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Sample records for additional driver mutation

  1. Driver Mutations in Uveal Melanoma

    PubMed Central

    Decatur, Christina L.; Ong, Erin; Garg, Nisha; Anbunathan, Hima; Bowcock, Anne M.; Field, Matthew G.; Harbour, J. William

    2016-01-01

    IMPORTANCE Frequent mutations have been described in the following 5 genes in uveal melanoma (UM): BAP1, EIF1AX, GNA11, GNAQ, and SF3B1. Understanding the prognostic significance of these mutations could facilitate their use in precision medicine. OBJECTIVE To determine the associations between driver mutations, gene expression profile (GEP) classification, clinicopathologic features, and patient outcomes in UM. DESIGN, SETTING, AND PARTICIPANTS Retrospective study of patients with UM treated by enucleation by a single ocular oncologist between November 1, 1998, and July 31, 2014. MAIN OUTCOMES AND MEASURES Clinicopathologic features, patient outcomes, GEP classification (class 1 or class 2), and mutation status were recorded. RESULTS The study cohort comprised 81 participants. Their mean age was 61.5 years, and 37% (30 of 81) were female. The GEP classification was class 1 in 35 of 81 (43%), class 2 in 42 of 81 (52%), and unknown in 4 of 81 (5%). BAP1 mutations were identified in 29 of 64 (45%), GNAQ mutations in 36 of 81 (44%), GNA11 mutations in 36 of 81 (44%), SF3B1 mutations in 19 of 81 (24%), and EIF1AX mutations in 14 of 81 (17%). Sixteen of the mutations in BAP1 and 6 of the mutations in EIF1AX were previously unreported in UM. GNAQ and GNA11 mutations were mutually exclusive. BAP1, SF3B1, and EIF1AX mutations were almost mutually exclusive with each other. Using multiple regression analysis, BAP1 mutations were associated with class 2 GEP and older patient. EIF1AX mutations were associated with class 1 GEP and the absence of ciliary body involvement. SF3B1 mutations were associated with younger patient age. GNAQ mutations were associated with the absence of ciliary body involvement and greater largest basal diameter. GNA11 mutations were not associated with any of the analyzed features. Using Cox proportional hazards modeling, class 2 GEP was the prognostic factor most strongly associated with metastasis (relative risk, 9.4; 95% CI, 3.1–28.5) and

  2. Driver mutations of cancer epigenomes.

    PubMed

    Roy, David M; Walsh, Logan A; Chan, Timothy A

    2014-04-01

    Epigenetic alterations are associated with all aspects of cancer, from tumor initiation to cancer progression and metastasis. It is now well understood that both losses and gains of DNA methylation as well as altered chromatin organization contribute significantly to cancer-associated phenotypes. More recently, new sequencing technologies have allowed the identification of driver mutations in epigenetic regulators, providing a mechanistic link between the cancer epigenome and genetic alterations. Oncogenic activating mutations are now known to occur in a number of epigenetic modifiers (i.e. IDH1/2, EZH2, DNMT3A), pinpointing epigenetic pathways that are involved in tumorigenesis. Similarly, investigations into the role of inactivating mutations in chromatin modifiers (i.e. KDM6A, CREBBP/EP300, SMARCB1) implicate many of these genes as tumor suppressors. Intriguingly, a number of neoplasms are defined by a plethora of mutations in epigenetic regulators, including renal, bladder, and adenoid cystic carcinomas. Particularly striking is the discovery of frequent histone H3.3 mutations in pediatric glioma, a particularly aggressive neoplasm that has long remained poorly understood. Cancer epigenetics is a relatively new, promising frontier with much potential for improving cancer outcomes. Already, therapies such as 5-azacytidine and decitabine have proven that targeting epigenetic alterations in cancer can lead to tangible benefits. Understanding how genetic alterations give rise to the cancer epigenome will offer new possibilities for developing better prognostic and therapeutic strategies. PMID:24622842

  3. A Landscape of Driver Mutations in Melanoma

    PubMed Central

    Hodis, Eran; Watson, Ian R.; Kryukov, Gregory V.; Arold, Stefan T.; Imielinski, Marcin; Theurillat, Jean-Philippe; Nickerson, Elizabeth; Auclair, Daniel; Li, Liren; Place, Chelsea; DiCara, Daniel; Ramos, Alex H.; Lawrence, Michael S.; Cibulskis, Kristian; Sivachenko, Andrey; Voet, Douglas; Saksena, Gordon; Stransky, Nicolas; Onofrio, Robert C.; Winckler, Wendy; Ardlie, Kristin; Wagle, Nikhil; Wargo, Jennifer; Chong, Kelly; Morton, Donald L.; Stemke-Hale, Katherine; Chen, Guo; Noble, Michael; Meyerson, Matthew; Ladbury, John E.; Davies, Michael A.; Gershenwald, Jeffrey E.; Wagner, Stephan N.; Hoon, Dave S.B.; Schadendorf, Dirk; Lander, Eric S.; Gabriel, Stacey B.; Getz, Gad; Garraway, Levi A.; Chin, Lynda

    2012-01-01

    SUMMARY Despite recent insights into melanoma genetics, systematic surveys for driver mutations are challenged by an abundance of passenger mutations caused by carcinogenic ultraviolet (UV) light exposure. We developed a permutation-based framework to address this challenge, employing mutation data from intronic sequences to control for passenger mutational load on a per gene basis. Analysis of large-scale melanoma exome data by this approach discovered six novel melanoma genes (PPP6C, RAC1, SNX31, TACC1, STK19 and ARID2), three of which - RAC1, PPP6C and STK19 - harbored recurrent and potentially targetable mutations. Integration with chromosomal copy number data contextualized the landscape of driver mutations, providing oncogenic insights in BRAF- and NRAS-driven melanoma as well as those without known NRAS/BRAF mutations. The landscape also clarified a mutational basis for RB and p53 pathway deregulation in this malignancy. Finally, the spectrum of driver mutations provided unequivocal genomic evidence for a direct mutagenic role of UV light in melanoma pathogenesis. PMID:22817889

  4. 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.

  5. Prediction of cancer driver mutations in protein kinases.

    PubMed

    Torkamani, Ali; Schork, Nicholas J

    2008-03-15

    A large number of somatic mutations accumulate during the process of tumorigenesis. A subset of these mutations contribute to tumor progression (known as "driver" mutations) whereas the majority of these mutations are effectively neutral (known as "passenger" mutations). The ability to differentiate between drivers and passengers will be critical to the success of upcoming large-scale cancer DNA resequencing projects. Here we show a method capable of discriminating between drivers and passengers in the most frequently cancer-associated protein family, protein kinases. We apply this method to multiple cancer data sets, validating its accuracy by showing that it is capable of identifying known drivers, has excellent agreement with previous statistical estimates of the frequency of drivers, and provides strong evidence that predicted drivers are under positive selection by various sequence and structural analyses. Furthermore, we identify particular positions in protein kinases that seem to play a role in oncogenesis. Finally, we provide a ranked list of candidate driver mutations. PMID:18339846

  6. Prioritization of driver mutations in pancreatic cancer using cancer-specific high-throughput annotation of somatic mutations (CHASM).

    PubMed

    Carter, Hannah; Samayoa, Josue; Hruban, Ralph H; Karchin, Rachel

    2010-09-15

    Over 20,000 genes were recently sequenced in a series of 24 pancreatic cancers. We applied CHASM (Cancer-specific High-throughput Annotation of Somatic Mutations) to 963 of the missense somatic missense mutations discovered in these 24 cancers. CHASM identified putative driver mutations (false discovery rate ≤0.3) in three known pancreatic cancer driver genes (P53, SMAD4, CDKN2A). An additional 15 genes with putative driver mutations include genes coding for kinases (PIK3CG, DGKA, STK33, TTK and PRKCG), for cell cycle related proteins (NEK8), and for proteins involved in cell adhesion (CMAS, PCDHB2). These and other mutations identified by CHASM point to potential "driver genes" in pancreatic cancer that should be prioritized for additional follow-up. PMID:20581473

  7. 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. PMID:26320871

  8. 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/ PMID:25414382

  9. 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. PMID:27118146

  10. Clonal architectures and driver mutations in metastatic melanomas.

    PubMed

    Ding, Li; Kim, Minjung; Kanchi, Krishna L; Dees, Nathan D; Lu, Charles; Griffith, Malachi; Fenstermacher, David; Sung, Hyeran; Miller, Christopher A; Goetz, Brian; Wendl, Michael C; Griffith, Obi; Cornelius, Lynn A; Linette, Gerald P; McMichael, Joshua F; Sondak, Vernon K; Fields, Ryan C; Ley, Timothy J; Mulé, James J; Wilson, Richard K; Weber, Jeffrey S

    2014-01-01

    To reveal the clonal architecture of melanoma and associated driver mutations, whole genome sequencing (WGS) and targeted extension sequencing were used to characterize 124 melanoma cases. Significantly mutated gene analysis using 13 WGS cases and 15 additional paired extension cases identified known melanoma genes such as BRAF, NRAS, and CDKN2A, as well as a novel gene EPHA3, previously implicated in other cancer types. Extension studies using tumors from another 96 patients discovered a large number of truncation mutations in tumor suppressors (TP53 and RB1), protein phosphatases (e.g., PTEN, PTPRB, PTPRD, and PTPRT), as well as chromatin remodeling genes (e.g., ASXL3, MLL2, and ARID2). Deep sequencing of mutations revealed subclones in the majority of metastatic tumors from 13 WGS cases. Validated mutations from 12 out of 13 WGS patients exhibited a predominant UV signature characterized by a high frequency of C->T transitions occurring at the 3' base of dipyrimidine sequences while one patient (MEL9) with a hypermutator phenotype lacked this signature. Strikingly, a subclonal mutation signature analysis revealed that the founding clone in MEL9 exhibited UV signature but the secondary clone did not, suggesting different mutational mechanisms for two clonal populations from the same tumor. Further analysis of four metastases from different geographic locations in 2 melanoma cases revealed phylogenetic relationships and highlighted the genetic alterations responsible for differential drug resistance among metastatic tumors. Our study suggests that clonal evaluation is crucial for understanding tumor etiology and drug resistance in melanoma. PMID:25393105

  11. Clonal Architectures and Driver Mutations in Metastatic Melanomas

    PubMed Central

    Dees, Nathan D.; Lu, Charles; Griffith, Malachi; Fenstermacher, David; Sung, Hyeran; Miller, Christopher A.; Goetz, Brian; Wendl, Michael C.; Griffith, Obi; Cornelius, Lynn A.; Linette, Gerald P.; McMichael, Joshua F.; Sondak, Vernon K.; Fields, Ryan C.; Ley, Timothy J.; Mulé, James J.; Wilson, Richard K.; Weber, Jeffrey S.

    2014-01-01

    To reveal the clonal architecture of melanoma and associated driver mutations, whole genome sequencing (WGS) and targeted extension sequencing were used to characterize 124 melanoma cases. Significantly mutated gene analysis using 13 WGS cases and 15 additional paired extension cases identified known melanoma genes such as BRAF, NRAS, and CDKN2A, as well as a novel gene EPHA3, previously implicated in other cancer types. Extension studies using tumors from another 96 patients discovered a large number of truncation mutations in tumor suppressors (TP53 and RB1), protein phosphatases (e.g., PTEN, PTPRB, PTPRD, and PTPRT), as well as chromatin remodeling genes (e.g., ASXL3, MLL2, and ARID2). Deep sequencing of mutations revealed subclones in the majority of metastatic tumors from 13 WGS cases. Validated mutations from 12 out of 13 WGS patients exhibited a predominant UV signature characterized by a high frequency of C->T transitions occurring at the 3′ base of dipyrimidine sequences while one patient (MEL9) with a hypermutator phenotype lacked this signature. Strikingly, a subclonal mutation signature analysis revealed that the founding clone in MEL9 exhibited UV signature but the secondary clone did not, suggesting different mutational mechanisms for two clonal populations from the same tumor. Further analysis of four metastases from different geographic locations in 2 melanoma cases revealed phylogenetic relationships and highlighted the genetic alterations responsible for differential drug resistance among metastatic tumors. Our study suggests that clonal evaluation is crucial for understanding tumor etiology and drug resistance in melanoma. PMID:25393105

  12. 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

  13. 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. PMID:27625789

  14. The Importance of Mutational Drivers in GBM.

    PubMed

    Kalkan, Rasime

    2016-01-01

    Glioblastoma (GBM) is the most aggressive primary brain tumor, providing few effective therapeutic options, given the tumor heterogeneity and the accumulation of different genetic abnormalities that cause treatment failure. The many different genetic and epigenetic alterations present in GBM lead to modification of several major signaling pathways resulting in brain tumor growth, progression, and therapeutic resistance. Many functionally important mutations have been discovered, known as neutral passengers. IDH1/2, EZH2, and DNMT3A are the best known epigenetic modifiers in cancer. These mutations are important in determining disease prognosis such that the status of the MGMT gene is a direct target of chemotherapy. For these reasons, newly developed technologies are necessary to determine new candidate targets for targeted-therapy development in GBM. The determination of mutations will aid in this and in the discovery of combinations of targeted and conventional therapies to improve GBM treatment. PMID:27278882

  15. Profiling of potential driver mutations in sarcomas by targeted next generation sequencing.

    PubMed

    Andersson, Carola; Fagman, Henrik; Hansson, Magnus; Enlund, Fredrik

    2016-04-01

    Comprehensive genetic profiling by massively parallel sequencing, commonly known as next generation sequencing (NGS), is becoming the foundation of personalized oncology. For sarcomas very few targeted treatments are currently in routine use. In clinical practice the preoperative diagnostic workup of soft tissue tumours largely relies on core needle biopsies. Although mostly sufficient for histopathological diagnosis, only very limited amounts of formalin fixated paraffin embedded tissue are often available for predictive mutation analysis. Targeted NGS may thus open up new possibilities for comprehensive characterization of scarce biopsies. We therefore set out to search for driver mutations by NGS in a cohort of 55 clinically and morphologically well characterized sarcomas using low input of DNA from formalin fixated paraffin embedded tissues. The aim was to investigate if there are any recurrent or targetable aberrations in cancer driver genes in addition to known chromosome translocations in different types of sarcomas. We employed a panel covering 207 mutation hotspots in 50 cancer-associated genes to analyse DNA from nine gastrointestinal stromal tumours, 14 synovial sarcomas, seven myxoid liposarcomas, 22 Ewing sarcomas and three Ewing-like small round cell tumours at a large sequencing depth to detect also mutations that are subclonal or occur at low allele frequencies. We found nine mutations in eight different potential driver genes, some of which are potentially actionable by currently existing targeted therapies. Even though no recurrent mutations in driver genes were found in the different sarcoma groups, we show that targeted NGS-based sequencing is clearly feasible in a diagnostic setting with very limited amounts of paraffin embedded tissue and may provide novel insights into mesenchymal cell signalling and potentially druggable targets. Interestingly, we also identify five non-synonymous sequence variants in 4 established cancer driver genes in DNA

  16. ATRX driver mutation in a composite malignant pheochromocytoma.

    PubMed

    Comino-Méndez, Iñaki; Tejera, Águeda M; Currás-Freixes, María; Remacha, Laura; Gonzalvo, Pablo; Tonda, Raúl; Letón, Rocío; Blasco, María A; Robledo, Mercedes; Cascón, Alberto

    2016-06-01

    Pheochromocytomas (PCCs) and paragangliomas (PGLs) are tumors arising from the adrenal medulla and sympathetic/parasympathetic paraganglia, respectively. Approximately 40% of PCCs/PGLs are due to germline mutations in one of 16 susceptibility genes, and a further 30% are due to somatic alterations in 5 main genes. Recently, somatic ATRX mutations have been found in succinate dehydrogenase (SDH)-associated hereditary PCCs/PGLs. In the present study we applied whole-exome sequencing to the germline and tumor DNA of a patient with metastatic composite PCC and no alterations in known PCC/PGL susceptibility genes. A somatic loss-of-function mutation affecting ATRX was identified in tumor DNA. Transcriptional profiling analysis classified the tumor within cluster 2 of PCCs/PGLs (without SDH gene mutations) and identified downregulation of genes involved in neuronal development and homeostasis (NLGN4, CD99 and CSF2RA) as well as upregulation of Drosha, an important gene involved in miRNA and rRNA processing. CpG island methylator phenotype typical of SDH gene-mutated tumors was ruled out, and SNP array data revealed a unique profile of gains and losses. Finally, we demonstrated the presence of alternative lengthening of telomeres in the tumor, probably associated with the failure of ATRX functions. In conclusion, somatic variants affecting ATRX may play a driver role in sporadic PCC/PGL. PMID:27209355

  17. CanDrA: cancer-specific driver missense mutation annotation with optimized features.

    PubMed

    Mao, Yong; Chen, Han; Liang, Han; Meric-Bernstam, Funda; Mills, Gordon B; Chen, Ken

    2013-01-01

    Driver mutations are somatic mutations that provide growth advantage to tumor cells, while passenger mutations are those not functionally related to oncogenesis. Distinguishing drivers from passengers is challenging because drivers occur much less frequently than passengers, they tend to have low prevalence, their functions are multifactorial and not intuitively obvious. Missense mutations are excellent candidates as drivers, as they occur more frequently and are potentially easier to identify than other types of mutations. Although several methods have been developed for predicting the functional impact of missense mutations, only a few have been specifically designed for identifying driver mutations. As more mutations are being discovered, more accurate predictive models can be developed using machine learning approaches that systematically characterize the commonality and peculiarity of missense mutations under the background of specific cancer types. Here, we present a cancer driver annotation (CanDrA) tool that predicts missense driver mutations based on a set of 95 structural and evolutionary features computed by over 10 functional prediction algorithms such as CHASM, SIFT, and MutationAssessor. Through feature optimization and supervised training, CanDrA outperforms existing tools in analyzing the glioblastoma multiforme and ovarian carcinoma data sets in The Cancer Genome Atlas and the Cancer Cell Line Encyclopedia project. PMID:24205039

  18. [Driver gene mutation and targeted therapy of lung cancer].

    PubMed

    Mitsudomi, Tetsuya

    2013-03-01

    Although cancers may have many genetic alterations, there are only a few mutations actually associated with essential traits of cancer cells such as cell proliferation or evasion from apoptosis. Because cancer cells are "addicted" to these "drive genes" , pharmacologic inhibition of these gene function is highly effective. Epidermal growth factor receptor(EGFR)-tyrosine kinase inhibitor(TKI)(such as gefitinib or erlotinib)treatment of lung cancer harboring EGFR gene mutation is one of the prototypes of such therapies. Several clinical trials clearly demonstrated that progression-free survival of patients treated with EGFR-TKI is significantly longer than that of those treated by conventional platinum doublet chemotherapy. EGFR-TKI therapy dramatically changed the paradigm of lung cancer treatment. Furthermore, in 2012, crizotinib was approved for lung cancer treatment with anaplastic lymphoma kinase(ALK)gene translocation. Targeted therapies for lung cancers "addicted" to other driver gene mutations including ROS1, RET or HER2 are also under development. Through these personalized approaches, lung cancer is changing from an acute fatal disease to a more chronic disease, and eventually we might be able to cure it. PMID:23507588

  19. Multi-institutional oncogenic driver mutation analysis in lung adenocarcinoma: The Lung Cancer Mutation Consortium experience

    PubMed Central

    Dias-Santagata, Dora; Wistuba, Ignacio I.; Chen, Heidi; Fujimoto, Junya; Kugler, Kelly; Franklin, Wilbur A.; Iafrate, A. John; Ladanyi, Marc; Kris, Mark G.; Johnson, Bruce E.; Bunn, Paul A.; Minna, John D.; Kwiatkowski, David J.

    2015-01-01

    Introduction Molecular genetic analyses of lung adenocarcinoma have recently become standard of care for treatment selection. The Lung Cancer Mutation Consortium was formed to enable collaborative multi-institutional analyses of 10 potential oncogenic driver mutations. Technical aspects of testing, and clinicopathologic correlations are presented. Methods Mutation testing in at least one of 8 genes (EGFR, KRAS, ERBB2, AKT1, BRAF, MEK1, NRAS, PIK3CA) using SNaPshot, mass spectrometry, Sanger sequencing +/− PNA and/or sizing assays, along with ALK and/or MET FISH were performed in 6 labs on 1007 patients from 14 institutions. Results 1007 specimens had mutation analysis performed, and 733 specimens had all 10 genes analyzed. Mutation identification rates did not vary by analytic method. Biopsy and cytology specimens were inadequate for testing in 26% and 35% of cases compared to 5% of surgical specimens. Among the 1007 cases with mutation analysis performed, EGFR, KRAS, ALK, and ERBB2 alterations were detected in 22, 25, 8.5, and 2.4% of cases, respectively. EGFR mutations were highly associated with female sex, Asian race, and never smoking status; and less strongly associated with stage IV disease, presence of bone metastases, and absence of adrenal metastases. ALK rearrangements were strongly associated with never smoking status, and more weakly associated with presence of liver metastases. ERBB2 mutations were strongly associated with Asian race and never smoking status. Two mutations were seen in 2.7% of samples, all but one of which involved one or more of PIK3CA, ALK or MET. Conclusion Multi-institutional molecular analysis across multiple platforms, sample types, and institutions can yield consistent results and novel clinicopathological observations. PMID:25738220

  20. Evolutionary triage governs fitness in driver and passenger mutations and suggests targeting never mutations

    PubMed Central

    Gatenby, R A.; Cunningham, J. J.; Brown, J. S.

    2014-01-01

    Genetic and epigenetic changes in cancer cells are typically divided into “drivers” and “passengers”. Drug development strategies target driver mutations, but inter- and intra-tumoral heterogeneity usually results in emergence of resistance. Here we model intratumoral evolution in the context of a fecundity/survivorship trade-off. Simulations demonstrate the fitness value, of any genetic change is not fixed but dependent on evolutionary triage governed by initial cell properties, current selection forces, and prior genotypic/phenotypic trajectories. We demonstrate spatial variations in molecular properties of tumor cells are the result of changes in environmental selection forces such as blood flow. Simulated therapies targeting fitness-increasing (driver) mutations usually decrease the tumor burden but almost inevitably fail due to population heterogeneity. An alternative strategy targets gene mutations that are never observed. Because up or down regulation of these genes unconditionally reduces cellular fitness, they are eliminated by evolutionary triage but can be exploited for targeted therapy. PMID:25407411

  1. 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. PMID:25877892

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

    PubMed Central

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

    2015-01-01

    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-mTORsignaling. 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. PMID:25877892

  3. 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

  4. Simulated annealing based algorithm for identifying mutated driver pathways in cancer.

    PubMed

    Li, Hai-Tao; Zhang, Yu-Lang; Zheng, Chun-Hou; Wang, Hong-Qiang

    2014-01-01

    With the development of next-generation DNA sequencing technologies, large-scale cancer genomics projects can be implemented to help researchers to identify driver genes, driver mutations, and driver pathways, which promote cancer proliferation in large numbers of cancer patients. Hence, one of the remaining challenges is to distinguish functional mutations vital for cancer development, and filter out the unfunctional and random "passenger mutations." In this study, we introduce a modified method to solve the so-called maximum weight submatrix problem which is used to identify mutated driver pathways in cancer. The problem is based on two combinatorial properties, that is, coverage and exclusivity. Particularly, we enhance an integrative model which combines gene mutation and expression data. The experimental results on simulated data show that, compared with the other methods, our method is more efficient. Finally, we apply the proposed method on two real biological datasets. The results show that our proposed method is also applicable in real practice. PMID:24982873

  5. Driver Gene Mutations in Stools of Colorectal Carcinoma Patients Detected by Targeted Next-Generation Sequencing.

    PubMed

    Armengol, Gemma; Sarhadi, Virinder K; Ghanbari, Reza; Doghaei-Moghaddam, Masoud; Ansari, Reza; Sotoudeh, Masoud; Puolakkainen, Pauli; Kokkola, Arto; Malekzadeh, Reza; Knuutila, Sakari

    2016-07-01

    Detection of driver gene mutations in stool DNA represents a promising noninvasive approach for screening colorectal cancer (CRC). Amplicon-based next-generation sequencing (NGS) is a good option to study mutations in many cancer genes simultaneously and from a low amount of DNA. Our aim was to assess the feasibility of identifying mutations in 22 cancer driver genes with Ion Torrent technology in stool DNA from a series of 65 CRC patients. The assay was successful in 80% of stool DNA samples. NGS results showed 83 mutations in cancer driver genes, 29 hotspot and 54 novel mutations. One to five genes were mutated in 75% of cases. TP53, KRAS, FBXW7, and SMAD4 were the top mutated genes, consistent with previous studies. Of samples with mutations, 54% presented concomitant mutations in different genes. Phosphatidylinositol 3-kinase/mitogen-activated protein kinase pathway genes were mutated in 70% of samples, with 58% having alterations in KRAS, NRAS, or BRAF. Because mutations in these genes can compromise the efficacy of epidermal growth factor receptor blockade in CRC patients, identifying mutations that confer resistance to some targeted treatments may be useful to guide therapeutic decisions. In conclusion, the data presented herein show that NGS procedures on stool DNA represent a promising tool to detect genetic mutations that could be used in the future for diagnosis, monitoring, or treating CRC. PMID:27155048

  6. 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. PMID:26995027

  7. Comprehensive identification of mutational cancer driver genes across 12 tumor types

    PubMed Central

    Tamborero, David; Gonzalez-Perez, Abel; Perez-Llamas, Christian; Deu-Pons, Jordi; Kandoth, Cyriac; Reimand, Jüri; Lawrence, Michael S.; Getz, Gad; Bader, Gary D.; Ding, Li; Lopez-Bigas, Nuria

    2013-01-01

    With the ability to fully sequence tumor genomes/exomes, the quest for cancer driver genes can now be undertaken in an unbiased manner. However, obtaining a complete catalog of cancer genes is difficult due to the heterogeneous molecular nature of the disease and the limitations of available computational methods. Here we show that the combination of complementary methods allows identifying a comprehensive and reliable list of cancer driver genes. We provide a list of 291 high-confidence cancer driver genes acting on 3,205 tumors from 12 different cancer types. Among those genes, some have not been previously identified as cancer drivers and 16 have clear preference to sustain mutations in one specific tumor type. The novel driver candidates complement our current picture of the emergence of these diseases. In summary, the catalog of driver genes and the methodology presented here open new avenues to better understand the mechanisms of tumorigenesis. PMID:24084849

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

    PubMed Central

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

    2016-01-01

    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 PMID:26802430

  9. Tug-of-war between driver and passenger mutations in cancer and other adaptive processes.

    PubMed

    McFarland, Christopher D; Mirny, Leonid A; Korolev, Kirill S

    2014-10-21

    Cancer progression is an example of a rapid adaptive process where evolving new traits is essential for survival and requires a high mutation rate. Precancerous cells acquire a few key mutations that drive rapid population growth and carcinogenesis. Cancer genomics demonstrates that these few driver mutations occur alongside thousands of random passenger mutations--a natural consequence of cancer's elevated mutation rate. Some passengers are deleterious to cancer cells, yet have been largely ignored in cancer research. In population genetics, however, the accumulation of mildly deleterious mutations has been shown to cause population meltdown. Here we develop a stochastic population model where beneficial drivers engage in a tug-of-war with frequent mildly deleterious passengers. These passengers present a barrier to cancer progression describable by a critical population size, below which most lesions fail to progress, and a critical mutation rate, above which cancers melt down. We find support for this model in cancer age-incidence and cancer genomics data that also allow us to estimate the fitness advantage of drivers and fitness costs of passengers. We identify two regimes of adaptive evolutionary dynamics and use these regimes to understand successes and failures of different treatment strategies. A tumor's load of deleterious passengers can explain previously paradoxical treatment outcomes and suggest that it could potentially serve as a biomarker of response to mutagenic therapies. The collective deleterious effect of passengers is currently an unexploited therapeutic target. We discuss how their effects might be exacerbated by current and future therapies. PMID:25277973

  10. Systematic analysis of mutation distribution in three dimensional protein structures identifies cancer driver genes

    PubMed Central

    Fujimoto, Akihiro; Okada, Yukinori; Boroevich, Keith A.; Tsunoda, Tatsuhiko; Taniguchi, Hiroaki; Nakagawa, Hidewaki

    2016-01-01

    Protein tertiary structure determines molecular function, interaction, and stability of the protein, therefore distribution of mutation in the tertiary structure can facilitate the identification of new driver genes in cancer. To analyze mutation distribution in protein tertiary structures, we applied a novel three dimensional permutation test to the mutation positions. We analyzed somatic mutation datasets of 21 types of cancers obtained from exome sequencing conducted by the TCGA project. Of the 3,622 genes that had ≥3 mutations in the regions with tertiary structure data, 106 genes showed significant skew in mutation distribution. Known tumor suppressors and oncogenes were significantly enriched in these identified cancer gene sets. Physical distances between mutations in known oncogenes were significantly smaller than those of tumor suppressors. Twenty-three genes were detected in multiple cancers. Candidate genes with significant skew of the 3D mutation distribution included kinases (MAPK1, EPHA5, ERBB3, and ERBB4), an apoptosis related gene (APP), an RNA splicing factor (SF1), a miRNA processing factor (DICER1), an E3 ubiquitin ligase (CUL1) and transcription factors (KLF5 and EEF1B2). Our study suggests that systematic analysis of mutation distribution in the tertiary protein structure can help identify cancer driver genes. PMID:27225414

  11. Systematic analysis of mutation distribution in three dimensional protein structures identifies cancer driver genes.

    PubMed

    Fujimoto, Akihiro; Okada, Yukinori; Boroevich, Keith A; Tsunoda, Tatsuhiko; Taniguchi, Hiroaki; Nakagawa, Hidewaki

    2016-01-01

    Protein tertiary structure determines molecular function, interaction, and stability of the protein, therefore distribution of mutation in the tertiary structure can facilitate the identification of new driver genes in cancer. To analyze mutation distribution in protein tertiary structures, we applied a novel three dimensional permutation test to the mutation positions. We analyzed somatic mutation datasets of 21 types of cancers obtained from exome sequencing conducted by the TCGA project. Of the 3,622 genes that had ≥3 mutations in the regions with tertiary structure data, 106 genes showed significant skew in mutation distribution. Known tumor suppressors and oncogenes were significantly enriched in these identified cancer gene sets. Physical distances between mutations in known oncogenes were significantly smaller than those of tumor suppressors. Twenty-three genes were detected in multiple cancers. Candidate genes with significant skew of the 3D mutation distribution included kinases (MAPK1, EPHA5, ERBB3, and ERBB4), an apoptosis related gene (APP), an RNA splicing factor (SF1), a miRNA processing factor (DICER1), an E3 ubiquitin ligase (CUL1) and transcription factors (KLF5 and EEF1B2). Our study suggests that systematic analysis of mutation distribution in the tertiary protein structure can help identify cancer driver genes. PMID:27225414

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

    PubMed Central

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

    2016-01-01

    Abstract 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

  13. Discrepancies in Cancer Genomic Sequencing Highlight Opportunities for Driver Mutation Discovery

    PubMed Central

    Hudson, Andrew M.; Yates, Tim; Fawdar, Shameem; Chapman, Phil; Lorigan, Paul; Biankin, Andrew; Miller, Crispin J.; Brognard, John

    2014-01-01

    Cancer genome sequencing is being employed at an increasing rate to identify actionable driver mutations that can inform therapeutic intervention strategies. A comparison of two of the most prominent cancer genome sequencing databases from different institutes (CCLE and COSMIC) revealed marked discrepancies in the detection of missense mutations in identical cell lines (57.38% conformity). The main reason for this discrepancy is inadequate sequencing of GC-rich areas of the exome. We have therefore mapped over 400 regions of consistent inadequate sequencing (cold-spots) in known cancer-causing genes and kinases, in 368 of which neither institute finds mutations. We demonstrate, using a newly identified PAK4 mutation as proof of principle, that specific targeting and sequencing of these GC-rich cold-spot regions can lead to the identification of novel driver mutations in known tumor suppressors and oncogenes. We highlight that cross-referencing between genomic databases is required to comprehensively assess genomic alterations in commonly used cell lines and that there are still significant opportunities to identify novel drivers of tumorigenesis in poorly sequenced areas of the exome. Finally we assess other reasons for the observed discrepancy, such as variations in dbSNP filtering and the acquisition/loss of mutations, to give explanations as to why there is discrepancy in pharmacogenomic studies given recent concerns with poor reproducibility of data. PMID:25256751

  14. 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

  15. Spectrum and prognostic relevance of driver gene mutations in acute myeloid leukemia.

    PubMed

    Metzeler, Klaus H; Herold, Tobias; Rothenberg-Thurley, Maja; Amler, Susanne; Sauerland, Maria C; Görlich, Dennis; Schneider, Stephanie; Konstandin, Nikola P; Dufour, Annika; Bräundl, Kathrin; Ksienzyk, Bianka; Zellmeier, Evelyn; Hartmann, Luise; Greif, Philipp A; Fiegl, Michael; Subklewe, Marion; Bohlander, Stefan K; Krug, Utz; Faldum, Andreas; Berdel, Wolfgang E; Wörmann, Bernhard; Büchner, Thomas; Hiddemann, Wolfgang; Braess, Jan; Spiekermann, Karsten

    2016-08-01

    The clinical and prognostic relevance of many recently identified driver gene mutations in adult acute myeloid leukemia (AML) is poorly defined. We sequenced the coding regions or hotspot areas of 68 recurrently mutated genes in a cohort of 664 patients aged 18 to 86 years treated on 2 phase 3 trials of the German AML Cooperative Group (AMLCG). The median number of 4 mutations per patient varied according to cytogenetic subgroup, age, and history of previous hematologic disorder or antineoplastic therapy. We found patterns of significantly comutated driver genes suggesting functional synergism. Conversely, we identified 8 virtually nonoverlapping patient subgroups, jointly comprising 78% of AML patients, that are defined by mutually exclusive genetic alterations. These subgroups, likely representing distinct underlying pathways of leukemogenesis, show widely divergent outcomes. Furthermore, we provide detailed information on associations between gene mutations, clinical patient characteristics, and therapeutic outcomes in this large cohort of uniformly treated AML patients. In multivariate analyses including a comprehensive set of molecular and clinical variables, we identified DNMT3A and RUNX1 mutations as important predictors of shorter overall survival (OS) in AML patients <60 years, and particularly in those with intermediate-risk cytogenetics. NPM1 mutations in the absence of FLT3-ITD, mutated TP53, and biallelic CEBPA mutations were identified as important molecular prognosticators of OS irrespective of patient age. In summary, our study provides a comprehensive overview of the spectrum, clinical associations, and prognostic relevance of recurrent driver gene mutations in a large cohort representing a broad spectrum and age range of intensively treated AML patients. PMID:27288520

  16. OncodriveFML: a general framework to identify coding and non-coding regions with cancer driver mutations.

    PubMed

    Mularoni, Loris; Sabarinathan, Radhakrishnan; Deu-Pons, Jordi; Gonzalez-Perez, Abel; López-Bigas, Núria

    2016-01-01

    Distinguishing the driver mutations from somatic mutations in a tumor genome is one of the major challenges of cancer research. This challenge is more acute and far from solved for non-coding mutations. Here we present OncodriveFML, a method designed to analyze the pattern of somatic mutations across tumors in both coding and non-coding genomic regions to identify signals of positive selection, and therefore, their involvement in tumorigenesis. We describe the method and illustrate its usefulness to identify protein-coding genes, promoters, untranslated regions, intronic splice regions, and lncRNAs-containing driver mutations in several malignancies. PMID:27311963

  17. Tug-of-war between driver and passenger mutations in cancer and other adaptive processes

    PubMed Central

    McFarland, Christopher D.; Mirny, Leonid A.; Korolev, Kirill S.

    2014-01-01

    Cancer progression is an example of a rapid adaptive process where evolving new traits is essential for survival and requires a high mutation rate. Precancerous cells acquire a few key mutations that drive rapid population growth and carcinogenesis. Cancer genomics demonstrates that these few driver mutations occur alongside thousands of random passenger mutations—a natural consequence of cancer’s elevated mutation rate. Some passengers are deleterious to cancer cells, yet have been largely ignored in cancer research. In population genetics, however, the accumulation of mildly deleterious mutations has been shown to cause population meltdown. Here we develop a stochastic population model where beneficial drivers engage in a tug-of-war with frequent mildly deleterious passengers. These passengers present a barrier to cancer progression describable by a critical population size, below which most lesions fail to progress, and a critical mutation rate, above which cancers melt down. We find support for this model in cancer age–incidence and cancer genomics data that also allow us to estimate the fitness advantage of drivers and fitness costs of passengers. We identify two regimes of adaptive evolutionary dynamics and use these regimes to understand successes and failures of different treatment strategies. A tumor’s load of deleterious passengers can explain previously paradoxical treatment outcomes and suggest that it could potentially serve as a biomarker of response to mutagenic therapies. The collective deleterious effect of passengers is currently an unexploited therapeutic target. We discuss how their effects might be exacerbated by current and future therapies. PMID:25277973

  18. 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

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

    PubMed

    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

    2016-03-14

    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

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

    PubMed

    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

    2016-02-15

    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

  1. 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

  2. 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

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

    PubMed

    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

  4. Discrimination of driver and passenger mutations in epidermal growth factor receptor in cancer.

    PubMed

    Anoosha, P; Huang, Liang-Tsung; Sakthivel, R; Karunagaran, D; Gromiha, M Michael

    2015-10-01

    Cancer is one of the most life-threatening diseases and mutations in several genes are the vital cause in tumorigenesis. Protein kinases play essential roles in cancer progression and specifically, epidermal growth factor receptor (EGFR) is an important target for cancer therapy. In this work, we have developed a method to classify single amino acid polymorphisms (SAPs) in EGFR into disease-causing (driver) and neutral (passenger) mutations using both sequence and structure based features of the mutation site by machine learning approaches. We compiled a set of 222 features and selected a set of 21 properties utilizing feature selection methods, for maximizing the prediction performance. In a set of 540 mutants, we obtained an overall classification accuracy of 67.8% with 10 fold cross validation using support vector machines. Further, the mutations have been grouped into four sets based on secondary structure and accessible surface area, which enhanced the overall classification accuracy to 80.2%, 81.9%, 77.9% and 75.1% for helix, strand, coil-buried and coil-exposed mutants, respectively. The method was tested with a blind dataset of 60 mutations, which showed an average accuracy of 85.4%. These accuracy levels are superior to other methods available in the literature for EGFR mutants, with an increase of more than 30%. Moreover, we have screened all possible single amino acid polymorphisms (SAPs) in EGFR and suggested the probable driver and passenger mutations, which would help in the development of mutation specific drugs for cancer treatment. PMID:26264175

  5. CRISPR-Barcoding for Intratumor Genetic Heterogeneity Modeling and Functional Analysis of Oncogenic Driver Mutations.

    PubMed

    Guernet, Alexis; Mungamuri, Sathish Kumar; Cartier, Dorthe; Sachidanandam, Ravi; Jayaprakash, Anitha; Adriouch, Sahil; Vezain, Myriam; Charbonnier, Françoise; Rohkin, Guy; Coutant, Sophie; Yao, Shen; Ainani, Hassan; Alexandre, David; Tournier, Isabelle; Boyer, Olivier; Aaronson, Stuart A; Anouar, Youssef; Grumolato, Luca

    2016-08-01

    Intratumor genetic heterogeneity underlies the ability of tumors to evolve and adapt to different environmental conditions. Using CRISPR/Cas9 technology and specific DNA barcodes, we devised a strategy to recapitulate and trace the emergence of subpopulations of cancer cells containing a mutation of interest. We used this approach to model different mechanisms of lung cancer cell resistance to EGFR inhibitors and to assess effects of combined drug therapies. By overcoming intrinsic limitations of current approaches, CRISPR-barcoding also enables investigation of most types of genetic modifications, including repair of oncogenic driver mutations. Finally, we used highly complex barcodes inserted at a specific genome location as a means of simultaneously tracing the fates of many thousands of genetically labeled cancer cells. CRISPR-barcoding is a straightforward and highly flexible method that should greatly facilitate the functional investigation of specific mutations, in a context that closely mimics the complexity of cancer. PMID:27453044

  6. Somatic PIK3CA mutations as a driver of sporadic venous malformations

    PubMed Central

    Castel, Pau; Carmona, F. Javier; Grego-Bessa, Joaquim; Berger, Michael F.; Viale, Agnès; Anderson, Kathryn V.; Bague, Silvia; Scaltriti, Maurizio; Antonescu, Cristina R.; Baselga, Eulàlia; Baselga, José

    2016-01-01

    Venous malformations (VM) are vascular malformations characterized by enlarged and distorted blood vessel channels. VM grow over time and cause substantial morbidity because of disfigurement, bleeding, and pain, representing a clinical challenge in the absence of effective treatments (Nguyen et al., 2014; Uebelhoer et al., 2012). Somatic mutations may act as drivers of these lesions, as suggested by the identification of TEK mutations in a proportion of VM (Limaye et al., 2009). We report that activating PIK3CA mutations gives rise to sporadic VM in mice, which closely resemble the histology of the human disease. Furthermore, we identified mutations in PIK3CA and related genes of the PI3K (phosphatidylinositol 3-kinase)/AKT pathway in about 30% of human VM that lack TEK alterations. PIK3CA mutations promote downstream signaling and proliferation in endothelial cells and impair normal vasculogenesis in embryonic development. We successfully treated VM in mouse models using pharmacological inhibitors of PI3Kα administered either systemically or topically. This study elucidates the etiology of a proportion of VM and proposes a therapeutic approach for this disease. PMID:27030594

  7. [Treatment of advanced non-small-cell lung cancer with driver mutations].

    PubMed

    Tessmer, Antje; Kollmeier, Jens

    2015-03-01

    Advanced non-small-cell lung cancer is no longer one disease but the collective name for different diseases defined by clinical, histological, immunohistochemical and, to an increasing extent, molecular biomarkers. This article deals with the treatment options we gained by identifying so called driver mutations in a growing subset of these cancers. For patients whose tumors are characterized by a targetable molecular alteration such as an activating EGFR-Mutation, an ALK-translocation or a ROS1-rearrangement, we see prolonged survival and oral treatments with tyrosine kinase inhibitors demonstrate superiority to chemotherapy in terms of response (remission rate), progression free survival and quality of life. We provide a review of the literature and discuss the status quo of the diagnostic need and the therapeutic options in Germany and Europe. PMID:25734673

  8. '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.

