Evaluation de la prise en charge des accidents vasculaires cérébraux ischémiques aux urgences (étude rétrospective)

BREST-BU Médecine-Odontologie (290192102) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Hybrid metal-polymer nanoparticles as promising radiosensitizers for cancer treatment

International audienceNanotechnologies are being widely studied for medical applications, both diagnosis and treatment. They have already shown great promise, especially to treat cancer through various strategies such as chemotherapy, photothermal therapy or radiation therapies. High-Z elements nanoparticles are of particular interest for the latter, considering their ability to amplify the damaging effects of both photon and ion radiations: gold, platinum and gadolinium are amongst the most investigated elements. A well-controlled synthesis is key to obtain stable and scalable nano-objects. Here, various polymers were grafted onto metallic nanoparticles to improve stability and biocompatibility and to facilitate subsequent functionalization. Advanced methods of characterization attested to the robustness and reproducibility of the synthesis procedure. Moreover, promising results were obtained regarding the radioenhancing properties of these hybrid nanocompounds. Polymers mainly synthesized via controlled radical polymerization were grafted onto gold and platinum nanoparticles by a "grafting to" or "grafting from" method. Subsequent grafting of a chemotherapy drug onto the polymer corona was also successfully carried out. The resulting nano-objects were fully characterized by thermogravimetric analysis, transmission electronic microscopy and small-angle x-ray scattering. Small-angle neutron scattering was also performed, taking advantage of possible contrast matching. The impact of various radiation doses on the nanoparticles structure was studied. Finally, radiosensitizing effects were investigated through in vitro tests. Under irradiation, uncoupling and cleavage of polymer chains were demonstrated, leading to an overall size reduction of the hybrid nano-objects. The location of target sites during irradiation was determined and helped to better understand the underlying mechanism of the radiosensitization assessed by the in vitro results. The synthesized nano-objects have therefore shown great potential to enhance radiation cancer treatment. Their stability and controlled surface chemistry will allow to develop multiple strategies to further improve their radiosensitizing effect and in vitro behavior. In vivo tests are currently under study, as well as experiments regarding radioenhancement for proton therapy

How do surface properties of nanoparticles influence their diffusion in the extracellular matrix? A model study in Matrigel using polymer-grafted nanoparticles

International audienceDiffusion of nanomedicines inside the extracellular matrix (ECM) has been identified as a key factor to achieve homogeneous distribution and therefore therapeutic efficacy. Here, we sought to determine the impact of nanoparticles surface properties on their ability to diffuse in the ECM. As model nano-objects, we used a library of gold nanoparticles grafted with a versatile polymethacrylate corona which enabled to modify the surface properties. To accurately recreate the features of native ECM, diffusion studies were carried out in a tumor-derived gel (Matrigel®). We developed two methods to evaluate the diffusion ability of NPs inside this model gel: an easy to implement one based on optical monitoring and another one using small-angle X-ray scattering (SAXS) measurements. Both enabled to determine the diffusion coefficients of NPs and compare the influence of their various surface properties, while the SAXS technique also allowed to monitor the NPs structure as they diffused inside the gel. Positive charges and hydrophobicity were found to particularly hinder diffusion, and the different results suggested on the whole the presence of NPs-matrix interactions, therefore underlying the importance of the ECM model. The accuracy of the tumor-derived gels used in this study was evidenced by in vivo experiments involving intratumoral injections of NPs on mice, which showed that diffusion patterns in the peripheral tumor tissues were quite similar to the ones obtained within the chosen ECM model

Stroke with atrial fibrillation or atrial flutter: a descriptive population-based study from the Brest stroke registry

International audienceIn the 1990s, epidemiological studies estimated the prevalence of stroke caused by atrial fibrillation (AF) at about 15 %. Given the aging population, there is a rise in the number of AF patients. AF prevention guidelines based on clinical practice and the literature have been published and updated since 2001. Implementation seems to have an impact on the prescription of vitamin K antagonist (VKA). During the last 20 years, few population-based studies have focused on the prevalence of atrial arrhythmia (AA) in patients with stroke. The objective of the present prospective study, using data from 2008, was to evaluate the prevalence of AA (atrial fibrillation/flutter) in patients with stroke and the impact of implementing AF guidelines. The prevalence of AA was studied in patients diagnosed with stroke from January 1 to December 31, 2008 in the population-based Stroke Registry of Brest, France (total population, 363,760 according to the 2008 census, with 295,553 aged 15 years or older). Guidelines implementation was assessed in terms of antithrombotic therapy (VKA, antiplatelet agent, none), and the CHADS2 (Congestive heart failure, Hypertension, Age > 75 years, Diabetes mellitus, and prior Stroke or transient ischemic attack). 851 cases of stroke were identified. The prevalence of AA was 31.7 % (n = 264), and increased with age from < 20 % in patients aged 45 to 54 years to nearly 50 % in patients ≥ 85 years. In patients with AA, 231 strokes were ischemic, 28 hemorrhagic and 5 undetermined. At time of stroke, AA was known in 207 patients (78.4 %). 54 of the 152 patients with CHADS2 score ≥ 2 (35.5 %) were treated with VKA; this proportion decreased with age: 50 % between 50 and 74 years, 43.8 % between 75 and 84 years, and 25 % at 85 years and older. The prevalence of AA in the population-based Brest Stroke Registry in 2008 was higher than that reported by studies conducted 20 years ago. Despite publication of AF prevention guidelines, VKA prescription and use in elderly patients were significantly low

Combining surface chemistry modification and in situ small-angle scattering characterization to understand and optimize the biological behavior of nanomedicines

