for IL-6 and IL-16 (p=0.024, p=0.039; respectively), while MMP-9 was no longer significantly altered (p=0.846). Comparison between IL-6, IL-16 and current standard delivery room markers (pH, base deficit and 10 minute Apgar score), found IL-16 and the 10 minute Apgar score to be the strongest predictors of a moderate/severely encephalopathic EEG background with an Area under the receiver operator curve (AUC) of 0.842 (0.671-1.00) and 0.903 (0.795-1.00) respectively.
Analysis of the metabolomic profile within the umbilical cord blood was conducted in 142 infants (HIE=31, asphyxia=40, matched controls=71). This found 29 metabolites to be significantly altered from 3 distinct classes (Amino Acids, Acylcarnitines, and Glycerophospholipids). Nine of these metabolites were only significantly altered between HIE and matched controls, while 14 were significantly altered in both HIE and asphyxia vs. matched controls. A Cross-validated Partial Least Square Discriminant Analysis (PLS-DA) model for HIE versus all other outcomes (asphyxia and control) was constructed. This showed that the metabolite profile could accurately predict HIE with an AUC of 0.92 (95% CI: 0.84-0.97). The associated variable importance plot for the model showed that Acylcarnitines and Amino Acids contributed most.
Exploratory analysis of the micro RNA (miRNA) profile present in the cord blood was performed using microarray. The microarray could analyse samples from 24 infants (Moderate/severe encephalopathy=6, asphyxia=8, control=10), detailing the profile of 909 miRNA in each of these infants cord blood. 70 miRNA were significantly altered between moderate/severely encephalopathic infants and controls, 65 of which had decreased expression among moderate/severely encephalopathic infants, and 5 increased expression among them. Using miRNA target prediction databases, potential targets for the altered miRNA included pathways involved in cellular metabolism, cell cycle and apoptosis, cell signalling, and the inflammatory cascade.

Conclusions:
It can be difficult to accurately determine severity of hypoxic ischaemic injury in the immediate post-natal period. The aEEG is the one of the commonest used early methods of assessing severity of encephalopathy within the neonatal unit. Despite this we found that there was only moderate agreement between the aEEG grade assigned and the cEEG grade. This was particularly true for those with a moderate degree of encephalopathy, which is concerning as it is often these infants who are clinically most difficult to accurately grade. For these reasons alternate biomarkers of HIE severity are required.
The post-natal NRBC count was the first alternate biomarker studied, however I found that its levels could be altered by post-natal interventions. Due to this I would advocate that biomarker discovery should be conducted in the earliest available sample to limit such confounding influences. Use of umbilical cord blood samples would avoid such issues.
I have further demonstrated for the first time, that there is a disturbance in the metabolomic profile of umbilical cord blood following HIE, and that this alteration in the metabolite profile can be used to accurately predict which infants will develop HIE. Analysis of inflammatory proteins demonstrated that umbilical cord blood, IL-6 and IL-16, were both able to distinguish moderate/severely encephalopathic infants in separate exploratory and validation samples. IL-16 has not been previously described in neonatal HIE. Both were superior to the current standard markers of pH and Base Deficit to determine HIE severity.
MiRNA has not been previously analysed in neonatal HIE. I found a significant alteration in 70 miRNA associated with moderate/severe encephalopathy. The exact targets of many of these miRNA have not been experimentally validated, but target prediction databases suggest that the altered miRNA are involved in pathways which we have demonstrated to be disturbed by HIE and asphyxia including the inflammatory cascade, and cellular metabolism. Further experimental validation of these findings will be required.
Dr Nuala Healy (NUI Galway) - Investigation of MicroRNA Expression Patterns as Novel Biomarkers for Breast Cancer
Supervisors:
Professor Michael J Kerin, Professor of Surgery, Department of Surgery Clinical Science Institute, National University of Ireland Galway
Dr Nicola Miller, Senior Scientist, Department of Surgery, Clinical Science Institute, National University of Ireland Galway
Thesis Abstract:
MiRNAs are small single stranded RNA molecules that function at the cellular level to control gene expression. This is accomplished by sequence-specific target recognition and subsequent translational repression or mRNA degradation. As a result miRNAs modulate key cellular processes including apoptosis, growth, development and differentiation. Dysregulated miRNA expression has been reported as a novel mechanism underlying the development of malignancy, including breast cancer.

The aims of this study were to firstly evaluate the expression levels of miR-195, let-7a, miR-181c and miR-342 s in the circulation of breast cancer patients.

Relative expression levels of candidate miRNAs were determined by RQ-PCR on blood samples from 212 women with breast cancer and 59 matched control subjects. Each of the four miRNAs, miR-195, miR-181c, miR-342 and let-7a was found to be upregulated in cases compared to controls (p<0.001) with sensitivity and specificity to predict breast cancer of 94% and 90% respectively.
Functional studies were conducted on two of these miRNAs, miR-195 and miR-181c, to investigate possible mechanistic roles in breast cancer. This was achieved by selectively knocking down target miRNAs with LNA oligonucleotides and characterising subsequent effects on cell growth and apoptosis using Celigo in situ cytometry. Potential target genes for both miRNAs identified using online bioinformatic databases were evaluated using RQ-PCR.

The involvement of miRNA expression in therapeutic resistance in breast cancer was investigated by microarray screening of drug sensitive cells in vitro. Two miRNAs that were found to be upregulated in tamoxifen resistance, miR-1285 and miR-181c were then when knocked down, and found to inhibit cell growth. Furthermore, targeted knockdown of miR-1285 significantly impacted on apoptosis. This indicates that these miRNAs play a role in tamoxifen resistance in breast cancer.

A signature of 4 miRNAs may be useful in detecting the presence of breast cancer. Modulation of miR-1285 and miR-181c may prove useful in enhancing sensitivity to tamoxifen in the treatment of breast cancer.

Research Publications

2016
“Radiation-Induced Heart Disease: A Review of Current Literature and a Practical Approach to Diagnosis and Management..” E. Donnellan, D. Phelan, P. Collier, M. Desai, B. Griffin. Cleve Clin J Med. Accepted for publication 2016 Feb 17 PMID: Awaited
“Prognostic implication of relative regional strain Ratio in cardiac amyloidosis.” A. Senapati, B. Sperry, J. Grodin, K. Kusunose, P. Thavendiranathan, W. Jaber, P. Collier, M. Hanna, Z. Popovic, D. Phelan. Heart. 2016 Feb 1 [Epub ahead of print]. PMID: 26830665
2015
“Characteristics and long-term outcomes of contemporary patients with bicuspid aortic valves.” A. Masri, V. Kalahasti, S. Alkharabsheh, L. Svensson, J. Sabik, E. Roselli, D. Hammer, D. Johnston, P. Collier, L. Rodriguez, B. Griffin, M. Desai. J Thorac Cardiovasc Surg. 2015 Dec 19. [Epub ahead of print]. PMID: 26825434
“Serum Amyloid P-Component Prevents Cardiac Remodeling in Hypertensive Heart Disease.” S. Horgan, C. Watson, N. Glezeva, P. Collier, R. Neary, I. Tea, Corrigan N, M. Ledwidge, K. McDonald, J. Baugh. J Cardiovasc Transl Res. 2015 Dec;8(9):554-66. PMID: 26577946
“Letter re Mugnai et al, iatrogenic atrial septal defect after radiofrequency or cryoballoon ablation of atrial fibrillation.” E. Cronin, P. Collier, O. Wazni, B. Griffin, W. Jaber, W. Saliba. Pacing Clin Electrophysiol. 2015 Nov 12 PMID: 26561216
“Strain imaging to detect cancer therapeutics-related cardiac dysfunction - Are we there yet?” P. Collier, S. Koneru, B. Tamarappoo, B. Griffin. Future Cardiol. 2015 Jul;11(4):401-5 PMID: 26239809
“Isolated Non-compaction of the Left Ventricle in Adults: An Updated Review.” A. Hussein, A. Karimianpour, P. Collier, R. Krasuski. J Am Coll Cardiol. 2015 Aug 4;66(5):578-585 PMID: 26227197
“Grading Diastolic Function by Echocardiography: Hemodynamic Validation of Existing Guidelines.” A. Grant, K. Negishi, T. Negishi, P. Collier, S. Kapadia, J. Thomas, T. Marwick, B. Griffin, Z. Popovic. Cardiovasc Ultrasound. 2015 Jun 24;13(1):28. PMID: 26099810
“Comprehensive Echocardiographic Detection of Treatment-related Cardiac Dysfunction in Adult Survivors of Childhood Cancer: Results from the St. Jude Lifetime Cohort Study.” G. Armstrong, V. Joshi, K. Ness, T. Marwick, N. Zhang, D. Srivastava, B. Griffin, R. Grimm, J. Thomas, D. Phelan, P. Collier, K. Krull, D. Mulrooney, D. Green, M. Hudson, L. Robison, J. Plana. J Am Coll Cardiol. 2015 Jun 16;65(23):2511-22. PMID: 26065990
“Cardiac MR imaging in constrictive pericarditis: multiparametric assessment in patients with surgically proven constriction.” M. Bolen, P. Rajiah, K. Kusunose,
P. Collier, A. Klein, Z. Popović, S. Flamm. Int J Cardiovasc Imaging. 2015 Feb 12. Int J Cardiovasc Imaging. 2015 Apr;31(4):859-66. PMID: 25672267
O'Brien FM, Fortune GM, Dicker P, O'Hanlon E, Cassidy E, Delanty N, Garavan H, Murphy KC. Psychiatric and neuropsychological profiles of people with psychogenic nonepileptic seizures. Epilepsy Behav. 2015 Feb;43:39-45. doi:10.1016/j.yebeh.2014.11.012. Epub 2014 Dec 29. PubMed PMID: 25553390.
