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Sample records for additional driver mutation

  1. The effect of one additional driver mutation on tumor progression.

    PubMed

    Reiter, Johannes G; Bozic, Ivana; Allen, Benjamin; Chatterjee, Krishnendu; Nowak, Martin A

    2013-01-01

    Tumor growth is caused by the acquisition of driver mutations, which enhance the net reproductive rate of cells. Driver mutations may increase cell division, reduce cell death, or allow cells to overcome density-limiting effects. We study the dynamics of tumor growth as one additional driver mutation is acquired. Our models are based on two-type branching processes that terminate in either tumor disappearance or tumor detection. In our first model, both cell types grow exponentially, with a faster rate for cells carrying the additional driver. We find that the additional driver mutation does not affect the survival probability of the lesion, but can substantially reduce the time to reach the detectable size if the lesion is slow growing. In our second model, cells lacking the additional driver cannot exceed a fixed carrying capacity, due to density limitations. In this case, the time to detection depends strongly on this carrying capacity. Our model provides a quantitative framework for studying tumor dynamics during different stages of progression. We observe that early, small lesions need additional drivers, while late stage metastases are only marginally affected by them. These results help to explain why additional driver mutations are typically not detected in fast-growing metastases.

  2. Spatial evolution of tumors with successive driver mutations

    NASA Astrophysics Data System (ADS)

    Antal, Tibor; Krapivsky, P. L.; Nowak, M. A.

    2015-08-01

    We study the influence of driver mutations on the spatial evolutionary dynamics of solid tumors. We start with a cancer clone that expands uniformly in three dimensions giving rise to a spherical shape. We assume that cell division occurs on the surface of the growing tumor. Each cell division has a chance to give rise to a mutation that activates an additional driver gene. The resulting clone has an enhanced growth rate, which generates a local ensemble of faster growing cells, thereby distorting the spherical shape of the tumor. We derive formulas for the abundance and diversity of additional driver mutations as function of time. Our model is semi-deterministic: the spatial growth of cancer clones is deterministic, while mutants arise stochastically.

  3. Synonymous mutations frequently act as driver mutations in human cancers.

    PubMed

    Supek, Fran; Miñana, Belén; Valcárcel, Juan; Gabaldón, Toni; Lehner, Ben

    2014-03-13

    Synonymous mutations change the sequence of a gene without directly altering the sequence of the encoded protein. Here, we present evidence that these "silent" mutations frequently contribute to human cancer. Selection on synonymous mutations in oncogenes is cancer-type specific, and although the functional consequences of cancer-associated synonymous mutations may be diverse, they recurrently alter exonic motifs that regulate splicing and are associated with changes in oncogene splicing in tumors. The p53 tumor suppressor (TP53) also has recurrent synonymous mutations, but, in contrast to those in oncogenes, these are adjacent to splice sites and inactivate them. We estimate that between one in two and one in five silent mutations in oncogenes have been selected, equating to ~6%- 8% of all selected single-nucleotide changes in these genes. In addition, our analyses suggest that dosage-sensitive oncogenes have selected mutations in their 3' UTRs.

  4. Cancer Driver Log (CanDL): Catalog of Potentially Actionable Cancer Mutations.

    PubMed

    Damodaran, Senthilkumar; Miya, Jharna; Kautto, Esko; Zhu, Eliot; Samorodnitsky, Eric; Datta, Jharna; Reeser, Julie W; Roychowdhury, Sameek

    2015-09-01

    Massively parallel sequencing technologies have enabled characterization of genomic alterations across multiple tumor types. Efforts have focused on identifying driver mutations because they represent potential targets for therapy. However, because of the presence of driver and passenger mutations, it is often challenging to assign the clinical relevance of specific mutations observed in patients. Currently, there are multiple databases and tools that provide in silico assessment for potential drivers; however, there is no comprehensive resource for mutations with functional characterization. Therefore, we created an expert-curated database of potentially actionable driver mutations for molecular pathologists to facilitate annotation of cancer genomic testing. We reviewed scientific literature to identify variants that have been functionally characterized in vitro or in vivo as driver mutations. We obtained the chromosome location and all possible nucleotide positions for each amino acid change and uploaded them to the Cancer Driver Log (CanDL) database with associated literature reference indicating functional driver evidence. In addition to a simple interface, the database allows users to download all or selected genes as a comma-separated values file for incorporation into their own analysis pipeline. Furthermore, the database includes a mechanism for third-party contributions to support updates for novel driver mutations. Overall, this freely available database will facilitate rapid annotation of cancer genomic testing in molecular pathology laboratories for mutations.

  5. DriverNet: uncovering the impact of somatic driver mutations on transcriptional networks in cancer.

    PubMed

    Bashashati, Ali; Haffari, Gholamreza; Ding, Jiarui; Ha, Gavin; Lui, Kenneth; Rosner, Jamie; Huntsman, David G; Caldas, Carlos; Aparicio, Samuel A; Shah, Sohrab P

    2012-12-22

    Simultaneous interrogation of tumor genomes and transcriptomes is underway in unprecedented global efforts. Yet, despite the essential need to separate driver mutations modulating gene expression networks from transcriptionally inert passenger mutations, robust computational methods to ascertain the impact of individual mutations on transcriptional networks are underdeveloped. We introduce a novel computational framework, DriverNet, to identify likely driver mutations by virtue of their effect on mRNA expression networks. Application to four cancer datasets reveals the prevalence of rare candidate driver mutations associated with disrupted transcriptional networks and a simultaneous modulation of oncogenic and metabolic networks, induced by copy number co-modification of adjacent oncogenic and metabolic drivers. DriverNet is available on Bioconductor or at http://compbio.bccrc.ca/software/drivernet/.

  6. Kin-Driver: a database of driver mutations in protein kinases.

    PubMed

    Simonetti, Franco L; Tornador, Cristian; Nabau-Moretó, Nuria; Molina-Vila, Miguel A; Marino-Buslje, Cristina

    2014-01-01

    Somatic mutations in protein kinases (PKs) are frequent driver events in many human tumors, while germ-line mutations are associated with hereditary diseases. Here we present Kin-driver, the first database that compiles driver mutations in PKs with experimental evidence demonstrating their functional role. Kin-driver is a manual expert-curated database that pays special attention to activating mutations (AMs) and can serve as a validation set to develop new generation tools focused on the prediction of gain-of-function driver mutations. It also offers an easy and intuitive environment to facilitate the visualization and analysis of mutations in PKs. Because all mutations are mapped onto a multiple sequence alignment, analogue positions between kinases can be identified and tentative new mutations can be proposed for studying by transferring annotation. Finally, our database can also be of use to clinical and translational laboratories, helping them to identify uncommon AMs that can correlate with response to new antitumor drugs. The website was developed using PHP and JavaScript, which are supported by all major browsers; the database was built using MySQL server. Kin-driver is available at: http://kin-driver.leloir.org.ar/

  7. Detection of driver pathways using mutated gene network in cancer.

    PubMed

    Li, Feng; Gao, Lin; Ma, Xiaoke; Yang, Xiaofei

    2016-06-21

    Distinguishing driver pathways has been extensively studied because they are critical for understanding the development and molecular mechanisms of cancers. Most existing methods for driver pathways are based on high coverage as well as high mutual exclusivity, with the underlying assumption that mutations are exclusive. However, in many cases, mutated driver genes in the same pathways are not strictly mutually exclusive. Based on this observation, we propose an index for quantifying mutual exclusivity between gene pairs. Then, we construct a mutated gene network for detecting driver pathways by integrating the proposed index and coverage. The detection of driver pathways on the mutated gene network consists of two steps: raw pathways are obtained using a CPM method, and the final driver pathways are selected using a strict testing strategy. We apply this method to glioblastoma and breast cancers and find that our method is more accurate than state-of-the-art methods in terms of enrichment of KEGG pathways. Furthermore, the detected driver pathways intersect with well-known pathways with moderate exclusivity, which cannot be discovered using the existing algorithms. In conclusion, the proposed method provides an effective way to investigate driver pathways in cancers.

  8. Mutation analysis of 13 driver genes of colorectal cancer-related pathways in Taiwanese patients

    PubMed Central

    Chang, Yuli Christine; Chang, Jan-Gowth; Liu, Ta-Chih; Lin, Chien-Yu; Yang, Shu-Fen; Ho, Cheng-Mao; Chen, William Tzu-Liang; Chang, Ya-Sian

    2016-01-01

    AIM: To investigate the driver gene mutations associated with colorectal cancer (CRC) in the Taiwanese population. METHODS: In this study, 103 patients with CRC were evaluated. The samples consisted of 66 men and 37 women with a median age of 59 years and an age range of 26-86 years. We used high-resolution melting analysis (HRM) and direct DNA sequencing to characterize the mutations in 13 driver genes of CRC-related pathways. The HRM assays were conducted using the LightCycler® 480 Instrument provided with the software LightCycler® 480 Gene Scanning Software Version 1.5. We also compared the clinicopathological data of CRC patients with the driver gene mutation status. RESULTS: Of the 103 patients evaluated, 73.79% had mutations in one of the 13 driver genes. We discovered 18 novel mutations in APC, MLH1, MSH2, PMS2, SMAD4 and TP53 that have not been previously reported. Additionally, we found 16 de novo mutations in APC, BMPR1A, MLH1, MSH2, MSH6, MUTYH and PMS2 in cancerous tissues previously reported in the dbSNP database; however, these mutations could not be detected in peripheral blood cells. The APC mutation correlates with lymph node metastasis (34.69% vs 12.96%, P = 0.009) and cancer stage (34.78% vs 14.04%, P = 0.013). No association was observed between other driver gene mutations and clinicopathological features. Furthermore, having two or more driver gene mutations correlates with the degree of lymph node metastasis (42.86% vs 24.07%, P = 0.043). CONCLUSION: Our findings confirm the importance of 13 CRC-related pathway driver genes in the development of CRC in Taiwanese patients. PMID:26900293

  9. Clinical and biological implications of driver mutations in myelodysplastic syndromes

    PubMed Central

    Papaemmanuil, Elli; Gerstung, Moritz; Malcovati, Luca; Tauro, Sudhir; Gundem, Gunes; Van Loo, Peter; Yoon, Chris J.; Ellis, Peter; Wedge, David C.; Pellagatti, Andrea; Shlien, Adam; Groves, Michael John; Forbes, Simon A.; Raine, Keiran; Hinton, Jon; Mudie, Laura J.; McLaren, Stuart; Hardy, Claire; Latimer, Calli; Della Porta, Matteo G.; O’Meara, Sarah; Ambaglio, Ilaria; Galli, Anna; Butler, Adam P.; Walldin, Gunilla; Teague, Jon W.; Quek, Lynn; Sternberg, Alex; Gambacorti-Passerini, Carlo; Cross, Nicholas C. P.; Green, Anthony R.; Boultwood, Jacqueline; Vyas, Paresh; Hellstrom-Lindberg, Eva; Bowen, David; Cazzola, Mario; Stratton, Michael R.

    2013-01-01

    Myelodysplastic syndromes (MDS) are a heterogeneous group of chronic hematological malignancies characterized by dysplasia, ineffective hematopoiesis and a variable risk of progression to acute myeloid leukemia. Sequencing of MDS genomes has identified mutations in genes implicated in RNA splicing, DNA modification, chromatin regulation, and cell signaling. We sequenced 111 genes across 738 patients with MDS or closely related neoplasms (including chronic myelomonocytic leukemia and MDS–myeloproliferative neoplasms) to explore the role of acquired mutations in MDS biology and clinical phenotype. Seventy-eight percent of patients had 1 or more oncogenic mutations. We identify complex patterns of pairwise association between genes, indicative of epistatic interactions involving components of the spliceosome machinery and epigenetic modifiers. Coupled with inferences on subclonal mutations, these data suggest a hypothesis of genetic “predestination,” in which early driver mutations, typically affecting genes involved in RNA splicing, dictate future trajectories of disease evolution with distinct clinical phenotypes. Driver mutations had equivalent prognostic significance, whether clonal or subclonal, and leukemia-free survival deteriorated steadily as numbers of driver mutations increased. Thus, analysis of oncogenic mutations in large, well-characterized cohorts of patients illustrates the interconnections between the cancer genome and disease biology, with considerable potential for clinical application. PMID:24030381

  10. Integrative analysis of mutational and transcriptional profiles reveals driver mutations of metastatic breast cancers

    PubMed Central

    Lee, Ji-Hyun; Zhao, Xing-Ming; Yoon, Ina; Lee, Jin Young; Kwon, Nam Hoon; Wang, Yin-Ying; Lee, Kyung-Min; Lee, Min-Joo; Kim, Jisun; Moon, Hyeong-Gon; In, Yongho; Hao, Jin-Kao; Park, Kyung-Mii; Noh, Dong-Young; Han, Wonshik; Kim, Sunghoon

    2016-01-01

    Despite the explosion in the numbers of cancer genomic studies, metastasis is still the major cause of cancer mortality. In breast cancer, approximately one-fifth of metastatic patients survive 5 years. Therefore, detecting the patients at a high risk of developing distant metastasis at first diagnosis is critical for effective treatment strategy. We hereby present a novel systems biology approach to identify driver mutations escalating the risk of metastasis based on both exome and RNA sequencing of our collected 78 normal-paired breast cancers. Unlike driver mutations occurring commonly in cancers as reported in the literature, the mutations detected here are relatively rare mutations occurring in less than half metastatic samples. By supposing that the driver mutations should affect the metastasis gene signatures, we develop a novel computational pipeline to identify the driver mutations that affect transcription factors regulating metastasis gene signatures. We identify driver mutations in ADPGK, NUP93, PCGF6, PKP2 and SLC22A5, which are verified to enhance cancer cell migration and prompt metastasis with in vitro experiments. The discovered somatic mutations may be helpful for identifying patients who are likely to develop distant metastasis. PMID:27625789

  11. Integrative analysis of mutational and transcriptional profiles reveals driver mutations of metastatic breast cancers.

    PubMed

    Lee, Ji-Hyun; Zhao, Xing-Ming; Yoon, Ina; Lee, Jin Young; Kwon, Nam Hoon; Wang, Yin-Ying; Lee, Kyung-Min; Lee, Min-Joo; Kim, Jisun; Moon, Hyeong-Gon; In, Yongho; Hao, Jin-Kao; Park, Kyung-Mii; Noh, Dong-Young; Han, Wonshik; Kim, Sunghoon

    2016-01-01

    Despite the explosion in the numbers of cancer genomic studies, metastasis is still the major cause of cancer mortality. In breast cancer, approximately one-fifth of metastatic patients survive 5 years. Therefore, detecting the patients at a high risk of developing distant metastasis at first diagnosis is critical for effective treatment strategy. We hereby present a novel systems biology approach to identify driver mutations escalating the risk of metastasis based on both exome and RNA sequencing of our collected 78 normal-paired breast cancers. Unlike driver mutations occurring commonly in cancers as reported in the literature, the mutations detected here are relatively rare mutations occurring in less than half metastatic samples. By supposing that the driver mutations should affect the metastasis gene signatures, we develop a novel computational pipeline to identify the driver mutations that affect transcription factors regulating metastasis gene signatures. We identify driver mutations in ADPGK, NUP93, PCGF6, PKP2 and SLC22A5, which are verified to enhance cancer cell migration and prompt metastasis with in vitro experiments. The discovered somatic mutations may be helpful for identifying patients who are likely to develop distant metastasis.

  12. Altered oncomodules underlie chromatin regulatory factors driver mutations.

    PubMed

    Frigola, Joan; Iturbide, Ane; Lopez-Bigas, Nuria; Peiro, Sandra; Gonzalez-Perez, Abel

    2016-05-24

    Chromatin regulatory factors (CRFs), are known to be involved in tumorigenesis in several cancer types. Nevertheless, the molecular mechanisms through which driver alterations of CRFs cause tumorigenesis remain unknown. Here, we developed a CRFs Oncomodules Discovery approach, which mines several sources of cancer genomics and perturbaomics data. The approach prioritizes sets of genes significantly miss-regulated in primary tumors (oncomodules) bearing mutations of driver CRFs. We applied the approach to eleven TCGA tumor cohorts and uncovered oncomodules potentially associated to mutations of five driver CRFs in three cancer types. Our results revealed, for example, the potential involvement of the mTOR pathway in the development of tumors with loss-of-function mutations of MLL2 in head and neck squamous cell carcinomas. The experimental validation that MLL2 loss-of-function increases the sensitivity of cancer cell lines to mTOR inhibition lends further support to the validity of our approach. The potential oncogenic modules detected by our approach may guide experiments proposing ways to indirectly target driver mutations of CRFs.

  13. Altered oncomodules underlie chromatin regulatory factors driver mutations

    PubMed Central

    Frigola, Joan; Iturbide, Ane; Lopez-Bigas, Nuria; Peiro, Sandra; Gonzalez-Perez, Abel

    2016-01-01

    Chromatin regulatory factors (CRFs), are known to be involved in tumorigenesis in several cancer types. Nevertheless, the molecular mechanisms through which driver alterations of CRFs cause tumorigenesis remain unknown. Here, we developed a CRFs Oncomodules Discovery approach, which mines several sources of cancer genomics and perturbaomics data. The approach prioritizes sets of genes significantly miss-regulated in primary tumors (oncomodules) bearing mutations of driver CRFs. We applied the approach to eleven TCGA tumor cohorts and uncovered oncomodules potentially associated to mutations of five driver CRFs in three cancer types. Our results revealed, for example, the potential involvement of the mTOR pathway in the development of tumors with loss-of-function mutations of MLL2 in head and neck squamous cell carcinomas. The experimental validation that MLL2 loss-of-function increases the sensitivity of cancer cell lines to mTOR inhibition lends further support to the validity of our approach. The potential oncogenic modules detected by our approach may guide experiments proposing ways to indirectly target driver mutations of CRFs. PMID:27095575

  14. Dynamic changes of driver genes' mutations across clinical stages in nine cancer types.

    PubMed

    Li, Xia

    2016-07-01

    The driver genes play critical roles for tumorigenesis, and the number of identified driver genes reached plateau. But how they act during different cancer development stages is lack of knowledge. We investigated 138 driver genes' mutation changes across clinical stages using 3,477 cases in nine cancer types from the Cancer Genome Atlas (TCGA) and constructed their temporal order relationships. We also examined the codon changes for the widely mutated TP53 and PIK3CA in tumor stages. Combinations of one to three driver genes specifically dominated in each cancer. Across the clinical stages, we categorized three patterns for the behaviors of driver genes' mutation changes in the nine cancer types: recurrently mutated in all the stages and triggering other mutations; certain mutations lost meanwhile other mutations emerged; mutations dominated across entire stages, while other mutations gradually appeared or disappeared. We observed different codon changes dominated in different stages and revealed mutations recurrently occurring on the hotspot regions of the coding sequence may be the core factor for driver genes' tumorigenesis. Our results highlighted the dynamic changes of oncogenesis roles in different clinical stages and suggested different diagnostic decision making according to the clinical stages of patients.

  15. Multiregion sequencing reveals the intratumor heterogeneity of driver mutations in TP53-driven non-small cell lung cancer.

    PubMed

    Zhang, Le-Le; Kan, Mengyuan; Zhang, Man-Man; Yu, Sha-Sha; Xie, Hui-Jun; Gu, Zhao-Hui; Wang, Hai-Ning; Zhao, Shuang-Xia; Zhou, Guang-Biao; Song, Huai-Dong; Zheng, Cui-Xia

    2017-01-01

    Intratumor heterogeneity (ITH) in non-small cell lung cancer (NSCLC) may account for resistance after a period of targeted therapies because drugs destroy only a portion of tumor cells. The recognition of ITH helps identify high-risk patients to make effective treatment decisions. However, ITH studies are confounded by interpatient heterogeneity in NSCLC and a large amount of passenger mutations. To address these issues, we recruited NSCLC patients carrying TP53 mutations and selected driver mutations within recurrently mutated genes in NSCLC. A total of 12-paired normal-tumor tissues were subjected to whole-genome/whole-exome sequencing. From these, 367 non-silent mutations were selected as driver mutations and deeply sequenced in 61 intratumoral microdissections. We identified a universal prevalence of heterogeneity in all 12 tumors, indicating branched evolution. Although TP53 mutations were observed in single biopsy of all 12 tumors, most tumors consist of both TP53 mutated and non-mutated cells in separate regions within the same tumor. This suggests the late molecular timing of the acquisition of TP53 mutations; therefore, the detection of TP53 mutations in a single biopsy may simply not reflect the early malignant potential. In addition, we identified regions of loss of heterozygosity surrounding TP53 and CDKN2A mutations in tumor 711, which also exhibited heterogeneity in different regional samples. Because the ITH of driver mutations likely has clinical consequences, further efforts are needed to limit the impact of ITH and to improve therapeutic efficiency, which will benefit NSCLC patients receiving targeted treatments.

  16. Clonal status of actionable driver events and the timing of mutational processes in cancer evolution.

    PubMed

    McGranahan, Nicholas; Favero, Francesco; de Bruin, Elza C; Birkbak, Nicolai Juul; Szallasi, Zoltan; Swanton, Charles

    2015-04-15

    Deciphering whether actionable driver mutations are found in all or a subset of tumor cells will likely be required to improve drug development and precision medicine strategies. We analyzed nine cancer types to determine the subclonal frequencies of driver events, to time mutational processes during cancer evolution, and to identify drivers of subclonal expansions. Although mutations in known driver genes typically occurred early in cancer evolution, we also identified later subclonal "actionable" mutations, including BRAF (V600E), IDH1 (R132H), PIK3CA (E545K), EGFR (L858R), and KRAS (G12D), which may compromise the efficacy of targeted therapy approaches. More than 20% of IDH1 mutations in glioblastomas, and 15% of mutations in genes in the PI3K (phosphatidylinositol 3-kinase)-AKT-mTOR (mammalian target of rapamycin) signaling axis across all tumor types were subclonal. Mutations in the RAS-MEK (mitogen-activated protein kinase kinase) signaling axis were less likely to be subclonal than mutations in genes associated with PI3K-AKT-mTOR signaling. Analysis of late mutations revealed a link between APOBEC-mediated mutagenesis and the acquisition of subclonal driver mutations and uncovered putative cancer genes involved in subclonal expansions, including CTNNA2 and ATXN1. Our results provide a pan-cancer census of driver events within the context of intratumor heterogeneity and reveal patterns of tumor evolution across cancers. The frequent presence of subclonal driver mutations suggests the need to stratify targeted therapy response according to the proportion of tumor cells in which the driver is identified.

  17. Putative Breast Cancer Driver Mutations in TBX3 Cause Impaired Transcriptional Repression

    PubMed Central

    Fischer, Kathrin; Pflugfelder, Gert O.

    2015-01-01

    The closely related T-box transcription factors TBX2 and TBX3 are frequently overexpressed in melanoma and various types of human cancers, in particular, breast cancer. The overexpression of TBX2 and TBX3 can have several cellular effects, among them suppression of senescence, promotion of epithelial–mesenchymal transition, and invasive cell motility. In contrast, loss of function of TBX3 and most other human T-box genes causes developmental haploinsufficiency syndromes. Stephens and colleagues (1), by exome sequencing of breast tumor samples, identified five different mutations in TBX3, all affecting the DNA-binding T-domain. One in-frame deletion of a single amino acid, p.N212delN, was observed twice. Due to the clustering of these mutations to the T-domain and for statistical reasons, TBX3 was inferred to be a driver gene in breast cancer. Since mutations in the T-domain generally cause loss of function and because the tumorigenic action of TBX3 has generally been attributed to overexpression, we determined whether the putative driver mutations had loss- or gain-of-function properties. We tested two in-frame deletions, one missense, and one frameshift mutant protein for DNA-binding in vitro, and for target gene repression in cell culture. In addition, we performed an in silico analysis of somatic TBX mutations in breast cancer, collected in The Cancer Genome Atlas (TCGA). Both the experimental and the in silico analysis indicate that the observed mutations predominantly cause loss of TBX3 function. PMID:26579496

  18. Identification of mutated driver pathways in cancer using a multi-objective optimization model.

    PubMed

    Zheng, Chun-Hou; Yang, Wu; Chong, Yan-Wen; Xia, Jun-Feng

    2016-05-01

    New-generation high-throughput technologies, including next-generation sequencing technology, have been extensively applied to solve biological problems. As a result, large cancer genomics projects such as the Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium are producing large amount of rich and diverse data in multiple cancer types. The identification of mutated driver genes and driver pathways from these data is a significant challenge. Genome aberrations in cancer cells can be divided into two types: random 'passenger mutation' and functional 'driver mutation'. In this paper, we introduced a Multi-objective Optimization model based on a Genetic Algorithm (MOGA) to solve the maximum weight submatrix problem, which can be employed to identify driver genes and driver pathways promoting cancer proliferation. The maximum weight submatrix problem defined to find mutated driver pathways is based on two specific properties, i.e., high coverage and high exclusivity. The multi-objective optimization model can adjust the trade-off between high coverage and high exclusivity. We proposed an integrative model by combining gene expression data and mutation data to improve the performance of the MOGA algorithm in a biological context.

  19. Breast ductal carcinoma in situ carry mutational driver events representative of invasive breast cancer.

    PubMed

    Pang, Jia-Min B; Savas, Peter; Fellowes, Andrew P; Mir Arnau, Gisela; Kader, Tanjina; Vedururu, Ravikiran; Hewitt, Chelsee; Takano, Elena A; Byrne, David J; Choong, David Yh; Millar, Ewan Ka; Lee, C Soon; O'Toole, Sandra A; Lakhani, Sunil R; Cummings, Margaret C; Mann, G Bruce; Campbell, Ian G; Dobrovic, Alexander; Loi, Sherene; Gorringe, Kylie L; Fox, Stephen B

    2017-03-24

    The spectrum of genomic alterations in ductal carcinoma in situ (DCIS) is relatively unexplored, but is likely to provide useful insights into its biology, its progression to invasive carcinoma and the risk of recurrence. DCIS (n=20) with a range of phenotypes was assessed by massively parallel sequencing for mutations and copy number alterations and variants validated by Sanger sequencing. PIK3CA mutations were identified in 11/20 (55%), TP53 mutations in 6/20 (30%), and GATA3 mutations in 9/20 (45%). Screening an additional 91 cases for GATA3 mutations identified a final frequency of 27% (30/111), with a high proportion of missense variants (8/30). TP53 mutations were exclusive to high grade DCIS and more frequent in PR-negative tumors compared with PR-positive tumors (P=0.037). TP53 mutant tumors also had a significantly higher fraction of the genome altered by copy number than wild-type tumors (P=0.005), including a significant positive association with amplification or gain of ERBB2 (P<0.05). The association between TP53 mutation and ERBB2 amplification was confirmed in a wider DCIS cohort using p53 immunohistochemistry as a surrogate marker for TP53 mutations (P=0.03). RUNX1 mutations and MAP2K4 copy number loss were novel findings in DCIS. Frequent copy number alterations included gains on 1q, 8q, 17q, and 20q and losses on 8p, 11q, 16q, and 17p. Patterns of genomic alterations observed in DCIS were similar to those previously reported for invasive breast cancers, with all DCIS having at least one bona fide breast cancer driver event. However, an increase in GATA3 mutations and fewer copy number changes were noted in DCIS compared with invasive carcinomas. The role of such alterations as prognostic and predictive biomarkers in DCIS is an avenue for further investigation.Modern Pathology advance online publication, 24 March 2017; doi:10.1038/modpathol.2017.21.

  20. Identifying driver mutations in sequenced cancer genomes: computational approaches to enable precision medicine

    PubMed Central

    2014-01-01

    High-throughput DNA sequencing is revolutionizing the study of cancer and enabling the measurement of the somatic mutations that drive cancer development. However, the resulting sequencing datasets are large and complex, obscuring the clinically important mutations in a background of errors, noise, and random mutations. Here, we review computational approaches to identify somatic mutations in cancer genome sequences and to distinguish the driver mutations that are responsible for cancer from random, passenger mutations. First, we describe approaches to detect somatic mutations from high-throughput DNA sequencing data, particularly for tumor samples that comprise heterogeneous populations of cells. Next, we review computational approaches that aim to predict driver mutations according to their frequency of occurrence in a cohort of samples, or according to their predicted functional impact on protein sequence or structure. Finally, we review techniques to identify recurrent combinations of somatic mutations, including approaches that examine mutations in known pathways or protein-interaction networks, as well as de novo approaches that identify combinations of mutations according to statistical patterns of mutual exclusivity. These techniques, coupled with advances in high-throughput DNA sequencing, are enabling precision medicine approaches to the diagnosis and treatment of cancer. PMID:24479672

  1. Network-Based Analysis of eQTL Data to Prioritize Driver Mutations.

    PubMed

    De Maeyer, Dries; Weytjens, Bram; De Raedt, Luc; Marchal, Kathleen

    2016-01-23

    In clonal systems, interpreting driver genes in terms of molecular networks helps understanding how these drivers elicit an adaptive phenotype. Obtaining such a network-based understanding depends on the correct identification of driver genes. In clonal systems, independent evolved lines can acquire a similar adaptive phenotype by affecting the same molecular pathways, a phenomenon referred to as parallelism at the molecular pathway level. This implies that successful driver identification depends on interpreting mutated genes in terms of molecular networks. Driver identification and obtaining a network-based understanding of the adaptive phenotype are thus confounded problems that ideally should be solved simultaneously. In this study, a network-based eQTL method is presented that solves both the driver identification and the network-based interpretation problem. As input the method uses coupled genotype-expression phenotype data (eQTL data) of independently evolved lines with similar adaptive phenotypes and an organism-specific genome-wide interaction network. The search for mutational consistency at pathway level is defined as a subnetwork inference problem, which consists of inferring a subnetwork from the genome-wide interaction network that best connects the genes containing mutations to differentially expressed genes. Based on their connectivity with the differentially expressed genes, mutated genes are prioritized as driver genes. Based on semisynthetic data and two publicly available data sets, we illustrate the potential of the network-based eQTL method to prioritize driver genes and to gain insights in the molecular mechanisms underlying an adaptive phenotype. The method is available at http://bioinformatics.intec.ugent.be/phenetic_eqtl/index.html.

  2. Malignancy of Cancers and Synthetic Lethal Interactions Associated With Mutations of Cancer Driver Genes.

    PubMed

    Wang, Xiaosheng; Zhang, Yue; Han, Ze-Guang; He, Kun-Yan

    2016-02-01

    The mutation status of cancer driver genes may correlate with different degrees of malignancy of cancers. The doubling time and multidrug resistance are 2 phenotypes that reflect the degree of malignancy of cancer cells. Because most of cancer driver genes are hard to target, identification of their synthetic lethal partners might be a viable approach to treatment of the cancers with the relevant mutations.The genome-wide screening for synthetic lethal partners is costly and labor intensive. Thus, a computational approach facilitating identification of candidate genes for a focus synthetic lethal RNAi screening will accelerate novel anticancer drug discovery.We used several publicly available cancer cell lines and tumor tissue genomic data in this study.We compared the doubling time and multidrug resistance between the NCI-60 cell lines with mutations in some cancer driver genes and those without the mutations. We identified some candidate synthetic lethal genes to the cancer driver genes APC, KRAS, BRAF, PIK3CA, and TP53 by comparison of their gene phenotype values in cancer cell lines with the relevant mutations and wild-type background. Further, we experimentally validated some of the synthetic lethal relationships we predicted.We reported that mutations in some cancer driver genes mutations in some cancer driver genes such as APC, KRAS, or PIK3CA might correlate with cancer proliferation or drug resistance. We identified 40, 21, 5, 43, and 18 potential synthetic lethal genes to APC, KRAS, BRAF, PIK3CA, and TP53, respectively. We found that some of the potential synthetic lethal genes show significantly higher expression in the cancers with mutations of their synthetic lethal partners and the wild-type counterparts. Further, our experiments confirmed several synthetic lethal relationships that are novel findings by our methods.We experimentally validated a part of the synthetic lethal relationships we predicted. We plan to perform further experiments to validate

  3. Variation in KRAS driver substitution distributions between tumor types is determined by both mutation and natural selection

    PubMed Central

    Ostrow, Sheli L.; Simon, Einav; Prinz, Elad; Bick, Tova; Shentzer, Talia; Nagawkar, Sima S.; Sabo, Edmond; Ben-Izhak, Ofer; Hershberg, Ruth; Hershkovitz, Dov

    2016-01-01

    Different tumor types vary greatly in their distribution of driver substitutions. Here, we analyzed how mutation and natural selection contribute to differences in the distribution of KRAS driver substitutions between lung, colon and pancreatic adenocarcinomas. We were able to demonstrate that both differences in mutation and differences in selection drive variation in the distribution of KRAS driver substitutions between tumor types. By accounting for the effects of mutation on the distribution of KRAS driver substitutions, we could identify specific KRAS driver substitutions that are more favored by selection in specific tumor types. Such driver substitutions likely improve fitness most when they occur within the context of the tumor type in which they are preferentially favored. Fitting with this, we found that driver substitutions that are more favored by natural selection in a specific type of tumor tend to associate with worse clinical outcomes specifically in that type of tumor. PMID:26902163

  4. Variation in KRAS driver substitution distributions between tumor types is determined by both mutation and natural selection.

    PubMed

    Ostrow, Sheli L; Simon, Einav; Prinz, Elad; Bick, Tova; Shentzer, Talia; Nagawkar, Sima S; Sabo, Edmond; Ben-Izhak, Ofer; Hershberg, Ruth; Hershkovitz, Dov

    2016-02-23

    Different tumor types vary greatly in their distribution of driver substitutions. Here, we analyzed how mutation and natural selection contribute to differences in the distribution of KRAS driver substitutions between lung, colon and pancreatic adenocarcinomas. We were able to demonstrate that both differences in mutation and differences in selection drive variation in the distribution of KRAS driver substitutions between tumor types. By accounting for the effects of mutation on the distribution of KRAS driver substitutions, we could identify specific KRAS driver substitutions that are more favored by selection in specific tumor types. Such driver substitutions likely improve fitness most when they occur within the context of the tumor type in which they are preferentially favored. Fitting with this, we found that driver substitutions that are more favored by natural selection in a specific type of tumor tend to associate with worse clinical outcomes specifically in that type of tumor.

  5. Inhibiting Drivers of Non-mutational Drug Tolerance Is a Salvage Strategy for Targeted Melanoma Therapy

    PubMed Central

    Smith, Michael P.; Brunton, Holly; Rowling, Emily J.; Ferguson, Jennifer; Arozarena, Imanol; Miskolczi, Zsofia; Lee, Jessica L.; Girotti, Maria R.; Marais, Richard; Levesque, Mitchell P.; Dummer, Reinhard; Frederick, Dennie T.; Flaherty, Keith T.; Cooper, Zachary A.; Wargo, Jennifer A.; Wellbrock, Claudia

    2016-01-01

    Summary Once melanomas have progressed with acquired resistance to mitogen-activated protein kinase (MAPK)-targeted therapy, mutational heterogeneity presents a major challenge. We therefore examined the therapy phase before acquired resistance had developed and discovered the melanoma survival oncogene MITF as a driver of an early non-mutational and reversible drug-tolerance state, which is induced by PAX3-mediated upregulation of MITF. A drug-repositioning screen identified the HIV1-protease inhibitor nelfinavir as potent suppressor of PAX3 and MITF expression. Nelfinavir profoundly sensitizes BRAF and NRAS mutant melanoma cells to MAPK-pathway inhibitors. Moreover, nelfinavir is effective in BRAF and NRAS mutant melanoma cells isolated from patients progressed on MAPK inhibitor (MAPKi) therapy and in BRAF/NRAS/PTEN mutant tumors. We demonstrate that inhibiting a driver of MAPKi-induced drug tolerance could improve current approaches of targeted melanoma therapy. PMID:26977879

  6. Mutation of cancer driver MLL2 results in transcription stress and genome instability

    PubMed Central

    Kantidakis, Theodoros; Saponaro, Marco; Mitter, Richard; Horswell, Stuart; Kranz, Andrea; Boeing, Stefan; Aygün, Ozan; Kelly, Gavin P.; Matthews, Nik; Stewart, Aengus; Stewart, A. Francis; Svejstrup, Jesper Q.

    2016-01-01

    Genome instability is a recurring feature of tumorigenesis. Mutation in MLL2, encoding a histone methyltransferase, is a driver in numerous different cancer types, but the mechanism is unclear. Here, we present evidence that MLL2 mutation results in genome instability. Mouse cells in which MLL2 gene deletion can be induced display elevated levels of sister chromatid exchange, gross chromosomal aberrations, 53BP1 foci, and micronuclei. Human MLL2 knockout cells are characterized by genome instability as well. Interestingly, MLL2 interacts with RNA polymerase II (RNAPII) and RECQL5, and, although MLL2 mutated cells have normal overall H3K4me levels in genes, nucleosomes in the immediate vicinity of RNAPII are hypomethylated. Importantly, MLL2 mutated cells display signs of substantial transcription stress, and the most affected genes overlap with early replicating fragile sites, show elevated levels of γH2AX, and suffer frequent mutation. The requirement for MLL2 in the maintenance of genome stability in genes helps explain its widespread role in cancer and points to transcription stress as a strong driver in tumorigenesis. PMID:26883360

  7. Recurrent chromosomal gains and heterogeneous driver mutations characterise papillary renal cancer evolution

    PubMed Central

    Kovac, Michal; Navas, Carolina; Horswell, Stuart; Salm, Max; Bardella, Chiara; Rowan, Andrew; Stares, Mark; Castro-Giner, Francesc; Fisher, Rosalie; de Bruin, Elza C.; Kovacova, Monika; Gorman, Maggie; Makino, Seiko; Williams, Jennet; Jaeger, Emma; Jones, Angela; Howarth, Kimberley; Larkin, James; Pickering, Lisa; Gore, Martin; Nicol, David L.; Hazell, Steven; Stamp, Gordon; O’Brien, Tim; Challacombe, Ben; Matthews, Nik; Phillimore, Benjamin; Begum, Sharmin; Rabinowitz, Adam; Varela, Ignacio; Chandra, Ashish; Horsfield, Catherine; Polson, Alexander; Tran, Maxine; Bhatt, Rupesh; Terracciano, Luigi; Eppenberger-Castori, Serenella; Protheroe, Andrew; Maher, Eamonn; El Bahrawy, Mona; Fleming, Stewart; Ratcliffe, Peter; Heinimann, Karl; Swanton, Charles; Tomlinson, Ian

    2015-01-01

    Papillary renal cell carcinoma (pRCC) is an important subtype of kidney cancer with a problematic pathological classification and highly variable clinical behaviour. Here we sequence the genomes or exomes of 31 pRCCs, and in four tumours, multi-region sequencing is undertaken. We identify BAP1, SETD2, ARID2 and Nrf2 pathway genes (KEAP1, NHE2L2 and CUL3) as probable drivers, together with at least eight other possible drivers. However, only ~10% of tumours harbour detectable pathogenic changes in any one driver gene, and where present, the mutations are often predicted to be present within cancer sub-clones. We specifically detect parallel evolution of multiple SETD2 mutations within different sub-regions of the same tumour. By contrast, large copy number gains of chromosomes 7, 12, 16 and 17 are usually early, monoclonal changes in pRCC evolution. The predominance of large copy number variants as the major drivers for pRCC highlights an unusual mode of tumorigenesis that may challenge precision medicine approaches. PMID:25790038

  8. Genomic characterization of pediatric T-cell acute lymphoblastic leukemia reveals novel recurrent driver mutations

    PubMed Central

    Spinella, Jean-François; Cassart, Pauline; Richer, Chantal; Saillour, Virginie; Ouimet, Manon; Langlois, Sylvie; St-Onge, Pascal; Sontag, Thomas; Healy, Jasmine; Minden, Mark D.; Sinnett, Daniel

    2016-01-01

    T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy with variable prognosis. It represents 15% of diagnosed pediatric ALL cases and has a threefold higher incidence among males. Many recurrent alterations have been identified and help define molecular subgroups of T-ALL, however the full range of events involved in driving transformation remain to be defined. Using an integrative approach combining genomic and transcriptomic data, we molecularly characterized 30 pediatric T-ALLs and identified common recurrent T-ALL targets such as FBXW7, JAK1, JAK3, PHF6, KDM6A and NOTCH1 as well as novel candidate T-ALL driver mutations including the p.R35L missense mutation in splicesome factor U2AF1 found in 3 patients and loss of function mutations in the X-linked tumor suppressor genes MED12 (frameshit mutation p.V167fs, splice site mutation g.chrX:70339329T>C, missense mutation p.R1989H) and USP9X (nonsense mutation p.Q117*). In vitro functional studies further supported the putative role of these novel T-ALL genes in driving transformation. U2AF1 p.R35L was shown to induce aberrant splicing of downstream target genes, and shRNA knockdown of MED12 and USP9X was shown to confer resistance to apoptosis following T-ALL relevant chemotherapy drug treatment in Jurkat leukemia cells. Interestingly, nearly 60% of novel candidate driver events were identified among immature T-ALL cases, highlighting the underlying genomic complexity of pediatric T-ALL, and the need for larger integrative studies to decipher the mechanisms that contribute to its various subtypes and provide opportunities to refine patient stratification and treatment. PMID:27602765

  9. Clinical effect of driver mutations of JAK2, CALR, or MPL in primary myelofibrosis

    PubMed Central

    Rumi, Elisa; Pietra, Daniela; Pascutto, Cristiana; Guglielmelli, Paola; Martínez-Trillos, Alejandra; Casetti, Ilaria; Colomer, Dolors; Pieri, Lisa; Pratcorona, Marta; Rotunno, Giada; Sant’Antonio, Emanuela; Bellini, Marta; Cavalloni, Chiara; Mannarelli, Carmela; Milanesi, Chiara; Boveri, Emanuela; Ferretti, Virginia; Astori, Cesare; Rosti, Vittorio; Cervantes, Francisco; Barosi, Giovanni; Vannucchi, Alessandro M.

    2014-01-01

    We studied the impact of driver mutations of JAK2, CALR, (calreticulin gene) or MPL on clinical course, leukemic transformation, and survival of patients with primary myelofibrosis (PMF). Of the 617 subjects studied, 399 (64.7%) carried JAK2 (V617F), 140 (22.7%) had a CALR exon 9 indel, 25 (4.0%) carried an MPL (W515) mutation, and 53 (8.6%) had nonmutated JAK2, CALR, and MPL (so-called triple-negative PMF). Patients with CALR mutation had a lower risk of developing anemia, thrombocytopenia, and marked leukocytosis compared with other subtypes. They also had a lower risk of thrombosis compared with patients carrying JAK2 (V617F). At the opposite, triple-negative patients had higher incidence of leukemic transformation compared with either CALR-mutant or JAK2-mutant patients. Median overall survival was 17.7 years in CALR-mutant, 9.2 years in JAK2-mutant, 9.1 years in MPL-mutant, and 3.2 years in triple-negative patients. In multivariate analysis corrected for age, CALR-mutant patients had better overall survival than either JAK2-mutant or triple-negative patients. The impact of genetic lesions on survival was independent of current prognostic scoring systems. These observations indicate that driver mutations define distinct disease entities within PMF. Accounting for them is not only relevant to clinical decision-making, but should also be considered in designing clinical trials. PMID:24986690

  10. Clinical effect of driver mutations of JAK2, CALR, or MPL in primary myelofibrosis.

    PubMed

    Rumi, Elisa; Pietra, Daniela; Pascutto, Cristiana; Guglielmelli, Paola; Martínez-Trillos, Alejandra; Casetti, Ilaria; Colomer, Dolors; Pieri, Lisa; Pratcorona, Marta; Rotunno, Giada; Sant'Antonio, Emanuela; Bellini, Marta; Cavalloni, Chiara; Mannarelli, Carmela; Milanesi, Chiara; Boveri, Emanuela; Ferretti, Virginia; Astori, Cesare; Rosti, Vittorio; Cervantes, Francisco; Barosi, Giovanni; Vannucchi, Alessandro M; Cazzola, Mario

    2014-08-14

    We studied the impact of driver mutations of JAK2, CALR, (calreticulin gene) or MPL on clinical course, leukemic transformation, and survival of patients with primary myelofibrosis (PMF). Of the 617 subjects studied, 399 (64.7%) carried JAK2 (V617F), 140 (22.7%) had a CALR exon 9 indel, 25 (4.0%) carried an MPL (W515) mutation, and 53 (8.6%) had nonmutated JAK2, CALR, and MPL (so-called triple-negative PMF). Patients with CALR mutation had a lower risk of developing anemia, thrombocytopenia, and marked leukocytosis compared with other subtypes. They also had a lower risk of thrombosis compared with patients carrying JAK2 (V617F). At the opposite, triple-negative patients had higher incidence of leukemic transformation compared with either CALR-mutant or JAK2-mutant patients. Median overall survival was 17.7 years in CALR-mutant, 9.2 years in JAK2-mutant, 9.1 years in MPL-mutant, and 3.2 years in triple-negative patients. In multivariate analysis corrected for age, CALR-mutant patients had better overall survival than either JAK2-mutant or triple-negative patients. The impact of genetic lesions on survival was independent of current prognostic scoring systems. These observations indicate that driver mutations define distinct disease entities within PMF. Accounting for them is not only relevant to clinical decision-making, but should also be considered in designing clinical trials.

  11. 'GAIM' - Gas-addition, impedance-matched arc driver. [shock tube gas dynamics

    NASA Technical Reports Server (NTRS)

    Dannenberg, R. E.

    1980-01-01

    A conceptual view for a GAIM energy/driver system to maximize shock-tube performance through efficient interfacing of the energy source with the gas dynamics of the arc driver is presented. Electrical and arc-chamber requirements are evaluated utilizing two new computer codes. One code calculates the shock wave generated for a selected time rate and magnitude of arc-energy input; the other computes the values of external circuit elements required to produce the selected energy input, with the driver represented as the load element of the electrical discharge circuit. Results indicate that the energy-storage capability and the driver arrangement needed to produce the highest shock Mach number can be achieved by means of driver gas addition and by impedance matching (GAIM). Design criteria are presented for arc energy requirements necessary to produce given shock-wave speeds. Shock velocities as high as the 70 km/sec required for simulating Jovian entry now seem possible in shock-tube operation. Practical implementation of a GAIM system is discussed.

  12. Identification of outcome-related driver mutations in cancer using conditional co-occurrence distributions

    PubMed Central

    Treviño, Victor; Martínez-Ledesma, Emmanuel; Tamez-Peña, José

    2017-01-01

    Previous methods proposed for the detection of cancer driver mutations have been based on the estimation of background mutation rate, impact on protein function, or network influence. In this paper, we instead focus on those factors influencing patient survival. To this end, an approximation of the log-rank test has been systematically applied, even though it assumes a large and similar number of patients in both risk groups, which is violated in cancer genomics. Here, we propose VALORATE, a novel algorithm for the estimation of the null distribution for the log-rank, independent of the number of mutations. VALORATE is based on conditional distributions of the co-occurrences between events and mutations. The results, achieved through simulations, comparisons with other methods, analyses of TCGA and ICGC cancer datasets, and validations, suggest that VALORATE is accurate, fast, and can identify both known and novel gene mutations. Our proposal and results may have important implications in cancer biology, bioinformatics analyses, and ultimately precision medicine. PMID:28240231

  13. Computational DNA hole spectroscopy: A new tool to predict mutation hotspots, critical base pairs, and disease 'driver' mutations.

    PubMed

    Villagrán, Martha Y Suárez; Miller, John H

    2015-08-27

    We report on a new technique, computational DNA hole spectroscopy, which creates spectra of electron hole probabilities vs. nucleotide position. A hole is a site of positive charge created when an electron is removed. Peaks in the hole spectrum depict sites where holes tend to localize and potentially trigger a base pair mismatch during replication. Our studies of mitochondrial DNA reveal a correlation between L-strand hole spectrum peaks and spikes in the human mutation spectrum. Importantly, we also find that hole peak positions that do not coincide with large variant frequencies often coincide with disease-implicated mutations and/or (for coding DNA) encoded conserved amino acids. This enables combining hole spectra with variant data to identify critical base pairs and potential disease 'driver' mutations. Such integration of DNA hole and variance spectra could ultimately prove invaluable for pinpointing critical regions of the vast non-protein-coding genome. An observed asymmetry in correlations, between the spectrum of human mtDNA variations and the L- and H-strand hole spectra, is attributed to asymmetric DNA replication processes that occur for the leading and lagging strands.

  14. Systematic analysis of somatic mutations in phosphorylation signaling predicts novel cancer drivers

    PubMed Central

    Reimand, Jüri; Bader, Gary D

    2013-01-01

    Large-scale cancer genome sequencing has uncovered thousands of gene mutations, but distinguishing tumor driver genes from functionally neutral passenger mutations is a major challenge. We analyzed 800 cancer genomes of eight types to find single-nucleotide variants (SNVs) that precisely target phosphorylation machinery, important in cancer development and drug targeting. Assuming that cancer-related biological systems involve unexpectedly frequent mutations, we used novel algorithms to identify genes with significant phosphorylation-associated SNVs (pSNVs), phospho-mutated pathways, kinase networks, drug targets, and clinically correlated signaling modules. We highlight increased survival of patients with TP53 pSNVs, hierarchically organized cancer kinase modules, a novel pSNV in EGFR, and an immune-related network of pSNVs that correlates with prolonged survival in ovarian cancer. Our findings include multiple actionable cancer gene candidates (FLNB, GRM1, POU2F1), protein complexes (HCF1, ASF1), and kinases (PRKCZ). This study demonstrates new ways of interpreting cancer genomes and presents new leads for cancer research. PMID:23340843

  15. Pan-cancer transcriptomic analysis associates long non-coding RNAs with key mutational driver events

    PubMed Central

    Ashouri, Arghavan; Sayin, Volkan I.; Van den Eynden, Jimmy; Singh, Simranjit X.; Papagiannakopoulos, Thales; Larsson, Erik

    2016-01-01

    Thousands of long non-coding RNAs (lncRNAs) lie interspersed with coding genes across the genome, and a small subset has been implicated as downstream effectors in oncogenic pathways. Here we make use of transcriptome and exome sequencing data from thousands of tumours across 19 cancer types, to identify lncRNAs that are induced or repressed in relation to somatic mutations in key oncogenic driver genes. Our screen confirms known coding and non-coding effectors and also associates many new lncRNAs to relevant pathways. The associations are often highly reproducible across cancer types, and while many lncRNAs are co-expressed with their protein-coding hosts or neighbours, some are intergenic and independent. We highlight lncRNAs with possible functions downstream of the tumour suppressor TP53 and the master antioxidant transcription factor NFE2L2. Our study provides a comprehensive overview of lncRNA transcriptional alterations in relation to key driver mutational events in human cancers.

  16. Drunk driving among novice drivers, possible prevention with additional psychological module in driving school curriculum.

    PubMed

    Eensoo, Diva; Paaver, Marika; Harro, Jaanus

    2011-01-01

    Road traffic collisions caused by drunk driving pose a significant public health problem all over the world. Therefore additional preventive activities against drunk driving should be worked out. The aim of the study was to assess drunk driving in novice drivers after a psychological intervention taking into account also impulsivity, law obedience, and alcohol-related measures. An intervention study was started with 1889 car driver's license attempters during their driving school studies. Subjects were classified as intervention group (n=1083, mean age 23.1 (SD=7.4) years), control group (n=517, mean age 22.8 (SD=7.1) years) and "lost" group (n=289, mean age 23.0 (SD=6.9) years). "Lost" group subjects had been assigned into the intervention group, but they did not participate in the intervention. Subjects of the intervention group participated in a psychological intervention on the dangers of impulsive behavior in traffic. After a three year follow-up period it appeared that in the control group and in the lost group there was a significantly higher proportion of drunk drivers than in the intervention group, 3.3% (n=17), 3.5% (n=10) and 1.5% (n=10) (p=0.026), respectively. Survival analysis confirmed that psychological intervention had a significant impact on drunk driving (p=0.015), and the impact of the intervention was persistent also in the case of higher scores in Mild social deviance. In subjects with higher scores in impulsivity measures and alcohol-related problems the impact of short psychological intervention was not sufficient for preventing drunk driving. It can be concluded that psychological intervention used during the driving school studies is an effective primary prevention activity against drunk driving. However, for drivers with high scores in impulsivity measures and alcohol-related problems, the short psychological intervention is not sufficient in reducing drunk driving behavior.

  17. Low frequency KRAS mutations in colorectal cancer patients and the presence of multiple mutations in oncogenic drivers in non-small cell lung cancer patients.

    PubMed

    Jiang, Liyan; Huang, Jiaqi; Morehouse, Chris; Zhu, Wei; Korolevich, Susana; Sui, Dan; Ge, Xiaoxiao; Lehmann, Kim; Liu, Zheng; Kiefer, Christine; Czapiga, Meggan; Su, Xinying; Brohawn, Philip; Gu, Yi; Higgs, Brandon W; Yao, Yihong

    2013-01-01

    Intratumor heterogeneity can confound the results of mutation analyses in oncodriver genes using traditional methods thereby challenging the application of targeted cancer therapy strategies for patients Ultradeep sequencing can detect low frequency and expanded clonal mutations in primary tumors to better inform treatment decisions. KRAS coding exons in 61 treatment-naive colorectal cancer (CRC) tumors and KRAS, EGFR, ALK, and MET in lung tumors from three Chinese non-small cell lung cancer (NSCLC) patients were sequenced using ultradeep sequencing methods. Forty-one percent of CRC patients (25/61) harbored mutations in the KRAS active domain, eight of which (13%) were not detected by Sanger sequencing. Three (of eight) had frequencies less than 10% and one patient harbored more than one mutation. Low frequency KRAS active (G12R) and EGFR kinase domain mutations (G719A) were identified in one NSCLC patient. A second NSCLC patient showed an EML4-ALK fusion with ALK, EGFR, and MET mutations. A third NSCLC patient harbored multiple low frequency mutations in KRAS, EGFR, and MET as well as ALK gene copy number increases. Within the same patient, multiple low frequency mutations occurred within a gene. A complex pattern of intrinsic low frequency driver mutations in well-known tumor oncogenes may exist prior to treatment, resulting in resistance to targeted therapies. Ultradeep sequencing can characterize intratumor heterogeneity and identify such mutations to ultimately affect treatment decisions.

  18. Addition of molecular methods to mutation studies with Drosophila melanogaster

    SciTech Connect

    Lee, W.R. )

    1989-01-01

    For 80 years, Drosophila melanogaster has been used as a major tool in analyzing Mendelian genetics. By using chromosome inversions that suppress crossing over, geneticists have developed a large number of stocks for mutation analysis. These stocks permit numerous tests for specific locus mutations, lethals at multiple loci on any chromosome, chromosome exchanges, insertions, and deletions. The entire genome can be manipulated for a degree of genetic control not found in other germ-line systems. Recombinant DNA techniques now permit analysis of mutations to the nucleotide level. By combining classical genetic analysis with recombinant DNA techniques, it is possible to analyze mutations that range from chromosome aberrations and multilocus deficiencies to single nucleotide transitions.

  19. Addition of molecular methods to mutation studies with Drosophila melanogaster.

    PubMed

    Lee, W R

    1989-01-01

    For 80 years, Drosophila melanogaster has been used as a major tool in analyzing Mendelian genetics. By using chromosome inversions that suppress crossing over, geneticists have developed a large number of stocks for mutation analysis. These stocks permit numerous tests for specific locus mutations, lethals at multiple loci on any chromosome, chromosome exchanges, insertions, and deletions. The entire genome can be manipulated for a degree of genetic control not found in other germ-line systems. Recombinant DNA techniques now permit analysis of mutations to the nucleotide level. By combining classical genetic analysis with recombinant DNA techniques, it is possible to analyze mutations that range from chromosome aberrations and multilocus deficiencies to single nucleotide transitions.

  20. Driver mutations and differential sensitivity to targeted therapies: a new approach to the treatment of lung adenocarcinoma.

    PubMed

    Bronte, Giuseppe; Rizzo, Sergio; La Paglia, Laura; Adamo, Vincenzo; Siragusa, Sergio; Ficorella, Corrado; Santini, Daniele; Bazan, Viviana; Colucci, Giuseppe; Gebbia, Nicola; Russo, Antonio

    2010-11-01

    The adenocarcinoma of the lung has recently shown peculiar molecular characteristics, which relate with both carcinogenesis and response to targeted drugs. Several molecular alterations have been defined as "driver mutations". These are responsible for both the initiation and maintenance of the malignancy. The epidermal growth factor receptor (EGFR) pathway is the main regulator of cell function and cancer development. It has a widely defined role in the occurrence of driver mutations. Up till now EGFR gene mutations, KRAS gene mutations and EML4-ALK fusion genes are the most widely recognized alterations involved in both the biology and the clinical management of lung adenocarcinoma. In this review we report the molecular bases that have led to the clinical application of the detection for such genetic impairments. Subsequently we discuss the clinical studies regarding the prognostic role and the predictive value for response to anti-EGFR tyrosine kinase inhibitors (TKI) of the same mutations. We also provide a potential algorithm as a guide in the choice of the best treatment for patients with adenocarcinoma.

  1. Driver mutations among never smoking female lung cancer tissues in China identify unique EGFR and KRAS mutation pattern associated with household coal burning.

    PubMed

    Hosgood, H Dean; Pao, William; Rothman, Nathaniel; Hu, Wei; Pan, Yumei Helen; Kuchinsky, Kyle; Jones, Kirk D; Xu, Jun; Vermeulen, Roel; Simko, Jeff; Lan, Qing

    2013-11-01

    Lung cancer in never smokers, which has been partially attributed to household solid fuel use (i.e., coal), is etiologically and clinically different from lung cancer attributed to tobacco smoking. To explore the spectrum of driver mutations among lung cancer tissues from never smokers, specifically in a population where high lung cancer rates have been attributed to indoor air pollution from domestic coal use, multiplexed assays were used to detect >40 point mutations, insertions, and deletions (EGFR, KRAS, BRAF, HER2, NRAS, PIK3CA, MEK1, AKT1, and PTEN) among the lung tumors of confirmed never smoking females from Xuanwei, China [32 adenocarcinomas (ADCs), 7 squamous cell carcinomas (SCCs), 1 adenosquamous carcinoma (ADSC)]. EGFR mutations were detected in 35% of tumors. 46% of these involved EGFR exon 18 G719X, while 14% were exon 21 L858R mutations. KRAS mutations, all of which were G12C_34G>T, were observed in 15% of tumors. EGFR and KRAS mutations were mutually exclusive, and no mutations were observed in the other tested genes. Most point mutations were transversions and were also found in tumors from patients who used coal in their homes. Our high mutation frequencies in EGFR exon 18 and KRAS and low mutation frequency in EGFR exon 21 are strikingly divergent from those in other smoking and never smoking populations from Asia. Given that our subjects live in a region where coal is typically burned indoors, our findings provide new insights into the pathogenesis of lung cancer among never smoking females exposed to indoor air pollution from coal.

  2. Accounting for additive genetic mutations on litter size in Ripollesa sheep.

    PubMed

    Casellas, J; Caja, G; Piedrafita, J

    2010-04-01

    Little is known about mutational variability in livestock, among which only a few mutations with relatively large effects have been reported. In this manuscript, mutational variability was analyzed in 1,765 litter size records from 404 Ripollesa ewes to characterize the magnitude of this genetic source of variation and check the suitability of including mutational effects in genetic evaluations of this breed. Threshold animal models accounting for additive genetic mutations were preferred to models without mutational contributions, with an average difference in the deviance information criterion of more than 5 units. Moreover, the statistical relevance of the additive genetic mutation term was checked through a Bayes factor approach, which showed that the models with mutational variability were 8.5 to 22.7 times more probable than the others. The mutational heritability (percentage of the phenotypic variance accounted for by mutational variance) was 0.6 or 0.9%, depending on whether genetic dominance effects were accounted for by the analytical model. The inclusion of mutational effects in the genetic model for evaluating litter size in Ripollesa ewes called for some minor modifications in the genetic merit order of the individuals evaluated, which suggested that the continuous uploading of new additive mutations could be taken into account to optimize the selection scheme. This study is the first attempt to estimate mutational variances in a livestock species and thereby contribute to better characterization of the genetic background of productive traits of interest.

  3. Cross-species genomics matches driver mutations and cell compartments to model ependymoma.

    PubMed

    Johnson, Robert A; Wright, Karen D; Poppleton, Helen; Mohankumar, Kumarasamypet M; Finkelstein, David; Pounds, Stanley B; Rand, Vikki; Leary, Sarah E S; White, Elsie; Eden, Christopher; Hogg, Twala; Northcott, Paul; Mack, Stephen; Neale, Geoffrey; Wang, Yong-Dong; Coyle, Beth; Atkinson, Jennifer; DeWire, Mariko; Kranenburg, Tanya A; Gillespie, Yancey; Allen, Jeffrey C; Merchant, Thomas; Boop, Fredrick A; Sanford, Robert A; Gajjar, Amar; Ellison, David W; Taylor, Michael D; Grundy, Richard G; Gilbertson, Richard J

    2010-07-29

    Understanding the biology that underlies histologically similar but molecularly distinct subgroups of cancer has proven difficult because their defining genetic alterations are often numerous, and the cellular origins of most cancers remain unknown. We sought to decipher this heterogeneity by integrating matched genetic alterations and candidate cells of origin to generate accurate disease models. First, we identified subgroups of human ependymoma, a form of neural tumour that arises throughout the central nervous system (CNS). Subgroup-specific alterations included amplifications and homozygous deletions of genes not yet implicated in ependymoma. To select cellular compartments most likely to give rise to subgroups of ependymoma, we matched the transcriptomes of human tumours to those of mouse neural stem cells (NSCs), isolated from different regions of the CNS at different developmental stages, with an intact or deleted Ink4a/Arf locus (that encodes Cdkn2a and b). The transcriptome of human supratentorial ependymomas with amplified EPHB2 and deleted INK4A/ARF matched only that of embryonic cerebral Ink4a/Arf(-/-) NSCs. Notably, activation of Ephb2 signalling in these, but not other, NSCs generated the first mouse model of ependymoma, which is highly penetrant and accurately models the histology and transcriptome of one subgroup of human supratentorial tumour. Further, comparative analysis of matched mouse and human tumours revealed selective deregulation in the expression and copy number of genes that control synaptogenesis, pinpointing disruption of this pathway as a critical event in the production of this ependymoma subgroup. Our data demonstrate the power of cross-species genomics to meticulously match subgroup-specific driver mutations with cellular compartments to model and interrogate cancer subgroups.

  4. Balancing protein stability and activity in cancer: a new approach for identifying driver mutations affecting CBL ubiquitin ligase activation

    PubMed Central

    Li, Minghui; Kales, Stephen C.; Ma, Ke; Shoemaker, Benjamin A.; Crespo-Barreto, Juan; Cangelosi, Andrew L.; Lipkowitz, Stanley; Panchenko, Anna R.

    2015-01-01

    Oncogenic mutations in the monomeric Casitas B-lineage lymphoma (Cbl) gene have been found in many tumors, but their significance remains largely unknown. Several human c-Cbl (CBL) structures have recently been solved depicting the protein at different stages of its activation cycle and thus provide mechanistic insight underlying how stability-activity tradeoffs in cancer-related proteins may influence disease onset and progression. In this study, we computationally modeled the effects of missense cancer mutations on structures representing four stages of the CBL activation cycle to identify driver mutations that affect CBL stability, binding, and activity. We found that recurrent, homozygous, and leukemia-specific mutations had greater destabilizing effects on CBL states than did random non-cancer mutations. We further tested the ability of these computational models assessing the changes in CBL stability and its binding to ubiquitin conjugating enzyme E2, by performing blind CBL-mediated EGFR ubiquitination assays in cells. Experimental CBL ubiquitin ligase activity was in agreement with the predicted changes in CBL stability and, to a lesser extent, with CBL-E2 binding affinity. Two-thirds of all experimentally tested mutations affected the ubiquitin ligase activity by either destabilizing CBL or disrupting CBL-E2 binding, whereas about one-third of tested mutations were found to be neutral. Collectively, our findings demonstrate that computational methods incorporating multiple protein conformations and stability and binding affinity evaluations can successfully predict the functional consequences of cancer mutations on protein activity, and provide a proof of concept for mutations in CBL. PMID:26676746

  5. An atomic view of additive mutational effects in a protein structure

    SciTech Connect

    Skinner, M.M.; Terwilliger, T.C.

    1996-04-01

    Substitution of a single amino acid in a protein will often lead to substantial changes in properties. If these properties could be altered in a rational way then proteins could be readily generated with functions tailored to specific uses. When amino acid substitutions are made at well-separated locations in a single protein, their effects are generally additive. Additivity of effects of amino acid substitutions is very useful because the properties of proteins with any combination of substitutions can be inferred directly from those of the proteins with single changes. It would therefore be of considerable interest to have a means of knowing whether substitutions at a particular pair of sites in a protein are likely to lead to additive effects. The structural basis for additivity of effects of mutations on protein function was examined by determining crystal structures of single and double mutants in the hydrophobic core of gene V protein. Structural effects of mutations were found to be cumulative when two mutations were made in a single protein. Additivity occurs in this case because the regions structurally affected by mutations at the two sites do not overlap even though the sites are separated by only 9 {angstrom}. Structural distortions induced by mutations in gene V protein decrease rapidly, but not isotropically, with distance from the site of mutation. It is anticipated that cases where structural and functional effects of mutations will be additive could be identified simply by examining whether the regions structurally affected by each component mutation overlap.

  6. MTHFR homozygous mutation and additional risk factors for cerebral infarction in a large Italian family.

    PubMed

    Del Balzo, Francesca; Spalice, Alberto; Perla, Massimo; Properzi, Enrico; Iannetti, Paola

    2009-01-01

    Several cases with cerebral infarctions associated with the C677T mutation in the methylenetetrahydrofolate reductase gene (MTHFR) have been reported. Given the large number of asymptomatic individuals with the MTHFR mutation, additional risk factors for cerebral infarction should be considered. This study describes a large family with the MTHFR mutation and a combination of heterozygous factor V Leiden mutations and different additional exogenous and endogenous thrombogenic risk factors. Psychomotor retardation and a left fronto-insular infarct associated with the MTHFR mutation together with diminished factor VII and low level of protein C was documented in the first patient. In the second patient, generalized epilepsy and a malacic area in the right nucleus lenticularis was associated with the MTHFR mutation and a low level of protein C. In the third patient, right hemiparesis and a left fronto-temporal porencephalic cyst were documented, together with the MTHFR mutation and hyperhomocysteinemia. An extensive search of additional circumstantial and genetic thrombogenic risk factors should be useful for prophylaxis and prognosis of infants with cerebral infarctions associated with the MTHFR mutation and of their related family members.

  7. The search for cis-regulatory driver mutations in cancer genomes.

    PubMed

    Poulos, Rebecca C; Sloane, Mathew A; Hesson, Luke B; Wong, Jason W H

    2015-10-20

    With the advent of high-throughput and relatively inexpensive whole-genome sequencing technology, the focus of cancer research has begun to shift toward analyses of somatic mutations in non-coding cis-regulatory elements of the cancer genome. Cis-regulatory elements play an important role in gene regulation, with mutations in these elements potentially resulting in changes to the expression of linked genes. The recent discoveries of recurrent TERT promoter mutations in melanoma, and recurrent mutations that create a super-enhancer regulating TAL1 expression in T-cell acute lymphoblastic leukaemia (T-ALL), have sparked significant interest in the search for other somatic cis-regulatory mutations driving cancer development. In this review, we look more closely at the TERT promoter and TAL1 enhancer alterations and use these examples to ask whether other cis-regulatory mutations may play a role in cancer susceptibility. In doing so, we make observations from the data emerging from recent research in this field, and describe the experimental and analytical approaches which could be adopted in the hope of better uncovering the true functional significance of somatic cis-regulatory mutations in cancer.

  8. Simultaneous Estimation of Additive and Mutational Genetic Variance in an Outbred Population of Drosophila serrata

    PubMed Central

    McGuigan, Katrina; Aguirre, J. David; Blows, Mark W.

    2015-01-01

    How new mutations contribute to genetic variation is a key question in biology. Although the evolutionary fate of an allele is largely determined by its heterozygous effect, most estimates of mutational variance and mutational effects derive from highly inbred lines, where new mutations are present in homozygous form. In an attempt to overcome this limitation, middle-class neighborhood (MCN) experiments have been used to assess the fitness effect of new mutations in heterozygous form. However, because MCN populations harbor substantial standing genetic variance, estimates of mutational variance have not typically been available from such experiments. Here we employ a modification of the animal model to analyze data from 22 generations of Drosophila serrata bred in an MCN design. Mutational heritability, measured for eight cuticular hydrocarbons, 10 wing-shape traits, and wing size in this outbred genetic background, ranged from 0.0006 to 0.006 (with one exception), a similar range to that reported from studies employing inbred lines. Simultaneously partitioning the additive and mutational variance in the same outbred population allowed us to quantitatively test the ability of mutation-selection balance models to explain the observed levels of additive and mutational genetic variance. The Gaussian allelic approximation and house-of-cards models, which assume real stabilizing selection on single traits, both overestimated the genetic variance maintained at equilibrium, but the house-of-cards model was a closer fit to the data. This analytical approach has the potential to be broadly applied, expanding our understanding of the dynamics of genetic variance in natural populations. PMID:26384357

  9. Exome sequence analysis of Kaposiform hemangioendothelioma: identification of putative driver mutations*

    PubMed Central

    Egashira, Sho; Jinnin, Masatoshi; Harada, Miho; Masuguchi, Shinichi; Fukushima, Satoshi; Ihn, Hironobu

    2016-01-01

    BACKGROUND Kaposiform hemangioendothelioma is a rare, intermediate, malignant tumor. The tumor's etiology remains unknown and there are no specific treatments. OBJECTIVE In this study, we performed exome sequencing using DNA from a Kaposiform hemangioendothelioma patient, and found putative candidates for the responsible mutations. METHOD The genomic DNA for exome sequencing was obtained from the tumor tissue and matched normal tissue from the same individual. Exome sequencing was performed on HiSeq2000 sequencer platform. RESULTS Among oncogenes, germline missense single nucleotide variants were observed in the TP53 and APC genes in both the tumor and normal tissue. As tumor-specific somatic mutations, we identified 81 candidate genes, including 4 nonsense changes, 68 missense changes and 9 insertions/deletions. The mutations in ITGB2, IL-32 and DIDO1 were included in them. CONCLUSION This is a pilot study, and future analysis with more patients is needed to clarify: the detailed pathogenesis of this tumor, the novel diagnostic methods by detecting specific mutations, and the new therapeutic strategies targeting the mutation. PMID:28099595

  10. Additive genetic breeding values correlate with the load of partially deleterious mutations.

    PubMed

    Tomkins, Joseph L; Penrose, Marissa A; Greeff, Johan; LeBas, Natasha R

    2010-05-14

    The mutation-selection-balance model predicts most additive genetic variation to arise from numerous mildly deleterious mutations of small effect. Correspondingly, "good genes" models of sexual selection and recent models for the evolution of sex are built on the assumption that mutational loads and breeding values for fitness-related traits are correlated. In support of this concept, inbreeding depression was negatively genetically correlated with breeding values for traits under natural and sexual selection in the weevil Callosobruchus maculatus. The correlations were stronger in males and strongest for condition. These results confirm the role of existing, partially recessive mutations in maintaining additive genetic variation in outbred populations, reveal the nature of good genes under sexual selection, and show how sexual selection can offset the cost of sex.

