NF-κB Signaling Regulates Expression of Epstein-Barr Virus BART MicroRNAs and Long Noncoding RNAs in Nasopharyngeal Carcinoma

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Defective peroxisome biogenesis with a neuromuscular disorder resembling Werdnig-Hoffmann disease.

OBJECTIVE: Characterization of the defect in a patient presenting a peripheral neuropathy with atypical features of distal motor involvement mimicking Werdnig-Hoffmann disease. PATIENT: Clinical signs included generalized hypotonia and floppiness, absence of stretch reflexes, muscle wasting, lack of head control and lingual fasciculations associated with unaffected facial muscles, and normal intellectual development. RESULTS: Normal muscle histology ruled out Werdnig-Hoffmann disease. Elevated plasma concentrations of very long-chain fatty acids and bile acid intermediates combined with normal plasmalogen levels in erythrocytes suggested defective peroxisomal beta-oxidation directly demonstrated by deficient pristanic acid and partially deficient C26:0 was present oxidation in cultured fibroblasts. Severely impaired pipecolic acid oxidation in liver and phytanic acid oxidation in fibroblasts was present. On light and electron microscopy of the liver tissue, rare peroxisomal membrane ghosts and trilamellar inclusions but absence of peroxisomes was noted. Immunoblot analysis revealed absence of peroxisomal beta-oxidation enzymes in liver tissue but normal results in fibroblasts. Remarkably, expression of the peroxisomal defect in fibroblasts was indicated by the finding of mainly cytoplasmatic catalase, as in liver. Preliminary studies excluded classification of this patient within the large PEX1 complementation group. CONCLUSIONS: The results suggest a novel peroxisome biogenesis disorder involving peroxisomal beta-oxidation as well as phytanic and pipecolic acid oxidation rather than an isolated defect of peroxisomal beta-oxidation. The association of a clinical picture mimicking Werdnig-Hoffmann disease with a novel peroxisomal disorder raises the question of whether investigation for peroxisomal function should be considered in every patient with an enigmatic spinal muscular atrophy-like syndrom

Characterization of extracellular secreted Epstein-Barr virus BART microRNAs as serological markers for nasopharyngeal carcinoma diagnosis and treatment

Celebrating 50 years of Epstein-Barr virus discovery (1964-2014)Session 3: Nasopharyngeal Carcinoma – Population studies and emerging therapiesNasopharyngeal carcinoma (NPC) exhibits a distinct geographical and ethnic distribution. It is recognized that 75-90% of NPC patients have already developed local or regional spread at diagnosis, which hampers effective treatment and results in a poor prognosis. It is essential to characterize more sensitive and specific biomarkers for NPC screening of high risk individuals and for differentiation of treatment options upon diagnosis. One of the hallmarks of NPC is the ubiquitous association with Epstein-Barr virus (EBV). In NPC cells, EBV expresses only very essential viral proteins, but more than 20 BART microRNAs (miRNAs) at abundant levels. This study characterized NPC specific BART miRNAs through a comprehensive analysis of EBV BART microRNA expression profiles in EBV infected cells, including latency I and III EBV infected BL cells, EBV transformed LCLs, EBV-harbouring NPC cells and non-cancerous nasopharyngeal cells. We further characterized the BART miRNAs secreted into culture supernatants and determined that BART-3, BART-7 and BART-13 miRNAs are regularly secreted into the extracellular environment, implicating these BART miRNAs as potential serological biomarkers for use in NPC screening. Analysis of plasma specimens obtained from NPC patients and healthy and non-NPC tumor patient controls found levels of both BART-7 and BART-13 to be significantly higher among NPC patients, with elevated levels being particularly apparent among patients with advanced disease. Levels of BART-3 were indistinguishable between NPC and control groups. We further confirmed that BART-7 and BART-13 are NPC associated. Analysis of 41 NPC patients before and after successful radiotherapy treatment showed that BART-7 and BART-13, but not BART-3, were diminished after treatment. Receiver Operating Characteristic (ROC) curve analysis combining BART-7 and BART-13 levels produces a 90% predictive value for the presence of NPC. These results indicate that BART-7 and BART-13 may be useful new serological biomarkers for diagnosis of NPC and prediction of treatment efficacy

Circulating Epstein-Barr virus microRNAs miR-BART7 and miR-BART13 as biomarkers for nasopharyngeal carcinoma diagnosis and treatment

