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Sample records for amyloid-beta oligomers neuroblastoma

  1. Insulin Promotes Survival of Amyloid-Beta Oligomers Neuroblastoma Damaged Cells via Caspase 9 Inhibition and Hsp70 Upregulation

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    M. Di Carlo

    2010-01-01

    Full Text Available Alzheimer's disease (AD and type 2 diabetes are connected in a way that is still not completely understood, but insulin resistance has been implicated as a risk factor for developing AD. Here we show an evidence that insulin is capable of reducing cytotoxicity induced by Amyloid-beta peptides (A-beta in its oligomeric form in a dose-dependent manner. By TUNEL and biochemical assays we demonstrate that the recovery of the cell viability is obtained by inhibition of intrinsic apoptotic program, triggered by A-beta and involving caspase 9 and 3 activation. A protective role of insulin on mitochondrial damage is also shown by using Mito-red vital dye. Furthermore, A-beta activates the stress inducible Hsp70 protein in LAN5 cells and an overexpression is detectable after the addition of insulin, suggesting that this major induction is the necessary condition to activate a cell survival program. Together, these results may provide opportunities for the design of preventive and therapeutic strategies against AD.

  2. A hydrogel biosensor for high selective and sensitive detection of amyloid-beta oligomers

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    Sun LP

    2018-02-01

    Full Text Available Liping Sun,1 Yong Zhong,1 Jie Gui,1 Xianwu Wang,1 Xiaorong Zhuang,2 Jian Weng1 1Key Laboratory of Biomedical Engineering of Fujian Province, Research Center of Biomedical Engineering of Xiamen, Department of Biomaterials, College of Materials, Xiamen University, 2Department of Neurology, The Affiliated Zhongshan Hospital of Xiamen University, Xiamen, People’s Republic of China Background: Alzheimer’s disease (AD is a neurodegenerative disorder characterized by progressive cognitive and memory impairment. It is the most common neurological disease that causes dementia. Soluble amyloid-beta oligomers (AβO in blood or cerebrospinal fluid (CSF are the pathogenic biomarker correlated with AD. Methods: A simple electrochemical biosensor using graphene oxide/gold nanoparticles (GNPs hydrogel electrode was developed in this study. Thiolated cellular prion protein (PrPC peptide probe was immobilized on GNPs of the hydrogel electrode to construct an AβO biosensor. Electrochemical impedance spectroscopy was utilized for AβO analysis. Results: The specific binding between AβO and PrPC probes on the hydrogel electrode resulted in an increase in the electron-transfer resistance. The biosensor showed high specificity and sensitivity for AβO detection. It could selectively differentiate AβO from amyloid-beta (Aβ monomers or fibrils. Meanwhile, it was highly sensitive to detect as low as 0.1 pM AβO in artificial CSF or blood plasma. The linear range for AβO detection is from 0.1 pM to 10 nM. Conclusion: This biosensor could be used as a cost-effective tool for early diagnosis of AD due to its high electrochemical performance and bionic structure. Keywords: Alzheimer’s disease, amyloid-beta oligomer, graphene, gold nanoparticles, biosensor

  3. Natural Amyloid-Beta Oligomers Acutely Impair the Formation of a Contextual Fear Memory in Mice

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    Kittelberger, Kara A.; Piazza, Fabrizio; Tesco, Giuseppina; Reijmers, Leon G.

    2012-01-01

    Memory loss is one of the hallmark symptoms of Alzheimer's disease (AD). It has been proposed that soluble amyloid-beta (Abeta) oligomers acutely impair neuronal function and thereby memory. We here report that natural Abeta oligomers acutely impair contextual fear memory in mice. A natural Abeta oligomer solution containing Abeta monomers, dimers, trimers, and tetramers was derived from the conditioned medium of 7PA2 cells, a cell line that expresses human amyloid precursor protein containing the Val717Phe familial AD mutation. As a control we used 7PA2 conditioned medium from which Abeta oligomers were removed through immunodepletion. Separate groups of mice were injected with Abeta and control solutions through a cannula into the lateral brain ventricle, and subjected to fear conditioning using two tone-shock pairings. One day after fear conditioning, mice were tested for contextual fear memory and tone fear memory in separate retrieval trials. Three experiments were performed. For experiment 1, mice were injected three times: 1 hour before and 3 hours after fear conditioning, and 1 hour before context retrieval. For experiments 2 and 3, mice were injected a single time at 1 hour and 2 hours before fear conditioning respectively. In all three experiments there was no effect on tone fear memory. Injection of Abeta 1 hour before fear conditioning, but not 2 hours before fear conditioning, impaired the formation of a contextual fear memory. In future studies, the acute effect of natural Abeta oligomers on contextual fear memory can be used to identify potential mechanisms and treatments of AD associated memory loss. PMID:22238679

  4. Cu K-edge X-ray Absorption Spectroscopy Reveals Differential Copper Coordimation Within Amyloid-beta Oligomers Compared to Amyloid-beta Monomers

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    J Shearer; P Callan; T Tran; V Szalai

    2011-12-31

    The fatal neurodegenerative disorder Alzheimer's disease (AD) has been linked to the formation of soluble neurotoxic oligomers of amyloid-{beta} (A{beta}) peptides. These peptides have high affinities for copper cations. Despite their potential importance in AD neurodegeneration few studies have focused on probing the Cu{sup 2+/1+} coordination environment within A{beta} oligomers. Herein we present a Cu K-edge X-ray absorption spectroscopic study probing the copper-coordination environment within oligomers of A{beta}(42) (sequence: DAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIA). We find that the Cu{sup 2+} cation is contained within a square planar mixed N/O ligand environment within A{beta}(42) oligomers, which is similar to the copper coordination environment of the monomeric forms of {l_brace}Cu{sup II}A{beta}(40){r_brace} and {l_brace}Cu{sup II}A{beta}(16){r_brace}. Reduction of the Cu{sup 2+} cation within the A{beta}(42) oligomers to Cu{sup 1+} yields a highly dioxygen sensitive copper-species that contains Cu{sup 1+} in a tetrahedral coordination geometry. This can be contrasted with monomers of {l_brace}Cu{sup I}A{beta}(40){r_brace} and {l_brace}Cu{sup I}A{beta}(16){r_brace}, which contain copper in a dioxygen inert linear bis-histidine ligand environment [Shearer and Szalai, J. Am. Chem. Soc., 2008, 130, 17826]. The biological implications of these findings are discussed.

  5. Donepezil inhibits the amyloid-beta oligomer-induced microglial activation in vitro and in vivo.

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    Kim, Hyo Geun; Moon, Minho; Choi, Jin Gyu; Park, Gunhyuk; Kim, Ae-Jung; Hur, Jinyoung; Lee, Kyung-Tae; Oh, Myung Sook

    2014-01-01

    Recent studies on Alzheimer's disease (AD) have focused on soluble oligomeric forms of amyloid-beta (Aβ oligomer, AβO) that are directly associated with AD-related pathologies, such as cognitive decline, neurodegeneration, and neuroinflammation. Donepezil is a well-known anti-dementia agent that increases acetylcholine levels through inhibition of acetylcholinesterase. However, a growing body of experimental and clinical studies indicates that donepezil may also provide neuroprotective and disease-modifying effects in AD. Additionally, donepezil has recently been demonstrated to have anti-inflammatory effects against lipopolysaccharides and tau pathology. However, it remains unknown whether donepezil has anti-inflammatory effects against AβO in cultured microglial cells and the brain in animals. Further, the effects of donepezil against AβO-mediated neuronal death, astrogliosis, and memory impairment have also not yet been investigated. Thus, in the present study, we examined the anti-inflammatory effect of donepezil against AβO and its neuroinflammatory mechanisms. Donepezil significantly attenuated the release of inflammatory mediators (prostaglandin E2, interleukin-1 beta, tumor necrosis factor-α, and nitric oxide) from microglia. Donepezil also decreased AβO-induced up-regulation of inducible nitric oxide synthase and cyclooxygenase-2 protein and phosphorylation of p38 mitogen-activated protein kinase as well as translocation of nuclear factor-kappa B. We next showed that donepezil suppresses activated microglia-mediated toxicity in primary hippocampal cells using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. In intrahippocampal AβO-injected mice, donepezil significantly inhibited microgliosis and astrogliosis. Furthermore, behavioral tests revealed that donepezil (2 mg/kg/day, 5 days, p.o.) significantly ameliorated AβO-induced memory impairment. These results suggest that donepezil directly inhibits microglial activation

  6. Alzheimer's therapeutics targeting amyloid beta 1-42 oligomers II: Sigma-2/PGRMC1 receptors mediate Abeta 42 oligomer binding and synaptotoxicity.

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    Nicholas J Izzo

    Full Text Available Amyloid beta (Abeta 1-42 oligomers accumulate in brains of patients with Mild Cognitive Impairment (MCI and disrupt synaptic plasticity processes that underlie memory formation. Synaptic binding of Abeta oligomers to several putative receptor proteins is reported to inhibit long-term potentiation, affect membrane trafficking and induce reversible spine loss in neurons, leading to impaired cognitive performance and ultimately to anterograde amnesia in the early stages of Alzheimer's disease (AD. We have identified a receptor not previously associated with AD that mediates the binding of Abeta oligomers to neurons, and describe novel therapeutic antagonists of this receptor capable of blocking Abeta toxic effects on synapses in vitro and cognitive deficits in vivo. Knockdown of sigma-2/PGRMC1 (progesterone receptor membrane component 1 protein expression in vitro using siRNA results in a highly correlated reduction in binding of exogenous Abeta oligomers to neurons of more than 90%. Expression of sigma-2/PGRMC1 is upregulated in vitro by treatment with Abeta oligomers, and is dysregulated in Alzheimer's disease patients' brain compared to age-matched, normal individuals. Specific, high affinity small molecule receptor antagonists and antibodies raised against specific regions on this receptor can displace synthetic Abeta oligomer binding to synaptic puncta in vitro and displace endogenous human AD patient oligomers from brain tissue sections in a dose-dependent manner. These receptor antagonists prevent and reverse the effects of Abeta oligomers on membrane trafficking and synapse loss in vitro and cognitive deficits in AD mouse models. These findings suggest sigma-2/PGRMC1 receptors mediate saturable oligomer binding to synaptic puncta on neurons and that brain penetrant, small molecules can displace endogenous and synthetic oligomers and improve cognitive deficits in AD models. We propose that sigma-2/PGRMC1 is a key mediator of the pathological

  7. Alzheimer's therapeutics targeting amyloid beta 1-42 oligomers II: Sigma-2/PGRMC1 receptors mediate Abeta 42 oligomer binding and synaptotoxicity.

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    Izzo, Nicholas J; Xu, Jinbin; Zeng, Chenbo; Kirk, Molly J; Mozzoni, Kelsie; Silky, Colleen; Rehak, Courtney; Yurko, Raymond; Look, Gary; Rishton, Gilbert; Safferstein, Hank; Cruchaga, Carlos; Goate, Alison; Cahill, Michael A; Arancio, Ottavio; Mach, Robert H; Craven, Rolf; Head, Elizabeth; LeVine, Harry; Spires-Jones, Tara L; Catalano, Susan M

    2014-01-01

    Amyloid beta (Abeta) 1-42 oligomers accumulate in brains of patients with Mild Cognitive Impairment (MCI) and disrupt synaptic plasticity processes that underlie memory formation. Synaptic binding of Abeta oligomers to several putative receptor proteins is reported to inhibit long-term potentiation, affect membrane trafficking and induce reversible spine loss in neurons, leading to impaired cognitive performance and ultimately to anterograde amnesia in the early stages of Alzheimer's disease (AD). We have identified a receptor not previously associated with AD that mediates the binding of Abeta oligomers to neurons, and describe novel therapeutic antagonists of this receptor capable of blocking Abeta toxic effects on synapses in vitro and cognitive deficits in vivo. Knockdown of sigma-2/PGRMC1 (progesterone receptor membrane component 1) protein expression in vitro using siRNA results in a highly correlated reduction in binding of exogenous Abeta oligomers to neurons of more than 90%. Expression of sigma-2/PGRMC1 is upregulated in vitro by treatment with Abeta oligomers, and is dysregulated in Alzheimer's disease patients' brain compared to age-matched, normal individuals. Specific, high affinity small molecule receptor antagonists and antibodies raised against specific regions on this receptor can displace synthetic Abeta oligomer binding to synaptic puncta in vitro and displace endogenous human AD patient oligomers from brain tissue sections in a dose-dependent manner. These receptor antagonists prevent and reverse the effects of Abeta oligomers on membrane trafficking and synapse loss in vitro and cognitive deficits in AD mouse models. These findings suggest sigma-2/PGRMC1 receptors mediate saturable oligomer binding to synaptic puncta on neurons and that brain penetrant, small molecules can displace endogenous and synthetic oligomers and improve cognitive deficits in AD models. We propose that sigma-2/PGRMC1 is a key mediator of the pathological effects of

  8. Conformational stability of fibrillar amyloid-beta oligomers via protofilament pair formation - a systematic computational study.

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    Anna Kahler

    Full Text Available Amyloid-[Formula: see text] (A[Formula: see text] oligomers play a crucial role in Alzheimer's disease due to their neurotoxic aggregation properties. Fibrillar A[Formula: see text] oligomerization can lead to protofilaments and protofilament pairs via oligomer elongation and oligomer association, respectively. Small fibrillar oligomers adopt the protofilament topology, whereas fibrils contain at least protofilament pairs. To date, the underlying growth mechanism from oligomers to the mature fibril still remains to be elucidated. Here, we performed all-atom molecular dynamics simulations in explicit solvent on single layer-like protofilaments and fibril-like protofilament pairs of different size ranging from the tetramer to the 48-mer. We found that the initial U-shaped topology per monomer is maintained over time in all oligomers. The observed deviations of protofilaments from the starting structure increase significantly with size due to the twisting of the in-register parallel [Formula: see text]-sheets. This twist causes long protofilaments to be unstable and leads to a breakage. Protofilament pairs, which are stabilized by a hydrophobic interface, exhibit more fibril-like properties such as the overall structure and the twist angle. Thus, they can act as stable conformational templates for further fibril growth. Key properties like the twist angle, shape complementarity, and energetics show a size-dependent behavior so that small oligomers favor the protofilament topology, whereas large oligomers favor the protofilament pair topology. The region for this conformational transition is at the size of approximately twelve A[Formula: see text] monomers. From that, we propose the following growth mechanism from A[Formula: see text] oligomers to fibrils: (1 elongation of short protofilaments; (2 breakage of large protofilaments; (3 formation of short protofilament pairs; and (4 elongation of protofilament pairs.

  9. Amyloid-beta oligomer detection by ELISA in cerebrospinal fluid and brain tissue

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    Bruggink, K.A.; Jongbloed, W.; Biemans, E.A.L.M.; Veerhuis, R.; Claassen, J.A.H.R.; Kuiperij, H.B.; Verbeek, M.M.

    2013-01-01

    Amyloid-β (Aβ) deposits are important pathological hallmarks of Alzheimer's disease (AD). Aβ aggregates into fibrils; however, the intermediate oligomers are believed to be the most neurotoxic species and, therefore, are of great interest as potential biomarkers. Here, we have developed an

  10. Alzheimer's Toxic Amyloid Beta Oligomers: Unwelcome Visitors to the Na/K ATPase alpha3 Docking Station.

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    DiChiara, Thomas; DiNunno, Nadia; Clark, Jeffrey; Bu, Riana Lo; Cline, Erika N; Rollins, Madeline G; Gong, Yuesong; Brody, David L; Sligar, Stephen G; Velasco, Pauline T; Viola, Kirsten L; Klein, William L

    2017-03-01

    Toxic amyloid beta oligomers (AβOs) are known to accumulate in Alzheimer's disease (AD) and in animal models of AD. Their structure is heterogeneous, and they are found in both intracellular and extracellular milieu. When given to CNS cultures or injected ICV into non-human primates and other non-transgenic animals, AβOs have been found to cause impaired synaptic plasticity, loss of memory function, tau hyperphosphorylation and tangle formation, synapse elimination, oxidative and ER stress, inflammatory microglial activation, and selective nerve cell death. Memory loss and pathology in transgenic models are prevented by AβO antibodies, while Aducanumab, an antibody that targets AβOs as well as fibrillar Aβ, has provided cognitive benefit to humans in early clinical trials. AβOs have now been investigated in more than 3000 studies and are widely thought to be the major toxic form of Aβ. Although much has been learned about the downstream mechanisms of AβO action, a major gap concerns the earliest steps: How do AβOs initially interact with surface membranes to generate neuron-damaging transmembrane events? Findings from Ohnishi et al (PNAS 2005) combined with new results presented here are consistent with the hypothesis that AβOs act as neurotoxins because they attach to particular membrane protein docks containing Na/K ATPase-α3, where they inhibit ATPase activity and pathologically restructure dock composition and topology in a manner leading to excessive Ca++ build-up. Better understanding of the mechanism that makes attachment of AβOs to vulnerable neurons a neurotoxic phenomenon should open the door to therapeutics and diagnostics targeting the first step of a complex pathway that leads to neural damage and dementia.

  11. Specific Triazine Herbicides Induce Amyloid-beta(42) Production

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    Portelius, Erik; Durieu, Emilie; Bodin, Marion; Cam, Morgane; Pannee, Josef; Leuxe, Charlotte; Mabondzo, Aloise; Oumata, Nassima; Galons, Herve; Lee, Jung Yeol; Chang, Young-Tae; Stuber, Kathrin; Koch, Philipp; Fontaine, Gaelle; Potier, Marie-Claude; Manousopoulou, Antigoni; Garbis, Spiros D.; Covaci, Adrian; Van Dam, Debby; De Deyn, Peter; Karg, Frank; Flajolet, Marc; Omori, Chiori; Hata, Saori; Suzuki, Toshiharu; Blennow, Kaj; Zetterberg, Henrik; Meijer, Laurent

    2016-01-01

    Proteolytic cleavage of the amyloid-beta protein precursor (A beta PP) ecretases leads to extracellular release of amyloid-beta (A beta) peptides. Increased production of A beta(42) over A beta(40) and aggregation into oligomers and plaques constitute an Alzheimer's disease (AD) hallmark.

  12. Alzheimer's therapeutics targeting amyloid beta 1-42 oligomers I: Abeta 42 oligomer binding to specific neuronal receptors is displaced by drug candidates that improve cognitive deficits.

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    Nicholas J Izzo

    Full Text Available Synaptic dysfunction and loss caused by age-dependent accumulation of synaptotoxic beta amyloid (Abeta 1-42 oligomers is proposed to underlie cognitive decline in Alzheimer's disease (AD. Alterations in membrane trafficking induced by Abeta oligomers mediates reduction in neuronal surface receptor expression that is the basis for inhibition of electrophysiological measures of synaptic plasticity and thus learning and memory. We have utilized phenotypic screens in mature, in vitro cultures of rat brain cells to identify small molecules which block or prevent the binding and effects of Abeta oligomers. Synthetic Abeta oligomers bind saturably to a single site on neuronal synapses and induce deficits in membrane trafficking in neuronal cultures with an EC50 that corresponds to its binding affinity. The therapeutic lead compounds we have found are pharmacological antagonists of Abeta oligomers, reducing the binding of Abeta oligomers to neurons in vitro, preventing spine loss in neurons and preventing and treating oligomer-induced deficits in membrane trafficking. These molecules are highly brain penetrant and prevent and restore cognitive deficits in mouse models of Alzheimer's disease. Counter-screening these compounds against a broad panel of potential CNS targets revealed they are highly potent and specific ligands of the sigma-2/PGRMC1 receptor. Brain concentrations of the compounds corresponding to greater than 80% receptor occupancy at the sigma-2/PGRMC1 receptor restore cognitive function in transgenic hAPP Swe/Ldn mice. These studies demonstrate that synthetic and human-derived Abeta oligomers act as pharmacologically-behaved ligands at neuronal receptors--i.e. they exhibit saturable binding to a target, they exert a functional effect related to their binding and their displacement by small molecule antagonists blocks their functional effect. The first-in-class small molecule receptor antagonists described here restore memory to normal in

  13. Alzheimer's therapeutics targeting amyloid beta 1-42 oligomers I: Abeta 42 oligomer binding to specific neuronal receptors is displaced by drug candidates that improve cognitive deficits.

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    Izzo, Nicholas J; Staniszewski, Agnes; To, Lillian; Fa, Mauro; Teich, Andrew F; Saeed, Faisal; Wostein, Harrison; Walko, Thomas; Vaswani, Anisha; Wardius, Meghan; Syed, Zanobia; Ravenscroft, Jessica; Mozzoni, Kelsie; Silky, Colleen; Rehak, Courtney; Yurko, Raymond; Finn, Patricia; Look, Gary; Rishton, Gilbert; Safferstein, Hank; Miller, Miles; Johanson, Conrad; Stopa, Edward; Windisch, Manfred; Hutter-Paier, Birgit; Shamloo, Mehrdad; Arancio, Ottavio; LeVine, Harry; Catalano, Susan M

    2014-01-01

    Synaptic dysfunction and loss caused by age-dependent accumulation of synaptotoxic beta amyloid (Abeta) 1-42 oligomers is proposed to underlie cognitive decline in Alzheimer's disease (AD). Alterations in membrane trafficking induced by Abeta oligomers mediates reduction in neuronal surface receptor expression that is the basis for inhibition of electrophysiological measures of synaptic plasticity and thus learning and memory. We have utilized phenotypic screens in mature, in vitro cultures of rat brain cells to identify small molecules which block or prevent the binding and effects of Abeta oligomers. Synthetic Abeta oligomers bind saturably to a single site on neuronal synapses and induce deficits in membrane trafficking in neuronal cultures with an EC50 that corresponds to its binding affinity. The therapeutic lead compounds we have found are pharmacological antagonists of Abeta oligomers, reducing the binding of Abeta oligomers to neurons in vitro, preventing spine loss in neurons and preventing and treating oligomer-induced deficits in membrane trafficking. These molecules are highly brain penetrant and prevent and restore cognitive deficits in mouse models of Alzheimer's disease. Counter-screening these compounds against a broad panel of potential CNS targets revealed they are highly potent and specific ligands of the sigma-2/PGRMC1 receptor. Brain concentrations of the compounds corresponding to greater than 80% receptor occupancy at the sigma-2/PGRMC1 receptor restore cognitive function in transgenic hAPP Swe/Ldn mice. These studies demonstrate that synthetic and human-derived Abeta oligomers act as pharmacologically-behaved ligands at neuronal receptors--i.e. they exhibit saturable binding to a target, they exert a functional effect related to their binding and their displacement by small molecule antagonists blocks their functional effect. The first-in-class small molecule receptor antagonists described here restore memory to normal in multiple AD models

  14. Alzheimer's Therapeutics Targeting Amyloid Beta 1–42 Oligomers I: Abeta 42 Oligomer Binding to Specific Neuronal Receptors Is Displaced by Drug Candidates That Improve Cognitive Deficits

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    Izzo, Nicholas J.; Staniszewski, Agnes; To, Lillian; Fa, Mauro; Teich, Andrew F.; Saeed, Faisal; Wostein, Harrison; Walko, Thomas; Vaswani, Anisha; Wardius, Meghan; Syed, Zanobia; Ravenscroft, Jessica; Mozzoni, Kelsie; Silky, Colleen; Rehak, Courtney; Yurko, Raymond; Finn, Patricia; Look, Gary; Rishton, Gilbert; Safferstein, Hank; Miller, Miles; Johanson, Conrad; Stopa, Edward; Windisch, Manfred; Hutter-Paier, Birgit; Shamloo, Mehrdad; Arancio, Ottavio; LeVine, Harry; Catalano, Susan M.

    2014-01-01

    Synaptic dysfunction and loss caused by age-dependent accumulation of synaptotoxic beta amyloid (Abeta) 1–42 oligomers is proposed to underlie cognitive decline in Alzheimer's disease (AD). Alterations in membrane trafficking induced by Abeta oligomers mediates reduction in neuronal surface receptor expression that is the basis for inhibition of electrophysiological measures of synaptic plasticity and thus learning and memory. We have utilized phenotypic screens in mature, in vitro cultures of rat brain cells to identify small molecules which block or prevent the binding and effects of Abeta oligomers. Synthetic Abeta oligomers bind saturably to a single site on neuronal synapses and induce deficits in membrane trafficking in neuronal cultures with an EC50 that corresponds to its binding affinity. The therapeutic lead compounds we have found are pharmacological antagonists of Abeta oligomers, reducing the binding of Abeta oligomers to neurons in vitro, preventing spine loss in neurons and preventing and treating oligomer-induced deficits in membrane trafficking. These molecules are highly brain penetrant and prevent and restore cognitive deficits in mouse models of Alzheimer's disease. Counter-screening these compounds against a broad panel of potential CNS targets revealed they are highly potent and specific ligands of the sigma-2/PGRMC1 receptor. Brain concentrations of the compounds corresponding to greater than 80% receptor occupancy at the sigma-2/PGRMC1 receptor restore cognitive function in transgenic hAPP Swe/Ldn mice. These studies demonstrate that synthetic and human-derived Abeta oligomers act as pharmacologically-behaved ligands at neuronal receptors - i.e. they exhibit saturable binding to a target, they exert a functional effect related to their binding and their displacement by small molecule antagonists blocks their functional effect. The first-in-class small molecule receptor antagonists described here restore memory to normal in multiple AD

  15. Reactive oxygen species released from astrocytes treated with amyloid beta oligomers elicit neuronal calcium signals that decrease phospho-Ser727-STAT3 nuclear content.

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    Muñoz, Yorka; Paula-Lima, Andrea C; Núñez, Marco T

    2018-03-01

    The transcription factor STAT3 has a crucial role in the development and maintenance of the nervous system. In this work, we treated astrocytes with oligomers of the amyloid beta peptide (AβOs), which display potent synaptotoxic activity, and studied the effects of mediators released by AβOs-treated astrocytes on the nuclear location of neuronal serine-727-phosphorylated STAT3 (pSerSTAT3). Treatment of mixed neuron-astrocyte cultures with 0.5µMAβOs induced in neurons a significant decrease of nuclear pSerSTAT3, but not of phosphotyrosine-705 STAT3, the other form of STAT3 phosphorylation. This decrease did not occur in astrocyte-poor neuronal cultures revealing a pivotal role for astrocytes in this response. To test if mediators released by astrocytes in response to AβOs induce pSerSTAT3 nuclear depletion, we used conditioned medium derived from AβOs-treated astrocyte cultures. Treatment of astrocyte-poor neuronal cultures with this medium caused pSerSTAT3 nuclear depletion but did not modify overall STAT3 levels. Extracellular catalase prevented the pSerSTAT3 nuclear depletion caused by astrocyte-conditioned medium, indicating that reactive oxygen species (ROS) mediate this response. This conditioned medium also increased neuronal oxidative tone, leading to a ryanodine-sensitive intracellular calcium signal that proved to be essential for pSerSTAT3 nuclear depletion. In addition, this depletion decreased BCL2 and Survivin transcription and significantly increased BAX/BCL2 ratio. This is the first description that ROS generated by AβOs-treated astrocytes and neuronal calcium signals jointly regulate pSerSTAT3 nuclear distribution in neurons. We propose that astrocytes release ROS in response to AβOs, which by increasing neuronal oxidative tone, generate calcium signals that cause pSerSTAT3 nuclear depletion and loss of STAT3 protective transcriptional activity. Copyright © 2018 Elsevier Inc. All rights reserved.

  16. A disulfide-linked amyloid-beta peptide dimer forms a protofibril-like oligomer through a distinct pathway from amyloid fibril formation.

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    Yamaguchi, Takahiro; Yagi, Hisashi; Goto, Yuji; Matsuzaki, Katsumi; Hoshino, Masaru

    2010-08-24

    The conversion of the soluble, nontoxic amyloid-beta (Abeta) peptide into an aggregated, toxic form rich in beta-sheets is considered a key step in the development of Alzheimer's disease. Whereas growing evidence indicates that the Abeta amyloid fibrils consist of in-register parallel beta-sheets, little is known about the structure of soluble oligomeric intermediates because of their transient nature. To understand the mechanism by which amyloid fibrils form, especially the initial development of the "nucleus" oligomeric intermediates, we prepared covalently linked dimeric Abeta peptides and analyzed the kinetics of the fibril-forming process. A covalent bond introduced between two Abeta molecules dramatically facilitated the spontaneous formation of aggregates with a beta-sheet structure and affinity for thioflavin T. Transmission electron microscopy revealed, however, that these aggregates differed in morphology from amyloid fibrils, more closely resembling protofibrils. The protofibril-like aggregates were not the most thermodynamically stable state but were a kinetically trapped state. The results emphasize the importance of the conformational flexibility of the Abeta molecule and a balance in the association and dissociation rate for the formation of rigid amyloid fibrils.

  17. Keampferol-3-O-rhamnoside abrogates amyloid beta toxicity by modulating monomers and remodeling oligomers and fibrils to non-toxic aggregates

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    Sharoar Md

    2012-12-01

    Full Text Available Abstract Background Aggregation of soluble, monomeric β- amyloid (Aβ to oligomeric and then insoluble fibrillar Aβ is a key pathogenic feature in development of Alzheimer’s disease (AD. Increasing evidence suggests that toxicity is linked to diffusible Aβ oligomers, rather than to insoluble fibrils. The use of naturally occurring small molecules for inhibition of Aβ aggregation has recently attracted significant interest for development of effective therapeutic strategies against the disease. A natural polyphenolic flavone, Kaempferol-3-O-rhamnoside (K-3-rh, was utilized to investigate its effects on aggregation and cytotoxic effects of Aβ42 peptide. Several biochemical techniques were used to determine the conformational changes and cytotoxic effect of the peptide in the presence and absence of K-3-rh. Results K-3-rh showed a dose-dependent effect against Aβ42 mediated cytotoxicity. Anti-amyloidogenic properties of K-3-rh were found to be efficient in inhibiting fibrilogenesis and secondary structural transformation of the peptide. The consequence of these inhibitions was the accumulation of oligomeric structural species. The accumulated aggregates were smaller, soluble, non-β-sheet and non-toxic aggregates, compared to preformed toxic Aβ oligomers. K-3-rh was also found to have the remodeling properties of preformed soluble oligomers and fibrils. Both of these conformers were found to remodel into non-toxic aggregates. The results showed that K-3-rh interacts with different Aβ conformers, which affects fibril formation, oligomeric maturation and fibrillar stabilization. Conclusion K-3-rh is an efficient molecule to hinder the self assembly and to abrogate the cytotoxic effects of Aβ42 peptide. Hence, K-3-rh and small molecules with similar structure might be considered for therapeutic development against AD.

  18. Amyloid Beta Mediates Memory Formation

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    Garcia-Osta, Ana; Alberini, Cristina M.

    2009-01-01

    The amyloid precursor protein (APP) undergoes sequential cleavages to generate various polypeptides, including the amyloid [beta] (1-42) peptide (A[beta][1-42]), which is believed to play a major role in amyloid plaque formation in Alzheimer's disease (AD). Here we provide evidence that, in contrast with its pathological role when accumulated,…

  19. The effect of tachykinin neuropeptides on amyloid {beta} aggregation

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    Flashner, Efrat [The Institute of Chemistry, The Hebrew University of Jerusalem, Edmond J. Safra Campus, Givat Ram, Jerusalem 91904 (Israel); Raviv, Uri, E-mail: raviv@chem.ch.huji.ac.il [The Institute of Chemistry, The Hebrew University of Jerusalem, Edmond J. Safra Campus, Givat Ram, Jerusalem 91904 (Israel); Friedler, Assaf, E-mail: assaf@chem.ch.huji.ac.il [The Institute of Chemistry, The Hebrew University of Jerusalem, Edmond J. Safra Campus, Givat Ram, Jerusalem 91904 (Israel)

    2011-04-01

    Research highlights: {yields} Mechanistic explanation of how tachykinin neuropeptides reduce A{beta}-induced neurotoxicity. {yields} Biophysical studies suggest that tachykinins do not modulate the distribution of A{beta} oligomeric states, but rather may incorporate into the fibrils. {yields} A possible strategy to inhibit toxicity of amyloid fibrils. -- Abstract: A hallmark of Alzheimer's disease is production of amyloid {beta} peptides resulting from aberrant cleavage of the amyloid precursor protein. Amyloid {beta} assembles into fibrils under physiological conditions, through formation of neurotoxic intermediate oligomers. Tachykinin peptides are known to affect amyloid {beta} neurotoxicity in cells. To understand the mechanism of this effect, we studied how tachykinins affect A{beta}(1-40) aggregation in vitro. Fibrils grown in the presence of tachykinins exhibited reduced thioflavin T (ThT) fluorescence, while their morphology, observed in transmission electron microscopy (TEM), did not alter. Cross linking studies revealed that the distribution of low molecular weight species was not affected by tachykinins. Our results suggest that there may be a specific interaction between tachykinins and A{beta}(1-40) that allows them to co-assemble. This effect may explain the reduction of A{beta}(1-40) neurotoxicity in cells treated with tachykinins.

  20. Amyloid Beta Peptide Slows Down Sensory-Induced Hippocampal Oscillations

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    Fernando Peña-Ortega

    2012-01-01

    Full Text Available Alzheimer’s disease (AD progresses with a deterioration of hippocampal function that is likely induced by amyloid beta (Aβ oligomers. Hippocampal function is strongly dependent on theta rhythm, and disruptions in this rhythm have been related to the reduction of cognitive performance in AD. Accordingly, both AD patients and AD-transgenic mice show an increase in theta rhythm at rest but a reduction in cognitive-induced theta rhythm. We have previously found that monomers of the short sequence of Aβ (peptide 25–35 reduce sensory-induced theta oscillations. However, considering on the one hand that different Aβ sequences differentially affect hippocampal oscillations and on the other hand that Aβ oligomers seem to be responsible for the cognitive decline observed in AD, here we aimed to explore the effect of Aβ oligomers on sensory-induced theta rhythm. Our results show that intracisternal injection of Aβ1–42 oligomers, which has no significant effect on spontaneous hippocampal activity, disrupts the induction of theta rhythm upon sensory stimulation. Instead of increasing the power in the theta band, the hippocampus of Aβ-treated animals responds to sensory stimulation (tail pinch with an increase in lower frequencies. These findings demonstrate that Aβ alters induced theta rhythm, providing an in vivo model to test for therapeutic approaches to overcome Aβ-induced hippocampal and cognitive dysfunctions.

  1. The prion protein as a receptor for amyloid-beta

    NARCIS (Netherlands)

    Kessels, Helmut W.; Nguyen, Louis N.; Nabavi, Sadegh; Malinow, Roberto

    2010-01-01

    Increased levels of brain amyloid-beta, a secreted peptide cleavage product of amyloid precursor protein (APP), is believed to be critical in the aetiology of Alzheimer's disease. Increased amyloid-beta can cause synaptic depression, reduce the number of spine protrusions (that is, sites of synaptic

  2. Amyloid Beta Peptide Folding in Reverse Micelles.

    Science.gov (United States)

    Eskici, Gözde; Axelsen, Paul H

    2017-07-19

    Previously published experimental studies have suggested that when the 40-residue amyloid beta peptide is encapsulated in a reverse micelle, it folds into a structure that may nucleate amyloid fibril formation (Yeung, P. S.-W.; Axelsen, P. H. J. Am. Chem. Soc. 2012, 134, 6061 ). The factors that induce the formation of this structure have now been identified in a multi-microsecond simulation of the same reverse micelle system that was studied experimentally. Key features of the polypeptide-micelle interaction include the anchoring of a hydrophobic residue cluster into gaps in the reverse micelle surface, the formation of a beta turn at the anchor point that brings N- and C-terminal segments of the polypeptide into proximity, high ionic strength that promotes intramolecular hydrogen bond formation, and deformation of the reverse micelle surface to facilitate interactions with the surface along the entire length of the polypeptide. Together, these features cause the simulation-derived vibrational spectrum to red shift in a manner that reproduces the red-shift previously reported experimentally. On the basis of these findings, a new mechanism is proposed whereby membranes nucleate fibril formation and facilitate the in-register alignment of polypeptide strands that is characteristic of amyloid fibrils.

  3. Electrochemistry of Alzheimer disease amyloid beta peptides.

    Science.gov (United States)

    Chiorcea-Paquim, Ana-Maria; Enache, Teodor Adrian; Oliveira-Brett, Ana Maria

    2018-02-13

    Alzheimer's disease (AD) is a widespread form of dementia that is estimated to affect 44.4 million people worldwide. AD pathology is closely related to the accumulation of amyloid beta (Aβ) peptides in fibrils and plagues, the small oligomeric intermediate species formed during the Aβ peptides aggregation presenting the highest neurotoxicity. This review discusses the recent advances on the Aβ peptides electrochemical characterisation. The Aβ peptides oxidation at a glassy carbon electrode occurs in one or two steps, depending on the amino acid sequence, length and content. The first electron transfer reaction corresponds to the tyrosine Tyr10 amino acid residue oxidation, and the second to all three histidine (His6, His13 and His14) and one methionine (Met35) amino acid residues. The Aβ peptides aggregation and amyloid fibril formation is electrochemically detected via the electroactive amino acids oxidation peak currents decrease that occurs in a time dependent manner. The Aβ peptides redox behaviour is correlated with changes in the adsorption morphology from initially random coiled structures, corresponding to the Aβ peptide monomers in random coil or in α-helix conformations, to aggregates and protofibrils and two types of fibrils, corresponding to the Aβ peptides in a β-sheet configuration, observed by atomic force microscopy. Electrochemical studies of Aβ peptides aggregation, mediated by the interaction with metal ions, in particular zinc, copper, and iron, and different methodologies concerning the detection of Aβ peptide biomarkers of AD in biological fluids, using electrochemical biosensors, are also discussed. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  4. New Insights in the Amyloid-Beta Interaction with Mitochondria

    Directory of Open Access Journals (Sweden)

    Carlos Spuch

    2012-01-01

    Full Text Available Biochemical and morphological alterations of mitochondria may play an important role in the pathogenesis of Alzheimer’s disease (AD. Particularly, mitochondrial dysfunction is a hallmark of amyloid-beta-induced neuronal toxicity in Alzheimer’s disease. The recent emphasis on the intracellular biology of amyloid-beta and its precursor protein (APP has led researchers to consider the possibility that mitochondria-associated and mitochondrial amyloid-beta may directly cause neurotoxicity. Both proteins are known to localize to mitochondrial membranes, block the transport of nuclear-encoded mitochondrial proteins to mitochondria, interact with mitochondrial proteins, disrupt the electron transport chain, increase reactive oxygen species production, cause mitochondrial damage, and prevent neurons from functioning normally. In this paper, we will outline current knowledge of the intracellular localization of amyloid-beta. Moreover, we summarize evidence from AD postmortem brain as well as animal AD models showing that amyloid-beta triggers mitochondrial dysfunction through a number of pathways such as impairment of oxidative phosphorylation, elevation of reactive oxygen species production, alteration of mitochondrial dynamics, and interaction with mitochondrial proteins. Thus, this paper supports the Alzheimer cascade mitochondrial hypothesis such as the most important early events in this disease, and probably one of the future strategies on the therapy of this neurodegenerative disease.

  5. Perforin Promotes Amyloid Beta Internalisation in Neurons.

    Science.gov (United States)

    Lana, Erica; Khanbolouki, Mahbod; Degavre, Charline; Samuelsson, Eva-Britt; Åkesson, Elisabet; Winblad, Bengt; Alici, Evren; Lithner, Christina Unger; Behbahani, Homira

    2017-03-01

    Studies on the mechanisms of neuronal amyloid-β (Aβ) internalisation are crucial for understanding the neuropathological progression of Alzheimer's disease (AD). We here investigated how extracellular Aβ peptides are internalised and focused on three different pathways: (i) via endocytic mechanisms, (ii) via the receptor for advanced glycation end products (RAGE) and (iii) via the pore-forming protein perforin. Both Aβ 40 and Aβ 42 were internalised in retinoic acid differentiated neuroblastoma (RA-SH-SY5Y) cells. A higher concentration was required for Aβ 40 (250 nM) compared with Aβ 42 (100 nM). The internalised Aβ 40 showed a dot-like pattern of distribution whereas Aβ 42 accumulated in larger and distinct formations. By confocal microscopy, we showed that Aβ 40 and Aβ 42 co-localised with mitochondria, endoplasmic reticulum (ER) and lysosomes. Aβ treatment of human primary cortical neurons (hPCN) confirmed our findings in RA-SH-SY5Y cells, but hPCN were less sensitive to Aβ; therefore, a 20 (Aβ 40 ) and 50 (Aβ 42 ) times higher concentration was needed for inducing uptake. The blocking of endocytosis completely inhibited the internalisation of Aβ peptides in RA-SH-SY5Y cells and hPCN, indicating that this is a major pathway by which Aβ enters the cells. In addition, the internalisation of Aβ 42 , but not Aβ 40 , was reduced by 55 % by blocking RAGE. Finally, for the first time we showed that pore formation in cell membranes by perforin led to Aβ internalisation in hPCN. Understanding how Aβ is internalised sheds light on the pathological role of Aβ and provides further ideas of inhibitory strategies for preventing Aβ internalisation and the spreading of neurodegeneration in AD.

  6. 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

  7. Neurine, an acetylcholine autolysis product, elevates secreted amyloid-beta protein precursor and amyloid-beta peptide levels, and lowers neuronal cell viability in culture: a role in Alzheimer's disease?

    Science.gov (United States)

    Tweedie, David; Brossi, Arnold; Chen, DeMoa; Ge, Yuan-Wen; Bailey, Jason; Yu, Qian-Sheng; Kamal, Mohammad A; Sambamurti, Kumar; Lahiri, Debomoy K; Greig, Nigel H

    2006-09-01

    Classical hallmarks of Alzheimer's disease (AD) are a synaptic loss, cholinergic neuron death, and abnormal protein deposition, particularly of toxic amyloid-beta peptide (Abeta) that is derived from amyloid-beta protein precursor (AbetaPP) by the action of beta- and gamma-secretases. The trigger(s) initiating the biochemical cascades that underpin these hallmarks have yet to be fully elucidated. The typical forebrain cholinergic cell demise associated with AD brain results in a loss of presynaptic cholinergic markers and acetylcholine (ACh). Neurine (vinyl-trimethyl-ammonium hydroxide) is a breakdown product of ACh, consequent to autolysis and is an organic poison found in cadavre brain. The time- and concentration-dependent actions of neurine were assessed in human neuroblastoma (NB, SK-N-SH) cells in culture by quantifying cell viability by lactate dehydrogenase (LDH) and MTS assay, and AbetaPP and Abeta levels by Western blot and ELISA. NB cells displayed evidence of toxicity to neurine at > or = 3 mg/ml, as demonstrated by elevated LDH levels in the culture media and a reduced cell viability shown by the MTS assay. Using subtoxic concentrations of neurine, elevations in AbetaPP and Abeta1-40 peptide levels were detected in conditioned media samples.

  8. Neuroblastoma

    International Nuclear Information System (INIS)

    Thomas, P.R.M.

    1987-01-01

    Neuroblastoma is a complex disease with prognosis varying not only with stage, but also with age, site, and histology. Dissemination is the main problem. For stage I tumors, complete surgical excision alone is likely to be curative. For stage II tumors, postoperative irradiation is not clearly established, but it should be considered for patients over 1 year of age with incompletely resected tumors or positive lymph nodes. For stage III tumors, radiation therapy is indicated, with possible second-look surgery after treatment. Adjuvant chemotherapy is being tested. The prognosis is uncertain and may depend partly on the lymph node status. For stage IV tumors, chemotherapy is preferred. Remissions are usually obtained, although cure is very unlikely, except in infants. Radiation has a definite palliative role. For stage IV-S tumors, a conservative approach is preferred, with active treatment being reserved for complications of tumor bulk or obvious progression. New approaches include the use of total-body irradiation with chemotherapy, with or without transplantation, in stage IV patients in an attempt to maintain remissions. Tumor market such as N-myc help to define the indications for aggressive therapy. Once it is possible to maintain complete remissions, a dramatic improvement in the overall prognosis is likely

  9. Aloe arborescens Extract Protects IMR-32 Cells against Alzheimer Amyloid Beta Peptide via Inhibition of Radical Peroxide Production.

    Science.gov (United States)

    Clementi, Maria Elisabetta; Tringali, Giuseppe; Triggiani, Doriana; Giardina, Bruno

    2015-11-01

    Aloe arborescens is commonly used as a pharmaceutical ingredient for its effect in burn treatment and ability to increase skin wound healing properties. Besides, it is well known to have beneficial phytotherapeutic, anticancer, and radio-protective properties. In this study, we first provided evidence that A. arborescens extract protects IMR32, a neuroblastoma human cellular line, from toxicity induced by beta amyloid, the peptide responsible for Alzheimer's disease. In particular, pretreatment with A. arborescens maintains an elevated cell viability and exerts a protective effect on mitochondrial functionality, as evidenced by oxygen consumption experiments. The protective mechanism exerted by A. arborescens seems be related to lowering of oxidative potential of the cells, as demonstrated by the ROS measurement compared with the results obtained in the presence of amyloid beta (1-42) peptide alone. Based on these preliminary observations we suggest that use ofA. arborescens extract could be developed as agents for the management of AD.

  10. Interaction of amyloid inhibitor proteins with amyloid beta peptides: insight from molecular dynamics simulations.

    Directory of Open Access Journals (Sweden)

    Payel Das

    Full Text Available Knowledge of the detailed mechanism by which proteins such as human αB- crystallin and human lysozyme inhibit amyloid beta (Aβ peptide aggregation is crucial for designing treatment for Alzheimer's disease. Thus, unconstrained, atomistic molecular dynamics simulations in explicit solvent have been performed to characterize the Aβ17-42 assembly in presence of the αB-crystallin core domain and of lysozyme. Simulations reveal that both inhibitor proteins compete with inter-peptide interaction by binding to the peptides during the early stage of aggregation, which is consistent with their inhibitory action reported in experiments. However, the Aβ binding dynamics appear different for each inhibitor. The binding between crystallin and the peptide monomer, dominated by electrostatics, is relatively weak and transient due to the heterogeneous amino acid distribution of the inhibitor surface. The crystallin-bound Aβ oligomers are relatively long-lived, as they form more extensive contact surface with the inhibitor protein. In contrast, a high local density of arginines from lysozyme allows strong binding with Aβ peptide monomers, resulting in stable complexes. Our findings not only illustrate, in atomic detail, how the amyloid inhibitory mechanism of human αB-crystallin, a natural chaperone, is different from that of human lysozyme, but also may aid de novo design of amyloid inhibitors.

  11. Biological markers of amyloid beta-related mechanisms in Alzheimer's disease.

    LENUS (Irish Health Repository)

    Hampel, Harald

    2012-02-01

    Recent research progress has given detailed knowledge on the molecular pathogenesis of Alzheimer\\'s disease (AD), which has been translated into an intense, ongoing development of disease-modifying treatments. Most new drug candidates are targeted on inhibiting amyloid beta (Abeta) production and aggregation. In drug development, it is important to co-develop biomarkers for Abeta-related mechanisms to enable early diagnosis and patient stratification in clinical trials, and to serve as tools to identify and monitor the biochemical effect of the drug directly in patients. Biomarkers are also requested by regulatory authorities to serve as safety measurements. Molecular aberrations in the AD brain are reflected in the cerebrospinal fluid (CSF). Core CSF biomarkers include Abeta isoforms (Abeta40\\/Abeta42), soluble APP isoforms, Abeta oligomers and beta-site APP-cleaving enzyme 1 (BACE1). This article reviews recent research advances on core candidate CSF and plasma Abeta-related biomarkers, and gives a conceptual review on how to implement biomarkers in clinical trials in AD.

  12. Biological markers of amyloid beta-related mechanisms in Alzheimer's disease.

    LENUS (Irish Health Repository)

    Hampel, Harald

    2010-06-01

    Recent research progress has given detailed knowledge on the molecular pathogenesis of Alzheimer\\'s disease (AD), which has been translated into an intense, ongoing development of disease-modifying treatments. Most new drug candidates are targeted on inhibiting amyloid beta (Abeta) production and aggregation. In drug development, it is important to co-develop biomarkers for Abeta-related mechanisms to enable early diagnosis and patient stratification in clinical trials, and to serve as tools to identify and monitor the biochemical effect of the drug directly in patients. Biomarkers are also requested by regulatory authorities to serve as safety measurements. Molecular aberrations in the AD brain are reflected in the cerebrospinal fluid (CSF). Core CSF biomarkers include Abeta isoforms (Abeta40\\/Abeta42), soluble APP isoforms, Abeta oligomers and beta-site APP-cleaving enzyme 1 (BACE1). This article reviews recent research advances on core candidate CSF and plasma Abeta-related biomarkers, and gives a conceptual review on how to implement biomarkers in clinical trials in AD.

  13. Microbiosensor for Alzheimer's disease diagnostics: detection of amyloid beta biomarkers.

    Science.gov (United States)

    Prabhulkar, Shradha; Piatyszek, Rudolph; Cirrito, John R; Wu, Ze-Zhi; Li, Chen-Zhong

    2012-07-01

    Alzheimer's disease (AD) affects about 35.6 million people worldwide, and if current trends continue with no medical advancement, one in 85 people will be affected by 2050. Thus, there is an urgent need to develop a cost-effective, easy to use, sensor platform to diagnose and study AD. The measurement of peptide amyloid beta (Aβ) found in CSF has been assessed as an avenue to diagnose and study the disease. The quantification of the ratio of Aβ1-40/42 (or Aβ ratio) has been established as a reliable test to diagnose AD through human clinical trials. Therefore, we have developed a multiplexed, implantable immunosensor to detect amyloid beta (Aβ) isoforms using triple barrel carbon fiber microelectrodes as the sensor platform. Antibodies act as the biorecognition element of the sensor and selectively capture and bind Aβ1-40 and Aβ1-42 to the electrode surface. Electrochemistry was used to measure the intrinsic oxidation signal of Aβ at 0.65 V (vs. Ag/AgCl), originating from a single tyrosine residue found at position 10 in its amino acid sequence. Using the proposed immunosensor Aβ1-40 and Aβ1-42 could be specifically detected in CSF from mice within a detection range of 20-50 nM and 20-140 nM respectively. The immunosensor enables real-time, highly sensitive detection of Aβ and opens up the possibilities for diagnostic ex vivo applications and research-based in vivo studies. © 2012 The Authors. Journal of Neurochemistry © 2012 International Society for Neurochemistry.

  14. Amyloid Beta Peptides Differentially Affect Hippocampal Theta Rhythms In Vitro

    Directory of Open Access Journals (Sweden)

    Armando I. Gutiérrez-Lerma

    2013-01-01

    Full Text Available Soluble amyloid beta peptide (Aβ is responsible for the early cognitive dysfunction observed in Alzheimer's disease. Both cholinergically and glutamatergically induced hippocampal theta rhythms are related to learning and memory, spatial navigation, and spatial memory. However, these two types of theta rhythms are not identical; they are associated with different behaviors and can be differentially modulated by diverse experimental conditions. Therefore, in this study, we aimed to investigate whether or not application of soluble Aβ alters the two types of theta frequency oscillatory network activity generated in rat hippocampal slices by application of the cholinergic and glutamatergic agonists carbachol or DHPG, respectively. Due to previous evidence that oscillatory activity can be differentially affected by different Aβ peptides, we also compared Aβ25−35 and Aβ1−42 for their effects on theta rhythms in vitro at similar concentrations (0.5 to 1.0 μM. We found that Aβ25−35 reduces, with less potency than Aβ1−42, carbachol-induced population theta oscillatory activity. In contrast, DHPG-induced oscillatory activity was not affected by a high concentration of Aβ25−35 but was reduced by Aβ1−42. Our results support the idea that different amyloid peptides might alter specific cellular mechanisms related to the generation of specific neuronal network activities, instead of exerting a generalized inhibitory effect on neuronal network function.

  15. Reducing the Levels of Akt Activation by PDK1 Knock-in Mutation Protects Neuronal Cultures against Synthetic Amyloid-Beta Peptides

    Directory of Open Access Journals (Sweden)

    Shaobin Yang

    2018-01-01

    Full Text Available The Akt kinase has been widely assumed for years as a key downstream effector of the PI3K signaling pathway in promoting neuronal survival. This notion was however challenged by the finding that neuronal survival responses were still preserved in mice with reduced Akt activity. Moreover, here we show that the Akt signaling is elevated in the aged brain of two different mice models of Alzheimer Disease. We manipulate the rate of Akt stimulation by employing knock-in mice expressing a mutant form of PDK1 (phosphoinositide-dependent protein kinase 1 with reduced, but not abolished, ability to activate Akt. We found increased membrane localization and activity of the TACE/ADAM17 α-secretase in the brain of the PDK1 mutant mice with concomitant TNFR1 processing, which provided neurons with resistance against TNFα-induced neurotoxicity. Opposite to the Alzheimer Disease transgenic mice, the PDK1 knock-in mice exhibited an age-dependent attenuation of the unfolding protein response, which protected the mutant neurons against endoplasmic reticulum stressors. Moreover, these two mechanisms cooperatively provide the mutant neurons with resistance against amyloid-beta oligomers, and might singularly also contribute to protect these mice against amyloid-beta pathology.

  16. Effect of ionic strength on the aggregation kinetics of the amidated amyloid beta peptide Aβ (1-40) in aqueous solutions.

    Science.gov (United States)

    Campos-Ramírez, Adriana; Márquez, Maripaz; Quintanar, Liliana; Rojas-Ochoa, Luis F

    2017-09-01

    In this work we study the effect of solution ionic strength on the structural evolution of amidated amyloid beta peptide Aβ (1-40) oligomers at the early stages of fibril formation. By light scattering, we follow the time evolution of the structure and short-time dynamics of peptide structures at low ionic strengths. Our results allow identifying initial oligomer structures as the effective building blocks in the amyloid fibrils formation and indicate that the oligomers growth pathway, from compact structures to flexible chain-like structures, becomes faster as the solution ionic strength is increased. Furthermore, we find no evidence of structural branching what suggests that elongation of amyloid fibrils is dominated by linear association. To describe our results we adapt a phenomenological model based on population balance equations and linear polymer growth, where the parameters required are obtained from the experiments. Model calculations are in good agreement with experimentally-obtained estimates for the radius of gyration of Aβ (1-40) oligomers, thus further supporting our findings. Additionally, we introduce a model for the effective interaction among initial Aβ structures that captures the dependence of the effective association rates on solution ionic strength. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. PEGylated nanoparticles bind to and alter amyloid-beta peptide conformation

    DEFF Research Database (Denmark)

    Brambilla, Davide; Verpillot, Romain; Le Droumaguet, Benjamin

    2012-01-01

    We have demonstrated that the polyethylene glycol (PEG) corona of long-circulating polymeric nanoparticles (NPs) favors interaction with the amyloid-beta (Aß(1-42)) peptide both in solution and in serum. The influence of PEGylation of poly(alkyl cyanoacrylate) and poly(lactic acid) NPs on the int......We have demonstrated that the polyethylene glycol (PEG) corona of long-circulating polymeric nanoparticles (NPs) favors interaction with the amyloid-beta (Aß(1-42)) peptide both in solution and in serum. The influence of PEGylation of poly(alkyl cyanoacrylate) and poly(lactic acid) NPs...

  18. Accumulation of Exogenous Amyloid-Beta Peptide in Hippocampal Mitochondria Causes Their Dysfunction: A Protective Role for Melatonin

    Directory of Open Access Journals (Sweden)

    Sergio Rosales-Corral

    2012-01-01

    Full Text Available Amyloid-beta (Aβ pathology is related to mitochondrial dysfunction accompanied by energy reduction and an elevated production of reactive oxygen species (ROS. Monomers and oligomers of Aβ have been found inside mitochondria where they accumulate in a time-dependent manner as demonstrated in transgenic mice and in Alzheimer’s disease (AD brain. We hypothesize that the internalization of extracellular Aβ aggregates is the major cause of mitochondrial damage and here we report that following the injection of fibrillar Aβ into the hippocampus, there is severe axonal damage which is accompanied by the entrance of Aβ into the cell. Thereafter, Aβ appears in mitochondria where it is linked to alterations in the ionic gradient across the inner mitochondrial membrane. This effect is accompanied by disruption of subcellular structure, oxidative stress, and a significant reduction in both the respiratory control ratio and in the hydrolytic activity of ATPase. Orally administrated melatonin reduced oxidative stress, improved the mitochondrial respiratory control ratio, and ameliorated the energy imbalance.

  19. Inhibition of amyloid-beta-induced cell death in human brain pericytes in vitro.

    NARCIS (Netherlands)

    Rensink, A.A.M.; Verbeek, M.M.; Otte-Holler, I.; Donkelaar, H.J. ten; Waal, R.M.W. de; Kremer, H.P.H.

    2002-01-01

    Amyloid-beta protein (A beta) deposition in the cerebral vascular walls is one of the key features of Alzheimer's disease and hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D). A beta(1-40) carrying the 'Dutch' mutation (HCHWA-D A beta(1-40)) induces pronounced degeneration of

  20. Calpain inhibition prevents amyloid-beta-induced neurodegeneration and associated behavioral dysfunction in rats

    NARCIS (Netherlands)

    Granic, Ivica; Nyakas, Csaba; Luiten, Paul G. M.; Eisel, Ulrich L. M.; Halmy, Laszlo G.; Gross, Gerhard; Schoemaker, Hans; Moeller, Achim; Nimmrich, Volker

    2010-01-01

    Amyloid-beta (A beta) is toxic to neurons and such toxicity is - at least in part - mediated via the NMDA receptor. Calpain, a calcium dependent cystein protease, is part of the NMDA receptor-induced neurodegeneration pathway, and we previously reported that inhibition of calpain prevents

  1. Insulin inhibits amyloid beta-induced cell death in cultured human brain pericytes

    NARCIS (Netherlands)

    Rensink, Annemieke A M; Otte-Höller, Irene; de Boer, Roelie; Bosch, Remko R; ten Donkelaar, Hans J; de Waal, Robert M W; Verbeek, Marcel M; Kremer, Berry

    Amyloid-beta (Abeta) deposition in the cerebral arterial and capillary walls is one of the characteristics of Alzheimer's disease and hereditary cerebral hemorrhage with amyloidosis-Dutch type. In vitro, Abeta1-40, carrying the "Dutch" mutation (DAbeta1-40), induced reproducible degeneration of

  2. Diagnostic Accuracy of Cerebrospinal Fluid Amyloid-beta Isoforms for Early and Differential Dementia Diagnosis

    NARCIS (Netherlands)

    Struyfs, Hanne; Van Broeck, Bianca; Timmers, Maarten; Fransen, Erik; Sleegers, Kristel; Van Broeckhoven, Christine; De Deyn, Peter P.; Streffer, Johannes R.; Mercken, Marc; Engelborghs, Sebastiaan

    2015-01-01

    Background: Overlapping cerebrospinal fluid biomarkers (CSF) levels between Alzheimer's disease (AD) and non-AD patients decrease differential diagnostic accuracy of the AD core CSF biomarkers. Amyloid-beta (A beta) isoforms might improve the AD versus non-AD differential diagnosis. Objective: To

  3. Influence of hydrophobic Teflon particles on the structure of amyloid beta-peptide

    NARCIS (Netherlands)

    Giacomelli, C.E.; Norde, W.

    2003-01-01

    The amyloid beta-protein (Abeta) constitutes the major peptide component of the amyloid plaque deposits of Alzheimer's disease in humans. The Abeta changes from a nonpathogenic to a pathogenic conformation resulting in self-aggregation and deposition of the peptide. It has been established that

  4. Neuroinflammation and Complexes of 17 beta-Hydroxysteroid Dehydrogenase type 10-Amyloid beta in Alzheimer's Disease

    Czech Academy of Sciences Publication Activity Database

    Krištofíková, Z.; Řípová, D.; Bartoš, A.; Bocková, Markéta; Hegnerová, Kateřina; Říčný, J.; Čechová, L.; Vrajová, M.; Homola, Jiří

    2013-01-01

    Roč. 10, č. 2 (2013), s. 165-173 ISSN 1567-2050 R&D Projects: GA MZd(CZ) NT11225 Institutional support: RVO:67985882 Keywords : Amyloid beta * mitochondrial enzyme * Alzheimer 's disease Subject RIV: JB - Sensors, Measurment, Regulation Impact factor: 3.796, year: 2013

  5. Nasal administration of amyloid-beta peptide decreases cerebral amyloid burden in a mouse model of Alzheimer's disease

    DEFF Research Database (Denmark)

    Weiner, H L; Lemere, C A; Maron, R

    2000-01-01

    Progressive cerebral deposition of amyloid-beta (Abeta) peptide, an early and essential feature of Alzheimer's disease (AD), is accompanied by an inflammatory reaction marked by microgliosis, astrocytosis, and the release of proinflammatory cytokines. Mucosal administration of disease-implicated ......Progressive cerebral deposition of amyloid-beta (Abeta) peptide, an early and essential feature of Alzheimer's disease (AD), is accompanied by an inflammatory reaction marked by microgliosis, astrocytosis, and the release of proinflammatory cytokines. Mucosal administration of disease...

  6. S14G-humanin restored cellular homeostasis disturbed by amyloid-beta protein.

    Science.gov (United States)

    Li, Xue; Zhao, Wencong; Yang, Hongqi; Zhang, Junhong; Ma, Jianjun

    2013-09-25

    Humanin is a potential therapeutic agent for Alzheimer's disease, and its derivative, S14G-humanin, is 1 000-fold stronger in its neuroprotective effect against Alzheimer's disease-relevant insults. Al-though effective, the detailed molecular mechanism through which S14G-humanin exerts its effects remains unclear. Data from this study showed that fibrillar amyloid-beta 40 disturbed cellular ho-meostasis through the cell membrane, increasing intracellular calcium, generating reactive oxygen species, and decreasing the mitochondrial membrane potential. S14G-humanin restored these responses. The results suggested that S14G-humanin blocked the effects of amyloid-beta 40 on the neuronal cell membrane, and restored the disturbed cellular homeostasis, thereby exerting a neu-roprotective effect on hippocampal neurons.

