Comprehensive analysis of T cell leukemia signals reveals heterogeneity in the PI3 kinase-Akt pathway and limitations of PI3 kinase inhibitors as monotherapy.

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic cancer. Poly-chemotherapy with cytotoxic and genotoxic drugs causes substantial toxicity and more specific therapies targeting the underlying molecular lesions are highly desired. Perturbed Ras signaling is prevalent in T-ALL and occurs via oncogenic RAS mutations or through overexpression of the Ras activator RasGRP1 in ~65% of T-ALL patients. Effective small molecule inhibitors for either target do not currently exist. Genetic and biochemical evidence link phosphoinositide 3-kinase (PI3K) signals to T-ALL, PI3Ks are activated by Ras-dependent and Ras-independent mechanisms, and potent PI3K inhibitors exist. Here we performed comprehensive analyses of PI3K-Akt signaling in T-ALL with a focus on class I PI3K. We developed a multiplex, multiparameter flow cytometry platform with pan- and isoform-specific PI3K inhibitors. We find that pan-PI3K and PI3K γ-specific inhibitors effectively block basal and cytokine-induced PI3K-Akt signals. Despite such inhibition, GDC0941 (pan-PI3K) or AS-605240 (PI3Kγ-specific) as single agents did not efficiently induce death in T-ALL cell lines. Combination of GDC0941 with AS-605240, maximally targeting all p110 isoforms, exhibited potent synergistic activity for clonal T-ALL lines in vitro, which motivated us to perform preclinical trials in mice. In contrast to clonal T-ALL lines, we used a T-ALL cancer model that recapitulates the multi-step pathogenesis and inter- and intra-tumoral genetic heterogeneity, a hallmark of advanced human cancers. We found that the combination of GDC0941 with AS-605240 fails in such trials. Our results reveal that PI3K inhibitors are a promising avenue for molecular therapy in T-ALL, but predict the requirement for methods that can resolve biochemical signals in heterogeneous cell populations so that combination therapy can be designed in a rational manner

Effect of uniaxial stress on ferroelectric behavior of (Bi1/2Na1/2)TiO3-based lead-free piezoelectric ceramics

Prior studies have shown that a field-induced ferroelectricity in ceramics with general chemical formula (1-x-y) (Bi1/2 Na1/2) TiO3 -x BaTiO3 -y (K0.5 Na0.5) NbO3 and a very low remanent strain can produce very large piezoelectric strains. Here we show that both the longitudinal and transverse strains gradually change with applied electric fields even during the transition from the nonferroelectric to the ferroelectric state, in contrast to known Pb-containing antiferroelectrics. Hence, the volume change and, in turn, the phase transition can be affected using uniaxial compressive stresses, and the effect on ferroelectricity can thus be assessed. It is found that the 0.94 (Bi1/2 Na1/2) TiO3 -0.05 BaTiO3 -0.01 (K0.5 Na0.5) NbO3 ceramic (largely ferroelectric), with a rhombohedral R3c symmetry, displays large ferroelectric domains, significant ferroelastic deformation, and large remanent electrical polarizations even at a 250 MPa compressive stress. In comparison, the 0.91 (Bi1/2 Na1/2) TiO3 -0.07 BaTiO3 -0.02 (K0.5 Na0.5) NbO3 ceramic (largely nonferroelectric) possesses characteristics of a relaxor ferroelectric ceramic, including a pseudocubic structure, limited ferroelastic deformation, and low remanent polarization. The results are discussed with respect of the proposed antiferroelectric nature of the nonferroelectric state.open291

Electric-field-induced antiferroelectric to ferroelectric phase transition in mechanically confined Pb0.99Nb0.02[(Zr0.57Sn0.43)(0.94)Ti-0.06](0.98)O-3

