Computational purification of individual tumor gene expression profiles leads to significant improvements in prognostic prediction.

Tumor heterogeneity is a limiting factor in cancer treatment and in the discovery of biomarkers to personalize it. We describe a computational purification tool, ISOpure, to directly address the effects of variable normal tissue contamination in clinical tumor specimens. ISOpure uses a set of tumor expression profiles and a panel of healthy tissue expression profiles to generate a purified cancer profile for each tumor sample and an estimate of the proportion of RNA originating from cancerous cells. Applying ISOpure before identifying gene signatures leads to significant improvements in the prediction of prognosis and other clinical variables in lung and prostate cancer

18F-FAC PET Visualizes Brain-Infiltrating Leukocytes in a Mouse Model of Multiple Sclerosis.

Brain-infiltrating leukocytes contribute to multiple sclerosis (MS) and autoimmune encephalomyelitis and likely play a role in traumatic brain injury, seizure, and stroke. Brain-infiltrating leukocytes are also primary targets for MS disease-modifying therapies. However, no method exists for noninvasively visualizing these cells in a living organism. 1-(2'-deoxy-2'-18F-fluoroarabinofuranosyl) cytosine (18F-FAC) is a PET radiotracer that measures deoxyribonucleoside salvage and accumulates preferentially in immune cells. We hypothesized that 18F-FAC PET could noninvasively image brain-infiltrating leukocytes. Methods: Healthy mice were imaged with 18F-FAC PET to quantify if this radiotracer crosses the blood-brain barrier (BBB). Experimental autoimmune encephalomyelitis (EAE) is a mouse disease model with brain-infiltrating leukocytes. To determine whether 18F-FAC accumulates in brain-infiltrating leukocytes, EAE mice were analyzed with 18F-FAC PET, digital autoradiography, and immunohistochemistry, and deoxyribonucleoside salvage activity in brain-infiltrating leukocytes was analyzed ex vivo. Fingolimod-treated EAE mice were imaged with 18F-FAC PET to assess if this approach can monitor the effect of an immunomodulatory drug on brain-infiltrating leukocytes. PET scans of individuals injected with 2-chloro-2'-deoxy-2'-18F-fluoro-9-β-d-arabinofuranosyl-adenine (18F-CFA), a PET radiotracer that measures deoxyribonucleoside salvage in humans, were analyzed to evaluate whether 18F-CFA crosses the human BBB. Results: 18F-FAC accumulates in the healthy mouse brain at levels similar to 18F-FAC in the blood (2.54 ± 0.2 and 3.04 ± 0.3 percentage injected dose per gram, respectively) indicating that 18F-FAC crosses the BBB. EAE mice accumulate 18F-FAC in the brain at 180% of the levels of control mice. Brain 18F-FAC accumulation localizes to periventricular regions with significant leukocyte infiltration, and deoxyribonucleoside salvage activity is present at similar levels in brain-infiltrating T and innate immune cells. These data suggest that 18F-FAC accumulates in brain-infiltrating leukocytes in this model. Fingolimod-treated EAE mice accumulate 18F-FAC in the brain at 37% lower levels than control-treated EAE mice, demonstrating that 18F-FAC PET can monitor therapeutic interventions in this mouse model. 18F-CFA accumulates in the human brain at 15% of blood levels (0.08 ± 0.01 and 0.54 ± 0.07 SUV, respectively), indicating that 18F-CFA does not cross the BBB in humans. Conclusion: 18F-FAC PET can visualize brain-infiltrating leukocytes in a mouse MS model and can monitor the response of these cells to an immunomodulatory drug. Translating this strategy into humans will require exploring additional radiotracers

Quantification of carbonic anhydrase gene expression in ventricle of hypertrophic and failing human heart