Schmidt-Martin D, Crosbie O, Kenny-Walsh E, Fanning L. J. Intensive temporal mapping of hepatitis C hypervariable region 1 quasispecies provides novel insights into hepatitis C virus evolution in chronic infection. Gen. Virol. Aug 2015 96(8):2145-2156 doi:10.1099/vir.0.000149
Palmer BA1, Schmidt-Martin D1, Dimitrova Z2, Skums P2, Crosbie O3, Kenny-Walsh E3, Fanning LJ4.Network Analysis of the Chronic Hepatitis C Virome Defines Hypervariable Region 1 Evolutionary Phenotypes in the Context of Humoral Immune Responses. J Virol. 2015 Dec 30;90(7):3318-29. doi: 10.1128/JVI.02995-15.
2014
Gleeson EM, O'Donnell JS, Hams E, Ní Áinle F, Kenny BA, Fallon PG, Preston RJ. Activated Factor X Signaling via Protease-activated Receptor 2 Suppresses Pro-inflammatory Cytokine Production from Lipopolysaccharide-stimulated Myeloid Cells. Haematologica 2014 Jan;99(1):185-93 PMID: 23872307
Higgins G, Buchanan P, Perriere M, Al-Alawi M, Costello R, Verriere V, McNally P, Harvey BJ, Urbach V. Activation of P2RY11 and ATP Release by LXA4 Restores the Airway Surface Liquid Layer and Epithelial Repair in Cystic Fibrosis Am J Respir Cell Mol Biol 2014 Mar 3 PMID: 24588705
Chotirmall SH, Mirkovic B, Lavelle GM, McElvaney NG. Immunoevasive Aspergillys Virulence Factors. Mycopathologia 2014 Jun 28 PMID: 24972669
Chotirmall SH, McElvaney NG. Fungi in the Cystic Fibrosis Lung: Bystanders or Pathogens? Int J Biochem Cell Biol 2014 Jul;52:161-73 PMID: 24625547
“Application of a Parametric Display of 2D Speckle Tracking Longitudinal Strain to Impove the Etiologic Diagnosis of Mild to Moderate Left Ventricular Hypertrophy.” D. Phelan, P. Thavendiranathan, P. Collier, Z. Popovic, B. Griffin, T. Marwick. J Am Soc Echocardiogr. 2014 Aug;27(8):888-95. PMID: 24874973
Watson C, Phelan D, Collier P, Horgan S, Glezeva N, Cooke G, Xu M, Ledwidge M, McDonald K, Baugh J. Extracellular Matrix Sub-types and Mechanical Stretch Impact Human Cardiac Fibroblast Responses to Transforming Growth Factor Beta. Connect Tissue Res 2014 Mar 13. PMID: 24621314
McAuley DF*, Curley GF*, Hamid UI, Laffey JG, Abbott J, McKenna DH, Fang X, Matthay MA, Lee JW. Intravenous Allogeneic Human Mesenchymal Stem Cells Restore Alveolar Fluid Clearance through a KGF mechanism in Ex Vivo Perfused Human Lungs Rejected for Transplant. Am J Physiol Lung Cell Mol Physiol 2014 May1;306(9):L809-15 *Co-Principal Author PMID: 24532289
Curley GF, Scott JA, Laffey JG. Therapeutic Potential and Mechanisms of Action of Mesenchymal Stromal Cells for Acute Respiratory Distress Syndrome. Curr Stem Cell Res Ther 2014 Feb28 PMID: 24588087
Masterson C, Jerkic M, Curley GF, Laffey JG. Mesenchymal Stromal Cell Therapies – Potential and Pitfalls for ARDS Minerva Anesthesiology 2014 Feb4 PMID: 24492665
Hayes M, Curley GF, Devaney J, Ansari B, O’Toole D, Laffey JG. Inhibition of Pulmonary Nuclear Factor kappa-B Activity Diminishes Ventilator Induced Lung Injury in the Rat. British Journal of Anaesthesia 2014 (In Press)
Curley GF, Laffey JG. Acidosis in the critically ill - balancing risks and benefits to optimize outcome. Crit Care 2014 18:129
Kulkami M, O'Louglin A, Vazquez R, Mashayekhi K, Rooney P, Greiser U, O'Toole E, O'Brien T, Malagon MM, Pandit A. Use of Fibrin-based Systems for Enhancing Angiogenesis and Modulatong Inflammation in the Treatment of Hyperglycemic Wounds. Biomaterials 2014 Feb;35(6):2001-2010 PMID: 24331702
Davey GC, Patil SB, O'Loughlin A, O'Brien T. Mesenchymal Stem Cell-based Treatment for Microvascular and Secondary Complications of Diabetes Mellitus. Front Endocrinol 2014 Jun 6;5:86 PMID: 24936198
Walsh CA, Bolger JC, Byrne C, Cocchiglia S, Hao Y, Fagan A, Qin L, Cahalin A, McCartan D, McIlroy M, O'Gaora P, Xu J, Hill AD, Young LS. Gobal Gene Repression by the Steroid Receptor Coactivator SRC-1 Promotes Oncogenesis. Cancer Res 2014 May1;74(9):2533-44 PMID: 24648347

2013
Neary E, Okafor I, Al-Awaysheh F, Kirkham C, Sheehan K, Mooney C, Foran A, Corcoran JD, Ni Ainle F, Cotter M, McCallion N. Laboratory Coagulation Parameters in Extremely Premature Infants Born Earlier than 27 Gestational Weeks Upon Admission to a Neonatal Intensive Care Unit. Neonatology 2013 104(3):222-7 PMID: 24030102
Chotirmall SH, Al-Alawi M, Mirkovic B, Lavelle G, Logan PM, Greene CM, McElvaney NG. Aspergillus-associated Airway Disease, Inflammation, and the Innate Immune Response. Biomed Res Int 2013 2013:723129 PMID: 23971044
Oglesby IK, Chotirmall SH, McElvaney NG, Greene CM. Regulation of Cystic Fibrosis Transmembrane Conductance Regulator by microRNA-145, -223, and -494 is Altered in ΔF508 Cystic Fibrosis Airway Epithelium. J Immunol 2013 Apr1;190(7):3354-62 PMID: 23436935
Watson C, Collier P, Tea I, Neary R, Watson J, Robinson C, Phelan D,Ledwidge M, McDonald K, McCann A, Sharaf O, Baugh J. Hypoxia-induced Epigenetic Modifications are Associated with Cardiac Tissue Fibrosis and the Development of a Myofibroblast-like Phenotype. Human Mol Genet 2013 Dec 16. PMID: 24301681
Glezeva N, Collier P, Voon V, Ledwidge M, McDonald K, Watson C, Baugh J. Attenuation of Monocyte Chemotaxis - A Novel Anti-inflammatory Mechanism of Action for the Cardio-protective Hormone B-type Natriuretic Peptide. J Cardiovasc Transl Res 2013 Aug;6(4):545-57. PMID: 23625718
Natomi A, Coyne MR, Jacobsen A, Rainey MD, O'Brien G, Healy S, Montagnoli A, Moll J, O'Dwyer M, Santocanale C. Characterization of a Dual CDC7/CDK9 Inhibitor in Multiple Myeloma Cellular Models. Cancers 2013 Jul24;5(3):901-18 PMID: 24202326
Devaney J, Curley GF, Hayes M, Ansari B, O’Brien T, O’Toole D, Laffey JG. Inhibition of Pulmonary Nuclear Factor kappa-B Activity Decreases Acute but Worsens Prolonged Pneumonia Induced Acute Lung Injury. Critical Care 2013 Apr 27;17(2):R82
Curley GF, Ansari B, Hayes M, Devaney J, O’Toole D, O’Brien T, Laffey JG. Effects of Intratracheal Mesenchymal Stem Cells therapy during recovery and resolution following Ventilator Induced Lung Injury. Anesthesiology 2013 Apr;118(4):924-932. PMID: 23377221
Curley GF, Laffey JG. Cell Therapy Demonstrates Promise for Acute Respiratory Distress Syndrome - But Which Cell is Best? Stem Cell Research and Therapy 2013 Mar22;4(2):29 PMID: 23672885
Curley GF, Laffey JG, Kavanagh BP. CrossTalk Proposal: There is Added Benefit to Providing Permissive Hypercapnia in the Treatment of ARDS. J Physiol 2013 Jun1;591:2763-5 PMID:23729790
Feeney ER, McAuley N, O’Halloran JA, Rock C, Low J, Satchell CS, Lambert JS, Sheehan GJ, Mallon PW. The Expression of Cholesterol Metabolism Genes in Monocytes From HIV-infected Subjects Suggests Intracellular Cholesterol Accumulation. J Infect Dis 2013 15:628-37. PMID 23204179
Kelly BD, Miller N, Healy NA, Walsh K, Kerin MJ. A Review of Expression Profiling of Circulating microRNAs in Men with Prostate Cancer. BJU Int 2013 Jan;111(1):17-21. PMID: 22612403
