Kinetics of the membrane current mediated by serotonin 5-HT3 receptors in cultured mouse neuroblastoma cells.

NARCIS (Netherlands)

Neijt, H.C.; Plomp, J.J.; Vijverberg, H.P.M.

1989-01-01

1. Ionic currents mediated by serotonin 5-HT3 receptors were studied in the mouse neuroblastoma cell line N1E-115, using suction pipettes for intracellular perfusion and voltage clamp recording. The dependence of the kinetics of the membrane current on serotonin concentration was investigated. 2. At

Dehydroepiandrosterone protects male and female hippocampal neurons and neuroblastoma cells from glucose deprivation.

Science.gov (United States)

Vieira-Marques, Claudia; Arbo, Bruno Dutra; Ruiz-Palmero, Isabel; Ortiz-Rodriguez, Ana; Ghorbanpoor, Samar; Kucharski, Luiz Carlos; Arevalo, Maria A; Garcia-Segura, Luis Miguel; Ribeiro, Maria Flávia M

2016-08-01

Dehydroepiandrosterone (DHEA) modulates neurogenesis, neuronal function, neuronal survival and metabolism, enhancing mitochondrial oxidative capacity. Glucose deprivation and hypometabolism have been implicated in the mechanisms that mediate neuronal damage in neurological disorders, and some studies have shown that these mechanisms are sexually dimorphic. It was also demonstrated that DHEA is able to attenuate the hypometabolism that is related to some neurodegenerative diseases, eliciting neuroprotective effects in different experimental models of neurodegeneration. The aim of this study was to evaluate the effect of DHEA on the viability of male and female hippocampal neurons and SH-SY5Y neuroblastoma cells exposed to glucose deprivation. It was observed that after 12h of pre-treatment, DHEA was able to protect SH-SY5Y cells from glucose deprivation for 6h (DHEA 10(-12), 10(-8) and 10(-6)M) and 8h (DHEA 10(-8)M). In contrast, DHEA was not neuroprotective against glucose deprivation for 12 or 24h. DHEA (10(-8)M) also protected SH-SY5Y cells when added together or even 1h after the beginning of glucose deprivation (6h). Furthermore, DHEA (10(-8)M) also protected primary neurons from both sexes against glucose deprivation. In summary, our findings indicate that DHEA is neuroprotective against glucose deprivation in human neuroblastoma cells and in male and female mouse hippocampal neurons. These results suggest that DHEA could be a promising candidate to be used in clinical studies aiming to reduce neuronal damage in people from both sexes. Copyright © 2016 Elsevier B.V. All rights reserved.

Treatment and outcome of adult-onset neuroblastoma.

Science.gov (United States)

Suzuki, Maya; Kushner, Brian H; Kramer, Kim; Basu, Ellen M; Roberts, Stephen S; Hammond, William J; LaQuaglia, Michael P; Wolden, Suzanne L; Cheung, Nai-Kong V; Modak, Shakeel

2018-03-25

Adult-onset neuroblastoma is rare and little is known about its biology and clinical course. There is no established therapy for adult-onset neuroblastoma. Anti-GD2 immunotherapy is now standard therapy in children with high-risk neuroblastoma; however, its use has not been reported in adults. Forty-four adults (18-71 years old) diagnosed with neuroblastoma between 1979 and 2015 were treated at Memorial Sloan Kettering Cancer Center. Five, 1, 5 and 33 patients had INSS stage 1, 2, 3 and 4 diseases, respectively. Genetic abnormalities included somatic ATRX (58%) and ALK mutations (42%) but not MYCN-amplification. In the 11 patients with locoregional disease, 10-year progression-free (PFS) and overall survival (OS) was 35.4 ± 16.1% and 61.4 ± 15.3%, respectively. Among 33 adults with stage 4 neuroblastoma, 7 (21%) achieved complete response (CR) after induction chemotherapy and/or surgery. Seven patients with primary refractory neuroblastoma (all with osteomedullary but no soft tissue disease) received anti-GD2 antibodies, mouse or humanized 3F8. Antibody-related adverse events were similar to those in children, response rate being 71.4%. In patients with stage 4 disease at diagnosis, 5-year PFS was 9.7± 5.3% and most patients who were alive with disease at 5 years died of neuroblastoma over the next 5 years, 10-year OS being only 19.0 ± 8.2%. Patients who achieved CR after induction had superior PFS and OS (p = 0.006, p = 0.031, respectively). Adult-onset neuroblastoma appeared to have different biology from pediatric or adolescent NB, and poorer outcome. Complete disease control appeared to improve long-term survival. Anti-GD2 immunotherapy was well tolerated and might be beneficial. © 2018 UICC.

Significance of clinical and biologic features in Stage 3 neuroblastoma: a report from the International Neuroblastoma Risk Group project.

Science.gov (United States)

Meany, Holly J; London, Wendy B; Ambros, Peter F; Matthay, Katherine K; Monclair, Tom; Simon, Thorsten; Garaventa, Alberto; Berthold, Frank; Nakagawara, Akira; Cohn, Susan L; Pearson, Andrew D J; Park, Julie R

2014-11-01

International Neuroblastoma Staging System (INSS) Stage 3 neuroblastoma is a heterogeneous disease. Data from the International Neuroblastoma Risk Group (INRG) database were analyzed to define patient and tumor characteristics predictive of outcome. Of 8,800 patients in the INRG database, 1,483 with INSS Stage 3 neuroblastoma and complete follow-up data were analyzed. Secondary analysis was performed in 1,013 patients (68%) with MYCN-non-amplified (NA) tumors. Significant prognostic factors were identified via log-rank test comparisons of survival curves. Multivariable Cox proportional hazards regression model was used to identify factors independently predictive of event-free survival (EFS). Age at diagnosis (P INSS Stage 3 neuroblastoma patients, age at diagnosis, MYCN status and histology predict outcome. Patients <547 days of age with MYCN-NA tumors that lack chromosome 11q aberrations or those with serum ferritin <96 ng/ml have excellent prognosis and should be considered for therapy reduction. Prospective clinical trials are needed to identify optimal therapy for those patients ≥ 547 days of age with undifferentiated histology or elevated serum ferritin. © 2014 Wiley Periodicals, Inc.

Malformation/dysplasia syndrome (neural tube defect, hypospadias neuroblastoma) associated with an extra dicentric marker chromosome 15 ({open_quotes}inversion duplication 15{close_quotes})

Energy Technology Data Exchange (ETDEWEB)

Reitnauer, P.J.; Rao, K.W.; Tepperberg, J.H. [Univ. of North Carolina, Chapel Hill, NC (United States)

1994-09-01

Extra dicentric 15 marker chromosomes are associated with variable degrees of mental retardation but not major structural birth defects. We have studied a unique patient, a male infant who was prenatally diagnosed with lumbar meningomyelocele and an extra pseudodicentric marker chromosome: 47,XY,+psu dic(15)t(15;15)(?q12,?q12)mat. Hairy ears and a coronal hypospadias were noted at birth. At three months of age, a stage I thoracic neuroblastoma was primarily resected. Tumor cells, skin fibroblasts and peripheral blood lymphocytes contained the dicentric 15. The mother is mosaic for the marker chromosome. Fluorescence in situ hybridization (FISH) studies using a classic 15 satellite probe (D15Z1 [Oncor]) confirmed the presence of 2 number 15 centromeres in the marker. The marker is felt to be the result of a translocation rather than an inverted duplication because the G-band morphology of the short arm/satellite complexes differ from one another, implying that the arms originate from 2 different number 15s. FISH analysis using cosmid probes for the Prader-Willi/Angelman critical region (D15S11 and GABRB3 [Oncor]) revealed 2 copies of this region, indicating that these loci are duplicated in the marker. Although some features of the patient`s phenotype such as developmental delay and hypotonia have been associated with dicentric chromosome 15 markers, this is the first malformation/dysplasia syndrome or neuroblastoma reported to our knowledge. The association of neuroblastoma with chromosome 15 aberrations in this case provides speculation as to the role of chromosome 15 loci in cell division control.

(R-(+-α-Lipoic acid protected NG108-15 cells against H2O2-induced cell death through PI3K-Akt/GSK-3β pathway and suppression of NF-κβ-cytokines

Directory of Open Access Journals (Sweden)

Kamarudin MNA

2014-10-01

Full Text Available Muhamad Noor Alfarizal Kamarudin, Nur Afiqah Mohd Raflee, Sharifah Salwa Syed Hussein, Jia Ye Lo, Hadi Supriady, Habsah Abdul KadirInstitute of Biological Sciences, Faculty of Science, University of Malaya, Kuala Lumpur, MalaysiaAbstract: Alpha-lipoic acid, a potent antioxidant with multifarious pharmacological benefits has been reported to be neuroprotective in several neuronal models and used to treat neurological disorders such as Alzheimer’s disease. Nonetheless, conclusive mechanisms of alpha-lipoic acid for its protective effects particularly in NG108-15 cells have never been investigated. In this study, the intricate neuroprotective molecular mechanisms by (R-(+-alpha-lipoic acid (R-LA against H2O2-induced cell death in an in vitro model of neurodegeneration were elucidated. Pretreatment with R-LA (2 hours significantly increased NG108-15 cell viability as compared to H2O2-treated cells and mitigated the induction of apoptosis as evidenced by Hoechst 33342/propidium iodide staining. R-LA (12.5–50 µM aggrandized the reduced glutathione over glutathione disulfide ratio followed by a reduction in the intracellular reactive oxygen species level and an increase in mitochondrial membrane potential following H2O2 exposure. Moreover, pretreatment with R-LA stimulated the activation of PI3K-Akt through mTORC1 and mTORC2 components (mTOR, rictor and raptor and production of antiinflammatory cytokine, IL-10 which led to the inactivation of glycogen synthase kinase-3β (GSK-3β and reduction of both Bax/Bcl2 and Bax/Bcl-xL ratios, accompanied by inhibition of the cleaved caspase-3. Additionally, this observation was preceded by the suppression of NF-κβ p65 translocation and production of proinflammatory cytokines (IL-6 and TNF-α. The current findings accentuate new mechanistic insight of R-LA against apoptogenic and brain inflammatory factors in a neuronal model. These results further advocate the therapeutic potential of R-LA for

Dinutuximab in the Treatment of High-Risk Neuroblastoma in Children

Directory of Open Access Journals (Sweden)

Hazal Gur

2017-06-01

Full Text Available Neuroblastoma is the most common extracranial tumor derived from neural crest cells in childhood, and treatment of high-risk neuroblastoma is a difficulty in oncology field. The discovery of new treatment strategies to treat pediatric patients with high-risk neuroblastoma is important. Dinutuximab (ch14.18; Unituxin, a chimeric human-mouse monoclonal antibody, is approved by Food and Drug Administration in 2015 to be used specifically in the treatment of high-risk neuroblastoma. It binds the disialoganglioside (GD2 antigen on the surface of neuroblastoma cells and induces lysis of GD2-expressed neuroblastoma cells via antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity. To enhance its activity, it is used with a combination of granulocyte-macrophage colony-stimulating factor, interleukin 2, and 13- cis -retinoic acid. In this review, we discuss the use of dinutuximab in the treatment of high-risk neuroblastoma.

The second-generation ALK inhibitor alectinib effectively induces apoptosis in human neuroblastoma cells and inhibits tumor growth in a TH-MYCN transgenic neuroblastoma mouse model.

Science.gov (United States)

Lu, Jiaxiong; Guan, Shan; Zhao, Yanling; Yu, Yang; Woodfield, Sarah E; Zhang, Huiyuan; Yang, Kristine L; Bieerkehazhi, Shayahati; Qi, Lin; Li, Xiaonan; Gu, Jerry; Xu, Xin; Jin, Jingling; Muscal, Jodi A; Yang, Tianshu; Xu, Guo-Tong; Yang, Jianhua

2017-08-01

Activating germline mutations of anaplastic lymphoma kinase (ALK) occur in most cases of hereditary neuroblastoma (NB) and the constitutively active kinase activity of ALK promotes cell proliferation and survival in NB. Therefore, ALK kinase is a potential therapeutic target for NB. In this study, we show that the novel ALK inhibitor alectinib effectively suppressed cell proliferation and induces apoptosis in NB cell lines with either wild-type ALK or mutated ALK (F1174L and D1091N) by blocking ALK-mediated PI3K/Akt/mTOR signaling. In addition, alectinib enhanced doxorubicin-induced cytotoxicity and apoptosis in NB cells. Furthermore, alectinib induced apoptosis in an orthotopic xenograft NB mouse model. Also, in the TH-MYCN transgenic mouse model, alectinib resulted in decreased tumor growth and prolonged survival time. These results indicate that alectinib may be a promising therapeutic agent for the treatment of NB. Copyright © 2017 Elsevier B.V. All rights reserved.

Genomewide analysis of gene expression associated with Tcof1 in mouse neuroblastoma

International Nuclear Information System (INIS)

Mogass, Michael; York, Timothy P.; Li, Lin; Rujirabanjerd, Sinitdhorn; Shiang, Rita

2004-01-01

Mutations in the Treacher Collins syndrome gene, TCOF1, cause a disorder of craniofacial development. We manipulated the levels of Tcof1 and its protein treacle in a murine neuroblastoma cell line to identify downstream changes in gene expression using a microarray platform. We identified a set of genes that have similar expression with Tcof1 as well as a set of genes that are negatively correlated with Tcof1 expression. We also showed that the level of Tcof1 and treacle expression is downregulated during differentiation of neuroblastoma cells into neuronal cells. Inhibition of Tcof1 expression by siRNA induced morphological changes in neuroblastoma cells that mimic differentiation. Thus, expression of Tcof1 and treacle synthesis play an important role in the proliferation of neuroblastoma cells and we have identified genes that may be important in this pathway

Nanosensors for label-free measurement of sodium ion fluxes of neuronal cells

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Gebinoga, Michael, E-mail: michael.gebinoga@tu-ilmenau.de [ZIK MacroNano Microfluidics and Biosensors, Technical University Ilmenau, P.O. Box 100565, D-98684 Ilmenau (Germany); Silveira, Liele; Cimalla, Irina [ZIK MacroNano Microfluidics and Biosensors, Technical University Ilmenau, P.O. Box 100565, D-98684 Ilmenau (Germany); Dumitrescu, Andreea [University of Pennsylvania - School of Engineering and Applied Science, Philadelphia, PA 19104-6391 (United States); Kittler, Mario; Luebbers, Benedikt; Becker, Annette [ZIK MacroNano Microfluidics and Biosensors, Technical University Ilmenau, P.O. Box 100565, D-98684 Ilmenau (Germany); Lebedev, Vadim [Fraunhofer Institute for Solid State Physics, Tullastr. 7, D-79108 Freiburg (Germany); Schober, Andreas [ZIK MacroNano Microfluidics and Biosensors, Technical University Ilmenau, P.O. Box 100565, D-98684 Ilmenau (Germany)

2010-05-25

Novel nanosensors based on aluminium gallium nitrides (AlGaN/GaN) high electron mobility transistors have been of high interest during the last years, especially for their electrical characteristics as open gate field effect transistors. These nanosensors provide a valuable tool for high content screening in drug discovery, cell monitoring and liquid analyses focusing on applications of electrochemical detection technology. Our own measurements with these sensors confirm their pH sensitivity and in addition the possibility of detection of other ions in aqueous media. These measurements deal with the reactions of NG 108-15 (mouse neuroblastoma x rat glioma hybrid) neuronal cells in response to different acetylcholinesterase inhibitors. Our experimental approach shows some advantages. The first advantage is the label-free measurement of ion fluxes, and another advantage is the possibility non-destructively to estimate cell signals.

Nanosensors for label-free measurement of sodium ion fluxes of neuronal cells

International Nuclear Information System (INIS)

Gebinoga, Michael; Silveira, Liele; Cimalla, Irina; Dumitrescu, Andreea; Kittler, Mario; Luebbers, Benedikt; Becker, Annette; Lebedev, Vadim; Schober, Andreas

2010-01-01

Novel nanosensors based on aluminium gallium nitrides (AlGaN/GaN) high electron mobility transistors have been of high interest during the last years, especially for their electrical characteristics as open gate field effect transistors. These nanosensors provide a valuable tool for high content screening in drug discovery, cell monitoring and liquid analyses focusing on applications of electrochemical detection technology. Our own measurements with these sensors confirm their pH sensitivity and in addition the possibility of detection of other ions in aqueous media. These measurements deal with the reactions of NG 108-15 (mouse neuroblastoma x rat glioma hybrid) neuronal cells in response to different acetylcholinesterase inhibitors. Our experimental approach shows some advantages. The first advantage is the label-free measurement of ion fluxes, and another advantage is the possibility non-destructively to estimate cell signals.

Th-MYCN Mice with Caspase-8 Deficiency Develop Advanced Neuroblastoma with Bone Marrow Metastasis

OpenAIRE

Teitz, Tal; Inoue, Madoka; Valentine, Marcus B.; Zhu, Kejin; Rehg, Jerold E.; Zhao, Wei; Finkelstein, David; Wang, Yong-Dong; Johnson, Melissa D.; Calabrese, Christopher; Rubinstein, Marcelo; Hakem, Razqallah; Weiss, William A.; Lahti, Jill M.

2016-01-01

Neuroblastoma, the most common extracranial pediatric solid tumor, is responsible for 15% of all childhood cancer deaths. Patients frequently present at diagnosis with metastatic disease, particularly to the bone marrow (BM). Advances in therapy and understanding of the metastatic process have been limited due in part, to the lack of animal models harboring BM disease. The widely employed transgenic model, the Th-MYCN mouse, exhibits limited metastasis to this site. Here we establish th...

Adolescent Neuroblastoma of Lower Limb

Directory of Open Access Journals (Sweden)

Rajeshwari K

2013-04-01

Full Text Available Neuroblastoma is an embryonic tumour of neural crest origin, commonly seen in children with upper abdomen involvement. Rarely neuroblastomas present in adolescents and adults involving lower limb. Histopathologically neuroblastoma of lower limb can be confused with other small round cell tumour especially with Ewing's sarcoma and rhabdomyosarcoma. A 16 year old male presented with 15x11cm swelling, pain and multiple discharging sinuses of right leg since 4 months. Routine haematological and biochemical analysis were within normal limits. Radiology of right leg showed large soft tissue swelling encompassing the pathological fracture of tibia and bowing of fibula. Fine needle aspiration of the swelling revealed malignant small round cell tumour. Histopathology revealed poorly differentiated neuroblastoma of lower limb. The immunohistochemistry of Synaptophysin and Chromogranin were positive and CD 99 was negative. Neuroblastoma diagnosed at unusual site with uncommon age has poor prognosis. Hence, one must keep in mind the differential diagnosis of neuroblastoma as one of the differential diagnosis in evaluating the soft tissue tumours of lower limb.

Differential alterations of phospholipid metabolism in cultured cells of neural origin by phorbol esters, fatty acids, diacylglycerols and related compounds

International Nuclear Information System (INIS)

Cook, H.W.; Spence, M.W.

1986-01-01

The uptake and metabolism of [ 3 H]methylcholine, [1,2- 14 C]-ethanolamine, [1- 14 C]fatty acids and [ 32 P] were studied in glioma (C6), neuroblastoma (N1E-115) and neuroblastoma-glioma hybrid (NG108-15) cells in culture in the presence of tetradecanoylphorbolacetate (TPA) and related analogues, fatty acids and diacylglycerol (DAG) to assess mechanisms of stimulation of phospholipid synthesis. Choline incorporation into phosphatidylcholine (PC) was stimulated 1.5-3 fold by phorbol esters and 3-10 fold by 18:1(n-9) in C6 cultures; these agents were without effect on N1E-115 and had intermediate effects on NG108-15 cells. Stimulation of [ 32 P] incorporation was predominantly into PC, ethanolamine incorporation into phosphatidylethanolamine (PE) was less stimulated ( 3 H]choline and its incorporation via intracellular phosphocholine into PC whereas exogenous 18:1(n-9) stimulated only utilization of intracellular P-choline in C6 cells. Choline incorporation into PC and relative stimulation by TPA or 18:1 was influenced by medium glucose and choline. Thus, metabolism of phospholipids and their precursors in neural cells can be markedly influenced by phorbol esters and fatty acids but this stimulation is dependent on cell type, growth medium, phospholipid class and nature of the stimulator

Characterization and therapeutic evaluation of a Nestin⁺ CNP⁺ NG2⁺ cell population on mouse spinal cord injury.

Science.gov (United States)

Liu, Rui; Zhang, Si; Yang, Haijie; Ju, Peijun; Xia, Yinyan; Shi, Yu; Lim, Tse Hui; Lim, Alvin St; Liang, Fengyi; Feng, Zhiwei

2015-07-01

The NG2 chondroitin sulfate proteoglycan-expressing neural cells (NG2 cells) have originally been considered as oligodendrocyte progenitor cells (OPCs). However, recent findings on their diverse functions and lineage heterogeneity demonstrated that the NG2 cells contain various sub-populations whose concrete features and therapeutic potential yet remained elucidated. In the present study, we characterized a Nestin(+) 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP)(+) NG2(+) subpopulation from embryonic rat cerebral cortex. The Nestin(+) CNP(+) NG2(+) cells exhibited remarkable progenitor characteristics. Having been immortalized by human telomerase reverse transcriptase (hTERT), the life span of Nestin(+) CNP(+) NG2(+) cells was extended to 230 population doublings (PDs). With immortalized NG2 cells, we demonstrated their differentiation capacities to oligodendrocytes, astrocytes and neurons. Furthermore, transplanted into injured spinal cord of a mouse model, they were able to promote remyelination and neuronal regeneration, thereby enhancing the functional recovery. Our findings suggest that the Nestin(+) CNP(+) NG2(+) progenitor cells could be a good alternative cell source of cell therapy for neurological disorders. Copyright © 2015 Elsevier Inc. All rights reserved.

Neuroblastoma : Crossing borders in targeted therapy

NARCIS (Netherlands)

Bate-Eya, L.T.

2017-01-01

Neuroblastoma is the most commonly diagnosed childhood cancer and accounts for about 15% of all pediatric malignancies deaths. Thus far, the treatment options of neuroblastoma is limited with only a 30-40% long term survival rate in high-risk patients. In this thesis, we describe the isolation and

The Checkpoint Kinase 1 Inhibitor Prexasertib Induces Regression of Preclinical Models of Human Neuroblastoma.

Science.gov (United States)

Lowery, Caitlin D; VanWye, Alle B; Dowless, Michele; Blosser, Wayne; Falcon, Beverly L; Stewart, Julie; Stephens, Jennifer; Beckmann, Richard P; Bence Lin, Aimee; Stancato, Louis F

2017-08-01

Purpose: Checkpoint kinase 1 (CHK1) is a key regulator of the DNA damage response and a mediator of replication stress through modulation of replication fork licensing and activation of S and G 2 -M cell-cycle checkpoints. We evaluated prexasertib (LY2606368), a small-molecule CHK1 inhibitor currently in clinical testing, in multiple preclinical models of pediatric cancer. Following an initial assessment of prexasertib activity, this study focused on the preclinical models of neuroblastoma. Experimental Design: We evaluated the antiproliferative activity of prexasertib in a panel of cancer cell lines; neuroblastoma cell lines were among the most sensitive. Subsequent Western blot and immunofluorescence analyses measured DNA damage and DNA repair protein activation. Prexasertib was investigated in several cell line-derived xenograft mouse models of neuroblastoma. Results: Within 24 hours, single-agent prexasertib promoted γH2AX-positive double-strand DNA breaks and phosphorylation of DNA damage sensors ATM and DNA-PKcs, leading to neuroblastoma cell death. Knockdown of CHK1 and/or CHK2 by siRNA verified that the double-strand DNA breaks and cell death elicited by prexasertib were due to specific CHK1 inhibition. Neuroblastoma xenografts rapidly regressed following prexasertib administration, independent of starting tumor volume. Decreased Ki67 and increased immunostaining of endothelial and pericyte markers were observed in xenografts after only 6 days of exposure to prexasertib, potentially indicating a swift reduction in tumor volume and/or a direct effect on tumor vasculature. Conclusions: Overall, these data demonstrate that prexasertib is a specific inhibitor of CHK1 in neuroblastoma and leads to DNA damage and cell death in preclinical models of this devastating pediatric malignancy. Clin Cancer Res; 23(15); 4354-63. ©2017 AACR . ©2017 American Association for Cancer Research.

Cell Survival Signaling in Neuroblastoma

Science.gov (United States)

Megison, Michael L.; Gillory, Lauren A.; Beierle, Elizabeth A.

2013-01-01

Neuroblastoma is the most common extracranial solid tumor of childhood and is responsible for over 15% of pediatric cancer deaths. Neuroblastoma tumorigenesis and malignant transformation is driven by overexpression and dominance of cell survival pathways and a lack of normal cellular senescence or apoptosis. Therefore, manipulation of cell survival pathways may decrease the malignant potential of these tumors and provide avenues for the development of novel therapeutics. This review focuses on several facets of cell survival pathways including protein kinases (PI3K, AKT, ALK, and FAK), transcription factors (NF-κB, MYCN and p53), and growth factors (IGF, EGF, PDGF, and VEGF). Modulation of each of these factors decreases the growth or otherwise hinders the malignant potential of neuroblastoma, and many therapeutics targeting these pathways are already in the clinical trial phase of development. Continued research and discovery of effective modulators of these pathways will revolutionize the treatment of neuroblastoma. PMID:22934706

Marrow Derived Antibody Library for the Treatment of Neuroblastoma

Science.gov (United States)

2015-12-01

Award Number: W81XWH-12-1-0332 TITLE: Marrow-Derived Antibody Library for the Treatment of Neuroblastoma PRINCIPAL INVESTIGATOR: Giselle...Marrow-Derived Antibody Library for Treatment of Neuroblastoma 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S...to Spectrum Health. 14. ABSTRACT Neuroblastoma (NB) is the most common solid tumor in children, which accounts for 15% of all pediatric cancer deaths

A recombinant endogenous retrovirus amplified in a mouse neuroblastoma is involved in tumor growth in vivo.

Science.gov (United States)

Pothlichet, Julien; Heidmann, Thierry; Mangeney, Marianne

2006-08-15

The theory of immunoediting postulates that tumor cells exhibit a reduced immunogenicity to escape eradication by the host immune system. It has been proposed that endogenous retroviruses--provided that they are active--could play a role in this process, via the immunosuppressive domain carried by their envelope protein. Here, we demonstrate that the Neuro-2a tumor cell line--originating from a spontaneous A/J mouse neuroblastoma--produces an infectious retrovirus that most probably results from a recombination event between 2 mouse endogenous retroviral elements. This Neuro-2a-associated recombinant retrovirus derives from the unique ecotropic provirus located at the Emv-1 locus, but with a gag sequence conferring B-tropism, thus allowing its high-level amplification in Neuro-2a cells. We show that knocking down -by RNA interference- this endogenous retrovirus in Neuro-2a cells has no effect on the transformed phenotype of the cells, but results in delayed tumor growth and prolonged animal survival, following engraftment of the cells into immunocompetent mice. Recombination between endogenous retroviruses, amplification of the resulting element and high-level expression of its immunosuppressive activity are therefore likely steps of an immunoediting process, leading to an invading tumor. Copyright 2006 Wiley-Liss, Inc.

Ammonium-induced calcium mobilization in 1321N1 astrocytoma cells

International Nuclear Information System (INIS)

Hillmann, Petra; Koese, Meryem; Soehl, Kristina; Mueller, Christa E.

2008-01-01

High blood levels of ammonium/ammonia (NH 4 + /NH 3 ) are associated with severe neurotoxicity as observed in hepatic encephalopathy (HE). Astrocytes are the main targets of ammonium toxicity, while neuronal cells are less vulnerable. In the present study, an astrocytoma cell line 1321N1 and a neuroblastoma glioma hybrid cell line NG108-15 were used as model systems for astrocytes and neuronal cells, respectively. Ammonium salts evoked a transient increase in intracellular calcium concentrations ([Ca 2+ ] i ) in astrocytoma (EC 50 = 6.38 mM), but not in NG108-15 cells. The ammonium-induced increase in [Ca 2+ ] i was due to an intracellular effect of NH 4 + /NH 3 and was independent of extracellular calcium. Acetate completely inhibited the ammonium effect. Ammonium potently reduced calcium signaling by G q protein-coupled receptors (H 1 and M3) expressed on the cells. Ammonium (5 mM) also significantly inhibited the proliferation of 1321N1 astrocytoma cells. While mRNA for the mammalian ammonium transporters RhBG and RhCG could not be detected in 1321N1 astrocytoma cells, both transporters were expressed in NG108-15 cells. RhBG and RhBC in brain may promote the excretion of NH 3 /NH 4 + from neuronal cells. Cellular uptake of NH 4 + /NH 3 was mainly by passive diffusion of NH 3 . Human 1321N1 astrocytoma cells appear to be an excellent, easily accessible human model for studying HE, which can substitute animal studies, while NG108-15 cells may be useful for investigating the role of the recently discovered Rhesus family type ammonium transporters in neuronal cells. Our findings may contribute to the understanding of pathologic ammonium effects in different brain cells, and to the treatment of hyperammonemia

Distinguishing neuroblastoma invading the kidney from nephroblastoma: evaluation in computed tomography

International Nuclear Information System (INIS)

Qiao Zhongwei; Li Guoping; Mamier; Wang Kang'an; Lv Zhibao; Miao Fei

2005-01-01

Objective: To evaluate the CT findings in the differential diagnosis between neuroblastoma invading the kidney and nephroblastoma. Methods: CT morphologic details in 13 patients with neuroblastoma invading the kidney confirmed by surgical operation and pathology were studied, and CT findings in 15 patients with nephroblastoma confirmed by surgery and pathology were compared. Results: In 13 cases of neuroblastoma, CT showed irregular mass in 12 cases, tumor with poorly defined margins in 11 cases, tumorous calcifications in 10 cases, invasion of retroperitoneal vessels in 9 cases, and retroperitoneal and retrocrural lymph nodes invasion in 12 cases. In 15 cases of nephroblastoma, round mass was p resented in 12 cases, tumor with poorly defined margins in 2 cases, tumorous calcifications in 2 cases, involvement of retroperitoneal vessels in 2 cases, and invasion of retroperitoneal lymph nodes in 3 cases. None of the nephroblastoma invaded retrocrural lymph nodes. Irregular mass with calcifications, involvement of retroperitoneal vessels, retrocrural and retroperitoneal lymph nodes were more common in cases of neuroblastoma than in nephroblastoma. Moreover, involvement of retrocrural lymph nodes and encasement of retroperitoneal vessels had higher positive prediction value on neuroblastoma. Conclusion: Involvement of retrocrural lymph nodes and encasement of retroperitoneal vessels were the specific CT findings of neuroblastoma and the most valuable evidence in distinguishing neuroblastoma from nephroblastoma. (authors)

Theranostic gas-generating nanoparticles for targeted ultrasound imaging and treatment of neuroblastoma.

Science.gov (United States)

Lee, Jangwook; Min, Hyun-Su; You, Dong Gil; Kim, Kwangmeyung; Kwon, Ick Chan; Rhim, Taiyoun; Lee, Kuen Yong

2016-02-10

The development of safe and efficient diagnostic/therapeutic agents for treating cancer in clinics remains challenging due to the potential toxicity of conventional agents. Although the annual incidence of neuroblastoma is not that high, the disease mainly occurs in children, a population vulnerable to toxic contrast agents and therapeutics. We demonstrate here that cancer-targeting, gas-generating polymeric nanoparticles are useful as a theranostic tool for ultrasound (US) imaging and treating neuroblastoma. We encapsulated calcium carbonate using poly(d,l-lactide-co-glycolide) and created gas-generating polymer nanoparticles (GNPs). These nanoparticles release carbon dioxide bubbles under acidic conditions and enhance US signals. When GNPs are modified using rabies virus glycoprotein (RVG) peptide, a targeting moiety to neuroblastoma, RVG-GNPs effectively accumulate at the tumor site and substantially enhance US signals in a tumor-bearing mouse model. Intravenous administration of RVG-GNPs also reduces tumor growth in the mouse model without the use of conventional therapeutic agents. This approach to developing theranostic agents with disease-targeting ability may provide useful strategy for the detection and treatment of cancers, allowing safe and efficient clinical applications with fewer side effects than may occur with conventional agents. Copyright © 2015 Elsevier B.V. All rights reserved.

Suppression of the ATP-binding cassette transporter ABCC4 impairs neuroblastoma tumour growth and sensitises to irinotecan in vivo.

Science.gov (United States)

Murray, Jayne; Valli, Emanuele; Yu, Denise M T; Truong, Alan M; Gifford, Andrew J; Eden, Georgina L; Gamble, Laura D; Hanssen, Kimberley M; Flemming, Claudia L; Tan, Alvin; Tivnan, Amanda; Allan, Sophie; Saletta, Federica; Cheung, Leanna; Ruhle, Michelle; Schuetz, John D; Henderson, Michelle J; Byrne, Jennifer A; Norris, Murray D; Haber, Michelle; Fletcher, Jamie I

2017-09-01

The ATP-binding cassette transporter ABCC4 (multidrug resistance protein 4, MRP4) mRNA level is a strong predictor of poor clinical outcome in neuroblastoma which may relate to its export of endogenous signalling molecules and chemotherapeutic agents. We sought to determine whether ABCC4 contributes to development, growth and drug response in neuroblastoma in vivo. In neuroblastoma patients, high ABCC4 protein levels were associated with reduced overall survival. Inducible knockdown of ABCC4 strongly inhibited the growth of human neuroblastoma cells in vitro and impaired the growth of neuroblastoma xenografts. Loss of Abcc4 in the Th-MYCN transgenic neuroblastoma mouse model did not impact tumour formation; however, Abcc4-null neuroblastomas were strongly sensitised to the ABCC4 substrate drug irinotecan. Our findings demonstrate a role for ABCC4 in neuroblastoma cell proliferation and chemoresistance and provide rationale for a strategy where inhibition of ABCC4 should both attenuate the growth of neuroblastoma and sensitise tumours to ABCC4 chemotherapeutic substrates. Copyright © 2017 Elsevier Ltd. All rights reserved.

Bupivacaine-induced apoptosis independently of WDR35 expression in mouse neuroblastoma Neuro2a cells

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2012-01-01

Background Bupivacaine-induced neurotoxicity has been shown to occur through apoptosis. Recently, bupivacaine was shown to elicit reactive oxygen species (ROS) production and induce apoptosis accompanied by activation of p38 mitogen-activated protein kinase (MAPK) in a human neuroblastoma cell line. We have reported that WDR35, a WD40-repeat protein, may mediate apoptosis through caspase-3 activation. The present study was undertaken to test whether bupivacaine induces apoptosis in mouse neuroblastoma Neuro2a cells and to determine whether ROS, p38 MAPK, and WDR35 are involved. Results Our results showed that bupivacaine induced ROS generation and p38 MAPK activation in Neuro2a cells, resulting in apoptosis. Bupivacaine also increased WDR35 expression in a dose- and time-dependent manner. Hydrogen peroxide (H2O2) also increased WDR35 expression in Neuro2a cells. Antioxidant (EUK-8) and p38 MAPK inhibitor (SB202190) treatment attenuated the increase in caspase-3 activity, cell death and WDR35 expression induced by bupivacaine or H2O2. Although transfection of Neuro2a cells with WDR35 siRNA attenuated the bupivacaine- or H2O2-induced increase in expression of WDR35 mRNA and protein, in contrast to our previous studies, it did not inhibit the increase in caspase-3 activity in bupivacaine- or H2O2-treated cells. Conclusions In summary, our results indicated that bupivacaine induced apoptosis in Neuro2a cells. Bupivacaine induced ROS generation and p38 MAPK activation, resulting in an increase in WDR35 expression, in these cells. However, the increase in WDR35 expression may not be essential for the bupivacaine-induced apoptosis in Neuro2a cells. These results may suggest the existence of another mechanism of bupivacaine-induced apoptosis independent from WDR35 expression in Neuro2a cells. PMID:23227925

Mutations in PIK3CA are infrequent in neuroblastoma

International Nuclear Information System (INIS)

Dam, Vincent; Morgan, Brian T; Mazanek, Pavel; Hogarty, Michael D

2006-01-01

Neuroblastoma is a frequently lethal pediatric cancer in which MYCN genomic amplification is highly correlated with aggressive disease. Deregulated MYC genes require co-operative lesions to foster tumourigenesis and both direct and indirect evidence support activated Ras signaling for this purpose in many cancers. Yet Ras genes and Braf, while often activated in cancer cells, are infrequent targets for activation in neuroblastoma. Recently, the Ras effector PIK3CA was shown to be activated in diverse human cancers. We therefore assessed PIK3CA for mutation in human neuroblastomas, as well as in neuroblastomas arising in transgenic mice with MYCN overexpressed in neural-crest tissues. In this murine model we additionally surveyed for Ras family and Braf mutations as these have not been previously reported. Sixty-nine human neuroblastomas (42 primary tumors and 27 cell lines) were sequenced for PIK3CA activating mutations within the C2, helical and kinase domain 'hot spots' where 80% of mutations cluster. Constitutional DNA was sequenced in cases with confirmed alterations to assess for germline or somatic acquisition. Additionally, Ras family members (Hras1, Kras2 and Nras) and the downstream effectors Pik3ca and Braf, were sequenced from twenty-five neuroblastomas arising in neuroblastoma-prone transgenic mice. We identified mutations in the PIK3CA gene in 2 of 69 human neuroblastomas (2.9%). Neither mutation (R524M and E982D) has been studied to date for effects on lipid kinase activity. Though both occurred in tumors with MYCN amplification the overall rate of PIK3CA mutations in MYCN amplified and single-copy tumors did not differ appreciably (2 of 31 versus 0 of 38, respectively). Further, no activating mutations were identified in a survey of Ras signal transduction genes (including Hras1, Kras2, Nras, Pik3ca, or Braf genes) in twenty-five neuroblastic tumors arising in the MYCN-initiated transgenic mouse model. These data suggest that activating

Heat shock gene expression and cytoskeletal alterations in mouse neuroblastoma cells

NARCIS (Netherlands)

Bergen en Henegouwen, P.M.P. van; Linnemans, W.A.M.

The cytoskeleton of neuroblastoma cells, clone Neuro 2A, is altered by two stress conditions: heat shock and arsenite treatment. Microtubules are reorganized, intermediate filaments are aggregated around the nucleus, and the number of stress fibers is reduced. Since both stress modalities induce

FGF1 protects neuroblastoma SH-SY5Y cells from p53-dependent apoptosis through an intracrine pathway regulated by FGF1 phosphorylation

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Pirou, Caroline; Montazer-Torbati, Fatemeh; Jah, Nadège; Delmas, Elisabeth; Lasbleiz, Christelle; Mignotte, Bernard; Renaud, Flore

2017-01-01

Neuroblastoma, a sympathetic nervous system tumor, accounts for 15% of cancer deaths in children. In contrast to most human tumors, p53 is rarely mutated in human primary neuroblastoma, suggesting impaired p53 activation in neuroblastoma. Various studies have shown correlations between fgf1 expression levels and both prognosis severity and tumor chemoresistance. As we previously showed that fibroblast growth factor 1 (FGF1) inhibited p53-dependent apoptosis in neuron-like PC12 cells, we initiated the study of the interaction between the FGF1 and p53 pathways in neuroblastoma. We focused on the activity of either extracellular FGF1 by adding recombinant rFGF1 in media, or of intracellular FGF1 by overexpression in human SH-SY5Y and mouse N2a neuroblastoma cell lines. In both cell lines, the genotoxic drug etoposide induced a classical mitochondrial p53-dependent apoptosis. FGF1 was able to inhibit p53-dependent apoptosis upstream of mitochondrial events in SH-SY5Y cells by both extracellular and intracellular pathways. Both rFGF1 addition and etoposide treatment increased fgf1 expression in SH-SY5Y cells. Conversely, rFGF1 or overexpressed FGF1 had no effect on p53-dependent apoptosis and fgf1 expression in neuroblastoma N2a cells. Using different FGF1 mutants (that is, FGF1K132E, FGF1S130A and FGF1S130D), we further showed that the C-terminal domain and phosphorylation of FGF1 regulate its intracrine anti-apoptotic activity in neuroblastoma SH-SY5Y cells. This study provides the first evidence for a role of an intracrine growth factor pathway on p53-dependent apoptosis in neuroblastoma, and could lead to the identification of key regulators involved in neuroblastoma tumor progression and chemoresistance. PMID:29048426

Neuroblastoma: computed tomographic findings

International Nuclear Information System (INIS)

Yoon, Choon Sik; Ahn, Chang Su; Kim, Myung Jun; Oh, Ki Keun

1994-01-01

To evaluate the characteristic CT findings of neuroblastoma, we studied neuroblastomas. We analysed CT findings of available 25 cases among pathologically proved 51 neuroblastomas from Jan. 1983 to Sept. 1990. The most frequent site of origin is adrenal gland (40%) and the second is retroperitoneum (32%) and the third ismediastinum (16%). Characteristic CT findings are as follows: Calcifications within the tumor is detected in 86% of abdominal neuroblastomas and 50% of mediastinal origin. Hemorrhagic and necrotic changes within the tumor is noted at 86% in the tumor of abdominal origin and 25% in mediastinal neuroblastomas. Contrast enhanced study showed frequently seperated enhanced appearance with/without solid contrast enhancement. Encasements of major great vessels such as aorta and IVC with/without displacement by metastatic lymph nodes or tumor are frequently seen in 90% of abdominal neuroblastomas. Multiple lymphadenopathy are detected in 95% of abdominal neuroblastomas and 25% of mediastinal neuroblastomas. The most common organ or contiguous direct invasion is kidney in 6 cases and the next one is liver but intraspinal canal invasion is also noted in 2 cases. We concluded that diagnosis of neuroblastoma would be easily obtained in masses of pediatric group from recognition of above characteristic findings

Telomerase activation by genomic rearrangements in high-risk neuroblastoma

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Peifer, Martin; Hertwig, Falk; Roels, Frederik; Dreidax, Daniel; Gartlgruber, Moritz; Menon, Roopika; Krämer, Andrea; Roncaioli, Justin L.; Sand, Frederik; Heuckmann, Johannes M.; Ikram, Fakhera; Schmidt, Rene; Ackermann, Sandra; Engesser, Anne; Kahlert, Yvonne; Vogel, Wenzel; Altmüller, Janine; Nürnberg, Peter; Thierry-Mieg, Jean; Thierry-Mieg, Danielle; Mariappan, Aruljothi; Heynck, Stefanie; Mariotti, Erika; Henrich, Kai-Oliver; Glöckner, Christian; Bosco, Graziella; Leuschner, Ivo; Schweiger, Michal R.; Savelyeva, Larissa; Watkins, Simon C.; Shao, Chunxuan; Bell, Emma; Höfer, Thomas; Achter, Viktor; Lang, Ulrich; Theissen, Jessica; Volland, Ruth; Saadati, Maral; Eggert, Angelika; de Wilde, Bram; Berthold, Frank; Peng, Zhiyu; Zhao, Chen; Shi, Leming; Ortmann, Monika; Büttner, Reinhard; Perner, Sven; Hero, Barbara; Schramm, Alexander; Schulte, Johannes H.; Herrmann, Carl; O’Sullivan, Roderick J.; Westermann, Frank; Thomas, Roman K.; Fischer, Matthias

2016-01-01

Neuroblastoma is a malignant paediatric tumour of the sympathetic nervous system1. Roughly half of these tumours regress spontaneously or are cured by limited therapy. By contrast, high-risk neuroblastomas have an unfavourable clinical course despite intensive multimodal treatment, and their molecular basis has remained largely elusive2–4. Here we have performed whole-genome sequencing of 56 neuroblastomas (high-risk, n = 39; low-risk, n = 17) and discovered recurrent genomic rearrangements affecting a chromosomal region at 5p15.33 proximal of the telomerase reverse transcriptase gene (TERT). These rearrangements occurred only in high-risk neuroblastomas (12/39, 31%) in a mutually exclusive fashion with MYCN amplifications and ATRX mutations, which are known genetic events in this tumour type1,2,5. In an extended case series (n = 217), TERT rearrangements defined a subgroup of high-risk tumours with particularly poor outcome. Despite a large structural diversity of these rearrangements, they all induced massive transcriptional upregulation of TERT. In the remaining high-risk tumours, TERT expression was also elevated in MYCN-amplified tumours, whereas alternative lengthening of telomeres was present in neuroblastomas without TERT or MYCN alterations, suggesting that telomere lengthening represents a central mechanism defining this subtype. The 5p15.33 rearrangements juxtapose the TERT coding sequence to strong enhancer elements, resulting in massive chromatin remodelling and DNA methylation of the affected region. Supporting a functional role of TERT, neuroblastoma cell lines bearing rearrangements or amplified MYCN exhibited both upregulated TERT expression and enzymatic telomerase activity. In summary, our findings show that remodelling of the genomic context abrogates transcriptional silencing of TERT in high-risk neuroblastoma and places telomerase activation in the centre of transformation in a large fraction of these tumours. PMID:26466568

Inhibition of Neuroblastoma Tumor Growth by Ketogenic Diet and/or Calorie Restriction in a CD1-Nu Mouse Model.

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Raphael Johannes Morscher

Full Text Available Neuroblastoma is a malignant pediatric cancer derived from neural crest cells. It is characterized by a generalized reduction of mitochondrial oxidative phosphorylation. The goal of the present study was to investigate the effects of calorie restriction and ketogenic diet on neuroblastoma tumor growth and monitor potential adaptive mechanisms of the cancer's oxidative phosphorylation system.Xenografts were established in CD-1 nude mice by subcutaneous injection of two neuroblastoma cell lines having distinct genetic characteristics and therapeutic sensitivity [SH-SY5Y and SK-N-BE(2]. Mice were randomized to four treatment groups receiving standard diet, calorie-restricted standard diet, long chain fatty acid based ketogenic diet or calorie-restricted ketogenic diet. Tumor growth, survival, metabolic parameters and weight of the mice were monitored. Cancer tissue was evaluated for diet-induced changes of proliferation indices and multiple oxidative phosphorylation system parameters (respiratory chain enzyme activities, western blot analysis, immunohistochemistry and mitochondrial DNA content.Ketogenic diet and/or calorie restriction significantly reduced tumor growth and prolonged survival in the xenograft model. Neuroblastoma growth reduction correlated with decreased blood glucose concentrations and was characterized by a significant decrease in Ki-67 and phospho-histone H3 levels in the diet groups with low tumor growth. As in human tumor tissue, neuroblastoma xenografts showed distinctly low mitochondrial complex II activity in combination with a generalized low level of mitochondrial oxidative phosphorylation, validating the tumor model. Neuroblastoma showed no ability to adapt its mitochondrial oxidative phosphorylation activity to the change in nutrient supply induced by dietary intervention.Our data suggest that targeting the metabolic characteristics of neuroblastoma could open a new front in supporting standard therapy regimens

Inhibition of Neuroblastoma Tumor Growth by Ketogenic Diet and/or Calorie Restriction in a CD1-Nu Mouse Model.

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Morscher, Raphael Johannes; Aminzadeh-Gohari, Sepideh; Feichtinger, René Gunther; Mayr, Johannes Adalbert; Lang, Roland; Neureiter, Daniel; Sperl, Wolfgang; Kofler, Barbara

2015-01-01

Neuroblastoma is a malignant pediatric cancer derived from neural crest cells. It is characterized by a generalized reduction of mitochondrial oxidative phosphorylation. The goal of the present study was to investigate the effects of calorie restriction and ketogenic diet on neuroblastoma tumor growth and monitor potential adaptive mechanisms of the cancer's oxidative phosphorylation system. Xenografts were established in CD-1 nude mice by subcutaneous injection of two neuroblastoma cell lines having distinct genetic characteristics and therapeutic sensitivity [SH-SY5Y and SK-N-BE(2)]. Mice were randomized to four treatment groups receiving standard diet, calorie-restricted standard diet, long chain fatty acid based ketogenic diet or calorie-restricted ketogenic diet. Tumor growth, survival, metabolic parameters and weight of the mice were monitored. Cancer tissue was evaluated for diet-induced changes of proliferation indices and multiple oxidative phosphorylation system parameters (respiratory chain enzyme activities, western blot analysis, immunohistochemistry and mitochondrial DNA content). Ketogenic diet and/or calorie restriction significantly reduced tumor growth and prolonged survival in the xenograft model. Neuroblastoma growth reduction correlated with decreased blood glucose concentrations and was characterized by a significant decrease in Ki-67 and phospho-histone H3 levels in the diet groups with low tumor growth. As in human tumor tissue, neuroblastoma xenografts showed distinctly low mitochondrial complex II activity in combination with a generalized low level of mitochondrial oxidative phosphorylation, validating the tumor model. Neuroblastoma showed no ability to adapt its mitochondrial oxidative phosphorylation activity to the change in nutrient supply induced by dietary intervention. Our data suggest that targeting the metabolic characteristics of neuroblastoma could open a new front in supporting standard therapy regimens. Therefore, we propose

Cyclin-Dependent Kinase Inhibitor AT7519 as a Potential Drug for MYCN-Dependent Neuroblastoma.

Science.gov (United States)

Dolman, M Emmy M; Poon, Evon; Ebus, Marli E; den Hartog, Ilona J M; van Noesel, Carel J M; Jamin, Yann; Hallsworth, Albert; Robinson, Simon P; Petrie, Kevin; Sparidans, Rolf W; Kok, Robbert J; Versteeg, Rogier; Caron, Huib N; Chesler, Louis; Molenaar, Jan J

2015-11-15

MYCN-dependent neuroblastomas have low cure rates with current multimodal treatment regimens and novel therapeutic drugs are therefore urgently needed. In previous preclinical studies, we have shown that targeted inhibition of cyclin-dependent kinase 2 (CDK2) resulted in specific killing of MYCN-amplified neuroblastoma cells. This study describes the in vivo preclinical evaluation of the CDK inhibitor AT7519. Preclinical drug testing was performed using a panel of MYCN-amplified and MYCN single copy neuroblastoma cell lines and different MYCN-dependent mouse models of neuroblastoma. AT7519 killed MYCN-amplified neuroblastoma cell lines more potently than MYCN single copy cell lines with a median LC50 value of 1.7 compared to 8.1 μmol/L (P = 0.0053) and a significantly stronger induction of apoptosis. Preclinical studies in female NMRI homozygous (nu/nu) mice with neuroblastoma patient-derived MYCN-amplified AMC711T xenografts revealed dose-dependent growth inhibition, which correlated with intratumoral AT7519 levels. CDK2 target inhibition by AT7519 was confirmed by significant reductions in levels of phosphorylated retinoblastoma (p-Rb) and nucleophosmin (p-NPM). AT7519 treatment of Th-MYCN transgenic mice resulted in improved survival and clinically significant tumor regression (average tumor size reduction of 86% at day 7 after treatment initiation). The improved efficacy of AT7519 observed in Th-MYCN mice correlated with higher tumor exposure to the drug. This study strongly suggests that AT7519 is a promising drug for the treatment of high-risk neuroblastoma patients with MYCN amplification. ©2015 American Association for Cancer Research.

A Model for Spheroid versus Monolayer Response of SK-N-SH Neuroblastoma Cells to Treatment with 15-Deoxy-PGJ2

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Dorothy I. Wallace

2016-01-01

Full Text Available Researchers have observed that response of tumor cells to treatment varies depending on whether the cells are grown in monolayer, as in vitro spheroids or in vivo. This study uses data from the literature on monolayer treatment of SK-N-SH neuroblastoma cells with 15-deoxy-PGJ2 and couples it with data on growth rates for untreated SK-N-SH neuroblastoma cells grown as multicellular spheroids. A linear model is constructed for untreated and treated monolayer data sets, which is tuned to growth, death, and cell cycle data for the monolayer case for both control and treatment with 15-deoxy-PGJ2. The monolayer model is extended to a five-dimensional nonlinear model of in vitro tumor spheroid growth and treatment that includes compartments of the cell cycle (G1,S,G2/M as well as quiescent (Q and necrotic (N cells. Monolayer treatment data for 15-deoxy-PGJ2 is used to derive a prediction of spheroid response under similar treatments. For short periods of treatment, spheroid response is less pronounced than monolayer response. The simulations suggest that the difference in response to treatment of monolayer versus spheroid cultures observed in laboratory studies is a natural consequence of tumor spheroid physiology rather than any special resistance to treatment.

The ALK inhibitor PF-06463922 is effective as a single agent in neuroblastoma driven by expression of ALK and MYCN

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J. Guan

2016-09-01

Full Text Available The first-in-class inhibitor of ALK, c-MET and ROS1, crizotinib (Xalkori, has shown remarkable clinical efficacy in treatment of ALK-positive non-small cell lung cancer. However, in neuroblastoma, activating mutations in the ALK kinase domain are typically refractory to crizotinib treatment, highlighting the need for more potent inhibitors. The next-generation ALK inhibitor PF-06463922 is predicted to exhibit increased affinity for ALK mutants prevalent in neuroblastoma. We examined PF-06463922 activity in ALK-driven neuroblastoma models in vitro and in vivo. In vitro kinase assays and cell-based experiments examining ALK mutations of increasing potency show that PF-06463922 is an effective inhibitor of ALK with greater activity towards ALK neuroblastoma mutants. In contrast to crizotinib, single agent administration of PF-06463922 caused dramatic tumor inhibition in both subcutaneous and orthotopic xenografts as well as a mouse model of high-risk neuroblastoma driven by Th-ALKF1174L/MYCN. Taken together, our results suggest PF-06463922 is a potent inhibitor of crizotinib-resistant ALK mutations, and highlights an important new treatment option for neuroblastoma patients.

Therapeutically targeting glypican-2 via single-domain antibody-based chimeric antigen receptors and immunotoxins in neuroblastoma.

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Li, Nan; Fu, Haiying; Hewitt, Stephen M; Dimitrov, Dimiter S; Ho, Mitchell

2017-08-08

Neuroblastoma is a childhood cancer that is fatal in almost half of patients despite intense multimodality treatment. This cancer is derived from neuroendocrine tissue located in the sympathetic nervous system. Glypican-2 (GPC2) is a cell surface heparan sulfate proteoglycan that is important for neuronal cell adhesion and neurite outgrowth. In this study, we find that GPC2 protein is highly expressed in about half of neuroblastoma cases and that high GPC2 expression correlates with poor overall survival compared with patients with low GPC2 expression. We demonstrate that silencing of GPC2 by CRISPR-Cas9 or siRNA results in the inhibition of neuroblastoma tumor cell growth. GPC2 silencing inactivates Wnt/β-catenin signaling and reduces the expression of the target gene N-Myc, an oncogenic driver of neuroblastoma tumorigenesis. We have isolated human single-domain antibodies specific for GPC2 by phage display technology and found that the single-domain antibodies can inhibit active β-catenin signaling by disrupting the interaction of GPC2 and Wnt3a. To explore GPC2 as a potential target in neuroblastoma, we have developed two forms of antibody therapeutics, immunotoxins and chimeric antigen receptor (CAR) T cells. Immunotoxin treatment was demonstrated to inhibit neuroblastoma growth in mice. CAR T cells targeting GPC2 eliminated tumors in a disseminated neuroblastoma mouse model where tumor metastasis had spread to multiple clinically relevant sites, including spine, skull, legs, and pelvis. This study suggests GPC2 as a promising therapeutic target in neuroblastoma.

Surgical outcome analysis of paediatric thoracic and cervical neuroblastoma.

Science.gov (United States)

Parikh, Dakshesh; Short, Melissa; Eshmawy, Mohamed; Brown, Rachel

2012-03-01

To identify factors determining the surgical outcome of primary cervical and thoracic neuroblastoma. Twenty-six children with primary thoracic neuroblastoma presented over the last 14 years were analysed for age, mode of presentation, tumour histopathology, biology and outcome. Primary thoracic neuroblastoma was presented in 16 boys and 10 girls at a median age of 2 years (range 6 weeks-15 years). The International Neuroblastoma Staging System (INSS) classified these as Stage 1 (8), Stage 2 (5), Stage 3 (6) and Stage 4 (7). Computed tomography defined the tumour location at the thoracic inlet (11), cervical (2), cervico-thoracic (3), mid-thorax (9) and thoraco-abdominal (1). Twenty-two children underwent surgery that allowed an adequate exposure and resection. Surgical resection was achieved after initial biopsy and preoperative chemotherapy in 15 children, whereas primary resection was performed in 7 children. Four patients with Stage 4 disease underwent chemotherapy alone after initial biopsy; of which, two died despite chemotherapy. Favourable outcome after surgical resection and long-term survival was seen in 19 (86.4%) of the 22 children. Three had local recurrence (14 to 21 months postoperatively), all with unfavourable histology on initial biopsy. The prognostic factors that determined the outcome were age and INSS stage at presentation. In this series, all patients under 2 years of age are still alive, while mortality was seen in five older children. Thoracic neuroblastoma in children under 2 years of age irrespective of stage and histology of the tumour results in long-term survival.

Stage 4S neuroblastoma, a disseminated tumor with excellent outcome

International Nuclear Information System (INIS)

Elimam, Najla A.; Atra, Ayad A.; Fayea, Najwa Y.; Al-Asaad, Tareq G.; Khattab, Taha M.; Al-Sulami, Ganadeel A.; Felimban, Sami K.

2006-01-01

To review the clinical features and outcome of all cases of stage 4S neuroblastoma treated at our center. We retrospectively reviewed the files of all patients (n=75) with neuroblastoma treated at King Abdul-Aziz Medical City, Jeddah, Kingdom of Saudi Arabia between 1986 and 2005. We studied the clinical features and outcome of patients with stage 4S neuroblastoma. Six patients (8%) were confirmed to have stage 4S neuroblastoma. Three were boys with a median age at diagnosis of 4.5 months (range 28 days-11 moths). Four patients required no intervention. The remaining 2 patients were treated chemotherapy due to progressive hepatomegaly and respiratory distress. No patient required radiotherapy or surgical intervention. With a median follow up of four years (range 9 months --- 15.5 years), all patients are alive and well. Two patients continue to have a residual abdominal mass, while complete resolution occurred in the others. Stage 4S neuroblastoma is special tumor that carries excellent prognosis. Spontaneous regression may occur and intervention is only required in symptomatic patients. (author)

Cell Proliferation in Neuroblastoma

Science.gov (United States)

Stafman, Laura L.; Beierle, Elizabeth A.

2016-01-01

Neuroblastoma, the most common extracranial solid tumor of childhood, continues to carry a dismal prognosis for children diagnosed with advanced stage or relapsed disease. This review focuses upon factors responsible for cell proliferation in neuroblastoma including transcription factors, kinases, and regulators of the cell cycle. Novel therapeutic strategies directed toward these targets in neuroblastoma are discussed. PMID:26771642

Neuroblastoma and MYCN

Science.gov (United States)

Huang, Miller; Weiss, William A.

2013-01-01

Neuroblastoma, the most common extracranial solid tumor of childhood, is thought to originate from undifferentiated neural crest cells. Amplification of the MYC family member, MYCN, is found in ∼25% of cases and correlates with high-risk disease and poor prognosis. Currently, amplification of MYCN remains the best-characterized genetic marker of risk in neuroblastoma. This article reviews roles for MYCN in neuroblastoma and highlights recent identification of other driver mutations. Strategies to target MYCN at the level of protein stability and transcription are also reviewed. PMID:24086065

Omega-3 fatty acid supplementation delays the progression of neuroblastoma in vivo.

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Gleissman, Helena; Segerström, Lova; Hamberg, Mats; Ponthan, Frida; Lindskog, Magnus; Johnsen, John Inge; Kogner, Per

2011-04-01

Epidemiological and preclinical studies have revealed that omega-3 fatty acids have anticancer properties. We have previously shown that the omega-3 fatty acid docosahexaenoic acid (DHA) induces apoptosis of neuroblastoma cells in vitro by mechanisms involving intracellular peroxidation of DHA by means of 15-lipoxygenase or autoxidation. In our study, the effects of DHA supplementation on neuroblastoma tumor growth in vivo were investigated using two complementary approaches. For the purpose of prevention, DHA as a dietary supplement was fed to athymic rats before the rats were xenografted with human neuroblastoma cells. For therapeutic purposes, athymic rats with established neuroblastoma xenografts were given DHA daily by gavage and tumor growth was monitored. DHA levels in plasma and tumor tissue were analyzed by gas liquid chromatography. DHA delayed neuroblastoma xenograft development and inhibited the growth of established neuroblastoma xenografts in athymic rats. A revised version of the Pediatric Preclinical Testing Program evaluation scheme used as a measurement of treatment response showed that untreated control animals developed progressive disease, whereas treatment with DHA resulted in stable disease or partial response, depending on the DHA concentration. In conclusion, prophylactic treatment with DHA delayed neuroblastoma development, suggesting that DHA could be a potential agent in the treatment of minimal residual disease and should be considered for prevention in selected cases. Treatment results on established aggressive neuroblastoma tumors suggest further studies aiming at a clinical application in children with high-risk neuroblastoma. Copyright © 2010 UICC.

Neuroblastoma

International Nuclear Information System (INIS)

Hall-Craggs, M.A.; Finn, J.P.; Dicks-Mireaux, C.; Kiely, E.M.; Pritchard, J.

1989-01-01

Twenty-one children with neuroblastoma (mean age, 36.7 months) were examined with high-field strength (1.5 T) MR imaging to define how accurately disease could be documented and to establish optimum sequences. Twenty-eight studies were obtained with T1- and T2-weighted spin-echo and short inversion-recovery (STIR) sequences. Thirteen children underwent surgery, 16 CT. MR imaging exactly predicted tumor extent and involvement of adjacent organs, vessels, and the spine in all patients undergoing surgery. STIR images defined tumor margins and node involvement most clearly. Following chemotherapy, MR imaging could not differentiate active tumor from maturing ganglioneuroma or residual hyperplasia. MR imaging was superior to CT in assessing intraabdominal, marrow, and spinal disease

Imaging evaluation of infants with neuroblastoma detected by VMA screening spot test

International Nuclear Information System (INIS)

Fujioka, M.; Saiki, N.; Aihara, T.; Yamamoto, K.

1988-01-01

In the Saitama Prefecture in Japan, VMA (vanillyl manderic acid) screening spot test for detection of neuroblastoma has been performed in 173,046 infants in the years 1981-1986 and 15 infants were found to have neuroblastoma. Two infants had mediastinal tumors and the remainder, 13, had intraabdominal tumors. Only 7 infants had palpable masses. Although CT was documented to be the best imaging procedure to provide sufficient information for treatment, conventional radiographic examinations of the chest and abdomen, and abdominal ultrasonography were able, as initial imaging procedures, to detect reasonably small neuroblastomas in infants with a positive VMA screening test. (orig.)

Meta-iodobenzylguanidine scintigraphy in neuroblastoma--a comparison with conventional X-ray and ultrasound

International Nuclear Information System (INIS)

Mueller-Gaertner, H.W.Er.; Erttmann, R.; Helmke, K.

1986-01-01

To evaluate the accuracy of meta-iodobenzylguanidine (MIBG) imaging in comparison with bone X-ray and ultrasound, 15 patients with histologically verified neuroblastoma were investigated using 123- or 131MIBG scintigraphy. 123MIBG and 131MIBG are used as the abbreviations for 123-iodine-labeled-MIBG and 131-iodine-labeled-MIBG, respectively. Either 7.4 MBq 131MIBG (n = 4) or 111-185 MBq 123MIBG (n = 11) was applied, and scans were performed 24 and 48 h PI. Anatomical orientation was provided in selected cases by single-photon emission CT or scintigraphy of other organs. X-ray procedures or ultrasound depicted 27 neuroblastoma manifestations (primary tumors and metastatic deposits); 24 of these (89%) were identified by MIBG scintigraphy. Of 42 primary neuroblastomas and metastatic deposits, 27 (64%) were detected by corresponding bone X-ray or ultrasound. The 15 neuroblastoma lesions depicted solely by MIBG scans were mainly (80%) situated in the skeletal system. Because of the pronounced physiological MIBG uptake by liver tissue, detection of intrahepatic or perihepatic tumor involvement is difficult. MIBG scintigraphy is a safe and noninvasive means of locating a wide range of neuroblastoma lesions. Its main diagnostic advantage in comparison with bone X-ray lies in the detection of bone marrow infiltration

Olfactory Neuroblastoma: Diagnostic Difficulty

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Vidya MN,

2011-01-01

Full Text Available Olfactory neuroblastoma is an uncommon malignant tumor of sinonasal tract arising from the olfactory neuro epithelium. The olfactory neuroblastomas presenting with divergent histomorphologies like, epithelial appearance of cells, lacking a neuro fibrillary background and absence of rosettes are difficult to diagnose. Such cases require immunohistochemistry to establish the diagnosis. We describe the clinical features, pathological and immunohistochemical findings of grade IV Olfactory neuroblastoma in a 57 year old man

Chemotherapy-Induced Apoptosis in a Transgenic Model of Neuroblastoma Proceeds Through p53 Induction

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Louis Chesler

2008-11-01

Full Text Available Chemoresistance in neuroblastoma is a significant issue complicating treatment of this common pediatric solid tumor. MYCN-amplified neuroblastomas are infrequently mutated at p53 and are chemosensitive at diagnosis but acquire p53 mutations and chemoresistance with relapse. Paradoxically, Myc-driven transformation is thought to require apoptotic blockade. We used the TH-MYCN transgenic murine model to examine the role of p53-driven apoptosis on neuroblastoma tumorigenesis and the response to chemotherapy. Tumors formed with high penetrance and low latency in p53-haploinsufficient TH-MYCN mice. Cyclophosphamide (CPM induced a complete remission in p53 wild type TH-MYCN tumors, mirroring the sensitivity of childhood neuroblastoma to this agent. Treated tumors showed a prominent proliferation block, induction of p53 protein, and massive apoptosis proceeding through induction of the Bcl-2 homology domain-3-only proteins PUMA and Bim, leading to the activation of Bax and cleavage of caspase-3 and -9. Apoptosis induced by CPM was reduced in p53-haploinsufficient tumors. Treatment of MYCN-expressing human neuroblastoma cell lines with CPM induced apoptosis that was suppressible by siRNA to p53. Taken together, the results indicate that the p53 pathway plays a significant role in opposing MYCN-driven oncogenesis in a mouse model of neuroblastoma and that basal inactivation of the pathway is achieved in progressing tumors. This, in part, explains the striking sensitivity of such tumors to chemotoxic agents that induce p53-dependent apoptosis and is consistent with clinical observations that therapy-associated mutations in p53 are a likely contributor to the biology of tumors at relapse and secondarily mediate resistance to therapy.

CASE REPORT Proptosis as a manifestation of neuroblastoma ...

African Journals Online (AJOL)

in children less than 15 years of age, with 90% of all neuroblastomas occurring before ... Examination of the eyes showed a left axial, non-pulsatile proptosis with full ... robulbar enhancing masses (white arrows) with sphenoid bone involve-.

MYCN and HDAC5 transcriptionally repress CD9 to trigger invasion and metastasis in neuroblastoma.

Science.gov (United States)

Fabian, Johannes; Opitz, Desirée; Althoff, Kristina; Lodrini, Marco; Hero, Barbara; Volland, Ruth; Beckers, Anneleen; de Preter, Katleen; Decock, Anneleen; Patil, Nitin; Abba, Mohammed; Kopp-Schneider, Annette; Astrahantseff, Kathy; Wünschel, Jasmin; Pfeil, Sebastian; Ercu, Maria; Künkele, Annette; Hu, Jamie; Thole, Theresa; Schweizer, Leonille; Mechtersheimer, Gunhild; Carter, Daniel; Cheung, Belamy B; Popanda, Odilia; von Deimling, Andreas; Koster, Jan; Versteeg, Rogier; Schwab, Manfred; Marshall, Glenn M; Speleman, Frank; Erb, Ulrike; Zoeller, Margot; Allgayer, Heike; Simon, Thorsten; Fischer, Matthias; Kulozik, Andreas E; Eggert, Angelika; Witt, Olaf; Schulte, Johannes H; Deubzer, Hedwig E

2016-10-11

The systemic and resistant nature of metastatic neuroblastoma renders it largely incurable with current multimodal treatment. Clinical progression stems mainly from the increasing burden of metastatic colonization. Therapeutically inhibiting the migration-invasion-metastasis cascade would be of great benefit, but the mechanisms driving this cycle are as yet poorly understood. In-depth transcriptome analyses and ChIP-qPCR identified the cell surface glycoprotein, CD9, as a major downstream player and direct target of the recently described GRHL1 tumor suppressor. CD9 is known to block or facilitate cancer cell motility and metastasis dependent upon entity. High-level CD9 expression in primary neuroblastomas correlated with patient survival and established markers for favorable disease. Low-level CD9 expression was an independent risk factor for adverse outcome. MYCN and HDAC5 colocalized to the CD9 promoter and repressed transcription. CD9 expression diminished with progressive tumor development in the TH-MYCN transgenic mouse model for neuroblastoma, and CD9 expression in neuroblastic tumors was far below that in ganglia from wildtype mice. Primary neuroblastomas lacking MYCN amplifications displayed differential CD9 promoter methylation in methyl-CpG-binding domain sequencing analyses, and high-level methylation was associated with advanced stage disease, supporting epigenetic regulation. Inducing CD9 expression in a SH-EP cell model inhibited migration and invasion in Boyden chamber assays. Enforced CD9 expression in neuroblastoma cells transplanted onto chicken chorioallantoic membranes strongly reduced metastasis to embryonic bone marrow. Combined treatment of neuroblastoma cells with HDAC/DNA methyltransferase inhibitors synergistically induced CD9 expression despite hypoxic, metabolic or cytotoxic stress. Our results show CD9 is a critical and indirectly druggable suppressor of the invasion-metastasis cycle in neuroblastoma.

Amine functionalized nanodiamond promotes cellular adhesion, proliferation and neurite outgrowth

International Nuclear Information System (INIS)

Hopper, A P; Dugan, J M; Gill, A A; Haycock, J W; Claeyssens, F; Fox, O J L; May, P W

2014-01-01

In this study, we report the production of amine functionalized nanodiamond. The amine functionalized nanodiamond forms a conformal monolayer on a negatively charged surface produced via plasma polymerization of acrylic acid. Nanodiamond terminated surfaces were studied as substrates for neuronal cell culture. NG108-15 neuroblastoma-glyoma hybrid cells were successfully cultured upon amine functionalized nanodiamond coated surfaces for between 1 and 7 d. Additionally, primary dorsal root ganglion (DRG) neurons and Schwann cells isolated from Wistar rats were also successfully cultured over a period of 21 d illustrating the potential of the coating for applications in the treatment of peripheral nerve injury. (paper)

CT diagnosis of neuroblastoma in childhood

International Nuclear Information System (INIS)

Li Xin; Zhang Liqun; Yang Zhiyong

1997-01-01

Purpose: To evaluate CT in the diagnosis of neuroblastoma in childhood. Materials and methods: Analysis of CT manifestations in 26 cases proved by operation and pathology, including neuroblastoma 21 cases, ganglioneuroblastoma 5 cases. Thorax 7 cases (27%), adrenal gland 16 cases (62%), abdomen-pelvis paravertebral sympathetic chain 3 cases (11%). Bolus injection of contrast medium was given in all cases. Results: Adrenal gland and posterior superior mediastinum were the most common sites for neuroblastoma. 73% of neuroblastoma had calcifications. Neuroblastoma was more commonly calcified than ganglioneuroblastoma. Metastases were also calcified. Degree of enhancement was associated with the type of neuroblastoma. Tumor extension into the spinal canal was seen in 2 cases. 43% neuroblastoma of adrenal directly invaded the kidney in 7 cases. Right lobe of liver was involved in 3 cases, metastases to liver in 1 case, enlargement of lymph nodes 19 cases. Approximately 68% of patients showed increase of urinary Vanilly-mandelic acid (VMA). Preoperative diagnostic accuracy was 92%. Conclusion: CT is recognized as a useful technique for the diagnosis of neuroblastoma. The site of predilection, calcification, lymph node metastases and VMA increase in urine or serum are important basis for diagnosis

A case of neonatal neuroblastoma

International Nuclear Information System (INIS)

Nounaka, Osamu; Gotoh, Toshiaki; Takahashi, Kazuaki; Koyanagi, Tomohiko; Kakizaki, Hidehiro; Nakanishi, Shoichiro.

1987-01-01

A two-day-old male infant was referred to us for probable neuroblastoma, because of upper abdominal mass and positive urinary vanillylmandelic acid (VMA). Primary site of neuroblastoma was not found, but clinically IV-S stage neuroblastoma was strongly suspected, so 131 I-metaiodobenzylguanidine (MIBG) scan was performed. RI accumulation was found near the left adrenal region. Thus laparotomy was performed and left adrenal was resected. Liver biopsy was also performed. Microscopically multiple in situ foci of neuroblastoma cells were found in the left adrenal and tumor involvement was also seen in the liver. Skin and bone marrow metastasis were ruled out. Minimal chemotherapy was intended but abandoned soon because of possible spontaneous regression of stage IV-S neuroblastoma. Thereafter liver has been getting smaller and the patient has been doing well. Urinary VMA and homovanillic acid (HVA) per creatinine, which were used for follow-up, have also normalized after 3 months. Treatment of stage IV-S neuroblastoma and early diagnosis by 131 I-MIBG scan were reviewed. (author)

A comparison of targetting of neuroblastoma with MIBG and anti L1-CAM antibody mAb chCE7: therapeutic efficacy in a neuroblastoma xenograft model and imaging of neuroblastoma patients

International Nuclear Information System (INIS)

Hoefnagel, C.A.; Rutgers, M.; Buitenhuis, C.K.M.; Smets, L.A.; Kraker, J. de; Meli, M.; Carrel, F.; Schubiger, P.A.; Novak-Hofer, I.; Amstutz, H.

2001-01-01

Modine-131 labelled anti L1-CAM antibody mAb chCE7 was compared with the effective neuroblastoma-seeking agent 131 I-labelled metaiodobenzylguanidine (MIBG) with regard to (a) its therapeutic efficacy in treating nude mice with neuroblastoma xenografts and (b) its tumour targetting ability in neuroblastoma patients. The SK-N-SH tumour cells used in the mouse experiments show good MIBG uptake and provide a relatively low number of 6,300 binding sites/cell for mAb chCE7. Tumours were treated with single injections of 131 I-MIBG (110 MBq) and with 131 I-labelled mAb chCE7 (17 MBq) and both agents showed antitumour activity. After therapy with 131 I-chCE7, the subcutaneous tumours nearly disappeared; treatment with 131 I-MIBG was somewhat less effective, resulting in a 70% reduction in tumour volume. A calculated tumour regrowth delay of 9 days occurred with a radioactivity dose of 17 MBq of an irrelevant control antibody mAb 35, which does not bind to SK-N-SH cells, compared with a regrowth delay of 34 days with 131 I-mAb chCE7 and of 24 days with 131 I-MIBG. General toxicity appeared to be mild, as assessed by a transient, approximate 10% maximum decrease in body weight during the treatments. The superior growth inhibition achieved by 131 I-chCE7 compared with 131 I-MIBG can be explained by its prolonged retention in the tumours, due to slower normal tissue and plasma clearance. Cross-reaction of mAb chCE7 with L1-CAM present in normal human tissues was investigated by direct binding of radioiodinated mAb to frozen tissue sections. Results showed a strong reaction with normal human brain tissue and weak but detectable binding to normal adult kidney sections. Seven patients with recurrent neuroblastoma were sequentially imaged with 131 I-MIBG and 131 I-chCE7. The results underlined the heterogeneity of neuroblastoma and showed the two imaging modalities to be complementary. 131 I-chCE7 scintigraphy may have clinical utility in detecting metastases which do not

Axonal degeneration stimulates the formation of NG2+ cells and oligodendrocytes in the mouse

DEFF Research Database (Denmark)

Nielsen, Helle Hvilsted; Ladeby, Rune; Drøjdahl, Nina

2006-01-01

the response of the NG2+ cells to the different components of demyelinating pathology, we investigated the response of adult NG2+ cells to axonal degeneration in the absence of primary myelin or oligodendrocyte pathology. Axonal degeneration was induced in the hippocampal dentate gyrus of adult mice...... by transection of the entorhino-dentate perforant path projection. The acutely induced degeneration of axons and terminals resulted in a prompt response of NG2+ cells, consisting of morphological transformation, cellular proliferation, and upregulation of NG2 expression days 2-3 after surgery. This was followed...

