ABSTRACT
Neuroblastomas are pediatric tumors that develop from sympathetic precursors and express neuronal proteins, such as neuropeptide Y (NPY). NPY is a sympathetic neurotransmitter acting via multiple receptors (Y1-Y5R). Both NPY and Y2Rs are commonly expressed in neuroblastoma cell lines and tissues. The peptide secreted from neuroblastomas stimulates tumor cell proliferation and angiogenesis. As both processes are Y2R-mediated, the aim of this study was to assess Y2R as a potential therapeutic target for neuroblastoma. In vitro, Y2R antagonist (BIIE0246) prevented activation of p44/42 mitogen-activated protein kinase (MAPK) induced by endogenous NPY, which resulted in decreased proliferation and induction of Bim-mediated apoptosis. Similar growth-inhibitory effects were achieved with NPY small interfering RNA (siRNA) and Y2R siRNA. In vivo, Y2R antagonist significantly inhibited growth of SK-N-BE(2) and SK-N-AS xenografts, which was associated with decreased activation of p44/42 MAPK, as well as reduced proliferation (Ki67) and increased apoptosis (TdT-mediated dUTP nick end labeling; TUNEL). The Y2R antagonist also exerted an antiangiogenic effect. In vitro, it reduced the proliferation of endothelial cells induced by neuroblastoma-conditioned media. Consequently, the Y2R antagonist-treated xenografts had decreased vascularization and a high degree of focal fibrosis. In human neuroblastoma tissues, the expression of Y2R was observed in both tumor and endothelial cells, while NPY was predominantly expressed in neuroblastoma cells. In summary, Y2R is a promising new target for neuroblastoma therapy affecting both cancer cells and tumor vasculature.
Subject(s)
Neuroblastoma/genetics , Neuropeptide Y/genetics , RNA Interference , Receptors, Neuropeptide Y/genetics , Animals , Apoptosis/drug effects , Arginine/analogs & derivatives , Arginine/pharmacology , Benzazepines/pharmacology , Blotting, Western , Cell Line , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Enzyme Activation/drug effects , Gene Expression Regulation, Neoplastic , Humans , Immunohistochemistry , Mice , Mice, Nude , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/metabolism , Neovascularization, Pathologic/prevention & control , Neuroblastoma/metabolism , Neuroblastoma/pathology , Neuropeptide Y/metabolism , Receptors, Neuropeptide Y/antagonists & inhibitors , Receptors, Neuropeptide Y/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Xenograft Model Antitumor AssaysABSTRACT
OBJECTIVE: As Ureaplasmas may be pathogens in preterm infants, this study was conducted to determine the incidence of invasive disease with Ureaplasma parvum and Ureaplasma urealyticum and the relationship with adverse outcomes in a prospective cohort of very low birth weight (VLBW) infants. STUDY DESIGN: DNA was extracted from the cord or venous blood and cerebrospinal fluid (CSF) samples obtained from 313 VLBW infants. PCR was performed using primers for the mba gene to detect all 14 serovars and then repeated for all positive samples using species-specific primers. RESULT: Ureaplasma species were detected in serum and/or CSF samples from 74 of 313 (23.6%) infants. U. parvum was the predominant species (70%). Presence of Ureaplasma was significantly associated with elevated interleukin-1beta in cord blood (odds ratio (OR) 2.6, 1.05 to 6.45, P=0.039). Ureaplasma serum-positive infants had a 2.3-fold increased risk of intraventicular hemorrhage > or =grade 3 (OR 2.50; 1.06 to 5.89, P=0.036). CONCLUSION: Invasive Ureaplasma occurs commonly in VLBW infants and may increase the risk for severe intraventricular hemorrhage.
Subject(s)
Bacteremia/complications , Cerebral Hemorrhage/microbiology , Cerebrospinal Fluid/microbiology , Infant, Premature, Diseases , Ureaplasma Infections/complications , Bacteremia/microbiology , Bronchopulmonary Dysplasia/microbiology , Cerebral Hemorrhage/complications , Female , Fetal Blood/microbiology , Humans , Infant, Newborn , Infant, Premature , Infant, Premature, Diseases/microbiology , Infant, Very Low Birth Weight , Placenta/microbiology , Placenta/pathology , Prospective Studies , Ureaplasma/isolation & purificationABSTRACT
Vanishing bone disease is a rare condition of unknown aetiology. It can affect almost any bone, including those of the maxillofacial region. It is most commonly seen in the second and third decades of life. To the author's knowledge, this is the second case reported in the maxillofacial region of a child within the first decade of life, and the first who survived.