  9. Spatial and temporal homogeneity of driver mutations in diffuse intrinsic pontine glioma.

    PubMed

    Nikbakht, Hamid; Panditharatna, Eshini; Mikael, Leonie G; Li, Rui; Gayden, Tenzin; Osmond, Matthew; Ho, Cheng-Ying; Kambhampati, Madhuri; Hwang, Eugene I; Faury, Damien; Siu, Alan; Papillon-Cavanagh, Simon; Bechet, Denise; Ligon, Keith L; Ellezam, Benjamin; Ingram, Wendy J; Stinson, Caedyn; Moore, Andrew S; Warren, Katherine E; Karamchandani, Jason; Packer, Roger J; Jabado, Nada; Majewski, Jacek; Nazarian, Javad

    2016-01-01

    Diffuse Intrinsic Pontine Gliomas (DIPGs) are deadly paediatric brain tumours where needle biopsies help guide diagnosis and targeted therapies. To address spatial heterogeneity, here we analyse 134 specimens from various neuroanatomical structures of whole autopsy brains from nine DIPG patients. Evolutionary reconstruction indicates histone 3 (H3) K27M--including H3.2K27M--mutations potentially arise first and are invariably associated with specific, high-fidelity obligate partners throughout the tumour and its spread, from diagnosis to end-stage disease, suggesting mutual need for tumorigenesis. These H3K27M ubiquitously-associated mutations involve alterations in TP53 cell-cycle (TP53/PPM1D) or specific growth factor pathways (ACVR1/PIK3R1). Later oncogenic alterations arise in sub-clones and often affect the PI3K pathway. Our findings are consistent with early tumour spread outside the brainstem including the cerebrum. The spatial and temporal homogeneity of main driver mutations in DIPG implies they will be captured by limited biopsies and emphasizes the need to develop therapies specifically targeting obligate oncohistone partnerships. PMID:27048880

  10. Spatial and temporal homogeneity of driver mutations in diffuse intrinsic pontine glioma

    PubMed Central

    Nikbakht, Hamid; Panditharatna, Eshini; Mikael, Leonie G.; Li, Rui; Gayden, Tenzin; Osmond, Matthew; Ho, Cheng-Ying; Kambhampati, Madhuri; Hwang, Eugene I.; Faury, Damien; Siu, Alan; Papillon-Cavanagh, Simon; Bechet, Denise; Ligon, Keith L.; Ellezam, Benjamin; Ingram, Wendy J.; Stinson, Caedyn; Moore, Andrew S.; Warren, Katherine E.; Karamchandani, Jason; Packer, Roger J.; Jabado, Nada; Majewski, Jacek; Nazarian, Javad

    2016-01-01

    Diffuse Intrinsic Pontine Gliomas (DIPGs) are deadly paediatric brain tumours where needle biopsies help guide diagnosis and targeted therapies. To address spatial heterogeneity, here we analyse 134 specimens from various neuroanatomical structures of whole autopsy brains from nine DIPG patients. Evolutionary reconstruction indicates histone 3 (H3) K27M—including H3.2K27M—mutations potentially arise first and are invariably associated with specific, high-fidelity obligate partners throughout the tumour and its spread, from diagnosis to end-stage disease, suggesting mutual need for tumorigenesis. These H3K27M ubiquitously-associated mutations involve alterations in TP53 cell-cycle (TP53/PPM1D) or specific growth factor pathways (ACVR1/PIK3R1). Later oncogenic alterations arise in sub-clones and often affect the PI3K pathway. Our findings are consistent with early tumour spread outside the brainstem including the cerebrum. The spatial and temporal homogeneity of main driver mutations in DIPG implies they will be captured by limited biopsies and emphasizes the need to develop therapies specifically targeting obligate oncohistone partnerships. PMID:27048880

  11. PRDM14 promotes RAG-dependent Notch1 driver mutations in mouse T-ALL.

    PubMed

    Carofino, Brandi L; Ayanga, Bernard; Tracey, Lauren J; Brooke-Bisschop, Travis; Justice, Monica J

    2016-01-01

    PRDM14 is an epigenetic regulator known for maintaining embryonic stem cell identity and resetting potency in primordial germ cells. However, hematopoietic expression of Prdm14 at supraphysiological levels results in fully penetrant and rapid-onset T-cell acute lymphoblastic leukemia (T-ALL) in the mouse. Here, we show that PRDM14-induced T-ALLs are driven by NOTCH1, a frequently mutated driver of human T-ALL. Notch1 is activated in this murine model via RAG-dependent promoter deletions and subsequent production of truncated, ligand-independent protein from downstream regions of the Notch1 locus. These T-ALLs also have focal changes in H3K4me3 deposition at the Notch1 locus and global increases in both H3K4me1 and H3K4me3. Using a PRDM14-FLAG mouse model, we show that PRDM14 binds within an intron of Notch1 prior to leukemia development. Our data support the idea that PRDM14 binding promotes a chromatin state that allows access of the RAG recombinase complex to cryptic RAG signal sequences embedded at the Notch1 locus. Indeed, breeding into a RAG recombination-deficient background abrogates T-ALL development and prevents Notch1 deletions, while allowing for transient hematopoietic stem cell (HSC)-like pre-leukemia cell expansion. Together, our data suggest that PRDM14 expands a progenitor cell population while promoting a permissive epigenetic state for the creation of driver mutations (here, in Notch1), enabling cancer development through the misappropriation of endogenous cellular DNA recombination machinery. PMID:27106930

  12. PRDM14 promotes RAG-dependent Notch1 driver mutations in mouse T-ALL

    PubMed Central

    Carofino, Brandi L.; Ayanga, Bernard; Tracey, Lauren J.; Brooke-Bisschop, Travis

    2016-01-01

    ABSTRACT PRDM14 is an epigenetic regulator known for maintaining embryonic stem cell identity and resetting potency in primordial germ cells. However, hematopoietic expression of Prdm14 at supraphysiological levels results in fully penetrant and rapid-onset T-cell acute lymphoblastic leukemia (T-ALL) in the mouse. Here, we show that PRDM14-induced T-ALLs are driven by NOTCH1, a frequently mutated driver of human T-ALL. Notch1 is activated in this murine model via RAG-dependent promoter deletions and subsequent production of truncated, ligand-independent protein from downstream regions of the Notch1 locus. These T-ALLs also have focal changes in H3K4me3 deposition at the Notch1 locus and global increases in both H3K4me1 and H3K4me3. Using a PRDM14-FLAG mouse model, we show that PRDM14 binds within an intron of Notch1 prior to leukemia development. Our data support the idea that PRDM14 binding promotes a chromatin state that allows access of the RAG recombinase complex to cryptic RAG signal sequences embedded at the Notch1 locus. Indeed, breeding into a RAG recombination-deficient background abrogates T-ALL development and prevents Notch1 deletions, while allowing for transient hematopoietic stem cell (HSC)-like pre-leukemia cell expansion. Together, our data suggest that PRDM14 expands a progenitor cell population while promoting a permissive epigenetic state for the creation of driver mutations (here, in Notch1), enabling cancer development through the misappropriation of endogenous cellular DNA recombination machinery. PMID:27106930

  13. Somatic PIK3CA mutations as a driver of sporadic venous malformations.

    PubMed

    Castel, Pau; Carmona, F Javier; Grego-Bessa, Joaquim; Berger, Michael F; Viale, Agnès; Anderson, Kathryn V; Bague, Silvia; Scaltriti, Maurizio; Antonescu, Cristina R; Baselga, Eulàlia; Baselga, José

    2016-03-30

    Venous malformations (VM) are vascular malformations characterized by enlarged and distorted blood vessel channels. VM grow over time and cause substantial morbidity because of disfigurement, bleeding, and pain, representing a clinical challenge in the absence of effective treatments (Nguyenet al, 2014; Uebelhoeret al, 2012). Somatic mutations may act as drivers of these lesions, as suggested by the identification ofTEKmutations in a proportion of VM (Limayeet al, 2009). We report that activatingPIK3CAmutations gives rise to sporadic VM in mice, which closely resemble the histology of the human disease. Furthermore, we identified mutations inPIK3CAand related genes of the PI3K (phosphatidylinositol 3-kinase)/AKT pathway in about 30% of human VM that lackTEKalterations.PIK3CAmutations promote downstream signaling and proliferation in endothelial cells and impair normal vasculogenesis in embryonic development. We successfully treated VM in mouse models using pharmacological inhibitors of PI3Kα administered either systemically or topically. This study elucidates the etiology of a proportion of VM and proposes a therapeutic approach for this disease. PMID:27030594

  14. 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.

  15. Drunk Driving Among Novice Drivers, Possible Prevention with Additional Psychological Module in Driving School Curriculum

    PubMed Central

    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. PMID:22105403

  16. Identification of Five Driver Gene Mutations in Patients with Treatment-Naïve Lung Adenocarcinoma in Taiwan

    PubMed Central

    Su, Kang-Yi; Wu, Ming-Fang; Chiu, Kuo-Liang; Yang, Tsung-Ying; Chen, Kun-Chieh; Ooi, Hean; Wu, Tzu-Chin; Chen, Hung-Jen; Chen, Hsuan-Yu; Chang, Chi-Sheng; Hsu, Chung-Ping; Hsia, Jiun-Yi; Chuang, Cheng-Yen; Lin, Chin-Hung; Chen, Jeremy J. W.; Chen, Kuan-Yu; Liao, Wei-Yu; Shih, Jin-Yuan; Yu, Sung-Liang; Yu, Chong-Jen; Yang, Pan-Chyr; Chang, Gee-Chen

    2015-01-01

    Background It is important to select appropriate targeted therapies for subgroups of patients with lung adenocarcinoma who have specific gene alterations. Methods This prospective study was a multicenter project conducted in Taiwan for assessment of lung adenocarcinoma genetic tests. Five oncogenic drivers, including EGFR, KRAS, BRAF, HER2 and EML4-ALK fusion mutations, were tested. EGFR, KRAS, BRAF and HER2 mutations were assessed by MALDI-TOF MS (Cohort 1). EML4-ALK translocation was tested by Ventana method in EGFR-wild type patients (Cohort 2). Results From August 2011 to November 2013, a total of 1772 patients with lung adenocarcinoma were enrolled. In Cohort 1 analysis, EGFR, KRAS, HER2 and BRAF mutations were identified in 987 (55.7%), 93 (5.2%), 36 (2.0%) and 12 (0.7%) patients, respectively. Most of these mutations were mutually exclusive, except for co-mutations in seven patients (3 with EGFR + KRAS, 3 with EGFR + HER2 and 1 with KRAS + BRAF). In Cohort 2 analysis, 29 of 295 EGFR-wild type patients (9.8%) were positive for EML4-ALK translocation. EGFR mutations were more common in female patients and non-smokers and KRAS mutations were more common in male patients and smokers. Gender and smoking status were not correlated significantly with HER2, BRAF and EML4-ALK mutations. EML4-ALK translocation was more common in patients with younger age. Conclusion This was the first study in Taiwan to explore the incidence of five oncogenic drivers in patients with lung adenocarcinoma and the results could be valuable for physicians in consideration of targeted therapy and inclusion of clinical trials. PMID:25789627

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

    PubMed Central

    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

    2013-01-01

    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. PMID:24055406

  18. Balancing Protein Stability and Activity in Cancer: A New Approach for Identifying Driver Mutations Affecting CBL Ubiquitin Ligase Activation.

    PubMed

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

    2016-02-01

    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 providing 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 random noncancer 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

  19. 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.

  20. Aberrant RNA splicing in cancer; expression changes and driver mutations of splicing factor genes.

    PubMed

    Sveen, A; Kilpinen, S; Ruusulehto, A; Lothe, R A; Skotheim, R I

    2016-05-12

    Alternative splicing is a widespread process contributing to structural transcript variation and proteome diversity. In cancer, the splicing process is commonly disrupted, resulting in both functional and non-functional end-products. Cancer-specific splicing events are known to contribute to disease progression; however, the dysregulated splicing patterns found on a genome-wide scale have until recently been less well-studied. In this review, we provide an overview of aberrant RNA splicing and its regulation in cancer. We then focus on the executors of the splicing process. Based on a comprehensive catalog of splicing factor encoding genes and analyses of available gene expression and somatic mutation data, we identify cancer-associated patterns of dysregulation. Splicing factor genes are shown to be significantly differentially expressed between cancer and corresponding normal samples, and to have reduced inter-individual expression variation in cancer. Furthermore, we identify enrichment of predicted cancer-critical genes among the splicing factors. In addition to previously described oncogenic splicing factor genes, we propose 24 novel cancer-critical splicing factors predicted from somatic mutations. PMID:26300000

  1. Steroid 21-hydroxylase deficiency: three additional mutated alleles and establishment of phenotype-genotype relationships of common mutations.

    PubMed Central

    Wedell, A; Ritzén, E M; Haglund-Stengler, B; Luthman, H

    1992-01-01

    Lesions in the gene encoding steroid 21-hydroxylase [steroid hydrogen-donor: oxygen oxidoreductase (21-hydroxylating), EC 1.14.99.10] result in defective adrenal steroid synthesis; the severe forms are known as congenital adrenal hyperplasia. To facilitate complete characterization of mutations in this region of tandemly repeated genes, we have developed selective PCR amplification and direct sequencing of full-length nonpseudogene steroid 21-hydroxylase genes. This technique identifies known mutations, characterizes or excludes unknown mutations, and determines the gene-copy number. Three additional defective alleles were found. A Gly-292----Ser mutation and a frameshift mutation at Arg-484 (GG----C) were identified in patients with severe steroid 21-hydroxylase deficiency. An allele with three additional sequence variations--C----T at 4 bases upstream of translation initiation, Pro-106----Leu, and Pro-454----Ser--were identified in two siblings with late-onset deficiency. Pro-454 is conserved in four species, indicating its importance for normal enzyme function. Functional consequences of individual alleles have been determined in vivo by studying individuals with only one steroid 21-hydroxylase gene. Detailed analyses of clinical data revealed that genotyping could predict the clinical course of the disease. The locations of disease-causing mutations on different haplotypes of the steroid 21-hydroxylase gene region are described. Images PMID:1496017

  2. Somatic mutation profiles in primary colorectal cancers and matching ovarian metastases: Identification of driver and passenger mutations

    PubMed Central

    Crobach, Stijn; Ruano, Dina; van Eijk, Ronald; Schrumpf, Melanie; Fleuren, Gertjan; van Wezel, Tom

    2016-01-01

    Abstract The mutational profiles of primary colorectal cancers (CRCs) and corresponding ovarian metastases were compared. Using a custom‐made next generation sequencing panel, 115 cancer‐driving genes were analyzed in a cohort of 26 primary CRCs and 30 matching ovarian metastases (four with bilateral metastases). To obtain a complete overview of the mutational profile, low thresholds were used in bioinformatics analysis to prevent low frequency passenger mutations from being filtered out. A subset of variants was validated using Sanger and/or hydrolysis probe assays. The mutational landscape of CRC that metastasized to the ovary was not strikingly different from CRC in consecutive series. When comparing primary CRCs and their matching ovarian metastases, there was considerable overlap in the mutations of early affected genes. A subset of mutations demonstrated less overlap, presumably being passenger mutations. In particular, primary CRCs showed a substantially high number of passenger mutations. We also compared the primary CRCs and matching metastases for stratifying variants of six genes (KRAS, NRAS, BRAF, FBXW7, PTEN and PIK3CA) that select for established (EGFR directed) or future targeted therapies. In a total of 31 variants 12 were not found in either of the two locations. Tumours thus differed in the number of discordant variants between the primary tumours and matching metastases. Half of these discordant variants were definitive class 4/5 pathogenic variants. However, in terms of temporal heterogeneity, no clear relationship was observed between the number of discordant variants and the time interval between primary CRCs and the detection of ovarian metastases. This suggests that dormant metastases may be present from the early days of the primary tumours. PMID:27499925

  3. 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. PMID:19068258

  4. 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. PMID:26356674

  5. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma.

    PubMed

    Schwartzentruber, Jeremy; Korshunov, Andrey; Liu, Xiao-Yang; Jones, David T W; Pfaff, Elke; Jacob, Karine; Sturm, Dominik; Fontebasso, Adam M; Quang, Dong-Anh Khuong; Tönjes, Martje; Hovestadt, Volker; Albrecht, Steffen; Kool, Marcel; Nantel, Andre; Konermann, Carolin; Lindroth, Anders; Jäger, Natalie; Rausch, Tobias; Ryzhova, Marina; Korbel, Jan O; Hielscher, Thomas; Hauser, Peter; Garami, Miklos; Klekner, Almos; Bognar, Laszlo; Ebinger, Martin; Schuhmann, Martin U; Scheurlen, Wolfram; Pekrun, Arnulf; Frühwald, Michael C; Roggendorf, Wolfgang; Kramm, Christoph; Dürken, Matthias; Atkinson, Jeffrey; Lepage, Pierre; Montpetit, Alexandre; Zakrzewska, Magdalena; Zakrzewski, Krzystof; Liberski, Pawel P; Dong, Zhifeng; Siegel, Peter; Kulozik, Andreas E; Zapatka, Marc; Guha, Abhijit; Malkin, David; Felsberg, Jörg; Reifenberger, Guido; von Deimling, Andreas; Ichimura, Koichi; Collins, V Peter; Witt, Hendrik; Milde, Till; Witt, Olaf; Zhang, Cindy; Castelo-Branco, Pedro; Lichter, Peter; Faury, Damien; Tabori, Uri; Plass, Christoph; Majewski, Jacek; Pfister, Stefan M; Jabado, Nada

    2012-02-01

    Glioblastoma multiforme (GBM) is a lethal brain tumour in adults and children. However, DNA copy number and gene expression signatures indicate differences between adult and paediatric cases. To explore the genetic events underlying this distinction, we sequenced the exomes of 48 paediatric GBM samples. Somatic mutations in the H3.3-ATRX-DAXX chromatin remodelling pathway were identified in 44% of tumours (21/48). Recurrent mutations in H3F3A, which encodes the replication-independent histone 3 variant H3.3, were observed in 31% of tumours, and led to amino acid substitutions at two critical positions within the histone tail (K27M, G34R/G34V) involved in key regulatory post-translational modifications. Mutations in ATRX (α-thalassaemia/mental retardation syndrome X-linked) and DAXX (death-domain associated protein), encoding two subunits of a chromatin remodelling complex required for H3.3 incorporation at pericentric heterochromatin and telomeres, were identified in 31% of samples overall, and in 100% of tumours harbouring a G34R or G34V H3.3 mutation. Somatic TP53 mutations were identified in 54% of all cases, and in 86% of samples with H3F3A and/or ATRX mutations. Screening of a large cohort of gliomas of various grades and histologies (n = 784) showed H3F3A mutations to be specific to GBM and highly prevalent in children and young adults. Furthermore, the presence of H3F3A/ATRX-DAXX/TP53 mutations was strongly associated with alternative lengthening of telomeres and specific gene expression profiles. This is, to our knowledge, the first report to highlight recurrent mutations in a regulatory histone in humans, and our data suggest that defects of the chromatin architecture underlie paediatric and young adult GBM pathogenesis. PMID:22286061

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

    PubMed

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

    2015-11-01

    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

  7. Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer.

    PubMed

    Peifer, Martin; Fernández-Cuesta, Lynnette; Sos, Martin L; George, Julie; Seidel, Danila; Kasper, Lawryn H; Plenker, Dennis; Leenders, Frauke; Sun, Ruping; Zander, Thomas; Menon, Roopika; Koker, Mirjam; Dahmen, Ilona; Müller, Christian; Di Cerbo, Vincenzo; Schildhaus, Hans-Ulrich; Altmüller, Janine; Baessmann, Ingelore; Becker, Christian; de Wilde, Bram; Vandesompele, Jo; Böhm, Diana; Ansén, Sascha; Gabler, Franziska; Wilkening, Ines; Heynck, Stefanie; Heuckmann, Johannes M; Lu, Xin; Carter, Scott L; Cibulskis, Kristian; Banerji, Shantanu; Getz, Gad; Park, Kwon-Sik; Rauh, Daniel; Grütter, Christian; Fischer, Matthias; Pasqualucci, Laura; Wright, Gavin; Wainer, Zoe; Russell, Prudence; Petersen, Iver; Chen, Yuan; Stoelben, Erich; Ludwig, Corinna; Schnabel, Philipp; Hoffmann, Hans; Muley, Thomas; Brockmann, Michael; Engel-Riedel, Walburga; Muscarella, Lucia A; Fazio, Vito M; Groen, Harry; Timens, Wim; Sietsma, Hannie; Thunnissen, Erik; Smit, Egbert; Heideman, Daniëlle A M; Snijders, Peter J F; Cappuzzo, Federico; Ligorio, Claudia; Damiani, Stefania; Field, John; Solberg, Steinar; Brustugun, Odd Terje; Lund-Iversen, Marius; Sänger, Jörg; Clement, Joachim H; Soltermann, Alex; Moch, Holger; Weder, Walter; Solomon, Benjamin; Soria, Jean-Charles; Validire, Pierre; Besse, Benjamin; Brambilla, Elisabeth; Brambilla, Christian; Lantuejoul, Sylvie; Lorimier, Philippe; Schneider, Peter M; Hallek, Michael; Pao, William; Meyerson, Matthew; Sage, Julien; Shendure, Jay; Schneider, Robert; Büttner, Reinhard; Wolf, Jürgen; Nürnberg, Peter; Perner, Sven; Heukamp, Lukas C; Brindle, Paul K; Haas, Stefan; Thomas, Roman K

    2012-10-01

    Small-cell lung cancer (SCLC) is an aggressive lung tumor subtype with poor prognosis. We sequenced 29 SCLC exomes, 2 genomes and 15 transcriptomes and found an extremely high mutation rate of 7.4±1 protein-changing mutations per million base pairs. Therefore, we conducted integrated analyses of the various data sets to identify pathogenetically relevant mutated genes. In all cases, we found evidence for inactivation of TP53 and RB1 and identified recurrent mutations in the CREBBP, EP300 and MLL genes that encode histone modifiers. Furthermore, we observed mutations in PTEN, SLIT2 and EPHA7, as well as focal amplifications of the FGFR1 tyrosine kinase gene. Finally, we detected many of the alterations found in humans in SCLC tumors from Tp53 and Rb1 double knockout mice. Our study implicates histone modification as a major feature of SCLC, reveals potentially therapeutically tractable genomic alterations and provides a generalizable framework for the identification of biologically relevant genes in the context of high mutational background. PMID:22941188

  8. Integrative genome analyses identify key somatic driver mutations of small cell lung cancer

    PubMed Central

    Peifer, Martin; Fernández-Cuesta, Lynnette; Sos, Martin L; George, Julie; Seidel, Danila; Kasper, Lawryn H; Plenker, Dennis; Leenders, Frauke; Sun, Ruping; Zander, Thomas; Menon, Roopika; Koker, Mirjam; Dahmen, Ilona; Müller, Christian; Di Cerbo, Vincenzo; Schildhaus, Hans-Ulrich; Altmüller, Janine; Baessmann, Ingelore; Becker, Christian; de Wilde, Bram; Vandesompele, Jo; Böhm, Diana; Ansén, Sascha; Gabler, Franziska; Wilkening, Ines; Heynck, Stefanie; Heuckmann, Johannes M; Lu, Xin; Carter, Scott L; Cibulskis, Kristian; Banerji, Shantanu; Getz, Gad; Park, Kwon-Sik; Rauh, Daniel; Grütter, Christian; Fischer, Matthias; Pasqualucci, Laura; Wright, Gavin; Wainer, Zoe; Russell, Prudence; Petersen, Iver; Chen, Yuan; Stoelben, Erich; Ludwig, Corinna; Schnabel, Philipp; Hoffmann, Hans; Muley, Thomas; Brockmann, Michael; Engel-Riedel, Walburga; Muscarella, Lucia A; Fazio, Vito M; Groen, Harry; Timens, Wim; Sietsma, Hannie; Thunnissen, Erik; Smit, Egbert; Heideman, Daniëlle AM; Snijders, Peter JF; Cappuzzo, Federico; Ligorio, Claudia; Damiani, Stefania; Field, John; Solberg, Steinar; Brustugun, Odd Terje; Lund-Iversen, Marius; Sänger, Jörg; Clement, Joachim H; Soltermann, Alex; Moch, Holger; Weder, Walter; Solomon, Benjamin; Soria, Jean-Charles; Validire, Pierre; Besse, Benjamin; Brambilla, Elisabeth; Brambilla, Christian; Lantuejoul, Sylvie; Lorimier, Philippe; Schneider, Peter M; Hallek, Michael; Pao, William; Meyerson, Matthew; Sage, Julien; Shendure, Jay; Schneider, Robert; Büttner, Reinhard; Wolf, Jürgen; Nürnberg, Peter; Perner, Sven; Heukamp, Lukas C; Brindle, Paul K; Haas, Stefan; Thomas, Roman K

    2016-01-01

    Small-cell lung cancer (SCLC) is an aggressive lung tumor subtype with poor survival1–3. We sequenced 29 SCLC exomes, two genomes and 15 transcriptomes and found an extremely high mutation rate of 7.4±1 protein-changing mutations per million basepairs. Therefore, we conducted integrated analyses of the various data sets to identify pathogenetically relevant mutated genes. In all cases we found evidence for inactivation of TP53 and RB1 and identified recurrent mutations in histone-modifying genes, CREBBP, EP300, and MLL. Furthermore, we observed mutations in PTEN, in SLIT2, and EPHA7, as well as focal amplifications of the FGFR1 tyrosine kinase gene. Finally, we detected many of the alterations found in humans in SCLC tumors from p53/Rb1-deficient mice4. Our study implicates histone modification as a major feature of SCLC, reveals potentially therapeutically tractable genome alterations, and provides a generalizable framework for identification of biologically relevant genes in the context of high mutational background. PMID:22941188

  9. Exome and whole-genome sequencing of esophageal adenocarcinoma identifies recurrent driver events and mutational complexity.

    PubMed

    Dulak, Austin M; Stojanov, Petar; Peng, Shouyong; Lawrence, Michael S; Fox, Cameron; Stewart, Chip; Bandla, Santhoshi; Imamura, Yu; Schumacher, Steven E; Shefler, Erica; McKenna, Aaron; Carter, Scott L; Cibulskis, Kristian; Sivachenko, Andrey; Saksena, Gordon; Voet, Douglas; Ramos, Alex H; Auclair, Daniel; Thompson, Kristin; Sougnez, Carrie; Onofrio, Robert C; Guiducci, Candace; Beroukhim, Rameen; Zhou, Zhongren; Lin, Lin; Lin, Jules; Reddy, Rishindra; Chang, Andrew; Landrenau, Rodney; Pennathur, Arjun; Ogino, Shuji; Luketich, James D; Golub, Todd R; Gabriel, Stacey B; Lander, Eric S; Beer, David G; Godfrey, Tony E; Getz, Gad; Bass, Adam J

    2013-05-01

    The incidence of esophageal adenocarcinoma (EAC) has risen 600% over the last 30 years. With a 5-year survival rate of ~15%, the identification of new therapeutic targets for EAC is greatly important. We analyze the mutation spectra from whole-exome sequencing of 149 EAC tumor-normal pairs, 15 of which have also been subjected to whole-genome sequencing. We identify a mutational signature defined by a high prevalence of A>C transversions at AA dinucleotides. Statistical analysis of exome data identified 26 significantly mutated genes. Of these genes, five (TP53, CDKN2A, SMAD4, ARID1A and PIK3CA) have previously been implicated in EAC. The new significantly mutated genes include chromatin-modifying factors and candidate contributors SPG20, TLR4, ELMO1 and DOCK2. Functional analyses of EAC-derived mutations in ELMO1 identifies increased cellular invasion. Therefore, we suggest the potential activation of the RAC1 pathway as a contributor to EAC tumorigenesis. PMID:23525077

  10. 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

  11. 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...

  12. 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...

  13. 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...

  14. 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...

  15. 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...

  16. Mutations in RIT1 cause Noonan syndrome - additional functional evidence and expanding the clinical phenotype.

    PubMed

    Koenighofer, M; Hung, C Y; McCauley, J L; Dallman, J; Back, E J; Mihalek, I; Gripp, K W; Sol-Church, K; Rusconi, P; Zhang, Z; Shi, G-X; Andres, D A; Bodamer, O A

    2016-03-01

    RASopathies are a clinically heterogeneous group of conditions caused by mutations in 1 of 16 proteins in the RAS-mitogen activated protein kinase (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

  17. Aging-Induced Stem Cell Mutations as Drivers for Disease and Cancer.

    PubMed

    Adams, Peter D; Jasper, Heinrich; Rudolph, K Lenhard

    2015-06-01

    Aging is characterized by a decrease in genome integrity, impaired organ maintenance, and an increased risk of cancer, which coincide with clonal dominance of expanded mutant stem and progenitor cell populations in aging tissues, such as the intestinal epithelium, the hematopoietic system, and the male germline. Here we discuss possible explanations for age-associated increases in the initiation and/or progression of mutant stem/progenitor clones and highlight the roles of stem cell quiescence, replication-associated DNA damage, telomere shortening, epigenetic alterations, and metabolic challenges as determinants of stem cell mutations and clonal dominance in aging. PMID:26046760

  18. Molecular Genetic Analysis of Ovarian Brenner Tumors and Associated Mucinous Epithelial Neoplasms: High Variant Concordance and Identification of Mutually Exclusive RAS Driver Mutations and MYC Amplification.

    PubMed

    Tafe, Laura J; Muller, Kristen E; Ananda, Guruprasad; Mitchell, Talia; Spotlow, Vanessa; Patterson, Sara E; Tsongalis, Gregory J; Mockus, Susan M

    2016-03-01

    Benign ovarian Brenner tumors often are associated with mucinous cystic neoplasms, which are hypothesized to share a histogenic origin and progression, however, supporting molecular characterization is limited. Our goal was to identify molecular mechanisms linking these tumors. DNA from six Brenner tumors with paired mucinous tumors, two Brenner tumors not associated with a mucinous neoplasm, and two atypical proliferative (borderline) Brenner tumors was extracted from formalin-fixed, paraffin-embedded tumor samples and sequenced using a 358-gene next-generation sequencing assay. Variant calls were compared within tumor groups to assess somatic mutation profiles. There was high concordance of the variants between paired samples (40% to 75%; P < 0.0001). Four of the six tumor pairs showed KRAS hotspot driver mutations specifically in the mucinous tumor. In the two paired samples that lacked KRAS mutations, MYC amplification was detected in both of the mucinous and the Brenner components; MYC amplification also was detected in a third Brenner tumor. Five of the Brenner tumors had no reportable potential driver alterations. The two atypical proliferative (borderline) Brenner tumors both had RAS mutations. The high degree of coordinate variants between paired Brenner and mucinous tumors supports a shared origin or progression. Differences observed in affected genes and pathways, particularly involving RAS and MYC, may point to molecular drivers of a divergent phenotype and progression of these tumors. PMID:26797085

  19. Second-Line Treatment of Non-Small Cell Lung Cancer: New Developments for Tumours Not Harbouring Targetable Oncogenic Driver Mutations.

    PubMed

    Barnfield, Paul C; Ellis, Peter M

    2016-09-01

    Platinum-based doublet chemotherapy with or without bevacizumab is the standard of care for the initial management of advanced and metastatic non-small cell lung cancer (NSCLC) without a targetable molecular abnormality. However, the majority of patients with NSCLC will ultimately develop resistance to initial platinum-based chemotherapy, and many remain candidates for subsequent lines of therapy. Randomised trials over the past 10-15 years have established pemetrexed (non-squamous histology), docetaxel, erlotinib and gefitinib as approved second-line agents in NSCLC without targetable driver mutations or rearrangements. Trials comparing these agents with other chemotherapy, evaluating the addition of an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) to chemotherapy or the addition of another targeted agent to erlotinib or gefitinib have all failed to demonstrate an improvement in overall survival for patients with NSCLC. In contrast, recent data comparing therapy with novel monoclonal antibodies against programmed cell death 1 (PD-1) or PD ligand (PD-L1) pathway versus standard chemotherapy following platinum failure have demonstrated significant improvements in overall survival. Therapy with nivolumab or pembrolizumab would now be considered standard second-line therapy in patients without contraindication to immune checkpoint inhibitors. Atezolizumab also appears promising in this setting. PMID:27557830

  20. Beyond Mutations: Additional Mechanisms and Implications of SWI/SNF Complex Inactivation

    PubMed Central

    Marquez, Stefanie B.; Thompson, Kenneth W.; Lu, Li; Reisman, David

    2015-01-01

    SWI/SNF is a major regulator of gene expression. Its role is to facilitate the shifting and exposure of DNA segments within the promoter and other key domains to transcription factors and other essential cellular proteins. This complex interacts with a wide range of proteins and does not function within a single, specific pathway; thus, it is involved in a multitude of cellular processes, including DNA repair, differentiation, development, cell adhesion, and growth control. Given SWI/SNF’s prominent role in these processes, many of which are important for blocking cancer development, it is not surprising that the SWI/SNF complex is targeted during cancer initiation and progression both by mutations and by non-mutational mechanisms. Currently, the understanding of the types of alterations, their frequency, and their impact on the SWI/SNF subunits is an area of intense research that has been bolstered by a recent cadre of NextGen sequencing studies. These studies have revealed mutations in SWI/SNF subunits, indicating that this complex is thus important for cancer development. The purpose of this review is to put into perspective the role of mutations versus other mechanisms in the silencing of SWI/SNF subunits, in particular, BRG1 and BRM. In addition, this review explores the recent development of synthetic lethality and how it applies to this complex, as well as how BRM polymorphisms are becoming recognized as potential clinical biomarkers for cancer risk. Significance: Recent reviews have detailed the occurrence of mutations in nearly all SWI/SNF subunits, which indicates that this complex is an important target for cancer. However, when the frequency of mutations in a given tumor type is compared to the frequency of subunit loss, it becomes clear that other non-mutational mechanisms must play a role in the inactivation of SWI/SNF subunits. Such data indicate that epigenetic mechanisms that are known to regulate BRM may also be involved in the loss of

  1. 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

  2. Additive dominant effect of a SOX10 mutation underlies a complex phenotype of PCWH.

    PubMed

    Ito, Yukiko; Inoue, Naoko; Inoue, Yukiko U; Nakamura, Shoko; Matsuda, Yoshiki; Inagaki, Masumi; Ohkubo, Takahiro; Asami, Junko; Terakawa, Youhei W; Kohsaka, Shinichi; Goto, Yu-ichi; Akazawa, Chihiro; Inoue, Takayoshi; Inoue, Ken

    2015-08-01

    Distinct classes of SOX10 mutations result in peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, and Hirschsprung disease, collectively known as PCWH. Meanwhile, SOX10 haploinsufficiency caused by allelic loss-of-function mutations leads to a milder non-neurological disorder, Waardenburg-Hirschsprung disease. The cellular pathogenesis of more complex PCWH phenotypes in vivo has not been thoroughly understood. To determine the pathogenesis of PCWH, we have established a transgenic mouse model. A known PCWH-causing SOX10 mutation, c.1400del12, was introduced into mouse Sox10-expressing cells by means of bacterial artificial chromosome (BAC) transgenesis. By crossing the multiple transgenic lines, we examined the effects produced by various copy numbers of the mutant transgene. Within the nervous systems, transgenic mice revealed a delay in the incorporation of Schwann cells in the sciatic nerve and the terminal differentiation of oligodendrocytes in the spinal cord. Transgenic mice also showed defects in melanocytes presenting as neurosensory deafness and abnormal skin pigmentation, and a loss of the enteric nervous system. Phenotypes in each lineage were more severe in mice carrying higher copy numbers, suggesting a gene dosage effect for mutant SOX10. By uncoupling the effects of gain-of-function and haploinsufficiency in vivo, we have demonstrated that the effect of a PCWH-causing SOX10 mutation is solely pathogenic in each SOX10-expressing cellular lineage in a dosage-dependent manner. In both the peripheral and central nervous systems, the primary consequence of SOX10 mutations is hypomyelination. The complex neurological phenotypes in PCWH patients likely result from a combination of haploinsufficiency and additive dominant effect. PMID:25959061

  3. 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

    Piscuoglio, Salvatore; Ng, Charlotte Ky; 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; Bruijn, Ino De; 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

    2016-03-01

    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, six 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 (eg 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 diagnosis

  4. Leveraging a Multi-Omics Strategy for Prioritizing Personalized Candidate Mutation-Driver Genes: A Proof-of-Concept Study

    PubMed Central

    Ding, Keyue; Wu, Songfeng; Ying, Wantao; Pan, Qi; Li, Xiaoyuan; Zhao, Dachun; Li, Xianyu; Zhao, Qing; Zhu, Yunping; Ren, Hong; Qian, Xiaohong

    2015-01-01

    The expression of mutant forms of proteins (e.g., oncogenes and tumor suppressors) has implications in cancer biology and clinical practice. Initial efforts have been made to characterize the transcription of tumor-mutated alleles; however, few studies have been reported to link tumor-mutated alleles to proteomics. We aimed to characterize the transcriptional and translational patterns of tumor-mutated alleles. We performed whole-exome sequencing, RNA-seq, and proteome profiling in a hyper-mutated patient of hepatocellular carcinoma. Using the patient as a model, we show that only a small proportion of tumor-mutated alleles were expressed. In this case, 42% and 3.5% of the tumor-mutated alleles were identified to be transcribed and translated, respectively. Compared with genes with germline variations or without mutations, somatic mutations significantly reduced protein expression abundance. Using the transcriptional and translational patterns of tumor-mutated alleles, we classified the mutations into four types, and only one type may be associated with the liver cancer and lead to hepatocarcinogenesis in the patient. Our results demonstrate how tumor-mutated alleles are transcribed and translated, and how the expression enables the classification of somatic mutations that cause cancer. Leveraging multiple ‘omics’ datasets provides a new avenue for understanding patient-specific mutations that underlie carcinogenesis. PMID:26631547

  5. Pulmonary adenocarcinoma in situ: analyses of a large series with reference to smoking, driver mutations, and receptor tyrosine kinase pathway activation.

    PubMed

    Sato, Seijiro; Motoi, Noriko; Hiramatsu, Miyako; Miyauchi, Eisaku; Ono, Hiroshi; Saito, Yuichi; Nagano, Hiroko; Ninomiya, Hironori; Inamura, Kentaro; Uehara, Hirofumi; Mun, Mingyon; Sakao, Yukinori; Okumura, Sakae; Tsuchida, Masanori; Ishikawa, Yuichi

    2015-07-01

    Lung adenocarcinomas in situ (AISs) often occur in individuals who have never smoked, although smoking is one of the main causes of lung cancer. To characterize AIS and, in particular, determine how AIS might be related to smoking, we collected a large number of AIS cases and examined clinicopathologic features, EGFR and KRAS mutation status, and activation status of receptor tyrosine kinase downstream signal pathways, including pAkt, pERK, and pStat3, using immunohistochemistry. We identified 110 AISs (36 smokers and 74 nonsmokers) among 1549 adenocarcinomas resected surgically during 1995 to 2010. Between the AIS of smokers and nonsmokers, only the sex ratio was significantly different; all the other clinicopathologic factors including TTF-1 and driver mutations were not significantly different: EGFR and KRAS mutation rates (smokers:nonsmokers) were 61:58 (%) (P=0.7) and 6.1:1.4 (%) (P=0.2), respectively, whereas, in invasive adenocarcinomas, the rates were 41:69 (%) (P<0.001) and 9.4:2.3 (%) (P<0.04), respectively. For pAkt and pERK, around 40% to 50% of AISs were positive, and for pStat3, >80% were positive, with no significant differences between smokers and nonsmokers with AIS. Mucinous AIS (n=8) rarely harbored KRAS mutations and expressed significantly less pStat3 (P<0.001) than nonmucinous AIS. Taken together, AIS occurs predominantly in female individuals and nonsmokers. However, characteristics of AIS arising in smokers and nonsmokers were similar in terms of cell lineage, driver mutations, and receptor tyrosine kinase pathway activation. Our results suggest that smoking is not a major cause of AIS. Rather, smoking may play a role in progression of AIS to invasive adenocarcinoma with AIS features. PMID:25970685

  6. 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.

  7. 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.

  8. 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

    2016-01-01

    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. PMID:26635391

  9. Mutation analysis of TMC1 identifies four new mutations and suggests an additional deafness gene at locus DFNA36-DFNB7/11

    PubMed Central

    Hilgert, Nele; Alasti, Fatemeh; Dieltjens, Nele; Pawlik, Barbara; Wollnik, Bernd; Uyguner, Oya; Delmaghani, Sedigheh; Weil, Dominique; Petit, Christine; Danis, Evi; Yang, Tao; Pandelia, Efthimia; Petersen, Michael B.; Goossens, Dirk; Favero, Jurgen Del; Sanati, Mohammad Hossein; Smith, Richard JH; Van Camp, Guy

    2016-01-01

    Hearing loss is the most frequent sensorineural disorder, affecting 1 in 1000 newborns. In more than half of these babies, the hearing loss is inherited. Hereditary hearing loss is a very heterogeneous trait, with about 100 gene localizations and 44 gene identifications for nonsyndromic hearing loss. TMC1 has been identified as the disease-causing gene for autosomal dominant and autosomal recessive nonsyndromic hearing loss at the DFNA36 and DFNB7/11 loci, respectively. To date, two dominant and 18 recessive TMC1 mutations have been reported as the cause of hearing loss in 34 families. In this report, we describe linkage to DFNA36 and DFNB7/11 in one family with dominant and 10 families with recessive nonsyndromic sensorineural hearing loss. In addition, mutation analysis of TMC1 was performed in 51 familial Turkish patients with autosomal recessive hearing loss. TMC1 mutations were identified in seven of the families segregating recessive hearing loss. The pathogenic variants we found included two known mutations, c.100C>T and c.1165C>T, and four new mutations, c.2350C>T, c.776+1G>A, c.767_768del and c.1166G>A. The absence of TMC1 mutations in the remaining six linked families implies the presence of mutations outside the coding region of this gene, or alternatively, at least one additional deafness-causing gene in this region. The analysis of copy number variations in TMC1 as well as DNA sequencing of 15 additional candidate genes did not reveal any proven pathogenic changes, leaving both hypotheses open. PMID:18616530

  10. Examining the nonparametric effect of drivers' age in rear-end accidents through an additive logistic regression model.