Can Image-Defined Risk Factors Predict Surgical Complications in Localized Neuroblastoma?

Science.gov (United States)

Yoneda, Akihiro; Nishikawa, Masanori; Uehara, Shuichiro; Oue, Takaharu; Usui, Noriaki; Inoue, Masami; Fukuzawa, Masahiro; Okuyama, Hiroomi

2016-02-01

Image-defined risk factors (IDRFs) have been propounded for predicting the surgical risks associated with localized neuroblastoma (NB) since 2009. In 2011, a new guideline (NG) for assessing IDRFs was published. According to the NG, the situation in which "the tumor is only in contact with renal vessels," should be considered to be "IDRF-present." Previously, this situation was diagnosed as "IDRF absent." In this study, we evaluated the IDRFs in localized NB patients to clarify the predictive capability of IDRFs for surgical complications, as well as the usefulness of the NG. Materials and A total of 107 localized patients with NB were included in this study. The enhanced computed tomography and magnetic resonance images from the time of their diagnoses were evaluated by a single radiologist. We also analyzed the association of clinical factors, including the IDRFs (before and after applying the NG), with surgical complications. Of the 107 patients, 33 and 74 patients were diagnosed as IDRF-present (OP group), and IDRF-absent (ON group) before the NG, respectively. According to the NG, there were 76 and 31 patients who were classified as IDRF-present (NP group) and IDRF absent (NN group), respectively. Thus, 43 (40%) patients in the ON group were reassigned to the NP group after the NG. Surgical complications were observed in 17 of 82 patients who underwent surgical resection. Of the patients who underwent secondary operations, surgical complication rates were 55% in the OP group and 44% in the NP group. According to a univariate analysis, non-INSS 1, IDRFs before and after the NG and secondary operations were significantly associated with surgical complications. In a multivariate analysis, non-INSS 1 status and IDRFs after the NG were significantly associated with surgical complications. Georg Thieme Verlag KG Stuttgart · New York.

Neonatal acute megakaryoblastic leukemia mimicking congenital neuroblastoma

OpenAIRE

Kawasaki, Yukako; Makimoto, Masami; Nomura, Keiko; Hoshino, Akihiro; Hamashima, Takeru; Hiwatari, Mitsuteru; Nakazawa, Atsuko; Takita, Junko; Yoshida, Taketoshi; Kanegane, Hirokazu

2014-01-01

Key Clinical Message We describe a neonate with abdominal distension, massive hepatomegaly, and high serum neuron-specific enolase level suggestive of congenital neuroblastoma. The patient died of pulmonary hemorrhage after therapy. Autopsy revealed that the tumor cells in the liver indicated acute megakaryocytic leukemia with the RBM15-MKL1 fusion gene.

Congenital bilateral neuroblastoma (stage IV-S): case report

International Nuclear Information System (INIS)

Lee, Jeong Hee; Lee, Hee Jung; Woo, Seong Ku; Lee, Sang Rak; Kim, Heung Sik

2002-01-01

Congenital neonatal neuroblastoma is not uncommon but bilateral adrenal neuroblastoma is rare, accounting for about ten percent of neuroblastomas in children. We report the US the MR findings of a stage IV-S congenital bilateral neuroblastoma occurring in a one-day-old neonate

A Genetically Engineered Mouse Model of Neuroblastoma Driven by Mutated ALK and MYCN

Science.gov (United States)

2014-09-01

super-enhancer driven transcriptional programs in MYCN- amplified cells. George RE. Advances in Neuroblastoma Research Conference, Cologne, Germany ...crizotinib in ALK-mutated cells The above results suggested that deregulated MYCN could contribute to the sustained upregulation of mTORC1 activity in...incomplete inhibition of mTORC1 limits the activity of crizotinib in NB cells that express both ALKF1174L and deregulated MYCN. This interpretation is

Treatment of Neuroblastoma with an Engineered "Obligate" Anaerobic Salmonella typhimurium Strain YB1.

Science.gov (United States)

Ning, Bo-Tao; Yu, Bin; Chan, Shing; Chan, Jian-Liang; Huang, Jian-Dong; Chan, Godfrey Chi-Fung

2017-01-01

Purpose Neuroblastoma is an embryonic solid tumor derived from the progenitors of the sympathetic nervous system. More than half of the patients developed metastatic disease at the time of initial diagnosis and had poor outcome with current therapeutic approaches. In recent years, some obligate and facultative anaerobic bacteria were reported to target the hypoxic and necrotic region of solid tumor models and caused tumor regression. We recently successfully constructed an "obligate" anaerobic Salmonella strain YB1 that was applied in breast cancer nude mice model by us. Here, we report the application of YB1 in neuroblastoma treatment. Methods The anti-cancer effect and side-effects of YB1 was examined in both in vitro and in vivo experiment. Previous established orthotopic neuroblastoma SCID/beige murine model using SK-NLP/luciferase cell line was adopted. Results In vitro , YB1 induced apoptosis for up to 31.4% of the neuroblastoma cells under anaerobic condition, three times more than that under aerobic condition (10.9%). The expression of both Toll like Receptor 4 and 5 (TLR4 and TLR5) in cancer cells were significantly up-regulated ( p anaerobic condition. In mouse model, YB1 preferentially accumulated inside the core of the tumors, rather than in normal tissues as our previous reported. This is suggestive of the hypoxic nature of tumor core. Tumor growth was significantly retarded in YB1 treatment group ( n=6, P<0.01 ). Furthermore, there was no long-term organ damage noted in all the organs examined including heart, lung, liver, spleen and brain in the YB1 treated mice. Conclusion The genetic modified Salmonella strain YB1 is a promising anti-tumor strategy against the tumor bulk for neuroblastoma. Future study can be extended to other common cancer types to verify the relative efficacy on different neoplastic cells.

Biokinetic and therapeutic use of 131I-MIBG in nude mice hosting human neuroblastoma xenografts

International Nuclear Information System (INIS)

Laubenbacher, C.; Kriegel, H.; Moellenstaedt, S.; Senekowitsch, R.; Technische Univ. Muenchen

1988-01-01

The biological halflife of 131 I-MIBG in nude mice with xenotransplanted human neuroblastoma derived from the SK-N-SH cell line comes to 6 h. The adrenal gland and the neuroblastoma show the highest uptake of MIBG. Based on these datas it could be calculated that 185 MBq would be necessary to get 60 Gy radiation absorbed dose in the tumor. 15-20 days after injection of this activity the tumors could no longer be palpated and they remained missing over the whole observation period. 92.5 MBq weren't enough getting a stable remission. Eleven days p.i. neuroblastoma started growing again. For the first time it could be shown that only high activity of 131 I-MIBG is able to restrain neuroblastoma totally. (orig.)

24 CFR 108.25 - Compliance meeting.

Science.gov (United States)

2010-04-01

... 24 Housing and Urban Development 1 2010-04-01 2010-04-01 false Compliance meeting. 108.25 Section... COMPLIANCE PROCEDURES FOR AFFIRMATIVE FAIR HOUSING MARKETING § 108.25 Compliance meeting. (a) Scheduling meeting. If an applicant fails to comply with requirements under § 108.15 or § 108.20 or it appears that...

Mdm2 Deficiency Suppresses MYCN-Driven Neuroblastoma Tumorigenesis In Vivo

Directory of Open Access Journals (Sweden)

Zaowen Chen

2009-08-01

Full Text Available Neuroblastoma is derived from neural crest precursor components of the peripheral sympathetic nervous system and accounts for more than 15% of all pediatric cancer deaths. A clearer understanding of the molecular basis of neuroblastoma is required for novel therapeutic approaches to improve morbidity and mortality. Neuroblastoma is uniformly p53 wild type at diagnosis and must overcome p53-mediated tumor suppression during pathogenesis. Amplification of the MYCN oncogene correlates with the most clinically aggressive form of the cancer, and MDM2, a primary inhibitor of the p53 tumor suppressor, is a direct transcriptional target of, and positively regulated by, both MYCN and MYCC. We hypothesize that MDM2 contributes to MYCN-driven tumorigenesis helping to ameliorate p53-dependent apoptotic oncogenic stress during tumor initiation and progression. To study the interaction of MYCN and MDM2, we generated an Mdm2 haploinsufficient transgenic animal model of neuroblastoma. In Mdm2+/-MYCN transgenics, tumor latency and animal survival are remarkably extended, whereas tumor incidence and growth are reduced. Analysis of the Mdm2/p53 pathway reveals remarkable p53 stabilization counterbalanced by epigenetic silencing of the p19Arf gene in the Mdm2 haploinsufficient tumors. In human neuroblastoma xenograft models, conditional small interfering RNA-mediated knockdown of MDM2 in cells expressing wild-type p53 dramatically suppresses tumor growth in a p53-dependent manner. In summary, we provided evidence for a crucial role for direct inhibition of p53 by MDM2 and suppression of the p19ARF/p53 axis in neuroblastoma tumorigenesis, supporting the development of therapies targeting these pathways.

Advances in the translational genomics of neuroblastoma

Science.gov (United States)

Bosse, Kristopher R.; Maris, John M.

2015-01-01

Neuroblastoma is an embryonal malignancy that commonly affects young children and is remarkably heterogenous in its malignant potential. Recently, the genetic basis of neuroblastoma has come into focus, which has catalyzed not only a more comprehensive understanding of neuroblastoma tumorigenesis, but has also revealed novel oncogenic vulnerabilities that are being leveraged therapeutically. Neuroblastoma is a model pediatric solid tumor in its use of recurrent genomic alterations, such as high-level MYCN amplification, for risk stratification. Given the relative paucity of recurrent activating somatic point mutations or gene fusions in primary neuroblastoma tumors studied at initial diagnosis, innovative treatment approaches beyond small molecules targeting mutated or dysregulated kinases will be required moving forward to achieve noticeable improvements in overall patient survival. However, the clonally acquired, oncogenic aberrations in relapsed neuroblastomas are currently being defined and may offer an opportunity to improve patient outcomes with molecularly targeted therapy directed towards aberrantly regulated pathways in relapsed disease. This review will summarize the current state of knowledge of neuroblastoma genetics and genomics, highlighting the improved prognostication and potential therapeutic opportunities that have arisen from recent advances in understanding germline predisposition, recurrent segmental chromosomal alterations, somatic point mutations and translocations, and clonal evolution in relapsed neuroblastoma. PMID:26539795

A protein in neuroblastoma could be a target of immunotoxins or immunotherapy | Center for Cancer Research

Science.gov (United States)

A cell surface protein, glycoprotein glypican-2 (GPC2), has been found to be an effective therapeutic target in cell cultures and mouse models that mimic childhood neuroblastoma.  The CCR scientists who made this discovery, reported July 24, 2017, in PNAS, have also produced immunotoxins and chimeric antigen receptor (CAR) T cells, a type of immunotherapy, that have shown

Assessment of MYCN amplification status in Tunisian neuroblastoma: CISH and MLPA combining approach.

Science.gov (United States)

H'Mida Ben Brahim, Dorra; Trabelsi, Saoussen; Chabchoub, Imen; Gargouri, Inesse; Harrabi, Imed; Moussa, Adnene; Chourabi, Maroua; Haddaji, Marwa; Sassi, Sihem; Mougou, Soumaya; Gribaa, Moez; Ben Ahmed, Slim; Zakhama, Abdelfattah; Nouri, Abdellatif; Saad, Ali

2015-01-01

Neuroblastoma (NB) shows a complex combination of genetic aberrations. Some of them represent poor genetic prognosis factors that require specific and intensive chemotherapy. MYCN amplification consists of the major bad outcome prognostic factor, it is indeed frequently observed in aggressive neuroblastomas. To date different methods are used for MYCN status detection. The primary aim of our study was to provide a critical assessment of MYCN status using 2 molecular techniques CISH and MLPA. We also focused on the correlation between neuroblastoma genetic markers and patient's clinical course among 15 Tunisian patients. we developed a descriptive study that includes 15 pediatric Tunisian patients referred to our laboratory from 2004 to 2011. We reported the analysis of fresh and FFPE NB tumors tissues. No significant correlation was found between COG grade and patients overall survival. Assessment of NMYC gene copy number by kappa statistic test revealed high concordance between CISH and MLPA tests (kappa coefficient = 0.02). Despite misdiagnosing of MYCN status fewer than 5 copies, MLPA remains an effective molecular technique that enables a large panel of genomic aberrations screening. Thus combining CISH and MLPA is an effective molecular approach adopted in our laboratory. Our results allow pediatric oncologists to set up the first Neuroblastoma therapeutic strategy based on molecular markers in Tunisia.

Conditional Expression of Human 15-Lipoxygenase-1 in Mouse Prostate Induces Prostatic Intraepithelial Neoplasia: The FLiMP Mouse Model

Directory of Open Access Journals (Sweden)

Uddhav P. Kelavkar

2006-06-01

Full Text Available The incidence and mortality of prostate cancer (PCa vary greatly in different geographic regions, for which lifestyle factors, such as dietary fat intake, have been implicated. Human 15-lipoxygenase-1 (h15-LO-1, which metabolizes polyunsaturated fatty acids, is a highly regulated, tissue-specific, lipid-peroxidating enzyme that functions in physiological membrane remodeling and in the pathogenesis of atherosclerosis, inflammation, and carcinogenesis. We have shown that aberrant overexpression of 15-LO-1 occurs in human PCa, particularly high-grade PCa, and in high-grade prostatic intraepithelial neoplasia (HGPIN, and that the murine orthologue is increased in SV40-based genetically engineered mouse (GEM models of PCa, such as LADY and TRansgenic Adenocarcinoma of Mouse Prostate. To further define the role of 15-LO-1 in prostate carcinogenesis, we established a novel GEM model with targeted overexpression of h15-LO-1 in the prostate [human fifteen lipoxygenase-1 in mouse prostate (FLiMP]. We used a Cre- mediated and a loxP-mediated recombination strategy to target h15-LO-1 specifically to the prostate of C57BL/6 mice. Wild-type (wt, FLiMP+/-, and FLiMP+/+ mice aged 7 to 21, 24 to 28, and 35 weeks were characterized by histopathology, immunohistochemistry (IHC, and DNA/RNA and enzyme analyses. Compared to wt mice, h15-LO-1 enzyme activity was increased similarly in both homozygous FLiMP+/+ and hemizygous FLiMP+/- prostates. Dorsolateral and ventral prostates of FLiMP mice showed focal and progressive epithelial hyperplasia with nuclear atypia, indicative of the definition of mouse prostatic intraepithelial neoplasia (mPIN according to the National Cancer Institute. These foci showed increased proliferation by Ki-67 IHC. No progression to invasive PCa was noted up to 35 weeks. By IHC, h15-LO-1 expression was limited to luminal epithelial cells, with increased expression in mPIN foci (similar to human HGPIN. In summary, targeted overexpression of h

Cystic neuroblastoma: a case report

International Nuclear Information System (INIS)

Duran, A.; Lorente, M.L.; Fernandez, C.

1997-01-01

Neuroblastoma is the most common neonatal malignant tumor. Hemorrhage and necrosis are usual features of this lesion, but it rarely presents a totally cyst form. We report a case of cystic neuroblastoma detected on prenatal ultrasound and stress the need to include it in the differential diagnosis of cystic abdominal masses in the newborn. Ultrasound is the method of choice for assessing abdominal masses in children. However, magnetic resonance has been shown to be more advantageous for the study and follow-up of neuroblastomas. (Author) 16 refs

MEIS homeobox genes in neuroblastoma

NARCIS (Netherlands)

Geerts, Dirk; Revet, Ingrid; Jorritsma, Gerda; Schilderink, Nathalie; Versteeg, Rogier

2005-01-01

The common pediatric tumor neuroblastoma originates from primitive neural crest-derived precursor cells of the peripheral nervous system. Neuroblastoma especially affects very young children, and can already be present at birth. Its early onset and cellular origin predict the involvement of

Binimetinib inhibits MEK and is effective against neuroblastoma tumor cells with low NF1 expression

International Nuclear Information System (INIS)

Woodfield, Sarah E.; Zhang, Linna; Scorsone, Kathleen A.; Liu, Yin; Zage, Peter E.

2016-01-01

Novel therapies are needed for children with high-risk and relapsed neuroblastoma. We hypothesized that MAPK/ERK kinase (MEK) inhibition with the novel MEK1/2 inhibitor binimetinib would be effective in neuroblastoma preclinical models. Levels of total and phosphorylated MEK and extracellular signal-regulated kinase (ERK) were examined in primary neuroblastoma tumor samples and in neuroblastoma cell lines by Western blot. A panel of established neuroblastoma tumor cell lines was treated with increasing concentrations of binimetinib, and their viability was determined using MTT assays. Western blot analyses were performed to examine changes in total and phosphorylated MEK and ERK and to measure apoptosis in neuroblastoma tumor cells after binimetinib treatment. NF1 protein levels in neuroblastoma cell lines were determined using Western blot assays. Gene expression of NF1 and MEK1 was examined in relationship to neuroblastoma patient outcomes. Both primary neuroblastoma tumor samples and cell lines showed detectable levels of total and phosphorylated MEK and ERK. IC 50 values for cells sensitive to binimetinib ranged from 8 nM to 1.16 μM, while resistant cells did not demonstrate any significant reduction in cell viability with doses exceeding 15 μM. Sensitive cells showed higher endogenous expression of phosphorylated MEK and ERK. Gene expression of NF1, but not MEK1, correlated with patient outcomes in neuroblastoma, and NF1 protein expression also correlated with responses to binimetinib. Neuroblastoma tumor cells show a range of sensitivities to the novel MEK inhibitor binimetinib. In response to binimetinib, sensitive cells demonstrated complete loss of phosphorylated ERK, while resistant cells demonstrated either incomplete loss of ERK phosphorylation or minimal effects on MEK phosphorylation, suggesting alternative mechanisms of resistance. NF1 protein expression correlated with responses to binimetinib, supporting the use of NF1 as a biomarker to identify

MicroRNA-34a is a potent tumor suppressor molecule in vivo in neuroblastoma.

LENUS (Irish Health Repository)

Tivnan, Amanda

2011-01-01

Neuroblastoma is a paediatric cancer which originates from precursor cells of the sympathetic nervous system and accounts for 15% of childhood cancer mortalities. With regards to the role of miRNAs in neuroblastoma, miR-34a, mapping to a chromosome 1p36 region that is commonly deleted, has been found to act as a tumor suppressor through targeting of numerous genes associated with cell proliferation and apoptosis.

Treatment of Neuroblastoma with an Engineered “Obligate” Anaerobic Salmonella typhimurium Strain YB1

Science.gov (United States)

Ning, Bo-Tao; Yu, Bin; Chan, Shing; Chan, Jian-liang; Huang, Jian-Dong; Chan, Godfrey Chi-Fung

2017-01-01

Purpose Neuroblastoma is an embryonic solid tumor derived from the progenitors of the sympathetic nervous system. More than half of the patients developed metastatic disease at the time of initial diagnosis and had poor outcome with current therapeutic approaches. In recent years, some obligate and facultative anaerobic bacteria were reported to target the hypoxic and necrotic region of solid tumor models and caused tumor regression. We recently successfully constructed an “obligate” anaerobic Salmonella strain YB1 that was applied in breast cancer nude mice model by us. Here, we report the application of YB1 in neuroblastoma treatment. Methods The anti-cancer effect and side-effects of YB1 was examined in both in vitro and in vivo experiment. Previous established orthotopic neuroblastoma SCID/beige murine model using SK-NLP/luciferase cell line was adopted. Results In vitro, YB1 induced apoptosis for up to 31.4% of the neuroblastoma cells under anaerobic condition, three times more than that under aerobic condition (10.9%). The expression of both Toll like Receptor 4 and 5 (TLR4 and TLR5) in cancer cells were significantly up-regulated (panaerobic condition. In mouse model, YB1 preferentially accumulated inside the core of the tumors, rather than in normal tissues as our previous reported. This is suggestive of the hypoxic nature of tumor core. Tumor growth was significantly retarded in YB1 treatment group (n=6, P<0.01). Furthermore, there was no long-term organ damage noted in all the organs examined including heart, lung, liver, spleen and brain in the YB1 treated mice. Conclusion The genetic modified Salmonella strain YB1 is a promising anti-tumor strategy against the tumor bulk for neuroblastoma. Future study can be extended to other common cancer types to verify the relative efficacy on different neoplastic cells. PMID:28775780

Assessment of plasminogen synthesis in vitro by mouse tumor cells using a competition radioimmunoassay for mouse plasminogen

International Nuclear Information System (INIS)

Roblin, R.O.; Bell, T.E.; Young, P.L.

1978-01-01

A sensitive, specific competition radioimmunoassay for mouse plasmin(ogen) has been developed in order to determine whether mouse tumor cells can synthesize plasminogen in vitro. The rabbit anti-BALB/c mouse plasminogen antibodies used in the assay react with the plasminogen present in serum from BALB/c, C3H, AKR and C57BL/6 mice, and also recognized mouse plasmin. The competition radiommunoassay can detect as little as 50 ng of mouse plasminogen. No competition was observed with preparations of fetal calf, human and rabbit plasminogens. A variety of virus-transformed and mouse tumor cell lines were all found to contain less than 100 ng mouse plasminogen/mg of cell extract protein. Thus, if the plasminogen activator/plasmin system is important in the growth or movement of this group of tumor cells, the cells will be dependent upon the circulatory system of the host for their plasminogen supply. (Auth.)

Neuroblastoma: biology, prognosis, and treatment

NARCIS (Netherlands)

Park, Julie R.; Eggert, Angelika; Caron, Huib

2010-01-01

Neuroblastoma, a neoplasm of the sympathetic nervous system, is the second most common extracranial malignant tumor of childhood and the most common solid tumor of infancy. Neuroblastoma is a heterogeneous malignancy with prognosis ranging from near uniform survival to high risk for fatal demise.

Neuroblastoma: biology, prognosis, and treatment

NARCIS (Netherlands)

Park, Julie R.; Eggert, Angelika; Caron, Huib

2008-01-01

Neuroblastoma, a neoplasm of the sympathetic nervous system, is the second most common extracranial malignant tumor of childhood and the most common solid tumor of infancy. Neuroblastoma is a heterogeneous malignancy with prognosis ranging from near uniform survival to high risk for fatal demise.

Radiation-Guided Peptide Delivery in a Mouse Model of Nasopharyngeal Carcinoma

Directory of Open Access Journals (Sweden)

Pei-cheng Lin

2016-01-01

Full Text Available Purpose. This study aimed to evaluate the characteristics of the HVGGSSV peptide, exploring radiation-guided delivery in a mouse model of nasopharyngeal carcinoma. Methods. Mice with CNE-1 nasopharyngeal carcinoma were assigned to two different groups treated with Cy7-NHS and Cy7-HVGGSSV, respectively. Meanwhile, each mouse received a single dose of 3 Gy radiation. Biological distribution of the recombinant peptide was assessed on an in vivo small animal imaging system. Results. The experimental group showed maximum fluorescence intensity in irradiated tumors treated with Cy7-labeled HVGGSSV, while untreated (0 Gy control tumors showed lower intensity levels. Fluorescence intensities of tumors in the right hind limbs of experimental animals were 7.84×107±1.13×107, 1.35×108±2.66×107, 4.05×108±1.75×107, 5.57×108±3.47×107, and 9.26×107±1.73×107 photons/s/cm2 higher compared with left hind limb values at 1, 2, 15, 24, and 48 h, respectively. Fluorescence intensities of tumor in the right hind limbs of the experimental group were 1.66×108±1.71×107, 1.51×108±3.23×107, 5.38×108±1.96×107, 5.89×108±3.57×107, and 1.62×108±1.69×107 photons/s/cm2 higher compared with control group values at 1, 2, 15, 24, and 48 h, respectively. Fluorescence was not specifically distributed in the control group. Compared with low fluorescence intensity in the heart, lungs, and tumors, high fluorescence distribution was found in the liver and kidney at 48 h. Conclusions. HVGGSSV was selectively bound to irradiated nasopharyngeal carcinoma, acting as a targeting transport carrier for radiation-guided drugs that are mainly metabolized in the kidney and liver.

Reactivating TP53 signaling by the novel MDM2 inhibitor DS-3032b as a therapeutic option for high-risk neuroblastoma

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Arnhold, Viktor; Schmelz, Karin; Proba, Jutta; Winkler, Annika; Wünschel, Jasmin; Toedling, Joern; Deubzer, Hedwig E.; Künkele, Annette; Eggert, Angelika; Schulte, Johannes H.; Hundsdoerfer, Patrick

2018-01-01

Fewer than 50% of patients with high-risk neuroblastoma survive five years after diagnosis with current treatment protocols. Molecular targeted therapies are expected to improve survival. Although MDM2 has been validated as a promising target in preclinical models, no MDM2 inhibitors have yet entered clinical trials for neuroblastoma patients. Toxic side effects, poor bioavailability and low efficacy of the available MDM2 inhibitors that have entered phase I/II trials drive the development of novel MDM2 inhibitors with an improved risk-benefit profile. We investigated the effect of the novel MDM2 small molecular inhibitor, DS-3032b, on viability, proliferation, senescence, migration, cell cycle arrest and apoptosis in a panel of six neuroblastoma cell lines with different TP53 and MYCN genetic backgrounds, and assessed efficacy in a murine subcutaneous model for high-risk neuroblastoma. Re-analysis of existing expression data from 476 primary neuroblastomas showed that high-level MDM2 expression correlated with poor patient survival. DS-3032b treatment enhanced TP53 target gene expression and induced G1 cell cycle arrest, senescence and apoptosis. CRISPR-mediated MDM2 knockout in neuroblastoma cells mimicked DS-3032b treatment. TP53 signaling was selectively activated by DS-3032b in neuroblastoma cells with wildtype TP53, regardless of the presence of MYCN amplification, but was significantly reduced by TP53 mutations or expression of a dominant-negative TP53 mutant. Oral DS-3032b administration inhibited xenograft tumor growth and prolonged mouse survival. Our in vitro and in vivo data demonstrate that DS-3032b reactivates TP53 signaling even in the presence of MYCN amplification in neuroblastoma cells, to reduce proliferative capacity and cause cytotoxicity. PMID:29416773

Risk factors for scoliosis in children with neuroblastoma

International Nuclear Information System (INIS)

Paulino, Arnold C.; Fowler, B. Zach

2005-01-01

Purpose: To determine the risk factors for scoliosis in children treated for neuroblastoma. Methods and materials: From 1957 to 1997, 58 children with neuroblastoma were treated at one institution and have survived a minimum of 5 years. There were 35 boys and 23 girls with a median age of 6 months (range, 2 weeks to 15 years) at initial diagnosis. Primary site was located in the adrenal gland in 25 (43.1%), abdominal/nonadrenal in 16 (27.6%), thoracic in 12 (20.7%), cervical in 3 (5.3%), and pelvic region in 2 (3.5%). The International Neuroblastoma Staging System (INSS) stage was Stage 1 in 10 (17.2%), Stage 2A in 7 (12.1%), Stage 2B in 5 (8.6%), Stage 3 in 22 (37.9%), Stage 4 in 4 (6.9%), and Stage 4S in 10 (17.2%). Thirty-three (56.9%) received chemotherapy whereas 5 (8.6%) had a laminectomy as part of the surgical procedure. Twenty-seven (46.6%) received radiotherapy (RT). Beam energy was 1.25 MV in 11 (41%), 250 kV in 10 (37%), 4 MV in 4 (15%), and 6-MV photons in 1 patient. One patient received 300 cGy in 1 fraction total skin RT using 6-MeV electrons. For the remaining patients, fraction size was 100 cGy in 6 (22%), 150-180 cGy in 11 (41%), 200 cGy in 4 (15%), and 250-300 cGy in 3. Three patients had total body irradiation at 333 cGy for 3 fractions. For all children who received RT, median total dose was 2000 cGy (range, 300-3900 cGy). Patients who were treated with RT had plain films of the irradiated area every 1 to 2 years until at least the age of puberty. Median follow-up was 10 years (range, 5-46 years). Results: The overall 5-, 10-, and 15-year scoliosis-free rates were 87.6%, 79.0%, and 76.0% respectively. Twelve (21%) developed scoliosis at a median time of 51 months (range, 8-137 months). The degree of scoliosis was mild (≤20 deg ) in 8 (67%). Four had scoliosis ranging from 30 deg to 66 deg ; 3 of these patients required surgical intervention, whereas 1 had an underlying Duchenne muscular dystrophy which manifested itself 8 years after

Rho-associated kinase is a therapeutic target in neuroblastoma.

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Dyberg, Cecilia; Fransson, Susanne; Andonova, Teodora; Sveinbjörnsson, Baldur; Lännerholm-Palm, Jessika; Olsen, Thale K; Forsberg, David; Herlenius, Eric; Martinsson, Tommy; Brodin, Bertha; Kogner, Per; Johnsen, John Inge; Wickström, Malin

2017-08-08

Neuroblastoma is a peripheral neural system tumor that originates from the neural crest and is the most common and deadly tumor of infancy. Here we show that neuroblastoma harbors frequent mutations of genes controlling the Rac/Rho signaling cascade important for proper migration and differentiation of neural crest cells during neuritogenesis. RhoA is activated in tumors from neuroblastoma patients, and elevated expression of Rho-associated kinase (ROCK)2 is associated with poor patient survival. Pharmacological or genetic inhibition of ROCK1 and 2, key molecules in Rho signaling, resulted in neuroblastoma cell differentiation and inhibition of neuroblastoma cell growth, migration, and invasion. Molecularly, ROCK inhibition induced glycogen synthase kinase 3β-dependent phosphorylation and degradation of MYCN protein. Small-molecule inhibition of ROCK suppressed MYCN -driven neuroblastoma growth in TH- MYCN homozygous transgenic mice and MYCN gene-amplified neuroblastoma xenograft growth in nude mice. Interference with Rho/Rac signaling might offer therapeutic perspectives for high-risk neuroblastoma.

Tumor-homing effect of human mesenchymal stem cells in a TH-MYCN mouse model of neuroblastoma.

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Kimura, Koseki; Kishida, Tsunao; Wakao, Junko; Tanaka, Tomoko; Higashi, Mayumi; Fumino, Shigehisa; Aoi, Shigeyoshi; Furukawa, Taizo; Mazda, Osam; Tajiri, Tatsuro

2016-12-01

Human mesenchymal stem cells (hMSCs) are multipotent stem-like cells that are reported to have tumor-suppression effects and migration ability toward damaged tissues or tumors. The aim of this study was to analyze the tumor-homing ability of hMSCs and antitumor potency in a transgenic TH-MYCN mouse model of neuroblastoma (NB). hMSCs (3×10 6 ) labeled with DiR, a lipophilic near-infrared dye, were intraperitoneally (i.p.) or intravenously (i.v.) administered to the TH-MYCN mice. hMSC in vivo kinetics were assayed using the IVIS® imaging system for 24h after injection. Immunohistochemistry using human CD90 antibody was also performed to confirm the location of hMSCs in various organs and tumors. Furthermore, the survival curve of TH-MYCN mice treated with hMSCs was compared to a control group administered PBS. i.p. hMSCs were recognized in the tumors of TH-MYCN mice by IVIS. hMSCs were also located inside the tumor tissue. Conversely, most of the i.v. hMSCs were captured by the lungs, and migration into the tumors was not noted. There was no significant difference in the survival between the hMSC and control groups. The present study suggested that hMSCs may be potential tumor-specific therapeutic delivery vehicles in NB according to their homing potential to tumors. Copyright © 2016 Elsevier Inc. All rights reserved.

Dual targeting of MDM2 and BCL2 as a therapeutic strategy in neuroblastoma.

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Van Goethem, Alan; Yigit, Nurten; Moreno-Smith, Myrthala; Vasudevan, Sanjeev A; Barbieri, Eveline; Speleman, Frank; Shohet, Jason; Vandesompele, Jo; Van Maerken, Tom

2017-08-22

Wild-type p53 tumor suppressor activity in neuroblastoma tumors is hampered by increased MDM2 activity, making selective MDM2 antagonists an attractive therapeutic strategy for this childhood malignancy. Since monotherapy in cancer is generally not providing long-lasting clinical responses, we here aimed to identify small molecule drugs that synergize with idasanutlin (RG7388). To this purpose we evaluated 15 targeted drugs in combination with idasanutlin in three p53 wild type neuroblastoma cell lines and identified the BCL2 inhibitor venetoclax (ABT-199) as a promising interaction partner. The venetoclax/idasanutlin combination was consistently found to be highly synergistic in a diverse panel of neuroblastoma cell lines, including cells with high MCL1 expression levels. A more pronounced induction of apoptosis was found to underlie the synergistic interaction, as evidenced by caspase-3/7 and cleaved PARP measurements. Mice carrying orthotopic xenografts of neuroblastoma cells treated with both idasanutlin and venetoclax had drastically lower tumor weights than mice treated with either treatment alone. In conclusion, these data strongly support the further evaluation of dual BCL2/MDM2 targeting as a therapeutic strategy in neuroblastoma.

BET inhibition silences expression of MYCN and BCL2 and induces cytotoxicity in neuroblastoma tumor models.

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Anastasia Wyce

Full Text Available BET family proteins are epigenetic regulators known to control expression of genes involved in cell growth and oncogenesis. Selective inhibitors of BET proteins exhibit potent anti-proliferative activity in a number of hematologic cancer models, in part through suppression of the MYC oncogene and downstream Myc-driven pathways. However, little is currently known about the activity of BET inhibitors in solid tumor models, and whether down-regulation of MYC family genes contributes to sensitivity. Here we provide evidence for potent BET inhibitor activity in neuroblastoma, a pediatric solid tumor associated with a high frequency of MYCN amplifications. We treated a panel of neuroblastoma cell lines with a novel small molecule inhibitor of BET proteins, GSK1324726A (I-BET726, and observed potent growth inhibition and cytotoxicity in most cell lines irrespective of MYCN copy number or expression level. Gene expression analyses in neuroblastoma cell lines suggest a role of BET inhibition in apoptosis, signaling, and N-Myc-driven pathways, including the direct suppression of BCL2 and MYCN. Reversal of MYCN or BCL2 suppression reduces the potency of I-BET726-induced cytotoxicity in a cell line-specific manner; however, neither factor fully accounts for I-BET726 sensitivity. Oral administration of I-BET726 to mouse xenograft models of human neuroblastoma results in tumor growth inhibition and down-regulation MYCN and BCL2 expression, suggesting a potential role for these genes in tumor growth. Taken together, our data highlight the potential of BET inhibitors as novel therapeutics for neuroblastoma, and suggest that sensitivity is driven by pleiotropic effects on cell growth and apoptotic pathways in a context-specific manner.

Neuroblastoma | Office of Cancer Genomics

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The TARGET Neuroblastoma projects elucidate comprehensive molecular characterization to determine the genetic changes that drive the initiation and progression of high-risk or hard-to-treat childhood cancers. Neuroblastoma (NBL) is a cancer that arises in immature nerve cells of the sympathetic nervous system, primarily affecting infants and children.

Sublethal irradiation promotes invasiveness of neuroblastoma cells

International Nuclear Information System (INIS)

Schweigerer, Lothar; Rave-Fraenk, Margret; Schmidberger, Heinz; Hecht, Monica

2005-01-01

Neuroblastoma is the most frequent extracranial solid tumour of childhood. Despite multiple clinical efforts, clinical outcome has remained poor. Neuroblastoma is considered to be radiosensitive, but some clinical studies including the German trial NB90 failed to show a clinical benefit of radiation therapy. The mechanisms underlying this apparent discrepancy are still unclear. We have therefore investigated the effects of radiation on neuroblastoma cell behaviour in vitro. We show that sublethal doses of irradiation up-regulated the expression of the hepatocyte growth factor (HGF) and its receptor c-Met in some neuroblastoma cell lines. The increase in HGF/c-Met expression was correlated with enhanced invasiveness and activation of proteases degrading the extracellular matrix. Thus, irradiation at sublethal doses may promote the metastatic dissemination of neuroblastoma cells through activating the HGF/c-Met pathway and triggering matrix degradation

Natural killer cells facilitate PRAME-specific T-cell reactivity against neuroblastoma

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Spel, Lotte; Boelens, Jaap-Jan; van der Steen, Dirk M.; Blokland, Nina J.G.; van Noesel, Max M.; Molenaar, Jan J.; Heemskerk, Mirjam H.M.

2015-01-01

Neuroblastoma is the most common solid tumor in children with an estimated 5-year progression free survival of 20–40% in stage 4 disease. Neuroblastoma actively avoids recognition by natural killer (NK) cells and cytotoxic T lymphocytes (CTLs). Although immunotherapy has gained traction for neuroblastoma treatment, these immune escape mechanisms restrain clinical results. Therefore, we aimed to improve neuroblastoma immunogenicity to further the development of antigen-specific immunotherapy against neuroblastoma. We found that neuroblastoma cells significantly increase surface expression of MHC I upon exposure to active NK cells which thereby readily sensitize neuroblastoma cells for recognition by CTLs. We show that oncoprotein PRAME serves as an immunodominant antigen for neuroblastoma as NK-modulated neuroblastoma cells are recognized by PRAMESLLQHLIGL/A2-specific CTL clones. Furthermore, NK cells induce MHC I upregulation in neuroblastoma through contact-dependent secretion of IFNγ. Our results demonstrate remarkable plasticity in the peptide/MHC I surface expression of neuroblastoma cells, which is reversed when neuroblastoma cells experience innate immune attack by sensitized NK cells. These findings support the exploration of NK cells as adjuvant therapy to enforce neuroblastoma-specific CTL responses. PMID:26452036

Advances In Neuroblastoma Diagnostics And Treatment

International Nuclear Information System (INIS)

Mazanek, P.; Bajciova, V.; Sterba, J.; Kuglik, P.; Veselsky, R.

2008-01-01

Neuroblastoma is the most common extracranial solid tumor of a childhood. Neuroblastoma is well known for its variability in clinical behavioral and distinct biological features. In a history of pediatric oncology it is a first disease, where the biological marker (NMYC amplification) was used for a prospective therapeutical randomisation. Current research is focused on detection of a new biological prognostic markers in neuroblastoma and implementation of a new therapeutical approaches into a clinical practise (eg. antiangiogenic therapies, metronomic chemotherapy, biotherapy, immunotherapy. (author)

High-Risk Prostate Cancer With Gleason Score 8–10 and PSA Level ≤15 ng/ mL Treated With Permanent Interstitial Brachytherapy

International Nuclear Information System (INIS)

Fang, L. Christine; Merrick, Gregory S.; Butler, Wayne M.; Galbreath, Robert W.; Murray, Brian C.; Reed, Joshua L.; Adamovich, Edward; Wallner, Kent E.

2011-01-01

Purpose: With widespread prostate-specific antigen (PSA) screening, there has been an increase in men diagnosed with high-risk prostate cancer defined by a Gleason score (GS) ≥8 coupled with a relatively low PSA level. The optimal management of these patients has not been defined. Cause-specific survival (CSS), biochemical progression-free survival (bPFS), and overall survival (OS) were evaluated in brachytherapy patients with a GS ≥8 and a PSA level ≤15 ng/mL with or without androgen-deprivation therapy (ADT). Methods and Materials: From April 1995 to October 2005, 174 patients with GS ≥8 and a PSA level ≤15 ng/mL underwent permanent interstitial brachytherapy. Of the patients, 159 (91%) received supplemental external beam radiation, and 113 (64.9%) received ADT. The median follow-up was 6.6 years. The median postimplant Day 0 minimum percentage of the dose covering 90% of the target volume was 121.1% of prescription dose. Biochemical control was defined as a PSA level ≤0.40 ng/mL after nadir. Multiple parameters were evaluated for impact on survival. Results: Ten-year outcomes for patients without and with ADT were 95.2% and 92.5%, respectively, for CSS (p = 0.562); 86.5% and 92.6%, respectively, for bPFS (p = 0.204); and 75.2% and 66.0%, respectively, for OS (p = 0.179). The median post-treatment PSA level for biochemically controlled patients was <0.02 ng/mL. Multivariate analysis failed to identify any predictors for CSS, whereas bPFS and OS were most closely related to patient age. Conclusions: Patients with GS ≥8 and PSA level ≤15 ng/mL have excellent bPFS and CSS after brachytherapy with supplemental external beam radiotherapy. The use of ADT did not significantly impact bPFS, CSS, or OS.

Neuroblastoma in Children: Just Diagnosed Information

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... Financial Reports Watchdog Ratings Feedback Contact Select Page Neuroblastoma in Children – Just Diagnosed Home > Cancer Resources > Types ... Diagnosed Just Diagnosed In Treatment After Treatment Diagnosing Neuroblastoma Depending on the location of the tumor and ...

Reversible adaptive plasticity: A mechanism for neuroblastoma cell heterogeneity and chemo-resistance

Directory of Open Access Journals (Sweden)

Lina eChakrabarti

2012-08-01

Full Text Available We describe a novel form of tumor cell plasticity characterized by reversible adaptive plasticity in murine and human neuroblastoma. Two cellular phenotypes were defined by their ability to exhibit adhered, anchorage dependent (AD or sphere forming, anchorage independent (AI growth. The tumor cells could transition back and forth between the two phenotypes and the transition was dependent on the culture conditions. Both cell phenotypes exhibited stem-like features such as expression of nestin, self-renewal capacity and mesenchymal differentiation potential. The AI tumorspheres were found to be more resistant to chemotherapy and proliferated slower in vitro compared to the AD cells. Identification of specific molecular markers like MAP2, β-catenin and PDGFRβ enabled us to characterize and observe both phenotypes in established mouse tumors. Irrespective of the phenotype originally implanted in mice, tumors grown in vivo show phenotypic heterogeneity in molecular marker signatures and are indistinguishable in growth or histologic appearance. Similar molecular marker heterogeneity was demonstrated in primary human tumor specimens. Chemotherapy or growth factor receptor inhibition slowed tumor growth in mice and promoted initial loss of AD or AI heterogeneity, respectively. Simultaneous targeting of both phenotypes led to further tumor growth delay with emergence of new unique phenotypes. Our results demonstrate that neuroblastoma cells are plastic, dynamic and may optimize their ability to survive by changing their phenotype. Phenotypic switching appears to be an adaptive mechanism to unfavorable selection pressure and could explain the phenotypic and functional heterogeneity of neuroblastoma.

Reversible Adaptive Plasticity: A Mechanism for Neuroblastoma Cell Heterogeneity and Chemo-Resistance

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Chakrabarti, Lina; Abou-Antoun, Thamara; Vukmanovic, Stanislav; Sandler, Anthony D., E-mail: asandler@childrensnational.org [The Joseph E. Robert Center for Surgical Care, Children’s National Medical Center, Washington, DC (United States); The Sheikh Zayed Institute for Pediatric Surgical Innovation, Children’s National Medical Center, Washington, DC (United States)

2012-08-02

We describe a novel form of tumor cell plasticity characterized by reversible adaptive plasticity in murine and human neuroblastoma. Two cellular phenotypes were defined by their ability to exhibit adhered, anchorage dependent (AD) or sphere forming, anchorage independent (AI) growth. The tumor cells could transition back and forth between the two phenotypes and the transition was dependent on the culture conditions. Both cell phenotypes exhibited stem-like features such as expression of nestin, self-renewal capacity, and mesenchymal differentiation potential. The AI tumorspheres were found to be more resistant to chemotherapy and proliferated slower in vitro compared to the AD cells. Identification of specific molecular markers like MAP2, β-catenin, and PDGFRβ enabled us to characterize and observe both phenotypes in established mouse tumors. Irrespective of the phenotype originally implanted in mice, tumors grown in vivo show phenotypic heterogeneity in molecular marker signatures and are indistinguishable in growth or histologic appearance. Similar molecular marker heterogeneity was demonstrated in primary human tumor specimens. Chemotherapy or growth factor receptor inhibition slowed tumor growth in mice and promoted initial loss of AD or AI heterogeneity, respectively. Simultaneous targeting of both phenotypes led to further tumor growth delay with emergence of new unique phenotypes. Our results demonstrate that neuroblastoma cells are plastic, dynamic, and may optimize their ability to survive by changing their phenotype. Phenotypic switching appears to be an adaptive mechanism to unfavorable selection pressure and could explain the phenotypic and functional heterogeneity of neuroblastoma.

Heterogeneity of neuroblastoma cell identity defined by transcriptional circuitries.

Science.gov (United States)

Boeva, Valentina; Louis-Brennetot, Caroline; Peltier, Agathe; Durand, Simon; Pierre-Eugène, Cécile; Raynal, Virginie; Etchevers, Heather C; Thomas, Sophie; Lermine, Alban; Daudigeos-Dubus, Estelle; Geoerger, Birgit; Orth, Martin F; Grünewald, Thomas G P; Diaz, Elise; Ducos, Bertrand; Surdez, Didier; Carcaboso, Angel M; Medvedeva, Irina; Deller, Thomas; Combaret, Valérie; Lapouble, Eve; Pierron, Gaelle; Grossetête-Lalami, Sandrine; Baulande, Sylvain; Schleiermacher, Gudrun; Barillot, Emmanuel; Rohrer, Hermann; Delattre, Olivier; Janoueix-Lerosey, Isabelle

2017-09-01

Neuroblastoma is a tumor of the peripheral sympathetic nervous system, derived from multipotent neural crest cells (NCCs). To define core regulatory circuitries (CRCs) controlling the gene expression program of neuroblastoma, we established and analyzed the neuroblastoma super-enhancer landscape. We discovered three types of identity in neuroblastoma cell lines: a sympathetic noradrenergic identity, defined by a CRC module including the PHOX2B, HAND2 and GATA3 transcription factors (TFs); an NCC-like identity, driven by a CRC module containing AP-1 TFs; and a mixed type, further deconvoluted at the single-cell level. Treatment of the mixed type with chemotherapeutic agents resulted in enrichment of NCC-like cells. The noradrenergic module was validated by ChIP-seq. Functional studies demonstrated dependency of neuroblastoma with noradrenergic identity on PHOX2B, evocative of lineage addiction. Most neuroblastoma primary tumors express TFs from the noradrenergic and NCC-like modules. Our data demonstrate a previously unknown aspect of tumor heterogeneity relevant for neuroblastoma treatment strategies.

Thoracic neuroblastoma: what is the best imaging modality for evaluating extent of disease?

International Nuclear Information System (INIS)

Slovis, T.L.; Meza, M.P.; Cushing, B.; Elkowitz, S.S.; Leonidas, J.C.; Festa, R.; Kogutt, M.S.; Fletcher, B.D.

1997-01-01

Thoracic neuroblastoma accounts for 15% of all cases of neuroblastoma. A minority of children with thoracic neuroblastoma will have dumbbell tumors, i.e., intraspinal extension, but only half these patients will have neurologic signs or symptoms. Hypothesis. MR imaging is the single best test to evaluate the extent of thoracic and spinal disease in thoracid neuroblastoma after the diagnosis of a mass is estbalished on plain film. A retrospective multi-institutional investigation over 7 years of all cases of thoracic neuroblastoma (n=26) imaged with CT and/or MR were reviewed for detection of the extent of disease. The chest film, nuclear bone scan, and other imaging modalities were also reviewed. The surgical and histologic correlation in each case, as well as the patients' staging and outcome, were tabulated. The chest radiography was 100% sensitive in suggesting the diagnosis. MR imaging was 100% sensitive in predicting enlarged lymph nodes, intraspinal extension, and chest wall involvement. CT was 88% sensitive for intraspinal extension but only 20% sensitive for lymph node enlargement. CT was 100% sensitive in detecting chest wall involvement. Direct comparison of CT and MR imaging in six cases revealed no difference in detection of enlarged lymph nodes or chest wall involvement. Neither test was able to detect remote disease, as noted by bone scan. The chest film is 100% sensitive in suggesting the diagnosis of thoracic neuroblastoma; MR imaging appears to be the single best test for detecting nodal involvement, intraspinal extension, and chest wall involvement. (orig.)

Antitumor Effect of Burchellin Derivatives Against Neuroblastoma.

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Kurita, Masahiro; Takada, Tomomi; Wakabayashi, Noriko; Asami, Satoru; Ono, Shinichi; Uchiyama, Taketo; Suzuki, Takashi

2018-02-01

Neuroblastoma is one of the most commonly encountered malignant solid tumors in the pediatric age group. We examined the antitumor effects of five burchellin derivatives against human neuroblastoma cell lines. We evaluated cytotoxicity by the MTT assay for four human neuroblastoma and two normal cell lines. We also performed analysis of the apoptotic induction effect by flow cytometry, and examined the expression levels of apoptosis- and cell growth-related proteins by western blot analysis. We found that one of the burchellin derivatives (compound 4 ) exerted cytotoxicity against the neuroblastoma cell lines. Compound 4 induced caspase-dependent apoptosis via a mitochondrial pathway. The apoptosis mechanisms induced by compound 4 involved caspase-3, -7 and -9 activation and poly (ADP-ribose) polymerase cleavage. In addition, compound 4 induced cell death through inhibition of the cell growth pathway (via extracellular signal-regulated kinase 1 and 2, AKT8 virus oncogene cellular homolog, and signal transducer and activator of transcription 3). Compound 4 exerted cellular cytotoxicity against neuroblastoma cells via induction of caspase-dependent apoptosis, and may offer promise for further development as a useful drug for the treatment of advanced neuroblastoma. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Needle aspiration biopsy in the diagnosis of lytic bone lesions in histiocytosis X, Ewing's sarcoma and neuroblastoma

International Nuclear Information System (INIS)

Thommesen, P.; Frederiksen, P.; Loewhagen, T.; Willems, J.S.

1978-01-01

Cytologic smears obtained by needle aspiration biopsy of lytic bone lesions in 15 patients with histiocytosis X, Ewing's sarcoma and neuroblastoma were reviewed. After conventional staining, histiocytosis X could be diagnosed and differentiated from small cell tumours such as Ewing's sarcoma and neuroblastoma. The need for sampling material for cytochemical and ultrastructural analysis of these small cell tumours by needle aspiration is emphasized. (Auth.)

Hepatic imaging in stage IV-S neuroblastoma

International Nuclear Information System (INIS)

Franken, E.A. Jr.; Smith, W.L.; Iowa Univ., Iowa City; Cohen, M.D.; Kisker, C.T.; Platz, C.E.

1986-01-01

Stage IV-S neuroblastoma describes a group of infants with tumor spread limited to liver, skin, or bone marrow. Such patients, who constitute about 25% of affected infants with neuroblastoma, may expect spontaneous tumor remission. We report 18 infants with Stage IV-S neuroblastoma, 83% of whom had liver involvement. Imaging investigations included Technetium 99m sulfur colloid scan, ultrasound, and CT. Two patterns of liver metastasis were noted: ill-defined nodules or diffuse tumor throughout the liver. Distinction of normal and abnormal liver with diffuse type metastasis could be quite difficult, particularly with liver scans. We conclude that patients with Stage IV-S neuroblastoma have ultrasound or CT examination as an initial workup, with nuclear medicine scans reserved for followup studies. (orig.)

Lung Metastases in Neuroblastoma at Initial Diagnosis: A Report from the International Neuroblastoma Risk Group (INRG) Project

Science.gov (United States)

DuBois, Steven G.; London, Wendy B.; Zhang, Yang; Matthay, Katherine K.; Monclair, Tom; Ambros, Peter F.; Cohn, Susan L.; Pearson, Andrew; Diller, Lisa

2009-01-01

Background Neuroblastoma is the most common extracranial pediatric solid cancer. Lung metastasis is rarely detected in children with newly diagnosed neuroblastoma. We aimed to describe the incidence, clinical characteristics, and outcome of patients with lung metastasis at initial diagnosis using a large international database. Procedure The subset of patients from the International Neuroblastoma Risk Group database with INSS stage 4 neuroblastoma and known data regarding lung metastasis at diagnosis was selected for analysis. Clinical and biological characteristics were compared between patients with and without lung metastasis. Survival for patients with and without lung metastasis was estimated by Kaplan-Meier methods. Cox proportional hazards methods were used to determine the independent prognostic value of lung metastasis at diagnosis. Results Of the 2,808 patients with INSS stage 4 neuroblastoma diagnosed between 1990 and 2002, 100 patients (3.6%) were reported to have lung metastasis at diagnosis. Lung metastasis was more common among patients with MYCN amplified tumors, adrenal primary tumors, or elevated lactate dehydrogenase (LDH) levels (p < 0.02 in each case). Five-year overall survival ± standard error for patients with lung metastasis was 34.5% ± 6.8% compared to 44.7% ± 1.3% for patients without lung metastasis (p=0.0002). However, in multivariable analysis, the presence of lung metastasis was not independently predictive of outcome. Conclusions Lung metastasis at initial diagnosis of neuroblastoma is associated with MYCN amplification and elevated LDH levels. Although lung metastasis at diagnosis was not independently predictive of outcome in this analysis, it remains a useful prognostic marker of unfavorable outcome. PMID:18649370

Oral supplementation of Bifidobacterium longum strain BR-108 alters cecal microbiota by stimulating gut immune system in mice irrespectively of viability.

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Makioka, Yuko; Tsukahara, Takamitsu; Ijichi, Tetsuo; Inoue, Ryo

2018-03-20

Effect on cecal microbiota and gene expression of various cytokines in ileal Peyer's patches and cecal tissues were compared between viable and heat-killed Bifidobacterium longum strain BR-108 (BR-108) using a mouse model. Irrespectively of viability, oral supplementation of BR-108 altered the cecal microbiota and stimulated gene expression of cytokines such as IL-6 and IL-10 in ileal Peyer's patches and cecal tissue of mice. In addition, BR-108 supplementation significantly affected the relative abundance of bacterial genera and family, Oscillospira, Bacteroides and S24-7. The abundance of these bacterial genera and family strongly correlated with gene expression induced by BR-108. This study demonstrated that the effect of heat-killed BR-108 on the mouse cecal microbiota is similar to that of viable BR-108, most likely due to stimulation of the gut immune system by both heat-killed and viable BR-108 is also similar.

Treatment of extradural paraspinal neuroblastoma with an intraspinal component

International Nuclear Information System (INIS)

Ho, K.S.Y.; Wara, W.M.; Ablin, A.R.

1982-01-01

Neuroblastoma originates from neural crest cells and can be found wherever sympathetic neural tissue is normally located. When the tumor arises from a paraspinal sympathetic ganglion, it has a propensity to extend through the intervertebral foramina, producing an extradural paraspinal neuroblastoma with an interspinal component (''dumbell'' neuroblastoma) which may result in spinal cord compression. The records of all children with neuroblastomas referred to the UCSF Department of Radiation Oncology and the Division of Pediatric Oncology from January 1, 1970, to December 31, 1979, are reviewed in this report. Patients who at initial presentation had a ''dumbell'' neuroblastoma were selected for study. Neuroblastoma was diagnosed histologically in all patients except one. Disease-free interval and length of survival was measured from the date of completion of radiotherapy, mostly after surgery. The results of diagnostic X-rays and laboratory studies are shown. Radiotherapeutic doses and results are tabulated. (Auth.)

Newly-derived neuroblastoma cell lines propagated in serum-free media recapitulate the genotype and phenotype of primary neuroblastoma tumours.

Science.gov (United States)

Bate-Eya, Laurel T; Ebus, Marli E; Koster, Jan; den Hartog, Ilona J M; Zwijnenburg, Danny A; Schild, Linda; van der Ploeg, Ida; Dolman, M Emmy M; Caron, Huib N; Versteeg, Rogier; Molenaar, Jan J

2014-02-01

Recently protocols have been devised for the culturing of cell lines from fresh tumours under serum-free conditions in defined neural stem cell medium. These cells, frequently called tumour initiating cells (TICs) closely retained characteristics of the tumours of origin. We report the isolation of eight newly-derived neuroblastoma TICs from six primary neuroblastoma tumours and two bone marrow metastases. The primary tumours from which these TICs were generated have previously been fully typed by whole genome sequencing (WGS). Array comparative genomic hybridisation (aCGH) analysis showed that TIC lines retained essential characteristics of the primary tumours and exhibited typical neuroblastoma chromosomal aberrations such as MYCN amplification, gain of chromosome 17q and deletion of 1p36. Protein analysis showed expression for neuroblastoma markers MYCN, NCAM, CHGA, DBH and TH while haematopoietic markers CD19 and CD11b were absent. We analysed the growth characteristics and confirmed tumour-forming potential using sphere-forming assays, subcutaneous and orthotopic injection of these cells into immune-compromised mice. Affymetrix mRNA expression profiling of TIC line xenografts showed an expression pattern more closely mimicking primary tumours compared to xenografts from classical cell lines. This establishes that these neuroblastoma TICs cultured under serum-free conditions are relevant and useful neuroblastoma tumour models. Copyright © 2013 Elsevier Ltd. All rights reserved.

MMSET is highly expressed and associated with aggressiveness in neuroblastoma

DEFF Research Database (Denmark)

Hudlebusch, Heidi Rye; Skotte, Julie; Santoni-Rugiu, Eric

2011-01-01

tumor types as well. We have performed immunohistochemical staining of tissue microarrays and found that MMSET protein is frequently and highly expressed in neuroblastoma (MMSET positive in 75% of neuroblastomas, n=164). The expression level of MMSET in neuroblastomas was significantly associated...... with poor survival, negative prognostic factors, and metastatic disease. Moreover, a subset of neuroblastomas for which pre- and post-chemotherapy biopsies were available displayed a strong decrease in MMSET protein levels after chemotherapy. In agreement with neuroblastomas becoming more differentiated...... after treatment, we show that retinoic acid-induced differentiation of human neuroblastoma cells in vitro also leads to a strong decrease in MMSET levels. Furthermore, we demonstrate that the high levels of MMSET in normal neural progenitor cells are strongly downregulated during differentiation...

Typical skeletal changes due to metastasising neuroblastomas

International Nuclear Information System (INIS)

Eggerath, A.; Persigehl, M.; Mertens, R.; Technische Hochschule Aachen

1983-01-01

Compared with other solid tumours in childhood, neuroblastomas show a marked tendency to metastasise to the skeleton. The differentiation of these lesions from inflammatory and other malignant bone lesions in this age group is often difficult. The radiological findings in ten patients with metastasing and histologically confirmed neuroblastomas have been reviewed and the typical appearances in the skeleton are described. The most important features in the differential diagnosies are discussed and the significance of bone changes in the diagnosis of neuroblastoma have been evaluated. (orig.) [de

The effect of interferon on the receptor sites to rabies virus on mouse neuroblastoma cells

International Nuclear Information System (INIS)

Briggs, D.J.

1989-01-01

The binding of rabies virus to mouse neuroblastoma cells (MNA) primed with alpha interferon (IFN-α), beta interferon (IFN-β), or alpha bungarotoxin (BTX) was examined. A saturable number of receptor sites to rabies virus was calculated by increasing the amount of 3 H-CVS added to a constant number of untreated MNA cells. MNA cells were then exposed to 20 I.U. of IFN-α, IFN-β, or 1 μg of BTX and assayed to determine if these treatments had an effect on the number of receptor sites to rabies virus. Total amount of 3 H-CVS bound to MNA cells was determined during a three hour incubation period. Cold competition assays using 1,000 fold excess unlabeled CVS were used to determine non-specific binding for each treatment. Specific binding was then calculated by subtracting non-specific binding from the total amount of CVS bound to MNA cells. A similar amount of total viral protein bound to untreated and IFN-β, and BTX treated cells after 180 minutes of incubation. The bound protein varied by only 0.07 μg. However, the amount of specific and non-specific binding varied a great deal between treatments. BTX caused an increase in non-specific and a decrease in specific binding of rabies virus. IFN-β produced variable results in non-specific and specific binding while IFN-α caused mainly specific binding to occur. The most significant change brought about by IFN-α was an increase in the rate of viral attachment. At 30 minutes post-infection, IFN-α treated cells had bound 90% of the total amount of virus bound to untreated cells after 180 minutes. The increased binding rate did not cause a productive infection of rabies virus. No viral production was evident after an incubation period of 48 hours in either IFN-α or IFN-β treated cells

Current strategy for the imaging of neuroblastoma

International Nuclear Information System (INIS)

Brisse, H.; Neuenschwander, S.; Edeline, V.; Michon, J.; Zucker, J.M.; Couanet, D.

2001-01-01

Advances in the management of neuroblastoma lead radiologists and nuclear medicine specialists to optimize their procedures in order to propose a rational use of their techniques, adjusted to the various clinical presentations and to therapeutic management. The aim of this paper is to assess the imaging procedures for the diagnosis and follow-up of neuroblastoma in children according to current therapeutic European protocols. An imaging strategy at diagnosis is first proposed: optimal assessment of local extension of the primary tumour is made with MRI, or spiral-CT when MRI is not available, for all locations except for abdominal tumours for which CT remains the best imaging modality. Metastatic extension is assessed with mlBG scan and liver sonography. Indications for bone metastasis evaluation with either radiological or radionuclide techniques are detailed. Imaging follow-up during treatment for metastatic or unresectable tumours is described. A check-list of radiological main points to be evaluated before surgery is proposed for localized neuroblastoma. The imaging strategy for the diagnosis of 'occult' neuroblastoma is considered. Finally, we explain the management of neuroblastoma detected during the prenatal or neonatal period. (authors)

Metastatic neuroblastoma in the brain parenchyma; a case report

International Nuclear Information System (INIS)

Kim, Ho Sung; Choi, Choong Gon; Shin, Ji Hoon; Lee, Ho Kyu; Suh, Dae Chul

2000-01-01

During childhood, neuroblastoma is a relatively common malignant neoplasm which commonly metastasizes to other organs. Metastasis to the central nervous system from an extracranial neuroblastoma is rare, however, and brain parenchymal metastasis is very rare. We describe a case of brain parenchymal metastasis from primary abdominal neuroblastoma, and review the literature

Prospective evaluation of the International Neuroblastoma Staging System (INSS) and the International Neuroblastoma Response Criteria (INRC) in a multicentre setting.

Science.gov (United States)

Castel, V; García-Miguel, P; Cañete, A; Melero, C; Navajas, A; Ruíz-Jiménez, J I; Navarro, S; Badal, M D

1999-04-01

The aim of this study was to classify prospectively a series of neuroblastoma tumours according to the International Neuroblastoma Staging System (INSS) and the International Neuroblastoma Response Criteria (INRC) and to evaluate the difficulties and pitfalls involved in a multicentre setting. Each hospital provided their data for central review. The surgical procedures and their complications were reported. Kaplan-Meier estimates of survival and event-free survival were calculated according to stage and response to therapy. From June 1992 to December 1996, 194 patients were included in the study, with a mean age of 2 years. Initial studies were performed according to INSS recommendations without major problems. INSS stage was correctly applied to all patients except for 9 (95%). Post-operative complications were observed in 15 patients (8.3%). Response to therapy (INRC) was studied in 63 stage 4 patients, 11 of whom were not classified correctly (17%). Differences in survival according to stage (INSS) and group of response to therapy (INRC) were statistically significant (P INSS was easy to use and separated different prognostic groups. Surgical complications and mortality did not increase in this series because of using the INSS. The feasibility of INRC was evaluated in a small series of stage 4 patients and the designation of response was problematic in a relatively high proportion of cases. The prognostic value of the different responses was highly significant, but less informative than had been hoped for.

131I-MIBG in Neuroblastoma, is Not Simply the Uptake in the Primary Mass

International Nuclear Information System (INIS)

El-Maghraby, T.A.; Nasr, H.A.; Hassan, M.

2003-01-01

Neuroblastoma is the third most common malignancy of childhood. Nowadays. MlBG has become a central procedure for staging and defining extent and location of neuroblastoma tumors. The recommendations of the International Neuroblastoma Staging System (INSS) indicate that MlBG scintigraphy must be performed in patients with neuroblastoma at the time of initial staging and as a followup tool during therapy. Purpose: Of this study is to identify the role of 131 I M lBG scintigraphy in neuroblastoma patients and to correlate it with other diagnostic modalities for staging and follow up of neuroblastoma. Methods: The study was conducted on 26 patients provisionally diagnosed to have neuroblastoma. On histopathologic verification 5 of these 26 patients were re diagnosed as non-neuroblastoma. Since the study aims at assessing the diagnostic power of 131 I M IBG scan, these 5 cases were not excluded. The 21 histopathologically diagnosed as neuroblastoma were 11 patients in stage IV, 7 in stage III and 1 patient in each of stages I, 11 and IVS. Each. patient underwent a standard comprehensive diagnostic work up, Radiological imaging by conventional X-ray. ultrasound. CT and/or MRI was carried out. In all patients I3II M IBG scintigraphy was performed, among them 15 patients underwent additional 99m Tc-MDP bone scan as well. The 21 neuroblastoma patients were studied according to the results obtained from CT, MRI and 131 I M lBG scanning. The outcome demonstrated that CT and MR1 were able to detect lesions in 19 out of 2] patients; while in 2 patients no lesions were detected. 131 I M IBG scan showed actively functioning lesions in ] 6 out of the above] 9 patients. while in 3 patients MIBG scan was negative. There was no false positive result by 131 I M IBG scan. Accordingly. 131 1 M IBG is able to detect neuroblastoma lesions with an overall sensitivity of 84.2%. specificity of 100% and an accuracy of 85.7%. Detection of primary lesions by 131 I M lBG was significantly

Neuroblastoma Treatment (PDQ®)—Health Professional Version

Science.gov (United States)

Neuroblastoma treatment depends on the assigned risk category (low, intermediate, high, stage 4S). Get detailed information about the genomic/biologic features, presentation, diagnosis/staging, risk groups, prognosis and treatment of newly diagnosed and recurrent neuroblastoma in this summary for clinicians.

/sup 131/I-meta-iodobenzylguanidine scintigraphy of neuroblastomas

International Nuclear Information System (INIS)

Munkner, T.

1986-01-01

Sixteen neuroblastoma patients have been studied by /sup 131/I-meta-iodobenzylguanidine scintigraphy. Three patients were possibly cured, and their scintigraphy results were normal. Thirteen patients had tumors and metastases demonstrated by /sup 131/I-MIBG, two of these patients had a normal vanillylmandelic acid excretion levels. One patient has been treated by /sup 131/I-MIBG, but died. /sup 131/I-MIBG was concentrated in other cells too, e.g., in erythrocytes and platelets. Neuroblastoma is the most common solid malignant disease in children. It has a poor prognosis in patients more than one year old. Early detection and a display of the spread of the tumor is of utmost importance for planning and controlling the treatment. Mass screening for neuroblastoma in infants has been suggested and tried in Japan. Scintigraphy after injection of /sup 131/I-meta-iodobenzylguanidine has been used successfully for locating neuroblastomas. An initial study failed to demonstrate neuroblastoma by means of MIBG in two patients. Since the latter part of 1983, MIBG has been used in a number of European centers for imaging neuroblastomas with very promising results, and a multicenter investigation has been initiated. The Ann Arbor group has recently extended its studies to a group of ten patients and has confirmed the European results

OPEC/OJEC for stage 4 neuroblastoma in children over 1 year of age.

Science.gov (United States)

Tweddle, D A; Pinkerton, C R; Lewis, I J; Ellershaw, C; Cole, M; Pearson, A D

2001-01-01

This paper reports the toxicity of OPEC/OJEC chemotherapy in stage 4 neuroblastoma patients over 1 year of age. Ninety-five patients with stage 4 neuroblastoma received alternating courses of OPEC/OJEC--vincristine 1.5 mg/m2 (O), cisplatin 80 mg/m2 (P), etoposide 200 mg/m2 (E), cyclophosphamide 600 mg/m2 (C), and carboplatin 500 mg/m2 (J), every 21 days if there was haematological recovery. Seventy out of ninety-five (74%) patients completed seven or more courses and were evaluable for toxicity. Of these 70 patients, 33% had more than three episodes of fever and sepsis, 35% required more than five blood or platelet transfusions, 36% had grade 2 or more gastrointestinal toxicity and 9% had neurotoxicity. There was a median reduction in GFR of 32 ml/min/1.73 m2 (-46 to 134) and there was one toxic death. OPEC/OJEC is a well-tolerated therapy for stage 4 neuroblastoma over 1 year of age.

Role of 131-1 MIBG Therapy in the Treatment of Advanced Neuroblastoma

International Nuclear Information System (INIS)

Riad, R.; Kotb, M.; Omar, W.; Zaher, A.; Khalafalla, Kh.; Fawzy, M.; Ebeid, E.; El-Wakil, M.

2009-01-01

Introduction: Neuroblastoma, a neoplasm of the sympathetic nervous system, is the second most extra-cranial malignant solid tumor of childhood. Many therapeutic strategies has evolved over the last 20 years, based upon work by international cooperative groups and smaller cohort studies. Novel therapies to improve initial disease response and treatment of minimal residual disease are required to improve survival for these children with high-risk neuroblastoma. Radio-labeled MIBG therapy has been tried in the treatment of advanced stage 3 and 4 neuroblastoma in an attempt to improve patients outcome. The use of radio-labeled MIBG to treat neuroblastoma has arisen from the high sensitivity and specificity of in-vivo MIBG imaging for detection of primary and metastatic tumors. Aim of the Work: To determine the impact of MIBG therapy on neuroblastoma patients outcome and its impact on their quality of life. Patients and Methods: Thirty pediatric patients with stage 4 pathologically proven neuroblastoma are included in this study. Eighteen of the study patients (60%) were males and 12 (40%) were females. All the patients had partially responsive tumor to first-line therapy + surgery. 131-1 Mibg doses ranged from 100 to 150 mCi with number of courses ranged from 1-7 according to response and toxicity. Results: Two patients achieved complete remission (CR) and were still disease-free after 64 and 69 months. Nine patients showed partial remission (PR) to 131-1 MIBG, all the nine patients were alive at 16-57 months (mean 30.6 months) among whom seven were alive with stable disease and two patients were alive with progressive disease (PD) at the end of study. Eighteen patients remained stable after 131-I MIBG therapy, among them six were alive with PD and four were alive with stable disease at the end of study, while the remaining eight patients died. The last patient developed PD and died within 15 months. The 5 years event free survival (EPS) was 48.2% and the overall

Multidisciplinary management of cervical neuroblastoma in infants.

Science.gov (United States)

Csanády, Miklós; Vass, Gábor; Bartyik, Katalin; Majoros, Valéria; Rovó, László

2014-12-01

Neuroblastoma is the most common malignancy in infancy, it is a histologically and genetically heterogeneous tumor, the therapy and outcome of which is influenced by age, histological variant and genetic background as well. We present two consecutive infant patients with neuroblastoma of the neck discussing the etiology, the diagnosis and the surgical and oncological treatment of the tumor, which was observed in a relatively rare manifestation in the head-neck region. Our first patient (age: 5.5 months) was MYCN (v-myc myelocytomatosis viral related oncogene, neuroblastoma derived) negative, INSS (International Neuroblastoma Staging System) Stage 3 and INRGSS (International Neuroblastoma Risk Group Staging System) Stage 3 because of the contralateral lymph node involvement while the complete gross resection of the primary tumor mass was feasible. The patient is tumor free after three years of follow-up. Our second patient (age: 5 months) was MYCN negative, INSS Stage 2 and INRGSS Stage 1, as both the primary tumor and the ipsilateral lymph nodes were totally removed via a modified radical neck dissection. The patient is tumor free after three years of follow-up. For MYCN negative patients, especially in early age, the prognosis of neuroblastoma is good, surgical resection and chemotherapy together is an adequate treatment protocol (as in our two patients). While MYCN-amplified patients require a combined and aggressive treatment with surgery, chemotherapy, radiotherapy, and immunotherapy to be able to obtain a favorable survival rate according to the literature. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Nuclear medicine therapy of neuroblastoma

International Nuclear Information System (INIS)

Hoefnagel, C.A.

1999-01-01

Specific targeting of radionuclides to neuroblastoma, a neural crest tumor occurring predominantly in young children and associated with a relatively poor prognosis, may be achieved via the metabolic route (Mibg), receptor binding (peptides) or immunological approach (antibodies). The clinical role of 1 31 I -Mibg therapy and radioimmunotherapy in neuroblastoma is discussed. In recurrent or progressive metastatic disease after conventional treatment modalities have failed, 1 31 I -Mibg therapy, with an overall objective response rate of 35%, is probably the best palliative treatment, as the invasiveness and toxicity of this therapy compare favourably with that of chemotherapy, immunotherapy and external beam radiotherapy. In patients presenting with inoperable stage III and IV neuroblastoma, 1 31 I -Mibg therapy at diagnosis is at least as effective as combination chemotherapy but is associated with much less toxicity. In patients with recurrent disease 1 31 I -Mibg therapy in combination with hyperbaric oxygen therapy proved feasible and encouraging effects on survival have ben observed. Attempts to intensify the treatment in relapsed patients by combination of 1 31 I -Mibg therapy with high dose chemotherapy and/or total body irradiation have met with considerable toxicity. Developments in Mibg therapy aiming at improving the therapeutic index are mentioned. Early results of radioimmunotherapy using 1 31 I -UJ13A or 1 31 I -3F8 monoclonal antibodies have shown moderate objective response and considerable side effects in patients with stage IV neuroblastoma, who had relapsed or failed conventional therapy. New developments in radioimmunotherapy of neuroblastoma include the use of chimeric antibodies, the enhancement of tumor uptake by modulation of antigen expression or by increasing the tumor perfusion/vascularity/permeability, the use of other labels and multistep targeting techniques, e.g. using bispecific monoclonal antibodies

Disseminated peripheral neuroblastoma in a Rhodesian Ridgeback dog.

Science.gov (United States)

Cook, R W; Abraham, L A; McCowan, C I

2017-04-01

A 4-year-old neutered male Rhodesian Ridgeback dog with right-sided Horner's syndrome, bilateral laryngeal paralysis, neck pain and bilateral hindlimb ataxia was euthanased following deterioration of its neurological status. Necropsy examination revealed an off-white retropharyngeal neoplastic mass (100 × 30 × 30 mm) attached to the base of the skull on the right side and macroscopic nodular metastases in the spleen and three vertebral bodies (C6, C7 and T6), including a nodule attached to the dura at C7. Histological evidence of neuroblastic tumour was detected in these macroscopic lesions, a regional lymph node, bone marrow of a femur and all 15 vertebral bodies (C1-T8) examined, including the three with macroscopic metastases, and in the lumens of small blood vessels in the lungs and liver. Ganglion cell differentiation was detected only in the primary retropharyngeal mass, one splenic nodule and the C7 dural nodule. Neoplastic cells were immunoreactive to neurofilament protein (ganglion cells only), vimentin and synaptophysin, and were negative for S100 protein, GFAP, CD3 and Pax5. The diagnosis was disseminated peripheral neuroblastoma, differentiating subtype (International Neuroblastoma Pathology Classification), with likely primary involvement of the right cranial cervical ganglion. This appears to be the first report of neuroblastoma in a dog with widespread occult haematogenous metastasis to bone marrow. © 2017 Australian Veterinary Association.

