From Poly(Alkyl Cyanoacrylate) to Squalene as Core Material to Design Nanomedicines

International audienceThe discovery of biodegradable poly(alkyl cyanoacrylate) (PACA) nanoparticles by Patrick Couvreur has opened large perspectives in nanomedicine. Nanoparticles made from different types of PACA monomers have been used in different applications such as the treatment of intracellular infections or the treatment of multidrug resistant hepatocarcinoma. This latest application led to a Phase 3 clinical trial of Livatag ® , a PACA nanoparticulate formulation of doxorubicin. Despite the success of PACA nanoparticles, the need to develop novel type of nanoparticles with higher drug loadings and lower burst release was tackled by the discovery of squalene-based nanoparticles where the drug is covalently linked to the lipid derivative and the resulting conjugate self-assemble into nanoparticles. This pioneering work was accompanied by a wide range of novel applications which mainly dealt with the management of unmet medical needs (e.g., pancreatic cancer, brain ischemia and spinal cord injury). The present Review Article covers the most important steps of the pioneering work of Patrick Couvreur by trying to shed light on his outstanding career that has been a source of inspiration for many decades

Multicellular tumor spheroids: a relevant 3D model for the in vitro preclinical investigation of polymer nanomedicines

International audienceThe application of nanotechnology to medicine, usually termed nanomedicine, has given a crucial impulse to the design of various drug-loaded nanocarriers driven by the aim to overcome the limits associated with traditional drug delivery modalities, in particular, in the field of cancer treatment. However, an appropriate preclinical evaluation of the real therapeutic potential of nanomedicines suffers from the lack of relevant models that are well representative of the human disease and good predictors of the therapeutic response in patients. In this context, great emphasis has been directed toward 3D tumor models aiming to surmount the insufficient predictive power of traditional 2D monolayer cultures of cancer cells. This review focuses on multicellular tumor spheroids (MCTS), which are currently the most widely employed 3D tumor model in preclinical studies. After a brief discussion on spheroid construction strategies and analytical/imaging techniques employed in experimental settings, the application of 3D MCTS to the evaluation of nanomedicines displaying various physico-chemical properties is reviewed. Finally, relevant examples of scaffold and microfluidic systems in which MCTS have been included are described

The Occurrence of Skeletons of Silicoflagellata and Other Siliceous Bioparticles in Floral Honeys

International audienceSiliceous marine microfossils were unexpectedly discovered during the analysis of flower honey samples from Poland and Tunisia. The microfossils were represented by protist with siliceous skeletons: silicoflagellates, diatoms, and endoskeletal dinoflagellates. This is the first record of such microfossils in honeys. Based on the high percent of anemophilous pollen grains and spores in the sample, it was hypothesized that silicoflagellates were deposited from the air onto the nectariferous flowers, then bees harvested them with the nectar. Based on the comparison of pollen content of honeys and flowering calendar of Tunisia, the harvest time of honey was identified as a period between 1 April and 31 May 2011. Trajectory analysis of air masses in this period confirmed that siliceous microfossils could be aerosolized by wind from the rocks of the so-called Tripoli Formation of Messinian age (6–7 Ma). Similar to the Tunisian case, the Polish trajectory simulation also supports the hypothesis of atmospheric transport of silicoflagellates from outcrops of Oligocene age in the Polish Outer Carpathians. In the case of diatom content of honey, however, the source can be both natural (wind) and artificial (diatomaceous earth filters). For a correct determination, natural sources of siliceous bioparticles, such as wind transport from nearby outcrops should be also considered. Silicoflagellates could be used as complementary indicators of the geographical origin of honeys collected in areas characterized by diatomite outcrops, supporting the results obtained with other methods; thus, such indicators merit further studies within the area of honey authenticity

Characterization of upper limb use in health care workers during regular shifts: A quantitative approach based on wrist-worn accelerometers

Despite the high prevalence of upper limb (UL) work-related musculoskeletal disorders (WRMSD) among health care workers (HCWs), little is known about their relationship with exposure to biomechanical risk factors. This study aimed to assess UL activity features under actual working conditions using two wrist-worn accelerometers. Accelerometric data were processed to obtain duration, intensity, and asymmetry of UL use in 32 HCWs during the execution of commonly performed tasks (e.g., patient hygiene, transfer, and meal distribution) within a regular shift. The results show that such tasks are characterized by significantly different patterns of UL use, in particular, higher intensities and larger asymmetries were observed respectively for patient hygiene and meal distribution. The proposed approach appears, thus, suitable to discriminate tasks characterized by different UL motion patterns. Future studies could benefit from the integration of such measures with self-reported workers’ perception to elucidate the relationship between dynamic UL movements and WRMSD

