Nuclear Factor \u3baB-Dependent Neurite Remodeling Is Mediated by Notch Pathway

In this study, we evaluated whether a cross talk between nuclear factor \u3baB (NF-\u3baB) and Notch may take place and contribute to regulate cell morphology and/or neuronal network in primary cortical neurons. We found that lack of p50, either induced acutely by inhibiting p50 nuclear translocation or genetically in p50(-/-) mice, results in cortical neurons characterized by reduced neurite branching, loss of varicosities, and Notch1 signaling hyperactivation. The neuronal morphological effects found in p50(-/-) cortical cells were reversed after treatment with the \u3b3-secretase inhibitor DAPT (N-[N-(3,5-difluorophenacetyl)-1-alanyl 1]-S-phenylglycine t-butyl ester) or Notch RNA interference. Together, these data suggested that morphological abnormalities in p50(-/-) cortical neurons were dependent on Notch pathway hyperactivation, with Notch ligand Jagged1 being a major player in mediating such effect. In this line, we demonstrated that the p50 subunit acts as transcriptional repressor of Jagged1. We also found altered distribution of Notch1 and Jagged1 immunoreactivity in the cortex of p50(-/-) mice compared with wild-type littermates at postnatal day 1. These data suggest the relevance of future studies on the role of Notch/NF-\u3baB cross talk in regulating cortex structural plasticity in physiological and pathological conditions

Medical physics challenges in clinical MR-guided radiotherapy

The integration of magnetic resonance imaging (MRI) for guidance in external beam radiotherapy has faced significant research and development efforts in recent years. The current availability of linear accelerators with an embedded MRI unit, providing volumetric imaging at excellent soft tissue contrast, is expected to provide novel possibilities in the implementation of image-guided adaptive radiotherapy (IGART) protocols. This study reviews open medical physics issues in MR-guided radiotherapy (MRgRT) implementation, with a focus on current approaches and on the potential for innovation in IGART.Daily imaging in MRgRT provides the ability to visualize the static anatomy, to capture internal tumor motion and to extract quantitative image features for treatment verification and monitoring. Those capabilities enable the use of treatment adaptation, with potential benefits in terms of personalized medicine. The use of online MRI requires dedicated efforts to perform accurate dose measurements and calculations, due to the presence of magnetic fields. Likewise, MRgRT requires dedicated quality assurance (QA) protocols for safe clinical implementation.Reaction to anatomical changes in MRgRT, as visualized on daily images, demands for treatment adaptation concepts, with stringent requirements in terms of fast and accurate validation before the treatment fraction can be delivered. This entails specific challenges in terms of treatment workflow optimization, QA, and verification of the expected delivered dose while the patient is in treatment position. Those challenges require specialized medical physics developments towards the aim of fully exploiting MRI capabilities. Conversely, the use of MRgRT allows for higher confidence in tumor targeting and organs-at-risk (OAR) sparing.The systematic use of MRgRT brings the possibility of leveraging IGART methods for the optimization of tumor targeting and quantitative treatment verification. Although several challenges exist, the intrinsic benefits of MRgRT will provide a deeper understanding of dose delivery effects on an individual basis, with the potential for further treatment personalization

Conformational altered p53 as an early marker of oxidative stress in Alzheimer\u27s disease

