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Astolfo A.,Swiss Light Source | Astolfo A.,Australian Synchrotron | Qie F.,Beijing University of Chemical Technology | Qie F.,CSIRO | And 13 more authors.
Nanomedicine: Nanotechnology, Biology, and Medicine | Year: 2014

The use of alginate based microcapsules to deliver drugs and cells with a minimal host interaction is increasingly being proposed. A proficient method to track the position of the microcapsules during such therapies, particularly if they are amenable to commonly used instrumentation, would greatly help the development of such treatments. Here we propose to label the microcapsules with gold nanoparticles to provide a bright contrast on small animal x-ray micro-CT systems enabling single microcapsule detection. The microcapsules preparation is based on a simple protocol using inexpensive compounds. This, combined with the widespread availability of micro-CT apparatus, renders our method more accessible compared with other methods. Our labeled microcapsules showed good mechanical stability and low cytotoxicity in-vitro. Our post-mortem rodent model data strongly suggest that the high signal intensity generated by the labeled microcapsules permits the use of a reduced radiation dose yielding a method fully compatible with longitudinal in-vivo studies. From the Clinical Editor: The authors of this study report the development of a micro-CT based tracking method of alginate-based microcapsules by incorporating gold nanoparticles in the microcapsules. They demonstrate the feasibility of this system in rodent models, where due to the high signal intensity, even reduced radiation dose is sufficient to track these particles, providing a simple and effective method to track these commonly used microcapsules and allowing longitudinal studies. © 2014.

PubMed | University of Padua, University of Milan Bicocca, Grenoble Institute des Neurosciences, Lund University and 3 more.
Type: | Journal: Scientific reports | Year: 2016

-Synuclein is a presynaptic protein associated to Parkinsons disease, which is unstructured when free in the cytoplasm and adopts helical conformation when bound to vesicles. After decades of intense studies, -Synuclein physiology is still difficult to clear up due to its interaction with multiple partners and its involvement in a pletora of neuronal functions. Here, we looked at the remarkably neglected interplay between -Synuclein and microtubules, which potentially impacts on synaptic functionality. In order to identify the mechanisms underlying these actions, we investigated the interaction between purified -Synuclein and tubulin. We demonstrated that -Synuclein binds to microtubules and tubulin 22 tetramer; the latter interaction inducing the formation of helical segment(s) in the -Synuclein polypeptide. This structural change seems to enable -Synuclein to promote microtubule nucleation and to enhance microtubule growth rate and catastrophe frequency, both in vitro and in cell. We also showed that Parkinsons disease-linked -Synuclein variants do not undergo tubulin-induced folding and cause tubulin aggregation rather than polymerization. Our data enable us to propose -Synuclein as a novel, foldable, microtubule-dynamase, which influences microtubule organisation through its binding to tubulin and its regulating effects on microtubule nucleation and dynamics.

PubMed | Grenoble Institute des Neurosciences, Center Hospitalier University and DOSIsoft
Type: Journal Article | Journal: Medical physics | Year: 2016

Iodine-enhanced radiotherapy is an innovative treatment combining the selective accumulation of an iodinated contrast agent in brain tumors with irradiations using monochromatic medium energy x-rays. The aim of this study is to compare dynamic stereotactic arc-therapy and iodineenhanced SSRT.Five patients bearing brain metastasis received a standard helical 3D-scan without iodine. A second scan was acquired 13 min after an 80 g iodine infusion. Two SSRT treatment plans (with/without iodine) were performed for each patient using a dedicated Monte Carlo (MC) treatment planning system (TPS) based on the ISOgray TPS. Ten coplanar beams (66 cm2, shaped with collimator) were simulated. MC statistical error objective was less than 5% in the 50% isodose. The dynamic arc-therapy plan was achieved on the Iplan Brainlab TPS. The treatment plan validation criteria were fixed such that 100% of the prescribed dose is delivered at the beam isocentre and the 70% isodose contains the whole target volume. The comparison elements were the 70% isodose volume, the average and maximum doses delivered to organs at risk (OAR): brainstem, optical nerves, chiasma, eyes, skull bone and healthy brain parenchyma.The stereotactic dynamic arc-therapy remains the best technique in terms of dose conformation. Iodine-enhanced SSRT presents similar performances to dynamic arc-therapy with increased brainstem and brain parenchyma sparing. One disadvantage of SSRT is the high dose to the skull bone. Iodine accumulation in metastasis may increase the dose by 20-30%, allowing a normal tissue sparing effect at constant prescribed dose. Treatment without any iodine enhancement (medium-energy stereotactic radiotherapy) is not relevant with degraded HDVs (brain, parenchyma and skull bone) comparing to stereotactic dynamic arc-therapy.Iodine-enhanced SSRT exhibits a good potential for brain metastasis treatment regarding the dose distribution and OAR criteria.