More than 75% of nasopharyngeal carcinoma (NPC) patients have already developed local or regional spread at diagnosis, which hampers effective treatment and results in a poor prognosis. It is essential to characterize more sensitive and specific biomarkers for screening of high risk individuals and assessment of NPC treatment effectiveness. NPC is an Epstein–Barr virus (EBV) associated tumor in which only a few viral proteins but more than 20 BamHI A rightward transcripts (BART) microRNAs are detected, at abundant levels. We hypothesized that these BART microRNAs may be novel biomarkers for NPC. Systematic analysis of EBV BART microRNA expression profiles in EBV latently infected Mutu I and Mutu III cell lines, EBV-harboring NPC and noncancerous NP cells found that miR-BART3, miR-BART7 and miR-BART13 microRNAs are highly expressed and regularly secreted into the extracellular environment of NPC cells. These BART microRNAs were evaluated for used as potential NPC biomarkers. Analysis of plasma specimens obtained from NPC patients (n = 89), and healthy (n = 28) and non-NPC tumor patient controls (n = 18) found levels of both miR-BART7 and miR-BART13, but not miR-BART3, to be distinctly presence among NPC patients, with elevated levels being particularly apparent among patients with advanced disease. Receiver operating characteristic curve analysis combining miR-BART7 and miR-BART13 levels produces a 90% predictive value for the presence of NPC. Analysis of 41 NPC patients before and after radiotherapy showed that miR-BART7 and miR-BART13, but not miR-BART3, were diminished after treatment. These results indicate that EBV microRNAs, miR-BART7 and miR-BART13, may constitute useful new serological biomarkers for diagnosis of NPC and prediction of treatment efficacy.More than 75% of nasopharyngeal carcinoma (NPC) patients have already developed local or regional spread at diagnosis, which hampers effective treatment and results in a poor prognosis. It is essential to characterize more sensitive and specific biomarkers for screening of high risk individuals and assessment of NPC treatment effectiveness. NPC is an Epstein-Barr virus (EBV) associated tumor in which only a few viral proteins but more than 20 BamHI A rightward transcripts (BART) microRNAs are detected, at abundant levels. We hypothesized that these BART microRNAs may be novel biomarkers for NPC. Systematic analysis of EBV BART microRNA expression profiles in EBV latently infected Mutu I and Mutu III cell lines, EBV-harboring NPC and noncancerous NP cells found that miR-BART3, miR-BART7 and miR-BART13 microRNAs are highly expressed and regularly secreted into the extracellular environment of NPC cells. These BART microRNAs were evaluated for used as potential NPC biomarkers. Analysis of plasma specimens obtained from NPC patients (n=89), and healthy (n=28) and non-NPC tumor patient controls (n=18) found levels of both miR-BART7 and miR-BART13, but not miR-BART3, to be distinctly presence among NPC patients, with elevated levels being particularly apparent among patients with advanced disease. Receiver operating characteristic curve analysis combining miR-BART7 and miR-BART13 levels produces a 90% predictive value for the presence of NPC. Analysis of 41 NPC patients before and after radiotherapy showed that miR-BART7 and miRBART13, but not miR-BART3, were diminished after treatment. These results indicate that EBV microRNAs, miR-BART7 and miRBART13, may constitute useful new serological biomarkers for diagnosis of NPC and prediction of treatment efficacy. © 2014 UICC.link_to_subscribed_fulltex

Clinical approach to inherited peroxisomal disorders: A series of 27 patients.

To illustrate the clinical and biochemical heterogeneity of peroxisomal disorders, we report our experience with 27 patients seen personally between 1982 and 1997. Twenty patients presented with a phenotype corresponding either to Zellweger syndrome, neonatal adrenoleukodystrophy, or infantile Refsum disease, 3 of whom had a peroxisomal disorder due to a single enzyme defect. One patient had a mild form of rhizomelic chondrodysplasia punctata, 1 had classic Refsum disease. Finally, 5 patients presented with clinical manifestations that were either unusually mild or completely atypical, and initially did not arouse suspicion of a peroxisomal disorder. They showed multiple defects of peroxisomal functions with one or several functions remaining intact, suggesting a peroxisome biogenesis disorder. The defect in peroxisome biogenesis was further characterized by variable expression in different tissues and/or individual cells in 5 patients. Studies restricted to fibroblasts failed to identify abnormalities in this group. We demonstrate that clinical manifestations of peroxisomal disorders may be very mild or completely atypical, and therefore, peroxisomal disorders should be considered in a variety of clinical settings. Furthermore, we suggest performing extensive peroxisomal investigations in every patient suspected of suffering from a peroxisomal disorder, even when the clinical presentation is typica

Peroxisomes and their central role in metabolic interaction networks in humans

Peroxisomes catalyze a number of essential metabolic functions and impairments in any of these are usually associated with major clinical signs and symptoms. In contrast to mitochondria which are autonomous organelles that can catalyze the degradation of fatty acids, certain amino acids and other compounds all by themselves, peroxisomes are non-autonomous organelles which are highly dependent on the interaction with other organelles and compartments to fulfill their role in metabolism. This includes mitochondria, the endoplasmic reticulum, lysosomes, and the cytosol. In this paper we will discuss the central role of peroxisomes in different metabolic interaction networks in humans, including fatty acid oxidation, ether phospholipid biosynthesis, bile acid synthesis, fatty acid alpha-oxidation and glyoxylate metabolism