A Solar Powered Wireless Computer Mouse: Design, Assembly and Preliminary Testing of 15 Prototypes

NARCIS (Netherlands)

van Sark, W.G.J.H.M.; Reich, N.H.; Alsema, E.A.; Netten, M.P.; Veefkind, M.; Silvester, S.; Elzen, B.; Verwaal, M.

2007-01-01

The concept and design of a solar powered wireless computer mouse has been completed, and 15 prototypes have been successfully assembled. After necessary cutting, the crystalline silicon cells show satisfactory efficiency: up to 14% when implemented into the mouse device. The implemented voltage

Oral Metronomic Topotecan Sensitizes Crizotinib Antitumor Activity in ALKF1174L Drug-Resistant Neuroblastoma Preclinical Models

Directory of Open Access Journals (Sweden)

Libo Zhang

2017-08-01

Full Text Available BACKGROUND: Anaplastic lymphoma kinase (ALK inhibitor crizotinib has proven to be effective in the treatment of ALK-mutated neuroblastoma, but crizotinib resistance was commonly observed in patients. We aimed to overcome crizotinib resistance by combining with the MEK inhibitor trametinib or low-dose metronomic (LDM topotecan in preclinical neuroblastoma models. METHODS: We selected a panel of neuroblastoma cell lines carrying various ALK genetic aberrations to assess the therapeutic efficacy on cell proliferation in vitro. Downstream signals of ALK activation, including phosphorylation of ERK1/2, Akt as well as HIF-1α expression were evaluated under normoxic and hypoxic conditions. Tumor growth inhibition was further assessed in NOD/SCID xenograft mouse models. RESULTS: All NBL cell lines responded to crizotinib treatment but at variable ED50 levels, ranging from 0.25 to 5.58 μM. ALK-mutated cell lines SH-SY5Y, KELLY, LAN-5, and CHLA-20 are more sensitive than ALK wild-type cell lines. In addition, we demonstrated that under hypoxic conditions, all NBL cell lines showed marked decrease of ED50s when compared to normoxia except for KELLY cells. Taking into consideration the hypoxia sensitivity to crizotinib, combined treatment with crizotinib and LDM topotecan demonstrated a synergistic effect in ALKF1174L-mutated SH-SY5Y cells. In vivo, single-agent crizotinib showed limited antitumor activity in ALKF1174L-mutated SH-SY5Y and KELLY xenograft models; however, when combined with topotecan, significantly delayed tumor development was achieved in both SH-SY5Y and KELLY tumor models. CONCLUSIONS: Oral metronomic topotecan reversed crizotinib drug resistance in the ALKF1174L-mutated neuroblastoma preclinical model.

Differentiation of the SH-SY5Y Human Neuroblastoma Cell Line.

Science.gov (United States)

Shipley, Mackenzie M; Mangold, Colleen A; Szpara, Moriah L

2016-02-17

Having appropriate in vivo and in vitro systems that provide translational models for human disease is an integral aspect of research in neurobiology and the neurosciences. Traditional in vitro experimental models used in neurobiology include primary neuronal cultures from rats and mice, neuroblastoma cell lines including rat B35 and mouse Neuro-2A cells, rat PC12 cells, and short-term slice cultures. While many researchers rely on these models, they lack a human component and observed experimental effects could be exclusive to the respective species and may not occur identically in humans. Additionally, although these cells are neurons, they may have unstable karyotypes, making their use problematic for studies of gene expression and reproducible studies of cell signaling. It is therefore important to develop more consistent models of human neurological disease. The following procedure describes an easy-to-follow, reproducible method to obtain homogenous and viable human neuronal cultures, by differentiating the chromosomally stable human neuroblastoma cell line, SH-SY5Y. This method integrates several previously described methods(1-4) and is based on sequential removal of serum from media. The timeline includes gradual serum-starvation, with introduction of extracellular matrix proteins and neurotrophic factors. This allows neurons to differentiate, while epithelial cells are selected against, resulting in a homogeneous neuronal culture. Representative results demonstrate the successful differentiation of SH-SY5Y neuroblastoma cells from an initial epithelial-like cell phenotype into a more expansive and branched neuronal phenotype. This protocol offers a reliable way to generate homogeneous populations of neuronal cultures that can be used for subsequent biochemical and molecular analyses, which provides researchers with a more accurate translational model of human infection and disease.

TIAM1 variants improve clinical outcome in neuroblastoma.

Science.gov (United States)

Sanmartín, Elena; Yáñez, Yania; Fornés-Ferrer, Victoria; Zugaza, José L; Cañete, Adela; Castel, Victoria; Font de Mora, Jaime

2017-07-11

Identification of tumor driver mutations is crucial for improving clinical outcome using a personalized approach to the treatment of cancer. Neuroblastoma is a tumor of the peripheral sympathetic nervous system for which only a few driver alterations have been described including MYCN amplification and ALK mutations. We assessed 106 primary neuroblastoma tumors by next generation sequencing using a customized amplicon-based gene panel. Our results reveal that genetic variants in TIAM1 gene associate with better clinical outcome, suggesting a role for these TIAM1 variants in preventing progression of this disease. The detected variants are located within the different domains of TIAM1 that signal to the upstream regulator RAS and downstream effector molecules MYC and RAC, which are all implicated in neuroblastoma etiology and progression. Clinical outcome was improved in tumors where a TIAM1 variant was present concomitantly with either ALK mutation or MYCN amplification. Given the function of these signaling molecules in cell survival, proliferation, differentiation and neurite outgrowth, our data suggest that the TIAM1-mediated network is essential to neuroblastoma and thus, inhibiting TIAM1 reflects a rational strategy for improving therapy efficacy in neuroblastoma.

Heparin-binding epidermal growth factor-like growth factor promotes neuroblastoma differentiation.

Science.gov (United States)

Gaviglio, Angela L; Knelson, Erik H; Blobe, Gerard C

2017-05-01

High-risk neuroblastoma is characterized by undifferentiated neuroblasts and low schwannian stroma content. The tumor stroma contributes to the suppression of tumor growth by releasing soluble factors that promote neuroblast differentiation. Here we identify heparin-binding epidermal growth factor-like growth factor (HBEGF) as a potent prodifferentiating factor in neuroblastoma. HBEGF mRNA expression is decreased in human neuroblastoma tumors compared with benign tumors, with loss correlating with decreased survival. HBEGF protein is expressed only in stromal compartments of human neuroblastoma specimens, with tissue from high-stage disease containing very little stroma or HBEGF expression. In 3 human neuroblastoma cell lines (SK-N-AS, SK-N-BE2, and SH-SY5Y), soluble HBEGF is sufficient to promote neuroblast differentiation and decrease proliferation. Heparan sulfate proteoglycans and heparin derivatives further enhance HBEGF-induced differentiation by forming a complex with the epidermal growth factor receptor, leading to activation of the ERK1/2 and STAT3 pathways and up-regulation of the inhibitor of DNA binding transcription factor. These data support a role for loss of HBEGF in the neuroblastoma tumor microenvironment in neuroblastoma pathogenesis.-Gaviglio, A. L., Knelson, E. H., Blobe, G. C. Heparin-binding epidermal growth factor-like growth factor promotes neuroblastoma differentiation. © FASEB.

The association between neuroblastoma and opsoclonus-myoclonus syndrome: a historical review

International Nuclear Information System (INIS)

Rothenberg, Alexis B.; Berdon, Walter E.; D'Angio, Giulio J.; Yamashiro, Darrell J.; Cowles, Robert A.

2009-01-01

An association between neuroblastoma and opsoclonus-myoclonus syndrome (OMS) was described as early as 1927 within the first report on the transformation of malignant neuroblastoma to a benign ganglioneuroma. It was not recognized at that time nor was it appreciated in the subsequent follow-up report on the same patient in 1959. Myoclonic encephalopathy of infancy, an alternative name for OMS, was described by a pediatric neurologist in 1962; however, its connection to neuroblastoma was not known. It was only in 1968 that the association between these two conditions was first reported. The neuroblastoma tumors associated with OMS are almost all small, stage I-II with no associated MYCN amplification or metastases. OMS occurs in 2-3% of patients with neuroblastoma, but neuroblastoma is found in as many as 50% of children who present with OMS. Nearly 100% of the children with neuroblastoma associated with OMS survive, and this has led to speculation that the OMS is a result of an autoimmune process, not metastases. Affected children are treated with steroids, ACTH, or intravenous immunoglobulin, but many have persistent neurologic and developmental deficits. Using the original case reported in 1927, we summarize a century of literature in this review on OMS and its association with neuroblastoma. (orig.)

Evaluation of potential prognostic value of Bmi-1 gene product and selected markers of proliferation (Ki-67 and apoptosis (p53 in the neuroblastoma group of tumors

Directory of Open Access Journals (Sweden)

Katarzyna Taran

2016-02-01

Full Text Available Introduction: Cancer in children is a very important issue in pediatrics. The least satisfactory treatment outcome occurs among patients with clinically advanced neuroblastomas. Despite much research, the biology of this tumor still remains unclear, and new prognostic factors are sought. The Bmi-1 gene product is a currently highly investigated protein which belongs to the Polycomb group (PcG and has been identified as a regulator of primary neural crest cells. It is believed that Bmi‑1 and N-myc act together and are both involved in the pathogenesis of neuroblastoma. The aim of the study was to assess the potential prognostic value of Bmi-1 protein and its relations with mechanisms of proliferation and apoptosis in the neuroblastoma group of tumors.Material/Methods: 29 formalin-fixed and paraffin-embedded neuroblastoma tissue sections were examined using mouse monoclonal antibodies anti-Bmi-1, anti-p53 and anti-Ki-67 according to the manufacturer’s instructions.Results: There were found statistically significant correlations between Bmi-1 expression and tumor histology and age of patients.Conclusions: Bmi-1 seems to be a promising marker in the neuroblastoma group of tumors whose expression correlates with widely accepted prognostic parameters. The pattern of BMI-1 expression may indicate that the examined protein is also involved in maturation processes in tumor tissue.

Pancreatic Metastasis in a Child Suffering with Treated Stage 4 Neuroblastoma

International Nuclear Information System (INIS)

Kim, Eun Young; Yoo, So Young; Kim, Ji Hye; Sung, Ki Woong

2008-01-01

Neuroblastoma is the most common extracranial solid tumor of childhood, and its metastasis to distant organs such as bone, bone marrow and liver is well documented. However, pancreatic metastasis of neuroblastoma has not yet been reported in the medical literature. We report here on a 4-year old boy who had a metastatic relapse in his pancreas, combined with pancreatitis, after remission of stage 4 neuroblastoma. In conclusion, we present here a very rare case of neuroblastoma that metastasized to the pancreas in a 4- year-old boy. Pancreatic metastasis should be taken into consideration for those patients who are found to have pancreatic nodules concurrent with neuroblastoma

A comparison of targeting of neuroblastoma with mIBG and anti L1-CAM antibody mAb chCE7: therapeutic efficacy in a neuroblastoma xenograft model and imaging of neuroblastoma patients

NARCIS (Netherlands)

Hoefnagel, C. A.; Rutgers, M.; Buitenhuis, C. K.; Smets, L. A.; de Kraker, J.; Meli, M.; Carrel, F.; Amstutz, H.; Schubiger, P. A.; Novak-Hofer, I.

2001-01-01

Iodine-131 labelled anti L1-CAM antibody mAb chCE7 was compared with the effective neuroblastoma-seeking agent 131I-labelled metaiodobenzylguanidine (MIBG) with regard to (a) its therapeutic efficacy in treating nude mice with neuroblastoma xenografts and (b) its tumour targeting ability in

The association of congenital neuroblastoma and congenital heart disease

International Nuclear Information System (INIS)

Bellah, R.; D'Andrea, A.; Children's Hospital, Boston, MA; Darillis, E.; Fellows, K.E.

1989-01-01

Several authors have reported an association between neuroblastoma and congenital heart disease; others contend that, unlike specific wellknown associations between malignancy and congenital defects (Wilm's tumor and aniridia, leukemia and Down's syndrome), no real relationship exists. We present three cases of cyanotic congenital heart disease in which subclinical neuroblastoma was found. We speculate that abnormal neural crest cell migration and development may be a common link between cardiac malformations and congenital neuroblastoma. (orig.)

POSTTREATMENT NEUROBLASTOMA MATURATION TO GANGLIONIC CELL TUMOR

Directory of Open Access Journals (Sweden)

M. V. Ryzhova

2012-01-01

Full Text Available Tumor cells can differentiate into more mature forms in undifferentiated or poorly differentiated tumors, such as medulloblastomas with increased nodularity, as well as neuroblastomas. The authors describe 2 cases of neuroblastoma maturation into ganglioneuroblastoma 5 months after chemotherapy in a 2-year-old girl and 3 years after radiotherapy in a 16-year-old girl.

Stage IVN neuroblastoma: MRI diagnosis of left supraclavicular ''Virchow's'' nodal spread

International Nuclear Information System (INIS)

Abramson, S.J.; Berdon, W.E.; Stolar, C.; Ruzal-Shapiro, C.; Garvin, J.

1996-01-01

Stage IV neuroblastoma is associated with high mortality; an exception are patients whose stage IV status includes distant positive nodes, but no skeletal metastases - stage IVN neuroblastoma. We describe our experience with preoperative MRI in three patients with extensive abdominal neuroblastoma without cortical bony involvement but with unsuspected metastatic involvement to the left supraclavicular (Virchow's) node. We review findings of left supraclavicular nodal spread in five earlier cases of IVN neuroblastoma. (orig.). With 3 figs., 1 tab

Mechanisms of neuroblastoma regression

Science.gov (United States)

Brodeur, Garrett M.; Bagatell, Rochelle

2014-01-01

Recent genomic and biological studies of neuroblastoma have shed light on the dramatic heterogeneity in the clinical behaviour of this disease, which spans from spontaneous regression or differentiation in some patients, to relentless disease progression in others, despite intensive multimodality therapy. This evidence also suggests several possible mechanisms to explain the phenomena of spontaneous regression in neuroblastomas, including neurotrophin deprivation, humoral or cellular immunity, loss of telomerase activity and alterations in epigenetic regulation. A better understanding of the mechanisms of spontaneous regression might help to identify optimal therapeutic approaches for patients with these tumours. Currently, the most druggable mechanism is the delayed activation of developmentally programmed cell death regulated by the tropomyosin receptor kinase A pathway. Indeed, targeted therapy aimed at inhibiting neurotrophin receptors might be used in lieu of conventional chemotherapy or radiation in infants with biologically favourable tumours that require treatment. Alternative approaches consist of breaking immune tolerance to tumour antigens or activating neurotrophin receptor pathways to induce neuronal differentiation. These approaches are likely to be most effective against biologically favourable tumours, but they might also provide insights into treatment of biologically unfavourable tumours. We describe the different mechanisms of spontaneous neuroblastoma regression and the consequent therapeutic approaches. PMID:25331179

Diagnosis and treatment of neuroblastoma using metaiodobenzylguanidine

International Nuclear Information System (INIS)

Edeling, C.J.; Frederiksen, P.B.; Kamper, J.; Jeppesen, P.

1987-01-01

Neuroblastoma is a lethal and not uncommon tumor in childhood. Early detection and display of the spread of the tumor is highly desirable for proper treatment. Nine children suspected of having neuroblastomas were examined by I-131 metaiodobenzylguanidine (I-131 MIBG) imaging. In two recent studies I-123 metaiodobenzylguanidine (I-123 MIBG) was used. A primary adrenal neuroblastoma was correctly identified in three cases. In two patients additional tumor sites were found. In one patient, who was in complete remission, no pathologic accumulation of I-131 MIBG was found. I-131 MIBG images were also normal in four patients with other types of neoplastic diseases. A boy with multiple metastases was treated with 100 mCi of I-131 MIBG. He developed transient gastrointestinal illness and there was no regression of the tumor deposits. In one girl with a large adrenal neuroblastoma high uptake of I-131 MIBG was observed. She received two therapy doses of I-131 MIBG (35 mCi and 75 mCi) with curative intention giving a total absorbed dose in the tumor of approximately 76 Gy. In spite of high retention of radioactivity in the tumor, regression did not occur, but her general condition was improved. In the present study, images of superior quality were obtained with I-123 MIBG imaging. It is concluded that imaging using I-131 MIBG or I-123 MIBG should be used in both the initial evaluation and the follow-up of children with neuroblastoma

Autoantibody signature differentiates Wilms tumor patients from neuroblastoma patients.

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Jana Schmitt

Full Text Available Several studies report autoantibody signatures in cancer. The majority of these studies analyzed adult tumors and compared the seroreactivity pattern of tumor patients with the pattern in healthy controls. Here, we compared the autoimmune response in patients with neuroblastoma and patients with Wilms tumor representing two different childhood tumors. We were able to differentiate untreated neuroblastoma patients from untreated Wilms tumor patients with an accuracy of 86.8%, a sensitivity of 87.0% and a specificity of 86.7%. The separation of treated neuroblastoma patients from treated Wilms tumor patients' yielded comparable results with an accuracy of 83.8%. We furthermore identified the antigens that contribute most to the differentiation between both tumor types. The analysis of these antigens revealed that neuroblastoma was considerably more immunogenic than Wilms tumor. The reported antigens have not been found to be relevant for comparative analyses between other tumors and controls. In summary, neuroblastoma appears as a highly immunogenic tumor as demonstrated by the extended number of antigens that separate this tumor from Wilms tumor.

Multiple mechanisms disrupt the let-7 microRNA family in neuroblastoma

Science.gov (United States)

Powers, John T; Tsanov, Kaloyan M; Pearson, Daniel S; Roels, Frederik; Spina, Catherine S; Ebright, Richard; Seligson, Marc; de Soysa, Yvanka; Cahan, Patrick; Theiβen, Jessica; Tu, Ho-Chou; Han, Areum; Kurek, Kyle C; LaPier, Grace S; Osborne, Jihan K; Ross, Samantha J; Cesana, Marcella; Collins, James J; Berthold, Frank; Daley, George Q

2016-01-01

Poor prognosis in neuroblastoma is associated with genetic amplification of MYCN. MYCN is itself a target of let-7, a tumor suppressor family of microRNAs implicated in numerous cancers. LIN28B, an inhibitor of let-7 biogenesis, is overexpressed in neuroblastoma and has been reported to regulate MYCN. However, here we show that LIN28B is dispensable in MYCN-amplified neuroblastoma cell lines, despite de-repression of let-7. We further demonstrate that MYCN mRNA levels in amplified disease are exceptionally high and sufficient to sponge let-7, which reconciles the dispensability of LIN28B. We found that genetic loss of let-7 is common in neuroblastoma, inversely associated with MYCN-amplification, and independently associated with poor outcomes, providing a rationale for chromosomal loss patterns in neuroblastoma. We propose that let-7 disruption by LIN28B, MYCN sponging, or genetic loss is a unifying mechanism of neuroblastoma pathogenesis with broad implications for cancer pathogenesis. PMID:27383785

Neuron-NG2 Cell Synapses: Novel Functions for Regulating NG2 Cell Proliferation and Differentiation

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Qian-Kun Yang

2013-01-01

Full Text Available NG2 cells are a population of CNS cells that are distinct from neurons, mature oligodendrocytes, astrocytes, and microglia. These cells can be identified by their NG2 proteoglycan expression. NG2 cells have a highly branched morphology, with abundant processes radiating from the cell body, and express a complex set of voltage-gated channels, AMPA/kainate, and GABA receptors. Neurons notably form classical and nonclassical synapses with NG2 cells, which have varied characteristics and functions. Neuron-NG2 cell synapses could fine-tune NG2 cell activities, including the NG2 cell cycle, differentiation, migration, and myelination, and may be a novel potential therapeutic target for NG2 cell-related diseases, such as hypoxia-ischemia injury and periventricular leukomalacia. Furthermore, neuron-NG2 cell synapses may be correlated with the plasticity of CNS in adulthood with the synaptic contacts passing onto their progenies during proliferation, and synaptic contacts decrease rapidly upon NG2 cell differentiation. In this review, we highlight the characteristics of classical and nonclassical neuron-NG2 cell synapses, the potential functions, and the fate of synaptic contacts during proliferation and differentiation, with the emphasis on the regulation of the NG2 cell cycle by neuron-NG2 cell synapses and their potential underlying mechanisms.

Neuroblastoma: morphological pattern, molecular genetic features, and prognostic factors

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A. M. Stroganova

2016-01-01

Full Text Available Neuroblastoma, the most common extracranial tumor of childhood, arises from the developing neurons of the sympathetic nervous system (neural cress stem cells and has various biological and clinical characteristics. The mean age at disease onset is 18 months. Neuroblastoma has a number of unique characteristics: a capacity for spontaneous regression in babies younger than 12 months even in the presence of distant metastases, for differentiation (maturation into ganglioneuroma in infants after the first year of life, and for swift aggressive development and rapid metastasis. There are 2 clinical classifications of neuroblastoma: the International neuroblastoma staging system that is based on surgical results and the International Neuroblastoma Risk Group Staging System. One of the fundamentally important problems for the clinical picture of neuroblastoma is difficulties making its prognosis. Along with clinical parameters (a patient’s age, tumor extent and site, some histological, molecular biochemical (ploidy and genetic (chromosomal aberrations, MYCN gene status, deletion of the locus 1p36 and 11q, the longer arm of chromosome 17, etc. characteristics of tumor cells are of considerable promise. MYCN gene amplification is observed in 20–30 % of primary neuroblastomas and it is one of the major indicators of disease aggressiveness, early chemotherapy resistance, and a poor prognosis. There are 2 types of MYCN gene amplification: extrachromosomal (double acentric chromosomes and intrachromosomal (homogenically painted regions. Examination of double acentric chromosomes revealed an interesting fact that it may be eliminated (removed from the nucleus through the formation of micronuclei. MYCN oncogene amplification is accompanied frequently by 1p36 locus deletion and longer 17q arm and less frequently by 11q23 deletion; these are poor prognostic factors for the disease. The paper considers in detail the specific, unique characteristics of the

Opioid receptors in human neuroblastoma SH-SY5Y cells: evidence for distinct morphine (. mu. ) and enkephalin (delta) binding sites

Energy Technology Data Exchange (ETDEWEB)

Kazmi, S.M.I.; Mishra, R.K.

1986-06-13

Human neuroblastoma SH-SY5Y cells exhibited a heterogeneous population of ..mu.. and delta types of opioid binding sites. These specific binding sites displayed the characteristic saturability, stereospecificity and reversibility, expected of a receptor. Scatchard analysis of (/sup 3/H)-D-Ala/sup 2/-D-Leu/sup 5/-enkephalin (DADLE) in the presence of 10/sup -5/M D-Pro/sup 4/-morphiceptin (to block the ..mu.. receptors) and the competitive displacement by various highly selective ligands yielded the binding parameters of delta sites which closely resemble those of the delta receptors in brain and mouse neuroblastoma clones. Similarly, the high affinity binding of (/sup 3/H)-dihydromorphine, together with the higher potency of morphine analogues to displace (/sup 3/H)-naloxone binding established the presence of ..mu.. sites. Guanine nucleotides and NaCl significantly inhibited the association and increased the dissociation of (/sup 3/H)-DADLE binding.

High dose melphalan in the treatment of advanced neuroblastoma: results of a randomised trial (ENSG-1) by the European Neuroblastoma Study Group

NARCIS (Netherlands)

Pritchard, Jon; Cotterill, Simon J.; Germond, Shirley M.; Imeson, John; de Kraker, Jan; Jones, David R.

2005-01-01

High dose myeloablative chemotherapy ("megatherapy"), with haematopoietic stem cell support, is now widely used to consolidate response to induction chemotherapy in patients with advanced neuroblastoma. In this study (European Neuroblastoma Study Group, ENSG1), the value of melphalan myeloablative

Integrated imaging using MRI and 123I metaiodobenzylguanidine scintigraphy to improve sensitivity and specificity in the diagnosis of pediatric neuroblastoma.

Science.gov (United States)

Pfluger, Thomas; Schmied, Christoph; Porn, Ute; Leinsinger, Gerda; Vollmar, Christian; Dresel, Stefan; Schmid, Irene; Hahn, Klaus

2003-10-01

The objectives of this study were to compare MRI and iodine-123 ((123)I) metaiodobenzylguanidine (MIBG) scintigraphy in the detection of neuroblastoma lesions in pediatric patients and to assess the additional value of combined imaging. Fifty MRI and 50 (123)I MIBG examinations (mean interval, 6.4 days) were analyzed retrospectively with regard to suspected or proven neuroblastoma lesions (n = 193) in 28 patients. MRI and MIBG scans were reviewed by two independent observers each. Separate and combined analyses of MRI and MIBG scintigraphy were compared with clinical and histologic findings. With regard to the diagnosis of neuroblastoma lesion, MIBG scintigraphy, MRI, and combined analysis showed a sensitivity of 69%, 86%, and 99% and a specificity of 85%, 77%, and 95%, respectively. On MRI, 15 false-positive findings were recorded: posttherapeutic reactive changes (n = 10), benign adrenal tumors (n = 3), and enlarged lymph nodes (n = 2). On MIBG scintigraphy, 10 false-positive findings occurred: ganglioneuromas (n = 2), benign liver tumors (n = 2), and physiologic uptake (n = 6). Thirteen neuroblastoma metastases and two residual masses under treatment with chemotherapy were judged to be false-negative findings on MRI. Two primary or residual neuroblastomas and one orbital metastasis were misinterpreted as Wilms' tumor, reactive changes after surgery, and rhabdomyosarcoma on MRI. Thirty-two bone metastases, six other neuroblastoma metastases, and one adrenal neuroblastoma showed no MIBG uptake. On combined imaging, one false-negative (bone metastasis) and three false-positive (two ganglioneuromas and one pheochromocytoma) findings remained. In the assessment of neuroblastoma lesions in pediatric patients, MRI showed a higher sensitivity and MIBG scintigraphy a higher specificity. However, integrated imaging showed an increase in both sensitivity and specificity.

International consensus for neuroblastoma molecular diagnostics: report from the International Neuroblastoma Risk Group (INRG) Biology Committee

Science.gov (United States)

Ambros, P F; Ambros, I M; Brodeur, G M; Haber, M; Khan, J; Nakagawara, A; Schleiermacher, G; Speleman, F; Spitz, R; London, W B; Cohn, S L; Pearson, A D J; Maris, J M

2009-01-01

Neuroblastoma serves as a paradigm for utilising tumour genomic data for determining patient prognosis and treatment allocation. However, before the establishment of the International Neuroblastoma Risk Group (INRG) Task Force in 2004, international consensus on markers, methodology, and data interpretation did not exist, compromising the reliability of decisive genetic markers and inhibiting translational research efforts. The objectives of the INRG Biology Committee were to identify highly prognostic genetic aberrations to be included in the new INRG risk classification schema and to develop precise definitions, decisive biomarkers, and technique standardisation. The review of the INRG database (n=8800 patients) by the INRG Task Force finally enabled the identification of the most significant neuroblastoma biomarkers. In addition, the Biology Committee compared the standard operating procedures of different cooperative groups to arrive at international consensus for methodology, nomenclature, and future directions. Consensus was reached to include MYCN status, 11q23 allelic status, and ploidy in the INRG classification system on the basis of an evidence-based review of the INRG database. Standardised operating procedures for analysing these genetic factors were adopted, and criteria for proper nomenclature were developed. Neuroblastoma treatment planning is highly dependant on tumour cell genomic features, and it is likely that a comprehensive panel of DNA-based biomarkers will be used in future risk assignment algorithms applying genome-wide techniques. Consensus on methodology and interpretation is essential for uniform INRG classification and will greatly facilitate international and cooperative clinical and translational research studies. PMID:19401703

Neuroprotective Effect of Arctigenin via Upregulation of P-CREB in Mouse Primary Neurons and Human SH-SY5Y Neuroblastoma Cells

Science.gov (United States)

Zhang, Nan; Wen, Qingping; Ren, Lu; Liang, Wenbo; Xia, Yang; Zhang, Xiaodan; Zhao, Dan; Sun, Dong; Hu, Yv; Hao, Haiguang; Yan, Yaping; Zhang, Guangxian; Yang, Jingxian; Kang, Tingguo

2013-01-01

Arctigenin (Arc) has been shown to act on scopolamine-induced memory deficit mice and to provide a neuroprotective effect on cultured cortical neurons from glutamate-induced neurodegeneration through mechanisms not completely defined. Here, we investigated the neuroprotective effect of Arc on H89-induced cell damage and its potential mechanisms in mouse cortical neurons and human SH-SY5Y neuroblastoma cells. We found that Arc prevented cell viability loss induced by H89 in human SH-SY5Y cells. Moreover, Arc reduced intracellular beta amyloid (Aβ) production induced by H89 in neurons and human SH-SY5Y cells, and Arc also inhibited the presenilin 1(PS1) protein level in neurons. In addition, neural apoptosis in both types of cells, inhibition of neurite outgrowth in human SH-SY5Y cells and reduction of synaptic marker synaptophysin (SYN) expression in neurons were also observed after H89 exposure. All these effects induced by H89 were markedly reversed by Arc treatment. Arc also significantly attenuated downregulation of the phosphorylation of CREB (p-CREB) induced by H89, which may contribute to the neuroprotective effects of Arc. These results demonstrated that Arc exerted the ability to protect neurons and SH-SY5Y cells against H89-induced cell injury via upregulation of p-CREB. PMID:24025424

Neuroprotective Effect of Arctigenin via Upregulation of P-CREB in Mouse Primary Neurons and Human SH-SY5Y Neuroblastoma Cells

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Tingguo Kang

2013-09-01

Full Text Available Arctigenin (Arc has been shown to act on scopolamine-induced memory deficit mice and to provide a neuroprotective effect on cultured cortical neurons from glutamate-induced neurodegeneration through mechanisms not completely defined. Here, we investigated the neuroprotective effect of Arc on H89-induced cell damage and its potential mechanisms in mouse cortical neurons and human SH-SY5Y neuroblastoma cells. We found that Arc prevented cell viability loss induced by H89 in human SH-SY5Y cells. Moreover, Arc reduced intracellular beta amyloid (Aβ production induced by H89 in neurons and human SH-SY5Y cells, and Arc also inhibited the presenilin 1(PS1 protein level in neurons. In addition, neural apoptosis in both types of cells, inhibition of neurite outgrowth in human SH-SY5Y cells and reduction of synaptic marker synaptophysin (SYN expression in neurons were also observed after H89 exposure. All these effects induced by H89 were markedly reversed by Arc treatment. Arc also significantly attenuated downregulation of the phosphorylation of CREB (p-CREB induced by H89, which may contribute to the neuroprotective effects of Arc. These results demonstrated that Arc exerted the ability to protect neurons and SH-SY5Y cells against H89-induced cell injury via upregulation of p-CREB.

Comparative Neuroprotective Effects of Dietary Curcumin and Solid Lipid Curcumin Particles in Cultured Mouse Neuroblastoma Cells after Exposure to Aβ42

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Panchanan Maiti

2017-01-01

Full Text Available Aggregation of amyloid beta protein (Aβ and phosphorylated tau (p-Tau plays critical roles in pathogenesis of Alzheimer’s disease (AD. As an antiamyloid natural polyphenol, curcumin (Cur has a potential role in prevention of neurodegeneration in AD. However, due to limited absorption of the dietary Cur, the solid lipid Cur particles (SLCP have been suggested as being more effective for AD therapy. In the present study, we compared the role of dietary Cur and SLCP on oxidative stress, neuronal death, p-Tau level, and certain cell survival markers in vitro, after exposure to Aβ42. Mouse neuroblastoma cells were exposed to Aβ42 for 24 h and incubated with or without dietary Cur and/or SLCP. Reactive oxygen species (ROS, apoptotic cell death, p-Tau, and tau kinase (including GSK-3β and cell survival markers, such as total Akt, phosphorylated Akt, and PSD95 levels were investigated. SLCP showed greater permeability than dietary Cur in vitro, decreased ROS production, and prevented apoptotic death. In addition, SLCP also inhibited p-Tau formation and significantly decreased GSK-3β levels. Further, the cell survival markers, such as total Akt, p-Akt, and PSD95 levels, were more effectively maintained by SLCP than dietary Cur in Aβ42 exposed cells. Therefore, SLCP may provide greater neuroprotection than dietary Cur in Alzheimer’s disease.

Clinical experiences in the treatment of neuroblastoma with 131I-metaiodobenzylguanidine

International Nuclear Information System (INIS)

Treuner, J.; Klingebiel, T.; Feine, U.; Buck, J.; Bruchelt, G.; Dopfer, R.; Girgert, R.; Mueller-Schauenburg, W.M.; Meinke, J.; Kaiser, W.

1986-01-01

Treatment of neuroblastoma is an unsolved problem of pediatric oncology. In spite of highly intensified chemotherapy, the long-term survival rate of children with a metastatic neuroblastoma is below 10%. We therefore used 131 I-metaiodobenzylguanidine (MIBG) for the first time to treat children with a neuroblastoma in relapse or primary unresponsiveness to chemotherapy. We had previously demonstrated that MIBG is useful for the scintigraphic imaging of neuroblastoma lesions and had investigated the cytotoxicity and uptake of MIBG in various neuroblastoma cell lines. We treated 6 children with neuroblastoma in a total of 19 courses. Three of the children suffered from a relapse of neuroblastoma; 3 had never gained a remission. Four of the 6 children lost their bone pain and fever during the first 3 days. In 5 of the 6 children the solid tumor as well as the bone marrow infiltration responded to MIBG treatment, with responses ranging from transitory decrease of the tumor mass to complete disappearance of abdominal tumors. We also witnessed a stabilization of osteolytic lesions, a decrease in elevated serum catecholamines, and a decrease in bone marrow infiltration. Five of the 6 children died of tumor progression 55-249 days after the first MIBG treatment

PI3K/AKT and ERK regulate retinoic acid-induced neuroblastoma cellular differentiation

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Qiao, Jingbo [Department of Pediatric Surgery, Vanderbilt University Medical Center, Nashville, TN 37232 (United States); Paul, Pritha; Lee, Sora [Department of Pediatric Surgery, Vanderbilt University Medical Center, Nashville, TN 37232 (United States); Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN 37232 (United States); Qiao, Lan; Josifi, Erlena; Tiao, Joshua R. [Department of Pediatric Surgery, Vanderbilt University Medical Center, Nashville, TN 37232 (United States); Chung, Dai H., E-mail: dai.chung@vanderbilt.edu [Department of Pediatric Surgery, Vanderbilt University Medical Center, Nashville, TN 37232 (United States); Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN 37232 (United States)

2012-08-03

Highlights: Black-Right-Pointing-Pointer Retinoic acid (RA) induces neuroblastoma cells differentiation, which is accompanied by G0/G1 cell cycle arrest. Black-Right-Pointing-Pointer RA resulted in neuroblastoma cell survival and inhibition of DNA fragmentation; this is regulated by PI3K pathway. Black-Right-Pointing-Pointer RA activates PI3K and ERK1/2 pathway; PI3K pathway mediates RA-induced neuroblastoma cell differentiation. Black-Right-Pointing-Pointer Upregulation of p21 is necessary for RA-induced neuroblastoma cell differentiation. -- Abstract: Neuroblastoma, the most common extra-cranial solid tumor in infants and children, is characterized by a high rate of spontaneous remissions in infancy. Retinoic acid (RA) has been known to induce neuroblastoma differentiation; however, the molecular mechanisms and signaling pathways that are responsible for RA-mediated neuroblastoma cell differentiation remain unclear. Here, we sought to determine the cell signaling processes involved in RA-induced cellular differentiation. Upon RA administration, human neuroblastoma cell lines, SK-N-SH and BE(2)-C, demonstrated neurite extensions, which is an indicator of neuronal cell differentiation. Moreover, cell cycle arrest occurred in G1/G0 phase. The protein levels of cyclin-dependent kinase inhibitors, p21 and p27{sup Kip}, which inhibit cell proliferation by blocking cell cycle progression at G1/S phase, increased after RA treatment. Interestingly, RA promoted cell survival during the differentiation process, hence suggesting a potential mechanism for neuroblastoma resistance to RA therapy. Importantly, we found that the PI3K/AKT pathway is required for RA-induced neuroblastoma cell differentiation. Our results elucidated the molecular mechanism of RA-induced neuroblastoma cellular differentiation, which may be important for developing novel therapeutic strategy against poorly differentiated neuroblastoma.

Identification of membrane-type 1 matrix metalloproteinase tyrosine phosphorylation in association with neuroblastoma progression

International Nuclear Information System (INIS)

Nyalendo, Carine; Sartelet, Hervé; Barrette, Stéphane; Ohta, Shigeru; Gingras, Denis; Béliveau, Richard

2009-01-01

Neuroblastoma is a pediatric tumor of neural crest cells that is clinically characterized by its variable evolution, from spontaneous regression to malignancy. Despite many advances in neuroblastoma research, 60% of neuroblastoma, which are essentially metastatic cases, are associated with poor clinical outcome due to the lack of effectiveness of current therapeutic strategies. Membrane-type 1 matrix metalloproteinase (MT1-MMP, MMP-14), an enzyme involved in several steps in tumor progression, has previously been shown to be associated with poor clinical outcome for neuroblastoma. Based on our recent demonstration that MT1-MMP phosphorylation is involved in the growth of fibrosarcoma tumors, we examined the potential role of phosphorylated MT1-MMP in neuroblastoma progression. Tyrosine phosphorylated MT1-MMP was immunostained on tissue microarray samples from 55 patients with neuroblastoma detected by mass screening (known to be predominantly associated with favourable outcome), and from 234 patients with standard diagnosed neuroblastoma. In addition, the effects of a non phosphorylable version of MT1-MMP on neuroblastoma cell migration and proliferation were investigated within three-dimensional collagen matrices. Although there is no correlation between the extent of tyrosine phosphorylation of MT1-MMP (pMT1-MMP) and MYCN amplification or clinical stage, we observed greater phosphorylation of pMT1-MMP in standard neuroblastoma, while it is less evident in neuroblastoma from mass screening samples (P = 0.0006) or in neuroblastoma samples from patients younger than one year (P = 0.0002). In vitro experiments showed that overexpression of a non-phosphorylable version of MT1-MMP reduced MT1-MMP-mediated neuroblastoma cell migration and proliferation within a three-dimensional type I collagen matrix, suggesting a role for the phosphorylated enzyme in the invasive properties of neuroblastoma cells. Overall, these results suggest that tyrosine phosphorylated MT1-MMP

Cholinergic regulation of VIP gene expression in human neuroblastoma cells

DEFF Research Database (Denmark)

Kristensen, Bo; Georg, Birgitte; Fahrenkrug, Jan

1997-01-01

Vasoactive intestinal polypeptide, muscarinic receptor, neuroblastoma cell, mRNA, gene expression, peptide processing......Vasoactive intestinal polypeptide, muscarinic receptor, neuroblastoma cell, mRNA, gene expression, peptide processing...

A novel homologous model for gene therapy of dwarfism by non-viral transfer of the mouse growth hormone gene into immunocompetent dwarf mice.

Science.gov (United States)

Cecchi, Claudia R; Higuti, Eliza; Oliveira, Nelio A J; Lima, Eliana R; Jakobsen, Maria; Dagnaes-Hansen, Frederick; Gissel, Hanne; Aagaard, Lars; Jensen, Thomas G; Jorge, Alexander A L; Bartolini, Paolo; Peroni, Cibele N

2014-02-01

The possibilities for non-viral GH gene therapy are studied in immunocompetent dwarf mice (lit/lit). As expression vector we used a plasmid previously employed in immunodeficient dwarf mice (pUBI-hGH-gDNA) by replacing the human GH gene with the genomic sequence of mouse-GH DNA (pUBI-mGH-gDNA). HEK-293 human cells transfected with pUBI-mGH-gDNA produced 3.0 µg mGH/10(6) cells/day compared to 3.7 µg hGH/10(6) cells/day for pUBIhGH- gDNA transfected cells. The weight of lit/lit mice treated with the same two plasmids (50 µg DNA/mouse) by electrotransfer into the quadriceps muscle was followed for 3 months. The weight increase up to 15 days for mGH, hGH and saline treated mice were 0.130, 0.112 and 0.027 g/mouse/day. Most sera from hGH-treated mice contained anti-hGH antibodies already on day 15, with the highest titers on day 45, while no significant anti-mGH antibodies were observed in mGH-treated mice. At the end of 3 months, the weight increase for mGH-treated mice was 34.3%, while the nose-to-tail and femur lengths increased 9.5% and 24.3%. Mouse-GH and hGH circulating levels were 4-5 ng/mL 15 days after treatment, versus control levels of ~0.7 ng GH/mL (Pdeficiency.

Upregulation of LYAR induces neuroblastoma cell proliferation and survival.

Science.gov (United States)

Sun, Yuting; Atmadibrata, Bernard; Yu, Denise; Wong, Matthew; Liu, Bing; Ho, Nicholas; Ling, Dora; Tee, Andrew E; Wang, Jenny; Mungrue, Imran N; Liu, Pei Y; Liu, Tao

2017-09-01

The N-Myc oncoprotein induces neuroblastoma by regulating gene transcription and consequently causing cell proliferation. Paradoxically, N-Myc is well known to induce apoptosis by upregulating pro-apoptosis genes, and it is not clear how N-Myc overexpressing neuroblastoma cells escape N-Myc-mediated apoptosis. The nuclear zinc finger protein LYAR has recently been shown to modulate gene expression by forming a protein complex with the protein arginine methyltransferase PRMT5. Here we showed that N-Myc upregulated LYAR gene expression by binding to its gene promoter. Genome-wide differential gene expression studies revealed that knocking down LYAR considerably upregulated the expression of oxidative stress genes including CHAC1, which depletes intracellular glutathione and induces oxidative stress. Although knocking down LYAR expression with siRNAs induced oxidative stress, neuroblastoma cell growth inhibition and apoptosis, co-treatment with the glutathione supplement N-acetyl-l-cysteine or co-transfection with CHAC1 siRNAs blocked the effect of LYAR siRNAs. Importantly, high levels of LYAR gene expression in human neuroblastoma tissues predicted poor event-free and overall survival in neuroblastoma patients, independent of the best current markers for poor prognosis. Taken together, our data suggest that LYAR induces proliferation and promotes survival of neuroblastoma cells by repressing the expression of oxidative stress genes such as CHAC1 and suppressing oxidative stress, and identify LYAR as a novel co-factor in N-Myc oncogenesis.

Advances in Risk Classification and Treatment Strategies for Neuroblastoma

Science.gov (United States)

Pinto, Navin R.; Applebaum, Mark A.; Volchenboum, Samuel L.; Matthay, Katherine K.; London, Wendy B.; Ambros, Peter F.; Nakagawara, Akira; Berthold, Frank; Schleiermacher, Gudrun; Park, Julie R.; Valteau-Couanet, Dominique; Pearson, Andrew D.J.

2015-01-01

Risk-based treatment approaches for neuroblastoma have been ongoing for decades. However, the criteria used to define risk in various institutional and cooperative groups were disparate, limiting the ability to compare clinical trial results. To mitigate this problem and enhance collaborative research, homogenous pretreatment patient cohorts have been defined by the International Neuroblastoma Risk Group classification system. During the past 30 years, increasingly intensive, multimodality approaches have been developed to treat patients who are classified as high risk, whereas patients with low- or intermediate-risk neuroblastoma have received reduced therapy. This treatment approach has resulted in improved outcome, although survival for high-risk patients remains poor, emphasizing the need for more effective treatments. Increased knowledge regarding the biology and genetic basis of neuroblastoma has led to the discovery of druggable targets and promising, new therapeutic approaches. Collaborative efforts of institutions and international cooperative groups have led to advances in our understanding of neuroblastoma biology, refinements in risk classification, and stratified treatment strategies, resulting in improved outcome. International collaboration will be even more critical when evaluating therapies designed to treat small cohorts of patients with rare actionable mutations. PMID:26304901

Remaining Sites Verification Package for the 100-F-36, 108-F Biological Laboratory, and for the 116-F-15, 108-F Radiation Crib. Attachment to Waste Site Reclassification Form 2007-002 and 2007-003

International Nuclear Information System (INIS)

Dittmer, L.M.

2007-01-01

The 116-F-15 waste site is the former location of the 108-F Radiation Crib that was located in the first floor of the 108-F Biological Laboratory. In accordance with this evaluation, the verification sampling results support a reclassification of this site to Interim Closed Out. The current site conditions achieve the remedial action objectives and the corresponding remedial action goals established in the Remaining Sites ROD. The results of verification sampling show that residual contaminant concentrations do not preclude any future uses and allow for unrestricted use of shallow zone soils. The results also demonstrate that residual contaminant concentrations are protective of groundwater and the Columbia River

Identification of two distinct chromosome 12-derived amplification units in neuroblastoma cell line NGP

NARCIS (Netherlands)

van Roy, N.; Forus, A.; Myklebost, O.; Cheng, N. C.; Versteeg, R.; Speleman, F.

1995-01-01

The neuroblastoma cell line NGP contains two homogeneously staining regions (hsr). One of these hsrs contains MYCN sequences. Reverse painting experiments demonstrated that the second HSR consisted of two chromosome 12-derived amplification units, located at 12q14-15 and 12q24. Southern blot and

Drugs Approved for Neuroblastoma

Science.gov (United States)

This page lists cancer drugs approved by the Food and Drug Administration (FDA) for neuroblastoma. The list includes generic names and brand names. The drug names link to NCI's Cancer Drug Information summaries.

Radiosensitivity of neuroblastoma

International Nuclear Information System (INIS)

Deacon, J.M.; Wilson, P.; Steel, G.G.

1985-01-01

Neuroblastoma is known to be clinically radioresponsive: it is possible to obtain local tumour control with relatively small doses of radiation. The main therapeutic problem, however, is one of metastatic disease, where in spite of modern combination chemotherapy, the prognosis remains poor. Systemic therapy with either drugs or radiation is dose-limited by toxicity to bone marrow stem cells. However, the advent of new technology which enables tumour cells to be removed from infiltrated marrow prior to autologous bone marrow ''rescue'' allows dose escalation, and makes the use of systemic irradiation in the treatment of stage IV disease feasible. The objective of this study was to investigate the radiobiology of neuroblastoma in detail, including intrinsic cellular radiosensitivity, repair capacity, and extrinsic dose-modifying factors which may affect tumour response in vivo. Cells at three levels of organisation were used: single cell suspensions multicellular tumour spheroids; and xenografts grown in immune-suppressed mice

Intrarenal neuroblastoma mimics Wilms' tumor

International Nuclear Information System (INIS)

Muniz, Maria T. Cartaxo; Soares, Andrezza B.; Freitas, Elizabete M.; Araujo, Marcela; Pureza, Leda M.M.; Morais, Adriana; Antunes, Consuelo; Salles, Terezinha de J. Marques; Borges, Josenilda C.; Morais, Vera L.L. de; Romualdo Filho, Jose; Magalhaes, Mario H.

2005-01-01

This work reports the case history of a child with intrarenal neuroblastoma, initially diagnosed as Wilms' tumor. The patient, a one year and three months old girl, presented a hard abdominal mass on the left flank that extended to the meso gastric region, plus fever and paleness. The ultrasound of the entire abdomen revealed an intrarenal mass. Biopsy with fine needle in many points of the tumor revealed Wilms' tumor. The scarcely of the material, however, made immunohistoquemistry impossible at that moment. Because of the child's severe condition the SIOP protocol was started. As no clinical response was observed, an exploratory laparotomy was indicated with partial resection of the tumor and bone marrow aspiration (MO). The histopathologic study revealed a malignant neoplasia of small cells, poorly differentiated. IHQ was negative for WT-1 and positive for NB-84, synaptofisin, cromogranine. N-myc amplification was observed by molecular biology. The bone marrow aspiration identified metastatic small round cells infiltration. Intrarenal neuroblastoma is a rare entity that clinically and radiographically resembles Wilms' tumor. The objective of this case report is to show the importance of immunohistochemical and molecular analysis in the diagnosis of intrarenal neuroblastoma. (author)

7 CFR 3550.108 - Security requirements (loans only).

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2010-01-01

... 7 Agriculture 15 2010-01-01 2010-01-01 false Security requirements (loans only). 3550.108 Section..., DEPARTMENT OF AGRICULTURE DIRECT SINGLE FAMILY HOUSING LOANS AND GRANTS Section 504 Origination and Section 306C Water and Waste Disposal Grants § 3550.108 Security requirements (loans only). When the total...

Magnetic resonance imaging of olfactory neuroblastoma

International Nuclear Information System (INIS)

Iio, Mitsuhiro; Homma, Akihiro; Furuta, Yasushi; Fukuda, Satoshi

2006-01-01

Olfactory neuroblastoma is an uncommon intranasal tumor originating from olfactory neuroepithelium. Despite the development of electron microscopy and immunohistochemical testing, the pathological diagnosis of this tumor is still difficult because of the wide range of histological features. Magnetic resonance imaging (MR) of this tumor and the pattern of contrast enhancement have not been well described. The purpose of this report was to analyze the MR characteristics of olfactory neuroblastomas. The MR signal, pattern of contrast enhancement, and correlation with high-resolution computed tomography (CT) imaging were examined. Seventeen patients with olfactory neuroblastoma were treated at Hokkaido University Hospital and a related hospital during the past 25 years. MR images taken in 12 patients and CT images taken in 9 patients with histologically confirmed olfactory neuroblastoma were retrospectively reviewed. Compared with brain gray matter, 11 tumors were hypointense on T1-weighted images, 9 homogeneously and 2 heterogeneously. Eight tumors were hyperintense on T2-weighted images, 3 homogeneously and 5 heterogeneously, although their appearance was less intense than that of sinusitis. Gadolinium enhancement was moderate in one case and marked in 10 of the 11 cases, 9 homogeneously and 2 heterogeneously. Nine of the 11 tumors showed smooth regular shaped margins; 2 of these tumors exhibited irregular infiltrating margins on gadolinium-enhanced images, compared to the pre-contrast T1-weighted images. Eight of the 11 tumors had clearly demarcated margins, while 3 of the 11 tumors did not exhibit gadolinium enhancement. Six of the 12 cases (50%) exhibited intracranial cysts on the gadolinium-enhanced images. T2-weighted or gadolinium-enhanced images successfully distinguished sinusitis from tumors in 4 cases whereas the CT images failed. Gadolinium enhancement, particularly in the tangential plane, demonstrated intracranial extension not apparent on the CT images

Ataxia-telangiectasia mutated (ATM) silencing promotes neuroblastoma progression through a MYCN independent mechanism

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Mandriota, Stefano J.; Valentijn, Linda J.; Lesne, Laurence; Betts, David R.; Marino, Denis; Boudal-Khoshbeen, Mary; London, Wendy B.; Rougemont, Anne-Laure; Attiyeh, Edward F.; Maris, John M.; Hogarty, Michael D.; Koster, Jan; Molenaar, Jan J.; Versteeg, Rogier

2015-01-01

Neuroblastoma, a childhood cancer with highly heterogeneous biology and clinical behavior, is characterized by genomic aberrations including amplification of MYCN. Hemizygous deletion of chromosome 11q is a well-established, independent marker of poor prognosis. While 11q22-q23 is the most frequently deleted region, the neuroblastoma tumor suppressor in this region remains to be identified. Chromosome bands 11q22-q23 contain ATM, a cell cycle checkpoint kinase and tumor suppressor playing a pivotal role in the DNA damage response. Here, we report that haploinsufficiency of ATM in neuroblastoma correlates with lower ATM expression, event-free survival, and overall survival. ATM loss occurs in high stage neuroblastoma without MYCN amplification. In SK-N-SH, CLB-Ga and GI-ME-N human neuroblastoma cells, stable ATM silencing promotes neuroblastoma progression in soft agar assays, and in subcutaneous xenografts in nude mice. This effect is dependent on the extent of ATM silencing and does not appear to involve MYCN. Our findings identify ATM as a potential haploinsufficient neuroblastoma tumor suppressor, whose inactivation mirrors the increased aggressiveness associated with 11q deletion in neuroblastoma. PMID:26053094

Novel targeted therapy for neuroblastoma: silencing the MXD3 gene using siRNA.

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Duong, Connie; Yoshida, Sakiko; Chen, Cathy; Barisone, Gustavo; Diaz, Elva; Li, Yueju; Beckett, Laurel; Chung, Jong; Antony, Reuben; Nolta, Jan; Nitin, Nitin; Satake, Noriko

2017-09-01

BackgroundNeuroblastoma is the second most common extracranial cancer in children. Current therapies for neuroblastoma, which use a combination of chemotherapy drugs, have limitations for high-risk subtypes and can cause significant long-term adverse effects in young patients. Therefore, a new therapy is needed. In this study, we investigated the transcription factor MXD3 as a potential therapeutic target in neuroblastoma.MethodsMXD3 expression was analyzed in five neuroblastoma cell lines by immunocytochemistry and quantitative real-time reverse transcription PCR, and in 18 primary patient tumor samples by immunohistochemistry. We developed nanocomplexes using siRNA and superparamagnetic iron oxide nanoparticles to target MXD3 in neuroblastoma cell lines in vitro as a single-agent therapeutic and in combination with doxorubicin, vincristine, cisplatin, or maphosphamide-common drugs used in current neuroblastoma treatment.ResultsMXD3 was highly expressed in neuroblastoma cell lines and in patient tumors that had high-risk features. Neuroblastoma cells treated in vitro with the MXD3 siRNA nanocomplexes showed MXD3 protein knockdown and resulted in cell apoptosis. Furthermore, on combining MXD3 siRNA nanocomplexes with each of the four drugs, all showed additive efficacy.ConclusionThese results indicate that MXD3 is a potential new target and that the use of MXD3 siRNA nanocomplexes is a novel therapeutic approach for neuroblastoma.

RSRC1 and CPZ gene polymorphisms with neuroblastoma susceptibility in Chinese children.

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Tang, Jue; Liu, Wei; Zhu, Jinhong; Zhang, Jiao; Wang, Feng-Hua; Liang, Jiang-Hua; Zeng, Jia-Hang; Wang, Hui; Xia, Huimin; He, Jing

2018-07-01

Two new neuroblastoma susceptibility loci at 3q25 (RSRC1 rs6441201 G > A) and 4p16 (CPZ rs3796725 T > C and rs3796727 A > G) were identified by a genome-wide association study (GWAS) involving Italians, African Americans and European Americans. In this case-control study with 393 neuroblastoma cases and 812 controls, we investigated the association between these three polymorphisms and neuroblastoma susceptibility in Chinese population. We found that participants harboring the RSRC1 rs6441201A allele were associated with an increased risk of neuroblastoma (AA vs. GG: adjusted OR = 1.55, 95% CI = 1.03-2.34, P = 0.036). No significant association between the CPZ polymorphisms (rs3796725 T > C and rs3796727A > G) and neuroblastoma susceptibility was observed. In conclusion, our results confirm that the RSRC1 rs6441201A allele is associated with neuroblastoma susceptibility in Chinese population. Copyright © 2018 Elsevier B.V. All rights reserved.

Somatic PTPN11 Mutation in a Child With Neuroblastoma and Protein Losing Enteropathy.

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Obasaju, Patience; Brondon, Jennifer; Mir, Sabina; Fordham, Lynn A; Lee, Sang; Blatt, Julie

2018-05-01

Neuroblastoma and protein losing enteropathy (PLE) are diagnoses commonly seen by oncologists and gastroenterologists, respectively. The concurrence of these 2 entities is rare, and not well explained. We describe the sixth case of PLE in a child with neuroblastoma, and the first for which genetic information is available. Tumor DNA had a mutation in the PTPN11 gene, which has been described in neuroblastoma, and in Noonan syndrome-a diagnosis in which neuroblastoma and PLE independently have been reported. Constitutional DNA was normal. Genetic studies in future patients will be needed to support the link between neuroblastoma and PLE.

Anti-angiogenic SPARC peptides inhibit progression of neuroblastoma tumors

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Tian Yufeng

2010-06-01

Full Text Available Abstract Background New, more effective strategies are needed to treat highly aggressive neuroblastoma. Our laboratory has previously shown that full-length Secreted Protein Acidic and Rich in Cysteine (SPARC and a SPARC peptide corresponding to the follistatin domain of the protein (FS-E potently block angiogenesis and inhibit the growth of neuroblastoma tumors in preclinical models. Peptide FS-E is structurally complex and difficult to produce, limiting its potential as a therapeutic in the clinic. Results In this study, we synthesized two smaller and structurally more simple SPARC peptides, FSEN and FSEC, that respectively correspond to the N-and C-terminal loops of peptide FS-E. We show that both peptides FSEN and FSEC have anti-angiogenic activity in vitro and in vivo, although FSEC is more potent. Peptide FSEC also significantly inhibited the growth of neuroblastoma xenografts. Histologic examination demonstrated characteristic features of tumor angiogenesis with structurally abnormal, tortuous blood vessels in control neuroblastoma xenografts. In contrast, the blood vessels observed in tumors, treated with SPARC peptides, were thin walled and structurally more normal. Using a novel method to quantitatively assess blood vessel abnormality we demonstrated that both SPARC peptides induced changes in blood vessel architecture that are consistent with blood vessel normalization. Conclusion Our results demonstrate that SPARC peptide FSEC has potent anti-angiogenic and anti-tumorigenic effects in neuroblastoma. Its simple structure and ease of production indicate that it may have clinical utility in the treatment of high-risk neuroblastoma and other types of pediatric and adult cancers, which depend on angiogenesis.

Noscapine induced apoptosis via downregulation of survivin in human neuroblastoma cells having wild type or null p53.

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Shiwang Li

Full Text Available Neuroblastoma is the most common extracranial solid tumor of childhood. It accounts for 15% of pediatric cancer deaths. Chemotherapy is the mainstay of treatment in children with advanced neuroblastoma. Noscapine, a nontoxic natural compound, can trigger apoptosis in many cancer types. We now show that p53 is dispensable for Noscapine-induced cell death in neuroblastoma cell lines, proapoptotic response to this promising chemopreventive agent is mediated by suppression of survivin protein expression. The Noscapine treatment increased levels of total and Ser(15-phosphorylated p53 protein in SK-SY5Y cells, but the proapoptotic response to this agent was maintained even after knockdown of the p53 protein level. Exposure of SK-SY5Y and LA1-5S cells to Noscapine resulted in a marked decrease in protein and mRNA level of survivin as early as 12 hours after treatment. Ectopic expression of survivin conferred statistically significant protection against Noscapine-mediated cytoplasmic histone-associated apoptotic DNA fragmentation. Also, the Noscapine-induced apoptosis was modestly but statistically significantly augmented by RNA interference of survivin in both cell lines. Furthermore, Noscapine-induced apoptotic cell death was associated with activation of caspase-3 and cleavage of PARP. In conclusion, the present study provides novel insight into the molecular circuitry of Noscapine-induced apoptosis to indicate suppression of survivin expression as a critical mediator of this process.

Targeted BCL2 inhibition effectively inhibits neuroblastoma tumour growth

NARCIS (Netherlands)

Lamers, Fieke; Schild, Linda; den Hartog, Ilona J. M.; Ebus, Marli E.; Westerhout, Ellen M.; Ora, Ingrid; Koster, Jan; Versteeg, Rogier; Caron, Huib N.; Molenaar, Jan J.

2012-01-01

Genomic aberrations of key regulators of the apoptotic pathway have hardly been identified in neuroblastoma. We detected high BCL2 mRNA and protein levels in the majority of neuroblastoma tumours by Affymetrix expression profiling and Tissue Micro Array analysis. This BCL2 mRNA expression is

Neuroblastoma arginase activity creates an immunosuppressive microenvironment that impairs autologous and engineered immunity

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Mussai, Francis; Egan, Sharon; Hunter, Stuart; Webber, Hannah; Fisher, Jonathan; Wheat, Rachel; McConville, Carmel; Sbirkov, Yordan; Wheeler, Kate; Bendle, Gavin; Petrie, Kevin; Anderson, John; Chesler, Louis; De Santo, Carmela

2015-01-01

Neuroblastoma is the most common extra cranial solid tumour of childhood, and survival remains poor for patients with advanced disease. Novel immune therapies are currently in development, but clinical outcomes have not matched preclinical results. Here, we describe key mechanisms in which neuroblastoma inhibits the immune response. We show that murine and human neuroblastoma tumour cells suppress T cell proliferation, through increased arginase activity. Arginase II is the predominant isoform expressed and creates an arginine deplete local and systemic microenvironment. Neuroblastoma arginase activity results in inhibition of myeloid cell activation and suppression of bone marrow CD34+ progenitor proliferation. Finally we demonstrate that the arginase activity of neuroblastoma impairs NY-ESO-1 specific TCR and GD2-specific CAR engineered T cell proliferation and cytotoxicity. High arginase II expression correlates with poor survival for neuroblastoma patients. The results support the hypothesis that neuroblastoma creates an arginase-dependent immunosuppressive microenvironment in both the tumour and blood that leads to impaired immune surveillance and sub-optimal efficacy of immunotherapeutic approaches. PMID:26054597

Neuroblastoma trial to overcome a rare malignant disease

International Nuclear Information System (INIS)

Fukushima, Takashi; Shichino, Hiroyuki; Kumagai, Masaaki

2007-01-01

Neuroblastoma is one of the main causes of children's deaths in Japan and many developed countries, although it is a rather rare pediatric cancer. Many clinical studies have been carried out and reported. The clinical study system of Japan is much different from the systems of the other countries. In Japan, the main hospitals, where clinical study including clinical trials have been conducted, are not only national centers but also many regional or prefectural centers. Progression-free survival has been achieved in over 80% of low-risk patients, and in about 40% of high-risk patients. These are the same as the outcomes of neuroblastoma patients in European countries and North America. Further clinical studies and translational research should be planned especially regarding high-risk neuroblastomas. (author)

A Hybrid Robotic Control System Using Neuroblastoma Cultures

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Ferrández, J. M.; Lorente, V.; Cuadra, J. M.; Delapaz, F.; Álvarez-Sánchez, José Ramón; Fernández, E.

The main objective of this work is to analyze the computing capabilities of human neuroblastoma cultured cells and to define connection schemes for controlling a robot behavior. Multielectrode Array (MEA) setups have been designed for direct culturing neural cells over silicon or glass substrates, providing the capability to stimulate and record simultaneously populations of neural cells. This paper describes the process of growing human neuroblastoma cells over MEA substrates and tries to modulate the natural physiologic responses of these cells by tetanic stimulation of the culture. We show that the large neuroblastoma networks developed in cultured MEAs are capable of learning: establishing numerous and dynamic connections, with modifiability induced by external stimuli and we propose an hybrid system for controlling a robot to avoid obstacles.

Fator de diferenciação de crescimento 15: um novo biomarcador em pacientes com disfunção diastólica? Factor de diferenciación de crecimiento 15: ¿un nuevo biomarcador en pacientes con disfunción diastólica? Growth-differentiation factor-15: a novel biomarker in patients with diastolic dysfunction?

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Wilfried Dinh

2011-07-01

Full Text Available FUNDAMENTO: O fator de diferenciação de crescimento-15 ou GDF-15, uma citocina de resposta ao estresse relacionada ao fator transformador de crescimento beta (TGF-ß, está elevado e independentemente relacionado à prognóstico adverso na insuficiência cardíaca sistólica. OBJETIVO: O objetivo do presente estudo é investigar os níveis plasmáticos de GDF-15 em pacientes com disfunção diastólica pré-clínica ou insuficiência cardíaca com fração de ejeção normal (ICFEN. MÉTODOS: Avaliamos 119 pacientes com fração de ejeção (FE normal, encaminhados à angiografia coronariana eletiva, dos quais 75 (63% tinham doença arterial coronariana (DAC. Os indivíduos foram classificados como tendo disfunção diastólica ventricular esquerda leve (DDVE grau I, n = 61, ICFEN (DDVE grau II ou III, n = 38 ou função diastólica normal (controles, n = 20. Em um subgrupo de 20 indivíduos, alterações no débito cardíaco (DC foram medidas através de reinalação de gás inerte (Innocor® em resposta a um teste hemodinâmico ortostático. RESULTADOS: Os níveis de GDF-15 na ICFEN [mediana 1,08, variação interquartil (0,88-1,30 ng/ml] eram significantemente mais altos do que nos controles [0,60 (0,50-0,71 ng/ml, p = 0,003] e em pacientes com DDVE grau I [0,78 (0,62-1,04 ng/ml, p FUNDAMENTO: El factor de diferenciación de crecimiento-15 o GDF-15, una citocina de respuesta al estrés relacionada con el factor transformador de crecimiento beta (TGF-ß, es elevado y está independientemente relacionado con el pronóstico adverso en la insuficiencia cardíaca sistólica. OBJETIVO: El objetivo del presente estudio es investigar los niveles plasmáticos de GDF-15 en pacientes con disfunción diastólica preclínica o insuficiencia cardíaca con fracción de eyección normal (ICFEN. MÉTODOS: Evaluamos a 119 pacientes con fracción de eyección (FE normal, derivados a angiografía coronaria electiva, de los cuales 75 (63%, tenían enfermedad

Evidence of chromaffin oxygen sensing in neuroblastoma.

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Hedborg, F; Franklin, G; Norrman, J; Grimelius, L; Wassberg, E; Hero, B; Schilling, F; Berthold, F; Harms, D; Sandstedt, B

2001-01-01

With the aid of IGF2 and VEGF in situ hybridization; tyrosine hydroxylase, chromogranin A, and Ki67 immunohistochemistry; and TUNEL staining applied to a large series of clinical neuroblastomas and to an animal model, we show here that stroma-poor neuroblastomas show evidence of chromaffin differentiation similar to that of type 1 small intensely fluorescent (SIF) cells and that this occurs in a vascular-dependent fashion, indicating a role for local tumor hypoxia in the differentiation process.

[Cervical neuroblastoma in an infant].

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Arvai, Krisztina; Tóth, Judit; Németh, Tamás; Kiss, Csongor; Molnár, Péter; Oláh, Eva

2004-01-01

The case of a one-month-old patient admitted to the Department of Pediatrics (Medical and Health Science Center, Debrecen University) because of respiratory distress caused by a cervical mass compressing the upper respiratory pathways is presented. The mass could only be partially removed, the histological diagnosis proved to be neuroblastoma (SBCT: "small blue cell tumor"). Despite the fact that the DNA index of tumor cells (ploidy measurements) and the age of the patient suggested a favourable prognosis, the tumor continued to grow and metastases appeared. Because of symptoms of compression exerted on the respiratory system by the tumor, chemotherapy had to be applied. Since a standard OPEC/OJEC chemotherapeutic protocol proved to be not entirely effective and a residual tumor was still present, retinoic acid and interferon treatment was introduced. Presently, 4 years after the diagnosis, the patient is in complete remission and can be considered to be cured. The case presented here demonstrates that despite the favorable prognosis of the majority of infant neuroblastomas, in some cases the anatomic location of the tumor, leading to disturbance of vital functions, may serve as indication of chemotherapy. Our experience also proved the efficacy of retinoic acid and interferon treatment in relapsed neuroblastoma.

Seleno methionine-75 as a scanning agent for neuroblastoma

International Nuclear Information System (INIS)

Covington, E.E.; D'Angio, G.J.; Helson, L.; Romano, R.W.

1974-01-01

Neuroblastoma is a functioning tumor and patients with this tumor are known to excrete vanilmandelic acid and other degradation products of norepinephrine. It also accumulates and produces excess cystathionine for which methionine is a precursor in the normal anabolic pathway. This was the rationale for testing 75 Se-methionine as a possible scanning agent in patients with neuroblastoma. D'Angio et al reported the results of a preliminary investigation in which 3 of 4 patients with neuroblastoma, all with known metastases of the skull, had positive scans correctly localizing the disease. These preliminary data seemed encouraging, and further investigation was undertaken. The results are reported

Exploring the Nature of Silicon-Noble Gas Bonds in H3SiNgNSi and HSiNgNSi Compounds (Ng = Xe, Rn

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Sudip Pan

2015-03-01

Full Text Available Ab initio and density functional theory-based computations are performed to investigate the structure and stability of H3SiNgNSi and HSiNgNSi compounds (Ng = Xe, Rn. They are thermochemically unstable with respect to the dissociation channel producing Ng and H3SiNSi or HSiNSi. However, they are kinetically stable with respect to this dissociation channel having activation free energy barriers of 19.3 and 23.3 kcal/mol for H3SiXeNSi and H3SiRnNSi, respectively, and 9.2 and 12.8 kcal/mol for HSiXeNSi and HSiRnNSi, respectively. The rest of the possible dissociation channels are endergonic in nature at room temperature for Rn analogues. However, one three-body dissociation channel for H3SiXeNSi and one two-body and one three-body dissociation channels for HSiXeNSi are slightly exergonic in nature at room temperature. They become endergonic at slightly lower temperature. The nature of bonding between Ng and Si/N is analyzed by natural bond order, electron density and energy decomposition analyses. Natural population analysis indicates that they could be best represented as (H3SiNg+(NSi− and (HSiNg+(NSi−. Energy decomposition analysis further reveals that the contribution from the orbital term (ΔEorb is dominant (ca. 67%–75% towards the total attraction energy associated with the Si-Ng bond, whereas the electrostatic term (ΔEelstat contributes the maximum (ca. 66%–68% for the same in the Ng–N bond, implying the covalent nature of the former bond and the ionic nature of the latter.

Identification of ALK as the Major Familial Neuroblastoma Predisposition Gene

Science.gov (United States)

Mossë, Yalë P; Laudenslager, Marci; Longo, Luca; Cole, Kristina A; Wood, Andrew; Attiyeh, Edward F; Laquaglia, Michael J; Sennett, Rachel; Lynch, Jill E; Perri, Patrizia; Laureys, Geneviève; Speleman, Frank; Hakonarson, Hakon; Torkamani, Ali; Schork, Nicholas J; Brodeur, Garrett M; Tonini, Gian Paolo; Rappaport, Eric; Devoto, Marcella; Maris, John M

2009-01-01

SUMMARY Survival rates for the childhood cancer neuroblastoma have not substantively improved despite dramatic escalation in chemotherapy intensity. Like most human cancers, this embryonal malignancy can be inherited, but the genetic etiology of familial and sporadically occurring neuroblastoma was largely unknown. Here we show that germline mutations in the anaplastic lymphoma kinase gene (ALK) explain the majority of hereditary neuroblastomas, and that activating mutations can also be somatically acquired. We first identified a significant linkage signal at the short arm of chromosome 2 (maximum nonparametric LOD=4.23 at rs1344063) using a whole-genome scan in neuroblastoma pedigrees. Resequencing of regional candidate genes identified three separate missense mutations in the tyrosine kinase domain of ALK (G1128A, R1192P and R1275Q) that segregated with the disease in eight separate families. Examination of 491 sporadically occurring human neuroblastoma samples showed that the ALK locus was gained in 22.8%, and highly amplified in an additional 3.3%, and that these aberrations were highly associated with death from disease (P=0.0003). Resequencing of 194 high-risk neuroblastoma samples showed somatically acquired mutations within the tyrosine kinase domain in 12.4%. Nine of the ten mutations map to critical regions of the kinase domain and were predicted to be oncogenic drivers with high probability. Mutations resulted in constitutive phosphorylation consistent with activation, and targeted knockdown of ALK mRNA resulted in profound growth inhibition of 4 of 4 cell lines harboring mutant or amplified ALK, as well as 2 of 6 wild type for ALK. Our results demonstrate that heritable mutations of ALK are the major cause of familial neuroblastoma, and that germline or acquired activation of this cell surface kinase is a tractable therapeutic target for this lethal pediatric malignancy. PMID:18724359

Early detection of tumor relapse/regrowth by consecutive minimal residual disease monitoring in high-risk neuroblastoma patients

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Hirase, Satoshi; Saitoh, Atsuro; Hartomo, Tri Budi; Kozaki, Aiko; Yanai, Tomoko; Hasegawa, Daiichiro; Kawasaki, Keiichiro; Kosaka, Yoshiyuki; Matsuo, Masafumi; Yamamoto, Nobuyuki; Mori, Takeshi; Hayakawa, Akira; Iijima, Kazumoto; Nishio, Hisahide; Nishimura, Noriyuki

2016-01-01

Neuroblastoma is an aggressive pediatric tumor accounting for ~15% of cancer-associated mortalities in children. Despite the current intensive therapy, >50% of high-risk patients experience tumor relapse or regrowth caused by the activation of minimal residual disease (MRD). Although several MRD detection protocols using various reverse transcription-quantitative polymerase chain reaction (RT-qPCR) markers have been reported to evaluate the therapeutic response and disease status of neuroblastoma patients, their clinical significance remains elusive. The present study reports two high-risk neuroblastoma patients, whose MRD was consecutively monitored using 11 RT-qPCR markers (CHRNA3, CRMP1, DBH, DCX, DDC, GABRB3, GAP43, ISL1, KIF1A, PHOX2B and TH) during their course of treatment. The two patients initially responded to the induction therapy and reached MRD-negative status. The patients' MRD subsequently became positive with no elevation of their urinary homovanillic acid, urinary vanillylmandelic acid and serum neuron-specific enolase levels at 13 or 19 weeks prior to the clinical diagnosis of tumor relapse or regrowth. The present cases highlight the possibility of consecutive MRD monitoring using 11 markers to enable an early detection of tumor relapse or regrowth in high-risk neuroblastoma patients. PMID:27446404

Identification of BIRC6 as a novel intervention target for neuroblastoma therapy

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Lamers Fieke

2012-07-01

Full Text Available Abstract Background Neuroblastoma are pediatric tumors of the sympathetic nervous system with a poor prognosis. Apoptosis is often deregulated in cancer cells, but only a few defects in apoptotic routes have been identified in neuroblastoma. Methods Here we investigated genomic aberrations affecting genes of the intrinsic apoptotic pathway in neuroblastoma. We analyzed DNA profiling data (CGH and SNP arrays and mRNA expression data of 31 genes of the intrinsic apoptotic pathway in a dataset of 88 neuroblastoma tumors using the R2 bioinformatic platform (http://r2.amc.nl. BIRC6 was selected for further analysis as a tumor driving gene. Knockdown experiments were performed using BIRC6 lentiviral shRNA and phenotype responses were analyzed by Western blot and MTT-assays. In addition, DIABLO levels and interactions were investigated with immunofluorescence and co-immunoprecipitation. Results We observed frequent gain of the BIRC6 gene on chromosome 2, which resulted in increased mRNA expression. BIRC6 is an inhibitor of apoptosis protein (IAP, that can bind and degrade the cytoplasmic fraction of the pro-apoptotic protein DIABLO. DIABLO mRNA expression was exceptionally high in neuroblastoma but the protein was only detected in the mitochondria. Upon silencing of BIRC6 by shRNA, DIABLO protein levels increased and cells went into apoptosis. Co-immunoprecipitation confirmed direct interaction between DIABLO and BIRC6 in neuroblastoma cell lines. Conclusion Our findings indicate that BIRC6 may have a potential oncogenic role in neuroblastoma by inactivating cytoplasmic DIABLO. BIRC6 inhibition may therefore provide a means for therapeutic intervention in neuroblastoma.