Gottschalk M.,Lund University | Tropres I.,Grenoble University Hospital Center | Lamalle L.,Grenoble University Hospital Center | Grand S.,Joseph Fourier University | And 2 more authors.
NMR in Biomedicine | Year: 2016

Short-TE 1H MRS has great potential for brain cancer diagnostics. A major difficulty in the analysis of the spectra is the contribution from short-T2 signal components, mainly coming from mobile lipids. This complicates the accurate estimation of the spectral parameters of the resonance lines from metabolites, so that a qualitative to semi-quantitative interpretation of the spectra dominates in practice. One solution to overcome this difficulty is to measure and estimate the short-T2 signal component and to subtract it from the total signal, thus leaving only the metabolite signals. The technique works well when applied to spectra obtained from healthy individuals, but requires some optimisation during data acquisition. In the clinical setting, time constraints hardly allow this. Here, we propose an iterative estimation of the short-T2 signal component, acquired in a single acquisition after measurement of the full spectrum. The method is based on QUEST (quantitation based on quantum estimation) and allows the refinement of the estimate of the short-T2 signal component after measurement. Thus, acquisition protocols used on healthy volunteers can also be used on patients without further optimisation. The aim is to improve metabolite detection and, ultimately, to enable the estimation of the glutamine and glutamate signals distinctly. These two metabolites are of great interest in the characterisation of brain cancer, gliomas in particular. When applied to spectra from healthy volunteers, the new algorithm yields similar results to QUEST and direct subtraction of the short-T2 signal component. With patients, up to 12 metabolites and, at least, seven can be quantified in each individual brain tumour spectrum, depending on the metabolic state of the tumour. The refinement of the short-T2 signal component significantly improves the fitting procedure and produces a separate short-T2 signal component that can be used for the analysis of mobile lipid resonances. Thus, in brain tumour spectra, distinct estimates of signals from glutamate and glutamine are possible. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

PubMed | Grenoble University Hospital Center and Grenoble Institute des neurosciences
Type: | Journal: Annals of physical and rehabilitation medicine | Year: 2016

Arthrogryposis multiplex congenita (AMC) is a clinical diagnosis characterized by the presence of at least two joint contractures at birth. Causes of AMC are numerous involving CNS, neuromuscular system, connective and bone tissue. This study is the first to describe disability patterns of a cohort of adults with AMC.Thirty-nine patients (age 33.811.5 years; 23 females) underwent between 2010 and 2016 a 4 day evaluation in the PMR ward during the multidisciplinary consultations for AMC at the Reference Centre of Congenital Anomalies in Grenoble: 25 with amyoplasia, 8 with distal arthrogryposis (DA), and 6 with other atypical diseases. All underwent the following functional assessments: functional independence measure (FIM) scale, functional ambulance classification (FAC) modified, six-minute walk test (SMWT), and a battery of functional tests for the upper limb (reaching, grasping, and pinches).Most patients suffering from AMC had modified independence, with an average FIM= 113.812.3 (min=71, max=126, median=117). Nearly all subjects had satisfactory Cognitive-FIM (34.9, min=33, max=35), while motor items of the FIM were altered (motor-FIM =78.4, min=36, max=91) especially bathing (5.9), upper body dressing (5.7), lower body dressing (5.3), toileting (5.4) and stairs (5.3). Regarding mobility limitation, the mean FAC score was 6.1/8. Only 34 patients could complete SMWT, with a limited mean distance: 338.6134m (min=100m, max=700m). Walking was a major activity limitation for many patients, 28 patients needed to walk slowly on plain ground with surveillance or technical aids, 3 patients couldnt walk. Regarding the upper limb, they could achieve 11.05.5 of 16 tasks testing reaching movements (min=1, max=16), and 17.96.8 of 22 tasks testing bilateral fine hand and finger movements (min=0, max=22). Activity limitations tended to be less severe in patients with DA.Despite obvious disabilities, most persons with AMC can live independently with few technical aids and compensations. Rehabilitation options were proposed accordingly, and patients satisfaction for this expert evaluation was high.

