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Sample records for rigidity modulates neuroblastoma

  1. 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

  2. Assessment of citalopram and escitalopram on neuroblastoma cell lines: Cell toxicity and gene modulation

    Science.gov (United States)

    Sakka, Laurent; Delétage, Nathalie; Chalus, Maryse; Aissouni, Youssef; Sylvain-Vidal, Valérie; Gobron, Stéphane; Coll, Guillaume

    2017-01-01

    Selective serotonin reuptake inhibitors (SSRI) are common antidepressants which cytotoxicity has been assessed in cancers notably colorectal carcinomas and glioma cell lines. We assessed and compared the cytotoxicity of 2 SSRI, citalopram and escitalopram, on neuroblastoma cell lines. The study was performed on 2 non-MYCN amplified cell lines (rat B104 and human SH-SY5Y) and 2 human MYCN amplified cell lines (IMR32 and Kelly). Citalopram and escitalopram showed concentration-dependent cytotoxicity on all cell lines. Citalopram was more cytotoxic than escitalopram. IMR32 was the most sensitive cell line. The absence of toxicity on human primary Schwann cells demonstrated the safety of both molecules for myelin. The mechanisms of cytotoxicity were explored using gene-expression profiles and quantitative real-time PCR (qPCR). Citalopram modulated 1 502 genes and escitalopram 1 164 genes with a fold change ≥ 2. 1 021 genes were modulated by both citalopram and escitalopram; 481 genes were regulated only by citalopram while 143 genes were regulated only by escitalopram. Citalopram modulated 69 pathways (KEGG) and escitalopram 42. Ten pathways were differently modulated by citalopram and escitalopram. Citalopram drastically decreased the expression of MYBL2, BIRC5 and BARD1 poor prognosis factors of neuroblastoma with fold-changes of -107 (pescitalopram. PMID:28467792

  3. Assessment of citalopram and escitalopram on neuroblastoma cell lines. Cell toxicity and gene modulation.

    Science.gov (United States)

    Sakka, Laurent; Delétage, Nathalie; Chalus, Maryse; Aissouni, Youssef; Sylvain-Vidal, Valérie; Gobron, Stéphane; Coll, Guillaume

    2017-06-27

    Selective serotonin reuptake inhibitors (SSRI) are common antidepressants which cytotoxicity has been assessed in cancers notably colorectal carcinomas and glioma cell lines. We assessed and compared the cytotoxicity of 2 SSRI, citalopram and escitalopram, on neuroblastoma cell lines. The study was performed on 2 non-MYCN amplified cell lines (rat B104 and human SH-SY5Y) and 2 human MYCN amplified cell lines (IMR32 and Kelly). Citalopram and escitalopram showed concentration-dependent cytotoxicity on all cell lines. Citalopram was more cytotoxic than escitalopram. IMR32 was the most sensitive cell line. The absence of toxicity on human primary Schwann cells demonstrated the safety of both molecules for myelin. The mechanisms of cytotoxicity were explored using gene-expression profiles and quantitative real-time PCR (qPCR). Citalopram modulated 1 502 genes and escitalopram 1 164 genes with a fold change ≥ 2. 1 021 genes were modulated by both citalopram and escitalopram; 481 genes were regulated only by citalopram while 143 genes were regulated only by escitalopram. Citalopram modulated 69 pathways (KEGG) and escitalopram 42. Ten pathways were differently modulated by citalopram and escitalopram. Citalopram drastically decreased the expression of MYBL2, BIRC5 and BARD1 poor prognosis factors of neuroblastoma with fold-changes of -107 (pescitalopram.

  4. Distinct Pattern of Solar Modulation of Galactic Cosmic Rays above a High Geomagnetic Cutoff Rigidity

    Science.gov (United States)

    Mangeard, Pierre-Simon; Clem, John; Evenson, Paul; Pyle, Roger; Mitthumsiri, Warit; Ruffolo, David; Sáiz, Alejandro; Nutaro, Tanin

    2018-05-01

    Solar modulation refers to Galactic cosmic-ray variations with the ∼11 yr sunspot cycle and ∼22 yr solar magnetic cycle and is relevant to the space radiation environment and effects on Earth’s atmosphere. Its complicated dependence on solar and heliospheric conditions is only roughly understood and has been empirically modeled in terms of a single modulation parameter. Most analyses of solar modulation use neutron monitor (NM) data from locations with relatively low geomagnetic cutoff rigidity, i.e., the threshold for cosmic rays to penetrate Earth’s magnetic field. The Princess Sirindhorn Neutron Monitor at Doi Inthanon, Thailand, has the world’s highest cutoff rigidity (≈17 GV) where observations span a complete solar modulation cycle (since late 2007). The pattern of solar modulation at Doi Inthanon during 2011–2014 was qualitatively very different from that at a low geomagnetic cutoff and is not well described by the same modulation parameter. At other times, NM count rates from Doi Inthanon and McMurdo, Antarctica (cutoff ∼1 GV), were linearly correlated and confirm the observation from latitude surveys in the previous solar cycle that the slope of the correlation changes with solar magnetic polarity. Low solar magnetic tilt angles (magnetic field, which is consistent with an increase in diffusion at high rigidity short-circuiting the effects of drifts and the heliospheric current sheet.

  5. Salicin from Willow Bark can Modulate Neurite Outgrowth in Human Neuroblastoma SH-SY5Y Cells.

    Science.gov (United States)

    Wölfle, Ute; Haarhaus, Birgit; Kersten, Astrid; Fiebich, Bernd; Hug, Martin J; Schempp, Christoph M

    2015-10-01

    Salicin from willow bark has been used throughout centuries in China and Europe for the treatment of pain, headache, and inflammatory conditions. Recently, it could be demonstrated that salicin binds and activates the bitter taste receptor TAS2R16. Studies on rodent tissues showed the general expression of bitter taste receptors (TAS2Rs) in rodent brain. Here, we demonstrate the expression of hTAS2R16 in human neuronal tissues and the neuroblastoma cell line SH-SY5Y. The functionality was analyzed in the neuroblastoma cell line SH-SY5Y after stimulation with salicin, a known TAS2R16 agonist. In this setting salicin induced in SH-SY5Y cells phosphorylation of ERK and CREB, the key transcription factor of neuronal differentiation. PD98059, an inhibitor of the ERK pathway, as well as probenecid, a TAS2R16 antagonist, inhibited receptor phosphorylation as well as neurite outgrowth. These data show that salicin might modulate neurite outgrowth by bitter taste receptor activation. Copyright © 2015 John Wiley & Sons, Ltd.

  6. Infection of neuroblastoma cells by rabies virus is modulated by the virus titer.

    Science.gov (United States)

    Fuoco, Natalia Langenfeld; Dos Ramos Silva, Sandriana; Fernandes, Elaine Raniero; Luiz, Fernanda Guedes; Ribeiro, Orlando Garcia; Katz, Iana Suly Santos

    2018-01-01

    Rabies is a lethal viral infection that can affect almost all mammals, including humans. To better understand the replication of Rabies lyssavirus, we investigated if the viral load in brains naturally infected with rabies influences viral internalization and viral growth kinetics in neuroblastoma cells, and if the viral load affects mortality in mice after intradermal infection. We noted that high initial viral loads in brains (group II) were unfavourable for increasing viral titers during serial passages in neuroblastoma cells when compared to low initial viral loads in brains (group I). In addition, group I strains showed higher viral growth and enhanced internalization efficiency in neuroblastoma cells than group II strains. However, we observed that the dominant virus subpopulation in group II promoted efficient viral infection in the central nervous system in the new host, providing a selective advantage to the virus. Our data indicate that rabies infection in animal models depends on not only the virus strain but also the amount of virus. This study may serve as a basis for understanding the biologic proprieties of Rabies lyssavirus strains with respect to the effects on viral replication and the impact on pathogenesis, improving virus yields for use in vaccine development. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. ATP/P2X7 axis modulates myeloid-derived suppressor cell functions in neuroblastoma microenvironment.

    Science.gov (United States)

    Bianchi, G; Vuerich, M; Pellegatti, P; Marimpietri, D; Emionite, L; Marigo, I; Bronte, V; Di Virgilio, F; Pistoia, V; Raffaghello, L

    2014-03-20

    Tumor microenvironment of solid tumors is characterized by a strikingly high concentration of adenosine and ATP. Physiological significance of this biochemical feature is unknown, but it has been suggested that it may affect infiltrating immune cell responses and tumor progression. There is increasing awareness that many of the effects of extracellular ATP on tumor and inflammatory cells are mediated by the P2X7 receptor (P2X7R). Aim of this study was to investigate whether: (i) extracellular ATP is a component of neuroblastoma (NB) microenvironment, (ii) myeloid-derived suppressor cells (MDSCs) express functional P2X7R and (iii) the ATP/P2X7R axis modulates MDSC functions. Our results show that extracellular ATP was detected in NB microenvironment in amounts that increased in parallel with tumor progression. The percentage of CD11b(+)/Gr-1(+) cells was higher in NB-bearing mice compared with healthy animals. Within the CD11b/Gr-1(+) population, monocytic MDSCs (M-MDSCs) produced higher levels of reactive oxygen species (ROS), arginase-1 (ARG-1), transforming growth factor-β1 (TGF-β1) and stimulated more potently in vivo tumor growth, as compared with granulocytic MDSCs (G-MDSCs). P2X7R of M-MDSCs was localized at the plasma membrane, coupled to increased functionality, upregulation of ARG-1, TGF-β1 and ROS. Quite surprisingly, the P2X7R in primary MDSCs as well as in the MSC-1 and MSC-2 lines was uncoupled from cytotoxicity. This study describes a novel scenario in which MDSC immunosuppressive functions are modulated by the ATP-enriched tumor microenvironment.

  8. 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

  9. Microenvironmental Modulation of Decorin and Lumican in Temozolomide-Resistant Glioblastoma and Neuroblastoma Cancer Stem-Like Cells.

    Directory of Open Access Journals (Sweden)

    Cristiano Farace

    Full Text Available The presence of cancer stem cells (CSCs or tumor-initiating cells can lead to cancer recurrence in a permissive cell-microenvironment interplay, promoting invasion in glioblastoma (GBM and neuroblastoma (NB. Extracellular matrix (ECM small leucine-rich proteoglycans (SLRPs play multiple roles in tissue homeostasis by remodeling the extracellular matrix (ECM components and modulating intracellular signaling pathways. Due to their pan-inhibitory properties against receptor tyrosine kinases (RTKs, SLRPs are reported to exert anticancer effects in vitro and in vivo. However, their roles seem to be tissue-specific and they are also involved in cancer cell migration and drug resistance, paving the way to complex different scenarios. The aim of this study was to determine whether the SLRPs decorin (DCN and lumican (LUM are recruited in cell plasticity and microenvironmental adaptation of differentiated cancer cells induced towards stem-like phenotype. Floating neurospheres were generated by applying CSC enrichment medium (neural stem cell serum-free medium, NSC SFM to the established SF-268 and SK-N-SH cancer cell lines, cellular models of GBM and NB, respectively. In both models, the time-dependent synergistic activation of DCN and LUM was observed. The highest DCN and LUM mRNA/protein expression was detected after cell exposure to NSC SFM for 8/12 days, considering these cells as SLRP-expressing (SLRP+ CSC-like. Ultrastructural imaging showed the cellular heterogeneity of both the GBM and NB neurospheres and identified the inner living cells. Parental cell lines of both GBM and NB grew only in soft agar + NSC SFM, whereas the secondary neurospheres (originated from SLRP+ t8 CSC-like showed lower proliferation rates than primary neurospheres. Interestingly, the SLRP+ CSC-like from the GBM and NB neurospheres were resistant to temozolomide (TMZ at concentrations >750 μM. Our results suggest that GBM and NB CSC-like promote the activation of huge

  10. Microenvironmental Modulation of Decorin and Lumican in Temozolomide-Resistant Glioblastoma and Neuroblastoma Cancer Stem-Like Cells.

    Science.gov (United States)

    Farace, Cristiano; Oliver, Jaime Antonio; Melguizo, Consolacion; Alvarez, Pablo; Bandiera, Pasquale; Rama, Ana Rosa; Malaguarnera, Giulia; Ortiz, Raul; Madeddu, Roberto; Prados, Jose

    2015-01-01

    The presence of cancer stem cells (CSCs) or tumor-initiating cells can lead to cancer recurrence in a permissive cell-microenvironment interplay, promoting invasion in glioblastoma (GBM) and neuroblastoma (NB). Extracellular matrix (ECM) small leucine-rich proteoglycans (SLRPs) play multiple roles in tissue homeostasis by remodeling the extracellular matrix (ECM) components and modulating intracellular signaling pathways. Due to their pan-inhibitory properties against receptor tyrosine kinases (RTKs), SLRPs are reported to exert anticancer effects in vitro and in vivo. However, their roles seem to be tissue-specific and they are also involved in cancer cell migration and drug resistance, paving the way to complex different scenarios. The aim of this study was to determine whether the SLRPs decorin (DCN) and lumican (LUM) are recruited in cell plasticity and microenvironmental adaptation of differentiated cancer cells induced towards stem-like phenotype. Floating neurospheres were generated by applying CSC enrichment medium (neural stem cell serum-free medium, NSC SFM) to the established SF-268 and SK-N-SH cancer cell lines, cellular models of GBM and NB, respectively. In both models, the time-dependent synergistic activation of DCN and LUM was observed. The highest DCN and LUM mRNA/protein expression was detected after cell exposure to NSC SFM for 8/12 days, considering these cells as SLRP-expressing (SLRP+) CSC-like. Ultrastructural imaging showed the cellular heterogeneity of both the GBM and NB neurospheres and identified the inner living cells. Parental cell lines of both GBM and NB grew only in soft agar + NSC SFM, whereas the secondary neurospheres (originated from SLRP+ t8 CSC-like) showed lower proliferation rates than primary neurospheres. Interestingly, the SLRP+ CSC-like from the GBM and NB neurospheres were resistant to temozolomide (TMZ) at concentrations >750 μM. Our results suggest that GBM and NB CSC-like promote the activation of huge quantities

  11. RGS2 modulates the activity and internalization of dopamine D2 receptors in neuroblastoma N2A cells.

    Science.gov (United States)

    Luessen, Deborah J; Hinshaw, Tyler P; Sun, Haiguo; Howlett, Allyn C; Marrs, Glen; McCool, Brian A; Chen, Rong

    2016-11-01

    Dysregulated expression and function of dopamine D2 receptors (D2Rs) are implicated in drug addiction, Parkinson's disease and schizophrenia. In the current study, we examined whether D2Rs are modulated by regulator of G protein signaling 2 (RGS2), a member of the RGS family that regulates G protein signaling via acceleration of GTPase activity. Using neuroblastoma 2a (N2A) cells, we found that RGS2 was immunoprecipitated by aluminum fluoride-activated Gαi2 proteins. RGS2 siRNA knockdown enhanced membrane [(35)S] GTPγS binding to activated Gαi/o proteins, augmented inhibition of cAMP accumulation and increased ERK phosphorylation in the presence of a D2/D3R agonist quinpirole when compared to scrambled siRNA treatment. These data suggest that RGS2 is a negative modulator of D2R-mediated Gαi/o signaling. Moreover, RGS2 knockdown slightly increased constitutive D2R internalization and markedly abolished quinpirole-induced D2R internalization assessed by immunocytochemistry. RGS2 knockdown did not compromise agonist-induced β-arrestin membrane recruitment; however, it prevents β-arrestin dissociation from the membrane after prolonged quinpirole treatment during which time β-arrestin moved away from the membrane in control cells. Additionally, confocal microscopy analysis of β-arrestin post-endocytic fate revealed that quinpirole treatment caused β-arrestin to translocate to the early and the recycling endosome in a time-dependent manner in control cells whereas translocation of β-arrestin to these endosomes did not occur in RGS2 knockdown cells. The impaired β-arrestin translocation likely contributed to the abolishment of quinpirole-stimulated D2R internalization in RGS2 knockdown cells. Thus, RGS2 is integral for β-arrestin-mediated D2R internalization. The current study revealed a novel regulation of D2R signaling and internalization by RGS2 proteins. Copyright © 2016 Elsevier Ltd. All rights reserved.

  12. Matrix rigidity regulates cancer cell growth by modulating cellular metabolism and protein synthesis.

    Directory of Open Access Journals (Sweden)

    Robert W Tilghman

    Full Text Available Tumor cells in vivo encounter diverse types of microenvironments both at the site of the primary tumor and at sites of distant metastases. Understanding how the various mechanical properties of these microenvironments affect the biology of tumor cells during disease progression is critical in identifying molecular targets for cancer therapy.This study uses flexible polyacrylamide gels as substrates for cell growth in conjunction with a novel proteomic approach to identify the properties of rigidity-dependent cancer cell lines that contribute to their differential growth on soft and rigid substrates. Compared to cells growing on more rigid/stiff substrates (>10,000 Pa, cells on soft substrates (150-300 Pa exhibited a longer cell cycle, due predominantly to an extension of the G1 phase of the cell cycle, and were metabolically less active, showing decreased levels of intracellular ATP and a marked reduction in protein synthesis. Using stable isotope labeling of amino acids in culture (SILAC and mass spectrometry, we measured the rates of protein synthesis of over 1200 cellular proteins under growth conditions on soft and rigid/stiff substrates. We identified cellular proteins whose syntheses were either preferentially inhibited or preserved on soft matrices. The former category included proteins that regulate cytoskeletal structures (e.g., tubulins and glycolysis (e.g., phosphofructokinase-1, whereas the latter category included proteins that regulate key metabolic pathways required for survival, e.g., nicotinamide phosphoribosyltransferase, a regulator of the NAD salvage pathway.The cellular properties of rigidity-dependent cancer cells growing on soft matrices are reminiscent of the properties of dormant cancer cells, e.g., slow growth rate and reduced metabolism. We suggest that the use of relatively soft gels as cell culture substrates would allow molecular pathways to be studied under conditions that reflect the different mechanical

  13. Modulation by calcineurin of 5-HT3 receptor function in NG108-15 neuroblastoma x glioma cells

    NARCIS (Netherlands)

    Boddeke, HWGM; Meigel, [No Value; Boeijinga, P; Arbuckle, J; Docherty, RJ

    1 We have investigated the mechanism of regulation of 5-HT3 receptor channel sensitivity in voltage-clamped (-80 mV) NG108-15 neuroblastoma cells. 2 The 5-HT-induced inward current activated rapidly. The fast onset was followed by a biphasic decay which was characterized by two time constants,

  14. Modulation by calcineurin of 5-HT3receptor function in NG108-15 neuroblastoma x glioma cells

    NARCIS (Netherlands)

    Boddeke, H.W.G.M.; Meigel, I.; Boeijinga, P.; Arbuckle, J.; Docherty, R.J.

    1996-01-01

    1. We have investigated the mechanism of regulation of 5-HT3receptor channel sensitivity in voltage-clamped (-80 mV) NG108-15 neuroblastoma cells. 2. The 5-HT-induced inward current activated rapidly. The fast onset was followed by a biphasic decay which was characterized by two time constants,

  15. Modulation of intracellular calcium homeostasis by trimethyltin chloride in human tumour cells: Neuroblastoma SY5Y and cervix adenocarcinoma HeLa S3

    International Nuclear Information System (INIS)

    Florea, Ana-Maria; Splettstoesser, Frank; Dopp, Elke; Rettenmeier, Albert W.; Buesselberg, Dietrich

    2005-01-01

    Physiological modifications of intracellular Ca 2+ ([Ca 2+ ] i ) levels trigger and/or regulate a diversity of cellular activities (e.g. neurotransmitter release, synaptic plasticity, muscular contraction, cell proliferation), while calcium overloads could result in cytotoxicity. Previously, we have shown that trimethyltin chloride (Me 3 SnCl; TMT) modulates calcium homeostasis in cervix adenocarcinoma (HeLa S3) cells [Florea, A.-M., Dopp, E., Buesselberg, D., 2005. TMT induces elevated calcium transients in HeLa cells: types and levels of response. Cell Calcium 37, 252-258]. Here we compare [Ca 2+ ] i -changes induced by trimethyltin chloride in neuroblastoma SY5Y and HeLa S3 cells using calcium-sensitive dyes (fluo-4/AM (fluo-4) and rhod-2/AM (rhod-2)) and laser scanning microscopy (LSM). TMT-induced calcium elevations in neuroblastoma SY5Y as well as in HeLa S3 cells. [Ca 2+ ] i rose to a sustained plateau or to transient spikes. Overall, the detected averaged increase of the maximum calcium elevation were: 0.5 μM ∼125.6%; 5 μM ∼130.1%; 500 μM ∼145% in HeLa S3 cells and 0.5 μM ∼133.3%; 5 μM ∼136.1%; 500 μM ∼147.1% in neuroblastoma SY5Y cells. The calcium rise derived from internal stores did not significantly depend on the presence of calcium in the external solution: ∼109% (no calcium added) versus ∼117% (2 mM calcium; 5 μM TMT) in HeLa cells. This difference was similar in neuroblastoma SY5Y cells, were ∼127% versus ∼136% increase (5 μM TMT) were measured. Staining of calcium stores with rhod-2 showed a TMT-induced [Ca 2+ ] i -decrease in the stores followed by an increase of the calcium concentration in the nuclei of the two cell lines tested. Our results suggest that toxic effects in human tumour cells after exposure to trimethyltin compounds might be due to an elevation of [Ca 2+ ] i

  16. Launch and Functional Considerations Guiding the Scaling and Design of Rigid Inflatable Habitat Modules

    Science.gov (United States)

    Bell, L.

    2002-01-01

    The Sasakawa International Center for Space Architecture (SICSA) has a long history of projects that involve design of space structures, including habitats for low-Earth orbit (LEO) and planetary applications. Most of these facilities and component systems are planned to comply with size, geometry and mass restrictions imposed by the Space Shuttle Orbiter's payload and lift/landing abort restrictions. These constraints limit launch elements to approximately 15 ft. diameter, 40 ft. long cylindrical dimensions weighing no more than approximately 25 metric tons. It is clear that future success of commercial space programs such as tourism will hinge upon the availability of bigger and more efficient Earth to LEO launch vehicles which can greatly reduce transportation and operational costs. This will enable development and utilization of larger habitat modules and other infrastructure elements which can be deployed with fewer launches and on-orbit assembly procedures. The sizing of these new heavy lift launchers should be scaled to optimize habitat functionality and efficiency, just as the habitat designs must consider optimization of launch vehicle economy. SICSA's planning studies address these vehicle and habitat optimization priorities as parallel and interdependent considerations. The allowable diameter of habitat modules established by launch vehicle capacity dictates functionally acceptable internal configuration options. Analyses of these options relative to practical dimensions for Earth-to-orbit launch vehicle scaling were conducted for two general schemes. The "bologna slice" configuration stacks the floors within a predominately cylindrical or spherical envelope, producing circular areas. The "banana split" approach divides a cylindrical module longitudinally, creating floors that are generally rectangular in shape. The assessments established minimum sizes for reasonable utility and efficiency. The bologna slice option. This configuration is only acceptable

  17. Assessment of organ dose reduction and secondary cancer risk associated with the use of proton beam therapy and intensity modulated radiation therapy in treatment of neuroblastomas

    International Nuclear Information System (INIS)

    Fuji, Hiroshi; Harada, Hideyuki; Asakura, Hirofumi; Nishimura, Tetsuo; Schneider, Uwe; Ishida, Yuji; Konno, Masahiro; Yamashita, Haruo; Kase, Yuki; Murayama, Shigeyuki; Onoe, Tsuyoshi; Ogawa, Hirofumi

    2013-01-01

    To compare proton beam therapy (PBT) and intensity-modulated radiation therapy (IMRT) with conformal radiation therapy (CRT) in terms of their organ doses and ability to cause secondary cancer in normal organs. Five patients (median age, 4 years; range, 2–11 years) who underwent PBT for retroperitoneal neuroblastoma were selected for treatment planning simulation. Four patients had stage 4 tumors and one had stage 2A tumor, according to the International Neuroblastoma Staging System. Two patients received 36 Gy, two received 21.6 Gy, and one received 41.4 Gy of radiation. The volume structures of these patients were used for simulations of CRT and IMRT treatment. Dose–volume analyses of liver, stomach, colon, small intestine, pancreas, and bone were performed for the simulations. Secondary cancer risks in these organs were calculated using the organ equivalent dose (OED) model, which took into account the rates of cell killing, repopulation, and the neutron dose from the treatment machine. In all evaluated organs, the mean dose in PBT was 20–80% of that in CRT. IMRT also showed lower mean doses than CRT for two organs (20% and 65%), but higher mean doses for the other four organs (110–120%). The risk of secondary cancer in PBT was 24–83% of that in CRT for five organs, but 121% of that in CRT for pancreas. The risk of secondary cancer in IMRT was equal to or higher than CRT for four organs (range 100–124%). Low radiation doses in normal organs are more frequently observed in PBT than in IMRT. Assessments of secondary cancer risk showed that PBT reduces the risk of secondary cancer in most organs, whereas IMRT is associated with a higher risk than CRT

  18. Single or combined treatment with L-DOPA and quinpirole differentially modulate expression and phosphorylation of key regulatory kinases in neuroblastoma cells.

    Science.gov (United States)

    Fuzzati-Armentero, Marie Therese; Ghezzi, Cristina; Nisticò, Robert; Oda, Adriano; Blandini, Fabio

    2013-09-27

    In the past decades, the clinical use of dopamine agonists has expanded from adjunct therapy in patients with a deteriorating response to L-3,4-dihydroxyphenylalanine (L-DOPA) to monotherapy for the treatment of early PD. Dopamine agonists provide their antiparkinsonian benefit through stimulation of brain postsynaptic type 2 dopamine receptors that exert their effect through classical cAMP-dependent mechanisms, as well as cAMP-independent cellular signaling cascades, including the Akt/glycogen synthase kinase 3 (GSK3) pathway. Alterations of Akt/GSK3 have been observed and may contribute to the neurodegenerative processes and the development of L-DOPA-induced dyskinesia. The effects L-DOPA and quinpirole, a dopamine agonist, on the two key regulatory kinases, Akt and GSK3, were evaluated in neuroblastoma cell line. L-DOPA and dopamine agonist dose-dependently and differentially modulated Akt and GSK3 expression and phosphorylation when added alone or combined. The combined treatment inverted or potentiated the modulatory properties of the single compound. The drug- and concentration-dependent balance of dopamine receptor stimulation over auto-oxidation may distinctively modulate GSK3 isoforms and Akt. Our results indicate that particular attention must be given to drug concentration and combination when multiple therapies are applied for the clinical treatment of PD patients. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  19. 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)

  20. 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

  1. Rigidity of tilting modules

    DEFF Research Database (Denmark)

    Haahr Andersen, Henning; Kaneda, Masaharu

    Let $U_q$ denote the quantum group associated with a finite dimensional semisimple Lie algebra. Assume that $q$ is a complex root of unity of odd order and that $U_q$ is %the quantum group version obtained via Lusztig's $q$-divided powers construction. We prove that all regular projective (tilting...

  2. Intensity modulated radiotherapy for localized prostate cancer: rigid compliance to dose-volume constraints as a warranty of acceptable toxicity?

    International Nuclear Information System (INIS)

    Chen, Michael J; Nadalin, Wladmir; Weltman, Eduardo; Hanriot, Rodrigo M; Luz, Fábio P; Cecílio, Paulo J; Cruz, José C da; Moreira, Frederico R; Santos, Adriana S; Martins, Lidiane C

    2007-01-01

    To report the toxicity after intensity modulated radiotherapy (IMRT) for patients with localized prostate cancer, as a sole treatment or after radical prostatectomy. Between August 2001 and December 2003, 132 patients with prostate cancer were treated with IMRT and 125 were evaluable to acute and late toxicity analysis, after a minimum follow-up time of one year. Clinical and treatment data, including normal tissue dose-volume histogram (DVH) constraints, were reviewed. Gastro-intestinal (GI) and genito-urinary (GU) signs and symptoms were evaluated according to the Radiation Therapy Oncology Group (RTOG) toxicity scales. Median prescribed dose was 76 Gy. Median follow-up time was of 26.1 months. From the 125 patients, 73 (58.4%) presented acute Grade 1 or Grade 2 GI and 97 (77.2%) presented acute Grade 1 or Grade 2 GU toxicity. Grade 3 GI acute toxicity occurred in only 2 patients (1.6%) and Grade 3 GU acute toxicity in only 3 patients (2.4%). Regarding Grade 1 and 2 late toxicity, 26 patients (20.8%) and 21 patients (16.8%) presented GI and GU toxicity, respectively. Grade 2 GI late toxicity occurred in 6 patients (4.8%) and Grade 2 GU late toxicity in 4 patients (3.2%). None patient presented any Grade 3 or higher late toxicity. Non-conformity to DVH constraints occurred in only 11.2% of treatment plans. On univariate analysis, no significant risk factor was identified for Grade 2 GI late toxicity, but mean dose delivered to the PTV was associated to higher Grade 2 GU late toxicity (p = 0.042). IMRT is a well tolerable technique for routine treatment of localized prostate cancer, with short and medium-term acceptable toxicity profiles. According to the data presented here, rigid compliance to DHV constraints might prevent higher incidences of normal tissue complication

  3. 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

  4. Metformin inhibition of neuroblastoma cell proliferation is differently modulated by cell differentiation induced by retinoic acid or overexpression of NDM29 non-coding RNA

    OpenAIRE

    Costa, Delfina; Gigoni, Arianna; Würth, Roberto; Cancedda, Ranieri; Florio, Tullio; Pagano, Aldo

    2014-01-01

    Background Metformin is a widely used oral hypoglycemizing agent recently proposed as potential anti-cancer drug. In this study we report the antiproliferative effect of metformin treatment in a high risk neuroblastoma cell model, focusing on possible effects associated to different levels of differentiation and/or tumor initiating potential. Methods Antiproliferative and cytotoxic effects of metformin were tested in human SKNBE2 and SH-SY5Y neuroblastoma cell lines and in SKNBE2 cells in whi...

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

    Science.gov (United States)

    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

  6. Olfactory Neuroblastoma: Diagnostic Difficulty

    Directory of Open Access Journals (Sweden)

    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

  7. 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

  8. 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.

  9. Nuclear cereblon modulates transcriptional activity of Ikaros and regulates its downstream target, enkephalin, in human neuroblastoma cells

    International Nuclear Information System (INIS)

    Wada, Takeyoshi; Asahi, Toru; Sawamura, Naoya

    2016-01-01

    The gene coding cereblon (CRBN) was originally identified in genetic linkage analysis of mild autosomal recessive nonsyndromic intellectual disability. CRBN has broad localization in both the cytoplasm and nucleus. However, the significance of nuclear CRBN remains unknown. In the present study, we aimed to elucidate the role of CRBN in the nucleus. First, we generated a series of CRBN deletion mutants and determined the regions responsible for the nuclear localization. Only CRBN protein lacking the N-terminal region was localized outside of the nucleus, suggesting that the N-terminal region is important for its nuclear localization. CRBN was also identified as a thalidomide-binding protein and component of the cullin-4-containing E3 ubiquitin ligase complex. Thalidomide has been reported to be involved in the regulation of the transcription factor Ikaros by CRBN-mediated degradation. To investigate the nuclear functions of CRBN, we performed co-immunoprecipitation experiments and evaluated the binding of CRBN to Ikaros. As a result, we found that CRBN was associated with Ikaros protein, and the N-terminal region of CRBN was required for Ikaros binding. In luciferase reporter gene experiments, CRBN modulated transcriptional activity of Ikaros. Furthermore, we found that CRBN modulated Ikaros-mediated transcriptional repression of the proenkephalin gene by binding to its promoter region. These results suggest that CRBN binds to Ikaros via its N-terminal region and regulates transcriptional activities of Ikaros and its downstream target, enkephalin. - Highlights: • We found that CRBN is a nucleocytoplasmic shutting protein and identified the key domain for nucleocytoplasmic shuttling. • CRBN associates with the transcription factor Ikaros via the N-terminal domain. • CRBN modulates Ikaros-mediated transcriptional regulation and its downstream target, enkephalin.

