Common-Cause Failure Analysis in Event Assessment

This paper describes the approach taken by the U. S. Nuclear Regulatory Commission to the treatment of common-cause failure in probabilistic risk assessment of operational events. The approach is based upon the Basic Parameter Model for common-cause failure, and examples are illustrated using the alpha-factor parameterization, the approach adopted by the NRC in their Standardized Plant Analysis Risk (SPAR) models. The cases of a failed component (with and without shared common-cause failure potential) and a component being unavailable due to preventive maintenance or testing are addressed. The treatment of two related failure modes (e.g., failure to start and failure to run) is a new feature of this paper. These methods are being applied by the NRC in assessing the risk significance of operational events for the Significance Determination Process (SDP) and the Accident Sequence Precursor (ASP) program

Integrated Initiating Event Performance Indicators

The U.S. Nuclear Regulatory Commission Industry Trends Program (ITP) collects and analyses industry-wide data, assesses the safety significance of results, and communicates results to Congress and other stakeholders. This paper outlines potential enhancements in the ITP to comprehensively cover the Initiating Events Cornerstone of Safety. Future work will address other cornerstones of safety. The proposed Tier 1 activity involves collecting data on ten categories of risk-significant initiating events, trending the results, and comparing early performance with prediction limits (allowable numbers of events, above which NRC action may occur). Tier 1 results would be used to monitor industry performance at the level of individual categories of initiating events. The proposed Tier 2 activity involves integrating the information for individual categories of initiating events into a single risk-based indicator, termed the Baseline Risk Index for Initiating Events or BRIIE. The BRIIE would be evaluated yearly and compared against a threshold. BRIIE results would be reported to Congress on a yearly basis

Estimating Loss-of-Coolant Accident Frequencies for the Standardized Plant Analysis Risk Models

The U.S. Nuclear Regulatory Commission maintains a set of risk models covering the U.S. commercial nuclear power plants. These standardized plant analysis risk (SPAR) models include several loss-of-coolant accident (LOCA) initiating events such as small (SLOCA), medium (MLOCA), and large (LLOCA). All of these events involve a loss of coolant inventory from the reactor coolant system. In order to maintain a level of consistency across these models, initiating event frequencies generally are based on plant-type average performance, where the plant types are boiling water reactors and pressurized water reactors. For certain risk analyses, these plant-type initiating event frequencies may be replaced by plant-specific estimates. Frequencies for SPAR LOCA initiating events previously were based on results presented in NUREG/CR-5750, but the newest models use results documented in NUREG/CR-6928. The estimates in NUREG/CR-6928 are based on historical data from the initiating events database for pressurized water reactor SLOCA or an interpretation of results presented in the draft version of NUREG-1829. The information in NUREG-1829 can be used several ways, resulting in different estimates for the various LOCA frequencies. Various ways NUREG-1829 information can be used to estimate LOCA frequencies were investigated and this paper presents two methods for the SPAR model standard inputs, which differ from the method used in NUREG/CR-6928. In addition, results obtained from NUREG-1829 are compared with actual operating experience as contained in the initiating events database

Atlantic bluefin tuna spawn at suboptimal temperatures for their offspring

Life-history traits such as spawning migrations and timing of reproduction are adaptations to specific environmental constraints and seasonal cycles in many organisms’ annual routines. In this study we analyse how offspring fitness constrains spawning phenology in a large migratory apex predator, the Atlantic bluefin tuna. The reproductive schedule of Atlantic bluefin tuna varies between spawning sites, suggesting plasticity to local environ- mental conditions. Generally, temperature is considered to be the main constraint on tuna spawning phenology. We combine evidence from long- term field data, temperature-controlled rearing experiments on eggs and larvae, and a model of egg fitness, and show that Atlantic bluefin tuna do not spawn to optimize egg and larval temperature exposure. The timing of spawning leads to temperature exposure considerably lower than optimal at all spawning grounds across the Atlantic Ocean. The early spawning is constrained by thermal inhibition of egg hatching and larval growth rates, but some other factors must prevent later spawning. Matching offspring with ocean productivity and the prey peak might be an important driver for bluefin tuna spawning phenology. This finding is important for predictions of reproductive timing in future climate warming scenarios for bluefin tuna.Versión del edito