  7. Antibody-based PET imaging of amyloid beta in mouse models of Alzheimer's disease

    OpenAIRE

    Sehlin, Dag; Fang, Xiaotian T.; Cato, Linda; Antoni, Gunnar; Lannfelt, Lars; Syvänen, Stina

    2016-01-01

    Owing to their specificity and high-affinity binding, monoclonal antibodies have potential as positron emission tomography (PET) radioligands and are currently used to image various targets in peripheral organs. However, in the central nervous system, antibody uptake is limited by the blood-brain barrier (BBB). Here we present a PET ligand to be used for diagnosis and evaluation of treatment effects in Alzheimer's disease. The amyloid beta (A beta) antibody mAb158 is radiolabelled and conjuga...

  8. Amyloid-beta binds catalase with high affinity and inhibits hydrogen peroxide breakdown.

    OpenAIRE

    Milton, N G

    1999-01-01

    Amyloid-beta (Abeta) specifically bound purified catalase with high affinity and inhibited catalase breakdown of H(2)O(2). The Abeta-induced catalase inhibition involved formation of the inactive catalase Compound II and was reversible. CatalaseAbeta interactions provide rapid functional assays for the cytotoxic domain of Abeta and suggest a mechanism for some of the observed actions of Abeta plus catalase in vitro.

  9. Oxidative stress induces macroautophagy of amyloid beta-protein and ensuing apoptosis

    DEFF Research Database (Denmark)

    Zheng, Lin; Kågedal, Katarina; Dehvari, Nodi

    2009-01-01

    There is increasing evidence for the toxicity of intracellular amyloid beta-protein (Abeta) to neurons and the involvement of lysosomes in this process in Alzheimer disease (AD). We have recently shown that oxidative stress, a recognized determinant of AD, enhances macroautophagy and leads to int...... to normoxic conditions. The rate of apoptosis in all three cell lines demonstrated dependence on intralysosomal Abeta content (Vector...

  10. S14G-humanin restored cellular homeostasis disturbed by amyloid-beta protein

    OpenAIRE

    Li, Xue; Zhao, Wencong; Yang, Hongqi; Zhang, Junhong; Ma, Jianjun

    2013-01-01

    Humanin is a potential therapeutic agent for Alzheimer's disease, and its derivative, S14G-humanin, is 1 000-fold stronger in its neuroprotective effect against Alzheimer's disease-relevant insults. Al-though effective, the detailed molecular mechanism through which S14G-humanin exerts its effects remains unclear. Data from this study showed that fibrillar amyloid-beta 40 disturbed cellular ho-meostasis through the cell membrane, increasing intracellular calcium, generating reactive oxygen sp...

  11. Sex-dependent actions of amyloid beta peptides on hippocampal choline carriers of postnatal rats

    Czech Academy of Sciences Publication Activity Database

    Krištofíková, Z.; Říčný, Jan; Kozmiková, I.; Řípová, D.; Zach, P.; Klaschka, Jan

    2006-01-01

    Roč. 31, č. 3 (2006), s. 351-360 ISSN 0364-3190 R&D Projects: GA ČR(CZ) GA305/03/1547 Institutional research plan: CEZ:AV0Z50110509; CEZ:AV0Z10300504 Keywords : amyloid beta peptide * high affinity choline transport * rat hippocampus Subject RIV: ED - Physiology Impact factor: 2.139, year: 2006

  12. Amyloid beta dimers/trimers potently induce cofilin-actin rods that are inhibited by maintaining cofilin-phosphorylation

    Directory of Open Access Journals (Sweden)

    Podlisny Marcia

    2011-01-01

    Full Text Available Abstract Background Previously we reported 1 μM synthetic human amyloid beta1-42 oligomers induced cofilin dephosphorylation (activation and formation of cofilin-actin rods within rat hippocampal neurons primarily localized to the dentate gyrus. Results Here we demonstrate that a gel filtration fraction of 7PA2 cell-secreted SDS-stable human Aβ dimers and trimers (Aβd/t induces maximal neuronal rod response at ~250 pM. This is 4,000-fold more active than traditionally prepared human Aβ oligomers, which contain SDS-stable trimers and tetramers, but are devoid of dimers. When incubated under tyrosine oxidizing conditions, synthetic human but not rodent Aβ1-42, the latter lacking tyrosine, acquires a marked increase (620 fold for EC50 in rod-inducing activity. Gel filtration of this preparation yielded two fractions containing SDS-stable dimers, trimers and tetramers. One, eluting at a similar volume to 7PA2 Aβd/t, had maximum activity at ~5 nM, whereas the other, eluting at the void volume (high-n state, lacked rod inducing activity at the same concentration. Fractions from 7PA2 medium containing Aβ monomers are not active, suggesting oxidized SDS-stable Aβ1-42 dimers in a low-n state are the most active rod-inducing species. Aβd/t-induced rods are predominantly localized to the dentate gyrus and mossy fiber tract, reach significance over controls within 2 h of treatment, and are reversible, disappearing by 24 h after Aβd/t washout. Overexpression of cofilin phosphatases increase rod formation when expressed alone and exacerbate rod formation when coupled with Aβd/t, whereas overexpression of a cofilin kinase inhibits Aβd/t-induced rod formation. Conclusions Together these data support a mechanism by which Aβd/t alters the actin cytoskeleton via effects on cofilin in neurons critical to learning and memory.

  13. Cationization increases brain distribution of an amyloid-beta protofibril selective F(ab')2 fragment

    OpenAIRE

    Syvänen, Stina; Edén, Desireé; Sehlin, Dag

    2017-01-01

    Antibodies and fragments thereof are, because of high selectivity for their targets, considered as potential therapeutics and biomarkers for several neurological disorders. However, due to their large molecular size, antibodies/fragments do not easily penetrate into the brain. The aim of the present study was to improve the brain distribution via adsorptive-mediated transcytosis of an amyloid-beta (A beta) protofibril selective F(ab')2 fragment (F(ab')2-h158). F(ab')2-h158 was cationized to d...

  14. Oxidative stress and the amyloid beta peptide in Alzheimer’s disease

    Directory of Open Access Journals (Sweden)

    C. Cheignon

    2018-04-01

    Full Text Available Oxidative stress is known to play an important role in the pathogenesis of a number of diseases. In particular, it is linked to the etiology of Alzheimer’s disease (AD, an age-related neurodegenerative disease and the most common cause of dementia in the elderly. Histopathological hallmarks of AD are intracellular neurofibrillary tangles and extracellular formation of senile plaques composed of the amyloid-beta peptide (Aβ in aggregated form along with metal-ions such as copper, iron or zinc. Redox active metal ions, as for example copper, can catalyze the production of Reactive Oxygen Species (ROS when bound to the amyloid-β (Aβ. The ROS thus produced, in particular the hydroxyl radical which is the most reactive one, may contribute to oxidative damage on both the Aβ peptide itself and on surrounding molecule (proteins, lipids, …. This review highlights the existing link between oxidative stress and AD, and the consequences towards the Aβ peptide and surrounding molecules in terms of oxidative damage. In addition, the implication of metal ions in AD, their interaction with the Aβ peptide and redox properties leading to ROS production are discussed, along with both in vitro and in vivo oxidation of the Aβ peptide, at the molecular level. Keywords: Oxidative stress, Amyloid beta peptide, Metal-ions, Reactive oxygen species, Oxidative damages

  15. Amyloid-beta 1-40 is associated with alterations in NG2+ pericyte population ex vivo and in vitro.

    Science.gov (United States)

    Schultz, Nina; Brännström, Kristoffer; Byman, Elin; Moussaud, Simon; Nielsen, Henrietta M; Olofsson, Anders; Wennström, Malin

    2018-02-17

    The population of brain pericytes, a cell type important for vessel stability and blood brain barrier function, has recently been shown altered in patients with Alzheimer's disease (AD). The underlying reason for this alteration is not fully understood, but progressive accumulation of the AD characteristic peptide amyloid-beta (Aβ) has been suggested as a potential culprit. In the current study, we show reduced number of hippocampal NG2+ pericytes and an association between NG2+ pericyte numbers and Aβ1-40 levels in AD patients. We further demonstrate, using in vitro studies, an aggregation-dependent impact of Aβ1-40 on human NG2+ pericytes. Fibril-EP Aβ1-40 exposure reduced pericyte viability and proliferation and increased caspase 3/7 activity. Monomer Aβ1-40 had quite the opposite effect: increased pericyte viability and proliferation and reduced caspase 3/7 activity. Oligomer-EP Aβ1-40 had no impact on either of the cellular events. Our findings add to the growing number of studies suggesting a significant impact on pericytes in the brains of AD patients and suggest different aggregation forms of Aβ1-40 as potential key regulators of the brain pericyte population size. © 2018 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  16. A bifunctional curcumin analogue for two-photon imaging and inhibiting crosslinking of amyloid beta in Alzheimer's disease.

    Science.gov (United States)

    Zhang, Xueli; Tian, Yanli; Yuan, Peng; Li, Yuyan; Yaseen, Mohammad A; Grutzendler, Jaime; Moore, Anna; Ran, Chongzhao

    2014-10-09

    In this report, we designed a highly bright bifunctional curcumin analogue CRANAD-28. In vivo two-photon imaging suggested that CRANAD-28 could penetrate the blood brain barrier (BBB) and label plaques and cerebral amyloid angiopathies (CAAs). We also demonstrated that this imaging probe could inhibit the crosslinking of amyloid beta induced either by copper or by natural conditions.

  17. The coding sequence of amyloid-beta precursor protein APP contains a neural-specific promoter element.

    NARCIS (Netherlands)

    Collin, R.W.J.; Martens, G.J.M.

    2006-01-01

    The amyloid-beta precursor protein APP is generally accepted to be involved in the pathology of Alzheimer's disease. Since its physiological role is still unclear, we decided to study the function of APP via stable transgenesis in the amphibian Xenopus laevis. However, the application of constructs

  18. A systematic review of amyloid-beta peptides as putative mediators of the association between affective disorders and Alzheimer's disease

    DEFF Research Database (Denmark)

    Abbasowa, Leda; Heegaard, N. H. H.

    2014-01-01

    was to explore clinically founded evidence for amyloid-beta peptides in cerebrospinal fluid and blood as putative biomarkers for affective disorders. Method: Systematic searches in Embase and PubMed databases yielded 23 eligible, observational studies. Results: Despite inconsistencies that were partly ascribed...

  19. Role of caspase-12 in amyloid beta-peptide-induced toxicity in organotypic hippocampal slices cultured for long periods.

    NARCIS (Netherlands)

    Ishige, K.; Takagi, N.; Imai, T.; Rausch, W.D.; Kosuge, Y.; Kihara, T.; Kusama-Eguchi, K.; Ikeda, H.; Cools, A.R.; Waddington, J.L.; Koshikawa, N.; Ito, Y.

    2007-01-01

    Amyloid beta (Abeta) toxicity has been implicated in cell death in the hippocampus, but its specific mechanisms are poorly understood. In this study, Abeta-induced cell death was investigated in organotypic hippocampal slice cultures (OHCs) that were cultured for various periods in vitro. There were

  20. Effect of four medicinal plants on amyloid-beta induced neurotoxicity in SH-SY5Y Cells

    CSIR Research Space (South Africa)

    Adewusi, EA

    2013-01-01

    Full Text Available Amyloid-beta peptide (Aß) is implicated in the pathogenesis of Alzheimer’s disease (AD), a neurodegenerative disorder. This study was designed to determine the effect of four medicinal plants used to treat neurodegenerative diseases on Aß...

  1. Bloodstream Amyloid-beta (1-40) Peptide, Cognition, and Outcomes in Heart Failure.

    Science.gov (United States)

    Bayes-Genis, Antoni; Barallat, Jaume; de Antonio, Marta; Domingo, Mar; Zamora, Elisabet; Vila, Joan; Subirana, Isaac; Gastelurrutia, Paloma; Pastor, M Cruz; Januzzi, James L; Lupón, Josep

    2017-11-01

    In the brain, amyloid-beta generation participates in the pathophysiology of cognitive disorders; in the bloodstream, the role of amyloid-beta is uncertain but may be linked to sterile inflammation and senescence. We explored the relationship between blood levels of amyloid-beta 1-40 peptide (Aβ40), cognition, and mortality (all-cause, cardiovascular, and heart failure [HF]-related) in ambulatory patients with HF. Bloodstream Aβ40 was measured in 939 consecutive patients with HF. Cognition was evaluated with the Pfeiffer questionnaire (adjusted for educational level) at baseline and during follow-up. Multivariate Cox regression analyses and measurements of performance (discrimination, calibration, and reclassification) were used, with competing risk for specific causes of death. Over 5.1 ± 2.9 years, 471 patients died (all-cause): 250 from cardiovascular causes and 131 HF-related. The median Aβ40 concentration was 519.1 pg/mL [Q1-Q3: 361.8-749.9 pg/mL]. The Aβ40 concentration correlated with age, body mass index, renal dysfunction, and New York Heart Association functional class (all P < .001). There were no differences in Aβ40 in patients with and without cognitive impairment at baseline (P = .97) or during follow-up (P = .20). In multivariable analysis, including relevant clinical predictors and N-terminal pro-B-type natriuretic peptide, Aβ40 remained significantly associated with all-cause death (HR, 1.22; 95%CI, 1.10-1.35; P < .001) and cardiovascular death (HR, 1.18; 95%CI, 1.03-1.36; P = .02), but not with HF-related death (HR, 1.13; 95%CI, 0.93-1.37; P = .22). Circulating Aβ40 improved calibration and patient reclassification. Blood levels of Aβ40 are not associated with cognitive decline in HF. Circulating Aβ40 was predictive of mortality and may indicate systemic aging. Copyright © 2017 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.

  2. Effect of copper (II) ion against elongation behavior of amyloid {beta} fibrils on liposome membranes

    Energy Technology Data Exchange (ETDEWEB)

    Shimanouchi, T.; Onishi, R.; Kitaura, N.; Umakoshi, H.; Kuboi, R. [Division of Chemical Engineering, Graduate School of Engineering Science, Osaka University, 1-3 Machikaneyama-cho, Toyonaka, Osaka (Japan)

    2012-01-15

    The fibril growth behavior of amyloid {beta} protein (A{beta}) on cell membranes is relating to the progression of Alzheimer's disease. This growth behavior of A{beta} fibrils is sensitively affected by the metal ions, neurotransmitters, or bioreactive substrate. The inhibitory effect of those materials was quantitatively estimated from the viewpoints of ''crystal growth''. In a bulk aqueous solution, copper (II) ion showed the strong inhibitory effect on the growth of A{beta} fibrils. Meanwhile, the addition of a closed-phospholipid bilayer membrane (liposome) could reduce the above inhibitory effect of copper (II) ion. (copyright 2012 WILEY-VCH Verlag GmbH and Co. KGaA, Weinheim) (orig.)

  3. Amyloid beta-peptide(25-35) changes [Ca2+] in hippocampal neurons

    DEFF Research Database (Denmark)

    Mogensen, Helle Smidt; Beatty, D M; Morris, S J

    1998-01-01

    Insoluble aggregates of the amyloid beta-peptide (A beta) is a major constituent of senile plaques found in brains of Alzheimer disease (AD) patients. The detrimental effects of aggregated A beta is associated with an increased intracellular Ca2+ concentration ([Ca2+]i). We examined the effects...... of A beta(25-35) on [Ca2+]i and intracellular H+ concentration ([H+]i) in single hippocampal neurons by real time fluorescence imaging using the Ca(2+)- and H(+)-specific ratio dyes, indo-1 and SNARF-1. Incubation of these cultures with A beta(25-35) for 3-12 days in vitro increased [Ca2+]i and [H+]i...

  4. Red mold rice ameliorates impairment of memory and learning ability in intracerebroventricular amyloid beta-infused rat by repressing amyloid beta accumulation.

    Science.gov (United States)

    Lee, Chun-Lin; Kuo, Tzong-Fu; Wang, Jyh-Jye; Pan, Tzu-Ming

    2007-11-01

    Amyloid beta (Abeta) peptide related to the onset of Alzheimer's disease (AD) damaged neurons and further resulted in dementia. Monascus-fermented red mold rice (RMR), a traditional Chinese medicine as well as health food, includes monacolins (with the same function as statins) and multifunctional metabolites. In this study, ethanol extract of RMR (RE) was used to evaluate neuroprotection against Abeta40 neurotoxicity in PC12 cells. Furthermore, the effects of dietary administration of RMR on memory and learning abilities are confirmed in an animal model of AD rats infused with Abeta40 into the cerebral ventricle. During continuous Abeta40 infusion for 28 days, the rats of test groups were administered RMR or lovastatin. Memory and learning abilities were evaluated in the water maze and passive avoidance tasks. After sacrifice, cerebral cortex and hippocampus were collected for the examination of AD risk factors. The in vitro results clearly indicate that RE provides stronger neuroprotection in rescuing cell viability as well as repressing inflammatory response and oxidative stress. RMR administration potently reverses the memory deficit in the memory task. Abeta40 infusion increases acetylcholinesterase activity, reactive oxygen species, and lipid peroxidation and decreases total antioxidant status and superoxide dismutase activity in brain, but these damages were potently reversed by RMR administration, and the protection was more significant than that with lovastatin administration. The protection provided by RMR is able to prevent Abeta fibrils from being formed and deposited in hippocampus and further decrease Abeta40 accumulation, even though Abeta40 solution was infused into brain continuously. (c) 2007 Wiley-Liss, Inc.

  5. The role of mutated amyloid beta 1-42 stimulating dendritic cells in a PDAPP transgenic mouse

    Directory of Open Access Journals (Sweden)

    LI Jia-lin

    2012-06-01

    Full Text Available Background Amyloid plaque is one of the pathological hallmarks of Alzheimer's disease (AD. Anti-beta-amyloid (Aβ immunotherapy is effective in removing brain Aβ, but has shown to be associated with detrimental effects. To avoid severe adverse effects such as meningoencephalitis induced by amyloid beta vaccine with adjuvant, and take advantage of amyloid beta antibody's therapeutic effect on Alzheimer's disease sufficiently, our group has developed a new Alzheimer vaccine with mutated amyloid beta 1-42 peptide stimulating dendritic cells (DC. Our previous work has confirmed that DC vaccine can induce adequate anti-amyloid beta antibody in PDAPP Tg mice safely and efficiently. The DC vaccine can improve impaired learning and memory in the Alzheimer's animal model, and did not cause microvasculitis, microhemorrhage or meningoencephalitis in the animal model. However, the exact mechanism of immunotherapy which reduces Aβ deposition remains unknown. In this report, we studied the mechanism of the vaccine, thinking that this may have implications for better understanding of the pathogenesis of Alzheimer's disease. Methods A new Alzheimer vaccine with mutated amyloid beta 1-42 peptide stimulating DC which were obtained from C57/B6 mouse bone marrow was developed. Amyloid beta with Freund's adjuvant was inoculated at the same time to act as positive control. After the treatment was done, the samples of brains were collected, fixed, cut. Immunohistochemical staining was performed to observe the expression of the nuclear hormone liver X receptor (LXR, membrane-bound protein tyrosine phosphatase (CD45, the ATP-binding cassette family of active transporters (ABCA1, receptor for advanced glycation end products (RAGE, β-site APP-cleaving enzyme (BACE and Aβ in mouse brain tissue. Semi-quantitative analysis was used to defect CA1, CA2, CA3, DG, Rad in hippocampus region and positive neuron in cortex region. Results Aβ was significantly reduced in the

  6. Xanthene food dye, as a modulator of Alzheimer's disease amyloid-beta peptide aggregation and the associated impaired neuronal cell function.

    Directory of Open Access Journals (Sweden)

    H Edward Wong

    Full Text Available Alzheimer's disease (AD is the most common form of dementia. AD is a degenerative brain disorder that causes problems with memory, thinking and behavior. It has been suggested that aggregation of amyloid-beta peptide (Aβ is closely linked to the development of AD pathology. In the search for safe, effective modulators, we evaluated the modulating capabilities of erythrosine B (ER, a Food and Drug Administration (FDA-approved red food dye, on Aβ aggregation and Aβ-associated impaired neuronal cell function.In order to evaluate the modulating ability of ER on Aβ aggregation, we employed transmission electron microscopy (TEM, thioflavin T (ThT fluorescence assay, and immunoassays using Aβ-specific antibodies. TEM images and ThT fluorescence of Aβ samples indicate that protofibrils are predominantly generated and persist for at least 3 days. The average length of the ER-induced protofibrils is inversely proportional to the concentration of ER above the stoichiometric concentration of Aβ monomers. Immunoassay results using Aβ-specific antibodies suggest that ER binds to the N-terminus of Aβ and inhibits amyloid fibril formation. In order to evaluate Aβ-associated toxicity we determined the reducing activity of SH-SY5Y neuroblastoma cells treated with Aβ aggregates formed in the absence or in the presence of ER. As the concentration of ER increased above the stoichiometric concentration of Aβ, cellular reducing activity increased and Aβ-associated reducing activity loss was negligible at 500 µM ER.Our findings show that ER is a novel modulator of Aβ aggregation and reduces Aβ-associated impaired cell function. Our findings also suggest that xanthene dye can be a new type of small molecule modulator of Aβ aggregation. With demonstrated safety profiles and blood-brain permeability, ER represents a particularly attractive aggregation modulator for amyloidogenic proteins associated with neurodegenerative diseases.

  7. Amyloid beta1–42 and the phoshorylated tau threonine 231 in brains of aged cynomolgus monkeys (Macaca fascicularis)

    DEFF Research Database (Denmark)

    Darusman, Huda Shalahudin; Gjedde, Albert; Sajuthi, Dondin

    2014-01-01

    Pathological hallmarks indicative of Alzheimer's disease (AD), which are the plaques of amyloid beta1-42 and neurofibrillary tangles, were found in brain of aged cynomolgus monkey. The aim of this study was to investigate if aged monkeys exhibiting spatial memory impairment and levels of biomarkers...... angiopathy, and the tauopathy, to possible neurofibrillary tangles. Six aged monkeys were selected based on their spatial memory performance and profile of biomarkers of AD, divided equally to affected aged subject - with Memory-affected and low amyloid level, and aged with higher performance in memory...... and amyloid, as the age-matched subjects. Using immunohistochemistry, plaques of amyloid beta1-42 were observed in two out of three brains of aged subjects with memory impairment and biomarkers indicative of AD. The cerebral amyloid angiopathy was observed in both aged monkey groups, and unlike in the human...

  8. Modeling clustered activity increase in amyloid-beta positron emission tomographic images with statistical descriptors

    Directory of Open Access Journals (Sweden)

    Shokouhi S

    2015-04-01

    Full Text Available Sepideh Shokouhi,1 Baxter P Rogers,1 Hakmook Kang,2 Zhaohua Ding,1 Daniel O Claassen,3 John W Mckay,1 William R Riddle1On behalf of the Alzheimer’s Disease Neuroimaging Initiative1Department of Radiology and Radiological Sciences, Vanderbilt University Institute of Imaging Science, 2Department of Biostatistics, 3Department of Neurology, Vanderbilt University, Nashville, TN, USABackground: Amyloid-beta (Aβ imaging with positron emission tomography (PET holds promise for detecting the presence of Aβ plaques in the cortical gray matter. Many image analyses focus on regional average measurements of tracer activity distribution; however, considerable additional information is available in the images. Metrics that describe the statistical properties of images, such as the two-point correlation function (S2, have found wide applications in astronomy and materials science. S2 provides a detailed characterization of spatial patterns in images typically referred to as clustering or flocculence. The objective of this study was to translate the two-point correlation method into Aβ-PET of the human brain using 11C-Pittsburgh compound B (11C-PiB to characterize longitudinal changes in the tracer distribution that may reflect changes in Aβ plaque accumulation.Methods: We modified the conventional S2 metric, which is primarily used for binary images and formulated a weighted two-point correlation function (wS2 to describe nonbinary, real-valued PET images with a single statistical function. Using serial 11C-PiB scans, we calculated wS2 functions from two-dimensional PET images of different cortical regions as well as three-dimensional data from the whole brain. The area under the wS2 functions was calculated and compared with the mean/median of the standardized uptake value ratio (SUVR. For three-dimensional data, we compared the area under the wS2 curves with the subjects’ cerebrospinal fluid measures.Results: Overall, the longitudinal changes in wS2

  9. Differential effect of amyloid beta peptides on mitochondrial axonal trafficking depends on their state of aggregation and binding to the plasma membrane.

    Science.gov (United States)

    Zhang, Liang; Trushin, Sergey; Christensen, Trace A; Tripathi, Utkarsh; Hong, Courtney; Geroux, Rachel E; Howell, Kyle G; Poduslo, Joseph F; Trushina, Eugenia

    2018-02-26

    Inhibition of mitochondrial axonal trafficking by amyloid beta (Aβ) peptides has been implicated in early pathophysiology of Alzheimer's Disease (AD). Yet, it remains unclear whether the loss of motility inevitably induces the loss of mitochondrial function, and whether restoration of axonal trafficking represents a valid therapeutic target. Moreover, while some investigations identify Aβ oligomers as the culprit of trafficking inhibition, others propose that fibrils play the detrimental role. We have examined the effect of a panel of Aβ peptides with different mutations found in familial AD on mitochondrial motility in primary cortical mouse neurons. Peptides with higher propensity to aggregate inhibit mitochondrial trafficking to a greater extent with fibrils inducing the strongest inhibition. Binding of Aβ peptides to the plasma membrane was sufficient to induce trafficking inhibition where peptides with reduced plasma membrane binding and internalization had lesser effect on mitochondrial motility. We also found that Aβ peptide with Icelandic mutation A673T affects axonal trafficking of mitochondria but has very low rates of plasma membrane binding and internalization in neurons, which could explain its relatively low toxicity. Inhibition of mitochondrial dynamics caused by Aβ peptides or fibrils did not instantly affect mitochondrial bioenergetic and function. Our results support a mechanism where inhibition of axonal trafficking is initiated at the plasma membrane by soluble low molecular weight Aβ species and is exacerbated by fibrils. Since trafficking inhibition does not coincide with the loss of mitochondrial function, restoration of axonal transport could be beneficial at early stages of AD progression. However, strategies designed to block Aβ aggregation or fibril formation alone without ensuring the efficient clearance of soluble Aβ may not be sufficient to alleviate the trafficking phenotype. Copyright © 2018 The Authors. Published by

  10. Rational design of amyloid beta peptide-binding proteins: pseudo-Abeta beta-sheet surface presented in green fluorescent protein binds tightly and preferentially to structured Abeta.

    Science.gov (United States)

    Takahashi, Tsuyoshi; Ohta, Kenichi; Mihara, Hisakazu

    2010-02-01

    Some neurodegenerative diseases such as Alzheimer disease (AD) and Parkinson disease are caused by protein misfolding. In AD, amyloid beta-peptide (Abeta) is thought to be a toxic agent by self-assembling into a variety of aggregates involving soluble oligomeric intermediates and amyloid fibrils. Here, we have designed several green fluorescent protein (GFP) variants that contain pseudo-Abeta beta-sheet surfaces and evaluated their abilities to bind to Abeta and inhibit Abeta oligomerization. Two GFP variants P13H and AP93Q bound tightly to Abeta, K(d) = 260 nM and K(d) = 420 nM, respectively. Moreover, P13H and AP93Q were capable of efficiently suppressing the generation of toxic Abeta oligomers as shown by a cell viability assay. By combining the P13H and AP93Q mutations, a super variant SFAB4 comprising four strands of Abeta-derived sequences was designed and bound more tightly to Abeta (K(d) = 100 nM) than those having only two pseudo-Abeta strands. The SFAB4 protein preferentially recognized the soluble oligomeric intermediates of Abeta more than both unstructured monomer and mature amyloid fibrils. Thus, the design strategy for embedding pseudo-Abeta beta-sheet structures onto a protein surface arranged in the beta-barrel structure is useful to construct molecules capable of binding tightly to Abeta and inhibiting its aggregation. This strategy may provide implication for the diagnostic and therapeutic development in the treatment of AD. (c) 2009 Wiley-Liss, Inc.

  11. Aluminum complexing enhances amyloid beta protein penetration of blood-brain barrier.

    Science.gov (United States)

    Banks, William A; Niehoff, Michael L; Drago, Denise; Zatta, Paolo

    2006-10-20

    A significant co-morbidity of Alzheimer's disease and cerebrovascular impairment suggests that cerebrovascular dysregulation is an important feature of dementia. Amyloid beta protein (Abeta), a relevant risk factor in Alzheimer's disease, has neurotoxic properties and is thought to play a critical role in the cognitive impairments. Previously, we demonstrated that the 42mer of Abeta (Abeta42) complexed with aluminum (Al-Abeta42) is much more cytotoxic than non-complexed Abeta42. The level of Abeta in the brain is a balance between synthesis, degradation, and fluxes across the blood-brain barrier (BBB). In the present paper, we determined whether complexing with aluminum affected the ability of radioactively iodinated Abeta to cross the in vivo BBB. We found that the rates of uptake of Al-Abeta42 and Abeta42 were similar, but that Al-Abeta42 was sequestered by brain endothelial cells much less than Abeta42 and so more readily entered the parenchymal space of the brain. Al-Abeta42 also had a longer half-life in blood and had increased permeation at the striatum and thalamus. Brain-to-blood transport was similar for Al-Abeta42 and Abeta42. In conclusion, complexing with aluminum affects some aspects of blood-to-brain permeability so that Al-Abeta42 would have more ready access to brain cells than Abeta42.

  12. Monomeric Amyloid Beta Peptide in Hexafluoroisopropanol Detected by Small Angle Neutron Scattering.

    Directory of Open Access Journals (Sweden)

    Bo Zhang-Haagen

    Full Text Available Small proteins like amyloid beta (Aβ monomers are related to neurodegenerative disorders by aggregation to insoluble fibrils. Small angle neutron scattering (SANS is a nondestructive method to observe the aggregation process in solution. We show that SANS is able to resolve monomers of small molecular weight like Aβ for aggregation studies. We examine Aβ monomers after prolonged storing in d-hexafluoroisopropanol (dHFIP by using SANS and dynamic light scattering (DLS. We determined the radius of gyration from SANS as 1.0±0.1 nm for Aβ1-40 and 1.6±0.1 nm for Aβ1-42 in agreement with 3D NMR structures in similar solvents suggesting a solvent surface layer with 5% increased density. After initial dissolution in dHFIP Aβ aggregates sediment with a major component of pure monomers showing a hydrodynamic radius of 1.8±0.3 nm for Aβ1-40 and 3.2±0.4 nm for Aβ1-42 including a surface layer of dHFIP solvent molecules.

  13. Alzheimer's disease and amyloid beta-peptide deposition in the brain: a matter of 'aging'?

    Science.gov (United States)

    Moro, Maria Luisa; Collins, Matthew J; Cappellini, Enrico

    2010-04-01

    Biomolecules can experience aging processes that limit their long-term functionality in organisms. Typical markers of protein aging are spontaneous chemical modifications, such as AAR (amino acid racemization) and AAI (amino acid isomerization), mainly involving aspartate and asparagine residues. Since these modifications may affect folding and turnover, they reduce protein functionality over time and may be linked to pathological conditions. The present mini-review describes evidence of AAR and AAI involvement in the misfolding and brain accumulation of Abeta (amyloid beta-peptide), a central event in AD (Alzheimer's disease) synaptic dysfunctions. Structural alterations introduced by site-specific modifications linked to protein aging may affect Abeta production, polymerization and clearance, and therefore play a pivotal role in the pathogenesis of sporadic and genetic forms of AD. Early changes associated with molecular aging also have significant long-term consequences for Abeta folding and turnover. New fast, reproducible and accurate methods for the screening of protein aging markers in biological samples may contribute to improve diagnostic and therapeutic approaches in AD.

  14. Pulsed hydrogen-deuterium exchange mass spectrometry probes conformational changes in amyloid beta (Aβ) peptide aggregation.

    Science.gov (United States)

    Zhang, Ying; Rempel, Don L; Zhang, Jun; Sharma, Anuj K; Mirica, Liviu M; Gross, Michael L

    2013-09-03

    Probing the conformational changes of amyloid beta (Aβ) peptide aggregation is challenging owing to the vast heterogeneity of the resulting soluble aggregates. To investigate the formation of these aggregates in solution, we designed an MS-based biophysical approach and applied it to the formation of soluble aggregates of the Aβ42 peptide, the proposed causative agent in Alzheimer's disease. The approach incorporates pulsed hydrogen-deuterium exchange coupled with MS analysis. The combined approach provides evidence for a self-catalyzed aggregation with a lag phase, as observed previously by fluorescence methods. Unlike those approaches, pulsed hydrogen-deuterium exchange does not require modified Aβ42 (e.g., labeling with a fluorophore). Furthermore, the approach reveals that the center region of Aβ42 is first to aggregate, followed by the C and N termini. We also found that the lag phase in the aggregation of soluble species is affected by temperature and Cu(2+) ions. This MS approach has sufficient structural resolution to allow interrogation of Aβ aggregation in physiologically relevant environments. This platform should be generally useful for investigating the aggregation of other amyloid-forming proteins and neurotoxic soluble peptide aggregates.

  15. Structural heterogeneity in familial Alzheimer's disease mutants of amyloid-beta peptides.

    Science.gov (United States)

    Chong, Song-Ho; Yim, Janghyun; Ham, Sihyun

    2013-05-01

    Alzheimer's disease is a neurodegenerative disorder characterized by progressive deposition of amyloid-beta (Aβ) peptides in brain parenchyma and cerebral blood vessels. Several pathogenic familial mutations of Aβ peptides have been identified that exhibit enhanced neurotoxicity and aggregative ability. However, knowledge of the structural characteristics of those Aβ mutants is still limited. Here, we report multiple all-atom molecular dynamics simulations of the wild-type 42-residue Aβ peptide (Aβ42) and its Flemish (A21G), Arctic (E22G), Dutch (E22Q), Italian (E22K), and Iowa (D23N) familial mutants in explicit water. After validating our simulations by comparison with available experimental data, we examined common/different features in the secondary and tertiary structures of the wild-type and five familial mutants of Aβ42. We found that Aβ42 peptides display quite heterogeneous secondary and tertiary structure ensembles. Such structural heterogeneity in the monomeric state would facilitate interconversions between various secondary structures during the formation of a β-sheet-rich amyloid fibril, and may also serve as a structural basis of the amyloid polymorphism.

  16. Detection of Alzheimer’s disease amyloid-beta plaque deposition by deep brain impedance profiling

    Science.gov (United States)

    Béduer, Amélie; Joris, Pierre; Mosser, Sébastien; Fraering, Patrick C.; Renaud, Philippe

    2015-04-01

    Objective. Alzheimer disease (AD) is the most common form of neurodegenerative disease in elderly people. Toxic brain amyloid-beta (Aß) aggregates and ensuing cell death are believed to play a central role in the pathogenesis of the disease. In this study, we investigated if we could monitor the presence of these aggregates by performing in situ electrical impedance spectroscopy measurements in AD model mice brains. Approach. In this study, electrical impedance spectroscopy measurements were performed post-mortem in APPPS1 transgenic mice brains. This transgenic model is commonly used to study amyloidogenesis, a pathological hallmark of AD. We used flexible probes with embedded micrometric electrodes array to demonstrate the feasibility of detecting senile plaques composed of Aß peptides by localized impedance measurements. Main results. We particularly focused on deep brain structures, such as the hippocampus. Ex vivo experiments using brains from young and old APPPS1 mice lead us to show that impedance measurements clearly correlate with the percentage of Aβ plaque load in the brain tissues. We could monitor the effects of aging in the AD APPPS1 mice model. Significance. We demonstrated that a localized electrical impedance measurement constitutes a valuable technique to monitor the presence of Aβ-plaques, which is complementary with existing imaging techniques. This method does not require prior Aβ staining, precluding the risk of variations in tissue uptake of dyes or tracers, and consequently ensuring reproducible data collection.

  17. Monomeric Amyloid Beta Peptide in Hexafluoroisopropanol Detected by Small Angle Neutron Scattering.

    Science.gov (United States)

    Zhang-Haagen, Bo; Biehl, Ralf; Nagel-Steger, Luitgard; Radulescu, Aurel; Richter, Dieter; Willbold, Dieter

    2016-01-01

    Small proteins like amyloid beta (Aβ) monomers are related to neurodegenerative disorders by aggregation to insoluble fibrils. Small angle neutron scattering (SANS) is a nondestructive method to observe the aggregation process in solution. We show that SANS is able to resolve monomers of small molecular weight like Aβ for aggregation studies. We examine Aβ monomers after prolonged storing in d-hexafluoroisopropanol (dHFIP) by using SANS and dynamic light scattering (DLS). We determined the radius of gyration from SANS as 1.0±0.1 nm for Aβ1-40 and 1.6±0.1 nm for Aβ1-42 in agreement with 3D NMR structures in similar solvents suggesting a solvent surface layer with 5% increased density. After initial dissolution in dHFIP Aβ aggregates sediment with a major component of pure monomers showing a hydrodynamic radius of 1.8±0.3 nm for Aβ1-40 and 3.2±0.4 nm for Aβ1-42 including a surface layer of dHFIP solvent molecules.

  18. In vitro screening on amyloid beta modulation of aqueous extracts from plant seeds

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    Yoshinori Okada

    2016-01-01

    Full Text Available Introduction: Glycation process might contribute to both extensive protein cross-linking and oxidative stress in Alzheimer's disease (AD. The amyloid-like aggregation of glycated bovine serum albumin induces apoptosis in the neuronal cell. Dietary supplementation of antioxidants, vitamins, and polyphenols are beneficial to AD, and consumption of fruits and vegetables reduce the risk of AD. We conducted a screening of 14 aqueous extracts from plant seeds (PSAE for inhibitory activity on amyloid beta (Aβ. Materials and Methods: To examine the effects of PSAE on the Aβ (1–42 concentration, PSAE were analyzed by Aβ (1–42 enzyme-linked immunosorbent assay. Furthermore, we carried out an antiglycation experiment of PSAE and an antiaggregation experiment of PSAE to confirm the modification mechanism of PSAE. PSAE were added to buffer containing D-ribose and albumins. The solutions were incubated at 37 °C for 10 days. After incubation, the products were assayed on a fluorophotometer. Results: PSAE associated differential reduction in the levels of Aβ (1–42 (lettuce; 98.7% ± 2.4%, bitter melon; 95.9% ± 2.6%, and corn; 93.9% ± 2.1%, demonstrating that treatment with lettuce seeds extracts (LSE effectively decreases Aβ (1–42 concentration. Among the 14 PSAE, LSE exhibited the second greatest potential for antiglycation. Inhibition of aggregates was not recognized in LSE. Conclusion: These results suggest that LSE reduces the toxicity of Aβ by modifying Aβ.

  19. A role for 12/15 lipoxygenase in the amyloid beta precursor protein metabolism.

    Science.gov (United States)

    Succol, Francesca; Praticò, Domenico

    2007-10-01

    12/15 Lipoxygenase (12/15LO) protein levels and activity are increased in pathologically affected regions of Alzheimer's disease (AD) brains, compared with controls. Its metabolic products are elevated in cerebrospinal fluid of patients with AD and individuals with mild cognitive impairment, suggesting that this enzyme may be involved early in AD pathogenesis. Herein, we investigate the effect of pharmacologic inhibition of 12/15LO on the amyloid beta precursor protein (APP) metabolism. To this end, we used CHO and N2A cells stably expressing human APP with the Swedish mutant, and two structurally distinct and selective 12/15LO inhibitors, PD146176 and CDC. Our results demonstrated that both drugs dose-dependently reduced Abeta formation without affecting total APP levels. Interestingly, in the same cells we observed a significant reduction in secreted (s)APPbeta and beta-secretase (BACE), but not sAPPalpha and ADAM10 protein levels. Together, these data show for the first time that this enzymatic pathway influences Abeta formation whereby modulating the BACE proteolytic cascade. We conclude that specific pharmacologic inhibition of 12/15LO could represent a novel therapeutic target for treating or preventing AD pathology in humans.

  20. Amyloid-Beta Induced Changes in Vesicular Transport of BDNF in Hippocampal Neurons

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    Bianca Seifert

    2016-01-01

    Full Text Available The neurotrophin brain derived neurotrophic factor (BDNF is an important growth factor in the CNS. Deficits in transport of this secretory protein could underlie neurodegenerative diseases. Investigation of disease-related changes in BDNF transport might provide insights into the cellular mechanism underlying, for example, Alzheimer’s disease (AD. To analyze the role of BDNF transport in AD, live cell imaging of fluorescently labeled BDNF was performed in hippocampal neurons of different AD model systems. BDNF and APP colocalized with low incidence in vesicular structures. Anterograde as well as retrograde transport of BDNF vesicles was reduced and these effects were mediated by factors released from hippocampal neurons into the extracellular medium. Transport of BDNF was altered at a very early time point after onset of human APP expression or after acute amyloid-beta(1-42 treatment, while the activity-dependent release of BDNF remained unaffected. Taken together, extracellular cleavage products of APP induced rapid changes in anterograde and retrograde transport of BDNF-containing vesicles while release of BDNF was unaffected by transgenic expression of mutated APP. These early transport deficits might lead to permanently impaired brain functions in the adult brain.

  1. Neuroblastoma Treatment

    Science.gov (United States)

    ... adrenal glands. Signs and symptoms of neuroblastoma include bone pain and a lump in the abdomen, neck, ... options for neuroblastoma are also affected by tumor biology, which includes: The patterns of the tumor cells. ...

  2. Amyloid beta inhibits olfactory bulb activity and the ability to smell.

    Directory of Open Access Journals (Sweden)

    Reynaldo Alvarado-Martínez

    Full Text Available Early olfactory dysfunction has been consistently reported in both Alzheimer's disease (AD and in transgenic mice that reproduce some features of this disease. In AD transgenic mice, alteration in olfaction has been associated with increased levels of soluble amyloid beta protein (Aβ as well as with alterations in the oscillatory network activity recorded in the olfactory bulb (OB and in the piriform cortex. However, since AD is a multifactorial disease and transgenic mice suffer a variety of adaptive changes, it is still unknown if soluble Aβ, by itself, is responsible for OB dysfunction both at electrophysiological and behavioral levels. Thus, here we tested whether or not Aβ directly affects OB network activity in vitro in slices obtained from mice and rats and if it affects olfactory ability in these rodents. Our results show that Aβ decreases, in a concentration- and time-dependent manner, the network activity of OB slices at clinically relevant concentrations (low nM and in a reversible manner. Moreover, we found that intrabulbar injection of Aβ decreases the olfactory ability of rodents two weeks after application, an effect that is not related to alterations in motor performance or motivation to seek food and that correlates with the presence of Aβ deposits. Our results indicate that Aβ disrupts, at clinically relevant concentrations, the network activity of the OB in vitro and can trigger a disruption in olfaction. These findings open the possibility of exploring the cellular mechanisms involved in early pathological AD as an approach to reduce or halt its progress.

  3. Tau, Amyloid Beta and Deep Brain Stimulation: Aiming to Restore Cognitive Deficit in Alzheimer's Disease.

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    Mondragón-Rodríguez, Siddhartha; Perry, George; Pena-Ortega, Fernando; Williams, Sylvain

    2017-01-01

    The last two decades have seen a great advance in the data that supports the two current hypotheses in Alzheimer`s disease field, the amyloid beta hypothesis and the tau hypothesis. Not surprisingly, Aβ and tau proteins are currently the major therapeutic research targets for AD treatment. Unfortunately, nothing but moderate success has emerged from such therapeutic approaches. With this in mind, we will discuss deep brain stimulation as a promising therapeutic strategy that aims to restore brain activity. Lastly, in the scope of cognitive deficit restoration, we will discuss the relevance of the limbic formation as a promising neuroanatomical target for deep brain stimulation. Immunohistochemistry for modified tau (phosphorylated at Ser199-202-Thr205 labelled by the antibody AT8) was performed on paraffin-embedded human brain sections providing a detailed characterization of NFT pathology. Abnormally phosphorylated tau protein is the key common marker in several brain diseases such as Alzheimer's disease, Parkinson`s disease, Pick Disease, Down syndrome and frontotemporal dementia and is capable of affecting synaptic events that are critical for memory formation. With this in mind, therapeutic strategies aiming to restore synaptic events could offer better outcomes. The humble success of current therapeutic strategies along with the lack of basic knowledge of the brain disease mechanisms calls for alternatives that benefit patients in the present moment. One of particular interest is the neurostimulation strategy that is already a well-established treatment for several movement disorders and when compared to current Alzheimer`s therapeutic strategies, deep brain stimulation does not directly interfere with the normal protein function, therefore increasing the probability of success.

  4. A Humanin Derivative Reduces Amyloid Beta Accumulation and Ameliorates Memory Deficit in Triple Transgenic Mice

    Science.gov (United States)

    Niikura, Takako; Sidahmed, Elkhansa; Hirata-Fukae, Chiho; Aisen, Paul S.; Matsuoka, Yasuji

    2011-01-01

    Humanin (HN), a 24-residue peptide, was identified as a novel neuroprotective factor and shows anti-cell death activity against a wide spectrum of Alzheimer's disease (AD)-related cytotoxicities, including exposure to amyloid beta (Abeta), in vitro. We previously demonstrated that the injection of S14G-HN, a highly potent HN derivative, into brain ameliorated memory loss in an Abeta-injection mouse model. To fully understand HN's functions under AD-associated pathological conditions, we examined the effect of S14G-HN on triple transgenic mice harboring APPswe, tauP310L, and PS-1M146V that show the age-dependent development of multiple pathologies relating to AD. After 3 months of intranasal treatment, behavioral analyses showed that S14G-HN ameliorated cognitive impairment in male mice. Moreover, ELISA and immunohistochemical analyses showed that Abeta levels in brains were markedly lower in S14G-HN-treated male and female mice than in vehicle control mice. We also found the expression level of neprilysin, an Abeta degrading enzyme, in the outer molecular layer of hippocampal formation was increased in S14G-HN-treated mouse brains. NEP activity was also elevated by S14G-HN treatment in vitro. These findings suggest that decreased Abeta level in these mice is at least partly attributed to S14G-HN-induced increase of neprilysin level. Although HN was identified as an anti-neuronal death factor, these results indicate that HN may also have a therapeutic effect on amyloid accumulation in AD. PMID:21264226

  5. A humanin derivative reduces amyloid beta accumulation and ameliorates memory deficit in triple transgenic mice.

    Directory of Open Access Journals (Sweden)

    Takako Niikura

    Full Text Available Humanin (HN, a 24-residue peptide, was identified as a novel neuroprotective factor and shows anti-cell death activity against a wide spectrum of Alzheimer's disease (AD-related cytotoxicities, including exposure to amyloid beta (Abeta, in vitro. We previously demonstrated that the injection of S14G-HN, a highly potent HN derivative, into brain ameliorated memory loss in an Abeta-injection mouse model. To fully understand HN's functions under AD-associated pathological conditions, we examined the effect of S14G-HN on triple transgenic mice harboring APP(swe, tau(P310L, and PS-1(M146V that show the age-dependent development of multiple pathologies relating to AD. After 3 months of intranasal treatment, behavioral analyses showed that S14G-HN ameliorated cognitive impairment in male mice. Moreover, ELISA and immunohistochemical analyses showed that Abeta levels in brains were markedly lower in S14G-HN-treated male and female mice than in vehicle control mice. We also found the expression level of neprilysin, an Abeta degrading enzyme, in the outer molecular layer of hippocampal formation was increased in S14G-HN-treated mouse brains. NEP activity was also elevated by S14G-HN treatment in vitro. These findings suggest that decreased Abeta level in these mice is at least partly attributed to S14G-HN-induced increase of neprilysin level. Although HN was identified as an anti-neuronal death factor, these results indicate that HN may also have a therapeutic effect on amyloid accumulation in AD.

  6. Amyloid-beta transporter expression at the blood-CSF barrier is age-dependent

    Directory of Open Access Journals (Sweden)

    Pascale Crissey L

    2011-07-01

    Full Text Available Abstract Background Age is the major risk factor for many neurodegenerative diseases, including Alzheimer's disease (AD. There is an accumulation of amyloid-beta peptides (Aβ in both the AD brain and the normal aging brain. Clearance of Aβ from the brain occurs via active transport at the blood-brain barrier (BBB and blood-cerebrospinal fluid barrier (BCSFB. With increasing age, the expression of the Aβ efflux transporters is decreased and the Aβ influx transporter expression is increased at the BBB, adding to the amyloid burden in the brain. Expression of the Aβ transporters at the choroid plexus (CP epithelium as a function of aging was the subject of this study. Methods This project investigated the changes in expression of the Aβ transporters, the low density lipoprotein receptor-related protein-1 (LRP-1, P-glycoprotein (P-gp, LRP-2 (megalin and the receptor for advanced glycation end-products (RAGE at the BCSFB in Brown-Norway/Fischer rats at ages 3, 6, 9, 12, 20, 30 and 36 months, using real time RT-PCR to measure transporter mRNA expression, and immunohistochemistry (IHC to measure transporter protein in isolated rat CP. Results There was an increase in the transcription of the Aβ efflux transporters, LRP-1 and P-gp, no change in RAGE expression and a decrease in LRP-2, the CP epithelium influx transporter, at the BCSFB with aging. Decreased Aβ42 concentration in the CP, as measured by quantitative IHC, was associated with these Aβ transporter alterations. Conclusions Age-dependent alterations in the CP Aβ transporters are associated with a decrease in Aβ42 accumulation in the CP, and are reciprocal to the changes seen in these transporters at the BBB, suggesting a possible compensatory role for the BCSFB in Aβ clearance in aging.

  7. Evaluation of the Expression of Amyloid Precursor Protein and the Ratio of Secreted Amyloid Beta 42 to Amyloid Beta 40 in SH-SY5Y Cells Stably Transfected with Wild-Type, Single-Mutant and Double-Mutant Forms of the APP Gene for the Study of Alzheimer's Disease Pathology.

    Science.gov (United States)

    Pahrudin Arrozi, Aslina; Shukri, Siti Nur Syazwani; Wan Ngah, Wan Zurinah; Mohd Yusof, Yasmin Anum; Ahmad Damanhuri, Mohd Hanafi; Makpol, Suzana

    2017-11-01

    Neuroblastoma cell lines such as SH-SY5Y are the most frequently utilized models in neurodegenerative research, and their use has advanced the understanding of the pathology of neurodegeneration over the past few decades. In Alzheimer's disease (AD), several pathogenic mutations have been described, all of which cause elevated levels of pathological hallmarks such as amyloid-beta (Aβ). Although the genetics of Alzheimer's disease is well known, familial AD only accounts for a small number of cases in the population, with the rest being sporadic AD, which contains no known mutations. Currently, most of the in vitro models used to study AD pathogenesis only examine the level of Aβ42 as a confirmation of successful model generation and only perform comparisons between wild-type APP and single mutants of the APP gene. Recent findings have shown that the Aβ42/40 ratio in cerebrospinal fluid (CSF) is a better diagnostic indicator for AD patients than is Aβ42 alone and that more extensive Aβ formation, such as accumulation of intraneuronal Aβ, Aβ plaques, soluble oligomeric Aβ (oAβ), and insoluble fibrillar Aβ (fAβ) occurs in TgCRND8 mice expressing a double-mutant form (Swedish and Indiana) of APP, later leading to greater progressive impairment of the brain. In this study, we generated SH-SY5Y cells stably transfected separately with wild-type APP, the Swedish mutation of APP, and the Swedish and Indiana mutations of APP and evaluated the APP expression as well as the Aβ42/40 ratio in those cells. The double-mutant form of APP (Swedish/Indiana) expressed markedly high levels of APP protein and showed a high Aβ2/40 ratio compared to wild-type and single-mutant cells.

  8. Structure-Based Peptide Design to Modulate Amyloid Beta Aggregation and Reduce Cytotoxicity.

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    Jitendra Kumar

    Full Text Available The deposition of Aβ peptide in the brain is the key event in Alzheimer disease progression. Therefore, the prevention of Aβ self assembly into disease-associated oligomers is a logical strategy for treatment. π stacking is known to provide structural stability to many amyloids; two phenylalanine residues within the Aβ 14-23 self recognition element are in such an arrangement in many solved structures. Therefore, we targeted this structural stacking by substituting these two phenylalanine residues with their D-enantiomers. The resulting peptides were able to modulate Aβ aggregation in vitro and reduce Aβ cytotoxicity in primary neuronal cultures. Using kinetic analysis of fibril formation, electron microscopy and dynamic light scattering characterization of oligomer size distributions, we demonstrate that, in addition to altering fibril structural characteristics, these peptides can induce the formation of larger amorphous aggregates which are protective against toxic oligomers, possibly because they are able to sequester the toxic oligomers during co-incubation. Alternatively, they may alter the surface structure of the oligomers such that they can no longer interact with cells to induce toxic pathways.

  9. Dual Targeting of Amyloid-beta Clearance and Neuroinflammation as a Novel Therapeutic Approach against Alzheimer's Disease

    Science.gov (United States)

    Batarseh, Yazan S.

    Amyloid-beta (Abeta) cascade hypothesis suggests that Alzheimer's disease (AD) is related to an imbalance between the production and clearance of Abeta peptide. Sporadic AD has been related to faulty clearance of Abeta. Accumulation of Abeta oligomers (Abetao) has been linked to several downstream toxic effects including neuroinflammation, synaptic loss, and cellular death. Abeta transport across the blood-brain barrier (BBB) is one of the primary pathways for reducing Abeta load in the brain, which work hand in hand with other parenchymal mechanisms to reduce Abeta levels including intra and extracellular degradation by a family of Abeta degrading enzymes. Established AD drugs, such as the cholinesterase inhibitor donepezil, have been reported to have several additional non-cholinergic effects that alter Abeta pathology; reduce Abeta load, anti-inflammatory response, and attenuate synaptic loss. However, their limited effect only lead to minor improvements in AD symptoms without improving the prognosis of the disease. The lack of effective medical treatment for AD led to several studies focusing on establishing new therapeutic approaches to reduce Abeta pathology. We aimed to identify and characterize natural products that are capable of enhancing the BBB clearance of Abeta in addition to reducing neuroinflammation. Our first project was to investigate the role of oleocanthal (one of the active ingredients in extra-virgin olive oil; EVOO) on attenuating Abeta toxic effects on neurons and astrocytes. We developed Abeta oligomers (Abetao) induced inflammatory environment by exposing neurons and astrocytes to accumulative doses of Abetao to investigate oleocanthal effect on modulating Abetao pathological changes in neurons and astrocytes. Our findings demonstrated oleocanthal prevented Abetao-induced synaptic proteins, SNAP-25 and PSD-95, down-regulation in neurons, attenuated Abetao-induced inflammation, and restored glutamine transporter (GLT1) and glucose

  10. Amyloid beta 1-42 and phoshorylated tau threonin 231 in brains of aged cynomolgus monkeys (Macaca fascicularis

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    Huda Shalahudin Darusman

    2014-11-01

    Full Text Available Pathological hallmarks indicative of Alzheimer’s disease, which are the plaques of Amyloid Beta 1-42 and neurofibrillary tangles, were found in brain of aged cynomolgus monkey. The aim of the study was to investigate if aged monkeys exhibiting spatial memory impairment and levels of biomarkers indicative of Alzheimer’s disease, had brain lesions similar to human patients suffering from senile dementia. Generating immunohistochemistry technique to biomarkers of Amyloid beta 1-42 and the phosphorylated tau 231, our study assessed the amyloidopathy, such as indicative to the senile plaques and cerebral amyloid angiopathy, and the tauopathy, to possible neurofibrillary tangles. Six aged monkeys were selected based on their spatial memory performance and profile of biomarkers of Alzheimer’s disease, divided equally to affected aged subject - with Memory-affected and low amyloid level, and aged with higher performance in memory and amyloid, as the age-matched subjects. Using immunohistochemistry, plaques of Amyloid Beta 1-42 were observed in two out of three brains of aged subjects with memory impairment and biomarkers indicative of Alzheimer’s disease. The cerebral amyloid angiopathy was observed in both aged monkey groups, and unlike in the human, the amyloids were found to deposit in the small veins and capillaries. In one of the affected individuals, phosphorylated tau was positively stained intracellularly of the neurons, indicating a possibility of an early stage of the formation of tangles. These findings add to the body of evidence of the utility of the aged cynomolgus monkeys as a spontaneous model for Alzheimer-related disease.

  11. The Role of Neutrophil Proteins on the Amyloid Beta-RAGE Axis

    Science.gov (United States)

    Stock, Amanda J.; Kasus-Jacobi, Anne; Wren, Jonathan D.; Sjoelund, Virginie H.; Prestwich, Glenn D.

    2016-01-01

    We previously showed an elevated expression of the neutrophil protein, cationic antimicrobial protein of 37kDa (CAP37), in brains of patients with Alzheimer’s disease (AD), suggesting that CAP37 could be involved in AD pathogenesis. The first step in determining how CAP37 might contribute to AD pathogenesis was to identify the receptor through which it induces cell responses. To identify a putative receptor, we performed GAMMA analysis to determine genes that positively correlated with CAP37 in terms of expression. Positive correlations with ligands for the receptor for advanced glycation end products (RAGE) were observed. Additionally, CAP37 expression positively correlated with two other neutrophil proteins, neutrophil elastase and cathepsin G. Enzyme-linked immunosorbent assays (ELISAs) demonstrated an interaction between CAP37, neutrophil elastase, and cathepsin G with RAGE. Amyloid beta 1–42 (Aβ1–42), a known RAGE ligand, accumulates in AD brains and interacts with RAGE, contributing to Aβ1–42 neurotoxicity. We questioned whether the binding of CAP37, neutrophil elastase and/or cathepsin G to RAGE could interfere with Aβ1–42 binding to RAGE. Using ELISAs, we determined that CAP37 and neutrophil elastase inhibited binding of Aβ1–42 to RAGE, and this effect was reversed by protease inhibitors in the case of neutrophil elastase. Since neutrophil elastase and cathepsin G have enzymatic activity, mass spectrometry was performed to determine the proteolytic activity of all three neutrophil proteins on Aβ1–42. All three neutrophil proteins bound to Aβ1–42 with different affinities and cleaved Aβ1–42 with different kinetics and substrate specificities. We posit that these neutrophil proteins could modulate neurotoxicity in AD by cleaving Aβ1–42 and influencing the Aβ1–42 –RAGE interaction. Further studies will be required to determine the biological significance of these effects and their relevance in neurodegenerative diseases such as

  12. Ginkgo biloba leaf extract reverses amyloid beta-peptide-induced isoprostane production in rat brain in vitro.

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    Brunetti, Luigi; Orlando, Giustino; Menghini, Luigi; Ferrante, Claudio; Chiavaroli, Annalisa; Vacca, Michele

    2006-11-01

    Isoprostanes are prostaglandin (PG) isomers generated from oxygen radical peroxidation of arachidonic acid, which are reliable markers of membrane oxidative damage. Aging is characterized by an imbalance between the generation of reactive oxygen species and antioxidant detoxification pathways. Ginkgo biloba leaf extract is reputed as a neuroprotective antioxidant agent. We have tested the effects of a Ginkgo biloba extract {containing 24.1 % flavonoids and 181 % terpene lactones [bilobalide (0.542 %), ginkgolide A (0.570 %), ginkgolide B (0.293 %), ginkgolide C (0.263 %), and ginkgolide J (0.138 %)]} on the production of 8-iso-PGF2alpha from rat brain synaptosomes obtained from young (3 months old) or aged (12 and 24 months old) rats, both in the basal state and after oxidative stress induced by either hydrogen peroxide or amyloid beta-peptide. Our findings show that Ginkgo biloba extract pretreatment is able to completely reverse both basal and hydrogen peroxide-stimulated isoprostane production (IC50 of 81.92 microM and 31.89 microM, respectively). Amyloid beta-peptide-induced isoprostane production was also inhibited, both in young and aged rats, to a level even lower than that in unstimulated synaptosomes. This suggests that the oxygen radical scavenging properties of the Ginkgo biloba extract are fully effective in young, as well as in old rats, showing a greater inhibition of isoprostane production in the latter.

  13. HIV-1 stimulates nuclear entry of amyloid beta via dynamin dependent EEA1 and TGF-β/Smad signaling

    International Nuclear Information System (INIS)

    András, Ibolya E.; Toborek, Michal

    2014-01-01

    Clinical evidence indicates increased amyloid deposition in HIV-1-infected brains, which contributes to neurocognitive dysfunction in infected patients. Here we show that HIV-1 exposure stimulates amyloid beta (Aβ) nuclear entry in human brain endothelial cells (HBMEC), the main component of the blood–brain barrier (BBB). Treatment with HIV-1 and/or Aβ resulted in concurrent increase in early endosomal antigen-1 (EEA1), Smad, and phosphorylated Smad (pSmad) in nuclear fraction of HBMEC. A series of inhibition and silencing studies indicated that Smad and EEA1 closely interact by influencing their own nuclear entry; the effect that was attenuated by dynasore, a blocker of GTP-ase activity of dynamin. Importantly, inhibition of dynamin, EEA1, or TGF-β/Smad effectively attenuated HIV-1-induced Aβ accumulation in the nuclei of HBMEC. The present study indicates that nuclear uptake of Aβ involves the dynamin-dependent EEA1 and TGF-β/Smad signaling pathways. These results identify potential novel targets to protect against HIV-1-associated dysregulation of amyloid processes at the BBB level. - Highlights: • HIV-1 induces nuclear accumulation of amyloid beta (Aβ) in brain endothelial cells. • EEA-1 and TGF-Β/Smad act in concert to regulate nuclear entry of Aβ. • Dynamin appropriates the EEA-1 and TGF-Β/Smad signaling. • Dynamin serves as a master regulator of HIV-1-induced nuclear accumulation of Aβ

  14. Nasal administration of amyloid-beta peptide decreases cerebral amyloid burden in a mouse model of Alzheimer's disease

    DEFF Research Database (Denmark)

    Weiner, H L; Lemere, C A; Maron, R

    2000-01-01

    Progressive cerebral deposition of amyloid-beta (Abeta) peptide, an early and essential feature of Alzheimer's disease (AD), is accompanied by an inflammatory reaction marked by microgliosis, astrocytosis, and the release of proinflammatory cytokines. Mucosal administration of disease-implicated ......Progressive cerebral deposition of amyloid-beta (Abeta) peptide, an early and essential feature of Alzheimer's disease (AD), is accompanied by an inflammatory reaction marked by microgliosis, astrocytosis, and the release of proinflammatory cytokines. Mucosal administration of disease......-implicated proteins can induce antigen-specific anti-inflammatory immune responses in mucosal lymphoid tissue which then act systemically. We hypothesized that chronic mucosal administration of Abeta peptide might induce an anti-inflammatory process in AD brain tissue that could beneficially affect...... Abeta plaque burden and Abeta42 levels in mice treated intranasally with Abeta peptide versus controls treated with myelin basic protein or left untreated. This lower Abeta burden was associated with decreased local microglial and astrocytic activation, decreased neuritic dystrophy, serum anti...

