UMLS:C0027819 - FACTA Search

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Query: UMLS:C0027819 (neuroblastoma)
27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have elucidated a biochemical mechanism whereby changes in iron metabolism cause changes in folate-dependent one-carbon metabolism. Although animal and clinical studies have demonstrated that perturbations in iron status and metabolism alter folate metabolism, the biochemical mechanisms underlying these associations have yet to be identified. The effect of altered ferritin expression on folate metabolism was determined in human MCF-7 cells and SH-SY5Y neuroblastoma. Cells expressing rat heavy chain ferritin (HCF) exhibited markedly increased expression of the folate-dependent enzyme cytoplasmic serine hydroxymethyltransferase (cSHMT). These effects were not seen when rat light chain ferritin was expressed. Additionally, cSHMT expression was not altered when HCF expression was induced in MCF-7 cells cultured with supplemental ferric citrate. This indicates that cSHMT expression is increased by elevated HCF concentrations, independent of increased iron availability, suggesting that cSHMT expression may respond to HCF-induced chelation of the regulatory iron pool. Increased HCF expression did not alter cSHMT mRNA levels, but did increase translation rates of cSHMT mRNA. The increase in translation was mediated, at least in part, through the cSHMT 5'-untranslated region of the transcript. MCF-7 cells with increased expression of cSHMT displayed increased efficiency of de novo thymidylate biosynthesis, indicating that thymidylate synthesis is normally limited by cSHMT activity in MCF-7 cells. Our data suggest that the iron regulatory pool may play an important role in regulating folate metabolism and thereby thymidine biosynthesis.
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PMID:Heavy chain ferritin enhances serine hydroxymethyltransferase expression and de novo thymidine biosynthesis. 1127 96

Neuroblastoma treatment remains challenging but has been advanced by the establishment of clinical and biological variables that determine prognostic risk. Risk-based therapy currently is the hallmark of neuroblastoma treatment. Initially, stage and age were the prime determinants of survival used in clinical practice. The Shimada histopathologic classification added to the former 2 and biochemical markers like the serum ferritin, lactic dehydrogenase, and neuron-specific enolase also provided information regarding prognosis. The current era of neuroblastoma therapy has been influenced heavily by advances in molecular biology, most notably the identification of the MYCN oncogene and the application of recombinant DNA methods to identification of chromosomal deletions. Current risk assessment includes age, stage, histopathology, and biochemical markers but also analyses performed on DNA extracted from fresh tumors. This places the onus of obtaining an adequate quantity and quality of fresh neuroblastoma tissue directly on the pediatric surgeon who performs the initial biopsy.
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PMID:Surgical management of neuroblastoma. 1148 50

Iron-responsive elements (IREs) are the RNA stem loops that control cellular iron homeostasis by regulating ferritin translation and transferrin receptor mRNA stability. We mapped a novel iron-responsive element (IRE-Type II) within the 5'-untranslated region (5'-UTR) of the Alzheimer's amyloid precursor protein (APP) transcript (+51 to +94 from the 5'-cap site). The APP mRNA IRE is located immediately upstream of an interleukin-1 responsive acute box domain (+101 to +146). APP 5'-UTR conferred translation was selectively down-regulated in response to intracellular iron chelation using three separate reporter assays (chloramphenicol acetyltransferase, luciferase, and red fluorescent protein reflecting an inhibition of APP holoprotein translation in response to iron chelation. Iron influx reversed this inhibition. As an internal control to ensure specificity, a viral internal ribosome entry sequence was unresponsive to intracellular iron chelation with desferrioxamine. Using RNA mobility shift assays, the APP 5'-UTRs, encompassing the IRE, bind specifically to recombinant iron-regulatory proteins (IRP) and to IRP from neuroblastoma cell lysates. IRP binding to the APP 5'-UTR is reduced after treatment of cells with desferrioxamine and increased after interleukin-1 stimulation. IRP binding is abrogated when APP cRNA probe is mutated in the core IRE domain (Delta4 bases:Delta83AGAG86). Iron regulation of APP mRNA through the APP 5'-UTR points to a role for iron in the metabolism of APP and confirms that this RNA structure can be a target for the selection of small molecule drugs, such as desferrioxamine (Fe chelator) and clioquinol (Fe, Cu, and Zn chelator), which reduce Abeta peptide burden during Alzheimer's disease.
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PMID:An iron-responsive element type II in the 5'-untranslated region of the Alzheimer's amyloid precursor protein transcript. 1219 35

