Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027819 (neuroblastoma)
 27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neuroblastoma is one of the most intensely studied solid malignancies that affect the pediatric age groups; its clinical presentation, treatment strategies and ultimate prognosis vary greatly. The biologic and genetic character of each tumor has an important impact on disease behavior, and clinical staging now incorporates these factors to generate an overall therapy plan. The clinical presentation of neuroblastoma is related to primary tumor location, production of metabolically active substances, and the presence of metastatic disease. There are also prognostically important associated syndromes including opsoclonus-myoclonus, Horner's syndrome, neurofibromatosis, and a variety of other neurocristopathies. The histologic features of the tumor are of prognostic significance and are utilized in treatment stratification. The International Neuroblastoma Staging System (INSS) has unified classic clinical staging. Features at diagnosis and those determined by initial operation are combined with biologic prognostic factors to achieve risk group assignment for virtually all patients. There are groups of children in which limited therapy is curative and intermediate-risk situations where standard multimodality treatment provides favorable outcomes. Unfortunately, there are many patients with high-risk disease that require intensive strategies, but success is still limited. It is in these most resistant patients that innovative approaches are being undertaken and novel strategies are being investigated.
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PMID:Current aspects of biology, risk assessment, and treatment of neuroblastoma. 998 66

Cervicothoracic lesions are not uncommon in children. All cervicothoracic lesions except superficial lesions extend from the neck to the thorax through the thoracic inlet. Evaluation of this area involves multiple imaging modalities: plain radiography, ultrasonography, nuclear medicine, computed tomography, and magnetic resonance (MR) imaging. However, MR imaging is the method of choice for assessing the full extents of cervicothoracic lesions and their relationships to neurovascular structures. Cervicothoracic lesions can be classified as congenital lesions, inflammatory lesions, benign tumors, malignant tumors, and traumatic lesions. Lymphangioma is the most common cervicothoracic mass in children; other congenital lesions include hemangioma, thymic cyst, and vascular anomalies. Inflammatory adenopathy reactive to tuberculosis, mononucleosis, tularemia, cat-scratch fever, infection with human immunodeficiency virus, or other upper respiratory tract infections can manifest as cervicothoracic lesions; tuberculous abscesses and abscesses of other origins can also be seen. Lipoma, lipoblastoma, aggressive fibromatosis, and nerve sheath tumors (either isolated lesions or those associated with neurofibromatosis) can also occur as cervicothoracic masses. Malignant cervicothoracic tumors include lymphoma, thyroid carcinoma, neuroblastoma, and chest wall tumors (rhabdomyosarcoma, Ewing sarcoma, and neuroectodermal tumor). Traumatic cervicothoracic lesions include pneumomediastinum of traumatic origin, traumatic pharyngeal pseudodiverticulum, esophageal foreign-body granuloma, and cervicothoracic hematoma.
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PMID:Cervicothoracic lesions in infants and children. 1033 90