Gonzalez-Gonzalez I.M.,University of Bristol | Jaskolski F.,University of Bristol | Jaskolski F.,Grenoble Institute des Neurosciences | Goldberg Y.,University of Bristol | And 2 more authors.
Methods in Enzymology | Year: 2012

The use of genetically encoded fluorescent tags such as green fluorescent protein (GFP) as reporters to monitor processes in living cells has transformed cell biology. One major application for these tools has been to analyze protein dynamics in neurons. In particular, fluorescence recovery after photobleach (FRAP) of surface expressed fluorophore-tagged proteins has been instrumental to addressing outstanding questions about how neurons orchestrate the synaptic delivery of proteins. Here, we provide an overview of the methodology, equipment, and analysis required to perform, analyze, and interpret these experiments. © 2012 Elsevier Inc.

Nugue G.,Grenoble Institute des Neurosciences | Nugue G.,Joseph Fourier University | Bidart M.,Grenoble Institute des Neurosciences | Bidart M.,Center Hospitalier University | And 12 more authors.
PLoS ONE | Year: 2013

Developing therapeutic monoclonal antibodies paves the way for new strategies in oncology using targeted therapy which should improve specificity. However, due to a lack of biomarkers, a personalized therapy scheme cannot always be applied with monoclonal antibodies. As a consequence, the efficacy or side effects associated with this type of treatment often appear to be sporadic. Bevacizumab is a therapeutic monoclonal antibody targeting Vascular Endothelial Growth Factor (VEGF). It is used to limit tumor vascularization. No prognosis or response biomarker is associated with this antibody, we therefore assessed whether the administration protocol could be a possible cause of heterogeneous responses (or variable efficacy). To do this, we developed a bevacizumab assay with a broad sensitivity range to measure blood bevacizumab concentrations. We then analyzed bevacizumab concentrations in 17 patients throughout the first quarter of treatment. In line with previously published data, average blood concentrations were 88+/-27 mg/L following the first dose administered, and 213+/-105 mg/L after the last (6th) dose administered. However, the individual values were scattered, with a mean 4-fold difference between the lowest and the highest concentration for each dose administered. We demonstrated that the bevacizumab administration schedule results in a high inter-individual variability in terms of blood concentrations. Comparison of assay data with clinical data indicates that blood concentrations above the median are associated with side effects, whereas values below the median favor inefficacy. In conclusion, bevacizumab-based therapy could benefit from a personalized administration schedule including follow-up and adjustment of circulating bevacizumab concentrations. © 2013 Nugue et al.

PubMed | Grenoble Institute des Neurosciences and Center Hospitalier University
Type: Journal Article | Journal: Medical physics | Year: 2016