Identification of BIRC6 as a novel intervention target for neuroblastoma therapy

International Nuclear Information System (INIS)

Lamers, Fieke; Molenaar, Jan J; Schild, Linda; Koster, Jan; Speleman, Frank; Øra, Ingrid; Westerhout, Ellen M; Sluis, Peter van; Versteeg, Rogier; Caron, Huib N

2012-01-01

Neuroblastoma are pediatric tumors of the sympathetic nervous system with a poor prognosis. Apoptosis is often deregulated in cancer cells, but only a few defects in apoptotic routes have been identified in neuroblastoma. Here we investigated genomic aberrations affecting genes of the intrinsic apoptotic pathway in neuroblastoma. We analyzed DNA profiling data (CGH and SNP arrays) and mRNA expression data of 31 genes of the intrinsic apoptotic pathway in a dataset of 88 neuroblastoma tumors using the R2 bioinformatic platform. BIRC6 was selected for further analysis as a tumor driving gene. Knockdown experiments were performed using BIRC6 lentiviral shRNA and phenotype responses were analyzed by Western blot and MTT-assays. In addition, DIABLO levels and interactions were investigated with immunofluorescence and co-immunoprecipitation. We observed frequent gain of the BIRC6 gene on chromosome 2, which resulted in increased mRNA expression. BIRC6 is an inhibitor of apoptosis protein (IAP), that can bind and degrade the cytoplasmic fraction of the pro-apoptotic protein DIABLO. DIABLO mRNA expression was exceptionally high in neuroblastoma but the protein was only detected in the mitochondria. Upon silencing of BIRC6 by shRNA, DIABLO protein levels increased and cells went into apoptosis. Co-immunoprecipitation confirmed direct interaction between DIABLO and BIRC6 in neuroblastoma cell lines. Our findings indicate that BIRC6 may have a potential oncogenic role in neuroblastoma by inactivating cytoplasmic DIABLO. BIRC6 inhibition may therefore provide a means for therapeutic intervention in neuroblastoma

Neuroblastoma, a Paradigm for Big Data Science in Pediatric Oncology.

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Salazar, Brittany M; Balczewski, Emily A; Ung, Choong Yong; Zhu, Shizhen

2016-12-27

Pediatric cancers rarely exhibit recurrent mutational events when compared to most adult cancers. This poses a challenge in understanding how cancers initiate, progress, and metastasize in early childhood. Also, due to limited detected driver mutations, it is difficult to benchmark key genes for drug development. In this review, we use neuroblastoma, a pediatric solid tumor of neural crest origin, as a paradigm for exploring "big data" applications in pediatric oncology. Computational strategies derived from big data science-network- and machine learning-based modeling and drug repositioning-hold the promise of shedding new light on the molecular mechanisms driving neuroblastoma pathogenesis and identifying potential therapeutics to combat this devastating disease. These strategies integrate robust data input, from genomic and transcriptomic studies, clinical data, and in vivo and in vitro experimental models specific to neuroblastoma and other types of cancers that closely mimic its biological characteristics. We discuss contexts in which "big data" and computational approaches, especially network-based modeling, may advance neuroblastoma research, describe currently available data and resources, and propose future models of strategic data collection and analyses for neuroblastoma and other related diseases.

Neuroblastoma, a Paradigm for Big Data Science in Pediatric Oncology

Directory of Open Access Journals (Sweden)

Brittany M. Salazar

2016-12-01

Full Text Available Pediatric cancers rarely exhibit recurrent mutational events when compared to most adult cancers. This poses a challenge in understanding how cancers initiate, progress, and metastasize in early childhood. Also, due to limited detected driver mutations, it is difficult to benchmark key genes for drug development. In this review, we use neuroblastoma, a pediatric solid tumor of neural crest origin, as a paradigm for exploring “big data” applications in pediatric oncology. Computational strategies derived from big data science–network- and machine learning-based modeling and drug repositioning—hold the promise of shedding new light on the molecular mechanisms driving neuroblastoma pathogenesis and identifying potential therapeutics to combat this devastating disease. These strategies integrate robust data input, from genomic and transcriptomic studies, clinical data, and in vivo and in vitro experimental models specific to neuroblastoma and other types of cancers that closely mimic its biological characteristics. We discuss contexts in which “big data” and computational approaches, especially network-based modeling, may advance neuroblastoma research, describe currently available data and resources, and propose future models of strategic data collection and analyses for neuroblastoma and other related diseases.

Post treatment PSA nadirs support continuing dose escalation study in patients with pretreatment PSA levels >10 ng/ml, but not in those with PSA <10 NG/ML

International Nuclear Information System (INIS)

Herold, D.H.; Hanlon, A.L.; Movsas, B.; Hanks, G.E.

1996-01-01

Purpose: We have recently shown that ICRU reporting point radiation doses above 71 Gy are not associated with improved bNED survival in prostate cancer patients with pretreatment PSA level 20 ng/ml we found a strong correlation between dose and nadir values < 1.0 ng/ml (p=.003) as well as for nadir's < 0.5 ng/ml (p=.04). This dose/nadir effect held at several dose levels, but 74 Gy for nadir values < 1.0 ng/ml and 72 Gy for nadir's < 0.5 ng/ml remained the most significant. 32% of these patients achieved a nadir < 1.0ng/ml and 15% < 0.5ng/ml. Conclusions: This analysis provides strong additional support that patients with pretreatment PSA values of < 10 ng/ml do not benefit from dose escalation beyond an ICRU reporting point dose of 71 Gy. For patients with pretreatment PSA's of 10-19.9 ng/ml there is no dose/nadir response evaluated at a nadir of 1.0 ng/ml; however, there is a borderline effect observed at a nadir of 0.5 ng/ml. Patients with pretreatment PSA's of 20 ng/ml or greater clearly benefit from higher doses as evaluated by PSA nadirs of 1.0 ng/ml, and 0.5 ng/ml. These studies support the continued investigation of dose escalation in treating patients with PSA levels over 10 ng/ml, they do not support continued investigation of dose escalation beyond 71 Gy in patients with pretreatment PSA levels < 10 ng/ml. The failure to demonstrate any dose response for the low PSA group and the finding of only a borderline effect for the intermediate PSA group may be influenced by the relatively small number of patients in our series treated to doses < 70 Gy and the fact that none of our patients were treated to doses below 65.98 Gy. The lower limit of acceptible dose has yet to be defined

Convolutional deep belief network with feature encoding for classification of neuroblastoma histological images

Directory of Open Access Journals (Sweden)

Soheila Gheisari

2018-01-01

Full Text Available Background: Neuroblastoma is the most common extracranial solid tumor in children younger than 5 years old. Optimal management of neuroblastic tumors depends on many factors including histopathological classification. The gold standard for classification of neuroblastoma histological images is visual microscopic assessment. In this study, we propose and evaluate a deep learning approach to classify high-resolution digital images of neuroblastoma histology into five different classes determined by the Shimada classification. Subjects and Methods: We apply a combination of convolutional deep belief network (CDBN with feature encoding algorithm that automatically classifies digital images of neuroblastoma histology into five different classes. We design a three-layer CDBN to extract high-level features from neuroblastoma histological images and combine with a feature encoding model to extract features that are highly discriminative in the classification task. The extracted features are classified into five different classes using a support vector machine classifier. Data: We constructed a dataset of 1043 neuroblastoma histological images derived from Aperio scanner from 125 patients representing different classes of neuroblastoma tumors. Results: The weighted average F-measure of 86.01% was obtained from the selected high-level features, outperforming state-of-the-art methods. Conclusion: The proposed computer-aided classification system, which uses the combination of deep architecture and feature encoding to learn high-level features, is highly effective in the classification of neuroblastoma histological images.

Neuroblastoma na Criança: Relato de Caso/Neuroblastoma in Children: Case Report

Directory of Open Access Journals (Sweden)

Maysa Carla Mendonça Tame

2013-03-01

Full Text Available Introdução: o neuroblastoma é uma neoplasia maligna, que apresenta ampla variedade em termos de localização, característica histopatológica e biológica. A apresentação clínica, extremamente variável, reflete as possíveis localizações do tumor primário dentro do sistema nervoso simpático. Os sintomas mais frequentes incluem, dor e distensão abdominais, dores ósseas localizadas, sintomas sistêmicos (anorexia, mal-estar geral, febre e diarreia. É um tumor raro, com uma incidência de 10 casos por milhão de crianças entre zero e quatro anos de idade. Casuística: Relatou-se o caso de um paciente, atualmente com quatro anos e oito meses, com neuroblastoma, tumor primário de supra-adrenal esquerda, metastático para medula óssea bilateral e múltiplos ossos, que iniciou tratamento quimioterápico-neoadjuvante, imediatamente após o diagnóstico, com posterior avaliação para cirurgia, quimioterapia adjuvante e radioterapia, e transplante autólogo de medula óssea. O tratamento se baseia na estratificação do grupo de risco, podendo envolver: quimioterapia, radioterapia, cirurgia para ressecção do tumor e transplante autólogo de medula óssea. O prognóstico está relacionado com a idade da criança ao diagnóstico, determinadas características histológicas, estadiamento e com alterações genéticas do tumor. Discussão: Seguindo o protocolo, o tumor foi estadiado em nível 4, segundo o International Neuroblastoma Staging System (INSS, e proposto o tratamento com multimodalidade, que inclui quimioterapia intensiva com uma combinação de agentes, seguida de ressecção cirúrgica, doses elevadas de quimioterapia, e radioterapia para posterior transplante autólogo de medula óssea. Este tratamento foi iniciado pela paciente no dia 24/08/2011, e tem previsão de duração de no mínimo um ano. Introduction: Neuroblastoma is a malignant neoplasm that presents a wide variety in terms of location, histopathological and

Effects of 1950 MHz radiofrequency electromagnetic fields on Aβ processing in human neuroblastoma and mouse hippocampal neuronal cells

International Nuclear Information System (INIS)

Park, Jeongyeon; Kwon, Jong Hwa; Kim, Nam; Song, Kiwon

2018-01-01

Alzheimer’s disease (AD) is a neurodegenerative disease leading to progressive loss of memory and other cognitive functions. One of the well-known pathological markers of AD is the accumulation of amyloid-beta protein (Aβ), and its plaques, in the brain. Recent studies using Tg-5XFAD mice as a model of AD have reported that exposure to radiofrequency electromagnetic fields (RF-EMF) from cellular phones reduced Aβ plaques in the brain and showed beneficial effects on AD. In this study, we examined whether exposure to 1950 MHz RF-EMF affects Aβ processing in neural cells. We exposed HT22 mouse hippocampal neuronal cells and SH-SY5Y human neuroblastoma cells to RF-EMF (SAR 6 W/kg) for 2 h per day for 3 days, and analyzed the mRNA and protein expression of the key genes related to Aβ processing. When exposed to RF-EMF, mRNA levels of APP, BACE1, ADAM10 and PSEN1 were decreased in HT22, but the mRNA level of APP was not changed in SH-SY5Y cells. The protein expression of APP and BACE1, as well as the secreted Aβ peptide, was not significantly different between RF-EMF–exposed 7w-PSML, HT22 and SH-SY5Y cells and the unexposed controls. These observations suggest that RF-EMF exposure may not have a significant physiological effect on Aβ processing of neural cells in the short term. However, considering that we only exposed HT22 and SH-SY5Y cells to RF-EMF for 2 h per day for 3 days, we cannot exclude the possibility that 1950 MHz RF-EMF induces physiological change in Aβ processing with long-term and continuous exposure.

Ectopic olfactory neuroblastoma: report of four cases and a review of the literature.

LENUS (Irish Health Repository)

Wormald, R

2011-04-01

Our objective is to present a short series of four rare cases of ectopic olfactory neuroblastoma. Our methods present four case reports of ectopic olfactory neuroblastoma and a review of the literature for management and treatment of this disease. The results indicate short case series reports of ectopic olfactory neuroblastoma arising from the anterior ethmoidal sinuses, the nasopharynx, the lateral nasal wall and the floor of the nose. The discussion focuses on likely origins of ectopic olfactory neuroblastoma, its clinical features and management. We conclude that ectopic olfactory neuroblastoma is a rare disease. Treatment principles are the same for non-ectopic disease and guided by extension into adjacent structures such as the orbit or anterior cranial fossa and usually involves surgery with or without adjuvant radiotherapy.

PD-L1 Is a Therapeutic Target of the Bromodomain Inhibitor JQ1 and, Combined with HLA Class I, a Promising Prognostic Biomarker in Neuroblastoma.

Science.gov (United States)

Melaiu, Ombretta; Mina, Marco; Chierici, Marco; Boldrini, Renata; Jurman, Giuseppe; Romania, Paolo; D'Alicandro, Valerio; Benedetti, Maria C; Castellano, Aurora; Liu, Tao; Furlanello, Cesare; Locatelli, Franco; Fruci, Doriana

2017-08-01

Purpose: This study sought to evaluate the expression of programmed cell death-ligand-1 (PD-L1) and HLA class I on neuroblastoma cells and programmed cell death-1 (PD-1) and lymphocyte activation gene 3 (LAG3) on tumor-infiltrating lymphocytes to better define patient risk stratification and understand whether this tumor may benefit from therapies targeting immune checkpoint molecules. Experimental Design: In situ IHC staining for PD-L1, HLA class I, PD-1, and LAG3 was assessed in 77 neuroblastoma specimens, previously characterized for tumor-infiltrating T-cell density and correlated with clinical outcome. Surface expression of PD-L1 was evaluated by flow cytometry and IHC in neuroblastoma cell lines and tumors genetically and/or pharmacologically inhibited for MYC and MYCN. A dataset of 477 human primary neuroblastomas from GEO and ArrayExpress databases was explored for PD-L1, MYC, and MYCN correlation. Results: Multivariate Cox regression analysis demonstrated that the combination of PD-L1 and HLA class I tumor cell density is a prognostic biomarker for predicting overall survival in neuroblastoma patients ( P = 0.0448). MYC and MYCN control the expression of PD-L1 in neuroblastoma cells both in vitro and in vivo Consistently, abundance of PD-L1 transcript correlates with MYC expression in primary neuroblastoma. Conclusions: The combination of PD-L1 and HLA class I represents a novel prognostic biomarker for neuroblastoma. Pharmacologic inhibition of MYCN and MYC may be exploited to target PD-L1 and restore an efficient antitumor immunity in high-risk neuroblastoma. Clin Cancer Res; 23(15); 4462-72. ©2017 AACR . ©2017 American Association for Cancer Research.

Differential regulation of cyclin-dependent kinase inhibitors in neuroblastoma cells

Energy Technology Data Exchange (ETDEWEB)

Qiao, Lan [Department of Pediatric Surgery, Vanderbilt University Medical Center, Nashville, TN 37232 (United States); Department of Pharmaceutical Sciences, Jilin University, Changchun 130021 (China); Paul, Pritha; Lee, Sora [Department of Pediatric Surgery, Vanderbilt University Medical Center, Nashville, TN 37232 (United States); Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN 37232 (United States); Qiao, Jingbo [Department of Pediatric Surgery, Vanderbilt University Medical Center, Nashville, TN 37232 (United States); Wang, Yongsheng [Department of Pharmaceutical Sciences, Jilin University, Changchun 130021 (China); Chung, Dai H., E-mail: dai.chung@vanderbilt.edu [Department of Pediatric Surgery, Vanderbilt University Medical Center, Nashville, TN 37232 (United States); Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN 37232 (United States)

2013-05-31

Highlights: •GRP-R signaling differentially regulated the expression of p21 and p27. •Silencing GRP/GRP-R downregulated p21, while p27 expression was upregulated. •Inhibition of GRP/GRP-R signaling enhanced PTEN expression, correlative to the increased expression of p27. •PTEN and p27 co-localized in cytoplasm and silencing PTEN decreased p27 expression. -- Abstract: Gastrin-releasing peptide (GRP) and its receptor (GRP-R) are highly expressed in undifferentiated neuroblastoma, and they play critical roles in oncogenesis. We previously reported that GRP activates the PI3K/AKT signaling pathway to promote DNA synthesis and cell cycle progression in neuroblastoma cells. Conversely, GRP-R silencing induces cell cycle arrest. Here, we speculated that GRP/GRP-R signaling induces neuroblastoma cell proliferation via regulation of cyclin-dependent kinase (CDK) inhibitors. Surprisingly, we found that GRP/GRP-R differentially induced expressions of p21 and p27. Silencing GRP/GRP-R decreased p21, but it increased p27 expressions in neuroblastoma cells. Furthermore, we found that the intracellular localization of p21 and p27 in the nuclear and cytoplasmic compartments, respectively. In addition, we found that GRP/GRP-R silencing increased the expression and accumulation of PTEN in the cytoplasm of neuroblastoma cells where it co-localized with p27, thus suggesting that p27 promotes the function of PTEN as a tumor suppressor by stabilizing PTEN in the cytoplasm. GRP/GRP-R regulation of CDK inhibitors and tumor suppressor PTEN may be critical for tumoriogenesis of neuroblastoma.

Differential regulation of cyclin-dependent kinase inhibitors in neuroblastoma cells

International Nuclear Information System (INIS)

Qiao, Lan; Paul, Pritha; Lee, Sora; Qiao, Jingbo; Wang, Yongsheng; Chung, Dai H.

2013-01-01

Highlights: •GRP-R signaling differentially regulated the expression of p21 and p27. •Silencing GRP/GRP-R downregulated p21, while p27 expression was upregulated. •Inhibition of GRP/GRP-R signaling enhanced PTEN expression, correlative to the increased expression of p27. •PTEN and p27 co-localized in cytoplasm and silencing PTEN decreased p27 expression. -- Abstract: Gastrin-releasing peptide (GRP) and its receptor (GRP-R) are highly expressed in undifferentiated neuroblastoma, and they play critical roles in oncogenesis. We previously reported that GRP activates the PI3K/AKT signaling pathway to promote DNA synthesis and cell cycle progression in neuroblastoma cells. Conversely, GRP-R silencing induces cell cycle arrest. Here, we speculated that GRP/GRP-R signaling induces neuroblastoma cell proliferation via regulation of cyclin-dependent kinase (CDK) inhibitors. Surprisingly, we found that GRP/GRP-R differentially induced expressions of p21 and p27. Silencing GRP/GRP-R decreased p21, but it increased p27 expressions in neuroblastoma cells. Furthermore, we found that the intracellular localization of p21 and p27 in the nuclear and cytoplasmic compartments, respectively. In addition, we found that GRP/GRP-R silencing increased the expression and accumulation of PTEN in the cytoplasm of neuroblastoma cells where it co-localized with p27, thus suggesting that p27 promotes the function of PTEN as a tumor suppressor by stabilizing PTEN in the cytoplasm. GRP/GRP-R regulation of CDK inhibitors and tumor suppressor PTEN may be critical for tumoriogenesis of neuroblastoma

1H, 15N and 13C NMR Assignments of Mouse Methionine Sulfoxide Reductase B2

Science.gov (United States)

Breivik, Åshild S.; Aachmann, Finn L.; Sal, Lena S.; Kim, Hwa-Young; Del Conte, Rebecca; Gladyshev, Vadim N.; Dikiy, Alexander

2011-01-01

A recombinant mouse methionine-r-sulfoxide reductase 2 (MsrB2ΔS) isotopically labeled with 15N and 15N/13C was generated. We report here the 1H, 15N and 13C NMR assignments of the reduced form of this protein. PMID:19636904

The circling mutant Pcdh15roda is a new mouse model for hearing loss.

Science.gov (United States)

Torres, Adriana Amorim; Rzadzinska, Agnieszka K; Ribeiro, Andrea Frozino; Silva, Daniel Almeida da Silva E; Guénet, Jean-Louis; Massironi, Sílvia Maria Gomes; Godard, Ana Lúcia Brunialti

2013-01-01

Mouse mutagenesis is a key tool for studying gene function and several mutant alleles have been described and constitute mouse models for human hereditary diseases. Genetic hearing loss represents over 50% of all hearing loss cases in children and, due to the heterogeneity of the disorder, there is still a demand for the isolation and characterization of new genes and alleles. Here we report phenotypic and molecular characterization of a new mouse model for hereditary hearing loss. The mutant rodador, isolated by Massironi and colleagues in 2006, presents an autosomal recessive disorder characterized by deafness and balance dysfunction associated with abnormal stereocilia in the inner ear. The mutation was mapped to mouse chromosome 10, and characterization of the gene Pcdh15 revealed an AT-to-GC transition in intron 23 of mutant animals. The alteration led to the switch of a dinucleotide ApA for ApG, creating a novel intronic acceptor splice site, which leads to incorporation of eight intronic bases into the processed mRNA and alteration of the downstream reading frame. In silico analysis indicated that the mutated protein is truncated and lacks two cadherin domains, and the transmembrane and cytoplasmic domains. Real Time PCR analyses revealed a significantly reduced Pcdh15 mRNA level in the brain of mutant mice, which might be due to the mechanism of non-sense mediated decay. In man, mutations in the orthologue PCDH15 cause non-syndromic deafness and Usher Syndrome Type 1F, a genetic disorder characterized by hearing loss and retinitis pigmentosa. Rodador mouse constitutes a new model for studying deafness in these conditions and may help in the comprehension of the pathogeneses of the disease, as well as of the mechanisms involved in the morphogenesis and function of inner ear stereocilia. This is a new ENU-induced allele and the first isolated in a BALB/c background. Copyright © 2013 Elsevier B.V. All rights reserved.

Kinome expression profiling of human neuroblastoma tumors identifies potential drug targets for ultra high-risk patients

NARCIS (Netherlands)

Russo, Roberta; Cimmino, Flora; Pezone, Lucia; Manna, Francesco; Avitabile, Marianna; Langella, Concetta; Koster, Jan; Casale, Fiorina; Raia, Maddalena; Viola, Giampietro; Fischer, Matthias; Iolascon, Achille; Capasso, Mario

2017-01-01

Neuroblastoma (NBL) accounts for >7% of malignancies in patients younger than 15 years. Low- and intermediate-risk patients exhibit excellent or good prognosis after treatment, whereas for high-risk (HR) patients, the estimated 5-year survival rates is still <40%. The ability to stratify HR patients

Scalable and template-free synthesis of nanostructured Na{sub 1.08}V{sub 6}O{sub 15} as high-performance cathode material for lithium-ion batteries

Energy Technology Data Exchange (ETDEWEB)

Zheng, Shili, E-mail: slzheng@ipe.ac.cn [National Engineering Laboratory for Hydrometallurgical Cleaner Production Technology, Key Laboratory of Green Process and Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing (China); Wang, Xinran; Yan, Hong [National Engineering Laboratory for Hydrometallurgical Cleaner Production Technology, Key Laboratory of Green Process and Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing (China); University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing (China); Du, Hao; Zhang, Yi [National Engineering Laboratory for Hydrometallurgical Cleaner Production Technology, Key Laboratory of Green Process and Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing (China)

2016-09-15

Highlights: • Nanostructured Na{sub 1.08}V{sub 6}O{sub 15} was synthesized through additive-free sol-gel process. • Prepared Na{sub 1.08}V{sub 6}O{sub 15} demonstrated high capacity and sufficient cycling stability. • The reaction temperature was optimized to allow scalable Na{sub 1.08}V{sub 6}O{sub 15} fabrication. - Abstract: Developing high-capacity cathode material with feasibility and scalability is still challenging for lithium-ion batteries (LIBs). In this study, a high-capacity ternary sodium vanadate compound, nanostructured NaV{sub 6}O{sub 15}, was template-free synthesized through sol-gel process with high producing efficiency. The as-prepared sample was systematically post-treated at different temperature and the post-annealing temperature was found to determine the cycling stability and capacity of NaV{sub 6}O{sub 15}. The well-crystallized one exhibited good electrochemical performance with a high specific capacity of 302 mAh g{sup −1} when cycled at current density of 0.03 mA g{sup −1}. Its relatively long-term cycling stability was characterized by the cell performance under the current density of 1 A g{sup −1}, delivering a reversible capacity of 118 mAh g{sup −1} after 300 cycles with 79% capacity retention and nearly 100% coulombic efficiency: all demonstrating its significant promise of proposed strategy for large-scale synthesis of NaV{sub 6}O{sub 15} as cathode with high-capacity and high energy density for LIBs.

Identification of epigenetically regulated genes that predict patient outcome in neuroblastoma

International Nuclear Information System (INIS)

Carén, Helena; Djos, Anna; Nethander, Maria; Sjöberg, Rose-Marie; Kogner, Per; Enström, Camilla; Nilsson, Staffan; Martinsson, Tommy

2011-01-01

Epigenetic mechanisms such as DNA methylation and histone modifications are important regulators of gene expression and are frequently involved in silencing tumor suppressor genes. In order to identify genes that are epigenetically regulated in neuroblastoma tumors, we treated four neuroblastoma cell lines with the demethylating agent 5-Aza-2'-deoxycytidine (5-Aza-dC) either separately or in conjunction with the histone deacetylase inhibitor trichostatin A (TSA). Expression was analyzed using whole-genome expression arrays to identify genes activated by the treatment. These data were then combined with data from genome-wide DNA methylation arrays to identify candidate genes silenced in neuroblastoma due to DNA methylation. We present eight genes (KRT19, PRKCDBP, SCNN1A, POU2F2, TGFBI, COL1A2, DHRS3 and DUSP23) that are methylated in neuroblastoma, most of them not previously reported as such, some of which also distinguish between biological subsets of neuroblastoma tumors. Differential methylation was observed for the genes SCNN1A (p < 0.001), PRKCDBP (p < 0.001) and KRT19 (p < 0.01). Among these, the mRNA expression of KRT19 and PRKCDBP was significantly lower in patients that have died from the disease compared with patients with no evidence of disease (fold change -8.3, p = 0.01 for KRT19 and fold change -2.4, p = 0.04 for PRKCDBP). In our study, a low methylation frequency of SCNN1A, PRKCDBP and KRT19 is significantly associated with favorable outcome in neuroblastoma. It is likely that analysis of specific DNA methylation will be one of several methods in future patient therapy stratification protocols for treatment of childhood neuroblastomas

A comprehensive characterization of rare mitochondrial DNA variants in neuroblastoma.

Science.gov (United States)

Calabrese, Francesco Maria; Clima, Rosanna; Pignataro, Piero; Lasorsa, Vito Alessandro; Hogarty, Michael D; Castellano, Aurora; Conte, Massimo; Tonini, Gian Paolo; Iolascon, Achille; Gasparre, Giuseppe; Capasso, Mario

2016-08-02

Neuroblastoma, a tumor of the developing sympathetic nervous system, is a common childhood neoplasm that is often lethal. Mitochondrial DNA (mtDNA) mutations have been found in most tumors including neuroblastoma. We extracted mtDNA data from a cohort of neuroblastoma samples that had undergone Whole Exome Sequencing (WES) and also used snap-frozen samples in which mtDNA was entirely sequenced by Sanger technology. We next undertook the challenge of determining those mutations that are relevant to, or arisen during tumor development. The bioinformatics pipeline used to extract mitochondrial variants from matched tumor/blood samples was enriched by a set of filters inclusive of heteroplasmic fraction, nucleotide variability, and in silico prediction of pathogenicity. Our in silico multistep workflow applied both on WES and Sanger-sequenced neuroblastoma samples, allowed us to identify a limited burden of somatic and germline mitochondrial mutations with a potential pathogenic impact. The few singleton germline and somatic mitochondrial mutations emerged, according to our in silico analysis, do not appear to impact on the development of neuroblastoma. Our findings are consistent with the hypothesis that most mitochondrial somatic mutations can be considered as 'passengers' and consequently have no discernible effect in this type of cancer.

Narcolepsy/Cataplexy and Occult Neuroblastoma

Directory of Open Access Journals (Sweden)

J Gordon Millichap

2013-11-01

Full Text Available Investigators at the University of Chicago and Northwestern University, Chicago, IL; University Hospital Southampton, UK; and Kiev Paediatric Hospital, Ukraine, report three children with narcolepsy and cataplexy subsequently diagnosed with neuroblastoma.

[Analysis of the role of various components of culture media during the proliferation of mouse neuroblastoma NIE-115 cells].

Science.gov (United States)

Aslanidi, K B; Miakisheva, S N

2010-01-01

The values of the parameters of serum-free media (concentration of Na+, amino acids, and carbohydrates, as well as the pH values) have been determined at which the rate of the differentiation of neuroblastoma cells is minimal, and the rate of proliferation is maximal. It was shown that media inducing the differentiation of 70% of cells during the cell cycle provide the maximal time of survival of differentiated cells.

131I-metaiodobenzylguanidine in the treatment of neuroblastoma at diagnosis

International Nuclear Information System (INIS)

Mastrangelo, R.; Troncone, L.; Lasorella, A.; Riccardi, R.; Montemaggi, P.; Rufini, V.

1989-01-01

Radioactive metaiodobenzylguanidine ( 131 I-MIBG) is taken up specifically by neuroblastoma cells and appears to represent a new treatment modality in patients with advanced neuroblastoma. Taking into account the fact that all patients so far treated were heavily pretreated and resistant to chemotherapy, the results obtained appear encouraging. In order to explore further the potential role of this new drug in untreated patients, we treated with 131 I-MIBG a child with stage III neuroblastoma at diagnosis. We observed the complete disappearance of a large abdominal tumor mass after a relatively low dosage of 131 I-MIBG, with minimal hematologic toxicity. No further treatment was given and, at present, the patient is alive with no evidence of disease 18 months from diagnosis. This child represents, to our knowledge, the only case of neuroblastoma thus far treated at diagnosis and the excellent response obtained suggests the need for further investigations of this therapy in untreated patients

The Role of Intracellular Calcium for the Development and Treatment of Neuroblastoma

International Nuclear Information System (INIS)

Satheesh, Noothan Jyothi; Büsselberg, Dietrich

2015-01-01

Neuroblastoma is the second most common paediatric cancer. It develops from undifferentiated simpatico-adrenal lineage cells and is mostly sporadic; however, the aetiology behind the development of neuroblastoma is still not fully understood. Intracellular calcium ([Ca 2+ ] i ) is a secondary messenger which regulates numerous cellular processes and, therefore, its concentration is tightly regulated. This review focuses on the role of [Ca 2+ ] i in differentiation, apoptosis and proliferation in neuroblastoma. It describes the mechanisms by which [Ca 2+ ] i is regulated and how it modulates intracellular pathways. Furthermore, the importance of [Ca 2+ ] i for the function of anti-cancer drugs is illuminated in this review as [Ca 2+ ] i could be a target to improve the outcome of anti-cancer treatment in neuroblastoma. Overall, modulations of [Ca 2+ ] i could be a key target to induce apoptosis in cancer cells leading to a more efficient and effective treatment of neuroblastoma

The Role of Intracellular Calcium for the Development and Treatment of Neuroblastoma

Energy Technology Data Exchange (ETDEWEB)

Satheesh, Noothan Jyothi; Büsselberg, Dietrich, E-mail: dib2015@qatar-med.cornell.edu [Weill Cornell Medical College in Qatar, Qatar Foundation-Education City, POB 24144, Doha (Qatar)

2015-05-22

Neuroblastoma is the second most common paediatric cancer. It develops from undifferentiated simpatico-adrenal lineage cells and is mostly sporadic; however, the aetiology behind the development of neuroblastoma is still not fully understood. Intracellular calcium ([Ca{sup 2+}]{sub i}) is a secondary messenger which regulates numerous cellular processes and, therefore, its concentration is tightly regulated. This review focuses on the role of [Ca{sup 2+}]{sub i} in differentiation, apoptosis and proliferation in neuroblastoma. It describes the mechanisms by which [Ca{sup 2+}]{sub i} is regulated and how it modulates intracellular pathways. Furthermore, the importance of [Ca{sup 2+}]{sub i} for the function of anti-cancer drugs is illuminated in this review as [Ca{sup 2+}]{sub i} could be a target to improve the outcome of anti-cancer treatment in neuroblastoma. Overall, modulations of [Ca{sup 2+}]{sub i} could be a key target to induce apoptosis in cancer cells leading to a more efficient and effective treatment of neuroblastoma.

MicroRNA-34a is a potent tumor suppressor molecule in vivo in neuroblastoma

LENUS (Irish Health Repository)

Tivnan, Amanda

2011-01-25

ABSTRACT Background Neuroblastoma is a paediatric cancer which originates from precursor cells of the sympathetic nervous system and accounts for 15% of childhood cancer mortalities. With regards to the role of miRNAs in neuroblastoma, miR-34a, mapping to a chromosome 1p36 region that is commonly deleted, has been found to act as a tumor suppressor through targeting of numerous genes associated with cell proliferation and apoptosis. Methods A synthetic miR-34a (or negative control) precursor molecule was transfected into NB1691luc and SK-N-ASluc neuroblastoma cells. Quantitative PCR was used to verify increased miR-34a levels in NB1691luc and SK-N-ASluc cell lines prior to in vitro and in vivo analysis. In vitro analysis of the effects of miR-34a over expression on cell growth, cell cycle and phosphoprotein activation in signal transduction pathways was performed. Neuroblastoma cells over expressing miR-34a were injected retroperitoneally into immunocompromised CB17-SCID mice and tumor burden was assessed over a 21 day period by measuring bioluminescence (photons\\/sec\\/cm2). Results Over expression of miR-34a in both NB1691luc and SK-N-ASluc neuroblastoma cell lines led to a significant decrease in cell number relative to premiR-negative control treated cells over a 72 hour period. Flow cytometry results indicated that miR-34a induced cell cycle arrest and subsequent apoptosis activation. Phosphoprotein analysis highlighted key elements involved in signal transduction, whose activation was dysregulated as a result of miR-34a introduction into cells. As a potential mechanism of miR-34a action on phosphoprotein levels, we demonstrate that miR-34a over-expression results in a significant reduction of MAP3K9 mRNA and protein levels. Although MAP3K9 is a predicted target of miR-34a, direct targeting could not be validated with luciferase reporter assays. Despite this fact, any functional effects of reduced MAP3K9 expression as a result of miR-34a would be expected to

Selective elimination of neuroblastoma cells by synergistic effect of Akt kinase inhibitor and tetrathiomolybdate.

Science.gov (United States)

Navrátilová, Jarmila; Karasová, Martina; Kohutková Lánová, Martina; Jiráková, Ludmila; Budková, Zuzana; Pacherník, Jiří; Šmarda, Jan; Beneš, Petr

2017-09-01

Neuroblastoma is the most common extracranial solid tumour of infancy. Pathological activation of glucose consumption, glycolysis and glycolysis-activating Akt kinase occur frequently in neuroblastoma cells, and these changes correlate with poor prognosis of patients. Therefore, several inhibitors of glucose utilization and the Akt kinase activity are in preclinical trials as potential anti-cancer drugs. However, metabolic plasticity of cancer cells might undermine efficacy of this approach. In this work, we identified oxidative phosphorylation as compensatory mechanism preserving viability of neuroblastoma cells with inhibited glucose uptake/Akt kinase. It was oxidative phosphorylation that maintained intracellular level of ATP and proliferative capacity of these cells. The oxidative phosphorylation inhibitors (rotenone, tetrathiomolybdate) synergized with inhibitor of the Akt kinase/glucose uptake in down-regulation of both viability of neuroblastoma cells and clonogenic potential of cells forming neuroblastoma spheroids. Interestingly, tetrathiomolybdate acted as highly specific inhibitor of oxygen consumption and activator of lactate production in neuroblastoma cells, but not in normal fibroblasts and neuronal cells. Moreover, the reducing effect of tetrathiomolybdate on cell viability and the level of ATP in the cells with inhibited Akt kinase/glucose uptake was also selective for neuroblastoma cells. Therefore, efficient elimination of neuroblastoma cells requires inhibition of both glucose uptake/Akt kinase and oxidative phosphorylation activities. The use of tetrathiomolybdate as a mitochondrial inhibitor contributes to selectivity of this combined treatment, preferentially targeting neuroblastoma cells. © 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Multi-omic profiling of MYCN-amplified neuroblastoma cell-lines

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Erik Dassi

2015-12-01

Full Text Available Neuroblastoma is the most common pediatric cancer, arising from the neural crest cells of the sympathetic nervous system. Its most aggressive subtype, characterized by the amplification of the MYCN oncogene, has a dismal prognosis and no effective treatment is available. Understanding the alterations induced by the tumor on the various layers of gene expression is therefore important for a complete characterization of this neuroblastoma subtype and for the discovery of new therapeutic opportunities. Here we describe the profiling of 13 MYCN-amplified neuroblastoma cell lines at the genome (copy number, transcriptome, translatome and miRome levels (GEO series GSE56654, GSE56552 and GSE56655. We provide detailed experimental and data analysis procedures by means of which we derived the results described in [1].

Impact of plant extracts tested in attention-deficit/hyperactivity disorder treatment on cell survival and energy metabolism in human neuroblastoma SH-SY5Y cells.

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Schmidt, Andreas Johannes; Krieg, Jürgen-Christian; Hemmeter, Ulrich Michael; Kircher, Tilo; Schulz, Eberhard; Clement, Hans-Willi; Heiser, Philip

2010-10-01

Plant extracts such as Hypericum perforatum and Pycnogenol have been tested as alternatives to the classical ADHD drugs. It has been possible to describe neuroprotective effects of such plant extracts. A reduction of ADHD symptoms could be shown in clinical studies after the application of Pycnogenol, which is a pine bark extract. The impacts of the standardized herbal extracts Hypericum perforatum, Pycnogenol and Enzogenol up to a concentration of 5000 ng/mL on cell survival and energy metabolism in human SH-SY5Y neuroblastoma cells has been investigated in the present examination. Hypericum perforatum significantly decreased the survival of cells after treatment with a concentration of 5000 ng/mL, whereas lower concentrations exerted no significant effects. Pycnogenol( induced a significant increase of cell survival after incubation with a concentration of 32.25 ng/mL and a concentration of 250 ng/mL. Other applied concentrations of Pycnogenol failed to exert significant effects. Treatment with Enzogenol did not lead to significant changes in cell survival.Concerning energy metabolism, the treatment of cells with a concentration of 5000 ng/mL Hypericum perforatum led to a significant increase of ATP levels, whereas treatment with a concentration of 500 ng/mL had no significant effect. Incubation of cells with Pycnogenol and Enzogenol exerted no significant effects.None of the tested substances caused any cytotoxic effect when used in therapeutically relevant concentrations. Copyright © 2010 John Wiley & Sons, Ltd.

Freud-2/CC2D1B mediates dual repression of the serotonin-1A receptor gene.

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Hadjighassem, Mahmoud R; Galaraga, Kimberly; Albert, Paul R

2011-01-01

The serotonin-1A (5-HT1A) receptor functions as a pre-synaptic autoreceptor in serotonin neurons that regulates their activity, and is also widely expressed on non-serotonergic neurons as a post-synaptic heteroreceptor to mediate serotonin action. The 5-HT1A receptor gene is strongly repressed by a dual repressor element (DRE), which is recognized by two proteins: Freud-1/CC2D1A and another unknown protein. Here we identify mouse Freud-2/CC2D1B as the second repressor of the 5-HT1A-DRE. Freud-2 shares 50% amino acid identity with Freud-1, and contains conserved structural domains. Mouse Freud-2 bound specifically to the rat 5-HT1A-DRE adjacent to, and partially overlapping, the Freud-1 binding site. By supershift assay using nuclear extracts from L6 myoblasts, Freud-2-DRE complexes were distinguished from Freud-1-DRE complexes. Freud-2 mRNA and protein were detected throughout mouse brain and peripheral tissues. Freud-2 repressed 5-HT1A promoter-reporter constructs in a DRE-dependent manner in non-neuronal (L6) or 5-HT1A-expressing neuronal (NG108-15, RN46A) cell models. In NG108-15 cells, knockdown of Freud-2 using a specific short-interfering RNA reduced endogenous Freud-2 protein levels and decreased Freud-2 bound to the 5-HT1A-DRE as detected by chromatin immunoprecipitation assay, but increased 5-HT1A promoter activity and 5-HT1A protein levels. Taken together, these data show that Freud-2 is the second component that, with Freud-1, mediates dual repression of the 5-HT1A receptor gene at the DRE. © 2010 The Authors. European Journal of Neuroscience © 2010 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

Iodine-131 Metaiodobenzylguanidine Therapy for Neuroblastoma: Reports So Far and Future Perspective

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Daiki Kayano

2015-01-01

Full Text Available Neuroblastoma, which derives from neural crest, is the most common extracranial solid cancer in childhood. The tumors express the norepinephrine (NE transporters on their cell membrane and take in metaiodobenzylguanidine (MIBG via a NE transporter. Since iodine-131 (I-131 MIBG therapy was firstly reported, many trails of MIBG therapy in patients with neuroblastoma were performed. Though monotherapy with a low dose of I-131 MIBG could achieve high-probability pain reduction, the objective response was poor. In contrast, more than 12 mCi/kg I-131 MIBG administrations with or without hematopoietic cell transplantation (HCT obtain relatively good responses in patients with refractory or relapsed neuroblastoma. The combination therapy with I-131 MIBG and other modalities such as nonmyeloablative chemotherapy and myeloablative chemotherapy with HCT improved the therapeutic response in patients with refractory or relapsed neuroblastoma. In addition, I-131 MIBG therapy incorporated in the induction therapy was proved to be feasible in patients with newly diagnosed neuroblastoma. To expand more the use of MIBG therapy for neuroblastoma, further studies will be needed especially in the use at an earlier stage from diagnosis, in the use with other radionuclide formations of MIBG, and in combined use with other therapeutic agents.

Phase I study of vorinostat in combination with isotretinoin in patients with refractory/recurrent neuroblastoma: A new approaches to Neuroblastoma Therapy (NANT) trial.

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Pinto, Navin; DuBois, Steven G; Marachelian, Araz; Diede, Scott J; Taraseviciute, Agne; Glade Bender, Julia L; Tsao-Wei, Denice; Groshen, Susan G; Reid, Joel M; Haas-Kogan, Daphne A; Reynolds, C Patrick; Kang, Min H; Irwin, Meredith S; Macy, Margaret E; Villablanca, Judith G; Matthay, Katherine K; Park, Julie R

2018-03-30

Vorinostat combined with retinoids produces additive antitumor effects in preclinical studies of neuroblastoma. Higher systemic exposures of vorinostat than achieved in pediatric phase I trials with continuous daily dosing are necessary for in vivo increased histone acetylation and cytotoxic activity. We conducted a phase I trial in children with relapsed/refractory neuroblastoma to determine the maximum tolerated dose (MTD) of vorinostat on an interrupted schedule, escalating beyond the previously identified pediatric MTD. Isotretinoin (cis-13-retinoic acid) 80 mg/m 2 /dose was administered by mouth twice daily on days 1-14 in combination with escalating doses of daily vorinostat up to 430 mg/m 2 /dose (days 1-4; 8-11) in each 28-day cycle using the standard 3 + 3 design. Vorinostat pharmacokinetic testing and histone acetylation assays were performed. Twenty-nine patients with refractory or relapsed neuroblastoma were enrolled and 28 were evaluable for dose escalation decisions. Median number of cycles completed was two (range 1-15); 11 patients received four or more cycles. Three patients experienced cycle 1 dose-limiting toxicities. A total of 18 patients experienced grade 3/4 toxicities related to study therapy. The maximum intended dose of vorinostat (430 mg/m 2 /day, days 1-4; 8-11) was tolerable and led to increased histone acetylation in surrogate tissues when compared to lower doses of vorinostat (P = 0.009). No objective responses were seen. Increased dose vorinostat (430 mg/m 2 /day) on an interrupted schedule is tolerable in combination with isotretinoin. This dose led to increased vorinostat exposures and demonstrated increased histone acetylation. Prolonged stable disease in patients with minimal residual disease warrants further investigation. © 2018 Wiley Periodicals, Inc.

The genetic landscape of high-risk neuroblastoma.

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Pugh, Trevor J; Morozova, Olena; Attiyeh, Edward F; Asgharzadeh, Shahab; Wei, Jun S; Auclair, Daniel; Carter, Scott L; Cibulskis, Kristian; Hanna, Megan; Kiezun, Adam; Kim, Jaegil; Lawrence, Michael S; Lichenstein, Lee; McKenna, Aaron; Pedamallu, Chandra Sekhar; Ramos, Alex H; Shefler, Erica; Sivachenko, Andrey; Sougnez, Carrie; Stewart, Chip; Ally, Adrian; Birol, Inanc; Chiu, Readman; Corbett, Richard D; Hirst, Martin; Jackman, Shaun D; Kamoh, Baljit; Khodabakshi, Alireza Hadj; Krzywinski, Martin; Lo, Allan; Moore, Richard A; Mungall, Karen L; Qian, Jenny; Tam, Angela; Thiessen, Nina; Zhao, Yongjun; Cole, Kristina A; Diamond, Maura; Diskin, Sharon J; Mosse, Yael P; Wood, Andrew C; Ji, Lingyun; Sposto, Richard; Badgett, Thomas; London, Wendy B; Moyer, Yvonne; Gastier-Foster, Julie M; Smith, Malcolm A; Guidry Auvil, Jaime M; Gerhard, Daniela S; Hogarty, Michael D; Jones, Steven J M; Lander, Eric S; Gabriel, Stacey B; Getz, Gad; Seeger, Robert C; Khan, Javed; Marra, Marco A; Meyerson, Matthew; Maris, John M

2013-03-01

Neuroblastoma is a malignancy of the developing sympathetic nervous system that often presents with widespread metastatic disease, resulting in survival rates of less than 50%. To determine the spectrum of somatic mutation in high-risk neuroblastoma, we studied 240 affected individuals (cases) using a combination of whole-exome, genome and transcriptome sequencing as part of the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative. Here we report a low median exonic mutation frequency of 0.60 per Mb (0.48 nonsilent) and notably few recurrently mutated genes in these tumors. Genes with significant somatic mutation frequencies included ALK (9.2% of cases), PTPN11 (2.9%), ATRX (2.5%, and an additional 7.1% had focal deletions), MYCN (1.7%, causing a recurrent p.Pro44Leu alteration) and NRAS (0.83%). Rare, potentially pathogenic germline variants were significantly enriched in ALK, CHEK2, PINK1 and BARD1. The relative paucity of recurrent somatic mutations in neuroblastoma challenges current therapeutic strategies that rely on frequently altered oncogenic drivers.

The genetic landscape of high-risk neuroblastoma

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Pugh, Trevor J.; Morozova, Olena; Attiyeh, Edward F.; Asgharzadeh, Shahab; Wei, Jun S.; Auclair, Daniel; Carter, Scott L.; Cibulskis, Kristian; Hanna, Megan; Kiezun, Adam; Kim, Jaegil; Lawrence, Michael S.; Lichenstein, Lee; McKenna, Aaron; Pedamallu, Chandra Sekhar; Ramos, Alex H.; Shefler, Erica; Sivachenko, Andrey; Sougnez, Carrie; Stewart, Chip; Ally, Adrian; Birol, Inanc; Chiu, Readman; Corbett, Richard D.; Hirst, Martin; Jackman, Shaun D.; Kamoh, Baljit; Khodabakshi, Alireza Hadj; Krzywinski, Martin; Lo, Allan; Moore, Richard A.; Mungall, Karen L.; Qian, Jenny; Tam, Angela; Thiessen, Nina; Zhao, Yongjun; Cole, Kristina A.; Diamond, Maura; Diskin, Sharon J.; Mosse, Yael P.; Wood, Andrew C.; Ji, Lingyun; Sposto, Richard; Badgett, Thomas; London, Wendy B.; Moyer, Yvonne; Gastier-Foster, Julie M.; Smith, Malcolm A.; Auvil, Jaime M. Guidry; Gerhard, Daniela S.; Hogarty, Michael D.; Jones, Steven J. M.; Lander, Eric S.; Gabriel, Stacey B.; Getz, Gad; Seeger, Robert C.; Khan, Javed; Marra, Marco A.; Meyerson, Matthew; Maris, John M.

2013-01-01

Neuroblastoma is a malignancy of the developing sympathetic nervous system that often presents with widespread metastatic disease, resulting in survival rates of less than 50%1. To determine the spectrum of somatic mutation in high-risk neuroblastoma, we studied 240 cases using a combination of whole exome, genome and transcriptome sequencing as part of the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative. Here we report a low median exonic mutation frequency of 0.60 per megabase (0.48 non-silent), and remarkably few recurrently mutated genes in these tumors. Genes with significant somatic mutation frequencies included ALK (9.2% of cases), PTPN11 (2.9%), ATRX (2.5%, an additional 7.1% had focal deletions), MYCN (1.7%, a recurrent p.Pro44Leu alteration), and NRAS (0.83%). Rare, potentially pathogenic germline variants were significantly enriched in ALK, CHEK2, PINK1, and BARD1. The relative paucity of recurrent somatic mutations in neuroblastoma challenges current therapeutic strategies reliant upon frequently altered oncogenic drivers. PMID:23334666

Ablation of NG2 proteoglycan leads to deficits in brown fat function and to adult onset obesity.

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Yunchao Chang

Full Text Available Obesity is a major health problem worldwide. We are studying the causes and effects of obesity in C57Bl/6 mice following genetic ablation of NG2, a chondroitin sulfate proteoglycan widely expressed in progenitor cells and also in adipocytes. Although global NG2 ablation delays early postnatal adipogenesis in mouse skin, adult NG2 null mice are paradoxically heavier than wild-type mice, exhibiting larger white fat deposits. This adult onset obesity is not due to NG2-dependent effects on CNS function, since specific ablation of NG2 in oligodendrocyte progenitors yields the opposite phenotype; i.e. abnormally lean mice. Metabolic analysis reveals that, while activity and food intake are unchanged in global NG2 null mice, O(2 consumption and CO(2 production are decreased, suggesting a decrease in energy expenditure. Since brown fat plays important roles in regulating energy expenditure, we have investigated brown fat function via cold challenge and high fat diet feeding, both of which induce the adaptive thermogenesis that normally occurs in brown fat. In both tests, body temperatures in NG2 null mice are reduced compared to wild-type mice, indicating a deficit in brown fat function in the absence of NG2. In addition, adipogenesis in NG2 null brown pre-adipocytes is dramatically impaired compared to wild-type counterparts. Moreover, mRNA levels for PR domain containing 16 (PRDM16 and peroxisome proliferator-activated receptor γ coactivator (PGC1-α, proteins important for brown adipocyte differentiation, are decreased in NG2 null brown fat deposits in vivo and NG2 null brown pre-adipocytes in vitro. Altogether, these results indicate that brown fat dysfunction in NG2 null mice results from deficits in the recruitment and/or development of brown pre-adipocytes. As a consequence, obesity in NG2 null mice may occur due to disruptions in brown fat-dependent energy homeostasis, with resulting effects on lipid storage in white adipocytes.

Etoposide-induced apoptosis in murine neuroblastoma (N2A cells infected with Paramyxoviruses Apoptose induzida por etoposídeo em células de neuroblastoma murino (N2A infectadas por paramixovírus

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L. Moro

2003-02-01

Full Text Available The present study aimed to determine whether measles virus can induce apoptosis in murine neuroblastoma cells and the behavior of these cells under acute infection with measles virus or persistent infection with canine distemper virus upon treatment with etoposide. Measles virus induced necrosis in murine neuroblastoma cells. Canine distemper virus-persistent infection did not alter murine neuroblastoma cells behavior when treated with etoposide.O presente trabalho foi realizado tendo como objetivo determinar se o vírus de sarampo induz apoptose em células de neuroblastoma murino e avaliar o comportamento de células de neuroblastoma murino agudamente infectadas com vírus do sarampo ou persistentemente infectadas com o vírus da cinomose canina quando tratadas com etoposídeo. A infecção pelo vírus de sarampo induziu principalmente necrose em células de neuroblastoma murino. A infecção persistente pelo vírus de cinomose canina não alterou o comportamento de células de neuroblastoma murino tratadas com etoposídeo.

LMO1 Synergizes with MYCN to Promote Neuroblastoma Initiation and Metastasis.

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Zhu, Shizhen; Zhang, Xiaoling; Weichert-Leahey, Nina; Dong, Zhiwei; Zhang, Cheng; Lopez, Gonzalo; Tao, Ting; He, Shuning; Wood, Andrew C; Oldridge, Derek; Ung, Choong Yong; van Ree, Janine H; Khan, Amish; Salazar, Brittany M; Lummertz da Rocha, Edroaldo; Zimmerman, Mark W; Guo, Feng; Cao, Hong; Hou, Xiaonan; Weroha, S John; Perez-Atayde, Antonio R; Neuberg, Donna S; Meves, Alexander; McNiven, Mark A; van Deursen, Jan M; Li, Hu; Maris, John M; Look, A Thomas

2017-09-11

A genome-wide association study identified LMO1, which encodes an LIM-domain-only transcriptional cofactor, as a neuroblastoma susceptibility gene that functions as an oncogene in high-risk neuroblastoma. Here we show that dβh promoter-mediated expression of LMO1 in zebrafish synergizes with MYCN to increase the proliferation of hyperplastic sympathoadrenal precursor cells, leading to a reduced latency and increased penetrance of neuroblastomagenesis. The transgenic expression of LMO1 also promoted hematogenous dissemination and distant metastasis, which was linked to neuroblastoma cell invasion and migration, and elevated expression levels of genes affecting tumor cell-extracellular matrix interaction, including loxl3, itga2b, itga3, and itga5. Our results provide in vivo validation of LMO1 as an important oncogene that promotes neuroblastoma initiation, progression, and widespread metastatic dissemination. Copyright © 2017 Elsevier Inc. All rights reserved.

Survival of children with neuroblastoma treated at the Institute of oncology in Ljubljana in two periods

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Jasna Perković

2014-04-01

Full Text Available Background: Neuroblastoma is a malignant tumor of the sympathetic nervous system, representning about 5 % of all childhood malignancies. The aim of our study was to compare the survival of neuroblastoma patients treated in Slovenia in two time periods, 1994–2007 and 1980–1993, and analyze the influence of different factors on survival. The hypothesis was that there has been an improvement in the survival of neuroblastoma patients treated after 1994.Methods: Seventy-eight neuroblastoma patients, treated at the Department of Pediatrics and at the Institute of Oncology in Ljubljana in the period 1980–2007 were included in the retrospective study. The list of patients and their basic data were collected from the Cancer Registry of Slovenia. Furtjer data about the patients, tumor characteristics and treatment were collected from patients’ records.Results: Thirty-nine (50 % out of seventy-eight neuroblastoma patients included in the study are alive; of the 39 (50 % dead, 23 (29.5 % died during primary tumor treatment, 15 (19.2 % died after recurrent disease, and the cause of death in one (1.3 % patient remained unknown. The survival rates according to stage of disease, site of primary tumor and tumor size have improved in children treated after 1994, as compared to those treated before 1994. The most important factors influencing the prognosis in both time periods were stage of disease, patients’ age and tumor size at diagnosis while there was no statistical difference in survival according to age at diagnosis and the extent of surgery.Conclusions: The retrospective study confirmed our hypothesis that the survival of our patients treated after 1994 was better than the survival of those treated before. The most important prognostic factors in both periods were stage of the disease, age at diagnosis and tumor size.

Radiofrequency radiation-induced calcium-ion-efflux enhancement from human and other neuroblastoma cells in culture: [Final technical report

International Nuclear Information System (INIS)

Dutta, S.K.; Ghosh, B.; Blackman, C.F.

1988-01-01

In order to test the generality of radiofrequency-radiation-induced change in alternation of 45 Ca/sup 2/plus// efflux from avian and feline brain tissues, human neuroblastoma cells were exposed to electromagnetic radiation at 147 MHz, amplitude modulated (AM) at 16 Hz, at specific absorption rates (SAR) of 0.1, 0.05, 0.01, 0.005, 0.001, and 0.0005 Wkg. Significant 45 Ca/sup 2/plus// efflux was obtained at SAR values of 0.05 and 0.005 Wkg. Enchanced efflux at 0.05 Wkg peaked at the 13-to-16 Hz and at the 57.5-to-60 Hz modulation ranges. A Chinese hamster-mouse hybrid neuroblastoma was also shown to exhibit enchanced radiation-induced 45 Ca/sup 2/plus// efflux at an SAR of 0.05 Wkg, using 147 MHz, AM at 16 hz. These results confirm that amplitude-modulated radiofrequency radiation can induce response in cells of nervous tissue origin from widely different animal species including humans. The results are also consistent with reports of similar findings in avian and feline brain tissue reported by others and indicate the general nature of the phenomenon. 9 refs., 3 tabs

Ballistic V50 Evaluation of TIMET Ti108

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2018-02-01

threat by 1 m/s. Future studies or adjustments to the chemistry of the Ti108 can be conducted to optimize ballistic performance. 15. SUBJECT TERMS...10 Fig. A-2 30-mm APDS overall back of plate .................................................... 10 List of Tables Table 1 Chemistry of Ti108...performance of different titanium alloys. Conventional Ti-6Al-4V is commonly used in aerospace frames and engine components, but has difficulty passing

Local Control With 21-Gy Radiation Therapy for High-Risk Neuroblastoma

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Casey, Dana L.; Kushner, Brian H.; Cheung, Nai-Kong V.; Modak, Shakeel; LaQuaglia, Michael P.; Wolden, Suzanne L.

2016-01-01

Purpose: To evaluate local control after 21-Gy radiation therapy (RT) to the primary site in patients with high-risk neuroblastoma. Methods and Materials: After receiving dose-intensive chemotherapy and gross total resection (GTR), 246 patients (aged 1.2-17.9 years, median 4.0 years) with high-risk neuroblastoma underwent RT to the primary site at Memorial Sloan Kettering from 2000 to 2014. Radiation therapy consisted of 21 Gy in twice-daily fractions of 1.5 Gy each. Local failure (LF) was correlated with biologic prognostic factors and clinical findings at the time of diagnosis and start of RT. Results: Median follow-up of surviving patients was 6.4 years. Cumulative incidence of LF was 7.1% at 2 years after RT and 9.8% at 5 years after RT. The isolated LF rate was 3.0%. Eighty-six percent of all local failures were within the RT field. Local control was worse in patients who required more than 1 surgical resection to achieve GTR (22.4% vs 8.3%, P=.01). There was also a trend toward inferior local control with MYCN-amplified tumors or serum lactate dehydrogenase ≥1500 U/L (P=.09 and P=.06, respectively). Conclusion: After intensive chemotherapy and maximal surgical debulking, hyperfractionated RT with 21 Gy in high-risk neuroblastoma results in excellent local control. Given the young patient age, concern for late effects, and local control >90%, dose reduction may be appropriate for patients without MYCN amplification who achieve GTR.

Local Control With 21-Gy Radiation Therapy for High-Risk Neuroblastoma

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Casey, Dana L. [Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York (United States); Kushner, Brian H.; Cheung, Nai-Kong V.; Modak, Shakeel [Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York (United States); LaQuaglia, Michael P. [Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York (United States); Wolden, Suzanne L., E-mail: woldens@mskcc.org [Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York (United States)

2016-10-01

Purpose: To evaluate local control after 21-Gy radiation therapy (RT) to the primary site in patients with high-risk neuroblastoma. Methods and Materials: After receiving dose-intensive chemotherapy and gross total resection (GTR), 246 patients (aged 1.2-17.9 years, median 4.0 years) with high-risk neuroblastoma underwent RT to the primary site at Memorial Sloan Kettering from 2000 to 2014. Radiation therapy consisted of 21 Gy in twice-daily fractions of 1.5 Gy each. Local failure (LF) was correlated with biologic prognostic factors and clinical findings at the time of diagnosis and start of RT. Results: Median follow-up of surviving patients was 6.4 years. Cumulative incidence of LF was 7.1% at 2 years after RT and 9.8% at 5 years after RT. The isolated LF rate was 3.0%. Eighty-six percent of all local failures were within the RT field. Local control was worse in patients who required more than 1 surgical resection to achieve GTR (22.4% vs 8.3%, P=.01). There was also a trend toward inferior local control with MYCN-amplified tumors or serum lactate dehydrogenase ≥1500 U/L (P=.09 and P=.06, respectively). Conclusion: After intensive chemotherapy and maximal surgical debulking, hyperfractionated RT with 21 Gy in high-risk neuroblastoma results in excellent local control. Given the young patient age, concern for late effects, and local control >90%, dose reduction may be appropriate for patients without MYCN amplification who achieve GTR.

Protection against β-amyloid neurotoxicity by a non-toxic endogenous N-terminal β-amyloid fragment and its active hexapeptide core sequence.

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Forest, Kelly H; Alfulaij, Naghum; Arora, Komal; Taketa, Ruth; Sherrin, Tessi; Todorovic, Cedomir; Lawrence, James L M; Yoshikawa, Gene T; Ng, Ho-Leung; Hruby, Victor J; Nichols, Robert A

2018-01-01

High levels (μM) of beta amyloid (Aβ) oligomers are known to trigger neurotoxic effects, leading to synaptic impairment, behavioral deficits, and apoptotic cell death. The hydrophobic C-terminal domain of Aβ, together with sequences critical for oligomer formation, is essential for this neurotoxicity. However, Aβ at low levels (pM-nM) has been shown to function as a positive neuromodulator and this activity resides in the hydrophilic N-terminal domain of Aβ. An N-terminal Aβ fragment (1-15/16), found in cerebrospinal fluid, was also shown to be a highly active neuromodulator and to reverse Aβ-induced impairments of long-term potentiation. Here, we show the impact of this N-terminal Aβ fragment and a shorter hexapeptide core sequence in the Aβ fragment (Aβcore: 10-15) to protect or reverse Aβ-induced neuronal toxicity, fear memory deficits and apoptotic death. The neuroprotective effects of the N-terminal Aβ fragment and Aβcore on Aβ-induced changes in mitochondrial function, oxidative stress, and apoptotic neuronal death were demonstrated via mitochondrial membrane potential, live reactive oxygen species, DNA fragmentation and cell survival assays using a model neuroblastoma cell line (differentiated NG108-15) and mouse hippocampal neuron cultures. The protective action of the N-terminal Aβ fragment and Aβcore against spatial memory processing deficits in amyloid precursor protein/PSEN1 (5XFAD) mice was demonstrated in contextual fear conditioning. Stabilized derivatives of the N-terminal Aβcore were also shown to be fully protective against Aβ-triggered oxidative stress. Together, these findings indicate an endogenous neuroprotective role for the N-terminal Aβ fragment, while active stabilized N-terminal Aβcore derivatives offer the potential for therapeutic application. © 2017 International Society for Neurochemistry.

Gene therapy as a potential tool for treating neuroblastoma-a focused review.

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Kumar, M D; Dravid, A; Kumar, A; Sen, D

2016-05-01

Neuroblastoma, a solid tumor caused by rapid division of undifferentiated neuroblasts, is the most common childhood malignancy affecting children aged genes is restored to normalcy. Gene therapy is a powerful tool with the potential to inhibit the deleterious effects of oncogenes by inserting corrected/normal genes into the genome. Both viral and non-viral vector-based gene therapies have been developed and adopted to deliver the target genes into neuroblastoma cells. These attempts have given hope to bringing in a new regime of treatment against neuroblastoma. A few gene-therapy-based treatment strategies have been tested in limited clinical trials yielding some positive results. This mini review is an attempt to provide an overview of the available options of gene therapy to treat neuroblastoma.

Intracellular fragment of NLRR3 (NLRR3-ICD) stimulates ATRA-dependent neuroblastoma differentiation

International Nuclear Information System (INIS)

Akter, Jesmin; Takatori, Atsushi; Islam, Md. Sazzadul; Nakazawa, Atsuko; Ozaki, Toshinori; Nagase, Hiroki; Nakagawara, Akira

2014-01-01

Highlights: • NLRR3 is a membrane protein highly expressed in favorable neuroblastoma. • NLRR3-ICD was produced through proteolytic processing by secretases. • NLRR3-ICD was induced to be translocated into cell nucleus following ATRA exposure. • NLRR3-ICD plays a pivotal role in ATRA-mediated neuroblastoma differentiation. - Abstract: We have previously identified neuronal leucine-rich repeat protein-3 (NLRR3) gene which is preferentially expressed in favorable human neuroblastomas as compared with unfavorable ones. In this study, we have found for the first time that NLRR3 is proteolytically processed by secretases and its intracellular domain (NLRR3-ICD) is then released to translocate into cell nucleus during ATRA-mediated neuroblastoma differentiation. According to our present observations, NLRR3-ICD was induced to accumulate in cell nucleus of neuroblastoma SH-SY5Y cells following ATRA treatment. Since the proteolytic cleavage of NLRR3 was blocked by α- or γ-secretase inhibitor, it is likely that NLRR3-ICD is produced through the secretase-mediated processing of NLRR3. Intriguingly, forced expression of NLRR3-ICD in neuroblastoma SK-N-BE cells significantly suppressed their proliferation as examined by a live-cell imaging system and colony formation assay. Similar results were also obtained in neuroblastoma TGW cells. Furthermore, overexpression of NLRR3-ICD stimulated ATRA-dependent neurite elongation in SK-N-BE cells. Together, our present results strongly suggest that NLRR3-ICD produced by the secretase-mediated proteolytic processing of NLRR3 plays a crucial role in ATRA-mediated neuronal differentiation, and provide a clue to develop a novel therapeutic strategy against aggressive neuroblastomas

Intracellular fragment of NLRR3 (NLRR3-ICD) stimulates ATRA-dependent neuroblastoma differentiation

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Akter, Jesmin [Laboratory of Innovative Cancer Therapeutics, Chiba Cancer Center Research Institute, Chiba 260-8717 (Japan); Takatori, Atsushi, E-mail: atakatori@chiba-cc.jp [Laboratory of Cancer Genetics, Chiba Cancer Center Research Institute, Chiba 260-8717 (Japan); Islam, Md. Sazzadul [Laboratory of Innovative Cancer Therapeutics, Chiba Cancer Center Research Institute, Chiba 260-8717 (Japan); Nakazawa, Atsuko [Department of Pathology, National Center for Child Health and Development, Tokyo (Japan); Ozaki, Toshinori, E-mail: tozaki@chiba-cc.jp [Laboratory of DNA Damage Signaling, Chiba Cancer Center Research Institute, Chiba 260-8717 (Japan); Nagase, Hiroki [Laboratory of Cancer Genetics, Chiba Cancer Center Research Institute, Chiba 260-8717 (Japan); Nakagawara, Akira [Saga Medical Centre, 840-8571 (Japan)

2014-10-10

Highlights: • NLRR3 is a membrane protein highly expressed in favorable neuroblastoma. • NLRR3-ICD was produced through proteolytic processing by secretases. • NLRR3-ICD was induced to be translocated into cell nucleus following ATRA exposure. • NLRR3-ICD plays a pivotal role in ATRA-mediated neuroblastoma differentiation. - Abstract: We have previously identified neuronal leucine-rich repeat protein-3 (NLRR3) gene which is preferentially expressed in favorable human neuroblastomas as compared with unfavorable ones. In this study, we have found for the first time that NLRR3 is proteolytically processed by secretases and its intracellular domain (NLRR3-ICD) is then released to translocate into cell nucleus during ATRA-mediated neuroblastoma differentiation. According to our present observations, NLRR3-ICD was induced to accumulate in cell nucleus of neuroblastoma SH-SY5Y cells following ATRA treatment. Since the proteolytic cleavage of NLRR3 was blocked by α- or γ-secretase inhibitor, it is likely that NLRR3-ICD is produced through the secretase-mediated processing of NLRR3. Intriguingly, forced expression of NLRR3-ICD in neuroblastoma SK-N-BE cells significantly suppressed their proliferation as examined by a live-cell imaging system and colony formation assay. Similar results were also obtained in neuroblastoma TGW cells. Furthermore, overexpression of NLRR3-ICD stimulated ATRA-dependent neurite elongation in SK-N-BE cells. Together, our present results strongly suggest that NLRR3-ICD produced by the secretase-mediated proteolytic processing of NLRR3 plays a crucial role in ATRA-mediated neuronal differentiation, and provide a clue to develop a novel therapeutic strategy against aggressive neuroblastomas.

Ras-MAPK signaling in differentiating SH-SY5Y human neuroblastoma cells

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Olsson, Anna-Karin

2000-01-01

Neuroblastoma is a malignant childhood cancer, originating from sympathetic neuroblasts of the peripheral nervous system. Neuroblastoma is a heterogenous group of tumours, while some are highly malignant others can spontaneosly mature into a more benign form or regress. Less than half of the patients survive and this statistics has improved only modestly over the past 20 years. SH-SY5Y is a human neuroblastoma cell line established from a highly malignant tumour. The cells have retained a ca...

Identification of GPC2 as an Oncoprotein and Candidate Immunotherapeutic Target in High-Risk Neuroblastoma.

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Bosse, Kristopher R; Raman, Pichai; Zhu, Zhongyu; Lane, Maria; Martinez, Daniel; Heitzeneder, Sabine; Rathi, Komal S; Kendsersky, Nathan M; Randall, Michael; Donovan, Laura; Morrissy, Sorana; Sussman, Robyn T; Zhelev, Doncho V; Feng, Yang; Wang, Yanping; Hwang, Jennifer; Lopez, Gonzalo; Harenza, Jo Lynne; Wei, Jun S; Pawel, Bruce; Bhatti, Tricia; Santi, Mariarita; Ganguly, Arupa; Khan, Javed; Marra, Marco A; Taylor, Michael D; Dimitrov, Dimiter S; Mackall, Crystal L; Maris, John M

2017-09-11

We developed an RNA-sequencing-based pipeline to discover differentially expressed cell-surface molecules in neuroblastoma that meet criteria for optimal immunotherapeutic target safety and efficacy. Here, we show that GPC2 is a strong candidate immunotherapeutic target in this childhood cancer. We demonstrate high GPC2 expression in neuroblastoma due to MYCN transcriptional activation and/or somatic gain of the GPC2 locus. We confirm GPC2 to be highly expressed on most neuroblastomas, but not detectable at appreciable levels in normal childhood tissues. In addition, we demonstrate that GPC2 is required for neuroblastoma proliferation. Finally, we develop a GPC2-directed antibody-drug conjugate that is potently cytotoxic to GPC2-expressing neuroblastoma cells. Collectively, these findings validate GPC2 as a non-mutated neuroblastoma oncoprotein and candidate immunotherapeutic target. Copyright © 2017 Elsevier Inc. All rights reserved.

Analysis of axonal regeneration in the central and peripheral nervous systems of the NG2-deficient mouse

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Lieberman Alexander R

2007-09-01

Full Text Available Abstract Background The chondroitin sulphate proteoglycan NG2 blocks neurite outgrowth in vitro and has been proposed as a major inhibitor of axonal regeneration in the CNS. Although a substantial body of evidence underpins this hypothesis, it is challenged by recent findings including strong expression of NG2 in regenerating peripheral nerve. Results We studied axonal regeneration in the PNS and CNS of genetically engineered mice that do not express NG2, and in sex and age matched wild-type controls. In the CNS, we used anterograde tracing with BDA to study corticospinal tract (CST axons after spinal cord injury and transganglionic labelling with CT-HRP to trace ascending sensory dorsal column (DC axons after DC lesions and a conditioning lesion of the sciatic nerve. Injury to these fibre tracts resulted in no difference between knockout and wild-type mice in the ability of CST axons or DC axons to enter or cross the lesion site. Similarly, after dorsal root injury (with conditioning lesion, most regenerating dorsal root axons failed to grow across the dorsal root entry zone in both transgenic and wild-type mice. Following sciatic nerve injuries, functional recovery was assessed by analysis of the toe-spreading reflex and cutaneous sensitivity to Von Frey hairs. Anatomical correlates of regeneration were assessed by: retrograde labelling of regenerating dorsal root ganglion (DRG cells with DiAsp; immunostaining with PGP 9.5 to visualise sensory reinnervation of plantar hindpaws; electron microscopic analysis of regenerating axons in tibial and digital nerves; and by silver-cholinesterase histochemical study of motor end plate reinnervation. We also examined functional and anatomical correlates of regeneration after injury of the facial nerve by assessing the time taken for whisker movements and corneal reflexes to recover and by retrograde labelling of regenerated axons with Fluorogold and DiAsp. None of the anatomical or functional analyses

Computed tomography as a supplement to urography in the evaluation of suspected neuroblastoma

International Nuclear Information System (INIS)

Siegel, M. J.; Sagel, S.S.

1982-01-01

Eleven children in whom a retropertioneal neuroblastoma was suspected on the basis of plain radiographic or urographic findings underwent computed tomography (CT). CT identified and localized a neurogenic tumor in eight patients. Calcifications were demonstrated by CT in six lesions, but by urography in only four. One neuroblastoma detected by CT was not seen on the urogram; in five patients greater extent of the tumor was defined by CT than by conventional radiologic procedures. In three patients CT excluded a neuroblastoma, but diagnosed other disorders (hepatic tumor, pancreatitis, and retrocaval ureter). Our results confirm that CT is a simple and accurate method for diagnosis, delineation of extent, or exclusion of neuroblastoma

Local delivery of 131I-MIBG to treat peritoneal neuroblastoma

International Nuclear Information System (INIS)

Kinuya, Seigo; Li, Xiao-Feng; Yokoyama, Kunihiko; Michigishi, Takatoshi; Tonami, Norihisa; Mori, Hirofumi; Shiba, Kazuhiro; Watanabe, Naoto; Shuke, Noriyuki; Bunko, Hisashi

2003-01-01

Internal radiotherapy involving systemic administration of iodine-131 metaiodobenzylguanidine ( 131 I-MIBG) in neural crest tumours such as neuroblastoma has shown considerable success. Although peritoneal seeding of neuroblastoma occurs less often than metastases to organs such as the liver, no effective treatments exist in this clinical setting. Previous reports have demonstrated the effectiveness of peritoneal application of chemotherapeutic drugs or radiolabelled monoclonal antibodies in several kinds of carcinomas. Local delivery of 131 I-MIBG should produce more favourable dosimetry in comparison with its systemic administration in the treatment of peritoneal neuroblastoma. In the current investigation, a peritoneal model of neuroblastoma was established in Balb/c nu/nu mice by i.p. injection of SK-N-SH neuroblastoma cells. Two weeks after cell inoculation, comparative biodistribution studies were performed following i.v. or i.p. administration of 131 I-MIBG. Mice were treated with 55.5 MBq of 131 I-MIBG administered either i.v. or i.p. at 2 weeks. Intraperitoneal injection of 131 I-MIBG produced significantly higher tumour accumulation than did i.v. injection (P 131 I-MIBG failed to improve the survival of mice; mean survival of untreated mice and mice treated with i.v. administration of 131 I-MIBG was 59.3±3.9 days and 60.6±2.8 days, respectively. On the other hand, radiotherapy delivered via i.p. administration of 131 I-MIBG prolonged survival of mice to 94.7±17.5 days (P 131 I-MIBG therapy). Radiation doses absorbed by tumours at 55.5 MBq of 131 I-MIBG were estimated to be 4,140 cGy with i.p. injection and 450 cGy with i.v. injection. These results indicate the benefits of locoregional delivery of 131 I-MIBG in the treatment of peritoneal neuroblastoma. (orig.)