  15. The Aggregation Potential of the 1-15-and 1-16-Fragments of the Amyloid beta Peptide and Their Influence on the Aggregation of A beta 40

    NARCIS (Netherlands)

    Shabestari, M.; Plug, T.; Motazacker, M. M.; Meeuwenoord, N. J.; Filippov, D. V.; Meijers, J. C. M.; Huber, M.

    2013-01-01

    The aggregation of amyloid beta (A beta) peptide is important in Alzheimer's disease. Shorter A beta fragments may reduce A beta's cytotoxicity and are used in diagnostics. The aggregation of A beta 16 is controversial; Liu et al. (J. Neurosci. Res. 75:162-171, 2004) and Liao et al. (FEBS Lett.

  16. Two distinct β-sheet structures in Italian-mutant amyloid-beta fibrils : a potential link to different clinical phenotypes

    NARCIS (Netherlands)

    Hubin, Ellen; Deroo, Stéphanie; Schierle, Gabriele Kaminksi; Kaminski, Clemens; Serpell, Louise; Subramaniam, Vinod; van Nuland, Nico; Broersen, Kerensa; Raussens, Vincent; Sarroukh, Rabia

    2015-01-01

    Most Alzheimer's disease (AD) cases are late-onset and characterized by the aggregation and deposition of the amyloid-beta (Aβ) peptide in extracellular plaques in the brain. However, a few rare and hereditary Aβ mutations, such as the Italian Glu22-to-Lys (E22K) mutation, guarantee the development

  17. Chronic exposure of NG108-15 cells to amyloid beta peptide (A beta(1-42)) abolishes calcium influx via N-type calcium channels

    Czech Academy of Sciences Publication Activity Database

    Kašparová, Jana; Lisá, Věra; Tuček, Stanislav; Doležal, Vladimír

    2001-01-01

    Roč. 26, 8-9 (2001), s. 1079-1084 ISSN 0364-3190 R&D Projects: GA MZd NF5183 Institutional research plan: CEZ:AV0Z5011922 Keywords : amyloid beta peptide * Alzheimer's disease * calcium Subject RIV: FH - Neurology Impact factor: 1.638, year: 2001

  18. Amyloid Beta and Tau Proteins as Therapeutic Targets for Alzheimer’s Disease Treatment: Rethinking the Current Strategy

    Directory of Open Access Journals (Sweden)

    Siddhartha Mondragón-Rodríguez

    2012-01-01

    Full Text Available Alzheimer’s disease (AD is defined by the concurrence of accumulation of abnormal aggregates composed of two proteins: Amyloid beta (Aβ and tau, and of cellular changes including neurite degeneration and loss of neurons and cognitive functions. Based on their strong association with disease, genetically and pathologically, it is not surprising that there has been a focus towards developing therapies against the aggregated structures. Unfortunately, current therapies have but mild benefit. With this in mind we will focus on the relationship of synaptic plasticity with Aβ and tau protein and their role as potential targets for the development of therapeutic drugs. Finally, we will provide perspectives in developing a multifactorial strategy for AD treatment.

  19. Decreased rhythmic GABAergic septal activity and memory-associated theta oscillations after hippocampal amyloid-beta pathology in the rat.

    Science.gov (United States)

    Villette, Vincent; Poindessous-Jazat, Frédérique; Simon, Axelle; Léna, Clément; Roullot, Elodie; Bellessort, Brice; Epelbaum, Jacques; Dutar, Patrick; Stéphan, Aline

    2010-08-18

    The memory deficits associated with Alzheimer's disease result to a great extent from hippocampal network dysfunction. The coordination of this network relies on theta (symbol) oscillations generated in the medial septum. Here, we investigated in rats the impact of hippocampal amyloid beta (Abeta) injections on the physiological and cognitive functions that depend on the septohippocampal system. Hippocampal Abeta injections progressively impaired behavioral performances, the associated hippocampal theta power, and theta frequency response in a visuospatial recognition test. These alterations were associated with a specific reduction in the firing of the identified rhythmic bursting GABAergic neurons responsible for the propagation of the theta rhythm to the hippocampus, but without loss of medial septal neurons. Such results indicate that hippocampal Abeta treatment leads to a specific functional depression of inhibitory projection neurons of the medial septum, resulting in the functional impairment of the temporal network.

  20. Triptolide Inhibited Cytotoxicity of Differentiated PC12 Cells Induced by Amyloid-Beta25–35 via the Autophagy Pathway

    Science.gov (United States)

    Xu, Pengjuan; Li, Zhigui; Wang, Hui; Zhang, Xiaochen; Yang, Zhuo

    2015-01-01

    Evidence shows that an abnormal deposition of amyloid beta-peptide25–35 (Aβ25–35) was the primary cause of the pathogenesis of Alzheimer’s disease (AD). And the elimination of Aβ25–35 is considered an important target for the treatment of AD. Triptolide (TP), isolated from Tripterygium wilfordii Hook.f. (TWHF), has been shown to possess a broad spectrum of biological profiles, including neurotrophic and neuroprotective effects. In our study investigating the effect and potential mechanism of triptolide on cytotoxicity of differentiated rat pheochromocytoma cell line (the PC12 cell line is often used as a neuronal developmental model) induced by Amyloid-Beta25–35 (Aβ25–35), we used 3-(4, 5-dimethylthiazol-2-yl)-2, 5- diphenyltetrazolium bromide (MTT) assay, flow cytometry, Western blot, and acridine orange staining to detect whether triptolide could inhibit Aβ25–35–induced cell apoptosis. We focused on the potential role of the autophagy pathway in Aβ25–35-treated differentiated PC12 cells. Our experiments show that cell viability is significantly decreased, and the apoptosis increased in Aβ25–35-treated differentiated PC12 cells. Meanwhile, Aβ25–35 treatment increased the expression of microtubule-associated protein light chain 3 II (LC3 II), which indicates an activation of autophagy. However, triptolide could protect differentiated PC12 cells against Aβ25–35-induced cytotoxicity and attenuate Aβ25–35-induced differentiated PC12 cell apoptosis. Triptolide could also suppress the level of autophagy. In order to assess the effect of autophagy on the protective effects of triptolide in differentiated PC12 cells treated with Aβ25–35, we used 3-Methyladenine (3-MA, an autophagy inhibitor) and rapamycin (an autophagy activator). MTT assay showed that 3-MA elevated cell viability compared with the Aβ25–35-treated group and rapamycin inhibits the protection of triptolide. These results suggest that triptolide will repair the

  1. Age-related toxicity of amyloid-beta associated with increased pERK and pCREB in primary hippocampal neurons: reversal by blueberry extract

    Science.gov (United States)

    Brewer, Gregory J.; Torricelli, John R.; Lindsey, Amanda L.; Kunz, Elizabeth Z.; Neuman, A.; Fisher, Derek R.; Joseph, James A.

    2009-01-01

    Further clarification is needed to address the paradox that memory formation, aging and neurodegeneration all involve calcium influx, oxyradical production (ROS) and activation of certain signaling pathways. In aged rats and in APP/PS-1 mice, cognitive and hippocampal Ca2+ dysregulation were reversed by food supplementation with a high antioxidant blueberry extract. Here, we studied whether neurons were an important target of blueberry extract and whether the mechanism involved altered ROS signaling through MAPK and CREB, pathways known to be activated in response to amyloid-beta. Primary hippocampal neurons were isolated and cultured from embryonic, middle-age or old-age (24 months) rats. Blueberry extract was found to be equally neuroprotective against amyloid-beta neurotoxicity at all ages. Increases in amyloid-beta toxicity with age were associated with age-related increases in immunoreactivity of neurons to pERK and an age-independent increase in pCREB. Treatment with blueberry extract strongly inhibited these increases in parallel with neuroprotection. Simultaneous labeling for ROS and for glutathione with dichlorofluorescein and monocholorobimane showed a mechanism of action of blueberry extract to involve transient ROS generation with an increase in the redox buffer, glutathione. We conclude that the increased age-related susceptibility of old-age neurons to amyloid-beta toxicity may be due to higher levels of activation of pERK and pCREB pathways that can be protected by blueberry extract through inhibition of both these pathways through an ROS stress response. These results suggest that the beneficial effects of blueberry extract may involve transient stress signaling and ROS protection that may translate into improved cognition in aging rats and APP/PS1 mice given blueberry extract. PMID:19954954

  2. Docosahexaenoic acid-induced amelioration on impairment of memory learning in amyloid beta-infused rats relates to the decreases of amyloid beta and cholesterol levels in detergent-insoluble membrane fractions.

    Science.gov (United States)

    Hashimoto, Michio; Hossain, Shahdat; Agdul, Haqu; Shido, Osamu

    2005-12-30

    We investigated the effects of dietary administration of docosahexaenoic acid (DHA; C22:6n-3) on the levels of amyloid beta (A beta) peptide (1-40) and cholesterol in the nonionic detergent Triton 100 x-insoluble membrane fractions (DIFs) of the cerebral cortex and, also, on learning-related memory in an animal model of Alzheimer's disease (AD) rats infused with A beta peptide (1-40) into the cerebral ventricle. The infusion increased the levels of A beta peptide and cholesterol in the DIFs concurrently with a significant increase in reference memory errors (measured by eight-arm radial-maze tasks) compared with those of vehicle rats. Conversely, the dietary administration of DHA to AD-model rats decreased the levels of A beta peptide and cholesterol in the DIFs, with the decrease being more prominent in the DHA-administered rats. Regression analysis revealed a significant positive correlation between A beta peptide and each of cholesterol, palmitic acid and stearic acid, and between the number of reference memory errors and each of cholesterol, palmitic, stearic and oleic acid; moreover, a significant negative correlation was observed between the number of reference memory errors and the molar ratio of DHA to palmitic plus stearic acid. These results suggest that DHA-induced protection of memory deficits in AD-model rats is related to the interactions of cholesterol, palmitic acid or stearic acid with A beta peptides in DIFs where DHA ameliorates these interactions.

  3. Acute gamma-secretase inhibition of nonhuman primate CNS shifts amyloid precursor protein (APP) metabolism from amyloid-beta production to alternative APP fragments without amyloid-beta rebound.

    Science.gov (United States)

    Cook, Jacquelynn J; Wildsmith, Kristin R; Gilberto, David B; Holahan, Marie A; Kinney, Gene G; Mathers, Parker D; Michener, Maria S; Price, Eric A; Shearman, Mark S; Simon, Adam J; Wang, Jennifer X; Wu, Guoxin; Yarasheski, Kevin E; Bateman, Randall J

    2010-05-12

    The accumulation of amyloid beta (Abeta) in Alzheimer's disease is caused by an imbalance of production and clearance, which leads to increased soluble Abeta species and extracellular plaque formation in the brain. Multiple Abeta-lowering therapies are currently in development: an important goal is to characterize the molecular mechanisms of action and effects on physiological processing of Abeta, as well as other amyloid precursor protein (APP) metabolites, in models which approximate human Abeta physiology. To this end, we report the translation of the human in vivo stable-isotope-labeling kinetics (SILK) method to a rhesus monkey cisterna magna ported (CMP) nonhuman primate model, and use the model to test the mechanisms of action of a gamma-secretase inhibitor (GSI). A major concern of inhibiting the enzymes which produce Abeta (beta- and gamma-secretase) is that precursors of Abeta may accumulate and cause a rapid increase in Abeta production when enzyme inhibition discontinues. In this study, the GSI MK-0752 was administered to conscious CMP rhesus monkeys in conjunction with in vivo stable-isotope-labeling, and dose-dependently reduced newly generated CNS Abeta. In contrast to systemic Abeta metabolism, CNS Abeta production was not increased after the GSI was cleared. These results indicate that most of the CNS APP was metabolized to products other than Abeta, including C-terminal truncated forms of Abeta: 1-14, 1-15 and 1-16; this demonstrates an alternative degradation pathway for CNS amyloid precursor protein during gamma-secretase inhibition.

  4. Methanolic extract of Piper nigrum fruits improves memory impairment by decreasing brain oxidative stress in amyloid beta(1-42) rat model of Alzheimer's disease.

    Science.gov (United States)

    Hritcu, Lucian; Noumedem, Jaurès A; Cioanca, Oana; Hancianu, Monica; Kuete, Victor; Mihasan, Marius

    2014-04-01

    The present study analyzed the possible memory-enhancing and antioxidant proprieties of the methanolic extract of Piper nigrum L. fruits (50 and 100 mg/kg, orally, for 21 days) in amyloid beta(1-42) rat model of Alzheimer's disease. The memory-enhancing effects of the plant extract were studied by means of in vivo (Y-maze and radial arm-maze tasks) approaches. Also, the antioxidant activity in the hippocampus was assessed using superoxide dismutase-, catalase-, glutathione peroxidase-specific activities and the total content of reduced glutathione, malondialdehyde, and protein carbonyl levels. The amyloid beta(1-42)-treated rats exhibited the following: decrease of spontaneous alternations percentage within Y-maze task and increase of working memory and reference memory errors within radial arm-maze task. Administration of the plant extract significantly improved memory performance and exhibited antioxidant potential. Our results suggest that the plant extract ameliorates amyloid beta(1-42)-induced spatial memory impairment by attenuation of the oxidative stress in the rat hippocampus.

  5. Degradation of amyloid beta by human induced pluripotent stem cell-derived macrophages expressing Neprilysin-2

    Directory of Open Access Journals (Sweden)

    Koutaro Takamatsu

    2014-11-01

    Full Text Available The purpose of this study was to evaluate the therapeutic potential of human induced pluripotent stem (iPS cell-derived macrophage-like cells for Alzheimer's disease (AD. In previous studies, we established the technology to generate macrophage-like myeloid lineage cells with proliferating capacity from human iPS cells, and we designated the cells iPS-ML. iPS-ML reduced the level of Aβ added into the culture medium, and the culture supernatant of iPS-ML alleviated the neurotoxicity of Aβ. We generated iPS-ML expressing the Fc-receptor-fused form of a single chain antibody specific to Aβ. In addition, we made iPS-ML expressing Neprilysin-2 (NEP2, which is a protease with Aβ-degrading activity. In vitro, expression of NEP2 but not anti-Aβ scFv enhanced the effect to reduce the level of soluble Aβ oligomer in the culture medium and to alleviate the neurotoxicity of Aβ. To analyze the effect of iPS-ML expressing NEP2 (iPS-ML/NEP2 in vivo, we intracerebrally administered the iPS-ML/NEP2 to 5XFAD mice, which is a mouse model of AD. We observed significant reduction in the level of Aβ in the brain interstitial fluid following administration of iPS-ML/NEP2. These results suggested that iPS-ML/NEP2 may be a potential therapeutic agent in the treatment of AD.

  6. Acceleration of Amyloidosis by Inflammation in the Amyloid-Beta Marmoset Monkey Model of Alzheimer’s Disease

    Science.gov (United States)

    Philippens, Ingrid H.; Ormel, Paul R.; Baarends, Guus; Johansson, Maja; Remarque, Ed J.; Doverskog, Magnus

    2016-01-01

    Background: The immune system is increasingly mentioned as a potential target for Alzheimer’s disease (AD) treatment. Objective: In the present pilot study, the effect of (neuro)inflammation on amyloidopathy was investigated in the marmoset monkey, which has potential as an AD animal model due to its natural cerebral amyloidosis similar to humans. Methods: Six adult/aged marmosets (Callithrix jacchus) were intracranial injected with amyloid-beta (Aβ) fibrils at three cortical locations in the right hemisphere. Additionally, in half of the monkeys, lipopolysaccharide (LPS) was co-injected with the Aβ fibrils and injected in the other hemisphere without Aβ fibrils. The other three monkeys received phosphate buffered saline instead of LPS, as a control for the inflammatory state. The effect of inflammation on amyloidopathy was also investigated in an additional monkey that suffered from chronic inflammatory wasting syndrome. Mirror histology sections were analyzed to assess amyloidopathy and immune reaction, and peripheral blood for AD biomarker expression. Results: All LPS-injected monkeys showed an early AD immune blood cell expression profile on CD95 and CD45RA. Two out of three monkeys injected with Aβ and LPS and the additional monkey, suffering from chronic inflammation, developed plaques. None of the controls, injected with Aβ only, developed any plaques. Conclusion: This study shows the importance of immune modulation on the susceptibility for amyloidosis, a hallmark of AD, which offers new perspectives for disease modifying approaches in AD. PMID:27662314

  7. Acceleration of Amyloidosis by Inflammation in the Amyloid-Beta Marmoset Monkey Model of Alzheimer's Disease.

    Science.gov (United States)

    Philippens, Ingrid H; Ormel, Paul R; Baarends, Guus; Johansson, Maja; Remarque, Ed J; Doverskog, Magnus

    2017-01-01

    The immune system is increasingly mentioned as a potential target for Alzheimer's disease (AD) treatment. In the present pilot study, the effect of (neuro)inflammation on amyloidopathy was investigated in the marmoset monkey, which has potential as an AD animal model due to its natural cerebral amyloidosis similar to humans. Six adult/aged marmosets (Callithrix jacchus) were intracranial injected with amyloid-beta (Aβ) fibrils at three cortical locations in the right hemisphere. Additionally, in half of the monkeys, lipopolysaccharide (LPS) was co-injected with the Aβ fibrils and injected in the other hemisphere without Aβ fibrils. The other three monkeys received phosphate buffered saline instead of LPS, as a control for the inflammatory state. The effect of inflammation on amyloidopathy was also investigated in an additional monkey that suffered from chronic inflammatory wasting syndrome. Mirror histology sections were analyzed to assess amyloidopathy and immune reaction, and peripheral blood for AD biomarker expression. All LPS-injected monkeys showed an early AD immune blood cell expression profile on CD95 and CD45RA. Two out of three monkeys injected with Aβ and LPS and the additional monkey, suffering from chronic inflammation, developed plaques. None of the controls, injected with Aβ only, developed any plaques. This study shows the importance of immune modulation on the susceptibility for amyloidosis, a hallmark of AD, which offers new perspectives for disease modifying approaches in AD.

  8. Novel neuroprotective function of apical-basal polarity gene crumbs in amyloid beta 42 (aβ42 mediated neurodegeneration.

    Directory of Open Access Journals (Sweden)

    Andrew M Steffensmeier

    Full Text Available Alzheimer's disease (AD, OMIM: 104300, a progressive neurodegenerative disorder with no cure to date, is caused by the generation of amyloid-beta-42 (Aβ42 aggregates that trigger neuronal cell death by unknown mechanism(s. We have developed a transgenic Drosophila eye model where misexpression of human Aβ42 results in AD-like neuropathology in the neural retina. We have identified an apical-basal polarity gene crumbs (crb as a genetic modifier of Aβ42-mediated-neuropathology. Misexpression of Aβ42 caused upregulation of Crb expression, whereas downregulation of Crb either by RNAi or null allele approach rescued the Aβ42-mediated-neurodegeneration. Co-expression of full length Crb with Aβ42 increased severity of Aβ42-mediated-neurodegeneration, due to three fold induction of cell death in comparison to the wild type. Higher Crb levels affect axonal targeting from the retina to the brain. The structure function analysis identified intracellular domain of Crb to be required for Aβ42-mediated-neurodegeneration. We demonstrate a novel neuroprotective role of Crb in Aβ42-mediated-neurodegeneration.

  9. Nanoscale size dependence in the conjugation of amyloid beta and ovalbumin proteins on the surface of gold colloidal particles

    Energy Technology Data Exchange (ETDEWEB)

    Yokoyama, K; Briglio, N M; Hartati, D Sri; Tsang, S M W; MacCormac, J E; Welchons, D R [Department of Chemistry, State University of New York College at Geneseo, One College Circle, Geneseo, NY 14454 (United States)], E-mail: yokoyama@geneseo.edu

    2008-09-17

    Absorption spectroscopy was utilized to investigate the conjugation of amyloid {beta} protein solution (A{beta}{sub 1-40}) and chicken egg albumin (ovalbumin) with various sizes of gold colloidal nanoparticles for various pHs, ranging from pH 2 to pH 10. The pH value that indicates the colour change, pH{sub o}, exhibited colloidal size dependence for both A{beta}{sub 1-40} and ovalbumin coated particles. In particular, A{beta}{sub 1-40} coated gold colloidal particles exhibited non-continuous size dependence peaking at 40 and 80 nm, implying that their corresponding cage-like structures provide efficient net charge cancellation at these core sizes. Remarkably, only the pH{sub o} value for ovalbumin coated 80 nm gold colloid was pH>7, and a specific cage-like structure is speculated to have a positive net charge facing outward when ovalbumin self-assembles over this particular gold colloid. The previously reported reversible colour change between pH 4 and 10 took place only with A{beta}{sub 1-40} coated 20 nm gold colloids; this was also explored with ovalbumin coated gold colloids. Interestingly, gold colloidal nanoparticles showed a quasi-reversible colour change when they were coated with ovalbumin for all test sizes. The ovalbumin coated gold colloid was found to maintain reversible properties longer than A{beta}{sub 1-40} coated gold colloid.

  10. Phosphodiesterase 5 inhibition improves synaptic function, memory, and amyloid-beta load in an Alzheimer's disease mouse model.

    Science.gov (United States)

    Puzzo, Daniela; Staniszewski, Agnieszka; Deng, Shi Xian; Privitera, Lucia; Leznik, Elena; Liu, Shumin; Zhang, Hong; Feng, Yan; Palmeri, Agostino; Landry, Donald W; Arancio, Ottavio

    2009-06-24

    Memory loss, synaptic dysfunction, and accumulation of amyloid beta-peptides (A beta) are major hallmarks of Alzheimer's disease (AD). Downregulation of the nitric oxide/cGMP/cGMP-dependent protein kinase/c-AMP responsive element-binding protein (CREB) cascade has been linked to the synaptic deficits after A beta elevation. Here, we report that the phosphodiesterase 5 inhibitor (PDE5) sildenafil (Viagra), a molecule that enhances phosphorylation of CREB, a molecule involved in memory, through elevation of cGMP levels, is beneficial against the AD phenotype in a mouse model of amyloid deposition. We demonstrate that the inhibitor produces an immediate and long-lasting amelioration of synaptic function, CREB phosphorylation, and memory. This effect is also associated with a long-lasting reduction of A beta levels. Given that side effects of PDE5 inhibitors are widely known and do not preclude their administration to a senile population, these drugs have potential for the treatment of AD and other diseases associated with elevated A beta levels.

  11. Metabolic Characterization of Intact Cells Reveals Intracellular Amyloid Beta but Not Its Precursor Protein to Reduce Mitochondrial Respiration.

    Directory of Open Access Journals (Sweden)

    Patrick M Schaefer

    Full Text Available One hallmark of Alzheimer´s disease are senile plaques consisting of amyloid beta (Aβ, which derives from the processing of the amyloid precursor protein (APP. Mitochondrial dysfunction has been linked to the pathogenesis of Alzheimer´s disease and both Aβ and APP have been reported to affect mitochondrial function in isolated systems. However, in intact cells, considering a physiological localization of APP and Aβ, it is pending what triggers the mitochondrial defect. Thus, the aim of this study was to dissect the impact of APP versus Aβ in inducing mitochondrial alterations with respect to their subcellular localization. We performed an overexpression of APP or beta-site amyloid precursor protein cleaving enzyme 1 (BACE1, increasing APP and Aβ levels or Aβ alone, respectively. Conducting a comprehensive metabolic characterization we demonstrate that only APP overexpression reduced mitochondrial respiration, despite lower extracellular Aβ levels compared to BACE overexpression. Surprisingly, this could be rescued by a gamma secretase inhibitor, oppositionally indicating an Aβ-mediated mitochondrial toxicity. Analyzing Aβ localization revealed that intracellular levels of Aβ and an increased spatial association of APP/Aβ with mitochondria are associated with reduced mitochondrial respiration. Thus, our data provide marked evidence for a prominent role of intracellular Aβ accumulation in Alzheimer´s disease associated mitochondrial dysfunction. Thereby it highlights the importance of the localization of APP processing and intracellular transport as a decisive factor for mitochondrial function, linking two prominent hallmarks of neurodegenerative diseases.

  12. Amyloid Beta Peptides Block New Synapse Assembly by Nogo Receptor-Mediated Inhibition of T-Type Calcium Channels.

    Science.gov (United States)

    Zhao, Yanjun; Sivaji, Sivaprakash; Chiang, Michael C; Ali, Haadi; Zukowski, Monica; Ali, Sareen; Kennedy, Bryan; Sklyar, Alex; Cheng, Alice; Guo, Zihan; Reed, Alexander K; Kodali, Ravindra; Borowski, Jennifer; Frost, Georgia; Beukema, Patrick; Wills, Zachary P

    2017-10-11

    Compelling evidence links amyloid beta (Aβ) peptide accumulation in the brains of Alzheimer's disease (AD) patients with the emergence of learning and memory deficits, yet a clear understanding of the events that drive this synaptic pathology are lacking. We present evidence that neurons exposed to Aβ are unable to form new synapses, resulting in learning deficits in vivo. We demonstrate the Nogo receptor family (NgR1-3) acts as Aβ receptors mediating an inhibition of synapse assembly, plasticity, and learning. Live imaging studies reveal Aβ activates NgRs on the dendritic shaft of neurons, triggering an inhibition of calcium signaling. We define T-type calcium channels as a target of Aβ-NgR signaling, mediating Aβ's inhibitory effects on calcium, synapse assembly, plasticity, and learning. These studies highlight deficits in new synapse assembly as a potential initiator of cognitive pathology in AD, and pinpoint calcium dysregulation mediated by NgRs and T-type channels as key components. VIDEO ABSTRACT. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. Non-fibrillar amyloid-{beta} peptide reduces NMDA-induced neurotoxicity, but not AMPA-induced neurotoxicity

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    Niidome, Tetsuhiro, E-mail: tniidome@pharm.kyoto-u.ac.jp [Department of Neuroscience for Drug Discovery, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501 (Japan); Goto, Yasuaki; Kato, Masaru; Wang, Pi-Lin [Department of Neuroscience for Drug Discovery, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501 (Japan); Goh, Saori; Tanaka, Naoki [Department of Biomolecular Engineering, Kyoto Institute of Technology, Kyoto 606-8585 (Japan); Akaike, Akinori [Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501 (Japan); Kihara, Takeshi; Sugimoto, Hachiro [Department of Neuroscience for Drug Discovery, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501 (Japan)

    2009-09-04

    Amyloid-{beta} peptide (A{beta}) is thought to be linked to the pathogenesis of Alzheimer's disease. Recent studies suggest that A{beta} has important physiological roles in addition to its pathological roles. We recently demonstrated that A{beta}42 protects hippocampal neurons from glutamate-induced neurotoxicity, but the relationship between A{beta}42 assemblies and their neuroprotective effects remains largely unknown. In this study, we prepared non-fibrillar and fibrillar A{beta}42 based on the results of the thioflavin T assay, Western blot analysis, and atomic force microscopy, and examined the effects of non-fibrillar and fibrillar A{beta}42 on glutamate-induced neurotoxicity. Non-fibrillar A{beta}42, but not fibrillar A{beta}42, protected hippocampal neurons from glutamate-induced neurotoxicity. Furthermore, non-fibrillar A{beta}42 decreased both neurotoxicity and increases in the intracellular Ca{sup 2+} concentration induced by N-methyl-D-aspartate (NMDA), but not by {alpha}-amino-3-hydrozy-5-methyl-4-isoxazole propionic acid (AMPA). Our results suggest that non-fibrillar A{beta}42 protects hippocampal neurons from glutamate-induced neurotoxicity through regulation of the NMDA receptor.

  14. Icariin Prevents Amyloid Beta-Induced Apoptosis via the PI3K/Akt Pathway in PC-12 Cells

    Directory of Open Access Journals (Sweden)

    Dongdong Zhang

    2015-01-01

    Full Text Available Icariin is a prenylated flavonol glycoside derived from the Chinese herb Epimedium sagittatum that exerts a variety of pharmacological activities and shows promise in the treatment and prevention of Alzheimer’s disease. In this study, we investigated the neuroprotective effects of icariin against amyloid beta protein fragment 25–35 (Aβ25–35 induced neurotoxicity in cultured rat pheochromocytoma PC12 cells and explored potential underlying mechanisms. Our results showed that icariin dose-dependently increased cell viability and decreased Aβ25–35-induced apoptosis, as assessed by MTT assay and Annexin V/propidium iodide staining, respectively. Results of western blot analysis revealed that the selective phosphatidylinositol 3-kinase (PI3K inhibitor LY294002 suppressed icariin-induced Akt phosphorylation, suggesting that the protective effects of icariin are associated with activation of the PI3K/Akt signaling pathway. LY294002 also blocked the icariin-induced downregulation of proapoptotic factors Bax and caspase-3 and upregulation of antiapoptotic factor Bcl-2 in Aβ25–35-treated PC12 cells. These findings provide further evidence for the clinical efficacy of icariin in the treatment of Alzheimer’s disease.

  15. Computational identification of potential multitarget treatments for ameliorating the adverse effects of amyloid-beta on synaptic plasticity

    Directory of Open Access Journals (Sweden)

    Thomas J. Anastasio

    2014-05-01

    Full Text Available The leading hypothesis on Alzheimer Disease (AD is that it is caused by buildup of the peptide amyloid-beta (Abeta, which initially causes dysregulation of synaptic plasticity and eventually causes destruction of synapses and neurons. Pharmacological efforts to limit Abeta buildup have proven ineffective, and this raises the twin challenges of understanding the adverse effects of Abeta on synapses and of suggesting pharmacological means to prevent it. The purpose of this paper is to initiate a computational approach to understanding the dysregulation by Abeta of synaptic plasticity and to offer suggestions whereby combinations of various chemical compounds could be arrayed against it. This data-driven approach confronts the complexity of synaptic plasticity by representing findings from the literature in a course-grained manner, and focuses on understanding the aggregate behavior of many molecular interactions. The same set of interactions is modeled by two different computer programs, each written using a different programming modality: one imperative, the other declarative. Both programs compute the same results over an extensive test battery, providing an essential crosscheck. Then the imperative program is used for the computationally intensive purpose of determining the effects on the model of every combination of ten different compounds, while the declarative program is used to analyze model behavior using temporal logic. Together these two model implementations offer new insights into the mechanisms by which Abeta dysregulates synaptic plasticity and suggest many drug combinations that potentially may reduce or prevent it.

  16. Mitochondrial Ca2+ overload underlies Abeta oligomers neurotoxicity providing an unexpected mechanism of neuroprotection by NSAIDs.

    Directory of Open Access Journals (Sweden)

    Sara Sanz-Blasco

    Full Text Available Dysregulation of intracellular Ca(2+ homeostasis may underlie amyloid beta peptide (Abeta toxicity in Alzheimer's Disease (AD but the mechanism is unknown. In search for this mechanism we found that Abeta(1-42 oligomers, the assembly state correlating best with cognitive decline in AD, but not Abeta fibrils, induce a massive entry of Ca(2+ in neurons and promote mitochondrial Ca(2+ overload as shown by bioluminescence imaging of targeted aequorin in individual neurons. Abeta oligomers induce also mitochondrial permeability transition, cytochrome c release, apoptosis and cell death. Mitochondrial depolarization prevents mitochondrial Ca(2+ overload, cytochrome c release and cell death. In addition, we found that a series of non-steroidal anti-inflammatory drugs (NSAIDs including salicylate, sulindac sulfide, indomethacin, ibuprofen and R-flurbiprofen depolarize mitochondria and inhibit mitochondrial Ca(2+ overload, cytochrome c release and cell death induced by Abeta oligomers. Our results indicate that i mitochondrial Ca(2+ overload underlies the neurotoxicity induced by Abeta oligomers and ii inhibition of mitochondrial Ca(2+ overload provides a novel mechanism of neuroprotection by NSAIDs against Abeta oligomers and AD.

  17. Genetics Home Reference: neuroblastoma

    Science.gov (United States)

    ... Share: Email Facebook Twitter Home Health Conditions Neuroblastoma Neuroblastoma Printable PDF Open All Close All Enable Javascript to view the expand/collapse boxes. Description Neuroblastoma is a type of cancer that most often ...

  18. Low background and high contrast PET imaging of amyloid-{beta} with [{sup 11}C]AZD2995 and [{sup 11}C]AZD2184 in Alzheimer's disease patients

    Energy Technology Data Exchange (ETDEWEB)

    Forsberg, Anton; Andersson, Jan; Varnaes, Katarina; Halldin, Christer [Karolinska Institutet, Centre for Psychiatry Research, Department of Clinical Neuroscience, Stockholm (Sweden); Jureus, Anders; Swahn, Britt-Marie; Sandell, Johan; Julin, Per; Svensson, Samuel [AstraZeneca Research and Development, Neuroscience Research and Therapy Area, Soedertaelje (Sweden); Cselenyi, Zsolt; Schou, Magnus; Johnstroem, Peter; Farde, Lars [Karolinska Institutet, Centre for Psychiatry Research, Department of Clinical Neuroscience, Stockholm (Sweden); Karolinska Hospital, AstraZeneca Translational Sciences Centre, PET CoE, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm (Sweden); Eriksdotter, Maria; Freund-Levi, Yvonne [Karolinska Institutet, Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Stockholm (Sweden); Karolinska University Hospital, Department of Geriatric Medicine, Stockholm (Sweden); Jeppsson, Fredrik [AstraZeneca Research and Development, Neuroscience Research and Therapy Area, Soedertaelje (Sweden); Karolinska Institutet, Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Stockholm (Sweden)

    2013-04-15

    The aim of this study was to evaluate AZD2995 side by side with AZD2184 as novel PET radioligands for imaging of amyloid-{beta} in Alzheimer's disease (AD). In vitro binding of tritium-labelled AZD2995 and AZD2184 was studied and compared with that of the established amyloid-{beta} PET radioligand PIB. Subsequently, a first-in-human in vivo PET study was performed using [{sup 11}C]AZD2995 and [{sup 11}C]AZD2184 in three healthy control subjects and seven AD patients. AZD2995, AZD2184 and PIB were found to share the same binding site to amyloid-{beta}. [{sup 3}H]AZD2995 had the highest signal-to-background ratio in brain tissue from patients with AD as well as in transgenic mice. However, [{sup 11}C]AZD2184 had superior imaging properties in PET, as shown by larger effect sizes comparing binding potential values in cortical regions of AD patients and healthy controls. Nevertheless, probably due to a lower amount of nonspecific binding, the group separation of the distribution volume ratio values of [{sup 11}C]AZD2995 was greater in areas with lower amyloid-{beta} load, e.g. the hippocampus. Both AZD2995 and AZD2184 detect amyloid-{beta} with high affinity and specificity and also display a lower degree of nonspecific binding than that reported for PIB. Overall [{sup 11}C]AZD2184 seems to be an amyloid-{beta} radioligand with higher uptake and better group separation when compared to [{sup 11}C]AZD2995. However, the very low nonspecific binding of [{sup 11}C]AZD2995 makes this radioligand potentially interesting as a tool to study minute levels of amyloid-{beta}. This sensitivity may be important in investigating, for example, early prodromal stages of AD or in the longitudinal study of a disease modifying therapy. (orig.)

  19. Effects of an amyloid-beta 1-42 oligomers antibody screened from a phage display library in APP/PS1 transgenic mice.

    Science.gov (United States)

    Wang, Jianping; Li, Nan; Ma, Jun; Gu, Zhiqiang; Yu, Lie; Fu, Xiaojie; Liu, Xi; Wang, Jian

    2016-03-15

    We screened anti-Aβ1-42 antibodies from a human Alzheimer's disease (AD) specific single chain variable fragment (scFv) phage display library and assessed their effects in APP/PS1 transgenic mice. Reverse transcription-PCR was used to construct the scFv phage display library, and screening identified 11A5 as an anti-Aβ1-42 antibody. We mixed 11A5 and the monoclonal antibody 6E10 with Aβ1-42 and administered the mixture to Sprague-Dawley rats via intracerebroventricular injection. After 30 days, rats injected with the antibody/Aβ1-42 mixture and those injected with Aβ1-42 alone were tested on the Morris water maze. We also injected 11A5 and 6E10 into APP/PS1 transgenic mice and assessed the concentrations of Aβ in brain and peripheral blood by ELISA at 1-month intervals for 3 months. Finally we evaluated behavior changes in the Morris water maze. Rats injected with Aβ1-42 and mixed antibodies showed better performance in the Morris water maze than did rats injected with Aβ1-42 alone. In APP/PS1 transgenic mice, Aβ concentration was lower in the brains of the antibody-treated group than in the control group, but higher in the peripheral blood. The antibody-treated mice also exhibited improved behavioral performance in the Morris water maze. In conclusion, anti-Aβ1-42 antibodies (11A5) screened from the human scFv antibody phage display library promoted the efflux or clearance of Aβ1-42 and effectively decreased the cerebral Aβ burden in an AD mouse model. Copyright © 2016 Elsevier B.V. All rights reserved.

  20. Reduced amyloidogenic processing of the amyloid beta-protein precursor by the small-molecule Differentiation Inducing Factor-1.

    Science.gov (United States)

    Myre, Michael A; Washicosky, Kevin; Moir, Robert D; Tesco, Giuseppina; Tanzi, Rudolph E; Wasco, Wilma

    2009-04-01

    The detection of cell cycle proteins in Alzheimer's disease (AD) brains may represent an early event leading to neurodegeneration. To identify cell cycle modifiers with anti-Abeta properties, we assessed the effect of Differentiation-Inducing Factor-1 (DIF-1), a unique, small-molecule from Dictyostelium discoideum, on the proteolysis of the amyloid beta-protein precursor (APP) in a variety of different cell types. We show that DIF-1 slows cell cycle progression through G0/G1 that correlates with a reduction in cyclin D1 protein levels. Western blot analysis of DIF-treated cells and conditioned medium revealed decreases in the levels of secreted APP, mature APP, and C-terminal fragments. Assessment of conditioned media by sandwich ELISA showed reduced levels of Abeta40 and Abeta42, also demonstrating that treatment with DIF-1 effectively decreases the ratio of Abeta42 to Abeta40. In addition, DIF-1 significantly diminished APP phosphorylation at residue T668. Interestingly, site-directed mutagenesis of APP residue Thr668 to alanine or glutamic acid abolished the effect of DIF-1 on APP proteolysis and restored secreted levels of Abeta. Finally, DIF-1 prevented the accumulation of APP C-terminal fragments induced by the proteasome inhibitor lactacystin, and calpain inhibitor N-acetyl-leucyl-leucyl-norleucinal (ALLN). Our findings suggest that DIF-1 affects G0/G1-associated amyloidogenic processing of APP by a gamma-secretase-, proteasome- and calpain-insensitive pathway, and that this effect requires the presence of residue Thr668.

  1. Repair of amyloid beta(25-35)-induced memory impairment and synaptic loss by a Kampo formula, Zokumei-to.

    Science.gov (United States)

    Tohda, Chihiro; Tamura, Takayuki; Komatsu, Katsuko

    2003-11-14

    Although Zokumei-to (ZMT), a Kampo formula, has been used for postapopletic sequelae such as paralysis and logopathy, only few studies of this drug have been carried out. We hypothesized that ZMT may affect neuronal plasticity and investigated whether or not this drug is capable of improving learning impairment and synaptic loss observed in patients with Alzheimer's disease (AD). Amyloid beta(25-35) [Abeta(25-35)] (4.7 nmol) was intracerebroventricularly injected into ddY mice (male, 6 weeks old). Fourteen days after the injection, mice were given ZMT extract (500 mg/kg/day) per os for 15 days. In a memory acquisition test, the Abeta(25-35)-injected mice required more time to master this task than did mice in the saline- or reverse peptide Abeta(35-25)-treated groups. ZMT-treated mice shortened escape latencies during trial days 3-5, but not significantly. Three days after the last drug treatment, a retention test was performed. Following ZMT, the number of crossings over a platform was significantly decreased in Abeta(25-35)-injected mice compared with those in the control groups. However, ZMT-treated mice showed complete recovery of this number. Although Abeta(25-35) injection decreased synaptophysin expression in the cerebral cortex and the hippocampus, ZMT treatment significantly increased the level of expression of synaptophysin up to the control level. Donepezil hydrochloride (DNP, 0.5 mg/kg/day, p.o.) clinically used for AD had no effect on memory retention and synaptophysin levels. Abeta(25-35)-induced neuronal loss was not observed in any region of the brain. The present results suggest that memory impairment and synaptic loss in AD patients may be improved by treatment with ZMT, even after such impairment has already progressed.

  2. Phase 2 safety trial targeting amyloid beta production with a gamma-secretase inhibitor in Alzheimer disease.

    Science.gov (United States)

    Fleisher, Adam S; Raman, Rema; Siemers, Eric R; Becerra, Lida; Clark, Christopher M; Dean, Robert A; Farlow, Martin R; Galvin, James E; Peskind, Elaine R; Quinn, Joseph F; Sherzai, Abdullah; Sowell, B Brooke; Aisen, Paul S; Thal, Leon J

    2008-08-01

    To evaluate the safety, tolerability, and amyloid beta (Abeta) response to the gamma-secretase inhibitor LY450139 in Alzheimer disease. Multicenter, randomized, double-blind, dose-escalation, placebo-controlled trial. Community-based clinical research centers. Patients Fifty-one individuals with mild to moderate Alzheimer disease were randomized to receive placebo (n=15) or LY450139 (100 mg [n=22] or 140 mg [n=14]), with 43 completing the treatment phase. Intervention The LY450139 groups received 60 mg/d for 2 weeks, then 100 mg/d for 6 weeks, and then either 100 or 140 mg/d for 6 additional weeks. Primary outcome measures were adverse events, plasma and cerebrospinal fluid Abeta levels, vital signs, electrocardiographic data, and laboratory safety test results. Secondary outcome measures included the Alzheimer's Disease Assessment Scale cognitive subscale and the Alzheimer's Disease Cooperative Study Activities of Daily Living Scale. Group differences were seen in skin and subcutaneous tissue concerns (P=.05), including 3 possible drug rashes and 3 reports of hair color change in the treatment groups. There were 3 adverse event-related discontinuations, including 1 transient bowel obstruction. The plasma Abeta(40) concentration was reduced by 58.2% for the 100-mg group and 64.6% for the 140-mg group (P<.001). No significant reduction was seen in cerebrospinal fluid Abeta levels. No group differences were seen in cognitive or functional measures. LY450139 was generally well tolerated at doses of up to 140 mg/d for 14 weeks, with several findings indicating the need for close clinical monitoring in future studies. Decreases in plasma Abeta concentrations were consistent with inhibition of gamma-secretase. Trial Registration clinicaltrials.gov Identifier: NCT00244322.

  3. Phase II safety trial targeting amyloid beta production with a gamma-secretase inhibitor in Alzheimer's disease

    Science.gov (United States)

    Fleisher, Adam S.; Raman, Rema; Siemers, Eric R.; Becerra, Lida; Clark, Christopher M.; Dean, Robert A; Farlow, Martin R.; Galvin, James E.; Peskind, Elaine R.; Quinn, Joseph F.; Sherzai, Abdullah; Sowell, B. Brooke; Aisen, Paul S.; Thal, Leon J.

    2009-01-01

    Objective Evaluate the safety, tolerability and amyloid beta (Aβ) response to a γ-secretase inhibitor (LY450139) in Alzheimer's disease. Design Multi-center, randomized, double-blind, dose-escalation, placebo-controlled trial. Setting Community based clinical research centers. Participants 51 participants with mild to moderate AD were randomized (placebo=15, 100mg=22, 140mg=14), with 43 completing the treatment phase. Intervention Subjects randomized to LY450139 received 60mg daily for 2 weeks followed by 100mg for 6 weeks, then re-randomized to 100mg or 140mg for 6 additional weeks. Main Outcome Measures Primary outcome measures consisted of adverse events, plasma and cerebrospinal fluid Aβ levels, vital signs, electrocardiogram data, and laboratory safety tests. Secondary outcome measures included the ADAS-cognitive subscale and the ADCS-Activities of Daily Living scale. Results Group differences were seen in “skin and subcutaneous tissue” complaints (p=0.052). These included 3 possible drug rashes and 3 reports of hair color change in the treatment groups. There were 3 adverse-event-related discontinuations, including one report of transient bowel obstruction. Plasma Aβ40 was reduced by 58.2% for the 100mg group and 64.6% for the 140mg group (P<0.001). No significant reduction was seen in CSF Aβ. No group differences were seen in cognitive or functional measures. Conclusions LY450139 was generally well tolerated at doses of up to 140mg taken daily for 14 weeks with several findings indicating the need for close clinical monitoring in future studies. Decreases in plasma Aβ concentrations were consistent with inhibition of γ-secretase. PMID:18695053

  4. Nanoformulated alpha-mangostin ameliorates Alzheimer's disease neuropathology by elevating LDLR expression and accelerating amyloid-beta clearance.

    Science.gov (United States)

    Yao, Lei; Gu, Xiao; Song, Qingxiang; Wang, Xiaolin; Huang, Meng; Hu, Meng; Hou, Lina; Kang, Ting; Chen, Jun; Chen, Hongzhuan; Gao, Xiaoling

    2016-03-28

    Alzheimer's disease (AD), the most common form of dementia, is now representing one of the largest global healthcare challenges. However, an effective therapy is still lacking. Accumulation of amyloid-beta (Aβ) in the brain is supposed to trigger pathogenic cascades that eventually lead to AD. Therefore, Aβ clearance strategy is being actively pursued as a promising disease modifying therapy. Here, we found that α-mangostin (α-M), a polyphenolic xanthone derivative from mangosteen, up-regulated low density lipoprotein receptor (LDLR) expression in microglia and liver cells, and efficiently facilitated Aβ clearance. However, the in vivo application of α-M is limited due to its hydrophobic nature, poor aqueous solubility and stability, and thus low bioavailability and accumulation in the target organs. To overcome this limitation, α-M was encapsulated into the core of poly(ethylene glycol)-poly(l-lactide) (PEG-PLA) nanoparticles [NP(α-M)]. Such nanoencapsulation improved the biodistribution of α-M in both the brain and liver, enhanced the brain clearance of (125)I-radiolabeled Aβ1-42 in an LDLR-dependent manner, reduced Aβ deposition, attenuated neuroinflammatory responses, ameliorated neurologic changes and reversed behavioral deficits in AD model mice. These findings justified the concept that polyphenol-mediated modulation of LDLR expression might serve as a safe and efficient disease-modifying therapy for AD by accelerating Aβ clearance. It also demonstrated the powerful capacity of nanotechnology in modulating the biodistribution behavior of drug to improve its therapeutic efficacy in AD. Copyright © 2016 Elsevier B.V. All rights reserved.

  5. Voluntary Exercise Promotes Glymphatic Clearance of Amyloid Beta and Reduces the Activation of Astrocytes and Microglia in Aged Mice.

    Science.gov (United States)

    He, Xiao-Fei; Liu, Dong-Xu; Zhang, Qun; Liang, Feng-Ying; Dai, Guang-Yan; Zeng, Jin-Sheng; Pei, Zhong; Xu, Guang-Qing; Lan, Yue

    2017-01-01

    Age is characterized by chronic inflammation, leading to synaptic dysfunction and dementia because the clearance of protein waste is reduced. The clearance of proteins depends partly on the permeation of the blood-brain barrier (BBB) or on the exchange of water and soluble contents between the cerebrospinal fluid (CSF) and the interstitial fluid (ISF). A wealth of evidence indicates that physical exercise improves memory and cognition in neurodegenerative diseases during aging, such as Alzheimer's disease (AD), but the influence of physical training on glymphatic clearance, BBB permeability and neuroinflammation remains unclear. In this study, glymphatic clearance and BBB permeability were evaluated in aged mice using in vivo two-photon imaging. The mice performed voluntary wheel running exercise and their water-maze cognition was assessed; the expression of the astrocytic water channel aquaporin 4 (AQP4), astrocyte and microglial activation, and the accumulation of amyloid beta (Aβ) were evaluated with immunofluorescence or an enzyme-linked immunosorbent assay (ELISA); synaptic function was investigated with Thy1 -green fluorescent protein (GFP) transgenic mice and immunofluorescent staining. Voluntary wheel running significantly improved water-maze cognition in the aged mice, accelerated the efficiency of glymphatic clearance, but which did not affect BBB permeability. The numbers of activated astrocytes and microglia decreased, AQP4 expression increased, and the distribution of astrocytic AQP4 was rearranged. Aβ accumulation decreased, whereas dendrites, dendritic spines and postsynaptic density protein (PSD95) increased. Our study suggests that voluntary wheel running accelerated glymphatic clearance but not BBB permeation, improved astrocytic AQP4 expression and polarization, attenuated the accumulation of amyloid plaques and neuroinflammation, and ultimately protected mice against synaptic dysfunction and a decline in spatial cognition. These data suggest

  6. Voluntary Exercise Promotes Glymphatic Clearance of Amyloid Beta and Reduces the Activation of Astrocytes and Microglia in Aged Mice

    Directory of Open Access Journals (Sweden)

    Xiao-fei He

    2017-05-01

    Full Text Available Age is characterized by chronic inflammation, leading to synaptic dysfunction and dementia because the clearance of protein waste is reduced. The clearance of proteins depends partly on the permeation of the blood–brain barrier (BBB or on the exchange of water and soluble contents between the cerebrospinal fluid (CSF and the interstitial fluid (ISF. A wealth of evidence indicates that physical exercise improves memory and cognition in neurodegenerative diseases during aging, such as Alzheimer’s disease (AD, but the influence of physical training on glymphatic clearance, BBB permeability and neuroinflammation remains unclear. In this study, glymphatic clearance and BBB permeability were evaluated in aged mice using in vivo two-photon imaging. The mice performed voluntary wheel running exercise and their water-maze cognition was assessed; the expression of the astrocytic water channel aquaporin 4 (AQP4, astrocyte and microglial activation, and the accumulation of amyloid beta (Aβ were evaluated with immunofluorescence or an enzyme-linked immunosorbent assay (ELISA; synaptic function was investigated with Thy1–green fluorescent protein (GFP transgenic mice and immunofluorescent staining. Voluntary wheel running significantly improved water-maze cognition in the aged mice, accelerated the efficiency of glymphatic clearance, but which did not affect BBB permeability. The numbers of activated astrocytes and microglia decreased, AQP4 expression increased, and the distribution of astrocytic AQP4 was rearranged. Aβ accumulation decreased, whereas dendrites, dendritic spines and postsynaptic density protein (PSD95 increased. Our study suggests that voluntary wheel running accelerated glymphatic clearance but not BBB permeation, improved astrocytic AQP4 expression and polarization, attenuated the accumulation of amyloid plaques and neuroinflammation, and ultimately protected mice against synaptic dysfunction and a decline in spatial cognition

  7. Cortical Amyloid Beta in Cognitively Normal Elderly Adults is Associated with Decreased Network Efficiency within the Cerebro-Cerebellar System.

    Science.gov (United States)

    Steininger, Stefanie C; Liu, Xinyang; Gietl, Anton; Wyss, Michael; Schreiner, Simon; Gruber, Esmeralda; Treyer, Valerie; Kälin, Andrea; Leh, Sandra; Buck, Alfred; Nitsch, Roger M; Prüssmann, Klaas P; Hock, Christoph; Unschuld, Paul G

    2014-01-01

    Deposition of cortical amyloid beta (Aβ) is a correlate of aging and a risk factor for Alzheimer disease (AD). While several higher order cognitive processes involve functional interactions between cortex and cerebellum, this study aims to investigate effects of cortical Aβ deposition on coupling within the cerebro-cerebellar system. We included 15 healthy elderly subjects with normal cognitive performance as assessed by neuropsychological testing. Cortical Aβ was quantified using (11)carbon-labeled Pittsburgh compound B positron-emission-tomography late frame signals. Volumes of brain structures were assessed by applying an automated parcelation algorithm to three dimensional magnetization-prepared rapid gradient-echo T1-weighted images. Basal functional network activity within the cerebro-cerebellar system was assessed using blood-oxygen-level dependent resting state functional magnetic resonance imaging at the high field strength of 7 T for measuring coupling between cerebellar seeds and cerebral gray matter. A bivariate regression approach was applied for identification of brain regions with significant effects of individual cortical Aβ load on coupling. Consistent with earlier reports, a significant degree of positive and negative coupling could be observed between cerebellar seeds and cerebral voxels. Significant positive effects of cortical Aβ load on cerebro-cerebellar coupling resulted for cerebral brain regions located in inferior temporal lobe, prefrontal cortex, hippocampus, parahippocampal gyrus, and thalamus. Our findings indicate that brain amyloidosis in cognitively normal elderly subjects is associated with decreased network efficiency within the cerebro-cerebellar system. While the identified cerebral regions are consistent with established patterns of increased sensitivity for Aβ-associated neurodegeneration, additional studies are needed to elucidate the relationship between dysfunction of the cerebro-cerebellar system and risk for AD.

  8. Cerebrospinal Fluid Amyloid Beta and Tau Concentrations Are Not Modulated by 16 Weeks of Moderate- to High-Intensity Physical Exercise in Patients with Alzheimer Disease

    DEFF Research Database (Denmark)

    Jensen, Camilla Steen; Portelius, Erik; Siersma, Volkert

    2016-01-01

    Background: Physical exercise may have some effect on cognition in patients with Alzheimer disease (AD). However, the underlying biochemical effects are unclear. Animal studies have shown that amyloid beta (Aβ), one of the pathological hallmarks of AD, can be altered with high levels of physical...... of Life, Physical Health and Functional Ability in Alzheimer's Disease: The Effect of Physical Exercise (ADEX) study we analyzed cerebrospinal fluid samples for Aβ species, total tau (t-tau), phosphorylated tau (p-tau) and soluble amyloid precursor protein (sAPP) species. We also assessed the patients...

  9. Chemokines, macrophage inflammatory protein-2 and stromal cell-derived factor-1{alpha}, suppress amyloid {beta}-induced neurotoxicity

    Energy Technology Data Exchange (ETDEWEB)

    Raman, Dayanidhi; Milatovic, Snjezana-Zaja [Department of Cancer Biology, Vanderbilt University, School of Medicine, Nashville, TN 37232 (United States); Milatovic, Dejan [Department of Pediatrics/Pediatric Toxicology, Vanderbilt University, School of Medicine, Nashville, TN 37232 (United States); Splittgerber, Ryan [Department of Cancer Biology, Vanderbilt University, School of Medicine, Nashville, TN 37232 (United States); Fan, Guo-Huang [Department of Neurobiology and Neurotoxicology, Meharry Medical College, Nashville, TN 37221 (United States); Richmond, Ann, E-mail: ann.richmond@vanderbilt.edu [VA Medical Center, Nashville, TN 37232 (United States); Department of Cancer Biology, Vanderbilt University, School of Medicine, Nashville, TN 37232 (United States)

    2011-11-15

    Alzheimer's disease (AD) is characterized by a progressive cognitive decline and accumulation of neurotoxic oligomeric peptides amyloid-{beta} (A{beta}). Although the molecular events are not entirely known, it has become evident that inflammation, environmental and other risk factors may play a causal, disruptive and/or protective role in the development of AD. The present study investigated the ability of the chemokines, macrophage inflammatory protein-2 (MIP-2) and stromal cell-derived factor-1{alpha} (SDF-1{alpha}), the respective ligands for chemokine receptors CXCR2 and CXCR4, to suppress A{beta}-induced neurotoxicity in vitro and in vivo. Pretreatment with MIP-2 or SDF-1{alpha} significantly protected neurons from A{beta}-induced dendritic regression and apoptosis in vitro through activation of Akt, ERK1/2 and maintenance of metalloproteinase ADAM17 especially with SDF-1{alpha}. Intra-cerebroventricular (ICV) injection of A{beta} led to reduction in dendritic length and spine density of pyramidal neurons in the CA1 area of the hippocampus and increased oxidative damage 24 h following the exposure. The A{beta}-induced morphometric changes of neurons and increase in biomarkers of oxidative damage, F{sub 2}-isoprostanes, were significantly inhibited by pretreatment with the chemokines MIP-2 or SDF-1{alpha}. Additionally, MIP-2 or SDF-1{alpha} was able to suppress the aberrant mislocalization of p21-activated kinase (PAK), one of the proteins involved in the maintenance of dendritic spines. Furthermore, MIP-2 also protected neurons against A{beta} neurotoxicity in CXCR2-/- mice, potentially through observed up regulation of CXCR1 mRNA. Understanding the neuroprotective potential of chemokines is crucial in defining the role for their employment during the early stages of neurodegeneration. -- Research highlights: Black-Right-Pointing-Pointer Neuroprotective ability of the chemokines MIP2 and CXCL12 against A{beta} toxicity. Black-Right-Pointing-Pointer MIP

  10. 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)

  11. 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

  12. SDS-PAGE analysis of Aβ oligomers is disserving research into Alzheimer´s disease: appealing for ESI-IM-MS

    Science.gov (United States)

    Pujol-Pina, Rosa; Vilaprinyó-Pascual, Sílvia; Mazzucato, Roberta; Arcella, Annalisa; Vilaseca, Marta; Orozco, Modesto; Carulla, Natàlia

    2015-10-01

    The characterization of amyloid-beta peptide (Aβ) oligomer forms and structures is crucial to the advancement in the field of Alzheimer´s disease (AD). Here we report a critical evaluation of two methods used for this purpose, namely sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), extensively used in the field, and ion mobility coupled to electrospray ionization mass spectrometry (ESI-IM-MS), an emerging technique with great potential for oligomer characterization. To evaluate their performance, we first obtained pure cross-linked Aβ40 and Aβ42 oligomers of well-defined order. Analysis of these samples by SDS-PAGE revealed that SDS affects the oligomerization state of Aβ42 oligomers, thus providing flawed information on their order and distribution. In contrast, ESI-IM-MS provided accurate information, while also reported on the chemical nature and on the structure of the oligomers. Our findings have important implications as they challenge scientific paradigms in the AD field built upon SDS-PAGE characterization of Aβ oligomer samples.

  13. The soluble transcobalamin receptor (sCD320) is present in cerebrospinal fluid and correlates to dementia-related biomarkers tau proteins and amyloid-beta

    DEFF Research Database (Denmark)

    Abuyaman, Omar; Nexo, Ebba

    2015-01-01

    BACKGROUND: Cellular uptake of vitamin B12 (B12) demands binding of the vitamin to transcobalamin (TC) and recognition of TC-B12 (holoTC) by the receptor CD320. Recently, we identified a soluble form of CD320 (sCD320) in human plasma. Here we present data on the occurrence of this soluble receptor...... phospho-tau (181P) (p-tau), total tau (t-tau) and amyloid-beta 1-42 (Aβ) (n = 177) employing commercial ELISA kits (Innogenetics Company). Size exclusion chromatography was performed on a Superdex 200 column. RESULTS: The median sCD320 concentration in CSF (14 pmol/L) is around five times lower than...

  14. Poor Memory Performance in Aged Cynomolgus Monkeys with Hippocampal Atrophy, Depletion of Amyloid Beta 1-42 and Accumulation of Tau Proteins in Cerebrospinal Fluid

    DEFF Research Database (Denmark)

    Darusman, Huda S; Pandelaki, Jacub; Mulyadi, Rahmad

    2014-01-01

    , aged cynomolgus monkeys were divided into two groups to compare high-performing (n=6) and low-performing (n=6) subjects. Both groups were tested for biomarkers related to Alzheimer's disease and their brains were scanned using structural magnetic resonance imaging. RESULTS: The subjects with poor DRT......BACKGROUND: Due to their similarities in behavior and disease pathology to humans, non-human primate models are desirable to complement small animals as models for the study of age-related dementia. MATERIALS AND METHODS: Based on their performance on delayed response task (DRT) tests of memory...... performance had evidence of atrophy in the hippocampus and cortical areas, significantly lower cerebrospinal fluid levels of amyloid beta amino acid 1-42 (pmemory...

  15. Amyloid-beta (25-35) peptide induces the release of pro-matrix metalloprotease 9 (pro-MMP-9) from human neutrophils.

    Science.gov (United States)

    Achilli, Cesare; Ciana, Annarita; Minetti, Giampaolo

    2014-12-01

    Alzheimer's disease (AD) is a degenerative process of the brain, leading to increasing impairment of cognitive functions, and is associated with accumulation in the brain of several amyloid-beta (Aβ) peptides (as amyloid plaques), including Aβ25-35. Neutrophils, the most abundant immune cell type infiltrated in the brain of AD patients, accumulate behind amyloid plaques. Aβ peptides can trigger activation of chemotaxis and oxidative burst in neutrophils, suggesting a role in modulating the neuroinflammation process. We have shown that Aβ25-35 can induce the release from human neutrophils of pro-MMP-9, a metalloprotease involved in the onset of inflammation, corroborating the hypothesis of the involvement of infiltrated neutrophils in the inflammatory processes, which occur in the AD brain.