Purse-string approximation is superior to primary skin closure following stoma reversal: a systematic review and meta-analysis. McCartan DP, Burke JP, Walsh SR, Coffey JC. Tech Coloproctol. 2013;17(4):345-51
O'Loughlin A, Kulkarni M, Creane M, Vaughan EE, Mooney E, Shaw G, Murphy M, Dockery P, Pandit A, O'Brien T. Topical Administration of Allogeneic Mesenchymal Stem Cells Seeded in a Collagen Scaffold Augments Wound Healing and Increases Angiogenesis in the Diabetic Rabbit Ulcer. Diabetes 2013 PMID: 23423568
O'Loughlin A, Kulkarni M, Vaughan EE, Creane M, Liew A, Dockery P, Pandit A, O'Brien T. Autologous Circulating Angiogenic Cells Treating with Osteopontin and Delivered via a Collagen Scaffold Enhance Wound Healing in the Alloxan-induced Diabetic Rabbit Ear Ulcer Model. Stem Cell Res Ther 2013 4(6):158 PMID: 24444259
McCarthy FP, Delany AC, Kenny LC, Walsh SK. PPAR-γ - A Possible Drug Target for Complicated Pregnancies. Br J Pharmacol 2013 Mar;168(5):1074-85 PMID: 23186152
English FA, McCarthy FP, McSweeney CL, Quon AL, Morton JS, Sawamura T, Davidge ST, Kenny LC. Inhibition of Lectin-like Oxidized Low-density Lipoprotein-1 Receptor Protects Against Plasma-mediated Vascular Dysfunction Associated with Pre-eclampsia. Am J Hypertens 2013 Feb;26(2):279-86 PMID: 23382414
McCarthy FP, OʼKeeffe LM, Khashan AS, North RA, Poston L, McCowan LM, Baker PN, Dekker GA, Roberts CT, Walker JJ, Kenny LC. Association Between Maternal Alcohol Consumption in Early Pregnancy and Pregnancy Outcomes. Obstet Gynecol 2013 Oct;122(4):830-7 PMID: 24084541
McCarthy FP, Khashan AS, North RA, Rahma MB, Walker JJ, Baker PN, Dekker G, Poston L, McCowan LM, O'Donoghue K, Kenny LC; SCOPE Consortium. Pregnancy Loss Managed by Cervical Dilatation and Curettage Increases the Risk of Spontaneous Preterm Birth. Hum Reprod 2013 Dec;28(12):3197-206 PMID: 24052504
McCarthy FP, Delany AC, Kenny LC, Walsh SK. PPAR-γ - A Possible Drug Target for Complicated Pregnancies. Br J Pharmacol 2013 Mar;168(5):1074-85 PMID: 23186152
English FA, McCarthy FP, McSweeney CL, Quon AL, Morton JS, Sawamura T, Davidge ST, Kenny LC. Inhibition of Lectin-like Oxidized Low-density Lipoprotein-1 Receptor Protects Against Plasma-mediated Vascular Dysfunction Associated with Pre-eclampsia. Am J Hypertens 2013 Feb;26(2):279-86 PMID: 23382414
McCarthy FP, OʼKeeffe LM, Khashan AS, North RA, Poston L, McCowan LM, Baker PN, Dekker GA, Roberts CT, Walker JJ, Kenny LC. Association Between Maternal Alcohol Consumption in Early Pregnancy and Pregnancy Outcomes. Obstet Gynecol 2013 Oct;122(4):830-7 PMID: 24084541
McCarthy FP, Khashan AS, North RA, Rahma MB, Walker JJ, Baker PN, Dekker G, Poston L, McCowan LM, O'Donoghue K, Kenny LC; SCOPE Consortium. Pregnancy Loss Managed by Cervical Dilatation and Curettage Increases the Risk of Spontaneous Preterm Birth. Hum Reprod 2013 Dec;28(12):3197-206 PMID: 24052504
McGrath J, Johnson K, O'Hanlon E, Garavan H, Leemans A, Gallagher L. Abnormal Functional Connectivity During Visuospatial Processing is Associated with Disrupted Organisation of White Matter in Autism. Front Hum Neurosci 2013 Sep26;7:434 PMID: 24133425
Delmonte S, Gallagher L, O'Hanlon E, McGrath J, Balsters JH. Functional and Structural Connectivity of Frontostriatal Circuitry in Autism Spectrum Disorder. Front Hum Neurosci 2013 Aug6;7:430 PMID: 23964221
McGrath J, Johnson K, O'Hanlon E, Garavan H, Gallagher L, Leemans A. White Matter and Visuospatial Processing in Autism: A Constrained Spherical Deconvolution Tractography Study. Autism Res 2013 Oct;6(5):307-19 PMID: 23509018
Jan A, Dawkins I, Murphy N, Collier P, Baugh J, Ledwidge M, McDonald K, Watson C. Associates of an elevated natriuretic peptide level in stable heart failure patients; implications for targeted management. Scientific World Journal 2013 Dec 25;2013:562763 PMID: 24453873
O'Sullivan JF, Leblond AL, O'Dea J, Hristova I, Kumar S, Martin K, Kumar AH, Caplice NM. Multidetectro Computed Tomography Accurately Defines Infarct Size, but not Microvascular Obstruction After Myocardial Infarction. J Am Coll Cardiol 2013 Jan15;61(2):208-210 PMID: 23177294
Hynes B, Kumar AH, O'Sullivan J, Klein Buneker C, Leblond AL, Weiss S, Schmeckpeper J, Martin K, Caplice NM. Potent Endothelial Progenitor Cell-conditioned Media-related Anti-apoptotic, Cardiotrophic, and Pro-angiogenic Effects Post-myocardial Infarction are Mediated by Insulin-like Growth Factor-1. Eur Heart J 2013 Mar;34(10):782-9 PMID: 22173909
Hawkes CP, Walsh BH, Ryan CA, Dempsey EM. Smartphone Technology Enhances Newborn Intubation Knowledge and Performance Amongst Paediatric Trainees. Resuscitation 2013 Feb;84(2):223-6 PMID: 22796404
Denihan NM, Looney A, Boylan GB, Walsh BH, Murray DM. Normative Levels of Interleukin-16 in Umbilical Cord Blood. Clin Biochem 2013 Dec;46(18):1857-9 PMID: 23891891
Reinke SN, Walsh BH, Boylan GB, Sykes BD, Kenny LC, Murray DM, Broadhurst DI. 1H NMR Derived Metabolomic Profile of Neonatal Asphyxia in Umbilical Cord Serum: Implications for Hypoxic Ischemic Encephalopathy. J Proteome Res 2013 Sep6;12(9):4320-9 PMID: 23931672
Walsh BH, Boylan GB, Dempsey EM, Murray DM. Association of Nucleated Red Blood Cells and Severity of Encephalopathy in Normothermic and Hypothermic Infants. Acta Paediatr 2013 Feb;102(2):e64-7 PMID: 23157330
Walsh BH, Boylan GB, Livingstone V, Kenny LC, Dempsey EM, Murray DM. Cord Blood Proteins and Multichannel-electroencephalography in Hypoxic-ischemic Encephalopathy. Pediatr Crit Care Med 2013 Jul;14(6):621-30 PMID: 23823198

2012
Verriere V, Higgins G, Al-Alawi M, Costello RW, McNally P, Harvey BJ, Urbach V.Lipoxin A4 Stimulates Calcium-activated Chloride Currents and Increases Airwary Surface Liquid Height in Normal and Cystic Fibrosis Airway Epithelia. PLoS One 2012 7(5):e37746 PMID:22662206
Khoo SG, Al-Alawi M, Walsh MT, Hannigan K, Glynn S, Thornton M, McQuaid S, Wang Y, Hamilton PW, Verriere V, Gleich GJ, Harvey BJ, Costello RW, McGarvey LP. Eosinophil Peroxidase Induces the Expression and Function of Aid-sensing Ion Channel-3 in Allergic Rhinitis: in vtro Evidence in Cultured Epithelial Cells. Clin Exp Allergy 2012 Jul 42(7); 1028-39 PMID: 22702502
Jennings CJ, O'Grady A, Cummins R, Murer B, Al-Alawi M, Madden SF, Mutti L, Harvey BJ, Thomas W, Kay EW. Sustained Expression of Steroid Receptor Coactivator SRC-2/TIF-2 is Associated with Better Prognosis on Malignant Pleural Mesothelioma. J Thorac Oncol 2012 Jan;7(1):243-8 PMID: 22011668
Chotirmall SH, Greene CM, McElvaney NG. Immune, Inflammatory and Infectious Consequences of Estrogen in Women with Cystic Fibrosis. Expert Rev Respir Med 2012 Dec;6(6):573-5. PMID: 23234443
Coughlan CA, Chotirmall SH, Renwick J, Hassan T, Low TB, Bergsson G, Eshwika A, Bennett K, Dunne K, Greene CM, Gunaratnam C, Kavanagh K, Logan PM, Murphy P, Reeves EP, McElvaney NG. The effect of Aspergillus Fumigatus Infection on Vitamin D Receptor Expression in Cystic Fibrosis. Am J Respir Crit Care Med 2012 Nov15;186(10):999-1007 PMID: 22904183
