Integrated Approach Reveals Role of Mitochondrial Germ-Line Mutation F18L in Respiratory Chain, Oxidative Alterations, Drug Sensitivity, and Patient Prognosis in Glioblastoma

Glioblastoma is the most common and malignant primary brain tumour in adults, with a dismal prognosis. This is partly due to considerable inter- and intra-tumour heterogeneity. Changes in the cellular energy-producing mitochondrial respiratory chain complex (MRC) activities are a hallmark of glioblastoma relative to the normal brain, and associate with differential survival outcomes. Targeting MRC complexes with drugs can also facilitate anti-glioblastoma activity. Whether mutations in the mitochondrial DNA (mtDNA) that encode several components of the MRC contribute to these phenomena remains underexplored. We identified a germ-line mtDNA mutation (m. 14798T > C), enriched in glioblastoma relative to healthy controls, that causes an amino acid substitution F18L within the core mtDNA-encoded cytochrome b subunit of MRC complex III. F18L is predicted to alter corresponding complex III activity, and sensitivity to complex III-targeting drugs. This could in turn alter reactive oxygen species (ROS) production, cell behaviour and, consequently, patient outcomes. Here we show that, despite a heterogeneous mitochondrial background in adult glioblastoma patient biopsy-derived cell cultures, the F18L substitution associates with alterations in individual MRC complex activities, in particular a 75% increase in MRC complex II_III activity, and a 34% reduction in CoQ10, the natural substrate for MRC complex III, levels. Downstream characterisation of an F18L-carrier revealed an 87% increase in intra-cellular ROS, an altered cellular distribution of mitochondrial-specific ROS, and a 64% increased sensitivity to clomipramine, a repurposed MRC complex III-targeting drug. In patients, F18L-carriers that received the current standard of care treatment had a poorer prognosis than non-carriers (373 days vs. 415 days, respectively). Single germ-line mitochondrial mutations could predispose individuals to differential prognoses, and sensitivity to mitochondrial targeted drugs. Thus, F18L, which is present in blood could serve as a useful non-invasive biomarker for the stratification of patients into prognostically relevant groups, one of which requires a lower dose of clomipramine to achieve clinical effect, thus minimising side-effects

The Windsurf Software Library

The Windsurf Java library (Copyright (c) 2009 DEIS - Alma Mater Studiorum, Universit\ue0 di Bologna, Italy) is a general framework for efficiently processing content-based image queries. With particular emphasis to the region-based paradigm, Windsurf provides an environment where different alternatives of the paradigm can be implemented. Such flexibility is given by a number of different templates that can be appropriately instantiated in order to realize the particular retrieval model needed by the user. This allows such implementations to be compared on a fair basis, from the points of view of both effectiveness and efficiency. The library is released under the "QPL" license and is freely available for your own use only, for education and research purposes only. For commercial purposes, we are able to grant a differently licensed version of the library that does not contain the above restrictions

The Windsurf Library for the Efficient Retrieval of Multimedia Hierarchical Data

Several modern multimedia applications require the management of complex data, that can be defined as hierarchical objects consisting of several component elements. In such scenarios, the concept of similarity between complex objects clearly recursively depends on the similarity between component data, making difficult the resolution of several common tasks, like processing of queries and understanding the impact of different alternatives available for the definition of similarity between objects. To overcome such limitations, in this paper we present the Windsurf library for management of multimedia hierarchical data. The goal of the library is to provide a general framework for assessing the performance of alternative query processing techniques for efficient retrieval of complex data that arise in several multimedia applications, such as image/video retrieval and the comparison of collection of documents. We designed the library so as to include characteristics of generality, flexibility, and extensibility: these are provided by way of a number of different templates that can be appropriately instantiated in order to realize the particular retrieval model needed by the user

Cone beam computed tomography for dental and maxillofacial imaging: technique improvement and low-dose protocols

Objective: The aim of this study was to evaluate images quality and radiation doses of Cone Beam Computed Tomography (CBCT) for dental and maxillofacial imaging testing five different acquisition protocols. Methods: Dose measurements of different acquisition protocols were calculated for Pax Zenith three-dimensional (3D) Cone Beam (Vatech, Korea) and for conventional orthopantomography (OPT) and cephalometric skull imaging Ortophos (Sirona Dental Systems, Bernsheim, Germany). The absorbed organ doses were measured using an anthropomorphic phantom loaded with thermoluminescent dosimeters at 58 sites related to sensitive organs. Five different CBCT protocols were evaluated for image quality and radiation doses. They differed in FOV, image resolution, kVp, mA, acquisition time in seconds and radiation dose. Measurements were then carried out with the orthopantomograph. Equivalent and effective doses were calculated. Results: The reference protocol with large FOV, high resolution quality images, 95 kVp, 5 mA and acquisition time of 24 s resulted in a DAP value of 1556 mGy cm2 instead the protocol with reduced kVp from 95 to 80 kVp translated into a value of DAP inferior to 35% (from 1556 to 1013 mGy cm2). Going from a high resolution to a normal resolution, there was a reduction of the acquisition time to 15 s which allowed further dose reduction of approximately 40% (628 mGy cm2); this protocol resulted in a value of effective dose of 35 microSievert (μSv). Moreover, the effect of changing FOV has been evaluated, considering two scans with a reduced FOV (160 × 140 and 120 × 90 mm, respectively). Conclusions: CBCT low-dose protocol with large FOV, normal resolution quality images, 80 kVp, 5 mA and acquisition time of 15 s resulted in a value of effective dose of 35 microSievert (μSv). This protocol allows the study of maxillofacial region with high quality of images and a very low radiation dose and, therefore, could be proposed in selected case where a complete assessment of dental and maxillofacial region is useful for treatment planning