  16. Antibody responses, amyloid-beta peptide remnants and clinical effects of AN-1792 immunization in patients with AD in an interrupted trial.

    Science.gov (United States)

    Kokjohn, Tyler A; Roher, Alex E

    2009-04-01

    Post mortem examinations of AN-1792-vaccinated humans revealed this therapy produced focal senile plaque disruption. Despite the dispersal of substantial plaque material, vaccination did not constitute even a partial eradication of brain amyloid as water soluble amyloid-beta (Abeta) 40/42 increased in the gray matter compared to sporadic Alzheimer's disease (AD) patients and total brain Abeta levels were not decreased. Significant aspects of AD pathology were unaffected by vaccination with both vascular amyloid and hyper-phosphorylated tau deposits appeared refractory to this therapy. In addition, vaccination resulted in the consequential and drastic expansion of the white matter (WM) amyloid pool to levels without precedent in sporadic AD patients. Although vaccination disrupted amyloid plaques, this therapy did not enhance long-term cognitive function or necessarily halt neurodegeneration. The intricate involvement of vascular pathology in AD evolution and the firm recalcitrance of vessel-associated amyloid to antibody-mediated disruption suggest that immunization therapies might be more effective if administered on a prophylactic basis before vascular impairment and well ahead of any clinically evident cognitive decline. Amyloid-beta is viewed as pathological based on the postmortem correlation of senile plaques with an AD diagnosis. It remains uncertain which of the various forms of this peptide is the most toxic and whether Abeta or senile plaques themselves serve any desirable or protective functions. The long-term cognitive effects of chronic immunotherapy producing a steadily accumulating and effectively permanent pool of disrupted Abeta peptides within the human brain are unknown. In addition, the side effects of such therapy provided on a chronic basis could extend far beyond the brain. Eagerly seeking new therapies, critical knowledge gaps should prompt us to take a more wholistic perspective viewing Abeta and the amyloid cascade as aspects of complex

  17. Thermodynamically stable amyloid-β monomers have much lower membrane affinity than the small oligomers

    Directory of Open Access Journals (Sweden)

    Bidyut eSarkar

    2013-04-01

    Full Text Available Amyloid beta (Aβ is an extracellular 39-43 residue long peptide present in the mammalian cerebrospinal fluid, whose aggregation is associated with Alzheimer’s disease. Small oligomers of Aβ are currently thought to be the key to toxicity. However, it is not clear why the monomers of Aβ are non-toxic, and at what stage of aggregation toxicity emerges. Interactions of Aβ with cell membranes is thought to be the initiator of toxicity, but membrane-binding studies with different preparations of monomers and oligomers have not settled this issue. We have earlier found that thermodynamically stable Aβ monomers emerge spontaneously from oligomeric mixtures upon long term incubation in physiological solutions (Nag et al, JBC, 2011. Here we show that the membrane-affinity of these stable Aβ monomers is much lower than that of a mixture of small oligomers (containing dimers to decamers, providing a clue to the emergence of toxicity. Fluorescently labeled Aβ40 monomers show negligible binding to cell membranes of a neuronal cell line (RN46A at physiological concentrations (250 nM, while oligomers at the same concentrations show strong binding within 30 minutes of incubation. The increased affinity most likely does not require any specific neuronal receptor, since this difference in membrane-affinity was also observed in a somatic cell-line (HEK 293T. Similar results are also obtained for Aβ42 monomers and oligomers. Minimal amount of cell death is observed at these concentrations even after 36 hours of incubation. It is likely that membrane binding precedes subsequent slower toxic events induced by Aβ. Our results a provide an explanation for the non-toxic nature of Aβ monomers, b suggest that Aβ toxicity emerges at the initial oligomeric phase, and c provide a quick assay for monitoring the benign-to-toxic transformation of Aβ.

  18. Natural amyloid-β oligomers acutely impair the formation of a contextual fear memory in mice.

    Science.gov (United States)

    Kittelberger, Kara A; Piazza, Fabrizio; Tesco, Giuseppina; Reijmers, Leon G

    2012-01-01

    Memory loss is one of the hallmark symptoms of Alzheimer's disease (AD). It has been proposed that soluble amyloid-beta (Abeta) oligomers acutely impair neuronal function and thereby memory. We here report that natural Abeta oligomers acutely impair contextual fear memory in mice. A natural Abeta oligomer solution containing Abeta monomers, dimers, trimers, and tetramers was derived from the conditioned medium of 7PA2 cells, a cell line that expresses human amyloid precursor protein containing the Val717Phe familial AD mutation. As a control we used 7PA2 conditioned medium from which Abeta oligomers were removed through immunodepletion. Separate groups of mice were injected with Abeta and control solutions through a cannula into the lateral brain ventricle, and subjected to fear conditioning using two tone-shock pairings. One day after fear conditioning, mice were tested for contextual fear memory and tone fear memory in separate retrieval trials. Three experiments were performed. For experiment 1, mice were injected three times: 1 hour before and 3 hours after fear conditioning, and 1 hour before context retrieval. For experiments 2 and 3, mice were injected a single time at 1 hour and 2 hours before fear conditioning respectively. In all three experiments there was no effect on tone fear memory. Injection of Abeta 1 hour before fear conditioning, but not 2 hours before fear conditioning, impaired the formation of a contextual fear memory. In future studies, the acute effect of natural Abeta oligomers on contextual fear memory can be used to identify potential mechanisms and treatments of AD associated memory loss.

  19. Natural amyloid-β oligomers acutely impair the formation of a contextual fear memory in mice.

    Directory of Open Access Journals (Sweden)

    Kara A Kittelberger

    Full Text Available Memory loss is one of the hallmark symptoms of Alzheimer's disease (AD. It has been proposed that soluble amyloid-beta (Abeta oligomers acutely impair neuronal function and thereby memory. We here report that natural Abeta oligomers acutely impair contextual fear memory in mice. A natural Abeta oligomer solution containing Abeta monomers, dimers, trimers, and tetramers was derived from the conditioned medium of 7PA2 cells, a cell line that expresses human amyloid precursor protein containing the Val717Phe familial AD mutation. As a control we used 7PA2 conditioned medium from which Abeta oligomers were removed through immunodepletion. Separate groups of mice were injected with Abeta and control solutions through a cannula into the lateral brain ventricle, and subjected to fear conditioning using two tone-shock pairings. One day after fear conditioning, mice were tested for contextual fear memory and tone fear memory in separate retrieval trials. Three experiments were performed. For experiment 1, mice were injected three times: 1 hour before and 3 hours after fear conditioning, and 1 hour before context retrieval. For experiments 2 and 3, mice were injected a single time at 1 hour and 2 hours before fear conditioning respectively. In all three experiments there was no effect on tone fear memory. Injection of Abeta 1 hour before fear conditioning, but not 2 hours before fear conditioning, impaired the formation of a contextual fear memory. In future studies, the acute effect of natural Abeta oligomers on contextual fear memory can be used to identify potential mechanisms and treatments of AD associated memory loss.

  20. Neuroblastoma: A neurochemical approach

    International Nuclear Information System (INIS)

    Schor, N.F.

    1991-01-01

    Neuroblastoma is among the most common malignancies of childhood. Despite greatly improved therapy for some pediatric tumors, the prognosis for children with metastatic neuroblastoma has not changed significantly in the past 10 years. With conventional chemotherapy, radiation therapy, and surgery, children with metastatic neuroblastoma have a 20% long-term survival rate. The authors describe here approaches to neuroblastoma that target its neuronal characteristics. On the one hand, the neurotransmitter receptors on the surface of the neuroblastoma cells and, on the other hand, specific isozymes that distinguish neuroblastoma cells from their normal counterparts are the focus of these experimental therapies. In the former case, specificity for tumor cells is effected by (1) selective protection of normal neuronal elements from toxicity, or (2) selective potentiation of toxicity for neural tumor cells. It is hoped that these strategies will be generalizable to other neural crest-derived tumors. 32 references

  1. 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

  2. CD147 is a regulatory subunit of the gamma-secretase complex inAlzheimer's disease amyloid beta-peptide production

    Energy Technology Data Exchange (ETDEWEB)

    Zhou, Shuxia; Zhou, Hua; Walian, Peter J.; Jap, Bing K.

    2005-04-06

    {gamma}-secretase is a membrane protein complex that cleaves the {beta}-amyloid precursor protein (APP) within the transmembrane region, following prior processing by {beta}-secretase, producing amyloid {beta}-peptides (A{beta}{sub 40} and A{beta}{sub 42}). Errant production of A{beta}-peptides that substantially increases A{beta}{sub 42} production has been associated with the formation of amyloid plaques in Alzheimer's disease patients. Biophysical and genetic studies indicate that presenilin-1 (Psn-1), which contains the proteolytic active site, and three other membrane proteins, nicastrin (Nct), APH-1, and PEN-2 are required to form the core of the active {gamma}-secretase complex. Here, we report the purification of the native {gamma}-secretase complexes from HeLa cell membranes and the identification of an additional {gamma}-secretase complex subunit, CD147, a transmembrane glycoprotein with two immunoglobulin-like domains. The presence of this subunit as an integral part of the complex itself was confirmed through co-immunoprecipitation studies of the purified protein from HeLa cells and solubilized complexes from other cell lines such as neural cell HCN-1A and HEK293. Depletion of CD147 by RNA interference was found to increase the production of A{beta} peptides without changing the expression level of the other {gamma}-secretase components or APP substrates while CD147 overexpression had no statistically significant effect on amyloid {beta}-peptide production, other {gamma}-secretase components or APP substrates, indicating that the presence of the CD147 subunit within the {gamma}-secretase complex directly down-modulates the production of A{beta}-peptides. {gamma}-secretase was first recognized through its role in the production of the A{beta} peptides that are pathogenic in Alzheimer's disease (AD) (1). {gamma}-secretase is a membrane protein complex with unusual aspartyl protease activity that cleaves a variety of type I membrane proteins

  3. Pelargonidin Improves Passive Avoidance Task Performance in a Rat Amyloid Beta25-35 Model of Alzheimer’s Disease Via Estrogen Receptor Independent Pathways

    Directory of Open Access Journals (Sweden)

    Hamid Sohanaki

    2016-05-01

    Full Text Available Alzheimer’s disease (AD is a disorder with multiple pathophysiological causes, destructive outcomes, and no available definitive cure. Pelargonidin (Pel, an anthocyanin derivative, is an estrogen receptor agonist with little estrogen side effects. This study was designed to assess Pel memory enhancing effects on the a rat Amyloid Beta25-35 (Aβ intrahippocampal microinjections model of AD in the passive avoidance task performance paradigm and further evaluate the potential estrogen receptor role on the memory-evoking compound. Equally divided rats were assigned to 5 groups of sham, Aβ intrahippocampal microinjected, Pel pretreated (10 mg/kg; P.O, α estrogen antagonist intra-cerebrovascular (i.c.v. microinjected, and β estrogen antagonist (i.c.v microinjected animals. Intrahippocampal microinjections of Aβ were adopted to provoke AD model. Passive avoidance task test was also used to assess memory performance. Pel pretreatment prior to Aβ microinjections significantly improved step-through latency (P<0.001 in passive avoidance test. In α and β estrogen, antagonists received animals, passive avoidance task performance was not statistically changed (P=0.11 & P=0.41 respectively compared to Pel pretreated and sham animals. Our results depicted that Pel improves Aβ induced memory dysfunction in passive avoidance test performance through estrogen receptor independently related pathways.

  4. Aniracetam restores the effects of amyloid-beta protein or ageing on membrane fluidity and intracellular calcium concentration in mice synaptosomes.

    Science.gov (United States)

    Li, Y; Wang, J-J; Cai, J-X

    2007-01-01

    In the present study, we observed the in vitro effect of aniracetam on membrane fluidity and free calcium concentrations ([Ca(2+)]i) of frontal cortical (FC) and hippocampal (HP) synaptosomes of aged mice and young mice treated with amyloid-beta protein (Abeta) Membrane fluidity was measured by using fluorescence anisotropy of the lipophilic probe, 1,6-diphenyl-1,3,5-hexatriene (DPH). [Ca(2+)]i was measured by using Fura 2-AM fluorescent spectrophotometry. We found that membrane fluidity of the FC and HP synaptosomes was decreased in 14 months old mice compared with that in 3 months old mice. Similarly, Abeta25-35 (1 microM) decreased the membrane fluidity in 3 months old mice. These effects of ageing and Abeta25-35 on membrane fluidity were restored by aniracetam in a concentration-dependent manner. Furthermore, Abeta25-35 (1 microM) largely increased [Ca(2+)]i in FC and HP synaptosomes in 3 months old mice, but this effect on HP synaptosomes was effectively reversed by aniracetam (1-4 mM). The present findings suggest that aniracetam restores age- and Abeta-induced alterations in membrane fluidity or Abeta-induced increase in [Ca(2+)]i, demonstrating a possible beneficial role of aniracetam in the clinic treatment for senile dementia or Alzheimer's disease.

  5. Amyloid beta and the longest-lived rodent: the naked mole-rat as a model for natural protection from Alzheimer's disease.

    Science.gov (United States)

    Edrey, Yael H; Medina, David X; Gaczynska, Maria; Osmulski, Pawel A; Oddo, Salvatore; Caccamo, Antonella; Buffenstein, Rochelle

    2013-10-01

    Amyloid beta (Aβ) is implicated in Alzheimer's disease (AD) as an integral component of both neural toxicity and plaque formation. Brains of the longest-lived rodents, naked mole-rats (NMRs) approximately 32 years of age, had levels of Aβ similar to those of the 3xTg-AD mouse model of AD. Interestingly, there was no evidence of extracellular plaques, nor was there an age-related increase in Aβ levels in the individuals examined (2-20+ years). The NMR Aβ peptide showed greater homology to the human sequence than to the mouse sequence, differing by only 1 amino acid from the former. This subtle difference led to interspecies differences in aggregation propensity but not neurotoxicity; NMR Aβ was less prone to aggregation than human Aβ. Nevertheless, both NMR and human Aβ were equally toxic to mouse hippocampal neurons, suggesting that Aβ neurotoxicity and aggregation properties were not coupled. Understanding how NMRs acquire and tolerate high levels of Aβ with no plaque formation could provide useful insights into AD, and may elucidate protective mechanisms that delay AD progression. Copyright © 2013 Elsevier Inc. All rights reserved.

  6. Effects of breviscapine on amyloid beta 1-42 induced Alzheimer's disease mice: A HPLC-QTOF-MS based plasma metabonomics study.

    Science.gov (United States)

    Xia, Hongjun; Wu, Lingling; Chu, Mengying; Feng, Huimin; Lu, Chunliang; Wang, Qinghe; He, Minghai; Ge, Xiaoqun

    2017-07-01

    Herba Erigerontis has long been used to cure apoplexy hemiplegia and precordial pain in China. In addition, the bioactivities of its total flavonoids-breviscapine included inhibiting amyloid beta (Aβ) fibril formation, antioxidation and metal chelating, which are beneficial to treat Alzheimer's disease (AD). Hence, A HPLC-QTOF-MS based plasma metabonomics approach was applied to investigate the neuroprotective effects of breviscapine on intracerebroventricular injection of aggregated Aβ 1-42 induced AD mice for the first time in the study. Ten potential biomarkers were screened out by multivariate statistical analysis, eight of which were further identified as indoleacrylic acid, C16 sphinganine, LPE (22:6), sulfolithocholic acid, LPC (16:0), PA (22:1/0:0), taurodeoxycholic acid, and PC (0:0/18:0). According to their metabolic pathways, it was supposed that breviscapine ameliorated the learning and memory deficits of AD mice predominantly by regulating phospholipids metabolism, elevating serotonin level and lowering cholesterols content in vivo. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Antiamnesic Effect of Broccoli (Brassica oleracea var. italica) Leaves on Amyloid Beta (Aβ)1-42-Induced Learning and Memory Impairment.

    Science.gov (United States)

    Park, Seon Kyeong; Ha, Jeong Su; Kim, Jong Min; Kang, Jin Yong; Lee, Du Sang; Guo, Tian Jiao; Lee, Uk; Kim, Dae-Ok; Heo, Ho Jin

    2016-05-04

    To examine the antiamnesic effects of broccoli (Brassica oleracea var. italica) leaves, we performed in vitro and in vivo tests on amyloid beta (Aβ)-induced neurotoxicity. The chloroform fraction from broccoli leaves (CBL) showed a remarkable neuronal cell-protective effect and an inhibition against acetylcholinesterase (AChE). The ameliorating effect of CBL on Aβ1-42-induced learning and memory impairment was evaluated by Y-maze, passive avoidance, and Morris water maze tests. The results indicated improving cognitive function in the CBL group. After the behavioral tests, antioxidant effects were detected by superoxide dismutase (SOD), oxidized glutathione (GSH)/total GSH, and malondialdehyde (MDA) assays, and inhibition against AChE was also presented in the brain. Finally, oxo-dihydroxy-octadecenoic acid (oxo-DHODE) and trihydroxy-octadecenoic acid (THODE) as main compounds were identified by quadrupole time-of-flight ultraperformance liquid chromatography (Q-TOF UPLC-MS) analysis. Therefore, our studies suggest that CBL could be used as a natural resource for ameliorating Aβ1-42-induced learning and memory impairment.

  8. Cerebrospinal Fluid Amyloid Beta and Tau Concentrations Are Not Modulated by 16 Weeks of Moderate- to High-Intensity Physical Exercise in Patients with Alzheimer Disease.

    Science.gov (United States)

    Steen Jensen, Camilla; Portelius, Erik; Siersma, Volkert; Høgh, Peter; Wermuth, Lene; Blennow, Kaj; Zetterberg, Henrik; Waldemar, Gunhild; Gregers Hasselbalch, Steen; Hviid Simonsen, Anja

    2016-01-01

    Physical exercise may have some effect on cognition in patients with Alzheimer disease (AD). However, the underlying biochemical effects are unclear. Animal studies have shown that amyloid beta (Aβ), one of the pathological hallmarks of AD, can be altered with high levels of physical activity. The objective of this study was to elucidate the effect of 16 weeks of moderate- to high-intensity physical exercise on the biomarkers of AD, with special emphasis on the amyloidogenic pathway. From a total of 53 patients with AD participating in the Preserving Cognition, Quality of Life, Physical Health and Functional Ability in Alzheimer's Disease: The Effect of Physical Exercise (ADEX) study we analyzed cerebrospinal fluid samples for Aβ species, total tau (t-tau), phosphorylated tau (p-tau) and soluble amyloid precursor protein (sAPP) species. We also assessed the patients for apolipoprotein E ε4 (ApoE ε4) genotype. We found no effect of 16 weeks of physical exercise on the selected biomarkers, and no effect of ApoE ε4 genotype. Our findings suggest that the possible effect of physical exercise on cognition in patients with AD is not due to modulation of Aβ, t-tau, p-tau and sAPP species. © 2016 S. Karger AG, Basel.

  9. Protective effects of components of the Chinese herb grassleaf sweetflag rhizome on PC12 cells incubated with amyloid-beta42

    Directory of Open Access Journals (Sweden)

    Zi-hao Liang

    2015-01-01

    Full Text Available The major ingredients of grassleaf sweetflag rhizome are β-asarone and eugenol, which can cross the blood-brain barrier and protect neurons. This study aimed to observe the neuroprotective effects and mechanisms of β-asarone and eugenol, components of the Chinese herb grassleaf sweetflag rhizome, on PC12 cells. First, PC12 cells were cultured with different concentrations (between 1 × 10 -10 M and 1 × 10 -5 M of β-asarone and eugenol. Survival rates of PC12 cells were not significantly affected. Second, PC12 cells incubated with amyloid-beta42, which reduced cell survival, were cultured under the same conditions (1 × 10 -6 M β-asarone and eugenol. The survival rates of PC12 cells significantly increased, while expression levels of the mRNAs for the pro-apoptotic protein Bax decreased, and those for the anti-apoptotic protein Bcl mRNA increased. In addition, the combination of β-asarone with eugenol achieved better results than either component alone. Our experimental findings indicate that both β-asarone and eugenol protect PC12 cells through inhibiting apoptosis, and that the combination of the two is better than either alone.

  10. Pharmacokinetic Profile of Orally Administered Scyllo-Inositol (Elnd005) in Plasma, Cerebrospinal Fluid and Brain, and Corresponding Effect on Amyloid-Beta in Healthy Subjects.

    Science.gov (United States)

    Liang, Earvin; Garzone, Pamela; Cedarbaum, Jesse M; Koller, Martin; Tran, Thao; Xu, Victor; Ross, Brian; Jhee, Stanford S; Ereshefsky, Larry; Pastrak, Aleksandra; Abushakra, Susan

    2013-04-01

    ELND005 (scyllo-inositol), an endogenous inositol stereoisomer, is being investigated as an oral treatment for Alzheimer's disease (AD). Pharmacokinetics of ELND005 in plasma, cerebrospinal fluid (CSF), and brain was characterized in healthy young subjects. Eight men received 2000 mg ELND005 every 12 hours for 10 days. Plasma and CSF samples were collected at predetermined time points; ELND005 and amyloid-beta (Aβ) fragments were measured by validated bioanalytical methods. Brain ELND005 levels, estimated by (1) H Magnetic Resonance Spectroscopy (MRS) scans were obtained from gray/white matter voxels at baseline and Day 8. ELND005 was well-tolerated during the study. During the apparent steady state, ELND005 plasma levels rapidly peaked at 39.8 µg/mL and decreased to an average trough concentration of 10.6 µg/mL at the end of the 12-hour dosing regimen. In contrast, CSF drug levels slowly peaked at 13.7 µg/mL and remained near the same level with average trough concentrations of 12.4 µg/mL. At Day 8, Brain ELND005 concentrations increased by 58-76% compared to baseline levels. The CSF concentrations achieved in this study were similar to those associated with efficacy in transgenic models of AD. No changes were detected in plasma and CSF levels of Aβ fragments. © The Author(s) 2013.

  11. The effect of acori graminei rhizoma and extract fractions on spatial memory and hippocampal neurogenesis in amyloid beta 1-42 injected mice.

    Science.gov (United States)

    Ma, Yuxin; Tian, Sumin; Sun, Lingzhi; Yao, Shizhang; Liang, Zihao; Li, Shanshan; Liu, Jing; Zang, Linquan; Li, Guoying

    2015-01-01

    Acori graminei Rhizoma (AGR), the dry rhizoma of Acorus gramineus Soland (Araceae), has been used as an Asian traditional herbal medicine against senile dementia, stroke, and cardiovascular disease. Previous studies have revealed neuroprotective effects of AGR on neuronal damage and learning impairment, while mostly focused on the effect of volatile oil fraction of AGR. This study aimed to investigate the neuroprotective effects of different extract fractions from AGR against Alzheimer disease-like symptoms induced by Amyloid Beta (Aß) 1-42 intra-hippocampal injection. On day 7 after intra-hippocampal injection of saline or Aβ1-42, spatial memory was assessed by the first Morris water maze, followed by 3-week intra-gastric administration of saline or water extract, volatile oil fraction, or defatted decoction fraction of AGR respectively. Mice were subsequently subjected to the second Morris water maze task. Levels of Aβ1-42 and expressions of doublecortin and nestin in the hippocampus were examined using immunohistochemistry. Our results suggested that treatment with these different extract fractions from AGR could ameliorate cognitive impairment and down-regulate expressions of doublecortin and nestin in the hippocampus of Aβ1-42 injected mice, in which water extract and volatile oil fractions were more effective in spatial memory than defatted decoction fraction.

  12. Characteristics of tau oligomers

    Directory of Open Access Journals (Sweden)

    Yan eRen

    2013-07-01

    Full Text Available In Alzheimer disease (AD and other tauopathies, microtubule-associated protein tau becomes hyperphosphorylated, undergoes conformational changes, aggregates, eventually becoming neurofibrillary tangles (NFTs. As accumulating evidence suggests that NFTs themselves may not be toxic, attention is now turning toward the role of intermediate tau oligomers in AD pathophysiology. Sarkosyl extraction is a standard protocol for investigating insoluble tau aggregates in brains. There is a growing consensus that sarkosyl-insoluble tau correlates with the pathological features of tauopathy. While sarkosyl-insoluble tau from tauopathy brains has been well characterized as a pool of filamentous tau, other dimers, multimers, and granules of tau are much less well understood. There are protocols for identifying these tau oligomers. In this mini review, we discuss the characteristics of tau oligomers isolated via different methods and materials.

  13. 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

  14. Monofunctional hyperbranched ethylene oligomers.

    Science.gov (United States)

    Wiedemann, Thomas; Voit, Gregor; Tchernook, Alexandra; Roesle, Philipp; Göttker-Schnetmann, Inigo; Mecking, Stefan

    2014-02-05

    The neutral κ(2)N,O-salicylaldiminato Ni(II) complexes [κ(2)N,O-{(2,6-(3',5'-R2C6H3)2C6H3-N═C(H)-(3,5-I2-2-O-C6H2)}]NiCH3(pyridine)] (1a-pyr, R = Me; 1b-pyr, R = Et; 1c-pyr, R = iPr) convert ethylene to hyperbranched low-molecular-weight oligomers (Mn ca. 1000 g mol(-1)) with high productivities. While all three catalysts are capable of generating hyperbranched structures, branching densities decrease significantly with the nature of the remote substituent along Me > Et > iPr and oligomer molecular weights increase. Consequently, only 1a-pyr forms hyperbranched structures over a wide range of reaction conditions (ethylene pressure 5-30 atm and 20-70 °C). An in situ catalyst system achieves similar activities and identical highly branched oligomer microstructures, eliminating the bottleneck given by the preparation and isolation of Ni-Me catalyst precursor species. Selective introduction of one primary carboxylic acid ester functional group per highly branched oligoethylene molecule was achieved by isomerizing ethoxycarbonylation and alternatively cross metathesis with ethyl acrylate followed by hydrogenation. The latter approach results in complete functionalization and no essential loss of branched oligomer material and molecular weight, as the reacting double bonds are close to a chain end. Reduction yielded a monoalcohol-functionalized oligomer. Introduction of one reactive epoxide group per branched oligomer occurs completely and selectively under mild conditions. All reaction steps involved in oligomerization and monofunctionalization are efficient and readily scalable.

  15. 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.

  16. Electrorheology of aniline oligomers

    Czech Academy of Sciences Publication Activity Database

    Mrlík, M.; Sedlačík, M.; Pavlínek, V.; Bober, Patrycja; Trchová, Miroslava; Stejskal, Jaroslav; Sáha, P.

    2013-01-01

    Roč. 291, č. 9 (2013), s. 2079-2086 ISSN 0303-402X R&D Projects: GA ČR GA202/09/1626 Institutional support: RVO:61389013 Keywords : anilin e oligomers * polyaniline * electrorheology Subject RIV: JI - Composite Materials Impact factor: 2.410, year: 2013

  17. Hippocampal Mutant APP and Amyloid Beta Induced Cognitive Decline, Dendritic Spine Loss, Defective Autophagy, Mitophagy and Mitochondrial Abnormalities in a Mouse Model of Alzheimer's Disease.

    Science.gov (United States)

    Manczak, Maria; Kandimalla, Ramesh; Yin, Xiangling; Reddy, P Hemachandra

    2018-02-01

    The purpose of our study was to determine the toxic effects of hippocampal mutant APP and amyloid beta (Aβ) in 12-month-old APP transgenic mice. Using rotarod and Morris Water Maze tests, immunoblotting & immunofluorescence, Golgi-cox staining and transmission electron microscopy, we assessed cognitive behavior, protein levels of synaptic, autophagy, mitophagy, mitochondrial dynamics, biogenesis, dendritic protein MAP2, and quantified dendritic spines and mitochondrial number and length in 12-month-old APP mice that express swedish mutation. Mitochondrial function was assessed by measuring the levels of hydrogen peroxide, lipid peroxidation, cytochrome c oxidase activity and mitochondrial ATP. Morris Water Maze and rotarod tests revealed that hippocampal learning and memory and motor learning & coordination were impaired in APP mice relative to wild-type (WT) mice. Increased levels of mitochondrial fission proteins, Drp1 and Fis1 and decreased levels fusion (Mfn1, Mfn2 and Opa1) biogenesis (PGC1α, NRF1, NRF2 & TFAM), autophagy (ATG5 & LC3BI, LC3BII), Mitophagy (PINK1 & TERT), synaptic (synaptophysin & PSD95) and dendritic (MAP2) proteins were found in 12-month-old APP mice relative to age-matched non-transgenic WT mice. Golgi-cox staining analysis revealed that dendritic spines are significantly reduced. Transmission electron microscopy revealed significantly increased mitochondrial numbers and reduced mitochondrial length in APP mice. These findings suggest that hippocampal accumulation of mutant APP and Aβ is responsible for abnormal mitochondrial dynamics and defective biogenesis, reduced MAP2, autophagy, mitophagy and synaptic proteins & reduced dendritic spines and hippocampal based learning and memory impairments, and mitochondrial structural and functional changes in 12-month-old APP mice. © The Author 2018. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  18. The Na+/K+-ATPase and the amyloid-beta peptide aβ1-40 control the cellular distribution, abundance and activity of TRPC6 channels.

    Science.gov (United States)

    Chauvet, Sylvain; Boonen, Marielle; Chevallet, Mireille; Jarvis, Louis; Abebe, Addis; Benharouga, Mohamed; Faller, Peter; Jadot, Michel; Bouron, Alexandre

    2015-11-01

    The Na(+)/K(+)-ATPase interacts with the non-selective cation channels TRPC6 but the functional consequences of this association are unknown. Experiments performed with HEK cells over-expressing TRPC6 channels showed that inhibiting the activity of the Na(+)/K(+)-ATPase with ouabain reduced the amount of TRPC6 proteins and depressed Ca(2+) entry through TRPC6. This effect, not mimicked by membrane depolarization with KCl, was abolished by sucrose and bafilomycin-A, and was partially sensitive to the intracellular Ca(2+) chelator BAPTA/AM. Biotinylation and subcellular fractionation experiments showed that ouabain caused a multifaceted redistribution of TRPC6 to the plasma membrane and to an endo/lysosomal compartment where they were degraded. The amyloid beta peptide Aβ(1-40), another inhibitor of the Na(+)/K(+)-ATPase, but not the shorter peptide Aβ1-16, reduced TRPC6 protein levels and depressed TRPC6-mediated responses. In cortical neurons from embryonic mice, ouabain, veratridine (an opener of voltage-gated Na(+) channel), and Aβ(1-40) reduced TRPC6-mediated Ca(2+) responses whereas Aβ(1-16) was ineffective. Furthermore, when Aβ(1-40) was co-added together with zinc acetate it could no longer control TRPC6 activity. Altogether, this work shows the existence of a functional coupling between the Na(+)/K(+)-ATPase and TRPC6. It also suggests that the abundance, distribution and activity of TRPC6 can be regulated by cardiotonic steroids like ouabain and the naturally occurring peptide Aβ(1-40) which underlines the pathophysiological significance of these processes. Copyright © 2015 Elsevier B.V. All rights reserved.

  19. Protective effect of systemic L-kynurenine and probenecid administration on behavioural and morphological alterations induced by toxic soluble amyloid beta (25-35) in rat hippocampus.

    Science.gov (United States)

    Carrillo-Mora, Paul; Méndez-Cuesta, Luis A; Pérez-De La Cruz, Verónica; Fortoul-van Der Goes, Teresa I; Santamaría, Abel

    2010-07-11

    Amyloid beta (Abeta) peptide exerts different toxic effects at a cellular level, including over-activation of N-methyl-D-aspartate receptor (NMDAr) and excitotoxicity, synaptic dysfunction and neuronal death. Kynurenic acid (KYNA) is an endogenous antagonist of NMDAr and alpha7 nicotinic receptors. Systemic administrations of both the immediate metabolic precursor of KYNA, L-kynurenine (L-KYN), and a proved inhibitor of KYNA's brain transport, probenecid (PROB), have shown to produce neuroprotective effects in a considerable number of experimental toxic conditions; however, this strategy has not been tested in the toxic model Abeta peptide so far. In this study we evaluated the effects of systemic administration of PROB (50 mg/kg/day for 7 days), L-KYN (75 mg/kg/day for 7 days) and their combination, on behavioural (locomotor activity and spatial memory) and morphological alterations induced by an intrahippocampal infusion of Abeta 25-35 to rats. An additional group was administered with the potent NMDAr antagonist dizocilpine (MK-801, 0.8 mg/kg/day for 7 days) for comparative purposes. A significant improvement of spatial memory was evident in Abeta-lesioned rats since post-lesion day 21 with all treatments tested and this effect was correlated with a reduction of cell damage and a decrease in reactive gliosis in hippocampal CA1 area. Neither L-KYN, nor PROB, or their combination, produced major alterations in motor function when given alone to rats. These results suggest that modulation of NMDAr activity by mean of therapeutic strategies designed to enhance KYNA in the brain may help to counteract neurodegenerative events coursing with Abeta toxicity and excitotoxic patterns. Copyright 2010 Elsevier B.V. All rights reserved.

  20. Regional Fluid-Attenuated Inversion Recovery (FLAIR) at 7 Tesla correlates with amyloid beta in hippocampus and brainstem of cognitively normal elderly subjects

    Science.gov (United States)

    Schreiner, Simon J.; Liu, Xinyang; Gietl, Anton F.; Wyss, Michael; Steininger, Stefanie C.; Gruber, Esmeralda; Treyer, Valerie; Meier, Irene B.; Kälin, Andrea M.; Leh, Sandra E.; Buck, Alfred; Nitsch, Roger M.; Pruessmann, Klaas P.; Hock, Christoph; Unschuld, Paul G.

    2014-01-01

    Background: Accumulation of amyloid beta (Aβ) may occur during healthy aging and is a risk factor for Alzheimer Disease (AD). While individual Aβ-accumulation can be measured non-invasively using Pittsburgh Compund-B positron emission tomography (PiB-PET), Fluid-attenuated inversion recovery (FLAIR) is a Magnetic Resonance Imaging (MRI) sequence, capable of indicating heterogeneous age-related brain pathologies associated with tissue-edema. In the current study cognitively normal elderly subjects were investigated for regional correlation of PiB- and FLAIR intensity. Methods: Fourteen healthy elderly subjects without known history of cognitive impairment received 11C-PiB-PET for estimation of regional Aβ-load. In addition, whole brain T1-MPRAGE and FLAIR-MRI sequences were acquired at high field strength of 7 Tesla (7T). Volume-normalized intensities of brain regions were assessed by applying an automated subcortical segmentation algorithm for spatial definition of brain structures. Statistical dependence between FLAIR- and PiB-PET intensities was tested using Spearman's rank correlation coefficient (rho), followed by Holm–Bonferroni correction for multiple testing. Results: Neuropsychological testing revealed normal cognitive performance levels in all participants. Mean regional PiB-PET and FLAIR intensities were normally distributed and independent. Significant correlation between volume-normalized PiB-PET signals and FLAIR intensities resulted for Hippocampus (right: rho = 0.86; left: rho = 0.84), Brainstem (rho = 0.85) and left Basal Ganglia vessel region (rho = 0.82). Conclusions: Our finding of a significant relationship between PiB- and FLAIR intensity mainly observable in the Hippocampus and Brainstem, indicates regional Aβ associated tissue-edema in cognitively normal elderly subjects. Further studies including clinical populations are necessary to clarify the relevance of our findings for estimating individual risk for age-related neurodegenerative

  1. Design and synthesis of curcumin analogues for in vivo fluorescence imaging and inhibiting copper-induced cross-linking of amyloid beta species in Alzheimer's disease.

    Science.gov (United States)

    Zhang, Xueli; Tian, Yanli; Li, Zeng; Tian, Xiaoyu; Sun, Hongbin; Liu, Hong; Moore, Anna; Ran, Chongzhao

    2013-11-06

    In this article, we first designed and synthesized curcumin-based near-infrared (NIR) fluorescence imaging probes for detecting both soluble and insoluble amyloid beta (Aβ) species and then an inhibitor that could attenuate cross-linking of Aβ induced by copper. According to our previous results and the possible structural stereohindrance compatibility of the Aβ peptide and the hydrophobic/hydrophilic property of the Aβ13-20 (HHQKLVFF) fragment, NIR imaging probe CRANAD-58 was designed and synthesized. As expected CRANAD-58 showed significant fluorescence property changes upon mixing with both soluble and insoluble Aβ species in vitro. In vivo NIR imaging revealed that CRANAD-58 was capable of differentiating transgenic and wild-type mice as young as 4 months old, the age that lacks apparently visible Aβ plaques and Aβ is likely in its soluble forms. According to our limited studies on the interaction mechanism between CRANAD-58 and Aβ, we also designed CRANAD-17 to attenuate the cross-linking of Aβ42 induced by copper. It is well-known that the coordination of copper with imidazoles on Histidine-13 and 14 (H13, H14) of Aβ peptides could initialize covalent cross-linking of Aβ. In CRANAD-17, a curcumin scaffold was used as an anchoring moiety to usher the designed compound to the vicinity of H13 and H14 of Aβ, and imidazole rings were incorporated to compete with H13/H14 for copper binding. The results of SDS-PAGE gel and Western blot indicated that CRANAD-17 was capable of inhibiting Aβ42 cross-linking induced by copper. This raises a potential for CRANAD-17 to be considered for AD therapy.

  2. The anti-tumor histone deacetylase inhibitor SAHA and the natural flavonoid curcumin exhibit synergistic neuroprotection against amyloid-beta toxicity.

    Science.gov (United States)

    Meng, Jia; Li, Yan; Camarillo, Cynthia; Yao, Yue; Zhang, Yina; Xu, Chun; Jiang, Lihong

    2014-01-01

    With the trend of an increasing aged population worldwide, Alzheimer's disease (AD), an age-related neurodegenerative disorder, as one of the major causes of dementia in elderly people is of growing concern. Despite the many hard efforts attempted during the past several decades in trying to elucidate the pathological mechanisms underlying AD and putting forward potential therapeutic strategies, there is still a lack of effective treatments for AD. The efficacy of many potential therapeutic drugs for AD is of main concern in clinical practice. For example, large bodies of evidence show that the anti-tumor histone deacetylase (HDAC) inhibitor, suberoylanilidehydroxamic acid (SAHA), may be of benefit for the treatment of AD; however, its extensive inhibition of HDACs makes it a poor therapeutic. Moreover, the natural flavonoid, curcumin, may also have a potential therapeutic benefit against AD; however, it is plagued by low bioavailability. Therefore, the integrative effects of SAHA and curcumin were investigated as a protection against amyloid-beta neurotoxicity in vitro. We hypothesized that at low doses their synergistic effect would improve therapeutic selectivity, based on experiments that showed that at low concentrations SAHA and curcumin could provide comprehensive protection against Aβ25-35-induced neuronal damage in PC12 cells, strongly implying potent synergism. Furthermore, network analysis suggested that the possible mechanism underlying their synergistic action might be derived from restoration of the damaged functional link between Akt and the CBP/p300 pathway, which plays a crucial role in the pathological development of AD. Thus, our findings provided a feasible avenue for the application of a synergistic drug combination, SAHA and curcumin, in the treatment of AD.

  3. The anti-tumor histone deacetylase inhibitor SAHA and the natural flavonoid curcumin exhibit synergistic neuroprotection against amyloid-beta toxicity.

    Directory of Open Access Journals (Sweden)

    Jia Meng

    Full Text Available With the trend of an increasing aged population worldwide, Alzheimer's disease (AD, an age-related neurodegenerative disorder, as one of the major causes of dementia in elderly people is of growing concern. Despite the many hard efforts attempted during the past several decades in trying to elucidate the pathological mechanisms underlying AD and putting forward potential therapeutic strategies, there is still a lack of effective treatments for AD. The efficacy of many potential therapeutic drugs for AD is of main concern in clinical practice. For example, large bodies of evidence show that the anti-tumor histone deacetylase (HDAC inhibitor, suberoylanilidehydroxamic acid (SAHA, may be of benefit for the treatment of AD; however, its extensive inhibition of HDACs makes it a poor therapeutic. Moreover, the natural flavonoid, curcumin, may also have a potential therapeutic benefit against AD; however, it is plagued by low bioavailability. Therefore, the integrative effects of SAHA and curcumin were investigated as a protection against amyloid-beta neurotoxicity in vitro. We hypothesized that at low doses their synergistic effect would improve therapeutic selectivity, based on experiments that showed that at low concentrations SAHA and curcumin could provide comprehensive protection against Aβ25-35-induced neuronal damage in PC12 cells, strongly implying potent synergism. Furthermore, network analysis suggested that the possible mechanism underlying their synergistic action might be derived from restoration of the damaged functional link between Akt and the CBP/p300 pathway, which plays a crucial role in the pathological development of AD. Thus, our findings provided a feasible avenue for the application of a synergistic drug combination, SAHA and curcumin, in the treatment of AD.

  4. Blood amyloid beta levels in healthy, mild cognitive impairment and Alzheimer's disease individuals: replication of diastolic blood pressure correlations and analysis of critical covariates.

    Directory of Open Access Journals (Sweden)

    Agustín Ruiz

    Full Text Available Plasma amyloid beta (Aβ levels are being investigated as potential biomarkers for Alzheimer's disease. In AB128 cross-sectional study, a number of medical relevant correlates of blood Aβ40 or Aβ42 were analyzed in 140 subjects (51 Alzheimer's disease patients, 53 healthy controls and 36 individuals diagnosed with mild cognitive impairment. We determined the association between multiple variables with Aβ40 and Aβ42 levels measured in three different blood compartments called i Aβ directly accessible (DA in the plasma, ii Aβ recovered from the plasma matrix (RP after diluting the plasma sample in a formulated buffer, and iii associated with the remaining cellular pellet (CP. We confirmed that diastolic blood pressure (DBP is consistently correlated with blood DA Aβ40 levels (r=-0.19, P=0.032. These results were consistent in the three phenotypic groups studied. Importantly, the observation resisted covariation with age, gender or creatinine levels. Observed effect size and direction of Aβ40 levels/DBP correlation are in accordance with previous reports. Of note, DA Aβ40 and the RP Aβ40 were also strongly associated with creatinine levels (r=0.599, P<<0.001 and to a lesser extent to urea, age, hematocrit, uric acid and homocysteine (p<0.001. DBP and the rest of statistical significant correlates identified should be considered as potential confounder factors in studies investigating blood Aβ levels as potential AD biomarker. Remarkably, the factors affecting Aβ levels in plasma (DA, RP and blood cell compartments (CP seem completely different.

  5. Tuning the stereo-hindrance of a curcumin scaffold for the selective imaging of the soluble forms of amyloid beta species.

    Science.gov (United States)

    Li, Yuyan; Yang, Jian; Liu, Hongwu; Yang, Jing; Du, Lei; Feng, Haiwei; Tian, Yanli; Cao, Jianqin; Ran, Chongzhao

    2017-11-01

    Amyloid peptides and proteins are associated with the pathologies of numerous diseases. In the progression of a disease, amyloids exist in soluble and insoluble forms, which are the dominant species at different stages of the disease and they have different degrees of toxicity. However, differentiating between the soluble and insoluble forms is very challenging with small molecule probes due to multiple obstacles that need to be overcome. Inspired by the recognition principle of antibodies for sAβ, we hypothesized that the accessibility/tightness of soluble and insoluble amyloids could be utilized to design imaging probes to recognize different amyloid forms and the stereo-hindrance tuning strategy could be used to design imaging probes for selectively detecting the soluble amyloid beta (sAβ) species in Alzheimer's disease (AD). Herein, we demonstrated that tuning the stereo-hindrance of the phenoxy-alkyl chains at the 4-position of a curcumin scaffold could lead to certain selectivity for sAβ over insoluble Aβs (insAβ). Among the designed compounds, CRANAD-102 showed a 68-fold higher affinity for sAβ than for insAβ (7.5 ± 10 nM vs. 505.9 ± 275.9 nM). Moreover, our imaging data indicated that CRANAD-102 was indeed capable of detecting sAβ in vivo using 4 month old APP/PS1 mice, in which sAβ is the predominant species in the brain. In addition, we also demonstrated that CRANAD-102 could be used to monitor the increase in sAβ loading from the ages of 4 months old to 12 months old. We believe that CRANAD-102 can be a useful probe for selectively detecting sAβ species in AD and that our probe designing strategy can be applied to other amyloids and will have tremendous impact on AD drug development and other amyloid research.

  6. [18F]Flutemetamol amyloid-beta PET imaging compared with [11C]PIB across the spectrum of Alzheimer's disease.

    Science.gov (United States)

    Hatashita, Shizuo; Yamasaki, Hidetomo; Suzuki, Yutaka; Tanaka, Kumiko; Wakebe, Daichi; Hayakawa, Hideki

    2014-02-01

    The aim was to identify the amyloid beta (Aβ) deposition by positron emission tomography (PET) imaging with the (18)F-labeled Pittsburgh compound B (PIB) derivative [(18)F]flutemetamol (FMM) across a spectrum of Alzheimer's disease (AD) and to compare Aβ deposition between [(18)F]FMM and [(11)C]PIB PET imaging. The study included 36 patients with AD, 68 subjects with mild cognitive impairment (MCI), 41 older healthy controls (HC) (aged ≥56), 11 young HC (aged ≤45), and 10 transitional HC (aged 46-55). All 166 subjects underwent 30-min static [(18)F]FMM PET 85 min after injection, 60-min dynamic [(11)C]PIB PET, and cognitive testing. [(18)F]FMM scans were assessed visually, and standardized uptake value ratios (SUVR) were defined quantitatively in regions of interest identified on coregistered MRI (cerebellar cortex as a reference region). The PIB distribution volume ratios (DVR) were determined in the same regions. Of 36 AD patients, 35 had positive scans, while 36 of 41 older HC subjects had negative scans. [(18)F]FMM scans had a sensitivity of 97.2% and specificity of 85.3% in distinguishing AD patients from older HC subjects, and a specificity of 100% for young and transitional HC subjects. The [(11)C]PIB scan had the same results. Interreader agreement was excellent (kappa score = 0.81). The cortical FMM SUVR in AD patients was significantly greater than in older HC subjects (1.76 ± 0.23 vs 1.30 ± 0.26, p PIB DVR (r = 0.94, n = 145, p PIB PET.

  7. Age-related toxicity of amyloid-beta associated with increased pERK and pCREB in primary hippocampal neurons: reversal by blueberry extract.

    Science.gov (United States)

    Brewer, Gregory J; Torricelli, John R; Lindsey, Amanda L; Kunz, Elizabeth Z; Neuman, A; Fisher, Derek R; Joseph, James A

    2010-10-01

    Further clarification is needed to address the paradox that memory formation, aging and neurodegeneration all involve calcium influx, oxyradical production (ROS) and activation of certain signaling pathways. In aged rats and in APP/PS-1 mice, cognitive and hippocampal Ca(2+) dysregulation was reversed by food supplementation with a high antioxidant blueberry extract. Here, we studied whether neurons were an important target of blueberry extract and whether the mechanism involved altered ROS signaling through MAP kinase and cyclic-AMP response element binding protein (CREB), pathways known to be activated in response to amyloid-beta (Aβ). Primary hippocampal neurons were isolated and cultured from embryonic, middle-age or old-age (24 months) rats. Blueberry extract was found to be equally neuroprotective against Aβ neurotoxicity at all ages. Increases in Aβ toxicity with age were associated with age-related increases in immunoreactivity of neurons to pERK and an age-independent increase in pCREB. Treatment with blueberry extract strongly inhibited these increases in parallel with neuroprotection. Simultaneous labeling for ROS and for glutathione with dichlorofluorescein and monochlorobimane showed a mechanism of action of blueberry extract to involve transient ROS generation with an increase in the redox buffer glutathione. We conclude that the increased age-related susceptibility of old-age neurons to Aβ toxicity may be due to higher levels of activation of pERK and pCREB pathways that can be protected by blueberry extract through inhibition of both these pathways through an ROS stress response. These results suggest that the beneficial effects of blueberry extract may involve transient stress signaling and ROS protection that may translate into improved cognition in aging rats and APP/PS1 mice given blueberry extract. Copyright © 2010 Elsevier Inc. All rights reserved.

  8. Regional Fluid-Attenuated Inversion Recovery (FLAIR at 7 Tesla correlates with Amyloid beta in Hippocampus and Brainstem of cognitively normal elderly subjects.

    Directory of Open Access Journals (Sweden)

    Simon J Schreiner

    2014-09-01

    Full Text Available Background: Accumulation of amyloid beta (Aβ may occur during healthy aging and is a risk factor for Alzheimer Disease (AD. While individual Aβ-accumulation can be measured non-invasively using Pittsburgh compound-B positron-emission-tomography (PiB-PET, Fluid-Attenuated Inversion Recovery (FLAIR is a Magnetic Resonance Imaging (MRI sequence, capable of indicating heterogeneous age-related brain pathologies associated with tissue-edema. In the current study cognitively normal elderly subjects were investigated for regional correlation of PiB- and FLAIR- intensity. Methods: 14 healthy elderly subjects without known history of cognitive impairment received 11C-PiB-PET for estimation of regional Aβ-load. In addition, whole brain T1-MPRAGE and FLAIR-MRI sequences were acquired at high field strength of 7 Tesla (7T. Volume-normalized intensities of brain regions were assessed by applying an automated subcortical segmentation algorithm for spatial definition of brain structures. Statistical dependence between FLAIR- and PiB-PET intensities was tested using Spearman's rank correlation coefficient (rho, followed by Holm-Bonferroni correction for multiple testing. Results: Neuropsychological testing revealed normal cognitive performance levels in all participants. Mean regional PiB-PET and FLAIR intensities were normally distributed and independent. Significant correlation between volume-normalized PiB-PET signals and FLAIR intensities resulted for Hippocampus (right:rho=0.86; left:rho=0.84, Brainstem (rho=0.85 and left Basal Ganglia vessel region (rho=0.82. Conclusions: Our finding of a significant relationship between PiB- and FLAIR-intensity mainly observable in the Hippocampus and Brainstem, indicates regional Aβ associated tissue-edema in cognitively normal elderly subjects. Further studies including clinical populations are necessary to clarify the relevance of our findings for estimating individual risk for age-related neurodegenerative

  9. Effect of stent-assisted angioplasty on cognitive status and serum levels of amyloid beta in patients with intracranial and/or extracranial artery stenosis

    Directory of Open Access Journals (Sweden)

    Zhao L

    2015-02-01

    Full Text Available Liandong Zhao,1 Ying Zhao,1 Haijun Zhang2 1Department of Neurology, The Second People’s Hospital of Huai’an and The Affiliated Huai’an Hospital of Xuzhou Medical College, Huai’an, Jiangsu, 2Department of Oncology, Zhongda Hospital, Medical School, Southeast University, Nanjing, People’s Republic of China Aim: The study reported here aimed to examine how stent-assisted angioplasty affects cognitive status and serum levels of amyloid betas (Aβs 1-40 and 1-42 in patients with cerebral arterial stenosis.Methods: Patients with cerebral arterial stenosis were given stent-assisted angioplasty plus conventional treatment (stent-assisted angioplasty group or conventional treatment alone (control group. Cognitive status and Aβ1-40 and Aβ1-42 serum levels were determined before treatment and at 4 and 8 weeks after treatment.Results: At 4 weeks after treatment, cognitive status in patients with stent-assisted angioplasty had clearly improved. Aβ1-42 serum levels changed insignificantly in all patients. However, Aβ1-40 serum levels and Aβ1-40/Aβ1-42 ratio decreased further in patients with stent-assisted angioplasty than in patients who received conventional treatment (controls. Eight weeks after treatment, cognitive status in patients who had undergone stent-assisted angioplasty were continuing to improve, Aβ1-42 serum levels had begun to increase dramatically, and Aβ1-40 serum levels and Aβ1-40/Aβ1-42 ratio had declined further.Conclusion: Stent-assisted angioplasty could improve cognitive status and decrease Aβ1-40 serum levels and Aβ1-40/Aβ1-42 ratio. Keywords: arterial stenosis, Alzheimer’s disease, Aβ1-40, Aβ1-42, Aβ1-40/Aβ1-42 ratio

  10. In Vitro Restoration of an Amyloid-Beta Altered Network Circuitry in a 'Mutated Biomimetic Acetylcholinesterase' Memristor/Memcapacitor Neural Prosthesis

    Directory of Open Access Journals (Sweden)

    John THORNTON

    2015-08-01

    Full Text Available Many diseases involve the ysregulation of acetylcholinesterase (ACHE causing inappropriate production of the neurotransmitter acetylcholine (ACH. Study of how the ACH actually restores a life threatening neural circuitry damage will provide valuable information for study Alzhermer’s disease. An artificial neuronal device was developed with nanostructured biomimetic mutated ACHE gorge membrane on gold chips having memristor/memcapacitor’s characteristics, served as a model for damaged brain circuitry prosthesis, compared before and after ACH treatments, for in vitro evaluation of the memory restoration in the presence of Amyloid-beta (Ab under the conditions of free from tracers and antibodies in NIST human serum. The results are presented in three categories in “Energy-Sensory” images. Before ACH treatments, images showed four stages of circuitry damages from non symptomatic to life threatening. After a 15 nM ACH treatment, the circuitry was restored due to the ACH removed Pathological High Frequency Oscillation (pHFO center during Slow- Waving Sleeping (SWS. After the prosthesis increased hydrophobicity, the High Frequency Oscillation (HFO was created. Results were compared between the recovered and the “normal brain”: 0.14 vs. 0.47 pJ/bit/µm3 for long-term and 14.0 vs.7.0 aJ/bit/µm3 for short-term memory restoration, respectively. The ratio of Rmax/Rmin value is 6.3-fold higher after the treatment of ACH compared without the treatment in the presence of Ab and the reentry sensitivity increased by 613.8- fold.

  11. Near-infrared fluorescence molecular imaging of amyloid beta species and monitoring therapy in animal models of Alzheimer’s disease

    Science.gov (United States)

    Zhang, Xueli; Tian, Yanli; Zhang, Can; Tian, Xiaoyu; Ross, Alana W.; Moir, Robert D.; Sun, Hongbin; Tanzi, Rudolph E.; Moore, Anna; Ran, Chongzhao

    2015-01-01

    Near-infrared fluorescence (NIRF) molecular imaging has been widely applied to monitoring therapy of cancer and other diseases in preclinical studies; however, this technology has not been applied successfully to monitoring therapy for Alzheimer’s disease (AD). Although several NIRF probes for detecting amyloid beta (Aβ) species of AD have been reported, none of these probes has been used to monitor changes of Aβs during therapy. In this article, we demonstrated that CRANAD-3, a curcumin analog, is capable of detecting both soluble and insoluble Aβ species. In vivo imaging showed that the NIRF signal of CRANAD-3 from 4-mo-old transgenic AD (APP/PS1) mice was 2.29-fold higher than that from age-matched wild-type mice, indicating that CRANAD-3 is capable of detecting early molecular pathology. To verify the feasibility of CRANAD-3 for monitoring therapy, we first used the fast Aβ-lowering drug LY2811376, a well-characterized beta-amyloid cleaving enzyme-1 inhibitor, to treat APP/PS1 mice. Imaging data suggested that CRANAD-3 could monitor the decrease in Aβs after drug treatment. To validate the imaging capacity of CRANAD-3 further, we used it to monitor the therapeutic effect of CRANAD-17, a curcumin analog for inhibition of Aβ cross-linking. The imaging data indicated that the fluorescence signal in the CRANAD-17–treated group was significantly lower than that in the control group, and the result correlated with ELISA analysis of brain extraction and Aβ plaque counting. It was the first time, to our knowledge, that NIRF was used to monitor AD therapy, and we believe that our imaging technology has the potential to have a high impact on AD drug development. PMID:26199414

  12. Viewing ageing eyes: diverse sites of amyloid Beta accumulation in the ageing mouse retina and the up-regulation of macrophages.

    Directory of Open Access Journals (Sweden)

    Jaimie Hoh Kam

    Full Text Available BACKGROUND: Amyloid beta (Aβ accumulates in the ageing central nervous system and is associated with a number of age-related diseases, including age-related macular degeneration (AMD in the eye. AMD is characterised by accumulation of extracellular deposits called drusen in which Aβ is a key constituent. Aβ activates the complement cascade and its deposition is associated with activated macrophages. So far, little is known about the quantitative measurements of Aβ accumulation and definitions of its relative sites of ocular deposition in the normal ageing mouse. METHODOLOGY/PRINCIPAL FINDINGS: We have traced Aβ accumulation quantitatively in the ageing mouse retina using immunohistochemistry and Western blot analysis. We reveal that it is not only deposited at Bruch's membrane and along blood vessels, but unexpectedly, it also coats photoreceptor outer segments. While Aβ is present at all sites of deposition from 3 months of age, it increases markedly from 6 months onward. Progressive accumulation of deposits on outer segments was confirmed with scanning electron microscopy, revealing age-related changes in their morphology. Such progress of accumulation of Aβ on photoreceptor outer segments with age was also confirmed in human retinae using immunohistochemistry. We also chart the macrophage response to increases in Aβ showing up-regulation in their numbers using both confocal laser imaging of the eye in vivo followed by in vitro immunostaining. With age macrophages become bloated with cellular debris including Aβ, however, their increasing numbers fail to stop Aβ accumulation. CONCLUSIONS: Increasing Aβ deposition in blood vessels and Bruch's membrane will impact upon retinal perfusion and clearance of cellular waste products from the outer retina, a region of very high metabolic activity. This accumulation of Aβ may contribute to the 30% reduction of photoreceptors found throughout life and the shortening of those that remain. The

  13. Aniline oligomers versus polyaniline

    Czech Academy of Sciences Publication Activity Database

    Stejskal, Jaroslav; Trchová, Miroslava

    2012-01-01

    Roč. 61, č. 2 (2012), s. 240-251 ISSN 0959-8103 R&D Projects: GA AV ČR IAA400500905; GA AV ČR IAA100500902; GA ČR GA203/08/0686; GA ČR GA202/09/1626 Institutional research plan: CEZ:AV0Z40500505 Keywords : polyaniline * anilin e oligomers * anilin e Subject RIV: CD - Macromolecular Chemistry Impact factor: 2.125, year: 2012

  14. Neuroblastoma in children

    International Nuclear Information System (INIS)

    Hoermann, M.

    2008-01-01

    Neuroblastomas have a very heterogenic clinical presentation, ranging from relatively benign forms with the potential of spontaneous regression, to foudroyant malignant forms. Over half of neuroblastomas must be classified as high-risk tumors with a markedly high rate of recurrence. Despite multidisciplinary therapeutic approaches, the survival rate of children with this type of tumor is still below 40%. An ever-growing amount of data from international studies dating from the early 1970s onwards, points to the necessity of re-evaluating the medical approach in establishing the diagnosis and staging, understanding tumor biology and pathology, as well as therapy planning. (orig.) [de

  15. Cholesterol enhances amyloid {beta} deposition in mouse retina by modulating the activities of A{beta}-regulating enzymes in retinal pigment epithelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Jiying [Department of Ophthalmology and Visual Science, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519 (Japan); Ohno-Matsui, Kyoko, E-mail: k.ohno.oph@tmd.ac.jp [Department of Ophthalmology and Visual Science, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519 (Japan); Morita, Ikuo [Section of Cellular Physiological Chemistry, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519 (Japan)

    2012-08-10

    Highlights: Black-Right-Pointing-Pointer Cholesterol-treated RPE produces more A{beta} than non-treated RPE. Black-Right-Pointing-Pointer Neprilysin expression and activity decreased in cholesterol-treated RPE. Black-Right-Pointing-Pointer {alpha}-Secretase expression and activity decreased in cholesterol-treated RPE. Black-Right-Pointing-Pointer Cholesterol-enriched diet induced subRPE deposits in aged mice. Black-Right-Pointing-Pointer A{beta} were present in cholesterol-enriched-diet-induced subRPE deposits in aged mice. -- Abstract: Subretinally-deposited amyloid {beta} (A{beta}) is a main contributor of developing age-related macular degeneration (AMD). However, the mechanism causing A{beta} deposition in AMD eyes is unknown. Hypercholesterolemia is a significant risk for developing AMD. Thus, we investigated the effects of cholesterol on A{beta} production in retinal pigment epithelial (RPE) cells in vitro and in the mouse retina in vivo. RPE cells isolated from senescent (12-month-old) C57BL/6 mice were treated with 10 {mu}g/ml cholesterol for 48 h. A{beta} amounts in culture supernatants were measured by ELISA. Activity and expression of enzymes and proteins that regulate A{beta} production were examined by activity assay and real time PCR. The retina of mice fed cholesterol-enriched diet was examined by transmission electron microscopy. Cholesterol significantly increased A{beta} production in cultured RPE cells. Activities of A{beta} degradation enzyme; neprilysin (NEP) and anti-amyloidogenic secretase; {alpha}-secretase were significantly decreased in cell lysates of cholesterol-treated RPE cells compared to non-treated cells, but there was no change in the activities of {beta}- or {gamma}-secretase. mRNA levels of NEP and {alpha}-secretase (ADAM10 and ADAM17) were significantly lower in cholesterol-treated RPE cells than non-treated cells. Senescent (12-month-old) mice fed cholesterol-enriched chow developed subRPE deposits containing A{beta}, whereas

  16. [{sup 18}F]Flutemetamol amyloid-beta PET imaging compared with [{sup 11}C]PIB across the spectrum of Alzheimer's disease

    Energy Technology Data Exchange (ETDEWEB)

    Hatashita, Shizuo; Yamasaki, Hidetomo [Shonan-Atsugi Hospital, Neurology, PET Center, Atsugi (Japan); Suzuki, Yutaka; Wakebe, Daichi; Hayakawa, Hideki [Shonan-Atsugi Hospital, Radiology, PET Center, Atsugi (Japan); Tanaka, Kumiko [Shonan-Atsugi Hospital, Pharmacology, PET Center, Atsugi (Japan)

    2014-02-15

    The aim was to identify the amyloid beta (Aβ) deposition by positron emission tomography (PET) imaging with the {sup 18}F-labeled Pittsburgh compound B (PIB) derivative [{sup 18}F]flutemetamol (FMM) across a spectrum of Alzheimer's disease (AD) and to compare Aβ deposition between [{sup 18}F]FMM and [{sup 11}C]PIB PET imaging. The study included 36 patients with AD, 68 subjects with mild cognitive impairment (MCI), 41 older healthy controls (HC) (aged ≥56), 11 young HC (aged ≤45), and 10 transitional HC (aged 46-55). All 166 subjects underwent 30-min static [{sup 18}F]FMM PET 85 min after injection, 60-min dynamic [{sup 11}C]PIB PET, and cognitive testing. [{sup 18}F]FMM scans were assessed visually, and standardized uptake value ratios (SUVR) were defined quantitatively in regions of interest identified on coregistered MRI (cerebellar cortex as a reference region). The PIB distribution volume ratios (DVR) were determined in the same regions. Of 36 AD patients, 35 had positive scans, while 36 of 41 older HC subjects had negative scans. [{sup 18}F]FMM scans had a sensitivity of 97.2 % and specificity of 85.3 % in distinguishing AD patients from older HC subjects, and a specificity of 100 % for young and transitional HC subjects. The [{sup 11}C]PIB scan had the same results. Interreader agreement was excellent (kappa score = 0.81). The cortical FMM SUVR in AD patients was significantly greater than in older HC subjects (1.76 ± 0.23 vs 1.30 ± 0.26, p < 0.01). Of the MCI patients, 68 had a bimodal distribution of SUVR, and 29 of them (42.6 %) had positive scans. Cortical FMM SUVR values were strongly correlated with PIB DVR (r = 0.94, n = 145, p < 0.001). [{sup 18}F]FMM PET imaging detects Aβ deposition in patients along the continuum from normal cognitive status to dementia of AD and discriminates AD patients from HC subjects, similar to [{sup 11}C]PIB PET. (orig.)