  11. Whole Exome Sequencing of Rapid Autopsy Tumors and Xenograft Models Reveals Possible Driver Mutations Underlying Tumor Progression

    PubMed Central

    Xie, Tao; Musteanu, Monica; Lopez-Casas, Pedro P.; Shields, David J.; Olson, Peter; Rejto, Paul A.; Hidalgo, Manuel

    2015-01-01

    Pancreatic Ductal Adenocarcinoma (PDAC) is a highly lethal malignancy due to its propensity to invade and rapidly metastasize and remains very difficult to manage clinically. One major hindrance towards a better understanding of PDAC is the lack of molecular data sets and models representative of end stage disease. Moreover, it remains unclear how molecularly similar patient-derived xenograft (PDX) models are to the primary tumor from which they were derived. To identify potential molecular drivers in metastatic pancreatic cancer progression, we obtained matched primary tumor, metastases and normal (peripheral blood) samples under a rapid autopsy program and performed whole exome sequencing (WES) on tumor as well as normal samples. PDX models were also generated, sequenced and compared to tumors. Across the matched data sets generated for three patients, there were on average approximately 160 single-nucleotide mutations in each sample. The majority of mutations in each patient were shared among the primary and metastatic samples and, importantly, were largely retained in the xenograft models. Based on the mutation prevalence in the primary and metastatic sites, we proposed possible clonal evolution patterns marked by functional mutations affecting cancer genes such as KRAS, TP53 and SMAD4 that may play an important role in tumor initiation, progression and metastasis. These results add to our understanding of pancreatic tumor biology, and demonstrate that PDX models derived from advanced or end-stage likely closely approximate the genetics of the disease in the clinic and thus represent a biologically and clinically relevant pre-clinical platform that may enable the development of effective targeted therapies for PDAC. PMID:26555578

  12. 49 CFR 391.1 - Scope of the rules in this part; additional qualifications; duties of carrier-drivers.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... qualifications; duties of carrier-drivers. 391.1 Section 391.1 Transportation Other Regulations Relating to... MOTOR CARRIER SAFETY REGULATIONS QUALIFICATIONS OF DRIVERS AND LONGER COMBINATION VEHICLE (LCV) DRIVER...-drivers. (a) The rules in this part establish minimum qualifications for persons who drive...

  13. 49 CFR 391.1 - Scope of the rules in this part; additional qualifications; duties of carrier-drivers.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... qualifications; duties of carrier-drivers. 391.1 Section 391.1 Transportation Other Regulations Relating to... MOTOR CARRIER SAFETY REGULATIONS QUALIFICATIONS OF DRIVERS AND LONGER COMBINATION VEHICLE (LCV) DRIVER...-drivers. (a) The rules in this part establish minimum qualifications for persons who drive...

  14. 49 CFR 391.1 - Scope of the rules in this part; additional qualifications; duties of carrier-drivers.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... qualifications; duties of carrier-drivers. 391.1 Section 391.1 Transportation Other Regulations Relating to... MOTOR CARRIER SAFETY REGULATIONS QUALIFICATIONS OF DRIVERS AND LONGER COMBINATION VEHICLE (LCV) DRIVER...-drivers. (a) The rules in this part establish minimum qualifications for persons who drive...

  15. 49 CFR 391.1 - Scope of the rules in this part; additional qualifications; duties of carrier-drivers.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... qualifications; duties of carrier-drivers. 391.1 Section 391.1 Transportation Other Regulations Relating to... MOTOR CARRIER SAFETY REGULATIONS QUALIFICATIONS OF DRIVERS AND LONGER COMBINATION VEHICLE (LCV) DRIVER...-drivers. (a) The rules in this part establish minimum qualifications for persons who drive...

  16. 49 CFR 391.1 - Scope of the rules in this part; additional qualifications; duties of carrier-drivers.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... qualifications; duties of carrier-drivers. 391.1 Section 391.1 Transportation Other Regulations Relating to... MOTOR CARRIER SAFETY REGULATIONS QUALIFICATIONS OF DRIVERS AND LONGER COMBINATION VEHICLE (LCV) DRIVER...-drivers. (a) The rules in this part establish minimum qualifications for persons who drive...

  17. High frequency of additional gene mutations in acute myeloid leukemia with MLL partial tandem duplication: DNMT3A mutation is associated with poor prognosis.

    PubMed

    Kao, Hsiao-Wen; Liang, D Cherng; Kuo, Ming-Chung; Wu, Jin-Hou; Dunn, Po; Wang, Po-Nan; Lin, Tung-Liang; Shih, Yu-Shu; Liang, Sung-Tzu; Lin, Tung-Huei; Lai, Chen-Yu; Lin, Chun-Hui; Shih, Lee-Yung

    2015-10-20

    The mutational profiles of acute myeloid leukemia (AML) with partial tandem duplication of mixed-lineage leukemia gene (MLL-PTD) have not been comprehensively studied. We studied 19 gene mutations for 98 patients with MLL-PTD AML to determine the mutation frequency and clinical correlations. MLL-PTD was screened by reverse-transcriptase PCR and confirmed by real-time quantitative PCR. The mutational analyses were performed with PCR-based assays followed by direct sequencing. Gene mutations of signaling pathways occurred in 63.3% of patients, with FLT3-ITD (44.9%) and FLT3-TKD (13.3%) being the most frequent. 66% of patients had gene mutations involving epigenetic regulation, and DNMT3A (32.7%), IDH2 (18.4%), TET2 (18.4%), and IDH1 (10.2%) mutations were most common. Genes of transcription pathways and tumor suppressors accounted for 23.5% and 10.2% of patients. RUNX1 mutation occurred in 23.5% of patients, while none had NPM1 or double CEBPA mutation. 90.8% of MLL-PTD AML patients had at least one additional gene mutation. Of 55 MLL-PTD AML patients who received standard chemotherapy, age older than 50 years and DNMT3A mutation were associated with inferior outcome. In conclusion, gene mutations involving DNA methylation and activated signaling pathway were common co-existed gene mutations. DNMT3A mutation was a poor prognostic factor in MLL-PTD AML.

  18. Mutations in RIT1 cause Noonan syndrome – additional functional evidence and expanding the clinical phenotype

    PubMed Central

    Koenighofer, Martin; Hung, Christina Y.; McCauley, Jacob L.; Dallman, Julia; Back, Emma J.; Mihalek, Ivana; Gripp, Karen W.; Sol-Church, Katia; Rusconi, Paolo; Zhang, Zhaiyi; Shi, Geng-Xian; Andres, Douglas A.; Bodamer, Olaf A.

    2015-01-01

    RASopathies are a clinically heterogeneous group of conditions caused by mutations in one of sixteen proteins in the RAS-MAPK pathway. Recently, mutations in RIT1 were identified as a novel cause for Noonan syndrome. Here we provide additional functional evidence for a causal role of RIT1 mutations and expand the associated phenotypic spectrum. We identified two de novo missense variants p.Met90Ile and, p.Ala57Gly. Both variants resulted in increased MEK-ERK signaling compared to wild-type, underscoring gain-of-function as the primary functional mechanism. Introduction of p.Met90Ile and p.Ala57Gly into zebrafish embryos reproduced not only aspects of the human phenotype but also revealed abnormalities of eye development, emphasizing the importance of RIT1 for spatial and temporal organization of the growing organism. In addition, we observed severe lymphedema of the lower extremity and genitalia in one patient. We provide additional evidence for a causal relationship between pathogenic mutations in RIT1, increased RAS-MAPK/MEK-ERK signaling and the clinical phenotype. The mutant RIT1 protein may possess reduced GTPase activity or a diminished ability to interact with cellular GTPase activating proteins, however the precise mechanism remains unknown. The phenotypic spectrum is likely to expand and includes lymphedema of the lower extremities in addition to nuchal hygroma. PMID:25959749

  19. Targeted ultra-deep sequencing unveils a lack of driver-gene mutations linking non-hereditary gastrointestinal stromal tumors and highly prevalent second primary malignancies: random or nonrandom, that is the question

    PubMed Central

    Kuo, Yung-Chia; Hsu, Hung-Chih; Chen, Jen-Shi; Chen, Tse-Ching; Wu, Ren-Chin; Chiu, Cheng-Tang; Yeh, Chun-Nan; Yeh, Ta-Sen

    2016-01-01

    The association of non-hereditary (sporadic) gastrointestinal stromal tumors (GISTs) and second primary malignancies is known to be nonrandom, although the underlying molecular mechanisms remain unknown. In this study, 136 of 749 (18.1%) patients with sporadic GISTs were found to have additional associated cancers, with gastrointestinal and genitourinary/gynecologic/breast cancers being the most prevalent. Gene mutations in GISTs and their associated colorectal cancers (CRCs) (n=9) were analyzed using a panel of 409 cancer-related genes, while a separate group of 40 sporadic CRCs not associated with GISTs served as controls. All 9 of the GISTs had either KIT (8 of 9) or PDGFRA (1 of 9) mutations that were not present in their associated CRCs. Conversely, all but one of the 9 GIST-associated CRCs exhibited an APC mutation, a TP53 mutation or both, while none of their corresponding GISTs harbored either APC or TP53 mutations. The genetic profile of CRCs with and without associated GISTs did not differ. Although population-based studies and case series worldwide, including ours, have unanimously indicated that the GIST-CRC association is nonrandom, our targeted ultra-deep sequencing unveiled a lack of driver-gene mutations linking sporadic GISTs to highly prevalent second primaries. Further studies are needed to elucidate other genetic alterations that may be responsible for this puzzling contradiction. PMID:27806309

  20. High frequency of additional gene mutations in acute myeloid leukemia with MLL partial tandem duplication: DNMT3A mutation is associated with poor prognosis

    PubMed Central

    Kao, Hsiao-Wen; Liang, Der-Cherng; Kuo, Ming-Chung; Wu, Jin-Hou; Dunn, Po; Wang, Po-Nan; Lin, Tung-Liang; Shih, Yu-Shu; Liang, Sung-Tzu; Lin, Tung-Huei; Lai, Chen-Yu; Lin, Chun-Hui; Shih, Lee-Yung

    2015-01-01

    The mutational profiles of acute myeloid leukemia (AML) with partial tandem duplication of mixed-lineage leukemia gene (MLL-PTD) have not been comprehensively studied. We studied 19 gene mutations for 98 patients with MLL-PTD AML to determine the mutation frequency and clinical correlations. MLL-PTD was screened by reverse-transcriptase PCR and confirmed by real-time quantitative PCR. The mutational analyses were performed with PCR-based assays followed by direct sequencing. Gene mutations of signaling pathways occurred in 63.3% of patients, with FLT3-ITD (44.9%) and FLT3-TKD (13.3%) being the most frequent. 66% of patients had gene mutations involving epigenetic regulation, and DNMT3A (32.7%), IDH2 (18.4%), TET2 (18.4%), and IDH1 (10.2%) mutations were most common. Genes of transcription pathways and tumor suppressors accounted for 23.5% and 10.2% of patients. RUNX1 mutation occurred in 23.5% of patients, while none had NPM1 or double CEBPA mutation. 90.8% of MLL-PTD AML patients had at least one additional gene mutation. Of 55 MLL-PTD AML patients who received standard chemotherapy, age older than 50 years and DNMT3A mutation were associated with inferior outcome. In conclusion, gene mutations involving DNA methylation and activated signaling pathway were common co-existed gene mutations. DNMT3A mutation was a poor prognostic factor in MLL-PTD AML. PMID:26375248

  1. Massively parallel sequencing of phyllodes tumours of the breast reveals actionable mutations, and TERT promoter hotspot mutations and TERT gene amplification as likely drivers of progression

    PubMed Central

    Piscuoglio, Salvatore; Ng, Charlotte K Y; Murray, Melissa; Burke, Kathleen A; Edelweiss, Marcia; Geyer, Felipe C; Macedo, Gabriel S; Inagaki, Akiko; Papanastasiou, Anastasios D; Martelotto, Luciano G; Marchio, Caterina; Lim, Raymond S; Ioris, Rafael A; Nahar, Pooja K; De Bruijn, Ino; Smyth, Lillian; Akram, Muzaffar; Ross, Dara; Petrini, John H; Norton, Larry; Solit, David B; Baselga, Jose; Brogi, Edi; Ladanyi, Marc; Weigelt, Britta; Reis-Filho, Jorge S

    2015-01-01

    Phyllodes tumours (PTs) are breast fibroepithelial lesions that are graded based on histological criteria as benign, borderline or malignant. PTs may recur locally. Borderline PTs and malignant PTs may metastasize to distant sites. Breast fibroepithelial lesions, including PTs and fibroadenomas, are characterized by recurrent MED12 exon 2 somatic mutations. We sought to define the repertoire of somatic genetic alterations in PTs and whether these may assist in the differential diagnosis of these lesions. We collected 100 fibroadenomas, 40 benign PTs, 14 borderline PTs and 22 malignant PTs. Six, 6 and 13 benign, borderline and malignant PTs respectively and their matched normal tissue were subjected to targeted massively parallel sequencing (MPS) using the MSK-IMPACT sequencing assay. Recurrent MED12 mutations were found in 56% of PTs; in addition, mutations affecting cancer genes (e.g. TP53, RB1, SETD2 and EGFR) were exclusively detected in borderline and malignant PTs. We found a novel recurrent clonal hotspot mutation in the TERT promoter (−124 C>T) in 52% and TERT gene amplification in 4% of PTs. Laser capture microdissection revealed that these mutations were restricted to the mesenchymal component of PTs. Sequencing analysis of the entire cohort revealed that the frequency of TERT alterations increased from benign (18%), to borderline (57%) and to malignant PTs (68%; P<0.01), and TERT alterations were associated with increased levels of TERT mRNA (P<0.001). No TERT alterations were observed in fibroadenomas. An analysis of TERT promoter sequencing and gene amplification distinguished PTs from fibroadenomas with a sensitivity and a positive predictive value of 100% (CI 95.38%–100%) and 100% (CI 85.86%–100%), respectively, and a sensitivity and a negative predictive value of 39% (CI 28.65%–51.36%) and 68% (CI 60.21%–75.78%), respectively. Our results suggest that TERT alterations may drive the progression of PTs, and may assist in the differential

  2. Understanding drivers of the export of dissolved organic carbon from headwater catchments in Germany using Generalised Additive Models

    NASA Astrophysics Data System (ADS)

    Selle, Benny; Tittel, Jörg; Musolff, Andreas

    2015-04-01

    In the literature, several causes of recently increasing concentrations of dissolved organic carbon (DOC) in headwaters across eastern North America and northern and central Europe have been debated. One likely driver of the widespread increase of DOC concentrations since the early to mid 1990s are decreasing depositions of acid rain resulting in an increased solubility of organic carbon compounds including humic acids. Here, we tested the hypothesis if the reduced availability of both nitrate and sulfate stimulated the reduction of ferric iron soil minerals and the mobilisation of DOC. Decreasing depositions often resulted in a reduced availability of both nitrate and sulphate, which are preferred electron acceptors in microbial decomposition processes. As iron minerals act as efficient sorbents of organic compounds in soils its reduction may have caused a release of humic substances and hence an increasing export of DOC from headwater catchments. To test this hypothesis, time series of DOC, dissolved iron, sulfate and nitrate from several German headwater catchments were examined using Generalised Additive Models. Using this modelling technique, discharge corrected time series of concentrations were represented as a sum of a seasonal and a non-linear trend component. Both, the computed trends and seasonalities supported the redox hypothesis.

  3. Understanding drivers of the export of dissolved organic carbon from a German headwater catchment using Generalised Additive Models

    NASA Astrophysics Data System (ADS)

    Selle, Benny; Musolff, Andreas; Tittel, Jörg

    2016-04-01

    In the literature, several causes of recently increasing concentrations of dissolved organic carbon (DOC) in headwaters across eastern North America and northern and central Europe have been debated. One likely driver of the widespread increase of DOC concentrations since the early 1990s are decreasing depositions of acid rain resulting in an increased solubility of organic carbon compounds including humic acids. Here, we tested the hypothesis if the reduced availability of nitrate stimulated the microbial reduction of ferric iron soil minerals and the mobilisation of DOC. Forested catchments are relatively unaffected by agricultural and urban nitrate inputs. In these catchments, decreasing depositions often resulted in a reduced availability of nitrate, which are preferred electron acceptors in microbial decomposition processes. As ferric iron minerals act as efficient sorbents of organic compounds in soils its reduction may cause a release of humic substances and hence an export of DOC. To test this hypothesis, time series of DOC, dissolved iron and nitrate from a forested headwater catchment in Germany were examined using Generalised Additive Models. We found that rising DOC concentrations most likely resulted from a reductive dissolution of iron(III) minerals in soils and the associated mobilisation of adsorbed organic carbon. Phosphate, which can trigger undesired algal growth and is also known to be adsorbed by particulate iron(III), was released as well.

  4. Older paternal age and fresh gene mutation: data on additional disorders.

    PubMed

    Jones, K L; Smith, D W; Harvey, M A; Hall, B D; Quan, L

    1975-01-01

    Older paternal age has previously been documented as a factor in sporadic fresh mutational cases of several autosomal dominant disorders. In this collaborative study, an older mean paternal age has been documented in sporadic cases of at least five additional dominantly inheritable disorders; the basal cell nevus syndrome, the Waardenburg syndrome, the Crouzon syndrome, the oculo-dental-digital sysdrome, and the Treacher-Collins syndrome. It was also found to be a factor in acrodysostosis and progeria, suggesting a fresh mutant gene etiology for these two conditions in which virtually all cases have been sporadic and the mode of genetic etiology has been unknown.

  5. Driver Education Saves Gas.

    ERIC Educational Resources Information Center

    American Automobile Association, Falls Church, VA. Traffic Engineering and Safety Dept.

    The argument that driver education should be dropped because driver education cars use gas is shortsighted. High school driver education is an excellent vehicle for teaching concepts of energy conservation. A small investment in fuel now can result in major savings of gasoline over a student's lifetime. In addition good driver education courses…

  6. DriverDBv2: a database for human cancer driver gene research.

    PubMed

    Chung, I-Fang; Chen, Chen-Yang; Su, Shih-Chieh; Li, Chia-Yang; Wu, Kou-Juey; Wang, Hsei-Wei; Cheng, Wei-Chung

    2016-01-04

    We previously presented DriverDB, a database that incorporates ∼ 6000 cases of exome-seq data, in addition to annotation databases and published bioinformatics algorithms dedicated to driver gene/mutation identification. The database provides two points of view, 'Cancer' and 'Gene', to help researchers visualize the relationships between cancers and driver genes/mutations. In the updated DriverDBv2 database (http://ngs.ym.edu.tw/driverdb) presented herein, we incorporated >9500 cancer-related RNA-seq datasets and >7000 more exome-seq datasets from The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC), and published papers. Seven additional computational algorithms (meaning that the updated database contains 15 in total), which were developed for driver gene identification, are incorporated into our analysis pipeline, and the results are provided in the 'Cancer' section. Furthermore, there are two main new features, 'Expression' and 'Hotspot', in the 'Gene' section. 'Expression' displays two expression profiles of a gene in terms of sample types and mutation types, respectively. 'Hotspot' indicates the hotspot mutation regions of a gene according to the results provided by four bioinformatics tools. A new function, 'Gene Set', allows users to investigate the relationships among mutations, expression levels and clinical data for a set of genes, a specific dataset and clinical features.

  7. A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects?

    PubMed Central

    van der Put, N M; Gabreëls, F; Stevens, E M; Smeitink, J A; Trijbels, F J; Eskes, T K; van den Heuvel, L P; Blom, H J

    1998-01-01

    Recently, we showed that homozygosity for the common 677(C-->T) mutation in the methylenetetrahydrofolate reductase (MTHFR) gene, causing thermolability of the enzyme, is a risk factor for neural-tube defects (NTDs). We now report on another mutation in the same gene, the 1298(A-->C) mutation, which changes a glutamate into an alanine residue. This mutation destroys an MboII recognition site and has an allele frequency of .33. This 1298(A-->C) mutation results in decreased MTHFR activity (one-way analysis of variance [ANOVA] P < .0001), which is more pronounced in the homozygous than heterozygous state. Neither the homozygous nor the heterozygous state is associated with higher plasma homocysteine (Hcy) or a lower plasma folate concentration-phenomena that are evident with homozygosity for the 677(C-->T) mutation. However, there appears to be an interaction between these two common mutations. When compared with heterozygosity for either the 677(C-->T) or 1298(A-->C) mutations, the combined heterozygosity for the 1298(A-->C) and 677(C-->T) mutations was associated with reduced MTHFR specific activity (ANOVA P < .0001), higher Hcy, and decreased plasma folate levels (ANOVA P <.03). Thus, combined heterozygosity for both MTHFR mutations results in similar features as observed in homozygotes for the 677(C-->T) mutation. This combined heterozygosity was observed in 28% (n =86) of the NTD patients compared with 20% (n =403) among controls, resulting in an odds ratio of 2.04 (95% confidence interval: .9-4.7). These data suggest that the combined heterozygosity for the two MTHFR common mutations accounts for a proportion of folate-related NTDs, which is not explained by homozygosity for the 677(C-->T) mutation, and can be an additional genetic risk factor for NTDs. PMID:9545395

  8. Genomic Analysis of Uterine Lavage Fluid Detects Early Endometrial Cancers and Reveals a Prevalent Landscape of Driver Mutations in Women without Histopathologic Evidence of Cancer: A Prospective Cross-Sectional Study

    PubMed Central

    Camacho, Sandra Catalina; Schumacher, Cassie A.; Irish, Jonathan C.; Harkins, Timothy T.; Belfer, Rachel; Kalir, Tamara; Reva, Boris; Dottino, Peter; Martignetti, John A.

    2016-01-01

    in tumor but at allele fractions significantly less than 1%. Of the remaining 95 patients diagnosed with benign or non-cancer pathology, 44 had no significant cancer mutations detected. Intriguingly, 51 patients without histopathologic evidence of cancer had relatively high allele fraction (1.0%–30.4%), cancer-associated mutations. Participants with detected driver and potential driver mutations were significantly older (mean age mutated = 57.96, 95% confidence interval [CI]: 3.30–∞, mean age no mutations = 50.35; p-value = 0.002; Benjamini-Hochberg [BH] adjusted p-value = 0.015) and more likely to be post-menopausal (p-value = 0.004; BH-adjusted p-value = 0.015) than those without these mutations. No associations were detected between mutation status and race/ethnicity, body mass index, diabetes, parity, and smoking status. Long-term follow-up was not presently available in this prospective study for those women without histopathologic evidence of cancer. Conclusions Using ultra-deep NGS, we identified somatic mutations in DNA extracted both from cell pellets and a never previously reported cfDNA fraction from the uterine lavage. Using our targeted sequencing approach, endometrial driver mutations were identified in all seven women who received a cancer diagnosis based on classic histopathology of tissue curettage obtained at the time of hysteroscopy. In addition, relatively high allele fraction driver mutations were identified in the lavage fluid of approximately half of the women without a cancer diagnosis. Increasing age and post-menopausal status were associated with the presence of these cancer-associated mutations, suggesting the prevalent existence of a premalignant landscape in women without clinical evidence of cancer. Given that a uterine lavage can be easily and quickly performed even outside of the operating room and in a physician’s office-based setting, our findings suggest the future possibility of this approach for screening women for the

  9. A Systems Biology Comparison of Ovarian Cancers Implicates Putative Somatic Driver Mutations through Protein-Protein Interaction Models

    PubMed Central

    Yang, Mary Qu; Elnitski, Laura

    2016-01-01

    Ovarian carcinomas can be aggressive with a high mortality rate (e.g., high-grade serous ovarian carcinomas, or HGSOCs), or indolent with much better long-term outcomes (e.g., low-malignant-potential, or LMP, serous ovarian carcinomas). By comparing LMP and HGSOC tumors, we can gain insight into the mechanisms underlying malignant progression in ovarian cancer. However, previous studies of the two subtypes have been focused on gene expression analysis. Here, we applied a systems biology approach, integrating gene expression profiles derived from two independent data sets containing both LMP and HGSOC tumors with protein-protein interaction data. Genes and related networks implicated by both data sets involved both known and novel disease mechanisms and highlighted the different roles of BRCA1 and CREBBP in the two tumor types. In addition, the incorporation of somatic mutation data revealed that amplification of PAK4 is associated with poor survival in patients with HGSOC. Thus, perturbations in protein interaction networks demonstrate differential trafficking of network information between malignant and benign ovarian cancers. The novel network-based molecular signatures identified here may be used to identify new targets for intervention and to improve the treatment of invasive ovarian cancer as well as early diagnosis. PMID:27788148

  10. Imaging Characteristics of Driver Mutations in EGFR, KRAS, and ALK among Treatment-Naïve Patients with Advanced Lung Adenocarcinoma

    PubMed Central

    Park, Jangchul; Kobayashi, Yoshihisa; Urayama, Kevin Y.; Yamaura, Hidekazu; Yatabe, Yasushi; Hida, Toyoaki

    2016-01-01

    This study aimed to identify the computed tomography characteristics of treatment-naïve patients with lung adenocarcinoma and known driver mutations in EGFR, KRAS, or ALK. Patients with advanced lung adenocarcinoma (stage IIIB–IV) and known mutations in EGFR, KRAS, or ALK were assessed. The radiological findings for the main tumor and intra-thoracic status were retrospectively analyzed in each group, and the groups’ characteristics were compared. We identified 265 treatment-naïve patients with non-small-cell carcinoma, who had EGFR mutations (n = 159), KRAS mutations (n = 55), or ALK rearrangements (n = 51). Among the three groups, we evaluated only patients with stage IIIB–IV lung adenocarcinoma who had EGFR mutations (n = 126), KRAS mutations (n = 35), or ALK rearrangements (n = 47). We found that ground-glass opacity at the main tumor was significantly more common among EGFR-positive patients, compared to ALK-positive patients (p = 0.009). Lymphadenopathy was significantly more common among ALK-positive patients, compared to EGFR-positive patients (p = 0.003). Extranodal invasion was significantly more common among ALK-positive patients, compared to EGFR-positive patients and KRAS-positive patients (p = 0.001 and p = 0.049, respectively). Lymphangitis was significantly more common among ALK-positive patients, compared to EGFR-positive patients (p = 0.049). Pleural effusion was significantly less common among KRAS-positive patients, compared to EGFR-positive patients and ALK-positive patients (p = 0.046 and p = 0.026, respectively). Lung metastases were significantly more common among EGFR-positive patients, compared to KRAS-positive patients and ALK-positive patients (p = 0.007 and p = 0.04, respectively). In conclusion, EGFR mutations were associated with ground-glass opacity, KRAS-positive tumors were generally solid and less likely to metastasize to the lung and pleura, and ALK-positive tumors tended to present with lymphadenopathy, extranodal

  11. Frequent mutations of KRAS in addition to BRAF in colorectal serrated adenocarcinoma

    PubMed Central

    Stefanius, Karoliina; Ylitalo, Laura; Tuomisto, Anne; Kuivila, Rami; Kantola, Tiina; Sirniö, Päivi; Karttunen, Tuomo J; Mäkinen, Markus J

    2011-01-01

    Aims To define the occurrence of KRAS and BRAF mutations, microsatellite instability (MSI), and MGMT and hMLH1 methylation and expression in colorectal serrated adenocarcinoma. Methods and results KRAS codon 12/13 and 59/61 and BRAF V600E mutations, MSI, and MGMT and hMLH1 methylation and expression in 42 serrated adenocarcinomas and 17 serrated adenomas were compared with those in 59 non-serrated colorectal carcinomas (CRCs) and nine adenomas. KRAS and BRAF mutations were observed in 45% and 33% of serrated adenocarcinomas and in 27% and 0% of non-serrated CRCs (P < 0.001). The KRAS c12G→A transition was the predominant type of mutation in serrated adenocarcinomas. Forty-two per cent of BRAF-mutated serrated adenocarcinomas showed high-level MSI (MSI-H) (P = 0.075), 100% showed hMLH1 methylation (P = 0.001) and 90.9% showed MGMT methylation (P = 0.019). Fifty-six per cent of serrated adenocarcinomas with microsatellite stability/low-level microsatellite instability harboured KRAS mutations. In non-serrated cancers, KRAS mutations were not associated with MSI status. Conclusions A high combined mutation rate (79–82%) of KRAS and BRAF in serrated adenomas and adenocarcinomas indicates that mitogen-activated protein kinase activation is a crucial part of the serrated pathway. BRAF mutations are specific for serrated adenocarcinoma and identify a subset of serrated adenocarcinomas with gene methylation and a tendency for MSI-H. A high frequency of KRAS mutations in serrated adenocarcinomas suggests that a significant proportion of KRAS-mutated CRCs originate from serrated precursors, thus challenging the traditional model of Vogelstein. PMID:21457162

  12. Co-existence of BRAF and NRAS driver mutations in the same melanoma cells results in heterogeneity of targeted therapy resistance

    PubMed Central

    Raaijmakers, Marieke I. G.; Widmer, Daniel S.; Narechania, Apurva; Eichhoff, Ossia; Freiberger, Sandra N.; Wenzina, Judith; Cheng, Phil F.; Mihic-Probst, Daniela; Desalle, Rob; Dummer, Reinhard; Levesque, Mitchell P.

    2016-01-01

    Acquired chemotherapeutic resistance of cancer cells can result from a Darwinistic evolution process in which heterogeneity plays an important role. In order to understand the impact of genetic heterogeneity on acquired resistance and second line therapy selection in metastatic melanoma, we sequenced the exomes of 27 lesions which were collected from 3 metastatic melanoma patients treated with targeted or non-targeted inhibitors. Furthermore, we tested the impact of a second NRAS mutation in 7 BRAF inhibitor resistant early passage cell cultures on the selection of second line therapies. We observed a rapid monophyletic evolution of melanoma subpopulations in response to targeted therapy that was not observed in non-targeted therapy. We observed the acquisition of NRAS mutations in the BRAF mutated patient treated with a BRAF inhibitor in 1 of 5 of his post-resistant samples. In an additional cohort of 5 BRAF-inhibitor treated patients we detected 7 NRAS mutations in 18 post-resistant samples. No NRAS mutations were detected in pre-resistant samples. By sequencing 65 single cell clones we prove that NRAS mutations co-occur with BRAF mutations in single cells. The double mutated cells revealed a heterogeneous response to MEK, ERK, PI3K, AKT and multi RTK - inhibitors. We conclude that BRAF and NRAS co-mutations are not mutually exclusive. However, the sole finding of double mutated cells in a resistant tumor is not sufficient to determine follow-up therapy. In order to target the large pool of heterogeneous cells in a patient, we think combinational therapy targeting different pathways will be necessary. PMID:27791198

  13. Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production

    PubMed Central

    Brehm, Anja; Liu, Yin; Sheikh, Afzal; Marrero, Bernadette; Omoyinmi, Ebun; Zhou, Qing; Montealegre, Gina; Biancotto, Angelique; Reinhardt, Adam; Almeida de Jesus, Adriana; Pelletier, Martin; Tsai, Wanxia L.; Remmers, Elaine F.; Kardava, Lela; Hill, Suvimol; Kim, Hanna; Lachmann, Helen J.; Megarbane, Andre; Chae, Jae Jin; Brady, Jilian; Castillo, Rhina D.; Brown, Diane; Casano, Angel Vera; Gao, Ling; Chapelle, Dawn; Huang, Yan; Stone, Deborah; Chen, Yongqing; Sotzny, Franziska; Lee, Chyi-Chia Richard; Kastner, Daniel L.; Torrelo, Antonio; Zlotogorski, Abraham; Moir, Susan; Gadina, Massimo; McCoy, Phil; Wesley, Robert; Rother, Kristina; Hildebrand, Peter W.; Brogan, Paul; Krüger, Elke; Aksentijevich, Ivona; Goldbach-Mansky, Raphaela

    2015-01-01

    Autosomal recessive mutations in proteasome subunit β 8 (PSMB8), which encodes the inducible proteasome subunit β5i, cause the immune-dysregulatory disease chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE), which is classified as a proteasome-associated autoinflammatory syndrome (PRAAS). Here, we identified 8 mutations in 4 proteasome genes, PSMA3 (encodes α7), PSMB4 (encodes β7), PSMB9 (encodes β1i), and proteasome maturation protein (POMP), that have not been previously associated with disease and 1 mutation in PSMB8 that has not been previously reported. One patient was compound heterozygous for PSMB4 mutations, 6 patients from 4 families were heterozygous for a missense mutation in 1 inducible proteasome subunit and a mutation in a constitutive proteasome subunit, and 1 patient was heterozygous for a POMP mutation, thus establishing a digenic and autosomal dominant inheritance pattern of PRAAS. Function evaluation revealed that these mutations variably affect transcription, protein expression, protein folding, proteasome assembly, and, ultimately, proteasome activity. Moreover, defects in proteasome formation and function were recapitulated by siRNA-mediated knockdown of the respective subunits in primary fibroblasts from healthy individuals. Patient-isolated hematopoietic and nonhematopoietic cells exhibited a strong IFN gene-expression signature, irrespective of genotype. Additionally, chemical proteasome inhibition or progressive depletion of proteasome subunit gene transcription with siRNA induced transcription of type I IFN genes in healthy control cells. Our results provide further insight into CANDLE genetics and link global proteasome dysfunction to increased type I IFN production. PMID:26524591

  14. Whole-exome and targeted sequencing identify ROBO1 and ROBO2 mutations as progression-related drivers in myelodysplastic syndromes.

    PubMed

    Xu, Feng; Wu, Ling-Yun; Chang, Chun-Kang; He, Qi; Zhang, Zheng; Liu, Li; Shi, Wen-Hui; Guo, Juan; Zhu, Yang; Zhao, You-Shan; Gu, Shu-Cheng; Fei, Cheng-Ming; Wu, Dong; Zhou, Li-Yu; Su, Ji-Ying; Song, Lu-Xi; Xiao, Chao; Li, Xiao

    2015-11-26

    The progressive mechanism underlying myelodysplastic syndrome remains unknown. Here we identify ROBO1 and ROBO2 as novel progression-related somatic mutations using whole-exome and targeted sequencing in 6 of 16 (37.5%) paired MDS patients with disease progression. Further deep sequencing detects 20 (10.4%) patients with ROBO mutations in a cohort of 193 MDS patients. In addition, copy number loss and loss of heterogeneity (LOH) of ROBO1 and ROBO2 are frequently observed in patients with progression or carrying ROBO mutations. In in vitro experiments, overexpression of ROBO1 or ROBO2 produces anti-proliferative and pro-apoptotic effects in leukaemia cells. However, this effect was lost in ROBO mutants and ROBO-SLIT2 signalling is impaired. Multivariate analysis shows that ROBO mutations are independent factors for predicting poor survival. These findings demonstrate a novel contribution of ROBO mutations to the pathogenesis of MDS and highlight a key role for ROBO-SLIT2 signalling in MDS disease progression.

  15. Additives

    NASA Technical Reports Server (NTRS)

    Smalheer, C. V.

    1973-01-01

    The chemistry of lubricant additives is discussed to show what the additives are chemically and what functions they perform in the lubrication of various kinds of equipment. Current theories regarding the mode of action of lubricant additives are presented. The additive groups discussed include the following: (1) detergents and dispersants, (2) corrosion inhibitors, (3) antioxidants, (4) viscosity index improvers, (5) pour point depressants, and (6) antifouling agents.

  16. Teen Driver Safety: Additional Research Could Help States Strengthen Graduated Driver Licensing Systems. Report to the Committee on Transportation and Infrastructure and Its Subcommittee on Highways and Transit, House of Representatives. GAO-10-544

    ERIC Educational Resources Information Center

    Fleming, Susan A.

    2010-01-01

    Teen drivers ages 16 to 20 have the highest fatality rate of any age group in the United States. As a result, states have increasingly adopted laws to limit teen driving exposure, such as Graduated Driver Licensing (GDL) systems, which consist of three stages: a learner's permit allowing driving only under supervision; intermediate licensure…

  17. Mutations in the Spliceosome Component CWC27 Cause Retinal Degeneration with or without Additional Developmental Anomalies.

    PubMed

    Xu, Mingchu; Xie, Yajing Angela; Abouzeid, Hana; Gordon, Christopher T; Fiorentino, Alessia; Sun, Zixi; Lehman, Anna; Osman, Ihab S; Dharmat, Rachayata; Riveiro-Alvarez, Rosa; Bapst-Wicht, Linda; Babino, Darwin; Arno, Gavin; Busetto, Virginia; Zhao, Li; Li, Hui; Lopez-Martinez, Miguel A; Azevedo, Liliana F; Hubert, Laurence; Pontikos, Nikolas; Eblimit, Aiden; Lorda-Sanchez, Isabel; Kheir, Valeria; Plagnol, Vincent; Oufadem, Myriam; Soens, Zachry T; Yang, Lizhu; Bole-Feysot, Christine; Pfundt, Rolph; Allaman-Pillet, Nathalie; Nitschké, Patrick; Cheetham, Michael E; Lyonnet, Stanislas; Agrawal, Smriti A; Li, Huajin; Pinton, Gaëtan; Michaelides, Michel; Besmond, Claude; Li, Yumei; Yuan, Zhisheng; von Lintig, Johannes; Webster, Andrew R; Le Hir, Hervé; Stoilov, Peter; Amiel, Jeanne; Hardcastle, Alison J; Ayuso, Carmen; Sui, Ruifang; Chen, Rui; Allikmets, Rando; Schorderet, Daniel F

    2017-04-06

    Pre-mRNA splicing factors play a fundamental role in regulating transcript diversity both temporally and spatially. Genetic defects in several spliceosome components have been linked to a set of non-overlapping spliceosomopathy phenotypes in humans, among which skeletal developmental defects and non-syndromic retinitis pigmentosa (RP) are frequent findings. Here we report that defects in spliceosome-associated protein CWC27 are associated with a spectrum of disease phenotypes ranging from isolated RP to severe syndromic forms. By whole-exome sequencing, recessive protein-truncating mutations in CWC27 were found in seven unrelated families that show a range of clinical phenotypes, including retinal degeneration, brachydactyly, craniofacial abnormalities, short stature, and neurological defects. Remarkably, variable expressivity of the human phenotype can be recapitulated in Cwc27 mutant mouse models, with significant embryonic lethality and severe phenotypes in the complete knockout mice while mice with a partial loss-of-function allele mimic the isolated retinal degeneration phenotype. Our study describes a retinal dystrophy-related phenotype spectrum as well as its genetic etiology and highlights the complexity of the spliceosomal gene network.

  18. Genetic analysis of colon tumors induced by a dietary carcinogen PhIP in CYP1A humanized mice: Identification of mutation of β-catenin/Ctnnb1 as the driver gene for the carcinogenesis.

    PubMed

    Wang, Hong; Zhou, Hong; Liu, Anna; Guo, Xiangyi; Yang, Chung S

    2015-11-01

    Replacing mouse Cyp1a with human CYP1A enables the humanized CYP1A mice to mimic human metabolism of the dietary carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), by N(2) -hydroxylation to a proximate carcinogen. Our previous study demonstrated that PhIP, combined with the dextrin sulfate sodium (DSS)-induced colitis, induces colon carcinogenesis in hCYP1A mice. Here, we employed whole exome sequencing and found multiple gene mutations in PhIP/DSS-induced colon tumors. Mutations in the exon 3 of Ctnnb1/β-catenin, however, were the predominant events. We further sequenced the key fragments of Apc, Ctnnb1, and Kras, because mutations of these genes in the humans are commonly found as the drivers of colorectal cancer. Mutations on either codon 32 or 34 in the exon 3 of Ctnnb1 were found in 39 out of 42 tumors, but no mutation was found in either Apc or Kras. The sequence context of codons 32 and 34 suggests that PhIP targets +3G in a TGGA motif of Ctnnb1. Since mutations that activate Wnt signal is a major driving force for human colorectal cancers, we conclude that the mutated β-catenin is the driver in PhIP/DSS-induced colon carcinogenesis. This result suggests that the colon tumors in hCYP1A mice mimic human colorectal carcinogenesis not only in the dietary etiology involving PhIP, but also in the aberrant activation of the Wnt signaling pathway as the driving force.

  19. Older Drivers

    MedlinePlus

    ... Affects Driving Tips for Safe Driving Making Your Vehicle Safe Regulations Affecting Older Drivers When Driving Skills ... Like drivers of any age, they use their vehicles to go shopping, do errands, and visit the ...

  20. CBL, CBLB, TET2, ASXL1, and IDH1/2 mutations and additional chromosomal aberrations constitute molecular events in chronic myelogenous leukemia

    PubMed Central

    Makishima, Hideki; Jankowska, Anna M.; McDevitt, Michael A.; O'Keefe, Christine; Dujardin, Simon; Cazzolli, Heather; Przychodzen, Bartlomiej; Prince, Courtney; Nicoll, John; Siddaiah, Harish; Shaik, Mohammed; Szpurka, Hadrian; Hsi, Eric; Advani, Anjali; Paquette, Ronald

    2011-01-01

    Progression of chronic myelogenous leukemia (CML) to accelerated (AP) and blast phase (BP) is because of secondary molecular events, as well as additional cytogenetic abnormalities. On the basis of the detection of JAK2, CBL, CBLB, TET2, ASXL1, and IDH1/2 mutations in myelodysplastic/myeloproliferative neoplasms, we hypothesized that they may also contribute to progression in CML. We screened these genes for mutations in 54 cases with CML (14 with chronic phase, 14 with AP, 20 with myeloid, and 6 with nonmyeloid BP). We identified 1 CBLB and 2 TET2 mutations in AP, and 1 CBL, 1 CBLB, 4 TET2, 2 ASXL1, and 2 IDH family mutations in myeloid BP. However, none of these mutations were found in chronic phase. No cases with JAK2V617F mutations were found. In 2 cases, TET2 mutations were found concomitant with CBLB mutations. By single nucleotide polymorphism arrays, uniparental disomy on chromosome 5q, 8q, 11p, and 17p was found in AP and BP but not involving 4q24 (TET2) or 11q23 (CBL). Microdeletions on chromosomes 17q11.2 and 21q22.12 involved tumor associated genes NF1 and RUNX1, respectively. Our results indicate that CBL family, TET2, ASXL1, and IDH family mutations and additional cryptic karyotypic abnormalities can occur in advanced phase CML. PMID:21346257

  1. Identifying Cancer Driver Genes Using Replication-Incompetent Retroviral Vectors.

    PubMed

    Bii, Victor M; Trobridge, Grant D

    2016-10-25

    Identifying novel genes that drive tumor metastasis and drug resistance has significant potential to improve patient outcomes. High-throughput sequencing approaches have identified cancer genes, but distinguishing driver genes from passengers remains challenging. Insertional mutagenesis screens using replication-incompetent retroviral vectors have emerged as a powerful tool to identify cancer genes. Unlike replicating retroviruses and transposons, replication-incompetent retroviral vectors lack additional mutagenesis events that can complicate the identification of driver mutations from passenger mutations. They can also be used for almost any human cancer due to the broad tropism of the vectors. Replication-incompetent retroviral vectors have the ability to dysregulate nearby cancer genes via several mechanisms including enhancer-mediated activation of gene promoters. The integrated provirus acts as a unique molecular tag for nearby candidate driver genes which can be rapidly identified using well established methods that utilize next generation sequencing and bioinformatics programs. Recently, retroviral vector screens have been used to efficiently identify candidate driver genes in prostate, breast, liver and pancreatic cancers. Validated driver genes can be potential therapeutic targets and biomarkers. In this review, we describe the emergence of retroviral insertional mutagenesis screens using replication-incompetent retroviral vectors as a novel tool to identify cancer driver genes in different cancer types.

  2. Identifying Cancer Driver Genes Using Replication-Incompetent Retroviral Vectors

    PubMed Central

    Bii, Victor M.; Trobridge, Grant D.

    2016-01-01

    Identifying novel genes that drive tumor metastasis and drug resistance has significant potential to improve patient outcomes. High-throughput sequencing approaches have identified cancer genes, but distinguishing driver genes from passengers remains challenging. Insertional mutagenesis screens using replication-incompetent retroviral vectors have emerged as a powerful tool to identify cancer genes. Unlike replicating retroviruses and transposons, replication-incompetent retroviral vectors lack additional mutagenesis events that can complicate the identification of driver mutations from passenger mutations. They can also be used for almost any human cancer due to the broad tropism of the vectors. Replication-incompetent retroviral vectors have the ability to dysregulate nearby cancer genes via several mechanisms including enhancer-mediated activation of gene promoters. The integrated provirus acts as a unique molecular tag for nearby candidate driver genes which can be rapidly identified using well established methods that utilize next generation sequencing and bioinformatics programs. Recently, retroviral vector screens have been used to efficiently identify candidate driver genes in prostate, breast, liver and pancreatic cancers. Validated driver genes can be potential therapeutic targets and biomarkers. In this review, we describe the emergence of retroviral insertional mutagenesis screens using replication-incompetent retroviral vectors as a novel tool to identify cancer driver genes in different cancer types. PMID:27792127

  3. An Individual with Blepharophimosis-Ptosis-Epicanthus Inversus Syndrome (BPES) and Additional Features Expands the Phenotype Associated with Mutations in KAT6B

    PubMed Central

    Yu, Hung-Chun; Geiger, Elizabeth A.; Medne, Livija; Zackai, Elaine H.; Shaikh, Tamim H.

    2015-01-01

    Blepharophimosis-Ptosis-Epicanthus Inversus Syndrome (BPES) is an autosomal dominant disorder caused by mutations in FOXL2. We identified an individual with BPES and additional phenotypic features who did not have a FOXL2 mutation. We used whole exome sequencing to identify a de novo mutation in KAT6B (lysine acetyltransferase 6B) in this individual. The mutation was a 2 bp insertion leading to a frameshift which resulted in a premature stop codon. The resulting truncated protein does not have the C-terminal serine/methionine transcription activation domain necessary for interaction with other transcriptional and epigenetic regulators. This mutation likely has a dominant-negative or gain-of-function effect, similar to those observed in other genetic disorders resulting from KAT6B mutations, including Say-Barber-Biesecker-Young-Simpson (SBBYSS) and Genitopatellar syndrome (GTPTS). Thus, our subject’s phenotype broadens the spectrum of clinical findings associated with mutations in KAT6B. Furthermore, our results suggest that individuals with BPES without a FOXL2 mutation should be tested for KAT6B mutations. The transcriptional and epigenetic regulation mediated by KAT6B appears crucial to early developmental processes, which when perturbed can lead to a wide spectrum of phenotypic outcomes. PMID:24458743

  4. An individual with blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) and additional features expands the phenotype associated with mutations in KAT6B.

    PubMed

    Yu, Hung-Chun; Geiger, Elizabeth A; Medne, Livija; Zackai, Elaine H; Shaikh, Tamim H

    2014-04-01

    Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is an autosomal dominant disorder caused by mutations in FOXL2. We identified an individual with BPES and additional phenotypic features who did not have a FOXL2 mutation. We used whole exome sequencing to identify a de novo mutation in KAT6B (lysine acetyltransferase 6B) in this individual. The mutation was a 2-bp insertion leading to a frameshift which resulted in a premature stop codon. The resulting truncated protein does not have the C-terminal serine/methionine transcription activation domain necessary for interaction with other transcriptional and epigenetic regulators. This mutation likely has a dominant-negative or gain-of-function effect, similar to those observed in other genetic disorders resulting from KAT6B mutations, including Say-Barber-Biesecker-Young-Simpson (SBBYSS) and genitopatellar syndrome (GTPTS). Thus, our subject's phenotype broadens the spectrum of clinical findings associated with mutations in KAT6B. Furthermore, our results suggest that individuals with BPES without a FOXL2 mutation should be tested for KAT6B mutations. The transcriptional and epigenetic regulation mediated by KAT6B appears crucial to early developmental processes, which when perturbed can lead to a wide spectrum of phenotypic outcomes.

  5. Exomic Sequencing of Medullary Thyroid Cancer Reveals Dominant and Mutually Exclusive Oncogenic Mutations in RET and RAS

    PubMed Central

    Jiao, Yuchen; Sausen, Mark; Leary, Rebecca; Bettegowda, Chetan; Roberts, Nicholas J.; Bhan, Sheetal; Ho, Allen S.; Khan, Zubair; Bishop, Justin; Westra, William H.; Wood, Laura D.; Hruban, Ralph H.; Tufano, Ralph P.; Robinson, Bruce; Dralle, Henning; Toledo, Sergio P. A.; Toledo, Rodrigo A.; Morris, Luc G. T.; Ghossein, Ronald A.; Fagin, James A.; Chan, Timothy A.; Velculescu, Victor E.; Vogelstein, Bert; Kinzler, Kenneth W.; Papadopoulos, Nickolas; Nelkin, Barry D.; Ball, Douglas W.

    2013-01-01

    Context: Medullary thyroid cancer (MTC) is a rare thyroid cancer that can occur sporadically or as part of a hereditary syndrome. Objective: To explore the genetic origin of MTC, we sequenced the protein coding exons of approximately 21,000 genes in 17 sporadic MTCs. Patients and Design: We sequenced the exomes of 17 sporadic MTCs and validated the frequency of all recurrently mutated genes and other genes of interest in an independent cohort of 40 MTCs comprised of both sporadic and hereditary MTC. Results: We discovered 305 high-confidence mutations in the 17 sporadic MTCs in the discovery phase, or approximately 17.9 somatic mutations per tumor. Mutations in RET, HRAS, and KRAS genes were identified as the principal driver mutations in MTC. All of the other additional somatic mutations, including mutations in spliceosome and DNA repair pathways, were not recurrent in additional tumors. Tumors without RET, HRAS, or KRAS mutations appeared to have significantly fewer mutations overall in protein coding exons. Conclusions: Approximately 90% of MTCs had mutually exclusive mutations in RET, HRAS, and KRAS, suggesting that RET and RAS are the predominant driver pathways in MTC. Relatively few mutations overall and no commonly recurrent driver mutations other than RET, HRAS, and KRAS were seen in the MTC exome. PMID:23264394

  6. Identification of novel driver mutations of the discoidin domain receptor 2 (DDR2) gene in squamous cell lung cancer of Chinese patients

    PubMed Central

    2014-01-01

    Background Although many of the recently approved genomically targeted therapies have improved outcomes for patients in non–small-cell lung cancer (NSCLC) with lung adenocarcinoma, little is known about the genomic alterations that drive lung squamous cell cancer (SCC) and development of effective targeted therapies in lung SCC is a promising area to be further investigated. Discoidin domain receptor 2 (DDR2), is a novel receptor tyrosine kinases that respond to several collagens and involved in tissue repair, primary and metastatic cancer progression. Methods Expression of DDR2 mRNA was analyzed in 54 lung SCC tissues by qRT-PCR. Over-expression approaches were used to investigate the biological functions of DDR2 and its’ mutations in lung SCC cells. Conventional Sanger sequencing was used to investigate the mutations of DDR2 gene in 86 samples. The effect of DDR2 and its’ mutations on proliferation was evaluated by MTT and colony formation assays; cell migration and invasion was evaluated by trasnwell assays. Lung SCC cells stably transfected with pEGFP-DDR2 WT, pEGFP-DDR2-S131C or empty vector were injection into nude mice to study the effect of DDR2 and its’ mutation on tumorigenesis in vivo. Protein and mRNA expression levels of E-cadherin and MMP2 were determined by qRT-PCR and western blot analysis. Differences between groups were tested for significance using Student’s t-test (two-tailed). Results In this study, we found that DDR2 mRNA levels were significantly decreased in 54 lung SCC tissues compared with normal lung tissues. Moreover, there were 3 novel DDR2 mutations (G531V, S131C, T681I) in 4 patients and provide the mutation rate of 4.6% in the 86 patients with lung SCC. The mutation of S131C in DDR2 could promote lung SCC cells proliferation, migration and invasion via inducing MMP-2, but reducing E-cadherin expression. Conclusions These data indicated that the novel DDR2 mutation may contribute to the development and progression of lung

  7. Growth behavior of additional offspring with a beneficial reversal allele in the asymmetric sharply-peaked landscape in the coupled discrete-time mutation-selection model

    NASA Astrophysics Data System (ADS)

    Gill, Wonpyong

    2013-01-01

    The probability of additional offspring with a beneficial reversal allele for growing to a size NC for a range of population sizes N, sequence lengths L, selective advantages s, and measuring parameters C was calculated for a haploid, asexual population in the coupled discrete-time mutation-selection model in an asymmetric sharply-peaked landscape with a positive selective advantage of the reversal allele over the optimal allele. The growing probability in the stochastic region was inversely proportional to the measuring parameter when C < 1 /Ns, bent when C ≈ 1/ Ns and saturated when C > 1/ Ns. The crossing time and the time dependence of the increase in relative density of the reversal allele in the coupled discrete-time mutation-selection model was approximated using the Wright-Fisher two-allele model with the same selective advantage and corresponding effective mutation rate. The growth behavior of additional offspring with the reversal allele in the asymmetric sharply-peaked landscape in the coupled discrete-time mutation-selection model was controlled by the selective advantage of the reversal allele compared to the optimal allele and could be described by using the Wright-Fisher two-allele model, in spite of there being many other alleles with lower fitness, and in spite of there being two alleles, the optimal and reversal allele, separated by a low-fitness valley with a tunable depth and width.

  8. DriverDB: an exome sequencing database for cancer driver gene identification

    PubMed Central

    Cheng, Wei-Chung; Chung, I-Fang; Chen, Chen-Yang; Sun, Hsing-Jen; Fen, Jun-Jeng; Tang, Wei-Chun; Chang, Ting-Yu; Wong, Tai-Tong; Wang, Hsei-Wei

    2014-01-01

    Exome sequencing (exome-seq) has aided in the discovery of a huge amount of mutations in cancers, yet challenges remain in converting oncogenomics data into information that is interpretable and accessible for clinical care. We constructed DriverDB (http://ngs.ym.edu.tw/driverdb/), a database which incorporates 6079 cases of exome-seq data, annotation databases (such as dbSNP, 1000 Genome and Cosmic) and published bioinformatics algorithms dedicated to driver gene/mutation identification. We provide two points of view, ‘Cancer’ and ‘Gene’, to help researchers to visualize the relationships between cancers and driver genes/mutations. The ‘Cancer’ section summarizes the calculated results of driver genes by eight computational methods for a specific cancer type/dataset and provides three levels of biological interpretation for realization of the relationships between driver genes. The ‘Gene’ section is designed to visualize the mutation information of a driver gene in five different aspects. Moreover, a ‘Meta-Analysis’ function is provided so researchers may identify driver genes in customer-defined samples. The novel driver genes/mutations identified hold potential for both basic research and biotech applications. PMID:24214964

  9. The recurrent PPP1CB mutation p.Pro49Arg in an additional Noonan-like syndrome individual: Broadening the clinical phenotype.

    PubMed

    Bertola, Débora; Yamamoto, Guilherme; Buscarilli, Michelle; Jorge, Alexander; Passos-Bueno, Maria Rita; Kim, Chong

    2017-03-01

    We report on a 12-year-old Brazilian boy with the p.Pro49Arg mutation in PPP1CB, a novel gene associated with RASopathies. This is the fifth individual described, and the fourth presenting the same variant, suggesting a mutational hotspot. Phenotypically, he also showed the same hair pattern-sparse, thin, and with slow growing-, similar to the typical ectodermal finding observed in Noonan syndrome-like disorder with loose anagen hair. Additionally, he presented craniosynostosis, a rare clinical finding in RASopathies. This report gives further support that this novel RASopathy-PPP1CB-related Noonan syndrome with loose anagen hair-shares great similarity to Noonan syndrome-like disorder with loose anagen hair, and expands the phenotypic spectrum by adding the cranial vault abnormality. © 2017 Wiley Periodicals, Inc.

  10. Computer simulation for the growing probability of additional offspring with an advantageous reversal allele in the decoupled continuous-time mutation-selection model

    NASA Astrophysics Data System (ADS)

    Gill, Wonpyong

    2016-01-01

    This study calculated the growing probability of additional offspring with the advantageous reversal allele in an asymmetric sharply-peaked landscape using the decoupled continuous-time mutation-selection model. The growing probability was calculated for various population sizes, N, sequence lengths, L, selective advantages, s, fitness parameters, k and measuring parameters, C. The saturated growing probability in the stochastic region was approximately the effective selective advantage, s*, when C≫1/Ns* and s*≪1. The present study suggests that the growing probability in the stochastic region in the decoupled continuous-time mutation-selection model can be described using the theoretical formula for the growing probability in the Moran two-allele model. The selective advantage ratio, which represents the ratio of the effective selective advantage to the selective advantage, does not depend on the population size, selective advantage, measuring parameter and fitness parameter; instead the selective advantage ratio decreases with the increasing sequence length.

  11. Gene mutations in chronic lymphocytic leukemia.

    PubMed

    Amin, Nisar A; Malek, Sami N

    2016-04-01

    The recent discovery of genes mutated in chronic lymphocytic leukemia (CLL) has stimulated new research into the role of these genes in CLL pathogenesis. CLL cases carry approximately 5-20 mutated genes per exome, a lower number than detected in many human tumors. Of the recurrently mutated genes in CLL, all are mutated in 10% or less of patients when assayed in unselected CLL cohorts at diagnosis. Mutations in TP53 are of major clinical relevance, are often associated with del17p and gain in frequency over time. TP53 mutated and associated del17p states substantially lower response rates, remission duration, and survival in CLL. Mutations in NOTCH1 and SF3B1 are recurrent, often associated with progressive CLL that is also IgVH unmutated and ZAP70-positive and are under investigation as targets for novel therapies and as factors influencing CLL outcome. There are an estimated 20-50 additional mutated genes with frequencies of 1%-5% in CLL; more work is needed to identify these and to study their significance. Finally, of the major biological aberration categories influencing CLL as a disease, gene mutations will need to be placed into context with regard to their ultimate role and importance. Such calibrated appreciation necessitates studies incorporating multiple CLL driver aberrations into biological and clinical analyses.

  12. Mutations in the Kinase Domain of the HER2/ERBB2 Gene Identified in a Wide Variety of Human Cancers.

    PubMed

    Wen, Wenhsiang; Chen, Wangjuh Sting; Xiao, Nick; Bender, Ryan; Ghazalpour, Anatole; Tan, Zheng; Swensen, Jeffrey; Millis, Sherri Z; Basu, Gargi; Gatalica, Zoran; Press, Michael F

    2015-09-01

    The HER2 (official name ERBB2) gene encodes a membrane receptor in the epidermal growth factor receptor family amplified and overexpressed in adenocarcinoma. Activating mutations also occur in several cancers. We report mutation analyses of the HER2 kinase domain in 7497 histologically diverse cancers. Forty-five genes, including the kinase domain of HER2 with HER2 IHC and dual in situ hybridization, were analyzed in tumors from 7497 patients with cancer, including 850 breast, 770 colorectal, 910 non-small cell lung, 823 uterine or cervical, 1372 ovarian, and 297 pancreatic cancers, as well as 323 melanomas and 2152 other solid tumors. Sixty-nine HER2 kinase domain mutations were identified in tumors from 68 patients (approximately 1% of all cases, ranging from absent in sarcomas to 4% in urothelial cancers), which included previously published activating mutations and 13 novel mutations. Fourteen cases with coexisting HER2 mutation and amplification and/or overexpression were identified. Fifty-two of 68 patients had additional mutations in other analyzed genes, whereas 16 patients (23%) had HER2 mutations identified as the sole driver mutation. HER2 mutations coexisted with HER2 gene amplification and overexpression and with mutations in other functionally important genes. HER2 mutations were identified as the only driver mutation in a significant proportion of solid cancers. Evaluation of anti-HER2 therapies in nonamplified, HER2-mutated cancers is warranted.

  13. Functional annotation of rare gene aberration drivers of pancreatic cancer

    PubMed Central

    Tsang, Yiu Huen; Dogruluk, Turgut; Tedeschi, Philip M.; Wardwell-Ozgo, Joanna; Lu, Hengyu; Espitia, Maribel; Nair, Nikitha; Minelli, Rosalba; Chong, Zechen; Chen, Fengju; Chang, Qing Edward; Dennison, Jennifer B.; Dogruluk, Armel; Li, Min; Ying, Haoqiang; Bertino, Joseph R.; Gingras, Marie-Claude; Ittmann, Michael; Kerrigan, John; Chen, Ken; Creighton, Chad J.; Eterovic, Karina; Mills, Gordon B.; Scott, Kenneth L.

    2016-01-01

    As we enter the era of precision medicine, characterization of cancer genomes will directly influence therapeutic decisions in the clinic. Here we describe a platform enabling functionalization of rare gene mutations through their high-throughput construction, molecular barcoding and delivery to cancer models for in vivo tumour driver screens. We apply these technologies to identify oncogenic drivers of pancreatic ductal adenocarcinoma (PDAC). This approach reveals oncogenic activity for rare gene aberrations in genes including NAD Kinase (NADK), which regulates NADP(H) homeostasis and cellular redox state. We further validate mutant NADK, whose expression provides gain-of-function enzymatic activity leading to a reduction in cellular reactive oxygen species and tumorigenesis, and show that depletion of wild-type NADK in PDAC cell lines attenuates cancer cell growth in vitro and in vivo. These data indicate that annotating rare aberrations can reveal important cancer signalling pathways representing additional therapeutic targets. PMID:26806015

  14. A spatial simulation approach to account for protein structure when identifying non-random somatic mutations

    PubMed Central

    2014-01-01

    Background Current research suggests that a small set of “driver” mutations are responsible for tumorigenesis while a larger body of “passenger” mutations occur in the tumor but do not progress the disease. Due to recent pharmacological successes in treating cancers caused by driver mutations, a variety of methodologies that attempt to identify such mutations have been developed. Based on the hypothesis that driver mutations tend to cluster in key regions of the protein, the development of cluster identification algorithms has become critical. Results We have developed a novel methodology, SpacePAC (Spatial Protein Amino acid Clustering), that identifies mutational clustering by considering the protein tertiary structure directly in 3D space. By combining the mutational data in the Catalogue of Somatic Mutations in Cancer (COSMIC) and the spatial information in the Protein Data Bank (PDB), SpacePAC is able to identify novel mutation clusters in many proteins such as FGFR3 and CHRM2. In addition, SpacePAC is better able to localize the most significant mutational hotspots as demonstrated in the cases of BRAF and ALK. The R package is available on Bioconductor at: http://www.bioconductor.org/packages/release/bioc/html/SpacePAC.html. Conclusion SpacePAC adds a valuable tool to the identification of mutational clusters while considering protein tertiary structure. PMID:24990767

  15. Evaluating the evaluation of cancer driver genes

    PubMed Central

    Tokheim, Collin J.; Papadopoulos, Nickolas; Kinzler, Kenneth W.; Vogelstein, Bert; Karchin, Rachel

    2016-01-01

    Sequencing has identified millions of somatic mutations in human cancers, but distinguishing cancer driver genes remains a major challenge. Numerous methods have been developed to identify driver genes, but evaluation of the performance of these methods is hindered by the lack of a gold standard, that is, bona fide driver gene mutations. Here, we establish an evaluation framework that can be applied to driver gene prediction methods. We used this framework to compare the performance of eight such methods. One of these methods, described here, incorporated a machine-learning–based ratiometric approach. We show that the driver genes predicted by each of the eight methods vary widely. Moreover, the P values reported by several of the methods were inconsistent with the uniform values expected, thus calling into question the assumptions that were used to generate them. Finally, we evaluated the potential effects of unexplained variability in mutation rates on false-positive driver gene predictions. Our analysis points to the strengths and weaknesses of each of the currently available methods and offers guidance for improving them in the future. PMID:27911828

  16. Evaluating the evaluation of cancer driver genes.

    PubMed

    Tokheim, Collin J; Papadopoulos, Nickolas; Kinzler, Kenneth W; Vogelstein, Bert; Karchin, Rachel

    2016-12-13

    Sequencing has identified millions of somatic mutations in human cancers, but distinguishing cancer driver genes remains a major challenge. Numerous methods have been developed to identify driver genes, but evaluation of the performance of these methods is hindered by the lack of a gold standard, that is, bona fide driver gene mutations. Here, we establish an evaluation framework that can be applied to driver gene prediction methods. We used this framework to compare the performance of eight such methods. One of these methods, described here, incorporated a machine-learning-based ratiometric approach. We show that the driver genes predicted by each of the eight methods vary widely. Moreover, the P values reported by several of the methods were inconsistent with the uniform values expected, thus calling into question the assumptions that were used to generate them. Finally, we evaluated the potential effects of unexplained variability in mutation rates on false-positive driver gene predictions. Our analysis points to the strengths and weaknesses of each of the currently available methods and offers guidance for improving them in the future.

  17. Teaching Driver Education Technology to Novice Drivers.

    ERIC Educational Resources Information Center

    Young, Anthony

    A cybernetic unit in driver education was developed to help grade 10 students develop the skills needed to acquire and process driver education information and prepare for the driving phase of driver education in grade 11. Students used a simulator to engage in a series of scenarios designed to promote development of social, behavioral, and mental…

  18. The 3' addition of CCA to mitochondrial tRNASer(AGY) is specifically impaired in patients with mutations in the tRNA nucleotidyl transferase TRNT1.

    PubMed

    Sasarman, Florin; Thiffault, Isabelle; Weraarpachai, Woranontee; Salomon, Steven; Maftei, Catalina; Gauthier, Julie; Ellazam, Benjamin; Webb, Neil; Antonicka, Hana; Janer, Alexandre; Brunel-Guitton, Catherine; Elpeleg, Orly; Mitchell, Grant; Shoubridge, Eric A

    2015-05-15

    Addition of the trinucleotide cytosine/cytosine/adenine (CCA) to the 3' end of transfer RNAs (tRNAs) is essential for translation and is catalyzed by the enzyme TRNT1 (tRNA nucleotidyl transferase), which functions in both the cytoplasm and mitochondria. Exome sequencing revealed TRNT1 mutations in two unrelated subjects with different clinical features. The first presented with acute lactic acidosis at 3 weeks of age and developed severe developmental delay, hypotonia, microcephaly, seizures, progressive cortical atrophy, neurosensorial deafness, sideroblastic anemia and renal Fanconi syndrome, dying at 21 months. The second presented at 3.5 years with gait ataxia, dysarthria, gross motor regression, hypotonia, ptosis and ophthalmoplegia and had abnormal signals in brainstem and dentate nucleus. In subject 1, muscle biopsy showed combined oxidative phosphorylation (OXPHOS) defects, but there was no OXPHOS deficiency in fibroblasts from either subject, despite a 10-fold-reduction in TRNT1 protein levels in fibroblasts of the first subject. Furthermore, in normal controls, TRNT1 protein levels are 10-fold lower in muscle than in fibroblasts. High resolution northern blots of subject fibroblast RNA suggested incomplete CCA addition to the non-canonical mitochondrial tRNA(Ser(AGY)), but no obvious qualitative differences in other mitochondrial or cytoplasmic tRNAs. Complete knockdown of TRNT1 in patient fibroblasts rendered mitochondrial tRNA(Ser(AGY)) undetectable, and markedly reduced mitochondrial translation, except polypeptides lacking Ser(AGY) codons. These data suggest that the clinical phenotypes associated with TRNT1 mutations are largely due to impaired mitochondrial translation, resulting from defective CCA addition to mitochondrial tRNA(Ser(AGY)), and that the severity of this biochemical phenotype determines the severity and tissue distribution of clinical features.

  19. Mutational dichotomy in desmoplastic malignant melanoma corroborated by multigene panel analysis.

    PubMed

    Jahn, Stephan W; Kashofer, Karl; Halbwedl, Iris; Winter, Gerlinde; El-Shabrawi-Caelen, Laila; Mentzel, Thomas; Hoefler, Gerald; Liegl-Atzwanger, Bernadette

    2015-07-01

    Desmoplastic malignant melanoma is a distinct melanoma entity histologically subtyped into mixed and pure forms due to significantly reduced lymph node metastases in the pure form. Recent reports investigating common actionable driver mutations have demonstrated a lack of BRAF, NRAS, and KIT mutation in pure desmoplastic melanoma. In search for alternative driver mutations next generation amplicon sequencing for hotspot mutations in 50 genes cardinal to tumorigenesis was performed and in addition the RET G691S polymorphism was investigated. Data from 21 desmoplastic melanomas (12 pure and 9 mixed) were retrieved. Pure desmoplastic melanomas were either devoid of mutations (50%) or displayed mutations in tumor suppressor genes (TP53, CDKN2A, and SMAD4) singularly or in combination with the exception of a PIK3CA double-mutation lacking established biological relevance. Mixed desmoplastic melanomas on the contrary were frequently mutated (89%), and 67% exhibited activating mutations similar to common-type cutaneous malignant melanomas (BRAF, NRAS, FGFR2, and ERBB2). Separate analysis of morphologically heterogeneous tumor areas in four mixed desmoplastic malignant melanomas displayed no difference in mutation status and RET G691 status. GNAQ and GNA11, two oncogenes in BRAF and NRAS wild-type uveal melanomas, were not mutated in our cohort. The RET G691S polymorphism was found in 25% of pure and 38% of mixed desmoplastic melanomas. Apart from RET G691S our findings demonstrate absence of activating driver mutations in pure desmoplastic melanoma beyond previously investigated oncogenes (BRAF, NRAS, and KIT). The findings underline the therapeutic dichotomy of mixed versus pure desmoplastic melanoma with regard to activating mutations primarily of the mitogen-activated protein kinase pathway.

  20. Craniosynostosis with tracheal sleeve: a patient with Pfeiffer syndrome, tracheal sleeve and additional malformations in whom an FGFR2 mutation was found.

    PubMed

    Zackai, Elaine H; McDonald-McGinn, Donna M; Stolle, Catherine; Huff, Dale S

    2003-07-01

    We discuss a patient with Pfeiffer syndrome who had a tracheal sleeve and an FGFR2 mutation. In the light of our findings, and previous reports of patients with craniosynostosis that also reported similar mutations, we suggest that genomic screening for FGFR2 may be useful in cases with negative FGFR2 mutation testing.

  1. Mutation profiling of adenoid cystic carcinomas from multiple anatomical sites identifies mutations in the RAS pathway, but no KIT mutations

    PubMed Central

    Wetterskog, Daniel; Wilkerson, Paul M; Rodrigues, Daniel N; Lambros, Maryou B; Fritchie, Karen; Andersson, Mattias K; Natrajan, Rachael; Gauthier, Arnaud; Di Palma, Silvana; Shousha, Sami; Gatalica, Zoran; Töpfer, Chantal; Vukovic, Vesna; A’Hern, Roger; Weigelt, Britta; Vincent-Salomon, Anne; Stenman, Göran; Rubin, Brian P; Reis-Filho, Jorge S

    2016-01-01

    Aims The majority of adenoid cystic carcinomas (AdCCs), regardless of anatomical site, harbour the MYB–NFIB fusion gene. The aim of this study was to characterize the repertoire of somatic genetic events affecting known cancer genes in AdCCs. Methods and results DNA was extracted from 13 microdissected breast AdCCs, and subjected to a mutation survey using the Sequenom OncoCarta Panel v1.0. Genes found to be mutated in any of the breast AdCCs and genes related to the same canonical molecular pathways, as well as KIT, a proto-oncogene whose protein product is expressed in AdCCs, were sequenced in an additional 68 AdCCs from various anatomical sites by Sanger sequencing. Using the Sequenom MassARRAY platform and Sanger sequencing, mutations in BRAF and HRAS were identified in three and one cases, respectively (breast, and head and neck). KIT, which has previously been reported to be mutated in AdCCs, was also investigated, but no mutations were identified. Conclusions Our results demonstrate that mutations in genes pertaining to the canonical RAS pathway are found in a minority of AdCCs, and that activating KIT mutations are either absent or remarkably rare in these cancers, and unlikely to constitute a driver and therapeutic target for patients with AdCC. PMID:23398044

  2. Fatal traffic accidents among trailer truck drivers and accident causes as viewed by other truck drivers.

    PubMed

    Häkkänen, H; Summala, H

    2001-03-01

    Causality factors, the responsibility of the driver and driver fatigue-related factors were studied in fatal two-vehicle accidents where a trailer truck driver was involved during the period of 1991-1997 (n = 337). In addition, 251 long-haul truck drivers were surveyed in order to study their views regarding contributing factors in accidents involving trucks and the development of possible countermeasure against driver fatigue. Trailer truck drivers were principally responsible for 16% of all the accidents. Younger driver age and driving during evening hours were significant predictors of being principally responsible. In addition, the probability of being principally responsible for the accident increased by a factor of over three if the driver had a chronic illness. Prolonged driving preceding the accident, accident history or traffic offence history did not have a significant effect. Only 2% of the drivers were estimated to have fallen asleep while driving just prior to the accident, and altogether 4% of the drivers had been tired prior to the accident. Of the drivers 13% had however, been driving over 10 h preceding the accident (which has been criminally punishably in Finland since 1995 under the EC regulation) but no individual factors had a significant effect in predicting prolonged driving. The surveyed views regarding causes of truck accidents correspond well with the accident analysis. Accidents were viewed as being most often caused by other road users and driver fatigue was viewed to be no more than the fifth (out of eight) common cause of accidents. The probability of viewing fatigue as a more common cause increased significantly if the driver had experienced fatigue-related problems while driving. However, nearly half of the surveyed truck drivers expressed a negative view towards developing a technological countermeasure against driver fatigue. The negative view was not related to personal experiences of fatigue-related problems while driving.

  3. 49 CFR 177.816 - Driver training.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 2 2010-10-01 2010-10-01 false Driver training. 177.816 Section 177.816... Information and Regulations § 177.816 Driver training. (a) In addition to the training requirements of § 177... employee who will operate a motor vehicle has been trained in the applicable requirements of 49 CFR...

