Bellini C.,Gaslini Institute
Advances in Anatomy Embryology and Cell Biology | Year: 2014
Primary lymphedema is defined as lymphedema caused by dysplasia of the lymph vessels. This complex group of diseases is discussed in detail from a clinical perspective. A review of the epidemiology and classification of lymphedema on the backdrop of its clinical presentation reveals weaknesses of the present classification system, which, however, is the basis for the choice of optimal patient care. Non-syndrome and syndrome types of primary lymphedema are presented in detail and related molecular findings are summarized. © Springer-Verlag Wien 2014.
Domingo-Fernandez R.,Royal College of Surgeons in Ireland |
Domingo-Fernandez R.,National Childrens Research Center |
Lindner S.,Childrens Hospital Essen |
Mestdagh P.,Ghent University |
And 17 more authors.
Nature Genetics | Year: 2012
LIN28B regulates developmental processes by modulating microRNAs (miRNAs) of the let-7 family. A role for LIN28B in cancer has been proposed but has not been established in vivo. Here, we report that LIN28B showed genomic aberrations and extensive overexpression in high-risk neuroblastoma compared to several other tumor entities and normal tissues. High LIN28B expression was an independent risk factor for adverse outcome in neuroblastoma. LIN28B signaled through repression of the let-7 miRNAs and consequently resulted in elevated MYCN protein expression in neuroblastoma cells. LIN28B-let-7-MYCN signaling blocked differentiation of normal neuroblasts and neuroblastoma cells. These findings were fully recapitulated in a mouse model in which LIN28B expression in the sympathetic adrenergic lineage induced development of neuroblastomas marked by low let-7 miRNA levels and high MYCN protein expression. Interference with this pathway might offer therapeutic perspectives. © 2012 Nature America, Inc. All rights reserved.
Le Goff C.,French Institute of Health and Medical Research |
Mahaut C.,French Institute of Health and Medical Research |
Abhyankar A.,Rockefeller University |
Le Goff W.,University Pierre and Marie Curie |
And 14 more authors.
Nature Genetics | Year: 2012
Myhre syndrome (MIM 139210) is a developmental disorder characterized by short stature, short hands and feet, facial dysmorphism, muscular hypertrophy, deafness and cognitive delay. Using exome sequencing of individuals with Myhre syndrome, we identified SMAD4 as a candidate gene that contributes to this syndrome on the basis of its pivotal role in the bone morphogenetic pathway (BMP) and transforming growth factor (TGF)-β signaling. We identified three distinct heterozygous missense SMAD4 mutations affecting the codon for Ile500 in 11 individuals with Myhre syndrome. All three mutations are located in the region of SMAD4 encoding the Mad homology 2 (MH2) domain near the site of monoubiquitination at Lys519, and we found a defect in SMAD4 ubiquitination in fibroblasts from affected individuals. We also observed decreased expression of downstream TGF-β target genes, supporting the idea of impaired TGF-β-mediated transcriptional control in individuals with Myhre syndrome.
Stigliani S.,Italian National Cancer Institute |
Coco S.,Italian National Cancer Institute |
Moretti S.,French National Center for Scientific Research |
Moretti S.,University of Paris Dauphine |
And 9 more authors.
Neoplasia (United States) | Year: 2012
We aimed to identify novel molecular prognostic markers to better predict relapse risk estimate for children with high-risk (HR) metastatic neuroblastoma (NB). We performed genome- and/or transcriptome-wide analyses of 129 stage 4 HR NBs. Children older than 1 year of age were categorized as "short survivors" (dead of disease within 5 years from diagnosis) and "long survivors" (alive with an overall survival time ≥ 5 years). We reported that patients with less than three segmental copy number aberrations in their tumor represent a molecularly defined subgroup with a high survival probability within the current HR group of patients. The complex genomic pattern is a prognostic marker independent of NB-associated chromosomal aberrations, i.e., MYCN amplification, 1p and 11q losses, and 17q gain. Integrative analysis of genomic and expression signatures demonstrated that fatal outcome is mainly associated with loss of cell cycle control and deregulation of Rho guanosine triphosphates (GTPases) functioning in neuritogenesis. Tumors with MYCN amplification show a lower chromosome instability compared to MYCN single-copy NBs (P =.0008), dominated by 17q gain and 1p loss. Moreover, our results suggest that the MYCN amplification mainly drives disruption of neuronal differentiation and reduction of cell adhesion process involved in tumor invasion and metastasis. Further validation studies are warranted to establish this as a risk stratification for patients. © 2012 Neoplasia Press, Inc. All rights reserved.
