Agency: Cordis | Branch: H2020 | Program: RIA | Phase: PHC-18-2015 | Award Amount: 8.19M | Year: 2016
Liver cancer in the paediatric population is rare with an incidence approximately 1-1.5 per million population. The commonest tumour seen in the childhood population is hepatoblastoma (HB), usually seen in young children and infants. Much rarer (about 10% of paediatric liver cancers) is hepatocellular carcinoma (HCC), usually seen in the teenage population and sometimes associated with underlying cirrhotic liver diseases. The ChiLTERN project relates to topic PHC 18 establishing effectiveness of health care interventions in the paediatric population. The ChiLTERN project builds on a unique opportunity to undertake a comprehensive research programme linked to an ambitious global partnership which will see the single largest clinical trial (the Paediatric Hepatic International Tumour Trial - PHITT) ever undertaken in this population of patients, with several randomised questions in six subgroups of patients. ChiLTERN will allow us to move towards an era of personalised therapy in which each patient will receive the correct amount of chemotherapy and will undergo has the best surgical operation (surgical resection or liver transplant). By using both clinical and biological information, we can assign patients more accurately to risk groups based on their survival. Using genetic tests and biomarkers, we will determine those children who may be at risk of developing long term side effects (deafness, heart failure, kidney damage). In addition, biomarkers will allow us to monitor during therapy and detect toxicities early before serious damage is done so that we can adapt treatment and prevent these problems. Finally, we will be using imaging technology tools which will help our surgeons plan liver operations more safely and effectively. Ultimately ChiLTERN will allow us to cure more children with liver cancer, expose fewer children to toxic chemotherapy and ensure their surgery is both effective and safe.
James A.T.,Rotunda Hospital |
Bee C.,Rotunda Hospital |
Corcoran J.D.,Rotunda Hospital |
Mcnamara P.J.,Hospital for Sick Children |
And 3 more authors.
Journal of Perinatology | Year: 2015
Objective:Milrinone has been proposed as an effective treatment for pulmonary hypertension (PH) and right ventricular (RV) dysfunction. We aimed to determine the effect of milrinone therapy on clinical and echocardiography parameters of PH in preterm infants with elevated pulmonary pressures.Study Design:A retrospective case review was conducted on infants <32 weeks gestation who received milrinone for the treatment of PH and reduced RV function. Echocardiographic data were collected before and after treatment with milrinone, and serial clinical parameters were recorded over a 72hperiod.Result:Seven infants met the inclusion criteria with a median gestation and birth weight of 27.3 weeks and 1140 g, respectively. Four infants had a diagnosis of pulmonary hypoplasia with PH, and three infants were recipients in twin-to-twin transfusion syndrome who also developed PH. Nitric oxide was used in six infants before commencement of milrinone. Milrinone was commenced at a dose of 0.33 μg kg -1 min -1 to 0.5 μg kg -1 min -1 and continued for a median duration of 70 h. Use of milrinone was associated with a fall in oxygenation index and inhaled nitric oxide dose. Following an initial fall in blood pressure over the first 6 h, there was an increase in blood pressure over the subsequent 72 h. Echocardiographic data demonstrated an increase in indicators of myocardial performance and PH. One infant died before discharge.Conclusion:This case series suggests that milrinone may be a useful therapy for premature infants with echocardiography findings of PH and/or RH dysfunction. This data support the need for a randomised control trial to confirm its efficacy. © 2015 Nature America, Inc.
Spence S.,Queen's University of Belfast |
Fitzsimons A.,Queen's University of Belfast |
Boyd C.R.,Queen's University of Belfast |
Kessler J.,Queen's University of Belfast |
And 16 more authors.
