Hypoxic Cell Waves around Necrotic Cores in Glioblastoma: A Biomathematical Model and its Therapeutic Implications

Glioblastoma is a rapidly evolving high-grade astrocytoma that is distinguished pathologically from lower grade gliomas by the presence of necrosis and microvascular hiperplasia. Necrotic areas are typically surrounded by hypercellular regions known as "pseudopalisades" originated by local tumor vessel occlusions that induce collective cellular migration events. This leads to the formation of waves of tumor cells actively migrating away from central hypoxia. We present a mathematical model that incorporates the interplay among two tumor cell phenotypes, a necrotic core and the oxygen distribution. Our simulations reveal the formation of a traveling wave of tumor cells that reproduces the observed histologic patterns of pseudopalisades. Additional simulations of the model equations show that preventing the collapse of tumor microvessels leads to slower glioma invasion, a fact that might be exploited for therapeutic purposes.Comment: 29 pages, 9 figure

Combined therapies of antithrombotics and antioxidants delay in silico brain tumor progression

Glioblastoma multiforme, the most frequent type of primary brain tumor, is a rapidly evolving and spatially heterogeneous high-grade astrocytoma that presents areas of necrosis, hypercellularity and microvascular hyperplasia. The aberrant vasculature leads to hypoxic areas and results in an increase of the oxidative stress selecting for more invasive tumor cell phenotypes. In our study we assay in silico different therapeutic approaches which combine antithrombotics, antioxidants and standard radiotherapy. To do so, we have developed a biocomputational model of glioblastoma multiforme that incorporates the spatio-temporal interplay among two glioma cell phenotypes corresponding to oxygenated and hypoxic cells, a necrotic core and the local vasculature whose response evolves with tumor progression. Our numerical simulations predict that suitable combinations of antithrombotics and antioxidants may diminish, in a synergetic way, oxidative stress and the subsequent hypoxic response. This novel therapeutical strategy, with potentially low or no toxicity, might reduce tumor invasion and further sensitize glioblastoma multiforme to conventional radiotherapy or other cytotoxic agents, hopefully increasing median patient overall survival time.Comment: 8 figure

Functionalised graphene sheets as effective high dielectric constant fillers

A new functionalised graphene sheet (FGS) filled poly(dimethyl)siloxane insulator nanocomposite has been developed with high dielectric constant, making it well suited for applications in flexible electronics. The dielectric permittivity increased tenfold at 10 Hz and 2 wt.% FGS, while preserving low dielectric losses and good mechanical properties. The presence of functional groups on the graphene sheet surface improved the compatibility nanofiller/polymer at the interface, reducing the polarisation process. This study demonstrates that functionalised graphene sheets are ideal nanofillers for the development of new polymer composites with high dielectric constant values

Delay effects in the response of low-grade gliomas to radiotherapy: a mathematical model and its therapeutical implications

Low-grade gliomas (LGGs) are a group of primary brain tumours usually encountered in young patient populations. These tumours represent a difficult challenge because many patients survive a decade or more and may be at a higher risk for treatment-related complications. Specifically, radiation therapy is known to have a relevant effect on survival but in many cases it can be deferred to avoid side effects while maintaining its beneficial effect. However, a subset of LGGs manifests more aggressive clinical behaviour and requires earlier intervention. Moreover, the effectiveness of radiotherapy depends on the tumour characteristics. Recently Pallud et al. (2012. Neuro-Oncology, 14, 1-10) studied patients with LGGs treated with radiation therapy as a first-line therapy and obtained the counterintuitive result that tumours with a fast response to the therapy had a worse prognosis than those responding late. In this paper, we construct a mathematical model describing the basic facts of glioma progression and response to radiotherapy. The model provides also an explanation to the observations of Pallud et al. Using the model, we propose radiation fractionation schemes that might be therapeutically useful by helping to evaluate tumour malignancy while at the same time reducing the toxicity associated to the treatmen

Potential of alternate wetting and drying irrigation practices for the mitigation of ghg emissions from rice fields: Two cases in central luzon (philippines)

Reducing methane (CH$_{4}$) emission from paddy rice production is an important target for many Asian countries in order to comply with their climate policy commitments. National greenhouse gas (GHG) inventory approaches like the Tier-2 approach of the Intergovernmental Panel on Climate Change (IPCC) are useful to assess country-scale emissions from the agricultural sector. In paddy rice, alternate wetting and drying (AWD) is a promising and well-studied water management technique which, as shown in experimental studies, can effectively reduce CH$_{4}$) emissions. However, so far little is known about GHG emission rates under AWD when the technique is fully controlled by farmers. This study assesses CH$_{4}$) and nitrous oxide (N$_{2}$)O) fluxes under continuous flooded (CF) and AWD treatments for seven subsequent seasons on farmers’ fields in a pumped irrigation system in Central Luzon, Philippines. Under AWD management, CH$_{4}$) emissions were substantially reduced (73% in dry season (DS), 21% in wet season (WS)). In all treatments, CH$_{4}$) is the major contributor to the total GHG emission and is, thus, identified as the driving force to the global warming potential (GWP). The contribution of N$_{2}$)O emissions to the GWP was higher in CF than in AWD, however, these only offset 15% of the decrease in CH$_{4}$) emission and, therefore, did not jeopardize the strong reduction in the GWP. The study proves the feasibility of AWD under farmers’ management as well as the intended mitigation effect. Resulting from this study, it is recommended to incentivize dissemination strategies in order to improve the effectiveness of mitigation initiatives. A comparison of single CH$_{4}$) emissions to calculated emissions with the IPCC Tier-2 inventory approach identified that, although averaged values showed a sufficient degree of accuracy, fluctuations for single measurement points have high variation which limit the use of the method for field-level assessments

