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Introduction The new frontier of tumor diagnosis and treatment relies on the development of delivery strategies capable of allowing the specific targeting of the diagnostic agents/chemotherapeutics, avoiding side effects. In the case of brain tumors, achieving this goal is made more difficult by the presence of the blood–brain barrier (BBB). Peptides have been revealed as excellent candidates for both BBB crossing and specific cancer homing. Nanoparticles (NPs), functionalized with BBB crossing and tumor homing (TH) peptides, are emerging as smart theranostic systems. However, there is still poor knowledge concerning the molecular structure and dynamical properties of these peptides, essential requirements for a suitable functionalization of the delivery systems themselves. Methods In this work, by means of molecular dynamics (MD) simulations, we have extensively characterized the structural and dynamical behavior of several peptides, known to be endowed of BBB crossing and TH properties. Results The simulations point out that, on the basis of their conformational dynamics, the peptides can be classified in two main groups: 1) peptides assuming a specific structural conformation, a feature that could be important for interacting with the molecular target but that may limit their use as functionalizing molecules and 2) highly flexible peptides whose interaction with the target may be independent of a particular structural conformation and that may represent good candidates for the functionalization of theranostic NP-based platforms. Discussion Such findings may be useful for the de novo designing of NP-based delivery systems., Video abstract Point your SmartPhone at the code above. If you have a QR code reader the video abstract will appear. Or use: https://youtu.be/wp8npbWb754

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Caterina Arcangeli,1 Chiara Lico,2 Selene Baschieri,2 Mariateresa Mancuso3 1Laboratory of Health and Environment, Italian National Agency for New Technologies, Energy and Sustainable Economic Development, ENEA, Rome, Italy; 2Laboratory of Biotechnology, Italian National Agency for New Technologies, Energy and Sustainable Economic Development, ENEA, Rome, Italy; 3Laboratory of Biomedical Technologies, Italian National Agency for New Technologies, Energy and Sustainable Economic Development, ENEA, Rome, ItalyCorrespondence: Caterina Arcangeli; Mariateresa MancusoENEA, Italian National Agency for New Technologies, Energy and Sustainable Economic Development, Casaccia Research Centre, Via Anguillarese 301, Rome 00123, ItalyTel +39 06 3048 6898/4993Fax +39 06 3048 6559/3644Email caterina.arcangeli@enea.it; mariateresa.mancuso@enea.itIntroduction: The new frontier of tumor diagnosis and treatment relies on the development of delivery strategies capable of allowing the specific targeting of the diagnostic agents/chemotherapeutics, avoiding side effects. In the case of brain tumors, achieving this goal is made more difficult by the presence of the blood–brain barrier (BBB). Peptides have been revealed as excellent candidates for both BBB crossing and specific cancer homing. Nanoparticles (NPs), functionalized with BBB crossing and tumor homing (TH) peptides, are emerging as smart theranostic systems. However, there is still poor knowledge concerning the molecular structure and dynamical properties of these peptides, essential requirements for a suitable functionalization of the delivery systems themselves.Methods: In this work, by means of molecular dynamics (MD) simulations, we have extensively characterized the structural and dynamical behavior of several peptides, known to be endowed of BBB crossing and TH properties.Results: The simulations point out that, on the basis of their conformational dynamics, the peptides can be classified in two main groups: 1) peptides assuming a specific structural conformation, a feature that could be important for interacting with the molecular target but that may limit their use as functionalizing molecules and 2) highly flexible peptides whose interaction with the target may be independent of a particular structural conformation and that may represent good candidates for the functionalization of theranostic NP-based platforms.Discussion: Such findings may be useful for the de novo designing of NP-based delivery systems.Keywords: conformational flexibility, free energy landscapes, essential dynamics, peptides, brain, theranostic platform

Presentation of conference paper entitled "High-Frequency Dielectrophoresis Characterizationof Differentiated vs UndifferentiatedMedulloblastoma Cells" at the 1st EMF-Med World Conference on Biomedical Applications of Electromagnetic Fields. Split, Croatia. Presented by Dr A. Pothier on10thSeptember 2018.