Immunity | Year: 2013
Suppressors of cytokine signaling (SOCS) are important regulators of lipopolysaccharide (LPS) and cytokine responses but their role in macrophage polarization is unknown. We have shown here that myeloid-restricted Socs3 deletion (Socs3Lyz2cre) resulted in resistance to LPS-induced endotoxic shock, whereas Socs2-/- mice were highly susceptible. We observed striking bias toward M2-like macrophages in Socs3Lyz2cre mice, whereas the M1-like population was enriched in Socs2-/- mice. Adoptive transfer experiments showed that responses to endotoxic shock and polymicrobial sepsis were transferable and macrophage dependent. Critically, this dichotomous response was associated with enhanced regulatory T (Treg) cell recruitment by Socs3Lyz2cre cells, whereas Treg cell recruitment was absent in the presence of Socs2-/- macrophages. In addition, altered polarization coincided with enhanced interferon-gamma (IFN-γ)-induced signal transducer and activator of transcription-1 (STAT1) activation in Socs2-/- macrophages and enhanced interleukin-4 (IL-4) plus IL-13-induced STAT6 phosphorylation in Socs3Lyz2cre macrophages. SOCS, therefore, are essential controllers of macrophage polarization, regulating inflammatory responses. © 2013 Elsevier Inc.
Rowland M.,Dublin Academic Medical Center |
Bourke B.,Our Ladys Childrens Hospital Crumlin |
Bourke B.,University College Dublin
Current Opinion in Pulmonary Medicine | Year: 2011
Purpose of Review: This review looks at what is currently known about liver disease in cystic fibrosis (CF) in light of the literature over the past year, and what the ongoing challenges are from a clinical and research perspective for the optimal management of cystic fibrosis liver disease (CFLD). Recent Findings: Patients with CF who develop clinically significant liver disease have a worse overall phenotype, and whereas there is no definite evidence that they have a shorter life expectancy, longer follow-up is required to determine if liver disease is a risk factor for mortality in CF.The development of the ferret and pig animal models of CF with multiorgan involvement is an important breakthrough which will enhance our understanding of the pathogenesis of CFLD, and with which it is hoped novel therapeutic targets for the treatment of CFLD will be identified. Summary: Whereas there is still no effective treatment for liver disease in CF, recent developments of animal models of CFLD will enhance our capacity to develop new therapeutic targets and reduce the impact of liver disease on mortality in CF. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.
Linehan E.,Queen's University of Belfast |
Dombrowski Y.,Queen's University of Belfast |
Snoddy R.,Queen's University of Belfast |
Fallon P.G.,St James's Hospital |
And 3 more authors.
Aging Cell | Year: 2014
Aging results in deterioration of the immune system, which is associated with increased susceptibility to infection and impaired wound healing in the elderly. Phagocytosis is an essential process in both wound healing and immune defence. As such, age-related impairments in phagocytosis impact on the health of the elderly population. Phagocytic efficiency in peritoneal macrophages, bone marrow-derived macrophages and bone marrow monocytes from young and old mice was investigated. Aging significantly impaired phagocytosis by peritoneal macrophages, both in vitro and in vivo. However, bone marrow-derived macrophages and bone marrow monocytes did not exhibit age-related impairments in phagocytosis, suggesting no intrinsic defect in these cells. We sought to investigate underlying mechanisms in age-related impairments in phagocytosis by peritoneal macrophages. We hypothesized that microenvironmental factors in the peritoneum of old mice impaired macrophage phagocytosis. Indeed, macrophages from young mice injected into the peritoneum of old mice exhibited impaired phagocytosis. Proportions of peritoneal immune cells were characterized, and striking increases in numbers of T cells, B1 and B2 cells were observed in the peritoneum of old mice compared with young mice. In addition, B cell-derived IL-10 was increased in resting and LPS-activated peritoneal cell cultures from old mice. These data demonstrate that aging impairs phagocytosis by tissue-resident peritoneal macrophages, but not by bone marrow-derived macrophages/monocytes, and suggest that age-related defects in macrophage phagocytosis may be due to extrinsic factors in the tissue microenvironment. As such, defects may be reversible and macrophages could be targeted therapeutically in order to boost immune function in the elderly. © 2014 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
Mislovic B.,Our Ladys Childrens Hospital Crumlin
Paediatric Anaesthesia | Year: 2015
We report a 2-year-old patient with Opitz-GBBB syndrome scheduled for a posterior sagittal anorectoplasty (PSARP). The ultrasound scan revealed the inferior end of dural sac just below sacrococcygeal membrane, although the patient had previously two successful caudal epidural blocks. Consequently, the epidural catheter was inserted under a real-time ultrasound guidance without dural puncture. Our patient had excellent pain relief without any side effects. © 2015 John Wiley & Sons Ltd.