  4. Psychological reactions of drivers to railway suicide.

    PubMed

    Tranah, T; Farmer, R D

    1994-02-01

    Around 90 London Underground train drivers experience a person jumping or falling in front of their train each year. The majority of these incidents are suicides or attempted suicides. 76 drivers were interviewed in order to assess the range of responses to these incidents. The following psychometric instruments were used: Present State Examination (PSE9); Post-Traumatic Stress Disorder (PTSD) Interview; General Health Questionnaire (GHQ-28); Impact of Events Scale (IES); Post-Traumatic Symptom Scale; Recent Difficulties/Events scale; Perceived Stress Scale and Eysenck Personality Questionnaire (EPQ). When interviewed 1 month after the incident 13 (17.11%) drivers presented with PTSD. Diagnoses other than PTSD e.g. neurotic depression and phobic state were present in 24 (31.58%) drivers (including 12 of the 13 PTSD cases who had one additional diagnosis). On the basis of diagnoses three groups were identified: Group 1 drivers had PTSD and in most cases an additional PSE9 diagnosis; Group 2 drivers had a PSE9 diagnosis only; Group 3 drivers were not cases. 56 drivers were again interviewed 6 months after the incident to assess duration of caseness and/or symptoms and to identify any cases of delayed onset. Two drivers were still cases at 6 months (neurotic depression and phobic state), no driver presented with PTSD at 6 months. At 6 months there was a significant drop in symptom scores compared with measures taken at 1 month. These results suggest that although approximately one-third of drivers suffered a severe psychological reaction following a railway suicide, when interviewed again 6 months after the incident most drivers reported a marked reduction in symptoms.

  5. Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells

    SciTech Connect

    Severson, Paul L.; Vrba, Lukas; Stampfer, Martha R.; Futscher, Bernard W.

    2014-11-04

    Genetic mutations are known to drive cancer progression and certain tumors have mutation signatures that reflect exposures to environmental carcinogens. Benzo[a]pyrene (BaP) has a known mutation signature and has proven capable of inducing changes to DNA sequence that drives normal pre-stasis human mammary epithelial cells (HMEC) past a first tumor suppressor barrier (stasis) and toward immortality. We analyzed normal, pre-stasis HMEC, three independent BaP-derived post-stasis HMEC strains (184Aa, 184Be, 184Ce) and two of their immortal derivatives(184A1 and 184BE1) by whole exome sequencing. The independent post-stasis strains exhibited between 93 and 233 BaP-induced mutations in exons. Seventy percent of the mutations were C:G>A:T transversions, consistent with the known mutation spectrum of BaP. Mutations predicted to impact protein function occurred in several known and putative cancer drivers including p16, PLCG1, MED12, TAF1 in 184Aa; PIK3CG, HSP90AB1, WHSC1L1, LCP1 in 184Be and FANCA, LPP in 184Ce. Biological processes that typically harbor cancer driver mutations such as cell cycle, regulation of cell death and proliferation, RNA processing, chromatin modification and DNA repair were found to have mutations predicted to impact function in each of the post-stasis strains. Spontaneously immortalized HMEC lines derived from two of the BaP-derived post-stasis strains shared greater than 95% of their BaP-induced mutations with their precursor cells. These immortal HMEC had 10 or fewer additional point mutations relative to their post-stasis precursors, but acquired chromosomal anomalies during immortalization that arose independent of BaP. In conclusion, the results of this study indicate that acute exposures of HMEC to high dose BaP recapitulate mutation patterns of human tumors and can induce mutations in a number of cancer driver genes.

  6. The semidominant Mi(b) mutation identifies a role for the HLH domain in DNA binding in addition to its role in protein dimerization.

    PubMed Central

    Steingrímsson, E; Nii, A; Fisher, D E; Ferré-D'Amaré, A R; McCormick, R J; Russell, L B; Burley, S K; Ward, J M; Jenkins, N A; Copeland, N G

    1996-01-01

    The mouse microphthalmia (mi) locus encodes a basic helix-loop-helix-leucine zipper (bHLH-Zip) transcription factor called MITF (microphthalmia transcription factor). Mutations at mi affect the development of several different cell types, including melanocytes, mast cells, osteoclasts and pigmented epithelial cells of the eye. Here we describe the phenotypic and molecular characterization of the semidominant Microphthalmia(brwnish) (Mi(b)) mutation. We show that this mutation primarily affects melanocytes and produces retinal degeneration. The mutation is a G to A transition leading to a Gly244Glu substitution in helix 2 of the HLH dimerization domain. This location is surprising since other semidominant mi mutations characterized to date have been shown to affect DNA binding or transcriptional activation domains of MITF and act as dominant negatives, while mutations that affect MITF dimerization are inherited recessively. Gel retardation assays showed that while the mutant MITF(Mi-b) protein retains its dimerization potential, it is defective in its ability to bind DNA. Computer modeling suggested that the Gly244Glu mutation might disrupt DNA binding by interfering with productive docking of the protein dimer onto DNA. The Mi(b) mutation therefore appears to dissociate a DNA recognition function of the HLH domain from its role in protein dimerization. Images PMID:8947051

  7. Mutational landscape of EGFR-, MYC-, and Kras-driven genetically engineered mouse models of lung adenocarcinoma

    PubMed Central

    McFadden, David G.; Politi, Katerina; Bhutkar, Arjun; Chen, Frances K.; Song, Xiaoling; Pirun, Mono; Santiago, Philip M.; Kim-Kiselak, Caroline; Platt, James T.; Lee, Emily; Hodges, Emily; Rosebrock, Adam P.; Bronson, Roderick T.; Socci, Nicholas D.; Hannon, Gregory J.; Jacks, Tyler; Varmus, Harold

    2016-01-01

    Genetically engineered mouse models (GEMMs) of cancer are increasingly being used to assess putative driver mutations identified by large-scale sequencing of human cancer genomes. To accurately interpret experiments that introduce additional mutations, an understanding of the somatic genetic profile and evolution of GEMM tumors is necessary. Here, we performed whole-exome sequencing of tumors from three GEMMs of lung adenocarcinoma driven by mutant epidermal growth factor receptor (EGFR), mutant Kirsten rat sarcoma viral oncogene homolog (Kras), or overexpression of MYC proto-oncogene. Tumors from EGFR- and Kras-driven models exhibited, respectively, 0.02 and 0.07 nonsynonymous mutations per megabase, a dramatically lower average mutational frequency than observed in human lung adenocarcinomas. Tumors from models driven by strong cancer drivers (mutant EGFR and Kras) harbored few mutations in known cancer genes, whereas tumors driven by MYC, a weaker initiating oncogene in the murine lung, acquired recurrent clonal oncogenic Kras mutations. In addition, although EGFR- and Kras-driven models both exhibited recurrent whole-chromosome DNA copy number alterations, the specific chromosomes altered by gain or loss were different in each model. These data demonstrate that GEMM tumors exhibit relatively simple somatic genotypes compared with human cancers of a similar type, making these autochthonous model systems useful for additive engineering approaches to assess the potential of novel mutations on tumorigenesis, cancer progression, and drug sensitivity. PMID:27702896

  8. Diagnostic value of H3F3A mutations in giant cell tumour of bone compared to osteoclast‐rich mimics

    PubMed Central

    Presneau, Nadège; Baumhoer, Daniel; Behjati, Sam; Pillay, Nischalan; Tarpey, Patrick; Campbell, Peter J; Jundt, Gernot; Hamoudi, Rifat; Wedge, David C; Loo, Peter Van; Hassan, A Bassim; Khatri, Bhavisha; Ye, Hongtao; Tirabosco, Roberto; Amary, M Fernanda

    2015-01-01

    Abstract Driver mutations in the two histone 3.3 (H3.3) genes, H3F3A and H3F3B, were recently identified by whole genome sequencing in 95% of chondroblastoma (CB) and by targeted gene sequencing in 92% of giant cell tumour of bone (GCT). Given the high prevalence of these driver mutations, it may be possible to utilise these alterations as diagnostic adjuncts in clinical practice. Here, we explored the spectrum of H3.3 mutations in a wide range and large number of bone tumours (n = 412) to determine if these alterations could be used to distinguish GCT from other osteoclast‐rich tumours such as aneurysmal bone cyst, nonossifying fibroma, giant cell granuloma, and osteoclast‐rich malignant bone tumours and others. In addition, we explored the driver landscape of GCT through whole genome, exome and targeted sequencing (14 gene panel). We found that H3.3 mutations, namely mutations of glycine 34 in H3F3A, occur in 96% of GCT. We did not find additional driver mutations in GCT, including mutations in IDH1, IDH2, USP6, TP53. The genomes of GCT exhibited few somatic mutations, akin to the picture seen in CB. Overall our observations suggest that the presence of H3F3A p.Gly34 mutations does not entirely exclude malignancy in osteoclast‐rich tumours. However, H3F3A p.Gly34 mutations appear to be an almost essential feature of GCT that will aid pathological evaluation of bone tumours, especially when confronted with small needle core biopsies. In the absence of H3F3A p.Gly34 mutations, a diagnosis of GCT should be made with caution. PMID:27499898

  9. Diagnostic value of H3F3A mutations in giant cell tumour of bone compared to osteoclast-rich mimics.

    PubMed

    Presneau, Nadège; Baumhoer, Daniel; Behjati, Sam; Pillay, Nischalan; Tarpey, Patrick; Campbell, Peter J; Jundt, Gernot; Hamoudi, Rifat; Wedge, David C; Loo, Peter Van; Hassan, A Bassim; Khatri, Bhavisha; Ye, Hongtao; Tirabosco, Roberto; Amary, M Fernanda; Flanagan, Adrienne M

    2015-04-01

    Driver mutations in the two histone 3.3 (H3.3) genes, H3F3A and H3F3B, were recently identified by whole genome sequencing in 95% of chondroblastoma (CB) and by targeted gene sequencing in 92% of giant cell tumour of bone (GCT). Given the high prevalence of these driver mutations, it may be possible to utilise these alterations as diagnostic adjuncts in clinical practice. Here, we explored the spectrum of H3.3 mutations in a wide range and large number of bone tumours (n = 412) to determine if these alterations could be used to distinguish GCT from other osteoclast-rich tumours such as aneurysmal bone cyst, nonossifying fibroma, giant cell granuloma, and osteoclast-rich malignant bone tumours and others. In addition, we explored the driver landscape of GCT through whole genome, exome and targeted sequencing (14 gene panel). We found that H3.3 mutations, namely mutations of glycine 34 in H3F3A, occur in 96% of GCT. We did not find additional driver mutations in GCT, including mutations in IDH1, IDH2, USP6, TP53. The genomes of GCT exhibited few somatic mutations, akin to the picture seen in CB. Overall our observations suggest that the presence of H3F3A p.Gly34 mutations does not entirely exclude malignancy in osteoclast-rich tumours. However, H3F3A p.Gly34 mutations appear to be an almost essential feature of GCT that will aid pathological evaluation of bone tumours, especially when confronted with small needle core biopsies. In the absence of H3F3A p.Gly34 mutations, a diagnosis of GCT should be made with caution.

  10. Driver Behavior and Motivation.

    ERIC Educational Resources Information Center

    Thomas, Patricia

    School bus driver behavior and motivation are continuing concerns for leaders/administrators in the field of transportation. Motivation begins with selection of a potential new driver. Drivers must like children and be patient, loyal, and punctual. The applicant's background must be verified, in view of the national concern for child safety.…

  11. Driver behaviour at roadworks.

    PubMed

    Walker, Guy; Calvert, Malcolm

    2015-11-01

    There is an incompatibility between how transport engineers think drivers behave in roadworks and how they actually behave. As a result of this incompatibility we are losing approximately a lane's worth of capacity in addition to those closed by the roadworks themselves. The problem would have little significance were it not for the fact a lane of motorway costs approx. £30 m per mile to construct and £43 k a year to maintain, and that many more roadworks are planned as infrastructure constructed 40 or 50 years previously reaches a critical stage in its lifecycle. Given current traffic volumes, and the sensitivity of road networks to congestion, the effects of roadworks need to be accurately assessed. To do this requires a new ergonomic approach. A large-scale observational study of real traffic conditions was used to identify the issues and impacts, which were then mapped to the ergonomic knowledge-base on driver behaviour, and combined to developed practical guidelines to help in modelling future roadworks scenarios with greater behavioural accuracy. Also stemming from the work are novel directions for the future ergonomic design of roadworks themselves.

  12. Teenaged Drivers and Fatal Crash Responsibility. Preliminary Report.

    ERIC Educational Resources Information Center

    Williams, Allan F.; Karpf, Ronald S.

    According to data obtained for the year 1978 from the Fatal Accident Reporting System (FARS) and from state governments under contract to the National Highway Traffic Safety Administration, teenaged drivers (especially males) have much higher rates of fatal crash involvement than older drivers. In addition, teenaged drivers are more likely than…

  13. Cancer3D: understanding cancer mutations through protein structures.

    PubMed

    Porta-Pardo, Eduard; Hrabe, Thomas; Godzik, Adam

    2015-01-01

    The new era of cancer genomics is providing us with extensive knowledge of mutations and other alterations in cancer. The Cancer3D database at http://www.cancer3d.org gives an open and user-friendly way to analyze cancer missense mutations in the context of structures of proteins in which they are found. The database also helps users analyze the distribution patterns of the mutations as well as their relationship to changes in drug activity through two algorithms: e-Driver and e-Drug. These algorithms use knowledge of modular structure of genes and proteins to separately study each region. This approach allows users to find novel candidate driver regions or drug biomarkers that cannot be found when similar analyses are done on the whole-gene level. The Cancer3D database provides access to the results of such analyses based on data from The Cancer Genome Atlas (TCGA) and the Cancer Cell Line Encyclopedia (CCLE). In addition, it displays mutations from over 14,700 proteins mapped to more than 24,300 structures from PDB. This helps users visualize the distribution of mutations and identify novel three-dimensional patterns in their distribution.

  14. Approaches of truck drivers and non-truck drivers toward reckless on-road behavior.

    PubMed

    Rosenbloom, Tova; Eldror, Ehud; Shahar, Amit

    2009-07-01

    The purpose of the study was to compare the reported approaches of truck drivers to those of non-truck drivers toward reckless on-road behaviors. One hundred and sixty-seven adult males, including 70 non-truck drivers, completed the questionnaires voluntarily. The truck drivers were employees of a concrete manufacturing company working at various company plants throughout Israel. Seventy were professional mixer truckers and 27 were tip-truckers. The participants completed the Reckless Driving Self-Report Scale based on Taubman Ben-Ari et al. [Taubman Ben-Ari, O., Florian, V., Mikulincer, M., 1999. The impact of mortality salience on reckless driving: a test of terror management mechanisms. Journal of Personality and Social Psychology 76, 35-45], adapted for truck drivers for this study. It was expected that non-professional, as compared to professional (truck) drivers, would be more permissive regarding reckless driving, since driving risks are less prominent in their daily driving experience. An ANOVA performed on mean reckless-driving scores yielded significant results. The post hoc Schéffe test indicated significantly higher reckless-driving scores for automobile drivers as compared to both mixer-truck driver scores and tip-truck driver scores. In addition, the reckless-driving scores for mixer-truck drivers were significantly higher than the tip-truck driver scores. We discuss various explanations for the findings and consider possible implications for training strategies in organizations as well as for media campaigns focused on mutual safe road use of truck drivers and private vehicle drivers.

  15. Thermally Activated Driver

    NASA Technical Reports Server (NTRS)

    Kinard, William H.; Murray, Robert C.; Walsh, Robert F.

    1987-01-01

    Space-qualified, precise, large-force, thermally activated driver (TAD) developed for use in space on astro-physics experiment to measure abundance of rare actinide-group elements in cosmic rays. Actinide cosmic rays detected using thermally activated driver as heart of event-thermometer (ET) system. Thermal expansion and contraction of silicone oil activates driver. Potential applications in fluid-control systems where precise valve controls are needed.

  16. Non-coding recurrent mutations in chronic lymphocytic leukaemia.

    PubMed

    Puente, Xose S; Beà, Silvia; Valdés-Mas, Rafael; Villamor, Neus; Gutiérrez-Abril, Jesús; Martín-Subero, José I; Munar, Marta; Rubio-Pérez, Carlota; Jares, Pedro; Aymerich, Marta; Baumann, Tycho; Beekman, Renée; Belver, Laura; Carrio, Anna; Castellano, Giancarlo; Clot, Guillem; Colado, Enrique; Colomer, Dolors; Costa, Dolors; Delgado, Julio; Enjuanes, Anna; Estivill, Xavier; Ferrando, Adolfo A; Gelpí, Josep L; González, Blanca; González, Santiago; González, Marcos; Gut, Marta; Hernández-Rivas, Jesús M; López-Guerra, Mónica; Martín-García, David; Navarro, Alba; Nicolás, Pilar; Orozco, Modesto; Payer, Ángel R; Pinyol, Magda; Pisano, David G; Puente, Diana A; Queirós, Ana C; Quesada, Víctor; Romeo-Casabona, Carlos M; Royo, Cristina; Royo, Romina; Rozman, María; Russiñol, Nuria; Salaverría, Itziar; Stamatopoulos, Kostas; Stunnenberg, Hendrik G; Tamborero, David; Terol, María J; Valencia, Alfonso; López-Bigas, Nuria; Torrents, David; Gut, Ivo; López-Guillermo, Armando; López-Otín, Carlos; Campo, Elías

    2015-10-22

    Chronic lymphocytic leukaemia (CLL) is a frequent disease in which the genetic alterations determining the clinicobiological behaviour are not fully understood. Here we describe a comprehensive evaluation of the genomic landscape of 452 CLL cases and 54 patients with monoclonal B-lymphocytosis, a precursor disorder. We extend the number of CLL driver alterations, including changes in ZNF292, ZMYM3, ARID1A and PTPN11. We also identify novel recurrent mutations in non-coding regions, including the 3' region of NOTCH1, which cause aberrant splicing events, increase NOTCH1 activity and result in a more aggressive disease. In addition, mutations in an enhancer located on chromosome 9p13 result in reduced expression of the B-cell-specific transcription factor PAX5. The accumulative number of driver alterations (0 to ≥4) discriminated between patients with differences in clinical behaviour. This study provides an integrated portrait of the CLL genomic landscape, identifies new recurrent driver mutations of the disease, and suggests clinical interventions that may improve the management of this neoplasia.

  17. A Linear Magnetic Field Scan Driver.

    PubMed

    Quine, Richard W; Czechowski, Tomasz; Eaton, Gareth R

    2009-02-01

    A linear magnetic field scan driver was developed to provide a rapidly scanning magnetic field for use in electron paramagnetic resonance (EPR) spectroscopy. The driver consists of two parts: a digitally synthesized ramp waveform generator and a power amplifier to drive the magnetic field coils. Additionally, the driver provides a trigger signal to a data collection digitizer that is synchronized to the ramp waveform. The driver can also drive an arbitrary current waveform supplied from an external source. The waveform generator is computer controlled through a serial data interface. Additional functions are controlled by the user from the driver front panel. The frequency and amplitude of the waveform are each separately controlled with 12-bit resolution (one part in 4,096). Several versions of the driver have been built with different frequency and amplitude ranges. Frequencies range from 500 to 20,000 Hz. Field sweep amplitudes range up to 80 G(pp). This article also gives a brief description of the field coils that are driven by the driver.

  18. A Linear Magnetic Field Scan Driver

    PubMed Central

    QUINE, RICHARD W.; CZECHOWSKI, TOMASZ; EATON, GARETH R.

    2009-01-01

    A linear magnetic field scan driver was developed to provide a rapidly scanning magnetic field for use in electron paramagnetic resonance (EPR) spectroscopy. The driver consists of two parts: a digitally synthesized ramp waveform generator and a power amplifier to drive the magnetic field coils. Additionally, the driver provides a trigger signal to a data collection digitizer that is synchronized to the ramp waveform. The driver can also drive an arbitrary current waveform supplied from an external source. The waveform generator is computer controlled through a serial data interface. Additional functions are controlled by the user from the driver front panel. The frequency and amplitude of the waveform are each separately controlled with 12-bit resolution (one part in 4,096). Several versions of the driver have been built with different frequency and amplitude ranges. Frequencies range from 500 to 20,000 Hz. Field sweep amplitudes range up to 80 Gpp. This article also gives a brief description of the field coils that are driven by the driver. PMID:19838315

  19. Driver drowsiness detection using multimodal sensor fusion

    NASA Astrophysics Data System (ADS)

    Andreeva, Elena O.; Aarabi, Parham; Philiastides, Marios G.; Mohajer, Keyvan; Emami, Majid

    2004-04-01

    This paper proposes a multi-modal sensor fusion algorithm for the estimation of driver drowsiness. Driver sleepiness is believed to be responsible for more than 30% of passenger car accidents and for 4% of all accident fatalities. In commercial vehicles, drowsiness is blamed for 58% of single truck accidents and 31% of commercial truck driver fatalities. This work proposes an innovative automatic sleep-onset detection system. Using multiple sensors, the driver"s body is studied as a mechanical structure of springs and dampeners. The sleep-detection system consists of highly sensitive triple-axial accelerometers to monitor the driver"s upper body in 3-D. The subject is modeled as a linear time-variant (LTV) system. An LMS adaptive filter estimation algorithm generates the transfer function (i.e. weight coefficients) for this LTV system. Separate coefficients are generated for the awake and asleep states of the subject. These coefficients are then used to train a neural network. Once trained, the neural network classifies the condition of the driver as either awake or asleep. The system has been tested on a total of 8 subjects. The tests were conducted on sleep-deprived individuals for the sleep state and on fully awake individuals for the awake state. When trained and tested on the same subject, the system detected sleep and awake states of the driver with a success rate of 95%. When the system was trained on three subjects and then retested on a fourth "unseen" subject, the classification rate dropped to 90%. Furthermore, it was attempted to correlate driver posture and sleepiness by observing how car vibrations propagate through a person"s body. Eight additional subjects were studied for this purpose. The results obtained in this experiment proved inconclusive which was attributed to significant differences in the individual habitual postures.

  20. Association between Supervisory Driver Offences and Novice Driver Crashes Post-Licensure.

    PubMed

    Senserrick, Teresa; Boufous, Soufiane; Ivers, Rebecca; Stevenson, Mark; Norton, Robyn; Williamson, Anne

    2010-01-01

    This research explore associations between driving offences of learner supervisory drivers and subsequent crashes as novice independent drivers in a prospective cohort of 20,822 drivers aged 17-24 in New South Wales, Australia, on their first independent driver licence. Information on demographics, primary supervisory drivers, and various risk factors was collected via an online questionnaire and subsequently linked to police-reported crashes two years later. Poisson regression determined that the unadjusted relative risk of crash was 1.35 (CI 1.14-1.60) for novices whose supervisors had offences, with this association remaining when adjusting for supervisor age, gender and relationship to the novice (RR=1.37, CI 1.16-1.63), but not when additionally controlling for novice driver demographics and characteristics (RR=1.50, CI 0.83-2.70). These findings suggest newly-licensed drivers previously supervised by drivers with recent traffic offences have a one-third higher risk of crashing. This risk is independent of the supervisor demographics, but mitigated by the young drivers' personal characteristics. Careful consideration should be given to policy developments regarding supervised driving requirements that rely heavily on parents to adopt this role.

  1. HER2 mutations in Chinese patients with non-small cell lung cancer

    PubMed Central

    Song, Zhengbo; Yu, Xinmin; Shi, Zhiyong; Zhao, Jun; Zhang, Yiping

    2016-01-01

    Background ERBB2 (HER2) is a driver gene identified in non-small cell lung cancer (NSCLC). The prevalence, clinicopathology, genetic variability and treatment of HER2-positive NSCLC in Chinese population are unclear. Patients and Methods Eight hundred and fifty-nine patients with pathologically confirmed NSCLC were screened for HER2 mutations using Sanger sequencing. Next-generation sequencing (NGS) was performed in positive cases. HER2 amplification was detected with FISH. Overall survival (OS) was evaluated using Kaplan-Meier methods and compared with log-rank tests. Results Twenty-one cases carrying HER2 mutations were identified with a prevalence of 2.4%. HER2 mutations were more frequently encountered in females, non-smokers and adenocarcinoma. NGS was performed in 19 out of 21 patients, The results showed 16 cases with additional genetic aberrations, most commonly associated with TP53 (n = 6), followed by EGFR (n = 3), NF1 (n = 3), KRAS (n = 2) and other mutations. One patient harbored HER2 amplification. Four patients with stage IV received afatinib treatment, and three showed stable disease with a median progression-free survival of 4 months and one patient was diagnosed with progressive disease. Conclusion HER2 mutations represent a distinct subset of NSCLC. NGS showed that HER2 mutations commonly co-existed with other driver genes. Afatinib treatment displayed moderate efficacy in patients with HER2 mutations. PMID:27825109

  2. New recA mutations that dissociate the various RecA protein activities in Escherichia coli provide evidence for an additional role for RecA protein in UV mutagenesis.

    PubMed Central

    Dutreix, M; Moreau, P L; Bailone, A; Galibert, F; Battista, J R; Walker, G C; Devoret, R

    1989-01-01

    To isolate strains with new recA mutations that differentially affect RecA protein functions, we mutagenized in vitro the recA gene carried by plasmid mini-F and then introduced the mini-F-recA plasmid into a delta recA host that was lysogenic for prophage phi 80 and carried a lac duplication. By scoring prophage induction and recombination of the lac duplication, we isolated new recA mutations. A strain carrying mutation recA1734 (Arg-243 changed to Leu) was found to be deficient in phi 80 induction but proficient in recombination. The mutation rendered the host not mutable by UV, even in a lexA(Def) background. Yet, the recA1734 host became mutable upon introduction of a plasmid encoding UmuD*, the active carboxyl-terminal fragment of UmuD. Although the recA1734 mutation permits cleavage of lambda and LexA repressors, it renders the host deficient in the cleavage of phi 80 repressor and UmuD protein. Another strain carrying mutation recA1730 (Ser-117 changed to Phe) was found to be proficient in phi 80 induction but deficient in recombination. The recombination defect conferred by the mutation was partly alleviated in a cell devoid of LexA repressor, suggesting that, when amplified, RecA1730 protein is active in recombination. Since LexA protein was poorly cleaved in the recA1730 strain while phage lambda was induced, we conclude that RecA1730 protein cannot specifically mediate LexA protein cleavage. Our results show that the recA1734 and recA1730 mutations differentially affect cleavage of various substrates. The recA1730 mutation prevented UV mutagenesis, even upon introduction into the host of a plasmid encoding UmuD* and was dominant over recA+. With respect to other RecA functions, recA1730 was recessive to recA+. This demonstrates that RecA protein has an additional role in mutagenesis beside mediating the cleavage of LexA and UmuD proteins. Images PMID:2651400

  3. 49 CFR 395.11 - Supporting documents for drivers using EOBRs.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 5 2010-10-01 2010-10-01 false Supporting documents for drivers using EOBRs. 395... REGULATIONS HOURS OF SERVICE OF DRIVERS § 395.11 Supporting documents for drivers using EOBRs. (a) Motor... additional supporting documents (e.g., driver payroll records, fuel receipts) that provide the ability...

  4. 49 CFR 395.11 - Supporting documents for drivers using EOBRs.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 5 2011-10-01 2011-10-01 false Supporting documents for drivers using EOBRs. 395... REGULATIONS HOURS OF SERVICE OF DRIVERS § 395.11 Supporting documents for drivers using EOBRs. (a) Motor... additional supporting documents (e.g., driver payroll records, fuel receipts) that provide the ability...

  5. A Simple Wave Driver

    ERIC Educational Resources Information Center

    Temiz, Burak Kagan; Yavuz, Ahmet

    2015-01-01

    This study was done to develop a simple and inexpensive wave driver that can be used in experiments on string waves. The wave driver was made using a battery-operated toy car, and the apparatus can be used to produce string waves at a fixed frequency. The working principle of the apparatus is as follows: shortly after the car is turned on, the…

  6. Help Wanted: Drivers.

    ERIC Educational Resources Information Center

    Hoober, Scott

    1999-01-01

    A booming economy and low unemployment make it harder than ever before to lure and retain good school-bus drivers. Lack of money for good wages has prompted some innovative recruitment and retention tactics. Chicago has turned to the rolls of people going off welfare as a source of bus-driver candidates. The Trans Group, headquartered in Chestnut…

  7. Mortality among professional drivers.

    PubMed

    Rafnsson, V; Gunnarsdóttir, H

    1991-10-01

    The mortality of truck drivers and taxi drivers was studied in Reykjavík. The national mortality rate was used for comparison, and the follow-up lasted until 1 December 1988. The 868 truck drivers (28,788.0 person-years) had an excess of lung cancer deaths [24 observed, 11.2 expected, standardized mortality ratio (SMR) 2.14], but fewer deaths than expected from respiratory diseases (15 observed versus 30.1 expected). The SMR from lung cancer did not steadily increase as the duration of employment increased, nor did it change with the length of follow-up. The SMR values did not deviate substantially from unity for the taxi drivers. Since the high mortality from lung cancer among the truck drivers did not seem to be due to their smoking habits, it might have been caused by one or more occupational factors, especially in light of this group's exposure to engine exhaust gases.

  8. Discovering potential cancer driver genes by an integrated network-based approach.

    PubMed

    Shi, Kai; Gao, Lin; Wang, Bingbo

    2016-08-16

    Although a lot of methods have been proposed to identify driver genes, how to separate the driver mutations from the passenger mutations is still a challenging problem in cancer genomics. The detection of driver genes with rare mutation and low accuracy is unsolved better. In this study, we present an integrated network-based approach to locate potential driver genes in a cohort of patients. The approach is composed of two steps including a network diffusion step and an aggregated ranking step, which fuses the correlation between the gene mutations and gene expression, the relationship between the mutated genes and the heterogeneous characteristic of the patient mutation. We analyze three cancer datasets including Glioblastoma multiforme, Ovarian cancer and Breast cancer. Our method has not only identified the known driver genes with high-frequency mutations, but also discovered the potential driver genes with a rare mutation. At the same time, validation by literature search and functional enrichment analysis reveal that the predicted genes are obviously related to these three kinds of cancers.

  9. Deep targeted sequencing in pediatric acute lymphoblastic leukemia unveils distinct mutational patterns between genetic subtypes and novel relapse-associated genes

    PubMed Central

    Lindqvist, C. Mårten; Lundmark, Anders; Nordlund, Jessica; Freyhult, Eva; Ekman, Diana; Almlöf, Jonas Carlsson; Raine, Amanda; Övernäs, Elin; Abrahamsson, Jonas; Frost, Britt-Marie; Grandér, Dan; Heyman, Mats; Palle, Josefine; Forestier, Erik; Lönnerholm, Gudmar

    2016-01-01

    To characterize the mutational patterns of acute lymphoblastic leukemia (ALL) we performed deep next generation sequencing of 872 cancer genes in 172 diagnostic and 24 relapse samples from 172 pediatric ALL patients. We found an overall greater mutational burden and more driver mutations in T-cell ALL (T-ALL) patients compared to B-cell precursor ALL (BCP-ALL) patients. In addition, the majority of the mutations in T-ALL had occurred in the original leukemic clone, while most of the mutations in BCP-ALL were subclonal. BCP-ALL patients carrying any of the recurrent translocations ETV6-RUNX1, BCR-ABL or TCF3-PBX1 harbored few mutations in driver genes compared to other BCP-ALL patients. Specifically in BCP-ALL, we identified ATRX as a novel putative driver gene and uncovered an association between somatic mutations in the Notch signaling pathway at ALL diagnosis and increased risk of relapse. Furthermore, we identified EP300, ARID1A and SH2B3 as relapse-associated genes. The genes highlighted in our study were frequently involved in epigenetic regulation, associated with germline susceptibility to ALL, and present in minor subclones at diagnosis that became dominant at relapse. We observed a high degree of clonal heterogeneity and evolution between diagnosis and relapse in both BCP-ALL and T-ALL, which could have implications for the treatment efficiency. PMID:27590521

  10. The novel R347g pathogenic mutation of aromatic amino acid decarboxylase provides additional molecular insights into enzyme catalysis and deficiency.

    PubMed

    Montioli, Riccardo; Paiardini, Alessandro; Kurian, Manju A; Dindo, Mirco; Rossignoli, Giada; Heales, Simon J R; Pope, Simon; Voltattorni, Carla Borri; Bertoldi, Mariarita

    2016-06-01

    We report here a clinical case of a patient with a novel mutation (Arg347→Gly) in the gene encoding aromatic amino acid decarboxylase (AADC) that is associated with AADC deficiency. The variant R347G in the purified recombinant form exhibits, similarly to the pathogenic mutation R347Q previously studied, a 475-fold drop of kcat compared to the wild-type enzyme. In attempting to unravel the reason(s) for this catalytic defect, we have carried out bioinformatics analyses of the crystal structure of AADC-carbidopa complex with the modelled catalytic loop (residues 328-339). Arg347 appears to interact with Phe103, as well as with both Leu333 and Asp345. We have then prepared and characterized the artificial F103L, R347K and D345A mutants. F103L, D345A and R347K exhibit about 13-, 97-, and 345-fold kcat decrease compared to the wild-type AADC, respectively. However, unlike F103L, the R347G, R347K and R347Q mutants as well as the D345A variant appear to be more defective in catalysis than in protein folding. Moreover, the latter mutants, unlike the wild-type protein and the F103L variant, share a peculiar binding mode of dopa methyl ester consisting of formation of a quinonoid intermediate. This finding strongly suggests that their catalytic defects are mainly due to a misplacement of the substrate at the active site. Taken together, our results highlight the importance of the Arg347-Leu333-Asp345 hydrogen-bonds network in the catalysis of AADC and reveal the molecular basis for the pathogenicity of the variants R347. Following the above results, a therapeutic treatment for patients bearing the mutation R347G is proposed.

  11. Synchrotron based proton drivers

    SciTech Connect

    Weiren Chou

    2002-09-19

    Proton drivers are the proton sources that produce intense short proton bunches. They have a wide range of applications. This paper discusses the proton drivers based on high-intensity proton synchrotrons. It gives a review of the high-intensity proton sources over the world and a brief report on recent developments in this field in the U.S. high-energy physics (HEP) community. The Fermilab Proton Driver is used as a case study for a number of challenging technical design issues.

  12. Innovation Driver Nanoelectronics

    NASA Astrophysics Data System (ADS)

    Lakner, Hubert

    2013-03-01

    When addressing the global societal challenges most solutions will require Nano electronics and Smart Systems - therefore innovation today is mainly based on nanoelectronics which has become one of the most important key enabling technologies and innovation drivers. Nanoelectronics has been extended by other microtechnologies. This results in additional functionalities. The combination of analog and digital electronics, the integration of sensors and actuators, of power devices and rf components on wafer level makes it possible to shrink shoebox sized systems to the size of a matchbox. But there is no innovation without research. Europe (Germany) is top in invention but poor in commercialization - many good ideas fail when going from research to production within the so-called Valley of Death. To overcome this, a clear strategy is necessary. Silicon Saxony, the big Saxonian cluster on micro- and nanoelectronics is presented as a best practice example: clear focus, addressing whole value chains and establishing joint technology platforms has led to a remarkable commercial success in the Dresden area.

  13. Association between Supervisory Driver Offences and Novice Driver Crashes Post-Licensure

    PubMed Central

    Senserrick, Teresa; Boufous, Soufiane; Ivers, Rebecca; Stevenson, Mark; Norton, Robyn; Williamson, Anne

    2010-01-01

    This research explore associations between driving offences of learner supervisory drivers and subsequent crashes as novice independent drivers in a prospective cohort of 20,822 drivers aged 17–24 in New South Wales, Australia, on their first independent driver licence. Information on demographics, primary supervisory drivers, and various risk factors was collected via an online questionnaire and subsequently linked to police-reported crashes two years later. Poisson regression determined that the unadjusted relative risk of crash was 1.35 (CI 1.14–1.60) for novices whose supervisors had offences, with this association remaining when adjusting for supervisor age, gender and relationship to the novice (RR=1.37, CI 1.16–1.63), but not when additionally controlling for novice driver demographics and characteristics (RR=1.50, CI 0.83–2.70). These findings suggest newly-licensed drivers previously supervised by drivers with recent traffic offences have a one-third higher risk of crashing. This risk is independent of the supervisor demographics, but mitigated by the young drivers’ personal characteristics. Careful consideration should be given to policy developments regarding supervised driving requirements that rely heavily on parents to adopt this role. PMID:21050613

  14. Profiling of somatic mutations in acute myeloid leukemia with FLT3-ITD at diagnosis and relapse

    PubMed Central

    Nagata, Yasunobu; Kanojia, Deepika; Mayakonda, Anand; Yoshida, Kenichi; Haridas Keloth, Sreya; Zang, Zhi Jiang; Okuno, Yusuke; Shiraishi, Yuichi; Chiba, Kenichi; Tanaka, Hiroko; Miyano, Satoru; Ding, Ling-Wen; Alpermann, Tamara; Sun, Qiao-Yang; Lin, De-Chen; Chien, Wenwen; Madan, Vikas; Liu, Li-Zhen; Tan, Kar-Tong; Sampath, Abhishek; Venkatesan, Subhashree; Inokuchi, Koiti; Wakita, Satoshi; Yamaguchi, Hiroki; Chng, Wee Joo; Kham, Shirley-Kow Yin; Yeoh, Allen Eng-Juh; Sanada, Masashi; Schiller, Joanna; Kreuzer, Karl-Anton; Kornblau, Steven M.; Kantarjian, Hagop M.; Haferlach, Torsten; Lill, Michael; Kuo, Ming-Chung; Shih, Lee-Yung; Blau, Igor-Wolfgang; Blau, Olga; Yang, Henry; Ogawa, Seishi; Koeffler, H. Phillip

    2015-01-01

    Acute myeloid leukemia (AML) with an FLT3 internal tandem duplication (FLT3-ITD) mutation is an aggressive hematologic malignancy with a grave prognosis. To identify the mutational spectrum associated with relapse, whole-exome sequencing was performed on 13 matched diagnosis, relapse, and remission trios followed by targeted sequencing of 299 genes in 67 FLT3-ITD patients. The FLT3-ITD genome has an average of 13 mutations per sample, similar to other AML subtypes, which is a low mutation rate compared with that in solid tumors. Recurrent mutations occur in genes related to DNA methylation, chromatin, histone methylation, myeloid transcription factors, signaling, adhesion, cohesin complex, and the spliceosome. Their pattern of mutual exclusivity and cooperation among mutated genes suggests that these genes have a strong biological relationship. In addition, we identified mutations in previously unappreciated genes such as MLL3, NSD1, FAT1, FAT4, and IDH3B. Mutations in 9 genes were observed in the relapse-specific phase. DNMT3A mutations are the most stable mutations, and this DNMT3A-transformed clone can be present even in morphologic complete remissions. Of note, all AML matched trio samples shared at least 1 genomic alteration at diagnosis and relapse, suggesting common ancestral clones. Two types of clonal evolution occur at relapse: either the founder clone recurs or a subclone of the founder clone escapes from induction chemotherapy and expands at relapse by acquiring new mutations. Relapse-specific mutations displayed an increase in transversions. Functional assays demonstrated that both MLL3 and FAT1 exert tumor-suppressor activity in the FLT3-ITD subtype. An inhibitor of XPO1 synergized with standard AML induction chemotherapy to inhibit FLT3-ITD growth. This study clearly shows that FLT3-ITD AML requires additional driver genetic alterations in addition to FLT3-ITD alone. PMID:26438511

  15. Mass drivers. 3: Engineering

    NASA Technical Reports Server (NTRS)

    Arnold, W.; Bowen, S.; Cohen, S.; Fine, K.; Kaplan, D.; Kolm, M.; Kolm, H.; Newman, J.; Oneill, G. K.; Snow, W.

    1979-01-01

    The last of a series of three papers by the Mass-Driver Group of the 1977 Ames Summer Study is presented. It develops the engineering principles required to implement the basic mass-driver. Optimum component mass trade-offs are derived from a set of four input parameters, and the program used to design a lunar launcher. The mass optimization procedures is then incorporated into a more comprehensive mission optimization program called OPT-4, which evaluates an optimized mass-driver reaction engine and its performance in a range of specified missions. Finally, this paper discusses, to the extent that time permitted, certain peripheral problems: heating effects in buckets due to magnetic field ripple; an approximate derivation of guide force profiles; the mechanics of inserting and releasing payloads; the reaction mass orbits; and a proposed research and development plan for implementing mass drivers.

  16. Electronic Driver Education Simulator.

    ERIC Educational Resources Information Center

    Spence, Keith R.

    1980-01-01

    Describes the collision avoidance simulator, which provides both a hands-on prolect for digital electronics students and a motivation device for driver education students. Gives details of the electrical construction and operation of the simulator. (JOW)

  17. Evaluating Driver Drowsiness Countermeasures.

    PubMed

    Gaspar, John G; Brown, Timothy L; Schwarz, Chris W; Lee, John D; Kang, Julie; Higgins, James S

    2017-03-21

    Objective Driver drowsiness contributes to a substantial number of fatal and non-fatal crashes, with recent estimates attributing up to 21% of fatal crashes to drowsiness. This paper describes recent NHTSA research on in-vehicle drowsiness countermeasures. Recent advances in technology and state detection algorithms have shown success in detecting drowsiness using a variety of data sources, including camera-based eye tracking, steering wheel position, yaw rate, and vehicle lane position. However, detection is just the first step in reducing drowsy driving crashes. Countermeasures are also needed to provide feedback to the driver, modify driver behavior, and prevent crashes. The goal of this study was to evaluate the effectiveness of in-vehicle drowsiness countermeasures in reducing drowsy lane departures. The tested countermeasures included different warning modalities in either a discrete or staged interface. Methods Data were collected from 72 young adult drivers (age 21-32) in the high-fidelity full-motion National Advanced Driving Simulator. Drivers completed a 45-minute simulated nighttime drive at two time points, late night and early morning, where drowsiness was manipulated by continuous hours awake. 48 drivers were exposed to one of six countermeasures that varied along two dimensions, type and modality. The countermeasures relied on a steering-based drowsiness detection algorithm developed in prior NHTSA research. 24 drivers received no countermeasure and were used as a baseline comparison. System effectiveness was measured by lane departures and standard deviation in lateral position (SDLP). Results There was a reduction in drowsy lane departure frequency and lane position variability for drivers with countermeasures compared to the baseline no-countermeasure group. Importantly, the data suggest that multi-stage alerts, which provide an indication of increasing urgency, were more effective in reducing drowsy lane departures than single-stage discrete

  18. Drunk Driver Testing

    NASA Technical Reports Server (NTRS)

    1984-01-01

    Systems Technology, Inc. developed a technique to study/measure behavioral changes brought on by long term isolation is now being used in a system for determining whether a driver is too drunk to drive. Device is intended to discourage intoxicated drivers from taking to the road by advising them they are in no condition to operate a vehicle. System is being tested experimentally in California.

  19. Driver Adaptive Warning Systems

    DTIC Science & Technology

    1998-03-01

    this threshold, an alarm is triggered. Since TLC based systems can have user defined thresholds, a warning can be given as early as desired. However, the...Driver Adaptive Warning Systems Thesis Proposal Parag H. Batavia CMU-RI-TR-98-07 The Robotics Institute Carnegie Mellon University Pittsburgh...control number. 1. REPORT DATE MAR 1998 2. REPORT TYPE 3. DATES COVERED 00-00-1998 to 00-00-1998 4. TITLE AND SUBTITLE Driver Adaptive Warning

  20. Graduated Driver Licensing

    PubMed Central

    Bates, Lyndel J.; Allen, Siobhan; Armstrong, Kerry; Watson, Barry; King, Mark J.; Davey, Jeremy

    2014-01-01

    Graduated driver licensing (GDL) aims to gradually increase the exposure of new drivers to more complex driving situations and typically consists of learner, provisional and open licence phases. The first phase, the learner licence, is designed to allow novice drivers to obtain practical driving experience in lower risk situations. The learner licence can delay licensure, encourage novice drivers to learn under supervision, mandate the number of hours of practice required to progress to the next phase and encourage parental involvement. The second phase, the provisional licence, establishes various driving restrictions and thereby reduces exposure to situations of higher risk, such as driving at night, with passengers or after drinking alcohol. Parental involvement with a GDL system appears essential in helping novices obtain sufficient practice and in enforcing compliance with restrictions once the new driver obtains a provisional licence. Given the significant number of young drivers involved in crashes within Oman, GDL is one countermeasure that may be beneficial in reducing crash risk and involvement for this group. PMID:25364543

  1. Driver Improvement Training and Evaluation.

    ERIC Educational Resources Information Center

    Whittenburg, John A.; And Others

    The last phase of the NHTSA-U.S. Coast Guard Driver Improvement Training and Evaluation Project is described. Begun in July 1970, the project had two basic objectives. The first was to determine whether or not driver training programs do, in fact, significantly reduce driver errors and accidents and improve overall driver efficiency. The second…

  2. Functional annotation of rare gene aberration drivers of pancreatic cancer | Office of Cancer Genomics

    Cancer.gov

    As we enter the era of precision medicine, characterization of cancer genomes will directly influence therapeutic decisions in the clinic. Here we describe a platform enabling functionalization of rare gene mutations through their high-throughput construction, molecular barcoding and delivery to cancer models for in vivo tumour driver screens. We apply these technologies to identify oncogenic drivers of pancreatic ductal adenocarcinoma (PDAC).

  3. Clinical Impact of Additional Cytogenetic Aberrations, cKIT and RAS Mutations, and Treatment Elements in Pediatric t(8;21)-AML: Results From an International Retrospective Study by the International Berlin-Frankfurt-Münster Study Group

    PubMed Central

    Klein, Kim; Kaspers, Gertjan; Harrison, Christine J.; Beverloo, H. Berna; Reedijk, Ardine; Bongers, Mathilda; Cloos, Jacqueline; Pession, Andrea; Reinhardt, Dirk; Zimmerman, Martin; Creutzig, Ursula; Dworzak, Michael; Alonzo, Todd; Johnston, Donna; Hirsch, Betsy; Zapotocky, Michal; De Moerloose, Barbara; Fynn, Alcira; Lee, Vincent; Taga, Takashi; Tawa, Akio; Auvrignon, Anne; Zeller, Bernward; Forestier, Erik; Salgado, Carmen; Balwierz, Walentyna; Popa, Alexander; Rubnitz, Jeffrey; Raimondi, Susana; Gibson, Brenda

    2015-01-01

    Purpose This retrospective cohort study aimed to determine the predictive relevance of clinical characteristics, additional cytogenetic aberrations, and cKIT and RAS mutations, as well as to evaluate whether specific treatment elements were associated with outcomes in pediatric t(8;21)-positive patients with acute myeloid leukemia (AML). Patients and Methods Karyotypes of 916 pediatric patients with t(8;21)-AML were reviewed for the presence of additional cytogenetic aberrations, and 228 samples were screened for presence of cKIT and RAS mutations. Multivariable regression models were used to assess the relevance of anthracyclines, cytarabine, and etoposide during induction and overall treatment. End points were the probability of achieving complete remission, cumulative incidence of relapse (CIR), probability of event-free survival, and probability of overall survival. Results Of 838 patients included in final analyses, 92% achieved complete remission. The 5-year overall survival, event-free survival, and CIR were 74%, 58%, and 26%, respectively. cKIT mutations and RAS mutations were not significantly associated with outcome. Patients with deletions of chromosome arm 9q [del(9q); n = 104] had a lower probability of complete remission (P = .01). Gain of chromosome 4 (+4; n = 21) was associated with inferior CIR and survival (P < .01). Anthracycline doses greater than 150 mg/m2 and etoposide doses greater than 500 mg/m2 in the first induction course and high-dose cytarabine 3 g/m2 during induction were associated with better outcomes on various end points. Cumulative doses of cytarabine greater than 30 g/m2 and etoposide greater than 1,500 mg/m2 were associated with lower CIR rates and better probability of event-free survival. Conclusion Pediatric patients with t(8;21)-AML and additional del(9q) or additional +4 might not be considered at good risk. Patients with t(8;21)-AML likely benefit from protocols that have high doses of anthracyclines, etoposide, and

  4. The genetic heterogeneity and mutational burden of engineered melanomas in zebrafish models

    PubMed Central

    2013-01-01

    Background Melanoma is the most deadly form of skin cancer. Expression of oncogenic BRAF or NRAS, which are frequently mutated in human melanomas, promote the formation of nevi but are not sufficient for tumorigenesis. Even with germline mutated p53, these engineered melanomas present with variable onset and pathology, implicating additional somatic mutations in a multi-hit tumorigenic process. Results To decipher the genetics of these melanomas, we sequence the protein coding exons of 53 primary melanomas generated from several BRAFV600E or NRASQ61K driven transgenic zebrafish lines. We find that engineered zebrafish melanomas show an overall low mutation burden, which has a strong, inverse association with the number of initiating germline drivers. Although tumors reveal distinct mutation spectrums, they show mostly C > T transitions without UV light exposure, and enrichment of mutations in melanogenesis, p53 and MAPK signaling. Importantly, a recurrent amplification occurring with pre-configured drivers BRAFV600E and p53-/- suggests a novel path of BRAF cooperativity through the protein kinase A pathway. Conclusion This is the first analysis of a melanoma mutational landscape in the absence of UV light, where tumors manifest with remarkably low mutation burden and high heterogeneity. Genotype specific amplification of protein kinase A in cooperation with BRAF and p53 mutation suggests the involvement of melanogenesis in these tumors. This work is important for defining the spectrum of events in BRAF or NRAS driven melanoma in the absence of UV light, and for informed exploitation of models such as transgenic zebrafish to better understand mechanisms leading to human melanoma formation. PMID:24148783

  5. Identification of driver model parameters.

    PubMed

    Reński, A

    2001-01-01

    The paper presents a driver model, which can be used in a computer simulation of a curved ride of a car. The identification of the driver parameters consisted in a comparison of the results of computer calculations obtained for the driver-vehicle-environment model with different driver data sets with test results of the double lane-change manoeuvre (Standard No. ISO/TR 3888:1975, International Organization for Standardization [ISO], 1975) and the wind gust manoeuvre. The optimisation method allows to choose for each real driver a set of driver model parameters for which the differences between test and calculation results are smallest. The presented driver model can be used in investigating the driver-vehicle control system, which allows to adapt the car construction to the psychophysical characteristics of a driver.

  6. A Genetic Interaction Screen for Breast Cancer Progression Driver Genes

    DTIC Science & Technology

    2013-06-01

    AD_________________ Award Number: W81XWH-12-1-0082 TITLE: A Genetic Interaction Screen for Breast...COVERED 1 2012 - 3 2013 4. TITLE AND SUBTITLE A Genetic Interaction Screen for Breast Cancer Progression Driver Genes 5a. CONTRACT NUMBER...analysis of genetic alterations in human breast cancers has revealed that individual tumors accumulate mutations in approximately ninety different genes

  7. Discrete Driver Assistance

    NASA Astrophysics Data System (ADS)

    Klette, Reinhard; Jiang, Ruyi; Morales, Sandino; Vaudrey, Tobi

    Applying computer technology, such as computer vision in driver assistance, implies that processes and data are modeled as being discretized rather than being continuous. The area of stereo vision provides various examples how concepts known in discrete mathematics (e.g., pixel adjacency graphs, belief propagation, dynamic programming, max-flow/min-cut, or digital straight lines) are applied when aiming for efficient and accurate pixel correspondence solutions. The paper reviews such developments for a reader in discrete mathematics who is interested in applied research (in particular, in vision-based driver assistance). As a second subject, the paper also discusses lane detection and tracking, which is a particular task in driver assistance; recently the Euclidean distance transform proved to be a very appropriate tool for obtaining a fairly robust solution.

  8. Traffic Safety Facts, 2001: Young Drivers.

    ERIC Educational Resources Information Center

    National Highway Traffic Safety Administration (DOT), Washington, DC.

    This document provides statistical information on U.S. traffic accidents involving young drivers. Data tables include: (1) driver fatalities and drivers involved in fatal crashes among drivers 15 to 20 years old, 1991-2001; (2) drivers involved in fatal crashes and driver involvement rates by age group, 2001; (3) drivers 15 to 20 years old…

  9. Young Drivers. Traffic Safety Facts, 2000.

    ERIC Educational Resources Information Center

    National Highway Traffic Safety Administration (DOT), Washington, DC.

    This document provides statistical information on U.S. traffic accidents involving young drivers. Data tables include: (1) driver fatalities and drivers involved in fatal crashes among drivers 15 to 20 years old, 1990-2000; (2) drivers involved in fatal crashes and driver involvement rates by age group, 2000; (3) drivers 15 to 20 years old…

  10. Identification of Variant-Specific Functions of PIK3CA by Rapid Phenotyping of Rare Mutations | Office of Cancer Genomics

    Cancer.gov

    Large-scale sequencing efforts are uncovering the complexity of cancer genomes, which are composed of causal "driver" mutations that promote tumor progression along with many more pathologically neutral "passenger" events. The majority of mutations, both in known cancer drivers and uncharacterized genes, are generally of low occurrence, highlighting the need to functionally annotate the long tail of infrequent mutations present in heterogeneous cancers.

  11. Landscape of somatic mutations in 560 breast cancer whole-genome sequences

    SciTech Connect

    Nik-Zainal, Serena; Davies, Helen; Staaf, Johan; Ramakrishna, Manasa; Glodzik, Dominik; Zou, Xueqing; Martincorena, Inigo; Alexandrov, Ludmil B.; Martin, Sancha; Wedge, David C.; Van Loo, Peter; Ju, Young Seok; Smid, Marcel; Brinkman, Arie B.; Morganella, Sandro; Aure, Miriam R.; Lingjærde, Ole Christian; Langerod, Anita; Ringner, Markus; Ahn, Sung -Min; Boyault, Sandrine; Brock, Jane E.; Broeks, Annegien; Butler, Adam; Desmedt, Christine; Dirix, Luc; Dronov, Serge; Fatima, Aquila; Foekens, John A.; Gerstung, Moritz; Hooijer, Gerrit K. J.; Jang, Se Jin; Jones, David R.; Kim, Hyung -Yong; King, Tari A.; Krishnamurthy, Savitri; Lee, Hee Jin; Lee, Jeong -Yeon; Li, Yilong; McLaren, Stuart; Menzies, Andrew; Mustonen, Ville; O’Meara, Sarah; Pauporte, Iris; Pivot, Xavier; Purdie, Colin A.; Raine, Keiran; Ramakrishnan, Kamna; Rodríguez-Gonzalez, F. German; Romieu, Gilles; Sieuwerts, Anieta M.; Simpson, Peter T.; Shepherd, Rebecca; Stebbings, Lucy; Stefansson, Olafur A.; Teague, Jon; Tommasi, Stefania; Treilleux, Isabelle; Van den Eynden, Gert G.; Vermeulen, Peter; Vincent-Salomon, Anne; Yates, Lucy; Caldas, Carlos; Veer, Laura van’t; Tutt, Andrew; Knappskog, Stian; Tan, Benita Kiat Tee; Jonkers, Jos; Borg, Ake; Ueno, Naoto T.; Sotiriou, Christos; Viari, Alain; Futreal, P. Andrew; Campbell, Peter J.; Span, Paul N.; Van Laere, Steven; Lakhani, Sunil R.; Eyfjord, Jorunn E.; Thompson, Alastair M.; Birney, Ewan; Stunnenberg, Hendrik G.; van de Vijver, Marc J.; Martens, John W. M.; Borresen-Dale, Anne -Lise; Richardson, Andrea L.; Kong, Gu; Thomas, Gilles; Stratton, Michael R.

    2016-05-02

    Here, we analysed whole-genome sequences of 560 breast cancers to advance understanding of the driver mutations conferring clonal advantage and the mutational processes generating somatic mutations. We found that 93 protein-coding cancer genes carried probable driver mutations. Some non-coding regions exhibited high mutation frequencies, but most have distinctive structural features probably causing elevated mutation rates and do not contain driver mutations. Mutational signature analysis was extended to genome rearrangements and revealed twelve base substitution and six rearrangement signatures. Three rearrangement signatures, characterized by tandem duplications or deletions, appear associated with defective homologous-recombination-based DNA repair: one with deficient BRCA1 function, another with deficient BRCA1 or BRCA2 function, the cause of the third is unknown. This analysis of all classes of somatic mutation across exons, introns and intergenic regions highlights the repertoire of cancer genes and mutational processes operating, and progresses towards a comprehensive account of the somatic genetic basis of breast cancer.

  12. Landscape of somatic mutations in 560 breast cancer whole genome sequences

    PubMed Central

    Nik-Zainal, Serena; Davies, Helen; Staaf, Johan; Ramakrishna, Manasa; Glodzik, Dominik; Zou, Xueqing; Martincorena, Inigo; Alexandrov, Ludmil B.; Martin, Sancha; Wedge, David C.; Van Loo, Peter; Ju, Young Seok; Smid, Marcel; Brinkman, Arie B; Morganella, Sandro; Aure, Miriam R.; Lingjærde, Ole Christian; Langerød, Anita; Ringnér, Markus; Ahn, Sung-Min; Boyault, Sandrine; Brock, Jane E.; Broeks, Annegien; Butler, Adam; Desmedt, Christine; Dirix, Luc; Dronov, Serge; Fatima, Aquila; Foekens, John A.; Gerstung, Moritz; Hooijer, Gerrit KJ; Jang, Se Jin; Jones, David R.; Kim, Hyung-Yong; King, Tari A.; Krishnamurthy, Savitri; Lee, Hee Jin; Lee, Jeong-Yeon; Li, Yilong; McLaren, Stuart; Menzies, Andrew; Mustonen, Ville; O’Meara, Sarah; Pauporté, Iris; Pivot, Xavier; Purdie, Colin A.; Raine, Keiran; Ramakrishnan, Kamna; Rodríguez-González, F. Germán; Romieu, Gilles; Sieuwerts, Anieta M.; Simpson, Peter T; Shepherd, Rebecca; Stebbings, Lucy; Stefansson, Olafur A; Teague, Jon; Tommasi, Stefania; Treilleux, Isabelle; Van den Eynden, Gert G.; Vermeulen, Peter; Vincent-Salomon, Anne; Yates, Lucy; Caldas, Carlos; van’t Veer, Laura; Tutt, Andrew; Knappskog, Stian; Tan, Benita Kiat Tee; Jonkers, Jos; Borg, Åke; Ueno, Naoto T; Sotiriou, Christos; Viari, Alain; Futreal, P. Andrew; Campbell, Peter J; Span, Paul N.; Van Laere, Steven; Lakhani, Sunil R; Eyfjord, Jorunn E.; Thompson, Alastair M.; Birney, Ewan; Stunnenberg, Hendrik G; van de Vijver, Marc J; Martens, John W.M.; Børresen-Dale, Anne-Lise; Richardson, Andrea L.; Kong, Gu; Thomas, Gilles; Stratton, Michael R.

    2016-01-01

    We analysed whole genome sequences of 560 breast cancers to advance understanding of the driver mutations conferring clonal advantage and the mutational processes generating somatic mutations. 93 protein-coding cancer genes carried likely driver mutations. Some non-coding regions exhibited high mutation frequencies but most have distinctive structural features probably causing elevated mutation rates and do not harbour driver mutations. Mutational signature analysis was extended to genome rearrangements and revealed 12 base substitution and six rearrangement signatures. Three rearrangement signatures, characterised by tandem duplications or deletions, appear associated with defective homologous recombination based DNA repair: one with deficient BRCA1 function; another with deficient BRCA1 or BRCA2 function; the cause of the third is unknown. This analysis of all classes of somatic mutation across exons, introns and intergenic regions highlights the repertoire of cancer genes and mutational processes operative, and progresses towards a comprehensive account of the somatic genetic basis of breast cancer. PMID:27135926

  13. Driver Education in the Schools. Automotive Safety Foundation's Monitor.

    ERIC Educational Resources Information Center

    Hartman, Charles H.

    Over the past 30 years, high school driver education has grown from a single-purpose experimental course offered in one public school to a multi-faceted program considered part of the regular curriculum in 14,000 public schools. The driver education curriculum is intended to achieve numerous, sometimes diverse goals. In addition to the obvious…

  14. Clinicopathological differences exist between CALR- and JAK2-mutated myeloproliferative neoplasms despite a similar molecular landscape: data from targeted next-generation sequencing in the diagnostic laboratory.

    PubMed

    Agarwal, Rishu; Blombery, Piers; McBean, Michelle; Jones, Kate; Fellowes, Andrew; Doig, Ken; Forsyth, Cecily; Westerman, David A

    2017-02-04

    Mutations in CALR have recently been detected in JAK2-negative myeloproliferative neoplasms (MPNs) and are key pathological drivers in these diseases. CALR-mutated MPNs are shown to have numerous clinicopathological differences to JAK2-mutated MPNs. The basis of these differences is poorly understood. It is unknown whether these differences result directly from any differences in intracellular signalling abnormalities induced by JAK2/CALR mutations or whether they relate to other phenomena such as a differing spectrum of genetic lesions between the two groups. We aimed to review the clinicopathological and molecular features of CALR- and JAK2-mutated MPNs from samples referred for diagnostic testing using a custom-designed targeted next-generation sequencing (NGS) panel. Eighty-nine CALR-mutated cases were compared with 70 JAK2-mutated cases. CALR-mutated MPNs showed higher platelet counts and a female predominance as compared to JAK2-mutated MPNs in our cohort. We have also observed differences between CALR mutation subtypes in terms of disease phenotype, mutational frequency and allelic burden. Type 1 CALR mutations were found to be more common in myelofibrosis, associated with a higher frequency and number of additional mutations and a higher mutant allelic burden as compared to type 2 CALR mutations. Despite these biological differences, our molecular characterisation suggests that CALR- and JAK2-mutated MPNs are broadly similar in terms of the quantity, frequency and spectrum of co-occurring mutations and therefore observed biological differences are likely to not be heavily influenced by the nature and quantity of co-mutated genes.

  15. UV Signature Mutations

    PubMed Central

    2014-01-01

    Sequencing complete tumor genomes and exomes has sparked the cancer field's interest in mutation signatures for identifying the tumor's carcinogen. This review and meta-analysis discusses signatures and their proper use. We first distinguish between a mutagen's canonical mutations – deviations from a random distribution of base changes to create a pattern typical of that mutagen – and the subset of signature mutations, which are unique to that mutagen and permit inference backward from mutations to mutagen. To verify UV signature mutations, we assembled literature datasets on cells exposed to UVC, UVB, UVA, or solar simulator light (SSL) and tested canonical UV mutation features as criteria for clustering datasets. A confirmed UV signature was: ≥60% of mutations are C→T at a dipyrimidine site, with ≥5% CC→TT. Other canonical features such as a bias for mutations on the non-transcribed strand or at the 3' pyrimidine had limited application. The most robust classifier combined these features with criteria for the rarity of non-UV canonical mutations. In addition, several signatures proposed for specific UV wavelengths were limited to specific genes or species; non-signature mutations induced by UV may cause melanoma BRAF mutations; and the mutagen for sunlight-related skin neoplasms may vary between continents. PMID:25354245

  16. [Current topics in mutations in the cancer genome].

    PubMed

    Iwaya, Takeshi; Mimori, Koshi; Wakabayashi, Go

    2012-03-01

    Several oncogenes and tumor suppressor genes are involved in the multistep process of carcinogenesis in many cancer types. Recently, global mutational analyses have revealed that the cancer genome has far greater numbers of mutations than previously thought. Furthermore, the next-generation sequencing method, which has a different principle from conventional Sanger sequencing, has provided more information on the cancer genome such as new cancer-related genes and the existence of many rearrangements in solid cancers. Somatic mutations occurring in cancer cells are divided into "driver" and "passenger" mutations. Driver mutations confer a growth advantage upon the neoplastic clone and are crucial for carcinogenesis. The remaining large majority of mutations are passengers, which, by definition, do not confer a growth advantage. Driver genes with low-frequency mutation rates (less than 10%) are also involved in carcinogenesis along with well-known drivers with high-frequency mutations. There are now several celebrated examples of anticancer drugs of which the efficacy in cancer patients can be predicted based on the genotype of several driver genes, such as EGFR, KRAS, and BRAF on the EGFR signaling pathway. The complete catalogs of somatic mutations provided by the sequencing of the cancer genome are expected to prompt new approaches to diagnosis, therapy, and potentially prevention.

  17. Spectrum of EGFR gene mutations and ALK rearrangements in lung cancer patients in Turkey.

    PubMed

    Sag, Sebnem Ozemri; Gorukmez, Ozlem; Ture, Mehmet; Gorukmez, Orhan; Deligonul, Adem; Sahinturk, Serdar; Topak, Ali; Gulten, Tuna; Kurt, Ender; Yakut, Tahsin

    2016-01-01

    The EGFR gene and ALK rearrangements are two genetic drivers of non-small cell lung cancer (NSCLC). The frequency of EGFR mutations and ALK rearrangement varies according to not only ethnicity but also gender, smoking status and the histological type of NSCLC. In the present study, we demonstrated the distribution of EGFR mutations in 132 NSCLC patients by using a pyrosequencing technique and the distribution of ALK rearrangements in 51 NSCLC patients by using fluorescent in situ hybridization technique in Turkey. Additionally, we compared the clinicopathological data of NSCLC patients with the mutation status of EGFR in their cancerous tissues. Both EGFR mutations and ALK rearrangements were identified in 19 (14.39 %) and 1 (1.96 %) patients, respectively. We found EGFR mutations in codon 861, 719 and 858 with the ratios of 10.52 % (2/19), 10.52 % (2/19) and 31.58 % (6/19), respectively, and deletion of exon 19 in 47.37 % (9/19) of the patients. We found the frequency of EGFR mutations to be significantly higher in female patients and nonsmokers (p = 0.043, p = 0.027, respectively). Consequently, we found EGFR mutations to be more frequent in female patients and nonsmokers. Future studies on larger patient groups would provide more accurate data to exhibit the relationship between EGFR mutations and ALK rearrangements and the clinicopathological status.

  18. Improving Driver Performance. A Curriculum for Licensed Drivers.

    ERIC Educational Resources Information Center

    Highway Users Federation for Safety and Mobility, Washington, DC.

    Curriculum material presented in this manual is for use in the development of an instructional program for drivers who either want or need to improve their driving performance. Three principal units are included: man and highway transportation, driver performance, and factors influencing driver behavior. Each unit is further divided into episodes…

  19. The Bicycle Driver's Guide.

    ERIC Educational Resources Information Center

    Pennsylvania State Dept. of Education, Harrisburg. Bureau of Curriculum Services.

    Designed to emphasize the concept of the bicycle driver vs. the popular term, bicycle rider, this manual contains guidelines on bicycle safety, addressing itself both to parents and children. The main section topics are: (1) parent responsibility; (2) choosing a bicycle, fitting it to the child, and learning to drive; (3) bicycle equipment,…

  20. Florida Driver Education Handbook.

    ERIC Educational Resources Information Center

    Mick, Susan H.

    This student edition contains the same basic information as the official Florida Driver Handbook, but the reading difficulty of the material has been sharply reduced. It also provides activity-oriented exercises and review tests on this material. Introductory materials include a complete listing of all activities given, some vocabulary exercises…

  1. Seven Performance Drivers.

    ERIC Educational Resources Information Center

    Ross, Linda

    2003-01-01

    Recent work with automotive e-commerce clients led to the development of a performance analysis methodology called the Seven Performance Drivers, including: standards, incentives, capacity, knowledge and skill, measurement, feedback, and analysis. This methodology has been highly effective in introducing and implementing performance improvement.…

  2. FXYD5 is a Marker for Poor Prognosis and a Potential Driver for Metastasis in Ovarian Carcinomas

    PubMed Central

    Raman, Pichai; Purwin, Timothy; Pestell, Richard; Tozeren, Aydin

    2015-01-01

    Ovarian cancer (OC) is a leading cause of cancer mortality, but aside from a few well-studied mutations, very little is known about its underlying causes. As such, we performed survival analysis on ovarian copy number amplifications and gene expression datasets presented by The Cancer Genome Atlas in order to identify potential drivers and markers of aggressive OC. Additionally, two independent datasets from the Gene Expression Omnibus web platform were used to validate the identified markers. Based on our analysis, we identified FXYD5, a glycoprotein known to reduce cell adhesion, as a potential driver of metastasis and a significant predictor of mortality in OC. As a marker of poor outcome, the protein has effective antibodies against it for use in tissue arrays. FXYD5 bridges together a wide variety of cancers, including ovarian, breast cancer stage II, thyroid, colorectal, pancreatic, and head and neck cancers for metastasis studies. PMID:26494976

  3. Exome-Scale Discovery of Hotspot Mutation Regions in Human Cancer Using 3D Protein Structure.

    PubMed

    Tokheim, Collin; Bhattacharya, Rohit; Niknafs, Noushin; Gygax, Derek M; Kim, Rick; Ryan, Michael; Masica, David L; Karchin, Rachel

    2016-07-01

    The impact of somatic missense mutation on cancer etiology and progression is often difficult to interpret. One common approach for assessing the contribution of missense mutations in carcinogenesis is to identify genes mutated with statistically nonrandom frequencies. Even given the large number of sequenced cancer samples currently available, this approach remains underpowered to detect drivers, particularly in less studied cancer types. Alternative statistical and bioinformatic approaches are needed. One approach to increase power is to focus on localized regions of increased missense mutation density or hotspot regions, rather than a whole gene or protein domain. Detecting missense mutation hotspot regions in three-dimensional (3D) protein structure may also be beneficial because linear sequence alone does not fully describe the biologically relevant organization of codons. Here, we present a novel and statistically rigorous algorithm for detecting missense mutation hotspot regions in 3D protein structures. We analyzed approximately 3 × 10(5) mutations from The Cancer Genome Atlas (TCGA) and identified 216 tumor-type-specific hotspot regions. In addition to experimentally determined protein structures, we considered high-quality structural models, which increase genomic coverage from approximately 5,000 to more than 15,000 genes. We provide new evidence that 3D mutation analysis has unique advantages. It enables discovery of hotspot regions in many more genes than previously shown and increases sensitivity to hotspot regions in tumor suppressor genes (TSG). Although hotspot regions have long been known to exist in both TSGs and oncogenes, we provide the first report that they have different characteristic properties in the two types of driver genes. We show how cancer researchers can use our results to link 3D protein structure and the biologic functions of missense mutations in cancer, and to generate testable hypotheses about driver mechanisms. Our results

  4. CRAF R391W is a melanoma driver oncogene

    PubMed Central

    Atefi, Mohammad; Titz, Bjoern; Tsoi, Jennifer; Avramis, Earl; Le, Allison; Ng, Charles; Lomova, Anastasia; Lassen, Amanda; Friedman, Michael; Chmielowski, Bartosz; Ribas, Antoni; Graeber, Thomas G.