Conference paper entitled "Permittivity measurements of brain cancer cell towards the electric characterisation of single Cancer Stem Cells" accepted in the 1st EMF-Med World Conference on Biomedical Applications of Electromagnetic Fields. Split, Croatia, 10-13 September 2018., Bangor University also gratefully acknowledges the financial support provided by the Welsh Government and Higher Education Funding Council for Wales through the Sêr Cymru National Research Network in Advanced Engineering and Materials.

International audience

Presentation of paper entitled "Permittivity measurements of brain cancer cell towards the electric characterisation of single Cancer Stem Cells" at the 1st EMF-Med World Conference on Biomedical Applications of Electromagnetic Fields. Presented by Dr C. Palego in Split, Croatia, September 10th 2018., Bangor University also gratefully acknowledges the financial support provided by the Welsh Government and Higher Education Funding Council for Wales through the Sêr Cymru National Research Network in Advanced Engineering and Materials.

Presentation of paper entitled "Permittivity measurements of brain cancer celltowards the electric characterisation ofsingle Cancer Stem Cells" at the 1st EMF-Med World Conference on Biomedical Applications of Electromagnetic Fields. Presented by Dr C. Palego inSplit, Croatia,September 10th 2018.

// Barbara Tanno 1, * , Gabriele Babini 2, * , Simona Leonardi 1 , Paola Giardullo 3, 4 , Ilaria De Stefano 3 , Emanuela Pasquali 1 , Andrea Ottolenghi 2 , Michael J. Atkinson 5 , Anna Saran 1 , Mariateresa Mancuso 1 1 Laboratory of Biomedical Technologies, Agenzia Nazionale per le Nuove Tecnologie, l'Energia e lo Sviluppo Economico Sostenibile (ENEA), Rome, Italy 2 Department of Physics, University of Pavia, Pavia, Italy 3 Department of Radiation Physics, Guglielmo Marconi University, Rome, Italy 4 Department of Sciences, Roma Tre University, Rome, Italy 5 Helmholtz Zentrum Munchen, German Research Center for Environmental Health, Institute of Radiation Biology, Neuherberg, Germany * These authors contributed equally to this work Correspondence to: Mariateresa Mancuso, email: mariateresa.mancuso@enea.it Anna Saran, email: anna.saran@enea.it Keywords: miRNA, X-rays, medulloblastoma, Shh, GCPs Received: June 08, 2016 Accepted: September 05, 2016 Published: September 10, 2016 ABSTRACT It has historically been accepted that incorrectly repaired DNA double strand breaks (DSBs) are the principal lesions of importance regarding mutagenesis, and long-term biological effects associated with ionizing radiation. However, radiation may also cause dysregulation of epigenetic processes that can lead to altered gene function and malignant transformation, and epigenetic alterations are important causes of miRNAs dysregulation in cancer. Patched1 heterozygous ( Ptch1 +/− ) mice, characterized by aberrant activation of the Sonic hedgehog (Shh) signaling pathway, are a well-known murine model of spontaneous and radiation-induced medulloblastoma (MB), a common pediatric brain tumor originating from neural granule cell progenitors (GCPs). The high sensitivity of neonatal Ptch1 +/− mice to radiogenic MB is dependent on deregulation of the Ptch1 gene function. Ptch1 activates a growth and differentiation programme that is a strong candidate for regulation through the non-coding genome. Therefore we carried out miRNA next generation sequencing in ex vivo irradiated and control GCPs, isolated and purified from cerebella of neonatal WT and Ptch1 +/− mice. We identified a subset of miRNAs, namely let-7 family and miR-17~92 cluster members, whose expression is altered in GCPs by radiation alone, or by synergistic interaction of radiation with Shh-deregulation. The same miRNAs were further validated in spontaneous and radiation-induced MBs from Ptch1 +/− mice, confirming persistent deregulation of these miRNAs in the pathogenesis of MB. Our results support the hypothesis that miRNAs dysregulation is associated with radiosensitivity of GCPs and their neoplastic transformation in vivo .