Chotirmall SH, Smith SG, Gunaratnam C, Cosgrove S, Dimitrov BD, O'Neill SJ, Harvey BJ, Greene CM, McElvaney NG. Effect of Estrogen on Pseudomonas Mucoidy and Exacerbations in Cystic Fibrosis. N Eng J Med 2012 May24;366(21):1978-86 PMID: 22607135
Hassan T, Al-Alawi M, Chotirmall SH, McElvaney NG. Pleural Fluid Analysis: Standstill or a Work in Progress? Pulm Med 2012 2012:716235 PMID: 22448326
McMahon MA, Chotirmall SH, McCullagh B, Branagan P, McElvaney NG, Logan PM. Radiological Abnormalities Associated with Aspergillus Colonization in a Cystic Fibrosis Population. Eur J Radiol 2012 Mar;81(3) PMID: 21349668
Chotirmall SH, Branagan P, Logan MP, O'Neill SJ. A Deceiving Wheeze. Ir J Med Sci 2012 Sep;181(3):337-9 PMID: 19662488
Phelan D, Watson C, Martos R, Collier P, Patle A, Donnelly S, Ledwidge M, Baugh J, McDonald K. Modest Elevation in BNP in Asymptomatic Hypertensive Patients Reflects Sub-clinical Cardiac Remodeling, Inflammation and Extracellular Matrix Changes. PLoS One 2012 7(11):e49259. PMID: 23152884
Watson C, Phelan D, Xu M, Collier P, Smolenski A, Ledwidge M, McDonald K, Baugh J. Mechanical stretch up-regulates the B-type natriuretic peptide system in human cardiac fibroblasts: A possible defense against transforming growth factor-β mediated fibrosis. Fibrogenesis Tissue Repair 2012 Jul 7;5(1):9. PMID: 22768849
Collier P, Watson CJ, Waterhouse DF, Dawkins IR, Patle AK, Horgan S, Conlon CM, O'Hanlon R, Baugh JA, Ledwidge MT, McDonald K. Progression of Left Atrial Volume Index in a Population at Risk for Heart Failure: A Substudy of the STOP-HF (St Vincents Screening TO Prevent Heart Failure) Trial. European Journal of Heart Failure 2012 14 (9) PMID: 22759444
Collier P, Ledwidge M, McDonald K. Diagnostics and Therapeutic Interventions in Myocardial Interstitial Disease, A Previously Neglected Pathology. QJM-An International Journal Of Medicine 2012 105(8) 721-724 PMID: 22647762
Collier P, McDonald KM. The Role of Renin Angiotensin System Intervention in Stage B Heart Failure Source Heart Failure Clinics 2012 8(2) 225-236. PMID: 22405662
Collier P, Watson CJ, van Es MH, Phelan D, McGorrian C, Tolan M, Ledwidge MT, McDonald KM, Baugh JA. Getting to the heart of cardiac remodeling; how collagen subtypes may contribute to phenotype Journal of Molecular And Cellular Cardiology 2012 52(1)148-153. PMID: 22008391
Contreras M, Ansari B, Curley G, Higgins BD, Hassett P, O'Toole D, Laffey JG. Hypercapnic Acidosis Attenuates Ventilation-induced Lung Injury by a Nuclear Factor- kappa B Dependent Mechanism Critical Care Med 2012 40(9) 2622-30 PMID: 22732277
Curley GF, Hayes M, Ansari B, Shaw G, Ryan Barry F, O'Brien T, O'Toole D, Laffey J. Gansari Mesenchymal Stem Cells Enhance Recovery and Repair Following Ventilator-induced Lung Injury in the Rat. Thorax 2012 67(6)496-501 PMID: 22106021
Hayes M, Curley G, Ansari B, Laffey JG. Clinical Review: Stem Cell Therapies for Acute Lung Injury/Acute Respiratory Distress Syndrome - Hope or Hype? Crit Care 2012 Mar 16;16(2):205 PMID: 22424108
Hayes M, Curley G, Leffey JG. Mesenchymal Stem Cells – A Promising Therapy for Acute Respiratory Distress Syndrome. F1000 Med Rep 2012 4:2 PMID: 22238514
Feeney ER, van Vonderen MG, Wit F, Danner SA, van Agtmael MA, Villaroya F, Domingo P, Capeau J, Reiss P, Mallon PW. Zidovudine/Lamivudine but not Nevirapine in Combination with Lopinavir/Ritonavir Decreases Subcutaneous Adipose Tissue Mitochondrial DNA. AIDS 2012 26: 2165-74 PMID: 22874517
Healy NA, Heneghan HM, Miller N, Osborne CK, Schiff R, Kerin MJ. Systemic Mirnas as Potential Biomarkers for Malignancy. Int J Cancer 2012 Nov 15;131(10):2215-22. PMID: 22618667
Lowery AJ, Kell MR, Glynn RW, Kerin MJ, Sweeney KJ. Locoreginal Recurrance after Breast Cancer Surgery; a Systematic Review by Receptor Phenotype. Breast Cancer Res Treat 2012 June;133(3);831-41 PMID: 22147079
McVeigh T, Lowery AJ, Quill DS, Kerin MJ. Changing Practices in the Surgical Management of Hyperthyroidism - a 10 Year Review. Surgeon 2012 Dec; 10(6):314-20 PMID: 22105046
McCartan D, Bolger JC, Fagan A, Byrne C, Hao Y, Qin L, McIlroy M, Xu JM, Hill AD, Gaora PO, Young LS. Global Characterization of the SRC-1 Transcriptome Identifies ADAM22 as an ER-Independent Mediator of Endocrine-Resistant Breast Cancer Cancer Research 2012 72(1) 220-229 PMID: 22072566
English FA, McCarthy FP, Andersson IJ, Stanley JL, Davidge ST, Baker PN, Walsh SK, Kenny LC. Administration of the PARP Inhibitor Pj34 Ameliorates the Impaired Vascular Function Associated With Enos(-/-) Mice Reproductive Sciences 2012 19(8):806-813 PMID: 22421449
Khashan AS, Quigley EM, McNamee R, McCarthy FP, Shanahan F, Kenny LC. Increased Risk of Miscarriage and Ectopic Pregnancy among Women with Irritable Bowel Syndrome. Clin Gastroenterol Hepatol 2012 Feb 25. PMID: 22373726
Lausman A, McCarthy FP, Walker M, Kingdom JC, Screening, Diagnosis and Management of Intrauterine Growth Restriction. J Obstet Gynaecol Can 2012 Jan;34(1):17-28. PMID: 22260759
McGrath J, Johnson K, Ecker C, O'Hanlon E, Gill M, Gallagher L, Garavan H. Atypical Visuospatial Processing in Autism: Insights from Functional Connectivity Analysis. Autism Res 2012 Oct;5(5):314-30 PMID: 22865697
Rose EJ, Greene C, Kelly S, Morris DW, Robertson IH, Fahey C, Jacobson S, O'Doherty J, Newell FN, McGrath J, Bokde A, Garavan H, Frodl T, Gill M, Corvin AP, Donohoe G. The NOS1 Variant rs6490121 is Associated with Variation in Prefrontal Function and Grey Matter Density in Healthy Individuals. Neuroimage 2012 Mar;60(1):614-22 PMID: 22227051
Delmonte S, Balsters JH, McGrath J, Fitzgerald J, Brennan S, Fagan AJ, Gallagher L. Social and Monetary Reward Processing in Autism Spectrum Disorders. Mol Autism 2012 Sep26;3(1):7 PMID: 23014171
Casey JP1, Magalhaes T, Conroy JM, Regan R, Shah N, Anney R, Shields DC, Abrahams BS, Almeida J, Bacchelli E, Bailey AJ, Baird G, Battaglia A, Berney T, Bolshakova N, Bolton PF, Bourgeron T, Brennan S, Cali P, Correia C, Corsello C, Coutanche M, Dawson G, de Jonge M, Delorme R, Duketis E, Duque F, Estes A, Farrar P, Fernandez BA, Folstein SE, Foley S, Fombonne E, Freitag CM, Gilbert J, Gillberg C, Glessner JT, Green J, Guter SJ, Hakonarson H, Holt R, Hughes G, Hus V, Igliozzi R, Kim C, Klauck SM, Kolevzon A, Lamb JA, Leboyer M, Le Couteur A, Leventhal BL, Lord C, Lund SC, Maestrini E, Mantoulan C, Marshall CR, McConachie H, McDougle CJ, McGrath J, McMahon WM, Merikangas A, Miller J, Minopoli F, Mirza GK, Munson J, Nelson SF, Nygren G, Oliveira G, Pagnamenta AT, Papanikolaou K, Parr JR, Parrini B, Pickles A, Pinto D, Piven J, Posey DJ, Poustka A, Poustka F, Ragoussis J, Roge B, Rutter ML, Sequeira AF, Soorya L, Sousa I, Sykes N, Stoppioni V, Tancredi R, Tauber M, Thompson AP, Thomson S, Tsiantis J, Van Engeland H, Vincent JB, Volkmar F, Vorstman JA, Wallace S, Wang K, Wassink TH, White K, Wing K, Wittemeyer K, Yaspan BL, Zwaigenbaum L, Betancur C, Buxbaum JD, Cantor RM, Cook EH, Coon H, Cuccaro ML, Geschwind DH, Haines JL, Hallmayer J, Monaco AP, Nurnberger JI Jr, Pericak-Vance MA, Schellenberg GD, Scherer SW, Sutcliffe JS, Szatmari P, Vieland VJ, Wijsman EM, Green A, Gill M, Gallagher L, Vicente A, Ennis S. A Novel Approach of Homozygous Haplotype Sharing Identifies Candidate Genes in Autism Spectrum Disorder. Hum Genet 2012 Apr;131(4):565-79 PMID: 21996756