Bilateral adrenal cystic neuroblastoma with superior vena cava syndrome and massive intracystic haemorrhage

International Nuclear Information System (INIS)

Pinarli, Faruk Guclu; Danaci, Murat; Diren, Baris; Tander, Burak; Rizalar, Riza; Dagdemir, Ayhan; Acar, Sabri

2004-01-01

Bilateral cystic adrenal tumours are a rare presentation of neuroblastoma. Intratumoural haemorrhage is a frequent finding in neuroblastoma, but is rarely symptomatic. We present an 11-month-old girl with predominantly cystic bilateral neuroblastomas and distant lymph-node metastasis. Massive intracystic haemorrhage and superior vena cava (SVC) syndrome were ominous prognostic factors, leading to death. Large tumours with intracystic haemorrhage might require a conservative approach. (orig.)

Enzyme-treated Asparagus officinalis extract shows neuroprotective effects and attenuates cognitive impairment in senescence-accelerated mice.

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Sakurai, Takuya; Ito, Tomohiro; Wakame, Koji; Kitadate, Kentaro; Arai, Takashi; Ogasawara, Junetsu; Kizaki, Takako; Sato, Shogo; Ishibashi, Yoshinaga; Fujiwara, Tomonori; Akagawa, Kimio; Ishida, Hitoshi; Ohno, Hideki

2014-01-01

Increases in the number of patients with dementia involving Alzheimer's disease (AD) are seen as a grave public health problem. In neurodegenerative disorders involving AD, biological stresses, such as oxidative and inflammatory stress, induce neural cell damage. Asparagus (Asparagus officinalis) is a popular vegetable, and an extract prepared from this reportedly possesses various beneficial biological activities. In the present study, we investigated the effects of enzyme-treated asparagus extract (ETAS) on neuronal cells and early cognitive impairment of senescence-accelerated mouse prone 8 (SAMP8) mice. The expression of mRNAs for factors that exert cytoprotective and anti-apoptotic functions, such as heat-shock protein 70 and heme oxygenase-1, was upregulated in NG108-15 neuronal cells by treatment with ETAS. Moreover, when release of lactate dehydrogenase from damaged NG108-15 cells was increased for cells cultured in medium containing either the nitric oxide donor sodium nitroprusside or the hypoxia mimic reagent cobalt chloride, ETAS significantly attenuated this cell damage. Also, when contextual fear memory, which is considered to be a hippocampus-dependent memory, was significantly impaired in SAMP8 mice, ETAS attenuated the cognitive impairment. These results suggest that ETAS produces cytoprotective effects in neuronal cells and attenuates the effects on the cognitive impairment of SAMP8 mice.

LINC00673 rs11655237 C>T confers neuroblastoma susceptibility in Chinese population.

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Zhang, Zhuorong; Chang, Yitian; Jia, Wei; Zhang, Jiao; Zhang, Ruizhong; Zhu, Jinhong; Yang, Tianyou; Xia, Huimin; Zou, Yan; He, Jing

2018-02-28

Neuroblastoma, which accounts for approximately 10% of all pediatric cancer-related deaths, has become a therapeutic challenge and global burden attributed to poor outcomes and mortality rates of its high-risk form. Previous genome-wide association studies (GWASs) identified the LINC00673 rs11655237 C>T polymorphism to be associated with the susceptibility of several malignant tumors. However, the association between this polymorphism and neuroblastoma susceptibility is not clear. We genotyped LINC00673 rs11655237 C>T in 393 neuroblastoma patients in comparison with 812 age-, gender-, and ethnicity-matched healthy controls. We found a significant association between the LINC00673 rs11655237 C>T polymorphism and neuroblastoma risk (TT compared with CC: adjusted odds ratio (OR) =1.80, 95% confidence interval (CI) =1.06-3.06, P =0.029; TT/CT compared with CC: adjusted OR =1.31, 95% CI =1.02-1.67, P =0.033; and T compared with C: adjusted OR =1.29, 95% CI =1.06-1.58, P =0.013). Furthermore, stratified analysis indicated that the rs11655237 T allele carriers were associated with increased neuroblastoma risk for patients with tumor originating from the adrenal gland (adjusted OR =1.51, 95% CI =1.06-2.14, P =0.021) and International Neuroblastoma Staging System (INSS) stage IV disease (adjusted OR =1.60, 95% CI =1.12-2.30, P =0.011). In conclusion, we verified that the LINC00673 rs11655237 C>T polymorphism might be associated with neuroblastoma susceptibility. Prospective studies with a large sample size and different ethnicities are needed to validate our findings. © 2018 The Author(s).

Natural killer cells facilitate PRAME-specific T-cell reactivity against neuroblastoma

NARCIS (Netherlands)

Spel, Lotte; Boelens, Jaap Jan; Van Der Steen, Dirk M.; Blokland, Nina J G; van Noesel, Max M.; Molenaar, Jan J.; Heemskerk, Mirjam H M; Boes, Marianne; Nierkens, Stefan

2015-01-01

Neuroblastoma is the most common solid tumor in children with an estimated 5-year progression free survival of 20-40% in stage 4 disease. Neuroblastoma actively avoids recognition by natural killer (NK) cells and cytotoxic T lymphocytes (CTLs). Although immunotherapy has gained traction for

Left atrial mass 16 years after radiation therapy for mediastinal neuroblastoma

International Nuclear Information System (INIS)

Ensing, G.J.; Driscoll, D.J.; Smithson, W.A.

1987-01-01

Tumors involving the heart during childhood are rare. However, neuroblastoma, a common pediatric malignancy, has been described to involve the cardiovascular system in 3%-12% of patients dying with this tumor. Rarely is such involvement diagnosed ante mortem and never, to our knowledge, has a benign cardiac tumor been reported to present in childhood after successful eradication of neuroblastoma. We describe the identification and surgical resection of a nodular, hypertrophied, calcified, pedunculated left atrial mass in a 16-year-old boy who was complaining of exercise-associated presyncope and headaches 16 years after irradiation and chemotherapy for mediastinal neuroblastoma

The therapeutic use of I-131 meta-iodobenzylguanidine (MIBG) in neuroblastoma

International Nuclear Information System (INIS)

Hartmann, O.; Lumbroso, J.D.; Lemerle, J.; Schlumberger, M.; Parmentier, C.; Ricard, M.; Aubert, B.; Coornaert, S.; Merlin, L.

1988-01-01

Despite the use of intensified conventional chemotherapy the complete response rate of advanced neuroblastoma remains low. The use of high-dose chemo-radiotherapy followed by bone marrow transplantation (BMT) improved the duration of disease free survival but, even after these high-dose regimens the relapse rate remains high. Metaiodobenzylguanidine (MIBG) labelled with I-131 or I-123 can be used for scintigraphic imaging of neuroblastoma. In order to evaluate the therapeutic role of I-131-MIBG in the treatment of neuroblastoma patients, a phase II study was performed in 12 patients. Results are presented in this paper

Iodine-131 MIBG scintigraphy of the extremities in metastatic pheochromocytoma and neuroblastoma

International Nuclear Information System (INIS)

Shulkin, B.L.; Shen, S.W.; Sisson, J.C.; Shapiro, B.

1987-01-01

Iodine-131 MIBG scintigraphy may be used to determine the presence or absence of metastases to the appendicular skeleton in malignant pheochromocytoma and neuroblastoma. Normal bones show no uptake of [ 131 I]MIBG and the joints are seen as photon-deficient areas surrounded by background muscle activity. Discrete concentrations of radioactivity in bone are often seen in patients with malignant pheochromocytoma and neuroblastoma. Bone marrow involvement in neuroblastoma may be indicated by diffuse uptake of [ 131 I]MIBG or focal accumulation at the metaphyses. Uncommonly, bone involvement may not be displayed by the [ 131 I]MIBG images. Since conventional bone scanning agents may also fail to detect these tumors, skeletal scintigraphy with both [ 131 I]MIBG and [/sup 99m/Tc]MDP is necessary to reliably stage malignant pheochromocytoma and neuroblastoma

Therapeutic Innovations for Targeting Childhood Neuroblastoma: Implications of the Neurokinin-1 Receptor System.

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Berger, Michael; VON Schweinitz, Dietrich

2017-11-01

Neuroblastoma is the most common solid extracranial malignant tumor in children. Despite recent advances in the treatment of this heterogenous tumor with surgery and chemotherapy, the prognosis in advanced stages remains poor. Interestingly, neuroblastoma is one of the few solid tumors, to date, in which an effect for targeted immunotherapy has been proven in controlled clinical trials, giving hope for further advances in the treatment of this and other tumors by targeted therapy. A large array of novel therapeutic options for targeted therapy of neuroblastoma is on the horizon. To this repεrtoirε, the neurokinin-1 receptor (NK1R) system was recently added. The present article explores the most recent developments in targeting neuroblastoma cells via the NK1R and how this new knowledge could be helpful to create new anticancer therapies agains neuroblastoma and other cancers. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

MYCN-driven regulatory mechanisms controlling LIN28B in neuroblastoma

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Beckers, Anneleen; Van Peer, Gert; Carter, Daniel R.; Gartlgruber, Moritz; Herrmann, Carl; Agarwal, Saurabh; Helsmoortel, Hetty H.; Althoff, Kristina; Molenaar, Jan J.; Cheung, Belamy B.; Schulte, Johannes H.; Benoit, Yves; Shohet, Jason M.; Westermann, Frank; Marshall, Glenn M.; Vandesompele, Jo; De Preter, Katleen; Speleman, Frank

2016-01-01

LIN28B has been identified as an oncogene in various tumor entities, including neuroblastoma, a childhood cancer that originates from neural crest-derived cells, and is characterized by amplification of the MYCN oncogene. Recently, elevated LIN28B expression levels were shown to contribute to neuroblastoma tumorigenesis via let-7 dependent de-repression of MYCN. However, additional insight in the regulation of LIN28B in neuroblastoma is lacking. Therefore, we have performed a comprehensive analysis of the regulation of LIN28B in neuroblastoma, with a specific focus on the contribution of miRNAs. We show that MYCN regulates LIN28B expression in neuroblastoma tumors via two distinct parallel mechanisms. First, through an unbiased LIN28B-3′UTR reporter screen, we found that miR-26a-5p and miR-26b-5p regulate LIN28B expression. Next, we demonstrated that MYCN indirectly affects the expression of miR-26a-5p, and hence regulates LIN28B, therefor establishing a MYCN-miR-26a-5p-LIN28B regulatory axis. Second, we provide evidence that MYCN regulates LIN28B expression via interaction with the LIN28B promotor, establishing a direct MYCN-LIN28B regulatory axis. We believe that these findings mark LIN28B as an important effector of the MYCN oncogenic phenotype and underlines the importance of MYCN-regulated miRNAs in establishing the MYCN-driven oncogenic process. PMID:26123663

123I-Mibg scintigraphy and 18F-Fdg-Pet imaging for diagnosing neuroblastoma

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Bleeker, Gitta; Tytgat, Godelieve Am; Adam, Judit A; Caron, Huib N; Kremer, Leontien Cm; Hooft, Lotty; van Dalen, Elvira C

2015-01-01

Background Neuroblastoma is an embryonic tumour of childhood that originates in the neural crest. It is the second most common extracranial malignant solid tumour of childhood. Neuroblastoma cells have the unique capacity to accumulate Iodine-123-metaiodobenzylguanidine (123I-MIBG), which can be used for imaging the tumour. Moreover, 123I-MIBG scintigraphy is not only important for the diagnosis of neuroblastoma, but also for staging and localization of skeletal lesions. If these are present, MIBG follow-up scans are used to assess the patient's response to therapy. However, the sensitivity and specificity of 123I-MIBG scintigraphy to detect neuroblastoma varies according to the literature. Prognosis, treatment and response to therapy of patients with neuroblastoma are currently based on extension scoring of 123I-MIBG scans. Due to its clinical use and importance, it is necessary to determine the exact diagnostic accuracy of 123I-MIBG scintigraphy. In case the tumour is not MIBG avid, fluorine-18-fluorodeoxy-glucose (18F-FDG) positron emission tomography (PET) is often used and the diagnostic accuracy of this test should also be assessed. Objectives Primary objectives: 1.1 To determine the diagnostic accuracy of 123I-MIBG (single photon emission computed tomography (SPECT), with or without computed tomography (CT)) scintigraphy for detecting a neuroblastoma and its metastases at first diagnosis or at recurrence in children from 0 to 18 years old. 1.2 To determine the diagnostic accuracy of negative 123I-MIBG scintigraphy in combination with 18F-FDG-PET(-CT) imaging for detecting a neuroblastoma and its metastases at first diagnosis or at recurrence in children from 0 to 18 years old, i.e. an add-on test. Secondary objectives: 2.1 To determine the diagnostic accuracy of 18F-FDG-PET(-CT) imaging for detecting a neuroblastoma and its metastases at first diagnosis or at recurrence in children from 0 to 18 years old. 2.2 To compare the diagnostic accuracy of 123I

The effects of radiation therapy on height and spine MRI characteristics in children with neuroblastoma

International Nuclear Information System (INIS)

Yu, Jeong Il; Lim, Do Hoon; Jung, Sang Hoon; Sung, Ki Woong; Yoo, So-Young; Nam, Heerim

2015-01-01

Purpose: To investigate the effect of radiotherapy (RT) on height and spine using magnetic resonance imaging (MRI) analysis in children with neuroblastoma and to identify parameters related to patient height. Methods and materials: We performed a retrospective cohort study of neuroblastoma patients treated between January 1997 and December 2007. Twenty-seven children were enrolled. Whole spine MRI was completed and height percentiles were compared with national growth charts. Results: The median ages were 28, 43, and 126 months at diagnosis, RT, and analysis, respectively. All of the enrolled children received local RT, and 15 patients received total body irradiation (TBI). Median growth percentiles were 67.0, 54.0, and 4.9 at diagnosis, RT, and analysis, respectively. The number of irradiated vertebrae (P = 0.009) and having undergone TBI (P = 0.03) were significantly associated with shorter stature. Among the MRI parameters for irradiated vertebrae, signal intensity was higher (P = 0.05) and more heterogeneous (P = 0.02) in T1-weighted images and roundness was lower (P = 0.03) in T2-weighted images. Conclusions: Height of children with neuroblastoma was significantly affected by RT. The number of irradiated vertebrae and having undergone TBI were significantly associated with lower height. Irradiated spine showed changes in both signal and shape on MRI

Binding of mouse immunoglobulin G to polylysine-coated glass substrate for immunodiagnosis

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Vashist, Sandeep Kumar; Tewari, Rupinder; Bajpai, Ram Prakash; Bharadwaj, Lalit Mohan; Raiteri, Roberto

2006-12-01

We report a method for immobilizing mouse immunoglobulin G (IgG) on polylysine-coated glass substrate for immunodiagnostic applications. Mouse IgG molecules were immobilized on polylysine-coated glass substrate employing 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) and protein A. The amino groups of the polylysine-coated glass slide were cross linked to the carboxyl groups of protein A employing EDC crosslinker. Protein A was employed as it binds to the constant Fc region of antibodies keeping their antigen binding sites on the variable F ab region free to bind to antigens. The qualitative analysis of surface immobilized mouse IgG was done by fluorescent microscopy employing fluorescein isothiocyanate (FITC) labeled mouse IgG molecules. The immobilization densities of protein A and mouse IgG were determined by 3, 3', 4, 4'-tetramethyl benzidine (TMB) substrate assay employing horse radish peroxidise labelled molecules and were found to be 130 +/- 17 ng/cm2 and 596 +/- 31 ng/cm2 respectively. The biomolecular coatings analyzed by atomic force microscopy (AFM) were found to be uniform.

Analysis of 1;17 translocation breakpoints in neuroblastoma: implications for mapping of neuroblastoma genes

NARCIS (Netherlands)

van Roy, N.; Laureys, G.; van Gele, M.; Opdenakker, G.; Miura, R.; van der Drift, P.; Chan, A.; Versteeg, R.; Speleman, F.

1997-01-01

Deletions and translocations resulting in loss of distal 1p-material are known to occur frequently in advanced neuroblastomas. Fluorescence in situ hybridisation (FISH) showed that 17q was most frequently involved in chromosome 1p translocations. A review of the literature shows that 10 of 27 cell

PHOX2B reliably distinguishes neuroblastoma among small round blue cell tumours.

Science.gov (United States)

Hung, Yin P; Lee, John P; Bellizzi, Andrew M; Hornick, Jason L

2017-11-01

Neuroblastoma shows considerable histological overlap with other small round blue cell tumours. PHOX2B, a transcription factor that is essential for autonomic nervous system development, has been reported as an immunohistochemical marker for neuroblastoma. The aim of this study was to validate the specificity and diagnostic utility of PHOX2B for peripheral neuroblastic tumours. We evaluated 240 cases (133 in whole-tissue sections; 107 in tissue microarrays), including 76 peripheral neuroblastic tumours (median age 2 years; including four adults) and 164 other tumours: 44 Wilms tumours; 20 Ewing sarcomas; 10 each of CIC-rearranged round cell sarcomas, poorly differentiated synovial sarcomas, lymphoblastic lymphomas, alveolar rhabdomyosarcomas, embryonal rhabdomyosarcomas, mesenchymal chondrosarcomas, Merkel cell carcinomas, olfactory neuroblastomas, and melanomas; and five each of NUT midline carcinomas and desmoplastic small round cell tumours. Immunohistochemistry for PHOX2B was performed with a rabbit monoclonal antibody. PHOX2B positivity was defined as the presence of nuclear immunoreactivity in ≥5% of cells. PHOX2B was positive in 70 (92%) peripheral neuroblastic tumours, including 68 of 72 (94%) paediatric and two of four (50%) adult cases. Furthermore, PHOX2B was consistently negative in all non-peripheral neuroblastic tumours, with staining being absent in 160 cases and limited in four cases. PHOX2B is a highly sensitive and specific immunohistochemical marker for peripheral neuroblastic tumours, including neuroblastoma. PHOX2B reliably distinguishes neuroblastoma from histological mimics such as Wilms tumour, Ewing sarcoma, and CIC-rearranged round cell sarcoma. PHOX2B negativity in two of four adult neuroblastoma cases raises the possibility that some adult neuroblastomas are of a different lineage than paediatric cases. © 2017 John Wiley & Sons Ltd.

I-131 metaiodobenzylguanidine: diagnostic use in neuroblastoma patients in relapse

International Nuclear Information System (INIS)

Heyman, S.; Evans, A.E.; D'Angio, G.J.

1988-01-01

Metaiodobenzylguanidine (MIBG) has been used for the detection and treatment of neuroectodermal tumors, including neuroblastoma. We report our experience with 131 I-MIBG used diagnostically in neuroblastoma patients with relapse. Thirty-eight studies were performed in 26 patients. There were 24 children (range 3 months-14 years) and two adults. While the study was found to be both sensitive and specific for the presence of disease, there are instances of discordance. False-negative studies were found with a markedly anaplastic tumor and with two mature ganglioneuromas. A bone lesion was negative with 131 I-MIBG, but positive on bone scan. A biopsy confirmed the presence of neuroblastoma. Caution should be exercised when scanning pretreated patients, and perhaps with newly diagnosed patients as well

The effect of organolead and -tin compounds on signal transduction in vitro: Investigations on the cytosolic free calcium concentration; Der Einfluss von organischen Blei- und Zinnverbindungen auf die Signaltransduktion in vitro: Untersuchungen zur Veraenderung der zytosolischen freien Calciumkonzentration

Energy Technology Data Exchange (ETDEWEB)

Ade, T.

1996-03-01

The cellular effects of organolead and -tin compounds are not yet precisely understood. However, on the basis of their immuno- and neurotoxicity it is most likely that these substances interfere with cellular signal transduction. For this reason the effect on cytosolic free calcium concentration was investigated in this study. The organometals used induce a persistent increase in cytosolic free calcium concentration in human leukaemia HL-60 cells as well as in neuroblastoma NG-108-15 cells. Studies of the mechanism of the organometal effect with EGTA and calcium channel blockers revealed that an influx of calcium from the extracellular space is responsible for the organometal-induced calcium elevation in HL-60 cells. The effect of the investigated lead compounds and tributyltin is due to calcium channel opening in the plasma membrane. The same is true for the NG108-15 cells. Activation of distinct receptor-mediated signal transduction is not the reason for channel opening. The regulation of cytosolic free calcium concentration was affected by inhibition of plasmamembrane Ca{sup 2+}-ATPases as well as by disturbance of other ion gradients. A consequence of the organometal effect on the cytosolic calcium concentration is the activation of a cPLA{sub 2} and perhaps the induction of apoptosis. These results contribute towards the understanding of biochemical mechanisms causing the injury of vells by organometals. (orig.) [Deutsch] Die zellulaeren Wirkungsmechanismen organischer Blei- und Zinnverbindungen sind zum grossen Teil nicht verstanden. Die immuno- und neurotoxischen Effekte dieser Xenobiotika lassen jedoch die Beeinflussung der Signalwege in den Zellen vermuten. Daher lag der Schwerpunkt dieser Arbeit in der Untersuchung der Signaluebertragungswege und der damit verbundenen Regulation des Calciums. Sowohl in immunkompetenten Zellen (HL-60) wie auch in neuronalen Zellen (NG108-15) induzierten die untersuchten Organometalle eine persistente Erhoehung der

Nuclear medicine and multimodality imaging of pediatric neuroblastoma

Energy Technology Data Exchange (ETDEWEB)

Mueller, Wolfgang Peter; Pfluger, Thomas [Ludwig-Maximilians-University of Munich, Department of Nuclear Medicine, Munich (Germany); Coppenrath, Eva [Ludwig-Maximilians-University of Munich, Department of Radiology, Munich (Germany)

2013-04-15

Neuroblastoma is an embryonic tumor of the peripheral sympathetic nervous system and is metastatic or high risk for relapse in nearly 50% of cases. Therefore, exact staging with radiological and nuclear medicine imaging methods is crucial for defining the adequate therapeutic choice. Tumor cells express the norepinephrine transporter, which makes metaiodobenzylguanidine (MIBG), an analogue of norepinephrine, an ideal tumor specific agent for imaging. MIBG imaging has several disadvantages, such as limited spatial resolution, limited sensitivity in small lesions and the need for two or even more acquisition sessions. Most of these limitations can be overcome with positron emission tomography (PET) using [F-18]2-fluoro-2-deoxyglucose [FDG]. Furthermore, new tracers, such as fluorodopa or somatostatin receptor agonists, have been tested for imaging neuroblastoma recently. However, MIBG scintigraphy and PET alone are not sufficient for operative or biopsy planning. In this regard, a combination with morphological imaging is indispensable. This article will discuss strategies for primary and follow-up diagnosis in neuroblastoma using different nuclear medicine and radiological imaging methods as well as multimodality imaging. (orig.)

Neuroblastoma Treatment (PDQ®)—Patient Version

Science.gov (United States)

Neuroblastoma treatment may include surgery, observation, chemotherapy, radiation therapy, radioactive iodine, and high-dose chemotherapy with stem cell transplant and targeted therapy. Treatment also depends on risk category. Learn more in this expert-reviewed summary.

Variability in surface antigen expression on neuroblastoma cells as revealed by monoclonal antibodies

International Nuclear Information System (INIS)

Malpas, J.S.; Kemshead, J.T.; Pritchard, J.; Greaves, M.F.

1982-01-01

In treatment programmes for neuroblastoma involving autologous bone marrow transplantation, a problem exists in the identification of small numbers of metastatic tumour cells present in the marrow aspirates. Reinfusion of tumour cells along with normal bone marrow may reseed the tumour within a patient who has received high dose chemotherapy. Formalin-induced fluorescence in neuroblastoma is a possible diagnostic aid, but this method has no therapeutic potential. Other methods of detecting tumour relying on gross physiological changes in the patient are not suitable for diagnosis of minimal metastatic disease. As an immunological approach to the problem, rabbit antisera to neuroblastoma have been raised but these reagents suffer from low titre after absorption to make them specific. The authors have used the technique of somatic cell hybridisation to raise monoclonal antibodies which bind to neuroblastoma cells and not to normal haemopoietic progenitors. A panel of such reagents to demonstrate heterogeneity in antigen expression amongst metastatic neuroblastoma cells was employed in a radioimmunoassay as diagnostic aid for this problem. (Auth.)

Tissue factor/FVIIa activates Bcl-2 and prevents doxorubicin-induced apoptosis in neuroblastoma cells

International Nuclear Information System (INIS)

Fang, Jun; Gu, Lubing; Zhu, Ningxi; Tang, Hao; Alvarado, Carlos S; Zhou, Muxiang

2008-01-01

Tissue factor (TF) is a transmembrane protein that acts as a receptor for activated coagulation factor VII (FVIIa), initiating the coagulation cascade. Recent studies demonstrate that expression of tumor-derived TF also mediates intracellular signaling relevant to tumor growth and apoptosis. Our present study investigates the possible mechanism by which the interaction between TF and FVIIa regulates chemotherapy resistance in neuroblastoma cell lines. Gene and siRNA transfection was used to enforce TF expression in a TF-negative neuroblastoma cell line and to silence endogenous TF expression in a TF-overexpressing neuroblastoma line, respectively. The expression of TF, Bcl-2, STAT5, and Akt as well as the phosphorylation of STAT5 and Akt in gene transfected cells or cells treated with JAK inhibitor and LY294002 were determined by Western blot assay. Tumor cell growth was determined by a clonogenic assay. Cytotoxic and apoptotic effect of doxorubicin on neuroblastoma cell lines was analyzed by WST assay and annexin-V staining (by flow cytometry) respectively. Enforced expression of TF in a TF-negative neuroblastoma cell line in the presence of FVIIa induced upregulation of Bcl-2, leading to resistance to doxorubicin. Conversely, inhibition of endogenous TF expression in a TF-overexpressing neuroblastoma cell line using siRNA resulted in down-regulation of Bcl-2 and sensitization to doxorubicin-induced apoptosis. Additionally, neuroblastoma cells expressing high levels of either endogenous or transfected TF treated with FVIIa readily phosphorylated STAT5 and Akt. Using selective pharmacologic inhibitors, we demonstrated that JAK inhibitor I, but not the PI3K inhibitor LY294002, blocked the TF/FVIIa-induced upregulation of Bcl-2. This study shows that in neuroblastoma cell lines overexpressed TF ligated with FVIIa produced upregulation of Bcl-2 expression through the JAK/STAT5 signaling pathway, resulting in resistance to apoptosis. We surmise that this TF

Gene expression profiling in response to the histone deacetylase inhibitor BL1521 in neuroblastoma

International Nuclear Information System (INIS)

Ruijter, Annemieke J.M. de; Meinsma, Rutger J.; Bosma, Peter; Kemp, Stephan; Caron, Huib N.; Kuilenburg, Andre B.P. van

2005-01-01

Neuroblastoma is a childhood tumor with a poor survival in advanced stage disease despite intensive chemotherapeutic regimes. The new histone deacetylase (HDAC) inhibitor BL1521 has shown promising results in neuroblastoma. Inhibition of HDAC resulted in a decrease in proliferation and metabolic activity, induction of apoptosis and differentiation of neuroblastoma cells. In order to elucidate the mechanism mediating the effects of BL1521 on neuroblastoma cells, we investigated the gene expression profile of an MYCN single copy (SKNAS) and an MYCN amplified (IMR32) neuroblastoma cell line after treatment with BL1521 using the Affymetrix oligonucleotide array U133A. An altered expression of 255 genes was observed in both neuroblastoma cell lines. The majority of these genes were involved in gene expression, cellular metabolism, and cell signaling. We observed changes in the expression of vital genes belonging to the cell cycle (cyclin D1 and CDK4) and apoptosis (BNIP3, BID, and BCL2) pathway in response to BL1521. The expression of 37 genes was altered by both BL1521 and Trichostatin A, which could indicate a common gene set regulated by different HDAC inhibitors. BL1521 treatment changed the expression of a number of MYCN-associated genes. Several genes in the Wnt and the Delta/Notch pathways were changed in response to BL1521 treatment, suggesting that BL1521 is able to induce the differentiation of neuroblastoma cells into a more mature phenotype

Enhancement MRI evaluation of neuroblastoma staging in children

International Nuclear Information System (INIS)

Li Xin; Wang Chunxiang; Zhao Bin; Liu Peifang

2002-01-01

Objective: To evaluate the value and limitation of Gd-DTPA enhanced MRI for neuroblastoma staging in children. Methods: Twelve cases of neuroblastoma proved by operation or bone marrow aspiration were examined by gadolinium-enhanced MRI. The age ranged from seven months to five years, mean 3.7 years. Eight tumors originated from adrenal, and four from posterior mediastinum. Conventional sequences, double dose gadolinium-enhanced MRI, and 3D CEMRA were used in all patients. Six cases were examined by CT in same time. Imaging staging on surgic-histopathological-based International Neuroblastoma Staging System (INSS) was performed. Results: Six patients were staged by CT, including stage I-II in 2 cases, stage III in 4 cases, and stage IV in none. Twelve patients were staged by conventional MRI, including stage I-II in 2 cases, stage III in 9 cases, and stage IV in 1 case. Twelve patients were staged by double dose gadolinium-enhanced MRI, including stage I-II in 1 case, stage III in 1 case, and stage IV in 10 cases. Conclusion: Gadolinium-enhanced MRI was a single best imaging modality for neuroblastoma, most useful for distal to diaphragm metastasis, dumbbell tumor intraspinal extension, and bone marrow metastasis that was not detected by aspirate examination. Enhancement MRI was important in evaluating the therapy and was also helpful in assessing the therapeutic efficacy and relapse. 3D CEMRA helps demonstrate large vascular encasement and tumor erosion into important organs, and it is useful in assessing the respectability. Long examination time and lack in showing the characteristic calcium were the limitations

Lapatinib potentiates cytotoxicity of YM155 in neuroblastoma via inhibition of the ABCB1 efflux transporter

DEFF Research Database (Denmark)

Radic-Sarikas, Branka; Halasz, Melinda; Huber, Kilian V. M.

2017-01-01

and simultaneously help to overcome drug resistance. Neuroblastoma is the most common cancer in infancy and extremely heterogeneous in clinical presentation and features. Applying a systematic pairwise drug combination screen we observed a highly potent synergy in neuroblastoma cells between the EGFR kinase...... inhibitor lapatinib and the anticancer compound YM155 that is preserved across several neuroblastoma variants. Mechanistically, the synergy was based on a lapatinib induced inhibition of the multidrug-resistance efflux transporter ABCB1, which is frequently expressed in resistant neuroblastoma cells, which...... allowed prolonged and elevated cytotoxicity of YM155. In addition, the drug combination (i.e. lapatinib plus YM155) decreased neuroblastoma tumor size in an in vivo model....

CT on diagnosis and differential diagnosis of adrenal neuroblastoma from nephroblastoma in children

International Nuclear Information System (INIS)

Han Jingtian; Shen Guoqiang; Yang Huayuan

2000-01-01

Objective: To evaluate the effect of CT on diagnosis and differential diagnosis of children's adrenal neuroblastoma from nephroblastoma. Materials and Method: To analyse the CT manifestations on 36 cases of adrenal neuroblastoma and 32 cases of nephroblastoma both confirmed by postoperative pathologic diagnosis. Results: The adrenal neuroblastoma is a kind of extrarenal tumor, so the kidney kept its original form and showed some compressive features. The incidence of tumor calcification appeared mostly in rough and speckle-piece form was high. While the nephroblastoma is a renal tumor. The surrounding renal parenchyma showed a specific 'new-moon shape' intensification. Conclusion: CT is one of the most valuable and effective means of examination to diagnose adrenal neuroblastoma and differentiate it from nephroblastoma. It can provide important information for making correct diagnosis, planning proper therapy and assessing prognosis

Effective combination treatment of GD2-expressing neuroblastoma and Ewing's sarcoma using anti-GD2 ch14.18/CHO antibody with Vγ9Vδ2+ γδT cells.

Science.gov (United States)

Fisher, Jonathan P H; Flutter, Barry; Wesemann, Florian; Frosch, Jennifer; Rossig, Claudia; Gustafsson, Kenth; Anderson, John

Gamma delta T lymphocytes (γδT cells) have pleiotropic properties including innate cytotoxicity, which make them attractive effectors for cancer immunotherapy. Combination treatment with zoledronic acid and IL-2 can activate and expand the most common subset of blood γδT, which express the Vγ9Vδ2 T cell receptor (TCR) (Vδ2 T cells). Vγ9Vδ2 T cells are equipped for antibody-dependent cell-mediated cytotoxicity (ADCC) through expression of the low-affinity FcγR CD16. GD2 is a highly ranked tumor associated antigen for immunotherapy due to bright expression on the cell surface, absent expression on normal tissues and availability of therapeutic antibodies with known efficacy in neuroblastoma. To explore the hypothesis that zoledronic acid, IL-2 and anti-GD2 antibodies will synergize in a therapeutic combination, we evaluated in vitro cytotoxicity and tumor growth inhibition in the GD2 expressing cancers neuroblastoma and Ewing's sarcoma. Vδ2 T cells exert ADCC against GD2-expressing Ewing's sarcoma and neuroblastoma cell lines, an effect which correlates with the brightness of GD2 expression. In an immunodeficient mouse model of small established GD2-expressing Ewing's sarcoma or neuroblastoma tumors, the combination of adoptively transferred Vδ2+ T cells, expanded in vitro with zoledronic acid and IL-2, with anti-GD2 antibody ch14.18/CHO, and with systemic zoledronic acid, significantly suppressed tumor growth compared to antibody or γδT cell-free controls. Combination treatment using ch14.18/CHO, zoledronic acid and IL-2 is more effective than their use in isolation. The already-established safety profiles of these agents make testing of the combination in GD2 positive cancers such as neuroblastoma or Ewing's sarcoma both rational and feasible.

TestNG beginner's guide

CERN Document Server

Menon, Varun

2013-01-01

This book is written in a friendly, beginner's guide style with plenty of step-by-step instructions with appropriate examples.This book is great for developers and testers who are new to TestNg and want to learn how to use TestNG for writing their application as well as functional tests. This book assumes that you have experience in Java and OOPs concepts and have worked with certain IDE.

Interleukin-24 induces neuroblastoma SH-SY5Y cell differentiation, growth inhibition, and apoptosis by promoting ROS production.

Science.gov (United States)

Li, Yuan; Zhang, Hongwei; Zhu, Xiaoyu; Feng, Dongchuan; Gong, Jinchao; Han, Tao

2013-11-01

Neuroblastoma is among the most aggressive tumors that occur in childhood and infancy. The clinical prognosis of children with advanced-stage neuroblastoma is still poor. Interleukin-24 (IL-24) is emerging as a new cytokine involved in tumor cellular proliferation, differentiation, and apoptosis and has been widely studied as a tumor inhibitor. However, little is known about this cytokine's role in neuroblastoma. In this study, we investigated the possible effects of IL-24 on inducing neuroblastoma cell differentiation, growth inhibition, and apoptosis in vitro. Our data show that IL-24 promotes neuroblastoma SH-SY5Y cell differentiation, growth inhibition, and apoptosis. Furthermore, we found that the differentiation- and apoptosis-inducing action of IL-24 depends on the accumulation of reactive oxygen species (ROS). These results suggest that IL-24 can induce neuroblastoma cell differentiation and apoptosis and may be a potential therapeutic agent for neuroblastoma.

Image changes of the cases with neuroblastoma observed without therapy

International Nuclear Information System (INIS)

Takeuchi, Maho; Aida, Noriko

1999-01-01

Fifteen cases (10 males and 5 females) of neuroblastoma diagnosed by mass screening from November 1993 to October 1997, were observed without therapy. The mean age was 7.9 months. There were tumors in para-aortic area in 4 cases, in adrenal parts in 7 cases, in mediastinum in 3 cases. The other case had tumors in mediastinum and adrenal parts, bilaterally. The observation was executed by the ultrasonography in cases with the abdominal tumor and by MRI in cases with the mediastinal tumor. CT, MRI and US were performed in the first examination by radiologist. MIBG scintigraphy was used mainly for the detection of distant metastases. Imaging was performed at every one or two months in the beginning of observation, and at every three or four months afterwards. Tumors reduced in 9 cases, unchanged in 1 case and increased in 5 cases (8 tumors). The change of tumor size could be evaluated accurately, but the prediction of benignity or malignancy was difficult. Pathological findings were obtained from 5 cases who underwent surgical resection. Four cases had increased tumor. Two of them had benign neuroblastoma or ganglioma, and 2 cases had malignant neuroblastoma of low differentiation. One case with decreased tumor had neuroblastoma and became benign. (K.H.)

Comparison of Clinico-Radiological Features between Congenital Cystic Neuroblastoma and Neonatal Adrenal Hemorrhagic Pseudocyst

Energy Technology Data Exchange (ETDEWEB)

Eo, Hong; Kim, Ji Hye; Jang, Kyung Mi; Yoo, So Young [Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of); Lim, Gye Yeon [St. Mary' s Hospital Catholic University, Seoul (Korea, Republic of); Kim, Myung Joon [Severance Hospital Yonsei University, Seoul (Korea, Republic of); Kim, Ok Hwa [Ajou University Hospital, Suwon (Korea, Republic of)

2011-02-15

To evaluate the radiological and clinical findings of congenital cystic neuroblastomas as compared with those of the cystic presentation of neonatal adrenal hemorrhage. We analyzed the US (n = 52), CT (n = 24), and MR (n = 4) images as well as the medical records of 28 patients harboring congenital cystic neuroblastomas (n = 16) and neonatal adrenal hemorrhagic pseudocysts (n = 14). The history of prenatal detection, location, size, presence of outer wall enhancement, internal septations, solid portion, calcification, turbidity, vascular flow on a Doppler examination, and evolution patterns were compared in two groups of cystic lesions, by Fischer's exact test. All (100%) neuroblastomas and three (21%) of the 14 hemorrhagic pseudocysts were detected prenatally. Both groups of cystic lesions occurred more frequently on the right side; 11 of 16 (69%) for neuroblastomas and 11 of 14 (79%) for hemorrhagic pseudocysts. The size, presence of solid portion, septum, enhancement, and turbidity did not differ significantly (p > 0.05) between the two groups of cystic lesions. However, tiny calcifications (n = 3) and vascular flow on color Doppler US (n = 3) were noted in only neuroblastomas. The cystic neuroblastomas became complex solid and cystic masses, and did not disappear for up to 90 days in the three following cases, whereas 11 of the 14 (79%) hemorrhagic pseudocysts disappeared completely and the three remaining (27%) evolved to calcifications only. Although the imaging findings of two groups of cystic lesions were similar, prenatal detection, the presence of calcification on initial images, vascularity on color Doppler US, and evolution to a more complex mass may all favor neuroblastomas

Comparison of Clinico-Radiological Features between Congenital Cystic Neuroblastoma and Neonatal Adrenal Hemorrhagic Pseudocyst

International Nuclear Information System (INIS)

Eo, Hong; Kim, Ji Hye; Jang, Kyung Mi; Yoo, So Young; Lim, Gye Yeon; Kim, Myung Joon; Kim, Ok Hwa

2011-01-01

To evaluate the radiological and clinical findings of congenital cystic neuroblastomas as compared with those of the cystic presentation of neonatal adrenal hemorrhage. We analyzed the US (n = 52), CT (n = 24), and MR (n = 4) images as well as the medical records of 28 patients harboring congenital cystic neuroblastomas (n = 16) and neonatal adrenal hemorrhagic pseudocysts (n = 14). The history of prenatal detection, location, size, presence of outer wall enhancement, internal septations, solid portion, calcification, turbidity, vascular flow on a Doppler examination, and evolution patterns were compared in two groups of cystic lesions, by Fischer's exact test. All (100%) neuroblastomas and three (21%) of the 14 hemorrhagic pseudocysts were detected prenatally. Both groups of cystic lesions occurred more frequently on the right side; 11 of 16 (69%) for neuroblastomas and 11 of 14 (79%) for hemorrhagic pseudocysts. The size, presence of solid portion, septum, enhancement, and turbidity did not differ significantly (p > 0.05) between the two groups of cystic lesions. However, tiny calcifications (n = 3) and vascular flow on color Doppler US (n = 3) were noted in only neuroblastomas. The cystic neuroblastomas became complex solid and cystic masses, and did not disappear for up to 90 days in the three following cases, whereas 11 of the 14 (79%) hemorrhagic pseudocysts disappeared completely and the three remaining (27%) evolved to calcifications only. Although the imaging findings of two groups of cystic lesions were similar, prenatal detection, the presence of calcification on initial images, vascularity on color Doppler US, and evolution to a more complex mass may all favor neuroblastomas

Monoclonal Antibody Therapy for Advanced Neuroblastoma

Science.gov (United States)

NCI is sponsoring two clinical trials of a monoclonal antibody called ch14.18, in combination with other drugs, to see if the antibody may be helpful for children or young adults (up to age 21) with relapsed or refractory neuroblastoma.

Neuroblastoma mRNAs predict outcome in children with stage 4 neuroblastoma: a European HR-NBL1/SIOPEN study.

Science.gov (United States)

Viprey, Virginie F; Gregory, Walter M; Corrias, Maria V; Tchirkov, Andrei; Swerts, Katrien; Vicha, Ales; Dallorso, Sandro; Brock, Penelope; Luksch, Roberto; Valteau-Couanet, Dominique; Papadakis, Vassilios; Laureys, Genevieve; Pearson, Andrew D; Ladenstein, Ruth; Burchill, Susan A

2014-04-01

To evaluate the hypothesis that detection of neuroblastoma mRNAs by reverse transcriptase quantitative polymerase chain reaction (RTqPCR) in peripheral blood (PB) and bone marrow aspirates (BM) from children with stage 4 neuroblastoma are clinically useful biomarkers of risk. RTqPCR for paired-like homeobox 2b (PHOX2B), tyrosine hydroxylase (TH), and doublecortin (DCX) mRNA in PB and BM of children enrolled onto the High-Risk Neuroblastoma Trial-1 of the European Society of Pediatric Oncology Neuroblastoma Group (HR-NBL1/SIOPEN) was performed at diagnosis and after induction therapy. High levels of TH, PHOX2B, or DCX mRNA in PB or BM at diagnosis strongly predicted for worse event-free survival (EFS) and overall survival (OS) in a cohort of 290 children. After induction therapy, high levels of these mRNAs predicted worse EFS and OS in BM but not in PB. Combinations of mRNAs in BM did not add to the predictive power of any single mRNA. However, in the original (n = 182) and validation (n = 137) PB cohorts, high TH (log10TH > 0.8) or high PHOX2B (log10PHOX2B > 0.28) identify 19% of children as ultrahigh risk, with 5-year EFS and OS rates of 0%; OS rate was 25% (95% CI, 16% to 36%) and EFS rate was 38% (95% CI, 28% to 49%) in the remaining children. The magnitude of reduction in mRNA level between diagnosis and postinduction therapy in BM or PB was not of additional predictive value. High levels of TH and PHOX2B mRNA in PB at diagnosis objectively identify children with ultrahigh-risk disease who may benefit from novel treatment approaches. The level of TH, PHOX2B, and DCX mRNA in BM and/or PB at diagnosis might contribute to an algorithm to improve stratification of children for treatment.

Collective dipole motion in highly excited (272)Hs (Z=108) nuclei

NARCIS (Netherlands)

Tveter, TS; Gaardhoje, JJ; Maj, A; Ramsay, T; Atac, A; Bacelar, J; Bracco, A; Buda, A; Camera, F; Herskind, B; Korten, W; Krolas, W; Menthe, A; Million, B; Nifenecker, H; Pignanelli, M; Pinston, JA; vanderPloeg, H; Schussler, F; Sletten, G

1996-01-01

The heavy nucleus (272)(108)Hs (Z = 108) and its evaporation daughters were produced using the reaction Th-232(Ar-40, gamma xn) with beam energies 10.5 and 15.0 MeV/A. The giant dipole resonance gamma radiation from the hot composite system prior to fission has been isolated using a differential

Ultra-high Density SNParray in Neuroblastoma Molecular Diagnostics

Directory of Open Access Journals (Sweden)

Inge M. Ambros

2014-08-01

Full Text Available Neuroblastoma serves as a paradigm for applying tumor genomic data for determining patient prognosis and thus for treatment allocation. MYCN status, i.e. amplified vs. non-amplified, was one of the very first biomarkers in oncology to discriminate aggressive from less aggressive or even favorable clinical courses of neuroblastoma. However, MYCN amplification is by far not the only genetic change associated with unfavorable clinical courses: so called segmental chromosomal aberrations, i.e. gains or losses of chromosomal fragments, can also indicate tumor aggressiveness. The clinical use of these genomic aberrations has, however, been hampered for many years by methodical and interpretational problems. Only after reaching worldwide consensus on markers, methodology, and data interpretation, information on SCAs has recently been implemented in clinical studies. Now, a number of collaborative studies within COG, GPOH and SIOPEN use genomic information to stratify therapy for patients with localized and metastatic disease. Recently, new types of DNA based aberrations influencing the clinical behavior of neuroblastomas have been described. Deletions or mutations of genes like ATRX and a phenomenon referred to as chromothripsis are all assumed to correlate with an unfavorable clinical behavior. However, these genomic aberrations need to be scrutinized in larger studies applying the most appropriate techniques. Single nucleotide polymorphism (SNP arrays have proven successful in deciphering genomic aberrations of cancer cells; these techniques, however, are usually not applied in the daily routine. Here, we present an ultra-high density (UHD SNParray technique which is, because of its high specificity and sensitivity and the combined copy number and allele information, highly appropriate for the genomic diagnosis of neuroblastoma and other malignancies.

Protein tyrosine phosphatase receptor delta acts as a neuroblastoma tumor suppressor by destabilizing the aurora kinase a oncogene

LENUS (Irish Health Repository)

Meehan, Maria

2012-02-05

Abstract Background Protein tyrosine phosphatase receptor delta (PTPRD) is a member of a large family of protein tyrosine phosphatases which negatively regulate tyrosine phosphorylation. Neuroblastoma is a major childhood cancer arising from precursor cells of the sympathetic nervous system which is known to acquire deletions and alterations in the expression patterns of PTPRD, indicating a potential tumor suppressor function for this gene. The molecular mechanism, however, by which PTPRD renders a tumor suppressor effect in neuroblastoma is unknown. Results As a molecular mechanism, we demonstrate that PTPRD interacts with aurora kinase A (AURKA), an oncogenic protein that is over-expressed in multiple forms of cancer, including neuroblastoma. Ectopic up-regulation of PTPRD in neuroblastoma dephosphorylates tyrosine residues in AURKA resulting in a destabilization of this protein culminating in interfering with one of AURKA\\'s primary functions in neuroblastoma, the stabilization of MYCN protein, the gene of which is amplified in approximately 25 to 30% of high risk neuroblastoma. Conclusions PTPRD has a tumor suppressor function in neuroblastoma through AURKA dephosphorylation and destabilization and a downstream destabilization of MYCN protein, representing a novel mechanism for the function of PTPRD in neuroblastoma.

Hans Küng: "Projekt Weltethos "

OpenAIRE

Altmanninger, Maria

2002-01-01

Bei dieser Arbeit werde ich mich vor Allem auf zwei Werke beziehen: Küng,Hans:Projekt Weltethos.Piper.München 1990. Küng,Hans;Kuschel,Karl-Josef (Hg.):Weltfrieden durch Religionsfrieden.Die unter Punkt Acht aufgeführte Stellungnahme wurde ausschließlich von mir verfasst.

Long-Term Outcome and Toxicities of Intraoperative Radiotherapy for High-Risk Neuroblastoma

International Nuclear Information System (INIS)

Gillis, Amy M.; Sutton, Elizabeth; DeWitt, Kelly D.; Matthay, Katherine K.; Weinberg, Vivian; Fisch, Benjamin M.; Chan, Albert; Gooding, Charles; Daldrup-Link, Heike; Wara, William M.; Farmer, Diana L.; Harrison, Michael R.; Haas-Kogan, Daphne

2007-01-01

Purpose: To review a historical cohort of consecutively accrued patients with high-risk neuroblastoma treated with intraoperative radiotherapy (IORT) to determine the therapeutic effect and late complications of this treatment. Methods and Materials: Between 1986 and 2002, 31 patients with newly diagnosed high-risk neuroblastoma were treated with IORT as part of multimodality therapy. Their medical records were reviewed to determine the outcome and complications. Kaplan-Meier probability estimates of local control, progression-free survival, and overall survival at 36 months after diagnosis were recorded. Results: Intraoperative radiotherapy to the primary site and associated lymph nodes achieved excellent local control at a median follow-up of 44 months. The 3-year estimate of the local recurrence rate was 15%, less than that of most previously published series. Only 1 of 22 patients who had undergone gross total resection developed recurrence at the primary tumor site. The 3-year estimate of local control, progression-free survival, and overall survival was 85%, 47%, and 60%, respectively. Side effects attributable to either the disease process or multimodality treatment were observed in 7 patients who developed either hypertension or vascular stenosis. These late complications resulted in the death of 2 patients. Conclusions: Intraoperative radiotherapy at the time of primary resection offers effective local control in patients with high-risk neuroblastoma. Compared with historical controls, IORT achieved comparable control and survival rates while avoiding many side effects associated with external beam radiotherapy in young children. Although complications were observed, additional analysis is needed to determine the relative contributions of the disease process and specific components of the multimodality treatment to these adverse events

Neuroblastoma originating from soft tissue at the crus and its radiological feature

International Nuclear Information System (INIS)

Hirota, Shozo; Hanaguri, Katsuro; Hase, Mamoru; Sako, Masao.

1984-01-01

A very rare case of neuroblastoma originated from soft tissue at the crus in an adult man was reported especially about its radiological feature. Plain X-ray film of the leg showed slight distension of the distance between the tibia and fibula at the proximal portion of the crus. Bone scintigram using sup(99m)Tc-MDP revealed abnormal accumulation at the right upper crus. CT showed a low density mass with smooth margin being at the right upper crus. In femoral angiography, irregular arterial encasement, hypervascular fine tumor vessels, inhomogeneous tumor stain and venous obstruction were shown. Radiological findings made sure the mass to be a primary malignant soft tissue tumor at the right upper crus. Operative finding corroborated the mass to be a malignant one and the tumor extent to correspond to the angiographic diagnosis. The mass was microscopically diagnosed as neuroblastoma. It has been noted that neuroblastoma in childhood had shown extraosseous accumulation of bone seeking agent in a high frequency. Even if in an adult patient, extraosseous accumulation of bone seeking agent in soft tissue tumor, shown in this case, would suggest a mass to be indicative of neuroblastoma. Angiographically, neuroblastoma was said not to show a constant pattern. In the presented case, angiography was very significant in diagnosis of malignancy and tumor extent. (author)

Metastatic neuroblastoma presenting as refusal to use the left upper extremity in a six-year-old girl

Directory of Open Access Journals (Sweden)

Casey Grover

2014-12-01

Full Text Available Neuroblastoma is the most common extracranial neoplasm in children, commonly presenting at an advanced stage. Despite the high prevalence of metastatic disease with neuroblastoma, metastases to the central nervous system are rare and predominantly involve the spinal cord. We present a case of neuroblastoma with metastases to the brain presenting as refusal to move the left arm. The lesion initially appeared to be both a subdural and epidural hematoma on computed tomography of the head, but upon magnetic resonance imaging, was found to represent metastatic neuroblastoma. In pediatric patients with systemic symptoms and neurologic deficits, metastatic disease, such as neuroblastoma, should be included in the differential diagnosis and appropriate imaging should be obtained.

Dextran-Catechin: An anticancer chemically-modified natural compound targeting copper that attenuates neuroblastoma growth

Science.gov (United States)

Vittorio, Orazio; Brandl, Miriam; Cirillo, Giuseppe; Kimpton, Kathleen; Hinde, Elizabeth; Gaus, Katharina; Yee, Eugene; Kumar, Naresh; Duong, Hien; Fleming, Claudia; Haber, Michelle; Norris, Murray; Boyer, Cyrille; Kavallaris, Maria

2016-01-01

Neuroblastoma is frequently diagnosed at advanced stage disease and treatment includes high dose chemotherapy and surgery. Despite the use of aggressive therapy survival rates are poor and children that survive their disease experience long term side effects from their treatment, highlighting the need for effective and less toxic therapies. Catechin is a natural polyphenol with anti-cancer properties and limited side effects, however its mechanism of action is unknown. Here we report that Dextran-Catechin, a conjugated form of catechin that increases serum stability, is preferentially and markedly active against neuroblastoma cells having high levels of intracellular copper, without affecting non-malignant cells. Copper transporter 1 (CTR1) is the main transporter of copper in mammalian cells and it is upregulated in neuroblastoma. Functional studies showed that depletion of CTR1 expression reduced intracellular copper levels and led to a decrease in neuroblastoma cell sensitivity to Dextran-Catechin, implicating copper in the activity of this compound. Mechanistically, Dextran-Catechin was found to react with copper, inducing oxidative stress and decreasing glutathione levels, an intracellular antioxidant and regulator of copper homeostasis. In vivo, Dextran-Catechin significantly attenuated tumour growth in human xenograft and syngeneic models of neuroblastoma. Thus, Dextran-Catechin targets copper, inhibits tumour growth, and may be valuable in the treatment of aggressive neuroblastoma and other cancers dependent on copper for their growth. PMID:27374085

Infrared Spectra of Novel NgBeSO2 Complexes (Ng = Ne, Ar, Kr, Xe) in Low Temperature Matrixes.

Science.gov (United States)

Yu, Wenjie; Liu, Xing; Xu, Bing; Xing, Xiaopeng; Wang, Xuefeng

2016-11-03

The novel noble-gas complexes NgBeSO 2 (Ng = Ne, Ar, Kr, Xe) have been prepared in the laser-evaporated beryllium atom reactions with SO 2 in low-temperature matrixes. Doped with heavier noble gas, the guest (Ar, Kr, Xe) atom can substitute neon to form more stable complex. Infrared spectroscopy and theoretical calculations are used to confirm the band assignment. The dissociation energies are calculated at 0.9, 4.0, 4.7, and 6.0 kcal/mol for NeBeSO 2 , ArBeSO 2 , KrBeSO 2 , and XeBeSO 2 , respectively, at the CCSD(T) level. Quantum chemical calculations demonstrate that the Ng-Be bonds in NgBeSO 2 could be formed by the combination of electron-donation and ion-induced dipole interactions. The Wiberg bond index (WBI) values of Ng-Be bonds and LOL (localized orbital locator) profile indicate that the Ng-Be bond exhibits a gradual increase in covalent character along Ne to Xe.

Graphene Oxide Nanoribbons Induce Autophagic Vacuoles in Neuroblastoma Cell Lines

Directory of Open Access Journals (Sweden)

Emanuela Mari

2016-11-01

Full Text Available Since graphene nanoparticles are attracting increasing interest in relation to medical applications, it is important to understand their potential effects on humans. In the present study, we prepared graphene oxide (GO nanoribbons by oxidative unzipping of single-wall carbon nanotubes (SWCNTs and analyzed their toxicity in two human neuroblastoma cell lines. Neuroblastoma is the most common solid neoplasia in children. The hallmark of these tumors is the high number of different clinical variables, ranging from highly metastatic, rapid progression and resistance to therapy to spontaneous regression or change into benign ganglioneuromas. Patients with neuroblastoma are grouped into different risk groups that are characterized by different prognosis and different clinical behavior. Relapse and mortality in high risk patients is very high in spite of new advances in chemotherapy. Cell lines, obtained from neuroblastomas have different genotypic and phenotypic features. The cell lines SK-N-BE(2 and SH-SY5Y have different genetic mutations and tumorigenicity. Cells were exposed to low doses of GO for different times in order to investigate whether GO was a good vehicle for biological molecules delivering individualized therapy. Cytotoxicity in both cell lines was studied by measuring cellular oxidative stress (ROS, mitochondria membrane potential, expression of lysosomial proteins and cell growth. GO uptake and cytoplasmic distribution of particles were studied by Transmission Electron Microscopy (TEM for up to 72 h. The results show that GO at low concentrations increased ROS production and induced autophagy in both neuroblastoma cell lines within a few hours of exposure, events that, however, are not followed by growth arrest or death. For this reason, we suggest that the GO nanoparticle can be used for therapeutic delivery to the brain tissue with minimal effects on healthy cells.

Introduction of in vitro transcribed ENO1 mRNA into neuroblastoma cells induces cell death

International Nuclear Information System (INIS)

Ejeskär, Katarina; Krona, Cecilia; Carén, Helena; Zaibak, Faten; Li, Lingli; Martinsson, Tommy; Ioannou, Panayiotis A

2005-01-01

Neuroblastoma is a solid tumour of childhood often with an unfavourable outcome. One common genetic feature in aggressive tumours is 1p-deletion. The α-enolase (ENO1) gene is located in chromosome region 1p36.2, within the common region of deletion in neuroblastoma. One alternative translated product of the ENO1 gene, known as MBP-1, acts as a negative regulator of the c-myc oncogene, making the ENO1 gene a candidate as a tumour suppressor gene. Methods used in this study are transfection of cDNA-vectors and in vitro transcribed mRNA, cell growth assay, TUNEL-assay, real-time RT-PCR (TaqMan) for expression studies, genomic sequencing and DHPLC for mutation detection. Here we demonstrate that transfection of ENO1 cDNA into 1p-deleted neuroblastoma cell lines causes' reduced number of viable cells over time compared to a negative control and that it induces apoptosis. Interestingly, a similar but much stronger dose-dependent reduction of cell growth was observed by transfection of in vitro transcribed ENO1 mRNA into neuroblastoma cells. These effects could also be shown in non-neuroblastoma cells (293-cells), indicating ENO1 to have general tumour suppressor activity. Expression of ENO1 is detectable in primary neuroblastomas of all different stages and no difference in the level of expression can be detected between 1p-deleted and 1p-intact tumour samples. Although small numbers (11 primary neuroblastomas), there is some evidence that Stage 4 tumours has a lower level of ENO1-mRNA than Stage 2 tumours (p = 0.01). However, mutation screening of 44 primary neuroblastomas of all different stages, failed to detect any mutations. Our studies indicate that ENO1 has tumour suppressor activity and that high level of ENO1 expression has growth inhibitory effects

Transcription factor activating protein 2 beta (TFAP2B) mediates noradrenergic neuronal differentiation in neuroblastoma.

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Ikram, Fakhera; Ackermann, Sandra; Kahlert, Yvonne; Volland, Ruth; Roels, Frederik; Engesser, Anne; Hertwig, Falk; Kocak, Hayriye; Hero, Barbara; Dreidax, Daniel; Henrich, Kai-Oliver; Berthold, Frank; Nürnberg, Peter; Westermann, Frank; Fischer, Matthias

2016-02-01

Neuroblastoma is an embryonal pediatric tumor that originates from the developing sympathetic nervous system and shows a broad range of clinical behavior, ranging from fatal progression to differentiation into benign ganglioneuroma. In experimental neuroblastoma systems, retinoic acid (RA) effectively induces neuronal differentiation, and RA treatment has been therefore integrated in current therapies. However, the molecular mechanisms underlying differentiation are still poorly understood. We here investigated the role of transcription factor activating protein 2 beta (TFAP2B), a key factor in sympathetic nervous system development, in neuroblastoma pathogenesis and differentiation. Microarray analyses of primary neuroblastomas (n = 649) demonstrated that low TFAP2B expression was significantly associated with unfavorable prognostic markers as well as adverse patient outcome. We also found that low TFAP2B expression was strongly associated with CpG methylation of the TFAP2B locus in primary neuroblastomas (n = 105) and demethylation with 5-aza-2'-deoxycytidine resulted in induction of TFAP2B expression in vitro, suggesting that TFAP2B is silenced by genomic methylation. Tetracycline inducible re-expression of TFAP2B in IMR-32 and SH-EP neuroblastoma cells significantly impaired proliferation and cell cycle progression. In IMR-32 cells, TFAP2B induced neuronal differentiation, which was accompanied by up-regulation of the catecholamine biosynthesizing enzyme genes DBH and TH, and down-regulation of MYCN and REST, a master repressor of neuronal genes. By contrast, knockdown of TFAP2B by lentiviral transduction of shRNAs abrogated RA-induced neuronal differentiation of SH-SY5Y and SK-N-BE(2)c neuroblastoma cells almost completely. Taken together, our results suggest that TFAP2B is playing a vital role in retaining RA responsiveness and mediating noradrenergic neuronal differentiation in neuroblastoma. Copyright © 2015 Federation of European Biochemical Societies

The distribution of alternative agents for targeted radiotherapy within human neuroblastoma spheroids

International Nuclear Information System (INIS)

Mairs, R.J.; Gaze, M.N.; Murray, T.; Reid, R.; McSharry, C.; Babich, J.W.

1991-01-01

This study aims to select the radiopharmaceutical vehicle for targeted radiotherapy of neuroblastoma which is most likely to penetrate readily the centre of micrometastases in vivo. The human neuroblastoma cell line NB1-G, grown as multicellular spheroids provided an in vitro model for micrometastases. The radiopharmaceuticals studied were the catecholamine analogue metaiodobenzyl guanidine (mIBG), a specific neuroectodermal monoclonal antibody (UJ13A) and β nerve growth factor (βNGF). Following incubation of each drug with neuroblastoma spheroids, autoradiographs of frozen sections were prepared to demonstrate their relative distributions. mIBG and βNGF were found to penetrate the centre of spheroids readily although the concentration of mIBG greatly exceeded that of βNGF. In contrast, UJ13A was only bound peripherally. We conclude that mIBG is the best available vehicle for targeted radiotherapy of neuroblastoma cells with active uptake mechanisms for catecholimines. It is suggested that radionuclides with a shorter range of emissions than 131 I may be conjugated to benzyl guanidine to constitute more effective targeting agents with potentially less toxicity to adjacent normal tissues. (author)

Physically disconnected non-diffusible cell-to-cell communication between neuroblastoma SH-SY5Y and DRG primary sensory neurons.

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Chaban, Victor V; Cho, Taehoon; Reid, Christopher B; Norris, Keith C

2013-01-01

Cell-cell communication occurs via a variety of mechanisms, including long distances (hormonal), short distances (paracrine and synaptic) or direct coupling via gap junctions, antigen presentation, or ligand-receptor interactions. We evaluated the possibility of neuro-hormonal independent, non-diffusible, physically disconnected pathways for cell-cell communication using dorsal root ganglion (DRG) neurons. We assessed intracellular calcium ([Ca(2+)]) in primary culture DRG neurons that express ATP-sensitive P2X3, capsaicinsensitive TRPV1 receptors modulated by estradiol. Physically disconnected (dish-in-dish system; inner chamber enclosed) mouse DRG were cultured for 12 hours near: a) media alone (control 1), b) mouse DRG (control 2), c) human neuroblastoma SHSY-5Y cells (cancer intervention), or d) mouse DRG treated with KCl (apoptosis intervention). Chemosensitive receptors [Ca(2+)](i) signaling did not differ between control 1 and 2. ATP (10 μM) and capsaicin (100nM) increased [Ca(2+)](i) transients to 425.86 + 49.5 nM, and 399.21 ± 44.5 nM, respectively. 17β-estradiol (100 nM) exposure reduced ATP (171.17 ± 48.9 nM) and capsaicin (175.01±34.8 nM) [Ca(2+)](i) transients. The presence of cancer cells reduced ATP- and capsaicin-induced [Ca(2+)](i) by >50% (pcommunication.

NCYM promotes calpain-mediated Myc-nick production in human MYCN-amplified neuroblastoma cells

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Shoji, Wataru [Division of Biochemistry and Innovative Cancer Therapeutics and Children' s Cancer Research Center, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuo-ku, Chiba 260-8717 (Japan); Department of Pediatric Surgery, Graduate School of Medicine, Tohoku University, Sendai 980-8574 (Japan); Suenaga, Yusuke, E-mail: ysuenaga@chiba-cc.jp [Division of Biochemistry and Innovative Cancer Therapeutics and Children' s Cancer Research Center, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuo-ku, Chiba 260-8717 (Japan); Cancer Genome Center, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuo-ku, Chiba 260-8717 (Japan); Kaneko, Yoshiki; Islam, S.M. Rafiqul; Alagu, Jennifer [Division of Biochemistry and Innovative Cancer Therapeutics and Children' s Cancer Research Center, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuo-ku, Chiba 260-8717 (Japan); Yokoi, Sana [Cancer Genome Center, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuo-ku, Chiba 260-8717 (Japan); Nio, Masaki [Department of Pediatric Surgery, Graduate School of Medicine, Tohoku University, Sendai 980-8574 (Japan); Nakagawara, Akira, E-mail: nakagawara-a@koseikan.jp [Division of Biochemistry and Innovative Cancer Therapeutics and Children' s Cancer Research Center, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuo-ku, Chiba 260-8717 (Japan)

2015-06-05

NCYM is a cis-antisense gene of MYCN and is amplified in human neuroblastomas. High NCYM expression is associated with poor prognoses, and the NCYM protein stabilizes MYCN to promote proliferation of neuroblastoma cells. However, the molecular mechanisms of NCYM in the regulation of cell survival have remained poorly characterized. Here we show that NCYM promotes cleavage of MYCN to produce the anti-apoptotic protein, Myc-nick, both in vitro and in vivo. NCYM and Myc-nick were induced at G2/M phase, and NCYM knockdown induced apoptotic cell death accompanied by Myc-nick downregulation. These results reveal a novel function of NCYM as a regulator of Myc-nick production in human neuroblastomas. - Highlights: • NCYM promotes cleavages of MYC and MYCN to produce Myc-nick in vitro. • NCYM increases Myc-nick production in MYCN-amplified neuroblastoma cells. • NCYM knockdown decreases Myc-nick production and induces apoptosis at G2/M phase.

NCYM promotes calpain-mediated Myc-nick production in human MYCN-amplified neuroblastoma cells

International Nuclear Information System (INIS)

Shoji, Wataru; Suenaga, Yusuke; Kaneko, Yoshiki; Islam, S.M. Rafiqul; Alagu, Jennifer; Yokoi, Sana; Nio, Masaki; Nakagawara, Akira

2015-01-01

NCYM is a cis-antisense gene of MYCN and is amplified in human neuroblastomas. High NCYM expression is associated with poor prognoses, and the NCYM protein stabilizes MYCN to promote proliferation of neuroblastoma cells. However, the molecular mechanisms of NCYM in the regulation of cell survival have remained poorly characterized. Here we show that NCYM promotes cleavage of MYCN to produce the anti-apoptotic protein, Myc-nick, both in vitro and in vivo. NCYM and Myc-nick were induced at G2/M phase, and NCYM knockdown induced apoptotic cell death accompanied by Myc-nick downregulation. These results reveal a novel function of NCYM as a regulator of Myc-nick production in human neuroblastomas. - Highlights: • NCYM promotes cleavages of MYC and MYCN to produce Myc-nick in vitro. • NCYM increases Myc-nick production in MYCN-amplified neuroblastoma cells. • NCYM knockdown decreases Myc-nick production and induces apoptosis at G2/M phase

Clinical potentials of methylator phenotype in stage 4 high-risk neuroblastoma: an open challenge.

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Barbara Banelli

Full Text Available Approximately 20% of stage 4 high-risk neuroblastoma patients are alive and disease-free 5 years after disease onset while the remaining experience rapid and fatal progression. Numerous findings underline the prognostic role of methylation of defined target genes in neuroblastoma without taking into account the clinical and biological heterogeneity of this disease. In this report we have investigated the methylation of the PCDHB cluster, the most informative member of the "Methylator Phenotype" in neuroblastoma, hypothesizing that if this epigenetic mark can predict overall and progression free survival in high-risk stage 4 neuroblastoma, it could be utilized to improve the risk stratification of the patients, alone or in conjunction with the previously identified methylation of the SFN gene (14.3.3sigma that can accurately predict outcome in these patients. We have utilized univariate and multivariate models to compare the prognostic power of PCDHB methylation in terms of overall and progression free survival, quantitatively determined by pyrosequencing, with that of other markers utilized for the patients' stratification utilizing methylation thresholds calculated on neuroblastoma at stage 1-4 and only on stage 4, high-risk patients. Our results indicate that PCDHB accurately distinguishes between high- and intermediate/low risk stage 4 neuroblastoma in agreement with the established risk stratification criteria. However PCDHB cannot predict outcome in the subgroup of stage 4 patients at high-risk whereas methylation levels of SFN are suggestive of a "methylation gradient" associated with tumor aggressiveness as suggested by the finding of a higher threshold that defines a subset of patients with an extremely severe disease (OS <24 months. Because of the heterogeneity of neuroblastoma we believe that clinically relevant methylation markers should be selected and tested on homogeneous groups of patients rather than on patients at all stages.

A sensitive radioimmunoassay for a component of mouse casein

International Nuclear Information System (INIS)

Enami, Jumpei; Nandi, S.; California Univ. Berkeley

1977-01-01

Mouse casein (m.w. 22,000 daltons) has been purified by employing Sephadex G-100 and DEAE-cellulose column chromatographies. A sensitive radioimmunoassay method has been developed by using [ 125 I]-labelled casein and antiserum elicited in rabbits after injection of glutaraldehyde-treated casein. The assay method is capable of detecting as little as 0.1 ng of casein. The use of the present radioimmunoassay method in detecting casein production in cultured mouse mammary explants has also been demonstrated

The value of anterior displacement of the abdominal aorta in diagnosing neuroblastoma in children

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Schiavon, Jose Luiz de Oliveira; Caran, Eliana Maria Monteiro; Lederman, Henrique Manoel, E-mail: schiavon00@gmail.com [Universidade Federal de Sao Paulo (EPM/UNIFESP), Sao Paulo, SP (Brazil). Escola Paulista de Medicina; Odone Filho, Vicente [Universidade de Sao Paulo (FM/USP), Sao Paulo, SP (Brazil). Faculdade de Medicina

2016-11-15

Objective: To determine the value of anterior displacement of the abdominal aorta, when present at any level or only at the level of the adrenal gland, contralateral to the mass, in diagnosing neuroblastoma on computed tomography or magnetic resonance imaging in children up to 7 years of age. Materials and Methods: Imaging examinations of 66 patients were classified by consensus as for the presence of anterior aorta displacement and were compared with the pathology report. Results: We found anterior abdominal aorta displacement in 26 (39.39%) of the 66 patients evaluated. Among those 26 patients, we identified neuroblastoma in 22 (84.62%), nephroblastoma in 3 (11.54%), and Burkitt lymphoma in 1 (3.85%). The positive predictive value was 84.62%, and the specificity was 88.24%. The displacement of the aorta was at the adrenal level, contralateral to the mass, in 14 cases, all of which were attributed to neuroblastoma. Conclusion: When the abdominal aorta is displaced at the level of the adrenal gland, contralateral to the mass, it can be said that the diagnosis is neuroblastoma, whereas abdominal aorta displacement occurring at other abdominal levels has a positive predictive value for neuroblastoma of approximately 85%. (author)

The value of anterior displacement of the abdominal aorta in diagnosing neuroblastoma in children

International Nuclear Information System (INIS)

Schiavon, Jose Luiz de Oliveira; Caran, Eliana Maria Monteiro; Lederman, Henrique Manoel; Odone Filho, Vicente

2016-01-01

Objective: To determine the value of anterior displacement of the abdominal aorta, when present at any level or only at the level of the adrenal gland, contralateral to the mass, in diagnosing neuroblastoma on computed tomography or magnetic resonance imaging in children up to 7 years of age. Materials and Methods: Imaging examinations of 66 patients were classified by consensus as for the presence of anterior aorta displacement and were compared with the pathology report. Results: We found anterior abdominal aorta displacement in 26 (39.39%) of the 66 patients evaluated. Among those 26 patients, we identified neuroblastoma in 22 (84.62%), nephroblastoma in 3 (11.54%), and Burkitt lymphoma in 1 (3.85%). The positive predictive value was 84.62%, and the specificity was 88.24%. The displacement of the aorta was at the adrenal level, contralateral to the mass, in 14 cases, all of which were attributed to neuroblastoma. Conclusion: When the abdominal aorta is displaced at the level of the adrenal gland, contralateral to the mass, it can be said that the diagnosis is neuroblastoma, whereas abdominal aorta displacement occurring at other abdominal levels has a positive predictive value for neuroblastoma of approximately 85%. (author)

Quantitative estimation of 123I-MIBG scintigraphy in neuroblastoma. Usefulness of the total body retention rate

International Nuclear Information System (INIS)

Okuyama, Chio; Ushijima, Yo; Sugihara, Hiroki; Nishimura, Tunehiko

2000-01-01

A new method of easily and simply quantifying 123 I-MIBG accumulation as a criterion for curative effect of chemotherapy in infants with neuroblastoma was developed. This method uses the data from two images: an early image (at 5-7.5 hr) and a delayed image (at 25-32 hr). Twenty infants with untreated neuroblastoma which showed clear accumulation of 123 I-MIBG at the primary site were examined. The differences between the accumulation counts on the early image and the delayed image showed that washout of 123 I-MIBG in the neuroblastomas was delayed in tumor regions. This finding indicated that the total body 123 I-MIBG retention rate reflects the total volume of the neuroblastoma. The 123 I-MIBG retention rate was significantly higher in patients with advanced stage neuroblastoma with systemic metastases, and there was a good correlation between the retention rate and tumor markers (VMA and HVA values in urine). The response to chemotherapy paralleled the change in markers. These results suggested that the total body 123 I-MIBG retention rate is useful as a criterion for curative effect in advanced neuroblastoma. (K.H.)

Anti-cancer effect of oncolytic adenovirus-armed shRNA targeting MYCN gene on doxorubicin-resistant neuroblastoma cells.

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Li, Yuan; Zhuo, Baobiao; Yin, Yiyu; Han, Tao; Li, Shixian; Li, Zhengwei; Wang, Jian

2017-09-09

Chemotherapy is one of the few effective choices for patients with neuroblastoma. However, the development of muti-drug resistance (MDR) to chemotherapy is a major obstacle to the effective treatment of advanced or recurrent neuroblastoma. The muti-drug resistance-associated protein (MRP), which encodes a transmembrane glycoprotein, is a key regulator of MDR. The expression of MRP is a close correlation with MYCN oncogene in neuroblastoma. We have recently shown ZD55-shMYCN (oncolytic virus armed with shRNA against MYCN) can down-regulate MYCN to inhibit tumor cells proliferation and induce apoptosis in neuroblastoma. Here we further report ZD55-shMYCN re-sensitized doxorubicin-resistant cells to doxorubicin (as shown by reduced proliferation, increased apoptosis, and inhibited cell migration), and reduced the in vivo growth rate of neuroblastoma xenografts by down-regulation of MRP expression. Sequential therapy with doxorubicin did not affect the replication of ZD55-shMYCN in doxorubicin-resistant neuroblastoma cells, but decreased the expression of Bcl-2, Bcl-X L , MMP-1. Thus, this synergistic effect of ZD55-shMYCN in combination with doxorubicin provides a novel therapy strategy for doxorubicin-resistant neuroblastoma, and is a promising approach for further clinical development. Copyright © 2017 Elsevier Inc. All rights reserved.

Long-term follow-up of children with high-risk neuroblastoma: the ENSG5 trial experience.