  17. Valeriana amurensis improves Amyloid-beta 1-42 induced cognitive deficit by enhancing cerebral cholinergic function and protecting the brain neurons from apoptosis in mice.

    Science.gov (United States)

    Wang, Qiuhong; Wang, Changfu; Shu, Zunpeng; Chan, Kelvin; Huang, Shuming; Li, Yan; Xiao, Yang; Wu, Lihua; Kuang, Haixue; Sun, Xiaobo

    2014-04-28

    Valeriana amurensis, a perennial medicinal herb, has been widely used as anxiolytic, antidepressant, antispasmodic, and sedative in traditional Chinese medicines (TCMs). Moreover, it has been used to treat dementia in Mongolia preparations. In our previous study, we reported that AD-effective fraction of Valeriana amurensis (AD-EFV) has protective effect on Aβ-induced toxicity in PC12 cells. Up to now, however, the therapeutic effect of Valeriana amurensis on Alzheimer disease (AD) has not been explored. This study was designed to determine whether the AD-EFV could improve the Amyloid-beta (Aβ)-induced cognitive deficit and to explore the mechanism of AD-EFV improves cognitive deficit in intact animals. The constituents of AD-EFV were isolated with silica gel, octadecyl silica gel (ODS) column chromatography (CC) and preparative HPLC. The structures of compounds were determined by detailed NMR and ESI-MS data analyses. AD mice model was established by injecting A(β1-42) (1 μL, 200 μmol) into the bilateral ventricle. Cognitive performance was evaluated by the Morris water maze (MWM) test. The level of cerebral acetylcholine (ACh), the activities of acetylcholinesterase (AChE) and choline acetyltransferase (ChAT) were investigated using Enzyme-linked immunoassay (ELISA) kits. Brain sections were processed and neuronal apoptosis in hippocampus were evaluated by Hematoxylin and Eosin (HE), Nissl, and Tunel stainings. The analyses of p-ERK/ERK and Bcl-2/Bax protein expression by western blot assay were used to explore the anti-neuronal apoptosis mechanism of AD-EFV. Seventeen compounds (15 lignans and two iridoids) were isolated from AD-EFV. A significant improvement in cognitive function was observed in administrated AD-EFV AD model mice. AD-EFV increased the ACh level by enhancing the ChAT activity but has no effect on AChE activity in the cerebral cortex and hippocampus in mice. Moreover, the histological injury in hippocampus CA1 induced by A(β1-42) was

  18. 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

  19. PIPERIDINE OLIGOMERS AND COMBINATORIAL LIBRARIES THEREOF

    DEFF Research Database (Denmark)

    1999-01-01

    The present invention relates to piperidine oligomers, methods for the preparation of piperidine oligomers and compound libraries thereof, and the use of piperidine oligomers as drug substances. The present invention also relates to the use of combinatorial libraries of piperidine oligomers...... in libraries (arrays) of compounds especially suitable for screening purposes....

  20. 11C-PiB PET assessment of change in fibrillar amyloid-beta load in patients with Alzheimer's disease treated with bapineuzumab: a phase 2, double-blind, placebo-controlled, ascending-dose study.

    Science.gov (United States)

    Rinne, Juha O; Brooks, David J; Rossor, Martin N; Fox, Nick C; Bullock, Roger; Klunk, William E; Mathis, Chester A; Blennow, Kaj; Barakos, Jerome; Okello, Aren A; Rodriguez Martinez de Liano, Sofia; Liu, Enchi; Koller, Martin; Gregg, Keith M; Schenk, Dale; Black, Ronald; Grundman, Michael

    2010-04-01

    Carbon-11-labelled Pittsburgh compound B ((11)C-PiB) PET is a marker of cortical fibrillar amyloid-beta load in vivo. We used (11)C-PiB PET to investigate whether bapineuzumab, a humanised anti-amyloid-beta monoclonal antibody, would reduce cortical fibrillar amyloid-beta load in patients with Alzheimer's disease. Patients with mild-to-moderate Alzheimer's disease were randomly assigned to receive intravenous bapineuzumab or placebo in a ratio of seven to three in three ascending dose groups (0.5, 1.0, or 2.0 mg/kg). Each dose group was enrolled after safety review of the previous group. Randomisation was by interactive voice response system; masking was achieved with numbered kit allocation. Patients, investigators, study site personnel, sponsor staff, and carers were masked to treatment. Patients received up to six infusions, 13 weeks apart, and had (11)C-PiB PET scans at baseline and at weeks 20, 45, and 78. The primary outcome was the difference between the pooled bapineuzumab group and the pooled placebo group in mean change from screening to week 78 in (11)C-PiB cortical to cerebellar retention ratio averaged across six cortical regions of interest. Analysis was by modified intention to treat. This study is registered with EudraCT, number 2004-004120-12; ISRCTN17517446. 28 patients were assigned to bapineuzumab (n=20) or placebo (n=8). 19 patients in the bapineuzumab group and seven in the placebo group were included in the modified intention-to-treat analysis. Estimated mean (11)C-PiB retention ratio change from baseline to week 78 was -0.09 (95% CI -0.16 to -0.02; p=0.014) in the bapineuzumab group and 0.15 (95% CI 0.02 to 0.28; p=0.022) in the placebo group. Estimated mean difference in (11)C-PiB retention ratio change from baseline to week 78 between the bapineuzumab group and the placebo group was -0.24 (95% CI -0.39 to -0.09; p=0.003). Differences between the bapineuzumab group and the placebo group in the individual regions of interest were similar to

  1. 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

  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. Prefibrillar transthyretin oligomers and cold stored native tetrameric transthyretin are cytotoxic in cell culture

    International Nuclear Information System (INIS)

    Soergjerd, Karin; Klingstedt, Therese; Lindgren, Mikael; Kagedal, Katarina; Hammarstroem, Per

    2008-01-01

    Recent studies suggest that soluble, oligomeric species, which are intermediates in the fibril formation process in amyloid disease, might be the key species in amyloid pathogenesis. Soluble oligomers of human wild type transthyretin (TTR) were produced to elucidate oligomer properties. Employing ThT fluorescence, time-resolved fluorescence anisotropy of pyrene-labeled TTR, chemical cross-linking, and electron microscopy we demonstrated that early formed soluble oligomers (within minutes) from A-state TTR comprised on the average 20-30 TTR monomers. When administered to neuroblastoma cells these early oligomers proved highly cytotoxic and induced apoptosis after 48 h of incubation. More mature fibrils (>24 h of fibrillation) were non-toxic. Surprisingly, we also found that native tetrameric TTR, when purified and stored under cold conditions (4 deg. C) was highly cytotoxic. The effect could be partially restored by increasing the temperature of the protein. The cytotoxic effects of native tetrameric TTR likely stems from a hitherto unexplored low temperature induced rearrangement of the tetramer conformation that possibly is related to the conformation of misfolded TTR in amyloigogenic oligomers.

  4. Mechanisms of hybrid oligomer formation in the pathogenesis of combined Alzheimer's and Parkinson's diseases.

    Directory of Open Access Journals (Sweden)

    Igor F Tsigelny

    Full Text Available BACKGROUND: Misfolding and pathological aggregation of neuronal proteins has been proposed to play a critical role in the pathogenesis of neurodegenerative disorders. Alzheimer's disease (AD and Parkinson's disease (PD are frequent neurodegenerative diseases of the aging population. While progressive accumulation of amyloid beta protein (Abeta oligomers has been identified as one of the central toxic events in AD, accumulation of alpha-synuclein (alpha-syn resulting in the formation of oligomers and protofibrils has been linked to PD and Lewy body Disease (LBD. We have recently shown that Abeta promotes alpha-syn aggregation and toxic conversion in vivo, suggesting that abnormal interactions between misfolded proteins might contribute to disease pathogenesis. However the molecular characteristics and consequences of these interactions are not completely clear. METHODOLOGY/PRINCIPAL FINDINGS: In order to understand the molecular mechanisms involved in potential Abeta/alpha-syn interactions, immunoblot, molecular modeling, and in vitro studies with alpha-syn and Abeta were performed. We showed in vivo in the brains of patients with AD/PD and in transgenic mice, Abeta and alpha-synuclein co-immunoprecipitate and form complexes. Molecular modeling and simulations showed that Abeta binds alpha-syn monomers, homodimers, and trimers, forming hybrid ring-like pentamers. Interactions occurred between the N-terminus of Abeta and the N-terminus and C-terminus of alpha-syn. Interacting alpha-syn and Abeta dimers that dock on the membrane incorporated additional alpha-syn molecules, leading to the formation of more stable pentamers and hexamers that adopt a ring-like structure. Consistent with the simulations, under in vitro cell-free conditions, Abeta interacted with alpha-syn, forming hybrid pore-like oligomers. Moreover, cells expressing alpha-syn and treated with Abeta displayed increased current amplitudes and calcium influx consistent with the

  5. Self-propagative replication of Aβ oligomers suggests potential transmissibility in Alzheimer disease.

    Directory of Open Access Journals (Sweden)

    Amit Kumar

    Full Text Available The aggregation of amyloid-β (Aβ peptide and its deposition in parts of the brain form the central processes in the etiology of Alzheimer disease (AD. The low-molecular weight oligomers of Aβ aggregates (2 to 30 mers are known to be the primary neurotoxic agents whose mechanisms of cellular toxicity and synaptic dysfunction have received substantial attention in the recent years. However, how these toxic agents proliferate and induce widespread amyloid deposition throughout the brain, and what mechanism is involved in the amplification and propagation of toxic oligomer species, are far from clear. Emerging evidence based on transgenic mice models indicates a transmissible nature of Aβ aggregates and implicates a prion-like mechanism of oligomer propagation, which manifests as the dissemination and proliferation of Aβ toxicity. Despite accumulating evidence in support of a transmissible nature of Aβ aggregates, a clear, molecular-level understanding of this intriguing mechanism is lacking. Recently, we reported the characterization of unique replicating oligomers of Aβ42 (12-24 mers in vitro called Large Fatty Acid-derived Oligomers (LFAOs (Kumar et al., 2012, J. Biol. Chem. In the current report, we establish that LFAOs possess physiological activity by activating NF-κB in human neuroblastoma cells, and determine the experimental parameters that control the efficiency of LFAO replication by self-propagation. These findings constitute the first detailed report on monomer - oligomer lateral propagation reactions that may constitute potential mechanism governing transmissibility among Aβ oligomers. These data support the previous reports on transmissible mechanisms observed in transgenic animal models.

  6. 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

  7. Immunosuppressive microenvironment in neuroblastoma

    Directory of Open Access Journals (Sweden)

    Vito ePistoia

    2013-06-01

    Full Text Available According to the cancer immunoediting model, the interplay between tumor cells and the host immune system is crucial for the control of tumor growth. NB is a pediatric tumor that presents with metastatic disease at diagnosis in about 50% of the cases, the majority of which have poor prognosis. In this Review article, immune escape pathways adopted by human neuroblastoma (NB cells are reviewed. These include intrinsic defects of tumor cells such impaired expression of the HLA class I related antigen processing machinery and functional alterations of the tumor microenvironment induced by NB cell-derived immunosuppressive molecules as MICA and HLA-G. Finally, examples of therapeutic interventions targeting the tumor microenvironment are discussed to emphasize the concept that successful cancer treatment may be achieved using this strategy.

  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. 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.

  10. Alzheimer's Disease Brain-Derived Amyloid-{beta}-Mediated Inhibition of LTP In Vivo Is Prevented by Immunotargeting Cellular Prion Protein.

    LENUS (Irish Health Repository)

    Barry, Andrew E

    2011-05-18

    Synthetic amyloid-β protein (Aβ) oligomers bind with high affinity to cellular prion protein (PrP(C)), but the role of this interaction in mediating the disruption of synaptic plasticity by such soluble Aβ in vitro is controversial. Here we report that intracerebroventricular injection of Aβ-containing aqueous extracts of Alzheimer\\'s disease (AD) brain robustly inhibits long-term potentiation (LTP) without significantly affecting baseline excitatory synaptic transmission in the rat hippocampus in vivo. Moreover, the disruption of LTP was abrogated by immunodepletion of Aβ. Importantly, intracerebroventricular administration of antigen-binding antibody fragment D13, directed to a putative Aβ-binding site on PrP(C), prevented the inhibition of LTP by AD brain-derived Aβ. In contrast, R1, a Fab directed to the C terminus of PrP(C), a region not implicated in binding of Aβ, did not significantly affect the Aβ-mediated inhibition of LTP. These data support the pathophysiological significance of SDS-stable Aβ dimer and the role of PrP(C) in mediating synaptic plasticity disruption by soluble Aβ.

  11. Cerebrospinal fluid levels of amyloid beta 1-43 in patients with amnestic mild cognitive impairment or early Alzheimer’s disease: a 2-year follow-up study

    Directory of Open Access Journals (Sweden)

    Camilla eLauridsen

    2016-03-01

    Full Text Available Abstract IntroductionBiomarkers that will reliably predict the onset of Alzheimer’s disease (AD are urgently needed. Although cerebrospinal fluid (CSF amyloid beta 1-42 (Aβ42, total tau and phosphorylated tau can be used to complement the clinical diagnosis of AD, amnestic mild cognitive impairment (aMCI, the prodromal phase of AD, is heterogeneous. Biomarkers should be able to determine which patients with aMCI are at greatest risk of AD. Histological studies and animal models indicate that amyloid beta 1-43 (Aβ43 aggregates early, and may play a role in the pathological process of AD. We have examined levels of CSF Aβ43 in a two-year longitudinal study of aMCI and early AD. Materials and methodsCSF was collected at baseline, and after one and two years from patients with AD (n=19, and patients with aMCI (n=42. Of these, 21 progressed to AD during the two years of study, whereas 21 did not. Controls (n=32 were lumbar punctured at baseline only. CSF analyses of Aβ43, Aβ42 and total tau were carried out with ELISA.ResultsAt baseline, CSF Aβ43, CSF Aβ42 and ratios with total tau could be used to separate controls from all three patient groups. CSF Aβ43, but not Aβ42, could separate patients with aMCI who progressed to AD during the two years of follow-up, from those that did not. The CSF total tau/Aβ43 ratio had a slightly but significantly larger area under the receiver operating characteristic curve when compared to the CSF total tau/Aβ42 ratio. CSF Aβ43 levels, but not Aβ42 levels, decreased from baseline to two years in the AD group.Discussion and conclusionCSF Aβ43 was demonstrated to be significantly reduced in patients already by the time that aMCI or AD was diagnosed, compared to controls, and this change must have occurred during the preclinical period. Since our results suggested that CSF Aβ43 distinguishes between subgroups of patients with aMCI better than CSF Aβ42, it may prove to be a useful additional biomarker for

  12. Ciliary neurotrophic factor protects SH-SY5Y neuroblastoma cells against Aβ1-42-induced neurotoxicity via activating the JAK2/STAT3 axis.

    Science.gov (United States)

    Wang, Ke; Xie, Minhao; Zhu, Ling; Zhu, Xue; Zhang, Kai; Zhou, Fanfan

    2015-01-01

    The neurotoxicity of aggregated amyloid beta (Aβ) has been implicated as a critical cause in the pathogenesis of Alzheimer's disease (AD), which leads to neuronal cell damage by inducing oxidative stress and consequently triggering cell apoptosis. Recently, Aβ-dependent inactivation of the Janus tyrosine kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway was found to play a critical role in the memory impairment related to AD. Previous research indicated that JAK2/STAT3 axis inactivation might be the result of aberrant reactive oxygen species (ROS) generation induced by Aβ in neurons. As the JAK2/STAT3 axis is a major transducer of ciliary neurotrophic factor (CNTF)-mediated neuroprotective activity, this study extensively evaluated whether activation of the JAK2/STAT3 axis by CNTF was responsible for the neuroprotective effect of this protein against Aβ1-42-induced cytotoxicity, oxidative injury and cell apoptosis in human SH-SY5Y neuroblastoma cells. Our data showed that CNTF could attenuate or restore cell injury induced by Aβ1-42 in human SH-SY5Y neuroblastoma cells through activating the JAK2/STAT3 signaling pathway. Furthermore, CNTF strikingly prevented Aβ1-42-induced mitochondrial dysfunction and activation of mitogen-activated protein kinases (MAPKs), an effect that could be potently attenuated by the specific JAK2 inhibitor AG490. In summary, this study confirmed the detailed mechanism accounting for CNTF's protective effect against Aβ1-42-induced cytotoxic events in human SH-SY5Y neuroblastoma cells - information which might significantly contribute to better understanding of the mechanism of action of CNTF as well as providing a novel target in AD therapy.

  13. Neuroblastoma and Its Zebrafish Model.

    Science.gov (United States)

    Zhu, Shizhen; Thomas Look, A

    2016-01-01

    Neuroblastoma, an important developmental tumor arising in the peripheral sympathetic nervous system (PSNS), accounts for approximately 10 % of all cancer-related deaths in children. Recent genomic analyses have identified a spectrum of genetic alterations in this tumor. Amplification of the MYCN oncogene is found in 20 % of cases and is often accompanied by mutational activation of the ALK (anaplastic lymphoma kinase) gene, suggesting their cooperation in tumor initiation and spread. Understanding how complex genetic changes function together in oncogenesis has been a continuing and daunting task in cancer research. This challenge was addressed in neuroblastoma by generating a transgenic zebrafish model that overexpresses human MYCN and activated ALK in the PSNS, leading to tumors that closely resemble human neuroblastoma and new opportunities to probe the mechanisms that underlie the pathogenesis of this tumor. For example, coexpression of activated ALK with MYCN in this model triples the penetrance of neuroblastoma and markedly accelerates tumor onset, demonstrating the interaction of these modified genes in tumor development. Further, MYCN overexpression induces adrenal sympathetic neuroblast hyperplasia, blocks chromaffin cell differentiation, and ultimately triggers a developmentally-timed apoptotic response in the hyperplastic sympathoadrenal cells. In the context of MYCN overexpression, activated ALK provides prosurvival signals that block this apoptotic response, allowing continued expansion and oncogenic transformation of hyperplastic neuroblasts, thus promoting progression to neuroblastoma. This application of the zebrafish model illustrates its value in rational assessment of the multigenic changes that define neuroblastoma pathogenesis and points the way to future studies to identify novel targets for therapeutic intervention.

  14. PrP(Sc-specific antibodies with the ability to immunodetect prion oligomers.

    Directory of Open Access Journals (Sweden)

    Mourad Tayebi

    Full Text Available The development of antibodies with binding capacity towards soluble oligomeric forms of PrPSc recognised in the aggregation process in early stage of the disease would be of paramount importance in diagnosing prion diseases before extensive neuropathology has ensued. As blood transfusion appears to be efficient in the transmission of the infectious prion agent, there is an urgent need to develop reagents that would specifically recognize oligomeric forms of the abnormally folded prion protein, PrPSc.To that end, we show that anti-PrP monoclonal antibodies (called PRIOC mAbs derived from mice immunised with native PrP-coated microbeads are able to immunodetect oligomers/multimers of PrPSc. Oligomer-specific immunoreactivity displayed by these PRIOC mAbs was demonstrated as large aggregates of immunoreactive deposits in prion-permissive neuroblastoma cell lines but not in equivalent non-infected or prn-p(0/0 cell lines. In contrast, an anti-monomer PrP antibody displayed diffuse immunoreactivity restricted to the cell membrane. Furthermore, our PRIOC mAbs did not display any binding with monomeric recombinant and cellular prion proteins but strongly detected PrPSc oligomers as shown by a newly developed sensitive and specific ELISA. Finally, PrioC antibodies were also able to bind soluble oligomers formed of Aβ and α-synuclein. These findings demonstrate the potential use of anti-prion antibodies that bind PrPSc oligomers, recognised in early stage of the disease, for the diagnosis of prion diseases in blood and other body fluids.

  15. Congenital neuroblastoma with placental involvement

    OpenAIRE

    Kume, Ayako; Morikawa, Teppei; Ogawa, Makiko; Yamashita, Aki; Yamaguchi, Shunichi; Fukayama, Masashi

    2014-01-01

    We describe an extremely rare case of congenital neuroblastoma with placental involvement. A fetus with a left abdominal mass detected during ultrasonography at 23 weeks’ gestation developed hydrops fetalis by 26 weeks’ gestation. The mother developed hypertension at 26 5/7 weeks’ gestation. Based on a clinical diagnosis of pregnancy-induced hypertension, labor was induced at 26 6/7 weeks. However, intrauterine fetal death was diagnosed during delivery. Postmortern examination revealed a soli...

  16. 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)

  17. Targeting α-synuclein oligomers

    DEFF Research Database (Denmark)

    van Diggelen, Femke

    Parkinson’s Disease (PD) is a complex disease, characterised by degeneration of neocortical, limbic and nigrostriatal neurons. It is unknown what initiates neurodegeneration, but soluble oligomers of the protein α-synuclein (αSn) seem to be particularly toxic, compared to insoluble fibrils...... unique characteristics, e.g. they were recognized by different conformational antibodies and DHA–αSOs also formed a second elongated species in addition to the dominant spherical species. Although further functional testing is needed, this suggests that each species has its own distinct toxic mechanism......+/K+ ATPase, V-type ATPase, VDAC, CaMKII and Rab-3A. The identification of these targets is a first step towards unravelling the toxic pathways which are activated upon synaptic binding of extracellularly added αSOs, and hopefully will contribute to the discovery of new disease modifying compounds, which can...

  18. 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

  19. 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

  20. 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 (3) enhanced apoptosis. Oxidant-induced apoptosis positively correlated with cellular Aβ production, being the highest in cells that were stably transfected with APP Swedish KM670/671NL double mutation. Inhibition of γ-secretase, prior and/or in parallel to hyperoxia, suggested that the increase...... 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....

  1. Adding Effects of Reactive Oligomers for Epoxy Resin

    OpenAIRE

    山田, 英介; 稲垣, 慎二; 岡本, 弘

    1991-01-01

    Reactive oligomers with both functional end groups were prepared by the radical telomerization and the effect of oligomers added to bisphenol-A-glycidylehter type epoxy resin was investigated by measuring mechanical properties, adhesive properties and dynamic viscoelasticities. These oligomers were high viscous liquid except the one prepared from methyl methacrylate, therefore the blend of oligomers with epoxy resin is easy. Adding oligomers, the cured epoxy resins showed the lower glass-tran...

  2. Boron-rich oligomers for BNCT

    International Nuclear Information System (INIS)

    Gula, M.; Perleberg, O.; Gabel, D.

    2000-01-01

    The synthesis of two BSH derivatives is described, which can be used for oligomerization in DNA-synthesizers. Synthesis pathways lead to final products in five and six steps, respectively. Because of chirality interesting results were expected. NMR-measurements confirm this expectation. Possible oligomers with high concentrations of boron can be attached to biomolecules. These oligomers can be explored with several imaging methods (EELS, PEM) to determine the lower detection limit of boron with these methods. (author)

  3. Amyloid beta peptide immunotherapy in Alzheimer disease.

    Science.gov (United States)

    Delrieu, J; Ousset, P J; Voisin, T; Vellas, B

    2014-12-01

    Recent advances in the understanding of Alzheimer's disease pathogenesis have led to the development of numerous compounds that might modify the disease process. Amyloid β peptide represents an important molecular target for intervention in Alzheimer's disease. The main purpose of this work is to review immunotherapy studies in relation to the Alzheimer's disease. Several types of amyloid β peptide immunotherapy for Alzheimer's disease are under investigation, active immunization and passive administration with monoclonal antibodies directed against amyloid β peptide. Although immunotherapy approaches resulted in clearance of amyloid plaques in patients with Alzheimer's disease, this clearance did not show significant cognitive effect for the moment. Currently, several amyloid β peptide immunotherapy approaches are under investigation but also against tau pathology. Results from amyloid-based immunotherapy studies in clinical trials indicate that intervention appears to be more effective in early stages of amyloid accumulation in particular solanezumab with a potential impact at mild Alzheimer's disease, highlighting the importance of diagnosing Alzheimer's disease as early as possible and undertaking clinical trials at this stage. In both phase III solanezumab and bapineuzumab trials, PET imaging revealed that about a quarter of patients lacked fibrillar amyloid pathology at baseline, suggesting that they did not have Alzheimer's disease in the first place. So a new third phase 3 clinical trial for solanezumab, called Expedition 3, in patients with mild Alzheimer's disease and evidence of amyloid burden has been started. Thus, currently, amyloid intervention is realized at early stage of the Alzheimer's disease in clinical trials, at prodromal Alzheimer's disease, or at asymptomatic subjects or at risk to develop Alzheimer's disease and or at asymptomatic subjects with autosomal dominant mutation. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  4. 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.

  5. 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

  6. Electron beam curing of acrylic oligomers

    International Nuclear Information System (INIS)

    Seto, J.; Arakawa, S.; Ishimoto, C.; Miyashita, M.; Nagai, T.; Noguchi, T.; Shibata, A.

    1984-01-01

    The electron-beam curing process of acrylic oligomers, with and without γ-Fe 2 O 3 pigment filler and blended linear polymer, was investigated in terms of molecular structure and reaction mechanism. The polymerized fraction of trimethylolpropane-triacrylate (TMPTA) oligomers increases with increasing total dose, and is independent of the dose rate. Since the reaction rate is linearly dependent on the dose rate, the reaction mechanism involves monomolecular termination. The reaction rate does not depend on the number of functional groups of the oligomer at low doses, but above 0.3 Mrad the rate is slower for oligomers of higher functionality. A gel is formed more readily upon curing of a polyfunctional than a monofunctional oligomer, especially at high conversion to polymer; the resulting loss of flexibility of the polymer chains slows the reaction. Decrease of the molecular weight per functional group results in lower conversion; this is also due to the loss of chain flexibility, which is indicated as well by a higher glass-transition temperature. Modification of the acrylate oligomers with urethane results in more effective cross-linking reactions because of the more rigid molecular chains. Addition of γ-Fe 2 O 3 pigment reduces the reaction rate very little, but has the effect of providing added structural integrity, as indicated by the decrease of solvent-extractable material and the improvement of anti-abrasion properties. However, the flexibility of the coating and its adhesion to a PET base film are diminished. To increase the flexibility, linear polyvinylchloride and/or polyurethane were added to the acrylic oligomers. Final conversion to polymer was nearly 100 percent, and a higher elastic modulus and better antiabrasion properties were realized

  7. 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.

  8. 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.

  9. Emitting oligomer containing quinoline group: Synthesis and photophysical properties of conjugated oligomer obtained by Wittig reaction

    Energy Technology Data Exchange (ETDEWEB)

    Karpagam, S., E-mail: skarpagam80@yahoo.com [Organic Chemistry Division, School of Advanced Science, VIT University, Vellore 14, Tamil Nadu (India); Guhanathan, S. [Department of Chemistry, Muthurangam Government Arts College, Vellore, Tamil Nadu (India)

    2014-01-15

    Dichloro quinoline substituted phenylene vinylene oligomer (QUI-OPV) was synthesized via Wittig route. Formation of the oligomer was characterized by spectral (FTIR, {sup 1}H and {sup 13}C NMR), elemental and gel permeation chromatography analysis. The oligomer possesses excellent thermal stability (decomposition temperature 470 °C), solubility in common organic solvents and high glass transition temperature (61 °C). The morphology of the oligomer film of one dimensional (1D) and three dimensional (3D) architectures was observed using atomic force microscopy (AFM). In CHCl{sub 3} solution, the oligomer showed the absorption maxima at 382 nm and also observed excellent photoluminescence (PL) with bluish green emission maxima at shorter wavelengths of 477 nm. The introduction of quinoline to the main chain resulted in a slight decrease of effective conjugation length and exhibited the blue shift in both the absorption and emission spectra. -- Highlights: • Simple synthesis of quinoline functionalized phenylene vinylene oligomer by Wittig route. • The materials had good organosolubility and intrinsic viscosity. • High thermal stability and good surface roughness morphology were observed. • Performance of luminescence improved via introducing quinoline into PPV. • Electrochemical and optical band gap of the oligomer were consistent with each other.

  10. Neuroblastoma

    Science.gov (United States)

    ... the eyes Profuse sweating Rapid heart rate ( tachycardia ) Brain and nervous system problems may include: Inability to empty the bladder Loss of movement ( paralysis ) of the hips, legs, or feet (lower extremities) ...

  11. 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 ...

  12. Early long-term administration of the CSF1R inhibitor PLX3397 ablates microglia and reduces accumulation of intraneuronal amyloid, neuritic plaque deposition and pre-fibrillar oligomers in 5XFAD mouse model of Alzheimer's disease.

    Science.gov (United States)

    Sosna, Justyna; Philipp, Stephan; Albay, Ricardo; Reyes-Ruiz, Jorge Mauricio; Baglietto-Vargas, David; LaFerla, Frank M; Glabe, Charles G

    2018-03-01

    Besides the two main classical features of amyloid beta aggregation and tau-containing neurofibrillary tangle deposition, neuroinflammation plays an important yet unclear role in the pathophysiology of Alzheimer's disease (AD). Microglia are believed to be key mediators of neuroinflammation during AD and responsible for the regulation of brain homeostasis by balancing neurotoxicity and neuroprotective events. We have previously reported evidence that neuritic plaques are derived from dead neurons that have accumulated intraneuronal amyloid and further recruit Iba1-positive cells, which play a role in either neuronal demise or neuritic plaque maturation or both. To study the impact of microglia on neuritic plaque development, we treated two-month-old 5XFAD mice with a selective colony stimulation factor 1 receptor (CSF1R) inhibitor, PLX3397, for a period of 3 months, resulting in a significant ablation of microglia. Directly after this treatment, we analyzed the amount of intraneuronal amyloid and neuritic plaques and performed behavioral studies including Y-maze, fear conditioning and elevated plus maze. We found that early long-term PLX3397 administration results in a dramatic reduction of both intraneuronal amyloid as well as neuritic plaque deposition. PLX3397 treated young 5XFAD mice also displayed a significant decrease of soluble fibrillar amyloid oligomers in brain lysates, a depletion of soluble pre-fibrillar oligomers in plasma and an improvement in cognitive function measured by fear conditioning tests. Our findings demonstrate that CSF1R signaling, either directly on neurons or mediated by microglia, is crucial for the accumulation of intraneuronal amyloid and formation of neuritic plaques, suggesting that these two events are serially linked in a causal pathway leading to neurodegeneration and neuritic plaque formation. CSF1R inhibitors represent potential preventative or therapeutic approach that target the very earliest stages of the formation of

  13. Statistical mechanics of thermal denaturation of DNA oligomers

    Indian Academy of Sciences (India)

    Double stranded DNA chain is known to have non-trivial elasticity. We study the effect of this elasticity on the denaturation profile of DNA oligomer by constraining one base pair at one end of the oligomer to remain in unstretched (or intact) state. The effect of this constraint on the denaturation profile of the oligomer has been ...

  14. α-Synuclein oligomers distinctively permeabilize complex model membranes

    NARCIS (Netherlands)

    Stefanovic, Anja N D; Stöckl, Martin T; Claessens, Mireille M A E; Subramaniam, Vinod

    α-Synuclein oligomers are increasingly considered to be responsible for the death of dopaminergic neurons in Parkinson's disease. The toxicity mechanism of α-synuclein oligomers likely involves membrane permeabilization. Even though it is well established that α-synuclein oligomers bind and

  15. 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...

  16. Epigenetic regulation of neuroblastoma development.

    Science.gov (United States)

    Durinck, Kaat; Speleman, Frank

    2018-01-19

    In recent years, technological advances have enabled a detailed landscaping of the epigenome and the mechanisms of epigenetic regulation that drive normal cell function, development and cancer. Rather than merely a structural entity to support genome compaction, we now look at chromatin as a very dynamic and essential constellation that is actively participating in the tight orchestration of transcriptional regulation as well as DNA replication and repair. The unique feature of chromatin flexibility enabling fast switches towards more or less restricted epigenetic cellular states is, not surprisingly, intimately connected to cancer development and treatment resistance, and the central role of epigenetic alterations in cancer is illustrated by the finding that up to 50% of all mutations across cancer entities affect proteins controlling the chromatin status. We summarize recent insights into epigenetic rewiring underlying neuroblastoma (NB) tumor formation ranging from changes in DNA methylation patterns and mutations in epigenetic regulators to global effects on transcriptional regulatory circuits that involve key players in NB oncogenesis. Insights into the disruption of the homeostatic epigenetic balance contributing to developmental arrest of sympathetic progenitor cells and subsequent NB oncogenesis are rapidly growing and will be exploited towards the development of novel therapeutic strategies to increase current survival rates of patients with high-risk NB.

  17. Neuroblastoma management in Chinese children.

    Science.gov (United States)

    Li, Kai; Dong, Kuiran; Gao, Jiechun; Yao, Wei; Xiao, Xianmin; Zheng, Shan

    2012-04-01

    This study assesses the clinical features of neuroblastoma and survival. Data for 98 patients between January 2000 and December 2006 at Children's Hospital of Fudan University, Shanghai, China, were retrospectively analyzed. Diagnostic methods included imaging, 24-hr urine catecholamines, bone marrow biopsies, and histopathology analyses. Treatment followed the modified Japanese Study Group Protocol. Clinical characteristics, treatment, and outcome were depicted, and difficulties encountered were analyzed. The median age of patients was 48 months. There were 3, 13, 31, 49, and 2 patients in stages 1, 2, 3, 4, and 4s disease, respectively. Positive urinary vanillylmandelic acid (VMA) prevalence was low in localized disease (51.1%) and high in disseminated disease (70.6%, p = .03). Gross total resection rate was 60.8%. The five-year overall survival (OS) rate was 80% for stages 1 and 2, 48.3% for stage 3, and 20% for stage 4. The five-year OS rates significantly decreased in children older than 18 months (p indigence were the main causes for poorer outcome in late stages.

  18. Bilateral cystic neuroblastoma: imaging features and differential diagnoses

    International Nuclear Information System (INIS)

    Cassady, C.; Winters, W.D.

    1997-01-01

    Neuroblastoma is one of the most common malignant tumors of childhood, with 40 % arising in the adrenal glands. Bilateral adrenal involvement from synchronous development or metastatic spread of the tumor is seen in less than 10 % of children with neuroblastoma [1[. Neuroblastoma rarely presents as a cystic suprarenal mass that is difficult to differentiate from adrenal hemorrhage, extralobar sequestration, or dilated upper-pole renal calyces. To our knowledge, bilateral cystic neuroblastoma has not been previously reported. We present a case of bilateral cystic adrenal neuroblastoma to demonstrate the imaging features of this unusual entity, and to expand the differential diagnosis of bilateral cystic suprarenal masses in an infant. (orig.). With 2 figs

  19. Neuroblastoma presenting with the nephrotic syndrome.

    Science.gov (United States)

    Zheng, H L; Maruyama, T; Matsuda, S; Satomura, K

    1979-08-01

    A case of neuroblastoma in a 4-yr-old boy presenting with the nephrotic syndrome is reported. Nether thrombosis nor stenosis of the renal veins and the inferior vena cava was present. Electron microscopy revealed lumps of subepithelial deposits as well as thickening and tortuosity of the glomerular basement membrane compatible with membranous nephropathy. It is postulated that deposition of neuroblastoma-associated immune complexes on the glomerular basement membrane-was responsible for the development of the nephrotic syndrome in this patient. Five pediatric cases of nephrotic syndrome associated with extrarenal neoplasia were collected from the world literature and are briefly discussed.

  20. Oligomer functionalized nanotubes and composites formed therewith

    Science.gov (United States)

    Zettl, Alexander K; Sainsbury, Toby; Frechet, Jean M.J.

    2014-03-18

    Disclosed herein is a sequential functionalization methodology for the covalent modification of nanotubes with between one and four repeat units of a polymer. Covalent attachment of oligomer units to the surface of nanotubes results in oligomer units forming an organic sheath around the nanotubes, polymer-functionalized-nanotubes (P-NTs). P-NTs possess chemical functionality identical to that of the functionalizing polymer, and thus provide nanoscale scaffolds which may be readily dispersed within a monomer solution and participate in the polymerization reaction to form a polymer-nanotube/polymer composite. Formation of polymer in the presence of P-NTs leads to a uniform dispersion of nanotubes within the polymer matrix, in contrast to aggregated masses of nanotubes in the case of pristine-NTs. The covalent attachment of oligomeric units to the surface of nanotubes represents the formation of a functional nanoscale building block which can be readily dispersed and integrated within the polymer to form a novel composite material.

  1. Peptide oligomers for holographic data storage

    DEFF Research Database (Denmark)

    Berg, Rolf Henrik; Hvilsted, Søren; Ramanujam, P.S.

    1996-01-01

    SEVERAL classes of organic materials (such as photoanisotropic liquid-crystalline polymers(1-4) and photorefractive polymers(5-7)) are being investigated for the development of media for optical data storage. Here we describe a new family of organic materials-peptide oligomers containing azobenzene...... chromophores-which appear particularly promising for erasable holographic data storage applications. The rationale for our approach is to use the structural properties of peptide-like molecules to impose orientational order on the chromophores, and thereby optimize the optical properties of the resulting...... materials. Here we show that holographic gratings with large first-order diffraction efficiencies (up to 80%) can be written and erased optically in oligomer films only a few micrometres thick. The holograms also exhibit good thermal stability, and are not erased after heating to 180 degrees C for one month...

  2. Cure Chemistry of Phenylethynyl Terminated Oligomers

    Science.gov (United States)

    Wood, Karen H.; Orwoll, Robert A.; Young, Philip R.; Jensen, Brian J.; McNair, Harold M.

    1997-01-01

    The ability to process high performance polymers into quality, void-free composites has been significantly advanced using oligomers terminated with reactive groups which cure or crosslink at elevated temperature without the evolution of volatile byproducts. Several matrix resin systems of considerable interest to the aerospace community utilize phenylethynyl-terminated imide (PETI) technology to achieve this advantage. The present paper addresses the cure chemistry of PETI oligomers. The thermal cure of a low molecular weight model compound was studied using a variety of analytical techniques including differential scanning calorimetry, Fourier transform infrared spectroscopy, and liquid chromatography-mass spectroscopy. The studies indicate an extremely complex cure process. Many stable products were isolated and this paper reports current work on identification of those products. The intent of this research is to provide fundamental insight into the molecular structure of the cured PETI engineering materials so that performance and durability can be more fully assessed.

  3. Self-assembly of aniline oligomers

    Czech Academy of Sciences Publication Activity Database

    Zhao, Y.; Tomšík, Elena; Wang, J.; Morávková, Zuzana; Zhigunov, Alexander; Stejskal, Jaroslav; Trchová, Miroslava

    2013-01-01

    Roč. 8, č. 1 (2013), s. 129-137 ISSN 1861-4728 R&D Projects: GA ČR GA202/09/1626; GA ČR GAP205/12/0911 Institutional research plan: CEZ:AV0Z40500505 Institutional support: RVO:61389013 Keywords : morphology * oligoaniline * oligomers Subject RIV: CD - Macromolecular Chemistry Impact factor: 3.935, year: 2013

  4. Cervical neonatal neuroblastoma with recurrent SVT.

    Science.gov (United States)

    Al-Shammari, N F; Redha, E; Al Hajeri, M H

    2009-07-01

    Neuroblastoma is the most common extracranial solid tumor of childhood and the third most common paediatric malignancy after leukemia and central nervous system (CNS) tumors. It constitutes 10% of all paediatric malignancies and 75% of them present in children below 4 years of age. Seventy five percent of neuroblastoma arise in the abdomen and pelvis, 20% in the thorax and 5% in the neck. The median age at diagnosis is 22 months. Up to 95% of cases are diagnosed by the age of ten years. Neuroblastomas have been diagnosed in utero as early as 19 weeks of gestational age. They can arise anywhere along the sympathetic chain. They occur most commonly in the adrenal medulla (35%). Neuroblastomas also occur as primary tumors in the extra-adrenal retroperitoneum in 30% of cases, in the posterior mediastinum in 20% of cases , in the neck up to 5% of cases and in the pelvis in 5% of cases. Approximately 50% of patients will have metastasis at presentation.

  5. 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.

  6. Imaging of abdominal neuroblastoma in children

    International Nuclear Information System (INIS)

    Hugosson, C.; Nyman, R.; Jorulf, H.; McDonald, P.; Rifai, A.; Jacobsson, B.; Kofide, A.

    1999-01-01

    Purpose: The aims of the study were: (1) to assess the efficacy of different imaging methods for use prior to treatment; (2) to compare the surgico-histopathologically-based International Neuroblastoma Staging System (INSS) staging with the imaging results; and (3) to suggest a localisation scheme for abdominal neuroblastoma. Material and Methods: Thirty-one children with an abdominal neuroblastoma (median age 2 years), underwent abdominal US, CT of chest and abdomen, MR imaging of abdomen and spine, chest radiography, skeletal survey, radionuclide bone scintigraphy, MIBG scintigraphy, and bone marrow biopsy. Results: In the evaluation of local disease, CT and MR were superior to US. There was no significant difference between CT and MR in assessment of the location or size of the tumour. Evaluation of invasive growth and lymphadenopathy was uncertain irrespective of imaging modality. Intraspinal extension was more distinctly demonstrated with MR. Tissue characterization with CT and MR did not contribute in the assessment of the tumours. Contrast enhancement at CT and MR examinations both improved demarcation between tumour and kidney, and was a necessity for evaluation of vessel encasement with CT. The local disease was best assessed by either CT or MR, while metastatic disease was best revealed by CT, MR, scintigraphy or bone marrow biopsy. Conclusion: Imaging may be a valuable basis for clinical assessment and pretreatment staging of abdominal neuroblastoma. (orig.)

  7. 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.

  8. Molecular events during tumor progression in neuroblastoma

    NARCIS (Netherlands)

    Bernards, R.A.; Lenardo, M.

    1990-01-01

    The N-myc oncogene was first identified as an amplified DNA element with homology to c-myc in human neuroblastoma. Since this initial observation, amplification of N-myc has also been observed in other types of human cancer, predominantly in retinoblastoma and small cell lung cancer. The

  9. Overcoming the Mechanism of Radioresistance in Neuroblastoma

    Science.gov (United States)

    2014-06-01

    expression in human neuroblastoma: up- regulation by hypoxia. Int J Cancer, 1999. 81(1): p. 113-7. 4. Yang, Q.W., et al., Methylation -associated silencing...64. 11. Martin, L., et al., Recognition of O6MeG lesions by MGMT and mismatch repair proficiency may be a prerequisite for low-dose radiation

  10. Structural studies on HCN oligomers. [catalysts for prebiotic processes

    Science.gov (United States)

    Ferris, J. P.; Edelson, E. H.; Auyeung, J. M.; Joshi, P. C.

    1981-01-01

    NMR spectral studies on the HCN oligomers suggest the presence of carboxamide and urea groupings. The release of CO2, H2O, HCN, CH3CN, HCONH2 and pyridine on pyrolysis is consistent with the presence of these groupings as well as carboxylic acid groups. No basic primary amine groupings could be detected with fluorescamine. Hydrazinolysis of the HCN oligomers releases 10% of the amino acids normally released by acid hydrolysis. The oligomers give a positive biuret test but this is not due to the presence of peptide bonds. There is no conclusive evidence for the presence of peptide bonds in the HCN oligomers. No diglycine was detected on partial hydrolysis of the HCN oligomers at pH 8.5 suggesting that HCN oligomers were not a source of prebiotic peptides.

  11. Pigments and oligomers for inks - moving towards the best combination

    International Nuclear Information System (INIS)

    Hutchinson, I.; Smith, S.; Grierson, W.; Devine, E.

    1999-01-01

    The formulation of UV curable printing inks depends on several complex factors. If the individual components of the ink are not complementary, then performance problems can arise. One critical combination is that between the pigment and the oligomer. In a new approach to improve understanding of pigment/oligomer interactions, the resources of a pigment manufacturer and an oligomer manufacturer have been combined to investigate the problem. Initial screening of process yellow pigments and several oligomer types highlighted performance variations which were then examined in more detail

  12. Overview and recent advances in the treatment of neuroblastoma.

    Science.gov (United States)

    Whittle, Sarah B; Smith, Valeria; Doherty, Erin; Zhao, Sibo; McCarty, Scott; Zage, Peter E

    2017-04-01

    Children with neuroblastoma have widely divergent outcomes, ranging from cure in >90% of patients with low risk disease to neuroblastoma, allowing for more accurate risk stratification and treatment reduction in many cases, although newer treatment strategies for children with high-risk and relapsed neuroblastoma are needed to improve outcomes. Areas covered: Neuroblastoma epidemiology, diagnosis, risk stratification, and recent advances in treatment of both newly diagnosed and relapsed neuroblastoma. Expert commentary: The identification of newer tumor targets and of novel cell-mediated immunotherapy agents may lead to novel therapeutic approaches, and clinical trials for regimens designed to target individual genetic aberrations in tumors are underway. A combination of therapeutic modalities will likely be required to improve survival and cure rates for patients with high-risk neuroblastoma.

  13. 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.)

  14. 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.)

  15. Neuroblastoma treatment in the post-genomic era.

    Science.gov (United States)

    Esposito, Maria Rosaria; Aveic, Sanja; Seydel, Anke; Tonini, Gian Paolo

    2017-02-08

    Neuroblastoma is an embryonic malignancy of early childhood originating from neural crest cells and showing heterogeneous biological, morphological, genetic and clinical characteristics. The correct stratification of neuroblastoma patients within risk groups (low, intermediate, high and ultra-high) is critical for the adequate treatment of the patients.High-throughput technologies in the Omics disciplines are leading to significant insights into the molecular pathogenesis of neuroblastoma. Nonetheless, further study of Omics data is necessary to better characterise neuroblastoma tumour biology. In the present review, we report an update of compounds that are used in preclinical tests and/or in Phase I-II trials for neuroblastoma. Furthermore, we recapitulate a number of compounds targeting proteins associated to neuroblastoma: MYCN (direct and indirect inhibitors) and downstream targets, Trk, ALK and its downstream signalling pathways. In particular, for the latter, given the frequency of ALK gene deregulation in neuroblastoma patients, we discuss on second-generation ALK inhibitors in preclinical or clinical phases developed for the treatment of neuroblastoma patients resistant to crizotinib.We summarise how Omics drive clinical trials for neuroblastoma treatment and how much the research of biological targets is useful for personalised medicine. Finally, we give an overview of the most recent druggable targets selected by Omics investigation and discuss how the Omics results can provide us additional advantages for overcoming tumour drug resistance.

  16. The Challenge of Synthesizing Oligomers for Molecular Wires

    DEFF Research Database (Denmark)

    Søndergaard, Roar; Krebs, Frederik C

    2011-01-01

    molecules with a molecular length up to 9–10 nm which allow for the introduction of aromatic thioacetate functionality in fully conjugated oligomer systems. Oligomers containing 3–15 phenyl units were synthesized by step wise Horner-Wadsworth-Emmons (HWE) reactions of a bifunctional OPV-monomer, which...

  17. Highly Stable Foams from Block Oligomers Synthesized by Enzymatic Reactions

    NARCIS (Netherlands)

    Sagis, L.M.C.; Boeriu, C.G.; Frissen, A.E.; Schols, H.A.; Wierenga, P.A.

    2008-01-01

    We have synthesized a new amphiphilic block oligomer by the enzymatic linking of a fatty acid (lauric acid) to a fructan oligomer (inulin) and tested the functionality of this carbohydrate derivative in foam stabilization. The structure of the modified oligosaccharide was found to be

  18. Synthesis and characterization of thermally stable oligomer-metal ...

    African Journals Online (AJOL)

    Synthesis and characterization of thermally stable oligomer-metal complexes of copper(II), nickel(II), zinc(II) and cobalt(II) derived from oligo- p - nitrophenylazomethinephenol. ... Based on half degradation temperature parameters Cu(II) and Zn(II) complexes were more resistant than the others. KEY WORDS: Oligomer metal ...

  19. Environment-Mediated Drug Resistance in Neuroblastoma

    Science.gov (United States)

    2013-10-01

    neuroblastoma. Five specimens were classified as positive for tumor involvement in themarrow (as assessed by the presence of tyrosine hydroxylase –positive cells ...presence of tyrosine hydroxylase – positive tumor cells (black arrow; bar, 50 mm). Right, the data represent the mean percentage (SD) of positive...H, et al. Tyrosine hydroxylase indicates cell differentiation of catechol- amine biosynthesis in neuroendocrine tumors. J Endocrinol Invest 1994;17

  20. Transcriptional Profiling Reveals a Common Metabolic Program in High-Risk Human Neuroblastoma and Mouse Neuroblastoma Sphere-Forming Cells

    Directory of Open Access Journals (Sweden)

    Mengling Liu

    2016-10-01

    Full Text Available High-risk neuroblastoma remains one of the deadliest childhood cancers. Identification of metabolic pathways that drive or maintain high-risk neuroblastoma may open new avenues of therapeutic interventions. Here, we report the isolation and propagation of neuroblastoma sphere-forming cells with self-renewal and differentiation potential from tumors of the TH-MYCN mouse, an animal model of high-risk neuroblastoma with MYCN amplification. Transcriptional profiling reveals that mouse neuroblastoma sphere-forming cells acquire a metabolic program characterized by transcriptional activation of the cholesterol and serine-glycine synthesis pathways, primarily as a result of increased expression of sterol regulatory element binding factors and Atf4, respectively. This metabolic reprogramming is recapitulated in high-risk human neuroblastomas and is prognostic for poor clinical outcome. Genetic and pharmacological inhibition of the metabolic program markedly decreases the growth and tumorigenicity of both mouse neuroblastoma sphere-forming cells and human neuroblastoma cell lines. These findings suggest a therapeutic strategy for targeting the metabolic program of high-risk neuroblastoma.

  1. PT-symmetry management in oligomer systems

    International Nuclear Information System (INIS)

    Horne, R L; Cuevas, J; Kevrekidis, P G; Whitaker, N; Abdullaev, F Kh; Frantzeskakis, D J

    2013-01-01

    We study the effects of management of the PT-symmetric part of the potential within the setting of Schrödinger dimer and trimer oligomer systems. This is done by rapidly modulating in time the gain/loss profile. This gives rise to a number of interesting properties of the system, which are explored at the level of an averaged equation approach. Remarkably, this rapid modulation provides for a controllable expansion of the region of exact PT-symmetry, depending on the strength and frequency of the imposed modulation. The resulting averaged models are analysed theoretically and their exact stationary solutions are translated into time-periodic solutions through the averaging reduction. These are, in turn, compared with the exact periodic solutions of the full non-autonomous PT-symmetry managed problem and very good agreement is found between the two. (paper)

  2. Design, synthesis, and characterization of biomimetic oligomers

    DEFF Research Database (Denmark)

    Laursen, Jonas Striegler

    been considered unsuitable for drug discovery. Circumventing the inherent stability problems, non-natural peptide analogues have shown significant potential for the development of new materials and pharmacologically active ligands. Mimics of natural amino acids have received considerable attention...... of thioamides, and trifluoroacetylation, on the cis-trans amide bond rotamer equilibria in monomer model systems. The latter systems revealed an increase in the preference for cis-amides as compared to their parent compounds and thus provide novel strategies for affecting the folding of peptoid constructs....... Using NMR spectroscopy, X-ray crystallographic analysis, and density functional theory (DFT) calculations, we found evidence for the presence of thioamide–aromatic interactions through Csp2-H···Samide hydrogen bonding. Based on these studies we designed a ß-peptoid oligomer from residues prone to fit...

  3. Proptosis as a manifestation of neuroblastoma | Hlongwane | SA ...

    African Journals Online (AJOL)

    Neuroblastoma occurs mainly in childhood and approximately 20% of cases have orbital metastases. Proptosis can be the only manifestation of metastatic neuroblastoma. Early investigation is important, as metastatic disease requires aggressive management. We present a case of a 7-yearold girl initially presenting with ...

  4. 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

  5. Enzymatic sequencing of partially acetylated chitosan oligomers.

    Science.gov (United States)

    Hamer, Stefanie Nicole; Moerschbacher, Bruno Maria; Kolkenbrock, Stephan

    2014-06-17

    Chitosan oligosaccharides have diverse biological activities with potentially valuable applications, for example, in the fields of medicine and agriculture. These functionalities are thought to depend on their degree of polymerization and acetylation, and possibly on specific patterns of acetylation. Chitosan oligomers with fully defined architecture are difficult to produce, and their complete analysis is demanding. Analysis is typically done using MS or NMR, requiring access to expensive infrastructure, and yielding unequivocal results only in the case of rather small oligomers. We here describe a simple and cost-efficient method for the sequencing of μg amounts of chitosan oligosaccharides which is based on the sequential action of two recombinant glycosidases, namely an exo-β-N-acetylhexosaminidase (GlcNAcase) from Bacillus subtilis 168 and an exo-β-d-glucosaminidase (GlcNase) from Thermococcus kodakarensis KOD1. Starting from the non-reducing end, GlcNAcase and GlcNase specifically remove N-acetyl glucosamine (A) and glucosamine (D) units, respectively. By the sequential addition and removal of these enzymes in an alternating way followed by analysis of the products using high-performance thin-layer chromatography, the sequence of chitosan oligosaccharides can be revealed. Importantly, both enzymes work under identical conditions so that no buffer exchange is required between steps, and the enzyme can be removed conveniently using simple ultra-filtration devices. As proof-of-principle, the method was used to sequence the product of enzymatic deacetylation of chitin pentamer using a recombinant chitin deacetylase from Vibrio cholerae which specifically removes the acetyl group from the second unit next to the non-reducing end of the substrate, yielding mono-deacetylated pentamer with the sequence ADAAA. Copyright © 2014 Elsevier Ltd. All rights reserved.

  6. Azure C Targets and Modulates Toxic Tau Oligomers.

    Science.gov (United States)

    Lo Cascio, Filippa; Kayed, Rakez

    2018-03-01

    Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder affecting millions of people worldwide. Therefore, finding effective interventions and therapies is extremely important. AD is one of over 20 different disorders known as tauopathies, characterized by the pathological aggregation and accumulation of tau, a microtubule-associated protein. Tau aggregates are heterogeneous and can be divided into two major groups: large metastable fibrils, including neurofibrillary tangles, and oligomers. The smaller, soluble and dynamic tau oligomers have been shown to be more toxic with more proficient seeding properties for the propagation of tau pathology as compared to the fibrillar Paired Helical Filaments (PHFs). Therefore, developing small molecules that target and interact with toxic tau oligomers can be beneficial to modulate their aggregation pathways and toxicity, preventing progression of the pathology. In this study, we show that Azure C (AC) is capable of modulating tau oligomer aggregation pathways at micromolar concentrations and rescues tau oligomers-induced toxicity in cell culture. We used both biochemical and biophysical in vitro techniques to characterize preformed tau oligomers in the presence and absence of AC. Interestingly, AC prevents toxicity not by disassembling the oligomers but rather by converting them into clusters of aggregates with nontoxic conformation.

  7. Toxic species in amyloid disorders: Oligomers or mature fibrils

    Directory of Open Access Journals (Sweden)

    Meenakshi Verma

    2015-01-01

    Full Text Available Protein aggregation is the hallmark of several neurodegenerative disorders. These protein aggregation (fibrillization disorders are also known as amyloid disorders. The mechanism of protein aggregation involves conformation switch of the native protein, oligomer formation leading to protofibrils and finally mature fibrils. Mature fibrils have long been considered as the cause of disease pathogenesis; however, recent evidences suggest oligomeric intermediates formed during fibrillization to be toxic. In this review, we have tried to address the ongoing debate for these toxic amyloid species. We did an extensive literature search and collated information from Pubmed (http://www.ncbi.nlm.nih.gov and Google search using various permutations and combinations of the following keywords: Neurodegeneration, amyloid disorders, protein aggregation, fibrils, oligomers, toxicity, Alzheimer′s Disease, Parkinson′s Disease. We describe different instances showing the toxicity of mature fibrils as well as oligomers in Alzheimer′s Disease and Parkinson′s Disease. Distinct structural framework and morphology of amyloid oligomers suggests difference in toxic effect between oligomers and fibrils. We highlight the difference in structure and proposed toxicity pathways for fibrils and oligomers. We also highlight the evidences indicating that intermediary oligomeric species can act as potential diagnostic biomarker. Since the formation of these toxic species follow a common structural switch among various amyloid disorders, the protein aggregation events can be targeted for developing broad-range therapeutics. The therapeutic trials based on the understanding of different protein conformers (monomers, oligomers, protofibrils and fibrils in amyloid cascade are also described.

  8. 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

  9. Rare MYC-amplified Neuroblastoma With Large Cell Histology.

    Science.gov (United States)

    Matsuno, Ryosuke; Gifford, Andrew J; Fang, Junming; Warren, Mikako; Lukeis, Robyn E; Trahair, Toby; Sugimoto, Tohru; Marachelian, Araz; Asgharzadeh, Shahab; Maris, John M; Ikegaki, Naohiko; Shimada, Hiroyuki

    2018-01-01

    Background Although MYCN (aka N-myc) amplification is reported in ∼20% of neuroblastomas, MYC (aka C-myc) amplification appears to be a rare event in this disease. As of today, only 2 MYC-amplified neuroblastomas have been briefly mentioned in the literature. Methods We studied here the clinicopathological features of 3 MYC-amplified neuroblastomas. Results All 3 patients (2 females and 1 male) had stage 4 disease. One female is currently alive and well 52 months after the diagnosis, while the other female and male patients died of disease 24 and 20 months after the diagnosis, respectively. Further analysis on 2 tumors revealed unfavorable histology with MYC protein overexpression but with neither MYCN amplification nor MYCN protein overexpression. Both of these tumors exhibited "large cell neuroblastoma" histology with enlarged, uniquely open nuclei and nucleolar hypertrophy, along with "aberrant" desmin expression. Conclusions MYC-amplified neuroblastomas are extremely rare and seem to present with distinct clinicopathological features.

  10. ESI and MALDI Mass Spectrometry of Large POSS Oligomers (Preprint)

    Science.gov (United States)

    2010-03-10

    Soxhlet extraction in methanol or acetonitrile for 5 days. The white polymer powder was vacuum dried. 1H NMR (CDCl3, 300 MHz): δ 0.54 (d, 14H, SiCH2CH...Discussion 3.1 POSS PMA Oligomers The simplest series of POSS PMA oligomers include the isobutyl and phenyl oligomers, synthesized by the ATRP method ... method In fact, this series represents the molecular mass limit under the ATRP conditions employed. The repeat mass of 944 is common in both the

  11. Electron beam curing polyurethane acrylate oligomer in air

    International Nuclear Information System (INIS)

    Zhu, Zhenkang; Chen, Xing; Zhou, Jichun; Ma, Zue-Teh

    1988-01-01

    It has been found according to our synthesis that a novel kind of polyurethane acrylate oligomer can be cured by electron beam in the presence of oxygen, even at normal atomospheric levels, without any additives. Irradiation of the oligomer with substantially complete cure to a solid non-tacky state is quite remarkable. It has the same gel content (90 %) in air as in nitrogen at dose of 33 kGy. Double bond conversion of the oligomer is about 50 % by I.R. (author)

  12. Binding Sites for Amyloid-β Oligomers and Synaptic Toxicity

    Science.gov (United States)

    Smith, Levi M.; Strittmatter, Stephen M.