Pelagic habitat and offspring survival in the eastern stock of Atlantic bluefin tuna

In this manuscript, we test how an understanding of geographical variation in larval fitness in relation to temperature and habitat use could be a useful method to improve our understanding of recruitment and develop better indices of annual recruitment. On the basis of the assumption that growth and survival of tuna larvae are influenced by temperature, we have developed a potential larval survival index for Atlantic bluefin tuna (Thunnus thynnus) by combining empirical data from egg and larval rearing experiments with temperature data from hydrodynamic models. The experiments were designed to test the full range of temperature variability that bluefin larvae would experience in the field and provide a mechanistic understanding of the processes driving egg and larval survival. We then developed a biological model using the temperature-related growth expressions and a size-dependent survival function for the larvae. The biological model was applied to a time-series of spatially explicit temperature data for the western Mediterranean from the Strait of Gibraltar to 6 E, which includes the major recognized bluefin tuna eastern stock spawning area, the Balearic Sea. Our results show that areas with high probabilities of larval survival coincide with those that would be considered as optimal based on other data sources (ichthyoplankton surveys, spawning female locations from commercial fisheries data, and adult tracking data). However, evidence of spawning has been found in areas with suboptimal thermal habitats, as predicted by the model, which we discuss regarding sampling effort and salinity fronts. There was a good match between the survival index and recruitment indices from standardized CPUE fisheries data. These results have implications for our understanding of the recruitment process of the eastern stock of Atlantic bluefin tuna, since they suggest that the combined effects of temporal and spatial variability of the environment drive recruitment success, which has important implications for the management of the species.Versión del editor2,27

Evaluation of neuroendocrine markers in renal cell carcinoma

<p>Abstract</p> <p>Background</p> <p>The purpose of the study was to examine serotonin, CD56, neurone-specific enolase (NSE), chromogranin A and synaptophysin by immunohistochemistry in renal cell carcinomas (RCCs) with special emphasis on patient outcome.</p> <p>Methods</p> <p>We studied 152 patients with primary RCCs who underwent surgery for the removal of kidney tumours between 1990 and 1999. The mean follow-up was 90 months. The expression of neuroendocrine (NE) markers was determined by immunohistochemical staining using commercially available monoclonal antibodies. Results were correlated with patient age, clinical stage, Fuhrman grade and patient outcome.</p> <p>Results</p> <p>Eight percent of tumours were positive for serotonin, 18% for CD56 and 48% for NSE. Chromogranin A immunostaining was negative and only 1% of the tumours were synaptophysin immunopositive. The NSE immunopositivity was more common in clear cell RCCs than in other subtypes (<it>p </it>= 0.01). The other NE markers did not show any association with the histological subtype. Tumours with an immunopositivity for serotonin had a longer RCC-specific survival and tumours with an immunopositivity for CD56 and NSE had a shorter RCC-specific survival but the difference was not significant. There was no relationship between stage or Fuhrman grade and immunoreactivity for serotonin, CD56 and NSE.</p> <p>Conclusions</p> <p>Serotonin, CD56 and NSE but not synaptophysin and chromogranin A are expressed in RCCs. However, the prognostic potential of these markers remains obscure.</p

Autocrine Prostaglandin E2 Signaling Promotes Tumor Cell Survival and Proliferation in Childhood Neuroblastoma