    PubMed

    Ma, Lu; Yan, Xuedong

    2014-06-01

    This study seeks to inspect the nonparametric characteristics connecting the age of the driver to the relative risk of being an at-fault vehicle, in order to discover a more precise and smooth pattern of age impact, which has commonly been neglected in past studies. Records of drivers in two-vehicle rear-end collisions are selected from the general estimates system (GES) 2011 dataset. These extracted observations in fact constitute inherently matched driver pairs under certain matching variables including weather conditions, pavement conditions and road geometry design characteristics that are shared by pairs of drivers in rear-end accidents. The introduced data structure is able to guarantee that the variance of the response variable will not depend on the matching variables and hence provides a high power of statistical modeling. The estimation results exhibit a smooth cubic spline function for examining the nonlinear relationship between the age of the driver and the log odds of being at fault in a rear-end accident. The results are presented with respect to the main effect of age, the interaction effect between age and sex, and the effects of age under different scenarios of pre-crash actions by the leading vehicle. Compared to the conventional specification in which age is categorized into several predefined groups, the proposed method is more flexible and able to produce quantitatively explicit results. First, it confirms the U-shaped pattern of the age effect, and further shows that the risks of young and old drivers change rapidly with age. Second, the interaction effects between age and sex show that female and male drivers behave differently in rear-end accidents. Third, it is found that the pattern of age impact varies according to the type of pre-crash actions exhibited by the leading vehicle. PMID:24642249

  11. 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…

  12. The 5q deletion size in myeloid malignancies is correlated to additional chromosomal aberrations and to TP53 mutations.

    PubMed

    Stengel, Anna; Kern, Wolfgang; Haferlach, Torsten; Meggendorfer, Manja; Haferlach, Claudia

    2016-10-01

    Deletions in the long arm of chromosome 5 (del(5q)) are recurrent abnormalities in myeloid malignancies. We analyzed del(5q) and accompanying molecular mutations in MDS, MPN and MDS/MPN cases. A high del(5q) frequency was revealed in MDS (1869/11398 cases; 16%), followed by MDS/MPN (37/1107; 3%) and MPN (97/6373; 2%). To investigate potential associations of the del(5q) size with the respective phenotypes, we applied array CGH analyses in selected cohorts of 61 MDS, 22 MDS/MPN and 23 MPN cases. The size varied between 16 and 119 Mb with no differences between the entities. However, MPN and MDS/MPN cases with del(5q) sole showed a significantly smaller del(5q) than cases with additional aberrations. Sequence analysis of 27 genes revealed ≥1 mutation in 91% of patients. The highest mutation frequencies in the total cohort were observed for TP53 (31%), JAK2 (23%) and DNMT3A (18%). The molecular mutation patterns in the del(5q) cohorts were different between the entities but resembled known patterns of cohorts not selected for del(5q). Further, TP53 mutations were significantly more frequent in cases with a larger deletion size (P = 0.003). The results suggest a correlation of large del(5q) with TP53 mutations and with additional chromosomal aberrations possibly contributing to more severe courses of these cases. © 2016 Wiley Periodicals, Inc. PMID:27218649

  13. A novel CFTR disease-associated mutation causes addition of an extra N-linked oligosaccharide.

    PubMed

    Hämmerle, M M; Aleksandrov, A A; Chang, X B; Riordan, J R

    2000-11-01

    We have examined the influence of a novel missense mutation in the fourth extracytoplasmic loop (EL4) of CFTR detected in a patient with cystic fibrosis. This substitution (T908N) creates a consensus sequence (N X S/T) for addition of an N-linked oligosaccharide chain near the C-terminal end of EL4. Oligosaccharyl transferase generally does not have access to this consensus sequence if it is closer than about twelve amino acids from the membrane. However, the T908N site is used, even though it is within four residues of the predicted membrane interface and the oligosaccharide chain added binds calnexin, a resident chaperone of the ER membrane. The chloride channel activity of this variant CFTR is abnormal as evidenced by a reduced rate of (36)Cl(-) efflux and a noisy single channel open state. This may reflect some displacement of the membrane spanning sequence C-terminal of EL4 since it contains residues influencing the ion pore. PMID:11443282

  14. 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

  15. Compound mutations in BCR-ABL1 are not major drivers of primary or secondary resistance to ponatinib in CP-CML patients

    PubMed Central

    Hodgson, J. Graeme; Shah, Neil P.; Cortes, Jorge E.; Kim, Dong-Wook; Nicolini, Franck E.; Talpaz, Moshe; Baccarani, Michele; Müller, Martin C.; Li, Jin; Parker, Wendy T.; Lustgarten, Stephanie; Clackson, Tim; Haluska, Frank G.; Guilhot, Francois; Kantarjian, Hagop M.; Soverini, Simona; Hochhaus, Andreas; Hughes, Timothy P.; Rivera, Victor M.; Branford, Susan

    2016-01-01

    BCR-ABL1 kinase domain mutations can confer resistance to first- and second-generation tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML). In preclinical studies, clinically achievable concentrations of the third-generation BCR-ABL1 TKI ponatinib inhibit T315I and all other single BCR-ABL1 mutants except T315M, which generates a single amino acid exchange, but requires 2 sequential nucleotide exchanges. In addition, certain compound mutants (containing ≥2 mutations in cis) confer resistance. Initial analyses based largely on conventional Sanger sequencing (SS) have suggested that the preclinical relationship between BCR-ABL1 mutation status and ponatinib efficacy is generally recapitulated in patients receiving therapy. Thus far, however, such analyses have been limited by the inability of SS to definitively identify compound mutations or mutations representing less than ∼20% of total alleles (referred to as “low-level mutations”), as well as limited patient follow-up. Here we used next-generation sequencing (NGS) to define the baseline BCR-ABL1 mutation status of 267 heavily pretreated chronic phase (CP)-CML patients from the PACE trial, and used SS to identify clonally dominant mutants that may have developed on ponatinib therapy (30.1 months median follow-up). Durable cytogenetic and molecular responses were observed irrespective of baseline mutation status and included patients with compound mutations. No single or compound mutation was identified that consistently conferred primary and/or secondary resistance to ponatinib in CP-CML patients. Ponatinib is effective in CP-CML irrespective of baseline mutation status. PMID:26603839

  16. Whole-exome sequencing of polycythemia vera revealed novel driver genes and somatic mutation shared by T-cells and granulocytes

    PubMed Central

    Wang, Linghua; Swierczek, Sabina I.; Drummond, Jennifer; Hickman, Kimberly; Walker, Kimberly; Doddapaneni, Harshavardhan; Muzny, Donna M.; Gibbs, Richard A.; Wheeler, David A.; Prchal, Josef T.

    2015-01-01

    To better understand the underlying molecular basis of polycythemia vera (PV), we performed whole-exome sequencing and DNA copy-number analysis of 31 JAK2V617F-positive patients and further investigated the evolution of somatic mutations using longitudinal samples. In addition to JAK2V617F and 9pUPD, we identified frequent recurrent somatic mutation in ASXL1, TET2, DNMT3A, SF3B1 and NF1. Forty two percent of patients had a somatic mutation in at least one epigenetic modifier gene. In 4 of 31 patients, variant allele abundance suggested mutation of JAK2V617F was preceded by other somatic mutations including ASXL1, DNMT3A and SF3B1. Strikingly, in 7 patients, apparent germline variants were detected at COSMIC codons in one or more PV-related genes in which we had also discovered somatic mutations across the cohort, suggesting that some pre-JAK2V617F mutations contribute to substantial T-lymphocyte progeny. This study contributes to novel understanding of the complexity of PV pathogenesis. PMID:24413320

  17. C. elegans rrf-1 mutations maintain RNAi efficiency in the soma in addition to the germline.

    PubMed

    Kumsta, Caroline; Hansen, Malene

    2012-01-01

    Gene inactivation through RNA interference (RNAi) has proven to be a valuable tool for studying gene function in C. elegans. When combined with tissue-specific gene inactivation methods, RNAi has the potential to shed light on the function of a gene in distinct tissues. In this study we characterized C. elegans rrf-1 mutants to determine their ability to process RNAi in various tissues. These mutants have been widely used in RNAi studies to assess the function of genes specifically in the C. elegans germline. Upon closer analysis, we found that two rrf-1 mutants carrying different loss-of-function alleles were capable of processing RNAi targeting several somatically expressed genes. Specifically, we observed that the intestine was able to process RNAi triggers efficiently, whereas cells in the hypodermis showed partial susceptibility to RNAi in rrf-1 mutants. Other somatic tissues in rrf-1 mutants, such as the muscles and the somatic gonad, appeared resistant to RNAi. In addition to these observations, we found that the rrf-1(pk1417) mutation induced the expression of several transgenic arrays, including the FOXO transcription factor DAF-16. Unexpectedly, rrf-1(pk1417) mutants showed increased endogenous expression of the DAF-16 target gene sod-3; however, the lifespan and thermo-tolerance of rrf-1(pk1417) mutants were similar to those of wild-type animals. In sum, these data show that rrf-1 mutants display several phenotypes not previously appreciated, including broader tissue-specific RNAi-processing capabilities, and our results underscore the need for careful characterization of tissue-specific RNAi tools. PMID:22574120

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

    PubMed

    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 I; Rother, Kristina; Hildebrand, Peter W; Brogan, Paul; Krüger, Elke; Aksentijevich, Ivona; Goldbach-Mansky, Raphaela

    2015-11-01

    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

  19. 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

  20. A cross-sectional observation study regarding patients and their physician willingness to wait for driver mutation report in nonsmall-cell lung cancer

    PubMed Central

    Joshi, Amit; Patil, Vijay M.; Noronha, Vanita; Ghosh, Joydeep; Bhattacharjee, Atanu; Prabhash, Kumar

    2016-01-01

    Background: Palliative chemotherapy +/− targeted therapy in accordance with mutation profile is the norm in nonsmall-cell lung cancer (NSCLC). The objective of this audit was to determine the proportion of patients and physicians, who are unwilling to wait for the mutation report and the reasons thereof. Materials and Methods: All newly diagnosed NSCLC patients, post biopsy, seen at our center between November 2014 and January 2015 were included. The relationship between patient and physician decision and objective factors was explored by Fisher's exact test. The factors considered were Eastern Cooperative Oncology Group performance status (ECOG PS), the presence of a cough, hemoptysis, fatigue, and breathlessness. The agreement between patients and physician decision was tested by contingency table. Results: Out of 168 patients, 57 were unwilling to wait for driver mutation report (33.9% 95% confidence interval [CI] 27.2-41.4%). The most common reason provided by patients was symptomatic status (23, 40.1%). No other objective factor except PS (P = 0.00) was associated with patient's decision. In 56 patients (33.4% 95% CI 26.6-40.7%), physicians were unwilling to wait. Among the tested factors ECOG PS (P = 0.000), breathlessness (P = 0.00) and fatigue (P = 0.00) were associated with the decision of not waiting for the report. The percentage corrected value of contingency between patients and physician decision was 78.74%. Conclusion: At present, in our setup, nearly one-third of our NSCLC patients opt for immediate chemotherapy treatment and are unwilling to wait for mutation analysis report. The major reasons for such attitude is poor symptom control and deteriorating general condition. PMID:27168703

  1. 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.

  2. 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…

  3. The Evolving Context of Driver Mutations: ROS1 Rearrangement in Metastatic Non-Small Cell Lung Cancer.

    PubMed

    DeCaire, Ximena; Streu, Erin

    2016-09-01

    A previously healthy, 30-year-old Filipino woman presented to an emergency department with complaints of shortness of breath and mild cough. She denied constitutional symptoms, such as night sweats, fevers, loss of appetite, or weight loss. Additional investigation revealed bilateral pleural and pericardial effusions with no obvious lung lesions or masses. The pericardial fluid was drained and preliminary cytology revealed atypical carcinoma cells. Her past medical history included an embryonic pregnancy and a benign breast cyst that was biopsied in the Philippines. She had immigrated to Canada two years earlier, was working full-time, and was living with her sister. She was planning on returning to the Philippines to wed and had a strong support system in Canada. She had never smoked cigarettes or consumed alcohol and had no family history of cancer. The patient was exposed to secondhand smoke as a child.
. PMID:27541546

  4. Additional mutations in SRSF2, ASXL1 and/or RUNX1 identify a high-risk group of patients with KIT D816V(+) advanced systemic mastocytosis.

    PubMed

    Jawhar, M; Schwaab, J; Schnittger, S; Meggendorfer, M; Pfirrmann, M; Sotlar, K; Horny, H-P; Metzgeroth, G; Kluger, S; Naumann, N; Haferlach, C; Haferlach, T; Valent, P; Hofmann, W-K; Fabarius, A; Cross, N C P; Reiter, A

    2016-01-01

    Most patients with KIT D816V(+) advanced systemic mastocytosis (SM) are characterized by somatic mutations in additional genes. We sought to clarify the prognostic impact of such mutations. Genotype and clinical characteristics of 70 multi-mutated KIT D816V(+) advanced SM patients were included in univariate and multivariate analyses. The most frequently identified mutated genes were TET2 (n=33 of 70 patients), SRSF2 (n=30), ASXL1 (n=20), RUNX1 (n=16) and JAK2 (n=11). In univariate analysis, overall survival (OS) was adversely influenced by mutations in SRSF2 (P<0.0001), ASXL1 (P=0.002) and RUNX1 (P=0.03), but was not influenced by mutations in TET2 or JAK2. In multivariate analysis, SRSF2 and ASXL1 remained the most predictive adverse indicators concerning OS. Furthermore, we found that inferior OS and adverse clinical characteristics were significantly influenced by the number of mutated genes in the SRSF2/ASXL1/RUNX1 (S/A/R) panel (P<0.0001). In conclusion, the presence and number of mutated genes within the S/A/R panel are adversely associated with advanced disease and poor survival in KIT D816V(+) SM. On the basis of these findings, inclusion of molecular markers should be considered in upcoming prognostic scoring systems for patients with SM. PMID:26464169

  5. 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 ...

  6. The mini-driver model of polygenic cancer evolution.

    PubMed

    Castro-Giner, Francesc; Ratcliffe, Peter; Tomlinson, Ian

    2015-11-01

    Much of cancer genetics research has focused on the identification of the most-important somatic mutations ('major drivers') that cause tumour growth. However, many mutations found in cancer might not be major drivers or 'passenger' mutations, but instead might have relatively weak tumour-promoting effects. Our aim is to highlight the existence of these mutations (termed 'mini drivers' herein), as multiple mini-driver mutations might substitute for a major-driver change, especially in the presence of genomic instability or high mutagen exposure. The mini-driver model has clinical implications: for example, the effects of therapeutically targeting such genes may be limited. However, the main importance of the model lies in helping to provide a complete understanding of tumorigenesis, especially as we anticipate that an increasing number of mini-driver mutations will be found by cancer genome sequencing. PMID:26456849

  7. Genomic Sequencing Identifies ELF3 as a Driver of Ampullary Carcinoma.

    PubMed

    Yachida, Shinichi; Wood, Laura D; Suzuki, Masami; Takai, Erina; Totoki, Yasushi; Kato, Mamoru; Luchini, Claudio; Arai, Yasuhito; Nakamura, Hiromi; Hama, Natsuko; Elzawahry, Asmaa; Hosoda, Fumie; Shirota, Tomoki; Morimoto, Nobuhiko; Hori, Kunio; Funazaki, Jun; Tanaka, Hikaru; Morizane, Chigusa; Okusaka, Takuji; Nara, Satoshi; Shimada, Kazuaki; Hiraoka, Nobuyoshi; Taniguchi, Hirokazu; Higuchi, Ryota; Oshima, Minoru; Okano, Keiichi; Hirono, Seiko; Mizuma, Masamichi; Arihiro, Koji; Yamamoto, Masakazu; Unno, Michiaki; Yamaue, Hiroki; Weiss, Matthew J; Wolfgang, Christopher L; Furukawa, Toru; Nakagama, Hitoshi; Vogelstein, Bert; Kiyono, Tohru; Hruban, Ralph H; Shibata, Tatsuhiro

    2016-02-01

    Ampullary carcinomas are highly malignant neoplasms that can have either intestinal or pancreatobiliary differentiation. To characterize somatic alterations in ampullary carcinomas, we performed whole-exome sequencing and DNA copy-number analysis on 60 ampullary carcinomas resected from clinically well-characterized Japanese and American patients. We next selected 92 genes and performed targeted sequencing to validate significantly mutated genes in an additional 112 cancers. The prevalence of driver gene mutations in carcinomas with the intestinal phenotype is different from those with the pancreatobiliary phenotype. We identified a characteristic significantly mutated driver gene (ELF3) as well as previously known driver genes (TP53, KRAS, APC, and others). Functional studies demonstrated that ELF3 silencing in normal human epithelial cells enhances their motility and invasion. PMID:26806338

  8. 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.

  9. 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

  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. In situ mapping of the effect of additional mutations on starch granule structure in amylose-extender (ae) maize kernels.

    PubMed

    Liu, Dongli; Wellner, Nikolaus; Parker, Mary L; Morris, Victor J; Cheng, Fang

    2015-03-15

    Optical (KI/I2-staining, polarised) and FTIR microscopy has been used to monitor starch granule structure within wild-type (wt), GEMS-0067 and waxy-amylose-extender (wx-ae) maize mutant kernels. In the GEMS-0067 mutant containing the high amylose modifier (HAM) gene(s) plus the recessive ae gene, structural heterogeneity characteristic of the ae mutation was reduced markedly. However, enhanced variation in granule shape and size was observed distributed spatially within the kernel, which appears to be related to new heterogeneity in internal starch granule structure. In wx-ae starch mutants the ae gene led to heterogeneity of starch granule structure equivalent to that in single ae mutants, plus new structural heterogeneity coincident with novel induced variation in granule size and shape. PMID:25542125

  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. PMID:26320869

  13. Laser driver

    SciTech Connect

    Culpepper, C.F.

    1989-03-14

    A laser driver for a laser diode is described, consisting of: an impedance matched input buffer amplifier to which a modulation signal is applied; and a current source coupled to the output of the impedance matched input buffer amplifier, the output of the current source providing an essentially constant amplitude a.c. current component coupled to drive the laser diode.

  14. Crash involvement of drivers with multiple crashes.

    PubMed

    Chandraratna, Susantha; Stamatiadis, Nikiforos; Stromberg, Arnold

    2006-05-01

    A goal for any licensing agency is the ability to identify high-risk drivers. Kentucky data show that a significant number of drivers are repeatedly involved in crashes. The objective of this study is the development of a crash prediction model that can be used to estimate the likelihood of a driver being at fault for a near future crash occurrence. Multiple logistic regression techniques were employed using the available data for the Kentucky licensed drivers. This study considers as crash predictors the driver's total number of previous crashes, citations accumulated, the time gap between the latest two crashes, crash type, and demographic factors. The driver's total number of previous crashes was further disaggregated into the drivers' total number of previous at-fault and not-at-fault crashes. The model can be used to correctly classify at-fault drivers up to 74.56% with an overall efficiency of 63.34%. The total number of previous at-fault crash involvements, and having previous driver license suspensions and traffic school referrals are strongly associated with a driver being responsible for a subsequent crash. In addition, a driver's likelihood to be at fault in a crash is higher for very young or very old, males, drivers with both speeding and non-speeding citations, and drivers that had a recent crash involvement. Thus, the model presented here enables agencies to more actively monitor the likelihood of a driver to be at fault in a crash. PMID:16405858

  15. 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. PMID:25769001

  16. MRP1 and P-glycoprotein expression assays would be useful in the additional detection of treatment non-responders in CML patients without ABL1 mutation.

    PubMed

    Park, Sang Hyuk; Park, Chan-Jeoung; Kim, Dae-Young; Lee, Bo-Ra; Kim, Young Jin; Cho, Young-Uk; Jang, Seongsoo

    2015-10-01

    We evaluated the ability of the rhodamine-123 efflux assay, multidrug resistance-associated protein-1 (MRP1) expression assay and P-glycoprotein (Pgp) expression assay to discriminate chronic myelogenous leukemia (CML) patients who had failed treatment or were at risk of failure. Each assay was performed in blood samples from CML patients (n=224) treated with tyrosine kinase inhibitors, taken at diagnosis (n=14) and follow-up (n=210). Patient samples were categorized as optimal response (n=120), suboptimal response (n=54), and treatment failure (n=36). Treatment-failed patients had a significantly higher MRP1 expression (5.24% vs. 3.54%, P=0.006) and Pgp expression (5.25% vs. 3.48%, P=0.005) than responders. Both MRP1 (%) and Pgp (%) were highly specific (95.2% and 94.5%) and relatively accurate (83.0% and 82.5%) in the detection of treatment non-responders. Of treatment-failed patients, 41.2% had a positive result in at least one assay and of these patients without ABL1 kinase domain mutation, 51.9% were positive in at least one assay. However, the rhodamine-123 efflux assay failed to discriminate two patient groups. Thus, both MRP1 and Pgp expression assays could be useful for additional identification of treatment non-responders in CML patients without ABL1 mutation. PMID:26248945

  17. 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

  18. Cancer Missense Mutations Alter Binding Properties of Proteins and Their Interaction Networks

    PubMed Central

    Nishi, Hafumi; Tyagi, Manoj; Teng, Shaolei; Shoemaker, Benjamin A.; Hashimoto, Kosuke; Alexov, Emil; Wuchty, Stefan; Panchenko, Anna R.

    2013-01-01

    Many studies have shown that missense mutations might play an important role in carcinogenesis. However, the extent to which cancer mutations might affect biomolecular interactions remains unclear. Here, we map glioblastoma missense mutations on the human protein interactome, model the structures of affected protein complexes and decipher the effect of mutations on protein-protein, protein-nucleic acid and protein-ion binding interfaces. Although some missense mutations over-stabilize protein complexes, we found that the overall effect of mutations is destabilizing, mostly affecting the electrostatic component of binding energy. We also showed that mutations on interfaces resulted in more drastic changes of amino acid physico-chemical properties than mutations occurring outside the interfaces. Analysis of glioblastoma mutations on interfaces allowed us to stratify cancer-related interactions, identify potential driver genes, and propose two dozen additional cancer biomarkers, including those specific to functions of the nervous system. Such an analysis also offered insight into the molecular mechanism of the phenotypic outcomes of mutations, including effects on complex stability, activity, binding and turnover rate. As a result of mutated protein and gene network analysis, we observed that interactions of proteins with mutations mapped on interfaces had higher bottleneck properties compared to interactions with mutations elsewhere on the protein or unaffected interactions. Such observations suggest that genes with mutations directly affecting protein binding properties are preferably located in central network positions and may influence critical nodes and edges in signal transduction networks. PMID:23799087

  19. 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

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

    PubMed

    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

  1. CALR mutation profile in Irish patients with myeloproliferative neoplasms.

    PubMed

    Haslam, Karl; Conneally, Eibhlin; Flynn, Catherine M; Cahill, Mary R; Gilligan, Oonagh; O'Shea, Derville; Langabeer, Stephen E

    2016-09-01

    Insertion and/or deletion mutations of the CALR gene have recently been demonstrated to be the second most common driver mutations in the myeloproliferative neoplasms (MPNs) of essential thrombocythemia (ET) and primary myelofibrosis (PMF). Given the diagnostic and emerging prognostic significance of these mutations, in addition to the geographical heterogeneity reported, the incidence of CALR mutations was determined in an Irish cohort of patients with MPNs with a view to incorporate this analysis into a prospective screening program. A series of 202 patients with known or suspected ET and PMF were screened for the presence of CALR mutations. CALR mutations were detected in 58 patients. Type 1 and Type 1-like deletion mutations were the most common (n=40) followed by Type 2 and Type 2-like insertion mutations (n=17). The CALR mutation profile in Irish ET and PMF patients appears similar to that in other European populations. Establishment of this mutational profile allows the introduction of a rational, molecular diagnostic algorithm in cases of suspected ET and PMF that will improve clinical management. PMID:27352261

  2. Deep sequencing reveals stepwise mutation acquisition in paroxysmal nocturnal hemoglobinuria

    PubMed Central

    Shen, Wenyi; Clemente, Michael J.; Hosono, Naoko; Yoshida, Kenichi; Przychodzen, Bartlomiej; Yoshizato, Tetsuichi; Shiraishi, Yuichi; Miyano, Satoru; Ogawa, Seishi; Maciejewski, Jaroslaw P.; Makishima, Hideki

    2014-01-01

    Paroxysmal nocturnal hemoglobinuria (PNH) is a nonmalignant clonal disease of hematopoietic stem cells that is associated with hemolysis, marrow failure, and thrombophilia. PNH has been considered a monogenic disease that results from somatic mutations in the gene encoding PIGA, which is required for biosynthesis of glycosylphosphatidylinisotol-anchored (GPI-anchored) proteins. The loss of certain GPI-anchored proteins is hypothesized to provide the mutant clone with an extrinsic growth advantage, but some features of PNH argue that there are intrinsic drivers of clonal expansion. Here, we performed whole-exome sequencing of paired PNH+ and PNH– fractions on samples taken from 12 patients as well as targeted deep sequencing of an additional 36 PNH patients. We identified additional somatic mutations that resulted in a complex hierarchical clonal architecture, similar to that observed in myeloid neoplasms. In addition to mutations in PIGA, mutations were found in genes known to be involved in myeloid neoplasm pathogenesis, including TET2, SUZ12, U2AF1, and JAK2. Clonal analysis indicated that these additional mutations arose either as a subclone within the PIGA-mutant population, or prior to PIGA mutation. Together, our data indicate that in addition to PIGA mutations, accessory genetic events are frequent in PNH, suggesting a stepwise clonal evolution derived from a singular stem cell clone. PMID:25244093

  3. 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…

  4. Targetable signaling pathway mutations are associated with malignant phenotype in IDH-mutant gliomas

    PubMed Central

    Wakimoto, Hiroaki; Tanaka, Shota; Curry, William T.; Loebel, Franziska; Zhao, Dan; Tateishi, Kensuke; Chen, Juxiang; Klofas, Lindsay K.; Lelic, Nina; Kim, James C.; Dias-Santagata, Dora; Ellisen, Leif W.; Borger, Darrell R.; Fendt, Sarah-Maria; Heiden, Matthew G. Vander; Batchelor, Tracy T.; Iafrate, A. John; Cahill, Daniel P.; Chi, Andrew S.

    2014-01-01

    PURPOSE Isocitrate dehydrogenase (IDH) gene mutations occur in low-grade and high-grade gliomas. We sought to identify the genetic basis of malignant phenotype heterogeneity in IDH-mutant gliomas. METHODS We prospectively implanted tumor specimens from 20 consecutive IDH1-mutant glioma resections into mouse brains and genotyped all resection specimens using a CLIA-certified molecular panel. Gliomas with cancer driver mutations were tested for sensitivity to targeted inhibitors in vitro. Associations between genomic alterations and outcomes were analyzed in patients. RESULTS By 10 months, 8 of 20 IDH1-mutant gliomas developed intracerebral xenografts. All xenografts maintained mutant IDH1 and high levels of 2-hydroxyglutarate on serial transplantation. All xenograft-producing gliomas harbored “lineage-defining” mutations in CIC (oligodendroglioma) or TP53 (astrocytoma), and 6 of 8 additionally had activating mutations in PIK3CA or amplification of PDGFRA, MET or N-MYC. Only IDH1 and CIC/TP53 mutations were detected in non-xenograft-forming gliomas (P=.0007). Targeted inhibition of the additional alterations decreased proliferation in vitro. Moreover, we detected alterations in known cancer driver genes in 13.4% of IDH-mutant glioma patients, including PIK3CA, KRAS, AKT or PTEN mutation or PDGFRA, MET or N-MYC amplification. IDH/CIC mutant tumors were associated with PIK3CA/KRAS mutations while IDH/TP53 tumors correlated with PDGFRA/MET amplification. Presence of driver alterations at progression was associated with shorter subsequent progression-free survival (median 9.0 vs. 36.1 months, P=.0011). CONCLUSION A subset of IDH-mutant gliomas with mutations in driver oncogenes has a more malignant phenotype in patients. Identification of these alterations may provide an opportunity for use of targeted therapies in these patients. PMID:24714777

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

    PubMed

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

    2014-12-01

    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. 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. PMID:25435355

  7. 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.

  8. A meta-analysis of somatic mutations from next generation sequencing of 241 melanomas: a road map for the study of genes with potential clinical relevance

    PubMed Central

    Xia, Junfeng; Jia, Peilin; Hutchinson, Katherine E.; Dahlman, Kimberly B.; Johnson, Douglas; Sosman, Jeffrey; Pao, William; Zhao, Zhongming

    2014-01-01

    Next generation sequencing (NGS) has been used to characterize the overall genomic landscape of melanomas. Here, we systematically examined mutations from recently published melanoma NGS data involving 241 paired tumor-normal samples to identify potentially clinically relevant mutations. Melanomas were characterized according to an in-house clinical assay that identifies well-known specific recurrent mutations in five driver genes: BRAF (affecting V600), NRAS (G12, G13, and Q61), KIT (W557, V559, L576, K642, and D816), GNAQ (Q209), and GNA11 (Q209). Tumors with none of these mutations are termed “pan-negative”. We then mined the driver mutation-positive and pan-negative melanoma NGS data for mutations in 632 cancer genes that could influence existing or emerging targeted therapies. First, we uncovered several genes whose mutations were more likely associated with BRAF- or NRAS-driven melanomas, including TP53 and COL1A1 with BRAF, and PPP6C, KALRN, PIK3R4, TRPM6, GUCY2C, and PRKAA2 with NRAS. Second, we found that the 69 “pan-negative” melanoma genomes harbored alternate infrequent mutations in the 5 known driver genes along with many mutations in genes encoding guanine nucleotide binding protein α-subunits. Third, we identified 12 significantly mutated genes in “pan-negative” samples (ALK, STK31, DGKI, RAC1, EPHA4, ADAMTS18, EPHA7, ERBB4, TAF1L, NF1, SYK, and KDR), including 5 genes (RAC1, ADAMTS18, EPHA7, TAF1L, and NF1) with a recurrent mutation in at least 2 “pan-negative” tumor samples. This meta-analysis provides a road map for the study of additional potentially actionable genes in both driver mutation-positive and pan-negative melanomas. PMID:24755198

  9. Mutation rates, spectra, and genome-wide distribution of spontaneous mutations in mismatch repair deficient yeast.

    PubMed

    Lang, Gregory I; Parsons, Lance; Gammie, Alison E

    2013-09-01

    DNA mismatch repair is a highly conserved DNA repair pathway. In humans, germline mutations in hMSH2 or hMLH1, key components of mismatch repair, have been associated with Lynch syndrome, a leading cause of inherited cancer mortality. Current estimates of the mutation rate and the mutational spectra in mismatch repair defective cells are primarily limited to a small number of individual reporter loci. Here we use the yeast Saccharomyces cerevisiae to generate a genome-wide view of the rates, spectra, and distribution of mutation in the absence of mismatch repair. We performed mutation accumulation assays and next generation sequencing on 19 strains, including 16 msh2 missense variants implicated in Lynch cancer syndrome. The mutation rate for DNA mismatch repair null strains was approximately 1 mutation per genome per generation, 225-fold greater than the wild-type rate. The mutations were distributed randomly throughout the genome, independent of replication timing. The mutation spectra included insertions/deletions at homopolymeric runs (87.7%) and at larger microsatellites (5.9%), as well as transitions (4.5%) and transversions (1.9%). Additionally, repeat regions with proximal repeats are more likely to be mutated. A bias toward deletions at homopolymers and insertions at (AT)n microsatellites suggests a different mechanism for mismatch generation at these sites. Interestingly, 5% of the single base pair substitutions might represent double-slippage events that occurred at the junction of immediately adjacent repeats, resulting in a shift in the repeat boundary. These data suggest a closer scrutiny of tumor suppressors with homopolymeric runs with proximal repeats as the potential drivers of oncogenesis in mismatch repair defective cells. PMID:23821616

  10. 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. PMID:8153752

  11. 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.…

  12. 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. PMID:26200345

  13. 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. PMID:26154200

  14. Limitations of the Driver/Passenger Model in Cancer Prevention.

    PubMed

    Kuhner, Mary K; Kostadinov, Rumen; Reid, Brian J

    2016-05-01

    Mutations detected in cancers are often divided into "drivers" and "passengers." We suggest that this classification is potentially misleading for purposes of early detection and prevention. Specifically, some mutations are frequent in tumors and thus appear to be drivers, but are poor predictors of cancer; other mutations are individually rare and thus appear to be passengers, but may collectively explain a large proportion of risk. The assumptions bundled into the terms "driver" and "passenger" can lead to misunderstandings of neoplastic progression, with unintended consequences including overdiagnosis, overtreatment, and failure to identify the true sources of risk. We argue that samples from healthy, benign, or neoplastic tissues are critical for evaluating the risk of future cancer posed by mutations in a given gene. Cancer Prev Res; 9(5); 335-8. ©2016 AACR. PMID:26932841

  15. 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…

  16. LANL GPIB Driver

    SciTech Connect

    2004-04-15

    This driver code adds a GPIB infrastructure and API features to 2.6 series Linux kernels. Currently supported hardware is National Instruments PCI-GPIB cards built on either the TNT4882 controller chip, or the TNT5004 controller chip. This driver is an improvement over previous GPIB drivers in Linux because it has all the features of the GPL, high performance DMA, supports Linux 2.6 and the new driver model, and has a cleaner API than the previous drivers. GPIB is the "general purpose interface bus", commonly used to control oscilloscopes, digital multimeters, function generators, and other electronic test equipment.

  17. LANL GPIB Driver

    2004-04-15

    This driver code adds a GPIB infrastructure and API features to 2.6 series Linux kernels. Currently supported hardware is National Instruments PCI-GPIB cards built on either the TNT4882 controller chip, or the TNT5004 controller chip. This driver is an improvement over previous GPIB drivers in Linux because it has all the features of the GPL, high performance DMA, supports Linux 2.6 and the new driver model, and has a cleaner API than the previous drivers.more » GPIB is the "general purpose interface bus", commonly used to control oscilloscopes, digital multimeters, function generators, and other electronic test equipment.« less

  18. The Mutational Landscape of Head and Neck Squamous Cell Carcinoma

    PubMed Central

    Stransky, Nicolas; Egloff, Ann Marie; Tward, Aaron D.; Kostic, Aleksandar D.; Cibulskis, Kristian; Sivachenko, Andrey; Kryukov, Gregory V.; Lawrence, Michael; Sougnez, Carrie; McKenna, Aaron; Shefler, Erica; Ramos, Alex H.; Stojanov, Petar; Carter, Scott L.; Voet, Douglas; Cortés, Maria L; Auclair, Daniel; Berger, Michael F.; Saksena, Gordon; Guiducci, Candace; Onofrio, Robert; Parkin, Melissa; Romkes, Marjorie; Weissfeld, Joel L.; Seethala, Raja R.; Wang, Lin; Rangel-Escareño, Claudia; Fernandez-Lopez, Juan Carlos; Hidalgo-Miranda, Alfredo; Melendez-Zajgla, Jorge; Winckler, Wendy; Ardlie, Kristin; Gabriel, Stacey B.; Meyerson, Matthew; Lander, Eric S.; Getz, Gad; Golub, Todd R.; Garraway, Levi A.; Grandis, Jennifer R.

    2012-01-01

    Head and neck squamous cell carcinoma (HNSCC) is a common, morbid, and frequently lethal malignancy. To uncover its mutational spectrum, we analyzed whole-exome sequencing data from 74 tumor-normal pairs. The majority exhibited a mutational profile consistent with tobacco exposure; human papilloma virus was detectable by sequencing of DNA from infected tumors. In addition to identifying previously known HNSCC genes (TP53, CDKN2A, PTEN, PIK3CA, and HRAS), the analysis revealed many genes not previously implicated in this malignancy. At least 30% of cases harbored mutations in genes that regulate squamous differentiation (e.g., NOTCH1, IRF6, and TP63), implicating its dysregulation as a major driver of HNSCC carcinogenesis. More generally, the results indicate the ability of large-scale sequencing to reveal fundamental tumorigenic mechanisms. PMID:21798893

  19. The Conundrum of Genetic "Drivers" in Benign Conditions.

    PubMed

    Kato, Shumei; Lippman, Scott M; Flaherty, Keith T; Kurzrock, Razelle

    2016-08-01

    Advances in deep genomic sequencing have identified a spectrum of cancer-specific passenger and driver aberrations. Clones with driver anomalies are believed to be positively selected during carcinogenesis. Accumulating evidence, however, shows that genomic alterations, such as those inBRAF,RAS,EGFR,HER2,FGFR3,PIK3CA,TP53,CDKN2A, andNF1/2, all of which are considered hallmark drivers of specific cancers, can also be identified in benign and premalignant conditions, occasionally at frequencies higher than in their malignant counterparts. Targeting these genomic drivers can produce dramatic responses in advanced cancer, but the effects on their benign counterparts are less clear. This benign-malignant phenomenon is well illustrated in studies ofBRAFV600E mutations, which are paradoxically more frequent in benign nevi (∼80%) than in dysplastic nevi (∼60%) or melanoma (∼40%-45%). Similarly, human epidermal growth factor receptor 2 is more commonly overexpressed in ductal carcinoma in situ (∼27%-56%) when compared with invasive breast cancer (∼11%-20%).FGFR3mutations in bladder cancer also decrease with tumor grade (low-grade tumors, ∼61%; high-grade, ∼11%). "Driver" mutations also occur in nonmalignant settings:TP53mutations in synovial tissue from rheumatoid arthritis andFGFR3mutations in seborrheic keratosis. The latter observations suggest that the oncogenicity of these alterations may be tissue context-dependent. The conversion of benign conditions to premalignant disease may involve other genetic events and/or epigenetic reprogramming. Putative driver mutations can also be germline and associated with increased cancer risk (eg, germlineRASorTP53alterations), but germlineFGFR3orNF2abnormalities do not predispose to malignancy. We discuss the enigma of genetic "drivers" in benign and premalignant conditions and the implications for prevention strategies and theories of tumorigenesis. PMID:27059373

  20. 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. PMID:19540960

  1. The Mutational Landscape of Acute Promyelocytic Leukemia Reveals an Interacting Network of Co-Occurrences and Recurrent Mutations.

    PubMed

    Ibáñez, Mariam; Carbonell-Caballero, José; García-Alonso, Luz; Such, Esperanza; Jiménez-Almazán, Jorge; Vidal, Enrique; Barragán, Eva; López-Pavía, María; LLop, Marta; Martín, Iván; Gómez-Seguí, Inés; Montesinos, Pau; Sanz, Miguel A; Dopazo, Joaquín; Cervera, José

    2016-01-01

    Preliminary Acute Promyelocytic Leukemia (APL) whole exome sequencing (WES) studies have identified a huge number of somatic mutations affecting more than a hundred different genes mainly in a non-recurrent manner, suggesting that APL is a heterogeneous disease with secondary relevant changes not yet defined. To extend our knowledge of subtle genetic alterations involved in APL that might cooperate with PML/RARA in the leukemogenic process, we performed a comprehensive analysis of somatic mutations in APL combining WES with sequencing of a custom panel of targeted genes by next-generation sequencing. To select a reduced subset of high confidence candidate driver genes, further in silico analysis were carried out. After prioritization and network analysis we found recurrent deleterious mutations in 8 individual genes (STAG2, U2AF1, SMC1A, USP9X, IKZF1, LYN, MYCBP2 and PTPN11) with a strong potential of being involved in APL pathogenesis. Our network analysis of multiple mutations provides a reliable approach to prioritize genes for additional analysis, improving our knowledge of the leukemogenesis interactome. Additionally, we have defined a functional module in the interactome of APL. The hypothesis is that the number, or the specific combinations, of mutations harbored in each patient might not be as important as the disturbance caused in biological key functions, triggered by several not necessarily recurrent mutations. PMID:26886259

  2. The Mutational Landscape of Acute Promyelocytic Leukemia Reveals an Interacting Network of Co-Occurrences and Recurrent Mutations

    PubMed Central

    García-Alonso, Luz; Such, Esperanza; Jiménez-Almazán, Jorge; Vidal, Enrique; Barragán, Eva; López-Pavía, María; LLop, Marta; Martín, Iván; Gómez-Seguí, Inés; Montesinos, Pau; Sanz, Miguel A.; Dopazo, Joaquín; Cervera, José

    2016-01-01

    Preliminary Acute Promyelocytic Leukemia (APL) whole exome sequencing (WES) studies have identified a huge number of somatic mutations affecting more than a hundred different genes mainly in a non-recurrent manner, suggesting that APL is a heterogeneous disease with secondary relevant changes not yet defined. To extend our knowledge of subtle genetic alterations involved in APL that might cooperate with PML/RARA in the leukemogenic process, we performed a comprehensive analysis of somatic mutations in APL combining WES with sequencing of a custom panel of targeted genes by next-generation sequencing. To select a reduced subset of high confidence candidate driver genes, further in silico analysis were carried out. After prioritization and network analysis we found recurrent deleterious mutations in 8 individual genes (STAG2, U2AF1, SMC1A, USP9X, IKZF1, LYN, MYCBP2 and PTPN11) with a strong potential of being involved in APL pathogenesis. Our network analysis of multiple mutations provides a reliable approach to prioritize genes for additional analysis, improving our knowledge of the leukemogenesis interactome. Additionally, we have defined a functional module in the interactome of APL. The hypothesis is that the number, or the specific combinations, of mutations harbored in each patient might not be as important as the disturbance caused in biological key functions, triggered by several not necessarily recurrent mutations. PMID:26886259

  3. 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.

