2,425 research outputs found
Anti-tubulin drugs conjugated to anti-ErbB antibodies selectively radiosensitize.
Tumour resistance to radiotherapy remains a barrier to improving cancer patient outcomes. To overcome radioresistance, certain drugs have been found to sensitize cells to ionizing radiation (IR). In theory, more potent radiosensitizing drugs should increase tumour kill and improve patient outcomes. In practice, clinical utility of potent radiosensitizing drugs is curtailed by off-target side effects. Here we report potent anti-tubulin drugs conjugated to anti-ErbB antibodies selectively radiosensitize to tumours based on surface receptor expression. While two classes of potent anti-tubulins, auristatins and maytansinoids, indiscriminately radiosensitize tumour cells, conjugating these potent anti-tubulins to anti-ErbB antibodies restrict their radiosensitizing capacity. Of translational significance, we report that a clinically used maytansinoid ADC, ado-trastuzumab emtansine (T-DM1), with IR prolongs tumour control in target expressing HER2+ tumours but not target negative tumours. In contrast to ErbB signal inhibition, our findings establish an alternative therapeutic paradigm for ErbB-based radiosensitization using antibodies to restrict radiosensitizer delivery
On the algebraic structure of conditional events: 13th European conference, ECSQARU 2015, CompiĂšgne, France, July 15-17, 2015.
This paper initiates an investigation of conditional measures as simple measures on conditional events. As a first step towards this end we investigate the construction of conditional algebras which allow us to distinguish between the logical properties of conditional events and those of the conditional measures which we can be attached to them. This distinction, we argue, helps us clarifying both concepts
A Brownian particle in a microscopic periodic potential
We study a model for a massive test particle in a microscopic periodic
potential and interacting with a reservoir of light particles. In the regime
considered, the fluctuations in the test particle's momentum resulting from
collisions typically outweigh the shifts in momentum generated by the periodic
force, and so the force is effectively a perturbative contribution. The
mathematical starting point is an idealized reduced dynamics for the test
particle given by a linear Boltzmann equation. In the limit that the mass ratio
of a single reservoir particle to the test particle tends to zero, we show that
there is convergence to the Ornstein-Uhlenbeck process under the standard
normalizations for the test particle variables. Our analysis is primarily
directed towards bounding the perturbative effect of the periodic potential on
the particle's momentum.Comment: 60 pages. We reorganized the article and made a few simplifications
of the conten
Shear Modes, Criticality and Extremal Black Holes
We consider a (2+1)-dimensional field theory, assumed to be holographically
dual to the extremal Reissner-Nordstrom AdS(4) black hole background, and
calculate the retarded correlators of charge (vector) current and
energy-momentum (tensor) operators at finite momentum and frequency. We show
that, similar to what was observed previously for the correlators of scalar and
spinor operators, these correlators exhibit emergent scaling behavior at low
frequency. We numerically compute the electromagnetic and gravitational
quasinormal frequencies (in the shear channel) of the extremal
Reissner-Nordstrom AdS(4) black hole corresponding to the spectrum of poles in
the retarded correlators. The picture that emerges is quite simple: there is a
branch cut along the negative imaginary frequency axis, and a series of
isolated poles corresponding to damped excitations. All of these poles are
always in the lower half complex frequency plane, indicating stability. We show
that this analytic structure can be understood as the proper limit of finite
temperature results as T is taken to zero holding the chemical potential fixed.Comment: 28 pages, 7 figures, added reference
Poloxomer 188 Has a Deleterious Effect on Dystrophic Skeletal Muscle Function