Rose EJ, Morris DW, Fahey C, Robertson IH, Greene C, O'Doherty J, Newell FN, Garavan H, McGrath J, Bokde A, Tropea D, Gill M, Corvin AP, Donohoe G. The Effect of the Neurogranin Schizophrenia Risk Variant rs12807809 on Brain Structure and Function. Twin Res Hum Genet 2012 Jun;15(3):296-303 PMID: 22856365
Murphy CM, Deeley Q, Daly EM, Ecker C, O'Brien FM, Hallahan B, Loth E, Toal F, Reed S, Hales S, Robertson DM, Craig MC, Mullins D, Barker GJ, Lavender T, Johnston P, Murphy KC, Murphy DG. Anatomy and Aging of the Amygdala and Hippocampus in Autism Spectrum Disorder: an in vivo Magnetic Resonance Imaging Study of Asperger Syndrome Autism Research 2012 5 (1): 3-12
McLaughlin PD, Ryan J, Hodnett PA, O'Halloran D, Maher MM. Quantitative Whole-Body MRI in Familial Partial Lipodystrophy Type 2: Changes in Adipose Tissue Distribution Coincide with Biochemical Improvement. Am J Roentgenol 2012 199(5) W602-6
Schmidt-Martin D, Crosbie O, Kenny-Walsh E, Fanning LJ. Hepatitis C Quasispecies Adaptation in the Setting of a Variable Fidelity Polymerase. Virus Adaptation and Treatment 2012 4:43-50
Walsh BH, Broadhurst DI, Mandal R, Wishart DS, Boylan GB, Kenny LC, Murray DM. The Metabolomic Profile of Umbilical Cord Blood in Neonatal Hypoxic Ischaemic Encephalopathy. PLoS One 2012 7(12):e50520 PMID: 23227182

2011
Ní Ainle F, O'Donnell JS, Johnson JA, Brown L, Gleeson EM, Smith OP, Preston RJ. Activated Protein C N-linked Glycans Modulate Cytoprotective Signaling Function on Endothelial Cells. J Biol Chem 2011 Jan14;286(2):1323-30 PMID: 21044954
Cosgrove S, Chotirmall SH, Greene CM, McElvaney NG. Pulmonary Proteases in the Cystic Fibrosis Lung Induce Interleukin 8 Expression from Bronchial Epithelial Cells via a Heme/Meprin/Epidermal Growth Factor Receptor/Toll-like Receptor Pathway. J Biol Chem 2011 Mar4;286(9):7692-704 PMID: 21193404
Chotirmall SH, Low TB, Hassan T, Branagan P, Kernekamp C, Flynn MG, Gunaratnam C, McElvaney NG. Cystic Fibrosis, Common Variable Immunodeficiency and Aspergers Syndrome: an Immunological and Behavioural Challenge. Ir J Med Sci 2011 Jun;180(2):607-9 PMID: 19662491
Chotirmall SH, Harvey BJ, McElvaney NG, Greene CM. Pulmonary Inflammation in Cystic Fibrosis: Impact of Innate Immunity and Estrogen. CML – Cystic Fibrosis 2011 1(2):37-48. ISN 2045–712X (Print); ISN 2045–7138 (Online)
Collier P, Watson C, Voon V, Phelan D, Jan A, Mak G, Martos R, Baugh J,Ledwidge M, McDonald K. Can emerging biomarkers of myocardial remodeling identify asymptomatic hypertensive patients at risk for diastolic dysfunction and diastolic heart failure? Eur J Heart Fail 2011 13(10):1087-95. PMID: 21719449
Watson C, Ledwidge M, Phelan D, Collier P, Byrne J, Dunne M, McDonald K, Baugh J. Proteomic analysis of coronary sinus serum reveals Leucine-rich alpha-r as a novel biomarker of ventricular dysfunction and heart failure. Circ Heart Fail 2011 4(2):188-97. PMID: 21282491
Curley G, Kavanagh BP, Laffey JG. Hypocapnia and the Injured Brain: Evidence for Harm. Critical Care Med 2011 Jan;39(1):229-230 PMID: 21178560
Curley G, Hayes M, Laffey JG. Can 'Permissive' Hypercapnia Modulate the Severity of Sepsis Induced ALI/ARDS? Critical Care 2011 Mar 22;15(2):212 PMID: 21457509
Curley G, Laffey JG. Hypocapnia Induced Cerebral Ischaemia During Therapeutic Hypothermia-Potential for Harm? Resuscitation 2011 Sep;82(9):1122-3 PMID: 21700377
Hayes M, Curley G, Laffey JG. Lung Stem Cells - From an Evolving Understanding to a Paradigm Shift? Stem Cell Res Ther 2011 Oct 20;2(5):41 PMID: 22017959
Curley GF. Rapid Sequence Induction with Rocuronium - A Challenge to the Gold Standard. Crit Care 2011 15(5):190 PMID: 22112346
Curley GF, Contreras M, Higgins B, O'Kane C, McAuley DF, O'Toole D, Laffey JG. Evolution of the Inflammatory and Fibroproliferative Responses during Resolution and Repair after Ventilator-induced Lung Injury in The Rat. Anesthesiology 2011 115;(5)1022-32 PMID: 21952251
Hassett P, Curley GF, Contreras M, Masterson C, Higgins BD, O'Brien T, Devaney J, O'Toole D, Laffey JG. Overexpression of Pulmonary Extracellular Superoxide Dismutase Attenuates Endotoxin-induced Acute Lung Injury. Intensive Care Med 2011 Oct;37(10):1680-7 PMID: 21755396
Cotter AG, Satchell CS, O’Halloran JA, Feeney ER, Sabin CA, Mallon PWG. High Density Lipoprotein Levels and 10-year Cardiovascular Risk in HIV-1 Infected Patients. AIDS 2011;25:867-9
Satchell CS, O'Halloran JA, Cotter AG, Peace AJ, O'Connor EF, Tedesco AF, Feeney E, Lambert JS, Sheehan GJ, Kenny D, Mallon PWG. Increased Platelet Reactivity in HIV-1-Infected Patients Receiving Abacavir-Containing Antiretroviral Therapy J Infect Dis 2011;204:1202-10. PMID 21917893
Feeney ER, Mallon PW. Insulin Resistance in Treated HIV Infection. Best Pract Res Clin Endocrinol Metab 2011 25(3):443-58 PMID: 21663838
Feeney ER, Mallon PW. HIV and HAART-Associated Dyslipidemia. Open Cardiovasc Med J 2011 5:49-63. PMID: 21643501
Feeney E, Chazallon C, O'Brien N, Meiffrédy V, Goodall R, Aboulker JP, Cooper D, Yeni P, Mallon PWG. Hyperlactataemia in HIV-infected Subjects Initiating Antiretroviral Therapy in a Large Randomized Study (A Substudy of the INITIO Trial). HIV Med 2011 12:602-9 PMID 21599820
Neary M, Lowery AJ, O'Conghaile A, Pervaz M, Kerin MJ, Sweeney KJ. NCCP Breast Cancer Referral Guidelines - Are Breast Cancer Patients Prioritised? Ir Med J 2011 Feb;104(2):39-41 PMID: 21465872
Wang Y, Morrison G, Gillihan R, Guo J, Ward RM, Fu X, Botero MF, Healy NA, Hilsenbeck SG, Phillips GL, Chamness GC, Rimawi MF, Osborne CK, Schiff R. Different Mechanisms for Resistance to Trastuzumab Versus Lapatinib in HER2-positive Breast Cancers — Role of Estrogen Receptor and HER2 Reactivation. Breast Cancer Res 2011 13(6):R121.PMID: 22123186
Healy NA, Glynn RW, Scutaru C, Groneberg D, Kerin MJ, Sweeney KJ. The h Index and The Identification of Global Benchmarks for Breast Cancer Research Output. Breast Cancer Res Treat 2011 Jun;127(3):845-51
Czikk MJ, McCarthy FP, Murphy KE. Chorioamnionitis: From Pathogenesis to Treatment Clin Microbiol Infect 2011 Sep;17(9):1304-11 PMID: 21672080
McCarthy FP, Drewlo S, Kingdom J, Johns EJ, Walsh SK, Kenny LC. Peroxisome Proliferator-Activated Receptor-{gamma} as a Potential Therapeutic Target in the Treatment of Preeclampsia. Hypertension 2011 58(2):280-6. PMID: 21690483.