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Moreno, Lucas; Vaidya, Sucheta J; Pinkerton, C Ross; Lewis, Ian J; Imeson, John; Machin, David; Pearson, Andrew D J

2013-07-01

Therapy for high-risk neuroblastoma is intensive and multimodal, and significant long-term adverse effects have been described. The aim of this study was to identify the nature and severity of late complications of metastatic neuroblastoma survivors included in the ENSG5 clinical trial. The trial protocol included induction chemotherapy (randomized "Standard" OPEC/OJEC vs. "Rapid" COJEC), surgery of primary tumor and high-dose melphalan with stem cell rescue. Two hundred and sixty-two children were randomized, 69 survived >5 years, and 57 were analyzed. Data were obtained from the ENSG5 trial database and verified with questionnaires sent to participating centers. Median follow-up was 12.9 (6.9-16.5) years. No differences were found in late toxicities between treatment arms. Twenty-eight children (49.1%) developed hearing loss. Nine patients (15.8%) developed glomerular filtration rate <80 ml/min/1.73 m(2), but no cases of chronic renal failure were documented. Endocrine complications (28.1% of children) included mainly hypogonadism and delayed growth. Four children developed second malignancies, three of them 5 years after diagnosis: one osteosarcoma, one carcinoma of the parotid gland and one ependymoma. There were no hematological malignancies or deaths in remission. This study analyzed a wide cohort of high-risk neuroblastoma survivors from a multi-institutional randomized trial and established the profile of long-term toxicity within the setting of an international clinical trial. Copyright © 2012 Wiley Periodicals, Inc.

Abnormal brain MRI in a case of acute ataxia as the only sign of abdominal neuroblastoma

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Molla Mohammadi, M.; Karimzadeh, P.; Khatami, A.; Jadali, F.

2010-01-01

Ataxia is a movement disorder that may manifest an acute, intermittent, non progressive or chronic progressive course. Ataxia alone is rare as a para neoplastic sign, especially if it is due to neuroblastoma (abdominal or chest). We report an abdominal neuroblastoma in a two-year-old girl presenting with only acute ataxia and abnormal neuroimaging. Brain MRI showed abnormal signal finding in the medulla, pons, cortico spinal tract and the periventricular space. In the abdominal CT, a mass was detected in the right adrenal gland with calcification and the histopathologic examination re-vealed neuroblastoma. We suggest in children with acute ataxia, with or without opalescence-myoclonus, neuroblastoma should be considered.

CDDO and ATRA Instigate Differentiation of IMR32 Human Neuroblastoma Cells

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Namrata Chaudhari

2017-09-01

Full Text Available Neuroblastoma is the most common solid extra cranial tumor in infants. Improving the clinical outcome of children with aggressive tumors undergoing one of the multiple treatment options has been a major concern. Differentiating neuroblastoma cells holds promise in inducing tumor growth arrest and treating minimal residual disease. In this study, we investigated the effect of partial PPARγ agonist 2-cyano-3,12-dioxooleana-1,9(11-dien-28-oic acid (CDDO on human neuroblastoma IMR32 cells. Our results demonstrate that treatment with low concentration of CDDO and particularly in combination with all trans retinoic acid (ATRA induced neurite outgrowth, increased the percentage of more than two neurites bearing cells, and decreased viability in IMR32 cells. These morphological changes were associated with an increase in expression of bonafide differentiation markers like β3-tubulin and Neuron Specific Enolase (NSE. The differentiation was accompanied by a decrease in the expression of MYCN whose amplification is known to contribute to the pathogenesis of neuroblastoma. MYCN is known to negatively regulate NMYC downstream-regulated gene 1 (NDRG1 in neuroblastomas. MYCN down-regulation induced by CDDO correlated with increased expression of NDRG1. CDDO decreased Anaplastic Lymphoma Kinase (ALK mRNA expression without affecting its protein level, while ATRA significantly down-regulated ALK. Antagonism of PPARγ receptor by T0070907 meddled with differentiation inducing effects of CDDO as observed by stunted neurite growth, increased viability and decreased expression of differentiation markers. Our findings indicate that IMR32 differentiation induced by CDDO in combination with ATRA enhances, differentiation followed by cell death via cAMP-response-element binding protein (CREB independent and PPARγ dependent signaling mechanisms.

Antagonizing Bcl-2 family members sensitizes neuroblastoma and Ewing's sarcoma to an inhibitor of glutamine metabolism.

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Rachelle R Olsen

Full Text Available Neuroblastomas (NBL and Ewing's sarcomas (EWS together cause 18% of all pediatric cancer deaths. Though there is growing interest in targeting the dysregulated metabolism of cancer as a therapeutic strategy, this approach has not been fully examined in NBL and EWS. In this study, we first tested a panel of metabolic inhibitors and identified the glutamine antagonist 6-diazo-5-oxo-L-norleucine (DON as the most potent chemotherapeutic across all NBL and EWS cell lines tested. Myc, a master regulator of metabolism, is commonly overexpressed in both of these pediatric malignancies and recent studies have established that Myc causes cancer cells to become "addicted" to glutamine. We found DON strongly inhibited tumor growth of multiple tumor lines in mouse xenograft models. In vitro, inhibition of caspases partially reversed the effects of DON in high Myc expressing cell lines, but not in low Myc expressing lines. We further showed that induction of apoptosis by DON in Myc-overexpressing cancers is via the pro-apoptotic factor Bax. To relieve inhibition of Bax, we tested DON in combination with the Bcl-2 family antagonist navitoclax (ABT-263. In vitro, this combination caused an increase in DON activity across the entire panel of cell lines tested, with synergistic effects in two of the N-Myc amplified neuroblastoma cell lines. Our study supports targeting glutamine metabolism to treat Myc overexpressing cancers, such as NBL and EWS, particularly in combination with Bcl-2 family antagonists.

A primary sellar neuroblastoma mimicking a pituitary adenoma: A case report

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Kim, Dong Gun; Heo, Young Jin; Kim, Eun Kyoung; Baek, Jin Wook; Jeong, Hae Woong; Jung, Hyun Seok [Busan Paik Hospital, Inje University College of Medicine, Busan (Korea, Republic of)

2016-12-15

Intracranial neuroblastomas are uncommon malignant tumors that usually arise in the supratentorial parenchymal or paraventricular location. A primary neuroblastoma arising in the sella turcica is extremely rare. We report a case of a 76-year-old man who presented with progressive bitemporal hemianopsia. His pituitary hormone levels were within the normal range, except for slightly increased prolactin. Pituitary magnetic resonance imaging revealed a solitary sellar mass with supra- and parasellar extension that mimicked a non-functioning pituitary adenoma or meningioma. The tumor was excised by transsphenoidal resection. Histopathologic analysis revealed small cells surrounded by a dense fibrillary stroma as well as strong expression of neural markers. Hence, the patient was diagnosed with sellar neuroblastoma. Prolactin levels normalized in the immediate postoperative period, although visual disturbances persisted. Herein, we describe the clinical manifestations, MRI characteristics, and histopathologic findings of this case.

Synergistic interaction between cisplatin and gemcitabine in neuroblastoma cell lines and multicellular tumor spheroids

NARCIS (Netherlands)

Besançon, Odette G.; Tytgat, Godelieve A. M.; Meinsma, Rutger; Leen, René; Hoebink, Jerry; Kalayda, Ganna V.; Jaehde, Ulrich; Caron, Huib N.; van Kuilenburg, André B. P.

2012-01-01

The efficacy and mechanism of action of cisplatin and gemcitabine were investigated in a panel of neuroblastoma cell lines and multicellular tumor spheroids. In neuroblastoma spheroids, the combination of cisplatin and gemcitabine induced a complete cytostasis at clinical relevant concentrations. A

Transcription instability in high-risk neuroblastoma is associated with a global perturbation of chromatin domains.

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Zanon, Carlo; Tonini, Gian Paolo

2017-11-01

Chromosome instability has a pivotal role among the hallmarks of cancer, but its transcriptional counterpart is rarely considered a relevant factor in cell destabilization. To examine transcription instability (TIN), we first devised a metric we named TIN index and used it to evaluate TIN on a dataset containing more than 500 neuroblastoma samples. We found that metastatic tumors from high-risk (HR) patients are characterized by significantly different TIN index values compared to low/intermediate-risk patients. Our results indicate that the TIN index is a good predictor of neuroblastoma patient's outcome, and a related TIN index gene signature (TIN-signature) is also able to predict the neuroblastoma patient's outcome with high confidence. Interestingly, we find that TIN-signature genes have a strong positional association with superenhancers in neuroblastoma tumors. Finally, we show that TIN is linked to chromatin structural domains and interferes with their integrity in HR neuroblastoma patients. This novel approach to gene expression analysis broadens the perspective of genome instability investigations to include functional aspects. © 2017 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.

Galectin-3 impairment of MYCN-dependent apoptosis-sensitive phenotype is antagonized by nutlin-3 in neuroblastoma cells.

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Veronica Veschi

Full Text Available MYCN amplification occurs in about 20-25% of human neuroblastomas and characterizes the majority of the high-risk cases, which display less than 50% prolonged survival rate despite intense multimodal treatment. Somehow paradoxically, MYCN also sensitizes neuroblastoma cells to apoptosis, understanding the molecular mechanisms of which might be relevant for the therapy of MYCN amplified neuroblastoma. We recently reported that the apoptosis-sensitive phenotype induced by MYCN is linked to stabilization of p53 and its proapoptotic kinase HIPK2. In MYCN primed neuroblastoma cells, further activation of both HIPK2 and p53 by Nutlin-3 leads to massive apoptosis in vitro and to tumor shrinkage and impairment of metastasis in xenograft models. Here we report that Galectin-3 impairs MYCN-primed and HIPK2-p53-dependent apoptosis in neuroblastoma cells. Galectin-3 is broadly expressed in human neuroblastoma cell lines and tumors and is repressed by MYCN to induce the apoptosis-sensitive phenotype. Despite its reduced levels, Galectin-3 can still exert residual antiapoptotic effects in MYCN amplified neuroblastoma cells, possibly due to its specific subcellular localization. Importantly, Nutlin-3 represses Galectin-3 expression, and this is required for its potent cell killing effect on MYCN amplified cell lines. Our data further characterize the apoptosis-sensitive phenotype induced by MYCN, expand our understanding of the activity of MDM2-p53 antagonists and highlight Galectin-3 as a potential biomarker for the tailored p53 reactivation therapy in patients with high-risk neuroblastomas.

Mesenchymal change and drug resistance in neuroblastoma.

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Naiditch, Jessica A; Jie, Chunfa; Lautz, Timothy B; Yu, Songtao; Clark, Sandra; Voronov, Dimitry; Chu, Fei; Madonna, Mary Beth

2015-01-01

Metastatic initiation has many phenotypic similarities to epithelial-to-mesenchymal transition, including loss of cell-cell adhesion, increased invasiveness, and increased cell mobility. We have previously demonstrated that drug resistance is associated with a metastatic phenotype in neuroblastoma (NB). The purpose of this project was to determine if the development of doxorubicin resistance is associated with characteristics of mesenchymal change in human NB cells. Total RNA was isolated from wild type (WT) and doxorubicin-resistant (DoxR) human NB cell lines (SK-N-SH and SK-N-BE(2)C) and analyzed using the Illumina Human HT-12 version 4 Expression BeadChip. Differentially expressed genes (DEGs) were identified. Volcano plots and heat maps were generated. Genes of interest with a fold change in expression >1.5 and an adjusted P change via multiple pathways in the transition to a drug-resistant state. Copyright © 2015 Elsevier Inc. All rights reserved.

Genome‐wide DNA methylation analysis identifies MEGF10 as a novel epigenetically repressed candidate tumor suppressor gene in neuroblastoma

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Charlet, Jessica; Tomari, Ayumi; Dallosso, Anthony R.; Szemes, Marianna; Kaselova, Martina; Curry, Thomas J.; Almutairi, Bader; Etchevers, Heather C.; McConville, Carmel; Malik, Karim T. A.

2016-01-01

Neuroblastoma is a childhood cancer in which many children still have poor outcomes, emphasising the need to better understand its pathogenesis. Despite recent genome‐wide mutation analyses, many primary neuroblastomas do not contain recognizable driver mutations, implicating alternate molecular pathologies such as epigenetic alterations. To discover genes that become epigenetically deregulated during neuroblastoma tumorigenesis, we took the novel approach of comparing neuroblastomas to neural crest precursor cells, using genome‐wide DNA methylation analysis. We identified 93 genes that were significantly differentially methylated of which 26 (28%) were hypermethylated and 67 (72%) were hypomethylated. Concentrating on hypermethylated genes to identify candidate tumor suppressor loci, we found the cell engulfment and adhesion factor gene MEGF10 to be epigenetically repressed by DNA hypermethylation or by H3K27/K9 methylation in neuroblastoma cell lines. MEGF10 showed significantly down‐regulated expression in neuroblastoma tumor samples; furthermore patients with the lowest‐expressing tumors had reduced relapse‐free survival. Our functional studies showed that knock‐down of MEGF10 expression in neuroblastoma cell lines promoted cell growth, consistent with MEGF10 acting as a clinically relevant, epigenetically deregulated neuroblastoma tumor suppressor gene. © 2016 The Authors. Molecular Carcinogenesis Published by Wiley Periodicals, Inc. PMID:27862318

Chemoresistance, Cancer Stem Cells, and miRNA Influences: The Case for Neuroblastoma

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Alfred Buhagiar

2015-01-01

Full Text Available Neuroblastoma is a type of cancer that develops most often in infants and children under the age of five years. Neuroblastoma originates within the peripheral sympathetic ganglia, with 30% of the cases developing within the adrenal medulla, although it can also occur within other regions of the body such as nerve tissue in the spinal cord, neck, chest, abdomen, and pelvis. MicroRNAs (miRNAs regulate cellular pathways, differentiation, apoptosis, and stem cell maintenance. Such miRNAs regulate genes involved in cellular processes. Consequently, they are implicated in the regulation of a spectrum of signaling pathways within the cell. In essence, the role of miRNAs in the development of cancer is of utmost importance for the understanding of dysfunctional cellular pathways that lead to the conversion of normal cells into cancer cells. This review focuses on highlighting the recent, important implications of miRNAs within the context of neuroblastoma basic research efforts, particularly concerning miRNA influences on cancer stem cell pathology and chemoresistance pathology for this condition, together with development of translational medicine approaches for novel diagnostic tools and therapies for this neuroblastoma.

Expression of Five Neuroblastoma Genes in Bone Marrow or Blood of Patients with Relapsed/Refractory Neuroblastoma Provides a New Biomarker for Disease and Prognosis.

Science.gov (United States)

Marachelian, Araz; Villablanca, Judith G; Liu, Cathy W; Liu, Betty; Goodarzian, Fariba; Lai, Hollie A; Shimada, Hiroyuki; Tran, Hung C; Parra, Jaime A; Gallego, Richard; Bedrossian, Nora; Young, Sabrina; Czarnecki, Scarlett; Kennedy, Rebekah; Weiss, Brian D; Goldsmith, Kelly; Granger, Meaghan; Matthay, Katherine K; Groshen, Susan; Asgharzadeh, Shahab; Sposto, Richard; Seeger, Robert C

2017-09-15

Purpose: We determined whether quantifying neuroblastoma-associated mRNAs (NB-mRNAs) in bone marrow and blood improves assessment of disease and prediction of disease progression in patients with relapsed/refractory neuroblastoma. Experimental Design: mRNA for CHGA, DCX, DDC, PHOX2B, and TH was quantified in bone marrow and blood from 101 patients concurrently with clinical disease evaluations. Correlation between NB-mRNA (delta cycle threshold, Δ C t , for the geometric mean of genes from the TaqMan Low Density Array NB5 assay) and morphologically defined tumor cell percentage in bone marrow, 123 I-meta-iodobenzylguanidine (MIBG) Curie score, and CT/MRI-defined tumor longest diameter was determined. Time-dependent covariate Cox regression was used to analyze the relationship between Δ C t and progression-free survival (PFS). Results: NB-mRNA was detectable in 83% of bone marrow (185/223) and 63% (89/142) of blood specimens, and their Δ C t values were correlated (Spearman r = 0.67, P neuroblastoma. Clin Cancer Res; 23(18); 5374-83. ©2017 AACR . ©2017 American Association for Cancer Research.

N Güngör

Indian Academy of Sciences (India)

Home; Journals; Bulletin of Materials Science. N Güngör. Articles written in Bulletin of Materials Science. Volume 27 Issue 3 June 2004 pp 317-322 Surfactants. Effect of sodium dodecyl sulfate on flow and electrokinetic properties of Na-activated bentonite dispersions · E Günıster S İşçı A Alemdar N Güngör · More Details ...

Refractory Post-Herpetic Neuralgia As An Initial Presentation Of Olfactory Neuroblastoma-Related Ectopic ACTH Syndrome

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Hsiang-Hung Lin

2009-03-01

Full Text Available We report a woman aged 64 years with ectopic adrenocorticotropic hormone (ACTH syndrome caused by olfactory neuroblastoma as an initial presentation of refractory post-herpetic neuralgia. The manifestations such as cushingoid appearance and endocrine abnormalities are compatible with Cushing's syndrome. Brain computed tomography revealed a sellar mass. A biopsy revealed olfactory neuroblastoma. Immunohistochemical staining further defined the tumor as an ACTH-secreting neuroblastoma. Subsequent opportunistic infections by Candida glabrata fungemia and multiple drug-resistant Acinetobacter baumannii pneumonia occurred during hospitalization as a complication of severe hypercortisolism. Before any therapy for Cushing's syndrome and neuroblastoma could be initiated, the patient died from sepsis and multiorgan failure. We propose that Cushing's syndrome is more complex than what clinicians thought, and that meticulous cerebral imaging studies are crucial.

Functional dissection of HOXD cluster genes in regulation of neuroblastoma cell proliferation and differentiation.

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Yunhong Zha

Full Text Available Retinoic acid (RA can induce growth arrest and neuronal differentiation of neuroblastoma cells and has been used in clinic for treatment of neuroblastoma. It has been reported that RA induces the expression of several HOXD genes in human neuroblastoma cell lines, but their roles in RA action are largely unknown. The HOXD cluster contains nine genes (HOXD1, HOXD3, HOXD4, and HOXD8-13 that are positioned sequentially from 3' to 5', with HOXD1 at the 3' end and HOXD13 the 5' end. Here we show that all HOXD genes are induced by RA in the human neuroblastoma BE(2-C cells, with the genes located at the 3' end being activated generally earlier than those positioned more 5' within the cluster. Individual induction of HOXD8, HOXD9, HOXD10 or HOXD12 is sufficient to induce both growth arrest and neuronal differentiation, which is associated with downregulation of cell cycle-promoting genes and upregulation of neuronal differentiation genes. However, induction of other HOXD genes either has no effect (HOXD1 or has partial effects (HOXD3, HOXD4, HOXD11 and HOXD13 on BE(2-C cell proliferation or differentiation. We further show that knockdown of HOXD8 expression, but not that of HOXD9 expression, significantly inhibits the differentiation-inducing activity of RA. HOXD8 directly activates the transcription of HOXC9, a key effector of RA action in neuroblastoma cells. These findings highlight the distinct functions of HOXD genes in RA induction of neuroblastoma cell differentiation.

Olfactory neuroblastoma

International Nuclear Information System (INIS)

Rashid, D.; Ahmed, B.; Malik, S.M.; Khan, M.

2000-01-01

Olfactory neuroblastoma/esthesioneuroblastoma in a rare malignant tumour of the olfactory neuroepithelium. This is a report of 5 cases managed over the last 10 years at Combined Military Hospital, Rawalpindi. Age of the patients at presentation ranged from 27 to 70 years. The main symptoms were unilateral nasal obstruction and intermittent epistaxis. The mean duration of symptoms at presentation was 11 months. Two patients were staged as B and 3 as C at presentation. The stage of the disease correlated with the duration of symptoms. All the cases were diagnosed on histopathology. Three were offered combination of surgery and radiotherapy. One patient received only surgical treatment and one patient received radiotherapy and chemotherapy. Combination of surgery and radiotherapy showed best results. (author)

Symmetry breaking in human neuroblastoma cells

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Izumi, Hideki; Kaneko, Yasuhiko

2014-01-01

Asymmetric cell division (ACD) is a characteristic of cancer stem cells, which exhibit high malignant potential. However, the cellular mechanisms that regulate symmetric (self-renewal) and asymmetric cell divisions are mostly unknown. Using human neuroblastoma cells, we found that the oncosuppressor protein tripartite motif containing 32 (TRIM32) positively regulates ACD. PMID:27308367

Neuroblastoma in early childhood: A rare case report and review of literature

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Ritesh R Kalaskar

2016-01-01

Full Text Available Neuroblastoma is an extremely rare pediatric neoplasm whose prognosis becomes poor and poor as the age advances. It can be sporadic or nonfamilial in origin. It is primarily a tumor of abdominal origin from where it metastasis to lymph nodes, liver, intracranial and orbital sites, and central nervous system. There is no standard dental treatment protocol for the management of neuroblastoma due to its poor survival rate and rarity. However, dental treatment may follow the protocol of preventive and restorative. Surgicals should be performed under supervision as it may trigger metastasis. We report a rare case of neuroblastoma in a 3-year-old child presenting classical oral manifestations such as bilateral palatal swelling, rolled border ulcer on the posterior part of hard palate adjacent to primary molars, and bilateral proptosis.

Natural and molecular history of prolactinoma: insights from a Prlr-/- mouse model.

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Bernard, Valérie; Villa, Chiara; Auguste, Aurélie; Lamothe, Sophie; Guillou, Anne; Martin, Agnès; Caburet, Sandrine; Young, Jacques; Veitia, Reiner A; Binart, Nadine

2018-01-19

Lactotroph adenoma, also called prolactinoma, is the most common pituitary tumor but little is known about its pathogenesis. Mouse models of prolactinoma can be useful to better understand molecular mechanisms involved in abnormal lactotroph cell proliferation and secretion. We have previously developed a prolactin receptor deficient ( Prlr -/- ) mouse, which develops prolactinoma. The present study aims to explore the natural history of prolactinoma formation in Prlr -/- mice, using hormonal, radiological, histological and molecular analyses to uncover mechanisms involved in lactotroph adenoma development. Prlr -/- females develop large secreting prolactinomas from 12 months of age, with a penetrance of 100%, mimicking human aggressive densely granulated macroprolactinoma, which is a highly secreting subtype. Mean blood PRL measurements reach 14 902 ng/mL at 24 months in Prlr -/- females while PRL levels were below 15 ng/mL in control mice ( p model in ACI rats, we pinpointed 218 concordantly differentially expressed (DE) genes involved in cell cycle, mitosis, cell adhesion molecules, dopaminergic synapse and estrogen signaling. Pathway/gene-set enrichment analyses suggest that the transcriptomic dysregulation in both models of prolactinoma might be mediated by a limited set of transcription factors (i.e., STAT5, STAT3, AhR, ESR1, BRD4, CEBPD, YAP, FOXO1) and kinases (i.e., JAK2, AKT1, BRAF, BMPR1A, CDK8, HUNK, ALK, FGFR1, ILK). Our experimental results and their bioinformatic analysis provide insights into early genomic changes in murine models of the most frequent human pituitary tumor.

Effect of potassium channel modulators in mouse forced swimming test

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Galeotti, Nicoletta; Ghelardini, Carla; Caldari, Bernardetta; Bartolini, Alessandro

1999-01-01

The effect of intracerebroventricular (i.c.v.) administration of different potassium channel blockers (tetraethylammonium, apamin, charybdotoxin, gliquidone), potassium channel openers (pinacidil, minoxidil, cromakalim) and aODN to mKv1.1 on immobility time was evaluated in the mouse forced swimming test, an animal model of depression. Tetraethylammonium (TEA; 5 μg per mouse i.c.v.), apamin (3 ng per mouse i.c.v.), charybdotoxin (1 μg per mouse i.c.v.) and gliquidone (6 μg per mouse i.c.v.) administered 20 min before the test produced anti-immobility comparable to that induced by the tricyclic antidepressants amitriptyline (15 mg kg−1 s.c.) and imipramine (30 mg kg−1 s.c.). By contrast pinacidil (10–20 μg per mouse i.c.v.), minoxidil (10–20 μg per mouse i.c.v.) and cromakalim (20–30 μg per mouse i.c.v.) increased immobility time when administered in the same experimental conditions. Repeated administration of an antisense oligonucleotide (aODN) to the mKv1.1 gene (1 and 3 nmol per single i.c.v. injection) produced a dose-dependent increase in immobility time of mice 72 h after the last injection. At day 7, the increasing effect produced by aODN disappeared. A degenerate mKv1.1 oligonucleotide (dODN), used as control, did not produce any effect in comparison with saline- and vector-treated mice. At the highest effective dose, potassium channels modulators and the mKv1.1 aODN did not impair motor coordination, as revealed by the rota rod test, nor did they modify spontaneous motility as revealed by the Animex apparatus. These results suggest that modulation of potassium channels plays an important role in the regulation of immobility time in the mouse forced swimming test. PMID:10323599

Selection of optimal therapy for neuroblastoma: a study of the immunomodulatory effects of surgery and irradiation in the murine C1300 neuroblastoma model

International Nuclear Information System (INIS)

Topalian, S.L.; Ziegler, M.M.

1987-01-01

Human neuroblastoma is an immunogenic tumor for which therapy directed in an immunologic context may offer some advantage over conventional treatment. This study examines the immunomodulatory effects of surgery and irradiation in the murine C1300 neuroblastoma model. In vivo studies of primary tumor growth characteristics after treatment demonstrated no superiority of either therapeutic modality in control of local tumor or prolongation of host survival. However, irradiated hosts showed an increased ability to reject a secondary tumor challenge, compared to their surgical counterparts. That this phenomenon may be immune-related is suggested by in vitro studies of T lymphocyte function utilizing mixed lymphocyte-tumor cell cultures and PHA lymphoblastogenesis

Comparative study between 131I-MIBG scintigraphy and other tumor markers in diagnosis of neuroblastoma

International Nuclear Information System (INIS)

Ohsawa, Yoshihiro; Iwafuchi, Makoto; Odano, Ikuo; Yamagiwa, Iwao.

1989-01-01

In order to prove the clinical usefulness in diagnosis of neuroblastoma, comparative studies between iodine-131 metaiodobenzylguanidine ( 131 I-MIBG) scintigraphy and other related tumor markers were attempted. Sixteen children diagnosed as having a neuroblastoma in recent 2 years were examined. In 5 postoperative patients in complete remission, who were negative to other tumor markers, showed no pathological accumulation of 131 I-MIBG (specificity 100%). In other 11 patients with remains of neuroblastoma, 131 I-MIBG was negative only in 2 patients (sensitivity 82%) and these 2 patients showed negative urinary excretion of catecholamine metabolites (VMA). (Negative urinary VMA was proved in 3 of 11 patients). Serum neuron-specific enolase (NSE) was elevated in all 8 preoperative patients, but only in 2 of 11 postoperative patients. On the other hand 131 I-MIBG was positive in 9 among these 11 postoperative patients in whom neuroblastoma remained. Similar relationship was obtained between 131 I-MIBG scintigraphy and serum LDH. On the basis of our present experience, we like to regard 131 I-MIBG scintigraphy as one of the most sensitive parameters for neuroblastoma during a follow-up period after treatment. (author)

Clinical experience with radiation enhancement by hyperbaric oxygen in children with recurrent neuroblastoma stage IV

International Nuclear Information System (INIS)

Voute, P.A.; Kleij, A.J. van der; De Kraker, J.; Hoefnagel, C.A.; Tiel-van Buul, M.M.C.; Gennip, H. van

1995-01-01

The high risk group of patients with neuroblastoma are children over 1 year with stage IV disease. Most series report a maximum of 20% survival at 5 years. For recurrent neuroblastoma stage IV, cure rates are not reported in the literature, but they are nil. Any treatment for recurrent neuroblastoma stage IV remains a therapeutic dilemma. The outcome of radiation therapy is variable. A very important factor in tumour treatment remains tumour hypoxia, and others, such as metabolic factors, also play a role. Combined application of radiation modifiers may influence the final survival rate. In an attempt to improve the survival of recurrent neuroblastoma stage IV, hyperbaric oxygen and radioionated meta-Iodobenzylguanidine (MIBG) was used in a clinical setting. Although survival may not be used as a determinant of the usefulness of a treatment for stage IV neuroblastoma disease, a better one is not available. In this study, at 28 months, a cumulative probability of survival of 32% was recorded for patients treated with [ 131 I]MIBG and hyperbaric oxygen compared to 12% for [ 131 I]MIBG treatment alone. These preliminary results are promising but further studies are needed to reveal substantial therapeutic gain. (Author)

The influence of fluorides on mouse sperm capacitation

Czech Academy of Sciences Publication Activity Database

Dvořáková-Hortová, K.; Šandera, M.; Jursová, M.; Vašínová, J.; Pěknicová, Jana

2008-01-01

Roč. 108, 1-2 (2008), s. 157-170 ISSN 0378-4320 R&D Projects: GA MŠk(CZ) 1M06011 Institutional research plan: CEZ:AV0Z50520701 Keywords : Mouse spermatozoa * Capacitation * Fluorides Subject RIV: DN - Health Impact of the Environment Quality Impact factor: 1.890, year: 2008

The influence of fluorides on mouse sperm capacitation

Czech Academy of Sciences Publication Activity Database

Dvořáková-Hortová, K.; Šandera, M.; Jursová, M.; Vašinová, J.; Pěknicová, Jana

2008-01-01

Roč. 108, 1-2 (2008), s. 157-170 ISSN 0378-4320 R&D Projects: GA MŠk 1M06011 Institutional research plan: CEZ:AV0Z50520514; CEZ:AV0Z50520701 Keywords : mouse spermatozoa * capacitation * fluorides Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 1.890, year: 2008

Neutron flux stabilization in the NG-150 neutron generators

International Nuclear Information System (INIS)

Kuz'min, L.E.; Makarov, S.A.; Pronman, I.M.

1986-01-01

Problem of metal tritium target lifetime increase and neutron flux stabilization in the NG-150 neutron generators is studied. Possibility on neutron flux stabilization using the mass analyzer for low-angle (4 deg and 41 deg) mass separation of a beam in thre components, which fall on a target simultaneously, is confirmed experimentally. Basic generator parameters are: accelerating voltage of 150 kV, total beam current on a target of 1.5 mA, beam current density of 0.3-1.6 mA/cm 2 , beam diameter of 8 mm. The initial neutron flux on the targets of 0.73 mg/cm 2 thick constituted 1.1x10 11 ssup(-1). The neutron flux monitoring was accomplished from recoil proton recording by a plastic scintillator. Flux decrease by more than 5% served as a signel for measuring mass analyzer magnetic field providing beam displacement on a target and restoration of the given flux. The NG-150 generator neutron flux stabilization was attained during 2h

Neuroblastoma: treatment outcome after incomplete resection of primary tumors.

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Moon, Suk-Bae; Park, Kwi-Won; Jung, Sung-Eun; Youn, Woong-Jae

2009-09-01

For International Neuroblastoma Staging System (INSS) stages III or IV neuroblastoma (intermediate or high risk), complete excision of the primary tumor is not always feasible. Most current studies on the treatment outcome of these patients have reported on the complete excision status. The aim of this study is to review the treatment outcome after the incomplete resection. The medical records of 37 patients that underwent incomplete resection between January 1986 and December 2005 were reviewed retrospectively. Incomplete resection was assessed by review of the operative notes and postoperative computerized tomography. Age, gender, tumor location, INSS stage, N-myc gene copy number, pre- and postoperative therapy, and treatment outcome were reviewed. The treatment outcome was evaluated according to the postoperative treatment protocol in the high-risk group. Intermediate-risk patients were treated with conventional chemotherapy, isotretinoin (ITT) and interleukin-2 (IL-2). High-risk patients were treated with peripheral blood stem cell transplantation (PBSCT), ITT, and IL-2 (N = 11). Before the introduction of PBSCT, the high-risk patients were also treated with the conventional chemotherapy (N = 19). Intermediate-risk patients (N = 5) currently have no evidence of disease (NED). For the high-risk patients (N = 32), 19 patients were treated with chemotherapy alone; 15 patients died of their disease while four patients currently have an NED status. Eight of 11 patients that underwent PBSCT are currently alive. For intermediate risk, conventional chemotherapy appears to be acceptable treatment. However, for high-risk patients, every effort should be made to control residual disease including the use of myeloablative chemotherapy, differentiating agents and immune-modulating agents.

Treatment of localised resectable neuroblastoma. Results of the LNESG1 study by the SIOP Europe Neuroblastoma Group

NARCIS (Netherlands)

de Bernardi, B.; Mosseri, V.; Rubie, H.; Castel, V.; Foot, A.; Ladenstein, R.; Laureys, G.; Beck-Popovic, M.; de Lacerda, A. F.; Pearson, A. D. J.; de Kraker, J.; Ambros, P. F.; de Rycke, Y.; Conte, M.; Bruzzi, P.; Michon, J.

2008-01-01

Main objective of this study was to confirm that surgery alone is an effective and safe treatment for localised resectable neuroblastoma except stage 2 with amplified MYCN gene (MYCNA). Of 427 eligible stages 1-2 patients, 411 had normal MYCN and 16 had MYCNA. Of the 288 stage 1 patients with normal

Is complete resection of high-risk stage IV neuroblastoma associated with better survival?

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Yeung, Fanny; Chung, Patrick Ho Yu; Tam, Paul Kwong Hang; Wong, Kenneth Kak Yuen

2015-12-01

The role of surgery in the management of stage IV neuroblastoma is controversial. In this study, we attempted to study if complete tumor resection had any impact on event-free survival (EFS) and overall survival (OS). A retrospective analysis of patients with stage IV neuroblastoma between November 2000 and July 2014 in a tertiary referral center was performed. Demographics data, extent of surgical resection, and outcomes were analyzed. A total of 34 patients with stage IV neuroblastoma according to International Neuroblastoma Staging System (INSS) were identified. The median age at diagnosis and operation was 3.5 (±1.9) years and 3.8 (±2.0) years, respectively. Complete gross tumor resection (CTR) was achieved in twenty-four patients (70.1%), in which one of the patients had nephrectomy and another had distal pancreatectomy. Gross total resection (GTR) with removal of >95% of tumor was performed in six patients (17.6%) and subtotal tumor resection (STR) with removal of >50%, but <95% of tumor was performed in four patients (11.8%). There was no statistical significance in terms of 5-year EFS and OS among the 3 groups. There was no surgery-related mortality or morbidity. From our center's experience, as there was no substantial survival benefit in stage IV neuroblastoma patients undergoing complete tumor resection, organ preservation and minimalization of morbidity should also be taken into consideration. Copyright © 2015. Published by Elsevier Inc.

Identification of Protein Targets of 12/15-Lipoxygenase-Derived Lipid Electrophiles in Mouse Peritoneal Macrophages Using Omega-Alkynyl Fatty Acid.

Science.gov (United States)

Isobe, Yosuke; Kawashima, Yusuke; Ishihara, Tomoaki; Watanabe, Kenji; Ohara, Osamu; Arita, Makoto

2018-04-20

The 12/15-lipoxygenase (12/15-LOX) enzyme introduces peroxyl groups, in a position-specific manner, into polyunsaturated fatty acids to form various kinds of bioactive lipid metabolites, including lipid-derived electrophiles (LDE). The resident peritoneal macrophage is the site of highest 12/15-LOX expression in the mouse. However, the role of the enzyme in the regulation of resident macrophages is not fully understood. Here, we describe a chemoproteomic method to identify the targets of enzymatically generated LDE. By treating mouse peritoneal macrophages with omega-alkynyl arachidonic acid (aAA), we identified a series of proteins adducted by LDE generated through a 12/15-LOX catalyzed reaction. Pathway analysis revealed a dramatic enrichment of proteins involved in energy metabolism and found that glycolytic flux and mitochondrial respiration were significantly affected by the expression of 12/15-LOX. Our findings thus highlight the utility of chemoproteomics using aAA for identifying intracellular targets of enzymatically generated LDE.

Codon 201Gly Polymorphic Type of the DCC Gene is Related to Disseminated Neuroblastoma

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Xiao-Tang Kong

2001-01-01

Full Text Available The deleted in colorectal carcinoma (DCC gene is a potential tumor- suppressor gene on chromosome 18821.3. The relatively high frequency of loss of heterozygosity (LOH and loss of expression of this gene in neuroblastoma, especially in the advanced stages, imply the possibility of involvement of the DCC gene in progression of neuroblastoma. However, only few typical mutations have been identified in this gene, indicating that other possible mechanisms for the inactivation of this gene may exist. A polymorphic change (Arg to Gly at DCC codon 201 is related to advanced colorectal carcinoma and increases in the tumors with absent DCC protein expression. In order to understand whether this change is associated with the development or progression of neuroblastoma, we investigated codon 201 polymorphism of the DCC gene in 102 primary neuroblastomas by polymerase chain reaction single-strand conformation polymorphism. We found no missense or nonsense mutations, but a polymorphic change from CGA (Arg to GGA (Gly at codon 201 resulting in three types of polymorphism: codon 201Gly type, codon 201Arg/Gly type, and codon 201Arg type. The codon 201Gly type occurred more frequently in disseminated (stages IV and IVs neuroblastomas (72% than in localized (stages I, II, and III tumors (48% (P=.035, and normal controls (38% (P=.024. In addition, the codon 201Gly type was significantly more common in tumors found clinically (65% than in those found by mass screening (35% (P=.002. The results suggested that the codon 201Gly type of the DCC gene might be associated with a higher risk of disseminating neuroblastoma.

Targeting neuroblastoma stem cells with retinoic acid and proteasome inhibitor.

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Barbara Hämmerle

Full Text Available Neuroblastma cell lines contain a side-population of cells which express stemness markers. These stem-like cells may represent the potential underlying mechanism for resistance to conventional therapy and recurrence of neuroblastoma in patients.To develop novel strategies for targeting the side-population of neurobastomas, we analyzed the effects of 13-cis-retinoic acid (RA combined with the proteasome inhibitor MG132. The short-term action of the treatment was compared with effects after a 5-day recovery period during which both chemicals were withdrawn. RA induced growth arrest and differentiation of SH-SY5Y and SK-N-BE(2 neuroblastoma cell lines. Inhibition of the proteasome caused apoptosis in both cell lines, thus, revealing the critical role of this pathway in the regulated degradation of proteins involved in neuroblastoma proliferation and survival. The combination of RA with MG132 induced apoptosis in a dose-dependent manner, in addition to promoting G2/M arrest in treated cultures. Interestingly, expression of stem cell markers such as Nestin, Sox2, and Oct4 were reduced after the recovery period of combined treatment as compared with untreated cells or treated cells with either compound alone. Consistent with this, neurosphere formation was significantly impaired by the combined treatment of RA and MG132.Given that stem-like cells are associated with resistant to conventional therapy and are thought to be responsible for relapse, our results suggest that dual therapy of RA and proteasome inhibitor might be beneficial for targeting the side-population of cells associated residual disease in high-risk neuroblastoma.

Expression of Truncated Neurokinin-1 Receptor in Childhood Neuroblastoma is Independent of Tumor Biology and Stage.

Science.gov (United States)

Pohl, Alexandra; Kappler, Roland; Mühling, Jakob; VON Schweinitz, Dietrich; Berger, Michael

2017-11-01

Neuroblastoma is an embryonal malignancy arising from the aberrant growth of neural crest progenitor cells of the sympathetic nervous system. The tachykinin receptor 1 (TACR1) - substance P complex is associated with tumoral angiogenesis and cell proliferation in a variety of cancer types. Inhibition of TACR1 was recently described to impede growth of NB cell lines. However, the relevance of TACR1 in clinical settings is unknown. We investigated gene expression levels of full-length and truncated TACR1 in 59 neuroblastomas and correlated these data with the patients' clinical parameters such as outcome, metastasis, International Neuroblastoma Staging System (INSS) status, MYCN proto-oncogene, bHLH transcription factor (MYCN) status, gender and age. Our results indicated that TACR1 is ubiquitously expressed in neuroblastoma but expression levels are independent of clinical parameters. Our data suggest that TACR1 might serve as a potent anticancer target in a large variety of patients with neuroblastoma, independent of tumor biology and clinical stage. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

DNA-Dependent Protein Kinase As Molecular Target for Radiosensitization of Neuroblastoma Cells.

Science.gov (United States)

Dolman, M Emmy M; van der Ploeg, Ida; Koster, Jan; Bate-Eya, Laurel Tabe; Versteeg, Rogier; Caron, Huib N; Molenaar, Jan J

2015-01-01

Tumor cells might resist therapy with ionizing radiation (IR) by non-homologous end-joining (NHEJ) of IR-induced double-strand breaks. One of the key players in NHEJ is DNA-dependent protein kinase (DNA-PK). The catalytic subunit of DNA-PK, i.e. DNA-PKcs, can be inhibited with the small-molecule inhibitor NU7026. In the current study, the in vitro potential of NU7026 to radiosensitize neuroblastoma cells was investigated. DNA-PKcs is encoded by the PRKDC (protein kinase, DNA-activated, catalytic polypeptide) gene. We showed that PRKDC levels were enhanced in neuroblastoma patients and correlated with a more advanced tumor stage and poor prognosis, making DNA-PKcs an interesting target for radiosensitization of neuroblastoma tumors. Optimal dose finding for combination treatment with NU7026 and IR was performed using NGP cells. One hour pre-treatment with 10 μM NU7026 synergistically sensitized NGP cells to 0.63 Gy IR. Radiosensitizing effects of NU7026 increased in time, with maximum effects observed from 96 h after IR-exposure on. Combined treatment of NGP cells with 10 μM NU7026 and 0.63 Gy IR resulted in apoptosis, while no apoptotic response was observed for either of the therapies alone. Inhibition of IR-induced DNA-PK activation by NU7026 confirmed the capability of NGP cells to, at least partially, resist IR by NHEJ. NU7026 also synergistically radiosensitized other neuroblastoma cell lines, while no synergistic effect was observed for low DNA-PKcs-expressing non-cancerous fibroblasts. Results obtained for NU7026 were confirmed by PRKDC knockdown in NGP cells. Taken together, the current study shows that DNA-PKcs is a promising target for neuroblastoma radiosensitization.

Neuroblastoma cell lines contain pluripotent tumor initiating cells that are susceptible to a targeted oncolytic virus.

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Yonatan Y Mahller

Full Text Available Although disease remission can frequently be achieved for patients with neuroblastoma, relapse is common. The cancer stem cell theory suggests that rare tumorigenic cells, resistant to conventional therapy, are responsible for relapse. If true for neuroblastoma, improved cure rates may only be achieved via identification and therapeutic targeting of the neuroblastoma tumor initiating cell. Based on cues from normal stem cells, evidence for tumor populating progenitor cells has been found in a variety of cancers.Four of eight human neuroblastoma cell lines formed tumorspheres in neural stem cell media, and all contained some cells that expressed neurogenic stem cell markers including CD133, ABCG2, and nestin. Three lines tested could be induced into multi-lineage differentiation. LA-N-5 spheres were further studied and showed a verapamil-sensitive side population, relative resistance to doxorubicin, and CD133+ cells showed increased sphere formation and tumorigenicity. Oncolytic viruses, engineered to be clinically safe by genetic mutation, are emerging as next generation anticancer therapeutics. Because oncolytic viruses circumvent typical drug-resistance mechanisms, they may represent an effective therapy for chemotherapy-resistant tumor initiating cells. A Nestin-targeted oncolytic herpes simplex virus efficiently replicated within and killed neuroblastoma tumor initiating cells preventing their ability to form tumors in athymic nude mice.These results suggest that human neuroblastoma contains tumor initiating cells that may be effectively targeted by an oncolytic virus.

Role of trace metals in cell proliferation in the human neuroblastoma: relations with the oncogene N-myc

International Nuclear Information System (INIS)

Moretto, Ph.; Michelet, C.; Gouget, B.; Ortega, R.; Sergiant, C.; Llabador, Y.; Simonoff, M.; Benard, J.

1997-01-01

Neuroblastoma is one of the most common tumors in young children. Iron is known to be necessary for cellular proliferation. Several studies have suggested that neuroblastoma cells appear to be relatively sensitive to growth inhibition by specific Fe chelators, in vitro. In addition, it appeared that an increased serum ferritin level at diagnosis was associated with a poorer outcome than a normal level. On the other hand it was reported that untreated primary neuroblastoma had multiple copies of the N-myc oncogene. A significant association between genomic amplification and rapid tumor progression after diagnosis has been demonstrated. In order to study the relationship between iron N-myc amplification, we propose to determine the trace metal content of neuroblastoma cells. Preliminary results obtained with two distinct cell lines: SK-N-SH, a neuroblastoma cell line with a single copy of N-myc and IGR-N-91, a metastatic cell line exhibiting 60 copies of N-myc are presented. (authors)

Lapatinib potentiates cytotoxicity of  YM155 in neuroblastoma via inhibition of the ABCB1 efflux transporter.

Science.gov (United States)

Radic-Sarikas, Branka; Halasz, Melinda; Huber, Kilian V M; Winter, Georg E; Tsafou, Kalliopi P; Papamarkou, Theodore; Brunak, Søren; Kolch, Walter; Superti-Furga, Giulio

2017-06-08

Adverse side effects of cancer agents are of great concern in the context of childhood tumors where they can reduce the quality of life in young patients and cause life-long adverse effects. Synergistic drug combinations can lessen potential toxic side effects through lower dosing and simultaneously help to overcome drug resistance. Neuroblastoma is the most common cancer in infancy and extremely heterogeneous in clinical presentation and features. Applying a systematic pairwise drug combination screen we observed a highly potent synergy in neuroblastoma cells between the EGFR kinase inhibitor lapatinib and the anticancer compound YM155 that is preserved across several neuroblastoma variants. Mechanistically, the synergy was based on a lapatinib induced inhibition of the multidrug-resistance efflux transporter ABCB1, which is frequently expressed in resistant neuroblastoma cells, which allowed prolonged and elevated cytotoxicity of YM155. In addition, the drug combination (i.e. lapatinib plus YM155) decreased neuroblastoma tumor size in an in vivo model.

HIF2A and IGF2 Expression Correlates in Human Neuroblastoma Cells and Normal Immature Sympathetic Neuroblasts

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Sofie Mohlin

2013-03-01

Full Text Available During normal sympathetic nervous system (SNS development, cells of the ganglionic lineage can malignantly transform and develop into the childhood tumor neuroblastoma. Hypoxia-inducible transcription factors (HIFs mediate cellular responses during normal development and are central in the adaptation to oxygen shortage. HIFs are also implicated in the progression of several cancer forms, and high HIF-2α expression correlates with disseminated disease and poor outcome in neuroblastoma. During normal SNS development, HIF2A is transiently expressed in neuroblasts and chromaffin cells. SNS cells can, during development, be distinguished by distinct gene expression patterns, and insulin-like growth factor 2 (IGF2 is a marker of sympathetic chromaffin cells, whereas sympathetic neuroblasts lack IGF2 expression. Despite the neuronal derivation of neuroblastomas, we show that neuroblastoma cell lines and specimens express IGF2 and that expression of HIF2A and IGF2 correlates, with the strongest correlation in high-stage tumors. In neuroblastoma, both IGF2 and HIF2A are hypoxia-driven and knocking down IGF2 at hypoxia resulted in downregulated HIF2A levels. HIF-2α and IGF2 were strongly expressed in subsets of immature neuroblastoma cells, suggesting that these two genes could be co-expressed also at early stages of SNS development. We show that IGF2 is indeed expressed in sympathetic chain ganglia at embryonic week 6.5, a developmental stage when HIF-2α is present. These findings provide a rationale for the unexpected IGF2 expression in neuroblastomas and might suggest that IGF2 and HIF2A positive neuroblastoma cells are arrested at an embryonic differentiation stage corresponding to the stage when sympathetic chain ganglia begins to coalesce.

Accelerating drug development for neuroblastoma - New Drug Development Strategy: an Innovative Therapies for Children with Cancer, European Network for Cancer Research in Children and Adolescents and International Society of Paediatric Oncology Europe Neuroblastoma project.

Science.gov (United States)

Moreno, Lucas; Caron, Hubert; Geoerger, Birgit; Eggert, Angelika; Schleiermacher, Gudrun; Brock, Penelope; Valteau-Couanet, Dominique; Chesler, Louis; Schulte, Johannes H; De Preter, Katleen; Molenaar, Jan; Schramm, Alexander; Eilers, Martin; Van Maerken, Tom; Johnsen, John Inge; Garrett, Michelle; George, Sally L; Tweddle, Deborah A; Kogner, Per; Berthold, Frank; Koster, Jan; Barone, Giuseppe; Tucker, Elizabeth R; Marshall, Lynley; Herold, Ralf; Sterba, Jaroslav; Norga, Koen; Vassal, Gilles; Pearson, Andrew Dj

2017-08-01

Neuroblastoma, the commonest paediatric extra-cranial tumour, remains a leading cause of death from cancer in children. There is an urgent need to develop new drugs to improve cure rates and reduce long-term toxicity and to incorporate molecularly targeted therapies into treatment. Many potential drugs are becoming available, but have to be prioritised for clinical trials due to the relatively small numbers of patients. Areas covered: The current drug development model has been slow, associated with significant attrition, and few new drugs have been developed for neuroblastoma. The Neuroblastoma New Drug Development Strategy (NDDS) has: 1) established a group with expertise in drug development; 2) prioritised targets and drugs according to tumour biology (target expression, dependency, pre-clinical data; potential combinations; biomarkers), identifying as priority targets ALK, MEK, CDK4/6, MDM2, MYCN (druggable by BET bromodomain, aurora kinase, mTORC1/2) BIRC5 and checkpoint kinase 1; 3) promoted clinical trials with target-prioritised drugs. Drugs showing activity can be rapidly transitioned via parallel randomised trials into front-line studies. Expert opinion: The Neuroblastoma NDDS is based on the premise that optimal drug development is reliant on knowledge of tumour biology and prioritisation. This approach will accelerate neuroblastoma drug development and other poor prognosis childhood malignancies.

Meta-analysis of Neuroblastomas Reveals a Skewed ALK Mutation Spectrum in Tumors with MYCN Amplification

NARCIS (Netherlands)

de Brouwer, Sara; de Preter, Katleen; Kumps, Candy; Zabrocki, Piotr; Porcu, Michaël; Westerhout, Ellen M.; Lakeman, Arjan; Vandesompele, Jo; Hoebeeck, Jasmien; van Maerken, Tom; de Paepe, Anne; Laureys, Geneviève; Schulte, Johannes H.; Schramm, Alexander; van den Broecke, Caroline; Vermeulen, Joëlle; van Roy, Nadine; Beiske, Klaus; Renard, Marleen; Noguera, Rosa; Delattre, Olivier; Janoueix-Lerosey, Isabelle; Kogner, Per; Martinsson, Tommy; Nakagawara, Akira; Ohira, Miki; Caron, Huib N.; Eggert, Angelika; Cools, Jan; Versteeg, Rogier; Speleman, Frank

2010-01-01

Purpose: Activating mutations of the anaplastic lymphoma kinase (ALK) were recently described in neuroblastoma. We carried out a meta-analysis of 709 neuroblastoma tumors to determine their frequency and mutation spectrum in relation to genomic and clinical parameters, and studied the prognostic

Rapid COJEC Induction Therapy for High-risk Neuroblastoma Patients - Cochrane Review.

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Peinemann, F; van Dalen, E C; Berthold, F

2016-04-01

Neuroblastoma is a rare malignant disease and patients with high-risk neuroblastoma have a poor prognosis. Rapid COJEC induction chemotherapy means (almost) the same total doses given within a shorter time period. In theory, rapid COJEC could reduce the risk of drug resistance and it has been considered as a potential candidate for improving the outcome. The objective was to evaluate effects of rapid COJEC compared to standard induction chemotherapy in patients with high-risk neuroblastoma. We searched the databases CENTRAL, MEDLINE, and EMBASE from inception to 11 November 2014 and included randomized controlled trials. We identified one relevant randomized controlled trial with 130 participants receiving rapid COJEC and 132 participants receiving standard OPEC/COJEC induction chemotherapy. There was no statistically significant difference between the treatment groups in complete response (risk ratio 0.99, 95% confidence interval 0.71 to 1.38, P=0.94) and treatment-related mortality (risk ratio 1.21, 95% confidence interval 0.33 to 4.39, P=0.77). A statistically significant difference in favor of the standard treatment arm was identified for the following early toxicities: febrile neutropenia, septicemia, and renal toxicity. The differences in complete response and treatment-related mortality between treatment alternatives were not statistically significantly different. Based on the currently available evidence, we are uncertain about the effects of rapid COJEC induction chemotherapy in patients with high-risk neuroblastoma. © Georg Thieme Verlag KG Stuttgart · New York.

Suberoylanilide hydroxamic acid sensitizes neuroblastoma to paclitaxel by inhibiting thioredoxin-related protein 14-mediated autophagy.

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Zhen, Zijun; Yang, Kaibin; Ye, Litong; You, Zhiyao; Chen, Rirong; Liu, Ying; He, Youjian

2017-07-01

Paclitaxel is not as effective for neuroblastoma as most of the front-line chemotherapeutics due to drug resistance. This study explored the regulatory mechanism of paclitaxel-associated autophagy and potential solutions to paclitaxel resistance in neuroblastoma. The formation of autophagic vesicles was detected by scanning transmission electron microscopy and flow cytometry. The autophagy-associated proteins were assessed by western blot. Autophagy was induced and the autophagy-associated proteins LC3-I, LC3-II, Beclin 1, and thioredoxin-related protein 14 (TRP14), were found to be upregulated in neuroblastoma cells that were exposed to paclitaxel. The inhibition of Beclin 1 or TRP14 by siRNA increased the sensitivity of the tumor cells to paclitaxel. In addition, Beclin 1-mediated autophagy was regulated by TRP14. Furthermore, the TRP14 inhibitor suberoylanilide hydroxamic acid (SAHA) downregulated paclitaxel-induced autophagy and enhanced the anticancer effects of paclitaxel in normal control cancer cells but not in cells with upregulated Beclin 1 and TRP14 expression. Our findings showed that paclitaxel-induced autophagy in neuroblastoma cells was regulated by TRP14 and that SAHA could sensitize neuroblastoma cells to paclitaxel by specifically inhibiting TRP14. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Sox2-Mediated Conversion of NG2 Glia into Induced Neurons in the Injured Adult Cerebral Cortex

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Christophe Heinrich

2014-12-01

Full Text Available The adult cerebral cortex lacks the capacity to replace degenerated neurons following traumatic injury. Conversion of nonneuronal cells into induced neurons has been proposed as an innovative strategy toward brain repair. Here, we show that retrovirus-mediated expression of the transcription factors Sox2 and Ascl1, but strikingly also Sox2 alone, can induce the conversion of genetically fate-mapped NG2 glia into induced doublecortin (DCX+ neurons in the adult mouse cerebral cortex following stab wound injury in vivo. In contrast, lentiviral expression of Sox2 in the unlesioned cortex failed to convert oligodendroglial and astroglial cells into DCX+ cells. Neurons induced following injury mature morphologically and some acquire NeuN while losing DCX. Patch-clamp recording of slices containing Sox2- and/or Ascl1-transduced cells revealed that a substantial fraction of these cells receive synaptic inputs from neurons neighboring the injury site. Thus, NG2 glia represent a potential target for reprogramming strategies toward cortical repair.

S(+)-ibuprofen destabilizes MYC/MYCN and AKT, increases p53 expression, and induces unfolded protein response and favorable phenotype in neuroblastoma cell lines.

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Ikegaki, Naohiko; Hicks, Sakeenah L; Regan, Paul L; Jacobs, Joshua; Jumbo, Amina S; Leonhardt, Payton; Rappaport, Eric F; Tang, Xao X

2014-01-01

Neuroblastoma is a common pediatric solid tumor that exhibits a striking clinical bipolarity: favorable and unfavorable. The survival rate of children with unfavorable neuroblastoma remains low among all childhood cancers. MYCN and MYC play a crucial role in determining the malignancy of unfavorable neuroblastomas, whereas high-level expression of the favorable neuroblastoma genes is associated with a good disease outcome and confers growth suppression of neuroblastoma cells. A small fraction of neuroblastomas harbors TP53 mutations at diagnosis, but a higher proportion of the relapse cases acquire TP53 mutations. In this study, we investigated the effect of S(+)-ibuprofen on neuroblastoma cell lines, focusing on the expression of the MYCN, MYC, AKT, p53 proteins and the favorable neuroblastoma genes in vitro as biomarkers of malignancy. Treatment of neuroblastoma cell lines with S(+)-ibuprofen resulted in a significant growth suppression. This growth effect was accompanied by a marked decrease in the expression of MYC, MYCN, AKT and an increase in p53 expression in neuroblastoma cell lines without TP53 mutation. In addition, S(+)-ibuprofen enhanced the expression of some favorable neuroblastoma genes (EPHB6, CD44) and genes involved in growth suppression and differentiation (EGR1, EPHA2, NRG1 and SEL1L). Gene expression profile and Ingenuity pathway analyses using TP53-mutated SKNAS cells further revealed that S(+)-ibuprofen suppressed molecular pathways associated with cell growth and conversely enhanced those of cell cycle arrest and the unfolded protein response. Collectively, these results suggest that S(+)-ibuprofen or its related compounds may have the potential for therapeutic and/or palliative use for unfavorable neuroblastoma.

Imaging defined risk factors in neuroblastoma -guidelines for optimising imaging interpretations

International Nuclear Information System (INIS)

Valchev, G.; Balev, B.

2017-01-01

Neuroblastoma is the most frequent extracranial tumor in children, arising from the primitive sympathetic cells and the adrenal medulla. Two separate mutually complementing staging systems exist - INSS and INRGSS - one is based on post-operative findings, the other - on pre-treatment imaging. INRGSS consists of a list of 20 separate imaging defined risk factors (IDRF), the presence of which could alter the treatment plan. Radiologists need to be aware of certain intricacies in interpreting the individual IDRFs in order to optimise clinical decision-making. Key words: neuroblastoma. imaging defined risk factors (IDRF). interpretation guidelines [bg

Protein kinase Cepsilon is important for migration of neuroblastoma cells

International Nuclear Information System (INIS)

Stensman, Helena; Larsson, Christer

2008-01-01

Migration is important for the metastatic capacity and thus for the malignancy of cancer cells. There is limited knowledge on regulatory factors that promote the migration of neuroblastoma cells. This study investigates the hypothesis that protein kinase C (PKC) isoforms regulate neuroblastoma cell motility. PKC isoforms were downregulated with siRNA or modulated with activators and inhibitors. Migration was analyzed with scratch and transwell assays. Protein phosphorylation and expression levels were measured with Western blot. Stimulation with 12-O-tetradecanoylphorbol-13-acetate (TPA) induced migration of SK-N-BE(2)C neuroblastoma cells. Treatment with the general protein kinase C (PKC) inhibitor GF109203X and the inhibitor of classical isoforms Gö6976 inhibited migration while an inhibitor of PKCβ isoforms did not have an effect. Downregulation of PKCε, but not of PKCα or PKCδ, with siRNA led to a suppression of both basal and TPA-stimulated migration. Experiments using PD98059 and LY294002, inhibitors of the Erk and phosphatidylinositol 3-kinase (PI3K) pathways, respectively, showed that PI3K is not necessary for TPA-induced migration. The Erk pathway might be involved in TPA-induced migration but not in migration driven by PKCε. TPA induced phosphorylation of the PKC substrate myristoylated alanine-rich C kinase substrate (MARCKS) which was suppressed by the PKC inhibitors. Treatment with siRNA oligonucleotides against different PKC isoforms before stimulation with TPA did not influence the phosphorylation of MARCKS. PKCε is important for migration of SK-N-BE(2)C neuroblastoma cells. Neither the Erk pathway nor MARCKS are critical downstream targets of PKCε but they may be involved in TPA-mediated migration

DNA-Dependent Protein Kinase As Molecular Target for Radiosensitization of Neuroblastoma Cells.

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M Emmy M Dolman

Full Text Available Tumor cells might resist therapy with ionizing radiation (IR by non-homologous end-joining (NHEJ of IR-induced double-strand breaks. One of the key players in NHEJ is DNA-dependent protein kinase (DNA-PK. The catalytic subunit of DNA-PK, i.e. DNA-PKcs, can be inhibited with the small-molecule inhibitor NU7026. In the current study, the in vitro potential of NU7026 to radiosensitize neuroblastoma cells was investigated. DNA-PKcs is encoded by the PRKDC (protein kinase, DNA-activated, catalytic polypeptide gene. We showed that PRKDC levels were enhanced in neuroblastoma patients and correlated with a more advanced tumor stage and poor prognosis, making DNA-PKcs an interesting target for radiosensitization of neuroblastoma tumors. Optimal dose finding for combination treatment with NU7026 and IR was performed using NGP cells. One hour pre-treatment with 10 μM NU7026 synergistically sensitized NGP cells to 0.63 Gy IR. Radiosensitizing effects of NU7026 increased in time, with maximum effects observed from 96 h after IR-exposure on. Combined treatment of NGP cells with 10 μM NU7026 and 0.63 Gy IR resulted in apoptosis, while no apoptotic response was observed for either of the therapies alone. Inhibition of IR-induced DNA-PK activation by NU7026 confirmed the capability of NGP cells to, at least partially, resist IR by NHEJ. NU7026 also synergistically radiosensitized other neuroblastoma cell lines, while no synergistic effect was observed for low DNA-PKcs-expressing non-cancerous fibroblasts. Results obtained for NU7026 were confirmed by PRKDC knockdown in NGP cells. Taken together, the current study shows that DNA-PKcs is a promising target for neuroblastoma radiosensitization.

Clinical significance of pretreatment FDG PET/CT IN MOBG-avid pediatric neuroblastoma

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Kang, Seo Young; Kim, Yong Il; Cheon, Gi Jeong; Kang, Keon Wook; Chung, June Key; Lee, Dong Soo; Kang, Hyoung Jin; Shin, Hee Young [Seoul National University Hospital, Seoul (Korea, Republic of); Kim, E. Edmund [Seoul National University, Seoul (Korea, Republic of); Rahim, Muhammad Kashif [Nishtar Medical College and Hospital, Multan (Pakistan)

2017-06-15

{sup 18}F-fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging is well known to have clinical significance in the initial staging and response evaluation of the many kinds of neoplasms. However, its role in the pediatric neuroblastoma is not clearly defined. In the present study, the clinical significance of FDG-PET/computed tomography (CT) in 123I- or 131I-metaiodobenzylguanidine (MIBG)-avid pediatric neuroblastoma was investigated. Twenty patients with neuroblastoma who undertook pretreatment FDG PET/CT at our institute between 2008 and 2015 and showed MIBG avidity were retrospectively enrolled in the present study. Clinical information—including histopathology, and serum markers—and several PET parameters—including SUVmax of the primary lesion (Psuv), target-to-background ratio (TBR), metabolic tumor volume (MTV), and coefficient of variation (CV)—were analyzed. The prognostic effect of PET parameters was evaluated in terms of progression-free survival (PFS). Total 20 patients (4.5 ± 3.5 years) were divided as two groups by disease progression. Six patients (30.0 %) experienced disease progression and one patient (5.0 %) died during follow-up period. There were not statistically significant in age, stage, MYCN status, primary tumor size, serum lactate dehydrogenase (LDH), neuron-specific enolase (NSE), and ferritin level between two groups with progression or no progression. However, Psuv (p = 0.017), TBR (p = 0.09), MTV (p = 0.02), and CV (p = 0.036) showed significant differences between two groups. In univariate analysis, PFS was significantly associated with Psuv (p = 0.021) and TBR (p = 0.023). FDG-PET parameters were significantly related with progression of neuroblastoma. FDG-PET/CT may have the potential as a valuable modality for evaluating prognosis in the patients with MIBG-avid pediatric neuroblastoma.

L-DOPA therapy interferes with urine catecholamine analysis in children with suspected neuroblastoma: a case series.

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Kelly, Alison U; Srivastava, Rajeev; Dow, Ellie; Davidson, D Fraser

2017-09-01

Neuroblastoma is the most common solid extracranial malignancy diagnosed in childhood. Clinical presentation is variable, and metastatic disease is common at diagnosis. Analyses of urinary catecholamines and their metabolites are commonly requested as a first-line investigation when clinical suspicion exists. Levodopa (L-Dopa) therapy is utilized as a treatment for a number of disorders in childhood, including Dopa-responsive dystonia. Neuroblastoma may mimic some of the clinical features of this disorder. L-Dopa can interfere with analysis of urinary catecholamines and their metabolites and complicate the interpretation of results. We present the cases of three children who were prescribed L-dopa at the time of analysis of urinary catecholamines and metabolites as a screen for neuroblastoma, but who did not have the disease. Comparison of their results with those from cases with true neuroblastoma reveal that it is impossible to reliably distinguish true neuroblastoma from L-Dopa therapy using these tests. We recommend that patients should be off L-dopa therapy, if possible when these tests are performed. These cases illustrate the importance of providing clinical details and drug history to the laboratory in order to avoid diagnostic confusion.

Intrarenal neuroblastoma - a diagnostic dilemma: A report of three cases

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Anupam Lall

2001-01-01

Full Text Available Differentiation between the Wilms′ tumor (WT and the intrarenal neuroblastoma (IRNB is imperative, as the prognosis and the treatment are different for these condi-tions. It may pose a diagnostic challenge to distinguish them pre-operatively. Over the period of last 10 years (1990-1999, 3 children aged 2 months to 4 years were diagnosed to have IRNB. 2 cases were operated with a provisional diagnosis of WT, but on histology were found to have neuroblastoma. Taking benefit from our previous experience, the third case we encountered with a renal lump and bony metastasis with clinical features not con-sistent with the diagnosis of Wilms′ tumor was further investigated. Urinary catecholamines were significantly elevated and there was bone marrow involvement and positive bone scan for multiple bony metastasis. 2 pa-tients are on chemotherapy and follow-up for last 6 months, while 1 died 6 years back after a follow-up of 2 years. Patients who have a renal mass on imaging, with clinical features of rapid deterioration in general condi-tion and evidence of bony secondaries, should undergo work-up for neuroblastoma pre-operatively to confirm the diagnosis.

[The reaction of the neuroblastoma cells in the culture on the influence of tretionine and neurotoxine].

Science.gov (United States)

Magakian, Iu A; Karalian, Z A; Karalova, E M; Abroian, L O; Akopian, L A; Avetisian, A C; Semerdzhian, Z B

2011-01-01

Effect of the tretionine (retinoid) and aluminum chloride (neurotoxin) on the growth and differentiation of neuroblastoma cells in culture after their introduction into the medium separately and in combination was studied. The introduction of these substances creates a new information field in the medium, which becomes apparent by the reactions of neuroblastoma found on the populational and cellular levels of its organization. The presence of tretionine stimulates proliferation and induces differentiation of the cells into astrocytes. Aluminum chloride inhibits cell proliferation and enhances the process of their destruction in the monolayer. The variety of the reactions of neuroblastoma cells to the presence of these substances in the medium indicates the existence and functioning of a mechanism that selects from the information introduced only the portion which may contribute to adaptation of neuroblastoma cells to the changed culture conditions.

Planar cell polarity gene expression correlates with tumor cell viability and prognostic outcome in neuroblastoma

International Nuclear Information System (INIS)

Dyberg, Cecilia; Papachristou, Panagiotis; Haug, Bjørn Helge; Lagercrantz, Hugo; Kogner, Per; Ringstedt, Thomas; Wickström, Malin; Johnsen, John Inge

2016-01-01

The non-canonical Wnt/Planar cell polarity (PCP) signaling pathway is a major player in cell migration during embryonal development and has recently been implicated in tumorigenesis. Transfections with cDNA plasmids or siRNA were used to increase and suppress Prickle1 and Vangl2 expression in neuroblastoma cells and in non-tumorigenic cells. Cell viability was measured by trypan blue exclusion and protein expression was determined with western blotting. Transcriptional activity was studied with luciferase reporter assay and mRNA expression with real-time RT-PCR. Immunofluorescence stainings were used to study the effects of Vangl2 overexpression in non-tumorigenic embryonic cells. Statistical significance was tested with t-test or one-way ANOVA. Here we show that high expression of the PCP core genes Prickle1 and Vangl2 is associated with low-risk neuroblastoma, suppression of neuroblastoma cell growth and decreased Wnt/β-catenin signaling. Inhibition of Rho-associated kinases (ROCKs) that are important in mediating non-canonical Wnt signaling resulted in increased expression of Prickle1 and inhibition of β-catenin activity in neuroblastoma cells. In contrast, overexpression of Vangl2 in MYC immortalized neural stem cells induced accumulation of active β-catenin and decreased the neural differentiation marker Tuj1. Similarly, genetically modified mice with forced overexpression of Vangl2 in nestin-positive cells showed decreased Tuj1 differentiation marker during embryonal development. Our experimental data demonstrate that high expression of Prickle1 and Vangl2 reduce the growth of neuroblastoma cells and indicate different roles of PCP proteins in tumorigenic cells compared to normal cells. These results suggest that the activity of the non-canonical Wnt/PCP signaling pathway is important for neuroblastoma development and that manipulation of the Wnt/PCP pathway provides a possible therapy for neuroblastoma. The online version of this article (doi:10.1186/s

Tumorigenic and Antiproliferative Properties of the TALE-Transcription Factors MEIS2D and MEIS2A in Neuroblastoma.

Science.gov (United States)

Groß, Anja; Schulz, Catrine; Kolb, Jasmine; Koster, Jan; Wehner, Sibylle; Czaplinski, Sebastian; Khilan, Abdulghani; Rohrer, Hermann; Harter, Patrick N; Klingebiel, Thomas; Langer, Julian D; Geerts, Dirk; Schulte, Dorothea

2018-04-15

Neuroblastoma is one of only a few human cancers that can spontaneously regress even after extensive dissemination, a poorly understood phenomenon that occurs in as many as 10% of patients. In this study, we identify the TALE-homeodomain transcription factor MEIS2 as a key contributor to this phenomenon. We identified MEIS2 as a MYCN-independent factor in neuroblastoma and showed that in this setting the alternatively spliced isoforms MEIS2A and MEIS2D exert antagonistic functions. Specifically, expression of MEIS2A was low in aggressive stage 4 neuroblastoma but high in spontaneously regressing stage 4S neuroblastoma. Moderate elevation of MEIS2A expression reduced proliferation of MYCN -amplified human neuroblastoma cells, induced neuronal differentiation and impaired the ability of these cells to form tumors in mice. In contrast, MEIS2A silencing or MEIS2D upregulation enhanced the aggressiveness of the tumor phenotype. Mechanistically, MEIS2A uncoupled a negative feedback loop that restricts accumulation of cellular retinoic acid, an effective agent in neuroblastoma treatment. Overall, our results illuminate the basis for spontaneous regression in neuroblastoma and identify an MEIS2A-specific signaling network as a potential therapeutic target in this common pediatric malignancy. Significance: This study illuminates the basis for spontaneous regressions that can occur in a common pediatric tumor, with implications for the development of new treatment strategies. Cancer Res; 78(8); 1935-47. ©2018 AACR . ©2018 American Association for Cancer Research.

Crystal structures of human 108V and 108M catechol O-methyltransferase

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Rutherford, K.; Le Trong, I.; Stenkamp, R.E.; Parson, W.W. (UWASH)

2008-08-01

Catechol O-methyltransferase (COMT) plays important roles in the metabolism of catecholamine neurotransmitters and catechol estrogens. The development of COMT inhibitors for use in the treatment of Parkinson's disease has been aided by crystallographic structures of the rat enzyme. However, the human and rat proteins have significantly different substrate specificities. Additionally, human COMT contains a common valine-methionine polymorphism at position 108. The methionine protein is less stable than the valine polymorph, resulting in decreased enzyme activity and protein levels in vivo. Here we describe the crystal structures of the 108V and 108M variants of the soluble form of human COMT bound with S-adenosylmethionine (SAM) and a substrate analog, 3,5-dinitrocatechol. The polymorphic residue 108 is located in the {alpha}5-{beta}3 loop, buried in a hydrophobic pocket {approx}16 {angstrom} from the SAM-binding site. The 108V and 108M structures are very similar overall [RMSD of C{sup {alpha}} atoms between two structures (C{sup {alpha}} RMSD) = 0.2 {angstrom}], and the active-site residues are superposable, in accord with the observation that SAM stabilizes 108M COMT. However, the methionine side chain is packed more tightly within the polymorphic site and, consequently, interacts more closely with residues A22 ({alpha}2) and R78 ({alpha}4) than does valine. These interactions of the larger methionine result in a 0.7-{angstrom} displacement in the backbone structure near residue 108, which propagates along {alpha}1 and {alpha}5 toward the SAM-binding site. Although the overall secondary structures of the human and rat proteins are very similar (C{sup {alpha}} RMSD = 0.4 {angstrom}), several nonconserved residues are present in the SAM-(I89M, I91M, C95Y) and catechol- (C173V, R201M, E202K) binding sites. The human protein also contains three additional solvent-exposed cysteine residues (C95, C173, C188) that may contribute to intermolecular disulfide bond

Constitutional 11q14-q22 chromosome deletion syndrome in a child with neuroblastoma MYCN single copy.

Science.gov (United States)

Passariello, Annalisa; De Brasi, Daniele; Defferrari, Raffaella; Genesio, Rita; Tufano, Maria; Mazzocco, Katia; Capasso, Maria; Migliorati, Roberta; Martinsson, Tommy; Siani, Paolo; Nitsch, Lucio; Tonini, Gian Paolo

2013-11-01

Constitutional 11q deletion is a chromosome imbalance possibly found in MCA/MR patients analyzed for chromosomal anomalies. Its role in determining the phenotype depends on extension and position of deleted region. Loss of heterozygosity of 11q (region 11q23) is also associated with neuroblastoma, the most frequent extra cranial cancer in children. It represents one of the most frequent cytogenetic abnormalities observed in the tumor of patients with high-risk disease even if germline deletion of 11q in neuroblastoma is rare. Hereby, we describe a 18 months old girl presenting with trigonocephaly and dysmorphic facial features, including hypotelorism, broad depressed nasal bridge, micrognathia, synophrys, epicanthal folds, and with a stage 4 neuroblastoma without MYCN amplification, carrying a germline 11q deletion (11q14.1-q22.3), outside from Jacobsen syndrome and from neuroblastoma 11q critical regions. The role of 11q deletion in determining the clinical phenotype and its association with neuroblastoma development in the patient are discussed. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

The pre-rRNA processing factor DEF is rate limiting for the pathogenesis of MYCN-driven neuroblastoma.

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Tao, T; Sondalle, S B; Shi, H; Zhu, S; Perez-Atayde, A R; Peng, J; Baserga, S J; Look, A T

2017-07-06

The nucleolar factor, digestive organ expansion factor (DEF), has a key role in ribosome biogenesis, functioning in pre-ribosomal RNA (pre-rRNA) processing as a component of the small ribosomal subunit (SSU) processome. Here we show that the peripheral sympathetic nervous system (PSNS) is very underdeveloped in def-deficient zebrafish, and that def haploinsufficiency significantly decreases disease penetrance and tumor growth rate in a MYCN-driven transgenic zebrafish model of neuroblastoma that arises in the PSNS. Consistent with these findings, DEF is highly expressed in human neuroblastoma, and its depletion in human neuroblastoma cell lines induces apoptosis. Interestingly, overexpression of MYCN in zebrafish and in human neuroblastoma cells results in the appearance of intermediate pre-rRNAs species that reflect the processing of pre-rRNAs through Pathway 2, a pathway that processes pre-rRNAs in a different temporal order than the more often used Pathway 1. Our results indicate that DEF and possibly other components of the SSU processome provide a novel site of vulnerability in neuroblastoma cells that could be exploited for targeted therapy.

