Stability analysis of a hyperbolic stochastic Galerkin formulation for the Aw-Rascle-Zhang model with relaxation

We investigate the propagation of uncertainties in the Aw-Rascle-Zhang model, which belongs to a class of second order traffic flow models described by a system of nonlinear hyperbolic equations. The stochastic quantities are expanded in terms of wavelet-based series expansions. Then, they are projected to obtain a deterministic system for the coefficients in the truncated series. Stochastic Galerkin formulations are presented in conservative form and for smooth solutions also in the corresponding non-conservative form. This allows to obtain stabilization results, when the system is relaxed to a first-order model. Computational tests illustrate the theoretical results

Establishing operant conflict tests for the translational study of anxiety in mice

Rationale In conflict-based anxiety tests, rodents decide between actions with simultaneous rewarding and aversive outcomes. In humans, computerised operant conflict tests have identified response choice, latency, and vigour as distinct behavioural components. Animal operant conflict tests for measurement of these components would facilitate translational study. Objectives In C57BL/6 mice, two operant conflict tests for measurement of response choice, latency, and vigour were established, and effects of chlordiazepoxide (CDZ) thereon investigated. Methods Mice were moderately diet-restricted to increase sucrose reward salience. A 1-lever test required responding under medium-effort reward/threat conditions of variable ratio 2–10 resulting in sucrose at p = 0.7 and footshock at p = 0.3. A 2-lever test mandated a choice between low-effort reward/threat with a fixed-ratio (FR) 2 lever yielding sucrose at p = 0.7 and footshock at p = 0.3 versus high-effort reward/no threat with a FR 20 lever yielding sucrose at p = 1. Results In the 1-lever test, CDZ (7.5 or 15 mg/kg i.p.) reduced post-trial pause (response latency) following either sucrose or footshock and reduced inter-response interval (increased response vigour) after footshock. In the 2-lever test, mice favoured the FR2 lever and particularly at post-reward trials. CDZ increased choice of FR2 and FR20 responding after footshock, reduced response latency overall, and increased response vigour at the FR2 lever and after footshock specifically. Conclusions Mouse operant conflict tests, especially 2-lever choice, allow for the translational study of distinct anxiety components. CDZ influences each component by ameliorating the impact of both previous punishment and potential future punishment

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

Polo-like kinase 1 (PLK1) inhibition suppresses cell growth and enhances radiation sensitivity in medulloblastoma cells

<p>Abstract</p> <p>Background</p> <p>Medulloblastoma is the most common malignant brain tumor in children and remains a therapeutic challenge due to its significant therapy-related morbidity. Polo-like kinase 1 (<it>PLK1</it>) is highly expressed in many cancers and regulates critical steps in mitotic progression. Recent studies suggest that targeting PLK1 with small molecule inhibitors is a promising approach to tumor therapy.</p> <p>Methods</p> <p>We examined the expression of <it>PLK1 </it>mRNA in medulloblastoma tumor samples using microarray analysis. The impact of PLK1 on cell proliferation was evaluated by depleting expression with RNA interference (RNAi) or by inhibiting function with the small molecule inhibitor BI 2536. Colony formation studies were performed to examine the impact of BI 2536 on medulloblastoma cell radiosensitivity. In addition, the impact of depleting <it>PLK1 </it>mRNA on tumor-initiating cells was evaluated using tumor sphere assays.</p> <p>Results</p> <p>Analysis of gene expression in two independent cohorts revealed that <it>PLK1 </it>mRNA is overexpressed in some, but not all, medulloblastoma patient samples when compared to normal cerebellum. Inhibition of PLK1 by RNAi significantly decreased medulloblastoma cell proliferation and clonogenic potential and increased cell apoptosis. Similarly, a low nanomolar concentration of BI 2536, a small molecule inhibitor of PLK1, potently inhibited cell growth, strongly suppressed the colony-forming ability, and increased cellular apoptosis of medulloblastoma cells. Furthermore, BI 2536 pretreatment sensitized medulloblastoma cells to ionizing radiation. Inhibition of PLK1 impaired tumor sphere formation of medulloblastoma cells and decreased the expression of SRY (sex determining region Y)-box 2 (<it>SOX2</it>) mRNA in tumor spheres indicating a possible role in targeting tumor inititiating cells.</p> <p>Conclusions</p> <p>Our data suggest that targeting PLK1 with small molecule inhibitors, in combination with radiation therapy, is a novel strategy in the treatment of medulloblastoma that warrants further investigation.</p

Observation of a low energy nuclear recoil peak in the neutron calibration data of the CRESST-III Experiment

New-generation direct searches for low mass dark matter feature detection thresholds at energies well below 100 eV, much lower than the energies of commonly used X-ray calibration sources. This requires new calibration sources with sub-keV energies. When searching for nuclear recoil signals, the calibration source should ideally cause mono-energetic nuclear recoils in the relevant energy range. Recently, a new calibration method based on the radiative neutron capture on $^{182}$W with subsequent de-excitation via single $\gamma$-emission leading to a nuclear recoil peak at 112 eV was proposed. The CRESST-III dark matter search operated several CaWO$_{4}$-based detector modules with detection thresholds below 100 eV in the past years. We report the observation of a peak around the expected energy of 112 eV in the data of three different detector modules recorded while irradiated with neutrons from different AmBe calibration sources. We compare the properties of the observed peaks with Geant-4 simulations and assess the prospects of using this for the energy calibration of CRESST-III detectors.Comment: 8 pages, 4 figures; submitted to Phys. Rev.