Torrente F.,Addenbrookes Hospital |
Barabino A.,Gaslini Institute |
Bellini T.,Gaslini Institute |
Murch S.H.,University of Warwick
Journal of Pediatric Gastroenterology and Nutrition | Year: 2014
OBJECTIVES: Allergic colitis shows overlap with classic inflammatory bowel disease (IBD). Clinically, allergic colitis is associated with dysmotility and abdominal pain, and mucosal eosinophilia is characteristic. We thus aimed to characterise mucosal changes in children with allergic colitis compared with normal tissue and classic IBD, focusing on potential interaction between eosinophils and mast cells with enteric neurones. METHODS: A total of 15 children with allergic colitis, 10 with Crohn disease (CD), 10 with ulcerative colitis (UC), and 10 histologically normal controls were studied. Mucosal biopsies were stained for CD3 T cells, Ki-67, eotaxin-1, and eotaxin-2. Eotaxin-2, IgE, and tryptase were localised compared with mucosal nerves, using neuronal markers neurofilament protein, neuron-specific enolase, and nerve growth factor receptor. RESULTS: Overall inflammation was greater in patients with CD and UC than in patients with allergic colitis. CD3 T-cell density was increased in patients with allergic colitis, similar to that in patients with CD but lower than in patients with UC, whereas eosinophil density was higher than in all other groups. Eotaxin-1 and -2 were localised to basolateral crypt epithelium in all specimens, with eotaxin-1+ lamina propria cells found in all of the colitis groups. Eotaxin-2+ intraepithelial lymphocyte (IEL) density was significantly higher in allergic colitis specimens than in all other groups. Mast cell degranulation was strikingly increased in patients with allergic colitis (12/15) compared with that in patients with UC (1/10) and CD (0/1). Tryptase and IgE colocalised on enteric neurons in patients with allergic colitis but rarely in patients with IBD. CONCLUSIONS: Eotaxin-2+ IELs may contribute to the periepithelial eosinophil accumulation characteristic of allergic colitis. The colocalisation of IgE and tryptase with mucosal enteric nerves is likely to promote the dysmotility and visceral hyperalgesia classically seen in allergic gastrointestinal inflammation. © 2014 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.
Giuffrida G.,University of Catania |
Cappellini M.D.,Foundation Medicine |
Carubbi F.,University of Modena and Reggio Emilia |
Di Rocco M.,Gaslini Institute |
Iolascon G.,The Second University of Naples
Advances in Therapy | Year: 2014
Gaucher disease is a rare autosomal recessive disorder of glycosphingolipid metabolism resulting from deficient activity of the lysosomal enzyme beta-glucocerebrosidase that causes accumulation of glucosylceramide in tissue macrophage with damage to hematological, visceral, and skeletal organ systems. Severity and progression may vary independently among these domains, necessitating individualized therapy. Skeletal involvement is highly prevalent and often associated with intense pain, impaired mobility, and reduced quality of life. Enzyme replacement therapy improves parameters in all affected domains, but skeletal involvement requires longer treatment and higher dosages to obtain significant results. Despite numerous papers on bone complications in patients with Gaucher disease, there are no specific indications on how to assess properly bone involvement in such condition, the frequency of assessment, the use of markers for osteoblast and osteoclast activity, or the administration of bisphosphonates or other symptomatic drugs in adult and pediatric patients. Starting from a re-evaluation of cases with bone involvement, we have identified some common errors in the diagnostic approach and management. The aim of this paper was to propose a methodological and critical approach to the diagnosis, follow-up and treatment of bone disease in patients with Gaucher disease type 1. © 2014, Springer Healthcare.