  10. Nuclear cereblon modulates transcriptional activity of Ikaros and regulates its downstream target, enkephalin, in human neuroblastoma cells

    Energy Technology Data Exchange (ETDEWEB)

    Wada, Takeyoshi [Faculty of Science and Engineering, Waseda University, TWIns, 2-2 Wakamatsu, Shinjuku, Tokyo, 162-8480 (Japan); Asahi, Toru [Faculty of Science and Engineering, Waseda University, TWIns, 2-2 Wakamatsu, Shinjuku, Tokyo, 162-8480 (Japan); Research Organization for Nano & Life Innovation, Waseda University #03C309, TWIns, 2-2 Wakamatsu, Shinjuku, Tokyo, 162-8480 (Japan); Sawamura, Naoya, E-mail: naoya.sawamura@gmail.com [Faculty of Science and Engineering, Waseda University, TWIns, 2-2 Wakamatsu, Shinjuku, Tokyo, 162-8480 (Japan); Research Organization for Nano & Life Innovation, Waseda University #03C309, TWIns, 2-2 Wakamatsu, Shinjuku, Tokyo, 162-8480 (Japan)

    2016-08-26

    The gene coding cereblon (CRBN) was originally identified in genetic linkage analysis of mild autosomal recessive nonsyndromic intellectual disability. CRBN has broad localization in both the cytoplasm and nucleus. However, the significance of nuclear CRBN remains unknown. In the present study, we aimed to elucidate the role of CRBN in the nucleus. First, we generated a series of CRBN deletion mutants and determined the regions responsible for the nuclear localization. Only CRBN protein lacking the N-terminal region was localized outside of the nucleus, suggesting that the N-terminal region is important for its nuclear localization. CRBN was also identified as a thalidomide-binding protein and component of the cullin-4-containing E3 ubiquitin ligase complex. Thalidomide has been reported to be involved in the regulation of the transcription factor Ikaros by CRBN-mediated degradation. To investigate the nuclear functions of CRBN, we performed co-immunoprecipitation experiments and evaluated the binding of CRBN to Ikaros. As a result, we found that CRBN was associated with Ikaros protein, and the N-terminal region of CRBN was required for Ikaros binding. In luciferase reporter gene experiments, CRBN modulated transcriptional activity of Ikaros. Furthermore, we found that CRBN modulated Ikaros-mediated transcriptional repression of the proenkephalin gene by binding to its promoter region. These results suggest that CRBN binds to Ikaros via its N-terminal region and regulates transcriptional activities of Ikaros and its downstream target, enkephalin. - Highlights: • We found that CRBN is a nucleocytoplasmic shutting protein and identified the key domain for nucleocytoplasmic shuttling. • CRBN associates with the transcription factor Ikaros via the N-terminal domain. • CRBN modulates Ikaros-mediated transcriptional regulation and its downstream target, enkephalin.

  11. Modulation of chemotherapy-induced cytotoxicity in SH-SY5Y neuroblastoma cells by caffeine and chlorogenic acid.

    Science.gov (United States)

    Hall, Susan; Anoopkumar-Dukie, Shailendra; Grant, Gary D; Desbrow, Ben; Lai, Richard; Arora, Devinder; Hong, Yinna

    2017-06-01

    Chemotherapy is an important treatment modality for malignancy but is limited by significant toxicity and it susceptibility to numerous drug interactions. While the interacting effects with medications are well known, there is limited evidence on the interaction with commonly consumed food and natural products. The aim of this study was to evaluate the bioactive constituents of coffee (caffeine and chlorogenic acid) on the cytotoxicity of doxorubicin, gemcitabine, and paclitaxel in vitro. Pretreatment with caffeine (100 nM and 10 μM) sensitized SH-SY5Y cells to doxorubicin-induced toxicity and increased apoptosis and sensitized PC3 cells to gemcitabine-induced toxicity. Pretreatment with 10 μM caffeine decreased total cell reactive oxygen species (ROS) production but increased mitochondrial ROS production. In contrast, caffeine (10 nM and 10 μM) protected cells against gemcitabine-induced toxicity and apoptosis. Similarly, 1 μM and 10 μM caffeine protected cells against paclitaxel-induced toxicity and mitochondrial ROS production. Chlorogenic acid had no effect on chemotherapy-induced toxicity in SH-SY5Y cells. In conclusion, this study provides preliminary evidence that caffeine, not chlorogenic acid, modulates the cytotoxicity of doxorubicin, gemcitabine, and paclitaxel in SH-SY5Y cells via different mechanisms.

  12. 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

  13. 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.

  14. Study Modules for Calculus-Based General Physics. [Includes Modules 11-14: Collisions; Equilibrium of Rigid Bodies; Rotational Dynamics; and Fluid Mechanics].

    Science.gov (United States)

    Fuller, Robert G., Ed.; And Others

    This is part of a series of 42 Calculus Based Physics (CBP) modules totaling about 1,000 pages. The modules include study guides, practice tests, and mastery tests for a full-year individualized course in calculus-based physics based on the Personalized System of Instruction (PSI). The units are not intended to be used without outside materials;…

  15. Heat shock protein 70 modulates neural progenitor cells dynamics in human neuroblastoma SH-SY5Y cells exposed to high glucose content.

    Science.gov (United States)

    Salimi, Leila; Rahbarghazi, Reza; Jafarian, Vahab; Biray Avci, Çıgır; Goker Bagca, Bakiye; Pinar Ozates, Neslihan; Khaksar, Majid; Nourazarian, Alireza

    2018-01-18

    In the current experiment, detrimental effects of high glucose condition were investigated on human neuroblastoma cells. Human neuroblastoma cell line SH-SY5Y were exposed to 5, 40, and 70 mM glucose over a period of 72 h. Survival rate and the proliferation of cells were analyzed by MTT and BrdU incorporation assays. Apoptosis was studied by the assays of flow cytometry and PCR array. In order to investigate the trans-differentiation capacity of the cell into mature neurons, we used immunofluorescence imaging to follow NeuN protein level. The transcription level of HSP70 was shown by real-time PCR analysis. MMP-2 and -9 activities were shown by gelatin Zymography. According to data from MTT and BrdU incorporation assay, 70 mM glucose reduced cell viability and proliferation rate as compared to control (5 mM glucose) and cells treated with 40 mM glucose (P Cell exposure to 70 mM glucose had potential to induced apoptosis after 72 h (P SH-SY5Y cells to detrimental effects of high glucose condition during trans-differentiation into mature neuron-like cells. Real-time PCR analysis confirmed the expression of HSP70 in cells under high content glucose levels, demonstrating the possible cell compensatory response to an insulting condition (p control vs 70 mM group  cells being exposed to 70 mM glucose. High glucose condition could abrogate the dynamics of neural progenitor cells. The intracellular level of HSP70 was proportional to cell damage in high glucose condition. © 2018 Wiley Periodicals, Inc.

  16. 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.

  17. 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

  18. 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

  19. 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

  20. 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.

  1. 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.

  2. Neuroblastoma | Office of Cancer Genomics

    Science.gov (United States)

    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.

  3. 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

  4. A Hybrid Robotic Control System Using Neuroblastoma Cultures

    Science.gov (United States)

    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.

  5. 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

  6. Structural modulation and luminescent properties of four Cd{sup II} coordination architectures based on 3-(pyridin-4-yl)-5-(pyrazin-2-yl)-1H-1,2,4-triazole and flexible/rigid dicarboxylate ligands

    Energy Technology Data Exchange (ETDEWEB)

    Xia, Liang; Dong, Wen-Wen, E-mail: dongww1@126.com; Ye, Xiao; Zhao, Jun; Li, Dong-Sheng, E-mail: lidongsheng1@126.com

    2016-10-15

    To systematically investigate the influence of the flexible or rigid auxiliary ligands on the structures and properties of transition metal compounds, we synthesized four new d{sup 10} coordination polymers (CPs) from 3-(pyridin-4-yl)-5-(pyrazin-2-yl)-1H-1,2,4-triazole (4-Hpzpt) and flexible/rigid dicarboxylate ligands, [Cd(4-pzpt){sub 2}]{sub n} (1), [Cd{sub 3}(4-pzpt){sub 2}(suc){sub 2}]{sub n} (2), [Cd{sub 2}(4-Hpzpt)(nbc){sub 2}(H{sub 2}O)]{sub n} (3) and ([Cd{sub 2}(4-pzpt){sub 2}(tfbdc)(H{sub 2}O){sub 4}]·H{sub 2}O){sub n} (4) (H{sub 2}suc=1,2-ethanedicarboxylic acid, H{sub 2}nbc=hthalene-1,4-dicarboxylic acid, H{sub 2}tfbdc =2,3,5,6-tetrafluoroterephthalic acid). Single crystal X-ray analysis indicates that compound 1 shows a 4{sup 4}-sql layer, which is extended to a 3D network via nonclassical C–H{sup …}N hydrogen bonds. Compound 2 possesses a 6-connected pcu-4{sup 12}0.6{sup 3} net composed of trinuclear Cd{sup II}-clusters. Compound 3 represents a rare 3D (3,4,4,5)-connected topology with a Schläfli symbol of (4·6·7)(4·5{sup 3}·7{sup 2})(5{sup 3}·6·7·9)(4{sup 2}·5{sup 5}·6·7{sup 2}). Compound 4 exhibits a 2D+2D→2D parallel interpenetrated 6{sup 3}-hcb network. The adjacent 2D networks are interdigitated with each other to form the resulting 3D supramolecular architecture through classical O–H{sup …}N and O–H{sup …}O hydrogen bonds. Structural diversities indicate that the nature of flexible/rigid-dicarboxlates plays crucial roles in modulating structures of these compounds. Moreover, the luminescent properties of them have been briefly investigated. - Graphical abstract: Four new Cd{sup II} coordination architectures constructed from the primary ligand 4-Hpzpt and flexible/rigid dicarboxylate coligands. Structural diversities indicate that the nature of flexible/rigid-dicarboxlates plays crucial roles in modulating structures of these compounds. And more, the thermal stability and luminescence are discussed. - Highlights:

  7. 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.

  8. 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)

  9. Neuroblastoma in Children: Just Diagnosed Information

    Science.gov (United States)

    ... 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 ...

  10. Structural modulation and luminescent properties of four CdII coordination architectures based on 3-(pyridin-4-yl)-5-(pyrazin-2-yl)-1H-1,2,4-triazole and flexible/rigid dicarboxylate ligands

    Science.gov (United States)

    Xia, Liang; Dong, Wen-Wen; Ye, Xiao; Zhao, Jun; Li, Dong-Sheng

    2016-10-01

    To systematically investigate the influence of the flexible or rigid auxiliary ligands on the structures and properties of transition metal compounds, we synthesized four new d10 coordination polymers (CPs) from 3-(pyridin-4-yl)-5-(pyrazin-2-yl)-1H-1,2,4-triazole (4-Hpzpt) and flexible/rigid dicarboxylate ligands, [Cd(4-pzpt)2]n (1), [Cd3(4-pzpt)2(suc)2]n (2), [Cd2(4-Hpzpt)(nbc)2(H2O)]n (3) and {[Cd2(4-pzpt)2(tfbdc)(H2O)4]·H2O}n (4) (H2suc=1,2-ethanedicarboxylic acid, H2nbc=hthalene-1,4-dicarboxylic acid, H2tfbdc =2,3,5,6-tetrafluoroterephthalic acid). Single crystal X-ray analysis indicates that compound 1 shows a 44-sql layer, which is extended to a 3D network via nonclassical C-H…N hydrogen bonds. Compound 2 possesses a 6-connected pcu-4120.63 net composed of trinuclear CdII-clusters. Compound 3 represents a rare 3D (3,4,4,5)-connected topology with a Schläfli symbol of (4·6·7)(4·53·72)(53·6·7·9)(42·55·6·72). Compound 4 exhibits a 2D+2D→2D parallel interpenetrated 63-hcb network. The adjacent 2D networks are interdigitated with each other to form the resulting 3D supramolecular architecture through classical O-H…N and O-H…O hydrogen bonds. Structural diversities indicate that the nature of flexible/rigid-dicarboxlates plays crucial roles in modulating structures of these compounds. Moreover, the luminescent properties of them have been briefly investigated.

  11. The Using of Scientific Based Physics Module in Learning to Enhance High School Students’ Critical Thinking Skills on Rotation Dynamics and Equilibrium of Rigid Body

    Directory of Open Access Journals (Sweden)

    Dhimas Nur Setyawan

    2017-05-01

    Full Text Available The purpose of this study was to determine the effectiveness of using a scientific based physics module to improve high school students' critical thinking skills. This study is a quasi experimental study which uses two classes taken at random experiment consists of one class and the control class. Class experiments using the scientific study using scientific-based modules and classroom experiments using books that have been owned by students. Experimental class numbered 25 students and control class numbered 28 students. The research was conducted in the first half (one Academic Year 2016/2017. The method used is the test method with a pretest-posttest design. Data were analyzed with quantitative and qualitative methods. Data were analyzed using a pretest form of the homogeneity test to find out that the experimental class and controls used homogeneous. Posttest results were analyzed using normality test to determine the normally distributed data, N-gain to determine the increase critical thinking skills, as well as test two parties not bound to determine whether or not there is a difference in the increase in critical thinking skills. Conclusions and recommendations are the use of scientifically-based modules effectively improve the ability to think critically and use physics-based scientific modules should be adjusted to the prevailing syllabus and curriculum so that learning can take place properly.

  12. 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)

  13. 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.

  14. 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)

  15. [Cervical neuroblastoma in an infant].

    Science.gov (United States)

    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.

  16. 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

  17. 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

  18. 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

  19. 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

  20. 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.

  1. 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

  2. Rigidity and symmetry

    CERN Document Server

    Weiss, Asia; Whiteley, Walter

    2014-01-01

    This book contains recent contributions to the fields of rigidity and symmetry with two primary focuses: to present the mathematically rigorous treatment of rigidity of structures, and to explore the interaction of geometry, algebra, and combinatorics. Overall, the book shows how researchers from diverse backgrounds explore connections among the various discrete structures with symmetry as the unifying theme.  Contributions present recent trends and advances in discrete geometry, particularly in the theory of polytopes. The rapid development of abstract polytope theory has resulted in a rich theory featuring an attractive interplay of methods and tools from discrete geometry, group theory, classical geometry, hyperbolic geometry and topology.  The volume will also be a valuable source as an introduction to the ideas of both combinatorial and geometric rigidity theory and its applications, incorporating the surprising impact of symmetry. It will appeal to students at both the advanced undergraduate and gradu...

  3. Birationally rigid varieties

    CERN Document Server

    Pukhlikov, Aleksandr

    2013-01-01

    Birational rigidity is a striking and mysterious phenomenon in higher-dimensional algebraic geometry. It turns out that certain natural families of algebraic varieties (for example, three-dimensional quartics) belong to the same classification type as the projective space but have radically different birational geometric properties. In particular, they admit no non-trivial birational self-maps and cannot be fibred into rational varieties by a rational map. The origins of the theory of birational rigidity are in the work of Max Noether and Fano; however, it was only in 1970 that Iskovskikh and Manin proved birational superrigidity of quartic three-folds. This book gives a systematic exposition of, and a comprehensive introduction to, the theory of birational rigidity, presenting in a uniform way, ideas, techniques, and results that so far could only be found in journal papers. The recent rapid progress in birational geometry and the widening interaction with the neighboring areas generate the growing interest ...

  4. 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

  5. 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.

  6. 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.

  7. 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

  8. 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

  9. Rigid supersymmetry with boundaries

    Energy Technology Data Exchange (ETDEWEB)

    Belyaev, D.V. [Deutsches Elektronen-Synchrotron (DESY), Hamburg (Germany); Van Nieuwenhuizen, P. [State Univ. of New York, Stony Brook, NY (United States). C.N. Yang Inst. for Theoretical Physics

    2008-01-15

    We construct rigidly supersymmetric bulk-plus-boundary actions, both in x-space and in superspace. For each standard supersymmetric bulk action a minimal supersymmetric bulk-plus-boundary action follows from an extended F- or D-term formula. Additional separately supersymmetric boundary actions can be systematically constructed using co-dimension one multiplets (boundary superfields). We also discuss the orbit of boundary conditions which follow from the Euler-Lagrange variational principle. (orig.)

  10. 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.

  11. 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.

  12. Evidence of chromaffin oxygen sensing in neuroblastoma.

    Science.gov (United States)

    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.

  13. 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.

  14. Antitumor Effect of Burchellin Derivatives Against Neuroblastoma.

    Science.gov (United States)

    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.

  15. 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.

  16. 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...

  17. Neuroblastoma

    Science.gov (United States)

    ... the cancer has spread to the bones or bone marrow) weakness, numbness, inability to move a body part, or difficulty walking (if the cancer presses on the spinal cord) drooping eyelid, unequal pupils, sweating, and red ...

  18. 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

  19. 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)

  20. 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

  1. 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

  2. Torsional Rigidity of Minimal Submanifolds

    DEFF Research Database (Denmark)

    Markvorsen, Steen; Palmer, Vicente

    2006-01-01

    We prove explicit upper bounds for the torsional rigidity of extrinsic domains of minimal submanifolds $P^m$ in ambient Riemannian manifolds $N^n$ with a pole $p$. The upper bounds are given in terms of the torsional rigidities of corresponding Schwarz symmetrizations of the domains in warped...

  3. Quantum charged rigid membrane

    Energy Technology Data Exchange (ETDEWEB)

    Cordero, Ruben [Departamento de Fisica, Escuela Superior de Fisica y Matematicas del I.P.N., Unidad Adolfo Lopez Mateos, Edificio 9, 07738 Mexico, D.F. (Mexico); Molgado, Alberto [Unidad Academica de Fisica, Universidad Autonoma de Zacatecas, Zacatecas Zac. (Mexico); Rojas, Efrain, E-mail: cordero@esfm.ipn.mx, E-mail: amolgado@fisica.uaz.edu.mx, E-mail: efrojas@uv.mx [Departamento de Fisica, Facultad de Fisica e Inteligencia Artificial, Universidad Veracruzana, 91000 Xalapa, Veracruz (Mexico)

    2011-03-21

    The early Dirac proposal to model the electron as a charged membrane is reviewed. A rigidity term, instead of the natural membrane tension, involving linearly the extrinsic curvature of the worldvolume swept out by the membrane is considered in the action modeling the bubble in the presence of an electromagnetic field. We set up this model as a genuine second-order derivative theory by considering a non-trivial boundary term which plays a relevant part in our formulation. The Lagrangian in question is linear in the bubble acceleration and by means of the Ostrogradski-Hamiltonian approach, we observed that the theory comprises the management of both first- and second-class constraints. We thus show that our second-order approach is robust allowing for a proper quantization. We found an effective quantum potential which permits us to compute bounded states for the system. We comment on the possibility of describing brane world universes by invoking this kind of second-order correction terms.

  4. Quantum charged rigid membrane

    International Nuclear Information System (INIS)

    Cordero, Ruben; Molgado, Alberto; Rojas, Efrain

    2011-01-01

    The early Dirac proposal to model the electron as a charged membrane is reviewed. A rigidity term, instead of the natural membrane tension, involving linearly the extrinsic curvature of the worldvolume swept out by the membrane is considered in the action modeling the bubble in the presence of an electromagnetic field. We set up this model as a genuine second-order derivative theory by considering a non-trivial boundary term which plays a relevant part in our formulation. The Lagrangian in question is linear in the bubble acceleration and by means of the Ostrogradski-Hamiltonian approach, we observed that the theory comprises the management of both first- and second-class constraints. We thus show that our second-order approach is robust allowing for a proper quantization. We found an effective quantum potential which permits us to compute bounded states for the system. We comment on the possibility of describing brane world universes by invoking this kind of second-order correction terms.

  5. Modeling the Flexural Rigidity of Rod Photoreceptors

    Science.gov (United States)

    Haeri, Mohammad; Knox, Barry E.; Ahmadi, Aphrodite

    2013-01-01

    In vertebrate eyes, the rod photoreceptor has a modified cilium with an extended cylindrical structure specialized for phototransduction called the outer segment (OS). The OS has numerous stacked membrane disks and can bend or break when subjected to mechanical forces. The OS exhibits axial structural variation, with extended bands composed of a few hundred membrane disks whose thickness is diurnally modulated. Using high-resolution confocal microscopy, we have observed OS flexing and disruption in live transgenic Xenopus rods. Based on the experimental observations, we introduce a coarse-grained model of OS mechanical rigidity using elasticity theory, representing the axial OS banding explicitly via a spring-bead model. We calculate a bending stiffness of ∼105 nN⋅μm2, which is seven orders-of-magnitude larger than that of typical cilia and flagella. This bending stiffness has a quadratic relation to OS radius, so that thinner OS have lower fragility. Furthermore, we find that increasing the spatial frequency of axial OS banding decreases OS rigidity, reducing its fragility. Moreover, the model predicts a tendency for OS to break in bands with higher spring number density, analogous to the experimental observation that transgenic rods tended to break preferentially in bands of high fluorescence. We discuss how pathological alterations of disk membrane properties by mutant proteins may lead to increased OS rigidity and thus increased breakage, ultimately contributing to retinal degeneration. PMID:23442852

  6. 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.

  7. 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.

  8. Symmetry breaking in human neuroblastoma cells

    Science.gov (United States)

    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

  9. On flexible and rigid nouns

    DEFF Research Database (Denmark)

    Rijkhoff, Jan

    2010-01-01

    classes. Finally this article wants to claim that the distinction between rigid and flexible noun categories (a) adds a new dimension to current classifications of parts of speech systems, (b) correlates with certain grammatical phenomena (e.g. so-called number discord), and (c) helps to explain the parts......This article argues that in addition to the major flexible lexical categories in Hengeveld’s classification of parts of speech systems (Contentive, Non-Verb, Modifier), there are also flexible word classes within the rigid lexical category Noun (Set Noun, Sort Noun, General Noun). Members...... by the flexible item in the external world. I will then argue that flexible word classes constitute a proper category (i.e. they are not the result of a merger of some rigid word classes) in that members of flexible word categories display the same properties regarding category membership as members of rigid word...

  10. 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.)

  11. 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...

  12. 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.

  13. 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.)

  14. 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

  15. 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

  16. Neuroblastoma: treatment outcome after incomplete resection of primary tumors.

    Science.gov (United States)

    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.

  17. Rigid multibody system dynamics with uncertain rigid bodies

    Energy Technology Data Exchange (ETDEWEB)

    Batou, A., E-mail: anas.batou@univ-paris-est.fr; Soize, C., E-mail: christian.soize@univ-paris-est.fr [Universite Paris-Est, Laboratoire Modelisation et Simulation Multi Echelle, MSME UMR 8208 CNRS (France)

    2012-03-15

    This paper is devoted to the construction of a probabilistic model of uncertain rigid bodies for multibody system dynamics. We first construct a stochastic model of an uncertain rigid body by replacing the mass, the center of mass, and the tensor of inertia by random variables. The prior probability distributions of the stochastic model are constructed using the maximum entropy principle under the constraints defined by the available information. The generators of independent realizations corresponding to the prior probability distribution of these random quantities are further developed. Then several uncertain rigid bodies can be linked to each other in order to calculate the random response of a multibody dynamical system. An application is proposed to illustrate the theoretical development.

  18. Rigidity of Glasses and Macromolecules

    Science.gov (United States)

    Thorpe, M. F.

    1998-03-01

    The simple yet powerful ideas of percolation theory have found their way into many different areas of research. In this talk we show how RIGIDITY PERCOLATION can be studied at a similar level of sophistication, using a powerful new program THE PEBBLE GAME (D. J. Jacobs and M. F. Thorpe, Phys. Rev. E) 53, 3682 (1996). that uses an integer algorithm. This program can analyse the rigidity of two and three dimensional networks containing more than one million bars and joints. We find the total number of floppy modes, and find the critical behavior as the network goes from floppy to rigid as more bars are added. We discuss the relevance of this work to network glasses, and how it relates to experiments that involve the mechanical properties like hardness and elasticity of covalent glassy networks like Ge_xAs_ySe_1-x-y and dicuss recent experiments that suggest that the rigidity transition may be first order (Xingwei Feng, W. J.Bresser and P. Boolchand, Phys. Rev. Lett 78), 4422 (1997).. This approach is also useful in macromolecules and proteins, where detailed information about the rigid domain structure can be obtained.

  19. 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

  20. Rigidly foldable origami gadgets and tessellations

    Science.gov (United States)

    Evans, Thomas A.; Lang, Robert J.; Magleby, Spencer P.; Howell, Larry L.

    2015-01-01

    Rigidly foldable origami allows for motion where all deflection occurs at the crease lines and facilitates the application of origami in materials other than paper. In this paper, we use a recently discovered method for determining rigid foldability to identify existing flat-foldable rigidly foldable tessellations, which are also categorized. We introduce rigidly foldable origami gadgets which may be used to modify existing tessellations or to create new tessellations. Several modified and new rigidly foldable tessellations are presented. PMID:26473037

  1. 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

  2. Rho-associated kinase is a therapeutic target in neuroblastoma.

    Science.gov (United States)

    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.

  3. 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

  4. 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.

  5. Rigidity-tuning conductive elastomer

    Science.gov (United States)

    Shan, Wanliang; Diller, Stuart; Tutcuoglu, Abbas; Majidi, Carmel

    2015-06-01

    We introduce a conductive propylene-based elastomer (cPBE) that rapidly and reversibly changes its mechanical rigidity when powered with electrical current. The elastomer is rigid in its natural state, with an elastic (Young’s) modulus of 175.5 MPa, and softens when electrically activated. By embedding the cPBE in an electrically insulating sheet of polydimethylsiloxane (PDMS), we create a cPBE-PDMS composite that can reversibly change its tensile modulus between 37 and 1.5 MPa. The rigidity change takes ˜6 s and is initiated when a 100 V voltage drop is applied across the two ends of the cPBE film. This magnitude of change in elastic rigidity is similar to that observed in natural skeletal muscle and catch connective tissue. We characterize the tunable load-bearing capability of the cPBE-PDMS composite with a motorized tensile test and deadweight experiment. Lastly, we demonstrate the ability to control the routing of internal forces by embedding several cPBE-PDMS ‘active tendons’ into a soft robotic pneumatic bending actuator. Selectively activating the artificial tendons controls the neutral axis and direction of bending during inflation.

  6. Rigidity-tuning conductive elastomer

    International Nuclear Information System (INIS)

    Shan, Wanliang; Diller, Stuart; Tutcuoglu, Abbas; Majidi, Carmel

    2015-01-01

    We introduce a conductive propylene-based elastomer (cPBE) that rapidly and reversibly changes its mechanical rigidity when powered with electrical current. The elastomer is rigid in its natural state, with an elastic (Young’s) modulus of 175.5 MPa, and softens when electrically activated. By embedding the cPBE in an electrically insulating sheet of polydimethylsiloxane (PDMS), we create a cPBE–PDMS composite that can reversibly change its tensile modulus between 37 and 1.5 MPa. The rigidity change takes ∼6 s and is initiated when a 100 V voltage drop is applied across the two ends of the cPBE film. This magnitude of change in elastic rigidity is similar to that observed in natural skeletal muscle and catch connective tissue. We characterize the tunable load-bearing capability of the cPBE–PDMS composite with a motorized tensile test and deadweight experiment. Lastly, we demonstrate the ability to control the routing of internal forces by embedding several cPBE–PDMS ‘active tendons’ into a soft robotic pneumatic bending actuator. Selectively activating the artificial tendons controls the neutral axis and direction of bending during inflation. (paper)

  7. PKA, novel PKC isoforms, and ERK is mediating PACAP auto-regulation via PAC1R in human neuroblastoma NB-1 cells

    DEFF Research Database (Denmark)

    Georg, Birgitte; Falktoft, Birgitte; Fahrenkrug, Jan

    2016-01-01

    The neuropeptide PACAP is expressed throughout the central and peripheral nervous system where it modulates diverse physiological functions including neuropeptide gene expression. We here report that in human neuroblastoma NB-1 cells PACAP transiently induces its own expression. Maximal PACAP m...... induction. Experiments using siRNA against EGR1 to lower the expression did however not affect the PACAP auto-regulation indicating that this immediate early gene product is not part of PACAP auto-regulation in NB-1 cells. We here reveal that in NB-1 neuroblastoma cells, PACAP induces its own expression...

  8. 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

  9. 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

  10. Proton Radiotherapy for High-Risk Pediatric Neuroblastoma: Early Outcomes and Dose Comparison

    Energy Technology Data Exchange (ETDEWEB)

    Hattangadi, Jona A. [Harvard Radiation Oncology Program, Boston, MA (United States); Rombi, Barbara [Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA (United States); Provincial Agency for Proton Therapy, Trento (Italy); Yock, Torunn I.; Broussard, George [Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA (United States); Friedmann, Alison M.; Huang, Mary [Department of Pediatric Hematology-Oncology, Massachusetts General Hospital, Boston, MA (United States); Chen, Yen-Lin E.; Lu, Hsiao-Ming; Kooy, Hanne [Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA (United States); MacDonald, Shannon M., E-mail: smacdonald@partners.org [Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA (United States)

    2012-07-01

    Purpose: To report the early outcomes for children with high-risk neuroblastoma treated with proton radiotherapy (RT) and to compare the dose distributions for intensity-modulated photon RT (IMRT), three-dimensional conformal proton RT (3D-CPT), and intensity-modulated proton RT to the postoperative tumor bed. Methods and Materials: All patients with high-risk (International Neuroblastoma Staging System Stage III or IV) neuroblastoma treated between 2005 and 2010 at our institution were included. All patients received induction chemotherapy, surgical resection of residual disease, high-dose chemotherapy with stem cell rescue, and adjuvant 3D-CPT to the primary tumor sites. The patients were followed with clinical examinations, imaging, and laboratory testing every 6 months to monitor disease control and side effects. IMRT, 3D-CPT, and intensity-modulated proton RT plans were generated and compared for a representative case of adjuvant RT to the primary tumor bed followed by a boost. Results: Nine patients were treated with 3D-CPT. The median age at diagnosis was 2 years (range 10 months to 4 years), and all patients had Stage IV disease. All patients had unfavorable histologic characteristics (poorly differentiated histologic features in 8, N-Myc amplification in 6, and 1p/11q chromosomal abnormalities in 4). The median tumor size at diagnosis was 11.4 cm (range 7-16) in maximal dimension. At a median follow-up of 38 months (range 11-70), there were no local failures. Four patients developed distant failure, and, of these, two died of disease. Acute side effects included Grade 1 skin erythema in 5 patients and Grade 2 anorexia in 2 patients. Although comparable target coverage was achieved with all three modalities, proton therapy achieved substantial normal tissue sparing compared with IMRT. Intensity-modulated proton RT allowed additional sparing of the kidneys, lungs, and heart. Conclusions: Preliminary outcomes reveal excellent local control with proton therapy

  11. 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

  12. On flexible and rigid nouns

    DEFF Research Database (Denmark)

    Rijkhoff, Jan

    2008-01-01

    Studies in Language 32-3 (2008), 727-752. Special issue: Parts of Speech: Descriptive tools, theoretical constructs Jan Rijkhoff - On flexible and rigid nouns This article argues that in addition to the flexible lexical categories in Hengeveld’s classification of parts-of-speech systems (Contentive......, Non-Verb, Modifier), there are also flexible word classes within the rigid lexical category Noun (Set Noun, Sort Noun, General Noun). Members of flexible word classes are characterized by their vague semantics, which in the case of nouns means that values for the semantic features Shape...... and Homogeneity are either left undetermined or they are specified in such a way that they do not quite match the properties of the kind of entity denoted by the flexible item in the external world. I will then argue that flexible word classes constitute a proper category (i.e. they are not the result of a merger...