    2017-01-01

    In Alzheimer’s disease (AD), insoluble and fibrillary amyloid-β (Aβ) peptide accumulates in plaques. However, soluble Aβ oligomers are most potent in creating synaptic dysfunction and loss. Therefore, receptors for Aβ oligomers are hypothesized to be the first step in a neuronal cascade leading to dementia. A number of cell-surface proteins have been described as Aβ binding proteins, and one or more are likely to mediate Aβ oligomer toxicity in AD. Cellular prion protein (PrPC) is a high-affinity Aβ oligomer binding site, and a range of data delineates a signaling pathway leading from Aβ complexation with PrPC to neuronal impairment. Further study of Aβ binding proteins will define the molecular basis of this crucial step in AD pathogenesis. PMID:27940601

  13. Organic heterostructures based on arylenevinylene oligomers deposited by MAPLE

    Czech Academy of Sciences Publication Activity Database

    Socol, M.; Preda, N.; Vacareanu, L.; Grigoras, M.; Socol, G.; Mihailescu, I. N.; Stanculescu, F.; Jelínek, Miroslav; Stanculescu, A.; Stoicanescu, M.

    2014-01-01

    Roč. 302, May (2014), s. 216-222 ISSN 0169-4332 Institutional support: RVO:68378271 Keywords : organic heterostructures * MAPLE * oligomer * optoelectronica Subject RIV: BM - Solid Matter Physics ; Magnetism Impact factor: 2.711, year: 2014

  14. Crystalline particles from self-assembled divinyl oligomers

    International Nuclear Information System (INIS)

    Naves, Alliny F.; Carmona-Ribeiro, Ana M.; Casarano, Romeu; Catalani, Luiz Henrique; Kawano, Yoshio; Petri, Denise F.S.

    2009-01-01

    Ethylene glycol dimethacrylate (EGDMA) and/or triethylene glycol dimethacrylate (TEGDMA) oligomers formation was catalyzed in aqueous medium by horseradish peroxidase (HRP) in the presence of H 2 O 2 at room temperature. EGDMA and/or TEGDMA oligomers were characterized by means of gel permeation chromatography, infrared vibrational spectroscopy and 1 H NMR spectroscopy. Self-assembling of oligomers led to right-angled crystalline particles, as evidenced by scanning electron microscopy and differential scanning calorimetry. EGDMA, TEGDMA and EGDMA-co-TEGDMA oligomers synthesized in the presence of HRP-H 2 O 2 system presented pendant vinyl groups along the chains, good solubility in chloroform, and well-defined melting point. These features evidenced few cross-linking or cyclization and revealed that the catalytic properties of HRP led to oligomeric materials with new characteristics

  15. 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.

  16. YAP promotes tumorigenesis and cisplatin resistance in neuroblastoma.

    Science.gov (United States)

    Yang, Chao; Tan, Juan; Zhu, Jun; Wang, Shan; Wei, Guanghui

    2017-06-06

    The transcriptional co-activator Yes-associated protein (YAP) is essential for Hippo pathway-driven tumorigenesis in various cancers. However, the expression and function of YAP in neuroblastoma remains elusive. Here, we show that YAP was highly expressed in Neuroblastoma (NB) and expression levels correlated with advanced tumor staging. Knockdown of YAP significantly impaired neuroblastoma proliferation, tumorigenesis, and invasion in vitro. Injection of the YAP inhibitor, Peptide 17, dramatically prevented neuroblastoma subcutaneous tumor growth by efficiently downregulating YAP expression in tumors. Additionally, less proliferative and more apoptotic cells were found in the Peptide 17 treatment group. Furthermore, YAP inhibition significantly inhibited cisplatin-resistant neuroblastoma proliferation, tumorigenesis, and invasion in vitro. The combination of Peptide 17 with low-dose cisplatin efficiently impaired cisplatin-resistant NB subcutaneous tumor growth, being as effective as high-dose cisplatin. Notably, the combination therapy caused lesser liver toxicity in mice compared to the high-dose cisplatin treatment group. Collectively, this work identifies YAP as a novel regulator of neuroblastoma proliferation, tumorigenesis, and invasion and indicates that YAP is a potential therapeutic target for cisplatin-resistant neuroblastoma.

  17. A Combined Photochemical and Multicomponent Reaction Approach to Precision Oligomers.

    Science.gov (United States)

    Konrad, Waldemar; Bloesser, Fabian R; Wetzel, Katharina S; Boukis, Andreas C; Meier, Michael A R; Barner-Kowollik, Christopher

    2018-03-07

    We introduce the convergent synthesis of linear monodisperse sequence-defined oligomers through a unique approach, combining the Passerini three-component reaction (P-3CR) and a Diels-Alder (DA) reaction based on photocaged dienes. A set of oligomers is prepared resting on a Passerini linker unit carrying an isocyano group for chain extension by P-3CR and a maleimide moiety for photoenol conjugation enabling a modular approach for chain growth. Monodisperse oligomers are accessible in a stepwise fashion by switching between both reaction types. Employing sebacic acid as a core unit allows the synthesis of a library of symmetric sequence-defined oligomers. The oligomers consist of alternating P-3CR and photoblocks with molecular weights up to 3532.16 g mol -1 , demonstrating the successful switching from P-3CR to photoenol conjugation. In-depth characterization was carried out including size-exclusion chromatography (SEC), high-resolution electrospray ionization mass spectrometry (ESI-MS) and NMR spectroscopy, evidencing the monodisperse nature of the precision oligomers. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  18. 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

  19. Biophysical characterization data on Aβ soluble oligomers produced through a method enabling prolonged oligomer stability and biological buffer conditions

    Directory of Open Access Journals (Sweden)

    Amanda C. Crisostomo

    2015-09-01

    Aβ1-40 soluble oligomers are produced that are suitable for biophysical studies requiring sufficient transient stability to exist in their “native” conformation in biological phosphate-saline buffers for extended periods of time. The production involves an initial preparation of highly monomeric Aβ in a phosphate saline buffer that transitions to fibrils and oligomers through time incubation alone, without added detergents or non-aqueous chemicals. This criteria ensures that the only difference between initial monomeric Aβ reactant and subsequent Aβ oligomer products is their degree of peptide assembly. A number of chemical and biophysical methods were used to characterize the monomeric reactants and soluble oligomer and amyloid fibril products, including chemical cross-linking, Western blots, fraction solubility, thioflvain T binding, size exclusion chromatography, transmission electron micrscopy, circular dichroism spectroscopy, and fluorescence resonance energy transfer.

  20. Amphipathic helices from aromatic amino acid oligomers.

    Science.gov (United States)

    Gillies, Elizabeth R; Dolain, Christel; Léger, Jean-Michel; Huc, Ivan

    2006-10-13

    Synthetic helical foldamers are of significant interest for mimicking the conformations of naturally occurring molecules while at the same time introducing new structures and properties. In particular, oligoamides of aromatic amino acids are attractive targets, as their folding is highly predictable and stable. Here the design and synthesis of new amphipathic helical oligoamides based on quinoline-derived amino acids having either hydrophobic or cationic side chains are described. Their structures were characterized in the solid state by single-crystal X-ray diffraction and in solution by NMR. Results of these studies suggest that an oligomer as short as a pentamer folds into a stable helical conformation in protic solvents, including MeOH and H(2)O. The introduction of polar proteinogenic side chains to these foldamers, as described here for the first time, promises to provide possibilities for the biological applications of these molecules. In particular, amphipathic helices are versatile targets to explore due to their importance in a variety of biological processes, and the unique structure and properties of the quinoline-derived oligoamides may allow new structure-activity relationships to be developed.

  1. 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

  2. Primary pancreatic neuroblastoma presenting with opsoclonus–myoclonus syndrome

    Directory of Open Access Journals (Sweden)

    Samuel Galgano, MD

    2016-03-01

    Full Text Available Although neuroblastoma is a common solid organ malignancy in children, primary pancreatic neuroblastoma is a rare entity in children, with very few cases reported in the literature. The case discusses the presentation of a 21-month-old female presenting to the neurology clinic with ataxia and erratic eye movements. Our case illustrates the computed tomography, ultrasound, and scintigraphic findings of primary pancreatic neuroblastoma presenting as opsoclonus–myoclonus syndrome. Computed tomography and ultrasound demonstrated a vascular, enhancing mass in the pancreatic body clearly separate from the adrenal gland. Metaiodobenzylguanidine scan demonstrates focal intense uptake in the pancreatic body. The patient's diagnosis was confirmed with biopsy, and her malignancy responded well to conventional chemotherapy. The case is important in that it demonstrates the unusual imaging appearance of a primary pancreatic neuroblastoma.

  3. Immune response to racotumomab in a child with relapsed neuroblastoma

    Directory of Open Access Journals (Sweden)

    CLAUDIA VANESA SAMPOR

    2012-12-01

    Full Text Available Immunotherapy targeting ganglioside antigens is a powerful tool for the treatment of high risk neuroblastoma. However, only treatment with anti-GD2 antibodies has been used in clinical practice and other options may be pursued. We report the use of racotumomab, an anti-idiotype vaccine against N-glycolyl neuraminic acid (NeuGc- containing gangliosides, eliciting an immune response in a child with relapsed neuroblastoma expressing the NeuGcGM3 ganglioside.

  4. 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

  5. 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.

  6. 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

  7. 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

  8. Gas chromatographic retention characteristics of different polysiloxane oligomers

    Energy Technology Data Exchange (ETDEWEB)

    Van Lenten, F. J.; Conaway, J. E.; Rogers, L. B.

    1975-01-01

    The effects on the Kovats and McReynolds indices for a modified set of Rohrschneider solutes have been examined using two different batches of a commercial polysiloxane stationary phase, Dow-Corning DC-710, and five pure oligomers isolated from the mixture. The significant differences that were found between batches appear to be due primarily to changes in the percentage of one oligomer, the cyclic pentamer. This finding emphasizes the desirability of using a pure stationary phase as well as carefully specifying the column temperature in order to improve intra- and inter- laboratory comparisons of retention indices.

  9. 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

  10. 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

  11. 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.

  12. Integrative analysis of neuroblastoma and pheochromocytoma genomics data

    Directory of Open Access Journals (Sweden)

    Szabó Peter M

    2012-10-01

    Full Text Available Abstract Background Pheochromocytoma and neuroblastoma are the most common neural crest-derived tumors in adults and children, respectively. We have performed a large-scale in silico analysis of altogether 1784 neuroblastoma and 531 pheochromocytoma samples to establish similarities and differences using analysis of mRNA and microRNA expression, chromosome aberrations and a novel bioinformatics analysis based on cooperative game theory. Methods Datasets obtained from Gene Expression Omnibus and ArrayExpress have been subjected to a complex bioinformatics analysis using GeneSpring, Gene Set Enrichment Analysis, Ingenuity Pathway Analysis and own software. Results Comparison of neuroblastoma and pheochromocytoma with other tumors revealed the overexpression of genes involved in development of noradrenergic cells. Among these, the significance of paired-like homeobox 2b in pheochromocytoma has not been reported previously. The analysis of similar expression patterns in neuroblastoma and pheochromocytoma revealed the same anti-apoptotic strategies in these tumors. Cancer regulation by stathmin turned out to be the major difference between pheochromocytoma and neuroblastoma. Underexpression of genes involved in neuronal cell-cell interactions was observed in unfavorable neuroblastoma. By the comparison of hypoxia- and Ras-associated pheochromocytoma, we have found that enhanced insulin like growth factor 1 signaling may be responsible for the activation of Src homology 2 domain containing transforming protein 1, the main co-factor of RET. Hypoxia induced factor 1α and vascular endothelial growth factor signaling included the most prominent gene expression changes between von Hippel-Lindau- and multiple endocrine neoplasia type 2A-associated pheochromocytoma. Conclusions These pathways include previously undescribed pathomechanisms of neuroblastoma and pheochromocytoma and associated gene products may serve as diagnostic markers and therapeutic

  13. The proton-pump inhibitor lansoprazole enhances amyloid beta production.

    Science.gov (United States)

    Badiola, Nahuai; Alcalde, Victor; Pujol, Albert; Münter, Lisa-Marie; Multhaup, Gerd; Lleó, Alberto; Coma, Mireia; Soler-López, Montserrat; Aloy, Patrick

    2013-01-01

    A key event in the pathogenesis of Alzheimer's disease (AD) is the accumulation of amyloid-β (Aβ) species in the brain, derived from the sequential cleavage of the amyloid precursor protein (APP) by β- and γ-secretases. Based on a systems biology study to repurpose drugs for AD, we explore the effect of lansoprazole, and other proton-pump inhibitors (PPIs), on Aβ production in AD cellular and animal models. We found that lansoprazole enhances Aβ37, Aβ40 and Aβ42 production and lowers Aβ38 levels on amyloid cell models. Interestingly, acute lansoprazole treatment in wild type and AD transgenic mice promoted higher Aβ40 levels in brain, indicating that lansoprazole may also exacerbate Aβ production in vivo. Overall, our data presents for the first time that PPIs can affect amyloid metabolism, both in vitro and in vivo.

  14. Amyloid-beta immunotherapy: the hope for Alzheimer disease?

    Science.gov (United States)

    Barrera-Ocampo, Alvaro; Lopera, Francisco

    2016-12-30

    Alzheimer disease (AD) is the most prevalent form of dementia of adult-onset, characterized by progressive impairment in cognition and memory. There is no cure for the disease and the current treatments are only symptomatic. Drug discovery is an expensive and time-consuming process; in the last decade no new drugs have been found for AD despite the efforts of the scientific community and pharmaceutical companies. The Aβ immunotherapy is one of the most promising approaches to modify the course of AD. This therapeutic strategy uses synthetic peptides or monoclonal antibodies (mAb) to decrease the Aβ load in the brain and slow the progression of the disease. Therefore, this article will discuss the main aspects of AD neuropathogenesis, the classical pharmacologic treatment, as well as the active and passive immunization describing drug prototypes evaluated in different clinical trials.

  15. Glutamate carboxypeptidase II does not process amyloid-beta peptide

    Czech Academy of Sciences Publication Activity Database

    Sedlák, František; Šácha, Pavel; Blechová, Miroslava; Březinová, Anna; Šafařík, Martin; Šebestík, Jaroslav; Konvalinka, Jan

    2013-01-01

    Roč. 27, č. 7 (2013), s. 2626-2632 ISSN 0892-6638 R&D Projects: GA ČR GAP304/12/0847 Institutional support: RVO:61388963 Keywords : PSMA * Alzheimer's disease * disaggregation * exopeptidase * substrate specificity * depsipeptide Subject RIV: CE - Biochemistry Impact factor: 5.480, year: 2013

  16. Imaging amyloid beta peptide oligomeric particles in solution.

    Science.gov (United States)

    Dong, Jijun; Apkarian, Robert P; Lynn, David G

    2005-09-01

    While all protein misfolding diseases are characterized by fibrous amyloid deposits, the favorable free energy and strongly cooperative nature of the self-assembly have complicated the development of therapeutic strategies aimed at preventing their formation. As structural models for the amyloid fibrils approach atomic resolution, increasing evidence suggests that early folding intermediates, rather than the final structure, are more strongly associated with the loss of neuronal function. For that reason we now demonstrate the use of cryo-etch high-resolution scanning electron microscopy (cryo-HRSEM) for the direct observation of pathway intermediates in amyloid assembly. A congener of the Abeta peptide of Alzheimer's disease, Abeta(13-21), samples a variety of time-dependent self-assembles in a manner similar to those seen for larger proteins. A morphological description of these intermediates is the first step towards their structural characterization and the definition of their role in both amyloid assembly and neurotoxicity.

  17. File list: ALL.Neu.05.AllAg.Neuroblastoma [Chip-atlas[Archive

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  1. File list: InP.Neu.10.AllAg.Neuroblastoma [Chip-atlas[Archive

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  8. File list: InP.Neu.05.AllAg.Neuroblastoma [Chip-atlas[Archive

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  9. Cyclin D1 is a direct transcriptional target of GATA3 in neuroblastoma tumor cells

    NARCIS (Netherlands)

    Molenaar, J. J.; Ebus, M. E.; Koster, J.; Santo, E.; Geerts, D.; Versteeg, R.; Caron, H. N.

    2010-01-01

    Almost all neuroblastoma tumors express excess levels of Cyclin D1 (CCND1) compared to normal tissues and other tumor types. Only a small percentage of these neuroblastoma tumors have high-level amplification of the Cyclin D1 gene. The other neuroblastoma tumors have equally high Cyclin D1

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

    NARCIS (Netherlands)

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

    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

  11. 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

  12. Does I-131-MIBG underestimate skeletal disease burden in neuroblastoma?

    Directory of Open Access Journals (Sweden)

    Barai Sukanta

    2004-10-01

    Full Text Available Background: Controversy persists as to the need for both MIBG and bone scanning in routine evaluation of neuroblastoma. Aim: To compare the efficacy of I-131- metaiodobenzylguanidine (MIBG scan against that of conventional Tc99m- methylene diphosphonate (MDP bone scan for the detection of skeletal deposition of neuroblastoma. Methods and Material: The study included 57 patients (36 boys, 21 girls: age range 1-14 years of neuroblastoma who underwent both bone scan with Tc99m-MDP and I-131-MIBG scan within 15 days of each other at presentation and during follow-up. Results: At presentation 11(19.2% patients had evidence of skeletal metastases on MDP scan against 7 patients who showed bony secondaries on MIBG scan. Of the 7 patients, with positive MIBG and MDP scans, MDP scan detected 11 sites whereas MIBG scan detected 7 sites. On follow-up study, 3 patients with initial abnormal MDP scan but normal MIBG scan, developed skeletal metastases detectable on MIBG scan, whereas 3 of the 46 patients who had normal MDP and MIBG scan at presentation; developed skeletal metastases detectable on MDP scan. MIBG scan was concordant in 2 of them but was normal in the third patient. Conclusion: I-131-MIBG underestimates skeletal disease burden in neuroblastoma. Therefore, Tc99m-MDP bone scan should remain a part of routine assessment of patients with neuroblastoma.

  13. 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.

  14. 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.

  15. 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.

  16. Small Glycosylated Lignin Oligomers Are Stored in Arabidopsis Leaf Vacuoles

    Science.gov (United States)

    Dima, Oana; Morreel, Kris; Vanholme, Bartel; Kim, Hoon; Ralph, John; Boerjan, Wout

    2015-01-01

    Lignin is an aromatic polymer derived from the combinatorial coupling of monolignol radicals in the cell wall. Recently, various glycosylated lignin oligomers have been revealed in Arabidopsis thaliana. Given that monolignol oxidation and monolignol radical coupling are known to occur in the apoplast, and glycosylation in the cytoplasm, it raises questions about the subcellular localization of glycosylated lignin oligomer biosynthesis and their storage. By metabolite profiling of Arabidopsis leaf vacuoles, we show that the leaf vacuole stores a large number of these small glycosylated lignin oligomers. Their structural variety and the incorporation of alternative monomers, as observed in Arabidopsis mutants with altered monolignol biosynthesis, indicate that they are all formed by combinatorial radical coupling. In contrast to the common believe that combinatorial coupling is restricted to the apoplast, we hypothesized that the aglycones of these compounds are made within the cell. To investigate this, leaf protoplast cultures were cofed with 13C6-labeled coniferyl alcohol and a 13C4-labeled dimer of coniferyl alcohol. Metabolite profiling of the cofed protoplasts provided strong support for the occurrence of intracellular monolignol coupling. We therefore propose a metabolic pathway involving intracellular combinatorial coupling of monolignol radicals, followed by oligomer glycosylation and vacuolar import, which shares characteristics with both lignin and lignan biosynthesis. PMID:25700483

  17. Statistical mechanics of thermal denaturation of DNA oligomers

    Indian Academy of Sciences (India)

    Statistical mechanics of thermal denaturation of DNA oligomers. NAVIN SINGH and YASHWANT SINGH. Department of Physics, Banaras Hindu University, Varanasi 221 005, India. Email: ysingh@bhu.ac.in. Abstract. Double stranded DNA chain is known to have non-trivial elasticity. We study the effect of this elasticity on ...

  18. Mass Spectrometric Characterization of Oligomers in Pseudomonas aeruginosa Azurin Solutions

    Czech Academy of Sciences Publication Activity Database

    Sokolová, L.; Williamson, H.; Sýkora, Jan; Hof, Martin; Gray, H. B.; Brutschy, B.; Vlček, Antonín

    2011-01-01

    Roč. 115, č. 16 (2011), s. 4790-4800 ISSN 1520-6106 R&D Projects: GA MŠk(CZ) ME10124; GA MŠk(CZ) LC06063 Institutional research plan: CEZ:AV0Z40400503 Keywords : mass spectrometry * oligomers * pseudomonas aeruginosa azurin solutions Subject RIV: CF - Physical ; Theoretical Chemistry Impact factor: 3.696, year: 2011

  19. Microdroplet temperature calibration via thermal dissociation of quenched DNA oligomers.

    Science.gov (United States)

    Hall, Eric W; Faris, Gregory W

    2014-03-01

    The development of microscale analytical techniques has created an increasing demand for reliable and accurate heating at the microscale. Here, we present a novel method for calibrating the temperature of microdroplets using quenched, fluorescently labeled DNA oligomers. Upon melting, the 3' fluorophore of the reporter oligomer separates from the 5' quencher of its reverse complement, creating a fluorescent signal recorded as a melting curve. The melting temperature for a given oligomer is determined with a conventional quantitative polymerase chain reaction (qPCR) instrument and used to calibrate the temperature within a microdroplet, with identical buffer concentrations, heated with an infrared laser. Since significant premelt fluorescence prevents the use of a conventional (single-term) sigmoid or logistic function to describe the melting curve, we present a three-term sigmoid model that provides a very good match to the asymmetric fluorescence melting curve with premelting. Using mixtures of three oligomers of different lengths, we fit multiple three-term sigmoids to obtain precise comparison of the microscale and macroscale fluorescence melting curves using "extrapolated two-state" melting temperatures.

  20. Coronavirus nucleocapsid proteins assemble constitutively in high molecular oligomers

    NARCIS (Netherlands)

    Cong, Yingying; Kriegenburg, Franziska; de Haan, Cornelis A. M.; Reggiori, Fulvio

    2017-01-01

    Coronaviruses (CoV) are enveloped viruses and rely on their nucleocapsid N protein to incorporate the positive-stranded genomic RNA into the virions. CoV N proteins form oligomers but the mechanism and relevance underlying their multimerization remain to be fully understood. Using in vitro pull-down

  1. Refractory diarrhea: A paraneoplastic syndrome of neuroblastoma.

    Science.gov (United States)

    Han, Wei; Wang, Huan-Min

    2015-07-07

    Neuroblastoma (NB) is the most common extracranial solid tumor in children. Diarrheal NB is quite rare and is not easy to diagnose in the early stage. Six cases of diarrheal NB in our hospital treated from 1996 to 2006 were retrospectively analyzed, including characteristics such as electrolyte imbalance, pathologic features, vasoactive intestinal peptide (VIP) immunohistochemical staining results, treatment, and prognosis. All patients were boys with 3-8 loose or watery stools each day and routine fecal tests were normal. Abdominal tumors were identified by B-ultrasound. Drugs were ineffective. Three patients underwent surgery, and the remaining three patients received surgery and chemotherapy. Diarrhea stopped after treatment in five patients. Two patients died due to intractable hypokalemia. The tumor was located in the adrenal gland in four patients, in the upper retroperitoneum in one patient, and in the presacral area in one patient. Pathologic findings were NB and ganglioneuroblastoma. Five patients were at clinical stage I-II, and one was at stage III. Four patients survived (followed-up for 6 mo to 4 years). Immunohistochemical staining for VIP was positive. Refractory diarrhea is a paraneoplastic syndrome of NB and is rare. Patients aged 1-3 years who present with chronic intractable diarrhea should be followed closely. Intractable diarrhea, hypokalemia, and dysplasia are the initial clinical manifestations. Increased VIP is characteristic of this disease. Potassium supplementation plays a vital role in the treatment procedure, especially preoperatively. The prognosis of diarrheal NB is good following appropriate treatment.

  2. Cytopathogenicity of Naegleria for cultured neuroblastoma cells

    Energy Technology Data Exchange (ETDEWEB)

    Fulford, D.E.

    1985-01-01

    The cytopathic activity of live Naegleria amoebae and cell-free lysates of Naegleria for B-103 rat neuroblastoma cells was investigated using a /sup 51/Cr release assay. Live amoebae and cell-free lysates of N. fowleri, N. australiensis, N. lovaniensis, and N. gruberi all induced sufficient damage to radiolabeled B-103 cells to cause a significant release of chromium. The cytotoxic activity present in the cell-free lysates of N. fowleri can be recovered in the supernatant fluid following centrifugation at 100,000xg and precipitation of the 100,000xg supernatant fluid with ammonium sulfate. Initial characterization of the cytotoxic factor indicates that it is a heat labile, pH sensitive, soluble protein. The cytotoxic activity is abolished by either extraction, unaffected by repeated freeze-thawing, and is not sensitive to inhibitors of proteolytic enzymes. Phospholipase A activity was detected in the cytotoxic ammonium sulfate precipitable material, suggesting that this enzyme activity may have a role in the cytotoxic activity of the cell-free lysates.

  3. Unique Properties of the Rabbit Prion Protein Oligomer.

    Directory of Open Access Journals (Sweden)

    Ziyao Yu

    Full Text Available Prion diseases, also known as transmissible spongiform encephalopathies (TSEs, are a group of fatal neurodegenerative disorders infecting both humans and animals. Recent works have demonstrated that the soluble prion protein oligomer (PrPO, the intermediate of the conformational transformation from the host-derived cellular form (PrPC to the disease-associated Scrapie form (PrPSc, exerts the major neurotoxicity in vitro and in vivo. Rabbits show strong resistance to TSEs, the underlying mechanism is unclear to date. It is expected that the relative TSEs-resistance of rabbits is closely associated with the unique properties of rabbit prion protein oligomer which remain to be addressed in detail. In the present work, we prepared rabbit prion protein oligomer (recRaPrPO and human prion protein oligomer (recHuPrPO under varied conditions, analyzed the effects of pH, NaCl concentration and incubation temperature on the oligomerization, and compared the properties of recRaPrPO and recHuPrPO. We found that several factors facilitated the formation of prion protein oligomers, including low pH, high NaCl concentration, high incubation temperature and low conformational stability of monomeric prion protein. RecRaPrPO was formed more slowly than recHuPrPO at physiological-like conditions (< 57°C, < 150 mM NaCl. Furthermore, recRaPrPO possessed higher susceptibility to proteinase K and lower cytotoxicity in vitro than recHuPrPO. These unique properties of recRaPrPO might substantially contribute to the TSEs-resistance of rabbits. Our work sheds light on the oligomerization of prion proteins and is of benefit to mechanistic understanding of TSEs-resistance of rabbits.

  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. Beta-synuclein occurs in vivo in lipid-associated oligomers and forms hetero-oligomers with alpha-synuclein.

    Science.gov (United States)

    Israeli, Eitan; Sharon, Ronit

    2009-01-01

    Alpha-synuclein (alphaS) and beta-synuclein (betaS) are homologous proteins implicated in Parkinson's disease and related synucleinopathies. While alphaS is neurotoxic and its aggregation and deposition in Lewy bodies is related to neurodegeneration, betaS is considered as a potent inhibitor of alphaS aggregation and toxicity. No mechanism for the neuroprotective role of betaS has been described before. Here, we report that similar to alphaS, betaS normally occurs in lipid-associated, soluble oligomers in wild-type (WT) mouse brains. We partially purified betaS and alphaS proteins from whole mouse brain by size exclusion followed by ion exchange chromatography and found highly similar elution profiles. Using this technique, we were able to partially separate betaS from alphaS and further separate betaS monomer from its own oligomers. Importantly, we show that although alphaS and betaS share high degree of similarities, betaS oligomerization is not affected by increasing cellular levels of polyunsaturated fatty acids (PUFAs), while alphaS oligomerization is dramatically enhanced by PUFA. We show the in vivo occurrence of hetero-oligomers of alphaS and betaS and suggest that betaS expression inhibits PUFA-enhanced alphaS oligomerization by forming hetero-oligomers up to a quatramer that do not further propagate.

  6. Evaluation of Genetic Predisposition for MYCN-Amplified Neuroblastoma.

    Science.gov (United States)

    Hungate, Eric A; Applebaum, Mark A; Skol, Andrew D; Vaksman, Zalman; Diamond, Maura; McDaniel, Lee; Volchenboum, Samuel L; Stranger, Barbara E; Maris, John M; Diskin, Sharon J; Onel, Kenan; Cohn, Susan L

    2017-10-01

    To investigate genetic predispositions for MYCN-amplified neuroblastoma, we performed a meta-analysis of three genome-wide association studies totaling 615 MYCN-amplified high-risk neuroblastoma cases and 1869 MYCN-nonamplified non-high-risk neuroblastoma cases as controls using a fixed-effects model with inverse variance weighting. All statistical tests were two-sided. We identified a novel locus at 3p21.31 indexed by the single nucleotide polymorphism (SNP) rs80059929 (odds ratio [OR] = 2.95, 95% confidence interval [CI] = 2.17 to 4.02, Pmeta = 6.47 × 10-12) associated with MYCN-amplified neuroblastoma, which was replicated in 127 MYCN-amplified cases and 254 non-high-risk controls (OR = 2.30, 95% CI = 1.12 to 4.69, Preplication = .02). To confirm this signal is exclusive to MYCN-amplified tumors, we performed a second meta-analysis comparing 728 MYCN-nonamplified high-risk patients to identical controls. rs80059929 was not statistically significant in MYCN-nonamplified high-risk patients (OR = 1.24, 95% CI = 0.90 to 1.71, Pmeta = .19). SNP rs80059929 is within intron 16 in the KIF15 gene. Additionally, the previously reported LMO1 neuroblastoma risk locus was statistically significant only in patients with MYCN-nonamplified high-risk tumors (OR = 0.63, 95% CI = 0.53 to 0.75, Pmeta = 1.51 × 10-8; Pmeta = .95). Our results indicate that common genetic variation predisposes to different neuroblastoma genotypes, including the likelihood of somatic MYCN-amplification. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  7. Neuroblastoma in adults. Three case reports and a review of the literature.

    Science.gov (United States)

    Kaye, J A; Warhol, M J; Kretschmar, C; Landsberg, L; Frei, E

    1986-09-01

    Three adult patients with neuroblastoma have been treated recently at the Dana-Farber Cancer Institute. One adult neuroblastoma patient experienced two distinct paraneoplastic syndromes that have not been reported previously in association with neuroblastoma. The clinical data on our three patients are presented in detail and the important features of 27 cases that have been described in the literature are summarized. This study suggests that the distribution of primary neuroblastoma sites in adults is similar to that seen in pediatric cases but that the natural history of the disease may be longer. Furthermore, this study suggests that neuroblastoma in adults may be less sensitive to chemotherapy than is the childhood disease.

  8. Probenecid Sensitizes Neuroblastoma Cancer Stem Cells to Cisplatin.

    Science.gov (United States)

    Campos-Arroyo, Denise; Maldonado, Vilma; Bahena, Ivan; Quintanar, Valeria; Patiño, Nelly; Carlos Martinez-Lazcano, Juan; Melendez-Zajgla, Jorge

    2016-01-01

    We used both in vitro cultures of neuroblastoma cell lines and nude-mice xenotransplants to explore the effects of co-administration of cisplatin and probenecid. Probenecid sensitized neuroblastoma cells, including tumor cells with stem features, to the effects of cisplatin, both in vitro and in vivo. This effect was mediated by an increase in the apoptotic cell death and a concomitant decrease in cell proliferation. This effect is accompanied by modulation of the mRNA and protein of the drug efflux transporters MDR1, MRP2, and BCRP. The co-administration of probenecid with cisplatin should be explored as a possible therapeutic strategy.

  9. Central nervous system relapse of treated stage IV neuroblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Palasis, S.; Egelhoff, J.C.; Koch, B.L.; Ball, W.S. Jr. [Department of Radiology, Children`s Hospital Medical Center, Cincinnati, OH (United States); Morris, J.D. [Department of Pediatrics, Children`s Hospital Medical Center, Cincinnati, OH (United States)

    1998-12-01

    Neuroblastoma is the most common extracranial solid tumor in pediatrics. The long-term survival of patients with advanced-stage neurobastoma has remarkably improved secondary to aggressive treatment protocols including autologous bone marrow transplant (BMT). As a result, a different natural history of this disease is being reported with unusual, late manifestations. The central nervous system (CNS), once a rare site of disease, is being involved with increasing frequency. Appropriate neuroimaging in these patients is important. Two cases of patients with treated stage IV neuroblastoma who developed isolated CNS metastases are presented. The proposed pathogenesis and neuroradiologic manifestations of this complication are reviewed. (orig.) With 2 figs., 23 refs.

  10. 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.

  11. Localized but unresectable neuroblastoma: treatment and outcome of 145 cases. Italian Cooperative Group for Neuroblastoma.

    Science.gov (United States)

    Garaventa, A; De Bernardi, B; Pianca, C; Donfrancesco, A; Cordero di Montezemolo, L; Di Tullio, M T; Bagnulo, S; Mancini, A; Carli, M; Pession, A; Arrighini, A; Di Cataldo, A; Tamaro, P; Iasonni, V; Taccone, A; Rogers, D; Boni, L

    1993-09-01

    To define factors that influence outcome in children with localized but unresectable neuroblastoma by retrospective investigation of response to therapy and outcome in 21 Italian institutions. Of 145 assessable children diagnosed between 1979 and 1990, 77 were treated between 1979 and 1984 with three consecutive standard-dose (SD) protocols, and 68 between 1985 and 1990 with a high-dose (HD) protocol. All protocols included chemotherapy, followed by resection of primary tumor if feasible. If at least partial resection was achieved, consolidation therapy followed, except that from 1985 onward, patients considered disease-free following surgery received no further treatment. Ninety-four of 145 patients (65%) achieved a complete response (CR) or partial response (PR) with chemotherapy and 75 (52%) subsequently underwent complete resection of the primary tumor. Eighty-one patients are alive (73 without disease, eight with disease), 63 have died, and one is lost to follow-up. The 5-year overall survival (OS) rate is 55% and progression-free survival (PFS) rate 50%. Both OS and PFS correlated with response to chemotherapy, removal of primary tumor, HD therapy, and serum lactate dehydrogenase (LDH) levels. Infants (< 1 year), independent of primary tumor site, and children aged 1 to 15 years with a nonabdominal primary tumor, did better compared with children aged 1 to 15 years with an abdominal primary tumor (PFS, 72% and 64% v 30%; P < .001 and < .01, respectively). Outcome of this last group improved with the HD protocol (PFS, 40% v 23%; P = .01). In children with unresectable neuroblastoma, risk categories can be defined by age and primary tumor site. HD chemotherapy should be investigated for the poor-risk category age 1 to 15 years with an abdominal primary tumor.

  12. 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

  13. Charge transfer in conjugated oligomers encapsulated into carbon nanotubes

    Energy Technology Data Exchange (ETDEWEB)

    Almadori, Y.; Alvarez, L.; Michel, T.; Le Parc, R.; Bantignies, J.L.; Hermet, P.; Sauvajol, J.L. [Laboratoire Charles Coulomb UMR 5521, Universite Montpellier 2, 34095 Montpellier (France); Laboratoire Charles Coulomb UMR 5521, CNRS, 34095 Montpellier (France); Arenal, R. [Laboratoire d' Etude des Microstructures, CNRS-ONERA, 92322 Chatillon (France); Laboratorio de Microscopias Avanzadas, Instituto de Nanociencia de Aragon, U. Zaragoza, 50018 Zaragoza (Spain); Babaa, R. [Laboratoire de Chimie des Surfaces et Interfaces, CEA, IRAMIS, SPCSI, 91191 Gif-sur-Yvette Cedex (France); Chemical Engineering Department, University of Technology PETRONAS, UTP, Ipoh-Perak (Malaysia); Jouselme, B.; Palacin, S. [Laboratoire de Chimie des Surfaces et Interfaces, CEA, IRAMIS, SPCSI, 91191 Gif-sur-Yvette Cedex (France)

    2011-11-15

    This study deals with a hybrid system consisting in quaterthiophene derivative encapsulated inside single-walled and multi-walled carbon nanotubes. Investigations of the encapsulation step are performed by transmission electron microscopy. Raman spectroscopy data point out different behaviors depending on the laser excitation energy with respect to the optical absorption of quaterthiophene. At low excitation energy (far from the oligomer resonance window) there is no significant modification of the Raman spectra before and after encapsulation. By contrast, at high excitation energy (close to the oligomer resonance window), Raman spectra exhibit a G-band shift together with an important RBM intensity loss, suggesting a significant charge transfer between the inserted molecule and the host nanotubes. Those results suggest a photo induced process leading to a significant charge transfer. (Copyright copyright 2011 WILEY-VCH Verlag GmbH and Co. KGaA, Weinheim)

  14. 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.

  15. 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

  16. CASE REPORT Proptosis as a manifestation of neuroblastoma ...

    African Journals Online (AJOL)

    disease requires aggressive management. We present a case of a 7-year- old girl initially presenting ... present initially with evidence of metastatic disease without a readily identifiable primary lesion. Neuroblastoma commonly ... Usually one adrenal gland is involved; bilateral involvement is rare.2. Symptoms may be due to ...

  17. Cytokines Synergize to Combat Metastatic Neuroblastoma | Center for Cancer Research

    Science.gov (United States)

    Neuroblastoma is the most common extracranial solid tumor in children, and clinical outcomes of patients with this disease are quite variable. Prognosis is particularly poor for patients with high-risk tumors (classification based on patients’ age, extent of disease spread, and other biological features).

  18. Resveratrol Oligomers for the Prevention and Treatment of Cancers

    OpenAIRE

    Xue, You-Qiu; Di, Jin-Ming; Luo, Yun; Cheng, Ke-Jun; Wei, Xing; Shi, Zhi

    2014-01-01

    Resveratrol (3,4′,5-trihydroxystilbene) is a naturally derived phytoalexin stilbene isolated from grapes and other plants, playing an important role in human health and is well known for its extensive bioactivities, such as antioxidation, anti-inflammatory, anticancer. In addition to resveratrol, scientists also pay attention to resveratrol oligomers, derivatives of resveratrol, which are characterized by the polymerization of two to eight, or even more resveratrol units, and are the largest ...

  19. Some biological actions of PEG-conjugated RNase A oligomers

    Czech Academy of Sciences Publication Activity Database

    Poučková, P.; Škvor, J.; Gotte, G.; Vottariello, F.; Slavík, Tomáš; Matoušek, Josef; Laurents, D. V.; Libonati, M.; Souček, J.

    2006-01-01

    Roč. 53, č. 1 (2006), s. 79-85 ISSN 0028-2685 R&D Projects: GA ČR GA523/04/0755; GA MZd NR8233 Grant - others:Spanish Ministerio de Ciencia y Technologia BQU2003-05227 Institutional research plan: CEZ:AV0Z50450515 Keywords : RNase A oligomers * polyethylene glycol conjugates * anti-tumour activity Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 1.247, year: 2006

  20. Computationally Designed Oligomers for High Contrast Black Electrochromic Polymers

    Science.gov (United States)

    2017-05-05

    AFRL-AFOSR-VA-TR-2017-0097 Computationally Designed Oligomers for High Contrast Black Electrochromic Polymers Aimee Tomlinson University Of North...Black Electrochromic FA9550-15-1-0181 Polymers 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6.AUTHO~ 5d. PROJECT NUMBER AimeeL. T . Se. TASK...neraly black neutral state. Additionally, upon oxidation these polymers would have litte to no tailing form the near IR thereby guaranteeing nearly a I

  1. α-Synuclein oligomers and clinical implications for Parkinson disease

    Science.gov (United States)

    Kalia, Lorraine V.; Kalia, Suneil K.; McLean, Pamela J.; Lozano, Andres M.; Lang, Anthony E.

    2012-01-01

    Protein aggregation within the central nervous system has been recognized as a defining feature of neurodegenerative diseases since the early 20th century. Since that time, there has been a growing list of neurodegenerative disorders, including Parkinson disease, which are characterized by inclusions of specific pathogenic proteins. This has led to the long-held dogma that these characteristic protein inclusions, which are composed of large insoluble fibrillar protein aggregates and visible by light microscopy, are responsible for cell death in these diseases. However, the correlation between protein inclusion formation and cytotoxicity is inconsistent suggesting another form of the pathogenic proteins may be contributing to neurodegeneration. There is emerging evidence implicating soluble oligomers, smaller protein aggregates not detectable by conventional microscopy, as potential culprits in the pathogenesis of neurodegenerative diseases. The protein α-synuclein is well recognized to contribute to the pathogenesis of Parkinson disease and is the major component of Lewy bodies and Lewy neurites. However, α-synuclein also forms oligomeric species with certain conformations being toxic to cells. The mechanisms by which these α-synuclein oligomers cause cell death are being actively investigated as they may provide new strategies for diagnosis and treatment of Parkinson disease and related disorders. Here we review the possible role of α-synuclein oligomers in cell death in Parkinson disease and discuss the potential clinical implications. PMID:23225525

  2. 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

  3. 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.

  4. Influence of thermalization on thermal conduction through molecular junctions: Computational study of PEG oligomers

    Science.gov (United States)

    Pandey, Hari Datt; Leitner, David M.

    2017-08-01

    Thermalization in molecular junctions and the extent to which it mediates thermal transport through the junction are explored and illustrated with computational modeling of polyethylene glycol (PEG) oligomer junctions. We calculate rates of thermalization in the PEG oligomers from 100 K to 600 K and thermal conduction through PEG oligomer interfaces between gold and other materials, including water, motivated in part by photothermal applications of gold nanoparticles capped by PEG oligomers in aqueous and cellular environments. Variation of thermalization rates over a range of oligomer lengths and temperatures reveals striking effects of thermalization on thermal conduction through the junction. The calculated thermalization rates help clarify the scope of applicability of approaches that can be used to predict thermal conduction, e.g., where Fourier's law breaks down and where a Landauer approach is suitable. The rates and nature of vibrational energy transport computed for PEG oligomers are compared with available experimental results.

  5. Effects of lattice fluctuations on electronic transmission in metal/conjugated-oligomer/metal structures

    International Nuclear Information System (INIS)

    Yu, Z.G.; Smith, D.L.; Saxena, A.; Bishop, A.R.

    1997-01-01

    The electronic transmission across metal/conjugated-oligomer/metal structures in the presence of lattice fluctuations is studied for short oligomer chains. The lattice fluctuations are approximated by static white noise disorder. Resonant transmission occurs when the energy of an incoming electron coincides with a discrete electronic level of the oligomer. The corresponding transmission peak diminishes in intensity with increasing disorder strength. Because of disorder there is an enhancement of the electronic transmission for energies that lie within the electronic gap of the oligomer. If fluctuations are sufficiently strong, a transmission peak within the gap is found at the midgap energy E=0 for degenerate conjugated oligomers (e.g., trans-polyacetylene) and E≠0 for AB-type degenerate oligomers. These results can be interpreted in terms of soliton-antisoliton states created by lattice fluctuations. copyright 1997 The American Physical Society

  6. A mimotope of Aβ oligomers may also behave as a β-sheet inhibitor.

    Science.gov (United States)

    Zhang, Yang-Xin; Wang, Shao-Wei; Lu, Shuai; Zhang, Ling-Xiao; Liu, Dong-Qun; Ji, Mei; Wang, Wei-Yun; Liu, Rui-Tian

    2017-11-01

    Beta-amyloid (Aβ) oligomers are strongly associated with the cascade of harmful events leading to neurodegeneration in Alzheimer's disease (AD). Elimination of Aβ oligomers or inhibition of Aβ assembly is a valuable therapeutic approach for the treatment of AD. Here, we obtained a mimotope of Aβ oligomers, AOEP2, by screening a peptide library using oligomer-specific antibodies. The antibodies induced by AOEP2 specifically recognize Aβ oligomers rather than monomers and fibrils. Interestingly, the AOEP2 peptide binds to Aβ monomers and inhibits the formation of Aβ oligomers and β-sheet structure, reduces Aβ42-induced neurotoxicity, and decreases the release of proinflammatory cytokines. Taken together, AOEP2, a novel multifunctional peptide directly or indirectly targeting Aβ, has promising therapeutic potential for AD. © 2017 Federation of European Biochemical Societies.

  7. MicroRNA-184-mediated inhibition of tumour growth in an orthotopic murine model of neuroblastoma.

    Science.gov (United States)

    Tivnan, Amanda; Foley, Niamh H; Tracey, Lorraine; Davidoff, Andrew M; Stallings, Raymond L

    2010-11-01

    Neuroblastoma is a paediatric cancer which originates from precursor cells of the sympathetic nervous system. Previous studies have shown that miR-184 expression has anti-proliferative effects in neuroblastoma cells grown in culture. Therefore, it was of interest to evaluate this effect in vivo. Neuroblastoma cells overexpressing miR-184 were injected retroperitoneally into CB17-SCID mice and tumour burden was assessed by measuring bioluminescence. Overall survival was also evaluated. Ectopic overexpression of miR-184 in neuroblastoma cell lines is anti-proliferative. In addition, overexpression of miR-184 led to a significant reduction in tumour growth relative to negative control-treated cohorts in a xenograft model of neuroblastoma. This study demonstrated for the first time that miR-184 significantly reduces tumour growth and increases overall survival in an orthotopic murine model of neuroblastoma through assessment of tumour growth and moribundity relative to control miRNA-treated cohorts.

  8. 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.

  9. Adult Neuroblastoma Complicated by Increased Intracranial Pressure: A Case Report and Review of the Literature

    OpenAIRE

    Stevens, Patrick L.; Johnson, Douglas B.; Thompson, Mary Ann; Keedy, Vicki L.; Frangoul, Haydar A.; Snyder, Kristen M.

    2014-01-01

    Neuroblastoma is the third most commonly occurring malignancy of the pediatric population, although it is extremely rare in the adult population. In adults, neuroblastoma is often metastatic and portends an extremely poor overall survival. Our case report documents metastatic neuroblastoma occurring in a healthy 29-year-old woman whose course was complicated by an unusual presentation of elevated intracranial pressures. The patient was treated with systemic chemotherapy, I131 metaiodobenzylgu...

  10. Proteome and Acetylome Analysis Identifies Novel Pathways and Targets Regulated by Perifosine in Neuroblastoma

    OpenAIRE

    Gu, Xiao; Hua, Zhongyan; Dong, Yudi; Zhan, Yue; Zhang, Xiaowen; Tian, Wei; Liu, Zhihui; Thiele, Carol J.; Li, Zhijie

    2017-01-01

    Perifosine, an Akt inhibitor, has been shown to be effective in controlling neuroblastoma tumor growth. However, studies indicate that in addition to the ability to inhibit Akt, other mechanisms contribute to perifosine?s anti-tumor activity. To gain insight into perifosine anti-tumor activity in neuroblastoma we have studied changes in the proteome and acetylome after perifosine treatment in SK-N-AS neuroblastoma cells using SILAC labeling, affinity enrichment, high-resolution and LC-MS/MS a...

  11. 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.

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

    Science.gov (United States)

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

    2016-03-01

    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. IC50 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

  13. Fibril specific, conformation dependent antibodies recognize a generic epitope common to amyloid fibrils and fibrillar oligomers that is absent in prefibrillar oligomers

    Directory of Open Access Journals (Sweden)

    Rasool Suhail

    2007-09-01

    Full Text Available Abstract Background Amyloid-related degenerative diseases are associated with the accumulation of misfolded proteins as amyloid fibrils in tissue. In Alzheimer disease (AD, amyloid accumulates in several distinct types of insoluble plaque deposits, intracellular Aβ and as soluble oligomers and the relationships between these deposits and their pathological significance remains unclear. Conformation dependent antibodies have been reported that specifically recognize distinct assembly states of amyloids, including prefibrillar oligomers and fibrils. Results We immunized rabbits with a morphologically homogeneous population of Aβ42 fibrils. The resulting immune serum (OC specifically recognizes fibrils, but not random coil monomer or prefibrillar oligomers, indicating fibrils display a distinct conformation dependent epitope that is absent in prefibrillar oligomers. The fibril epitope is also displayed by fibrils of other types of amyloids, indicating that the epitope is a generic feature of the polypeptide backbone. The fibril specific antibody also recognizes 100,000 × G soluble fibrillar oligomers ranging in size from dimer to greater than 250 kDa on western blots. The fibrillar oligomers recognized by OC are immunologically distinct from prefibrillar oligomers recognized by A11, even though their sizes overlap broadly, indicating that size is not a reliable indicator of oligomer conformation. The immune response to prefibrillar oligomers and fibrils is not sequence specific and antisera of the same specificity are produced in response to immunization with islet amyloid polypeptide prefibrillar oligomer mimics and fibrils. The fibril specific antibodies stain all types of amyloid deposits in human AD brain. Diffuse amyloid deposits stain intensely with anti-fibril antibody although they are thioflavin S negative, suggesting that they are indeed fibrillar in conformation. OC also stains islet amyloid deposits in transgenic mouse models of type

  14. 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

  15. 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.

  16. Molecular determinants of S100B oligomer formation.

    Directory of Open Access Journals (Sweden)

    Eva Thulin

    Full Text Available BACKGROUND: S100B is a dimeric protein that can form tetramers, hexamers and higher order oligomers. These forms have been suggested to play a role in RAGE activation. METHODOLOGY/PRINCIPAL FINDINGS: Oligomerization was found to require a low molecular weight trigger/cofactor and could not be detected for highly pure dimer, irrespective of handling. Imidazol was identified as a substance that can serve this role. Oligomerization is dependent on both the imidazol concentration and pH, with optima around 90 mM imidazol and pH 7, respectively. No oligomerization was observed above pH 8, thus the protonated form of imidazol is the active species in promoting assembly of dimers to higher species. However, disulfide bonds are not involved and the process is independent of redox potential. The process was also found to be independent of whether Ca(2+ is bound to the protein or not. Tetramers that are purified from dimers and imidazol by gel filtration are kinetically stable, but dissociate into dimers upon heating. Dimers do not revert to tetramer and higher oligomer unless imidazol is again added. Both tetramers and hexamers bind the target peptide from p53 with retained stoichiometry of one peptide per S100B monomer, and with high affinity (lgK = 7.3±0.2 and 7.2±0.2, respectively in 10 mM BisTris, 5 mM CaCl(2, pH 7.0, which is less than one order of magnitude reduced compared to dimer under the same buffer conditions. CONCLUSION/SIGNIFICANCE: S100B oligomerization requires protonated imidazol as a trigger/cofactor. Oligomers are kinetically stable after imidazol is removed but revert back to dimer if heated. The results underscore the importance of kinetic versus thermodynamic control of S100B protein aggregation.

  17. Structural Transitions of Solvent-Free Oligomer-Grafted Nanoparticles

    KAUST Repository

    Chremos, Alexandros

    2011-09-01

    Novel structural transitions of solvent-free oligomer-grafted nanoparticles are investigated by using molecular dynamics simulations of a coarse-grained bead-spring model. Variations in core size and grafting density lead to self-assembly of the nanoparticles into a variety of distinct structures. At the boundaries between different structures, the nanoparticle systems undergo thermoreversible transitions. This structural behavior, which has not been previously reported, deviates significantly from that of simple liquids. The reversible nature of these transitions in solvent-free conditions offers new ways to control self-assembly of nanoparticles at experimentally accessible conditions. © 2011 American Physical Society.

  18. Conjugated Polymers and Oligomers: Structural and Soft Matter Aspects

    DEFF Research Database (Denmark)

    This book identifies modern topics and current trends of structural and soft matter aspects of conjugated polymers and oligomers. Each chapter recognizes an active research line where structural perspective dominates research and therefore the book covers fundamental aspects of persistent...... conjugated polymer backbone, water soluble conjugated polyelectrolytes and surfactants, conjugated molecules and biomolecules and DNA and the advanced use of synchrotron radiation and electron microscopy to find out structural details in conjugated molecule films and devices as well as under ambient...... and extreme conditions....

  19. Expression of enzymes in yeast for lignocellulose derived oligomer CBP

    Energy Technology Data Exchange (ETDEWEB)

    McBride, John E.; Wiswall, Erin; Shikhare, Indraneel; Xu, Haowen; Thorngren, Naomi; Hau, Heidi H.; Stonehouse, Emily

    2017-08-29

    The present invention provides a multi-component enzyme system that hydrolyzes hemicellulose oligomers from hardwood which can be expressed, for example, in yeast such as Saccharomyces cerevisiae. In some embodiments, this invention provides for the engineering of a series of biocatalysts combining the expression and secretion of components of this enzymatic system with robust, rapid xylose utilization, and ethanol fermentation under industrially relevant process conditions for consolidated bioprocessing. In some embodiments, the invention utilizes co-cultures of strains that can achieve significantly improved performance due to the incorporation of additional enzymes in the fermentation system.

  20. Sodium valproate does not augment Prpsc in murine neuroblastoma cells.

    Science.gov (United States)

    Legendre, C; Casagrande, F; Andrieu, T; Dormont, D; Clayette, P

    2007-10-01

    Sodium valproate (VPA) has been reported to increase the accumulation of the pathologic isoform of prion protein (PrPsc) in scrapie-infected murine neuroblastoma cells. In this study, the effect of VPA on PrPsc accumulation was investigated in murine N2a neuroblastoma cells chronically infected with scrapie strain 22L (N2a-22L). No accumulation of PrPsc was detected after short-term (3 days) or long-term (21 days) treatment of N2a-22L cells with 4.8, 12, 18 or 24 microM VPA. Higher VPA concentrations (240 and 600 microM) also failed to augment PrPsc expression. In conclusion, in our experimental conditions, no deleterious effect was induced by VPA on prions replication.

  1. Optimization of liposomal topotecan for use in treating neuroblastoma.

    Science.gov (United States)

    Chernov, Lina; Deyell, Rebecca J; Anantha, Malathi; Dos Santos, Nancy; Gilabert-Oriol, Roger; Bally, Marcel B

    2017-06-01

    The purpose of this work was to develop an optimized liposomal formulation of topotecan for use in the treatment of patients with neuroblastoma. Drug exposure time studies were used to determine that topotecan (Hycamtin) exhibited great cytotoxic activity against SK-N-SH, IMR-32 and LAN-1 neuroblastoma human cell lines. Sphingomyelin (SM)/cholesterol (Chol) and 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC)/Chol liposomes were prepared using extrusion methods and then loaded with topotecan by pH gradient and copper-drug complexation. In vitro studies showed that SM/Chol liposomes retained topotecan significantly better than DSPC/Chol liposomes. Decreasing the drug-to-lipid ratio engendered significant increases in drug retention. Dose-range finding studies on NRG mice indicated that an optimized SM/Chol liposomal formulation of topotecan prepared with a final drug-to-lipid ratio of 0.025 (mol: mol) was better tolerated than the previously described DSPC/Chol topotecan formulation. Pharmacokinetic studies showed that the optimized SM/Chol liposomal topotecan exhibited a 10-fold increase in plasma half-life and a 1000-fold increase in AUC 0-24 h when compared with Hycamtin administered at equivalent doses (5 mg/kg). In contrast to the great extension in exposure time, SM/Chol liposomal topotecan increased the life span of mice with established LAN-1 neuroblastoma tumors only modestly in a subcutaneous and systemic model. The extension in exposure time may still not be sufficient and the formulation may require further optimization. In the future, liposomal topotecan will be assessed in combination with high-dose radiotherapy such as 131 I-metaiodobenzylguanidine, and immunotherapy treatment modalities currently used in neuroblastoma therapy. © 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

  2. 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...

  3. 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.

  4. Enhanced chromosomal fragility in neuroblastoma: correlation with poor prognosis.

    Science.gov (United States)

    Vernole, P; Tedeschi, B; Melino, G; Pianca, C; Nicoletti, B

    1992-01-01

    In a previous study we demonstrated spontaneous fragility and hypersensitivity to fragile site induction by aphidicolin in lymphocytes from some neuroblastoma patients and their parents. Here we report data based on a total of 40 patients and 37 families. Possible correlations between higher sensitivity to aphidicolin and a variety of personal and clinical characteristics were verified. Patients with a poor prognosis generally proved to be more susceptible to fragile site induction.

  5. 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.

  6. Identifying microRNAs that Regulate Neuroblastoma Cell Differentiation

    Science.gov (United States)

    2015-10-01

    System (Promega). Firefly lucifer - ase activity was normalized to Renilla luciferase activity to evalu- ate the effect of the miRNAs. Biotinylated-miR...objective of Aim 1. We further validated the effect of miR-449a on the expression of molecular differentiation markers, on cell cycle distribution, and on...inducing effect in neuroblastoma cell lines regardless of the genetic backgrounds of the cell lines. We have completed the screen in the MYCN-amplified

  7. Marrow Derived Antibody Library for the Treatment of Neuroblastoma

    Science.gov (United States)

    2015-12-01

    identified with strong binding to tumor cells. In Figure 1, the positive binding of phage clones to MGT-003 cells were visualized using anti- M13 phage ...neuroblastoma patients using phage display and B cell hybridoma technologies. The scope of this project is to use NB patient-derived materials to...create NB cell lines, xenograft models, NB specific phage display libraries and to identify and amplify functional anti-NB specific antibodies for future

  8. 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.

  9. 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

  10. Neuroblastoma in children: Update on clinicopathologic and genetic prognostic factors.

    Science.gov (United States)

    Ahmed, Atif A; Zhang, Lei; Reddivalla, Naresh; Hetherington, Maxine

    2017-04-01

    Neuroblastoma is the most common extracranial solid tumor in childhood accounting for 8-10% of all childhood malignancies. The tumor is characterized by a spectrum of histopathologic features and a heterogeneous clinical phenotype. Modern multimodality therapy results in variable clinical response ranging from cure in localized tumors to limited response in aggressive metastatic disease. Accurate clinical staging and risk assessment based on clinical, surgical, biologic and pathologic criteria are of pivotal importance in assigning prognosis and planning effective treatment approaches. Numerous studies have analyzed the presence of several clinicopathologic and biologic factors in association with the patient's prognosis and outcome. Although patient's age, tumor stage, histopathologic classification, and MYCN amplification are the most commonly validated prognostic markers, several new gene mutations have been identified in sporadic and familial neuroblastoma cases that show association with an adverse outcome. Novel molecular studies have also added data on chromosomal segmental aberrations in MYCN nonamplified tumors. In this review, we provide an updated summary of the clinical, serologic and genetic prognostic indicators in neuroblastoma including classic factors that have consistently played a role in risk stratification of patients as well as newly discovered biomarkers that may show a potential significance in patients' management.

  11. 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.

  12. 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.

  13. 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.)

  14. Amyloid oligomer structure characterization from simulations: A general method

    Energy Technology Data Exchange (ETDEWEB)

    Nguyen, Phuong H., E-mail: phuong.nguyen@ibpc.fr [Laboratoire de Biochimie Théorique, UPR 9080, CNRS Université Denis Diderot, Sorbonne Paris Cité IBPC, 13 rue Pierre et Marie Curie, 75005 Paris (France); Li, Mai Suan [Institute of Physics, Polish Academy of Sciences, Al. Lotnikow 32/46, 02-668 Warsaw (Poland); Derreumaux, Philippe, E-mail: philippe.derreumaux@ibpc.fr [Laboratoire de Biochimie Théorique, UPR 9080, CNRS Université Denis Diderot, Sorbonne Paris Cité IBPC, 13 rue Pierre et Marie Curie, 75005 Paris (France); Institut Universitaire de France, 103 Bvd Saint-Germain, 75005 Paris (France)

    2014-03-07

    Amyloid oligomers and plaques are composed of multiple chemically identical proteins. Therefore, one of the first fundamental problems in the characterization of structures from simulations is the treatment of the degeneracy, i.e., the permutation of the molecules. Second, the intramolecular and intermolecular degrees of freedom of the various molecules must be taken into account. Currently, the well-known dihedral principal component analysis method only considers the intramolecular degrees of freedom, and other methods employing collective variables can only describe intermolecular degrees of freedom at the global level. With this in mind, we propose a general method that identifies all the structures accurately. The basis idea is that the intramolecular and intermolecular states are described in terms of combinations of single-molecule and double-molecule states, respectively, and the overall structures of oligomers are the product basis of the intramolecular and intermolecular states. This way, the degeneracy is automatically avoided. The method is illustrated on the conformational ensemble of the tetramer of the Alzheimer's peptide Aβ{sub 9−40}, resulting from two atomistic molecular dynamics simulations in explicit solvent, each of 200 ns, starting from two distinct structures.

  15. Charge transfer interactions in oligomer coated gold nanoclusters

    International Nuclear Information System (INIS)

    Newmai, M. Boazbou; Kumar, Pandian Senthil

    2016-01-01

    Gold nanoclusters were synthesized by a bottom-up synergistic approach of in-situ oligomerization of the monomer, N-vinyl pyrrolidone (NVP) and simultaneous weak reduction of Au-NVP complexes in the absence of any other external energy sources, thereby making these tiny gold clusters as the most elemental building blocks to construct further novel nano/microstructures with application potentials. It is well-known that metal clusters with less than 2 nm size do not show the usual surface plasmon band, because of the presence of a band-gap at the fermi level. Nevertheless, our present oligomer coated gold clusters show a discrete intense band at around 630 nm, which could very well be attributed to the charge transfer between the oligomer chain and the surface Au atoms. Such kind of sacrificial plasmon induced charge transfer interaction, observed for the very first time to the best of our knowledge, were also strongly corroborated through the enhancement / shifting of specific vibrational / rotational peaks as observed from the FTIR and Raman measurements as a function of the metal oxidation states, thus representing a new prototype for an efficient solar energy conversion probe.