Functional imaging in radiation therapy planning for head and neck cancer

Functional imaging and its application to radiotherapy (RT) is a rapidly expanding field with new modalities and techniques constantly developing and evolving. As technologies improve, it will be important to pay attention to their implementation. This review describes the main achievements in the field of head and neck cancer (HNC) with particular remarks on the unsolved problems

A positive cooperativity binding model between Ly49 natural killer cell receptors and the viral immunoevasin m157: kinetic and thermodynamic studies

Natural killer (NK) cells discriminate between healthy and virally infected or transformed cells using diverse surface receptors that are both activating and inhibitory. Among them, the homodimeric Ly49 NK receptors, which can adopt two distinct conformations (backfolded and extended), are of particular importance for detecting cells infected with mouse cytomegalovirus (CMV) via recognition of the viral immunoevasin m157. The interaction of m157 with activating (Ly49H) and inhibitory (Ly49I) receptors governs the spread of mouseCMV.Wecarried out kinetic and thermodynamic experiments to elucidate the Ly49/m157 binding mechanism. Combining surface plasmon resonance, fluorescence anisotropy, and circular dichroism (CD), we determined that the best model to describe both the Ly49H/m157 and Ly49I/m157 interactions is a conformational selection mechanism where only the extended conformation of Ly49 (Ly49*) is able to bind the first m157 ligand followed by binding of the Ly49*/m157 complex to the second m157. The interaction is characterized by strong positive cooperativity such that the second m157 binds the Ly49 homodimer with a 1000-fold higher sequential constant than the first m157 (108 versus 105 M-1). Using far-UV CD, we obtained evidence for a conformational change in Ly49 upon binding m157 that could explain the positive cooperativity. The rate-limiting step of the overall mechanism is a conformational transition in Ly49 from its backfolded to extended form. The global thermodynamic parameters from the initial state (backfolded Ly49 and m157) to the final state (Ly49*/(m157)2) are characterized by an unfavorable enthalpy that is compensated by a favorable entropy, making the interaction spontaneous.Fil: Romasanta, Pablo Nicolas. Consejo Nacional de Investigaciones Cientiâ­ficas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Estudios de la Inmunidad Humoral "profesor R. A. Margni"; ArgentinaFil: Curto, Lucrecia María. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Fisicoquímica Biológicas; ArgentinaFil: Urtasun, Nicolás. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; ArgentinaFil: Sarratea, Maria Belén. Consejo Nacional de Investigaciones Cientiâ­ficas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Estudios de la Inmunidad Humoral "profesor R. A. Margni"; ArgentinaFil: Chiappini, Santiago Andrés. Consejo Nacional de Investigaciones Cientiâ­ficas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Estudios de la Inmunidad Humoral "profesor R. A. Margni"; ArgentinaFil: Miranda, Maria Victoria. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; ArgentinaFil: Delfino, Jose Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Fisicoquímica Biológicas; ArgentinaFil: Mariuzza, Roy A.. University Of Maryland. Biotechnology Institute; Estados UnidosFil: Fernández, Marisa Mariel. Consejo Nacional de Investigaciones Cientiâ­ficas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Estudios de la Inmunidad Humoral "profesor R. A. Margni"; ArgentinaFil: Malchiodi, Emilio Luis. Consejo Nacional de Investigaciones Cientiâ­ficas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Estudios de la Inmunidad Humoral "profesor R. A. Margni"; Argentin

Graphene materials with different structures prepared from the same graphite by the Hummers and Brodie methods

[EN] Graphene materials containing different functional groups were prepared from a natural graphite, by means of two different oxidation methods (Hummers and Brodie). It was observed that the differences in the structure of the resultant graphite oxides (GOs) greatly affect the structure of the graphenes resulting from their thermal exfoliation/reduction. Although the oxidation of the graphite was more effective with the modified Hummers method than with Brodie’s method (C/O of 1.8 vs 2.9, as determined by XPS), the former generated a lower residual oxygen content after thermal exfoliation/reduction and a better reconstruction of the 2D graphene structure (with fewer defects). This is explained by the presence of conjugated epoxy and hydroxyl groups in the GO obtained by Brodie’s method, which upon thermal treatment, lead to the incorporation of oxygen into the carbon lattice preventing its complete restoration. Additionally, graphene materials obtained with Brodie’s method exhibit, in general, smaller sheet size and larger surface area.The authors thank MICINN and European Union (CONSOLIDER INGENIO 2010, Ref. CSD2009-00050, MAT2010-16194) for their financial support. Dr. Patricia Alvarez thanks MICINN for her Ramon y Cajal contract.Peer reviewe

Towards materials with enhanced electro-mechanical response: CaCu3Ti4O12-polydimethylsiloxane composites

We describe a straightforward production pathway of polymer matrix composites with increased dielectric constant for dielectric elastomer actuators (DEAs). Up to date, the approach of using composites made of high dielectric constant ceramics and insulating polymers has not evidenced any improvement in the performance of DEA devices, mainly as a consequence of the ferroelectric nature of the employed ceramics. We propose here an unexplored alternative to these traditional fillers, introducing calcium copper titanate (CCTO) CaCu3Ti4O12, which has a giant dielectric constant making it very suitable for capacitive applications. All CCTO-polydimethylsiloxane (PDMS) composites developed display an improved electro-mechanical performance. The largest actuation improvement was achieved for the composite with 5.1 vol% of CCTO, having an increment in the actuation strain of about 100% together with a reduction of 25% in the electric field compared to the raw PDMS matrix