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Mesenchymal chondrosarcoma (MCS) is a high-grade malignancy that represents 2-9% of chondrosarcomas and mostly affects children and young adults. HEY1-NCoA2 gene fusion is considered to be a driver of tumorigenesis and it has been identified in 80% of MCS tumors. The shortage of MCS samples and biological models creates a challenge for the development of effective therapeutic strategies to improve the low survival rate of MCS patients. Previous molecular studies using immunohistochemical staining of patient samples suggest that activation of PDGFR signaling could be involved in MCS tumorigenesis. This work presents the development of two independent in vitro and in vivo models of HEY1-NCoA2-driven MCS and their application in a drug repurposing strategy. The in vitro model was characterized by RNA sequencing at the single-cell level and successfully recapitulated relevant MCS features. Imatinib, as well as specific inhibitors of ABL and PDGFR, demonstrated a highly selective cytotoxic effect targeting the HEY1-NCoA2 fusion-driven cellular model. In addition, patient-derived xenograft (PDX) models of MCS harboring the HEY1-NCoA2 fusion were developed from a primary tumor and its distant metastasis. In concordance with in vitro observations, imatinib was able to significantly reduce tumor growth in MCS-PDX models. The conclusions of this study serve as preclinical results to revisit the clinical efficacy of imatinib in the treatment of HEY1-NCoA2-driven MCS., (© 2021. The Author(s), under exclusive licence to United States and Canadian Academy of Pathology.)

Molecular characterization of diffuse gliomas has thus far largely focused on genomic and transcriptomic interrogations. Here, we utilized mass spectrometry and overlay protein-level information onto genomically defined cohorts of diffuse gliomas to improve our downstream molecular understanding of these lethal malignancies. Bulk and macrodissected tissues were utilized to quantitate 5,496 unique proteins over three glioma cohorts subclassified largely based on their IDH and 1p19q codeletion status (IDH wild type (IDHwt), n = 7; IDH mutated (IDHmt), 1p19q non-codeleted, n = 7; IDH mutated, 1p19q-codeleted, n = 10). Clustering analysis highlighted proteome and systems-level pathway differences in gliomas according to IDH and 1p19q-codeletion status, including 287 differentially abundant proteins in macrodissection-enriched tumor specimens. IDHwt tumors were enriched for proteins involved in invasiveness and epithelial to mesenchymal transition (EMT), while IDHmt gliomas had increased abundances of proteins involved in mRNA splicing. Finally, these abundance changes were compared with IDH-matched GBM stem-like cells (GSCs) to better pinpoint protein patterns enriched in putative cellular drivers of gliomas. Using this integrative approach, we outline specific proteins involved in chloride transport ( e.g. chloride intracellular channel 1, CLIC1) and EMT ( e.g. procollagen-lysine, 2-oxoglutarate 5-dioxygenase 3, PLOD3, and serpin peptidase inhibitor clade H member 1, SERPINH1) that showed concordant IDH-status-dependent abundance differences in both primary tissue and purified GSC cultures. Given the downstream position proteins occupy in driving biology and phenotype, understanding the proteomic patterns operational in distinct glioma subtypes could help propose more specific, personalized, and effective targets for the management of patients with these aggressive malignancies., (© 2019 Djuric et al.)

Amyloid-beta peptide (Aβ) plays a critical role in the pathogenesis of Alzheimer's disease (AD). Here, we explored the use of a combination treatment to reduce amyloid load through microglial phagocytosis in a mouse model of AD. We hypothesized that using an initial treatment of magnetic resonance image guided focused ultrasound (MRIgFUS) to transiently increase the blood-brain barrier (BBB) permeability and enhance the delivery of an Aβ-antibody (BAM-10), followed by scyllo-inositol treatment would result in accelerated clearance. TgCRND8 mice expressing both Swedish (KM670/671NL) and Indiana (V717F) APP mutations under the hamster prion (PrP) promoter at 5 months of age were either treated with scyllo-inositol or received an initial MRIgFUS treatment delivering BAM-10 prior to scyllo-inositol treatment for one month. Treated animals and untreated TgCRND8 littermates were then sacrificed at 6 months of age, and their brains were processed for immunohistochemistry and immunofluorescence. Amyloid load was quantified and analyzed through immunohistochemical staining. Astrocyte and microglial activation were quantified and analyzed through immunofluorescent staining. We found that both the scyllo-inositol treatment and combination treatment, MRIgFUS/BAM10+scyllo-inositol, significantly reduced amyloid load and astrocyte activation in the hippocampus and the cortex. Furthermore, in both treatment paradigms microglial activation and phagocytosis was increased in comparison to the untreated mice. There were no differences detected between the two treatment paradigms. We propose that the 30-day scyllo-inositol treatment saturated the early benefit of the MRIgFUS/BAM-10 treatment. In the future, multiple FUS treatments combined with BAM-10 throughout the duration of scyllo-inositol treatment may lead to more effective amyloid clearance., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The immune system is now considered a major factor in Alzheimer Disease (AD). This review seeks to demonstrate how various aspects of the immune system, both in the brain and peripherally, interact to contribute to AD. We highlight classical nervous system immune components, such as complement and microglia, as well as novel aspects of the peripheral immune system that can influence disease, such as monocytes and lymphocytes. By detailing the roles of various immune cells in AD, we summarize an emerging perspective for disease etiology and future therapeutic targets., (Copyright © 2017. Published by Elsevier B.V.)