McCarthy FP, Drewlo S, English FA, Kingdom J, Johns EJ, Kenny LC, Walsh SK. Evidence Implicating Peroxisome Proliferator-Activated Receptor-gamma in the Pathogenesis of Preeclampsia. Hypertension 2011 58;(5):882-U447 PMID:21931072
McCarthy FP, Kingdom JC, Kenny LC, Walsh SK. Animal Models of Preeclampsia; Uses and Limitations. Placenta 2011 Jun;32(6):413-9 PMID: 21497901
McCarthy FP, Giles ML, Rowlands S, Purcell KJ, Jones CA. Antenatal Interventions for Preventing the Transmission of Cytomegalovirus (CMV) from the Mother to Fetus During Pregnancy and Adverse Outcomes in the Congenitally Infected Infant. Cochrane Database Syst Rev 2011 Mar 16;3:CD008371. PMID: 21412919
McCarthy FP, Khashan AS, North RA, Moss-Morris R, Baker PN, Dekker G, Poston L, Kenny LC. Group Author(s): SCOPE Consortium. A Prospective Cohort Study Investigating Associations between Hyperemesis Gravidarum and Cognitive, Behavioural and Emotional Well-Being in Pregnancy PLoS One 2011 6(11):e27678
Butler MM, Kenny LC, McCarthy FP. Coeliac Disease and Pregnancy outcomes. Obstet Med 2011 4:95-98
Martin K, O'Sullivan JF, Caplice NM. New Therapeutic Potential of microRNA Treatment to Target Vulnerable Lesions and Plaque Ruptures. Curr Opin Cardiol 2011 Nov;26(6):569-75 PMID: 21918434
O'Sullivan JF, Leblond AL, Kelly G, Kumar AH, Metharom P, Büneker CK, Alizadeh- Vikali N, Hristova I, Hynes BG, O'Connor R, Caplice NM. Potent Long-term Cardioprotective Effects of Single Low-dose Insulin-like Growth Factor-1 Treatment Postmyocardial Infarction. Circ Cardiovasc Interv 2011 4(4):327-35. PMID: 21712526.
O'Sullivan JF, Martin K, Caplice NM. Microribonucleic Acids for Prevention of Plaque Rupture and in-stent Restenosis: 'A Finger in the Dam'. J Am Coll Cardiol 2011 Jan 25;57(4):383-9 PMID: 21251577
Petrovic D, Stamataki Z, Dempsey E, Golden-Mason L, Freeley M, Doherty D, Prichard D, Keogh C, Conroy J, Mitchell S, Volkov Y, McKeating JA, O'Farrelly C, Kelleher D, Long A. Hepatitis C Virus Targets the T Cell Secretory Machinery as a Mechanism of Immune Evasion Hepatology 2011 53(6) 1846-1853 PMID:21452285
Sharma R, Prichard D, Majer F, Byrne AM, Kelleher D, Long A. Gilmer JF Ursodeoxycholic Acid Amides As Novel Glucocorticoid Receptor Modulators Journal of Medicinal Chemistry 2011 54(1) 122-130. PMID:21158453
Börgeson E, Docherty NG, Murphy M, Rodgers K, Ryan A, O'Sullivan TP, Guiry PJ, Goldschmeding R, Higgins DF, Godson C. Lipoxin A4 and benzo-lipoxin A4 Attenuate Experimental Renal Fibrosis. FASEB J 2011 Sep;25(9):2967-79. PMID: 21628447
Korotchikova I, Stevenson NJ, Walsh BH, Murray DM, Boylan GB. Quantitative EEG Analysis in Neonatal Hypoxic Ischaemic Encephalopathy. Clin Neurophysiol 2011 Aug;122(8):1671-8 PMID: 21334256
Walsh BH, Boylan GB, Murray DM. Nucleated Red Blood Cells and Early EEG: Predicting Sarnat Stage and Two Year Outcome. Early Hum Dev 2011 May;87(5):335-9 PMID: 21333469
Walsh BH, Low E, Bogue CO, Murray DM, Boylan GB. Early Continuous Video Electroencephalography in Neonatal Stroke. Dev Med Child Neurol 2011 Jan;53(1):89-92 PMID: 21087242
Walsh BH, Murray DM, Boylan GB. The Use of Conventional EEG for the Assessment of Hypoxic Ischaemic Encephalopathy in the Newborn: A Review Clin Neurophysiol 2011 Jul;122(7):1284-94

2010
Chotirmall SH, Greene CM, McElvaney NG. Candida Species in Cystic Fibrosis: A Road Less Travelled. Med Mycol 2010 Nov;48Suppl1:S114-24 PMID: 21067323
Bergin DA, Reeves EP, Meleady P, Henry M, McElvaney OJ, Carroll TP, Condron C, Chotirmall SH, Clynes M, O'Neill SJ, McElvaney NG. α-1 Antitrypsin Regulates Human Neutrophil Chemotaxis Induced by Soluble Immune Complexes and IL-8. J Clin Invest 2010 Dec;120(12):4236-50 PMID: 21060150
Hassan T, Chotirmall SH, Low TB, Flynn MG, McElvaney NG, Gunaratnam C. Thrombolysis for Indwelling Catheter Related Thrombosis and Superior vena cava Obstruction in Cystic Fibrosis: A Case Series. Ir J Med Sci 2010 Sep;179(3):469-70 PMID: 20563759
Chotirmall SH, O'Donoghue E, Bennett K, Gunaratnam C, O'Neill SJ, McElvaney NG. Sputum Candida Albicans Presages FEV₁ Decline and Hospital-treated Exacerbations in Cystic Fibrosis. Chest 2010 Nov;138(5):1186-95 PMID: 20472859
Chotirmall SH, Greene CM, Oglesby IK, Thomas W, O'Neill SJ, Harvey BJ, McElvaney NG. 17Beta-estradiol Inhibits IL-8 in Cystic Fibrosis by Up-regulating Secretory Leucoprotease Inhibitor. Am J Respir Crit Care Med 2010 Jul 1;182(1):62-72 PMID: 20378727
Oglesby IK, Bray IM, Chotirmall SH, Stallings RL, O'Neill SJ, McElvaney NG, Greene CM. miR-126 is Downregulated in Cystic Fibrosis Airway Epithelial Cells and Regulates TOM1 Expression. J Immunol 2010 Feb15;184(4):1702-9. PMID: 20083669
Chotirmall SH, Flynn MG, Donegan CF, Smith D, O'Neill SJ, McElvaney NG. Extubation Versus Tracheostomy in Withdrawal of Treatment-ethical, Clinical, and Legal Perspectives. J Crit Care 2010 Jun;25(2):360 PMID: 19850443
Carney J, Finnerty O, Rauf J, Curley G, McDonnell JG, Laffey JG. Ipsilateral Transversus Abdominis Plane Block Provides Effective Analgesia after Appendectomy in Children: a Randomized Controlled Trial. Anesth Analg 2010 Oct;111(4):998-1003 PMID: 20802056
Curley G, Contreras MM, Nichol AD, Higgins BD, Laffey JG. Hypercapnia and Acidosis in Sepsis: a Double-edged Sword? Anesthesiology 2010 Feb;112(2):462-72 PMID: 20068449
Curley G, Kavanagh BP, Laffey JG. Hypocapnia and the Injured Brain: More Harm than Benefit. Critical Care Med 2010 May;38(5):1348-59. PMID: 20228681
Curley G, Laffey JG, Kavanagh BP. Bench-to-Bedside Review: Carbon Dioxide. Crit Care 2010 14(2):220 PMID: 20497620
McIlroy M, McCartan D, Early S, O Gaora P, Pennington S, Hill AD, Young LS. Interaction of Developmental Transcription Factor HOXC11 with Steroid Receptor Coactivator SRC-1 Mediates Resistance to Endocrine Therapy in Breast Cancer Cancer Res 2010 Feb 15;70(4):1585-94. Erratum in: Cancer Res. 2010 Apr 15;70(8):3413.PMID: 20145129
