Gene Expression Meta-Analysis Identifies VDAC1 as a Predictor of Poor Outcome in Early Stage Non-Small Cell Lung Cancer

The bioenergetic status of non-small cell lung cancer correlates with tumour aggressiveness. The voltage dependent anion channel type 1 (VDAC1) is a component of the mitochondrial permeability transition pore, regulates mitochondrial ATP/ADP exchange suggesting that its over-expression could be associated with energy dependent processes including increased proliferation and invasiveness. To test this hypothesis, we conducted an in vivo gene-expression meta-analysis of surgically resected non-small cell lung cancer (NSCLC) using 602 individual expression profiles, to examine the impact of VDAC1 on survival.High VDAC1 expression was associated with shorter overall survival with hazard ratio (HR) = 0.6639 (95% confidence interval (CI) 0.4528 to 0.9721), p = 0.035352 corresponding to 52 versus 101 months. VDAC1 predicted shorter time to recurrence and was shown to be an independent prognostic factor compared with histology, gender, age, nodal stage and tumour stage in a Cox multivariate analysis. Supervised analysis of all the datasets identified a 6-gene signature comprising HNRNPC, HSPA4, HSPA9, UBE2D2, CSNK1A1 and G3BP1 with overlapping functions involving regulation of protein turnover, RAS-RAF-MEK pathway and transcription. VDAC1 predicted survival in breast cancer and myeloma and an unsupervised analysis revealed enrichment of the VDAC1 signature in specific subsets.In summary, gene expression analysis identifies VDAC1 gene expression as a predictor of poor outcome in NSCLC and other cancers and is associated with dysregulation of a conserved set of biological pathways, which may be causally associated with aggressive tumour behaviour

A TMA De-Arraying Method for High Throughput Biomarker Discovery in Tissue Research

BACKGROUND: Tissue MicroArrays (TMAs) represent a potential high-throughput platform for the analysis and discovery of tissue biomarkers. As TMA slides are produced manually and subject to processing and sectioning artefacts, the layout of TMA cores on the final slide and subsequent digital scan (TMA digital slide) is often disturbed making it difficult to associate cores with their original position in the planned TMA map. Additionally, the individual cores can be greatly altered and contain numerous irregularities such as missing cores, grid rotation and stretching. These factors demand the development of a robust method for de-arraying TMAs which identifies each TMA core, and assigns them to their appropriate coordinates on the constructed TMA slide. METHODOLOGY: This study presents a robust TMA de-arraying method consisting of three functional phases: TMA core segmentation, gridding and mapping. The segmentation of TMA cores uses a set of morphological operations to identify each TMA core. Gridding then utilises a Delaunay Triangulation based method to find the row and column indices of each TMA core. Finally, mapping correlates each TMA core from a high resolution TMA whole slide image with its name within a TMAMap. CONCLUSION: This study describes a genuine robust TMA de-arraying algorithm for the rapid identification of TMA cores from digital slides. The result of this de-arraying algorithm allows the easy partition of each TMA core for further processing. Based on a test group of 19 TMA slides (3129 cores), 99.84% of cores were segmented successfully, 99.81% of cores were gridded correctly and 99.96% of cores were mapped with their correct names via TMAMaps. The gridding of TMA cores were also extensively tested using a set of 113 pseudo slide (13,536 cores) with a variety of irregular grid layouts including missing cores, rotation and stretching. 100% of the cores were gridded correctly

Using Participatory Mapping to Diagnose Upstream Determinants of Health and Prescribe Downstream Policy-Based Interventions