The electric-field-induced phase transition was investigated under mechanical confinements in bulk samples of an antiferroelectric perovskite oxide at room temperature. Profound impacts of mechanical confinements on the phase transition are observed due to the interplay of ferroelasticity and the volume expansion at the transition. The uniaxial compressive prestress delays while the radial compressive prestress suppresses it. The difference is rationalized with a phenomenological model of the phase transition accounting for the mechanical confinement.open241

Concentration or representation : the struggle for popular sovereignty

There is a tension in the notion of popular sovereignty, and the notion of democracy associated with it, that is both older than our terms for these notions themselves and more fundamental than the apparently consensual way we tend to use them today. After a review of the competing conceptions of 'the people' that underlie two very different understandings of democracy, this article will defend what might be called a 'neo-Jacobin' commitment to popular sovereignty, understood as the formulation and imposition of a shared political will. A people's egalitarian capacity to concentrate both its collective intelligence and force, from this perspective, takes priority over concerns about how best to represent the full variety of positions and interests that differentiate and divide a community

Marsilius of Inghen

Marsilius of Inghen, master at the Universities of Paris (1362–1378) and Heidelberg (1386–1396), wrote a number of treatises on logic, natural philosophy and theology popular at many late medieval and early modern universities. He adopted the logico-semantic approach of William of Ockham and John Buridan while at the same time defending the traditional views of Thomas Aquinas and Bonaventure. His thinking sheds light on the discussion between nominalists and realists and allows insight into the changing interests of philosophy and theology, from the critical attitude of many fourteenth-century authors to the search for tradition which was characteristic of the fifteenth century

Marsilius of Inghen

Marsilius of Inghen belonged with William of Ockham and John Buridan to those thinkers who substantially shaped late-medieval Nominalism. He taught in Paris and Heidelberg and left behind a significant number of writings that were used as set texts at many universities in the fifteenth and sixteenth centuries, especially in the German Empire. Characteristic was his rejection of real universals outside the human mind (Realism) and his distinction between the approaches of natural reason and faith. He was also known for his dismissal of the notion of suppositio simplex, his defense of an eleventh category, and his criticism of the Aristotelian theory of motion. His thought was appreciated by humanists and Spanish scholastics

Quantitative comparison between the degree of domain orientation and nonlinear properties of a PZT ceramic during electrical and mechanical loading

The macroscopic electromechanical coupling properties of ferroelectric polycrystals are composed of linear and nonlinear contributions. The nonlinear contribution is typically associated with the extrinsic effects related to the creation and motion of domain walls. To quantitatively compare the macroscopic nonlinear properties of a lead zirconate titanate ceramic and the degree of domain orientation, in-situ neutron and high-energy x-ray diffraction experiments are performed and they provide the domain orientation density as a function of the external electric field and mechanical compression. Furthermore, the macroscopic strain under the application of external electrical and mechanical loads is measured and the nonlinear strain is calculated by means of the linear intrinsic piezoelectric effect and the linear intrinsic elasticity. The domain orientation density and the nonlinear strain show the same dependence on the external load. The scaling factor that relates to the two values is constant and is the same for both electrical and mechanical loadings. © 2011, Cambridge University Pres

Glassy relaxation and excess wing in mode-coupling theory: The dynamic susceptibility of propylene carbonate above and below Tc

We explore the possibility of describing experimental susceptibility spectra of the glass former propylene carbonate with a two-component schematic model of mode-coupling theory (MCT) from above the melting point down to temperatures far below the critical temperature of MCT. By introducing a phenomenological time-dependent hopping rate, the spectra are reproduced in the full frequency and temperature range available. Literature data of dielectric susceptibilities and depolarized Brillouin light-scattering spectra are combined with our measurements of photon correlation spectroscopy to cover up to 18 decades in frequency of spectra for two different dynamical variables. A consistent description of all data sets is obtained by adjusting only a few physically motivated parameters. In particular the excess wing or slow β-relaxation commonly observed in the susceptibility spectra can consistently be modeled as originating from a coupling of the individual experimental probe correlator to the collective density fluctuations