  4. 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. PMID:26994895

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

    PubMed

    Garg, Manoj; 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

    2015-11-26

    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

  6. Next generation sequencing in synovial sarcoma reveals novel gene mutations.

    PubMed

    Vlenterie, Myrella; Hillebrandt-Roeffen, Melissa H S; Flucke, Uta E; Groenen, Patricia J T A; Tops, Bastiaan B J; Kamping, Eveline J; Pfundt, Rolph; de Bruijn, Diederik R H; Geurts van Kessel, Ad H M; van Krieken, Han J H J M; van der Graaf, Winette T A; Versleijen-Jonkers, Yvonne M H

    2015-10-27

    Over 95% of all synovial sarcomas (SS) share a unique translocation, t(X;18), however, they show heterogeneous clinical behavior. We analyzed multiple SS to reveal additional genetic alterations besides the translocation. Twenty-six SS from 22 patients were sequenced for 409 cancer-related genes using the Comprehensive Cancer Panel (Life Technologies, USA) on an Ion Torrent platform. The detected variants were verified by Sanger sequencing and compared to matched normal DNAs. Copy number variation was assessed in six tumors using the Oncoscan array (Affymetrix, USA). In total, eight somatic mutations were detected in eight samples. These mutations have not been reported previously in SS. Two of these, in KRAS and CCND1, represent known oncogenic mutations in other malignancies. Additional mutations were detected in RNF213, SEPT9, KDR, CSMD3, MLH1 and ERBB4. DNA alterations occurred more often in adult tumors. A distinctive loss of 6q was found in a metastatic lesion progressing under pazopanib, but not in the responding lesion. Our results emphasize t(X;18) as a single initiating event in SS and as the main oncogenic driver. Our results also show the occurrence of additional genetic events, mutations or chromosomal aberrations, occurring more frequently in SS with an onset in adults. PMID:26415226

  7. Next generation sequencing in synovial sarcoma reveals novel gene mutations

    PubMed Central

    Vlenterie, Myrella; Hillebrandt-Roeffen, Melissa H.S.; Flucke, Uta E.; Groenen, Patricia J.T.A.; Tops, Bastiaan B.J.; Kamping, Eveline J.; Pfundt, Rolph; de Bruijn, Diederik R.H.; van Kessel, Ad H.M. Geurts; van Krieken, Han J.H.J.M.; van der Graaf, Winette T.A.; Versleijen-Jonkers, Yvonne M.H.

    2015-01-01

    Over 95% of all synovial sarcomas (SS) share a unique translocation, t(X;18), however, they show heterogeneous clinical behavior. We analyzed multiple SS to reveal additional genetic alterations besides the translocation. Twenty-six SS from 22 patients were sequenced for 409 cancer-related genes using the Comprehensive Cancer Panel (Life Technologies, USA) on an Ion Torrent platform. The detected variants were verified by Sanger sequencing and compared to matched normal DNAs. Copy number variation was assessed in six tumors using the Oncoscan array (Affymetrix, USA). In total, eight somatic mutations were detected in eight samples. These mutations have not been reported previously in SS. Two of these, in KRAS and CCND1, represent known oncogenic mutations in other malignancies. Additional mutations were detected in RNF213, SEPT9, KDR, CSMD3, MLH1 and ERBB4. DNA alterations occurred more often in adult tumors. A distinctive loss of 6q was found in a metastatic lesion progressing under pazopanib, but not in the responding lesion. Our results emphasize t(X;18) as a single initiating event in SS and as the main oncogenic driver. Our results also show the occurrence of additional genetic events, mutations or chromosomal aberrations, occurring more frequently in SS with an onset in adults. PMID:26415226

  8. 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. PMID:19838315

  9. 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

  10. Proteome-wide analysis of human disease mutations in short linear motifs: neglected players in cancer?† †Electronic supplementary information (ESI) available: Supplementary files 1–22 and supplementary Fig. 1–3. See DOI: 10.1039/c4mb00290c Click here for additional data file. Click here for additional data file. Click here for additional data file.

    PubMed Central

    Weatheritt, Robert J.; Dinkel, Holger; Davey, Norman E.

    2014-01-01

    Disease mutations are traditionally thought to impair protein functionality by disrupting the folded globular structure of proteins. However, 22% of human disease mutations occur in natively unstructured segments of proteins known as intrinsically disordered regions (IDRs). This therefore implicates defective IDR functionality in various human diseases including cancer. The functionality of IDRs is partly attributable to short linear motifs (SLiMs), but it remains an open question how much defects in SLiMs contribute to human diseases. A proteome-wide comparison of the distribution of missense mutations from disease and non-disease mutation datasets revealed that, in IDRs, disease mutations are more likely to occur within SLiMs than neutral missense mutations. Moreover, compared to neutral missense mutations, disease mutations more frequently impact functionally important residues of SLiMs, cause changes in the physicochemical properties of SLiMs, and disrupt more SLiM-mediated interactions. Analysis of these mutations resulted in a comprehensive list of experimentally validated or predicted SLiMs disrupted in disease. Furthermore, this in-depth analysis suggests that ‘prostate cancer pathway’ is particularly enriched for proteins with disease-related SLiMs. The contribution of mutations in SLiMs to disease may currently appear small when compared to mutations in globular domains. However, our analysis of mutations in predicted SLiMs suggests that this contribution might be more substantial. Therefore, when analysing the functional impact of mutations on proteins, SLiMs in proteins should not be neglected. Our results suggest that an increased focus on SLiMs in the coming decades will improve our understanding of human diseases and aid in the development of targeted treatments. PMID:25057855

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

    PubMed

    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

  12. 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.

  13. 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...

  14. 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...

  15. Dynamic Discharge Arc Driver. [computerized simulation

    NASA Technical Reports Server (NTRS)

    Dannenberg, R. E.; Slapnicar, P. I.

    1975-01-01

    A computer program using nonlinear RLC circuit analysis was developed to accurately model the electrical discharge performance of the Ames 1-MJ energy storage and arc-driver system. Solutions of circuit parameters are compared with experimental circuit data and related to shock speed measurements. Computer analysis led to the concept of a Dynamic Discharge Arc Driver (DDAD) capable of increasing the range of operation of shock-driven facilities. Utilization of mass addition of the driver gas offers a unique means of improving driver performance. Mass addition acts to increase the arc resistance, which results in better electrical circuit damping with more efficient Joule heating, producing stronger shock waves. Preliminary tests resulted in an increase in shock Mach number from 34 to 39 in air at an initial pressure of 2.5 torr.

  16. 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. PMID:27426053

  17. 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…

  18. 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…

  19. Dolutegravir-Selected HIV-1 Containing the N155H and R263K Resistance Substitutions Does Not Acquire Additional Compensatory Mutations under Drug Pressure That Lead to Higher-Level Resistance and Increased Replicative Capacity

    PubMed Central

    Anstett, Kaitlin; Fusco, Robert; Cutillas, Vincent; Mesplède, Thibault

    2015-01-01

    ABSTRACT We have previously shown that the addition of the raltegravir/elvitegavir (RAL/EVG) primary resistance mutation N155H to the R263K dolutegravir (DTG) resistance mutation partially compensated for the fitness cost imposed by R263K while also slightly increasing DTG resistance in vitro (K. Anstett, T. Mesplede, M. Oliveira, V. Cutillas, and M. A. Wainberg, J Virol 89:4681–4684, 2015, doi:10.1128/JVI.03485-14). Since many patients failing RAL/EVG are given DTG as part of rescue therapy, and given that the N155H substitution often is found in combination with other compensatory resistance mutations in such individuals, we investigated the effects of multiple such substitutions within integrase (IN) on each of integrase function, HIV-1 infectivity, and levels of drug resistance. To this end, each of the L74M, E92Q, T97A, E157Q, and G163R substitutions were introduced into NL4.3 subtype B HIV-1 vectors harboring N155H and R263K in tandem [termed NL4.3IN(N155H/R263K)]. Relevant recombinant integrase enzymes also were expressed, and purified and biochemical assays of strand transfer efficiency as well as viral infectivity and drug resistance studies were performed. We found that the addition of T97A, E157Q, or G163R somewhat improved the affinity of INN155H/R263K for its target DNA substrate, while the presence of L74M or E92Q had a negative effect on this process. However, viral infectivity was significantly decreased from that of NL4.3IN(N155H/R263K) after the addition of each tertiary mutation, and no increases in levels of DTG resistance were observed. This work shows that the compensatory mutations that evolve after N155H under continued DTG or RAL/EVG pressure in patients are unable to improve either enzyme efficiency or viral infectivity in an N155H/R263K background. IMPORTANCE In contrast to other drugs, dolutegravir has not selected for resistance in HIV-positive individuals when used in first-line therapy. We had previously shown that HIV containing

  20. Exome sequencing of oral squamous cell carcinoma in users of Arabian snuff reveals novel candidates for driver genes.

    PubMed

    Al-Hebshi, Nezar Noor; Li, Shiyong; Nasher, Akram Thabet; El-Setouhy, Maged; Alsanosi, Rashad; Blancato, Jan; Loffredo, Christopher

    2016-07-15

    The study sought to identify genetic aberrations driving oral squamous cell carcinoma (OSCC) development among users of shammah, an Arabian preparation of smokeless tobacco. Twenty archival OSCC samples, 15 of which with a history of shammah exposure, were whole-exome sequenced at an average depth of 127×. Somatic mutations were identified using a novel, matched controls-independent filtration algorithm. CODEX and Exomedepth coupled with a novel, Database of Genomic Variant-based filter were employed to call somatic gene-copy number variations. Significantly mutated genes were identified with Oncodrive FM and the Youn and Simon's method. Candidate driver genes were nominated based on Gene Set Enrichment Analysis. The observed mutational spectrum was similar to that reported by the TCGA project. In addition to confirming known genes of OSCC (TP53, CDKNA2, CASP8, PIK3CA, HRAS, FAT1, TP63, CCND1 and FADD) the analysis identified several candidate novel driver events including mutations of NOTCH3, CSMD3, CRB1, CLTCL1, OSMR and TRPM2, amplification of the proto-oncogenes FOSL1, RELA, TRAF6, MDM2, FRS2 and BAG1, and deletion of the recently described tumor suppressor SMARCC1. Analysis also revealed significantly altered pathways not previously implicated in OSCC including Oncostatin-M signalling pathway, AP-1 and C-MYB transcription networks and endocytosis. There was a trend for higher number of mutations, amplifications and driver events in samples with history of shammah exposure particularly those that tested EBV positive, suggesting an interaction between tobacco exposure and EBV. The work provides further evidence for the genetic heterogeneity of oral cancer and suggests shammah-associated OSCC is characterized by extensive amplification of oncogenes. PMID:26934577

  1. 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

  2. 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.

  3. 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.

  4. The EGFR-HER2 module: a stem cell approach to understanding a prime target and driver of solid tumors

    PubMed Central

    Schneider, Marlon R.; Yarden, Yosef

    2015-01-01

    The epidermal growth factor receptor (EGFR) and a co-receptor denoted HER2/ERBB2, are frequently overexpressed or mutated in solid tumors, such as carcinomas and gliomas. In line with driver roles, cancer drugs intercepting EGFR or HER2 currently outnumber therapies targeting other hubs of signal transduction. To explain the roles for EGFR and HER2 as prime drivers and targets, we take lessons from invertebrates and refer to homeostatic regulation of several mammalian tissues. The model we infer ascribes to the EGFR-HER2 module pivotal functions in rapid clonal expansion of progenitors called transient amplifying cells (TACs). Accordingly, TACs of tumors suffer from replication stress, hence accumulate mutations. In addition, several lines of evidence propose that in response to EGF and related mitogens, TACs might undergo de-differentiation into tissue stem cells, which might enable entry of oncogenic mutations into the stem cell compartment. According to this view, antibodies or kinase inhibitors targeting EGFR-HER2 effectively retard some solid tumors because they arrest mutation-enriched TACs and possibly inhibit their dedifferentiation. Deeper understanding of the EGFR-HER2 module and relations between cancer stem cells and TACs will enhance our ability to control a broad spectrum of human malignancies. PMID:26434585

  5. The EGFR-HER2 module: a stem cell approach to understanding a prime target and driver of solid tumors.

    PubMed

    Schneider, M R; Yarden, Y

    2016-06-01

    The epidermal growth factor receptor (EGFR) and a coreceptor denoted HER2/ERBB2 are frequently overexpressed or mutated in solid tumors, such as carcinomas and gliomas. In line with driver roles, cancer drugs intercepting EGFR or HER2 currently outnumber therapies targeting other hubs of signal transduction. To explain the roles for EGFR and HER2 as prime drivers and targets, we take lessons from invertebrates and refer to homeostatic regulation of several mammalian tissues. The model we infer ascribes to the EGFR-HER2 module pivotal functions in rapid clonal expansion of progenitors called transient amplifying cells (TACs). Accordingly, TACs of tumors suffer from replication stress, and hence accumulate mutations. In addition, several lines of evidence propose that in response to EGF and related mitogens, TACs might undergo dedifferentiation into tissue stem cells, which might enable entry of oncogenic mutations into the stem cell compartment. According to this view, antibodies or kinase inhibitors targeting EGFR-HER2 effectively retard some solid tumors because they arrest mutation-enriched TACs and possibly inhibit their dedifferentiation. Deeper understanding of the EGFR-HER2 module and relations between cancer stem cells and TACs will enhance our ability to control a broad spectrum of human malignancies. PMID:26434585

  6. Integrative genomic characterization of oral squamous cell carcinomaidentifies frequent somatic drivers

    PubMed Central

    Pickering, Curtis R.; Zhang, Jiexin; Yoo, Suk Young; Bengtsson, Linnea; Moorthy, Shhyam; Neskey, David M.; Zhao, Mei; Alves, Marcus V Ortega; Chang, Kyle; Drummond, Jennifer; Cortez, Elsa; Xie, Tong-xin; Zhang, Di; Chung, Woonbok; Issa, Jean-Pierre J.; Zweidler-McKay, Patrick A.; Wu, Xifeng; El-Naggar, Adel K.; Weinstein, John N.; Wang, Jing; Muzny, Donna M.; Gibbs, Richard A.; Wheeler, David A.; Myers, Jeffrey N.; Frederick, Mitchell J.

    2013-01-01

    The survival of patients with oral squamous cell carcinoma (OSCC) has not changed significantly in several decades, leading clinicians and investigators to search for promising molecular targets. To this end, we performed comprehensive genomic analysis of gene expression, copy number, methylation and point mutations in OSCC. Integrated analysis revealed more somatic events than previously reported, identifying four major driver pathways (mitogenic signaling, Notch, cell cycle, TP53) and two additional key genes (FAT1, CASP8). The Notch pathway was defective in 66% of patients, and in follow-up studies of mechanism, functional NOTCH1 signaling inhibited proliferation of OSCC cell lines. Frequent mutation of CASP8 defines a new molecular subtype of OSCC with few copy number changes. Although genomic alterations are dominated by loss of tumor suppressor genes, 80% of patients harbored at least one genomic alteration in a targetable gene, suggesting that novel approaches to treatment may be possible for this debilitating disease. PMID:23619168

  7. 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.

  8. 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.

  9. 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.

  10. Commercial Driver Medical Examinations

    PubMed Central

    Moffitt, Gary; Hanowski, Richard J.; Kales, Stefanos N.; Porter, Richard J.; Hegmann, Kurt T.

    2015-01-01

    Objective: The objective of this study was to assess relationships between body mass index (BMI) and comorbid conditions within a large sample of truck drivers. Methods: Commercial driver medical examination data from 88,246 commercial drivers between 2005 and 2012 were analyzed for associations between BMI, medical disorders, and driver certification. Results: Most drivers were obese (53.3%, BMI >30.0 kg/m2) and morbidly obese (26.6%, BMI >35.0 kg/m2), higher than prior reports. Obese drivers were less likely to be certified for 2 years and more likely to report heart disease, hypertension, diabetes mellitus, nervous disorders, sleep disorders, and chronic low back pain (all P < 0.0001). There are relationships between multiple potentially disqualifying conditions and increasing obesity (P < 0.0001). Morbid obesity prevalence increased 8.9% and prevalence of three or more multiple conditions increased fourfold between 2005 and 2012. Conclusions: Obesity is related to multiple medical factors as well as increasing numbers of conditions that limit driving certification. PMID:25710607

  11. Drivers license display system

    NASA Astrophysics Data System (ADS)

    Prokoski, Francine J.

    1997-01-01

    Carjackings are only one of a growing class of law enforcement problems associated with increasingly violent crimes and accidents involving automobiles plays weapons, drugs and alcohol. Police traffic stops have become increasingly dangerous, with an officer having no information about a vehicle's potentially armed driver until approaching him. There are 15 million alcoholics in the US and 90 percent of them have drivers licenses. Many of them continue driving even after their licenses have ben revoked or suspended. There are thousands of unlicensed truck drivers in the country, and also thousands who routinely exceed safe operating periods without rest; often using drugs in an attempt to stay alert. MIKOS has developed the Drivers License Display Systems to reduce these and other related risks. Although every state requires the continuous display of vehicle registration information on every vehicle using public roads, no state yet requires the display of driver license information. The technology exists to provide that feature as an add-on to current vehicles for nominal cost. An initial voluntary market is expected to include: municipal, rental, and high value vehicles which are most likely to be mis-appropriated. It is anticipated that state regulations will eventually require such systems in the future, beginning with commercial vehicles, and then extending to high risk drivers and eventually all vehicles. The MIKOS system offers a dual-display approach which can be deployed now, and which will utilize all existing state licenses without requiring standardization.

  12. 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

  13. 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…

  14. 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

  15. 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).

  16. Differential association of STK11 and TP53 with KRAS mutation-associated gene expression, proliferation and immune surveillance in lung adenocarcinoma.

    PubMed

    Schabath, M B; Welsh, E A; Fulp, W J; Chen, L; Teer, J K; Thompson, Z J; Engel, B E; Xie, M; Berglund, A E; Creelan, B C; Antonia, S J; Gray, J E; Eschrich, S A; Chen, D-T; Cress, W D; Haura, E B; Beg, A A

    2016-06-16

    While mutations in the KRAS oncogene are among the most prevalent in human cancer, there are few successful treatments to target these tumors. It is also likely that heterogeneity in KRAS-mutant tumor biology significantly contributes to the response to therapy. We hypothesized that the presence of commonly co-occurring mutations in STK11 and TP53 tumor suppressors may represent a significant source of heterogeneity in KRAS-mutant tumors. To address this, we utilized a large cohort of resected tumors from 442 lung adenocarcinoma patients with data including annotation of prevalent driver mutations (KRAS and EGFR) and tumor suppressor mutations (STK11 and TP53), microarray-based gene expression and clinical covariates, including overall survival (OS). Specifically, we determined impact of STK11 and TP53 mutations on a new KRAS mutation-associated gene expression signature as well as previously defined signatures of tumor cell proliferation and immune surveillance responses. Interestingly, STK11, but not TP53 mutations, were associated with highly elevated expression of KRAS mutation-associated genes. Mutations in TP53 and STK11 also impacted tumor biology regardless of KRAS status, with TP53 strongly associated with enhanced proliferation and STK11 with suppression of immune surveillance. These findings illustrate the remarkably distinct ways through which tumor suppressor mutations may contribute to heterogeneity in KRAS-mutant tumor biology. In addition, these studies point to novel associations between gene mutations and immune surveillance that could impact the response to immunotherapy. PMID:26477306

  17. UV signature mutations.

    PubMed

    Brash, Douglas E

    2015-01-01

    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 nontranscribed 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; UV's nonsignature mutations may cause melanoma BRAF mutations; and the mutagen for sunlight-related skin neoplasms may vary between continents. PMID:25354245

  18. Effectiveness evaluation of simulative workshops for newly licensed drivers.

    PubMed

    Rosenbloom, Tova; Eldror, Ehud

    2014-02-01

    The current study set to examine the effects of simulator use in driving instruction on newly licensed drivers, comparing the road safety knowledge and reported intended behavior, as well as the actual driving performance of new drivers. Participants consisted of 280 newly licensed driver, of which 140 whose drivers license training included additional simulator-based lessons, and 140 drivers whose training precluded simulator-based lessons. All drivers answered questionnaires pertaining to their intended safe driving behaviors (according to Ajzen's (2000) theory of planned behavior), and to their traffic safety knowledge. Of the initial sample, 40 drivers received actual driving performance evaluation by an expert driving instructor, as well as by in-vehicle data recorders (IVDRs). We assumed that safer drivers report safer driving intentions, demonstrate greater traffic safety knowledge, evaluated as safer drivers by the driving instructor, and display lower and stable driving parameters on the IVDRs. We hypothesized that theoretical driving studies combined with practical training on simulators will elevate the safety level of novices driving. Hierarchical regression analyses on driving intentions indicated that drivers who did not receive simulator-based lessons demonstrated safer driving intentions compared to drivers who received simulator-based lessons. This pattern possibly indicating the drivers who received simulator-based lessons felt more confident in their driving abilities compared to drivers who did not receive simulated training. No significant difference was found in traffic safety knowledge, or in the evaluation of the expert driving instructor. IDVR data comparisons indicated drivers who received simulator-based lessons braked more often and were less prone to headway events, suggesting a more responsive driving style. These findings do not point to any significant advantage or disadvantage of the current simulator-based driving training over

  19. Missing Drivers with Dementia: Antecedents and Recovery

    PubMed Central

    Rowe, Meredeth A.; Greenblum, Catherine A.; Boltz, Marie; Galvin, James E.

    2013-01-01

    OBJECTIVES To determine the circumstance in which persons with dementia become lost while driving, how missing drivers are found, and how Silver Alert notificationsare instrumental in those discoveries. DESIGN A retrospective, descriptive study. SETTING Retrospective record review. PARTICIPANTS Conducted using 156 records from the Florida Silver Alert program for the time period October, 2008 through May 2010. These alerts were issued in Florida for a missing driver with dementia. MEASUREMENTS Information derived from the reports on characteristics of the missing driver, antecedents to missing event and discovery of a missing driver. RESULTS and CONCLUSION The majority of missing drivers were males, with ages ranging from 58’94, who were being cared for by a spouse. Most drivers became lost on routine, caregiver-sanctioned trips to usual locations. Only 15% were in the act of driving when found with most being found in or near a parked car and the large majority were found by law enforcement officers. Only 40% were found in the county they went missing and 10% were found in a different state. Silver Alert notifications were most effective for law enforcement; citizen alerts resulted in a few discoveries. There was a 5% mortality rate in the study population with those living alone more likely to be found dead than alive. An additional 15% were found in dangerous situations such as stopped on railroad tracks. Thirty-two percent had documented driving or dangerous errors such as, driving thewrong way or into secluded areas, or walking in or near roadways. PMID:23134069

  20. Drugged drivers in Norway with benzodiazepine detections.

    PubMed

    Skurtveit, Svetlana; Abotnes, Bjørg; Christophersen, Asbjørg S

    2002-01-24

    Norwegian drugged drivers with benzodiazepine (BZD) detections have been studied with regard to drug use pattern and rearrest rate. During 1995, 3343 drivers were apprehended by the police in Norway due to the suspicion of influence by drugs. Blood samples from all drivers were sent to the National Institute of Forensic Toxicology (NIFT). The samples were analysed using a standard program covering the most commonly abused drugs on the marked in Norway. BZDs, representing some of the most frequently detected drugs, were found in approximately 30% (n = 1051) of the cases, represented by 14% (n = 150) female and 86% (n = 901) male drivers. In 8% of the cases, one BZD only was detected, half of these cases with one BZD could reflect therapeutic use. One or more BZDs were combined with illegal drug(s) (73%), other prescribed drugs (10%), and/or alcohol (24%). 62% of the drivers with BZD detections, had earlier been arrested for the same offence, or six cases per rearrested driver. The frequency of earlier arrests were lower for female (34%) than for male (67%) drivers. Alcohol was most frequently found for those arrested for the first time before 1992, while BZD or illegal drugs were most frequently found for those with their first arrest during 1992-1995. Our study shows that apprehended drivers using BZD are mainly represented by drug abusers due to frequent multi-drug use, blood concentrations representing doses above therapeutic levels and high rearrest rate for the same offence. A treatment program or other reactions, are thus necessary in addition to fines, prison penalty and suspension of driving licence. PMID:11852205

  1. DNMT3A R882 mutation is associated with elevated expression of MAFB and M4/M5 immunophenotype of acute myeloid leukemia blasts.

    PubMed

    Yang, Li; Liu, Ya'Nan; Zhu, Li; Xiao, Min

    2015-01-01

    Researchers have recognized that aberrant methylation is an important initiating event in the pathogenesis of hematological malignancies. DNMT3A is a DNA methyltransferase that plays a vital role in de novo methylation of DNA. Somatic mutation of DNMT3A, especially at the Arg882 (R882) site of the DNMT3A coding sequence, has been identified in pre-leukemic stem cell clones as one of the driver mutations of acute myeloid leukemia (AML). Statistical analysis has indicated that patients with AML with DNMT3A mutation tend to have the M4/M5 subtype of AML according to the French-American-British classification. In this study we aimed to investigate the association between the typical immunophenotype of leukemic blasts and mutation of DNMT3A R882. In addition, we further determined the relationship between DNMT3A R882 mutation and the expression of monocytic differentiation genes, and its clinical significance. PMID:25721756

  2. Evaluation of the butter flavoring chemical diacetyl and a fluorochemical paper additive for mutagenicity and toxicity using the mammalian cell gene mutation assay in L5178Y mouse lymphoma cells.

    PubMed

    Whittaker, Paul; Clarke, Jane J; San, Richard H C; Begley, Timothy H; Dunkel, Virginia C

    2008-08-01

    Diacetyl (2,3-butanedione) is a yellowish liquid that is usually mixed with other ingredients to produce butter flavor or other flavors in a variety of food products. Inhalation of butter flavoring vapors was first associated with clinical bronchiolitis obliterans among workers in microwave popcorn production. Recent findings have shown irreversible obstructive lung disease among workers not only in the microwave popcorn industry, but also in flavoring manufacture, and in chemical synthesis of diacetyl, a predominant chemical for butter flavoring. It has been reported that perfluorochemicals utilized in food packaging are migrating into foods and may be sources of oral exposure. Relatively small quantities of perfluorochemicals are used in the manufacturing of paper or paperboard that is in direct contact with food to repel oil or grease and water. Because of recent concerns about perfluorochemicals such as those found on microwave popcorn bags (e.g. Lodyne P208E) and diacetyl in foods, we evaluated both compounds for mutagenicity using the mammalian cell gene mutation assay in L5178Y mouse lymphoma cells. Lodyne P208E was less toxic than diacetyl and did not induce a mutagenic response. Diacetyl induced a highly mutagenic response in the L5178Y mouse lymphoma mutation assay in the presence of human liver S9 for activation. The increase in the frequency of small colonies in the assay with diacetyl indicates that diacetyl causes damage to multiple loci on chromosome 11 in addition to functional loss of the thymidine kinase locus. PMID:18585428

  3. 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…

  4. 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…

  5. Mutational patterns in oncogenes and tumour suppressors.

    PubMed

    Baeissa, Hanadi M; Benstead-Hume, Graeme; Richardson, Christopher J; Pearl, Frances M G

    2016-06-15

    All cancers depend upon mutations in critical genes, which confer a selective advantage to the tumour cell. Knowledge of these mutations is crucial to understanding the biology of cancer initiation and progression, and to the development of targeted therapeutic strategies. The key to understanding the contribution of a disease-associated mutation to the development and progression of cancer, comes from an understanding of the consequences of that mutation on the function of the affected protein, and the impact on the pathways in which that protein is involved. In this paper we examine the mutation patterns observed in oncogenes and tumour suppressors, and discuss different approaches that have been developed to identify driver mutations within cancers that contribute to the disease progress. We also discuss the MOKCa database where we have developed an automatic pipeline that structurally and functionally annotates all proteins from the human proteome that are mutated in cancer. PMID:27284061

  6. 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

  7. 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

  8. A multinomial choice model approach for dynamic driver vision transitions.

    PubMed

    Huang, Shih-Hsuan; Wong, Jinn-Tsai

    2015-01-01

    Exploring the continual process of drivers allocating their attention under varying conditions could be vital for preventing motor vehicle crashes. This study aims to model visual behaviors and to estimate the effects of various contributing factors on driver's vision transitions. A visual attention allocation framework, based on certain contributing attributes related to driving tasks and environmental conditions, has been developed. The associated logit type models for determining driver choices for focal points were successfully formulated and estimated by using naturalistic glance data from the 100-car event database. The results offer insights into driver visual behavior and patterns of visual attention allocation. The three focal points that drivers most frequently rely on and glance at are the forward, left and rear view mirror. The sample drivers were less likely to demonstrate troublesome transition patterns, particularly in mentally demanding situations. Additionally, instead of shifting vision directly between two non-forward focal points, the sample drivers frequently had an intermediate forward glance. Thus, seemingly unrelated paths could be grouped into explanatory patterns of driver attention allocation. Finally, in addition to the vision-transition patterns, the potential pitfalls of such patterns and possible countermeasures to improving safety are illustrated, focusing on situations when drivers are distracted, traveling at high speeds and approaching intersections. PMID:25463950

  9. 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…

  10. Driver distraction and driver inattention: definition, relationship and taxonomy.

    PubMed

    Regan, Michael A; Hallett, Charlene; Gordon, Craig P

    2011-09-01

    There is accumulating evidence that driver distraction and driver inattention are leading causes of vehicle crashes and incidents. However, as applied psychological constructs, they have been inconsistently defined and the relationship between them remains unclear. In this paper, driver distraction and driver inattention are defined and a taxonomy is presented in which driver distraction is distinguished from other forms of driver inattention. The taxonomy and the definitions provided are intended (a) to provide a common framework for coding different forms of driver inattention as contributing factors in crashes and incidents, so that comparable estimates of their role as contributing factors can be made across different studies, and (b) to make it possible to more accurately interpret and compare, across studies, the research findings for a given form of driver inattention. PMID:21658505

  11. Whole Exome Sequencing Identifies TSC1/TSC2 Biallelic Loss as the Primary and Sufficient Driver Event for Renal Angiomyolipoma Development.

    PubMed

    Giannikou, Krinio; Malinowska, Izabela A; Pugh, Trevor J; Yan, Rachel; Tseng, Yuen-Yi; Oh, Coyin; Kim, Jaegil; Tyburczy, Magdalena E; Chekaluk, Yvonne; Liu, Yang; Alesi, Nicola; Finlay, Geraldine A; Wu, Chin-Lee; Signoretti, Sabina; Meyerson, Matthew; Getz, Gad; Boehm, Jesse S; Henske, Elizabeth P; Kwiatkowski, David J

    2016-08-01

    Renal angiomyolipoma is a kidney tumor in the perivascular epithelioid (PEComa) family that is common in patients with Tuberous Sclerosis Complex (TSC) and Lymphangioleiomyomatosis (LAM) but occurs rarely sporadically. Though histologically benign, renal angiomyolipoma can cause life-threatening hemorrhage and kidney failure. Both angiomyolipoma and LAM have mutations in TSC2 or TSC1. However, the frequency and contribution of other somatic events in tumor development is unknown. We performed whole exome sequencing in 32 resected tumor samples (n = 30 angiomyolipoma, n = 2 LAM) from 15 subjects, including three with TSC. Two germline and 22 somatic inactivating mutations in TSC2 were identified, and one germline TSC1 mutation. Twenty of 32 (62%) samples showed copy neutral LOH (CN-LOH) in TSC2 or TSC1 with at least 8 different LOH regions, and 30 of 32 (94%) had biallelic loss of either TSC2 or TSC1. Whole exome sequencing identified a median of 4 somatic non-synonymous coding region mutations (other than in TSC2/TSC1), a mutation rate lower than nearly all other cancer types. Three genes with mutations were known cancer associated genes (BAP1, ARHGAP35 and SPEN), but they were mutated in a single sample each, and were missense variants with uncertain functional effects. Analysis of sixteen angiomyolipomas from a TSC subject showed both second hit point mutations and CN-LOH in TSC2, many of which were distinct, indicating that they were of independent clonal origin. However, three tumors had two shared mutations in addition to private somatic mutations, suggesting a branching evolutionary pattern of tumor development following initiating loss of TSC2. Our results indicate that TSC2 and less commonly TSC1 alterations are the primary essential driver event in angiomyolipoma/LAM, whereas other somatic mutations are rare and likely do not contribute to tumor development. PMID:27494029

  12. Whole Exome Sequencing Identifies TSC1/TSC2 Biallelic Loss as the Primary and Sufficient Driver Event for Renal Angiomyolipoma Development

    PubMed Central

    Tseng, Yuen-Yi; Oh, Coyin; Kim, Jaegil; Tyburczy, Magdalena E.; Chekaluk, Yvonne; Liu, Yang; Alesi, Nicola; Finlay, Geraldine A.; Wu, Chin-Lee; Signoretti, Sabina; Meyerson, Matthew; Getz, Gad; Kwiatkowski, David J.

    2016-01-01

    Renal angiomyolipoma is a kidney tumor in the perivascular epithelioid (PEComa) family that is common in patients with Tuberous Sclerosis Complex (TSC) and Lymphangioleiomyomatosis (LAM) but occurs rarely sporadically. Though histologically benign, renal angiomyolipoma can cause life-threatening hemorrhage and kidney failure. Both angiomyolipoma and LAM have mutations in TSC2 or TSC1. However, the frequency and contribution of other somatic events in tumor development is unknown. We performed whole exome sequencing in 32 resected tumor samples (n = 30 angiomyolipoma, n = 2 LAM) from 15 subjects, including three with TSC. Two germline and 22 somatic inactivating mutations in TSC2 were identified, and one germline TSC1 mutation. Twenty of 32 (62%) samples showed copy neutral LOH (CN-LOH) in TSC2 or TSC1 with at least 8 different LOH regions, and 30 of 32 (94%) had biallelic loss of either TSC2 or TSC1. Whole exome sequencing identified a median of 4 somatic non-synonymous coding region mutations (other than in TSC2/TSC1), a mutation rate lower than nearly all other cancer types. Three genes with mutations were known cancer associated genes (BAP1, ARHGAP35 and SPEN), but they were mutated in a single sample each, and were missense variants with uncertain functional effects. Analysis of sixteen angiomyolipomas from a TSC subject showed both second hit point mutations and CN-LOH in TSC2, many of which were distinct, indicating that they were of independent clonal origin. However, three tumors had two shared mutations in addition to private somatic mutations, suggesting a branching evolutionary pattern of tumor development following initiating loss of TSC2. Our results indicate that TSC2 and less commonly TSC1 alterations are the primary essential driver event in angiomyolipoma/LAM, whereas other somatic mutations are rare and likely do not contribute to tumor development. PMID:27494029

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

    DOE PAGESBeta

    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 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

  14. 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…

  15. Energy Efficiency Handbook for Driver's Education.

    ERIC Educational Resources Information Center

    Berlowitz, Dan; And Others

    Presented are suggestions to help the automobile driver attain the saving of fuel and money. Discussed are starting and stopping; anticipation of traffic conditions; use of accessories; trip planning; and accomodation of pedestrians and cyclists. Additional topics covered include systematic car maintenance and safety considerations. (RE)

  16. 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…

  17. 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,…

  18. Driver Education Curriculum Guide.

    ERIC Educational Resources Information Center

    Brum, Herbert D.; And Others

    Intended for driver education instructors in Ohio, the guide is designed to acquaint teachers with special characteristics, capacities, and needs of the handicapped student population and to provide resources, information, and ideas for meeting those special needs. An introductory section discusses the purpose and use of the curriculum. Section 2…

  19. Assessment of older drivers.

    PubMed

    Reuben, D B

    1993-05-01

    As concern increases about the safety of the aging driver, it is clear that the principal goal of assessment is to identify the unsafe driver and provide effective medical and rehabilitative services to enable the resumption of safe driving. When adequate restorative therapy is not possible, it is necessary to restrict or revoke the privilege of driving. Assessment also can reassure the safe older driver that he or she can continue operating a motor vehicle without restrictions. The process of assessing the older driver is best accomplished through the collaboration of health professionals and governmental agencies. The former identify and treat, if possible, medical conditions that may pose threats to safe driving; the latter establish guidelines of competency for driving tasks. These roles are complementary, although the settings and methods for these assessments are different. Moreover, the responsibilities of the physician and other health care professionals extend beyond the decision regarding driving and must consider the individual needs for driving, as well as the ramifications associated with its cessation. PMID:8504391

  20. 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.…

  1. Space Age Driver Education

    ERIC Educational Resources Information Center

    Gray, Walter W.

    1970-01-01

    Describes experimental Driver and Traffic Safety Education Center--a project involving a five-phase instructional program, a variety of teaching innovations, and a specially-constructed facility which includes a classroom building, multiple car driving range, simulators, communications equipment, and the most recent electronic teaching devices.…

  2. Driver views on speed and enforcement.

    PubMed

    Schechtman, Edna; Bar-Gera, Hillel; Musicant, Oren

    2016-04-01

    This paper reports on the results of a drivers' survey regarding the effects of speed cameras for speed enforcement in Israel. The survey was part of a larger study that accompanied the introduction of digital speed cameras. Speed camera deployment started in 2011, and till the end of 2013 twenty-one cameras were deployed in interurban road sections. Yearly surveys were taken between 2010 and 2013 in 9 gas stations near speed camera installation sites in order to capture drivers' opinions about speed and enforcement. Overall, 1993 drivers were interviewed. In terms of admitted speed behavior, 38% of the drivers in 2010, 21% in 2011, 13% in 2012 and 11% in 2013 reported that their driving speed was above the perceived posted speed limit. The proportion of drivers indicating some speed camera influence on driving decreased over the years. In addition, the majority of drivers (61%) predicted positive impact of speed cameras on safety. This result did not change significantly over the years. The main stated explanation for speed limit violations was time pressure, while the main stated explanation for respecting the posted speed was enforcement, rather than safety concerns. Linear regression and sigmoidal models were applied to describe the linkage between the reported driving speed (dependent) and the perceived posted speed (independent). The sigmoidal model fitted the data better, especially at high levels of the perceived posted speeds. That is, although the perceived posted speed increased, at some point the actual driving speed levels off (asymptote) and did not increase. Moreover, we found that the upper asymptote of the sigmoidal model decreased over the years: from 113.22 (SE=18.84)km/h in 2010 to 88.92 (SE=1.55)km/h in 2013. A wide variance in perceived speed limits suggest that drivers may not know what the speed limits really are. PMID:26773696

  3. Road accidents caused by drivers falling asleep.

    PubMed

    Sagberg, F

    1999-11-01

    About 29600 Norwegian accident-involved drivers received a questionnaire about the last accident reported to their insurance company. About 9200 drivers (31%) returned the questionnaire. The questionnaire contained questions about sleep or fatigue as contributing factors to the accident. In addition, the drivers reported whether or not they had fallen asleep some time whilst driving. and what the consequences had been. Sleep or drowsiness was a contributing factor in 3.9% of all accidents, as reported by drivers who were at fault for the accident. This factor was strongly over-represented in night-time accidents (18.6%), in running-off-the-road accidents (8.3%), accidents after driving more than 150 km on one trip (8.1%), and personal injury accidents (7.3%). A logistic regression analysis showed that the following additional factors made significant and independent contributions to increasing the odds of sleep involvement in an accident: dry road, high speed limit, driving one's own car, not driving the car daily, high education, and few years of driving experience. More male than female drivers were involved in sleep-related accidents, but this seems largely to be explained by males driving relatively more than females on roads with high speed limits. A total of 10% of male drivers and 4% of females reported to have fallen asleep while driving during the last 12 months. A total of 4% of these events resulted in an accident. The most frequent consequence of falling asleep--amounting to more than 40% of the reported incidents--was crossing of the right edge-line before awaking, whereas crossing of the centreline was reported by 16%. Drivers' lack of awareness of important precursors of falling asleep--like highway hypnosis, driving without awareness, and similar phenomena--as well as a reluctance to discontinue driving despite feeling tired are pointed out as likely contributors to sleep-related accidents. More knowledge about the drivers' experiences immediately

  4. Mutation rates as adaptations.

    PubMed

    Maley, C

    1997-06-01

    In order to better understand life, it is helpful to look beyond the envelop of life as we know it. A simple model of coevolution was implemented with the addition of a gene for the mutation rate of the individual. This allowed the mutation rate itself to evolve in a lineage. The model shows that when the individuals interact in a sort of zero-sum game, the lineages maintain relatively high mutation rates. However, when individuals engage in interactions that have greater consequences for one individual in the interaction than the other, lineages tend to evolve relatively low mutation rates. This model suggests that one possible cause for differential mutation rates across genes may be the coevolutionary pressure of the various forms of interactions with other genes. PMID:9219670

  5. 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

  6. 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.

  7. Porocarcinomas harbor recurrent HRAS-activating mutations and tumor suppressor inactivating mutations.

    PubMed

    Harms, Paul W; Hovelson, Daniel H; Cani, Andi K; Omata, Kei; Haller, Michaela J; Wang, Michael L; Arps, David; Patel, Rajiv M; Fullen, Douglas R; Wang, Min; Siddiqui, Javed; Andea, Aleodor; Tomlins, Scott A

    2016-05-01

    Porocarcinomas are a rare eccrine carcinoma with significant metastatic potential. Oncogenic drivers of porocarcinomas have been underexplored, with PIK3CA-activating mutation reported in 1 case. We analyzed 5 porocarcinomas by next-generation sequencing using the DNA component of the Oncomine Comprehensive Assay, which provides data on copy number changes and mutational events in 126 cancer-relevant genes through multiplex polymerase chain reaction. We detected an average of 3.3 high-confidence nonsynonymous mutations per tumor (range, 1-6), including a spectrum of oncogenic activation and tumor suppressor inactivation events. Tumor suppressor mutations included TP53 (4/5, 80%), RB1 (3/5, 60%), ATM (2/5, 40%), ARID1A (1/5, 20%), and CDKN2A (1/5, 20%). In 4 (80%) of 5 tumors, at least 1 potential oncogenic driver was identified. Activating HRAS mutations were detected in 2 (40%) of 5, including G13D and Q61L hotspot mutations. Mutations of EGFR were identified in 2 (40%) of 5; these mutations have been previously reported in cancer but did not affect classic activation hotspot sites. EGFR and HRAS mutations were mutually exclusive. HRAS mutations were detected by targeted sequencing in a minority of benign eccrine poromas (2/17; 11.7%), suggesting that HRAS activation may rarely be an early event in sweat gland neoplasia. Together, our data suggest roles for HRAS and EGFR as drivers in a subset of poroma and porocarcinoma. TP53 and RB1 inactivation events are also likely to contribute to tumorigenesis. These findings suggest that porocarcinomas display diversity with respect to oncogenic drivers, which may have implications for targeted therapy in metastatic or unresectable cases. PMID:27067779

  8. 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.

  9. Multiregion Whole-Exome Sequencing Uncovers the Genetic Evolution and Mutational Heterogeneity of Early-Stage Metastatic Melanoma.