Alzheimer's disease (AD) is characterized by the aggregation of the amyloid beta-peptide (Abeta) which is generated from a larger beta-amyloid precursor protein (betaAPP). An overexpression of the betaAPP gene in certain areas of the AD brain has been suggested to be an important factor in the neuropathology of AD. Here we have further characterized an upstream regulatory element (URE) located between -2257 and -2234 of the human betaAPP promoter. In addition to its location in the promoter, BLAST search reveals that URE is present in several introns of the betaAPP gene and is also detected in many other genes. For functional studies, two promoter regions were cloned upstream of the reporter gene, chloramphenicol acetyl transferase (CAT): (i) phbetaE-B - the plasmid that contains the human (h) promoter region (-2832 to +101) including URE, and (ii) prhbetaE-B - the plasmid that contains the rhesus (rh) promoter region excluding URE as it lacks a 270 bp region of the hbetaAPP promoter (-2435 to -2165). Transient transfection studies indicate that phbetaE-B displayed significantly less CAT-promoter activity than prhbetaE-B in C6, PC12 and SK-N-SH cells. To determine the role of URE in a heterologous promoter, a pbetaURE construct was made by subcloning URE in an enhancerless promoter vector pCATP. The pbetaURE-CAT construct displayed threefold to fourfold less promoter activity than pCATP when different cell lines were transfected with the plasmids. URE interacts with a novel protein(s) as determined by the electrophoretic mobility shift assay (EMSA). Although the core DNA region of URE resembles with the NF-kB element, URE-binding protein is not related to the NF-kB transcription factor. When EMSA was performed with specific competitors in different cell lines, the labeled URE probe was not competed by the oligonucleotides specific for either the AP3, NF-1 or NF-kB transcription factor. The migration of the URE-protein complex was different from the NF-kB-protein complex in the EMSA gel. A distinct URE-specific nuclear factor was also detected in frontal cortex of a normal human brain. These results suggest that the URE region acts as a repressor element, that the URE-binding protein is not related to the known transcription factors tested, and that the protein is present in astrocytic, neuroblastoma, PC12 cells and in the human brain.
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PMID:Promoter activity of the beta-amyloid precursor protein gene is negatively modulated by an upstream regulatory element. 1040 84

Neuroblastoma is the second-most common solid tumor in childhood. The majority of patients have a very poor outcome due to aggressive growth and metastatic spread. In contrast, in rare cases, spontaneous regression or differentiation towards a benign ganglioneuroma are observed. The mechanism leading to differentiation of neuroblastoma is of particular therapeutic interest. In this paper we report the results of our attempts to induce the expression of genes necessary for differentiation of neuroblastoma cells. TrkA codes for the high affinity receptor of NGF, a neurotrophin known to promote differentiation. Treatment with retinoic acid caused a 3-fold increase of the trkA expression in neuroblastoma cell lines. Neurofibromin, the gene product of the NF-1 gene, is involved in downregulation of the activity of ras-proteins. In contrast to immature neuronal tissues in mature brain, the type II isoform of neurofibromin is predominantly expressed. Retinoic acid was able to raise the proportion of type II NF-1 expressed in neuroblastoma cells.
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PMID:Neuroblastoma: induction of differentiation (Part I). Basical science in pediatric surgery. 1087 72

Composite tumor of pheochromocytoma and neuroblastoma, or ganglioneuroma, or ganglioneuroblastoma (composite pheochromocytoma), also known as mixed neuroendocrine and neural tumor, are sometimes combined with neurofibromatosis type 1 (NF1). To better understand the relationship between NF1 and composite pheochromocytoma, an immunohistochemical study using anti-neuro-fibromin that is an NF1 gene product and DNA sequence of NF1 Exon 31 were carried out in five cases of composite pheochromocytoma and in various tumors from five patients with NF1. Neurofibromin was not expressed in Schwann cells and sustentacular cells of composite pheochromocytomas and was very weakly or negatively expressed in neurofibroma of NF1 patients. However, it was strongly expressed in ganglionic cells and pheochromocytoma cells of the composite pheochromocytomas and also in mucosal ganglioneuromas, a gangliocytic paraganglioma, and in pheochromocytomas from the patients with NF1. Although there was no mutation in NF1 Exon 31, it could not be ruled out that there were mutations in other sites of the NF1 gene. Neurofibromin insufficiency may induce abnormal proliferation of Schwann cells in composite pheochromocytomas as well as in neurofibromatosis.
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PMID:Neurofibromin and NF1 gene analysis in composite pheochromocytoma and tumors associated with von Recklinghausen's disease. 1190 34