  13. Elasticity of Relativistic Rigid Bodies?

    Science.gov (United States)

    Smarandache, Florentin

    2013-10-01

    In the classical Twin Paradox, according to the Special Theory of Relativity, when the traveling twin blasts off from the Earth to a relative velocity v =√{/3 } 2 c with respect to the Earth, his measuring stick and other physical objects in the direction of relative motion shrink to half their lengths. How is that possible in the real physical world to have let's say a rigid rocket shrinking to half and then later elongated back to normal as an elastic material when it stops? What is the explanation for the traveler's measuring stick and other physical objects, in effect, return to the same length to their original length in the Stay-At-Home, but there is no record of their having shrunk? If it's a rigid (not elastic) object, how can it shrink and then elongate back to normal? It might get broken in such situation.

  14. Functionally rigid bistable [2]rotaxanes

    DEFF Research Database (Denmark)

    Nygaard, Sune; Leung, Ken C-F; Aprahamian, Ivan

    2007-01-01

    defines an unambiguous distance of 1.5 nm over which the ring moves between the MPTTF and NP units. The degenerate NP/NP [2]rotaxane was used to investigate the shuttling barrier by dynamic 1H NMR spectroscopy for the movement of the CBPQT4+ ring across the new rigid spacer. It is evident from...... better control over the position of the ring component in the ground state but also for control over the location of the CBPQT4+ ring during solution-state switching experiments, triggered either chemically (1H NMR) or electrochemically (cyclic voltammetry). In this instance, the use of the rigid spacer......Two-station [2]rotaxanes in the shape of a degenerate naphthalene (NP) shuttle and a nondegenerate monopyrrolotetrathiafulvalene (MPTTF)/NP redox-controllable switch have been synthesized and characterized in solution. Their dumbbell-shaped components are composed of polyether chains interrupted...

  15. Rigid body dynamics of mechanisms

    CERN Document Server

    Hahn, Hubert

    2003-01-01

    The second volume of Rigid Body Dynamics of Mechanisms covers applications via a systematic method for deriving model equations of planar and spatial mechanisms. The necessary theoretical foundations have been laid in the first volume that introduces the theoretical mechanical aspects of mechatronic systems. Here the focus is on the application of the modeling methodology to various examples of rigid-body mechanisms, simple planar ones as well as more challenging spatial problems. A rich variety of joint models, active constraints, plus active and passive force elements is treated. The book is intended for self-study by working engineers and students concerned with the control of mechanical systems, i.e. robotics, mechatronics, vehicles, and machine tools. The examples included are a likely source from which to choose models for university lectures.

  16. Associative memory through rigid origami

    Science.gov (United States)

    Murugan, Arvind; Brenner, Michael

    2015-03-01

    Mechanisms such as Miura Ori have proven useful in diverse contexts since they have only one degree of freedom that is easily controlled. We combine the theory of rigid origami and associative memory in frustrated neural networks to create structures that can ``learn'' multiple generic folding mechanisms and yet can be robustly controlled. We show that such rigid origami structures can ``recall'' a specific learned mechanism when induced by a physical impulse that only need resemble the desired mechanism (i.e. robust recall through association). Such associative memory in matter, seen before in self-assembly, arises due to a balance between local promiscuity (i.e., many local degrees of freedom) and global frustration which minimizes interference between different learned behaviors. Origami with associative memory can lead to a new class of deployable structures and kinetic architectures with multiple context-dependent behaviors.

  17. Rigidity spectrum of Forbush decrease

    International Nuclear Information System (INIS)

    Sakakibara, S.; Munakata, K.; Nagashima, K.

    1985-01-01

    Using data from neutron monitors and muon telescopes at surface and underground stations, the average rigidity spectrum of Forbush decreases (Fds) during the period of 1978-1982 were obtained. Thirty eight Ed-events are classified into two groups, Hard Fd and Soft FD according to size of Fd at the Sakashita station. It is found that a spectral form of a fractional-power type (P to the-gamma sub 1 (P+P sub c) to the -gamma sub2) is more suitable than that of a power-exponential type or of a power type with an upper limiting rigidity. The best fitted spectrum of the fractional-power type is expressed by gamma sub1 = 0.37, gamma sub2 = 0.89 and P subc = 10 GV for Hard Fd and gamma sub1 = 0.77, gamma sub2 = 1.02 and P sub c - 14GV for Soft Fd

  18. Signature of Thermal Rigidity Percolation

    International Nuclear Information System (INIS)

    Huerta, Adrián

    2013-01-01

    To explore the role that temperature and percolation of rigidity play in determining the macroscopic properties, we propose a model that adds translational degrees of freedom to the spins of the well known Ising hamiltonian. In particular, the Ising model illustrate the longstanding idea that the growth of correlations on approach to a critical point could be describable in terms of the percolation of some sort of p hysical cluster . For certain parameters of this model we observe two well defined peaks of C V , that suggest the existence of two kinds of p hysical percolation , namely connectivity and rigidity percolation. Thermal fluctuations give rise to two different kinds of elementary excitations, i.e. droplets and configuron, as suggested by Angell in the framework of a bond lattice model approach. The later is reflected in the fluctuations of redundant constraints that gives stability to the structure and correlate with the order parameter

  19. Torsional rigidity, isospectrality and quantum graphs

    International Nuclear Information System (INIS)

    Colladay, Don; McDonald, Patrick; Kaganovskiy, Leon

    2017-01-01

    We study torsional rigidity for graph and quantum graph analogs of well-known pairs of isospectral non-isometric planar domains. We prove that such isospectral pairs are distinguished by torsional rigidity. (paper)

  20. 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

  1. Rigidity of monodromies for Appell's hypergeometric functions

    Directory of Open Access Journals (Sweden)

    Yoshishige Haraoka

    2015-01-01

    Full Text Available For monodromy representations of holonomic systems, the rigidity can be defined. We examine the rigidity of the monodromy representations for Appell's hypergeometric functions, and get the representations explicitly. The results show how the topology of the singular locus and the spectral types of the local monodromies work for the study of the rigidity.

  2. 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

  3. Geometry, rigidity, and group actions

    CERN Document Server

    Farb, Benson; Zimmer, Robert J

    2011-01-01

    The study of group actions is more than a hundred years old but remains to this day a vibrant and widely studied topic in a variety of mathematic fields. A central development in the last fifty years is the phenomenon of rigidity, whereby one can classify actions of certain groups, such as lattices in semi-simple Lie groups. This provides a way to classify all possible symmetries of important spaces and all spaces admitting given symmetries. Paradigmatic results can be found in the seminal work of George Mostow, Gergory Margulis, and Robert J. Zimmer, among others.The p

  4. 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-.

  5. 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.)

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

    Directory of Open Access Journals (Sweden)

    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

  7. 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.

  8. /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

  9. Olfactory neuroblastoma complicated by postirradiation pneumocephalus

    Energy Technology Data Exchange (ETDEWEB)

    Fusejima, Toru; Matsumura, Kenichirou; Hayano, Makoto [Mito Saiseikai Hospital (Japan)

    1990-11-01

    A 56-year-old male was admitted with the complaints of nasal bleeding, gait disturbance, and disturbance of consciousness. Neurological examination revealed drowsiness, right hemiparesis, and choked discs. Computed tomography scan showed an enhanced mass at the frontal base, which extended to the left nasal and paranasal cavities. Angiography showed a tumor stain with a mass sign. The intracranial part of the tumor was removed completely and he was discharged ambulatorily. Two months after surgery, however, he was admitted again for the regrowth of the tumor. Ventriculoperitoneal shunting was emplaced and radiation therapy was given to the brain and nasal cavity. After 3000 rad irradiation the clinical condition suddenly became worse because of pneumocephalus. The cranial tumor disappeared after irradiation but he died of metastases and general prostration. Clinically this case was diagnosed as an olfactory groove meningioma at first, but immunohistochemical diagnosis was olfactory neuroblastoma. (author).

  10. Mesenchymal change and drug resistance in neuroblastoma.

    Science.gov (United States)

    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.

  11. Proton-Beam Therapy for Olfactory Neuroblastoma

    International Nuclear Information System (INIS)

    Nishimura, Hideki; Ogino, Takashi; Kawashima, Mitsuhiko; Nihei, Keiji; Arahira, Satoko; Onozawa, Masakatsu; Katsuta, Shoichi; Nishio, Teiji

    2007-01-01

    Purpose: To analyze the feasibility and efficacy of proton-beam therapy (PBT) for olfactory neuroblastoma (ONB) as a definitive treatment, by reviewing our preliminary experience. Olfactory neuroblastoma is a rare disease, and a standard treatment strategy has not been established. Radiation therapy for ONB is challenging because of the proximity of ONBs to critical organs. Proton-beam therapy can provide better dose distribution compared with X-ray irradiation because of its physical characteristics, and is deemed to be a feasible treatment modality. Methods and Materials: A retrospective review was performed on 14 patients who underwent PBT for ONB as definitive treatment at the National Cancer Center Hospital East (Kashiwa, Chiba, Japan) from November 1999 to February 2005. A total dose of PBT was 65 cobalt Gray equivalents (Gy E ), with 2.5-Gy E once-daily fractionations. Results: The median follow-up period for surviving patients was 40 months. One patient died from disseminated disease. There were two persistent diseases, one of which was successfully salvaged with surgery. The 5-year overall survival rate was 93%, the 5-year local progression-free survival rate was 84%, and the 5-year relapse-free survival rate was 71%. Liquorrhea was observed in one patient with Kadish's stage C disease (widely destroying the skull base). Most patients experienced Grade 1 to 2 dermatitis in the acute phase. No other adverse events of Grade 3 or greater were observed according to the RTOG/EORTC acute and late morbidity scoring system. Conclusions: Our preliminary results of PBT for ONB achieved excellent local control and survival outcomes without serious adverse effects. Proton-beam therapy is considered a safe and effective modality that warrants further study

  12. 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

  13. Rigid-beam model of a high-efficiency magnicon

    International Nuclear Information System (INIS)

    Rees, D.E.; Tallerico, P.J.; Humphries, S.J. Jr.

    1993-01-01

    The magnicon is a new type of high-efficiency deflection-modulated amplifier developed at the Institute of Nuclear Physics in Novosibirsk, Russia. The prototype pulsed magnicon achieved an output power of 2.4 MW and an efficiency of 73% at 915 MHz. This paper presents the results of a rigid-beam model for a 700-MHz, 2.5-MW 82%-efficient magnicon. The rigid-beam model allows for characterization of the beam dynamics by tracking only a single electron. The magnicon design presented consists of a drive cavity; passive cavities; a pi-mode, coupled-deflection cavity; and an output cavity. It represents an optimized design. The model is fully self-consistent, and this paper presents the details of the model and calculated performance of a 2.5-MW magnicon

  14. Partial ring currents and cosmic ray magnetic cutoff rigidity variations

    International Nuclear Information System (INIS)

    Arens, M.

    1978-01-01

    A short introduction on cosmic ray modulation and a description of the magnetosphere, and of some physical processes occurring within its boundaries are presented. 20 geomagnetic storms are analysed together with the cosmic ray intensities during these storms as measured by Neutron Monitors. Using a semi-empirical method, the variations in the magnetic cutoff rigidity for the mountain stations Pic du Midi and Jungfraujoch are deduced. These stations are the most sensitive for measuring these variations. The analysis shows that all analyzed storms have an asymmetric development phase. Often the asymmetry even continues during part of the recovery phase. It is shown that variations in magnetic cutoff rigidity occur only during the asymmetric phase of the storm. The largest variations are found when the cosmic ray station is located in the late afternoon-midnight sector. (Auth.)

  15. Matrix rigidity regulates cancer cell growth and cellular phenotype.

    Directory of Open Access Journals (Sweden)

    Robert W Tilghman

    2010-09-01

    Full Text Available The mechanical properties of the extracellular matrix have an important role in cell growth and differentiation. However, it is unclear as to what extent cancer cells respond to changes in the mechanical properties (rigidity/stiffness of the microenvironment and how this response varies among cancer cell lines.In this study we used a recently developed 96-well plate system that arrays extracellular matrix-conjugated polyacrylamide gels that increase in stiffness by at least 50-fold across the plate. This plate was used to determine how changes in the rigidity of the extracellular matrix modulate the biological properties of tumor cells. The cell lines tested fall into one of two categories based on their proliferation on substrates of differing stiffness: "rigidity dependent" (those which show an increase in cell growth as extracellular rigidity is increased, and "rigidity independent" (those which grow equally on both soft and stiff substrates. Cells which grew poorly on soft gels also showed decreased spreading and migration under these conditions. More importantly, seeding the cell lines into the lungs of nude mice revealed that the ability of cells to grow on soft gels in vitro correlated with their ability to grow in a soft tissue environment in vivo. The lung carcinoma line A549 responded to culture on soft gels by expressing the differentiated epithelial marker E-cadherin and decreasing the expression of the mesenchymal transcription factor Slug.These observations suggest that the mechanical properties of the matrix environment play a significant role in regulating the proliferation and the morphological properties of cancer cells. Further, the multiwell format of the soft-plate assay is a useful and effective adjunct to established 3-dimensional cell culture models.

  16. Matrix Rigidity Regulates Cancer Cell Growth and Cellular Phenotype

    Science.gov (United States)

    Tilghman, Robert W.; Cowan, Catharine R.; Mih, Justin D.; Koryakina, Yulia; Gioeli, Daniel; Slack-Davis, Jill K.; Blackman, Brett R.; Tschumperlin, Daniel J.; Parsons, J. Thomas

    2010-01-01

    Background The mechanical properties of the extracellular matrix have an important role in cell growth and differentiation. However, it is unclear as to what extent cancer cells respond to changes in the mechanical properties (rigidity/stiffness) of the microenvironment and how this response varies among cancer cell lines. Methodology/Principal Findings In this study we used a recently developed 96-well plate system that arrays extracellular matrix-conjugated polyacrylamide gels that increase in stiffness by at least 50-fold across the plate. This plate was used to determine how changes in the rigidity of the extracellular matrix modulate the biological properties of tumor cells. The cell lines tested fall into one of two categories based on their proliferation on substrates of differing stiffness: “rigidity dependent” (those which show an increase in cell growth as extracellular rigidity is increased), and “rigidity independent” (those which grow equally on both soft and stiff substrates). Cells which grew poorly on soft gels also showed decreased spreading and migration under these conditions. More importantly, seeding the cell lines into the lungs of nude mice revealed that the ability of cells to grow on soft gels in vitro correlated with their ability to grow in a soft tissue environment in vivo. The lung carcinoma line A549 responded to culture on soft gels by expressing the differentiated epithelial marker E-cadherin and decreasing the expression of the mesenchymal transcription factor Slug. Conclusions/Significance These observations suggest that the mechanical properties of the matrix environment play a significant role in regulating the proliferation and the morphological properties of cancer cells. Further, the multiwell format of the soft-plate assay is a useful and effective adjunct to established 3-dimensional cell culture models. PMID:20886123

  17. 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

  18. Silencing Intersectin 1 Slows Orthotopic Neuroblastoma Growth in Mice.

    Science.gov (United States)

    Harris, Jamie; Herrero-Garcia, Erika; Russo, Angela; Kajdacsy-Balla, Andre; O'Bryan, John P; Chiu, Bill

    2017-11-01

    Neuroblastoma accounts for 15% of all pediatric cancer deaths. Intersectin 1 (ITSN1), a scaffold protein involved in phosphoinositide 3-kinase (PI3K) signaling, regulates neuroblastoma cells independent of MYCN status. We hypothesize that by silencing ITSN1 in neuroblastoma cells, tumor growth will be decreased in an orthotopic mouse tumor model. SK-N-AS neuroblastoma cells transfected with empty vector (pSR), vectors expressing scrambled shRNA (pSCR), or shRNAs targeting ITSN1 (sh#1 and sh#2) were used to create orthotopic neuroblastoma tumors in mice. Volume was monitored weekly with ultrasound. End-point was tumor volume >1000 mm. Tumor cell lysates were analyzed with anti-ITSN1 antibody by Western blot. Orthotopic tumors were created in all cell lines. Twenty-five days post injection, pSR tumor size was 917.6±247.7 mm, pSCR was 1180±159.9 mm, sh#1 was 526.3±212.8 mm, and sh#2 was 589.2±74.91 mm. sh#1-tumors and sh#2-tumors were smaller than pSCR (P=0.02), no difference between sh#1 and sh#2. Survival was superior in sh#2-tumors (P=0.02), trended towards improved survival in sh#1-tumors (P=0.09), compared with pSCR-tumors, no difference in pSR tumors. Western blot showed decreased ITSN1 expression in sh#1 and sh#2 compared with pSR and pSCR. Silencing ITSN1 in neuroblastoma cells led to decreased tumor growth in an orthotopic mouse model. Orthotopic animal models can provide insight into the role of ITSN1 pathways in neuroblastoma tumorigenesis.

  19. Telomerase activation by genomic rearrangements in high-risk neuroblastoma

    Science.gov (United States)

    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

  20. 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

  1. 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

  2. Involvement of triacylglycerol in the metabolism of fatty acids by cultured neuroblastoma and glioma cells

    International Nuclear Information System (INIS)

    Cook, H.W.; Clarke, J.T.; Spence, M.W.

    1982-01-01

    The metabolism (chain elongation, desaturation, and incorporation into complex lipids) of thirteen different radiolabeled fatty acids and acetate was examined in N1E-115 neuroblastoma and C-6 glioma cell lines in culture. During 6-hr incubations, all fatty acids were extensively (14-80%) esterified to complex lipids, mainly choline phosphoglycerides and triacylglycerol. With trienoic and tetraenoic substrates, inositol and ethanolamine phosphoglycerides also contained up to 30% of the labeled fatty acids; plasmalogen contained up to half of the label in the ethanolamine phosphoglyceride fraction of neuroblastoma cells. Chain elongation and delta 9, delta 6, and delta 5 desaturation occurred in both cell lines; delta 4 desaturation was not observed. Seemingly anomalous utilization of arachidic acid and some selectivity based on the geometric configuration of double bonds was observed. These studies indicate that these cell lines are capable of modulating cellular membrane composition by a combination of selective exclusion and removal of inappropriate acyl chains and of modification of other acyl chains by desaturation and chain elongation. The time courses and patterns of modification and incorporation of exogenous substrates into phospholipids and triacylglycerol suggest that exogenous unsaturated fatty acid may be incorporated into triacylglycerol and later released for further metabolism and incorporation into phospholipids. This supports a role for triacylglycerol in the synthesis of membrane complex lipids in cell lines derived from neural tissue

  3. 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.

  4. Autoantibody signature differentiates Wilms tumor patients from neuroblastoma patients.

    Directory of Open Access Journals (Sweden)

    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.

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

    Science.gov (United States)

    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.

  6. 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.

  7. 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.

  8. 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)

  9. 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

  10. Topological orders in rigid states

    International Nuclear Information System (INIS)

    Wen, X.G.

    1990-01-01

    The authors study a new kind of ordering topological order in rigid states (the states with no local gapless excitations). This paper concentrates on characterization of the different topological orders. As an example the authors discuss in detail chiral spin states of 2+1 dimensional spin systems. Chiral spin states are described by the topological Chern-Simons theories in the continuum limit. The authors show that the topological orders can be characterized by a non-Abelian gauge structure over the moduli space which parametrizes a family of the model Hamiltonians supporting topologically ordered ground states. In 2 + 1 dimensions, the non-Abelian gauge structure determines possible fractional statistics of the quasi-particle excitations over the topologically ordered ground states. The dynamics of the low lying global excitations is shown to be independent of random spatial dependent perturbations. The ground state degeneracy and the non-Abelian gauge structures discussed in this paper are very robust, even against those perturbations that break translation symmetry. The authors also discuss the symmetry properties of the degenerate ground states of chiral spin states. The authors find that some degenerate ground states of chiral spin states on torus carry non-trivial quantum numbers of the 90 degrees rotation

  11. 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

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

    Science.gov (United States)

    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.

  13. 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

  14. 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.

  15. 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)

  16. 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

  17. Anti-angiogenic SPARC peptides inhibit progression of neuroblastoma tumors

    Directory of Open Access Journals (Sweden)

    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.

  18. 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.

  19. 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

  20. Estrogen receptor α enhances the transcriptional activity of ETS-1 and promotes the proliferation, migration and invasion of neuroblastoma cell in a ligand dependent manner

    International Nuclear Information System (INIS)

    Cao, Peng; Feng, Fan; Dong, Guofu; Yu, Chunyong; Feng, Sizhe; Song, Erlin; Shi, Guobing; Liang, Yong; Liang, Guobiao

    2015-01-01

    It is well known that estrogen receptor α (ERα) participates in the pathogenic progress of breast cancer, hepatocellular carcinoma and head and neck squamous cell carcinoma. In neuroblastoma cells and related cancer clinical specimens, moreover, the ectopic expression of ERα has been identified. However, the detailed function of ERα in the proliferation of neuroblastoma cell is yet unclear. The transcriptional activity of ETS-1 (E26 transformation specific sequence 1) was measured by luciferase analysis. Western blot assays and Real-time RT-PCR were used to examine the expression of ERα, ETS-1 and its targeted genes. The protein-protein interaction between ERα and ETS-1 was determined by co-IP and GST-Pull down assays. The accumulation of ETS-1 in nuclear was detected by western blot assays, and the recruitment of ETS-1 to its targeted gene’s promoter was tested by ChIP assays. Moreover, SH-SY5Y cells’ proliferation, anchor-independent growth, migration and invasion were quantified using the MTT, soft agar or Trans-well assay, respectively. The transcriptional activity of ETS-1 was significantly increased following estrogen treatment, and this effect was related to ligand-mediated activation of ERα. The interaction between the ERα and ETS-1 was identified, and enhancement of ERα activation would up-regulate the ETS-1 transcription factor activity via modulating its cytoplasm/nucleus translocation and the recruitment of ETS-1 to its target gene’s promoter. Furthermore, treatment of estrogen increased proliferation, migration and invasion of neuroblastoma cells, whereas the antagonist of ERα reduced those effects. In this study, we provided evidences that activation of ERα promoted neuroblastoma cells proliferation and up-regulated the transcriptional activity of ETS-1. By investigating the role of ERα in the ETS-1 activity regulation, we demonstrated that ERα may be a novel ETS-1 co-activator and thus a potential therapeutic target in human

  1. 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

  2. Hedgehog signaling pathway in neuroblastoma differentiation.

    Science.gov (United States)

    Souzaki, Ryota; Tajiri, Tatsuro; Souzaki, Masae; Kinoshita, Yoshiaki; Tanaka, Sakura; Kohashi, Kenichi; Oda, Yoshinao; Katano, Mitsuo; Taguchi, Tomoaki

    2010-12-01

    The hedgehog (Hh) signaling pathway is activated in some adult cancers. On the other hand, the Hh signaling pathway plays an important role in the development of the neural crest in embryos. The aim of this study is to show the activation of Hh signaling pathway in neuroblastoma (NB), a pediatric malignancy arising from neural crest cells, and to reveal the meaning of the Hh signaling pathway in NB development. This study analyzed the expression of Sonic hedgehog (Shh), GLI1, and Patched 1 (Ptch1), transactivators of Hh signaling pathway, by immunohistochemistry in 82 NB and 10 ganglioneuroblastoma cases. All 92 cases were evaluated for the status of MYCN amplification. Of the 92 cases, 67 (73%) were positive for Shh, 62 cases (67%) were positive for GLI1, and 73 cases (79%) were positive for Ptch1. Only 2 (10%) of the 20 cases with MYCN amplification were positive for Shh and GLI1, and 4 cases (20%) were positive for Ptch1 (MYCN amplification vs no MYCN amplification, P ≦ .01). The percentage of GLI1-positive cells in the cases with INSS stage 1 without MYCN amplification was significantly higher than that with INSS stage 4. Of 72 cases without MYCN amplification, 60 were GLI1-positive. Twelve cases were GLI1-negative, and the prognosis of the GLI1-positive cases was significantly better than that of the GLI1-negative cases (P = .015). Most of NBs without MYCN amplification were positive for Shh, GLI1, and Ptch1. In the cases without MYCN amplification, the high expression of GLI1 was significantly associated with early clinical stage and a good prognosis of the patients. In contrast to adult cancers, the activation of the Hh signaling pathway in NB may be associated with the differentiation of the NB. Copyright © 2010 Elsevier Inc. All rights reserved.

  3. Analysis of Switched-Rigid Floating Oscillator

    Directory of Open Access Journals (Sweden)

    Prabhakar R. Marur

    2009-01-01

    Full Text Available In explicit finite element simulations, a technique called deformable-to-rigid (D2R switching is used routinely to reduce the computation time. Using the D2R option, the deformable parts in the model can be switched to rigid and reverted back to deformable when needed during the analysis. The time of activation of D2R however influences the overall dynamics of the system being analyzed. In this paper, a theoretical basis for the selection of time of rigid switching based on system energy is established. A floating oscillator problem is investigated for this purpose and closed-form analytical expressions are derived for different phases in rigid switching. The analytical expressions are validated by comparing the theoretical results with numerical computations.

  4. Rigid pricing and rationally inattentive consumer

    Czech Academy of Sciences Publication Activity Database

    Matějka, Filip

    158 B, July (2015), s. 656-678 ISSN 0022-0531 Institutional support: PRVOUK-P23 Keywords : rational inattention * imperfect information * nominal rigidity Subject RIV: AH - Economics Impact factor: 1.097, year: 2015

  5. Rigid pricing and rationally inattentive consumer

    Czech Academy of Sciences Publication Activity Database

    Matějka, Filip

    158 B, July (2015), s. 656-678 ISSN 0022-0531 Institutional support: RVO:67985998 Keywords : rational inattention * imperfect information * nominal rigidity Subject RIV: AH - Economics Impact factor: 1.097, year: 2015

  6. Soft soils reinforced by rigid vertical inclusions

    Directory of Open Access Journals (Sweden)

    Iulia-Victoria NEAGOE

    2013-12-01

    Full Text Available Reinforcement of soft soils by rigid vertical inclusions is an increasingly used technique over the last few years. The system consists of rigid or semi-rigid vertical inclusions and a granular platform for the loads transfer from the structure to the inclusions. This technique aims to reduce the differential settlements both at ground level as below the structure. Reinforcement by rigid inclusions is mainly used for foundation works for large commercial and industrial platforms, storage tanks, wastewater treatment plants, wind farms, bridges, roads, railway embankments. The subject is one of interest as it proves the recently concerns at international level in research and design; however, most studies deal more with the static behavior and less with the dynamic one.

  7. 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

  8. Flexible and rigid cystoscopy in women.

    Science.gov (United States)

    Gee, Jason R; Waterman, Bradley J; Jarrard, David F; Hedican, Sean P; Bruskewitz, Reginald C; Nakada, Stephen Y

    2009-01-01

    Previous studies have evaluated the tolerability of rigid versus flexible cystoscopy in men. Similar studies, however, have not been performed in women. We sought to determine whether office-based flexible cystoscopy was better tolerated than rigid cystoscopy in women. Following full IRB approval, women were prospectively randomized in a single-blind manner. Patients were randomized to flexible or rigid cystoscopy and draped in the lithotomy position to maintain blinding of the study. Questionnaires evaluated discomfort before, during, and after cystoscopy. Thirty-six women were randomized to flexible (18) or rigid (18) cystoscopy. Indications were surveillance (16), hematuria (15), recurrent UTIs (2), voiding dysfunction (1), and other (2). All questionnaires were returned by 31/36 women. Using a 10-point visual analog scale (VAS), median discomfort during the procedure for flexible and rigid cystoscopy were 1.4 and 1.8, respectively, in patients perceiving pain. Median recalled pain 1 week later was similar at 0.8 and 1.15, respectively. None of these differences were statistically significant. Flexible and rigid cystoscopy are well tolerated in women. Discomfort during and after the procedure is minimal in both groups. Urologists should perform either procedure in women based on their preference and skill level.

  9. KIF1Bβ and Neuroblastoma: Failure to Divide and Cull

    OpenAIRE

    Blackstone, Craig

    2016-01-01

    Neuroblastomas are associated with KIF1Bβ mutations within tumor suppressor region 1p36. In this issue of Developmental Cell, Li et al. (2016) show that KIF1Bβ binding releases calcineurin autoinhibition, leading to dephosphorylation of the DRP1 GTPase and subsequent mitochondrial fragmentation. KIF1Bβ impairment causes mitochondrial hyperfusion, impairing developmental apoptosis and promoting tumorigenesis.

  10. Intracranial route of a cervical neuroblastoma through skull base foramina

    International Nuclear Information System (INIS)

    Goldberg, R.M.; Keller, I.A.; Schonfeld, S.M.; Mezrich, R.S.; Rosenfeld, D.L.

    1996-01-01

    A case of primary cervical neuroblastoma gaining access to the cerebellopontine angle via direct perineural spread is described. MRI effectively delineated soft tissues, while CT demonstrated tumor calcifications and the integrity of adjacent bones. Both imaging modalities were beneficial in predicting the unique histology and pattern of disease confirmed at surgery. (orig.). With 1 fig

  11. 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.)

  12. 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.

  13. Rigid Body Sampling and Individual Time Stepping for Rigid-Fluid Coupling of Fluid Simulation

    Directory of Open Access Journals (Sweden)

    Xiaokun Wang

    2017-01-01

    Full Text Available In this paper, we propose an efficient and simple rigid-fluid coupling scheme with scientific programming algorithms for particle-based fluid simulation and three-dimensional visualization. Our approach samples the surface of rigid bodies with boundary particles that interact with fluids. It contains two procedures, that is, surface sampling and sampling relaxation, which insures uniform distribution of particles with less iterations. Furthermore, we present a rigid-fluid coupling scheme integrating individual time stepping to rigid-fluid coupling, which gains an obvious speedup compared to previous method. The experimental results demonstrate the effectiveness of our approach.

  14. 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.

  15. 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.