    PubMed

    Harbst, Katja; Lauss, Martin; Cirenajwis, Helena; Isaksson, Karolin; Rosengren, Frida; Törngren, Therese; Kvist, Anders; Johansson, Maria C; Vallon-Christersson, Johan; Baldetorp, Bo; Borg, Åke; Olsson, Håkan; Ingvar, Christian; Carneiro, Ana; Jönsson, Göran

    2016-08-15

    Cancer genome sequencing has shed light on the underlying genetic aberrations that drive tumorigenesis. However, current sequencing-based strategies, which focus on a single tumor biopsy, fail to take into account intratumoral heterogeneity. To address this challenge and elucidate the evolutionary history of melanoma, we performed whole-exome and transcriptome sequencing of 41 multiple melanoma biopsies from eight individual tumors. This approach revealed heterogeneous somatic mutations in the range of 3%-38% in individual tumors. Known mutations in melanoma drivers BRAF and NRAS were always ubiquitous events. Using RNA sequencing, we found that the majority of mutations were not expressed or were expressed at very low levels, and preferential expression of a particular mutated allele did not occur frequently. In addition, we found that the proportion of ultraviolet B (UVB) radiation-induced C>T transitions differed significantly (P < 0.001) between early and late mutation acquisition, suggesting that different mutational processes operate during the evolution of metastatic melanoma. Finally, clinical history reports revealed that patients harboring a high degree of mutational heterogeneity were associated with more aggressive disease progression. In conclusion, our multiregion tumor-sequencing approach highlights the genetic evolution and non-UVB mutational signatures associated with melanoma development and progression, and may provide a more comprehensive perspective of patient outcome. Cancer Res; 76(16); 4765-74. ©2016 AACR. PMID:27216186

  10. Recurrent inactivating RASA2 mutations in melanoma

    PubMed Central

    Arafeh, Rand; Qutob, Nouar; Emmanuel, Rafi; Keren-Paz, Alona; Madore, Jason; Elkahloun, Abdel; Wilmott, James S.; Gartner, Jared J.; Di Pizio, Antonella; Winograd-Katz, Sabina; Sindiri, Sivasish; Rotkopf, Ron; Dutton-Regester, Ken; Johansson, Peter; Pritchard, Antonia; Waddell, Nicola; Hill, Victoria K.; Lin, Jimmy C.; Hevroni, Yael; Rosenberg, Steven A.; Khan, Javed; Ben-Dor, Shifra; Niv, Masha Y.; Ulitsky, Igor; Mann, Graham J; Scolyer, Richard A.; Hayward, Nicholas K.; Samuels, Yardena

    2016-01-01

    Analysis of 501 melanoma exomes revealed RASA2, encoding a RasGAP, as a tumor-suppressor gene mutated in 5% of melanomas. Recurrent loss-of-function mutations in RASA2 were found to increase RAS activation, melanoma cell growth and migration. RASA2 expression was lost in ≥30% of human melanomas and was associated with reduced patient survival. These findings reveal RASA2 inactivation as a melanoma driver and highlight the importance of Ras GAPs in cancer. PMID:26502337

  11. 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.

  12. 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. PMID:25615851

  13. 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. PMID:25057442

  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. Whole-genome sequencing reveals oncogenic mutations in mycosis fungoides

    PubMed Central

    McGirt, Laura Y.; Jia, Peilin; Baerenwald, Devin A.; Duszynski, Robert J.; Dahlman, Kimberly B.; Zic, John A.; Zwerner, Jeffrey P.; Hucks, Donald; Dave, Utpal; Zhao, Zhongming

    2015-01-01

    The pathogenesis of mycosis fungoides (MF), the most common cutaneous T-cell lymphoma (CTCL), is unknown. Although genetic alterations have been identified, none are considered consistently causative in MF. To identify potential drivers of MF, we performed whole-genome sequencing of MF tumors and matched normal skin. Targeted ultra-deep sequencing of MF samples and exome sequencing of CTCL cell lines were also performed. Multiple mutations were identified that affected the same pathways, including epigenetic, cell-fate regulation, and cytokine signaling, in MF tumors and CTCL cell lines. Specifically, interleukin-2 signaling pathway mutations, including activating Janus kinase 3 (JAK3) mutations, were detected. Treatment with a JAK3 inhibitor significantly reduced CTCL cell survival. Additionally, the mutation data identified 2 other potential contributing factors to MF, ultraviolet light, and a polymorphism in the tumor suppressor p53 (TP53). Therefore, genetic alterations in specific pathways in MF were identified that may be viable, effective new targets for treatment. PMID:26082451

  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. Two Innovations in Bus Driver Training

    ERIC Educational Resources Information Center

    School Management, 1972

    1972-01-01

    Discusses driver and human relations training for school bus drivers. A driver training program in California aims at reaching all 19,000 school bus drivers. A human relations training program in Seattle focuses on bettering student-driver and driver-administrator relations. (DN)

  18. 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

  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. Epidemiology and clinical relevance of mutations in postpolycythemia vera and postessential thrombocythemia myelofibrosis: A study on 359 patients of the AGIMM group.

    PubMed

    Rotunno, Giada; Pacilli, Annalisa; Artusi, Valentina; Rumi, Elisa; Maffioli, Margherita; Delaini, Federica; Brogi, Giada; Fanelli, Tiziana; Pancrazzi, Alessandro; Pietra, Daniela; Bernardis, Isabella; Belotti, Clara; Pieri, Lisa; Sant'Antonio, Emanuela; Salmoiraghi, Silvia; Cilloni, Daniela; Rambaldi, Alessandro; Passamonti, Francesco; Barbui, Tiziano; Manfredini, Rossella; Cazzola, Mario; Tagliafico, Enrico; Vannucchi, Alessandro M; Guglielmelli, Paola

    2016-07-01

    Transformation to secondary myelofibrosis (MF) occurs as part of the natural history of polycythemia vera (PPV-MF) and essential thrombocythemia (PET-MF). Although primary (PMF) and secondary MF are considered similar diseases and managed similarly, there are few studies specifically focused on the latter. The aim of this study was to characterize the mutation landscape, and describe the main clinical correlates and prognostic implications of mutations, in a series of 359 patients with PPV-MF and PET-MF. Compared with PV and ET, the JAK2V617F and CALR mutated allele burden was significantly higher in PPV-MF and/or PET-MF, indicating a role for accumulation of mutated alleles in the process of transformation to MF. However, neither the allele burden nor the type of driver mutation influenced overall survival (OS), while absence of any driver mutation (triple negativity) was associated with significant reduction of OS in PET-MF, similar to PMF. Of the five interrogated subclonal mutations (ASXL1, EZH2, SRSF2, IDH1, and IDH2), that comprise a prognostically detrimental high molecular risk (HMR) category in PMF, only SRSF2 mutations were associated with reduced survival in PET-MF, and no additional mutation profile with prognostic relevance was highlighted. Overall, these data indicate that the molecular landscape of secondary forms of MF is different from PMF, suggesting that unknown mutational events might contribute to the progression from chronic phase disease to myelofibrosis. These findings also support more extended genotyping approaches aimed at identifying novel molecular abnormalities with prognostic relevance for patients with PPV-MF and PET-MF. Am. J. Hematol. 91:681-686, 2016. © 2016 Wiley Periodicals, Inc. PMID:27037840

  2. An examination of the environmental, driver and vehicle factors associated with the serious and fatal crashes of older rural drivers.

    PubMed

    Thompson, J P; Baldock, M R J; Mathias, J L; Wundersitz, L N

    2013-01-01

    Motor vehicle crashes involving rural drivers aged 75 years and over are more than twice as likely to result in a serious or fatal injury as those involving their urban counterparts. The current study examined some of the reasons for this using a database of police-reported crashes (2004-2008) to identify the environmental (lighting, road and weather conditions, road layout, road surface, speed limit), driver (driver error, crash type), and vehicle (vehicle age) factors that are associated with the crashes of older rural drivers. It also determined whether these same factors are associated with an increased likelihood of serious or fatal injury in younger drivers for whom frailty does not contribute to the resulting injury severity. A number of environmental (i.e., undivided, unsealed, curved and inclined roads, and areas with a speed limit of 100km/h or greater) and driver (i.e., collision with a fixed object and rolling over) factors were more frequent in the crashes of older rural drivers and additionally associated with increased injury severity in younger drivers. Moreover, when these environmental factors were entered into a logistic regression model to predict whether older drivers who were involved in crashes did or did not sustain a serious or fatal injury, it was found that each factor independently increased the likelihood of a serious or fatal injury. Changes, such as the provision of divided and sealed roads, greater protection from fixed roadside objects, and reduced speed limits, appear to be indicated in order to improve the safety of the rural driving environment for drivers of all ages. Additionally, older rural drivers should be encouraged to reduce their exposure to these risky circumstances. PMID:22818779

  3. 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.

  4. Genome Destabilizing Mutator Alleles Drive Specific Mutational Trajectories in Saccharomyces cerevisiae

    PubMed Central

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

    2014-01-01

    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. PMID:24336748

  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. PMID:26513336

  7. 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.

  8. Sandia Material Model Driver

    2005-09-28

    The Sandia Material Model Driver (MMD) software package allows users to run material models from a variety of different Finite Element Model (FEM) codes in a standalone fashion, independent of the host codes. The MMD software is designed to be run on a variety of different operating system platforms as a console application. Initial development efforts have resulted in a package that has been shown to be fast, convenient, and easy to use, with substantialmore » growth potential.« less

  9. KRAS Mutation

    PubMed Central

    Franklin, Wilbur A.; Haney, Jerry; Sugita, Michio; Bemis, Lynne; Jimeno, Antonio; Messersmith, Wells A.

    2010-01-01

    Treatment of colon carcinoma with the anti-epidermal growth factor receptor antibody Cetuximab is reported to be ineffective in KRAS-mutant tumors. Mutation testing techniques have therefore become an urgent concern. We have compared three methods for detecting KRAS mutations in 59 cases of colon carcinoma: 1) high resolution melting, 2) the amplification refractory mutation system using a bifunctional self-probing primer (ARMS/Scorpion, ARMS/S), and 3) direct sequencing. We also evaluated the effects of the methods of sectioning and coring of paraffin blocks to obtain tumor DNA on assay sensitivity and specificity. The most sensitive and specific combination of block sampling and mutational analysis was ARMS/S performed on DNA derived from 1-mm paraffin cores. This combination of tissue sampling and testing method detected KRAS mutations in 46% of colon tumors. Four samples were positive by ARMS/S, but initially negative by direct sequencing. Cloned DNA samples were retested by direct sequencing, and in all four cases KRAS mutations were identified in the DNA. In six cases, high resolution melting abnormalities could not be confirmed as specific mutations either by ARMS/S or direct sequencing. We conclude that coring of the paraffin blocks and testing by ARMS/S is a sensitive, specific, and efficient method for KRAS testing. PMID:20007845

  10. 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. PMID:17558671

  11. Cancer systems biology of TCGA SKCM: efficient detection of genomic drivers in melanoma.

    PubMed

    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

  12. Management of tyrosine kinase inhibitor resistance in lung cancer with EGFR mutation

    PubMed Central

    Becker, Kevin; Xu, Yiqing

    2014-01-01

    The identification of driver mutations and drugs that inhibit their activity has been a major therapeutic advance for patients with advanced lung adenocarcinoma. Unfortunately, the success of these drugs is limited by the universal development of resistance. Treatment failure can result from inadequate drug exposure or selection of resistant malignant clones. Clinically distinct mechanisms of disease progression have been identified and can inform treatment decisions. Investigations into the biochemical mechanisms of tyrosine kinase inhibitor resistance may provide additional therapeutic targets by which the efficacy of targeted therapy can be improved. PMID:25302160

  13. 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.

  14. 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.

  15. The distracted driver.

    PubMed

    Peters, G A; Peters, B J

    2001-03-01

    A serious health problem is developing from automobile collisions caused by distracted drivers. This is a result of the rapid proliferation of portable cellular telephones and personal organisers used while driving, the development of more sophisticated entertainment systems and instrument panel controls, the advent of navigation and television displays in vehicles and promises of sophisticated wireless e-mail, FAX and Internet services in the vehicle. Preoccupation with electronic gadgets may also degrade human driving performance. Many drivers however, sincerely believe they have the talent to do several things at the same time, such as hold and look at a cellular telephone in one hand and drive with a beverage container in the other hand whilst at the same time, exercise their personal skills. Obviously, they believe that they do not need two hands on the steering wheel and two eyes on the road. This is a unique situation requiring intensive health promotion as distracted or 'offensive driving' may be habit forming and difficult to change, any significant design remedies will be slow to arrive and may be circumvented, and the regulatory laws have proved difficult or impossible to enforce. This special need may require research to determine the most effective techniques for health promotion. PMID:11329694

  16. 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. PMID:26485003

  17. 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

  18. 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. PMID:26277411

  19. 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.

  20. Resonant gate driver with efficient gate energy recovery and switching loss reduction

    NASA Astrophysics Data System (ADS)

    Kim, I.-G.; Kwak, S.-S.

    2016-04-01

    This article describes a novel resonant gate driver for charging the gate capacitor of power metal-oxide semiconductor field-effect-transistors (MOSFETs) that operate at a high switching frequency in power converters. The proposed resonant gate driver is designed with three small MOSFETs to build up the inductor current in addition to an inductor for temporary energy storage. The proposed resonant gate driver recovers the CV2 gate loss, which is the largest loss dissipated in the gate resistance in conventional gate drivers. In addition, the switching loss is reduced at the instants of turn on and turn off in the power MOSFETs of power converters by using the proposed gate driver. Mathematical analyses of the total loss appearing in the gate driver circuit and the switching loss reduction in the power switch of power converters are discussed. Finally, the proposed resonant gate driver is verified with experimental results at a switching frequency of 1 MHz.

  1. Lung cancer with concurrent EGFR mutation and ROS1 rearrangement: a case report and review of the literature

    PubMed Central

    Zhu, You-cai; Xu, Chun-wei; Ye, Xiao-qian; Yin, Man-xiang; Zhang, Jin-xian; Du, Kai-qi; Zhang, Zhi-hao; Hu, Jian

    2016-01-01

    ROS1 rearrangement has recently emerged as a new molecular subtype in non-small cell lung cancer, and is predominantly found in lung adenocarcinomas compared with other oncogenes such as EGFR, KRAS, or ALK. Patients who have both mutations are extremely rare. Here we report a 50-year-old female diagnosed with adenocarcinoma with sarcomatoid differentiation, who was shown to have EGFR and ROS1 mutations. The patient was treated surgically and received three cycles of adjuvant postoperative chemotherapy. In addition, we reviewed the previously reported cases and related literature. This presentation will provide further understanding of the underlying molecular biology and optimal treatment for non-small cell lung cancer patients with more than one driver mutation. PMID:27486332

  2. 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;…

  3. 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.

  4. Identification of Driver Genes in Hepatocellular Carcinoma by Exome Sequencing

    PubMed Central

    Cleary, Sean P.; Jeck, William R.; Zhao, Xiaobei; Chen, Kui; Selitsky, Sara R.; Savich, Gleb L.; Tan, Ting-Xu; Wu, Michael C.; Getz, Gad; Lawrence, Michael S.; Parker, Joel S.; Li, Jinyu; Powers, Scott; Kim, Hyeja; Fischer, Sandra; Guindi, Maha; Ghanekar, Anand; Chiang, Derek Y.

    2013-01-01

    Genetic alterations in specific driver genes lead to disruption of cellular pathways and are critical events in the instigation and progression of hepatocellular carcinoma. As a prerequisite for individualized cancer treatment, we sought to characterize the landscape of recurrent somatic mutations in hepatocellular carcinoma. We performed whole exome sequencing on 87 hepatocellular carcinomas and matched normal adjacent tissues to anaverage coverage of 59x. The overall mutation rate was roughly 2 mutations per Mb, with a median of 45 non-synonymous mutations that altered the amino acid sequence (range 2 to 381). We found recurrent mutations in several genes with high transcript levels: TP53 (18%), CTNNB1 (10%), KEAP1 (8%), C16orf62 (8%), MLL4(7%) and RAC2 (5%). Significantly affected gene families include the nucleotide-binding domain and leucine rich repeat containing family, calcium channel subunits, and histone methyltransferases. In particular, the MLL family of methyltransferases for histone H3 lysine 4 were mutated in 20% of tumors. Conclusion The NFE2L2-KEAP1 and MLL pathways are recurrently mutated in multiple cohorts of hepatocellular carcinoma. PMID:23728943

  5. Improving School Bus Driver Performance.

    ERIC Educational Resources Information Center

    Farmer, Ernest

    This reference source is intended to assist the school bus driver training instructor in course preparation. Instructional units for program planning each contain pertinent course questions, a summary, and evaluation questions. Unit 1, "Introduction to the School Bus Driver Training Program," focuses on basic course objectives and requirements and…

  6. Deciphering intra-tumor heterogeneity of lung adenocarcinoma confirms that dominant, branching, and private gene mutations occur within individual tumor nodules.

    PubMed

    Pelosi, Giuseppe; Pellegrinelli, Alessio; Fabbri, Alessandra; Tamborini, Elena; Perrone, Federica; Settanni, Giulio; Busico, Adele; Picciani, Benedetta; Testi, Maria Adele; Militti, Lucia; Maisonneuve, Patrick; Valeri, Barbara; Sonzogni, Angelica; Proto, Claudia; Garassino, Marina; De Braud, Filippo; Pastorino, Ugo

    2016-06-01

    While pulmonary adenocarcinoma (ADC) is morphologically heterogeneous, little is known about intra-tumor gene mutation heterogeneity (ITH). We therefore subjected 20 ADC nodules, 5 mutated for EGFR and 5 for KRAS, 5 with an ALK translocation, and 5 wild type (WT) for these alterations, to unsupervised next-generation sequencing of tumor regions from diverse architectural patterns. When 2 or more different gene mutations were found in a single tumor, this fulfilled the criteria for ITH. In the 84 studied tumor regions with diverse architecture, 71 gene mutations and 34 WT profiles were found. ITH was observed in 9/15 (60 %) ADC, 3 with an EGFR, 3 with a KRAS, and 3 with an ALK aberration, as reflected in 5, 6, and 9 additional mutations, respectively, detected in these tumors. EGFR mutations were observed in 21/22 and KRAS mutations in 18/22 tumor regions, suggesting that they appear early and have a driver role (dominant or trunk mutations). Branching mutations (in EZH2, PIK3CA, TP53, and EGFR exon 18) occurred in two or more regions, while private mutations (in ABL1, ALK, BRAF, HER2, KDR, LKB1, PTEN, MET, SMAD4, SMARCB1, and SRC) were confined to unique tumor samples of individual lesions, suggesting that they occurred later on during tumor progression. Patients with a tumor showing branching mutations ran a worse clinical course, independent of confounding factors. We conclude that in ADC, ITH exists in a pattern suggesting spatial and temporal hierarchy with dominant, branching, and private mutations. This is consistent with diverse intra-tumor clonal evolution, which has potential implications for patient prognosis or development of secondary therapy resistance. PMID:27056568

  7. The older adult driver.

    PubMed

    Carr, D B

    2000-01-01

    More adults aged 65 and older will be driving in the next few decades. Many older drivers are safe behind the wheel and do not need intensive testing for license renewal. Others, however, have physiologic or cognitive impairments that can affect their mobility and driving safety. When an older patient's driving competency is questioned, a comprehensive, step-by-step assessment is recommended. Many diseases that impair driving ability can be detected and treated effectively by family physicians. Physicians should take an active role in assessing and reducing the risk for injury in a motor vehicle and, when possible, prevent or delay driving cessation in their patients. Referral to other health care professionals, such as an occupational or physical therapist, may be helpful for evaluation and treatment. When an older patient is no longer permitted or able to drive, the physician should counsel the patient about using alternative methods of transportation. PMID:10643955

  8. 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. PMID:25803362

  9. 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. PMID:25460091

  10. 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

  11. What happens when drivers face hazards on the road?

    PubMed

    Ventsislavova, Petya; Gugliotta, Andres; Peña-Suarez, Elsa; Garcia-Fernandez, Pedro; Eisman, Eduardo; Crundall, David; Castro, Candida

    2016-06-01

    The current study aims to obtain knowledge about the nature of the processes involved in Hazard Perception, using measurement techniques to separate and independently quantify these suspected sub-processes: Sensation, Situation Awareness (recognition, location and projection) and decision-making. It applies Signal Detection Theory analysis to Hazard Perception and Prediction Tasks. To enable the calculation of Signal Detection Theory parameters, video-recorded hazardous vs. quasi-hazardous situations were presented to the participants. In the hazardous situations it is necessary to perform an evasive action, for instance, braking or swerving abruptly, while the quasi-hazardous situations do not require the driver to make any evasive manoeuvre, merely to carry on driving at the same speed and following the same trajectory. A first Multiple Choice Hazard Perception and Prediction test was created to measure participants' performance in a What Happens Next? Task. The sample comprised 143 participants, 47 females and 94 males. Groups of non-offender drivers (learner, novice and experienced) and offender drivers (novice and experienced) were recruited. The Multiple Choice Hazard Perception and Prediction test succeeded in finding differences between drivers according to their driving experience. In fact, differences exist with regard to the level of hazard discrimination (d' prime) by drivers with different experience (learner, novice and experienced drivers) and profile (offenders and non-offenders) and these differences emerge from Signal Detection Theory analysis. In addition, it was found that experienced drivers show higher Situation Awareness than learner or novice drivers. On the other hand, although offenders do worse than non-offenders on the hazard identification question, they do just as well when their Situation Awareness is probed (in fact, they are as aware as non-offenders of what the obstacles on the road are, where they are and what will happen next

  12. Drivers within natural drinking groups: an exploration of role selection, motivation, and group influence on driver sobriety.

    PubMed

    Lange, James E; Johnson, Mark B; Reed, Mark B

    2006-01-01

    Young people consume alcohol almost exclusively in social contexts, but natural drinking group dynamics are poorly understood. Our research focuses on the drivers' role within natural drinking groups. We conducted breath-test surveys of existing groups of young people at the US/Mexico border crossing before they headed to Tijuana bars, and surveyed them again upon their return. Results indicated an individual's perception of other group member's drinking plans predicts drinking intentions to a greater degree for passengers than drivers. Additionally, drivers who anticipated heavy drinking among other group members returned to the United States with BACs nearly identical to drivers who reported that other group members would not drink at all. This suggests drivers were resistant to normative pressures to drink. Evidence that group-dynamic variables may impact drinking behavior underscores the importance of systematic exploration of natural drinking groups. Furthermore, the knowledge gleaned from studying the dynamics and decision making processes of natural drinking groups could be used to design intervention designed to increase designated driver use and to reduce drinking among designated drivers. PMID:16595327

  13. [ 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. PMID:26710785

  14. Mutations in lettuce improvement.

    PubMed

    Mou, Beiquan

    2011-01-01

    Lettuce is a major vegetable in western countries. Mutations generated genetic variations and played an important role in the domestication of the crop. Many traits derived from natural and induced mutations, such as dwarfing, early flowering, male sterility, and chlorophyll deficiency, are useful in physiological and genetic studies. Mutants were also used to develop new lettuce products including miniature and herbicide-tolerant cultivars. Mutant analysis was critical in lettuce genomic studies including identification and cloning of disease-resistance genes. Mutagenesis combined with genomic technology may provide powerful tools for the discovery of novel gene alleles. In addition to radiation and chemical mutagens, unconventional approaches such as tissue or protoplast culture, transposable elements, and space flights have been utilized to generate mutants in lettuce. Since mutation breeding is considered nontransgenic, it is more acceptable to consumers and will be explored more in the future for lettuce improvement. PMID:22287955

  15. Mutations in Lettuce Improvement

    PubMed Central

    Mou, Beiquan

    2011-01-01

    Lettuce is a major vegetable in western countries. Mutations generated genetic variations and played an important role in the domestication of the crop. Many traits derived from natural and induced mutations, such as dwarfing, early flowering, male sterility, and chlorophyll deficiency, are useful in physiological and genetic studies. Mutants were also used to develop new lettuce products including miniature and herbicide-tolerant cultivars. Mutant analysis was critical in lettuce genomic studies including identification and cloning of disease-resistance genes. Mutagenesis combined with genomic technology may provide powerful tools for the discovery of novel gene alleles. In addition to radiation and chemical mutagens, unconventional approaches such as tissue or protoplast culture, transposable elements, and space flights have been utilized to generate mutants in lettuce. Since mutation breeding is considered nontransgenic, it is more acceptable to consumers and will be explored more in the future for lettuce improvement. PMID:22287955

  16. The Influence of Individual Driver Characteristics on Congestion Formation

    NASA Astrophysics Data System (ADS)

    Wang, Lanjun; Zhang, Hao; Meng, Huadong; Wang, Xiqin

    Previous works have pointed out that one of the reasons for the formation of traffic congestion is instability in traffic flow. In this study, we investigate theoretically how the characteristics of individual drivers influence the instability of traffic flow. The discussions are based on the optimal velocity model, which has three parameters related to individual driver characteristics. We specify the mappings between the model parameters and driver characteristics in this study. With linear stability analysis, we obtain a condition for when instability occurs and a constraint about how the model parameters influence the unstable traffic flow. Meanwhile, we also determine how the region of unstable flow densities depends on these parameters. Additionally, the Langevin approach theoretically validates that under the constraint, the macroscopic characteristics of the unstable traffic flow becomes a mixture of free flows and congestions. All of these results imply that both overly aggressive and overly conservative drivers are capable of triggering traffic congestion.

  17. Rosalind Driver studentships

    NASA Astrophysics Data System (ADS)

    1999-11-01

    The School of Education at King's College London can now offer funded studentships to those wishing to undertake research in science education. These studentships, which are funded through the generous benefaction of the late Rosalind Driver, can be for a full-time student (over a maximum of three years) or several part-time students (a maximum of six years). Applications from anyone working in science education are welcome but preference will be given to those originating from practising science teachers. Applicants will be expected to register for the award of a MPhil/PhD or EdD and are normally expected to have a first degree. Preliminary ideas about a topic for investigation would also be helpful. Further details and application forms are obtainable from Chiz Dube, School of Education, King's College London, Franklin - Wilkins Building, Waterloo Road, London SE1 8WA (tel: 020-7848-3089, e-mail: chiz.dube@kcl.ac.uk). The deadline for the first round of applications was the middle of October, but preliminary informal enquiries may be made to Dr Jonathan Osborne at the School of Education (tel: 020-7848-3094, e-mail: jonathan.osborne@kcl.ac.uk).

  18. "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. PMID:21819853

  19. Personality predictors of driver vengeance.

    PubMed

    Wickens, Christine M; Wiesenthal, David L; Roseborough, James E W

    2015-01-01

    The purpose of this study was to identify personality and individual difference measures related to driver vengeance, as measured by the Driver Vengeance Questionnaire (DVQ; Wiesenthal, Hennessy, & Gibson, 2000). There were 170 undergraduate students who completed paper-and-pencil questionnaires including the DVQ and measures of narcissism, impulsivity, and trait driver stress. A hierarchical linear regressidn predicting DVQ score revealed that being male (β = .25), narcissism (β = .19), and trait driver stress (β = .41) were significantly associated with vengeance. Impulsivity was significant in the third block of the regression but was not a significant predictor of vengeance in the final block. Interactions between gender and the individual difference measures were not significant. The final model accounted for 34% of the variance. Implications of the results and directions for future research are discussed. PMID:25774420

  20. Biodiversity: Interacting global change drivers

    NASA Astrophysics Data System (ADS)

    Settele, Josef; Wiemers, Martin

    2015-10-01

    Climate change impacts on species do not occur in isolation. Now research on drought-sensitive British butterflies uses citizen science to attribute the drivers of population changes and shows landscape management to be a key part of the solution.

  1. Syringe driver in terminal care.

    PubMed Central

    Dover, S B

    1987-01-01

    Continuous subcutaneous infusions of drugs by syringe driver are used often and successfully in the terminal care of patients when drugs cannot be given orally. Diamorphine is the opioid of choice because of its high solubility. If other drugs such as antiemetics, anticholinergics, sedatives, or steroids are required they may also be given by syringe driver. This method is particularly useful for domiciliary care, where the practical difficulties of providing regular parenteral analgesia are otherwise formidable. PMID:3103774

  2. Seventeen novel mutations that cause profound biotinidase deficiency.

    PubMed

    Wolf, B; Jensen, K; Hüner, G; Demirkol, M; Baykal, T; Divry, P; Rolland, M-O; Perez-Cerdá, C; Ugarte, M; Straussberg, R; Basel-Vanagaite, L; Baumgartner, E R; Suormala, T; Scholl, S; Das, A M; Schweitzer, S; Pronicka, E; Sykut-Cegielska, J

    2002-01-01

    We report 17 novel mutations that cause profound biotinidase deficiency. Six of the mutations are due to deletions, whereas the remaining 11 mutations are missense mutations located throughout the gene and encode amino acids that are conserved in mammals. Our results increase the total number of different mutations that cause biotinidase deficiency to 79. These additional mutations will undoubtedly be helpful in identifying structure/function relationships once the three-dimensional structure of biotinidase is determined. PMID:12359137

  3. How do drivers overtake cyclists?

    PubMed

    Dozza, Marco; Schindler, Ron; Bianchi-Piccinini, Giulio; Karlsson, Johan

    2016-03-01

    In Europe, the number of road crashes is steadily decreasing every year. However, the incidence of bicycle crashes is not declining as fast as that of car crashes. In Sweden, cyclists are the most frequently injured road users. Collisions between bicycles and motorized vehicles are of particular concern because the high speed and large mass of motorized vehicles create a high risk of serious injury to cyclists. In Sweden's urban areas, bicycle lanes keep bicycles separated from motorized vehicles, but on rural roads bicycle lanes are often absent, requiring drivers to interact with cyclists-usually by overtaking them. During this maneuver, drivers regulate speed and lateral position, negotiating with potential oncoming traffic to stay within their comfort zones while approaching and passing cyclists. In this study an instrumented bicycle recorded 145 overtaking maneuvers performed by car and truck drivers on public rural roads in Sweden. The bicycle was equipped with a LIDAR and two cameras to assess how drivers approached and circumvented the bicycle. The collected data allowed us to identify four overtaking phases and quantify the corresponding driver comfort zones. The presence of an oncoming vehicle was the factor that most influenced the maneuver, whereas neither vehicle speed, lane width, shoulder width nor posted speed limit significantly affected the driver comfort zone or the overtaking dynamics. PMID:26717348

  4. 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…

  5. 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....

  6. 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...

  7. 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....

  8. 49 CFR 380.507 - Driver responsibilities.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 5 2010-10-01 2010-10-01 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....

  9. 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....

  10. 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...

  11. 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...

  12. 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...

  13. 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...

  14. 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....

  15. 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

    2016-06-01

    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. PMID:27251275

  16. Recurrent inactivating RASA2 mutations in melanoma.

    PubMed

    Arafeh, Rand; Qutob, Nouar; Emmanuel, Rafi; Keren-Paz, Alona; Madore, Jason; Elkahloun, Abdel; Wilmott, James S; Gartner, Jared J; Di Pizio, Antonella; Winograd-Katz, Sabina; Sindiri, Sivasish; Rotkopf, Ron; Dutton-Regester, Ken; Johansson, Peter; Pritchard, Antonia L; Waddell, Nicola; Hill, Victoria K; Lin, Jimmy C; Hevroni, Yael; Rosenberg, Steven A; Khan, Javed; Ben-Dor, Shifra; Niv, Masha Y; Ulitsky, Igor; Mann, Graham J; Scolyer, Richard A; Hayward, Nicholas K; Samuels, Yardena

    2015-12-01

    Analysis of 501 melanoma exomes identified RASA2, encoding a RasGAP, as a tumor-suppressor gene mutated in 5% of melanomas. Recurrent loss-of-function mutations in RASA2 were found to increase RAS activation, melanoma cell growth and migration. RASA2 expression was lost in ≥30% of human melanomas and was associated with reduced patient survival. These findings identify RASA2 inactivation as a melanoma driver and highlight the importance of RasGAPs in cancer. PMID:26502337

  17. Oncogenically active MYD88 mutations in human lymphoma

    PubMed Central

    Ngo, Vu N.; Young, Ryan M.; Schmitz, Roland; Jhavar, Sameer; Xiao, Wenming; Lim, Kian-Huat; Kohlhammer, Holger; Xu, Weihong; Yang, Yandan; Zhao, Hong; Shaffer, Arthur L.; Romesser, Paul; Wright, George; Powell, John; Rosenwald, Andreas; Muller-Hermelink, Hans Konrad; Ott, German; Gascoyne, Randy D.; Connors, Joseph M.; Rimsza, Lisa M.; Campo, Elias; Jaffe, Elaine S.; Delabie, Jan; Smeland, Erlend B.; Fisher, Richard I.; Braziel, Rita M.; Tubbs, Raymond R.; Cook, J. R.; Weisenburger, Denny D.; Chan, Wing C.; Staudt, Louis M.

    2016-01-01

    The activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) remains the least curable form of this malignancy despite recent advances in therapy1. Constitutive nuclear factor (NF)-κB and JAK kinase signalling promotes malignant cell survival in these lymphomas, but the genetic basis for this signalling is incompletely understood. Here we describe the dependence of ABC DLBCLs on MYD88, an adaptor protein that mediates toll and interleukin (IL)-1 receptor signalling2,3, and the discovery of highly recurrent oncogenic mutations affecting MYD88 in ABC DLBCL tumours. RNA interference screening revealed that MYD88 and the associated kinases IRAK1 and IRAK4 are essential for ABC DLBCL survival. High-throughput RNA resequencing uncovered MYD88 mutations in ABC DLBCL lines. Notably, 29% of ABC DLBCL tumours harboured the same amino acid substitution, L265P, in the MYD88 Toll/IL-1 receptor (TIR) domain at an evolutionarily invariant residue in its hydrophobic core. This mutation was rare or absent in other DLBCL subtypes and Burkitt’s lymphoma, but was observed in 9% of mucosa-associated lymphoid tissue lymphomas. At a lower frequency, additional mutations were observed in the MYD88 TIR domain, occurring in both the ABC and germinal centre B-cell-like (GCB) DLBCL subtypes. Survival of ABC DLBCL cells bearing the L265P mutation was sustained by the mutant but not the wild-type MYD88 isoform, demonstrating that L265P is a gain-of-function driver mutation. The L265P mutant promoted cell survival by spontaneously assembling a protein complex containing IRAK1 and IRAK4, leading to IRAK4 kinase activity, IRAK1 phosphorylation, NF-κB signalling, JAK kinase activation of STAT3, and secretion of IL-6, IL-10 and interferon-β. Hence, theMYD88 signalling pathway is integral to the pathogenesis of ABC DLBCL, supporting the development of inhibitors of IRAK4 kinase and other components of this pathway for the treatment of tumours bearing oncogenic MYD88 mutations

  18. Augmented reality cues to assist older drivers with gap estimation for left-turns.

    PubMed

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

    2014-10-01

    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

  19. 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

  20. MUFFINN: cancer gene discovery via network analysis of somatic mutation data.

    PubMed

    Cho, Ara; Shim, Jung Eun; Kim, Eiru; Supek, Fran; Lehner, Ben; Lee, Insuk

    2016-01-01

    A major challenge for distinguishing cancer-causing driver mutations from inconsequential passenger mutations is the long-tail of infrequently mutated genes in cancer genomes. Here, we present and evaluate a method for prioritizing cancer genes accounting not only for mutations in individual genes but also in their neighbors in functional networks, MUFFINN (MUtations For Functional Impact on Network Neighbors). This pathway-centric method shows high sensitivity compared with gene-centric analyses of mutation data. Notably, only a marginal decrease in performance is observed when using 10 % of TCGA patient samples, suggesting the method may potentiate cancer genome projects with small patient populations. PMID:27333808

  1. 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. PMID:26482894

  2. 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.

  3. 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

  4. 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

  5. Efficiency of carcinogenesis: is the mutator phenotype inevitable?

    PubMed

    Beckman, Robert A

    2010-10-01

    Cancer development requires multiple oncogenic mutations. Pathogenic mechanisms which accelerate this process may be favored carcinogenic pathways. Mutator mutations are mutations in genetic stability genes, and increase the mutation rate, speeding up the accumulation of oncogenic mutations. The mutator hypothesis states that mutator mutations play a critical role in carcinogenesis. Alternatively, tumors might arise by mutations occurring at the normal rate followed by selection and expansion of various premalignant lineages on the path to cancer. This alternative pathway is a significant argument against the mutator hypothesis. Mutator mutations may also lead to accumulation of deleterious mutations, which could lead to extinction of premalignant lineages before they become cancerous, another argument against the mutator hypothesis. Finally, the need for acquisition of a mutator mutation imposes an additional step on the carcinogenic process. Accordingly, the mutator hypothesis has been a seminal but controversial idea for several decades despite considerable experimental and theoretical work. To resolve this debate, the concept of efficiency has been introduced as a metric for comparing carcinogenic mechanisms, and a new theoretical approach of focused quantitative modeling has been applied. The results demonstrate that, given what is already known, the predominance of mutator mechanisms is likely inevitable, as they overwhelm less efficient non-mutator pathways to cancer. PMID:20934514

  6. 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

  7. Sexual behavior among truck drivers.

    PubMed

    Singh, Rajiv Kumar; Joshi, Hari Shankar

    2012-01-01

    A cross-sectional study was conducted on Lucknow highway in Bareilly district of Uttar Pradesh to study the knowledge of truck drivers about HIV transmission and prevention and to study the sexual behaviour of these drivers with reference to HIV/AIDS. Age, marital status, education, income, drinking alcohol, length of stay away from home, knowledge about transmission and prevention of HIV, and HIV-prone behavior of truck drivers were studied. Chi-square, mean, and SD were calculated. In all, 289 (97.6%) drivers had heard about HIV/AIDS. Only 242 (81.8%) were aware of HIV transmission by heterosexual route. Misconceptions such as HIV transmission by mosquito bites, living in same room, shaking hands, and sharing food were found. Out of 174 (58.8%) who visited Commercial Sex Workers (CSW), 146 (83.9%) used a condom. 38 (12.8%) visited more than 5 CSW in the last 3 months. Time away from home on the road, marital status, alcohol use, and income class were associated with visiting CSW. High-risk behavior was established in the study population. Safe sex and use of condoms need to be promoted among the truck drivers and better condom availability needs to be assured on highways. PMID:22684174

  8. PIK3CA mutations, phosphatase and tensin homolog, human epidermal growth factor receptor 2, and insulin-like growth factor 1 receptor and adjuvant tamoxifen resistance in postmenopausal breast cancer patients

    PubMed Central

    2014-01-01

    Introduction Inhibitors of the phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway can overcome endocrine resistance in estrogen receptor (ER) α-positive breast cancer, but companion diagnostics indicating PI3K/AKT/mTOR activation and consequently endocrine resistance are lacking. PIK3CA mutations frequently occur in ERα-positive breast cancer and result in PI3K/AKT/mTOR activation in vitro. Nevertheless, the prognostic and treatment-predictive value of these mutations in ERα-positive breast cancer is contradictive. We tested the clinical validity of PIK3CA mutations and other canonic pathway drivers to predict intrinsic resistance to adjuvant tamoxifen. In addition, we tested the association between these drivers and downstream activated proteins. Methods Primary tumors from 563 ERα-positive postmenopausal patients, randomized between adjuvant tamoxifen (1 to 3 years) versus observation were recollected. PIK3CA hotspot mutations in exon 9 and exon 20 were assessed with Sequenom Mass Spectometry. Immunohistochemistry was performed for human epidermal growth factor receptor 2 (HER2), phosphatase and tensin homolog (PTEN), and insulin-like growth factor 1 receptor (IGF-1R). We tested the association between these molecular alterations and downstream activated proteins (like phospho-protein kinase B (p-AKT), phospho-mammalian target of rapamycin (p-mTOR), p-ERK1/2, and p-p70S6K). Recurrence-free interval improvement with tamoxifen versus control was assessed according to the presence or absence of canonic pathway drivers, by using Cox proportional hazard models, including a test for interaction. Results PIK3CA mutations (both exon 9 and exon 20) were associated with low tumor grade. An enrichment of PIK3CA exon 20 mutations was observed in progesterone receptor- positive tumors. PIK3CA exon 20 mutations were not associated with downstream-activated proteins. No significant interaction between PIK3CA mutations or any

  9. The impact on outcome of the addition of all-trans retinoic acid to intensive chemotherapy in younger patients with nonacute promyelocytic acute myeloid leukemia: overall results and results in genotypic subgroups defined by mutations in NPM1, FLT3, and CEBPA.

    PubMed

    Burnett, Alan K; Hills, Robert K; Green, Claire; Jenkinson, Sarah; Koo, Kenneth; Patel, Yashma; Guy, Carol; Gilkes, Amanda; Milligan, Donald W; Goldstone, Anthony H; Prentice, Archibald G; Wheatley, Keith; Linch, David C; Gale, Rosemary E

    2010-02-01

    We investigated the benefit of adding all-trans retinoic acid (ATRA) to chemotherapy for younger patients with nonacute promyelocytic acute myeloid leukemia and high-risk myelodysplastic syndrome, and considered interactions between treatment and molecular markers. Overall, 1075 patients less than 60 years of age were randomized to receive or not receive ATRA in addition to daunorubicin/Ara-C/thioguanine chemotherapy with Ara-C at standard or double standard dose. There were data on FLT3 internal tandem duplications and NPM1 mutations (n = 592), CEBPA mutations (n = 423), and MN1 expression (n = 195). The complete remission rate was 68% with complete remission with incomplete count recovery in an additional 16%; 8-year overall survival was 32%. There was no significant treatment effect for any outcome, with no significant interactions between treatment and demographics, or cytarabine randomization. Importantly, there were no interactions by FLT3/internal tandem duplications, NPM1, or CEBPA mutation. There was a suggestion that ATRA reduced relapse in patients with lower MN1 levels, but no significant effect on overall survival. Results were consistent when restricted to patients with normal karyotype. ATRA has no overall effect on treatment outcomes in this group of patients. The study did not identify any subgroup of patients likely to derive a significant survival benefit from the addition of ATRA to chemotherapy. PMID:19965647

  10. Mutational profiling of colorectal cancers with microsatellite instability

    PubMed Central

    Lin, Elaine I.; Tseng, Li-Hui; Gocke, Christopher D.; Reil, Stacy; Le, Dung T.; Azad, Nilofer S.; Eshleman, James R.

