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Introduction: The percentage of patients diagnosed with pheochromocytoma and paraganglioma (altogether PPGL) carrying known germline mutations in one of the over fifteen susceptibility genes identified to date has dramatically increased during the last two decades, accounting for up to 35-40% of PPGL patients. Moreover, the application of NGS to the diagnosis of PPGL detects unexpected co-occurrences of pathogenic allelic variants in different susceptibility genes. Methods: Herein we uncover several cases with dual mutations in NF1 and other PPGL genes by targeted sequencing. We studied the molecular characteristics of the tumours with co-occurrent mutations, using omic tools to gain insight into the role of these events in tumour development. Results: Amongst 23 patients carrying germline NF1 mutations, targeted sequencing revealed additional pathogenic germline variants in DLST (n=1) and MDH2 (n=2), and two somatic mutations in H3-3A and PRKAR1A. Three additional patients, with somatic mutations in NF1 were found carrying germline pathogenic mutations in SDHB or DLST, and a somatic truncating mutation in ATRX. Two of the cases with dual germline mutations showed multiple pheochromocytomas or extra-adrenal paragangliomas - an extremely rare clinical finding in NF1 patients. Transcriptional and methylation profiling and metabolite assessment showed an “intermediate signature” to suggest that both variants had a pathological role in tumour development. Discussion: In conclusion, mutations affecting genes involved in different pathways (pseudohypoxic and receptor tyrosine kinase signalling) co-occurring in the same patient could provide a selective advantage for the development of PPGL, and explain the variable expressivity and incomplete penetrance observed in some patients.

BACKGROUND AND PURPOSE In patients with recurrent ventricular tachycardia (VT), STereotactic Arrhythmia Radioablation (STAR) shows promising results. The STOPSTORM consortium was established to investigate and harmonise STAR treatment in Europe. The primary goals of this benchmark study were to standardise contouring of organs at risk (OAR) for STAR, including detailed substructures of the heart, and accredit each participating centre. MATERIALS AND METHODS Centres within the STOPSTORM consortium were asked to delineate 31 OAR in three STAR cases. Delineation was reviewed by the consortium expert panel and after a dedicated workshop feedback and accreditation was provided to all participants. Further quantitative analysis was performed by calculating DICE similarity coefficients (DSC), median distance to agreement (MDA), and 95th percentile distance to agreement (HD95). RESULTS Twenty centres participated in this study. Based on DSC, MDA and HD95, the delineations of well-known OAR in radiotherapy were similar, such as lungs (median DSC=0.96, median MDA=0.1mm and median HD95=1.1mm) and aorta (median DSC=0.90, median MDA=0.1mm and median HD95=1.5mm). Some centres did not include the gastro-oesophageal junction, leading to differences in stomach and oesophagus delineations. For cardiac substructures, such as chambers (median DSC=0.83, median MDA=0.2mm and median HD95=0.5mm), valves (median DSC=0.16, median MDA=4.6mm and median HD95=16.0mm), coronary arteries (median DSC=0.4, median MDA=0.7mm and median HD95=8.3mm) and the sinoatrial and atrioventricular nodes (median DSC=0.29, median MDA=4.4mm and median HD95=11.4mm), deviations between centres occurred more frequently. After the dedicated workshop all centres were accredited and contouring consensus guidelines for STAR were established. CONCLUSION This STOPSTORM multi-centre critical structure contouring benchmark study showed high agreement for standard radiotherapy OAR. However, for cardiac substructures larger dis

Iron oxide magnetic nanoparticles with diameters d, 7 nm LT = d LT = 12 nm, were synthesized by thermal decomposition of Fe(acac)(3). Different experimental conditions, keeping constant concetration of Fe ions in solvent, showed that the heating rates is the most important parameter determining the final particle size. Use of two different solvents, 1-eicosene and 1-octadecene, yielded similar nanoparticle sizes (7.1 nm LT = d LT = 7.5 nm), but different magnetic anisotropies. All samples were superparamagnetic at room temperature. Spin disordering was inferred in samples coated with trioctylphosphine oxide (TOPO) co-ligand in addition to oleic acid and oleyamine. The heating ability of similar to 12 nm-sized nanoparticles dispersed in hexane under alternating magnetic fields (3.98 kA/m LT = H-0 LT = 23.87 kA/m; 229.3 kHz LT = f LT = 828 kHz) has been studied, finding a nearly quadratic dependence upon H-0, as expected from the linear response theory. (C) 2017 Elsevier B.V. All rights reserved.

Two different types of magnetic nanoparticles (MNPs) were synthesized in order to compare their efficiency as radioactive vectors, Fe3O4-Naked (80 +/- 5 nm) and polyethylene glycol 600 diacid functionalized Fe3O4 (Fe3O4-PEG600) MNPs (46 +/- 0.6 nm). They were characterized based on the external morphology, size distribution, and colloidal and magnetic properties. The obtained specific power absorption value for Fe3O4-PEG600 MNPs was 200 W/g, indicated their potential in hyperthermia based cancer treatments. The labeling yield, in vitro stability and in vivo biodistribution profile of Y-90-MNPs were compared. Both types of MNPs were Y-90-labeled in reproducible high yield ( GT 97%). The stability of the obtained radioactive nanoparticles was evaluated in saline and human serum media in order to optimize the formulations for in vivo use. The biodistribution in Wistar rats showed different pharmacokinetic behaviors of nanoparticles: a large fraction of both injected MNPs ended in the liver (14.58%ID/g for Y-90-Fe3O4-Naked MNPs and 19.61%ID/g for Y-90-Fe3O4-PEG600 MNPs) whereas minor fractions attained in other organs. The main difference between the two types of MNPs was the higher accumulation of Y-90-Fe3O4-Naked MNPs in the lungs (12.14%ID/g vs. 2.00%ID/g for Y-90-Fe3O4-PEG600 MNPs) due to their in vivo agglomeration. The studied radiolabeled magnetic complexes such as Y-90-Fe3O4-PEG600 MNPs constitute a great promise for multiple diagnostic-therapeutic uses combining, for example, MRI-magnetic hyperthermia and regional radiotherapy. (c) 2014 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 103A: 126-134, 2015.