In order to study oxidative stress in peripheral cells of Alzheimer\u27s disease (AD) patients, immortalized lymphocytes derived from two peculiar cohorts of patients, referring to early onset AD (EOSAD) and subjects harboured AD related mutation (ADmut), were used. Oxidative stress was evaluated measuring i) the typical oxidative markers, such as HNE Michel adducts, 3 Nitro-Tyrosine residues and protein carbonyl on protein extracts, ii) and the antioxidant capacity, following the enzymatic kinetic of superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione reductase (GRD). We found that the signs of oxidative stress, measured as oxidative marker levels, were evident only in ADmut but not in EOSAD patients. However, oxidative imbalance in EOSAD as well as ADmut lymphocytes was underlined by a reduced SOD activity and GRD activity in both pathological groups in comparison with cells derived from healthy subjects. Furthermore, a redox modulated p53 protein was found conformational altered in both EOSAD and ADmut B lymphocytes in comparison with control cells. This conformational altered p53 isoform, named unfolded p53 , was recognized by the use of two specific conformational anti-p53 antibodies. Immunoprecipitation experiments, performed with the monoclonal antibodies PAb1620 (that recognizes p53wt) and PAb240 (that is direct towards unfolded p53), and followed by the immunoblotting with anti-4-hydroxynonenal (HNE) and anti- 3-nitrotyrosine (3NT) antibodies, showed a preferential increase of nitrated tyrosine residues in unfolded p53 isoform comparing to p53 wt protein, in both ADmut and EOSAD. In addition, a correlation between unfolded p53 and SOD activity was further found. Thus this study suggests that ROS/RNS contributed to change of p53 tertiary structure and that unfolded p53 can be considered as an early marker of oxidative imbalance in these patients

Ultrafast Excited-State Localization in Cs2AgBiBr6 Double Perovskite

Cs2AgBiBr6 is a promising metal halide double perovskite offering the possibility of efficient photovoltaic devices based on lead-free materials. Here, we report on the evolution of photoexcited charge carriers in Cs2AgBiBr6 using a combination of temperature-dependent photoluminescence, absorption and optical pump–terahertz probe spectroscopy. We observe rapid decays in terahertz photoconductivity transients that reveal an ultrafast, barrier-free localization of free carriers on the time scale of 1.0 ps to an intrinsic small polaronic state. While the initially photogenerated delocalized charge carriers show bandlike transport, the self-trapped, small polaronic state exhibits temperature-activated mobilities, allowing the mobilities of both to still exceed 1 cm2 V–1 s–1 at room temperature. Self-trapped charge carriers subsequently diffuse to color centers, causing broad emission that is strongly red-shifted from a direct band edge whose band gap and associated exciton binding energy shrink with increasing temperature in a correlated manner. Overall, our observations suggest that strong electron–phonon coupling in this material induces rapid charge-carrier localization

Charge-Carrier Mobility and Localization in Semiconducting Cu2AgBiI6 for Photovoltaic Applications

Lead-free silver–bismuth semiconductors have become increasingly popular materials for optoelectronic applications, building upon the success of lead halide perovskites. In these materials, charge-lattice couplings fundamentally determine charge transport, critically affecting device performance. In this study, we investigate the optoelectronic properties of the recently discovered lead-free semiconductor Cu2AgBiI6 using temperature-dependent photoluminescence, absorption, and optical-pump terahertz-probe spectroscopy. We report ultrafast charge-carrier localization effects, evident from sharp THz photoconductivity decays occurring within a few picoseconds after excitation and a rise in intensity with decreasing temperature of long-lived, highly Stokes-shifted photoluminescence. We conclude that charge carriers in Cu2AgBiI6 are subject to strong charge-lattice coupling. However, such small polarons still exhibit mobilities in excess of 1 cm2 V–1 s–1 at room temperature because of low energetic barriers to formation and transport. Together with a low exciton binding energy of ∼29 meV and a direct band gap near 2.1 eV, these findings highlight Cu2AgBiI6 as an attractive lead-free material for photovoltaic applications

Conformational Altered p53 as an Early Marker of Oxidative Stress in Alzheimer's Disease