    2015-01-01

    Microsatellite instability (MSI) is caused by defective mismatch repair in 15–20% of colorectal cancers (CRCs). Higher mutation loads in tumors with mismatch repair deficiency can predict response to pembrolizumab, an anti-programmed death 1 (PD-1) immune checkpoint inhibitor. We analyzed the mutations in 113 CRCs without MSI (MSS) and 29 CRCs with MSI-High (MSI-H) using the 50-gene AmpliSeq cancer panel. Overall, MSI-H CRCs showed significantly higher mutations than MSS CRCs, including insertion/deletion mutations at repeat regions. MSI-H CRCs showed higher incidences of mutations in the BRAF, PIK3CA, and PTEN genes as well as mutations in the receptor tyrosine kinase families. While the increased mutations in BRAF and PTEN in MSI-H CRCs are well accepted, we also support findings of mutations in the mTOR pathway and receptor tyrosine kinase family genes. MSS CRCs showed higher incidences of mutations in the APC, KRAS and TP53 genes, confirming previous findings. NGS assays may be designed to detect driver mutations for targeted therapeutics and to identify tumors with high mutation loads for potential treatment with immune checkpoint blockade therapies. Further studies may be warranted to elucidate potential targeted therapeutics against mutations in the mTOR pathway and the receptor tyrosine kinase family in MSI-H CRCs as well as the benefit of anti-PD-1 immunotherapy in hypermutated MSS CRCs or other cancers. PMID:26517354

  11. Mutational landscape of aggressive cutaneous squamous cell carcinoma

    PubMed Central

    Pickering, Curtis R.; Zhou, Jane H.; Lee, J. Jack; Drummond, Jennifer A.; Peng, S. Andrew; Saade, Rami E.; Tsai, Kenneth Y.; Curry, Jonathan L.; Tetzlaff, Michael T.; Lai, Stephen Y; Yu, Jun; Muzny, Donna M.; Doddapaneni, Harshavardhan; Shinbrot, Eve; Covington, Kyle R.; Zhang, Jianhua; Seth, Sahil; Caulin, Carlos; Clayman, Gary L.; El-Naggar, Adel K.; Gibbs, Richard A.; Weber, Randal S.; Myers, Jeffrey N.; Wheeler, David A.; Frederick, Mitchell J.

    2015-01-01

    Purpose Aggressive cutaneous squamous cell carcinoma (cSCC) is often a disfiguring and lethal disease. Very little is currently known about the mutations that drive aggressive cSCC. Experimental Design Whole exome sequencing was performed on 39 cases of aggressive cSCC to identify driver genes and novel therapeutic targets. Significantly mutated genes were identified with MutSig or complementary methods developed to specifically identify candidate tumor suppressors based upon their inactivating mutation bias. Results Despite the very high mutational background caused by UV exposure, 23 candidate drivers were identified including the well-known cancer-associated genes TP53, CDKN2A, NOTCH1, AJUBA, HRAS, CASP8, FAT1, and KMT2C (MLL3). Three novel candidate tumor suppressors with putative links to cancer or differentiation, NOTCH2, PARD3 and RASA1, were also identified as possible drivers in cSCC. KMT2C mutations were associated with poor outcome and increased bone invasion. Conclusions The mutational spectrum of cSCC is similar to that of head and neck squamous cell carcinoma and dominated by tumor suppressor genes. These results improve the foundation for understanding this disease and should aid in identifying and treating aggressive cSCC. PMID:25303977

  12. Key drivers of airline loyalty

    PubMed Central

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

    2011-01-01

    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. PMID:27064618

  13. Drivers of the primate thalamus

    PubMed Central

    Rovó, Zita; Ulbert, István; Acsády, László

    2012-01-01

    The activity of thalamocortical neurons is largely determined by giant excitatory terminals, called drivers. These afferents may arise from neocortex or from subcortical centers; however their exact distribution, segregation or putative absence in given thalamic nuclei are unknown. To unravel the nucleus-specific composition of drivers, we mapped the entire macaque thalamus utilizing vesicular glutamate transporters 1 and 2 to label cortical and subcortical afferents, respectively. Large thalamic territories were innervated exclusively either by giant vGLUT2- or vGLUT1-positive boutons. Co-distribution of drivers with different origin was not abundant. In several thalamic regions, no giant terminals of any type could be detected at light microscopic level. Electron microscopic observation of these territories revealed either the complete absence of large multisynaptic excitatory terminals (basal ganglia-recipient nuclei) or the presence of both vGLUT1- and vGLUT2-positive terminals, which were significantly smaller than their giant counterparts (intralaminar nuclei, medial pulvinar). In the basal ganglia-recipient thalamus, giant inhibitory terminals replaced the excitatory driver inputs. The pulvinar and the mediodorsal nucleus displayed subnuclear heterogeneity in their driver assemblies. These results show that distinct thalamic territories can be under pure subcortical or cortical control; however there is significant variability in the composition of major excitatory inputs in several thalamic regions. Since thalamic information transfer depends on the origin and complexity of the excitatory inputs, this suggests that the computations performed by individual thalamic regions display considerable variability. Finally, the map of driver distribution may help to resolve the morphological basis of human diseases involving different parts of the thalamus. PMID:23223308

  14. Injury patterns associated with direction of impact: drivers admitted to trauma centers.

    PubMed

    Dischinger, P C; Cushing, B M; Kerns, T J

    1993-09-01

    Clinical data on the nature and severity of injuries was linked with data from police crash reports for 3675 car or truck drivers admitted to trauma centers. Different patterns of injuries were noted for drivers in frontal compared with left lateral collisions. Injuries to the face and lower extremities were significantly greater in frontal collisions; thorax, abdominal, and pelvic injuries were significantly greater in lateral collisions. In addition, drivers in lateral collisions were found to have significantly more multiple injuries to the abdomen and thorax. Despite no difference in mean injury Severity Score, drivers in left lateral collisions had a significantly higher mortality rate; moreover, this increased mortality was not merely a reflection of the increased incidence of lateral collisions among older drivers. In conclusion, information on direction of impact has potential use for clinical decision making, since drivers in lateral collisions have a higher incidence of occult abdominal and thoracic injuries. PMID:8371306

  15. A new switched-capacitor frequency modulated driver for light emitting diodes.

    PubMed

    Feng, Weifeng; Shi, Frank G

    2007-11-01

    A new type of drivers for light emitting diodes (LEDs) is introduced based on the switched-capacitor frequency modulation. In contrast to conventional constant dc current drivers, the current pulse is provided by this new switched-capacitor LED driver. In the present driver, the charging capacitor is charged and discharged through a LED and the current flow direction is controlled by a metal oxide semiconductor switch. The input current (and thus the LED brightness) is proportional to the switch clock frequency at relatively low frequencies and becomes saturated at relatively high frequencies. This new driver circuit is simple and robust and maintains high efficiency for a wide range of input powers. In addition, the dimming control is easily realized by modulating clock frequency. Finally, this LED driver consumes no dc current and thus provides inherent protection to LED in standby mode. PMID:18052494

  16. 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.

  17. Inflammation as a Driver of Clonal Evolution in Myeloproliferative Neoplasm

    PubMed Central

    Fleischman, Angela G.

    2015-01-01

    Our understanding of inflammation's role in the pathogenesis of myeloproliferative neoplasm (MPN) is evolving. The impact of chronic inflammation, a characteristic feature of MPN, likely goes far beyond its role as a driver of constitutional symptoms. An inflammatory response to the neoplastic clone may be responsible for some pathologic aspects of MPN. Moreover, JAK2V617F mutated hematopoietic stem and progenitor cells are resistant to inflammation, and this gives the neoplastic clone a selective advantage allowing for its clonal expansion. Because inflammation plays a central role in MPN inflammation is a logical therapeutic target in MPN. PMID:26538830

  18. 32 CFR 636.16 - Detection, apprehension, and testing of intoxicated drivers.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 32 National Defense 4 2011-07-01 2011-07-01 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...

  19. 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...

  20. 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...

  1. 32 CFR 636.16 - Detection, apprehension, and testing of intoxicated drivers.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 4 2010-07-01 2010-07-01 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...

  2. 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...

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

    PubMed

    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

    2016-04-19

    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

  4. 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

  5. Food additives

    MedlinePlus

    Food additives are substances that become part of a food product when they are added during the processing or making of that food. "Direct" food additives are often added during processing to: Add nutrients ...

  6. Identification of High-Impact cis-Regulatory Mutations Using Transcription Factor Specific Random Forest Models

    PubMed Central

    Svetlichnyy, Dmitry; Imrichova, Hana; Fiers, Mark; Kalender Atak, Zeynep; Aerts, Stein

    2015-01-01

    Cancer genomes contain vast amounts of somatic mutations, many of which are passenger mutations not involved in oncogenesis. Whereas driver mutations in protein-coding genes can be distinguished from passenger mutations based on their recurrence, non-coding mutations are usually not recurrent at the same position. Therefore, it is still unclear how to identify cis-regulatory driver mutations, particularly when chromatin data from the same patient is not available, thus relying only on sequence and expression information. Here we use machine-learning methods to predict functional regulatory regions using sequence information alone, and compare the predicted activity of the mutated region with the reference sequence. This way we define the Predicted Regulatory Impact of a Mutation in an Enhancer (PRIME). We find that the recently identified driver mutation in the TAL1 enhancer has a high PRIME score, representing a “gain-of-target” for MYB, whereas the highly recurrent TERT promoter mutation has a surprisingly low PRIME score. We trained Random Forest models for 45 cancer-related transcription factors, and used these to score variations in the HeLa genome and somatic mutations across more than five hundred cancer genomes. Each model predicts only a small fraction of non-coding mutations with a potential impact on the function of the encompassing regulatory region. Nevertheless, as these few candidate driver mutations are often linked to gains in chromatin activity and gene expression, they may contribute to the oncogenic program by altering the expression levels of specific oncogenes and tumor suppressor genes. PMID:26562774

  7. Identification of High-Impact cis-Regulatory Mutations Using Transcription Factor Specific Random Forest Models.

    PubMed

    Svetlichnyy, Dmitry; Imrichova, Hana; Fiers, Mark; Kalender Atak, Zeynep; Aerts, Stein

    2015-11-01

    Cancer genomes contain vast amounts of somatic mutations, many of which are passenger mutations not involved in oncogenesis. Whereas driver mutations in protein-coding genes can be distinguished from passenger mutations based on their recurrence, non-coding mutations are usually not recurrent at the same position. Therefore, it is still unclear how to identify cis-regulatory driver mutations, particularly when chromatin data from the same patient is not available, thus relying only on sequence and expression information. Here we use machine-learning methods to predict functional regulatory regions using sequence information alone, and compare the predicted activity of the mutated region with the reference sequence. This way we define the Predicted Regulatory Impact of a Mutation in an Enhancer (PRIME). We find that the recently identified driver mutation in the TAL1 enhancer has a high PRIME score, representing a "gain-of-target" for MYB, whereas the highly recurrent TERT promoter mutation has a surprisingly low PRIME score. We trained Random Forest models for 45 cancer-related transcription factors, and used these to score variations in the HeLa genome and somatic mutations across more than five hundred cancer genomes. Each model predicts only a small fraction of non-coding mutations with a potential impact on the function of the encompassing regulatory region. Nevertheless, as these few candidate driver mutations are often linked to gains in chromatin activity and gene expression, they may contribute to the oncogenic program by altering the expression levels of specific oncogenes and tumor suppressor genes. PMID:26562774

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

    DOE PAGESBeta

    Nik-Zainal, Serena; Davies, Helen; Staaf, Johan; Ramakrishna, Manasa; Glodzik, Dominik; Zou, Xueqing; Martincorena, Inigo; Alexandrov, Ludmil B.; Martin, Sancha; Wedge, David C.; et al

    2016-06-02

    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

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

    PubMed

    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 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; 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

    2016-06-01

    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. 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. PMID:27135926

  10. 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

  11. Children's Understanding of Drivers' Intentions

    ERIC Educational Resources Information Center

    Foot, Hugh C.; Thomson, James A.; Tolmie, Andrew K.; Whelan, Kirstie M.; Morrison, Sheila; Sarvary, Penelope

    2006-01-01

    To become more skilled as pedestrians, children need to acquire a view of the traffic environment as one in which road users are active agents with different intentions and objectives. This paper describes a simulation study designed to explore children's understanding of drivers' intentions. It also investigated the effect of training children's…

  12. 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…

  13. Young Drivers: Reckless or Unprepared?

    ERIC Educational Resources Information Center

    Waller, Patricia F.

    Because it is a well-accepted fact that young persons have more than their share of automobile crashes and because the task of driving is a complex one that requires practice to be mastered, it is proposed that a careful human factors analysis of the task of driving be undertaken based on empirically demonstrated differences among driver groups.…

  14. Transporting Handicapped Students: Driver Manual.

    ERIC Educational Resources Information Center

    Turner, Dayton Ray

    The document offers guidelines for van or bus drivers transporting handicapped students to and from school. Part 1 offers an overview of adaptive transportation services and gives specifics on providing services to the blind/visually impaired, hearing impaired, mentally retarded, physically handicapped, behaviorally disordered, learning disabled,…

  15. The Indian Proton Driver Project

    NASA Astrophysics Data System (ADS)

    Krishnagopal, Srinivas

    2005-06-01

    There are two new proton accelerator projects being considered in India. One is a 20 MeV, 30 mA, front end of a proton linac driver for nuclear transmutation applications. The second is a 1 GeV, 100 kW rapid cycling synchrotron for a spallation neutron source. We present the current design status of both these projects.

  16. Addition of a UL5 helicase-primase subunit point mutation eliminates bursal-thymic atrophy of Marek's disease virus ∆Meq recombinant virus but reduces vaccinal protection.

    PubMed

    Hildebrandt, Evin; Dunn, John R; Cheng, Hans H

    2015-01-01

    Marek's disease virus (MDV) is an oncogenic alphaherpesvirus and the causative agent of Marek's disease (MD), characterized by immunosuppression, paralysis, nerve enlargement and induction of T-cell lymphomas in chickens. Despite widespread usage of vaccines since the 1970s to control MD, more virulent field strains of MDV have emerged that overcome vaccinal protection, necessitating the development of new and more protective MD vaccines. The ∆Meq virus, a recombinant Md5 strain MDV lacking the viral oncogene Meq, is one candidate MD vaccine with great potential but unfortunately it also causes bursal-thymic atrophy (BTA) in maternal antibody negative chickens, raising concerns that impede commercial use as a vaccine. Previously, we identified a point mutation within UL5 that reduced in vivo replication in attenuated viruses. We proposed that introduction of the UL5 point mutation into the ∆Meq virus would reduce in vivo replication and eliminate BTA yet potentially retain high protective abilities. In birds, the ∆Meq+UL5 recombinant MDV had reduced replication compared to the original ∆Meq virus, while weights of lymphoid organs indicated that ∆Meq+UL5 did not induce BTA, supporting the hypothesis that reduction of in vivo replication would also abolish BTA. Vaccine trials of the ∆Meq+UL5 virus compared to other ∆Meq-based viruses and commercial vaccines show that, while the ∆Meq+UL5 does provide vaccinal protection, this protection was also reduced compared to the original ∆Meq virus. Therefore, it appears that a very delicate balance is required between levels of replication able to induce high vaccinal protection, yet not so high as to induce BTA. PMID:25968878

  17. ENVIRONMENTAL DRIVERS AND MONITORING OF RANGELANDS

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Environmental drivers are factors that cause measurable changes in properties of biological communities. Examples of drivers can include environmental factors such as rainfall variability and available soil nitrogen, management factors such as livestock grazing practices and prescribed burning, gov...

  18. 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.

  19. Systematic analysis of somatic mutations impacting gene expression in 12 tumour types

    PubMed Central

    Ding, Jiarui; McConechy, Melissa K.; Horlings, Hugo M.; Ha, Gavin; Chun Chan, Fong; Funnell, Tyler; Mullaly, Sarah C.; Reimand, Jüri; Bashashati, Ali; Bader, Gary D.; Huntsman, David; Aparicio, Samuel; Condon, Anne; Shah, Sohrab P.

    2015-01-01

    We present a novel hierarchical Bayes statistical model, xseq, to systematically quantify the impact of somatic mutations on expression profiles. We establish the theoretical framework and robust inference characteristics of the method using computational benchmarking. We then use xseq to analyse thousands of tumour data sets available through The Cancer Genome Atlas, to systematically quantify somatic mutations impacting expression profiles. We identify 30 novel cis-effect tumour suppressor gene candidates, enriched in loss-of-function mutations and biallelic inactivation. Analysis of trans-effects of mutations and copy number alterations with xseq identifies mutations in 150 genes impacting expression networks, with 89 novel predictions. We reveal two important novel characteristics of mutation impact on expression: (1) patients harbouring known driver mutations exhibit different downstream gene expression consequences; (2) expression patterns for some mutations are stable across tumour types. These results have critical implications for identification and interpretation of mutations with consequent impact on transcription in cancer. PMID:26436532

  20. Promoting designated drivers: the Harvard Alcohol Project.

    PubMed

    Winsten, J A

    1994-01-01

    The designated driver concept is a new component of the nation's comprehensive strategy for reducing alcohol-related traffic fatalities through prevention, deterrence, and treatment. This article explains how the designated driver concept serves as a vehicle for changing social norms, describes the national designated driver campaign and the involvement of the public and private sectors, and presents public opinion findings documenting the wide popularity and growing usage of the designated driver concept. PMID:7917447

  1. Estimating mutation rate: how to count mutations?

    PubMed Central

    Fu, Yun-Xin; Huai, Haying

    2003-01-01

    Mutation rate is an essential parameter in genetic research. Counting the number of mutant individuals provides information for a direct estimate of mutation rate. However, mutant individuals in the same family can share the same mutations due to premeiotic mutation events, so that the number of mutant individuals can be significantly larger than the number of mutation events observed. Since mutation rate is more closely related to the number of mutation events, whether one should count only independent mutation events or the number of mutants remains controversial. We show in this article that counting mutant individuals is a correct approach for estimating mutation rate, while counting only mutation events will result in underestimation. We also derived the variance of the mutation-rate estimate, which allows us to examine a number of important issues about the design of such experiments. The general strategy of such an experiment should be to sample as many families as possible and not to sample much more offspring per family than the reciprocal of the pairwise correlation coefficient within each family. To obtain a reasonably accurate estimate of mutation rate, the number of sampled families needs to be in the same or higher order of magnitude as the reciprocal of the mutation rate. PMID:12807798

  2. Persistent atrial fibrillation ablation: conventional versus driver-guided strategy.

    PubMed

    Lim, Han S; Sacher, Frédéric; Zellerhoff, Stephan; Jesel, Laurence; Shah, Ashok J; Komatsu, Yuki; Daly, Matthew; Denis, Arnaud; Derval, Nicolas; Hocini, Mélèze; Jaïs, Pierre; Haïssaguerre, Michel

    2015-01-01

    While pulmonary vein isolation for paroxysmal atrial fibrillation (AF) is highly effective, catheter ablation for persistent AF remains a challenge with varying clinical success reported. Several ablation techniques have been proposed to target persistent AF, with the additional ablation of complex fractionated electrograms and linear lesions shown to provide incremental success to pulmonary vein isolation alone. Recently, several studies have suggested the presence of localized drivers (re-entrant or focal) in AF. By targeting these drivers, clinical outcomes may be maintained while minimizing the extent of ablation. This article will focus on the conventional stepwise ablation approach for persistent AF versus driver-guided ablation with the use of newer mapping technologies. PMID:26610158

  3. 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. PMID:26141907

  4. Wireless and wearable EEG system for evaluating driver vigilance.

    PubMed

    Lin, Chin-Teng; Chuang, Chun-Hsiang; Huang, Chih-Sheng; Tsai, Shu-Fang; Lu, Shao-Wei; Chen, Yen-Hsuan; Ko, Li-Wei

    2014-04-01

    Brain activity associated with attention sustained on the task of safe driving has received considerable attention recently in many neurophysiological studies. Those investigations have also accurately estimated shifts in drivers' levels of arousal, fatigue, and vigilance, as evidenced by variations in their task performance, by evaluating electroencephalographic (EEG) changes. However, monitoring the neurophysiological activities of automobile drivers poses a major measurement challenge when using a laboratory-oriented biosensor technology. This work presents a novel dry EEG sensor based mobile wireless EEG system (referred to herein as Mindo) to monitor in real time a driver's vigilance status in order to link the fluctuation of driving performance with changes in brain activities. The proposed Mindo system incorporates the use of a wireless and wearable EEG device to record EEG signals from hairy regions of the driver conveniently. Additionally, the proposed system can process EEG recordings and translate them into the vigilance level. The study compares the system performance between different regression models. Moreover, the proposed system is implemented using JAVA programming language as a mobile application for online analysis. A case study involving 15 study participants assigned a 90 min sustained-attention driving task in an immersive virtual driving environment demonstrates the reliability of the proposed system. Consistent with previous studies, power spectral analysis results confirm that the EEG activities correlate well with the variations in vigilance. Furthermore, the proposed system demonstrated the feasibility of predicting the driver's vigilance in real time. PMID:24860041

  5. Distracted Driving in Elderly and Middle-Aged Drivers

    PubMed Central

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

    2011-01-01

    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. PMID:22269561

  6. 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. PMID:23727553

  7. Leukoaraiosis Significantly Worsens Driving Performance of Ordinary Older Drivers

    PubMed Central

    Zheng, Rencheng; Fang, Fang; Ohori, Masanori; Nakamura, Hiroki; Kumagai, Yasuhiho; Okada, Hiroshi; Teramura, Kazuhiko; Nakayama, Satoshi; Irimajiri, Akinori; Taoka, Hiroshi; Okada, Satoshi

    2014-01-01

    Background Leukoaraiosis is defined as extracellular space caused mainly by atherosclerotic or demyelinated changes in the brain tissue and is commonly found in the brains of healthy older people. A significant association between leukoaraiosis and traffic crashes was reported in our previous study; however, the reason for this is still unclear. Method This paper presents a comprehensive evaluation of driving performance in ordinary older drivers with leukoaraiosis. First, the degree of leukoaraiosis was examined in 33 participants, who underwent an actual-vehicle driving examination on a standard driving course, and a driver skill rating was also collected while the driver carried out a paced auditory serial addition test, which is a calculating task given verbally. At the same time, a steering entropy method was used to estimate steering operation performance. Results The experimental results indicated that a normal older driver with leukoaraiosis was readily affected by external disturbances and made more operation errors and steered less smoothly than one without leukoaraiosis during driving; at the same time, their steering skill significantly deteriorated. Conclusions Leukoaraiosis worsens the driving performance of older drivers because of their increased vulnerability to distraction. PMID:25295736

  8. 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. PMID:25115604

  9. TCF12 is mutated in anaplastic oligodendroglioma.

    PubMed

    Labreche, Karim; Simeonova, Iva; Kamoun, Aurélie; Gleize, Vincent; Chubb, Daniel; Letouzé, Eric; Riazalhosseini, Yasser; Dobbins, Sara E; Elarouci, Nabila; Ducray, Francois; de Reyniès, Aurélien; Zelenika, Diana; Wardell, Christopher P; Frampton, Mathew; Saulnier, Olivier; Pastinen, Tomi; Hallout, Sabrina; Figarella-Branger, Dominique; Dehais, Caroline; Idbaih, Ahmed; Mokhtari, Karima; Delattre, Jean-Yves; Huillard, Emmanuelle; Mark Lathrop, G; Sanson, Marc; Houlston, Richard S

    2015-01-01

    Anaplastic oligodendroglioma (AO) are rare primary brain tumours that are generally incurable, with heterogeneous prognosis and few treatment targets identified. Most oligodendrogliomas have chromosomes 1p/19q co-deletion and an IDH mutation. Here we analysed 51 AO by whole-exome sequencing, identifying previously reported frequent somatic mutations in CIC and FUBP1. We also identified recurrent mutations in TCF12 and in an additional series of 83 AO. Overall, 7.5% of AO are mutated for TCF12, which encodes an oligodendrocyte-related transcription factor. Eighty percent of TCF12 mutations identified were in either the bHLH domain, which is important for TCF12 function as a transcription factor, or were frameshift mutations leading to TCF12 truncated for this domain. We show that these mutations compromise TCF12 transcriptional activity and are associated with a more aggressive tumour type. Our analysis provides further insights into the unique and shared pathways driving AO. PMID:26068201

  10. TCF12 is mutated in anaplastic oligodendroglioma

    PubMed Central

    Labreche, Karim; Simeonova, Iva; Kamoun, Aurélie; Gleize, Vincent; Chubb, Daniel; Letouzé, Eric; Riazalhosseini, Yasser; Dobbins, Sara E.; Elarouci, Nabila; Ducray, Francois; de Reyniès, Aurélien; Zelenika, Diana; Wardell, Christopher P.; Frampton, Mathew; Saulnier, Olivier; Pastinen, Tomi; Hallout, Sabrina; Figarella-Branger, Dominique; Dehais, Caroline; Idbaih, Ahmed; Mokhtari, Karima; Delattre, Jean-Yves; Huillard, Emmanuelle; Mark Lathrop, G.; Sanson, Marc; Houlston, Richard S.; Adam, Clovis; Andraud, Marie; Aubriot-Lorton, Marie-Hélène; Bauchet, Luc; Beauchesne, Patrick; Blechet, Claire; Campone, Mario; Carpentier, Antoine; Carpentier, Catherine; Carpiuc, Ioana; Chenard, Marie-Pierre; Chiforeanu, Danchristian; Chinot, Olivier; Cohen-Moyal, Elisabeth; Colin, Philippe; Dam-Hieu, Phong; Desenclos, Christine; Desse, Nicolas; Dhermain, Frederic; Diebold, Marie-Danièle; Eimer, Sandrine; Faillot, Thierry; Fesneau, Mélanie; Fontaine, Denys; Gaillard, Stéphane; Gauchotte, Guillaume; Gaultier, Claude; Ghiringhelli, Francois; Godard, Joel; Marcel Gueye, Edouard; Sebastien Guillamo, Jean; Hamdi-Elouadhani, Selma; Honnorat, Jerome; Louis Kemeny, Jean; Khallil, Toufik; Jouvet, Anne; Labrousse, Francois; Langlois, Olivier; Laquerriere, Annie; Lechapt-Zalcman, Emmanuelle; Le Guérinel, Caroline; Levillain, Pierre-Marie; Loiseau, Hugues; Loussouarn, Delphine; Maurage, Claude-Alain; Menei, Philippe; Janette Motsuo Fotso, Marie; Noel, Georges; Parker, Fabrice; Peoc'h, Michel; Polivka, Marc; Quintin-Roué, Isabelle; Ramirez, Carole; Ricard, Damien; Richard, Pomone; Rigau, Valérie; Rousseau, Audrey; Runavot, Gwenaelle; Sevestre, Henri; Christine Tortel, Marie; Uro-Coste, Emmanuelle; Burel-Vandenbos, Fanny; Vauleon, Elodie; Viennet, Gabriel; Villa, Chiara; Wager, Michel

    2015-01-01

    Anaplastic oligodendroglioma (AO) are rare primary brain tumours that are generally incurable, with heterogeneous prognosis and few treatment targets identified. Most oligodendrogliomas have chromosomes 1p/19q co-deletion and an IDH mutation. Here we analysed 51 AO by whole-exome sequencing, identifying previously reported frequent somatic mutations in CIC and FUBP1. We also identified recurrent mutations in TCF12 and in an additional series of 83 AO. Overall, 7.5% of AO are mutated for TCF12, which encodes an oligodendrocyte-related transcription factor. Eighty percent of TCF12 mutations identified were in either the bHLH domain, which is important for TCF12 function as a transcription factor, or were frameshift mutations leading to TCF12 truncated for this domain. We show that these mutations compromise TCF12 transcriptional activity and are associated with a more aggressive tumour type. Our analysis provides further insights into the unique and shared pathways driving AO. PMID:26068201

  11. Digenic mutations in severe congenital neutropenia

    PubMed Central

    Germeshausen, Manuela; Zeidler, Cornelia; Stuhrmann, Manfred; Lanciotti, Marina; Ballmaier, Matthias; Welte, Karl

    2010-01-01

    Severe congenital neutropenia a clinically and genetically heterogeneous disorder. Mutations in different genes have been described as causative for severe neutropenia, e.g. ELANE, HAX1 and G6PC3. Although congenital neutropenia is considered to be a group of monogenic disorders, the phenotypic heterogeneity even within the yet defined genetic subtypes points to additional genetic and/or epigenetic influences on the disease phenotype. We describe congenital neutropenia patients with mutations in two candidate genes each, including 6 novel mutations. Two of them had a heterozygous ELANE mutation combined with a homozygous mutation in G6PC3 or HAX1, respectively. The other 2 patients combined homozygous or compound heterozygous mutations in G6PC3 or HAX1 with a heterozygous mutation in the respective other gene. Our results suggest that digenicity may underlie this disorder of myelopoiesis at least in some congenital neutropenia patients. PMID:20220065

  12. School Bus Accidents and Driver Age.

    ERIC Educational Resources Information Center

    McMichael, Judith

    The study examines the rates and types of school bus accidents according to the age of the school bus driver. Accident rates in North Carolina for the school year 1971-72 were analyzed using three sources of data: accident reports, driver and mileage data, and questionnaires administered to a sample of school bus drivers. Data were obtained on…

  13. Eaton AF5000+Genesis Communication Driver

    1995-05-25

    Communication driver allows the Genesis Control Series software to interact with Eaton AF5000+ frequency drives via RS-232 communications. All Eaton AF5000+ parameters that support communications are supported by the Genesis driver. Multidrop addressing to multiple units is available with the Genesis communication driver.

  14. Driver Education and the Learning Disabled.

    ERIC Educational Resources Information Center

    Wirths, Claudine G.; Leonard, Steven

    1982-01-01

    A project of the University of Maryland has developed a driver education curriculum for the learning disabled. Several states are making efforts to improve driver education, including rewriting materials and providing oral tests for drivers' licenses. Options for future safety programs include parent-student seminars, multidiscipline teaching, and…

  15. 49 CFR 380.109 - Driver testing.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ....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 an LCV, must be administered by a qualified LCV skills instructor. (1) All tests shall be constructed...

  16. 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....

  17. 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....

  18. 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. PMID:24952744

  19. Combined use of PI3K and MEK inhibitors synergistically inhibits lung cancer with EGFR and KRAS mutations.

    PubMed

    Jiang, Ze-Bo; Huang, Jun; Xie, Chun; Li, Xia; Liu, Liping; He, Jiaxi; Pan, Hui; Huang, Liyan; Fan, Xing-Xing; Yao, Xiao-Jun; Xie, Ying; Li, Na; Liu, Liang; He, Jian-Xing; Leung, Elaine Lai-Han

    2016-07-01

    EGFR and KRAS mutations are the two most common driver mutations in non-small cell lung cancer (NSCLC). Molecular target-based therapy using small molecules such as gefitinib has been used for inhibiting EGFR with good initial responses; however, drug resistance is common when using a mono-targeting strategy. At present, KRAS remains an undruggable target. As such, the development of new drugs targeting the downstream of KRAS and EGFR and their crosstalk pathways is critically needed to effectively treat NSCLC. The present study aimed to elucidate the anticancer effects of PI3K (BKM120) and MEK (PD1056309) inhibitors on NSCLC cell lines with KRAS or EGFR mutations. Inhibition of the EGFR and KRAS downstream P13K pathway using BKM120 significantly inhibited the growth of NSCLC cell lines with either EGFR or KRAS mutations. In addition, significant cell cycle arrest and induction of apoptosis were observed following BKM120 treatment. Notably, although the A549 and H358 NSCLC cell lines harbor the same KRAS mutation, A549 cells were less sensitive than H358 cells in the response to BKM120 treatment. Similarly, PC-9 and H1650 cells harbor the same EGFR mutation, however, H1650 was less sensitive to BKM120. Different sensitivity between NSCLC cell lines with the same oncogenic mutation suggests that multiple crosstalk pathways exit. Combined usage of BKM120 and PD1056309 synergistically enhanced apoptosis in the A549 cells and mildly enhanced apoptosis in the H1650 and H358 cells, suggesting the crosstalk of the MEK pathway with the P13K/Akt pathways in these cell lines. Overall, our findings suggest that inhibition of EGFR and KRAS downstream with a P13K/Akt inhibitor could be useful for treating NSCLC. However, for NSCLC exhibiting crosstalk with other survival pathways, such as the MEK pathway, combination treatment is required. PMID:27121230

  20. 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

  1. 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.

  2. Genetics Home Reference: familial acute myeloid leukemia with mutated CEBPA

    MedlinePlus

    ... N. A family harboring a germ-line N-terminal C/EBPalpha mutation and development of acute myeloid leukemia with an additional somatic C-terminal C/EBPalpha mutation. Genes Chromosomes Cancer. 2010 Mar; ...

  3. Glucocerebrosidase mutations in Gaucher disease.

    PubMed Central

    Beutler, E.; Demina, A.; Gelbart, T.

    1994-01-01

    BACKGROUND: Thirty-six mutations that cause Gaucher disease, the most common glycolipid storage disorder, are known. Although both alleles of most patients with the disease contain one of these mutations, in a few patients one or both disease-producing alleles have remained unidentified. Identification of mutations in these patients is useful for genetic counseling. MATERIALS AND METHODS: The DNA from 23 Gaucher disease patients in whom at least one glucocerebrosidase allele did not contain any of the 36 previously described mutations has been examined by single strand conformation polymorphism (SSCP) analysis, followed by sequencing of regions in which abnormalities were detected. RESULTS: Eight previously undescribed mutations were detected. In exon 3, a deletion of a cytosine at cDNA nt 203 was found. In exon 6, three missense mutations were identified: a C-->A transversion at cDNA nt 644 (Ala176-->Asp), a C-->A transversion at cDNA nt 661 that resulted in a (Pro182-->Thr), and a G-->A transition at cDNA nt 721 (Gly202-->Arg). Two missense mutations were found in exon 7: a G-->A transition at cDNA nt 887 (Arg257-->Gln) and a C-->T at cDNA nt 970 (Arg285-->Cys). Two missense mutations were found in exon 9: a T-->G at cDNA nt 1249 (Trp378-->Gly) and a G-->A at cDNA nt 1255 (Asp380-->Asn). In addition to these disease-producing mutations, a silent C-->G transversion at cDNA nt 1431, occurring in a gene that already contained the 1226G mutation, was found in one family. CONCLUSIONS: The mutations described here and previously known can be classified as mild, severe, or lethal, on the basis of their effect on enzyme production and on clinical phenotype, and as polymorphic or sporadic, on the basis of the haplotype in which they are found. Rare mutations such as the new ones described here are sporadic in nature. PMID:8790604

  4. 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

  5. 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. PMID:25209666

  6. 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

    ... for public comment (75 FR 33661). No comments were received in the public docket by the close of the... are equipped with onboard sleeping and eating facilities. The drivers, in addition to operating...

  7. Food additives.

    PubMed

    Berglund, F

    1978-01-01

    The use of additives to food fulfils many purposes, as shown by the index issued by the Codex Committee on Food Additives: Acids, bases and salts; Preservatives, Antioxidants and antioxidant synergists; Anticaking agents; Colours; Emulfifiers; Thickening agents; Flour-treatment agents; Extraction solvents; Carrier solvents; Flavours (synthetic); Flavour enhancers; Non-nutritive sweeteners; Processing aids; Enzyme preparations. Many additives occur naturally in foods, but this does not exclude toxicity at higher levels. Some food additives are nutrients, or even essential nutritents, e.g. NaCl. Examples are known of food additives causing toxicity in man even when used according to regulations, e.g. cobalt in beer. In other instances, poisoning has been due to carry-over, e.g. by nitrate in cheese whey - when used for artificial feed for infants. Poisonings also occur as the result of the permitted substance being added at too high levels, by accident or carelessness, e.g. nitrite in fish. Finally, there are examples of hypersensitivity to food additives, e.g. to tartrazine and other food colours. The toxicological evaluation, based on animal feeding studies, may be complicated by impurities, e.g. orthotoluene-sulfonamide in saccharin; by transformation or disappearance of the additive in food processing in storage, e.g. bisulfite in raisins; by reaction products with food constituents, e.g. formation of ethylurethane from diethyl pyrocarbonate; by metabolic transformation products, e.g. formation in the gut of cyclohexylamine from cyclamate. Metabolic end products may differ in experimental animals and in man: guanylic acid and inosinic acid are metabolized to allantoin in the rat but to uric acid in man. The magnitude of the safety margin in man of the Acceptable Daily Intake (ADI) is not identical to the "safety factor" used when calculating the ADI. The symptoms of Chinese Restaurant Syndrome, although not hazardous, furthermore illustrate that the whole ADI

  8. Experimental Research in Boost Driver with EDLCs

    NASA Astrophysics Data System (ADS)

    Matsumoto, Hirokazu

    The supply used in servo systems tends to have a high voltage in order to reduce loss and improve the response of motor drives. We propose a new boost motor driver that comprises EDLCs. The proposed driver has a simple structure, wherein the EDLCs are connected in series to the supply, and comprises a charge circuit to charge the EDLCs. The proposed driver has three advantages over conventional boost drivers. The first advantage is that the driver can easily attain the stable boost voltage. The second advantage is that the driver can reduce input power peaks. In a servo system, the input power peaks become greater than the rated power in order to accelerate the motor rapidly. This implies that the equipments that supply power to servo systems must have sufficient power capacity to satisfy the power peaks. The proposed driver can suppress the increase of the power capacity of supply facilities. The third advantage is that the driver can store almost all of the regenerative energy. Conventional drivers have a braking resistor to suppress the increase in the DC link voltage. This causes a considerable reduction in the efficiency. The proposed driver is more efficient than conventional drivers. In this study, the experimental results confirmed the effectiveness of the proposed driver and showed that the drive performance of the proposed driver is the same as that of a conventional driver. Furthermore, it was confirmed that the results of the simulation of a model of the EDLC module, whose capacitance is dependent on the frequency, correspond well with the experimental results.

  9. Distinct clinical characteristics of myeloproliferative neoplasms with calreticulin mutations

    PubMed Central

    Andrikovics, Hajnalka; Krahling, Tunde; Balassa, Katalin; Halm, Gabriella; Bors, Andras; Koszarska, Magdalena; Batai, Arpad; Dolgos, Janos; Csomor, Judit; Egyed, Miklos; Sipos, Andrea; Remenyi, Peter; Tordai, Attila; Masszi, Tamas

    2014-01-01

    Somatic insertions/deletions in the calreticulin gene have recently been discovered to be causative alterations in myeloproliferative neoplasms. A combination of qualitative and quantitative allele-specific polymerase chain reaction, fragment-sizing, high resolution melting and Sanger-sequencing was applied for the detection of three driver mutations (in Janus kinase 2, calreticulin and myeloproliferative leukemia virus oncogene genes) in 289 cases of essential thrombocythemia and 99 cases of primary myelofibrosis. In essential thrombocythemia, 154 (53%) Janus kinase 2 V617F, 96 (33%) calreticulin, 9 (3%) myeloproliferative leukemia virus oncogene gene mutation-positive and 30 triple-negative (11%) cases were identified, while in primary myelofibrosis 56 (57%) Janus kinase 2 V617F, 25 (25%) calreticulin, 7 (7%) myeloproliferative leukemia virus oncogene gene mutation-positive and 11 (11%) triple-negative cases were identified. Patients positive for the calreticulin mutation were younger and had higher platelet counts compared to Janus kinase 2 mutation-positive counterparts. Calreticulin mutation-positive patients with essential thrombocythemia showed a lower risk of developing venous thrombosis, but no difference in overall survival. Calreticulin mutation-positive patients with primary myelofibrosis had a better overall survival compared to that of the Janus kinase 2 mutation-positive (P=0.04) or triple-negative cases (P=0.01). Type 2 calreticulin mutation occurred more frequently in essential thrombocythemia than in primary myelofibrosis (P=0.049). In essential thrombocythemia, the calreticulin mutational load was higher than the Janus kinase 2 mutational load (P<0.001), and increased gradually in advanced stages. Calreticulin mutational load influenced blood counts even at the time point of diagnosis in essential thrombocythemia. We confirm that calreticulin mutation is associated with distinct clinical characteristics and explored relationships between mutation

  10. 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. PMID:26444273

  11. Measurement of whole-body vibration in taxi drivers.

    PubMed

    Funakoshi, Mitsuhiko; Taoda, Kazushi; Tsujimura, Hiroji; Nishiyama, Katsuo

    2004-03-01

    In a previous epidemiological study we reported that the prevalence (45.8%) of low-back pain (LBP) and the two-year incidence (25.9%) of LBP in 284 male taxi drivers in Japan was comparable with rates reported for other occupational drivers in which LBP frequently occurs. LBP was significantly related with the level of uncomfortable road vibrations, and, importantly, increased with total mileage. The aim of this study was to measure whole-body vibration (WBV) on the driver's seat pan of 12 taxis operating under actual working conditions. The results were evaluated according to the health guidelines in International Standard ISO 2631-1:1997. Finally, the relation between total mileage and WBV was investigated. The majority of the frequency-weighted r.m.s. accelerations of the taxis fell into the "potential health risks" zone, under ISO 2631-1:1997. It was clear that the taxi drivers were exposed to serious WBV magnitudes. Therefore, occupational health and safety management should be carried out to help prevent adverse health effects in taxi drivers. In particular, reduction of WBV in taxis and shortening of driving time to reduce duration of WBV exposure should be considered. Moreover, because many taxi drivers work 18 h every other day, the shortening of working hours and taking of rest breaks while working should be considered. Frequency-weighted r.m.s. accelerations of taxis had a tendency to decrease as total mileage increased. The relation between total mileage and WBV should be investigated by taking measurements on the floor and the back rest in addition to the seat pan. PMID:15090686

  12. 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.

  13. 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. PMID:25746036

  14. Mutation and the environment

    SciTech Connect

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

    1990-01-01

    This book is organized under the following headings: Plenary lectures; Brook mutational mechanisms; Adduction and DNA damage; Recombination and gene conversion; Repair: Prokoyote mechanisms and induction; Repair: Lower eukaryote and plant mechanisms; Repair: Higher eukaryote mechanisms and selectivity; Repair: Human genes and mechanisms; Mutation: Spectra and mechanisms; Mutation: Shuttle vectors; Mutation: Transgenic animals; New methods: Polymerase chain reaction.