  16. Cosmic ray modulation

    Science.gov (United States)

    Agarwal Mishra, Rekha; Mishra, Rajesh Kumar

    2016-07-01

    Propagation of cosmic rays to and inside the heliosphere, encounter an outward moving solar wind with cyclic magnetic field fluctuation and turbulence, causing convection and diffusion in the heliosphere. Cosmic ray counts from the ground ground-based neutron monitors at different cut of rigidity show intensity changes, which are anti-correlated with sunspot numbers. They also lose energy as they propagate towards the Earth and experience various types of modulations due to different solar activity indices. In this work, we study the first three harmonics of cosmic ray intensity on geo-magnetically quiet days over the period 1965-2014 for Beijing, Moscow and Tokyo neutron monitoring stations located at different cut off rigidity. The amplitude of first harmonic remains high for low cutoff rigidity as compared to high cutoff rigidity on quiet days. The diurnal amplitude significantly decreases during solar activity minimum years. The diurnal time of maximum significantly shifts to an earlier time as compared to the corotational direction having different cutoff rigidities. The time of maximum for first harmonic significantly shifts towards later hours and for second harmonic it shifts towards earlier hours at low cutoff rigidity station as compared to the high cut off rigidity station on quiet days. The amplitude of second/third harmonics shows a good positive correlation with solar wind velocity, while the others (i.e. amplitude and phase) have no significant correlation on quiet days. The amplitude and direction of the anisotropy on quiet days does not show any significant dependence on high-speed solar wind streams for these neutron monitoring stations of different cutoff rigidity threshold. Keywords: cosmic ray, cut off rigidity, quiet days, harmonics, amplitude, phase.

  17. 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

  18. Olfactory neuroblastoma: a single-center experience.

    Science.gov (United States)

    König, Marton; Osnes, Terje; Jebsen, Peter; Evensen, Jan Folkvard; Meling, Torstein R

    2018-01-01

    Olfactory neuroblastoma (ONB) is a potentially curable disease, despite being an aggressive malignancy with a poor natural history. Our goal was to evaluate management outcomes for patients with ONB treated at our institution. Our prospective database for brain tumors and the pathology registry of head and neck cancers at Oslo University Hospital were searched to identify all patients treated for ONB between 1998 and 2016. Variables extracted from these databases, supplemented by retrospective chart reviews, underwent thorough analysis. All cases were formally re-examined by a dedicated head and neck pathologist. Twenty patients were identified. Follow-up was 100%. Mean follow-up was 81.5 months for the entire cohort and 120.3 months for patients with no evidence of disease. Fourteen patients underwent treatment of choice including craniofacial resection (CFR) with or without radiotherapy (XRT). Six patients could only receive less extensive treatment; three patients underwent lateral rhinotomy (LR) with or without XRT after being deemed medically unsuitable for CFR, while another three patients received only supportive, non-surgical treatment (due to positive lymph node status in two and to extensive tumor size in one case). Overall and disease-specific survival rates were 100% after 10 years of follow-up when negative surgical margins were achieved by CFR. Positive margins were associated with poorer outcome with no patients surviving longer than 44 months. Long-term survival was also achieved in two cases among patients not eligible for CFR: one case after radical LR and one case after radio-chemotherapy. Advanced disease at presentation (tumor size ≥40 mm, Kadish grades C and D, or TNM IVa and IVb) and positive surgical margins were correlated to significantly dismal survival. Our study suggests that CFR with or without adjuvant XRT is safe and leads to excellent long-time overall and disease-specific survival. Negative surgical margins, tumor size <40

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

    Science.gov (United States)

    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.

  20. Identifying Floppy and Rigid Regions in Proteins

    Science.gov (United States)

    Jacobs, D. J.; Thorpe, M. F.; Kuhn, L. A.

    1998-03-01

    In proteins it is possible to separate hard covalent forces involving bond lengths and bond angles from other weak forces. We model the microstructure of the protein as a generic bar-joint truss framework, where the hard covalent forces and strong hydrogen bonds are regarded as rigid bar constraints. We study the mechanical stability of proteins using FIRST (Floppy Inclusions and Rigid Substructure Topography) based on a recently developed combinatorial constraint counting algorithm (the 3D Pebble Game), which is a generalization of the 2D pebble game (D. J. Jacobs and M. F. Thorpe, ``Generic Rigidity: The Pebble Game'', Phys. Rev. Lett.) 75, 4051-4054 (1995) for the special class of bond-bending networks (D. J. Jacobs, "Generic Rigidity in Three Dimensional Bond-bending Networks", Preprint Aug (1997)). This approach is useful in identifying rigid motifs and flexible linkages in proteins, and thereby determines the essential degrees of freedom. We will show some preliminary results from the FIRST analysis on the myohemerythrin and lyozyme proteins.

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

    OpenAIRE

    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...

  2. 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.)

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

  4. Quantum mechanics of a generalised rigid body

    International Nuclear Information System (INIS)

    Gripaios, Ben; Sutherland, Dave

    2016-01-01

    We consider the quantum version of Arnold’s generalisation of a rigid body in classical mechanics. Thus, we quantise the motion on an arbitrary Lie group manifold of a particle whose classical trajectories correspond to the geodesics of any one-sided-invariant metric. We show how the derivation of the spectrum of energy eigenstates can be simplified by making use of automorphisms of the Lie algebra and (for groups of type I) by methods of harmonic analysis. We show how the method can be extended to cosets, generalising the linear rigid rotor. As examples, we consider all connected and simply connected Lie groups up to dimension 3. This includes the universal cover of the archetypical rigid body, along with a number of new exactly solvable models. We also discuss a possible application to the topical problem of quantising a perfect fluid. (paper)

  5. Durable bistable auxetics made of rigid solids

    Science.gov (United States)

    Shang, Xiao; Liu, Lu; Rafsanjani, Ahmad; Pasini, Damiano

    2018-02-01

    Bistable Auxetic Metamaterials (BAMs) are a class of monolithic perforated periodic structures with negative Poisson's ratio. Under tension, a BAM can expand and reach a second state of equilibrium through a globally large shape transformation that is ensured by the flexibility of its elastomeric base material. However, if made from a rigid polymer, or metal, BAM ceases to function due to the inevitable rupture of its ligaments. The goal of this work is to extend the unique functionality of the original kirigami architecture of BAM to a rigid solid base material. We use experiments and numerical simulations to assess performance, bistability and durability of rigid BAMs at 10,000 cycles. Geometric maps are presented to elucidate the role of the main descriptors of BAM architecture. The proposed design enables the realization of BAM from a large palette of materials, including elastic-perfectly plastic materials and potentially brittle materials.

  6. Molecular galactose-galectin association in neuroblastoma cells: An unconventional tool for qualitative/quantitative screening.

    Science.gov (United States)

    Pastorino, Fabio; Ponzoni, Mirco; Simone, Giuseppina

    2017-05-01

    Galectin decorates the cell membrane and forms an extracellular molecular association with galactoside units. Here, galactoside probes have been used to study galectin expression in neuroblastoma cells. The hypothesis behind this investigation has been that the molecular mechanisms by which glycans modulate neural metastatic cells involve a protein-carbohydrate association, galectin-galactose. Preliminary screening to validate the hypothesis has been performed with galactose moieties anchored to beads. The molecular association has been studied by FACS. In vitro experiments reveal the molecular binding preferences of the metastatic neuroblastoma cells. Ex vivo, the galactose probes discriminate healthy tissues. The unconventional assay in microfluidics used in this study displayed results analogous to the above (GI-LI-N cell capture efficiency overcomes IMR-32). At the point of equilibrium of shear and binding forces, the capture yield inside the chamber was measured to 60 ± 4.4% in GI-LI-N versus 40 ± 2.1% in IMR-32. Staining of the fished cells and subsequent conjugation with red beads bearing the galactose also have evidenced that microfluidics can be used to study and quantify the molecular association of galectin-galactose. Most importantly, a crucial insight for obtaining single-cell qualitative/quantitative glycome analysis has been achieved. Finally, the specificity of the assay performed in microfluidics is demonstrated by comparing GI-LI-N fishing efficiency in galactose and fucose environments. The residual adhesion to fucose confirmed the existence of receptors for this glycan and that its eventual unspecific binding (i.e. due to electrostatic interactions) is insignificant compared with the molecular binding. Identification and understanding of this mechanism of discrimination can be relevant for diagnostic monitoring and for producing probes tailored to interfere with galectin activities associated with the malignant phenotype. Besides, the given

  7. 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.

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

    Science.gov (United States)

    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.

  9. 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

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

    Science.gov (United States)

    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.

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

    International Nuclear Information System (INIS)

    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.

  12. Effect of rigid inclusions on sintering

    International Nuclear Information System (INIS)

    Rahaman, M.N.; De Jonghe, L.C.

    1988-01-01

    The predictions of recent theoretical studies on the effect of inert, rigid inclusions on the sintering of ceramic powder matrices are examined and compared with experimental data. The densification of glass matrix composites with inclusion volume fractions of ≤0.15 can be adequately explained by Scherer's theory for viscous sintering with rigid inclusions. Inclusions cause a vast reduction in the densification rates of polycrystalline matrix composites even at low inclusion volume fractions. Models put forward to explain the sintering of polycrystalline matrix composites are discussed

  13. Type number and rigidity of fibred surfaces

    International Nuclear Information System (INIS)

    Markov, P E

    2001-01-01

    Infinitesimal l-th order bendings, 1≤l≤∞, of higher-dimensional surfaces are considered in higher-dimensional flat spaces (for l=∞ an infinitesimal bending is assumed to be an analytic bending). In terms of the Allendoerfer type number, criteria are established for the (r,l)-rigidity (in the terminology of Sabitov) of such surfaces. In particular, an (r,l)-infinitesimal analogue is proved of the classical theorem of Allendoerfer on the unbendability of surfaces with type number ≥3 and the class of (r,l)-rigid fibred surfaces is distinguished

  14. Rigid origami vertices: conditions and forcing sets

    Directory of Open Access Journals (Sweden)

    Zachary Abel

    2016-04-01

    Full Text Available We develop an intrinsic necessary and sufficient condition for single-vertex origami crease patterns to be able to fold rigidly.  We classify such patterns in the case where the creases are pre-assigned to be mountains and valleys as well as in the unassigned case.  We also illustrate the utility of this result by applying it to the new concept of minimal forcing sets for rigid origami models, which are the smallest collection of creases that, when folded, will force all the other creases to fold in a prescribed way.

  15. Evaluating a method for automated rigid registration

    DEFF Research Database (Denmark)

    Darkner, Sune; Vester-Christensen, Martin; Larsen, Rasmus

    2007-01-01

    to point distance. T-test for common mean are used to determine the performance of the two methods (supported by a Wilcoxon signed rank test). The performance influence of sampling density, sampling quantity, and norms is analyzed using a similar method.......We evaluate a novel method for fully automated rigid registration of 2D manifolds in 3D space based on distance maps, the Gibbs sampler and Iterated Conditional Modes (ICM). The method is tested against the ICP considered as the gold standard for automated rigid registration. Furthermore...

  16. Nucleolar protein PES1 is a marker of neuroblastoma outcome and is associated with neuroblastoma differentiation

    Science.gov (United States)

    Nakaguro, Masato; Kiyonari, Shinichi; Kishida, Satoshi; Cao, Dongliang; Murakami-Tonami, Yuko; Ichikawa, Hitoshi; Takeuchi, Ichiro; Nakamura, Shigeo; Kadomatsu, Kenji

    2015-01-01

    Neuroblastoma (NB) is a childhood malignant tumor that arises from precursor cells of the sympathetic nervous system. Spontaneous regression is a phenomenon unique to NBs and is caused by differentiation of tumor cells. PES1 is a multifunctional protein with roles in both neural development and ribosome biogenesis. Various kinds of models have revealed the significance of PES1 in neurodevelopment. However, the roles of PES1 in NB tumorigenesis and differentiation have remained unknown. Here we show that NB cases with MYCN amplification and clinically unfavorable stage (INSS stage 4) express higher levels of PES1. High PES1 expression was associated with worse overall and relapse-free survival. In NB cell lines, PES1 knockdown suppressed tumor cell growth and induced apoptosis. This growth inhibition was associated with the expression of NB differentiation markers. However, when the differentiation of NB cell lines was induced by the use of all-trans retinoic acid, there was a corresponding decrease in PES1 expression. Pes1 expression of tumorspheres originated from MYCN transgenic mice also diminished after the induction of differentiation with growth factors. We also reanalyzed the distribution of PES1 in the nucleolus. PES1 was localized in the dense fibrillar component, but not in the granular component of nucleoli. After treatment with the DNA-damaging agent camptothecin, this distribution was dramatically changed to diffuse nucleoplasmic. These data suggest that PES1 is a marker of NB outcome, that it regulates NB cell proliferation, and is associated with NB differentiation. PMID:25557119

  17. A 6-gene signature identifies four molecular subgroups of neuroblastoma

    OpenAIRE

    Abel, Frida; Dalevi, Daniel; Nethander, Maria; Jörnsten, Rebecka; De Preter, Katleen; Vermeulen, Joëlle; Stallings, Raymond; Kogner, Per; Maris, John; Nilsson, Staffan

    2011-01-01

    Abstract Background There are currently three postulated genomic subtypes of the childhood tumour neuroblastoma (NB); Type 1, Type 2A, and Type 2B. The most aggressive forms of NB are characterized by amplification of the oncogene MYCN (MNA) and low expression of the favourable marker NTRK1. Recently, mutations or high expression of the familial predisposition gene Anaplastic Lymphoma Kinase (ALK) was associated to unfavourable biology of sporadic NB. Also, various other genes have been linke...

  18. 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.

  19. PPAR Gamma in Neuroblastoma: The Translational Perspectives of Hypoglycemic Drugs

    OpenAIRE

    Vella, Serena; Conaldi, Pier Giulio; Florio, Tullio; Pagano, Aldo

    2016-01-01

    Neuroblastoma (NB) is the most common and aggressive pediatric cancer, characterized by a remarkable phenotypic diversity and high malignancy. The heterogeneous clinical behavior, ranging from spontaneous remission to fatal metastatic disease, is attributable to NB biology and genetics. Despite major advances in therapies, NB is still associated with a high morbidity and mortality. Thus, novel diagnostic, prognostic, and therapeutic approaches are required, mainly to improve treatment outcome...

  20. Targeting neuroblastoma stem cells with retinoic acid and proteasome inhibitor.

    Directory of Open Access Journals (Sweden)

    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.

  1. 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

  2. Rapidly Evoluting Congenital Cystic Neuroblastoma in a Neonate

    Energy Technology Data Exchange (ETDEWEB)

    Yun, Tae Jun; Kim, Myung Jun; Han, Seok Joo; Lee, Mi Jung [Severance Children' s Hospital, Yonsei University, College of Medicine, Seoul(Korea, Republic of)

    2012-08-15

    Perinatal detection of neonatal suprarenal masses has increased. Here, we report an unusual case of an adrenal cystic neuroblastoma that presented as a purely cystic lesion upon initial postnatal ultrasonography (US) and showed rapid evolution to a mixed cystic and solid mass during follow-up US and MRI. We suggest a short-term (two weeks) follow-up US for neonatal adrenal cystic lesions, even if they appear as purely cystic.

  3. Geometric integrators for stochastic rigid body dynamics

    KAUST Repository

    Tretyakov, Mikhail

    2016-01-05

    Geometric integrators play an important role in simulating dynamical systems on long time intervals with high accuracy. We will illustrate geometric integration ideas within the stochastic context, mostly on examples of stochastic thermostats for rigid body dynamics. The talk will be mainly based on joint recent work with Rusland Davidchak and Tom Ouldridge.

  4. Combinatorial and Algorithmic Rigidity: Beyond Two Dimensions

    Science.gov (United States)

    2012-12-01

    44]. Theorems of Maxwell- Laman type were ob- tained in [9, 15, 43]. 2 3. Counting and Enumeration. As anticipated in the project, we relied on methods...decompositions. Graphs and Combinatorics, 25:219–238, 2009. [43] I. Streinu and L. Theran. Slider-pinning rigidity: a Maxwell- Laman -type theorem. Discrete and

  5. Birationally rigid varieties. I. Fano varieties

    International Nuclear Information System (INIS)

    Pukhlikov, A V

    2007-01-01

    The theory of birational rigidity of rationally connected varieties generalises the classical rationality problem. This paper gives a survey of the current state of this theory and traces its history from Noether's theorem and the Lueroth problem to the latest results on the birational superrigidity of higher-dimensional Fano varieties. The main components of the method of maximal singularities are considered.

  6. Rigid polyurethane and kenaf core composite foams

    Science.gov (United States)

    Rigid polyurethane foams are valuable in many construction applications. Kenaf is a bast fiber plant where the surface stem skin provides bast fibers whose strength-to-weight ratio competes with glass fiber. The higher volume product of the kenaf core is an under-investigated area in composite appli...

  7. Geometric integrators for stochastic rigid body dynamics

    KAUST Repository

    Tretyakov, Mikhail

    2016-01-01

    Geometric integrators play an important role in simulating dynamical systems on long time intervals with high accuracy. We will illustrate geometric integration ideas within the stochastic context, mostly on examples of stochastic thermostats for rigid body dynamics. The talk will be mainly based on joint recent work with Rusland Davidchak and Tom Ouldridge.

  8. Rigidity Sensing Explained by Active Matter Theory

    OpenAIRE

    Marcq, Philippe; Yoshinaga, Natsuhiko; Prost, Jacques

    2011-01-01

    The magnitude of traction forces exerted by living animal cells on their environment is a monotonically increasing and approximately sigmoidal function of the stiffness of the external medium. We rationalize this observation using active matter theory, and propose that adaptation to substrate rigidity results from an interplay between passive elasticity and active contractility.

  9. About deformation and rigidity in relativity

    International Nuclear Information System (INIS)

    Coll, Bartolome

    2007-01-01

    The notion of deformation involves that of rigidity. In relativity, starting from Born's early definition of rigidity, some other ones have been proposed, offering more or less interesting aspects but also accompanied of undesired or even pathological properties. In order to clarify the origin of these difficulties presented by the notion of rigidity in relativity, we analyze with some detail significant aspects of the unambiguous classical, Newtonian, notion. In particular, the relative character of its kinetic definition is pointed out, allowing to predict and to understand the limitations imposed by Herglotz-Noether theorem. Also, its equivalent dynamic definition is obtained and, in contrast, its absolute character is shown. But in spite of this absolute character, the dynamic definition is shown to be not extensible to relativity. The metric deformation of Minkowski space by the presence of a gravitational field is interpreted as a universal deformation, and it is shown that, under natural conditions, only a simple deformation law is possible, relating locally, but in an one-to-one way, gravitational fields and gauge classes of two-forms. We argue that fields of unit vectors associated to the internal gauge class of two-forms of every space-time (and, in particular, of Minkowski space-time) are the relativistic analogues of the classical accelerated observers, i.e. of the classical rigid motions. Some other consequences of the universal law of gravitational deformation are commented

  10. Rigid pricing and rationally inattentive consumer

    Czech Academy of Sciences Publication Activity Database

    Matějka, Filip

    2010-01-01

    Roč. 20, č. 2 (2010), s. 1-40 ISSN 1211-3298 R&D Projects: GA MŠk LC542 Institutional research plan: CEZ:AV0Z70850503 Keywords : rational inattention * nominal rigidity Subject RIV: AH - Economics http://www.cerge-ei.cz/pdf/wp/Wp409.pdf

  11. Cracking of open traffic rigid pavement

    Directory of Open Access Journals (Sweden)

    Niken Chatarina

    2017-01-01

    Full Text Available The research is done by observing the growth of real structure cracking in Natar, Lampung, Indonesia compared to C. Niken’s et al research and literature study. The rigid pavement was done with open traffic system. There are two main crack types on Natar rigid pavement: cracks cross the road, and cracks spreads on rigid pavement surface. The observation of cracks was analyzed by analyzing material, casting, curing, loading and shrinkage mechanism. The relationship between these analysis and shrinkage mechanism was studied in concrete micro structure. Open traffic make hydration process occur under vibration; therefore, fresh concrete was compressed and tensioned alternately since beginning. High temperature together with compression, cement dissociation, the growth of Ca2+ at very early age leads abnormal swelling. No prevention from outside water movement leads hydration process occur with limited water which caused spreads fine cracks. Limited water improves shrinkage and plastic phase becomes shorter; therefore, rigid pavement can’t accommodate the abnormal swelling and shrinking alternately and creates the spread of cracks. Discontinuing casting the concrete makes both mix under different condition, the first is shrink and the second is swell and creates weak line on the border; so, the cracks appear as cracks across the road.

  12. 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.

  13. The genetic landscape of high-risk neuroblastoma.

    Science.gov (United States)

    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.

  14. The genetic landscape of high-risk neuroblastoma

    Science.gov (United States)

    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

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

    Directory of Open Access Journals (Sweden)

    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.

  16. 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.)

  17. Rigid Spine Syndrome among Children in Oman

    Directory of Open Access Journals (Sweden)

    Roshan Koul

    2015-08-01

    Full Text Available Objectives: Rigidity of the spine is common in adults but is rarely observed in children. The aim of this study was to report on rigid spine syndrome (RSS among children in Oman. Methods: Data on children diagnosed with RSS were collected consecutively at presentation between 1996 and 2014 at the Sultan Qaboos University Hospital (SQUH in Muscat, Oman. A diagnosis of RSS was based on the patient’s history, clinical examination, biochemical investigations, electrophysiological findings, neuro-imaging and muscle biopsy. Atrophy of the paraspinal muscles, particularly the erector spinae, was the diagnostic feature; this was noted using magnetic resonance imaging of the spine. Children with disease onset in the paraspinal muscles were labelled as having primary RSS or rigid spinal muscular dystrophy. Secondary RSS was classified as RSS due to the late involvement of other muscle diseases. Results: Over the 18-year period, 12 children were included in the study, with a maleto- female ratio of 9:3. A total of 10 children were found to have primary RSS or rigid spinal muscular dystrophy syndrome while two had secondary RSS. Onset of the disease ranged from birth to 18 months of age. A family history was noted, with two siblings from one family and three siblings from another (n = 5. On examination, children with primary RSS had typical features of severe spine rigidity at onset, with the rest of the neurological examination being normal. Conclusion: RSS is a rare disease with only 12 reported cases found at SQUH during the study period. Cases of primary RSS should be differentiated from the secondary type.

  18. 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.

  19. The two-body problem of a pseudo-rigid body and a rigid sphere

    DEFF Research Database (Denmark)

    Kristiansen, Kristian Uldall; Vereshchagin, M.; Gózdziewski, K.

    2012-01-01

    n this paper we consider the two-body problem of a spherical pseudo-rigid body and a rigid sphere. Due to the rotational and "re-labelling" symmetries, the system is shown to possess conservation of angular momentum and circulation. We follow a reduction procedure similar to that undertaken...... in the study of the two-body problem of a rigid body and a sphere so that the computed reduced non-canonical Hamiltonian takes a similar form. We then consider relative equilibria and show that the notions of locally central and planar equilibria coincide. Finally, we show that Riemann's theorem on pseudo......-rigid bodies has an extension to this system for planar relative equilibria....

  20. Molecular mechanisms of MYCN-dependent apoptosis and the MDM2–p53 pathway: an Achille’s heel to be exploited for the therapy of MYCN-amplified neuroblastoma

    International Nuclear Information System (INIS)

    Petroni, Marialaura; Veschi, Veronica; Gulino, Alberto; Giannini, Giuseppe

    2012-01-01

    The p53 oncosuppressor is very seldom mutated in neuroblastoma, but several mechanisms cooperate to its functional inactivation in this tumor. Increased MDM2 levels, due to genetic amplification or constitutive inhibition of p14 ARF , significantly contribute to this event highlighting p53 reactivation as an attractive perspective for neuroblastoma treatment. In addition to its role in tumorigenesis, MYCN sensitizes untransformed and cancer cells to apoptosis. This is associated to a fine modulation of the MDM2–p53 pathway. Indeed MYCN induces p53 and MDM2 transcription, and, by evoking a DNA damage response (DDR), it stabilizes p53 and its proapoptotic kinase Homeodomain Interacting Protein Kinase 2 (HIPK2). Through the regulation of the HIPK2-p53 inhibitor High Mobility Group protein A1 (HMGA1) and the homeobox proteins BMI-1 and TWIST-1, MYCN establishes a delicate balance between pro- and antiapoptotic molecules that might be easily perturbed by a variety of insults, leading to cell death. MDM2–p53 antagonists, such as Nutlin-3, are strikingly prone to inducing death in MYCN-amplified neuroblastoma, by further pushing on HIPK2 accumulation. Here we discuss implications and caveats of exploiting this pathway and its connections to MYCN-induced DDR for a tailored therapy of MYCN-amplified neuroblastoma.

  1. Molecular mechanisms of MYCN-dependent apoptosis and the MDM2-p53 pathway: an Achille’s heel to be exploited for the therapy of MYCN amplified neuroblastoma

    Directory of Open Access Journals (Sweden)

    Marialaura ePetroni

    2012-10-01

    Full Text Available The p53 oncosuppressor is very seldom mutated in neuroblastoma, but several mechanisms cooperate to its functional inactivation in this tumor. Increased MDM2 levels, due to genetic amplification or constitutive inhibition of p14ARF, significantly contribute to this event highlighting p53 reactivation as an attractive perspective for neuroblastoma treatment.In addition to its role in tumorigenesis, MYCN sensitizes untransformed and cancer cells to apoptosis. This is associated to a fine modulation of the MDM2-p53 pathway. Indeed MYCN induces p53 and MDM2 transcription, and, by evoking a DNA damage response (DDR, it stabilizes p53 and its proapoptotic kinase HIPK2. Through the regulation of the HIPK2-p53 inhibitor HMGA1 and the homeobox proteins BMI-1 and TWIST-1, MYCN establishes a delicate balance between pro- and anti-apoptotic molecules that might be easily perturbed by a variety of insults, leading to cell death. MDM2-p53 antagonists, such as Nutlin-3, are strikingly prone to inducing death in MYCN-amplified neuroblastoma, by further pushing on HIPK2 accumulation. Here we discuss implications and caveats of exploiting this pathway and its connections to MYCN-induced DDR for a tailored therapy of MYCN-amplified neuroblastoma.

  2. Molecular mechanisms of MYCN-dependent apoptosis and the MDM2–p53 pathway: an Achille’s heel to be exploited for the therapy of MYCN-amplified neuroblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Petroni, Marialaura; Veschi, Veronica; Gulino, Alberto; Giannini, Giuseppe, E-mail: giuseppe.giannini@uniroma1.it [Department of Molecular Medicine, University “La Sapienza”, Rome (Italy)

    2012-10-12

    The p53 oncosuppressor is very seldom mutated in neuroblastoma, but several mechanisms cooperate to its functional inactivation in this tumor. Increased MDM2 levels, due to genetic amplification or constitutive inhibition of p14{sup ARF}, significantly contribute to this event highlighting p53 reactivation as an attractive perspective for neuroblastoma treatment. In addition to its role in tumorigenesis, MYCN sensitizes untransformed and cancer cells to apoptosis. This is associated to a fine modulation of the MDM2–p53 pathway. Indeed MYCN induces p53 and MDM2 transcription, and, by evoking a DNA damage response (DDR), it stabilizes p53 and its proapoptotic kinase Homeodomain Interacting Protein Kinase 2 (HIPK2). Through the regulation of the HIPK2-p53 inhibitor High Mobility Group protein A1 (HMGA1) and the homeobox proteins BMI-1 and TWIST-1, MYCN establishes a delicate balance between pro- and antiapoptotic molecules that might be easily perturbed by a variety of insults, leading to cell death. MDM2–p53 antagonists, such as Nutlin-3, are strikingly prone to inducing death in MYCN-amplified neuroblastoma, by further pushing on HIPK2 accumulation. Here we discuss implications and caveats of exploiting this pathway and its connections to MYCN-induced DDR for a tailored therapy of MYCN-amplified neuroblastoma.

  3. From Wage Rigidities to Labour Market Rigidities: A Turning-Point in Explaining Equilibrium Unemployment?

    OpenAIRE

    Marco Guerrazzi; Nicola Meccheri

    2009-01-01

    This paper offers a critical discussion of the concept of labour market rigidity relevant to explaining unemployment. Starting from Keynes’s own view, we discuss how the concept of labour market flexibility has changed over time, involving nominal or real wage flexibility, contract flexibility or labour market institution flexibility. We also provide a critical assessment of the factors that lead the search framework highlighting labour market rigidities (frictions) to challenge the more wide...

  4. 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

  5. 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

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

    Science.gov (United States)

    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

  7. 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.

  8. 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.

  9. 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

  10. 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.)

  11. 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

  12. 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

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

    Science.gov (United States)

    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.

  14. 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....

  15. 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.

  16. Financial Constraints and Nominal Price Rigidities

    DEFF Research Database (Denmark)

    Menno, Dominik Francesco; Balleer, Almut; Hristov, Nikolay

    This paper investigates how financial market imperfections and the frequency of price adjustment interact. Based on new firm-level evidence for Germany, we document that financially constrained firms adjust prices more often than their unconstrained counterparts, both upwards and downwards. We show...... that these empirical patterns are consistent with a partial equilibrium menu-cost model with a working capital constraint. We then use the model to show how the presence of financial frictions changes profits and the price distribution of firms compared to a model without financial frictions. Our results suggest...... that tighter financial constraints are associated with higher nominal rigidities, higher prices and lower output. Moreover, in response to aggregate shocks, aggregate price rigidity moves substantially, the response of inflation is dampened, while output reacts more in the presence of financial frictions...

  17. Rigidity of the magic pentagram game

    Science.gov (United States)

    Kalev, Amir; Miller, Carl A.

    2018-01-01

    A game is rigid if a near-optimal score guarantees, under the sole assumption of the validity of quantum mechanics, that the players are using an approximately unique quantum strategy. Rigidity has a vital role in quantum cryptography as it permits a strictly classical user to trust behavior in the quantum realm. This property can be traced back as far as 1998 (Mayers and Yao) and has been proved for multiple classes of games. In this paper we prove ridigity for the magic pentagram game, a simple binary constraint satisfaction game involving two players, five clauses and ten variables. We show that all near-optimal strategies for the pentagram game are approximately equivalent to a unique strategy involving real Pauli measurements on three maximally-entangled qubit pairs.

  18. Rigidity of the magic pentagram game.

    Science.gov (United States)

    Kalev, Amir; Miller, Carl A

    2018-01-01

    A game is rigid if a near-optimal score guarantees, under the sole assumption of the validity of quantum mechanics, that the players are using an approximately unique quantum strategy. Rigidity has a vital role in quantum cryptography as it permits a strictly classical user to trust behavior in the quantum realm. This property can be traced back as far as 1998 (Mayers and Yao) and has been proved for multiple classes of games. In this paper we prove ridigity for the magic pentagram game, a simple binary constraint satisfaction game involving two players, five clauses and ten variables. We show that all near-optimal strategies for the pentagram game are approximately equivalent to a unique strategy involving real Pauli measurements on three maximally-entangled qubit pairs.

  19. Rigid cohomology over Laurent series fields

    CERN Document Server

    Lazda, Christopher

    2016-01-01

    In this monograph, the authors develop a new theory of p-adic cohomology for varieties over Laurent series fields in positive characteristic, based on Berthelot's theory of rigid cohomology. Many major fundamental properties of these cohomology groups are proven, such as finite dimensionality and cohomological descent, as well as interpretations in terms of Monsky-Washnitzer cohomology and Le Stum's overconvergent site. Applications of this new theory to arithmetic questions, such as l-independence and the weight monodromy conjecture, are also discussed. The construction of these cohomology groups, analogous to the Galois representations associated to varieties over local fields in mixed characteristic, fills a major gap in the study of arithmetic cohomology theories over function fields. By extending the scope of existing methods, the results presented here also serve as a first step towards a more general theory of p-adic cohomology over non-perfect ground fields. Rigid Cohomology over Laurent Series Fields...