Neuritogenic and neuroprotective effects of polar steroids from the Far East starfishes Patiria pectinifera and Distolasterias nipon.

Science.gov (United States)

Palyanova, Natalia V; Pankova, Tatyana M; Starostina, Marina V; Kicha, Alla A; Ivanchina, Natalia V; Stonik, Valentin A

2013-05-03

The neuritogenic and neuroprotective activities of six starfish polar steroids, asterosaponin Р₁, (25S)-5α-cholestane-3β,4β,6α,7α,8,15α,16β,26-octaol, and (25S)-5α-cholestane-3β,6α,7α,8,15α,16β,26-heptaol (1-3) from the starfish Patiria pectinifera and distolasterosides D₁-D₃ (4-6) from the starfish Distolasterias nipon were analyzed using the mouse neuroblastoma (NB) C-1300 cell line and an organotypic rat hippocampal slice culture (OHSC). All of these compounds enhanced neurite outgrowth in NB cells. Dose-dependent responses to compounds 1-3 were observed within the concentration range of 10-100 nM, and dose-dependent responses to glycosides 4-6 were observed at concentrations of 1-50 nM. All the tested substances exhibited notable synergistic effects with trace amounts of nerve growth factor (NGF, 1 ng/mL) or brain-derived neurotrophic factor (BDNF, 0.1 ng/mL). Using NB cells and OHSCs, it was shown for the first time that starfish steroids 1-6 act as neuroprotectors against oxygen-glucose deprivation (OGD) by increasing the number of surviving cells. Altogether, these results suggest that neurotrophin-like neuritogenic and neuroprotective activities are most likely common properties of starfish polyhydroxysteroids and the related glycosides, although the magnitude of the effect depended on the particular compound structure.

Parallel Changes in Intracellular Water Volume and pH Induced by NH3/NH4+ Exposure in Single Neuroblastoma Cells

Directory of Open Access Journals (Sweden)

Víctor M. Blanco

2013-12-01

Full Text Available Background: Increased blood levels of ammonia (NH3 and ammonium (NH4+, i.e. hyperammonemia, leads to cellular brain edema in humans with acute liver failure. The pathophysiology of this edema is poorly understood. This is partly due to incomplete understanding of the osmotic effects of the pair NH3/NH4+ at the cellular and molecular levels. Cell exposure to solutions containing NH3/NH4+ elicits changes in intracellular pH (pHi, which can in turn affect cell water volume (CWV by activating transport mechanisms that produce net gain or loss of solutes and water. The occurrence of CWV changes caused by NH3/NH4+ has long been suspected, but the mechanisms, magnitude and kinetics of these changes remain unknown. Methods: Using fluorescence imaging microscopy we measured, in real time, parallel changes in pHi and CWV caused by brief exposure to NH3/NH4+ of single cells (N1E-115 neuroblastoma or NG-108 neuroblastoma X glioma loaded with the fluorescent indicator BCECF. Changes in CWV were measured by exciting BCECF at its intracellular isosbestic wavelength (∼438 nm, and pHi was measured ratiometrically. Results: Brief exposure to isosmotic solutions (i.e. having the same osmolality as that of control solutions containing NH4Cl (0.5- 30 mM resulted in a rapid, dose-dependent swelling, followed by isosmotic regulatory volume decrease (iRVD. NH4Cl solutions in which either extracellular [NH3] or [NH4+] was kept constant while the other was changed by varying the pH of the solution, demonstrated that [NH3]o rather than [NH4+]o is the main determinant of the NH4Cl-induced swelling. The iRVD response was sensitive to the anion channel blocker NPPB, and partly dependent on external Ca2+. Upon removal of NH4Cl, cells shrank and displayed isosmotic regulatory volume increase (iRVI. Regulatory volume responses could not be activated by comparable CWV changes produced by anisosmotic solutions, suggesting that membrane stretch or contraction by themselves are

Comparison of I-131 MIBG scintigrapy and F-18 FDG PET in neuroblastoma

Energy Technology Data Exchange (ETDEWEB)

Pai, M.; Lee, S.; Yoo, E [Seoul National University College of Medicine, Seoul (Korea, Republic of)

2004-07-01

The purpose of this preliminary study was to compare the utility of metaiodobenzylguanidine(MIBG) scintigraphy and F-18 FDG PET for the detection of primary and metastatic lesions of neuroblatoma. F-18 FDG PET and I-131 MIBG scan or SPECT were performed with in 1 month of each other in 4 patients (age: 4-5, all female) with known neuroblastoma after primary treatment. In 3 of 4 patients with confirmed neuroblastoma, FDG PET and MIBG scans were concordant for the presence or absence of diseased sites. In two cases, residual abdominal masses less than 1cm in which the X -ray computed tomography showed no change in tumor volume had a simultaneous negative uptake in both MIBG scan and FDG PET. In a patient with histologic evidence of bone marrow involvement, there was no skeletal uptake of both MIBG and FDG but Tc-99m HDP bone scan revealed disseminated bone marrow involvement, while a large mediastinal primary mass of this patient showed intense MIBG and FDG uptake. In one patient whose large abdominal mass of neuroblastoma failed to accumulate FDG, MIBG uptake in the tumor was intense. We concluded that FDG PET could reveal metabolic state of primary or residual neuroblastoma as much as MIBG in majority of our cases but it did not show any advantages over MIBG or even bone scan. FDG PET had an obvious defect in detection of residual viable disease in one patient. FDG PET may not replace MIBG or bone scan for evaluation of primary or metastatic disease of neuroblastoma in the diagnostic and staging procedure from INSS recommendation.

Comparison of I-131 MIBG scintigrapy and F-18 FDG PET in neuroblastoma

International Nuclear Information System (INIS)

Pai, M.; Lee, S.; Yoo, E

2004-01-01

The purpose of this preliminary study was to compare the utility of metaiodobenzylguanidine(MIBG) scintigraphy and F-18 FDG PET for the detection of primary and metastatic lesions of neuroblatoma. F-18 FDG PET and I-131 MIBG scan or SPECT were performed with in 1 month of each other in 4 patients (age: 4-5, all female) with known neuroblastoma after primary treatment. In 3 of 4 patients with confirmed neuroblastoma, FDG PET and MIBG scans were concordant for the presence or absence of diseased sites. In two cases, residual abdominal masses less than 1cm in which the X -ray computed tomography showed no change in tumor volume had a simultaneous negative uptake in both MIBG scan and FDG PET. In a patient with histologic evidence of bone marrow involvement, there was no skeletal uptake of both MIBG and FDG but Tc-99m HDP bone scan revealed disseminated bone marrow involvement, while a large mediastinal primary mass of this patient showed intense MIBG and FDG uptake. In one patient whose large abdominal mass of neuroblastoma failed to accumulate FDG, MIBG uptake in the tumor was intense. We concluded that FDG PET could reveal metabolic state of primary or residual neuroblastoma as much as MIBG in majority of our cases but it did not show any advantages over MIBG or even bone scan. FDG PET had an obvious defect in detection of residual viable disease in one patient. FDG PET may not replace MIBG or bone scan for evaluation of primary or metastatic disease of neuroblastoma in the diagnostic and staging procedure from INSS recommendation

Tobacco, alcohol and illicit drugs during pregnancy and risk of neuroblastoma: systematic review.

Science.gov (United States)

Müller-Schulte, Eloise; Kurlemann, Gerhard; Harder, Anja

2017-11-21

To determine whether prenatal and perinatal maternal consumption of alcohol, tobacco and/or illicit drugs is associated with risk of neuroblastoma. Medline and Embase (both from inception to February 2017), and reference lists of included studies. To be eligible, a study had to be an original report including data on intake of alcohol, tobacco smoking and/or consumption of illicit drugs during pregnancy and risk of neuroblastoma in the child. From eligible studies, data study characteristics as well as effect measures and confounders were extracted. We assessed unadjusted and confounder-adjusted estimates, performed risk of bias analysis, constructed random-effects models and assessed heterogeneity. We identified 14 case-control studies (1987-2016) involving a total of 3114 children with neuroblastoma. Meta-analysis of unadjusted estimates showed an association between alcohol (OR 1.26; 95% CI 1.07 to 1.49), tobacco (OR 1.22; 95% CI 1.04 to 1.44) and illicit drug consumption during pregnancy and risk of neuroblastoma during childhood, with illicit drug consumption showing the strongest association (OR 3.26; 95% CI 1.36 to 7.86). However, adjusted estimates were highly heterogeneous. All studies were at high risk of bias. Smoking, alcohol or illicit drugs during pregnancy might play a role in the development of neuroblastoma. However, well-designed studies are needed to assess whether these exposures are causal and whether time period during pregnancy, dose or co-consumption of substances is critical. Registration number CRD42016036165. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

A biology-driven approach identifies the hypoxia gene signature as a predictor of the outcome of neuroblastoma patients

Directory of Open Access Journals (Sweden)

Fardin Paolo

2010-07-01

Full Text Available Abstract Background Hypoxia is a condition of low oxygen tension occurring in the tumor microenvironment and it is related to poor prognosis in human cancer. To examine the relationship between hypoxia and neuroblastoma, we generated and tested an in vitro derived hypoxia gene signature for its ability to predict patients' outcome. Results We obtained the gene expression profile of 11 hypoxic neuroblastoma cell lines and we derived a robust 62 probesets signature (NB-hypo taking advantage of the strong discriminating power of the l1-l2 feature selection technique combined with the analysis of differential gene expression. We profiled gene expression of the tumors of 88 neuroblastoma patients and divided them according to the NB-hypo expression values by K-means clustering. The NB-hypo successfully stratifies the neuroblastoma patients into good and poor prognosis groups. Multivariate Cox analysis revealed that the NB-hypo is a significant independent predictor after controlling for commonly used risk factors including the amplification of MYCN oncogene. NB-hypo increases the resolution of the MYCN stratification by dividing patients with MYCN not amplified tumors in good and poor outcome suggesting that hypoxia is associated with the aggressiveness of neuroblastoma tumor independently from MYCN amplification. Conclusions Our results demonstrate that the NB-hypo is a novel and independent prognostic factor for neuroblastoma and support the view that hypoxia is negatively correlated with tumors' outcome. We show the power of the biology-driven approach in defining hypoxia as a critical molecular program in neuroblastoma and the potential for improvement in the current criteria for risk stratification.

18F-DOPA PET/CT for assessment of response to induction chemotherapy in a child with high-risk neuroblastoma

International Nuclear Information System (INIS)

Piccardo, Arnoldo; Lopci, Egesta; Foppiani, Luca; Morana, Giovanni; Conte, Massimo

2014-01-01

Functional imaging plays a crucial role in the assessment of neuroblastoma. The evaluation of response to induction chemotherapy is a cornerstone in scheduling proper treatment management in patients affected by high-risk neuroblastoma. 123 I-metaiodobenzylguanidine has been recognized as the radiopharmaceutical of choice in neuroblastoma assessment. To date, the clinical role of PET/CT in pediatric malignancy is not well established. 18 F-DOPA-PET/CT has been recently used in neuroblastoma, and compared with 123 I-MIBG-scan. Scant new data are available about the role of this tool in the evaluation of treatment response after induction chemotherapy. We investigate the role of 18 F-DOPA-PET/CT in characterizing the response to induction chemotherapy in a child affected by high-risk-neuroblastoma, in whom the rare association of 123 I-MIBG-negative primary tumor and MIBG-positive bone marrow metastases was observed. (orig.)

Hydrogen-rich Water Exerting a Protective Effect on Ovarian Reserve Function in a Mouse Model of Immune Premature Ovarian Failure Induced by Zona Pellucida 3

Science.gov (United States)

He, Xin; Wang, Shu-Yu; Yin, Cheng-Hong; Wang, Tong; Jia, Chan-Wei; Ma, Yan-Min

2016-01-01

Background: Premature ovarian failure (POF) is a disease that affects female fertility but has few effective treatments. Ovarian reserve function plays an important role in female fertility. Recent studies have reported that hydrogen can protect male fertility. Therefore, we explored the potential protective effect of hydrogen-rich water on ovarian reserve function through a mouse immune POF model. Methods: To set up immune POF model, fifty female BALB/c mice were randomly divided into four groups: Control (mice consumed normal water, n = 10), hydrogen (mice consumed hydrogen-rich water, n = 10), model (mice were immunized with zona pellucida glycoprotein 3 [ZP3] and consumed normal water, n = 15), and model-hydrogen (mice were immunized with ZP3 and consumed hydrogen-rich water, n = 15) groups. After 5 weeks, mice were sacrificed. Serum anti-Müllerian hormone (AMH) levels, granulosa cell (GC) apoptotic index (AI), B-cell leukemia/lymphoma 2 (Bcl-2), and BCL2-associated X protein (Bax) expression were examined. Analyses were performed using SPSS 17.0 (SPSS Inc., Chicago, IL, USA) software. Results: Immune POF model, model group exhibited markedly reduced serum AMH levels compared with those of the control group (5.41 ± 0.91 ng/ml vs. 16.23 ± 1.97 ng/ml, P = 0.033) and the hydrogen group (19.65 ± 7.82 ng/ml, P = 0.006). The model-hydrogen group displayed significantly higher AMH concentrations compared with that of the model group (15.03 ± 2.75 ng/ml vs. 5.41 ± 0.91 ng/ml, P = 0.021). The GC AI was significantly higher in the model group (21.30 ± 1.74%) than those in the control (7.06 ± 0.27%), hydrogen (5.17 ± 0.41%), and model-hydrogen groups (11.24 ± 0.58%) (all P hydrogen group compared with that of the hydrogen group (11.24 ± 0.58% vs. 5.17 ± 0.41%, P = 0.021). Compared with those of the model group, ovarian tissue Bcl-2 levels increased (2.18 ± 0.30 vs. 3.01 ± 0.33, P = 0.045) and the Bax/Bcl-2 ratio decreased in the model-hydrogen group

Allelic loss of chromosome 1p as a predictor of unfavorable outcome in patients with neuroblastoma

NARCIS (Netherlands)

H.N. Caron (Huib); P. van Sluis (Peter); J. de Kraker (Jan); J.P. Bökkerink (Jos); R.M. Egeler (Maarten); G. Laureys (Geneviève); R. Slater (Rosalyn); A. Westerveld (Andries); M.T. Voûte (Michiel); R. Versteeg (Rogier)

1996-01-01

textabstractBackground. Neuroblastoma is a childhood tumor derived from cells of the neural crest, with a widely variable outcome. Differences in the behavior and prognosis of the tumor suggest that neuroblastoma can be divided into several biologic subgroups. We evaluated the most frequent genetic

Allelic loss of chromosome 1p as a predictor of unfavorable outcome in patients with neuroblastoma

NARCIS (Netherlands)

Caron, H.; van Sluis, P.; de Kraker, J.; Bökkerink, J.; Egeler, M.; Laureys, G.; Slater, R.; Westerveld, A.; Voûte, P. A.; Versteeg, R.

1996-01-01

Neuroblastoma is a childhood tumor derived from cells of the neural crest, with a widely variable outcome. Differences in the behavior and prognosis of the tumor suggest that neuroblastoma can be divided into several biologic subgroups. We evaluated the most frequent genetic abnormalities in

49 CFR 24.108 - Donations.

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2010-10-01

... 49 Transportation 1 2010-10-01 2010-10-01 false Donations. 24.108 Section 24.108 Transportation Office of the Secretary of Transportation UNIFORM RELOCATION ASSISTANCE AND REAL PROPERTY ACQUISITION FOR FEDERAL AND FEDERALLY-ASSISTED PROGRAMS Real Property Acquisition § 24.108 Donations. An owner whose real...

46 CFR 108.235 - Construction.

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2010-10-01

... 46 Shipping 4 2010-10-01 2010-10-01 false Construction. 108.235 Section 108.235 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) A-MOBILE OFFSHORE DRILLING UNITS DESIGN AND EQUIPMENT Construction and Arrangement Helicopter Facilities § 108.235 Construction. (a) Each helicopter deck must be...

Search for first 0 excited states in /sup 108/Cd and /sup 106/Cd

CERN Document Server

Roussière, B; Duffait, R; Genevey-Rivier, J; Kilcher, P; Meyer, M; Sauvage-Letessier, J; Tréherne, J

1981-01-01

The /sup 108/Cd and /sup 106/Cd isotopes have been studied from the beta /sup +//EC decay of /sup 108/In and /sup 106/In. gamma -rays, conversion electrons, gamma - gamma -t and e/sup -/- gamma -t coincidence measurements have been performed. Level schemes of /sup 108/Cd and /sup 106/Cd have been deduced from these results. A 0/sup + / level has been unambiguously established at 1.913 MeV in /sup 108/Cd and a new 0/sup +/ level proposed at 2.035 MeV in /sup 106/Cd. The energies and branching ratios are discussed in terms of vibrator +particles approach, interacting boson approximation and rotor +quasiparticles model. (15 refs).

Activation of transglutaminase 2 by nerve growth factor in differentiating neuroblastoma cells: A role in cell survival and neurite outgrowth.

Science.gov (United States)

Algarni, Alanood S; Hargreaves, Alan J; Dickenson, John M

2018-02-05

NGF (nerve growth factor) and tissue transglutaminase (TG2) play important roles in neurite outgrowth and modulation of neuronal cell survival. In this study, we investigated the regulation of TG2 transamidase activity by NGF in retinoic acid-induced differentiating mouse N2a and human SH-SY5Y neuroblastoma cells. TG2 transamidase activity was determined using an amine incorporation and a peptide cross linking assay. In situ TG2 activity was assessed by visualising the incorporation of biotin-X-cadaverine using confocal microscopy. The role of TG2 in NGF-induced cytoprotection and neurite outgrowth was investigated by monitoring hypoxia-induced cell death and appearance of axonal-like processes, respectively. The amine incorporation and protein crosslinking activity of TG2 increased in a time and concentration-dependent manner following stimulation with NGF in N2a and SH-SY5Y cells. NGF mediated increases in TG2 activity were abolished by the TG2 inhibitors Z-DON (Z-ZON-Val-Pro-Leu-OMe; Benzyloxycarbonyl-(6-Diazo-5-oxonorleucinyl)-l-valinyl-l-prolinyl-l-leucinmethylester) and R283 (1,3,dimethyl-2[2-oxo-propyl]thio)imidazole chloride) and by pharmacological inhibition of extracellular signal-regulated kinases 1 and 2 (ERK1/2), protein kinase B (PKB) and protein kinase C (PKC), and removal of extracellular Ca 2+ . Fluorescence microscopy demonstrated NGF induced in situ TG2 activity. TG2 inhibition blocked NGF-induced attenuation of hypoxia-induced cell death and neurite outgrowth in both cell lines. Together, these results demonstrate that NGF stimulates TG2 transamidase activity via a ERK1/2, PKB and PKC-dependent pathway in differentiating mouse N2a and human SH-SY5Y neuroblastoma cells. Furthermore, NGF-induced cytoprotection and neurite outgrowth are dependent upon TG2. These results suggest a novel and important role of TG2 in the cellular functions of NGF. Copyright © 2017 Elsevier B.V. All rights reserved.

Management and outcome of stage 3 neuroblastoma

Science.gov (United States)

Modak, Shakeel; Kushner, Brian H.; LaQuaglia, Michael P.; Kramer, Kim; Cheung, Nai-Kong V.

2013-01-01

Purpose The management of patients with International Neuroblastoma Staging System (INSS) stage 3 neuroblastoma (NB) is not consistent worldwide. We describe a single centre approach at Memorial Sloan-Kettering Cancer Centre (MSKCC) from 1991 to 2007 that minimizes therapy except for those patients with MYCN-amplified NB. Methods In this retrospective analysis of 69 patients, tumour MYCN was not amplified in 53 and amplified in 16. Event-free survival (EFS) and overall survival (OS) were determined by Kaplan–Meier analysis. Results Fourteen patients with non-MYCN-amplified tumours were treated with surgery alone (group A) and the remaining 39 (group B) with surgery following chemotherapy that was initiated and administered at non-MSKCC institutions. Chemotherapy was discontinued after surgery in 38/39 of the latter. The 10-year EFS and OS for all patients with MYCN-non-amplified NB were 74.9 ± 16.9% and 92.6 ± 5.5%, respectively. There was no difference in OS between groups A and B (p = 0.2; 10-year OS for groups A and B was 84.6 ± 14% and 97.1 ± 2.9%, respectively). Patients with MYCN-amplified disease (group C) underwent dose-intensive induction, tumour resection and local radiotherapy: 13 achieved complete or very good partial remission, and 10 received myeloablative chemotherapy. 11/16 patients also received 3F8-based immunotherapy: 10 remain free of disease. The 10-year EFS and OS for patients with MYCN-amplified neuroblastoma treated with immunotherapy were both 90.9 ± 8.7%. Conclusion Patients with MYCN-non-amplified stage 3 NB can be successfully treated with surgery without the need for radiotherapy or continuation of chemotherapy. Combination of dose-intensive chemotherapy, surgery, radiotherapy and immunotherapy was associated with a favourable outcome for most patients with MYCN-amplified stage 3 NB. PMID:18996003

Bitcoin-NG: A Scalable Blockchain Protocol

OpenAIRE

Eyal, Ittay; Gencer, Adem Efe; Sirer, Emin Gun; van Renesse, Robbert

2015-01-01

Cryptocurrencies, based on and led by Bitcoin, have shown promise as infrastructure for pseudonymous online payments, cheap remittance, trustless digital asset exchange, and smart contracts. However, Bitcoin-derived blockchain protocols have inherent scalability limits that trade-off between throughput and latency and withhold the realization of this potential. This paper presents Bitcoin-NG, a new blockchain protocol designed to scale. Based on Bitcoin's blockchain protocol, Bitcoin-NG is By...

18 CFR 286.108 - Determination.

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2010-04-01

... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Determination. 286.108 Section 286.108 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT... Contested Audit Findings and Proposed Remedies § 286.108 Determination. If no formal hearing is had the...

N-Myc knockdown and apigenin treatment controlled growth of malignant neuroblastoma cells having N-Myc amplification.

Science.gov (United States)

Hossain, Md Motarab; Banik, Naren L; Ray, Swapan K

2013-10-15

Malignant neuroblastomas mostly occur in children and are frequently associated with N-Myc amplification. Oncogene amplification, which is selective increase in copy number of the oncogene, provides survival advantages in solid tumors including malignant neuroblastoma. We have decreased expression of N-Myc oncogene using short hairpin RNA (shRNA) plasmid to increase anti-tumor efficacy of the isoflavonoid apigenin (APG) in human malignant neuroblastoma SK-N-DZ and SK-N-BE2 cell lines that harbor N-Myc amplification. N-Myc knockdown induced morphological and biochemical features of neuronal differentiation. Combination of N-Myc knockdown and APG most effectively induced morphological and biochemical features of apoptotic death. This combination therapy also prevented cell migration and decreased N-Myc driven survival, angiogenic, and invasive factors. Collectively, N-Myc knockdown and APG treatment is a promising strategy for controlling the growth of human malignant neuroblastoma cell lines that harbor N-Myc amplification. © 2013 Elsevier B.V. All rights reserved.

CADM1 is a strong neuroblastoma candidate gene that maps within a 3.72 Mb critical region of loss on 11q23

International Nuclear Information System (INIS)

Michels, Evi; Speleman, Frank; Hoebeeck, Jasmien; De Preter, Katleen; Schramm, Alexander; Brichard, Bénédicte; De Paepe, Anne; Eggert, Angelika; Laureys, Geneviève; Vandesompele, Jo

2008-01-01

Recurrent loss of part of the long arm of chromosome 11 is a well established hallmark of a subtype of aggressive neuroblastomas. Despite intensive mapping efforts to localize the culprit 11q tumour suppressor gene, this search has been unsuccessful thus far as no sufficiently small critical region could be delineated for selection of candidate genes. To refine the critical region of 11q loss, the chromosome 11 status of 100 primary neuroblastoma tumours and 29 cell lines was analyzed using a BAC array containing a chromosome 11 tiling path. For the genes mapping within our refined region of loss, meta-analysis on published neuroblastoma mRNA gene expression datasets was performed for candidate gene selection. The DNA methylation status of the resulting candidate gene was determined using re-expression experiments by treatment of neuroblastoma cells with the demethylating agent 5-aza-2'-deoxycytidine and bisulphite sequencing. Two small critical regions of loss within 11q23 at chromosomal band 11q23.1-q23.2 (1.79 Mb) and 11q23.2-q23.3 (3.72 Mb) were identified. In a first step towards further selection of candidate neuroblastoma tumour suppressor genes, we performed a meta-analysis on published expression profiles of 692 neuroblastoma tumours. Integration of the resulting candidate gene list with expression data of neuroblastoma progenitor cells pinpointed CADM1 as a compelling candidate gene. Meta-analysis indicated that CADM1 expression has prognostic significance and differential expression for the gene was noted in unfavourable neuroblastoma versus normal neuroblasts. Methylation analysis provided no evidence for a two-hit mechanism in 11q deleted cell lines. Our study puts CADM1 forward as a strong candidate neuroblastoma suppressor gene. Further functional studies are warranted to elucidate the role of CADM1 in neuroblastoma development and to investigate the possibility of CADM1 haploinsufficiency in neuroblastoma

Incidence, Survival, and Treatment of Localized and Metastatic Neuroblastoma in Germany 1979-2015.

Science.gov (United States)

Berthold, Frank; Spix, Claudia; Kaatsch, Peter; Lampert, Fritz

2017-12-01

A comprehensive clinical long-term survey over the complete spectrum of neuroblatoma disease is lacking in the literature. Our objective was to describe the incidence, risk profiles, therapies, and outcomes for the total cohort of German patients with neuroblastoma including all clinical stages and risk groups. Epidemiological, clinical, and outcome data of neuroblastoma patients who participated in one of the six consecutive national trials between 1979 and 2015 were analyzed retrospectively. Of all German neuroblastoma patients known to the national childhood cancer registry, ninety seven percent enrolled in one of the trials. The absolute neuroblastoma rate has increased slightly, whereas the median age at diagnosis has decreased. Except for the screening period (1995-2000), the risk factors lactate dehydrogenase (LDH), ferritin, chromosome 1p, and the MYCN oncogene have remained largely constant, with the exception of an increase in MYCN amplification at stage 4 for those aged ≥18 months between trials NB97 (27%) and NB2004 (35%). The 10-year overall survival increased in patients with stage 1-3 neuroblastoma from 83 to 91%, for stage 4S from 80 to 85%, and for stage 4 aged ≥18 months from 2 to 38%. The fraction of patients in stages 1-3 who never received chemotherapy (neither for frontline nor at recurrence) increased from 35 to 60%. The proportion of macroscopically complete surgical resections of the primary tumor decreased for the total population as well as for patients with stage 4 aged ≥18 months. The impact of chemotherapy response on the outcome was trial dependent. The overall proportion of toxic death during the time of the protocol therapy was 6% for stage 4 patients aged ≥18 months and 2% for low-/intermediate-risk patients. The most frequently reported late sequelae in stage 4 patients aged ≥18 months were renal dysfunctions, hypothyroidism, major hearing impairment, and second malignancies. The body of data for incidences, risk

46 CFR 108.493 - Location.

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2010-10-01

... 46 Shipping 4 2010-10-01 2010-10-01 false Location. 108.493 Section 108.493 Shipping COAST GUARD... Extinguishing Systems Hand Portable and Semiportable Fire Extinguishing Systems § 108.493 Location. (a) Each... this subpart and installed in the locations prescribed in the table. (b) Each portable and semi...

Knockdown of astrocyte elevated gene-1 inhibits proliferation and enhancing chemo-sensitivity to cisplatin or doxorubicin in neuroblastoma cells

Directory of Open Access Journals (Sweden)

Xie Li

2009-02-01

Full Text Available Abstract Background Astrocyte elevated gene-1 (AEG-1 was originally characterized as a HIV-1-inducible gene in primary human fetal astrocyte. Recent studies highlight a potential role of AEG-1 in promoting tumor progression and metastasis. The aim of this study was to investigate if AEG-1 serves as a potential therapeutic target of human neuroblastoma. Methods We employed RNA interference to reduce AEG-1 expression in human neuroblastoma cell lines and analyzed their phenotypic changes. Results We found that the knockdown of AEG-1 expression in human neuroblastoma cells significantly inhibited cell proliferation and apoptosis. The specific downregulation induced cell arrest in the G0/G1 phase of cell cycle. In the present study, we also observed a significant enhancement of chemo-sensitivity to cisplatin and doxorubicin by knockdown of AEG-1. Conclusion Our study suggests that overexpressed AEG-1 enhance the tumorogenic properties of neuroblastoma cells. The inhibition of AEG-1 expression could be a new adjuvant therapy for neuroblastoma.

Case report: value of gene expression profiling in the diagnosis of atypical neuroblastoma.

Science.gov (United States)

Harttrampf, Anne C; Chen, Qingrong; Jüttner, Eva; Geiger, Julia; Vansant, Gordon; Khan, Javed; Kontny, Udo

2017-08-17

Nephroblastoma and neuroblastoma belong to the most common abdominal malignancies in childhood. Similarities in the initial presentation may provide difficulties in distinguishing between these two entities, especially if unusual variations to prevalent patterns of disease manifestation occur. Because of the risk of tumor rupture, European protocols do not require biopsy for diagnosis, which leads to misdiagnosis in some cases. We report on a 4½-year-old girl with a renal tumor displaying radiological and laboratory characteristics supporting the diagnosis of nephroblastoma. Imaging studies showed tumor extension into the inferior vena cava and bilateral lung metastases while urine catecholamines and MIBG-scintigraphy were negative. Preoperative chemotherapy with vincristine, actinomycine D and adriamycin according to the SIOP2001/GPOH protocol for the treatment of nephroblastoma was initiated and followed by surgical tumor resection. Histopathology revealed an undifferentiated tumor with expression of neuronal markers, suggestive of neuroblastoma. MYCN amplification could not be detected. DNA-microarray analysis was performed using Affymetrix genechip human genome U133 plus 2.0 and artificial neural network analysis. Results were confirmed by multiplex RT-PCR. Principal component analysis using 84 genes showed that the patient sample was clearly clustering with neuroblastoma tumors. This was confirmed by hierarchical clustering of the multiplex RT-PCR data. The patient underwent treatment for high-risk neuroblastoma comprising chemotherapy including cisplatin, etoposide, vindesine, dacarbacine, ifosfamide, vincristine, adriamycine and autologous stem cell transplantation followed by maintenance therapy with 13-cis retinoic acid (GPOH NB2004 High Risk Trial Protocol) and is in complete long-term remission. The use of gene expression profiling in an individual patient strongly contributed to clarification in a diagnostic dilemma which finally led to a change of

24 CFR 908.108 - Cost.

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2010-04-01

... 24 Housing and Urban Development 4 2010-04-01 2010-04-01 false Cost. 908.108 Section 908.108..., RENTAL VOUCHER, AND MODERATE REHABILITATION PROGRAMS § 908.108 Cost. (a) General. The costs of the... computer hardware or software, or both, the cost of contracting for those services, or the cost of...

In vitro photothermal destruction of neuroblastoma cells using carbon nanotubes conjugated with GD2 monoclonal antibody

International Nuclear Information System (INIS)

Wang, Chung-Hao; Huang, Yao-Jhang; Chang, Chia-Wei; Peng, Ching-An; Hsu, Wen-Ming

2009-01-01

Despite aggressive multimodality therapy, most neuroblastoma-bearing patients relapse and survival rate remains poor. Exploration of alternative therapeutic modalities is needed. Carbon nanotubes (CNTs), revealing optical absorbance in the near-infrared region, warrant their merits in photothermal therapy. In order to specifically target disialoganglioside (GD2) overexpressed on the surface of neuroblastoma stNB-V1 cells, GD2 monoclonal antibody (anti-GD2) was conjugated to acidified CNTs. To examine the fate of anti-GD2 bound CNTs after incubation with stNB-V1 cells, rhodamine B was labeled on carboxylated CNTs functionalized with and without anti-GD2. Our results illustrated that anti-GD2-linked CNTs were extensively internalized by neuroblastoma cells via GD2-mediated endocytosis. In addition, we showed that anti-GD2 bound CNTs were not ingested by PC12 cells without GD2 expression. After anti-GD2 conjugated CNTs were incubated with neuroblastoma cells for 6 h and endocytosed by the cells, CNT-laden neuroblastoma cells were further irradiated with an 808 nm near-infrared (NIR) laser with intensity ramping from 0.6 to 6 W cm -2 for 10 min which was then maintained at 6 W cm -2 for an additional 5 min. Post-NIR laser exposure, and after being examined by calcein-AM dye, stNB-V1 cells were all found to undergo necrosis, while non-GD2 expressing PC12 cells all remained viable. Based on the in vitro study, CNTs bound with anti-GD2 have the potential to be utilized as a therapeutic thermal coupling agent that generates heat sufficient to selectively kill neuroblastoma cells under NIR laser light exposure.

Identification of the genetic and clinical characteristics of neuroblastomas using genome-wide analysis.

Science.gov (United States)

Uryu, Kumiko; Nishimura, Riki; Kataoka, Keisuke; Sato, Yusuke; Nakazawa, Atsuko; Suzuki, Hiromichi; Yoshida, Kenichi; Seki, Masafumi; Hiwatari, Mitsuteru; Isobe, Tomoya; Shiraishi, Yuichi; Chiba, Kenichi; Tanaka, Hiroko; Miyano, Satoru; Koh, Katsuyoshi; Hanada, Ryoji; Oka, Akira; Hayashi, Yasuhide; Ohira, Miki; Kamijo, Takehiko; Nagase, Hiroki; Takimoto, Tetsuya; Tajiri, Tatsuro; Nakagawara, Akira; Ogawa, Seishi; Takita, Junko

2017-12-08

To provide better insight into the genetic signatures of neuroblastomas, we analyzed 500 neuroblastomas (included specimens from JNBSG) using targeted-deep sequencing for 10 neuroblastoma-related genes and SNP arrays analysis. ALK expression was evaluated using immunohistochemical analysis in 259 samples. Based on genetic alterations, the following 6 subgroups were identified: groups A ( ALK abnormalities), B (other gene mutations), C ( MYCN amplification), D (11q loss of heterozygosity [LOH]), E (at least 1 copy number variants), and F (no genetic changes). Groups A to D showed advanced disease and poor prognosis, whereas groups E and F showed excellent prognosis. Intriguingly, in group A, MYCN amplification was not a significant prognostic marker, while high ALK expression was a relevant indicator for prognosis ( P = 0.033). Notably, the co-existence of MYCN amplification and 1p LOH, and the co-deletion of 3p and 11q were significant predictors of relapse ( P = 0.043 and P = 0.040). Additionally, 6q/8p LOH and 17q gain were promising indicators of survival in patients older than 5 years, and 1p, 4p, and 11q LOH potentially contributed to outcome prediction in the intermediate-risk group. Our genetic overview clarifies the clinical impact of genetic signatures and aids in the better understanding of genetic basis of neuroblastoma.

A three-gene expression signature model for risk stratification of patients with neuroblastoma.

Science.gov (United States)

Garcia, Idoia; Mayol, Gemma; Ríos, José; Domenech, Gema; Cheung, Nai-Kong V; Oberthuer, André; Fischer, Matthias; Maris, John M; Brodeur, Garrett M; Hero, Barbara; Rodríguez, Eva; Suñol, Mariona; Galvan, Patricia; de Torres, Carmen; Mora, Jaume; Lavarino, Cinzia

2012-04-01

Neuroblastoma is an embryonal tumor with contrasting clinical courses. Despite elaborate stratification strategies, precise clinical risk assessment still remains a challenge. The purpose of this study was to develop a PCR-based predictor model to improve clinical risk assessment of patients with neuroblastoma. The model was developed using real-time PCR gene expression data from 96 samples and tested on separate expression data sets obtained from real-time PCR and microarray studies comprising 362 patients. On the basis of our prior study of differentially expressed genes in favorable and unfavorable neuroblastoma subgroups, we identified three genes, CHD5, PAFAH1B1, and NME1, strongly associated with patient outcome. The expression pattern of these genes was used to develop a PCR-based single-score predictor model. The model discriminated patients into two groups with significantly different clinical outcome [set 1: 5-year overall survival (OS): 0.93 ± 0.03 vs. 0.53 ± 0.06, 5-year event-free survival (EFS): 0.85 ± 0.04 vs. 0.042 ± 0.06, both P model was an independent marker for survival (P model robustly classified patients in the total cohort and in different clinically relevant risk subgroups. We propose for the first time in neuroblastoma, a technically simple PCR-based predictor model that could help refine current risk stratification systems. ©2012 AACR.

{sup 18}F-DOPA PET/CT for assessment of response to induction chemotherapy in a child with high-risk neuroblastoma

Energy Technology Data Exchange (ETDEWEB)

Piccardo, Arnoldo [Galliera Hospital, Nuclear Medicine Unit, Genoa (Italy); E.O. Ospedali Galliera, Department of Nuclear Medicine, Genoa (Italy); Lopci, Egesta [Humanitas Clinical and Research Center, Nuclear Medicine Department, Rozzano, MI (Italy); Foppiani, Luca [Galliera Hospital, Internal Medicine and Endocrinology, Genoa (Italy); Morana, Giovanni [G. Gaslini Children' s Hospital, Department of Pathology and Radiology, Genoa (Italy); Conte, Massimo [G. Gaslini Children' s Hospital, Department of Hematology-Oncology, Genoa (Italy)

2014-03-15

Functional imaging plays a crucial role in the assessment of neuroblastoma. The evaluation of response to induction chemotherapy is a cornerstone in scheduling proper treatment management in patients affected by high-risk neuroblastoma. {sup 123}I-metaiodobenzylguanidine has been recognized as the radiopharmaceutical of choice in neuroblastoma assessment. To date, the clinical role of PET/CT in pediatric malignancy is not well established.{sup 18}F-DOPA-PET/CT has been recently used in neuroblastoma, and compared with {sup 123}I-MIBG-scan. Scant new data are available about the role of this tool in the evaluation of treatment response after induction chemotherapy. We investigate the role of {sup 18}F-DOPA-PET/CT in characterizing the response to induction chemotherapy in a child affected by high-risk-neuroblastoma, in whom the rare association of {sup 123}I-MIBG-negative primary tumor and MIBG-positive bone marrow metastases was observed. (orig.)

Signaling pathways in PACAP regulation of VIP gene expression in human neuroblastoma cells

DEFF Research Database (Denmark)

Falktoft, B.; Georg, B.; Fahrenkrug, J.

2009-01-01

Ganglia expressing the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) innervate vasoactive intestinal peptide (VIP) containing neurons suggesting a role of PACAP in regulating VIP expression. Human NB-1 neuroblastoma cells were applied to study PACAP regulated VIP gene...... in PACAP regulation of the FOS and VIP gene expressions suggest for the first time a role of FOS in PACAP-induced VIP gene expression in human NB-1 neuroblastoma cells. (C) 2009 Elsevier Ltd. All rights reserved Udgivelsesdato: 2009/10...

Unusual fatty metamorphosis observed in diffuse liver metastases of stage 4S neuroblastoma

Energy Technology Data Exchange (ETDEWEB)

Tazoe, Jun; Okuyama, Chio; Nishimura, Tsunehiko [Kyoto Prefectural University of Medicine, Department of Radiology, Graduate School of Medical Science, Kyoto City (Japan); Iehara, Tomoko; Hosoi, Hajime [Kyoto Prefectural University of Medicine, Department of Paediatrics, Graduate School of Medical Science, Kyoto City (Japan)

2010-05-15

We report a case of stage 4S neuroblastoma in which CT showed diffuse liver metastases containing a geographical fatty area in the periportal region. MRI showed this abnormality to correspond to an area with an unusual pattern of fatty change. {sup 123}I-metaiodobenzylguanidine (MIBG) scintigraphy demonstrated increased accumulation throughout the liver, except for the region showing fatty change. To the best of our knowledge, this is the first report of liver metastases from neuroblastoma with geographical fatty infiltration. (orig.)

Unusual fatty metamorphosis observed in diffuse liver metastases of stage 4S neuroblastoma

International Nuclear Information System (INIS)

Tazoe, Jun; Okuyama, Chio; Nishimura, Tsunehiko; Iehara, Tomoko; Hosoi, Hajime

2010-01-01

We report a case of stage 4S neuroblastoma in which CT showed diffuse liver metastases containing a geographical fatty area in the periportal region. MRI showed this abnormality to correspond to an area with an unusual pattern of fatty change. 123 I-metaiodobenzylguanidine (MIBG) scintigraphy demonstrated increased accumulation throughout the liver, except for the region showing fatty change. To the best of our knowledge, this is the first report of liver metastases from neuroblastoma with geographical fatty infiltration. (orig.)

High dose melphalan in the treatment of advanced neuroblastoma: results of a randomised trial (ENSG-1) by the European Neuroblastoma Study Group.

Science.gov (United States)

Pritchard, Jon; Cotterill, Simon J; Germond, Shirley M; Imeson, John; de Kraker, Jan; Jones, David R

2005-04-01

High dose myeloablative chemotherapy ("megatherapy"), with haematopoietic stem cell support, is now widely used to consolidate response to induction chemotherapy in patients with advanced neuroblastoma. In this study (European Neuroblastoma Study Group, ENSG1), the value of melphalan myeloablative "megatherapy" was evaluated in a randomised, multi-centre trial. Between 1982 and 1985, 167 children with stages IV and III neuroblastoma (123 stage IV > 1 year old at diagnosis and 44 stage III and stage IV from 6 to 12 months old at diagnosis) were treated with oncovin, cisplatin, epipodophyllotoxin, and cyclophosphamide (OPEC) induction chemotherapy every 3 weeks. After surgical excision of primary tumour, the 90 patients (69% of the total) who achieved complete response (CR) or good partial response (GPR) were eligible for randomisation either to high dose melphalan (180 mg per square meter) with autologous bone marrow support or to no further treatment. Sixty-five (72%) of eligible children were actually randomised and 21 of these patients were surviving at time of this analysis, with median follow-up from randomisation of 14.3 years. Five year event-free survival (EFS) was 38% (95% confidence interval (CI) 21-54%) in the melphalan-treated group and 27% (95% CI 12-42%) in the "no-melphalan" group. This difference was not statistically significant (P = 0.08, log rank test) but for the 48 randomised stage IV patients aged >1 year at diagnosis outcome was significantly better in the melphalan-treated group-5 year EFS 33% versus 17% (P = 0.01, log rank test). In this trial, high dose melphalan improved the length of EFS and overall survival of children with stage IV neuroblastoma >1 year of age who achieved CR or GPR after OPEC induction therapy and surgery. Multi-agent myeloablative regimens are now widely used as consolidation therapy for children with stage IV disease and in those with other disease stages when the MYCN gene copy number in tumour cells is amplified

In situ monitoring of PTHLH secretion in neuroblastoma cells cultured onto nanoporous membranes.

Science.gov (United States)

de la Escosura-Muñiz, Alfredo; Espinoza-Castañeda, Marisol; Chamorro-García, Alejandro; Rodríguez-Hernández, Carlos J; de Torres, Carmen; Merkoçi, Arben

2018-06-01

In this work, we propose for the first time the use of anodic aluminum oxide (AAO) nanoporous membranes for in situ monitoring of parathyroid hormone-like hormone (PTHLH) secretion in cultured human cells. The biosensing system is based on the nanochannels blockage upon immunocomplex formation, which is electrically monitored through the voltammetric oxidation of Prussian blue nanoparticles (PBNPs). Models evaluated include a neuroblastoma cell line (SK-N-AS) and immortalized keratinocytes (HaCaT) as a control of high PTHLH production. The effect of total number of seeded cells and incubation time on the secreted PTHLH levels is assessed, finding that secreted PTHLH levels range from approximately 60 to 400 ng/mL. Moreover, our methodology is also applied to analyse PTHLH production following PTHLH gene knockdown upon transient cell transfection with a specific silencing RNA (siRNA). Given that inhibition of PTHLH secretion reduces cell proliferation, survival and invasiveness in a number of tumors, our system provides a powerful tool for the preclinical evaluation of therapies that regulate PTHLH production. This nanoporous membrane - based sensing technology might be useful to monitor the active secretion of other proteins as well, thus contributing to characterize their regulation and function. Copyright © 2018 Elsevier B.V. All rights reserved.

Environment Mediated Drug Resistance in Neuroblastoma

Science.gov (United States)

2015-12-01

activate STAT3 and MYC in neuroblastomas independently of IL6). Figure 9: Effect of IL-6 knockout crossing with NB- Tag mice. (A) MRI of abdominal...production. (D) Representative MRI images of NB-Tag and NB- Tag/IL-6KO pre-chemotherapy, post 3 and 6 weeks of chemotherapy. Task 6. Contribution of bone...described (16). Cells were lysed in radioimmunoprecipitation assay (RIPA) buffer supplemented with 1 tablet of complete mini-EDTA protease inhibitor

City-gas development in China. An NG perspective

International Nuclear Information System (INIS)

Wong, James W.K.

2010-01-01

Supply of piped gas in China has a long history but development was slow until the 21st century. The growing demand for cleaner fuel in the past ten years has encouraged domestic exploration and production of natural gas (NG) and the construction of long-haul pipelines linking upstream western regions of the country to downstream city-gas consumers in the eastern coastal areas. However, demand for NG in the cities is increasing so fast that recent winters have seen severe supply difficulties. This led to a government directive which set constraints on the domestic NG supplies and discouragement to gas power and petrochemical projects, and eventually to the Chinese government's willingness to accept the higher prices commanded by the international NG market. Nevertheless, the over demand situation has created a dominant market position for upstream NG producers and long-haul pipeline operators favouring their forward integration into downstream city-gas markets. Accordingly, pressures are building that may yet result in substantial pricing and regulatory reform in the city-gas industry. (author)

MIBG-treatment in neuroblastoma

International Nuclear Information System (INIS)

Treuner, J.; Gerein, V.; Klingebiel, T.; Schwabe, D.; Feine, U; Happ, J.; Niethammer, D.; Maul, F.; Dopfer, R.; Kornhuber, B.; Berthold, F.; Jurgens, H.; Hor, G.

1988-01-01

This paper reports the results of 27 children with neuroblastoma treated with 131 I-Metaiodobenzylguanidine (MIBG). They were either refractory to conventional therapy or experienced relapse after initially successful treatment. 7 children revealed stage IV and 20 stage III at the beginning of MIBG-treatment. MIBG was administered by infusion lasting from 30 min to 30 hrs. In most children the dose was split into two portions each infused over a period of 4 hrs with a 24 hrs interval between. Courses were repeated up to 6 times and maximum activity given to one patient cumulatively was 38,221 MBq. 24 patients were valuable for analysis of results

Validation of an accelerated solvent extraction liquid chromatography-tandem mass spectrometry method for Pacific ciguatoxin-1 in fish flesh and comparison with the mouse neuroblastoma assay.

Science.gov (United States)

Wu, Jia Jun; Mak, Yim Ling; Murphy, Margaret B; Lam, James C W; Chan, Wing Hei; Wang, Mingfu; Chan, Leo L; Lam, Paul K S

2011-07-01

Ciguatera fish poisoning (CFP) is a global foodborne illness caused by consumption of seafood containing ciguatoxins (CTXs) originating from dinoflagellates such as Gambierdiscus toxicus. P-CTX-1 has been suggested to be the most toxic CTX, causing ciguatera at 0.1 μg/kg in the flesh of carnivorous fish. CTXs are structurally complex and difficult to quantify, but there is a need for analytical methods for CFP toxins in coral reef fishes to protect human health. In this paper, we describe a sensitive and rapid extraction method using accelerated solvent extraction combined with high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) for the detection and quantification of P-CTX-1 in fish flesh. By the use of a more sensitive MS system (5500 QTRAP), the validated method has a limit of quantification (LOQ) of 0.01 μg/kg, linearity correlation coefficients above 0.99 for both solvent- and matrix-based standard solutions as well as matrix spike recoveries ranging from 49% to 85% in 17 coral reef fish species. Compared with previous methods, this method has better overall recovery, extraction efficiency and LOQ. Fish flesh from 12 blue-spotted groupers (Cephalopholis argus) was assessed for the presence of CTXs using HPLC-MS/MS analysis and the commonly used mouse neuroblastoma assay, and the results of the two methods were strongly correlated. This method is capable of detecting low concentrations of P-CTX-1 in fish at levels that are relevant to human health, making it suitable for monitoring of suspected ciguateric fish both in the environment and in the marketplace.

The effect of cisplatin pretreatment on the accumulation of MIBG by neuroblastoma cells in vitro.

Science.gov (United States)

Armour, A; Cunningham, S H; Gaze, M N; Wheldon, T E; Mairs, R J

1997-01-01

[131I]meta-iodobenzylguanidine ([131I]MIBG) provides a means of selectively delivering radiation to neuroblastoma cells and is a promising addition to the range of agents used to treat neuroblastoma. As MIBG is now being incorporated into multimodal approaches to therapy, important questions arise about the appropriate scheduling and sequencing of the various agents employed. As the ability of neuroblastoma cells to actively accumulate MIBG is crucial to the success of this therapy, the effect of chemotherapeutic agents on this uptake capacity needs to be investigated. We report here our initial findings on the effect of cisplatin pretreatment on the neuroblastoma cell line SK-N-BE (2c). After treating these cells with therapeutically relevant concentrations of cisplatin (2 microM and 20 microM), a stimulation in uptake of [131I]MIBG was observed. Reverse transcription-polymerase chain reaction (RT-PCR) analysis demonstrated that this effect was due to increased expression of the noradrenaline transporter. These results suggest that appropriate scheduling of cisplatin and [131I]MIBG may lead to an increase in tumour uptake of this radiopharmaceutical with consequent increases in radiation dose to the tumour.

Intestinal Lymphangiectasia Secondary to Neuroblastoma

Directory of Open Access Journals (Sweden)

RM Reifen

1994-01-01

Full Text Available An eight month-old infant presented with a 10-day history of vomiting and diarrhea, and a one-week history of swelling of the lower extremities. Laboratory evaluations revealed hypoproteinemia and lymphocytopenia due to protein-losing enteropathy. Peroral small bowel biopsy showed intestinal lymphangiectasia. Subsequent onset of unexplained ecchymosis and obstructive jaundice resulted in additional studies which revealed an omental neuroblastoma as the underlying etiology of the infant’s symptoms. This report emphasizes the importance of considering secondary, obstructive causes for lymphangiectasia and protein-losing enteropathy.

Image-defined Risk Factors Correlate with Surgical Radicality and Local Recurrence in Patients with Neuroblastoma.

Science.gov (United States)

Pohl, A; Erichsen, M; Stehr, M; Hubertus, J; Bergmann, F; Kammer, B; von Schweinitz, D

2016-04-01

Neuroblastoma is the second most common solid pediatric tumor and the most common cancer to be detected in children younger than 12 months of age. To date, 2 different staging systems describe the extent of the disease: the International Neuroblastoma Staging System (INSS) and the International Neuroblastoma Risk Group Staging System (INRGSS). The INRGSS-system is characterized by the presence or absence of so called image-defined risk factors (IDRFs), which are described as surgical risk factors. We hypothesized that IDRFs correlate with surgical complications, surgical radicality, local recurrence and overall survival (OS). Between 2003 and 2010, 102 patients had neuroblastoma surgery performed in our department. We analyzed medical records for IDRF-status and above named data. 16 patients were IDRF-negative, whereas 86 patients showed one or more IDRF. Intra- or postoperative complications have been reported in 21 patients (21%). 19 of them showed one or more IDRF and 2 patients were IDRF-negative (p=n.s.). Patients who suffered from intra- or postoperative complications demonstrated a decreased OS (p=0.011). Statistical analysis revealed an inverse correlation between the extent of macroscopical removal and IDRF-status (p=0.001). Furthermore, the number of IDRFs were associated with a decreased likelihood of radical tumor resection (p<0.001). 19 patients had local recurrence; all of them were IDRF-positive (p=0.037). Pediatric surgeons should consider IDRFs as a useful tool for risk assessment and therefore planning for neuroblastoma surgery. © Georg Thieme Verlag KG Stuttgart · New York.

Anti-Neuroblastoma Activity of Gold Nanorods Bound with GD2 Monoclonal Antibody under Near-Infrared Laser Irradiation

International Nuclear Information System (INIS)

Peng, Ching-An; Wang, Chung-Hao

2011-01-01

High-risk neuroblastoma is one of the most common deaths in pediatric oncology. Current treatment of this disease involves a coordinated sequence of chemotherapy, surgery, and radiation. Further advances in therapy will require the targeting of tumor cells in a more selective and efficient way so that survival can be improved without substantially increasing toxicity. To achieve tumor-selective delivery, disialoganglioside (GD2) expressed by almost all neuroblastoma tumors represents a potential molecular target that can be exploited for tumor-selective delivery. In this study, GD2 monoclonal antibody (anti-GD2) was conjugated to gold nanorods (GNRs) which are one of anisotropic nanomaterials that can absorb near-infrared (NIR) laser light and convert it to energy for photothermolysis of tumor cells. Thiolated chitosan, due to its biocompatibility, was used to replace cetyltrimethylammonium bromide (CTAB) originally used in the synthesis of gold nanorods. In order to specifically target GD2 overexpressed on the surface of neuroblastoma stNB-V1 cells, anti-GD2 was conjugated to chitosan modified GNRs (CGNRs). To examine the fate of CGNRs conjugated with anti-GD2 after incubation with neuroblastoma cells, rhadoamine B was labeled on CGNRs functionalized with anti-GD2. Our results illustrated that anti-GD2-conjugated CGNRs were extensively endocytosed by GD2 + stNB-V1 neuroblastoma cells via antibody-mediated endocytosis. In addition, we showed that anti-GD2 bound CGNRs were not internalized by GD2 − SH-SY5Y neuroblastoma cells. After anti-GD2-linked CGNRs were incubated with neuroblatoma cells for six hours, the treated cells were further irradiated with 808 nm NIR laser. Post-NIR laser exposure, when examined by calcein-AM dye, stNB-V1 cells all underwent necrosis, while non-GD2 expressing SH-SY5Y cells all remained viable. Based on the in vitro study, CGNRs bound with anti-GD2 has the potential to be utilized as a therapeutic thermal coupling agent that generates

Functional roles of CSPG4/NG2 in chondrosarcoma.

Science.gov (United States)

Jamil, Nuor S M; Azfer, Asim; Worrell, Harrison; Salter, Donald M

2016-04-01

CSPG4/NG2 is a multifunctional transmembrane protein with limited distribution in adult tissues including articular cartilage. The purpose of this study was to investigate the possible roles of CSPG4/NG2 in chondrosarcomas and to establish whether this molecule may have potential for targeted therapy. Stable knock-down of CSPG4/NG2 in the JJ012 chondrosarcoma cell line by shRNA resulted in decreased cell proliferation and migration as well as a decrease in gene expression of the MMP (matrix metalloproteinase) 3 protease and ADAMTS4 (aggrecanase). Chondrosarcoma cells in which CSPG4/NG2 was knocked down were more sensitive to doxorubicin than wild-type cells. The results indicate that CSPG4/NG2 has roles in regulating chondrosarcoma cell function in relation to growth, spread and resistance to chemotherapy and that anti-CSPG4/NG2 therapies may have potential in the treatment of surgically unresectable chondrosarcoma. © 2016 The Authors. International Journal of Experimental Pathology © 2016 International Journal of Experimental Pathology.

Decreased aortic growth and middle aortic syndrome in patients with neuroblastoma after radiation therapy

International Nuclear Information System (INIS)

Sutton, Elizabeth J.; Tong, Ricky T.; Gillis, Amy M.; Haas-Kogan, Daphne A.; Henning, Tobias D.; Boddington, Sophie; Sha, Vinil; Gooding, Charles; Coakley, Fergus V.; Daldrup-Link, Heike; Weinberg, Vivian A.; Matthay, Katherine

2009-01-01

Long-term CT follow-up studies are required in pediatric patients who have received intraoperative radiation therapy (IORT) and external beam radiation therapy (EBRT) to assess vascular toxicities and to determine the exact complication rate. To analyze with CT the effects of radiation therapy (RT) on the growth of the aorta in neuroblastoma patients. Abdominal CT scans of 31 patients with intraabdominal neuroblastoma (stage II-IV), treated with RT (20 IORT±EBRT, 11 EBRT alone), were analyzed retrospectively. The diameter of the abdominal aorta was measured before and after RT. These data were compared to normal and predicted normal aortic diameters of children, according to the model of Fitzgerald, Donaldson and Poznanski (aortic diameter in centimeters = 0.844+0.0599 x age in years), and to the diameters of a control group of children who had not undergone RT. Statistical analyses for the primary aims were performed using the chi-squared test, t-test, Mann-Whitney test, nonparametric Wilcoxon matched-pairs test and analysis of variance for repeated measures. Clinical files and imaging studies were evaluated for signs of late vascular complications of neuroblastoma patients who had received RT. The mean diameter before and after RT and the growth of the aorta were significantly lower than expected in patients with neuroblastoma (P<0.05 for each) and when compared to the growth in a control group with normal and nonirradiated aortas. Among the patients who had received RT, there was no difference due to the type of RT. Seven patients from the IORT±EBRT group developed vascular complications, which included hypertension (five), middle aortic syndrome (two), death due to mesenteric ischemia (one) and critical aortic stenosis, which required aortic bypass surgery (two). Patients with neuroblastoma who had received RT showed impaired growth of the abdominal aorta. Significant long-term vascular complications occurred in seven patients who received IORT±EBRT. Thus

Locoregional control in infants with neuroblastoma: role of radiation therapy and late toxicity

International Nuclear Information System (INIS)

Paulino, Arnold C.; Mayr, Nina A.; Simon, James H.; Buatti, John M.

2002-01-01

Purpose: To review patterns of failure in infants with neuroblastoma and determine late toxicity and efficacy of radiotherapy (RT) on locoregional control. Methods and Materials: From 1955 to 1998, 53 children (35 males and 18 females) 1 month), and primary site were not found to impact on survival or progression. None of the Stage 1, 2A, or 2B patients recurred. One of 15 Stage 3 and 5 of 6 Stage 4 children recurred (6 distant metastases, 4 local failure). Four of 6 (67%) LN+ patients treated with locoregional RT and 8 of 10 (80%) LN+ patients treated without RT were locally controlled. There was no isolated locoregional relapse. Two Stage 4S patients died of respiratory compromise secondary to hepatomegaly. RT toxicity: For the 20 infants who received RT, 13 are alive with long-term follow-up ranging from 9.3 to 41 years, median 23 years. The 10 and 15-year musculoskeletal toxicity rates were 38.5% and 47.3% for those receiving RT and 3.3% for no RT (p=0.02, log-rank test). Five of 6 infants <6 months of age and 1 of 7 ≥6 months developed musculoskeletal toxicity. Musculoskeletal effects were seen in 6 RT patients and included bony hypoplasia in 6, scoliosis in 5, soft tissue hypoplasia in 3, slipped capital femoral epiphysis in 2, kyphosis in 1, and osteochondroma in 1. Three required orthopedic intervention, all receiving ≥20 Gy. One child developed bowel obstruction at 21 months and another developed a leiomyosarcoma in the treatment field 34 years after RT. Conclusions: Our study shows that most LN+ infants achieve locoregional control without RT. Infants <6 months receiving RT were the most susceptible to musculoskeletal abnormalities. Further studies are needed to determine if cardiovascular anomalies are more frequently seen in children with neuroblastoma

Discovery – Ch14.18 Immunotherapy to Treat Neuroblastoma

Science.gov (United States)

Neuroblastoma is rare yet it's the most common cancer affecting infants. Prior to a discovery 20 years in the making, there was little hope for survival in children with advanced stages of the disease. Today, research is leading to a brighter outlook.

Iodine 131 labeled GD2 monoclonal antibody in the diagnosis and therapy of human neuroblastoma

International Nuclear Information System (INIS)

Cheung, N.K.V.; Miraldi, F.D.

1988-01-01

High dose marrow ablative therapy followed by autologous bone marrow transplantation (ABMT) has prolonged survival in patients with neuroblastoma. Total body and focal irradiation play an integral role in the overall treatment of this disease. The biological basis for radiation is the radiosensitivity and the lack of sublethal repair in neuroblastoma cells. However, radiation therapy has not by itself been adequate because of the usual widespread nature of neuroblastoma and the inability to achieve selective tumor versus normal tissue delivery, especially at multiple tumor sites. Monoclonal antibodies are agents selected for their specificity for human tumors. In vivo they have the ability of targeting selectively to occult metastases. This paper discusses how the availability of radioisotopes and the development of conjugation chemistries have greatly expanded the potentials of these antibodies

PPARbeta agonists trigger neuronal differentiation in the human neuroblastoma cell line SH-SY5Y.

Science.gov (United States)

Di Loreto, S; D'Angelo, B; D'Amico, M A; Benedetti, E; Cristiano, L; Cinque, B; Cifone, M G; Cerù, M P; Festuccia, C; Cimini, A

2007-06-01

Neuroblastomas are pediatric tumors originating from immature neuroblasts in the developing peripheral nervous system. Differentiation therapies could help lowering the high mortality due to rapid tumor progression to advanced stages. Oleic acid has been demonstrated to promote neuronal differentiation in neuronal cultures. Herein we report on the effects of oleic acid and of a specific synthetic PPARbeta agonist on cell growth, expression of differentiation markers and on parameters responsible for the malignancy such as adhesion, migration, invasiveness, BDNF, and TrkB expression of SH-SY5Y neuroblastoma cells. The results obtained demonstrate that many, but not all, oleic acid effects are mediated by PPARbeta and support a role for PPARbeta in neuronal differentiation strongly pointing towards PPAR ligands as new therapeutic strategies against progression and recurrences of neuroblastoma.

Profile and outcome of neuroblastoma with convertional chemotherapy in children older than one year: a 15-years experience.

Science.gov (United States)

Bansal, Deepak; Marwaha, R K; Trehan, Amita; Rao, K L N; Gupta, Vishal

2008-02-01

The clinical profile and outcome of neuroblastoma in 103 children, older than one-year is presented. 74 had Stage IV, 27 Stage III and one patient each had Stage I or II disease. Treatment included chemotherapy followed by surgical resection/debulking. Radiotherapy was administered to those with residual tumor. Chemotherapy consisted of OPEC (vincristine, cyclophosphamide, cisplatin and etoposide). The caretakers of 54 (52.4%) children either did not opt for or defaulted therapy, whilst 3 patients died before chemotherapy could be initiated. Of the remaining 46 patients, the tumor progressed during therapy in 19 (41.3%). Relapse of disease was documented in 22 (47.8%) cases. Merely 4 (8.7%) children are disease free for a period of 16.5+/-6.7 months. Majority of children presented with advanced disease and the outcome was dismal with conventional non-myloablative chemotherapy.

Radiobiological considerations in the treatment of neuroblastoma by total body irradiation

International Nuclear Information System (INIS)

Wheldon, T.E.; O'Donoghue, J.; Gregor, A.; Livingstone, A.; Wilson, L.; West of Scotland Health Boards, Glasgow

1986-01-01

Neuroblastoma is a radiosensitive neoplasm for which total body irradiation (TBI) is presently under clinical consideration. Collated data on the radiobiology of human neuroblastoma cells in vitro indicates moderate cellular radiosensitivity and low capacity for accumulation of sublethal damage. Mathematical studies incorporating these parameters suggest that low dose fractionated TBI is unlikely to achieve significant levels of tumour cell kill. When high dose TBI is used in conjuction with bone marrow rescue a tumour 'log cell kill' of 4-5 should be achievable. This effect would be additional to that acheived by chemotherapy. Fractionated TBI with bone marrow rescue may be curative for some patients in clinical remission who are presently destined to relapse. (Auth.)

MAX to MYCN intracellular ratio drives the aggressive phenotype and clinical outcome of high risk neuroblastoma.

Science.gov (United States)

Ferrucci, Francesca; Ciaccio, Roberto; Monticelli, Sara; Pigini, Paolo; di Giacomo, Simone; Purgato, Stefania; Erriquez, Daniela; Bernardoni, Roberto; Norris, Murray; Haber, Michelle; Milazzo, Giorgio; Perini, Giovanni

2018-03-01

Childhood neuroblastoma, a disease of the sympathetic nervous system, is the most common solid tumour of infancy, remarkably refractory to therapeutic treatments. One of the most powerful independent prognostic indicators for this disease is the amplification of the MYCN oncogene, which occurs at high levels in approximately 25% of neuroblastomas. Interestingly, amplification and not just expression of MYCN has a strong prognostic value, although this fact appears quite surprising as MYCN is a transcription factor that requires dimerising with its partner MAX, to exert its function. This observation greatly suggests that the role of MYCN in neuroblastoma should be examined in the context of MAX expression. In this report, we show that, in contrast to what is found in normal cells, MAX expression is significantly different among primary NBs, and that its level appears to correlate with the clinical outcome of the disease. Importantly, controlled modulation of MAX expression in neuroblastoma cells with different extents of MYCN amplification, demonstrates that MAX can instruct gene transcription programs that either reinforce or weaken the oncogenic process enacted by MYCN. In general, our work illustrates that it is the MAX to MYCN ratio that can account for tumour progression and clinical outcome in neuroblastoma and proposes that such a ratio should be considered as an important criterion to the design and development of anti-MYCN therapies. Copyright © 2018 Elsevier B.V. All rights reserved.

Biodistribution of upconversion/magnetic silica-coated NaGdF4:Yb3+/Er3+ nanoparticles in mouse models

Czech Academy of Sciences Publication Activity Database

Kostiv, Uliana; Rajsiglová, Lenka; Luptáková, Dominika; Pluháček, Tomáš; Vannucci, Luca; Havlíček, Vladimír; Engstová, Hana; Jirák, D.; Šlouf, Miroslav; Makovický, Peter; Sedláček, Radislav; Horák, Daniel

2017-01-01

Roč. 7, č. 73 (2017), s. 45997-46006 ISSN 2046-2069 R&D Projects: GA ČR(CZ) GA15-01897S; GA MŠk(CZ) LD15135; GA TA ČR(CZ) TE01020118 EU Projects: European Commission(XE) MiMed Cost Action TD1301 Institutional support: RVO:61389013 ; RVO:61388971 ; RVO:68378050 ; RVO:67985823 Keywords : upconversion nanoparticles * gadolinium * tumor mouse Subject RIV: CD - Macromolecular Chemistry; EE - Microbiology, Virology (MBU-M); FD - Oncology ; Hematology (UMG-J); JJ - Other Materials (FGU-C) OBOR OECD: Polymer science; Microbiology (MBU-M); Oncology (UMG-J); Nano-materials (production and properties) (FGU-C) Impact factor: 3.108, year: 2016

Hypertension complicating 131I-meta-iodobenzylguanidine therapy for neuroblastoma

International Nuclear Information System (INIS)

Kosmin, Michael A.; Cork, Nicholas J.; Gaze, Mark N.; Bomanji, Jamshed B.; Shankar, Ananth

2012-01-01

Radiolabelled meta-iodobenzylguanidine (mIBG), used as targeted therapy for neuroblastoma, is known to have effects on blood pressure (BP). In this study we audited BP changes in patients receiving 131 I-mIBG therapy for neuroblastoma to identify BP-related adverse events (AE) and possible predictive factors. Between 2003 and 2010, 50 patients with neuroblastoma received 110 131 I-mIBG administrations. BP measurements before and after administration were compared with age- and sex-matched centile values. AE were analysed, and possible predisposing factors identified. This population had a baseline BP distribution higher than that of their age- and sex-matched peers, with 16% of preadministration systolic BP values above the 95th centile. Changes in BP after administration showed an approximately normal distribution with similar numbers of reduced and increased values. Four AE, all related to hypertension, occurred with one patient having generalized seizures. One AE was immediate, others occurred between 20 and 25 h after administration. No significant association between AE and patient age or sex was demonstrated. However, a significant association between AE and high preadministration BP was shown, both above the 90th centile (p = 0.0022) and above the 95th centile (p = 0.0135). Clinically relevant hypertension following 131 I-mIBG therapy affected less than 5% of administrations, but was more common in those patients with preexisting hypertension. As hypertensive episodes may occur many hours after treatment, close monitoring of BP needs to be continued for at least 48 h after administration of 131 I-mIBG. (orig.)

A new algorithm for histopathological diagnosis of periprosthetic infection using CD15 focus score and computer program CD15 Quantifier

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V. Krenn

2015-01-01

Full Text Available Introduction. A simple microscopic diagnostic quantification system for neutrophile granulocytes (NG was developed evaluating a single focal point (CD15 focus score which enables the detection of bacterial infection in SLIM (synoviallike interface membrane Additionally a diagnostic algorithm is proposed how to use the CD15 focus score and the quantification software (CD15 Quantifier. Methods. 91 SLIM removed during revision surgery for histopathological diagnosis (hip; n=59 and knee; n=32 underwent histopathological classification according to the SLIM-consensus classification. NG where identified immunohistochemically by means of a CD15-specific monoclonal antibody exhibiting an intense granular cytoplasmic staining pattern. This pattern is different from CD15 expression in macrophages showing a pale and homogenous expression in mononuclear cells. The quantitative evaluation of CD15-positive neutrophils granulocytes (CD15NG used the principle of maximum focal infiltration (focus together with an assessment of a single focal point (approximately 0.3 mm2. This immunohistochemical data made it possible to develop CD15 Quantifier software which automatically quantifies CD15NG. Results. SLIM-cases with positive microbiological diagnosis (n=47 have significantly (p<0.001, Mann-Whitney U test more CD15NG/focal point than cases with negative microbiological diagnosis (n=44. 50 CD15NG/focal point were identified as the optimum threshold when diagnosing infection of periprosthetic joints using the CD15 focus score. If the microbiological findings are used as a ‘gold standard’ the diagnostic sensitivity is 0.83, specificity is 0.864. (PPV: 0.87; NPV: 0.83; accuracy 0.846; AUC: 0.878. The evaluation findings for the preparations using the CD15 Quantifier (n=31 deviated in an average of 12 cells from the histopathological evaluation findings (CD15focus score. From a cell-count greater 62 CD15 Quantifier needs on average 32 seconds less than the

7 CFR 1150.108 - Eligible organization.

Science.gov (United States)

2010-01-01

... 7 Agriculture 9 2010-01-01 2009-01-01 true Eligible organization. 1150.108 Section 1150.108 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Marketing... Order Definitions § 1150.108 Eligible organization. Eligible organization means any organization which...

Accelerated high-frame-rate mouse heart cine-MRI using compressed sensing reconstruction

NARCIS (Netherlands)

Motaal, Abdallah G.; Coolen, Bram F.; Abdurrachim, Desiree; Castro, Rui M.; Prompers, Jeanine J.; Florack, Luc M. J.; Nicolay, Klaas; Strijkers, Gustav J.

2013-01-01

We introduce a new protocol to obtain very high-frame-rate cinematographic (Cine) MRI movies of the beating mouse heart within a reasonable measurement time. The method is based on a self-gated accelerated fast low-angle shot (FLASH) acquisition and compressed sensi ng reconstruction. Key to our

TAZ promotes epithelial to mesenchymal transition via the upregulation of connective tissue growth factor expression in neuroblastoma cells.

Science.gov (United States)

Wang, Qiang; Xu, Zhilin; An, Qun; Jiang, Dapeng; Wang, Long; Liang, Bingxue; Li, Zhaozhu

2015-02-01

Neuroblastoma (NB) is a neuroendocrine cancer that occurs most commonly in infants and young children. The Hippo signaling pathway regulates cell proliferation and apoptosis, and its primary downstream effectors are TAZ and yes‑associated protein 1 (YAP). The effect of TAZ on the metastatic progression of neuroblastoma and the underlying mechanisms involved remain elusive. In the current study, it was determined by western blot analysis that the migratory and invasive properties of SK‑N‑BE(2) human neuroblastoma cells are associated with high expression levels of TAZ. Repressed expression of TAZ in SK‑N‑BE(2) cells was shown to result in a reduction in aggressiveness of the cell line, by Transwell migration and invasion assay. In contrast, overexpression of TAZ in SK‑N‑SH human neuroblastoma cells was shown by Transwell migration and invasion assays, and western blot analysis, to result in epithelial‑mesenchymal transition (EMT) and increased invasiveness. Mechanistically, the overexpression of TAZ was demonstrated to upregulate the expression levels of connective tissue growth factor (CTGF), by western blot analysis and chromatin immunoprecipitation assay, while the knockdown of TAZ downregulated it. Furthermore, TAZ was shown by luciferase assay to induce CTGF expression by modulating the activation of the TGF‑β/Smad3 signaling pathway. In conclusion, the present study is, to the best of our knowledge, the first to demonstrate that the overexpression of TAZ induces EMT, increasing the invasive abilities of neuroblastoma cells. This suggests that TAZ may serve as a potential target in the development of novel therapies for the treatment of neuroblastoma.

FOXO3a is a major target of inactivation by PI3K/AKT signaling in aggressive neuroblastoma

NARCIS (Netherlands)

Santo, Evan E.; Stroeken, Peter; Sluis, Peter V.; Koster, Jan; Versteeg, Rogier; Westerhout, Ellen M.

2013-01-01

Neuroblastoma is a pediatric tumor of the peripheral sympathetic nervous system with a highly variable prognosis. Activation of the phosphoinositide 3-kinase (PI3K)/AKT pathway in neuroblastoma is correlated with poor patient prognosis, but the precise downstream effectors mediating this effect have

The antimicrobial peptide, lactoferricin B, is cytotoxic to neuroblastoma cells in vitro and inhibits xenograft growth in vivo.

Science.gov (United States)

Eliassen, Liv Tone; Berge, Gerd; Leknessund, Arild; Wikman, Mari; Lindin, Inger; Løkke, Cecilie; Ponthan, Frida; Johnsen, John Inge; Sveinbjørnsson, Baldur; Kogner, Per; Flaegstad, Trond; Rekdal, Øystein

2006-08-01

Antimicrobial peptides have been shown to exert cytotoxic activity towards cancer cells through their ability to interact with negatively charged cell membranes. In this study the cytotoxic effect of the antimicrobial peptide, LfcinB was tested in a panel of human neuroblastoma cell lines. LfcinB displayed a selective cytotoxic activity against both MYCN-amplified and non-MYCN-amplified cell lines. Non-transformed fibroblasts were not substantially affected by LfcinB. Treatment of neuroblastoma cells with LfcinB induced rapid destabilization of the cytoplasmic membrane and formation of membrane blebs. Depolarization of the mitochondria membranes and irreversible changes in the mitochondria morphology was also evident. Immuno- and fluorescence-labeled LfcinB revealed that the peptide co-localized with mitochondria. Furthermore, treatment of neuroblastoma cells with LfcinB induced cleavage of caspase-6, -7 and -9 followed by cell death. However, neither addition of the pan-caspase inhibitor, zVAD-fmk, or specific caspase inhibitors could reverse the cytotoxic effect induced by LfcinB. Treatment of established SH-SY-5Y neuroblastoma xenografts with repeated injections of LfcinB resulted in significant tumor growth inhibition. These results revealed a selective destabilizing effect of LfcinB on two important targets in the neuroblastoma cells, the cytoplasmic- and the mitochondria membrane. Copyright (c) 2006 Wiley-Liss, Inc.