Participatory mapping is a powerful methodology for working with community residents to examine social and environmental determinants of public health disparities. However, this empowering methodology has only been applied sparingly in public health research and practice, with limited examples in the literature. To address this literature gap, we 1) review participatory mapping approaches that may be applied to exploring place-based factors that affect community health, and 2) present a mixed-methods participatory geographic information systems (PGIS) examination of neighborhood assets (eg, streetlights) and challenges (eg, spaces of crime and violence) related to access to public parks in South Los Angeles, California. By taking a participatory, fine-grained spatial approach to examining public park access with input from 40 South Los Angeles adolescent and adult residents, our community-engaged PGIS approach identified tobacco shops as previously unrecognized community institutions that are associated with increased neighborhood crime and violence. Our investigation revealed unique challenges in community-level public park access that would likely have been overlooked by conventional spatial epidemiology and social science methods, such as surveys and questionnaires. Furthermore, our granular community-informed approach supported resident and stakeholder advocacy efforts toward reducing the proliferation of tobacco shops through community organizing and policy change initiatives. We thus contend that it would benefit public health research and practice to further integrate empowering, grassroots-based participatory mapping approaches toward informing advocacy efforts and policies that promote health and well-being in disadvantaged communities

Variability in spine radiosurgery treatment planning - results of an international multi-institutional study

Background: The aim of this study was to quantify the variability in spinal radiosurgery (SRS) planning practices between five international institutions, all member of the Elekta Spine Radiosurgery Research Consortium. Methods: Four institutions provided one representative patient case each consisting of the medical history, CT and MR imaging. A step-wise planning approach was used where, after each planning step a consensus was generated that formed the basis for the next planning step. This allowed independent analysis of all planning steps of CT-MR image registration, GTV definition, CTV definition, PTV definition and SRS treatment planning. In addition, each institution generated one additional SRS plan for each case based on intra-institutional image registration and contouring, independent of consensus results. Results: Averaged over the four cases, image registration variability ranged between translational 1.1 mm and 2.4 mm and rotational 1.1° and 2.0° in all three directions. GTV delineation variability was 1.5 mm in axial and 1.6 mm in longitudinal direction averaged for the four cases. CTV delineation variability was 0.8 mm in axial and 1.2 mm in longitudinal direction. CTV-to-PTV margins ranged between 0 mm and 2 mm according to institutional protocol. Delineation variability was 1 mm in axial directions for the spinal cord. Average PTV coverage for a single fraction18 Gy prescription was 87 ± 5 %; Dmin to the PTV was 7.5 ± 1.8 Gy averaged over all cases and institutions. Average Dmax to the PRV_SC (spinal cord + 1 mm) was 10.5 ± 1.6 Gy and the average Paddick conformity index was 0.69 ± 0.06. Conclusions: Results of this study reflect the variability in current practice of spine radiosurgery in large and highly experienced academic centers. Despite close methodical agreement in the daily workflow, clinically significant variability in all steps of the treatment planning process was demonstrated. This may translate into differences in patient clinical outcome and highlights the need for consensus and established delineation and planning criteria

Parent and child agreement for acute stress disorder, post-traumatic stress disorder and other psychopathology in a prospective study of children and adolescents exposed to single-event trauma

Examining parent-child agreement for Acute Stress Disorder (ASD) and Post-Traumatic Stress Disorder (PTSD) in children and adolescents is essential for informing the assessment of trauma-exposed children, yet no studies have examined this relationship using appropriate statistical techniques. Parent-child agreement for these disorders was examined by structured interview in a prospective study of assault and motor vehicle accident (MVA) child survivors, assessed at 2-4 weeks and 6 months post-trauma. Children were significantly more likely to meet criteria for ASD, as well as other ASD and PTSD symptom clusters, based on their own report than on their parent's report. Parent-child agreement for ASD was poor (Cohen's κ = -.04), but fair for PTSD (Cohen's κ = .21). Agreement ranged widely for other emotional disorders (Cohen's κ = -.07-.64), with generalised anxiety disorder found to have superior parent-child agreement (when assessed by phi coefficients) relative to ASD and PTSD. The findings support the need to directly interview children and adolescents, particularly for the early screening of posttraumatic stress, and suggest that other anxiety disorders may have a clearer presentation post-trauma