In order to study oxidative stress in peripheral cells of Alzheimer's disease (AD) patients, immortalized lymphocytes derived from two peculiar cohorts of patients, referring to early onset AD (EOSAD) and subjects harboured AD related mutation (ADmut), were used. Oxidative stress was evaluated measuring i) the typical oxidative markers, such as HNE Michel adducts, 3 Nitro-Tyrosine residues and protein carbonyl on protein extracts, ii) and the antioxidant capacity, following the enzymatic kinetic of superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione reductase (GRD). We found that the signs of oxidative stress, measured as oxidative marker levels, were evident only in ADmut but not in EOSAD patients. However, oxidative imbalance in EOSAD as well as ADmut lymphocytes was underlined by a reduced SOD activity and GRD activity in both pathological groups in comparison with cells derived from healthy subjects. Furthermore, a redox modulated p53 protein was found conformational altered in both EOSAD and ADmut B lymphocytes in comparison with control cells. This conformational altered p53 isoform, named “unfolded p53”, was recognized by the use of two specific conformational anti-p53 antibodies. Immunoprecipitation experiments, performed with the monoclonal antibodies PAb1620 (that recognizes p53wt) and PAb240 (that is direct towards unfolded p53), and followed by the immunoblotting with anti-4-hydroxynonenal (HNE) and anti- 3-nitrotyrosine (3NT) antibodies, showed a preferential increase of nitrated tyrosine residues in unfolded p53 isoform comparing to p53 wt protein, in both ADmut and EOSAD. In addition, a correlation between unfolded p53 and SOD activity was further found. Thus this study suggests that ROS/RNS contributed to change of p53 tertiary structure and that unfolded p53 can be considered as an early marker of oxidative imbalance in these patients

Klassificering av patienters respons på tumörbehandling från PET/CT-data med hjälp av maskininlärning

Early assessment of tumour response has lately acquired big interest in the medical field, given the possibility to modify treatments during their delivery. Radiomics aims to quantitatively describe images in radiology by automatically extracting a large number of image features. In this context, PET/CT (Positron Emission Tomography/Computed Tomography) images are of great interest since they encode functional and anatomical information, respectively. In order to assess the patients' responses from many image features appropriate methods should be applied. Machine learning offers different procedures that can deal with this, possibly high dimensional, problem. The main objective of this work was to develop a method to classify lung cancer patients as responding or not to chemoradiation treatment, relying on repeated PET/CT images. Patients were divided in two groups, based on the type of chemoradiation treatment they underwent (sequential or concurrent radiation therapy with respect to chemotherapy), but image features were extracted using the same procedure. Support vector machines performed classification using features from the Radiomics field, mostly describing tumour texture, or from handcrafted features, which described image intensity changes as a function of tumour depth. Classification performance was described by the area under the curve (AUC) of ROC (Receiving Operator Characteristic) curves after leave-one-out cross-validation. For sequential patients, 0.98 was the best AUC obtained, while for concurrent patients 0.93 was the best one. Handcrafted features were comparable to those from Radiomics and from previous studies, as for classification results. Also, features from PET alone and CT alone were found to be suitable for the task, entailing a performance better than random

Perfusion and diffusion in meningioma tumors: a preliminary multiparametric analysis with Dynamic Susceptibility Contrast and IntraVoxel Incoherent Motion MRI

Multiparametric MRI is a remarkable imaging method for the assessment of patho-physiological processes. In particular, brain tumor characterization has taken advantage of the development of advanced techniques such as diffusion- (DWI) and perfusion- (PWI) weighted imaging, but a thorough analysis of meningiomas is still lacking despite the variety of computational methods proposed. We compute perfusion and diffusion parametric maps relying on a well-defined methodological workflow, investigating possible correlations between pure and diffusion-based perfusion parameters in a cohort of 26 patients before proton therapy. A preliminary investigation of meningioma staging biomarkers based on IntraVoxel Incoherent Motion and Dynamic Susceptibility Contrast is also reported. We observed significant differences between the gross target volume and the normal appearing white matter for every investigated parameter, confirming the higher vascularization of the neoplastic tissue. DWI and PWI parameters appeared to be weakly correlated and we found that diffusion parameters - the perfusion fraction in particular - could be promising biomarkers for tumor staging