In vivo bioluminescence imaging using orthotopic xenografts towards patient's derived-xenograft Medulloblastoma models

BACKGROUND: Medulloblastoma is a cerebellar neoplasia of the central nervous system. Four molecular subgrups have been identified (MBWNT, MBSHH, MBgroup3 and MBgroup4) with distinct genetics and clinical outcome. Among these, MBgroup3-4 are highly metastatic with the worst prognosis. The current standard therapy includes surgery, radiation and chemotherapy. Thus, specific treatments adapted to cure those different molecular subgroups are needed. The use of orthotopic xenograft models, together with the non-invasive in vivo biolumiscence imaging (BLI) technology, is emerging during preclinical studies to test novel therapeutics for medulloblastoma treatment. METHODS: Orthotopic MB xenografts were performed by injection of Daoy-luc cells, that had been previously infected with lentiviral particles to stably express luciferase gene, into the fourth right ventricle of the cerebellum of ten nude mice. For the implantation, specific stereotactic coordinates were used. Seven days after the implantation the mice were imaged by acquisitions of bioluminescence imaging (BLI) using IVIS 3D Illumina Imaging System (Xenogen). Tumor growth was evaluated by quantifying the bioluminescence signals using the integrated fluxes of photons within each area of interest using the Living Images Software Package 3.2 (Xenogen-Perkin Elmer). Finally, histological analysis using hematoxylin-eosin staining was performed to confirm the presence of tumorigenic cells into the cerebellum of the mice. RESULTS: We describe a method to use the in vivo bioluminescent imaging (BLI) showing the potential to be used to investigate the potential antitumorigenic effects of a drug for in vivo medulloblastoma treatment. We also discuss other studies in which this technology has been applied to obtain a more comprehensive knowledge of medulloblastoma using orthotopic xenograft mouse models. CONCLUSIONS: There is a need to develop patient's derived-xenograft (PDX) model systems to test novel drugs for medulloblastoma treatment within each molecular sub-groups with a higher predictive value. Here we show how this technology should be applied with hopes on generations of new treatments to be applied then in human

Phase diagram of the XXZ ferrimagnetic spin-(1/2, 1) chain in the presence of transverse magnetic field

We investigate the phase diagram of an anisotropic ferrimagnet spin-(1/2, 1) in the presence of a non-commuting (transverse) magnetic field. We find a magnetization plateau for the isotropic case while there is no plateau for the anisotropic ferrimagnet. The magnetization plateau can appear only when the Hamiltonian has the U(1) symmetry in the presence of the magnetic field. The anisotropic model is driven by the magnetic field from the N\'{e}el phase for low fields to the spin-flop phase for intermediate fields and then to the paramagnetic phase for high fields. We find the quantum critical points and their dependence on the anisotropy of the aforementioned field-induced quantum phase transitions. The spin-flop phase corresponds to the spontaneous breaking of Z2 symmetry. We use the numerical density matrix renormalization group and analytic spin wave theory to find the phase diagram of the model. The energy gap, sublattice magnetization, and total magnetization parallel and perpendicular to the magnetic field are also calculated. The elementary excitation spectrums of the model are obtained via the spin wave theory in the three different regimes depending on the strength of the magnetic field.Comment: 14 pages, 11 eps figure

An N-of-1 Evaluation Framework for Behaviour Change Applications

Mobile behaviour change applications should be evaluated for their effectiveness in promoting the intended behavior changes. In this paper we argue that the 'gold standard' form of effectiveness evaluation, the randomised controlled trial, has shortcomings when applied to mobile applications. We propose that N-of-1 (also known as single case design) based approaches have advantages. There is currently a lack of guidance for researchers and developers on how to take this approach. We present a framework encompassing three phases and two related checklists for performing N-of-1 evaluations. We also present our analysis of using this framework in the development and deployment of an app that encourages people to walk more. Our key findings are that there are challenges in designing engaging apps that automate N-of-1 procedures, and that there are challenges in collecting sufficient data of good quality. Further research should address these challenges

A competitive cell-permeable peptide impairs Nme-1 (NDPK-A) and Prune-1 interaction: therapeutic applications in cancer.