Background: Carbonic anhydrase enzymes (CA) catalyze the reversible hydration of carbon dioxide to bicarbonate in mammalian cells. Trans-membrane transport of CA-produced bicarbonate contributes significantly to cellular pH regulation. A body of evidence implicates pH-regulatory processes in the hypertrophic growth pathway characteristic of hearts as they fail. In particular, Na+ /H+ exchange (NHE) activation is pro-hypertrophic and CA activity activates NHE. Recently Cardrase (6-ethoxyzolamide), a CA inhibitor, was found to prevent and revert agonist-stimulated cardiac hypertrophy (CH) in cultured cardiomyocytes. Our goal thus was to determine whether hypertrophied human hearts have altered expression of CA isoforms. Methods: We measured CA expression in hypertrophied human hearts to begin to examine the role of carbonic anhydrase in progression of human heart failure. Ventricular biopsies were obtained from patients undergoing cardiac surgery (CS, n = 14), or heart transplantation (HT, n = 13). CS patients presented mild/moderate concentric left ventricular hypertrophy and normal right ventricles, with preserved ventricular function; ejection fractions were ~60%. Conversely, HT patients with failing hearts presented CH or ventricular dilation accompanied by ventricular dysfunction and EF values of 20%. Non-hypertrophic, non-dilated ventricular samples served as controls. Results: Expression of atrial and brain natriuretic peptide (ANP and BNP) were markers of CH. Hypertrophic ventricles presented increased expression of CAII, CAIV, ANP, and BNP, mRNA levels, which increased in failing hearts, measured by quantitative real-time PCR. CAII, CAIV, and ANP protein expression also increased approximately two-fold in hypertrophic/dilated ventricles. Conclusions: These results, combined with in vitro data that CA inhibition prevents and reverts CH, suggest that increased carbonic anhydrase expression is a prognostic molecular marker of cardiac hypertrophy.Fil: Alvarez, Bernardo. Universidad Nacional de la Plata. Facultad de Ciencias Médicas; Argentina. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Centro Cientifico Tecnológico La Plata. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani"; ArgentinaFil: Quon, Anita L.. University Of Alberta. Faculty Of Medicine And Oral Health Sciences; CanadáFil: Mullen, John. University of Alberta; CanadáFil: Casey, Joseph R.. University Of Alberta. Faculty Of Medicine And Oral Health Sciences; Canad

Computational Analysis of the Transonic Dynamics Tunnel Using FUN3D

This paper presents results from an exploratory two-year effort of applying Computational Fluid Dynamics (CFD) to analyze the empty-tunnel flow in the NASA Langley Research Center Transonic Dynamics Tunnel (TDT). The TDT is a continuous-flow, closed circuit, 16- x 16-foot slotted-test-section wind tunnel, with capabilities to use air or heavy gas as a working fluid. In this study, experimental data acquired in the empty tunnel using the R-134a test medium was used to calibrate the computational data. The experimental calibration data includes wall pressures, boundary-layer profiles, and the tunnel centerline Mach number profiles. Subsonic and supersonic flow regimes were considered, focusing on Mach 0.5, 0.7 and Mach 1.1 in the TDT test section. This study discusses the computational domain, boundary conditions, and initial conditions selected and the resulting steady-state analyses using NASA's FUN3D CFD software

Regularizing Face Verification Nets For Pain Intensity Regression

Limited labeled data are available for the research of estimating facial expression intensities. For instance, the ability to train deep networks for automated pain assessment is limited by small datasets with labels of patient-reported pain intensities. Fortunately, fine-tuning from a data-extensive pre-trained domain, such as face verification, can alleviate this problem. In this paper, we propose a network that fine-tunes a state-of-the-art face verification network using a regularized regression loss and additional data with expression labels. In this way, the expression intensity regression task can benefit from the rich feature representations trained on a huge amount of data for face verification. The proposed regularized deep regressor is applied to estimate the pain expression intensity and verified on the widely-used UNBC-McMaster Shoulder-Pain dataset, achieving the state-of-the-art performance. A weighted evaluation metric is also proposed to address the imbalance issue of different pain intensities.Comment: 5 pages, 3 figure; Camera-ready version to appear at IEEE ICIP 201