  20. Blast wave interaction with a rigid surface

    International Nuclear Information System (INIS)

    Josey, T.; Whitehouse, D.R.; Ripley, R.C.; Dionne, J.P.

    2004-01-01

    A simple model used to investigate blast wave interactions with a rigid surface is presented. The model uses a constant volume energy source analogue to predict pressure histories at gauges located directly above the charge. A series of two-dimensional axi-symmetric CFD calculations were performed, varying the height of the charge relative to the ground. Pressure histories, along with isopycnic plots are presented to evaluate the effects of placing a charge in close proximity to a rigid surface. When a charge is placed near a solid surface the pressure histories experienced at gauges above the charge indicate the presence of two distinct pressure peaks. The first peak is caused by the primary shock and the second peak is a result of the wave reflections from the rigid surface. As the distance from the charge to the wall is increased the magnitude of the second pressure peak is reduced, provided that the distance between the charge and the gauge is maintained constant. The simple model presented is able to capture significant, predictable flow features. (author)

  1. Lateral rigidity of cracked concrete structures

    International Nuclear Information System (INIS)

    Castellani, A.; Chesi, C.

    1979-01-01

    Numerical results are discussed on the lateral rigidity of reinforced concrete structures with a given crack distribution. They have been favourably checked with experimental results for cylindrical shells under the effect of a thermal gradient producing vertical cracking or vertical plus horizontal cracking. The main effects characterizing the concrete behaviour are: (1) The shear transfer across a crack; (2) The shear transfer degradation after cyclic loading; (3) The tension stiffening provided by the concrete between crack and crack, in the normal stress transfer; (4) The temperature effect on the elastic moduli of concrete, when cracks are of thermal origin. Only the 1st effect is discussed on an experimental basis. Two broad cathegories of reinforced concrete structures have been investigated in this respect: shear walls of buildings and cylindrical containment structures. The main conclusions so far reached are: (1) Vertical cracks are unlikely to decrease the lateral rigidity to less than 80% of the original one, and to less than 90% when they do not involve the entire thickness of the wall; (2) The appearence of horizontal cracks can reduce the lateral rigidity by some 30% or more; (3) A noticeable but not yet evaluated influence is shown by cyclic loading. (orig.)

  2. Stresses in Circular Plates with Rigid Elements

    Science.gov (United States)

    Velikanov, N. L.; Koryagin, S. I.; Sharkov, O. V.

    2018-05-01

    Calculations of residual stress fields are carried out by numerical and static methods, using the flat cross-section hypothesis. The failure of metal when exposed to residual stresses is, in most cases, brittle. The presence in the engineering structures of rigid elements often leads to the crack initiation and structure failure. This is due to the fact that rigid elements under the influence of external stresses are stress concentrators. In addition, if these elements are fixed by welding, the residual welding stresses can lead to an increase in stress concentration and, ultimately, to failure. The development of design schemes for such structures is a very urgent task for complex technical systems. To determine the stresses in a circular plate with a welded circular rigid insert under the influence of an external load, one can use the solution of the plane stress problem for annular plates in polar coordinates. The polar coordinates of the points are the polar radius and the polar angle, and the stress state is determined by normal radial stresses, tangential and shearing stresses. The use of the above mentioned design schemes, formulas, will allow more accurate determination of residual stresses in annular welded structures. This will help to establish the most likely directions of failure and take measures at the stages of designing, manufacturing and repairing engineering structures to prevent these failures. However, it must be taken into account that the external load, the presence of insulation can lead to a change in the residual stress field.

  3. 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.

  4. 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.

  5. 49 CFR 587.18 - Dimensions of fixed rigid barrier.

    Science.gov (United States)

    2010-10-01

    ... TRAFFIC SAFETY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION (CONTINUED) DEFORMABLE BARRIERS Offset Deformable Barrier § 587.18 Dimensions of fixed rigid barrier. (a) The fixed rigid barrier has a mass of not... 49 Transportation 7 2010-10-01 2010-10-01 false Dimensions of fixed rigid barrier. 587.18 Section...

  6. Association of telomerase activity with radio- and chemosensitivity of neuroblastomas

    Directory of Open Access Journals (Sweden)

    Willich Normann

    2010-07-01

    Full Text Available Abstract Background Telomerase activity compensates shortening of telomeres during cell division and enables cancer cells to escape senescent processes. It is also supposed, that telomerase is associated with radio- and chemoresistance. In the here described study we systematically investigated the influence of telomerase activity (TA and telomere length on the outcome of radio- and chemotherapy in neuroblastoma. Methods We studied the effects on dominant negative (DN mutant, wild type (WT of the telomerase catalytic unit (hTERT using neuroblastoma cell lines. The cells were irradiated with 60Co and treated with doxorubicin, etoposide, cisplatin and ifosfamide, respectively. Viability was determined by MTS/MTT-test and the GI50 was calculated. Telomere length was measured by southernblot analysis and TA by Trap-Assay. Results Compared to the hTERT expressing cells the dominant negative cells showed increased radiosensitivity with decreased telomere length. Independent of telomere length, telomerase negative cells are significantly more sensitive to irradiation. The effect of TA knock-down or overexpression on chemosensitivity were dependent on TA, the anticancer drug, and the chemosensitivity of the maternal cell line. Conclusions Our results supported the concept of telomerase inhibition as an antiproliferative treatment approach in neuroblastomas. Telomerase inhibition increases the outcome of radiotherapy while in combination with chemotherapy the outcome depends on drug- and cell line and can be additive/synergistic or antagonistic. High telomerase activity is one distinct cancer stem cell feature and the here described cellular constructs in combination with stem cell markers like CD133, Aldehyddehydrogenase-1 (ALDH-1 or Side population (SP may help to investigate the impact of telomerase activity on cancer stem cell survival under therapy.

  7. 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.)

  8. 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.)

  9. CT-3DRA registration for radiosurgery treatments: a comparison among rigid, affine and non rigid approaches

    International Nuclear Information System (INIS)

    Stancanello, J.; Loeckx, D.; Francescon, P.; Calvedon, C.; Avanzo, M.; Cora, S.; Scalchi, P.; Cerveri, P.; Ferrigno, G.

    2004-01-01

    This work aims at comparing rigid, affine and Local Non Rigid (LNR) CT-3D Rotational Angiography (CT-3DRA) registrations based on mutual information. 10 cranial and 1 spinal cases have been registered by rigid and affine transformations; while LNR has been applied to the cases where residual deformation must be corrected. An example of CT-3DRA registration without regularization term and an example of LNR using the similarity criterion and the regularization term as well as 3D superposition of the 3DRA before and after the registration without the regularization term are presented. All the registrations performed by rigid transformation converged to an acceptable solution. The results about the robustness test in axial direction are reported. Conclusions: For cranial cases, affine transformation endowed with threshold-segmentation pre-processing can be considered the most favourable solution for almost all registrations; for some cases, LNR provides more accurate results. For the spinal case rigid transformation is the most suitable when immobilizing patient during examinations; in this case the increase of accuracy by using LNR registrations seems to be not significant

  10. Treatment of neuroblastoma. Role of total Body Irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Dini, G; Perin, G P; Franzone, P; Corvo, R; Scarpati, D

    1986-01-01

    Advanced neuroblastoma, scarcely responsive to conventional therapies, can take advantage of high dose chemio-radiotherapic treatment followed by bone marrow transplant. Nineteen young patients underwent an ablative chemotherapy with high dose Vincristine and Melphalan plus Total Body Irradiation in Genoa, Italy; all of them underwent autologus bone marrow transplantation. Fourteen children were in complete remission (CR), 5 had residual disease. Thirteen are alive after a median of 7 months following transplant; 9 are in CR; 4 have disease; 1 died for toxicity; 5 for relapse. The results seem to suggest that ablative therapy should be given to patients in CR. Toxicity was not remarkable mainly as far as TBI is concerned.

  11. Influence of flock coating on bending rigidity of woven fabrics

    Science.gov (United States)

    Ozdemir, O.; Kesimci, M. O.

    2017-10-01

    This work presents the preliminary results of our efforts that focused on the effect of the flock coating on the bending rigidity of woven fabrics. For this objective, a laboratory scale flocking unit is designed and flocked samples of controlled flock density are produced. Bending rigidity of the samples with different flock densities are measured on both flocked and unflocked sides. It is shown that the bending rigidity depends on both flock density and whether the side to be measured is flocked or not. Adhesive layer thickness on the bending rigidity is shown to be dramatic. And at higher basis weights, flock density gets less effective on bending rigidity.

  12. Understanding geological processes: Visualization of rigid and non-rigid transformations

    Science.gov (United States)

    Shipley, T. F.; Atit, K.; Manduca, C. A.; Ormand, C. J.; Resnick, I.; Tikoff, B.

    2012-12-01

    Visualizations are used in the geological sciences to support reasoning about structures and events. Research in cognitive sciences offers insights into the range of skills of different users, and ultimately how visualizations might support different users. To understand the range of skills needed to reason about earth processes we have developed a program of research that is grounded in the geosciences' careful description of the spatial and spatiotemporal patterns associated with earth processes. In particular, we are pursuing a research program that identifies specific spatial skills and investigates whether and how they are related to each other. For this study, we focus on a specific question: Is there an important distinction in the geosciences between rigid and non-rigid deformation? To study a general spatial thinking skill we employed displays with non-geological objects that had been altered by rigid change (rotation), and two types of non-rigid change ("brittle" (or discontinuous) and "ductile" (or continuous) deformation). Disciplinary scientists (geosciences and chemistry faculty), and novices (non-science faculty and undergraduate psychology students) answered questions that required them to visualize the appearance of the object before the change. In one study, geologists and chemists were found to be superior to non-science faculty in reasoning about rigid rotations (e.g., what an object would look like from a different perspective). Geologists were superior to chemists in reasoning about brittle deformations (e.g., what an object looked like before it was broken - here the object was a word cut into many fragments displaced in different directions). This finding is consistent with two hypotheses: 1) Experts are good at visualizing the types of changes required for their domain; and 2) Visualization of rigid and non-rigid changes are not the same skill. An additional important finding is that there was a broad range of skill in both rigid and non-rigid

  13. 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)

  14. 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

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

    Science.gov (United States)

    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

  16. 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

  17. 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.

  18. 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

  19. A rigid porous filter and filtration method

    Energy Technology Data Exchange (ETDEWEB)

    Chiang, Ta-Kuan; Straub, Douglas, Straub L.; Dennis, Richard A.

    1998-12-01

    The present invention involves a porous rigid filter comprising a plurality of concentric filtration elements having internal flow passages and forming external flow passages there between. The present invention also involves a pressure vessel containing the filter for the removal of particulate from high pressure particulate containing gases, and further involves a method for using the filter to remove such particulate. The present filter has the advantage of requiring fewer filter elements due to the high surface area- to-volume ratio provided by the filter, requires a reduced pressure vessel size, and exhibits enhanced mechanical design properties, improved cleaning properties, configuration options, modularity and ease of fabrication.

  20. Mechanical Characterization of Rigid Polyurethane Foams

    Energy Technology Data Exchange (ETDEWEB)

    Lu, Wei-Yang [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States). Mechanics of Materials

    2014-12-01

    Foam materials are used to protect sensitive components from impact loading. In order to predict and simulate the foam performance under various loading conditions, a validated foam model is needed and the mechanical properties of foams need to be characterized. Uniaxial compression and tension tests were conducted for different densities of foams under various temperatures and loading rates. Crush stress, tensile strength, and elastic modulus were obtained. A newly developed confined compression experiment provided data for investigating the foam flow direction. A biaxial tension experiment was also developed to explore the damage surface of a rigid polyurethane foam.

  1. Rigidity of complete generic shrinking Ricci solitons

    Science.gov (United States)

    Chu, Yawei; Zhou, Jundong; Wang, Xue

    2018-01-01

    Let (Mn , g , X) be a complete generic shrinking Ricci soliton of dimension n ≥ 3. In this paper, by employing curvature inequalities, the formula of X-Laplacian for the norm square of the trace-free curvature tensor, the weak maximum principle and the estimate of the scalar curvature of (Mn , g) , we prove some rigidity results for (Mn , g , X) . In particular, it is showed that (Mn , g , X) is isometric to Rn or a finite quotient of Sn under a pointwise pinching condition. Moreover, we establish several optimal inequalities and classify those shrinking solitons for equalities.

  2. 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.

  3. Complex molecular mechanisms cooperate to mediate histone deacetylase inhibitors anti-tumour activity in neuroblastoma cells

    Directory of Open Access Journals (Sweden)

    Nardou Katya

    2008-06-01

    Full Text Available Abstract Background Histone deacetylase inhibitors (HDACi are a new class of promising anti-tumour agent inhibiting cell proliferation and survival in tumour cells with very low toxicity toward normal cells. Neuroblastoma (NB is the second most common solid tumour in children still associated with poor outcome in higher stages and, thus NB strongly requires novel treatment modalities. Results We show here that the HDACi Sodium Butyrate (NaB, suberoylanilide hydroxamic acid (SAHA and Trichostatin A (TSA strongly reduce NB cells viability. The anti-tumour activity of these HDACi involved the induction of cell cycle arrest in the G2/M phase, followed by the activation of the intrinsic apoptotic pathway, via the activation of the caspases cascade. Moreover, HDACi mediated the activation of the pro-apoptotic proteins Bid and BimEL and the inactivation of the anti-apoptotic proteins XIAP, Bcl-xL, RIP and survivin, that further enhanced the apoptotic signal. Interestingly, the activity of these apoptosis regulators was modulated by several different mechanisms, either by caspases dependent proteolytic cleavage or by degradation via the proteasome pathway. In addition, HDACi strongly impaired the hypoxia-induced secretion of VEGF by NB cells. Conclusion HDACi are therefore interesting new anti-tumour agents for targeting highly malignant tumours such as NB, as these agents display a strong toxicity toward aggressive NB cells and they may possibly reduce angiogenesis by decreasing VEGF production by NB cells.

  4. 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

  5. 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

  6. 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.)

  7. 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

  8. Vitamin K3 analogs induce selective tumor cytotoxicity in neuroblastoma.

    Science.gov (United States)

    Kitano, Toru; Yoda, Hiroyuki; Tabata, Keiichi; Miura, Motofumi; Toriyama, Masaharu; Motohashi, Shigeyasu; Suzuki, Takashi

    2012-01-01

    We investigated the cytotoxicity of eight vitamin K3 (VK3) analogs against neuroblastoma cell lines (IMR-32, LA-N-1, NB-39, and SK-N-SH) and normal cell lines (human umbilical vein endothelial cells (HUVEC) and human dermal fibroblasts (HDF)) using a 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay. 2-[(2-Methoxy)ethylthio]-3-methyl-1,4-naphthoquinone (VK3-OCH(3)) showed especially potent cytotoxic activities against neuroblastoma cells compared with normal cells. In a Hoechst 33342 staining experiment, apoptotic morphologies characterized by cell shrinkage, nuclear condensation, and nuclear fragmentation were observed in IMR-32 and LA-N-1 cells after 48 h of treatment with 10(-5) M of VK3-OCH(3). To clarify the molecular mechanisms of apoptosis induced by VK3-OCH(3), we examined the expression of apoptosis related proteins using a Proteome Profiler Array and western blotting. Heme oxygenase (HO)-1 was remarkably increased by VK3-OCH(3) compared with the control (173% in IMR-32 and 170% in LA-N-1 at 24 h). Moreover, caveolin-1 was induced by VK3-OCH(3) at 48 h. In addition, VK3-OCH(3) arrested the cell cycle at the G2/M phase in IMR-32 cells. These results suggest that VK3-OCH(3) exhibited a selective antitumor activity via HO-1-related mechanisms.

  9. Outcome of children older than one year with neuroblastoma.

    Science.gov (United States)

    Fayea, Najwa Y; Atra, Ayad A; Khattab, Taha; Elimam, Najla A; Felimban, Sami; Yousef, Abdelmoutaleb; Basheer, Ahmed; Zayed, Abdullah; Baothman, Abdullah; Al-Sheikh, Nada; Hussen, Wafa

    2008-01-01

    To assess the outcome of children older than one year with neuroblastoma treated at King Abdul-Aziz Medical City, Jeddah, Kingdom of Saudi Arabia. We retrospectively reviewed the files of 52 children older than one year with neuroblastoma (NBL) treated at our center between September 1987 and May 2003. Treatment consisted of OPEC chemotherapy regimen (vincristine, cisplatin, etoposide, and cyclophosphamide) or alternating OPEC/OJEC (carboplatin in place of cisplatin), surgical resection +/- radiotherapy (RT). No patient received high dose therapy (HDT). Thirty-four patients (65%) were stage 4, 12 (23%) stage 3, and 6 (11%) stage 2. Three stage 2 patients were treated with surgery only, all are alive in complete remission (CR). All stage 3 and 4 patients were treated with chemotherapy and surgery +/- RT. After induction chemotherapy, CR was achieved in 17 patients (32%) and partial remission in 10 (19%). Complete surgical resection was possible in 11 patients (22%). Disease recurrence or progression occurred in 27 patients (51%). With a median follow-up of 24 months (range 4-120), the 2-year event free survival was 10%, 82%, and 87% and the overall survival was 12%, 83%, and 100% for stage 4, 3, and 2. Children older than one year with localized NBL have good prognosis compared to those with stage 4. The use of HDT may improve the outcome in the latter group. Toxicity was significant, and adoption of risk-stratified treatment may help to reduce treatment complications.

  10. Treatment of neuroblastoma with metaiodobenzylguanidine: results and side effects

    International Nuclear Information System (INIS)

    Treuner, J.; Klingebiel, T.; Bruchelt, G.; Feine, U.; Niethammer, D.

    1987-01-01

    Between April 1984 and December 1985 we treated ten children suffering from neuroblastoma in a total of 25 metaiodobenzylguanidine (MIBG) courses. Five had had a relapse of neuroblastoma stage III or IV, three had never achieved a remission in spite of intensive chemotherapy, and two were treated with an unstable remission. The children were each administered from 1 to 5 courses with a dosage per course of between 1295 and 9065 MBq. The sum of the single doses during the whole course of therapy ranged between 3145 and 21,904 MBq per child. Five of five children suffering from bone pain and fever became free of complaints during the first three treatment days. Six of eight children with manifest tumor at onset of therapy responded well to the treatment: response extended from transitory decrease in elevated catecholamine levels in serum and urine to complete disappearance of large abdominal tumor masses. We also observed a decrease in bone marrow involvement and a stabilization of osteolytic lesions. Seven of these eight children died in spite of a good response from 55 to 350 days after the first MIBG treatment course. The only side effect we witnessed was a reversible bone marrow depression. In three children we combined the MIBG therapy with bone marrow transplantation

  11. ARID1B alterations identify aggressive tumors in neuroblastoma.

    Science.gov (United States)

    Lee, Soo Hyun; Kim, Jung-Sun; Zheng, Siyuan; Huse, Jason T; Bae, Joon Seol; Lee, Ji Won; Yoo, Keon Hee; Koo, Hong Hoe; Kyung, Sungkyu; Park, Woong-Yang; Sung, Ki W

    2017-07-11

    Targeted panel sequencing was performed to determine molecular targets and biomarkers in 72 children with neuroblastoma. Frequent genetic alterations were detected in ALK (16.7%), BRCA1 (13.9%), ATM (12.5%), and PTCH1 (11.1%) in an 83-gene panel. Molecular targets for targeted therapy were identified in 16 of 72 patients (22.2%). Two-thirds of ALK mutations were known to increase sensitivity to ALK inhibitors. Sequence alterations in ARID1B were identified in 5 of 72 patients (6.9%). Four of five ARID1B alterations were detected in tumors of high-risk patients. Two of five patients with ARID1B alterations died of disease progression. Relapse-free survival was lower in patients with ARID1B alterations than in those without (p = 0.01). In analysis confined to high-risk patients, 3-year overall survival was lower in patients with an ARID1B alteration (33.3 ± 27.2%) or MYCN amplification (30.0 ± 23.9%) than in those with neither ARID1B alteration nor MYCN amplification (90.5 ± 6.4%, p = 0.05). These results provide possibilities for targeted therapy and a new biomarker identifying a subgroup of neuroblastoma patients with poor prognosis.

  12. A 6-gene signature identifies four molecular subgroups of neuroblastoma

    Science.gov (United States)

    2011-01-01

    Background There are currently three postulated genomic subtypes of the childhood tumour neuroblastoma (NB); Type 1, Type 2A, and Type 2B. The most aggressive forms of NB are characterized by amplification of the oncogene MYCN (MNA) and low expression of the favourable marker NTRK1. Recently, mutations or high expression of the familial predisposition gene Anaplastic Lymphoma Kinase (ALK) was associated to unfavourable biology of sporadic NB. Also, various other genes have been linked to NB pathogenesis. Results The present study explores subgroup discrimination by gene expression profiling using three published microarray studies on NB (47 samples). Four distinct clusters were identified by Principal Components Analysis (PCA) in two separate data sets, which could be verified by an unsupervised hierarchical clustering in a third independent data set (101 NB samples) using a set of 74 discriminative genes. The expression signature of six NB-associated genes ALK, BIRC5, CCND1, MYCN, NTRK1, and PHOX2B, significantly discriminated the four clusters (p INSS stage 4 and/or dead of disease, p < 0.05, Fisher's exact test). Conclusions Based on expression profiling we have identified four molecular subgroups of neuroblastoma, which can be distinguished by a 6-gene signature. The fourth subgroup has not been described elsewhere, and efforts are currently made to further investigate this group's specific characteristics. PMID:21492432

  13. A 6-gene signature identifies four molecular subgroups of neuroblastoma

    Directory of Open Access Journals (Sweden)

    Kogner Per

    2011-04-01

    Full Text Available Abstract Background There are currently three postulated genomic subtypes of the childhood tumour neuroblastoma (NB; Type 1, Type 2A, and Type 2B. The most aggressive forms of NB are characterized by amplification of the oncogene MYCN (MNA and low expression of the favourable marker NTRK1. Recently, mutations or high expression of the familial predisposition gene Anaplastic Lymphoma Kinase (ALK was associated to unfavourable biology of sporadic NB. Also, various other genes have been linked to NB pathogenesis. Results The present study explores subgroup discrimination by gene expression profiling using three published microarray studies on NB (47 samples. Four distinct clusters were identified by Principal Components Analysis (PCA in two separate data sets, which could be verified by an unsupervised hierarchical clustering in a third independent data set (101 NB samples using a set of 74 discriminative genes. The expression signature of six NB-associated genes ALK, BIRC5, CCND1, MYCN, NTRK1, and PHOX2B, significantly discriminated the four clusters (p ALK, BIRC5, and PHOX2B, and was significantly associated with higher tumour stage, poor outcome and poor survival compared to the Type 1-corresponding favourable group (INSS stage 4 and/or dead of disease, p Conclusions Based on expression profiling we have identified four molecular subgroups of neuroblastoma, which can be distinguished by a 6-gene signature. The fourth subgroup has not been described elsewhere, and efforts are currently made to further investigate this group's specific characteristics.

  14. Anti-Neuroblastoma Properties of a Recombinant Sunflower Lectin

    Directory of Open Access Journals (Sweden)

    Marcela Pinedo

    2017-01-01

    Full Text Available According to their sugar recognition specificity, plant lectins are proposed as bioactive proteins with potential in cancer treatment and diagnosis. Helja is a mannose-specific jacalin-like lectin from sunflower which was shown to inhibit the growth of certain fungi. Here, we report its recombinant expression in a prokaryotic system and its activity in neurobalstoma cells. Helja coding sequence was fused to the pET-32 EK/LIC, the enterokinase/Ligation-independent cloning vector and a 35 kDa protein was obtained in Escherichia coli representing Helja coupled to thioredoxin (Trx. The identity of this protein was verified using anti-Helja antibodies. This chimera, named Trx-rHelja, was enriched in the soluble bacterial extracts and was purified using Ni+2-Sepharose and d-mannose-agarose chromatography. Trx-rHelja and the enterokinase-released recombinant Helja (rHelja both displayed toxicity on human SH-SY5Y neuroblastomas. rHelja decreased the viability of these tumor cells by 75% according to the tetrazolium reduction assay, and microscopic analyses revealed that the cell morphology was disturbed. Thus, the stellate cells of the monolayer became spheroids and were isolated. Our results indicate that rHelja is a promising tool for the development of diagnostic or therapeutic methods for neuroblastoma cells, the most common solid tumors in childhood.

  15. Identification of nuclear τ isoforms in human neuroblastoma cells

    International Nuclear Information System (INIS)

    Loomis, P.A.; Howard, T.H.; Castleberry, R.P.; Binder, L.I.

    1990-01-01

    The τ proteins have been reported only in association with microtubules and with ribosomes in situ, in the normal central nervous system. In addition, τ has been shown to be an integral component of paired helical filaments, the principal constituent of the neurofibrillary tangles found in brains of patients with Alzheimer's disease and of most aged individuals with Down syndrome (trisomy 21). The authors report here the localization of the well-characterized Tau-1 monoclonal antibody to the nucleolar organizer regions of the acrocentric chromosomes and to their interphase counterpart, the fibrillar component of the nucleolus, in human neuroblastoma cells. Similar localization to the nucleolar organizer regions was also observed in other human cell lines and in one monkey kidney cell line but was not seen in non-primate species. Immunochemically, they further demonstrated the existence of the entire τ molecule in the isolated nuclei of neuroblastoma cells. Nuclear τ proteins, like the τ proteins of the paired helical filaments, cannot be extracted in standard SDS-containing electrophoresis sample buffer but require pretreatment with formic acid prior to immunoblot analysis. This work indicates that τ may function in processes not directly associated with microtubules and that highly insoluble complexes of τ may also play a role in normal cellular physiology

  16. 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

  17. Public policies targeting labour market rigidities

    Directory of Open Access Journals (Sweden)

    Andreea Claudia ŞERBAN

    2013-02-01

    Full Text Available Labour market rigidity becomes an issue of increasing importance under conditions of shocks associated with the economic crisis due to the need to increase the adaptability and responsiveness to them. Thus, labour market policies must be directed towards mitigating rigidities caused by institutional or demographic factors or certain mismatch between demand and supply of education qualifications. This paper highlights the major role of the active labour market policies targeting the increase of labour flexibility, stressing the importance and impact on the ability to adapt quickly and effectively to macroeconomic shocks. Located on a declining trend in the years preceding the crisis, spending on labour market policies increased in 2009 in all the Member States of the European Union. Spending differences are significant between countries, Romania being at the lowest end of the European Union. This requires special attention because the increased adaptability of workers through training, as active measure, is of major importance considering the increased speed of changes in the labour market.

  18. Vertebral Column Resection for Rigid Spinal Deformity.

    Science.gov (United States)

    Saifi, Comron; Laratta, Joseph L; Petridis, Petros; Shillingford, Jamal N; Lehman, Ronald A; Lenke, Lawrence G

    2017-05-01

    Broad narrative review. To review the evolution, operative technique, outcomes, and complications associated with posterior vertebral column resection. A literature review of posterior vertebral column resection was performed. The authors' surgical technique is outlined in detail. The authors' experience and the literature regarding vertebral column resection are discussed at length. Treatment of severe, rigid coronal and/or sagittal malalignment with posterior vertebral column resection results in approximately 50-70% correction depending on the type of deformity. Surgical site infection rates range from 2.9% to 9.7%. Transient and permanent neurologic injury rates range from 0% to 13.8% and 0% to 6.3%, respectively. Although there are significant variations in EBL throughout the literature, it can be minimized by utilizing tranexamic acid intraoperatively. The ability to correct a rigid deformity in the spine relies on osteotomies. Each osteotomy is associated with a particular magnitude of correction at a single level. Posterior vertebral column resection is the most powerful posterior osteotomy method providing a successful correction of fixed complex deformities. Despite meticulous surgical technique and precision, this robust osteotomy technique can be associated with significant morbidity even in the most experienced hands.

  19. Optimized imaging using non-rigid registration

    International Nuclear Information System (INIS)

    Berkels, Benjamin; Binev, Peter; Blom, Douglas A.; Dahmen, Wolfgang; Sharpley, Robert C.; Vogt, Thomas

    2014-01-01

    The extraordinary improvements of modern imaging devices offer access to data with unprecedented information content. However, widely used image processing methodologies fall far short of exploiting the full breadth of information offered by numerous types of scanning probe, optical, and electron microscopies. In many applications, it is necessary to keep measurement intensities below a desired threshold. We propose a methodology for extracting an increased level of information by processing a series of data sets suffering, in particular, from high degree of spatial uncertainty caused by complex multiscale motion during the acquisition process. An important role is played by a non-rigid pixel-wise registration method that can cope with low signal-to-noise ratios. This is accompanied by formulating objective quality measures which replace human intervention and visual inspection in the processing chain. Scanning transmission electron microscopy of siliceous zeolite material exhibits the above-mentioned obstructions and therefore serves as orientation and a test of our procedures. - Highlights: • Developed a new process for extracting more information from a series of STEM images. • An objective non-rigid registration process copes with distortions. • Images of zeolite Y show retrieval of all information available from the data set. • Quantitative measures of registration quality were implemented. • Applicable to any serially acquired data, e.g. STM, AFM, STXM, etc

  20. 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

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

    Science.gov (United States)

    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.

  2. [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.

  3. 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

  4. 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

  5. LMO1 Synergizes with MYCN to Promote Neuroblastoma Initiation and Metastasis.

    Science.gov (United States)

    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.

  6. 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

  7. 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.)

  8. Thermostability in rubredoxin and its relationship to mechanical rigidity

    Science.gov (United States)

    Rader, A. J.

    2010-03-01

    The source of increased stability in proteins from organisms that thrive in extreme thermal environments is not well understood. Previous experimental and theoretical studies have suggested many different features possibly responsible for such thermostability. Many of these thermostabilizing mechanisms can be accounted for in terms of structural rigidity. Thus a plausible hypothesis accounting for this remarkable stability in thermophilic enzymes states that these enzymes have enhanced conformational rigidity at temperatures below their native, functioning temperature. Experimental evidence exists to both support and contradict this supposition. We computationally investigate the relationship between thermostability and rigidity using rubredoxin as a case study. The mechanical rigidity is calculated using atomic models of homologous rubredoxin structures from the hyperthermophile Pyrococcus furiosus and mesophile Clostridium pasteurianum using the FIRST software. A global increase in structural rigidity (equivalently a decrease in flexibility) corresponds to an increase in thermostability. Locally, rigidity differences (between mesophilic and thermophilic structures) agree with differences in protection factors.

  9. Thermostability in rubredoxin and its relationship to mechanical rigidity

    International Nuclear Information System (INIS)

    Rader, A J

    2010-01-01

    The source of increased stability in proteins from organisms that thrive in extreme thermal environments is not well understood. Previous experimental and theoretical studies have suggested many different features possibly responsible for such thermostability. Many of these thermostabilizing mechanisms can be accounted for in terms of structural rigidity. Thus a plausible hypothesis accounting for this remarkable stability in thermophilic enzymes states that these enzymes have enhanced conformational rigidity at temperatures below their native, functioning temperature. Experimental evidence exists to both support and contradict this supposition. We computationally investigate the relationship between thermostability and rigidity using rubredoxin as a case study. The mechanical rigidity is calculated using atomic models of homologous rubredoxin structures from the hyperthermophile Pyrococcus furiosus and mesophile Clostridium pasteurianum using the FIRST software. A global increase in structural rigidity (equivalently a decrease in flexibility) corresponds to an increase in thermostability. Locally, rigidity differences (between mesophilic and thermophilic structures) agree with differences in protection factors

  10. Identification of BIRC6 as a novel intervention target for neuroblastoma therapy

    Directory of Open Access Journals (Sweden)

    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.

