DNA double-strand breaks cooperate with loss of Ink4 and Arf tumor suppressors to generate glioblastomas with frequent Met amplification

Glioblastomas (GBM) are highly radioresistant and lethal brain tumors. Ionizing radiation (IR)- induced DNA double-strand breaks (DSBs) are a risk factor for the development of GBM. In this study, we systematically examined the contribution of IR-induced DSBs to GBM development using transgenic mouse models harboring brain-targeted deletions of key tumor suppressors frequently lost in GBM, namely Ink4a, Ink4b, Arf, and/or PTEN. Using low linear energy transfer (LET) X-rays to generate simple breaks or high LET Fe ions to generate complex breaks, we found that DSBs induce high-grade gliomas in these mice which, otherwise, do not develop gliomas spontaneously. Loss of Ink4a and Arf was sufficient to trigger IR-induced glioma development but additional loss of Ink4b significantly increased tumor incidence. We analyzed IR-induced tumors for copy number alterations (CNAs) to identify oncogenic changes that were generated and selected for as a consequence of stochastic DSB events. We found Met amplification to be the most significant oncogenic event in these radiation-induced gliomas. Importantly, Met activation resulted in expression of Sox2, a GBM cancer stem cell (CSC) marker, and was obligatory for tumor formation. In sum, these results indicate that radiation-induced DSBs cooperate with loss of Ink4 and Arf tumor suppressors to generate high-grade gliomas that are commonly driven by Met amplification and activation

Network Properties of Ureasil-Based Polymer Matrixes for Construction of Amperometric Biosensors as Probed by PALS and Swelling Experiments

Network properties of ureasil-based polymer matrixes suitable for construction of amperometric biosensors were probed by positron annihilation lifetime spectroscopy and swelling experiments. Temperature dependences of the ortho-positronium (o-Ps) lifetimes and their relative intensities were measured in a temperature range of 15-350 K. Glass transition temperatures and expansion coefficients of microscopical free-volume for the investigated polymers were determined. Differences in network behavior for the aged samples and the effect of chalcogenide (As₂S₃) particles on the free volume of ureasil network were observed. Swelling experiments using ethyl alcohol showed that the structure of the aged sample network had less swelling ability for the pure ureasil as well as composite. This suggests that the one of factors influencing swelling is the change of the basic ureasil network due to ageing. It is supposed that the network properties obtained by positron annihilation lifetime spectroscopy and swelling experiments could be very helpful to understand better the bio-functionality of the constructed biosensor based on the ureasil-chalcogenide glass composite

Network Properties of Ureasil-Based Polymer Matrixes for Construction of Amperometric Biosensors as Probed by PALS and Swelling Experiments

Network properties of ureasil-based polymer matrixes suitable for construction of amperometric biosensors were probed by positron annihilation lifetime spectroscopy and swelling experiments. Temperature dependences of the ortho-positronium (o-Ps) lifetimes and their relative intensities were measured in a temperature range of 15-350 K. Glass transition temperatures and expansion coefficients of microscopical free-volume for the investigated polymers were determined. Differences in network behavior for the aged samples and the effect of chalcogenide (As₂S₃) particles on the free volume of ureasil network were observed. Swelling experiments using ethyl alcohol showed that the structure of the aged sample network had less swelling ability for the pure ureasil as well as composite. This suggests that the one of factors influencing swelling is the change of the basic ureasil network due to ageing. It is supposed that the network properties obtained by positron annihilation lifetime spectroscopy and swelling experiments could be very helpful to understand better the bio-functionality of the constructed biosensor based on the ureasil-chalcogenide glass composite

Structural and free volume characterization of sol gel organic inorganic hybrids, obtained by co condensation of two ureasilicate stoichiometric precursors

Abstract In this study two hybrid organic inorganic ureasilicate monomers with different length of polymer segments were chosen for preparation of sol gel material that includes two moieties blended on the molecular scale. The first monomer was obtained by crosslinking a double terminated polyoxyalkyleneamine with an isocyanate modified silicone ethoxide and the second one by crosslinking between the isocyanate modified silicone ethoxide with an amino modified silicone ethoxide. Sol gel route was applied for transformation of the liquid monomer blends in transparent materials with varying degree of rigidity. The prepared samples were characterized by small angle X ray scattering, Fouriertransform infrared spectroscopy, positron annihilation lifetime spectroscopy, and swelling experiments. The results demonstrate that the structure of the obtained materials could be tuned by a simple variation of molar fraction ratio between these two monomers. This makes it possible to obtain nanostructured materials with predictable propertie