  16. Broadband terahertz dynamics of propylene glycol monomer and oligomers

    Science.gov (United States)

    Koda, Shota; Mori, Tatsuya; Kojima, Seiji

    2016-12-01

    We investigated the broadband terahertz spectra (0.1-5.0 THz) of glass-forming liquids, propylene glycol (PG), its oligomers poly (propylene glycol)s (PPGs), and poly (propylene glycol) diglycidyl ether (PPG-de) using broadband terahertz time-domain spectroscopy and low-frequency Raman scattering. The numerical value of the dielectric loss at around 1.5 THz, which is the peak position of broad peaks in all samples, decreased as the molecular weight increased. Furthermore, the peak at around 1.5 THz is insensitive to the molecular weight. For PPGs, the side chain effect of the oligomer was observed in the terahertz region. Based on the experimental and calculation results for the PPGs and PPG-de, whose end groups are epoxy groups, the beginnings of the increases in the observed dielectric loss above 3.5 THz of the PPGs are assigned to the OH bending vibration. The higher value of the dielectric loss in the terahertz region for the PPG-de can be the tail of a broad peak located in the MHz region. The difference between the Raman susceptibility and dielectric loss reflects the difference in the observable molecular dynamics between the infrared and Raman spectroscopies.

  17. Asymmetric wave propagation through nonlinear PT-symmetric oligomers

    Science.gov (United States)

    D'Ambroise, J.; Kevrekidis, P. G.; Lepri, S.

    2012-11-01

    In the present paper, we consider nonlinear PT-symmetric dimers and trimers (more generally, oligomers) embedded within a linear Schrödinger lattice. We examine the stationary states of such chains in the form of plane waves, and analytically compute their reflection and transmission coefficients through the nonlinear PT symmetric oligomer, as well as the corresponding rectification factors which clearly illustrate the asymmetry between left and right propagation in such systems. We examine not only the existence but also the dynamical stability of the plane wave states and interestingly find them to be unstable except in the vicinity of the linear limit. Lastly, we generalize our numerical considerations to the more physically relevant case of Gaussian initial wavepackets and confirm that the asymmetry in the transmission properties persists in the case of such wavepackets, as well. The role of potential asymmetries in the nonlinearity or in the gain/loss pattern is also considered. This article is part of a special issue of Journal of Physics A: Mathematical and Theoretical devoted to ‘Quantum physics with non-Hermitian operators’.

  18. Supersymmetry theory of microphase separation in homopolymer-oligomer mixtures

    Science.gov (United States)

    Olemskoi, Alexander; Krakovsky, Ivan; Savelyev, Alexey

    2004-02-01

    The mesoscopic structure of periodically alternating layers of stretched homopolymer chains surrounded by perpendicularly oriented oligomeric tails is studied for systems with both strong (ionic) and weak (hydrogen) interactions. We focus on the consideration of the distribution of oligomers along the homopolymer chains that is described by the effective equation of motion with the segment number playing the role of imaginary time. The supersymmetry technique is developed to consider associative hydrogen bonding, self-action effects, inhomogeneity, and temperature fluctuations in the oligomer distribution. Making use of the self-consistent approach allows one to explain experimentally observed temperature dependence of the structure period and the order-disorder transition temperature and period as functions of the oligomeric fraction for systems with different bonding strengths. A whole set of parameters of the model used is found for strong, intermediate, and weak coupled systems being Poly (4-vinyl pyridine) dodecyl benzene sulfonic acid [P4VP-(DBSA)x], P4VP-[Zn(DBS)2]x, and P4VP- 3-pentadecyl Phenolx, respectively. A passage from the former two to the latter is shown to cause a crucial decrease in the magnitude of both parameters of hydrogen bonding and self-action, as well as the order-disorder transition temperature.

  19. Amyloid-β oligomer detection by ELISA in cerebrospinal fluid and brain tissue.

    Science.gov (United States)

    Bruggink, Kim A; Jongbloed, Wesley; Biemans, Elisanne A L M; Veerhuis, Rob; Claassen, Jurgen A H R; Kuiperij, H Bea; Verbeek, Marcel M

    2013-02-15

    Amyloid-β (Aβ) deposits are important pathological hallmarks of Alzheimer's disease (AD). Aβ aggregates into fibrils; however, the intermediate oligomers are believed to be the most neurotoxic species and, therefore, are of great interest as potential biomarkers. Here, we have developed an enzyme-linked immunosorbent assay (ELISA) specific for Aβ oligomers by using the same capture and (labeled) detection antibody. The ELISA predominantly recognizes relatively small oligomers (10-25 kDa) and not monomers. In brain tissue of APP/PS1 transgenic mice, we found that Aβ oligomer levels increase with age. However, for measurements in human samples, pretreatment to remove human anti-mouse antibodies (HAMAs) was required. In HAMA-depleted human hippocampal extracts, the Aβ oligomer concentration was significantly increased in AD compared with nondemented controls. Aβ oligomer levels could also be quantified in pretreated cerebrospinal fluid (CSF) samples; however, no difference was detected between AD and control groups. Our data suggest that levels of small oligomers might not be suitable as biomarkers for AD. In addition, we demonstrate the importance of avoiding HAMA interference in assays to quantify Aβ oligomers in human body fluids. Copyright © 2012 Elsevier Inc. All rights reserved.

  20. ADSORPTION-DESORPTION KINETICS IN NANOSCOPICALLY CONFINED OLIGOMER FILMS UNDER SHEAR

    NARCIS (Netherlands)

    Manias, E; Subbotin, A.V.; Hadziioannou, G; ten Brinke, G.

    1995-01-01

    The method of molecular dynamics computer simulations is employed to study oligomer melts confined in ultra-thin films and subjected to shear. The focus is on the self-diffusion of oligomers near attractive surfaces and on their desorption, together with the effects of increasing energy of

  1. Aggregation Effects on the Emission Spectra and Dynamics of Model Oligomers of MEH-PPV

    NARCIS (Netherlands)

    Sherwood, Gizelle A.; Cheng, Ryan; Smith, Timothy M.; Werner, James H.; Shreve, Andrew P.; Peteanu, Linda A.; Wildeman, Jurjen

    2009-01-01

    The effects of aggregate formation on the photophysical properties of oligomers of MEH-PPV were studied in bulk solution to better understand the effects of aggregation on the emission properties of the polymer. Nanoaggregates of oligomers from 3 to 17 repeat units in length were formed using a

  2. Tau oligomers impair memory and induce synaptic and mitochondrial dysfunction in wild-type mice

    Directory of Open Access Journals (Sweden)

    Jackson George R

    2011-06-01

    Full Text Available Abstract Background The correlation between neurofibrillary tangles of tau and disease progression in the brains of Alzheimer's disease (AD patients remains an area of contention. Innovative data are emerging from biochemical, cell-based and transgenic mouse studies that suggest that tau oligomers, a pre-filament form of tau, may be the most toxic and pathologically significant tau aggregate. Results Here we report that oligomers of recombinant full-length human tau protein are neurotoxic in vivo after subcortical stereotaxic injection into mice. Tau oligomers impaired memory consolidation, whereas tau fibrils and monomers did not. Additionally, tau oligomers induced synaptic dysfunction by reducing the levels of synaptic vesicle-associated proteins synaptophysin and septin-11. Tau oligomers produced mitochondrial dysfunction by decreasing the levels of NADH-ubiquinone oxidoreductase (electron transport chain complex I, and activated caspase-9, which is related to the apoptotic mitochondrial pathway. Conclusions This study identifies tau oligomers as an acutely toxic tau species in vivo, and suggests that tau oligomers induce neurodegeneration by affecting mitochondrial and synaptic function, both of which are early hallmarks in AD and other tauopathies. These results open new avenues for neuroprotective intervention strategies of tauopathies by targeting tau oligomers.

  3. Theory of microphase separation in homopolymer-oligomer mixtures

    International Nuclear Information System (INIS)

    Olemskoi, Alexander; Savelyev, Alexey

    2005-01-01

    This work starts with the review of theoretical methods proposed, during past decades, for description of phase behavior in different polymer systems, involving variety of linear polymers (regular and polydisperse block (co)polymers, random polymers) and the polymer systems with non-covalent bonds of different strength. Microphase separation (MS) into different ordered mesophases is known to be the principal property of such systems. It is shown that most of the theoretical approaches proposed for description of the MS are based on the simple random phase approximation (RPA). It turns out, however, that mean field RPA method applied to description of the systems with non-covalent bonds does not provide the whole picture of MS. We show that the problem here arises when one treats both Flory-Huggins non-associated interactions and non-covalent bonds (hydrogen, ionic) within the unified RPA scheme, which is obviously rough for description of the latter type of interactions. Such a theory was developed in a few recent papers for the systems involving weak hydrogen bonds between homopolymer chains and the low molecular weight oligomers (surfactants). However, it leaves some experimental data unaccounted. The purpose of this review is to consider more detailed theory which is able to explain not only all the experimental data for the above systems but also to take into account the strength variation of non-bonding interactions. In particular, we consider the strong ionic interactions, weak hydrogen bonding, and the interactions of intermediate strength between polymer chain and short oligomers within our unifying theory. To develop such a description in a self-consistent way we propose to use a general field theory of stochastic systems. The mesoscopic (lamellar) structure of the periodically alternating layers of stretched homopolymer chains surrounded by perpendicularly oriented oligomeric tails is studied for the systems with both strong (ionic) and weak (hydrogen

  4. Theory of microphase separation in homopolymer oligomer mixtures

    Science.gov (United States)

    Olemskoi, Alexander; Savelyev, Alexey

    2005-11-01

    This work starts with the review of theoretical methods proposed, during past decades, for description of phase behavior in different polymer systems, involving variety of linear polymers (regular and polydisperse block (co)polymers, random polymers) and the polymer systems with non-covalent bonds of different strength. Microphase separation (MS) into different ordered mesophases is known to be the principal property of such systems. It is shown that most of the theoretical approaches proposed for description of the MS are based on the simple random phase approximation (RPA). It turns out, however, that mean field RPA method applied to description of the systems with non-covalent bonds does not provide the whole picture of MS. We show that the problem here arises when one treats both Flory-Huggins non-associated interactions and non-covalent bonds (hydrogen, ionic) within the unified RPA scheme, which is obviously rough for description of the latter type of interactions. Such a theory was developed in a few recent papers for the systems involving weak hydrogen bonds between homopolymer chains and the low molecular weight oligomers (surfactants). However, it leaves some experimental data unaccounted. The purpose of this review is to consider more detailed theory which is able to explain not only all the experimental data for the above systems but also to take into account the strength variation of non-bonding interactions. In particular, we consider the strong ionic interactions, weak hydrogen bonding, and the interactions of intermediate strength between polymer chain and short oligomers within our unifying theory. To develop such a description in a self-consistent way we propose to use a general field theory of stochastic systems. The mesoscopic (lamellar) structure of the periodically alternating layers of stretched homopolymer chains surrounded by perpendicularly oriented oligomeric tails is studied for the systems with both strong (ionic) and weak (hydrogen

  5. Star-shaped tetrathiafulvalene oligomers towards the construction of conducting supramolecular assembly.

    Science.gov (United States)

    Iyoda, Masahiko; Hasegawa, Masashi

    2015-01-01

    The construction of redox-active supramolecular assemblies based on star-shaped and radially expanded tetrathiafulvalene (TTF) oligomers with divergent and extended conjugation is summarized. Star-shaped TTF oligomers easily self-aggregate with a nanophase separation to produce supramolecular structures, and their TTF units stack face-to-face to form columnar structures using the fastener effect. Based on redox-active self-organizing supramolecular structures, conducting nanoobjects are constructed by doping of TTF oligomers with oxidants after the formation of such nanostructures. Although radical cations derived from TTF oligomers strongly interact in solution to produce a mixed-valence dimer and π-dimer, it seems to be difficult to produce nanoobjects of radical cations different from those of neutral TTF oligomers. In some cases, however, radical cations form nanostructured fibers and rods by controlling the supramolecular assembly, oxidation states, and counter anions employed.

  6. Preparation of Chito-Oligomers by Hydrolysis of Chitosan in the Presence of Zeolite as Adsorbent

    Directory of Open Access Journals (Sweden)

    Khalid A. Ibrahim

    2016-07-01

    Full Text Available An increasing interest has recently been shown to use chitin/chitosan oligomers (chito-oligomers in medicine and food fields because they are not only water-soluble, nontoxic, and biocompatible materials, but they also exhibit numerous biological properties, including antibacterial, antifungal, and antitumor activities, as well as immuno-enhancing effects on animals. Conventional depolymerization methods of chitosan to chito-oligomers are either chemical by acid-hydrolysis under harsh conditions or by enzymatic degradation. In this work, hydrolysis of chitosan to chito-oligomers has been achieved by applying adsorption-separation technique using diluted HCl in the presence of different types of zeolite as adsorbents. The chito-oligomers were retrieved from adsorbents and characterized by differential scanning calorimetry (DSC, liquid chromatography/mass spectroscopy (LC/MS, and ninhydrin test.

  7. Gnetin-C and other resveratrol oligomers with cancer chemopreventive potential.

    Science.gov (United States)

    Espinoza, J Luis; Inaoka, Pleiades T

    2017-09-01

    Resveratrol has been extensively studied to investigate its biological effects, including its chemopreventive potential against cancer. Over the past decade, various resveratrol oligomers, both naturally occurring and synthetic, have been described. These resveratrol oligomers result from the polymerization of two or more resveratrol units to form dimers, trimers, tetramers, or even more complex derivatives. Some oligomers appear to have antitumor activities that are similar or superior to monomeric resveratrol. In this review, we discuss resveratrol oligomers with anticancer potential, with emphasis on well-characterized compounds, such as the dimer gnetin-C and other oligomers from Gnetum gnemon, whose safety, pharmacokinetic, and biological activities have been studied in humans. © 2017 New York Academy of Sciences.

  8. Preparation of Chito-Oligomers by Hydrolysis of Chitosan in the Presence of Zeolite as Adsorbent

    Science.gov (United States)

    Ibrahim, Khalid A.; El-Eswed, Bassam I.; Abu-Sbeih, Khaleel A.; Arafat, Tawfeeq A.; Al Omari, Mahmoud M. H.; Darras, Fouad H.; Badwan, Adnan A.

    2016-01-01

    An increasing interest has recently been shown to use chitin/chitosan oligomers (chito-oligomers) in medicine and food fields because they are not only water-soluble, nontoxic, and biocompatible materials, but they also exhibit numerous biological properties, including antibacterial, antifungal, and antitumor activities, as well as immuno-enhancing effects on animals. Conventional depolymerization methods of chitosan to chito-oligomers are either chemical by acid-hydrolysis under harsh conditions or by enzymatic degradation. In this work, hydrolysis of chitosan to chito-oligomers has been achieved by applying adsorption-separation technique using diluted HCl in the presence of different types of zeolite as adsorbents. The chito-oligomers were retrieved from adsorbents and characterized by differential scanning calorimetry (DSC), liquid chromatography/mass spectroscopy (LC/MS), and ninhydrin test. PMID:27455287

  9. Measuring Single-Bond Rupture Forces Using High Electric Fields in Microfluidic Channels and DNA Oligomers as Force Tags

    OpenAIRE

    Breisch, Stefanie; Gonska, Julian; Deissler, Helmut; Stelzle, Martin

    2005-01-01

    The disruption force of specific biotin-streptavidin bonds was determined using DNA oligomers as force tags. Forces were generated by an electric field acting on a biotinylated fluorescently labeled DNA oligomer. DNA oligomers were immobilized via biotin-streptavidin bonds on the walls of microfluidic channels. Channel layout and fluid-based deposition process were designed to enable well-defined localized deposition of the oligomers in a narrow gap of the microchannel. Electric fields of up ...

  10. 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

  11. 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.

  12. Olfactory Neuroblastoma (ONB) in a 2 year old child: A case Report ...

    African Journals Online (AJOL)

    A case of olfactory neuroblastoma (ONB) presenting in a 2 year old girl as a nasal mass is presented. Although olfactory neuroblastomas have been reported from various parts of the world, this, to our knowledge is the first report from Midwestern Nigeria. We wish to emphasize the importance of histological examination of ...

  13. [Biological markers for the prognosis of neuroblastoma: proposal of a method of analysis].

    Science.gov (United States)

    Combaret, V; Delattre, O; Bénard, J; Favrot, M C

    1998-03-01

    The prognosis of pediatric neuroblastoma depends both on clinical presentation and on certain cellular and molecular characteristics. At the present time, two hypotheses can be drawn to explain both clinical and biological heterogeneity. In the first hypothesis, neuroblastoma progresses from early to late clinical stages through a classical multistep process linked to an accumulation of molecular abnormalities. In the second hypothesis, neuroblastoma represents an heterogeneous group of unrelated diseases, where most of stages I and II or stage IVS neuroblastomas can rather be considered as benign tumors, and stage IV neuroblastoma as a true malignant proliferation. To ascertain relevant biological factors for the prognosis of the disease, it is uppermost important that all investigators agree on biological criteria for analysis when neuroblastoma tissue is available in screened and unscreened populations. This paper reviews the biological tools available for prognosis in neuroblastoma, the priority for analysis of biological markers according to reliability, feasibility, and reproducibility of analysis procedure, and the conditions of tissue storage for further analysis of these biological markers. The standardized biological evaluation of neuroblastoma will allow, first, to collect sufficient data for multivariate analysis of prognostic factors and, second, to better define the putative links between various forms of the disease.

  14. N-myc amplification causes down-modulation of MHC class I antigen expression in neuroblastoma

    NARCIS (Netherlands)

    Bernards, R.A.; Dessain, S.K.; Weinberg, R.A.

    1986-01-01

    Amplification of the N-myc gene is correlated with increased metastatic ability of human neuroblastomas. We show here that overexpression of the N-myc gene in a rat neuroblastoma cell line following gene transfer causes down-modulation of class I histocompatibility antigen expression and increases

  15. N-myc down regulates neural cell adhesion molecule expression in rat neuroblastoma

    NARCIS (Netherlands)

    Akeson, R.; Bernards, R.A.

    1990-01-01

    In human neuroblastoma, amplification of the N-myc oncogene is correlated with increased metastatic ability. We recently showed that transfection of the rat neuroblastoma cell line B104 with an N-myc expression vector resulted in an increase in metastatic ability and a significant reduction in the

  16. TLR3 triggering regulates PD-L1 (CD274) expression in human neuroblastoma cells

    NARCIS (Netherlands)

    Boes, Marianne; Meyer-Wentrup, Friederike

    2015-01-01

    Neuroblastoma is the most common extracranial solid tumor in children, causing 12% of all pediatric cancer mortality. Neuroblastoma specific T-cells have been detected in patients, but usually fail to attack and eradicate the tumors. Tumor immune evasion may thus play an important role in

  17. Adult Neuroblastoma Complicated by Increased Intracranial Pressure: A Case Report and Review of the Literature

    Directory of Open Access Journals (Sweden)

    Patrick L. Stevens

    2014-01-01

    Full Text Available Neuroblastoma is the third most commonly occurring malignancy of the pediatric population, although it is extremely rare in the adult population. In adults, neuroblastoma is often metastatic and portends an extremely poor overall survival. Our case report documents metastatic neuroblastoma occurring in a healthy 29-year-old woman whose course was complicated by an unusual presentation of elevated intracranial pressures. The patient was treated with systemic chemotherapy, I131 metaiodobenzylguanidine (MIBG radiotherapy, and autologous stem cell transplant (SCT. Unfortunately the patient’s response to therapy was limited and she subsequently died. We aim to review neuroblastoma in the context of increased intracranial pressure and the limited data of neuroblastoma occurring in the adult population, along with proposed treatment options.

  18. 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.

  19. 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.

  20. An Open-Circuit Voltage and Power Conversion Efficiency Study of Fullerene Ternary Organic Solar Cells Based on Oligomer/Oligomer and Oligomer/Polymer.

    Science.gov (United States)

    Zhang, Guichuan; Zhou, Cheng; Sun, Chen; Jia, Xiaoe; Xu, Baomin; Ying, Lei; Huang, Fei; Cao, Yong

    2017-07-01

    Variations in the open-circuit voltage (V oc ) of ternary organic solar cells are systematically investigated. The initial study of these devices consists of two electron-donating oligomers, S2 (two units) and S7 (seven units), and the electron-accepting [6,6]-phenyl C71 butyric acid methyl ester (PC 71 BM) and reveals that the V oc is continuously tunable due to the changing energy of the charge transfer state (E ct ) of the active layers. Further investigation suggests that V oc is also continuously tunable upon change in E ct in a ternary blend system that consists of S2 and its corresponding polymer (P11):PC 71 BM. It is interesting to note that higher power conversion efficiencies can be obtained for both S2:S7:PC 71 BM and S2:P11:PC 71 BM ternary systems compared with their binary systems, which can be ascribed to an improved V oc due to the higher E ct and an improved fill factor due to the improved film morphology upon the incorporation of S2. These findings provide a new guideline for the future design of conjugated polymers for achieving higher performance of ternary organic solar cells. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  1. Autocrine prostaglandin E2 signaling promotes tumor cell survival and proliferation in childhood neuroblastoma.

    Directory of Open Access Journals (Sweden)

    Agnes Rasmuson

    Full Text Available BACKGROUND: Prostaglandin E(2 (PGE(2 is an important mediator in tumor-promoting inflammation. High expression of cyclooxygenase-2 (COX-2 has been detected in the embryonic childhood tumor neuroblastoma, and treatment with COX inhibitors significantly reduces tumor growth. Here, we have investigated the significance of a high COX-2 expression in neuroblastoma by analysis of PGE(2 production, the expression pattern and localization of PGE(2 receptors and intracellular signal transduction pathways activated by PGE(2. PRINCIPAL FINDINGS: A high expression of the PGE(2 receptors, EP1, EP2, EP3 and EP4 in primary neuroblastomas, independent of biological and clinical characteristics, was detected using immunohistochemistry. In addition, mRNA and protein corresponding to each of the receptors were detected in neuroblastoma cell lines. Immunofluorescent staining revealed localization of the receptors to the cellular membrane, in the cytoplasm, and in the nuclear compartment. Neuroblastoma cells produced PGE(2 and stimulation of serum-starved neuroblastoma cells with PGE(2 increased the intracellular concentration of calcium and cyclic AMP with subsequent phosphorylation of Akt. Addition of 16,16-dimethyl PGE(2 (dmPGE(2 increased cell viability in a time, dose- and cell line-dependent manner. Treatment of neuroblastoma cells with a COX-2 inhibitor resulted in a diminished cell growth and viability that was reversed by the addition of dmPGE(2. Similarly, PGE(2 receptor antagonists caused a decrease in neuroblastoma cell viability in a dose-dependent manner. CONCLUSIONS: These findings demonstrate that PGE(2 acts as an autocrine and/or paracrine survival factor for neuroblastoma cells. Hence, specific targeting of PGE(2 signaling provides a novel strategy for the treatment of childhood neuroblastoma through the inhibition of important mediators of tumor-promoting inflammation.

  2. Diffusivities and Viscosities of Poly(ethylene oxide) Oligomers

    KAUST Repository

    Hong, Bingbing

    2010-10-14

    Diffusivities and viscosities of poly(ethylene oxide) (PEO) oligomer melts with 1 to 12 repeat units have been obtained from equilibrium molecular dynamics simulations using the TraPPE-UA force field. The simulations generated diffusion coefficients with high accuracy for all of the molar masses studied, but the statistical uncertainties in the viscosity calculations were significantly larger for longer chains. There is good agreement of the calculated viscosities and densities with available experimental data, and thus, the simulations can be used to bridge gaps in the data and for extrapolations with respect to chain length, temperature, and pressure. We explored the convergence characteristics of the Green-Kubo formulas for different chain lengths and propose minimal production times required for convergence of the transport properties. The chain-length dependence of the transport properties suggests that neither Rouse nor reptation models are applicable in the short-chain regime investigated. © 2010 American Chemical Society.

  3. Subunit conformational variation within individual GroEL oligomers resolved by Cryo-EM.

    Science.gov (United States)

    Roh, Soung-Hun; Hryc, Corey F; Jeong, Hyun-Hwan; Fei, Xue; Jakana, Joanita; Lorimer, George H; Chiu, Wah

    2017-08-01

    Single-particle electron cryo-microscopy (cryo-EM) is an emerging tool for resolving structures of conformationally heterogeneous particles; however, each structure is derived from an average of many particles with presumed identical conformations. We used a 3.5-Å cryo-EM reconstruction with imposed D7 symmetry to further analyze structural heterogeneity among chemically identical subunits in each GroEL oligomer. Focused classification of the 14 subunits in each oligomer revealed three dominant classes of subunit conformations. Each class resembled a distinct GroEL crystal structure in the Protein Data Bank. The conformational differences stem from the orientations of the apical domain. We mapped each conformation class to its subunit locations within each GroEL oligomer in our dataset. The spatial distributions of each conformation class differed among oligomers, and most oligomers contained 10-12 subunits of the three dominant conformation classes. Adjacent subunits were found to more likely assume the same conformation class, suggesting correlation among subunits in the oligomer. This study demonstrates the utility of cryo-EM in revealing structure dynamics within a single protein oligomer.

  4. The role of local irradiation for advanced neuroblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Masunaga, Ken; Mugishima, Hideo; Harada, Kensuke [Nihon Univ., Tokyo (Japan). School of Medicine

    1995-06-01

    Since 1985, 30 patients with advanced neuroblastoma were treated with a comprehensive therapy including chemotherapy, radiotherapy, operation, and autologous bone marrow transplant (A-BMT). After surgery, many patients received local irradiation at the primary tumor site. We investigated the role of local irradiation for advanced neuroblastoma. Of the 30 patients, 22 received local irradiation. These patients included 2 with stage III, 17 with stage IV{sub A}, and 3 with stage IV{sub B}. Most patients were 1 year of age or older at the time of diagnosis. Adrenal tumors were present in 13, retroperitoneal in 5, thoracic in 3, and both retroperitoneal and thoracic in 1. N-myc amplification was present in 8 patients. In terms of patient characteristics, there were no difference between local irradiation group and non-local irradiation group. All patients received induction chemotherapy, as described by Sawaguchi and others. After surgery, 22 patients received local irradiation of 10 to 26 Gy in 1 to 16 fractions at the primary tumor site. Intraoperative irradiation in a dose of 10 to 15 Gy in single fraction had been administered to 15 patients. Most patients received purged marrow using immunomagnetic beads. All patients received preconditioning regimen (VAMP, modified VAMP with or without TBI) and then transplanted. Following A-BMT, 13-cis-retinoic acid was administered for the purpose of tumor differentiation. Of the 22 patients with local irradiation, 6 relapsed and 5 died. Of the 8 patients without local irradiation, 2 relapsed and 1 died. Patients who completely received local irradiation showed no evidence of primary tumor recurrence. Patients who did not receive or incompletely received local irradiation showed primary tumor recurrence. Local irradiation for advanced neuroblastoma is very useful treatment to prevent primary tumor recurrence. (author).

  5. 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.

  6. WT1 Alternative Splicing: Role of Its Isoforms in Neuroblastoma.

    Science.gov (United States)

    Rasà, Daniela Maria; D'Amico, Agata Grazia; Maugeri, Grazia; Cavallaro, Sebastiano; D'Agata, Velia

    2017-06-01

    Wilms tumor 1 (WT1), a tumor suppressor gene, was originally identified in the homonymous renal neoplasm but is also involved in other cancers. Its function is still unclear, since it acts both as a pro- and an anti-oncogene. At least 14 WT1 transcriptional variants have been described; yet most investigations have focused on a small number of isoforms. We describe their structural features and review the evidence of their involvement in cancer with emphasis on neuroblastoma. In future, full characterization of all WT1 isoforms is expected to identify new molecular tumor markers and/or therapeutic targets.

  7. Determination of oligomers in virgin and recycled polyethylene terephthalate (PET) samples by UPLC-MS-QTOF.

    Science.gov (United States)

    Ubeda, Sara; Aznar, Margarita; Nerín, Cristina

    2018-03-01

    An oligomer is a molecule that consists of a few monomer units. It can be formed during polymer manufacturing and also due to polymer degradation processes or even during use conditions. Since oligomers are not included in chemical databases, their identification is a complex process. In this work, the oligomers present in 20 different PET pellet samples have been determined. Two different sample treatment procedures, solvent extraction and total dissolution, were applied in order to select the most efficient one. The analyses were carried out by UPLC-MS-QTOF. The use of high resolution mass spectrometry allowed the structural elucidation of these compounds and their correct identification. The main oligomers identified were cyclic as well as lineal from the first, second, and third series. All of them were composed of terephthalic acid (TPA), diethylene glycol (DEG), and ethylene glycol (EG). Quantitative values were very different in both procedures. In total dissolution of PET samples, the concentration of oligomers was always, at least, 10 times higher than in solvent extraction; some of the compounds were only detected when total dissolution was used. Results showed that the oligomers with the highest concentration values were dimers and trimers, cyclic, as well as lineal, from the first and second series. The oligomer with the maximum concentration value was TPA 2 -EG-DEG that was found in all the samples in a concentration range from 2493 to 19,290 ng/g PET. No differences between virgin and recycled PET were found. Migration experiments were performed in two PET bottles, and results showed the transference of most of these oligomers to a fat food simulant (ethanol 95%). Graphical abstract Graphical abstract of the two procedures developd and optimized for identifying oligomers in PET pellets and in migration form PET bottles.

  8. Modelling Ser129 phosphorylation inhibits membrane binding of pore-forming alpha-synuclein oligomers.

    Directory of Open Access Journals (Sweden)

    Georg Sebastian Nübling

    Full Text Available BACKGROUND: In several neurodegenerative diseases, hyperphosphorylation at position Ser129 is found in fibrillar deposits of alpha-synuclein (asyn, implying a pathophysiological role of asyn phosphorylation in neurodegeneration. However, recent animal models applying asyn phosphorylation mimics demonstrated a protective effect of phosphorylation. Since metal-ion induced asyn oligomers were identified as a potential neurotoxic aggregate species with membrane pore-forming abilities, the current study was undertaken to determine effects of asyn phosphorylation on oligomer membrane binding. METHODS: We investigated the influence of S129 phosphorylation on interactions of metal-ion induced asyn oligomers with small unilamellar lipid vesicles (SUV composed of POPC and DPPC applying the phosphorylation mimic asyn129E. Confocal single-particle fluorescence techniques were used to monitor membrane binding at the single-particle level. RESULTS: Binding of asyn129E monomers to gel-state membranes (DPPC-SUV is slightly reduced compared to wild-type asyn, while no interactions with membranes in the liquid-crystalline state (POPC-SUV are seen for both asyn and asyn129E. Conversely, metal-ion induced oligomer formation is markedly increased in asyn129E. Surprisingly, membrane binding to POPC-SUV is nearly absent in Fe(3+ induced asyn129E oligomers and markedly reduced in Al(3+ induced oligomers. CONCLUSION: The protective effect of pseudophosphorylation seen in animal models may be due to impeded oligomer membrane binding. Phosphorylation at Ser129 may thus have a protective effect against neurotoxic asyn oligomers by preventing oligomer membrane binding and disruption of the cellular electrophysiological equilibrium. Importantly, these findings put a new complexion on experimental pharmaceutical interventions against POLO-2 kinase.

  9. Phenylethynyl Terminated Arylene Ether Oxadiazole and Triazole Oligomers and Their Cured Polymers

    Science.gov (United States)

    Thompson, C. M.; Hergenrother, P. M.

    2001-01-01

    Several novel phenylethynyl terminated arylene ether oligomers containing oxadiazole and triazole rings were prepared as part of an effort to develop high performance polymers with an attractive combination of properties (e.g. processability and mechanical performance) for future NASA applications. The oligomers displayed low melt viscosities and good solubilities. Thin films cast from solutions of the oligomers and cured for one hour at 350 C in air gave good tensile properties. Titanium to titanium (6Al-4V) tensile shear specimens were readily fabricated and provided moderate strengths. The chemistry and properties of these new materials are discussed.

  10. Direct Correlation Between Ligand-Induced α-Synuclein Oligomers and Amyloid-like Fibril Growth

    DEFF Research Database (Denmark)

    Pedersen, Martin Nors; Foderà, Vito; Horvath, Istvan

    2015-01-01

    link to disease related degenerative activity. Fibrils formed in the presence and absence of FN075 are indistinguishable on microscopic and macroscopic levels. Using small angle X-ray scattering, we reveal that FN075 induced oligomers are similar, but not identical, to oligomers previously observed......Aggregation of proteins into amyloid deposits is the hallmark of several neurodegenerative diseases such as Alzheimer's and Parkinson's disease. The suggestion that intermediate oligomeric species may be cytotoxic has led to intensified investigations of pre-fibrillar oligomers, which...

  11. Synthesis and Electronic Properties of Length-Defined 9,10-Anthrylene-Butadiynylene Oligomers.

    Science.gov (United States)

    Nagaoka, Maiko; Tsurumaki, Eiji; Nishiuchi, Mai; Iwanaga, Tetsuo; Toyota, Shinji

    2018-04-18

    Linear π-conjugated oligomers consisting of anthracene and diacetylene units were readily synthesized by a one-pot process that involved desilylation and oxidative coupling from appropriate building units. We were able to isolate length-defined oligomers ranging from 2-mer to 6-mer as stable and soluble solids having characteristic colors. X-ray analysis and DFT calculations revealed that these oligomers had linear structures and coplanar conformations. The bathochromic shifts in the UV-vis spectra suggested that the π-conjugation was extended with elongation of the linear chain. Cyclic voltammetric measurements showed characteristic reversible oxidation waves that were dependent on the number of anthracene units.

  12. Gami-Chunghyuldan ameliorates memory impairment and neurodegeneration induced by intrahippocampal Aβ 1-42 oligomer injection.

    Science.gov (United States)

    Choi, Jin Gyu; Moon, Minho; Kim, Hyo Geun; Mook-Jung, Inhee; Chung, Sun Yong; Kang, Tong Ho; Kim, Sun Yeou; Lee, Eunjoo H; Oh, Myung Sook

    2011-09-01

    Soluble oligomeric forms of amyloid beta (AβO) are regarded as a main cause of synaptic and cognitive dysfunction in Alzheimer's disease (AD) and have been a primary target in the development of drug treatments for AD. The present study utilized a mouse model of AD induced by intrahippocampal injection of AβO (10 μM) to investigate the effects of Gami-Chunghyuldan (GCD), a standardized multi-herbal medicinal formula, on the presentation of memory deficits and neurohistological pathogenesis. GCD (10 and 50mg/kg/day, 5 days, p.o.) improved AβO-induced memory impairment as well as reduced neuronal cell death, astrogliosis, and microgliosis in the hippocampus. In addition, GCD prevented AβO-triggered synaptic disruption and cholinergic fiber loss. These results suggest that GCD may be useful in the prevention and treatment of AD. Copyright © 2011 Elsevier Inc. All rights reserved.

  13. Neuroblastoma survivors are at increased risk for second malignancies: A report from the International Neuroblastoma Risk Group Project.

    Science.gov (United States)

    Applebaum, Mark A; Vaksman, Zalman; Lee, Sang Mee; Hungate, Eric A; Henderson, Tara O; London, Wendy B; Pinto, Navin; Volchenboum, Samuel L; Park, Julie R; Naranjo, Arlene; Hero, Barbara; Pearson, Andrew D; Stranger, Barbara E; Cohn, Susan L; Diskin, Sharon J

    2017-02-01

    The incidence of second malignant neoplasm (SMN) within the first ten years of diagnosis in high-risk neuroblastoma patients treated with modern, intensive therapy is unknown. Further, the underlying germline genetics that contribute to SMN in these survivors are not known. The International Neuroblastoma Risk Group (INRG) database of patients diagnosed from 1990 to 2010 was analysed. SMN risk was accessed by cumulative incidence, standardised incidence ratios (SIRs) and absolute excess risk. A candidate gene-based association study evaluated genetic susceptibility to SMN in neuroblastoma survivors. Of the 5987 patients in the INRG database with SMN data enrolled in a clinical trial, 43 (0.72%) developed a SMN. The 10-year cumulative incidence of SMN for high-risk patients was 1.8% (95% confidence interval [CI] 1.0-2.6%) compared with 0.38% (95% CI: 0.22-0.94%) for low-risk patients (P = 0.01). High-risk patients had an almost 18-fold higher incidence of SMN compared to age- and sex-matched controls (SIR = 17.5 (95% CI: 11.4-25.3), absolute excess risk = 27.6). For patients treated on high- and intermediate-risk clinical trials, the SIR of acute myelogenous leukaemia was 106.8 (95% CI: 28.7-273.4) and 127.7 (95%CI: 25.7-373.3), respectively. Variants implicating DNA repair genes XRCC3 (rs861539: P = 0.006; odds ratio: 2.04, 95%CI: 1.19-3.46) and MSH2 (rs17036651: P = 0.009; odds ratio: 0.26, 95% CI: 0.08-0.81) were associated with SMN. The intensive multi-modality treatment strategy currently used to treat high-risk neuroblastoma is associated with a significantly increased risk of secondary acute myelogenous leukaemia. Defining the interactions of treatment exposures and genetic factors that promote the development of SMN is critical for optimising survivorship care. Copyright © 2016 Elsevier Ltd. All rights reserved.

  14. 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

  15. 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

  16. 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.

  17. A case of primary cerebral neuroblastoma in adolescence

    International Nuclear Information System (INIS)

    White, B.D.; Pozza, C.H.; Davies, R.; Hanieh, A.

    2002-01-01

    Primary cerebral neuroblastoma is one of a group of highly malignant undifferentiated primitive neuroectodermal tumours arising from germinal matrix cells of the embryonic neural tube. They occur primarily in young children and are extremely rare in adults. They may be multicentric and have often spread throughout the central nervous system at the time of diagnosis. A case of a 16-year-old man is described, and the recent literature is reviewed. On MRI examination, these lesions demonstrated heterogeneous low signal intensity on T1 -weighted sequences and heterogeneous high signal intensity on T2-weighted and fluid attenuated inversion recovery (FLAIR) sequences. There was no enhancement following IV contrast administration. A MRI of the spine was normal. Areas of low T1 and T2 signal intensity in the right temporo-occipital region were consistent with haemorrhage within the lesion. The patient underwent complete resection of the lesion in the right lateral ventricle and subtotal resection of the lesions in the right temporal-occipital lobes and suprasellar region. Histo-pathological findings confirmed primary cerebral neuroblastoma. Copyright (2002) Blackwell Science Pty Ltd

  18. 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.

  19. 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

  20. Neuroblastoma in a Case with Congenital Horner’s Syndrome

    Directory of Open Access Journals (Sweden)

    Hüseyin Mayalı

    2014-08-01

    Full Text Available Miosis, ptosis, and ipsilateral facial anhidrosis are normally present in Horner’s syndrome. Pathologies which show central, preganglionic and postganglionic residence in sympathetic chain are present in its etiology. A 3-month-old girl baby was admitted to our clinic for ptosis in the left eye. Heterochromia, ptosis in the left eye, myosis and, ipsilateral anhidrosis were detected in her examination. In view of these findings, it seemed possible that her disease could be congenital Horner’s syndrome. Brachial plexus injury due to birth trauma plays a major role in the etiology of congenital Horner’s syndrome. There was not any birth trauma history in our patient. The patient was diagnosed to have neuroblastoma as a result of etiologic tests. In conclusion, Horner’s syndrome can be the presenting sign of childhood neuroblastoma. Therefore, it is advisable to examine the oculosympathetic system in detail in order to leave out any underlying serious disorder. (Turk J Ophthalmol 2014; 44: 325-6

  1. The mechanism of epithelial-mesenchymal transition induced by TGF-β1 in neuroblastoma cells.

    Science.gov (United States)

    Shao, Jing-Bo; Gao, Zhi-Mei; Huang, Wen-Yan; Lu, Zhi-Bao

    2017-05-01

    Neuroblastoma is the second most common extracranial malignant solid tumor that occurs in childhood, and metastasis is one of the major causes of death in neuroblastoma patients. The epithelial-mesenchymal transition (EMT) is an important mechanism for both the initiation of tumor invasion and subsequent metastasis. Therefore, this study investigated the mechanism by which transforming growth factor (TGF)-β1 induces EMT in human neuroblastoma cells. Using quantitative RT-qPCR and western blot analyses, we found that the mRNA and protein expression levels of E-cadherin were significantly decreased, whereas that of α-SMA was significantly increased after neuroblastoma cells were treated with different concentrations of TGF-β1. A scratch test and Transwell migration assay revealed that cell migration significantly and directly correlated with the concentration of TGF-β1 indicating that TGF-β1 induced EMT in neuroblastoma cells and led to their migration. Inhibiting Smad2/3 expression did not affect the expression of the key molecules involved in EMT. Further investigation found that the expression of the glioblastoma transcription factor (Gli) significantly increased in TGF-β1-stimulated neuroblastoma cells undergoing EMT, accordingly, interfering with Gli1/2 expression inhibited TGF-β1-induced EMT in neuroblastoma cells. GANT61, which is a targeted inhibitor of Gli1 and Gli2, decreased cell viability and promoted cell apoptosis. Thus, TGF-β1 induced EMT in neuroblastoma cells to increase their migration. Specifically, EMT induced by TGF-β1 in neuroblastoma cells did not depend on the Smad signaling pathway, and the transcription factor Gli participated in TGF-β1-induced EMT independent of Smad signaling.

  2. Recommendations for the standardization of bone marrow disease assessment and reporting in children with neuroblastoma on behalf of the International Neuroblastoma Response Criteria Bone Marrow Working Group.

    Science.gov (United States)

    Burchill, Susan A; Beiske, Klaus; Shimada, Hiroyuki; Ambros, Peter F; Seeger, Robert; Tytgat, Godelieve A M; Brock, Penelope R; Haber, Michelle; Park, Julie R; Berthold, Frank

    2017-04-01

    The current study was conducted to expedite international standardized reporting of bone marrow disease in children with neuroblastoma and to improve equivalence of care. A multidisciplinary International Neuroblastoma Response Criteria Bone Marrow Working Group was convened by the US National Cancer Institute in January 2012 with representation from Europe, North America, and Australia. Practical transferable recommendations to standardize the reporting of bone marrow disease were developed. To the authors' knowledge, the current study is the first to comprehensively present consensus criteria for the collection, analysis, and reporting of the percentage area of bone marrow parenchyma occupied by tumor cells in trephine-biopsies. The quantitative analysis of neuroblastoma content in bone marrow aspirates by immunocytology and reverse transcriptase-quantitative polymerase chain reaction are revised. The inclusion of paired-like homeobox 2b (PHOX2B) for immunohistochemistry and reverse transcriptase-quantitative polymerase chain reaction is recommended. Recommendations for recording bone marrow response are provided. The authors endorse the quantitative assessment of neuroblastoma cell content in bilateral core needle biopsies-trephines and aspirates in all children with neuroblastoma, with the exception of infants, in whom the evaluation of aspirates alone is advised. It is interesting to note that 5% disease is accepted as an internationally achievable level for disease assessment. The quantitative assessment of neuroblastoma cells is recommended to provide data from which evidence-based numerical criteria for the reporting of bone marrow response can be realized. This is particularly important in the minimal disease setting and when neuroblastoma detection in bone marrow is intermittent, where clinical impact has yet to be validated. The wide adoption of these harmonized criteria will enhance the ability to compare outcomes from different trials and facilitate

  3. Expression of granulocyte colony-stimulating factor and its receptor in childhood neuroblastoma

    OpenAIRE

    Xin WU; Da-wei HE; Yong-bo ZHANG; Wen-fei HE; Ze-dong BIAN; Qin-jun YI; Guang-hui WEI

    2012-01-01

    Objective  To study the expression of granulocyte colony-stimulating factor (G-CSF) and its receptor (G-CSFR) in neuroblastoma of children. Methods  Twenty-five specimens of neuroblastoma were collected in our department during 2009.1–2011.6. G-CSF and G-CSFR were determined by immunohistochemistry. The correlation between expressions of G-CSF and G-CSFR and age, gender and clinical stage were analyzed. Results  The expression of G-CSF and G-CSFR in neuroblastoma specimens was 68%, 72% respec...

  4. Genome-wide analysis of HOXC9-induced neuronal differentiation of neuroblastoma cells

    Directory of Open Access Journals (Sweden)

    Xiangwei Wang

    2014-12-01

    Full Text Available Induction of differentiation is a therapeutic strategy in neuroblastoma, a common pediatric cancer of the sympathetic nervous system. The homeobox protein HOXC9 is a key regulator of neuroblastoma differentiation. To gain a molecular understanding of the function of HOXC9 in promoting differentiation of neuroblastoma cells, we conducted a genome-wide analysis of the HOXC9-induced differentiation program by microarray gene expression profiling and chromatin immunoprecipitation in combination with massively parallel sequencing (ChIP-seq. Here we describe in detail the experimental system, methods, and quality control for the generation of the microarray and ChIP-seq data associated with our recent publication [1].

  5. Acrylate oligomers in ultraviolet cured PSA's glass transition, molecular weight versus peel strength

    International Nuclear Information System (INIS)

    Miller, H.C.

    1999-01-01

    Typically those not skilled in the art relate Glass Transition Temperature to Pressure Sensitive Adhesives. You need a low Tg material to prepare good pressure sensitive adhesives. This report deals with a wide range acrylate terminated oligomers in a standard formulation. Molecular weight, chemical structure variations are examined versus the Glass Transition of the oligomers and final peel strength. Each formulated adhesive will require unique oligomer properties to reach one hundred newtons per 100 millimeters (5.71 pounds per square inch) peel strength. Excellent peel strengths may be obtained with oligomer molecular weight ranging from six thousand to one thousand molecular weight and glass transition temperatures ranging from minus seventy four degrees centigrade up to thirteen degrees centigrade

  6. Enhanced Circular Dichroism via Symmetry Breaking in a Chiral Plasmonic Nanoparticle Oligomer

    Science.gov (United States)

    Le, Khai Q.

    2018-02-01

    A chiral plasmonic nanoparticle oligomer, consisting of four symmetrically arranged nanodisks of different heights and having different optical absorption responses to left and right-handed circularly polarized light illumination, has been experimentally reported in the literature. The resulting circular dichroism (CD) signal was detectable with state of the art CD spectrometers but was much weaker than those of existing chiral nanostructures, i.e., three-dimensional (3-D) chiral metamaterials. In this letter, via symmetry breaking in such an oligomer, the author demonstrates that the CD can be enhanced up to six times compared to that of a symmetric oligomer, and is in the range of a relevant 3-D chiral metamolecule. Through investigation of geometrical parameters including particle size, asymmetric and symmetric gaps, the CD evolution was reported, which provides a useful guideline for design of two-dimensional chiral oligomers adopted as efficient probes for CD spectroscopic applications.

  7. Charge transport and dielectric relaxation processes in anilin-based oligomers

    Czech Academy of Sciences Publication Activity Database

    Mrlík, M.; Moučka, R.; Ilčíková, M.; Bober, Patrycja; Kazantseva, N.; Špitálský, Z.; Trchová, Miroslava; Stejskal, Jaroslav

    2014-01-01

    Roč. 192, June (2014), s. 37-42 ISSN 0379-6779 Institutional support: RVO:61389013 Keywords : aniline-based oligomers * conductivity * dielectric properties Subject RIV: CD - Macromolecular Chemistry Impact factor: 2.252, year: 2014

  8. Polyphenols protect mitochondrial membrane against permeabilization induced by HEWL oligomers: Possible mechanism of action.

    Science.gov (United States)

    Roqanian, Shaqayeq; Meratan, Ali Akbar; Ahmadian, Shahin; Shafizadeh, Mahshid; Ghasemi, Atiyeh; Karami, Leila

    2017-10-01

    Increasing body of evidence suggests that polyphenols frequently interacting with amyloid aggregates and/or interfering with aggregate species to bind biomembranes may serve as a therapeutic approach for the treatment of amyloid-related diseases. Hence, in the present study, the possible effects of three naturally occurring polyphenols including Curcumin, Quercetin, and Resveratrol on mitochondrial membrane permeabilization induced by Hen Egg White Lysozyme (HEWL) oligomers were investigated. Our results indicated that pre-incubation of mitochondrial homogenate with polyphenols considerably inhibit membrane permeabilization in a concentration dependent manner. In parallel, HEWL oligomers, which were co-incubated with the polyphenols, showed less effectiveness on membrane permeabilization, suggesting that toxicity of oligomers was hindered. Using a range of techniques including fluorescence quenching, Nile red binding assay, zeta potential and size measurements, CD (far- and near-UV) spectroscopy, and molecular docking, we found that the polyphenols, structure-dependently, interact with and induce conformational changes in HEWL oligomers, thereby inhibit their toxicity. We proposed a mechanism by which selected polyphenols induce their protective effects through binding to mitochondria and interfering with HEWL oligomer-membrane interactions and/or by direct interaction with HEWL oligomers, induction of conformational changes, and generating far less toxic species. However, additional studies are needed to elucidate the detailed mechanisms involved. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. α-Synuclein oligomers induced by docosahexaenoic acid affect membrane integrity.

    Directory of Open Access Journals (Sweden)

    Chiara Fecchio

    Full Text Available A key feature of Parkinson disease is the aggregation of α-synuclein and its intracellular deposition in fibrillar form. Increasing evidence suggests that the pathogenicity of α-synuclein is correlated with the activity of oligomers formed in the early stages of its aggregation process. Oligomers toxicity seems to be associated with both their ability to bind and affect the integrity of lipid membranes. Previously, we demonstrated that α-synuclein forms oligomeric species in the presence of docosahexaenoic acid and that these species are toxic to cells. Here we studied how interaction of these oligomers with membranes results in cell toxicity, using cellular membrane-mimetic and cell model systems. We found that α-synuclein oligomers are able to interact with large and small unilamellar negatively charged vesicles acquiring an increased amount of α-helical structure, which induces small molecules release. We explored the possibility that oligomers effects on membranes could be due to pore formation, to a detergent-like effect or to fibril growth on the membrane. Our biophysical and cellular findings are consistent with a model where α-synuclein oligomers are embedded into the lipid bilayer causing transient alteration of membrane permeability.

  10. Morphology of a self-doped conducting oligomer for green energy applications.

    Science.gov (United States)

    Franco-Gonzalez, Juan Felipe; Pavlopoulou, Eleni; Stavrinidou, Eleni; Gabrielsson, Roger; Simon, Daniel T; Berggren, Magnus; Zozoulenko, Igor V

    2017-09-21

    A recently synthesized self-doped conducting oligomer, salt of bis[3,4-ethylenedioxythiophene]3thiophene butyric acid, ETE-S, is a novel promising material for green energy applications. Recently, it has been demonstrated that it can polymerize in vivo, in plant systems, leading to a formation of long-range conducting wires, charge storage and supercapacitive behaviour of living plants. Here we investigate the morphology of ETE-S combining the experimental characterisation using Grazing Incidence Wide Angle X-ray Scattering (GIWAXS) and atomistic molecular dynamics (MD) simulations. The GIWAXS measurements reveal a formation of small crystallites consisting of π-π stacked oligomers (with the staking distance 3.5 Å) that are further organized in h00 lamellae. These experimental results are confirmed by MD calculations, where we calculated the X-ray diffraction pattern and the radial distribution function for the distance between ETE-S chains. Our MD simulations also demonstrate the formation of the percolative paths for charge carriers that extend throughout the whole structure, despite the fact that the oligomers are short (6-9 rings) and crystallites are thin along the π-π stacking direction, consisting of only two or three π-π stacked oligomers. The existence of the percolative paths explains the previously observed high conductivity in in vivo polymerized ETE-S. We also explored the geometrical conformation of ETE-S oligomers and the bending of their aliphatic chains as a function of the oligomer lengths.

  11. Carboxybetaine methacrylate oligomer modified nylon for circulating tumor cells capture.

    Science.gov (United States)

    Dong, Chaoqun; Wang, Huiyu; Zhang, Zhuo; Zhang, Tao; Liu, Baorui

    2014-10-15

    Circulating tumor cells (CTC) capture is one of the most effective approaches in diagnosis and treatment of cancers in the field of personalized cancer medicine. In our study, zwitterionic carboxybetaine methacrylate (CBMA) oligomers were grafted onto nylon via atomic transfer random polymerization (ATRP) which would serve as a novel material for the development of convenient CTC capture interventional medical devices. The chemical, physical and biological properties of pristine and modified nylon surfaces were assessed by Fourier transform infrared spectra, atomic force microscope, water contact angle measurements, X-ray photoelectron spectroscopy, protein adsorption, platelet adhesion, and plasma recalcification time (PRT) determinations, etc. The results, including the significant decrease of proteins adsorption and platelets adhesion, as well as prolonged PRTs demonstrated the extraordinary biocompatibility and blood compatibility of the modified surface. Furthermore, we showed that upon immobilization of anti-epithelial cell adhesion molecular (anti-EpCAM) antibody onto the CBMA moiety, the modified nylon surface can selectively capture EpCAM positive tumor cells from blood with high efficiency, indicating the potential of the modified nylon in the manufacture of convenient interventional CTC capture medical devices. Copyright © 2014 Elsevier Inc. All rights reserved.

  12. Dopamine induces soluble α-synuclein oligomers and nigrostriatal degeneration

    Science.gov (United States)

    Mor, Danielle E.; Tsika, Elpida; Mazzulli, Joseph R.; Gould, Neal S.; Kim, Hanna; Daniels, Malcolm J.; Doshi, Shachee; Gupta, Preetika; Grossman, Jennifer L.; Tan, Victor X.; Kalb, Robert G.; Caldwell, Kim A.; Caldwell, Guy A.; Wolfe, John H.; Ischiropoulos, Harry

    2018-01-01

    Parkinson’s disease is defined by the loss of dopaminergic neurons in the substantia nigra and formation of Lewy body inclusions containing aggregated α-synuclein. Efforts to explain dopamine neuron vulnerability are hindered by the lack of dopaminergic cell death in α-synuclein transgenic mice. To address this, we manipulated dopamine levels in addition to α-synuclein expression. Nigra-targeted expression of mutant tyrosine hydroxylase with enhanced catalytic activity increased dopamine without damaging neurons in non-transgenic mice. In contrast, raising dopamine in mice expressing human A53T mutant α-synuclein induced progressive nigrostriatal degeneration and reduced locomotion. Dopamine elevation in A53T mice increased levels of potentially toxic α-synuclein oligomers, resulting in conformationally and functionally modified species. Moreover, in genetically tractable C. elegans models expression of α-synuclein mutated at the site of interaction with dopamine prevented dopamine-induced toxicity. The data suggest a unique mechanism linking two cardinal features of Parkinson’s disease, dopaminergic cell death and α-synuclein aggregation. PMID:28920936

  13. Solid-state nanopore studies of hybridized DNA oligomers

    Science.gov (United States)

    Balagurusamy, Venkat; Weinger, Paul; Kim, Sungcheol; Ling, Xinsheng Sean

    2010-03-01

    Hybridization-assisted nanopore sequencing (HANS) uses short oligomers of DNA bound to a long single-stranded DNA in order to obtain the positional information of the bases that make up the long DNA molecule. To test the feasibility of the HANS approach, we carried out experiments to detect 12-base hybridizations in a tri-mer complex consisting of three single-stranded oligos hybridized at their ends sequenctially. These DNA complexes are connected to polystyrene beads through biotin-streptavidin bonds to enable their detection by nanopores. The experiment is to measure the time dependence of the nanopore ionic current at fixed voltage when the cis side is filled with the oligo-attached beads. Computer simulations are used as guides in the identification of translocation dynamics. Distinct features are found that can be attributed to tri-mers, dimmers, and monomers attached to the beads. The measured mean-first-passage time between two hybridization segments is extracted and is found to be consistent with theoretical estimates.

  14. Dopamine induces soluble α-synuclein oligomers and nigrostriatal degeneration.

    Science.gov (United States)

    Mor, Danielle E; Tsika, Elpida; Mazzulli, Joseph R; Gould, Neal S; Kim, Hanna; Daniels, Malcolm J; Doshi, Shachee; Gupta, Preetika; Grossman, Jennifer L; Tan, Victor X; Kalb, Robert G; Caldwell, Kim A; Caldwell, Guy A; Wolfe, John H; Ischiropoulos, Harry

    2017-11-01

    Parkinson's disease (PD) is defined by the loss of dopaminergic neurons in the substantia nigra and the formation of Lewy body inclusions containing aggregated α-synuclein. Efforts to explain dopamine neuron vulnerability are hindered by the lack of dopaminergic cell death in α-synuclein transgenic mice. To address this, we manipulated both dopamine levels and α-synuclein expression. Nigrally targeted expression of mutant tyrosine hydroxylase with enhanced catalytic activity increased dopamine levels without damaging neurons in non-transgenic mice. In contrast, raising dopamine levels in mice expressing human A53T mutant α-synuclein induced progressive nigrostriatal degeneration and reduced locomotion. Dopamine elevation in A53T mice increased levels of potentially toxic α-synuclein oligomers, resulting in conformationally and functionally modified species. Moreover, in genetically tractable Caenorhabditis elegans models, expression of α-synuclein mutated at the site of interaction with dopamine prevented dopamine-induced toxicity. These data suggest that a unique mechanism links two cardinal features of PD: dopaminergic cell death and α-synuclein aggregation.

  15. Update on Phytochemistry and Pharmacology of Naturally Occurring Resveratrol Oligomers.

    Science.gov (United States)

    Shen, Jie; Zhou, Qiang; Li, Pei; Wang, Zhiqiang; Liu, Shuangshuang; He, Chunnian; Zhang, Chunhong; Xiao, Peigen

    2017-11-24

    Resveratrol oligomers (REVs), a major class of stilbenoids, are biosynthesized by regioselective oxidative coupling of two to eight units of resveratrol monomer. Due to their unique structures and pleiotropic biological activities, natural product chemists are increasingly focusing on REVs in the last few decades. This study presents a detailed and thorough examination of REVs, including chemical structures, natural resources, and biological activities, during the period of 2010-2017. Ninety-two new REVs compounds, including 39 dimers, 23 trimers, 13 tetramers, six resveratrol monomers, six hexamers, four pentamers, and one octamer, have been reported from the families of Dipterocarpaceae, Paeoniaceae, Vitaceae, Leguminosae, Gnetaceae, Cyperaceae, Polygonaceae Gramineae, and Poaceae. Amongst these families, Dipterocarpaceae, with 50 REVs, accounts for the majority, and seven genera of Dipterocarpaceae are involved, including Vatica , Vateria , Shorea , Hopea , Neobalanocarpus , Dipterocarpus , and Dryobalanops . These REVs have shown a wide range of bioactivities. Pharmacological studies have mainly focused on potential efficacy on tumors, bacteria, Alzheimer's disease, cardiovascular diseases, and others. The information updated in this review might assist further research and development of novel REVs as potential therapeutic agents.

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

    NARCIS (Netherlands)

    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.

    2016-01-01

    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

  17. 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.

  18. Genomewide analysis of gene expression associated with Tcof1 in mouse neuroblastoma.

    Science.gov (United States)

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

    2004-12-03

    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.

  19. 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.

  20. 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.

  1. A high-content morphological screen identifies novel microRNAs that regulate neuroblastoma cell differentiation.

    Science.gov (United States)

    Zhao, Zhenze; Ma, Xiuye; Hsiao, Tzu-Hung; Lin, Gregory; Kosti, Adam; Yu, Xiaojie; Suresh, Uthra; Chen, Yidong; Tomlinson, Gail E; Pertsemlidis, Alexander; Du, Liqin

    2014-05-15

    Neuroblastoma, the most common extracranial solid tumor of childhood, arises from neural crest cell precursors that fail to differentiate. Inducing cell differentiation is an important therapeutic strategy for neuroblastoma. We developed a direct functional high-content screen to identify differentiation-inducing microRNAs, in order to develop microRNA-based differentiation therapy for neuroblastoma. We discovered novel microRNAs, and more strikingly, three microRNA seed families that induce neuroblastoma cell differentiation. In addition, we showed that microRNA seed families were overrepresented in the identified group of fourteen differentiation-inducing microRNAs, suggesting that microRNA seed families are functionally more important in neuroblastoma differentiation than microRNAs with unique sequences. We further investigated the differentiation-inducing function of the microRNA-506-3p/microRNA-124-3p seed family, which was the most potent inducer of differentiation. We showed that the differentiation-inducing function of microRNA-506-3p/microRNA-124-3p is mediated, at least partially, by down-regulating expression of their targets CDK4 and STAT3. We further showed that expression of miR-506-3p, but not miR-124-3p, is dramatically upregulated in differentiated neuroblastoma cells, suggesting the important role of endogenous miR-506-3p in differentiation and tumorigenesis. Overall, our functional screen on microRNAs provided the first comprehensive analysis on the involvements of microRNA species in neuroblastoma cell differentiation and identified novel differentiation-inducing microRNAs. Further investigations are certainly warranted to fully characterize the function of the identified microRNAs in order to eventually benefit neuroblastoma therapy.

  2. 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

  3. 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.

  4. The genetic landscape of high-risk neuroblastoma | Office of Cancer Genomics

    Science.gov (United States)

    Abstract: 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.

  5. Altered expression of miRNAs and methylation of their promoters are correlated in neuroblastoma.

    Science.gov (United States)

    Maugeri, Marco; Barbagallo, Davide; Barbagallo, Cristina; Banelli, Barbara; Di Mauro, Stefania; Purrello, Francesco; Magro, Gaetano; Ragusa, Marco; Di Pietro, Cinzia; Romani, Massimo; Purrello, Michele

    2016-12-13

    Neuroblastoma is the most common human extracranial solid tumor during infancy. Involvement of several miRNAs in its pathogenesis has been ascertained. Interestingly, most of their encoding genes reside in hypermethylated genomic regions: thus, their tumor suppressor function is normally disallowed in these tumors. To date, the therapeutic role of the demethylating agent 5'-Aza-2 deoxycytidine (5'-AZA) and its effects on miRNAome modulation in neuroblastoma have not been satisfactorily explored. Starting from a high-throughput expression profiling of 754 miRNAs and based on a proper selection, we focused on miR-29a-3p, miR-34b-3p, miR-181c-5p and miR-517a-3p as candidate miRNAs for our analysis. They resulted downregulated in four neuroblastoma cell lines with respect to normal adrenal gland. MiRNAs 29a-3p and 34b-3p also resulted downregulated in vivo in a murine neuroblastoma progression model. Unlike the amount of methylation of their encoding gene promoters, all these miRNAs were significantly overexpressed following treatment with 5'-AZA. Transfection with candidate miRNAs mimics significantly decreased neuroblastoma cells proliferation rate. A lower expression of miR-181c was significantly associated to a worse overall survival in a public dataset of 498 neuroblastoma samples (http://r2.amc.nl). Our data strongly suggest that CDK6, DNMT3A, DNMT3B are targets of miR-29a-3p, while CCNE2 and E2F3 are targets of miR-34b-3p. Based on all these data, we propose that miR-29a-3p, miR-34b-3p, miR-181c-5p and miR-517a-3p are disallowed tumor suppressor genes in neuroblastoma and suggest them as new therapeutic targets in neuroblastoma.