Between overt and covert research: concealment and disclosure in an ethnographic study of commercial hospitality

This article examines the ways in which problems of concealment emerged in an ethnographic study of a suburban bar and considers how disclosure of the research aims, the recruitment of informants, and elicitation of information was negotiated throughout the fieldwork. The case study demonstrates how the social context and the relationships with specific informants determined overtness or covertness in the research. It is argued that the existing literature on covert research and covert methods provides an inappropriate frame of reference with which to understand concealment in fieldwork. The article illustrates why concealment is sometimes necessary, and often unavoidable, and concludes that the criticisms leveled against covert methods should not stop the fieldworker from engaging in research that involves covertness

Substantial Dose-response Relationship with Clinical Outcome for Lung Stereotactic Body Radiotherapy (SBRT) Delivered via Online Image Guidance

Purpose: To examine potential tumor dose-response relationships with various non-small cell lung cancer (NSCLC) SBRT fractionation regimens delivered with online CT-based image guidance. American Society for Therapeutic Radiation Oncology (ASTRO) 52nd Annual Meeting October 31 - November 4, San Diego, C

Nanosecond Mid-Infrared Detection for Pulse Radiolysis

Pulse radiolysis, utilizing electron pulses from accelerators, is the definitive method for adding single positive or negative charges to molecules. It is also among the most effective means for creating free radicals. Such species are particularly important in applications such as redox catalysis relevant to solar energy conversion and advanced nuclear energy systems. Coupled with fast UV-visible detection, pulse radiolysis has become an extremely powerful method for monitoring the kinetics of the subsequent reactions of these species on timescales ranging from picoseconds to seconds. However, in many important contexts the radicals formed are difficult to identify due to their broad and featureless UV-visible absorption spectra. Time-resolved infrared (TRIR) absorption spectroscopy is a powerful structural probe of short-lived intermediates, which allows multiple transient species to be clearly identified and simultaneously monitored in a single process. Unfortunately, due to technical challenges the coupling of fast (sub-millisecond) TRIR with pulse radiolysis has received little attention, being confined to gas-phase studies. Taking advantage of recent developments in mid-IR laser technology, we have recently begun developing nanosecond TRIR detection methodologies for condensed-phase samples at our Laser Electron Accelerator Facility (LEAF). The results of preliminary pulse radiolysis-TRIR investigations on the formation of the one-electron reduced forms of CO{sub 2} reduction catalysts (e.g. see above) and their interactions with CO{sub 2} will be presented

Correlating metabolic and anatomic responses of primary lung cancers to radiotherapy by combined F-18 FDG PET-CT imaging

<p>Abstract</p> <p>Background</p> <p>To correlate the metabolic changes with size changes for tumor response by concomitant PET-CT evaluation of lung cancers after radiotherapy.</p> <p>Methods</p> <p>36 patients were studied pre- and post-radiotherapy with¹⁸FDG PET-CT scans at a median interval of 71 days. All of the patients were followed clinically and radiographically after a mean period of 342 days for assessment of local control or failure rates. Change in size (sum of maximum orthogonal diameters) was correlated with that of maximum standard uptake value (SUV) of the primary lung cancer before and after conventional radiotherapy.</p> <p>Results</p> <p>There was a significant reduction in both SUV and size of the primary cancer after radiotherapy (p < 0.00005). Among the 20 surviving patients, the sensitivity, specificity, and accuracy using PET (SUV) were 94%, 50%, 90% respectively and the corresponding values using and CT (size criteria) were 67%, 50%, and 65% respectively. The metabolic change (SUV) was highly correlated with the change in size by a quadratic function. In addition, the mean percentage metabolic change was significantly larger than that of size change (62.3 ± 32.7% vs 47.1 ± 26.1% respectively, p = 0.03)</p> <p>Conclusion</p> <p>Correlating and incorporating metabolic change by PET into size change by concomitant CT is more sensitive in assessing therapeutic response than CT alone.</p