During the last two decades new diagnostic and therapeutic tools have been utilized to improve the poor survival chances of children with stage 4 neuroblastoma. This study reviews the risk profiles and the long-term outcome of patients from five consecutive German neuroblastoma trials. A total of 96% of all German patients registered at the German childhood cancer registry with neuroblastoma stage 4 over 1 year of age at diagnosis entered one of the trials during 1979-2001. Eight hundred and twenty-eight consecutive children were analyzed retrospectively. In spite of having significantly improved diagnostic tools like bone marrow superstaging and mIBG scintigraphy the stage 4 incidence did not increase after reaching completeness of the registry (5.4 cases/100,000 children at 1-14 years of age; P=0.52). The distribution of the primary tumors and of metastases was constant over the periods. The amount of bone marrow infiltration did not change with time. The risk factors lactate dehydrogenase, ferritin and MYCN, and the clinical risk groups 4A, 4B, 4C also remained constant over the trials with a few exceptions for NB97. The 5-year event free survival increased from 0.01+/-0.01 (NB79) to 0.14+/-0.03 (NB85), 0.16+/-0.04 (NB82), 0.27+/-0.02 (NB90), and 0.33+/-0.04 (NB97). The overall survival rates improved similarly from 0.04 (NB79) to 0.44 (NB97). In conclusion, the improved survival was associated with better treatment and not caused by lower risk profiles in stage 4 neuroblastoma patients.
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PMID:Long-term results and risk profiles of patients in five consecutive trials (1979-1997) with stage 4 neuroblastoma over 1 year of age. 1288 Sep 54

The striking differences in the natural history of clinical subgroups of neuroblastoma (NB), and the evolving therapeutic approaches for each, makes it imperative for prognostic markers to be reevaluated within individual clinical categories. At least one third of NB cases present without distant metastasis and cytotoxic therapy does not alter the natural history. We carried out a retrospective analysis of archived tumor samples. Fifty-seven of these patients had local-regional (LR) NB and were managed conservatively, initially treated with surgery alone. Among the biologic and clinical features analyzed including age, stage, histology, ploidy, MYCN, and 1p36, 1p22, 11q, 14q, 9p and 19q loss of heterozygosity (LOH) in multivariate analysis, diploidy was one of the most significant factors associated with progression-free survival and stage 4 progression. Clonal ploidy heterogeneity was common in LR NB. A predominant near-triploid clonal population was found in most cases of non-progressing LR NB tumors whereas progressing LR NB cases had a predominant diploid clone. We also reviewed the prognostic factors among 84 stage 4 NB cases treated with the N5, N6 or N7 protocols at MSKCC from 1987 to 1999. Traditional markers such as lactate dehydrogenase (LDH), ferritin, age and MYCN status were not prognostic in the univariate analysis. 11q23 and 1p22 LOH were correlated with better survival. These results highlight the evolving significance of prognostic analysis in homogeneous clinical groups undergoing similar treatments. To further characterize the gene expression profile between local-regional and metastatic NB, we carried out Microarray analysis of 41 NB tumors and 12 NB cell lines, using the Affymetrix Genechip Human Genome U95 Set. Distinct gene expression patterns between metastatic and non-metastatic NB tumors have been identified. Validation of these results and further mechanistic studies may shed new light on the biology of metastasis in human NB.
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PMID:Evolving significance of prognostic markers associated with new treatment strategies in neuroblastoma. 1288 Sep 70

