Combination of Vandetanib, Radiotherapy, and Irinotecan in the LoVo Human Colorectal Cancer Xenograft Model

Purpose: The tumor growth kinetics of the human LoVo colorectal xenograft model was assessed in response to vandetanib, an orally available receptor tyrosine kinase inhibitor, radiotherapy (RT), or irinotecan (CPT-11), as single therapies and in combination. Methods and Materials: LoVo cells were injected subcutaneously into the right hind limb (5x106 cells in 100μL phosphate-buffered saline) of athymic NCR NUM mice and tumors were grown to a volume of 200–300mm3 before treatment. Vandetanib was administered at 50 mg/kg daily orally for 14 days starting on Day 1. RT was given as three fractions (3x3 Gy) on Days 1, 2, and 3. CPT-11 was given at 15 mg/kg intraperitoneally on Days 1 and 3. Tumor volumes were measured on a daily basis and calculated by measuring tumor diameters with digital calipers in two orthogonal dimensions. Results: All three single treatments (vandetanib, CPT-11, and radiation) significantly slowed LoVo colorectal tumor growth. Vandetanib significantly increased the antitumor effects of CPT-11 and radiation when given in combination with either of these treatments. These treatment combinations resulted in a slow tumor growth rate during the 2 weeks of vandetanib administration. The triple combination of vandetanib, CPT-11, and radiation produced the most marked improvement in response as observed by measurable shrinkage of tumors during the first week of treatment. Conclusions: The tumor growth delay kinetics observed in this study of the LoVo colorectal model suggest concurrent and sustained post-sequencing of vandetanib with cytotoxic therapy may be beneficial in tumors of this type. Reprinted from International Journal of Radiation Oncology*Biology*Physics, Volume 75, Edition 3, Wachsberger P, Burd R, Ryan A, Daskalakis C, Dicker AP: “Combination of Vandetanib, Radiotherapy, and Irinotecan in the LoVo Human Colorectal Cancer Xenograft Model”, pages 843-853, November 1, 2009

Chaotic Friedmann-Robertson-Walker Cosmology

We show that the dynamics of a spatially closed Friedmann - Robertson - Walker Universe conformally coupled to a real, free, massive scalar field, is chaotic, for large enough field amplitudes. We do so by proving that this system is integrable under the adiabatic approximation, but that the corresponding KAM tori break up when non adiabatic terms are considered. This finding is confirmed by numerical evaluation of the Lyapunov exponents associated with the system, among other criteria. Chaos sets strong limitations to our ability to predict the value of the field at the Big Crunch, from its given value at the Big Bang. (Figures available on request)Comment: 28 pages, 11 figure

Axially Symmetric Bianchi I Yang-Mills Cosmology as a Dynamical System

We construct the most general form of axially symmetric SU(2)-Yang-Mills fields in Bianchi cosmologies. The dynamical evolution of axially symmetric YM fields in Bianchi I model is compared with the dynamical evolution of the electromagnetic field in Bianchi I and the fully isotropic YM field in Friedmann-Robertson-Walker cosmologies. The stochastic properties of axially symmetric Bianchi I-Einstein-Yang-Mills systems are compared with those of axially symmetric YM fields in flat space. After numerical computation of Liapunov exponents in synchronous (cosmological) time, it is shown that the Bianchi I-EYM system has milder stochastic properties than the corresponding flat YM system. The Liapunov exponent is non-vanishing in conformal time.Comment: 18 pages, 6 Postscript figures, uses amsmath,amssymb,epsfig,verbatim, to appear in CQ

Superstring Cosmology

Aspects of superstring cosmology are reviewed with an emphasis on the cosmological implications of duality symmetries in the theory. The string effective actions are summarized and toroidal compactification to four dimensions reviewed. Global symmetries that arise in the compactification are discussed and the duality relationships between the string effective actions are then highlighted. Higher-dimensional Kasner cosmologies are presented and interpreted in both string and Einstein frames, and then given in dimensionally reduced forms. String cosmologies containing both non-trivial Neveu-Schwarz/Neveu-Schwarz and Ramond-Ramond fields are derived by employing the global symmetries of the effective actions. Anisotropic and inhomogeneous cosmologies in four-dimensions are also developed. The review concludes with a detailed analysis of the pre-big bang inflationary scenario. The generation of primordial spectra of cosmological perturbations in such a scenario is discussed. Possible future directions offered in the Horava-Witten theory are outlined.Comment: 161 pages, latex with epsf, 15 figures. Minor changes, additional references and figures. Version to appear in Physics Report