    2016-01-01

    Approximately 75% of melanomas have known driver oncogenic mutations in BRAF, NRAS, GNA11 or GNAQ, while the mutations providing constitutive oncogenic signaling in the remaining melanomas are not known. We established a melanoma cell line from a tumor with none of the common driver mutations. This cell line demonstrated a signaling profile similar to BRAF-mutants, but lacked sensitivity to the BRAF inhibitor vemurafenib. RNA-seq mutation data implicated CRAF R391W as the alternative driver mutation of this melanoma. CRAF R391W was homozygous and over expressed. These melanoma cells were highly sensitive to CRAF, but not BRAF knockdown. In reconstitution experiments, CRAF R391W, but not CRAF WT, transformed NIH3T3 cells in soft-agar colony formation assays, increased kinase activity in vitro, induced MAP kinase signaling and conferred vemurafenib resistance. MAP kinase inducing activity was dependent on CRAF dimerization. Thus, CRAF is a bona fide alternative oncogene for BRAF/NRAS/GNAQ/GNA11 wild type melanomas. PMID:27273450

  5. Identification of novel candidate drivers connecting different dysfunctional levels for lung adenocarcinoma using protein-protein interactions and a shortest path approach

    PubMed Central

    Chen, Lei; Huang, Tao; Zhang, Yu-Hang; Jiang, Yang; Zheng, Mingyue; Cai, Yu-Dong

    2016-01-01

    Tumors are formed by the abnormal proliferation of somatic cells with disordered growth regulation under the influence of tumorigenic factors. Recently, the theory of “cancer drivers” connects tumor initiation with several specific mutations in the so-called cancer driver genes. According to the differentiation of four basic levels between tumor and adjacent normal tissues, the cancer drivers can be divided into the following: (1) Methylation level, (2) microRNA level, (3) mutation level, and (4) mRNA level. In this study, a computational method is proposed to identify novel lung adenocarcinoma drivers based on dysfunctional genes on the methylation, microRNA, mutation and mRNA levels. First, a large network was constructed using protein-protein interactions. Next, we searched all of the shortest paths connecting dysfunctional genes on different levels and extracted new candidate genes lying on these paths. Finally, the obtained candidate genes were filtered by a permutation test and an additional strict selection procedure involving a betweenness ratio and an interaction score. Several candidate genes remained, which are deemed to be related to two different levels of cancer. The analyses confirmed our assertions that some have the potential to contribute to the tumorigenesis process on multiple levels. PMID:27412431

  6. Identification of novel candidate drivers connecting different dysfunctional levels for lung adenocarcinoma using protein-protein interactions and a shortest path approach

    NASA Astrophysics Data System (ADS)

    Chen, Lei; Huang, Tao; Zhang, Yu-Hang; Jiang, Yang; Zheng, Mingyue; Cai, Yu-Dong

    2016-07-01

    Tumors are formed by the abnormal proliferation of somatic cells with disordered growth regulation under the influence of tumorigenic factors. Recently, the theory of “cancer drivers” connects tumor initiation with several specific mutations in the so-called cancer driver genes. According to the differentiation of four basic levels between tumor and adjacent normal tissues, the cancer drivers can be divided into the following: (1) Methylation level, (2) microRNA level, (3) mutation level, and (4) mRNA level. In this study, a computational method is proposed to identify novel lung adenocarcinoma drivers based on dysfunctional genes on the methylation, microRNA, mutation and mRNA levels. First, a large network was constructed using protein-protein interactions. Next, we searched all of the shortest paths connecting dysfunctional genes on different levels and extracted new candidate genes lying on these paths. Finally, the obtained candidate genes were filtered by a permutation test and an additional strict selection procedure involving a betweenness ratio and an interaction score. Several candidate genes remained, which are deemed to be related to two different levels of cancer. The analyses confirmed our assertions that some have the potential to contribute to the tumorigenesis process on multiple levels.

  7. Whole-genome reconstruction and mutational signatures in gastric cancer

    PubMed Central

    2012-01-01

    Background Gastric cancer is the second highest cause of global cancer mortality. To explore the complete repertoire of somatic alterations in gastric cancer, we combined massively parallel short read and DNA paired-end tag sequencing to present the first whole-genome analysis of two gastric adenocarcinomas, one with chromosomal instability and the other with microsatellite instability. Results Integrative analysis and de novo assemblies revealed the architecture of a wild-type KRAS amplification, a common driver event in gastric cancer. We discovered three distinct mutational signatures in gastric cancer - against a genome-wide backdrop of oxidative and microsatellite instability-related mutational signatures, we identified the first exome-specific mutational signature. Further characterization of the impact of these signatures by combining sequencing data from 40 complete gastric cancer exomes and targeted screening of an additional 94 independent gastric tumors uncovered ACVR2A, RPL22 and LMAN1 as recurrently mutated genes in microsatellite instability-positive gastric cancer and PAPPA as a recurrently mutated gene in TP53 wild-type gastric cancer. Conclusions These results highlight how whole-genome cancer sequencing can uncover information relevant to tissue-specific carcinogenesis that would otherwise be missed from exome-sequencing data. PMID:23237666

  8. Comparison of Visual Status of Iranian Military and Commercial Drivers

    PubMed Central

    Ghasemi, Mohammad; Hoseini Yazdi, Seyed Hosein; Heravian, Javad; Jafarzadehpur, Ebrahim; Rezaee, Maryam

    2015-01-01

    Background: There is no legal requirement for Iranian military truck drivers to undergo regular visual checkups as compared to commercial truck drivers. Objectives: This study aimed to evaluate the impact of drivers’ visual checkups by comparing the visual function of Iranian military and commercial truck drivers. Patients and Methods: In this comparative cross-sectional study, two hundred military and 200 commercial truck drivers were recruited and their Visual Acuity (VA), Visual Field (VF), color vision and Contrast Sensitivity (CS) were assessed and compared using the Snellen chart, confrontation screening method, D15 test and Pelli-Robson letter chart, respectively. A questionnaire regarding driving exposure and history of motor-vehicle crashes (MVCs) was also filled by drivers. Results were analyzed using an independent samples t-test, one-way ANOVA (assessing difference in number of MVCs across different age groups), chi-square test and Pearson correlation at statistical significance level of P < 0.05. Results: Mean age was 41.6 ± 9.2 for the military truck drivers and 43.4 ± 10.9 for commercial truck drivers (P > 0.05). No significant difference between military and commercial drivers was found in terms of driving experience, number of MVCs, binocular VA, frequency of color vision defects and CS scores. In contrast, the last ocular examination was significantly earlier in military drivers than commercial drivers (P < 0.001). In addition, 4% of military drivers did not meet the national standards to drive as opposed to 2% of commercial drivers. There was a significant but weak correlation between binocular VA and age (r = 0.175, P < 0.001). However, CS showed a significantly moderate correlation with age (r = -0.488, P < 0.001). Conclusions: The absence of legal requirement for regular eye examination in military drivers caused the incompetent drivers to be missed in contrast to commercial drivers. The need for scientific revision of VA standard for

  9. Driver irritation and aggressive behaviour.

    PubMed

    Björklund, Gunilla M

    2008-05-01

    A sample of 98 drivers responded to a Swedish version of the UK Driving Anger Scale [UK DAS; [Lajunen, T., Parker, D., Stradling, S.G., 1998. Dimensions of driver anger, aggressive and highway code violations and their mediation by safety orientation in UK drivers. Transport. Res. Part F 1, 107-121]. The results indicated that the Swedish version, like the British original, measures three sources of driver irritation: "progress impeded", "reckless driving", and "direct hostility". Structural equation modelling was used to investigate the relationships between the three sources of self-reported driver irritation, aggressive actions, speed, sex, age, and annual mileage. The models suggested a positive relationship between the amount of driver irritation and frequency of aggressive actions for all three sources of irritation. Female drivers tended to become more irritated than male drivers, while the male drivers tended to act aggressively more often. Surprisingly, drivers who reported that they enjoy fast speeds did not become more irritated than slower drivers when obstructed. The important conclusions are that experienced irritation often leads to openly aggressively actions, and that expression of aggressive behaviours may be a cause of other drivers' feeling of irritation.

  10. Analysis of driver performance under reduced visibility

    NASA Technical Reports Server (NTRS)

    Kaeppler, W. D.

    1982-01-01

    Mathematical models describing vehicle dynamics as well as human behavior may be useful in evaluating driver performance and in establishing design criteria for vehicles more compatible with man. In 1977, a two level model of driver steering behavior was developed, but its parameters were identified for clear visibility conditions only. Since driver performance degrades under conditions of reduced visibility, e.g., fog, the two level model should be investigated to determine its applicability to such conditions. The data analysis of a recently performed driving simulation experiment showed that the model still performed reasonably well under fog conditions, although there was a degradation in its predictive capacity during fog. Some additional parameters affecting anticipation and lag time may improve the model's performance for reduced visibility conditions.

  11. Drivers' perceptions and reactions to roadside memorials.

    PubMed

    Tay, Richard

    2009-07-01

    Despite their growing popularity in North America, little research has been conducted on understanding the effects of roadside memorials on drivers' behaviour. In this study, an online survey of 810 drivers found that public opinions on the policy options as well as drivers' self-reported reactions to the presence of roadside memorials were fairly divided. In addition, an on-road experiment was conducted to examine the short term effects of roadside memorials at two intersections. Our results showed that the number of red light violations was reduced by 16.7% in the 6 weeks after the installation of the mock memorials compared to the 6 weeks before whereas the number of violations at two comparison sites experienced an increase of 16.8%.

  12. Feasibility of a driver performance data acquisition system

    SciTech Connect

    Carter, R.J.; Spelt, P.F.; Goodman, M.J.

    1994-06-01

    The National Highway Traffic Safety Administration (NHTSA) envisions many future situations in which the effectiveness and consequences of new intelligent vehicle-highway systems technologies will need to be studied in actual production vehicles. Such studies will enable evaluations in vehicles which are familiar to drivers. These studies would be future enhanced by the availability of an instrumentation package that can be easily installed in these vehicles to enable specific vehicle configurations of interest to be evaluated, thereby increasing the variety of vehicle options that are available for study. Ideally, an approach is needed that would allow data collection from a variety of vehicle models and types, and would address the issue of driver familiarity. Such an approach is embodied in the concept of a driver performance data acquisition system that could be installed in a wide range of vehicles within a relatively short period of time. As a universally adaptable system, it would provide researchers with the ability to manually input data as well as directly record information on driver, vehicle, roadway, and environmental parameters. Furthermore, it would enable the measurement of driver performance in the driver`s own vehicle, thereby ensuring vehicle familiarity. In addition, it would be possible to measure driver performance in relation to any vehicle design characteristic at relatively little expense and effort, and would make it easy to update existing models of driver/vehicle behavior to reflect performance characteristics in vehicles of current manufacture.

  13. Mucoid Pseudomonas aeruginosa caused by mucA mutations result in activation of TLR2 in addition to TLR5 in airway epithelial cells.

    PubMed

    Beaudoin, Trevor; Lafayette, Shantelle; Nguyen, Dao; Rousseau, Simon

    2012-11-09

    The presence of the mucoid phenotype of Pseudomonas aeruginosa is a marker of poor survival in cystic fibrosis. As CF lung disease results from chronic infection leading to airway inflammation, we determined whether the switch to a mucoid phenotype by P. aeruginosa has an impact on the inflammatory response of airway epithelial cells. Exposure of airway epithelial cells to non-mucoid and mucoid P. aeruginosa-derived material leads to p38α MAPK activation, a key protein kinase involved in transmitting inflammatory signals. However, while the non-mucoid strain PAO1 activates p38α MAPK pathway solely via TLR5, the mucoid strain PACF508 activates p38α MAPK via both TLR5 and TLR2. Inactivation of mucA (the gene responsible for the mucoid phenotype) in PAO1 leads to p38α MAPK activation by both TLR2 and TLR5, as observed in the clinical mucoid isolate PACF508. Therefore, the switch to mucoid phenotype may contribute to more inflammation via TLR2 activation in addition to TLR5. Our findings highlight an important and under recognized role for TLR2 in the response of airway epithelial cells to infection.

  14. Negativity Bias in Dangerous Drivers

    PubMed Central

    Chai, Jing; Qu, Weina; Sun, Xianghong; Zhang, Kan; Ge, Yan

    2016-01-01

    The behavioral and cognitive characteristics of dangerous drivers differ significantly from those of safe drivers. However, differences in emotional information processing have seldom been investigated. Previous studies have revealed that drivers with higher anger/anxiety trait scores are more likely to be involved in crashes and that individuals with higher anger traits exhibit stronger negativity biases when processing emotions compared with control groups. However, researchers have not explored the relationship between emotional information processing and driving behavior. In this study, we examined the emotional information processing differences between dangerous drivers and safe drivers. Thirty-eight non-professional drivers were divided into two groups according to the penalty points that they had accrued for traffic violations: 15 drivers with 6 or more points were included in the dangerous driver group, and 23 drivers with 3 or fewer points were included in the safe driver group. The emotional Stroop task was used to measure negativity biases, and both behavioral and electroencephalograph data were recorded. The behavioral results revealed stronger negativity biases in the dangerous drivers than in the safe drivers. The bias score was correlated with self-reported dangerous driving behavior. Drivers with strong negativity biases reported having been involved in mores crashes compared with the less-biased drivers. The event-related potentials (ERPs) revealed that the dangerous drivers exhibited reduced P3 components when responding to negative stimuli, suggesting decreased inhibitory control of information that is task-irrelevant but emotionally salient. The influence of negativity bias provides one possible explanation of the effects of individual differences on dangerous driving behavior and traffic crashes. PMID:26765225

  15. Identifying potential cancer driver genes by genomic data integration

    NASA Astrophysics Data System (ADS)

    Chen, Yong; Hao, Jingjing; Jiang, Wei; He, Tong; Zhang, Xuegong; Jiang, Tao; Jiang, Rui

    2013-12-01

    Cancer is a genomic disease associated with a plethora of gene mutations resulting in a loss of control over vital cellular functions. Among these mutated genes, driver genes are defined as being causally linked to oncogenesis, while passenger genes are thought to be irrelevant for cancer development. With increasing numbers of large-scale genomic datasets available, integrating these genomic data to identify driver genes from aberration regions of cancer genomes becomes an important goal of cancer genome analysis and investigations into mechanisms responsible for cancer development. A computational method, MAXDRIVER, is proposed here to identify potential driver genes on the basis of copy number aberration (CNA) regions of cancer genomes, by integrating publicly available human genomic data. MAXDRIVER employs several optimization strategies to construct a heterogeneous network, by means of combining a fused gene functional similarity network, gene-disease associations and a disease phenotypic similarity network. MAXDRIVER was validated to effectively recall known associations among genes and cancers. Previously identified as well as novel driver genes were detected by scanning CNAs of breast cancer, melanoma and liver carcinoma. Three predicted driver genes (CDKN2A, AKT1, RNF139) were found common in these three cancers by comparative analysis.

  16. Redesign of Transjakarta Bus Driver's Cabin

    NASA Astrophysics Data System (ADS)

    Mardi Safitri, Dian; Azmi, Nora; Singh, Gurbinder; Astuti, Pudji

    2016-02-01

    Ergonomic risk at work stations with type Seated Work Control was one of the problems faced by Transjakarta bus driver. Currently “Trisakti” type bus, one type of bus that is used by Transjakarta in corridor 9, serving route Pinang Ranti - Pluit, gained many complaints from drivers. From the results of Nordic Body Map questionnaires given to 30 drivers, it was known that drivers feel pain in the neck, arms, hips, and buttocks. Allegedly this was due to the seat position and the button/panel bus has a considerable distance range (1 meter) to be achieved by drivers. In addition, preliminary results of the questionnaire using Workstation Checklist identified their complaints about uncomfortable cushion, driver's seat backrest, and the exact position of the AC is above the driver head. To reduce the risk level of ergonomics, then did research to design the cabin by using a generic approach to designing products. The risk analysis driver posture before the design was done by using Rapid Upper Limb Assessment (RULA), Rapid Entire Body Assessment (REBA), and Quick Exposure Checklist (QEC), while the calculation of the moment the body is done by using software Mannequin Pro V10.2. Furthermore, the design of generic products was done through the stages: need metric-matrix, house of quality, anthropometric data collection, classification tree concept, concept screening, scoring concept, design and manufacture of products in the form of two-dimensional. While the design after design risk analysis driver posture was done by using RULA, REBA, and calculation of moments body as well as the design visualized using software 3DMax. From the results of analysis before the draft design improvements cabin RULA obtained scores of 6, REBA 9, and the result amounted to 57.38% QEC and moment forces on the back is 247.3 LbF.inch and on the right hip is 72.9 LbF.in. While the results of the proposed improvements cabin design RULA obtained scores of 3, REBA 4, and the moment of force on

  17. Earning a driver's license.

    PubMed Central

    Williams, A F

    1997-01-01

    Teenage drivers in the United States have greatly elevated crash rates, primarily a result of qualities associated with immaturity and lack of driving experience. State licensing systems vary substantially, but most have allowed quick and easy access to driving with full privileges at a young age, contributing to the crash problem. Formal driver education has not been an effective crash prevention measure. Following the introduction of graduated licensing in New Zealand, Australia, and Canada, this system has been considered in many states and has been implemented in some. Graduated systems phase in full privilege driving, requiring initial experience to be gained under conditions of lower risk. The author describes the first five multistage graduated systems enacted in the United States in 1996 and 1997. Factors that will influence the acceptability and effectiveness of these new licensing systems are discussed. Images p[452]-a p454-a p456-a p457-a p460-a PMID:10822470

  18. Genome-wide prediction of cancer driver genes based on SNP and cancer SNV data.

    PubMed

    He, Quanze; He, Quanyuan; Liu, Xiaohui; Wei, Youheng; Shen, Suqin; Hu, Xiaohui; Li, Qiao; Peng, Xiangwen; Wang, Lin; Yu, Long

    2014-01-01

    Identifying cancer driver genes and exploring their functions are essential and the most urgent need in basic cancer research. Developing efficient methods to differentiate between driver and passenger somatic mutations revealed from large-scale cancer genome sequencing data is critical to cancer driver gene discovery. Here, we compared distinct features of SNP with SNV data in detail and found that the weighted ratio of SNV to SNP (termed as WVPR) is an excellent indicator for cancer driver genes. The power of WVPR was validated by accurate predictions of known drivers. We ranked most of human genes by WVPR and did functional analyses on the list. The results demonstrate that driver genes are usually highly enriched in chromatin organization related genes/pathways. And some protein complexes, such as histone acetyltransferase, histone methyltransferase, telomerase, centrosome, sin3 and U12-type spliceosomal complexes, are hot spots of driver mutations. Furthermore, this study identified many new potential driver genes (e.g. NTRK3 and ZIC4) and pathways including oxidative phosphorylation pathway, which were not deemed by previous methods. Taken together, our study not only developed a method to identify cancer driver genes/pathways but also provided new insights into molecular mechanisms of cancer development.

  19. Robotic Intelligence Kernel: Driver

    SciTech Connect

    2009-09-16

    The INL Robotic Intelligence Kernel-Driver is built on top of the RIK-A and implements a dynamic autonomy structure. The RIK-D is used to orchestrate hardware for sensing and action as well as software components for perception, communication, behavior and world modeling into a single cognitive behavior kernel that provides intrinsic intelligence for a wide variety of unmanned ground vehicle systems.

  20. Drivers, Trends and Mitigation

    SciTech Connect

    Blanco, Arthur S.; Gerlagh, Reyer; Suh, Sangwon; Barrett, John A.; de Coninck, Heleen; Diaz Morejon, Cristobal Felix; Mathur, Ritu; Nakicenovic, Nebojsa; Ahenkorah, Alfred Ofosu; Pan, Jiahua; Pathak, Himanshu; Rice, Jake; Richels, Richard G.; Smith, Steven J.; Stern, David; Toth, Ferenc L.; Zhou, Peter

    2014-12-01

    Chapter 5 analyzes the anthropogenic greenhouse gas (GHG) emission trends until the present and the main drivers that explain those trends. The chapter uses different perspectives to analyze past GHG-emissions trends, including aggregate emissions flows and per capita emissions, cumulative emissions, sectoral emissions, and territory-based vs. consumption-based emissions. In all cases, global and regional trends are analyzed. Where appropriate, the emission trends are contextualized with long-term historic developments in GHG emissions extending back to 1750.

  1. Operational cost drivers

    NASA Technical Reports Server (NTRS)

    Scholz, Arthur L.; Dickinson, William J.

    1988-01-01

    To be economically viable, the operations cost of launch vehicles must be reduced by an order of magnitude as compared to the Space Transportation System (STS). A summary of propulsion-related operations cost drivers derived from a two-year study of Shuttle ground operations is presented. Examples are given of the inordinate time and cost of launch operations caused by propulsion systems designs that did not adequately consider impacts on prelaunching processing. Typical of these cost drivers are those caused by central hydraulic systems, storable propellants, gimballed engines, multiple propellants, He and N2 systems and purges, hard starts, high maintenance turbopumps, accessibility problems, and most significantly, the use of multiple, nonintegrated RCS, OMS, and main propulsion systems. Recovery and refurbishment of SRBs have resulted in expensive crash and salvage operations. Vehicle system designers are encouraged to be acutely aware of these cost drivers and to incorporate solutions (beginning with the design concepts) to avoid business as usual and costs as usual.

  2. Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells

    DOE PAGES

    Severson, Paul L.; Vrba, Lukas; Stampfer, Martha R.; ...

    2014-11-04

    Genetic mutations are known to drive cancer progression and certain tumors have mutation signatures that reflect exposures to environmental carcinogens. Benzo[a]pyrene (BaP) has a known mutation signature and has proven capable of inducing changes to DNA sequence that drives normal pre-stasis human mammary epithelial cells (HMEC) past a first tumor suppressor barrier (stasis) and toward immortality. We analyzed normal, pre-stasis HMEC, three independent BaP-derived post-stasis HMEC strains (184Aa, 184Be, 184Ce) and two of their immortal derivatives(184A1 and 184BE1) by whole exome sequencing. The independent post-stasis strains exhibited between 93 and 233 BaP-induced mutations in exons. Seventy percent of the mutationsmore » were C:G>A:T transversions, consistent with the known mutation spectrum of BaP. Mutations predicted to impact protein function occurred in several known and putative cancer drivers including p16, PLCG1, MED12, TAF1 in 184Aa; PIK3CG, HSP90AB1, WHSC1L1, LCP1 in 184Be and FANCA, LPP in 184Ce. Biological processes that typically harbor cancer driver mutations such as cell cycle, regulation of cell death and proliferation, RNA processing, chromatin modification and DNA repair were found to have mutations predicted to impact function in each of the post-stasis strains. Spontaneously immortalized HMEC lines derived from two of the BaP-derived post-stasis strains shared greater than 95% of their BaP-induced mutations with their precursor cells. These immortal HMEC had 10 or fewer additional point mutations relative to their post-stasis precursors, but acquired chromosomal anomalies during immortalization that arose independent of BaP. In conclusion, the results of this study indicate that acute exposures of HMEC to high dose BaP recapitulate mutation patterns of human tumors and can induce mutations in a number of cancer driver genes.« less

  3. Recurrent somatic mutation in DROSHA induces microRNA profile changes in Wilms tumour

    PubMed Central

    Torrezan, Giovana T.; Ferreira, Elisa N.; Nakahata, Adriana M.; Barros, Bruna D. F.; Castro, Mayra T. M.; Correa, Bruna R.; Krepischi, Ana C. V.; Olivieri, Eloisa H. R.; Cunha, Isabela W.; Tabori, Uri; Grundy, Paul E.; Costa, Cecilia M. L.; de Camargo, Beatriz; Galante, Pedro A. F.; Carraro, Dirce M.

    2014-01-01

    Wilms tumour (WT) is an embryonal kidney neoplasia for which very few driver genes have been identified. Here we identify DROSHA mutations in 12% of WT samples (26/222) using whole-exome sequencing and targeted sequencing of 10 microRNA (miRNA)-processing genes. A recurrent mutation (E1147K) affecting a metal-binding residue of the RNase IIIb domain is detected in 81% of the DROSHA-mutated tumours. In addition, we identify non-recurrent mutations in other genes of this pathway (DGCR8, DICER1, XPO5 and TARBP2). By assessing the miRNA expression pattern of the DROSHA-E1147K-mutated tumours and cell lines expressing this mutation, we determine that this variant leads to a predominant downregulation of a subset of miRNAs. We confirm that the downregulation occurs exclusively in mature miRNAs and not in primary miRNA transcripts, suggesting that the DROSHA E1147K mutation affects processing of primary miRNAs. Our data underscore the pivotal role of the miRNA biogenesis pathway in WT tumorigenesis, particularly the major miRNA-processing gene DROSHA. PMID:24909261

  4. Versatile subnanosecond laser diode driver

    NASA Astrophysics Data System (ADS)

    Żbik, Mateusz; Wieczorek, Piotr Z.

    2016-09-01

    This article presents a laser diode driver that provides a fast modulation of a laser beam. A pulsed current source was designed and built to test Infra-Red (I-R) receivers in the Time Domain (TD). The proposed solution allows to estimate pulse responses of various photodetectors, whereas the testing was performed with a PiN photodetector. The pulse response brings the information on the behavior of the device under test in a wide frequency range. In addition, an experimental application of the proposed method is presented too. System discussed in this paper has been fully designed and manufactured in Warsaw University of Technology (WUT) in Institute of Electronic Systems (ISE).

  5. Displaceable Gear Torque Controlled Driver

    NASA Technical Reports Server (NTRS)

    Cook, Joseph S., Jr. (Inventor)

    1997-01-01

    Methods and apparatus are provided for a torque driver including a displaceable gear to limit torque transfer to a fastener at a precisely controlled torque limit. A biasing assembly biases a first gear into engagement with a second gear for torque transfer between the first and second gear. The biasing assembly includes a pressurized cylinder controlled at a constant pressure that corresponds to a torque limit. A calibrated gage and valve is used to set the desired torque limit. One or more coiled output linkages connect the first gear with the fastener adaptor which may be a socket for a nut. A gear tooth profile provides a separation force that overcomes the bias to limit torque at the desired torque limit. Multiple fasteners may be rotated simultaneously to a desired torque limit if additional output spur gears are provided. The torque limit is adjustable and may be different for fasteners within the same fastener configuration.

  6. Hazard prediction discriminates between novice and experienced drivers.

    PubMed

    Crundall, David

    2016-01-01

    Typical hazard perception tests often confound multiple processes in their responses. The current study tested hazard prediction in isolation to assess whether this component can discriminate between novice and experienced drivers. A variant of the hazard perception test, based on the Situation Awareness Global Assessment Technique, found experienced drivers to outperform novices across three experiments suggesting that the act of predicting an imminent hazard is a crucial part of the hazard-perception process. Furthermore three additional hypotheses were tested in these experiments. First, performance was compared across clips of different length. There was marginal evidence that novice drivers' performance suffered with the longest clips, but experienced drivers' performance did not, suggesting that experienced drivers find hazard prediction less effortful. Secondly, predictive accuracy was found to be dependent on the temporal proximity of visual precursors to the hazard. Thirdly the relationship between the hazard and its precursor was found to be important, with less obvious precursors improving the discrimination between novice and experience drivers. These findings demonstrate that a measure of hazard prediction, which is less confounded by the influence of risk appraisal than simple response time measures, can still discriminate between novice and experienced drivers. Application of this methodology under different conditions can produce insights into the underlying processes that may be at work, whilst also providing an alternative test of driver skill in relation to the detection of hazards.

  7. A novel active heads-up display for driver assistance.

    PubMed

    Doshi, Anup; Cheng, Shinko Yuanhsien; Trivedi, Mohan Manubhai

    2009-02-01

    In this paper, we introduce a novel laser-based wide-area heads-up windshield display which is capable of actively interfacing with a human as part of a driver assistance system. The dynamic active display (DAD) is a unique prototype interface that presents safety-critical visual icons to the driver in a manner that minimizes the deviation of his or her gaze direction without adding to unnecessary visual clutter. As part of an automotive safety system, the DAD presents alerts in the field of view of the driver only if necessary, which is based upon the state and pose of the driver, vehicle, and environment. This paper examines the effectiveness of DAD through a comprehensive comparative experimental evaluation of a speed compliance driver assistance system, which is implemented on a vehicular test bed. Three different types of display protocols for assisting a driver to comply with speed limits are tested on actual roadways, and these are compared with a conventional dashboard display. Given the inclination, drivers who are given an overspeed warning alert reduced the time required to slow down to the speed limit by 38% (p < 0.01) as compared with the drivers not given the alert. Additionally, certain alerts decreased distraction levels by reducing the time spent looking away from the road by 63% (p < 0.01). Ultimately, these alerts demonstrate the utility and promise of the DAD system.

  8. Heavy ion driver technology

    SciTech Connect

    Keefe, D.

    1988-09-01

    Major differences between fusion drivers and traditional accelerators include the following. The final beam current needed (/approximately/20 kA in a short pulse) is very much larger for a driver; such beams are dominated by repulsive space-charge effects since, even at 10 GeV, the ions are non-relativistic (v/c = 0.3). Also, the optical quality of the beams (called emittance by accelerator people) must be extremely good to ensure a suitably small focal spot at the pellet. Two schemes, one with a rf linac and storage rings, the other with a single-pass current-amplifying induction linac, are under study, the latter exclusively in the US. The induction linac approach lends itself to an examination in a sequence of scaled-down laboratory experiments since the most difficulties are expected to occur at the low energy end. Experiments and simulation have centered on a study of the transverse and longitudinal control of space-charge-dominated beams which are best described in terms of a non-neutral plasma rather than the traditional single-particle dynamics picture. An understanding of the high-current instability limits is required for arriving at a safe driver design. The final on-target beam current is so high that it must be carried in 16 separate focusing channels leading into the combustion chamber. While the energy deposition of the ions is expected to be entirely classical, there is a wealth of plasma physics phenomena to be explored (by theory and simulation) in the final propagation of these beams through the low-density gas in the chamber and in the environment of the hot target; it is important that none of these could result in a significant portion of the beam missing the focal spot. 13 refs., 9 figs., 1 tab.

  9. The RIA driver linac.

    SciTech Connect

    Shepard, K. W.

    2002-09-23

    The driver linac for the U.S. RIA project will be a 1.4 GV superconducting linac capable of accelerating the full mass range of ions from 900 MeV protons to 400 MeV/u uranium, and delivering a cw beam of 400 kW shared by at least two targets simultaneously. Elements of the linac are being developed at several U.S. laboratories. The current status of linac design and development is reviewed with emphasis on changes in the baseline design since the last linac conference.

  10. Mutational profiling of second primary lung cancers in patients who have received radiation for the treatment of Hodgkin's disease.

    PubMed

    Bond, David Alan; Dunavin, Neil; Otterson, Gregory Alan

    2015-03-01

    Lung cancer (LC) represents the most common solid tumor in survivors of Hodgkin's disease (HD), and the assessment of the mutational status of oncogenic driver mutations in LC is now standard. We compiled clinical and mutation data (EGFR, KRAS, and ALK) from the medical records of patients with LC and a remote history of HD. 13 cases of LC following HD were seen, including seven with mutational data. Two had EGFR mutations, none had KRAS mutations or ALK translocations. Our conclusions are limited by the small sample size, however this report reinforces the need to identify driver mutations in lung cancers.

  11. Vehicle automation: a remedy for driver stress?

    PubMed

    Funke, G; Matthews, G; Warm, J S; Emo, A K

    2007-08-01

    The present study addressed the effects of stress, vehicle automation and subjective state on driver performance and mood in a simulated driving task. A total of 168 college students participated. Participants in the stress-induction condition completed a 'winter' drive, which included periodic loss of control episodes. Participants in the no-stress-induction condition were not exposed to loss of control. An additional, independent manipulation of vehicle speed was also conducted, consisting of two control conditions requiring manual speed regulation and a third in which vehicle speed was automatically regulated by the simulation. Stress and automation both influenced subjective distress, but the two factors did not interact. Driver performance data indicated that vehicle automation impacted performance similarly in the stress and no-stress conditions. Individual differences in subjective stress response and performance were also investigated. Resource theory provides a framework that partially but not completely explains the relationship between vehicle automation and driver stress. Implications for driver workload, safety and training are discussed.

  12. Fast SCR Thyratron Driver

    SciTech Connect

    Nguyen, M.N.; /SLAC

    2007-06-18

    As part of an improvement project on the linear accelerator at SLAC, it was necessary to replace the original thyratron trigger generator, which consisted of two chassis, two vacuum tubes, and a small thyratron. All solid-state, fast rise, and high voltage thyratron drivers, therefore, have been developed and built for the 244 klystron modulators. The rack mounted, single chassis driver employs a unique way to control and generate pulses through the use of an asymmetric SCR, a PFN, a fast pulse transformer, and a saturable reactor. The resulting output pulse is 2 kV peak into 50 {Omega} load with pulse duration of 1.5 {mu}s FWHM at 180 Hz. The pulse risetime is less than 40 ns with less than 1 ns jitter. Various techniques are used to protect the SCR from being damaged by high voltage and current transients due to thyratron breakdowns. The end-of-line clipper (EOLC) detection circuit is also integrated into this chassis to interrupt the modulator triggering in the event a high percentage of line reflections occurred.

  13. A simple wave driver

    NASA Astrophysics Data System (ADS)

    Kağan Temiz, Burak; Yavuz, Ahmet

    2015-08-01

    This study was done to develop a simple and inexpensive wave driver that can be used in experiments on string waves. The wave driver was made using a battery-operated toy car, and the apparatus can be used to produce string waves at a fixed frequency. The working principle of the apparatus is as follows: shortly after the car is turned on, the wheel starts to turn at a constant angular speed. A rod that is fixed on the wheel turns at the same constant angular speed, too. A tight string that the wave will be created on is placed at a distance where the rod can touch the string. During each rotation of the wheel, the rod vibrates the string up and down. The vibration frequency of this rod equals the wheel’s rotation frequency, and this frequency value can be measured easily with a small magnet and a bicycle speedometer. In this way, the frequency of the waves formed in the rope can also be measured.

  14. Epigenomic annotation of noncoding mutations identifies mutated pathways in primary liver cancer

    PubMed Central

    Lowdon, Rebecca F.

    2017-01-01

    Evidence that noncoding mutation can result in cancer driver events is mounting. However, it is more difficult to assign molecular biological consequences to noncoding mutations than to coding mutations, and a typical cancer genome contains many more noncoding mutations than protein-coding mutations. Accordingly, parsing functional noncoding mutation signal from noise remains an important challenge. Here we use an empirical approach to identify putatively functional noncoding somatic single nucleotide variants (SNVs) from liver cancer genomes. Annotation of candidate variants by publicly available epigenome datasets finds that 40.5% of SNVs fall in regulatory elements. When assigned to specific regulatory elements, we find that the distribution of regulatory element mutation mirrors that of nonsynonymous coding mutation, where few regulatory elements are recurrently mutated in a patient population but many are singly mutated. We find potential gain-of-binding site events among candidate SNVs, suggesting a mechanism of action for these variants. When aggregating noncoding somatic mutation in promoters, we find that genes in the ERBB signaling and MAPK signaling pathways are significantly enriched for promoter mutations. Altogether, our results suggest that functional somatic SNVs in cancer are sporadic, but occasionally occur in regulatory elements and may affect phenotype by creating binding sites for transcriptional regulators. Accordingly, we propose that noncoding mutation should be formally accounted for when determining gene- and pathway-mutation burden in cancer. PMID:28333948

  15. MAJOR MOLECULAR GENETIC DRIVERS IN SPORADIC PRIMARY HYPERPARATHYROIDISM

    PubMed Central

    ARNOLD, ANDREW

    2016-01-01

    Primary hyperparathyroidism is primarily due to a solitary parathyroid adenoma but multi-gland disease, parathyroid carcinoma, and ectopic parathyroid hormone production can occur. Although primary hyperparathyroidism mostly presents sporadically, strong familial predispositions also exist. Much is known about heritable genetic mutations responsible for these syndromes, including multiple endocrine neoplasia types 1 and 2A, hyperparathyroidism-jaw tumor syndrome, and familial hypocalciuric hypercalcemia. Acquired mutations in common sporadic hyperparathyroidism have also been discovered. Here we focus on the most common and well-established genetic drivers: 1) involvement of the oncogene cyclin D1 in human neoplasia was first established in parathyroid adenomas, followed by recognition of its importance in other tumor types including breast cancer and B-lymphoid malignancy; and 2) somatic mutation of the MEN1 gene, first identified as the source of pathogenic germline mutations in patients with familial endocrinopathies, is found in a substantial fraction of non-familial parathyroid adenomas. PMID:28066056

  16. There is a world beyond protein mutations: the role of non-coding RNAs in melanomagenesis.

    PubMed

    Swoboda, Rolf K; Herlyn, Meenhard

    2013-05-01

    Until recently, the general perception has been that mutations in protein-coding genes are responsible for tumorigenesis. With the discovery of (V600E)BRAF in about 50% of cutaneous melanomas, there was an increased effort to find additional mutations. However, mutations characterized in melanoma to date cannot account for the development of all melanomas. With the discovery of microRNAs as important players in melanomagenesis, protein mutations are no longer considered the sole drivers of tumors. Recent research findings have expanded the view for tumor initiation and progression to additional non-coding RNAs. The data suggest that tumorigenesis is likely an interplay between mutated proteins and deregulation of non-coding RNAs in the cell with an additional role of the tumor environment. With the exception of microRNAs, our knowledge of the role of non-coding RNAs in melanoma is in its infancy. Using few examples, we will summarize some of the roles of non-coding RNAs in tumorigenesis. Thus, there is a whole world beyond protein-coding sequences and microRNAs, which can cause melanoma.

  17. Testing a structural model of young driver willingness to uptake Smartphone Driver Support Systems.

    PubMed

    Kervick, Aoife A; Hogan, Michael J; O'Hora, Denis; Sarma, Kiran M

    2015-10-01

    There is growing interest in the potential value of using phone applications that can monitor driver behaviour (Smartphone Driver Support Systems, 'SDSSs') in mitigating risky driving by young people. However, their value in this regard will only be realised if young people are willing to use this technology. This paper reports the findings of a study in which a novel structural model of willingness to use SDSSs was tested. Grounded in the driver monitoring and Technology Acceptance (TA) research literature, the model incorporates the perceived risks and gains associated with potential SDSS usage and additional social cognitive factors, including perceived usability and social influences. A total of 333 smartphone users, aged 18-24, with full Irish driving licenses completed an online questionnaire examining willingness or Behavioural Intention (BI) to uptake a SDSS. Following exploratory and confirmatory factor analyses, structural equation modelling indicated that perceived gains and social influence factors had significant direct effects on BI. Perceived risks and social influence also had significant indirect effects on BI, as mediated by perceived gains. Overall, this model accounted for 72.5% of the variance in willingness to uptake SDSSs. Multi-group structural models highlighted invariance of effects across gender, high and low risk drivers, and those likely or unlikely to adopt novel phone app technologies. These findings have implications for our understanding of the willingness of young drivers to adopt and use SDSSs, and highlight potential factors that could be targeted in behavioural change interventions seeking to improve usage rates.

  18. Voltage-Boosting Driver For Switching Regulator

    NASA Technical Reports Server (NTRS)

    Trump, Ronald C.

    1990-01-01

    Driver circuit assures availability of 10- to 15-V gate-to-source voltage needed to turn on n-channel metal oxide/semiconductor field-effect transistor (MOSFET) acting as switch in switching voltage regulator. Includes voltage-boosting circuit efficiently providing gate voltage 10 to 15 V above supply voltage. Contains no exotic parts and does not require additional power supply. Consists of NAND gate and dual voltage booster operating in conjunction with pulse-width modulator part of regulator.

  19. Idaho Driver Education Instructional Guide. Revised.

    ERIC Educational Resources Information Center

    Idaho State Dept. of Education, Boise.

    This driver education instructional safety guide is organized in three sections: Driver Education; Motorcycle Education; and Driver Education for the Handicapped. The driver education section contains 10 units dealing with the following topics: parent orientation; student orientation; basic control skills; driver performance; driving regulations;…

  20. 49 CFR 380.109 - Driver testing.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 5 2011-10-01 2011-10-01 false Driver testing. 380.109 Section 380.109... REQUIREMENTS Longer Combination Vehicle (LCV) Driver-Training and Driver-Instructor Requirements-General § 380.109 Driver testing. (a) Testing methods. The driver-student must pass knowledge and skills tests...

  1. 49 CFR 380.109 - Driver testing.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 5 2012-10-01 2012-10-01 false Driver testing. 380.109 Section 380.109... REQUIREMENTS Longer Combination Vehicle (LCV) Driver-Training and Driver-Instructor Requirements-General § 380.109 Driver testing. (a) Testing methods. The driver-student must pass knowledge and skills tests...

  2. 49 CFR 380.109 - Driver testing.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 5 2014-10-01 2014-10-01 false Driver testing. 380.109 Section 380.109... REQUIREMENTS Longer Combination Vehicle (LCV) Driver-Training and Driver-Instructor Requirements-General § 380.109 Driver testing. (a) Testing methods. The driver-student must pass knowledge and skills tests...

  3. 49 CFR 380.109 - Driver testing.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 5 2013-10-01 2013-10-01 false Driver testing. 380.109 Section 380.109... REQUIREMENTS Longer Combination Vehicle (LCV) Driver-Training and Driver-Instructor Requirements-General § 380.109 Driver testing. (a) Testing methods. The driver-student must pass knowledge and skills tests...

  4. Sparse expression bases in cancer reveal tumor drivers

    PubMed Central

    Logsdon, Benjamin A.; Gentles, Andrew J.; Miller, Chris P.; Blau, C. Anthony; Becker, Pamela S.; Lee, Su-In

    2015-01-01

    We define a new category of candidate tumor drivers in cancer genome evolution: ‘selected expression regulators’ (SERs)—genes driving dysregulated transcriptional programs in cancer evolution. The SERs are identified from genome-wide tumor expression data with a novel method, namely SPARROW (SPARse selected expRessiOn regulators identified With penalized regression). SPARROW uncovers a previously unknown connection between cancer expression variation and driver events, by using a novel sparse regression technique. Our results indicate that SPARROW is a powerful complementary approach to identify candidate genes containing driver events that are hard to detect from sequence data, due to a large number of passenger mutations and lack of comprehensive sequence information from a sufficiently large number of samples. SERs identified by SPARROW reveal known driver mutations in multiple human cancers, along with known cancer-associated processes and survival-associated genes, better than popular methods for inferring gene expression networks. We demonstrate that when applied to acute myeloid leukemia expression data, SPARROW identifies an apoptotic biomarker (PYCARD) for an investigational drug obatoclax. The PYCARD and obatoclax association is validated in 30 AML patient samples. PMID:25583238

  5. The landscape of cancer genes and mutational processes in breast cancer

    PubMed Central

    Stephens, Philip J.; Tarpey, Patrick S.; Davies, Helen; Loo, Peter Van; Greenman, Chris; Wedge, David C.; Nik-Zainal, Serena; Martin, Sancha; Varela, Ignacio; Bignell, Graham R.; Yates, Lucy R.; Papaemmanuil, Elli; Beare, David; Butler, Adam; Cheverton, Angela; Gamble, John; Hinton, Jonathan; Jia, Mingming; Jayakumar, Alagu; Jones, David; Latimer, Calli; Lau, King Wai; McLaren, Stuart; McBride, David J.; Menzies, Andrew; Mudie, Laura; Raine, Keiran; Rad, Roland; Chapman, Michael Spencer; Teague, Jon; Easton, Douglas; Langerød, Anita; OSBREAC; Lee, Ming Ta Michael; Shen, Chen-Yang; Tee, Benita Tan Kiat; Huimin, Bernice Wong; Broeks, Annegien; Vargas, Ana Cristina; Turashvili, Gulisa; Martens, John; Fatima, Aquila; Miron, Penelope; Chin, Suet-Feung; Thomas, Gilles; Boyault, Sandrine; Mariani, Odette; Lakhani, Sunil R.; van de Vijver, Marc; van ’t Veer, Laura; Foekens, John; Desmedt, Christine; Sotiriou, Christos; Tutt, Andrew; Caldas, Carlos; Reis-Filho, Jorge S.; Aparicio, Samuel A. J. R.; Salomon, Anne Vincent; Børresen-Dale, Anne-Lise; Richardson, Andrea L.; Campbell, Peter J.; Futreal, P. Andrew; Stratton, Michael R.

    2012-01-01

    All cancers carry somatic mutations in their genomes. A subset, known as driver mutations, confer clonal selective advantage on cancer cells and are causally implicated in oncogenesis1, and the remainder are passenger mutations. The driver mutations and mutational processes operative in breast cancer have not yet been comprehensively explored. Here we examine the genomes of 100 tumours for somatic copy number changes and mutations in the coding exons of protein-coding genes. The number of somatic mutations varied markedly between individual tumours. We found strong correlations between mutation number, age at which cancer was diagnosed and cancer histological grade, and observed multiple mutational signatures, including one present in about ten per cent of tumours characterized by numerous mutations of cytosine at TpC dinucleotides. Driver mutations were identified in several new cancer genes including AKT2, ARID1B, CASP8, CDKN1B, MAP3K1, MAP3K13, NCOR1, SMARCD1 and TBX3. Among the 100 tumours, we found driver mutations in at least 40 cancer genes and 73 different combinations of mutated cancer genes. The results highlight the substantial genetic diversity underlying this common disease. PMID:22722201

  6. Idaho Driver Education Administrative Guide.

    ERIC Educational Resources Information Center

    Idaho State Dept. of Education, Boise.

    This guide provides information for school administrators and directors of commercial driver training schools about conducting driver education courses in Idaho. The first part of the guide, which applies to both public schools and commercial schools, covers the following areas: administration, sample letters and forms, instructional time…

  7. Cancer systems biology of TCGA SKCM: Efficient detection of genomic drivers in melanoma

    PubMed Central

    Guan, Jian; Gupta, Rohit; Filipp, Fabian V.

    2015-01-01

    We characterized the mutational landscape of human skin cutaneous melanoma (SKCM) using data obtained from The Cancer Genome Atlas (TCGA) project. We analyzed next-generation sequencing data of somatic copy number alterations and somatic mutations in 303 metastatic melanomas. We were able to confirm preeminent drivers of melanoma as well as identify new melanoma genes. The TCGA SKCM study confirmed a dominance of somatic BRAF mutations in 50% of patients. The mutational burden of melanoma patients is an order of magnitude higher than of other TCGA cohorts. A multi-step filter enriched somatic mutations while accounting for recurrence, conservation, and basal rate. Thus, this filter can serve as a paradigm for analysis of genome-wide next-generation sequencing data of large cohorts with a high mutational burden. Analysis of TCGA melanoma data using such a multi-step filter discovered novel and statistically significant potential melanoma driver genes. In the context of the Pan-Cancer study we report a detailed analysis of the mutational landscape of BRAF and other drivers across cancer tissues. Integrated analysis of somatic mutations, somatic copy number alterations, low pass copy numbers, and gene expression of the melanogenesis pathway shows coordination of proliferative events by Gs-protein and cyclin signaling at a systems level. PMID:25600636

  8. Fast thyratron driver

    SciTech Connect

    Nguyen, M.N.; Cassel, R.L.

    1991-04-01

    A fast solid-state pulse generator used as a thyratron grid driver for kicker pulsers, has been developed and built with power MOSFETs and a transmission line transformer. The MOSFET, pulsed on and off by a pair of P-N channel HEXFETs, switches charged capacitors into the transformer connected in parallel on one end and in series on the other end to step up the voltage. The resulting output pulse parameters are 2 kilovolts peak (into 50 Ohms), 13 nanoseconds risetime (10--90%), 250 nanoseconds duration, and less than 50 picoseconds pulse-to-pulse jitter. Various methods are employed to protect the MOSFETs from thyratron arc back, including the use of TransZorbs and a magnetic diode. 3 refs., 3 figs.

  9. A Pan-Cancer Catalogue of Cancer Driver Protein Interaction Interfaces.

    PubMed

    Porta-Pardo, Eduard; Garcia-Alonso, Luz; Hrabe, Thomas; Dopazo, Joaquin; Godzik, Adam

    2015-10-01

    Despite their importance in maintaining the integrity of all cellular pathways, the role of mutations on protein-protein interaction (PPI) interfaces as cancer drivers has not been systematically studied. Here we analyzed the mutation patterns of the PPI interfaces from 10,028 proteins in a pan-cancer cohort of 5,989 tumors from 23 projects of The Cancer Genome Atlas (TCGA) to find interfaces enriched in somatic missense mutations. To that end we use e-Driver, an algorithm to analyze the mutation distribution of specific protein functional regions. We identified 103 PPI interfaces enriched in somatic cancer mutations. 32 of these interfaces are found in proteins coded by known cancer driver genes. The remaining 71 interfaces are found in proteins that have not been previously identified as cancer drivers even that, in most cases, there is an extensive literature suggesting they play an important role in cancer. Finally, we integrate these findings with clinical information to show how tumors apparently driven by the same gene have different behaviors, including patient outcomes, depending on which specific interfaces are mutated.

  10. A Pan-Cancer Catalogue of Cancer Driver Protein Interaction Interfaces

    PubMed Central

    Hrabe, Thomas; Dopazo, Joaquin; Godzik, Adam

    2015-01-01

    Despite their importance in maintaining the integrity of all cellular pathways, the role of mutations on protein-protein interaction (PPI) interfaces as cancer drivers has not been systematically studied. Here we analyzed the mutation patterns of the PPI interfaces from 10,028 proteins in a pan-cancer cohort of 5,989 tumors from 23 projects of The Cancer Genome Atlas (TCGA) to find interfaces enriched in somatic missense mutations. To that end we use e-Driver, an algorithm to analyze the mutation distribution of specific protein functional regions. We identified 103 PPI interfaces enriched in somatic cancer mutations. 32 of these interfaces are found in proteins coded by known cancer driver genes. The remaining 71 interfaces are found in proteins that have not been previously identified as cancer drivers even that, in most cases, there is an extensive literature suggesting they play an important role in cancer. Finally, we integrate these findings with clinical information to show how tumors apparently driven by the same gene have different behaviors, including patient outcomes, depending on which specific interfaces are mutated. PMID:26485003

  11. Rapid growth of a hepatocellular carcinoma and the driving mutations revealed by cell-population genetic analysis of whole-genome data.

    PubMed

    Tao, Yong; Ruan, Jue; Yeh, Shiou-Hwei; Lu, Xuemei; Wang, Yu; Zhai, Weiwei; Cai, Jun; Ling, Shaoping; Gong, Qiang; Chong, Zecheng; Qu, Zhengzhong; Li, Qianqian; Liu, Jiang; Yang, Jin; Zheng, Caihong; Zeng, Changqing; Wang, Hurng-Yi; Zhang, Jing; Wang, Sheng-Han; Hao, Lingtong; Dong, Lili; Li, Wenjie; Sun, Min; Zou, Wei; Yu, Caixia; Li, Chaohua; Liu, Guojing; Jiang, Lan; Xu, Jin; Huang, Huanwei; Li, Chunyan; Mi, Shuangli; Zhang, Bing; Chen, Baoxian; Zhao, Wenming; Hu, Songnian; Zhuang, Shi-Mei; Shen, Yang; Shi, Suhua; Brown, Christopher; White, Kevin P; Chen, Ding-Shinn; Chen, Pei-Jer; Wu, Chung-I

    2011-07-19

    We present the analysis of the evolution of tumors in a case of hepatocellular carcinoma. This case is particularly informative about cancer growth dynamics and the underlying driving mutations. We sampled nine different sections from three tumors and seven more sections from the adjacent nontumor tissues. Selected sections were subjected to exon as well as whole-genome sequencing. Putative somatic mutations were then individually validated across all 9 tumor and 7 nontumor sections. Among the mutations validated, 24 were amino acid changes; in addition, 22 large indels/copy number variants (>1 Mb) were detected. These somatic mutations define four evolutionary lineages among tumor cells. Separate evolution and expansion of these lineages were recent and rapid, each apparently having only one lineage-specific protein-coding mutation. Hence, by using a cell-population genetic definition, this approach identified three coding changes (CCNG1, P62, and an indel/fusion gene) as tumor driver mutations. These three mutations, affecting cell cycle control and apoptosis, are functionally distinct from mutations that accumulated earlier, many of which are involved in inflammation/immunity or cell anchoring. These distinct functions of mutations at different stages may reflect the genetic interactions underlying tumor growth.

  12. Mechanisms responsible for the chromosome and gene mutations driving carcinogenesis: Implications for dose-response characteristics of mutagenic carcinogens

    EPA Science Inventory

    Through the use of high throughput DNA sequencing techniques, it has been possible to characterize a number of tumor types at the molcular level. This has led to the concept that there are "driver" mutations and "passenger" mutations, with an estimate of the number of the driver...

  13. A Real-Time Case Study in Driver Science: Physiological Strain and Related Variables.

    PubMed

    Potkanowicz, Edward S

    2015-11-01

    This case study was conducted as an attempt to quantify racecar-driver core body temperature and heart rate (HR) in real time on a minute-by-minute basis and to expand the volume of work in the area of driver science. Three drivers were observed during a 15-lap, 25-min maximal event. Each driver competed in the closed-wheel, closed-cockpit sports-car category. Data on core body temperature and HR were collected continuously using the HQ Inc. ingestible core probe system and HR monitoring. Driver 1 pre- and postrace core temperatures were 37.80°C and 38.79°C, respectively. Driver 2 pre- and postrace core temperatures were 37.41°C and 37.99°C. Driver 1 pre- and postrace HRs were 102 and 161 beats/min. Driver 2 pre- and postrace HRs were 94.3 and 142 beats/min. Driver 1's physiological strain index (PSI) at the start was 3.51. Driver 2's PSI at the start was 3.10. Driver 1 finished with a PSI of 7.04 and driver 2 with a PSI of 3.67. Results show that drivers are continuously challenged minute by minute. In addition, before getting into their cars, the drivers already experience physiological and thermal challenges. The data suggest that drivers are getting hot quickly. In longer events, this represents the potential for severe heat injury. Investigating whether the HRs observed are indicative of work or evidence of a thermoregulatory-associated challenge is a direction for future work. The findings support the value of real-time data collection and offer strong evidence for the expansion of research on driver-athletes.

  14. Impact of mandating a driving lesson for older drivers at license renewal in Japan.

    PubMed

    Ichikawa, Masao; Nakahara, Shinji; Inada, Haruhiko

    2015-02-01

    In Japan, a driving lesson consisting of a lecture, a driver aptitude test, on-road driving assessment and a discussion session was added to the driving license renewal procedure for drivers aged 75 years or older in 1998 and for drivers aged 70 years or older in 2002. We investigated whether these additions contributed to a reduction in at-fault motor vehicle collisions (MVCs) by examining the trend of the at-fault MVC rates per licensed driver and the rate ratios of the older drivers relative to those aged 65-69 years for the years 1986-2011. All data were derived from nationwide traffic statistics. If the introduction of the lesson was effective in reducing at-fault MVCs of older drivers, the rate ratio should have declined, given that the lesson targeted only the older drivers. We found this was not the case, i.e., there was no declining trend in the at-fault MVC rate ratios of both drivers aged 75 years or older and drivers aged 70 years or older, relative to drivers aged 65-69 years, after the driving lesson at license renewal became mandatory for these older drivers. Therefore, the mandatory lesson for the older drivers at license renewal needs to be reconsidered.

  15. Genome destabilizing mutator alleles drive specific mutational trajectories in Saccharomyces cerevisiae.

    PubMed

    Stirling, Peter C; Shen, Yaoqing; Corbett, Richard; Jones, Steven J M; Hieter, Philip

    2014-02-01

    In addition to environmental factors and intrinsic variations in base substitution rates, specific genome-destabilizing mutations can shape the mutational trajectory of genomes. How specific alleles influence the nature and position of accumulated mutations in a genomic context is largely unknown. Understanding the impact of genome-destabilizing alleles is particularly relevant to cancer genomes where biased mutational signatures are identifiable. We first created a more complete picture of cellular pathways that impact mutation rate using a primary screen to identify essential Saccharomyces cerevisiae gene mutations that cause mutator phenotypes. Drawing primarily on new alleles identified in this resource, we measure the impact of diverse mutator alleles on mutation patterns directly by whole-genome sequencing of 68 mutation-accumulation strains derived from wild-type and 11 parental mutator genotypes. The accumulated mutations differ across mutator strains, displaying base-substitution biases, allele-specific mutation hotspots, and break-associated mutation clustering. For example, in mutants of POLα and the Cdc13-Stn1-Ten1 complex, we find a distinct subtelomeric bias for mutations that we show is independent of the target sequence. Together our data suggest that specific genome-instability mutations are sufficient to drive discrete mutational signatures, some of which share properties with mutation patterns seen in tumors. Thus, in a population of cells, genome-instability mutations could influence clonal evolution by establishing discrete mutational trajectories for genomes.

  16. Towards an Understanding of Driver Inattention: Taxonomy and Theory

    PubMed Central

    Regan, Michael. A.; Strayer, David. L.

    2014-01-01

    There is little agreement in the scientific literature about what the terms “driver distraction” and “driver inattention” mean, and what the relationship is between them. In 2011, Regan, Hallett and Gordon proposed a taxonomy of driver inattention in which driver distraction is conceptualized as just one of several processes that give rise to driver inattention. Since publication of that paper, two other papers have emerged that bear on the taxonomy. In one, the Regan et al taxonomy was used, for the first time, to classify data from an in-depth crash investigation in Australia. In the other, another taxonomy of driver inattention was proposed and described. In this paper we revisit the original taxonomy proposed by Regan et al. in light of these developments, and make recommendations for how the original taxonomy might be improved to make it more useful as a tool for classifying and coding crash and critical incident data. In addition, we attempt to characterize, theoretically, the processes within each category of the original taxonomy that are assumed to give rise to driver inattention. Recommendations are made for several lines of research: to further validate the original taxonomy; to understand the impact of each category of inattention in the taxonomy on driving performance, crash type and crash risk; and to revise and align with the original taxonomy existing crash and incident investigation protocols, so that they provide more comprehensive, reliable and consistent information regarding the contribution of inattention to crashes of all types. PMID:24776222

  17. Towards an understanding of driver inattention: taxonomy and theory.

    PubMed

    Regan, Michael A; Strayer, David L

    2014-01-01

    There is little agreement in the scientific literature about what the terms "driver distraction" and "driver inattention" mean, and what the relationship is between them. In 2011, Regan, Hallett and Gordon proposed a taxonomy of driver inattention in which driver distraction is conceptualized as just one of several processes that give rise to driver inattention. Since publication of that paper, two other papers have emerged that bear on the taxonomy. In one, the Regan et al taxonomy was used, for the first time, to classify data from an in-depth crash investigation in Australia. In the other, another taxonomy of driver inattention was proposed and described. In this paper we revisit the original taxonomy proposed by Regan et al. in light of these developments, and make recommendations for how the original taxonomy might be improved to make it more useful as a tool for classifying and coding crash and critical incident data. In addition, we attempt to characterize, theoretically, the processes within each category of the original taxonomy that are assumed to give rise to driver inattention. Recommendations are made for several lines of research: to further validate the original taxonomy; to understand the impact of each category of inattention in the taxonomy on driving performance, crash type and crash risk; and to revise and align with the original taxonomy existing crash and incident investigation protocols, so that they provide more comprehensive, reliable and consistent information regarding the contribution of inattention to crashes of all types.

  18. Modeling Driver Behavior near Intersections in Hidden Markov Model.

    PubMed

    Li, Juan; He, Qinglian; Zhou, Hang; Guan, Yunlin; Dai, Wei

    2016-12-21

    Intersections are one of the major locations where safety is a big concern to drivers. Inappropriate driver behaviors in response to frequent changes when approaching intersections often lead to intersection-related crashes or collisions. Thus to better understand driver behaviors at intersections, especially in the dilemma zone, a Hidden Markov Model (HMM) is utilized in this study. With the discrete data processing, the observed dynamic data of vehicles are used for the inference of the Hidden Markov Model. The Baum-Welch (B-W) estimation algorithm is applied to calculate the vehicle state transition probability matrix and the observation probability matrix. When combined with the Forward algorithm, the most likely state of the driver can be obtained. Thus the model can be used to measure the stability and risk of driver behavior. It is found that drivers' behaviors in the dilemma zone are of lower stability and higher risk compared with those in other regions around intersections. In addition to the B-W estimation algorithm, the Viterbi Algorithm is utilized to predict the potential dangers of vehicles. The results can be applied to driving assistance systems to warn drivers to avoid possible accidents.

  19. SF3B1 mutations constitute a novel therapeutic target in breast cancer.

    PubMed

    Maguire, Sarah L; Leonidou, Andri; Wai, Patty; Marchiò, Caterina; Ng, Charlotte Ky; Sapino, Anna; Salomon, Anne-Vincent; Reis-Filho, Jorge S; Weigelt, Britta; Natrajan, Rachael C

    2015-03-01

    Mutations in genes encoding proteins involved in RNA splicing have been found to occur at relatively high frequencies in several tumour types including myelodysplastic syndromes, chronic lymphocytic leukaemia, uveal melanoma, and pancreatic cancer, and at lower frequencies in breast cancer. To investigate whether dysfunction in RNA splicing is implicated in the pathogenesis of breast cancer, we performed a re-analysis of published exome and whole genome sequencing data. This analysis revealed that mutations in spliceosomal component genes occurred in 5.6% of unselected breast cancers, including hotspot mutations in the SF3B1 gene, which were found in 1.8% of unselected breast cancers. SF3B1 mutations were significantly associated with ER-positive disease, AKT1 mutations, and distinct copy number alterations. Additional profiling of hotspot mutations in a panel of special histological subtypes of breast cancer showed that 16% and 6% of papillary and mucinous carcinomas of the breast harboured the SF3B1 K700E mutation. RNA sequencing identified differentially spliced events expressed in tumours with SF3B1 mutations including the protein coding genes TMEM14C, RPL31, DYNL11, UQCC, and ABCC5, and the long non-coding RNA CRNDE. Moreover, SF3B1 mutant cell lines were found to be sensitive to the SF3b complex inhibitor spliceostatin A and treatment resulted in perturbation of the splicing signature. Albeit rare, SF3B1 mutations result in alternative splicing events, and may constitute drivers and a novel therapeutic target in a subset of breast cancers.

  20. Development drivers for waste management.

    PubMed

    Wilson, David C

    2007-06-01

    This paper identifies six broad groups of drivers for development in waste management. Public health led to the emergence of formalized waste collection systems in the nineteenth century, and remains a key driver in developing countries. Environmental protection came to the forefront in the 1970s, with an initial focus on eliminating uncontrolled disposal, followed by the systematic increasing of technical standards. Today, developing countries seem still to be struggling with these first steps; while climate change is also emerging as a key driver. The resource value of waste, which allows people to make a living from discarded materials, was an important driver historically, and remains so in developing countries today. A current trend in developed countries is closing the loop, moving from the concept of 'end-of-pipe' waste management towards a more holistic resource management. Two underpinning groups of drivers are institutional and responsibility issues, and public awareness. There is no, one single driver for development in waste management: the balance between these six groups of drivers has varied over time, and will vary between countries depending on local circumstances, and between stakeholders depending on their perspective. The next appropriate steps towards developing a sustainable, integrated waste management system will also vary in each local situation.

  1. Novel recurrently mutated genes in African American colon cancers

    PubMed Central

    Guda, Kishore; Veigl, Martina L.; Varadan, Vinay; Nosrati, Arman; Ravi, Lakshmeswari; Lutterbaugh, James; Beard, Lydia; Willson, James K. V.; Sedwick, W. David; Wang, Zhenghe John; Molyneaux, Neil; Miron, Alexander; Adams, Mark D.; Elston, Robert C.; Markowitz, Sanford D.; Willis, Joseph E.

    2015-01-01

    We used whole-exome and targeted sequencing to characterize somatic mutations in 103 colorectal cancers (CRC) from African Americans, identifying 20 new genes as significantly mutated in CRC. Resequencing 129 Caucasian derived CRCs confirmed a 15-gene set as a preferential target for mutations in African American CRCs. Two predominant genes, ephrin type A receptor 6 (EPHA6) and folliculin (FLCN), with mutations exclusive to African American CRCs, are by genetic and biological criteria highly likely African American CRC driver genes. These previously unsuspected differences in the mutational landscapes of CRCs arising among individuals of different ethnicities have potential to impact on broader disparities in cancer behaviors. PMID:25583493

  2. Prevalence of drug use in commercial tractor-trailer drivers.

    PubMed

    Couper, Fiona J; Pemberton, Melissa; Jarvis, Anjanette; Hughes, Marty; Logan, Barry K

    2002-05-01

    An enforcement emphasis project, "Operation Trucker Check," was established in order to determine the extent to which commercial tractor-trailer drivers were operating their vehicles while impaired by drugs. A total of 1079 drivers and their vehicles were assessed for driver and equipment violations, and drivers additionally underwent preliminary field sobriety tests conducted by drug recognition expert (DRE) officers. Anonymous urine specimens for drug analysis were requested, and 822 urine specimens were obtained in total. Compliance with the drug-testing portion was voluntary, and there was a 19% refusal rate. Overall, 21% of the urine specimens tested positive for either illicit, prescription, and/or over-the-counter drugs, and 7% tested positive for more than one drug. Excluding caffeine and nicotine, the largest number of positive findings (9.5%) were for CNS stimulants, such as methamphetamine, amphetamine, phentermine, ephedrine/pseudoephedrine, and cocaine. The second most frequently encountered drug class were the cannabinoids, with 4.3% of drivers testing positive for marijuana metabolites. Only 11 drivers (1.3%) were positive for alcohol. Sixteen truck drivers (1.6%) were charged with driving under the influence of drugs after a full DRE evaluation was conducted. The results indicate that in spite of comprehensive drug testing in the trucking industry, some tractor-trailer drivers are continuing to take illicit and other drugs with the potential of having a negative effect on their driving ability. On the other hand, only a few drivers were, in fact, deemed to be under the influence of drugs at the time of driving when evaluated by DRE officers.

  3. HUMAN KINASES DISPLAY MUTATIONAL HOTSPOTS AT COGNATE POSITIONS WITHIN CANCER.

    PubMed

    Gallion, Jonathan; Wilkins, Angela D; Lichtarge, Olivier

    2016-01-01

    The discovery of driver genes is a major pursuit of cancer genomics, usually based on observing the same mutation in different patients. But the heterogeneity of cancer pathways plus the high background mutational frequency of tumor cells often cloud the distinction between less frequent drivers and innocent passenger mutations. Here, to overcome these disadvantages, we grouped together mutations from close kinase paralogs under the hypothesis that cognate mutations may functionally favor cancer cells in similar ways. Indeed, we find that kinase paralogs often bear mutations to the same substituted amino acid at the same aligned positions and with a large predicted Evolutionary Action. Functionally, these high Evolutionary Action, non-random mutations affect known kinase motifs, but strikingly, they do so differently among different kinase types and cancers, consistent with differences in selective pressures. Taken together, these results suggest that cancer pathways may flexibly distribute a dependence on a given functional mutation among multiple close kinase paralogs. The recognition of this "mutational delocalization" of cancer drivers among groups of paralogs is a new phenomena that may help better identify relevant mechanisms and therefore eventually guide personalized therapy.

  4. Factors contributing to intercity commercial bus drivers' crash involvement risk.

    PubMed

    Besharati, Mohammad Mehdi; Kashani, Ali Tavakoli

    2017-03-20

    The aim of this study was to examine the influence of demographic, environmental and occupational factors as well as behavioural characteristics of intercity bus drivers, on their crash involvement risk. A total number of 107 intercity bus drivers from Tehran, Iran were participated in the study. Logistic regression model suggested that smokers, those who drive during night to morning, less experienced drivers as well as those who operate older buses are more likely to be involved in crashes. In addition, one unit increase in the weekly driving hours might significantly increase the drivers' crash involvement risk. The model results also indicated that hazard monitoring, fatigue proneness and thrill seeking might be considered as other significant predictors of crash involvement risk. Implications of results are discussed.

  5. "Teaching them a lesson?" A qualitative exploration of underlying motivations for driver aggression.

    PubMed

    Lennon, Alexia; Watson, Barry

    2011-11-01

    Aggressive driving is increasingly a concern for drivers in highly motorised countries. However, the role of driver intent in this behaviour is problematic and there is little research on driver cognitions in relation to aggressive driving incidents. In addition, while drivers who admit to behaving aggressively on the road also frequently report being recipients of similar behaviours, little is known about the relationship between perpetration and victimisation or about how road incidents escalate into the more serious events that feature in capture media attention. The current study used qualitative interviews to explore driver cognitions and underlying motivations for aggressive behaviours on the road. A total of 30 drivers aged 18-49 years were interviewed about their experiences with aggressive driving. A key theme identified in responses was driver aggression as an attempt to manage or modify the behaviour of other road users. Two subthemes were identified and appeared related to separate motivations for aggressive responses: 'teaching them a lesson' referred to situations where respondents intended to convey criticism or disapproval, usually of unintended behaviours by the other driver, and thus encourage self-correction; and 'justified retaliation' which referred to situations where respondents perceived deliberate intent on the part of the other driver and responded aggressively in return. Mildly aggressive driver behaviour appears to be common. Moreover such behaviour has a sufficiently negative impact on other drivers that it may be worth addressing because of its potential for triggering retaliation in kind or escalation of aggression, thus compromising safety.

  6. Association mining of mutated cancer genes in different clinical stages across 11 cancer types

    PubMed Central

    Wang, Tingzhang; Zheng, Shu

    2016-01-01

    Many studies have demonstrated that some genes (e.g. APC, BRAF, KRAS, PTEN, TP53) are frequently mutated in cancer, however, underlying mechanism that contributes to their high mutation frequency remains unclear. Here we used Apriori algorithm to find the frequent mutational gene sets (FMGSs) from 4,904 tumors across 11 cancer types as part of the TCGA Pan-Cancer effort and then mined the hidden association rules (ARs) within these FMGSs. Intriguingly, we found that well-known cancer driver genes such as BRAF, KRAS, PTEN, and TP53 were often co-occurred with other driver genes and FMGSs size peaked at an itemset size of 3∼4 genes. Besides, the number and constitution of FMGS and ARs differed greatly among different cancers and stages. In addition, FMGS and ARs were rare in endocrine-related cancers such as breast carcinoma, ovarian cystadenocarcinoma, and thyroid carcinoma, but abundant in cancers contact directly with external environments such as skin melanoma and stomach adenocarcinoma. Furthermore, we observed more rules in stage IV than in other stages, indicating that distant metastasis needed more sophisticated gene regulatory network. PMID:27556693

  7. Association mining of mutated cancer genes in different clinical stages across 11 cancer types.

    PubMed

    Hu, Wangxiong; Li, Xiaofen; Wang, Tingzhang; Zheng, Shu

    2016-10-18

    Many studies have demonstrated that some genes (e.g. APC, BRAF, KRAS, PTEN, TP53) are frequently mutated in cancer, however, underlying mechanism that contributes to their high mutation frequency remains unclear. Here we used Apriori algorithm to find the frequent mutational gene sets (FMGSs) from 4,904 tumors across 11 cancer types as part of the TCGA Pan-Cancer effort and then mined the hidden association rules (ARs) within these FMGSs. Intriguingly, we found that well-known cancer driver genes such as BRAF, KRAS, PTEN, and TP53 were often co-occurred with other driver genes and FMGSs size peaked at an itemset size of 3~4 genes. Besides, the number and constitution of FMGS and ARs differed greatly among different cancers and stages. In addition, FMGS and ARs were rare in endocrine-related cancers such as breast carcinoma, ovarian cystadenocarcinoma, and thyroid carcinoma, but abundant in cancers contact directly with external environments such as skin melanoma and stomach adenocarcinoma. Furthermore, we observed more rules in stage IV than in other stages, indicating that distant metastasis needed more sophisticated gene regulatory network.

  8. Drugs and chronic alcohol abuse in drivers.

    PubMed

    Appenzeller, Brice M R; Schneider, Serge; Yegles, Michel; Maul, Armand; Wennig, Robert

    2005-12-20

    Blood specimens from 210 drivers (179 male and 31 female) apprehended in Luxembourg from autumn 2001 to spring 2002 and requested for the determination of their blood alcohol concentration (BAC) were tested for medicinal drugs, illicit drugs, and chronic alcohol abuse (by quantification of the carbohydrate-deficient transferrin: CDT). These additional analyses were performed anonymously and with permission of state prosecutor. The 22.8% had consumed medicinal drugs, with benzodiazepines and antidepressants (10.9 and 7.6%, respectively) as main psychoactive classes. Cannabis was the most detected illicit drug (9.5%) but only one in three had THC detectable in their blood. Association of two or more psychoactive substances (poly-drug use) was observed in 27.6% of drivers (90.6% of drug consumers). On the basis of CDT values, 29.5% of drivers investigated were assumed to be chronic alcohol abusers. Statistical analysis revealed that chronic alcohol abuse and medicinal psychoactive drugs were associated with significantly higher BAC. Medicinal psychoactive drugs were clearly associated with poly-drug use, and were furthermore detected at supra-therapeutic levels in 34.9%.

  9. Exercise among commercial truck drivers.

    PubMed

    Turner, Lisa M; Reed, Deborah B

    2011-10-01

    This study examines the exercise habits and perceived barriers to exercise of a convenience sample of 300 commercial truck drivers. Participants reported minimal amounts of exercise, with nearly 20% not exercising in the past week. A high prevalence of obesity was found in this sample: 93.3% of study participants had a body mass index (BMI) of 25 or higher. Drivers with BMIs of greater than 30 were significantly more likely to rate the exercise environment as terrible/bad. Drivers who had at least one health condition engaged in significantly less aerobic exercise, used fewer strengthening exercises, did not exercise for 30 minutes continuously, and had a higher BMI. Drivers who spent most of their off-duty time in their truck while their partner drove were also significantly more likely to not exercise regularly. Most drivers cited lack of time and place as the primary barriers to exercising. This study adds to the limited knowledge about exercise behaviors among commercial truck drivers.

