Winners and Losers: Formula versus Competitive Funding of Agricultural Research

Research and Development/Tech Change/Emerging Technologies, O3, O4, Q16,

A Cell-Surface Membrane Protein Signature for Glioblastoma.

We present a systems strategy that facilitated the development of a molecular signature for glioblastoma (GBM), composed of 33 cell-surface transmembrane proteins. This molecular signature, GBMSig, was developed through the integration of cell-surface proteomics and transcriptomics from patient tumors in the REMBRANDT (n = 228) and TCGA datasets (n = 547) and can separate GBM patients from control individuals with a Matthew\u27s correlation coefficient value of 0.87 in a lock-down test. Functionally, 17/33 GBMSig proteins are associated with transforming growth factor β signaling pathways, including CD47, SLC16A1, HMOX1, and MRC2. Knockdown of these genes impaired GBM invasion, reflecting their role in disease-perturbed changes in GBM. ELISA assays for a subset of GBMSig (CD44, VCAM1, HMOX1, and BIGH3) on 84 plasma specimens from multiple clinical sites revealed a high degree of separation of GBM patients from healthy control individuals (area under the curve is 0.98 in receiver operating characteristic). In addition, a classifier based on these four proteins differentiated the blood of pre- and post-tumor resections, demonstrating potential clinical value as biomarkers

Comprehensive Analysis of MGMT Promoter Methylation: Correlation with MGMT Expression and Clinical Response in GBM

O6-methylguanine DNA-methyltransferase (MGMT) promoter methylation has been identified as a potential prognostic marker for glioblastoma patients. The relationship between the exact site of promoter methylation and its effect on gene silencing, and the patient's subsequent response to therapy, is still being defined. The aim of this study was to comprehensively characterize cytosine-guanine (CpG) dinucleotide methylation across the entire MGMT promoter and to correlate individual CpG site methylation patterns to mRNA expression, protein expression, and progression-free survival. To best identify the specific MGMT promoter region most predictive of gene silencing and response to therapy, we determined the methylation status of all 97 CpG sites in the MGMT promoter in tumor samples from 70 GBM patients using quantitative bisulfite sequencing. We next identified the CpG site specific and regional methylation patterns most predictive of gene silencing and improved progression-free survival. Using this data, we propose a new classification scheme utilizing methylation data from across the entire promoter and show that an analysis based on this approach, which we call 3R classification, is predictive of progression-free survival (HR  = 5.23, 95% CI [2.089–13.097], p<0.0001). To adapt this approach to the clinical setting, we used a methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) test based on the 3R classification and show that this test is both feasible in the clinical setting and predictive of progression free survival (HR  = 3.076, 95% CI [1.301–7.27], p = 0.007). We discuss the potential advantages of a test based on this promoter-wide analysis and compare it to the commonly used methylation-specific PCR test. Further prospective validation of these two methods in a large independent patient cohort will be needed to confirm the added value of promoter wide analysis of MGMT methylation in the clinical setting

The somatic genomic landscape of glioblastoma

We describe the landscape of somatic genomic alterations based on multidimensional and comprehensive characterization of more than 500 glioblastoma tumors (GBMs). We identify several novel mutated genes as well as complex rearrangements of signature receptors, including EGFR and PDGFRA. TERT promoter mutations are shown to correlate with elevated mRNA expression, supporting a role in telomerase reactivation. Correlative analyses confirm that the survival advantage of the proneural subtype is conferred by the G-CIMP phenotype, and MGMT DNA methylation may be a predictive biomarker for treatment response only in classical subtype GBM. Integrative analysis of genomic and proteomic profiles challenges the notion of therapeutic inhibition of a pathway as an alternative to inhibition of the target itself. These data will facilitate the discovery of therapeutic and diagnostic target candidates, the validation of research and clinical observations and the generation of unanticipated hypotheses that can advance our molecular understanding of this lethal cancer

The Somatic Genomic Landscape of Glioblastoma

We describe the landscape of somatic genomic alterations based on multi-dimensional and comprehensive characterization of more than 500 glioblastoma tumors (GBMs). We identify several novel mutated genes as well as complex rearrangements of signature receptors including EGFR and PDGFRA. TERT promoter mutations are shown to correlate with elevated mRNA expression, supporting a role in telomerase reactivation. Correlative analyses confirm that the survival advantage of the proneural subtype is conferred by the G-CIMP phenotype, and MGMT DNA methylation may be a predictive biomarker for treatment response only in classical subtype GBM. Integrative analysis of genomic and proteomic profiles challenges the notion of therapeutic inhibition of a pathway as an alternative to inhibition of the target itself. These data will facilitate the discovery of therapeutic and diagnostic target candidates, the validation of research and clinical observations and the generation of unanticipated hypotheses that can advance our molecular understanding of this lethal cancer

A sensor management architecture concept for monitoring emissions from open-air demil operations.

Sandia National Laboratories, CA proposed a sensor concept to detect emissions from open-burning/open-detonation (OB/OD) events. The system would serve two purposes: (1) Provide data to demilitarization operations about process efficiency, allowing process optimization for cleaner emissions and higher efficiency. (2) Provide data to regulators and neighboring communities about materials dispersing into the environment by OB/OD operations. The proposed sensor system uses instrument control hardware and data visualization software developed at Sandia National Laboratories to link together an array of sensors to monitor emissions from OB/OD events. The suite of sensors would consist of various physical and chemical detectors mounted on stationary or mobile platforms. The individual sensors would be wirelessly linked to one another and controlled through a central command center. Real-time data collection from the sensors, combined with integrated visualization of the data at the command center, would allow for feedback to the sensors to alter operational conditions to adjust for changing needs (i.e., moving plume position, increased spatial resolution, increased sensitivity). This report presents a systems study of the problem of implementing a sensor system for monitoring OB/OD emissions. The goal of this study was to gain a fuller understanding of the political, economic, and technical issues for developing and fielding this technology

Assembling the Echinoderm Tree of Life: Challenges and Plans

A multidisciplinary team of biologists have recently assembled to study echinoderm phylogeny. The team has an award from the National Science Foundation Program, Assembling the Tree of Life. The five living classes of echinoderms are Asteroidea, Crinoidea, Echinoidea, Holothuroidea, and Ophiuroidea. However, these classes represent a shadow of both the full morphological disparity and diversity of Lower Paleozoic echinoderms that includes as many as 21 classes. Phylogenetic analysis of living echinoderms remains challenging. Moreover a complete echinoderm evolutionary tree will have to incorporate all echinoderm lineages and key outgroups to link echinoderms into the broader tree of life. The project is organized with the following working groups: genomics, morphology, informatics, and outreach. Our goals include genomic sampling of numerous exemplars among the five living echinoderm classes, integration of genomic and morphologic data of living echinoderms with Cenozoic and Mesozoic fossil data, definition of Paleozoic clades, and positioning sister group relationships among the stem group echinoderm clades. Homology among distinctive echinoderm groups must be established first despite diverse nomenclature. Data will be analyzed with multiple hypotheses of outgroups and characters by teams of echinoderms specialists. Collaborations are welcome. Outreach will include videos and broadcasts about marine exploration and applications of fundamental biological research across the biomedical sciences