Khashan AS, Kenny LC, McNamee R, Mortensen PB, Pedersen MG, McCarthy FP, Henriksen TB. Undiagnosed Coeliac Disease in a Father Does not Influence Birthweight and Preterm Birth. Paediatr Perinat Epidemiol 2010 Jul 1;24(4):363-9. PMID: 20618726
Khashan AS, Henriksen TB, McNamee R, Mortensen PB, McCarthy FP, Kenny LC. Parental Celiac Disease and Offspring Sex Ratio. Epidemiology 2010 21(6):913-914. PMID: 20924235
McCarthy FP, Ciara N Magee, William D Plant, Louise C Kenny. Gitelman's Syndrome in Pregnancy: Case Report and Review of the Literature Nephrol Dial Transplant 2010 Apr;25(4):1338-40 PMID: 20100726
Khashan AS, Henriksen TB, Mortensen PB, McNamee R, McCarthy FP, Pedersen MG, Kenny LC. The Impact of Maternal Celiac Disease on Birthweight and Preterm Birth: a Danish Population-based Cohort Study. Hum Reprod 2010 25(2):528-34 PMID: 19939833
Feeney ER, Mallon PWG. Impact of Mitochondrial Toxicity of HIV-1 Antiretroviral Drugs on Lipodystrophy and Metabolic Dysregulation. Curr Pharm Des 2010 16(30):3339-51. PMID 20687890
Anney R, Klei L, Pinto D, Regan R, Conroy J, Magalhaes TR, Correia C, Abrahams BS, Sykes N, Pagnamenta AT, Almeida J, Bacchelli E, Bailey AJ, Baird G, Battaglia A, Berney T, Bolshakova N, Bölte S, Bolton PF, Bourgeron T, Brennan S, Brian J, Carson AR, Casallo G, Casey J, Chu SH, Cochrane L, Corsello C, Crawford EL, Crossett A, Dawson G, de Jonge M, Delorme R, Drmic I, Duketis E, Duque F, Estes A, Farrar P, Fernandez BA, Folstein SE, Fombonne E, Freitag CM, Gilbert J, Gillberg C, Glessner JT, Goldberg J, Green J, Guter SJ, Hakonarson H, Heron EA, Hill M, Holt R, Howe JL, Hughes G, Hus V, Igliozzi R, Kim C, Klauck SM, Kolevzon A, Korvatska O, Kustanovich V, Lajonchere CM, Lamb JA, Laskawiec M, Leboyer M, Le Couteur A, Leventhal BL, Lionel AC, Liu XQ, Lord C, Lotspeich L, Lund SC, Maestrini E, Mahoney W, Mantoulan C, Marshall CR, McConachie H, McDougle CJ, McGrath J, McMahon WM, Melhem NM, Merikangas A, Migita O, Minshew NJ, Mirza GK, Munson J, Nelson SF, Noakes C, Noor A, Nygren G, Oliveira G, Papanikolaou K, Parr JR, Parrini B, Paton T, Pickles A, Piven J, Posey DJ, Poustka A, Poustka F, Prasad A, Ragoussis J, Renshaw K, Rickaby J, Roberts W, Roeder K, Roge B, Rutter ML, Bierut LJ, Rice JP, Salt J, Sansom K, Sato D, Segurado R, Senman L, Shah N, Sheffield VC, Soorya L, Sousa I, Stoppioni V, Strawbridge C, Tancredi R, Tansey K, Thiruvahindrapduram B, Thompson AP, Thomson S, Tryfon A, Tsiantis J, Van Engeland H, Vincent JB, Volkmar F, Wallace S, Wang K, Wang Z, Wassink TH, Wing K, Wittemeyer K, Wood S, Yaspan BL, Zurawiecki D, Zwaigenbaum L, Betancur C, Buxbaum JD, Cantor RM, Cook EH, Coon H, Cuccaro ML, Gallagher L, Geschwind DH, Gill M, Haines JL, Miller J, Monaco AP, Nurnberger JI Jr, Paterson AD, Pericak-Vance MA, Schellenberg GD, Scherer SW, Sutcliffe JS, Szatmari P, Vicente AM, Vieland VJ, Wijsman EM, Devlin B, Ennis S, Hallmayer J. A Genome-wide Scan for Common Alleles Affecting Risk for Autism. Hum Mol Genet 2010 Oct15;19(20):4072-82. PMID: 20663923
Pinto D, Pagnamenta AT, Klei L, Anney R, Merico D, Regan R, Conroy J, Magalhaes TR, Correia C, Abrahams BS, Almeida J, Bacchelli E, Bader GD, Bailey AJ, Baird G, Battaglia A, Berney T, Bolshakova N, Bölte S, Bolton PF, Bourgeron T, Brennan S, Brian J, Bryson SE, Carson AR, Casallo G, Casey J, Chung BH, Cochrane L, Corsello C, Crawford EL, Crossett A, Cytrynbaum C, Dawson G, de Jonge M, Delorme R, Drmic I, Duketis E, Duque F, Estes A, Farrar P, Fernandez BA, Folstein SE, Fombonne E, Freitag CM, Gilbert J, Gillberg C, Glessner JT, Goldberg J, Green A, Green J, Guter SJ, Hakonarson H, Heron EA, Hill M, Holt R, Howe JL, Hughes G, Hus V, Igliozzi R, Kim C, Klauck SM, Kolevzon A, Korvatska O, Kustanovich V, Lajonchere CM, Lamb JA, Laskawiec M, Leboyer M, Le Couteur A, Leventhal BL, Lionel AC, Liu XQ, Lord C, Lotspeich L, Lund SC, Maestrini E, Mahoney W, Mantoulan C, Marshall CR, McConachie H, McDougle CJ, McGrath J, McMahon WM, Merikangas A, Migita O, Minshew NJ, Mirza GK, Munson J, Nelson SF, Noakes C, Noor A, Nygren G, Oliveira G, Papanikolaou K, Parr JR, Parrini B, Paton T, Pickles A, Pilorge M, Piven J, Ponting CP, Posey DJ, Poustka A, Poustka F, Prasad A, Ragoussis J, Renshaw K, Rickaby J, Roberts W, Roeder K, Roge B, Rutter ML, Bierut LJ, Rice JP, Salt J, Sansom K, Sato D, Segurado R, Sequeira AF, Senman L, Shah N, Sheffield VC, Soorya L, Sousa I, Stein O, Sykes N, Stoppioni V, Strawbridge C, Tancredi R, Tansey K, Thiruvahindrapduram B, Thompson AP, Thomson S, Tryfon A, Tsiantis J, Van Engeland H, Vincent JB, Volkmar F, Wallace S, Wang K, Wang Z, Wassink TH, Webber C, Weksberg R, Wing K, Wittemeyer K, Wood S, Wu J, Yaspan BL, Zurawiecki D, Zwaigenbaum L, Buxbaum JD, Cantor RM, Cook EH, Coon H, Cuccaro ML, Devlin B, Ennis S, Gallagher L, Geschwind DH, Gill M, Haines JL, Hallmayer J, Miller J, Monaco AP, Nurnberger JI Jr, Paterson AD, Pericak-Vance MA, Schellenberg GD, Szatmari P, Vicente AM, Vieland VJ, Wijsman EM, Scherer SW, Sutcliffe JS, Betancur C. Functional Impact of Global Rare Copy Number Variation in Autism Spectrum Disorders. Nature 2010 Jul15;466(7304):368-72. PMID: 20531469
O'Brien FM, Page L, O'Gorman RL, Bolton P, Sharma A, Baird G, Daly E, Hallahan B, Conroy RM, Foy C, Curran S, Robertson D, Murphy KC, Murphy DG. Maturation of Limbic Regions in Asperger Syndrome: a Preliminary Study Using Proton Magnetic Resonance Spectroscopy and Structural Magnetic Resonance Imaging. Psychiatry Res- Neuroimaging 2010 30;184(2):77-85. PMID: 20952166
O'Loughlin A, McIntosh C, Dinneen SF, O'Brien T. Basic Concepts to Novel Therapies, a Review of the Diabetic Foot. Int J Low Extrem Wounds 2010 9(2):90-102. PMID:20483808