Synchrotron stereotactic radiotherapy (SSRT) is an innovative treatment combining the selective accumulation of heavy elements in tumors with stereotactic irradiations using monochromatic medium energy x-rays from a synchrotron source. Phase I/II clinical trials on brain metastasis are underway using venous infusion of iodinated contrast agents. The radiation dose enhancement depends on the amount of iodine in the tumor and its time course. In the present study, the reproducibility of iodine concentrations between the CT planning scan day (Day 0) and the treatment day (Day 10) was assessed in order to predict dose errors.For each of days 0 and 10, three patients received a biphasic intravenous injection of iodinated contrast agent (40 ml, 4 ml/s, followed by 160 ml, 0.5 ml/s) in order to ensure stable intra-tumoral amounts of iodine during the treatment. Two volumetric CT scans (before and after iodine injection) and a multi-slice dynamic CT of the brain were performed using conventional radiotherapy CT (Day 0) or quantitative synchrotron radiation CT (Day 10). A 3D rigid registration was processed between images. The absolute and relative differences of absolute iodine concentrations and their corresponding dose errors were evaluated in the GTV and PTV used for treatment planning.The differences in iodine concentrations remained within the standard deviation limits. The 3D absolute differences followed a normal distribution centered at zero mg/ml with a variance (1 mg/ml) which is related to the image noise.The results suggest that dose errors depend only on the image noise. This study shows that stable amounts of iodine are achievable in brain metastasis for SSRT treatment in a 10 days interval.

PubMed | Grenoble Institute des Neurosciences
Type: Journal Article | Journal: Medical physics | Year: 2016

Iodine-enhanced radiotherapy is an innovative treatment combining the selective accumulation of an iodinated contrast agent in brain tumors with irradiations using monochromatic medium energy x-rays. The radiation dose enhancement depends on the time course of iodine in the tumors. A prolonged CT scanning (30 min) is required to follow-up iodine kinetics for recruited patients. This protocol could lead to substantial radiation dose to the patient. A novel method is proposed to reduce the acquisition time.12 patients received an intravenous bolus of iodinated contrast agent, followed by a steady-state infusion to ensure stable intra-tumoral amounts of iodine during the treatment. Absolute iodine concentrations (IC) were derived from 40 multi-slice dynamic conventional CT images of the brain. The impulse response function (IRF) to the bolus was estimated using the adiabatic approximation of the Johnson and Wilsons model. The arterial input function (AIF) of the steady-state infusion was fitted with several models: Gamma, Gamma with recirculation and hybrid. Estimated IC were calculated by convolving the IRF with the modeled AIF and were compared to the measured data.The gamma variate function was not relevant to model the AIF due to high differences with the measured AIF. The hybrid and the gamma with recirculation models provided differences below 8% during the whole acquisition time. The absolute difference between the measured and the estimated IC was lower than 0.5 mg/ml, which corresponds to 5% of dose enhancement error.The proposed method allows a good estimation of the iodine time course with reduced scanning delays (3 instead of 30 min) and dose to the patient. The results suggest that the dose errors may stay within the radiotherapy standards.

PubMed | University of Lausanne, CECS, French Institute of Health and Medical Research, Grenoble Institute des Neurosciences and University of Coimbra
Type: Journal Article | Journal: PloS one | Year: 2016

Mutations of the huntingtin protein (HTT) gene underlie both adult-onset and juvenile forms of Huntingtons disease (HD). HTT modulates mitotic spindle orientation and cell fate in mouse cortical progenitors from the ventricular zone. Using human embryonic stem cells (hESC) characterized as carrying mutations associated with adult-onset disease during pre-implantation genetic diagnosis, we investigated the influence of human HTT and of an adult-onset HD mutation on mitotic spindle orientation in human neural stem cells (NSCs) derived from hESCs. The RNAi-mediated silencing of both HTT alleles in neural stem cells derived from hESCs disrupted spindle orientation and led to the mislocalization of dynein, the p150Glued subunit of dynactin and the large nuclear mitotic apparatus (NuMA) protein. We also investigated the effect of the adult-onset HD mutation on the role of HTT during spindle orientation in NSCs derived from HD-hESCs. By combining SNP-targeting allele-specific silencing and gain-of-function approaches, we showed that a 46-glutamine expansion in human HTT was sufficient for a dominant-negative effect on spindle orientation and changes in the distribution within the spindle pole and the cell cortex of dynein, p150Glued and NuMA in neural cells. Thus, neural derivatives of disease-specific human pluripotent stem cells constitute a relevant biological resource for exploring the impact of adult-onset HD mutations of the HTT gene on the division of neural progenitors, with potential applications in HD drug discovery targeting HTT-dynein-p150Glued complex interactions.

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