Cell Line Derived 5-FU and Irinotecan Drug-Sensitivity Profiles Evaluated in Adjuvant Colon Cancer Trial Data.

This study evaluates whether gene signatures for chemosensitivity for irinotecan and 5-fluorouracil (5-FU) derived from in vitro grown cancer cell lines can predict clinical sensitivity to these drugs. To test if an irinotecan signature and a SN-38 signature could identify patients who benefitted from the addition of irinotecan to 5-FU, we used gene expression profiles based on cell lines and clinical tumor material. These profiles were applied to expression data obtained from pretreatment formalin fixed paraffin embedded (FFPE) tumor tissue from 636 stage III colon cancer patients enrolled in the PETACC-3 prospective randomized clinical trial. A 5-FU profile developed similarly was assessed by comparing the PETACC-3 cohort with a cohort of 359 stage II colon cancer patients who underwent surgery but received no adjuvant therapy. There was no statistically significant association between the irinotecan or SN-38 profiles and benefit from irinotecan. The 5-FU sensitivity profile showed a statistically significant association with relapse free survival (RFS) (hazard ratio (HR) = 0.54 (0.41-0.71), p<1e-05) and overall survival (HR = 0.47 (0.34-0.63), p<1e-06) in the PETACC-3 subpopulation. The effect of the 5-FU profile remained significant in a multivariable Cox Proportional Hazards model, adjusting for several relevant clinicopathological parameters. No statistically significant effect of the 5-FU profile was observed in the untreated cohort of 359 patients (relapse free survival, p = 0.671). The irinotecan predictor had no predictive value. The 5-FU predictor was prognostic in stage III patients in PETACC-3 but not in stage II patients with no adjuvant therapy. This suggests a potential predictive ability of the 5-FU sensitivity profile to identify colon cancer patients who may benefit from 5-FU, however, any biomarker predicting benefit for adjuvant 5-FU must be rigorously evaluated in independent cohorts. Given differences between the two study cohorts, the present results should be further validated

Analytical approximation of the stress-energy tensor of a quantized scalar field in static spherically symmetric spacetimes

Analytical approximations for ${}$ and ${}$ of a quantized scalar field in static spherically symmetric spacetimes are obtained. The field is assumed to be both massive and massless, with an arbitrary coupling $\xi$ to the scalar curvature, and in a zero temperature vacuum state. The expressions for ${}$ and ${}$ are divided into low- and high-frequency parts. The contributions of the high-frequency modes to these quantities are calculated for an arbitrary quantum state. As an example, the low-frequency contributions to ${}$ and ${}$ are calculated in asymptotically flat spacetimes in a quantum state corresponding to the Minkowski vacuum (Boulware quantum state). The limits of the applicability of these approximations are discussed.Comment: revtex4, 17 pages; v2: three references adde

Some general properties of the renormalized stress-energy tensor for static quantum states on (n+1)-dimensional spherically symmetric black holes

We study the renormalized stress-energy tensor (RSET) for static quantum states on (n+1)-dimensional, static, spherically symmetric black holes. By solving the conservation equations, we are able to write the stress-energy tensor in terms of a single unknown function of the radial co-ordinate, plus two arbitrary constants. Conditions for the stress-energy tensor to be regular at event horizons (including the extremal and ``ultra-extremal'' cases) are then derived using generalized Kruskal-like co-ordinates. These results should be useful for future calculations of the RSET for static quantum states on spherically symmetric black hole geometries in any number of space-time dimensions.Comment: 9 pages, no figures, RevTeX4, references added, accepted for publication in General Relativity and Gravitatio

Opto-mechanical measurement of micro-trap via nonlinear cavity enhanced Raman scattering spectrum

High-gain resonant nonlinear Raman scattering on trapped cold atoms within a high-fineness ring optical cavity is simply explained under a nonlinear opto-mechanical mechanism, and a proposal using it to detect frequency of micro-trap on atom chip is presented. The enhancement of scattering spectrum is due to a coherent Raman conversion between two different cavity modes mediated by collective vibrations of atoms through nonlinear opto-mechanical couplings. The physical conditions of this technique are roughly estimated on Rubidium atoms, and a simple quantum analysis as well as a multi-body semiclassical simulation on this nonlinear Raman process is conducted.Comment: 7 pages, 2 figure

Combined deletion of Glut1 and Glut3 impairs lung adenocarcinoma growth.