  10. Driver gene classification reveals a substantial overrepresentation of tumor suppressors among very large chromatin-regulating proteins

    PubMed Central

    Waks, Zeev; Weissbrod, Omer; Carmeli, Boaz; Norel, Raquel; Utro, Filippo; Goldschmidt, Yaara

    2016-01-01

    Compiling a comprehensive list of cancer driver genes is imperative for oncology diagnostics and drug development. While driver genes are typically discovered by analysis of tumor genomes, infrequently mutated driver genes often evade detection due to limited sample sizes. Here, we address sample size limitations by integrating tumor genomics data with a wide spectrum of gene-specific properties to search for rare drivers, functionally classify them, and detect features characteristic of driver genes. We show that our approach, CAnceR geNe similarity-based Annotator and Finder (CARNAF), enables detection of potentially novel drivers that eluded over a dozen pan-cancer/multi-tumor type studies. In particular, feature analysis reveals a highly concentrated pool of known and putative tumor suppressors among the <1% of genes that encode very large, chromatin-regulating proteins. Thus, our study highlights the need for deeper characterization of very large, epigenetic regulators in the context of cancer causality. PMID:28008934

  11. Driver gene classification reveals a substantial overrepresentation of tumor suppressors among very large chromatin-regulating proteins.

    PubMed

    Waks, Zeev; Weissbrod, Omer; Carmeli, Boaz; Norel, Raquel; Utro, Filippo; Goldschmidt, Yaara

    2016-12-23

    Compiling a comprehensive list of cancer driver genes is imperative for oncology diagnostics and drug development. While driver genes are typically discovered by analysis of tumor genomes, infrequently mutated driver genes often evade detection due to limited sample sizes. Here, we address sample size limitations by integrating tumor genomics data with a wide spectrum of gene-specific properties to search for rare drivers, functionally classify them, and detect features characteristic of driver genes. We show that our approach, CAnceR geNe similarity-based Annotator and Finder (CARNAF), enables detection of potentially novel drivers that eluded over a dozen pan-cancer/multi-tumor type studies. In particular, feature analysis reveals a highly concentrated pool of known and putative tumor suppressors among the <1% of genes that encode very large, chromatin-regulating proteins. Thus, our study highlights the need for deeper characterization of very large, epigenetic regulators in the context of cancer causality.

  12. Characteristics of Two Groups of Angry Drivers

    ERIC Educational Resources Information Center

    Deffenbacher, Jerry L.; Filetti, Linda B.; Richards, Tracy L.; Lynch, Rebekah S.; Oetting, Eugene R.

    2003-01-01

    High anger drivers acknowledging problems with driving anger and interest in counseling (high anger/problem [HP] drivers) were compared with high and low anger drivers not acknowledging problems with driving anger and seeking counseling (high and low/nonproblem [HNP and LNP, respectively] drivers). High anger groups reported more anger while…

  13. 49 CFR 396.13 - Driver inspection.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 5 2010-10-01 2010-10-01 false Driver inspection. 396.13 Section 396.13... MAINTENANCE § 396.13 Driver inspection. Before driving a motor vehicle, the driver shall: (a) Be satisfied that the motor vehicle is in safe operating condition; (b) Review the last driver vehicle...

  14. 49 CFR 396.13 - Driver inspection.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 5 2014-10-01 2014-10-01 false Driver inspection. 396.13 Section 396.13... MAINTENANCE § 396.13 Driver inspection. Before driving a motor vehicle, the driver shall: (a) Be satisfied that the motor vehicle is in safe operating condition; (b) Review the last driver vehicle...

  15. 49 CFR 396.13 - Driver inspection.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 5 2012-10-01 2012-10-01 false Driver inspection. 396.13 Section 396.13... MAINTENANCE § 396.13 Driver inspection. Before driving a motor vehicle, the driver shall: (a) Be satisfied that the motor vehicle is in safe operating condition; (b) Review the last driver vehicle...

  16. 49 CFR 396.13 - Driver inspection.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 5 2013-10-01 2013-10-01 false Driver inspection. 396.13 Section 396.13... MAINTENANCE § 396.13 Driver inspection. Before driving a motor vehicle, the driver shall: (a) Be satisfied that the motor vehicle is in safe operating condition; (b) Review the last driver vehicle...

  17. 49 CFR 396.13 - Driver inspection.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 5 2011-10-01 2011-10-01 false Driver inspection. 396.13 Section 396.13... MAINTENANCE § 396.13 Driver inspection. Before driving a motor vehicle, the driver shall: (a) Be satisfied that the motor vehicle is in safe operating condition; (b) Review the last driver vehicle...

  18. 49 CFR 380.507 - Driver responsibilities.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 5 2012-10-01 2012-10-01 false Driver responsibilities. 380.507 Section 380.507... REQUIREMENTS Entry-Level Driver Training Requirements § 380.507 Driver responsibilities. Each entry-level driver must receive training required by § 380.503....

  19. 49 CFR 380.507 - Driver responsibilities.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 5 2013-10-01 2013-10-01 false Driver responsibilities. 380.507 Section 380.507... REQUIREMENTS Entry-Level Driver Training Requirements § 380.507 Driver responsibilities. Each entry-level driver must receive training required by § 380.503....

  20. 49 CFR 380.507 - Driver responsibilities.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 5 2014-10-01 2014-10-01 false Driver responsibilities. 380.507 Section 380.507... REQUIREMENTS Entry-Level Driver Training Requirements § 380.507 Driver responsibilities. Each entry-level driver must receive training required by § 380.503....

  1. 49 CFR 380.507 - Driver responsibilities.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 5 2011-10-01 2011-10-01 false Driver responsibilities. 380.507 Section 380.507... REQUIREMENTS Entry-Level Driver Training Requirements § 380.507 Driver responsibilities. Each entry-level driver must receive training required by § 380.503....

  2. Modelling mutational landscapes of human cancers in vitro

    NASA Astrophysics Data System (ADS)

    Olivier, Magali; Weninger, Annette; Ardin, Maude; Huskova, Hana; Castells, Xavier; Vallée, Maxime P.; McKay, James; Nedelko, Tatiana; Muehlbauer, Karl-Rudolf; Marusawa, Hiroyuki; Alexander, John; Hazelwood, Lee; Byrnes, Graham; Hollstein, Monica; Zavadil, Jiri

    2014-03-01

    Experimental models that recapitulate mutational landscapes of human cancers are needed to decipher the rapidly expanding data on human somatic mutations. We demonstrate that mutation patterns in immortalised cell lines derived from primary murine embryonic fibroblasts (MEFs) exposed in vitro to carcinogens recapitulate key features of mutational signatures observed in human cancers. In experiments with several cancer-causing agents we obtained high genome-wide concordance between human tumour mutation data and in vitro data with respect to predominant substitution types, strand bias and sequence context. Moreover, we found signature mutations in well-studied human cancer driver genes. To explore endogenous mutagenesis, we used MEFs ectopically expressing activation-induced cytidine deaminase (AID) and observed an excess of AID signature mutations in immortalised cell lines compared to their non-transgenic counterparts. MEF immortalisation is thus a simple and powerful strategy for modelling cancer mutation landscapes that facilitates the interpretation of human tumour genome-wide sequencing data.

  3. Using Multiplexed Assays of Oncogenic Drivers in Lung Cancers to Select Targeted Drugs

    PubMed Central

    Kris, Mark G.; Johnson, Bruce E.; Berry, Lynne D.; Kwiatkowski, David J.; Iafrate, A. John; Wistuba, Ignacio I.; Varella-Garcia, Marileila; Franklin, Wilbur A.; Aronson, Samuel L.; Su, Pei-Fang; Shyr, Yu; Camidge, D. Ross; Sequist, Lecia V.; Glisson, Bonnie S.; Khuri, Fadlo R.; Garon, Edward B.; Pao, William; Rudin, Charles; Schiller, Joan; Haura, Eric B.; Socinski, Mark; Shirai, Keisuke; Chen, Heidi; Giaccone, Giuseppe; Ladanyi, Marc; Kugler, Kelly; Minna, John D.; Bunn, Paul A.

    2014-01-01

    IMPORTANCE Targeting oncogenic drivers (genomic alterations critical to cancer development and maintenance) has transformed the care of patients with lung adenocarcinomas. The Lung Cancer Mutation Consortium was formed to perform multiplexed assays testing adenocarcinomas of the lung for drivers in 10 genes to enable clinicians to select targeted treatments and enroll patients into clinical trials. OBJECTIVES To determine the frequency of oncogenic drivers in patients with lung adenocarcinomas and to use the data to select treatments targeting the identified driver(s) and measure survival. DESIGN, SETTING, AND PARTICIPANTS From 2009 through 2012, 14 sites in the United States enrolled patients with metastatic lung adenocarcinomas and a performance status of 0 through 2 and tested their tumors for 10 drivers. Information was collected on patients, therapies, and survival. INTERVENTIONS Tumors were tested for 10 oncogenic drivers, and results were used to select matched targeted therapies. MAIN OUTCOMES AND MEASURES Determination of the frequency of oncogenic drivers, the proportion of patients treated with genotype-directed therapy, and survival. RESULTS From 2009 through 2012, tumors from 1007 patients were tested for at least 1 gene and 733 for 10 genes (patients with full genotyping). An oncogenic driver was found in 466 of 733 patients (64%). Among these 733 tumors, 182 tumors (25%) had the KRAS driver; sensitizing EGFR, 122 (17%); ALK rearrangements, 57 (8%); other EGFR, 29 (4%); 2 or more genes, 24 (3%); ERBB2 (formerly HER2), 19 (3%); BRAF, 16 (2%); PIK3CA, 6 (<1%); MET amplification, 5 (<1%); NRAS, 5 (<1%); MEK1, 1 (<1%); AKT1, 0. Results were used to select a targeted therapy or trial in 275 of 1007 patients (28%). The median survival was 3.5 years (interquartile range [IQR], 1.96-7.70) for the 260 patients with an oncogenic driver and genotype-directed therapy compared with 2.4 years (IQR, 0.88-6.20) for the 318 patients with any oncogenic driver(s) who

  4. Identification of druggable cancer driver genes amplified across TCGA datasets.

    PubMed

    Chen, Ying; McGee, Jeremy; Chen, Xianming; Doman, Thompson N; Gong, Xueqian; Zhang, Youyan; Hamm, Nicole; Ma, Xiwen; Higgs, Richard E; Bhagwat, Shripad V; Buchanan, Sean; Peng, Sheng-Bin; Staschke, Kirk A; Yadav, Vipin; Yue, Yong; Kouros-Mehr, Hosein

    2014-01-01

    The Cancer Genome Atlas (TCGA) projects have advanced our understanding of the driver mutations, genetic backgrounds, and key pathways activated across cancer types. Analysis of TCGA datasets have mostly focused on somatic mutations and translocations, with less emphasis placed on gene amplifications. Here we describe a bioinformatics screening strategy to identify putative cancer driver genes amplified across TCGA datasets. We carried out GISTIC2 analysis of TCGA datasets spanning 16 cancer subtypes and identified 486 genes that were amplified in two or more datasets. The list was narrowed to 75 cancer-associated genes with potential "druggable" properties. The majority of the genes were localized to 14 amplicons spread across the genome. To identify potential cancer driver genes, we analyzed gene copy number and mRNA expression data from individual patient samples and identified 42 putative cancer driver genes linked to diverse oncogenic processes. Oncogenic activity was further validated by siRNA/shRNA knockdown and by referencing the Project Achilles datasets. The amplified genes represented a number of gene families, including epigenetic regulators, cell cycle-associated genes, DNA damage response/repair genes, metabolic regulators, and genes linked to the Wnt, Notch, Hedgehog, JAK/STAT, NF-KB and MAPK signaling pathways. Among the 42 putative driver genes were known driver genes, such as EGFR, ERBB2 and PIK3CA. Wild-type KRAS was amplified in several cancer types, and KRAS-amplified cancer cell lines were most sensitive to KRAS shRNA, suggesting that KRAS amplification was an independent oncogenic event. A number of MAP kinase adapters were co-amplified with their receptor tyrosine kinases, such as the FGFR adapter FRS2 and the EGFR family adapters GRB2 and GRB7. The ubiquitin-like ligase DCUN1D1 and the histone methyltransferase NSD3 were also identified as novel putative cancer driver genes. We discuss the patient tailoring implications for existing cancer

  5. AUGMENTED REALITY CUES TO ASSIST OLDER DRIVERS WITH GAP ESTIMATION FOR LEFT-TURNS

    PubMed Central

    Rusch, Michelle L.; Schall, Mark C.; Lee, John D.; Dawson, Jeffrey D.; Rizzo, Matthew

    2014-01-01

    The objective of this study was to assess the effects of augmented reality (AR) cues designed to assist middle-aged and older drivers with a range of UFOV impairments, judging when to make left-turns across oncoming traffic. Previous studies have shown that AR cues can help middle-aged and older drivers respond to potential roadside hazards by increasing hazard detection without interfering with other driving tasks. Intersections pose a critical challenge for cognitively impaired drivers, prone to misjudge time-to-contact with oncoming traffic. We investigated whether AR cues improve or interfere with hazard perception in left-turns across oncoming traffic for drivers with age-related cognitive decline. Sixty-four middle-aged and older drivers with a range of UFOV impairment judged when it would be safe to turn left across oncoming traffic approaching the driver from the opposite direction in a rural stop-sign controlled intersection scenario implemented in a static base driving simulator. Outcome measures used to evaluate the effectiveness of AR cueing included: Time-to-Contact (TTC), Gap Time Variation (GTV), Response Rate, and Gap Response Variation (GRV). All drivers estimated TTCs were shorter in cued than in uncued conditions. In addition, drivers responded more often in cued conditions than in uncued conditions and GRV decreased for all drivers in scenarios that contained AR cues. For both TTC and response rate, drivers also appeared to adjust their behavior to be consistent with the cues, especially drivers with the poorest UFOV scores (matching their behavior to be close to middle-aged drivers). Driver ratings indicated that cueing was not considered to be distracting. Further, various conditions of reliability (e.g., 15% miss rate) did not appear to affect performance or driver ratings. PMID:24950128

  6. Designing Fatigue Warning Systems: The perspective of professional drivers.

    PubMed

    Meng, Fanxing; Li, Shuling; Cao, Lingzhi; Peng, Qijia; Li, Musen; Wang, Chunhui; Zhang, Wei

    2016-03-01

    Professional drivers have been characterized as experiencing heavy fatigue resulting from long driving time in their daily work. This study aimed to explore the potential demand of Fatigue Warning Systems (FWSs) among professional drivers as a means of reducing the danger of fatigue driving and to examine their opinions regarding the design of FWSs. Six focus groups with 35 participants and a questionnaire survey with 600 respondents were conducted among Chinese truck and taxi drivers to collect qualitative and quantitative data concerning the current situation of fatigue driving and opinions regarding the design of FWSs. The results revealed that both truck and taxi drivers had a positive attitude toward FWSs, and they hoped this system could not only monitor and warn them regarding their fatigue but also somewhat relieve their fatigue before they could stop and rest. As for warning signals, participants preferred auditory warnings, as opposed to visual, vibrotactile or electric stimuli. Interestingly, it was proposed that verbal warnings involving the information regarding consequences of fatigue driving or the wishes of drivers' family members would be more effective. Additionally, different warning patterns, including graded, single and continuous warnings, were discussed in the focus group. Finally, the participants proposed many other suggestions, as well as their concerns regarding FWSs, which will provide valuable information for companies who wish to develop FWSs for professional drivers.

  7. Modeling Driver Behavior near Intersections in Hidden Markov Model

    PubMed Central

    Li, Juan; He, Qinglian; Zhou, Hang; Guan, Yunlin; Dai, Wei

    2016-01-01

    Intersections are one of the major locations where safety is a big concern to drivers. Inappropriate driver behaviors in response to frequent changes when approaching intersections often lead to intersection-related crashes or collisions. Thus to better understand driver behaviors at intersections, especially in the dilemma zone, a Hidden Markov Model (HMM) is utilized in this study. With the discrete data processing, the observed dynamic data of vehicles are used for the inference of the Hidden Markov Model. The Baum-Welch (B-W) estimation algorithm is applied to calculate the vehicle state transition probability matrix and the observation probability matrix. When combined with the Forward algorithm, the most likely state of the driver can be obtained. Thus the model can be used to measure the stability and risk of driver behavior. It is found that drivers’ behaviors in the dilemma zone are of lower stability and higher risk compared with those in other regions around intersections. In addition to the B-W estimation algorithm, the Viterbi Algorithm is utilized to predict the potential dangers of vehicles. The results can be applied to driving assistance systems to warn drivers to avoid possible accidents. PMID:28009838

  8. Musculoskeletal Symptoms among Drivers of All-Terrain Vehicles

    NASA Astrophysics Data System (ADS)

    REHN, B.; BERGDAHL, I. A.; AHLGREN, C.; FROM, C.; JÄRVHOLM, B.; LUNDSTRÖM, R.; NILSSON, T.; SUNDELIN, G.

    2002-05-01

    The aim of this cross-sectional study was to characterize the risk of experiencing musculoskeletal symptoms in the region of the neck, shoulders and upper and lower back for professional drivers of various categories of all-terrain vehicles and to assess the association between symptoms and duration of exposure to whole-body vibration (WBV) and shock from driving all-terrain vehicles. The study group consisted of 215 drivers of forest machines, 137 drivers of snowmobiles and 79 drivers of snowgroomers and a control group of 167 men randomly selected from the general population. The subjects were all from one of the four most northern counties in Sweden and they were all men. Musculoskeletal symptoms were assessed by use of a standardized questionnaire. In addition, the questionnaire held items about the driving time with all-terrain vehicles and a subjective estimation of exposure to unpleasant movements (shock, jolt, irregular sway). The job strain was measured according to Karasek's demands/control model. The prevalence ratios were adjusted for age, smoking and job strain. Among drivers, significantly increased prevalence ratios within the range of 1∂5-2·9 were revealed for symptoms from the neck-shoulder and thoracic regions during the previous year. None of the driver categories had a statistically significantly increased risk of low back pain. Forest vehicles were those most reported to cause unpleasant movements. In conclusion, drivers of all-terrain vehicles exhibit an increased risk of symptoms of musculoskeletal disorders in the neck-shoulder and thoracic regions. The increased risk is suggested to be related to physical factors such as exposure to whole-body vibration (WBV) and shock, static overload or extreme body postures. However, since symptoms of low back pain were not significantly increased, it appears that factors other than WBV would explain the occurrence of symptoms in the group of all-terrain drivers.

  9. Does attention capacity moderate the effect of driver distraction in older drivers?

    PubMed

    Cuenen, Ariane; Jongen, Ellen M M; Brijs, Tom; Brijs, Kris; Lutin, Mark; Van Vlierden, Karin; Wets, Geert

    2015-04-01

    With age, a decline in attention capacity may occur and this may impact driving performance especially while distracted. Although the effect of distraction on driving performance of older drivers has been investigated, the moderating effect of attention capacity on driving performance during distraction has not been investigated yet. Therefore, the aim was to investigate whether attention capacity has a moderating effect on older drivers' driving performance during visual distraction (experiment 1) and cognitive distraction (experiment 2). In a fixed-based driving simulator, older drivers completed a driving task without and with visual distraction (experiment 1, N=17, mean age 78 years) or cognitive distraction (experiment 2, N=35, mean age 76 years). Several specific driving measures of varying complexity (i.e., speed, lane keeping, following distance, braking behavior, and crashes) were investigated. In addition to these objective driving measures, subjective measures of workload and driving performance were also included. In experiment 1, crash occurrence increased with visual distraction and was negatively related to attention capacity. In experiment 2, complete stops at stop signs decreased, initiation of braking at pedestrian crossings was later, and crash occurrence increased with cognitive distraction. Interestingly, for a measure of lane keeping (i.e., standard deviation of lateral lane position (SDLP)), effects of both types of distraction were moderated by attention capacity. Despite the decrease of driving performance with distraction, participants estimated their driving performance during distraction as good. These results imply that attention capacity is important for driving. Driver assessment and training programs might therefore focus on attention capacity. Nonetheless, it is crucial to eliminate driver distraction as much as possible given the deterioration of performance on several driving measures in those with low and high attention capacity.

  10. 75 FR 45200 - Commercial Driver's License (CDL) Standards; Rotel North American Tours, LLC; Application for...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-08-02

    ... are equipped with onboard sleeping and eating facilities. The drivers, in addition to operating the... cuisine. In addition, each bus is equipped with sleeping accommodations for the passengers. Rotel...

  11. Discovery of Cancer Driver Long Noncoding RNAs across 1112 Tumour Genomes: New Candidates and Distinguishing Features

    PubMed Central

    Lanzós, Andrés; Carlevaro-Fita, Joana; Mularoni, Loris; Reverter, Ferran; Palumbo, Emilio; Guigó, Roderic; Johnson, Rory

    2017-01-01

    Long noncoding RNAs (lncRNAs) represent a vast unexplored genetic space that may hold missing drivers of tumourigenesis, but few such “driver lncRNAs” are known. Until now, they have been discovered through changes in expression, leading to problems in distinguishing between causative roles and passenger effects. We here present a different approach for driver lncRNA discovery using mutational patterns in tumour DNA. Our pipeline, ExInAtor, identifies genes with excess load of somatic single nucleotide variants (SNVs) across panels of tumour genomes. Heterogeneity in mutational signatures between cancer types and individuals is accounted for using a simple local trinucleotide background model, which yields high precision and low computational demands. We use ExInAtor to predict drivers from the GENCODE annotation across 1112 entire genomes from 23 cancer types. Using a stratified approach, we identify 15 high-confidence candidates: 9 novel and 6 known cancer-related genes, including MALAT1, NEAT1 and SAMMSON. Both known and novel driver lncRNAs are distinguished by elevated gene length, evolutionary conservation and expression. We have presented a first catalogue of mutated lncRNA genes driving cancer, which will grow and improve with the application of ExInAtor to future tumour genome projects. PMID:28128360

  12. CRAC channels, calcium, and cancer in light of the driver and passenger concept.

    PubMed

    Hoth, Markus

    2016-06-01

    Advances in next-generation sequencing allow very comprehensive analyses of large numbers of cancer genomes leading to an increasingly better characterization and classification of cancers. Comparing genomic data predicts candidate genes driving development, growth, or metastasis of cancer. Cancer driver genes are defined as genes whose mutations are causally implicated in oncogenesis whereas passenger mutations are defined as not being oncogenic. Currently, a list of several hundred cancer driver mutations is discussed including prominent members like TP53, BRAF, NRAS, or NF1. According to the vast literature on Ca(2+) and cancer, Ca(2+) signals and the underlying Ca(2+) channels and transporters certainly influence the development, growth, and metastasis of many cancers. In this review, I focus on the calcium release-activated calcium (CRAC) channel genes STIM and Orai and their role for cancer development, growth, and metastasis. STIM and Orai genes are being discussed in the context of current cancer concepts with a focus on the driver-passenger hypothesis. One result of this discussion is the hypothesis that a driver analysis of Ca(2+) homeostasis-related genes should not be carried out by looking at isolated genes. Rather a pool of “Ca(2+) genes” might be considered to act as one potential cancer driver. This article is part of a Special Issue entitled: Calcium and Cell Fate. Guest Editors: Jacques Haiech, Claus Heizmann, Joachim Krebs, Thierry Capiod and Olivier Mignen.

  13. Stress among package truck drivers.

    PubMed

    Orris, P; Hartman, D E; Strauss, P; Anderson, R J; Collins, J; Knopp, C; Xu, Y; Melius, J

    1997-02-01

    In 1992, a cross-sectional questionnaire study of package truck drivers in one company was conducted at four widely scattered sites throughout the US; 317 drivers participated, representing 82% of those eligible. The package truck drivers scored significantly above the US working population comparison norm on all summary and individual scales derived from the SCL 90-R, indicating a substantial increase in psychologic distress for this group. The Global Severity Index, the best single summary measure of psychological distress in the SCL 90-R, revealed a mean T score for the drivers of 64.20, 91st percentile of the normative population. The group perceived significantly more daily stressful events than the average working adult, and their sensitivity to these events was also increased. Role overload, a component of the Occupational Stress Inventory, was the most consistent factor associated with symptoms of psychological distress on multiple regression analysis. This study suggests that job stress is a psychological health hazard for these drivers.

  14. ERBB activation modulates sensitivity to MEK1/2 inhibition in a subset of driver-negative melanoma.

    PubMed

    Hutchinson, Katherine E; Johnson, Douglas B; Johnson, Adam S; Sanchez, Violeta; Kuba, Maria; Lu, Pengcheng; Chen, Xi; Kelley, Mark C; Wang, Qingguo; Zhao, Zhongming; Kris, Mark; Berger, Michael F; Sosman, Jeffrey A; Pao, William

    2015-09-08

    Melanomas are characterized by activating "driver" mutations in BRAF, NRAS, KIT, GNAQ, and GNA11. Resultant mitogen-activated protein kinase (MAPK) pathway signaling makes some melanomas susceptible to BRAF (BRAF V600 mutations), MEK1/2 (BRAF V600, L597, fusions; NRAS mutations), or other kinase inhibitors (KIT), respectively. Among driver-negative ("pan-negative") patients, an unexplained heterogeneity of response to MEK1/2 inhibitors has been observed. Analysis of 16 pan-negative melanoma cell lines revealed that 8 (50%; termed Class I) are sensitive to the MEK1/2 inhibitor, trametinib, similar to BRAF V600E melanomas. A second set (termed Class II) display reduced trametinib sensitivity, paradoxical activation of MEK1/2 and basal activation of ERBBs 1, 2, and 3 (4 lines, 25%). In 3 of these lines, PI3K/AKT and MAPK pathway signaling is abrogated using the ERBB inhibitor, afatinib, and proliferation is even further reduced upon the addition of trametinib. A potential mechanism of ERBB activation in Class II melanomas is minimal expression of the ERK1/2 phosphatase, DUSP4, as ectopic restoration of DUSP4 attenuated ERBB signaling through potential modulation of the ERBB ligand, amphiregulin (AREG). Consistent with these data, immunohistochemical analysis of patient melanomas revealed a trend towards lower overall DUSP4 expression in pan-negative versus BRAF- and NRAS-mutant tumors. This study is the first to demonstrate that differential ERBB activity in pan-negative melanoma may modulate sensitivity to clinically-available MEK1/2 inhibitors and provides rationale for the use of ERBB inhibitors, potentially in combination with MEK1/2 inhibitors, in subsets of this disease.

  15. [ Spectrum of oncogene mutations is different in melanoma subtypes].

    PubMed

    Mazurenko, N N; Tsyganova, I V; Lushnikova, A A; Ponkratova, D A; Anurova, O A; Cheremushkin, E A; Mikhailova, I N; Demidov, L V

    2015-01-01

    Melanoma is the most lethal malignancy of skin, which is comprised of clinically relevant molecular subsets defined by specific "driver" mutations in BRAF, NRAS, and KIT genes. Recently, the better results in melanoma treatment were obtained with the mutation-specific inhibitors that have been developed for clinical use and target only patients with particular tumor genotypes. The aim of the study was to characterize the spectrum of "driver" mutations in melanoma subtypes from 137 patients with skin melanoma and 14 patients with mucosal melanoma. In total 151 melanoma cases, the frequency of BRAF, NRAS, KIT, PDGFRA, and KRAS mutations was 55.0, 10.6, 4.0, 0.7, and 0.7%, respectively. BRAF mutations were found in 69% of cutaneous melanoma without UV exposure and in 43% of cutaneous melanoma with chronic UV exposure (p=0.045), rarely in acral and mucosal melanomas. Most of melanomas containing BRAF mutations, V600E (92%) and V600K (6.0%) were potentially sensitive to inhibitors vemurafenib and dabrafenib. NRAS mutations were more common in cutaneous melanoma with chronic UV exposure (26.0%), in acral and mucosal melanomas; the dominant mutations being Q61R/K/L (87.5%). KIT mutations were found in cutaneous melanoma with chronic UV exposure (8.7%) and mucosal one (28.6%), but not in acral melanoma. Most of KIT mutations were identified in exon 11; these tumors being sensitive to tyrosine kinase inhibitors. This is the first monitoring of BRAF, NRAS, KIT, PDGFRA, and KRAS hotspot mutations in different subtypes of melanoma for Russian population. On the base of data obtained, one can suppose that at the molecular level melanomas are heterogeneous tumors that should be tested for "driver" mutations in the each case for evaluation of the potential sensitivity to target therapy. The obtained results were used for treatment of melanoma patients.

  16. Key drivers of airline loyalty.

    PubMed

    Dolnicar, Sara; Grabler, Klaus; Grün, Bettina; Kulnig, Anna

    2011-10-01

    This study investigates drivers of airline loyalty. It contributes to the body of knowledge in the area by investigating loyalty for a number of a priori market segments identified by airline management and by using a method which accounts for the multi-step nature of the airline choice process. The study is based on responses from 687 passengers. Results indicate that, at aggregate level, frequent flyer membership, price, the status of being a national carrier and the reputation of the airline as perceived by friends are the variables which best discriminate between travellers loyal to the airline and those who are not. Differences in drivers of airline loyalty for a number of segments were identified. For example, loyalty programs play a key role for business travellers whereas airline loyalty of leisure travellers is difficult to trace back to single factors. For none of the calculated models satisfaction emerged as a key driver of airline loyalty.

  17. Management of advanced non-small cell lung cancers with known mutations or rearrangements: latest evidence and treatment approaches.

    PubMed

    Shea, Meghan; Costa, Daniel B; Rangachari, Deepa

    2016-04-01

    Precision oncology is now the evidence-based standard of care for the management of many advanced non-small cell lung cancers (NSCLCs). Expert consensus has defined minimum requirements for routine testing and identification of epidermal growth factor (EGFR) mutations (15% of tumors harbor EGFR exon 19 deletions or exon 21 L858R substitutions) and anaplastic lymphoma kinase (ALK) rearrangements (5% of tumors) in advanced lung adenocarcinomas (ACs). Application of palliative targeted therapies with oral tyrosine kinase inhibitors (TKIs) in advanced/metastatic lung ACs harboring abnormalities in EGFR (gefitinib, erlotinib, afatinib) and ALK/ROS1/MET (crizotinib) has consistently led to more favorable outcomes compared with traditional cytotoxic agents. In addition, mutations leading to resistance to first-line EGFR and ALK TKIs can now be successfully inhibited by soon to be approved third-generation EGFR TKIs (osimertinib, rociletinib) and second-generation ALK TKIs (ceritinib, alectinib). Notably, increasing feasibility, accessibility, and application of molecular profiling technologies has permitted dynamic growth in the identification of actionable driver oncogenes. Emerging genomic aberrations for which TKIs have shown impressive results in clinical trials and expansion of drug labels for approved agents are awaited include ROS1 rearrangements (1-2% of tumors, drug: crizotinib) and BRAF-V600E mutations (1-3% of tumors, drugs: vemurafenib, dafrafenib + trametinib). Evolving genomic events in which TKI responses have been reported in smaller series include MET exon 14 skipping mutations (2-4% of tumors, drug: crizotinib); high-level MET amplification (1-2% of tumors, drug: crizotinib); RET rearrangements (1% of tumors, drug: cabozantinib); and ERBB2 mutations (2-3% of tumors, drug: afatinib), among others. Unfortunately, the most common genomic event in NSCLC, KRAS mutations (25-30% of tumors), is not targetable with approved or in development small molecule

  18. Driven by Mutations: The Predictive Value of Mutation Subtype in EGFR-Mutated Non-Small Cell Lung Cancer.

    PubMed

    Castellanos, Emily; Feld, Emily; Horn, Leora

    2016-12-23

    EGFR-mutated NSCLC is a genetically heterogeneous disease that includes more than 200 distinct mutations. The implications of mutational subtype for both prognostic and predictive value are being increasingly understood. Although the most common EGFR mutations-exon 19 deletions or L858R mutations-predict sensitivity to EGFR tyrosine kinase inhibitors (TKIs), it is now being recognized that outcomes may be improved in patients with exon 19 deletions. Additionally, 10% of patients will have an uncommon EGFR mutation, and response to EGFR TKI therapy is highly variable depending on the mutation. Given the growing recognition of the genetic and clinical variation seen in this disease, the development of comprehensive bioinformatics-driven tools to both analyze response in uncommon mutation subtypes and inform clinical decision making will be increasingly important. Clinical trials of novel EGFR TKIs should prospectively account for the presence of uncommon mutation subtypes in study design.

  19. Progress in heavy-ion drivers for inertial fusion

    SciTech Connect

    Friedman, A.; Bangerter, R.O.; Herrmannsfeldt, W.B.

    1994-12-22

    Heavy-ion induction accelerators are being developed as fusion drivers for ICF power production in the US Inertial Fusion Energy (IFE) program, in the Office of Fusion Energy of the US Department of Energy. In addition, they represent an attractive driver option for a high-yield microfusion facility for defense research. This paper describes recent progress in induction drivers for Heavy-Ion Fusion (HIF), and plans for future work. It presents research aimed at developing drivers having reduced cost and size, specifically advanced induction linacs and recirculating induction accelerators (recirculators). The goals and design of the Elise accelerator being built at Lawrence Berkeley Laboratory (LBL), as the first stage of the ILSE (Induction Linac Systems Experiments) program, are described. Elise will accelerate, for the first time, space-charge-dominated ion beams which are of full driver scale in line-charge density and diameter. Elise will be a platform on which the critical beam manipulations of the induction approach can be explored. An experimental program at Lawrence Livermore National Laboratory (LLNL) exploring the recirculator principle on a small scale is described in some detail; it is expected that these studies will result ultimately in an operational prototype recirculating induction accelerator. In addition, other elements of the US HIF program are described.

  20. UWB dual burst transmit driver

    SciTech Connect

    Dallum, Gregory E; Pratt, Garth C; Haugen, Peter C; Zumstein, James M; Vigars, Mark L; Romero, Carlos E

    2012-04-17

    A dual burst transmitter for ultra-wideband (UWB) communication systems generates a pair of precisely spaced RF bursts from a single trigger event. An input trigger pulse produces two oscillator trigger pulses, an initial pulse and a delayed pulse, in a dual trigger generator. The two oscillator trigger pulses drive a gated RF burst (power output) oscillator. A bias driver circuit gates the RF output oscillator on and off and sets the RF burst packet width. The bias driver also level shifts the drive signal to the level that is required for the RF output device.

  1. Evaluation of the elderly driver.

    PubMed

    Craig, Kevin W; Zweig, Steven C

    2007-01-01

    Driving is a daily activity for people across the country. Most Americans, including the elderly, consider it a right. Driving, however, is dangerous and can become more challenging as people age. While evaluating the elderly driver is not a simple task, it is a responsibility that must be shared by Missouri physicians. This paper describes the epidemiology of this problem, common mistakes made by elderly drivers, risk factors that can cause unsafe driving, and strategies physicians can use to evaluate their elderly patients' ability to drive.

  2. A study of the mutational landscape of pediatric-type follicular lymphoma and pediatric nodal marginal zone lymphoma

    PubMed Central

    Ozawa, Michael G; Bhaduri, Aparna; Chisholm, Karen M; Baker, Steven A; Ma, Lisa; Zehnder, James L; Luna-Fineman, Sandra; Link, Michael P; Merker, Jason D; Arber, Daniel A; Ohgami, Robert S

    2016-01-01

    Pediatric-type follicular lymphoma and pediatric marginal zone lymphoma are two of the rarest B-cell lymphomas. These lymphomas occur predominantly in the pediatric population and show features distinct from their more common counterparts in adults: adult-type follicular lymphoma and adult-type nodal marginal zone lymphoma. Here we report a detailed whole-exome deep sequencing analysis of a cohort of pediatric-type follicular lymphomas and pediatric marginal zone lymphomas. This analysis revealed a recurrent somatic variant encoding p.Lys66Arg in the transcription factor interferon regulatory factor 8 (IRF8) in 3 of 6 cases (50%) of pediatric-type follicular lymphoma. This specific point mutation was not detected in pediatric marginal zone lymphoma or in adult-type follicular lymphoma. Additional somatic point mutations in pediatric-type follicular lymphoma were observed in genes involved in transcription, intracellular signaling, and cell proliferation. In pediatric marginal zone lymphoma, no recurrent mutation was identified; however, somatic point mutations were observed in genes involved in cellular adhesion, cytokine regulatory elements, and cellular proliferation. A somatic variant in AMOTL1, a recurrently mutated gene in splenic marginal zone lymphoma, was also identified in a case of pediatric marginal zone lymphoma. The overall non-synonymous mutational burden was low in both pediatric-type follicular lymphoma and pediatric marginal zone lymphoma (4.6 mutations per exome). Altogether, these findings support a distinctive genetic basis for pediatric-type follicular lymphoma and pediatric marginal zone lymphoma when compared with adult subtypes and to one another. Moreover, identification of a recurrent point mutation in IRF8 provides insight into a potential driver mutation in the pathogenesis of pediatric-type follicular lymphoma with implications for novel diagnostic or therapeutic strategies. PMID:27338637

  3. iCAGES: integrated CAncer GEnome Score for comprehensively prioritizing driver genes in personal cancer genomes.

    PubMed

    Dong, Chengliang; Guo, Yunfei; Yang, Hui; He, Zeyu; Liu, Xiaoming; Wang, Kai

    2016-12-22

    Cancer results from the acquisition of somatic driver mutations. Several computational tools can predict driver genes from population-scale genomic data, but tools for analyzing personal cancer genomes are underdeveloped. Here we developed iCAGES, a novel statistical framework that infers driver variants by integrating contributions from coding, non-coding, and structural variants, identifies driver genes by combining genomic information and prior biological knowledge, then generates prioritized drug treatment. Analysis on The Cancer Genome Atlas (TCGA) data showed that iCAGES predicts whether patients respond to drug treatment (P = 0.006 by Fisher's exact test) and long-term survival (P = 0.003 from Cox regression). iCAGES is available at http://icages.wglab.org .

  4. 32 CFR 636.16 - Detection, apprehension, and testing of intoxicated drivers.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 32 National Defense 4 2012-07-01 2011-07-01 true Detection, apprehension, and testing of intoxicated drivers. 636.16 Section 636.16 National Defense Department of Defense (Continued) DEPARTMENT OF... drivers. In addition to the requirements in § 634.36 of this subchapter, the standard field sobriety...

  5. 32 CFR 636.16 - Detection, apprehension, and testing of intoxicated drivers.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 32 National Defense 4 2014-07-01 2013-07-01 true Detection, apprehension, and testing of intoxicated drivers. 636.16 Section 636.16 National Defense Department of Defense (Continued) DEPARTMENT OF... drivers. In addition to the requirements in § 634.36 of this subchapter, the standard field sobriety...

  6. 32 CFR 636.16 - Detection, apprehension, and testing of intoxicated drivers.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 32 National Defense 4 2013-07-01 2013-07-01 false Detection, apprehension, and testing of intoxicated drivers. 636.16 Section 636.16 National Defense Department of Defense (Continued) DEPARTMENT OF... drivers. In addition to the requirements in § 634.36 of this subchapter, the standard field sobriety...

  7. Proteogenomics connects somatic mutations to signalling in breast cancer.

    PubMed

    Mertins, Philipp; Mani, D R; Ruggles, Kelly V; Gillette, Michael A; Clauser, Karl R; Wang, Pei; Wang, Xianlong; Qiao, Jana W; Cao, Song; Petralia, Francesca; Kawaler, Emily; Mundt, Filip; Krug, Karsten; Tu, Zhidong; Lei, Jonathan T; Gatza, Michael L; Wilkerson, Matthew; Perou, Charles M; Yellapantula, Venkata; Huang, Kuan-lin; Lin, Chenwei; McLellan, Michael D; Yan, Ping; Davies, Sherri R; Townsend, R Reid; Skates, Steven J; Wang, Jing; Zhang, Bing; Kinsinger, Christopher R; Mesri, Mehdi; Rodriguez, Henry; Ding, Li; Paulovich, Amanda G; Fenyö, David; Ellis, Matthew J; Carr, Steven A

    2016-06-02

    Somatic mutations have been extensively characterized in breast cancer, but the effects of these genetic alterations on the proteomic landscape remain poorly understood. Here we describe quantitative mass-spectrometry-based proteomic and phosphoproteomic analyses of 105 genomically annotated breast cancers, of which 77 provided high-quality data. Integrated analyses provided insights into the somatic cancer genome including the consequences of chromosomal loss, such as the 5q deletion characteristic of basal-like breast cancer. Interrogation of the 5q trans-effects against the Library of Integrated Network-based Cellular Signatures, connected loss of CETN3 and SKP1 to elevated expression of epidermal growth factor receptor (EGFR), and SKP1 loss also to increased SRC tyrosine kinase. Global proteomic data confirmed a stromal-enriched group of proteins in addition to basal and luminal clusters, and pathway analysis of the phosphoproteome identified a G-protein-coupled receptor cluster that was not readily identified at the mRNA level. In addition to ERBB2, other amplicon-associated highly phosphorylated kinases were identified, including CDK12, PAK1, PTK2, RIPK2 and TLK2. We demonstrate that proteogenomic analysis of breast cancer elucidates the functional consequences of somatic mutations, narrows candidate nominations for driver genes within large deletions and amplified regions, and identifies therapeutic targets.

  8. Teaching French via Driver Education.

    ERIC Educational Resources Information Center

    Berwald, Jean-Pierre

    1980-01-01

    Driver instruction through the medium of a foreign language is useful in teaching vocabulary, grammar, and culture. The maps, driving manuals, and cars stimulate discussion and communication. Course techniques can include Asher's concept of Total Physical Response wherein students act in response to commands in the foreign language. (PMJ)

  9. Fuel-Cell Drivers Wanted

    ERIC Educational Resources Information Center

    Clark, Todd; Jones, Rick

    2004-01-01

    While the political climate seems favorable for the development of fuel-cell vehicles for personal transportation, the market's demand may not be so favorable. Nonetheless, middle level students will be the next generation of drivers and voters, and they need to be able to make informed decisions regarding the nation's energy and transportation…

  10. Driver Education and Driving Simulators.

    ERIC Educational Resources Information Center

    Fox, James H.

    This study was concerned with--(1) the conditions of transfer of training, (2) armed forces research on the use of synthetic training devices in the learning of complex skills, (3) armed forces research on the use of training devices in learning judgmental skills, and (4) training devices used in driver education. A section with a summary,…

  11. Accelerating Mutational Load Is Not Due to Synergistic Epistasis or Mutator Alleles in Mutation Accumulation Lines of Yeast.

    PubMed

    Jasmin, Jean-Nicolas; Lenormand, Thomas

    2016-02-01

    Much of our knowledge about the fitness effects of new mutations has been gained from mutation accumulation (MA) experiments. Yet the fitness effect of single mutations is rarely measured in MA experiments. This raises several issues, notably for inferring epistasis for fitness. The acceleration of fitness decline in MA lines has been taken as evidence for synergistic epistasis, but establishing the role of epistasis requires measuring the fitness of genotypes carrying known numbers of mutations. Otherwise, accelerating fitness loss could be explained by increased genetic mutation rates. Here we segregated mutations accumulated over 4800 generations in haploid and diploid MA lines of the yeast Saccharomyces cerevisiae. We found no correspondence between an accelerated fitness decline and synergistic epistasis among deleterious mutations in haploid lines. Pairs of mutations showed no overall epistasis. Furthermore, several lines of evidence indicate that genetic mutation rates did not increase in the MA lines. Crucially, segregant fitness analyses revealed that MA accelerated in both haploid and diploid lines, even though the fitness of diploid lines was nearly constant during the MA experiment. This suggests that the accelerated fitness decline in haploids was caused by cryptic environmental factors that increased mutation rates in all lines during the last third of the lines' transfers. In addition, we provide new estimates of deleterious mutation rates, including lethal mutations, and highlight that nearly all the mutational load we observed was due to one or two mutations having a large effect on fitness.

  12. 49 CFR 380.507 - Driver responsibilities.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... Transportation Other Regulations Relating to Transportation (Continued) FEDERAL MOTOR CARRIER SAFETY ADMINISTRATION, DEPARTMENT OF TRANSPORTATION FEDERAL MOTOR CARRIER SAFETY REGULATIONS SPECIAL TRAINING REQUIREMENTS Entry-Level Driver Training Requirements § 380.507 Driver responsibilities. Each...

  13. Analytics For Distracted Driver Behavior Modeling in Dilemma Zone

    SciTech Connect

    Li, Jan-Mou; Malikopoulos, Andreas; Thakur, Gautam; Vatsavai, Raju

    2014-01-01

    In this paper, we present the results obtained and insights gained through the analysis of TRB contest data. We used exploratory analysis, regression, and clustering models for gaining insights into the driver behavior in a dilemma zone while driving under distraction. While simple exploratory analysis showed the distinguishing driver behavior patterns among different popu- lation groups in the dilemma zone, regression analysis showed statically signification relationships between groups of variables. In addition to analyzing the contest data, we have also looked into the possible impact of distracted driving on the fuel economy.

  14. Recurrent PTPRB and PLCG1 mutations in angiosarcoma

    PubMed Central

    Martincorena, Inigo; Van Loo, Peter; Gundem, Gunes; Wedge, David C; Ramakrishna, Manasa; Cooke, Susanna L; Pillay, Nischalan; Vollan, Hans Kristian M; Papaemmanuil, Elli; Koss, Hans; Bunney, Tom D; Hardy, Claire; Joseph, Olivia R; Martin, Sancha; Mudie, Laura; Butler, Adam; Teague, Jon W; Patil, Meena; Steers, Graham; Cao, Yu; Gumbs, Curtis; Ingram, Davis; Lazar, Alexander J; Little, Latasha; Mahadeshwar, Harshad; Protopopov, Alexei; Al Sannaa, Ghadah A; Seth, Sahil; Song, Xingzhi; Tang, Jiabin; Zhang, Jianhua; Ravi, Vinod; Torres, Keila E; Khatri, Bhavisha; Halai, Dina; Roxanis, Ioannis; Baumhoer, Daniel; Tirabosco, Roberto; Amary, M Fernanda; Boshoff, Chris; McDermott, Ultan; Katan, Matilda; Stratton, Michael R; Futreal, P Andrew; Flanagan, Adrienne M; Harris, Adrian; Campbell, Peter J

    2014-01-01

    Angiosarcoma is an aggressive malignancy that arises spontaneously or secondarily to ionising radiation or chronic lymphoedema1. Previous work has identified aberrant angiogenesis, including occasional somatic mutations in angiogenesis signalling genes, as a key driver of angiosarcoma1. Here, we employed whole genome, exome, and targeted sequencing to study the somatic changes underpinning primary and secondary angiosarcoma. We identified recurrent mutations in two genes, PTPRB and PLCG1, which are intimately linked to angiogenesis. The endothelial phosphatase PTPRB, a negative regulator of vascular growth factor tyrosine kinases, harboured predominantly truncating mutations in 10/39 (26%) tumours. PLCG1, a signal transducer of tyrosine kinases, presented with a recurrent, likely activating R707Q missense variant in 3/34 cases (9%). Overall, 15/39 (38%) tumours harboured at least one driver mutation in angiogenesis signalling genes. Our findings inform and reinforce current therapeutic efforts to target angiogenesis signalling in angiosarcoma. PMID:24633157

  15. Cancer-associated mutations are preferentially distributed in protein kinase functional sites.

    PubMed

    Izarzugaza, Jose M G; Redfern, Oliver C; Orengo, Christine A; Valencia, Alfonso

    2009-12-01

    Protein kinases are a superfamily involved in many crucial cellular processes, including signal transmission and regulation of cell cycle. As a consequence of this role, kinases have been reported to be associated with many types of cancer and are considered as potential therapeutic targets. We analyzed the distribution of pathogenic somatic point mutations (drivers) in the protein kinase superfamily with respect to their location in the protein, such as in structural, evolutionary, and functionally relevant regions. We find these driver mutations are more clearly associated with key protein features than other somatic mutations (passengers) that have not been directly linked to tumor progression. This observation fits well with the expected implication of the alterations in protein kinase function in cancer pathogenicity. To explain the relevance of the detected association of cancer driver mutations at the molecular level in the human kinome, we compare these with genetically inherited mutations (SNPs). We find that the subset of nonsynonymous SNPs that are associated to disease, but sufficiently mild to the point of being widespread in the population, tend to avoid those key protein regions, where they could be more detrimental for protein function. This tendency contrasts with the one detected for cancer associated-driver-mutations, which seems to be more directly implicated in the alteration of protein function. The detailed analysis of protein kinase groups and a number of relevant examples, confirm the relation between cancer associated-driver-mutations and key regions for protein kinase structure and function.

  16. Driver perceptions of the safety implications of quiet electric vehicles.

    PubMed

    Cocron, Peter; Krems, Josef F

    2013-09-01

    Previous research on the safety implications of quiet electric vehicles (EVs) has mostly focused on pedestrians' acoustic perception of EVs, and suggests that EVs are more difficult for pedestrians to hear and, therefore, compromise traffic safety. The two German field studies presented here examine the experiences of 70 drivers with low noise emissions of EVs and the drivers' long-term evaluation of the issue. Participants were surveyed via interviews and questionnaires before driving an EV for the first time, after 3 months of driving, and in the first study, again after 6 months. Based on participants' reports, a catalogue of safety-relevant incidents was composed in Study 1. The catalogue revealed that low noise-related critical incidents only rarely occur, and mostly take place in low-speed environments. The degree of hazard related to these incidents was rated as low to medium. In Study 1, driver concern for vulnerable road users as a result of low noise diminished with increasing driving experience, while perceived comfort due to this feature increased. These results were replicated in Study 2. In the second study, it was additionally examined, if drivers adjust their perceived risk of harming other road users over time. Results show that the affective assessment of risk also decreased with increased driving experience. Based on individual experience, drivers adjust their evaluation of noise-related hazards, suggesting that dangers associated with low noise emissions might be less significant than previously expected.

  17. Predicting Driver Behavior during the Yellow Interval Using Video Surveillance.

    PubMed

    Li, Juan; Jia, Xudong; Shao, Chunfu

    2016-12-06

    At a signalized intersection, drivers must make a stop/go decision at the onset of the yellow signal. Incorrect decisions would lead to red light running (RLR) violations or crashes. This study aims to predict drivers' stop/go decisions and RLR violations during yellow intervals. Traffic data such as vehicle approaching speed, acceleration, distance to the intersection, and occurrence of RLR violations are gathered by a Vehicle Data Collection System (VDCS). An enhanced Gaussian Mixture Model (GMM) is used to extract moving vehicles from target lanes, and the Kalman Filter (KF) algorithm is utilized to acquire vehicle trajectories. The data collected from the VDCS are further analyzed by a sequential logit model, and the relationship between drivers' stop/go decisions and RLR violations is identified. The results indicate that the distance of vehicles to the stop line at the onset of the yellow signal is an important predictor for both drivers' stop/go decisions and RLR violations. In addition, vehicle approaching speed is a contributing factor for stop/go decisions. Furthermore, the accelerations of vehicles after the onset of the yellow signal are positively related to RLR violations. The findings of this study can be used to predict the probability of drivers' RLR violations and improve traffic safety at signalized intersections.

  18. Distracted driving in elderly and middle-aged drivers.

    PubMed

    Thompson, Kelsey R; Johnson, Amy M; Emerson, Jamie L; Dawson, Jeffrey D; Boer, Erwin R; Rizzo, Matthew

    2012-03-01

    Automobile driving is a safety-critical real-world example of multitasking. A variety of roadway and in-vehicle distracter tasks create information processing loads that compete for the neural resources needed to drive safely. Drivers with mind and brain aging may be particularly susceptible to distraction due to waning cognitive resources and control over attention. This study examined distracted driving performance in an instrumented vehicle (IV) in 86 elderly (mean=72.5 years, SD=5.0 years) and 51 middle-aged drivers (mean=53.7 years, SD=9.3 year) under a concurrent auditory-verbal processing load created by the Paced Auditory Serial Addition Task (PASAT). Compared to baseline (no-task) driving performance, distraction was associated with reduced steering control in both groups, with middle-aged drivers showing a greater increase in steering variability. The elderly drove slower and showed decreased speed variability during distraction compared to middle-aged drivers. They also tended to "freeze up", spending significantly more time holding the gas pedal steady, another tactic that may mitigate time pressured integration and control of information, thereby freeing mental resources to maintain situation awareness. While 39% of elderly and 43% of middle-aged drivers committed significantly more driving safety errors during distraction, 28% and 18%, respectively, actually improved, compatible with allocation of attention resources to safety critical tasks under a cognitive load.

  19. Keep the driver in control: Automating automobiles of the future.

    PubMed

    Banks, Victoria A; Stanton, Neville A

    2016-03-01

    Automated automobiles will be on our roads within the next decade but the role of the driver has not yet been formerly recognised or designed. Rather, the driver is often left in a passive monitoring role until they are required to reclaim control from the vehicle. This research aimed to test the idea of driver-initiated automation, in which the automation offers decision support that can be either accepted or ignored. The test case examined a combination of lateral and longitudinal control in addition to an auto-overtake system. Despite putting the driver in control of the automated systems by enabling them to accept or ignore behavioural suggestions (e.g. overtake), there were still issues associated with increased workload and decreased trust. These issues are likely to have arisen due to the way in which the automated system has been designed. Recommendations for improvements in systems design have been made which are likely to improve trust and make the role of the driver more transparent concerning their authority over the automated system.

  20. Drivers influencing streamflow changes in the Upper Turia basin, Spain.

    PubMed

    Salmoral, Gloria; Willaarts, Bárbara A; Troch, Peter A; Garrido, Alberto

    2015-01-15

    Many rivers across the world have experienced a significant streamflow reduction over the last decades. Drivers of the observed streamflow changes are multiple, including climate change (CC), land use and land cover changes (LULCC), water transfers and river impoundment. Many of these drivers inter-act simultaneously, making it difficult to discern the impact of each driver individually. In this study we isolate the effects of LULCC on the observed streamflow reduction in the Upper Turia basin (east Spain) during the period 1973-2008. Regression models of annual streamflow are fitted with climatic variables and also additional time variant drivers like LULCC. The ecohydrological model SWAT is used to study the magnitude and sign of streamflow change when LULCC occurs. Our results show that LULCC does play a significant role on the water balance, but it is not the main driver underpinning the observed reduction on Turia's streamflow. Increasing mean temperature is the main factor supporting increasing evapotranspiration and streamflow reduction. In fact, LULCC and CC have had an offsetting effect on the streamflow generation during the study period. While streamflow has been negatively affected by increasing temperature, ongoing LULCC have positively compensated with reduced evapotranspiration rates, thanks to mainly shrubland clearing and forest degradation processes. These findings are valuable for the management of the Turia river basin, as well as a useful approach for the determination of the weight of LULCC on the hydrological response in other regions.

  1. 49 CFR 380.109 - Driver testing.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... ADMINISTRATION, DEPARTMENT OF TRANSPORTATION FEDERAL MOTOR CARRIER SAFETY REGULATIONS SPECIAL TRAINING....109 Driver testing. (a) Testing methods. The driver-student must pass knowledge and skills tests in... be administered by any qualified driver-instructor. The skills tests, based on actual operation of...

  2. Energy Education Resource Guide for Driver Education.

    ERIC Educational Resources Information Center

    Meyerhoff, Richard

    This guide is designed to help driver education teachers in Iowa to integrate energy conservation education into the traditional high school driver education course. Following an explanation of the necessity for teaching energy conservation with driver education, the course guide is divided into seven units. The units cover vehicle selection,…

  3. 40 CFR 1066.280 - Driver's aid.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 34 2013-07-01 2013-07-01 false Driver's aid. 1066.280 Section 1066... VEHICLE-TESTING PROCEDURES Dynamometer Specifications § 1066.280 Driver's aid. Use good engineering judgment to provide a driver's aid that facilitates compliance with the requirements of § 1066.430....

  4. 40 CFR 1066.280 - Driver's aid.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 34 2012-07-01 2012-07-01 false Driver's aid. 1066.280 Section 1066... VEHICLE-TESTING PROCEDURES Dynamometer Specifications § 1066.280 Driver's aid. Use good engineering judgment to provide a driver's aid that facilitates compliance with the requirements of § 1066.430....

  5. Food additives

    PubMed Central

    Spencer, Michael

    1974-01-01

    Food additives are discussed from the food technology point of view. The reasons for their use are summarized: (1) to protect food from chemical and microbiological attack; (2) to even out seasonal supplies; (3) to improve their eating quality; (4) to improve their nutritional value. The various types of food additives are considered, e.g. colours, flavours, emulsifiers, bread and flour additives, preservatives, and nutritional additives. The paper concludes with consideration of those circumstances in which the use of additives is (a) justified and (b) unjustified. PMID:4467857

  6. Additional Warning System for Cross Level

    NASA Astrophysics Data System (ADS)

    Lewiński, Andrzej; Bester, Lucyna

    The paper contains an analysis of the safety level crossing equipped with an additional warning system for drivers that are within the level crossing before the approaching train. The proposed system is based on wireless data standard, WiMax and sensor networks WSN, placed an additional warning helps to improve safety at unguarded railway crossings. Mathematical analysis was carried out for unguarded level crossing model, and then for system with signaling the level crossing ssp and for system equipped with additional warning system for drivers. For the analysis presented models used stochastic Markov processes which allowed estimating the indicators of probabilistic studied systems.

  7. OPTO-22 DRIVER. OPTO-22 Driver for LabView

    SciTech Connect

    Johnson, G.W.

    1991-01-28

    OPTO-22 DRIVER consists of a set of LabVIEW (National Instruments, Austin, TX) virtual instruments (VIs) that handle low-level communications with signal conditioning equipment by Opto-22 (Huntington Beach, CA). The OPTOMUX protocol is support, which requires the use of a serial port and supports multidrop communications. With this package, users can connect hundreds of Opto-22 modules to their LabVIEW system and access all features of the hardware, including analog and digital input and outputs.

  8. Can active navigation be as good as driving? A comparison of spatial memory in drivers and backseat drivers.

    PubMed

    von Stülpnagel, Rul; Steffens, Melanie C

    2012-06-01

    When driving a vehicle, either the driver or a passenger (henceforth: backseat driver) may be responsible for navigation. Research on active navigation, primarily addressed in virtual environments, suggests that controlling navigation is more central for spatial learning than controlling movement. To test this assumption in a real-world scenario, we manipulated movement control through seating participants in the front or the back position of a tandem bike, and navigation control by presenting differently detailed maps to participants unfamiliar (Experiment 1) or familiar (Experiment 2) with an environment. Landmark knowledge was tested with recognition tasks. For participants unfamiliar with the environment (Experiment 1), passive navigation enabled better landmark recognition than active navigation, but there was no effect of movement control. For participants more familiar with the environment (Experiment 2), there was no effect of navigation control, but drivers showed better landmark recognition than backseat drivers. These findings are discussed in relation to action memory research. Measures of route and survey knowledge demonstrated that good performance resulted from active navigation (Experiment 1-2). Moreover, with regard to these measures, driving compensated for passive navigation if the environment was familiar (Experiment 2). An additional experiment in a lab setting (Experiment 3) validated the manipulation of navigation control and the used tasks and demonstrated the importance of real environment exposure. As our findings suggest, driving may be more relevant for remembering landmarks, but actively controlling navigation (even as a backseat driver) is more relevant for remembering a route than maneuvering a vehicle.

  9. Somatic Mutation Patterns in Hemizygous Genomic Regions Unveil Purifying Selection during Tumor Evolution

    PubMed Central

    Basu, Swaraj; Larsson, Erik

    2016-01-01

    Identification of cancer driver genes using somatic mutation patterns indicative of positive selection has become a major goal in cancer genomics. However, cancer cells additionally depend on a large number of genes involved in basic cellular processes. While such genes should in theory be subject to strong purifying (negative) selection against damaging somatic mutations, these patterns have been elusive and purifying selection remains inadequately explored in cancer. Here, we hypothesized that purifying selection should be evident in hemizygous genomic regions, where damaging mutations cannot be compensated for by healthy alleles. Using a 7,781-sample pan-cancer dataset, we first confirmed this in POLR2A, an essential gene where hemizygous deletions are known to confer elevated sensitivity to pharmacological suppression. We next used this principle to identify several genes and pathways that show patterns indicative of purifying selection to avoid deleterious mutations. These include the POLR2A interacting protein INTS10 as well as genes involved in mRNA splicing, nonsense-mediated mRNA decay and other RNA processing pathways. Many of these genes belong to large protein complexes, and strong overlaps were observed with recent functional screens for gene essentiality in human cells. Our analysis supports that purifying selection acts to preserve the remaining function of many hemizygously deleted essential genes in tumors, indicating vulnerabilities that might be exploited by future therapeutic strategies. PMID:28027311

  10. Driver oncogenes in Sub-Saharan African patients with non-small cell lung cancer

    PubMed Central

    Legius, Barbara; Van Den Broecke, Sandra; Muylle, Inge; Ninane, Vincent

    2016-01-01

    Non-small cell lung cancer can exhibit driver oncogenes, including epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK), that are possible targets for therapy. The prevalence of these rearranged driver oncogenes is influenced by race, smoking habits, and gender. Most data come from Caucasian and Asian populations. To our knowledge, there is no literature available about the prevalence of driver oncogenes in Sub-Saharan Africa, where the tobacco epidemic is still in the early stage. In this small case series, 6 patients of Sub-Saharan African ethnicity with stage IV lung adenocarcinoma are described. EGFR mutation was present in 3/6 patients and ALK rearrangement in 1/6 patients. This incidence seems high but interestingly, all patients were non-smokers or light smokers. In this series, the high prevalence of driver oncogene was probably related to low smoking habits and these initial data in Sub-Saharan Africans suggest high prevalence of driver mutations for this reason. PMID:28210171

  11. Factors Contributing to Crashes among Young Drivers

    PubMed Central

    Bates, Lyndel J.; Davey, Jeremy; Watson, Barry; King, Mark J.; Armstrong, Kerry

    2014-01-01

    Young drivers are the group of drivers most likely to crash. There are a number of factors that contribute to the high crash risk experienced by these drivers. While some of these factors are intrinsic to the young driver, such as their age, gender or driving skill, others relate to social factors and when and how often they drive. This article reviews the factors that affect the risk of young drivers crashing to enable a fuller understanding of why this risk is so high in order to assist in developing effective countermeasures. PMID:25097763

  12. SSA-ME Detection of cancer driver genes using mutual exclusivity by small subnetwork analysis

    PubMed Central

    Pulido-Tamayo, Sergio; Weytjens, Bram; De Maeyer, Dries; Marchal, Kathleen

    2016-01-01

    Because of its clonal evolution a tumor rarely contains multiple genomic alterations in the same pathway as disrupting the pathway by one gene often is sufficient to confer the complete fitness advantage. As a result, many cancer driver genes display mutual exclusivity across tumors. However, searching for mutually exclusive gene sets requires analyzing all possible combinations of genes, leading to a problem which is typically too computationally complex to be solved without a stringent a priori filtering, restricting the mutations included in the analysis. To overcome this problem, we present SSA-ME, a network-based method to detect cancer driver genes based on independently scoring small subnetworks for mutual exclusivity using a reinforced learning approach. Because of the algorithmic efficiency, no stringent upfront filtering is required. Analysis of TCGA cancer datasets illustrates the added value of SSA-ME: well-known recurrently mutated but also rarely mutated drivers are prioritized. We show that using mutual exclusivity to detect cancer driver genes is complementary to state-of-the-art approaches. This framework, in which a large number of small subnetworks are being analyzed in order to solve a computationally complex problem (SSA), can be generically applied to any problem in which local neighborhoods in a network hold useful information. PMID:27808240

  13. Visualization drivers for Geant4

    SciTech Connect

    Beretvas, Andy; /Fermilab

    2005-10-01

    This document is on Geant4 visualization tools (drivers), evaluating pros and cons of each option, including recommendations on which tools to support at Fermilab for different applications. Four visualization drivers are evaluated. They are OpenGL, HepRep, DAWN and VRML. They all have good features, OpenGL provides graphic output without an intermediate file. HepRep provides menus to assist the user. DAWN provides high quality plots and even for large files produces output quickly. VRML uses the smallest disk space for intermediate files. Large experiments at Fermilab will want to write their own display. They should proceed to make this display graphics independent. Medium experiment will probably want to use HepRep because of it's menu support. Smaller scale experiments will want to use OpenGL in the spirit of having immediate response, good quality output and keeping things simple.

  14. Signatures of mutational processes in human cancer

    PubMed Central

    Alexandrov, Ludmil B.; Nik-Zainal, Serena; Wedge, David C.; Aparicio, Samuel A.J.R.; Behjati, Sam; Biankin, Andrew V.; Bignell, Graham R.; Bolli, Niccolo; Borg, Ake; Børresen-Dale, Anne-Lise; Boyault, Sandrine; Burkhardt, Birgit; Butler, Adam P.; Caldas, Carlos; Davies, Helen R.; Desmedt, Christine; Eils, Roland; Eyfjörd, Jórunn Erla; Foekens, John A.; Greaves, Mel; Hosoda, Fumie; Hutter, Barbara; Ilicic, Tomislav; Imbeaud, Sandrine; Imielinsk, Marcin; Jäger, Natalie; Jones, David T.W.; Jones, David; Knappskog, Stian; Kool, Marcel; Lakhani, Sunil R.; López-Otín, Carlos; Martin, Sancha; Munshi, Nikhil C.; Nakamura, Hiromi; Northcott, Paul A.; Pajic, Marina; Papaemmanuil, Elli; Paradiso, Angelo; Pearson, John V.; Puente, Xose S.; Raine, Keiran; Ramakrishna, Manasa; Richardson, Andrea L.; Richter, Julia; Rosenstiel, Philip; Schlesner, Matthias; Schumacher, Ton N.; Span, Paul N.; Teague, Jon W.; Totoki, Yasushi; Tutt, Andrew N.J.; Valdés-Mas, Rafael; van Buuren, Marit M.; van ’t Veer, Laura; Vincent-Salomon, Anne; Waddell, Nicola; Yates, Lucy R.; Zucman-Rossi, Jessica; Futreal, P. Andrew; McDermott, Ultan; Lichter, Peter; Meyerson, Matthew; Grimmond, Sean M.; Siebert, Reiner; Campo, Elías; Shibata, Tatsuhiro; Pfister, Stefan M.; Campbell, Peter J.; Stratton, Michael R.

    2013-01-01

    All cancers are caused by somatic mutations. However, understanding of the biological processes generating these mutations is limited. The catalogue of somatic mutations from a cancer genome bears the signatures of the mutational processes that have been operative. Here, we analysed 4,938,362 mutations from 7,042 cancers and extracted more than 20 distinct mutational signatures. Some are present in many cancer types, notably a signature attributed to the APOBEC family of cytidine deaminases, whereas others are confined to a single class. Certain signatures are associated with age of the patient at cancer diagnosis, known mutagenic exposures or defects in DNA maintenance, but many are of cryptic origin. In addition to these genome-wide mutational signatures, hypermutation localized to small genomic regions, kataegis, is found in many cancer types. The results reveal the diversity of mutational processes underlying the development of cancer with potential implications for understanding of cancer etiology, prevention and therapy. PMID:23945592

  15. Global desertification: Drivers and feedbacks

    NASA Astrophysics Data System (ADS)

    D'Odorico, Paolo; Bhattachan, Abinash; Davis, Kyle F.; Ravi, Sujith; Runyan, Christiane W.

    2013-01-01

    Desertification is a change in soil properties, vegetation or climate, which results in a persistent loss of ecosystem services that are fundamental to sustaining life. Desertification affects large dryland areas around the world and is a major cause of stress in human societies. Here we review recent research on the drivers, feedbacks, and impacts of desertification. A multidisciplinary approach to understanding the drivers and feedbacks of global desertification is motivated by our increasing need to improve global food production and to sustainably manage ecosystems in the context of climate change. Classic desertification theories look at this process as a transition between stable states in bistable ecosystem dynamics. Climate change (i.e., aridification) and land use dynamics are the major drivers of an ecosystem shift to a “desertified” (or “degraded”) state. This shift is typically sustained by positive feedbacks, which stabilize the system in the new state. Desertification feedbacks may involve land degradation processes (e.g., nutrient loss or salinization), changes in rainfall regime resulting from land-atmosphere interactions (e.g., precipitation recycling, dust emissions), or changes in plant community composition (e.g., shrub encroachment, decrease in vegetation cover). We analyze each of these feedback mechanisms and discuss their possible enhancement by interactions with socio-economic drivers. Large scale effects of desertification include the emigration of “environmental refugees” displaced from degraded areas, climatic changes, and the alteration of global biogeochemical cycles resulting from the emission and long-range transport of fine mineral dust. Recent research has identified some possible early warning signs of desertification, which can be used as indicators of resilience loss and imminent shift to desert-like conditions. We conclude with a brief discussion on some desertification control strategies implemented in different

  16. Exome and deep sequencing of clinically aggressive neuroblastoma reveal somatic mutations that affect key pathways involved in cancer progression

    PubMed Central

    Lasorsa, Vito Alessandro; Formicola, Daniela; Pignataro, Piero; Cimmino, Flora; Calabrese, Francesco Maria; Mora, Jaume; Esposito, Maria Rosaria; Pantile, Marcella; Zanon, Carlo; De Mariano, Marilena; Longo, Luca; Hogarty, Michael D.; de Torres, Carmen; Tonini, Gian Paolo; Iolascon, Achille; Capasso, Mario

    2016-01-01

    The spectrum of somatic mutation of the most aggressive forms of neuroblastoma is not completely determined. We sought to identify potential cancer drivers in clinically aggressive neuroblastoma. Whole exome sequencing was conducted on 17 germline and tumor DNA samples from high-risk patients with adverse events within 36 months from diagnosis (HR-Event3) to identify somatic mutations and deep targeted sequencing of 134 genes selected from the initial screening in additional 48 germline and tumor pairs (62.5% HR-Event3 and high-risk patients), 17 HR-Event3 tumors and 17 human-derived neuroblastoma cell lines. We revealed 22 significantly mutated genes, many of which implicated in cancer progression. Fifteen genes (68.2%) were highly expressed in neuroblastoma supporting their involvement in the disease. CHD9, a cancer driver gene, was the most significantly altered (4.0% of cases) after ALK. Other genes (PTK2, NAV3, NAV1, FZD1 and ATRX), expressed in neuroblastoma and involved in cell invasion and migration were mutated at frequency ranged from 4% to 2%. Focal adhesion and regulation of actin cytoskeleton pathways, were frequently disrupted (14.1% of cases) thus suggesting potential novel therapeutic strategies to prevent disease progression. Notably BARD1, CHEK2 and AXIN2 were enriched in rare, potentially pathogenic, germline variants. In summary, whole exome and deep targeted sequencing identified novel cancer genes of clinically aggressive neuroblastoma. Our analyses show pathway-level implications of infrequently mutated genes in leading neuroblastoma progression. PMID:27009842

  17. The drivers of tropical speciation.

    PubMed

    Smith, Brian Tilston; McCormack, John E; Cuervo, Andrés M; Hickerson, Michael J; Aleixo, Alexandre; Cadena, Carlos Daniel; Pérez-Emán, Jorge; Burney, Curtis W; Xie, Xiaoou; Harvey, Michael G; Faircloth, Brant C; Glenn, Travis C; Derryberry, Elizabeth P; Prejean, Jesse; Fields, Samantha; Brumfield, Robb T

    2014-11-20

    Since the recognition that allopatric speciation can be induced by large-scale reconfigurations of the landscape that isolate formerly continuous populations, such as the separation of continents by plate tectonics, the uplift of mountains or the formation of large rivers, landscape change has been viewed as a primary driver of biological diversification. This process is referred to in biogeography as vicariance. In the most species-rich region of the world, the Neotropics, the sundering of populations associated with the Andean uplift is ascribed this principal role in speciation. An alternative model posits that rather than being directly linked to landscape change, allopatric speciation is initiated to a greater extent by dispersal events, with the principal drivers of speciation being organism-specific abilities to persist and disperse in the landscape. Landscape change is not a necessity for speciation in this model. Here we show that spatial and temporal patterns of genetic differentiation in Neotropical birds are highly discordant across lineages and are not reconcilable with a model linking speciation solely to landscape change. Instead, the strongest predictors of speciation are the amount of time a lineage has persisted in the landscape and the ability of birds to move through the landscape matrix. These results, augmented by the observation that most species-level diversity originated after episodes of major Andean uplift in the Neogene period, suggest that dispersal and differentiation on a matrix previously shaped by large-scale landscape events was a major driver of avian speciation in lowland Neotropical rainforests.

