Mild malformations of cortical development in sleep-related hypermotor epilepsy due to KCNT1 mutations

open14siMutations in the sodium-activated potassium channel gene KCNT1 have been associated with nonlesional sleep-related hypermotor epilepsy (SHE). We report the co-occurrence of mild malformation of cortical development (mMCD) and KCNT1 mutations in four patients with SHE. Focal cortical dysplasia type I was neuropathologically diagnosed after epilepsy surgery in three unrelated MRI-negative patients, periventricular nodular heterotopia was detected in one patient by MRI. Our findings suggest that KCNT1 epileptogenicity may result not only from dysregulated excitability by controlling Na+K+ transport, but also from mMCD. Therefore, pathogenic variants in KCNT1 may encompass both lesional and nonlesional epilepsies.openRubboli G.; Plazzi G.; Picard F.; Nobili L.; Hirsch E.; Chelly J.; Prayson R.A.; Boutonnat J.; Bramerio M.; Kahane P.; Dibbens L.M.; Gardella E.; Baulac S.; Moller R.S.Rubboli, G.; Plazzi, G.; Picard, F.; Nobili, L.; Hirsch, E.; Chelly, J.; Prayson, R. A.; Boutonnat, J.; Bramerio, M.; Kahane, P.; Dibbens, L. M.; Gardella, E.; Baulac, S.; Moller, R. S

Sigma-2 receptor ligands potentiate conventional chemotherapies and improve survival in models of pancreatic adenocarcinoma

<p>Abstract</p> <p>Background</p> <p>We have previously reported that the sigma-2 receptor is highly expressed in pancreas cancer. Furthermore, we have demonstrated that sigma-2 receptor specific ligands induce apoptosis in a dose-dependent fashion. Here, we examined whether sigma-2 receptor ligands potentiate conventional chemotherapies such as gemcitabine and paclitaxel.</p> <p>Methods</p> <p>Mouse (Panc-02) and human (CFPAC-1, Panc-1, AsPC-1) pancreas cancer cell lines were used in this study. Apoptosis was determined by FACS or immunohistochemical analysis after TUNEL and Caspase-3 staining. Combination therapy with the sigma-2 ligand SV119 and the conventional chemotherapies gemcitabine and paclitaxel was evaluated in an allogenic animal model of pancreas cancer.</p> <p>Results</p> <p>SV119, gemcitabine, and paclitaxel induced apoptosis in a dose-dependent fashion in all pancreas cancer cell lines tested. Combinations demonstrated increases in apoptosis. Mice were treated with SV119 (1 mg/day) which was administered in combination with paclitaxel (300 μg/day) over 7 days to mice with established tumors. A survival benefit was observed with combination therapy (p = 0.0002). Every other day treatment of SV119 (1 mg/day) in combination with weekly treatment of gemcitabine (1.5 mg/week) for 2 weeks also showed a survival benefit (p = 0.046). Animals tolerated the combination therapy and no gross toxicity was noted in serum biochemistry data or on necropsy.</p> <p>Conclusion</p> <p>SV119 augments tumoricidal activity of paclitaxel and gemcitabine without major side effects. These results highlight the potential utility of the sigma-2 ligand as an adjuvant treatment in pancreas cancer.</p

Piperazinobenzopyranones and phenalkylaminobenzo- pyranones: potent inhibitors of breast cancer resistance protein (ABCG2).

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Evaluation of a Computed Assisted Medical Intervention (CAMI) systems in scientific autopsy

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3D-printed scaffold combined to 2D osteoinductive coatings to repair a critical-size mandibular bone defect

International audienceThe reconstruction of large bone defects (12 cm3) remains a challenge for clinicians. We developed a new critical-size mandibular bone defect model on a minipig, close to human clinical issues. We analyzed the bone reconstruction obtained by a 3D-printed scaffold made of clinical-grade polylactic acid (PLA), coated with a polyelectrolyte film delivering an osteogenic bioactive molecule (BMP-2). We compared the results (computed tomography scans, microcomputed tomography scans, histology) to the gold standard solution, bone autograft. We demonstrated that the dose of BMP-2 delivered from the scaffold significantly influenced the amount of regenerated bone and the repair kinetics, with a clear BMP-2 dose-dependence. Bone was homogeneously formed inside the scaffold without ectopic bone formation. The bone repair was as good as for the bone autograft. The BMP-2 doses applied in our study were reduced 20- to 75-fold compared to the commercial collagen sponges used in the current clinical applications, without any adverse effects. Three-dimensional printed PLA scaffolds loaded with reduced doses of BMP-2 may be a safe and simple solution for large bone defects faced in the clinic