Medulloblastoma (MB) is the most common pediatric brain tumor, comprising four distinct molecular variants, one of which characterized by activation of the Sonic Hedgehog (SHH) pathway, driving 25–30% of sporadic MB. SHH-dependent MBs arise from granule cell precursors (GCPs), are fatal in 40–70% of cases and radioresistance strongly contributes to poor prognosis and tumor recurrence. Patched1 heterozygous (Ptch1+/−) mice, carrying a germ-line heterozygous inactivating mutation in the Ptch1 gene, the Shh receptor and negative regulator of the pathway, are uniquely susceptible to MB development after radiation damage in neonatal cerebellum. Here, we irradiated ex-vivo GCPs isolated from cerebella of neonatal WT and Ptch1+/− mice. Our results highlight a less differentiated status of Ptch1-mutated cells after irradiation, influencing DNA damage response. Increased expression levels of pluripotency genes Nanog, Oct4 and Sal4, together with greater clonogenic potential, clearly suggest that radiation induces expansion of the stem-like cell compartment through cell-reprogramming and self-renewal maintenance, and that this mechanism is strongly dependent on Nanog. These results contribute to clarify the molecular mechanisms that control radiation-induced Shh-mediated tumorigenesis and may suggest Nanog as a potential target to inhibit for adjuvant radiotherapy in treatment of SHH-dependent MB.

// Mirella Tanori 1 , Arianna Casciati 1 , Francesco Berardinelli 2 , Simona Leonardi 1 , Emanuela Pasquali 1 , Francesca Antonelli 1 , Barbara Tanno 1 , Paola Giardullo 2,3 , Alessandro Pannicelli 4 , Gabriele Babini 5 , Ilaria De Stefano 3 , Antonella Sgura 2 , Mariateresa Mancuso 1 , Anna Saran 1 and Simonetta Pazzaglia 1 1 Laboratory of Biomedical Technologies, Agenzia Nazionale per le Nuove Tecnologie, l’Energia e lo Sviluppo Economico Sostenibile (ENEA), CR-Casaccia, Rome, Italy 2 Department of Science, University Roma Tre, Rome, Italy 3 Department of Radiation Physics, Universita degli Studi Guglielmo Marconi, Rome, Italy 4 Technical Unit of Energetic Efficiency, ENEA, Rome, Italy 5 Department of Physics, University of Pavia, Pavia, Italy Correspondence to: Simonetta Pazzaglia, email: // Keywords : cerebellum, expression profiles, medulloblastoma, apoptosis, senescence Received : June 14, 2016 Accepted : June 26, 2016 Published : July 07, 2016 Abstract Mutations in DNA repair pathways are frequent in human cancers. Hence, gaining insights into the interaction of DNA repair genes is key to development of novel tumor-specific treatment strategies. In this study, we tested the functional relationship in development and oncogenesis between the homologous recombination (HR) factor Rad54 and Parp-1 , a nuclear enzyme that plays a multifunctional role in DNA damage signaling and repair. We introduced single or combined Rad54 and Parp-1 inactivating germline mutations in Ptc1 heterozygous mice, a well-characterized model of medulloblastoma, the most common malignant pediatric brain tumor. Our study reveals that combined inactivation of Rad54 and Parp-1 causes a marked growth delay culminating in perinatallethality, providing for the first time evidence of synthetic lethal interactions between Rad54 and Parp-1 in vivo . Although the double mutation hampered investigation of Rad54 and Parp-1 interactions in cerebellum tumorigenesis, insights were gained by showing accumulation of endogenous DNA damage and increased apoptotic rate in granule cell precursors (GCPs). A network-based approach to detect differential expression of DNA repair genes in the cerebellum revealed perturbation of p53 signaling in Rad54 -/- / Parp-1 -/- / Ptc1 +/- , and MEFs from combined Rad54/Parp-1 mutants showed p53/p21-dependent typical senescent features. These findings help elucidate the genetic interplay between Rad54 and Parp-1 by suggesting that p53/p21-mediated apoptosis and/or senescence may be involved in synthetic lethal interactions occurring during development and inhibition of tumor growth.