The hydrogen transfer reaction catalysed by soybean lipoxygenase (SLO) has been the focus of intense study following observations of a high kinetic isotope effect (KIE). Today high KIEs are generally thought to indicate departure from classical rate theory and are seen as a strong signature of tunnelling of the transferring particle, hydrogen or one of its isotopes, through the reaction energy barrier. In this paper, we build a qualitative quantum rate model with few free parameters that describes the dynamics of the transferring particle when it is exposed to energetic potentials exerted by the donor and the acceptor. The enzyme's impact on the dynamics is modelled by an additional energetic term, an oscillatory contribution known as "gating." By varying two key parameters, the gating frequency and the mean donor-acceptor separation, the model is able to reproduce well the KIE data for SLO wild-type and a variety of SLO mutants over the experimentally accessible temperature range. While SLO-specific constants have been considered here, it is possible to adapt these for other enzymes.

After more than a century of research, the mouse remains the gold-standard model system, for it recapitulates human development and disease and is quickly and highly tractable to genetic manipulations. Fundamental to the power and success of using a mouse model is the ability to stage embryonic mouse development accurately. Past staging systems were limited by the technologies of the day, such that only surface features, visible with a light microscope, could be recognized and used to define stages. With the advent of high-throughput 3D imaging tools that capture embryo morphology in microscopic detail, we now present the first 4D atlas staging system for mouse embryonic development using optical projection tomography and image registration methods. By tracking 3D trajectories of every anatomical point in the mouse embryo from E11.5 to E14.0, we established the first 4D atlas compiled from ex vivo 3D mouse embryo reference images. The resulting 4D atlas comprises 51 interpolated 3D images in this gestational range, resulting in a temporal resolution of 72 min. From this 4D atlas, any mouse embryo image can be subsequently compared and staged at the global, voxel and/or structural level. Assigning an embryonic stage to each point in anatomy allows for unprecedented quantitative analysis of developmental asynchrony among different anatomical structures in the same mouse embryo. This comprehensive developmental data set offers developmental biologists a new, powerful staging system that can identify and compare differences in developmental timing in wild-type embryos and shows promise for localizing deviations in mutant development., (© 2015. Published by The Company of Biologists Ltd.)

We extend the exchange fluctuation theorem for energy exchange between thermal quantum systems beyond the assumption of molecular chaos, and describe the nonequilibrium exchange dynamics of correlated quantum states. The relation quantifies how the tendency for systems to equilibrate is modified in high-correlation environments. In addition, a more abstract approach leads us to a "correlation fluctuation theorem". Our results elucidate the role of measurement disturbance for such scenarios. We show a simple application by finding a semiclassical maximum work theorem in the presence of correlations. We also present a toy example of qubit-qudit heat exchange, and find that non-classical behaviour such as deterministic energy transfer and anomalous heat flow are reflected in our exchange fluctuation theorem.

The quantum steering ellipsoid of a two-qubit state is the set of Bloch vectors that Bob can collapse Alice's qubit to, considering all possible measurements on his qubit. We provide an elementary construction of the ellipsoid for arbitrary states, calculate its volume, and explain how this geometric representation can be made faithful. The representation provides a range of new results, and uncovers new features, such as the existence of "incomplete steering" in separable states. We show that entanglement can be analyzed in terms of three geometric features of the ellipsoid and prove that a state is separable if and only if it obeys a "nested tetrahedron" condition.

The amount of correlation attainable between the components of a quantum system is constrained if the system is closed. We provide some examples, largely from the field of quantum thermodynamics, where knowing the maximal possible variation in correlations is useful. The optimization problem it raises requires us to search for the maximally and minimally correlated states on a unitary orbit, with and without energy conservation. This is fully solvable for the smallest system of two qubits. For larger systems, the problem is reduced to a manageable, classical optimization.

The natural zeolite tuff from the Vranjska Banja deposit (Serbia) has been studied as sorbent for Mn(II) ions from aqueous solutions. The zeolite sample containing mainly clinoptilolite (more than 70%) removes Mn(II) ions by ion-exchange process, which was confirmed by X-ray photoelectron spectroscopy (XPS) and energy dispersive X-ray analysis (EDXS). XPS showed that there is no surface accumulation of Mn but an almost uniform distribution inside the sorbent; EDXS confirmed that Mn(II) replaced the clinoptilolite Na counter ions. The sorption isotherms were studied at 298 K by batch experiments showing that the Mn(II) removal is best described by the Langmuir-Freundlich or Sips model. The kinetics followed the pseudo-second-order model, the activation energy being 128 kJ mol(-1). The intra-particle diffusion is not the rate-controlling step in the sorption of Mn(II) on clinoptilolite. Thermodynamic data suggest spontaneity of the endothermic ion-exchange process in the 298-338 K range.