Stage 4s neuroblastoma (NB) is usually associated with a favourable outcome, despite a large tumour burden, as spontaneous regression frequently occurs. However, in some infants rapid disease progression can be observed with severe functional impairment. Thus, for all patients the potential risks of cytotoxic therapy must be weighed against the benefits of early medical intervention. We have retrospectively reviewed the charts of 94 infants treated for stage 4s NB in centres of the French Society of Paediatric Oncology between 1990 and 2000, and describe the different first-line treatment approaches that were, successively, liver irradiation, chemotherapy using a cyclophosphamide-vincristine regimen, and chemotherapy using a carboplatin-etoposide regimen. The overall survival was 88% (+/-7.6%), with a mean follow-up of 64 months. Elevated serum neuron-specific enolase (>100 nmol ml(-1)), ferritin (>280 ng ml(-1)) and urinary dopamine levels (>2500 nmol mmol(-1) creatinine) were associated with a poor outcome, as were the genetic markers N-myc amplification and chromosome 1p deletion (P<0.0005 and P=0.0016, respectively). Patients who required medical intervention at diagnosis fared worse than those who received supportive treatment only (P<0.005). The clinical evolution observed with the different successive treatment approaches suggests that if infants do require therapy, the prompt initiation of a more intensive regimen such as carboplatin-etoposide may be more beneficial.
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PMID:Treatment of stage 4s neuroblastoma--report of 10 years' experience of the French Society of Paediatric Oncology (SFOP). 1288 14

Ganglioside metabolism has been linked to the clinical and biological behavior of human neuroblastoma. This study investigated the importance of differences in complex "b" ganglioside (GD1b, GT1b, and GQ1b; designated CbG) expression in this tumor. Gangliosides of 74 neuroblastomas were analyzed by high-performance TLC. Associations of CbG expression with known prognostic markers and with event-free survival (EFS) were evaluated. Higher CbG expression characterized nonprogressive versus progressive tumors (median 41% versus 18% of total gangliosides; P = 0.001) and completely accounted for the observed higher overall "b" pathway ganglioside expression (median 81% versus 68%; P = 0.003). In contrast, expression of the structurally simpler "b" pathway gangliosides (GD2 and GD3) did not differ (median 31% versus 35%; P = 0.4). Absolute CbG content differed even more (median 93 versus 29 nmol/g among nonprogressive versus progressive tumors; P = 0.02) and was most striking in the case of GQ1b content (8-fold higher in nonprogressive tumors). High CbG (> or =35% of total gangliosides) expression was strongly predictive of a favorable outcome in: (a) the entire study population (90% versus 60% EFS at 25 months; P = 0.001); and (b) among patients assigned a low-risk status by a either single genetic or biochemical tumor marker (MYCN, DNA, NSE, or ferritin), or by both unamplified MYCN and aneuploid DNA (22-28% difference in EFS at 25 months). These data suggest that high tumor CbG content may substratify "good prognosis" neuroblastoma patients, identifying patients at very low risk of relapse or death, and that the biological roles of CbG in neuroblastoma will be of importance to define.
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PMID:Biological stratification of human neuroblastoma by complex "B" pathway ganglioside expression. 1461 23

The Alzheimer's amyloid precursor protein (APP) is the metalloprotein that is cleaved to generate the pathogenic Abeta peptide. We showed that iron closely regulated the expression of APP by 5'-untranslated region (5'-UTR) sequences in APP mRNA. Iron modulated APP holoprotein expression by a pathway similar to iron control of the translation of the ferritin-L and -H mRNAs by iron-responsive elements in their 5'-UTRs. APP gene transcription is also responsive to copper deficit where the Menkes protein depleted fibroblasts of copper to suppress transcription of APP through metal regulatory and copper regulatory sequences upstream of the APP 5' cap site. APP is a copper-zinc metalloprotein and chelation of Fe(3+) by desferrioxamine and Cu(2+) by clioquinol appeared to provide effective therapy for the treatment of AD in limited patient studies. We have introduced an RNA-based screen for small APP 5'-UTR binding molecules to identify leads that limit APP translation (but not APLP-1 and APLP-2) and amyloid Abeta peptide production. A library of 1200 drugs was screened to identify lead drugs that limited APP 5'-UTR-directed translation of a reporter gene. The efficacy of these leads was confirmed for specificity in a cell-based secondary assay to measure the steady-state levels of APP holoprotein relative to APLP-1/APLP-2 by Western blotting. Several chelators were identified among the APP 5'-UTR directed leads consistent with the presence of an IRE stem-loop in front of the start codon of the APP transcript. The APP 5'-UTR-directed drugs--desferrioxamine (Fe(3+) chelator), tetrathiomolybdate (Cu(2+) chelator), and dimercaptopropanol (Pb(2+) and Hg(2+) chelator)--each suppressed APP holoprotein expression (and lowered Abeta peptide secretion). The novel anticholinesterase phenserine also provided "proof of concept" for our strategy to target the APP 5'-UTR sequence to identify "anti-amyloid" drugs. We further defined the interaction between iron chelation and phenserine action to control APP 5'-UTR-directed translation in neuroblastoma (SY5Y) transfectants. Phenserine was most efficient to block translation under conditions of intracellular iron chelation with desferrioxamine suggesting that this anticholinesterase operated through an iron (metal)-dependent pathway at the APP 5'-UTR site.
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PMID:The integrated role of desferrioxamine and phenserine targeted to an iron-responsive element in the APP-mRNA 5'-untranslated region. 1568 99