  11. 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.

  12. 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

  13. 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

  14. 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

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

    Science.gov (United States)

    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

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

  17. 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...

  18. 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.)

  19. 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.)

  20. Coherent distributions for the rigid rotator

    Energy Technology Data Exchange (ETDEWEB)

    Grigorescu, Marius [CP 15-645, Bucharest 014700 (Romania)

    2016-06-15

    Coherent solutions of the classical Liouville equation for the rigid rotator are presented as positive phase-space distributions localized on the Lagrangian submanifolds of Hamilton-Jacobi theory. These solutions become Wigner-type quasiprobability distributions by a formal discretization of the left-invariant vector fields from their Fourier transform in angular momentum. The results are consistent with the usual quantization of the anisotropic rotator, but the expected value of the Hamiltonian contains a finite “zero point” energy term. It is shown that during the time when a quasiprobability distribution evolves according to the Liouville equation, the related quantum wave function should satisfy the time-dependent Schrödinger equation.

  1. Static friction between rigid fractal surfaces.

    Science.gov (United States)

    Alonso-Marroquin, Fernando; Huang, Pengyu; Hanaor, Dorian A H; Flores-Johnson, E A; Proust, Gwénaëlle; Gan, Yixiang; Shen, Luming

    2015-09-01

    Using spheropolygon-based simulations and contact slope analysis, we investigate the effects of surface topography and atomic scale friction on the macroscopically observed friction between rigid blocks with fractal surface structures. From our mathematical derivation, the angle of macroscopic friction is the result of the sum of the angle of atomic friction and the slope angle between the contact surfaces. The latter is obtained from the determination of all possible contact slopes between the two surface profiles through an alternative signature function. Our theory is validated through numerical simulations of spheropolygons with fractal Koch surfaces and is applied to the description of frictional properties of Weierstrass-Mandelbrot surfaces. The agreement between simulations and theory suggests that for interpreting macroscopic frictional behavior, the descriptors of surface morphology should be defined from the signature function rather than from the slopes of the contacting surfaces.

  2. Observational properties of rigidly rotating dust configurations

    Energy Technology Data Exchange (ETDEWEB)

    Ilyas, Batyr; Malafarina, Daniele [Nazarbayev University, Department of Physics, Astana (Kazakhstan); Yang, Jinye [Fudan University, Center for Field Theory and Particle Physics and Department of Physics, Shanghai (China); Bambi, Cosimo [Fudan University, Center for Field Theory and Particle Physics and Department of Physics, Shanghai (China); Eberhard-Karls Universitaet Tuebingen, Theoretical Astrophysics, Tuebingen (Germany)

    2017-07-15

    We study the observational properties of a class of exact solutions of Einstein's field equations describing stationary, axially symmetric, rigidly rotating dust (i.e. non-interacting particles). We ask the question whether such solutions can describe astrophysical rotating dark matter clouds near the center of galaxies and we probe the possibility that they may constitute an alternative to supermassive black holes at the center of galaxies. We show that light emission from accretion disks made of ordinary baryonic matter in this space-time has several differences with respect to the emission of light from similar accretion disks around black holes. The shape of the iron Kα line in the reflection spectrum of accretion disks can potentially distinguish this class of solutions from the Kerr metric, but this may not be possible with current X-ray missions. (orig.)

  3. On real structures on rigid surfaces

    International Nuclear Information System (INIS)

    Kulikov, Vik S; Kharlamov, V M

    2002-01-01

    We construct examples of rigid surfaces (that is, surfaces whose deformation class consists of a unique surface) with a particular behaviour with respect to real structures. In one example the surface has no real structure. In another it has a unique real structure, which is not maximal with respect to the Smith-Thom inequality. These examples give negative answers to the following problems: the existence of real surfaces in each deformation class of complex surfaces, and the existence of maximal real surfaces in every complex deformation class that contains real surfaces. Moreover, we prove that there are no real surfaces among surfaces of general type with p g =q=0 and K 2 =9. These surfaces also provide new counterexamples to the 'Dif = Def' problem

  4. On real structures on rigid surfaces

    Energy Technology Data Exchange (ETDEWEB)

    Kulikov, Vik S [Steklov Mathematical Institute, Russian Academy of Sciences (Russian Federation); Kharlamov, V M [Institut de Recherche Matematique Avanee Universite Louis Pasteur et CNRS 7 rue Rene Descartes (France)

    2002-02-28

    We construct examples of rigid surfaces (that is, surfaces whose deformation class consists of a unique surface) with a particular behaviour with respect to real structures. In one example the surface has no real structure. In another it has a unique real structure, which is not maximal with respect to the Smith-Thom inequality. These examples give negative answers to the following problems: the existence of real surfaces in each deformation class of complex surfaces, and the existence of maximal real surfaces in every complex deformation class that contains real surfaces. Moreover, we prove that there are no real surfaces among surfaces of general type with p{sub g}=q=0 and K{sup 2}=9. These surfaces also provide new counterexamples to the 'Dif = Def' problem.

  5. Management of rigid post-traumatic kyphosis.

    Science.gov (United States)

    Wu, S S; Hwa, S Y; Lin, L C; Pai, W M; Chen, P Q; Au, M K

    1996-10-01

    Rigid post-traumatic kyphosis after fracture of the thoracolumbar and lumbar spine represents a failure of initial management of the injury. Kyphosis moves the center of gravity anterior. The kyphosis and instability may result in pain, deformity, and increased neurologic deficits. Management for symptomatic post-traumatic kyphosis always has presented a challenge to orthopedic surgeons. To evaluate the surgical results of one stage posterior correction for rigid symptomatic post-traumatic kyphosis of the thoracolumbar and lumbar spine. The management for post-traumatic kyphosis remains controversial. Anterior, posterior, or combined anterior and posterior procedures have been advocated by different authors and show various degrees of success. One vertebra immediately above and below the level of the deformity was instrumented posteriorly by a transpedicular system (internal fixator AO). Posterior decompression was performed by excision of the spinal process and bilateral laminectomy. With the deformed vertebra through the pedicle, the vertebral body carefully is removed around the pedicle level, approximating a wedge shape. The extent to which the deformed vertebral body should be removed is determined by the attempted correction. Correction of the deformity is achieved by manipulation of the operating table and compression of the adjacent Schanz screws above and below the lesion. Thirteen patients with post-traumatic kyphosis with symptoms of fatigue and pain caused by slow progression of kyphotic deformities received posterior decompression, correction, and stabilization as a definitive treatment. The precorrection kyphosis ranged from 30-60 degrees, with a mean of 40 degrees +/- 10.8 degrees. After correction, kyphosis was reduced to an average of 1.5 degrees +/- 3.8 degrees, with a range from -5 degrees to 5 degrees. The average angle of correction was 38.8 degrees +/- 10.4 degrees, with a range from 25 degrees to 60 degrees. Significant difference was found

  6. Dual Quaternion Variational Integrator for Rigid Body Dynamic Simulation

    OpenAIRE

    Xu, Jiafeng; Halse, Karl Henning

    2016-01-01

    In rigid body dynamic simulations, often the algorithm is required to deal with general situations where both reference point and inertia matrix are arbitrarily de- fined. We introduce a novel Lie group variational integrator using dual quaternion for simulating rigid body dynamics in all six degrees of freedom. Dual quaternion is used to represent rigid body kinematics and one-step Lie group method is used to derive dynamic equations. The combination of these two becomes the first Lie group ...

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

    Directory of Open Access Journals (Sweden)

    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.

  8. 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

  9. 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

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

    Directory of Open Access Journals (Sweden)

    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.

  11. 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.)

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

    Science.gov (United States)

    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.

  13. Research on Rigid Body Motion Tracing in Space based on NX MCD

    Science.gov (United States)

    Wang, Junjie; Dai, Chunxiang; Shi, Karen; Qin, Rongkang

    2018-03-01

    In the use of MCD (Mechatronics Concept Designer) which is a module belong to SIEMENS Ltd industrial design software UG (Unigraphics NX), user can define rigid body and kinematic joint to make objects move according to the existing plan in simulation. At this stage, user may have the desire to see the path of some points in the moving object intuitively. In response to this requirement, this paper will compute the pose through the transformation matrix which can be available from the solver engine, and then fit these sampling points through B-spline curve. Meanwhile, combined with the actual constraints of rigid bodies, the traditional equal interval sampling strategy was optimized. The result shown that this method could satisfy the demand and make up for the deficiency in traditional sampling method. User can still edit and model on this 3D curve. Expected result has been achieved.

  14. Tile-based rigidization surface parametric design study

    Science.gov (United States)

    Giner Munoz, Laura; Luntz, Jonathan; Brei, Diann; Kim, Wonhee

    2018-03-01

    Inflatable technologies have proven useful in consumer goods as well as in more recent applications including civil structures, aerospace, medical, and robotics. However, inflatable technologies are typically lacking in their ability to provide rigid structural support. Particle jamming improves upon this by providing structures which are normally flexible and moldable but become rigid when air is removed. Because these are based on an airtight bladder filled with loose particles, they always occupy the full volume of its rigid state, even when not rigidized. More recent developments in layer jamming have created thin, compact rigidizing surfaces replacing the loose volume of particles with thinly layered surface materials. Work in this area has been applied to several specific applications with positive results but have not generally provided the broader understanding of the rigidization performance as a function of design parameters required for directly adapting layer rigidization technology to other applications. This paper presents a parametric design study of a new layer jamming vacuum rigidization architecture: tile-based vacuum rigidization. This form of rigidization is based on layers of tiles contained within a thin vacuum bladder which can be bent, rolled, or otherwise compactly stowed, but when deployed flat, can be vacuumed and form a large, flat, rigid plate capable of supporting large forces both localized and distributed over the surface. The general architecture and operation detailing rigidization and compliance mechanisms is introduced. To quantitatively characterize the rigidization behavior, prototypes rigidization surfaces are fabricated and an experimental technique is developed based on a 3-point bending test. Performance evaluation metrics are developed to describe the stiffness, load-bearing capacity, and internal slippage of tested prototypes. A set of experimental parametric studies are performed to better understand the impact of

  15. Pathological features of olfactory neuroblastoma in an axolotl (Ambystoma mexicanum).

    Science.gov (United States)

    Shioda, Chieko; Uchida, Kazuyuki; Nakayama, Hiroyuki

    2011-08-01

    A one-year-old, female Mexican axolotl (Ambystoma mexicanum) had a rough-surfaced, polypoid, pink tumor mass of approximately 10 mm in diameter in the oral cavity. Histologically, the tumor extended from the ethmoturbinate region and into the oral cavity and had replaced some of the maxillary bone tissue. The tumor mass was composed of a lobular architecture of small round-shaped tumor cells with occasional Flexner-Wintersteiner-like rosette formation. There were no metastatic lesions in the other organs. Immunohistochemically, the tumor cells were partly positive for several neural markers (class III beta-tubulin, S-100 protein, and doublecortin) and intensely positive for an epithelial marker (cytokeratin AE1/AE3). These results suggest that the present tumor originated from neuroectodermal tissue. Considering the location and histological and immunohistochemical features of the tumor, a diagnosis of olfactory neuroblastoma was made.

  16. Neuroblastoma in a patient with Coffin-Siris syndrome.

    Science.gov (United States)

    Pollono, Daniel; Drut, Ricardo; Cecotti, Norma; Pollono, Agustina

    2009-01-01

    We report the case of an 8-year-old boy with the phenotypic features of Coffin-Siris syndrome diffuse hypertrichosis, flat occiput, scant scalp hair, flat supraorbital arch, triangular eyebrows, horizontal palpebral fissure, anteverted nares, triangular philtrum, coarse lips, high-arched palate, micrognathia, low set and dorsaly rotated ears, short neck, wide thorax, widely set nipples, transverse palmar crease, psychomotor delay, urinary malformations (paraurethral diverticulum, hypoplasia of left kidney associated with vesicoureteral reflux grade 3-4), bilateral inguinal hernia, and dorsolumbar kyphoscoliosis. In the follow-up he presented a retroperitoneal neuroblastoma. Although this type of tumor has been referred to develop in several genetic and mutimalformative syndromes, it seems that present association has not been previously reported.

  17. Cell cycle control by the thyroid hormone in neuroblastoma cells

    International Nuclear Information System (INIS)

    Garcia-Silva, Susana; Perez-Juste, German; Aranda, Ana

    2002-01-01

    The thyroid hormone (T3) blocks proliferation and induces differentiation of neuroblastoma N2a-β cells that overexpress the β1 isoform of the T3 receptor. An element in the region responsible for premature termination of transcription mediates a rapid repression of c-myc gene expression by T3. The hormone also causes a decrease of cyclin D1 gene transcription, and is able to antagonize the activation of the cyclin D1 promoter by Ras. In addition, a strong and sustained increase of the levels of the cyclin kinase inhibitor (CKI) p27 Kip1 are found in T3-treated cells. The increased levels of p27 Kip1 lead to a marked inhibition of the kinase activity of the cyclin-CDK2 complexes. As a consequence of these changes, retinoblastoma proteins are hypophosphorylated in T3-treated N2a-β cells, and progression through the restriction point in the cell cycle is blocked

  18. JARID1B Expression Plays a Critical Role in Chemoresistance and Stem Cell-Like Phenotype of Neuroblastoma Cells.

    Directory of Open Access Journals (Sweden)

    Yung-Ting Kuo

    Full Text Available Neuroblastoma (NB is a common neural crest-derived extracranial solid cancer in children. Among all childhood cancers, NB causes devastating loss of young lives as it accounts for 15% of childhood cancer mortality. Neuroblastoma, especially high-risk stage 4 NB with MYCN amplification has limited treatment options and associated with poor prognosis. This necessitates the need for novel effective therapeutic strategy. JARID1B, also known as KDM5B, is a histone lysine demethylase, identified as an oncogene in many cancer types. Clinical data obtained from freely-accessible databases show a negative correlation between JARID1B expression and survival rates. Here, we demonstrated for the first time the role of JARID1B in the enhancement of stem cell-like activities and drug resistance in NB cells. We showed that JARID1B may be overexpressed in either MYCN amplification (SK-N-BE(2 or MYCN-non-amplified (SK-N-SH and SK-N-FI cell lines. JARID1B expression was found enriched in tumor spheres of SK-N-BE(2 and SK-N-DZ. Moreover, SK-N-BE(2 spheroids were more resistant to chemotherapeutics as compared to parental cells. In addition, we demonstrated that JARID1B-silenced cells acquired a decreased propensity for tumor invasion and tumorsphere formation, but increased sensitivity to cisplatin treatment. Mechanistically, reduced JARID1B expression led to the downregulation of Notch/Jagged signaling. Collectively, we provided evidence that JARID1B via modulation of stemness-related signaling is a putative novel therapeutic target for treating malignant NB.

  19. Dielectrophoretic capture and genetic analysis of single neuroblastoma tumor cells

    Directory of Open Access Journals (Sweden)

    Erica L Carpenter

    2014-07-01

    Full Text Available Our understanding of the diversity of cells that escape the primary tumor and seed micrometastases remains rudimentary, and approaches for studying circulating and disseminated tumor cells have been limited by low throughput and sensitivity, reliance on single parameter sorting, and a focus on enumeration rather than phenotypic and genetic characterization. Here we utilize a highly sensitive microfluidic and dielectrophoretic approach for the isolation and genetic analysis of individual tumor cells. We employed fluorescence labeling to isolate 208 single cells from spiking experiments conducted with 11 cell lines, including 8 neuroblastoma cell lines, and achieved a capture sensitivity of 1 tumor cell per 106 white blood cells. Sample fixation or freezing had no detectable effect on cell capture. Point mutations were accurately detected in the whole genome amplification product of captured single tumor cells but not in negative control white blood cells. We applied this approach to capture 144 single tumor cells from 10 bone marrow samples from patients suffering from neuroblastoma. In this pediatric malignancy, high-risk patients often exhibit wide-spread hematogenous metastasis, but access to primary tumor can be difficult or impossible. Here we used flow-based sorting to pre-enrich samples with tumor involvement below 0.02%. For all patients for whom a mutation in the Anaplastic Lymphoma Kinase gene had already been detected in their primary tumor, the same mutation was detected in single cells from their marrow. These findings demonstrate a novel, non-invasive, and adaptable method for the capture and genetic analysis of single tumor cells from cancer patients.

  20. In vitro assessment of curcumin against murine neuroblastoma cells.

    Science.gov (United States)

    Vanisree, Arambakkam Janardhanam; Ramanan, Ramya

    2007-04-01

    Neuroblastoma (NB) is a well-known malignant disease in infants, which comprises 10% of childhood malignancies. Despite recent advances in understanding the neuro-oncology, NB still accounts for more death in childhood than any other cancer. Research in childhood tumors should not only be focused on the malignant signatures of cancer cells but also novel drug prototypes using phytochemicals. The present study was aimed to determine the role of curcumin against murine neuroblastoma cell line (N2a). The in vitro assessment of curcumin against was made in N2a cell line in a dose-dependent manner (group I (control) and group II - IX (10 microM-80 microM). The efficacy of the drug was evaluated by estimating the levels of protein bound carbohydrates, glycoprotein, genomic DNA, total RNA levels, and inhibition of MMP-9 were studied. The gap junctional communication in the cells was also assessed. The levels of protein bound carbohydrates, DNA, RNA levels, glycoprotein were found to be altered on drug supplementation in NB cells. Inhibition of MMP-9 in curcumin-supplemented N2a cells was revealed by zymographic analysis. Assessment of Lucifer yellow dye uptake in curcumin-supplemented N2a cells showed the up-regulation of GJIC. These observations suggest that the curcumin, the active principle of curcuma longa, could be developed into an effective chemo preventive and chemotherapeutic agent. This selected concentration range needs further studies at molecular level, for conforming its role and its action against uncontrolled proliferation of NB.

  1. A 6-gene signature identifies four molecular subgroups of neuroblastoma

    LENUS (Irish Health Repository)

    Abel, Frida

    2011-04-14

    Abstract Background There are currently three postulated genomic subtypes of the childhood tumour neuroblastoma (NB); Type 1, Type 2A, and Type 2B. The most aggressive forms of NB are characterized by amplification of the oncogene MYCN (MNA) and low expression of the favourable marker NTRK1. Recently, mutations or high expression of the familial predisposition gene Anaplastic Lymphoma Kinase (ALK) was associated to unfavourable biology of sporadic NB. Also, various other genes have been linked to NB pathogenesis. Results The present study explores subgroup discrimination by gene expression profiling using three published microarray studies on NB (47 samples). Four distinct clusters were identified by Principal Components Analysis (PCA) in two separate data sets, which could be verified by an unsupervised hierarchical clustering in a third independent data set (101 NB samples) using a set of 74 discriminative genes. The expression signature of six NB-associated genes ALK, BIRC5, CCND1, MYCN, NTRK1, and PHOX2B, significantly discriminated the four clusters (p < 0.05, one-way ANOVA test). PCA clusters p1, p2, and p3 were found to correspond well to the postulated subtypes 1, 2A, and 2B, respectively. Remarkably, a fourth novel cluster was detected in all three independent data sets. This cluster comprised mainly 11q-deleted MNA-negative tumours with low expression of ALK, BIRC5, and PHOX2B, and was significantly associated with higher tumour stage, poor outcome and poor survival compared to the Type 1-corresponding favourable group (INSS stage 4 and\\/or dead of disease, p < 0.05, Fisher\\'s exact test). Conclusions Based on expression profiling we have identified four molecular subgroups of neuroblastoma, which can be distinguished by a 6-gene signature. The fourth subgroup has not been described elsewhere, and efforts are currently made to further investigate this group\\'s specific characteristics.

  2. Irradiation spine deformity in children treated for neuroblastoma

    International Nuclear Information System (INIS)

    Mayfield, J.K.; Riseborough, E.J.; Nehme, M.

    1978-01-01

    A retrospective long-term follow-up review of 56 children with neuroblastoma surviving five years and longer following treatment since 1946 revealed that 57% had developed spine deformity (S.D.) following treatment with 250 kilovolt irradiation at the time of review. The average age at diagnosis was 17 months. Irradiation therapy was delivered to most children before 24 months of age. Follow-up averaged 12.9 years with a range of 5-31 years. Eighty-five per cent of the children had developed structural spine deformity at skeletal maturity and 54% of these children had scoliosis greater than 20 degrees. Sixteen per cent of irradiated children developed structural kyphosis. Non-midline opposing anterior and posterior ports were used most frequently. Mean dosage in patients who developed scoliosis of 20 degrees or more was 3588 rads (spine dosage) and 3746 rads in patients who developed kyphosis. Irradiation through opposing anterior and posterior ports was more commonly associated with the development of S.D. Sixty-six per cent of children who had more than 2000 rads developed S.D. The adolescent growth spurt was associated with an increase in the frequency and severity of spine deformity. This study indicated that moderate to severe S.D. was produced by irradiation in excess of 2000 rads administered with a 250-kilovoltage machine. This study would also suggest that children with neuroblastoma treated with orthovoltage irradiation should be followed closely by the orthopaedic surgeon, the oncologist, the radiotherapist and the paediatrician until the completion of skeletal growth for the development of unsightly structural spine deformity. Early bracing and surgery may be helpful in controlling these deformities in the pre-adolescent to early adolescent years. Continued observation is necessary to determine if current irradiation techniques will minimize or eradicate the incidence and severity of these complications. (author)

  3. 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

  4. Synergistic efficacy of a novel combination therapy controls growth of Bcl-x(L) bountiful neuroblastoma cells by increasing differentiation and apoptosis.

    Science.gov (United States)

    Mohan, Nishant; Banik, Naren L; Ray, Swapan K

    2011-11-01

    Neuroblastoma is the most prevalent extracranial solid tumor mainly in pediatric patients. We explored the efficacy of the combination of 2[(3-[2,3-dichlorophenoxy]propyl)amino]ethanol (2,3-DCPE, a small molecule inhibitor of the anti-apoptotic protein Bcl-x(L)) and N-(4-hydroxyphenyl) retinamide (4-HPR, a synthetic retinoid) in inducing differentiation and apoptosis in human malignant neuroblastoma cells. Immunofluorescence confocal microscopy and flow cytometry showed that the highest level of Bcl-x(L) expression occurred in SK-N-DZ cells followed by SH-SY5Y and IMR-32 cells. Combination of 20 μM 2,3-DCPE and 1 μM 4-HPR acted synergistically in decreasing viability of SK-N-DZ and SH-SY5Y cells. In situ methylene blue staining and protein gel blotting showed the efficacy of this combination of drugs in inducing neuronal differentiation morphologically and also biochemically with upregulation of the neuronal markers such as neurofilament protein (NFP) and neuron specific enolase (NSE) and downregulation of the differentiation inhibiting molecules such as N-Myc and Notch-1 in SK-N-DZ and SH-SY5Y cells. Annexin V-FITC/PI staining showed the synergistic action of this combination therapy in increasing apoptosis in both cell lines. Protein gel blotting manifested that combination therapy increased apoptosis with downregulation of the anti-apoptotic proteins Bcl-x(L), Bcl-2 and Mcl-1 and upregulation of the pro-apoptotic proteins Bax, p53, Puma (p53 upregulated modulator of apoptosis), and Noxa, ultimately causing activation of caspase-3. In conclusion, our results appeared highly encouraging in advocating the use of 2,3-DCPE and 4-HPR as a novel combination therapy for increasing both differentiation and apoptosis in human malignant neuroblastoma cells having Bcl-x(L) overexpression.

  5. Algebraic Methods for Counting Euclidean Embeddings of Rigid Graphs

    NARCIS (Netherlands)

    I.Z. Emiris; E.P. Tsigaridas; A. Varvitsiotis (Antonios); E.R. Gasner

    2009-01-01

    textabstract The study of (minimally) rigid graphs is motivated by numerous applications, mostly in robotics and bioinformatics. A major open problem concerns the number of embeddings of such graphs, up to rigid motions, in Euclidean space. We capture embeddability by polynomial systems

  6. THE RIGIDITY OF THE EARTH'S INNER CORE

    Directory of Open Access Journals (Sweden)

    K. E. BULLEN

    1953-06-01

    Full Text Available The purpose of this paper is to examine and assess, in the
    light of recent evidence, the theory lliat the Earth's inner core has
    a significant rigidity.
    The presenee of an inner core in the Earth is revealed from
    observations of the seismie pliase PKP in the « sliadow zone » for
    which the epicentral distance A lies in the range 105" < A < 143".
    Miss I. Lehmann (r in 1936, followed by Gutenberg and Richter (2
    in 1938, atlrihuted these observations to tlie presence of an inner
    core; and Jeffreys (3 in 1939 applied Airy's theory of diffraetion
    near a caustic to sliow that the alternative theory of diffraetion
    round the outer boundary of the centrai core was not capable of
    explaining tlie observations in the shadow zone. The existence of the
    inner core has been fairly generallv accepted sinee tliis ealculation
    of Jeffreys.

  7. The theory of pseudo-rigid bodies

    CERN Document Server

    Cohen, Harley

    1988-01-01

    This monograph concerns the development, analysis, and application of the theory of pseudo-rigid bodies. It collects together our work on that subject over the last five years. While some results have appeared else­ where, much of the work is new. Our objective in writing this mono­ graph has been to present a new theory of the deformation of bodies, one that has not only a firm theoretical basis, but also the simplicity to serve as an effective tool in practical problems. Consequently, the main body of the treatise is a multifaceted development of the theory, from foundations to explicit solutions to linearizations to methods of approximation. The fact that this variety of aspects, each examined in considerable detail, can be collected together in a single, unified treat­ ment gives this theory an elegance that we feel sets it apart from many others. While our goal has always been to give a complete treatment of the theory as it now stands, the work here is not meant to be definitive. Theories are not ent...

  8. Almost Poisson integration of rigid body systems

    International Nuclear Information System (INIS)

    Austin, M.A.; Krishnaprasad, P.S.; Li-Sheng Wang

    1993-01-01

    In this paper we discuss the numerical integration of Lie-Poisson systems using the mid-point rule. Since such systems result from the reduction of hamiltonian systems with symmetry by lie group actions, we also present examples of reconstruction rules for the full dynamics. A primary motivation is to preserve in the integration process, various conserved quantities of the original dynamics. A main result of this paper is an O(h 3 ) error estimate for the Lie-Poisson structure, where h is the integration step-size. We note that Lie-Poisson systems appear naturally in many areas of physical science and engineering, including theoretical mechanics of fluids and plasmas, satellite dynamics, and polarization dynamics. In the present paper we consider a series of progressively complicated examples related to rigid body systems. We also consider a dissipative example associated to a Lie-Poisson system. The behavior of the mid-point rule and an associated reconstruction rule is numerically explored. 24 refs., 9 figs

  9. Rigid multipodal platforms for metal surfaces

    Directory of Open Access Journals (Sweden)

    Michal Valášek

    2016-03-01

    Full Text Available In this review the recent progress in molecular platforms that form rigid and well-defined contact to a metal surface are discussed. Most of the presented examples have at least three anchoring units in order to control the spatial arrangement of the protruding molecular subunit. Another interesting feature is the lateral orientation of these foot structures which, depending on the particular application, is equally important as the spatial arrangement of the molecules. The numerous approaches towards assembling and organizing functional molecules into specific architectures on metal substrates are reviewed here. Particular attention is paid to variations of both, the core structures and the anchoring groups. Furthermore, the analytical methods enabling the investigation of individual molecules as well as monomolecular layers of ordered platform structures are summarized. The presented multipodal platforms bearing several anchoring groups form considerably more stable molecule–metal contacts than corresponding monopodal analogues and exhibit an enlarged separation of the functional molecules due to the increased footprint, as well as restrict tilting of the functional termini with respect to the metal surface. These platforms are thus ideally suited to tune important properties of the molecule–metal interface. On a single-molecule level, several of these platforms enable the control over the arrangement of the protruding rod-type molecular structures (e.g., molecular wires, switches, rotors, sensors with respect to the surface of the substrate.

  10. Inflatable Tubular Structures Rigidized with Foams

    Science.gov (United States)

    Tinker, Michael L.; Schnell, Andrew R.

    2010-01-01

    Inflatable tubular structures that have annular cross sections rigidized with foams, and the means of erecting such structures in the field, are undergoing development. Although the development effort has focused on lightweight structural booms to be transported in compact form and deployed in outer space, the principles of design and fabrication are also potentially applicable to terrestrial structures, including components of ultralightweight aircraft, lightweight storage buildings and shelters, lightweight insulation, and sales displays. The use of foams to deploy and harden inflatable structures was first proposed as early as the 1960s, and has been investigated in recent years by NASA, the U.S. Air Force Research Laboratory, industry, and academia. In cases of deployable booms, most of the investigation in recent years has focused on solid cross sections, because they can be constructed relatively easily. However, solid-section foam-filled booms can be much too heavy for some applications. In contrast, booms with annular cross sections according to the present innovation can be tailored to obtain desired combinations of stiffness and weight through choice of diameters, wall thicknesses, and foam densities. By far the most compelling advantage afforded by this innovation is the possibility of drastically reducing weights while retaining or increasing the stiffnesses, relative to comparable booms that have solid foamfilled cross sections. A typical boom according to this innovation includes inner and outer polyimide film sleeves to contain foam that is injected between them during deployment.

  11. Spontaneous droplet trampolining on rigid superhydrophobic surfaces

    Science.gov (United States)

    Schutzius, Thomas M.; Jung, Stefan; Maitra, Tanmoy; Graeber, Gustav; Köhme, Moritz; Poulikakos, Dimos

    2015-11-01

    Spontaneous removal of condensed matter from surfaces is exploited in nature and in a broad range of technologies to achieve self-cleaning, anti-icing and condensation control. But despite much progress, our understanding of the phenomena leading to such behaviour remains incomplete, which makes it challenging to rationally design surfaces that benefit from its manifestation. Here we show that water droplets resting on superhydrophobic textured surfaces in a low-pressure environment can self-remove through sudden spontaneous levitation and subsequent trampoline-like bouncing behaviour, in which sequential collisions with the surface accelerate the droplets. These collisions have restitution coefficients (ratios of relative speeds after and before collision) greater than unity despite complete rigidity of the surface, and thus seemingly violate the second law of thermodynamics. However, these restitution coefficients result from an overpressure beneath the droplet produced by fast droplet vaporization while substrate adhesion and surface texture restrict vapour flow. We also show that the high vaporization rates experienced by the droplets and the associated cooling can result in freezing from a supercooled state that triggers a sudden increase in vaporization, which in turn boosts the levitation process. This effect can spontaneously remove surface icing by lifting away icy drops the moment they freeze. Although these observations are relevant only to systems in a low-pressure environment, they show how surface texturing can produce droplet-surface interactions that prohibit liquid and freezing water-droplet retention on surfaces.

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

    Directory of Open Access Journals (Sweden)

    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.

  13. 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.

  14. 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.

  15. 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

  16. 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

  17. 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

  18. 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.

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

    Science.gov (United States)

    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).