  6. 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

  7. 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.

  8. Management of VIP Associated Diarrhea in a Case with Neuroblastoma

    Directory of Open Access Journals (Sweden)

    Begul Yagci-Kupeli

    2013-06-01

    Full Text Available Watery diarrhea associated with hypokalemia and achlorhydria (WDHA syndrome is commonly caused by vasoactive intestinal peptide (VIP secreting tumors in adults and generally associated with neural crest tumors in pediatric population. VIP secretion is associated with neuroblastic cell differentiation. Octreotide treatment can be a choice for diarrhea in such cases. However, its benefit is controversial and surgery is usually needed. A 14-month-old female with diagnosis of inoperable undifferantiated intraabdominal neuroblastoma who developed chronic diarrhea at first year of chemotherapy is reported. Octreotide treatment was used to control diarrhea. Because of the failure of octreotide treatment, debulking surgery was performed and diarrhea subsided after the surgery. [Cukurova Med J 2013; 38(3.000: 528-530

  9. 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.

  10. 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

  11. 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.

  12. 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.

  13. 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)

  14. 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.

  15. 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.

  16. T cells targeting NY-ESO-1 demonstrate efficacy against disseminated neuroblastoma.

    Science.gov (United States)

    Singh, Nathan; Kulikovskaya, Irina; Barrett, David M; Binder-Scholl, Gwendolyn; Jakobsen, Bent; Martinez, Daniel; Pawel, Bruce; June, Carl H; Kalos, Michael D; Grupp, Stephan A

    The cancer-testis antigen NY-ESO-1 is expressed by many solid tumors and has limited expression by mature somatic tissues, making it a highly attractive target for tumor immunotherapy. Targeting NY-ESO-1 using engineered T cells has demonstrated clinical efficacy in the treatment of some adult tumors. Neuroblastoma is a significant cause of cancer mortality in children, and is a tumor type shown to be responsive to immunotherapies. We evaluated a large panel of primarily resected neuroblastoma samples and demonstrated that 23% express NY-ESO-1. After confirming antigen-specific activity of T cells genetically engineered to express an NY-ESO-1 directed high-affinity transgenic T cell receptor in vitro , we performed xenograft mouse studies assessing the efficacy of NY-ESO-1-targeted T cells in both localized and disseminated models of neuroblastoma. Disease responses were monitored by tumor volume measurement and in vivo bioluminescence. After delivery of NY-ESO-1 transgenic TCR T cells, we observed significant delay of tumor progression in mice bearing localized and disseminated neuroblastoma, as well as enhanced animal survival. These data demonstrate that NY-ESO-1 is an antigen target in neuroblastoma and that targeted T cells represent a potential therapeutic option for patients with neuroblastoma.

  17. 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.

  18. Solvent free low-melt viscosity imide oligomers and thermosetting polymide composites

    Science.gov (United States)

    Chuang, Chun-Hua (Inventor)

    2012-01-01

    .[.This invention relates to the composition and a solvent-free process for preparing novel imide oligomers and polymers specifically formulated with effective amounts of a dianhydride such as 2,3,3',4-biphenyltetra carboxylic dianydride (a-BPDA), at least one aromatic diamine and an endcapped of 4-phenylethynylphthalic anhydride (PEPA) or nadic anhydride to produce imide oligomers that possess a low-melt viscosity of 1-60 poise at 260-280.degree. C. When the imide oligomer melt is cured at about 371.degree. C. in a press or autoclave under 100-500 psi, the melt resulted in a thermoset polyimide having a glass transition temperature (T.sub.g) equal to and above 310.degree. C. A novel feature of this process is that the monomers; namely the dianhydrides, diamines and the endcaps, are melt processable to form imide oligomers at temperatures ranging between 232-280.degree. C. (450-535.degree. F.) without any solvent. These low-melt imide oligomers can be easily processed by resin transfer molding (RTM), vacuum-assisted resin transfer molding (VARTM) or the resin infusion process with fiber preforms e.g. carbon, glass or quartz preforms to produce polyimide matrix composites with 288-343.degree. C. (550-650.degree. F.) high temperature performance capability..]. .Iadd.This invention relates to compositions and a solvent-free reaction process for preparing imide oligomers and polymers specifically derived from effective amounts of dianhydrides such as 2,3,3',4'-biphenyltetracarboxylic dianhydride (a-BPDA), at least one aromatic polyamine and an end-cap such as 4-phenylethynyphthalic anhydride (PEPA) or nadic anhydride to produce imide oligomers that possess a low-melt viscosity of 1-60 poise at 260.degree. C.-280.degree. C..Iaddend.

  19. Humanin Specifically Interacts with Amyloid-β Oligomers and Counteracts Their in vivo Toxicity.

    Science.gov (United States)

    Romeo, Margherita; Stravalaci, Matteo; Beeg, Marten; Rossi, Alessandro; Fiordaliso, Fabio; Corbelli, Alessandro; Salmona, Mario; Gobbi, Marco; Cagnotto, Alfredo; Diomede, Luisa

    2017-01-01

    The 24-residue peptide humanin (HN) has been proposed as a peptide-based inhibitor able to interact directly with amyloid-β (Aβ) oligomers and interfere with the formation and/or biological properties of toxic Aβ species. When administered exogenously, HN, or its synthetic S14G-derivative (HNG), exerted multiple cytoprotective effects, counteracting the Aβ-induced toxicity. Whether these peptides interact directly with Aβ, particularly with the soluble oligomeric assemblies, remains largely unknown. We here investigated the ability of HN and HNG to interact directly with highly aggregating Aβ42, and interfere with the formation and toxicity of its oligomers. Experiments were run in cell-free conditions and in vivo in a transgenic C. elegans strain in which the Aβ toxicity was specifically due to oligomeric species. Thioflavin-T assay indicated that both HN and HNG delay the formation and reduce the final amount of Aβ42 fibrils. In vitro surface plasmon resonance studies indicated that they interact with Aβ42 oligomers favoring the formation of amorphous larger assemblies, observed with turbidity and electron microscopy. In vivo studies indicated that both HN and HNG decrease the relative abundance of A11-positive prefibrillar oligomers as well as OC-positive fibrillar oligomers and had similar protective effects. However, while HN possibly decreased the oligomers by promoting their assembly into larger aggregates, the reduction of oligomers caused by HNG can be ascribed to a marked decrease of the total Aβ levels, likely the consequence of the HNG-induced overexpression of the Aβ-degrading enzyme neprilysin. These findings provide information on the mechanisms underlying the anti-oligomeric effects of HN and HNG and illustrate the role of S14G substitution in regulating the in vivo mechanism of action.

  20. Separation of xylose oligomers using centrifugal partition chromatography with a butanol-methanol-water system.

    Science.gov (United States)

    Lau, Ching-Shuan; Clausen, Edgar C; Lay, Jackson O; Gidden, Jennifer; Carrier, Danielle Julie

    2013-01-01

    Xylose oligomers are the intermediate products of xylan depolymerization into xylose monomers. An understanding of xylan depolymerization kinetics is important to improve the conversion of xylan into monomeric xylose and to minimize the formation of inhibitory products, thereby reducing ethanol production costs. The study of xylan depolymerization requires copious amount of xylose oligomers, which are expensive if acquired commercially. Our approach consisted of producing in-house oligomer material. To this end, birchwood xylan was used as the starting material and hydrolyzed in hot water at 200 °C for 60 min with a 4 % solids loading. The mixture of xylose oligomers was subsequently fractionated by a centrifugal partition chromatography (CPC) with a solvent system of butanol:methanol:water in a 5:1:4 volumetric ratio. Operating in an ascending mode, the butanol-rich upper phase (the mobile phase) eluted xylose oligomers from the water-rich stationary phase at a 4.89 mL/min flow rate for a total fractionation time of 300 min. The elution of xylose oligomers occurred between 110 and 280 min. The yields and purities of xylobiose (DP 2), xylotriose (DP 3), xylotetraose (DP 4), and xylopentaose (DP 5) were 21, 10, 14, and 15 mg/g xylan and 95, 90, 89, and 68 %, respectively. The purities of xylose oligomers from this solvent system were higher than those reported previously using tetrahydrofuran:dimethyl sulfoxide:water in a 6:1:3 volumetric ratio. Moreover, the butanol-based solvent system improved overall procedures by facilitating the evaporation of the solvents from the CPC fractions, rendering the purification process more efficient.

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

    OpenAIRE

    Casey Grover; Elizabeth Crawford

    2014-01-01

    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 up...

  2. Distinct actin oligomers modulate differently the activity of actin nucleators.

    Science.gov (United States)

    Qu, Zheng; Silvan, Unai; Jockusch, Brigitte M; Aebi, Ueli; Schoenenberger, Cora-Ann; Mannherz, Hans Georg

    2015-10-01

    Polymerization of actin monomers into filaments requires the initial formation of nuclei composed of a few actin subunits; however, their instability has hindered their detailed study. Therefore we used chemically crosslinked actin oligomers to analyse their effect on actin polymerization. Actin dimer (upper dimer, UD), trimer and tetramer intermolecularly crosslinked by phenylene-bismaleimide along the genetic helix (between Lys199 and Cys374) were isolated by gel filtration and found to increasingly stimulate actin polymerization as shown by the pyrene assay and total internal reflection fluorescence microscopy. In contrast, the so-called lower actin dimer (LD) characterized by a Cys374-Cys374 crosslink stimulated actin polymerization only at low but inhibited it at high concentrations. UD and trimer stimulated the repolymerization of actin from complexes with thymosin β4 (Tβ4) or profilin, whereas the LD stimulated repolymerization only from the profilin : actin but not the actin : Tβ4 complex. In vivo, actin polymerization is stimulated by nucleation factors. Therefore the interaction and effects of purified LD, UD and trimer on the actin-nucleating activity of gelsolin, mouse diaphanous related (mDia) formin and the actin-related protein 2/3 (Arp2/3) complex were analysed. Native gel electrophoresis demonstrated binding of LD, UD and trimer to gelsolin and its fragment G1-3, to the FH2 domains of the formins mDia1 and mDia3, and to Arp2/3 complex. UD and trimer increased the nucleating activity of gelsolin and G1-3, but not of the mDia-FH2 domain nor of the Arp2/3 complex. In contrast, LD at equimolar concentration to Arp2/3 complex stimulated its nucleating activity, but inhibited that of mDia-FH2 domains, gelsolin and G1-3, demonstrating differential regulation of their nucleating activity by dimers containing differently oriented actin subunits. © 2015 FEBS.

  3. Notch ligand Delta-like 1 as a novel molecular target in childhood neuroblastoma.

    Science.gov (United States)

    Bettinsoli, P; Ferrari-Toninelli, G; Bonini, S A; Prandelli, C; Memo, M

    2017-05-19

    Neuroblastoma is the most common extracranial solid malignancy in childhood, responsible for 15% of all pediatric cancer deaths. It is an heterogeneous disease that does not always respond to classical therapy; so the identification of new and specific molecular targets to improve existing therapy is needed. We have previously demonstrated the involvement of the Notch pathway in the onset and progression of neuroblastoma. In this study we further investigated the role of Notch signaling and identified Delta-like 1 (DLL1) as a novel molecular target in neuroblastoma cells with a high degree of MYCN amplification, which is a major oncogenic driver in neuroblastoma. The possibility to act on DLL1 expression levels by using microRNAs (miRNAs) was assessed. DLL1 mRNA and protein expression levels were measured in three different neuroblastoma cell lines using quantitative real-time PCR and Western Blot analysis, respectively. Activation of the Notch pathway as a result of increased levels of DLL1 was analyzed by Immunofluorescence and Western Blot methods. In silico tools revealed the possibility to act on DLL1 expression levels with miRNAs, in particular with the miRNA-34 family. Neuroblastoma cells were transfected with miRNA-34 family members, and the effect of miRNAs transfection on DLL1 mRNA expression levels, on cell differentiation, proliferation and apoptosis was measured. In this study, the DLL1 ligand was identified as the Notch pathway component highly expressed in neuroblastoma cells with MYCN amplification. In silico analysis demonstrated that DLL1 is one of the targets of miRNA-34 family members that maps on chromosome regions that are frequently deregulated or deleted in neuroblastoma. We studied the possibility to use miRNAs to target DLL1. Among all miRNA-34 family members, miRNA-34b is able to significantly downregulate DLL1 mRNA expression levels, to arrest cell proliferation and to induce neuronal differentiation in malignant neuroblastoma cells

  4. Analysis of PEG oligomers in black gel inks: Discrimination and ink dating.

    Science.gov (United States)

    Sun, Qiran; Luo, Yiwen; Xiang, Ping; Yang, Xu; Shen, Min

    2017-08-01

    Carbon-based black gel inks are common samples in forensic practice of questioned document examination in China, but there are few analytical methods for this type of ink. In this study, a liquid chromatography-.high resolution mass spectrometry (LC-HRMS) method was established for the analysis of PEG oligomers in carbon-based black gel ink entries. The coupled instruments achieve both the identification and quantification of PEG oligomers in ink entries with reproducible results. Twenty carbon-based black gel inks, whose Raman spectra appeared identical, were analyzed using the LC-HRMS method. As a result, the twenty gel inks were classified into four groups according to the distribution of PEG oligomers. Artificially aging of PEG 400 and a gel ink showed that as PEG degraded, the relative amounts of low molecular weight PEG oligomers increased, while those of high molecular weight decreased. The degradation of PEG oligomers in a naturally aged gel ink was consistent with those in the artificially aged samples, but occurred more slowly. This study not only provided a new method for discriminating carbon-based black gel ink entries, but also offered a new approach for studying the relative ink dating of carbon-based black gel ink entries. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. Thin films of arylenevinylene oligomers prepared by MAPLE for applications in non-linear optics

    Energy Technology Data Exchange (ETDEWEB)

    Stanculescu, A., E-mail: sanca@infim.ro [National Institute of Materials Physics, Optics and Spectroscopy Laboratory, 105 bis Atomistilor Street, P.O. Box MG-7, Bucharest-Magurele 077125 (Romania); Vacareanu, L.; Grigoras, M. [P. Poni' Institute of Macromolecular Chemistry, 41 A Gr. Ghica Voda Alley, 700487 Iasi (Romania); Socol, M. [National Institute of Materials Physics, Optics and Spectroscopy Laboratory, 105 bis Atomistilor Street, P.O. Box MG-7, Bucharest-Magurele 077125 (Romania); Socol, G. [National Institute for Laser, Plasma and Radiation Physics, Str. Atomistilor, Nr. 409, P.O. Box MG-36, Magurele, Bucharest 077125 (Romania); Stanculescu, F. [Faculty of Physics, University of Bucharest, Str. Atomistilor nr.405, P.O. Box MG-11, Bucharest-Magurele 077125 (Romania); Preda, N.; Matei, E. [National Institute of Materials Physics, Optics and Spectroscopy Laboratory, 105 bis Atomistilor Street, P.O. Box MG-7, Bucharest-Magurele 077125 (Romania); Ionita, I. [Faculty of Physics, University of Bucharest, Str. Atomistilor nr.405, P.O. Box MG-11, Bucharest-Magurele 077125 (Romania); Girtan, M. [Laboratoire de Photonique d' Angers, Universite d' Angers, 2, Bd. Lavoisier, 49045 Angers (France); Mihailescu, I.N. [National Institute for Laser, Plasma and Radiation Physics, Str. Atomistilor, Nr. 409, P.O. Box MG-36, Magurele, Bucharest 077125 (Romania)

    2011-04-01

    This paper discusses two arylenevinylene oligomers with optical nonlinear properties. Their trans molecular structure was confirmed by Fourier Transform Infrared Spectroscopy and Nuclear Magnetic Resonance. Second Harmonic Generation and two-photon fluorescence have been observed on Matrix Assisted Pulsed Laser Evaporation-deposited thin films. We have seen two local maxima in UV-Vis spectra and a red shift of the photoluminescence peak for carbazole-based oligomer, which can be correlated with a higher conformational flexibility and with strong polarization interactions in the solid state. Scanning Electron Microscopy and Atomic Force Microscopy images have revealed a grainy morphology of the film deposited on titanium and a higher roughness for carbazole-based oligomer. Second harmonic measurements have shown nearly equal values of the second-order nonlinear optical coefficient for the triphenylamine and carbazole-based oligomers for P{sub laser} < 100 mW. z-Scan and x-scan representations of the carbazole-based oligomer film have shown strong two-photon fluorescence intensity inside the sample confirming a volume process, and a strong second harmonic at the surface of the sample determined by the surface morphology.

  6. Migration of oligomers from PET: determination of diffusion coefficients and comparison of experimental versus modelled migration.

    Science.gov (United States)

    Hoppe, Maria; Fornari, Roberta; de Voogt, Pim; Franz, Roland

    2017-07-01

    Polyethylene terephthalate (PET) is increasingly used as food-contact material in, for example, containers for beverage such as bottles for soft drinks, mineral water, juices and beer. Mass transport of substances present in packaging materials into the packed food and beverages is monitored to verify the food law compliance of the materials. PET is known to contain or give rise to migrants that are oligomers derived from the polymeric material. Until now their actual migration potential has been investigated only poorly. A convenient way to determine their migration would be by using models. To verify existing models with experimental data, a migration kinetic study of PET oligomers was conducted. PET bottle material was submerged in 50% ethanol at 80°C for 15 h. The oligomer content in the migration solutions was determined every hour using LC-MS with the first-series cyclic PET trimer as standard. Diffusion coefficients of five PET oligomers (first-series dimer and trimer, second-series dimer and trimer, and third-series dimer) were calculated from the obtained data and compared with the calculated diffusion coefficients using the models of Welle and Piringer. This is the first study to provide diffusion characteristics of oligomers in PET other than the first-series cyclic trimer.

  7. Extracellular Tau Oligomers Induce Invasion of Endogenous Tau into the Somatodendritic Compartment and Axonal Transport Dysfunction

    Science.gov (United States)

    Swanson, Eric; Breckenridge, Leigham; McMahon, Lloyd; Som, Sreemoyee; McConnell, Ian; Bloom, George S.

    2017-01-01

    Aggregates composed of the microtubule associated protein, tau, are a hallmark of Alzheimer’s disease and non-Alzheimer’s tauopathies. Extracellular tau can induce the accumulation and aggregation of intracellular tau, and tau pathology can be transmitted along neural networks over time. There are six splice variants of central nervous system tau, and various oligomeric and fibrillar forms are associated with neurodegeneration in vivo. The particular extracellular forms of tau capable of transferring tau pathology from neuron to neuron remain ill defined, however, as do the consequences of intracellular tau aggregation on neuronal physiology. The present study was undertaken to compare the effects of extracellular tau monomers, oligomers, and filaments comprising various tau isoforms on the behavior of cultured neurons. We found that 2N4R or 2N3R tau oligomers provoked aggregation of endogenous intracellular tau much more effectively than monomers or fibrils, or of oligomers made from other tau isoforms, and that a mixture of all six isoforms most potently provoked intracellular tau accumulation. These effects were associated with invasion of tau into the somatodendritic compartment. Finally, we observed that 2N4R oligomers perturbed fast axonal transport of membranous organelles along microtubules. Intracellular tau accumulation was often accompanied by increases in the run length, run time and instantaneous velocity of membranous cargo. This work indicates that extracellular tau oligomers can disrupt normal neuronal homeostasis by triggering axonal tau accumulation and loss of the polarized distribution of tau, and by impairing fast axonal transport. PMID:28482642

  8. In vivo application of beta amyloid oligomers: a simple tool to evaluate mechanisms of action and new therapeutic approaches.

    Science.gov (United States)

    Balducci, Claudia; Forloni, Gianluigi

    2014-01-01

    Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cerebral accumulation of extracellular amyloid β (Aβ) and neurofibrillary tangles made of hyperphosphorylated tau protein, two main lesions which appear sequentially during the disease progression. In the last decade numerous studies have proposed small soluble aggregates of Aβ, known as oligomers, as the species responsible for synaptic dysfunction, memory loss and neurodegeneration typical of AD. In vitro and in vivo experiments have identified Aβ oligomers as the elements that can alter synaptic function by a reversible mechanism, which gradually becomes permanent when exposure is continuous. Here we show that intracerebroventricular (ICV) injection in mice of a solution containing specifically Aβ1-42 oligomers substantially affects their memory when tested in the novel object recognition task. This acute mouse model enabled us to distinguish whether oligomers were affecting specific phases of the memory processing. A single injection of Aβ1-42 oligomers before memory consolidation abolished information processing, leading to memory impairment, whereas no such effects were observed when the injection was done once the information had been processed, indicating that the oligomers affect memory consolidation rather than retrieval. Beside Aβ1-42, Aβ1-40 oligomers also impaired memory, and both isoforms were antagonized by the anti-Aβ4G8 monoclonal antibody. This simple and reliable paradigm is useful to investigate the mechanisms through which Aβ oligomers interfere with neuronal processes and to test the efficacy of new therapeutic approaches specifically against these species. We tested several molecules by direct coincubation with Aβ oligomers, ICV injections preceding Aβ oligomers, and the systemic treatment with drugs that cross the blood brain barrier. We also examined the proposed involvement of cellular prion protein as a mediator of the oligomer-induced memory impairment.

  9. 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.

    2016-01-01

    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. PMID:27572323

  10. Improved therapy for neuroblastoma using a combination approach: superior efficacy with vismodegib and topotecan

    Science.gov (United States)

    Chaturvedi, Nagendra K.; McGuire, Timothy R.; Coulter, Don W.; Shukla, Ashima; McIntyre, Erin M.; Sharp, John Graham; Joshi, Shantaram S.

    2016-01-01

    Aberrant activation/expression of pathways/molecules including NF-kB, mTOR, hedgehog and polo-like-kinase-1 (PLK1) are correlated with poor-prognosis neuroblastoma. Therefore, to identify a most efficacious treatment for neuroblastoma, we investigated the efficacy of NF-kB/mTOR dual-inhibitor 13-197, hedgehog inhibitor vismodegib and PLK1 inhibitor BI2536 alone or combined with topotecan against high-risk neuroblastoma. The in vitro efficacy of the inhibitors alone or combined with topotecan on cell growth/apoptosis and molecular mechanism(s) were investigated. Results showed that as single agents 13-197, BI2536 and vismodegib significantly decreased neuroblastoma cell growth and induced apoptosis by targeting associated pathways/molecules. In combination with topotecan, 13-197 did not show significant additive/synergistic effects against neuroblastoma. However, BI2536 or vismodegib further significantly decreased neuroblastoma cell growth/survival. These results clearly showed that vismodegib combination with topotecan was synergistic and more efficacious compared with BI2536 in combination. Together, in vitro data demonstrated that vismodegib was most efficacious in potentiating topotecan-induced antineuroblastoma effects. Therefore, we tested the combined efficacy of vismodegib and topotecan against neuroblastoma in vivo using NSG mice. This resulted in significantly (p<0.001) reduced tumor growth and increased survival of mice. Together, the combination of vismodegib and topotecan showed a significant enhanced antineuroblastoma efficacy by targeting associated pathways/molecules which warrants further preclinical evaluation for translation to the clinic. PMID:26934655

  11. Activated ALK signals through the ERK-ETV5-RET pathway to drive neuroblastoma oncogenesis.

    Science.gov (United States)

    Lopez-Delisle, Lucille; Pierre-Eugène, Cécile; Louis-Brennetot, Caroline; Surdez, Didier; Raynal, Virginie; Baulande, Sylvain; Boeva, Valentina; Grossetête-Lalami, Sandrine; Combaret, Valérie; Peuchmaur, Michel; Delattre, Olivier; Janoueix-Lerosey, Isabelle

    2018-03-01

    Activating mutations of the ALK receptor occur in a subset of neuroblastoma tumors. We previously demonstrated that Alk mutations cooperate with MYCN overexpression to induce neuroblastoma in mice and identified Ret as being strongly upregulated in MYCN/Alk mut tumors. By a genetic approach in vivo, we now document an oncogenic cooperation between activated Ret and MYCN overexpression in neuroblastoma formation. We show that MYCN/Ret M919T tumors exhibit histological features and expression profiles close to MYCN/Alk mut tumors. We show that RET transcript levels decrease precedes RET protein levels decrease upon ALK inhibition in neuroblastoma cell lines. Etv5 was identified as a candidate transcription factor regulating Ret expression from murine MYCN/Alk mut tumor transcriptomic data. We demonstrate that ETV5 is regulated both at the protein and mRNA levels upon ALK activation or inhibition in neuroblastoma cell lines and that this regulation precedes RET modulation. We document that ALK activation induces ETV5 protein upregulation through stabilization in a MEK/ERK-dependent manner. We show that RNAi-mediated inhibition of ETV5 decreases RET expression. Reporter assays indicate that ETV5 is able to drive RET gene transcription. ChIP-seq analysis confirmed ETV5 binding on the RET promoter and identified an enhancer upstream of the promoter. Finally, we demonstrate that combining RET and ALK inhibitors reduces tumor growth more efficiently than each single agent in MYCN and Alk F1178L -driven murine neuroblastoma. Altogether, these results define the ERK-ETV5-RET pathway as a critical axis driving neuroblastoma oncogenesis downstream of activated ALK.

  12. 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

  13. 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

  14. A common mechanism of proteasome impairment by neurodegenerative disease-associated oligomers.

    Science.gov (United States)

    Thibaudeau, Tiffany A; Anderson, Raymond T; Smith, David M

    2018-03-15

    Protein accumulation and aggregation with a concomitant loss of proteostasis often contribute to neurodegenerative diseases, and the ubiquitin-proteasome system plays a major role in protein degradation and proteostasis. Here, we show that three different proteins from Alzheimer's, Parkinson's, and Huntington's disease that misfold and oligomerize into a shared three-dimensional structure potently impair the proteasome. This study indicates that the shared conformation allows these oligomers to bind and inhibit the proteasome with low nanomolar affinity, impairing ubiquitin-dependent and ubiquitin-independent proteasome function in brain lysates. Detailed mechanistic analysis demonstrates that these oligomers inhibit the 20S proteasome through allosteric impairment of the substrate gate in the 20S core particle, preventing the 19S regulatory particle from injecting substrates into the degradation chamber. These results provide a novel molecular model for oligomer-driven impairment of proteasome function that is relevant to a variety of neurodegenerative diseases, irrespective of the specific misfolded protein that is involved.

  15. ACTIN-DIRECTED TOXIN. ACD toxin-produced actin oligomers poison formin-controlled actin polymerization.

    Science.gov (United States)

    Heisler, David B; Kudryashova, Elena; Grinevich, Dmitry O; Suarez, Cristian; Winkelman, Jonathan D; Birukov, Konstantin G; Kotha, Sainath R; Parinandi, Narasimham L; Vavylonis, Dimitrios; Kovar, David R; Kudryashov, Dmitri S

    2015-07-31

    The actin cross-linking domain (ACD) is an actin-specific toxin produced by several pathogens, including life-threatening spp. of Vibrio cholerae, Vibrio vulnificus, and Aeromonas hydrophila. Actin cross-linking by ACD is thought to lead to slow cytoskeleton failure owing to a gradual sequestration of actin in the form of nonfunctional oligomers. Here, we found that ACD converted cytoplasmic actin into highly toxic oligomers that potently "poisoned" the ability of major actin assembly proteins, formins, to sustain actin polymerization. Thus, ACD can target the most abundant cellular protein by using actin oligomers as secondary toxins to efficiently subvert cellular functions of actin while functioning at very low doses. Copyright © 2015, American Association for the Advancement of Science.

  16. Synthesis of alginate oligomers by gamma irradiation and to investigate its antioxidant and prebiotic activity

    International Nuclear Information System (INIS)

    Bhoir, S.A.; Chawla, S.P.

    2016-01-01

    Alginate oligomers formed by alginate lyase have been reported to possess antioxidant activity as well as prebiotic activity. Hence, utility of gamma radiation to depolymerise alginate in its aqueous solution was investigated and its antioxidant and prebiotic activities were screened. 1% aqueous solution of sodium alginate was subjected to gamma irradiation and it's reducing power and ability to scavenge DPPH . and O 2 ..- , chelate iron and prevent heat induced β-carotene bleaching was determined. Prebiotic activity was determined by using alginate oligomers to promote prebiotic activity of Lactobacillus plantarum against E coli. Gamma radiation induced depolymerisation of alginate resulted in formation of oligomers with antioxidant and prebiotic activity. These polymers are potential candidates for utilization as natural preservatives and functional foods

  17. Biodegradable polyester-based eco-composites containing hemp fibers modified with macrocyclic oligomers

    Science.gov (United States)

    Conzatti, Lucia; Utzeri, Roberto; Hodge, Philip; Stagnaro, Paola

    2016-05-01

    An original compatibilizing pathway for hemp fibers/poly(1,4-butylene adipate-co-terephtalate) (PBAT) eco-composites was explored exploiting the capability of macrocyclic oligomers (MCOs), obtained by cyclodepolymerization (CDP) of PBAT at high dilution, of being re-converted into linear chains by entropically-driven ring-opening polymerization (ED-ROP) that occurs simply heating the MCOS in the bulk. CDP reaction of PBAT was carried out varying solvent, catalyst and reaction time. Selected MCOs were used to adjust the conditions of the ED-ROP reaction. The best experimental conditions were then adopted to modify hemp fibers. Eco-composites based on PBAT and hemp fibers as obtained or modified with PBAT macrocyclics or oligomers were prepared by different process strategies. The best fiber-PBAT compatibility was observed when the fibers were modified with PBAT oligomers before incorporation in the polyester matrix.

  18. Formation of nitrogen-containing oligomers by methylglyoxal and amines in simulated evaporating cloud droplets.

    Science.gov (United States)

    De Haan, David O; Hawkins, Lelia N; Kononenko, Julia A; Turley, Jacob J; Corrigan, Ashley L; Tolbert, Margaret A; Jimenez, Jose L

    2011-02-01

    Reactions of methylglyoxal with amino acids, methylamine, and ammonium sulfate can take place in aqueous aerosol and evaporating cloud droplets. These processes are simulated by drying droplets and bulk solutions of these compounds (at low millimolar and 1 M concentrations, respectively) and analyzing the residuals by scanning mobility particle sizing, nuclear magnetic resonance, aerosol mass spectrometry (AMS), and electrospray ionization MS. The results are consistent with imine (but not diimine) formation on a time scale of seconds, followed by the formation of nitrogen-containing oligomers, methylimidazole, and dimethylimidazole products on a time scale of minutes to hours. Measured elemental ratios are consistent with imidazoles and oligomers being major reaction products, while effective aerosol densities suggest extensive reactions take place within minutes. These reactions may be a source of the light-absorbing, nitrogen-containing oligomers observed in urban and biomass-burning aerosol particles.

  19. Resin adhesion strengths to zirconia ceramics after primer treatment with silane coupling monomer or oligomer.

    Science.gov (United States)

    Okada, Masahiro; Inoue, Kazusa; Irie, Masao; Taketa, Hiroaki; Torii, Yasuhiro; Matsumoto, Takuya

    2017-09-26

    Resin bonding to zirconia ceramics is difficult to achieve using the standard methods for conventional silica-based dental ceramics, which employ silane coupling monomers as primers. The hypothesis in this study was that a silane coupling oligomer -a condensed product of silane coupling monomers- would be a more suitable primer for zirconia. To prove this hypothesis, the shear bond strengths between a composite resin and zirconia were compared after applying either a silane coupling monomer or oligomer. The shear bond strength increased after applying a non-activated ethanol solution of the silane coupling oligomer compared with that achieved when applying the monomer. Thermal treatment of the zirconia at 110°C after application of the silane coupling agents was essential to improve the shear bond strength between the composite resin cement and zirconia.

  20. Detection of Misfolded Aβ Oligomers for Sensitive Biochemical Diagnosis of Alzheimer’s Disease

    Directory of Open Access Journals (Sweden)

    Natalia Salvadores

    2014-04-01

    Full Text Available Alzheimer's disease (AD diagnosis is hampered by the lack of early, sensitive, and objective laboratory tests. We describe a sensitive method for biochemical diagnosis of AD based on specific detection of misfolded Aβ oligomers, which play a central role in AD pathogenesis. The protein misfolding cyclic amplification assay (Aβ-PMCA, exploits the functional property of Aβ oligomers to seed the polymerization of monomeric Aβ. Aβ-PMCA allowed detection of as little as 3 fmol of Aβ oligomers. Most importantly, using cerebrospinal fluid, we were able to distinguish AD patients from control individuals affected by a variety of other neurodegenerative disorders or nondegenerative neurological diseases with overall sensitivity of 90% and specificity of 92%. These findings provide the proof-of-principle basis for developing a highly sensitive and specific biochemical test for AD diagnosis.

  1. Age dependence of tumor genetics in unfavorable neuroblastoma: arrayCGH profiles of 34 consecutive cases, using a Swedish 25-year neuroblastoma cohort for validation

    International Nuclear Information System (INIS)

    Cetinkaya, Cihan; Martinsson, Tommy; Sandgren, Johanna; Träger, Catarina; Kogner, Per; Dumanski, Jan; Díaz de Ståhl, Teresita; Hedborg, Fredrik

    2013-01-01

    Aggressive neuroblastoma remains a significant cause of childhood cancer death despite current intensive multimodal treatment protocols. The purpose of the present work was to characterize the genetic and clinical diversity of such tumors by high resolution arrayCGH profiling. Based on a 32K BAC whole-genome tiling path array and using 50-250K Affymetrix SNP array platforms for verification, DNA copy number profiles were generated for 34 consecutive high-risk or lethal outcome neuroblastomas. In addition, age and MYCN amplification (MNA) status were retrieved for 112 unfavorable neuroblastomas of the Swedish Childhood Cancer Registry, representing a 25-year neuroblastoma cohort of Sweden, here used for validation of the findings. Statistical tests used were: Fisher’s exact test, Bayes moderated t-test, independent samples t-test, and correlation analysis. MNA or segmental 11q loss (11q-) was found in 28/34 tumors. With two exceptions, these aberrations were mutually exclusive. Children with MNA tumors were diagnosed at significantly younger ages than those with 11q- tumors (mean: 27.4 vs. 69.5 months; p=0.008; n=14/12), and MNA tumors had significantly fewer segmental chromosomal aberrations (mean: 5.5 vs. 12.0; p<0.001). Furthermore, in the 11q- tumor group a positive correlation was seen between the number of segmental aberrations and the age at diagnosis (Pearson Correlation 0.606; p=0.037). Among nonMNA/non11q- tumors (n=6), one tumor displayed amplicons on 11q and 12q and three others bore evidence of progression from low-risk tumors due to retrospective evidence of disease six years before diagnosis, or due to tumor profiles with high proportions of numerical chromosomal aberrations. An early age at diagnosis of MNA neuroblastomas was verified by registry data, with an average of 29.2 months for 43 cases that were not included in the present study. MNA and segmental 11q loss define two major genetic variants of unfavorable neuroblastoma with apparent

  2. Thio-urethane oligomers improve the properties of light-cured resin cements.

    Science.gov (United States)

    Bacchi, Ataís; Consani, Rafael L; Martim, Gedalias C; Pfeifer, Carmem S

    2015-05-01

    Thio-urethanes were synthesized by combining 1,6-hexanediol-diissocyante (aliphatic) with pentaerythritol tetra-3-mercaptopropionate (PETMP) or 1,3-bis(1-isocyanato-1-methylethyl)benzene (aromatic) with trimethylol-tris-3-mercaptopropionate (TMP), at 1:2 isocyanate:thiol, leaving pendant thiols. Oligomers were added at 10-30 phr to BisGMA-UDMA-TEGDMA (5:3:2, BUT). 25 wt% silanated inorganic fillers were added. Commercial cement (Relyx Veneer, 3M-ESPE) was also evaluated with 10-20 phr of aromatic oligomer. Near-IR was used to follow methacrylate conversion (DC) and rate of polymerization (Rpmax). Mechanical properties were evaluated in three-point bending (ISO 4049) for flexural strength/modulus (FS/FM, and toughness), and notched specimens (ASTM Standard E399-90) for fracture toughness (KIC). Polymerization stress (PS) was measured on the Bioman. Volumetric shrinkage (VS, %) was measured with the bonded disk technique. Results were analyzed with ANOVA/Tukey's test (α=5%). In general terms, for BUT cements, conversion and mechanical properties in flexure increased for selected groups with the addition of thio-urethane oligomers. The aromatic versions resulted in greater FS/FM than aliphatic. Fracture toughness increased by two-fold in the experimental groups (from 1.17 ± 0.36 MPam(1/2) to around 3.23 ± 0.22 MPam(1/2)). Rpmax decreased with the addition of thio-urethanes, though the vitrification point was not statistically different from the control. VS and PS decreased with both oligomers. For the commercial cement, 20 phr of oligomer increased DC, vitrification, reduced Rpmax and also significantly increased KIC, and reduced PS and FM. Thio-urethane oligomers were shown to favorably modify conventional dimethacrylate networks. Significant reductions in polymerization stress were achieved at the same time conversion and fracture toughness increased. Copyright © 2015 Academy of Dental Materials. Published by Elsevier Ltd. All rights reserved.

  3. Energy Aspects of Thermal Molecular Switching: Molecular Thermal Hysteresis of Helicene Oligomers.

    Science.gov (United States)

    Shigeno, Masanori; Kushida, Yo; Yamaguchi, Masahiko

    2015-07-20

    Molecular switching is a phenomenon by which a molecule reversibly changes its structure and state in response to external stimuli or energy. Herein, molecular switching is discussed from thermodynamic and kinetic aspects in terms of energy supply with an emphasis on the thermal switching exhibited by helicene oligomers. It includes the inversion of relative thermodynamic stability induced by temperature changes and molecular thermal hysteresis in a closed system. The thermal phenomenon associated with the oligomers involves population/concentration changes between metastable states under nonequilibrium thermodynamic control. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  4. Electromagnetic field coupling characteristics in graphene plasmonic oligomers: from isolated to collective modes.

    Science.gov (United States)

    Ren, Junbo; Qiu, Weibin; Chen, Houbo; Qiu, Pingping; Lin, Zhili; Wang, Jia-Xian; Kan, Qiang; Pan, Jiao-Qing

    2017-06-07

    In this paper, we propose a plasmonic tetramer composed of coupled graphene nanodisks. The transformation from the isolated to the collective modes of the proposed structure is investigated by analysing the whispering-gallery modes and extinction spectra with various inter-nanodisk gap distances. In addition, the effect of introducing a central nanodisk into the tetramer on the extinction spectra is explored, which leads to Fano resonance. Furthermore, the refractive index sensing properties of the proposed graphene plasmonic oligomer have been demonstrated. The proposed nanostructures might pave the road toward the application of graphene plasmonic oligomers in fields such as nanophotonics, and chemical or biochemical sensing.

  5. Effect of particle size on the composition of lignin derived oligomers obtained by fast pyrolysis of beech wood

    NARCIS (Netherlands)

    Zhou, Shuai; Garcia-Perez, Manuel; Pecha, Brennan; McDonald, Armando G.; Westerhof, Roel Johannes Maria

    2014-01-01

    The effect of particle size on the yield and composition of lignin derived oligomers (also known as pyrolytic lignin (PL)) was studied in a fluidized bed reactor. Milled beech wood particles of sizes between 0.3 and 0.55 and cylinders of 3–14 mm were pyrolyzed at 500 °C. The lignin oligomers were

  6. Time-lapse imaging of neuroblastoma cells to determine cell fate upon gene knockdown.

    Directory of Open Access Journals (Sweden)

    Richa Batra

    Full Text Available Neuroblastoma is the most common extra-cranial solid tumor of early childhood. Standard therapies are not effective in case of poor prognosis and chemotherapy resistance. To improve drug therapy, it is imperative to discover new targets that play a substantial role in tumorigenesis of neuroblastoma. The mitotic machinery is an attractive target for therapeutic interventions and inhibitors can be developed to target mitotic entry, spindle apparatus, spindle activation checkpoint, and mitotic exit. We present an elaborate analysis pipeline to determine cancer specific therapeutic targets by first performing a focused gene expression analysis to select genes followed by a gene knockdown screening assay of live cells. We interrogated gene expression studies of neuroblastoma tumors and selected 240 genes relevant for tumorigenesis and cell cycle. With these genes we performed time-lapse screening of gene knockdowns in neuroblastoma cells. We classified cellular phenotypes and used the temporal context of the perturbation effect to determine the sequence of events, particularly the mitotic entry preceding cell death. Based upon this phenotype kinetics from the gene knockdown screening, we inferred dynamic gene functions in mitosis and cell proliferation. We identified six genes (DLGAP5, DSCC1, SMO, SNRPD1, SSBP1, and UBE2C with a vital role in mitosis and these are promising therapeutic targets for neuroblastoma. Images and movies of every time point of all screened genes are available at https://ichip.bioquant.uni-heidelberg.de.

  7. LMNA knock-down affects differentiation and progression of human neuroblastoma cells.

    Directory of Open Access Journals (Sweden)

    Giovanna Maresca

    Full Text Available BACKGROUND: Neuroblastoma (NB is one of the most aggressive tumors that occur in childhood. Although genes, such as MYCN, have been shown to be involved in the aggressiveness of the disease, the identification of new biological markers is still desirable. The induction of differentiation is one of the strategies used in the treatment of neuroblastoma. A-type lamins are components of the nuclear lamina and are involved in differentiation. We studied the role of Lamin A/C in the differentiation and progression of neuroblastoma. METHODOLOGY/PRINCIPAL FINDINGS: Knock-down of Lamin A/C (LMNA-KD in neuroblastoma cells blocked retinoic acid-induced differentiation, preventing neurites outgrowth and the expression of neural markers. The genome-wide gene-expression profile and the proteomic analysis of LMNA-KD cells confirmed the inhibition of differentiation and demonstrated an increase of aggressiveness-related genes and molecules resulting in augmented migration/invasion, and increasing the drug resistance of the cells. The more aggressive phenotype acquired by LMNA-KD cells was also maintained in vivo after injection into nude mice. A preliminary immunohistochemistry analysis of Lamin A/C expression in nine primary stages human NB indicated that this protein is poorly expressed in most of these cases. CONCLUSIONS/SIGNIFICANCE: We demonstrated for the first time in neuroblastoma cells that Lamin A/C plays a central role in the differentiation, and that the loss of this protein gave rise to a more aggressive tumor phenotype.

  8. Depletion of TFAP2E attenuates adriamycin-mediated apoptosis in human neuroblastoma cells.

    Science.gov (United States)

    Hoshi, Reina; Watanabe, Yosuke; Ishizuka, Yoshiaki; Hirano, Takayuki; Nagasaki-Maeoka, Eri; Yoshizawa, Shinsuke; Uekusa, Shota; Kawashima, Hiroyuki; Ohashi, Kensuke; Sugito, Kiminobu; Fukuda, Noboru; Nagase, Hiroki; Soma, Masayoshi; Ozaki, Toshinori; Koshinaga, Tsugumichi; Fujiwara, Kyoko

    2017-04-01

    Neuroblastoma is a childhood malignancy originating from the sympathetic nervous system and accounts for approximately 15% of all pediatric cancer-related deaths. To newly identify gene(s) implicated in the progression of neuroblastoma, we investigated aberrantly methylated genomic regions in mouse skin tumors. Previously, we reported that TFAP2E, a member of activator protein-2 transcription factor family, is highly methylated within its intron and its expression is strongly suppressed in mouse skin tumors compared with the normal skin. In the present study, we analyzed public data of neuroblastoma patients and found that lower expression levels of TFAP2E are significantly associated with a shorter survival. The data indicate that TFAP2E acts as a tumor suppressor of neuroblastoma. Consistent with this notion, TFAP2E-depleted neuroblastoma NB1 and NB9 cells displayed a substantial resistance to DNA damage arising from adriamycin (ADR), cisplatin (CDDP) and ionizing radiation (IR). Silencing of TFAP2E caused a reduced ADR-induced proteolytic cleavage of caspase-3 and PARP. Of note, compared with the untransfected control cells, ADR-mediated stimulation of CDK inhibitor p21WAF1 was markedly upregulated in TFAP2E‑knocked down cells. Therefore, our present findings strongly suggest that TFAP2E has a pivotal role in the regulation of DNA damage response in NB cells through the induction of p21WAF1.

  9. 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.

  10. 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.

  11. 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.

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

    Directory of Open Access Journals (Sweden)

    Jose Luiz de Oliveira Schiavon

    Full Text Available Abstract 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%.

  13. Orbital Metastasis Is Associated With Decreased Survival in Stage M Neuroblastoma.

    Science.gov (United States)

    Harreld, Julie H; Bratton, Emily M; Federico, Sara M; Li, Xingyu; Grover, William; Li, Yimei; Kerr, Natalie C; Wilson, Matthew W; Hoehn, Mary E

    2016-04-01

    Approximately 30% of patients with metastatic (stage M) neuroblastoma present with periorbital ecchymosis from orbital osseous disease. Though locoregional disease is staged by imaging, the prognostic significance of metastatic site in stage M disease is unknown. We hypothesize that, compared to nonorbital metastasis, orbital metastasis is associated with decreased survival in patients with stage M neuroblastoma, and that periorbital ecchymosis reflects location and extent of orbital disease. Medical records and imaging from 222 patients with stage M neuroblastoma seen at St. Jude Children's Research Hospital between January 1995 and May 2009 were reviewed. Thirty-seven patients were ecchymosis (log-rank test). Associations of periorbital ecchymosis with orbital metastasis location/extent were explored (Fisher's exact test, t-test). In patients ≥18 months of age, only orbital metastasis was associated with decreased 5YS (P = 0.0323) and OS (P = 0.0288). In patients ecchymosis was associated with higher number of involved orbital bones (P = 0.0135), but not location or survival. In patients ≥ 18 months of age with stage M neuroblastoma, orbital metastatic disease is associated with decreased 5YS and OS. In future clinical trials, orbital disease may be useful as an imaging-based risk factor for substratification of stage M neuroblastoma. © 2015 Wiley Periodicals, Inc.

  14. A multidisciplinary team care approach improves outcomes in high-risk pediatric neuroblastoma patients.

    Science.gov (United States)

    Chang, Hsiu-Hao; Liu, Yen-Lin; Lu, Meng-Yao; Jou, Shiann-Tarng; Yang, Yung-Li; Lin, Dong-Tsamn; Lin, Kai-Hsin; Tzen, Kai-Yuan; Yen, Ruoh-Fang; Lu, Ching-Chu; Liu, Chia-Ju; Peng, Steven Shinn-Forng; Jeng, Yung-Ming; Huang, Shiu-Feng; Lee, Hsinyu; Juan, Hsueh-Fen; Huang, Min-Chuan; Liao, Yung-Feng; Lee, Ya-Ling; Hsu, Wen-Ming

    2017-01-17

    We assessed the impact of a multidisciplinary team care program on treatment outcomes in neuroblastoma patients. Newly diagnosed neuroblastoma patients received treatment under the Taiwan Pediatric Oncology Group (TPOG) N2002 protocol at the National Taiwan University Hospital beginning in 2002. A multidisciplinary team care approach that included nurse-led case management for patients treated under this protocol began in January 2010. Fifty-eight neuroblastoma patients, including 29 treated between 2002 and 2009 (Group 1) and 29 treated between 2010 and 2014 (Group 2), were enrolled in the study. The 5-year overall survival (OS) and event-free survival (EFS) rates for all 58 patients were 59% and 54.7%, respectively. Group 2 patients, who were treated after implementation of the multidisciplinary team care program, had better 3-year EFS (P = 0.046), but not OS (P = 0.16), rates than Group 1 patients. In a multivariate analysis, implementation of the multidisciplinary team approach was the only significant independent prognostic factor for neuroblastoma patients. In further subgroup analyses, the multidisciplinary team approach improved EFS, but not OS, in patients with stage 4 disease, those in the high-risk group, and those with non-MYCN amplified tumors. These data indicate a multidisciplinary team care approach improved survival outcomes in high-risk neuroblastoma patients. However, further investigation will be required to evaluate the long-term effects of this approach over longer follow-up periods.

  15. 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)

  16. Targeted BIRC5 silencing using YM155 causes cell death in neuroblastoma cells with low ABCB1 expression

    NARCIS (Netherlands)

    Lamers, Fieke; Schild, Linda; Koster, Jan; Versteeg, Rogier; Caron, Huib N.; Molenaar, Jan J.

    2012-01-01

    The BIRC5 (Survivin) gene is located at chromosome 17q in the region that is frequently gained in high risk neuroblastoma. BIRC5 is strongly over expressed in neuroblastoma tumour samples, which correlates to a poor prognosis. We recently validated BIRC5 as a potential therapeutic target by showing

  17. 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

  18. 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; Brown, Keith W

    2017-04-01

    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. © 2016 The Authors. Molecular Carcinogenesis Published by Wiley Periodicals, Inc.

  19. 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

  20. 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

  1. 1;17 translocations and other chromosome 17 rearrangements in human primary neuroblastoma tumors and cell lines

    NARCIS (Netherlands)

    van Roy, N.; Laureys, G.; Cheng, N. C.; Willem, P.; Opdenakker, G.; Versteeg, R.; Speleman, F.

    1994-01-01

    We report on the finding of a t(1;17) in two primary neuroblastomas. Subsequent fluorescence in situ hybridization (FISH) analysis revealed the presence of 1;17 translocations in four out of nine neuroblastoma cell lines. The chromosome 1 short arm breakpoints were determined using region-specific

  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

    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...

  3. 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.

  4. Evaluation of the amyloid beta-GFP fusion protein as a model of amyloid beta peptides-mediated aggregation: A study of DNAJB6 chaperone

    Directory of Open Access Journals (Sweden)

    Rasha Mohamed Hussein

    2015-07-01

    Full Text Available Alzheimer’s disease is a progressive neurodegenerative disease characterized by the accumulation and aggregation of extracellular amyloid β (Aβ peptides and intracellular aggregation of hyper-phosphorylated tau protein. Recent evidence indicates that accumulation and aggregation of intracellular amyloid β peptides may also play a role in disease pathogenesis. This would suggest that intracellular Heat Shock Proteins (HSP that maintain cellular protein homeostasis might be candidates for disease amelioration. We recently found that DNAJB6, a member of DNAJ family of heat shock proteins, effectively prevented the aggregation of short aggregation-prone peptides containing large poly glutamines (associated with CAG repeat diseases both in vitro and in cells. Moreover, recent in vitro data showed that DNAJB6 can delay the aggregation of Aβ42 peptides. In this study, we investigated the ability of DNAJB6 to prevent the aggregation of extracellular and intracellular Aβ peptides using transfection of HEK293 cells with Aβ-GFP fusion construct and performing western blotting and immunofluorescence techniques. We found that DNAJB6 indeed suppresses Aβ-GFP aggregation, but not seeded aggregation initiated by extracellular Aβ peptides. Unexpectedly and unlike what we found for peptide-mediated aggregation, DNAJB6 required interaction with HSP70 to prevent the aggregation of the Aβ-GFP fusion protein and its J-domain was crucial for its anti-aggregation effect. In addition, other DNAJ proteins as well as HSPA1a overexpression also suppressed Aβ-GFP aggregation efficiently. Our findings suggest that Aβ aggregation differs from poly Q peptide induced aggregation in terms of chaperone handling and sheds doubt on the usage of Aβ-GFP fusion construct for studying Aβ peptide aggregation in cells.

  5. Evaluation of the Ultraviolet-Curing Kinetics of Ultraviolet-Polymerized Oligomers Cured Using Poly (Ethylene Glycol Dimethacrylate

    Directory of Open Access Journals (Sweden)

    Ji-Won Park

    2018-03-01

    Full Text Available Ultraviolet (UV-curable oligomers are increasingly being used in various industries because they can be applied rapidly and have excellent physical properties. Ultraviolet polymerization is used for manufacturing such oligomers. Reactive diluents, which are employed during the secondary curing of UV-curable oligomers, can help elucidate the curing behaviors of these oligomers. In this study, poly (ethylene glycol dimethacrylate (PEGDMA was used as the reactive diluent for UV-curable oligomers. Photodifferential scanning calorimetry (photo-DSC and shrinkage measurements revealed that the curing behavior of the polymers was dependent on the size and number of molecules of PEGDMA. The effect of the small-size PEGDMA on curing behavior was greater than that of the larger molecules. Further, in most cases, the use of a larger amount of PEGDMA resulted in lower reactivity.

  6. Outcomes in multifocal neuroblastoma as part of the neurocristopathy syndrome.

    Science.gov (United States)

    Williams, Phoebe; Wegner, Eva; Ziegler, David S

    2014-08-01

    The neurocristopathy syndrome occurs because of a germline mutation of the paired-like homeobox 2b (PHOX2B) gene at 4p12, a neurogenesis regulator gene. The result is abnormal neural crest cell development resulting in congenital central hypoventilation syndrome, Hirschsprung disease, and neuroblastoma (NB), which is often multifocal and disseminated in its presentation. Previously, such widespread disease was regarded as highly aggressive and treated either with palliative intent or, conversely, with very intense, high-dose chemotherapy. We now present a patient who had neurocristopathy syndrome who had multifocal NB associated with an underlying germline PHOX2B mutation. He was treated conservatively with surgery and low-dose chemotherapy. After treatment he had extensive residual disease that has continued to mature despite no further treatment. A literature review identified 26 similar patients presenting with multifocal NB as part of the neurocristopathy syndrome. In all cases the NB behaved in an indolent manner with no deaths from tumor reported when patients received appropriate treatment. These provocative findings suggest for the first time that children who have neurocristopathy-associated NB should be treated conservatively, despite the aggressive appearance of their disease. Copyright © 2014 by the American Academy of Pediatrics.

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

    Energy Technology Data Exchange (ETDEWEB)

    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 ..mu.. and 10,000 delta 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 ..mu.. 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. (/sup 3/H)Dopamine uptake was slightly enhanced only in RA-treated cells. Strikingly, the efficacy of PGE/sub 1/-stimulated accumulation of cAMP was enhanced by 15- to 30-fold upon RA treatment.

  8. 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)

  9. Acute application of cisplatin affects methylation status in neuroblastoma cells.

    Science.gov (United States)

    Tabata, Keiichi; Sakai, Hayato; Nakajima, Ryosuke; Saya-Nishimura, Reiko; Motani, Kou; Okano, Soichiro; Shibata, Yasuko; Abiko, Yoshimitsu; Suzuki, Takashi

    2011-06-01

    The pharmacological mechanism of the anti-cancer effect of cisplatin is well known to be DNA intercalation, but the direct or indirect effects of cisplatin on protein expression in cancer cells remain to be explained. In this study, we used a proteomic approach to clarify the early impact of cisplatin on protein expression. In a 2-dimensional gel electrophoresis proteomic experiment, the application of cisplatin for 24 h increased the expression of four proteins and decreased the levels of one protein in neuroblastoma IMR-32 cells. Levels of S-adenosyl-L-homocysteine hydrolase, a key enzyme in methylation metabolism, were increased the most. Therefore, we examined the methylation status of histone proteins. Histone H3K9 methylation was reduced by the application of cisplatin for 24 h. These results suggest that acute cisplatin treatment alters methylation status. Thus, these data can help clarify the unknown pharmacological mechanisms of cisplatin, including the anticancer effect, adverse effects and/or the mechanism of drug resistance.

  10. Trace metals and cancer: The case of neuroblastoma

    International Nuclear Information System (INIS)

    Gouget, B.; Sergeant, C.; Llabador, Y.; Deves, G.; Vesvres, M.H.; Simonoff, M.; Benard, J.

    2001-01-01

    N-myc oncogene amplification is one of the most established prognostic factors in neuroblastoma (NB), a young children solid tumor. Amounts of ferritin, an iron storage protein, are abnormally increased in serum of patients with advanced stage disease. N-myc amplified NB cells can synthesize zinc metalloenzymes allowing tumor invasion and metastases formation. The aim of this study was to find a relationship between N-myc amplification and trace metals in human neuroblasts. Coupling PIXE and RBS techniques, nuclear microprobe allowed to analyze elemental distributions and to determine trace metal concentrations within cultured neuroblasts characterized by various degrees of N-myc amplification. They were compared to trace metal distributions and concentrations in tumor xenograft models of human NB, after injection of cells from the same lines in athymic nude mice. Our data allowed to establish a relation between trace metal contents and mechanisms of NB oncogenesis, amplified cell lines representing more aggressive phenotypes of the disease. They should be confirmed by analysis of cultured neuroblasts and tumors issued from a non-amplified cell line transfected with the N-myc oncogene

  11. 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.

  12. microRNA-221 Enhances MYCN via Targeting Nemo-like Kinase and Functions as an Oncogene Related to Poor Prognosis in Neuroblastoma.

    Science.gov (United States)

    He, Xiao-Yan; Tan, Zheng-Lan; Mou, Qin; Liu, Fang-Jie; Liu, Shan; Yu, Chao-Wen; Zhu, Jin; Lv, Lin-Ya; Zhang, Jun; Wang, Shan; Bao, Li-Ming; Peng, Bin; Zhao, Hui; Zou, Lin

    2017-06-01

    Purpose: MYCN is one of the most well-characterized genetic markers of neuroblastoma. However, the mechanisms as to how MYCN mediate neuroblastoma tumorigenesis are not fully clear. Increasing evidence has confirmed that the dysregulation of miRNAs is involved in MYCN-mediated neuroblastoma tumorigenesis, supporting their potential as therapeutic targets for neuroblastoma. Although miR-221 has been reported as one of the upregulated miRNAs, the interplay between miR-221 and MYCN-mediated neuroblastoma progression remains largely elusive. Experimental Design: The expression of miR-221 in the formalin-fixed, paraffin-embedded tissues from 31 confirmed patients with neuroblastoma was detected by locked nucleic acid- in situ hybridization and qRT-PCR. The correlation between miR-221 expression and clinical features in patients with neuroblastoma was assessed. The mechanisms as to how miR-221 regulate MYCN in neuroblastoma were addressed. The effect of miR-221 on cellular proliferation in neuroblastoma was determined both in vitro and in vivo Results: miR-221 was significantly upregulated in neuroblastoma tumor cells and tissues that overexpress MYCN, and high expression of miR-221 was positively associated with poor survival in patients with neuroblastoma. Nemo-like kinase (NLK) as a direct target of miR-221 in neuroblastoma was verified. In addition, overexpression of miR-221 decreased LEF1 phosphorylation but increased the expression of MYCN via targeting of NLK and further regulated cell cycle, particularly in S-phase, promoting the growth of neuroblastoma cells. Conclusions: This study provides a novel insight for miR-221 in the control of neuroblastoma cell proliferation and tumorigenesis, suggesting potentials of miR-221 as a prognosis marker and therapeutic target for patients with MYCN overexpressing neuroblastoma. Clin Cancer Res; 23(11); 2905-18. ©2016 AACR . ©2016 American Association for Cancer Research.

  13. Clinical Responses to Rituximab in a Case of Neuroblastoma with Refractory Opsoclonus Myoclonus Ataxia Syndrome

    Directory of Open Access Journals (Sweden)

    Samin Alavi

    2012-01-01

    Full Text Available Opsoclonus myoclonus ataxia syndrome (OMS is a rare neurologic syndrome. In a high proportion of children, it is associated with neuroblastoma. The etiology of this condition is thought to be immune mediated. In children, immunotherapy with conventional treatments such as corticosteroids, intravenous immunoglobulin, adrenocorticotropic hormone, and even antiepileptic drugs has been tried. Recently rituximab has been used safely for refractory OMS in children with neuroblastoma. Our patient was a 3.5-year-old girl referred for ataxia and dancing eye movements starting since 1.5 years ago. She was diagnosed with neuroblastoma on imaging studies on admission. The OMS was refractory to surgical resection, chemotherapy, corticosteroids, and intravenous immunoglobulin. Patient received rituximab simultaneously with chemotherapy. The total severity score decreased by 61.1% after rituximab. Patient's ataxia markedly improved that she was able to walk independently after 6 months. Our case confirmed the clinical efficacy and safety of rituximab in a refractory case of OMS.

  14. 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.

  15. 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].

  16. 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.

  17. 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.

  18. 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

  19. Neuroblastomas and medulloblastomas exhibit more Coxsackie adenovirus receptor expression than gliomas and other brain tumors.

    Science.gov (United States)

    Persson, Annette; Fan, Xiaolong; Salford, Leif G; Widegren, Bengt; Englund, Elisabet

    2007-06-01

    Adenoviral vector-mediated treatment is a potential therapy for tumors of the central nervous system. To obtain a significant therapeutic effect by adenoviral vectors, a sufficient infection is required, the power of which depends predominantly on the level of Coxsackie adenovirus receptors. We stained surgical biopsies of central nervous system tumors and neuroblastomas for Coxsackie adenovirus receptors. For gliomas, the level of the receptor was low and markedly variable among individual tumors. By contrast, neuroblastomas and medulloblastomas exhibited a higher degree of Coxsackie adenovirus receptor expression than gliomas and other brain tumors. We conclude that neuroblastomas and medulloblastomas could be suitable for adenovirus-mediated gene therapy. Adverse effects of the treatment, however, must be considered because neurons and reactive astrocytes also express a significant amount of the receptor.

  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)