  15. Experimental Study on Forward Collision Warning System Adapted for Driver Characteristics

    NASA Astrophysics Data System (ADS)

    Kamada, Takayoshi; Miyoshi, Noboru; Nagai, Masao

    This paper describes forward-collision warning system adapted for individual driver characteristics. Conventional forward-collision warning system has the problem to output warning signals excessively though the driver intends to stop the vehicle. The driver feels irritated by these useless warnings. The objective of this study is to develop an algorithm which solves this problem. In this algorithm, the warning output timing is determined to a value that the driver conducts braking action for possible collision avoidance when looking aside. In addition, the warning output timing is changed by foot position of the driver. From experimental result by young and elderly subjects using driving simulator, excessive output of warning signal was reduced without collision.

  16. [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. PMID:26507715

  17. 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.

  18. Phosphazene additives

    SciTech Connect

    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.

  19. 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

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

    PubMed Central

    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

    2014-01-01

    Cancer genome sequencing studies have identified numerous driver genes but the relative timing of mutations in carcinogenesis remains unclear. The gradual progression from pre-malignant 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 two 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 were stage-specific, confined to HGD and EAC, respectively. Finally, we applied this knowledge to identify high-risk Barrett’s esophagus in a novel 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. PMID:24952744

  1. 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

  2. Temporal perspective on individual driver behavior using electronic records of undesirable events.

    PubMed

    Musicant, Oren; Bar-Gera, Hillel; Schechtman, Edna

    2014-09-01

    This paper explores In-Vehicle Data Recorders (IVDRs) information about the count of undesirable driving events (such as hard braking, lane changing, and sharp turning) of 148 individuals. The information was logged over three years and included time stamp information about the occurrence of undesirable driving events in each trip (N=573,238). The objective was to gain deeper understanding about the heterogeneity among drivers with respect to behavior change over time, the effect of trip duration and the distribution of events count. Our findings show that in some respects drivers are similar: for all drivers, the variance of the events count was larger than the mean, indicating that the negative binomial distribution is suitable to model the distribution of events count per trip. Most drivers (95%) had lower events rate during longer trips, suggesting that a 'simple' events rate index is problematic when comparing between those driving longer trips and drivers driving short trips. In addition, most drivers (87%) improved their driving behavior throughout the measurement period. However, there are important differences among drivers in terms of the frequency of behavior change and the trends in behavior over time. These findings demonstrate the need for personalized examination of individual drivers. Several tools for such personalized examination were developed and discussed in this study. PMID:24694900

  3. 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. PMID:16366240

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

    PubMed

    Chen, Han; Xing, Ke; He, Xionglei

    2015-08-01

    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

  5. 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.

  6. Transcending as a driver of development.

    PubMed

    Travis, Frederick

    2016-06-01

    This paper draws from three different bodies of research to discuss the hypothesis that age-appropriate experiences enhance brain and cognitive development throughout the life span. These age-appropriate experiences could be considered as the drivers of development at each age, including drivers to foster development beyond adult abstract thinking, as described in Piaget's formal operational stage. We explore how a nurturing caregiver is the driver in the first 2 years of life, how language learning is the driver from 3 to 10 years, and how problem solving is the driver in the teenage years. To develop beyond adult rational thinking, we suggest that the driver is transcending thought, which can result when practicing meditations in the automatic self-transcending category, such as Transcendental Meditation. PMID:27124274

  7. 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

  8. 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.

  9. The nuclear deubiquitinase BAP1 is commonly inactivated by somatic mutations and 3p21.1 losses in malignant pleural mesothelioma.

    PubMed

    Bott, Matthew; Brevet, Marie; Taylor, Barry S; Shimizu, Shigeki; Ito, Tatsuo; Wang, Lu; Creaney, Jenette; Lake, Richard A; Zakowski, Maureen F; Reva, Boris; Sander, Chris; Delsite, Robert; Powell, Simon; Zhou, Qin; Shen, Ronglai; Olshen, Adam; Rusch, Valerie; Ladanyi, Marc

    2011-07-01

    Malignant pleural mesotheliomas (MPMs) often show CDKN2A and NF2 inactivation, but other highly recurrent mutations have not been described. To identify additional driver genes, we used an integrated genomic analysis of 53 MPM tumor samples to guide a focused sequencing effort that uncovered somatic inactivating mutations in BAP1 in 23% of MPMs. The BAP1 nuclear deubiquitinase is known to target histones (together with ASXL1 as a Polycomb repressor subunit) and the HCF1 transcriptional co-factor, and we show that BAP1 knockdown in MPM cell lines affects E2F and Polycomb target genes. These findings implicate transcriptional deregulation in the pathogenesis of MPM. PMID:21642991

  10. The nuclear deubiquitinase BAP1 is commonly inactivated by somatic mutations and 3p21.1 losses in malignant pleural mesothelioma

    PubMed Central

    Bott, Matthew; Brevet, Marie; Taylor, Barry S; Shimizu, Shigeki; Ito, Tatsuo; Wang, Lu; Creaney, Jenette; Lake, Richard A; Zakowski, Maureen F; Reva, Boris; Sander, Chris; Delsite, Robert; Powell, Simon; Zhou, Qin; Shen, Ronglai; Olshen, Adam; Rusch, Valerie; Ladanyi, Marc

    2015-01-01

    Malignant pleural mesotheliomas (MPMs) often show CDKN2A and NF2 inactivation, but other highly recurrent mutations have not been described. To identify additional driver genes, we used an integrated genomic analysis of 53 MPM tumor samples to guide a focused sequencing effort that uncovered somatic inactivating mutations in BAP1 in 23% of MPMs. The BAP1 nuclear deubiquitinase is known to target histones (together with ASXL1 as a Polycomb repressor subunit) and the HCF1 transcriptional co-factor, and we show that BAP1 knockdown in MPM cell lines affects E2F and Polycomb target genes. These findings implicate transcriptional deregulation in the pathogenesis of MPM. PMID:21642991

  11. Emergence of constitutively active estrogen receptor-α mutations in pretreated advanced estrogen receptor positive breast cancer

    PubMed Central

    Meric-Bernstam, Funda; Gonzalez-Angulo, Ana Maria; Ferrer-Lozano, Jaime; Perez-Fidalgo, Jose A.; Cristofanilli, Massimo; Gómez, Henry; Arteaga, Carlos L.; Giltnane, Jennifer; Balko, Justin M.; Cronin, Maureen T; Jarosz, Mirna; Sun, James; Hawryluk, Matthew; Lipson, Doron; Otto, Geoff; Ross, Jeffrey S; Dvir, Addie; Soussan-Gutman, Lior; Wolf, Ido; Rubinek, Tamar; Gilmore, Lauren; Schnitt, Stuart; Come, Steven E.; Pusztai, Lajos; Stephens, Philip; Brown, Myles; Miller, Vincent A.

    2014-01-01

    Purpose We undertook this study to determine the prevalence of estrogen receptor (ER) α (ESR1) mutations throughout the natural history of hormone dependent breast cancer and to delineate the functional roles of the most commonly detected alterations. Experimental Design We studied a total of 249 tumor specimens from 208 patients. The specimens include 134 ER positive (ER+/HER2–) and, as controls, 115 ER negative (ER−) tumors. The ER+ samples consist of 58 primary breast cancers and 76 metastatic samples. All tumors were sequenced to high unique coverage using next generation sequencing targeting the coding sequence of the estrogen receptor and an additional 182 cancer-related genes. Results Recurring somatic mutations in codons 537 and 538 within the ligand-binding domain of ER were detected in ER+ metastatic disease. Overall, the frequency of these mutations was 12% (9/76, 95% CI 6%-21%) in metastatic tumors and in a subgroup of patients who received an average of 7 lines of treatment the frequency was 20% (5/25, 95% CI 7%-41%). These mutations were not detected in primary or treatment naïve ER+ cancer or in any stage of ER− disease. Functional studies in cell line models demonstrate that these mutations render estrogen receptor constitutive activity and confer partial resistance to currently available endocrine treatments. Conclusions In this study we show evidence for the temporal selection of functional ESR1 mutations as potential drivers of endocrine resistance during the progression of ER positive breast cancer. PMID:24398047

  12. 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.

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

    PubMed Central

    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

    2015-01-01

    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. PMID:26632267

  14. 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

    2015-01-01

    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. PMID:26632267

  15. The mutational landscape of hepatocellular carcinoma

    PubMed Central

    2015-01-01

    The development of hepatocellular carcinoma (HCC) is a complex process, and HCC arises from the accumulation of multiple genetic alterations leading to changes in the genomic landscape. Current advances in genomic technologies have revolutionized the search for genetic alterations in cancer genomes. Recent studies in which all coding exons in HCC were sequenced have shed new light on the genomic landscape of this malignant disease. Catalogues of these somatic mutations and systematic analysis of catalogued mutations will lead us to uncover candidate HCC driver genes, although further functional validation is needed to determine whether these genes play a causal role in the development of HCC. This review provides an overview of previously known oncogenes and new oncogene candidates in HCC that were uncovered from recent exome or whole-genome sequencing studies. This knowledge provides direction for future personalized treatment approaches for patients with HCC. PMID:26523267

  16. HPMV: human protein mutation viewer - relating sequence mutations to protein sequence architecture and function changes.

    PubMed

    Sherman, Westley Arthur; Kuchibhatla, Durga Bhavani; Limviphuvadh, Vachiranee; Maurer-Stroh, Sebastian; Eisenhaber, Birgit; Eisenhaber, Frank

    2015-10-01

    Next-generation sequencing advances are rapidly expanding the number of human mutations to be analyzed for causative roles in genetic disorders. Our Human Protein Mutation Viewer (HPMV) is intended to explore the biomolecular mechanistic significance of non-synonymous human mutations in protein-coding genomic regions. The tool helps to assess whether protein mutations affect the occurrence of sequence-architectural features (globular domains, targeting signals, post-translational modification sites, etc.). As input, HPMV accepts protein mutations - as UniProt accessions with mutations (e.g. HGVS nomenclature), genome coordinates, or FASTA sequences. As output, HPMV provides an interactive cartoon showing the mutations in relation to elements of the sequence architecture. A large variety of protein sequence architectural features were selected for their particular relevance to mutation interpretation. Clicking a sequence feature in the cartoon expands a tree view of additional information including multiple sequence alignments of conserved domains and a simple 3D viewer mapping the mutation to known PDB structures, if available. The cartoon is also correlated with a multiple sequence alignment of similar sequences from other organisms. In cases where a mutation is likely to have a straightforward interpretation (e.g. a point mutation disrupting a well-understood targeting signal), this interpretation is suggested. The interactive cartoon can be downloaded as standalone viewer in Java jar format to be saved and viewed later with only a standard Java runtime environment. The HPMV website is: http://hpmv.bii.a-star.edu.sg/ . PMID:26503432

  17. 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

  18. A hardware-independent data acquisition package incorporating a simulation driver and simulation description language.

    PubMed

    Krause, B R

    1993-09-01

    Device drivers for commercial data acquisition boards (DASH-16, DT2801) and a device driver for a virtual data acquisition board have been developed and incorporated in a single package for a multiple station anesthesia research laboratory. The package provides a compiler for a simulation description language which is used to program the virtual board. The package, written in C for the IBM PC, was designed to be easily extended with additional drivers. Applications using the package can control all supported devices without the programmer having to learn the details of the hardware. PMID:8222620

  19. Design and Fabrication of Large Scale Micro-LED Arrays and Silicon Driver for OEIC Devices

    NASA Astrophysics Data System (ADS)

    Shin, Sang-Baie; Iijima, Ko-Ichiro; Okada, Hiroshi; Iwayama, Sho; Wakahara, Akihiro

    In this paper, we designed and fabricated large scale micro-light-emitting-diode (LED) arrays and silicon driver for single chip device for realizing as prototypes of heterogeneous optoelectronic integrated circuits (OEICs). The large scale micro-LED arrays were separated by a dry etching method from mesa structure to 16,384 pixels of 128 × 128, each with a size of 15µm in radius. Silicon driver was designed the additional bonding pad on each driving transistor for bonding with micro-LED arrays. Fabricated micro-LED arrays and driver were flip-chip bonded using anisotropic conductive adhesive.

  20. SQSTM1 Mutations and Glaucoma

    PubMed Central

    Scheetz, Todd E.; Roos, Ben R.; Solivan-Timpe, Frances; Miller, Kathy; DeLuca, Adam P.; Stone, Edwin M.; Kwon, Young H.; Alward, Wallace L. M.; Wang, Kai; Fingert, John H.

    2016-01-01

    Glaucoma is the most common cause of irreversible blindness worldwide. One subset of glaucoma, normal tension glaucoma (NTG) occurs in the absence of high intraocular pressure. Mutations in two genes, optineurin (OPTN) and TANK binding kinase 1 (TBK1), cause familial NTG and have known roles in the catabolic cellular process autophagy. TKB1 encodes a kinase that phosphorylates OPTN, an autophagy receptor, which ultimately activates autophagy. The sequestosome (SQSTM1) gene also encodes an autophagy receptor and also is a target of TBK1 phosphorylation. Consequently, we hypothesized that mutations in SQSTM1 may also cause NTG. We tested this hypothesis by searching for glaucoma-causing mutations in a cohort of NTG patients (n = 308) and matched controls (n = 157) using Sanger sequencing. An additional 1098 population control samples were also analyzed using whole exome sequencing. A total of 17 non-synonymous mutations were detected which were not significantly skewed between cases and controls when analyzed separately, or as a group (p > 0.05). These data suggest that SQSTM1 mutations are not a common cause of NTG. PMID:27275741

  1. 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.

  2. Screening for major driver oncogene alterations in adenosquamous lung carcinoma using PCR coupled with next-generation and Sanger sequencing methods

    PubMed Central

    Shi, Xiaohua; Wu, Huanwen; Lu, Junliang; Duan, Huanli; Liu, Xuguang; Liang, Zhiyong

    2016-01-01

    We investigated the frequency of major driver oncogenes in lung adenosquamous cell carcinoma (ASC) cases. Frequency of EGFR, K-Ras, B-Raf, PIK3CA, DDR2, ALK, and PDGFRA gene mutations was examined in 56 patients using next-generation sequencing, polymerase chain reaction, and Sanger sequencing. Macrodissection or microdissection was performed in 37 cases to separate the adenomatous and squamous components of ASC. The overall mutation rate was 64.29%, including 55.36%, 7.14%, and 1.79% for EGFR, K-Ras, and B-Raf mutations, respectively. PIK3CA mutation was detected in three cases; all involved coexisting EGFR mutations. Of the 37 cases, 34 were convergent in two components, while three showed EGFR mutations in the glandular components and three showed PIK3CA mutations in the squamous components. With respect to EGFR mutations, the number of young female patients, nonsmokers, and those with positive pleural invasion was higher in the mutation-positive group than that in the mutation-negative. K-Ras mutation was significantly associated with smoking. Overall survival in the different EGFR mutation groups differed significantly. The frequency and clinicopathological characteristics of EGFR- and K-Ras-mutated adenosquamous lung carcinoma were similar to that noted in Asian adenocarcinomas patients. The high convergence mutation rate in both adenomatous and squamous components suggests monoclonality in ASC. PMID:26923333

  3. 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...

  4. 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...

  5. 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...

  6. 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...

  7. 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...

  8. Haplotypes and mutations in Wilson disease

    SciTech Connect

    Thomas, G.R.; Roberts, E.A.; Cox, D.W.

    1995-06-01

    Wilson disease is a disorder of copper transport, resulting in neurological and hepatic damage due to copper toxicity. We have recently identified >20 mutations in the copper-transporting ATPase defective in this disease. Given the difficulties of searching for mutations in a gene spanning >80 kb of genomic DNA, haplotype data are important as a guide to mutation detection. Here we examine the haplotypes associated with specific mutations. We have extended previous studies of DNA haplotypes of dinucleotide-repeat polymorphisms (CA repeats) in the Wilson disease region to include an additional marker, in 58 families. These haplotypes, combining three markers (D13S314, D12S316, and D13S301), are usually specific for each different mutation, even though highly polymorphic CA repeat markers have been used. Haplotypes, as well as their accompanying mutations, differ between populations. In the patients whom we have studied, the haplotype data indicate that as many as 20 mutations may still be unidentified. The use of the haplotypes that we have identified provides an important guide for the identification of known mutations and can facilitate future mutation searches. 15 refs., 1 fig., 2 tabs.

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

    PubMed Central

    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

    2015-01-01

    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. PMID:26084293

  10. CF Mutation Panel

    MedlinePlus

    ... page: Was this page helpful? Also known as: Cystic Fibrosis Genotyping; CF DNA Analysis; CF Gene Mutation Panel; CF Molecular Genetic Testing Formal name: Cystic Fibrosis Gene Mutation Panel Related tests: Sweat Test ; Trypsinogen ; ...

  11. 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

  12. Immunogenicity of somatic mutations in human gastrointestinal cancers.

    PubMed

    Tran, Eric; Ahmadzadeh, Mojgan; Lu, Yong-Chen; Gros, Alena; Turcotte, Simon; Robbins, Paul F; Gartner, Jared J; Zheng, Zhili; Li, Yong F; Ray, Satyajit; Wunderlich, John R; Somerville, Robert P; Rosenberg, Steven A

    2015-12-11

    It is unknown whether the human immune system frequently mounts a T cell response against mutations expressed by common epithelial cancers. Using a next-generation sequencing approach combined with high-throughput immunologic screening, we demonstrated that tumor-infiltrating lymphocytes (TILs) from 9 out of 10 patients with metastatic gastrointestinal cancers contained CD4(+) and/or CD8(+) T cells that recognized one to three neo-epitopes derived from somatic mutations expressed by the patient's own tumor. There were no immunogenic epitopes shared between these patients. However, we identified in one patient a human leukocyte antigen-C*08:02-restricted T cell receptor from CD8(+) TILs that targeted the KRAS(G12D) hotspot driver mutation found in many human cancers. Thus, a high frequency of patients with common gastrointestinal cancers harbor immunogenic mutations that can potentially be exploited for the development of highly personalized immunotherapies. PMID:26516200

  13. Mutational signatures of ionizing radiation in second malignancies.

    PubMed

    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; 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

  14. Heterogeneity of genomic evolution and mutational profiles in multiple myeloma.

    PubMed

    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

  15. 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

  16. Predictions of Geospace Drivers By the Probability Distribution Function Model

    NASA Astrophysics Data System (ADS)

    Bussy-Virat, C.; Ridley, A. J.

    2014-12-01

    Geospace drivers like the solar wind speed, interplanetary magnetic field (IMF), and solar irradiance have a strong influence on the density of the thermosphere and the near-Earth space environment. This has important consequences on the drag on satellites that are in low orbit and therefore on their position. One of the basic problems with space weather prediction is that these drivers can only be measured about one hour before they affect the environment. In order to allow for adequate planning for some members of the commercial, military, or civilian communities, reliable long-term space weather forecasts are needed. The study presents a model for predicting geospace drivers up to five days in advance. This model uses the same general technique to predict the solar wind speed, the three components of the IMF, and the solar irradiance F10.7. For instance, it uses Probability distribution functions (PDFs) to relate the current solar wind speed and slope to the future solar wind speed, as well as the solar wind speed to the solar wind speed one solar rotation in the future. The PDF Model has been compared to other models for predictions of the speed. It has been found that it is better than using the current solar wind speed (i.e., persistence), and better than the Wang-Sheeley-Arge Model for prediction horizons of 24 hours. Once the drivers are predicted, and the uncertainty on the drivers are specified, the density in the thermosphere can be derived using various models of the thermosphere, such as the Global Ionosphere Thermosphere Model. In addition, uncertainties on the densities can be estimated, based on ensembles of simulations. From the density and uncertainty predictions, satellite positions, as well as the uncertainty in those positions can be estimated. These can assist operators in determining the probability of collisions between objects in low Earth orbit.

  17. Colorectal cancer prognosis: is it all mutation, mutation, mutation?

    PubMed Central

    Hassan, A B; Paraskeva, C

    2005-01-01

    For the 500 000 new cases of colorectal cancer in the world each year, identification of patients with a worse prognosis and those who are more likely to respond to treatment is a challenge. There is an increasing body of evidence correlating genetic mutations with outcome in tumours derived from human colorectal cancer cohorts. K-ras, but not p53 or APC, mutations appear to be associated with poorer overall survival in colorectal cancer patients. PMID:16099785

  18. Spectrum of mutations in alpha-mannosidosis.

    PubMed Central

    Berg, T; Riise, H M; Hansen, G M; Malm, D; Tranebjaerg, L; Tollersrud, O K; Nilssen, O

    1999-01-01

    alpha-Mannosidosis is an autosomal recessive disorder caused by deficiency of lysosomal alpha-mannosidase (LAMAN). The resulting intracellular accumulation of mannose-containing oligosaccharides leads to mental retardation, hearing impairment, skeletal changes, and immunodeficiency. Recently, we reported the first alpha-mannosidosis-causing mutation affecting two Palestinian siblings. In the present study 21 novel mutations and four polymorphic amino acid positions were identified by the screening of 43 patients, from 39 families, mainly of European origin. Disease-causing mutations were identified in 72% of the alleles and included eight splicing, six missense, and three nonsense mutations, as well as two small insertions and two small deletions. In addition, Southern blot analysis indicated rearrangements in some alleles. Most mutations were private or occurred in two or three families, except for a missense mutation resulting in an R750W substitution. This mutation was found in 13 patients, from different European countries, and accounted for 21% of the disease alleles. Although there were clinical variations among the patients, no significant LAMAN activity could be detected in any of the fibroblast cultures. In addition, no correlation between the types of mutations and the clinical manifestations was evident. PMID:9915946

  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. PMID:27571422

  20. 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

  1. Identification of significantly mutated regions across cancer types highlights a rich landscape of functional molecular alterations

    PubMed Central

    Araya, Carlos L.; Cenik, Can; Reuter, Jason A.; Kiss, Gert; Pande, Vijay S.; Snyder, Michael P.; Greenleaf, William J.

    2015-01-01

    Cancer sequencing studies have primarily identified cancer-driver genes by the accumulation of protein-altering mutations. An improved method would be annotation-independent, sensitive to unknown distributions of functions within proteins, and inclusive of non-coding drivers. We employed density-based clustering methods in 21 tumor types to detect variably-sized significantly mutated regions (SMRs). SMRs reveal recurrent alterations across a spectrum of coding and non-coding elements, including transcription factor binding sites and untranslated regions mutated in up to ∼15% of specific tumor types. SMRs reveal spatial clustering of mutations at molecular domains and interfaces, often with associated changes in signaling. Mutation frequencies in SMRs demonstrate that distinct protein regions are differentially mutated among tumor types, as exemplified by a linker region of PIK3CA in which biophysical simulations suggest mutations affect regulatory interactions. The functional diversity of SMRs underscores both the varied mechanisms of oncogenic misregulation and the advantage of functionally-agnostic driver identification. PMID:26691984

  2. ASXL1 and DNMT3A mutation in a cytogenetically normal B3 thymoma.

    PubMed

    Belani, R; Oliveira, G; Erikson, G A; Ra, S; Schechter, M S; Lee, J K; Shipman, W J; Haaser, S M; Torkamani, A

    2014-01-01

    The molecular drivers of thymoma are poorly understood. Outside of the identification of rarely occurring epidermal growth factor receptor and v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog mutations via candidate gene sequencing, mutations in common cancer genes have yet to be observed. Only a single thymoma genome sequence has been previously reported, with no mutations in known cancer genes identified. Thus, we attempted to identify somatic driver mutations in a cytogenetically normal thymoma. A stage IVB type B3 thymoma from a 47-year-old male of Asian descent with no history of myasthenia gravis or other autoimmune condition was genomically evaluated. Exome sequencing and low-pass whole-genome sequencing was performed to identify somatic point mutations, copy number changes and structural variants. Mutations in known tumor suppressors DNMT3A (p.G728D) and ASXL1 (p.E657fs), consistent with mutations of known consequence in acute myeloid leukemia, were identified. Contrary to a previous report, this finding suggests the genetic etiology of thymomas may not be fundamentally distinct from other tumor types. Rather, these findings suggest that further sequencing of cytogenetically normal thymoma samples should reveal the specific molecular drivers of thymoma. PMID:25000259

  3. 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.

  4. 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…

  5. 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…

  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. 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

  8. 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

  9. Mutations driving CLL and their evolution in progression and relapse.

    PubMed

    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 L; Rosenberg, Mara; Hess, Julian M; Edelmann, Jennifer; Kless, Sabrina; Kneba, Michael; Ritgen, Matthias; Fink, Anna; Fischer, Kirsten; Gabriel, Stacey; Lander, Eric S; Nowak, Martin A; Döhner, Hartmut; Hallek, Michael; Neuberg, Donna; Getz, Gad; Stilgenbauer, Stephan; Wu, Catherine J

    2015-10-22

    Which genetic alterations drive tumorigenesis and how they evolve over the course of disease and therapy are central questions in cancer biology. Here we identify 44 recurrently mutated genes and 11 recurrent somatic copy number variations through whole-exome sequencing of 538 chronic lymphocytic leukaemia (CLL) and matched germline DNA samples, 278 of which were collected in a prospective clinical trial. These include previously unrecognized putative cancer drivers (RPS15, IKZF3), and collectively identify RNA processing and export, MYC activity, and MAPK signalling as central pathways involved in CLL. Clonality analysis of this large data set 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 data sets of clinically informative samples enable the discovery of novel genes associated with cancer, the network of relationships between the driver events, and their impact on disease relapse and clinical outcome. PMID:26466571

  10. Hazard awareness of construction site dumper drivers.

    PubMed

    Bohm, Jonathan; Harris, Don

    2012-01-01

    In UK's construction industry, site dumpers cause more serious accidents than in any other type of construction plant. Previous research has indicated that driver behaviour plays a pivotal role in the vast majority of these accidents. Using a mental models-based approach, 20 dumper drivers were interviewed with regard to the process by which several typical types of accident occurred. It was found that drivers were generally well-informed about the hazards of driving dumpers on a construction site. However, the findings also exposed some critical knowledge gaps, which could increase a driver's chances of an accident. Educational material relating to these knowledge deficiencies could easily be prepared and incorporated into revised construction information leaflets or driver training courses. PMID:22995134

  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. Driver alertness detection using Google Glasses

    NASA Astrophysics Data System (ADS)

    Liu, Kuang-Yu; Huang, Chung-Lin

    2015-03-01

    This paper proposes an intelligent vehicle system (ITS) to monitor the driver driving behavior. Based on the first-person vision (FPV) technology (or Google glasses), our system can detect the vehicle exterior/interior scene from driver's viewpoint and estimate driver gazing direction. First, we use "bag of words" image classification approach by applying FAST and BRIEF feature descriptor in the dataset. Then, we use vocabulary dictionary to encode an input image as feature vectors. Finally, we apply SVM classifier to identify whether the input image is vehicle interior scene or not to monitor the driver driving attention. Second, we find the correspondence between the images of the Google glasses and the camera mounted on the wind shield of the vehicle to estimate the gazing direction of the driver. In the experiments, we illustrate the effectiveness of our system.

  13. 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.

  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. 49 CFR 395.8 - Driver's record of duty status.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... SERVICE OF DRIVERS § 395.8 Driver's record of duty status. (a) Except for a private motor carrier of... connection with such duty activities shall make the driver and/or the carrier liable to prosecution. (f)...

  16. 49 CFR 395.8 - Driver's record of duty status.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... SERVICE OF DRIVERS § 395.8 Driver's record of duty status. (a) Except for a private motor carrier of... connection with such duty activities shall make the driver and/or the carrier liable to prosecution. (f)...

  17. Whole-genome mutational landscape and characterization of noncoding and structural mutations in liver cancer.

    PubMed

    Fujimoto, Akihiro; Furuta, Mayuko; Totoki, Yasushi; Tsunoda, Tatsuhiko; Kato, Mamoru; Shiraishi, Yuichi; Tanaka, Hiroko; Taniguchi, Hiroaki; Kawakami, Yoshiiku; Ueno, Masaki; Gotoh, Kunihito; Ariizumi, Shun-Ichi; Wardell, Christopher P; Hayami, Shinya; Nakamura, Toru; Aikata, Hiroshi; Arihiro, Koji; Boroevich, Keith A; Abe, Tetsuo; Nakano, Kaoru; Maejima, Kazuhiro; Sasaki-Oku, Aya; Ohsawa, Ayako; Shibuya, Tetsuo; Nakamura, Hiromi; Hama, Natsuko; Hosoda, Fumie; Arai, Yasuhito; Ohashi, Shoko; Urushidate, Tomoko; Nagae, Genta; Yamamoto, Shogo; Ueda, Hiroki; Tatsuno, Kenji; Ojima, Hidenori; Hiraoka, Nobuyoshi; Okusaka, Takuji; Kubo, Michiaki; Marubashi, Shigeru; Yamada, Terumasa; Hirano, Satoshi; Yamamoto, Masakazu; Ohdan, Hideki; Shimada, Kazuaki; Ishikawa, Osamu; Yamaue, Hiroki; Chayama, Kazuki; Miyano, Satoru; Aburatani, Hiroyuki; Shibata, Tatsuhiro; Nakagawa, Hidewaki

    2016-05-01

    Liver cancer, which is most often associated with virus infection, is prevalent worldwide, and its underlying etiology and genomic structure are heterogeneous. Here we provide a whole-genome landscape of somatic alterations in 300 liver cancers from Japanese individuals. Our comprehensive analysis identified point mutations, structural variations (STVs), and virus integrations, in noncoding and coding regions. We discovered mutational signatures related to liver carcinogenesis and recurrently mutated coding and noncoding regions, such as long intergenic noncoding RNA genes (NEAT1 and MALAT1), promoters, CTCF-binding sites, and regulatory regions. STV analysis found a significant association with replication timing and identified known (CDKN2A, CCND1, APC, and TERT) and new (ASH1L, NCOR1, and MACROD2) cancer-related genes that were recurrently affected by STVs, leading to altered expression. These results emphasize the value of whole-genome sequencing analysis in discovering cancer driver mutations and understanding comprehensive molecular profiles of liver cancer, especially with regard to STVs and noncoding mutations. PMID:27064257

  18. Evolution on a Lattice under Strong Mutation

    NASA Astrophysics Data System (ADS)

    Otwinowski, Jakub; Boettcher, Stefan

    2011-03-01

    The most common approach to study biological evolution in a population considers mutations to arise one at a time, and spread to the whole population. However, recent experimental work has shown that under conditions of strong mutation and strong selection, multiple mutations may arise simultaneously. Such overlapping mutations compete with each other and make the results difficult to analyse. Theorists are working on understanding the relationships between different parameters such as population size, mutation rate, and selection coefficients, in the way they affect observables such as the speed of evolution, and the probability of fixation. We have shown with simulations that under additional spatial constraints the dynamics are very different compared to well-mixed populations. A surface in fitness space evolves, akin to surface growth phenomena, with non-trivial power-law exponents. The result is that the speed of evolution is restricted and the probability of fixation is reduced. With support from the NSF through grant DMR-0812204.

  19. MutationAligner: a resource of recurrent mutation hotspots in protein domains in cancer.

    PubMed

    Gauthier, Nicholas Paul; Reznik, Ed; Gao, Jianjiong; Sumer, Selcuk Onur; Schultz, Nikolaus; Sander, Chris; Miller, Martin L

    2016-01-01

    The MutationAligner web resource, available at http://www.mutationaligner.org, enables discovery and exploration of somatic mutation hotspots identified in protein domains in currently (mid-2015) more than 5000 cancer patient samples across 22 different tumor types. Using multiple sequence alignments of protein domains in the human genome, we extend the principle of recurrence analysis by aggregating mutations in homologous positions across sets of paralogous genes. Protein domain analysis enhances the statistical power to detect cancer-relevant mutations and links mutations to the specific biological functions encoded in domains. We illustrate how the MutationAligner database and interactive web tool can be used to explore, visualize and analyze mutation hotspots in protein domains across genes and tumor types. We believe that MutationAligner will be an important resource for the cancer research community by providing detailed clues for the functional importance of particular mutations, as well as for the design of functional genomics experiments and for decision support in precision medicine. MutationAligner is slated to be periodically updated to incorporate additional analyses and new data from cancer genomics projects. PMID:26590264

  20. MutationAligner: a resource of recurrent mutation hotspots in protein domains in cancer

    PubMed Central

    Gauthier, Nicholas Paul; Reznik, Ed; Gao, Jianjiong; Sumer, Selcuk Onur; Schultz, Nikolaus; Sander, Chris; Miller, Martin L.

    2016-01-01

    The MutationAligner web resource, available at http://www.mutationaligner.org, enables discovery and exploration of somatic mutation hotspots identified in protein domains in currently (mid-2015) more than 5000 cancer patient samples across 22 different tumor types. Using multiple sequence alignments of protein domains in the human genome, we extend the principle of recurrence analysis by aggregating mutations in homologous positions across sets of paralogous genes. Protein domain analysis enhances the statistical power to detect cancer-relevant mutations and links mutations to the specific biological functions encoded in domains. We illustrate how the MutationAligner database and interactive web tool can be used to explore, visualize and analyze mutation hotspots in protein domains across genes and tumor types. We believe that MutationAligner will be an important resource for the cancer research community by providing detailed clues for the functional importance of particular mutations, as well as for the design of functional genomics experiments and for decision support in precision medicine. MutationAligner is slated to be periodically updated to incorporate additional analyses and new data from cancer genomics projects. PMID:26590264

  1. Targeting therapeutic liabilities engendered by PIK3R1 mutations for cancer treatment.

    PubMed

    Cheung, Lydia Wt; Mills, Gordon B

    2016-02-01

    The regulatory subunit of PI3K, p85α (encoded by PIK3R1), binds, stabilizes and inhibits the PI3K p110 catalytic subunit. Functional characterization of PIK3R1 mutations has identified not only hypomorphs with reduced inhibition of p110, but also hypomorphs and dominant negative mutants that disrupt a novel regulatory role of p85α on PTEN or neomorphs that activate unexpected signaling pathways. The diverse phenotypic spectrum of these PIK3R1 driver mutations underscores the need for different treatment strategies targeting tumors harboring these mutations. This article describes the functional consequences of the spectrum of PIK3R1 driver mutations and therapeutic liabilities they may engender. PMID:26807692

  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. 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.

  4. Proposal of Boost Motor Driver with Electric Double Layer Capacitor

    NASA Astrophysics Data System (ADS)

    Matsumoto, Hirokazu

    This paper proposes a boost motor driver with EDLC as a new boost motor driver. The boost motor driver has two advantages against conventional boost motor drivers. The first is that the boost motor driver can decrease an input power peak. The second is that the boost motor driver can charge almost all regeneration energy. The dynamic performance of boost voltage and these advantages of the boost motor driver is simulated. From the simulation, results that the boost motor driver has good performance are derived.

  5. 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. PMID:21376864

  6. [Drivers license qualification for epileptics].

    PubMed

    Egli, M; Hartmann, H; Hess, R

    1977-03-26

    The question whether a person with epilepsy qualified for a driving licence must be examined from the point of view of the individual as well as that of the community. The general public should be protected against unduly high risks from epileptic drivers, whereas the patient has a right to live as normal a life as possible, which includes driving an automobile. Too rigid criteria for obtaining the license increase the number of persons who evade medical control and drive "illegally". To require physicians to report their epileptic patients to the authorities would be counterproductive; it would also destroy the personal confidence between physician and patient which is so essential for successful treatment. Epileptic persons endanger safety on the road only slightly: 0.1-0.3% of all traffic accidents are due to epileptic seizures. In contrast, abuse of alcohol plays a major role in 6-9% of all accidents, whereas 80-90% are attributable to evident mistakes by the driver. Epileptic patients under regular medical supervision who are licenced on grounds of approved criteria do not cause more accidents than the general population. A dangerous group are, however, those with mental alterations (organic or reactive) and particularly patients with aggressive and expansive-compensatory traits, as well as those driving without permission. Prognostic criteria as to the further course of the disease are paramount for the assessment of qualification for the licence. The following rules have proved their worth: 2 years freedom from seizures (with or without therapy), no abnormalities specific for epilepsy in the EEG, no serious mental changes, regular medical supervision and treatment mus be guaranteed. Departures from these rules should be confined to exceptional cases with the consent of a physician specialized in epileptology. The same holds for admission to higher categories of driving licence, the only practical eventuality being category D (lorries), and even this only in

  7. 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. PMID:26771893

  8. 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

  9. Evaluating clinical change and visual function concerns in drivers and non-drivers with glaucoma

    PubMed Central

    Janz, Nancy K.; Musch, David C.; Gillespie, Brenda W.; Wren, Patricia A.; Niziol, Leslie M.

    2012-01-01

    Purpose To compare drivers and non-drivers, and describe the specific concerns of drivers, among individuals with glaucoma. Methods 607 newly-diagnosed glaucoma patients from 14 clinical centers of the Collaborative Initial Glaucoma Treatment Study were randomly assigned to initial medicine or surgery and followed every six months for < 5 years. Driving status (drivers vs. non-drivers) as well as patient-reported visual function was determined by the Visual Activities Questionnaire and the National Eye Institute Visual Function Questionnaire. Clinical evaluation included visual field mean deviation (MD) and visual acuity. Statistical comparisons were made using t, Chi-square, and exact tests, regression, and Rasch analyses. Results Drivers were more likely than non-drivers to be male, white, married, employed, and have more education, higher income, and fewer co-morbidities. Over 50% of drivers reported at least “some” difficulty performing tasks involving glare, whereas 22% reported at least “some” difficulty with tasks requiring peripheral vision. At 54 months, drivers with moderate/severe bilateral visual field loss (VFL) reported greater difficulty with night driving and tasks involving visual search and visual processing speed than drivers with less bilateral VFL (all p-values <0.05). While those who remained drivers over follow-up had better MD in both eyes than those who became non-drivers due to eyesight, a number of drivers had marked VFL. Conclusion Inquiring about specific difficulties with tasks related to glare, visual processing speed, visual search and peripheral vision in driving, especially among patients with substantial bilateral VF damage, will enable physicians to more effectively counsel patients regarding driving. PMID:19060263

  10. The role of mutation of metabolism-related genes in genomic hypermethylation.

    PubMed

    Waterfall, Joshua J; Killian, J Keith; Meltzer, Paul S

    2014-12-01

    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. PMID:25111818

  11. 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

  12. Validation of Deleterious Mutations in Vorderwald Cattle.

    PubMed

    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

  13. Important role of indels in somatic mutations of human cancer genes

    PubMed Central

    2010-01-01

    Background Cancer is clonal proliferation that arises owing to mutations in a subset of genes that confer growth advantage. More and more cancer related genes are found to have accumulated somatic mutations. However, little has been reported about mutational patterns of insertions/deletions (indels) in these genes. Results We analyzed indels' abundance and distribution, the relative ratio between indels and somatic base substitutions and the association between those two forms of mutations in a large number of somatic mutations in the Catalogue of Somatic Mutations in Cancer database. We found a strong correlation between indels and base substitutions in cancer-related genes and showed that they tend to concentrate at the same locus in the coding sequences within the same samples. More importantly, a much higher proportion of indels were observed in somatic mutations, as compared to meiotic ones. Furthermore, our analysis demonstrated a great diversity of indels at some loci of cancer-related genes. Particularly in the genes with abundant mutations, the proportion of 3n indels in oncogenes is 7.9 times higher than that in tumor suppressor genes. Conclusions There are three distinct patterns of indel distribution in somatic mutations: high proportion, great abundance and non-random distribution. Because of the great influence of indels on gene function (e.g., the effect of frameshift mutation), these patterns indicate that indels are frequently under positive selection and can often be the 'driver mutations' in oncogenesis. Such driver forces can better explain why much less frameshift mutations are in oncogenes while much more in tumor suppressor genes, because of their different function in oncogenesis. These findings contribute to our understanding of mutational patterns and the relationship between indels and cancer. PMID:20807447

  14. mutation3D: Cancer Gene Prediction Through Atomic Clustering of Coding Variants in the Structural Proteome.

    PubMed

    Meyer, Michael J; Lapcevic, Ryan; Romero, Alfonso E; Yoon, Mark; Das, Jishnu; Beltrán, Juan Felipe; Mort, Matthew; Stenson, Peter D; Cooper, David N; Paccanaro, Alberto; Yu, Haiyuan

    2016-05-01

    A new algorithm and Web server, mutation3D (http://mutation3d.org), proposes driver genes in cancer by identifying clusters of amino acid substitutions within tertiary protein structures. We demonstrate the feasibility of using a 3D clustering approach to implicate proteins in cancer based on explorations of single proteins using the mutation3D Web interface. On a large scale, we show that clustering with mutation3D is able to separate functional from nonfunctional mutations by analyzing a combination of 8,869 known inherited disease mutations and 2,004 SNPs overlaid together upon the same sets of crystal structures and homology models. Further, we present a systematic analysis of whole-genome and whole-exome cancer datasets to demonstrate that mutation3D identifies many known cancer genes as well as previously underexplored target genes. The mutation3D Web interface allows users to analyze their own mutation data in a variety of popular formats and provides seamless access to explore mutation clusters derived from over 975,000 somatic mutations reported by 6,811 cancer sequencing studies. The mutation3D Web interface is freely available with all major browsers supported. PMID:26841357

  15. 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.

  16. 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. PMID:22658949

  17. Recurrent neomorphic mutations of MTOR in central nervous system and testicular germ cell tumors may be targeted for therapy.