  20. RIGIDITY, SENSITIVITY AND QUALITY OF ATTACHMENT - THE ROLE OF MATERNAL RIGIDITY IN THE EARLY SOCIOEMOTIONAL DEVELOPMENT OF PREMATURE-INFANTS

    NARCIS (Netherlands)

    BUTCHER, PR; KALVERBOER, A; MINDERAA, RB; VANDOORMAAL, EF; TENWOLDE, Y

    1993-01-01

    The associations between a mother's rigidity, her sensitivity in early (3 month) interaction and the quality of her premature infant's attachment at 13 months were investigated. Rigidity as a personality characteristic was not found to be significantly associated with sensitivity or quality of

  1. Aryl hydrocarbon receptor downregulates MYCN expression and promotes cell differentiation of neuroblastoma.

    Directory of Open Access Journals (Sweden)

    Pei-Yi Wu

    Full Text Available Neuroblastoma (NB is the most common malignant disease of infancy. MYCN amplification is a prognostic factor for NB and is a sign of highly malignant disease and poor patient prognosis. In this study, we aimed to investigate novel MYCN-related genes and assess how they affect NB cell behavior. The different gene expression found in 10 MYCN amplification NB tumors and 10 tumors with normal MYCN copy number were analyzed using tissue oligonucleotide microarrays. Ingenuity Pathway Analysis was subsequently performed to identify the potential genes involved in MYCN regulation pathways. Aryl hydrocarbon receptor (AHR, a receptor for dioxin-like compounds, was found to be inversely correlated with MYCN expression in NB tissues. This correlation was confirmed in a further 14 human NB samples. Moreover, AHR expression in NB tumors was found to correlate highly with histological grade of differentiation. In vitro studies revealed that AHR overexpression in NB cells induced spontaneous cell differentiation. In addition, it was found that ectopic expression of AHR suppressed MYCN promoter activity resulting in downregulation of MYCN expression. The suppression effect of AHR on the transcription of MYCN was compensated for by E2F1 overexpression, indicating that E2F1 is involved in the AHR-regulating MYCN pathway. Furthermore, AHR shRNA promotes the expression of E2F1 and MYCN in NB cells. These findings suggest that AHR is one of the upstream regulators of MYCN. Through the modulation of E2F1, AHR regulates MYCN gene expression, which may in turn affect NB differentiation.

  2. Effects of all-trans-retinoic acid on human SH-SY5Y neuroblastoma as in vitro model in neurotoxicity research.

    Science.gov (United States)

    Cheung, Yuen-Ting; Lau, Way Kwok-Wai; Yu, Man-Shan; Lai, Cora Sau-Wan; Yeung, Sze-Chun; So, Kwok-Fai; Chang, Raymond Chuen-Chung

    2009-01-01

    Human neuroblastoma SH-SY5Y is a dopaminergic neuronal cell line which has been used as an in vitro model for neurotoxicity experiments. Although the neuroblastoma is usually differentiated by all-trans-retinoic acid (RA), both RA-differentiated and undifferentiated SH-SY5Y cells have been used in neuroscience research. However, the changes in neuronal properties triggered by RA as well as the subsequent responsiveness to neurotoxins have not been comprehensively studied. Therefore, we aim to re-evaluate the differentiation property of RA on this cell line. We hypothesize that modulation of signaling pathways and neuronal properties during RA-mediated differentiation in SH-SY5Y cells can affect their susceptibility to neurotoxins. The differentiation property of RA was confirmed by showing an extensive outgrowth of neurites, increased expressions of neuronal nuclei, neuron specific enolase, synaptophysin and synaptic associated protein-97, and decreased expression of inhibitor of differentiation-1. While undifferentiated SH-SY5Y cells were susceptible to 6-OHDA and MPP+, RA-differentiation conferred SH-SY5Y cells higher tolerance, potentially by up-regulating survival signaling, including Akt pathway as inhibition of Akt removed RA-induced neuroprotection against 6-OHDA. As a result, the real toxicity cannot be revealed in RA-differentiated cells. Therefore, undifferentiated SH-SY5Y is more appropriate for studying neurotoxicity or neuroprotection in experimental Parkinson's disease research.

  3. 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

  4. 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.

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Science.gov (United States)

    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

  7. 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

  8. 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.)

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

    Science.gov (United States)

    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.

  10. 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.

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

    Energy Technology Data Exchange (ETDEWEB)

    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)

  12. 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.)

  13. 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)

  14. 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

  15. 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)

  16. 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)

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    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.

  19. 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)

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

    Science.gov (United States)

    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.

  1. 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.

  2. 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.

  3. Reversible Rigidity Control Using Low Melting Temperature Alloys

    Science.gov (United States)

    Shan, Wanliang; Lu, Tong; Majidi, Carmel

    2013-03-01

    Inspired by nature, materials able to achieve rapid rigidity changes have important applications for human body protection in military and many other areas. This talk presents the fabrication and design of soft-matter technologies that exhibit rapid reversible rigidity control. Fabricated with a masked deposition technique, the soft-matter composite contains liquid-phase and phase-changing metal alloys embedded in a soft and highly stretchable elastomer. The composite material can reversibly change its rigidity by three orders of magnitude and sustain large deformation.

  4. The Almost Periodic Rigidity of Crystallographic Bar-Joint Frameworks

    Directory of Open Access Journals (Sweden)

    Ghada Badri

    2014-04-01

    Full Text Available A crystallographic bar-joint framework, C in Rd, is shown to be almost periodically infinitesimally rigid if and only if it is strictly periodically infinitesimally rigid and the rigid unit mode (RUM spectrum, Ω (C, is a singleton. Moreover, the almost periodic infinitesimal flexes of C are characterised in terms of a matrix-valued function, ΦC(z, on the d-torus, Td, determined by a full rank translation symmetry group and an associated motif of joints and bars.

  5. APPLICATION OF RIGID LINKS IN STRUCTURAL DESIGN MODELS

    Directory of Open Access Journals (Sweden)

    Sergey Yu. Fialko

    2017-09-01

    Full Text Available A special finite element modelling rigid links is proposed for the linear static and buckling analysis. Unlike the classical approach based on the theorems of rigid body kinematics, the proposed approach preserves the similarity between the adjacency graph for a sparse matrix and the adjacency graph for nodes of the finite element model, which allows applying sparse direct solvers more effectively. Besides, the proposed approach allows significantly reducing the number of nonzero entries in the factored stiffness matrix in comparison with the classical one, which greatly reduces the duration of the solution. For buckling problems of structures containing rigid bodies, this approach gives correct results. Several examples demonstrate its efficiency.

  6. PPAR Gamma in Neuroblastoma: The Translational Perspectives of Hypoglycemic Drugs

    Directory of Open Access Journals (Sweden)

    Serena Vella

    2016-01-01

    Full Text Available Neuroblastoma (NB is the most common and aggressive pediatric cancer, characterized by a remarkable phenotypic diversity and high malignancy. The heterogeneous clinical behavior, ranging from spontaneous remission to fatal metastatic disease, is attributable to NB biology and genetics. Despite major advances in therapies, NB is still associated with a high morbidity and mortality. Thus, novel diagnostic, prognostic, and therapeutic approaches are required, mainly to improve treatment outcomes of high-risk NB patients. Among neuroepithelial cancers, NB is the most studied tumor as far as PPAR ligands are concerned. PPAR ligands are endowed with antitumoral effects, mainly acting on cancer stem cells, and constitute a possible add-on therapy to antiblastic drugs, in particular for NB with unfavourable prognosis. While discussing clinical background, this review will provide a synopsis of the major studies about PPAR expression in NB, focusing on the potential beneficial effects of hypoglycemic drugs, thiazolidinediones and metformin, to reduce the occurrence of relapses as well as tumor regrowth in NB patients.

  7. Glycolysis-respiration relationships in a neuroblastoma cell line.

    Science.gov (United States)

    Swerdlow, Russell H; E, Lezi; Aires, Daniel; Lu, Jianghua

    2013-04-01

    Although some reciprocal glycolysis-respiration relationships are well recognized, the relationship between reduced glycolysis flux and mitochondrial respiration has not been critically characterized. We concomitantly measured the extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) of SH-SY5Y neuroblastoma cells under free and restricted glycolysis flux conditions. Under conditions of fixed energy demand ECAR and OCR values showed a reciprocal relationship. In addition to observing an expected Crabtree effect in which increasing glucose availability raised the ECAR and reduced the OCR, a novel reciprocal relationship was documented in which reducing the ECAR via glucose deprivation or glycolysis inhibition increased the OCR. Substituting galactose for glucose, which reduces net glycolysis ATP yield without blocking glycolysis flux, similarly reduced the ECAR and increased the OCR. We further determined how reduced ECAR conditions affect proteins that associate with energy sensing and energy response pathways. ERK phosphorylation, SIRT1, and HIF1a decreased while AKT, p38, and AMPK phosphorylation increased. These data document a novel intracellular glycolysis-respiration effect in which restricting glycolysis flux increases mitochondrial respiration. Since this effect can be used to manipulate cell bioenergetic infrastructures, this particular glycolysis-respiration effect can practically inform the development of new mitochondrial medicine approaches. Copyright © 2012 Elsevier B.V. All rights reserved.

  8. Molecular mechanism of action of opioids in human neuroblastoma cells

    International Nuclear Information System (INIS)

    Yu, V.C.K.

    1987-01-01

    A series of human neuroblastoma cell lines was screened for the presence of opioid receptor sites. Of these cell lines, SK-N-SH was found to express approximately 50,000 μ and 10,000 δ opioid receptor sites/cell. In vitro characterization revealed that the binding properties of these receptor sites closely resembled those of human and rodent brain. Phosphatidylinositol turnover as a potential second messenger system for the μ receptor was examined in SK-N-SH cells. Neurotransmitter receptor systems were determined in the three sub-clones of SK-N-SH cells. Cells of the SH-SY5Y line, a phenotypically stable subclone of SK-N-SH cells, were induced to differentiate by treatment with various inducing agents, and changes of several neurotransmitter receptor systems were determined. Nerve growth factor (NGF) and retinoic acid (RA) up-regulated, while dBcAMP down-regulated opioid receptor sites. [ 3 H]Dopamine uptake was slightly enhanced only in RA-treated cells. Strikingly, the efficacy of PGE 1 -stimulated accumulation of cAMP was enhanced by 15- to 30-fold upon RA treatment

  9. Neuroblastoma of the olfactory nerve - radiotherapeutic experiences with six patients

    International Nuclear Information System (INIS)

    Herzog, J.; Schmidt, B.; Petersen, D.; Schabet, M.

    1988-01-01

    Six patients with neuroblastomas of the olfactory nerve (aesthesioneuroblastoma) are presented who were irradiated between 1983 and 1986. Clinical manifestations, diagnostics, histology, therapy, and courses are compared and discused with regard to a survey of literature. An attempt is made to find out the value of radiotherapy in the treatment of this rare disease. In stage A (tumor restricted to the nasal cavity, 1 patient), a local tumor control of up to now 28 months could be achieved by a treatment combination of surgery and radiotherapy. A treatment consisting of surgery or radiotherapy alone should even in this stage only be performed in connection with a close follow-up because of the increased local recurrence risk. Five patients suffered from tumors of stage C (tumor extent beyond the paranasal sinuses). A good palliative effect was obtained temporarily by radiotherapy alone in three out of these patients showing large inoperable tumors and rapidly progressing clinical symptoms. A complete remission now lasting 16 months was achieved only in one patient by radical surgery with unilateral evisceration of orbit and homogenous postirradiation. In case of stage C tumors it is recommended to perform, if possible, a radical tumor excision with evisceration of orbit in case of unilateral manifestation in the orbit and a postirradiation applying a radical, largevolume technique. In order to reduce the risk of radiogenic cerebral necroses, it should be attempted to avoid dose maxima as they can occur when applying a combined ventro-dorsal and lateral irradiation technique. (orig./MG) [de

  10. Radiotherapy of the cephalic segment in patients with advanced neuroblastoma

    International Nuclear Information System (INIS)

    Weltman, Eduardo

    1995-01-01

    Although the treatment results have significantly improved for several pediatric malignant neoplasms, particularly Wilms's tumor, lymphomas and leukemia, in the last decade, the prognosis of the INSS, stage 4 neuroblastoma over one year one old patients remains poor. Even for the more advanced centers, using the more aggressive treatment schedules, such as bone marrow transplantation, the probability of a 2 year progression free interval varies from 6 to 50% and at 3 to 6 years, from 13 to 54%. Thereby, at least, 46 to 94% of these patients are expected to die due to the merciless neoplasm progression. The hypothesis here to be tested is regarding the impact of the cephalic irradiation on the outcome of stage 4 patients with skull metastasis at diagnosis. The end point was to establish, under the NEURO-III-85 protocol chemotherapy schedule, the possible benefit of this radiotherapy in preventing the cephalic recurrence, and its reflex on these patients total and diseases free survival. These results disclosed that the cephalic segment irradiation may prevent recurrences at this site. Unfortunately, the decrease in the cranial recurrence frequency did not affect either the disease free interval, or the total survival. The conclusion was that cephalic irradiation have the potential of avoiding these recurrences, without modifying the final outcome. This modality of radiotherapy must be reevaluated under more effective systemic treatments. (author)

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

    Directory of Open Access Journals (Sweden)

    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.

  12. 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.

  13. 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

  14. 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.

  15. DNA replication and post-replication repair in U.V.-sensitive mouse neuroblastoma cells

    International Nuclear Information System (INIS)

    Lavin, M.F.; McCombe, P.; Kidson, C.

    1976-01-01

    Mouse neuroblastoma cells differentiated when grown in the absence of serum; differentiation was reversed on the addition of serum. Differentiated cells were more sensitive to U.V.-radiation than proliferating cells. Whereas addition of serum to differentiated neuroblastoma cells normally resulted in immediate, synchronous entry into S phase, irradiation just before the addition of serum resulted in a long delay in the onset of DNA replication. During this lag period, incorporated 3 H-thymidine appeared in the light density region of CsCl gradients, reflecting either repair synthesis or abortive replication. Post-replication repair (gap-filling) was found to be present in proliferating cells and at certain times in differentiated cells. It is suggested that the sensitivity of differentiated neuroblastoma cells to U.V.-radiation may have been due to ineffective post-replication repair or to deficiencies in more than one repair mechanism, with reduction in repair capacity beyond a critical threshold. (author)

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

    Directory of Open Access Journals (Sweden)

    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].

  17. 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

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

  19. Verification of the Rigidity of the Coulomb Field in Motion

    Science.gov (United States)

    Blinov, S. V.; Bulyzhenkov, I. É.

    2018-06-01

    Laplace, analyzing the stability of the Solar System, was the first to calculate that the velocity of the motion of force fields can significantly exceed the velocity of light waves. In electrodynamics, the Coulomb field should rigidly accompany its source for instantaneous force action in distant regions. Such rigid motion was recently inferred from experiments at the Frascati Beam Test Facility with short beams of relativistic electrons. The comments of the authors on their observations are at odds with the comments of theoreticians on retarded potentials, which motivates a detailed study of the positions of both sides. Predictions of measurements, based on the Lienard-Wiechert potentials, are used to propose an unambiguous scheme for testing the rigidity of the Coulomb field. Realization of the proposed experimental scheme could independently refute or support the assertions of the Italian physicists regarding the rigid motion of Coulomb fields and likewise the nondual field approach to macroscopic reality.

  20. Oscillations of rigid bar in the special relativity

    International Nuclear Information System (INIS)

    Paiva, F.M.; Teixeira, A.F.F.

    2011-12-01

    In the special relativity, a rigid bar slides on herself, with a extreme oscillating harmonically. We have discovered at the movement amplitude and in the bar length, indispensable for the elimination of non physical solutions

  1. Rigid body motion in stereo 3D simulation

    International Nuclear Information System (INIS)

    Zabunov, Svetoslav

    2010-01-01

    This paper addresses the difficulties experienced by first-grade students studying rigid body motion at Sofia University. Most quantities describing the rigid body are in relations that the students find hard to visualize and understand. They also lose the notion of cause-result relations between vector quantities, such as the relation between torque and angular momentum. Consequently, the understanding of physical laws and conservation principles in free rigid body motion is hampered. This paper presents the capabilities of a 3D simulation, which aims to clarify these questions to the students, who are taught mechanics in the general physics course. The rigid body motion simulations may be observed at http://ialms.net/sim/, and are intended to complement traditional learning practices, not replace them, as the author shares the opinion that no simulation may fully resemble reality.

  2. Resin Infusion Rigidized Inflatable Concept Development and Demonstration

    Data.gov (United States)

    National Aeronautics and Space Administration — A novel concept utilizing resin infusion to rigidize inflatable structures was developed at JSC ES. This ICA project intends to complete manufacturing of a prototype...

  3. Genus Ranges of 4-Regular Rigid Vertex Graphs.

    Science.gov (United States)

    Buck, Dorothy; Dolzhenko, Egor; Jonoska, Nataša; Saito, Masahico; Valencia, Karin

    2015-01-01

    A rigid vertex of a graph is one that has a prescribed cyclic order of its incident edges. We study orientable genus ranges of 4-regular rigid vertex graphs. The (orientable) genus range is a set of genera values over all orientable surfaces into which a graph is embedded cellularly, and the embeddings of rigid vertex graphs are required to preserve the prescribed cyclic order of incident edges at every vertex. The genus ranges of 4-regular rigid vertex graphs are sets of consecutive integers, and we address two questions: which intervals of integers appear as genus ranges of such graphs, and what types of graphs realize a given genus range. For graphs with 2 n vertices ( n > 1), we prove that all intervals [ a, b ] for all a genus ranges. For graphs with 2 n - 1 vertices ( n ≥ 1), we prove that all intervals [ a, b ] for all a genus ranges. We also provide constructions of graphs that realize these ranges.

  4. Re-analysis of exponential rigid-rotor astron equilibria

    International Nuclear Information System (INIS)

    Lovelace, R.V.; Larrabee, D.A.; Fleischmann, H.H.

    1978-01-01

    Previous studies of exponential rigid-rotor astron equilibria include particles which are not trapped in the self-field of the configuration. The modification of these studies required to exclude untrapped particles is derived

  5. Rigidity theorem for Willmore surfaces in a sphere

    Indian Academy of Sciences (India)

    Home; Journals; Proceedings – Mathematical Sciences; Volume 126; Issue 2. Rigidity ... Center of Mathematical Sciences, Zhejiang University, Hangzhou 310027, People's Republic of China; College of Mathematics and Information Science, Jiangxi Normal University, Nanchang 330022, People's Republic of China ...

  6. Role of Rigid Endoscopic Detorsion in the Management of Sigmoid ...

    African Journals Online (AJOL)

    had emergency surgery, with gangrenous bowel noted in 43 (72%) ... of any stable patient with clinical and radiological features ... peritonitis, underwent repeat rigid sigmoidoscopy. ... endoscopic detorsion was successful in all six cases.

  7. Magnetism and magnetostriction in a degenerate rigid band

    International Nuclear Information System (INIS)

    Kulakowski, K.; Barbara, B.

    1990-09-01

    We investigate the influence of the spin-orbit coupling on the magnetic and magnetoelastic phenomena in ferromagnetic band systems. The description is within the Stoner model of a degenerate rigid band, for temperature T = O. (author). 14 refs

  8. Stabilization of Rigid Body Dynamics by Internal and External Torques

    National Research Council Canada - National Science Library

    Bloch, A. M; Krishnaprasad, P. S; Marsden, J. E; Sanchez de Alvarez, G

    1990-01-01

    ...] with quadratic feedback torques for internal rotors. We show that with such torques, the equations for the rigid body with momentum wheels are Hamiltonian with respect to a Lie-Poisson bracket structure. Further...

  9. Anti-synchronization of the rigid body exhibiting chaotic dynamics ...

    African Journals Online (AJOL)

    Based on a method derived from nonlinear control theory, we present a ... In this framework, the active control technique is modified and employed to design control ... state space of the two rigid bodies was verified by numerical simulations.

  10. 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.

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Directory of Open Access Journals (Sweden)

    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.

  14. 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.

  15. 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.

  16. 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

  17. 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.

  18. 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

  19. 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

  20. Radiotherapy of the cephalic segment in patients with advanced neuroblastoma; Radioterapia do segmento cefalico em pacientes portadores de neuroblastoma avancado

    Energy Technology Data Exchange (ETDEWEB)

    Weltman, Eduardo

    1995-07-01

    Although the treatment results have significantly improved for several pediatric malignant neoplasms, particularly Wilms's tumor, lymphomas and leukemia, in the last decade, the prognosis of the INSS, stage 4 neuroblastoma over one year one old patients remains poor. Even for the more advanced centers, using the more aggressive treatment schedules, such as bone marrow transplantation, the probability of a 2 year progression free interval varies from 6 to 50% and at 3 to 6 years, from 13 to 54%. Thereby, at least, 46 to 94% of these patients are expected to die due to the merciless neoplasm progression. The hypothesis here to be tested is regarding the impact of the cephalic irradiation on the outcome of stage 4 patients with skull metastasis at diagnosis. The end point was to establish, under the NEURO-III-85 protocol chemotherapy schedule, the possible benefit of this radiotherapy in preventing the cephalic recurrence, and its reflex on these patients total and diseases free survival. These results disclosed that the cephalic segment irradiation may prevent recurrences at this site. Unfortunately, the decrease in the cranial recurrence frequency did not affect either the disease free interval, or the total survival. The conclusion was that cephalic irradiation have the potential of avoiding these recurrences, without modifying the final outcome. This modality of radiotherapy must be reevaluated under more effective systemic treatments. (author)

  1. 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.

  2. Radiotherapy of the cephalic segment in patients with advanced neuroblastoma; Radioterapia do segmento cefalico em pacientes portadores de neuroblastoma avancado

    Energy Technology Data Exchange (ETDEWEB)

    Weltman, Eduardo

    1995-07-01

    Although the treatment results have significantly improved for several pediatric malignant neoplasms, particularly Wilms's tumor, lymphomas and leukemia, in the last decade, the prognosis of the INSS, stage 4 neuroblastoma over one year one old patients remains poor. Even for the more advanced centers, using the more aggressive treatment schedules, such as bone marrow transplantation, the probability of a 2 year progression free interval varies from 6 to 50% and at 3 to 6 years, from 13 to 54%. Thereby, at least, 46 to 94% of these patients are expected to die due to the merciless neoplasm progression. The hypothesis here to be tested is regarding the impact of the cephalic irradiation on the outcome of stage 4 patients with skull metastasis at diagnosis. The end point was to establish, under the NEURO-III-85 protocol chemotherapy schedule, the possible benefit of this radiotherapy in preventing the cephalic recurrence, and its reflex on these patients total and diseases free survival. These results disclosed that the cephalic segment irradiation may prevent recurrences at this site. Unfortunately, the decrease in the cranial recurrence frequency did not affect either the disease free interval, or the total survival. The conclusion was that cephalic irradiation have the potential of avoiding these recurrences, without modifying the final outcome. This modality of radiotherapy must be reevaluated under more effective systemic treatments. (author)

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

    Directory of Open Access Journals (Sweden)

    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.

  4. 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

  5. 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.

  6. Regulation of MYCN expression in human neuroblastoma cells

    International Nuclear Information System (INIS)

    Jacobs, Joannes FM; Bokhoven, Hans van; Leeuwen, Frank N van; Hulsbergen-van de Kaa, Christina A; Vries, I Jolanda M de; Adema, Gosse J; Hoogerbrugge, Peter M; Brouwer, Arjan PM de

    2009-01-01

    Amplification of the MYCN gene in neuroblastoma (NB) is associated with a poor prognosis. However, MYCN-amplification does not automatically result in higher expression of MYCN in children with NB. We hypothesized that the discrepancy between MYCN gene expression and prognosis in these children might be explained by the expression of either MYCN-opposite strand (MYCNOS) or the shortened MYCN-isoform (ΔMYCN) that was recently identified in fetal tissues. Both MYCNOS and ΔMYCN are potential inhibitors of MYCN either at the mRNA or at the protein level. Expression of MYCN, MYCNOS and ΔMYCN was measured in human NB tissues of different stages. Transcript levels were quantified using a real-time reverse transcriptase polymerase chain reaction assay (QPCR). In addition, relative expression of these three transcripts was compared to the number of MYCN copies, which was determined by genomic real-time PCR (gQPCR). Both ΔMYCN and MYCNOS are expressed in all NBs examined. In NBs with MYCN-amplification, these transcripts are significantly higher expressed. The ratio of MYCN:ΔMYCN expression was identical in all tested NBs. This indicates that ΔMYCN and MYCN are co-regulated, which suggests that ΔMYCN is not a regulator of MYCN in NB. However, the ratio of MYCNOS:MYCN expression is directly correlated with NB disease stage (p = 0.007). In the more advanced NB stages and NBs with MYCN-amplification, relatively more MYCNOS is present as compared to MYCN. Expression of the antisense gene MYCNOS might be relevant to the progression of NB, potentially by directly inhibiting MYCN transcription by transcriptional interference at the DNA level. The MYCNOS:MYCN-ratio in NBs is significantly correlated with both MYCN-amplification and NB-stage. Our data indicate that in NB, MYCN expression levels might be influenced by MYCNOS but not by ΔMYCN

  7. Protective effect of Pycnogenol in human neuroblastoma SH-SY5Y cells following acrolein-induced cytotoxicity.

    Science.gov (United States)

    Ansari, Mubeen A; Keller, Jeffrey N; Scheff, Stephen W

    2008-12-01

    Oxidative stress is one of the hypotheses involved in the etiology of Alzheimer's disease (AD). Considerable attention has been focused on increasing the intracellular glutathione (GSH) levels in many neurodegenerative diseases, including AD. Pycnogenol (PYC) has antioxidant properties and stabilizes intracellular antioxidant defense systems including glutathione levels. The present study investigated the protective effects of PYC on acrolein-induced oxidative cell toxicity in cultured SH-SY5Y neuroblastoma cells. Decreased cell survival in SH-SY5Y cultures treated with acrolein correlated with oxidative stress, increased NADPH oxidase activity, free radical production, protein oxidation/nitration (protein carbonyl, 3-nitrotyrosine), and lipid peroxidation (4-hydroxy-2-nonenal). Pretreatment with PYC significantly attenuated acrolein-induced cytotoxicity, protein damage, lipid peroxidation, and cell death. A dose-response study suggested that PYC showed protective effects against acrolein toxicity by modulating oxidative stress and increasing GSH. These findings provide support that PYC may provide a promising approach for the treatment of oxidative stress-related neurodegenerative diseases such as AD.

  8. Cyclophilin B protects SH-SY5Y human neuroblastoma cells against MPP(+)-induced neurotoxicity via JNK pathway.

    Science.gov (United States)

    Oh, Yoojung; Jeong, Kwon; Kim, Kiyoon; Lee, Young-Seok; Jeong, Suyun; Kim, Sung Soo; Yoon, Kyung-Sik; Ha, Joohun; Kang, Insug; Choe, Wonchae

    2016-09-23

    Parkinson's disease (PD) is the second most common neurodegenerative disorder of aging. PD involves a progressive loss of dopaminergic neurons in the substantia nigra pars compacta. 1-Methyl-4-phenyl-1, 2, 3, 6-tetrahydropyidine (MPTP) and its toxic metabolite 1-methyl-4-phenylpyridinium ion (MPP+) inhibit the complex I of the mitochondrial electron transport chain, and have been widely used to construct PD models. Cyclophilin B (CypB) is an endoplasmic reticulum protein that binds to cyclosporine A as a cyclophilin family member. CypB has peptidyl-prolyl cis-trans isomerase (PPIase) activity. We investigated the protective effects of overexpressed CypB on MPP+-induced neurocytotoxicity in SH-SY5Y human neuroblastoma cells. Overexpressed CypB decreased MPP(+)-induced oxidative stress through the modulation of antioxidant enzymes including manganese superoxide dismutase and catalase, and prevented neurocytotoxicity via mitogen-activated protein kinase, especially the c-Jun N-terminal kinase pathway. In addition, CypB inhibited the activation of MPP(+)-induced the pro-apoptotic molecules poly (ADP-ribose) polymerase, Bax, and Bcl-2, and attenuated MPP(+)-induced mitochondrial dysfunction. The data suggest that overexpressed CypB protects neuronal cells from MPP+-induced dopaminergic neuronal cell death. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. 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.

  10. 123I-Mibg scintigraphy and 18F-Fdg-Pet imaging for diagnosing neuroblastoma

    Science.gov (United States)

    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

  11. Logic Learning Machine creates explicit and stable rules stratifying neuroblastoma patients

    NARCIS (Netherlands)

    Cangelosi, Davide; Blengio, Fabiola; Versteeg, Rogier; Eggert, Angelika; Garaventa, Alberto; Gambini, Claudio; Conte, Massimo; Eva, Alessandra; Muselli, Marco; Varesio, Luigi

    2013-01-01

    Neuroblastoma is the most common pediatric solid tumor. About fifty percent of high risk patients die despite treatment making the exploration of new and more effective strategies for improving stratification mandatory. Hypoxia is a condition of low oxygen tension occurring in poorly vascularized

  12. Whole body dosimetry for treatment individualized neuroblastoma with 131I-MIBG

    International Nuclear Information System (INIS)

    Ferrer Gracia, C.; Luquero Llopis, N.; Sanchez Munoz, F.; Plaza Aparicio, R.; Huerga Cabrerizo, C.; Corredoira Silva, E.; Serrada Hierro, A.

    2013-01-01

    It according to in this study, that in therapy with 1 31I-MIBG for the treatment of neuroblastoma, it can prescribe and manage dose whole body accurately, allowing individualized treatments and major activities that in the treatments based on a fixed activity according to weight management. (Author)

  13. 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.

  14. 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.

  15. 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.

  16. Oncogenic activation of FOXR1 by 11q23 intrachromosomal deletion-fusions in neuroblastoma

    NARCIS (Netherlands)

    Santo, E. E.; Ebus, M. E.; Koster, J.; Schulte, J. H.; Lakeman, A.; van Sluis, P.; Vermeulen, J.; Gisselsson, D.; Øra, I.; Lindner, S.; Buckley, P. G.; Stallings, R. L.; Vandesompele, J.; Eggert, A.; Caron, H. N.; Versteeg, R.; Molenaar, J. J.

    2012-01-01

    Neuroblastoma tumors frequently show loss of heterozygosity of chromosome 11q with a shortest region of overlap in the 11q23 region. These deletions are thought to cause inactivation of tumor suppressor genes leading to haploinsufficiency. Alternatively, micro-deletions could lead to gene fusion

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

    Directory of Open Access Journals (Sweden)

    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.

  18. 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.

  19. 1-phenyl-2-decanoylamino-3-morpholino-1-propanol chemosensitizes neuroblastoma cells for taxol and vincristine

    NARCIS (Netherlands)

    Sietsma, H; Veldman, Robert; Ausema, B; Nijhof, W; Kamps, W; Vellenga, E; Kok, JW

    In this study, we show that an inhibitor of glycosphingolipid biosynthesis, D,L-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP), increases the chemosensitivity of neuroblastoma tumor cells for Taxol and vincristine. At noneffective low doses of Taxol or vincristine, the addition of a

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

    Science.gov (United States)

    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.

  1. 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.