Protein-Functionalized Nanoparticles Derived from End-Functional Polymers and Polymer Prodrugs for Crossing the Blood-Brain Barrier

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Application of epidemiolgical information system (epis) in the Slovak Republic within the surveillance of salmonellosis and campylobacteriosis outbreaks in the European Union (2001-2010)

The aim of the work was to analyze the changes in the epidemiology of salmonellosis and campylobacteriosis diseases in Slovakia over the past 10 years and evaluate them in the context of epidemiological changes comparing to the EU. Salmonellosis (A020) and campylobacteriosis (A045) belong to the diseases with the highest morbidity in Slovakia. For the period 2001-2010 was reported in Slovakia 109 304 salmonellosis cases in human and 3 327 cases of Salmonella carriage. The fiveyear EU-trend (2005-2009) showed a statistically significant decrease of salmonellosis disease (with a mean reduction of 12% per year). Campylobacteriosis remains a long time the most frequently reported zoonotic disease in humans in Slovakia as well as in EU. For the period of 2001-2010 25 574 campylobacteriosis cases was reported in Slovakia. Most diseases were reported in 2010 with the number 4 591 (84.63 morbidity/100 000 inhabitants). Increase in morbidity is evident since 2003 with an average annual increase of 22%. We focused on more in-depth epidemiological analysis of salmonellosis and campylobacteriosis cases in Slovak Republic in relation to the infection agens and the outbreak of disease transmission mechanism, age and gender, location and seasonality of disease

In Vivo FRET Imaging to Predict the Risk Associated with Hepatic Accumulation of Squalene-Based Prodrug Nanoparticles.

Förster resonance energy transfer (FRET) is used here for the first time to monitor the in vivo fate of nanoparticles made of the squalene-gemcitabine prodrug and two novel derivatives of squalene with the cyanine dyes 5.5 and 7.5, which behave as efficient FRET pair in the NIR region. Following intravenous administration, nanoparticles initially accumulate in the liver, then they show loss of their integrity within 2 h and clearance of the squalene bioconjugates is observed within 24 h. Such awareness is a key prerequisite before introduction into clinical settings.journal article2018 Feb2017 11 30importedSupporting information : librement accessible sur le site de l'éditeur

Gene- and variant-specific efficacy of serum/glucocorticoid-regulated kinase 1 inhibition in long QT syndrome types 1 and 2.

AIMS Current long QT syndrome (LQTS) therapy, largely based on beta-blockade, does not prevent arrhythmias in all patients; therefore, novel therapies are warranted. Pharmacological inhibition of the serum/glucocorticoid-regulated kinase 1 (SGK1-Inh) has been shown to shorten action potential duration (APD) in LQTS type 3. We aimed to investigate whether SGK1-Inh could similarly shorten APD in LQTS types 1 and 2. METHODS AND RESULTS Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and hiPSC-cardiac cell sheets (CCS) were obtained from LQT1 and LQT2 patients; CMs were isolated from transgenic LQT1, LQT2, and wild-type (WT) rabbits. Serum/glucocorticoid-regulated kinase 1 inhibition effects (300 nM-10 µM) on field potential durations (FPD) were investigated in hiPSC-CMs with multielectrode arrays; optical mapping was performed in LQT2 CCS. Whole-cell and perforated patch clamp recordings were performed in isolated LQT1, LQT2, and WT rabbit CMs to investigate SGK1-Inh (3 µM) effects on APD. In all LQT2 models across different species (hiPSC-CMs, hiPSC-CCS, and rabbit CMs) and independent of the disease-causing variant (KCNH2-p.A561V/p.A614V/p.G628S/IVS9-28A/G), SGK1-Inh dose-dependently shortened FPD/APD at 0.3-10 µM (by 20-32%/25-30%/44-45%). Importantly, in LQT2 rabbit CMs, 3 µM SGK1-Inh normalized APD to its WT value. A significant FPD shortening was observed in KCNQ1-p.R594Q hiPSC-CMs at 1/3/10 µM (by 19/26/35%) and in KCNQ1-p.A341V hiPSC-CMs at 10 µM (by 29%). No SGK1-Inh-induced FPD/APD shortening effect was observed in LQT1 KCNQ1-p.A341V hiPSC-CMs or KCNQ1-p.Y315S rabbit CMs at 0.3-3 µM. CONCLUSION A robust SGK1-Inh-induced APD shortening was observed across different LQT2 models, species, and genetic variants but less consistently in LQT1 models. This suggests a genotype- and variant-specific beneficial effect of this novel therapeutic approach in LQTS