    PubMed

    Ichimura, Koichi; Fukushima, Shintaro; Totoki, Yasushi; Matsushita, Yuko; Otsuka, Ayaka; Tomiyama, Arata; Niwa, Tohru; Takami, Hirokazu; Nakamura, Taishi; Suzuki, Tomonari; Fukuoka, Kohei; Yanagisawa, Takaaki; Mishima, Kazuhiko; Nakazato, Yoichi; Hosoda, Fumie; Narita, Yoshitaka; Shibui, Soichiro; Yoshida, Akihiko; Mukasa, Akitake; Saito, Nobuhito; Kumabe, Toshihiro; Kanamori, Masayuki; Tominaga, Teiji; Kobayashi, Keiichi; Shimizu, Saki; Nagane, Motoo; Iuchi, Toshihiko; Mizoguchi, Masahiro; Yoshimoto, Koji; Tamura, Kaoru; Maehara, Taketoshi; Sugiyama, Kazuhiko; Nakada, Mitsutoshi; Sakai, Keiichi; Kanemura, Yonehiro; Nonaka, Masahiro; Asai, Akio; Yokogami, Kiyotaka; Takeshima, Hideo; Kawahara, Nobutaka; Takayama, Tatsuya; Yao, Masahiro; Kato, Mamoru; Nakamura, Hiromi; Hama, Natsuko; Sakai, Ryuichi; Ushijima, Toshikazu; Matsutani, Masao; Shibata, Tatsuhiro; Nishikawa, Ryo

    2016-06-01

    Germ cell tumors constitute a heterogeneous group that displays a broad spectrum of morphology. They often arise in testes; however, extragonadal occurrence, in particular brain, is not uncommon, and whether they share a common pathogenesis is unknown. We performed whole exome sequencing in 41 pairs of central nervous system germ cell tumors (CNS GCTs) of various histology and their matched normal tissues. We then performed targeted sequencing of 41 selected genes in a total of 124 CNS GCTs, 65 testicular germ cell tumors (tGCTs) and 8 metastatic GCTs to the CNS. The results showed that mutually exclusive mutations of genes involved in the MAPK pathway were most common (48.4 %), typically in KIT (27.4 %), followed by those in the PI3K pathway (12.9 %), particularly in MTOR (6.5 %), among the 124 CNS GCTs. Pure germinomas and non-germinomatous germ cell tumors (NGGCTs), as well as CNS and testicular GCTs, showed similar mutational profiles, suggesting that GCTs share a common molecular pathogenesis. Mutated MTOR identified in CNS GCTs upregulated phosphorylation of the AKT pathway proteins including AKT and 4EBP1 in nutrient-deprived conditions and enhanced soft-agar colony formation; both events were suppressed in a dose-dependent manner by addition of the MTOR inhibitor pp242. Our findings indicate that the dominant genetic drivers of GCTs regardless of the site of origin are activation of the MAPK and/or PI3K pathways by somatic point mutations. Mutated MTOR represents a potential target for novel targeted therapies for refractory GCTs. PMID:26956871

  18. Timing, rates and spectra of human germline mutation

    PubMed Central

    Lindsay, Sarah J.; Hardwick, Robert J.; Alexandrov, Ludmil B.; Turki, Saeed Al; Dominiczak, Anna; Morris, Andrew; Porteous, David; Smith, Blair; Stratton, Michael R.; Hurles, Matthew E.

    2015-01-01

    Germline mutations are a driving force behind genome evolution and genetic disease. We investigated genome-wide mutation rates and spectra in multi-sibling families. Mutation rate increased with paternal age in all families, but the number of additional mutations per year differed more than two-fold between families. Meta-analysis of 6,570 mutations showed that germline methylation influences mutation rates. In contrast to somatic mutations, we found remarkable consistency of germline mutation spectra between the sexes and at different paternal ages. 3.8% of mutations were mosaic in the parental germline, resulting in 1.3% of mutations being shared between 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. PMID:26656846

  19. 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. PMID:26656846

  20. SOX10 mutations mimic isolated hearing loss.

    PubMed

    Pingault, V; Faubert, E; Baral, V; Gherbi, S; Loundon, N; Couloigner, V; Denoyelle, F; Noël-Pétroff, N; Ducou Le Pointe, H; Elmaleh-Bergès, M; Bondurand, N; Marlin, S

    2015-10-01

    Ninety genes have been identified to date that are involved in non-syndromic hearing loss, and more than 300 different forms of syndromic hearing impairment have been described. Mutations in SOX10, one of the genes contributing to syndromic hearing loss, induce a large range of phenotypes, including several subtypes of Waardenburg syndrome and Kallmann syndrome with deafness. In addition, rare mutations have been identified in patients with isolated signs of these diseases. We used the recent characterization of temporal bone imaging aspects in patients with SOX10 mutations to identify possible patients with isolated hearing loss due to SOX10 mutation. We selected 21 patients with isolated deafness and temporal bone morphological defects for mutational screening. We identified two SOX10 mutations and found that both resulted in a non-functional protein in vitro. Re-evaluation of the two affected patients showed that both had previously undiagnosed olfactory defects. Diagnosis of anosmia or hyposmia in young children is challenging, and particularly in the absence of magnetic resonance imaging (MRI), SOX10 mutations can mimic non-syndromic hearing impairment. MRI should complete temporal bones computed tomographic scan in the management of congenital deafness as it can detect brain anomalies, cochlear nerve defects, and olfactory bulb malformation in addition to inner ear malformations. PMID:25256313

  1. 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.

  2. 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. PMID:24587315

  3. 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.

  4. 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

  5. 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

  6. Adenoma development in familial adenomatous polyposis and MUTYH-associated polyposis: somatic landscape and driver genes.

    PubMed

    Rashid, Mamunur; Fischer, Andrej; Wilson, Cathy H; Tiffen, Jessamy; Rust, Alistair G; Stevens, Philip; Idziaszczyk, Shelley; Maynard, Julie; Williams, Geraint T; Mustonen, Ville; Sampson, Julian R; Adams, David J

    2016-01-01

    Familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP) are inherited disorders associated with multiple colorectal adenomas that lead to a very high risk of colorectal cancer. The somatic mutations that drive adenoma development in these conditions have not been investigated comprehensively. In this study we performed analysis of paired colorectal adenoma and normal tissue DNA from individuals with FAP or MAP, sequencing 14 adenoma whole exomes (eight MAP, six FAP), 55 adenoma targeted exomes (33 MAP, 22 FAP) and germline DNA from each patient, and a further 63 adenomas by capillary sequencing (41 FAP, 22 MAP). With these data we examined the profile of mutated genes, the mutational signatures and the somatic mutation rates, observing significant diversity in the constellations of mutated driver genes in different adenomas, and loss-of-function mutations in WTX (9%; p < 9.99e-06), a gene implicated in regulation of the WNT pathway and p53 acetylation. These data extend our understanding of the early events in colorectal tumourigenesis in the polyposis syndromes. PMID:26414517

  7. 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.

  8. 29 CFR 782.4 - Drivers' helpers.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... interstate or foreign commerce, because, in the case of an accident or other emergency and in other respects...-road operation).) It should be noted also that an employee, to be exempted as a driver's “helper”...

  9. 29 CFR 782.4 - Drivers' helpers.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... interstate or foreign commerce, because, in the case of an accident or other emergency and in other respects...-road operation).) It should be noted also that an employee, to be exempted as a driver's “helper”...

  10. 29 CFR 782.4 - Drivers' helpers.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... interstate or foreign commerce, because, in the case of an accident or other emergency and in other respects...-road operation).) It should be noted also that an employee, to be exempted as a driver's “helper”...

  11. 29 CFR 782.4 - Drivers' helpers.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... interstate or foreign commerce, because, in the case of an accident or other emergency and in other respects...-road operation).) It should be noted also that an employee, to be exempted as a driver's “helper”...

  12. 29 CFR 782.4 - Drivers' helpers.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... interstate or foreign commerce, because, in the case of an accident or other emergency and in other respects...-road operation).) It should be noted also that an employee, to be exempted as a driver's “helper”...

  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. A Superconducting Linac Proton Driver at Fermilab

    NASA Astrophysics Data System (ADS)

    Foster, G. William

    2004-05-01

    A proton driver has emerged as the leading candidate for Fermilab's next near-term accelerator project. The preferred technical solution is an 8 GeV superconducting linac based on technology developed for TESLA and the Spallation Neutron Source (SNS). Its primary mission is to serve as a single-stage H- injector to prepare 2 MW "Super-Beams" for Neutrino experiments using the Fermilab Main Injector. The linac can also accelerate electrons, protons, and relativistic muons, permitting future applications such as a driver for an FEL, a long-pulse spallation source, the driver for an intense 8 GeV neutrino or kaon program, and potential applications to a neutrino factory or muon collider. The technical design of the 8 GeV linac, as well as the design of an alternative synchrotron based proton driver, will be described along with plans for project proposal and construction.

  15. Stationary mutation models.

    PubMed

    Simonsson, Ivar; Mostad, Petter

    2016-07-01

    Probability calculations for relationship inference based on DNA tests are often performed with computer packages such as Familias. When mutations are assumed to be a possibility, one may notice a curious and problematic effect of including untested parents: results tend to change slightly. In this paper, we trace this effect back to fundamental model-formulating issues which can only be resolved by using stationary mutation models. We present several methods for obtaining such stationary mutation matrices from original mutation matrices, and evaluate essential properties of these methods. Our conclusion is that typically, stationary mutation models can be obtained, but for many types of markers, it may be impossible to combine specific biologically reasonable requirements for a mutation matrix with the requirement of stationarity. PMID:27231805

  16. Driving Decisions when Leaving Electronic Music Dance Events: Driver, Passenger, and Group Effects

    PubMed Central

    Johnson, Mark B.; Voas, Robert B.; Miller, Brenda A.

    2013-01-01

    Objectives The goal of this paper was to identify characteristics of drivers and passengers that predicted peer-groups whose drivers exit dance clubs with alcohol levels indicative of impairment (BAC ≥ .05 grams per deciliter ([g/dL]). Methods We used the portal survey methodology to randomly sample groups of EMDE patrons as they entered and exited a club. From May through November 2010, data were collected from 38 EMDEs hosted by 8 clubs in the San Francisco Bay area. Data included in these analyses are results from breath samples for measuring blood alcohol concentration (BAC) and self-report data on demographics, recent drinking history drinking, drinking intentions, travel to and from the clubs, and the familiarity/experience with other group members. These data were collected from a subset of 175 drivers and 272 passengers. Results Although drivers drank less than passengers, one driver in five groups had a BAC indicative of elevated crash risk (BAC ≥ .05 g/dL). Groups of drivers and/or passengers with a recent history of binge drinking were more likely to have drivers with BACs ≥ .05 g/dL. One unanticipated finding was that drivers who knew more group members relatively well were more likely to exit the club with a BAC ≥ .05 g/dL. Additionally, we found that groups with all female passengers were at greater risk for having a driver whose BAC was ≥ .05 g/dL. Conclusions Some group characteristics predicted drivers who exit clubs with BACs ≥ .05 g/dL. One intervention strategy to promote safety might be to encourage group members to reconsider who is sober enough to drive away from the club; for some groups, a change of drivers would be a safer choice, as a passenger may have a relatively safe BAC. Groups of females appear to have a particularly elevated risk of having a driver whose BAC exceeds .05 g/dL, and new intervention efforts should be particularly directed to these at-risk groups. PMID:23137088

  17. BRAF mutations in non-small cell lung cancer: has finally Janus opened the door?

    PubMed

    Caparica, Rafael; de Castro, Gilberto; Gil-Bazo, Ignacio; Caglevic, Christian; Calogero, Raffaele; Giallombardo, Marco; Santos, Edgardo S; Raez, Luis E; Rolfo, Christian

    2016-05-01

    B-Raf mutations occur in about 1-2% of non-small cell lung cancers (NSCLC). These mutations generate a permanent activation of the mitogen activated protein kinase (MAPK) pathway, which promotes tumor growth and proliferation. In the present review, we discuss B-Raf mutation epidemiology, diagnostic methods to detect B-Raf mutations, the role of B-Raf as a driver mutation and a potential therapeutic target in NSCLC. The results of clinical trials involving B-Raf or MAPK pathway inhibitors for the treatment of NSCLC are also discussed. Clinical trials evaluating B-Raf inhibitors in BRAF mutated NSCLC patients have shown promising results, and larger prospective studies are warranted to validate these findings. Enrollment of these patients in clinical trials is an interesting strategy to offer a potentially more effective and less toxic targeted therapy. PMID:26960735

  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. 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).

  20. Consistent drivers of plant biodiversity across managed ecosystems.

    PubMed

    Minden, Vanessa; Scherber, Christoph; Cebrián Piqueras, Miguel A; Trinogga, Juliane; Trenkamp, Anastasia; Mantilla-Contreras, Jasmin; Lienin, Patrick; Kleyer, Michael

    2016-05-19

    Ecosystems managed for production of biomass are often characterized by low biodiversity because management aims to optimize single ecosystem functions (i.e. yield) involving deliberate selection of species or cultivars. In consequence, considerable differences in observed plant species richness and productivity remain across systems, and the drivers of these differences have remained poorly resolved so far. In addition, it has remained unclear if species richness feeds back on ecosystem functions such as yield in real-world systems. Here, we establish N = 360 experimental plots across a broad range of managed ecosystems in several European countries, and use structural equation models to unravel potential drivers of plant species richness. We hypothesize that the relationships between productivity, total biomass and observed species richness are affected by management intensity, and that these effects differ between habitat types (dry grasslands, grasslands, and wetlands). We found that local management was an important driver of species richness across systems. Management caused system disturbance, resulting in reduced productivity yet enhanced total biomass. Plant species richness was directly and positively driven by management, with consistently negative effects of total biomass. Productivity effects on richness were positive, negative or neutral. Our study shows that management and total biomass drive plant species richness across real-world managed systems. PMID:27114585

  1. 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. PMID:20441810

  2. BRAF L597 mutations in melanoma are associated with sensitivity to MEK inhibitors

    PubMed Central

    Dahlman, Kimberly Brown; Xia, Junfeng; Hutchinson, Katherine; Ng, Charles; Hucks, Donald; Jia, Peilin; Atefi, Mohammad; Su, Zengliu; Branch, Suzanne; Lyle, Pamela L.; Hicks, Donna J.; Bozon, Viviana; Glaspy, John A.; Rosen, Neal; Solit, David B.; Netterville, James L.; Vnencak-Jones, Cindy L.; Sosman, Jeffrey A.; Ribas, Antoni; Zhao, Zhongming; Pao, William

    2012-01-01

    Kinase inhibitors are accepted treatment for metastatic melanomas that harbor specific driver mutations in BRAF or KIT, but only 40–50% of cases are positive. To uncover other potential targetable mutations, we performed whole-genome sequencing of a highly aggressive BRAF (V600) and KIT (W557, V559, L576, K642, D816) wildtype melanoma. Surprisingly, we found a somatic BRAF L597R mutation in exon 15. Analysis of BRAF exon 15 in 49 tumors negative for BRAF V600 mutations as well as driver mutations in KIT, NRAS, GNAQ, and GNA11, showed that 2 (4%) harbored L597 mutations and another 2 involved BRAF D594 and K601 mutations. In vitro signaling induced by L597R/S/Q mutants was suppressed by MEK inhibition. A patient with BRAF L597S mutant metastatic melanoma responded significantly to treatment with the MEK inhibitor, TAK-733. Collectively, these data demonstrate clinical significance to BRAF L597 mutations in melanoma. PMID:22798288

  3. Association of driver air bags with driver fatality: a matched cohort study

    PubMed Central

    Cummings, Peter; McKnight, Barbara; Rivara, Frederick P; Grossman, David C

    2002-01-01

    Objective To estimate the association of driver air bag presence with driver fatality in road traffic crashes. Design Matched pair cohort study. Setting All passenger vehicle crashes in the United States during 1990-2000 inclusive. Subjects 51 031 driver-passenger pairs in the same vehicle. Main outcome measures Relative risk of death within 30 days of a crash. Results Drivers with an air bag were less likely to die than drivers without an air bag (adjusted relative risk 0.92 (95% confidence interval 0.88 to 0.96)). This estimate was nearly the same whether drivers wore a seat belt (adjusted relative risk 0.93) or not (0.91). Air bags were associated with more protection for women (0.88 (0.82 to 0.93)), than for men (0.94 (0.90 to 0.99)). Drivers wearing a seat belt were less likely to die than unbelted drivers (0.35 (0.33 to 0.36)). Belted drivers with an air bag were less likely to die than unbelted drivers without an air bag (0.32 (0.30 to 0.34)). Conclusions If the associations are causal the average risk of driver death was reduced 8% (95% confidence interval 4% to 12%) by an air bag. Benefit was similar for belted and unbelted drivers and was slightly greater for women. However, seat belts offered much more protection than air bags. What is already known on this topicStudies have estimated that driver air bags reduce the risk of death in a road vehicle crash by 10-14%These studies disagree as to whether benefit is greater for drivers wearing a seat belt or for unbelted driversWhat this study addsHaving an air bag was associated with an 8% reduction in the risk of death, whether the driver was belted or notThe reduction in risk was greater for women (12%) than for men (6%)Seat belts provided much greater protection, with seat belt use reducing the risk of death by 65% (or by 68% in combination with an air bag) PMID:12003882

  4. Graduated Driver Licensing: An international review.

    PubMed

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

    2014-11-01

    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

  5. 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.

  6. 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.

  7. Targeting BTK for the treatment of FLT3-ITD mutated acute myeloid leukemia

    PubMed Central

    Pillinger, Genevra; Abdul-Aziz, Amina; Zaitseva, Lyubov; Lawes, Matthew; MacEwan, David J.; Bowles, Kristian M.; Rushworth, Stuart A.

    2015-01-01

    Approximately 20% of patients with acute myeloid leukaemia (AML) have a mutation in FMS-like-tyrosine-kinase-3 (FLT3). FLT3 is a trans-membrane receptor with a tyrosine kinase domain which, when activated, initiates a cascade of phosphorylated proteins including the SRC family of kinases. Recently our group and others have shown that pharmacologic inhibition and genetic knockdown of Bruton’s tyrosine kinase (BTK) blocks AML blast proliferation, leukaemic cell adhesion to bone marrow stromal cells as well as migration of AML blasts. The anti-proliferative effects of BTK inhibition in human AML are mediated via inhibition of downstream NF-κB pro-survival signalling however the upstream drivers of BTK activation in human AML have yet to be fully characterised. Here we place the FLT3-ITD upstream of BTK in AML and show that the BTK inhibitor ibrutinib inhibits the survival and proliferation of FLT3-ITD primary AML blasts and AML cell lines. Furthermore ibrutinib inhibits the activation of downstream kinases including MAPK, AKT and STAT5. In addition we show that BTK RNAi inhibits proliferation of FLT3-ITD AML cells. Finally we report that ibrutinib reverses the cyto-protective role of BMSC on FLT3-ITD AML survival. These results argue for the evaluation of ibrutinib in patients with FLT3-ITD mutated AML. PMID:26292723

  8. 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.

  9. 49 CFR 374.317 - Identification-bus and driver.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 5 2014-10-01 2014-10-01 false Identification-bus and driver. 374.317 Section 374...—bus and driver. Each bus and driver providing service shall be identified in a manner visible to passengers. The driver may be identified by name or company number....

  10. 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...

  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. 49 CFR 374.317 - Identification-bus and driver.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 5 2012-10-01 2012-10-01 false Identification-bus and driver. 374.317 Section 374...—bus and driver. Each bus and driver providing service shall be identified in a manner visible to passengers. The driver may be identified by name or company number....

  13. 49 CFR 374.317 - Identification-bus and driver.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 5 2010-10-01 2010-10-01 false Identification-bus and driver. 374.317 Section 374...—bus and driver. Each bus and driver providing service shall be identified in a manner visible to passengers. The driver may be identified by name or company number....

  14. 49 CFR 374.317 - Identification-bus and driver.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 5 2011-10-01 2011-10-01 false Identification-bus and driver. 374.317 Section 374...—bus and driver. Each bus and driver providing service shall be identified in a manner visible to passengers. The driver may be identified by name or company number....

  15. 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...

  16. 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...

  17. 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...

  18. 49 CFR 374.317 - Identification-bus and driver.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 5 2013-10-01 2013-10-01 false Identification-bus and driver. 374.317 Section 374...—bus and driver. Each bus and driver providing service shall be identified in a manner visible to passengers. The driver may be identified by name or company number....

  19. 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

  20. The somatic mutation profiles of 2,433 breast cancers refines their genomic and transcriptomic landscapes.

    PubMed

    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

  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. An investigation on motor-driven power steering-based crosswind disturbance compensation for the reduction of driver steering effort

    NASA Astrophysics Data System (ADS)

    Kim, Kyuwon; Kim, Boemjun; Go, Youngil; Park, Jaeyong; Park, Joonhong; Suh, Insoo; Yi, Kyongsu

    2014-07-01

    This paper describes a lateral disturbance compensation algorithm for an application to a motor-driven power steering (MDPS)-based driver assistant system. The lateral disturbance including wind force and lateral load transfer by bank angle reduces the driver's steering refinement and at the same time increases the possibility of an accident. A lateral disturbance compensation algorithm is designed to determine the motor overlay torque of an MDPS system for reducing the manoeuvreing effort of a human driver under lateral disturbance. Motor overlay torque for the compensation of driver's steering torque induced by the lateral disturbance consists of human torque feedback and feedforward torque. Vehicle-driver system dynamics have been investigated using a combined dynamic model which consists of a vehicle dynamic model, driver steering dynamic model and lateral disturbance model. The human torque feedback input has been designed via the investigation of the vehicle-driver system dynamics. Feedforward input torque is calculated to compensate additional tyre self-aligning torque from an estimated lateral disturbance. The proposed compensation algorithm has been implemented on a developed driver model which represents the driver's manoeuvreing characteristics under the lateral disturbance. The developed driver model has been validated with test data via a driving simulator in a crosswind condition. Human-in-the-loop simulations with a full-scale driving simulator on a virtual test track have been conducted to investigate the real-time performance of the proposed lateral disturbance compensation algorithm. It has been shown from simulation studies and human-in-the-loop simulation results that the driver's manoeuvreing effort and a lateral deviation of the vehicle under the lateral disturbance can be significantly reduced via the lateral disturbance compensation algorithm.

  3. Gestational mutations in radiation carcinogenesis

    NASA Astrophysics Data System (ADS)

    Meza, R.; Luebeck, G.; Moolgavkar, S.

    Mutations in critical genes during gestation could increase substantially the risk of cancer. We examine the consequences of such mutations using the Luebeck-Moolgavkar model for colorectal cancer and the Lea-Coulson modification of the Luria-Delbruck model for the accumulation of mutations during gestation. When gestational mutation rates are high, such mutations make a significant contribution to cancer risk even for adult tumors. Furthermore, gestational mutations ocurring at distinct times during emryonic developmemt lead to substantially different numbers of mutated cells at birth, with early mutations leading to a large number (jackpots) of mutated cells at birth and mutation occurring late leading to only a few mutated cells. Thus gestational mutations could confer considerable heterogeneity of the risk of cancer. If the fetus is exposed to an environmental mutagen, such as ionizing radiation, the gestational mutation rate would be expected to increase. We examine the consequences of such exposures during gestation on the subsequent development of cancer.

  4. GNAS gene mutation may be present only transiently during colorectal tumorigenesis

    PubMed Central

    Zauber, Peter; Marotta, Stephen P; Sabbath-Solitare, Marlene

    2016-01-01

    Mutations of the gene GNAS have been shown to activate the adenylate cyclase gene and lead to constitutive cAMP signaling. Several preliminary reports have suggested a role for GNAS gene mutations during colorectal carcinogenesis, particularly mucinous carcinomas. The aim of this study was to clarify the incidence of GNAS mutations in adenomas (tubular, tubulovillous, and villous), carcinomas with residual adenoma, and carcinomas, and to relate these findings to mutations of the KRAS gene and to the mucinous status of the tumors. We used standard PCR techniques and direct gene sequencing to evaluate tumors for gene mutations. No GNAS mutations were identified in 25 tubular adenomas, but were present in 6.4% of tubulovillous adenomas and 11.2% of villous adenomas. A GNAS mutation was found in 9.7% of the benign portion of carcinoma with residual adenoma, but in none of 86 carcinomas. A similar trend was seen for KRAS mutation across the five groups of tumors. GNAS mutations may function as an important driver mutation during certain phases of colorectal carcinogenesis, but may then be lost once the biological advantage gained by the mutated gene is no longer necessary to sustain or advance tumor development. PMID:27186325

  5. Protein Domain-Level Landscape of Cancer-Type-Specific Somatic Mutations

    PubMed Central

    Yang, Fan; Petsalaki, Evangelia; Rolland, Thomas; Hill, David E.; Vidal, Marc; Roth, Frederick P.

    2015-01-01

    Identifying driver mutations and their functional consequences is critical to our understanding of cancer. Towards this goal, and because domains are the functional units of a protein, we explored the protein domain-level landscape of cancer-type-specific somatic mutations. Specifically, we systematically examined tumor genomes from 21 cancer types to identify domains with high mutational density in specific tissues, the positions of mutational hotspots within these domains, and the functional and structural context where possible. While hotspots corresponding to specific gain-of-function mutations are expected for oncoproteins, we found that tumor suppressor proteins also exhibit strong biases toward being mutated in particular domains. Within domains, however, we observed the expected patterns of mutation, with recurrently mutated positions for oncogenes and evenly distributed mutations for tumor suppressors. For example, we identified both known and new endometrial cancer hotspots in the tyrosine kinase domain of the FGFR2 protein, one of which is also a hotspot in breast cancer, and found new two hotspots in the Immunoglobulin I-set domain in colon cancer. Thus, to prioritize cancer mutations for further functional studies aimed at more precise cancer treatments, we have systematically correlated mutations and cancer types at the protein domain level. PMID:25794154

  6. Comparative Oncogenomic Analysis of Copy Number Alterations in Human and Zebrafish Tumors Enables Cancer Driver Discovery

    PubMed Central

    Zhang, GuangJun; Hoersch, Sebastian; Amsterdam, Adam; Whittaker, Charles A.; Beert, Eline; Catchen, Julian M.; Farrington, Sarah; Postlethwait, John H.; Legius, Eric; Hopkins, Nancy; Lees, Jacqueline A.

    2013-01-01

    The identification of cancer drivers is a major goal of current cancer research. Finding driver genes within large chromosomal events is especially challenging because such alterations encompass many genes. Previously, we demonstrated that zebrafish malignant peripheral nerve sheath tumors (MPNSTs) are highly aneuploid, much like human tumors. In this study, we examined 147 zebrafish MPNSTs by massively parallel sequencing and identified both large and focal copy number alterations (CNAs). Given the low degree of conserved synteny between fish and mammals, we reasoned that comparative analyses of CNAs from fish versus human MPNSTs would enable elimination of a large proportion of passenger mutations, especially on large CNAs. We established a list of orthologous genes between human and zebrafish, which includes approximately two-thirds of human protein-coding genes. For the subset of these genes found in human MPNST CNAs, only one quarter of their orthologues were co-gained or co-lost in zebrafish, dramatically narrowing the list of candidate cancer drivers for both focal and large CNAs. We conclude that zebrafish-human comparative analysis represents a powerful, and broadly applicable, tool to enrich for evolutionarily conserved cancer drivers. PMID:24009526

  7. Comparative oncogenomic analysis of copy number alterations in human and zebrafish tumors enables cancer driver discovery.

    PubMed

    Zhang, GuangJun; Hoersch, Sebastian; Amsterdam, Adam; Whittaker, Charles A; Beert, Eline; Catchen, Julian M; Farrington, Sarah; Postlethwait, John H; Legius, Eric; Hopkins, Nancy; Lees, Jacqueline A

    2013-08-01

    The identification of cancer drivers is a major goal of current cancer research. Finding driver genes within large chromosomal events is especially challenging because such alterations encompass many genes. Previously, we demonstrated that zebrafish malignant peripheral nerve sheath tumors (MPNSTs) are highly aneuploid, much like human tumors. In this study, we examined 147 zebrafish MPNSTs by massively parallel sequencing and identified both large and focal copy number alterations (CNAs). Given the low degree of conserved synteny between fish and mammals, we reasoned that comparative analyses of CNAs from fish versus human MPNSTs would enable elimination of a large proportion of passenger mutations, especially on large CNAs. We established a list of orthologous genes between human and zebrafish, which includes approximately two-thirds of human protein-coding genes. For the subset of these genes found in human MPNST CNAs, only one quarter of their orthologues were co-gained or co-lost in zebrafish, dramatically narrowing the list of candidate cancer drivers for both focal and large CNAs. We conclude that zebrafish-human comparative analysis represents a powerful, and broadly applicable, tool to enrich for evolutionarily conserved cancer drivers. PMID:24009526

  8. Non-small Cell Lung Cancer with Concomitant EGFR, KRAS, and ALK Mutation: Clinicopathologic Features of 12 Cases

    PubMed Central

    Lee, Taebum; Lee, Boram; Choi, Yoon-La; Han, Joungho; Ahn, Myung-Ju; Um, Sang-Won

    2016-01-01

    Background: Although epidermal growth factor receptor (EGFR), v-Ki-ras2 Kirsten rat sarcoma viral oncogene (KRAS), and anaplastic lymphoma kinase (ALK) mutations in non-small cell lung cancer (NSCLC) were thought to be mutually exclusive, some tumors harbor concomitant mutations. Discovering a driver mutation on the basis of morphologic features and therapeutic responses with mutation analysis can be used to understand pathogenesis and predict resistance in targeted therapy. Methods: In 6,637 patients with NSCLC, 12 patients who had concomitant mutations were selected and clinicopathologic features were reviewed. Clinical characteristics included sex, age, smoking history, previous treatment, and targeted therapy with response and disease-free survival. Histologic features included dominant patterns, nuclear and cytoplasmic features. Results: All patients were diagnosed with adenocarcinoma and had an EGFR mutation. Six patients had concomitant KRAS mutations and the other six had KRAS mutations. Five of six EGFR-KRAS mutation patients showed papillary and acinar histologic patterns with hobnail cells. Three of six received EGFR tyrosine kinase inhibitor (TKI) and showed partial response for 7–29 months. All six EGFR-ALK mutation patients showed solid or cribriform patterns and three had signet ring cells. Five of six EGFR-ALK mutation patients received EGFR TKI and/or ALK inhibitor and four showed partial response or stable disease, except for one patient who had acquired an EGFR mutation. Conclusions: EGFR and ALK mutations play an important role as driver mutations in double mutated NSCLC, and morphologic analysis can be used to predict treatment response. PMID:27086595

  9. Analysis of SDHD promoter mutations in various types of melanoma

    PubMed Central

    Scholz, Simone L.; Horn, Susanne; Murali, Rajmohan; Möller, Inga; Sucker, Antje; Sondermann, Wiebke; Stiller, Mathias; Schilling, Bastian; Livingstone, Elisabeth; Zimmer, Lisa; Reis, Henning; Metz, Claudia H.; Zeschnigk, Michael; Paschen, Annette; Steuhl, Klaus-Peter; Schadendorf, Dirk; Westekemper, Henrike; Griewank, Klaus G.

    2015-01-01

    Objectives Recently, recurrent mutations in regulatory DNA regions, such as promoter mutations in the TERT gene were identified in melanoma. Subsequently, Weinhold et al. reported SDHD promoter mutations occurring in 10% of melanomas and being associated with a lower overall survival rate. Our study analyzes the mutation rate and clinico-pathologic associations of SDHD promoter mutations in a large cohort of different melanoma subtypes. Methods 451 melanoma samples (incl. 223 non-acral cutaneous, 38 acral, 33 mucosal, 43 occult, 43 conjunctival and 51 uveal melanoma) were analyzed for the presence of SDHD promoter mutations by Sanger-sequencing. Statistical analysis was performed to screen for potential correlations of SDHD promoter mutation status with various clinico-pathologic criteria. Results The SDHD promoter was successfully sequenced in 451 tumor samples. ETS binding site changing SDHD promoter mutations were identified in 16 (4%) samples, of which 5 mutations had not been described previously. Additionally, 5 point mutations not located in ETS binding elements were identified. Mutations in UV-exposed tumors were frequently C>T. One germline C>A SDHD promoter mutation was identified. No statistically significant associations between SDHD promoter mutation status and various clinico-pathologic variables or overall patient survival were observed. Conclusions Melanomas harbor recurrent SDHD promoter mutations, which occur primarily as C>T alterations in UV-exposed melanomas. In contrast to the initial report and promoter mutations in the TERT gene, our analysis suggests that SDHD promoter mutations are a relatively rare event in melanoma (4% of tumors) of unclear clinical and prognostic relevance. PMID:26327518

  10. Characteristics of fatal crashes of 16-year-old drivers: implications for licensure policies.

    PubMed

    Williams, A F; Preusser, D F; Ulmer, R G; Weinstein, H B

    1995-01-01

    Compared with older drivers, and even older teens, greater percentages of 16-year-old drivers in fatal crashes were involved in single-vehicle crashes, were responsible for their crashes, were cited for speeding, had high vehicle occupancy (especially other teenagers), and were female. Sixteen-year-olds were less likely than older drivers to have been drinking. In addition, their crashes occurred at different times than those of older drivers, crashes between 10:00 p.m. and 11:59 p.m. on Fridays and Saturdays being especially likely. Information about the characteristics of the crashes of 16-year-olds is important because this is the age at which most states currently allow teenagers to get an unrestricted driver's license. It is also the age at which restrictions on beginning licenses are being considered in some states. The results of this study suggest that restrictions on teenage passengers, and night-driving curfews with pre-midnight starting times--two provisions used in New Zealand's graduated licensing system--would be appropriate in attempts to reduce crashes of beginning 16-year-old drivers, who have the highest fatal crash rate of any single teen age. PMID:7499515

  11. WT1 mutations in T-ALL.

    PubMed

    Tosello, Valeria; Mansour, Marc R; Barnes, Kelly; Paganin, Maddalena; Sulis, Maria Luisa; Jenkinson, Sarah; Allen, Christopher G; Gale, Rosemary E; Linch, David C; Palomero, Teresa; Real, Pedro; Murty, Vundavalli; Yao, Xiaopan; Richards, Susan M; Goldstone, Anthony; Rowe, Jacob; Basso, Giuseppe; Wiernik, Peter H; Paietta, Elisabeth; Pieters, Rob; Horstmann, Martin; Meijerink, Jules P P; Ferrando, Adolfo A

    2009-07-30

    The molecular mechanisms involved in disease progression and relapse in T-cell acute lymphoblastic leukemia (T-ALL) are poorly understood. We used single nucleotide polymorphism array analysis to analyze paired diagnostic and relapsed T-ALL samples to identify recurrent genetic alterations in T-ALL. This analysis showed that diagnosis and relapsed cases have common genetic alterations, but also that relapsed samples frequently lose chromosomal markers present at diagnosis, suggesting that relapsed T-ALL emerges from an ancestral clone different from the major leukemic population at diagnosis. In addition, we identified deletions and associated mutations in the WT1 tumor suppressor gene in 2 of 9 samples. Subsequent analysis showed WT1 mutations in 28 of 211 (13.2%) of pediatric and 10 of 85 (11.7%) of adult T-ALL cases. WT1 mutations present in T-ALL are predominantly heterozygous frameshift mutations resulting in truncation of the C-terminal zinc finger domains of this transcription factor. WT1 mutations are most prominently found in T-ALL cases with aberrant rearrangements of the oncogenic TLX1, TLX3, and HOXA transcription factor oncogenes. Survival analysis demonstrated that WT1 mutations do not confer adverse prognosis in pediatric and adult T-ALL. Overall, these results identify the presence of WT1 mutations as a recurrent genetic alteration in T-ALL. PMID:19494353

  12. Mutational Analysis of TARDBP in Neurodegenerative Diseases

    PubMed Central

    Ticozzi, Nicola; LeClerc, Ashley Lyn; Van-Blitterswijk, Marka; Keagle, Pamela; McKenna-Yasek, Diane M.; Sapp, Peter C.; Silani, Vincenzo; Wills, Anne-Marie; Brown, Robert H.; Landers, John E.

    2010-01-01

    Neurodegenerative diseases are often characterized by the presence of aggregates of misfolded proteins. TDP-43 is a major component of these aggregates in Amyotrophic Lateral Sclerosis (ALS), but has also been observed in Alzheimer's (AD) and Parkinson's Diseases (PD). In addition, mutations in the TARDBP gene, encoding TDP-43, have been found to be a significant cause of familial ALS (FALS). All mutations, except for one, have been found in exon 6. To confirm this observation in ALS and to investigate whether TARDBP may play a role in the pathogenesis of AD and PD, we screened for mutations in exon 6 of the TARDBP gene in three cohorts composed of 376 AD, 463 PD (18% familial PD) and 376 ALS patients (50% FALS). We found mutations in ∼7% of FALS and ∼0.5% of sporadic ALS (SALS) patients, including two novel mutations, p.N352T and p.G384R. In contrast, we did not find TARDBP mutations in our cohort of AD and PD patients. These results suggest that mutations in TARDBP are not a significant cause of AD and PD. PMID:20031275

  13. Mutational Robustness of Gene Regulatory Networks

    PubMed Central

    van Dijk, Aalt D. J.; van Mourik, Simon; van Ham, Roeland C. H. J.

    2012-01-01

    Mutational robustness of gene regulatory networks refers to their ability to generate constant biological output upon mutations that change network structure. Such networks contain regulatory interactions (transcription factor – target gene interactions) but often also protein-protein interactions between transcription factors. Using computational modeling, we study factors that influence robustness and we infer several network properties governing it. These include the type of mutation, i.e. whether a regulatory interaction or a protein-protein interaction is mutated, and in the case of mutation of a regulatory interaction, the sign of the interaction (activating vs. repressive). In addition, we analyze the effect of combinations of mutations and we compare networks containing monomeric with those containing dimeric transcription factors. Our results are consistent with available data on biological networks, for example based on evolutionary conservation of network features. As a novel and remarkable property, we predict that networks are more robust against mutations in monomer than in dimer transcription factors, a prediction for which analysis of conservation of DNA binding residues in monomeric vs. dimeric transcription factors provides indirect evidence. PMID:22295094

  14. Proliferation of mutators in A cell population.

    PubMed Central

    Mao, E F; Lane, L; Lee, J; Miller, J H

    1997-01-01

    A Lac- strain of Escherichia coli that reverts by the addition of a G to a G-G-G-G-G-G sequence was used to study the proliferation of mutators in a bacterial culture. Selection for the Lac+ phenotype, which is greatly stimulated in mismatch repair-deficient strains, results in an increase in the percentage of mutators in the selected population from less than 1 per 100,000 cells to 1 per 200 cells. All the mutators detected were deficient in the mismatch repair system. Mutagenesis results in a similar increase in the percentage of mutators. Mutagenesis combined with a single selection can result in a population of more than 50% mutators when a sample of several thousand cells is grown out and selected. Mutagenesis combined with two or more successive selections can generate a population that is 100% mutator. These experiments are discussed in relation to ideas that an early step in carcinogenesis is the creation of a mutator phenotype. PMID:8990293

  15. New mutations in CMT 1 and HNPP

    SciTech Connect

    Vandenberghe, A.; Boucherat, M.; Bonnebouche, C.

    1994-09-01

    The majority of mutations in CMT 1 (Charcot-Marie-Tooth disease type 1) are due to a duplication of a 1.5 Mb fragment from chromosome 17 containing the PMP22 myelin gene. In addition, micromutations are found in the genes for PMP22 and myelin Po. We collected data from over one hundred families with a duplication in 17p11.2. In about 10% of these families, a de novo mutation was observed. All parents were clinically examined as normal and correct paternity was confirmed. Some families were informative for polymorphic probes located in the duplicated region, and we could deduce a majority of new mutations to be from paternal origin. HNPP (hereditary neuropathy with liability to pressure palsies) is believed to be the reciprocal product of an unequal crossing over underlying the CMT 1 mutation and is due to a deletion of the 1.5 Mb fragment. One new HNPP mutation was found among 7 deleted HNPP families. This mutation is of paternal origin. Clinically assigned CMT 1 patients without a duplication are screened for micromutations applying the SSCP technique. In one family, a de novo mutation was found in the gene for Po.

  16. Mutations in Lettuce Improvement.

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Mutations can make profound impact on the evolution and improvement of a self-pollinated crop such as lettuce. Since it is nontransgenic, mutation breeding is more acceptable to consumers. Combined with genomic advances in new technologies like TILLING, mutagenesis is becoming an even more powerfu...

  17. 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. PMID:25747338

  18. Hours of work, and perceptions of fatigue among truck drivers.

    PubMed

    Arnold, P K; Hartley, L R; Corry, A; Hochstadt, D; Penna, F; Feyer, A M

    1997-07-01

    Drivers and companies operating in the heavy road transport industry were surveyed about drivers' hours of work and perceptions of the causes and magnitude of fatigue as an industry problem. These drivers were operating in a state which, at the time of the survey, did not restrict driving hours for heavy haulage drivers. On the day of the interview, estimates based on retrospective and prospective reports, suggest that in a 24 hour period about 38% of drivers exceed 14 hours of driving, and 51% exceed 14 hours of driving plus other non-driving work. About 12% of drivers reported less than 4 hours of sleep on one or more working days in the week preceding the interview. These drivers are likely to be operating their vehicles while having a significant sleep debt. About 20% of drivers reported less than 6 hours sleep before starting their current journey, but nearly 40% of dangerous events that occurred on the journey were reported by these drivers (p < 0.05). Many drivers and company representatives reported fatigue to be a problem for other drivers, but considered themselves or their companies' drivers to be relatively unaffected by fatigue. There were differences between drivers' and companies' perceptions about causes of fatigue, and strategies that should be used to manage it. The results obtained from these drivers in an unregulated state were compared with earlier findings from drivers in states where driving hours restrictions are in place. PMID:9248505

  19. Long survival in a child with a mutated K27M-H3.3 pilocytic astrocytoma.

    PubMed

    Hochart, Audrey; Escande, Fabienne; Rocourt, Nathalie; Grill, Jacques; Koubi-Pick, Valérie; Beaujot, Juliette; Meignan, Samuel; Vinchon, Matthieu; Maurage, Claude Alain; Leblond, Pierre

    2015-04-01

    We report the first case of a child with a H3F3A K27M mutated pilocytic astrocytoma, who presented with a 10 years survival, and underwent spontaneous malignant transformation. The complex tumoral chromosomal rearrangements were consistent for genomic instability and for the histopathological features of malignant transformation into glioblastoma. H3F3A K27M mutations are rarely observed in benign neoplasms and may be associated with an adverse outcome. This mutation might not be the major driver that led to the onset of tumorigenesis, and we could consider that the associated TP53 mutation, would be required for malignant transformation. PMID:25909089

  20. Long survival in a child with a mutated K27M-H3.3 pilocytic astrocytoma

    PubMed Central

    Hochart, Audrey; Escande, Fabienne; Rocourt, Nathalie; Grill, Jacques; Koubi-Pick, Valérie; Beaujot, Juliette; Meignan, Samuel; Vinchon, Matthieu; Maurage, Claude Alain; Leblond, Pierre

    2015-01-01

    We report the first case of a child with a H3F3A K27M mutated pilocytic astrocytoma, who presented with a 10 years survival, and underwent spontaneous malignant transformation. The complex tumoral chromosomal rearrangements were consistent for genomic instability and for the histopathological features of malignant transformation into glioblastoma. H3F3A K27M mutations are rarely observed in benign neoplasms and may be associated with an adverse outcome. This mutation might not be the major driver that led to the onset of tumorigenesis, and we could consider that the associated TP53 mutation, would be required for malignant transformation. PMID:25909089