  2. ATP7A is a novel target of retinoic acid receptor β2 in neuroblastoma cells

    Science.gov (United States)

    Bohlken, A; Cheung, B B; Bell, J L; Koach, J; Smith, S; Sekyere, E; Thomas, W; Norris, M; Haber, M; Lovejoy, D B; Richardson, D R; Marshall, G M

    2009-01-01

    Increased retinoic acid receptor β (RARβ2) gene expression is a hallmark of cancer cell responsiveness to retinoid anticancer effects. Moreover, low basal or induced RARβ2 expression is a common feature of many human cancers, suggesting that RARβ2 may act as a tumour suppressor gene in the absence of supplemented retinoid. We have previously shown that low RARβ2 expression is a feature of advanced neuroblastoma. Here, we demonstrate that the ABC domain of the RARβ2 protein alone was sufficient for the growth inhibitory effects of RARβ2 on neuroblastoma cells. ATP7A, the copper efflux pump, is a retinoid-responsive gene, was upregulated by ectopic overexpression of RARβ2. The ectopic overexpression of the RARβ2 ABC domain was sufficient to induce ATP7A expression, whereas, RARβ2 siRNA blocked the induction of ATP7A expression in retinoid-treated neuroblastoma cells. Forced downregulation of ATP7A reduced copper efflux and increased viability of retinoid-treated neuroblastoma cells. Copper supplementation enhanced cell growth and reduced retinoid-responsiveness, whereas copper chelation reduced the viability and proliferative capacity. Taken together, our data demonstrates ATP7A expression is regulated by retinoic acid receptor β and it has effects on intracellular copper levels, revealing a link between the anticancer action of retinoids and copper metabolism. PMID:19127267

  3. A Rare Case Report of Bilateral Complex Macrocystic Adrenal Hemorrhage Mimicking Fetal Neuroblastoma

    OpenAIRE

    Sindhwani, Geetika; Patel, Viral; Jain, Abhinav

    2018-01-01

    Fetal and neonatal adrenal glands are large vascular organs, which make them vulnerable to frequent bleeding. Although neonatal adrenal hemorrhage is commonly reported, it is rarely diagnosed on antenatal sonography. We present a rare case of prenatally diagnosed bilateral adrenal hemorrhage, which mimicked antenatal neuroblastoma.

  4. 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

  5. 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)

  6. No mutations found by RET mutation scanning in sporadic and hereditary neuroblastoma

    NARCIS (Netherlands)

    Hofstra, R. M.; Cheng, N. C.; Hansen, C.; Stulp, R. P.; Stelwagen, T.; Clausen, N.; Tommerup, N.; Caron, H.; Westerveld, A.; Versteeg, R.; Buys, C. H.

    1996-01-01

    Neuroblastoma occasionally occurs in diseases associated with abnormal neurocrest differentiation, e.g. Hirschsprung disease. Expression studies in developing mice suggest that the proto-oncogene RET plays a role in neurocrest differentiation. In humans expression of RET is limited to certain tumor

  7. The use of both diagnostic and therapeutic MIBG in neuroblastoma patients

    NARCIS (Netherlands)

    Bleeker, G.

    2014-01-01

    Neuroblastoma is the most common extra-cranial malignant solid tumour of childhood. It is an embryonic tumour derived from the sympathetic adrenal lineage of the neural crest. Distant metastases are present at diagnosis in 50% of the patients. Metaiodobenzylguanidine (MIBG) is a compound

  8. No mutations found by RET mutation scanning in sporadic and hereditary neuroblastoma

    NARCIS (Netherlands)

    Hofstra, RMW; Cheng, NC; Stulp, RP; Stelwagen, T; Clausen, N; Tommerup, N; Caron, H; Westerveld, A; Buys, CHCM

    Neuroblastoma occasionally occurs in diseases associated with abnormal neurocrest differentiation, e.g. Hirschsprung disease. Expression studies in developing mice suggest that the proto-oncogene RET plays a role in neurocrest differentiation. In humans expression of RT is limited to certain tumor

  9. 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.

  10. 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

  11. Combinations of genetic data in a study of neuroblastoma risk genotypes

    DEFF Research Database (Denmark)

    Capasso, Mario; Calabrese, Francesco Maria; Iolascon, Achille

    2014-01-01

    Analysis of combinations of genetic changes that occur exclusively in patients may be a supplementary strategy to the single-locus strategy used in many genetic studies. The genotypes of 16 SNPs within susceptibility loci for neuroblastoma (NB) were analyzed in a previous study. In the present...

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

  13. PRAF2 stimulates cell proliferation and migration and predicts poor prognosis in neuroblastoma

    NARCIS (Netherlands)

    Yco, Lisette P.; Geerts, Dirk; Koster, Jan; Bachmann, André S.

    2013-01-01

    Prenylated Rab acceptor 1 domain family, member 2 (PRAF2) is a novel 19-kDa protein with four transmembrane-spanning domains that belongs to the PRAF protein family. Neuroblastoma (NB) is the most common malignant extracranial solid tumor of childhood that originates in primitive cells of the

  14. Effect of sulfasalazine on human neuroblastoma: Analysis of sepiapterin reductase (SPR) as a new therapeutic target

    NARCIS (Netherlands)

    L.P. Yco (Lisette P.); D. Geerts (Dirk); G. Mocz (Gabor); J. Koster (Jan); A.S. Bachmann (André)

    2015-01-01

    textabstractBackground: Neuroblastoma (NB) is an aggressive childhood malignancy in children up to 5 years of age. High-stage tumors frequently relapse even after aggressive multimodal treatment, and then show therapy resistance, typically resulting in patient death. New molecular-targeted compounds

  15. Effect of sulfasalazine on human neuroblastoma: analysis of sepiapterin reductase (SPR) as a new therapeutic target

    NARCIS (Netherlands)

    Yco, Lisette P.; Geerts, Dirk; Mocz, Gabor; Koster, Jan; Bachmann, André S.

    2015-01-01

    Neuroblastoma (NB) is an aggressive childhood malignancy in children up to 5 years of age. High-stage tumors frequently relapse even after aggressive multimodal treatment, and then show therapy resistance, typically resulting in patient death. New molecular-targeted compounds that effectively

  16. Survival outcome of intermediate risk neuroblastoma at Children Cancer Hospital Egypt

    Directory of Open Access Journals (Sweden)

    Hossam Elzomor

    2018-03-01

    Conclusion: A very high rate of survival is currently achievable in patients with intermediate risk neuroblastoma by chemotherapy or chemotherapy and surgery. In addition to response, our plan is to adopt biologically-based treatment to reduce treatment-induced complications among survivors.

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

    NARCIS (Netherlands)

    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; Ansari, Marc; Gumy-Pause, Fabienne

    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

  18. 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

  19. 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

  20. 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

  1. Sensitive and reliable detection of genomic imbalances in human neuroblastomas using comparative genomic hybridisation analysis

    NARCIS (Netherlands)

    van Gele, M.; van Roy, N.; Jauch, A.; Laureys, G.; Benoit, Y.; Schelfhout, V.; de Potter, C. R.; Brock, P.; Uyttebroeck, A.; Sciot, R.; Schuuring, E.; Versteeg, R.; Speleman, F.

    1997-01-01

    Deletions of the short arm of chromosome 1, extra copies of chromosome 17q and MYCN amplification are the most frequently encountered genetic changes in neuroblastomas. Standard techniques for detection of one or more of these genetic changes are karyotyping, FISH analysis and LOH analysis by

  2. 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)

  3. Anti-GD2 mAb and Vorinostat synergize in the treatment of neuroblastoma

    NARCIS (Netherlands)

    Kroesen, M.; Bull, C.; Gielen, P.R.; Brok, I.C.; Armandari, I.; Wassink, M.; Looman, M.W.G.; Boon, L.; Brok, M.H.M.G.M. den; Hoogerbrugge, P.M.; Adema, G.J.

    2016-01-01

    Neuroblastoma (NBL) is a childhood malignancy of the sympathetic nervous system. For high-risk NBL patients, the mortality rate is still over 50%, despite intensive multimodal treatment. Anti-GD2 monoclonal antibody (mAB) in combination with systemic cytokine immunotherapy has shown clinical

  4. 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

  5. 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.

  6. Soft-matter composites with electrically tunable elastic rigidity

    International Nuclear Information System (INIS)

    Shan, Wanliang; Lu, Tong; Majidi, Carmel

    2013-01-01

    We use a phase-changing metal alloy to reversibly tune the elastic rigidity of an elastomer composite. The elastomer is embedded with a sheet of low-melting-point Field’s metal and an electric Joule heater composed of a serpentine channel of liquid-phase gallium–indium–tin (Galinstan ® ) alloy. At room temperature, the embedded Field’s metal is solid and the composite remains elastically rigid. Joule heating causes the Field’s metal to melt and allows the surrounding elastomer to freely stretch and bend. Using a tensile testing machine, we measure that the effective elastic modulus of the composite reversibly changes by four orders of magnitude when powered on and off. This dramatic change in rigidity is accurately predicted with a model for an elastic composite. Reversible rigidity control is also accomplished by replacing the Field’s metal with shape memory polymer. In addition to demonstrating electrically tunable rigidity with an elastomer, we also introduce a new technique to rapidly produce soft-matter electronics and multifunctional materials in several minutes with laser-patterned adhesive film and masked deposition of liquid-phase metal alloy. (paper)

  7. Soft-matter composites with electrically tunable elastic rigidity

    Science.gov (United States)

    Shan, Wanliang; Lu, Tong; Majidi, Carmel

    2013-08-01

    We use a phase-changing metal alloy to reversibly tune the elastic rigidity of an elastomer composite. The elastomer is embedded with a sheet of low-melting-point Field’s metal and an electric Joule heater composed of a serpentine channel of liquid-phase gallium-indium-tin (Galinstan®) alloy. At room temperature, the embedded Field’s metal is solid and the composite remains elastically rigid. Joule heating causes the Field’s metal to melt and allows the surrounding elastomer to freely stretch and bend. Using a tensile testing machine, we measure that the effective elastic modulus of the composite reversibly changes by four orders of magnitude when powered on and off. This dramatic change in rigidity is accurately predicted with a model for an elastic composite. Reversible rigidity control is also accomplished by replacing the Field’s metal with shape memory polymer. In addition to demonstrating electrically tunable rigidity with an elastomer, we also introduce a new technique to rapidly produce soft-matter electronics and multifunctional materials in several minutes with laser-patterned adhesive film and masked deposition of liquid-phase metal alloy.

  8. Unified Creep Plasticity Damage (UCPD) Model for Rigid Polyurethane Foams.

    Energy Technology Data Exchange (ETDEWEB)

    Neilsen, Michael K. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Lu, Wei-Yang [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Scherzinger, William M. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Hinnerichs, Terry D. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Lo, Chi S. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States)

    2015-06-01

    Numerous experiments were performed to characterize the mechanical response of several different rigid polyurethane foams (FR3712, PMDI10, PMDI20, and TufFoam35) to large deformation. In these experiments, the effects of load path, loading rate, and temperature were investigated. Results from these experiments indicated that rigid polyurethane foams exhibit significant volumetric and deviatoric plasticity when they are compressed. Rigid polyurethane foams were also found to be very strain-rate and temperature dependent. These foams are also rather brittle and crack when loaded to small strains in tension or to larger strains in compression. Thus, a new Unified Creep Plasticity Damage (UCPD) model was developed and implemented into SIERRA with the name Foam Damage to describe the mechanical response of these foams to large deformation at a variety of temperatures and strain rates. This report includes a description of recent experiments and experimental findings. Next, development of a UCPD model for rigid, polyurethane foams is described. Selection of material parameters for a variety of rigid polyurethane foams is then discussed and finite element simulations with the new UCPD model are compared with experimental results to show behavior that can be captured with this model.

  9. Evaluation for rigidity of box construction of nuclear reactor building

    International Nuclear Information System (INIS)

    Yamakawa, Tetsuo

    1979-01-01

    A huge box-shaped structure (hereafter, called box construction) of reinforced concrete is presently utilized as the reactor building structure in nuclear power plants. Evaluation of the rigidity of the huge box construction is required for making a vibration analysis model of nuclear reactor buildings. It is necessary to handle the box construction as the plates to which the force in plane is applied. This paper describes that the bending theory in elementary beam theory is equivalent to a peculiar, orthogonally anisotropic plate, the shearing rigidity and film rigidity in y direction of which are put to infinity and the Poisson's ratio is put to zero, viewed from the two-dimensional theory of elasticity. The form factor of 1.2 for shearing deformation in rectangular cross section was calculated from the parabolic distribution of shearing stress intensity, and it is the maximum value. The factor is equal to 1.2 for slender beams, but smaller than 1.2 for short and thick beams, having tendency to converge to 1.0. The non-conformity of boundary conditions regarding the shearing force at the both ends of cantilevers does not affect very seriously the evaluation of shearing rigidity. From the above results, it was found that the application of the theory to the box construction was able to give the rigidity evaluation with sufficient engineering accuracy. The theory can also be applied to the evaluation of tube type ultrahigh buildings. (Wakatsuki, Y.)

  10. 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

  11. 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

  12. 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

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Directory of Open Access Journals (Sweden)

    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.

  15. 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.

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

    Directory of Open Access Journals (Sweden)

    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.

  17. 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

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

  19. MYCN-driven regulatory mechanisms controlling LIN28B in neuroblastoma

    Science.gov (United States)

    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

  20. 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

  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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

  6. CDDO and ATRA Instigate Differentiation of IMR32 Human Neuroblastoma Cells

    Directory of Open Access Journals (Sweden)

    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.

  7. 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.

  8. Rigid external maxillary distraction and rhinoplasty for pyknodysostosis.

    Science.gov (United States)

    Varol, Altan; Sabuncuoglu, Fidan Alakus; Sencimen, Metin; Akcam, Timur; Olmez, Hüseyin; Basa, Selçuk

    2011-05-01

    This article reports the treatment of an 33-year-old female patient with pyknodysostosis by rigid external distraction II midface distraction system. The patient with pyknodysostosis described in this report had severe midfacial hypoplasia. Correction of this by use of routine orthognathic surgery would require osteosynthesis and bone grafting. Risk of infection and/or nonunion after such a surgical procedure was considered too great, and therefore the possibility of treatment by distraction osteogenesis of the maxilla was evaluated. The rigid external distraction II midface distraction system was used to relocate the hypoplastic maxilla at anterior-inferior projection. Distraction osteogenesis should be considered as the primary reconstructive method for maxillofacial deformities in patients with sclerosing bone dysplasias, since this is the second reported case treated successfully with rigid external distraction.

  9. Rigidity of outermost MOTS: the initial data version

    Science.gov (United States)

    Galloway, Gregory J.

    2018-03-01

    In the paper Commun Anal Geom 16(1):217-229, 2008, a rigidity result was obtained for outermost marginally outer trapped surfaces (MOTSs) that do not admit metrics of positive scalar curvature. This allowed one to treat the "borderline case" in the author's work with R. Schoen concerning the topology of higher dimensional black holes (Commun Math Phys 266(2):571-576, 2006). The proof of this rigidity result involved bending the initial data manifold in the vicinity of the MOTS within the ambient spacetime. In this note we show how to circumvent this step, and thereby obtain a pure initial data version of this rigidity result and its consequence concerning the topology of black holes.

  10. Authoritarianism, cognitive rigidity, and the processing of ambiguous visual information.

    Science.gov (United States)

    Duncan, Lauren E; Peterson, Bill E

    2014-01-01

    Intolerance of ambiguity and cognitive rigidity are unifying aspects of authoritarianism as defined by Adorno, Frenkel-Brunswik, Levinson, and Sanford (1982/1950), who hypothesized that authoritarians view the world in absolute terms (e.g., good or evil). Past studies have documented the relationship between authoritarianism and intolerance of ambiguity and rigidity. Frenkel-Brunswik (1949) hypothesized that this desire for absolutism was rooted in perceptual processes. We present a study with three samples that directly tests the relationship between right wing authoritarianism (RWA) and the processing of ideologically neutral but ambiguous visual stimuli. As hypothesized, in all three samples we found that RWA was related to the slower processing of visual information that required participants to recategorize objects. In a fourth sample, RWA was unrelated to speed of processing visual information that did not require recategorization. Overall, results suggest a relationship between RWA and rigidity in categorization.

  11. Mitral stenosis due to pannus overgrowth after rigid ring annuloplasty.

    Science.gov (United States)

    Oda, Takeshi; Kato, Seiya; Tayama, Eiki; Fukunaga, Shuji; Akashi, Hidetoshi; Aoyagi, Shigeaki

    2010-03-01

    Although mitral stenosis (MS) due to pannus overgrowth after mitral valve repair for rheumatic mitral regurgitation (MR) is not uncommon, it is extremely rare in relation to non-rheumatic mitral regurgitation. Whilst it has been suggested that the rigid annuloplasty ring induces pannus overgrowth in the same manner as the flexible ring, to date only in cases using the flexible ring has pannus formation been confirmed by a pathological examination after redo surgery. The case is described of a woman who had undergone mitral valve repair using a 28 mm rigid ring three years previously because of non-rheumatic MR, and subsequently suffered from MS due to pannus formation over the annuloplasty ring. To the present authors' knowledge, this is the first report of MS due to pannus formation after mitral valve repair using a rigid annuloplasty ring to treat non-rheumatic MR documented at reoperation.

  12. Rigid-plastic seismic design of reinforced concrete structures

    DEFF Research Database (Denmark)

    Costa, Joao Domingues; Bento, R.; Levtchitch, V.

    2007-01-01

    structural strength with respect to a pre-defined performance parameter using a rigid-plastic response spectrum, which is characteristic of the ground motion alone. The maximum strength demand at any point is solely dependent on the intensity of the ground motion, which facilitates the task of distributing......In this paper a new seismic design procedure for Reinforced Concrete (R/C) structures is proposed-the Rigid-Plastic Seismic Design (RPSD) method. This is a design procedure based on Non-Linear Time-History Analysis (NLTHA) for systems expected to perform in the non-linear range during a lifetime...... earthquake event. The theoretical background is the Theory of Plasticity (Rigid-Plastic Structures). Firstly, a collapse mechanism is chosen and the corresponding stress field is made safe outside the regions where plastic behaviour takes place. It is shown that this allows the determination of the required...

  13. A concise introduction to mechanics of rigid bodies multidisciplinary engineering

    CERN Document Server

    Huang, L

    2017-01-01

    This updated second edition broadens the explanation of rotational kinematics and dynamics — the most important aspect of rigid body motion in three-dimensional space and a topic of much greater complexity than linear motion. It expands treatment of vector and matrix, and includes quaternion operations to describe and analyze rigid body motion which are found in robot control, trajectory planning, 3D vision system calibration, and hand-eye coordination of robots in assembly work, etc. It features updated treatments of concepts in all chapters and case studies. The textbook retains its comprehensiveness in coverage and compactness in size, which make it easily accessible to the readers from multidisciplinary areas who want to grasp the key concepts of rigid body mechanics which are usually scattered in multiple volumes of traditional textbooks. Theoretical concepts are explained through examples taken from across engineering disciplines and links to applications and more advanced courses (e.g. industrial rob...

  14. Topology-Preserving Rigid Transformation of 2D Digital Images.

    Science.gov (United States)

    Ngo, Phuc; Passat, Nicolas; Kenmochi, Yukiko; Talbot, Hugues

    2014-02-01

    We provide conditions under which 2D digital images preserve their topological properties under rigid transformations. We consider the two most common digital topology models, namely dual adjacency and well-composedness. This paper leads to the proposal of optimal preprocessing strategies that ensure the topological invariance of images under arbitrary rigid transformations. These results and methods are proved to be valid for various kinds of images (binary, gray-level, label), thus providing generic and efficient tools, which can be used in particular in the context of image registration and warping.

  15. Non-rigid image registration using bone growth model

    DEFF Research Database (Denmark)

    Bro-Nielsen, Morten; Gramkow, Claus; Kreiborg, Sven

    1997-01-01

    Non-rigid registration has traditionally used physical models like elasticity and fluids. These models are very seldom valid models of the difference between the registered images. This paper presents a non-rigid registration algorithm, which uses a model of bone growth as a model of the change...... between time sequence images of the human mandible. By being able to register the images, this paper at the same time contributes to the validation of the growth model, which is based on the currently available medical theories and knowledge...

  16. Rigid particle revisited: Extrinsic curvature yields the Dirac equation

    Energy Technology Data Exchange (ETDEWEB)

    Deriglazov, Alexei, E-mail: alexei.deriglazov@ufjf.edu.br [Depto. de Matemática, ICE, Universidade Federal de Juiz de Fora, MG (Brazil); Laboratory of Mathematical Physics, Tomsk Polytechnic University, 634050 Tomsk, Lenin Ave. 30 (Russian Federation); Nersessian, Armen, E-mail: arnerses@ysu.am [Yerevan State University, 1 Alex Manoogian St., Yerevan 0025 (Armenia); Laboratory of Mathematical Physics, Tomsk Polytechnic University, 634050 Tomsk, Lenin Ave. 30 (Russian Federation)

    2014-03-01

    We reexamine the model of relativistic particle with higher-derivative linear term on the first extrinsic curvature (rigidity). The passage from classical to quantum theory requires a number of rather unexpected steps which we report here. We found that, contrary to common opinion, quantization of the model in terms of so(3.2)-algebra yields massive Dirac equation. -- Highlights: •New way of canonical quantization of relativistic rigid particle is proposed. •Quantization made in terms of so(3.2) angular momentum algebra. •Quantization yields massive Dirac equation.

  17. Elastic properties of rigid fiber-reinforced composites

    Science.gov (United States)

    Chen, J.; Thorpe, M. F.; Davis, L. C.

    1995-05-01

    We study the elastic properties of rigid fiber-reinforced composites with perfect bonding between fibers and matrix, and also with sliding boundary conditions. In the dilute region, there exists an exact analytical solution. Around the rigidity threshold we find the elastic moduli and Poisson's ratio by decomposing the deformation into a compression mode and a rotation mode. For perfect bonding, both modes are important, whereas only the compression mode is operative for sliding boundary conditions. We employ the digital-image-based method and a finite element analysis to perform computer simulations which confirm our analytical predictions.

  18. Extremal surfaces and the rigidity of null geodesic incompleteness

    International Nuclear Information System (INIS)

    Silva, I P Costa e; Flores, J L

    2015-01-01

    An important, if relatively less well known aspect of the singularity theorems in Lorentzian geometry, is to understand how their conclusions fare upon weakening or suppression of one or more of their hypotheses. Then, theorems with modified conclusion may arise, showing that those conclusions will fail only in special cases, at least some of which may be described. These are the so-called rigidity theorems, and have many important examples in the specialized literature. In this paper, we prove rigidity results for generalized plane waves and certain globally hyperbolic spacetimes in the presence of extremal compact surfaces. (paper)

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

    Directory of Open Access Journals (Sweden)

    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.

  20. Cystatins - Extra- and intracellular cysteine protease inhibitors: High-level secretion and uptake of cystatin C in human neuroblastoma cells

    DEFF Research Database (Denmark)

    Wallin, Hanna; Bjarnadottir, Maria; Vogel, Lotte

    2010-01-01

    signal peptides) for cellular export following translation. Results indicating existence of systems for significant internalisation of type 2 cystatins from the extracellular to intracellular compartments are reviewed. Data showing that human neuroblastoma cell lines generally secrete high levels...

  1. Segmentation and Estimation of the Histological Composition of the Tumor Mass in Computed Tomographic Images of Neuroblastoma

    National Research Council Canada - National Science Library

    Ayres, Fabio

    2001-01-01

    The problem that we investigate in the present paper Is the improvement of the analysis of the primary tumor mass, in patients with advanced neuroblastoma, using X-ray computed tomography (CT) exams...

  2. 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...

  3. MicroRNAs define distinct human neuroblastoma cell phenotypes and regulate their differentiation and tumorigenicity

    International Nuclear Information System (INIS)

    Samaraweera, Leleesha; Grandinetti, Kathryn B; Huang, Ruojun; Spengler, Barbara A; Ross, Robert A

    2014-01-01

    Neuroblastoma (NB) is the most common extracranial solid tumor in children. NB tumors and derived cell lines are phenotypically heterogeneous. Cell lines are classified by phenotype, each having distinct differentiation and tumorigenic properties. The neuroblastic phenotype is tumorigenic, has neuronal features and includes stem cells (I-cells) and neuronal cells (N-cells). The non-neuronal phenotype (S-cell) comprises cells that are non-tumorigenic with features of glial/smooth muscle precursor cells. This study identified miRNAs associated with each distinct cell phenotypes and investigated their role in regulating associated differentiation and tumorigenic properties. A miRNA microarray was performed on the three cell phenotypes and expression verified by qRT-PCR. miRNAs specific for certain cell phenotypes were modulated using miRNA inhibitors or stable transfection. Neuronal differentiation was induced by RA; non-neuronal differentiation by BrdU. Changes in tumorigenicity were assayed by soft agar colony forming ability. N-myc binding to miR-375 promoter was assayed by chromatin-immunoprecipitation. Unsupervised hierarchical clustering of miRNA microarray data segregated neuroblastic and non-neuronal cell lines and showed that specific miRNAs define each phenotype. qRT-PCR validation confirmed that increased levels of miR-21, miR-221 and miR-335 are associated with the non-neuronal phenotype, whereas increased levels of miR-124 and miR-375 are exclusive to neuroblastic cells. Downregulation of miR-335 in non-neuronal cells modulates expression levels of HAND1 and JAG1, known modulators of neuronal differentiation. Overexpression of miR-124 in stem cells induces terminal neuronal differentiation with reduced malignancy. Expression of miR-375 is exclusive for N-myc-expressing neuroblastic cells and is regulated by N-myc. Moreover, miR-375 downregulates expression of the neuronal-specific RNA binding protein HuD. Thus, miRNAs define distinct NB cell phenotypes

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

    Directory of Open Access Journals (Sweden)

    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

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

    Science.gov (United States)

    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

  6. 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.

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

    Directory of Open Access Journals (Sweden)

    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.

  8. 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....

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

    Science.gov (United States)

    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.

  10. Mouse neuroblastoma cell based model and the effect of epileptic events on calcium oscillations and neural spikes

    Science.gov (United States)

    Kim, Suhwan; Baek, Juyeong; Jung, Unsang; Lee, Sangwon; Jung, Woonggyu; Kim, Jeehyun; Kang, Shinwon

    2013-05-01

    Recently, Mouse neuroblastoma cells are considered as an attractive model for the study of human neurological and prion diseases, and intensively used as a model system in different areas. Among those areas, differentiation of neuro2a (N2A) cells, receptor mediated ion current, and glutamate induced physiological response are actively investigated. The reason for the interest to mouse neuroblastoma N2A cells is that they have a fast growing rate than other cells in neural origin with a few another advantages. This study evaluated the calcium oscillations and neural spikes recording of mouse neuroblastoma N2A cells in an epileptic condition. Based on our observation of neural spikes in mouse N2A cell with our proposed imaging modality, we report that mouse neuroblastoma N2A cells can be an important model related to epileptic activity studies. It is concluded that the mouse neuroblastoma N2A cells produce the epileptic spikes in vitro in the same way as produced by the neurons or the astrocytes. This evidence advocates the increased and strong level of neurotransmitters release by enhancement in free calcium using the 4-aminopyridine which causes the mouse neuroblastoma N2A cells to produce the epileptic spikes and calcium oscillation.

  11. 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.)

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Science.gov (United States)

    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.

  14. Viscoelastic materials with anisotropic rigid particles: stress-deformation behavior

    NARCIS (Netherlands)

    Sagis, L.M.C.; Linden, van der E.

    2001-01-01

    In this paper we have derived constitutive equations for the stress tensor of a viscoelastic material with anisotropic rigid particles. We have assumed that the material has fading memory. The expressions are valid for slow and small deformations from equilibrium, and for systems that are nearly

  15. Rigidity and bradykinesia reduce interlimb coordination in Parkinsonian gait

    NARCIS (Netherlands)

    Winogrodzka, Ania; Wagenaar, Robert C.; Booij, Jan; Wolters, Eric C.

    2005-01-01

    Objective: To assess the influence of rigidity and bradykinesia and the extent of dopaminergic degeneration on interlimb coordination during walking in early, drug-naive patients with Parkinson's disease (PD). Design: The interlimb coordination was examined during a systematic manipulation of

  16. Calculating ensemble averaged descriptions of protein rigidity without sampling.

    Directory of Open Access Journals (Sweden)

    Luis C González

    Full Text Available Previous works have demonstrated that protein rigidity is related to thermodynamic stability, especially under conditions that favor formation of native structure. Mechanical network rigidity properties of a single conformation are efficiently calculated using the integer body-bar Pebble Game (PG algorithm. However, thermodynamic properties require averaging over many samples from the ensemble of accessible conformations to accurately account for fluctuations in network topology. We have developed a mean field Virtual Pebble Game (VPG that represents the ensemble of networks by a single effective network. That is, all possible number of distance constraints (or bars that can form between a pair of rigid bodies is replaced by the average number. The resulting effective network is viewed as having weighted edges, where the weight of an edge quantifies its capacity to absorb degrees of freedom. The VPG is interpreted as a flow problem on this effective network, which eliminates the need to sample. Across a nonredundant dataset of 272 protein structures, we apply the VPG to proteins for the first time. Our results show numerically and visually that the rigidity characterizations of the VPG accurately reflect the ensemble averaged [Formula: see text] properties. This result positions the VPG as an efficient alternative to understand the mechanical role that chemical interactions play in maintaining protein stability.

  17. Calculating ensemble averaged descriptions of protein rigidity without sampling.

    Science.gov (United States)

    González, Luis C; Wang, Hui; Livesay, Dennis R; Jacobs, Donald J

    2012-01-01

    Previous works have demonstrated that protein rigidity is related to thermodynamic stability, especially under conditions that favor formation of native structure. Mechanical network rigidity properties of a single conformation are efficiently calculated using the integer body-bar Pebble Game (PG) algorithm. However, thermodynamic properties require averaging over many samples from the ensemble of accessible conformations to accurately account for fluctuations in network topology. We have developed a mean field Virtual Pebble Game (VPG) that represents the ensemble of networks by a single effective network. That is, all possible number of distance constraints (or bars) that can form between a pair of rigid bodies is replaced by the average number. The resulting effective network is viewed as having weighted edges, where the weight of an edge quantifies its capacity to absorb degrees of freedom. The VPG is interpreted as a flow problem on this effective network, which eliminates the need to sample. Across a nonredundant dataset of 272 protein structures, we apply the VPG to proteins for the first time. Our results show numerically and visually that the rigidity characterizations of the VPG accurately reflect the ensemble averaged [Formula: see text] properties. This result positions the VPG as an efficient alternative to understand the mechanical role that chemical interactions play in maintaining protein stability.

  18. Patient satisfaction related to rigid external distraction osteogenesis

    NARCIS (Netherlands)

    van Eggermont, Bas; Jansma, J.; Bierman, M. W. J.; Stegenga, B.

    2007-01-01

    The aim of this study was to evaluate satisfaction with treatment among cleft lip and palate patients who underwent maxillary advancement using a rigid external distraction (RED) device. Nine patients (four boys, five girls), mean age 17.7 years (SD 4.0), were included in the study. Outcome measures

  19. Short Communication: Statistical determination of the rigidity in ...

    African Journals Online (AJOL)

    From the graph of load against displacement, the rigidity in flexion at different moisture levels was determined from which the Young modulus was calculated. Linear regression models were fitted to the data and the results showed significant correlation coefficients between the Young modulus and moisture content for each ...

  20. Connect-disconnect coupling for preadjusted rigid shafts

    Science.gov (United States)

    Bajkowski, F. W.; Holmberg, A.

    1969-01-01

    Coupling device enables a rigid shaft to be connected to or disconnected from a fixed base without disturbing the point of adjustment of the shaft in a socket or causing the shaft to rotate. The coupling consists of an externally threaded, internally slotted boss extending from the fixed base.