35 research outputs found

    Inhibition of histone deacetylase 6 (HDAC6) protects against vincristine-induced peripheral neuropathies and inhibits tumor growth

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    As cancer is becoming more and more a chronic disease, a large proportion of patients is confronted with devastating side effects of certain anti-cancer drugs. The most common neurological complications are painful peripheral neuropathies. Chemotherapeutics that interfere with microtubules, including plant-derived vinca-alkaloids such as vincristine, can cause these chemotherapy-induced peripheral neuropathies (CIPN). Available treatments focus on symptom alleviation and pain reduction rather than prevention of the neuropathy. The aim of this study was to investigate the potential of specific histone deacetylase 6 (HDAC6) inhibitors as a preventive therapy for CIPN using multiple rodent models for vincristine-induced peripheral neuropathies (VIPN). HDAC6 inhibition increased the level of acetylated Ī±-tubulin in tissues of rodents undergoing vincristine-based chemotherapy, which correlates to a reduced severity of the neurological symptoms, both at the electrophysiological and the behavioral level. Mechanistically, disturbances in axonal transport of mitochondria is considered as an important contributing factor in the pathophysiology of VIPN. As vincristine interferes with the polymerization of microtubules, we investigated whether disturbances in axonal transport could contribute to VIPN. We observed that increasing Ī±-tubulin acetylation through HDAC6 inhibition restores vincristine-induced defects of axonal transport in cultured dorsal root ganglion neurons. Finally, we assured that HDAC6-inhibition offers neuroprotection without interfering with the anti-cancer efficacy of vincristine using a mouse model for acute lymphoblastic leukemia. Taken together, our results emphasize the therapeutic potential of HDAC6 inhibitors with beneficial effects both on vincristine-induced neurotoxicity, as well as on tumor proliferation. ispartof: Neurobiology of Disease vol:111 pages:59-69 ispartof: location:United States status: publishe

    Experimental validation of depletion calculations with VESTA 2.1.5 using JEFF-3.2

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    The removal of decay heat is a significant safety concern in nuclear engineering for the operation of a nuclear reactor both in normal and accidental conditions and for intermediate and long term waste storage facilities. The correct evaluation of the decay heat produced by an irradiated material requires first of all the calculation of the composition of the irradiated material by depletion codes such as VESTA 2.1, currently under development at IRSN in France. A set of PWR assembly decay heat measurements performed by the Swedish Central Interim Storage Facility (CLAB) located in Oskarshamm (Sweden) have been calculated using different nuclear data libraries: ENDF/B-VII.0, JEFF-3.1, JEFF-3.2 and JEFF-3.3T1. Using these nuclear data libraries, VESTA 2.1 calculates the assembly decay heat for almost all cases within 4% of the measured decay heat. On average, the ENDF/B-VII.0 calculated decay heat values appear to give a systematic underestimation of only 0.5%. When using the JEFF-3.1 library, this results a systematic underestimation of about 2%. By switching to the JEFF-3.2 library, this systematic underestimation is improved slighty (up to 1.5%). The changes made in the JEFF-3.3T1 beta library appear to be overcorrecting, as the systematic underestimation is transformed into a systematic overestimation of about 1.5%

    Experimental validation of depletion calculations with VESTA 2.1.5 using JEFF-3.2

    No full text
    The removal of decay heat is a significant safety concern in nuclear engineering for the operation of a nuclear reactor both in normal and accidental conditions and for intermediate and long term waste storage facilities. The correct evaluation of the decay heat produced by an irradiated material requires first of all the calculation of the composition of the irradiated material by depletion codes such as VESTA 2.1, currently under development at IRSN in France. A set of PWR assembly decay heat measurements performed by the Swedish Central Interim Storage Facility (CLAB) located in Oskarshamm (Sweden) have been calculated using different nuclear data libraries: ENDF/B-VII.0, JEFF-3.1, JEFF-3.2 and JEFF-3.3T1. Using these nuclear data libraries, VESTA 2.1 calculates the assembly decay heat for almost all cases within 4% of the measured decay heat. On average, the ENDF/B-VII.0 calculated decay heat values appear to give a systematic underestimation of only 0.5%. When using the JEFF-3.1 library, this results a systematic underestimation of about 2%. By switching to the JEFF-3.2 library, this systematic underestimation is improved slighty (up to 1.5%). The changes made in the JEFF-3.3T1 beta library appear to be overcorrecting, as the systematic underestimation is transformed into a systematic overestimation of about 1.5%

    Evaluation of AGNI SFR core neutronics parameters with VESTA and ERANOS

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    This paper presents the calculation of core neutronics parameters for so called AGNI Sodium Fast Reactor (SFR) model performed with ERANOS code and Monte Carlo depletion interface software VESTA. The AGNI core has been developed at IRSN for its own R&D needs, i.e. to test performance of calculation codes for safety assessment of a generation IV SFR project. The ERANOS code is used as reference code for SFR core calculations at IRSN. In this work, VESTA calculations have been performed and compared with corresponding ERANOS results. These calculations have a double purpose: mastering the use of tools for the evaluation of SFR core static neutronics parameters and validate the use of VESTA for SFR cores

    Use of integral experiments in support to the validation of JEFF-3.2 nuclear data evaluation

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    For many years now, IRSN has developed its own Monte Carlo continuous energy capability, which allows testing various nuclear data libraries. In that prospect, a validation database of 1136 experiments was built from cases used for the validation of the APOLLO2-MORET 5 multigroup route of the CRISTAL V2.0 package. In this paper, the keff obtained for more than 200 benchmarks using the JEFF-3.1.1 and JEFF-3.2 libraries are compared to benchmark keff values and main discrepancies are analyzed regarding the neutron spectrum. Special attention is paid on benchmarks for which the results have been highly modified between both JEFF-3 versions

    Use of integral experiments in support to the validation of JEFF-3.2 nuclear data evaluation

    No full text
    For many years now, IRSN has developed its own Monte Carlo continuous energy capability, which allows testing various nuclear data libraries. In that prospect, a validation database of 1136 experiments was built from cases used for the validation of the APOLLO2-MORET 5 multigroup route of the CRISTAL V2.0 package. In this paper, the keff obtained for more than 200 benchmarks using the JEFF-3.1.1 and JEFF-3.2 libraries are compared to benchmark keff values and main discrepancies are analyzed regarding the neutron spectrum. Special attention is paid on benchmarks for which the results have been highly modified between both JEFF-3 versions
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