Ryan A, Godson C. Lipoxins: Regulators of Resolution. Curr Opin Pharmacol 2010 Apr;10(2):166-72. PMID: 20226737

2009
Ni Ainle F, Preston RJ, Jenkins PV, Nel HJ, Johnson JA, Smith OP, White B, Fallon PG, O'Donnell JS. Protamine Sulfate Down-regulates Thrombin Generation by Inhibiting Factor V Activation. Blood 2009 Aug20;114(8):1658-65 PMID: 19531655
Preston RJ, Tran S, Johnson JA, Ní Áinle F, Harmon S, White B, Smith OP, Jenkins PV, Dahlbäck B, O'Donnell JS. Platelet Factor 4 Impairs the Anticoagulant Activity of Activated Protein C. J Biol Chem 2009 Feb27;284(9):5869-75 PMID: 19129181
Chotirmall SH, Watts M, Moore A, Kearney F, Brewer L, McElvaney NG, Donegan CF. Dispelling Myths Regarding the Safety of 'Bronchoscopy in Octogenerians'. Age Ageing 2009 Nov;38(6):764-5 PMID: 19797333
Chotirmall SH, Mann AK, Branagan P, O'Donohoe C, Lyons AM, Flynn MG, Gunaratnam C, O'Neill SJ, McElvaney NG. Male Fertility in Cystic Fibrosis. Ir Med J 2009 Jul-Aug;102(7):204-6 PMID: 19771998
Bergsson G, Reeves EP, McNally P, Chotirmall SH, Greene CM, Greally P, Murphy P, O'Neill SJ, McElvaney NG. LL-37 Complexation with Glycosaminoglycans in Cystic Fibrosis Lungs Inhibits Antimicrobial Activity, Which can be Restored by Hypertonic Saline. J Immunol 2009 Jul1;183(1):543-51 PMID: 19542465
Abuhusain H, Chotirmall SH, Hamid N, O'Neill SJ. Prepared for Internship? Ir Med J 2009 Mar;102(3):82-4. PMID: 19489196
Chotirmall SH, Watts M, Branagan P, Donegan CF, Moore A, McElvaney NG. Diagnosis and Management of Asthma in Older Adults. J Am Geriatr Soc 2009 May;57(5):901-9 PMID: 19484848
Chotirmall SH, Flynn MG, Kernekamp C, McElvaney NG. Obsessive-compulsive Disorder: Good for Cystic Fibrosis (CF)? Pediatr Pulmonol 2009 Mar;44(3):300-1 PMID: 19206183
Chotirmall SH, Montil WN, McElvaney NG. Dawn of the "Bone Phenotype" in Cystic Fibrosis. Pediatrics 2009 Feb;123(2):e353 PMID: 19171587
Curley GF, Kevin LG, Laffey JG. Mechanical Ventilation: Taking its Toll on the Lung. Anesthesiology 2009 Oct;111(4):701-3. PMID: 19707117
McCafferty MPJ, Healy N, Kerin MJ. Breast Cancer Subtypes and Molecular Biomarkers. Diagnostic Histopathology 2009 15(10):485-489
Lowery AJ, Kerin MJ. Graves' Opthalmopathy: The Case for Thyroid Surgery. Surgeon 2009 Oct;7(5):290-6 PMID: 19848063
Lowery AJ, Miller N, Devaney A, McNeill RE, Davoren PA, Lemetre C, Benes V, Schmidt S, Blake J, Ball G, Kerin MJ, MicroRNA Signatures Predict Estrogen Receptor, Progesterone Receptor and HER2/neu Receptor Status in Breast Cancer. Breast Cancer Res 2009 11(3):R27. PMID: 19432961.
Heneghan HM, Miller N, Lowery AJ, Sweeney KJ, Kerin MJ. MicroRNAs as Novel Biomarkers for Breast Cancer. J Oncol 2009 950201. PMID: 19639033.
McCarthy FP, Khashan AS, Quigley E, Shanahan F, Regan P, Cronin C, Kenny L. Undiagnosed Maternal Celiac Disease in Pregnancy and an Increased Risk of Fetal Growth Restriction. J Clin Gastroenterol 2009 Sep;43(8):792-3. PMID: 19561528
McCarthy FP, Khashan AS, Quigley E, Shanahan F, Kenny L. Coeliac disease. Don't Forget Increased Risk of Fetal Growth Restriction. BMJ 2009 Mar17;338:b1069 PMID: 19293210
Hallahan B, Daly EM, McAlonan G, Loth E, Toal F, O’Brien FM, Robertson D, Hales S, Murphy C, Murphy KC, Murphy DGM. Brain Morphometry Volume in Autistic Spectrum Disorder: An MRI Study of Adults; Psychological Medicine 2009 39(2), 337-346
O'Loughlin A,Waldron-Lynch F, Cronin KC, Dinneen S, Lee J, Griffin D, Casey M, Nusrat N, Jaffrey S, O'Brien T, Dunne F. When a Nephrectomy Cures Hypoglycemia. BMJ Case Rep 2009 May 17 PMID: 21687037
Leblond AL, O'Sullivan J, Caplice N. Bone Marrow Mononuclear Stem Cells: Potential in the Treatmet of Myocardial Infarction. Stem Cells Cloning 2009 Dec4;2:11-9 PMID: 24198506
Martin K, Weiss S, Metharom P, Schmeckpeper J, Hynes B, O’Sullivan J, Caplice NM. Thrombin Stimulates Smooth Muscle Cell Differentiation From Peripheral Blood Mononuclear Cells via Protease-Activated Receptor-1, RhoA, and Myocardin Circulation Research 2009 105(3) 214-24 PMID: 19574550
Ryan A, Murphy M, Godson C, Hickey FB. Diabetes mellitus and Apoptosis: Inflammatory Cells. Apoptosis 2009 14(12):1435-50

2008
Harmon S, Preston RJ, Ni Ainle F, Johnson JA, Cunningham MS, Smith OP, White B, O'Donnell JS. Dissociation of activated protein C functions by elimination of protein S cofactor enhancement. J Biol Chem 2008 Nov7;283(45):30531-9 PMID: 18779332
Ní Ainle F, Wong A, Appleby N, Byrne B, Regan C, Hassan T, Milner M, Sullivan AO, White B, O'Donnell J. Efficacy and Safety of Once Daily Low Molecular Weight Heparin (Tinzaparin Sodium) in High Risk Pregnancy. Blood Coagul Fibrinolysis 2008 Oct;19(7):689-92 PMID: 18832911
Chotirmall SH, Branagan P, Gunaratnam C, McElvaney NG. Aspergillus/allergic Bronchopulmonary Aspergillosis in an Irish Cystic Fibrosis Population: A Diagnostically Challenging Entity. Respir Care 2008 Aug;53(8):1035-41 PMID: 18655741
Bretschneider N, Brand H, Miller N, Lowery AJ, Kerin MJ, Gannon F, Denger S. Estrogen Induces Repression of the Breast Cancer and Salivary Gland Expression Gene in an Estrogen Receptor Alpha-Dpendent Manner. Cancer Res 2008 Jan 1;68(1):106-14 PMID: 18172302
Davoren PA, McNeill RE, Lowery AJ, Kerin MJ, Miller N. Identification of Suitable Endogenous Control Genes for microRNA Gene Expression Analysis in Human Breast Cancer. BMC Mol Bio 2008 9:76. PMID: 187180
Lowery AJ, Sweeney KJ, Molloy AP, Hennessy E, Curran C, Kerin MJ. The Effect of Menopuase and Hysterectomy on Systemic Vascular Endothelial Growth Factor in Women Undergoing Surgery for Breast Cancer. BMC Cancer 2008 Sep 30;8:279 PMID: 18826631

2007
Dywer RM, Potter-Beirne SM, Harrington KA, Lowery AJ, Hennessy E, Murphy JM, Barry FP, O'Brien T, Kerin MJ. Monocyte Chemotactic Protein-1 Secreted by Primary Breast Tumors Stimulates Migration of Mesenchymal Stem Cells. Clin Cancer Res 2007 Sep 1;13(17); 5020-7 PMID: 17785552