  18. Novel strategies for comprehensive mutation screening of the APC gene.

    PubMed

    Wachsmannova, L; Mego, M; Stevurkova, V; Zajac, V; Ciernikova, S

    2017-03-03

    Colorectal cancer is the 4th most common cause of cancer related deaths worldwide and new possibilities in accurate diagnosis and targeted treatment are highly required. Mutations in adenomatous polyposis coli (APC) gene play a pivotal role in adenoma-carcinoma pathway of colorectal tumorigenesis. The quarter century from its´ first cloning, APC became one of the most frequently mutated, known driver genes in colorectal cancer. Intensive routine molecular testing of APC has brought the benefits for patients with family history of polyposis or colorectal cancer. Nevertheless, multiple mutational disease-causing mechanisms make the genetic testing still challenging. This minireview is focused on implementation of novel APC mutation screening diagnostic strategies for polyposis families according to the current findings. A further understanding and improved algorithms may help to increase the mutation detection rate. APC germline mutations achieve close to 100% penetrance, so more comprehensive approach followed by preventive and therapeutic strategies might reflect in decrease in burden of colorectal cancer.

  19. 77 FR 30919 - Commercial Driver's License Testing and Commercial Learner's Permit Standards

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-05-24

    ...), DOT. ACTION: Notice of regulatory guidance and applicability of ``tank vehicle'' definition. SUMMARY... Commercial Learner's Permit Standards.'' Among other things, the rule revised the definition of ``tank vehicle.'' The change required additional drivers, primarily those transporting certain tanks...

  20. Landscape of somatic mutations in 560 breast cancer whole-genome sequences

    DOE PAGES

    Nik-Zainal, Serena; Davies, Helen; Staaf, Johan; ...

    2016-05-02

    Here, we analysed whole-genome sequences of 560 breast cancers to advance understanding of the driver mutations conferring clonal advantage and the mutational processes generating somatic mutations. We found that 93 protein-coding cancer genes carried probable driver mutations. Some non-coding regions exhibited high mutation frequencies, but most have distinctive structural features probably causing elevated mutation rates and do not contain driver mutations. Mutational signature analysis was extended to genome rearrangements and revealed twelve base substitution and six rearrangement signatures. Three rearrangement signatures, characterized by tandem duplications or deletions, appear associated with defective homologous-recombination-based DNA repair: one with deficient BRCA1 function, anothermore » with deficient BRCA1 or BRCA2 function, the cause of the third is unknown. This analysis of all classes of somatic mutation across exons, introns and intergenic regions highlights the repertoire of cancer genes and mutational processes operating, and progresses towards a comprehensive account of the somatic genetic basis of breast cancer.« less

  1. BINNING SOMATIC MUTATIONS BASED ON BIOLOGICAL KNOWLEDGE FOR PREDICTING SURVIVAL: AN APPLICATION IN RENAL CELL CARCINOMA

    PubMed Central

    Kim, Dokyoon; Li, Ruowang; Dudek, Scott M.; Wallace, John R.; Ritchie, Marylyn D.

    2014-01-01

    Enormous efforts of whole exome and genome sequencing from hundreds to thousands of patients have provided the landscape of somatic genomic alterations in many cancer types to distinguish between driver mutations and passenger mutations. Driver mutations show strong associations with cancer clinical outcomes such as survival. However, due to the heterogeneity of tumors, somatic mutation profiles are exceptionally sparse whereas other types of genomic data such as miRNA or gene expression contain much more complete data for all genomic features with quantitative values measured in each patient. To overcome the extreme sparseness of somatic mutation profiles and allow for the discovery of combinations of somatic mutations that may predict cancer clinical outcomes, here we propose a new approach for binning somatic mutations based on existing biological knowledge. Through the analysis using renal cell carcinoma dataset from The Cancer Genome Atlas (TCGA), we identified combinations of somatic mutation burden based on pathways, protein families, evolutionary conversed regions, and regulatory regions associated with survival. Due to the nature of heterogeneity in cancer, using a binning strategy for somatic mutation profiles based on biological knowledge will be valuable for improved prognostic biomarkers and potentially for tailoring therapeutic strategies by identifying combinations of driver mutations. PMID:25592572

  2. Battery electric vehicles - implications for the driver interface.

    PubMed

    Neumann, Isabel; Krems, Josef F

    2016-03-01

    The current study examines the human-machine interface of a battery electric vehicle (BEV) from a user-perspective, focussing on the evaluation of BEV-specific displays, the relevance of provided information and challenges for drivers due to the concept of electricity in a road vehicle. A sample of 40 users drove a BEV for 6 months. Data were gathered at three points of data collection. Participants perceived the BEV-specific displays as only moderately reliable and helpful for estimating the displayed parameters. This was even less the case after driving the BEV for 3 months. A taxonomy of user requirements was compiled revealing the need for improved and additional information, especially regarding energy consumption and efficiency. Drivers had difficulty understanding electrical units and the energy consumption of the BEV. On the background of general principles for display design, results provide implications how to display relevant information and how to facilitate drivers' understanding of energy consumption in BEVs. Practitioner Summary: Battery electric vehicle (BEV) displays need to incorporate new information. A taxonomy of user requirements was compiled revealing the need for improved and additional information in the BEV interface. Furthermore, drivers had trouble understanding electrical units and energy consumption; therefore, appropriate assistance is required. Design principles which are specifically important in the BEV context are discussed.

  3. Pressurized fluid torque driver control and method

    NASA Astrophysics Data System (ADS)

    Cook, Joseph S., Jr.

    1994-08-01

    Methods and apparatus are provided for a torque driver including a displaceable gear to limit torque transfer to a fastener at a precisely controlled torque limit. A biasing assembly biases a first gear into engagement with a second gear for torque transfer between the first and second gear. The biasing assembly includes a pressurized cylinder controlled at a constant pressure that corresponds to a torque limit. A calibrated gage and valve is used to set the desired torque limit. One or more coiled output linkages connect the first gear with the fastener adaptor which may be a socket for a nut. A gear tooth profile provides a separation force that overcomes the bias to limit torque at the desired torque limit. Multiple fasteners may be rotated simultaneously to a desired torque limit if additional output spur gears are provided. The torque limit is adjustable and may be different for fasteners within the same fastener configuration.

  4. Pressurized fluid torque driver control and method

    NASA Technical Reports Server (NTRS)

    Cook, Joseph S., Jr. (Inventor)

    1994-01-01

    Methods and apparatus are provided for a torque driver including a displaceable gear to limit torque transfer to a fastener at a precisely controlled torque limit. A biasing assembly biases a first gear into engagement with a second gear for torque transfer between the first and second gear. The biasing assembly includes a pressurized cylinder controlled at a constant pressure that corresponds to a torque limit. A calibrated gage and valve is used to set the desired torque limit. One or more coiled output linkages connect the first gear with the fastener adaptor which may be a socket for a nut. A gear tooth profile provides a separation force that overcomes the bias to limit torque at the desired torque limit. Multiple fasteners may be rotated simultaneously to a desired torque limit if additional output spur gears are provided. The torque limit is adjustable and may be different for fasteners within the same fastener configuration.

  5. Food additives

    MedlinePlus

    ... or natural. Natural food additives include: Herbs or spices to add flavor to foods Vinegar for pickling ... Certain colors improve the appearance of foods. Many spices, as well as natural and man-made flavors, ...

  6. Rapid Conversion of Mutant IDH1 from Driver to Passenger in a Model of Human Gliomagenesis.

    PubMed

    Johannessen, Tor-Christian Aase; Mukherjee, Joydeep; Viswanath, Pavithra; Ohba, Shigeo; Ronen, Sabrina M; Bjerkvig, Rolf; Pieper, Russell O

    2016-10-01

    Missense mutations in the active site of isocitrate dehydrogenase 1 (IDH1) biologically and diagnostically distinguish low-grade gliomas and secondary glioblastomas from primary glioblastomas. IDH1 mutations lead to the formation of the oncometabolite 2-hydroxyglutarate (2-HG) from the reduction of α-ketoglutarate (α-KG), which in turn facilitates tumorigenesis by modifying DNA and histone methylation as well blocking differentiation processes. Although mutant IDH1 expression is thought to drive the gliomagenesis process, the extent to which it remains a viable therapeutic target remains unknown. To address this question, we exposed immortalized (p53/pRb deficient), untransformed human astrocytes to the mutant IDH1 inhibitor AGI-5198 prior to, concomitant with, or at intervals after, introduction of transforming mutant IDH1, then measured effects on 2-HG levels, histone methylation (H3K4me3, H3K9me2, H3K9me3, or H3K27me3), and growth in soft agar. Addition of AGI-5198 prior to, or concomitant with, introduction of mutant IDH1 blocked all mutant IDH1-driven changes, including cellular transformation. Addition at time intervals as short as 4 days following introduction of mutant IDH1 also suppressed 2-HG levels, but had minimal effects on histone methylation, and lost the ability to suppress clonogenicity in a time-dependent manner. Furthermore, in two different models of mutant IDH1-driven gliomagenesis, AGI-5198 exposures that abolished production of 2-HG also failed to decrease histone methylation, adherent cell growth, or anchorage-independent growth in soft agar over a prolonged period. These studies show although mutant IDH1 expression drives gliomagenesis, mutant IDH1 itself rapidly converts from driver to passenger.

  7. Car drivers' attitudes towards motorcyclists: a survey.

    PubMed

    Crundall, David; Bibby, Peter; Clarke, David; Ward, Patrick; Bartle, Craig

    2008-05-01

    Motorcyclists are over-represented in UK traffic accident statistics. Many car-motorcycle accidents are however due to the inappropriate actions of car drivers. It is predicted that car drivers at risk of collision with motorcycles have divergent attitudes and beliefs about motorcyclists compared to safer drivers, which may lead to a deficient mental model guiding their interactions with motorcyclists. To assess car drivers' attitudes towards motorcyclists, a survey was undertaken. Respondents filled in 26 general and motorcycle-related items and the 24 items of the reduced Driver Behaviour Questionnaire. Compared to an experienced dual driver group (who both drive cars and ride motorcycles), all other drivers showed divergent beliefs and attitudes. Four factors were extracted from the motorcycle items: negative attitudes, empathic attitudes, awareness of perceptual problems, and spatial understanding. Car drivers with a moderate amount of experience (between 2 and 10 years driving) held the most negative views and reported the most violations. The results have lead to several suggestions for interventions aimed at decreasing the divergence between drivers' perceptions of motorcyclists, and the perceptions of experienced dual drivers.

  8. Hospital admissions among male drivers in Denmark

    PubMed Central

    Hannerz, H; Tuchsen, F

    2001-01-01

    OBJECTIVES—To facilitate decisions about interventions and to establish baseline values for future evaluation of preventive efforts, the aim of the present study was to elucidate the disease pattern among male professional drivers in Denmark. The study differentiated between drivers of goods vehicles and drivers of passenger transport.
METHODS—Cohorts of all 20-59 year old Danish male professional drivers in the years 1981, 1986, 1991, and 1994 were formed, to calculate age standardised hospital admission ratios (SHRs) and time trends (1981-97) for many diagnostic aggregations.
RESULTS—SHRs for diseases in practically all systems and organs of the body were higher among professional drivers than they were in the male working population at large. Also drivers of passenger transport, compared with drivers of goods vehicles, had significantly high SHRs due to infectious and parasitic diseases, diseases of the circulatory system, and diseases of the respiratory system, and significantly lower rates of injury. For both driver groups, the SHRs for acute myocardial infarction increased with time whereas the SHR for acute gastritis decreased, and for drivers of passenger transport an increasing SHR for chronic obstructive pulmonary disease, was found over time.
CONCLUSION—Drivers of passenger transport and drivers of goods vehicles differ in their disease patterns. The results support the hypothesis that preventive efforts are needed in both groups, but underline that different strategies are required for different categories of drivers.


Keywords: professional drivers; hospital admissions; surveillance system PMID:11245742

  9. Optical Flow and Driver's Kinematics Analysis for State of Alert Sensing

    PubMed Central

    Jiménez-Pinto, Javier; Torres-Torriti, Miguel

    2013-01-01

    Road accident statistics from different countries show that a significant number of accidents occur due to driver's fatigue and lack of awareness to traffic conditions. In particular, about 60% of the accidents in which long haul truck and bus drivers are involved are attributed to drowsiness and fatigue. It is thus fundamental to improve non-invasive systems for sensing a driver's state of alert. One of the main challenges to correctly resolve the state of alert is measuring the percentage of eyelid closure over time (PERCLOS), despite the driver's head and body movements. In this paper, we propose a technique that involves optical flow and driver's kinematics analysis to improve the robustness of the driver's alert state measurement under pose changes using a single camera with near-infrared illumination. The proposed approach infers and keeps track of the driver's pose in 3D space in order to ensure that eyes can be located correctly, even after periods of partial occlusion, for example, when the driver stares away from the camera. Our experiments show the effectiveness of the approach with a correct eyes detection rate of 99.41%, on average. The results obtained with the proposed approach in an experiment involving fifteen persons under different levels of sleep deprivation also confirm the discriminability of the fatigue levels. In addition to the measurement of fatigue and drowsiness, the pose tracking capability of the proposed approach has potential applications in distraction assessment and alerting of machine operators. PMID:23539029

  10. Optical flow and driver's kinematics analysis for state of alert sensing.

    PubMed

    Jiménez-Pinto, Javier; Torres-Torriti, Miguel

    2013-03-28

    Road accident statistics from different countries show that a significant number of accidents occur due to driver's fatigue and lack of awareness to traffic conditions. In particular, about 60% of the accidents in which long haul truck and bus drivers are involved are attributed to drowsiness and fatigue. It is thus fundamental to improve non-invasive systems for sensing a driver's state of alert. One of the main challenges to correctly resolve the state of alert is measuring the percentage of eyelid closure over time (PERCLOS), despite the driver's head and body movements. In this paper, we propose a technique that involves optical flow and driver's kinematics analysis to improve the robustness of the driver's alert state measurement under pose changes using a single camera with near-infrared illumination. The proposed approach infers and keeps track of the driver's pose in 3D space in order to ensure that eyes can be located correctly, even after periods of partial occlusion, for example, when the driver stares away from the camera. Our experiments show the effectiveness of the approach with a correct eyes detection rate of 99.41%, on average. The results obtained with the proposed approach in an experiment involving fifteen persons under different levels of sleep deprivation also confirm the discriminability of the fatigue levels. In addition to the measurement of fatigue and drowsiness, the pose tracking capability of the proposed approach has potential applications in distraction assessment and alerting of machine operators.

  11. Modeling of driver's collision avoidance maneuver based on controller switching model.

    PubMed

    Kim, Jong-Hae; Hayakawa, Soichiro; Suzuki, Tatsuya; Hayashi, Koji; Okuma, Shigeru; Tsuchida, Nuio; Shimizu, Masayuki; Kido, Shigeyuki

    2005-12-01

    This paper presents a modeling strategy of human driving behavior based on the controller switching model focusing on the driver's collision avoidance maneuver. The driving data are collected by using the three-dimensional (3-D) driving simulator based on the CAVE Automatic Virtual Environment (CAVE), which provides stereoscopic immersive virtual environment. In our modeling, the control scenario of the human driver, that is, the mapping from the driver's sensory information to the operation of the driver such as acceleration, braking, and steering, is expressed by Piecewise Polynomial (PWP) model. Since the PWP model includes both continuous behaviors given by polynomials and discrete logical conditions, it can be regarded as a class of Hybrid Dynamical System (HDS). The identification problem for the PWP model is formulated as the Mixed Integer Linear Programming (MILP) by transforming the switching conditions into binary variables. From the obtained results, it is found that the driver appropriately switches the "control law" according to the sensory information. In addition, the driving characteristics of the beginner driver and the expert driver are compared and discussed. These results enable us to capture not only the physical meaning of the driving skill but the decision-making aspect (switching conditions) in the driver's collision avoidance maneuver as well.

  12. Identification of Variant-Specific Functions of PIK3CA by Rapid Phenotyping of Rare Mutations

    PubMed Central

    Dogruluk, Turgut; Tsang, Yiu Huen; Espitia, Maribel; Chen, Fengju; Chen, Tenghui; Chong, Zechen; Appadurai, Vivek; Dogruluk, Armel; Eterovic, Agna Karina; Bonnen, Penelope E.; Creighton, Chad J.; Chen, Ken; Mills, Gordon B.; Scott, Kenneth L.

    2015-01-01

    Large-scale sequencing efforts are uncovering the complexity of cancer genomes, which are comprised of causal “driver” mutations that promote tumor progression along with many more pathologically-neutral “passenger” events. The majority of mutations, both in known cancer drivers and uncharacterized genes, are generally of low occurrence, highlighting the need to functionally annotate the long tail of infrequent mutations present in heterogeneous cancers. Here we describe a mutation assessment pipeline enabled by high-throughput engineering of molecularly-barcoded gene variant expression clones identified by tumor sequencing. We first used this platform to functionally assess tail mutations observed in PIK3CA, which encodes the catalytic subunit alpha of the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) frequently mutated in cancer. Orthogonal screening for PIK3CA variant activity using in vitro and in vivo cell growth and transformation assays differentiated driver from passenger mutations, revealing that PIK3CA variant activity correlates imperfectly with its mutation frequency across breast cancer populations. While PIK3CA mutations with frequencies above 5% were significantly more oncogenic than wild-type in all assays, mutations occurring at 0.07 – 5.0% included those with and without oncogenic activities that ranged from weak to strong in at least one assay. Proteomic profiling coupled with therapeutic sensitivity assays on PIK3CA variant-expressing cell models revealed variant-specific activation of PI3K signaling as well as other pathways that include the MEK1/2 module of Mitogen-Activated Protein (MAP) Kinase pathway. Our data indicate that cancer treatments will need to increasingly consider the functional relevance of specific mutations in driver genes rather than considering all mutations in drivers as equivalent. PMID:26627007

  13. Mutation and the environment

    SciTech Connect

    Mendelsohn, M.L. ); Albertini, R.J. )

    1990-01-01

    This book is covered under the following topics: Somatic Mutation: Animal Model; Somatic Mutation: Human; Heritable Mutation: Animal Model; Heritable Mutation: Approaches to Human Induction Rates; Heritable Mutation: Human Risk; Epidemiology: Population Studies on Genotoxicity; and Epidemiology: Workplace Studies of Genotoxicity.

  14. Somatic mutation spectrum of non-small cell lung cancer in African Americans: a pooled analysis

    PubMed Central

    Araujo, Luiz H.; Lammers, Philip E.; Matthews-Smith, Velmalia; Eisenberg, Rosana; Gonzalez, Adriana; Schwartz, Ann G.; Timmers, Cynthia; Shilo, Konstantin; Zhao, Weiqiang; Natarajan, Thanemozhi G.; Zhang, Jianying; Yilmaz, Ayse Selen; Liu, Tom; Coombes, Kevin; Carbone, David P.

    2015-01-01

    Introduction The mutational profile of non-small cell lung cancer (NSCLC) has become an important tool in tailoring therapy to patients, with clear differences according to the population of origin. African Americans have higher lung cancer incidence and mortality than Caucasians, yet discrepant results have been reported regarding the frequency of somatic driver mutations. We hypothesized that NSCLC has a distinct mutational profile in this group. Methods We collected NSCLC samples resected from self-reported African Americans in five sites from Tennessee, Michigan, and Ohio. Gene mutations were assessed by either SNaPshot or next generation sequencing, and ALK translocations were evaluated by fluorescence in situ hybridization. Results Two hundred sixty patients were included, mostly males (62.3%) and smokers (86.6%). Eighty-one samples (31.2%) were squamous cell carcinomas. The most frequently mutated genes were KRAS (15.4%), EGFR (5.0%), PIK3CA (0.8%), BRAF, NRAS, ERBB2, and AKT1 (0.4% each). ALK translocations were detected in 2 non-squamous tumors (1.7%), totaling 61 cases (23.5%) with driver oncogenic alterations. Among 179 non-squamous samples, 54 (30.2%) presented a driver alteration. The frequency of driver alterations altogether was lower than that reported in Caucasians, while no difference was detected in either EGFR or KRAS mutations. Overall survival was longer among patients with EGFR mutations. Conclusions We demonstrated that NSCLC from African Americans has a different pattern of somatic driver mutations than from Caucasians. The majority of driver alterations in this group are yet to be described, which will require more comprehensive panels and assessment of non-canonical alterations. PMID:26301800

  15. Recent developments in mass drivers

    NASA Technical Reports Server (NTRS)

    Oneill, G. K.

    1981-01-01

    In the past eight months a new mass driver concept has been explored through calculation and inductance model verification. It retains the linear synchronous principle and freedom from arcs, plasmas or physical contact between the accelerated bucket and accelerator. However, it discards passive magnetic flight and obtains transverse focussing from strong off-axis restoring forces produced by drive coils operating in a pull-only mode. This paper gives the reasoning on which the new concept is based, and applies the concept to a lunar catapult design.

  16. Mass drivers. 1: Electrical design

    NASA Technical Reports Server (NTRS)

    Arnold, W.; Bowen, S.; Fine, K.; Kaplan, D.; Kolm, M.; Kolm, H.; Newman, J.; Oneill, G. K.; Snow, W.

    1979-01-01

    A mass driver is an electrical device used to accelerate payloads of any material to a high velocity. Small vehicles (called buckets) containing superconducting coils carry the payloads. These buckets are accelerated by pulsed magnetic fields, timed by information on their position, and are guided by induced magnetic fields set up in a surrounding guideway. Upon reaching the correct velocity, the buckets release their payloads, then they are slowed for recirculation to be reused. A rationale is presented that leads to a relatively simple and near-optimum design, as well as basic programs for calculating acceleration. The transverse oscillation frequencies are found to be invariant to guideway transverse dimensions.

  17. Driver models for personalised driving assistance

    NASA Astrophysics Data System (ADS)

    Lefèvre, Stéphanie; Carvalho, Ashwin; Gao, Yiqi; Tseng, H. Eric; Borrelli, Francesco

    2015-12-01

    We propose a learning-based driver modelling approach which can identify manoeuvres performed by drivers on the highway and predict the future driver inputs. We show how this approach can be applied to provide personalised driving assistance. In a first example, the driver model is used to predict unintentional lane departures and a model predictive controller is used to keep the car in the lane. In a second example, the driver model estimates the preferred acceleration of the driver during lane keeping, and a model predictive controller is implemented to provide a personalised adaptive cruise control. For both applications, we use a combination of real data and simulation to evaluate the proposed approaches.

  18. Precise Characterization of a Laser Current Driver

    NASA Astrophysics Data System (ADS)

    Troxel, Daylin

    2009-10-01

    I will be presenting a characterization of our unique low-noise laser current driver. Our current driver improves on the typical model used in laboratories, giving extra current stability and lower noise. I will discuss our techniques for measuring the noise and drift and the results we obtained. The current driver has a lower noise and drift than any other current driver with a published value, so it has value in making precision measurements. Many other labs have expressed interest in our design as there is a need for this type of current driver in many applications. The current driver demonstrates some interesting applications of electronics principles and uses of electric components, as well as practical considerations in designing circuitry.

  19. Utilizing protein structure to identify non-random somatic mutations

    PubMed Central

    2013-01-01

    Background Human cancer is caused by the accumulation of somatic mutations in tumor suppressors and oncogenes within the genome. In the case of oncogenes, recent theory suggests that there are only a few key “driver” mutations responsible for tumorigenesis. As there have been significant pharmacological successes in developing drugs that treat cancers that carry these driver mutations, several methods that rely on mutational clustering have been developed to identify them. However, these methods consider proteins as a single strand without taking their spatial structures into account. We propose an extension to current methodology that incorporates protein tertiary structure in order to increase our power when identifying mutation clustering. Results We have developed iPAC (identification of Protein Amino acid Clustering), an algorithm that identifies non-random somatic mutations in proteins while taking into account the three dimensional protein structure. By using the tertiary information, we are able to detect both novel clusters in proteins that are known to exhibit mutation clustering as well as identify clusters in proteins without evidence of clustering based on existing methods. For example, by combining the data in the Protein Data Bank (PDB) and the Catalogue of Somatic Mutations in Cancer, our algorithm identifies new mutational clusters in well known cancer proteins such as KRAS and PI3KC α. Further, by utilizing the tertiary structure, our algorithm also identifies clusters in EGFR, EIF2AK2, and other proteins that are not identified by current methodology. The R package is available at: http://www.bioconductor.org/packages/2.12/bioc/html/iPAC.html. Conclusion Our algorithm extends the current methodology to identify oncogenic activating driver mutations by utilizing tertiary protein structure when identifying nonrandom somatic residue mutation clusters. PMID:23758891

  20. Ordering of mutations in preinvasive disease stages of esophageal carcinogenesis.

    PubMed

    Weaver, Jamie M J; Ross-Innes, Caryn S; Shannon, Nicholas; Lynch, Andy G; Forshew, Tim; Barbera, Mariagnese; Murtaza, Muhammed; Ong, Chin-Ann J; Lao-Sirieix, Pierre; Dunning, Mark J; Smith, Laura; Smith, Mike L; Anderson, Charlotte L; Carvalho, Benilton; O'Donovan, Maria; Underwood, Timothy J; May, Andrew P; Grehan, Nicola; Hardwick, Richard; Davies, Jim; Oloumi, Arusha; Aparicio, Sam; Caldas, Carlos; Eldridge, Matthew D; Edwards, Paul A W; Rosenfeld, Nitzan; Tavaré, Simon; Fitzgerald, Rebecca C

    2014-08-01

    Cancer genome sequencing studies have identified numerous driver genes, but the relative timing of mutations in carcinogenesis remains unclear. The gradual progression from premalignant Barrett's esophagus to esophageal adenocarcinoma (EAC) provides an ideal model to study the ordering of somatic mutations. We identified recurrently mutated genes and assessed clonal structure using whole-genome sequencing and amplicon resequencing of 112 EACs. We next screened a cohort of 109 biopsies from 2 key transition points in the development of malignancy: benign metaplastic never-dysplastic Barrett's esophagus (NDBE; n=66) and high-grade dysplasia (HGD; n=43). Unexpectedly, the majority of recurrently mutated genes in EAC were also mutated in NDBE. Only TP53 and SMAD4 mutations occurred in a stage-specific manner, confined to HGD and EAC, respectively. Finally, we applied this knowledge to identify high-risk Barrett's esophagus in a new non-endoscopic test. In conclusion, mutations in EAC driver genes generally occur exceptionally early in disease development with profound implications for diagnostic and therapeutic strategies.

  1. Driver behaviour profiles for road safety analysis.

    PubMed

    Ellison, Adrian B; Greaves, Stephen P; Bliemer, Michiel C J

    2015-03-01

    Driver behaviour is a contributing factor in over 90 percent of road crashes. As a consequence, there is significant benefit in identifying drivers who engage in unsafe driving practices. Driver behaviour profiles (DBPs) are introduced here as an approach for evaluating driver behaviour as a function of the risk of a casualty crash. They employ data collected using global positioning system (GPS) devices, supplemented with spatiotemporal information. These profiles are comprised of common risk scores that can be used to compare drivers between each other and across time and space. The paper details the development of these DBPs and demonstrates their use as an input into modelling the factors that influence driver behaviour. The results show that even having controlled for the influence of the road environment, these factors remain the strongest predictors of driver behaviour suggesting different spatiotemporal environments elicit a variety of psychological responses in drivers. The approach and outcomes will be of interest to insurance companies in enhancing the risk-profiling of drivers with on-road driving and government through assessing the impacts of behaviour-change interventions.

  2. Mass Driver Two - A status report

    NASA Technical Reports Server (NTRS)

    Snow, W. R.; Dunbar, R. S.; Kubby, J. A.; Oneill, G. K.

    1982-01-01

    The current status of Mass Driver Two, a linear synchronous motor for accelerating payloads or reaction mass, is discussed. Mass Driver Two combines all the essential elements of an operational mass driver with the exception of bucket recirculation and payload handling. These essential elements include: magnetic flight, vacuum environment, superconducting bucket coils, high acceleration (nominally 500 g's), optical position sensing and electronic triggering, power circuitry similar to that of a flight article, and regenerative braking. Mass Driver Two is operated on a single shot basis.

  3. Potlining Additives

    SciTech Connect

    Rudolf Keller

    2004-08-10

    In this project, a concept to improve the performance of aluminum production cells by introducing potlining additives was examined and tested. Boron oxide was added to cathode blocks, and titanium was dissolved in the metal pool; this resulted in the formation of titanium diboride and caused the molten aluminum to wet the carbonaceous cathode surface. Such wetting reportedly leads to operational improvements and extended cell life. In addition, boron oxide suppresses cyanide formation. This final report presents and discusses the results of this project. Substantial economic benefits for the practical implementation of the technology are projected, especially for modern cells with graphitized blocks. For example, with an energy savings of about 5% and an increase in pot life from 1500 to 2500 days, a cost savings of $ 0.023 per pound of aluminum produced is projected for a 200 kA pot.

  4. Phosphazene additives

    DOEpatents

    Harrup, Mason K; Rollins, Harry W

    2013-11-26

    An additive comprising a phosphazene compound that has at least two reactive functional groups and at least one capping functional group bonded to phosphorus atoms of the phosphazene compound. One of the at least two reactive functional groups is configured to react with cellulose and the other of the at least two reactive functional groups is configured to react with a resin, such as an amine resin of a polycarboxylic acid resin. The at least one capping functional group is selected from the group consisting of a short chain ether group, an alkoxy group, or an aryloxy group. Also disclosed are an additive-resin admixture, a method of treating a wood product, and a wood product.

  5. Thalamic Circuit Diversity: Modulation of the Driver/Modulator Framework

    PubMed Central

    Bickford, Martha E.

    2016-01-01

    The idea that dorsal thalamic inputs can be divided into “drivers”, which provide the primary excitatory drive for the relay of information to cortex, and “modulators”, which alter the gain of signal transmission, has provided a valuable organizing principle for the study of thalamic function. This view further promoted the identification of “first order” and “higher order” thalamic nuclei, based on the origin of their driving inputs. Since the introduction of this influential terminology, a number of studies have revealed the existence of a wide variety of thalamic organizational schemes. For example, some thalamic nuclei are not innervated by typical driver inputs, but instead receive input from terminals which exhibit features distinct from those of either classic drivers or modulators. In addition, many thalamic nuclei contain unique combinations of convergent first order, higher order, and/or other “driver-like” inputs that do not conform with the driver/modulator framework. The assortment of synaptic arrangements identified in the thalamus are reviewed and discussed from the perspective that this organizational diversity can dramatically increase the computational capabilities of the thalamus, reflecting its essential roles in sensory, motor, and sensory-motor circuits. PMID:26793068

  6. The dJ/dS Ratio Test Reveals Hundreds of Novel Putative Cancer Drivers

    PubMed Central

    Chen, Han; Xing, Ke; He, Xionglei

    2015-01-01

    Computational tools with a balanced sensitivity and specificity in identification of candidate cancer drivers are highly desired. In this study, we propose a new statistical test, namely the dJ/dS ratio test, to compute the relative mutation rate of exon/intron junction sites (dJ) to synonymous sites (dS); observation of dJ/dS ratio larger than 1 in cancer indicates positive selection for splicing deregulation, a signature of cancer driver genes. Using this method, we analyzed the data from The Cancer Genome Atlas and identified hundreds of novel putative cancer drivers. Interestingly, these genes are highly enriched in biological processes related to the development and maintenance of multicellularity, paralleling a previous finding that cancer evolves back to be unicellular by knocking down the multicellularity-associated genetic network. PMID:25873590

  7. Global environmental drivers of influenza

    PubMed Central

    Deyle, Ethan R.; Maher, M. Cyrus; Hernandez, Ryan D.; Basu, Sanjay; Sugihara, George

    2016-01-01

    In temperate countries, influenza outbreaks are well correlated to seasonal changes in temperature and absolute humidity. However, tropical countries have much weaker annual climate cycles, and outbreaks show less seasonality and are more difficult to explain with environmental correlations. Here, we use convergent cross mapping, a robust test for causality that does not require correlation, to test alternative hypotheses about the global environmental drivers of influenza outbreaks from country-level epidemic time series. By moving beyond correlation, we show that despite the apparent differences in outbreak patterns between temperate and tropical countries, absolute humidity and, to a lesser extent, temperature drive influenza outbreaks globally. We also find a hypothesized U-shaped relationship between absolute humidity and influenza that is predicted by theory and experiment, but hitherto has not been documented at the population level. The balance between positive and negative effects of absolute humidity appears to be mediated by temperature, and the analysis reveals a key threshold around 75 °F. The results indicate a unified explanation for environmental drivers of influenza that applies globally. PMID:27799563

  8. Economic drivers of mineral supply

    USGS Publications Warehouse

    Wagner, Lorie A.; Sullivan, Daniel E.; Sznopek, John L.

    2003-01-01

    The debate over the adequacy of future supplies of mineral resources continues in light of the growing use of mineral-based materials in the United States. According to the U.S. Geological Survey, the quantity of new materials utilized each year has dramatically increased from 161 million tons2 in 1900 to 3.2 billion tons in 2000. Of all the materials used during the 20th century in the United States, more than half were used in the last 25 years. With the Earth?s endowment of natural resources remaining constant, and increased demand for resources, economic theory states that as depletion approaches, prices rise. This study shows that many economic drivers (conditions that create an economic incentive for producers to act in a particular way) such as the impact of globalization, technological improvements, productivity increases, and efficient materials usage are at work simultaneously to impact minerals markets and supply. As a result of these economic drivers, the historical price trend of mineral prices3 in constant dollars has declined as demand has risen. When price is measured by the cost in human effort, the price trend also has been almost steadily downward. Although the United States economy continues its increasing mineral consumption trend, the supply of minerals has been able to keep pace. This study shows that in general supply has grown faster than demand, causing a declining trend in mineral prices.

  9. 49 CFR 391.11 - General qualifications of drivers.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 5 2012-10-01 2012-10-01 false General qualifications of drivers. 391.11 Section... QUALIFICATIONS OF DRIVERS AND LONGER COMBINATION VEHICLE (LCV) DRIVER INSTRUCTORS Qualification and Disqualification of Drivers § 391.11 General qualifications of drivers. (a) A person shall not drive a...

  10. 49 CFR 391.11 - General qualifications of drivers.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 5 2014-10-01 2014-10-01 false General qualifications of drivers. 391.11 Section... QUALIFICATIONS OF DRIVERS AND LONGER COMBINATION VEHICLE (LCV) DRIVER INSTRUCTORS Qualification and Disqualification of Drivers § 391.11 General qualifications of drivers. (a) A person shall not drive a...

  11. 49 CFR 395.13 - Drivers declared out of service.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 5 2011-10-01 2011-10-01 false Drivers declared out of service. 395.13 Section... SERVICE OF DRIVERS § 395.13 Drivers declared out of service. (a) Authority to declare drivers out of... to this subchapter) is authorized to declare a driver out of service and to notify the motor...

  12. 49 CFR 395.13 - Drivers declared out of service.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 5 2010-10-01 2010-10-01 false Drivers declared out of service. 395.13 Section... SERVICE OF DRIVERS § 395.13 Drivers declared out of service. (a) Authority to declare drivers out of... to this subchapter) is authorized to declare a driver out of service and to notify the motor...

  13. 49 CFR 395.13 - Drivers declared out of service.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 5 2013-10-01 2013-10-01 false Drivers declared out of service. 395.13 Section... SERVICE OF DRIVERS § 395.13 Drivers declared out of service. (a) Authority to declare drivers out of... to this subchapter) is authorized to declare a driver out of service and to notify the motor...

  14. 49 CFR 395.13 - Drivers declared out of service.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 5 2012-10-01 2012-10-01 false Drivers declared out of service. 395.13 Section... SERVICE OF DRIVERS § 395.13 Drivers declared out of service. (a) Authority to declare drivers out of... to this subchapter) is authorized to declare a driver out of service and to notify the motor...

  15. 49 CFR 395.13 - Drivers declared out of service.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 5 2014-10-01 2014-10-01 false Drivers declared out of service. 395.13 Section... SERVICE OF DRIVERS § 395.13 Drivers declared out of service. (a) Authority to declare drivers out of... to this subchapter) is authorized to declare a driver out of service and to notify the motor...

  16. Molecular driver alterations and their clinical relevance in cancer of unknown primary site.

    PubMed

    Löffler, Harald; Pfarr, Nicole; Kriegsmann, Mark; Endris, Volker; Hielscher, Thomas; Lohneis, Philipp; Folprecht, Gunnar; Stenzinger, Albrecht; Dietel, Manfred; Weichert, Wilko; Krämer, Alwin

    2016-07-12

    Cancer of unknown primary (CUP) is defined as metastatic solid malignancy where no primary tumor is detected despite appropriate staging. About 90% of CUP represent adenocarcinoma or undifferentiated carcinoma. Since therapy regimens are only modestly effective, identification of the molecular landscape of these neoplasms might be a promising approach to direct CUP therapy and aid in tumor classification. We screened a cohort of 128 patients with adenocarcinoma or undifferentiated carcinoma meeting the definition of CUP. Massive parallel multigene sequencing of 50 genes, which had been selected due to their relevance as oncogenic drivers or druggable molecular targets could ultimately be performed on samples from 55 patients for whom complete clinical datasets were also available. Overall, 60 tumor-specific mutations and 29 amplifications/deletions, as revealed by coverage analysis, were detected in 46 cases (84%). The most frequently mutated genes were TP53 (30 cases, 55%), KRAS (9 cases, 16%), CDKN2A (5 cases, 9%), and SMAD4 (5 cases, 9%). The most frequently deleted gene was CDKN2A (8 cases, 15%). KRAS and CDKN2A mutations significantly correlated with poor progression-free survival (PFS) and, in case of KRAS, overall survival (OS). WIldtype TP53 and female sex defined a relatively favorable category, with favorable PFS and OS. 8 cases (15%) harbored mutations that may be targetable by currently approved drugs. Taken together, Mutations of relevant driver genes are present in the vast majority of CUP tumors. Some of them impact on prognosis and a subset is putatively druggable.

  17. U.S. Truck Driver Anthropometric Study and Multivariate Anthropometric Models for Cab Designs

    PubMed Central

    Guan, Jinhua; Hsiao, Hongwei; Bradtmiller, Bruce; Kau, Tsui-Ying; Reed, Matthew R.; Jahns, Steven K.; Loczi, Josef; Hardee, H. Lenora; Piamonte, Dominic Paul T.

    2015-01-01

    Objective This study presents data from a large-scale anthropometric study of U.S. truck drivers and the multivariate anthropometric models developed for the design of next-generation truck cabs. Background Up-to-date anthropometric information of the U.S. truck driver population is needed for the design of safe and ergonomically efficient truck cabs. Method We collected 35 anthropometric dimensions for 1,950 truck drivers (1,779 males and 171 females) across the continental United States using a sampling plan designed to capture the appropriate ethnic, gender, and age distributions of the truck driver population. Results Truck drivers are heavier than the U.S. general population, with a difference in mean body weight of 13.5 kg for males and 15.4 kg for females. They are also different in physique from the U.S. general population. In addition, the current truck drivers are heavier and different in physique compared to their counterparts of 25 to 30 years ago. Conclusion The data obtained in this study provide more accurate anthropometric information for cab designs than do the current U.S. general population data or truck driver data collected 25 to 30 years ago. Multivariate anthropometric models, spanning 95% of the current truck driver population on the basis of a set of 12 anthropometric measurements, have been developed to facilitate future cab designs. Application The up-to-date truck driver anthropometric data and multivariate anthropometric models will benefit the design of future truck cabs which, in turn, will help promote the safety and health of the U.S. truck drivers. PMID:23156628

  18. EGFR kinase domain duplication (EGFR-KDD) is a novel oncogenic driver in lung cancer that is clinically responsive to afatinib

    PubMed Central

    Gallant, Jean-Nicolas; Sheehan, Jonathan H.; Shaver, Timothy M.; Bailey, Mark; Lipson, Doron; Chandramohan, Raghu; Brewer, Monica Red; York, Sally J.; Kris, Mark G.; Pietenpol, Jennifer A.; Ladanyi, Marc; Miller, Vincent A.; Ali, Siraj M.; Meiler, Jens; Lovly, Christine M.

    2015-01-01

    Oncogenic EGFR mutations are found in 10-35% of lung adenocarcinomas. Such mutations, which present most commonly as small in-frame deletions in exon 19 or point mutations in exon 21 (L858R), confer sensitivity to EGFR tyrosine kinase inhibitors (TKIs). In analyzing the tumor from a 33-year-old male never smoker, we identified a novel EGFR alteration in lung cancer: EGFR exon 18-25 kinase domain duplication (EGFR-KDD). Through analysis of a larger cohort of tumor samples, we detected additional cases of EGFR-KDD in lung, brain, and other cancers. In vitro, EGFR-KDD is constitutively active, and computational modeling provides potential mechanistic support for its auto-activation. EGFR-KDD-transformed cells are sensitive to EGFR TKIs and, consistent with these in vitro findings, the index patient had a partial response to the EGFR TKI, afatinib. The patient eventually progressed, at which time, re-sequencing revealed an EGFR-dependent mechanism of acquired resistance to afatinib, thereby validating EGFR-KDD as a driver alteration and therapeutic target. PMID:26286086

  19. Simulation of the interaction between driver and seat

    NASA Astrophysics Data System (ADS)

    Du, Xiaoming; Ren, Jindong; Sang, Chunlei; Li, Lemeng

    2013-11-01

    Test is one of methods to acquire human-seat pressure distribution in driving, with the deficiency of being uneasy to obtain the stress information of soft tissue inside human body and the sheer force of interface between human and seat, which can be obtained by simulation. But current simulation method focuses mainly on calculation itself other than combining it with posture prediction and cab packaging parameters, which cause it difficult to acquire accurate pressure calculation results without accurate posture of human body, and make it almost meaningless to design optimization. Therefore, a human body geometric model with posture change capability is built and linked up with Cascade Prediction Model(CPM), which takes cab packaging parameters as inputs. A detailed finite element model of driver human body is constructed and used to conduct the driver-seat interaction simulation between human body and seat. Good accordance of pressure distribution is observed between simulation and test, which validates the simulation. In addition to the distribution pattern, curves on key sections are used to analyze the pressure and shear stress on the seat surface, as well as soft tissue stress inside human body. The simulation shows that the maximum stress of buttocks locates under the ischial tuberosity, and the maximum stress of trunk occurs near the scapula posterior and the lower waist. These are the places where fatigue usually occurs. The maximum pressure of seat appears at the driver-seat contact area corresponding to the driver's maximum skin tissue stress. In order to guide the seat design and cab packaging and study the influence of posture to pressure distribution, finite element models for different levels of cab packaging parameters are created by using CPM. The pressure distributions are calculated and their tendencies varying with cab packaging parameters are obtained. The method presented provides a new way to accurately simulate the interaction between driver

  20. Impact Driver With Integral Sliding Hammer

    NASA Technical Reports Server (NTRS)

    Wallace, Bilby J.

    1987-01-01

    Tool combines impact driver with sliding dead-blow hammer. Used for any purpose for which ordinary impact driver used; tightening fasteners or driving starter holes for drill. Tool protects user from accidental injury and surrounding equipment from damage that might occur from ordinary arm-wielded hammer. Especially useful in underwater work.

  1. California's Bus Driver's Training Course. Instructor's Manual.

    ERIC Educational Resources Information Center

    California State Dept. of Education, Sacramento.

    This instructor's manual was designed to help graduates of the California Bus Driver Instructor Course provide effective instruction to school bus driver trainees. It contains enough material for 20-30 hours of classroom training. The information is organized in 12 instructional units that cover the following topics: introduction to the course;…

  2. Hallways to Highways. Driver Education 1982.

    ERIC Educational Resources Information Center

    Oklahoma State Dept. of Education, Oklahoma City.

    The purpose of this guide is to provide direction and assistance to driver education instructors and school administrators as they plan and implement quality programs of traffic safety instruction. Materials are divided into seven chapters conveying: (1) the organization and administration of driver and traffic safety education, (2) the driving…

  3. Tractor Trailer Driver's Training Programs. Performance Report.

    ERIC Educational Resources Information Center

    New Hampshire Vocational Technical Coll., Nashua.

    This document describes a project to develop a 320-hour tractor trailer driver training program and a 20-hour commercial driver licensing upgrade training program. Of 34 graduates from the training program, 28 secured employment in the trucking industry. From August 1989 to June 1990, 725 students were trained in the upgrade training program with…

  4. About Assessment Criteria of Driver's Accidental Abilities

    ERIC Educational Resources Information Center

    Lobanova, Yuliya I.; Glushko, Kirill V.

    2016-01-01

    The article points at the importance of studying the human factor as a cause of accidents of drivers, especially in loosely structured traffic situations. The description of the experiment on the measurement of driver's accidental abilities is given. Under accidental ability is meant the capability to ensure the security of driving as a behavior…

  5. Physics at an upgraded Fermilab proton driver

    SciTech Connect

    Geer, S.; /Fermilab

    2005-07-01

    In 2004 the Fermilab Long Range Planning Committee identified a new high intensity Proton Driver as an attractive option for the future, primarily motivated by the recent exciting developments in neutrino physics. Over the last few months a physics study has developed the physics case for the Fermilab Proton Driver. The potential physics opportunities are discussed.

  6. Graduated Driver Licensing: The New Zealand Experience.

    ERIC Educational Resources Information Center

    Begg, Dorothy; Stephenson, Shaun

    2003-01-01

    Evaluates the graduated driver-licensing (GDL) system in New Zealand. Describes driver licensing and crash fatality rates before and after the implementation of GDL in 1987. Reports that GDL has contributed to a reduction in crashes among young people. (Contains 2 figures and 6 references.) (AUTHOR/WFA)

  7. Evaluation of Driver Education and Training Programs.

    ERIC Educational Resources Information Center

    Harman, Harry H.; And Others

    What contributions do driver education and training programs make to the Nation's highway safety program? An answer to this question was sought through a synthesis of four feasibility studies concerning the effectiveness of current or proposed driver education programs. These preliminary investigations failed to identify any clear proof that…

  8. PDII- Additional discussion of the dynamic aperture

    SciTech Connect

    Norman M. Gelfand

    2002-07-23

    This note is in the nature of an addition to the dynamic aperture calculations found in the report on the Proton Driver, FERMILAB-TM-2169. A extensive discussion of the Proton Driver lattice, as well as the nomenclature used to describe it can be found in TM-2169. Basically the proposed lattice is a racetrack design with the two arcs joined by two long straight sections. The straight sections are dispersion free. Tracking studies were undertaken with the objective of computing the dynamic aperture for the lattice and some of the results have been incorporated into TM-2169. This note is a more extensive report of those calculations.

  9. TERT promoter mutations in sinonasal malignant melanoma: a study of 49 cases.

    PubMed

    Jangard, Mattias; Zebary, Abdlsattar; Ragnarsson-Olding, Boel; Hansson, Johan

    2015-06-01

    Sinonasal malignant melanoma (SNMM) comprises less than 1% of all melanomas and is located in the nasal cavity and the paranasal sinuses. The majority of SNMMs have unknown underlying oncogenic driver mutations. The recent identification of a high frequency of driver mutations in the promoter of the telomerase reverse transcriptase (TERT) gene in cutaneous melanoma led us to investigate whether these mutations also occur in SNMM. Our aim was to determine the TERT promoter mutation frequencies in primary SNMMs. Laser capture microdissection and manual dissection were used to isolate tumour cells from 49 formalin-fixed paraffin-embedded tissues. The tumours were screened for TERT promoter mutations by direct Sanger sequencing. Information on NRAS, BRAF and KIT mutation was available from an earlier study. Overall, 8% (4/49) of SNMMs harboured TERT promoter mutations. One of these mutated tumours had a coexistent NRAS mutation and one had a BRAF mutation. Our findings show that TERT promoter mutations are present in a moderate proportion of SNMM. No conclusion can be drawn on their potential influence on the clinical outcome or tumour progression.

  10. [HPV-associated head and neck cancer : mutational signature and genomic aberrations].

    PubMed

    Wagner, S; Würdemann, N; Hübbers, C; Reuschenbach, M; Prigge, E-S; Wichmann, G; Hess, J; Dietz, A; Dürst, M; Tinhofer, I; von Knebel-Döberitz, M; Wittekindt, C; Klussmann, J P

    2015-11-01

    A significantly increasing proportion of oropharyngeal head and neck carcinomas (OSCC) in North America and Europe are associated with human papillomavirus (HPV) infections. HPV-related OSCC is regarded as a distinct tumor type with regard to its cellular, biologic, and clinical characteristics. Patients with HPV-related OSCC have significantly better local control, but higher rates of regional lymph node and distant metastases as compared to patients with HPV-negative OSCC. Classical molecular genetic investigations demonstrated specific chromosomal aberration signatures in HPV-related OSCC, and recent developments in next generation sequencing (NGS) technology have rendered possible the sequencing of entire genomes, and thus detection of specific mutations, in just a few days. Initial data from The Cancer Genome Atlas (TCGA) project obtained by using genome-wide high throughput methods have confirmed that HPV-related OSCC contain fewer, albeit more specific mutations than HPV-negative tumors. Additionally, these data revealed the presence of specific-potentially therapeutically targetable-activating driver mutations in subgroups of HPV-positive OSCC, some of which have a prognostic impact. Specific targeted NGS technologies provide new possibilities for identification of diagnostic, prognostic, and predictive biomarkers and the development of personalized cancer treatment. Patients with HPV-positive tumors are likely to profit from these developments in the future, since the genetic alterations are relatively homogenous and frequently lead to signal pathway activation. There is an urgent need for network research activities to carry out the necessary basic research in prospective cohort studies.

  11. Stability analysis of automobile driver steering control

    NASA Technical Reports Server (NTRS)

    Allen, R. W.

    1981-01-01

    In steering an automobile, the driver must basically control the direction of the car's trajectory (heading angle) and the lateral deviation of the car relative to a delineated pathway. A previously published linear control model of driver steering behavior which is analyzed from a stability point of view is considered. A simple approximate expression for a stability parameter, phase margin, is derived in terms of various driver and vehicle control parameters, and boundaries for stability are discussed. A field test study is reviewed that includes the measurement of driver steering control parameters. Phase margins derived for a range of vehicle characteristics are found to be generally consistent with known adaptive properties of the human operator. The implications of these results are discussed in terms of driver adaptive behavior.

  12. Modeling of Driver Steering Operations in Lateral Wind Disturbances toward Driver Assistance System

    NASA Astrophysics Data System (ADS)

    Kurata, Yoshinori; Wada, Takahiro; Kamiji, Norimasa; Doi, Shun'ichi

    Disturbances decrease vehicle stability and increase driver's mental and physical workload. Especially unexpected disturbances such as lateral winds have severe effect on vehicle stability and driver's workload. This study aims at building a driver model of steering operations in lateral wind toward developing effective driver assistance system. First, the relationship between the driver's lateral motion and its reactive quick steering behavior is investigated using driving simulator with lateral 1dof motion. In the experiments, four different wind patterns are displayed by the simulator. As the results, strong correlation was found between the driver's head lateral jerk by the lateral disturbance and the angular acceleration of the steering wheel. Then, we build a mathematical model of driver's steering model from lateral disturbance input to steering torque of the reactive quick feed-forward steering based on the experimental results. Finally, validity of the proposed model is shown by comparing the steering torque of experimental results and that of simulation results.

  13. Mutations affecting enzymatic activity in liver arginase

    SciTech Connect

    Vockley, J.G.; Tabor, D.E.; Goodman, B.K.

    1994-09-01

    The hydrolysis of arginine to ornithine and urea is catalyzed by arginase in the last step of the urea cycle. We examined a group of arginase deficient patients by PCR-SSCP analysis to characterize the molecular basis of this disorder. A heterogeneous population of nonsense mutations, microdeletions, and missense mutations has been identified in our cohort. Microdeletions which introduce premature stop codons downstream of the deletion and nonsense mutations result in no arginase activity. These mutations occur randomly along the gene. The majority of missense mutations identified appear to occur in regions of high cross-species homology. To test the effect of these missense mutations on arginase activity, site-directed mutagenesis was used to re-create the patient mutations for in vivo expression studies in a prokaryotic fusion-protein expression system. Of 4 different missense mutations identified in 6 individuals, only one was located outside of a conserved region. The three substitution mutations within the conserved regions had a significant effect on enzymatic activity (0-3.1 nmole/30min, normal is 1300-1400 nmoles/30min, as determined by in vitro arginase assay), while the fourth mutation, a T to S substitution, did not. In addition, site-directed mutagenesis was utilized to create mutations not in residues postulated to play a significant role in the enzymatic function or active site formation in manganese-binding proteins such as arginase. We have determined that the substitution of glycine for a histidine residue, located in a very highly conserved region of exon 3, and the substitution of a histidine and an aspartic acid residue within a similarly conserved region in exon 4, totally abolishes enzymatic activity. Mutations substituting glycine for an additional histidine and aspartic acid residue in exon 4 and two aspartic acid residues in exon 7 have also been created. We are currently in the process of characterizing these mutations.

  14. Modeling aggressive driver behavior at unsignalized intersections.

    PubMed

    Kaysi, Isam A; Abbany, Ali S

    2007-07-01

    The processing of vehicles at unsignalized intersections is a complex and highly interactive process, whereby each driver makes individual decisions about when, where, and how to complete the required maneuver, subject to his perceptions of distances, velocities, and own car's performance. Typically, the performance of priority-unsignalized intersections has been modeled with probabilistic approaches that consider the distribution of gaps in the major-traffic stream and their acceptance by the drivers of minor street vehicles based on the driver's "critical gap". This paper investigates the aggressive behavior of minor street vehicles at intersections that are priority-unsignalized but operate with little respect of control measures. The objective is to formulate a behavioral model that predicts the probability that a driver performs an aggressive maneuver as a function of a set of driver and traffic attributes. Parameters that were tested and modeled include driver characteristics (gender and age), car characteristics (performance and model year), and traffic attributes (number of rejected gaps, total waiting time at head of queue, and major-traffic speed). Binary probit models are developed and tested, based on a collected data set from an unsignalized intersection in the city of Beirut, to determine which of the studied variables are statistically significant in determining the aggressiveness of a specific driver. Primary conclusions reveal that age, car performance, and average speed on the major road are the major determinants of aggressive behavior. Another striking conclusion is that the total waiting time of the driver while waiting for an acceptable gap is of little significance in incurring the "forcing" behavior. The obtained model is incorporated in a simple simulation framework that reflects driver behavior and traffic stream interactions in estimating delay and conflict measures at unsignalized intersections. The simulation results were then compared

  15. Mouse models for the discovery of colorectal cancer driver genes

    PubMed Central

    Clark, Christopher R; Starr, Timothy K

    2016-01-01

    Colorectal cancer (CRC) constitutes a major public health problem as the third most commonly diagnosed and third most lethal malignancy worldwide. The prevalence and the physical accessibility to colorectal tumors have made CRC an ideal model for the study of tumor genetics. Early research efforts using patient derived CRC samples led to the discovery of several highly penetrant mutations (e.g., APC, KRAS, MMR genes) in both hereditary and sporadic CRC tumors. This knowledge has enabled researchers to develop genetically engineered and chemically induced tumor models of CRC, both of which have had a substantial impact on our understanding of the molecular basis of CRC. Despite these advances, the morbidity and mortality of CRC remains a cause for concern and highlight the need to uncover novel genetic drivers of CRC. This review focuses on mouse models of CRC with particular emphasis on a newly developed cancer gene discovery tool, the Sleeping Beauty transposon-based mutagenesis model of CRC. PMID:26811627

  16. Mouse models for the discovery of colorectal cancer driver genes.

    PubMed

    Clark, Christopher R; Starr, Timothy K

    2016-01-14

    Colorectal cancer (CRC) constitutes a major public health problem as the third most commonly diagnosed and third most lethal malignancy worldwide. The prevalence and the physical accessibility to colorectal tumors have made CRC an ideal model for the study of tumor genetics. Early research efforts using patient derived CRC samples led to the discovery of several highly penetrant mutations (e.g., APC, KRAS, MMR genes) in both hereditary and sporadic CRC tumors. This knowledge has enabled researchers to develop genetically engineered and chemically induced tumor models of CRC, both of which have had a substantial impact on our understanding of the molecular basis of CRC. Despite these advances, the morbidity and mortality of CRC remains a cause for concern and highlight the need to uncover novel genetic drivers of CRC. This review focuses on mouse models of CRC with particular emphasis on a newly developed cancer gene discovery tool, the Sleeping Beauty transposon-based mutagenesis model of CRC.

  17. Relevance of ID3-TCF3-CCND3 pathway mutations in pediatric aggressive B-cell lymphoma treated according to the NHL-BFM protocols.

    PubMed

    Rohde, Marius; Bonn, Bettina R; Zimmermann, Martin; Lange, Jonas; Möricke, Anja; Klapper, Wolfram; Oschlies, Ilske; Szczepanowski, Monika; Nagel, Inga; Schrappe, Martin; Loeffler, Markus; Siebert, Reiner; Reiter, Alfred; Burkhardt, Birgit

    2017-02-16

    Mature B-cell Non-Hodgkin lymphoma is the most common subtype of Non-Hodgkin lymphoma in childhood and adolescence. B-cell Non-Hodgkin lymphoma are further classified into histological subtypes, with Burkitt lymphoma and Diffuse large B-cell lymphoma being the most common subgroups in pediatric patients. Translocations involving the MYC oncogene are known as relevant but not sufficient hit for Burkitt lymphoma pathogenesis. Recently published large-scale next-generation sequencing studies unveiled sets of additional recurrently mutated genes in samples of pediatric and adult B-cell Non-Hodgkin lymphoma patients. ID3, TCF3 and CCND3 are potential drivers of Burkitt-lymphomagenesis. In the present study frequency and clinical relevance of mutations in ID3, TCF3 and CCND3 were analyzed within a well-defined cohort of 84 uniformly diagnosed and treated pediatric B-cell Non-Hodgkin lymphoma patients of the Berlin-Frankfurt-Munster group (NHL-BFM). Mutation frequency was 78% (ID3), 13% (TCF3) and 36% (CCND3) in Burkitt lymphoma (including Burkitt leukemia). ID3 and CCND3 mutations were associated with more advanced stages of the disease in MYC rearrangement positive Burkitt lymphoma. In conclusion ID3-TCF3-CCND3 pathway genes are mutated in more than 88% of MYC-rearranged pediatric B-cell Non-Hodgkin lymphoma and the pathway may represent a highly relevant second hit of Burkitt lymphoma pathogenesis especially in children and adolescents.

  18. Chromatin accessibility contributes to simultaneous mutations of cancer genes

    PubMed Central

    Shi, Yi; Su, Xian-Bin; He, Kun-Yan; Wu, Bing-Hao; Zhang, Bo-Yu; Han, Ze-Guang

    2016-01-01

    Somatic mutations of many cancer genes tend to co-occur (termed co-mutations) in certain patterns during tumor initiation and progression. However, the genetic and epigenetic mechanisms that contribute to the co-mutations of these cancer genes have yet to be explored. Here, we systematically investigated the association between the somatic co-mutations of cancer genes and high-order chromatin conformation. Significantly, somatic point co-mutations in protein-coding genes were closely associated with high-order spatial chromatin folding. We propose that these regions be termed Spatial Co-mutation Hotspots (SCHs) and report their occurrence in different cancer types. The conserved mutational signatures and DNA sequences flanking these point co-mutations, as well as CTCF-binding sites, are also enriched within the SCH regions. The genetic alterations that are harboured in the same SCHs tend to disrupt cancer driver genes involved in multiple signalling pathways. The present work demonstrates that high-order spatial chromatin organisation may contribute to the somatic co-mutations of certain cancer genes during tumor development. PMID:27762310

  19. Comparison of teen and adult driver crash scenarios in a nationally representative sample of serious crashes.

    PubMed

    McDonald, Catherine C; Curry, Allison E; Kandadai, Venk; Sommers, Marilyn S; Winston, Flaura K

    2014-11-01

    Motor vehicle crashes are the leading cause of death and acquired disability during the first four decades of life. While teen drivers have the highest crash risk, few studies examine the similarities and differences in teen and adult driver crashes. We aimed to: (1) identify and compare the most frequent crash scenarios-integrated information on a vehicle's movement prior to crash, immediate pre-crash event, and crash configuration-for teen and adult drivers involved in serious crashes, and (2) for the most frequent scenarios, explore whether the distribution of driver critical errors differed for teens and adult drivers. We analyzed data from the National Motor Vehicle Crash Causation Survey, a nationally representative study of serious crashes conducted by the U.S. National Highway Traffic Safety Administration from 2005 to 2007. Our sample included 642 16- to 19-year-old and 1167 35- to 54-year-old crash-involved drivers (weighted n=296,482 and 439,356, respectively) who made a critical error that led to their crash's critical pre-crash event (i.e., event that made the crash inevitable). We estimated prevalence ratios (PR) and 95% confidence intervals (CI) to compare the relative frequency of crash scenarios and driver critical errors. The top five crash scenarios among teen drivers, accounting for 37.3% of their crashes, included: (1) going straight, other vehicle stopped, rear end; (2) stopped in traffic lane, turning left at intersection, turn into path of other vehicle; (3) negotiating curve, off right edge of road, right roadside departure; (4) going straight, off right edge of road, right roadside departure; and (5) stopped in lane, turning left at intersection, turn across path of other vehicle. The top five crash scenarios among adult drivers, accounting for 33.9% of their crashes, included the same scenarios as the teen drivers with the exception of scenario (3) and the addition of going straight, crossing over an intersection, and continuing on a

  20. Exome sequencing of osteosarcoma reveals mutation signatures reminiscent of BRCA deficiency.

    PubMed

    Kovac, Michal; Blattmann, Claudia; Ribi, Sebastian; Smida, Jan; Mueller, Nikola S; Engert, Florian; Castro-Giner, Francesc; Weischenfeldt, Joachim; Kovacova, Monika; Krieg, Andreas; Andreou, Dimosthenis; Tunn, Per-Ulf; Dürr, Hans Roland; Rechl, Hans; Schaser, Klaus-Dieter; Melcher, Ingo; Burdach, Stefan; Kulozik, Andreas; Specht, Katja; Heinimann, Karl; Fulda, Simone; Bielack, Stefan; Jundt, Gernot; Tomlinson, Ian; Korbel, Jan O; Nathrath, Michaela; Baumhoer, Daniel

    2015-12-03

    Osteosarcomas are aggressive bone tumours with a high degree of genetic heterogeneity, which has historically complicated driver gene discovery. Here we sequence exomes of 31 tumours and decipher their evolutionary landscape by inferring clonality of the individual mutation events. Exome findings are interpreted in the context of mutation and SNP array data from a replication set of 92 tumours. We identify 14 genes as the main drivers, of which some were formerly unknown in the context of osteosarcoma. None of the drivers is clearly responsible for the majority of tumours and even TP53 mutations are frequently mapped into subclones. However, >80% of osteosarcomas exhibit a specific combination of single-base substitutions, LOH, or large-scale genome instability signatures characteristic of BRCA1/2-deficient tumours. Our findings imply that multiple oncogenic pathways drive chromosomal instability during osteosarcoma evolution and result in the acquisition of BRCA-like traits, which could be therapeutically exploited.

  1. Melanomas of unknown primary frequently harbor TERT-promoter mutations.

    PubMed

    Egberts, Friederike; Krüger, Sandra; Behrens, Hans M; Bergner, Inka; Papaspyrou, Giorgios; Werner, Jochen A; Alkatout, Ibrahim; Haag, Jochen; Hauschild, Axel; Röcken, Christoph

    2014-04-01

    Commonly, in patients with melanoma metastases of an unknown primary tumor (MUP), an extensive search for the primary tumor is carried out. Recently, highly recurrent telomerase reverse transcriptase (TERT)-promoter mutations were found in malignant melanomas, which may function as driver mutations of skin cancer. The aim of this study was to test the hypothesis that MUP and mucosal melanomas harbor different prevalences of TERT-promoter mutations. Thirty-nine patients with MUP and 53 patients with mucosal melanomas were retrieved. In total, 152 paraffin samples of 92 patients were analyzed, and in 38 patients, multiple samples were tested. Mutational analysis of the TERT-promoter, BRAF, NRAS, and KIT genes was carried out. In total, 92 patients were eligible for mutational analysis. TERT-promoter mutations were found in 33 patients (35.9%): chr5, 1,295,228 C>T (18 patients); chr5, 1,295,250 C>T (11 patients); chr5, 1,295,228-229 CC>TT (three patients); chr5, 1,295,242-243 CC>TT (one patient). The mutations were significantly more prevalent in MUP [26 (66.7%)] than in mucosal melanomas [seven patients (13.2%); P<0.001]. In MUP, BRAF mutations were found in 46.2% of patients (18 patients) and NRAS mutations in 28.2% of patients (11 patients). In mucosal melanoma, NRAS mutations were found in 18.9% of patients (10), and BRAF and KIT mutations in 7.5% of patients (four patients), respectively. The prevalence of TERT-promoter mutations was associated with the patient's sex [23 (51.1%) men, 10 (21.3%) women; P=0.004]. No significant correlation was found between TERT-mutation and patient survival. The TERT-promoter genotype of MUP points toward a cutaneous and not mucosal origin. The significant sex differences merit further attention in having putative therapeutic implications.

  2. Evaluation of Driver Stress Using Motor-vehicle Driving Simulator

    NASA Astrophysics Data System (ADS)

    Deguchi, Mitsuo; Wakasugi, Junichi; Ikegami, Tatsuya; Nanba, Shinji; Yamaguchi, Masaki

    This paper proposes a method for evaluating driver stress using a motor-vehicle driving simulator and a biomarker as an index of stress. Software has been developed, which can deliberately control driving tasks, in addition to analyzing driving information, such as frequency of the use of accelerator and/or brakes and the degree of deviation from the driving course. Sympathetic nervous activity was noninvasively evaluated using a hand-held monitor of salivary amylase activity, which chemically measured a biomarker every few minutes. Using healthy 20 female adults, the appropriateness of the proposed method was evaluated in vivo. The experimental results showed that the driving stress might be caused to the drivers in only 20 minutes by adding more severe driving tasks than normally experienced by the subjects without endangering them. Furthermore, the result indicate that frequent measurements of sympathetic nervous activity were possible without putting the subjects under restraint by using salivary amylase activity as the index.

  3. Seasonal and Weather Effects on Older Drivers' Trip Distances.

    PubMed

    Smith, Glenys A; Porter, Michelle M; Cull, Andrew W; Mazer, Barbara L; Myers, Anita M; Naglie, Gary; Bédard, Michel; Tuokko, Holly A; Vrkljan, Brenda H; Gélinas, Isabelle; Marshall, Shawn C; Rapoport, Mark J

    2016-04-05

    The purpose of this study was to determine if season or weather affected the objectively measured trip distances of older drivers (≥ 70 years; n = 279) at seven Canadian sites. During winter, for all trips taken, trip distance was 7 per cent shorter when controlling for site and whether the trip occurred during the day. In addition, for trips taken within city limits, trip distance was 1 per cent shorter during winter and 5 per cent longer during rain when compared to no precipitation when controlling for weather (or season respectively), time of day, and site. At night, trip distance was about 30 per cent longer when controlling for season and site (and weather), contrary to expectations. Together, these results suggest that older Canadian drivers alter their trip distances based on season, weather conditions, and time of day, although not always in the expected direction.

  4. Effects of a driver enforcement program on yielding to pedestrians.

    PubMed Central

    Van Houten, Ron; Malenfant, J E Louis

    2004-01-01

    A driver-yielding enforcement program that included decoy pedestrians, feedback flyers, written and verbal warnings, and saturation enforcement for a 2-week period was evaluated in the city of Miami Beach using a multiple baseline design. During baseline, data were collected at crosswalks along two major corridors. Treatment was introduced first at selected crosswalks without traffic signals along one corridor. A week later, enforcement was shifted to crosswalks along the second corridor. Results indicated that the percentage of drivers yielding to pedestrians increased following the introduction of the enforcement program in each corridor and that these increases were sustained for a period of a year with minimal additional enforcement. The effects also generalized somewhat to untreated crosswalks in both corridors, as well as to crosswalks with traffic signals. PMID:15529891

  5. Displaceable spur gear torque controlled driver and method

    NASA Technical Reports Server (NTRS)

    Cook, Joseph S., Jr. (Inventor)

    1994-01-01

    Methods and apparatus are provided for a torque driver including a laterally displaceable gear support member to carry an output spur gear. A biasing assembly biases the output spur gear into engagement with a pinion to which is applied an input torque greater than a desired output torque limit for a threaded fastener such as a nut or screw. A coiled output linkage connects the output spur gear with a fastener adaptor which may be a socket for a nut. A gear tooth profile provides a separation force that overcomes the bias to limit torque at the desired torque limit. Multiple fasteners may be rotated simultaneously to a desired torque limit if additional output spur gears are provided. A gauged selector mechanism is provided to laterally displace multiple driver members for fasteners arranged in differing configurations. The torque limit is selectably adjustable and may be different for fasteners within the same fastener configuration.

  6. Displaceable spur gear torque controlled driver and method

    NASA Astrophysics Data System (ADS)

    Cook, Joseph S., Jr.

    1994-08-01

    Methods and apparatus are provided for a torque driver including a laterally displaceable gear support member to carry an output spur gear. A biasing assembly biases the output spur gear into engagement with a pinion to which is applied an input torque greater than a desired output torque limit for a threaded fastener such as a nut or screw. A coiled output linkage connects the output spur gear with a fastener adaptor which may be a socket for a nut. A gear tooth profile provides a separation force that overcomes the bias to limit torque at the desired torque limit. Multiple fasteners may be rotated simultaneously to a desired torque limit if additional output spur gears are provided. A gauged selector mechanism is provided to laterally displace multiple driver members for fasteners arranged in differing configurations. The torque limit is selectably adjustable and may be different for fasteners within the same fastener configuration.

  7. Does advanced driver training improve situational awareness?

    PubMed

    Walker, Guy H; Stanton, Neville A; Kazi, Tara A; Salmon, Paul M; Jenkins, Daniel P

    2009-07-01

    Over 70 years of experiential evidence suggests that a specific form of advanced driver training, one based on an explicit system of car control, improves driver situation awareness (SA). Five experimental hypotheses are developed. They propose that advanced driving should increase the number of information elements in the driver's working memory, increase the interconnection between those elements, increase the amount of 'new' information in memory as well as the prominence of existing information, and that finally, it should stimulate behaviours that help drivers evolve better situations to be aware of. An approach to SA based on Neisser's perceptual cycle theory is anchored to a network based methodology. This is applied within the context of a longitudinal on-road study involving three groups of 25 drivers, all of whom were measured pre- and post-intervention. One experimental group was subject to advanced driver training and two further groups provided control for time and for being accompanied whilst driving. Empirical support is found for all five hypotheses. Advanced driving does improve driver SA but not necessarily in the way that existing situation focused, closed loop models of the concept might predict.

  8. Drivers' behaviour at roundabouts in Riyadh.

    PubMed

    Al-Saleh, K; Bendak, S

    2012-01-01

    As is the case in many cities, roundabouts are used extensively in Riyadh. However, instead of improving safety, driving through roundabouts in Riyadh can be a dangerous experience as many drivers do not follow regulations. Unfortunately, no official statistics exist on accidents or violations at roundabouts and no studies have been done to assess this problem. A field study to collect data on drivers' behaviour at five roundabouts in Riyadh was done and a questionnaire was randomly distributed to drivers to explore this issue. Results showed that the percentage of drivers breaching at least one traffic regulation is approximately 90% of all drivers driving through these roundabouts, with leaving without flashing and entering the roundabout without giving way being the most frequent violation types. Questionnaire results from 384 respondents showed that there is a lack of information among most drivers on roundabout driving regulations and that driver training and licensing process does not include enough information related to this matter. Finally, practical suggestions as how to tackle this issue in terms of education, training and policing are given.

  9. Too Many Mutants with Multiple Mutations

    PubMed Central

    Drake, John W.