While most of the evidence for radiation-induced late health effects relates to cancer, there has been increasing interest recently in the development of non-cancer diseases, including lens opacity, observed in populations exposed to low-dose radiation. In a recent study, we reported that mice heterozygous for the Patched1 (Ptch1) gene represented a novel and powerful animal model for this disorder, and a useful tool for investigating the mechanisms of radiogenic cataract development. Given the ongoing and considerable uncertainty in allowable lens dose levels and the existence of a threshold for the development of cataracts, we tested the effects of a decreasing range of radiation doses (2 Gy, 1 Gy and 0.5 Gy X rays) by irradiating groups of Ptch1+/- mice at 2 days of age. Our findings showed that at this dose range, acute exposure of this highly susceptible mouse model did not induce macroscopically detectable cataracts, and only the 2 Gy irradiated mice showed microscopic alterations of the lens. Molecular analyses performed to evaluate the induction of epithelial-mesenchymal transition (EMT) and subsequent fibrotic alterations in mouse lens cells also indicated the existence of a dose threshold for such effects in the mouse model used. The mechanisms of cataractogenesis remain unclear, and further experimental studies are essential to elucidate those mechanisms specific for cataract initiation and development after irradiation, as well as the underlying genetic factors controlling cataract susceptibility. © 2016 by Radiation Research Society.

// Mariateresa Mancuso 1 , Emanuela Pasquali 1 , Ignacia Braga-Tanaka III 2 , Satoshi Tanaka 2 , Alessandro Pannicelli 3 , Paola Giardullo 4, 5 , Simonetta Pazzaglia 1 , Soile Tapio 6 , Michael J. Atkinson 6 , Anna Saran 1 1 Laboratory of Radiation Biology and Biomedicine, Agenzia Nazionale per le Nuove Tecnologie, l'Energia e lo Sviluppo Economico Sostenibile (ENEA), Rome, Italy 2 Institute for Environmental Sciences (IES), Rokkasho, Aomori, Japan 3 Technical Unit of Energetic Efficiency, ENEA, Rome, Italy 4 Department of Radiation Physics, Guglielmo Marconi University, Rome, Italy 5 Department of Sciences, Roma Tre University, Rome, Italy 6 Helmholtz Zentrum Munchen, German Research Center for Environmental Health, Institute of Radiation Biology, Neuherberg, Germany Correspondence to: Mariateresa Mancuso, e-mail: mariateresa.mancuso@enea.it Anna Saran, e-mail: anna.saran@enea.it Keywords: atherosclerosis, ApoE mice, radiation, aorta Received: June 04, 2015 Accepted: August 10, 2015 Published: August 22, 2015 ABSTRACT There is epidemiological evidence for increased non-cancer mortality, primarily due to circulatory diseases after radiation exposure above 0.5 Sv. We evaluated the effects of chronic low-dose rate versus acute exposures in a murine model of spontaneous atherogenesis. Female ApoE −/− mice (60 days) were chronically irradiated for 300 days with gamma rays at two different dose rates (1 mGy/day; 20 mGy/day), with total accumulated doses of 0.3 or 6 Gy. For comparison, age-matched ApoE −/− females were acutely exposed to the same doses and sacrificed 300 days post-irradiation. Mice acutely exposed to 0.3 or 6 Gy showed increased atherogenesis compared to age-matched controls, and this effect was persistent. When the same doses were delivered at low dose rate over 300 days, we again observed a significant impact on global development of atherosclerosis, although at 0.3 Gy effects were limited to the descending thoracic aorta. Our data suggest that a moderate dose of 0.3 Gy can have persistent detrimental effects on the cardiovascular system, and that a high dose of 6 Gy poses high risks at both high and low dose rates. Our results were clearly nonlinear with dose, suggesting that lower doses may be more damaging than predicted by a linear dose response.