Corcionivoschi N.,Our Ladys Childrens Hospital Crumlin
Cell host & microbe | Year: 2012
Reactive oxygen species (ROS) play key roles in mucosal defense, yet how they are induced and the consequences for pathogens are unclear. We report that ROS generated by epithelial NADPH oxidases (Nox1/Duox2) during Campylobacter jejuni infection impair bacterial capsule formation and virulence by altering bacterial signal transduction. Upon C. jejuni invasion, ROS released from the intestinal mucosa inhibit the bacterial phosphotyrosine network that is regulated by the outer-membrane tyrosine kinase Cjtk (Cj1170/OMP50). ROS-mediated Cjtk inactivation results in an overall decrease in the phosphorylation of C. jejuni outer-membrane/periplasmic proteins, including UDP-GlcNAc/Glc 4-epimerase (Gne), an enzyme required for N-glycosylation and capsule formation. Cjtk positively regulates Gne by phosphorylating an active site tyrosine, while loss of Cjtk or ROS treatment inhibits Gne activity, causing altered polysaccharide synthesis. Thus, epithelial NADPH oxidases are an early antibacterial defense system in the intestinal mucosa that modifies virulence by disrupting bacterial signaling. Copyright © 2012 Elsevier Inc. All rights reserved.
Ozaki E.,Trinity College Dublin |
Campbell M.,Trinity College Dublin |
Doyle S.L.,Trinity College Dublin |
Doyle S.L.,Our Ladys Childrens Hospital Crumlin
Journal of Inflammation Research | Year: 2015
The inflammasome is a molecular platform formed by activation of an innate immune pattern recognition receptor seed, such as NLRP3. Once activated, NLRP3 recruits the adapter ASC (apoptosis-related speck-like protein containing a caspase recruitment domain), which in turn recruits procaspase-1. Procaspase-1 autocatalyzes its cleavage and activation, resulting in maturation of the precursor forms of interleukin (IL)-1β and IL-18 into active proinflammatory cytokines and initiation of pyroptotic cell death. The NLRP3 inflammasome has been implicated in the pathogenesis of a wide variety of diseases, including genetically inherited autoinflammatory conditions as well as chronic diseases in which NLRP3 is abnormally activated. The NLRP3 inflammasome has been linked to diseases such as Alzheimer’s disease, atherosclerosis, metabolic syndrome, and age-related macular degeneration. In this review, we describe the NLRP3 inflammasome complex and its activation in disease, and detail the current therapies that modulate either the NLRP3 inflammasome complex itself or the two cytokines it is responsible for activating, ie, IL-1β and IL-18. © 2015 Ozaki et al.
Callaghan M.A.,Our Ladys Childrens Hospital Crumlin |
Mannion D.,Our Ladys Childrens Hospital Crumlin
Paediatric Anaesthesia | Year: 2012
A 15 month old boy with a ventricular septal defect (VSD) underwent percutaneous device closure of the VSD. Five days later he collapsed; on arrival to hospital he was asystolic and received prolonged cardio-pulmonary resuscitation (CPR) with intermittent return of spontaneous circulation (ROSC). He had recurrent episodic complete heart block with no ventricular escape rhythm, associated with loss of cardiac output, unresponsive to transcutaneous pacing. He was transferred to theatre, while receiving CPR, for urgent removal of the VSD device. Estimated total 'down time' was 70 min. The device was removed and patch closure of the VSD was performed. He made a full neurological recovery. Device closure of septal defects has become widespread. We discuss the incidence and type of arrythmias associated with their use. This case highlights an uncommon but life threatening complication of a VSD device. It also highlights that good quality CPR may lead to positive outcomes following pediatric cardiac arrest. © 2011 Blackwell Publishing Ltd.
Irvine A.D.,Our Ladys Childrens Hospital Crumlin |
Irvine A.D.,Trinity College Dublin
Journal of Investigative Dermatology | Year: 2014
In this issue of the Journal, Stout and colleagues report a novel and creative approach to replacement of genetically determined absence or deficiency of epidermal proteins. While these early data are certainly interesting, further validation work is required to determine the utility of this approach in genodermatoses. © 2014 The Society for Investigative Dermatology.