    2007-01-01

    It has recently become clear that the classical notion of the random nature of mutation does not hold for the distribution of mutations among genes: most collections of mutants contain more isolates with two or more mutations than predicted by the mutant frequency on the assumption of a random distribution of mutations. Excesses of multiples are seen in a wide range of organisms, including riboviruses, DNA viruses, prokaryotes, yeasts, and higher eukaryotic cell lines and tissues. In addition, such excesses are produced by DNA polymerases in vitro. These “multiples” appear to be generated by transient, localized hypermutation rather than by heritable mutator mutations. The components of multiples are sometimes scattered at random and sometimes display an excess of smaller distances between mutations. As yet, almost nothing is known about the mechanisms that generate multiples, but such mutations have the capacity to accelerate those evolutionary pathways that require multiple mutations where the individual mutations are neutral or deleterious. Examples that impinge on human health may include carcinogenesis and the adaptation of microbial pathogens as they move between individual hosts. PMID:17687667

  10. Too many mutants with multiple mutations.

    PubMed

    Drake, John W

    2007-01-01

    It has recently become clear that the classical notion of the random nature of mutation does not hold for the distribution of mutations among genes: most collections of mutants contain more isolates with two or more mutations than predicted by the mutant frequency on the assumption of a random distribution of mutations. Excesses of multiples are seen in a wide range of organisms, including riboviruses, DNA viruses, prokaryotes, yeasts, and higher eukaryotic cell lines and tissues. In addition, such excesses are produced by DNA polymerases in vitro. These "multiples" appear to be generated by transient, localized hypermutation rather than by heritable mutator mutations. The components of multiples are sometimes scattered at random and sometimes display an excess of smaller distances between mutations. As yet, almost nothing is known about the mechanisms that generate multiples, but such mutations have the capacity to accelerate those evolutionary pathways that require multiple mutations where the individual mutations are neutral or deleterious. Examples that impinge on human health may include carcinogenesis and the adaptation of microbial pathogens as they move between individual hosts.

  11. Evaluating the within-host fitness effects of mutations fixed during virus adaptation to different ecotypes of a new host

    PubMed Central

    Hillung, Julia; Cuevas, José M.; Elena, Santiago F.

    2015-01-01

    The existence of genetic variation for resistance in host populations is assumed to be essential to the spread of an emerging virus. Models predict that the rate of spread slows down with the increasing frequency and higher diversity of resistance alleles in the host population. We have been using the experimental pathosystem Arabidopsis thaliana—tobacco etch potyvirus (TEV) to explore the interplay between genetic variation in host's susceptibility and virus diversity. We have recently shown that TEV populations evolving in A. thaliana ecotypes that differ in susceptibility to infection gained within-host fitness, virulence and infectivity in a manner compatible with a gene-for-gene model of host–parasite interactions: hard-to-infect ecotypes were infected by generalist viruses, whereas easy-to-infect ecotypes were infected by every virus. We characterized the genomes of the evolved viruses and found cases of host-driven convergent mutations. To gain further insights in the mechanistic basis of this gene-for-gene model, we have generated all viral mutations individually as well as in specific combinations and tested their within-host fitness effects across ecotypes. Most of these mutations were deleterious or neutral in their local ecotype and only a very reduced number had a host-specific beneficial effect. We conclude that most of the mutations fixed during the evolution experiment were so by drift or by selective sweeps along with the selected driver mutation. In addition, we evaluated the ruggedness of the underlying adaptive fitness landscape and found that mutational effects were mostly multiplicative, with few cases of significant epistasis. PMID:26150658

  12. Evaluating the within-host fitness effects of mutations fixed during virus adaptation to different ecotypes of a new host.

    PubMed

    Hillung, Julia; Cuevas, José M; Elena, Santiago F

    2015-08-19

    The existence of genetic variation for resistance in host populations is assumed to be essential to the spread of an emerging virus. Models predict that the rate of spread slows down with the increasing frequency and higher diversity of resistance alleles in the host population. We have been using the experimental pathosystem Arabidopsis thaliana-tobacco etch potyvirus (TEV) to explore the interplay between genetic variation in host's susceptibility and virus diversity. We have recently shown that TEV populations evolving in A. thaliana ecotypes that differ in susceptibility to infection gained within-host fitness, virulence and infectivity in a manner compatible with a gene-for-gene model of host-parasite interactions: hard-to-infect ecotypes were infected by generalist viruses, whereas easy-to-infect ecotypes were infected by every virus. We characterized the genomes of the evolved viruses and found cases of host-driven convergent mutations. To gain further insights in the mechanistic basis of this gene-for-gene model, we have generated all viral mutations individually as well as in specific combinations and tested their within-host fitness effects across ecotypes. Most of these mutations were deleterious or neutral in their local ecotype and only a very reduced number had a host-specific beneficial effect. We conclude that most of the mutations fixed during the evolution experiment were so by drift or by selective sweeps along with the selected driver mutation. In addition, we evaluated the ruggedness of the underlying adaptive fitness landscape and found that mutational effects were mostly multiplicative, with few cases of significant epistasis.

  13. Determining the drivers' acceptance of EFTCD in highway work zones.

    PubMed

    Bai, Yong; Li, Yingfeng

    2011-05-01

    Traffic safety is a major concern in the temporary one-lane, two-way highway work zones due to the increasing of construction and maintenance operations. To prevent rear-end crashes and to mitigate the severity of these crashes caused by the inattentive driving, the utilization of the Emergency Flasher Traffic Control Device (EFTCD) was under consideration by government agencies, in addition to existing temporary traffic control devices installed in the one-lane, two-way highway work zones. The EFTCD was a newly proposed traffic warning device implemented through the use of vehicles' hazard warning flashers. The primary objective of the research project was to investigate the drivers' acceptance of the proposed EFTCD by measuring the mean speed changes of vehicles with and without EFTCD and by evaluating the drivers' opinions of the EFTCD using the survey method. Field experimental results revealed that the EFTCD effectively reduced the mean vehicle speeds in the upstream of two work zones. A slow speed is more likely to reduce the severity of a crash in work zones. In addition, survey results indicated that 60% of the drivers thought the EFTCD signified a need for speed reduction and 82% of drivers recommended the implementation of the EFTCD in one-lane, two-way work zones. These results provide the necessary scientific justifications for the government agencies to decide if the EFTCD should be implemented in the one-lane, two-way highway work zones to prevent rear-end crashes and to mitigate the severity of these crashes.

  14. Measurement of driver calibration and the impact of feedback on drivers' estimates of performance.

    PubMed

    Roberts, Shannon C; Horrey, William J; Liang, Yulan

    2016-03-01

    Recent studies focused on driver calibration show that drivers are often miscalibrated, either over confident or under confident, and the magnitude of this miscalibration changes under different conditions. Previous work has demonstrated behavioral and performance benefits of feedback, yet these studies have not explicitly examined the issue of calibration. The objective of this study was to examine driver calibration, i.e., the degree to which drivers are accurately aware of their performance, and determine whether feedback alters driver calibration. Twenty-four drivers completed a series of driving tasks (pace clocks, traffic light, speed maintenance, and traffic cones) on a test track. Drivers drove three different blocks around the test track: (1) baseline block, where no participants received feedback; (2) feedback block, where half of the participants received performance feedback while the other half received no feedback; (3) a no feedback block, where no participants received feedback. Results indicated that across two different calibration measures, drivers were sufficiently calibrated to the pace clocks, traffic light, and traffic cone tasks. Drivers were not accurately aware of their performance regarding speed maintenance, though receiving feedback on this task improved calibration. Proper and accurate measurements of driver calibration are needed before designing performance feedback to improve calibration as these feedback systems may not always yield the intended results.

  15. The sleep of commercial vehicle drivers under the 2003 hours-of-service regulations.

    PubMed

    Hanowski, Richard J; Hickman, Jeffery; Fumero, Maria C; Olson, Rebecca L; Dingus, Thomas A

    2007-11-01

    Previous research has found that commercial drivers get an average of 5.18 h of sleep per night. The revised hours-of-service (HOS) regulations (in the United States) are in place to provide drivers with more opportunities to get sleep. However, are drivers really getting more sleep under these new regulations? Also, is there a relationship between sleep quantity and involvement in critical incident (crashes, near-crashes, or crash-relevant conflicts)? Data from 73 truck drivers, collected during a naturalistic driving study after the implementation of the 2003 HOS regulations, were analyzed to determine overall sleep quantity (using actigraphy), along with sleep quantity prior to being involved in a critical incident. Sixty-two drivers had at least seven consecutive days (Monday through Sunday) of reliable actigraphy data; mean sleep quantity per 24-h period (midnight centered using the Cole-Kripke algorithm) for these drivers was 6.28 h (S.D.=1.42 h). Fifty-eight critical incidents were recorded in the 10th and 11th driving hours. Analysis results indicated that drivers received significantly less sleep in the period prior to a critical incident as compared to their mean overall sleep quantity. The results of this study indicate drivers may be getting more sleep under the revised 2003 HOS regulations as compared to the old regulations. In addition, significantly less sleep in the 24-h period prior to involvement in a critical incident suggests driver fatigue may have been a potential contributing factor in these critical incidents.

  16. A parametric duration model of the reaction times of drivers distracted by mobile phone conversations.

    PubMed

    Haque, Md Mazharul; Washington, Simon

    2014-01-01

    The use of mobile phones while driving is more prevalent among young drivers-a less experienced cohort with elevated crash risk. The objective of this study was to examine and better understand the reaction times of young drivers to a traffic event originating in their peripheral vision whilst engaged in a mobile phone conversation. The CARRS-Q advanced driving simulator was used to test a sample of young drivers on various simulated driving tasks, including an event that originated within the driver's peripheral vision, whereby a pedestrian enters a zebra crossing from a sidewalk. Thirty-two licensed drivers drove the simulator in three phone conditions: baseline (no phone conversation), hands-free and handheld. In addition to driving the simulator each participant completed questionnaires related to driver demographics, driving history, usage of mobile phones while driving, and general mobile phone usage history. The participants were 21-26 years old and split evenly by gender. Drivers' reaction times to a pedestrian in the zebra crossing were modelled using a parametric accelerated failure time (AFT) duration model with a Weibull distribution. Also tested where two different model specifications to account for the structured heterogeneity arising from the repeated measures experimental design. The Weibull AFT model with gamma heterogeneity was found to be the best fitting model and identified four significant variables influencing the reaction times, including phone condition, driver's age, license type (provisional license holder or not), and self-reported frequency of usage of handheld phones while driving. The reaction times of drivers were more than 40% longer in the distracted condition compared to baseline (not distracted). Moreover, the impairment of reaction times due to mobile phone conversations was almost double for provisional compared to open license holders. A reduction in the ability to detect traffic events in the periphery whilst distracted

  17. Cancer-associated noncoding mutations affect RNA G-quadruplex-mediated regulation of gene expression.

    PubMed

    Zeraati, Mahdi; Moye, Aaron L; Wong, Jason W H; Perera, Dilmi; Cowley, Mark J; Christ, Daniel U; Bryan, Tracy M; Dinger, Marcel E

    2017-04-06

    Cancer is a multifactorial disease driven by a combination of genetic and environmental factors. Many cancer driver mutations have been characterised in protein-coding regions of the genome. However, mutations in noncoding regions associated with cancer have been less investigated. G-quadruplex (G4) nucleic acids are four-stranded secondary structures formed in guanine-rich sequences and prevalent in the regulatory regions. In this study, we used published whole cancer genome sequence data to find mutations in cancer patients that overlap potential RNA G4-forming sequences in 5' UTRs. Using RNAfold, we assessed the effect of these mutations on the thermodynamic stability of predicted RNA G4s in the context of full-length 5' UTRs. Of the 217 identified mutations, we found that 33 are predicted to destabilise and 21 predicted to stabilise potential RNA G4s. We experimentally validated the effect of destabilising mutations in the 5' UTRs of BCL2 and CXCL14 and one stabilising mutation in the 5' UTR of TAOK2. These mutations resulted in an increase or a decrease in translation of these mRNAs, respectively. These findings suggest that mutations that modulate the G4 stability in the noncoding regions could act as cancer driver mutations, which present an opportunity for early cancer diagnosis using individual sequencing information.

  18. Camera-based driver assistance systems

    NASA Astrophysics Data System (ADS)

    Grimm, Michael

    2013-04-01

    In recent years, camera-based driver assistance systems have taken an important step: from laboratory setup to series production. This tutorial gives a brief overview on the technology behind driver assistance systems, presents the most significant functionalities and focuses on the processes of developing camera-based systems for series production. We highlight the critical points which need to be addressed when camera-based driver assistance systems are sold in their thousands, worldwide - and the benefit in terms of safety which results from it.

  19. The Candidate Cancer Gene Database: a database of cancer driver genes from forward genetic screens in mice.

    PubMed

    Abbott, Kenneth L; Nyre, Erik T; Abrahante, Juan; Ho, Yen-Yi; Isaksson Vogel, Rachel; Starr, Timothy K

    2015-01-01

    Identification of cancer driver gene mutations is crucial for advancing cancer therapeutics. Due to the overwhelming number of passenger mutations in the human tumor genome, it is difficult to pinpoint causative driver genes. Using transposon mutagenesis in mice many laboratories have conducted forward genetic screens and identified thousands of candidate driver genes that are highly relevant to human cancer. Unfortunately, this information is difficult to access and utilize because it is scattered across multiple publications using different mouse genome builds and strength metrics. To improve access to these findings and facilitate meta-analyses, we developed the Candidate Cancer Gene Database (CCGD, http://ccgd-starrlab.oit.umn.edu/). The CCGD is a manually curated database containing a unified description of all identified candidate driver genes and the genomic location of transposon common insertion sites (CISs) from all currently published transposon-based screens. To demonstrate relevance to human cancer, we performed a modified gene set enrichment analysis using KEGG pathways and show that human cancer pathways are highly enriched in the database. We also used hierarchical clustering to identify pathways enriched in blood cancers compared to solid cancers. The CCGD is a novel resource available to scientists interested in the identification of genetic drivers of cancer.

  20. Mutation testing for directing upfront targeted therapy and post-progression combination therapy strategies in lung adenocarcinoma

    PubMed Central

    Salgia, Ravi

    2016-01-01

    ABSTRACT Introduction: Advances in the biology of non-small-cell lung cancer, especially adenocarcinoma, reveal multiple molecular subtypes driving oncogenesis. Accordingly, individualized targeted therapeutics are based on mutational diagnostics. Areas covered: Advances in strategies and techniques for individualized treatment, particularly of adenocarcinoma, are described through literature review. Approved therapies are established for some molecular subsets, with new driver mutations emerging that represent increasing proportions of patients. Actionable mutations are de novo oncogenic drivers or acquired resistance mediators, and mutational profiling is important for directing therapy. Patients should be monitored for emerging actionable resistance mutations. Liquid biopsy and associated multiplex diagnostics will be important means to monitor patients during treatment. Expert commentary: Outcomes with targeted agents may be improved by integrating mutation screens during treatment to optimize subsequent therapy. In order for this to be translated into impactful patient benefit, appropriate platforms and strategies need to be optimized and then implemented universally. PMID:27139190

  1. Food consumption trends and drivers

    PubMed Central

    Kearney, John

    2010-01-01

    A picture of food consumption (availability) trends and projections to 2050, both globally and for different regions of the world, along with the drivers largely responsible for these observed consumption trends are the subject of this review. Throughout the world, major shifts in dietary patterns are occurring, even in the consumption of basic staples towards more diversified diets. Accompanying these changes in food consumption at a global and regional level have been considerable health consequences. Populations in those countries undergoing rapid transition are experiencing nutritional transition. The diverse nature of this transition may be the result of differences in socio-demographic factors and other consumer characteristics. Among other factors including urbanization and food industry marketing, the policies of trade liberalization over the past two decades have implications for health by virtue of being a factor in facilitating the ‘nutrition transition’ that is associated with rising rates of obesity and chronic diseases such as cardiovascular disease and cancer. Future food policies must consider both agricultural and health sectors, thereby enabling the development of coherent and sustainable policies that will ultimately benefit agriculture, human health and the environment. PMID:20713385

  2. The proton driver design study

    SciTech Connect

    Editors: W. Chou, C.M. Ankenbrandt and E.I. Malamud

    2001-03-08

    In a 1997 summer study, a team led by Steve Holmes formulated a development plan for the Fermilab proton source and described the results in TM-2021. Subsequently, at the end of 1998, a task group was formed to prepare a detailed design of a high intensity facility called the Proton Driver to replace the Fermilab Booster. In the past two years the design effort has attracted more than fifty participants, mostly from the Beams Division. Physicists and engineers from the Technical Division and FESS as well as other institutions, including the Illinois Institute of Technology (IIT), Stanford University, University of Hawaii, CERN in Switzerland, Rutherford Appleton Laboratory in England and the IHEP in Russia also contributed heavily. The results of that effort are summarized in this document describing the design of a 16 GeV synchrotron, two new beam transport lines (a 400 MeV injection line and a 12/16 GeV extraction line), and related improvements to the present negative ion source and the 400 MeV Linac. A construction cost estimate is presented in Appendix A.

  3. Cost/performance analysis of an induction linac driver system for inertial fusion

    SciTech Connect

    Hovingh, J.; Brady, V.O.; Faltens, A.; Hoyer, E.H.; Lee, E.P.

    1985-11-01

    A linear induction accelerator that produces a beam of energetic (approx. =10 GeV) heavy (CAapprox.200) ions is a prime candidate as a driver for inertial fusion. Continuing developments in amorphous iron for use in accelerating modules represent a potentially large reduction in the driver cost and an increase in the driver efficiency. Additional insulator developments may also represent a potentially large reduction in the driver cost. The efficiency and cost of the induction linac system is discussed as a function of output energy and pulse repetition frequency for several beam charge states, numbers of beams and beam particle species. Accelerating modules and transport modules will be described. Large cost leverage items will be identified as a guide to future research activities and technology of development that can yield further substantial reductions in the accelerator system cost and improvement in the accelerator system efficiency. 13 refs., 2 figs.

  4. Influencing driver chosen cornering speed by means of modified steering feel

    NASA Astrophysics Data System (ADS)

    Rothhämel, Malte; IJkema, Jolle; Drugge, Lars

    2014-04-01

    This paper presents an investigation about influencing the driver's behaviour intuitively by means of modified steering feel. For a rollover indication through haptic feedback a model was developed and tested that returned a warning to the driver about too high vehicle speed. This was realised by modifying the experienced steering wheel torque as a function of the lateral acceleration. The hypothesis for this work was that drivers of heavy vehicles will perform with more margin of safety to the rollover threshold if the steering feel is altered by means of decreased or additionally increased steering wheel torque at high lateral acceleration. Therefore, the model was implemented in a test truck with active steering with torque overlay and used for a track test. Thirty-three drivers took part in the investigation that showed, depending on the parameter setting, a significant decrease of lateral acceleration while cornering.

  5. Generalized drivers in the mammalian endangerment process.

    PubMed

    González-Suárez, Manuela; Revilla, Eloy

    2014-01-01

    An important challenge for conservation today is to understand the endangerment process and identify any generalized patterns in how threats occur and aggregate across taxa. Here we use a global database describing main current external threats in mammals to evaluate the prevalence of distinct threatening processes, primarily of anthropogenic origin, and to identify generalized drivers of extinction and their association with vulnerability status and intrinsic species' traits. We detect several primary threat combinations that are generally associated with distinct species. In particular, large and widely distributed mammals are affected by combinations of direct exploitation and threats associated with increasing landscape modification that go from logging to intense human land-use. Meanwhile, small, narrowly distributed species are affected by intensifying levels of landscape modification but are not directly exploited. In general more vulnerable species are affected by a greater number of threats, suggesting increased extinction risk is associated with the accumulation of external threats. Overall, our findings show that endangerment in mammals is strongly associated with increasing habitat loss and degradation caused by human land-use intensification. For large and widely distributed mammals there is the additional risk of being hunted.

  6. Biomass burning a driver for global change

    SciTech Connect

    Levine, J.S.; Cofer, W.R. III; Cahoon, D.R. Jr.; Winstead, E.L.

    1995-03-01

    Recent research has identified another biospheric process that has instantaneous and longer term effects on the production of atmospheric gases: biomass burning. Biomass burning includes the burning of the world`s vegetation-forests, savannas. and agricultural lands, to clear the land and change its use. Only in the past decade have researchers realized the important contributions of biomass burning to the global budgets of many radiatively and chemically active gases - carbon dioxide, methane, nitric oxide, tropospheric ozone, methyl chloride - and elemental carbon particulates. International field experiments and satellite data are yielding a clearer understanding of this important global source of atmospheric gases and particulates. It is seen that in addition to being a significant instantaneous global source of atmospheric gases and particulates, burning enhances the biogenic emissions of nitric oxide and nitrous oxide from the world`s soils. Biomass burning affects the reflectivity and emissivity of the Earth`s surface as well as the hydrological cycle by changing rates of land evaporation and water runoff. For these reasons, it appears that biomass burning is a significant driver of global change. 20 refs., 4 figs., 2 tabs.

  7. Global coccolithophore diversity: Drivers and future change

    NASA Astrophysics Data System (ADS)

    O'Brien, Colleen J.; Vogt, Meike; Gruber, Nicolas

    2016-01-01

    We use the MAREDAT global compilation of coccolithophore species distribution and combine them with observations of climatological environmental conditions to determine the global-scale distribution of coccolithophore species diversity, its underlying drivers, and potential future changes. To this end, we developed a feed-forward neural network, which predicts 78% of the observed variance in coccolithophore diversity from environmental input variables (temperature, PAR, nitrate, silicic acid, mixed layer depth, excess phosphate (P∗) and chlorophyll). Light and temperature are the strongest predictors of coccolithophore diversity. Coccolithophore diversity is highest in the low latitudes, where coccolithophores are a relatively dominant component of the total phytoplankton community. Particularly high diversity is predicted in the western equatorial Pacific and the southern Indian Ocean, with additional peaks at approximately 30°N and 30°S. The global, zonal mean pattern is dominated by the Pacific Ocean, which shows a clear latitudinal gradient with diversity peaking at the equator, whereas in the Atlantic Ocean diversity is highest in the subtropics. We find a unimodal relationship between coccolithophore diversity and biomass, as has previously been observed for total phytoplankton assemblages. In contrast, diversity shows a negative relationship with total chlorophyll. Applying our diversity model to projections from the CMIP5 climate models, we project an increase in the diversity of coccolithophore assemblages by the end of this century.

  8. Generalized Drivers in the Mammalian Endangerment Process

    PubMed Central

    González-Suárez, Manuela; Revilla, Eloy

    2014-01-01

    An important challenge for conservation today is to understand the endangerment process and identify any generalized patterns in how threats occur and aggregate across taxa. Here we use a global database describing main current external threats in mammals to evaluate the prevalence of distinct threatening processes, primarily of anthropogenic origin, and to identify generalized drivers of extinction and their association with vulnerability status and intrinsic species' traits. We detect several primary threat combinations that are generally associated with distinct species. In particular, large and widely distributed mammals are affected by combinations of direct exploitation and threats associated with increasing landscape modification that go from logging to intense human land-use. Meanwhile, small, narrowly distributed species are affected by intensifying levels of landscape modification but are not directly exploited. In general more vulnerable species are affected by a greater number of threats, suggesting increased extinction risk is associated with the accumulation of external threats. Overall, our findings show that endangerment in mammals is strongly associated with increasing habitat loss and degradation caused by human land-use intensification. For large and widely distributed mammals there is the additional risk of being hunted. PMID:24587315

  9. Exploring the safety implications of young drivers' behavior, attitudes and perceptions.

    PubMed

    Hassan, Hany M; Abdel-Aty, Mohamed A

    2013-01-01

    The present study aims at identifying and quantifying significant factors (i.e., demographic, aberrant driving behavior) associated with young drivers' involvement in at-fault crashes or traffic citations at the ages of 16-17 (while having the Operational License) and 18-24 years old (while having the Full License). A second objective was to investigate the main reason(s) for involvement in risky driving behavior by young drivers. The data used for the analyses were obtained from a self-reported questionnaire survey carried out among 680 young drivers in Central Florida. To achieve these goals, the structural equation modeling approach was adopted. The results revealed that aggressive violations, in-vehicle distractions and demographic characteristics were the significant factors affecting young drivers' involvement in at-fault crashes or traffic violations at the age of 16-17. However, in-vehicle distractions, attitudes toward speeding and demographic characteristics were the significant factors affecting young drivers' crash risk at 18-24. Additionally, the majority of participants reported that "running late" is the main reason for taking risk while driving (i.e., speeding, accept short gaps, or drive so close to the car in front) followed by "racing other cars". Additionally, "exceed speed limits" was the main reason for receiving traffic citations at 16-17 and 18-24 age groups. Practical suggestions on how to reduce crash risk and promote safe driving among young drivers are also discussed.

  10. Mutations driving CLL and their evolution in progression and relapse

    PubMed Central

    Landau, Dan A.; Tausch, Eugen; Taylor-Weiner, Amaro N; Stewart, Chip; Reiter, Johannes G.; Bahlo, Jasmin; Kluth, Sandra; Bozic, Ivana; Lawrence, Mike; Böttcher, Sebastian; Carter, Scott L.; Cibulskis, Kristian; Mertens, Daniel; Sougnez, Carrie; Rosenberg, Mara; Hess, Julian M.; Edelmann, Jennifer; Kless, Sabrina; Kneba, Michael; Ritgen, Matthias; Fink, Anna; Fischer, Kirsten; Gabriel, Stacey; Lander, Eric; Nowak, Martin A.; Döhner, Hartmut; Hallek, Michael; Neuberg, Donna; Getz, Gad; Stilgenbauer, Stephan; Wu, Catherine J.

    2015-01-01

    SUMMARY Which genetic alterations drive tumorigenesis and how they evolve over the course of disease and therapy are central questions in cancer biology. We identify 44 recurrently mutated genes and 11 recurrent somatic copy number variations through whole-exome sequencing of 538 chronic lymphocytic leukemia (CLL) and matched germline DNA samples, 278 of which were collected in a prospective clinical trial. These include previously unrecognized cancer drivers (RPS15, IKZF3) and collectively identify RNA processing and export, MYC activity and MAPK signaling as central pathways involved in CLL. Clonality analysis of this large dataset further enabled reconstruction of temporal relationships between driver events. Direct comparison between matched pre-treatment and relapse samples from 59 patients demonstrated highly frequent clonal evolution. Thus, large sequencing datasets of clinically informative samples enable the discovery of novel cancer genes and the network of relationships between the driver events and their impact on disease relapse and clinical outcome. PMID:26466571

  11. Comparative optimism among drivers: an intergenerational portrait.

    PubMed

    Gosselin, Dominique; Gagnon, Sylvain; Stinchcombe, Arne; Joanisse, Mélanie

    2010-03-01

    We describe a large cross-sectional study examining comparative optimism (CO) regarding the risk of car crash in three age cohorts (17-26, 27-64, 65 and older). The participants completed a questionnaire in which they were asked to indicate their personal risk of being in an at-fault crash over nine driving related events in comparison to young drivers, mid-aged drivers, and older drivers. The results indicated that all three age groups exhibited CO, but that the level varied according to the age group on which they had to base their comparative judgment. Interestingly, greater CO was constantly observed when the three age groups compared themselves to older drivers. Also, young males exhibited greater CO than female of the same age group.

  12. Physics at a new Fermilab proton driver

    SciTech Connect

    Geer, Steve; /Fermilab

    2006-04-01

    In 2004, motivated by the recent exciting developments in neutrino physics, the Fermilab Long Range Planning Committee identified a new high intensity Proton Driver as an attractive option for the future. At the end of 2004 the APS ''Study on the Physics of Neutrinos'' concluded that the future US neutrino program should have, as one of its components, ''A proton driver in the megawatt class or above and neutrino superbeam with an appropriate very large detector capable of observing Cp violation and measuring the neutrino mass-squared differences and mixing parameters with high precision''. The presently proposed Fermilab Proton Driver is designed to accomplish these goals, and is based on, and would help develop, Linear Collider technology. In this paper the Proton Driver parameters are summarized, and the potential physics program is described.

  13. Driver circuit for solid state light sources

    DOEpatents

    Palmer, Fred; Denvir, Kerry; Allen, Steven

    2016-02-16

    A driver circuit for a light source including one or more solid state light sources, a luminaire including the same, and a method of so driving the solid state light sources are provided. The driver circuit includes a rectifier circuit that receives an alternating current (AC) input voltage and provides a rectified AC voltage. The driver circuit also includes a switching converter circuit coupled to the light source. The switching converter circuit provides a direct current (DC) output to the light source in response to the rectified AC voltage. The driver circuit also includes a mixing circuit, coupled to the light source, to switch current through at least one solid state light source of the light source in response to each of a plurality of consecutive half-waves of the rectified AC voltage.

  14. The transcriptional landscape and mutational profile of lung adenocarcinoma

    PubMed Central

    Seo, Jeong-Sun; Ju, Young Seok; Lee, Won-Chul; Shin, Jong-Yeon; Lee, June Koo; Bleazard, Thomas; Lee, Junho; Jung, Yoo Jin; Kim, Jung-Oh; Shin, Jung-Young; Yu, Saet-Byeol; Kim, Jihye; Lee, Eung-Ryoung; Kang, Chang-Hyun; Park, In-Kyu; Rhee, Hwanseok; Lee, Se-Hoon; Kim, Jong-Il; Kang, Jin-Hyoung; Kim, Young Tae

    2012-01-01

    All cancers harbor molecular alterations in their genomes. The transcriptional consequences of these somatic mutations have not yet been comprehensively explored in lung cancer. Here we present the first large scale RNA sequencing study of lung adenocarcinoma, demonstrating its power to identify somatic point mutations as well as transcriptional variants such as gene fusions, alternative splicing events, and expression outliers. Our results reveal the genetic basis of 200 lung adenocarcinomas in Koreans including deep characterization of 87 surgical specimens by transcriptome sequencing. We identified driver somatic mutations in cancer genes including EGFR, KRAS, NRAS, BRAF, PIK3CA, MET, and CTNNB1. Candidates for novel driver mutations were also identified in genes newly implicated in lung adenocarcinoma such as LMTK2, ARID1A, NOTCH2, and SMARCA4. We found 45 fusion genes, eight of which were chimeric tyrosine kinases involving ALK, RET, ROS1, FGFR2, AXL, and PDGFRA. Among 17 recurrent alternative splicing events, we identified exon 14 skipping in the proto-oncogene MET as highly likely to be a cancer driver. The number of somatic mutations and expression outliers varied markedly between individual cancers and was strongly correlated with smoking history of patients. We identified genomic blocks within which gene expression levels were consistently increased or decreased that could be explained by copy number alterations in samples. We also found an association between lymph node metastasis and somatic mutations in TP53. These findings broaden our understanding of lung adenocarcinoma and may also lead to new diagnostic and therapeutic approaches. PMID:22975805

  15. Mutational signatures of ionizing radiation in second malignancies

    PubMed Central

    Behjati, Sam; Gundem, Gunes; Wedge, David C.; Roberts, Nicola D.; Tarpey, Patrick S.; Cooke, Susanna L.; Van Loo, Peter; Alexandrov, Ludmil B.; Ramakrishna, Manasa; Davies, Helen; Nik-Zainal, Serena; Hardy, Claire; Latimer, Calli; Raine, Keiran M.; Stebbings, Lucy; Menzies, Andy; Jones, David; Shepherd, Rebecca; Butler, Adam P.; Teague, Jon W.; Jorgensen, Mette; Khatri, Bhavisha; Pillay, Nischalan; Shlien, Adam; Futreal, P. Andrew; Badie, Christophe; Cooper, Colin S.; Eeles, Rosalind A.; Easton, Douglas; Foster, Christopher; Neal, David E.; Brewer, Daniel S.; Hamdy, Freddie; Lu, Yong-Jie; Lynch, Andrew G.; Massi, Charlie E.; Ng, Anthony; Whitaker, Hayley C.; Yu, Yongwei; Zhang, Hongwei; Bancroft, Elizabeth; Berney, Dan; Camacho, Niedzica; Corbishley, Cathy; Dadaev, Tokhir; Dennis, Nening; Dudderidge, Tim; Edwards, Sandra; Fisher, Cyril; Ghori, Jilur; Gnanapragasam, Vincent J.; Greenman, Christopher; Hawkins, Steve; Hazell, Steven; Howat, Will; Karaszi, Katalin; Kay, Jonathan; Kote-Jarai, Zsofia; Kremeyer, Barbara; Kumar, Pardeep; Lambert, Adam; Leongamornlert, Daniel; Livni, Naomi; Luxton, Hayley; Matthews, Lucy; Mayer, Erik; Merson, Susan; Nicol, David; Ogden, Christopher; O'Meara, Sarah; Pelvender, Gill; Shah, Nimish C.; Tavare, Simon; Thomas, Sarah; Thompson, Alan; Verrill, Claire; Warren, Anne; Zamora, Jorge; McDermott, Ultan; Bova, G. Steven; Richardson, Andrea L.; Flanagan, Adrienne M.; Stratton, Michael R.; Campbell, Peter J.

    2016-01-01

    Ionizing radiation is a potent carcinogen, inducing cancer through DNA damage. The signatures of mutations arising in human tissues following in vivo exposure to ionizing radiation have not been documented. Here, we searched for signatures of ionizing radiation in 12 radiation-associated second malignancies of different tumour types. Two signatures of somatic mutation characterize ionizing radiation exposure irrespective of tumour type. Compared with 319 radiation-naive tumours, radiation-associated tumours carry a median extra 201 deletions genome-wide, sized 1–100 base pairs often with microhomology at the junction. Unlike deletions of radiation-naive tumours, these show no variation in density across the genome or correlation with sequence context, replication timing or chromatin structure. Furthermore, we observe a significant increase in balanced inversions in radiation-associated tumours. Both small deletions and inversions generate driver mutations. Thus, ionizing radiation generates distinctive mutational signatures that explain its carcinogenic potential. PMID:27615322

  16. Heterogeneity of genomic evolution and mutational profiles in multiple myeloma

    PubMed Central

    Bolli, Niccolo; Avet-Loiseau, Hervé; Wedge, David C.; Van Loo, Peter; Alexandrov, Ludmil B.; Martincorena, Inigo; Dawson, Kevin J.; Iorio, Francesco; Nik-Zainal, Serena; Bignell, Graham R.; Hinton, Jonathan W.; Li, Yilong; Tubio, Jose M.C.; McLaren, Stuart; O' Meara, Sarah; Butler, Adam P.; Teague, Jon W.; Mudie, Laura; Anderson, Elizabeth; Rashid, Naim; Tai, Yu-Tzu; Shammas, Masood A.; Sperling, Adam S.; Fulciniti, Mariateresa; Richardson, Paul G.; Parmigiani, Giovanni; Magrangeas, Florence; Minvielle, Stephane; Moreau, Philippe; Attal, Michel; Facon, Thierry; Futreal, P Andrew; Anderson, Kenneth C.; Campbell, Peter J.; Munshi, Nikhil C.

    2014-01-01

    Multiple myeloma is an incurable plasma cell malignancy with a complex and incompletely understood molecular pathogenesis. Here we use whole-exome sequencing, copy-number profiling and cytogenetics to analyse 84 myeloma samples. Most cases have a complex subclonal structure and show clusters of subclonal variants, including subclonal driver mutations. Serial sampling reveals diverse patterns of clonal evolution, including linear evolution, differential clonal response and branching evolution. Diverse processes contribute to the mutational repertoire, including kataegis and somatic hypermutation, and their relative contribution changes over time. We find heterogeneity of mutational spectrum across samples, with few recurrent genes. We identify new candidate genes, including truncations of SP140, LTB, ROBO1 and clustered missense mutations in EGR1. The myeloma genome is heterogeneous across the cohort, and exhibits diversity in clonal admixture and in dynamics of evolution, which may impact prognostic stratification, therapeutic approaches and assessment of disease response to treatment. PMID:24429703

  17. Transport Device Driver's Assistance Vision Systems

    NASA Astrophysics Data System (ADS)

    Szpytko, Janusz; Gbyl, Michał

    2011-03-01

    The purpose of this paper is to review solutions whose task is to actively correct decision-making processes of the vehicle's driver on the basis of information obtained from the surroundings and the presentation of a tool that makes it possible to react to the changes of the psychophysical condition of the driver. The system is implemented by the Matlab application environment on the basis on the image activated by a webcam.

  18. Drivers of desertification and their impact

    NASA Astrophysics Data System (ADS)

    Mantel, S.; Van Lynden, G. V. L.; Karavitis, C. A.; Kosmas, C.; Van der Werff ten Bosch, M. J.

    2012-04-01

    Drivers of desertification and their impact An inventory was made of drivers of desertification and how they impact on the degradation process. The major drivers of desertification were analysed and compared between 16 sites around the globe. For each of these sites factors were scored with a perceived influence on desertification. Most of these factors, from the socio-cultural, environmental, and economic dimensions, appeared to be related to land management and planning and to (de-)population. They cause a number of temporary or permanent changes in the landscape, which, by themselves or in combination, lead to degradation of vegetation and soils. Most sites have several forms of land degradation occurring in and around their study area of which erosion by water is the dominant one. Other degradation types occurring in sites were: wind erosion, soil salinization, seawater intrusion in the groundwater, vegetation and biodiversity decline, groundwater depletion, decreased productivity/ carrying capacity, soil fertility decline, water logging and water pollution. As a first step, data and information was gathered on policies, desertification status and processes and on socio-economic conditions. The DPSIR framework (Driving force, Pressure, State, Impact, Response) provides a structure for assessment of the impact of past measures on the status of the environment or to formulate effective measures. In analysing the data, the different data items were structured in and formulated to elements fitting the DPSIR chain. Then possible connections between these different aspects were analysed. In our analysis nine major drivers were reported for the various sites, of which one was environmental, three drivers were related to land management, one driver was related to planning and policies, three drivers were related to socio-economic conditions, and one driver related to legal land status. Depending on the specific desertification process, factors may be positively or

  19. Aberrant driving behaviors: a study of drivers in Beijing.

    PubMed

    Shi, Jing; Bai, Yun; Ying, Xiwen; Atchley, Paul

    2010-07-01

    The addition of massive numbers of new drivers with varied driving experience to roads in China suggests it is important to understand the nature of aberrant driving behaviors for this new set of drivers. A paper-based and an Internet survey were administered. Factor analysis produced a five-factor structure for each survey. The distinction between violations and errors indicated in previous studies was confirmed. The violations included emotional violations, risky violations and self-willed violations, and the errors included inexperience errors and distraction errors. In contrast to previous work, age was not found to be a good predictor of violations though driving experience was. Contrary to expectations, non-automotive (bicycle) roadway experience or level of driving training failed to predict poor driving behavior. On-road experience is the key to risk for China's drivers. Good agreement between the paper-based and Internet surveys indicate online surveys to be a feasible way to conduct research of driving behavior at low cost.

  20. Young drivers' attitudes toward accompanied driving: a new multidimensional measure.

    PubMed

    Taubman-Ben-Ari, Orit

    2010-07-01

    Four studies were conducted in order to develop and validate a multidimensional instrument to assess attitudes toward accompanied driving among young drivers. Study 1 (n=841) focused on developing the Attitudes Toward Accompanied Driving Scale (ATADS), a self-report scale based on five previously conceptualized domains of attitudes. Factor analysis revealed the five hypothesized factors: Tension, Relatedness, Disapproval, Avoidance, and Anxiety. In addition, significant associations were found between these factors and gender, age, and the assessment of reckless driving as risky. Study 2 (n=651) adopted a developmental approach, comparing the attitudes of participants in various stages of licensure. Disapproval and Tension were found to be higher, and Relatedness lower, among participants who had not yet begun driving instruction than among those who were taking driving lessons or had already obtained a license. Study 3 (n=160) revealed associations between the five ATADS factors and perceived driving costs and benefits. In Study 4 (n=193), associations were found between these factors and driver's self-image, with a combination of ATADS factors, self-image, and gender contributing to the explained variance of two outcome variables: driving self-efficacy, and reported frequency of reckless driving. The discussion focuses on the validity and utility of the new measure of young drivers' attitudes toward accompanied driving, stressing its practical implications for road safety.

  1. S-Band POSIX Device Drivers for RTEMS

    NASA Technical Reports Server (NTRS)

    Lux, James P.; Lang, Minh; Peters, Kenneth J.; Taylor, Gregory H.

    2011-01-01

    This is a set of POSIX device driver level abstractions in the RTEMS RTOS (Real-Time Executive for Multiprocessor Systems real-time operating system) to SBand radio hardware devices that have been instantiated in an FPGA (field-programmable gate array). These include A/D (analog-to-digital) sample capture, D/A (digital-to-analog) sample playback, PLL (phase-locked-loop) tuning, and PWM (pulse-width-modulation)-controlled gain. This software interfaces to Sband radio hardware in an attached Xilinx Virtex-2 FPGA. It uses plug-and-play device discovery to map memory to device IDs. Instead of interacting with hardware devices directly, using direct-memory mapped access at the application level, this driver provides an application programming interface (API) offering that easily uses standard POSIX function calls. This simplifies application programming, enables portability, and offers an additional level of protection to the hardware. There are three separate device drivers included in this package: sband_device (ADC capture and DAC playback), pll_device (RF front end PLL tuning), and pwm_device (RF front end AGC control).

  2. License plate confiscation for persistent alcohol impaired drivers.

    PubMed

    Ross, H L; Simon, S; Cleary, J

    1996-01-01

    Minnesota cancels the registrations and confiscates the license plates of vehicles driven by repeat drinking drivers in a procedure which prior research has demonstrated to be effective in reducing subsequent recidivism. The research reported here concerns the problems experienced in the functioning of this law. Samples of officials and repeat driving under the influence (DUI) offenders were interviewed in Minnesota and in the neighboring state of Iowa, chosen for comparison because its laws also provide for plate confiscation, but using a judicial rather than an administrative procedure. In addition, representative samples of the driving and vehicle registration records of convicted drunk drivers and of routine traffic offenders were analyzed. The research found that evasion of plate impoundment orders by drivers, though apparently easy to accomplish, appeared to be rare. However, the orders were themselves not issued in a large proportion of cases where they were prescribed by statute, potentially weakening the effectiveness of the law. The reasons, with possible countermeasures, are explored in this report.

  3. SSL Luminaire with Novel Driver Architecture

    SciTech Connect

    Heikman, Sten; Robinson, Clark

    2011-07-07

    Cree has developed a new high-efficiency light emitting diode (LED) technology platform capable of providing low-cost, high performance luminaires that can be adopted across a variety of SSL applications. This development is built on Cree’s high brightness LED platform to design a novel LED chip that enables a high-efficiency driver architecture to improve the overall luminaire system efficacy. These system efficiency gains were realized using an integrated approach tailoring the LED chip characteristics to allow for the high-efficiency driver technology platform. The reliability of the new LED design was robust at the component level under accelerated testing conditions. Luminaires were assembled integrating the novel LED and driver technology to demonstrate the system improvement. Cree has successfully completed this project by developing a novel LED architecture that enables a new driver design with 93% efficiency. This technology was showcased in an LED luminaire that produced 725 lumens at an efficacy of 87.4 lumens per watt (LPW). The correlated color temperature (CCT) of the luminaire was 2708 K with a color rendering index (CRI) of 91. The novel LEDs and driver led to a 9% system performance improvement compared to the standard LEDs and driver scheme.

  4. Workshop on transport for a common ion driver

    SciTech Connect

    Olson, C.C.; Lee, E.; Langdon, B.

    1994-12-31

    This report contains research in the following areas related to beam transport for a common ion driver: multi-gap acceleration; neutralization with electrons; gas neutralization; self-pinched transport; HIF and LIF transport, and relevance to common ion driver; LIF and HIF reactor concepts and relevance to common ion driver; atomic physics for common ion driver; code capabilities and needed improvement.

  5. 49 CFR 380.111 - Substitute for driver training.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 5 2012-10-01 2012-10-01 false Substitute for driver training. 380.111 Section... TRAINING REQUIREMENTS Longer Combination Vehicle (LCV) Driver-Training and Driver-Instructor Requirements-General § 380.111 Substitute for driver training. (a) Grandfather clause. The LCV...

  6. 29 CFR 541.504 - Drivers who sell.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 29 Labor 3 2013-07-01 2013-07-01 false Drivers who sell. 541.504 Section 541.504 Labor Regulations... Outside Sales Employees § 541.504 Drivers who sell. (a) Drivers who deliver products and also sell such... sales. In determining the primary duty of drivers who sell, work performed incidental to and...

  7. 29 CFR 541.504 - Drivers who sell.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 29 Labor 3 2012-07-01 2012-07-01 false Drivers who sell. 541.504 Section 541.504 Labor Regulations... Outside Sales Employees § 541.504 Drivers who sell. (a) Drivers who deliver products and also sell such... sales. In determining the primary duty of drivers who sell, work performed incidental to and...

  8. 49 CFR 380.111 - Substitute for driver training.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 5 2011-10-01 2011-10-01 false Substitute for driver training. 380.111 Section... TRAINING REQUIREMENTS Longer Combination Vehicle (LCV) Driver-Training and Driver-Instructor Requirements-General § 380.111 Substitute for driver training. (a) Grandfather clause. The LCV...

  9. 49 CFR 383.71 - Driver application procedures.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 5 2010-10-01 2010-10-01 false Driver application procedures. 383.71 Section 383... DRIVER'S LICENSE STANDARDS; REQUIREMENTS AND PENALTIES Testing and Licensing Procedures § 383.71 Driver application procedures. (a) Initial Commercial Driver's License. Prior to obtaining a CDL, a person must...

  10. 29 CFR 541.504 - Drivers who sell.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 29 Labor 3 2014-07-01 2014-07-01 false Drivers who sell. 541.504 Section 541.504 Labor Regulations... Outside Sales Employees § 541.504 Drivers who sell. (a) Drivers who deliver products and also sell such... sales. In determining the primary duty of drivers who sell, work performed incidental to and...

  11. 29 CFR 541.504 - Drivers who sell.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 29 Labor 3 2010-07-01 2010-07-01 false Drivers who sell. 541.504 Section 541.504 Labor Regulations... Outside Sales Employees § 541.504 Drivers who sell. (a) Drivers who deliver products and also sell such... sales. In determining the primary duty of drivers who sell, work performed incidental to and...

  12. 29 CFR 541.504 - Drivers who sell.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 29 Labor 3 2011-07-01 2011-07-01 false Drivers who sell. 541.504 Section 541.504 Labor Regulations... Outside Sales Employees § 541.504 Drivers who sell. (a) Drivers who deliver products and also sell such... sales. In determining the primary duty of drivers who sell, work performed incidental to and...

  13. 49 CFR 380.111 - Substitute for driver training.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 5 2013-10-01 2013-10-01 false Substitute for driver training. 380.111 Section... TRAINING REQUIREMENTS Longer Combination Vehicle (LCV) Driver-Training and Driver-Instructor Requirements-General § 380.111 Substitute for driver training. (a) Grandfather clause. The LCV...

  14. 49 CFR 380.111 - Substitute for driver training.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 5 2014-10-01 2014-10-01 false Substitute for driver training. 380.111 Section... TRAINING REQUIREMENTS Longer Combination Vehicle (LCV) Driver-Training and Driver-Instructor Requirements-General § 380.111 Substitute for driver training. (a) Grandfather clause. The LCV...

  15. Electron holes appear to trigger cancer-implicated mutations

    NASA Astrophysics Data System (ADS)

    Miller, John; Villagran, Martha

    Malignant tumors are caused by mutations, which also affect their subsequent growth and evolution. We use a novel approach, computational DNA hole spectroscopy [M.Y. Suarez-Villagran & J.H. Miller, Sci. Rep. 5, 13571 (2015)], to compute spectra of enhanced hole probability based on actual sequence data. A hole is a mobile site of positive charge created when an electron is removed, for example by radiation or contact with a mutagenic agent. Peaks in the hole spectrum depict sites where holes tend to localize and potentially trigger a base pair mismatch during replication. Our studies of reveal a correlation between hole spectrum peaks and spikes in human mutation frequencies. Importantly, we also find that hole peak positions that do not coincide with large variant frequencies often coincide with cancer-implicated mutations and/or (for coding DNA) encoded conserved amino acids. This enables combining hole spectra with variant data to identify critical base pairs and potential cancer `driver' mutations. Such integration of DNA hole and variance spectra could also prove invaluable for pinpointing critical regions, and sites of driver mutations, in the vast non-protein-coding genome. Supported by the State of Texas through the Texas Ctr. for Superconductivity.

  16. Factors affecting the nature of induced mutations

    SciTech Connect

    Russell, L.B.; Russell, W.L.; Rinchik, E.M.; Hunsicker, P.R.

    1989-01-01

    The recent considerable expansion of specific-locus-mutation data has made possible an examination of the effects of germ-cell stage on both quantity of mutation yield and nature of mutations. For chemicals mutagenic in poststem-cell stages, three patterns have been identified according to the stages in which they elicit maximum response: (1) early spermatozoa and late spermatids; (2) early spermatids; and (3) differentiating spermatogonia. The majority of chemicals tested fall into Pattern 1. Chemicals that are also mutagenic in stem-cell spermatogonia do not preferentially belong to any one of these three categories. For only one chemical (CHL) has an entire set of mutations been analyzed molecularly. However, the results of genetic and molecular analyses of genomic regions surrounding six of the specific-locus markers allow us to conclude that any mutation that causes lethality of homozygotes (in the case of d, prenatal lethality, specifically) must involve one or more loci in addition to the marked one. Such mutations have been classified as large lesions'' (LL), the remainder as other lesions'' (OL). Analysis of the data shows that, regardless of the nature of the chemical (Pattern-1, -2, or -3), (1) LLs constitute a very low proportion of the mutations induced in either stem-cell or differentiating spermatogonia, and (b) LLs constitute a high proportion of mutations induced in postmeiotic stages. Chemicals that are active in both pre- and postmeiotic stages produce LL or OL mutations depending on cell stage.

  17. Tissue-specific mutation accumulation in human adult stem cells during life

    NASA Astrophysics Data System (ADS)

    Blokzijl, Francis; de Ligt, Joep; Jager, Myrthe; Sasselli, Valentina; Roerink, Sophie; Sasaki, Nobuo; Huch, Meritxell; Boymans, Sander; Kuijk, Ewart; Prins, Pjotr; Nijman, Isaac J.; Martincorena, Inigo; Mokry, Michal; Wiegerinck, Caroline L.; Middendorp, Sabine; Sato, Toshiro; Schwank, Gerald; Nieuwenhuis, Edward E. S.; Verstegen, Monique M. A.; van der Laan, Luc J. W.; de Jonge, Jeroen; Ijzermans, Jan N. M.; Vries, Robert G.; van de Wetering, Marc; Stratton, Michael R.; Clevers, Hans; Cuppen, Edwin; van Boxtel, Ruben

    2016-10-01

    The gradual accumulation of genetic mutations in human adult stem cells (ASCs) during life is associated with various age-related diseases, including cancer. Extreme variation in cancer risk across tissues was recently proposed to depend on the lifetime number of ASC divisions, owing to unavoidable random mutations that arise during DNA replication. However, the rates and patterns of mutations in normal ASCs remain unknown. Here we determine genome-wide mutation patterns in ASCs of the small intestine, colon and liver of human donors with ages ranging from 3 to 87 years by sequencing clonal organoid cultures derived from primary multipotent cells. Our results show that mutations accumulate steadily over time in all of the assessed tissue types, at a rate of approximately 40 novel mutations per year, despite the large variation in cancer incidence among these tissues. Liver ASCs, however, have different mutation spectra compared to those of the colon and small intestine. Mutational signature analysis reveals that this difference can be attributed to spontaneous deamination of methylated cytosine residues in the colon and small intestine, probably reflecting their high ASC division rate. In liver, a signature with an as-yet-unknown underlying mechanism is predominant. Mutation spectra of driver genes in cancer show high similarity to the tissue-specific ASC mutation spectra, suggesting that intrinsic mutational processes in ASCs can initiate tumorigenesis. Notably, the inter-individual variation in mutation rate and spectra are low, suggesting tissue-specific activity of common mutational processes throughout life.

  18. The Mutational Robustness of Influenza A Virus

    PubMed Central

    McCrone, John T.; Lauring, Adam S.

    2016-01-01

    A virus’ mutational robustness is described in terms of the strength and distribution of the mutational fitness effects, or MFE. The distribution of MFE is central to many questions in evolutionary theory and is a key parameter in models of molecular evolution. Here we define the mutational fitness effects in influenza A virus by generating 128 viruses, each with a single nucleotide mutation. In contrast to mutational scanning approaches, this strategy allowed us to unambiguously assign fitness values to individual mutations. The presence of each desired mutation and the absence of additional mutations were verified by next generation sequencing of each stock. A mutation was considered lethal only after we failed to rescue virus in three independent transfections. We measured the fitness of each viable mutant relative to the wild type by quantitative RT-PCR following direct competition on A549 cells. We found that 31.6% of the mutations in the genome-wide dataset were lethal and that the lethal fraction did not differ appreciably between the HA- and NA-encoding segments and the rest of the genome. Of the viable mutants, the fitness mean and standard deviation were 0.80 and 0.22 in the genome-wide dataset and best modeled as a beta distribution. The fitness impact of mutation was marginally lower in the segments coding for HA and NA (0.88 ± 0.16) than in the other 6 segments (0.78 ± 0.24), and their respective beta distributions had slightly different shape parameters. The results for influenza A virus are remarkably similar to our own analysis of CirSeq-derived fitness values from poliovirus and previously published data from other small, single stranded DNA and RNA viruses. These data suggest that genome size, and not nucleic acid type or mode of replication, is the main determinant of viral mutational fitness effects. PMID:27571422

  19. The Mutational Robustness of Influenza A Virus.

    PubMed

    Visher, Elisa; Whitefield, Shawn E; McCrone, John T; Fitzsimmons, William; Lauring, Adam S

    2016-08-01

    A virus' mutational robustness is described in terms of the strength and distribution of the mutational fitness effects, or MFE. The distribution of MFE is central to many questions in evolutionary theory and is a key parameter in models of molecular evolution. Here we define the mutational fitness effects in influenza A virus by generating 128 viruses, each with a single nucleotide mutation. In contrast to mutational scanning approaches, this strategy allowed us to unambiguously assign fitness values to individual mutations. The presence of each desired mutation and the absence of additional mutations were verified by next generation sequencing of each stock. A mutation was considered lethal only after we failed to rescue virus in three independent transfections. We measured the fitness of each viable mutant relative to the wild type by quantitative RT-PCR following direct competition on A549 cells. We found that 31.6% of the mutations in the genome-wide dataset were lethal and that the lethal fraction did not differ appreciably between the HA- and NA-encoding segments and the rest of the genome. Of the viable mutants, the fitness mean and standard deviation were 0.80 and 0.22 in the genome-wide dataset and best modeled as a beta distribution. The fitness impact of mutation was marginally lower in the segments coding for HA and NA (0.88 ± 0.16) than in the other 6 segments (0.78 ± 0.24), and their respective beta distributions had slightly different shape parameters. The results for influenza A virus are remarkably similar to our own analysis of CirSeq-derived fitness values from poliovirus and previously published data from other small, single stranded DNA and RNA viruses. These data suggest that genome size, and not nucleic acid type or mode of replication, is the main determinant of viral mutational fitness effects.

  20. Characteristics of Designated Drivers and their Passengers from the 2007 National Roadside Survey in the United States

    PubMed Central

    Bergen, Gwen; Yao, Jie; Shults, Ruth A.; Romano, Eduardo; Lacey, John

    2015-01-01

    Objective The objectives of this study were to estimate the prevalence of designated driving in the United States, compare these results with those from the 1996 National Roadside Survey, and explore the demographic, drinking, and trip characteristics of both designated drivers and their passengers. Methods The data used were from the 2007 National Roadside Survey which randomly stopped drivers, administered breath tests for alcohol, and administered a questionnaire to drivers and front seat passengers. Results Almost a third (30%) of nighttime drivers reported being designated drivers, with 84% of them having a blood alcohol concentration of zero. Drivers who were more likely to be designated drivers were those with a blood alcohol concentration that was over zero but still legal, who were under 35 years of age, who were African-American, Hispanic or Asian, and whose driving trip originated at a bar, tavern, or club. Over a third of passengers of designated drivers reported consuming an alcoholic drink the day of the survey compared with a fifth of passengers of non-designated drivers. One-fifth of designated driver passengers who reported drinking consumed five or more drinks that day. Conclusions Designated driving is widely used in the United States, with the majority of designated drivers abstaining from drinking alcohol. However as designated driving separates drinking from driving for passengers in a group travelling together, this may encourage passengers to binge drink, which is associated with many adverse health consequences in addition to those arising from alcohol-impaired driving. Designated driving programs and campaigns, although not proven to be effective when used alone, can complement proven effective interventions to help reduce excessive drinking and alcohol-impaired driving. PMID:24372499

  1. Validation of selected temperament and personality questionnaires for diagnosing drivers' aptitude for safe driving. A Polish study.

    PubMed

    Łuczak, Anna; Tarnowski, Adam

    2014-09-01

    This paper presents the results of a study aimed at validating psychological questionnaires evaluating temperamental and personality features. It discusses their usefulness in diagnosing drivers' aptitude for safe driving and working as professional drivers. Three psychological questionnaires were validated: the Formal Characteristics of Behaviour - Temperament Inventory (FCB-TI), the Eysenck Personality Questionnaire - Revised and Short Scale (EPQ-R (S)) and the Impulsiveness Questionnaire (IVE). Three groups of drivers (n=246) aged 19-75 participated in the study. Group I (professional drivers; n=96) and Group II (nonprofessional drivers; n=75) had never been involved in road crashes, whereas Group III (nonprofessional drivers; n=75) were offenders involved in fatal injury road crashes. Criterion-related validity, Cronbach's alpha and Guttman split-half reliability coefficient were in assessing the psychometric properties of the questionnaires. There were some significant differences between Groups II and III for most traits. However, contrary to expectations, higher Emotional Reactivity, Perseveration and lower Endurance as well as higher Neuroticism, Impulsiveness and Venturesomeness were determined for Group II than for Group III. Additionally, the temperament and personality profile of Group II turned out to be less fitted to the profile of safe drivers than that of Group III, whose profile was actually similar to that of Group I. This seems to result from a high tendency for a positive self-presentation among Group I and Group III (a significantly higher result on the Lie scale in comparison with Group II). The results suggest that if psychological tests are to decide on whether a person may be a professional driver or may drive vehicles, the three questionnaires (FCB-TI, EPQ-R(S) and IVE) do not provide a valid diagnosis of professional drivers' aptitude because of drivers' high tendency for positive self-presentation. However, they can be used in job

  2. Effect of long term driving on driver discomfort and its relationship with seat fidgets and movements (SFMs).

    PubMed

    Sammonds, George M; Fray, Mike; Mansfield, Neil J

    2017-01-01

    Discomfort in vehicle seats is a multifactorial problem with large increases in discomfort occurring during extended duration driving. Due to the nature of driver discomfort, previous research has found it difficult to accurately quantify long term driver discomfort via the use of objective measures. This paper reports a laboratory study that investigates a novel objective measure of long term driver discomfort and its correlation with subjective discomfort ratings. Analysis of driver's seat fidgets and movements was conducted over the duration of a 140 min drive on a driving simulator in addition to collecting subjective ratings of discomfort. It is shown that as subjects' subjective discomfort increases, the frequency of subjects' seat fidgets and movements increases congruently. A large correlation is observed between the subjective and objective measures of driver discomfort and provides the opportunity for long term discomfort evaluations to be made via remote monitoring; removing the need for subjective assessment.

  3. Reliability of drivers in urban intersections.

    PubMed

    Gstalter, Herbert; Fastenmeier, Wolfgang

    2010-01-01

    The concept of human reliability has been widely used in industrial settings by human factors experts to optimise the person-task fit. Reliability is estimated by the probability that a task will successfully be completed by personnel in a given stage of system operation. Human Reliability Analysis (HRA) is a technique used to calculate human error probabilities as the ratio of errors committed to the number of opportunities for that error. To transfer this notion to the measurement of car driver reliability the following components are necessary: a taxonomy of driving tasks, a definition of correct behaviour in each of these tasks, a list of errors as deviations from the correct actions and an adequate observation method to register errors and opportunities for these errors. Use of the SAFE-task analysis procedure recently made it possible to derive driver errors directly from the normative analysis of behavioural requirements. Driver reliability estimates could be used to compare groups of tasks (e.g. different types of intersections with their respective regulations) as well as groups of drivers' or individual drivers' aptitudes. This approach was tested in a field study with 62 drivers of different age groups. The subjects drove an instrumented car and had to complete an urban test route, the main features of which were 18 intersections representing six different driving tasks. The subjects were accompanied by two trained observers who recorded driver errors using standardized observation sheets. Results indicate that error indices often vary between both the age group of drivers and the type of driving task. The highest error indices occurred in the non-signalised intersection tasks and the roundabout, which exactly equals the corresponding ratings of task complexity from the SAFE analysis. A comparison of age groups clearly shows the disadvantage of older drivers, whose error indices in nearly all tasks are significantly higher than those of the other groups

  4. Whole-exome sequencing identifies recurrent AKT1 mutations in sclerosing hemangioma of lung

    PubMed Central

    Jung, Seung-Hyun; Kim, Min Sung; Lee, Sung-Hak; Park, Hyun-Chun; Choi, Hyun Joo; Maeng, Leeso; Min, Ki Ouk; Kim, Jeana; Park, Tae In; Shin, Ok Ran; Kim, Tae-Jung; Xu, Haidong; Lee, Kyo Young; Kim, Tae-Min; Song, Sang Yong; Lee, Charles; Chung, Yeun-Jun; Lee, Sug Hyung

    2016-01-01

    Pulmonary sclerosing hemangioma (PSH) is a benign tumor with two cell populations (epithelial and stromal cells), for which genomic profiles remain unknown. We conducted exome sequencing of 44 PSHs and identified recurrent somatic mutations of AKT1 (43.2%) and β-catenin (4.5%). We used a second subset of 24 PSHs to confirm the high frequency of AKT1 mutations (overall 31/68, 45.6%; p.E17K, 33.8%) and recurrent β-catenin mutations (overall 3 of 68, 4.4%). Of the PSHs without AKT1 mutations, two exhibited AKT1 copy gain. AKT1 mutations existed in both epithelial and stromal cells. In two separate PSHs from one patient, we observed two different AKT1 mutations, indicating they were not disseminated but independent arising tumors. Because the AKT1 mutations were not found to co-occur with β-catenin mutations (or any other known driver alterations) in any of the PSHs studied, we speculate that this may be the single-most common driver alteration to develop PSHs. Our study revealed genomic differences between PSHs and lung adenocarcinomas, including a high rate of AKT1 mutation in PSHs. These genomic features of PSH identified in the present study provide clues to understanding the biology of PSH and for differential genomic diagnosis of lung tumors. PMID:27601661

  5. [Social support and occupational stress relationship analysis of 1 413 train drivers in a railway bureau].

    PubMed

    Gu, G Z; Yu, S F; Zhou, W H; Wu, H; Kang, L; Chen, R

    2017-02-06

    Objective: To investigate the social support status of train drivers. Methods: Using cluster sampling, a cross-sectional study was conducted in 1 413 male train drivers (including 301 passenger train drivers, 683 freight train drivers, 85 guest scheduling train drivers, 265 cargo adjustable drivers, and 79 high-speed train drivers) from a railway bureau depot. The survey included individual factors, social support, occupational stressors, strains, personalities, and coping strategy using occupational stress instruments and effort-reward imbalance questionnaire. We compared the difference in social support scores between different drivers, who were divided according to job type and age. Additionally, the correlation between social support score and job strain-related factors was analyzed. The influence of depressive symptoms and job satisfaction were analyzed using a non-conditional logistic multivariate model. Results: The overall average age P(50) (P(25),P(75)) of 1 413 train drivers was 33.92 (27.83,43.58) years. The overall average length of service 12.25 (5.25,22.75) years. A significant difference in social support scores was observed according to job type (H=23.23, P<0.001). The specific scores were passenger driver(27 (23,32)), freight train driver (26 (22,30)), guest scheduling driver (27 (24,30)), cargo adjustable driver (26 (22,31)), and high-speed train driver (30 (26,36)) (P(50)(P(25),P(75))). Additionally, social support scores among different age groups were significantly different (H=6.64, P=0.036). The specific scores were ≤30 years (26 (22,31)), 30-40 years (27 (23,33)), and >40 years (27 (22,31)). Correlation analysis revealed that the social support score was negatively associated with job satisfaction (r=-0.43), reward (r=-0.22), working stability (r=-0.23), promotion opportunities (r=-0.12), positive affectivity (r=-0.31), esteem (r=-0.21), and self-esteem (r=-0.20) scores (P<0.001). The social support score was positively associated with

  6. An exactly solvable, spatial model of mutation accumulation in cancer

    PubMed Central

    Paterson, Chay; Nowak, Martin A.; Waclaw, Bartlomiej

    2016-01-01

    One of the hallmarks of cancer is the accumulation of driver mutations which increase the net reproductive rate of cancer cells and allow them to spread. This process has been studied in mathematical models of well mixed populations, and in computer simulations of three-dimensional spatial models. But the computational complexity of these more realistic, spatial models makes it difficult to simulate realistically large and clinically detectable solid tumours. Here we describe an exactly solvable mathematical model of a tumour featuring replication, mutation and local migration of cancer cells. The model predicts a quasi-exponential growth of large tumours, even if different fragments of the tumour grow sub-exponentially due to nutrient and space limitations. The model reproduces clinically observed tumour growth times using biologically plausible rates for cell birth, death, and migration rates. We also show that the expected number of accumulated driver mutations increases exponentially in time if the average fitness gain per driver is constant, and that it reaches a plateau if the gains decrease over time. We discuss the realism of the underlying assumptions and possible extensions of the model. PMID:28004754

  7. An exactly solvable, spatial model of mutation accumulation in cancer

    NASA Astrophysics Data System (ADS)

    Paterson, Chay; Nowak, Martin A.; Waclaw, Bartlomiej

    2016-12-01

    One of the hallmarks of cancer is the accumulation of driver mutations which increase the net reproductive rate of cancer cells and allow them to spread. This process has been studied in mathematical models of well mixed populations, and in computer simulations of three-dimensional spatial models. But the computational complexity of these more realistic, spatial models makes it difficult to simulate realistically large and clinically detectable solid tumours. Here we describe an exactly solvable mathematical model of a tumour featuring replication, mutation and local migration of cancer cells. The model predicts a quasi-exponential growth of large tumours, even if different fragments of the tumour grow sub-exponentially due to nutrient and space limitations. The model reproduces clinically observed tumour growth times using biologically plausible rates for cell birth, death, and migration rates. We also show that the expected number of accumulated driver mutations increases exponentially in time if the average fitness gain per driver is constant, and that it reaches a plateau if the gains decrease over time. We discuss the realism of the underlying assumptions and possible extensions of the model.

  8. Cognitive basis about risk level classifications for the self-assessment of older drivers

    PubMed Central

    Choi, Seong Youl; Lee, Jae Shin

    2017-01-01

    [Purpose] This study analyzed the cognitive functions according to risk level for the Driver 65 Plus measure, and examined the cognitive basis of self-assessment for screening the driving risk of elderly drivers. [Subjects and Methods] A total of 46 older drivers with a driver’s license participated in this study. All participants were evaluated with Driver 65 Plus. They were classified into three groups of “safe,” “caution” and “stop,” and examined for cognitive functions with Trail Making Test and Montreal Cognitive Assessment-K. The cognitive test results of the three groups were compared. [Results] Trail Making Test-A, Trail Making Test-B, and Montreal Cognitive Assessment-K showed a significant difference between the three groups. The safe group showed significantly higher ability than the caution and stop groups in the three cognitive tests. In addition, cognitive functions of naming, attention, language, and delayed recall were significantly different between the three groups. [Conclusion] Self-assessment of older drivers is a useful tool for screening the cognitive aspects of driving risk. The cognitive functions, such as attention and recall, are the critical factors for screening the driving risk of elderly drivers. PMID:28356619

  9. An extended macro traffic flow model accounting for the driver's bounded rationality and numerical tests

    NASA Astrophysics Data System (ADS)

    Tang, Tie-Qiao; Huang, Hai-Jun; Shang, Hua-Yan

    2017-02-01

    In this paper, we propose a macro traffic flow model to explore the effects of the driver's bounded rationality on the evolutions of traffic waves (which include shock and rarefaction waves) and small perturbation, and on the fuel consumption and emissions (that include CO, HC and NOX) during the evolution process. The numerical results illustrate that considering the driver's bounded rationality can prominently smooth the wavefront of the traffic waves and improve the stability of traffic flow, which shows that the driver's bounded rationality has positive impacts on traffic flow; but considering the driver's bounded rationality reduces the fuel consumption and emissions only at the upstream of the rarefaction wave while enhances the fuel consumption and emissions under other situations, which shows that the driver's bounded rationality has positive impacts on the fuel consumption and emissions only at the upstream of the rarefaction wave, while negative effects on the fuel consumption and emissions under other situations. In addition, the numerical results show that the driver's bounded rationality has little prominent impact on the total fuel consumption, and emissions during the whole evolution of small perturbation.

  10. Relationship Between Cognitive Perceptual Abilities and Accident and Penalty Histories Among Elderly Korean Drivers

    PubMed Central

    2016-01-01

    Objective To investigate the relationship between cognitive perceptual abilities of elderly drivers based on the Cognitive Perceptual Assessment for Driving (CPAD) test and their accident and penalty histories. Methods A total of 168 elderly drivers (aged ≥65 years) participated in the study. Participant data included CPAD scores and incidents of traffic accidents and penalties, attained from the Korea Road Traffic Authority and Korea National Police Agency, respectively. Results Drivers' mean age was 70.25±4.1 years and the mean CPAD score was 52.75±4.72. Elderly drivers' age was negatively related to the CPAD score (p<0.001). The accident history group had marginally lower CPAD scores, as compared to the non-accident group (p=0.051). However, incidence rates for traffic fines did not differ significantly between the two groups. Additionally, the group that passed the CPAD test had experienced fewer traffic accidents (3.6%), as compared to the group that failed (10.6%). The older age group (12.0%) had also experienced more traffic accidents, as compared to the younger group (2.4%). Conclusion Overall, elderly drivers who experienced driving accidents had lower CPAD scores than those who did not, without statistical significance. Thus, driving-related cognitive abilities of elderly drivers with insufficient cognitive ability need to be further evaluated to prevent traffic accidents. PMID:28119840

  11. a Design of the Driver Airbag Module with Floating Horn Assembly

    NASA Astrophysics Data System (ADS)

    Suh, Chang-Min; Lee, Young-Hoon; Suh, Duck-Young

    The driver airbag system is designed as a supplemental restraint system in addition to the seatbelt, and is designed to protect the driver's head and chest against severe injury by a device that is actuated in case of vehicle's fronted impact. Deployment of an airbag module with floating horn assembly is a highly dynamic process. The concept of driver airbag module with floating horn assembly and aluminum emblem is presented as a useful parameter when the airbag deploys and the energy is evaluated as performance factor in airbag module. Floating horn assembly is also one of the major factors for driver airbag module design to perform its horn function and check the package between driver airbag module and steering wheel. This study on the design of driver airbag module with floating horn assembly proved the feasibility as a new safety device. However, the system level study is needed for decrease of passenger injury. This study can be used for the implementation of a prototype of DABM with floating horn device.

  12. Parents' and peers' contribution to risky driving of male teen drivers.

    PubMed

    Taubman - Ben-Ari, Orit; Kaplan, Sigal; Lotan, Tsippy; Prato, Carlo Giacomo

    2015-05-01

    The current study joins efforts devoted to understanding the associations of parents' personality, attitude, and behavior, and to evaluating the added contribution of peers to the driving behavior of young drivers during their solo driving. The study combines data gathered using in-vehicle data recorders from actual driving of parents and their male teen driver with data collected from self-report questionnaires completed by the young drivers. The sample consists of 121 families, who participated in the study for 12 months, beginning with the licensure of the teen driver. The current examination concentrates on the last 3 months of this first year of driving. The experimental design was based on a random control assignment into three treatment groups (with different forms of feedback) and a control group (with no feedback). Findings indicate that the parents' (especially the fathers') sensation seeking, anxiety, and aggression, as well as their risky driving events rate were positively associated with higher risky driving of the young driver. In addition, parents' involvement in the intervention, either by feedback or by training, led to lower risky driving events rate of young drivers compared to the control group. Finally, higher cohesion and adaptability mitigated parents' model for risky driving, and peers norms' of risky driving were associated with higher risk by the teen drivers. We conclude by claiming that there is an unequivocal need to look at a full and complex set of antecedents in parents' personality, attitudes, and behavior, together with the contribution of peers to the young drivers' reckless driving, and address the practical implications for road safety.