Hybrid structures composed of exfoliated expanded graphite (EG) and iron oxide nanocrystals were produced by an ex situ process. The iron oxide nanoparticles coated with meso-2,3-dimercaptosuccinic acid (DMSA), or poly(acrylic acid) (PAA) were integrated onto the exfoliated EG flakes by mixing their aqueous suspensions at room temperature under the support of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and N-hydroxysuccinnimide (NHS). EG flakes both naked and functionalized with branched polyethylenimine (PEI) were employed. Complete integration of the two constituents was achieved and stability was maintained for more than 12 months. No preferential spatial distribution of anchoring sites for attachment of iron oxide nanoparticles was observed, regardless of whether the EG flakes were used naked or functionalized with PEI molecules. The structural and physicochemical characteristics of the exfoliated expanded graphite and its hybrid nano-structures were investigated by SEM, TEM, FTIR and Raman techniques.

Radio labeled albumin microspheres with encapsulated citric acid-coated magnetite nanoparticles were developed as a targeting approach to localize both radioactivity and magnetic energy at the tumor site. We present in vitro and in vivo studies of yttrium-90 (Y-90)-labeled human scrum albumin magnetic microspheres (HSAMMS) as a multifunctional agent for possible applications in a bimodal radionuclide-hyperthermia cancer therapy. The HSAMMS were produced using a modified emulsification-heat stabilization technique and contained 11 nm magnetite nanoparticles coated with citric acid, distributed as inhomogeneous clusters within the albumin microspheres. The size, size distribution and the morphology of magnetite nanoparticles and HSAMMS were determined by FESEM, HRTEM and SEM/FIB dual beam. The average particle size of the complete HSAMMS was 20 mu m, and they exhibited superparamagnetic behavior at room temperature. The in vitro experiments (in saline and human serum) revealed the high stability of the labeled HSAMMS in saline and human serum after 72 h. Following the intravenous administration of the Y-90-HSAMMS in rats, 88.81% of the activity localizes in the lungs after 1 h, with 82.67% remaining after 72 h. These data on Y-90-HSAMMS provide good evidence for their potential use in bimodal radionuclide-hyperthermia cancer therapy.

Cristina Riggio,1,* Maria Pilar Calatayud,2,* Clare Hoskins,3 Josephine Pinkernelle,4 Beatriz Sanz,2 Teobaldo Enrique Torres,2,5 Manuel Ricardo Ibarra,2,5 Lijun Wang,3 Gerburg Keilhoff,4 Gerardo Fabian Goya,2,5 Vittoria Raffa,1,6 Alfred Cuschieri1,3 1Institute of Life Science, Scuola Superiore Sant’Anna, Piazza Martiri della Libertà, Pisa, Italy; 2Instituto de Nanociencia de Aragón, Universidad de Zaragoza. Mariano Esquillor, Zaragoza, Spain; 3IMSaT, Institute for Medical Science and Technology, University of Dundee, Dundee, Scotland; 4Otto-von-Guericke University, Institute of Biochemistry and Cell Biology, Magdeburg, Germany; 5Departamento de Física de la Materia Condensada, Facultad de Ciencias, Universidad de Zaragoza. Cerbuna 12, Zaragoza, Spain; 6Department of Biology, Università di Pisa, Pisa, Italy*These authors contributed equally to this workPurpose: It has been proposed in the literature that Fe3O4 magnetic nanoparticles (MNPs) could be exploited to enhance or accelerate nerve regeneration and to provide guidance for regenerating axons. MNPs could create mechanical tension that stimulates the growth and elongation of axons. Particles suitable for this purpose should possess (1) high saturation magnetization, (2) a negligible cytotoxic profile, and (3) a high capacity to magnetize mammalian cells. Unfortunately, the materials currently available on the market do not satisfy these criteria; therefore, this work attempts to overcome these deficiencies.Methods: Magnetite particles were synthesized by an oxidative hydrolysis method and characterized based on their external morphology and size distribution (high-resolution transmission electron microscopy [HR-TEM]) as well as their colloidal (Z potential) and magnetic properties (Superconducting QUantum Interference Devices [SQUID]). Cell viability was assessed via Trypan blue dye exclusion assay, cell doubling time, and MTT cell proliferation assay and reac

Con este proyecto nos proponemos introducir un aspecto básico del diagnóstico protésico y estético, el encerado digital. El objetivo final es proporcionar al alumno material de trabajo y herramientas que le permitan estudiar, aprender y practicar este procedimiento diagnóstico sin su presencia física en la facultad, o sin la necesidad de utilizar herramientas analógicas como se viene haciendo desde hace años.

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