Glucose utilization increases in tumors, a metabolic process that is observed clinically by <sup>18</sup> F-fluorodeoxyglucose positron emission tomography ( <sup>18</sup> F-FDG-PET). However, is increased glucose uptake important for tumor cells, and which transporters are implicated in vivo? In a genetically-engineered mouse model of lung adenocarcinoma, we show that the deletion of only one highly expressed glucose transporter, Glut1 or Glut3, in cancer cells does not impair tumor growth, whereas their combined loss diminishes tumor development. <sup>18</sup> F-FDG-PET analyses of tumors demonstrate that Glut1 and Glut3 loss decreases glucose uptake, which is mainly dependent on Glut1. Using <sup>13</sup> C-glucose tracing with correlated nanoscale secondary ion mass spectrometry (NanoSIMS) and electron microscopy, we also report the presence of lamellar body-like organelles in tumor cells accumulating glucose-derived biomass, depending partially on Glut1. Our results demonstrate the requirement for two glucose transporters in lung adenocarcinoma, the dual blockade of which could reach therapeutic responses not achieved by individual targeting

The Nkx6.1 homeodomain transcription factor suppresses glucagon expression and regulates glucose-stimulated insulin secretion in islet beta cells

We have previously described rat insulinoma INS-1 derived cell lines with robust or poor glucose-stimulated insulin secretion (GSIS). In the current study, we have further resolved these lines into three classes: class 1, glucose-unresponsive glucagon-expressing; class 2, glucose-unresponsive glucagon-negative; and class 3, glucose-responsive glucagon-negative. The transcription factor Nkx2.2 was expressed with relative abundance of 3.3, 1.0, and 1.0 in class 1, class 2, and class 3 cells, respectively, whereas Nkx6.1 expression had the opposite trend: 1.0, 2.6, and 6.4 in class 1, class 2, and class 3 cells, respectively. In class 1 cells, overexpressed Nkx6.1 suppressed glucagon expression but did not affect the levels of several other prominent beta cell transcription factors. RNA interference (RNAi)-mediated suppression of Nkx6.1 in class 3 cells resulted in a doubling of glucagon mRNA, with no effect on Pdx1 levels, whereas suppression of Pdx1 in class 3 cells caused a 12-fold increase in glucagon transcript levels, demonstrating independent effects of Nkx6.1 and Pdx1 on glucagon expression in beta cell lines. RNAi-mediated suppression of Nkx6.1 expression in class 3 cells also caused a decrease in GSIS from 13.9- to 3.7-fold, whereas suppression of Pdx1 reduced absolute amounts of insulin secretion without affecting fold response. Finally, RNAi-mediated suppression of Nkx6.1 mRNA in primary rat islets was accompanied by a significant decrease in GSIS relative to control cells. In sum, our studies have revealed roles for Nkx6.1 in suppression of glucagon expression and control of GSIS in islet beta cells

Velocity-force characteristics of an interface driven through a periodic potential

We study the creep dynamics of a two-dimensional interface driven through a periodic potential using dynamical renormalization group methods. We find that the nature of weak-drive transport depends qualitatively on whether the temperature $T$ is above or below the equilibrium roughening transition temperature $T_c$. Above $T_c$, the velocity-force characteristics is Ohmic, with linear mobility exhibiting a jump discontinuity across the transition. For $T \le T_c$, the transport is highly nonlinear, exhibiting an interesting crossover in temperature and weak external force $F$. For intermediate drive, $F>F_*$, we find near $T_c^{-}$ a power-law velocity-force characteristics $v(F)\sim F^\sigma$, with $\sigma-1\propto \tilde{t}$, and well-below $T_c$, $v(F)\sim e^{-(F_*/F)^{2\tilde{t}}}$, with $\tilde{t}=(1-T/T_c)$. In the limit of vanishing drive ($F\ll F_*$) the velocity-force characteristics crosses over to $v(F)\sim e^{-(F_0/F)}$, and is controlled by soliton nucleation.Comment: 18 pages, submitted to Phys. Rev.

Non-monotonic variation with salt concentration of the second virial coefficient in protein solutions

The osmotic virial coefficient $B_2$ of globular protein solutions is calculated as a function of added salt concentration at fixed pH by computer simulations of the ``primitive model''. The salt and counter-ions as well as a discrete charge pattern on the protein surface are explicitly incorporated. For parameters roughly corresponding to lysozyme, we find that $B_2$ first decreases with added salt concentration up to a threshold concentration, then increases to a maximum, and then decreases again upon further raising the ionic strength. Our studies demonstrate that the existence of a discrete charge pattern on the protein surface profoundly influences the effective interactions and that non-linear Poisson Boltzmann and Derjaguin-Landau-Verwey-Overbeek (DLVO) theory fail for large ionic strength. The observed non-monotonicity of $B_2$ is compared to experiments. Implications for protein crystallization are discussed.Comment: 43 pages, including 17 figure