Duchenne muscular dystrophy (DMD) is an X-linked, fatal muscle wasting disease for which there is currently no cure and limited palliative treatments. Poloxomer 188 (P188) is a tri-block copolymer that has been proposed as a potential treatment for cardiomyopathy in DMD patients. Despite the reported beneficial effects of P188 on dystrophic cardiac muscle function, the effects of P188 on dystrophic skeletal muscle function are relatively unknown. Mdx mice were injected intraperitoneally with 460 mg/kg or 30 mg/kg P188 dissolved in saline, or saline alone (control). The effect of single-dose and 2-week daily treatment was assessed using a muscle function test on the Tibialis Anterior (TA) muscle in situ in anaesthetised mice. The test comprises a warm up, measurement of the force-frequency relationship and a series of eccentric contractions with a 10% stretch that have previously been shown to cause a drop in maximum force in mdx mice. After 2 weeks of P188 treatment at either 30 or 460 mg/kg/day the drop in maximum force produced following eccentric contractions was significantly greater than that seen in saline treated control mice (Pâ=â0.0001). Two week P188 treatment at either dose did not significantly change the force-frequency relationship or maximum isometric specific force produced by the TA muscle. In conclusion P188 treatment increases susceptibility to contraction-induced injury following eccentric contractions in dystrophic skeletal muscle and hence its suitability as a potential therapeutic for DMD should be reconsidered
Degenerate Rotating Black Holes, Chiral CFTs and Fermi Surfaces I - Analytic Results for Quasinormal Modes
In this work we discuss charged rotating black holes in
that degenerate to extremal black holes with zero entropy. These black holes
have scaling properties between charge and angular momentum similar to those of
Fermi surface operators in a subsector of SYM. We add a
massless uncharged scalar to the five dimensional supergravity theory, such
that it still forms a consistent truncation of the type IIB ten dimensional
supergravity and analyze its quasinormal modes. Separating the equation of
motion to a radial and angular part, we proceed to solve the radial equation
using the asymptotic matching expansion method applied to a Heun equation with
two nearby singularities. We use the continued fraction method for the angular
Heun equation and obtain numerical results for the quasinormal modes. In the
case of the supersymmetric black hole we present some analytic results for the
decay rates of the scalar perturbations. The spectrum of quasinormal modes
obtained is similar to that of a chiral 1+1 CFT, which is consistent with the
conjectured field-theoretic dual. In addition, some of the modes can be found
analytically.Comment: 41 pages, 1 figure, LaTeX; v2: typos corrected, references adde
The logic of the future in quantum theory
According to quantum mechanics, statements about the future made by sentient beings like us are, in general, neither true nor false; they must satisfy a many-valued logic. I propose that the truth value of such a statement should be identified with the probability that the event it describes will occur. After reviewing the history of related ideas in logic, I argue that it gives an understanding of probability which is particularly satisfactory for use in quantum mechanics. I construct a lattice of future-tense propositions, with truth values in the interval , and derive logical properties of these truth values given by the usual quantum-mechanical formula for the probability of a history
Regional respiratory time constants during lung recruitment in high-frequency oscillatory ventilated preterm infants
To assess the regional respiratory time constants of lung volume changes during stepwise lung recruitment before and after surfactant treatment in high-frequency oscillatory ventilated preterm infants. A stepwise oxygenation-guided recruitment procedure was performed before and after surfactant treatment in high-frequency oscillatory ventilated preterm infants. Electrical impedance tomography was used to continuously record changes in lung volume during the recruitment maneuver. Time constants were determined for all incremental and decremental pressure steps, using one-phase exponential decay curve fitting. Data were analyzed for the whole cross section of the chest and the ventral and dorsal lung regions separately. Before surfactant treatment, the time constants of the incremental pressure steps were significantly longer (median 27.3 s) than those in the decremental steps (16.1 s). Regional analysis showed only small differences between the ventral and dorsal lung regions. Following surfactant treatment, the time constants during decremental pressure steps almost tripled to 44.3 s. Furthermore, the time constants became significantly (p <0.01) longer in the dorsal (61.2 s) than into the ventral (40.3 s) lung region. Lung volume stabilization during stepwise oxygenation-guided lung recruitment in high-frequency oscillatory ventilated preterm infants with respiratory distress syndrome is usually completed within 5 min and is dependent on the position of ventilation on the pressure volume curve, the surfactant status, and the region of interest of the lun
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