Background: Prostaglandin E2 (PGE2) is an important mediator in tumor-promoting inflammation. High expression of cyclooxygenase-2 (COX-2) has been detected in the embryonic childhood tumor neuroblastoma, and treatment with COX inhibitors significantly reduces tumor growth. Here, we have investigated the significance of a high COX-2 expression in neuroblastoma by analysis of PGE2 production, the expression pattern and localization of PGE2 receptors and intracellular signal transduction pathways activated by PGE2. Principal Findings: A high expression of the PGE2 receptors, EP1, EP2, EP3 and EP4 in primary neuroblastomas, independent of biological and clinical characteristics, was detected using immunohistochemistry. In addition, mRNA and protein corresponding to each of the receptors were detected in neuroblastoma cell lines. Immunofluorescent staining revealed localization of the receptors to the cellular membrane, in the cytoplasm, and in the nuclear compartment. Neuroblastoma cells produced PGE2 and stimulation of serum-starved neuroblastoma cells with PGE2 increased the intracellular concentration of calcium and cyclic AMP with subsequent phosphorylation of Akt. Addition of 16,16-dimethyl PGE 2 (dmPGE2) increased cell viability in a time, dose- and cell line-dependent manner. Treatment of neuroblastoma cells with a COX-2 inhibitor resulted in a diminished cell growth and viability that was reversed by the addition of dmPGE2. Similarly, PGE 2 receptor antagonists caused a decrease in neuroblastoma cell viability in a dose-dependent manner

A Cre-conditional MYCN-driven neuroblastoma mouse model as an improved tool for preclinical studies

Neuroblastoma, a childhood cancer that originates from neural crest-derived cells, is the most common deadly solid tumor of infancy. Amplification of the MYCN oncogene, which occurs in approximately 20-25% of human neuroblastomas, is the most prominent genetic marker of high-stage disease. The availability of valid preclinical in vivo models is a prerequisite to develop novel targeted therapies. We here report on the generation of transgenic mice with Cre-conditional induction of MYCN in dopamine β-hydroxylase-expressing cells, termed LSL-MYCN;Dbh-iCre. These mice develop neuroblastic tumors with an incidence of >75%, regardless of strain background. Molecular profiling of tumors revealed upregulation of the MYCN-dependent miR-17-92 cluster as well as expression of neuroblastoma marker genes, including tyrosine hydroxylase and the neural cell adhesion molecule 1. Gene set enrichment analyses demonstrated significant correlation with MYC-associated expression patterns. Array comparative genome hybridization showed that chromosomal aberrations in LSL-MYCN;Dbh-iCre tumors were syntenic to those observed in human neuroblastomas. Treatment of a cell line established from a tumor derived from a LSL-MYCN;Dbh-iCre mouse with JQ1 or MLN8237 reduced cell viability and demonstrated oncogene addiction to MYCN. Here we report establishment of the first Cre-conditional human MYCN-driven mouse model for neuroblastoma that closely recapitulates the human disease with respect to tumor localization, histology, marker expression and genomic make up. This mouse model is a valuable tool for further functional studies and to assess the effect of targeted therapies

Fruit and vegetable consumption and lung cancer risk: updated information from the European Prospective Investigation into Cancer and Nutrition (EPIC)

The association of fruit and vegetable consumption and lung cancer incidence was evaluated using the most recent data from the European Prospective Investigation into Cancer and Nutrition (EPIC), applying a refined statistical approach (calibration) to account for measurement error potentially introduced by using food frequency questionnaire data. Between 1992 and 2000, detailed information on diet and life-style of 478,590 individuals participating in EPIC was collected. During a median follow-up of 6.4 years, 1,126 lung cancer cases were observed. Multivariate Cox proportional hazard models were applied for statistical evaluation. In the whole study population, fruit consumption was significantly inversely associated with lung cancer risk while no association was found for vegetable consumption. In current smokers, however, lung cancer risk significantly decreased with higher vegetable consumption; this association became more pronounced after calibration, the hazard ratio (HR) being 0.78 (95% CI 0.620.98) per 100 g increase in daily vegetable consumption. In comparison, the HR per 100 g fruit was 0.92 (0.85-0.99) in the entire cohort and 0.90 (0.81-0.99) in smokers. Exclusion of cases diagnosed during the first 2 years of follow-up strengthened these associations, the HR being 0.71 (0.55-0.94) for vegetables (smokers) and 0.86 (0.78-0.95) for fruit (entire cohort). Cancer incidence decreased with higher consumption of apples and pears (entire cohort) as well as root vegetables (smokers). In addition to an overall inverse association with fruit intake, the results of this evaluation add evidence for a significant inverse association of vegetable consumption and lung cancer incidence in smokers. (C) 2007 Wiley-Liss, Inc