The understanding of protein–protein interactions is crucial in order to generate a second level of functional genomic analysis in human disease. Within a cellular microenvironment, protein–protein interactions generate new functions that can be defined by single or multiple modes of protein interactions. We outline here the clinical importance of targeting of the Nme-1 (NDPK-A)–Prune-1 protein complex in cancer, where an imbalance in the formation of this protein–protein complex can result in inhibition of tumor progression. We discuss here recent functional data using a small synthetic competitive cell-permeable peptide (CPP) that has shown therapeutic efficacy for impairing formation of the Nme-1–Prune-1 protein complex in mouse preclinical xenograft tumor models (e.g., breast, prostate, colon, and neuroblastoma). We thus believe that further discoveries in the near future related to the identification of new protein–protein interactions will have great impact on the development of new therapeutic strategies against various cancers

On discontinuous Galerkin and discrete ordinates approximations for neutron transport equation and the critical eigenvalue

The objective of this paper is to give a mathematical framework for a fully discrete numerical approach for the study of the neutron transport equation in a cylindrical domain (container model). More specifically, we consider the discontinuous Galerkin (DG) finite element method for spatial approximation of the mono-energetic, critical neutron transport equation in an infinite cylindrical domain e Ω in R3 with a polygonal convex cross-section Ω. The velocity discretization relies on a special quadrature rule developed to give optimal estimates in discrete ordinate parameters compatible with the quasi-uniform spatial mesh. We use interpolation spaces and derive optimal error estimates, up to maximal available regularity, for the fully discrete scalar flux. Finally we employ a duality argument and prove superconvergence estimates for the critical eigenvalue

On stabilized P1 finite element approximation fortime harmonic Maxwell's equations

One way of improving the behavior of finite element schemes for classical, time-dependent Maxwell's equations, is to render them from their hyperbolic character to elliptic form. This paper is devoted to the study of the stabilized linear finite element method for the time harmonic Maxwell's equations in a dual form obtained through the Laplace transformation in time. The model problem is for the particular case of the dielectric permittivity function which is assumed to be constant in a boundary neighborhood. For the stabilized model a coercivity relation is derived that guarantee's the existence of a unique solution for the iscrete problem. The convergence is addressed both in a priori and a posteriori settings. In the a priori error estimates we confirm the theoretical convergence of the scheme in a L2-based, gradient dependent, triple norm. The order of convergence is O(h) in weighted Sobolev space and hence optimal. We also derive, similar, optimal a posteriori error estimates controlled by a certain, weighted, norm of the residual of the computed solution. The posteriori approach is used for constructing adaptive algorithms for the computational purposes. Further, assuming a sufficiently regular solution for the dual problem, we reach the same convergence of O(h). Finally, through implementing several numerical examples, we validate the robustness of the proposed scheme

Metastatic group 3 medulloblastoma is driven by PRUNE1 targeting NME1-TGF-β-OTX2-SNAIL via PTEN inhibition.

Genetic modifications during development of paediatric groups 3 and 4 medulloblastoma are responsible for their highly metastatic properties and poor patient survival rates. PRUNE1 is highly expressed in metastatic medulloblastoma group 3, which is characterized by TGF-β signalling activation, c-MYC amplification, and OTX2 expression. We describe the process of activation of the PRUNE1 signalling pathway that includes its binding to NME1, TGF-β activation, OTX2 upregulation, SNAIL (SNAI1) upregulation, and PTEN inhibition. The newly identified small molecule pyrimido-pyrimidine derivative AA7.1 enhances PRUNE1 degradation, inhibits this activation network, and augments PTEN expression. Both AA7.1 and a competitive permeable peptide that impairs PRUNE1/NME1 complex formation, impair tumour growth and metastatic dissemination in orthotopic xenograft models with a metastatic medulloblastoma group 3 cell line (D425-Med cells). Using whole exome sequencing technology in metastatic medulloblastoma primary tumour cells, we also define 23 common 'non-synonymous homozygous' deleterious gene variants as part of the protein molecular network of relevance for metastatic processes. This PRUNE1/TGF-β/OTX2/PTEN axis, together with the medulloblastoma-driver mutations, is of relevance for future rational and targeted therapies for metastatic medulloblastoma group 3

QCD ghost f(T)-gravity model

Within the framework of modified teleparallel gravity, we reconstruct a f(T) model corresponding to the QCD ghost dark energy scenario. For a spatially flat FRW universe containing only the pressureless matter, we obtain the time evolution of the torsion scalar T (or the Hubble parameter). Then, we calculate the effective torsion equation of state parameter of the QCD ghost f(T)-gravity model as well as the deceleration parameter of the universe. Furthermore, we fit the model parameters by using the latest observational data including SNeIa, CMB and BAO data. We also check the viability of our model using a cosmographic analysis approach. Moreover, we investigate the validity of the generalized second law (GSL) of gravitational thermodynamics for our model. Finally, we point out the growth rate of matter density perturbation. We conclude that in QCD ghost f(T)-gravity model, the universe begins a matter dominated phase and approaches a de Sitter regime at late times, as expected. Also this model is consistent with current data, passes the cosmographic test, satisfies the GSL and fits the data of the growth factor well as the LCDM model.Comment: 19 pages, 9 figures, 2 tables. arXiv admin note: substantial text overlap with arXiv:1111.726