Neuroblastoma belongs to the group of small blue round cell tumors and originates in precursor cells of the sympathetic neural tissue. This tumor occurs at the pediatric age and has fascinated and intrigued both clinicians and researchers because of its variable and often unpredictable clinical behaviour. Indeed, the clinical outcome of neuroblastoma patients not only depends on the clinical extension of the disease, but also on other factors including age at diagnosis, presence or absence in the tumor cells of molecular and biological characteristics with prognostic value (e.g. amplification of the oncogene MYCN, frequently associated with chromosome 1p-deletion is predictive for poor survival chance). In 1983 an abdominal stage 3 neuroblastoma was diagnosed in a 9-months old boy. He died of the disease 3 years later. Karyotyping studies in this patient revealed a constitutional chromosome translocation t(1;17) with a breakpoint involving the terminal part of the chromosome 1p arm. We hypothesized that this patient was predisposed to the development of neuroblastoma because he carried in all his somatic cells a chromosomal abnormality involving the region frequently deleted in neuroblastoma tumor cells. We assumed that the chromosomal translocation breakpoints might indicate the regions harbouring genes involved in neuroblastoma development. A somatic cell fusion experiment was performed between the patient's fibroblasts (the only remaining source of patient material) and a fast growing Chinese hamster ovary cell line to assure the possibilities to perform further research. These somatic cell hybrids indeed contained the human translocation chromosomes. Further characterization of the translocation breakpoints by FISH (fluorescent in situ hybridisation) resulted in the identification of NPPA (formerly PND, the gene for pronatriodilatine) and A12M2 (an adenovirus integration site) as flanking markers for the 1p breakpoint. The 17q breakpoint was located between the NF1 (neurofibromatosis 1) gene and the SCYA7 (harboring the gene encoding the monocyte chemotactic protein-3). Starting from these markers chromosome walking experiments furthered the characterization of the chromosomal breakpoint regions and enabled to identify breakpoint overlapping cosmids. Sequence analysis of these markers is ongoing and will reveal if the breakpoint regions indeed harbour a gene involved in neuroblastoma development.
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PMID:[The neuroblastoma, "enfant terrible" among pediatric tumors]. 1280 94

Regulation of N-myc oncogene expression is an important determinant of the biological behavior of neuroblastoma. The N-myc promoter contains several potential binding sites for transcription factors of the Sp1 family. Mutation of a CT-box motif contained within a 26 bp region required for N-myc downregulation by retinoic acid decreased basal transcriptional activity and altered DNA-protein interactions of the promoter, while mutations flanking this motif did neither. On super-shift, this region was shown to recruit Sp1 and Sp3 transcription factor proteins, while a functionally significant CT-box mutation resulted in their replacement by NF-1 transcription factor. Lysates from Drosophila S2 cells expressing exogenous Sp1, Sp3, and NF-1 proteins were able to partially mimic gel shift complexes seen with neuroblastoma nuclear extract and either wild type or mutant probes. Transient transfections of S2 cells showed that both individually and together, Sp1 and Sp3 were able to trans-activate a wild type CT-box-driven luciferase reporter construct in a dose-dependent manner. Transfection of the wild type but not mutant CT-box oligonucleotide was able to decrease endogenous N-myc expression in neuroblastoma cells. Together these results suggest that the CT-box element serves a critically functional role, and in the basal state, allows for N-myc trans-activation by Sp1 and Sp3. Moreover when mutated, the CT-box may still function as a binding motif for alternate transcription factors such as NF-1 that can allow persistent N-myc expression.
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PMID:N-myc oncogene expression in neuroblastoma is driven by Sp1 and Sp3. 1456 77

