Copy number signatures and mutational processes in ovarian carcinoma.

The genomic complexity of profound copy number aberrations has prevented effective molecular stratification of ovarian cancers. Here, to decode this complexity, we derived copy number signatures from shallow whole-genome sequencing of 117 high-grade serous ovarian cancer (HGSOC) cases, which were validated on 527 independent cases. We show that HGSOC comprises a continuum of genomes shaped by multiple mutational processes that result in known patterns of genomic aberration. Copy number signature exposures at diagnosis predict both overall survival and the probability of platinum-resistant relapse. Measurement of signature exposures provides a rational framework to choose combination treatments that target multiple mutational processes.NIHR, Ovarian Cancer Action, Cancer Research UK Cambridge Centre, Cambridge Experimental Cancer Medicine Centr

The CI-FLOW Project: A System for Total Water Level Prediction from the Summit to the Sea

Kildow et al. (2009) reported that coastal states support 81% of the U.S. population and generate 83 percent [$11.4 trillion (U.S. dollars) in 2007] of U.S. gross domestic product. Population trends show that a majority of coastal communities have transitioned from a seasonal, predominantly weekend, tourist-based economy to a year-round, permanently based, business economy where industry expands along shorelines and the workforce commutes from inland locations. As a result of this transition, costs associated with damage to the civil infrastructure and disruptions to local and regional economies due to coastal flooding events are escalating, pushing requirements for a new generation of flood prediction technologies and hydrologic decision support tools

The MHC class II transactivator: A negative regulator of IL-4 and Fas ligand.

The major histocompatibility complex class II transactivator (CIITA) is the master regulator of MHC class II genes and other genes involved in the antigen presentation pathway. In the absence of CIITA, MHC class II is not expressed on professional antigen presenting cells (APCs). However, it was not known if CIITA regulates other immune processes. To address this, we investigated whether CIITA plays a role in CD4 T cell function. CD4 T cells can differentiate into two functionally distinct lineages, T helper type 1 (Th1) and Th2. Th1 and Th2 cells are responsible for cell-mediated and humoral immunity, respectively. We found that CIITA is expressed during the Th1 differentiation process, which is required for the inhibition of Th2 cytokines. CIITA deficiency caused developing Th1 cells to produce Th2 cytokines, IL-4, IL-5, and IL-13 in addition to Th1 cytokine IFN-gamma. On the other hand, the constitutive expression of CIITA in the Th2 clone resulted in inhibition of IL-4 production. The inhibitory function of CIITA is due to its ability to interact with other transcription factors. CIITA repressed transcription from the IL-4 promoter by interfering with the interaction of the transcription factor nuclear factor of activated T cells (NF-AT) with the coactivator p300. CIITA also inhibits transcription of the Fas ligand gene whose expression is dependent on NF-AT. The Fas:Fas ligand pathway is critical in regulating immune homeostasis by eliminating activated T cells that have proliferated in response to an infection. CD4 T cells expressing CIITA were resistant to cell death due to the lower level of Fas ligand expression. CIITA deficient CD4 T cells had enhanced levels of Fas ligand on the cell surface during the Th1 differentiation process but not after reactivation. B cells without CIITA also expressed an increased level of Fas ligand. Our data show that CIITA plays an important role by regulating multiple immune responses including antigen presentation, the Th1 differentiation process, and lymphocyte homeostasis.Ph.D.Biological SciencesHealth and Environmental SciencesImmunologyMolecular biologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/129522/2/3042076.pd

Prototyping a Hurricane-Flood-Landslide-Continuum Prediction System: A CI-FLOW Contribution to North Carolina and Broader Coastal Regions

A partnership between NASA and the US Agency for International Development (USAID) is examining prototyping a hurricane-flood-landslide continuum as part of CI-FLOW (Coastal and Inland Flooding Observation and Warning project). Using high resolution satellites, hydrological data can be used to monitor global flooding. The Terra and Aqua satellites use a key instrument called MODIS (Moderate Resolution Imaging Spectroradiometer) to map flood inundation. Aster flood maps are used to calibrate hydrologic modeling. Additionally, inland river flow and storm surge modeling is being done as a part of CI-FLOW. Part of the problem with the models is determining how to calibrate them effectively. Researchers examined a full spectrum of data calibration techniques. The guided DREAM technique performed the best in terms of minimizing bias. They also examined Hurricane Floyd, and, using a discharge simulation, the guided DREAM preformed well. Landslides can accompany floods, and LIDAR (Light Detection and Ranging) data can be useful in examining slope stability and rainfall. In order to effectively manage hazards, an integrated approach is necessary, using hydrological data and flood prediction systems. Recently, the prediction system has been implemented successfully

Prototyping a Hurricane-Flood-Landslide-Continuum Prediction System: A CI-FLOW Contribution to North Carolina and Broader Coastal Regions

A partnership between NASA and the US Agency for International Development (USAID) is examining prototyping a hurricane-flood-landslide continuum as part of CI-FLOW (Coastal and Inland Flooding Observation and Warning project). Using high resolution satellites hydrological data can be used to monitor global flooding. The Terra and Aqua satellites use a key instrument called MODIS (Moderate Resolution Imaging Spectroradiometer) to map flood inundation. Aster flood maps are used to calibrate hydrologic modeling. Additionally inland river flow and storm surge modeling is being done as a part of CI-FLOW. Part of the problem with the models is determining how to calibrate them effectively. Researchers examined a full spectrum of data calibration techniques. The guided DREAM technique performed the best in terms of minimizing bias. They also examined Hurricane Floyd and using a discharge simulation the guided DREAM preformed well. Landslides can accompany floods and LIDAR (Light Detection and Ranging) data can be useful in examining slope stability and rainfall. In order to effectively manage hazards an integrated approach is necessary using hydrological data and flood prediction systems. Recently the prediction system has been implemented successfully

Structural variants at the BRCA1/2 loci are a common source of homologous repair deficiency in high grade serous ovarian carcinoma

PURPOSE: The abundance and effects of structural variation at BRCA1/2 in tumours are not well understood. In particular, the impact of these events on homologous recombination repair deficiency (HRD) has yet to be demonstrated. EXPERIMENTAL DESIGN: Exploiting a large collection of whole genome sequencing data from high grade serous ovarian carcinoma (N=205) together with matched RNA-seq for the majority of tumours (N=150), we have comprehensively characterised mutation and expression at BRCA1/2. RESULTS: In addition to the known spectrum of short somatic mutations (SSMs), we discover that multi-megabase structural variants (SVs) are a frequent, unappreciated source of BRCA1/2 disruption in these tumours, and we find a genome wide enrichment for large deletions at the BRCA1/2 loci across the cohort. These SVs independently affect a substantial proportion of patients (16%) in addition to those affected by SSMs (24%), conferring homologous recombination repair deficiency (HRD) and impacting patient survival. We also detail compound deficiencies involving SSMs and SVs at both loci, demonstrating that the strongest risk of HRD emerges from combined SVs at both BRCA1 and BRCA2 in the absence of SSMs. Further, these SVs are abundant and disruptive in other cancer types. CONCLUSIONS: These results extend our understanding of the mutational landscape underlying HRD, increase the number of patients predicted to benefit from therapies exploiting HRD, and suggest there is currently untapped potential in SV detection for patient stratification