Kakaibang Halimuyak: Iba't Ibang Imahe ng Pangangapital sa Balintawak

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Mariah Amour C. Miranda

2015-06-01

Full Text Available Ginagalugad ng sanaysay na ito ang isang pangunahing lugar na nadaraanan mula Norte patungong Maynila—ang Balintawak. Nagsisilbing manibela ng pagsusuri ang kontemporaneong pananaw sa lunan bilang pugad ng mga anyong may magkakasalungat na kahulugan. Binibigyang-pansin ng sanaysay ang iba't ibang imahe ng pagbebenta na matatagpuan sa Balintawak: ang billboard ng kumpanyang Bench na siyang pinakamalaki, ang mismong palengke, at ang mga lakong paninda sa tabing-kalsada. Sa pamamagitan nito, maipapakita ng sanaysay kung paano madadalumat ang Balintawak bilang isang panlipunang texto na sumasalamin sa mga magkakaibang pangangapital sa naturang lunan. This essay explores the space of Balintawak—a focal point of urban travel from northern Luzon to Manila. Using the contemporary view on space as a site of structures with contradictory meanings, the study seeks to understand how various images of market activities in Balintawak create meaningful representations. These images include the gigantic billboard of Bench, the central market itself, and flea markets in the area. The essay shows how Balintawak as a social text serves as a trading center of different forms of capital.

The imaging findings of metastatic neuroblastoma in the craniofacial bone in children

International Nuclear Information System (INIS)

Bian Xin; Wang Zhenchang; Xian Junfang; Li Mei; Yan Fei; Chen Qinghua; Yang Bentao; Chang Qinglin; Tian Qichang; Liu Zhonglin

2009-01-01

Objective: To investigate the characteristic imaging findings of metastatic neuroblastoma in the craniofacial bone in children. Methods: Imaging findings in 12 patients with metastatic neuroblastoma in the craniofacial bone were analyzed retrospectively. Among them, 10 patients undenvent plain CT scan, 6 underwent MRI and 7 underwent whole body single-photon emission computed tomography bone scanning. Results: In the 10 patients with CT images, lytic bone destruction and soft tissue masses were found in 9 eases, in which periosteal reaction was observed in 8 patients with spiculated periosteal reaction in 3 patients. The remaining 1 patient didn't show any abnormalities on CT images but had abnormal findings in bone scanning. Six patients with MR images showed abnormal signal intensity in the bone marrow of the craniofacial bone and adjacent soft tissue masses. Postcontrast T 1 -weighted imaging in 5 patients demonstrated remarkable enhancement of the bone marrow and soft tissue masses. Bone scanning of 7 patients showed abnormal foci of increased radionuclide activity of the craniofacial bone in 7 patients and metastasis at other body parts in 6 patients. Conclusion: The metastatic neuroblastoma in the craniofacial bone has its characteristic imaging findings which are helpful for correct diagnosis. (authors)

Meta-analysis of neuroblastomas reveals a skewed ALK mutation spectrum in tumors with MYCN amplification.

Science.gov (United States)

De Brouwer, Sara; De Preter, Katleen; Kumps, Candy; Zabrocki, Piotr; Porcu, Michaël; Westerhout, Ellen M; Lakeman, Arjan; Vandesompele, Jo; Hoebeeck, Jasmien; Van Maerken, Tom; De Paepe, Anne; Laureys, Geneviève; Schulte, Johannes H; Schramm, Alexander; Van Den Broecke, Caroline; Vermeulen, Joëlle; Van Roy, Nadine; Beiske, Klaus; Renard, Marleen; Noguera, Rosa; Delattre, Olivier; Janoueix-Lerosey, Isabelle; Kogner, Per; Martinsson, Tommy; Nakagawara, Akira; Ohira, Miki; Caron, Huib; Eggert, Angelika; Cools, Jan; Versteeg, Rogier; Speleman, Frank

2010-09-01

Activating mutations of the anaplastic lymphoma kinase (ALK) were recently described in neuroblastoma. We carried out a meta-analysis of 709 neuroblastoma tumors to determine their frequency and mutation spectrum in relation to genomic and clinical parameters, and studied the prognostic significance of ALK copy number and expression. The frequency and type of ALK mutations, copy number gain, and expression were analyzed in a new series of 254 neuroblastoma tumors. Data from 455 published cases were used for further in-depth analysis. ALK mutations were present in 6.9% of 709 investigated tumors, and mutations were found in similar frequencies in favorable [International Neuroblastoma Staging System (INSS) 1, 2, and 4S; 5.7%] and unfavorable (INSS 3 and 4; 7.5%) neuroblastomas (P = 0.087). Two hotspot mutations, at positions R1275 and F1174, were observed (49% and 34.7% of the mutated cases, respectively). Interestingly, the F1174 mutations occurred in a high proportion of MYCN-amplified cases (P = 0.001), and this combined occurrence was associated with a particular poor outcome, suggesting a positive cooperative effect between both aberrations. Furthermore, the F1174L mutant was characterized by a higher degree of autophosphorylation and a more potent transforming capacity as compared with the R1275Q mutant. Chromosome 2p gains, including the ALK locus (91.8%), were associated with a significantly increased ALK expression, which was also correlated with poor survival. ALK mutations occur in equal frequencies across all genomic subtypes, but F1174L mutants are observed in a higher frequency of MYCN-amplified tumors and show increased transforming capacity as compared with the R1275Q mutants.

28 CFR 551.108 - Performance pay.

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2010-07-01

... 28 Judicial Administration 2 2010-07-01 2010-07-01 false Performance pay. 551.108 Section 551.108 Judicial Administration BUREAU OF PRISONS, DEPARTMENT OF JUSTICE INSTITUTIONAL MANAGEMENT MISCELLANEOUS Pretrial Inmates § 551.108 Performance pay. The Warden may approve a pretrial inmate for performance pay...

40 CFR 211.108 - Sample label.

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2010-07-01

... 40 Protection of Environment 24 2010-07-01 2010-07-01 false Sample label. 211.108 Section 211.108 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) NOISE ABATEMENT PROGRAMS PRODUCT NOISE LABELING General Provisions § 211.108 Sample label. Examples of labels conforming to the requirements of...

Comparing oncologic outcomes after minimally invasive and open surgery for pediatric neuroblastoma and Wilms tumor.

Science.gov (United States)

Ezekian, Brian; Englum, Brian R; Gulack, Brian C; Rialon, Kristy L; Kim, Jina; Talbot, Lindsay J; Adibe, Obinna O; Routh, Jonathan C; Tracy, Elisabeth T; Rice, Henry E

2018-01-01

Minimally invasive surgery (MIS) has been widely adopted for common operations in pediatric surgery; however, its role in childhood tumors is limited by concerns about oncologic outcomes. We compared open and MIS approaches for pediatric neuroblastoma and Wilms tumor (WT) using a national database. The National Cancer Data Base from 2010 to 2012 was queried for cases of neuroblastoma and WT in children ≤21 years old. Children were classified as receiving open or MIS surgery for definitive resection, with clinical outcomes compared using a propensity matching methodology (two open:one MIS). For children with neuroblastoma, 17% (98 of 579) underwent MIS, while only 5% of children with WT (35 of 695) had an MIS approach for tumor resection. After propensity matching, there was no difference between open and MIS surgery for either tumor for 30-day mortality, readmissions, surgical margin status, and 1- and 3-year survival. However, in both tumors, open surgery more often evaluated lymph nodes and had larger lymph node harvest. Our retrospective review suggests that the use of MIS appears to be a safe method of oncologic resection for select children with neuroblastoma and WT. Further research should clarify which children are the optimal candidates for this approach. © 2017 Wiley Periodicals, Inc.

Papillary cystadenoma of the epididymis in a 12-year-old survivor of stage IV neuroblastoma

Directory of Open Access Journals (Sweden)

Nnenaya Agochukwu

2018-04-01

Full Text Available Papillary cystadenoma of the epididymis (PCE is the second most common benign neoplasm of the epididymis [1]. It is very uncommon and has never been reported in a prepubertal male. It may occur sporadically, but more often occurs in association with von Hippel- Lindau (VHL disease [2]. There have been over 60 reports of patients with such tumors, with the youngest patient being 16 years old.We present the case of a 12- year old male with a history of stage IV neuroblastoma. He presented with a left paratesticular mass that was discovered on routine follow up physical exam with his pediatric oncologist. He was asymptomatic at the time of presentation with no signs or symptoms of hypoandrogenism. A computed tomography scan of the abdomen and pelvis was negative for lymphadenopathy and additional disease sites. Given the patient's history of stage IV neuroblastoma, there was suspicion of yolk sac tumor or metastases; he underwent an open radical left orchiectomy. Frozen section was consistent with yolk sac tumor, however final pathology revealed normal testicle with PCE.To date, this patient is the youngest reported patient with this diagnosis; furthermore papillary cystadenoma of the epididymis has never been reported in a patient with neuroblastoma. Keywords: Papillary cystadenoma, Epididymis, Prepubertal male, Neuroblastoma

Allelic loss of the short arm of chromosome 4 in neuroblastoma suggests a novel tumour suppressor gene locus

NARCIS (Netherlands)

Caron, H.; van Sluis, P.; Buschman, R.; Pereira do Tanque, R.; Maes, P.; Beks, L.; de Kraker, J.; Voûte, P. A.; Vergnaud, G.; Westerveld, A.; Slater, R.; Versteeg, R.

1996-01-01

Neuroblastoma is a childhood neural crest tumour, genetically characterized by frequent deletions of the short arm of chromosome 1 and amplification of N-myc. Here we report the first evidence for a neuroblastoma tumour suppressor locus on 4pter. Cytogenetically we demonstrated rearrangements of 4p

Can Archival Tissue Reveal Answers to Modern Research Questions?: Computer-Aided Histological Assessment of Neuroblastoma Tumours Collected over 60 Years

Directory of Open Access Journals (Sweden)

Albert Chetcuti

2014-02-01

Full Text Available Despite neuroblastoma being the most common extracranial solid cancer in childhood, it is still a rare disease. Consequently, the unavailability of tissue for research limits the statistical power of studies. Pathology archives are possible sources of rare tissue, which, if proven to remain consistent over time, could prove useful to research of rare disease types. We applied immunohistochemistry to investigate whether long term storage caused any changes to antigens used diagnostically for neuroblastoma. We constructed and quantitatively assessed a tissue microarray containing neuroblastoma archival material dating between 1950 and 2007. A total of 119 neuroblastoma tissue cores were included spanning 6 decades. Fourteen antibodies were screened across the tissue microarray (TMA. These included seven positive neuroblastoma diagnosis markers (NB84, Chromogranin A, NSE, Ki-67, INI1, Neurofilament Protein, Synaptophysin, two anticipated to be negative (S100A, CD99, and five research antibodies (IL-7, IL-7R, JAK1, JAK3, STAT5. The staining of these antibodies was evaluated using Aperio ImageScope software along with novel pattern recognition and quantification algorithms. This analysis demonstrated that marker signal intensity did not decrease over time and that storage for 60 years had little effect on antigenicity. The construction and assessment of this neuroblastoma TMA has demonstrated the feasibility of using archival samples for research.

46 CFR 108.653 - Helicopter facilities.

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2010-10-01

... 46 Shipping 4 2010-10-01 2010-10-01 false Helicopter facilities. 108.653 Section 108.653 Shipping... EQUIPMENT Equipment Markings and Instructions § 108.653 Helicopter facilities. (a) Each helicopter fueling facility must be marked adjacent to the fueling hose storage: “WARNING—HELICOPTER FUELING STATION—KEEP...

46 CFR 108.241 - Visual aids.

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2010-10-01

... 46 Shipping 4 2010-10-01 2010-10-01 false Visual aids. 108.241 Section 108.241 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) A-MOBILE OFFSHORE DRILLING UNITS DESIGN AND EQUIPMENT Construction and Arrangement Helicopter Facilities § 108.241 Visual aids. (a) Each helicopter deck must— (1...

7 CFR 1260.108 - United States.

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2010-01-01

... 7 Agriculture 10 2010-01-01 2010-01-01 false United States. 1260.108 Section 1260.108 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING AGREEMENTS... Promotion and Research Order Definitions § 1260.108 United States. United States means the 50 States and the...

Excessive blinking and ataxia in a child with occult neuroblastoma and voltage-gated potassium channel antibodies.

LENUS (Irish Health Repository)

Allen, Nicholas M

2012-05-01

A previously healthy 9-year-old girl presented with a 10-day history of slowly progressive unsteadiness, slurred speech, and behavior change. On examination there was cerebellar ataxia and dysarthria, excessive blinking, subtle perioral myoclonus, and labile mood. The finding of oligoclonal bands in the cerebrospinal fluid prompted paraneoplastic serological evaluation and search for an occult neural crest tumor. Antineuronal nuclear autoantibody type 1 (anti-Hu) and voltage-gated potassium channel complex antibodies were detected in serum. Metaiodobenzylguanidine scan and computed tomography scan of the abdomen showed a localized abdominal mass in the region of the porta hepatis. A diagnosis of occult neuroblastoma was made. Resection of the stage 1 neuroblastoma and treatment with pulsed corticosteroids resulted in resolution of all symptoms and signs. Excessive blinking has rarely been described with neuroblastoma, and, when it is not an isolated finding, it may be a useful clue to this paraneoplastic syndrome. Although voltage-gated potassium channel complex autoimmunity has not been described previously in the setting of neuroblastoma, it is associated with a spectrum of paraneoplastic neurologic manifestations in adults, including peripheral nerve hyperexcitability disorders.

Implications of surgical intervention in the treatment of neuroblastomas. 20-year experience of a single institution

International Nuclear Information System (INIS)

Tajiri, Tatsuro; Souzaki, Ryota; Kinoshita, Yoshiaki; Koga, Yuhki; Suminoe, Aiko; Hara, Toshiro; Taguchi, Tomoaki

2012-01-01

The implications of surgical intervention for neuroblastomas were assessed in one institution. We analyzed the clinical characteristics and extension of resection in 123 pediatric patients with neuroblastoma diagnosed between 1985 and 2004. The 5-year survival rate of the 82 patients under 12 months of age, 59 of whom were treated with complete resection of the primary tumor, was 97%. The 5-year survival rate of the 41 patients over 12 months of age did not differ significantly according to whether complete (n=19) or incomplete resection (n=22) was performed (46 vs. 38%, respectively). No local recurrence was observed in ten patients over 12 months of age with stage 4 disease who underwent complete resection of the primary tumor; however, four of these ten patients died of metastatic recurrence. Considering that the majority of infantile neuroblastomas in this study had favorable biology, complete resection might be unnecessary for patients under 12 years of age. For advanced neuroblastomas in patients over 12 months of age, the main treatment for metastasis is systemic chemotherapy, although extirpation of the primary tumor without extensive surgery might prevent local recurrence when combined with radiation therapy. (author)

Functional characterization of a new p53 mutant generated by homozygous deletion in a neuroblastoma cell line

International Nuclear Information System (INIS)

Nakamura, Yohko; Ozaki, Toshinori; Niizuma, Hidetaka; Ohira, Miki; Kamijo, Takehiko; Nakagawara, Akira

2007-01-01

p53 is a key modulator of a variety of cellular stresses. In human neuroblastomas, p53 is rarely mutated and aberrantly expressed in cytoplasm. In this study, we have identified a novel p53 mutant lacking its COOH-terminal region in neuroblastoma SK-N-AS cells. p53 accumulated in response to cisplatin (CDDP) and thereby promoting apoptosis in neuroblastoma SH-SY5Y cells bearing wild-type p53, whereas SK-N-AS cells did not undergo apoptosis. We found another p53 (p53ΔC) lacking a part of oligomerization domain and nuclear localization signals in SK-N-AS cells. p53ΔC was expressed largely in cytoplasm and lost the transactivation function. Furthermore, a 3'-part of the p53 locus was homozygously deleted in SK-N-AS cells. Thus, our present findings suggest that p53 plays an important role in the DNA-damage response in certain neuroblastoma cells and it seems to be important to search for p53 mutations outside DNA-binding domain

42 CFR 401.108 - CMS rulings.

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2010-10-01

... 42 Public Health 2 2010-10-01 2010-10-01 false CMS rulings. 401.108 Section 401.108 Public Health... GENERAL ADMINISTRATIVE REQUIREMENTS Confidentiality and Disclosure § 401.108 CMS rulings. (a) After... regulations, but which has been adopted by CMS as having precedent, may be published in the Federal Register...

46 CFR 108.499 - Fire axes.

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2010-10-01

... 46 Shipping 4 2010-10-01 2010-10-01 false Fire axes. 108.499 Section 108.499 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) A-MOBILE OFFSHORE DRILLING UNITS DESIGN AND EQUIPMENT Fire Extinguishing Systems Miscellaneous Firefighting Equipment § 108.499 Fire axes. Each unit must have at least two...

13 CFR 108.100 - Business form.

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2010-01-01

... 13 Business Credit and Assistance 1 2010-01-01 2010-01-01 false Business form. 108.100 Section 108.100 Business Credit and Assistance SMALL BUSINESS ADMINISTRATION NEW MARKETS VENTURE CAPITAL (âNMVCâ) PROGRAM Qualifications for the NMVC Program Organizing A Nmvc Company § 108.100 Business form. A NMVC...

22 CFR 41.108 - Medical examination.

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2010-04-01

... 22 Foreign Relations 1 2010-04-01 2010-04-01 false Medical examination. 41.108 Section 41.108... AND NATIONALITY ACT, AS AMENDED Application for Nonimmigrant Visa § 41.108 Medical examination. (a) Requirements for medical examination. An applicant for a nonimmigrant visa shall be required to take a medical...

46 CFR 108.471 - Water pump.

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2010-10-01

... 46 Shipping 4 2010-10-01 2010-10-01 false Water pump. 108.471 Section 108.471 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) A-MOBILE OFFSHORE DRILLING UNITS DESIGN AND EQUIPMENT Fire Extinguishing Systems Foam Extinguishing Systems § 108.471 Water pump. Each water pump in a foam extinguishing...

12 CFR 347.108 - Portfolio investments.

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2010-01-01

... 12 Banks and Banking 4 2010-01-01 2010-01-01 false Portfolio investments. 347.108 Section 347.108... INTERNATIONAL BANKING § 347.108 Portfolio investments. (a) Portfolio investments. If a bank, directly or indirectly, acquires or holds an equity interest in a foreign organization as a portfolio investment and the...

Ifosfamide in previously untreated disseminated neuroblastoma. Results of Study 3A of the European Neuroblastoma Study Group.

Science.gov (United States)

Kellie, S J; De Kraker, J; Lilleyman, J S; Bowman, A; Pritchard, J

1988-05-01

A prospective study of the effectiveness of ifosfamide as a single agent in the management of previously untreated patients with Evans stage IV neuroblastoma was undertaken. Eighteen children aged more than 1 year were treated with ifosfamide (IFX) 3 g/m2 daily for 2 days immediately after diagnosis and 3 weeks later. Treatment was continued with combination chemotherapy using vincristine, cyclophosphamide, cisplatinum and etoposide (OPEC) or a variant. Mesna (2-mercaptoethane sulphonate) was given to all patients during IFX treatment to prevent urotoxicity. Eight of the 18 patients (44%) responded to IFX. Nine had greater than 66% reduction in baseline tumor volume. Of 15 evaluable patients with raised pre-treatment urinary catecholamine excretion, six (40%) achieved greater than 50% reduction in pretreatment levels. Two of 10 patients evaluable for bone marrow response had complete clearance. Toxicity was mild in all patients. Upon completing 'first line' therapy, only four patients (22%) achieved a good partial remission (GPR) or complete response (CR). Median survival was 11 months. There was a lower rate of attaining GPR and shortened median survival in patients receiving phase II IFX before OPEC or variant, compared to patients with similar pre-treatment characteristics treated with OPEC from diagnosis in an earlier study.

Pathophysiology of NG2-glia:a ‘Chicken and Egg’ scenario of altered neurotransmission and disruption of NG2-glial cell function

OpenAIRE

Rivera, Andrea Domenico; De La Rocha, Irene Chacon; Neville, Rebekah; Butt, Arthur Morgan

2016-01-01

Classically, the central nervous system (CNS) was considered to contain neurons and three main types of glial cells - astrocytes, oligodendrocytes, and microglia. Now, it has been clearly established that NG2-glia are a fourth glial cell type that are defined by their expression of the NG2 chondroitin sulfate proteoglycan (Cspg4). NG2-glia are also known as oligodendrocyte precursor cells (OPCs) and express the alpha receptor for platelet-derived growth factor (Pdgfra) as well as other oligod...

46 CFR 108.486 - Helicopter decks.

Science.gov (United States)

2010-10-01

... 46 Shipping 4 2010-10-01 2010-10-01 false Helicopter decks. 108.486 Section 108.486 Shipping COAST... Fire Extinguishing Systems Fire Protection for Helicopter Facilities § 108.486 Helicopter decks. At least two of the accesses to the helicopter landing deck must each have a fire hydrant on the unit's...

46 CFR 108.143 - Accommodation space.

Science.gov (United States)

2010-10-01

... 46 Shipping 4 2010-10-01 2010-10-01 false Accommodation space. 108.143 Section 108.143 Shipping... EQUIPMENT Construction and Arrangement Structural Fire Protection § 108.143 Accommodation space. (a) Each corridor bulkhead in an accommodation space must be an A class or B class bulkhead except if an A class...

46 CFR 108.601 - Crane design.

Science.gov (United States)

2010-10-01

... 46 Shipping 4 2010-10-01 2010-10-01 false Crane design. 108.601 Section 108.601 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) A-MOBILE OFFSHORE DRILLING UNITS DESIGN AND EQUIPMENT Cranes Cranes § 108.601 Crane design. (a) Each crane and crane foundation on a unit must be designed in...

46 CFR 108.213 - Heating requirements.

Science.gov (United States)

2010-10-01

... 46 Shipping 4 2010-10-01 2010-10-01 false Heating requirements. 108.213 Section 108.213 Shipping... EQUIPMENT Construction and Arrangement Accommodation Spaces § 108.213 Heating requirements. (a) Each accommodation space must be heated by a heating system that can maintain at least 20°C. (68°F.). (b) Radiators...

46 CFR 108.221 - Storm rails.

Science.gov (United States)

2010-10-01

... 46 Shipping 4 2010-10-01 2010-10-01 false Storm rails. 108.221 Section 108.221 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) A-MOBILE OFFSHORE DRILLING UNITS DESIGN AND EQUIPMENT Construction and Arrangement Rails § 108.221 Storm rails. Each unit must have a storm rail in the following...

40 CFR 94.108 - Test fuels.

Science.gov (United States)

2010-07-01

... 40 Protection of Environment 20 2010-07-01 2010-07-01 false Test fuels. 94.108 Section 94.108... EMISSIONS FROM MARINE COMPRESSION-IGNITION ENGINES Test Procedures § 94.108 Test fuels. (a) Distillate diesel test fuel. (1) The diesel fuels for testing Category 1 and Category 2 marine engines designed to...

Comparison of radionuclide bone scan with radiographic skeletal survey in detecting metastases in neuroblastoma

Energy Technology Data Exchange (ETDEWEB)

Tani, G.; Lucchi, A.; Pisi, P.; Boriani, F.; De Florio, L.; Turba, E.; Mancini, A.F.; Marchi, N.; Rossi, M.

1987-10-01

Neuroblastoma (NBL) with bone metastasis is in its IV (fourth) stage of development. In this study we discuss the radiological and scintigraphic data of 25 patients with neuroblastoma in the IV stage at diagnosis. All the patients had undergone a radiological examination of the whole skeleton and a bone scintigraphy. The aim of this work is to compare the sensitivity of the two methods. The authors conclude that both the examinations are important and complementary to define the IV stage of the disease to avoid underevaluations.

Influence of image-defined risk factors on the outcome of patients with localised neuroblastoma. A report from the LNESG1 study of the European International Society of Paediatric Oncology Neuroblastoma Group.

Science.gov (United States)

Monclair, Tom; Mosseri, Véronique; Cecchetto, Giovanni; De Bernardi, Bruno; Michon, Jean; Holmes, Keith

2015-09-01

The European multicenter study LNESG1 was designed to evaluate the safety and efficacy of surgical treatment alone in patients with localised neuroblastoma. In a retrospective, observational study we examined the impact of image-defined risk factors (IDRF) on operative complications and survival (EFS and OS). 534 patients with localised, non-MYCN amplified neuroblastoma were recruited between 1995 and 1999. Group 1 consisted of 291 patients without IDRF (Stage L1 in the International Neuroblastoma Risk Group (INRG) staging system), all treated with primary surgery. Group 2: 118 patients with IDRF (INRG Stage L2), also treated with primary surgery. Group 3: 125 patients in whom primary surgery was not attempted, 106 receiving neo-adjuvant chemotherapy. In L1 patients (Group 1) 5-year EFS was 92% and OS 98%. In L2 patients (Group 2 and 3) EFS was 79% and OS 89%. The differences in both EFS and OS were significant. EFS and OS in Group 2 (86% and 95%) were significantly better than 73% and 83% in Group 3. In INSS stage 1, 2 and 3, EFS were respectively 94%, 81% and 76%. Except between stage 2 and 3 the differences were significant. OS were respectively 99%, 93% and 83%, all significantly different. The 17% operative complication rate in L2 patients was significantly higher than 5% in L1 patients. In localised neuroblastoma, IDRF at diagnosis are associated with worse survival rates and higher rates of operative complications. The impact of IDRF should become an integrated part of therapy planning. © 2015 Wiley Periodicals, Inc.

46 CFR 108.467 - Water supply.

Science.gov (United States)

2010-10-01

... 46 Shipping 4 2010-10-01 2010-10-01 false Water supply. 108.467 Section 108.467 Shipping COAST... Fire Extinguishing Systems Foam Extinguishing Systems § 108.467 Water supply. The water supply of a foam extinguishing system must not be the water supply of the fire main system on the unit unless when...

Allelic variants of CAMTA1 and FLJ10737 within a commonly deleted region at 1p36 in neuroblastoma

DEFF Research Database (Denmark)

Henrich, Kai-Oliver; Claas, Andreas; Praml, Christian

2007-01-01

Deletion of a distal portion of 1p is seen in a wide range of human malignancies, including neuroblastoma. Here, a 1p36.3 commonly deleted region of 216 kb has been defined encompassing two genes, CAMTA1 and FLJ10737. Low expression of CAMTA1 has been recently shown to be an independent predictor...... of poor outcome in neuroblastoma patients. The present study surveys CAMTA1 and FLJ10737 for genetic alterations by fluorescence-based single strand conformation polymorphism (SSCP) using a panel of DNAs from 88 neuroblastomas, their matching blood samples and 97 unaffected individuals. Nucleotide...... variants encoding amino acid substitutions were found in both genes. One CAMTA1 variant (T1336I) was not detected in 97 unaffected individuals, another (N1177K) resides in a conserved domain of the CAMTA1 protein and was found hemizygous in six neuroblastomas. We found no evidence for somatic mutations...

Role of Radio-Iodinated Meta-Iodo Benzyl Guanidine in Assessment of Children with Neuroblastoma NEMROCK

International Nuclear Information System (INIS)

Abd El-Aal, H.

2006-01-01

Background: For more than ten years. M] BG has been successfully used in diagnosis and staging of children with neuroblastoma [1]. Aim of the Study: Identify the role of 131 I MIBG in the assessment of neuroblastoma and correlate its findings with other non-invasive tests. Patients and Methods: Twenty eight patients with. neuroblastoma attending the Pediatric Oncology Unit, Kasr EI-Aini Center of Radiation Oncology and Nuclear Medicine (NEMROCK), Cairo University, over a period of 5 years (2002-2006) were assessed by MlBG scanning. The age of patients ranged from 40 days to 12 years with a mean of 4.7years ± 1.1. They were 16 boys and 12 girls with a M:F ratio of J :3, none was stage I and II, 7 patients (25%) were stage III and 21 patients (75%) were stage IV (Evan's staging system). Clinically, 24 patients (85.7%) presented with an abdominal mass, and 3 patients (10.7%) with a mediastinal mass. Metastases were present in the bone marrow in II children (39.3%), lymph nodes in 5 (17.9%), CNS in 4 (14.3%), liver in 2 (7.1 %), soft tissues in 3 (10.7%), lungs and pleura in I (3.6%), brain in I (3.6%), and testis in I patient (3.8%). Results: 131 I M IBG could accurately diagnose local and distant neuroblastoma lesions in 23 patients with a sensitivity of 82.2%. High levels of VMA correlated with no cardiac uptake in the first 24 hours in 7/8 patients with a sensitivity of 87.5%. On the other hand, low VMA levels were associated with cardiac uptake of 131 I MIBG in 3/4 patients with a specificity of 75%, a PPV of 88% and NPV of 86.7%. 131 I MlBG scintigraphy and bone marrow aspiration agreed on detecting neuroblastoma lesions in 24/28 patients (85.7%) p 131 I MIBG scintigraphy, in a dose of 2 mci can be used with 87.5% accuracy in the diagnosis and follow-up of Children with neuroblastoma

IL-6 and mouse oocyte spindle.

Directory of Open Access Journals (Sweden)

Jashoman Banerjee

Full Text Available Interleukin 6 (IL-6 is considered a major indicator of the acute-phase inflammatory response. Endometriosis and pelvic inflammation, diseases that manifest elevated levels of IL-6, are commonly associated with higher infertility. However, the mechanistic link between elevated levels of IL-6 and poor oocyte quality is still unclear. In this work, we explored the direct role of this cytokine as a possible mediator for impaired oocyte spindle and chromosomal structure, which is a critical hurdle in the management of infertility. Metaphase-II mouse oocytes were exposed to recombinant mouse IL-6 (50, 100 and 200 ng/mL for 30 minutes and subjected to indirect immunofluorescent staining to identify alterations in the microtubule and chromosomal alignment compared to untreated controls. The deterioration in microtubule and chromosomal alignment were evaluated utilizing both fluorescence and confocal microscopy, and were quantitated with a previously reported scoring system. Our results showed that IL-6 caused a dose-dependent deterioration in microtubule and chromosomal alignment in the treated oocytes as compared to the untreated group. Indeed, IL-6 at a concentration as low as 50 ng/mL caused deterioration in the spindle structure in 60% of the oocytes, which increased significantly (P<0.0001 as IL-6 concentration was increased. In conclusion, elevated levels of IL-6 associated with endometriosis and pelvic inflammation may reduce the fertilizing capacity of human oocyte through a mechanism that involves impairment of the microtubule and chromosomal structure.

Improved outcome of 131I-mIBG treatment through combination with external beam radiotherapy in the SK-N-SH mouse model of neuroblastoma.

Science.gov (United States)

Corroyer-Dulmont, Aurélien; Falzone, Nadia; Kersemans, Veerle; Thompson, James; Allen, Danny P; Able, Sarah; Kartsonaki, Christiana; Malcolm, Javian; Kinchesh, Paul; Hill, Mark A; Vojnovic, Boris; Smart, Sean C; Gaze, Mark N; Vallis, Katherine A

2017-09-01

To assess the efficacy of different schedules for combining external beam radiotherapy (EBRT) with molecular radiotherapy (MRT) using 131 I-mIBG in the management of neuroblastoma. BALB/c nu/nu mice bearing SK-N-SH neuroblastoma xenografts were assigned to five treatment groups: 131 I-mIBG 24h after EBRT, EBRT 6days after 131 I-mIBG, EBRT alone, 131 I-mIBG alone and control (untreated). A total of 56 mice were assigned to 3 studies. Study 1: Vessel permeability was evaluated using dynamic contrast-enhanced (DCE)-MRI (n=3). Study 2: Tumour uptake of 131 I-mIBG in excised lesions was evaluated by γ-counting and autoradiography (n=28). Study 3: Tumour volume was assessed by longitudinal MR imaging and survival was analysed (n=25). Tumour dosimetry was performed using Monte Carlo simulations of absorbed fractions with the radiation transport code PENELOPE. Given alone, both 131 I-mIBG and EBRT resulted in a seven-day delay in tumour regrowth. Following EBRT, vessel permeability was evaluated by DCE-MRI and showed an increase at 24h post irradiation that correlated with an increase in 131 I-mIBG tumour uptake, absorbed dose and overall survival in the case of combined treatment. Similarly, EBRT administered seven days after MRT to coincide with tumour regrowth, significantly decreased the tumour volume and increased overall survival. This study demonstrates that combining EBRT and MRT has an enhanced therapeutic effect and emphasizes the importance of treatment scheduling according to pathophysiological criteria such as tumour vessel permeability and tumour growth kinetics. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Ligands for the peroxisome proliferator-activated receptor-γ have inhibitory effects on growth of human neuroblastoma cells in vitro

International Nuclear Information System (INIS)

Valentiner, Ursula; Carlsson, Margarita; Erttmann, Rudolf; Hildebrandt, Herbert; Schumacher, Udo

2005-01-01

The thiazolidinedione (TZD) or glitazone class of peroxisome proliferator-activated-γ (PPAR-γ) ligands not only induce adipocyte differentiation and increase insulin sensitivity, but also exert growth inhibitory effects on several carcinoma cell lines in vitro as well as in vivo. In the current study the in vitro effect of four PPAR-γ agonists (ciglitazone, pioglitazone, troglitazone, rosiglitazone) on the cell growth of seven human neuroblastoma cell lines (Kelly, LAN-1, LAN-5, LS, IMR-32, SK-N-SH, SH-SY5Y) was investigated. Growth rates were assessed by a colorimetric XTT-based assay kit. Expression of PPAR-γ protein was examined by immunohistochemistry and Western blot analysis. All glitazones inhibited in vitro growth and viability of the human neuroblastoma cell lines in a dose-dependent manner showing considerable effects only at high concentrations (10 μM and 100 μM). Effectiveness of the glitazones on neuroblastoma cell growth differed depending on the cell line and the agent. The presence of PPAR-γ protein was demonstrated in all cell lines. Our findings indicate that ligands for PPAR-γ may be useful therapeutic agents for the treatment of neuroblastoma. Thus the effect of glitazones on the growth of neuroblastoma should now be investigated in an in vivo animal model

Comparison of radionuclide bone scan with radiographic skeletal survey in detecting metastases in neuroblastoma

International Nuclear Information System (INIS)

Tani, G.; Lucchi, A.; Pisi, P.; Boriani, F.; De Florio, L.; Turba, E.; Mancini, A.F.; Marchi, N.; Rossi, M.

1987-01-01

Neuroblastoma (NBL) with bone metastasis is in its IV (fourth) stage of development. In this study we discuss the radiological and scintigraphic data of 25 patients with neuroblastoma in the IV stage at diagnosis. All the patients had undergone a radiological examination of the whole skeleton and a bone scintigraphy. The aim of this work is to compare the sensitivity of the two methods. The authors conclude that both the examinations are important and complementary to define the IV stage of the disease to avoid underevaluations. (orig.) [de

Understanding the NG2 glial scar after spinal cord injury

Directory of Open Access Journals (Sweden)

Amber R Hackett

2016-11-01

Full Text Available NG2 cells, also known as oligodendrocyte progenitor cells, are located throughout the central nervous system and serve as a pool of progenitors to differentiate into oligodendrocytes. In response to spinal cord injury, NG2 cells increase their proliferation and differentiation into remyelinating oligodendrocytes. While astrocytes are typically associated with being the major cell type in the glial scar, many NG2 cells also accumulate within the glial scar but their function remains poorly understood. Similar to astrocytes, these cells hypertrophy, upregulate expression of chondroitin sulfate proteoglycans, inhibit axon regeneration, contribute to the glial-fibrotic scar border, and some even differentiate into astrocytes. Whether NG2 cells also have a role in other astrocyte functions, such as preventing the spread of infiltrating leukocytes and expression of inflammatory cytokines, is not yet known. Thus, NG2 cells are not only important for remyelination after spinal cord injury, but are also a major component of the glial scar with functions that overlap with astrocytes in this region. In this review, we describe the signaling pathways important for the proliferation and differentiation of NG2 cells, as well as the role of NG2 cells in scar formation and tissue repair.

Topotecan-Vincristine-Doxorubicin in Stage 4 High-Risk Neuroblastoma Patients Failing to Achieve a Complete Metastatic Response to Rapid COJEC: A SIOPEN Study.

Science.gov (United States)

Amoroso, Loredana; Erminio, Giovanni; Makin, Guy; Pearson, Andrew D J; Brock, Penelope; Valteau-Couanet, Dominique; Castel, Victoria; Pasquet, Marlène; Laureys, Genevieve; Thomas, Caroline; Luksch, Roberto; Ladenstein, Ruth; Haupt, Riccardo; Garaventa, Alberto

2018-01-01

Metastatic response to induction therapy for high-risk neuroblastoma is a prognostic factor. In the International Society of Paediatric Oncology Europe Neuroblastoma (SIOPEN) HR-NBL-1 protocol, only patients with metastatic complete response (CR) or partial response (PR) with ≤ three abnormal skeletal areas on iodine 123-metaiodobenzylguanidine ([ 123 I]mIBG) scintigraphy and no bone marrow disease proceed to high dose therapy (HDT). In this study, topotecan-vincristine-doxorubicin (TVD) was evaluated in patients failing to achieve these criteria, with the aim of improving the metastatic response rate. Patients with metastatic high-risk neuroblastoma who had not achieved the SIOPEN criteria for HDT after induction received two courses of topotecan 1.5 mg/m 2 /day for 5 days, followed by a 48-hour infusion of vincristine, 2 mg/m 2 , and doxorubicin, 45 mg/m 2 . Sixty-three patients were eligible and evaluable. Following two courses of TVD, four (6.4%) patients had an overall CR, while 28 (44.4%) had a PR with a combined response rate of 50.8% (95% confidence interval [CI], 37.9 to 63.6). Of these, 23 patients achieved a metastatic CR or a PR with ≤ 3 mIBG skeletal areas and no bone marrow disease (36.5%; 95% CI, 24.7 to 49.6) and were eligible to receive HDT. Toxicity was mostly haematological, affecting 106 of the 126 courses (84.1%; 95% CI, 76.5 to 90.0), and dose reduction was necessary in six patients. Stomatitis was the second most common nonhematological toxicity, occurring in 20 patients (31.7%). TVD was effective in improving the response rate of high-risk neuroblastoma patients after induction with COJEC enabling them to proceed to HDT. However, the long-term benefits of TVD needs to be determined in randomized clinical trials.

Radical prostatectomy outcome when performed with PSA above 20 ng/ml.

LENUS (Irish Health Repository)

Connolly, S S

2012-02-01

Many centres currently do not offer radical prostatectomy (RP) to men with high-risk localised prostate cancer due to concerns regarding poor outcome, despite evidence to the contrary. We identified 18 men undergoing RP with serum PSA >20 ng\\/ml (high-risk by National Comprehensive Cancer Network definition) and minimum follow-up of 12 years (mean 13.5). Mean preoperative PSA was 37.0 ng\\/ml (Range 21.1-94.0). Prostatectomy pathology reported extracapsular disease in 16 (88.9%), positive surgical margins in 15 (83%) and positive pelvic lymph nodes in 5 (27.8%). Overall and cancer-specific survival at 5 and 10-years was 83.3%, 88.2%, 72% and 76.5% respectively. With complete follow-up 11 (61.1%) are alive, and 5 (27.8%) avoided any adjuvant therapy. Complete continence (defined as no involuntary urine leakage and no use of pads) was achieved in 60%, with partial continence in the remainder. We conclude that surgery for this aggressive variant of localised prostate cancer can result in satisfactory outcome.

Alteration of myocardial metaiodobenzylguanidine uptake after treatment of phaeochromocytoma and neuroblastoma

Energy Technology Data Exchange (ETDEWEB)

Suga, Kazuyoshi; Ogasawara, Nobuhiko; Ariga, Misako; Motoyama, Kazumi; Hara, Akiko; Kume, Norihiko; Matsunaga, Naofumi [Department of Radiology, Yamaguchi University School of Medicine, Ube, Yamaguchi (Japan)

2000-05-01

The relationships between changes in myocardial uptake of metaiodobenzylguanidine (MIBG) and those in circulating catecholamines and cardiac function after treatment of phaeochromocytoma and neuroblastoma were evaluated. Iodine-123 or iodine-131 MIBG scintigraphy was performed before and after surgical resection and/or chemotherapy for primary tumours in nine patients with phaeochromocytoma and 13 patients with neuroblastoma. Changes in myocardial MIBG uptake after treatment were estimated by the heart-to-upper mediastinum (H/M) uptake ratios on the images obtained 24 h after MIBG injection, which were compared with serum levels of noradrenaline (NA) and adrenaline (A). Cardiac function was assessed by echocardiography, with measurements of the left ventricular ejection fraction (LVEF). Before treatment, eight patients with phaeochromocytoma and three with neuroblastoma showed poor myocardial MIBG uptake, with highly elevated circulating NA and A. Echocardiography, however, did not show cardiac dysfunction in these patients with the exception of two patients with phaeochromocytoma. With normalization of NA and A levels after treatment, all of these patients except for the two with persistent cardiac dysfunction showed restoration of myocardial MIBG uptake. The H/M ratios increased significantly after treatment in both patient groups, i.e. with phaeochromocytoma and with neuroblastoma (P<0.0001 and P<0.05, respectively), and these ratios correlated inversely with circulating NA and A before and after treatment. By contrast, there was no significant correlation between H/M ratios and LVEF in these two groups. These results indicate that suppression of myocardial MIBG uptake usually may not be related to cardiac dysfunction and may be reversible following normalization of excess catecholamine levels after treatment in patients with neuroadrenergic tumours. However, the suppression may persist in the presence of catecholamine-induced cardiac dysfunction. The assessment

Chromosomal Localization of DNA Amplifications in Neuroblastoma Tumors Using cDNA Microarray Comparative Genomic Hybridization

Directory of Open Access Journals (Sweden)

Ben Beheshti

2003-01-01

Full Text Available Conventional comparative genomic hybridization (CGH profiling of neuroblastomas has identified many genomic aberrations, although the limited resolution has precluded a precise localization of sequences of interest within amplicons. To map high copy number genomic gains in clinically matched stage IV neuroblastomas, CGH analysis using a 19,200-feature cDNA microarray was used. A dedicated (freely available algorithm was developed for rapid in silico determination of chromosomal localizations of microarray cDNA targets, and for generation of an ideogram-type profile of copy number changes. Using these methodologies, novel gene amplifications undetectable by chromosome CGH were identified, and larger MYCN amplicon sizes (in one tumor up to 6 Mb than those previously reported in neuroblastoma were identified. The genes HPCAL1, LPIN1/KIAA0188, NAG, and NSE1/LOC151354 were found to be coamplified with MYCN. To determine whether stage IV primary tumors could be further subclassified based on their genomic copy number profiles, hierarchical clustering was performed. Cluster analysis of microarray CGH data identified three groups: 1 no amplifications evident, 2 a small MYCN amplicon as the only detectable imbalance, and 3 a large MYCN amplicon with additional gene amplifications. Application of CGH to cDNA microarray targets will help to determine both the variation of amplicon size and help better define amplification-dependent and independent pathways of progression in neuroblastoma.

15-Deoxy-Δ12,14-Prostaglandin J2 regulates leukemia inhibitory factor signaling through JAK-STAT pathway in mouse embryonic stem cells

International Nuclear Information System (INIS)

Rajasingh, Johnson; Bright, John J.

2006-01-01

Embryonic stem (ES) cells are genetically normal, pluripotent cells, capable of self-renewal and differentiation into all cell lineages. While leukemia inhibitory factor (LIF) maintains pluripotency in mouse ES cells, retinoic acid and other nuclear hormones induce neuro-glial differentiation in mouse and human ES cells in culture. Peroxisome-proliferator-activated receptors (PPARs) are ligand-dependent nuclear receptor transcription factors that regulate cell growth and differentiation in many cell types. However, the role of PPARs in the regulation of ES cell growth and differentiation is not known. In this study, we show that LIF induces proliferation and self-renewal of mouse D3-ES cells in culture. However, treatment with 15-Deoxy-Δ 12,14 -Prostaglandin J 2 (15d-PGJ2), a natural ligand for PPARγ, or all-trans retinoic acid (ATRA) results in a dose-dependent decrease in proliferation and self-renewal in D3-ES cells. Immunoprecipitation and Western blot analyses showed that LIF induces tyrosine phosphorylation of JAK1, TYK2 and STAT3 in 30 min and treatment with 15d-PGJ2 or ATRA results in a dose-dependent decrease in LIF-induced phosphorylation of JAK1 and STAT3 in D3-ES cells. However, treatment of D3-ES cells with Ciglitazone or 15d-PGJ2 for 48 h in culture resulted in a dose-dependent increase in PPARγ protein expression. These results suggest that PPARγ agonists regulate LIF signaling through JAK-STAT pathway leading to growth and self-renewal of ES cells

Downregulation of survivin by siRNA inhibits invasion and promotes apoptosis in neuroblastoma SH-SY5Y cells

Energy Technology Data Exchange (ETDEWEB)

Zhang, L.; Liang, H. [Department of Pediatrics, Qilu Hospital, Shandong University, Jinan (China); Cao, W. [Department of Obstetrics, Qingdao Central Hospital, Qingdao (China); Xu, R.; Ju, X.L. [Department of Pediatrics, Qilu Hospital, Shandong University, Jinan (China)

2014-05-23

Neuroblastoma is a solid tumor that occurs mainly in children. Malignant neuroblastomas have a poor prognosis because conventional chemotherapeutic agents are not very effective. Survivin, a member of the inhibitor of the apoptosis protein family, plays a significant role in cell division, inhibition of apoptosis, and promotion of cell proliferation and invasion. Previous studies found that survivin is highly expressed in some malignant neuroblastomas and is correlated with poor prognosis. The aim of this study was to investigate whether survivin could serve as a potential therapeutic target of human neuroblastoma. We employed RNA interference to reduce survivin expression in the human neuroblastoma SH-SY5Y cell line and analyzed the effect of RNA interference on cell proliferation and invasion in vitro and in vivo. RNA interference of survivin led to a significant decrease in invasiveness and proliferation and increased apoptosis in SH-SY5Y cells in vitro. RNA interference of survivin inhibited tumor growth in vivo by 68±13% (P=0.002) and increased the number of apoptotic cells by 9.8±1.2% (P=0.001) compared with negative small interfering RNA (siRNA) treatment controls. Moreover, RNA interference of survivin inhibited the formation of lung metastases by 92% (P=0.002) and reduced microvascular density by 60% (P=0.0003). Survivin siRNA resulted in significant downregulation of survivin mRNA and protein expression both in vitro and in vivo compared with negative siRNA treatment controls. RNA interference of survivin was found to be a potent inhibitor of SH-SY5Y tumor growth and metastasis formation. These results support further clinical development of RNA interference of survivin as a treatment of neuroblastoma and other cancer types.

Likelihood of Bone Recurrence in Prior Sites of Metastasis in Patients With High-Risk Neuroblastoma

Energy Technology Data Exchange (ETDEWEB)

Polishchuk, Alexei L. [Department of Radiation Oncology, University of California at San Francisco School of Medicine and UCSF Benioff Children' s Hospital, San Francisco, California (United States); Li, Richard [Division of Radiation Oncology, Dana Farber/Boston Children' s Cancer and Blood Disorders Center, Brigham and Women' s Hospital, Harvard Medical School, Boston, Massachusetts (United States); Hill-Kayser, Christine [Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania (United States); Little, Anthony [Division of Oncology, Children' s Hospital of Philadelphia, Philadelphia, Pennsylvania (United States); Hawkins, Randall A. [Department of Radiology, University of California at San Francisco School of Medicine and UCSF Benioff Children' s Hospital, San Francisco, California (United States); Hamilton, Jeffrey; Lau, Michael [Department of Radiation Oncology, University of California at San Francisco School of Medicine and UCSF Benioff Children' s Hospital, San Francisco, California (United States); Tran, Hung Chi [Division of Hematology/Oncology, Children' s Hospital of Los Angeles, Los Angeles, California (United States); Strahlendorf, Caron [Division of Hematology and Oncology, Department of Pediatrics, The University of British Columbia, Vancouver, British Columbia (Canada); Lemons, Richard S. [Division of Pediatric Hematology/Oncology, University of Utah School of Medicine, Salt Lake City, Utah (United States); Weinberg, Vivian [Department of Radiation Oncology, University of California at San Francisco School of Medicine and UCSF Benioff Children' s Hospital, San Francisco, California (United States); Matthay, Katherine K.; DuBois, Steven G. [Department of Pediatrics, University of California at San Francisco School of Medicine and UCSF Benioff Children' s Hospital, San Francisco, California (United States); and others

2014-07-15

Purpose/Objectives: Despite recent improvements in outcomes, 40% of children with high-risk neuroblastoma will experience relapse, facing a guarded prognosis for long-term cure. Whether recurrences are at new sites or sites of original disease may guide decision making during initial therapy. Methods and Materials: Eligible patients were retrospectively identified from institutional databases at first metastatic relapse of high-risk neuroblastoma. Included patients had disease involving metaiodobenzylguanidine (MIBG)-avid metastatic sites at diagnosis and first relapse, achieved a complete or partial response with no more than one residual MIBG-avid site before first relapse, and received no total body irradiation or therapy with {sup 131}I-MIBG before first relapse. Anatomically defined metastatic sites were tracked from diagnosis through first relapse to determine tendency of disease to recur at previously involved versus uninvolved sites and to assess whether this pattern was influenced by site irradiation. Results: Of 159 MIBG-avid metastatic sites identified among 43 patients at first relapse, 131 (82.4%) overlapped anatomically with the set of 525 sites present at diagnosis. This distribution was similar for bone sites, but patterns of relapse were more varied for the smaller subset of soft tissue metastases. Among all metastatic sites at diagnosis in our subsequently relapsed patient cohort, only 3 of 19 irradiated sites (15.8%) recurred as compared with 128 of 506 (25.3%) unirradiated sites. Conclusions: Metastatic bone relapse in neuroblastoma usually occurs at anatomic sites of previous disease. Metastatic sites identified at diagnosis that did not receive radiation during frontline therapy appeared to have a higher risk of involvement at first relapse relative to previously irradiated metastatic sites. These observations support the current paradigm of irradiating metastases that persist after induction chemotherapy in high-risk patients. Furthermore

Retinoic acid reduces human neuroblastoma cell migration and invasiveness: effects on DCX, LIS1, neurofilaments-68 and vimentin expression

International Nuclear Information System (INIS)

Messi, Elio; Florian, Maria C; Caccia, Claudio; Zanisi, Mariarosa; Maggi, Roberto

2008-01-01

Neuroblastoma is a severe pediatric tumor, histologically characterised by a variety of cellular phenotypes. One of the pharmacological approaches to neuroblastoma is the treatment with retinoic acid. The mechanism of action of retinoic acid is still unclear, and the development of resistance to this differentiating agent is a great therapy problem. Doublecortin, a microtubule-associated protein involved in neuronal migration, has recently been proposed as a molecular marker for the detection of minimal residual disease in human neuroblastoma. Nevertheless, no information is available on the expression of doublecortin in the different cell-types composing human neuroblastoma, its correlation with neuroblastoma cell motility and invasiveness, and the possible modulations exerted by retinoic acid treatment. We analysed by immunofluorescence and by Western blot analysis the presence of doublecortin, lissencephaly-1 (another protein involved in neuronal migration) and of two intermediate filaments proteins, vimentin and neurofilament-68, in SK-N-SH human neuroblastoma cell line both in control conditions and under retinoic acid treatment. Migration and cell invasiveness studies were performed by wound scratch test and a modified microchemotaxis assay, respectively. Doublecortin is expressed in two cell subtypes considered to be the more aggressive and that show high migration capability and invasiveness. Vimentin expression is excluded by these cells, while lissencephaly-1 and neurofilaments-68 are immunodetected in all the cell subtypes of the SK-N-SH cell line. Treatment with retinoic acid reduces cell migration and invasiveness, down regulates doublecortin and lissencephaly-1 expression and up regulates neurofilament-68 expression. However, some cells that escape from retinoic acid action maintain migration capability and invasiveness and express doublecortin. a) Doublecortin is expressed in human neuroblastoma cells that show high motility and invasiveness; b

The International Neuroblastoma Risk Group (INRG) staging system: an INRG Task Force report.

Science.gov (United States)

Monclair, Tom; Brodeur, Garrett M; Ambros, Peter F; Brisse, Hervé J; Cecchetto, Giovanni; Holmes, Keith; Kaneko, Michio; London, Wendy B; Matthay, Katherine K; Nuchtern, Jed G; von Schweinitz, Dietrich; Simon, Thorsten; Cohn, Susan L; Pearson, Andrew D J

2009-01-10

The International Neuroblastoma Risk Group (INRG) classification system was developed to establish a consensus approach for pretreatment risk stratification. Because the International Neuroblastoma Staging System (INSS) is a postsurgical staging system, a new clinical staging system was required for the INRG pretreatment risk classification system. To stage patients before any treatment, the INRG Task Force, consisting of neuroblastoma experts from Australia/New Zealand, China, Europe, Japan, and North America, developed a new INRG staging system (INRGSS) based on clinical criteria and image-defined risk factors (IDRFs). To investigate the impact of IDRFs on outcome, survival analyses were performed on 661 European patients with INSS stages 1, 2, or 3 disease for whom IDRFs were known. In the INGRSS, locoregional tumors are staged L1 or L2 based on the absence or presence of one or more of 20 IDRFs, respectively. Metastatic tumors are defined as stage M, except for stage MS, in which metastases are confined to the skin, liver, and/or bone marrow in children younger than 18 months of age. Within the 661-patient cohort, IDRFs were present (ie, stage L2) in 21% of patients with stage 1, 45% of patients with stage 2, and 94% of patients with stage 3 disease. Patients with INRGSS stage L2 disease had significantly lower 5-year event-free survival than those with INRGSS stage L1 disease (78% +/- 4% v 90% +/- 3%; P = .0010). Use of the new staging (INRGSS) and risk classification (INRG) of neuroblastoma will greatly facilitate the comparison of risk-based clinical trials conducted in different regions of the world.

Hypertension complicating {sup 131}I-meta-iodobenzylguanidine therapy for neuroblastoma

Energy Technology Data Exchange (ETDEWEB)

Kosmin, Michael A.; Cork, Nicholas J.; Gaze, Mark N. [University College London Hospitals NHS Foundation Trust, Department of Oncology, London (United Kingdom); Bomanji, Jamshed B. [University College London Hospitals NHS Foundation Trust, Department of Nuclear Medicine, London (United Kingdom); Shankar, Ananth [University College London Hospitals NHS Foundation Trust, Department of Paediatric Oncology, London (United Kingdom)

2012-04-15

Radiolabelled meta-iodobenzylguanidine (mIBG), used as targeted therapy for neuroblastoma, is known to have effects on blood pressure (BP). In this study we audited BP changes in patients receiving {sup 131}I-mIBG therapy for neuroblastoma to identify BP-related adverse events (AE) and possible predictive factors. Between 2003 and 2010, 50 patients with neuroblastoma received 110 {sup 131}I-mIBG administrations. BP measurements before and after administration were compared with age- and sex-matched centile values. AE were analysed, and possible predisposing factors identified. This population had a baseline BP distribution higher than that of their age- and sex-matched peers, with 16% of preadministration systolic BP values above the 95th centile. Changes in BP after administration showed an approximately normal distribution with similar numbers of reduced and increased values. Four AE, all related to hypertension, occurred with one patient having generalized seizures. One AE was immediate, others occurred between 20 and 25 h after administration. No significant association between AE and patient age or sex was demonstrated. However, a significant association between AE and high preadministration BP was shown, both above the 90th centile (p = 0.0022) and above the 95th centile (p = 0.0135). Clinically relevant hypertension following {sup 131}I-mIBG therapy affected less than 5% of administrations, but was more common in those patients with preexisting hypertension. As hypertensive episodes may occur many hours after treatment, close monitoring of BP needs to be continued for at least 48 h after administration of {sup 131}I-mIBG. (orig.)

Immunohistochemical evaluation of molecular radiotherapy target expression in neuroblastoma tissue

Energy Technology Data Exchange (ETDEWEB)

Gains, Jennifer E.; Gaze, Mark N. [University College London Hospitals NHS Foundation Trust, Department of Oncology, London (United Kingdom); Sebire, Neil J. [Great Ormond Street Hospital for Children NHS Foundation Trust, Department of Pathology, London (United Kingdom); Moroz, Veronica; Wheatley, Keith [University of Birmingham, Cancer Research UK Clinical Trials Unit, Birmingham (United Kingdom)

2018-03-15

Neuroblastoma may be treated with molecular radiotherapy, {sup 131}I meta-Iodobenzylguanidine and {sup 177}Lu Lutetium DOTATATE, directed at distinct molecular targets: Noradrenaline Transporter Molecule (NAT) and Somatostatin Receptor (SSTR2), respectively. This study used immunohistochemistry to evaluate target expression in archival neuroblastoma tissue, to determine whether it might facilitate clinical use of molecular radiotherapy. Tissue bank samples of formalin fixed paraffin embedded neuroblastoma tissue from patients for whom clinical outcome data were available were sectioned and stained with haematoxylin and eosin, and monoclonal antibodies directed against NAT and SSTR2. Sections were examined blinded to clinical information and scored for the percentage and intensity of tumour cells stained. These data were analysed in conjunction with clinical data. Tissue from 75 patients was examined. Target expression scores varied widely between patients: NAT median 45%, inter-quartile range 25% - 65%; and SSTR2 median 55%, interquartile range 30% - 80%; and in some cases heterogeneity of expression between different parts of a tumour was observed. A weak positive correlation was observed between the expression scores of the different targets: correlation coefficient = 0.23, p = 0.05. MYCN amplified tumours had lower SSTR2 scores: mean difference 23% confidence interval 8% - 39%, p < 0.01. Survival did not differ by scores. As expression of both targets is variable and heterogeneous, imaging assessment of both may yield more clinical information than either alone. The clinical value of immunohistochemical assessment of target expression requires prospective evaluation. Variable target expression within a patient may contribute to treatment failure. (orig.)

Cytoarchitecture of Zika virus infection in human neuroblastoma and Aedes albopictus cell lines

International Nuclear Information System (INIS)

Offerdahl, Danielle K.; Dorward, David W.; Hansen, Bryan T.; Bloom, Marshall E.

2017-01-01

The Zika virus (ZIKV) pandemic is a global concern due to its role in the development of congenital anomalies of the central nervous system. This mosquito-borne flavivirus alternates between mammalian and mosquito hosts, but information about the biogenesis of ZIKV is limited. Using a human neuroblastoma cell line (SK-N-SH) and an Aedes albopictus mosquito cell line (C6/36), we characterized ZIKV infection by immunofluorescence, transmission electron microscopy (TEM), and electron tomography (ET) to better understand infection in these disparate host cells. ZIKV replicated well in both cell lines, but infected SK-N-SH cells suffered a lytic crisis. Flaviviruses scavenge host cell membranes to serve as replication platforms and ZIKV showed the hallmarks of this process. Via TEM, we identified virus particles and 60–100 nm spherular vesicles. ET revealed these vesicular replication compartments contain smaller 20–30 nm spherular structures. Our studies indicate that SK-N-SH and C6/36 cells are relevant models for viral cytoarchitecture study. - Highlights: •First electron tomography of Zika virus cytoarchitecture. •Comparison of Zika virus infection in human neuroblastoma and mosquito cells. •Ultrastructure of Zika virus infection in human neuroblastoma and mosquito cells.

Noonan syndrome-like disorder with loose anagen hair: a second case with neuroblastoma.

Science.gov (United States)

Garavelli, Livia; Cordeddu, Viviana; Errico, Stefania; Bertolini, Patrizia; Street, Maria Elisabeth; Rosato, Simonetta; Pollazzon, Marzia; Wischmeijer, Anita; Ivanovski, Ivan; Daniele, Paola; Bacchini, Ermanno; Lombardi, Alfonsa Anna; Izzi, Giancarlo; Biasucci, Giacomo; Del Rossi, Carmine; Corradi, Domenico; Cazzaniga, Giovanni; Dominici, Carlo; Rossi, Cesare; De Luca, Alessandro; Bernasconi, Sergio; Riccardi, Riccardo; Legius, Eric; Tartaglia, Marco

2015-08-01

Noonan-like syndrome with loose anagen hair (NSLH), also known as Mazzanti syndrome, is a RASopathy characterized by craniofacial features resembling Noonan syndrome, cardiac defects, cognitive deficits and behavioral issues, reduced growth generally associated with GH deficit, darkly pigmented skin, and an unique combination of ectodermal anomalies. Virtually all cases of NSLH are caused by an invariant and functionally unique mutation in SHOC2 (c.4A>G, p.Ser2Gly). Here, we report on a child with molecularly confirmed NSLH who developed a neuroblastoma, first suspected at the age 3 months by abdominal ultrasound examination. Based on this finding, scanning of the SHOC2 coding sequence encompassing the c.4A>G change was performed on selected pediatric cohorts of malignancies documented to occur in RASopathies (i.e., neuroblastoma, brain tumors, rhabdomyosarcoma, acute lymphoblastic, and myeloid leukemia), but failed to identify a functionally relevant cancer-associated variant. While these results do not support a major role of somatic SHOC2 mutations in these pediatric cancers, this second instance of neuroblastoma in NSLAH suggests a possible predisposition to this malignancy in subjects heterozygous for the c.4A>G SHOC2 mutation. © 2015 Wiley Periodicals, Inc.

Cytoarchitecture of Zika virus infection in human neuroblastoma and Aedes albopictus cell lines

Energy Technology Data Exchange (ETDEWEB)

Offerdahl, Danielle K. [Laboratory of Virology, Rocky Mountain Laboratories, NIAID, NIH, Hamilton, MT (United States); Dorward, David W.; Hansen, Bryan T. [Microscopy Unit, Research Technology Branch, Rocky Mountain Laboratories, NIAID, NIH, Hamilton, MT (United States); Bloom, Marshall E., E-mail: mbloom@nih.gov [Laboratory of Virology, Rocky Mountain Laboratories, NIAID, NIH, Hamilton, MT (United States)

2017-01-15

The Zika virus (ZIKV) pandemic is a global concern due to its role in the development of congenital anomalies of the central nervous system. This mosquito-borne flavivirus alternates between mammalian and mosquito hosts, but information about the biogenesis of ZIKV is limited. Using a human neuroblastoma cell line (SK-N-SH) and an Aedes albopictus mosquito cell line (C6/36), we characterized ZIKV infection by immunofluorescence, transmission electron microscopy (TEM), and electron tomography (ET) to better understand infection in these disparate host cells. ZIKV replicated well in both cell lines, but infected SK-N-SH cells suffered a lytic crisis. Flaviviruses scavenge host cell membranes to serve as replication platforms and ZIKV showed the hallmarks of this process. Via TEM, we identified virus particles and 60–100 nm spherular vesicles. ET revealed these vesicular replication compartments contain smaller 20–30 nm spherular structures. Our studies indicate that SK-N-SH and C6/36 cells are relevant models for viral cytoarchitecture study. - Highlights: •First electron tomography of Zika virus cytoarchitecture. •Comparison of Zika virus infection in human neuroblastoma and mosquito cells. •Ultrastructure of Zika virus infection in human neuroblastoma and mosquito cells.

76 FR 27861 - Airworthiness Directives; Diamond Aircraft Industries GmbH Models DA 42, DA 42 NG, and DA 42 M-NG...

Science.gov (United States)

2011-05-13

... Airworthiness Directives; Diamond Aircraft Industries GmbH Models DA 42, DA 42 NG, and DA 42 M-NG Airplanes... on Diamond aeroplanes, the majority of which were DA 40. In additional, at least 18 doors have been... conditions) while the aeroplane was parked. All DA 40 and DA 42 aeroplanes have a system installed that...

Long-term control of olfactory neuroblastoma in a dog treated with surgery and radiation therapy.

Science.gov (United States)

Gumpel, E; Moore, A S; Simpson, D J; Hoffmann, K L; Taylor, D P

2017-07-01

Olfactory neuroblastoma is a rare malignancy of the nasal cavity in dogs that is thought to arise from specialised sensory neuroendocrine olfactory cells derived from the neural crest. An 8-year-old dog was presented for reclusiveness and pacing. On CT and MRI, a contract-enhancing mass was disclosed within the rostral fossa, extending caudally from the cribriform plate into the left nasal sinus. Surgical excision was performed and the diagnosis was histological grade III (Hyams grading scheme) olfactory neuroblastoma. Based on human CT criteria this was high stage (modified Kadish stage C). Surgical excision was incomplete and was followed by curative-intent radiation therapy using a linear accelerator to a total dose of 48 Gy. The dog survived 20 months after diagnosis. Although olfactory neuroblastoma is a rare tumour in dogs, aggressive local therapy may allow for prolonged survival, even when the tumour is advanced. © 2017 Australian Veterinary Association.

47 CFR 25.105-25.108 - [Reserved

Science.gov (United States)

2010-10-01

... 47 Telecommunication 2 2010-10-01 2010-10-01 false [Reserved] 25.105-25.108 Section 25.105-25.108 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) COMMON CARRIER SERVICES SATELLITE COMMUNICATIONS General §§ 25.105-25.108 [Reserved] ...

Rapid COJEC versus standard induction therapies for high-risk neuroblastoma

NARCIS (Netherlands)

Peinemann, Frank; Tushabe, Doreen A.; van Dalen, Elvira C.; Berthold, Frank

2015-01-01

Neuroblastoma is a rare malignant disease and mainly affects infants and very young children. The tumors mainly develop in the adrenal medullary tissue and an abdominal mass is the most common presentation. The high-risk group is characterized by metastasis and other characteristics that increase

42 CFR 93.108 - Confidentiality.

Science.gov (United States)

2010-10-01

... 42 Public Health 1 2010-10-01 2010-10-01 false Confidentiality. 93.108 Section 93.108 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES HEALTH ASSESSMENTS AND HEALTH EFFECTS STUDIES OF HAZARDOUS SUBSTANCES RELEASES AND FACILITIES PUBLIC HEALTH SERVICE POLICIES ON RESEARCH...

76 FR 12627 - Airworthiness Directives; Diamond Aircraft Industries GmbH Models DA 42, DA 42 NG, and DA 42 M-NG...

Science.gov (United States)

2011-03-08

... Industries GmbH Models DA 42, DA 42 NG, and DA 42 M-NG Airplanes AGENCY: Federal Aviation Administration (FAA... on Diamond aeroplanes, the majority of which were DA 40. In additional, at least 18 doors have been... conditions) while the aeroplane was parked. All DA 40 and DA 42 aeroplanes have a system installed that...

Locoregional Tumor Progression After Radiation Therapy Influences Overall Survival in Pediatric Patients With Neuroblastoma

International Nuclear Information System (INIS)

Pai Panandiker, Atmaram S.; McGregor, Lisa; Krasin, Matthew J.; Wu Shengjie; Xiong Xiaoping; Merchant, Thomas E.

2010-01-01

Purpose: There is renewed attention to primary site irradiation and local control for patients with high-risk neuroblastoma (NB). We conducted a retrospective review to identify factors that might predict for locoregional tumor control and its impact on overall survival. Methods and Materials: Between July 2000 through August 2006, a total of 44 pediatric patients with NB received radiation therapy (RT) with curative intent using computed tomography (CT)-based treatment planning. The median age was 3.4 years and the median cumulative dose was 23.4 Gy. Overall survival and locoregional tumor control were measured from the start of RT to the date of death or event as determined by CT/magnetic resonance imaging/meta-iodobenzylguanidine. The influence of age at irradiation, gender, race, cumulative radiation dose, International Neuroblastoma Staging System stage, treatment protocol and resection status was determined with respect to locoregional tumor control. Results: With a median follow-up of 34 months ± 21 months, locoregional tumor progression was observed in 11 (25%) and was evenly divided between primary site and adjacent nodal/visceral site failure. The influence of locoregional control reached borderline statistical significance (p = 0.06). Age (p = 0.5), dose (p = 0.6), resection status (p = 0.7), and International Neuroblastoma Staging System stage (p = 0.08) did not influence overall survival. Conclusions: Overall survival in high-risk neuroblastoma is influenced by locoregional tumor control. Despite CT-based planning, progression in adjacent nodal/visceral sites appears to be common; this requires further investigation regarding target volume definitions, dose, and the effects of systemic therapy.

RFC-1 80G>A polymorphism in case-mother/control-mother dyads is associated with risk of nephroblastoma and neuroblastoma.

Science.gov (United States)

Montalvão-de-Azevedo, Rafaela; Vasconcelos, Gisele M; Vargas, Fernando R; Thuler, Luiz Claudio; Pombo-de-Oliveira, Maria S; de Camargo, Beatriz

2015-02-01

Embryonic tumors are associated with an interruption during normal organ development; they may be related to disturbances in the folate pathway involved in DNA synthesis, methylation, and repair. Prenatal supplementation with folic acid is associated with a decreased risk of neuroblastoma, brain tumors, retinoblastoma, and nephroblastoma. The aim of this study was to investigate the association between MTHFR rs1801133 (C677T) and RFC-1 rs1051266 (G80A) genotypes with the risk of developing nephroblastoma and neuroblastoma. Case-mother/control-mother dyad study. Samples from Brazilian children with nephroblastoma (n=80), neuroblastoma (n=66), healthy controls (n=453), and their mothers (case n=93; control n=75) were analyzed. Genomic DNA was isolated from peripheral blood cells and/or buccal cells and genotyped to identify MTHFR C677T and RFC-1 G80A polymorphisms. Differences in genotype distribution between patients and controls were tested by multiple logistic regression analysis. Risk for nephroblastoma and neuroblastoma was two- to fourfold increased among children with RFC-1 polymorphisms. An increased four- to eightfold risk for neuroblastoma and nephroblastoma was seen when the child and maternal genotypes were combined. Our results suggest that mother and child RFC-1 G80A genotypes play a role on the risk of neuroblastoma and nephroblastoma since this polymorphism may impair the intracellular levels of folate, through carrying fewer folate molecules to the cell interior, and thus, the intracellular concentration is not enough to maintain regular DNA synthesis and methylation pathways.

I131-MIBG in early diagnose of neuroblastoma in symptomatic children

International Nuclear Information System (INIS)

Saddadi, F.S.; Kargarzadeh, F.K.; Yaghoobi, N.Y.

2002-01-01

Aim: Neuroblastoma is the second most common solid tumors in childhood which derivates from neural crest. It is very malignant and almost always patient comes with metastasis. However there are some diagnostic tools to detection of lesion in the early stage of tumor. We decided to have a review with using I-131 MIBG in patients suspected and/or proved to have neuroblastoma. Material and Methods: 300-500 μci I 131 MIBG was injected intravenously in patients (5 patients with age range 4 years old) referred for their bone pain and pelvic mass(detected with anatomical tools). Images were obtained 24 to 72 hours throughout the body with ADAC gamma camera and SPECT was performed in each local abnormal uptake. Each patient has already had a WBBS with TcMDP. Results: All abnormal tracer uptakes were seen in bone scan were revealed clearly in I131 MIBG. However, three to five other abnormal tracer activities were only seen in MIBG scan. The main tumoral lesions were showed perfectly in pelvic,that was not seen in WBBS. With a statistical analysis, I131 MIBG has 94% sensitivity 85-100% specificity, compare to Tc99m-MDP that was 78% and 51% respectively. Conclusions: We found that I131 MIBG is the most useful method to diagnose of patients with neuroblastoma and reproved that it has a competitive role in management, follow-up of these tumors especially in detection of metastasis

Macroautophagy-generated increase of lysosomal amyloid β-protein mediates oxidant-induced apoptosis of cultured neuroblastoma cells

DEFF Research Database (Denmark)

Zheng, Lin; Terman, Alexei; Hallbeck, Martin

2011-01-01

and accumulation of Aβ within lysosomes, induced apoptosis in differentiated SH-SY5Y neuroblastoma cells. Cells under hyperoxia showed: (1) increased numbers of autophagic vacuoles that contained amyloid precursor protein (APP) as well as Aβ monomers and oligomers, (2) increased reactive oxygen species production...... and resulting lysosomal Aβ accumulation are essential for oxidant-induced apoptosis in cultured neuroblastoma cells and provide additional support for the interactive role of oxidative stress and the lysosomal system in AD-related neurodegeneration....

Science Ready Data Products and the ngVLA

Science.gov (United States)

Kern, Jeffrey

2018-01-01

With angular resolution comparable to ALMA and future ELTs, the ngVLA will be the centimeter wavelength instrument contributing to multi-wavelength astronomy throughout the next decades. To maximize the impact of the ngVLA it is important that it be a facility available to all astronomers, not only to those who consider themselves radio astronomers. Building on the successes of the ALMA and VLA pipelines NRAO has undertaken a multi-year project to provide science ready products to the users of our telescopes and archive. The SRDP initiative addresses one of the technical risk areas of the ngVLA, and demonstrates the Observatories ability to deliver this critical functionality. The SRDP project is currently refining and reviewing the technical and scientific requirements for the existing NRAO telescopes. Capabilities will be made available to the community as they are developed and mature. As the project progresses, a rich archive of science quality radio images from both ALMA and the VLA will be provided to the astronomical community. The current status, concepts, and plans for the SRDP project are presented, as are the implications for the ngVLA facility.

Physician Perspectives on Palliative Care for Children With Neuroblastoma: An International Context.

Science.gov (United States)

Balkin, Emily M; Thompson, Daria; Colson, K Ellicott; Lam, Catherine G; Matthay, Katherine K

2016-05-01

Studies have shown that children with cancer globally lack access to palliative care. Little is known regarding physicians' perceptions of palliative care, treatment access, and self-reported competence in providing palliative care. Members of the Global Neuroblastoma Network (online tumor board) were surveyed. Eighty-three respondents met inclusion criteria; 53 (64%) completed the survey. Most respondents trained in high-income countries (HIC) but practice in low- and middle-income countries (LMIC), and care for more than five patients with neuroblastoma annually. WHO Essential Medicines in palliative care varied in availability, with incomplete access across LMIC centers. Nonpharmacologic therapies were inconsistently available. Contrary to international definitions, 17% of respondents inappropriately considered palliative care as that initiated only after curative therapy is stopped. Mean physician competence composite score (Likert scale 1-5, 5 = very competent) in providing symptomatic relief and palliative care across phases of care was 2.93 (95% CI 2.71-3.22). Physicians reported significantly greater competence in symptom management during cure-directed therapy than during end-of-life (P = 0.02) or when patients are actively dying (P = 0.007). Practicing in HIC, prior palliative care training, having access to radiotherapy, and not having to turn patients away due to bed shortages were significantly predictive of perceived competence in providing palliative care at end of life. An international sample identified gaps in treatment and palliative care service availability, in understanding the definition of palliative care, and in self-reported competence in providing palliative care. Increased perceived competence was associated with training, which supports the need for increased palliative care education and advocacy, especially in LMIC. © 2016 Wiley Periodicals, Inc.

NG2 proteoglycan increases mesangial cell proliferation and extracellular matrix production