  13. Driver Education Curriculum Guide. Administrative Guide for Driver and Traffic Safety Education.

    ERIC Educational Resources Information Center

    Ohio State Univ., Columbus. National Center for Research in Vocational Education.

    This guide is a practical and informative handbook designed to assist administrators in establishing effective driver and traffic safety education programs. It is concerned with the standards for driver and traffic safety education in Ohio and the organization, procedures, and guidelines for carrying out those responsibilities. Responsibilities…

  14. Novice drivers' individual trajectories of driver behavior over the first three years of driving.

    PubMed

    Roman, Gabriela D; Poulter, Damian; Barker, Edward; McKenna, Frank P; Rowe, Richard

    2015-09-01

    Identifying the changes in driving behavior that underlie the decrease in crash risk over the first few months of driving is key to efforts to reduce injury and fatality risk in novice drivers. This study represented a secondary data analysis of 1148 drivers who participated in the UK Cohort II study. The Driver Behavior Questionnaire was completed at 6 months and 1, 2 and 3 years after licensure. Linear latent growth models indicated significant increases across development in all four dimensions of aberrant driving behavior under scrutiny: aggressive violations, ordinary violations, errors and slips. Unconditional and conditional latent growth class analyses showed that the observed heterogeneity in individual trajectories was explained by the presence of multiple homogeneous groups of drivers, each exhibiting specific trajectories of aberrant driver behavior. Initial levels of aberrant driver behavior were important in identifying sub-groups of drivers. All classes showed positive slopes; there was no evidence of a group of drivers whose aberrant behavior decreased over time that might explain the decrease in crash involvement observed over this period. Male gender and younger age predicted membership of trajectories with higher levels of aberrant behavior. These findings highlight the importance of early intervention for improving road safety. We discuss the implications of our findings for understanding the behavioral underpinnings of the decrease in crash involvement observed in the early months of driving.

  15. Factors associated with self-reported driver sleepiness and incidents in city bus drivers.

    PubMed

    Anund, Anna; Ihlström, Jonas; Fors, Carina; Kecklund, Göran; Filtness, Ashleigh

    2016-08-05

    Driver fatigue has received increased attention during recent years and is now considered to be a major contributor to approximately 15-30% of all crashes. However, little is known about fatigue in city bus drivers. It is hypothesized that city bus drivers suffer from sleepiness, which is due to a combination of working conditions, lack of health and reduced sleep quantity and quality. The overall aim with the current study is to investigate if severe driver sleepiness, as indicated by subjective reports of having to fight sleep while driving, is a problem for city based bus drivers in Sweden and if so, to identify the determinants related to working conditions, health and sleep which contribute towards this. The results indicate that driver sleepiness is a problem for city bus drivers, with 19% having to fight to stay awake while driving the bus 2-3 times each week or more and nearly half experiencing this at least 2-4 times per month. In conclusion, severe sleepiness, as indicated by having to fight sleep during driving, was common among the city bus drivers. Severe sleepiness correlated with fatigue related safety risks, such as near crashes.

  16. Factors associated with self-reported driver sleepiness and incidents in city bus drivers

    PubMed Central

    ANUND, Anna; IHLSTRÖM, Jonas; FORS, Carina; KECKLUND, Göran; FILTNESS, Ashleigh

    2016-01-01

    Driver fatigue has received increased attention during recent years and is now considered to be a major contributor to approximately 15–30% of all crashes. However, little is known about fatigue in city bus drivers. It is hypothesized that city bus drivers suffer from sleepiness, which is due to a combination of working conditions, lack of health and reduced sleep quantity and quality. The overall aim with the current study is to investigate if severe driver sleepiness, as indicated by subjective reports of having to fight sleep while driving, is a problem for city based bus drivers in Sweden and if so, to identify the determinants related to working conditions, health and sleep which contribute towards this. The results indicate that driver sleepiness is a problem for city bus drivers, with 19% having to fight to stay awake while driving the bus 2–3 times each week or more and nearly half experiencing this at least 2–4 times per month. In conclusion, severe sleepiness, as indicated by having to fight sleep during driving, was common among the city bus drivers. Severe sleepiness correlated with fatigue related safety risks, such as near crashes. PMID:27098307

  17. The role of mutation of metabolism-related genes in genomic hypermethylation.

    PubMed

    Waterfall, Joshua J; Killian, J Keith; Meltzer, Paul S

    2014-12-05

    Genetic mutations, metabolic dysfunction, and epigenetic misregulation are commonly considered to play distinct roles in tumor development and maintenance. However, intimate relationships between these mechanisms are now emerging. In particular, mutations in genes for the core metabolic enzymes IDH, SDH, and FH are significant drivers of diverse tumor types. In each case, the resultant accumulation of particular metabolites inhibits TET enzymes responsible for oxidizing 5-methylcytosine, leading to pervasive DNA hypermethylation.

  18. Mutation studies in ascidians: a review.

    PubMed

    Crocetta, Fabio; Marino, Rita; Cirino, Paola; Macina, Alberto; Staiano, Leopoldo; Esposito, Rosaria; Pezzotti, Maria Rosa; Racioppi, Claudia; Toscano, Francesco; De Felice, Elena; Locascio, Annamaria; Ristoratore, Filomena; Spagnuolo, Antonietta; Zanetti, Laura; Branno, Margherita; Sordino, Paolo

    2015-01-01

    Historically, mutations have had a significant impact on the study of developmental processes and phenotypic evolution. Lesions in DNA are created by artificial methods or detected by natural genetic variation. Random mutations are then ascribed to genetic change by direct sequencing or positional cloning. Tunicate species of the ascidian genus Ciona represent nearly fully realized model systems in which gene function can be investigated in depth. Additionally, tunicates are valuable organisms for the study of naturally occurring mutations due to the capability to exploit genetic variation down to the molecular level. Here, we summarize the available information about how mutations are studied in ascidians with examples of insights that have resulted from these applications. We also describe notions and methodologies that might be useful for the implementation of easy and tight procedures for mutations studies in Ciona.

  19. Mutational screening of the RB1 gene in Italian patients with retinoblastoma reveals 11 novel mutations.

    PubMed

    Sampieri, Katia; Hadjistilianou, Theodora; Mari, Francesca; Speciale, Caterina; Mencarelli, Maria Antonietta; Cetta, Francesco; Manoukian, Siranoush; Peissel, Bernard; Giachino, Daniela; Pasini, Barbara; Acquaviva, Antonio; Caporossi, Aldo; Frezzotti, Renato; Renieri, Alessandra; Bruttini, Mirella

    2006-01-01

    Retinoblastoma (RB, OMIM#180200) is the most common intraocular tumour in infancy and early childhood. Constituent mutations in the RB1 gene predispose individuals to RB development. We performed a mutational screening of the RB1 gene in Italian patients affected by RB referred to the Medical Genetics of the University of Siena. In 35 unrelated patients, we identified germline RB1 mutations in 6 out of 9 familial cases (66%) and in 7 out of 26 with no family history of RB (27%). Using the single-strand conformational polymorphism (SSCP) technique, 11 novel mutations were detected, including 3 nonsense, 5 frameshift and 4 splice-site mutations. Only two of these mutations (1 splice site and 1 missense) were previously reported. The mutation spectrum reflects the published literature, encompassing predominately nonsense or frameshift and splicing mutations. RB1 germline mutation was detected in 37% of our cases. Gross rearrangements outside the investigated region, altered DNA methylation, or mutations in non-coding regions, may be the cause of disease in the remainder of the patients. Some cases, e.g. a case of incomplete penetrance, or variable expressivity ranging from retinoma to multiple tumours, are discussed in detail. In addition, a case of pre-conception genetic counselling resolved by rescue of banked cordonal blood of the affected deceased child is described.

  20. Clinicopathologic features and outcomes of patients with lung adenocarcinomas harboring BRAF mutations in the Lung Cancer Mutation Consortium

    PubMed Central

    Villaruz, Liza C.; Socinski, Mark A.; Abberbock, Shira; Berry, Lynne D.; Johnson, Bruce E.; Kwiatkowski, David J; Iafrate, A. John; Varella-Garcia, Marileila; Franklin, Wilbur A.; Camidge, D. Ross; Sequist, Lecia V.; Haura, Eric B.; Ladanyi, Mark; Kurland, Brenda F.; Kugler, Kelly; Minna, John D; Bunn, Paul A.; Kris, Mark G.

    2014-01-01

    (1) PURPOSE The advent of effective targeted therapy in BRAFV600E mutant lung adenocarcinomas necessitates further exploration of the unique clinical features and behavior of advanced stage BRAF mutant lung adenocarcinomas. (2) PATIENTS AND METHODS We reviewed data from patients with advanced lung adenocarcinomas enrolled in the Lung Cancer Mutation Consortium whose tumors underwent testing for mutations in EGFR, KRAS, HER2, AKT1, BRAF, MEK1, NRAS, PIK3CA, ALK translocations, and MET amplification. (3) RESULTS Twenty-one BRAF mutations were identified in 951 patients with adenocarcinomas (2.2%: 95% CI 1.4 to 3.4%); 17 (81%: 95% CI 60 to 92%) were BRAFV600E and 4 were non-BRAFV600E mutations. Among the 733 cases tested for all 10 genes, BRAF mutations were more likely to occur in current or former smokers than most other genotypic abnormalities (BRAF versus sensitizing EGFR: 82% versus 36%, mid-P<0.001; versus ALK: 39%, mid-P=0.003; versus other mutations: 49%, mid-P=0.02; versus patients with more than one oncogenic driver (doubleton): 46%, mid-P=0.04.) The double mutation rate among patients with BRAF mutations was 16%, compared with 5% in patients with other genomic abnormalities (mid-P=0.045). Differences were not found in survival between patients with BRAF mutations and those with other genomic abnormalities (P>0.20). (4) CONCLUSIONS We demonstrate BRAF mutations occur in 2.2% of advanced stage lung adenocarcinomas, were most commonly V600E, were associated with distinct clinicopathologic features compared with other genomic subtypes and a high mutation rate in more than one gene, underscoring the importance of comprehensive genomic profiling in assessing patients with advanced lung adenocarcinomas. PMID:25273224

  1. Conceptual Drivers for an Exploration Medical System

    NASA Technical Reports Server (NTRS)

    Antonsen, Erik; Hanson, Andrea; Shah, Ronak; Reed, Rebekah; Canga, Michael

    2016-01-01

    Interplanetary spaceflight, such as NASA's proposed three-year mission to Mars, provides unique and novel challenges when compared with human spaceflight to date. Extended distance and multi-year missions introduce new elements of operational complexity and additional risk. These elements include: inability to resupply medications and consumables, inability to evacuate injured or ill crew, uncharted psychosocial conditions, and communication delays that create a requirement for some level of autonomous medical capability. Because of these unique challenges, the approaches used in prior programs have limited application to a Mars mission. On a Mars mission, resource limitations will significantly constrain available medical capabilities, and require a paradigm shift in the approach to medical system design and risk mitigation for crew health. To respond to this need for a new paradigm, the Exploration Medical Capability (ExMC) Element is assessing each Mars mission phase-transit, surface stay, rendezvous, extravehicular activity, and return-to identify and prioritize medical needs for the journey beyond low Earth orbit (LEO). ExMC is addressing both planned medical operations, and unplanned contingency medical operations that meld clinical needs and research needs into a single system. This assessment is being used to derive a gap analysis and studies to support meaningful medical capabilities trades. These trades, in turn, allow the exploration medical system design to proceed from both a mission centric and ethics-based approach, and to manage the risks associated with the medical limitations inherent in an exploration class mission. This paper outlines the conceptual drivers used to derive medical system and vehicle needs from an integrated vision of how medical care will be provided within this paradigm. Keywords: (Max 6 keywords: exploration, medicine, spaceflight, Mars, research, NASA)

  2. Directing driver attention with augmented reality cues

    PubMed Central

    Rusch, Michelle L.; Schall, Mark C.; Gavin, Patrick; Lee, John D.; Dawson, Jeffrey D.; Vecera, Shaun; Rizzo, Matthew

    2013-01-01

    This simulator study evaluated the effects of augmented reality (AR) cues designed to direct the attention of experienced drivers to roadside hazards. Twenty-seven healthy middle-aged licensed drivers with a range of attention capacity participated in a 54 mile (1.5 hour) drive in an interactive fixed-base driving simulator. Each participant received AR cues to potential roadside hazards in six simulated straight (9 mile long) rural roadway segments. Drivers were evaluated on response time for detecting a potentially hazardous event, detection accuracy for target (hazard) and non-target objects, and headway with respect to the hazards. Results showed no negative outcomes associated with interference. AR cues did not impair perception of non-target objects, including for drivers with lower attentional capacity. Results showed near significant response time benefits for AR cued hazards. AR cueing increased response rate for detecting pedestrians and warning signs but not vehicles. AR system false alarms and misses did not impair driver responses to potential hazards. PMID:24436635

  3. Railway suicide: the psychological effects on drivers.

    PubMed

    Farmer, R; Tranah, T; O'Donnell, I; Catalan, J

    1992-05-01

    People have jumped (or fallen) in front of trains on the London Underground system in increasing numbers throughout the twentieth century. During the past decade there have been about 100 such incidents each year, of which around 90 would involve the train driver witnessing his train strike the person on the track. Most are suicides or attempts at suicide. They represent major unexpected and violent events in the lives of the train drivers and it might be expected that some of them would respond by developing a post-traumatic stress reaction of the type identified by Horowitz (1976) or other adverse psychological reactions or both. The research reported in this paper was designed to characterize the range of responses of drivers to the experiences of killing or injuring members of the public during the course of their daily work. It was found that 16.3% of the drivers involved in incidents did develop post-traumatic stress disorder and that other diagnoses, e.g. depression and phobic states, were present in 39.5% of drivers when interviewed one month after the incident.

  4. Driver anger on the information superhighway: A content analysis of online complaints of offensive driver behaviour.

    PubMed

    Wickens, Christine M; Wiesenthal, David L; Hall, Ashley; Roseborough, James E W

    2013-03-01

    In recent years, several websites have been developed allowing drivers to post their complaints about other motorists online. These websites allow drivers to describe the nature of the offensive behaviour and to identify the offending motorist by vehicle type, colour, and license plate number. Some websites also ask drivers to list the location where the event took place and the exact date and time of the offence. The current study was a content analysis of complaints posted to RoadRagers.com between 1999 and 2007 (N=5624). The purpose of the study was to: (1) assess the research value of this novel data source; (2) demonstrate the value of content analysis to the study of driver behaviour; (3) further validate an existing coding scheme; (4) determine whether this new data source would replicate previous research findings regarding the most frequent types of driver complaints and temporal distribution of these reports; (5) provide recommendations for improved driver training and public safety initiatives based on these data. A coding scheme that was originally developed for an assessment of complaints submitted to the Ontario Provincial Police (OPP) (Wickens et al., 2005) was revised to accommodate the new dataset. The inter-rater reliability of the revised coding scheme as applied to the website complaints was very good (kappa=.85). The most frequently reported improper driver behaviours were cutting/weaving, speeding, perceived displays of hostility, and tailgating. Reports were most frequent on weekdays and during the morning and afternoon rush hour. The current study replicated several findings from the analysis of reports to the OPP, but possible differences in the sample and data collection method also produced some differences in findings. The value of content analysis to driver behaviour research and of driver complaint websites as a data source was demonstrated. Implications for driver safety initiatives and future research will be discussed.

  5. Transglutaminase 1 mutations in autosomal recessive congenital ichthyosis: private and recurrent mutations in an isolated population.

    PubMed Central

    Laiho, E; Ignatius, J; Mikkola, H; Yee, V C; Teller, D C; Niemi, K M; Saarialho-Kere, U; Kere, J; Palotie, A

    1997-01-01

    Autosomal recessive congenital ichthyosis (ARCI) is a rare, heterogenous keratinization disorder of the skin, classically divided into two clinical subtypes, lamellar ichthyosis (LI) and nonbullous congenital ichthyosiformis erythroderma (CIE). Recently, strong evidence for the involvement of the transglutaminase 1 gene (TGM1) in LI has evolved. We have studied ARCI in the isolated Finnish population, in which recessive disorders are often caused by single mutations enriched by a founder effect. Surprisingly, five different mutations of TGM1 (Arg141His, Arg142Cys, Gly217Ser, Val378Leu, and Arg395Leu) were found in Finnish ARCI patients. In addition to affected LI patients, we also identified TGM1 mutations in CIE patients. Moreover, haplotype analysis of the chromosomes carrying the most common mutation, a C-->T transition changing Arg142 to Cys, revealed that the same mutation has been introduced twice in the Finnish population. In addition to this Arg142Cys mutation, three other mutations, in Arg141 and Arg142, have been described elsewhere, in other populations. These findings suggest that this region of TGM1 is more susceptible to mutation. The corresponding amino acid sequence is conserved in other transglutaminases, but, for example, coagulation factor XIII (FXIII) mutations do not cluster in this region. Protein modeling of the Arg142Cys mutation suggested disruption or destabilization of the protein. In transfection studies, the closely related transglutaminase FXIII protein with the corresponding mutation was shown to be susceptible to degradation in COS cells, further supporting evidence of the destabilizing effect of the Arg142Cys mutation in TGM1. Images Figure 3 Figure 4 PMID:9326318

  6. Mandatory driver training and road safety: the Quebec experience.

    PubMed Central

    Potvin, L; Champagne, F; Laberge-Nadeau, C

    1988-01-01

    In January 1983, the Quebec Government made driver training courses mandatory for any person seeking a first driver's license. Using accident and licensure data over a five-year period, we conducted an evaluation of the impact of the enactment of mandatory driver training on: the risk of accident for newly licensed drivers; the mortality and morbidity of these accidents; the number of new drivers; and the mean age of licensure. Results of our time series analyses show that this legislation had no appreciable effect on the risk of accident or on the mortality/morbidity rate per accident for newly licensed drivers aged 18 and over. However, since 1983, the number of women under 18 years of age getting their first driver's license has increased by 20 per cent, and their mean age has decreased from over 18 to under 18. Mandatory driver training may have increased the numbers and risks of accidents for young, primarily female, drivers. PMID:3407821

  7. Determinants and Drivers of Infectious Disease Threat Events in Europe

    PubMed Central

    Lindgren, Elisabet; Balkanyi, Laszlo; Espinosa, Laura; Almqvist, My S.; Penttinen, Pasi; Rocklöv, Joacim

    2016-01-01

    Infectious disease threat events (IDTEs) are increasing in frequency worldwide. We analyzed underlying drivers of 116 IDTEs detected in Europe during 2008–2013 by epidemic intelligence at the European Centre of Disease Prevention and Control. Seventeen drivers were identified and categorized into 3 groups: globalization and environment, sociodemographic, and public health systems. A combination of >2 drivers was responsible for most IDTEs. The driver category globalization and environment contributed to 61% of individual IDTEs, and the top 5 individual drivers of all IDTEs were travel and tourism, food and water quality, natural environment, global trade, and climate. Hierarchical cluster analysis of all drivers identified travel and tourism as a distinctly separate driver. Monitoring and modeling such disease drivers can help anticipate future IDTEs and strengthen control measures. More important, intervening directly on these underlying drivers can diminish the likelihood of the occurrence of an IDTE and reduce the associated human and economic costs. PMID:26982104

  8. Driver sleepiness on YouTube: A content analysis.

    PubMed

    Hawkins, A N; Filtness, A J

    2017-02-01

    Driver sleepiness is a major contributor to severe crashes and fatalities on our roads. Many people continue to drive despite being aware of feeling tired. Prevention relies heavily on education campaigns as it is difficult to police driver sleepiness. The video sharing social media site YouTube is extremely popular, particularly with at risk driver demographics. Content and popularity of uploaded videos can provide insight into the quality of publicly accessible driver sleepiness information. The purpose of this research was to answer two questions; firstly, how prevalent are driver sleepiness videos on YouTube? And secondly, what are the general characteristics of driver sleepiness videos in terms of (a) outlook on driver sleepiness, (b) tone, (c) countermeasures to driver sleepiness, and, (d) driver demographics. Using a keywords search, 442 relevant videos were found from a five year period (2nd December 2009-2nd December 2014). Tone, outlook, and countermeasure use were thematically coded. Driver demographic and video popularity data also were recorded. The majority of videos portrayed driver sleepiness as dangerous. However, videos that had an outlook towards driver sleepiness being amusing were viewed more often and had more mean per video comments and likes. Humorous videos regardless of outlook, were most popular. Most information regarding countermeasures to deal with driver sleepiness was accurate. Worryingly, 39.8% of videos with countermeasure information contained some kind of ineffective countermeasure. The use of humour to convey messages about the dangers of driver sleepiness may be a useful approach in educational interventions.

  9. Validation of Deleterious Mutations in Vorderwald Cattle

    PubMed Central

    Reinartz, Sina; Distl, Ottmar

    2016-01-01

    In Montbéliarde cattle two candidate mutations on bovine chromosomes 19 and 29 responsible for embryonic lethality have been detected. Montbéliarde bulls have been introduced into Vorderwald cattle to improve milk and fattening performance. Due to the small population size of Vorderwald cattle and the wide use of a few Montbéliarde bulls through artificial insemination, inbreeding on Montbéliarde bulls in later generations was increasing. Therefore, we genotyped an aborted fetus which was inbred on Montbéliarde as well as Vorderwald x Montbéliarde crossbred bulls for both deleterious mutations. The abortion was observed in an experimental herd of Vorderwald cattle. The objectives of the present study were to prove if one or both lethal mutations may be assumed to have caused this abortion and to show whether these deleterious mutations have been introduced into the Vorderwald cattle population through Montbéliarde bulls. The aborted fetus was homozygous for the SLC37A2:g.28879810C>T mutation (ss2019324563) on BTA29 and both parents as well as the paternal and maternal grandsire were heterozygous for this mutation. In addition, the parents and the paternal grandsire were carriers of the MH2-haplotype linked with the T-allele of the SLC37A2:g.28879810C>T mutation. For the SHBG:g.27956790C>T mutation (rs38377500) on BTA19 (MH1), the aborted fetus and its sire were heterozygous. Among all further 341 Vorderwald cattle genotyped we found 27 SLC37A2:g.28879810C>T heterozygous animals resulting in an allele frequency of 0.0396. Among the 120 male Vorderwald cattle, there were 12 heterozygous with an allele frequency of 0.05. The SLC37A2:g.28879810C>T mutation could not be found in further nine cattle breeds nor in Vorderwald cattle with contributions from Ayrshire bulls. In 69 Vorderwald cattle without genes from Montbéliarde bulls the mutated allele of SLC37A2:g.28879810C>T could not be detected. The SHBG:g.27956790C>T mutation appeared unlikely to be responsible

  10. Linear transformer driver for pulse generation

    SciTech Connect

    Kim, Alexander A; Mazarakis, Michael G; Sinebryukhov, Vadim A; Volkov, Sergey N; Kondratiev, Sergey S; Alexeenko, Vitaly M; Bayol, Frederic; Demol, Gauthier; Stygar, William A

    2015-04-07

    A linear transformer driver includes at least one ferrite ring positioned to accept a load. The linear transformer driver also includes a first power delivery module that includes a first charge storage devices and a first switch. The first power delivery module sends a first energy in the form of a first pulse to the load. The linear transformer driver also includes a second power delivery module including a second charge storage device and a second switch. The second power delivery module sends a second energy in the form of a second pulse to the load. The second pulse has a frequency that is approximately three times the frequency of the first pulse. The at least one ferrite ring is positioned to force the first pulse and the second pulse to the load by temporarily isolating the first pulse and the second pulse from an electrical ground.

  11. Hazard perception of motorcyclists and car drivers.

    PubMed

    Rosenbloom, Tova; Perlman, Amotz; Pereg, Avihu

    2011-05-01

    The current study compares hazard perception (HP) performance of 50 male drivers with and without a motorcycle license in order to generalize results. A video-based HP test, measuring reaction times to traffic scenes, was administered to these two groups of drivers. Participants with a motorcycle license performed better than participants without a motorcycle license. ANOVA indicated that learning improved linearly for participants with a motorcycle license but not for participants without a motorcycle license. No evidence that HP was predicted by age was found. HP scores for drivers who reported previous involvement in an accident were lower than for those who reported not being involved in an accident. The results are discussed in the context of sensitivity and response bias models.

  12. Why HID headlights bother older drivers

    PubMed Central

    Mainster, M A; Timberlake, G T

    2003-01-01

    Driving requires effective coordination of visual, motor, and cognitive skills. Visual skills are pushed to their limit at night by decreased illumination and by disabling glare from oncoming headlights. High intensity discharge (HID) headlamps project light farther down roads, improving their owner’s driving safety by increasing the time available for reaction to potential problems. Glare is proportional to headlamp brightness, however, so increasing headlamp brightness also increases potential glare for oncoming drivers, particularly on curving two lane roads. This problem is worse for older drivers because of their increased intraocular light scattering, glare sensitivity, and photostress recovery time. An analysis of automobile headlights, intraocular stray light, glare, and night driving shows that brightness rather than blueness is the primary reason for the visual problems that HID headlights can cause for older drivers who confront them. The increased light projected by HID headlights is potentially valuable, but serious questions remain regarding how and where it should be projected. PMID:12488274

  13. A model of Beijing drivers' scrambling behaviors.

    PubMed

    Shi, Jing; Bai, Yun; Tao, Li; Atchley, Paul

    2011-07-01

    A major, but unstudied, cause of crashes in China is drivers that "scramble" to gain the right of way in violation of traffic regulations. The motivation of this study is to explore the features of drivers' scrambling behaviors and the attitudes and driving skills that influence them. In this study, we established a scrambling behavior scale, and developed a driving attitude scale and a driving skill scale using factor analysis of an Internet survey of 486 drivers in Beijing. A structural equation model of scrambling behavior toward cars and pedestrians/cyclists was developed with attitudes and skills as predictors of behavior. Skills and attitudes of approval toward violations of traffic rules did not predict scrambling behaviors, while the motivation for safety and attitudes against violating traffic rules led to reduced scrambling behaviors. The current work highlights this peculiar aspect of Chinese roads and suggests methods to reduce the behavior.

  14. [Pathogenic mutation or polymorphism? (How to find criteria)].

    PubMed

    Kochański, Andrzej

    2006-01-01

    The classification of amino-acid substitutions into pathogenic mutations and harmless polymorphisms should be revised. In the recent years it was shown that some amino-acid substitutions considered as pathogenic mutations were polymorphisms. Similarly, some 'harmless' polymorphisms have been shown to be pathogenic mutations. Functional analysis considered as a good method to estimate the pathogenic nature of mutations is also limited. The selection of DNA samples for the control group is also difficult. Due to the molecular mechanism mediated by recently discovered exonic splicing enhancers and silencers (ESE and ESS) it is hard to predict a pathogenic effect of some mutations. In addition, the phenotype variability observed between unrelated patients harboring the same mutation may reflect the effects of modifying genes as well as the lack of association between mutation and "its" phenotype. The aim of this study is to describe the problem of the pathogenic effect of mutations.

  15. Molecular driver alterations and their clinical relevance in cancer of unknown primary site

    PubMed Central

    Endris, Volker; Hielscher, Thomas; Lohneis, Philipp; Folprecht, Gunnar; Stenzinger, Albrecht; Dietel, Manfred

    2016-01-01

    Cancer of unknown primary (CUP) is defined as metastatic solid malignancy where no primary tumor is detected despite appropriate staging. About 90% of CUP represent adenocarcinoma or undifferentiated carcinoma. Since therapy regimens are only modestly effective, identification of the molecular landscape of these neoplasms might be a promising approach to direct CUP therapy and aid in tumor classification. We screened a cohort of 128 patients with adenocarcinoma or undifferentiated carcinoma meeting the definition of CUP. Massive parallel multigene sequencing of 50 genes, which had been selected due to their relevance as oncogenic drivers or druggable molecular targets could ultimately be performed on samples from 55 patients for whom complete clinical datasets were also available. Overall, 60 tumor-specific mutations and 29 amplifications/deletions, as revealed by coverage analysis, were detected in 46 cases (84%). The most frequently mutated genes were TP53 (30 cases, 55%), KRAS (9 cases, 16%), CDKN2A (5 cases, 9%), and SMAD4 (5 cases, 9%). The most frequently deleted gene was CDKN2A (8 cases, 15%). KRAS and CDKN2A mutations significantly correlated with poor progression-free survival (PFS) and, in case of KRAS, overall survival (OS). WIldtype TP53 and female sex defined a relatively favorable category, with favorable PFS and OS. 8 cases (15%) harbored mutations that may be targetable by currently approved drugs. Taken together, Mutations of relevant driver genes are present in the vast majority of CUP tumors. Some of them impact on prognosis and a subset is putatively druggable. PMID:27322425

  16. Molecular profiling of low grade serous ovarian tumours identifies novel candidate driver genes.

    PubMed

    Hunter, Sally M; Anglesio, Michael S; Ryland, Georgina L; Sharma, Raghwa; Chiew, Yoke-Eng; Rowley, Simone M; Doyle, Maria A; Li, Jason; Gilks, C Blake; Moss, Phillip; Allan, Prue E; Stephens, Andrew N; Huntsman, David G; deFazio, Anna; Bowtell, David D; Gorringe, Kylie L; Campbell, Ian G

    2015-11-10

    Low grade serous ovarian tumours are a rare and under-characterised histological subtype of epithelial ovarian tumours, with little known of the molecular drivers and facilitators of tumorigenesis beyond classic oncogenic RAS/RAF mutations. With a move towards targeted therapies due to the chemoresistant nature of this subtype, it is pertinent to more fully characterise the genetic events driving this tumour type, some of which may influence response to therapy and/or development of drug resistance. We performed genome-wide high-resolution genomic copy number analysis (Affymetrix SNP6.0) and mutation hotspot screening (KRAS, BRAF, NRAS, HRAS, ERBB2 and TP53) to compare a large cohort of ovarian serous borderline tumours (SBTs, n = 57) with low grade serous carcinomas (LGSCs, n = 19). Whole exome sequencing was performed for 13 SBTs, nine LGSCs and one mixed low/high grade carcinoma. Copy number aberrations were detected in 61% (35/57) of SBTs, compared to 100% (19/19) of LGSCs. Oncogenic RAS/RAF/ERBB2 mutations were detected in 82.5% (47/57) of SBTs compared to 63% (12/19) of LGSCs, with NRAS mutations detected only in LGSC. Some copy number aberrations appeared to be enriched in LGSC, most significantly loss of 9p and homozygous deletions of the CDKN2A/2B locus. Exome sequencing identified BRAF, KRAS, NRAS, USP9X and EIF1AX as the most frequently mutated genes. We have identified markers of progression from borderline to LGSC and novel drivers of LGSC. USP9X and EIF1AX have both been linked to regulation of mTOR, suggesting that mTOR inhibitors may be a key companion treatment for targeted therapy trials of MEK and RAF inhibitors.

  17. Molecular profiling of low grade serous ovarian tumours identifies novel candidate driver genes

    PubMed Central

    Hunter, Sally M.; Anglesio, Michael S.; Ryland, Georgina L.; Sharma, Raghwa; Chiew, Yoke-Eng; Rowley, Simone M.; Doyle, Maria A.; Li, Jason; Gilks, C. Blake; Moss, Phillip; Allan, Prue E.; Stephens, Andrew N.; Huntsman, David G.; deFazio, Anna; Bowtell, David D.

    2015-01-01

    Low grade serous ovarian tumours are a rare and under-characterised histological subtype of epithelial ovarian tumours, with little known of the molecular drivers and facilitators of tumorigenesis beyond classic oncogenic RAS/RAF mutations. With a move towards targeted therapies due to the chemoresistant nature of this subtype, it is pertinent to more fully characterise the genetic events driving this tumour type, some of which may influence response to therapy and/or development of drug resistance. We performed genome-wide high-resolution genomic copy number analysis (Affymetrix SNP6.0) and mutation hotspot screening (KRAS, BRAF, NRAS, HRAS, ERBB2 and TP53) to compare a large cohort of ovarian serous borderline tumours (SBTs, n = 57) with low grade serous carcinomas (LGSCs, n = 19). Whole exome sequencing was performed for 13 SBTs, nine LGSCs and one mixed low/high grade carcinoma. Copy number aberrations were detected in 61% (35/57) of SBTs, compared to 100% (19/19) of LGSCs. Oncogenic RAS/RAF/ERBB2 mutations were detected in 82.5% (47/57) of SBTs compared to 63% (12/19) of LGSCs, with NRAS mutations detected only in LGSC. Some copy number aberrations appeared to be enriched in LGSC, most significantly loss of 9p and homozygous deletions of the CDKN2A/2B locus. Exome sequencing identified BRAF, KRAS, NRAS, USP9X and EIF1AX as the most frequently mutated genes. We have identified markers of progression from borderline to LGSC and novel drivers of LGSC. USP9X and EIF1AX have both been linked to regulation of mTOR, suggesting that mTOR inhibitors may be a key companion treatment for targeted therapy trials of MEK and RAF inhibitors. PMID:26506417

  18. New mutation to Huntington's disease.

    PubMed

    Wolff, G; Deuschl, G; Wienker, T F; Hummel, K; Bender, K; Lücking, C H; Schumacher, M; Hammer, J; Oepen, G

    1989-01-01

    We report a large family with an isolated case of Huntington's disease (HD), which is probably the result of a new mutation. The patient developed clinical signs typical of HD at the age of 36. The clinical course of the patient's disease is documented by several clinical admissions over a period of 14 years at present. The family history is strikingly negative with the parents having been clearly unaffected into their 80s and with 13 older and two younger, living, healthy sibs. Extensive testing of polymorphic markers (blood groups, red cell and serum proteins, HLA antigens) showed no indication of non-paternity, but rather gave strong support to the hypothesis that the proband is a full sib. In addition, DNA typing for several RFLPs known to be closely linked to the HD gene locus indicated that several clearly unaffected sibs share one or the other or both of the patient's haplotypes. This is further evidence in favour of the hypothesis of a new mutation at the HD locus. The posterior probability of a new mutation to HD in the patient exceeds 99%, even if an a priori probability of non-paternity of 10% and a mutation rate of HD of 10(-7) is assumed.

  19. Concealing their communication: exploring psychosocial predictors of young drivers' intentions and engagement in concealed texting.

    PubMed

    Gauld, Cassandra S; Lewis, Ioni; White, Katherine M

    2014-01-01

    Making a conscious effort to hide the fact that you are texting while driving (i.e., concealed texting) is a deliberate and risky behaviour involving attention diverted away from the road. As the most frequent users of text messaging services and mobile phones while driving, young people appear at heightened risk of crashing from engaging in this behaviour. This study investigated the phenomenon of concealed texting while driving, and utilised an extended Theory of Planned Behaviour (TPB) including the additional predictors of moral norm, mobile phone involvement, and anticipated regret to predict young drivers' intentions and subsequent behaviour. Participants (n=171) were aged 17-25 years, owned a mobile phone, and had a current driver's licence. Participants completed a questionnaire measuring their intention to conceal texting while driving, and a follow-up questionnaire a week later to report their behavioural engagement. The results of hierarchical multiple regression analyses showed overall support for the predictive utility of the TPB with the standard constructs accounting for 69% of variance in drivers' intentions, and the extended predictors contributing an additional 6% of variance in intentions over and above the standard constructs. Attitude, subjective norm, PBC, moral norm, and mobile phone involvement emerged as significant predictors of intentions; and intention was the only significant predictor of drivers' self-reported behaviour. These constructs can provide insight into key focal points for countermeasures including advertising and other public education strategies aimed at influencing young drivers to reconsider their engagement in this risky behaviour.

  20. Patterns of Somatic Mutations in Immunoglobulin Variable Genes

    PubMed Central

    Golding, G. Brian; Gearhart, Patricia J.; Glickman, Barry W.

    1987-01-01

    The mechanism responsible for somatic mutation in the variable genes of antibodies is unknown and may differ from previously described mechanisms that produce mutation in DNA. We have analyzed 421 somatic mutations from the rearranged immunoglobulin variable genes of mice to determine (1) if the nucleotide substitutions differ from those generated during meiosis and (2) if the presence of nearby direct and inverted repeated sequences could template mutations around the variable gene. The results reveal a difference in the pattern of substitutions obtained from somatic mutations vs. meiotic mutations. An increased frequency of T:A to C:G transitions and a decreased frequency of mutations involving a G in the somatic mutants compared to the meiotic mutants is indicated. This suggests that the mutational processes responsible for somatic mutation in antibody genes differs from that responsible for mutation during meiosis. An analysis of the local DNA sequences revealed many direct repeats and palindromic sequences that were capable of templating some of the known mutations. Although additional factors may be involved in targeting mutations to the variable gene, mistemplating by nearby repeats may provide a mechanism for the enhancement of somatic mutation. PMID:3557109

  1. Timing, rates and spectra of human germline mutation.

    PubMed

    Rahbari, Raheleh; Wuster, Arthur; Lindsay, Sarah J; Hardwick, Robert J; Alexandrov, Ludmil B; Al Turki, Saeed; Dominiczak, Anna; Morris, Andrew; Porteous, David; Smith, Blair; Stratton, Michael R; Hurles, Matthew E

    2016-02-01

    Germline mutations are a driving force behind genome evolution and genetic disease. We investigated genome-wide mutation rates and spectra in multi-sibling families. The mutation rate increased with paternal age in all families, but the number of additional mutations per year differed by more than twofold between families. Meta-analysis of 6,570 mutations showed that germline methylation influences mutation rates. In contrast to somatic mutations, we found remarkable consistency in germline mutation spectra between the sexes and at different paternal ages. In parental germ line, 3.8% of mutations were mosaic, resulting in 1.3% of mutations being shared by siblings. The number of these shared mutations varied significantly between families. Our data suggest that the mutation rate per cell division is higher during both early embryogenesis and differentiation of primordial germ cells but is reduced substantially during post-pubertal spermatogenesis. These findings have important consequences for the recurrence risks of disorders caused by de novo mutations.

  2. High performance thyratron driver with low jitter.

    PubMed

    Verma, Rishi; Lee, P; Springham, S V; Tan, T L; Rawat, R S

    2007-08-01

    We report the design and development of insulated gate bipolar junction transistor based high performance driver for operating thyratrons in grounded grid mode. With careful design, the driver meets the specification of trigger output pulse rise time less than 30 ns, jitter less than +/-1 ns, and time delay less than 160 ns. It produces a -600 V pulse of 500 ns duration (full width at half maximum) at repetition rate ranging from 1 Hz to 1.14 kHz. The developed module also facilitates heating and biasing units along with protection circuitry in one complete package.

  3. Tumor-Derived Suppressor of Fused Mutations Reveal Hedgehog Pathway Interactions.

    PubMed

    Urman, Nicole M; Mirza, Amar; Atwood, Scott X; Whitson, Ramon J; Sarin, Kavita Y; Tang, Jean Y; Oro, Anthony E

    2016-01-01

    The Hedgehog pathway is a potent regulator of cellular growth and plays a central role in the development of many cancers including basal cell carcinoma (BCC). The majority of BCCs arise from mutations in the Patched receptor resulting in constitutive activation of the Hedgehog pathway. Secondary driver mutations promote BCC oncogenesis and occur frequently due to the high mutational burden resulting from sun exposure of the skin. Here, we uncover novel secondary mutations in Suppressor of Fused (SUFU), the major negative regulator of the Hedgehog pathway. SUFU normally binds to a Hedgehog transcriptional activator, GLI1, in order to prevent it from initiating transcription of Hedgehog target genes. We sequenced tumor-normal pairs from patients with early sporadic BCCs. This resulted in the discovery of nine mutations in SUFU, which were functionally investigated to determine whether they help drive BCC formation. Our results show that four of the SUFU mutations inappropriately activate the Hedgehog pathway, suggesting they may act as driver mutations for BCC development. Indeed, all four of the loss of function SUFU variants were found to disrupt its binding to GLI, leading to constitutive pathway activation. Our results from functional characterization of these mutations shed light on SUFU's role in Hedgehog signaling, tumor progression, and highlight a way in which BCCs can arise.

  4. Tumor-Derived Suppressor of Fused Mutations Reveal Hedgehog Pathway Interactions

    PubMed Central

    Urman, Nicole M.; Mirza, Amar; Atwood, Scott X.; Whitson, Ramon J.; Sarin, Kavita Y.; Tang, Jean Y.; Oro, Anthony E.

    2016-01-01

    The Hedgehog pathway is a potent regulator of cellular growth and plays a central role in the development of many cancers including basal cell carcinoma (BCC). The majority of BCCs arise from mutations in the Patched receptor resulting in constitutive activation of the Hedgehog pathway. Secondary driver mutations promote BCC oncogenesis and occur frequently due to the high mutational burden resulting from sun exposure of the skin. Here, we uncover novel secondary mutations in Suppressor of Fused (SUFU), the major negative regulator of the Hedgehog pathway. SUFU normally binds to a Hedgehog transcriptional activator, GLI1, in order to prevent it from initiating transcription of Hedgehog target genes. We sequenced tumor-normal pairs from patients with early sporadic BCCs. This resulted in the discovery of nine mutations in SUFU, which were functionally investigated to determine whether they help drive BCC formation. Our results show that four of the SUFU mutations inappropriately activate the Hedgehog pathway, suggesting they may act as driver mutations for BCC development. Indeed, all four of the loss of function SUFU variants were found to disrupt its binding to GLI, leading to constitutive pathway activation. Our results from functional characterization of these mutations shed light on SUFU’s role in Hedgehog signaling, tumor progression, and highlight a way in which BCCs can arise. PMID:28030567

  5. Accumulation of Deleterious Passenger Mutations Is Associated with the Progression of Hepatocellular Carcinoma

    PubMed Central

    d’Avigdor, William M. H.; McCaughan, Geoffrey W.; Luciani, Fabio; Shackel, Nicholas A.

    2016-01-01

    In hepatocellular carcinoma (HCC), somatic genome-wide DNA mutations are numerous, universal and heterogeneous. Some of these somatic mutations are drivers of the malignant process but the vast majority are passenger mutations. These passenger mutations can be deleterious to individual protein function but are tolerated by the cell or are offset by a survival advantage conferred by driver mutations. It is unknown if these somatic deleterious passenger mutations (DPMs) develop in the precancerous state of cirrhosis or if it is confined to HCC. Therefore, we studied four whole-exome sequencing datasets, including patients with non-cirrhotic liver (n = 12), cirrhosis without HCC (n = 6) and paired HCC with surrounding non-HCC liver (n = 74 paired samples), to identify DPMs. After filtering out putative germline mutations, we identified 187±22 DPMs per non-diseased tissue. DPMs number was associated with liver disease progressing to HCC, independent of the number of exonic mutations. Tumours contained significantly more DPMs compared to paired non-tumour tissue (258–293 per HCC exome). Cirrhosis- and HCC-associated DPMs do not occur predominantly in specific genes, chromosomes or biological pathways and the effect on tumour biology is presently unknown. Importantly, for the first time we have shown a significant increase in DPMs with HCC. PMID:27631787

  6. Validation of the Driver Behaviour Questionnaire in a representative sample of drivers in Australia.

    PubMed

    Stephens, A N; Fitzharris, M

    2016-01-01

    The Driver Behaviour Questionnaire (DBQ) is a widely used measure of driving behaviours that may increase a driver's risk of crash involvement. However, there are several different versions of the DBQ varying in terms of number of items and factor structure. The aim of the current research was to assess the construct validity of the popular 28-item four-factor DBQ solution in a representative sample of drivers in Australia. A further aim was to test the factorial invariance of the measure across gender, age and also between fleet and non-fleet drivers using multigroup confirmatory factor analyses. Data on a range of attitudes towards road safety were collected using an online survey. A stratified sampling procedure was undertaken to ensure the age, gender and location distributions of participants were representative of the Australian population. A total of 2771 responses were obtained from fully licensed motor vehicle drivers (male: 46%). Confirmatory factor analysis supported the 28-item four-factor DBQ in the Australian sample. The DBQ was also found to be gender-invariant and strong partial measurement invariance was found for drivers aged from 26 to 64, but not for younger (17-25) or older (65-75) drivers. Modifications to the DBQ suggest how the DBQ can be improved for use in these two age groups.

  7. Efficacy of side air bags in reducing driver deaths in driver-side collisions.

    PubMed

    Braver, Elisa R; Kyrychenko, Sergey Y

    2004-03-15

    Side air bags, a relatively new technology designed to protect the head and/or torso in side-impact collisions, are becoming increasingly common in automobiles. Their efficacy in preventing US driver deaths among cars struck on the near (driver's) side was examined using data from the Fatality Analysis Reporting System and the General Estimates System. Risk ratios for driver death per nearside collision during 1999-2001 were computed for head/torso and torso-only side air bags in cars from model years 1997-2002, relative to cars without side air bags. Confounding was addressed by adjusting nearside risk ratios for front- and rear-impact mortality, which is unaffected by side air bags. Risk ratios were 0.55 (95% confidence interval: 0.43, 0.71) for head/torso air bags and 0.89 (95% confidence interval: 0.79, 1.01) for torso-only air bags. Risk was reduced when cars with head/torso air bags were struck by cars/minivans (significant) or pickup trucks/sport utility vehicles (nonsignificant). Risk was reduced in two-vehicle collisions and among male drivers and drivers aged 16-64 years. Protective effects associated with torso-only air bags were observed in single-vehicle crashes and among male and 16- to 64-year-old drivers. Head/torso side air bags appear to be very effective in reducing nearside driver deaths, whereas torso-only air bags appear less protective.

  8. Enhancing digital driver models: identification of distinct postural strategies used by drivers.

    PubMed

    Kyung, Gyouhyung; Nussbaum, Maury A; Babski-Reeves, Kari L

    2010-03-01

    Driver workspace design and evaluation is, in part, based on assumed driving postures of users and determines several ergonomic aspects of a vehicle, such as reach, visibility and postural comfort. Accurately predicting and specifying standard driving postures, hence, are necessary to improve the ergonomic quality of the driver workspace. In this study, a statistical clustering approach was employed to reduce driving posture simulation/prediction errors, assuming that drivers use several distinct postural strategies when interacting with automobiles. 2-D driving postures, described by 16 joint angles, were obtained from 38 participants with diverse demographics (age, gender) and anthropometrics (stature, body mass) and in two vehicle classes (sedans and SUVs). Based on the proximity of joint angle sets, cluster analysis yielded three predominant postural strategies in each vehicle class (i.e. 'lower limb flexed', 'upper limb flexed' and 'extended'). Mean angular differences between clusters ranged from 3.8 to 52.4 degrees for the majority of joints, supporting the practical relevance of the distinct clusters. The existence of such postural strategies should be considered when utilising digital human models (DHMs) to enhance and evaluate driver workspace design ergonomically and proactively. STATEMENT OF RELEVANCE: This study identified drivers' distinct postural strategies, based on actual drivers' behaviours. Such strategies can facilitate accurate positioning of DHMs and hence help design ergonomic driver workspaces.

  9. Amphetamine, cocaine and cannabinoids use among truck drivers on the roads in the State of Sao Paulo, Brazil.

    PubMed

    Leyton, V; Sinagawa, D M; Oliveira, K C B G; Schmitz, W; Andreuccetti, G; De Martinis, B S; Yonamine, M; Munoz, D R

    2012-02-10

    Drugs are important risk factors for traffic accidents. In Brazil, truck drivers report using amphetamines to maintain their extensive work schedule and stay awake. These drugs can be obtained without prescription easily on Brazilian roads. The use of these stimulants can result in health problems and can be associated with traffic accidents. There are Brazilian studies that show that drivers use drugs. However, these studies are questionnaire-based and do not always reflect real-life situations. The purpose of this study was to demonstrate the prevalence of drug use by truck drivers on the roads of Sao Paulo State, Brazil, during 2009. Drivers of large trucks were randomly stopped by police officers on the interstate roads during morning hours. After being informed of the goals of the study, the drivers gave written informed consent before providing a urine sample. In addition, a questionnaire concerning sociodemographic characteristics and health information was administered. Urine samples were screened for amphetamines, cocaine, and cannabinoids by immunoassay and the confirmation was performed using gas chromatography-mass spectrometry (GC-MS). Of the 488 drivers stopped, 456 (93.4%) provided urine samples, and 9.3% of them (n=42) tested positive for drugs. Amphetamines were the most commonly found (n=26) drug, representing 61.9% of the positive samples. Ten cases tested positive for cocaine (23.8%), and five for cannabinoids (11.9%). All drivers were male with a mean age of 40 ± 10.8 years, and 29.3% of them reported some health problem (diabetes, high blood pressure and/or stress). A high incidence of truck drivers who tested positive for drug use was found, among other reported health problems. Thus, there is an evident need to promote a healthier lifestyle among professional drivers and a need for preventive measures aimed at controlling the use of drugs by truck drivers in Brazil.

  10. The somatic mutation profiles of 2,433 breast cancers refines their genomic and transcriptomic landscapes

    PubMed Central

    Pereira, Bernard; Chin, Suet-Feung; Rueda, Oscar M.; Vollan, Hans-Kristian Moen; Provenzano, Elena; Bardwell, Helen A.; Pugh, Michelle; Jones, Linda; Russell, Roslin; Sammut, Stephen-John; Tsui, Dana W. Y.; Liu, Bin; Dawson, Sarah-Jane; Abraham, Jean; Northen, Helen; Peden, John F.; Mukherjee, Abhik; Turashvili, Gulisa; Green, Andrew R.; McKinney, Steve; Oloumi, Arusha; Shah, Sohrab; Rosenfeld, Nitzan; Murphy, Leigh; Bentley, David R.; Ellis, Ian O.; Purushotham, Arnie; Pinder, Sarah E.; Børresen-Dale, Anne-Lise; Earl, Helena M.; Pharoah, Paul D.; Ross, Mark T.; Aparicio, Samuel; Caldas, Carlos

    2016-01-01

    The genomic landscape of breast cancer is complex, and inter- and intra-tumour heterogeneity are important challenges in treating the disease. In this study, we sequence 173 genes in 2,433 primary breast tumours that have copy number aberration (CNA), gene expression and long-term clinical follow-up data. We identify 40 mutation-driver (Mut-driver) genes, and determine associations between mutations, driver CNA profiles, clinical-pathological parameters and survival. We assess the clonal states of Mut-driver mutations, and estimate levels of intra-tumour heterogeneity using mutant-allele fractions. Associations between PIK3CA mutations and reduced survival are identified in three subgroups of ER-positive cancer (defined by amplification of 17q23, 11q13–14 or 8q24). High levels of intra-tumour heterogeneity are in general associated with a worse outcome, but highly aggressive tumours with 11q13–14 amplification have low levels of intra-tumour heterogeneity. These results emphasize the importance of genome-based stratification of breast cancer, and have important implications for designing therapeutic strategies. PMID:27161491

  11. Young driver risky behaviour and predictors of crash risk in Australia, New Zealand and Colombia: Same but different?

    PubMed

    Scott-Parker, Bridie; Oviedo-Trespalacios, Oscar

    2017-02-01

    Young drivers remain overrepresented in road crashes around the world, with road injury the leading cause of death among adolescents. In addition, the majority of road traffic crashes, fatalities and injuries occur in low- and middle-income countries. All young drivers are at risk due to a breadth of age- and inexperience-related factors; however it is well recognised that young drivers may also intentionally engage in risky driving behaviours which increase their crash risk. The aim of this paper is to examine the self-reported risky driving behaviour of young drivers in Australia, New Zealand (high-income countries), and Colombia (middle-income country), and to explore the utility of a crash risk assessment model in these three countries. Young drivers aged 16-25 years completed the Behaviour of Young Novice Drivers Scale (BYNDS), in addition to self-reporting crash involvement and driving offences. A hierarchical segmentation analysis via decision trees was used to study the relationship between self-reported crashes and risky driving. Young drivers in Colombia reported more risky driving than young drivers in New Zealand, and considerably more risky driving than young drivers in Australia. Significant differences among and across countries in individual BYNDS items were found, and 23.5% of all participants reported they had been involved in a road crash. Handheld mobile phone usage was the strongest predictor of crashes, followed by driving after drinking alcohol, and carrying friends as passengers. Country of origin predicted mobile phone usage, with New Zealand and Colombia grouped in the same decision tree branch which implies no significant differences in the behaviour between these countries. Despite cultural differences in licensing programs and enforcement, young drivers reported engaging in a similar breadth of risky behaviours. Road crashes were explained by mobile phone usage, drink driving and driving with passengers, suggesting interventions should

  12. Differences in driver genes between smoking-related and non-smoking-related lung cancer in the Chinese population.

    PubMed

    Gou, Lan-Ying; Niu, Fei-Yu; Wu, Yi-Long; Zhong, Wen-Zhao

    2015-09-01

    Recently, non-smoking-related lung cancer was classified as an independent disease entity because it is different from tobacco-associated lung cancer. Non-smoking-related lung cancer occurs more often in women than men, and the predominant histological type is adenocarcinoma (ADC) rather than squamous cell carcinoma. Most of the driver gene alterations that have been identified in ADC in never-smokers include epidermal growth factor receptor mutations, KRAS mutations, echinoderm microtubule-associated protein like 4/anaplastic lymphoma kinase fusion, and ROS1 fusion, among others. Meanwhile, significant progress has been made in the treatment of ADC. However, in comparison with ADC, no such available molecular targets exist for smoking-associated lung cancer, for which treatment strategies are limited. Next-generation sequencing has been widely applied to the discovery of more genetic profiles of lung cancers. This review summarizes the differences between smoking-related and non-smoking-related lung cancer as follows: different somatic mutation burdens, C:G→A:T transversions, common and novel driver genes, and treatment strategies. Overall, smoking-related lung cancer is more complicated than non-smoking-related lung cancer. Furthermore, we review the prevalence of driver genes in smoking-associated and non-smoking-associated lung cancers in the Chinese population.

  13. Passive in-vehicle driver breath alcohol detection using advanced sensor signal acquisition and fusion.

    PubMed

    Ljungblad, Jonas; Hök, Bertil; Allalou, Amin; Pettersson, Håkan

    2017-04-03

    The research objective of the present investigation is to demonstrate the present status of passive in-vehicle driver breath alcohol detection and highlighting the necessary conditions for large scale implementation of such a system. Completely passive detection has remained a challenge mainly because of the requirements on signal resolution combined with the constraints of vehicle integration. The work is part of the DADSS (driver alcohol detection system for safety) program aiming at massive deployment of alcohol sensing systems which could potentially save thousands of American lives annually. The work reported here builds on earlier investigations, in which it has been shown that detection of alcohol vapor in the proximity of a human subject may be traced to that subject by means of simultaneous recording of carbon dioxide (CO2) at the same location. Sensors based on infrared spectroscopy were developed to detect and quantify low concentrations of alcohol and CO2. In the present investigation, alcohol and CO2 were recorded at various locations in a vehicle cabin while human subjects were performing normal in-step procedures and driving preparations. A video camera directed to the driver position was recording images of the driver's upper body parts including the face, and the images were analyzed with respect to features of significance to the breathing behavior and breath detection, such as mouth opening and head direction. Improvement of the sensor system with respect to signal resolution including algorithm and software development, and fusion of the sensor and camera signals was successfully implemented and tested before starting the human study. In addition, experimental tests and simulations were performed with the purpose of connecting human subject data with repeatable experimental conditions. The results include occurrence statistics of detected breaths by signal peaks of CO2 and alcohol. From the statistical data, the accuracy of breath alcohol

  14. [Investigation of Legionella pneumophila seropositivity in the professional long distance drivers as a risky occupation].

    PubMed

    Polat, Yusuf; Ergin, Cağri; Kaleli, Ilknur; Pinar, Ahmet

    2007-04-01

    Contaminated water sources, reservoirs and systems such as evaporative condensers of air-conditioners are known to be the main transmission routes of Legionella spp. which are ubiquitous aquatic bacteria. By virtue of this point the aim of this study was to investigate the rate of Legionella pneumophila seropositivity in a profession considered as risky due to the direct and prolonged exposure to air-conditioning and air-circulating systems. For this purpose, in the period of February-August 2004 a total of 79 male subjects (63 were bus drivers and 16 were driver assistants) who were continously travelling to two different route (South part as hot climate and Middle/North parts as cold climate of Turkey) from Denizli province coach station (a province located in internal Aegian where accepted as crossroads), were included to the study. The mean age and mean working duration of bus drivers were 43.0 +/- 1.1 years and 20.0 +/- 1.1 years, respectively, while these values were 22.5 +/- 0.9 years and 4.0 +/- 0.6 years, respectively, for the drivers' assistants. The serum samples collected from the subjects were screened by a commercial indirect immunofluorescence method (Euroimmun, Germany) using L. pneumophila serogrup 1-14 antigens for the presence of specific antibodies. Additionally, air-conditioners' moisture exhaust samples of the busses in which seropositive subjects travelling with have been examined by culture and 5S rRNA gene targeted polymerase chain reaction (PCR) methods, for the presence of Legionella spp. The overall L. pneumophila seropositivity rate was detected as 15.2% (12/79). This rate was 19% (12/63) for bus drivers while all of the drivers' assistants were found seronegative. The seropositivity rate was found statistically higher in the personnel who were travelling to the hot climates (10/36, 27.8%) than those who travel to cold climates (2/43, 4.6%), (p < 0.05). The culture and PCR yielded negative results for Legionella spp. in the exhaust

  15. Beyond BRAF(V600): clinical mutation panel testing by next-generation sequencing in advanced melanoma.

    PubMed

    Siroy, Alan E; Boland, Genevieve M; Milton, Denái R; Roszik, Jason; Frankian, Silva; Malke, Jared; Haydu, Lauren; Prieto, Victor G; Tetzlaff, Michael; Ivan, Doina; Wang, Wei-Lien; Torres-Cabala, Carlos; Curry, Jonathan; Roy-Chowdhuri, Sinchita; Broaddus, Russell; Rashid, Asif; Stewart, John; Gershenwald, Jeffrey E; Amaria, Rodabe N; Patel, Sapna P; Papadopoulos, Nicholas E; Bedikian, Agop; Hwu, Wen-Jen; Hwu, Patrick; Diab, Adi; Woodman, Scott E; Aldape, Kenneth D; Luthra, Rajyalakshmi; Patel, Keyur P; Shaw, Kenna R; Mills, Gordon B; Mendelsohn, John; Meric-Bernstam, Funda; Kim, Kevin B; Routbort, Mark J; Lazar, Alexander J; Davies, Michael A

    2015-02-01

    The management of melanoma has evolved owing to improved understanding of its molecular drivers. To augment the current understanding of the prevalence, patterns, and associations of mutations in this disease, the results of clinical testing of 699 advanced melanoma patients using a pan-cancer next-generation sequencing (NGS) panel of hotspot regions in 46 genes were reviewed. Mutations were identified in 43 of the 46 genes on the panel. The most common mutations were BRAFV600 (36%), NRAS (21%), TP53 (16%), BRAFNon-V600 (6%), and KIT (4%). Approximately one-third of melanomas had >1 mutation detected, and the number of mutations per tumor was associated with melanoma subtype. Concurrent TP53 mutations were the most frequent events in tumors with BRAFV600 and NRAS mutations. Melanomas with BRAFNon-V600mutations frequently harbored concurrent NRAS mutations (18%), which were rare in tumors with BRAFV600 mutations (1.6%). The prevalence of BRAFV600 and KIT mutations were significantly associated with melanoma subtypes, and BRAFV600 and TP53 mutations were significantly associated with cutaneous primary tumor location. Multiple potential therapeutic targets were identified in metastatic unknown primary and cutaneous melanomas that lacked BRAFV600 and NRAS mutations. These results enrich our understanding of the patterns and clinical associations of oncogenic mutations in melanoma.

  16. Mutational landscape, clonal evolution patterns, and role of RAS mutations in relapsed acute lymphoblastic leukemia

    PubMed Central

    Oshima, Koichi; Khiabanian, Hossein; da Silva-Almeida, Ana C.; Tzoneva, Gannie; Abate, Francesco; Ambesi-Impiombato, Alberto; Sanchez-Martin, Marta; Carpenter, Zachary; Penson, Alex; Perez-Garcia, Arianne; Eckert, Cornelia; Nicolas, Concepción; Balbin, Milagros; Sulis, Maria Luisa; Kato, Motohiro; Koh, Katsuyoshi; Paganin, Maddalena; Basso, Giuseppe; Gastier-Foster, Julie M.; Devidas, Meenakshi; Loh, Mignon L.; Kirschner-Schwabe, Renate; Palomero, Teresa; Rabadan, Raul; Ferrando, Adolfo A.

    2016-01-01

    Although multiagent combination chemotherapy is curative in a significant fraction of childhood acute lymphoblastic leukemia (ALL) patients, 20% of cases relapse and most die because of chemorefractory disease. Here we used whole-exome and whole-genome sequencing to analyze the mutational landscape at relapse in pediatric ALL cases. These analyses identified numerous relapse-associated mutated genes intertwined in chemotherapy resistance-related protein complexes. In this context, RAS-MAPK pathway-activating mutations in the neuroblastoma RAS viral oncogene homolog (NRAS), kirsten rat sarcoma viral oncogene homolog (KRAS), and protein tyrosine phosphatase, nonreceptor type 11 (PTPN11) genes were present in 24 of 55 (44%) cases in our series. Interestingly, some leukemias showed retention or emergence of RAS mutant clones at relapse, whereas in others RAS mutant clones present at diagnosis were replaced by RAS wild-type populations, supporting a role for both positive and negative selection evolutionary pressures in clonal evolution of RAS-mutant leukemia. Consistently, functional dissection of mouse and human wild-type and mutant RAS isogenic leukemia cells demonstrated induction of methotrexate resistance but also improved the response to vincristine in mutant RAS-expressing lymphoblasts. These results highlight the central role of chemotherapy-driven selection as a central mechanism of leukemia clonal evolution in relapsed ALL, and demonstrate a previously unrecognized dual role of RAS mutations as drivers of both sensitivity and resistance to chemotherapy. PMID:27655895

  17. Effective Temperature of Mutations

    NASA Astrophysics Data System (ADS)

    Derényi, Imre; Szöllősi, Gergely J.

    2015-02-01

    Biological macromolecules experience two seemingly very different types of noise acting on different time scales: (i) point mutations corresponding to changes in molecular sequence and (ii) thermal fluctuations. Examining the secondary structures of a large number of microRNA precursor sequences and model lattice proteins, we show that the effects of single point mutations are statistically indistinguishable from those of an increase in temperature by a few tens of kelvins. The existence of such an effective mutational temperature establishes a quantitative connection between robustness to genetic (mutational) and environmental (thermal) perturbations.

  18. Driver and Traffic Safety Education Policies.

    ERIC Educational Resources Information Center

    New York State Education Dept., Albany. Div. of General Education.

    The policy statement outlines New York State standards regarding: (1) the driver's education program; (2) vehicles in the program; (3) administration, supervision, and organization of summer school programs; (4) teachers in the program; and (5) pupils in the program. A glossary defines terms and instructional objectives. Program policies…

  19. Driver behaviour with adaptive cruise control.

    PubMed

    Stanton, Neville A; Young, Mark S

    2005-08-15

    This paper reports on the evaluation of adaptive cruise control (ACC) from a psychological perspective. It was anticipated that ACC would have an effect upon the psychology of driving, i.e. make the driver feel like they have less control, reduce the level of trust in the vehicle, make drivers less situationally aware, but workload might be reduced and driving might be less stressful. Drivers were asked to drive in a driving simulator under manual and ACC conditions. Analysis of variance techniques were used to determine the effects of workload (i.e. amount of traffic) and feedback (i.e. degree of information from the ACC system) on the psychological variables measured (i.e. locus of control, trust, workload, stress, mental models and situation awareness). The results showed that: locus of control and trust were unaffected by ACC, whereas situation awareness, workload and stress were reduced by ACC. Ways of improving situation awareness could include cues to help the driver predict vehicle trajectory and identify conflicts.

  20. Driver and Traffic Safety Education Curriculum Guide.

    ERIC Educational Resources Information Center

    Massachusetts State Dept. of Education, Boston. Bureau of Elementary and Secondary Education.

    Materials contained in this Massachusetts curriculum guide are based on concepts and procedures developed by the Highway Users Federation for Safety and Mobility. The guide examines the philosophy of driver education, discusses such legal aspects as certification of students and teachers, presents a comprehensive classroom and behind-the-wheel…

  1. Fail-safe bidirectional valve driver

    NASA Technical Reports Server (NTRS)

    Fujimoto, H.

    1974-01-01

    Cross-coupled diodes are added to commonly used bidirectional valve driver circuit to protect circuit and power supply. Circuit may be used in systems requiring fail-safe bidirectional valve operation, particularly in chemical- and petroleum-processing control systems and computer-controlled hydraulic or pneumatic systems.

  2. Multi-Phase Driver Education Teaching Guide.

    ERIC Educational Resources Information Center

    Hurst-Euless-Bedford Independent School District, Hurst, TX.

    For use in planning and conducting functional multi-phase driver education programs, this teacher's guide consists of four phases of instruction: classroom activities, simulated application, in-car range practice, and in-car public practice. Contents are divided into three instructional sections, with the first combining the classroom activities…

  3. Evasive and Emergency Curriculum for Driver Education.

    ERIC Educational Resources Information Center

    1976

    An advanced course to increase the student's driving ability and knowledge of the automobile is presented in this curriculum guide for use by high school driver education instructors. The course is designed for students who have been driving for 6 to 12 months or who have mastered basic driving skills. Focus is on advanced driving techniques,…

  4. What Are Drivers for Informal Learning?

    ERIC Educational Resources Information Center

    Schürmann, Eva; Beausaert, Simon

    2016-01-01

    Purpose: The topic of informal learning at work has received increasing attention in the past years. The purpose of this study is to explore in which informal learning activities employees engage and what are the drivers for informal learning. Design/Methodology/Approach: Semi-structured interviews were taken from ten human resources (HR) and ten…

  5. Michael Driver: A Career Life to Remember

    ERIC Educational Resources Information Center

    Sundby, Dianne; Derr, C. Brooklyn

    2007-01-01

    Purpose: The purpose of this paper is to present a retrospective of the career life of Michael Driver, from the time of his Princeton graduate studies and early faculty years at Purdue University through the over three decades he spent at USC. Design/methodology/approach: The history and development of his theoretical and research interests are…

  6. Driver Education for Motorcycle Operation. Final Report.

    ERIC Educational Resources Information Center

    Council, Forrest M.; And Others

    A three-year pilot project was conducted to evaluate the feasibility of implementing a statewide off-road motorcycle training program for beginning drivers in North Carolina. The first year of the program involved approximately 422 students from five locations, the second year involved seven sites across the State. The three basic criteria for the…

  7. 45 CFR 1310.16 - Driver qualifications.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 45 Public Welfare 4 2012-10-01 2012-10-01 false Driver qualifications. 1310.16 Section 1310.16 Public Welfare Regulations Relating to Public Welfare (Continued) OFFICE OF HUMAN DEVELOPMENT SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES THE ADMINISTRATION FOR CHILDREN, YOUTH AND FAMILIES, HEAD...

  8. 45 CFR 1310.16 - Driver qualifications.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 45 Public Welfare 4 2010-10-01 2010-10-01 false Driver qualifications. 1310.16 Section 1310.16 Public Welfare Regulations Relating to Public Welfare (Continued) OFFICE OF HUMAN DEVELOPMENT SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES THE ADMINISTRATION FOR CHILDREN, YOUTH AND FAMILIES, HEAD...

  9. Oncogenic PIK3CA mutations occur in epidermal nevi and seborrheic keratoses with a characteristic mutation pattern

    PubMed Central

    Hafner, Christian; López-Knowles, Elena; Luis, Nuno M.; Toll, Agustí; Baselga, Eulàlia; Fernández-Casado, Alex; Hernández, Silvia; Ribé, Adriana; Mentzel, Thomas; Stoehr, Robert; Hofstaedter, Ferdinand; Landthaler, Michael; Vogt, Thomas; Pujol, Ramòn M.; Hartmann, Arndt; Real, Francisco X.

    2007-01-01

    Activating mutations of the p110 α subunit of PI3K (PIK3CA) oncogene have been identified in a broad spectrum of malignant tumors. However, their role in benign or preneoplastic conditions is unknown. Activating FGF receptor 3 (FGFR3) mutations are common in benign skin lesions, either as embryonic mutations in epidermal nevi (EN) or as somatic mutations in seborrheic keratoses (SK). FGFR3 mutations are also common in low-grade malignant bladder tumors, where they often occur in association with PIK3CA mutations. Therefore, we examined exons 9 and 20 of PIK3CA and FGFR3 hotspot mutations in EN (n = 33) and SK (n = 62), two proliferative skin lesions lacking malignant potential. Nine of 33 (27%) EN harbored PIK3CA mutations; all cases showed the E545G substitution, which is uncommon in cancers. In EN, R248C was the only FGFR3 mutation identified. By contrast, 10 of 62 (16%) SK revealed the typical cancer-associated PIK3CA mutations E542K, E545K, and H1047R. The same lesions displayed a wide range of FGFR3 mutations. Corresponding unaffected tissue was available for four EN and two mutant SK: all control samples displayed a WT sequence, confirming the somatic nature of the mutations found in lesional tissue. Forty of 95 (42%) lesions showed at least one mutation in either gene. PIK3CA and FGFR3 mutations displayed an independent distribution; 5/95 lesions harbored mutations in both genes. Our findings suggest that, in addition to their role in cancer, oncogenic PIK3CA mutations contribute to the pathogenesis of skin tumors lacking malignant potential. The remarkable genotype–phenotype correlation as observed in this study points to a distinct etiopathogenesis of the mutations in keratinocytes occuring either during fetal development or in adult life. PMID:17673550

  10. Acquired TERT promoter mutations stimulate TERT transcription in mantle cell lymphoma.

    PubMed

    Panero, Julieta; Alves-Paiva, Raquel M; Roisman, Alejandro; Santana-Lemos, Barbara A; Falcão, Roberto P; Oliveira, Gustavo; Martins, Diego; Stanganelli, Carmen; Slavutsky, Irma; Calado, Rodrigo T

    2016-05-01

    Mantle cell lymphoma (MCL) is an aggressive lymphoid neoplasm with poor prognosis. Acquired telomerase reverse transcriptase gene promoter (TERTp) mutations are among the most frequent somatic non-coding mutations in cancers. In this study, the prevalence of TERTp mutations in 24 MCL and 21 other lymphoid neoplasias (oLN) was investigated. Eight MCL samples (33%) carried TERTp mutations, two homozygous and six heterozygous (seven C228T and one C250T), which directly correlated with higher TERT transcription, mitochondrial DNA copy number, and IGHV mutational status in MCL neoplastic cells. TERTp mutations were not found in oLN. TERTp mutations correlated with more lymphoma proliferation and tumor burden, as suggested by the higher number of lymphoma cells circulating in peripheral blood, and tended to associate with longer MCL telomeres, especially in homozygous mutants, although not statistically significant. Telomere-biology genes were overexpressed in MCL cells in comparison to healthy lymphocytes, but were not influenced by mutation status. The findings described for the first time that acquired TERTp mutations are common in MCL but not in other lymphoid neoplasms. It was also demonstrated that TERTp mutations are associated with higher TERT mRNA expression in MCL cells in vivo and higher tumor burden, suggesting these mutations as a driver event in MCL development and progression.

  11. Prevalence of drugs in oral fluid from truck drivers in Brazilian highways.

    PubMed

    Bombana, Henrique Silva; Gjerde, Hallvard; Dos Santos, Marcelo Filonzi; Jamt, Ragnhild Elén Gjulem; Yonamine, Mauricio; Rohlfs, Waldo José Caram; Muñoz, Daniel Romero; Leyton, Vilma

    2017-03-01

    Traffic accidents are responsible for 1.25 million deaths worldwide and are the most common cause of death among those aged 15-29 years. In Brazil, traffic accidents caused more than 44,000 deaths in 2014. The use of psychoactive drugs is an important risk factor for being involved in traffic accidents. Previous studies have found that psychoactive substances are commonly used by truck drivers in Brazil to maintain their extensive work schedule and stay awake while driving during nighttime hours. The state of Sao Paulo is one of the most important states regarding goods transportation. Important highways cross through Sao Paulo to other regions from Brazil and to other countries in Latin America. This study aims to determine the prevalence of illicit drug use by truck drivers in the state of Sao Paulo through toxicological analyses of oral fluid. Truck drivers were randomly stopped by police officers on federal roads during morning hours. Oral fluid samples were collected using the Quantisal™ device. In addition, a questionnaire concerning sociodemographic characteristics and health information was administered. Oral fluid samples were screened for amphetamine,