International audienceNanomedicines are considered as promising therapeutics for cancer treatment. However, clinical translation is still scarce, partly because their biological behavior is not well understood. Extracting general guidelines from the great variety of nanoparticles and conditions studied is indeed difficult, and relevant techniques are lacking to obtain in situ information. Here, both issues are solved by combining versatile model nanoparticles with in situ tools based on small-angle scattering techniques (SAS). The strategy was to develop a library of nanoparticles and perform systematic study of their interactions with biological systems. Considering the promising properties of gold nanoparticles as cancer therapeutics, polymethacrylate-grafted gold nanoparticles were chosen as models. Modulation of polymer chemistry was shown to change the surface properties while keeping the same structure for all nanoparticles. This unity allowed reliable comparison to extract general principles, while the synthesis versatility enabled to fine-tune the nanoparticles surface properties, especially through copolymerization, and thus to optimize their biological behavior. Two specific aspects were particularly examined: colloidal stability and cell uptake. Positive charges and hydrophobicity were identified as key parameters influencing toxicity and internalization. In situ SAS gave valuable information about nanoparticles evolution in biologically relevant environments. Good colloidal stability was thereby shown in cell culture media, while intracellular transformation and quantity of nanoparticles were monitored, highlighting the potential of these techniques for nanomedicines studies

Irradiation Effects on Polymer-Grafted Gold Nanoparticles for Cancer Therapy

International audienceIn the context of cancer treatment, gold nanoparticles (AuNPs) are considered as very promising radiosensitizers. Here, well-defined polymer-grafted AuNPs were synthesized and studied under gamma irradiation to better understand the involved radiosensitizing mechanisms. First, various water-soluble and well-defined thiol-functionalized homopolymers and copolymers were obtained through Atom Transfer Radical Polymerization. They were then used as ligands in the one-step synthesis of AuNPs, resulting in stable hybrid metal-polymer nanoparticles. Second, these nano-objects were irradiated in solution by gamma rays at different doses. Structures were fully characterized through SEC, SAXS and SANS measurements, prior and after irradiation. We were thus able to quantify and to localize radiation impacts onto the grafted polymers, revealing the production sites of reactive species around AuNPs. Both external and near-surface scissions were observed. Interestingly, the ratio between these two effects was found to vary according to the nature of polymer ligands. Medium-range and long-distance dose enhancements could not be identified from the calculated scission yields, but several mechanisms were considered to explain high yields found for near-surface scissions. Then, cytotoxicity was shown to be equivalent for both non-irradiated and irradiated polymer-grafted NPs, suggesting that released polymer fragments were non-toxic. Finally, the potential to add bioactive molecules such as anticancer drugs has been explored by grafting doxorubicin (DOX) onto the polymer corona. This may lead to nano-objects combining both radiosensitization and chemotherapy effects. This work is the first one to study in details the impact of radiation on radiosensitizing nano-objects combining physical, chemical and biological analyses

Improving I-131 Radioiodine Therapy By Hybrid Polymer-Grafted Gold Nanoparticles

International audienceBackground Human trials combining external radiotherapy (RT) and metallic nanoparticles are currently underway in cancer patients. For internal RT, in which a radioisotope such as radioiodine is systemically administered into patients, there is also a need for enhancing treatment efficacy, decreasing radiation-induced side effects and overcoming radio-resistance. However, if strategies vectorising radioiodine through nanocarriers have been documented, sensitizing the neoplasm through the use of nanotherapeutics easily translatable to the clinic in combination with the standard systemic radioiodine treatment has not been assessed yet. Method and materials The present study explored the potential of hybrid poly (methacrylic acid)-grafted gold nanoparticles to improve the performances of systemic I-131-mediated RT on cancer cells and in tumor-bearing mice. Such nanoparticles were chosen based on their ability previously described by our group to safely withstand irradiation doses while exhibiting good biocompatibility and enhanced cellular uptake. Results In vitro clonogenic assays performed on melanoma and colorectal cancer cells showed that poly(methacrylic acid)-grafted gold nanoparticles (PMAA-AuNPs) could efficiently lead to a marked tumor cell mortality when combined to a low activity of radioiodine, which alone appeared to be essentially ineffective on tumor cells. In vivo, tumor enrichment with PMAA-AuNPs significantly enhanced the killing potential of a systemic radioiodine treatment. Conclusion This is the first report of a simple and reliable nanomedicine-based approach to reduce the dose of radioiodine required to reach curability. In addition, these results open up novel perspectives for using high-Z metallic NPs in additional molecular radiation therapy demonstrating heterogeneous dose distributions

High completeness of the brest stroke registry evidenced by analysis of sources and capture-recapture method.

International audienceBACKGROUND: Population-based stroke registries are necessary to evaluate the precise burden of stroke. The methodology used in the Brest Stroke Registry and an estimation of its completeness are described. METHODS: 'Hot pursuit' as well as 'cold pursuit' were used, and five sources of identification were included: emergency wards, brain imaging, practitioners, death certificates and hospital-based electronic research. Ascertainment for each case was certified by a neurologist. Inclusion criteria were: (1) age >15 years; (2) a stroke defined by WHO criteria or all neurological deficits lasting at least 1 h. Completeness was estimated using capture-recapture method. RESULTS: For 2008, 2009 and 2010, 851, 898, 823 patients were collected, respectively. The number of sources of identification per patient was as follows: one source: 30.8, 24.1 and 18.7%; two sources: 54.5, 42.9 and 31.0%; three sources: 13.4, 30.1 and 46%; four sources: 1.3, 3.0 and 3.8%. Capture-recapture analysis showed data completeness over 90%. Standardized cumulative first-ever stroke incidence using a world standard population was 87 in 2008, 87 in 2009 and 84 in 2010. CONCLUSIONS: Case ascertainment by a neurologist, numerous sources, as well as 'hot' and 'cold' pursuit can provide a reliably large data set suitable for further epidemiological studies