Viprey V.F.,Leeds Institute of Molecular Medicine |
Corrias M.V.,Gaslini Institute |
Burchill S.A.,Leeds Institute of Molecular Medicine
Analytical Biochemistry | Year: 2012
In many cancers, including neuroblastoma, microRNA (miRNA) expression profiling of peripheral blood (PB) and bone marrow (BM) may increase understanding of the metastatic process and lead to the identification of clinically informative biomarkers. The quality of miRNAs in PB and BM samples archived in PAXgene™ blood RNA tubes from large-scale clinical studies and the identity of reference miRNAs for standard reporting of data are to date unknown. In this study, we evaluated the reliability of expression profiling of 377 miRNAs using quantitative polymerase chain reaction (qPCR) in PB and BM samples (n = 90) stored at -80°C for up to 5 years in PAXgene™ blood RNA tubes. There was no correlation with storage time and variation of expression for any single miRNA (r < 0.50). The profile of miRNAs isolated as small RNAs or co-isolated with small/large RNAs was highly correlated (r = 0.96). The mean expression of all miRNAs and the geNorm program identified miR-26a, miR-28-5p, and miR-24 as the most stable reference miRNAs. This study describes detailed methodologies for reliable miRNA isolation and profiling of PB and BM, including reference miRNAs for qPCR normalization, and demonstrates the suitability of clinical samples archived at -80°C into PAXgene™ blood RNA tubes for miRNA expression studies. © 2011 Elsevier Inc. All rights reserved.
Di Rocco M.,Gaslini Institute |
Andria G.,University of Naples Federico II |
Deodato F.,Bambino Gesu Childrens Hospital |
Giona F.,University of Rome La Sapienza |
And 2 more authors.
Pediatric Blood and Cancer | Year: 2014
Gaucher disease (GD) is caused by an enzyme deficiency that leads to the accumulation of glycolipids in various organs. Although the signs and symptoms of GD emerge in childhood in the majority of patients, the disease often remains unrecognized for many years with delay of benefits of therapy or development of irreversible complications. Based on published data and data from the International Collaborative Gaucher Group Registry, an algorithm has been drafted for early diagnosis of GD in pediatric patients. It will help hematologists in promoting a timely diagnosis and early access to therapy for pediatric patients with GD. © 2014 Wiley Periodicals, Inc.
Di Rocco M.,Gaslini Institute |
Dardis A.,University of Udine |
Madeo A.,Gaslini Institute |
Barone R.,University of Catania |
Fiumara A.,University of Catania
Pediatric Neurology | Year: 2012
Niemann-Pick disease type C is a rare inherited cholesterol trafficking disorder, where impaired intracellular lipid transport leads to storage of unesterified cholesterol and glycosphingolipids in many tissues, including the brain. Substrate reduction therapy with miglustat, an iminosugar that inhibits glycosphingolipid synthesis, was proposed to treat Niemann-Pick disease type C, based on evidence of slower disease progression and prolonged survival in animal models. Miglustat was subsequently approved in Europe to treat progressive neurologic manifestations in both children and adults in early 2009, based on clinical study data. We report on the early treatment of two pediatric Niemann-Pick type C patients with miglustat. Patient 1, a 7.5-year-old girl with early-infantile onset, began receiving miglustat at age 7 months. Patient 2, the brother of a girl diagnosed with late-infantile onset Niemann-Pick type C, began receiving miglustat at age 19 months, when he was asymptomatic for neurologic disease. After 7 and 5 years of miglustat therapy, respectively, both patients remain free of neurologic manifestations. These findings suggest that miglustat may be more effective if used to prevent, rather than treat, neurologic manifestations in infantile-onset Niemann-Pick type C. © 2012 Elsevier Inc. All rights reserved.
Bondanza S.,Gaslini Institute |
Derchi M.,Gaslini Institute |
Marasini M.,Gaslini Institute
Catheterization and Cardiovascular Interventions | Year: 2012
Acquired pulmonary vein occlusion is a rare complication of surgical correction of complex congenital heart diseases. Associated vascular remodeling of arterial and venous vessels includes medial thickening, intimal fibrosis, and progressive development of aorto-pulmonary collaterals. The consequent pulmonary perfusion changes impact more importantly on a low pressure circulation such as the Fontan circuit. The management of these patients is still controversial. We describe this condition in two patients with single ventricle who underwent staged cavopulmonary connection. In both cases, we found acquired occlusion of one pulmonary vein, poor antegrade flow in the involved hypoplastic pulmonary arteries due to a widespread thin collateral circulation producing a backward washout of unopacified blood flow with competitive mechanism. Percutaneous embolization of a segmental pulmonary artery was performed with restoration of a more homogeneous perfusion of both main pulmonary arteries. Extracardiac total cavopulmonary connection was successfully performed a few months later in both patients. Copyright © 2011 Wiley Periodicals, Inc.