The SH2 domain-containing protein-tyrosine phosphatase PTPN11 (Shp2) is required for normal development and is an essential component of signaling pathways initiated by growth factors, cytokines, and extracellular matrix. In many of these pathways, Shp2 acts upstream of Ras. About 50% of patients with Noonan syndrome have germ-line PTPN11 gain of function mutations. Associations between Noonan syndrome and an increased risk of some malignancies, notably leukemia and neuroblastoma, have been reported, and recent data indicate that somatic PTPN11 mutations occur in children with sporadic juvenile myelomonocytic leukemia, myelodysplasic syndrome, B-cell acute lymphoblastic leukemia, and acute myelogenous leukemia (AML). Juvenile myelomonocytic leukemia patients without PTPN11 mutations have either homozygotic NF-1 deletion or activating RAS mutations. Given the role of Shp2 in Ras activation and the frequent mutation of RAS in human tumors, these data raise the possibility that PTPN11 mutations play a broader role in cancer. We asked whether PTPN11 mutations occur in other malignancies in which activating RAS mutations occur at low but significant frequency. Sequencing of PTPN11 from 13 different human neoplasms including breast, lung, gastric, and neuroblastoma tumors and adult AML and acute lymphoblastic leukemia revealed 11 missense mutations. Five are known mutations predicted to result in an activated form of Shp2, whereas six are new mutations. Biochemical analysis confirmed that several of the new mutations result in increased Shp2 activity. Our data demonstrate that mutations in PTPN11 occur at low frequency in several human cancers, especially neuroblastoma and AML, and suggest that Shp2 may be a novel target for antineoplastic therapy.
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PMID:Activating mutations of the noonan syndrome-associated SHP2/PTPN11 gene in human solid tumors and adult acute myelogenous leukemia. 1560 38

Neural polypyrimidine tract-binding protein nPTB, originally identified as the neuronal counterpart of the hnRNPI/PTB protein, is an RNA binding protein involved into tissue-specific alternative splicing regulation. Here we describe the functional characterization of the promoter sequence of nPTB in HeLa and neuroblastoma cells. By means of genomic sequence analysis we have isolated and cloned a 1587-base pair region upstream the human nPTB coding region. The nPTB proximal promoter, although rich in G+C content and presenting putative binding sites for the transcription factors Sp1, NF-1, NF-kB and Oct-1, lacks a typical TATA box. Luciferase transient expression assays using deletion mutants have identified the proximal promoter region at -125 relative to the transcription start site. Alignment of human, murine and chimpanzee genomic sequences upstream the nPTB exon 1 has provided evidences for the evolutionary conservation of specific transcription factor binding sites.
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PMID:Identification and analysis of the human neural polypyrimidine tract binding protein (nPTB) gene promoter region. 1600 44

Hirschsprung's disease (HSCR) is a complex congenital disorder which, from a molecular perspective, appears to result due to disruption of normal signalling during development of enteric nerve cells, resulting in aganglionosis of the distal bowel. Associated congenital anomalies occur in at least 5-32% (mean 21%) of patients and certain syndromic phenotypes have been linked to distinct genetic sites, indicating underlying genetic associations of the disease and probable gene-gene interaction in its pathogenesis. Clear-cut associations with HSCR include Down's syndrome, dominant sensorineural deafness, Waardenburg syndrome, neurofibromatosis, neuroblastoma, phaeochromocytoma, the MEN type IIB syndrome and other abnormalities. Individual anomalies vary from 2.97% to 8%, the most frequent being the gastrointestinal tract (GIT) (8.05%), the central nervous system (CNS) and sensorineural anomalies (6.79%) and the genito-urinary tract (6.05%). Other associated systems include the musculoskeletal (5.12%), cardiovascular systems (4.99%), craniofacial and eye abnormalities (3%) and less frequently the skin and integumentary system (ectodermal dysplasia) and syndromes related to cholesterol and fat metabolism. In addition to associations with neuroblastoma and tumours related to MEN2B, HSCR may also be associated with tumours of neural origin such as ganglioneuroma, ganglioneuroblastoma, retinoblastoma and tumours associated with neurofibromatosis and other autonomic nervous system disturbances. The contribution of the major susceptibility genes on chromosome 10 (RET) and chromosome 13 (EDNRB) is well established in the phenotypic expression of HSCR. Whereas major RET mutations may result in HSCR by haploinsufficiency in 20-25% of cases, the etiology of the majority of sporadic HSCR is not as clear, appearing to arise from the combined cumulative effects of susceptibility loci at critical genes controlling the mechanisms of cell proliferation, differentiation and maturation. In addition, potential "modifying" associations exist with chromosome 2, 9, 20, 21 and 22, and we explore the importance of certain flanking genes of critical areas in the final phenotypic expression of HSCR.
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PMID:The contribution of associated congenital anomalies in understanding Hirschsprung's disease. 1651 96


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