3D printed cathodes for implantable abiotic biofuel cells

International audience3D printing has recently triggered huge attention in several fields such as construction, artificial tissue engineering, food fabrication, wearable electronics, and electrochemical energy storage. This work investigates the fabrication of a 3D-printed abiotic cathode for implantable glucose/oxygen biofuel cells. The ink formulation was optimized to get printable ink with high electro-catalytic activity. Electrode macro porosity was screened in order to identify the better compromise between electrode density and electrochemical performance. A maximum current density of 260 µA/cm 2 was obtained with cylindrical electrodes with linear mesh infill and a volumic infill rate of 40%. A complete biofuel cell was assembled using a 3D-printed abiotic cathode and an enzymatic anode in the form of a compressed pellet showing maximum power and current densities of 80 µW/cm 2 and 320 µA/cm 2 , respectively. Moreover, the hybrid biofuel cell was implanted in the intraabdominal region of a rat for three months and after cell explantation, the abiotic cathode displayed a 50% decrease in the current density while the enzymatic anode did not display any residual activity. The 3D printed electrode displayed a 2-3.6 fold increase in current density when compared to homolog 2D electrodes

Mild malformations of cortical development in sleep-related hypermotor epilepsy due to KCNT1 mutations

Mutations in the sodium-activated potassium channel gene KCNT1 have been associated with nonlesional sleep-related hypermotor epilepsy (SHE). We report the co-occurrence of mild malformation of cortical development (mMCD) and KCNT1 mutations in four patients with SHE. Focal cortical dysplasia type I was neuropathologically diagnosed after epilepsy surgery in three unrelated MRI-negative patients, periventricular nodular heterotopia was detected in one patient by MRI. Our findings suggest that KCNT1 epileptogenicity may result not only from dysregulated excitability by controlling Na+K+ transport, but also from mMCD. Therefore, pathogenic variants in KCNT1 may encompass both lesional and nonlesional epilepsies

Bioelectrodes modified with chitosan for long-term energy supply from the body

International audienceA 3D nanofibrous network of compressed chitosan in the presence of genipin as the cross-linker, carbon nanotubes and laccase constitutes a new design to enhance the stability and the biocompatibility of biocathodes. The in vitro delivered current was around À0.3 mA mL À1 for 20 days under continuous discharge. A thin film made of chitosan cross-linked with genipin was synthesized and optimized for oxygen and glucose diffusion. This film was used as a biocompatible barrier on the surface of biocathodes implanted in rats. The biocathodes remained operational after 167 days in vivo. This biocathode design minimised the inflammatory response in the first two weeks after implantation. After several months, the growth of macrophages was observed. The electrical connection and the catalytic activity of the enzyme entrapped into the biocathode were demonstrated after almost 6 months of implantation by the ex vivo measurement of the OCP (0.45 V to 0.48 V) and the delivered current (À0.6 mA mL À1) under optimal conditions. Broader context The next generation of implantable medical devices require sustainable ways to provide their energy. For an implanted energy supply, sustainability means that the device needs to be compatible with the environment inside the body, it should not cause any inammation and should be able to utilise biomolecules inside the body as a fuel to produce energy. Also, importantly, the implanted power supply should have a very long lifetime to continue to produce energy inside the body for other implanted medical devices. In this article we describe a 3D bioelectrode that continued to produce energy electrochemically for around 6 months when implanted inside a freely moving animal. This advance is based on improving the biocompatibility with an innovative design and use of biomaterials. Providing energy for such a long period of implantation, especially in a freely moving animal, is a novel result that addresses the existing issues in this eld for the future of implantable energy supplies, namely that is necessary to improve their stability and efficiency. Our results augur well for continuing improvements in the implanted lifetimes of biofuel cells, so as to enable these implantable biofuel cells to become viable and sustainable energy supplies for medical devices

Biodistribution and preliminary toxicity studies of nanoparticles made of Biotransesterified β–cyclodextrins and PEGylated phospholipids

International audienceBACKGROUND:The modification of β-cyclodextrins (βCDs) by grafting alkyl chains on the primary and/or secondary face yields derivatives (βCD-C10) able to self-organize under nanoprecipitating conditions into nanoparticles (βCD-C10-NP) potentially useful for drug delivery. The co-nanoprecipitation of βCD-C10 with polyethylene glycol (PEG) chains yields PEGylated NPs (βCD-C10-PEG-NP) with potentially improved stealthiness. The objectives of the present study were to characterize the in vivo biodistribution of βCD-C10-PEG-NP with PEG chain length of 2000 and 5000Da using nuclear imaging, and to preliminarily evaluate the in vivo acute and extended acute toxicity of the most suitable system.RESEARCH DESIGN AND METHODS:The in vivo and ex vivo biodistribution features of naked and decorated nanoparticles were investigated over time following intravenous injection of 125I-radiolabeled nanoparticles to mice. The potential toxicity of PEGylated βCD-C10 nanosuspensions was evaluated in a preliminary in vivo toxicity study involving blood assays and tissue histology following repeated intraperitoneal injections of nanoparticles to healthy mice.RESULTS:The results indicated that βCD-C10-PEG5000-NP presented increased stealthiness with decreased in vivo elimination and increased blood kinetics without inducing blood, kidney, spleen, and liver acute and extended acute toxicity.CONCLUSIONS:βCD-C10-PEG5000-NPs are stealth and safe systems with potential for drug delivery