G4 motifs correlate with promoter-proximal transcriptional pausing in human genes

The RNA Pol II transcription complex pauses just downstream of the promoter in a significant fraction of human genes. The local features of genomic structure that contribute to pausing have not been defined. Here, we show that genes that pause are more G-rich within the region flanking the transcription start site (TSS) than RefSeq genes or non-paused genes. We show that enrichment of binding motifs for common transcription factors, such as SP1, may account for G-richness upstream but not downstream of the TSS. We further show that pausing correlates with the presence of a GrIn1 element, an element bearing one or more G4 motifs at the 5′-end of the first intron, on the non-template DNA strand. These results suggest potential roles for dynamic G4 DNA and G4 RNA structures in cis-regulation of pausing, and thus genome-wide regulation of gene expression, in human cells

Numerical Approaches to Spacetime Singularities

This Living Review updates a previous version which its itself an update of a review article. Numerical exploration of the properties of singularities could, in principle, yield detailed understanding of their nature in physically realistic cases. Examples of numerical investigations into the formation of naked singularities, critical behavior in collapse, passage through the Cauchy horizon, chaos of the Mixmaster singularity, and singularities in spatially inhomogeneous cosmologies are discussed.Comment: 51 pages, 6 figures may be found in online version: Living Rev. Relativity 2002-1 at www.livingreviews.or

Chaos, decoherence and quantum cosmology

In this topical review we discuss the connections between chaos, decoherence and quantum cosmology. We understand chaos as classical chaos in systems with a finite number of degrees of freedom, decoherence as environment induced decoherence and quantum cosmology as the theory of the Wheeler - DeWitt equation or else the consistent history formulation thereof, first in mini super spaces and later through its extension to midi super spaces. The overall conclusion is that consideration of decoherence is necessary (and probably sufficient) to sustain an interpretation of quantum cosmology based on the Wave function of the Universe adopting a Wentzel - Kramers - Brillouin form for large Universes, but a definitive account of the semiclassical transition in classically chaotic cosmological models is not available in the literature yet.Comment: 40 page

Presbyopia:Effectiveness of correction strategies

Presbyopia is a global problem affecting over a billion people worldwide. The prevalence of unmanaged presbyopia is as high as 50% of those over 50 years of age in developing world populations due to a lack of awareness and accessibility to affordable treatment, and is even as high as 34% in developed countries. Definitions of presbyopia are inconsistent and varied, so we propose a redefinition that states “presbyopia occurs when the physiologically normal age-related reduction in the eye's focusing range reaches a point, when optimally corrected for distance vision, that the clarity of vision at near is insufficient to satisfy an individual's requirements”. Presbyopia is inevitable if one lives long enough, but intrinsic and extrinsic risk factors including cigarette smoking, pregnancy history, hyperopic or astigmatic refractive error, ultraviolet radiation, female sex (although accommodation is similar to males), hotter climates and some medical conditions such as diabetes can accelerate the onset of presbyopic symptoms. Whilst clinicians can ameliorate the symptoms of presbyopia with near vision spectacle correction, bifocal and progressive spectacle lenses, monovision, translating or multifocal contact lenses, monovision, extended depth of focus, multifocal (refractive, diffractive and asymmetric designs) or ‘accommodating’ intraocular lenses, corneal inlays, scleral expansion, laser refractive surgery (corneal monovision, corneal shrinkage, corneal multifocal profiles and lenticular softening), pharmacologic agents, and electro-stimulation of the ciliary muscle, none fully overcome presbyopia in all patients. While the restoration of natural accommodation or an equivalent remains elusive, guidance is gives on presbyopic correction evaluation techniques