Prion diseases are characterized by the conversion of the normal cellular prion protein PrP(C) into a pathogenic isoform, PrP(Sc). The mechanisms involved in neuronal cell death in prion diseases are largely unknown, but accumulating evidence has demonstrated oxidative impairment along with metal imbalances in scrapie-infected brains. In this study, we report changes in cellular iron metabolism in scrapie-infected mouse neuroblastoma N2a cells (ScN2a). We detected twofold lower total cellular iron and calcein-chelatable cytosolic labile iron pool (LIP) in ScN2a cells as compared to the N2a cells. We also measured in ScN2a cells significantly lower activities of iron regulatory proteins 1 and 2 (IRP1 and IRP2, respectively), regulators of cellular iron by sensing cytosolic free iron levels and controlling posttranscriptionally the expression of the major iron transport protein transferrin receptor 1 (TfR1) and the iron sequestration protein ferritin. IRP1 and IRP2 protein levels were decreased by 40% and 50%, respectively, in ScN2a cells. TfR1 protein levels were fourfold reduced and ferritin levels were threefold reduced in ScN2a cells. TfR1 and ferritin mRNA levels were significantly reduced in ScN2a cells. ScN2a cells responded normally to iron and iron chelator treatment with respect to the activities of IRP1 and IRP2, and biosynthesis of TfR1 and ferritin. However, the activities of IRP1 and IRP2, and protein levels of TfR1 and ferritin, were still significantly lower in iron-depleted ScN2a cells as compared to the N2a cells, suggesting lower need for iron in ScN2a cells. Our results demonstrate that scrapie infection leads to changes in cellular iron metabolism, affecting both total cellular and cytosolic free iron, and the activities and expression of major regulators of cellular iron homeostasis.
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PMID:Changed iron regulation in scrapie-infected neuroblastoma cells. 1571 Feb 43

The mechanisms behind the pathology of prion diseases are still unknown, but accumulating evidence suggests oxidative impairment along with metal imbalances in scrapie-infected brains. In this study, we have investigated iron-induced oxidative stress in scrapie-infected mouse neuroblastoma N2a (ScN2a) cells. Uninfected N2a and ScN2a cells were treated with ferric ammonium citrate (FAC) for 1-16 h, and the levels of labile iron pool (LIP), the formation of reactive oxygen species (ROS), cell viability and ferritin protein levels were measured. The increase in LIP in N2a cells was transient with a quick recovery to normal levels within 4h accompanied by a moderate increase of formation of ROS after 3h followed by the decrease to the basal level. In ScN2a cells, the increase in LIP was lower, but the process of recovery was prolonged and accompanied by high ROS formation and decreased cell viability. Ferritin protein levels were significantly lower in ScN2a cells than in wild-type cells in all iron treatments. These results suggest that ScN2a cells are more sensitive to iron treatment as compared to wild-type cells with respect to ROS formation and cell viability, and that ferritin deficiency in infected cells may contribute to iron-induced oxidative stress in scrapie-infected cells.
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PMID:Increased iron-induced oxidative stress and toxicity in scrapie-infected neuroblastoma cells. 1592 93

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